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(With examples of Pharmaceuticals)
by
DR ANTHONY MELVIN CRASTO
Principal Scientist
INDIA
MAR 2016
This is a vast topic and a short
overview is given
and
in no way complete justice can be
done for this
Prof. Akira Suzuki
Prof. Richard
F. Heck
Prof. Ei-ichi
Negishi
The Nobel Prize was awarded jointly to Richard F. Heck, Ei-
ichi Negishi and Akira Suzuki for Palladium- catalyzed C-C
cro...
 Coupling reactions occur between organometallic with
organic halide with the aid of a metal containing
catalyst.
 Coupl...
The C-C bond formation between an organic electrophile
(RX) and a nucleophile (Organometallic R’M or R’-C=C)
in the presen...
 Common metal used in this field is Pd, in
addition to Zn, Ni, Cu, B, and Sn.
 Most of coupling reactions are air and
wa...
Some thing about Palladium
5. HECK (1972)
4. SONOGASHIRA (1975)
3. NEGISHI (1977)
2. STILLE
(1978)
1. SUZUKI-
MIYAURA
(1979)
Negishi- M= Organiozincompound
Suzuki- M= Organoboran compound
Stille-M= organotin compound
Heck-Mizoroki
Negishi –R1-M= O...
CuI can
increase the
reaction rate
and ability to
scavenge the
free ligand.
• Variable oxidation states and coordination number
Metals are Lewis acid (electron deficient):- origin of
Chemical reacti...
RepulsionTwo major reasons are:-
1. Simultaneous availability of empty and filled non bonding orbitals ,
because of that S...
Palladium is a d-block transition metal.
Pd favours the formation of tetrahedral d10 and square planar
d8 complexes of l...
The oxidative addition of organic electrophiles (halides, sulfonates, and
related activated compounds) to Pd(0) is the fir...
Concerted Mechanism : Normally found in addition of non-
polar reagents and aryl halides. Retention of configuration is in...
 Predominant retention in noncoordinating solvents as benzene, CH2Cl2,
tetrahydrofuran (THF), or acetone.
 On the other ...
 Transmetallation reactions involve the transfer of an
organic group R from one metal M to another one
M.
Transmetallati...
 It is the reverse of oxidative addition.
 Reductive elimination involves the elimination or expulsion
of a molecule fro...
• A carbometallation reaction is defined by the addition of a
carbon-metal bond of an organometallic 1 across a carbon-
ca...
β-
The beta-hydride elimination can either be a vital step
in a reaction or an unproductive side reaction.
.
• β-Hydride elimination may occur if a β-hydrogen is accessible.
• C-C bond rotation of intermediate D is required, as wel...
Reaction Year Reactant 1 Reactant 2 Catalyst
Kumada 1972 R-MgBr RX Pd or Ni
Heck 1972 Alkene RX Pd
Sonogashira 1973 Alkyne...
 Cross coupling between aryl or alkyl Grignard with aryl or
vinyl halocarbon.
 The first Pd or Ni catalysed coupling rea...
Kumada coupling
Kumada coupling
Example of an iron-catalyzed Kumada reaction in the
synthesis of 122. Tetrahedron Lett.201460. , 5560. , 1376.
J. Med.
Che...
The coupling of organomagnesium compounds and organic electrophiles is known as the
Kumada reaction and is normally cataly...
 Pd catalyzed coupling between aryl or vinyl halides with
activated alkene in basic media.
Heck coupling
 Broadly defined as the palladium-catalyzed coupling of alkenyl or aryl (sp2) halides or
triflates with alkenes to yield ...
Mechanism of the Heck Reaction
neutral
PPh3
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd...
Mechanism of the Heck Reaction
cationic
PPh3
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
P...
 The type of mechanism in action is incredibly important, as it can manifest itself in a variety of ways, especially
the ...
The Heck Reaction: Dehydrotubifoline
a) V. H. Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115, 3030 – 3031
...
The Heck Reaction: Capnellene
a) K. Kagechika, M. Shibasaki, J. Org. Chem. 1991, 56, 4093 –4094
b) K. Kagechika, T. Ohshim...
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. Ju...
The Heck Reaction: Estrone
L. F. Tietze, T. NVbel, M. Spescha, J. Am. Chem. Soc. 1998, 120, 8971 – 8977.
MeO
Br
Br
Me Ot
B...
Domino Heck Reactions
Y. Zhang, G.Wu, G. Angel, E. Negishi, J. Am. Chem. Soc. 1990, 112, 8590 – 8592.
Me
EtO2C
EtO2C
I
Me
...
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,...
