5946
S. Syu et al. / Tetrahedron Letters 51 (2010) 5943–5946
CHO
OH
threo-5g (744772), erythro-5f (753480), and erythro-5h (748316))
and NMR spectra) associated with this article can be found, in
EtPPh2
(20 mol%)
O
CO2Me
OMe
OMe
MeOH
+
+
RT, 4 h
O2N
NO2
1a
References and notes
2a
10: 60% yield
1. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
Scheme 6. An EtPPh2-catalyzed three-component reaction of 1a, 2a, and MeOH.
2. (a) For an overview, see: Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005; For excellent reviews, see: (b) Dömling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168; (c) Bienaymé, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321; (d) Orru, R. V. A.; de Greef, M. Synthesis
2003, 1471; (e) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; (f) Ramón, D.
J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (g) Dömling, A. Chem. Rev.
2006, 106, 17.
chemoselectivity was shown in case of the Michael addition of 3b
toward 6a in the presence of 2a. Only the adduct 5a, resulting from
the addition of 3b toward 6a was observed without the occurrence
of the addition of 3b toward 2a.
3. (a) For an overview, see: Domino Reactions in Organic Synthesis; Tietze, L. F.,
Brasche, G., Gericke, K., Eds.; Wiley-VCH: Weinheim, 2006; Also see: (b) Posner,
G. H. Chem. Rev. 1986, 86, 831; (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem., Int. Ed. 2006, 45, 7134.
Interestingly, not only an amide, such as 3a or 3b, but also an
alcohol like MeOH, was a suitable nucleophile. A highly chemose-
lective three-component reaction via the addition of MeOH toward
6a resulting from 1a and 2a (1.5 equiv) was accomplished in 4 h in
the presence of EtPPh2, affording the corresponding product 10 in
60% yield without the competitive reaction of the Michael addition
of MeOH toward 2a (Scheme 6).12,13
In conclusion, we have developed a general procedure for a new
type of chemoselective three-component reaction with aromatic
aldehyde 1, alkyl acrylate 2, and amide 3 catalyzed by EtPPh2.
The reaction condition is very mild, and numerous aromatic alde-
hydes 1 can react efficiently with 2 and 3 in moderate to high
yields. The reaction mechanism is proposed to undergo the Mori-
ta–Baylis–Hillman reaction of 1 and 2 followed by the Michael
addition of 3 toward the corresponding adduct 6. Our study indi-
cated that in combination of EtPPh2, alkyl acrylate also catalyzed
this process. Further studies and the extensions of this work in imi-
nes or other activated alkenes, as well as the use of other nucleo-
philic reagents are currently underway.
4. Reviews for Morita–Baylis–Hillman reactions, see: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811, and references cited therein; (b)
Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049; (c) Basavaiah, D.; Rao, K. V.;
Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581; (d) Menozzi, C.; Dalko, P. I.
Organocatalytic Enantioselective Morita–Baylis–Hillman Reactions. In
Enantioselective Organocatalysis, Reactions and Experimental Procedures; Dalko,
P. I., Ed.; Wiley-VCH: Weinheim, 2007; Recent reviews for application of
Baylis–Hillman adduct, see: (e) Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 4614; (f) Batra, S.; Singh, V. Tetrahedron 2008, 64, 4511.
5. For selected literature about the addition of nitrogen nucleophile to Baylis–
Hillman adduct, see: (a) Roy, A. K.; Pathak, R.; Yadav, G. P.; Maulik, P. R.; Batra,
S. Synthesis 2006, 1021; (b) Nag, S.; Yadav, G. P.; Maulik, P. R.; Batra, S. Synthesis
2007, 911.
6. For selected reviews, see: (a) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J.
Chem. Rev. 2007, 107, 5759; (b) McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M.
A.; Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007, 107, 5841.
7. Wang, W.; Yu, M. Tetrahedron Lett. 2004, 45, 7141.
8. (a)For studies of b-peptides, see: Pseudo-peptides in Drug Discovery; Nielsen, P.
E., Ed.; Wiley-VCH: Weinheim, 2004; (b) Seebach, D.; Kimmerlin, T.; Šebesta,
R.; Campo, M. A.; Beck, A. K. Tetrahedron 2004, 60, 7455; (c) Cheng, R. P.;
Gellman, S. H.; DeGrado, W. F. J. Am. Chem. Soc. 2001, 101, 3219.
9. THF was used as solvent due to the poor solubility of 3b in tBuOH.
10. The reaction rate of 1a and 2a catalyzed by EtPPh2 (20 mol %) in tBuOH (full
conversion; 1 h; 66% yield) or in THF (full conversion; 24 h; 67% yield) is much
faster than that of DABCO-catalyzed reaction in tBuOH (60 h; 92% yield) or in
THF (90 h; 90% yield). In addition, an experiment of 6a in the presence of
EtPPh2 (20 mol %) in tBuOH or THF was examined, respectively; showing that
the decomposition of 6a occurred faster in tBuOH than in THF. See the
Supplementary data.
Acknowledgments
We thank the National Science Council of the Republic of China
(NSC Grant No. 97-2113-M-003-003-MY2) and National Taiwan
Normal University (99031019) for financial support.
11. For the detailed studies, please see the Supplementary data.
12. For addition of MeOH toward 2a catalyzed by PMe3 (36 h, 71% yield), please
see: Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696.
13. For Baylis–Hillman reaction of acrylamide with an aryl aldehyde catalyzed by
DBU or PBu3, which was accompanied with a highly competitive side reaction
of MeOH adding toward acrylamide. See: Faltin, C.; Fleming, E. M.; Connon, S. J.
J. Org. Chem. 2004, 69, 6496.
Supplementary data
Supplementary data (general experimental procedures, com-
pound characterization data, X-ray crystallographic data (CCDC
number: threo-4a (750223), threo-4c (744771), threo-4f (752968),