C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto, with examples of pharmaceuticals

1. (With examples of Pharmaceuticals)
by
DR ANTHONY MELVIN CRASTO
Principal Scientist
INDIA
MAR 2016

2. This is a vast topic and a short
overview is given
and
in no way complete justice can be
done for this

4. Prof. Akira Suzuki
Prof. Richard
F. Heck
Prof. Ei-ichi
Negishi

5. The Nobel Prize was awarded jointly to Richard F. Heck, Ei-
ichi Negishi and Akira Suzuki for Palladium- catalyzed C-C
cross coupling reaction in 2010.
The Nobel Prize was awarded jointly to
Richard F. Heck, Ei-ichi Negishi and Akira
Suzuki for Palladium- catalyzed C-C cross
coupling reaction in 2010.
1. Importance of chemical processes in the pharmaceutical
and industries.
2. The key steps in building complex molecules from
simple precursors.

6.  Coupling reactions occur between organometallic with
organic halide with the aid of a metal containing
catalyst.
 Coupling reactions can be divided into two main classes,
cross couplings in which two different molecules react
to form one new molecule.
 The other type of coupling is homocoupling, in this
reaction two similar molecules coupling together to
form a new molecule.
Coupling Reactions

7. The C-C bond formation between an organic electrophile
(RX) and a nucleophile (Organometallic R’M or R’-C=C)
in the presence of a transition metal catalyst, usually Pd
(even Cu, Ni, Fe etc. are also used).

8.  Common metal used in this field is Pd, in
addition to Zn, Ni, Cu, B, and Sn.
 Most of coupling reactions are air and
water sensitive ??
 But, some coupling reactions can be carried
out in aqueous solutions.
Main features

9. Some thing about Palladium

10. 5. HECK (1972)
4. SONOGASHIRA (1975)
3. NEGISHI (1977)
2. STILLE
(1978)
1. SUZUKI-
MIYAURA
(1979)

12. Negishi- M= Organiozincompound
Suzuki- M= Organoboran compound
Stille-M= organotin compound
Heck-Mizoroki
Negishi –R1-M= Organozinc compound
Stille- R1-M = Organotin compound
Suzuki- R1-M = Organoborane compound

14. CuI can
increase the
reaction rate
and ability to
scavenge the
free ligand.

15. • Variable oxidation states and coordination number
Metals are Lewis acid (electron deficient):- origin of
Chemical reactivity.
There are some other type of lewis acid.
One way
interaction only.

16. RepulsionTwo major reasons are:-
1. Simultaneous availability of empty and filled non bonding orbitals ,
because of that Synergic bonding occurres.
2. Ready and reversible oxidation and reduction under one set of reaction
condition.
Charge polarization can be cancelled. Hence required very less
energy barrier.
Two way
interaction

17. Palladium is a d-block transition metal.
Pd favours the formation of tetrahedral d10 and square planar
d8 complexes of low oxidation states (0 and II respectively).
This feature affords Pd good electron-donating and electron-
accepting capabilities, allowing fine-tuning by altering the
electronic properties of its ligands.
 Pd may easily participate in concerted processes due to its
closely lying HOMO and LUMO energies.
Pd complexes tend to be less sensitive to oxygen and are less
toxic.

18. The oxidative addition of organic electrophiles (halides, sulfonates, and
related activated compounds) to Pd(0) is the first step in cross-
coupling.
• Increases both the oxidation state and coordination number of a
metal centre.
• In order for the oxidative addition to succeed, the formation of a low-
coordinate Pd(0)-species is required (e.g. the formation of 14-electron
Pd-species, L2Pd(0)).
• Oxidative additions may proceed via two major pathways that depend
on the metal center and the substrates (also any added additives,
metal-bound ligands and solvent).

19. Concerted Mechanism : Normally found in addition of non-
polar reagents and aryl halides. Retention of configuration is in
case of chiral A-B reagents.
SN2 Mechanism : Its an associative bimolecular process. Often
found in oxidative additions of polar reagents and in polar
solvents. Oxidative addition of C(sp3)-X electrophiles to Pd(0)
complexes PdL4 (L =phosphine) takes place usually by this
mechanism. Results in inversion of configuration

20.  Predominant retention in noncoordinating solvents as benzene, CH2Cl2,
tetrahydrofuran (THF), or acetone.
 On the other hand, in coordinating solvents such as MeCN or
dimethylsulfoxide (DMSO), complete or near-complete inversion was
observed .
 Electron-withdrawing substituents on aryl electrophiles led to rate acceleration.
Higher the electron density on metal , more favours the oxidative addition.
Electron rich and bulky phosphine ligands, enhances reactivity of transition metal

21.  Transmetallation reactions involve the transfer of an
organic group R from one metal M to another one
M.
Transmetallation in the Suzuki Reaction:
• Due to the low nucleophilicity of the borane reagents
(compared with organostannanes, for example), the Suzuki
reaction requires the use of base in order to take place.
• The main role of base is to generate a more reactive borate by
coordination of hydroxide to boron, which will react with the
intermediate R-Pd(II)-X complex.

22.  It is the reverse of oxidative addition.
 Reductive elimination involves the elimination or expulsion
of a molecule from a transition metal complex. In the
process of this elimination, the metal centre is reduced by
two electrons.
 The groups being eliminated must be in a mutually cis
orientation

23. • A carbometallation reaction is defined by the addition of a
carbon-metal bond of an organometallic 1 across a carbon-
carbon multiple bond 2, leading to a new organometallic 3, in
which the newly formed carbon-metal bond can be used for
further transformations.
• This step is subsequently followed by a syn-insertion process
.(resulting in a σ-organopalladium intermediate ).
• This process is sensitive not only to steric but also electronic
factors, which in turn influences the regiochemical outcome of
the reaction.

24. β-
The beta-hydride elimination can either be a vital step
in a reaction or an unproductive side reaction.
.

25. • β-Hydride elimination may occur if a β-hydrogen is accessible.
• C-C bond rotation of intermediate D is required, as well as a coordination
vacancy on the metal centre.
• Then cis β-hydrogen elimination takes place, generating a coordinated
palladium hydride complex E. The hydridopalladium species is subsequently
liberated from E, producing complex F and the free Mizoroki-Heck product G

26. Reaction Year Reactant 1 Reactant 2 Catalyst
Kumada 1972 R-MgBr RX Pd or Ni
Heck 1972 Alkene RX Pd
Sonogashira 1973 Alkyne RX Pd or Cu
Nigishi 1977 R-Zn-X RX Pd or Ni
Stille 1977 R-Sn-R3` RX Pd
Suzuki 1979 R-B(OR)2 RX Pd
Hyiama 1988 R-Si-R3 RX Pd
Buchwald-Hartwig 1994 R2-N-R RX Pd
Important coupling reactions

27.  Cross coupling between aryl or alkyl Grignard with aryl or
vinyl halocarbon.
 The first Pd or Ni catalysed coupling reaction
Kumada coupling reaction

28. Kumada coupling

29. Kumada coupling

30. Example of an iron-catalyzed Kumada reaction in the
synthesis of 122. Tetrahedron Lett.201460. , 5560. , 1376.
J. Med.
Chem.200561. , 4861. ,
6887.
J. Org.
Chem.201062. , 7562. ,
5398.

31. The coupling of organomagnesium compounds and organic electrophiles is known as the
Kumada reaction and is normally catalyzed by palladium or nickel complexes.ST1535 (122)
is a highly selective adenosine A2Areceptor ligand antagonist with good pharmacological
properties, which might be considered a potential new drug for the treatment of
Parkinson's disease.
Previous approaches for its synthesis explored Stille or Suzuki couplings for the
installation of the alkyl side chain present in the final target.Despite the good yields
observed, both approaches suffered from major drawbacks such as drastic reaction
conditions, low turnover number and frequency for the palladium catalysts employed,
the need to prepare organoboron or tin reagents and the toxicity of starting materials
and by-products in the special case of Stille reaction.
In this context, in 2014, the authors described a new approach exploring the Kumada
coupling of a Grignard reagent, one of the cheapest organometallic reagents available,
catalyzed by Fe(acac)3, where acac = acetylacetonate, which is also a low-cost and easily
removable catalyst.
Besides the advantages regarding the cost of reagents and catalysts, the new procedure
also generates less waste, due to the intrinsic higher atom-economy and also by not
requiring an excess base, as seen for the Suzuki coupling approach. This procedure was
successfully employed in the preparation of 38.5 g of 123, which could be converted
to 122 through bromination and bromine displacement with triazole followed by benzyl
protecting group removal, as previously described in the literature

32.  Pd catalyzed coupling between aryl or vinyl halides with
activated alkene in basic media.
Heck coupling

33.  Broadly defined as the palladium-catalyzed coupling of alkenyl or aryl (sp2) halides or
triflates with alkenes to yield products which formally result from the substitution of a
hydrogen atom in the alkene coupling partner.
 First discovered by Mizoroki, though developed and applied more thoroughly by Richard F.
Heck in the early 1970s.[3]
 Generally thought of as the original palladium catalysed cross-coupling, and probably the best
evolved, including a multitude of asymmetric varients.[4]
The Heck Reaction
3. R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37, 2320
4. Review on asymmetric Heck reactions: A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 – 2963
H
R1
R2
R3
R4
X R4
R1
R2
R3
cat. [Pd0
Ln]
base
R4
= aryl, benzyl, vinyl
X = Cl, Br, I, OTf

34. Mechanism of the Heck Reaction
neutral
PPh3
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
Pd
Ph3P
Br PPh3
PdII
O
O
Pd
Ph3P
Br PPh3
O
O
PdII
-Complex
Pd
Ph3P
Br
O O
H H
PdII
-Intermediate
Pd
Ph3P H
Br PPh3
O
O
PdII
-Complex
Pd
Ph3P H
Br PPh3
B
HBr / B
PdIIO
O
Oxidative
Addition
-hydride
Elimination
Reductive
Elimination

35. Mechanism of the Heck Reaction
cationic
PPh3
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
Pd
Ph3P
Br PPh3
PdII
O
O
Pd
Ph3P
PPh3
O
O
PdII
-Complex
Pd
Ph3P
O O
H H
PdII
-Intermediate
Pd
Ph3P H
PPh3
O
O
PdII
-Complex
Pd
Ph3P H
PPh3
B
PdIIO
O
Oxidative
Addition
-hydride
Elimination
Reductive
Elimination
BrAg
HB
Ag
Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.