Heck coupling
Synthesis of idebenone (124) based on Heck reaction of 2-
bromo-3,4,5-trimethoxy-1-methylbenzene with dec-9-en-1-ol
under ...
The palladium-catalyzed olefination of a sp or benzylic carbon attached to a
(pseudo)halogen is known as the Heck reaction...
J. Agric. Food Chem.201366. , 6166. , 5347.
Synthesis of the
ginkgolic acid based
on the Heck reaction
of aryl triflate 130
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 ...
J. Org. Chem.201267. , 7767. , 6340.
Heck reaction in synthesis
of olopatadine (133)
and trans-olopatadine
(134).
An intramolecular Heck-based cyclization was used as a key step for
commendable synthesis of the antihistaminic drug olopa...
Synthesis of (R)-tolterodine based
on a Heck-Matsuda reaction and
enantioselective reduction of
compound 152.
A variation of the Heck reaction that has attracted considerable attention in recent
years is the so-called Heck-Matsuda a...
Mizoroki-Heck Reaction
The Mizoroki-Heck reaction between alkenyl bromide and methyl acrylate.
Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, ...
 Terminal alkynes with aryl or vinyl halides (triflate).
 Pd as a catalyst, Cu as co-catalyst and an amine as a base.
So...
Sonogashira coupling
Sonogashira coupling
 The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported
independently and...
Mechanism of the Sonogashira Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
Ph3P
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
P...
K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736
The Sonogashira Coupling: Eicosanoid 212
MeBr
OTBS
...
P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.
The Sonogashira Coupling: Disorazole C1
Me
PMBO
Me
OH
Me...
The Sonogashira Coupling: Dynemicin
MeO2CN
OMe
Me
O
O
Br
MeO2CN
OMe
Me
O
OIntramolecular
Sonogashira
Coupling
[Pd(PPh3)4] ...
Nishimura, K.; Kinugawa, M.; Org. Process
Res. Dev.201251. , 1651. , 225
Olopatadine hydrochloride
The construction of a new bond between sp2- and sp-hybridized carbons is known as the
Sonogashira reaction,and it is nowad...
GRN-529
Sperry, J. B.; ET AL Org. Process Res.
Dev.201252. , 1652. , 1854.
In 2012, in order to obtain necessary quantities for preclinical and
phase 1 clinical studies, investigators at Wyeth Rese...
A purification process involving the treatment of the crude
reaction with an aqueous cysteine and ammonia solution
followe...
MK-1220
Org. Process Res. Dev.201453. , 1853. , 423.
ACS Med. Chem. Lett.201154. , 254. , 207.
Process chemistry researchers from Merck recently employed Heck and Sonogashira
reactions in the multi-gram preparation of...
FILIBUVIR
Org. Process Res. Dev.201455. , 1855. , 26.
The Sonogashira reaction has also recently been used in the synthesis of Filibuvir (108),
a potential drug for hepatitis C...
 Pd or Ni catalyzed coupling organozinc compounds with
aryl, vinyl, benzyl halids.
Nigishi coupling
 The use of organozinc reagents as the nucleophilic component in palladium-catalyzed
cross-coupling reactions, known as t...
25.a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821 –
1823; for a discussion, see: b) E. Negishi, Acc. ...
Mechanism of the Negishi Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd0
Pd0
Pd0
I
Pd
Ph3...
The Negishi Coupling:
Discodermolide
a) A. B. Smith III, T. J. Beauchamp, M. J. LaMarche, M. D. Kaufman, Y. Qiu, H. Arimot...
The Negishi Coupling: Amphidinolide T1
a) C. Aïssa, R. Riveiros, J. Ragot, A. Fürstner, J. Am. Chem. Soc. 2003, 125, 15 51...
Nigishi coupling
The Negishi reaction is the coupling between an aryl (or
vinyl) halide and an organozinc compound.
This c...
BMS-599793
See description in next slide
Pikul, S et al Org. Process Res.
Dev.201346. , 1746. , 907.
In 2013, a Negishi coupling was employed as one of the key steps
in a new synthetic approach to BMS-599793 (84), an HIV en...
Synthesis of 88 with low loadings of Pd in a Negishi coupling.
Shu, L.; Org. Process Res.
Dev.201347. , 1747. , 651.
Acylation of the adduct's azaindole moiety with methyl chlorooxalate followed by ester
hydrolysis and amidation afforded t...
During the process development, a traditional zinc activation approach was found to be
effective, and by using trimethylch...
 Using tin (stannes) alkyl compounds, wide range of
R groups, but?????
 Less polar, more toxic???
Stille coupling
 Originally discovered by Kosugi et al[5] in the late 1970s, the Stille Coupling was later developed as a tool
for organi...
