Arabian Journal of Chemistry (2023) 16, 104472

King Saud University

Arabian Journal of Chemistry

www.ksu.edu.sa
www.sciencedirect.com

REVIEW ARTICLE

Reaction of 3-Acetylcoumarin: From methods to

mechanism
Narges Hosseini Nasab a, Fereshteh Azimian b,c, Hendrik G. Kruger d,
Song Ja Kim a,*

a
Department of Biological Sciences, Kongju National University, Gongju, Chungnam 32588, Republic of Korea
b
Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
c
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
d
Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa

Received 25 August 2022; accepted 26 November 2022

Available online 5 December 2022

KEYWORDS Abstract Coumarins are known as heterocyclic compounds with a benzo-a-pyrone moiety which
3-Acetylcoumarin; has been extensively applied in pharmacology, cosmetics, chemical and medicinal industry. The spe-
Reaction; cial characteristics and biological activities of coumarin lead to their usage in pharmacy and med-
Synthesis; icine. Hence, a variety of methods, reactions and techniques are applied in order to synthesize
Mechanism coumarin derivatives. Reaction of 3-acetylcoumarin with different reagents are reported herein.
Also, various reactions of 3-acetylcoumarin such as multicomponent, cycloaddition, a-
halogenation, aldol condensation, reduction and 1,2-addition reactions are covered in this review.
The synthesis of different classes of compounds starting from 3-acetylcoumarins through different
reactions and the achieved outcomes including the products and yields are presented. The prepared
compounds showed a range of activities such as antifungal, antimicrobial, anti-proliferative, and
anti-inflammatory. It is hoped that this review will be a useful resource for interested researchers
engaged in this area.
Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author at: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 32588, 56
GongjuDaehak-Ro, Republic of Korea.
E-mail address: ksj85@kongju.ac.kr (S.J. Kim).
Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

https://doi.org/10.1016/j.arabjc.2022.104472
1878-5352 Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2 N. Hosseini Nasab et al.
1. Introduction
Coumarins with one oxygen atom in their rings belong to the oxygen-
containing heterocycles, which are found in nature and synthetically
produced. The association of b-pyrone rings with benzene leads to
the formation of these phenolic compounds (O’Kennedy and
Zhorenes, 1997). The name of coumarin originates from French word
‘‘Coumarou” for the tonka bean, because coumarin was first isolated
from tonka beans (Bairagi et al., 2012; Kulkarni et al., 2006). Although
coumarins are found as secondary metabolites in many plants (Seo
et al., 2013), such as Dipteryx odorata, Anthoxanthum odoratum, Gal-
ium odoratum, also in roots, flowers, leaves, peels, seeds and fruits, sep-
aration and purification from multi-component mixtures cause some
problems (Sasidharan et al., 2011). Fig. 1 illustrates some natural cou-
marins isolated from plants. Warfarin (2), for example, is a well-known
coumarin that belongs to the anticoagulant class and is derived from
dicoumarol (3), which is isolated from sweet clover (Melilotus offici-
nalis and Melilotus alba). Calanolide A (4), isolated from the Calophyl-
lum lanigerum tree, has been found to be a potent non-nucleoside
reverse transcriptase inhibitor of HIV. Natural coumarin bioavailabil-
ity can be modulated by synthetic changes to improve the metabolic
stability. Generally, simple coumarin scaffolds have produced promis-
ing clinical trial candidates and will continue to affect medicinal chem-
istry and drug design in the future (Menezes and Diederich, 2019).
Fig. 1 Some of biological active natural coumarins.
Fig. 2 The number of publications per 10 year period that involve the 3-acetylcoumarin unit either as reagent, product or substructure.
(Search results from n-Scifinder). Many synthetic 3-acetylcoumarin related compounds show beneficial bioactive properties that will
prompt more research in future.
Coumarins have gained a reputation as a multifunctional scaffold
because of their broad range of biological activities from being anti-
oxidant (Borges Bubols et al., 2013), anti-inflammatory (Chen et al.,
2017), anti-microbial (Kharb et al., 2013), anti-fungal (Montagner
et al., 2008), anti-HIV (Olmedo et al., 2012), analgesic (Ghate
et al., 2005), anticancer (Emami and Dadashpour, 2015; Seo et al.,
2013), antiviral (Hassan et al., 2016), anticoagulant (Akoudad
et al., 2014), antituberculosis (Keri et al., 2015), insecticides (Wang
et al., 2012), dyes (Traven et al., 2003), herbicides (Zhao et al.,
2021), and sensitizers (Vekariya et al., 2017) Several studies revealed
that coumarins are able to regulate the growth and photosynthesis
(Eivgi et al., 2017), as well as defense against infection. Owing to
antioxidant and metal chelators properties, some coumarins with
phenolic hydroxyl group prevent the formation of free radicals
(Couttolenc et al., 2020; Matos et al., 2015). Researchers have
reported coumarin containing compounds as an acetylcholinesterase
(AchE) inhibitor with potential effects on Alzheimer disease
(Bagheri et al., 2015; Razavi et al., 2013). Coumarins derivatives have
been applied as lipid lowering agents that possess moderate triglyc-
eride lowering activity (Madhavan et al., 2003). Coumarins also
can be applied as solar energy collectors, laser dyes, fluorescent
probes and nonlinear optical chromophores (Trenor et al., 2004).
Fig. 3 Preparation and mechanism for the formation of 3-
acetylcoumarin (5) (Srikrishna et al., 2014).
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 4 Reaction of 3-acetylcoumarin (5) with alkyl phosphites (6(Osman et al., 1998) and 12(Yuan et al., 2015)) and phosphonium ylides
(10) (Osman et al., 1998).
These wide range of biological activities are attributed from various
types of substitutions pattern or pharmacophores in their basic nuclei
(Medina et al., 2015). The nucleus of 4-hydroxycoumarin can also be
substituted with different functional groups in order to increase their
biological activities. The susceptible nature of the coumarin core to
electrophilic substitution provides opportunities to design and synthe-
size more advanced classes of structural units for various medical and
industrial applications (Tolba et al., 2022). A variety of structure
have been synthesized using different methods and reactions utilizing
the versatile substitution options for the coumarin skeleton (Tolba
3
et al., 2022). The substitution of coumarins change the properties
of the parental material and the generated coumarin derivatives show
promising or even unprecedented properties (Borges et al., 2005;
Riveiro et al., 2010). Owing to the wide range of biological and phys-
ical properties, coumarin research is on an increase. Hence, straight-
forward and flexible synthetic methods toward functionalized
coumarins have been developed in order to facilitate the construction
of new coumarin derivatives (Eissa et al., 2009). Some reviews have
recently summarized many important medicinal properties of cou-
marins and its derivatives (Medina et al., 2015; Peng et al., 2013).
4 N. Hosseini Nasab et al.
3-Acetylcoumarin (5) has been employed as a starting material in
the synthesis of numerous scaffolds. As can be seen in Fig. 2, publica-
tions where the 3-acetylcoumarin moiety is involved (either as a
reagent, product or substructure) are experiencing a huge upward
trend.
We have previously reviewed the synthetic strategies and pharma-
cological properties of coumarin-chalcones generated from 3-
acetylcoumarin (Nasab et al., 2022). Considering the vastness of cou-
marin containing compounds, we also provided a review of the crucial
role of 3-bromoacetylcoumarin in the facial synthesis of biologically
active compounds (Hosseini Nasab et al., 2022). Herein, we focused
on various reaction of 3-acetylcoumarin for synthesis of organic com-
pounds. Different reaction conditions, techniques and methods for the
synthesis of coumarin derivatives were presented. The outcomes from
these reactions, such as products and yield as well as the biological
activities are summarized. We concluded the review by highlighting
challenges, limitations, and future directions of synthesis of
heterocyclic-fused coumarins.
The addition of an electron-withdrawing substituent at position 3,
such as COCH3, improves the photophysical, antimicrobial, antioxi-
dant and anticancer properties of coumarins (Cocchietto et al.,
2002). Several studies have been reported on various synthetic path-
ways for the preparation of 3-acetylcoumarin (5), including the reac-
tion of salicylaldehyde and ethyl acetoacetate at room temperature
(Yahaya et al., 2019), or under microwave irradiation (Ajani and
Nwinyi, 2010), in the presence of bismuth(III) nitrate–zinc(II) chlo-
ride–Al2O3 at 120 °C (Verma et al., 2007), or Fe3O(BPDC)3 in
dimethylformamide:water at 60 °C (Lieu et al., 2016), and in the pres-
ence of L-proline in triethanolamine at room temperature in 96 % yield
(Fig. 3) (Srikrishna et al., 2014).
2. Reaction of 3-Acetylcoumarin
2.1. Reaction with alkyl phosphites and phosphonium ylides
A novel and feasible procedure for the construction of phos-
phonates was reported by Osman et al. (Osman et al., 1998)
based, for the reaction of 3-acetylcoumarin (5) with dialkyl,
or trialkyl phosphites (6) in solvent-free conditions. The exis-
tence of an electron-withdrawing group at position 3 in 3-
acetylcoumarin (5) facilitates the nucleophilic attack of the
phosphite phosphorus to position 4 in 3-acetylcoumarin (5),
which gives the final products 7; 8 and 9 in 7–85 % yields.
Furthermore, employing benzoic acid as a catalyst in the
reaction medium, different phosphonium ylides (10) react with
3-acetylcoumarin (5) to produce two isomers (E)-allylic (11)
and (Z)-allylic (11´) in 15–60 % yields (Osman et al., 1998).
A similar synthesis to this reaction uses both trisdimethy-
lamino phosphine and trialkyl phosphites (6) to form more
novel ylides (Abdou and Sediek, 1999).
A reaction involving 3-acetylcoumarin (5) and diisopropy-
lphosphites (12) and catalyzed by AgNO3 for the synthesis of
selective 4-phosphorylated coumarin (13), was reported by
Yuan et al. (Yuan et al., 2015).
In another study, under similar conditions using a chelating
N-heterocyclic carbene (NHC) palladium complex, compound
13 is produced in 66 % yield (Yang et al., 2016).
Fahmy et al. (Fahmy et al., 1991) reported the reaction of
3-acetylcoumarin (5) and alkyl phosphite (6) to produce the
(3-acetyl-2-hydroxy-2H-benzopyran-2-yl) phosphonate deriva-
tives (14) in 75–80 % yields (Fig. 4).
Fig. 4-1 Mechanism for the production of compound 13(Yuan
et al., 2015).
The proposed mechanism (Yuan et al., 2015) pathways for
compound 13 is shown in Fig. 4-1. Diisopropyl H-phosphite
interacts with AgNO3 to yield the intermediate A, which is sub-
sequently used to generate the phosphorus radical B. The
intermediate C stabilized by the phenyl group is obtained by
adding the phosphorus radical to the 4-position of 3-
acetylcoumarin (5). The intermediate D would then be released
by a single-electron transfer (SET) from C to silver (I). The
nitrate anion then abstracts a proton from D, resulting in pro-
duct 13.
Under ultrasound irradiation, or reflux conditions, p-
toluenesulfonic acid (p-TSA) catalyzes the reaction of 3-
acetylcoumarin (5) with trialkyl phosphites (6) to give com-
pounds 15 and 15´ in 95 % yields (Nikolova et al., 2004).
The reaction between 3-acetylcoumarin (5) and N-
phenyliminovinylidene, oxotriphenylphosphorane (16), or
hexaphenylcarbodiphosphorane (19) in tetrahydrofuran was
studied by Maigali et al. (Maigali et al., 2011) to prepare phos-
phorus ylides compounds (17; 18 and 20) in 40–70 % yields.
Under solvent-free conditions, the one-pot ultrasound-
assisted reaction of 3-acetylcoumarin (5), substituted amines
and diethyl phosphite (21) results in the formation of 2-
oxochroman-phosphonic acid diethyl ester derivatives (22) in
76–90 % yields (Fig. 5) (Shaikh et al., 2020).
These compounds were screened as acetylcholinesterase
(AChE) and butyrylcholinesterase (BuChE) inhibitors against
Alzheimer’s disease and compound 22 (a; f; o; q) was shown
to be better AChE inhibitors than the control drugs galan-
tamine (IC50 = 3.9 mM) and rivastigmine (IC50 = 5.6 mM).
The IC50 values for these compounds range between 0.50
and 3.94 mM. The in vitro cytotoxicity of these compounds
was also tested against human embryonic kidney (HEK-293)
cells and these compounds displayed cytotoxicity in the same
range as the standard drugs in HEK-293 cells (Shaikh et al.,
2020).
The proposed mechanism (Shaikh et al., 2020) for the pro-
duction of compound 22 involves the conjugate attack of
diethyl phosphite (21) at C4 of 3-acetylcoumarin (5) to create
the 1,4-adduct (A). The conjugate 1,4-addition of amine then
follows to generate the adduct (B). The adduct (B) is subse-
Reaction of 3-Acetylcoumarin: From methods to mechanism 5

Fig. 5 Reaction of 3-acetylcoumarin (5) with phosphor reagents (6(Nikolova et al., 2004); 16; 19 (Maigali et al., 2011) and 21 (Shaikh
et al., 2020)).

