10 1039@d0ob01458c

Aldehydes: magnificent acyl equivalents
for direct acylation

Article
Accepted Version
Kumar, P., Dutta, S., Kumar, S., Bahadur, V., Van der Eycken,
E. V., Vimaleswaran, K. S., Parmar, V. S. and Singh, B. K.
(2020) Aldehydes: magnificent acyl equivalents for direct
acylation. Organic & Biomolecular Chemistry, 18 (40). ISSN
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ARTICLE
Received 00th January 20xx,

Accepted 00th January 20xx Aldehydes: magnificent acyl equivalents for direct acylation
Published on 07 September 2020. Downloaded by Karolinska Institutet University Library on 9/7/2020 12:45:51 PM.
DOI: 10.1039/x0xx00000x Prashant Kumar*,a,b Sriparna Dutta,b Sandeep Kumar,b Vijay Bahadur,a,b Erik V. Van der Eycken,c,d
Karani S Vimaleswaran,e Virinder S. Parmarf and Brajendra K. Singh*b
From the viewpoint of meeting the current Green Chemistry challenges in chemical synthesis, there is a need to disseminate
how the cocktail of acylation and activation can play a pivotal role in affording bioactive acylated products comprising of
substituted ketone motifs in fewer reaction steps, with higher atom-economy and improved selectivity. In recent years, a
significant number of articles employing the title compounds “aldehydes” as magnificent acylation surrogates have been
developed which are less toxic and widely applicable. This review sheds light on their use for selective acylation of arenes,
heteroarenes and alkyls (sp3, sp2 and sp) C-H bonds by proficient utilization of C-H activation strategy. Critical insights on
selective acylation of diverse moieties for the synthesis of bioactive compounds are presented in this review that will enable
the academic as well as the industrial researchers to understand the mechanistic aspects involved and fruitfully employ
these strategies in designing novel molecules.
1. Introduction Crafts acylation reaction include requirement of harsh

reaction conditions and super stoichiometric amounts of
The concise forging of substituted ketone motifs by means of
Lewis acids, low regioselectivity and the formation of
direct functionalization using C-H activation strategies
unwanted regioisomers.6,7 Although other alternative
presents the incredible state of the art in synthetic organic
methods have been established over the years comprising of
chemistry. Ketones are commonly used ubiquitous structural
the oxidation of alcohols,8,9 Grignard/Barbier reaction
units for developing pharmaceuticals, dyes, agrochemicals,
followed by oxidation,10 and reaction of Grignard reagents
electronic materials and natural products. These are the
with nitriles,10f these methods do not match the current Green
fundamental building blocks of various bioactive molecules
Chemistry requirements due to issues related to safety and
and drugs such as tiaprofenic acid and ketoprofen which are
economy.
used as anti-photoallergic agents1 and nonsteroidal anti-
inflammatory drugs,2 fenofibrate that is used as the classical Transition metal-catalyzed oxidative cross-coupling reactions
lipid regulating agent3, benzbromarone (BBR) which is for the direct functionalization of C-H bonds with high atom-
employed as a uricosuric agent4, and mebendazole that works efficiency have emerged as attractive, efficient and
as a broad-spectrum human anthelmintic agent.5 Over the straightforward strategies for access to desirable molecules
course of time, structural diversity of the disubstituted ketone from simple reaction substrates without any pre-modification
moieties has rapidly expanded as evident from the literature or pre-functionalization, thereby increasing the efficacy of the
reports. However, the practical challenges associated with the anticipated transformations. Therefore, in recent years these
conventional methodologies employed for the synthesis of cross-coupling strategies have been extensively explored for
these significant motifs have in turn engaged the researchers the direct synthesis of keto compounds by means of selective
in exploration of improved methods of synthesis. Some of the acylation of the starting materials. These approaches are
inherent drawbacks associated with the classical Friedel- found to be highly advantageous over classical methods used
for the acylation of alkyl, aryl or heteroaryls leading to the
a. Department
formation of desirable acylated compounds because of fewer
of Chemistry, SRM University Delhi-NCR, Sonepat Haryana-131029,
India reaction steps, higher atom-economy, improved selectivity
b. Department of Chemistry, University of Delhi, Delhi-110007, India
c. Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
and non-requirement of pre-functionalization of the starting
Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 materials. For direct acylation by following the C-H activation
Leuven, Belgium
d. Peoples’ Friendship University of Russia, (RUDN University) Miklukho-Maklaya, approach, several reagents including aldehydes, benzyl
street 6, Moscow, 117198, Russia
e. Hugh Sinclair Unit of Human Nutrition, School of Chemistry, Food and Pharmacy,
alcohols, -keto acids, acyl chlorides, etc. have been explored
University of Reading, UK extensively.11-14 Amongst these acylating surrogates,
f. Department of Chemistry and Environmental Science, Medgar Evers College, The
City University of New York, 1638 Bedford Avenue, Brooklyn, NY 11225, USA aldehydes (aliphatic and aromatic) have received profound
Please do not adjust margins

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Biomolecular Chemistry Page 2 of 59
ARTICLE Organic & Biomolecular Chemistry
attention because of their high stability, less toxicity, ease of routes provided better alternatives to anhydrides, acyl
View Article Online
availability, broad substrate scope and low cost. halides, -ketoacids and other acylatingDOI: 10.1039/D0OB01458C
agents. 32-34 Ideally, it
is well known that green chemistry helps in achieving

In fact, aldehydes consist of an important class of molecules
reduction of waste at source by redesigning existing processes

that are found extensively in nature. Amongst the aldehydes,
at the molecular level. These acylation reactions add to the
benzaldehyde is one of the most important motifs, which is
credentials of green chemistry. A major breakthrough in the
widely used in food industry as an ingredient in cherry and
use of aldehydes as acylating agents was achieved when
other natural fruity flavours. Naturally, aldehyde motifs are
Cheng et al. in 2009 reported the first direct oxidative
present in peach, black tea, bitter almond, and apricot

acylation of a C-H bond applying aromatic aldehydes as acyl
kernel.15 Benzaldehyde has been reported to act as an anti-
tumour agent for various kinds of tumours occurring in equivalents in the presence of a Pd-catalyst.35 During
humans16 and mice.17 The mechanism for the anti-tumour mechanistic investigation of the radical induced acylation
behaviour of benzaldehyde for cell growth inhibition has been reactions, it was postulated that the aldehyde moiety gets
well established using human NHIK 3025 cells.18 Aldehydes converted first into an acyl radical (Fig. 2) which then
can be formed endogenously by amine oxidases, combines to give the corresponding acylated product.
carbohydrate or ascorbate autoxidation, lipid peroxidation, O O
myeloperoxidase-catalyzed metabolic activation, Oxidant
R H R
carbohydrate metabolism or by cytochrome P-450s, etc.19,20
Acyl radical
In the year 1946, the first review21, which was published by
Fig. 2 Acyl radical formation from the aldehydes.
Lloyd N. Fergusoy from the University of California, on the
synthesis of aromatic aldehydes, covered essential The use of benzaldehydes in radical mediated as well as
information pertaining to both the direct as well as indirect oxidative cross-coupling reactions was reviewed by Xiao-Feng
method for the introduction of the formyl (CHO) group into Wu in 2015.33 This mini-review sheds light on recent work in
the aromatic nucleus. It was highlighted in this review that transition metal catalysed acylation of aryls,
Gattermann and Koch22 for the first time prepared aromatic heteroaryls/heteroarenes. Thereafter, in 2016, Kim and co-
aldehydes via reaction between benzene and its derivatives, workers published a review summarizing the recent progress
CO and HCl, using anhydrous AlCl3 as a catalyst. Thereafter, in oxidative and decarboxylative transition metal-catalysed
this protocol was modified further by Gattermann23 himself, acylation reactions by C-H activation.34
where he used cyanide instead of CO and produced aldimine
2. Scope of Review
hydrochloride as an intermediate that was hydrolysed to the
aldehyde. In due course, several other methods were There is a need to disseminate how wondrously the aldehyde
established for aldehyde synthesis. Also, meanwhile attempts moieties are employed in various acylation reactions using C-
were made towards utilizing aldehydes for their H activation and how they succumb to provide a better
transformation into valuable compounds. For instance, it was substitute of the irritating and toxic anhydrides, acyl halides
found that benzaldehyde could react with pyruvate and get and other acylating reagents. Although there are several
transformed into a chiral compound (R)-phenylacetylcarbinol reviews on C-H bonds activation and transition metal-
[(R)-PAC] with the help of pyruvate decarboxylase (PDC) catalysed reactions, yet, to the best of our knowledge, there
enzyme (Fig. 1).24, 25 is no single review that throws light on the use of aldehydes
as magnificent acylation surrogates compiling the acylation of
OH
O
O O
PDC CH3 arenes, heteroarenes and alkyls (sp3, sp2 and sp) C-H bonds
H CO2
O CH3 H O resulting in the synthesis of valuable C-X (X=C, O, N) bonds by
proficient use of C-H activation. This review presents some of
Fig. 1 Transformation of benzaldehyde and pyruvate into (R)-phenylacetylcarbinol
using pyruvate decarboxylase. the exciting discoveries accomplished during the past few
Henceforth, aldehydes were employed as starting materials in years (2012 to 2020) in the development of novel catalytic
important organic reactions such as addition, condensation, protocols, shedding light on some of the latest synthetic tools
hydrogenation, coupling, etc.26-31 Over the course of time, including flow chemistry and photochemical methodologies.
aldehydes were also employed in radical acylation and It includes a comprehensive discussion on the mechanistic
oxidative acylation reactions that result in the direct aspects that will enable the researchers to think creatively and
regioselective formation of new C-C and C-N bonds. These work in this exciting area. This review focusses on using
20 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Organic and Biomolecular Chemistry ARTICLE
greener tools and strategies, given that chemical waste has a 10 min and a 1.1 kH/kD value was observed (Scheme View1B). Other
Article Online
disastrous impact on human health as well as on the deuterium-labelling control experiments suggested the rapid
DOI: 10.1039/D0OB01458C
environment and eco-systems. and reversible metalation-proto(deutero)demetalation

before the cross-coupling reaction. This also suggested that

3. Aldehydes in acylation reactions
addition of the aldehyde to the cyclo-rhodated intermediate
3.1. Acylation of arenes is involved in the rate-limiting step of this conversion. A
In 2012, Kim and his team described the Rh-catalyzed possible reaction mechanism is depicted in Scheme 2.
regioselective acylation of secondary benzamides using
H/D O
aromatic aldehydes, which on subsequent intramolecular D O D3 N H/D

D
cyclization afforded 3-hydroxyisoindolin-1-ones (Scheme 1).36 N
H
HO
Authors have synthesized 21 derivatives of 3- D

D
D
hydroxyisoindolin-1-one by reacting several differently Rh(I)

H
O Rh(III)
Ag2CO3 O
substituted benzamides with aldehydes. Benzaldehydes H/D O
H/D N
D4 N D5 H
having electron-withdrawing groups such as NO2, CF3, D3
N
Rh(I)
Rh (III)
B
A D
COOMe, CN, etc. delivered the 3-hydroxyisoindolin-1-ones in H
O
high yields. On the other hand, aldehydes carrying the PhCHO
(III)Rh O
electron-releasing OMe group displayed inferior reactivity. H/D O N
H
Benzamides having electron-releasing groups delivered high H/D O
H/D D3 N
D4
C
yields in comparison to those bearing electron-withdrawing D3

N
Rh(I) H
Rh (V)
D
groups. O H/D O O
F
D
D3 N H/D HD
A O
[Cp*RhCl2]2 (5 mol %) Rh (III)
O AgSbF6 (20 mol %)
O O
R3 Ag2CO3 (300 mol %) R2 N R3
2
N
H R1 R H THF (0.3 M), 150 oC R1
HO E
H/D O
20 examples, 30-83% H/D
N
D3 H
R1= Ph, 4-CF3Ph, 4-CO2MePh, 4-NO2Ph, 4-COMePh,
4-CNPh, 4-FPh, 4-ClPh, 4-BrPh, 4-OMePh, -naphtyl O
R2= 5-Ph, 5-Cl, 4-OMe, 4-OBn, 4-Cl, 3-OMe, 3-F, Rh(III)

G
1,3-dioxolyl, etc. H
R3= i-Pr
Scheme 2: Plausible reaction mechanism of the Rh-catalyzed regioselective sp2 C-H acylation
B O
H O O process for the secondary benzamides with aryl aldehydes.
D O
i H i
Pr H R
D Pr N
(i)
N
H H H4/D4 N
In 2013, Zhang et al. developed a Pd-catalysed protocol for the
standard R
H H
D D
H
condition
10 min
OH synthesis of keto-carboxylic acids through an aryl amide
D
R = 4-(MeO2C)Ph
kH/kD = 1.1 directed C-H functionalization approach. The reaction
(27% D)
D O standard H/D O
proceeded by oxidative coupling between aryl amides and
(10% D)
D
N
i
Pr
O conditions
A-C
D aldehydes using TBHP as oxidant and resulted in imino
H N H/D
(ii)
D D
X R 20 h
D OH carboxylic acids, which on subsequent treatment with HCl
X = H, X = D
D R = 4-(MeO2C)Ph
D
D/H
solution gave keto carboxylic acids.37 The reactions
condition A: X = H, THF (8% D) progressed through benzamide directed o-acylation followed
condition B: X = D, THF CO2Me
condition C: X = D, THF-d8 by ring closing and opening to give keto-carboxylic acids. Both
benzamides as well as aldehydes bearing electron-releasing
(50% D)
D
D O
i
Pr standard
H/D O groups and electron-withdrawing groups were compatible for
H/D
(iii)
N
H
condition D
N
H (21% D) the reaction irrespective of the positions of the functional
D D without aldehyde
D
within 2h D H/D groups. The authors prepared 19 imino carboxylic acid
D (50% D)
derivatives in 46-84% yield and five keto-carboxylic acid
Scheme 1: Rh-catalyzed regioselective sp2 C-H acylation of secondary benzamides
using aryl aldehydes with intramolecular cyclization and mechanistic studies. derivatives in 50-80% yield (Scheme 3).
To probe the catalytic reaction pathway for this
Two closely related studies were disclosed by Patel et al. and
transformation, authors carried out intermolecular kinetic
Wu et al. in 2013 using Pd(II) catalyst and TBHP oxidant for
isotope experiment by treating equimolar amounts of
direct o-acylation of 2-arylbenzothiazoles and 2-
deuterated benzamide and simple benzamide with methyl
arylbenzoxazoles. In the first study,38 the authors reacted
terephthalaldehydate under standard reaction conditions for
This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 19

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benzothiazoles or benzoxazoles with aldehydes using H

R1
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O
R2
Pd(OAc)2 as catalyst and TBHP as oxidant in toluene as solvent O N Pd(OAc)2 , TBHP
DOI: R10.1039/D0OB01458C
2
N
(Scheme 4). A set of 38 o-acylated benzothiazoles and H R 1 + X

R3
toluene, 5-6 h
X
110 oC R3
benzoxazoles were prepared in moderate to good yields. The X= S & O

X= S & O
developed method was robust and adequate for diverse 38 examples, 40-84%
X=O
azoles and aldehydes. The method seemed to be insensitive X= S
R1= Ph, 4-MePh, 4-PhPh, 3-ClPh
R1= Ph, 4-OMEPh, 4-OBuPh, 4-MePH, 4-PhPh, 4-ClPh,
R2= H, 5-Me
to the electronic behaviour of the substituents present either 4-CO2MePh, 4-NO2Ph, 3-FPh, 3-ClPh, 3-NO2Ph, 2-ClPh,
R3= 4-Me, 4-OMe, 4-Cl
3,4-OMePh, 2,6-ClPh, 4-Cl-3-NO2Ph, naphthyl, furanyl,
on azoles or aldehydes. thiophenyl, ethylbenzene
R 2= H
O R3= H, 4-Me, 4-OMe, 4-O-t-Bu, 4-t-Bu, 4-Cl, 6-Cl, 5-F, 5-Br
O
O R3 OH Scheme 4: Pd(II)-catalyzed direct ortho-acylation of 2-arylbenzothiazoles and
N R2
R2 H Pd(OAc)2, TBHP N R3 2-arylbenzoxazoles.
R1 H
H BF3.Et2O
R1 In a second study,39 the authors reported the o-acylation of 2-
DMSO/dioxane, 130 oC
19 examples, 46-84%
arylbenzoxazoles using aldehydes as coupling partner in the
R1= Ph, 4-OMePh, 4-MePh, 4-ClPh, presence of Pd(OAc)2 catalyst, PPh3 as ligand and TBHP as
3,4,5-OMePh
R2= H, 4-OMe, 4-F, 4-Br, 4-Cl, 2-OMe,
oxidant (Scheme 5). 24 ortho-acylated benzoxazole
2-Me, 3-OMe, 3-Cl derivatives were obtained in 37-85% yield. Benzothiazole and
R3= OMe, OBn, O-i-Pr, O-t-Bu
benzo[h]quinoline were efficiently coupled with p-
O O
O R3
chlorobenzaldehyde giving the respective ortho-acylated
N OH
R1 H
R2 H
Pd(OAc)2, TBHP
R2
O products in 83% and 96% yield after 8 h at refluxed
H BF3.Et2O
DMSO/dioxane, 130 oC R1
temperature. Unfortunately, 2-(3-
then conc. HCl (aq), reflux
5 examples, 50-81% methylphenyl)benzimidazole was unable to give the acylated
R1= Ph, 4-ClPh, 4-OMePh
R2= 4-Cl, 4-OMe
product under the optimized reaction conditions.
Scheme 3: Pd-catalyzed synthesis of imino carboxylic acids and keto- Remarkably, 2-arylbenzoxazoles having substituents on the
carboxylic acids via aryl amide directed C-H activation reaction.
meta-position of the benzene ring exhibited high
regioselectivity and acylation achieved at the less crowded
ortho-C-H bond of the directing group. The steric hindrance at
the ortho-position of aromatic aldehydes influenced the
reaction efficiency and resulted in a lower yield of the
corresponding acylated products.

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DOI: 10.1039/D0OB01458C

ARTICLE
A
R1
Ph
CHO R 2
O O
N R3 Pd(OAc)2 (5 mol%) R2 R3 C
N N
+ TBHP (6 equiv)
R1 O PPh3 (10 mol%) O
PhCl, reflux, 8 h O O
N
24 examples, 37-85% Pd(OAc)2
R1= H, 3-OMe, 3,4-OMe, 4-Me, 4-Cl, 4-Br, 4-F,
2-OMe, 2-Cl, 2,4-Cl, 2-Br, 4-Cl HOAc
R2= H, 7-Me, 5-Cl
3
R = H, 2-Me, 3-Me, 3-OMe, 3-F, 3-Cl, 4-F O
AcOH
B Cl N
O Pd L = Ph3PO
O
N Pd(OAc)2 (5 mol%) AcO L
TBHP (6 equiv) N A
H O TBHP
X + PPh3 (10 mol%) O Pd L
Me Cl PhCl, reflux, 8 h N
Ph L OAc
X= S & NH t
BuO
O O
X B
Me Ph H
X = S; 83% t
BuOH
X = NH; 0%
t
PPh3 +
t
BuOOH Ph3PO + BuOH
O
Pd(OAc)2 (5 mol%)
TBHP (6 equiv)
H N
+ PPh3 (10 mol%) O
N Cl PhCl, reflux, 8 h
Cl 96%
Scheme 5: Pd-catalyzed ortho-acylation of 2-arylbenzoxazoles/ 2-arylbenzothiazoles/2-arylbenzimdazoles and plausible reaction mechanism.
For both the reactions similar reaction pathway was experiments were carried out. The observations suggested
suggested as presented in Scheme 5C. Mechanism starts with that the N-Boc hydrazone moiety is acting as directing group.
cyclopalladation of the 2-arylbenzoxazole or 2- The rate of the acylation reaction was found to be significantly
arylbenzothiazole to give intermediate A. In the second step, faster than that of the hydrolysis step. Scheme 6B also
the in-situ generated acyl radical reacts with intermediate A outlines the mechanism of this transformation.
to form either reactive PdIV or dimeric PdIII intermediate B. In
the last step, reductive elimination resulted o-acylated
derivatives of 2-arylbenzoxazole and redeveloped PdII salt to
maintain the catalytic cycle.
Kim and his group in 2013 reported the first catalytic acylation
protocol to synthesize 1,2-diacylbenzenes from N-Boc
hydrazones.40 This method involves the Pd(II)-catalysed
tandem regioselective acylation of N-Boc hydrazones and in-
situ dissociation of the directing N-Boc hydrazone group in the
presence of TBHP as oxidant delivering 1,2-diacylbenzenes
(Scheme 6). This approach was set up not only for various
aldehydes but also for several acetophenones and
benzophenone N-Boc hydrazones. Unfortunately, aliphatic
and heterocyclic aryl aldehydes were unable to give the
coupling products with this catalytic system. To acquire
greater understanding of the reaction pathway, various

Please&do
A O
R3 Boc R3 furan-2-carbaldehyde delivered the products in 86% and Online
View Article 66%
NH Pd(OAc)2 (10 mol%)
H R1 R 2
N TBHP (4 equiv) O yield, respectively. Cyclohexanecarbaldehyde
DOI: 10.1039/D0OB01458C
and
R2
O
H DCM, 70 oC, 10 h
propionaldehyde also reacted smoothly to give the
1
R
corresponding reaction products in 59% and 64% yield,

O
O O R1= Ph, 4-OMePh, 4-OBnPh, 4-MePh, 4-CF3Ph, respectively. The synthesized acylated azobenzenes were
4-FPh, 4-ClPh, 3-OMePh, 2-OMePh, 3,5- ClPh,
O
MeO
O
2-F-4-OMePh, -naphthyl converted into the indazoles using Zn/NH4Cl/MeOH as
R2= 4-CF3, 4-OMe, 4-Br, 4-Cl, 4-F, 4-NO2, 5-Me,
5-F, 6-F
reducing system at room temperature in just 5 min (Scheme
R3= Me, Ph
7).
35% 36%
R2 R2
B Me Boc
Me Boc O Pd(OAc)2 N
NH N N
NH N N
N 1
R H TBHP, DCE, N2 O
O R2 H R2
TBHP
Pd(OAc)2 R1
Ph
Me 23 examples, 41-86%
AcOH
O
R1= Ph, 4-OMePh, 4-MePh, 4-BrPh, 4-ClPh,
4-FPh, 4-CNPh, 4-NO2Ph, 4-PhPh, 3-OMePh, Zn-NH4Cl
O
Me Boc 2-MePh, 2-ClPh, 2-FPh, naphtyl, 3-NH2-4-ClPh, MeOH, rt, 5 min
Me Boc 3,5-OMePh, furanyl, cyclohexyl, propyl
Ph NH
N NH R2= H, Me, OMe, Cl
N N
[Pd]
N R2
[Pdll]
2
Ph O R
A
B R1
O t O
BuO 23 examples, 92-99%
H
Scheme 7: Pd-catalyzed azo group directed acylation of symmetrically
t substituted azobenzenes with aldehydes.
BuOH
Scheme 6: Pd(II)-catalyzed direct regioselective acylation of N-Boc hydrazones

and plausible reaction mechanism. Meanwhile, Sharma et al. reported a Pd-catalyzed oxidative o-
acylation of triflamide-protected benzylamines using aliphatic
In 2013, Li et al. reported an azo-group directed selective
and aromatic aldehydes via C-H activation strategy. It was
acylation of symmetrically substituted azobenzenes by
observed that benzylamines having triflamide as directing
aldehydes involving a Pd-catalysed C-H activation method.41
group delivered o-acyl-N-benzyltriflamides with high
Using optimized reaction conditions, the scope of various
regioselectivity applying Pd(OAc)2 as catalyst and TBHP as
azobenzenes and aldehydes was explored using Pd(OAc)2 and
ideal oxidant. They used AcOH as an additive and the reactions
TBHP. Aromatic aldehydes containing strong electron-
were carried out in the binary solvent system MeCN/DMF
withdrawing groups such as CN, NO2 at the para-position of
(1:1) (Scheme 8A).42
the aryl ring provided higher yields than those containing
electron-releasing groups (Me, OMe) at the para-position.
Reactions of azobenzene with -naphthaldehyde as well as

View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
TfHN
A TfHN Pd(OAc)2 (7.5 mol %)
O O
TBHP (4 equiv)
1 AcOH (50 mol%) R1

H R
R2 R2
MeCN/DMF (1:1)
100 oC, 40 h
20 examples, 16-75%
TfHN Me
O
R1= Ph, 4-OMePh, 4-MePh, 4-CO2MePh, 4-CF3Ph,
4-FPh, 4-ClPh, 2-OMePh, 3-OMePh, 4-OHPh,
OMe 2-F-4-OMePh, -naphtyl, pentyl, i-Pr,
2
16% R = 2-OMe, 2-Me, 3-Me, 2,4-OMe, 2-F, 2-Cl
B NHTf C
NHTf TfHN TfHN

O OH
R
1. MeI, K2CO3, acetone
Pd(OAc)2
AcOH 60 oC, 10 h, 84%
O
Cyclopalladation 2. LiAlH4, THF, 80 oC
Reductive 12 h, 56%
Elimination NTf
AcOH
Pd
NTf A Me
N
Pd
OAc Oxidation O
R O
B
t
BuO O
O 59
R H R
t
BuOH
Scheme 8: (A) Pd-catalyzed oxidative acylation of N-benzyltriflamides with aldehdyes via C-H activation; (B)
plausible reaction mechanism; (C) transformation of triflamides.
The substrate scope examination revealed that electron poor

aromatic aldehydes were less reactive in comparison to
electron rich aromatic aldehydes. In order to examine a
plausible reaction mechanism for this transformation, the
radical scavenger, ascorbic acid, was added in a dose-
dependent manner and it was found that the reaction
proceeds via a radical pathway as shown in Scheme 8B. They
have also established that o-acyl-N-benzyltriflamides are
effective synthetic precursors for the construction of the
analgesic drug nefopam and analogous (Scheme 8C).
Novàk and co-workers reported a Pd-catalysed cross-

dehydrogenative coupling of anilides with aromatic aldehydes
using mild reaction conditions for the selective o-acylation of
anilides (Scheme 9).43

Please&do
A O Pd(OAc)2 (5 mol %)
O
TBHP as oxidant (Scheme 10A).44 All the used Viewsubstrates
Article Online
SDS (5 mol %) Me NH O
O HN Me TFA (26 mol%)
R1
delivered the anticipated products in moderate to good yields
DOI: 10.1039/D0OB01458C
R1 R2
H
R2 TBHP (2 equiv), H2O,
rt to 40 oC, 24 h
regardless the nature of the substituents. Noticeably, 2-aryl-
30 examples, 32-98%
1,2,3-triazole and benzaldehyde both containing strong