Mechanism of the Stille Coupling
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
Ph3P
- PPh3
- PPh3
Pd0
Pd0
Pd0
Br
Pd
Ph3...
The Stille Coupling: Rapamycin
a) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato, J. Am. Chem....
The Stille Coupling: Dynamycin
a) M. D. Shair, T.-Y. Yoon, K. K. Mosny, T. C. Chou, S. J. Danishefsky, J. Am. Chem. Soc. 1...
The Stille Coupling: Sanglifehrin
a) K. C. Nicolaou, J. Xu, F. Murphy, S. Barluenga, O. Baudoin, H.-X.Wei, D. L. F. Gray, ...
The Stille Coupling: Manzamine A
a) S. F. Martin, J. M. Humphrey, A. Ali, M. C. Hillier, J. Am. Chem. Soc. 1999, 121, 866 ...
The Carbonylative Stille Coupling: Jatrophone
A. C. Gyorkos, J. K. Stille, L. S. Hegedus, J. Am. Chem. Soc. 1990, 112, 846...
Org. Biomol. Chem.201358. , 1158. , 7852.
Total synthesis of the HIV-1
integrase inhibitor 119 using a
Stille reaction to ...
In 2013, the total synthesis of the HIV-1 integrase inhibitor 119 was
described in a nine step route .
The authors employe...
 Using boronic acids or esters B(OR)3 .
 Needs base to activate boron species
Suzuki coupling
 The Suzuki reaction was formally developed by Suzuki Group in
1979[9], although the inspiration for this work can be tra...
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...
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
...
The Suzuki Coupling: Palytoxin
a) R.W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawk...
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...
a) N. K. Garg, D. D. Capsi, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 9552 – 9553.
b) For a failed alternative route with...
13) a) N. Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki, Tetrahedron Lett. 1986, 27, 6369 – 6372; b) not to be confused wit...
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,...
M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles, 2000, 53, 553 – 556
The Suzuki Coupling: Yuehhukene
N
O O
Directed
o-...
M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles, 2000, 53, 553 – 556
The Suzuki Coupling: Yuehhukene
N
O O
Directed
o-...
Suzuki coupling
Suzuki coupling
Suzuki-Miyaura Reactions
Dalby, A.; ET AL Tetrahedron Lett.201324. , 5424. , 2737. and WO2010059838-A2,
WO2010059838-A3,20...
Suzuki reaction for the
synthesis of PF-01367338
Contd…..
Gillmore, A. T.; et al Org. Process Res.
Dev.201228. , 1628. , 1...
Gillmore et al. developed a multi-kilogram preparation of PF-01367338 (14), a drug
candidate for the treatment of breast a...
Synthesis of GDC-0941 (24) through a Suzuki
reaction of THP-protected boronic acid 26.
Tian, Q.; Cheng, Z.;et al Org. Proc...
Tian et al. described a convergent synthesis for GDC-0941(24), a
phosphatidylinositol 3-kinase (PI3K) inhibitor . The PI3K...
En route to producing large quantities of Crizotinib (62), a c-
Met/anaplastic lymphoma kinase (ALK) inhibitor in advanced...
Then, once crizotinib (and its R isomer) had been identified as the most
promising candidate, the Suzuki cross-coupling wa...
The large-scale synthesis demanded further modifications: the preparation of multi-
kilogram amounts of imidazole 64 prese...
 Organosilanes (Si), with organohalids.
 Needs base or fluoride ion to activate
 Fluorinated, methoxyleted silanes more...
Hiyama coupling with a copper co-catalyst
Nakao, Y.; Takeda, M.; Matsumoto, T.; Hiyama, T. (2010), "Cross-Coupling Reactio...
Hyiama coupling
Denmark, S. E.; Yang, S.-M. (2002), "Intramolecular Silicon-Assisted Cross-Coupling Reactions:
General Syn...
 Pd catalyzed synthesis of aryl secondry or tertiary amines.
 Using primary or secondry amins and aryl halides (or
trifl...
Buchwald-Hartwig coupling
 Pd catalyzed synthesis of aryl secondry or tertiary amines.
 Using primary or secondry amins and aryl halides (or
trifl...
Buchwald-Hartwig coupling
An example of the reaction using relatively unreactive aryl chlorides. 1
The large scale synthesis of BINAP: Under similar...
 The Fukuyama Coupling is a
modification of the Negishi Coupling,
in which the electrophilic component is
a thioester.
 ...
 Pd catalyzed coupling of organozinc with thioesters to form
ketones.
Fukuyama Coupling*
The Fukuyama coupling is a coupling reaction taking place between a thioester and
an organozinc halide in the presence of ...
Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. (1998). "A novel ketone synthesis by a palladium-catalyzed
reacti...
 The palladium catalysed nucleophilic substitution of allylic compounds
was discovered independently by Trost and Tsuji, ...
Mechanism of the Tsuji-Trost Reaction
Pd
Ph3P PPh3
Ph3P PPh3
Pd
Ph3P
Ph3P PPh3
Pd
Ph3P
PPh3
- PPh3
- PPh3
Pd
PPh3Ph3P
R1
O...
The Tsuji-Trost Reaction: Strychnine
a) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293 – 92...
OTBS
MeO2C
PhO2S
O
[Pd2(dba)3] (1 mol%)
PPh3 (15 mol%)
NaH, THF, 23 °C
Tsuji-Trost
Macrocyclisation
TBSO
MeO2C
PhO2S
OLnPd...
The Tsuji-Trost Reaction: Hamigeran
B
B. M. Trost, C. Pissot-Soldermann, I. Chen, G.M. Schroeder, J. Am. Chem. Soc. 2004, ...
The Tsuji-Trost Reaction: (+)-g-lycorane
H. Yoshizaki, H. Satoh, Y. Sato, S. Nukui, M. Shibasaki, M. Mori, J. Org. Chem. 1...
HARD NUCLEOPHILE INVERSION,SOFT ONE GIVES
RETENTION
MIGITA COUPLING
Recently, Pfizer researchers described an efficient Heck- and Migita-based multi-
kilogram process for the...
Process for axitinib based on
palladium catalyzed Migita C-S
coupling and Heck reaction.Org. Process Res. Dev.2014,
70. , ...
 This review has highlighted only a small number of applications of palladium catalysis in organic
synthesis, but new exa...
• All the C-C cross-couplings reaction broadly
follow the same catalytic cycle, which
involves number of processes.
• Heck...
The ongoing efforts towards the use of Pd-catalyzed C-C cross-coupling reactions for the
synthesis of drug components or d...
However, when these reactions need to be applied for the synthesis of complex
molecules such as drug components or drug ca...
• Recently many C-C coupling reactions
catalyzed by Ni(0), Pt(0), or Cu(I)
also. May follow the similar reaction
schemes.
...
Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley -Edited by
Armin de Meijere, Franois Diederich
https://www.yo...
To take full advantage of Chemical Web content, it is essential
to use several Software:Winzip,Chemscape Chime, Shockwave,...
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 acut...
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C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto
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C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto

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

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C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto

  1. 1. (With examples of Pharmaceuticals) by DR ANTHONY MELVIN CRASTO Principal Scientist INDIA MAR 2016
  2. 2. This is a vast topic and a short overview is given and in no way complete justice can be done for this
  3. 3. Prof. Akira Suzuki Prof. Richard F. Heck Prof. Ei-ichi Negishi
  4. 4. 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.
  5. 5.  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
  6. 6. 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).
  7. 7.  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
  8. 8. Some thing about Palladium
  9. 9. 5. HECK (1972) 4. SONOGASHIRA (1975) 3. NEGISHI (1977) 2. STILLE (1978) 1. SUZUKI- MIYAURA (1979)
  10. 10. 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
  11. 11. CuI can increase the reaction rate and ability to scavenge the free ligand.
  12. 12. • 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.
  13. 13. 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
  14. 14. 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.
  15. 15. 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).
  16. 16. 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
  17. 17.  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
  18. 18.  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.
  19. 19.  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
  20. 20. • 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.
  21. 21. β- The beta-hydride elimination can either be a vital step in a reaction or an unproductive side reaction. .
  22. 22. • 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
  23. 23. 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
  24. 24.  Cross coupling between aryl or alkyl Grignard with aryl or vinyl halocarbon.  The first Pd or Ni catalysed coupling reaction Kumada coupling reaction
  25. 25. Kumada coupling
  26. 26. Kumada coupling
  27. 27. 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.
  28. 28. 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
  29. 29.  Pd catalyzed coupling between aryl or vinyl halides with activated alkene in basic media. Heck coupling
  30. 30.  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
  31. 31. 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
  32. 32. 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.
  33. 33.  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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. Heck coupling
  41. 41. 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.
  42. 42. 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.
  43. 43. J. Agric. Food Chem.201366. , 6166. , 5347. Synthesis of the ginkgolic acid based on the Heck reaction of aryl triflate 130
  44. 44. 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.
  45. 45. J. Org. Chem.201267. , 7767. , 6340. Heck reaction in synthesis of olopatadine (133) and trans-olopatadine (134).
