Bifunctional Catalysts for Nitro-Michael Addition
FULL PAPER
132.4, 131.1, 130.2, 129.9, 129.6, 127.8,127.4, 62.7, 59.8, 59.6, 31.3, 18.8,
17.2 ppm.
The irreversible formation of a cyclobutane side product 9
À
following the C C bond-forming step of the catalysis, as was
General procedure for the catalytic asymmetric nitro-Michael addition:
The appropriate Michael donor (0.5 mmol for aldehydes or 1.25 mmol
for other donors) and benzoic acid (0.025 mmol) were added to a mixture
of catalyst (0.075 mmol of the catalytic unit) and nitroolefin (0.25 mmol)
in toluene (2 mL). The suspension was stirred at room temperature for
4 days. After the reaction, the mixture was filtered and the catalyst was
washed with AcOEt (3ꢂ10 mL) and dried for reuse. The organic layer
was evaporated and the residue was analyzed by 1H NMR spectroscopy,
and then purified by flash column chromatography on silica gel (hexane/
AcOEt) to afford the Michael adduct. The ee value of the product was
determined by chiral HPLC analysis with Chiralcel OJ, Chiralcel OD, or
Chiralpak AD columns. The majority of the products are known and
were characterized by comparison of their NMR spectra to the corre-
sponding data in the literature.[8c,9c,17b,20f,21e,24g–i,30] Characterization of new
compounds is provided in the Supporting Information.
suggested by Jacobsen et al., can be one plausible explana-
tion for the catalyst deactivation in this type of catalytic re-
action.[11] However, the recently demonstrated reversibility
of such cyclobutane formation
under the reaction conditions
and, consequently, its postulated
role as the resting state of the
catalyst in the amine-catalyzed
nitro-Michael addition suggests
that other modes of catalyst de-
activation may also be possi-
ble.[28]
To the best of our knowledge, effective recycling of a sup-
ported catalyst in the addition of an aldehyde to nitroolefin
still remains a challenge. Most catalysts rapidly lose activity
upon recycling or require regenerating treatment between
the cycles.[4a] Only the peptide catalyst, recently reported by
Wennemers et al., could be reused numerous times without
loss of activity.[29]
Acknowledgements
This research was supported by Grant No. 2008193 from the United
States–Israel Binational Science Foundation (BSF) and Grant No. 960/06
from the Israel Science Foundation.
Conclusion
[1] a) R. Rios, A. Moyano in Catalytic Asymmetric Conjugate Reactions,
(Ed.: A. Cordova), Wiley-VCH, Weinheim, 2010, pp. 191–218;
b) H. Pellissier, Recent Development in Asymmetric Organocatalysis,
RSC Publishing, Cambridge, 2010, pp. 1–76.
[2] a) S. Sulzer-Mossꢃ, A. Alexakis, Chem. Commun. 2007, 3123–3135;
D. A. Alonso, C. Nꢅjera, Tetrahedron: Asymmetry 2007, 18, 299–
365.
[3] a) N. Ono, The Nitro Group in Organic Synthesis Wiley-VCH, New
York, 2001, p; b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
[4] a) E. Alza, M. A. Pericas, Adv. Synth. Catal. 2009, 351, 3051–3056;
3717–3720; d) P. Li, L. Wang, M. Wang, Y. Zhang, Eur. J. Org.
Chem. 2008, 2008, 1157–1160; e) P. Li, L. Wang, Y. Zhang, G.
K. Ren, L. Wang, G. Wang, Chirality 2010, 22, 432–441; i) Y. Chuan,
[5] For multiple examples, see: a) refs. [4b–i]; b) C. L. Cao, M. C. Ye,
e) F. Y. Liu, S. W. Wang, N. Wang, Y. G. Peng, Synlett 2007, 2415–
2045–2050; g) A. P. Carley, S. Dixon, J. D. Kilburn, Synthesis 2009,
2509–2516; h) A. D. Lu, P. Gao, Y. Wu, Y. M. Wang, Z. H. Zhou,
We have prepared, for the first time, polymer-supported bi-
functional catalysts incorporating a primary amine, for the
enantioselective nitro-Michael addition of aldehydes and ke-
tones. Introduction of simple l-a-amino acid spacers in the
structures of the “first-generation” catalyst that we prelimi-
narily communicated led to a substantially more active and
stereoselective catalytic system. The profiles of reactivity
and selectivity, which the new catalysts exhibit in the nitro-
Michael reaction of various ketones and aldehydes, empha-
sized the differences between the primary and secondary
amine-based catalysts.
Experimental Section
General procedure for the preparation of amino-urea catalysts: p-Nitro-
phenyl chloroformate (10 equiv per amino unit), DIPEA (20 equiv per
amino unit), and a catalytic amount of pyridine (0.1 equiv) were added to
a suspension of amine-terminated resin (1 equiv) in THF (10 mL per 1 g
resin). The suspension was stirred at room temperature for 2 h. The resin
was washed with water, THF/water, THF, and dichloromethane, and then
dried under vacuum. The resin was stirred in DMF (10 mL per 1 g resin)
and the appropriate chiral diamine (7 equiv per carbonate unit) was
added. The suspension was heated to 508C overnight. The resin was
washed with DMF/water, DMF, THF/water, THF, and dichloromethane,
and then dried under vacuum.
Catalyst 2: Starting materials: Wang-Val-NH2 resin (0.97 mmolgÀ1, pre-
loaded Fmoc-Val on Wang resin (ChemImpex), subjected to deprotec-
tion) and (1R, 2R)-(+)-1,2-diphenylethylenediamine. Yield >99%, load-
ing 0.78 mmolgÀ1. Following trifluoroacetic acid (TFA)-induced cleavage:
1H NMR (400 MHz, CDCl3/TFA 1:1): d=7.55 (brs, 3H), 7.35–7.37 (m,
4H), 7.25–7.34 (m, 4H), 7.15–7.17 (m, 4H), 5.43 (d, J=11.2 Hz, 1H),
4.81–4.82 (m, 1H), 4.37 (m, 1H), 2.29–2.31 (m, 1H), 0.98 ppm (d, J=
7.1 Hz, 6H); partial 13C NMR (100 MHz, CDCl3/TFA 1:1): d=135.7,
263, 186–194; b) B. K. Ni, Q. Y. Zhang, K. Dhungana, A. D. Head-
nabe, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas, J. Am. Chem.
Chem. Eur. J. 2012, 18, 2290 – 2296
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