more than three different Michael additions specifically to
acyclic R,â-unsaturated carbonyl compounds.14 Therefore,
a milder Lewis acid catalyst that can tolerate more nucleo-
phile classes for functionalized Michael acceptors remains
to be explored.
As part of our ongoing programs on the uses of vanadyl
and oxometallic species in catalyzing C-X bond formation,15a,b
asymmetric aerobic oxidation15c,d and oxidative coupling,15e
and DNA photocleavage,15f we sought to evaluate the
feasibility of catalyzing the conjugate addition event by using
amphoteric vanadyl triflate. Namely, the partial positively
charged V in VdO is Lewis acidic enough to first activate
an electrophile (i.e., Michael acceptor) (Scheme 1, step-I).
formation between enolates and imines (Mannich-type reac-
tion) is a powerful means for constructing this functional
subunit, the conjugate additions of amine equivalents to R,â-
unsaturated carbonyls (i.e., aza-Michael addition) constitute
another direct and efficient methodological strategy. Notably,
catalytic activation of weaker nitrogen-centered nucleophiles
such as carbamates proves to be more difficult and can be
realized only very recently by the use of some delicately
designed Brønsted14 and Lewis acids (e.g., Bi(III),5a Re(V),6
Ir(IV),6 Pd(II),12b Pt(IV),6 Fe(III),7 Cu(II),13a and Au(I)6).
But-2-enoylbenzene 1 was first chosen as a test Michael
acceptor, and EtOC(O)NH2 (1.2 equiv) was used as a test
carbamate-type Michael donor in the presence of catalytic
VO(OTf)2 in various solvent systems.17 It was found that
the conjugate addition proceeded smoothly by using 5 mol
% of VO(OTf)2 in 0.5 M CH3CN/CH2Cl2 (1/1) at ambient
temperature (entry 1, Table 1).
Scheme 1. Postulated Mechanism for Amphoteric Vanadyl
Triflate Catalyzed Conjugate Addition
Table 1. Aza-Michael Additions Catalyzed by VO(OTf)2
Conversely, the partial negatively charged O in VdO serves
as a Lewis base to promote a subsequent proton transfer
(step-II and step-III) of a coordinated protic nucleophile (i.e.,
Michael donor) during the addition event. Under such
circumstances, the mediated reaction can proceed in a
sequential push-pull-type mechanism toward the substrate
pairs (Scheme 1).
Herein we disclose our preliminary finding toward this
end. To the best of our knowledge, this is the first successful
demonstration of conjugate additions to R,â-unsaturated
carbonyl compounds by group V (i.e., nitrogen and phos-
phorus) and carbon nucleophiles catalyzed by an oxometallic
speciessvanadyl triflate.
Carbonyl compounds bearing â-amino and -amido as well
as their downstream derivatives such as â-lactams and 1,3-
amino alcohols are versatile precursors of many biologically
active natural products.16 Although the carbon-carbon bond
a Isolated, purified yield. b Performed in neat benzamide at 70 °C with
1.5 equiv of enone. c 2.0 M in CH3CN/CH2Cl2 (1/1). d 2.0 M at 40 °C with
10 mol % of VO(OTf)2 and 2.0 equiv of p-TsNH2.
(12) (a) Miller, K. J.; Kitagawa, T. T.; Abu-Omar, M. M. Organometallics
2001, 20, 4403. (b) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25. (c)
Takasu, K.; Nishida, N.; Ihara, M. Synlett 2004, 1844.
(13) (a) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891.
(b) Palomo, C.; Oiarbide, M.; Kardak, B. G.; GarcZJ. M.; Linden, A. J.
Am. Chem. Soc. 2005, 127, 4154. (c) Kantam, M. L.; Neeraja, V.; Kavita,
B.; Neelima, B.; Chaudhuri, M. K.; Hussainb, S. AdV. Synth. Catal. 2005,
347, 763.
(14) (a) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141. (b)
Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem.sEur. J. 2004, 10, 484.
(15) (a) Chen, C.-T.; Kuo, J.-H.; Pawar, V. D.; Munot, Y. S.; Weng,
S.-S.; Ku, C.-H.; Liu, C.-Y. J. Org. Chem. 2005, 70, 1188. (b) Weng, S.-
S.; Lin, Y.-D.; Chen, C.-T. Org. Lett. 2006, 8, 5633. (c) Weng, S.-S.; Shen,
M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-T. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 3522. (d) Pawar, V. D.; Bettigeri, S.; Weng, S.-S.; Kao, J.-Q.;
Chen, C.-T. J. Am. Chem. Soc. 2006, 128, 6308. (e) Barhate, N. B.; Chen,
C.-T. Org. Lett. 2002, 4, 2529. (f) Chen, C.-T.; Lin, J.-S.; Kuo, J.-H.; Weng,
S.-S.; Cuo, T.-S.; Lin, Y.-W.; Cheng, C.-C.; Huang, Y.-C.; Yu, J.-K.; Chou,
P.-T. Org. Lett. 2004, 6, 4471.
With the preliminary success, aza-Michael additions to
other Michael acceptor classes like N-but-2-enoyl-1,3,2-
oxazolidinone 2 and 2-cycloalkenones 3-5 by three different
N-centered weak nucleophiles including carbamates, ben-
zamide, and p-toluenesulfonamide (p-TsNH2) were further
explored (Table 1). It was found that all the catalytic
reactions, except the benzamide additions and the addition
(16) For reviews, see: (a) Georg, G. I. The Organic Chemistry of
â-Lactams; VCH: New York, 1997. (b) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991. (c) Sewald, N. Angew. Chem., Int. Ed. 2003, 42, 5794. (d)
Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633.
(17) (a) Among 14 different oxometallic species, only MoO2Cl2 and VO-
(OTf)2 show promising catalytic efficiency. (b) For X-ray crystal structure
of VO(OTf)2‚5H2O, see: Magnussen, M.; Brock-Nannestad, T.; Bendix,
J. Acta Crystallogr., Sec. C 2007, 63, m51.
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Org. Lett., Vol. 9, No. 25, 2007