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SCHEME 1. Chiral Triazolium Catalysts for the Benzoin Con-
densation
Highly Enantioselective Benzoin Condensation
Reactions Involving a Bifunctional Protic
Pentafluorophenyl-Substituted Triazolium
Precatalyst
Louise Baragwanath,† Christopher A. Rose,‡
Kirsten Zeitler,‡ and Stephen J. Connon*,†
†Centre for Synthesis and Chemical Biology, School of
Chemistry, University of Dublin, Trinity College, Dublin 2,
‡
Ireland and Institut fu€r Organische Chemie, Universita€t
€
Regensburg Universitatsstrasse 31, D-93053 Regensburg,
Germany
R-hydroxy ketone motif from two aldehyde molecules with
the formation of a new stereocenter. Initial attempts to
develop an asymmetric variant of the reaction with use of
chiral thiazolium ion precatalysts in the presence of a base
resulted in low-moderate product enantiomeric excess;3
however, seminal work by Enders4 and then by Leeper5 later
demonstrated the clear superiority of chiral triazolium ion
Received September 18, 2009
precatalysts
;which culminated in 2002 with the isolation of
benzoin from the condensation of benzaldehyde in greater
than 90% ee (83% yield) catalyzed by the carbene derived
from the chiral bicyclic triazolium ion 1 (Scheme 1).6 As had
been observed in previous systems, both catalyst efficacy and
selectivity were highly dependent on the steric and electronic
characteristics of the aromatic aldehyde used: activated
aldehydes gave lower product ee, while electron-rich analo-
gues afforded benzoins with higher levels of enantiopurity at
the expense of product yield.
Very recently three reports have emerged which have
prompted us to report our results in this field: Enders
disclosed that the pyroglutamic acid-derived precatalyst 2a
could promote the BC of benzaldehyde in an outstanding
95% ee (66% yield) in toluene using KHMDS as the
base; however, as has traditionally been the case, substrates
either more or less electron rich than benzaldehyde proved
problematic.7 You and co-workers8 demonstrated that the
bis-triazolium precatalyst 3 could promote BC reactions
with high-excellent enantioselectivity (84-95% ee) and
moderate-excellent product yields (41-95%) while also
very recently Ye et al. reported the use of 2a and its
desilylated derivative 2b (along with related analogues) for
the promotion of highly enantioselective ketene dimeri-
zations,9 Staudinger cycloadditions,10 and aza-Baylis-
Hillman reactions.11
Improved catalyst design by incorporating a hydrogen
bond donating substituent to improve enantiocontrol
together with an acidifying pentafluorophenyl substitu-
ent to enhance catalyst efficiency results in a triazolium
ion precatalyst that promotes the asymmetric archetypal
benzoin condensation with excellent efficiency and un-
precedented enantioselectivity.
First discovered in 1832,1 the benzoin condensation (BC)2
is a catalytic carbon-carbon bond forming process of con-
siderable synthetic utility that allows the construction of a
€
(1) Wohler, F.; Liebig, J. Ann. Pharm. 1832, 3, 249.
(2) Recent reviews: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev.
2007, 107, 5506. (b) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988. (c) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44,
7506. (d) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (e) Enders,
D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534. (f) Johnson, J. S. Angew.
Chem., Int. Ed. 2004, 43, 1326. (g) Zeitler, K. Ernst Schering Found. Symp.
Proc. 2007, 2, 183.
(3) (a) Sheehan, J.; Hunnemann, D. H. J. Am. Chem. Soc. 1966, 88, 3666.
(b) Sheehan, J.; Hara, T. J. Org. Chem. 1974, 39, 1196. (c) Dvorak, C. A.;
Rawal, V. H. Tetrahedron Lett. 1998, 39, 2925. (d) Takagi, W.; Tamura, Y.;
Yano, Y. Bull. Chem. Soc. Jpn. 1980, 53, 478. (e) Marti, J.; Castells, J.; Lopez-
Calahora, F. Tetrahedron Lett. 1993, 34, 521. (f) Tachibana, Y.; Kihara, N.;
Takata, T. J. Am. Chem. Soc. 2004, 126, 3438. (g) Knight, R. L.; Leeper, F. J.
Tetrahedron Lett. 1997, 38, 3611. (h) Gerhard, A. U.; Leeper, F. J. Tetra-
hedron Lett. 1997, 38, 3615. (i) Knight, R. L.; Leeper, F. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 1891. (j) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org.
Chem. 2004, 2025.
Recently Connon et al.12 reported the first example of the
use of hydrogen bond donation as a control element in an
(4) Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1217.
(5) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891.
(6) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743.
(7) Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367.
(8) Ma, Y.; Wei, S.; Wu, J.; Yang, F.; Liu, B.; Lan, J.; Yang, S.; You, J.
Adv. Synth. Catal. 2008, 350, 2645.
(9) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825.
(10) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008, 10,
277.
(11) Lv, H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Adv. Synth. Catal. 2008,
350, 2715.
(12) O’Toole, S. E.; Connon, S. J. Org. Biomol. Chem. 2009, 7, 3584.
9214 J. Org. Chem. 2009, 74, 9214–9217
Published on Web 11/06/2009
DOI: 10.1021/jo902018j
r
2009 American Chemical Society