O
Me NH O R1= Ph, 4-BrPh, 3-BrPh, 4-ClPh, 3-ClPh,

2-ClPh, 4-FPh, 3-FPh, 2-FPh, 4-MePh,
electron withdrawing groups such as COOMe (on triazole) and
4-OMePh, 3-NO2Ph, thiophenyl, styrenyl
R2= H, 2-Me, 3-Me, 4-Me, 4-i-Pr, 2-OMe,
CN (on benzaldehyde) gave the corresponding product in 82%
38%
3-OMe, 3-F, 3-Cl, 3-Br yield. However, the highest yield (85%) was obtained in two
B O cases: 1) when unsubstituted 2-aryl-1,2,3-triazole was treated
NH O with benzaldehdye and 2) coupling of benzaldehyde bearing a

Ph
strong withdrawing cyano (CN) group with 2-aryl-1,2,3-
dimeric path
monomeric path triazole having strong electron donating methoxy (OMe)
Pd(OAc)2
O group. Interestingly, high regioselectivity was observed with

O
O Ph
O
NH
O
Ph meta-substituted 2-aryl-1,2,3-triazole and acylation at the
Pd O O
HN O HN
Pd O para-position with respect to the meta-substituent was
HN Pd
O
O H
N achieved instead of ortho-position due to steric hindrance.
O reductive
S6b [TS2m]
elimination
O A
reductive
[TS2b] elimination
Pd N N Pd(OAc)2 (10 mol%) N N
H N O
O O N O N TBHP (1 equiv)
O
Ph S1 R1
O O o 2
Pd O R1 H R2 DCE, 15 h, 80 C R
HN
O carbopalladation [TS1] Ph Pd
O
H O O 26 examples, 25-85%
O
HN Pd N
O O S5m
R1= Ph, 4-t-BuPh, 2-OMePh, 2,5-OMePh,
S5b O
Pd 4-CF3Ph, 3-BrPh, 2-BrPh, 4-FPh, 2-FPh,
O
O 2-ClPh, 2,4-ClPh, 4-CNPh, -naphtyl,
Ph H O methyl, ethyl, ethylbenzene, styrenyl,
O N R2= H, 4-CO2Me, 5-Cl, 5-Me, 5-OMe, 5-CF3
O O
HN Pd S2 Ph
O H O B
Pd
O
N N
N N N
O
-2H -H O N O
HN Pd
O O S3m
dimerization
S3b
Pd(OAc)2
O O
TBHP
Ph H Ph
AcOH
Scheme 9: Pd-catalyzed cross-dehydrogenative coupling between anilides

and benzaldehydes, and proposed reaction mechanism.
N N Ac
N O
N N Pd
Remarkably, this reaction was accomplished at 25-40 oC N
Pd
OAc 2
R
temperature under aqueous conditions in 24 h. Utilization of
O A
the surfactant dodecyl sulphate (SDS) helped to upturn the B
solubility of the reaction substrates in water, and O
t
BuO O
trifluoroacetic acid (TFA) accelerated the reaction in water. R R H
The presence of electron releasing or electron withdrawing t

BuOH
groups on the anilide does not affect the reaction outcome Scheme 10: Pd-catalyzed acylation of 2-aryl-1,2,3-triazole
scaffolds with differently substituted aryl and alkyl aldehydes
and resulted in high yield of the products. Aromatic aldehydes and plausible reaction mechanism.
with weak electron-withdrawing groups (F, Cl, Br etc.)
provided higher product yield, than those containing electron- Based on the available reports and observations, the authors
releasing groups (Me, OMe). 3-nitrobenzaldehdye delivered designed a plausible reaction mechanism that starts with the
the desired product in just 39% yield. In order to support the formation of a five membered cyclopalladation intermediate
hypothesis regarding the probable reaction mechanism, A between 2-aryl-1,2,3-triazole and the Pd-catalyst.
authors have performed quantum mechanical density Subsequently, the generated benzoyl radical reacts with
functional calculations, which suggested the preference of intermediate A resulting in conversion of Pd(II) to the dimeric
bimetallic catalysis over a monomeric route (Scheme 9B). Pd(III) or Pd(IV) complex B. Lastly, this complex B undergoes
reductive elimination leading to the acylated product and
In 2014, Kuang and co-workers described the acylation of 2- Pd(II) get regenerated for the subsequent cycle (Scheme 10B).
aryl-1,2,3-triazole scaffolds with differently substituted aryl
and alkyl aldehydes using Pd(OAc)2 as effective catalyst and

In August 2014, Kuang et al. reported the first example of a prepared with 56-85% yield. The reactionViewproceededArticle Online
Pd-catalysed direct ortho-acylation of 2-benzyl-1,2,3-triazoles successfully with substrates having electron donating or
DOI: 10.1039/D0OB01458C
by aldehydes via C-H bond activation in the presence of electron withdrawing groups. However, 2-benzyl-1,2,3-
Pd(OAc)2 as catalyst and TBHP as oxidant.45 Using the triazole bearing a nitro group at the para-position was not

optimized reaction conditions, the substrate scope with found to be reactive and no acylated product was obtained
respect to aldehydes as effective acyl source, and 2-benzyl- (Scheme 11). The reaction was found to progress following
1,2,3-triazoles was explored, and 26 derivatives were the reaction pathway as shown by Kuang et al. (Scheme 10B).
R1 O
O N Pd(OAc)2 (10 mol%)

N TBHP (2.0 equiv) N
N
+ R2
R1 H N DCE, 80 oC, 16 h R2
N
26 examples, 56-85%
R1= Ph, 2-OMePh, 2,5-OMePh, 2-FPh, 4-FPh,

4-ClPh, 3-BrPh, 4-CNPh, 2-NO2Ph, 4-i-Pr,
furanyl, styrenyl, ethylbenzene, ethyl
2
R = H, 5-Me, 3-Me, 5-OMe, 5-F, 5-Cl,
4,5-ClPh, 5-CF3, 5-NO2
Scheme 11: Pd-catalyzed direct ortho-acylation of 2-benzyl-1,2,3-triazoles.
Sun et al. in 2014 introduced azoxy compounds for selective A

R3
R3
Pd(TFA)2 O
acylation. The authors developed an interesting approach for O
O (10 mol%) N
N N
the selective ortho-acylation of azoxybenzenes using various R1 H
N TBHP O
DCE, 60 oC
aromatic, heteroaromatic and aliphatic aldehydes in the R2
R1
R2
presence of Pd(TFA)2 as catalyst and TBHP as oxidant.46 They 18 examples, 23-91%
prepared 19 different mono-acylated azoxybenzenes with 23- R1= Ph, 4-CNPh, 4-NO2Ph, 4-FPh, 4-ClPh, 4-BrPh,
4-OMePh, 3,5-OMePh, 4-MePh, 3-MePh,
87% yield in 24 h at 60 oC. The presence of mild electron- 2-MePh, propyl, furanyl, thiophenyl,
R2= H, 4-F, 4-Cl, 4-Me, 4-OMePh
withdrawing groups (F, Cl, Br) at the para-position of the R3= H, 4-F, 4-Cl, 4-Me, 4-OMe
benzaldehydes positively affected the reaction giving higher B O
yields of the mono-acylated derivatives. However, strong N

N
O
N
electron-withdrawing groups (CN, NO2) had a reverse effect O N
resulting in very poor yields of the corresponding products. Pd(TFA)2

Unfortunately, other electron-withdrawing groups like CF3
Cyclopalladation
and CO2Me were not suitable for this transformation as no Reductive
AcOH
O
desired products were obtained. Besides the presence of two Elimination
N
ortho-C-H bonds, the reaction afforded exclusively the mono- O
N
N
acylation in the ring directly attached to the N=O group N
Pd
TFA
(Scheme 12A). The ortho-acylation product was converted Pd Oxidation A
TFA
into the indazole analogue by a reduction process. The R O t
BuO O
B
reaction was found to progress through a free radical pathway O
R H
(Scheme 12B). R
t
BuOH
Scheme 12: Regioselective ortho-acylation of azoxybenzenes with aldehydes
using Pd(TFA)2 and plausible reaction mechanism.
In 2014, Patel and his team established a strategy for the
regioselective ortho sp2 C-H acylation of 3,5-diarylisoxazole.47
From four sp2 C-H bonds and one interior sp2 C-H bond, the
functionalization occurred at one of the ortho C-H bonds near
to the N-atom in the presence of Pd(OAc)2 as catalyst and
TBHP as oxidant(Scheme 13A).

Please&do
A
O R2
extended to substituted 2,3-diarylquinoxalines with
View Article Online
R2 Pd(OAc)2, DCE
R1 H
+ Ph
Ph benzaldehydes and good yield of the desired products were
DOI: 10.1039/D0OB01458C
TBHP, 110 oC N O
N O
8-12 h R1 O achieved (Scheme 14).

13 examples, 39-73%
R3 R1
R1= Ph, 4-MePh, 4-t-BuPh, 4-OMePh, H
3-ClPh, 4PhPh, 4-CO2MePh, 2,6-ClPh, O R2 O
N Pd(OAc)2 (5 mol%) R2 R3
-naphtyl, thiophenyl, furanyl N
2
R = H, 5-Me, 5-OMe R 1
H + Toluene : DCE (1:1)
N TBHP (1.5 equiv)

B H N
110 oC, 8 h R3
H
3
R
Ph
N O 23-examples, 11-82%
Ph O X
R1= H, 4-MePh, 4-OMePh, 4-OBuPh, 4-PhPh,
Reductive 4-ClPh, 4-NO2Ph, 4-CO2MePh, 3-ClPh, 3-FPh,
Ph
H Elimination 3-NO2Ph, 3.4-OMePh, -naphtyl, thiophenyl
PdX2 R2= H, 6,7-Cl, 6-Me, 6-Cl
O X = counter R3= H, 4-Me, 4-Br, 3-Me-4-OMe
N anion or OAc
Scheme 14: Cross dehydrogenative coupling for directed mono ortho-acylation
Pd (I) of sp2 C-H bonds of 2,3-diarylquinoxaline.
X O
B Cyclopalladation
Ph N
Oxidative Ph
Methyl and chloro substituted unsymmetrical 2,3-
O
Addition H Ph
diarylquinoxalines after reaction with benzaldehyde provided
O HX
N N inseparable mono-acylated products in a ratio of 5:4 and 5:3,
O O
Ph
O Pd (I) respectively. Furthermore, when the reaction with 2,3-
Ph
A X
N O
BuO O t diarylquinoxaline having two electron-releasing groups (-Me
and -OMe) in one of the aryl ring was performed, mono ortho-
t
BuOH
Ph H
Scheme 13: Pd-catalyzed selective N-directed ortho-acylation of 3,5-diarylisoxazoleacylated products were obtained in a 6.7:1 ratio, revealing the
and proposed reaction mechanism.
favoured oxidative palladation at the more electron rich aryl
Authors reported 13 acylated products with high
ring. However, in the presence of bromine in one of the aryl
regioselectivity in 39-73% yield at 110 oC after 8-12 h in
rings, ortho-acylation was accomplished at the unsubstituted
dichloroethane (DCE) as solvent. The reaction progressed
aryl ring, resulting in only one product and reconfirming the
smoothly with the applied substrates and was found
favoured oxidative palladation of more electron rich aryl ring
compatible with all kinds of functional groups present on the
(Scheme 14).
aldehydes. Nevertheless, the electron-withdrawing groups
such as o-NO2, p-Cl, m-F in 3-aryl ring of 3,5-diarylisoxazole The reaction conditions applied in regioselective acylation of
suppressed the product formation completely under these azobenzenes (Scheme 15) were effectively installed by Wu
reaction conditions. The reaction mechanism was not and co-workers in 2015 during the acylation of azoxybenzenes
thoroughly probed but expected to proceed as outlined in by aldehydes using Pd(OAc)2 as catalyst at 80 C in the
o
Scheme 13B. presence of TBHP as oxidant (Scheme 15A). The authors

49
have prepared a library of derivatives using differently

In continuation of their work on selective N-directed acylation
substituted azoxybenzenes and aryl/alkyl aldehydes.
reactions, Patel and co-workers reported a cross
However, in comparison to Sun’s protocol46, aliphatic
dehydrogenative coupling methodology for the selective
aldehydes gave inferior yields and heterocyclic aldehydes
mono ortho-acylation of the sp2 C-H bond of 2,3-
could not be applied for this transformation, which shows the
diarylquinoxalines using aromatic aldehydes.48 The authors
significance of the reaction temperature. The authors also
developed a small library of 23 derivatives employing
performed some control experiments to investigate the
Pd(OAc)2, TBHP and toluene:DCE (1:1) at 110 oC. Various
reaction mechanism. When the reaction was carried out in the
functional groups were well tolerated on the benzaldehyde
presence of the radical scavenger 2,2,6,6-
and p-chlorobenzadehyde provided the highest yield (82%).
tetramethylpiperidyl-1-oxyl (TEMPO) no acylation product
Benzaldehydes bearing strong electron-withdrawing groups
was obtained revealing a free radical pathway (Scheme 15B).
like p-COOMe, p-NO2, m-NO2 also provided the desired
The probable reaction route for this conversion is shown in
products in good yields. The substrate scope was further
Scheme 15C.

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DOI: 10.1039/D0OB01458C

ARTICLE
A O O
R2 R2 R2
O N Pd(OAc)2 (5 mol%) N
N N
R2
1 TBHP (4 equiv) R C
R H
DCE, 80 oC, 12 h
O O
26 examples, 38-89% N
N
R1= Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CF3Ph, 4-PhPh, 4-MePh, 4-OMePh, 3-ClPh, O
O
3-MePh, 2-ClPh, 2-CF3Ph, 2-MePh, 2-OMePh, 3,4-MePh, 2,3-OMePh,
-naphthyl, cyclohexyl N
2
N
R = H, 4-OMe, 4-Me, 4-Et, 4-i-Pr, 4-CO2Et, 2-Me, 3-Me, 3,5-Me
B O Pd(OAc)2
O
O Pd(OAc)2 (5 mol%) N AcOH
N N
N
Ph H DCE, 80 oC, 12 h
O
O
Ph
NR O N
N
N
O O Pd(OAc)2 (5 mol%) O N
Pd A
N TBHP (4 equiv) N
N Pd OAc
N Ph H
TEMPO (2 equiv) t
Ph BuOH
O t
DCE, 80 oC, 12 h O BuO
B O
t
BuOOH
Ph CHO
NR OH
O Pd(OAc)2 (5 mol%) O
O PhCOOH
TBHP (4 equiv) N
N Ph OH N
N o
DCE, 80 C, 12 h
O
NR= No reaction Ph
NR
Scheme 15: (A) Regioselective ortho-acylation of azoxybenzenes with aldehydes; (B) Control experiments; (C) plausible reaction mechanism.
In 2015 Xiao et al., successfully carried out the acylation of the for the acylation of the aryl ring of 2-phenylpyridines,
aryl ring of acetophenone O-methyl oxime with aromatic diphenyldiazenes, aromatic azo-compounds and other aryl
aldehydes using almost similar reaction conditions as was ketone oximes with aromatic aldehydes (Scheme 16A-D). The
used by Novàk’s and co-workers as given in Scheme 9.50 In this reactions proceeded effectively in all these cases and
case reactions were carried out at 50 oC for 12 h and the electron-releasing or electron-withdrawing groups were
targeted products were achieved in 53-80% yields. The compatible under standard reaction conditions.
authors extended the application of the reaction conditions
OMe
A
Pd(OAc)2 (5 mol %) R2 N C
MeO
O N Ph
N TBHP (2 equiv) Pd(OAc)2 (5 mol %) N
O Ph O
SDS (5 mol%) O N TBHP (2 equiv)
3 1
R R SDS (5 mol%)
H R1 N
H2O (0.6 mL) H
R2 50 oC, 12 h H2O (0.6 mL)
50 oC, 12 h R1
R3 R1
14 examples, 53-78% 8 examples, 53-75%
R1= Ph, 4-MePh, 4-OMePh, 4-FPh, 4-ClPh, R1= H, 4-Me, 4-OMe, 4-F, 4-Cl,
4-BrPh, 4-t-BuPh, 2-ClPh, -naphtyl 4-Br, 2-Cl, 3-Me
R2= H, Me, C2H5
3
R = H, Me, OMe, Cl
B R2 D
R2
NOCH3 Pd(OAc)2 (5 mol %) O
O O NOCH3
Pd(OAc)2 (5 mol %) TBHP (2 equiv)
N SDS (5 mol%)
H TBHP (2 equiv) H
O
SDS (5 mol%) H2O (0.6 mL)
H2O (0.6 mL) 50 oC, 12 h
R 1 N
50 oC, 12 h 82%
R1
12 examples, 52-80% Pd(OAc)2 (5 mol %) N
O TBHP (2 equiv) O
R1= H, 4-Me- 4-OMe, 4-F, 4-Cl, SDS (5 mol%)
H
4-Br, 4-t-Bu, 2-Cl, 3-Me N H2O (0.6 mL)
R2= Me, OMe, Cl 50 oC, 12 h
51%
Scheme 16: Pd-catalyzed acylation of aryl ring (A) acetophenone O-methyl oximes; (B) 2-phenylpyridines; (C) diphenyldiazenes; (D) aryl
ketone oxime and aza phenanthrene with aromatic aldehydes.

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DOI: 10.1039/D0OB01458C

ARTICLE
Yi’s group in 2015 described the synthesis of ortho- the use of K2CO3 as base and PPh3 as additive in
acylphenols by performing an oxidative C-H coupling reaction chlorobenzene solvent for the smooth transformation at 110
between phenols and aldehydes using the cationic ruthenium oC (Scheme 17). Interestingly, the coupling of phenols with
hydride complex [(C6H6)(PCy3)(CO) RuH]+BF4 as an effective -unsaturated aldehydes under the optimized reaction
catalyst in the absence of metal oxidant.51 The reaction conditions resulted in flavonoids. The authors prepared 20
progressed significantly with the applied phenols and flavonoid derivatives successfully with 23-88% yield having
aldehydes comprising electron donating and electron various functional groups. The chemoselectivity of the
withdrawing groups, and resulted in the formation of 26 developed protocol was explored by treating estrone with
ortho-acylphenol derivatives in 35-78% yield. Besides the cyclohexanecarbaldehyde and 4-chlorobenzaldehdye and the
cationic ruthenium hydride complex, the reaction involved corresponding coupling products were obtained in a 1:2 ratio.
A OH OH O B
O
[(C6H6)(PCy3)(CO) RuH]+BF4 OH R4
R1 H O O R3
H R1 R2 [(C6H6)(PCy3)(CO) RuH]+BF4
R2
PPh3, K2CO3, PhCl, 110 oC R 1
R 1 R4 PPh3, K2CO3, PhCl
8-20 h R2 R2
18 examples, 43-78% 110-130 oC, 12-24 h
R3 20 examples, 23-88%
1
R = Ph, 4-MePh, 4-FPh, 4-ClPh,
4-CF3Ph, 2-BrPh, Et, n-Pr, i-Bu, R1= 7-OMe
cyclohexyl, CH(Me)Ph R2= H, Me, n-hexyl
R2= 4-OMe, 4,6-Me R3= H, Ph, n-Pr, Et, 4-FPh
MeO O R2= H, R3= n-Pr; 40% R4= H, Ph
OH OH O O R3 R2= Me, R3= Ph; 46%
O
[(C6H6)(PCy3)(CO) RuH]+BF4 R2= Me, R3= Ph; 42%
R1
H R1 R2= n-hexyl, R3=Ph; 59%
PPh3, K2CO3, PhCl, 110 oC 53% R2
8-20 h
6 examples, 33-61% R4 2 3 4
O R O R3 R = H, R = H, R = n-Pr; 71%
R2= Me, R3= H, R4= Ph; 60%
OH R1= Ph, 4-FPh, Et, cyclohexyl, R = H, R = Ph, R4= Ph; 56%
2 3
3-cyclohexenyl, CH(Me)Ph R2
R = Ph; 35%
R = Cy; 38%
Scheme 17: (A) Synthesis of 2-acylphenol via oxidative C-H coupling reaction of phenols with aldehydes; (B) Coupling between phenols and -unsaturated aldehydes.
In the same year Wu et al. reported a study for the direct to probe either the reaction was following an ionic pathway
ortho-acylation of 2-phenoxypyridines with aldehydes to or proceeding via a radical pathway. The results of
produce a series of novel aryl ketones in the presence of experiments strongly supported the radical pathway. In
Pd(OAc)2 as catalyst, TBHP as oxidant and chlorobenzene as addition to the above studies, some other control
solvent (Scheme 18).52 In order to gain an insight into the experiments were also performed by carrying out the reaction
reaction mechanism, authors performed intramolecular and between 2-phenoxypyridine palladacycle (A) with different
intermolecular kinetic isotope effect studies. The results of benzaldehydes in the presence and absence of TBHP. Based
experiments showed that the ortho C-H bond cleavage of 2- on all these experiments, a plausible mechanism was
phenoxypyridines does not participate in the rate determining proposed as shown in Scheme 18B. The authors also
steps of the reaction. The binding of 2-phenoxypyridines with demonstrated the synthetic utility of this protocol by
the palladium ion was considered as the crucial rate- synthesizing (2-hydroxyphenyl)(phenyl)methanones and 1-
determining step for the acylation. Furthermore, the effect of hydroxy-9H-fluoren-9-ones.
various radical scavengers on the reactivity was determined

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DOI: 10.1039/D0OB01458C

ARTICLE
A B
O N O O N N N
O Pd(OAc)2 (10 mol%)
PhCl R1
R2 + O O
H R1 TBHP (2 equiv), 140 oC R2 Pdll(OAc)2
20 h O
32 examples, 3-94%
R1
1
R = Ph, 4-MePh, 4-OMePh, 4-NO2Ph, 4-CF3Ph,
OAc O
4-AcPh, 4-FPh, 4-ClPh, 4-BrPh, 4-IPh, 2-FPh,
Pdlll or lVL
3-FPh, 3-ClPh, 3-BrPh, 3-CHOPh, 3,5-MePh, O R1
2,5-MePh, 3,5-OMePh, 5-OMePh, 3,4,5-OMePh, Ar N
C
N Pdll(OA
-naphthyl Pdlll or lVL c)2
R2= H, 5-Me, 5-OMe, 5-NO2, 5-F, 5-Cl, 5-Br, 5-I O
O OAc
D A
O O N O O N O O N
O R1
N
Pdlll or lV(OAc)2L O
AcOH
O O
94% 90% 27% R1
O
O TBHP
B
H R1
Scheme 18: Direct ortho-acylation of 2-phenoxypyridines with aldehydes and proposed reaction mechanism.
Triphathi et al. in 2015 reported a metal-free one pot radical Heterocyclic aldehydes such as furan-2-carboxyaldehyde and
approach for the cross coupling between aryl diazonium thiophen-2-carboxyaldedye provided the respective products
tetrafluoroborates and aldehydes to access the synthesis of in 65% and 88% yield. Bulkier aromatic aldehydes, -
diaryl ketones.53 A library of 20 derivatives was established by naphthaldehyde and - naphthaldehyde provided the 89%
coupling differently substituted aromatic aldehydes with and 79% yield, respectively. Aryl diazonium tetrafluoroborate
various derivatives of aryl diazonium tetrafluoroborate using having electron-withdrawing (F, Br) groups resulted higher
di-tert-butylperoxide (DTBP) as a radical initiator. The product yields than that of containing electron-releasing (Me)
presence of electron-releasing (Me, OMe) groups as well as group (Scheme 19A). Based on experimental data and
electron-withdrawing (F, Cl, NO2, COMe) groups on aromatic literature precedents, authors described a plausible reaction
aldehydes was well tolerated under the developed conditions mechanism for this transformation (Scheme 19B).
and afforded the corresponding products in 72-95% yield.

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DOI: 10.1039/D0OB01458C

ARTICLE
O O
A
DTBP, DCE
R2-N2BF4
1
R1 H R R2
80 oC, 0.5-1 h
20 examples, 65-95%
R1 = Ph, 4-OMePh, 4-MePh, 4-FPh, 4-ClPh,

2-MePh, 3-NO2Ph, 3-COMePh, 3,4-OMePh,
thionphenyl, furanyl, -naphthyl, -naphthyl
R2 = Ph, 4-FPh, 4-MePh, 2-MePh, 4-BrPh
B HF
F
F F
t O t
Bu B F Bu O B F
H F F
N2BF4
F
BF4 BF3 F t t
Bu O B F Bu O BF3
N2 F
O O
O t
Bu OH
t
Bu O O t
Bu 2tBu O
Scheme 19: (A) Metal-free cross coupling between aryl diazonium tetrafluoroborates and aldehydes to the
synthesis of diaryl ketones; (B) plausible reaction mechanism.
In early 2016, Jiao and co-workers reported the N- applied for benzo[h]quinolone, 1-phenylpyrazole, 2-
hydroxyphthalimide (NHPI) and palladium co-catalyzed phenylpyridine and 2-phenoxypyridine and the corresponding
oxidative acylation of acetophenone o-methyl oxime using targeted products were acquired in moderate to good yields
aldehydes via selective C-H functionalization. In this protocol (Scheme 20B). Unfortunately, azobenzene and acetanilide
molecular oxygen was used as terminal oxidant for C-H provided inferior yields of the acylated products and phenyl
acylation.54 A wide range of o-methyl oximes and aldehydes N,N-dimethylcarbamate was found to be unreactive under
(alkyl/aryl) was explored and various derivatives were these reaction conditions. The removal of the directing group
prepared bearing electron withdrawing and releasing groups using HCl/dioxane and subsequent intramolecular aldolization
at 80 oC within 24 h in 1,4-dioxane as solvent (Scheme 20A). in the presence of NaOH/DMSO converted the oxime ether
The developed acylation reaction conditions were also into the isoindoline (Scheme 20C).

