Coupling reactions

Transition Metal Catalyzed Coupling Reactions

mo coupling and hetero coupling Ho
A list of well known C-C and C-X bond forming reac7ons is given below
Transition Metal Catalyzed Coupling Reac
Ulmann coupling & condensation
• Catalytic nucleophilic substitution reactions comprise some of the most comm
Kumada catalytic processes in synthetic organic chemistry.
Negishi
Fukuyama
Mozoriki-Heck
Stille
• The original cross-coupling reactions formed C-C bonds, however catalytic ca
Suzuki-Miyaura heteroatom C-XThe originalhas
formation cross-coupling reactions
now been developed formed
where X = N, C-
O, S, P, Si, B
Sonogashira C bonds, however catalytic carbon heteroatom
Glaser & Hay • A list of well known (not comprehensive) C-C and C-X bond forming reactions
C-X formation has now been developed where
Hiyama-Denmark X = N, O, S, P, Si, B.
Buchwald-Hartwig ! Ulmann coupling & condensation ! Mozoriki-Heck
Chan-Lam
! Kumada ! Stille
! Negishi ! Suzuki-Miyaura
! Fukuyama ! Sonogashira
! Glaser & Hay ! Buchwald-Hartwig
 New or advanced catalytic systems
Coupling reactions
radical mechanism.
c mechanism.
In 2011, Karimi et al. developed that Au nanoparticles
supported on a bifunctional periodic mesoporous
Ullman coupling (1901) 17 Page 2 oforganosilica
dical mechanism 11 (Au@PMO) is an effective and reusable ChemTe
heterogeneous catalyst for Ullmann coupling reaction of
g to free radical mechanism, the copper generates aryl iodides Cu in good to excellent yields (Scheme 4) [10].results in the final biaryl p
elimination
radical (2.2) by a single electron transfer (SET) 2 I
Most interestingly, when iodobenzene (1.1) (Scheme was treated
3).
pper metal to the alkyl halide (2.1). Two aryl with phenol (4.3), the C–C
1.1 1.2homocoupling product (1.2)
then react to form the final biaryl products (2.3) was obtained in 52 % yield instead of C–O coupling Recent developments
pro- of synthetic methodo
NO 2 NO 2 NO 2 of Ullmann-type reaction
2). duct (4.4).
Cu
In a subsequent report, Maheswaran and co-workers
2 I Generally the harsh reaction conditions ([2
echanism described that the gold nanoparticles stabilized on a loading and poor functional gr
copper catalyst
1.3 1.4
nanocrystalline magnesium oxide support,hadNAP-Mg– limited the applications of Ullmann-t
A
g to the ionic mechanism, an aryl copper inter-similar reaction
Au(0), is has been usedreusable
an efficient, for ring heterogeneous
closure: catalyst since
for they have been discovered.
reactions
is formed. This mechanism begins with the I the Ullmann I homocoupling of aryl iodides developments
(Scheme 5) of sustainable, environmen
addition of the copper to the aryl halide (2.1) [11]. methodologies, reusable catalyst, etc. make
Cu possiblea toAu
be performed in mild conditions
by a single electron transfer to form an orga- Dabiri, Bazgir and co-workers also reported
e reagent (3.2). This organocuprate (3.2) per- nanoparticle grapheme oxide nanocomposite (Au NPs- and applied in organic synth
widely accepted
other oxidative addition on an aryl halide forms 1.5
RGO) as an effective and reusable 1.6 nal chemistry and natural product synthes
heterogeneous catalyst
presentation, the recently developed syntheti
pper halide complex (3.3) which after reductive for the Ullmann homocoupling of aryl
Scheme 1 Schematic representation of the Ullmann reactions
iodides.
giesThe extra
have been classified into two clas
Free radical mechanism: advanced catalytic systems and green technol
Proposed free Mechanism of Ullmann coupling reaction recent developments
R of the Ullmann-type
chanism of Ullmann cusing mainly on the publications during the
(I)
Cu Xfor the Ullmann reaction Reaction
The mechanism with
is not known a
with i.e., from 2006 to 2015) have been discussed
X 2nd aryl radical
certainty but there are two proposed popular mechanisms C–C bond formation.
[1, 9]:
R New2.3
or advanced catalytic systems
R SET 2.2
1. Free radical mechanism. R
2.1 2. Ionic mechanism.
Cu (0) R In 2011, Karimi et al. developed that Au
supported on a bifunctional periodic
Free radical mechanism organosilica (Au@PMO) is an effective
heterogeneous catalyst for Ullmann couplin
3 Mondal
According to free radical mechanism, the copper generates ChemTexts,
aryl iodides in good to2016, 2, yields
excellent 17 (Sch
an aryl radical (2.2) by a single electron transfer (SET) Most interestingly, when iodobenzene (1.1)
 Coupling reactions

Ullman coupling
Ionic mechanism:
17 Page 3 of 11 17

ionic (I)
(I)
nn (II) Cu X Cu
X Cu X
Cu (0)
Oxidative
addition SET R
R R 3.2
2.1 3.1
Cu (0) X
Oxidative
addition
R R
(I) X
CuX (III)
Cu

Reductive
2.3 elimination R
R 3.3 R

O catalyzed Au@PMO (1 mol%),

R I K3 PO4 (3 equiv.),
!
NMP (5 ml), 100 C, 16 h R R
(1 mmol) Mondal ChemTexts, 2016, 2, 17
1.1, 4.1a-d 1.2, 4.2a-d
 17 Page 8 of 11 ChemTexts (2016) 2:17

Coupling reactions
R 1 O R1
O R1
O O
O O O POPh2
O POPh2
Ullman coupling:BuSynthe7c
t I applica7ons
Cu, DMF,115 ! C
Bu t
MeO POPh2

t
But MeO POPh2
I
Synthesis
17 Page 8 ofof
11 BIPHEP
Bu
derivatives
POPh 2
via diastereospecific
O O intramolecular
POPh2 Ullmann coupling
ChemTexts (2016) 2:17
O O O 1
R
O O 1
O R 1
R 1 O R 13.3
R1 (one diastereomer)
O
13.1 R1
13.2 O
O (66-91% yield)
O
OR 1 = O
H, OMe, Otolyl,
O Ph, Mesityl POPh2
POPh2 t
t
Bu MeO POPh2
Scheme 13 SynthesisBu
I Cu,via
DMF,115 !
C tUllmann couplings
of BIPHEP derivatives diastereospecific intramolecular
Bu MeO POPh2
But I
O POPh2
Scheme 14 A CuAAC/ O POPh 2 O Ullmann C-C coupling
O CuAAC O R1
O Ullmann C–C
intramolecular Me O 1 Me
coupling tandem reactionO 1 Me Z R 13.3
R N Z CuI, RN 3 ,(one diastereomer) N Z
N
13.1 R1 K2CO3 , DMSO N R 1
13.2 (66-91%
R 1 yield) N
R 1 = H, OMe, Otolyl, Ph, Mesityl X
N N
X= I, Br X Cu
14.1 R N N
Z= O, H 2
Scheme 13 Synthesis of BIPHEP derivatives via diastereospecific intramolecular Ullmann couplings R
R= Bn, allyl, n-Bu, Ph
Indole synthesis via an Ullmann coupling/reductive cyclization sequence
R 1= H, Me, OMe, Cl, Br, NO2 , CO2Et, CN 14.3 (36-96% yield)
Scheme 14 A CuAAC/
CuAAC Ullmann C-C coupling
intramolecular Ullmann C–C Me Me
coupling tandem reaction Me Z
N Z CuI, RN 3 , N Z
I I N
R1 Pd catalyst, CuKpowder,2CO 3 , DMSO N R 1
+ 1
DMSO, X °C , 1 h R N
H 2 , Pd on
NC N N
NO2 O X= I, Br XCu
14.1 O H N N
Z= O, H 2 NO2 R
15.1 15.2 15.4 R
R= Bn, allyl, n-Bu, Ph
15.3 100% conversion
R 1= H, Me, OMe, Cl,(91% yield)
Br, NO 2 , CO2Et, CN 60% yield
14.3 (36-96% yield)

Scheme 15 Indole synthesis via an Ullmann coupling/reductive cyclization sequence

