CROSS COUPLING REACTIONS
The major objective of this session could be briefly summarized considering the
relevance of cross coupling reactions in organic chemistry, taking into account that
these reactions permit C-C bond formation but also other bond generations, a large
amount of these reactions have been developed in the last years with several
applications including synthesis of natural compounds or in medicinal chemistry. In
more detail the first part of this session will be focused on a general overview of cross
coupling reactions (Prof. S.L. Buchwald) and the use of palladium for the allylic C-H
activation (Prof. G. Poli). The second part of the session will be focused on the use of
palladium for the C-N bond formation (Prof. S.L. Buchwald) and palladium or copper
for generation of substituted indoles (Prof. G. Fabrizi). The last lesson will be focused
on the application of cross coupling reactions in medicinal chemistry
(Dr. M.
Biagetti)
1) The opening lecture (prof. S.L Buchwald) will be focused on an overview of cross
coupling and their applications in synthetic organic chemistry. This lecture
will provide information on a number of these that effect both carbon-carbon
(Suzuki-Miyaura, Negishi, Sonogashira, Heck and carbonyl enolate arylation)
and carbon-nitrogen bond formation (catalyzed by both Cu and Pd complexes).
A description of the mechanisms of these important transformations as well as
some applications of these processes will be presented.
2) The second lecture (Prof. G. Poli) will be dedicated to the Pd(0)-catalyzed
allylation. This transformation is amenable of asymmetric variants, and has been often
a key step in total and/or multistep syntheses of pharmaceutical interest, as
exemplified by the straightforward synthesis of the antiherpetic nucleoside analogue
famciclovir by Smith and coworkers at SmithKline Beecham Pharmaceuticals. In this
lecture both mechanistic aspects and several applications will be discussed.
3) In the third lesson, Prof. Buchwald will discuss the Pd-catalyzed formation of
carbon-nitrogen bonds, which has become a routinely practiced technique in both
academia and the pharmaceutical industry. This lecture will describe: 1) the basics of
this transformation, 2) the effect of ligand structure on the reactivity of palladium
complexes, 3) the development of novel precatalysts to perform carbon-nitrogen
coupling reactions and 4) several applications of this methodology.
4) The fourth lesson (Prof. G. Fabrizi) will be focused on applications of cross
coupling reaction catalyzed by Palladium or Copper for the generation of substitute
indoles. Several approaches to the transition metal-catalyzed synthesis of indole
derivatives which have been categorized into two main types: a) de novo indole
system construction from benzenoid precursors through cyclization reactions; b)
functionalization of preformed indole rings. Regarding the former section, the
following topics will be discussed:
1) Alkene-based palladium-catalyzed assemblies of the pyrrole ring
2) Alkyne-based palladium-catalyzed assemblies of the pyrrole ring
3) Main copper-catalyzed strategies of the pyrrole ring formations
5) In the last lesson, Dr. Biagetti will present an overview cross coupling reactions in
medicinal chemistry in particular dedicated to the discovery of drug candidate. In fact,
the fate of a drug candidate in clinical development is embedded in the chemical
structure. This truism is the foundation of each medicinal chemistry project. Therefore
the selection of the fundamental core element, the scaffold, or the identification of
ideal replacements, and then the following growing steps play an essential.
The tremendous number of properties combined in a single compound, the drug
candidate, is achieved by a daunting design/make/test/analyse cycle requiring the
production of thousands of molecules and, hence, diversity generating chemical
processes allowing a faster access to novel chemical space are privileged. Metal
catalysed cross-coupling reactions represent a powerful toolbox for the rapid analogue
synthesys of highly substituted molecules. Examples from academia and industries
illustrating application of this approach will be presented.
Prof. Stephen L. Buchwald (Massachusetts Institute of Technology-Cambridge,
USA)
Stephen L. Buchwald was born (1955) in Bloomington, Indiana. He received his
Sc.B. degree from Brown University in 1977 where he worked with Kathlyn A.