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DOI: 10.1039/D0OB01458C

ARTICLE
OMe B
A C
MeO R2 N R= Ph
N Pd(OAc)2 (5 mol %) O
O NHPI (20 mol%) O Me
R2 DG = N
1,4-dioxane, 80 oC, 24 h R1 N Ph O Me
R1 H R3 R3 N N O N
O2 (1atm) , , , H ZrCl4 N
NaBH4 Me
33 examples, 32-90% 88% 55% 60%
O 11% THF, rt
1
R = Ph, 4-MePh, 4-t-BuPh, 4-ClPh, 4-CF3Ph, 4-CNPh, 3-FPh,
O Ph OMe
N OH 3-ClPh, 3,4,5-OMePh, 3-Br-4-OMePh, -naphthyl, N i
Pr N 85%
N O
naphthyl, cyclopropyl, cyclohexyl, pentyl, 1-pentenyl, N N
2-methyl-1-propeneyl Me
O Me2N O 1) HCl, dioxane
R2= Me, Ph, C2H5, C6H13 N
N
, 50 oC HO
,
NHPI R3= 4-OMe, 4-t-Bu, 4-n-Bu, 4-CF3, 4-NO2, 4-Br, 4-Cl 27%
2) NaOH, DMSO,
0% rt
OMe OMe OMe 91%
N N Me N O
O N 51%
O O
O
,
90% 60% 58%
82%
Scheme 20: NHPI and palladium co-catalyzed aryl C-H bond aerobic oxidative acylation in presence of various directing group with aryl/alkyl aldehydes and
conversion of acylation product into isoindoline and 3-hydroxy-3-phenylindanone.
Zhao and Jiang in 2016 reported a proficient method for the gain insight into the reaction mechanism. The reaction
selective acylation of 1,4-disubstituted 1,2,3-triazoles between 4-phenyl-1-(p-tolyl)-1H-1,2,3-triazole and
applying the 1,2,3-triazole moiety as directing group using benzaldehyde in the presence of the free radical scavenger
aromatic aldehydes as acyl transfer agent in presence of Pd- TEMPO gave only traces of the desirable compound
catalyst (Scheme 21A).55 The best reaction conditions were demonstrating a radical pathway. Moreover, the
used to prepare 27 derivatives in 55-92% yield after 24 h of intermolecular kinetic isotope effect (kH/kD) was also
reaction at 120 oC. Reaction proceeded with almost equal determined and was found to be 6.3, suggesting that the cl
efficacy in case of aldehydes as well as 1,4-disubstituted 1,2,3- cleavage of the C-H bond may be the rate-limiting step
triazoles. However, aldehydes with strong electron (Scheme 21B). Based on outcomes of these experiments, a
withdrawing groups (NO2, MeS=O) afforded relatively lower plausible reaction mechanism was proposed as outlined in
yields. Further the authors carried out several experiments to Scheme 21C.

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ARTICLE
R3 R1
A O
N N
2 Pd(OAc)2 (10 mol%) 2 N N

O R R
N TBHP (4 equiv), X-Phos R3
N
R1 H DCE, 120 oC, 24 h
C
R1
27 examples, 55-92% O
N N
R1= 2-MePh, 2-OMePh, 2-ClPh, 3-MePh, 3-OMePh, N N N
3-BrPh, 3-ClPh, 3-NO2Ph, 4-MePh, 4-OMePh,
N
4-BrPh, 4-ClPh, 4-SOMePh, 4-i-PrPh
2 Me
R = 2-Cl, 2-I, 2-Me, 3-Me, 3-Br, 4-Me, 4-OMe, 4-NO2
PdllL
3
R = 2-Cl, 2-Me, 3-Me Me
B Ph AcOH
O
(i) Radical capture
O TEMPO N N Me
N N Me
(0.6 mmol) N N
N N L
Ph H N
optimized condition R1 Pd
N O
Me N
N L
Me Pd
Ph
(ii) Kinetic isotope effect A
O
N N t
BuO
N N B O
O
N
Pd(OAc)2,TBHP
N R1 H
O 1
R
X-Phos, DCE t
BuOH
Me Ph
D Ph H 120 oC, 8 h Me
D O
D
N N
N N
N D
N D
D D
Me D D
Me
Scheme 21: (A) Regioselective acylation of 1,4-disubstituted 1,2,3-triazoles with aromatic aldehydes; (B) control experiments; (C) plausible reaction
mechanism.
In contradiction of directing-group assisted direct acylation, in with pyridinecarboxaldehyde and thiophenecarboxaldehyde.

2016, Suchand and Satyanarayan described an Furthermore, product formation could not be observed with
environmentally benign protocol for the Pd-catalysed direct bromo arene implying that the more reactive iodo arenes are
acylation of an aryl system starting from simple and necessary for the achievement of this transformation. To
commercially available iodo arenes and aldehydes (alkyl/aryl), further demonstrate the synthetic utility of this newly
leading to the production of aryl-aryl and alkyl-aryl ketones developed protocol, it was extended to the synthesis of
(Scheme 22A).56 In total, 69 derivatives could be prepared in benzofuranones by selective reduction of the keto group with
45-89 % yield using of Pd(OAc)2 as catalyst, Ag2O as additive NaBH4, followed by in-situ intramolecular nucleophilic attack
and 70% aqueous solution of TBHP as oxidant after 12 h at 120 of the hydroxyl group to the ester group of selected acylated
oC, revealing a broad substrate scope and generality of the compound to afford the corresponding benzofuranones
developed method. However, p-nitrobenzaldehyde could not (Scheme 22B). This approach was also used for the
result in the corresponding product but reaction was found to preparation of the antispasmodic pitofenone a combined
be compatible with m-nitroiodobenzene. The reaction was drug in Spasmalon. Pitofenone was successfully prepared in
favorable with furan-2-carboxaldehyde, but was unsuccessful just two steps using this protocol (Scheme 22C).

View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
A R2
O Pd(OAc)2 (5 mol%) C COOMe
I CHO
Ag2O (1.2 equiv) (1)Pd(OAc)2 (5 mol%) O
2 Ag2O (1.2 equiv)

R1 H R O
70% TBHP in H2O (5 equiv) COOMe 70% TBHP in H2O (5 equiv)
120 oC, 12 h R 1 120 oC, 12 h
(2) pipeidine (3 equiv)
I O K2CO3 (3 equiv)
67 examples, 42-83% DMF, 50 oC, 1 h O
N
N
Br
O O R1= Ph, 4-MePh, 4-OMePh, 4-EtPh, 4-BrPh, 82%
S
4-ClPh, 4-FPh, 4-OHPh, 4-OC3H7Ph, 2-BrPh Pd(OAc)2 I
3-OMePh, 3,4-OMePh, benzo[d][1,3]dioxol-2-yl, D O
furanyl, i-Pr, i-Bu, cyclohexyl, n-Bu, n-Pr, solvent
R1
R2= 2-CO2Me, 4-CO2Me, 2-CO2Et, 2-CO2-i-Pr, R
R1 Pd(0)
42% 45% 2-CO2-n-Bu, 2-CO2-n-Amyl, 2-CO2NHPh, H,3-Me,
3-OMe, 4-OMe, 3,4-OMe, [1,3]dioxol-5-yl, 3-NO2
B
O Pd(II)
O CO2Et O
NaBH4 (2 equiv) R1
2 (II)
CeCl3 7H2O (1 equiv) R Pd
R
O A
MeOH, 0 oC to rt 12 h O
R1 O TBHP
R R H
R
78-95% B
Ag2O
R= Ph (95%); n-Bu (78%) TEMPO O
cyclohexyl (86%) AgI N
O R
Scheme 22: (A) Pd-catalyzed direct acylation of iodo arenes with aldehydes (alkyl/aryl) leading to the aryl-aryl and alkyl-aryl ketones; (B) Conversion to
benzofuranones by selective reduction of keto group; (C) conversion to pitofenone; (D) plausible reaction mechanism.
To investigate the reaction mechanism, the authors corresponding acylated products in good yields. Next, the
anticipated that the reaction may progress through the scope of aldehydes was also investigated by coupling a wide
development of an acyl radical of aldehyde due to TBHP. This range of aliphatic and aromatic aldehydes with 5-bromo-2-
hypothesis was proven by performing the reaction in the (trifluoromethyl)pyridine and the desired products were
presence of TEMPO under standard conditions, as no product obtained in good to excellent yields. A triple catalytic
formation was observed whereas the aldehyde radical- activation mechanism was proposed for this transformation
trapped ester was obtained in 95% yield. A plausible reaction (Scheme 23B). In the proposed mechanism, the photocatalyst
pathway for this transformation is shown (Scheme 22D). Ir[dF(CF3)ppy]2(dtbbpy)PF6 was excited into
*Ir[dF(CF3)ppy]2(dtbbpy) in presence of visible light. The
+
In 2017, Xiahng et al. established a protocol for direct C-H
excited *Ir(III) affected the oxidation of quinuclidine to form
functionalization of aldehyde via photoredox, nickel, and
radical cation and reduced Ir(II) complex. The formed radical
hydrogen atom transfer catalysis in a synergistic approach.57
cation then participates in hydrogen-atom transfer to
This simple and efficient protocol transforms a wide variety of
generate the corresponding acyl radical. Subsequently,
commercially available aldehydes with aryl or alkyl bromides
oxidative addition of aryl bromide to LnNi(0) species delivers
into the desired ketones in excellent yield (Scheme 23A). Aryl
the aryl-Ni(II) species, which is converted into acyl-Ni(III)
bromides containing electron-withdrawing groups such as
complex. After reductive elimination, the desired ketone
CO2Me, CN, CF3, SO2Me delivered the slightly higher product
product is obtained along with Ni(I) species. This is one of the
yield in comparison to those containing electron-releasing
crucial step where both nickel and photoredox catalytic cycles
Me, OMe groups. Monocyclic as well as bicyclic aromatics
would simultaneously turn over via single electron transfer
were also coupled effectively with tert-butyl-4-
from the reduced Ir(II) species to the Ni(I). Lastly, the
formylpiperidine-1-carboxylate to furnish the respective
quinuclidine catalyst is generated with the help of inorganic
products in good to excellent yields. Noticeably, vinyl
base via deprotonation of quinuclidinium ion.
bromides and alkyl bromides were also delivered the

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ARTICLE
A Ir photocatalyst
Ni catalyst O F 3C F
O
Br quinuclidine t
Bu
2 N
R1 H R
K2CO3, dioxane, rt R1 R2 t
Bu
F N Br
20 h, 34W blue LEDs Ni
N F
Ir Br
42 examples, 55-93%
N
R1 = tert-butyl piperidine-1-carboxylate, n-hexyl, n-Pr, Me, N
ethylbenzene, i-Pr, neopentanyl cyclohexyl, Ph, 4-FPh, N
t N
4-OMePh, tetrahydro-2H-pyranyl, cyclopentanyl, cyclopropyl etc. Bu
t F
R2 = 4-MePh, 4-OMePh, 4-AcPh, 4-CO2MePh, 4-CNPh, 4-CF3Ph, Bu
4-SO2MePh, 4-OCF3Ph, 2-CNPh, 3-CNPh, 3-MePh, 5-F-2-MePh, F 3C Ni catalyst quinuclidine
2-methoxypyridinyl, 2-fluoropyridinyl, 3-cyanopyridinyl, Ir photocatalyst
5-fluoropyrodinyl, quinolinyl, isoquinolinyl, pyrimidinyl,
2-methylprop-1-enyl, but-2-enyl, 4-(tert-butyl)cyclohex-1-enyl,
butyronitrile, tetrahydro-2H-pyranyl, oxetanyl
B Br O
+
-H
Br LnNiII Ar
BocN
N
N
H LnNio
Nickel catalytic Br
IrII Cycle
Organocatalytic Cycle reductant LnNiIII Ar
O SET
O alkyl
SET
HAT
BocN Photoredox
Catalytic Cycle LnNiI Br
O *IrIII
IrIII O
N oxident
H
BocN
BocN
Visible light
Scheme 23: (A) C-H functionalization of aldehyde via photoredox, nickel, and hydrogen atom transfer catalysis; (B) plausible
reaction mechanism.
Newman and co-workers accomplished the direct protocol also afforded benzothiophenes in good yield that
intramolecular coupling between organotriflates and showed a non-traditional/conventional disconnection for
aldehydes using an innovative catalytic system comprising of acquiring gateway to the synthetic precursor to raloxifene
Ni0 precatalyst, a phosphine based ligand and a base in 2017 which is a significant estrogen receptor modulator. The most
(Scheme 24A).58 This catalytic reaction pathway provided a notable aspect of this protocol was that it lied within the
ready access to a relatively large number of ketone-containing premises of sustainable synthesis by not involving the use of
compounds and prove to be superior to the conventional any directing group (DG) that prevented waste generation and
Friedel-Crafts reaction (FCRs). Unlike the FCRs, it did not pose also eliminated the need for stoichiometric activation or
any selectivity or reactivity related complexities. Both intramolecular reactivity. It was anticipated by the authors
electron donating, withdrawing and bulkier sterically that the mechanism primarily proceeded through a Heck type
hindered hypothesis- were well tolerated on both the mechanism involving the role of  bond of aldehyde moiety in
coupling partners. Interestingly, the aliphatic aldehydes were the insertion-elimination stage.
difficult to couple as they invariably lead to the formation of
Tishchenko-type side products in presence of TMP. However,
as the authors tried to switch to the quinuclidine motif, they
successfully managed to obtain desired ketones. Besides,
complex biologically active molecules could also be
synthesized and derivatized. It was striking to note that the

A R2 R2
R2 View Article Online
O DOI:N10.1039/D0OB01458C
N
O N Pd(OAc)2 (10 mol%) O R1
O Ni(cod)2 (10 mol%) TBHP (6 equiv)
R1 H
Triphos (12 mol%) N
N N
OTf R1 R2 R3
1,4-dioxane R3 R3
R 1
H 120 oC, 24 h R1
R2 TMP (1 equiv) R1

32 examples, 20-97% R4 R4 R4
PhMe, 20 h, 110 0C O
O
36 examples, 0-94%
R1 = Ph, 2-MePh, 4-CNPh, 3-FPh, 2,3-OMePh, pyridinyl,
thiophenyl, benzothiophenyl, furanyl, 3-hydroxyPh, 1
R = Ph, 4-OMePh, 4-NO2Ph, 4-CF3Ph, 4-AcPh, 2-FPh,
indiolyl, 4-ClPh, cyclohexyl, ethylbenzene, n-pentane, 3-FPh, 4-FPh, 2-ClPh, 3-ClPh, 3-BrPh, 4-BrPh,
3,5-MePh, 2,4-MePh, 3,4-OMePh, 3-CHOPh
1-benzylpiperidinyl, tert-butyl 1H-indolyl-1-carboxylate
R2 = H, Me, OMe,
6-methoxy-b-naphthyl, etc. 3
R = H, Boc, Moc, pivaloyl, acetyl, Bn
R2 = Ph, 4-OMePh, 4-COMePh, pyridinyl, 4-CNPh, 4-FPh, etc. R4 = 2-OMe, 3-OMe, 4-OMe, 4-F, 3-F, 2-F, 4-Cl, 4-Br
B R2
Scheme 24: Ni-catalyzed direct intramolecular coupling between
N
organotriflates and aldehydes.
N
R3 R2
In 2019 Chu et al. reported Pd(II)-catalyzed late stage ortho C- R1
N
H bond acylation of anilines with aromatic aldehydes using 3- O
N
methoxy-2-pyridinyl as removable directing group.59 A wide 2AcO
Pd(OAc)2 R3
I
substrate scope of differently substituted aryl aldehydes and R1
O
N-protected anilines was explored to synthesize 26 R2
PdIII or IV R2
PdII
monoacylated derivatives of aniline using Pd(OAc)2 as catalyst N
sol N
OAc
and TBHP as oxidant (Scheme 25A). However, in few cases R3

N
N
R3
along with monoacylated aniline formation diacylated IV
O
R 1 II
product was observed. Aromatic aldehydes bearing electron- R2

N
Pd III or IV
OAc O O
releasing as well as electron-donating groups reacted AcOH
TBHP
N R1 R1 H
smoothly to give corresponding acylated products in good R3
III
yields under optimized reaction conditions. Scope of Scheme 25: (A) Pd(II)-catalyzed late stage ortho C-H bond acylation of anilines with
aromatic aldehydes; (B) plausible reaction mechanism.
substituted N-protected anilines was determined by coupling
In 2020, Panda and his group reported direct o-acylation of N-
with benzaldehyde and aniline having electron releasing OMe
methoxysulfonamides with aromatic aldehydes in the
group provided slightly better result in comparison to anilines
presence of Pd(OAc)2 as catalyst and TBHP as oxidant.60 In this
having electron donating F, Cl and Br groups. To elucidate
transformation sulfonamide served as directing group. The
whether reaction is proceeding through radical pathway or
scope of various N-methoxysulfonamides was investigated
not radical trapping experiments were carried out using BHT
with aromatic aldehydes by synthesizing 22 o-acylated
(butylated hydroxytoulene), DPE (1,2-diphenylethylene) and
derivatives of N-methoxysulfonamides in 31-68% yields
TEMPO as free radical quencher. The results of the
(Scheme 26A). Aryl aldehydes as well as N-
experiments revealed that a radical species could be involved
methoxysulfonamides having electron-releasing groups or
in reaction. Furthermore, investigation of kinetic isotope
electron-withdrawing groups reacted smoothly and delivered
effect indicates that the Pd-catalyzed ortho C-H bond cleavage
the good yields of corresponding products. However, aliphatic
of aniline is not involved in rate-determining steps. On the
aldehydes such as heptanal and nonanal yielded the desired
basis of the results of these experiments a plausible reaction
products in poor yields. Unfortunately, in case of -NO2 group
mechanism was given by authors (Scheme 25A).
reaction failed due to the deactivation of the ring and starting
material was recovered.
To design the reaction mechanism some control experiments

such as deuterium exchange and kinetic isotope effect were
carried out (Scheme 26B). Deuterium exchange experiment
revealed that the initial cleavage of ortho C-H bond of N-
methoxysulfonamide produces aryl-Pd intermediate involving
a reversible process. Kinetic isotope effect suggested that
intial cleavage of C-H bond is a rate-limiting step. On the basis
of these experiments and literature precedents a plausible
reaction mechanism was proposed as shown in scheme 26C.

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ARTICLE
O
A O Pd(OAc)2 (10 mol%) O
O TBHP (2 equiv) S
O S NHOMe
NHOMe
1,4-dioxane (2 mL) O
R1 H C O
H 100 oC, 15 min R2 O
R2 R1 S
NHOMe O
O
20 examples, 28-68% S
O NHOMe
R1 = Ph, 4-MePh, 4-ClPh, 4-BrPh, 4-FPh, 4-NO2Ph, 2-BrPh, Me
4-CNPh, 4-CO2MePh, n-hexyl, n-octyl, styrenyl Ph Me
R2 = H, 4-Me, 4-Et, 4-Cl, 4-Br, 4-OMe, 3,4-OMe, 3,4-Me, Pd(OAc)2
3,4-Cl, 4-NO2,
B Control experiments AcOH

a) Deuterium exchange experiment AcOH
O
O Pd(OAc)2 (10 mol%) O
O S O O
S TBHP (2 equiv) O O O
NHOMe O S S
NHOMe D 2O S NHOMe NHOMe
1,4-dioxane (2 mL) NHOMe
Me D(H) lV
Me H 100 oC, 15 min lll
20 equiv. Me Pd OAc Me Pd
90% recovery Me Pd 2
0.5 mmol O 2 OAc O
7% deuterium inclusion Ph Ac
Ph O
O
b) Kinetic Isotops Effect (KIE)
O O t
O O BuO
S O
S
NHOMe NHOMe
O O Ph Ph H
H t
46% BuOH
O Ph
0.25 mmol Pd(OAc)2 (10 mol%)
TBHP (2 equiv)
Ph H
D O 1,4-dioxane (2 mL) D O
O 0.75 mmol O
D S 100 oC, 15 min D S
NHOMe NHOMe
kH/ kD = 3.3 O
D D D
14%
D 0.25 mmol D Ph
Scheme 26: (A) Pd-catalyzed direct o-acylation of N-methoxysulfonamides with aromatic aldehydes; (B) control experiments; (C) proposed reaction
mechanism.
In quest for exploring the efficacy of photoredox catalysis in and 2-bromobenzothiazole could render substantial amount
C-H activation, König and team in 2019 designed a of product. Benzaldehyde also permitted the benzoylation of
photocatalytic pathway involving Ni based catalyst and bromobenzene and electron rich bromides in good yield.
achieved the dual catalytic benzoylation of aryl bromides.61 Additionally, the scope of 4-bromobenzonitrile as the
This unique pathway involved the efficient and smart coupling partner was also explored. While most of the
amalgamation the concepts of photochemistry (395 nm LED benzaldehydes showed good reactivity including the
as photoirradiation source) and nickel-catalysis Ni(dmbpy)Br2. fluorinated benzaldehydes, yet 4-hydroxybenzaldehyde and
The investigation was initiated by targeting the coupling of 4- 4-aminobenzaldehyde could not react to furnish the desired
chlorobenzaldehydes and 4-bromobenzonitriles. The results ketone. Based on various computations and experimental
of the screening experiment revealed acetone as the optimal studies, a plausible mechanistic pathway was proposed
solvent, Ni(dmbpy)Br2 as the most efficient precatalyst and (Scheme 27B). During the photoredox catalytic cycle, the first
Na2CO3 as the preferred base. Thereafter, as the scope of the step involved the absorption of photon by benzophenone (BP)
reaction was examined, it was found that the electron which led to the generation of a triplet state BP*. This in turn
deficient substrates rendered the desired benzophenones in facilitated the abstraction of hydrogen atom from aldehyde,
good to excellent yields. In particular, the halogenated ketone leading to the formation of both the acyl radical as well as the
moieties were obtained in moderate to good yields. Also the radical BP-H. The acyl radical was trapped by the generated Ni
heteroaryl ketones could be synthesized in moderate yield (II) species B formed via the oxidative addition of the Ni(0)
(Scheme 27A). Notably, 2-bromo-4-(trifluoromethyl)pyridine complex A into the aryl bromide. The so formed Ni (III) species

C was anticipated to form benzophenone BP and complex D 3.2. Acylation of alkyls View Article Online
via reductive elimination. The catalytic cycle was finally DOI: 10.1039/D0OB01458C
3.2.1. Acylation of sp3 carbons
completed through the single electron transfer from BP-H to
the Ni(I) bromide D, that furnished Ni(0) complex A and BP Rovis and co-workers (2012) employed a dual-catalysis

(ground state). strategy for the asymmetric sp3 -acylation of 1,2,3,4-
A Ni(dmbpy)Br2 tetrahydroisoquinoline using aldehydes as acylating agents. A
O O
Br Na2CO3
R2
chiral N-heterocyclic carbene (NHC) in combination with
R1 H acetone, 395 nm LED R1 R2
photocatalyst [Ru(bpy)3]3+ was used in the presence of m-
8 h, 25 oC 27 examples, 40-98%
dinitrobenzene (m-DNB) under blue light irradiation.62 Various
R1 = Ph, 4-CNPh, 4-CO2MePh, 2-CNPh, 4-CF3Ph, 4-tBuOPh, aldehydes were reacted with substituted N-aryl-1,2,3,4-
4-MePh, 4-tBuPh, 4-CF3OPh, 3-FPh, 3-CF3Ph, 4-BzOPh
R2 = Ph, 4-OMePh, 4-tBuPh, 4-CNPh, 4-CF3OPh, 4-ClPh,
tetrahydroisoquinolines and 16 derivatives were prepared in
4-CF3Ph, 4-FPh, 4-CF3SO2Ph, 3,5-CF3Ph, 4-tBuCO2Ph, 51-94% yield at ambient temperature (Scheme 28A). Authors
pyridinyl, pyrimidinyl, 2-methylbenzo[d]thiazolyl, 6-chloropyridinyl
projected a catalytic cycle which involves irradiation of
B SET [Ru(bpy)3]2+ (III) using blue light resulting in excited
t N [Ru(bpy)3]*2+ (II) which generated a powerful oxidant
NiI
Br
[Ru(bpy)3]3+ (I).63 Afterwards, single electron oxidation of the
OH
N
Ni 0 BP-H
N tetrahydroisoquinoline followed by hydrogen abstraction
Ar' Ar D
O
resulted in iminium ion A and recovering of [Ru(bpy)3]2+ (III).
N
O
Ar' Ar' On the other hand, interaction between NHC and aldehyde
BP
A Ar' H generated the nucleophilic Breslow intermediate B, which
HAT hv
O then captured iminium ion A to form a new intermediate C.
ArBr
O Ar' Ar Elimination of the NHC from intermediate C provided -amino
N Ar Ar' BP* ketone D and allowed NHC E to re-enter in catalytic cycle again
NiII
Br
(Scheme 28B).
O Ar'
N
N Ar
NiIII
B Br
N
C
Scheme 27: (A) Ni-catalyzed photocatalytic dual benzoylation of
aryl bromides; (B) proposed reaction mechanism.

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ARTICLE
A NHC (5 mol%)
R2 O O
Ru(bpy)3Cl2 (1 mol%) R2
1
R 1
H m-DNB, CH2Cl2 R
N photons ~450 nm N
Ar Ar
O 15 examples, 5-91%
R1= Me, Et, n-Pr, CH2CH2SMe, ethylbenzene,
N Br
N 1-butenyl, cyclopropyl, CH2CH2CH2NPhth,
N CH2CH2CH2OAc, i-Pr
R2= H, 6,7-OMe
Br Ar= Ph, 4-MePh, 4-BrPh, 4-OMePh, 4-CF3Ph
Br
NHC
O
R' N Ox
O X N
N 3+ N
N Ru
R1 R' N Ox
H N N
HO N *
R1
B X R2 H
O I
R' N
NR2 2+
N N
N NHC Catalysis -H
N X 2 Photoredox Ru
R' R
N Catalysis
R2 O N
N
R' NR2 N
NR2 X X
H N A
O N
R' E R' N II
N
N X
N HO N 2 +
N
R' N O R1 Ru
R2 X
R 2 R2 NR2
N N
NR2 R1 N
C
X NR2
F D
Aza-Breslow III
Intermediate
Scheme 28: Photocatalyzed asymmetric sp3-acylation of tertiary amines and proposed catalytic cycle.
Suresh and co-workers developed a intermolecular tandem that bromo group as a better leaving group for this
Cu-catalyzed O-arylation-oxidative acylation protocol transformation. Afterwards, the scope of various differently
between 2,4-dihydro-3H-pyrazol-3-ones and O-halo aryl substituted 2-bromobenzaldehydes was explored and it was
carboxaldehydes to synthesize chromone fused pyrazoles found that electron donating groups on 2-
using air as an ideal oxidant.64 The reactions were carried out bromobenzaldehyde were well accepted and provided the
taking 0.5 mmol of 2,4-dihydro-3H-pyrazol-3-ones, 0.6 mmol resultant products in good yield. However, an electron-
of o-halo aryl carboxaldehydes in the presence of CuI as withdrawing group such as fluorine gave the corresponding
catalyst, 1,10-phenanthroline as ligand, K2CO3 as base at 120 chromone fused pyrazole in moderate yield. Tetracyclic
oC in DMSO as solvent. The reaction was used to prepare 25 chromone fused pyrazole was obtained in 66% yield with 1-
chromone fused pyrazoles in moderate to good yields pre- bromo-2-naphthaldehdye on the other hand the reaction of
setting countable tolerance towards diverse substituents in N-Boc pyrazolone with 2-bromobenzaldehdye failed to deliver
substrate. During the initial screening of substrates 2- product. Moreover, this methodology was not found suitable
bromobenzaldehdye provided better results than 2- in the case of heteroaromatic aldehyde like 2-
chlorobenzaldehdye and 2-iodobenzaldehdye, suggesting chloronicotinaldehdye (Scheme 29A).