36.  The type of mechanism in action is incredibly important, as it can manifest itself in a variety of ways, especially
the regioselectivity.
 In the neutral catalytic cycle, the regioselectivity is governed by steric factors – generally addition occurs to the
terminal end of the alkene.
 However, in the cationic cycle, regiochemistry is affected by electronics. The cationic Pd complex increases the
polarization of the alkene favouring transfer of the vinyl or aryl group to the site of least electron density.
 The type of mechanism in effect is generally controlled by choice of halide/pseudohalide acting as a leaving
group in the cationic cycle; triflate promotes, whereas bromide detracts.
Regioselectivity in the Heck Reaction
a) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481–1486.
Ph
Y N
CH3 OH
O
OH
100 90 100
10
100 60 80
40 20
Y = CO2R
CN
CONH2
Ph
Y N
CH3 OH
O
OH
60 5
95
100 10
100 90
Y = CO2R
CN
CONH2
40 100
Neutral Catalytic Cycle Cationic Catalytic Cycle

37. The Heck Reaction: Dehydrotubifoline
a) V. H. Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115, 3030 – 3031
b) V. H. Rawal, C. Michoud, J. Org. Chem. 1993, 58, 5583 – 5584.
N
R
H
N I
Me
H
N
N
Me
H
H
N
N
Me
H PdII
Ln
OMeO
H
N
N
H
H
MeO2C
PdII
Ln
Me
H
N
N
H
H
MeO2C
PdII
Ln
second 1,2-
insertion
-hydride
elimination
bond rotation,
rearrangement
Pd(OAc)2, K2CO3
nBu4NCl, DMF, 60 °C
N
N
Me
H
H
MeO2C
Heck Cyclisation
3: (±)-dehydrotubifoline
dehydrotubifoline
1: R=H
2: R=CO2Me
4
5 6
7

38. The Heck Reaction: Capnellene
a) K. Kagechika, M. Shibasaki, J. Org. Chem. 1991, 56, 4093 –4094
b) K. Kagechika, T. Ohshima, M. Shibasaki, Tetrahedron, 1993, 49, 1773 – 1782.
TfO
Me
Me
Pd
P
P
*
Me
Pd
P
P
*
Pd(OAc)2 (1.7 mol%)
(S)-binap (2.1 mol%)
nBu4NOAc
DMSO, 20 °C
major minor
OTf OTf
14
15 18
catalysic
asymmetric
Heck Cyclisation
P
P
*
H
Me
Pd
AcO
OAc
(89% yield,
80% ee)
anion
capture
16
H
Me
OAc
17
MeHO
Me
H
OH
H
HOMe
MeHO
H
OH
H
HOMe
HO
capnellene
9(12)-capnellene-
3,8,10-triol
9(12)-capnellene-
3,8,10,14-tetraol
H
Me
OAc
19
PPh2
PPh2
P
P
* =
(S)-binap

39. The Heck Reaction: Taxol
a) S. J. Danishefsky, J. J. Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K. Jung, R. C. A. Isaacs, W. G. Bornmann, C. A.
Alaimo, C. A. Coburn, M. J. Di Grandi, J. Am. Chem. Soc. 1996, 118, 2843 – 2859
b) J. J. Masters, J. T. Link, L. B. Snyder, W. B. Young, S. J. Danishefsky, Angew. Chem. Int. Ed. Engl. 1995, 34, 1723 – 1726.
O
O
O
OTf
Me
H
BnO
O
OTBS
Me
O
O
O
Me
H
BnO
O
OTBS
Me
HO
BzO
Me
H
AcO
O
OH
Me
AcO
O
O
BzHN
OH
Ph
O
taxol
[Pd(PPh3)4] (110 mol%)
M. S. (4 A)
K2CO3, MeCN, 90 °C
(49%)
Intramolecular
Heck Reaction
22
23
24: taxol

40. The Heck Reaction: Estrone
L. F. Tietze, T. NVbel, M. Spescha, J. Am. Chem. Soc. 1998, 120, 8971 – 8977.
MeO
Br
Br
Me Ot
Bu
Pd(OAc)2, PPh3
nBu4NOAc
DMF/MeCN/H2O
70 °C
Intermolecular
Heck Reaction
MeO
Br
PdLn
Br
Me
Ot
Bu
H
5
4
MeO
Br H
Me Ot
Bu
H
MeO
H
Me Ot
Bu
HH
HO
H
Me O
HHA
D
29, nBu4NOAc
DMF/MeCN/H2O
115 °C
(99%)
(50%)
Intramolecular
Heck Reaction
25
26
27
26
28
30
30: estrone
estroneP
Pd
o-Tol o-Tol
O
O P
Pd
o-Tolo-Tol
O
O
Me
Me

41. Domino Heck Reactions
Y. Zhang, G.Wu, G. Angel, E. Negishi, J. Am. Chem. Soc. 1990, 112, 8590 – 8592.
Me
EtO2C
EtO2C
I
Me
EtO2C
EtO2C
I
Me
EtO2C
EtO2C
[Pd(PPh3)4] (3 mol%)
Et3N (2 eq.)
MeCN, 85 °C
(76%)
Intramolecular
Domino Heck
Cyclisation32 33

42. Domino Heck Reactions
a) L. E. Overman, D. J. Ricca, V. D. Tran, J. Am. Chem. Soc. 1993, 115, 2042 – 2044
b) D. J. Kucera, S. J. OIConnor, L. E. Overman, J. Org. Chem. 1993, 58, 5304 – 5306.
O
O
I
TBSO
Me
H
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
Ag2CO3
THF, 70 °C
Oxidative
Addition
PdLn
TBSO
Me
H
I
1,2-insertion
OO
TBSO
Me
H
PdLn
I
1,2-insertion
TBSO
Me Ln
Pd
H
OO
I
TBSO
Me Ln
Pd
H
OO
I
OBz
Me
H
-Hydride
Elimination
scopadulic acid
O
HO2C
Me
H
HO
42: Scopadulic Acid B
4140
39
3837
(82% overall)
OO
Intramolecular Heck Cascade

43. Heck coupling

44. Synthesis of idebenone (124) based on Heck reaction of 2-
bromo-3,4,5-trimethoxy-1-methylbenzene with dec-9-en-1-ol
under microwave irradiation.
Org. Process Res. Dev.201165. , 1565. , 673.

45. The palladium-catalyzed olefination of a sp or benzylic carbon attached to a
(pseudo)halogen is known as the Heck reaction.
It is a powerful tool, mainly used for the synthesis of vinylarenes, and it has also been
employed for the construction of conjugated double bonds. The widespread application
of this reaction can be illustrated by numerous examples in both academia small-scale
and industrial syntheses.As an example, in 2011, a idebenone (124) total synthesis based
on a Heck reaction was described .
This compound, initially designed for the treatment of Alzheimer's and Parkinson's
diseases, presented a plethora of other interesting activities, such as free radical
scavenging and action against some muscular illnesses. The key step in the synthesis
was the coupling of 2-bromo-3,4,5-trimethoxy-1-methylbenzene (125) with dec-9-en-1-ol
affording products 126. Under non-optimized conditions (Pd(OAc)2, PPh3, Et3N, 120 ºC), a
mixture composed of 60% linear olefins 126 and 15% of the undesired branched
product 127 was obtained after three days of reaction.
Therefore, the conditions were optimized, allowing the preparation of 126 in 67% yield
with no detection of 127 after only 30 min of reaction employing DMF,
Pd(PPh3)4, iPr2NEt under microwave heating. To conclude the synthesis, the Heck
adducts were submitted to hydroxyl protection/deprotection, hydrogenation, and ring
oxidation. After these reactions, idebenone was obtained with 20% overall yield over 6
steps.

46. J. Agric. Food Chem.201366. , 6166. , 5347.
Synthesis of the
ginkgolic acid based
on the Heck reaction
of aryl triflate 130

47. A similar strategy to link an aryl and an alkyl group by means of a Heck reaction
was applied in 2013 in the synthesis of ginkgolic acid (13:0) (128), a tyrosinase
inhibitor, as shown in SCHEME
Benzoic acid 88 was used as starting material in order to obtain the triflate 130.
This intermediate and the 1-tridecene were employed as coupling partners in
the Heck reaction to obtain 131.
The system used was based on PdCl2(dppf) and K2CO3, affording the coupling
product in 78% yield after 12 h with 3.2 mol% of palladium.
An alternative pathway to link the alkyl and aryl fragments was also tested: the
coupling was performed in the presence of 9-borabicyclo(3,3,1)-nonane (9-
BBN) to generate an alkylborane in situ from olefin 132 and achieve Suzuki
coupling. However, this methodology was not productive.
Once the Heck reaction was performed, 128 was obtained with 34% overall
yield after the reduction of the double bond and the hydrolysis of the acetal
protecting group.

48. J. Org. Chem.201267. , 7767. , 6340.
Heck reaction in synthesis
of olopatadine (133)
and trans-olopatadine
(134).

49. An intramolecular Heck-based cyclization was used as a key step for
commendable synthesis of the antihistaminic drug olopatadine (133) and
its trans isomer (134).
Besides the Heck reaction, another vital step in this route was a stereoselective
Wittig olefination using a non-stabilized phosphorus ylide that afforded the
olefins 135 and 136 (E:Z ratio = 9:1 for 135, for instance).
Concerning the Heck reaction, Pd(OAc)2, K2CO3, and NBu4Cl (TBAC) were
allowed to react with 135 and 136 at 60 ºC during 24 h, providing the cyclic
adducts 137 and 138 with reasonable 60% and 55% yields, respectively.
However, it is important to note that in catalytic terms, the results were not
encouraging, considering that 20 mol% of palladium was used and a
disappointing turnover number (TON) of 3 was observed

50. Synthesis of (R)-tolterodine based
on a Heck-Matsuda reaction and
enantioselective reduction of
compound 152.

51. A variation of the Heck reaction that has attracted considerable attention in recent
years is the so-called Heck-Matsuda arylation, which is based on the use of
aryldiazonium salts as electrophiles.
These compounds have the advantages of lower cost and improved reactivity in
comparison to more traditional electrophiles like aryl halides.As an example, a Heck-
Matsuda based strategy via aryl-coumarins was used in the synthesis of (R)-tolterodine
(149), a drug that is employed in urinary incontinence treatment.
The coupling was employed in the first step of the route between the ortho-
substituted cinnamate 150 and the 4-bromo substituted arenediazonium salt 151, using
10 mol% of Pd(OAc)2 as a pre-catalyst and CaCO3 as base. It is important to note that
the target molecule tolterodine contains no bromine substituents, for this reason,
after completion of the Heck reaction, the product was not isolated, being directly
submitted to debromination under H2 atmosphere and subsequently isolated
as 152 with 63% over two steps .
The employment of the bromo-substituted aryldiazonium salt instead of
phenyldiazonium salt was justified by the lower yield of the Heck reaction using
PhN2BF4 (only 41% yield). Nonetheless, compound 152 had already been synthesized via
a Heck reaction with 77% yield without requirement of the debromination step.
With the desired coumarin 152 in hands, the synthesis was accomplished by a copper-
catalyzed enantioselective conjugate reduction, furnishing153, followed by reductive
amination. With this methodology, (R)-tolterodine was obtained in 30% overall yield
and 98% ee after four steps.