Parker and David E. Cane at Brown University as well as Professor Gilbert Stork at
Columbia University. He entered Harvard University as a National Science
Foundation Predoctoral Fellow in 1977 and received his Ph.D. in 1982. His thesis
work, with Jeremy R. Knowles, concerned the mechanism of phosphoryl transfer
reactions in chemistry and biochemistry. He then was a Myron A. Bantrell
postdoctoral fellow at Caltech with Professor Robert H. Grubbs where he studied
titanocene methylenes as reagents in organic synthesis and the mechanism of ZieglerNatta polymerization. In 1984 he began as an assistant professor of chemistry MIT.
He was promoted to the associate professor (1989) and to Professor (1993) and was
named the Camille Dreyfus Professor in 1997. During his time at MIT he has received
numerous honors including the Harold Edgerton Faculty Achievement Award of MIT,
an Arthur C. Cope Scholar Award, the 2000 Award in Organometallic Chemistry
from the American Chemical Society, a MERIT award from the National Institutes of
Health. He has also been the recipient of the Bristol-Myers Squibb Distinguished
Achievement Award and the CAS Science Spotlight Award, both received in 2005
and the American Chemical Society's Award for Creative Work in Synthetic Organic
Chemistry as well as the Siegfried Medal Award in Chemical Methods which Impact
Process Chemistry, both received in 2006. In 2010 he received the Gustavus J.
Esselen Award for Chemistry in the Public Interest. He received the 2013 Arthur C.
Cope Award from the American Chemical Society. In 2000, he was elected as a
fellow of the American Academy of Arts and Sciences and in 2008 he was elected as
a member of the National Academy of Science. He is the coauthor of over 390
published or accepted papers and 43 issued patents. He serves as a consultant to a
number of companies and is an associate editor of Advanced Synthesis and Catalysis
and Chemical Science.
9.15-10.10 Pd-catalyzed Cross Coupling Reactions: Fundamentals and Applications
selected references for the lecture:
1)
Martin, R. and Buchwald, S.L. " Palladium-Catalyzed Suzuki-Miyaura Crosscoupling Reactions Employing Dialkylbiaryl Phosphine Ligands." Acc. Chem.
Res. 2008, 41, 1461-1473.
2)
Surry, D.S. and Buchwald, S.L. "Diamine Ligands in Copper-Catalyzed
Reactions."Chem. Sci. 2010, 1, 13-31.
3)
Surry, D.S. and Buchwald, S.L. "Dialkylbiaryl Phosphines in Pd-Catalyzed
Amination: A User’s Guide." Chem. Sci. 2011, 2, 27-50.
4)
Johansson, C.C.C. and Colacot, T.J. "Metal-Catalyzed α-Arylation of
Carbonyl and Related Molecules: Novel Trends in C-C Bond Formation by CH Bond Functionalization." Angew. Chem. Int. Ed. 2010, 49, 676-707.
5)
Yang, Y.; Oldenhuis, N.J.; Buchwald, S.L. "Mild and General Conditions for
Negishi Cross-Coupling Enabled by the Use of Palladacycle Precatalysts."
Angew. Chem., Int.Ed., 2013, 52, 615-619.
11.20-12.05 Pd-Catalyzed Carbon-Nitrogen Bond forming reactions. Progress,
applications and mechanistic studies
selected references for the lecture:
1)
Surry, D.S. and Buchwald, S.L. "Dialkylbiaryl Phosphines in Pd-Catalyzed
Amination: AUser’s Guide." Chem. Sci. 2011, 2, 27-50.
2)
Wolfe, J.P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.L. "The Rational
Development of Practical Catalysts for Aromatic Carbon-Nitrogen Bond
Formation." Acc. Chem. Res.1998, 31, 805.
3)
Huang, X.; Anderson, K; Zim, D.; Jiang, L.; Klapars, A. and Buchwald, S.L.