View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
A R2 O R2 O
CuI (10 mol%)
1,10-Phen (20 mol%)

H C
N O N
N K2CO3
N O O S
X
R3 DMSO, 120 oC, 6 h R3 R2 R2
R1 R1 R3 R3
X= Br, Cl, I 27 examples, 25-74% Lawesson's
N reagent N
O Me O O N Toluene, reflux, N
Me Ph R1= Ph, 3-NO2Ph, Me, benzyl O O
R1 14 h R1
O O R2= Me, Ph, n-Pr, t-Bu, CF3 93-96%
N N N R3= H, 7-Me, 6-OMe, 6-F, 6-Br,
N O O N O N O O 8-Cl, 5-Cl, 7-F-6-OMe R1= Ph, Me
Ph Ph Ph R2= Ph, Me, Pr
51% 66% 51% R3= H, OMe
B O O
R2 D
Me O
H Me O
N R3 R3
N O X Pd/C, H2 N
N
X O R1 Cu(I)X + Ln
N O
O N O MeOH, rt, 16 h R3
(lll)
R3
LnCu
O
R2 R3 R3 R2 N
N R1
Reductive Oxidative X
O elimination LnCu(I)X addition NH2
N N Cu(III)Ln NO2
X 36-43%
E A
R1
R3= H, 6-OMe, [1,3]dioxolyl
O Base OH
R3
Oxidative cross-coupling O-Arylation
Ln(I)Cu O
R2 N
X N R1
O
R1 2
N R
Reductive Base HX
Ln(II)Cu N
R3 elimination O
R2 complexationN R3
X O C
(Air) N
R 1
O2 R1 O Cu(III)Ln
N X
B
N
R2 D
Scheme 29: (A) Cu-catalyzed ortho-arylation-oxidative acylation of 2,4-dihydro-3H-pyrazol-3-ones with ortho-halo aryl carboxaldehydes; (B) Plausible
reaction mechanism; (C) Thionation of few chromone fused pyrazoles; (D) conversion of chromone fused pyrazoles into an A2-subtype selective adenosine
receptor antagonist and its derivatives.
Based on the literature report and control experiments, a compounds were also treated with Lawesson’s reagent and
plausible mechanism was proposed for this methodology the thione derivative was obtained in 93% yield (Scheme 29C).
(Scheme 29B). The applicability of the developed method was The method had also been extended to synthesize an A2-
also checked for the gram scale and the targeted product was subtype selective adenosine receptor antagonist and its
obtained in 68% yield. Moreover, some synthesized derivatives (Scheme 29D).

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ARTICLE
B
Ag+ S2O82- Ag2+ SO42- SO4+
path1A
AgSO4 AgHSO4 O
OH
O
MeO B
MeO A
SO4+ HSO4
MeO OHC CN
path 1B
H2 O CN
MeO CN MeO
A O
O ( )n
AgNO3, Na2S2O8
R1
+ R2 ( )n
C
R1 H R2 OH DMSO/H2O (1:1), 50 oC O D O O O
O HOH
n = 1, 2 32 examples, 36-92%
path 2B path 2A
n= 1, 2
water-assisted 1,2-HAT 1,2-HAT
R1= Ph, 4-CNPh, 4-CO2MePh, 4-OMe, 4-CHOPh,
4-MsPh, 4-AcPh, 2-CNPh, 4-(C(Et)2OH)Ph MeO CN
MeO CN
R2= Ph, 2-OMePh, 4-MePh, 4-OMePh, 4-OPhPh, -H2O
4-SMePh, 4-FPh, 4-ClPh, 4-BrPh, H, Bn, n-Bu,
thiophenyl, benzpthiophenyl, benzofuranyl,
O F OH
cyclopropyl, cyclohexyl, cyclobutyl O O AgSO4
E AgSO4
H AgHSO4
H2 O
path 3A, ET
path 3B
AgSO4
PCET
MeO CN
O O AgHSO4 AgSO4
O G OH
MeO CN
MeO PT
CN
O H O
H
Scheme 30: (A) Ag-catalyzed ring opening acylation of cyclopropanols and cyclobutanols using aldehydes; (B) plausible reaction
mechanism.
Che et al. in 2018, described Ag-catalyzed ring opening outcomes and earlier reports, a probable mechanism was
acylation of cyclopropanols and cyclobutanols through proposed as displayed in scheme 30B.
intermolecular oxidative radical addition of aromatic
3.2.2. Acylation of sp2 carbons
aldehydes using mild and neutral reaction conditions.65 1-(4-
Methoxyphenyl)cyclobutan-1-ol and p-cynobenzaldehydye In 2013, Wang et al. developed an efficient and novel
were chosen as model reaction substrates to evaluate the approach for the synthesis of -unsaturated keto
reaction parameters. Using the optimized reaction conditions, compounds by Cu-catalysed direct oxidative coupling reaction
the substrate scope with respect to cyclopropanols, of alkenes and aldehydes with high atom economy.66 For the
cyclobutanols and aromatic aldehydes was explored and 32 successful transformation of alkenes and aldehydes into the
derivatives were prepared in 36-92% yield at 50 oC (Scheme desirable -unsaturated keto compounds, the authors
30A). The reactions proceeded smoothly with the applied carried out the reactions using CuCl2 as most suitable catalyst
substrates bearing distinct functional groups of varying and TBHP as oxidant under nitrogen atmosphere. All the
electronic behaviour. To investigate the reaction mechanism, employed aldehydes and alkenes underwent coupling
the reaction between model reaction substrates 1-(4- reaction effectively under the used reaction conditions
methoxyphenyl)cyclobutan-1-ol and p-cyanobenzaldehdye irrespective of the positions and electron behaviour of
was carried out using TEMPO under standard reaction substituents present either on the aromatic aldehydes or the
conditions and a mixture of products was obtained without alkenes resulting in 18 derivatives in 30-80% yield (Scheme
any acylated product. The results of control experiments ruled 31A). Authors investigated the possible mechanism by
out the formation of any possible acyl radical. Based on these performing the reaction in the presence of radical trapping

substance 2,6-di-tert-butyl-4-methylphenol (BHT) under a free radical pathway as shown in scheme 31B. View Article Online
standard reaction conditions, and the reaction found to follow DOI: 10.1039/D0OB01458C
B t
BuOOH
t
BuO

O
A
R 2 O R 2 R1 H
O CuCl2, TBHP
R3 R1 R3
R1 H N2, 80 oC
O
18 examples, 30-80%
n n+1
[Cu ] [Cu ]~OH R1
R1= Ph, 3-MePh, 4-SMePh, 4-OMePh, 4-ClPh, A B R2

4-MePh, 2-MePh, -naphthyl, thiophenyl
R2= H, Ph R3
3
R = Ph, 2-MePh, 4-MePh, 4-t-BuPh, 4-FPh,
4-ClPh, 4-OMePh, 4-OAcPh
O R2 O R2
R1 R3 R 1 R3
-H2O
A
Scheme 31: (A) Cu-catalyzed direct oxidative coupling between alkenes and aldehydes; (B)
plausible reaction mechanism.
In 2015, Li and co-workers developed a Fe-catalysed protocol oxygenated products in 22-65% yield after 1h of reaction at 50
for the acylation of terminal alkenes which undergoes oC (Scheme 32A).
subsequent intramolecular oxygenation in a tandem manner

Olefinic -diketones and olefinic -ketone esters smoothly
to deliver functionalized 2,3-dihydrofurans having a
reacted with benzaldehydes to provide theresultant
quaternary carbon.67 The method bears a few salient features,
dihydrofurans in moderate yields. However, the presence of a
which include the insertion of carbonyl substituents and a
SO2Ph group on the alkene suppressed the reaction with
quaternary carbon containing various functional groups like
benzaldehyde and the desired product was not observed.
alkyl, aryl and esters. To check the applicability of the newly
Moreover, the scope of aldehydes was also studied and both
developed method several aldehydes (aromatic and aliphatic)
aromatic as well as aliphatic aldehydes reacted effectively
were treated with a variety of terminal alkenes in the
under the optimized reaction conditions and afforded the
presence of FeCl2 as catalyst, di-tert-butylperoxide (DTBP) as
products in moderate to good yields. However, in the case of
oxidant and chlorobenzene as solvent under nitrogen
cyclohexane carboxaldehdye and pivaldehyde,
atmosphere. The authors prepared 17 different acylated-
decarbonylation products were obtained.

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ARTICLE
A R4 R3 cat. FeCl2 O C CO2Me

O R3 O
R1 CO2Me OMe
R2 O
+ Ph
R1 (tBuO)2 Ph
H
O PhCl, 120 oC R2 OMe
R4 O
1 h, N2 MeO2C HO
MeO2C HO B
A
17 examples, 22-65%
O CO2Me OMe O CO2Me OMe
R1= Ph, cyclopropyl, t-Bu, 4-MePh, 4-OMePh, 4-BrPh, thiopheyl
Ph Ph
R2= Ph, 4-MePh, 4-OMePh, 4-ClPh, naphthyl
OMe OMe
R3= COPh, (CO)-4-MePh, (CO)-4-OMePh, (CO)-4-ClPh, CO2Me, CO2Et, Me
R4= CO2Me, CO2Bn, Ph, Me MeO2C HO MeO2C O
C D
B O
MeO2C O Ph O
O cat. FeCl2 R Ph
+ Ph tt D
Ph H BuO)2
Ph R4 R3
O TEMPO (2.0 equiv) MeOOC O
or BHT (2.0 equiv) not observed R2
O R3 R1 R3
O O O
OMe O O
CO2Me
Ph R1 R2
O MeO2C O OMe OMe cat. FeCl2 R1 R2
OMe R4 R4 O
+ t E F
Ph ( BuO)2 t
H O BuOH
MeO2C
OMe (tBuO)2
[
O 55%
F
OH e
OMe
MeO CO2Me O ] [Fe]n
O OMe OMe * n
O cat. FeCl2 * t
BuO t
BuO
R 1 H R1 R1 R3
R3 O
+
Ph
+ * t
( BuO)2
MeO * O O
H * 1
MeO2C
OH R2 R2
Ph O R4 O
R4
t
BuOH G
PTSA
MeO CO2Me
MeO O
MeO2C
40% Ph
Scheme 32: (A) Fe-catalyzed tandem acylation of terminal alkenes; (B, C) comtrol experiments and (D) plausible reaction mechanism.
To get an insight in the reaction mechanism, few control The idea of visible light mediated dual photoredox
experiments were performed under standard conditions organocatalysis for the direct aldehyde Csp2 C-H
(Scheme 32B). The use of radical scavengers TEMPO and BHT functionalization was also fruitfully utilized by Liu et al.68 The
totally suppressed product formation and the alkene was protocol led to the generation of acyl radical species that
recovered quantitatively supporting the addition of an acyl either underwent addition to electrophilic alkenes or
radical to the C=C bond in the initial step. The reaction of participated in the Ni-catalysed cross coupling reactions,
benzaldehyde with the olefinic ketone resulted in the allowing the synthesis of a diverse range of unsymmetrical
preferred dihydrofuran in 55% yield. An alkene having a ketones, present predominantly in various organic building
hydroxyl group instead of a carbonyl group delivered a blocks. During the initial trials, benzaldehyde and 2-
tetrahydronaphthalene as the major product, which on cyclohexeneone were chosen as the model substrates for the
subsequent dehydration gave dihydronaphthalene. However, purpose of optimization and delightfully, moderate yields of
required the tetrahydrofuran product could not be obtained the desirable adduct could be formed. In order to investigate
via possible intermediates A and B. Based on these results, it the ability of quinuclidine as the HAT catalyst, a series of
wasclear that the formation of the dihydrofuran was not experiments were performed using a number of co-catalysts.
possible through the possible intermediate C or D (Scheme Also, a few photoredox catalysts were tested amongst which
32C). Based on the observations of experiments and literature [Ir[dF(3 )ppy]2(dtbbpy)]PF where (dF = 3,5-diFluoro; ppy = 2-
reports, a tentative reaction mechanism was established phenylpyridine; dtbbpy = 4,4’-ditert-butyl-2,2’-bipyridine)
(Scheme 32D). complex emerged to be a material of choice. Amongst the
various tested solvents, acetonitrile (MeCN) prove to be the
most favourable one resulting in high product yield. The

control experiments significantly re-inforced the need of both purpose of photo irradiation. The authors View began
Article their
Online
catalyst as well as visible light to mediate this transformation. investigation by questioning whether the photocatalyst could
DOI: 10.1039/D0OB01458C
Henceforth, the authors engaged themselves in the mission of provide the desired solution and in this endeavour they tested
evaluating the scope of the reaction by subjecting a diversity a wide range of photoinitiators in the model reaction between

of aldehydes and found the aliphatic linear as well as cyclohexaldehyde and diethyl maleate. Amongst all the tested
branched chain aldehydes to be more reactive and affording photocatalytic sources, phenylglyoxalic led to higher product
the desired products smoothly in moderate to good yields as yield with excellent selectivity. On further experimentation, it
compared to the aromatic aldehydes (Scheme 33A). It was was found that the reaction could also take place in water and
striking to note that in case of the weaker benzylic Csp3 C-H sunlight, but in the absence of either of these, the reaction
bonds, selective Csp2 C-H activation could be achieved. failed to proceed. After optimizing the reaction conditions,
Surprisingly, the branched aldehyde motifs yielded trace the authors examined the scope of substrates and found that
amounts of decarbonylated product. while the branched aldehydes led to higher product yield and
selectivity, linear aliphatic aldehydes also rendered single
The protocol was also applicable for an expansive range of
product with good to excellent yield (Scheme 34A).
olefin acceptor as evident from the obtained results. -
Thereafter, alkenes and aliphatic esters were also screened.
unsaturated ketones resulted in quantitative yields and
Despite showing a wide generality, the protocol failed in case
electron withdrawing substituents such as sulphones were
of amides of maleic acid and other esters such as methyl
well tolerated. However, in case of acrolein addition, the
acrylate, methyl crotonate, and N-phenyl maleimide due to
conversion was rather low. Also, wondrously, the
polymerization issues. Also, when dibenzyl fumarate was
cyclohexanecarboxyl radical was unable to open
subjected to the similar reaction conditions, the product was
cyclopropane ring and starting material could be procured as
obtained in lower yield.
such as it remained totally unreactive. Furthermore, to add to
the credentials, this strategy could also be extended to co- To probe the reaction mechanism, fluorescence quenching
operative catalysis with Ni catalysed cross coupling between studies and UV-Visible experiments were performed. Through
the generated acyl radical and organohalides (Scheme 33B). the results of the fluorescence test, it was interpreted that the
Ir(dFCF3ppy)2(dtbbpyPF6)
acyl radical was not generated directly by the excited
O
O
R3
quinclidine
phenylglyoxylic acid, unlike what had been observed in case
1
R R3
R1 H R2 MeCN, Ar, 34 W blue LED
R2
of literature precedents. However, in case of esters of maleic
12 h
20 examples, 31-99% acid (diethyl maleate and fumarate) quenching of
phenylglyoxylic acid was observed. On the basis of various
mechanistic studies, a mechanism was proposed (Scheme
R1 = Ph, 4-BrPh, ethylbenzene, cyclohexyl, cyclopentyl, n-hexyl, ethyl,
i
Pr, iBu, CH2CH(CH3)Ph, CHEt2, etc. 34B). The irradiation led to the excitation of phenylglyoxalic
R2 = CO2Me, H, Me
R3 = CO2Me, H, CO2Et, CO2tBu, COCH2Me, COMe, SO2Ph, CN
acid which formed an exciplex (inferred as a radical ion pair)
with diethyl maleate via a photoinduced electron transfer
Ir(dFCF3ppy)2(dtbbpyPF6)
(PET) process. The exciplex was found to be in equilibrium
Br
O
quinclidine O Br with another ion pair generated between PhCOCOOH and
NiCl2.DME, dtbbpy
R1 H
R 2
R 1 water. In absence of a HAT donor aldehyde,
DMSO, Ar, 34 W blue LED R2
N2, 24 h photodecomposition occurred, quickly leading to the
8 examples, 15-60% formation of benzaldehyde. On the other hand, when the HAT
R1 = Ph, ethylbenzene, cyclohexyl, cyclopentyl, n-hexyl, ethyl, donor (aldehyde) was present, a HAT process with the
CH2CH(CH3)Ph, CHEt2
R2 = 2-CN, 4-Ac aldehyde furnished the acyl and PhCOCOOH radical which
slowly underwent decomposition to form benzaldehyde. The
Scheme 33: Ir catalyzed aldehyde Csp2 C-H functionalization of (A)
alkenes and (B) arylhalides using aldehdyes. fluorescence quenching test also affirmed that the HAT
process could not be initiated by the phenylglyoxalic acid on
Kokotos and co-workers developed a green photo
its own. This could also be the reason behind the difference in
organocatalytic route for the C-H activation of aldehydes
selectivity exhibited by other photointiators and
which led to the selective hydroacylation of electron deprived
phenylglyoxalic acid. The authors reached to the conclusion
alkenes.69 For accomplishing this, phenylglyoxalic acid was
that exciplex formation between phenylglyoxylic acid and
utilized as the photocatalyst and household bulbs for the
dialkyl maleate is mandatory for this reaction.

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ARTICLE
B O * O
A H3 O Ph H
Ph COO
O R2 PhCOCOOH O
visible light
R1 H R1 R2
R3 H2O, 4-20 h
R3
R2
30 examples, 48-96%
O O * O R2
R1 = cyclohexyl, cyclopentyl, iPr, iBu, n-pentyl, nPr, CH(C2H5)2, hv R3
CH(CH3)CH2CH3, CH(CH3)CH2CH2CH3, ethylbenzene, Ph COOH Ph COOH Ph CO2H
PET R3
4-BrPh, 4-OMePh, etc.
2
R = CO2Et, CO2Bu, CO2CH(CH3)CH2CH3, CO2CH2CF3,
O
CO2CH2CH2OPh, CO2CH2Ph, CO2CH2(4-ClPh),
CO2CH2(4-MePh), CO2CH2(4-tBuPh), HAT
R2 R1 H
3
R = CO2Et, CO2Bu, CO2CH(CH3)CH2CH3, CO2CH2CF3,
O
CO2CH2CH2OPh, CO2CH2Ph, CO2CH2(4-ClPh),
O O
CO2CH2(4-MePh), CO2CH2(4-tBuPh), Ph, 4-ClPh, 4-OMePh R1 H R3 OH O
R1 R2 R1 R2 Ph COOH R1
R3 R3
Ph H
Scheme 34: (A) Photocatalytic hydroacylation of alkenes with aldehdyes; (B) proposed reaction mechanism.
Taking into account the fascinating advantages of (2,2,6,6-tetramethyl-1- piperidinyloxyl) -a radical scavenger
photocatalysis, Yadav and team designed a promising metal that quenched the reaction completely. The formation of
free, photocatalytic one-pot route to obtain chalcones via benzoyl-TEMPO adduct was confirmed by HRMS.
radical denitrative benzoylation of β-nitrostyrenes.70 Visible
To further gain an insight into the reaction mechanism,
light was utilized as the energy source, N-hydroxyphthalimide
electron paramagnetic resonance experiments were also
(NHPI) as the reusable photocatalyst and acetonitrile was
carried out, which also confirmed the involvement of radical
chosen as the green solvent. The primary reason for
species in the reaction (Scheme 35B). Additionally, a kinetic
employing NHPI as the catalyst was that it could readily
isotope experiment was also conducted, which gave a KH/KD
generate benzoyl radical photochemically from benzaldehyde
ratio of 5.2, indicating the aldehydic C-H bond activation.
and this in turn could cross couple with β-nitrostyrene to
Apart from this, an on/off experiment was also carried out
furnish chalcones. Sequentially, a number of control
which signified the role of visible light in this process. Based
experiments were performed that delineated the significance
on various mechanistic studies and previous literature
of employing visible light and NHPI to afford the target
reports, a plausible mechanism was proposed (Scheme 35C).
chalcone compounds. After establishing the optimal
As demonstrated, under visible light irradiation wherein 7
conditions for this visible light mediated synthesis, the
Watt LED was used under inert N2 atmosphere, a radical was
generality of the protocol was explored and it was found that
formed by the migration of H atom of NDPI from O of the CO
a broad range of β-nitrostyrenes and benzaldehydes
group of imide. The hydrogen transfer from the aldehyde
containing diverse electron donating as well as withdrawing
moiety formed acyl radical along with the radical species B.
substituents could be applied that demonstrated impressive
The acyl radical therefore underwent reaction with (E)-β-
tolerance (Scheme 35A). It was further appealing to note that
nitrostyrene to generate the benzylic radical, which
a choleretic drug named “metochalcone” could also be
eliminated the NO2 radical to form the targeted product.
obtained using similar reaction conditions by the team of
Thereafter, the NO2 radical abstracted H atom from B in order
researchers. The protocol followed a radical mechanistic
to regenerate NHPI that could further sustain the catalytic
pathway which was confirmed via the addition of TEMPO
cycle.

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ARTICLE
A
O white LED, 7 W O
NO2 C
R2 NHPI, MeCN, N2
1 1
R H R R2
rt, 8-16 h O H
18 examples, 0-96%
R1 = Ph, 2-MePh, 2-OMePh, 4-FPh, 4-tBuPh,

4-CO2MePh, 4-MePh, 4-NH2Ph, 3-OHPh,
4-OMePh, 2,4-OMePh, thiophenyl, furanyl,
O O
propyl
R2 = Ph, 4-tBuPh, 4-OMePh, 4-NO2Ph, 2-NO2Ph, white LED
4-FPh, 2-NH2Ph, a-naphthyl, b-naphthyl, N O N OH
1-cyclohexenyl,
A
B Control experiment OH O
O
(I) TEMPO trapping experiment
HNO2
O H O N OH
NO2 white LED, 7 W
B OH NO2
NHPI, MeCN, N2
rt, 8h O
O
TEMPO not observed
(II) Kinetic isotope effect experiment
NO2 NO2
O H
O
NO2
NO2 white LED, 7 W
O
NHPI, MeCN, N2
O D rt, 8h D O
D D D
D D D D
D D
Scheme 35: (A) photocatalytic one-pot benzoylation of -nitrostyrenes using aldehdyes; (B) control experiments; (C) plausible reaction
mechanism.
Encouraged by this idea as well as the splendid results was investigated wherein a broad spectrum of aldehydes and
encountered in case of sustainable photochemical olefins were subjected to the optimized conditions (Scheme
transformations, Jr. and co-workers set out in the task of 36A). Much to the delight of the researchers, the protocol
performing epoxyacylation and hydroacylation of olefins showed great efficacy in furnishing the target compounds
under visible light driven conditions employing methylene possessing either electron donating or withdrawing groups in
blue as the photoredox catalyst and persulphate (K2S2O8) as good to excellent yields. Aliphatic aldehydes and styrene
the oxidizing agent.71 They utilized a single set of reagents for particularly reacted very well and yielded the target product
two diverse set of transformations. While performing the in good yield.
optimization, the authors found that nearly 35% of the
This strategy was also extended to benzaldehydes and non-
epoxyketone moiety could be obtained using 2.5 mol % of
conjugated olefins and again both electron donating and
methylene blue as photocatalyst, 1.0 mol K2CO3 as the base
electron withdrawing substituents were well tolerated.
and 2.0 equiv of K2S2O8 under 100 W irradiation. An increase
Unfortunately, aliphatic aldehydes failed to give good results.
in product yield to 92% was observed on decreasing the
Sytrenes also when subjected to the hydroacylation gave the
amount of base employed for this protocol. A set of control
corresponding epoxyketone in only traces. The results clearly
experiments revealed the indispensable need of all the
suggested that only non-conjugated long chain olefins can
reagents as well as light to render the desired moiety with
participate in this transformation (Scheme 36B). Again a
good conversion percentage. The generality of the protocol
plausible mechanism was proposed. A triplet state electron

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acceptor MB* was generated via the photoexcitation of generate radical A. This further provided an Viewaccess to
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methylene blue using a household lamp (100 W), which peroxide (B) by combining with hydroxyperoxyl radical that
DOI: 10.1039/D0OB01458C
engaged in a single electron transfer (SET) with hydroperoxide was generated in the first step during SET. In the final step,
anion produced from the persulphate alkaline hydrolysis that the targeted epoxyketone molecule was produced via the

afforded the hydroperoxyl radical and methylene blue elimination of OH- from B under alkaline conditions.
radical. Thereafter, through a hydrogen atom transfer (HAT) Methylene blue was regenerated via oxidation either aerially
between benzaldehyde and hydroperoxyl radical, an acyl or in presence of persulphate (Scheme 36C). Similar
radical was produced, which added to the styrene molecule to mechanism was also proposed for the acylation reaction.
A O R2 methylene blue O B
K2S2O8, K2CO3 R2 O methylene blue
1 O K2S2O8, K2CO3 O
R 1
H R
H2O, 25 oC, 12 h Me Me
R 1
H H2O, 25 oC, 12 h R1
household bulb (100 W) n n
household bulb (100 W)
15 examples, 75-92% 9
exa
R1 = Ph, 2-ClPh, 3-ClPh, 4-ClPh, 4-MePh, 4-OMePh, n = 4, 5, 6 mple
4-FPh, 2-CF3Ph, -naphthyl, cyclohexyl R1 = Ph, 4-ClPh,s,4-MePh, 4-OMePh
67-
R2 = Ph, 4-MePh, 4-OMePh, 4-ClPh 89%
C N
N S N
Household bulb
MB
(100 W) S2O82- or O2
N
N
N S N
N S N
MB
MB*
OOH O
OOH
SET O
I R1
OOH B
R1
A
OOH
K2CO3
HAT III
O
II O
R1 H O
O
1
R
R1
Scheme 36: (A) Epoxyacylation and (B) hydroacylation of olefins under visible light driven conditions usingmethylene blue as the photoredox
catalyst; (C) proposed reaction mechanism.
Recently in 2019, Fe-catalyzed acyl-azidation of alkenes to delivering products in moderate to good yields. Styrenes
synthesize unsymmetrical -azido ketones has been reported having alkyl substituents performed better than those
by Ge et al. under mild reaction conditions. Aromatic and carrying halogens. Interestingly, vinylarenes containing an
aliphatic aldehydes were used as acyl radical precursors, ester or a free carboxylic group at the para-position also
azidotrimethylsilane (TMSN3) as azido source, and TBHP as an reacted effectively under the optimized reaction conditions
oxidant in this transformation (Scheme 37A).72 The effects of providing moderate yields of the products. Moreover,
various parameters including metal catalyst, solvent, additives heterocyclic compounds, -unsaturated carbonyl
and temperature was studied taking styrene and compounds and conjugated dienes also resulted in the
benzaldehyde as model substrates and TMSN3 as azido source corresponding azido ketones in moderate yields on treatment
to achieve the best reaction conditions. Interestingly, best with benzaldehyde and TMSN3. Subsequently, the scope of
product yield was obtained when styrene (0.5 mmol) was aromatic aldehydes, aliphatic aldehydes and -unsaturated
treated with benzaldehyde (2.5 mmol) in the presence of Fe aldehydes was investigated. Aryl aldehydes having either
(OTf)3 (2 mol%) catalyst and TBHP (1.25 mmol) oxidant using electron-releasing or electron-withdrawing groups reacted
TMSN3 (1.25 mmol) after 24 h at room temperature. smoothly with moderate to good yields; however, electron-
releasing groups were found to be more efficient than
Having the optimized reaction conditions in hand, initially the
electron-withdrawing groups.Few preliminary experiments
authors investigated the scope of alkenes, o-, m- and p-
were executed to investigate the reaction pathway and,
substituted styrenes (vinylarenes) with benzaldehyde
depending on these studies, a plausible reaction mechanism

for this acyl-azidation reaction was proposed as outlined in respective 3-acylspiro[4,5]trienone in 81% and 74% View yield. The
Article Online
scheme 37B. arylaldehydes bearing a Br, OH, OMe, Me, CN or CO2Me group
DOI: 10.1039/D0OB01458C
A H Fe(OTf)3 (2 mol%)
on the aryl ring were also found compatible with the optimal
N3 O
TBHP (2.5 equiv)
reaction conditions and the reactivity order was found to be