Scheme 16 TotalI synthesisI of Pd catalyst, Cu powder, Mondal ChemTexts,

Ullmann C-C 2016, 2, 17
bond formation
7,70 -linked bianthraquinone
+ DMSO, °C , 1 h
 Coupling reactions
Ullman coupling: Synthetic applications
Total synthesis
ChemTexts (2016) 2:17 of (S)-gossypol Page 9 of 11 17

But But
N Pr i Pri N Ullmann C-C bond formation
OMe Cu, DMF, MeO
O O
reflux, 1 h
OMe
OMe
Br OMe 80% yield
MeO OMe
OMe OMe
OMe MeO
17.1 O
(S,S)-17.2 OMe
(17:1 d.r.) N Pr i
But

Pri
HO Me
OH CHO
HO OH
CHO OH

(S)-(+)-gossypol Me OH
i
Pr

Scheme 17 Total synthesis of (S)-(?)-gossypol

Mondal ChemTexts, 2016, 2, 17
Ullmann C-C bond formation
 OH CHO
HO
Coupling reactions CHO OH
OH

(S)-(+)-gossypol Me OH
Ullman coupling: Synthe7c applica7ons Pr i

Total
Scheme synthesis of (-)-Mastigophorene
17 Total synthesis of (S)-(?)-gossypol A and (-)-mastigophorene B

Ullmann C-C bond formation

MeO OMe MeO OMe MeO OMe HO OH HO OH

Cu, DMF,
Br
64% yield
N
O N N O 18.3
18.1 O
–
( )-Mastigophorene A

18.2

MeO OMe MeO OMe MeO OMe HO OH HO OH

Cu, DMF,
Br
74% yield

N
O N N O 18.6
18.4 O
( –)-Mastigophorene B

18.5

Scheme 18 Total synthesis of (-)-Mastigophorene A and (-)-mastigophorene B

Based on the above methodology developed by Meyers’ DMSO at 70 !C using 5 g atom equiv. of copper powder
group on the asymmetric Ullmann coupling of bromo-ox- Mondal
and Pd2(dba)3 as catalyst ChemTexts,
(Scheme 20). 2016, 2, 17
azoline derivatives, Lin et al. succeed to synthesize both Xu and Lin et al. developed an unprecedented nickel-
 asymmetrical intramolecular reaction by means of inexpensive
Coupling reactions
Meyers et al. also successfully applied the aforementioned optically active auxiliary bridges. The most efficient chiral
strategy to the asymmetrical synthesis of many natural products auxiliary was found to beBeilstein J. Org. Chem.bridge
a C2-symmetrical 2015, 11, 2600–2615.
bearing two
[25-27] such as O-permethyl-tellimagrandin I (Scheme 6), stereogenic centers, derived from tartaric acid, giving the prod-
Ullman coupling:
(+)-gossypol (SchemeSynthetic applications
7), (−)-mastigophorene A (Scheme 8). uct as a single isomer in good yield (Scheme 11).

Enantioselective synthesis of trans-4,5,9,10-tetrahydroxy-9,10-dihydrophenanthrene

Scheme
Scheme 4: Chiral
12: Enantioselective synthesis
1,3-diol-derived of trans-4,5,9,10-tetrahydroxy-9,10-dihydrophenanthrene.
tethers in the diastereoselective synthesis of biaryl compounds.TC = thiophene 2-carboxylate
Synthesis of chiral unsymmetrically substituted biaryl compounds

Scheme 5: Copper-catalyzed coupling of oxazoline-substituted aromatics to afford biaryl products with high diastereomeric purity.

Scheme 13: Synthesis of chiral unsymmetrically substituted biaryl compounds.

Beilstein J. Org. Chem. 2015, 11, 2600–2615
2602
 are either sources of palladium(0) such as Pd(PPh3 )4 , Pd(dba)2 in situ, wh
Coupling
and Pd2 (dba)3 ,reactions
or sources of palladium(II) such as Pd(OAc)2 and has to be
PdCl2 (MeCN)2 . A wide range of solvents can be also used in the active
Heck-Mizoroki Coupling Reactions

Scheme 1 Comparison of HM mechanism with that of a generalised

32 | Org. Biomol. Chem., 2007, 5, 31–44 Chem. Rev. 2000, 100, 3009−3066
 Coupling reactions
(demonstrated by the positive Hammett parameter) has been It had been found using 31 P NMR
explained by a three centre transition state 13 (Scheme 3), which
palladium–phosphine complexes in so
Heck-Mizoroki Coupling Reactions
collapses to the oxidative addition product 14.101 shift depends on the anions present,8
is dependent upon the palladium(II) p
investigations have shown that only
Oxidative addition: acid per palladium View Articleis actually
Online generate
the effect of added chloride ion on th
oxidative addition has shown that the re
Scheme 3
than previously thought.108 It appear
This study also explains the relative lack of reactivity of aryl chloride ions, a number of palladium
Carbometallation: bromides and chlorides, suggesting that the electropositive iodine solution, all of which disappear to g
is a better ligand for palladium than either bromine or chlorine.101 product upon addition of iodobenzene
3018 Chemical Reviews, 2000, Vol. 100, No. 8
It has also been suggested that a transition state such as 13 occurs all species are active in the oxidative Bele
ad
following initial g -coordination of the aryl ring to palladium.
2 104
equilibrium with each other (or both).
ublished on 09 November 2006. Downloaded on 1/19/2020 12:54:23 PM.

t ive t r a n sit ion st a t es. Un less R is ver y sm a ll (CN is wh ich h a s been in t er pr et ed a s a r

This study also observed the disappearance of the palladium(0) palladium species with chloride ligands
t h e best kn own exa m ple), E -isom er is pr edom in a n t t ion a l ba se-in depen den t syn -elim in
astarting
n d t h e rmaterial,
ea ct ion is but did not isolate the resulting product or
h igh ly st er eospecific even for ver y t ionis in
little chemical evidence for the exis
t h e pr esen ce of a m in e ba se
provide information on the structure of oxidative
sim ple m odels, wh ich is on e of t h e m a jor a dva n t a ges addition species. indeed,
exclu sively theyt h have
e in tbeen
er n aproposed
l pr odu ct on. the
Th
However, based on the proposed transition
of t h e H eck pr ot ocol over su ch cla ssica l m et h ods of state 13, the cis-isomer expectations’ rather than
in deed m igh t h a ve r evea led t h a t st hard evidenc
woulda be
olefin expected
t ion a s t h eforWit t ig-H14.
product or n er r ea ct ion (Sch em e switdemonstrated
ch t h e pr ocess that thet otransition
ba se-castate t a lyzt
Reductive elimination:28).It has been found that co-ordinately unsaturated palladium givin addition
g a m or step
e stinvolving
a ble in t er iodobenzene
n a l olefin
(i.e. one triphenylphosphine per palladium) is unstable in solution Th presence
is conof cluchloride
sion isions veris ydifferent
im porto ta
Sandchem e 28 Scheme 7 Comparison of cationic
84 and neutral HM cycles.
ember 2006. Downloaded on 1/19/2020 12:54:23 PM.