quently subjected to an addition–elimination process, yielding oxaphosphole (23) from 3-acetylcoumarin (5) and
the target product (Fig. 5-1). dichlorophosphonite in acetic anhydride media. Their
Petrov et al. (Petrov et al., 2005) proposed a synthetic approach resulted in an intermediate (23) with > 99 % regio
route for the synthesis of coumarino-[3,4-c]-1,2- and diastereoselectivity. The latter is boiled in benzene and
6 N. Hosseini Nasab et al.
Fig. 5-1 Mechanism for the reaction of 3-acetylcoumarin (5)
with phosphor reagents (21) (Shaikh et al., 2020).
Fig. 6 Synthesis and mechanism of S and R oxaphospholo[4,3-c]chromen-oxide (23 and 24) (Petrov et al., 2005).
converted to the isomeric coumarino-[3,4-c]-1,2-oxaphosphole
(24 R and S) in 30–35 % yields.
The structures of the two isomers were ascertained using X-
ray crystallography. The 1,4 addition of dichlorophosphonite
to 3-acetylcoumarin (5), followed by two oxo-dehalogenation
steps of the phosphonium intermediate by the acetic anhy-
dride, is the most likely mechanism for this reaction (Fig. 6).
The use of proton transfers in the phosphine catalyzed reac-
tion of 3-acetylcoumarin (5) and dialkyl acetylenedicarboxy-
late (25), to form the 3-acetyl-4-ethylenylcoumarin (26) in
83–98 % yields. It is then accompanied by reaction with hydra-
zine derivatives to produce 2H-chromeno[3,4-c]pyridine-1,2-
dicarboxylate (27) (Alizadeh et al., 2018).
Chromenopyrido[1,2-a]pyrazine-carboxylates and
diazepine-carboxylates (28) are synthesized in 63–65 % yields
by reacting 26 with 1,n-diamines under the same reaction con-
ditions as for compound 27 (Fig. 7) (Alizadeh and Jamal,
2018).
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 7 Synthesis of 2H-chromeno[3,4-c]pyridine-1,2-dicarboxylate (27) (Alizadeh et al., 2018) and diazepine-carboxylates (28) (Alizadeh
and Jamal, 2018).
The proposed mechanism (Alizadeh et al., 2018; Alizadeh
and Jamal, 2018) for the formation of compounds 27 and 28
is shown in Fig. 7-1. A zwitterion (A) is formed upon nucle-
ophilic addition of triphenylphosphine to an activated acetyle-
nic molecule (25), which is trapped by the electrophilic 3-
acetylcoumarin (5) to create intermediate (B). The intermedi-
ate (C) is then obtained via 1,2-proton transfer, which isomer-
izes to form intermediate (D).
Then (D) is converted into another intermediate (E) via a
1,4-proton transfer. The elimination of the triphenylphosphine
results in the product F. Finally, compound F interacts with
hydrazine, or amine to form an imine intermediate (G, G´),
which undergoes cyclization to yield 27 and H. Moreover,
the 28 is formed by N-cyclization of chromenopyridine (H)
via attack on the C‚O double bond and the loss of methanol.
2.2. Reaction with amines
The reaction between 3-acetylcoumarin (5) and 3-
aminopropenoates (29) for generating tricyclic structures in
high yields was reported by Raev et al. (Raev et al., 2004).
The proposed mechanism (Raev et al., 2004) shows that the
initial intermediates (A; B and D) are thermodynamically
unstable and undergo intramolecular rearrangements to give
the 2-pyridones (30; C and E). The intermediates C and E
cyclize by intramolecular Michael addition of the phenolic
hydroxyl group to the conjugated double bond, yielding the
stable tricycles 31 and 32, respectively in 8–59 % yields. To
produce benzopyrano[3,4-c]pyridines (30), the intermediate A
is cyclized upon application of heat or a catalyst (Fig. 8).
6H-benzo[c]chromen-6-ones (33) are formed in 10–47 %
yields from the reaction of 3-acetylcoumarin (5), acetone and
various amines in acetic acid at room temperature (Koelsch
and Embree, 1958) (Fig. 9).
7
2.3. Reaction with secondary amines
Bolakatti et al. (Bolakatti et al., 2008) discovered that, in the
presence of paraformaldehyde and concentrated HCl in etha-
nol, the reaction of 3-acetylcoumarin (5) with different substi-
tuted secondary amines produces 3-(b-N-substituted amino
propanoyl)chromen-2-one Mannich bases (34) in 26–68 %
yields (Fig. 10).
The anti-inflammatory and analgesic properties of these
derivatives were screened and compared to the standard drug
diclofenac (CAS 15307–86-5, 68.8 %). Compounds 34 (a and
g) exhibited 63.1 and 66.7 % inhibition, respectively
(Bolakatti et al., 2008).
Patil et al. (Patil and Sawant, 2015) investigated the antimi-
crobial and antiproliferative properties of these products and
they found poor activity against gram negative organisms as
compared to standard drug ofloxacin.
The suggested mechanism for the formation of compound
34 involves the Mannich reaction. The secondary amine adds
to the carbonyl of formaldehyde in acidic medium, followed
by elimination of water to yields the iminium salt (A). The tau-
tomer form of 3-acetylcoumarin (5´) acts as a nucleophile to the
iminium salt (A) to form the final product (34) (Fig. 10).
In ethanol, dicyano-6H-dibenzo[b,d]pyran-methanides (35)
are formed in 57–77 % yields from a simple reaction between
3-acetylcoumarin (5), secondary amines and malononitrile
(Fig. 11) (Khoobi et al., 2013).
The proposed mechanism (Khoobi et al., 2013) of this reac-
tion is shown in Fig. 11-1. Intermediate A is formed after
nucleophilic attack of the anion of malononitrile on position
4 of 3-acetylcoumarin. This is followed by the Michael addi-
tion of the anion of malononitrile to intermediate (A), to pro-
duce adduct B. Then, the nucleophilic C-center in B attacks the
C-atom of a CN group in an intramolecular nucleophilic addi-
8 N. Hosseini Nasab et al.

Fig. 7-1 Mechanism for the reaction of 3-acetylcoumarin (5) with dialkyl acetylenedicarboxylate (25) (Alizadeh et al., 2018; Alizadeh
and Jamal, 2018).

tion, resulting in compound (C). Compound D is made by add-
ing another equiv. of malononitrile to compound C.
Intermediate E is produced via the elimination of hydrogen
cyanide, which is aided by the amine as a base. Compound F is
formed as a result of the amine nucleophilic attack on the
cyano substituent of intermediate E. Removal of N,N-
dialkylcyanamide and with aromatization as the driving force,
intermediate F generates compound G. The production of
compound 35 via H and I appears to follow a similar reaction
pathway.
Under reflux conditions, the reaction of 3-acetylcoumarin
(5) with piperidine produces open-chain 2-hydroxybenzyli
dene-piperidin-butane-1,3-dione (36) in 70 % yield (Fig. 12)
(El-Kholy et al., 1981).
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 8 Synthesis and mechanism of 6-oxo-tetrahydropyridine-3-carboxylate (30); tetrahydro-2H-2,6-methanobenzo[g][1,3]oxazocine-11-
carboxylate (31) and tetrahydro-2H-2,6-methanobenzo[g][1,3]oxazocin-acetate (32) (Raev et al., 2004).
Fig. 9 Synthesis of 6H-benzo[c]chromen-6-ones (33) (Koelsch
and Embree, 1958).
2.4. Synthesis of hydroxylamines, oximes, and their reactions
The formation of coumarin-oxime ether derivatives (38) is
achieved in 80–95 % yields using a simple method involving
the reaction of 3-acetylcoumarin (5) with o-substituted benzyl
hydroxylamines (37) in a pyridinium p-toluenesulfonate/dichl
9
oromethane (PPTS/DCM) solution at reflux temperature
(Bhargavi et al., 2017).
Molecular docking studies and anti-inflammatory activity
of all compounds were examined in vivo. When R = 2-CN,
good anti-inflammatory activity was observed (Bhargavi
et al., 2017).
Beckmann’s rearrangement (BKR) is used in the synthesis
of pharmaceuticals and natural products, and induces remark-
able transformation for the synthesis of amides from ketones
(Shin et al., 2013).
Hence, treatment of 3-acetylcoumarin (5) and hydroxy-
lamine hydrochloride with thiamine hydrochloride (as an envi-
ronmentally friendly catalyst), produce N-2H-chromen-
acetamide (39) in 95 % yields (Fig. 13) (Mahajan et al., 2020).
The proposed mechanism (Mahajan et al., 2020) involves
the production of oxime (A) that undergoes Beckmann rear-
rangement with the help of a catalyst (thiamine hydrochlo-
ride), to form the corresponding amide 39 in 95 % yield
(Fig. 13-1).
10 N. Hosseini Nasab et al.

Fig. 10 Synthesis and mechanism of 3-(substituted propanoyl)chromen-2-ones (34) (Bolakatti et al., 2008).

Fig. 11 Synthesis of dicyano-6H-dibenzo[b,d]pyran-methanides (35) (Khoobi et al., 2013).

Oximation of 3-acetylcoumarin (5) in the presence of
hydroxylamine hydrochloride and sodium acetate trihy-
drate generates 3-acetylcoumarin oxime (40). The conden-
sation of 3-acetylcoumarin oxime (40) and methyl
chloroformate in dry tetrahydrofuran produces oxy-imino-
2H-chromen-2-one (41) in 81 % yield (Fig. 14) (Krishnan
et al., 2015).
Neuroprotective factors have recently become a hot topic
among researchers, owing to the fact that neuroprotection is
one of the most effective treatments for neurodegenerative dis-
eases such as Parkinson’s, Alzheimer’s and Huntington’s dis-
ease (González-Muñoz et al., 2010).
Form this point of view, 3-acetylcoumarin oxime (40) con-
denses with propargyl bromide, producing oxyimino-2H-
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 11-1 Mechanism that accounts for the synthesis of dicyano-6H-dibenzo[b,d]pyran-methanides (35) (Khoobi et al., 2013).
Fig. 12 Synthesis of 2-hydroxybenzylidene-piperidin-butane-
1,3-dione (36) (El-Kholy et al., 1981).
chromen-2-one (42) in 85 % yield, which is then clicked with
aryl azide to produce 1,2,3-triazol-methoxyimino-2H-
chromen-2-one (43) in 50–80 % yields (Fig. 15) (Kumari
et al., 2018).
The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazo
lium bromide) reduction assay was used to evaluate the
in vitro neuroprotection and toxicity against H2O2-induced
PC12 cell lines. When R = 3-NO2, significant protectivity
and a half-maximal effective concentration (EC50) value of
14.04 mg/ml against injured PC12 cell lines and reduced toxic-
ity was discovered (Kumari et al., 2018).
11
2.5. Synthesis of enaminone and its reactions
Enaminones have received a lot of publicity because of their
usefulness in heterocyclic synthesis. The enaminone 44 was
used to make a series of 3-heteroaryl coumarin derivatives.
To make 3-coumarinyl-dimethylamino-propenone (44), the
reaction starts with 3-acetylcoumarin (5) and
dimethylformamide-dimethylacetal (DMF-DMA), with L-
proline (Kumar et al., 2012).
Enaminone (44) is also prepared in 92 % yield with 2-
guanidinoacetic acid as a catalyst in solvent-free conditions
(Bindal et al., 2011).
The enaminone 44 is participated in reactions with hydrox-
ylamine hydrochloride; hydrazine hydrate, or phenylhy-
drazine; benzamidine hydrochloride (47); 3-amino-triazole
(49); hippuric acid (51) and dithiocarboxylic acid (53), to pro-
duce 3-coumarin-isoxazole (45); 3-coumarin-pyrazole (46); 4-
coumarin-2-phenylpyrimidine (48); 4-coumarin-triazolo[4,3-a]
pyrimidine (50); 3-pyranylcoumarin derivatives (52) and 3-ben
zylthiocarboxamido-6-coumarin-pyran-2-one (54), respec-
tively, in 60–75 % yields (Fig. 16) (El-Taweel and Elnagdi,
2001).
12 N. Hosseini Nasab et al.

Fig. 13 Synthesis of oximes (38) (Bhargavi et al., 2017) and acetamide (39) (Mahajan et al., 2020).

Fig. 13-1 Mechanism for the synthesis of compound 39(Mahajan et al., 2020).

Fig. 14 Synthesis of oxy-imino-2H-chromen-2-one (41) (Krishnan et al., 2015).

Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 15 Synthesis of 1,2,3-triazole-tethered coumarin derivatives
(43) (Kumari et al., 2018).
For the reader’s convenience, a proposed mechanism
(Kumar et al., 2012) for the production of 3-coumarinyl-dime
thylamino-propenone 44, using L-proline as catalyst is pro-
vided in Fig. 16-1. The carbonyl group of 3-acetylcoumarin
(5) is nucleophilically activated by condensation with the
pyrrolidine moiety of L-proline via the cooperatively produced
hydrogen-bonded intermediates A and C, yielding enamine D
(nucleophilic activation). The carboxylic acid hydrogen atom
of D forms a hydrogen bond with one of the methoxy groups
of DMF-DMA, increasing the potential (electrophilic activa-
tion) for its removal via a nucleophilic attack by the a-
carbon atom in the enamine D moiety of intermediate E to
yield imminium intermediate F.
Through hydrogen-bonded intermediate G, the carboxylate
anion in F abstracts one of the a-hydrogen atoms of the immi-
nium moiety. The OCH3 group is then nucleophilically elimi-
nated to give imminium species H, which is then
hydrolytically cleaved by the water molecule generated during
the enamine synthesis to yield enaminone 44.
3-Coumarinyl-dimethylamino-propenone (44) is reacted
with acetic acid/ammonium acetate; 3-acetylcoumarin (5);
1,4-benzoquinone (57); 1,4-naphthoquinonone (59) and 4-
(dimethylamino)but-3-en-2-one (63), to produce 2-coumarin-
5-coumarin-pyridine (55); 2,6-bis(coumarin-pyridine (56); 5-
hydroxy-3-coumarin-benzo[b]furan (58); 5-hydroxy-3-
coumarin-naphtho[1,2-b]furan (60); dicyclopenta[b,d]pyrrole-
dione (62) and di(3-coumarinoyl)benzene (64), respectively,
in 60–85 % yields (Al-Zaydi, 2003; El-Taweel and Elnagdi,
2001).
By undergoing a Nenitzescu-like cyclization (Mukhanova
et al., 1997) and decarboxylation, the intermediate 2,4-
dicoumarinoyl pyrrole (61) is converted to the final product
dicyclopenta[b,d]pyrrole-dione (62) (Al-Zaydi, 2003).
13
Methylpyridin-2H-chromen-2-ones (65) are obtained in 69–
75 % yields by combining compound 44 with acetylacetone
and ethyl acetoacetate, ammonium acetate and acetic acid
(Fig. 17) (Al-Mousawi et al., 2003).
Microwave-assisted reaction of 3-coumarinyl-dimethyla
mino-propenone (44) with aminocyclohexenothiophene (66),
leads to the formation of 2H-chromen-propenylamino-tetrahy
drobenzo[b]thiophene-carboxylic acid ethyl ester (67) in 69 %
yield (Al-Zaydi, 2003). The presence of olefinic protons at 5.69
and 6.61 ppm with J = 9 Hz in the 1H NMR spectrum indi-
cates the cis form of the product was isolated.
2-Amino-4-coumarin-pyrimidine (68) is synthesized with
the aid of microwave heat from 44 and guanidine hydrochlo-
ride, in 60 % yield (Al-Zaydi, 2003).
When 3-coumarinyl-dimethylamino-propenone (44) and
nitrile oxide are treated in hydroximoyl chlorides, or hydra-
zonyl halides, the 3-coumarin-isoxazole (69) is obtained in
54 % yield, rather than the potential isomeric product 70.
Compound 69 reacts with hydrazine hydrate in ethanol to
form 4-coumarin-phenylisoxazolo[3,4-d]pyridazine (71) in
71 % yield (Fig. 18) (Al-Zaydi, 2003).
A similar reaction using enaminone (44) for the synthesis of
coumarin derivatives (62; 64; 65; 68; 69 and 71) was investi-
gated under solvent-free conditions and under microwave irra-
diation. The yields of products were reasonable (Al-Zaydi,
2003).
The suggested mechanism starts with a nucleophilic attack
of compound 66 to the a,b-unsaturated enaminone (44) gener-
ating intermediate A. The latter loses dimethylamine to form
the final product (67) (Fig. 18-1).
Combination of 3-coumarinyl-dimethylamino-propenone
(44) with various 4-aminobenzenesulfonamides (72) affords a
series of chromene-sulfonamide derivatives (73) in 84–91 %
yields (Ghorab et al., 2016).
These compounds exhibited anticancer activities against
breast cancer cell lines (T47D) and when R = 5-methoxypyri
midine (IC50 = 8.8 mM) the best activity compared to doxoru-
bicin (IC50 = 9.8 mM) was recorded (Ghorab et al., 2016).
El-Azab et al. (El-Azab et al., 2016) described the reaction
of precursor 3-coumarinyl-dimethylamino-propenone (44)
with primary aromatic amines, thiourea, o-aminothiophenol
(76); 2-cyanoacetic acid hydrazide (78) and 2-cyano-N-
phenylacetamide (80), to obtain acyclic secondary amine
derivatives (74); pyrimidine-2-thione (75); 3-benzo[b][1,4]
thiazepin-2H-chromen-2-one (77); 2H-chromen-pyrazol-
propanenitrile (79) and 2H-chromen-phenyl-dihydropyridine-
3-carbonitrile (81), respectively, in 63–90 % yields (Fig. 19).
The mechanism for these reactions is described in Fig. 18-1.
In 2011, Hamama et al. (Hamama et al., 2011) investigated
the reaction of 3-coumarinyl-dimethylamino-propenone (44)
with 2-aminobenzothiazole (82); 6-aminothiouracil (84); m-
anisidine and thiophenol to produce thiazolopyrimidine (83);
pyridopyrimidine (85); 3-methoxyphenyl-amino-acryloyl-2H-
chromen-2-one (86) and mercapto (87) compounds, respec-
tively, in 71–75 % yields. In dioxane as solvent, 3-
acetylcoumarin (5) is refluxed with dimethylformamide-dime
14 N. Hosseini Nasab et al.

