4298
J . Org. Chem. 1999, 64, 4298-4303
P (RNCH2CH2)3N: An Efficien t P r om oter for th e Nitr oa ld ol (Hen r y)
Rea ction
Philip B. Kisanga and J ohn G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received September 15, 1998
The use of catalytic amounts of the proazaphosphatranes P(MeNCH2CH2)3N, P(i-PrNCH2CH2)3N
and P(HNCH2CH2)(i-PrNCH2CH2)2N as nonionic bases in the reaction of nitroalkanes with carbonyl
compounds is reported. The reaction proceeds at room temperature in the presence of 2.2 equiv of
magnesium sulfate to produce the corresponding â-nitroalkanols in generally superior yields.
Aldehydes react quantitatively in 5-60 min, whereas ketones require up to 3 h to react with
nitromethane and up to 7 h for the reaction of ketones with higher nitroalkanes.
In tr od u ction
amines and triethylamine as condensing agents has also
been reported.1 Although this methodology leads to high
yields of the â-nitroalkanol, the production of unsaturated
nitro compounds through base-catalyzed elimination of
water has been observed as well as formation of 1,3-
dinitro compounds. The latter substances are also the
predominant products when diethylamine is used as a
base.1
â-Nitroalkanols are important and versatile intermedi-
ates in the synthesis of nitroalkenes, 2-amino alcohols,
and R-nitro ketones.1 2-Amino alcohols are of particular
significance in the synthesis of biologically important
compounds such as epinephrine2 and anthracycline an-
tibiotics,3 while R-nitroketones are valuable intermedi-
ates in the synthesis of several natural products.4 â-Ni-
troalkanols are also important because of their properties
as fungicides5 and because of their utility as intermedi-
ates in the synthesis of amino sugars,6 antibiotics such
as ezomycins7a and tunicamycin,7b and alkaloids.8
Classical methods for preparing â-nitroalkanols include
the condensation of the carbonyl substrates and a ni-
troalkane in the presence of an ionic base such as alkali
metal hydroxides, alkaline earth oxides, carbonates,
bicarbonates, alkoxides, alkaline earth hydroxides, or
magnesium and aluminum alkoxides.1 While this ap-
proach is quite simple and inexpensive, its limitations
often render it unattractive. For example, base-catalyzed
elimination of water can occur to form nitroolefins which
unfortunately polymerize readily. Moreover, it is not easy
to remove the base before workup because acidification
of the reaction mixture may lead to the Nef9 reaction if
it is not done with extreme care. The use of primary
Several variations of the nitroaldol reaction have
recently been developed which include the use of tetra-
methylguanidine,10 dendritic catalysts,11 Amberlyst A-21,12
and a sodium hydroxide-catalyzed process in the presence
of cetyltrimethylammonium chloride (CTACl).13 Although
these methods afford high yields of the nitroaldol with
aldehydes, they suffer from their inability to produce high
product yields with alicylic or aliphatic ketones when
such reactions are even observed. Self-condensation10 of
aliphatic ketones has been cited as a possible reason for
the inability of this class of compounds to form the
nitroaldol product in appreciable amounts.
The proazaphosphatranes 1a ,14 1b,15 and 1c16,17 have
recently been shown to be strong nonionic bases. Thus
(1) (a) Rosini, G. In Comprehensive Organic Synthesis, Trost, B. M.,
Ed.; Pergamon: New York, 1991; Vol. 2, pp 321-340. (b) For recent
publications on the utility of the Henry reaction, see: Iseki, K.; Oishi,
S.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 9081. Barco,
A.; Benetti, S.; Risi, C.; Polloni, G. Tetrahedron Lett. 1996, 37, 7599.
Sasai, H.; Hiroi, M.; Yamada, Y.; Shibasaki, M. Tetrahedron Lett. 1997,
38, 6031. Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1236.
they are able to deprotonate acetonitrile,18,19 benzyl
nitrile,18 and other activated methylene compounds,20
(2) Brittain, R.; J ack, D.; Ritchie, A. Adv. Drug Res. 1970, 5.
(3) Williams, T. M.; Mosher, S. H. Tetrahedron Lett. 1985, 26, 6269.
(4) (a) Ballini, R.; Bosica, G. J . Org. Chem. 1994, 59, 5466. (b) Ballini,
R. J . Chem. Soc., Perkin Trans. 1, 1991, 1419. (c) Ballini, R.; Bosica,
H. J . Chem. Res.; Synop. 1993, 371.
(5) Mikite, G.; J akucs, K.; Darvas, F.; Lopata A. Pestic. Sci. 1982,
13, 557.
(6) Hanessian, S.; Kloss, J . Tetrahedron Lett. 1985, 26, 1261.
(7) (a) Sakanaka, O.; Ohmorti, T.; Kazaki, S.; Suami, T.; Ishii, T.;
Ohba, S.; Saito, Y. Bull. Chem. Soc. J pn., 1986, 59, 1753. (b) Sasai,
H.; Matsuno, K.; Suami, T. J . Carbohydr. Chem. 1985, 4, 99.
(8) Rizzacasa, M. A.; Sargent, M. V. J . Chem. Soc. Chem. Commun.
1990, 12, 894.
(10) Simoni, D.; Invidiata, F. P.; Manfrenidi, S.; Ferroni, R.; Lam-
pronti, I.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1997, 38, 2749.
(11) Morao, I.; Cossio, F. P. Tetrahedron Lett. 1997, 38, 6461.
(12) Ballini, R.; Bosica, G.; Forconi, P. Tetrahedron 1996, 52, 1677.
(13) Ballini, R.; Bosica, G. J . Org. Chem. 1997, 62, 425.
(14) D’Sa, B.; Verkade, J . G. Phosphorus Sulfur Silicon 1997, 123,
301.
(15) Wroblewski, A.; Pinkas, J .; Verkade, J . G. Main Group Chem.
1995, 1, 69.
(16) (a) Schmidt, H.; Lensink, C.; Xi, S. K.; Verkade, J . G. Z. Anorg.
Allg. Chem. 1989, 578, 75. (b) Laramay, M. A. H.; Verkade, J . G. Z.
Anorg. Allg. Chem. 1991, 605, 163.
(9) (a) McMurry, J . E.; Melton, J . J . Org. Chem. 1973, 38, 4367. (b)
Hwu, J . R.; Gilbert, B. A. J . Am. Chem. Soc. 1991, 113, 5917 and
references therein. (c) For a review on the Nef reaction, see: Noland,
W. E. Chem. Rev. 1955, 55, 137. Pinnick, H. W. In Organic Synthesis;
Paquette, L. A., Ed.; J ohn Wiley: New York, 1990; Vol. 38, Chapter 3.
(17) Tang, J .-S.; Verkade, J . G. J . Am. Chem. Soc. 1993, 115, 341.
(18) (a) D’Sa, B.; Kisanga, P.; Verkade, J . G. J . Org. Chem. 1998,
63, 3691. (b) Kisanga, P.; McLeod, D. G.; D’Sa, B.; Verkade, J . G. J .
Org. Chem. accepted. (c) Kisanga, P.; D’Sa, B.; Verkade, J . G. J . Org.
Chem. 1998, 63, 10057.
10.1021/jo9818733 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/18/1999