A R T I C L E S
Bertelsen et al.
1
Almost 30 years later, List and Barbas rediscovered and
expanded the catalytic properties of proline by presenting the
first enantioselective, intermolecular aldol reaction of acetone
with aromatic aldehydes.10 The same year, MacMillan’s group
reported the application of chiral imidazolidinones derived from
phenylalanine in the organocatalytic, enantioselective Diels-
Alder reaction of R,â-unsaturated aldehydes with dienes.11
Despite the fundamental analogies in the structure of these
catalysts and substrates, the mechanisms of these reactions are
very different. In the case of the R-functionalization of aldehydes
and ketones, an enamine is formed by the optically active
catalyst and the carbonyl compound giving a chiral nucleophile,
which will attack the electrophile (Scheme 1, eq 1). In the case
of the R,â-unsaturated systems, the catalyst activates the sub-
strate by decreasing the energy of the LUMO in the intermediate
iminium-ion, thereby facilitating the transfer of the chirality by
addition of the nucleophile to the â-position (Scheme 1, eq 2).
Following these two inspiring articles, numerous innovative
and increasingly sophisticated examples of the use of amino-
catalysis have emerged in what can be called an explosive
expansion of the field of organocatalysis, thereby producing
a “nearly endless” number of optically active building blocks
by applying these ideas.12 Furthermore, the combination of
organocatalytic asymmetric â- and R-functionalization of R,â-
unsaturated carbonyl compounds has also been pursued in the
development of domino reactions,13 leading to the formation
of molecules of even higher complexity, having several chiral
centers. List recently described the potential and generality of
these complementary approaches, the enamine and iminium-
ion catalysis, as the Ying and Yang of aminocatalysis.12a
In this paper, we introduce a new concept in chiral amine-
catalyzed reactions, opening a new dimension in the field of
organocatalysis. Here, we wish to present the first direct
γ-functionalization of R,â-unsaturated carbonyl compounds
catalyzed by proline derivatives (Scheme 2), by describing the
reaction between R,â-unsaturated aldehydes and azodicarboxyl-
ates. Furthermore, to disclose the potential and possible limita-
tions of this new enantioselective γ-functionalization, a series
of experimental and computational studies on the mechanism
and on the properties of the reactive dienamine intermediate(s)
will be presented.
We therefore undertook H NMR spectroscopic investigations
in the attempt to characterize the expected iminium-ion inter-
mediate 3a formed by reaction of 2-pentenal 1a and the chiral
catalyst 2a. In contrast to our expectations, approximately 30
(12) For some recent feature articles, see, for example: (a) List, B. Chem.
Commun. 2006, 819. (b) Marigo, M.; Jørgensen, K. A. Chem. Commun.
2006, 2001. For application of enamine catalysis in Michael additions, see,
for example: (c) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253. (d)
Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598.
(e) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901.
(f) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077. (g) Luo,
S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed.
2006, 45, 3093. (h) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006,
128, 7170. (i) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966. For application of
enamine catalysis in Mannich reactions, see, for example: (j) Mitsumori,
S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2006, 128, 1040. (k) Kano, T.; Yamaguchi, Y.;
Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 16408. (l) List, B.
J. Am. Chem. Soc. 2000, 122, 9336. For application of enamine catalysis
in fluorinations, see, for example: (m) Enders, D.; Hu¨ttl, M. R. M. Synlett
2005, 991. (n) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Braunton, A.;
Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703.
(o) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed.
2005, 44, 3706. (p) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 8826. (q) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.;
Overgaard, J.; Jørgensen, K. A. Chem.-Eur. J. 2006, 12, 6039. For
application of enamine catalysis in chlorinations, see, for example: (r)
Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc.
2004, 126, 4108. (s) Halland, N.; Braunton, A.; Bachmann, S.; Marigo,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. (t) Halland, N.;
Lie, M. A.; Kjærsgaard, A.; Marigo, M.; Schiøtt, B.; Jørgensen, K. A.
Chem.-Eur. J. 2005, 11, 7083. (u) Marigo, M.; Bachmann, S.; Halland,
N.; Braunton, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 5507.
