M. Y. Lebede6, M. B. Erman / Tetrahedron Letters 43 (2002) 1397–1399
1399
In the case of MeOH and an excess of chlorosulfonic
acid (entry 10), the reactive intermediate is probably
methyl chlorosulfate MeOSO2Cl (see Ref. 10).
John Wiley & Sons: New York, 1969; Vol. 17; pp.
213–325; (b) Bishop, R. In Comprehensive Organic Syn-
thesis; Trost, B. M.; Fleming, I.; Eds.; Pergamon Press:
New York, 1991; Vol. 6, pp. 261–300.
In a further modification of the method, various alkyl
esters were successfully used as the donors of the alkyl
group in combinations with sulfuric, polyphosphoric,
and methanesulfonic acid (entries 11–16). In the latter
case, the most likely reactive species is methyl mesylate.
2. Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70,
4045–4048.
3. Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949, 71,
4128–4129.
4. (a) Parris, C. L.; Christenson, R. M. J. Org. Chem. 1960,
25, 331–334; (b) Sanguigni, J. A.; Levine, R. J. Med.
Chem. 1964, 7, 573–574.
5. Sasaki, T.; Eguchi, S.; Toru, T.; Ito, K. Bull. Chem. Soc.
Japan. 1970, 43, 1820–1824.
6. Barton, D. H. R.; Magnus, P. D.; Garbarino, J. A.;
Young, R. N. J. Chem. Soc., Perkin Trans. 1 1974,
2101–2107.
7. Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; Wiley–Interscience: New York, 2001;
p. 1244.
8. (a) Olah, G. A.; Gupta, B. G. B.; Narang, S. C. Synthesis
1979, 274–276; (b) Garcia Martinez, A.; Martinez
Alvarez, R.; Teso Vilar, E.; Garcia Fraile, A.; Haneck,
H.; Subramanian, L. R. Tetrahedron Lett. 1989, 37, 581–
582.
Table 1 illustrates numerous available options for the
economical and relatively environmentally benign con-
version of nitrile 1a into N-methylamide 2a. Although
this study has been originally focused at the nitriles
with a quaternary a-carbon, the resulting method is not
limited to only this family of substrates. Thus, menthyl-
nitrile 1d was successfully converted into the corre-
sponding N-ethylamide 2d in entries 17 and 18. An
isomeric neo-menthyl nitrile 1e gave a good yield of the
same amide 2d, apparently due to a rapid epimerization
at the a-carbon (entry 19). Benzonitrile gave N-methyl-
benzamide in a good yield (entry 20). The synthetic
applicability of the method to a-unbranched nitriles
warrants further investigation (see entry 21).
9. Watson, H. R.; Hems, R.; Rowsell, D. G.; Spring, D. J.
J. Soc. Cosmet. Chem. 1978, 29, 185–200.
10. Suter, C. M. The Organic Chemistry of Sulfur; John
Wiley & Sons: New York, 1944, pp. 6, 19.
11. The importance of acids in the process can be further
emphasized by our unsuccessful attempt to obtain amide
2a using dimethyl sulfate alone, in the absence of acid.
Heating nitrile 1a with a triple molar excess of Me2SO4
for 37 h at 100°C gave only about 18% conversion of 1a
and 5% yield of 2a (GLC).
12. Addition sequence is not important in most cases, how-
ever see, Table 1, footnote f for procedures involving
chlorosulfonic acid.
There is not enough data yet for a discussion of the
intimate mechanism of the reaction between the esters
and nitriles in acidic medium at elevated temperatures.
However, based on the generally accepted model for
the Ritter-type processes,1 we can assume that the
protonated ester reacts with the nitrile producing an
imidate intermediate RC(OX)=NR1. The latter is fur-
ther converted into the N-substituted amide during the
hydrolytic work-up. The role of acids in the reaction
may not be limited to the protonation only: they also
serve as solvents, especially when taken in excess with
respect to the other reagents.11
In a typical procedure, alcohol or ester was carefully
added to an acid (CAUTION: exothermic reaction,
especially with alcohols), followed by the addition of
the nitrile.12 The resulting mixture was stirred under
conditions specified in Table 1 and periodically sampled
for GLC analysis. Upon completion, the reaction mix-
ture was cooled, carefully quenched with water, neu-
tralized with dilute aqueous NaOH, and extracted with
ether or heptane.13 After evaporation of the solvent, the
product was purified by distillation or recrystalliza-
tion.14,15
13. Amount of heptane should be sufficient to ensure com-
plete extraction: some of the products have a limited
solubility in heptane.
14. Amides 2a, 2d, N-methylbenzamide and N-methyl-
acetamide were identified by a comparison with the
authentic samples. For 2a, see: Rowsell, D. G.; Spring,
D. J.; Hems, R. Brit. Patent 1,421,744, 1976; Chem.
Abstr. 1976, 84, 150224. For 2d, see: Watson, H. R.;
Rowsell, D. G.; Spring, D. J. Brit. Patent 1 351 762,
1972; Chem. Abstr. 1974, 81, 47583.
15. Amide 2b: mp 88.5–89°C (from heptane); 1H NMR
(CDCl3) l 0.87 d, (6.9 Hz, 6H), 0.89 d (6.9 Hz, 3H),
2.60 septet (6.9 Hz, 2H), 2.79 d (4.7 Hz, 3H), 3.71 s
In summary, we have developed a simple and efficient
procedure for obtaining N-primary-alkyl amides by a
Ritter-type reaction of nitriles with lower primary alka-
nols or their esters in acidic medium.
1
(3H), 7.76 br. s (1H). Amide 2c-Me: H NMR (CDCl3)
l 0.87 d (6.8 Hz, 6H), 0.89 d (6.8 Hz, 6H), 1.27 t (7.3
Hz, 3H), 2.59 septet (6.8 Hz, 2H), 2.77 d (4.9 Hz, 3H),
4.17 q (7.3 Hz, 2H), 7.83 br. s (1H). Amide 2c-Et: 1H
NMR (CDCl3) l 0.88 d (6.8 Hz, 6H), 0.90 d (6.8 Hz,
6H), 1.11 t (7.0 Hz, 3H), 1.27 t (7.0 Hz, 3H), 2.60 septet
(6.8 Hz, 2H), 3.28 m (2H), 4.17 q (7.0 Hz, 2H), 7.83 br.
s (1H).
References
1. For reviews on the Ritter reaction, see: (a) Krimen, L. I.;
Cota, D. J. In Organic Reactions; Dauben, W. G., Ed.;