reacts readily with aryl iodides. This provides further ca t aabsence. lyzed elim Thisin has
a t been
ion caclearly demonst
n in deed occu
support for the suggestion that the active species is co-ordinately a stHammett r on g in flu en ce botfor
parameters h ontwot hrelevant
e r ea ct
addition of triflates130 and diazonium and
unsaturated saltsthat
158
behave
it is indifferently
equilibrium with the inactive, saturated ochHammett em ist r y of H eck r eaofctqion
parameters = s.
+2.7Th ander e
to the neutral species generated from halides.129 Additionally,
species. A subsequent study of oxidative addition of aryl iodides dr aindicates w a t t en tthation there
t o a is m aorgreater
e con ser va t
degree
the nature of the phosphine (monodentate or bidentate) has a 105 a ddit
to Pd(PPh3 )4 in less polar solvents (toluene) gave a similar transition state when chloride is addi
ion a lly r evea lin g som e in t er est
marked effect on subsequent steps, some bidentate phosphines t h efree,
h ydrand ideiselim in a t ion pr ocess. F ir s
chelating so strongly that Hammett
they render parameter (q = +2.3)
the oxidative and kinetics, the lack of effect of
addition consistent with a chloride
2/3 is a ct u a lly n ot st a t ist ica l a s it m a
product unreactive.25 the change in solvent polarity indicating little charge development species being involved. The presence o
for m a l cou n t of h ydr ogen a t om s a
For a long time thereinhas thebeen transition
considerablestate.evidence
Because thatof this it was suggested that ca r to bonaccelerate
s (du e t othe rate ofinoxidative
pr edom a n t for madd at
oxidative addition is not transition
rate limitingstatein13HMwas unlikely
reactions.due Theto the development of charge 105
fr ompalladium
less st giving
er ica lly the hgreatest
in der ed levelconoffor
ac
observation of a reversal of the expected reactivity for aryl
but a similar three centre transition state must occur as the weigh absence
t s ofof chloride. A further
elim in additio
83
t wo r ou t es of a t ion
iodides92,159 is noteworthy,alternative
and the unexpectedly
SN Ar clearly low requires
reactivityaofgreater development of charge.
t h e on e lea din g t o Z -dia st er eomThe
shown to retard the reaction. ac
108
er ca
aryl chlorides in HM reactions,Th e when
ca sescompared
in wh to their
ich a nrates
on of r t in -H a m m et t dis-
-Cu
In contrast, the oxidative addition of aryl chlorides to pal- Moraddition eover , tstep h e elimby increasing
in a t ion ofthe t er m nega
in
oxidative addition, suggests that
t rladium(0)
ibu t even for
ion of these
isom species,
er s other
is forsteps
m ed pr esen t a specia
species has been found to proceed through a highly in t er lOrg. Biomol. Chem.,
(ton aal point)
h ydr ogen 2007,
is ina lso
5,
some
31–44
h aways
ve differunsur e
may limit the reaction rate.160
 rema ins a minor rea ction pa thwa y. An ingenious wa y
Coupling reactions
t o over com e n or m a l r egioselect ivit y h a s been r ecen t ly
pr oposed t o u t ilize exo cycliza t ion wit h su bsequ en t
clea va ge of t em por a r y cycle (Sch em e 17).74
Heck-Mizoroki Coupling Reac4ons
Synthetic applications:
S c h e m e 17

Th e p
coor din a
st ep h a s
en a n t ios
lyzed by
t h e pr oc
view 48 a n
a specia l
Over m a n
via t h e
plexes of
Enanti
a n d ee i
pr esen ce
h igh a n
st a t es t h
n eu t r a l a
len d a ssi
Chem. Rev. 2000, 100, 3009−3066
 a n d eficien cy wa s a pa r t ia l or fu ll su ppr ession of dou ble-bon d
ct ion of Coupling
br o- reactions
m igr a t ion . Th is pr ocedu r e h a s been a pplied t o a
by P d(OAc)2 pr ot ect ed glyca l givin g a n a ppr oa ch t o C-n u cleosides
a ve onHeck-Mizoroki
ly 12% (Sch emReac4ons
Coupling e 97).
dit ionSynthe4c
of 10% applica4ons:
S c h e m e 97
sed t o n ea r ly
er on the rate
wit h m et h yl
en t h a s been
been fou n d t o
a n opa r t icles,
st , sim ila r t o
em u lsion s (cf.
of Agricultural and Food Chemistry
oa r en es, su ch Th is exa m ple r epr esen t s a n ot h er field of a pplica -
king turnover t ion of a qu eou s pr ocedu r esst h e syn t h esis a n d m odi-
d(OAc)2 wa s fica t ion of n a t u r a lly ocu r r in g m olecu les. In deed,
ich is equ iva - compounds such as carbohydrates, nucleosides, amino
a cids, et c., a r e st r on gly h ydr oph ilic. To per for m
ch ieved in a r ea ct ion s in or ga n ic solven t s, su ch com pou n ds m u st
ion of K 2 CO 3 be fir st m odified a n d h ydr oph obized. It wou ld be
a r yl h a lide desir a ble t o h a ve m et h ods a llowin g t h e pr ocessin g
e of eit h er 10 of sureaction
ch com poupreparation
n ds u n der n ea r -t o-n a t ive con dit ion s,
.r Heck−Matsuda
oa d r a n ge ofcross-coupling in the of prosulfuron 4 .
e.g., in a qu eou s m edia wh er e n o h ea vy pr ot ect ion by
snda nisd essential,
iodides as it has J. Agric. Food Chem. 2018, 66, 8914−8934
la r ge h ydr ophimpact
a significant obic gronou ps catalyzed
is r equ ircross-coupling
ed. In a fureactions
r t h er were highlight
 Coupling reactions
Heck-Mizoroki Coupling Reac4ons
Synthetic and
of Agricultural applications:
Food Chemistry

Protoporphyrinogen Oxidase (PPO)