Fig. 16 Synthesis of 3-coumarinyl-dimethylamino-propenone (44) (Kumar et al., 2012); 3-coumarin-isoxazole (45); 3-coumarin-pyrazole
(46); 4-coumarin-2-phenylpyrimidine (48); 4-coumarin-triazolo[4,3-a]pyrimidine (50); 3-pyranylcoumarin derivatives (52) and 3-
benzylthiocarboxamido-6-coumarin-pyran-2-one (54) (El-Taweel and Elnagdi, 2001).

thylacetal (DMF-DMA) to produce 3-coumarinyl-dimethyla
mino-propenone (44).
Over the past decades, fluorescent organic compounds have
been a hot topic in materials science and the study of biological
interactions (Klymchenko, 2017). Because of several main
characteristics, such as a simpler and greener synthetic tech-
nique, pyrazolo[1,5-a]pyrimidine (PPs) (89) was described as
a strategic compound for optical applications. The fluo-
rophores (89) are isolated in 80 % yield by mixing the enami-
none (44) with 3-methyl-1H-pyrazol-5-amine (88) under reflux
conditions in acetic acid (Abdelhamid et al., 2013). The reac-
tion proceeds under microwave irradiation in good yield
(Tigreros et al., 2020).
Enaminoketones (44) react with 4-methyl-6-oxo-2-thioxo-
1,2,5,6-tetrahydropyridine-3-carbonitrile (90) and diethyl 3-
oxopentanedioate (92) to produce two new pyridine deriva-
tives (91) and 2H-chromen-nicotinate (93), respectively, in
65–75 %-yields (Fig. 20) (El-Taweel and Abou Elmaaty, 2015).
According to the proposed mechanism (Abdelhamid et al.,
2013), the acyclic non-isolable intermediate A is formed by a
Michael addition of the amino group in compound 88 to the
activated double bond in enaminone (44). Intermediate A
undergoes cyclization and aromatization via elimination of
dimethylamine and dehydration yielding the final product
(89) (Fig. 20-1).
The suggested mechanism for synthesis of compound 93
follows a nucleophilic attack of 3-oxopentanedioate (92) on
the double bond in intermediate A, which results in the forma-
tion of intermediate B. The latter loses dimethylamine to form
intermediate C, followed by nucleophilic attack of the NH to
the carbonyl group, and elimination of water to give the final
product (93) (Fig. 20-2).
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 16-1 Mechanism for the synthesis of 3-coumarinyl-dimethylamino-propenone (44) (Kumar et al., 2012).
2.6. Synthesis of dithiocarbamates and carbamodithioate
Dithiocarbamates display various biological activities, includ-
ing anti-fungal (Len et al., 1996); anti-bacterial (Imamura
et al., 2001); and carbonic anhydrase inhibiting activities
(Carta et al., 2012) and due to these properties, they have
received considerable attention in literature.
Accordingly, Chinese researchers (Li et al., 2015) used
acryloyl-2H-chromen-2-one hydrochloride (94) to react with
a mixture of dimethylamine hydrochloride, triethylamine, car-
bon disulfide and dimethylformamide to produce dual dithio-
carbamates (95) in 32 % yield. Intermediate 94 is obtained by
15
the reaction of 3-acetylcoumarin (5), paraformaldehyde and
dimethylamine hydrochloride under reflux conditions in acetic
acid.
The anticancer properties of these products were tested
in vitro on the human lung cancer cell line H460 which dis-
played the best inhibitory activity with IC50 = 0.66 mM (Li
et al., 2015).
One of the key proteins responsible for cancer’s Warburg
effect is Pyruvate Kinase M2 (PKM2). As a result, new types
of dithiocarbamatic acid esters were synthesized and identified
as PKM2 selective activators with remarkable anti-
proliferative effects on tumor cell lines (Zhang et al., 2015).
16 N. Hosseini Nasab et al.

Fig. 17 Synthesis of 2-coumarin-5-coumarin-pyridine (55); 2,6-bis-coumarin-pyridine (56); 5-hydroxy-3-coumarin-benzo[b]furan (58); 5-

hydroxy-3-coumarin-naphtho[1,2-b]furan (60) (El-Taweel and Elnagdi, 2001); dicyclopenta[b,d]pyrrole-dione (62); di(3-coumarinoyl)
benzene (64) (Al-Zaydi, 2003) and methylpyridin-2H-chromen-2-ones (65) (Al-Mousawi et al., 2003).

Treatment of 3-acetylcoumarin (5) with paraformalde- disulfide in the presence of triethylamine and DMF at
hyde in the presence of ammonium salts as catalyst, gives room temperature to give the 2H-chromen-propyl-pyridin-
access to intermediate acryloyl arenes (96). The latter com- carbamodithioate (98) in 6 % yield (Fig. 21) (Zhang
bines with 3-(aminomethyl)pyridine (97) and carbon- et al., 2015).
Reaction of 3-Acetylcoumarin: From methods to mechanism 17

Fig. 18 Synthesis of 2H-chromen-carboxylic acid ethyl ester (67); 2-amino-4-coumarin-pyrimidine (68); benzoylisoxazole-2H-chromen-
2-one (70) and 4-coumarin-phenylisoxazolo[3,4-d]pyridazine (71) (Al-Zaydi, 2003).

Fig. 18-1 Mechanism for the synthesis of 2H-chromen-propenylamino-tetrahydrobenzo[b]thiophene-carboxylic acid ethyl ester (67).
18 N. Hosseini Nasab et al.

Fig. 19 Synthesis of chromene-sulfonamide derivatives (73) (Ghorab et al., 2016); acyclic secondary amine derivatives (74); pyrimidine-
2-thione (75); thiazepin-2H-chromen-2-one (77); 2H-chromen-pyrazol-propanenitrile (79) and 2H-chromen-phenyl-dihydropyridine-
carbonitrile (81) (El-Azab et al., 2016).

2.7. Reaction with indoles addition/substitution sequence of 3-acetylcoumarin (5) to N-

substituted indole (99).
Wang et al. (Wang et al., 2016) used FeCl3
6H2O as an readily The proposed mechanism (Wang et al., 2016) is presented
available green catalyst to synthesize tetrasubstituted bis(in- in Fig. 22. FeCl3
6H2O is used to activate 3-acetylcoumarin
dolyl)methanes (100) in 56–99 % yields through a 1,2- (5), which is then trapped by N-substituted indole (99), to go
Reaction of 3-Acetylcoumarin: From methods to mechanism 19

Fig. 20 Synthesis of the thiazolopyrimidine (83); pyridopyrimidine (85); 3-methoxyphenyl-amino-acryloyl)–2H-chromen-2-one (86);

mercapto (87) (Hamama et al., 2011); pyrazolo[1,5-a]pyrimidine (89) (Abdelhamid et al., 2013); couamrin pyridine (91) and 2H-chromen-
nicotinate (93) (El-Taweel and Abou Elmaaty, 2015).
20 N. Hosseini Nasab et al.

Fig. 20-1 Mechanism for the synthesis of compound 88 (Abdelhamid et al., 2013).

Fig. 20-2 Mechanism for the synthesis of compound 93.

through a 1,2-addition process, resulting in intermediate B.
After that, a substitution reaction between intermediate B
and 99 occurs, resulting in the target compound 100 and the
release of the catalyst.
2.8. Reaction with isatin
Kusanur et al. (Kusanur et al., 2004) developed a method for
producing novel 3-coumarinylspiro[indolo-benzodiazepines]
(104) in 69–71 % yields. The reaction is started from 3-
acetylcoumarin (5) and isatin (101), followed by dehydrating
2H-chromen-indolin-2-one (102) and cyclocondensation of
2H-chromen-ethylidene-indolin-2-one (103) with o-
phenylenediamine (Fig. 23).
The antimicrobial and anti-anxiety properties of the pro-
duct were tested in vivo, when R = H, R1 = CH3, 77.77 %
of inhibition against Aspergillus niger as the fungal strain
was observed.
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 21 Synthesis of coumarin with dual dithiocarbamates (95) (Li et al., 2015) and dithiocarbamates (98) (Zhang et al., 2015).
Abbaraju et al. (Abbaraju and Zhao, 2014) investigated
bifunctional quinidine urea catalyst for generating compound
2H-chromen-indolin-2-one (102) in 75–99 % yields with simi-
lar reactants in tetrahydrofuran at 5 °C and 22 h.
2.9. Reaction at 3 and 4 position of 3-Acetylcoumarin
Marko and Rebiere (Marko and Rebière, 1992) designed a
simple synthesis to obtain 4-methyl-3-acetylcoumarin (105).
The [1, 4] Michael addition is used to generate 105 in 70 %
yield from 3-acetylcoumarin (5) and lithium tetramethyl thal-
lium in a diethyl ether medium.
For the development of 4-aroylcoumarin derivatives (107)
in 73–87 % yields, an effective transition metal-free oxidative
cross-dehydrogenative coupling (CDC) reaction was reported
(Adib et al., 2016). Aldehydes (106) are used as acylating
agents to form 3-acetylcoumarin (5) via a C(sp2)–C(sp2) bond.
Application of K2S2O8 as an oxidant and Aliquat 336 (tri-
caprylmethylammonium chloride) to the latter, yields the
desired product (107) in good yields.
21
Reduction-Alkylation of 3-acetylcoumarin (5) with bromo-
propyl benzenes (108) is catalyzed by bisguanidinium (BG)
and polymethylhydrosiloxane (PMHS) as a hydride source in
tert-butyl methyl ether (TBME) for 48 h, forming 3-acetyl-3-
cinnamylchroman-2-one (109) in 69–81 % yields. Further-
more, potassium fluoride is used as fluoride source to activate
silicon hydride (Chen et al., 2020).
The reaction of 3-acetylcoumarin (5) with sodium 1,1-
difluoroethane-1-sulfinate, tert-butyl Hydroperoxide (TBHP)
in dichloromethane and water produce difluoroethyl-3-(1-hyd
roxyethylidene)chroman-2-one (110) in 83 % yield (Fig. 24)
(Gianatassio et al., 2001; Zhou et al., 2013).
A proposed mechanism (Adib et al., 2016) for the forma-
tion of compound 107 is shown in Fig. 24-1. Initially,
potassium peroxodisulfate (K2S2O8) converts Aliquat 336
(A) to methyltrioctylammonium persulfate B. Heating pro-
duces the sulfate radical C, which abstracts the H atom
of an aldehyde (106) to create the acyl radical D. The acyl
radical D then interacts at the b-position of 3-
acetylcoumarin (5) to form radical E. Finally, another sul-
22
Fig. 22 Synthesis and mechanism of tetrasubstituted bis(indolyl)methanes (100) (Wang et al., 2016).
fate radical takes a hydrogen atom from radical E to yield
4-aroylcoumarin 107.
The cycloalkylation-peroxidation product (111) is obtained
in 41–60 % yields by combining 3-acetylcoumarin (5),
cycloalkanes and tert-butyl hydroperoxide (TBHP) in a
three-component reaction. Copper(I) promotes this reaction
via sp3 CAH functionalization with simultaneous generation
of two stereocentres: carbon–oxygen (CAO) and carbon–car-
bon (CAC) bonds are formed (Banerjee et al., 2015b).
The same reaction in the presence of di-tert-butylperoxide
(DTBP) and Fe (III) catalyst, leads to C-3 alkylation (CAC)
of 3-acetylcoumarin (112) in 44–65 % yields (Fig. 25)
(Banerjee et al., 2015a).
For the production of compounds 111 and 112, two possi-
ble mechanisms were proposed (Banerjee et al., 2015a). The
tert-butoxy radical (tBuO) forms when tert-butyl hydroperox-
ide absorbs a proton from cyclohexane, resulting in the forma-
tion of a cyclohexyl radical. Furthermore, the tert-butoxy
radical is converted to a tert-butylperoxy (tBuOO) radical
when it combines with tert-butyl hydroperoxide. The more
nucleophilic tert-butylperoxy (tBuOO) radical attacks the
bulky C-3 carbon of 3-acetylcoumarin (5), forming a stable
a-peroxy benzylic radical (A). Finally, the di-functionalized
product (111) is produced through radical cross-coupling
between the cycloalkyl radical and the peroxybenzylic radical
species (A).
On the other hand, for C-3 alkylation, Fe(III)(acac)3 facil-
itates the cleavage of di-tert-butylperoxide, resulting in the
N. Hosseini Nasab et al.
tert-butoxy (tBuO) radical, which abstracts a proton from
the cycloalkane, yielding the cycloalkyl radical and t-BuOH.
The cycloalkyl radical reacts with the C-3 carbon of 3-
acetylcoumarin (5) to form a coumarin benzylic radical (B).
The acetyl group from (B) is cleaved, regenerating the C3–
C4 double bond to yield the product (112) (Fig. 25-1).
The reaction of 3-acetylcoumarin (5) with the organozinc
reagent in the presence of an iodine catalyst and aided by ultra-
sound irradiation, produce tetrahydrobiscoumarin (113) in
92 % yield. The formation of a radical in the pyran ring, with
the help of the carbonyl group, presents a possible dimeriza-
tion mechanism (Koleva et al., 2018) for biscoumarin forma-
tion (Fig. 26).
The formation of 3-acetyl-4-benzoyl-2H-chromen-2-ones
(114) is achieved in 70–88 % yields from the carbonylation
of 3-acetylcoumarin (5) involving two CAC bond formations
with benzene halides. Using a palladium catalyst under CO
atmosphere, (2,20 -bis(diphenylphosphino)-1,10 -binaphthyl)
(BINAP) and toluene as solvent in the presence of silver acet-
ate promotes the reaction (Mirzaei et al., 2019).
Ruthenium-catalyzed CH alkenylation at the C4 site of 3-
acetylcoumarin (5) with various acrylates (115) in dichlor-
oethane, yields 2H-chromen-4-acrylates (116) in 47–66 %
yields. The additive and oxidation reagents are silver hexaflu-
oroantimonate (AgSbF6) and copper acetate monohydrate
(Cu(OAc)2
H2O), respectively(Wang et al., 2020).
Yuan et al. (Yuan et al., 2016) came up with a protocol for
the direct dehydrogenative radical arylation of 3-
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 23 Synthesis and mechanism of 3-coumarinylspiro-indolo-benzodiazepines (104) (Kusanur et al., 2004).
acetylcoumarin (5) with phenylboronic acid (117) using
KMnO4/CH3CO2H to produce 3-acetyl-4-phenyl-2H-
chromen-2-one (118) in 44 % yield.
The nucleophilic conjugate addition of chiral formaldehyde
N,N-dialkylhydrazones (119) to 3-acetylcoumarin (5) proceeds
smoothly, yielding 3-acetyl-pyrrolidin-1-imino-methyl-cou
marin (120) in 85 % yield (Vázquez et al., 2005).
Furthermore, the reaction of 3-acetylcoumarin (5) with
ethyl-4-amino-4-ethoxybut-2-enoate (121) leads to the for-
mation of ethyl 2-(3-acetylcoumarin)-3-ethoxy-3-iminopro
panoate (122) in 49 % yield (Fig. 27) (Ivanov and Raev,
1986).
23
The proposed mechanism (Mirzaei et al., 2019) starts with
Pd(0) that undergoes oxidative addition with iodobenzene to
form the organopalladium species (A), which coordinates with
CO to give coordinate complex (B). An acylpalladium complex
(C) is obtained via the insertion of carbon monoxide into the
Pd–C bond. Then, carbonyl palladation at the b-position of
3-acetylcoumarin (5) via migratory insertion happens, leading
to the formation of the intermediate D. Product 114 is pro-
duced through b-hydride elimination, removing the H–Pd
(II)–X species (Fig. 27-1).
According to the proposed mechanism (Wang et al., 2020),
in the presence of acetate, silver salt abstracts chloride from the
24 N. Hosseini Nasab et al.