R 1
O R2 TMSN3
MTBE, 25 oC, 24 h R2 R1
44 examples, 25-88% para>meta>ortho. Moreover, aliphatic aldehydes could be
R1= Ph, 4-OMePh, 4-t-BuPh, 4-ClPh, 4-OHPh, 2-Cl, easily reacted using the optimized reaction
3,4-MePh, 5-Cl-2-FPh, 3-F-6-MePh, -naphthyl,
-naphthyl, furanyl, thiophenyl, benzofuranyl, conditions,resulting in thecorresponding spiro[4,5]trienones
benzothiophenyl, 4-((trimethylsilyl)ethynyl)phenyl,
in good yields (Scheme 38A).
4-morpholinophenyl, cyclopropyl, propyl, cyclohex-3-en-1-yl,

3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl), etc.
R2= Ph, 4-MePh, 4-t-BuPh, 4-FPh, 4-ClPh, 4-CO2MePh,
4-CO2HPh, 3-MePh, 3-ClPh, 2-MePh, 2-ClPh, ethyl, OMe,
COOH, OC6H13, 4-methylthiazolyl, styrenyl, etc. A R4 O
R4
B Fe(lll)X2 O
N3 TBHP R1
O
O H + R1 H
R2 n-BuOAc N
O N O 110 oC, 36 h O
Fe(lll)X2 R3 R3 R2
O R1 R 2
TMSN3 28 examples, traces-92%

R1= Ph, 4-OMePh, 3-OMePh, 2-OMePh, 2-OHPh,
TMSOtBu
2-BrPh, 4-MePh, 4-CNPh, 4-CO2MePh, n-Pr,
N3 n-hexyl, undecanyl, 7-methoxy-3,7-dimethyloctanyl,
O
b 9-decenyl, 3,7-dimethyloct-6-enyl
h
R1 p at R2= H, Bn, Me, 2-iodobenzyl
a
th
pa O R3= H, 6-Me, 7-Me, 6-I, 6-OMe, 9-OMe, 9-F
R2 R2 H O c
th R4= Ph, 2-OMePh, 4-OMePh, 4-MePh, 4-CNPh,
pa
1
Me +
O R R 1 pyridinyl
A
O
TEMPO B t
TEMPO BuOOH t
BuO + OH
Fe(lll)X2(N3)
Ph
Fe(lll)X2(OH)
N N
O R1 O
Me
CHO CO N O O
O Ph
t
BuO Me
OMe
TMSOH TMSN3 N O
OMe t
BuOH Me B
OMe
Scheme 37: Iron catalyzed acyl-azidation of alkene and plausible
A
reaction mechanism.
3.2.3. Acylation of sp carbons Ph

O
OH
Ph
O
In 2014, Li and co-workers disclosed a metal-free protocol for HO

OMe
OMe N
N
the acylation of N-arylacrylamides with aldehdyes followed by Me
O
Me
O
D C
an intramolecular cyclization to synthesize 3- t
BuOH H2 O
+
acylspiro[4,5]trienones.73 The flexibility of reaction was t

BuOOH
demonstrated by the synthesis of 28 3-acylspiro[4,5]trienones O
Ph
in good to excellent yields. Reactions were performed
between several electron-rich and electron-deficient N- HO
N
OMe
O
arylacrylamides and aldehydes (aromatic and aliphatic) using Me
TBHP as optimum free-radical initiator oxidant without any Scheme 38: (A) Acylation of N-arylacrylamides with aldehdyes
followed by an intramolecular cyclization; (B) plausible reaction
catalyst under optimized reaction conditions giving the mechanism.
respective products in 66-94% yield. Extensive screening of N-
On the basis of control experiments and literature support,
arylacrylamides suggested that several groups including OMe,
the authors designed a plausible reaction mechanism
Me, CN on the aryl ring of the terminal alkyne were well
(Scheme 38B). The mechanism involves the formation of
tolerated, and electron-releasing groups showed better
carbonyl radical A from the aldehyde through a single-
reactivity in comparison to electron-withdrawing groups. N-
electron transfer (SET) process in the presence of TBHP.
arylacrylamides bearing substituents like o-Me/I, m-Me on
Subsequent acylation of the alkyne with carbonyl radical A
the aryl ring of nitrogen also performed well affording the
resulted in vinyl radical B, which on selective ipso-
good product yields. Moreover, the presence of a OMe or F
carbocyclization produced radical intermediate C. This
group at the para-position of the N-aryl ring delivered the

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intermediate C, after selective addition of OH radical, afforded R3 View Article Online

another intermediate D. Lastly, intermediate D on the R3
DOI: 10.1039/D0OB01458C
R2 O O
R2
oxidation in presence of TBHP, delivered the preferred 3- + TBAB(1 equiv), K2S2O8 (2 equiv)
H R1 R1
acylspiro[4,5]trienone.

DCE, 90 oC, N2, sealed tube
O O O O
35 examples, 37-86%
In 2015, Wu and co-workers also revealed a metal-free
R1= Ph, 4-MePh, 4-OMePh, 4-IPh, 4-ClPh, 4-ClPh,
tandem acylation of alkynoates with aldehydes followed by an 4-BrPh, 4-CF3Ph, 3-MePh, 3-OMePh, 3-ClPh, 2,4-ClPh,
2-MePh, 2-OHPh, n-propyl, i-Bu, cyclopropyl
intramolecular cyclization resulting in 3-acyl-4-arylcoumarins. R2= 5,7-Me, 6-Me, 6-t-Bu, 6-OMe, 6-OPh, 6-F, 6-Cl,
6-Br, 6-CF3, 5-Me, 8-Me, 7-OMe

The reaction proceeded under metal-free conditions in the R 3= H
presence of tetrabutylammonium bromide (TBAB) as additive Scheme 39: Metal-free tandem acylation of alkynoates with aldehydes followed
by an intramolecular cyclization.
and K2S2O8 as oxidant for the selective synthesis of biologically
attractive 3-acylcoumarins.74 Under the optimized reaction To gain insight in the reaction mechanism for this newly
conditions, various differently substituted aldehydes and aryl developed protocol, the authors performed some control
alkynoates could be coupled in a metal-free experiments. The intramolecular and intermolecular kinetic
acylation/cyclization process to obtain the 3-acylcoumarins in isotope, effects were measured using deuterium labeled
moderate to good yields. Aromatic aldehydes having electron- substrates in competing experiments and the kH/kD values
releasing groups at the para-position of the aromatic rings were found to be 0.9 and 1.3, respectively. The observed low
coupled more efficiently than those containing electron- kH/kD suggested that the C-H bond cleavage is not the rate-
withdrawing groups. Although, ortho- and meta-substituted limiting step in this transformation. Moreover, when the
benzaldehydes were also appropriate for this conversion but reactions were carried out in the presence of the free radical
a slight decrease in yields was found. Moreover, alkyl and scavengers TEMPO or BHT, no product formation was
cyclic aldehydes also provided coumarin derivatives in observed and the adduct of p-tolualdehdye with TEMPO or
moderate yields. BHT was observed, suggesting a free radical pathway of the
reaction (Scheme 40A). In accordance with the observations
Similarly, the aryl alkynoates with either electron-rich
of the control experiments, a plausible mechanism following
substituents or electron-poor substituents at the para-
the free radical pathway was proposed (Scheme 40B). Initially
position of the phenoxy ring reacted well and products were
bis(tertrabutylammonium) peroxysulfate is generated by the
obtained in good yields. However, in the presence of the
reaction between peroxysulfate and TBAB, which get
strong electron-withdrawing CF3-group on the phenoxy ring,
converted into the tetrabutylammonium sulfate radical anion
only 38% yield was obtained whereas, no product was formed
at high temperature. This radical reacted with p-
for the ortho-substituted system. Furthermore, aryl alkynoate
methylbenzaldehyde to give an acyl radical A. Subsequently,
with a methyl group at the meta-position of the phenoxy ring
the selective addition of acyl radical A to the position of the
resulted in a mixture of two regioisomers in a 1.6:1 ratio.
C=O bond in alkynoate Y, resulted in the vinyl radical B. This
However, the presence of a methoxy group at the meta-
intermediate B then cyclized to the arene and formed another
position delivered only one isomer in 76% yield (Scheme 39).
radical intermediate C. Next, a single-electron transfer from
intermediate C to another sulfate radical could give cation D.
This cation D upon deprotonation by the formed sulfate di-
anion provided the 3-acylcoumarin derivative and another
bisulfate anion.

View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
A D
O O CHO O Ph O
(a) optimal conditions

Ph
+
6 h, yield: 46% +
KIE = 0.9 O O O O
Ph
D
D
O O D Ph O
D O O CHO O
(b) D
optimal conditions Ph
+
D D + 6 h, yield: 46% +
D KIE = 1.3 D O O
Ph O O
Ph
D
CHO Ph O
O O
optimal conditions
(c)
+
TEMPO or BHT (2 equiv)
O O Me
Ph Me
B
O O O
heat
K2S2O8 + 2n-Bu4NBr 2KBr + (n-Bu4N+-O
) S O O S O (n-Bu4N+-) n-Bu4N+- O S O
O O O
Ph O
n-Bu4NOSO3H
n-Bu4NOSO3-
O O Me
Ph O
O
+ H
O O Me
D Me
n-Bu4NOSO3- O
n-Bu4N+- O S O
O
n-Bu4NOSO3H
Ph O O
O O Me Me
A Ph
C Ph O
O O Me O O
B
Scheme 40: (A) Control experiments; (B) plausible reaction mechanism.
3.3. Acylation of heteroarenes/heteroaryls biochemistry and synthetic chemistry, and are widely
distributed in natural products, biomolecules and other
Heterocyclic compounds represent the largest and one of the
bioactive molecules. Heterocyclic scaffolds are major
most vital classes of organic compounds used in many
constituents of biological molecules such as DNA, RNA,
biological fields due to their importance for the treatment of
vitamins, enzymes, chlorophyll, haemoglobin and many more.
multiple illnesses and building blocks for industries. Presently,
Therefore, pharmacists and organic chemists have been
several heterocyclic compounds are known and due to the
making extensive efforts for the formation and
enormous synthetic research as well as their synthetic utility
functionalization of heterocyclic molecules through
the number of heterocyclic molecules is increasing rapidly
developing versatile, atom- and step-economical efficient
day-by-day. Heterocyclic compounds play a significant role in
synthetic strategies. In this direction, Zhou and co-workers
almost all fields of science such as medicinal chemistry,
(2012) explored the first Rh-catalysed regioselective oxidative

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C2-acylation of the ubiquitous indole (N,N-dimethyl-1H- Later in 2014, Yan et al. described a Pd-catalyzed View
C-2 Article
acylation
Online
indole-1-carboxamide) by coupling with aryl/alkyl aldehydes of N-pyridinyl indoline with aliphatic and aromatic aldehydes
DOI: 10.1039/D0OB01458C
involving direct sp2 C-H bond cleavage and C-C bond by direct C-H functionalization.76 Various N-protected indoles
formation strategy.75 The scope of N-protected indoles was were coupled with various aliphatic and aromatic aldehydes

explored with various aldehydes using Cp*Rh(MeCN)3(SbF6)2 in the presence of Pd(OAc)2 as catalyst, TBHP as oxidant and
as optimum catalyst and Ag2CO3 as oxidant. The presence of PivOH as additive. Benzaldehydes having electron-
electron-releasing and electron-withdrawing groups at the withdrawing groups or electron-releasing groups at the para-
aryl ring of the benzaldehyde did not affect the outcome of position provided the corresponding products in good yields.
the reactions and good reactivity was demonstrated with N- However, relatively lower yield were observed in case of
protected indoles irrespective of the position of the ortho-substituted benzaldehydes, because of steric
substituents. Benzaldehydes having Me, OMe, NO2, CF3, hindrance. -naphthaldehdyde and -naphthaldehdyde also
COCH3, CHO and COOMe, etc. at the para-position gave the underwent the acylation reaction smoothly to afford the
corresponding products in 50-92% yields. Notably, 2- products in good yields. Interestingly, 5-methylfuran-2-
furaldehyde, thiopene-2-carbaldehyde and 2- carbaldehyde and thiophene-2-carbaldehyde also
naphthaldehdye underwent sp -sp coupling efficiently and
2 2
participated in this oxidative coupling to give the products in
delivered the respective products in 73%, 85% and 90% yield, 64% and 74% yields, respectively. The reaction scope was not
respectively. Interestingly, coupling between N,N-dimethyl- found to be limited to aryl aldehydes as several aliphatic as
1H-indole-1-carboxamide and paraformaldehdye resulted in well as conjugated aldehydes also effectively participated in
the formation of dimeric 2,2'-biindolyl product with complete the reaction to give the products in good yields (Scheme 42A).
regiocontrol in 54% yield. Moreover, N-protected indoles Likewise aldehydes, several indoles containing functional
having both electron-donating (OMe) and electron- groups such as methoxy, chloro, bromo, ester, etc. reacted
withdrawing (CF3, NO2, Br etc.) groups at the C6-position were smoothly to give products in moderate to good yields.
readily converted into the targeted products in good to However, 3-substituted indole afforded a lower yield of the
excellent yield (Scheme 41). acylated product due to steric crowding. The proposed
R1
mechanism for this protocol is depicted in scheme 42B.
O R2 Cp*Rh(MeCN)2(SbF6)2 R2
N N O
R1 H Ag2CO3, CH2Cl2, 85 oC
O O
N N
28 examples, 45-93%
N
O R1= Ph, 4-MePh, 4-OMePh, 4-NO2Ph, 4-CF3Ph,
4-COMePh, 4-CHOPh, 4-CO2MePh, 4-ClPh,
N
4-BrPh, 3-OMePh, 3-CF3Ph, 2-OMePh, 2-CF3Ph,
benzo[d][1,3]dioxolyl, -naphthyl, thiophenyl,
N N N O
furanyl, n-Pr, cyclohexyl,
O O R1= H, 6-NO2, 6-CF3, 6-OMe, 6-Br, 5-F, 4-F, 3-Me
N N
54% (3 days) 45%
Scheme 41: Rh-catalyzed regioseletive oxidative C2-acylation of indole by coupling with

aryl/alkyl aldehydes.

View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
R1 B
A R1
O R2 Pd(OAc)2 (10 mol%) R2
N TBHP (2.0 equiv) N O

H N O N N
R1
N PivOH (2.0 equiv) N R= Ac, Piv
toluene, 80 oC N
Pd(OR)2
30 examples, 40-95% ROH

Cyclopalladation
R1= Ph, 4-OMePh, 4-MePh, 4-BrPh, 4-ClPh,
ROH Reductive
4-CF3Ph, 4-CNPh,3-ClPh, 3-MePh,
Elimination
2-OMePh, 2-FPh, 2-ClPh, 3,4-MePh,
benzo[d][1,3]dioxol-5-yl,b-naphthyl,
N O N 2
O -naphthyl, 5-methylfuran-2-yl, thiophenyl, O R1 Pd OR
N cyclohexyl, n-hexyl, 2-methylprop-1-enyl, L N
O N
N 2,6-dimethylhepta-1,5-dienyl Pd OR N
N
R2= H, 6-CO2Me, 5-Br, 6-Cl, 5-OMe, L
3-Me, 3-CN, N
83% 77% Oxidation
A
t
O BuO O
B
R 1 R1 H
t
BuOH
Scheme 42: (A) Pd-catalyzed C-2 acylation of N-pyridinyl indoline with aliphatic and aromatic aldehydes; (B) plausible reaction
mechanism.
A method describing the selective C-2 monoacylation and C- furaldehyde and thiophene-2-carbaldehyde provided the
2, C-7 diacylation through C-H bond functionalization of 1- corresponding C-2 acylated products in 79 %, 58 % and 54 %
(pyrimidin-2-yl)-1H-indole using aldehydes was disclosed by yield, respectively. Indoles with electron-releasing and
Govindasamy Sekar and his group in 2015.77 The authors electron-withdrawing groups at the C-5 position coupled
synthesized fourteen C-2 monoacylated products, three C-2, effectively and yielded C2-acylated products in moderate
C-7 symmetric diacylated products and two C-2, C-7 yields. Moreover, aliphatic and -unsaturated aldehydes,
unsymmetric diacylated products in moderate to good yields when subjected to these reaction conditions, resulted in the
using PdCl2 catalyst and TBHP (70 % aqueous solution in expected products in good yield (Scheme 43A). The use of 3
toluene) as oxidant in toluene. For monoacylation, 3 equiv of aldehyde and 5 equiv of TBHP under the same
equivalents of TBHP were used, whereas, for diacylation, 5 reaction conditions provided the symmetric C2, C7-diacylated
equivalents of TBHP were required. Aromatic aldehydes products through dual C-H bond functionalization with good
containing both electron-releasing and electron-withdrawing yields (Scheme 43B). Whereas using two different aldehydes
groups yielded 2-acylated products of 1-(pyrimidin-2-yl)-1H- (1.5 equiv. each) one after another resulted in the formation
indole in moderate to good yields. Sterically hindered of unsymmetrical diacylated products (Scheme 43C).
naphthaldehyde and heteroaromatic aldehydes like 2-

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View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
A R1
O R2 R2
N PdCl2 (10 mol%)

TBHP N O
R1 H
N N
N toluene, 90 oC, 24 h N
14 examples, 45-80% C
R1= Ph, 4-MePh, 4-CNPh, 4-CO2MePh,
4-ClPh, 2-MePh, -naphthyl, furanyl, PdCl2 (10 mol%) Ar'
thiophenyl, pentyl, cyclohex-3-en-1-yl, TBHP
N Ar'CHO Ar''CHO
prop-1-enyl toluen N O
1
R = H, 5-OMe, 5-Br N e, 90
N N
o
C, Ar'' ON
B R1
O 24 h
PdCl2 (10 mol%)
N TBHP N O
R1 H
N o
N
toluene, 90 C, 24 h 1
N R ON
N O
N O
N
Me ON N
ON
NC
64% Me
68%
N O
N O N O N
N ON
ON N
ON
Me 50%
72% 52%
Scheme 43: (A) Selective C-2 monoacylation of 1-(pyrimidin-2-yl)-1H-indole with aldehydes; (B) Symmetric and (C) Unsymmetric C-2, C-7 diacylation
of 1-(pyrimidin-2-yl)-1H-indole with aldehydes.
Balachandran and co-workers in 2014 reported metal-free new carbon–carbon bond and produce the acylated
and solvent-free direct acylation of thiazoles through cross derivatives as a major products and homo-coupled side
dehydrogenative coupling (CDC) using TBHP as an oxidant.78 products as minor one in the terminating step (Scheme 44B).
In this method 16 acylated thiazole derivatives were O
A metal-free
R2
synthesized with moderate to good yield by coupling various O N TBHP N
R1
H R2
aldehydes with thiazoles (Scheme 44A). The reaction R1 H
R3 S neat, air S
100 oC, 16 h
R3
conditions worked well with ortho-, meta- and para-
16 examples, 47-80%
substituted aldehyde derivatives. There appeared no R1 = Ph, 4-MePh, 4-FPh, 4-CPhl, 4-OMePh, 2,6-MePh,
2,6-OMePh, 2,6-ClPh, 3,4-OMePh 3-FPh, 4-OMePh,
alteration in the product yield due to electronic and steric Me, thiophenyl
hindrance as all the 2-acylated thiazole derivatives were
2
R = CH3
3
R = H, CH3
obtained in good yield under optimized reaction conditions. B
Aldehydes having electron-donating groups and halides as O

OH
O
+ OH
substituents resulted in acylated products in good yields

whereas, hetero-aromatic and aliphatic aldehydes provided N t
BuOH N N N
H
products in moderate yield. S S S S
O
5%
O
While analyzing the mechanistic pathway, it appeared that OH O
O
S
the reaction proceeds with hydroxyl and alkoxyl radical H
H 2O
N
generation through hemolytic cleavage of TBHP. In the
70%
subsequent step, generated radicals abstract hydrogen from Scheme 44: (A) Metal and solvent-free direct acylation of thiazoles;
sp2 C-H of 4,5-dimethylthiazole and the aldehydic C–H of (B) proposed mechanism.
benzaldehyde, generating the corresponding free radicals. At

the closure, free radicals combines with each other to form a

In 2017, Van der Eycken and his group established a mild and obtained in good yields (54-89%) when benzaldehyde View Article Online
versatile method for C2 C-H acylation of N-pyrimidylindoles contained electron withdrawing groupsDOI: such as Br, CN, NO2
10.1039/D0OB01458C
with aldehydes through dual photoredox/transition-metal and CF3. Interestingly, heterocyclic aromatic aldehydes,
catalysis in batch and flow at room temperature.79 Initially the aliphatic acyclic and cyclic/heterocyclic aldehydes reacted

authors explored various reaction parameters including efficiently to afford C2-acylated N-pyrimidylindoles in good to
solvent, catalysts, photocatalysts and ligands to achieve excellent yields (Scheme 45A). Based on observations of
optimal reaction conditions. Finally, the use of 10 mol% control experiments performed by authors and available
Pd(OAc)2 catalyst, 2 mol% of photocatalyst fac-[Ir(ppy)3], 20 literature reports, a plausible SET (single electron transfer)
mol% Boc-Val-OH ligand and 4 equiv of 0.1 M TBHP in mechanism was designed as described in scheme 45B which
acetonitrile delivered the best outcome after 20 h of blue LED initiates by the formation of a five membered palladacycle A
irradiation in a batch process. Whereas in a flow process only via interaction between N-pyrimidylindole and Pd(OAc)2
0.5 mol% of photocatalyst fac-[Ir(ppy)3] with slight excess of catalyst. In the meantime, the photocatalytic process
oxidant (6 equiv. of 0.2 M TBHP in acetonitrile) along with the generated an acyl radical. The photo-excitation of the
rest of the other reagents was found to be enough to give photocatalyst produced an excited state (Ir3+*) which get
good product yields in just 2 h. With these optimized reaction oxidatively quenched by TBHP to generate a key radical
conditions in hand, the scope of the reaction was determined intermediate t-BuO. This radical abstracts a proton from the
by exploring various substituted benzaldehydes as coupling aldehyde to produce an acyl free radical, which on reaction
partners of N-protected indoles. C2-Acylation of indole with intermediate A resulted in intermediate B. This
derivatives with benzaldehyde bearing alkyl/aryl groups or a undergoes a single electron oxidation to PdIV, which closes the
methoxy group smoothly proceeded with good product photocatalytic cycle via a back-electron donation process.
yields. However, hydroxylated benzaldehydes delivered Finally, reductive elimination resulted in the targeted product
inferior yields. Furthermore, the acylated products were and regenerated the PdII catalyst.

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View Article Online

DOI: 10.1039/D0OB01458C

ARTICLE
A PFA microreactor*
R3 760 mM ID, 3 mL *Pd(OAc)2 (10 mol%)
R3 R3
fac-[Ir(ppy)3] (2 mol%)
R1
Batch* R1 Boc-Val-OH (20 mol%)
R2 TBHP (4.0 equiv)
R2
N O N R1CHO ACN (0.1M)
N O Blue LED, Ar atm.
DG R 2 2 h, rt
DG DG room temp, 20 h
29 examples, 0-81%
DG= pyrimidinyl, pyridinyl, Boc, methyl 18 examples, 0-95%
R1= Ph, 4- MePh, 4-PhPh, 4-OMePh, 4-OHPh, 4-FPh, 4-CF3Ph, R1= 4- MePh, 4-OMePh, 4-OHPh, 4-FPh, 4-CF3Ph, 4-CNPh,
4-BrPh, 4-NO2Ph, 4-CNPh, 2,4,6-MePh, 3-OHPh, 3-BrPh, 3-IPh, 3-IPh, 3-NO2Ph, -naphtyl, furanyl, furan-2-ylmethanol,
3-NO2Ph, -naphtyl, furanyl, thiophenyl, 2,6-dimethylhept-2-enyl, 2,6-dimethylhept-2-enyl, 2,6-dimethylheptan-2-ol, cyclohexyl,
cyclohexyl tert-butyl piperidine-1-carboxylate,
2
R = H, 5-OMe, 5-F, 6-F, 7-Me tert-butyl pyrrolidine-1-carboxylate,
2
R3= H, Me R = H, 6-F
3
R =H
B
F
N
N N
O N
N N Pd(OAc)2
Reductive
F Elimination
AcOH
C-H activation
O
PdIV L PdII
OAc
N OAc N
N N
N N
C
F A
3+ Oxidation t
H
Ir O Acylation BuOH t
BuO
O
Oxadative PdIII O
OAc
Quenching N F
Cycle
F
N
Ir3+ N
Ir4+
t
t
BuOOH BuO B
OH
Scheme 45: Acylation of N-pyrimidylindoles with aldehdyes via dual photoredox/transition-metal catalysis in
batch and flow and plausible reaction mechanism.
In early 2013, Antonchick and Matcha developed a metal-free reaction conditions. Moreover, aliphatic aldehydes could be
cross-dehydrogenative coupling reaction between various reacted competently with isoquinoline using smaller amount
heterocyclic compounds and aldehydes for selective sp2 C-H of iodide and TMSN3. Aromatic aldehydes with electron-
bond acylation (Scheme 46).80 The reaction proceeded releasing groups at the ortho, para and meta-position
efficiently with all the applied heterocyclic compounds and delivered comparable yields. Whereas, the benzaldehydes
aldehydes giving a library of 62 compounds in the presence of with electron-withdrawing groups at the para-position gave
PhI(OCOCF3)2 as oxidant and TMsN3 as additive. Employing the better yields of the corresponding products in comparison of
best reaction conditions, the scope of the isoquinoline their ortho- and meta-substituted derivatives. Moreover,
synthesis with various aldehydes was explored.. The reaction polymethoxy substituted benzaldehydes were also tolerated
provided a broad substrate scope and aromatic aldehydes and provided products in good to excellent yield. Notably,
having electron-releasing and electron-withdrawing groups at sulphur containing heterocyclic aldehydes provided cross-
the aryl ring were selectively coupled to isoquinolines under coupled products in good yields without over-oxidation to
metal-free conditions at ambient temperature. sulfoxides and sulfones (Scheme 46A). After exploring the
Polysubstituted benzaldehydes also provided the effect of aldehydes, the scope of various heterocyclic
desiredcoupling products efficiently under the developed molecules such as isoquinoline, quinoline, quinaxaline,

acridine, benzothiazole and caffeine was also explored and all A by azide ions give PhI(N3)2.Intermediate B, ViewonArticle
thermal
Online
the heterocyclic compounds coupled smoothly under the homolytic cleavage, generates an azideDOI:
radical and a radical
10.1039/D0OB01458C
optimized reaction conditions to yield the targeted molecules intermediate C. Reaction between azide radical and aldehyde
in good yields (Scheme 46B). generates nucleophilic acyl radical intermediate D.

