3090
J . Org. Chem. 1999, 64, 3090-3094
P (RNCH2CH2)3N-Ca ta lyzed Syn th esis of â-Hyd r oxy Nitr iles
Philip Kisanga, Dale McLeod, Bosco D’Sa, and J ohn Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111
Received September 14, 1998
We herein report the successful synthesis of â-hydroxy nitriles in very good to excellent yields
from aldehydes and ketones in a simple reaction that is promoted by strong nonionic bases of the
title type. The reaction occurs in the presence of magnesium salts which activate the carbonyl
group and stabilizes the enolate thus produced.
In tr od u ction
to 93%. A simple room-temperature procedure was
developed by Maasalu et al.10 which involves reacting
acetonitrile with carbonyl compounds in the presence of
powdered KOH. However, the yields were only moderate,
ranging from 43 to 68%. Although several other methods
exist for the preparation of â-hydroxy nitriles, they
involve a multistep synthesis,11,12 they make use of highly
toxic compounds,13-15 they proceed with poor to moderate
overall yields,16 or they require low17 temperatures.
The proazaphosphatranes 1a /1a ′,18 1b,19 and 1c20 have
recently been shown to be strong nonionic bases capable
of deprotonating acetonitrile,21 benzyl nitrile,21 nitro-
alkanes,22 and other activated methylenes,23 thereby
providing access to anions that we have successfully
employed in useful transformations. In our continued
search for reactions in which these bases provide im-
proved synthetic methodology over conventional ap-
proaches, we have found that compounds of type 1 are
efficient catalysts for the preparation of â-hydroxy
nitriles.
â-Hydroxy nitriles are useful intermediates in organic
synthesis as, for example, in the synthesis of 1,3-amino
alcohols.1 As a result, several methods have been devel-
oped for their synthesis. The most common methods for
preparing â-hydroxy nitriles involve the reaction of a 1,2
epoxide2 with a nitrile in the presence of metal salts such
as LiClO4/KCN,3 using lanthanide(III) alkoxides as cata-
lysts,4 or with acetone cyanohydrin under mildly basic
conditions.5 However, these approaches succeed only with
simple aliphatic epoxides and the yields range from poor
(35%) to very good (95%) with the exception of the LiClO4/
KCN reagent that leads to yields ranging from 80 to 98%.
Another recent method for the synthesis of â-hydroxy
nitriles includes the use of a manganese-lead system to
promote the coupling of an alkyl iodide, an acrylonitrile,
and a ketone.6 The toxicity of lead and DMF (used as the
solvent) makes this method environmentally unsafe. A
mercury-assisted reaction has also been reported. In this
process an electron deficient alkene is treated with
mercury fulminate and lithium bromide and the reaction
mixture is heated at 50 °C to afford the â-hydroxy nitriles
in low to moderate yields.7 However, the toxicity of
mercury, the explosive nature of mercury fulminate, and
the lengthy reaction times required render this method
unattractive. Bahradi et al.8 utilize aryl halides as the
precursors of electrogenerated bases which are then used
to deprotonate acetonitrile. The anion thus produced can
add to acetone or aldehydes in DMF to produce the title
compounds in 52-74% yield. â-Hydroxy nitriles can also
be synthesized by ionization of an hydrogen of acetonitrile
by n-butyllithium (sold as a flammable hydrocarbon
solution) or alkali amides followed by condensation with
ketones and aldehydes.9 When n-butyllithium is em-
ployed, a temperature of -80 °C is required to give the
best yields (47-89%), and if alkali amides are employed,
a temperature of -33 °C is required to provide yields up
Resu lts a n d Discu ssion s
We reported previously that ketones do not react with
acetonitrile in the presence of bases of type 1.21 In hopes
(10) Maasalu, A.; Valimae, T.; Loiveke, I.; Teng, S.; Laats, K. Easti
NSF Tead. Akad. Toim. Keem. 1988, 37, 248; Chem. Abstr. 1989, 111,
38854e.
(11) Wade, P.; Bereznak, J . J . Org. Chem. 1987, 52, 2973.
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1994, 67, 1126.
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Chem. Soc., Perkin Trans. 1 1995, 3, 189.
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N. S. Zh. Org. Khim. 1979, 15, 1101; Chem. Abstr. 1979, 91, 91318c.
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10.1021/jo981858y CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/09/1999