Fig. 24 Synthesis of 4-methyl-3-acetylcoumarin (105) (Marko and Rebière, 1992); 4-aroylcoumarin (107) (Adib et al., 2016); 3-acetyl-3-
cinnamylchroman-2-one (109) (Chen et al., 2020) and difluoroethyl-3-(1-hydroxyethylidene)chroman-2-one (110) (Gianatassio et al., 2001;
Zhou et al., 2013).

Fig. 24-1 Mechanism for the synthesis of 4-aroylcoumarin (107) (Adib et al., 2016).
Reaction of 3-Acetylcoumarin: From methods to mechanism 25

Fig. 25 Reaction of 3-acetylcoumarin (5), cycloalkanes with tert-butyl hydroperoxide and di-tert-butylperoxide(Banerjee et al., 2015b,
2015a).

Fig. 25-1 Mechanism that explains the reaction of 3-acetylcoumarin (5), cycloalkanes with tert-butyl hydroperoxide and di-tert-
butylperoxide (Banerjee et al., 2015a).

[RuCl2(p-cymene)2] complex leading to a cationic and catalyt-
ically active species (A). Then, a five-membered ruthenacycle
(B) is obtained via coordination of the oxygen atom of the
acetyl group of 3-acetylcoumarin (5) to the ruthenium cationic
species followed by C4 metalation. Subsequent insertion of the
alkene of acrylate (115) into the CARu bond of intermediate B
generates intermediate C. The latter undergoes b-hydride elim-
ination to produce the final product (116) (Fig. 27-2).
According to the proposed mechanism (Yuan et al., 2016),
the reaction of boronic acid (117) with Mn(III) salt gives rad-
ical intermediate (A), which attacks the C4-position of 3-
acetylcoumarin (5) to form the carbon radical intermediate
26
Fig. 26 Synthesis and mechanism of tetrahydrobiscoumarin (113) (Koleva et al., 2018).
(B). Subsequently, a single- electron transfer (SET) from the
carbon radical intermediate (B) to Mn(III) forms intermediate
C, simultaneously Mn(III) is reduced to Mn(II). After that, the
elimination of a proton from intermediate C generates the final
product (118) (Fig. 27-3).
2.10. Reaction with N-Trifluoromethylthiosulfonamide
Mono-a-trifluoromethylthiolation of 3-acetylcoumarin (5)
gives access to compound 124 through the condensation of
and N-trifluoromethylthiosulfonamide (123) under acidic con-
ditions and in 76 % yield (Chandak et al., 2016). The second
generation trifluoromethanesulfenamide (123) is a valuable
reagent for producing a-trifluoromethylthiolated carbonyl
compounds.
Furthermore, the reaction of 3-acetylcoumarin (5) and 4-
hydrazino-benzenesulfonamide hydrochloride (125) under
reflux conditions in ethanol produces benzenesulfonamido-
coumarinyl hydrazine (126) in 74 % yield (Chandak et al.,
2016). The proposed mechanism (Alazet et al., 2015) for pro-
ducing compound 124 is presented in Fig. 28.
The benzenesulfonamido-coumarinyl hydrazine (126) is be
a potent inhibitor of tumor-associated hCA IX and XII; and
in comparison with targeted isoforms hCA I and II, pharma-
cophore 126 proved to be the best inhibitor of tumor related
isoforms hCA IX and XII (Chandak et al., 2016).
N. Hosseini Nasab et al.
As shown in Fig. 29, a new sulfonamide and sulfinyl com-
pound (133) is synthesized in 38 % yield. 3-Acetylcoumarin
(5) first reacts with a solution of NaH in benzene and CS2 in
dry DMF for three hours before being added to methyl iodide.
Bis-methylthio-acryloyl-coumarin (127) is obtained in 63 %
yield and is then combined with thiourea and sodium ethoxide
to produce 2,3-dihydropyrimidin-coumarin (128), also in 51 %
yield (Abdel-Motaal and Raslan, 2014).
Compound 128 is reacted with 2-(chloromethyl)-benzo[d]
imidazole (129) and sodium ethoxide for three days to obtain
benzo[d]imidazol-thiopyrimidincoumarin (130). P-
Toluenesulfonylchloride (131) in pyridine is then added to pro-
duce tosyl benzo[d]imidazol-thiopyrimidincoumarin (132) in
94 % yield. The reaction is continued under the reflux condi-
tions in dichloromethane and H2O2 utilizing catalytic amounts
of acetic acid to generate tosyl benzo[d]imidazol-sulfinylpyrimi
dincoumarin (133) (Abdel-Motaal and Raslan, 2014).
Antibacterial (Staphylococcus aureus, Bacillus subtilis,
Escherichia coli, Neisseria lactamica and Salmonella typhi)
and antifungal (Altermaria altermata, Aspergillus terreus and
Fusarium nivale) activities of these compounds were examined.
Compound 133 inhibits the growth of Altermaria altermata
(2.6 cm compared to the growth on control culture 4.15 cm)
and Fusarium nivale (3.1 cm compared to the growth on con-
trol culture 5 cm) (Abdel-Motaal and Raslan, 2014). A short-
coming of this study is that they did not use a control drug.
Reaction of 3-Acetylcoumarin: From methods to mechanism 27

Fig. 27 Synthesis of 3-acetyl-4-benzoyl-2H-chromen-2-one (114) (Mirzaei et al., 2019); 3-acetyl-2-oxo-2H-chromen-acrylates (116)

(Wang et al., 2020); 3-acetyl-4-phenyl-2H-chromen-2-one (118) (Yuan et al., 2016); 3-acetyl-pyrrolidin-1-imino-methyl-coumarin (120)
(Vázquez et al., 2005) and ethyl 2-(3-acetyl-2-oxo-2H-chromen-4-yl)-3-ethoxy-3-iminopropanoate (122) (Ivanov and Raev, 1986).

2.11. Reaction with cyano groups
Tetrahydrochromeno[4,3-a]carbazole-8-carboxylate (135) and
dihydrochromeno[4,3-a]carbazole-8-carboxylate (136) are pro-
duced in 28–63 % yields from the reaction of 3-acetylcoumarin
(5) and methyl 3-(2-cyanophenyl)acrylate (134) (Fig. 30) (Men
et al., 2018).
Fig. 30-1 shows the proposed mechanism (Men et al., 2018)
for this reaction. First, the zwitterionic intermediate A is
formed via the nucleophilic attack of isocyanide 134 on the
3-acetylcoumarin (5). Then cyclization of A produces interme-
diate B, which undergoes a 1,3-proton shift to create the for-
mal product C. The bridging intermediate D is then
produced after an intramolecular Diels-Alder process, which
28 N. Hosseini Nasab et al.

Fig. 27-1 Mechanism for the synthesis of 3-acetyl-4-benzoyl-2H-chromen-2-one (114) (Mirzaei et al., 2019).

Fig. 27-2 Mechanism for the synthesis of 2H-chromen-acrylates (116) (Wang et al., 2020).

Fig. 27-3 Mechanism for the synthesis of 3-acetyl-4-phenyl-2H-chromen-2-one (118) (Yuan et al., 2016).
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 28 Reaction of 3-acetylcoumarin (5) with N-trifluoromethylthiosulfonamide (123) and 4-hydrazino-benzenesulfonamide
hydrochloride (125) (Chandak et al., 2016).
is followed by a CAO scission with a 1.3-proton shift to pro-
duce compound 135. Removal of water produce the final pro-
duct (136).
A Michael reaction of 3-acetylcoumarin (5), followed by a
reaction with cyanoacetylhydrazine (137) and its N-acetyl
and N-propionyl-derivatives in a basic medium, yields 3-
cyanocoumarin (138) in 32–63 % yields (Nemeryuk et al.,
1997).
3-Acetylcoumarin (5) is reacted with malononitrile in the
presence of piperidine to give (2,2-dicyano-1-methylvinyl)cou
marin (139) in 85 % yield (O’Callaghan and McMurry, 1999).
Through the reaction of compound 139 with phenylhy-
drazine; primary aromatic amines; hydrogen sulfide gas; vari-
ous substituted a-cyanocinnamonitriles (143); and sulfur in a
Gewald reaction, imino compound (140); 3-(2,2-dicyano-1-ary
lamino-1-methylethyl)-coumarins (141); 3-(2-cyano-1-methyl-
2-thiocarboxamidovinyl)coumarin (142); 3-(3-amino-2,4-dicya
no-5-arylphenyl)coumarins (144) and 3-(5-amino-4-cyano-3-t
29
hienyl)coumarin (145), respectively, are formed in 50–85 %
yields. Also, acetylation of 145 yields 3-(5-acetamido-4-cyan
o-3-thienyl)coumarin (146) in 85 % yield and the Diels-Alder
reaction of 145 with maleic anhydride in 1,4-dioxane gives 3-
amino-4-cyano-2H-chromen-phthalic anhydride (147), also in
70 % yield (Fig. 31) (Selim, 1998).
Furthermore, compound 145 can also be synthesized from
a one-pot reaction of 3-acetylcoumarin (5), malononitrile
and elemental sulfur in polyethylene glycol-600 (PEG-600) sol-
vent at 100 °C, with L-proline (Srikrishna and Dubey, 2014).
The mechanism for this reaction was reported before
(Kavitha et al., 2019).
The compound (145) is also obtained under microwave
irradiation in a slightly low yields (Yahaya et al., 2019).
3-(20 -Amino-30 -cyano-40 -arylpyran-60 -yl)coumarin (143) is
synthesized from chalcone and malononitrile by fusion with
piperidine under reflux conditions in ethanol (Mourad et al.,
2018).
30 N. Hosseini Nasab et al.

Fig. 29 Synthesis of sulfonamide and sulfinyl compound (133) (Abdel-Motaal and Raslan, 2014).

Fig. 30 Synthesis of tetrahydrochromeno[4,3-a]carbazole (135) and dihydrochromeno[4,3-a]carbazole (136) (Men et al., 2018).