Subsequent attack of generated acyl radical onto protonated
Through the observations of control experiments, a plausible
heterocyclic E delivers intermediate F. Finally, re-
mechanism has been proposed for this transformation
aromatization of the intermediate F results the anticipated
(Scheme 46C). The mechanism starts with a ligand exchange
products.
between PhI(OCOCF3) and TMSN3, which provides the

intermediate B. A double exchange of trifluoracetyl groups in
A PhI(OCOCF3)2
C
Phl(OCOCF3)2
H CF3CO2H O
TMSN3, rt, 2 h N TMSN3
+ O HN3
N R 1 PhI(OCOCF3)2 H R
O R1 A
33 examples, 40-94% N3
OCOCF3 O CF3CO2H
1 Ph I
R = Me, heptanyl, ethylbenzene, cyclopropyl, cyclohexyl, i-Pr,
CF3CO2TMS B N3 R
2,6-dimethylheptan-6-olyl, 2-MePh, 2-FPh, 2-PhPh, 3-MePh, D
4-MePh, 4-OMePh, 4-FPh, 4-IPh, 4-OBnPh, 4-OAcPh, 4-PhPh,
OCOCF3 N
3-FPh, 5-Cl-2-FPh, 2,4-MePh, 3,4-OMePh, 3,5-OMePh,
Ph I
2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,4,5-OMePh, 3,4,5-OMePh, C
4-OAc-2,6-OMePh, 2,2-difluorobenzo[d][1,3]dioxol-5-yl,
b-naphthyl, 2,4,6-OMePh, pentamethylphenyl, thiophen-3-yl,
N
dibenzo[b,d]thiophen-2-yl
O H
O
N HN CF3CO2
R
H R
2CF3CO2H E
PhI CF3CO2
F
B Phl(OCOCF3)2 O O
H TMSN3, rt, 2 h
R1 R2 =
N + O R1 N
Me
OMe
NO2
R2
MeO MeO O Ph N
N N N N
MeO MeO O Ph N N
2 2 2 N Me
60% R 66% R 58% R 90% R2 35% Ac 84%
R2 R2 Cl R2 CN
N
Br
N R2
N N Ph Cl N R2 N N R2
77% 63% 81%
72% 70% 65%
Ac Ac Ac O
N Cl N Me N Br N
N N
R2 Ac
N N
N R2 N R2 S N Ac O N
N Ac
75% 82% 67% 72% 74% 65% Ac 64%
Scheme 46: Metal-free cross-dehydrogenative coupling reaction between isoquinoline, isoquinoline, quinoline,
quinaxaline, acridine, benzothiazole and caffeine with aldehydes for the sp2 C-H bond acylation and plausible reaction
mechanism.
A similar transition metal-free cross-dehydrogenative underwent a facile coupling with 4-(p-methoxyphenyl)-

coupling reaction for acylation of isoquinoline, quinoline and isoquinoline to afford the product in 41% yield. Moreover,
quinoxalines using aldehydes as acylating agents was quinoxaline, when coupled with 4-methoxybenzaldehdye and
reported by Prabhu and his group in 2014.81 This method 4-methylbenzaldehdye delivered the acylated products were
involved the use of a substoichiometric amount of in 66% and 44% yield (Scheme 47A). To explore the further
tetrabutylammonium bromide (TBAB) as an additive and scope of the developed acylation method, quinoline was also
K2S2O8 as an oxidant. With optimized reaction conditions, subjected to this CDC strategy. Coupling of the quinoline with
several isoquinolines were acylated using aromatic and 4-methylbenzaldehyde and butanal furnished the mixture of
aliphatic aldehydes to give the respective acylated products 2-acylated and 2,4-diacylated products in 1.2:1 ratio. On the
with 32-78% yields. Notably, thiophene-2-carbaldehyde also

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other hand, 4-benzyloxybenzaldehyde provided only 2,4- acyl radical B. Further, the acyl radical reacts with Online
View Article the
diacylated product in just 24% yield (Scheme 47B). heteroarene resulting in the formationDOI:
of the corresponding
10.1039/D0OB01458C
amidyl radical C. The formed amidyl radical gets deprotonated

Based on the literature, the authors proposed a free radical
with the sulfate anion and forms radical anion D. This radical

mechanism (Scheme 48). The mechanism starts with the
anion D transfers an electron to the persulfate resulting in the
reaction between K2S2O8 and TBAB resulting in sulfate radical
desired product.
A, which abstracts hydrogen from the aldehyde to form the
A
O TBAB (30 mol%) R2
K2S2O8 (2 equiv) N
+ R2
R1 H N o
100-110 C, 2-12 h
DCE R1 O
30 examples, 32-78%
Br N N
R1= 4-OMePh, 4-OBnPh, 3,4-OMePh,
O O
N 4-Me, 2,3,4-OMePh, 3,4,5-OMePh,
N N
4-BrPh, 3-MePh, 3-OMePh,
2,3-OMePh, 2,3,4-OMePh, 3-OBnPh,
O i-Bu, n-Pr, pentyl, hexyl, thionphenyl
R2= H, 4-Ph, 4-OMePh, 5,6,7-OMe
77% 66%
OMe 44% Me
Me
B CHO
O
Me
Me
Me
BnO 8 h, 110 oC N +
CHO O N
O
69% (1.2:1) O
BnO BnO
N 12 h, 110 oC
O N
24% O Me
2 h, 100 oC
Me
CHO + Me
Me N
N
O
40% (1.2:1) O
Scheme 47: Metal-free cross-dehydrogenative coupling reaction for the acylation of isoquinoline, quinoxaline and
quinoline derivatives using aldehydes.
KBr
+ -
KO S
O
O O
O
S O-K+
properties.82 Moreover, benzofuran and benzothiopene
O O
(Bu)4+NO- S O O S O-N+(Bu)4
O O scaffolds containing an acyl group at the C-3 position are of
O O
2(Bu)4N Br+ - great interest for medicinal chemistry due to their
KHSO4
antibacterial, anti-tumor, anti-arhythmic activities.83
O O
O
O
KBr Therefore, the development of new efficient protocols for the
(Bu)4+NO- S O O S O-N+(Bu)4
O-N+(Bu)4
O O
O S
O
HO S - +
O N (Bu)4 synthesis of 3-acylbenzofurans and 3-acylbenzothiophenes is
O
A highly desirable.
SET
O
O O In 2013, Zhao et al. published a pyridinyl group-assisted Pd-
O S O-N+(Bu)4
O
N N
H R R catalyzed cross-dehydrogenative coupling reaction for the C-
B
O R O R 3 acylation of benzofuran and benzothiophene derivatives
D
KHS2O8
using TBHP as an oxidant under air.84 Several derivatives of
O K2S2O8 aldehyde were coupled with benzofuran and benzothiophene
N
R
N
in the presence of Pd(OAc)2 as catalyst, TBHP as oxidant in
chlorobenzene at 120 oC. The reaction exhibited a broad
O R
C
Scheme 48: Plausible reaction mechanism for metal-free cross-dehydrogenative
scope and high compatibility with the functional groups such
coupling reaction of the acylation of isoquinoline, quinoline and quinoxaline derivatives. as OMe, Me, NO2, CN and halogens, etc. and provided
Benzofurans and benzothiophenes are highly privileged excellent yields (89-97%) of the desired products regardless
structural moieties, which are present in several natural the position of the substituents on the benzene ring of
products and exhibit a broad spectrum of biological benzaldehydes. However, dimethoxy-substituted
benzaldehyde provided a slightly lower yield of acylated

products of benzofuran and benzothiophene. Moreover, gain mechanistic insight. The kinetic isotope effect (kH/k
View Article D =
Online
heterocyclic aldehydes such as thiopehen-2-carbaldehyde 2.79) revealed that C-H cleavage might be involved in the rate
DOI: 10.1039/D0OB01458C
and 2-furaldehyde also reacted smoothly and the limiting step.

corresponding products were obtained in good to excellent

R2
yields. Unfortunately, no product was formed in case of R3
O
R3
Pd(TFA)2, TBHP R2
aliphatic aldehyde (Scheme 49A). As per previous reports, the N + N
H R1 DCE, 80 oC, 16 h
t
authors designed a plausible mechanism to rationalize this O
Bu
R1 OO
t
Bu
methodology as presented in scheme 49B.

Cl 10 examples, 40-78%
A R1 1
O R = Ph
O
N
R2= H, 4-Me, 5-OMe, 5-Cl, 5-F
Pd(OAc)2 (5 mol%), TBHP N
+ R t
Bu R3= H, 2-Me, 3-Me, 3-Me-3-Ph,
X N H R1 PhCl, 120 oC, 20 h t OO
X N Bu 3,3-Me-2-Ph
Ph OO
X= O & S 50%
22 examples, 79-97%
69%
R1= Ph, 4-MePh, 4-OMePh, 4-FPh,
4-NO2Ph, 4-CNPh, 3-OMePh, Me
3,4-OMePh, 2-ClPh, furanyl, Me
thiophenyl O Pd(TFA)2, TBHP
+ DCE, 80 oC, 16 h
N
B N H R1
t
Bu
N t
Bu R 1
OO
X Pd O
O O
N HX X 13 examples, 28-81%
t
BuO + H
R1 R1
R1= Ph, 4-OMePh, 4-CF3Ph, 3-OMePh, 3-NO2Ph,
X 2-ClPh, 2-F-4-OMePh, benzo[d][1,3]dioxolyl,
A 5-methylfuran-2-yl, cyclohexyl, i-Pr, pentyl,
2-methylprop-1-enyl
PdX2 Scheme 50: Pd-catalyzed oxidative C-7 acylation of indolines and
O R1
carbazoles with aldehydes.
X X
R1
O L
N
Later, in 2014 Cheng et al. reported a regiospecific Minisci
X
acylation of phenanthridine based on a cross-
X N B
Scheme 49: Pd-catalyzed cross-dehydrogenative coupling reaction for the C-3 dehydrogenative coupling strategy via thermolysis or
acylation of benzofuran and benzothiophene derivatives and plausible reaction
mechanism. photolysis.86 Under thermal conditions (100 oC) the acylation
of phenanthridine with aldehydes was carried out using a
Kim and co-workers in 2014 disclosed a Pd-catalyzed oxidative substoichiometric amount of the phase transfer catalyst
coupling reaction for the selective C-7 acylation of substituted tetrabutylammonium bromide (TBAB, 30 mol%) and K2S2O8 as
indolines using aldehydes via a C-H activation approach.85 The oxidant. Interestingly, a preliminary research based on
reactions were carried out between various N-pivaloyl literature reports indicated that phenanthridine could be
indolines/N-pivaloyl carbazoles and aromatic/aliphatic acylated selectively at room temperature replacing the
aldehydes using Pd(TFA)2 as catalyst, TBHP as oxidant in DCE TBAB/K2S2O8 system with (NH4)2S2O8 and using 5 mol% of fac-
as solvent at 80 oC to prepare 24 derivatives. The coupling Ir(ppy)3 as photocatalyst under visible light irradiation.
reaction of C-2 or C-3 unsubstituted indolines with However, the reaction proceeded slowly (48 h) under
benzaldehyde afforded the corresponding acylated products photocatalytic reaction conditions in comparison to thermal
in moderate yields. C-2 and C-3 alkyl/aryl substituted reaction conditions (12 h). Several aromatic aldehydes with
indolines also underwent the oxidative acylation reaction to electron-releasing (Me, OMe) and electron-withdrawing (F, Cl,
provide products in moderate to good yields under the Br, OAc etc.) groups at the aromatic ring were coupled with
developed reaction conditions. Electron-rich as well as phenanthridine under the optimized thermal conditions as
electron-deficient benzaldehydes were found to favor the well as photo-catalytic conditions and targeted products
acylation reaction irrespective the position of the substituents could be obtained in moderate to good yields. Benzaldehydes
on the phenyl ring and afforded the products in good to high with di- and tri-methoxy substituents triggered good results in
yields. Isobutyraldehyde, cyclohexanecarbaldehyde and 1- both conditions. Interestingly, 4-fluorobenzaldehyde
hexanal provided moderate yields. However, 5-methylfuran- provided the maximum yield of 80% under thermal
2-carbaldehyde and 3-methylbut-2-enal delivered the conditions. Unfortunately, no product was obtained with 4-
products in poor yields (Scheme 50). Two parallel reactions of nitrobenzaldehdye and 4-N,N-dimethylbenzaldehydes in
N-protected carbazole derivatives and their deuterated
analogues with benzaldehyde were performed in order to

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either of the conditions. Aliphatic aldehydes provided inferior were achieved in moderate to good yields after 12View
h. Article
AromaticOnline
product yields (Scheme 51A). aldehydes with electron-releasing (CHDOI:
3, OCH3, OCH2O) and
10.1039/D0OB01458C
mild electron-withdrawing (F, Cl, Br) groups on the benzene

Based on the literature and experiments, a possible
ring smoothly favored the selective C3-acylation of coumarin

photocatalytic pathway was proposed (Scheme 51B). The
in moderate to good yields. However, aromatic aldehydes
persulfate anion can be reduced by visible light excited
with electron-withdrawing groups afforded inferior product
[Ir(ppy)3]3+* to give sulfate and the sulfate radical anion A
yields in comparison to aldehydes bearing electron-releasing
along with [Ir(ppy)3]4+. H-Atom abstraction from the aldehyde
groups at the aryl ring. The steric hindrance on aromatic
by radical A gives acyl radical B which on addition to

aldehydes did not affect this transformation since ortho-
phenanthridine afforded amidyl radical C. Deprotonation of
substituted aldehydes and -naphthaldehyde smoothly
the -proton in the amidyl radical C by the sulfate anion
generate the corresponding products in moderate yields.
generates radical anion D. Reductive quenching of [Ir(ppy)3]4+
Unfortunately, aliphatic aldehydes failed to deliver the
by radical anion D through SET generates [Ir(ppy)3]3+
targeted products. Furthermore, coumarin substituted with
sustaining the photocatalytic chain.
electron-rich (OCH3, OCH2CH3, etc.) and electron-poor (OH,
OCOCH3, NO2, etc.) groups at the C6 or C7-position were
A
K2S2O8, TBAB, DCE
found to give the corresponding products in moderate yields
O 110 oC, 3-12 h (Scheme 52A). A series of N-methyl quinolinone derivatives
+ or
N
R1 H (NH4)2S2O8, fac-Ir(ppy)3, DMSO, N
O
was also examined successfully using the optimized reaction
rt, visible light, 48 h
R1
conditions and acyl groups were exclusively attached to the
19 examples, 0-81% (0-73%)*
R1= Ph, 4-ClPh, 4-BrPh, 4-FPh, 4-MePh,
C3-position of 2-quinolinones delivering 55-77% yield of the
4-OMePh, 4-NO2Ph, 2-ClPh, 2-BrPh, products. On the bases of control experiments and previous
2-MePh, 2-OMePh 2-OAcPh, naphthyl,
-naphthyl, 3,4-OMePh, 3,4,5-OMePh, reports, a plausible reaction mechanism was proposed by
4-N(Me)2Ph, n-Bu, hexyl
authors as depicted in scheme 52B.
*photocatalysis yield is given in parenthesis
B HSO4 SO42- A R2
R2 O
R3
FeCl2 (10 mol%)
O TBHP (4 equiv) R1
+ R3
O O R 1
H PhCl, 120 oC, N2
N N X O O O
SET X= O & NMe
R1 D R1 25 examples, 38-72%
O
N R1= Ph, 4-MePh, 4-OMePh, 4-FPh, 4-ClPh,
C R 1 2-OMePh, 2-ClPh, 2-BrPh, 3,4-OMePh,
2,4-ClPh, -naphtyl, benzo[d][1,3]dioxolyl,
O 5-methylthiophene-2-yl, 5-methylfuran-2-yl
Ir(ppy)3+ Ir(ppy)4+ R2= H, Me.
1
R H R3= H, 7-OMe, 7-OH, 6-NO2, 7-OAc,
7-OC2H5, 6-Br
O
SO4
Fe(ll)X2
B
+
Ir(ppy)3 *
A
R 1 Initation: t
BuOOH
t
BuO + OH (or Fe(lll)X2OH)
B or heat
S2O82- SO42-
O
HSO4 O t
BuO O
X O R1
R1 H R1
N
t
X O
Scheme 51: (A) Acylation of phenanthridine with aldehydes via BuOH A
thermolysis or photolysis; (B) proposed reaction mechanism. Fe(lll)
In a span of four years (2015-2018), four individual studies87 Fe(ll)
on the application of aldehydes as acylating agents were O O
published for the selective direct C3-acylation of coumarins. R1 R1
In 2015, Fe-catalyzed cross-coupling of coumarins was carried X O X O

H+ B
out with aromatic aldehydes in the presence of TBHP oxidant
Scheme 52: (A) Fe(II)-catalyzed cross-coupling of coumarins for the
under N2-atmosphere by the team of Ling-Bo Qu.87a Initially, selective direct C3-acylation; (B) plausible reaction mechanism.
several aromatic aldehydes (1.0 mmol) were coupled with
Later in 2016, Aihua Zhou and co-workers developed a new
coumarin (0.25 mmol) under the optimized reaction
coupling reaction for the selective C3-acylation of coumarins
conditions using FeCl2 as catalyst, TBHP as oxidant in toluene
by a sp2 C-H functionalization process involving aldehydes in
at 120 oC under nitrogen atmosphere. The targeted molecules
the presence of a Cu-catalyst and TBHP as oxidant (Scheme

53A).87b Various coumarin derivatives were acylated OMe) groups or mild electron-withdrawing groups (F,Online
View Article Cl)
regioselectively at the C3 position by aldehydes and all reacted proficiently and delivered the products in high yields.
DOI: 10.1039/D0OB01458C
substrates reacted proficiently to produce the respective The scope of substituted coumarins was also explored using
products in moderate to good yields in the presence of CuO as 6-methyl-coumarin and 6-chlorocoumarin and the expected

catalyst and TBHP as oxidant at 90 oC after 24 h. Aromatic products could be obtained in good yields. Moreover,
aldehydes with electron-releasing groups (OMe, Me, tBu, etc.) treatment of acetaldehyde with coumarin afforded 88% of the
and the electron-withdrawing bromine group were found desired product. The control experiments revealed that the
suitable for this transformation. Nevertheless, in case of reaction followed a free-radical mechanism since the addition
nitrobenzaldehyde no expected product could be observed, of free radical scavenger TEMPO to the reaction mixture
whereas iso-butyraldehdye delivered the C3-acylated product inhibits the formation of the product completely. The
in 48% yield. Noticeably, 2-furaldehyde also afforded the proposed mechanism is depicted in scheme 54B. This starts
product upon coupling with coumarin, and 6-methyl coumarin with the reaction between Aliquat-336
in 65% and 63% yield, respectively. Moreover, the presence of (tricaprylmethylammonium chloride) A and K2S2O8 resulting in
substituents on the coumarin did not alter the reaction the formation of tricaprylmethylammonium persulfate B,
outcome and good yields were obtained. The proposed which generates tricaprylmethylammonium sulfate radical C
mechanism for this protocol is presented in scheme 53B. on heating. Then, acyl radical E is generatedvia the reaction
A R1
between benzaldehyde and the sulfate radical B and this
O
O
process is accompanied by the removal of
+ R2 CuO, TBHP R2
R1 H
O O 90 oC O O
tricaprylmethylammonium hydrogensulfate D. Radical
Br
15 examples, traces-68%
addition of E to the 3-position of coumarin forms resonance
R1= Ph, 4-OMePh, 4-MePh, 4-t-BuPh,
stabilized benzyl radical F. Finally, removal of a hydrogen atom
4-BrPh, 2-OMePh, 2-NO2Ph,
furanyl, t-Bu
from F by another sulfate radical C afforded the desired
O R2= H, 6-MePh, 6-OMePh, 6-t-Bu, product together with D. Tricaprylmethylammonium chloride
O O gets regenerated by the reaction between
52%
tricaprylmethylammonium hydrogensulfate D and KCl.
B O
O R1
R1 H A
t O R2 R2
BuOOH t
BuO + OH
1
K2S2O8 (1.2 equiv)
O
R Aliquat 336 (30 mol%)
H R1 +
O O PhCl, 100 oC, 8 h O O
13 examples, 70-90%
O O R1= Ph, 4-MePh, 4-OMePh, 4-FPh,
Cu(l) Cu(lI)
4-ClPh, 2-OMePh, 2-ClPh, Me
R2= H, Me, Cl
R1 O R1
R1 B
2KHSO4 2KCl
O O O
O
+
O O O O
O O 2R3MeNCl O
A 2R3MeNOSO3H O
B A H
2K2S2O8 D R R
Scheme 53: (A) Cu-catalyzed C3-acylation of coumarin; (B) plausible E
reaction mechanism. O O O
2KCl F R3MeNOSO3
(R3MeN)2S2O8
Subsequently in 2016, Peiman Mirzaei and his team worked B 2R3MeNOSO3
R H
O
C
C
on a transition metal-free cross-dehydrogenative coupling Heating R R3MeNOSO3H
R= Octyl
reaction for the synthesis of 3-acylcoumarins. Reactions were O O
D
carried out by heating a mixture of coumarins and aldehydes Scheme 54: (A) Metal-free cross-dehydrogenative coupling for C3-acylation of
in the presence of K2S2O8/Aliquat-336 system in coumarin; (B) proposed reaction mechanism.
chlorobenzene. Various substituted coumarin and aldehyde Recently, our group has developed a highly proficient, metal-
derivatives were coupled at 100 oC for 8 h to synthesize 14 free approach for the regioselective C3-acylation of coumarins
derivatives of 3-acylcoumarins in good to excellent yields with aromatic aldehydes using tert-butyl peroxybenoate
(Scheme 54A).87c The electronic behaviour of the substituents (TBPB) as free radical initiator (Scheme 55).87d Various
present on the benzene ring of the aromatic aldehydes played differently substituted aromatic aldehydes having electron-
a key role for the yields irrespective of their positions. releasing and electron-donating groups were reacted with 7-
Aromatic aldehydes having either electron-releasing (Me, methoxy coumarin under the optimized reaction conditions.