"Expanding Pd-Catalyzed C-N Bond-Forming Processes: The First Amidation
of Aryl Sulfonates, Aqueous Amination, and Complementarity with CuCatalyzed Reactions." J. Am. Chem. Soc. 2003, 125, 6653.
4)
Su, M.; Hoshiya, N. and Buchwald, S.L. "Palladium-Catalyzed Amination of
Unprotected Five-Membered Heterocyclic Bromides." Org. Lett. 2014, 16,
832-835.
Prof . Giovanni Poli (Université Pierre et Marie Curie-Paris, France)
1979 - 1980 Laurea, Università degli Studi di Milano (Directeur: Prof. Carlo
Scolastico), Italy.
1980 - 1985 PhD degree at Milan University (Supervisor: Prof. Carlo Scolastico)
1983 Degree in Specialty School in Fine Organic Chemistry (Polytechnic, Milan),
Italy.
1985 - 1987 1st postdoctoral stage at Geneva University (Supervisor: Prof. Wolfgang
Oppolzer), Switzerland.
1987 - 1988 2nd postdoctoral stage at Geneva University (Maître Assistant)
(Supervisor: Prof. Wolfgang Oppolzer), Switzerland.
1988 - 1989 Maitre Assistant at Lausanne University (independent position),
Switzerland.
1990 - 1992 Research Associate at Milan University, Italy.
1992 - 2000 Associate Professor at Florence University, Italy.
1999 - 2000 Invited Professor at Pierre et Marie Curie (UPMC) University, Paris,
France.
2000 - 2012 Full Professor (1st class) at UPMC, Paris, France.
From 2012 Full Professor (Exceptional class) at UPMC, Paris, France.
Research interests: Study of new transformations in organometallic catalysis
characterized by economy of steps and/or of atoms in organic synthesis.
Understanding
and
optimization
of
selectivity
(enantioselectivity
and
diastereoselectivity); Design of catalytic sequences enabling the creation of highly
complex molecules in a single synthetic operation; Synthesis of heterocyclic
structures with potential biological interest; Study of allylic CH activation reactions,
nucléopalladation, allylations, cross-couplings, carbonylations ...; Catalytic domino
sequences (pure type I and type II); Synthesis of targets belonging to podophyllotoxin
family; Organometallic catalysis under aerobic and/or isohypsic conditions
10.10-10.55 Allylic C-H activation and nucleopalladiation: a subtle competition
selected references for the lecture:
)
J. Tsuji, H. Takahashi, M. Morikawa, Tetrahedron Lett. 1965, 6, 4387-4388
2)
K. E. Atkins, W. E. Walker, R. M. Manyik Tetrahedron Lett. 1970, 11, 38213824.
3)
G. Hata, K. Takahashi, A. Miyake. J Chem Soc D: Chem Commun. 1970,
1392-1393.
4)
B. M. Trost, P. E. Strege, J. Am. Chem. Soc. 1977, 99, 1649-1651.
5)
Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic
Synthesis, Kazmaier U. Ed, Topics in Organometallics Chemistry, SpringerVerlag Berlin and Heidelberg GmbH & Co 2012.
6)
a) T. Greening, H.-G. Schmalz, Angew. Chem. Int. Ed. 2003, 42, 2580-2584.
b) B. M. Trost, Chem. Pharm. Bull., 2002, 50 , 1-14.
7)
R. Freer, G. R. Geen, T. W. Ramsay, A. C. Share, G. R. Slater, N. M. Smith,
Tetrahedron, 2000, 56, 4589-4595.
8)
For books and reviews see: a) G. Liu, Y. Wu, Top. Curr. Chem. 2010, 292,
195-209; b) Åkermark, B.; Zetterberg, K. Handbook of Palladium Chemistry
for Organic Synthesis, Negishi, E. Ed.; John Wiley and Sons Inc. NY, Use of
Alkenes as Precursors to π-Allylpalladium Derivatives in Allylic Substitution
with O, N, and Other Heteroatom Nucleophiles, 2002, 2, 1875-1885; c) T.