52. Mizoroki-Heck Reaction

53. The Mizoroki-Heck reaction between alkenyl bromide and methyl acrylate.
Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083. DOI: 10.1021/jo00896a020

54.  Terminal alkynes with aryl or vinyl halides (triflate).
 Pd as a catalyst, Cu as co-catalyst and an amine as a base.
Sonogashira coupling

55. Sonogashira coupling

57. Sonogashira coupling

58.  The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported
independently and simultaneously by the groups of Cassar[16] and Heck[17] in 1975.
 A few months later, Sonogashira and co-workers demonstrated that, in many cases, this cross-coupling
reaction could be accelerated by the addition of cocatalytic CuI salts to the reaction mixture.[18,19]
 This protocol, which has become known as the Sonogashira reaction, can be viewed as both an alkyne
version of the Heck reaction and an application of palladium catalysis to the venerable Stephens–Castro
reaction (the coupling of vinyl or aryl halides with stoichiometric amounts of copper(I) acetylides).[20]
 Interestingly, the utility of the “copperfree” Sonogashira protocol (i.e. the original Cassar–Heck version
of this reaction) has subsequently been “rediscovered” independently by a number of other
researchers in recent years.[21]
The Sonogashira Coupling
16. L. Cassar, J. Organomet. Chem. 1975, 93, 253 – 259.
17. H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259 – 263.
18. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467 – 4470.
19. For a brief historical overview of the development of the Sonogashira reaction, see: K. Sonogashira, J. Organomet. Chem. 2002, 653,
46 – 49.
20. R. D. Stephens, C. E. Castro, J. Org. Chem. 1963, 28, 3313 – 3315.
21. a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, 6403 – 6406; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992,
715 – 717; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431 – 434;
R2
X
cat. [Pd0
Ln]
base
R1
= alkyl, aryl, vinyl
R2
= alkyl, benzyl, vinyl
X = Br, Cl, I, OTf
R2
R1
H R2

59. Mechanism of the Sonogashira Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
Ph3P
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
Pd
Ph3P
Br PPh3
PdII
Pd
Ph3P
PPh3
R1
R1
Cu
CuBr
H
R1
NEt3
Pd
Ph3P
Ph3P
R1
R1
R1
NEt3H
PdII
PdII

60. K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736
The Sonogashira Coupling: Eicosanoid 212
MeBr
OTBS
TMS
Sonogashira
Coupling
[Pd(PPh3)4] (4 mol%)
CuI (16 mol%)
nPrNH2, C6H6, 25 °C
R
Me
OTBS
AgNO3,
KCN
208: R = TMS
209: R = H
210, [Pd(PPh3)4] (4 mol%)
CuI (16 mol%)
nPrNH2, C6H6, 25 °C
76% Overall from 208
Br
CO2Me
OTBS
Me
OTBS
CO2Me
OTBS
Me
OH
CO2H
OH
Sonogashira
Coupling
206
207
210
211212

61. P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.
The Sonogashira Coupling: Disorazole C1
Me
PMBO
Me
OH
Me
Me
PMBO
Me
OH
Me
MeO O
N
CO2Me
Sonogashira
Coupling
218
[Pd(PPh3)2Cl2] (4 mol%)
CuI (30 mol%), Et3N
MeCN, -20 °C, 94%
220, DCC, DMAP
80%
Me
PMBO
Me
O
Me
MeO O
N
CO2Me
O
N
O
I
OMe
218
[Pd(PPh3)2Cl2] (5 mol%)
CuI (20 mol%), Et3N
MeCN, -20 °C, 94%
Sonogashira
Coupling
Me
PMBO
Me
O
Me
MeO O
N
CO2Me
O
N
O OMe
OH
Me Me
OPMB
Me
Me
OH
Me
O
Me
MeO O
N
O
N
O OMe
O
Me Me
OH
Me
O
disorazole
N
O
RO
O
I
OMe
218: R = Me
220: R = H
217 219
221
222223: Disorazole C1

62. The Sonogashira Coupling: Dynemicin
MeO2CN
OMe
Me
O
O
Br
MeO2CN
OMe
Me
O
OIntramolecular
Sonogashira
Coupling
[Pd(PPh3)4] (2 mol%)
CuI (20 mol%)
toluene, 25 °C
243 244
MeO2CN
OMe
Me
O
O
244
H
H
H
H
MeO2CN
OMe
Me
OH
246
[Pd(PPh3)4] (2 mol %)
CuI (20 mol %)
toluene, 25 °C
Br
CO2Me
1)
2) LiOH, THF/H2O
65% overall
Sonogashira
Coupling
MeO2CN
OMe
Me
OH
CO2H
Diels-
Alder
2,4,6-Cl3C2H2COCl
DMAP, toluene, 25 °C
50%
248
247
Yamaguchi
Macrolactonisation/
Diels-Alder
HN
OMe
Me
H
O
O
O
OMe
OMe
OMe
CO2Me
dynemicin
249: tri-O- methyl dynemicin A
methyl ester
a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10 378 – 10379
b) J. L. Wood, J. A. Porco, Jr., J. Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc.
1992, 114, 5898 – 5900
c) H. Chikashita, J. A. Porco, Jr., T. J. Stout, J. Clardy, S. L. Schreiber, J. Org. Chem. 1991, 56, 1692 – 1694
d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 7410 –
7411.

63. Nishimura, K.; Kinugawa, M.; Org. Process
Res. Dev.201251. , 1651. , 225
Olopatadine hydrochloride

64. The construction of a new bond between sp2- and sp-hybridized carbons is known as the
Sonogashira reaction,and it is nowadays a widely employed methodology for the
construction of arylacetylenes. For example, a Sonogashira coupling was employed by the
research and development group of Kyowa Hakko Kirin in a new and concise synthetic
route for olopatadine hydrochloride (92), a commercial anti-allergic drug that was
previously developed by the same company.
The reported synthesis goes through the Sonogashira reaction between the easy
accessible aryl halide 93 and alkyne 94 leading to adduct 95 in 94% yield. This adduct is then
subjected to a second metal-catalyzed transformation, a stereospecific palladium-
catalyzed intramolecular cyclization, whose optimum conditions were identified based on
an elegant and comprehensive Design of Experiments (DoE) investigation to provide 96
Elaboration of the cyclization product 96 through aminomethylation and ester hydrolysis
followed by acid work-up completes the synthesis of the final target. Although the
presented synthetic route is very promising and concise, providing olopatadine
hydrochloride in 54% overall yield for 6 steps from commercially available materials, it has
so far been reported only on a laboratory scale (5 g for the Sonogashira coupling and 200
mg for the cyclization step).

65. GRN-529
Sperry, J. B.; ET AL Org. Process Res.
Dev.201252. , 1652. , 1854.

66. In 2012, in order to obtain necessary quantities for preclinical and
phase 1 clinical studies, investigators at Wyeth Research reported
the process implementation for the multi-kilogram preparation of
GRN-529 (97), a highly selective mGluR5 negative allosteric
modulator that was previously identified by the same company.
The authors opted for the development of the synthetic route
initially presented by the medicinal chemistry group, which
featured a Sonogashira coupling as one of the key steps. Despite
the good yield observed for this transformation, the conditions
originally employed were not amenable for the scale-up of the
reaction, requiring high loadings of metallic catalysts and drastic
reaction conditions, as well as chromatographic purification of
the product. During the developmental work, process friendly
conditions were identified for the effective coupling between aryl
halide 98 and alkyne 99, resulting in at least 10-fold reduction of
metal catalyst loadings and considerably lower reaction
temperatures

67. A purification process involving the treatment of the crude
reaction with an aqueous cysteine and ammonia solution
followed by crystallization of the product afforded the coupling
adduct 100 with high purity, acceptable levels of residual
palladium and copper, and an even higher yield (86%).
Elaboration of the coupling product100 through ester hydrolysis
followed by amidation furnished the final API, which was further
purified via crystallization, leading to even lower residual levels
of palladium and copper (< 1 and 15 ppm, respectively). This
process was successfully employed in the preparation of 5.5 kg
of 97.

68. MK-1220
Org. Process Res. Dev.201453. , 1853. , 423.
ACS Med. Chem. Lett.201154. , 254. , 207.

69. Process chemistry researchers from Merck recently employed Heck and Sonogashira
reactions in the multi-gram preparation of the macrocyclic compound MK-1220 (101), a
potent hepatitis C virus (HCV) protease inhibitor with good therapeutic profile which
has been evaluated as a potential new drug for the treatment of hepatitis C.
As an early synthetic step, a Heck reaction was used to introduce the nitrogen and two
carbon atoms of the isoquinoline moiety present in the final target. The presence of a
bulky substituent in the olefin 102 allowed the achievement of a 90:10 regioselectivity
favouring the arylation of the terminal carbon, leading to adduct 103 in 76% isolated
yield
A Sonogashira reaction was employed at a later stage of the synthesis, allowing the
coupling of the advanced fragments 104 and 105 in 90% yield. The reaction conditions for
this coupling were chosen based on a high throughput screening (HTS) study, which
evaluated, among other factors, the use of 12 distinct ligands. Among them, only
PtBu3.HBF4 led to a clean reaction and satisfactory conversion. The triple bond reduction
of the coupling adduct 106 with concomitant removal of carboxybenzyl (CBz) protecting
group led directly to the substrate for the key macrocyclization step (107). The side chain
installation in 107 completed the total synthesis of MK-1220. According to the authors,
this synthetic sequence could be successfully scaled-up to produce kilograms of the final
API.