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All applied aromatic aldehydes delivered the anticipated intermediate A via co-ordination of the palladiumView
with the
Article O-
Online
products in moderate to good yields at 90 oC after 24 h. Also, atom of quinoline-N-oxide and subsequent electrophilic
DOI: 10.1039/D0OB01458C
other derivatives of coumarin produced the desired products attack at the C8-position. Subsequently, complex A gets
in good yields upon treatment with benzaldehyde. converted into another intermediate B through nucleophilic

Unfortunately, neither aromatic aldehyde nor coumarin addition of H2O at the C2-position of the quinoline. In the
having strong electron-withdrawing NO2-group furnished the meantime, an acyl radical was generated from the aldehyde
corresponding acylated compound. Moreover, iso- in the presence of TBHP. The reaction between intermediate
butyraldehyde and pyridine-2-carbaldehyde also resulted in B and the acyl radical afforded the oxidative addition
the acylation of coumarin at C3-position in 41% and 60% yield, intermediate C as a Pd(III) or Pd(IV) complex. Finally,
respectively. Furthermore, N-methylquinolone also delivered intermediate C gave the desired product through reductive
the individual C3-acylated product upon treatment with elimination and regenerated Pd(II).
simple benzaldehyde under the optimized reaction
conditions. CHO
R2 PdCl2 (10 mol%)

X O X O + R2
O TBHP (4.5 equiv)
TBPB R1
R2 R2 N O N
+ R1 DCE/H2O (15:1) H
H R1 benzene, 24h O
90 oC 140 oC
O O
X= O & NMe R1
15 examples, 0-75%
R1= Ph, 4-MePh, 4-BrPh, 4-NO2Ph, 2-BrPh, 26 examples, 30-95%

2-FPh, i-Bu, pyridenyl O N 1
R2= H, 7-OMe, 7-Br, 7-OAc, 6-NO2 H R = H, 4-Me, 4-OMe, 4-F, 4-Cl, 4-Br
2-Me, 2-OMe, 2-F, 2-Cl, 2-Br, 3-Me,
O
3-OMe, 3-F, 3-Cl, 3-Br, 3-CF3, 3,4-Me,
Scheme 55: Regioselective C3-acylation of coumarin with aldehydes.
2,4-Cl
30% 2
R = H, 3-Me, 3-Br, 5-OMe, 6-Me, 6-F, 6-Cl
In 2016 Wu and his team described a one-pot process for the
selective formation of 8-acylated-2-quinolinones starting
from quinilone-N-oxides and aldehydes using a Pd-catalyst O N
H PdCl2
N
COPh O
and TBHP as oxidant via the formation of N-oxide-chelated
H 2O HCl
palladacycle.88 A total of 26 8-acylated-2-quinolinones were
synthesized in good to excellent yields starting from various HO N
quinoline-N-oxides and benzaldehydes in the presence of H N
O Pd Cl
O Pd COPh
PdCl2 catalyst, TBHP (5-6 M in decane) as oxidant, water as H
Cl A 2
additive and DCE as solvent at 140 oC for 24 h. (Scheme 56A). C

H 2O
Benzaldehydes having electron-releasing (Me and OMe) and t
BuO
HO
N
H O O H
weak electron-withdrawing (F, Cl and Br) groups at the para- O Pd Cl
R R H
position of the aryl ring gave the corresponding products in t B 2
BuOH
good to excellent yields. However, proficiency of acylation Scheme 56: (A) Pd-catalyzed selective C-8 acylation of quinilone-N-oxides
using aldehydes; (B) plausible reaction mechanism.
was slightly affected by steric hindrance as p-
methylbenzaldehyde gave a higher yield than o- and m- Manna et al. in 2017 developed visible light photoredox and
methylbenzaldehyde and a similar pattern was observed for palladium (II) catalyzed regioselective direct C-2 acylation of
methoxy and halogen-substituted benzadehydes. 3- N-pyrimidine protected indoles using aldehydes as acylating
(trifluoromethyl)benzaldehyde provided the acylated product agents and TBHP as acyl radical generator.89 Various
in just 43% yield. Furthermore, disubstituted aromatic differently substituted aromatic, heterocyclic and aliphatic
aldehydes also provided good yields of the desired products. aldehydes were coupled with N-pyrimidine protected indoles
Substituted quinoline-N-oxides were also coupled smoothly to synthesize a library of 27 acylated indole derivatives in good
with benzaldehyde and the positions of the substituents did to excellent yield (Scheme 57A). Aromatic aldehydes having
not interfere with reaction outcomes significantly improving electron-releasing (Me, OMe) groups resulted higher yield
the synthetic effectiveness of this protocol. than those of containing electron-withdrawing (Br, CN)
Based on several control experiments such as free radical groups. -Naphthaldehyde and thiophene-3-
trapping and kinetic isotope effect, a plausible mechanism carboxyaldehdye resulted the 75% and 74% yield of
was proposed by the authors as presented in scheme 56B. The corresponding products. Aliphatic aldehydes such as
mechanism starts with the formation of a palladacycle dimer cyclohexanecarbaldehdye, pentanal and 3-methylbut-2-enal

delivered good product yields. Similarly the scope of 57B). Initally, Ru2+ get excited to Ru2+* in presence of light,
View Article Online
substituted N-pyrimidine protected indoles was established which transfer a single electron to TBHPDOI:
(t-BuOOH) to produce
10.1039/D0OB01458C
and high product yields were achieved irrespective of nature OH- and t-BuO. via the cleavage of O-O bond and oxidized to
and position of substituent. Interestingly, protected Ru3+. Then t-BuO. abstracts hydrogen from aldehyde to

tryptophan and carbazole also delivered the desired mono generate acyl radical. On the other side, N-pyrimidyl indole
acylated products in moderate to good yields. undergoes cyclopalladation to form intermediate A.
To get insight into reaction mechanism authors performed Subsequent oxidative addition of intermediate A to acyl
few control experiments. When standard reaction was carried radical delivered cyclopalladated Pd(III) intermediate B, which
out in presence of 2 equiv of TEMPO the reaction quenched may be oxidized to Pd(IV) species C through a single electron
completely and no desired product could be obtained. transfer to Ru3+ resulting in reduction of Ru3+ to Ru2+. Species
Moreover, in the absence of photoredox catalyst very poor C finally delivered the corresponding acylated product and
yield was achieved and no reaction was observed in absence Pd(II) species by reductive elimination process.
of TBHP. With the help of these experiments and literature
reports a mechanism was given for this reaction (Scheme
A R3 R3
Pd(OAc)2 (10 mol%)
O TBHP (3 equiv) R1 B Me
R2 Ru(bpy)3Cl2.6H2O (2.5 mol%) R2
R1 H N N
N O
MeCN (0.1 M)
N blue LED, rt, 16-48 h N N
N N PdII(OAc)2 N
O
27 examples, 40-92% PdIV OAc
N
R1 = Ph, 4-MePh, 4-OMePh, 4-BrPh, 4-CNPh, 4-OAcPh, 4-CF3Ph, L
3-OPhPh, 3,4-ClPh, 3,4-OMePh, 3,5-OMePh, 3-benzothiophenyl, N
3-thiophenyl, -naphthyl, cyclohecyl, n-pentyl, 2-methylprop-1-enyl C N
Me PdII OAc
R2 = H, 5-Br, 5-OMe, 5-F, 4-CN, 5-Me, 5-Cl N
R3 = H, Me
N
CO2Et Me CO2Et N
PhthN Ru2+
PhthN S
O
A
Blue PdII OAc
N LED Ru 3+ N
N O N O N
N NO Me Ru 2+ N O
N N
N N t
BuO
t
68% BuOOH B
72% 50% OH TBHP Me

O
Me
Scheme 57: (A) visible light photoredox and palladium (II) catalyzed regioselective direct C-2 acylation of N-pyrimidine protected indoles using
aldehydes; (B) plausible reaction mechanism.
In 2017 Maiti et al. developed highly regioselective Pd- N-pyridyl carbazole resulted in monoacylated products on
catalyzed direct ortho-mono and diacylation of carbazole at coupling with aromatic aldehydes under optimized reaction
C1 and C8 positions using aldehydes as acylating agents via C- conditions (Scheme 58B). Authors have given a free-radical
H bond activation.90 Authors prepared 20 diacylatd and 4 promoted plausible reaction mechanism for the diacylation of
mono acylated derivatives in 27-94% yields by coupling N-pyridyl carbazoles (Scheme 58C).
various aromatic and aliphatic aldehydes with N-pyridyl
carbazoles (Scheme 58A). Aromatic aldehydes bearing
electron withdrawing (Cl, COOMe) at para-positions provided
higher yield of diacylated products in comparison of
aldehydes having electron-releasing (Me, OMe) groups. -
Naphthadehyde delivered the 92% yield of corresponding
diacylated product. Moreover, aliphatic aldehyde such as
cyclopropanecarboxaldehyde, cyclohexanecarboxaldehyde,
heptaldehyde and isobutaraldehyde afforded the moderate
to good yield. Substituted carbazoles also delivered their
respective products in good yields. Interestingly, halogenated

Please&do
A
R2 R2
acylation reaction, however pyridine and various derivatives
View Article Online
O
Pd(OAc)2 (10 mol%)
of pyridine were not very reactive and did not furnish the
DOI: 10.1039/D0OB01458C
R1 R1
target product in good yield. The synthetic methodology could
H t
N H BuOOH (4 equiv) N
O
H N Dichloroethane N
R1 O
also be extended for the formal synthesis of natural alkaloid

80 oC, 8 h
20 examples, 27-94% (±) angustureine. The homolytic activation of C-H bond

R1 = Ph, 4-ClPh, 3-ClPh, 4-BrPh, 2-BrPh, 4-FPh,
4-OMePh, 3-OMePh, 2,5-OMePh, 4-MePh, aldehyde using O2 as the oxidant led to the generation of acyl
4-CO2MePh, 4-COMePh, 4-CNPh, -naphthyl,
cyclopropyl, cyclohexyl, n-hexyl, iPr, radical. On the basis of literature reports and the
R2 = H, Me, COMe
experimental results obtained, a radical pathway was
B R2
R2
O H R1 suggested for the reaction (Scheme 59B). The mechanistic
R1 Pd(OAc)2 (10 mol%)
t
BuOOH (4 equiv)
N
OMe
studies suggested that the auto-oxidation of aldehyde lead to
N H O
H N
Dichloroethane
80 oC, 8 h
N
the formation of acyl radical which reacted with the
OMe
4 examples, 51-74%
protonated nitrogen heterocyclic moiety to form the radical
R1 = R2 = Br, I cation A, this cation formed the targeted acylated product
C
H O
post oxidation.
O O
Recently in 2020 Lete and co-workers described Pd(II)-
III
N
2 Pd 2 Pd(OAc)2
TBHP
Ph
N OAc catalyzed C-2 acylation of pyrrole by aldehydes using 2-
pyrimidine or 3-methyl-2-pyridine as directing groups using
N II
Ac
O TBHP as oxidant.92 Using 2-pyrimidine as directing group 15
Pd N
N
2 NO
Ph mono C-2 acylated derivatives of pyrrole were obtained in 14-
2 Pd(OAc)2 72% yield along with their corresponding C-2, C-5 diacylated
2 AcOH 2 AcOH byproducts (<5-41% yield) (Scheme 60A). Aromatic aldehydes
with having halogens (F, Cl, Br) on the para-position provided
N
2 Pd(OAc)2 N
III Ac
O moderate to good yields of mono-acylayed products along
N Pd
Ph
O N
2
with minor <5-8% yield of diacylated product. Aryl aldehydes
bearing strong electron-withdrawing CF3, NO2 and CN groups
O
provided solely monoacyalted product but in very poor yields
III
2 N
N Pd O
Ph
Ph
due to incompletion of the reaction. Although introduction of
O N OAc
O NO
electron-releasing group on aryl ring of aldehyde provided

Scheme 58: (A) & (B) Regioselective Pd-catalyzed direct ortho-mono and diacylation of
carbazole at C1 and C8 positions using aldehydes; (C) plausible reaction mchanism.
good results but ortho-substituted aldehydes delivered lower
Guin et al. attempted an aerobic radical approach for yield due to steric effect. -Naphthaldehyde resulted 51%
synthesizing unsymmetrical heteroaryl ketones. The approach yield of C-2 acylated product along with 19% diacylated
primarily involved cross-dehydrogenative coupling between product. To avoid the formation of byproduct authors tried 3-
aldehydes and heteroaromatic bases in presence of molecular methyl-2-pyridine as directing group for the selective
oxygen.91 A wide variety of nitrogen containing heterocyclic acylation of pyrrole and as was expected by authors all the
compounds were subjected to the aerobic radical acylation carried out reactions selectively delivered C-2 acylated
process and delightfully, the acylated products could be product without detection of formation of diacylated
successfully obtained in good yield showing excellent compound under the separately optimized. Aryl aldehydes
regioselectivity at positions 2 and 4 (Scheme 59A). In a few with both electron-releasing as well as electron-withdrawing
cases, even the alkylated products could be synthesized. Apart groups provided the corresponding derivatives in moderate to
from this, biologically relevant isoquinoline derivatives good yields. Heterocyclic aldehydes also provided the
containing sulphonamides could also be generated with corresponding acylated products in good yields resulting in
remarkable 99% selectivity. Several other nitrogen containing diheteroaryl ketones (Scheme 60B).
heterocycles including quinazoline, substituted quinazoline,
benzimidazole, thiazole, etc. also smoothly underwent the

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DOI: 10.1039/D0OB01458C

ARTICLE
R1
O R1
A O2
R1 H N
TFA, EtOAc N B
100 oC
R1 O
N
37 examples, traces-77% H
1 n n i
R = Pr, ethyl, Bu, ethylbenzene, n-pentanyl, Bu,
iso-pentyanyl, cyclohexyl, cyclopropyl, CHEt2,
N
cyclohex-3-enyl, Ph, 4-OMePh, 4-BrPh H
2
R = 4-Ph, 4-(4-Ph)Ph, 4-(4-OMe)Ph, 4-(2,4-F)Ph, 4-Me
1
-napthyl, 4-Br, 5-NHCOPh, 5-SO2NH(3-Cl-4-FPh), O R
O A
5-(4-sulfonylpiperazin-1-yl)(phenyl)methanone,
4-(1-(4-sulfonyl-1,4-diazepan-1-yl)ethan-1-one), etc.
R1
n ,
O Pr O n
Pr HOO
N N O2/HOO
n
N Pr
n
Pr N
N N N O
O O2 HO2/H2O2
N Me N Ph O Me
n
50% Pr O 52% 43%
34% 42% R1 H
N N N
N H
Me S O OBn OBn
OBn
1
O R
n MeO MeO
Me N Pr MeO
i
45% n Bu
Pr N N
N
57% 45% O 47% O
O
Scheme 59: (A) Aerobic cross-dehydrogenative coupling between heterocyclic compounds and aldehdyes; (B) plausible reaction
mechanism.
A
4. Miscellaneous
N
N N
O Pd(OAc)2 (10 mol%)
TBHP (4 equiv) O
N
O
N N
O
In 2012, Zhang and Hong reported the direct N-acylation of
N
N
Ar H Piv(OH) (0.75 equiv)
Ar Ar
N
lactams, oxazolidinones and imidzolidinones using aldehydes
toulene, 60 oC, 1.5-7 h Ar
in the presence of Shvo’s catalyst in toluene as solvent.93 The
14 examples, 14-72% 10 examples, 5-41%
best reaction conditions were defined as stirring a mixture of
Ar = 4-MePh, 4-tBuPh, 4-FPh, 4-ClPh, 4-BrPh, 4-CNPh,
4-NO2Ph, 3,5-OMePh, 3,4,5-OMePh, 2,6-OMePh,
2,4-OMePh, 4-CF3Ph, 3,5-CF3Ph, -naphthyl
lactam/oxazolidinone/imidzolidinone (0.25 mmol, 1 equiv.),
aldehyde (3.0 equiv) in the presence of Shvo’s catalyst (2.5
B
mol%) in toluene (0.5 mL) as solvent at 100 oC for 24 h. In total
Pd(OAc)2 (10 mol%) N
Me
N
O TBHP (4 equiv) O Me 33 N-acylated derivatives of lactams, oxazolidinones and
N N
Ar H Piv(OH) (0.75 equiv) Ar imidzolidinones were synthesized in moderate to excellent
toulene, 120 oC, 1-7 h
yields using several aromatic, aliphatic, heterocyclic and -
15 examples, 31-71%
Ar = 4-MePh, 4-tBuPh, 4-FPh, 4-ClPh, 4-BrPh, 4-CNPh,

unsaturated aldehydes as acylating agents (Scheme 61A).
4-NO2Ph, 3,5-OMePh, 3,4,5-OMePh, 2,6-OMePh,
4-OMePh, 4-OBnPh, 1-(tert-butyl)-1H-pyrrolyl, Based on the mechanism of Shvo’s catalyst, the authors
1-methyl-1H-pyrrolyl, furanyl
Scheme 60: Pd(II)-catalyzed C-2 acylation of pyrrole by aldehydes using

proposed a plausible mechanism for this method as presented
(A) 2-pyrimidine or; (B) 3-methyl-2-pyridine as directing groups. in scheme 61B. This involves nucleophilic attack of lactam A
to the carbonyl carbon of the activated aldehyde to form a
hemiaminal B, which further oxidizes via -hydride
elimination and undergoes proton transfer to produce the
acylation product and ruthenium species C3.

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DOI: 10.1039/D0OB01458C

ARTICLE
A
O O
H
O Shvo's catalyst (2.5%) O O O

X X Ph
NH N Ph
+ 1 toluene, 100 C, 24 ho
R 1 Ph
n R H n Ph
Ph
n = 0, 1, 2 Ru Ru Ph
Ph
X = NH, O & CH2 31 examples, 20-99% H Ph
OC CO OC CO
R1= Ph, phenylethyl, styrenyl, pentyl,
penta-1,3-dienyl, 1-phenylprop-1-en-2-yl, Shvo's catalyst (C1)
thiophenyl, 4-OMePh, 4-FPh, benzyl, H
O
O
O O
O
N
N
N N O
O
O O
80% 75% 61% 49%
O O O
O
O O O
N N N
N N N
63% O
86% 46%
B [C2]
O
O OH O O
C2 C3
R1 H OH O
X X X X
NH N N H N
n R1 n R1
n n
n = 0, 1, 2 A B
H
O O Ph Ph
Ph Ph Ph
Ph O OH
Ph Ph
Ph Ph Ph + Ph Ph
Ru Ru Ph Ru Ru
Ph
H Ph OC OC H
OC CO CO CO CO
OC
C1 C2 C3
Scheme 61: (A) Direct N-acylation of lactams, oxazolidinones and imidzolidinones with
aldehdyes using Shvo's catalyst; (B) proposed mechanism.
A copper catalyzed oxidative cross-coupling involving dual C- pathway for this protocol is described in scheme 62B. The
N/N-H functionalization for N-acylation of sulfoximines was proposed pathway involves the interaction of a Cu(II) catalyst
disclosed by Wang et al. in 2013 by treating aldehydes with with sulfoximine to give intermediate A. This intermediate A
sulfoximines in the presence of TBHP as oxidant under mild reacts with an acyl radical generated from the aldehyde in the
reaction conditions (Scheme 62A).94 A set of 14 derivatives of presence of TBHP. Subsequently, an electron transfer
N-acylsulfoximines was prepared with good functional group processes results in the construction of N-acylsulfoximine and
tolerance. In addition to S,S-methylphenyl sulfoximine, the a Cu(I) species. The later re-oxidizes to Cu(II) in the presence
reaction proceeded smoothly with S,S-dimethyl and S,S- of TBHP.
tetramethylenesulfoximines also and afforded their
respective products in excellent yields. Also, benzaldehyde
bearing a nitro group at the para- and meta-position furnished
the targeted compounds in excellent yields. Not only a nitro
group but also other electron-withdrawing groups such as F,
Cl and electron-releasing groups such as methoxy, alkyl, etc.
were well tolerated, delivering various N-benzoylsulfoximines
in good to excellent yields. A redox process based plausible

A CuBr (mol%)
O O O O A View Article Online
TBHP (2.0 equiv) R2
+ R2 S NH S O DOI: 10.1039/D0OB01458C
R1 H MeCN, 80 C o
R3 N R 1 PivOH (2.0 equiv)
+ X TBHP (2.0 equiv)
R3 R1
12 h H
14 examples, 72-95% CH3CN X
O O R2 Ar, 120 oC, 48 h R2

S R1= Ph, 4-NO2Ph, 3-NO2Ph, 4-PhPh,
X= C(COOMe)2, TsN & O 1
N 4-OMePh, 4-ClPh, 4-FPh, 4-t-BuPh, R
O
-naphtyl, i-Pr, COPh 33 examples, traces-70%
O2 N R2/R3= Me/Ph, Me/Me
85% R1= Ph, 4-MePh, 4-ClPh, 4-BrPh, 3-MePh, 3-OMePh,
3-ClPh, 3-BrPh, 2-MePh, 2-OMePh, 2-ClPh, 2-BrPh,
3,4-MePh, 2,4-ClPh, benzo[d][1,3]dioxolyl, thiophenyl,
B i-Pr, i-Bu,
O O TBHP
R2 Cu(l) Cu(ll) O R2= H, 8-Me, 7-Me, 7-OMe, 7-CO2Me, 7-CN, 7-Br,
R2
S 7-Cl, 7-Ph, 5-OMe, 5-F, etc.

R3 N R1 S
R3 NH B t t
BuOOH BuO + OH
R 2 O
O TBHP O S t
BuOOH
R3 O
1
HN Cu(ll)Ln
R H Cu(ll)Ln R1 MeOOC
A R1 O MeOOC
R1 H MeOOC
MeOOC
Scheme 62: (A) Cu(II)-catalyzed acylation of sulfoximines using t
BuOH + H2O
O
aldehydes; (B) proposed mechanism. R1 A

MeOOC R1
O
MeOOC B
In 2014, Luo and Liang developed a metal-free one-pot
cascade cyclization of 1,6-enynes with aldehydes involving H
t
BuOOH
MeOOC
MeOOC
simultaneous one C(sp2)-C(sp2) and two C(sp2)-C(sp3) bond MeOOC
MeOOC
formation for the synthesis of carbonylated tricyclic fluorene R1

t
BuO + H2O R1
O
derivatives by using PivOH and TBHP.95 The reaction O C
Scheme 63: (A) Metal-free one-pot cascade cyclization of 1,6-enynes with aldehydes; (B)
conditions were optimized as the reaction of a 1,6-enyne (0.2 plausible reaction mechanism.
mmol) with an aldehyde (1.0 mmol) in the presence of the To understand the mechanism, kinetic isotope effect and free-
oxidant TBHP (0.4 mmol, 70% aqueous solution), the additive radical quenching experiments were examined. No kinetic
PivOH (0.4 mmol) in acetonitrile as solvent (1 mL) at 120 oC for isotope effect (kH/kD = 1.0) was found by the outcome of
48 h under argon atmosphere. The developed reaction intramolecular and intermolecular reactions under standard
conditions were initially examined for exploitation of reaction conditions. This ultimately revealed a free-radical or
aldehydes in this cascade oxidative cyclization process. SEAR route for this reaction. Also, inhibition of the reaction in
Various aromatic aldehydes containing electron-releasing and the presence of 4 equiv of TEMPO clearly indicated that the
electron-withdrawing groups participated in this reaction to reaction proceeds via a free-radical route. A large kinetic
give the targeted fluorene derivatives in good yields isotope effect (KIE, kH/kD = 9.1) value for the 1:1 mixture of
regardless the positions of substituents on the aryl ring of the benzaldehyde and [D6]-benzaldehyde implied that cleavage of
benzaldehydes (Scheme 63A). Aliphatic aldehydes were not the carbonyl C-H bond is the rate-determining step for this
suited in this transformation and only traces of the products conversion. Depending on these observations and previous
could be obtained. Remarkably, benzo[d][1,3]dioxole-5- reports in this field,96 a plausible mechanism was proposed
carbaldehyde and thiophene-2-carboxyaldehyde could also (Scheme 63B). Initially, homolytic cleavage of TBHP under
undergo the reaction giving the products in 45% and 35% heating conditions generated alkyloxy and hydroxyl radicals.
yields, respectively. Delighted by these promising results, the These radicals capture a hydrogen atom from benzaldehyde
scope of 1,6-enyne substrates was examined with to form an acyl radical, and successive attack of this acyl
benzaldehyde and the reaction progressed efficiently in most radical at the CC bond of the enyne afford the radical
cases to give the desired products in moderate to good yields intermediate A. Next, an intramolecular cyclization process
(Scheme 63A). 1,6-Enynes substituted with electron-releasing generates a tertiary carbon radical B, which subsequently by
alkyl or alkoxy groups at the ortho, meta or para-position or another intramolecular cyclization with an aryl ring give rise
containing either halogen or an electron-withdrawing COOMe to radical intermediate C. Lastly, direct oxidation and
or CN group at the para-position were suitable for this deprotonation of intermediate C by TBHP furnishes the final
reaction affording the corresponding carbonylated fluorenes. product.
Tosylamides also react with benzaldehyde to give products in
moderate yield, whereas only trace amounts of the product Fuwei Li and his team in 2014 demonstrated a KI-catalyzed
(9,9-dimethyl-1,3,9,9a-tetrahydroindeno[2,1-c]pyran-4- oxidative cross-coupling of C-N and N-H bonds between azoles
yl)(phenyl)methanonewas obtained from the corresponding and aromatic aldehydes for the direct N-acylation of azoles in
enyne substrate. the presence of TBHP as oxidant.97 Various derivatives of azole

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(0.3 mmol) were reacted with aldehydes (0.45 mmol) in the To investigate the reaction mechanism, control View experiments
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presence of KI (0.06 mmol) as standard catalyst using TBHP were performed in the presence of free-radical scavengers
DOI: 10.1039/D0OB01458C
(0.9 mmol) as ideal oxidant in dichloroethane (DCE) as solvent like TEMPO and 1,1-diphenylethylene. These experiments
at 100 oC for 12 h. A total 28 derivatives were prepared in suggested the formation of an acyl radical and a free-radical

moderate to excellent yields irrespective of the positions and pathway for this conversion. Based on these results, two
nature of the substituents on the azoles as well as on the possible pathways were proposed as shown in scheme 64C. It
aldehydes (Scheme 64A). When the scope of aldehydes was was hypothesized that the tert-butoxyl and tert-butylperoxy
examined with pyrazoles, para-substituted benzaldehydes radicals are generated initially in the catalytic system, which
containing electron-donating (OMe, tBu) groups and electron- could abstract a hydrogen atom from the aldehyde to
withdrawing (Cl, Br, CN) groups reacted effectively with 3- generate the acyl radical. This acyl radical on reaction with the
phenyl pyrazole and delivered the products in 57% to 95% azole give the acyl azole radical anion A. Subsequently, radical
yield. Ortho-methoxybenzaldehydes resulted inferior yield in anion A by losing an electron via a SET process in the presence
comparison to para-methoxybenzaldehydes. - of the tert-butoxyl or tert-butylperoxy radical afforded the
naphthaldehdyde and thiophene-2-carbaldehdydes were also desired N-acyl azoles (Path A). In path B, it is represented that
found suitable for this transformation leading to 90% and 72% the tert-butoxyl and tert-butylperoxy could capture a single
yield of the products, respectively. Encouraged by these electron from the azoles leading to an azole cation species B,
findings, the authors further explored the scope of other which upon deprotonation with the help of tert-bytoxyl anion
azoles such as benzimidazole, benzotriazole and indazole with could convert to azole radical C. Finally, the coupling between
various substituted aromatic aldehydes. Benzaldehydes with acyl radical and azole radical cation B or azole radical C
electron-releasing groups provided products in 85% to 98% provided the desired product.
yield whereas electron-withdrawing substituents afforded
In 2015, Singh and co-workers for the first time developed a
yields of 24% to 78% upon reaction with benzimidazole.
mild oxidative amidation process of aldehydes using
Surprisingly, benzotriazole reacted only with ortho-
acetanilide as amine component in the presence of copper
substituted benzaldehydes and no product formation was
catalyst and TBHP as oxidant.98 Acetanilide and benzaldehyde
observed with para-substituted benzaldehydes. Furthermore,
were taken as model reactants and the reaction was carried
indazole upon treatment with para-bromobenzaldehyde gave
out using NBS catalyst and TBHP as oxidant in acetonitrile at
44% yield.
100oC, and 55% yield of benzanilide was obtained.
A C t
BuOOH t
BuO
KI (20 mol%) R1 OH
O TBHP (3 equiv) N
+ NH
R1 H DCE, 100 oC R2 N O
R2 N
I 1/2 I2
13 examples, 31-95%
R1= Ph, 4-OMePh, 4-t-BuPh, 4-BrPh,
4-ClPh, 4-CNPh, 2-OMePh, 3-FPh,
3,5-OMePh, thiophenyl, -naphthyl H 2O t
BuOO t
BuOOH OH
2
R = H, Ph Path A
Y X
B O X X NH
KI (20 mol%) O t O X R1 X R1
Y Y BuO Y t
BuO Y
+ TBHP (3 equiv) N
R1 H N N
N
H R1 H or R 1 or
O O
DCE, 100 oC t
BuOO t
X=N, Y= C R1 A
BuOO
X=N, Y= N O
Path B O
X=C, Y= N 13 derivatives, 24-98%
Y X t X X X R1
BuO Y Y R1 Y
R1=Ph, 4-BrPh, 4-CNPh, 2-BrPh, 2-OMePh, NH NH or N N
or
3-NO2Ph, 3,4-OMePh, -naphthyl, t O
BuOO B C
thiophenyl
Scheme 64: (A) & (B) KI-catalyzed oxidative cross-coupling of C-N and N-H bonds for N-acylation of azoles using aromatic
aldehydes; (C) plausible reaction mechanism.
To improve the product yield, several other catalysts, oxidants various substituted acetanilides and aldehydes, and finally a
and solvents were screened. Finally, by several combinations library of 24 benzanilide derivatives was prepared (Scheme
and permutations, the reaction conditions were optimized by 65A). Acetanilides as well as benzaldehydes containing
stirring of a mixture of acetanilide (0.5 mmol), benzaldehyde electron-releasing and electron-withdrawing groups such as
(1 mmol) in the presence of CuCl2.2H2O (10 mol%) catalyst Me, OMe, Cl, Br, NO2, CN, etc. underwent the reaction
using TBHP (2 equivalents) as oxidant in DCE as solvent at 100 smoothly delivering the products in moderate to good yields.
oC for 24 h. With these optimized reaction conditions, the Thiopene-2-carbaldehyde gave the product in 52% yield.
scope and versatility of the reaction was examined using However other heterocyclic aldehydes such as furfural and

indole-3-carboxyaldehyde showed no product formation respectively. Based on literature reports and experiments, a
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because of their decomposition in the presence of TBHP. plausible reaction mechanism was proposed as shown in
DOI: 10.1039/D0OB01458C
Aliphatic aldehydes such as heptanal and cinnamaldehyde scheme 65B.