Heck approaches toward carfentrazone-ethyl 11.
J. Agric. Food Chem. 2018, 66, 8914−8934
 Coupling reactions
Heck-Mizoroki Coupling Reac4ons
gure 2. Heck approaches toward carfentrazone-ethyl 11.
Synthetic applications:
gure 3. Synthesis of pyraflufen-ethyl 15 via the Heck cross-coupling reaction.
Journal of Agricultural and Food Chemistry
e reaction between o-diazoniumsulfonate 1 and 3,3,3-
fluoropropene 2 using the catalyst Pd2(dba)3 [0.5−1.5 mol
generated in situ from trans-dibenzylidenceacetone (dba)
d palladium(II) chloride in a stainless steel vessel at 60 °C]
d sodium acetate in n-pentanol at 70−75 °C. Charcoal was
ded after the arylation reaction to in situ produce the
eterogeneous hydrogenation catalyst of Pd on charcoal that
as able to catalyze the hydrogenation of the C−C double
ond. Hence, Pd was used in two consecutive reactions and
covered by filtration to give the key intermediate 3 of
Figure 4. One-pot synthesis of the fungicide fenpropimorph 21 using Heck coupling in an ionic liquid.
osulfuron 4 . The process produces 2 kg of waste/kg of
oduct for the sequential three steps (diazotization,
kenylation, and hydrogenation) in a one-pot sequence with
Carfentrazone-ethyl 11. The triazolinone class herbicid
carfentrazone-ethyl 11 (marketed as QuickSilver by the FMC
Corporation in 1997, Figure 2) targets the protoporphyrinoge
oxidase enzyme (commonly abbreviated as protox or PPO
providing excellent postemergence broadleaf and sedge wee
control in cereal and corn.127,128 Compound 11 is a chir
compound (administered as a racemate), and the building
block allylic alcohol ester is used to introduce the stereogen
center. Various synthetic methods have been reported for th
synthesis of carfentrazone-ethyl 11,128−132 among them ar
two synthetic methods that include the Heck reaction as a ke
step. Early in J.1999,
Agric.Crispino
Food Chem.et al. developed
2018, a synthet
66, 8914−8934
method (Figure 2) that involved the Heck reaction.131 Th
nt intermediate takes part inMe Bocspecifically,
a stable the catalyst
six-membered ring is recycled. TBAB, Et3 N
that
Boc
if, specifically, the catalyst is recycled. 
Me
N2 BF4
Coupling
1.10
10
(91,favourably
equ iv.)
reactions
delivers the desired product. After the Heck
144 H2 O/EtOH (9:1 )
Pd 2(dba)3 (4 mol%) 10N H2 ref lux, 5 h
he UsePdCl
of 2Pd-Catalyzed
OMe C-C Cross-CouplingOReactions
abamine-SG (160) J. Braz. Chem. Soc.N
s reaction,
(dppf ) (3.2 mol%)
a simple ester reduction
NaOAc (3 equiv.) 55% was
overall yieldnecessary to provide
Heck-Mizoroki
DMF, K CO (1.1
OMe
equ
CF3 2 3PhCN, r.t., 1 h Coupling
iv.) Reactions
O O H O Catalysts 2017, 7, 267 H O
He the
o target molecule in
F 68% yield. CF3 CF3
γ-tr ans
75 C, 12h Catalysts 2017, 7, 267   
N69 Synthe9c
O applica9ons:
Me Me
O
171 (98%, 2 steps)
131 (78%) COOH
N
170 OMe
Me HCl conc.
C COOMe The Heck reaction is described as a viny
OMe
164 (84%) 2CO Me
NaOH
Cl The N Heck CO H
2 reaction
S
O
is described
reflux, HO
12 h OH
143
olefins can be used, like derivatives of acrylat
as a viny
2O
% EtOH/H 2O quantitative
100% linear E Oisomer
gin kgolic acid (128,
N olefins can be used, like derivatives of acrylate
halide variants developed in addition to typica
OH Scheme 39.34%
Synthesis of piperidine analogues by Heck reactions.
e N Me(R)-Josiphos,
OH from
sy n 129)
Cu(OAc) 2.H 2O halide
N Me
Me
142
variants
chlorides, 
L-699,392
developed
aryl  sulfonyl  in
Me addition
chlorides,  to
OH
typica
aromatic 
143
d
Me β-e limination Me Resveratro
chlorides, aryl sulfonyl chlorides, aromatic d
t
PhMe/THF, BuOH, DEMS abamine (161)
on of aryl triflate 130 . arylsilanols. The catalyst is the essential part of
N
O vascular endothelial growth arylsilanols. factor O(VEGF) OHinhibitor have the advan
137 olopatadine (133) H.HCl Me
O r.t., 3 h 53 % overall yield O O
O The catalyst N is the essential part of
range of ligands is studied. Significant progres
S
axitinib
152 (63%, 2 steps)
H (147 ) (Scheme F 40).70 A Migita153
range of coupling
(74%) was used
ligands is studied. in
Significant
ligands and catalysts has been made for avoid compariso
N
H CF
progres
3
CO2Me Me
N H
in the
Ph
firstCOstep
2Me of the synthesis
N
in order
ligands to
144 assemble
N
the
allowing for syntheses to be carried out in few
and catalysts
Ph Eletriptan has been
Hcinacalcet aryl
made
hydrochloride
145
halides.
for ) avoid
(Cinacalcet
167
1
C
IPdmercaptobenzamide moiety of 147 . extensive mechanistic studies are summarized
In the last step of the strategy via a
H
of a Heck-Matsuda Reduction allowing for syntheses to be carried out
COONa in few
Me N Me reaction.
route, a HeckN(iPr) reaction
2 148researchers and reviewers as described in follo
betweenextensive and mechanistic
2-vinyl-piridine studies are (R)-tolterodin
summarized
Me as it tolerates a wide variety of functional gro
was designed. OH However,Ac the free NH ofAc148
researchers Clandimpaired
reviewers
N the asEtdescribed
S incontinenceOH
in follow
166 (85%) N bonds 
naft if ine (O162) N between  appropriately  N functionalized
100% linear reaction. Therefore, the 68%
authors as itdecided
tolerates toa acylate
wide the of functional
variety the firstgroup step
F4
E(R)-t olter odine
isomer (149,
overall yield
proceed  with  stereo‐  and  regioselectivity  an
Pd 2(dba)O3 (8 mol%)
72%, 98% ee) H2 AlH3
C NaOAcindazole
(3 equiv.)for both protecting
NaOH thebetween
NH group and THF
appropriatelyrendering functionalized cinnamatesubstrate 150
abamine and naftifine.
ction andPhCN,
enantioselective reduction of compound 152 . 2 CO H 146
2O
the oxidative
r.t., 3 h
CO2 Meaddition 2to palladium easier. The protection Montelukastsalt
EtOH/H O Catalysts 2017, 7, 267; doi:10.3390/catal7090267151,
Sodium
    usin
iv.)Me was achieved in situ with Ac2NOCatalysts
and
Figure 21.
when
21.  Additional
no
Additional  fine
more
fine  chemical
than
chemical  products
products  produced
http://dx.doi.org/10.5935/0103-5053.20140255
Figure
Me
2017, 7, 267;
produced  on
doi:10.3390/catal7090267
and
on  industrial
CaCO
industrial  scale
scale using
as
using Heck
3
Hec

steps. It is worth noting that the reduced steric volume alverineof

N reviewed by Zapf and Beller [79]. 
reviewed by Zapf and Beller [79].
174
Me 2% of 148 was present, theMe
Heck 175
reaction
(72%, 2 steps)
was started
Braz. Chem. Soc., Vol. 25, No. 12, 2186-2214, 2014.
(172, 96%)
molecule tolt
J.Much later, a review published by Picquet [82] edited by Beller and Blaser presen
ation en route to 172 .
sy n 4.2. Pharmaceuticals
oron compound and a halide or pseudohalide is
Coupling reactions
s Suzuki-Miyaura cross-coupling.22 This important
is well-known for the assembly of biphenyl
Other Coupling Reac2ons
For example, Dalby et al.24 reported a concise
s of D159687 (1), a partial allosteric modulator
disease and psoriasis. The original syntheti
presented some challenges for scaling-up, most no
employment of toxic carbon tetrachloride, silver
microwave irradiation. Therefore, the authors opti
route, on a kilogram scale, employing the aryl c

R-R1 HX R2 R
r eductive
elimination
R2 R
base
LnPd0 X PdIILn
R H
R-X syn β-h ydr ide eliminatio n
oxidative
LnPdII addition
R II
PdLnX R
1
R
LnPdII
R2 H
X
syn mi gratory insertion
M-X 1
R -M
tran smetalati on
R2

Negishi (M = ZnR) Heck-Mizoroki

Suzuki-Miyaura [M = B (OH)2 or B(O R)2] Heck-Matsud a (with [LnPdIIR]+ after oxid ative
Stille (M = SnR 3) addition)
Son ogashira (M = CuI)

General catalytic cycles for the Pd-catalysed reactions. http://dx.doi.org/10.5935/0103-5053.20140255

J. Braz. Chem. Soc., Vol. 25, No. 12, 2186-2214, 2014.
 Franzén, R. Can. J. Chem. 2000, 78, 957–962.

Coupling reactions • The Suzuki reaction is the coupling of an aryl or vinyl bo

or triflate using a palladium catalyst. It is a powerful cros
synthesis of conjugated olefins, styrenes, and biphenyls:
Suzuki Coupling Reactions
PPh3

Pd n-Bu benzen
PPh
Ph3P
3
B O + Br
PPh3
O 80 ˚

9
2PPh3 -2PPh3

Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun.

Ar' PPh3Mechanism:
I

Ph3P Pd
isomerization & n-Bu oxidative
r eductive addition
elimination Pd0Ln

PPh3 Reductive
PPh3 Elimination
'
Ar Pd I Pd
Ph3P Ph3P Ph
PdIILn
K+ OAc n-Bu
transmetalation KOAcO
B O EtO
PPh3 B
AcO
O AcO Pd O
Ph3P Ph
PdIILn
EtO
OAc KI
O KOAc n-Bu
Ar '
B B O K +
B O Tra
O Ar' O
O

Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749–1758.

t to provide 8 in yields between 70 and 81%. allowing a very clean reaction to be perform
Coupling
to the medicinal reactions
chemistry route, the final step high activity of this catalyst (Scheme 4).26 Thu
ploy a palladium-catalyzed reaction, allowing product 13 was obtained in 93% yield by tre
oval ofSuzuki Coupling
this metal: the Reactions:
synthesis ofSynthetic applications
9 employed the appropriate arylboronic acid in the prese
Vol. 25, No. 12, 2014 Biajoli et al. 2187