  46. 46. 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
  47. 47. Synthesis of (R)-tolterodine based on a Heck-Matsuda reaction and enantioselective reduction of compound 152.
  48. 48. 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.
  49. 49. Mizoroki-Heck Reaction
  50. 50. 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
  51. 51.  Terminal alkynes with aryl or vinyl halides (triflate).  Pd as a catalyst, Cu as co-catalyst and an amine as a base. Sonogashira coupling
  52. 52. Sonogashira coupling
  53. 53. Sonogashira coupling
  54. 54.  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
  55. 55. 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
  56. 56. 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
  57. 57. 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
  58. 58. 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.
  59. 59. Nishimura, K.; Kinugawa, M.; Org. Process Res. Dev.201251. , 1651. , 225 Olopatadine hydrochloride
  60. 60. 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).
  61. 61. GRN-529 Sperry, J. B.; ET AL Org. Process Res. Dev.201252. , 1652. , 1854.
  62. 62. 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
  63. 63. 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.
  64. 64. MK-1220 Org. Process Res. Dev.201453. , 1853. , 423. ACS Med. Chem. Lett.201154. , 254. , 207.
  65. 65. 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.
  66. 66. FILIBUVIR Org. Process Res. Dev.201455. , 1855. , 26.
  67. 67. 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.
  68. 68.  Pd or Ni catalyzed coupling organozinc compounds with aryl, vinyl, benzyl halids. Nigishi coupling
  69. 69.  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
  70. 70. 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.
  71. 71. 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
  72. 72. 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
  73. 73. 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
  74. 74. 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.
  75. 75. BMS-599793 See description in next slide Pikul, S et al Org. Process Res. Dev.201346. , 1746. , 907.
  76. 76. 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
  77. 77. Synthesis of 88 with low loadings of Pd in a Negishi coupling. Shu, L.; Org. Process Res. Dev.201347. , 1747. , 651.
  78. 78. 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 .
  79. 79. 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).
  80. 80.  Using tin (stannes) alkyl compounds, wide range of R groups, but?????  Less polar, more toxic??? Stille coupling
  81. 81.  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
  82. 82. 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
  83. 83. 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"
  84. 84. 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
  85. 85. 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
  86. 86. 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
  87. 87. 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
  88. 88. 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.
  89. 89. 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.
  90. 90.  Using boronic acids or esters B(OR)3 .  Needs base to activate boron species Suzuki coupling
  91. 91.  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
  92. 92. 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
  93. 93. 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.
  94. 94. 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
  95. 95. 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
  96. 96. 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
  97. 97. 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
  98. 98. 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
  99. 99. 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
  100. 100. 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
  101. 101. Suzuki coupling
  102. 102. Suzuki coupling
  103. 103. 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%.
  104. 104. Suzuki reaction for the synthesis of PF-01367338 Contd….. Gillmore, A. T.; et al Org. Process Res. Dev.201228. , 1628. , 1897
  105. 105. 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………..
  106. 106. 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.
  107. 107. 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
  108. 108. 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
  109. 109. 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
  110. 110. 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.
  111. 111.  Organosilanes (Si), with organohalids.  Needs base or fluoride ion to activate  Fluorinated, methoxyleted silanes more reactive than alkyl ones. Hyiama coupling
  112. 112. 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
  113. 113. 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[
  114. 114.  Pd catalyzed synthesis of aryl secondry or tertiary amines.  Using primary or secondry amins and aryl halides (or triflates) Buchwald-Hartwig coupling
  115. 115. Buchwald-Hartwig coupling
  116. 116.  Pd catalyzed synthesis of aryl secondry or tertiary amines.  Using primary or secondry amins and aryl halides (or triflates) Buchwald-Hartwig coupling
  117. 117. Buchwald-Hartwig coupling
  118. 118. 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.
  119. 119.  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
  120. 120.  Pd catalyzed coupling of organozinc with thioesters to form ketones. Fukuyama Coupling*
  121. 121. 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.
  122. 122. 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.
  123. 123.  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
  124. 124. 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
  125. 125. 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
  126. 126. 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.
  127. 127. 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
  128. 128. 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
  129. 129. HARD NUCLEOPHILE INVERSION,SOFT ONE GIVES RETENTION
  130. 130. 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.
  131. 131. Process for axitinib based on palladium catalyzed Migita C-S coupling and Heck reaction.Org. Process Res. Dev.2014, 70. , 1870. , 266.
  132. 132.  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.
  133. 133. • 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.
  134. 134. 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.
  135. 135. 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.
  136. 136. • 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.
  137. 137. 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)
  138. 138. 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
  139. 139. 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.
  140. 140. SUCCESS FORMULA

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