Jensen, P. Fristrup, Chem. Eur. J. 2009, 15, 9632-9636; d) C. J. Engelin, P.
Fristrup, Molecules 2011, 16, 951-969; e) J. Muzart, Bull. Soc. Chim. Fr.
1986, 65-77; f) H. Grennberg, J.-E. Bäckvall, in Transition Metals for Organic
Synthesis, Chapter 2.3.2 p 200, Palladium-Catalyzed Allylic Oxidation, (Eds:
M. Beller, C. Bolm), Wiley-VCH 2004. H. Grennberg, J.-E. Bäckvall, Allylic
oxidations: palladium-catalyzed allylic oxidation of olefins. In Transition
Metals for Organic Synthesis (2nd Edition), M. Beller, C. Bolm, Eds. WileyVCH: Weinheim, 2004; Vol 2, pp 243-255. g) I. I. Moiseev, M. N. Vargaftik,
Coord. Chem. Rev. 2004, 248, 2381-2391. h) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147-1169. i) R. Jazzar, J. Hitce, A. Renaudat, J.
Sofack-Kreutzer, O. Baudoin, Chem. Eur. J. 2010, 16, 2654-2672. j) H. Li, B.J. Li, Z.-J. Shi, Catal. Sci. Technol. 2011, 1, 191-206. k) A. Breder, Synlett
2014, DOI: 10.1055/s-0033-1340625.
9)
F. Liron, J. Oble, M. M. Lorion, G. Poli, Eur. J. Org. Chem, 2014, in print.
DOI: 10.1002/ejoc.201402049R1.
10)
S. Cacchi, A. Arcadi, in Handbook of Organopalladium Chemistry for
Organic Synthesis (Eds: E.-i. Negishi), John Wiley & Sons, 2002, 2289. For
review dealing with early works, see: a) J. Muzart, Bull. Soc. Chim. Fr. 1986,
65-77. b) D. J. Rawlinson, G. Sosnovsky, Synthesis 1973, 567-603. c) B.
Åkermark, K. Zetterberg, Handbook of Organopalladium Chemistry for
Organic Synthesis Ed.: E.-i. Negishi, John Wiley and Sons, New York, 2002,
1875-1885. d) T. Hosokawa and S.-I. Murahashi: Other Intramolecular
Oxypalladation-Dehydropalladation
Reactions,
In
Handbook
of
Organopalladium Chemistry for Organic Synthesis, Ed., E. Negishi, John
Wiley & Sons, New York, 2002, Vol. 2, 2141-2159. e) P. M. Henry,
Palladium Catalyzed Oxidation of Hydrocarbons, D. Reidel Publishing Co.,
Dordrecht, 1980.
1)
For reviews see: a) K. Muñiz, Angew. Chem. Int. Ed. 2009, 48, 9412-9423; b)
P. Sehnal, R. J. K. Taylor, I. J. S. Fairlamb, Chem. Rev. 2010, 110, 824-889; c)
T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147-1169; d) N. R.
Deprez, M. S. Sanford, Inorg. Chem. 2007, 46, 1924-1935.
2)
E. J. Alexanian, C. Lee, E. J. Sorensen, J. Am. Chem. Soc. 2005, 127, 76907691.
13)
For a seminal discussion about this point see: C. H. Heathcock, J. A. Stafford,
D. L. Clark, J. Org. Chem. 1992, 57, 2575-2585.
14)
E. M. Beccalli, G. Broggini, G. Paladino, A. Penoni, C. Zoni, J. Org. Chem.
2004, 69, 5627-5630.
15)
K. J. Fraunhoffer, M. C. White, J. Am. Chem. Soc. 2007, 129, 7274-7276.
16)
H. Grennberg, A. Gogoll, J.-E. Bäckvall, Organometallics, 1993, 12, 17901793.
17)
F. Nahra, F. Liron, G. Prestat, C. Mealli, A. Messaoudi, Poli, G. Chem. Eur. J.
2009, 15, 11078-11082.
