J . Org. Chem. 1998, 63, 3961-3967
3961
Dir ect Syn th esis of r,â-Un sa tu r a ted Nitr iles Ca ta lyzed by
Non ion ic Su p er ba ses
Bosco A. D’Sa, Philip Kisanga, and J ohn G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received December 31, 1997
We report herein the use of 3-30 mol % of a new class of tricyclic strong nonionic Lewis bases
P(MeNCH2CH2)3N and P(HNCH2CH2)(i-PrNCH2CH2)2N for the direct catalytic synthesis of a variety
of functionalized R,â-unsaturated nitriles in high yields from aldehydes and acetonitrile or benzyl
cyanide at 40-50 °C. Evidence for a novel mechanistic pathway proposed for this reaction in a
polar protic solvent such as methanol, and a nonpolar aprotic solvent such as benzene is also
presented. Under these conditions, primary and secondary aliphatic aldehydes do not condense
satisfactorily with acetonitrile to give the R,â-unsaturated nitrile, and ketones do not condense
with either benzyl cyanide or acetonitrile.
In tr od u ction
such as n-butyllithium in organic solvents giving the
â-hydroxy nitrile, which is then isolated and thermally
dehydrated in the presence of a strong acid such as
phosphoric acid.12 However, acetonitrile undergoes nu-
merous base-catalyzed side reactions, and the bases
required to deprotonate acetonitrile often nucleophilically
attack this reagent.6
The direct conversion of carbonyl compounds to R,â-
unsaturated nitriles in the presence of nitriles (i.e.,
without isolating and dehydrating the intermediate â-hy-
droxynitrile) is of considerable economic interest since
such nitriles serve as versatile intermediates in the
synthesis of a variety of products such as perfumes,1 sex
pheromones,2 vitamin A,3 and pigments.4 Classical meth-
ods leading directly to R,â-unsaturated nitriles generally
employ sodium hydroxide,5 potassium hydroxide6 or
potassium carbonate7 as a base and sodium ethoxide8 or
sodium methoxide9 as a catalyst. The base-promoted
condensations are carried out in heterogeneous media,
whereas the base-catalyzed condensations are carried out
in homogeneous media. However, side reactions occur
under these conditions, such as self-condensation of the
nitrile, aldol condensation of the carbonyl (in the case of
an enolizable aldehyde or ketone), the Cannizzaro reac-
tion (for aromatic aldehydes and aliphatic aldehydes with
no R-hydrogen), and retroreaction of the â-hydroxynitrile
intermediate.7,10 Hence, R,â-unsaturated nitriles are
generally obtained from aliphatic aldehydes by the Wit-
tig-Horner reaction.11 Moreover, the compatibility of the
classical routes with base-sensitive functional groups is
poor.6
Metals have also been employed to assist in the
formation of R,â-unsaturated nitriles. Thus, although
aldehydes in the presence of Cl(TMS)CHCN and Zn give
rise to R,â-unsaturated nitriles in refluxing THF, the
nitrile must be provided in the derivatized form shown.13
Similarly, RCH2CHCNCO2CH2CHdCH2 (preformed from
NCCH2CO2H in a two-step reaction) decomposes ther-
mally to RCHdCHCN, CO2, and C3H6 in the presence of
Pd and PPh3.14 At 60 °C, PhCH2CN has been found to
condense with PhCHO in the presence of RuH2(PPh3)4
and additives such as 1,2-bis(diphenylphosphino)ethane
to give PhCHdCPh(CN) (E/Z ) 1/6) in 87% yield.15
A
more recent synthesis of R,â-unsaturated nitriles utilizes
cationic surfactants such as cetyltrimethylammonium
chloride in the presence of sodium hydroxide as the
catalyst in an aqueous medium. The drawbacks here are
the same as those encountered in the classical methods.4
The above approaches are less convenient and less
versatile than the one we report herein. They also
provide only low to moderate yields of product, and routes
employing metallic species pose environmental problems.
An indirect approach for the preparation of R,â-
unsaturated nitriles involves the condensation of a car-
bonyl compound with acetonitrile using strong ionic bases
Recently, we discovered an efficient method for the
synthesis of esters using 1 (first reported from our
laboratories) as a promoter.16 A chiral fluorescent aux-
iliary,17 alkenes (via dehydrohalogenation),18 pyrroles,19
oxazoles,19 porphyrins,19 C-acyl-R-amino acid esters,19 and
(1) Fraysee, M. J . Perfume Flavor 1980, 4(6), 11.
(2) Liu, R. S. H.; Matsumoto, H.; Asato, A. E.; Denny, M.; Shichidia,
Y.; Yoshizawa, T. Dahlquist, F. W. J . Am. Chem. Soc. 1981, 103, 7195.
(3) Mori, K., Synthetic Chemistry of Insect Pheromone and J uvenile
Hormones. In Recent Developments in the Chemistry of Natural Carbon
Compounds Akademiai Kiado: Budapest, 1979; Vol. 9, p 11.
(4) Fringuelli, F.; Pani, G.; Piermatti, O.; Pizzo, F. Tetrahedron 1994,
50, 11499.
(5) Zupancic, B.; Kokalji, M. Synthesis 1981, 913.
(6) DiBiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, A. R.; Gokel, W.
G. J . Org. Chem. 1979, 44, 4640.
(7) Ladhar, F.; Gharbi, E. Synth. Commun. 1991, 21, 413.
(8) Wawzonek, S.; Smolin, E. Organic Syntheses; Wiley: New York,
1953; Collect. Vol. III, p 715.
(12) Kaiser, E. M.; Hauser, C. R. J . Org. Chem. 1968, 33, 3402.
(13) Palomo, C.; Azipurua, J . S.; Aurrekoetxea, N. Tetrahedron Lett.
1990, 31, 2209.
(14) Minami, I.; Yuhara, M.; Shimizu, I.; Tsuji, J . J . Chem. Soc.,
Chem. Commun. 1986, 118.
(15) Naota, T.; Taki, H.; Mizuno, M.; Murahashi, S. J . Am. Chem.
Soc. 1989, 111, 5954.
(9) Zaboienu, D. Analele Univ. Bucuresti, Ser. Stiint. Nat. 1963, 12,
167; Chem. Abstr. 1966, 65, 3787d.
(10) Arseniyadis, S.; Skyler, K.; Watt, D. S. Org. React., 1984, 31,
40-42, 193.
(11) Tanaka, K.; Ono, N.; Kubo, A.; Kaji, A. Synthesis 1979, 890.
(16) D’Sa, B. A.; Verkade, J . G. J . Org. Chem. 1996, 61, 2963.
(17) Tang, J . S.; Verkade, J . G. J . Org. Chem. 1996, 61, 8750.
(18) Mohan, T.; Arumugam, S.; Wang, T.; J acobson, R. A.; Verkade,
J . G. Heteroatom. Chem. 1996, 7, 455.
(19) Tang, J . S.; Verkade, J . G. J . Org. Chem. 1994, 59, 7793.
S0022-3263(97)02343-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/19/1998