afforded the corresponding products in 64% and 76% yield,

A B O
O O CuCl2 2H2O O
R 2 TBHP 2 NH
+ N Me R1 N
R
R1 H H H
O
24 examples, 0-82%
N
R1= Ph, 4-MePh, 4-OMePh, 4-ClPh, Cu(ll)Ln
4-NO2Ph, 3-ClPh, 3-BrPh, 2-BrPh, Cu(ll)Ln
A
2,4-ClPh, thiophenyl, furanyl, styrenyl, O
H TBHP
hexyl, 1H-indol-3-yl N
2 H R
R = Ph, 4-MePh, 4-ClPh, 4-NO2Ph, Cu(l)Ln
4-CNPh, 3-CF3Ph, 4-(COMe)Ph, O O
TBHP
3-ClPh, 2-BrPh, 3-MePh, pyridin-2-yl,
cyclohexyl N O O
Scheme 65: (A) Cu-catalyzed oxidative amidation of aldehydes using acetanilide; (B) plausible reaction
mechanism.
In the same year (2015), Achar et al. executed a metal-free In 2017, Cijil Raju and co-workers reported a Cu-catalyzed
oxidative cross-coupling for the amidation of aldehydes with double C-H/N-H activation protocol between
N-chloramines in the presence of TBAI (tetrabutylammonium sulfonimidamides and aldehydes affording a diversity of N-
iodide) in combination with TBHP under neat conditions at acyl sulfonimidamides in low to moderate yields (Scheme
50oC or ball-milling conditions at room temperature (Scheme 67).100 In this typical procedure, a mixture of
66A).99 Using this protocol, 19 amide derivatives were sulfonimidamides (4.0 equiv.), aldehydes (1.0 equiv.) in the
obtained in good yields by treating aromatic aldehydes, presence of CuBr (5 mol%) as catalyst and TBHP (2.0
heteroaromatic aldehydes and aliphatic aldehydes with equivalent) as oxidant in acetonitrile was stirred at 82 oC for 2
primary and secondary N-chloramines. Aryl aldehydes having h. Employing these optimal conditions, 26 different N-acyl
electron-donating Me and OMe substituents give 84% and sulfonimidamides were prepared in 18-56% yields, starting
82% yield of the respective amides. Furthermore, the from aromatic, heterocyclic and aliphatic aldehydes and
presence of electron-withdrawing substituents such as F, Cl, various sulfonimidamides. Various benzaldehydes with
Br, CF3, NO2, etc. on the aryl system of aromatic aldehydes was electron-donating and electron-withdrawing substituents in
found to be competent for this amidation reaction. different positions display identical ease towards the N-
Thiophene-2-carbaldehyde provided 76% yield of the product, acylation of sulfonimidamides. Both mono- and di-substituted
whereas in case of aliphatic aldehydes, inferior yields (53%- aromatic aldehydes worked well under these developed
64%) were obtained. Similarly, various N-chloramine reaction conditions. Interestingly, the presence of the bulky
derivatives such as N-chloro-1-phenylmethanamine, N- tBu group at the C-3 and C-5 position of the aryl aldehyde does
chloro-N-methyl-1-phenylmethanamine, N-benzyl-N-chloro- not inhibit the product formation and 47% yield was obtained.
1-phenylmethanamine etc. also reacted smoothly and The scope of the reaction was not limited only to aryl
enabled good product yields. To get insight into the reaction aldehydes as hetero-aromatic and aliphatic aldehydes were
mechanism, control experiments were performed under neat also found feasible for this transformation. The modifications
conditions (Scheme 66B). Based on the results of these in the aryl system of the sulfonimidamide moiety were well
experiments, a plausible reaction mechanism was proposed tolerated and replacement of the piperidine part with
as shown in scheme 66C. morpholine and pyrrolidine was also found to be compatible
and yielded the corresponding products smoothly.

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DOI: 10.1039/D0OB01458C

ARTICLE
A O R2 TBAI (20 mol%) O

N TBHP (2 equiv) R2
R1 H Cl R3 R1 N
neat, 50 oC, 1.5 h 3
R
19 examples, 53-84%
R1= Ph, 4-OMePh, 4-MePh, 4-ClPh, 4-CF3Ph,

C
4-BrPh, 4-NO2Ph, 4-FPh, 3-Br-4-OMePh,
O R2 TBAI O
3-BrPh, 3-NO2Ph, 3,4,5-OMePh, 3,4-OAcPh,
thiophenyl, nonanyl, cyclohexyl N
TBHP R2
R 1
H Cl R 3 R1 N HCl
2 3
R /R = benzyl, Me, H 3
R
B H2 N t
t
BuO BuOH OH
OH 1/2 I2
O
(i) O
H Cl 0%
N N (TBAI)
H H (TBHP) H 2O t
BuOO
F 73%
t
F BuOOH I
t t
Ph BuOO or BuO
t t
BuO R2
BuOO or
HN O O R2
N N
Ph Cl R3
(ii) O Ph R1 H R1 R3
t t
O BuOOCl or BuOCl
t or t
11% BuOOH BuOH
Ph N O
H
Cl N 73%
Ph R2
Ph R N
3
R
(iii) O
O
N
TBAI (20 mol%) O
H N TBHP (2 equiv)
O neat, 50 oC, 1.5 h Cl
Cl
TEMPO
Scheme 66: (A) Metal-free oxidative cross-coupling for the amidation of aldehydes using N-chloramines; (B) control experiments; (C) plausible reaction
mechanism.
O
catalyst, t-BuOK (0.8 mmol)/NaH (1.2 mmol) base in THF as
H
O N CuBr (5 mol%) O
S
N R1 solvent under N2 atmosphere at 25 oC followed by quenching
O S t
BuOOH (2.0 equiv)
N N using 1M HCl aqueous solution. The scope of the primary
H R 1 MeCN, 82 oC
R2
2h R2 amines with aldehydes was investigated by synthesizing 24 N-
25 derivatives, 18-54%
acylated derivatives of amines in high yields. Aryl aldehydes
N N R1= 4-MePh, 4-BrPh, 4-ClPh, 4-FPh,
N
=
N
4-NO2Ph, 3-ClPh, 3,4-ClPh, 3,4-FPh,
bearing substituents such as F, Cl, OMe and NO2 at different
O 3,5-t-BuPh, 3-NO2Ph, furanyl, thiophenyl,
n-Pr, ethyl
positions (ortho-, meta- and para-) of the aryl ring participated
2
R = H, 4-Me, 4-CF3 in the reaction with tosylamide to give the respective N-
Scheme 67: Cu-catalyzed double C-H/N-H activation between sulfonimidamides
and aldehydes for the synthesis of N-acyl sulfonimidamides. tosylcarboxamindes in high yields. Interestingly, thiophene-2-
carbaldehyde and 2-naphthaldehyde provided the respective
Later in 2017, Zheng and Ma published a direct oxidative N- imides in 87% and 91% yields with these newly developed
acylation reaction of primary amines with conditions. Moreover unsaturated aldehydes including
aryl/unsaturated aldehydes in the presence of the enals and ynals were well suited for this direct N-acylation
azolium salt of an N-heterocyclic carbene and base such as protocol of tosylamide and conjugated ynals having aliphatic
tBuOK or NaH using 3,3ʹ,5,5ʹ-tetra-tert-butyldiphenoquinone
or aromatic substituents exhibited a wide scope resulting in
(DPQ) as oxidant at 25 oC (Scheme 68).101 This methodology 71-87% yields of the products. Unfortunately, alkylated
provided a proficient approach for the synthesis of N- aldehydes were found inactive under the current reaction
sulfonylcarboxamides, N-sulfinylcarboxamides and conditions and could not afford the imide products probable
dicarboxyimides in good yields. The reactions were carried out due to competing enolization of the aldehyde substrate.
by reacting a mixture of the corresponding amine (0.4 mmol)
and aldehyde (0.6 mmol) in the presence of NHC (10 mol%) To expand the synthetic utility of this methodology, other
amide substrates were examined. Electron-rich

(unsubstituted) as well as electron-poor (p-NO2 and p-Cl In the meantime, Hu and co-workers developedView anArticle
efficient
Online
substituted) aryl sulfonamides upon reaction with 4- PhI(OAc)2-promoted double acylation (N- and O-acylation) of
DOI: 10.1039/D0OB01458C
chlorobenzaldehyde delivered the corresponding products in hydroxylamines with aldehydes at room temperature in acetic
93-96% yields. Besides, methanesulfonamide was also acid for the synthesis of N-acetoxy-N-arylamides in good to

witnessed as a competent reaction partner given that 92% excellent yields.102 The acylation of N-atoms in
yield of the product was obtained. Additionally, benzamide hydroxylamines are due to the acyl group of aldehydes
and its p-chloro and p-nitro derivatives could also be whereas the O-atoms get acylated by the acetyl group of
employed for the formation of dicarboxyamides using a PhI(OAc)2. This transformation exhibited great substrate
stronger base NaH (3.0 equiv.) instead of tBuOK, due to the scope under the optimized reaction conditions. Initially, the
inferior acidity of carboxamides compared with sulfonamides. effect of aromatic aldehydes was explored with N-
(S)-tert-butylsulfinamide (99% ee) suited efficiently in this phenylhydroxylamine and all the selected aryl aldehydes
protocol and yielded the (S)-tert-butylsulfinamide-4- could give the desired products regardless of the nature
chlorobenzamide in 81% yield with almost complete retention (electron-releasing or electron-donating) of the substituents
(98% ee) of configuration (Scheme 68A). present on the aromatic ring. However, in some cases, the
positions of the substituents on the aryl ring of the
A 10 mol% C
O O DPQ (1.5 equiv) O O benzaldehydes were found to influence the reaction yield. For
t
BuOK or NaH
R1 H +
R2
X
NH2 R2
X
N R1 example, m-nitrobenzaldehyde delivered 85% yield whereas
THF, N2, 25 oC H
X= C, SO & S p-nitrobenzaldehyde resulted in 73% yield but unfortunately
20 examples, 71-97%
no product formation took place with o-nitrobenzaldehyde.
N Cl
R1= Ph, 4-ClPh, 4-FPh, 3-OMePh, 3-NO2Ph, The 2-furaldehyde and pyridine-2-carboxaldehdye offered
N thiophenyl, -naphthyl, styrenyl, hept-1-ynyl,
C= N
MeS 1-ethynylcyclohex-1-ene, ethynylbenzene their respective products in good yields; on the other hand, no
R2= Ph, 4-MePh, 3-NO2Ph, 4-ClPh,
Me, 4-NO2Ph, t-Bu
product formation was observed with aliphatic aldehydes
B O O
(Scheme 69).
R1
S N
R N A
H O AcO OAc
N N R O I O
Mes
O
CH3COOH O
O A R2NHOH R1
R1 H + + N
Fragmentation N2, rt, 1 h
R1 S O R2 O
HN O OH 35 examples, 0-96%
N N
R R R1= Ph, 2-MePh, 3-MePh, 4-MePh, 3-OMePh, 4-OMePh,
2-ClPh, 3-ClPh, 4-ClPh, 2-NO2Ph, 3-NO2Ph, 4-NO2Ph,
D N N N N 4-CNPh, furanyl, pyridinyl, propyl, 4-CF3Ph
Mes Mes R2= Ph, Me, t-Bu, 2-MePh, 3-MePh, 4-MePh, 2-ClPh,
B
3-ClPh, 4-ClPh, 4-BrPh, 4-AcPh, 4-(CO2C2H5)Ph
1,2-Addition
Oxidation B
AcO OAc Ph
O
I
O O N DPQ I
-H Ph O O
R O O
R1 S NH2 R1 S NH Me
N N
O O
N N + PhNHOH Ph Ph O
R1 H
Mes
A' C R1 R1 B
A
Scheme 68: (A) N-acylation reaction of primary amines with aryl/-
unsaturated aldehydes using azolium salt of an N-heterocyclic carbene; -PhI
CH3COO
(B) plausible reaction mechanism.
The postulated catalytic cycle for this transformation is OAc Me O

O
presented in scheme 68B. The pathway initially involved the N R1
O H N
Ph
Ph N O R1
formation of Breslow intermediate B through nucleophilic O
Ph O Me
R1
addition of in situ generated carbene A to aldehyde. The D
-CH3COOH
C
O
intermediate B oxidized to form acylazolium species C upon Scheme 69: (A) PhI(OAc)2-promoted double acylation (N- and O-acylation)
of hydroxylamines with aldehydes; (B) plausible reaction mechanism.
treatment with DPQ. Then attack of the deprotonated amide
compound A' probably via 1,2-adduct D, on azolium Similarly, the applicability of various N-aromatic
intermediate C, followed by a fragmentation sequence gave hydroxylamines bearing an electron-rich methyl group or
the final compound along with the carbene catalyst A. electron-poor chloro, bromo, acetyl or ester group reacted
with benzaldehyde, and the corresponding products were
obtained in 45-75% yields. However, no product could be

Please&do
obtained with aliphatic hydroxylamines such as N- formation and provided the final compound.
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methylhydroxylamine and N-(t-butyl) hydroxylamine. The A
O
DOI: 10.1039/D0OB01458C
O
O
compatibility of the simultaneous in present substituents on O
O Pd(OAc)2 (5 mol%) R1
TBHP (5 mmol) N
aromatic aldehydes and aromatic hydroxylamine was also

1
R H
N 1,4-dioxane
120 oC, 18 h O
exploited. The aromatic aldehydes delivered a higher product
18 examples, 22-79%
yield when electron-withdrawing groups were present as R1= Ph, 2-FPh, 2-ClPh, 2-BrPh, 4-MePh, 4-OMePh,
4-FPh, 4-ClPh, 4-BrPh, 3,4-MePh, 3,4-OMePh,
substituents, compared to aromatic aldehydes having 3-ClPh, 2,4-FPh, 2,6-FPh, 2-F-4-ClPh,
2-F-4-BrPh, cyclohexyl, i-Pr
electron-withdrawing groups. On the other hand, aromatic
B O
hydroxylamines with electron-donating groups on their O
phenyl rings resulted in higher product yields than those with N
electron-withdrawing groups with the same aldehydes t

BuOOH
Pd(OAc)2
AcOH
(Scheme 69A). A plausible mechanism for this reaction is O Cyclopalladation

O
Pd(0)
shown in scheme 69B. At the beginning, the aldehyde reacted O
O
N
with hydroxylamine to form a nitrone intermediate A. Then a t
BuOOH O
Reductive
Elimination
N
Pd
ligand exchange process took place between nitrone A and O AcO
A
PhI(OAc)2 to produce intermediate B, which on intramolecular O O
rearrangement produced another intermediate C. The O C N

Pd
N O
deprotonation of intermediate C by an acetate resulted in O O
intermediate D, which on subsequent migration of the acyl D B

t
BuO + OH
group and isomerization gave the final product. Migration of

Pd(OAc)2
phenyl ring
O
In 2018, our lab disclosed a radical-induced Pd-catalysed O
t
BuOH t
BuOOH
O H O
approach for the direct functionalization of 2-phenyl-4H- O
N
N
benzo[d][1,3]oxazin-4-ones with aldehydes.103 The reaction O
O
proceeded through the formation of the o-acylated 2-phenyl- E
4H-benzo[d][1,3]oxazin-4-one intermediate to give 6a- Scheme 70: (A) Pd-catalyzed direct functionalization of 2-phenyl-4H-benzo[d][1,3]
oxazin-4-ones with aldehydes; (B) plausible reaction mechanism.
phenyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-
diones in the presence of the TBHP oxidant. Various aryl Segundo and Correa in 2019 reported Pd-catalyzed oxidative
aldehydes with electron-releasing groups (Me, OMe) and coupling between phenylalanine based peptides with
electron-withdrawing groups (F, Cl, Br, etc.) reacted smoothly aldehydes for site-selective C(sp2)-H acylation using DCP
with 2-phenyl-4H-benzo[d][1,3]oxazin-4-one in the presence (dicumyl peroxide) as oxidizing agent and Ag2CO3 as
of Pd(OAc)2 (5 mol%) as catalyst using TBHP (5 mmol) oxidant additive.104 With the optimized reaction conditions the scope
in 1,4-dioxane as solvent at 120 oC for 18 h to afford 19 of C(sp2)-H acylation of phenylalanine derivatives was
derivatives in 21-79% yields (Scheme 70A). Aliphatic investigated by coupling with a wide variety of aldehydes and
aldehydes such as cyclohexanecarboxaldehyde and the desired products could be obtained in moderate to
isobutyraldehyde delivered the corresponding products in excellent yields (Scheme 71A). Aryl aldehydes having
48% and 33% yields, respectively. A plausible reaction electron-releasing (Me, OMe, Et2N, 2,3-dihydrofuryl) groups
mechanism was proposed based on control experiments and resulted the mixture of mono- and di-acylated compounds,
previous literature reports (Scheme 70B). Initially, 2-phenyl- which could be easily separated. 2,4,6-
4H-benzo[d][1,3]oxazin-4-one underwent the ortho- trimethoxybenzaldehdye delivered only di-acylated
palladation reaction with Pd(OAc)2 to form complex A and by- compound in 67% yield. Similarly, p-hydroxybenzaldehyde, 2-
product AcOH. At the same time, an acyl radical is formed chlorobenzaldehyde and -naphthaldehyde delivered the
from the aldehyde by action of TBHP. A subsequent reaction mono-acylated products in 63%, 45% and 54% yield,
between complex A and acyl radical promoted the formation respectively. Heterocyclic and aliphatic aldehydes were also
of complex B, which goes through a reductive elimination smoothly reacted to give the corresponding products in good
process to give o-acylated intermediate C. In the next step, the yield. Moreover, substituted phenylalanine derivatives also
o-acylated intermediate underwent an aryl ring migration in afforded the monoacylated compounds in moderate to good
the presence of TBHP and gave intermediate D followed by yields. To expand the generality of the protocol the scope of
biradical intermediate E. Biradical E undertook C-N bond phenylalanine based di, tri and penta-peptides was also

explored with optimized reaction conditions and targeted reports authors have proposed a mechanism for Online
View Article this
products was obtained in good to excellent yield irrespective transformation (Scheme 71C). DOI: 10.1039/D0OB01458C
of the effect of nature of side chains present in peptide chain

(Scheme 71B). Based on control experiments and literature

A O O
H
R2 O
Pd(OAc)2 (10 mol%) R 1
R 1
R2 R2
+ H R1 DCP (2 equiv)
PA
N CO2Me Ag2CO3 (2 equiv)
H PA O R1
DMF (0.25 M) 100 oC N CO2Me PA
Ar, 16 h H N CO2Me
H
OH
17 examples, 30-81%
O
R1 = 4-MePh, 4-OMePh, 4-NEt2Ph, 2-OMePh,
OMe 4-OHPh, 2-ClPh, 2,4,6-OMePh, ethyl, n-hexyl,
O 2,3-dihydrobenzofuranyl, 3-indolyl, thiophenyl
R2 = 4-Cl, 3-F
MeN O
BnN
PA N PA = Picolinamide
N CO2Me N HN
H
CO2Me F
50%
72%
B H O O
O 1
Pd(OAc)2 (10 mol%) R1 R
+
H R1 DCP (2 equiv) +
PA Ag2CO3 (2 equiv)
O R1
DMF (0.25 M) 100 oC
* PA
Ar, 16 h PA
O O O O
R1
Me MeO Me MeS
H H H H
PA N CO2Me PA N CO2Me PA N CO2Me PA N CO2Me
N N N N
H H H H
O O O O
Ph Ph
57% 44% 33%
52%
from PA-Phe-Phe-OMe from PA-Phe-Leu-OMe from PA-Phe-Leu-OMe
from PA-Phe-Phe-OMe
O CO2Me CO2Me
N HN PA N
TMB TMB TMB O
Ar
O O O
H O H
PA N CO2Me PA N HN
N N OH Et2N
H Ar = H
O O CO2Me O N NBn
Ph N
43% O TMB 62%
31%
from PA-Phe-Leu-OMe from PA-Phe-Pro-OMe 39%
from PA-Phe-The-OMe
O from triazole-Phe-Pro-OMe
O O
TMB TMB
O O O
H H H H
PA N PA N PA N N CO2Me
N N CO2Me N N CO2Bn N N
H H H H H H
O O O O
Ph Ph
32% 52%
48%
from PA-Phe-Ala-Val-OBn from PA-Phe-Phe-Val-Phe-OMe
from PA-Phe-Ala-Leu-OMe
O O
Ar TMB
O O
H H Et2N
PA N N
N N N CO2Me PA O O
H H H N PA
O N O
O O H H
Ph Ph N N
N N Ph Ph
N N
31% H H
from PA-Phe-Phe-Leu-Phe-lle-OMe O O
70% O N CO2Me CO2Me
H N
from PA-Phe-Pro-Val-Pro-Phe-OMe 78% H
from PA-Phe-Pro-Val-Pro-Phe-OMe
2
Scheme 71: Pd-catalyzed oxidative coupling between phenylalanine based peptides with aldehydes for site-selective C(sp )-H
acylation.

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DOI: 10.1039/D0OB01458C

ARTICLE
O
post-functionalization of drug molecules and natural products
Ph
and transient directing group mediated acylations. Research
HN
N
Pd(OAc)2 CO2Me
in the fields of visible light mediated synthesis and continuous
AcOH
reductive
elimination
flow synthesis are still in their infancy. There is a room for
coordination
O
CO2Me O
further improvements via the use of alternative energy
N Ph sources like ultrasound and microwaves that have also played
N
N Pd lV N
CO2Me
a crucial role in achieving the green chemistry objectives in
Pd
O
R OAc organic synthesis via enhancing the efficiency and rapidity of
cyclopalladation
organic reactions.
oxidation
Me Me O
CO2Me
Ph O Nevertheless, we anticipate that in the upcoming years, the
O O N
N Pd
ll AcOH limitations and scope of these protocols shall be duly
R H R
addressed, fuelling more interest in this area. This review has
Me Me
been an attempt to propagate the key findings on the use of
Ph OH
less toxic and stable aldehyde motifs for the construction of a
Scheme 71(C): Plausible reaction mechanism for Pd-catalyzed oxidative
coupling between phenylalanine based peptides with aldehydes. plethora of keto compounds; few examples discussed herein
are quite motivating from the viewpoint of armouring the
Conclusions and Future Perspectives organic chemists with sustainable synthetic methodologies
which is the pre-requisite of the hour.
Over the past decades, aldehydes have emerged as excellent
acylation surrogates for the direct forging of acylated Conflicts of interest
compounds containing keto motifs. Consequently, there has
There are no conflicts to declare.
been a profitable interplay of acylation and C-H activation for
gaining a ready access to these bioactive molecules with Acknowledgements
enhanced selectivity and improved atom economy under
The authors gratefully acknowledge their respective
ambient reaction conditions. Also, considerable attention has universities/research organizations in particular, SRM
been devoted by researchers to the exploration of the University, Sonepat; Department of Chemistry, University of
mechanisms behind these fascinating transformations, Delhi and Peoples’ Friendship University of Russia (RUDN
opening new horizons for further research in this area. There University) Miklukho-Maklaya, Moscow, Russia for extending all
possible support for furtherance of research.
have been massive breakthroughs with more than 100
research articles published in high impact factor journals Notes and references
involving the selective acylation of arenes, heteroarenes and
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Aldehydes: magnificent acyl equivalents

for direct acylation

To link to this article DOI: http://dx.doi.org/10.1039/D0OB01458C

Publisher: Royal Society of Chemistry

All outputs in CentAUR are protected by Intellectual Property Rights law,

Central Archive at the University of Reading

You can find more information about Accepted Manuscripts in the

or omissions in this Accepted Manuscript or any consequences arising

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Organic & Biomolecular Chemistry Accepted Manuscript

Received 00th January 20xx,

1. Introduction Crafts acylation reaction include requirement of harsh

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ARTICLE Organic & Biomolecular Chemistry

is well known that green chemistry helps in achieving

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present in peach, black tea, bitter almond, and apricot

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Organic and Biomolecular Chemistry ARTICLE

environment and eco-systems. and reversible metalation-proto(deutero)demetalation

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aromatic aldehydes, which on subsequent intramolecular D O D3 N H/D

Authors have synthesized 21 derivatives of 3- D

hydroxyisoindolin-1-one by reacting several differently Rh(I)

high yields. On the other hand, aldehydes carrying the PhCHO

yields in comparison to those bearing electron-withdrawing D3

R2= 5-Ph, 5-Cl, 4-OMe, 4-OBn, 4-Cl, 3-OMe, 3-F, Rh(III)

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ARTICLE Organic & Biomolecular Chemistry

benzothiazoles or benzoxazoles with aldehydes using H

(Scheme 4). A set of 38 o-acylated benzothiazoles and H R 1 + X

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ARTICLE Organic & Biomolecular Chemistry

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Scheme 6: Pd(II)-catalyzed direct regioselective acylation of N-Boc hydrazones

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1 AcOH (50 mol%) R1

NHTf TfHN TfHN

The substrate scope examination revealed that electron poor

Novàk and co-workers reported a Pd-catalysed cross-

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Me NH O R1= Ph, 4-BrPh, 3-BrPh, 4-ClPh, 3-ClPh,

NH O with benzaldehdye and 2) coupling of benzaldehyde bearing a

O group. Interestingly, high regioselectivity was observed with

Scheme 9: Pd-catalyzed cross-dehydrogenative coupling between anilides

The presence of electron releasing or electron withdrawing t

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O N Pd(OAc)2 (10 mol%)

R1= Ph, 2-OMePh, 2,5-OMePh, 2-FPh, 4-FPh,

Scheme 11: Pd-catalyzed direct ortho-acylation of 2-benzyl-1,2,3-triazoles.

Sun et al. in 2014 introduced azoxy compounds for selective A

benzaldehydes positively affected the reaction giving higher B O

yields of the mono-acylated derivatives. However, strong N