70. FILIBUVIR
Org. Process Res. Dev.201455. , 1855. , 26.

71. The Sonogashira reaction has also recently been used in the synthesis of Filibuvir (108),
a potential drug for hepatitis C treatment, which acts as an inhibitor of RNA polymerase
and has been evaluated by clinical and toxicological studies.
The coupling between the alkyne 109 and aryl bromide 110 , employed to introduce the
pyridine moiety present in the final target, required the careful exclusion of oxygen
from the reaction medium and addition of the palladium source prior to the copper
catalyst, taking special care to avoid the formation of by-products through the oxidative
coupling of the alkyne coupling partner
The coupling adduct 111 was then subjected to an acylation reaction followed by
reduction of the triple bond to afford 112. One of the drawbacks initially observed in this
sequence was the high catalyst loading required for the hydrogenation step, which was
attributed to poisoning of the metallic catalyst by residues of copper and phosphine
derived from the initial Sonogashira coupling. Thus, previous purification of the acylated
coupling product by washes with aqueous ethylenediaminetetraacetic acid (EDTA)
followed by filtration through activated charcoal was necessary. This sequence of
reactions was carried out on a pilot scale, producing 11.95 kg of the advanced
intermediate 112.
It should be mentioned that alkyne 109 is prepared by an aldol addition to the
ketone 113 which, in turn, may also be prepared through a Sonogashira-type reaction
involving the acid chloride 114 followed by desilylation. Although the authors present
alternative and possibly more suitable synthetic routes for the preparation of this
alkynyl ketone, the procedure based on the coupling between 109 and 110 could be
successfully employed in the preparation of 100 kg of this material.

72.  Pd or Ni catalyzed coupling organozinc compounds with
aryl, vinyl, benzyl halids.
Nigishi coupling

73.  The use of organozinc reagents as the nucleophilic component in palladium-catalyzed
cross-coupling reactions, known as the Negishi coupling, actually predates both the
Stille and Suzuki processes, with the first examples published in the 1970s.[25]
 However, the stunning progress in the latter procedures left the Negishi process
behind, underappreciated and underutilised.
 Organozinc reagents exhibit a very high intrinsic reactivity in palladium-catalyzed
cross-coupling reactions, which combined with the availability of a number of
procedures for their preparation and their relatively low toxicity, makes the Negishi
coupling an exceedingly useful alternative to other cross-coupling procedures, as well
as constituting an important method for carbon–carbon bond formation in its own
right.[26]
The Negishi Coupling
R1
R3
X
cat. [Pd0
Ln]
R1
= alkyl, alkynyl, aryl, vinyl
R3
= acyl, aryl, benzyl, vinyl
X = Br, I, OTf, OTs
ZnR2
R1
R3

74. 25.a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821 –
1823; for a discussion, see: b) E. Negishi, Acc. Chem. Res. 1982, 15, 340 –
348.
26.a) E. Erdik, Tetrahedron 1992, 48, 9577 – 9648; b) E. Negishi, T.
Takahashi, S. Babu,D. E. Van Horn, N. Okukado, J. Am. Chem. Soc. 1987,
109, 2393 – 2401.

75. Mechanism of the Negishi Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
I
Pd
Ph3P
PPh3I
PdII
Pd
Ph3P PPh3
PdII
-Complex
R1
R2
ZnBr
R3
Pd
Ph3P
Ph3P
PdII
R3
R2
R1
R3
R2
R1
R3
R2
R1
Zn (dust) 1.5 eq
I2 (5 mol %)
DMA, 80 °C
ZnBrI
R1
R2
Br
R3
Pd
Ph3P
PPh3
R3
R2
R1
PdII

76. The Negishi Coupling:
Discodermolide
a) A. B. Smith III, T. J. Beauchamp, M. J. LaMarche, M. D. Kaufman, Y. Qiu, H. Arimoto, D. R. Jones, K. Kobayashi, J. Am. Chem. Soc. 2000,
122, 8654 – 8664;
b) A. B. Smith III, M. D. Kaufman, T. J. Beauchamp,M. J. LaMarche, H. Arimoto, Org. Lett. 1999, 1, 1823 – 1826.
c) For a review of the chemistry and biology of discodermolide, see: M. Kalesse, ChemBioChem 2000, 1, 171 – 175
d) For examples of other approaches to discodermolide, see: I. Paterson, G. J. Florence, Eur. J. Org. Chem. 2003, 2193 – 2208.
e) In the synthesis of discodermolide by the Marshall group, a B-alkyl Suzuki–Miyarua fragment-coupling strategy was employed to form the
C14C15 bond, in which 2.2 equivalents of an alkyl iodide structurally related to 309 was required: J. A. Marshall, B. A. Johns, J. Org.
Chem. 1998, 63, 7885 – 7892.
I
Me Me
TBSO O O
PMP
Me
t
BuLi, ZnCl2
Et2O
-78 °C Zn
Me Me
TBSO O O
PMP
Me
[Pd(PPh3)4] (5 mol%)
311
Et2O, 25 °C, 66%
Negishi Coupling
Me Me
OTBS O O
PMP
Me
Me
PMBO
Me
OTBS
Me
I
PMBO
Me
OTBS
Me
Me
= 311
Me Me
OH O
Me
MeMe
OH
Me
NH2
OO
O
HO
HO
Me
HO
discodermolide
313: discodermolide
312310309
1515
15
14
14
15
14

77. The Negishi Coupling: Amphidinolide T1
a) C. Aïssa, R. Riveiros, J. Ragot, A. Fürstner, J. Am. Chem. Soc. 2003, 125, 15 512 – 15520.
O
Me
R
OMOM
TBDPSO Me
314: R = ZnI
(315: R = I)
(316: R = H)
[Pd2(dba)3] (3 mol%)
285
P(2-furyl)3 (6 mol %)
toluene/DMA, 25 °C, 50%
Negishi Coupling
O
O
Me
Me
Cl O
O
Me
OMOM
TBDPSO Me
O
O
Me
Me
O
O
Me
OMOM
TBDPSO Me
O
O
Me
Me
O
317
318
319: Amphidinolide T1
amphidinolide

78. Nigishi coupling
The Negishi reaction is the coupling between an aryl (or
vinyl) halide and an organozinc compound.
This coupling presents a greater tolerance towards
sensitive groups like esters or amides when compared
to organomagnesium or organolithium-based reactions;
moreover, the enhanced reactivity of organozinc
compounds allows this reaction to be performed at or
even below room temperature,
while boron or tin coupling partners demand harsher
conditions.

79. BMS-599793
See description in next slide
Pikul, S et al Org. Process Res.
Dev.201346. , 1746. , 907.

80. In 2013, a Negishi coupling was employed as one of the key steps
in a new synthetic approach to BMS-599793 (84), an HIV entry
inhibitor licensed from Bristol-Myers Squibb (BMS) by the
International Partnership for Microbicides aiming towards its
further development as a topical microbicide candidate for use in
underdeveloped countries.
While the original medicinal chemistry route employed a Stille
coupling as the last step of the sequence, this new synthetic
approach anticipates the metal-catalyzed C-C bond forming
reaction using a Negishi coupling as the first step, which
eliminated the inconvenience of high levels of toxic tin residues
previously observed in the final product.
The coupling between diarylzinc reagent 85 and azaindol 86 led
to adduct 87, obtained in 41 to 59% yield for several batches of
400 g each. A single experiment carried out at a 1.5 kg scale
afforded 87 in 54% yield and 99.6% HPLC purity

81. Synthesis of 88 with low loadings of Pd in a Negishi coupling.
Shu, L.; Org. Process Res.
Dev.201347. , 1747. , 651.

82. Acylation of the adduct's azaindole moiety with methyl chlorooxalate followed by ester
hydrolysis and amidation afforded the final product which, however, still exhibited a
high residual content of palladium (16 ppm) and zinc (100 ppm), requiring additional
purification steps. At the end of the synthetic sequence, product treatment with
activated charcoal followed by several washes, a precipitation step and polymorphic
conversions led to the final active pharmaceutical ingredient (API) with Pd and Zn
contents of only 1 ppm each.
A Negishi reaction was also used in a multi-gram synthesis of compound 88, a CHRT2
receptor antagonist with good pharmacological profile that was previously identified by
Roche.
Since it is believed that CHTR2 plays a pro-inflammatory role in allergic processes, its
antagonists are viewed as potential new drugs for the treatment of asthma, allergic
rhinitis, chronic obstructive pulmonary disease (COPD) and atopic dermatitis, among
other diseases. En route to 88, the Negishi coupling between benzylzinc reagent 89 and
aryl triflate 90 represented a major challenge.
According to the previously developed medicinal chemistry synthetic route, the arylzinc
preparation required a highly exothermic zinc activation process and the subsequent
coupling step employed very high catalyst loadings, both of which are serious
drawbacks for the scaling-up of the synthesis .

83. During the process development, a traditional zinc activation approach was found to be
effective, and by using trimethylchlorosilane in DMF, 237 g of zinc dust could be activated
with only a 5 ºC temperature increase over a 30 min period.
Regarding the proper Negishi coupling step, in a first moment, the authors were able to
perform a 20-fold reduction in both palladium and phosphine quantities; however, the
high cost of SPhos ligand was still prohibitive for large-scale production, even at 1 mol%
loading. Fortunately, the inexpensive PdCl2(PPh3)2complex was equally effective when
employed as the sole catalyst at 0.5 mol% loading.
Due to safety reasons associated with transferring a high reactive zinc reagent, the
coupling reaction was performed at the same pot of zincate formation by the sequential
addition of the Pd source and aryl triflate followed by heating to 60-65 ºC, which initiated
the reaction.
Without further heating, a temperature increase of up to 30 ºC in a 10 min period was
observed for batches involving 500 g of trifate 90, which should be bypassed for further
scale-up. Filtration of the reaction crude trough Celite and treatment with N-acetyl-L-
cysteine followed by crystallization afforded the coupling product 91 in 95% yield and >
99% HPLC purity. The final hydrolysis step afforded the desired API, which displayed well-
controlled levels of residual palladium and zinc (6 and 20 ppm, respectively).