8)
With this substrate the proxicyclic β-H elimination product was observed as a
minor side product.
9)
E. Gómez-Bengoa, J. M. Cuerva, A. M. Echavarren, G. Martorell, Angew.
Chem. Int. Ed. Engl. 1997, 36, 767-769.
20)
E.-I. Negishi, C. Copéret, S. Ma, S. Y. Liou, F. Liu, Chem. Rev. 1996, 96,
365-393.
21)
For precedents of reversible aminopalladation, see ref 6 and: a) C. Hahn, P.
Morvillo, A. Vitagliano, Eur. J. Inorg. Chem. 2001, 419-429. b) C. Hahn, P.
Morvillo, E. Herdtweck, A. Vitagliano, Organometallics 2002, 21, 1807-1818.
c) M. E. Cucciolito, A. D’Amora, A. Vitagliano, Organometallics 2005, 24,
3359-3361. d) F. E. Michael, B. M. Cochran, J. Am. Chem. Soc. 2008, 130,
2786-2792. e) V. I. Timokhin, S. S. Stahl, J. Am. Chem. Soc. 2005, 127,
17888-17893. f) G. L. J. Bar, G. C. Lloyd-Jones, K. I. Booker-Milburn, J. Am.
Chem. Soc. 2005, 127, 7308-7309.
22)
For reviews, see: a) K. Muñiz, Angew. Chem. 2009, 121, 9576-9588; Angew.
Chem. Int. Ed. 2009, 48, 9412-9423; b) P. Sehnal, R. J. K. Taylor, I. J. S.
Fairlamb, Chem. Rev. 2010, 110, 824-889; c) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147-1169; d) N. R. Deprez, M. S. Sanford, Inorg.
Chem. 2007, 46, 1924-1935.
23)
J. Rajabi, M. M. Lorion, V. Linh Ly, F. Liron, J. Oble, G. Prestat, G. Poli,
Chem. Eur. J., 2014, 20, 1539-1546.
Prof. Giancarlo Fabrizi (University of Rome “La Sapienza”-Rome, Italy)
Born in Roma, Giancarlo Fabrizi began his university training at the University of
Roma where he obtained a Laurea summa cum laude in Pharmaceutical Chemistry in
1987 under the supervision of Prof. Cacchi. After doing his national service (19881989), from 1990 to 1994 he was researcher at the University of L’Aquila and, from
1994 to 2001, at the University “La Sapienza”, Rome. At the University “La
Sapienza” he became Associate Professor of Organic Chemistry in 2001 and,
subsequently (2011), full Professor of Organic Chemistry.
Dr. Fabrizi made a contribution in the field of organometallic chemistry, particularly
in the utilization of palladium catalysis in organic synthesis, developing new and
selective synthetic procedures directed towards the functionalization or preparation of
complex molecules, with particular emphasis on the chemistry of molecules of
biological interest.
His scientific contributions have involved the introduction of organotriflates in the
Heck reaction and other palladium-catalyzed reactions such as carbonylation,
reduction, Heck-Sonogashira-Cassar coupling of terminal alkynes; the development
of oxy- and aminopalladation/reductive elimination protocols for the construction of
functionalized heterocycles; pioneering work on the capture of carbopalladation
adducts with nucleophiles which led to the development of hydroarylation and
hydrovinylation
reactions
of
alkenes
and
alkynes,
including
domino
hydroarylation(hydrovinylation)/cyclization processes particularly suited for the
synthesis of heterocycles; the development of various domino coupling/cyclization
and vinylic substitution/cyclization procedures for the synthesis of heterocycles.