Aydiner et al. (Aydıner et al., 2017) published an efficient strongly fluorescent coumarin-involving 3,5-disubstituted-2,6-
solvent-free, one-pot, three-component synthesis for the dicyanoaniline derivatives (144) under microwave irradiation.
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 30-1 Mechanism for synthesis of the tetrahydrochromeno[4,3-a]carbazole (135) and dihydrochromeno[4,3-a]carbazole (136) (Men
et al., 2018).
At room temperature, L-proline is used as a base in ethanol
to make compound 139, which is then reacted with dimethyl-
formamide dimethyl acetal (DMF-DMA) to form compound
(148). When the latter is reacted with various aliphatic amines,
2-amino-4-(2-oxo-2H-chromen-3-yl)nicotinonitriles (149) are
produced in 68–77 % yields (Fig. 32). Microwave irradiation
ensures 91–98 % yields of these compounds (Srikrishna and
Dubey, 2018a).
Adib et al. (Adib et al., 2018) reported a new multi-
component diastereoselective one-pot synthesis of functional-
ized cyclopenta[c]chromenes (151) in excellent yields. The func-
tionalized cyclopenta[c]chromenes (151) are obtained by
combining compound 139, trimethyl phosphite and diethyl
acetylenedicarboxylate (150) in toluene at room temperature
(Fig. 32).
The mechanism for cyclization of 148 to 149 is proposed
(Srikrishna and Dubey, 2018a) via a series of reactions. First,
a condensation reaction between primary amines and one of
the nitrile groups of enaminonitrile 148 produces intermediate
A. Then the imine anion and the double bond of the enamine
of intermediate A undergoes intramolecular cyclization, fol-
lowed by elimination of dimethylamine. A tautomerization
step completes the reaction, yielding product 149 (Fig. 32-1).
The proposed mechanism (Adib et al., 2018) for the forma-
tion of compound 151 involves the nucleophilic addition of tri-
alkyl phosphite to dialkylacetylenedicarboxylate (150) to form
the zwitterionic intermediate A. Then, the adduct B is formed
via the Michael addition of A to 2-(1-(2-oxo-2H-chromen-3-yl)
31
alkylidene)malononitrile (139). Intramolecular cyclization of
the adduct leads to the corresponding product 151 (Fig. 32-2).
Tamam et al. (Tamam et al., 2005) employed a creative
methodology for the synthesis of new coumarin derivatives
(152; 153; 155 and 156). Treatment of 3-acetylcoumarin (5)
and malononitrile with ammonium acetate as a catalyst, gives
4-aminodihydrocoumarins (152) in 65 % yield. The latter then
forms the 4-amino-3-cyano-benzopyrano[4,3-b]pyridinone
(153) in 66 % yield under reflux conditions in acetic acid.
3-Acetylcoumarin (5) reacts with 3-iminobutyronitrile (154)
and a mixture of ammonium acetate and acetic acid (or a mix-
ture of sodium ethoxide and ethanol), to give benzopyrano
[4,3-b]pyridinone (155) and pyridine-3-carboxylic acid (156),
respectively, in 45 % yields (Tamam et al., 2005).
The corresponding 2-aminopyridine-3-carbonitriles (157)
are generated in 65–82 % yields from a one-pot, four-
component cyclocondensation of 3-acetylcoumarin (5); aryl
aldehydes; malononitrile; and ammonium acetate in the pres-
ence of recyclable FePO4 as a green catalyst (Zadpour and
Behbahani, 2015).
Additional catalytic conditions for the synthesis of 157 can
also be used: Magnetic cellulose/Ag nano biocomposite as a
recyclable heterogeneous nanocatalyst (Maleki et al., 2017);
nanocomposite zinc oxide-decorated superparamagnetic silica
joined to graphene oxide (Fe3O4/SiO2/PTS-GO-ZnO)
(Davoodi et al., 2019); an ionic nanomagnetic catalyst such
as Fe3O4@O2PO2(CH2)2NH+ 3 CF3CO
2
(Karimi et al.,
2019); glacial acetic acid (Fayed et al., 2019) and melamine-
32 N. Hosseini Nasab et al.

Fig. 31 Synthesis of cyanocoumarin (138) (Nemeryuk et al., 1997); dicyanocoumarin (139) (O’Callaghan and McMurry, 1999); imino
compound (140); dicyano-amino-coumarins (141); thiocarboxamidovinylcoumarin (142); dicyano-5-arylphenylcoumarins (144); cyano-
thienylcoumarin (141); acetamido-cyano-thienylcoumarin (146) and 2H-chromen-phthalic anhydride (147) (Selim, 1998).

functionalized chitosan as a bifunctional organocatalyst and when the aromatic ring was replaced with a 2-furyl group,
(Alirezvani et al., 2018). it displayed the same activity than the control drug CHS 828
Compound 157 was tested against six human cancer cell (Hjarnaa et al., 1999) against a breast cancer cell line
lines and normal fibroblasts for in vitro anticancer activity (IC50 = 18 nM) (Mohareb and Abdo, 2015).
Reaction of 3-Acetylcoumarin: From methods to mechanism 33

Fig. 32 Synthesis of 2-amino-2H-chromen-nicotinonitriles (149) (Srikrishna and Dubey, 2018a) and cyclopenta[c]chromenes (151) (Adib
et al., 2018).

Fig. 32-1 Mechanism for the synthesis of 2-amino-2H-chromen-nicotinonitriles (149) (Srikrishna and Dubey, 2018a).

Fig. 32-2 Mechanism for the synthesis of cyclopenta[c]chromenes (151) (Adib et al., 2018).
34
Fig. 33 Reaction of 3-acetylcoumarin (5) with nitrile and amino compounds(Ersßatır et al., 2020; Rohani et al., 2021; Tamam et al., 2005;
Zadpour and Behbahani, 2015).
When 3-acetylcoumarin (5) is treated with malononitrile and
selenium and a catalytic amount of diethylamine at room tem-
perature, it leads to the formation of coumarin-2-aminoseleno
phene–3–carbonitrile (158) in 50 % yield (Ersßatır et al., 2020).
The antitumor activity against MCF-7 cell line of the com-
pound 158 was evaluated. In comparable to standard drug 5-
F-uracil (Longley et al., 2003) (IC50 = 13.5 mM), this com-
N. Hosseini Nasab et al.
pound showed substantial antiproliferative action with IC50
values of 10.84 mM (Ersßatır et al., 2020).
An environmental friendly method for the synthesis of 2-
amino-4H-pyrans (159) in 70–90 % yields involves the treat-
ment of 3-acetylcoumarin (5), aldehydes and malononitrile
derivatives with tungstate sulfuric acid (TSA) as a solid acid
catalyst (Fig. 33) (Rohani et al., 2021).
Reaction of 3-Acetylcoumarin: From methods to mechanism 35

Fig. 34 Synthesis of imidazol-pyrazol-2H-chromen-nicotinonitrile (161) (Kalaria et al., 2014).

Fig. 34-1 Mechanism for the synthesis of imidazol-pyrazol-2H-chromen-nicotinonitrile (161) (Kalaria et al., 2014).
36 N. Hosseini Nasab et al.

Fig. 35 Synthesis and mechanism of 4-aminothieno[2,3-d]pyrimidin-coumarin (163) (Srikrishna and Dubey, 2018b).

Kalaria et al. (Kalaria et al., 2014) combined the 5-

Fig. 36 Synthesis of pyridine-3-carbonitriles (167) (Abdel-aziz
et al., 2019).
imidazopyrazole nucleus and 2-amino-3-cyanopyridine in the
same molecule (161) from a one-pot, four-component cyclo-
condensation reaction of 3-acetylcoumarin (5); malononitrile;
ammonium acetate; and 1H-pyrazole-4-carbaldehyde (160)
via ultrasound irradiation with 81–85 % yields (Fig. 34).
Biological properties like antibacterial, antitubercular and
antioxidant activity of the compounds were also investigated
and they exhibited better activity against gram positive bacte-
ria Bacillus subtilis than ampicillin i.e. 250 mg/mL (Kalaria
et al., 2014).
A mechanism for the synthesis of compound 161 is pro-
posed (Fig. 34-1) (Kalaria et al., 2014). First, Knoevenagel
condensation of aldehyde (160) and malononitrile forms the
alkylidene malononitrile (A). Then, through the reaction of
3-acetylcoumarin (5) and ammonium acetate, imine (B) is pro-
duced. After that, the condensation between compounds A and
B, followed by cycloaddition, isomerization and aromatization
give the targeted compound 161.
Srikrishna and Dubey (Srikrishna and Dubey, 2018b) used
a one-pot reaction to make 2H-chromen-thiophene-3-carboni
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 37 Synthesis of 4-methylsulfanyl-2-oxo-2H-chromene-2H-pyran-3-carbonitrile (169) (Badne and Belsare, 2018).
triles (162) and thieno[2,3-d]pyrimidin-coumarin (163) in 79–
94 % yields. The reaction of 3-acetylcoumarin (5), malononi-
trile and elemental sulfur in polyethylene glycol 600 with a cat-
alytic amount of L-proline produce the thiophene compound
(162). The latter when treated with ammonium acetate and
DMF-DMA at 115–120 °C gives thieno[2,3-d]pyrimidin-
coumarin (163) in 79 % yield (Fig. 35).
They also synthesized compound 163 in 15 min with an
86 % yield using microwave heating. According to the pro-
posed mechanism (Srikrishna and Dubey, 2018b) the nitrogen
supply for pyrimidine ring synthesis is provided by NH4OAc,
which dissociates into AcOH and NH3. Compound A is
attacked by NH3 in a nucleophilic addition process, resulting
in intermediate B. To obtain the desired product 163, the latter
undergoes cyclization with the loss of a dimethylamine
molecule.
The reaction of 3-acetylcoumarin (5) with ethyl formate in
ether involving sodium methoxide leads to the formation of a
novel series of 3-pyridinecarbonitriles (167). In acetic acid con-
taining piperidine acetate, treatment of sodium salt (164) with
the 2-cyano-N’-(1-aryl(heteryl)ethylidene)acetohydrazides
(165) yields product 166 in 78–83 % yields (Fig. 36) (Abdel-
aziz et al., 2019).
4-Methylsulfanyl-2-oxo-2H-chromene-2H-pyran-3-
carbonitrile (169) is produced in 80 % yield from the solid
phase reaction of 3-acetylcoumarin (5) with ethyl-2-
cyano,3,3-bismethyl thioacrylate (168) in the presence of
37
potassium hydroxide. The mixture is grinded at room temper-
ature for 3–4 h (Badne and Belsare, 2018).
The suggested mechanism for the formation of compound
169 involves nucleophilic addition of the methylene group of
3-acetylcoumarin (5) to ethyl-2-cyano,3,3-bismethyl thioacry-
late (168), followed by elimination of methanethiol to afford
intermediate A. Intramolecular nucleophilic attack of the tau-
tomeric hydroxyl group leads to the formation of intermediate
A (A´), followed by elimination of ethanol yielding the final
product (169) (Fig. 37).
A variety of substituted cyanothioacetamides and cyanoac-
etamides can be used to make a series of coumarin pyridi-
nethiones and pyridinones (171). Functionalized pyridine-2-
thione and pyridine-2-one coumarins (171) is produced in
88–99 % yields from the cyclisation of 3-acetylcoumarin (5)
with cyanothioacetamides and cyanoacetamides (170)
(Alharthy et al., 2016).
The proposed mechanism (Alharthy et al., 2016) involves a
1,4-Michael addition of the anionic carbon of 3-
acetylcoumarin (A) to cyanoacetamides (170) to produce inter-
mediate B. Intramolecular nucleophilic attack of the amine to
a carbonyl group of intermediate B, followed by loss of water,
forms the final compound (171) (Fig. 38).
According to the proposed mechanism (Hajos and Riedl,
2003), in the presence of zinc(II)chloride, coumarin-pyrazolo
[1,5-a]pyridine-4-carbonitrile (173) is produced in 70 % yield
from the reaction of 3-acetylcoumarin (5) with 1-
38 N. Hosseini Nasab et al.

Fig. 38 Synthesis and mechanism of pyridine-2-thione and pyridine-2-one coumarins (171) (Alharthy et al., 2016).