For application of enamine catalysis in brominations, see, for example:
(v) Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.;
Jørgensen, K. A. Chem. Commun. 2005, 4821. For application of enamine
catalysis in sulfenylations, see, for example: (w) Wang, J.; Li, H.; Mei,
Y.; Lou, B.; Xu, D.; Xie, D.; Gou, H.; Wang, W. J. Org. Chem. 2005, 70,
5678. (x) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. For application of enamine catalysis
in oxygenations, see, for example: (y) Zhong, G. Angew. Chem., Int. Ed.
2003, 42, 4247. (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 10808. (aa) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293.
(ab) Kumarn, S.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V. Org. Lett.
2005, 7, 4189. (ac) Cordova, A.; Sunden, H.; Enqvist, M.; Ibrahem, I.;
Casas, J. J. Am. Chem. Soc. 2004, 126, 8914. (ad) Mathew, S. P.; Iwamura,
H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004, 43, 3317. For
application of enamine catalysis in hydroxyaminations, see, for example:
(ae) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 6046. For application of enamine catalysis in alkylations, see, for
example: (af) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. For
applications of iminium-ion catalysis in cycloadditions, see, for example:
(ag) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240. (ah) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 11616. For applications of iminium-ion catalysis in
reductions, see, for example: (ai) Ouellet, S. G.; Tuttle, J. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 32. For applications of iminium-
ion catalysis in Mukaiyama-Michael reactions, see, for example: (aj)
Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 1192. For applications of iminium-ion catalysis in Michael
reactions, see, for example: (ak) Prieto, A.; Halland, N.; Jørgensen, K. A.
Org. Lett. 2005, 7, 3897. (al) Halland, N.; Hansen, T.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 4955. (am) Knudsen, K. R.; Mitchell, C.
E. T.; Ley, S. V. Chem. Commun. 2006, 66 and references therein.
(13) (a) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 5962. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2005, 127, 15051. (c) Yang, J. W.; Hechavarria
Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036. (d) Marigo,
M.; Schulte, T.; Franze´n, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 15710. (e) Sunde´n, H.; Ibrahem, I.; Eriksson, L.; Co´rdova, A. Angew.
Chem., Int. Ed. 2005, 44, 4877. (f) Enders, D.; Hu¨ttl, M. R. M.; Grondal,
C.; Raabe, G. Nature 2006, 441, 861. (g) Wang, W.; Li, H.; Wang, L.; Zu,
L. J. Am. Chem. Soc. 2006, 128, 10354.
Results and Discussion
1H NMR Investigations. We have recently reported a number
of enantioselective conjugated additions to R,â-unsaturated
aldehydes using 2-[bis(3,5-bistrifluoromethylphenyl)-trimeth-
ylsilanyloxymethyl]pyrrolidine 2a as the organocatalyst.13d,14
This organocatalyst, derived from proline, is proposed to activate
the Michael acceptor through the formation of a reactive
iminium-ion 3a as outlined in Scheme 3. During these studies,
we have often been surprised by the short reaction times
observed, even when the absence of a background reaction
indicated an intrinsic low reactivity of the chosen reagents.
To further extend the scope of our catalytic system, we
decided to investigate the reasons for this remarkable activity.
(14) (a) Brandau, S.; Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305. (b) Marigo, M.; Bertelsen, S.;
Landa, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475. (c) Marigo,
M.; Fra´nzen, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 6964. For application of 2a in enamine-catalyzed reactions,
see: (d) Fra´nzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (e)
Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2005, 44, 3703. (f) Marigo, M.; Wabnitz, T. C.;
Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794.
(g) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
2005, 44, 4212. (h) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128,
6804. (i) Ibrahem, I.; Zhao, G.-L.; Sunde´n, H.; Co´rdova, A. Tetrahedron
Lett. 2006, 47, 4659.
(9) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b) Eder,
U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496.
(10) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395.
(11) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243.
9
12974 J. AM. CHEM. SOC. VOL. 128, NO. 39, 2006