J . Org. Chem. 2002, 67, 3555-3560
3555
P (RNCH2CH2)3N: Efficien t 1,4-Ad d ition Ca ta lysts
Philip B. Kisanga,† Palanichamy Ilankumaran, Brandon M. Fetterly, and J ohn G. Verkade*
Department of Chemistry, Gilman Hall, Iowa State University, Ames, Iowa 50011
jverkade@iastate.edu
Received March 2, 2001
The 1,4-addition of primary alcohols, higher nitroalkanes, and a Schiff’s base of an R-amino ester
to R,â-unsaturated substrates produces the corresponding products in moderate to excellent yields
when carried out at -63 to 70 °C in the presence of catalytic amounts of the nonionic strong bases
P(RNCH2CH2)3N (R ) Me, i-Pr, i-Bu) in isobutyronitrile. Diastereoselectivity for the anti form of
the product is high in the case of the Schiff’s base in the absence of lithium ion. These catalysts are
easily removed from the product by either column filtration through silica gel or via aqueous workup.
In tr od u ction
product yields encountered10b) have been largely over-
come by newer methodologies.
Michael addition is one of the most efficient and
effective routes to the formation of C-C bonds.1 This
reaction is widely applied in organic synthesis,2 and
several new versions of the reaction have recently been
introduced.3 Michael addition reactions of electron-
deficient alkenes have been used to produce difunction-
alized synthons that have been used extensively in
organic synthesis.2 1,5-Diketones (prepared by Michael
addition of R-nitroketones to R,â-unsaturated ketones)4
have been used to prepare 2-cyclohexenones,5 and â-ni-
troketones can be reduced to â-aminoketones.1,6 Alter-
natively, the nitro group can be removed7 leaving behind
a â-alkyl substituent on the carbonyl product.
The commonly employed anionic alkyl synthons for
Michael addition are those derived from nitroalkanes,8
ethyl cyanocarboxylates,9 and malonates.10 Such Michael
donors have been extensively studied, and their limita-
tions (such as double additions,11 requirement for a large
excess of the nitroalkane,12 restrictions in the types of
Michael acceptors13 tolerated, and the low to moderate
The newer approaches are by no means devoid of
drawbacks, however. Among recent developments are the
use of Amberlyst A-27,14 and sodium hydroxide solution
in the presence of cetyltrimethylammonium chloride
(CTACl) as a cationic surfactant.15 However, the Am-
berlyst A-2714 process requires reaction times ranging
from 4 h (for MVK) to 25 h for the reactions of higher
nitroalkanes with â-substituted methyl vinyl ketones.
The sodium hydroxide method15 affords only modest
product yields in the reaction of secondary nitroalkanes,
even with MVK.15 The yields in both processes range from
moderate to high for most substrates. Michael addition
reactions of higher nitroalkanes to R,â-unsaturated car-
bonyl compounds generally require lengthy reaction
times and yields are only moderate. Although reactions
employing alumina are rapid, 4 equiv of the rather
expensive higher nitroalkanes are required.7b
Oxa-Michael addition reactions have been reported,
and the protected â-hydroxy carbonyl compounds so
produced are of significant importance in organic syn-
thesis.16 Reports describing such reactions include de-
scriptions of UV irradiation of cycloalkenones in metha-
nol to produce the â-methoxy cyclic ketones;16 reac-
tions promoted by NaOMe,17a KH,17b and potassium
t-butoxide;17c and the cyanoethylation of alcohols by a
Mg-Al hydrotalcite prepared in a process requiring 450
°C for up to 12 h.18a Several other catalysts have also
been used for the cyanoethylation of alcohols, but their
utility has not been extended to other R,â-unsaturated
* To whom correspondence should be addressed. Phone: 515-294-
5023; fax: 515-294-0105.
† Present address: Albany Molecular Research, Inc.; Syracuse
Research Center, 7001 Performance Dr., N. Syracuse, NY 13212.
(1) Reviews: (a) Ono, N.; Kaji, A. Synthesis 1986, 693. (b) Rosini,
G.; Ballini, R. ibid. 1988, 833. (c) Tamura, R.; Kamimura, A.; Ono, N.