84.  Using tin (stannes) alkyl compounds, wide range of
R groups, but?????
 Less polar, more toxic???
Stille coupling

85.  Originally discovered by Kosugi et al[5] in the late 1970s, the Stille Coupling was later developed as a tool
for organic transformations by the late Professor J. K. Stille.[6]
 Milder than the older Heck reaction, and more functional-group tolerant, the Stille coupling remains
popular in organic synthesis.
 A close relative of the Stille coupling is the Hiyama; this involves the palladium catalysed reaction of a
organosilicon with organic halides/triflates et c., but requires activation with fluoride (TBAF) or
hydroxide.[7]
 It is possible to couple bis-aryl halides using R3Sn-SnR3, in a varient known as a Stille-Kelly reaction, but
the toxicity of these species is a somewhat limiting factor.[8]
The Stille Coupling
5. Original Report; a) M. Kosugi, K. Sasazawa, Y. Shimizu, T. Migita, Chem. Lett. 1977, 301 – 302; b) M. Kosugi, K. Sasazawa, T. Migita,
Chem. Lett. 1977, 1423 – 1424.
6. a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636 – 3638; b) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4992 –
4998; c) For a review of Stille Reactions, see; V. Farina, V. Krishnamurthy,W. J. Scott, Org. React. 1997, 50, 1 – 652
7. T. Hiyama, Y. Hatanaka, Pure Appl. Chem. 1994, 66, 1471
8. T. R. Kelly, Tetrahedron Lett. 1990, 31, 161
R1
R2
X
cat. [Pd0
Ln]
base
R1
= alkyl, alkynyl, aryl, vinyl
R2
= acyl, alkynyl, allyl, aryl, benzyl, vinyl
X = Br, Cl, I, OAc, OP(=O)(OR)2, OTf
SnR3 R1
R3

86. Mechanism of the Stille Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
Ph3P
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
Pd
Ph3P
Br PPh3
PdII
Pd
Ph3P
PPh3
Pd
Ph3P
Ph3P
BrSnBu3
SnBu3
R2
R1
R3
R2
R3
R1
R2
R1
PdII
PdII
R1
R1
R2
R1

88. The Stille Coupling: Rapamycin
a) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato, J. Am. Chem. Soc. 1993, 115, 4419 – 4420; K. C. Nicolaou, A. D.
Piscopio, P. Bertinato, T. K. Chakraborty, , N. Minowa, K. Koide, Chem. Eur. J. 1995, 1, 318 –333.
b) A. B. Smith III, S. M. Condon, J. A. McCauley, J. L. Leazer, Jr.,J. W. Leahy, R. E. Maleczka, Jr., J. Am. Chem. Soc. 1995, 117, 5407 – 5408.
O
O
NO
I
Me
I
O
Me
O
O
O
H
OH
H
Me
Me
OH
MeOMe
Me
H OH
Me
OMe
OMe
Bu3Snn
Snn
Bu3
[PdCl2(MeCN)2]
(20 mol%)
iPr2NEt, DMF,
THF, 25°C
Intermolecular
Stille Coupling
O
O
NO
I
Me
O
Me
O
O
O
H
OH
H
Me
Me
OH
MeOMe
Me
H OH
Me
OMe
OMe
Snn
Bu3
Intramolecular
Stille Coupling
O
O
NO
Me
O
Me
O
O
O
H
OH
H
Me
Me
OH
MeOMe
Me
H OH
Me
OMe
OMe
O
O
NO
Me
O
Me
O
O
O
H
OTIPS
H
Me
Me
OTBS
MeOMe
Me
H TESO
Me
OMe
OMe
Snn
Bu3
I
1. [PdCl2(MeCN)2] (20 mol%)
iPr2NEt, DMF, THF, 25°C (74%)
Intramolecular
Stille Coupling
2. Deprotection (61%)
27%
Overall
rapamycin
76: Rapamycin75
7472
"Stitching Cyclisation"

89. The Stille Coupling: Dynamycin
a) M. D. Shair, T.-Y. Yoon, K. K. Mosny, T. C. Chou, S. J. Danishefsky, J. Am. Chem. Soc. 1996, 118, 9509 – 9525;
b) M. D. Shair, T.-Y. Yoon, S. J. Danishefsky, Angew. Chem. 1995, 107, 1883 – 1885; Angew. Chem. Int. Ed. Engl. 1995, 34, 1721 – 1723;
c) M. D. Shair, T. Yoon, S. J. Danishefsky, J. Org. Chem. 1994, 59, 3755 – 3757.
TeocN
O
OH
OH
H
Me
I
I
OTBS
Me3Sn SnMe3
[Pd(PPh3)4] (5 mol%)
DMF, 75 °C
81%
Tandem
Intermolecular
Stille Coupling
TeocN
O
OH
OH
H
Me
OTBS
HN
O
CO2H
OMe
H
Me
OH
O
O
OH
OH
79
dynemicin
81: (±) Dynamycin77
Teoc = 2-(trimethylsilyl)ethoxycarbonyl

90. The Stille Coupling: Sanglifehrin
a) K. C. Nicolaou, J. Xu, F. Murphy, S. Barluenga, O. Baudoin, H.-X.Wei, D. L. F. Gray, T. Ohshima, Angew. Chem. Int. Ed. 1999, 38, 2447 –
2451;
b) K. C. Nicolaou, F. Murphy, S. Barluenga, T. Ohshima, H. Wei, J. Xu, D. L. F. Gray, O. Baudoin, J. Am. Chem. Soc. 2000, 122, 3830 – 3838.
N
NH
OO
O
NH
O
OH
HN
O
Me
Me
O
Me
O Me
Snn
Bu3
Me
I
I
[Pd2(dba)3]•CHCl3
AsPh3, i
Pr2NEt
DMF, 25 °C, 62%
Chemoselective
Intramolecular
Stille macrocyclisation
N
NH
OO
O
NH
O
OH
HN
O
Me
Me
O
Me
O Me
Me
I
1. [Pd2(dba)3]•CHCl3
AsPh3, i
Pr2NEt
DMF, 40°C, 45%
2. aq. H2SO4
THF/H2O
(33%)
Intermolecular
Stille Coupling
N
NH
OO
O
NH
O
OH
HN
O
Me
Me
O
Me
O Me
MeMe
NH
O
O
Me
OH
Me
Me
Me
Me
Me
NH
O
O
Me
OH
Me
Me
Me
Me 88
86 87
87: sanglifehrin A
sanglifehrin
Snn
Bu3
23
22

91. The Stille Coupling: Manzamine A
a) S. F. Martin, J. M. Humphrey, A. Ali, M. C. Hillier, J. Am. Chem. Soc. 1999, 121, 866 – 867;
b) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-L. Wong, H.-J. Chen, A. K. Courtney, S. F. Martin, J. Am. Chem. Soc. 2002, 124, 8584 – 8592.
NBoc
OTBDPS
O
N
TBDPSO
Br
CO2Me
Snn
Bu3
[Pd(PPh3)4)] (4 mol%)
toluene, 120 °C
Intermolecular
Stille Coupling
109
NBoc
OTBDPS
O
N
TBDPSO
CO2Me
N
O
TBDPSO
N
OTBDPS
H
Boc E
110
N
O
OTBDPS
CO2Me
NBoc
OTBDPS
H
H
111
endo-intramolecular
Diels-Alder Reaction
(68% Overall)
N N
H
N
N
H
H
OH
H
A B
C
D
112: Manzamine A
manzamine

92. The Carbonylative Stille Coupling: Jatrophone
A. C. Gyorkos, J. K. Stille, L. S. Hegedus, J. Am. Chem. Soc. 1990, 112, 8465 – 8472.
O
O Me
Me O
Me
Me
Me
O
O Me
Me
Me
Me
Me O
O Me
Me
Me
Me
Me
[PdCl2(MeCN)2]
LiCl, CO (50 psi)
DMF, 25 °C
Intermolecular
Carbonylative
Stille CouplingSnn
Bu3
OTf
Snn
Bu3
PdLn
Cl
O
O Me
Me
Me
Me
Me
Snn
Bu3
53% Overall
8382
8485: (±)-2-epi-jatrophone
jatrophone
PdLn
O
Cl
Carbonyl
Insertion

93. Org. Biomol. Chem.201358. , 1158. , 7852.
Total synthesis of the HIV-1
integrase inhibitor 119 using a
Stille reaction to append the
carbonylated side-chain to
the central pyridine ring.

94. In 2013, the total synthesis of the HIV-1 integrase inhibitor 119 was
described in a nine step route .
The authors employed the bromopyridine120 as starting material
and the target compound was obtained with 18% overall yield. In
the insertion of a side chain in the pyridinone central ring, the
Stille cross-coupling of a vinyl stannane was applied and led to
the product 121 with 83% yield after 1 h of reaction in DMF.
A large amount (10 mol%) of the pre-catalyst PdCl2(PPh3)2 in
combination with a 20% excess of the tin reagent was necessary
to provide high yields.
It must be mentioned that the iodinated substrate was also
applied in the cross-coupling; however, according to the authors,
the bromo derivative was preferred due to a simpler
chromatographic purification.