Fig. 39 Mechanistic explanation of the synthesis of coumarin-pyrazolo[1,5-a]pyridine-4-carbonitrile (173) (Hajos and Riedl, 2003).
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 40 Synthesis of 4-oxo-4-(2-oxo-2H-chromen-3-yl)but-2-enoic acid (175) (Tolstoluzhsky et al., 2008).
Fig. 41 One-pot reaction of 3-acetylcoumarin (5) with heterylth-
iols (176) and benzothioles (178) (Srikrishna and Kumar Dubey,
2017).
aminopyridinone (172) followed by elimination of water
(Fig. 39).
2.12. Reaction with glyoxylic acid monohydrate
Tolstoluzhsky et al. (Tolstoluzhsky et al., 2008) published an
effective protocol for the synthesis of 4-oxo-4-(2-oxo-2H-
Fig. 41-1 Mechanism for the one-pot reaction of 3-acetylcoumarin (5) with heterylthiols (176) and benzothioles (178) (Srikrishna and
Kumar Dubey, 2017).
39
chromen-3-yl)but-2-enoic acid (175) in 60 % yield. The reac-
tion utilizes with 3-acetylcoumarin (5) and glyoxylic acid
monohydrate (174) in the presence of ytterbium triflate as a
catalyst under microwave irradiation (Fig. 40).
3. Multicomponent reaction of 3-Acetylcoumarin
Poly(ethyleneglycol) 600 (PEG-600) and tetrabutylammonium
tribromide (TBATB) as an effective solvent and efficient green
reagent are used to prepare S-2H-chromen-carbonodithioate
(177) and benzo[d]-thiocetyl-2H-chromen-2-one derivatives
(179) in 80–90 % yields. These products form when 3-
acetylcoumarin (5) reacts with different heterylthiols (176)
and benzothioles (178) (Fig. 41) (Srikrishna and Kumar
Dubey, 2017).
The proposed mechanism (Srikrishna and Kumar Dubey,
2017) for these one-pot reactions is illustrated in Fig. 41-1. A
general bromination agent which can be used in brominations
that are ordinarily performed with molecular bromine is
TBATB. In PEG- 600, TBATB combines with 3-
acetylcoumarin (5) to produce 3-bromoacetylcoumarin (180),
HBr and tetrabutylammonium bromide (TBAB).
3-Bromoacetylcoumarin (180) interacts with phenylth-
ioureas (176), or heterylthiols (178) to yield compounds 177
and 179, respectively. The beauty of this reaction is that
TBATB creates TBAB throughout its reaction, which will
40
Fig. 42 Synthesis of 2H-chromen-phenylpropyl-acetamide (182) (Soumya et al., 2014) and peptidomimetics (187) (Soumya et al., 2017).
remain in the reaction mass and act as a phase transfer cata-
lyst, accelerating the process in-situ.
A one-pot, four-component reaction of 3-acetylcoumarin
(5), benzaldehyde, acetyl chloride and acetonitrile at room
temperature, with phenylboronic acid (181) as a green catalyst,
forms fluorogenic coumarin alkyl amide (182) in 94 % yield
(Soumya et al., 2014).
To obtain 2H-chromen-1-phenylpropyl-propanamide
derivatives (184), a four-component reaction combining an ini-
tial Mannich reaction involving 3-acetylcoumarin (5), aro-
matic aldehydes (106), acetyl chloride and
bromopropionitrile (183), is applied with a catalytic volume
of BF3.Et2O. Replacing the bromine in compound 184 with
N. Hosseini Nasab et al.
an azide group is achieved by sodium azide under in basic solu-
tion to prepare 3-azido-2H-chromen-1-phenylpropyl-propana
mide derivatives (185) (Soumya et al., 2017).
In order to make a peptidomimetics (187) in 80–99 %
yields, click (Kolb et al., 2001) reagents [pyridine alkyne
(186) and coumarin azide (185)] are dissolved in a mixture of
DMSO, t-BuOH and H2O (4:2) containing 0.2 equivalent
CuSO4 and 0.4 equivalent sodium ascorbate and stirred for
12 h (Fig. 42) (Soumya et al., 2017).
The proposed reaction mechanism (Soumya et al., 2017)
starts with the coordination of the carbonyl group of 3-
acetylcoumarin (5) with catalyst to facilitate the formation of
the enolate A´. The addition of aldehyde (106) and acid chloride
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 43 Mechanism that accounts for the formation of 2H-chromen-phenylpropyl-acetamide (182) and 2H-chromen-1-phenylpropyl-
propanamide (184) (Soumya et al., 2017).
to A´ results in a carbon–carbon bond reaction to produce the
b-acyloxy ketone derivative (B). Then, the B replaces with the
more nucleophilic nitrogen of the nitrile to form a stable cation
intermediate (C). The production of the final compounds (182,
184) is aided by the presence of reactive entities such as water
molecules (Fig. 43).
Coumarin-linked nicotinonitrile derivatives (188) are syn-
thesized in the presence of sulfonic acid and Fe3O4@SiO2@
(CH2)3-urea-benzimidazole as a nanomagnetic catalyst. A
one-pot, four-component reaction between 3-acetylcoumarin
(5), various aldehydes (106), malononitrile, or ethyl cyanoac-
etate and ammonium acetate under solvent-free conditions
gives the products (188) in 55–88 % yields (Torabi et al., 2020).
In a similar reaction, using Brønsted acidic ionic liquid and
(4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogen sul-
fate as a catalyst, compound 188 is also obtained (Banothu
et al., 2013).
This reaction proceeds under microwave irradiation in
good yield (Zhou et al., 2009).
41
In a three-component Mannich reaction involving 3-
acetylcoumarin (5), p-substituted aromatic aldehydes (106)
and aromatic amines in ethanol solution, the use of cerium
ammonium nitrate (CAN) (Kenchappa et al., 2013), or zirco-
nium oxychloride (ZrOCl2
8H2O) (Logaiya et al., 2016) as an
effective catalyst results in the formation of b-amino carbonyl
compounds containing coumarin (189) in 75–91 % yields.
The cyclocondensation of 3-acetylcoumarin (5), aldehydes
(106) and urea under solvent-free conditions in the presence
of a catalyst (zirconyl chloride octahydrate supported by silica
gel as an effective and recyclable catalyst) was reported for the
synthesis of substituted 4-aryl-6-(3-coumarinyl)pyrimidinones
(190), in 90–96 % yields (Prasanna et al., 2012).
2,6-Bis(coumarin-4-substitutedphenyl)pyridine derivatives
(191) are synthesized in 75–91 % yields, using two equivalents
of 3-acetylcoumarin (5), one equivalent of aromatic aldehydes
(106) and 1.5 equivalents of ammonium acetate under reflux
conditions in acetic acid (Kenchappa et al., 2017), or under
microwave irradiation (Fig. 44) (Zhou et al., 2012).
42 N. Hosseini Nasab et al.

Fig. 44 Synthesis of coumarin-linked nicotinonitriles (188) (Torabi et al., 2020); b-amino carbonyl compounds (189) (Kenchappa et al.,
2013); 4-aryl-6-(3-coumarinyl)pyrimidinones (190) (Prasanna et al., 2012) and phenylpyridine-bis(2H-chromen-2-one) (191) (Kenchappa
et al., 2017).

Fig. 44-1 shows a proposed mechanism (Banothu et al.,
2013) for the synthesis of coumarin-linked nicotinonitrile
(188). The intermediate A is produced after nucleophilic attack
of ammonia to 3-acetylcoumarin (5). The intermediate aryli-
denemalononitrile (B), is then produced through the reaction
of arylaldehydes (106) with malononitrile. Intermediates A´
and B interact to produce C. The latter undergoes cyclization,
rearrangement and dehydrogenation to produce the final pro-
duct 188.
For the synthesis of three valuable pharmacophores (cou-
marins, pyrazoles and thiazoles) in one scaffold (194), Mah-
moodi and Ghodsi (Mahmoodi and Ghodsi, 2017) outlined a
simple three-component, one-pot, cyclocondensation reaction
of coumarin chalcone (192), thiosemicarbazide (193) and 3-
bromoacetylcoumarin (180) (Fig. 45). This method gives 75–
82 % yields.
The antioxidant, antibacterial and antifungal properties of
the resulting products were evaluated. In comparable to stan-
dard drug ascorbic acid (IC50 = 0.07 mg/mL), when Ar = C6-
H5 (IC50 = 6.16 mg/mL) the worst antioxidant activity was
recorded. When Ar = 2-ClC6H4 showed the best activity
against Staphylococcus aureus and Escherichia coli. Further-
more, Ar = 4-NO2C6H4 was effective against Micrococcus
luteus (Gram-positive bacteria) (Mahmoodi and Ghodsi,
2017).
According to the proposed mechanism (Mahmoodi and
Ghodsi, 2017), the reaction between chalcone (192), thiosemi-
carbazide (193), which is followed by dehydration and intracy-
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 44-1 Mechanism for the synthesis of coumarin-linked nicotinonitriles (188) (Banothu et al., 2013).
Fig. 45 Three-component reaction of chalcone (192), thiosemi-
carbazide (193) and 3-bromoacetylcoumarin (180) (Mahmoodi
and Ghodsi, 2017).
43
clization, forms pyrazolethioamide (A). Then, the isothiourea
(B) is produced upon nucleophilic substitution of the bromine
atom on 3-bromoacetylcoumarin (180) by the S-atom of the
thioamide (A). This is followed by cyclocondensation and
water removal to form the thiazole ring (C).
Surprisingly, in this reaction, dehydrogenation of interme-
diate D is followed by deprotonation of C-4 of the pyrazoline
ring (E) via anchimeric assistance, resulting in formation of the
aromatic pyrazole (F). Target product 194 is formed under the
acidic reaction conditions when the nitrogen of the pyrazole
ring is protonated (Fig. 45-1).
Some donor (D)–acceptor(A) type hydrazinyl thiazolyl
coumarins (HTCs) (196) are synthesized in 90–98 % yields
via the condensation reaction of 3-bromoacetylcoumarin
(180), aromatic aldehydes/ketones (106, 195) and thiosemicar-
bazide (193), which is catalyzed by montmorillonite (MMT)
K10 clay in a water solution at room temperature (Godugu
et al., 2020).
A proposed mechanism (Godugu et al., 2020) for the cre-
ation of HTCs (196) in the presence of MMT K10 clay is pre-
sented in Fig. 46. In water, diimine (A) is formed when the two
NH2 groups of thiosemicarbazide (193) react with the K10
clay-activated carbonyl group of both the aldehyde/ketone
(106, 195) and 3-bromoacetylcoumarin (180). The clay then
stimulates internal SN2 displacement of the diimine bromide
ion (A) to generate dihydro HTCs (B), which is followed by
a proton shift to obtain HTCs (8 3 7).
Suresh et al. (Suresh et al., 2016) used the ionic liquid 1-
butyl-3-methylimidazolium hydrogen sulfate [Bmim]HSO4 as
44
Fig. 45-1 Mechanism for the three-component reaction of chalcone (192), thiosemicarbazide (193) and 3-bromoacetylcoumarin (180)
(Mahmoodi and Ghodsi, 2017).
the reaction medium for the three-component reaction
between 3-acetylcoumarin (5), dimethylformamide-dimethyla
cetal (DMF-DMA) (197) and 5-aminotetrazole (198) to pro-
duce tetrazolo[1,5-a]pyrimidin-2H-chromen-2-one (199) in
88 % yield (Fig. 47).
According to the proposed mechanism (Suresh et al., 2016),
a,b-unsaturated ketone intermediate A is formed by the con-
densation of 3-acetylcoumarin (5) with N,Ndimethylfor-
N. Hosseini Nasab et al.
mamide dimethylacetal (197). Intermediate A combines with
5-aminotetrazole (198) to generate intermediate B, which then
loses dimethyl amine to form intermediate C. Finally, interme-
diate C undergoes keto-enol tautomerization, followed by
cyclization and elimination of water to provide product 199.
Indole-triazole-coumarin hybrids (201 and 203) were syn-
thesized in 81–86 % yields, by Pathoor and Bahulayan
(Pathoor and Bahulayan, 2018), as potential CDK2 inhibitors.
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 46 Synthesis and mechanism of hydrazinyl thiazolyl coumarins (HTCs) (196) (Godugu et al., 2020).
To create the indole-triazole-coumarin hybrid pep-
tidomimetics, they devised a four-step synthetic route. The
reaction of 3-acetylcoumarin (5), aromatic aldehydes (106)
and 3-bromopropanenitrile (183) in acetonitrile with copper
(II) sulfate as a catalyst results in the b-amidoketonebromide
(184). Treatment of 184 in dimethylacetamide with potassium
carbonate and sodium azide produces compound 185.
In the presence of CuSO4
5H2O and sodium ascorbate,
compound 185 participates in a 1,3-dipolar cycloaddition reac-
tion with 1-prop-1H-indole-3-carbaldehydes (200 and 202) to
form indole-triazole-coumarin hybrids (Fig. 48) (Pathoor and
Bahulayan, 2018).
Cytotoxicity studies of these compounds were conducted
against human breast cancer cell line (MCF-7) and the results
revealed that compound 201 with R = 2-Cl displays the best
activity (IC50 = 17.5 lM) (Pathoor and Bahulayan, 2018).
Compound (206) is obtained in 73 % yield from a one-pot,
solvent-free solid support reaction of 3-acetylcoumarin (5); 2-
cyanoacetohydrazide (204); ferrocenyl dialdehyde (205); and
45
Rice Husk Ash (RHA), as the solid support (Fig. 49)
(Ghosh et al., 2019).
Antibacterial and redox properties were also investigated
and good inhibitory activities against Bacillus subtilis and
Pseudomonas aeruginosa bacterial strains were exhibited
(Ghosh et al., 2019).
To produce coumarinyl-triazolo-triazines (208) in 90–94 %
yields, organoiodine (III) [hydroxy(tosyloxy)iodo]benzene
(HTIB, Koser’s reagent) mediated a one-pot reaction between
3-acetylcoumarin (5) and 5-phenyl-3,4-diamino-1,2,4-triazole
(207) (Pundeer and Kiran, 2016).
According to the proposed mechanism (Pundeer and Kiran,
2016), HTIB attacks 3-acetylcoumarin (5) to generate interme-
diate A. Tosylate derivatives (B) is obtained from the SN2
attack of TsOH and elimination of water and iodobenzene.
The attack of the amino group of the triazole (207) results in
nucleophilic substitution of 3-(-tosyloxyacetyl)-coumarins
(B), forming intermediate C. Intermediate C undergoes nucle-
ophilic intramolecular attack, resulting in intermediate D,
46
Fig. 47 Synthesis and mechanism of fused tetrazolo[1,5-a]pyrimidin-2H-chromen-2-one (199) (Suresh et al., 2016).
which is followed by the loss of a water molecule and aerial
oxidation to obtain triazolotriazines 208 (Fig. 50).
Shahcheragh et al. (Shahcheragh et al., 2017) designed a
one-pot, three-component route for the synthesis of novel
1,3,4-thiadiazole derivatives (211 and 213) in 65–68 % yields
using 3-acetylcoumarin (5), a ketene S,S-acetal (210 and
212) and thiocarbohydrazide (209) with choline chloride
and urea.
The proposed mechanism (Shahcheragh et al., 2017)
involves the reaction of thiocarbohydrazide (209) and 3-
acetylcoumarin (5) to form the thiocarbohydrazone (A). Then,
condensation of thiocarbohydrazone (A) with ketene-S,S-
acetal (210, or 212) takes place in two stages. An aza-
Michael addition of the thiocarbohydrazone nitrogen to the
ketene-S,S-acetal is followed by methanethiol elimination to
give intermediate (B), which then undergoes intramolecular
N. Hosseini Nasab et al.
cyclization and removal of the second methanethiol group to
give 211 and 213 (Fig. 51).
The 2H-chromen-4-yl-2H-chromen-3-yl-isophthalonitrile
(215) is obtained in 95 % yield, using a one-pot, three-
component reaction involving 3-acetylcoumarin (5), 4-formyl
coumarin (214) and malononitrile in 1:1 aqueous ethanol at
room temperature in the presence of triethylamine (Fig. 52)
(Kulkarni et al., 2016).
The first step of the proposed reaction mechanism
(Kulkarni et al., 2016) involves the Knoevenagel condensation
between the aldehyde (214) and 3-acetylcoumarin (5) with
malanonitrile to obtain adducts A and B. Further, Michael
addition of C to arylidenemalonodinitriles A gives intermedi-
ate D. Intramolecular nucleophilic attacks of the methylene
nitrile anion D to nitrile undergoes Thorpe–Ziegler cyclization
to make the highly substituted cyclohexadiene system F. The
Reaction of 3-Acetylcoumarin: From methods to mechanism 47

Fig. 48 Synthesis of indole-triazole-coumarin hybrids (201 and 203) (Pathoor and Bahulayan, 2018).