Ibid. 1991, 423.
(2) Angelo, J .; Revial, G.; Costa, P. R. R.; Castro, R. N.; Antunes, O.
A. C. Tetrahedron Asymmetry 1991, 2, 199. (b) Hagiwara, H.; Okamoto,
T.; Harada, N.; Uda, H. Tetrahedron, 1995, 51, 9891. (c) Seebach, D.;
Colvin, E. W.; Leher, F.; Weller, T. Chimia 1979, 33, 1.
(3) Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J . S. Synth.
Commun. 1998, 28, 653. (b) Yamagushi, M.; Igarashi, Y.; Reddy, R.
S.; Shiraishi, T.; Hirama, M. Tetrahedron 1997, 53, 11223. (c) Hanyuda,
K.; Hirai, K.; Nakai, T. Synlett. 1997, 31.
(12) Clark, J . H.; Cork, D. G.; Gibbs. H. W. J . Chem. Soc., Perkin
Trans. 1 1983, 2253.
(4) Ono, N.; Miyake, H.; Kaji, H. J . Chem. Soc., Chem. Commun.
1983, 875.
(13) Ballini, R.; Petrini, M.; Rosini, G. Synthesis 1987, 711.
(14) Ballini, R.; Marziali, P.; Mozzicafreddo, A. J . Org. Chem. 1996,
61, 3209.
(15) Ballini, R.; Bosica, G. Tetrahedron Lett. 1996, 37, 8027.
(16) Grangier, G.; Trigg, W. J .; Lewis, T.; Rowan, M. G.; Potter, B.
V. L.; Blagbrough, I. S. Tetrahedron Lett. 1998, 39, 889. (b) Noyori,
R.; Kato, M. Bull. Chem. Soc. J pn. 1974, 46, 1460.
(17) Titova, T. F.; Krysin, A. P.; Shakirov, M. M.; Mamatyuk, V. I.
J . Org. Chem. USSR (Engl. Transl.) 1984, 20, 294. (b) Duffy, J . L.;
Kurth, J . A.; Kurth, M. J . Tetrahedron Lett. 1993, 34, 1259. (c) Dumez,
E.; Rodriguez, J .; Dulce`re, J .-P. J . Chem. Soc., Chem. Commun. 1997,
1831.
(18) Kumbhar, P. S.; Sanchez-Valente, J .; Figueras, F. Chem.
Commun. 1998, 10, 1091. (b) Kabashima, H.; Hattori, H.; Catal. Today
1998, 44, 277. (c) Che, R.; Wei, R.; Liang, Y.; Zheng, S.; Yang, P.; Cui,
Y. Lizi J onhuan Yu Xifu 1995, 11, 18. Chem. Abstr. 124: 263979.
(5) Grieco, P. A.; Pogonowski, C. S. Synthesis 1973, 425.
(6) Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 2, pp 321-340.
(7) Ono, N.; Miyake, H.; Tamuta, R.; Kaji, A. Tetrahedron Lett. 1981,
22,1705. (b) Bryce, M. R.; Gardiner, J . M.; Horton, P. J .; Smith, S. A.
J . Chem. Res., Synop. 1989, 1, 1.
(8) Wada, M.; Tsuboi, A.; Nishimura, K.; Erabi, T. Nippon Kagaku
Kaishi 1987, 7, 1284. Chem. Abstr. 1987, 108, 149866.
(9) Ranu, B. C.; Saha, M.; Bahr, S. Synth. Commun. 1997, 27, 621.
(10) Sreekumar, R.; Rugmini, P.; Padmakumar, R. Tetrahedron Lett.
1997, 38, 6557. (b) Ranu, B. C.; Hamada, A. Tetrahedron 1992, 48,
1327.
(11) Pollini, G. P.; Barco, A.; De Giuli, G. Synthesis 1972, 44. (b)
Bergbreiter, D. E.; Lalonde, J . J . J . Org. Chem. 1987, 52, 1601.
10.1021/jo010228k CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002