a syn migratory insertion occurs and the organopalladium of phosphodiesterase 4 (PDE4), an enzyme related to
species formed undergoes β-hydride elimination to form the PCy2diseases. The first synthesis
inflammatory and respiratory
alkene product. Finally, a base-assisted elimination of HX of 1 involved
Me six steps, with one Suzuki reaction O step,
O
regenerate the Pd(0) catalyst.12-17 When an aryldiazonium with an overall yield of 8%.25 By using the benzyl aryl
salt is used in place of an aryl halide, the reaction is known dibromide 2 as starting material, the synthesis of 1 was
as Heck-Matsuda reaction.18-21 The difference in terms of shortened to two-steps with an overall yield of 47% N on the
(HO) 2 B CO 2 H N
mechanism is that the oxidative addition of aryldiazonium gram scaleMePhos
(Scheme 2). (7)
salts to the Pd zerovalent species+ generates a cationic The more reactive benzyl bromide moiety of Ndibromide
N Pdcoupled
[R1-Pd]Me+
intermediate. 2 was 2(dba)3, NaOH
with (aq),
a pinacol arylboronic ester,N providing CO 2H
In our opinion, the most important N and elegant EtOH,
diarylmethane 3 inreflu x Activation of the remaining
66% yield.
Cl
application of the coupling reactions is the synthesis of bromide in 3 was carried out using the same conditions,
pharmaceuticals. In this context, there is an excellent only changing the temperature and reaction time, and Me
review about the applications of Pd-catalyzed 6coupling furnishing 1 at a yield of 71%. The optimal conditions
8 (70-81%)
reactions. This review covers the period from 2001 to 2008, displayed
O in Scheme 2 were established after a screening of
and highlights examples that have been performed on at Pd sources [Pd(PPh3)4, PdCl2(PPh3)2 and Pd(OAc)2/PPh3],
least a kilogram scale in the chemical and pharmaceutical solvents [dimethoxyethane/EtOH/H2O, dioxane/H2O and
industries. In addition, Pfizer researchers have reviewed
5 N
dimethylformamide (DMF)] and bases (K3PO4, K2CO3,
1. CDI, imidazole,
the large-scale applications of transition metal-catalyzed Na2CO3 and Cs2CO3). It is worth noting that a reduction
EtOAc, r.t. - 50 ºC N amount of catalyst increasedOthe conversion in some
coupling reactions for the manufacture of drug components of the
in the pharmaceutical industry through to the
2. cyclopropylamine, r.t. end of cases,
N while higher amounts generally increased the level
August, 2010.4 This review is intended to give a picture N This process was
of impurities and difficult purification.
of the applications of Pd-catalyzed C-C cross-coupling H partial allosteric
applied to the synthesis of two new PDE4D
reactions for the synthesis of drug components or drug Me
modulators, D159404 (4) and D159153 (5) (Figure 1), with
candidates, regardless of scale, from 2011 through to the overall yields9of around 26% for the two Suzuki reactions.
(70% 2 steps)
end of July, 2014. Thiel et al. described the preparation of several
inhibitors of p38 mitogen-activated protein (MAP) kinases,
zuki reaction2.ofSuzuki-Miyaura
an aryl chloride en
Reactions route to 9. which are enzymes that positively regulate the production

The transition metal-catalyzed reaction between an

organoboron compound and a halide or pseudohalide is
known as Suzuki-Miyaura cross-coupling.22 This important
http://dx.doi.org/10.5935/0103-5053.20140255
of pro-inflammatory mediators (TNF-α and IL-1).26 These
mediators are involved in rheumatoid arthritis, Crohn’s
disease and psoriasis. The original synthetic route27
J. Braz. Chem. Soc., Vol. 25, No. 12, 2186-2214, 2014.
presented some challenges for scaling-up, most notably the
 60 employing 1 mol% of Pd2(dba)3 as a pre-catalyst and better use of the valuable chiral intermediate 65.
2.2 mol% of tricyclohexylphosphine as a ligand in a mixture The large-scale synthesis demanded further
Coupling reactions
of water and THF, 61 was obtained in an excellent yield of modifications: the preparation of multi-kilogram amounts
95% (Scheme 18). Hydroxyl displacement with SOBr2 then of imidazole 64 presented high levels of dimerization;
furnished biphenyl 54 in an overall yield of 86% starting therefore, the palladium-catalyzed borylation was
Suzuki Coupling
from the arylReactions:
chloride 59 . Synthetic applications abandoned in favour of a Knochel-type procedure.38
Me

F 3C Me CO2H

HO 55

CO 2H +

F3 C CF3
O Suzuki
coup ling R2
AMG 837 (53)
+

54 R1 R3
Br
R1 = B(OH)2 or Cl
R2 = B(OH)2 or Br
R3 = CO 2H or CH2OH
Scheme 16. Retrosynthetic plan for the final steps of the Walker et al.36 large-scale synthesis of AMG 837 (53 ).

F3 C F3 C
CF3
CO 2H
Pd/C cat. 1. Redu ction
+ Na2 CO 3 2. Bromination
Br
i
Pr2 NH/H 2O
B(OH)2 CO 2H Br
56 57 58 (91%) 54 (8 9%, 2 steps)

Scheme 17. Original Suzuki reaction employed for the synthesis of biphenyl 54 .

F3C F3C
CF3 OH
Pd2 (dba) 3 (1 mo l%)
PCy3 (2.2 mo l%) SOBr 2
+
K3PO4 , THF/H2 O Et 3N, PhMe
65 o C, 20 h 40 o C
Cl B(OH)2
HO Br
59 60 (1.1 eq uiv.) 61 (95%) 54 (90%)

Scheme 18. Optimized preparation of biphenyl 54 .

http://dx.doi.org/10.5935/0103-5053.20140255
J. Braz. Chem. Soc., Vol. 25, No. 12, 2186-2214, 2014.
Suzuki product 73 in excellent yield. After that, 73 is capable of interacting with chaperones that are essential
Coupling reactions
was submitted to ozonolysis, providing aldehyde 74
in 76% yield. The side chain was then installed by a
for the survival of cancer cells.41 In their synthesis, the
piperazino-iso-indoline 77 was assembled by a sp3-sp2
Wittig reaction, whose product 75 , after chemo- and Suzuki cross-coupling reaction employing the Molander
Suzuki Coupling
regioselective Reac1ons:
reductions Synthe1c
and deprotections, applica1ons
afforded 69 . protocol (Scheme 24).42

Me

Me Me
OH OH O
NH
ONa
Suzuki coupling
O N N

PF-03052334-02 (69)
F

Me (HO)2 B Me
Me Me
OTf 72 (1.07equiv.)
EtO2 C PdCl2 (PPh 3 )2 (2.5 mol%) EtO2 C
N N N N
KBr (0.2 equiv.), K2 CO 3 (3.0 equiv.)
Ph Me/H 2O/i PrOH
70 F 73 (91%) F

O O O
O 3, CH 2Cl2/MeOH,
(HO)2 B OR th en ester h ydrolysis
71 and amidation
no reaction Me
Me

Me Me
Me OTBSO O OTBS Me
CO2 Et Ph 3P CO2Et
NH NH O

N N
O N N Ph Me, 90 o C O

75 (95%) 74 (51%, 3 steps) F

F
http://dx.doi.org/10.5935/0103-5053.20140255
Scheme 23. A Suzuki reaction followed by ozonolysis for the preparation of 69 .

J. Braz. Chem. Soc., Vol. 25, No. 12, 2186-2214, 2014.

 to the peutic agent.[53] The total synthesis of Quebecol have
developments was transfigur
2012 till Coupling
reportedreactions
by Voyer and co‐workers inof2013 starting from and agro
pharmaceuticals
thwhile
have shown especial effects
rein, Suzuki
we Coupling Reactions: Synthetic applications
ments in biologically active natural pr
gic step Among these methodologies
products reaction (SMCR) dates from
e try to sents a mild and facile cou
ynthesis halide or sulfonates with bo
bridized
ge num-
ouplings Abbreviations: 9‐BBN, 9‐Borabicyc
his kind ferrocene; Dppf, 1,1'‐bis(diphenylpho
viewed, MOM, methoxymethyl; OTf, trifluor
RuPhos, 2‐Dicyclohexylphosphino‐2
mmense 2'‐6'‐dimethoxybiphenyl; TBAF, te
n of this tert‐Butyldimethylsilyl trifluorome
hesis of 2,2,6,6‐tetramethylpiperidinyl; XPhos
SCHEME 1 Total Synthesis of Camptothecin
Appl Organometal Chem. 2018;32:e4210.
 developments have transfigur
Coupling reactions
TAHERI KAL KOSHVANDI ET AL.
of pharmaceuticals and agro
Suzuki Coupling Reactions: Synthetic applications have shown especial effects
biologically active naturalLysi
pr
sides) 1
Among these methodologies
clethroid
reaction (SMCR) dates from
attentio
sents a mild and facile of 17cou
ha
halide or sulfonates with
17 bo wa
phlorog
an appr
was the
Abbreviations: 9‐BBN, 9‐Borabicyc
under S
ferrocene; Dppf, 1,1'‐bis(diphenylpho
MOM, methoxymethyl; OTf, co‐catal
trifluor
nitrogen
RuPhos, 2‐Dicyclohexylphosphino‐2
2'‐6'‐dimethoxybiphenyl; TBAF, ether 21te
tert‐Butyldimethylsilyl to the d
trifluorome
2,2,6,6‐tetramethylpiperidinyl;using
XPhosc
(Schem
Lod
Appl Organometal Chem. 2018;32:e4210.
SCHEME 2 Total Synthesis of Scalaridine Actinom
desired natural product, developments have transfigur
Coupling reactions
SCHEME 4 Total Synthesis ofof pharmaceuticals
Lysilactones A and agro
Suzuki Coupling Reactions: Synthetic applications have shown especial effects
biologically active natural pr
Among these methodologies
reaction (SMCR) dates from
sents a mild and facile cou
halide or sulfonates with bo

Abbreviations: 9‐BBN, 9‐Borabicyc

ferrocene; Dppf, 1,1'‐bis(diphenylpho
MOM, methoxymethyl; OTf, trifluor
RuPhos, 2‐Dicyclohexylphosphino‐2
2'‐6'‐dimethoxybiphenyl; TBAF, te
tert‐Butyldimethylsilyl trifluorome
2,2,6,6‐tetramethylpiperidinyl; XPhos

Appl Organometal Chem. 2018;32:e4210.