95.  Using boronic acids or esters B(OR)3 .
 Needs base to activate boron species
Suzuki coupling

96.  The Suzuki reaction was formally developed by Suzuki Group in
1979[9], although the inspiration for this work can be traced back to
publications by Heck[10] and Negishi,[11] and their earlier presentation
of these papers at conferences.
 The popularity of this reaction can be partially attributed to the ease
of preparation of the organoboron reagents required, their general
stability, and the lack of toxic by-products.
 Progress in the last quarter-century has shown that the Suzuki
reaction is incredibly powerful, with examples of C(sp2)–C(sp3) and
even C(sp3)–C(sp3) now well documented.[12]
The Suzuki Coupling
9. Original Report; a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437 – 3440; b) N. Miyaura, A. Suzuki, J. Chem.
Soc. Chem. Commun. 1979, 866 – 867
10. a) R. F. Heck in Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research XVII. Organic-Inorganic Reagents
in Synthetic Chemistry (Ed.W. O. Milligan), 1974, p. 53–98; b) H. A. Dieck, R. F. Heck, J. Org. Chem. 1975, 40, 1083 – 1090.
11. E. Negishi in Aspects of Mechanism and Organometallic Chemistry (Ed.: J. H. Brewster), Plenum, New York, 1978, p. 285.
12. a) T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Chem. Lett. 1992, 691 – 694. b) J. Zhou, G.C. Fu, J. Am. Chem. Soc. 2004, 126, 1340
– 1341, and references therein. c) A. C. Frisch, M. Beller, Angew. Chem. Int. Ed. 2005, 44, 674 – 688. d) For a relatively recent
review, see N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
R1
R2
X
cat. [Pd0
Ln]
base
R1
= alkyl, alkynyl, aryl, vinyl
R2
= alkyl, alkynyl, aryl, benzyl, vinyl
X = Br, Cl, I, OAc, OP(=O)(OR)2, OTf
BY2 R1
R2

97. Mechanism of the Suzuki Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
I
Pd
Ph3P
IPh3P
PdII
Pd
Ph3P PPh3
PdII
-Complex
NaOEtNaI
Pd
Ph3P
OEtPh3P
PdII
R1
R2
BF3
R3
K
BF3OEt
Pd
Ph3P
Ph3P
PdII
R3
R2
R1
R3
R2
R1
R3
R2
R1

98. The Suzuki Coupling: Palytoxin
O
O
OTBS
NHTeoc
O Me
Me
O
TBSO OTBS
OTBS
B
OTBS
TBSO
TBSO
OTBS
TBSO OTBS
HO
OH
O
IOAc
OTBS
OTBS
TBSO
OTBS
OTBSO
CO2Me
TBSO
TBSO
H
OTBS
OTBS
[Pd(PPh3)4] (40 mol%)
TlOH, THF/H2O, 25 °C
(70%)
Intermolecular
Suzuki Coupling
O
O
OTBS
TeocHN
O
Me
Me
O
TBSO
OTBSTBSO OTBS
TBSO
TBSO OTBS
OTBS
OTBS
O
OAc
OTBS
OTBS
OTBS
OTBS
TBSO
O
MeO2C
OTBS OTBS
HTBSO
OTBS
a) R.W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,
W. J. McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M.
Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 – 7530;
b) R.W. Armstrong, J.-M. Beau, S. H.Cheon,W. J. Christ, H. Fujioka,W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,W.
J. McWhorter, Jr.,M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White,
M.Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 – 7533;
c) E. M. Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205 – 11206.

99. The Suzuki Coupling: Palytoxin
a) R.W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,
W. J. McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M.
Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 – 7530;
b) R.W. Armstrong, J.-M. Beau, S. H.Cheon,W. J. Christ, H. Fujioka,W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,W.
J. McWhorter, Jr.,M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White,
M.Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 – 7533; c) E. M. Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205 – 11206.
O
O
OH
NH2
O Me
Me
O
HO OH
OH
OH
HO
OH
OH
OH OH
O
OH
O
OH
OH
OH
HO
O
OH
OH
H
HO
OH
OH
O
OH
HO
OH
OH
HO
O
O
Me OH
OH
OH
HO
OH
O
HO OH
OH
H
HN
OHMeOHMe
OH
O
HN O
OH
palytoxin

100. a) D. A. Evans, J. T. Starr, J. Am. Chem. Soc. 2003, 125, 13531 –13540
b) D. A. Evans, J. T. Starr, Angew. Chem. 2002, 114, 1865 – 1868; Angew. Chem. Int. Ed. 2002, 41, 1787 – 1790.
The Suzuki Coupling: FR182887
MeO
Me
O
Br
BrMeMe
OTBS
TBDPSO
B
OTBS
OTBS
Me
HO
OH
[Pd(PPh3)4)] (5 mol%)
Tl2CO3, THF/H2O, 23 °C
(84%)
Intermolecular
Suzuki Coupling
TBDPSO
OTBS
OTBS
Me
MeO
Me
O
BrMeMe
OTBS
O
HO
OH
H
Me
Br
H H
H
CO2Et
H
HO
Me
Me
H
B
O
B
O
B
O Me
Me
Me
[PdCl2(dppf))] (10 mol%)
Cs2CO3, DMF/H2O, 100 °C
(71%)
O
HO
OH
H
Me
Me
H H
H
CO2Et
H
HO
Me
Me
H O
HO
OH
H
Me
Me
H H
H
H
O
Me
Me
H
O
fr182887
132: FR182887131
130 129
128
127126
Intermolecular
Suzuki Coupling

101. a) N. K. Garg, D. D. Capsi, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 9552 – 9553.
b) For a failed alternative route without Pd Catalysis: N. K. Garg, R. Sarpong, B. M. Stoltz, J. Am. Chem. Soc. 2002, 124, 13179 – 13184.
The Suzuki Coupling: DragmacidinMe
TBSO
HO
O N
SEM
Br
[Pd(PPh3)4] (10 mol%)
toluene/MeOH/H2O, 23 °C
Intermolecular
Heck Reaction
Me
TBSO
HO
O N
SEM
PdOAc
TBSO
HO
O
N
SEM
H
(74%)
TBSO
MeO
O N
SEM
H
B O
O
[Pd(PPh3)4] (10 mol%)
161, toluene/MeOH/H2O
NaCO3, 50 °C, 77%
Intermolecular
Suzuki Reaction
TBSO
MeO
O N
SEM
H
NTs
Br
N
N
OMe
167
165166
162 164
HO
O N
H
H
Me
NH
Br
N
H
N
O
N
N
H2N
dragmacidin
168: dragmacidin
Ts
N
B
Br
OH
HO N
N I
Br OMe
[Pd(PPh3)4] (10 mol%)
toluene/MeOH/H2O, 23 °C
(71%)
Intermolecular
Suzuki
Coupling
NTs
Br
N
N
Br OMe
161
160159

102. 13) a) N. Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki, Tetrahedron Lett. 1986, 27, 6369 – 6372; b) not to be confused with the Miyaura
boration, in which an aryl halide is converted to an aryl boronate via palladium catalysis and a diboron reagent. However, this is a
useful preparation of the organoboron reagents required for the Suzuki reaction. See: T. Ishiyama, M. Murata, N. Miyuara. J. Org.
Chem. 1995, 60, 7508.
14) Review of the development, mechanistic background, and applications of the B-alkyl Suzuki-Miyaura cross-coupling reaction, see S. R.
Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40, 4544 – 4568.
15) Q. Tan, S. J. Danishefsky, Angew. Chem. Int. Ed. 2000, 39, 4509 – 4511.
 An important trend in Suzuki chemistry
is the development of a C(sp3)–C(sp2)
methodology, which has become
known as the Suzuki-Miyaura B-Alkyl
varient.[13-15]
 Often used as an alternative to RCM,
leaving a single isolated double bond,
rather than the conjugated systems
produced by a regular Suzuki coupling.
The Suzuki-Miyaura B-Alkyl Coupling: CP-236,114
O
ITBS
O
TBSO
H
O
TBS
O
H
OTBS
O
TBS
OTBS
H
OTBS
I
O
TBS
OTBS
H
OTBS
OBn
6
O
O
O
O O
O
CO2H
H
Me
O
H
Me
[Pd(OAc)2(PPh3)2]
Et3N, THF, 65 °C
(92%)
Intermolecular
Heck Reaction
B{(CH2)6OBn}3
[PdCl2(dppf)]
CsCO3, AsPh3, H2O, 25 °C
(70%)
Suzuki-Miyaura
B-Alkyl Reaction
174: CP-263,114
169 170
171173
CP-263,114

103. a) P. J. Mohr, R. L. Halcomb, J. Am. Chem. Soc. 2003, 125, 1712 – 1713
b) N. C. Callan, R. L. Halcomb, Org. Lett. 2000, 2, 2687 – 2690.
The Suzuki Coupling: Phomactin A
O
O
H
Me
Me
OTMS
OTES
Me
I
9-BBN
THF, 40 °C
O
O
H
Me
Me OTMS
OTES
Me
I
B
O
O
H
Me
OTMS
OTES
Me
Me
Me
O
O
H
Me
OH
OH
Me
Me
Me
TBAF
(78%)
Suzuki-Miyaura
B-Alkyl
Macrocyclisation
[PdCl2(dppf)] (100 mol%)
AsPh3(200 mol%), Tl2CO3
THF/DMF/H2O, 25 °C
(37%)
200: phomactin A
phomactin

104. M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles, 2000, 53, 553 – 556
The Suzuki Coupling: Yuehhukene
N
O O
Directed
o-Metallation
tBuLi, THF, then BEt3
N
Boc
BEt3
Li
Me
TfO
Me Me
[PdCl2(PPh3)2
CO (10 atm)
THF, 60 °C
75%
Carbonylative
Suzuki Coupling
N
Boc O
Me
Me Me
HN
Me
H
H
MeMe
NH
yuehchukene
205: yuehhukene
204
202
201
203

105. M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles, 2000, 53, 553 – 556
The Suzuki Coupling: Yuehhukene
N
O O
Directed
o-Metallation
t
BuLi, THF, then BEt3
N
Boc
BEt3
Li
Me
TfO
Me Me
[PdCl2(PPh3)2
CO (10 atm)
THF, 60 °C
75%
Carbonylative
Suzuki Coupling
N
Boc O
Me
Me Me
HN
Me
H
H
MeMe
NH
yuehchukene
205: yuehhukene
204
202
201
203

106. Suzuki coupling

107. Suzuki coupling

108. Suzuki-Miyaura Reactions
Dalby, A.; ET AL Tetrahedron Lett.201324. , 5424. , 2737. and WO2010059838-A2,
WO2010059838-A3,200925. .
The more reactive benzyl bromide moiety of dibromide 2 was coupled with a pinacol
arylboronic ester, providing diarylmethane 3 in 66% yield. Activation of the remaining
bromide in 3 was carried out using the same conditions, only changing the temperature
and reaction time, and furnishing 1 at a yield of 71%.

109. Suzuki reaction for the
synthesis of PF-01367338
Contd…..
Gillmore, A. T.; et al Org. Process Res.
Dev.201228. , 1628. , 1897

110. Gillmore et al. developed a multi-kilogram preparation of PF-01367338 (14), a drug
candidate for the treatment of breast and ovarian cancers.It is an inhibitor of poly(ADP
ribose) polymerase (PARP), an enzyme that is responsible for repairing damaged DNA
in normal and tumour cells.The described synthetic route delivered 2 kg of the salt 14,
and the authors described how they had to overcome some synthetic challenges in
order to scale up the synthesis to multi-kilogram scale.
The overcome problems include: understanding of the thermal hazards of the
Leimgruber-Batcho indole synthesis, installation of the side chain through a reductive
alkylation procedure, improvements in the robustness of the Suzuki coupling, removal
of hydrogen cyanide generation during a reductive amination reaction, and reliable
generation of good-quality free base for the final salt formation step.
The Suzuki reaction between the tricyclic bromide 15 and 4-formylphenylboronic acid
was first carried out in multi-kilogram scale using by Pd(PPh3)4 as catalyst. The reaction
did not reach completion requiring an additional catalyst charge. In the sequence, the
Suzuki reaction was performed with [PdCl2(dppf)·CH2Cl2] as a pre-catalyst, and full
conversion was obtained after 2 h at 90 ºC , providing 16 with yield of 92%.
Contd………..

