Chemoselective methylation of amides and heterocycles using chloromethyldimethylsilyl chloride

Article abstract of DOI:10.1016/S0040-4039(00)00731-0

The reaction of chloromethyldimethylsilyl chloride with an amide generates a pentacoordinate N-(amidomethyl)-halosilane that can be desilylated with cesium fluoride to give the N-methyl amide. This provides a selective method for the monoalkylation of amides in the presence of other, more nucleophilic groups. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00731-0

Tetrahedron Letters 41 (2000) 4933±4936
Chemoselective methylation of amides and heterocycles using
chloromethyldimethylsilyl chloride
Alan R. Bassindale, David J. Parker, Pravin Patel and Peter G. Taylor*
The Open University, Milton Keynes, MK6 7AA, UK
Received 28 February 2000; accepted 4 May 2000
Abstract
The reaction of chloromethyldimethylsilyl chloride with an amide generates a pentacoordinate N-(ami-
domethyl)-halosilane that can be desilylated with cesium ¯uoride to give the N-methyl amide. This pro-
vides a selective method for the monoalkylation of amides in the presence of other, more nucleophilic
groups. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkylation; amides; hypervalent elements; silicon halides.
N-Methylamides can be prepared by the reaction of methyl iodide with the free amide or its
metal salt.1 An alternative alkylating agent is iodomethyltrimethylsilane where the silicon acti-
vates the adjacent iodomethyl group to substitution.2 Treatment of the product with ¯uoride ion
leads to the N-methyl derivative. However, the resulting carbanionic species can be trapped by
other reagents such as aldehydes and ketones.3,4 Reaction of chloromethyldimethylsilyl chloride
with amides has been shown to give the corresponding pentacoordinate N-(amidomethyl)-halo-
silane, 1, as shown in Scheme 1.5 7
Scheme 1.
* Corresponding author. E-mail: p.g.taylor@open.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00731-0

4934
This reaction occurs quite readily irrespective of whether the amide is acyclic, cyclic or part of a
heteroaromatic system. For example, we have shown that pentacoordinate silicon species can be
prepared from a range of substituted pyridones.8 The proposed mechanism of this reaction
involves initial N±Si bond formation followed by O-alkylation and then rearrangement to give
the N-alkyl species.9 Thus, the adjacent carbonyl oxygen is actively involved in ensuring the alkyl
group ends up on the amide nitrogen. For example, reaction of chloromethyldimethylsilyl
chloride with 4-pyrimidinone gave only the 3-(chlorodimethylsilylmethyl)-4-pyrimidone in 86%
yield. In this case, unlike with chloromethyltrimethylsilane, none of the O-alkylated species was
observed.4
We have found that treatment of these pentacoordinate silicon species with cesium ¯uoride
leads to the corresponding N-methyl amides in high yields. From this we have developed a simple
protocol for the conversion of amides into N-methylamides in the absence of base, as shown in
Scheme 2.
Scheme 2.
In a typical reaction, the amide is re¯uxed with chloromethyldimethylsilyl chloride in the
presence of hexamethyldisilazane, in dry acetonitrile followed by treatment with cesium ¯uoride
in 2-methoxyethyl ether.10 Table 1 gives the results for a range of di€erent amides. Simple amides
such as propanamide, butanamide, 2-pyridone and 2-quinolinone are readily N-alkylated and
desilylated to give the N-methylamide in high yield without the formation of any O-alkylated
species. Methylation of acetanilide con®rms that the reaction can be used to prepare tertiary
amides. Reaction with 4-pyrimidinone and 2-quinoxalinone demonstrates the high selectivity of
this reaction. In the presence of other nucleophilic sites, alkylation only occurs at the nitrogen
adjacent to the carbonyl. This selectivity is also observed in non-heterocyclic systems such as
4-aminobenzamide. We found that reaction of 4-aminobenzamide with methyl iodide gives a
range of products. Indeed the only published synthesis of N-methyl-4-aminobenzamide started
with the 4-nitrobenzamide followed by methylation and reduction of the nitro group to an
amine.11
Thus, this route provides a selective method of alkylating amides in the presence of other, more
nucleophilic groups in the absence of base without any O-alkylation. Since an intermediate
coordination compound is produced and the alkylating agent destroyed before the N-methyl
amide is revealed, there is no possibility of dialkylation of primary amides, as observed on
alkylation of the free amide or metal salt. We are at present examining the desilylation step in the
presence of carbon electrophiles to provide a route for carbon±carbon bond formation and the
applicability of this reaction to other carboxylic acid derivatives.

4935
Table 1
Yields of N-methylamides obtained from reaction of an amide with chloromethyl-
dimethylsilyl chloride followed by ¯uorodesilylation

4936
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10. N,N-Hexamethyldisilazane (2 g, 2.6 ml 12.5 mmol) was added to a solution of p-aminobenzamide (3.4 g, 25 mmol)
in dry acetonitrile (150 ml). The mixture was re¯uxed for three hours and then chloro(chloromethyl)dimethyl
silane (3.5 g, 3.5 ml 25 mmol) was added dropwise. The mixture was re¯uxed overnight, cooled and the acetonitrile
removed on a rotatory-evaporator. Dry 2-methoxyethyl ether (150 ml) and cesium ¯uoride (3.8 g, 34 mmol) was
added to the residue and the mixture re¯uxed for 48 h. After cooling, water (10 ml) was added and the solvent
removed using a rotatory evaporator. The residue was extracted with ethyl acetate (2Â100 ml), dried and the
organic solvent evaporated to give the product (5.0 g). The crude product was column chromatographed using
hexane and ethyl acetate as the eluting solvent, which gave 3.2 g (85%) of the pure product (mp 180±182ꢀC); H
1
NMR (300 MHz, CDCl3) ꢀ=2.72 (s, 3H, CH3), 4.63 (s, 3H, NH), 6.47 (d, J 13.2, 2H, Ar), 7.46 (d, J 13.2, 2H, Ar);
13C NMR (300 MHz, CDCl3) ꢀ=25.381 (NCH3), 112.367 (Ar), 121.858 (Ar), 127.698 (Ar), 149.560 (Ar), 166.807
(CˆO); m/z (EI) 150 (M+), 120 (M+^CH3NH), 106, 91; IR (Nujol) ꢁ=1640, 1607, 1561, 1540 cm^1. Anal. calcd for
C8H10N2O: C 63.98, H 6.71, N 18.64. Found: C 63.84, H 6.72, N 18.43.
11. Wenker, H. J. Am. Chem. Soc. 1938, 60, 1081.