Coupling reactions
1 Suzuki Coupling Reactions:
Reac1ons Synthetic applications
developments have transfigur
of pharmaceuticals and agro
have shown especial effects
biologically active natural pr
Among these methodologies
reaction (SMCR) dates from
sents a mild and facile cou
halide or sulfonates with bo

Abbreviations: 9‐BBN, 9‐Borabicyc

ferrocene; Dppf, 1,1'‐bis(diphenylpho
MOM, methoxymethyl; OTf, trifluor
RuPhos, 2‐Dicyclohexylphosphino‐2
2'‐6'‐dimethoxybiphenyl; TBAF, te
tert‐Butyldimethylsilyl trifluorome
2,2,6,6‐tetramethylpiperidinyl; XPhos

Appl Organometal Chem. 2018;32:e4210.

product, which con- shows an especial chemical and biological properties.[81]
h as protein kinase CK2 inhibitors,[110] topoisomerase
Coupling
top1) inhibitors, [111,112]
reactions
pim kinase inhibitors,[112]
otoxity inhibitors.[113] A facile one‐step access to
Suzuki Coupling Reac1ons: Synthe1c applica1ons
HEME 29 Total Synthesis of Mulberrofurans B and L.
mushrooms can be found in many natural prod
developments have transfigur
exhibit various biological activities.[116] In 200
and of pharmaceuticals
co‐workers and agroo‐
isolated a new p‐terphenyl
have shown especial effects
biologically active natural pr
Among these methodologies
reaction (SMCR) dates from
sents a mild and facile cou
halide or sulfonates with bo
Abbreviations: 9‐BBN, 9‐Borabicyc
ferrocene; Dppf, 1,1'‐bis(diphenylpho
MOM, methoxymethyl; OTf, trifluor
RuPhos, 2‐Dicyclohexylphosphino‐2
2'‐6'‐dimethoxybiphenyl; TBAF, te
tert‐Butyldimethylsilyl trifluorome
2,2,6,6‐tetramethylpiperidinyl; XPhos
Appl Organometal Chem. 2018;32:e4210.

Coupling reactions
Suzuki Coupling Reactions: Synthetic applications
prescrribed druge so‐called Micardis.[215] In Appl
a study,
Organometal
developments have transfigurS
of pharmaceuticals and agroS
have shown especial effects
biologically active natural pr
Among these methodologies
reaction (SMCR) dates from
sents a mild and facile cou
halide or sulfonates with bo
Abbreviations: 9‐BBN, 9‐Borabicyc
ferrocene; Dppf, 1,1'‐bis(diphenylpho
MOM, methoxymethyl; OTf, trifluor
RuPhos, 2‐Dicyclohexylphosphino‐2
2'‐6'‐dimethoxybiphenyl; TBAF, teS
tert‐Butyldimethylsilyl trifluoromei
2,2,6,6‐tetramethylpiperidinyl; XPhosi
of Chem.
in of H2O/EtO
KOH 2018;32:e4210.
[2
ained from diverse afford desired bipyrrole 505 in 44% yield. have
developments The latter upon
transfigur
Coupling
hbn cluster) biosyn- reactions
hydrolysis of enamine and other functional group
of pharmaceuticals and agro
ted that, unexpect- transformations gave the desired natural product
Coupling Reactions: Synthetic applications have shown especial effects
n of Suzuki
antibacterial 501 in 20.08% yield. The obtaining of modest
biologically active natural pr
Among these methodologies
reaction (SMCR) dates from
sents a mild and facile cou
halide or sulfonates with bo

Abbreviations: 9‐BBN, 9‐Borabicyc

ferrocene; Dppf, 1,1'‐bis(diphenylpho
MOM, methoxymethyl; OTf, trifluor
RuPhos, 2‐Dicyclohexylphosphino‐2
2'‐6'‐dimethoxybiphenyl; TBAF, te
tert‐Butyldimethylsilyl trifluorome
2,2,6,6‐tetramethylpiperidinyl; XPhos

Appl Organometal Chem. 2018;32:e4210.

 hotovoltaic cells, and organic field-effect
. Organic Coupling
electronic and reactions
optoelectronic
several advantages over conventional
View Article Online
on Negishi Coupling
inorganic Reactions: two
semiconductors, Synthetic
of applications
ost of production and the flexibility of the Review
organics-based technologies, for instance,
or
ology, have been developed to a consider-
ic and have resulted in the marketing of
e,
25
s. Material development has made a major
o-
ancing these technologies. A number of
es
with applications of palladium-catalyzed
ct
tions (Kumada coupling,26 Negishi coup-
ic
27
and Suzuki coupling28) in the synthesis
al
igomeric electronic conducting and semi-
of 29
ls. Functional small molecules such as
he
Scheme 1 Mechanism of Negishi coupling with organozinc reage
e,redox-active, light-emitting and harvest-
cal
r- materials have also played important
of highly efficient organic electronic and
es. Negishi coupling, particularly with the typically a halide or a sulfonate ester, to palladium (0),
or
eagents,
of has enabled cross coupling of all metalation with an organozinc reagent, and reductive el
d namely sp, sp2, and sp3 carbons, and ation to release the cross-coupling product and regenera
ms,
p-
sible combinations of various types of catalyst. Negishi coupling becomes the choice of m
is
ctrophiles to form carbon–carbon bonds.16 mainly because of a few beneficial factors to organic syn
i-
coupling becomes a frequent choice in which distinguish it from other cross couplings using or
as
small functional molecules as well. This metals of Sn (Stille coupling), B (Suzuki
Org. Chem. Front., 2015,coupling),
2, 416–445an
t- Scheme 1 Mechanism of Negishi coupling with organozinc reagents.
 meric 1,3,5-tri(m-pyrid-3-yl-phenyl)benzene and 1,3,5-tri(m-
Coupling reactions
pyrid-4-yl-phenyl)benzene prepared by Suzuki coupling.
Similar Negishi coupling was applied to the synthesis of a 1,3,5-
Negishi Coupling Reactions: Synthetic applications
triazine-core-containing electron transporting material 37.61

he
o-
F
d
d
Scheme 11 Synthesis of 36 and 37.