Fig. 49 Synthesis of 1,10 -[HC(O)(g5-C5H4) Fe{(g5-C5H4)CH‚C(CN)C(O)N(H)N‚C (CH3) coumarin] (206) (Ghosh et al., 2019).
48
Fig. 50 Synthesis and mechanism of coumarinyl-triazolo-triazines (208) (Pundeer and Kiran, 2016).
intermediate F undergoes aromatization to yield the polysub-
stituted 2,6-dicyanoanilines 215 (Fig. 52-1).
For the synthesis of a library of coumarin-tagged macrocy-
cles with ring sizes ranging from 11 to 18, a three-step ‘MCR-
Click’ strategy was developed. 2-Coumarin amidoalkyne (184)
is formed in reasonable to 65–74 % yields, when 3-
acetylcoumarin (5) reacts with propargyl derivative of 2-
hydroxy benzaldehyde (106), 2-bromoacetonitrile (183), acetyl
chloride and BF3.OEt2. Then coumarin amidoalkyne (180),
K2CO3, sodium azide, dimethyl acetamide is reacted at room
temperature (Raj and Bahulayan, 2017).
The obtained acetamide (185) dissolves in t-BuOH/ water/
DMSO (4:2:1) and sodium ascorbate and Cu(II) sulfate pen-
tahydrate are added and stirred for 48 h (Fig. 53). Macrocycles
216 are isolated in 64–73 % yields.
The one-pot reaction of 3-acetylcoumarin (5), thiosemicar-
bazide (193) and various phenacylbromides (217), with the
methylimidazole propanesulfonic acid trifluoroacetic acid
(MIMPS-CF3COOH) forms arylthiazol-hydrazono-2H-
chromen-2-one (218) in 83–93 % yields (Fig. 54) (Dongnuan
et al., 2012).
N. Hosseini Nasab et al.
The reaction of 3-acetylcouamrin (5) and tert-butyl iso-
cyanide (219) is identified as a one-pot, three-component reac-
tion for the synthesis of pyrrole-fused chromanone (220) in
64 % yield (Ghandi et al., 2013).
According to the proposed mechanism (Ghandi et al.,
2013), when 2-aminofuran (A) is formed as the first product,
it quickly interacts with triplet oxygen to produce hydroperox-
ide (B) and molozonide C, respectively. Intermediate C breaks
into compound D in a similar way to the well-known classical
ozonalysis (Smith and Kulig, 1976) reaction. Rapid conversion
of D yields E and eventually hydroxyamide 220 forms
(Fig. 55).
A three-component reaction of cyclic diazoamide (221 and
223) and aldehydes (106) with 3-acetylcoumarin (5) and 3 mol
% of Rh2(OAc)4 was reported for the synthesis of spirooxin-
dolylfurocoumarins (222) and furocoumarins (224) in 78–
88 % yields (Fig. 56) (Karthik et al., 2014).
The proposed mechanism (Karthik et al., 2014) involves
Huisgen’s cycloaddition reaction. Initial intramolecular hydro-
gen bonding between the cyclic carbenoid A and the aromatic
aldehyde (106), stabilizes the carbonyl ylide B. The desired
Reaction of 3-Acetylcoumarin: From methods to mechanism 49

Fig. 51 Synthesis and mechanism of 1,3,4-thiadiazole derivatives (211 and 213) (Shahcheragh et al., 2017).

Fig. 52 Synthesis of 2H-chromen-4-yl-2H-chromen-3-yl-isophthalonitrile (215) (Kulkarni et al., 2016).

50
Fig. 52-1 Mechanism for the synthesis of 2H-chromen-4-yl-2H-chromen-3-yl-isophthalonitrile (215) (Kulkarni et al., 2016).
product (222, or 224) is obtained through cycloaddition reac-
tion of B with 3-acetylcoumarin (5) via a five-membered cyclic
transition state C (Fig. 56-1).
A simple and efficient one-pot reaction of 3-acetylcoumarin
(5), phenyltrimethylammonium tribromide (PTT) and sodium
azide in ionic liquid [bmim][BF4] forms 3-(2-azidoacetyl)–2H-
chromen-2-one (225) in 92 % yields (Kumar et al., 2009).
The proposed mechanism (Kumar et al., 2009) is shown in
Fig. 57.
The reaction of 3-acetylcoumarins (5) with alloxan mono-
hydrate (226) and hydrazine hydrate in acetic acid, results in
an easy and simple and versatile one-pot synthesis of
N. Hosseini Nasab et al.
pyrimido[4,5-c]pyridazine (227) in 84 % yield (Rao and
Reddy, 2005). The suggested mechanism for the formation of
227 involves a reaction between 3-acetylcoumarins (5) and
hydrazine hydrate, followed by elimination of a water mole-
cule to form compound A. The latter reacts with alloxan
monohydrate (226), cyclisation and the loss of two water mole-
cules to produce the final compound (227) (Fig. 58).
Nemeryuk et al. (Nemeryuk et al., 2005, 2000) documented
the one-pot synthesis of 2-hydroxybenzylidene-coumarin-3-car
bohydrazide (229); N’-(propan-2-ylidene)–2H-chromene-3-
carbohydrazide (231); and N’-acetyl-2-oxo-2H-chromene-3-
carbohydrazide (233) in 65–78 % yields, from 3-
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 53 Synthesis of coumarin amidoalkyne (184) and macrocycles (216) (Raj and Bahulayan, 2017).
Fig. 54 Synthesis of arylthiazol-hydrazono-2H-chromen-2-one (218) (Dongnuan et al., 2012).
acetylcoumarin (5) and malonic acid dihydrazide (228); diiso-
propylidene malonic acid dihydrazide (230); and diacetyl
malonic acid dihydrazide (232), in the presence of piperidine,
respectively (Fig. 59).
The formation of 3-(2-oxo-2H-chromen-3-yl)-indeno[2,1-c]
pyridazin-9-ones (235) in 94 % yield from a one-pot reaction
of 3-acetylcoumarins (5) with ninhydrin (234) and hydrazine
hydrate in acetic acid, was reported (Rao and Kumar, 2005).
According to the proposed mechanism (Rao and Kumar,
2005), 3-acetylcoumarin (5) reacts with ninhydrin (234) to pro-
duce the corresponding intermediate aldol adduct (A). Then
intermediate A reacts with hydrazine hydrate with the loss of
two water molecules, to produce the final compound (235)
(Fig. 60).
4. Cycloaddition and Diels-Alder reactions
In tetrahydrofuran (THF) as solvent, the [3 + 2] cycloaddition
reaction of the electron-deficient 3-acetylcoumarin (5) and
isopropyl-dimethyl-phenyl-dioxaspiro[2.5]oct-carboxylate
(236) as acetal, takes place. The only product of this reaction is
51
compound 237, which is formed in a 70 % yield. The resulting
cycloadduct is useful as an intermediate in organic synthesis
(Fig. 61) (Tokuyama et al., 1992).
Amanpour et al. (Amanpour et al., 2015) presented two
examples of different solvents for the [4 + 1] cycloaddition
reaction of 3-acetylcoumarin (5) and cyclohexyl isocyanide
(238). When the reaction is accomplished in toluene, or ethanol
under microwave irradiation, cyclohexylimino-3-hydroperoxy-
furo[3,4-c]chromen-4-one (239); ketoamide (240); and 5-
hydroxy-pyrrolidone (241) are formed in 6–70 % yields
(Fig. 62). The mechanism for this reaction was reported before
(Ghandi et al., 2013).
Inokuchi et al. (Inokuchi et al., 2000) published a simple
and efficient one-pot, Diels-Alder reaction strategy for the syn-
thesis of annulated enones (243), in 79 % yield, employing 3-
acetylcoumarin (5), 1-methoxy-3-trimethylsiloxy-1,3-butadiene
(242) and Yb(OTf)3 as Lewis acid catalyst.
Lanari et al. (Lanari et al., 2011) examined another Diels-
Alder reaction between 3-acetylcoumarin (5) and 2,3
dimethyl-1,3-butadiene (244) in the presence of hafnium chlo-
ride to obtain diastereoselective tetrahydrobenzo[c]chrome-
52
Fig. 55 Synthesis and mechanism of pyrrole-fused chromanone (220) (Ghandi et al., 2013).
nones (245) in 96 % yield, without any solvent. Tetrahy-
drobenzo[c]chromenones (245) are converted to tetrahydro-
6H-benzo[c]chromen-6-ol (246) in 88 % yield, in the presence
of tetrabutylammonium fluoride (TBAF) and tetrahydrofuran
(THF).
The [4 + 2] cycloaddition reaction of 3-acetylcoumarin (5)
and ethyl 2,3-butadienoate (247) is catalyzed by 1,4-
diazabicyclo[2.2.2]octane (DABCO), leading to the formation
of dihydropyran-fused chromen-2-one (248) in 87 % yield(Y.
Wang et al., 2012).
N. Hosseini Nasab et al.
Novel dihydrocoumarin-fused dihydropyran (250) with
privileged enantioselectivities is formed in 94 % yield, in the
presence of the dipeptide-based bifunctional phosphine as a
catalyst via a [4 + 2] annulation process involving 3-
acetylcoumarin (5) as C4-synthons and 2-methyl-
phenylbutadien-1-one (249), as C2-synthons (Fig. 63) (Han
et al., 2016).
The proposed mechanism (Lanari et al., 2011) for convert-
ing 245 to 246 is presented in Fig. 63-1. The ring-opening reac-
tion is caused by a competitive assault of the hydroxyl group
Reaction of 3-Acetylcoumarin: From methods to mechanism
Fig. 56 Synthesis of spirooxindolylfurocoumarins (222) and furocoumarins (224) (Karthik et al., 2014).
Fig. 56-1 Mechanism that accounts for the formation of
spirooxindolylfurocoumarins (222) and furocoumarins (224)
(Karthik et al., 2014).
on the lactonic moiety of 245, generating intermediate (A),
which is then transformed into the appropriate trans-
substituted cyclohexene by decarboxylation (B) after decar-
boxylation. The pyran ring is formed through a hemiketaliza-
tion process in the final step, yielding 246.
According to the proposed mechanism(Y. Wang et al.,
2012), DABCO is reacted with 2,3-butadienoate (247) to
produce the zwitterion A, in which the c-position carbanion
attacks the b-carbon of 3-acetylcoumarin (5) to produce
intermediate B. Intermediate B undergoes intramolecular
cyclization via nucleophilic substitution at the b-carbon of
the a,b-unsaturated ester, followed by elimination of
DABCO, to produce the [4 + 2] cycloadduct 248
(Fig. 63-2).
53
Benzocoumarin is a structural motif, which is found in nat-
ural products with remarkable bioactivities including as anal-
gesic action (Martin and Lichtman, 1998). 3,4-Benzo-
coumarins (252) is synthesized in 56–82 % yields, from the
[4 + 2] process of the 2-acetylcoumarin (5) and unsaturated
aldehydes (251) with air as the green oxidant and anhydrous
chloroform in basic medium (Fig. 64) (Mou et al., 2016).
According to the proposed mechanism (Mou et al., 2016),
in the presence of a base, deprotonation of the c-CH group
from the enal substrate 251 yields the dienolate intermediate
A. The enal c-carbon of intermediate A is added to 3-
acetylcoumarin (5) in a Michael-type reaction to generate
intermediate B, which then undergoes an intramolecular aldol
reaction to form the tricyclic intermediate C. Intermediate D is
formed as a result of intramolecular acetal formation. After
elimination of an acetate from D, intermediate E undergoes
spontaneous oxidative aromatization (with air as the oxidant)
to generate the 3,4-benzocoumarin product 252 (Fig. 64-1).
The tandem reaction of 3-acetylcoumarin (5) with
dimethylsulfoxonium methylide in DMF, or DMSO produces
novel cyclopenta[b]benzofuran (254) in 8 % yield. It is
obtained through the reaction of intermediate 253 with 1.1
equiv. of dimethylsulfoxonium methylide (Yamashita et al.,
2002).
Flores-Larios et al. (Flores-Larios et al., 2010) used a
[4 + 2] cycloadditions reaction of 3-acetylcoumarin (5) and
2,3-dimethyl-1,3-butadiene (244) under thermal, solvent-free
conditions to produce tetrahydro-6H-benzo[c]chromenone
(245) in 83 % yield. Epoxidation of compound 245 with m-
chloroperbenzoic acid (255) under reflux conditions in chloro-
form produce oxireno-benzo[1,2-c]chromen-6-one (256) in
70 % yield.
The diastereoselective cyclopentene (258) is synthesized in
58 % yield, through the reaction of the 3-acetylcoumarin (5)
and allenylboronic ester (257) with palladium as a catalyst
(Kohn and Jarvo, 2011).
54 N. Hosseini Nasab et al.

Fig. 57 Synthesis and mechanism of 3-(2-azidoacetyl)–2H-chromen-2-one (225) (Kumar et al., 2009).

Fig. 58 Synthesis and mechanism of pyrimido[4,5-c]pyridazine (227) (Rao and Reddy, 2005).
Reaction of 3-Acetylcoumarin: From methods to mechanism 55

Fig. 59 Synthesis of 2-hydroxybenzylidene-coumarin-3-carbohydrazide (229) (Nemeryuk et al., 2000); N’-(propan-2-ylidene)–2H-

chromene-3-carbohydrazide (231) and N’-acetyl-2-oxo-2H-chromene-3-carbohydrazide (233) (Nemeryuk et al., 2005).

