Potassium trimethylsilanolate mediated hydrolysis of nitriles to primary amides

Article abstract of DOI:10.1016/S0040-4039(00)00482-2

Treatment of nitriles with potassium trimethylsilanolate under mild anhydrous conditions readily yields the corresponding primary amides after a simple aqueous workup. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00482-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3747–3749
Potassium trimethylsilanolate mediated hydrolysis of nitriles to
primary amides
∗
Kevin J. Merchant
Department of Medicinal Chemistry, Merck Sharpe & Dohme Research Laboratories, Neuroscience Research Centre,
Terlings Park, Harlow, CM20 2QR, UK
Received 18 February 2000; accepted 21 March 2000
Abstract
Treatment of nitriles with potassium trimethylsilanolate under mild anhydrous conditions readily yields the
corresponding primary amides after a simple aqueous workup. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: hydrolysis; nitriles; amides; silicon and compounds.
Alkali trimethylsilanolates have for some time been recognised as hydroxide anion equivalents that
are conveniently soluble in organic solvents. Despite this unique property, there have been few reports
of the use of these compounds since Laganis and Chenard described their role in the preparation of
1
anhydrous carboxylate salts from the corresponding esters and acid chlorides. Apart from this valuable
2
application, trimethylsilanolates have been mainly reported as polymerisation initiators, as a base to
3
promote elimination of methanol from β-methoxyketones and in the deprotonation of propyne iminium
4
salts, and finally as an hydroxyl synthon for fluoride S Ar type displacements from certain activated
N
5
aromatics.
The reaction of benzonitriles with lithium (bis)trimethylsilylamide to form unsubstituted amidines
6
after an aqueous workup gave rise to speculation that the oxygen analogue, lithium trimethylsilanolate,
would achieve the corresponding transformation of benzonitrile to benzamide (Scheme 1). It was found
that on heating lithium, sodium or potassium trimethylsilanolate with a nitrile in either THF or toluene the
intermediate salt precipitates. This has two major advantages; firstly, the reaction is halted at the amide
stage and secondly, as the precipitate is insoluble in most aprotic solvents any impurities can conveniently
be washed away. The intermediate salt is then converted in good yield to the corresponding amide (Table
1).
In a typical procedure the trimethylsilanolate (2 mmol) was dissolved in anhydrous solvent (5 mL)
with the nitrile (1 mmol). The reaction was heated to reflux until the nitrile was consumed and the solid
∗
Corresponding author. Fax: +44 (0)1729 440187; e-mail: kevin_merchant@merck.com (K. J. Merchant)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00482-2
tetl 16760

3
748
Table 1
Transformation of nitriles to carboxamides by alkali metal silanolates
precipitate was filtered, washed with anhydrous solvent and then poured into water and extracted into
EtOAc. After drying over MgSO amides were obtained in fair to good yield.
4
Potassium trimethylsilanolate consistently gave higher yields than either lithium or sodium trimethyl-
silanolate. A possible explanation for these differences may be that the intermediates are more soluble in

3
749
Scheme 1.
the case of lithium and sodium trimethylsilanolates and that further reaction is taking place. Increasing
the temperature of the reaction by replacing THF with toluene increases the rate of the reaction without
compromising the yield and the higher temperature was necessary to accomplish reaction with non-
activated nitriles. This reagent gives good yields with nitriles that have an acidic α-proton such as
phenylacetonitrile or with substrates such as cinnamonitrile where 1,4-addition is possible. Finally, in
the case of fluorobenzonitriles only hydrolysis is observed with no fluoride S Ar displacement.
N
In conclusion, a convenient, mild, non-aqueous method of converting nitriles to their corresponding
primary amides has been developed. Good yields combined with a simple workup procedure make it an
attractive alternative to existing methods.
References
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