Org. Chem. Front., 2015, 2, 416–445

 Coupling reactions
Organic Chemistry Frontiers
Negishi Coupling Reactions: Synthetic applications
OLEDs as the host material
efficiency. A carbazolyl-subst
3,7-bis[4-(N-carbazolyl)phen
which was synthesized by us
Scheme 14, also displays bip
to fabricate efficient OLED
tion structure.65c

3. Organic optic
Organic optical/photonic m
can either interact with lig
refracting, and rotating light
Organic optical materials th
5. Downloaded on 2/10/2021 1:58:12 PM.

tronic and optoelectronic d

to nonlinear optical (NLO) m
ters, and light harvesting
absorbing visible light, is als
organic electronic materials
ponent in optoelectronic dev

3.1 Nonlinear optical mate

Scheme 14 Synthesis of 49–52 by the zinc-mediated annulation– A push–pull structure with
Negishi coupling tandem process. Org. Chem. Front.,
chain 2015,
57 was 2, 416–445
efficiently cons
 Coupling reactions
Negishi Coupling Reactions: Synthetic applications
eoselective Negishi Cross-Coupling Using Various Zinc Reagents

paration of Jackson’s Zinc Reagent in DMF

ACS Catal. 2016, 6, 1540−1552
 (30) using iPrMgCl·LiCl leads to the corresponding Grignard monoa
Coupling reactions
reagent (31). Transmetalation with ZnCl2, followed by Negishi 11).33
cross-coupling gives the bis-arylated pyridine (32) in 88% yield
Negishi Coupling 9).27 Synthetic applications
Reactions:
(Scheme Schem
Preparation of Jackson’s Zinc Reagent in DMF
A low-temperature I/Li-exchange of the aryl iodide (33) with with T
nBuLi provides after transmetalation with the THF soluble salt
ZnBr2·LiBr, the bis-zinc reagent (34) that is used in a
diastereoselective Negishi cross-coupling for the preparation
of canagliflozin (Scheme 10).28

Scheme 9. Regioselective Br/Mg-Exchange on a 3,5-

Dibromopyridine
7 8 9 10
wders such as Mg, In, Mn, and Al are also Scheme 5. Preparation of a Zinc Organometallic
activated by LiCl. It should be mentioned that the ZnCl2, LiCl
of additional Lewis acids, such as B(OR)311 or
nsfer acceptors,12 further accelerates the metal
The intermediate radicals resulting from the zinc
o not allow a stereoselective formation of secondary
eagents, such as in the case of the substituted
inc (8). However, the Negishi cross-coupling with
dobenzoate is stereoconvergent and produces in the
f RuPhos (2-dicyclohexylphosphino-2′,6′-diisopro- a
32,20 db
providing the bis-pyridine (20) in 78% yield. Si
yl)13 the trans-cyclohexane derivative (9) in 80%
chloromethyl isoxazole derivative (21) leads to the z
96:4; Scheme 3).14 (22), and Negishi cross-coupling1542 using Pd-P
case of the (Z)-alkenyl bromide (10), the zinc furnishes the ACS
desired product (23) in 87% yield (Sc
ppears to be stereoselective as a result of the chelate- Catal. 2016, 6, 1540−1552
2.2. Metal-Catalyzed Preparations of O
molecules bearing such a ring system. O’Brien and Campos
have developed a quite general methodology105 for the Due to the mild conditions required to form new carbon
Coupling reactions
preparation of various chiral pyrrolidines using sBuLi/ carbon bonds, the Negishi cross-coupling has found a
(−)-sparteine or its surrogate to obtain a chiral pyrrolidylzinc increased number of synthetic applications. Although palladiu
reagent, which is readily employed in a Negishi cross-coupling is still the most commonly used metal catalyst for these cros
Negishi Coupling Reac1ons: Synthe1c
with retention of configuration. This general method is applica1ons
couplings, alternative metals, such as nickel, cobalt, and iro
illustrated in a synthesis of (S)-nicotine. The metalation of may be useful complement methodologies in the futu
the pyrrolidine (131) with sBuLi in the presence of the chiral regarding toxicity, as well as ecological and price aspects. Th
Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation
Scheme 36. Preparation of Isodesmosine via Negishi Cross-Couplings

1549 DOI: 10.1021/acscatal.5b027

ACS Catal. 2016, 6, 1540−15

ACS Catal. 2016, 6, 1540−1552

 ic chemists as potential
e cross coupling reaction
[23–25].
Coupling reactions
ctions have also emerged
uction Kumuda Coupling
of C–C bonds, and Reactions: Synthetic applications
een conducted to under-
reactivity and selectivity
alysts not only enable to
ons of primary alkyl elec-
ed secondary and tertiary
hydrogens with different
uct carbon–carbon bonds.
g reaction was achieved
The Kumada and Tamao
e reaction of an appropri-
magnesium compound (a
corresponding cross-cou-
d or Ni as catalysts. In the
, independently reported
ostyrene with phenylmag-
ilbene in the presence of
mada cross coupling reac-
2 using either Pd or Ni as
reaction of Grignard rea-
ides was accomplished in
ve catalyst in comparison
oviding a more economic
Fig. 1 A Vahideh
was performed in chemical tion
The formation of the C–C bond is a major and important reaction in synthetic organic chemistry and freque
transition-metal catalysts. Among them, Kumada–Tamao–Corriu coupling reaction is providing a simple
Scheme 1
extensively employed in the art of organic synthesis. In this review, we try to highlight the recent advances i
of Kumada–Tamao–Corriu coupling reaction by updating of our previous review from 2012 up to date.
Graphical abstract
Keywords Carbon–carbon bond formation · Cross-coupling reaction · Grignard reagent · Kumada–Tamao
reaction · Nickel catalyst · Transition metal
Introduction These metal-catalyzed reactions also p
role in medicinal chemistry, nanotechnolog
Carbon–carbon bond formation is the closet reaction to chemistry [2–6]. Undoubtedly, the most
the heart of organic synthetic chemists. Metal-catalyzed catalyzed cross coupling reactions are th
cross coupling reactions are of great importance in the art alyzed cross coupling reactions since the
of organic synthesis. They are frequently used for the syn- Nobel prize was awarded to Heck, Negish
thesis of new polymeric materials, pharmaceutically active their achievements in palladium-catalyzed
complex molecules and total synthesis of virtually all natural in organic synthesis”. They have revolution
products, from commercially available or readily accessible chemists assemble carbon–carbon (C–C) b
starting materials. Thus, metal-catalyzed cross-coupling tions typically involve halogenated aroma
reactions are considered as a powerful and vital tool in the which represent a small subset of the react
C–C bond forming step (steps) in multi-step organic syn- in organic synthesis.
thesis [1]. Name reactions in organic chemistry
those reactions which are well-recognize
such status for being called as their explo
or developers. Examples are including the
* Majid M. Heravi
mmheravi@alzahra.ac.ir; mmh1331@yahoo.com tion, the Claisen condensation [7], Wittig
Grignard reaction [9], and the Friedel-Cra
plausible mechanism for für
Zadsirjan
Monatshe8e a Ni-catalyzed
Chemie - cross coupling
Chemical reac- reaction
Monthly
acylation (2019) 150:535–591
[10]. The name is simpl
z_zadsirjan@yahoo.com
important and distinguished name reactio
ng reaction was accompanied. Four novel Ni pincer sys- were suggested to be responsible for the construction
ms 28–31 with moderate to high
Coupling activity in alkyl–alkyl
reactions by-products. It should be mentioned that up to now (20
mada coupling reaction of primary alkyl halides were none of the proposed Fe intermediates have been dire

Kumuda Coupling Reactions: Synthetic applications

Scheme 6

13
Monatshe8e für Chemie - Chemical Monthly (2019) 150:535–591
 Coupling reactions
KumudaScheme
Coupling
8 Reactions: Synthetic applications

detected or identified and the nature of potential off-cycle alkyl halides, principally secondary alkyl iodides, with
species was not evaluated (Scheme 9) [59].
Monatshe8e für Chemie - Chemical Monthly (2019) 150:535–591
alkyl Grignard reagents. A transmetalation position in the
 Coupling reactions
Kumuda Coupling
Scheme 32
Reac1ons: Synthe1c applica1ons

Advances in Kumada–Tamao–Corriu cross-coupling reaction: an update

Scheme 33 enol phosphates in Pd-mediated Kumada-Co

pling reactions. Reaction of syn-123 with PhM
13 PdCl2(PPh3)2 under reflux in tetrahydrofuran aff
4-phenyl-functionalized 1,2-oxazine derivative
only 30% yield. Under ligand-free palladium(II)
mediated conditions no better result has been de
the desired product syn-124 was provided in
(Scheme 39).
The Kumada–Corriu coupling reaction was
fully improved under MWI [102]. 1,2-Oxazin
and phenylmagnesium chloride or 4-MeOC6H4M
Pd(PPh3)4 under MWI giving syn-126 and syn-12
tively, in 46–57% yield. A control test occurred
125 and phenylmagnesium chloride afforded a
ably poorer yield (35%) of the anticipated produc
demonstrating that conventional heating in te
furan under reflux for one day is less effective.
diastereomer anti-125 was subjected to the m
assisted coupling conditions and it supplied th
4-aryl-functionalized anti-126 and anti-127 in g
(55–64%). Efforts to perform the Kumada–Corri
with Ni catalysts were inadequately unsatisfac
Monatshe9e
Other alkenylation of Grignardfür Chemie -
compounds Chemical Monthly
afforded (2019)
the desired 150:535–591
4-aryl-functionalized 1,2-o
less than 10% yield (Scheme 40) [103–105].
 Coupling reactions
70 M. M. Heravi et al.
Kumuda Coupling Reac1ons: Synthe1c applica1ons
Scheme 83