111. Synthesis of GDC-0941 (24) through a Suzuki
reaction of THP-protected boronic acid 26.
Tian, Q.; Cheng, Z.;et al Org. Process Res.
Dev.201330. , 1730. , 97.

112. Tian et al. described a convergent synthesis for GDC-0941(24), a
phosphatidylinositol 3-kinase (PI3K) inhibitor . The PI3K pathway is frequently
activated in tumours and its inhibition has a role in human cancers. The
indazole-derived boronic acid 26 was employed as its tetrahydropyran-
protected derivative due to solubility issues and to render an easier
purification. Previous studies identified Pd- or Ni-catalyzed systems for this
Suzuki reaction. The first employed PdCl2(PPh3)2 with Na2CO3 as base and 1,4-
dioxane as solvent; regarding the economically more attractive nickel,
Ni(NO3)2.6H2O/PPh3 was identified as an optimal pre-catalyst, with K3PO4 as
base and acetonitrile as solvent. In the Ni-catalyzed reaction, boronic
acid 26 performed better than the corresponding boronate ester. The yield of
the Pd-catalyzed reaction was 60%, whereas the Ni-catalyzed reaction
provided 27 in 79% yield. Mild removal of the THP-protecting group then
provided 24. Regarding purification after the Suzuki reaction, residual Ni was
easily removed through an aqueous ammonia wash followed by crystallization,
while the removal of residual Pd demanded expensive scavengers and a large
volume of solvents. The easy removal of nickel traces compensated for the
high loadings of its pre-catalyst (30 mol%); Pd loadings were lower (4.5 mol%),
however the lower yield and difficult purification impaired the use of this noble
metal.
GDC-0941

113. En route to producing large quantities of Crizotinib (62), a c-
Met/anaplastic lymphoma kinase (ALK) inhibitor in advanced
clinical tests, De Koning et al. employed a Suzuki reaction in
order to generate an advanced intermediate.
However, before describing the large-scale synthesis itself, it is
worth noting some aspects of the initial medicinal chemistry
screening: compounds with the basic structure 63 were
obtained through a sequence of protection, palladium-
catalyzed borylation, deprotection and Suzuki reactions in
order to allow for late-stage functionalization with substituted
bromopyrazoles.
De Koning, P. D.; ET AL Org. Process Res. Dev.201137. , 1537. , 1018.
Crizotinib
Casestudy…
suzuki

115. Then, once crizotinib (and its R isomer) had been identified as the most
promising candidate, the Suzuki cross-coupling was performed in an inverse
way: the pyrazol moiety was employed as its boron pinacolate derivative
(64, ). Even though 64 was obtained in a moderate 40% yield, its Suzuki
reaction furnished the desired product in excellent quantities, thus allowing a
better use of the valuable chiral intermediate 65

116. The large-scale synthesis demanded further modifications: the preparation of multi-
kilogram amounts of imidazole 64 presented high levels of dimerization; therefore, the
palladium-catalyzed borylation was abandoned in favour of a Knochel-type procedure.The
Suzuki cross-coupling was performed in a different solvent system: in order to avoid the
undesirable DME, toluene and water were employed together with the phase-transfer
catalyst tetrabutylammonium bromide (TBAB). This new procedure allowed the catalyst
loading to be reduced to 0.9 mol% with a significant simplification of the purification
procedure, once the cross-coupling product was soluble in toluene and hence easily
separated from the water layer
Baron, O.; Knochel, P.; Angew. Chem., Int. Ed.200538. , 4438. , 3133.

117.  Organosilanes (Si), with organohalids.
 Needs base or fluoride ion to activate
 Fluorinated, methoxyleted silanes more reactive than alkyl
ones.
Hyiama coupling

118. Hiyama coupling with a copper co-catalyst
Nakao, Y.; Takeda, M.; Matsumoto, T.; Hiyama, T. (2010), "Cross-Coupling Reactions
through the Intramolecular Activation of Alkyl(triorgano)silanes", Angewandte
Chemie 122: 4549, doi:10.1002/ange.201000816

119. Hyiama coupling
Denmark, S. E.; Yang, S.-M. (2002), "Intramolecular Silicon-Assisted Cross-Coupling Reactions:
General Synthesis of Medium-Sized Rings Containing a 1,3-cis-cis Diene Unit",Journal of the
American Chemical Society 124: 2102, doi:10.1021/ja0178158
Hiyama coupling as a ring-closing reaction[

120.  Pd catalyzed synthesis of aryl secondry or tertiary amines.
 Using primary or secondry amins and aryl halides (or
triflates)
Buchwald-Hartwig coupling

121. Buchwald-Hartwig coupling

122.  Pd catalyzed synthesis of aryl secondry or tertiary amines.
 Using primary or secondry amins and aryl halides (or
triflates)
Buchwald-Hartwig coupling

123. Buchwald-Hartwig coupling

124. An example of the reaction using relatively unreactive aryl chlorides. 1
The large scale synthesis of BINAP: Under similar reaction conditions, phosphorus-
and sulfur-based groups can be introduced. Strong bases are unnecessary in those
cases.2
1 Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5,
2413. DOI: 10.1021/ol034561h
2 Org. Synth. 2000, 76, 6.

125.  The Fukuyama Coupling is a
modification of the Negishi Coupling,
in which the electrophilic component is
a thioester.
 The product of the coupling with a
Negishi-type organozinc reagent is
carbonyl compound, thus negating the
need for a carbon monoxide
atmosphere.
The Fukuyama Coupling
27) H. Tokuyama, S. Yokoshima, T. Yamashita, S.-C. Lin, L. Li, T. Fukuyama, J. Braz. Chem. Soc., 1998, 9, 381-387.
R1
R3 cat. [Pd0
Ln]
R1
= alkyl, alkynyl, aryl, vinyl
R3
= acyl, aryl, benzyl, vinyl
R4
= Me, Et, et c.
ZnR2
R1
R3
O
SR4
O
MeO
SEt
O ZnI [PdCl2(PPh3)2] (10 mol%)
toluene, 25 °C, 5 min, 87%
Fukuyama Coupling MeO
O

126.  Pd catalyzed coupling of organozinc with thioesters to form
ketones.
Fukuyama Coupling*

127. The Fukuyama coupling is a coupling reaction taking place between a thioester and
an organozinc halide in the presence of a palladium catalyst. The reaction product is
aketone. This reaction was discovered by Tohru Fukuyama et al. in 1998. Advantages are
high chemoselectivity, mild reaction conditions and the use of less-toxic reagents.
One advantage of this method is that the reaction stops at the ketone and does not proceed
to a tertiary alcohol. In addition, the protocol is compatible with functional groupssuch as
ketones, acetates, sulfides, aromatic bromides, chlorides and aldehydes.

128. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. (1998). "A novel ketone synthesis by a palladium-catalyzed
reaction of thiol esters and organozinc reagents". Tetrahedron Letters 39 (20): 3189–3192. doi:10.1016/S0040-
4039(98)00456-0.
Jump up^ Mori, Y.; Seki, M. (2007). "SYNTHESIS OF MULTI-FUNCTIONALIZED KETONES THROUGH THE FUKUYAMA
COUPLING REACTION CATALYZED BY PEARLMAN’S CATALYST: PREPARATION OF ETHYL 6-OXOTRIDECANOATE
(Tridecanoic acid, 6-oxo-, ethyl ester)" (PDF). Org. Synth. 84: 285–294.; Coll. Vol. 11, pp. 281–288
Jump up^ Shimizu, T.; Seki, M. (2000). "Facile synthesis of (+)-biotin via Fukuyama coupling reaction". Tetrahedron
Letters 41 (26): 5099–5101. doi:10.1016/S0040-4039(00)00781-4.

129.  The palladium catalysed nucleophilic substitution of allylic compounds
was discovered independently by Trost and Tsuji, and represents the first
example of a metalated species acting as an electrophile.[22]
 Originally developed as a stoichiometric process, Trost succeeded in
transforming the allylation of enolates with p-allyl–palladium complexes
into the catalytic process of renown.[23,24]
 A wide range of allylic substrates undergo this reaction with a
correspondingly wide range of carbanions, making this a versatile and
important process for the formation of carbon–carbon bonds.
 Whilst the most commonly employed substrates for palladium-catalyzed
allylic alkylation are allylic acetates, a variety of leaving groups also
function effectively—these include halides, sulfonates, carbonates,
carbamates, epoxides, and phosphates.
The Tsuji-Trost Reaction
22. For early reviews of the Tsuji-Trost reaction, see a) B. M. Trost, Acc. Chem. Res. 1980, 13, 385 – 393; b) J. Tsuji, Tetrahedron 1986,
42, 4361 – 4401.
23. J. Tsuji, H. Takahashi, Tetrahedron Lett. 1965, 6, 4387 – 4388.
24. For recent reviews of the palladium-catalyzed asymmetric alkylation reaction, see: a) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921 – 2943; b) B. M. Trost, J. Org. Chem. 2004, 69, 5813 – 5837.
cat. [Pd0
Ln]
base
X = Br, Cl, OCOR, OCO2R, CO2R, P(=O)(OR)2
NuH = -dicarbonyls, -ketosulfones, enamines, enolates
X NuH Nu

130. Mechanism of the Tsuji-Trost Reaction
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd
PPh3Ph3P
R1
OAc
R2
R1
OAc
R2
Pd
PPh3Ph3P
R1
R2
Pd
PPh3Ph3P
R1
R2
Pd
PPh3Ph3P
R1
R2
Pd
PPh3Ph3P
R1
R2
Nu
Nu
Nu
*
*
R1
R2
Nu
*
R1
R2
Nu
*
or
or

