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A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 505–506
nucleophilicity of the amine via the aminomagnesium
bromide derivative and its utility in the conversion of
acylimidazolides to amides was reported earlier.3 Here-
in, we further demonstrate the application of this meth-
odology to a convenient synthesis of arylamides from
the corresponding arylnitriles. The enhanced reactivity
of these magnesium reagents could be attributed to a
Ôpush–pullÕ mechanism, originating from the nucleophi-
licity of the magnesium amide coupled with the Lewis
acid activation of the MgBr2 produced from potential
disproportionation of the aminomagnesium bromide
moiety.4 The aminomagnesium bromides, which are
conveniently generated from equimolar amounts of
alkylamine and ethylmagnesium bromide in THF with
evolution of ethane, efficiently add to nitriles and afford
the desired amides in good to excellent yields after aque-
ous work-up. Interestingly, the corresponding lithium
amides were ineffective and the presence of a large excess
of amine stops the reaction. This methodology was
successfully utilized to prepare the insect repellant
N,N-diethyl-m-toluamide (DEETTM) in 90% yield.5
Representative examples are summarized in Table 1.7
A typical experimental procedure is as follows: n-butyl-
aminomagnesium bromide was prepared by dropwise
addition of n-butylamine (3.12 g, 42.7 mmol) in 5 mL
THF to a stirred solution of ethylmagnesium bromide
(5.17 g, 38.8 mmol, 12.8 mL of 3 M solution in ether)
under nitrogen. The mixture was stirred for 1 h at
30 ꢁC. The resulting magnesium amide solution was
added to a stirred solution of benzonitrile (1 g,
9.7 mmol) dissolved in THF (2 mL) and the mixture
was stirred for 1 h at 30 ꢁC. The reaction was quenched
by adding to a stirred mixture of dichloromethane
(20 mL) and aqueous HCl (10 mL of 2 M solution) at
22 ꢁC. The organic layer containing the product was
washed with brine (2 · 10 mL), dried over sodium sul-
fate, and evaporation of the solvent in vacuo produced
1.53 g of n-butylbenzamide (89% yield).
In summary, we have developed a simple, conceptually
distinct amidation of arylnitriles which complements
the existing technologies in terms of practicality, and
demonstrates yet another facet of the utility of amino-
magnesium derivatives in organic synthesis.8
Acknowledgements
Financial support provided by the Petroleum Research
Fund (PRF), National Institute of Health (NIH), Welch
Foundation, and Bristol Myers Squibb Corporation is
gratefully acknowledged.
References and notes
1. Chem. Eng. News; Education Concentrate, 2001, July 23, 41.
2. For nitriles to amidines by aluminum amide addition, see:
Gargipati, R. S. Tetrahedron Lett. 1990, 31, 1969.
3. Bhattacharya, A.; Williams, J. M.; Amato, J. S.; Dolling,
U.-H.; Grabowski, E. J. J. Synth. Commun. 1990, 2683.
4. The stoichiometry is based on assumed metathesis without
considering complexation, aggregation, etc.
5. DEET, In Merck Index; 12th ed. Budavari, S., Ed.; Merck,
1996; Vol. 2912, p 483.
6. All products exhibited satisfactory spectral properties
(Bruker 600 MHz 1H NMR and 13C NMR) fully in accord
with known or expected values and GC–MS analysis
(Shimadzu QP5050A) in the EI mode provided similarity
index match of >90% compared to the authentic samples in
the NIST-98 database.
7. The product amides were pure as evidenced by NMR and
no un-substituted benzamide was detected in the reaction as
evidenced by both NMR and HPLC.
8. (a) Carre, M. C.; Houmounou, J. P.; Caubre, P. Tetra-
hedron Lett. 1985, 26, 3107; (b) Birkofer, L. Liebigs Ann.
Chem. 1975, 2195; (c) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J.
Am. Chem. Soc. 1989, 111, 8016.