Scheme 84
Monatshe9e für Chemie - Chemical Monthly (2019) 150:535–591
 Coupling reactions
Kumuda Coupling Reac1ons: Synthe1c applica1ons
Advances in Kumada–Tamao–Corriu cross-coupling reaction: an update 585

Scheme 131

Scheme 132

Monatshe9e für Chemie - Chemical Monthly (2019) 150:535–591

 Coupling reactions
Kumuda Coupling Reac1ons: Synthe1c applica1ons

Scheme 132

ve with a wide range of functionalized cyclic sulfates d.e. was provided using the Ni pincer catalyst 319. T
ovide the corresponding products with enantioselec- is controlled by the conformational preference of t
rtiary carbon centers (Scheme 133) [223]. alkyl intermediates. Fortuitously, it was provided pro
012, Hu et al. established a Ni-mediated diastereose- the reversible activation of alkyl halide in the Ni ca
alkylalkyl Kumada coupling for 1,3- andMonatshe9e
1,4-func- für
that gave important
Chemie - Chemicaldata for mechanistic
Monthly considerati
(2019) 150:535–591
zed cyclohexyl halides and tetrahydropyrans. High
97% e.e.) and yield (96%). The arylated products were con- 339 with very analogous conversions and isolated yields
verted to α-arylcarboxylic acids and primary alcohols with-
Coupling reactions
out erosion of enantioselectivity. The novel enantioenriched
Similarly, direct comparison with the conventional repor
of Hayashi [234], e.g., transformation of Grignard 340 and

Kumuda Coupling Reac1ons: Synthe1c applica1ons

Scheme 137

Scheme 138

13
Monatshe9e für Chemie - Chemical Monthly (2019) 150:535–591
 Coupling reactions
Buchwald–Hartwig amina2on

Chem. Rev. 2016, 116, 12564−12649

 Coupling reactions
Buchwald–Hartwig
Chemical Reviews amina2on Review

Figure 2. Main fields of application of Pd-catalyzed C−N cross-coupling reactions.

reactions are employed in both the discovery and process

Chem. Rev. 2016, 116, 12564−12649
1.6. Applications in the Synthesis of Ligands and Catalysts
 Scheme 1a) using a single catalyst.58 Given the strong
Coupling reactions
Scheme 1. Synthesis of Heterocycles via the Coupling of
Buchwald–Hartwig amina2on
Primary Alkylamines
Jørgensen’s
Scheme 1a)
disubstitute
amine (R =
generated in
two N-aryla
palladium p
the inhere
compounds
the formati
reduced pro
reaction y
synthesized
primary alk
L11 or L13
reaction bet
compounds
for the trea
Additiona
alkylamines
(Wyeth) pr
Chem. Rev. 2016, 116, 12564−12649
agent by se
 Coupling reactions
Buchwald–Hartwig amina2on
Chemical Reviews Review

Scheme 3. Applications of the Coupling of Primary Alkylamines in Medicinal Chemistry

Chem. Rev. 2016, 116, 12564−12649

 Coupling reactions
Buchwald–Hartwig amina2on

different ligands, L6 and L7, were utilized. Similarly, but
employing an L14-based catalyst, Bamborough, Prinjha, and
their co-workers (GlaxoSmithKline) described the N-arylation
of chiral aminopiperidine 21 to access anti-inflammatory
68
of smaller cycles, the cyclization step was successfully
accomplished in 72% yield using L17, a first-generation
precatalyst. The reaction afforded the desired macrocycle as
Chem. Rev. 2016, 116, 12564−12649
nearly a single diastereomer. Additionally, Bringmann and co-
 Coupling reactions
Buchwald–Hartwig amina2on

mic chromop
unsuccessful a
corresponding
and primary am
L8-supported p
Diaminoanth
organic materi
double C−N b
Arslanov, Bes
designed a new
on this buildin
1,8-anthraquin
catalyst yield
Chem. Rev. 2016, 116, 12564−12649
Subsequent N
 chloroisoquinoline afforded a 1:1 mixture of diastereoisomers
Coupling reactions 55a and 55b, which were readily separable by fractional
recrystallization. Lastly, removal of the resolving agent
furnished the desired ligand in 63% yield and 96% ee.
Buchwald–Hartwig amina2on
Scheme 8. Synthesis of NHCs via the Coupling of Primary Alkylamines

12573 DOI: 10.1021/acs.chemrev.6b00512

Chem. Rev. 2016, 116, 12564−12649

Chem. Rev. 2016, 116, 12564−12649

 compounds and organic materials. Scheme 25 displays
Coupling reactions
Scheme 25. General Strategies for the Synthesis of Carbazole
Derivatives
Buchwald–Hartwig via the Coupling of Primary Anilines
amina2on

Chem. Rev. 2016, 116, 12564−12649

s in bioactive
25 displays
Coupling reactions
of Carbazole
es Buchwald–Hartwig amina2on

process: 1,2-
nes (Scheme
Chem. Rev. 2016, 116, 12564−12649
be combined
 Coupling reactions
Buchwald–Hartwig amina2on
Chemical Reviews Review

Scheme 67. Synthesis of Ligands via 2-Aminopyridine Coupling

Chem. Rev. 2016, 116, 12564−12649

 Coupling reactions
Scheme 81. Synthesis of Drug Candidates via Primary Amide 6.1.3. App
Buchwald–Hartwig amina2on
Coupling in Process C
process, Glas
procedure fo
yl)]carboxani
(Scheme 82)

Scheme 82. C

disclosed by
inhibitors of
improved to a
microwave-he
accelerated th
Chem. Rev. 2016, 116, 12564−12649
from days to
 anilines.
Chemicalreactions
Coupling Reviews
Scheme 109. General Reaction Scheme of the Use of
resulting
Buchwald–Hartwig
Ammonia
imines readily delivered the target primary anilines,
amina2on
Equivalents
stra
which were then carried on to the desired final compounds. pur
7.1.2. Applications of the Coupling of Benzophenone iod
Imine in Process Chemistry. The Pd-catalyzed cross- ach
coupling of benzophenone imine to 2-chloropyridine 443 was ary
a key step in Leahy and co-workers’s (Bristol-Myers Squibb) anil
large-scale synthesis of compound 445 (Scheme 111), a wit
12617 gro
Scheme 111. Large-Scale Coupling of Benzophenone Imine sub
at t
in t
7
Imi
use
esta
bio
452
(Sc
substructure present in >1000 CGRP receptor
Chem. Rev. antagonists
2016, 116, 12564−12649
385
 Coupling reactions
Buchwald–Hartwig amina2on
Scheme 115. Applications of the Coupling of Benzophenone Imine in the Synthesis of Organocatalysts
workers to access a new nanoporous polymer for selective CO2
uptake (457, Scheme 114b).390 The trigonal macromolecule
integrated a triptycene core with imidazole groups that were
rapidly assembled from hexaminotrypticene (456), which was
generated by six N-arylation reactions with benzophenone
imine followed by the corresponding deprotection steps.
Interestingly, the formation of 456 occurred in excellent overall
yield (90%) for this 6-fold process.
7.1.5. Applications of the Coupling of Benzophenone
obtaining the coupled product in protected form was
demonstrated in the synthesis of chiral amino sulfonamide
catalyst 463 (Scheme 115b), developed by Maruoka and co-
workers to effectively perform asymmetric Mannich reac-
tions.392 First, 1 equiv of benzophenone imine was coupled
with diaryl bromide 461 using a Pd2(dba)3/L6 catalyst.
Keeping the diarylimine as a protecting group, a second C−
N coupling reaction Chem.
Rev. 2016,
was performed between116, 12564−12649
the remaining aryl
bromide and pyrrolidine to form intermediate 462, which was
 Coupling reactions
Buchwald–Hartwig amina2on

Chem. Rev. 2016, 116, 12564−12649