131. The Tsuji-Trost Reaction: Strychnine
a) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293 – 9294
b) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1995, 117, 5776 – 5788.
PdLn
OAcO OMe
O
O
t
BuO CO2Et
[Pd2(dba)3] (1 mol%)
PPh3 (15 mol%)
NaH, THF, 23 °C
[-CO2, -MeO ]
Tsuji-Trost
Reaction
AcO
O
t
BuO CO2Et
AcO
Ot
Bu
O
CO2Et
H
91%
Me3Sn
TIPSO
Ot
Bu
[Pd2(dba)3] (3 mol%)
AsPh3 (22 mol%), CO (50 psi)
LiCl, NMP, 70 °C
80%
Carbonylative
Stille Coupling
TIPSO
Ot
Bu
O
N
Me
N
MeN
O
N
OO
H
H
H
H
strychnine
250
251
252
253
MeN
N
NMe
O
I
254256: Strychnine 255

132. OTBS
MeO2C
PhO2S
O
[Pd2(dba)3] (1 mol%)
PPh3 (15 mol%)
NaH, THF, 23 °C
Tsuji-Trost
Macrocyclisation
TBSO
MeO2C
PhO2S
OLnPd
TBSO
MeO2C
PhO2S
OHLnPd
O O
O
PhO2S PhO2S
HOMeO2C
OTBS
-[Pd0
Ln]
85%
BnNH2
[Pd(PPh3)4] (15 %)
THF, 35 °C, 70%
Tsuji-Trost
ReactionO
PhO2S
NBn
HO
N
O
NHCl
MeO
Me
Me
Roseophilin
263 264 265
266267268
269: Roseophilin
The Tsuji-Trost Reaction: Roseophilin
a) A. Fürstner, H. Weintritt, J. Am. Chem. Soc. 1998, 120, 2817 – 2825;
b) A. Fürstner, T. Gastner, H. Weintritt, J. Org. Chem. 1999, 64, 2361 – 2366.

133. The Tsuji-Trost Reaction: Hamigeran
B
B. M. Trost, C. Pissot-Soldermann, I. Chen, G.M. Schroeder, J. Am. Chem. Soc. 2004, 126, 4480 – 4481.
Pd
Me
O
Ot
Bu
OAc
[{3
-C3H5PdCl}2] (1 mol%)
ligand 285 (2 mol%)
LDA, t
BuOH, Me3SnCl
DME, 25 °C
Asymmetric
Allylic Alkylation
Me
O
t
BuO
P P
Pd
PP
a
b
*
*
O
Ot
Bu
Me
77%, 93% ee
OOMe
Me OTf
Me
Me
Me
Pd(OAc) (10 mol%)
dppb (20 mol%)
K2CO3
toluene, 110 °C, 58%
Intramolecular
Heck Reaction
OOMe
Me
H
Me
Me
Me
OOMe
Me
H
Me
Me
Me
NH
O
P
Ph
Ph
HN
O
P
Ph
Ph
hamigeran B
285
284
286
287
288
289290: hamigeran

134. The Tsuji-Trost Reaction: (+)-g-lycorane
H. Yoshizaki, H. Satoh, Y. Sato, S. Nukui, M. Shibasaki, M. Mori, J. Org. Chem. 1995, 60, 2016 – 2021.
OBz
OBzBzO
O
O Br
NH
MeO2C
O
[Pd2(OAc)3] (5 mol%)
293 (10 mol%)
LDA
THF/MeCN, 0 °C
Asymmetric
Allylic Alkylation
O
O
Br
NH
MeO2C
O
Pd
PP
* 66%, 54% ee
O
O
Br
NH
MeO2C
O
OBz
Pd(OAc) (5 mol%)
dppb (20 mol%)
NaH
DMF, 50 °C
Intramolecular
Allylic Alkylation/
Heck Reaction
Cascade
O
O
Br
N
MeO2C
O PdLn
O O
Br
N
MeO2C
O
H
H
i
Pr2NEt, 100 °C
O O
N
CO2Me
O H
H
H
O
O
N
H HH
lycorane
299: (+)-g-lycorane
298
297 296
295294
292
291
O
O
PPh2
PPh2
293

135. HARD NUCLEOPHILE INVERSION,SOFT ONE GIVES
RETENTION

136. MIGITA COUPLING
Recently, Pfizer researchers described an efficient Heck- and Migita-based multi-
kilogram process for the vascular endothelial growth factor (VEGF) inhibitor axitinib
(147)
A Migita coupling was used in the first step of the synthesis in order to assemble the
mercaptobenzamide moiety of 147. In the last step of the route, a Heck reaction
between 148 and 2-vinyl-piridine was designed. However, the free NH of 148impaired the
reaction.
Therefore, the authors decided to acylate the indazole for both protecting the NH group
and rendering the oxidative addition to palladium easier. The protection was achieved in
situ with Ac2O and when no more than 2% of 148 was present, the Heck reaction was
started using 4 mol% of Pd(OAc)2, 4 mol% of XantPhos and six equivalents of 2-vinyl-
pyridine. When the reaction was completed, 1,2-diaminopropane (DAP) was added in
THF for removal of the protective group and to chelate the palladium before product
crystallization.
With this strategy, 29 kg of axitinib could be obtained with 50% overall yield in a six steps
route.

137. Process for axitinib based on
palladium catalyzed Migita C-S
coupling and Heck reaction.Org. Process Res. Dev.2014,
70. , 1870. , 266.

138.  This review has highlighted only a small number of applications of palladium catalysis in organic
synthesis, but new examples are published every month.
 Each example pushes the field forwards, towards universal conditions, where application of them
results in a useful yield without prior optimisation.
 However, palladium is only one metal; the breadth of catalysis available from rhodium,[28] ruthenium[29]
and platinum based systems extend far further, and into the realms of metathesis.[30] Fürstner has
shown analogous procedures using Iron catalysts,[31] with obvious economic and toxicity benefits.
Palladium Catalysis: Outlook And Summary
28) For an example of palladium-mimicking rhodium catalysis, see: M. Lautens and J. Mancuso, Org. Lett. 2002, 4, 2105
29) For a recent review of "atom ecconomic" ruthenium catalysis, see: B. M. Trost, M. U. Frederiksen, M. T. Rudd, Angew. Chem. Int. Ed.,
2005, 41, 6630 – 6666.
30) For the complementary review on Metathesis Reactions in Total Synthesis, see: K. C. Nicolaou, P. G. Bulger, D. Sarlah , Angew. Chem. Int.
Ed., 2005, 41, 4490-4527.
31) A. Fürstner, R. Martin, Chem. Lett. 2005, 34, 624-629.

139. • All the C-C cross-couplings reaction broadly
follow the same catalytic cycle, which
involves number of processes.
• Heck reaction follows a slightly different
pathway from other C-C couplings.
• Rate-determining step depends on the
nature of the electrophile, nucleophile, and
the ligands on palladium.

140. The ongoing efforts towards the use of Pd-catalyzed C-C cross-coupling reactions for the
synthesis of drug components or drug candidates highlighted in this review
demonstrated how powerful these methodologies are.
The Suzuki reaction is the most exploited cross-coupling reactions, especially when the
creation of a biaryl motif is involved. One of the main advantages of this methodology is
the use of air- and water-stable, non-toxic and ease to manipulate organoboronic acid
and its derivatives. Heck reactions are also intensely exploited for inter or intramolecular
coupling involving Csp double bonds.
Despite the success of the coupling reactions, several challenges need to be overcome in
order to have an economic, robust and reliable industrial process.
Scale-up from the small (medicinal chemistry synthesis) to large scale usually requires
new Pd catalyst precursors and several modifications to the reaction parameters.
From the economic standpoint, in some cases, the cost of the precious metal palladium,
as well as the ligand itself, can be a problem.
There is a plethora of palladium catalyst precursors described in the literature that
promote the C-C cross-coupling reactions.

141. However, when these reactions need to be applied for the synthesis of complex
molecules such as drug components or drug candidates, a few simple catalyst
precursors are usually the first choice: Pd(OAc)2, Pd2(dba)3, Pd/C, PdCl2L2, Pd(PPh3)4.
For aryl iodides or some very activated aryl bromides, ligand-free Pd catalysts can be
used.
However, in most of the reactions involving the synthesis of drugs, a phosphine ligand
is necessary and triphenylphosphine is the most frequently used ligand. This cheap and
stable phosphine is usually used already complexed in the Pd precursor
(PdCl2(PPh3)2 and Pd(PPh3)4) or in association with a simple Pd precursor (Pd(OAc)2 or
Pd2(dba)3). When a bidentated ligand is necessary, dppf or other ferrocenil-based
bidentated phosphine ligands are used, with PdCl2(dppf)2 being the catalyst precursor
of choice.
Economically more attractive aryl chlorides have been used in some cases due to the
development of electron-rich- and steric demanding phosphine ligands. However, the
quest for precursor catalyst and ligands that allow high TON and turnover frequency
(TOF), that would make the process economically attractive is still a challenge.
Another important point that needs to be taken in account is the contamination of the
product with palladium and the need for further purification steps.
Therefore, practical and feasible catalytic systems that allow the easy recovery of
palladium or coupling reactions involving cheaper transition metals are welcomed.

142. • Recently many C-C coupling reactions
catalyzed by Ni(0), Pt(0), or Cu(I)
also. May follow the similar reaction
schemes.
• Future scope is that various transition
metals are available, you can try
some other organic reaction with
some other metal and can lead to be
a new Nobel prizes pathway.

143. Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley -Edited by
Armin de Meijere, Franois Diederich
https://www.youtube.com/watch?v=B3Oz90EfNO0(Nobel Prize Lectures
in Uppsala 2010 - Chemistry Laureate Ei-ichi Negishi)

144. To take full advantage of Chemical Web content, it is essential
to use several Software:Winzip,Chemscape Chime, Shockwave,
Adobe Acrobat, Cosmo Player, Web Lab Viewer,
Paint Shop Pro, Rasmol, ChemOffice, Quick Time,etc

145. LIONEL MY SON
He was only in first standard in school when I was hit by a
deadly one in a million spine stroke called acute transverse
mylitis, it made me 90% paralysed and bound to a wheel
chair, He cried bitterly and we had never seen him so
depressed
Now I keep Lionel as my source of inspiration and helping
millions, thanks to millions of my readers who keep me
going and help me to keep my son and family happy.
I will live and die for my family.

147. SUCCESS FORMULA