pubs.acs.org/joc
R-amino acid derivatives,4 β-aminocarbonyl compounds,5 or
Three-Component Synthesis of r-Branched Amines
under Barbier-like Conditions
amino alcohols.6 Concomitantly, other significant develop-
ments regarding nucleophile diversification have also been
disclosed. Thus, procedures related to the Mannich reaction,
employing an electron-rich aromatic compound (aromatic
Mannich reaction7), an organoboronic acid (Petasis reaction8),
or a preformed organometallic reagent9 as the nucleophile,
have been used in varioussynthetic processes. Furthermore, in
the latter area, the formation of organometallic intermediates
under Barbier-like conditions (in situ metalation of halides or
related compounds) has been the subject of significant interest
over the last few years owing to the important experimental
simplicity and the general efficiency of such procedures.10
As part of our work devoted to the development of MCRs
involving organometallic reagents, we recently developed a
Mannich-type three-component reaction among amines,
aldehyde derivatives, and preformed arylzinc or benzylzinc
reagents.11 In a very recent study, we also disclosed the
possibility of operating under Barbier-like conditions, star
ting from organic halides as organozinc precursors.12 Herein,
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Erwan Le Gall,* Caroline Haurena, Stephane Sengmany,
Thierry Martens, and Michel Troupel
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Electrochimie et Synthese Organique, Institut de Chimie et des
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Materiaux Paris Est (ICMPE)-UMR 7182 CNRS-Universite
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Paris 12, 2-8 rue Henri Dunant, 94320 Thiais, France
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Received August 5, 2009
(4) (a) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44,
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Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507–2515. (c) Mitsumori, S.;
Zhang, H.; Ha-Yeon Cheong, P.; Houk, K. N.; Tanaka, F.; Barbas, C. F. III
J. Am. Chem. Soc. 2006, 128, 1040–1041. (d) Cordova, A.; Barbas, C. F. III
Tetrahedron Lett. 2002, 43, 7749–7752. (e) Dhawan, R.; Dghaym, R. D.;
Arndtsen, B. A. J. Am. Chem. Soc. 2003, 125, 1474–1475. (f) Nanda, K. K.;
Trotter, B. W. Tetrahedron Lett. 2005, 46, 2025–2028.
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Ueno, M.; Shimizu, H. Tetrahedron 2001, 57, 861–866. (c) List, B. J. Am.
Chem. Soc. 2000, 122, 9336–9337. (d) Cordova, A.; Watanabe, S.; Tanaka,
F.; Notz, W.; Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, 1866–1867. (e)
Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292–9295.
An array of R-branched amines has been prepared by
using an expedient three-component Mannich-type reac-
tion among organic halides, aldehyde derivatives, and
amines. The experimental procedure, which is character-
ized by its simplicity, employs zinc dust for the in situ
generation of organozinc reagents. We show that this
Barbier-like protocol constitutes a useful entry to diaryl-
methylamines, 1,2-diarylethylamines, R- or β-amino
esters, benzylamines, and β-arylethylamines.
(6) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
2002, 124, 827–833. (b) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003,
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Multicomponent reactions (MCRs) do not only constitute
efficient tools for parallel synthesis in drug discovery, they
also represent a relevant methodology for the preparation of
important synthetic intermediates or natural products.1,2
The probably most renowned non-isocyanide-based MCR
is the Mannich reaction,3 which has been the subject of
constant development over the past decades, due to the
important synthetic perspectives induced by related pro-
cesses. Accordingly, some modern variants of the reaction
involve the use of additional catalysts to provide rate
enhancement and furnish a source of chirality for the stereo-
selective preparation of useful synthetic intermediates like
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(9) (a) Desrosier, J.-N.; Cote, A.; Charette, A. B. Tetrahedron 2005, 61,
^ ꢀ
6186–6192. (b) Cote, A.; Charette, A. B. J. Org. Chem. 2005, 70, 10864–
10867. (c) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409–10410. (d) Akullian, L. C.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4244–4247.
(10) For recent examples of Mannich-related reactions conducted in
Barbier conditions, see: (a) Aschwanden, P.; Stephenson, C. R. J.; Carreira,
E. M. Org. Lett. 2006, 8, 2437–2440. (b) Gommermann, N.; Knochel, P.
Tetrahedron 2005, 61, 11418–11426. (c) Estevam, I. H. S.; Bieber, L. W.
Tetrahedron Lett. 2003, 44, 667–670. (d) Wei, C.; Li, Z.; Li, C.-J. Org. Lett.
2003, 5, 4473–4475. (e) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584–
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2534–2536. (g) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
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N.; Knochel, P. Synthesis 2004, 2015–2025. (i) Bieber, L. W.; Da Silva, M. F.
Tetrahedron Lett. 2004, 45, 8281–8283. (j) Fan, R.; Pu, L.; Qin, L.; Wen, F.;
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(1) Zhu, J.; Bienayme, H., Eds. Multicomponent Reactions; Wiley-VCH:
Weinheim, Germany, 2005.
(2) For recent reviews on MCRs and Asymmetric MCRs (AMCRs), see:
(a) Guillena, G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18,
€
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693–700. (b) Domling, A. Chem. Rev. 2006, 106, 17–89. (c) Ramon, D. J.;
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€
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Chem., Int. Ed. 2000, 39, 3168–3210.
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Yao, G.; Wu, J. J. Org. Chem. 2007, 72, 3149–3151. (k) Choucair, B.; Leon,
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H.; Mire, M.-A.; Lebreton, C.; Mosset, P. Org. Lett. 2000, 2, 1851–1853.
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M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 2, pp 953-973. (c)
Overman, L. E.; Ricca, D. J. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 2, pp 1007-1046.
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(11) (a) Le Gall, E.; Troupel, M.; Nedelec, J.-Y. Tetrahedron Lett. 2006,
47, 2497–2500. (b) Le Gall, E.; Troupel, M.; Nedelec, J.-Y. Tetrahedron 2006,
62, 9953–9965. (c) Sengmany, S.; Le Gall, E.; Le Jean, C.; Troupel, M.;
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Nedelec, J.-Y. Tetrahedron 2007, 63, 3672–3681.
7970 J. Org. Chem. 2009, 74, 7970–7973
Published on Web 09/21/2009
DOI: 10.1021/jo901704s
r
2009 American Chemical Society