Fig. 60 Synthesis and mechanism of coumarin-indeno-[2,1-c]pyridazin (235) (Rao and Kumar, 2005).
56
Fig. 61 Synthesis of spiro[cyclopenta[c]chromene-3,20 -[1,3]dioxane]-1-carboxylate (237) (Tokuyama et al., 1992).
Fig. 62 Reaction of 3-acetylcoumarin (5) with cyclohexylisocyanide (238) (Amanpour et al., 2015).
The tetrahydrochromeno[3,4-c]pyrrol-4-one (260) is gener-
ated in 32 % yield via the [3 + 2] cycloaddition reaction of
the 3-acetylcoumarin (5), sarcosine (259) and formaldehyde
in anhydrous benzene (Buev et al., 2017).
Compound 260 is also obtained under reflux conditions in
o-xylene with spiroanthraceneoxazolidines instead of sarcosine
(Buev et al., 2016).
The [3 + 2] cycloaddition reaction of 3-acetylcoumarin (5)
with tosylmethyl isocyanides (261) in ethanol at room temper-
ature is accomplished, to form chromeno[3,4-c]pyrrol-4-one
(262) in 86 % yield (Fig. 65) (Shaabani et al., 2018).
A [3 + 2] cycloaddition reaction of 3-acetylcoumarin (5),
isatin (101) and sarcosine (263) under reflux conditions in
toluene and methanol is accomplished, to form tricyclic-
fused chromeno[3,4-c]spiropyrrolidine-oxindoles (264 and
265) in 68–83 % yields (Fig. 66) (Ghandi et al., 2010).
Fig. 66-1 shows the proposed mechanism (Ghandi et al.,
2010) for the target compounds 264 and 265. In case of com-
pound 265 the results indicate that the [3 + 2] cycloaddition
N. Hosseini Nasab et al.
in methanol is followed by deacetylation related to methanol’s
nucleophilic attack on the COMe group.
Yamashita et al. (Yamashita et al., 2006) investigated the
[2 + 2] photocycloaddition reaction between 3-
acetylcoumarin (5), styrene (266) and phenylacetylene (268)
to make tetrahydro-cyclobuta[c]chromen-3-one (267) and
dihydro-cyclobuta[c]chromen-3-one (269) in 91–92 % yields.
In addition, compound 269 is hydrogenated with Pd-C to pro-
duce 1R,2aS,8bS-tetrahydro-cyclobuta[c]chromen-3-one (270)
(Fig. 67).
The rhodium(III) catalytic system is used to develop an
effective, scalable method for producing chromeno[3,4-c]pyri-
dine frameworks (273) via redox-neutral [4 + 2] annulation
in 29–81 % yields, between coumarinyl ketoxime esters (272)
and internal alkynes (271). Reaction of 3-acetylcoumarin (5),
hydroxylamine hydrochloride and acetic anhydride forms the
coumarinyl ketoxime esters (271) (Li et al., 2019).
According to the proposed mechanism (Li et al., 2019), ini-
tially, orthoACAH rhodation of coumarinyl oxime ester (272)
Reaction of 3-Acetylcoumarin: From methods to mechanism 57

Fig. 63 Synthesis of annulated enones (243) (Inokuchi et al., 2000); tetrahydro-6H-benzo[c]chromen-6-ol (246) (Lanari et al., 2011);
dihydropyran-fused chromen-2-one (248) (Y. Wang et al., 2012) and dihydrocoumarin-fused dihydropyran (250) (Han et al., 2016).

occurs with the chelating aid of oxime ester sp2 nitrogen to
produce (2-oxo-2H-chromen-4-yl)rhodium intermediate A.
When A adds to the alkyne, it produces the rhodacyclic imi-
nium cation species B. The intermediate B then undergoes a
concerted redox cyclization process to produce chromenopy-
ridine 273 and regenerate the rhodium(III) species (Fig. 68).
Trost et al. (Trost et al., 2020) proposed a method for cat-
alytic, asymmetric [3 + 2] cycloadditions that takes advantage
of the peculiar charge distribution of p-allyl palladium com-
plexes to produce neighboring a-trifluoromethyl carbanions.
In tetrahydrofuran, 3-acetylcoumarin (5) and tert-butyl(4,4,4-
trifluoro-2-methylenebutyl) carbonate (274) is reacted with
the pre-catalyst (PdCpAllyl) and ligand (L) to generate 3-ace
tyl-2-methylene-1-(trifluoromethyl)-tetrahydrocyclopenta[c]
chromen-4(1H)-one (275) in 66 % yield (Fig. 69).
An energy-transfer protocol for the intermolecular [2 + 2]
cycloaddition reaction between 3-acetylcoumarin (5) and acry-
lamide (276) is achieved at room temperature using visible
light. Cyclobutabenzocypyranones (277 and 277´) are prepared
in 23–46 % yields, using an iridiumcomplex FIrPic as a photo-
sensitizer and a 3 W blue LED as the light source (Fig. 70) (Liu
et al., 2015).
5. a-Halogenation of 3-Acetylcoumarin
A regioselective halogenation process involving 3-
acetylcoumarin (5) and sodium chloride (or sodium bromide)
as the halogen source and potassium peroxymonosulfate (ox-
one) as an oxidant in a mixture of acetonitrile/water, was
58 N. Hosseini Nasab et al.

Fig. 63-1 Mechanism for the synthesis of compound 246 (Lanari et al., 2011).

Fig. 63-2 Mechanism for the synthesis of compound 248 (Y. Wang et al., 2012).

reported by Vanammoole et al. (Vanammoole et al., 2020).
This reaction leads to the formation of 3-(2-chloro/bromoace
tyl)–2H-chromen-2-one (180, 278) in 89–92 % yields.
The proposed radical mechanism (Prebil and Stavber,
2014a) of this reaction is shown in Fig. 71. Oxone (KHSO5)
decomposes into a hydroxyl ion and a sulfate radical while
heated. Following that, the stable intermediate A is formed
by adding the Cl. radical, which originates from NaCl in the
presence of OH. radical. The intermediate A is then cleaved
at the OAH bond to yield the final product 278.
3-Acetylcoumarin (5) is iodinated efficiently and selectively
in acetonitrile using a novel four-component reaction system
consisting of air/NH4NO3(cat.)/I2/H2SO4(cat.) to give
iodoacetyl-2H-chromen-2-one (279) in 90 % yield (Prebil and
Stavber, 2014b).
From the proposed mechanism (Prebil and Stavber, 2014b),
in catalytic cycle A, the enol form of the 3-acetylcoumarin (50 )
is iodinated with I2 at the alpha position and I2 is reduced to
HI. Catalytic cycle B illustrates the re-oxidation of iodide to
I2 using NO2. When NO2 completes the oxidation of iodide,
it is reduced to NO, whereas the oxidation of NO to NO2 is
achieved with aerial oxygen (Fig. 72).
6. Aldol condensation of 3-Acetylcoumarin
At room temperature, an aldol reaction is carried out between
two molecules of 3-acetylcoumarin (5) in the presence of piper-
idine and methanol as a solvent to from compound 280
(Stanchev and Manolov, 2014).
Reaction of 3-Acetylcoumarin: From methods to mechanism 59

Fig. 64 Synthesis of benzocoumarin (252) (Mou et al., 2016).

Fig. 64-1 Mechanism that explains the synthesis of benzocoumarin (252) (Mou et al., 2016).
60 N. Hosseini Nasab et al.

Fig. 65 Synthesis of cyclopenta[b]benzofuran (254) (Yamashita et al., 2002); benzo[1,2-c]chromen-6-one (256) (Flores-Larios et al.,
2010); tricyclic lactone (258) (Kohn and Jarvo, 2011), tetrahydrochromeno[3,4-c]pyrrol-4-one (260) (Buev et al., 2017) and chromeno[3,4-
c]pyrrol-4-one (262) (Shaabani et al., 2018).

Fig. 66 Synthesis of chromeno[3,4-c]spiropyrrolidine-oxindoles (264 and 265) (Ghandi et al., 2010).

Reaction of 3-Acetylcoumarin: From methods to mechanism 61

Fig. 66-1 Mechanism for the formation of compound 264 and 265 (Ghandi et al., 2010).

Fig. 67 Photocycloaddition reaction of 3-acetylcoumarin (5) and olefins (266 and 268) (Yamashita et al., 2006).
62 N. Hosseini Nasab et al.

Fig. 68 Synthesis and mechanism of chromeno[3,4-c]pyridines (273) (Li et al., 2019).

Fig. 69 Synthesis of 3-acetyl-2-methylene-1-(trifluoromethyl)-tetrahydrocyclopenta[c]chromen-4(1H)-one (275) (Trost et al., 2020).

Reaction of 3-Acetylcoumarin: From methods to mechanism 63

Fig. 70 Synthesis of cyclobutabenzocypyranones (277 and 277´) (Liu et al., 2015).

Fig. 71 Synthesis and radical mechanism to form 3-(2-chloro/bromoacetyl)–2H-chromen-2-one (278) (Prebil and Stavber, 2014a).

According to the proposed mechanism (Stanchev and
Manolov, 2014), the enol version of the initial compound
self-condenses into biscoumarins of the aldol type (A), which
then dehydrates to provide unsaturated 3,30 -(1-oxobut-2-ene-
1,3-diyl)bis(2H-chromen-2-one) (280) (Fig. 73).
7. Reduction of 3-Acetylcoumarin
The reagent 1,4-dihydropyridine (HEH) is useful for the
chemoselective reduction of 3-acetylcoumarin (5) to 3-
acetylchroman-2-one (284) in 92 % yield (Liu et al., 2006).
The use of 2-phenylbenzimidazoline (285) as an effective
reagent allows for the chemoselective reduction of 3-
acetylcoumarin (5) to dihydro derivatives (284) in 85 % yield
(Fig. 75) (Risitano et al., 2001).

As shown in Fig. 74, the secondary alcohol (281) is formed in
82 % yield when the 3-acetylcoumarin (5) is reduced under
Luche’s conditions (NaBH4, CeCl3). Bromination of 281 with
PBr3 generates bromocoumarin (282). Finally, compound 282
combines with cyclen to produce tetraazacyclododecan-2H-
chromen-2-one (283) in 93 % yield (Lim et al., 2005).
8. 1,2-Addition to 3-Acetylcoumarin
The addition of allyl iodide to 3-acetylcoumarin (5) with In/
InC13 as catalyst results in a 85 % yield of the 1,2-addition
component (286). This reaction is carried out in DMF, which
ensures optimum reaction time (30 min) and increased the
64
Fig. 72 Synthesis and mechanism of iodoacetyl-2H-chromen-2-
one (279) (Prebil and Stavber, 2014b).
yield (99 percent) (Yeon Kim et al., 2003). The suggested
mechanism based on Reformatsky reaction is presented in
Fig. 76.
Fig. 73 Aldol reaction of 3-acetylcoumarin(Stanchev and Manolov, 2014). (No yield was reported).
N. Hosseini Nasab et al.
9. Future directions
The diverse biological applications of 3-acetylcoumarin
derivatives leads to design and synthesis of more advanced
classes of coumarin units for various medical and industrial
applications. A variety of structures have been synthesized
using different methods and reactions due to the versatile
substitution options for the coumarin moiety. Despite using
different conditions in these reactions, improving the applied
methods via incorporating greener protocols, inexpensive
starting materials, new catalysts and efficient reaction condi-
tions seem essential for future development. Some optimized
condition reactions should be considered as a main future
perspective in order to decrease the cost, development time,
separation methods, and environmental impact of synthesis.
The relationship between structure and active biological
activity should be studied to provide some insights into the
mechanism of action of the most biologically active com-
pound and avoid the synthesis of inactive compounds. Some
research findings struggled with a lack of derivatization, lim-
iting the accurate Quantitative Structure-Activity Relation-
ship (QSAR), and more research is needed to fully
comprehend the biological mechanisms. Future research pur-
poses for this field of study include the discovery, synthesis,
and development of compounds with increased potency, rec-
ognizing the modes of action of the most biologically active
members of these classes of products, using organocatalysts,
enantioselectivity, better purification methods such as super
Reaction of 3-Acetylcoumarin: From methods to mechanism 65

Fig. 74 Synthesis of tetraazacyclododecan-2H-chromen-2-one (283) (Lim et al., 2005).

critical fluid chromatography, considering green chemistry,

improving the yields of products and testing more bio-
activities in different cell lines and fields. Moreover, using a
computer-aided drug design methods, the structure of com-
pounds with 3-acetylcoumarin core can be optimized to
potentially improve their efficiency and pharmacokinetic
properties. Since the toxicity of biologically active com-
pounds is a matter of concern, it is important that the
designed compounds be filtered based on drug-likeness prop-
erties using Lipinski’s rule of five and other indices before the
selected compound are synthesized. Overall, the combination
of computational and synthetic methods will be a promising
strategy in the design and synthesis of 3-acetylcoumarin con-
Fig. 75 Reaction of 3-acetylcoumarin (5) with 1,4-dihydropy-
taining compounds.
ridine (HEH) (Liu et al., 2006) and 2-phenylbenzimidazoline (285)
(Risitano et al., 2001).

Fig. 76 Synthesis (and mechanism) of 3-(2-hydroxypent-4-en-2-yl)–2H-chromen-2-one (286) (Yeon Kim et al., 2003).
66
10. Conclusion
Coumarin ring systems are versatile synthetic targets and essential
structural units in medicinal and synthetic organic chemistry due to
their range of biological activities. This is why scientists have been fas-
cinated by research involving this ring structure for decades. The reac-
tions of 3-acetylcoumarin have been identified using a variety of novel
synthetic techniques and reagents. Scientists were able to synthesize a
wide range of analogs with antimicrobial, anticancer, anti-
inflammatory, antioxidant, anti-tumor and other properties, thanks
to the availability of certain synthetic methods. In this review, we have
attempted to focus on the reactions of 3-acetylcoumarin and the
observed biological activities of synthesized compounds. The major
achievements are as follows: (1) Reaction with alkyl phosphites and
phosphonium ylides generally led to the substitution of 4-position of
the coumarin ring in 3-acetylcoumarin (5). (2) Reaction of 5 with ami-
nes involved various reactions such as Michael addition and the Man-
nich reaction. Among the compounds synthesized in this series,
compound 34 showed anti-inflammatory and analgesic properties. (3)
Compound 5 reacted with various reagents to produce hydroxylamines
and oxime compounds. Among the compounds produced, 38 and 43
demonstrated significant protective and anti-inflammatory activities,
respectively. (4) A wide variety of enaminone compounds were synthe-
sized using several reagents, and they all reacted with the acetyl moiety
of 3-acetylcoumarin. In enaminones compounds, compound 72
demonstrated potent anticancer activity against breast cancer cell lines.
(5) Dithiocarbamate and carbamodithioate compounds were obtained
in low yields and compound 95 was found to possess anti-cancer activ-
ity. (6) 3-Acetylcoumarin reacted with indoles and isatin, and com-
pound 103 inhibited Aspergillus niger as the fungal strain. (7) Similar
to the reaction of 5 with enaminone, its reaction with sulfonamide
and cyano groups containing compounds incorporated with the acetyl
moiety of 3-acetylcoumarin. (8) Multicomponent reactions of 3-
acetylcoumarin led to diverse structures, generally in more than
80 % yields. Some generated structures, such as compound 180,
showed antioxidant, antibacterial and antifungal properties, while
compound 201 showed cytotoxicity. Considering the above-
mentioned summary, various compounds have been synthesized from
3-acetylcoumarin (5) using a broad range of reagents. In particular, the
acetyl group in compound 5 played a significant role in the synthesis of
diverse compounds. The detailed reaction conditions, mechanism and
biological activity of the target product provide insights for synthetic
chemists and drug discovery and development team. It is hoped that
the emphasis of this review on various reactions of 3-acetylcoumarin
will facilitate further research into the development of new bio-active
coumarin-containing compounds.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by the National Research Founda-
tion of Korea (NRF) funded by the Korean Government
(MEST) (2020R1I1A306969913).
Author contributions
N.H.N and F.A wrote the draft of the paper, H.G.K edited it
with significant help and S.J.K led the project.
N. Hosseini Nasab et al.
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