The development of environmentally friendly processes is also one of his main
current scientific interests and some of his recent studies investigated the utilization of
unusual media, such as supercritical carbon dioxide and ionic liquids, in palladiumcatalyzed reactions. Recently, the utilization of nanoparticles based catalysts
(palladium, gold) has been also proposed in conjunction with bioorganic processes.
12.05-12.50 Palladium- and Copper-catalyzed routes to substituted indoles
selected references for the lecture:
1)
Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 313.
2)
Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: New York,
2000.Pergamon: New York, 2000.
3)
For some major review articles on palladium catalysis in the synthesis and
functionalization of heterocycles, see: (a) Li, J. J. Alkaloids: Chemical and
Biological Perspectives 1999, 14, 437. (b) Cacchi, S.; Fabrizi, G.;
Goggiamani, A. Heterocycles 2002, 56, 613. (c) Cacchi, S.; Fabrizi, G.; Parisi,
L. M. Heterocycles 2002, 58, 667. (d) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127 (e) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev.
2004, 104, 3079. (f) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (g)
Cacchi, S., Fabrizi, G., Chem. Rev. 2005, 105, 2873-2920, Chem. Rev. 2011,
111, PR215–PR28.
4)
(a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (b) Martin, A.
R.; Zheng, Q. Adv. Nitrogen Heterocycl. 1995, 1, 71. (c) Li, J. J. Alkaloids:
Chem. Biol. Perspect. 1999, 14, 437. (d) Gribble, G. W. J. Chem. Soc., Perkin
Trans 1 2000, 1045. (e) Minoru, I. Trends Heterocycl. Chem. 2001, 7, 75. (f)
Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671.
5)
Cacchi, S., Fabrizi, G.; Goggiamani, A. Org. & Biom. Chem 2011, 9, 641.
6)
Undheim, K. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley & Sons: New York, 2002; p 409.
Dr. Matteo Biagetti (Chiesi Farmaceutici S.p.A.-Parma, Italy)
Matteo Biagetti graduated in Organic Chemistry at the University of Pisa under the
supervision of Prof. Renzo Rossi. He obtained the PhD degree in Chemistry
supervised by prof. Rossi and prof. J-L. Parrain from University of Aix-MarseilleFrance developing new general methods for the selective synthesis of natural and
non-natural oxygen containing heterocycles, leading to the first total synthesis of
lissoclinolide, cleviolide and incrustoporin.
In 2003, he started his medicinal chemistry career at the Centre of Excellence for
Drug Discovery of GlaxoSmithKline in Verona, where he worked on various
medicinal chemistry programmes within the CNS area. During this period he was
visiting scientist at GSK Molecular Discovery Research in Harlow and at Centre of
Excellence for Macrolide Discovery in Zagreb.
In 2010, he moved to the Research Centre for Agriculture and Forestry in Laimburg
(South Tyrol) as Discipline Leader in the Plant Protection department.
He is currently Team Leader of the Lead Optimization Unit 2 of Chemistry research
& Drug Design Department of Chiesi Farmaceutici in Parma managing discovery
projects targeting respiratory diseases.
15.00-15.45 Cross-Coupling reactions from a medicinal chemistry perspective:
exploiting SAR on valuable scaffolds
Selected references for the lecture:
1)
Rossi, Biagetti et al. Tet.Lett 2000, 41, 5281
2)
Rossi, Biagetti et al Tetrahedron 2002, 5023
3)
Collins, J.Chem.Soc., Perking Trans I, 2002, 1921-1940
4)
Biagetti, Leslie et al, Bioorg.Med.Chem.Lett. 2010, 6103
5)
Handy and Zhang Method, Chem.Commun. 2006, 299
6)
Houk, Merlic JACS, 2009, 6632
7)
Acta Chem.Scan. 1989, 62-68
8)
Bamborough J.Med.Chem. 2011, 54, 5131
9)
Bioorg. Med. Chem Lett. 2011, 4059
10)
Org. Lett. 2004, 277
11)
J. Med. Chem. 2008, 3066
12)
J.Med.Chem. 2012,1662