Weygand/Hilgetag Preparative Organic Chemistry

Replacement of oxygen by nitrogen 491
in place of the free amines. In the aromatic series these derivatives are readily
accessible from the amine and the metal in an inert solvent and can be used
without isolation. 776
Diethylmalonanilide is obtained, in accord with this method, in good yield by boiling diethyl
diethylmalonate for 0.5 h with sodium anilide (2 moles) in toluene. 776 Analogously,
A^N-diethylglycine ethyl ester and the sodio derivative of aniline, TV-ethylaniline, or 2,6-dimethylaniline
in boiling toluene give the corresponding anilides in 65-90% yield. 776
The halomagnesium derivatives, NR2—MgHal, may replace the alkali
derivatives (the Boudroux reaction): 777
R"\ XMgO\ 7R" +H2O
RCOOR' + >N—MgX > R^C—N( Mgxrom* RCO-NR"R'"
Tw/// R'O' R'" OH,-MgX(OH)
Weygand 778 has prepared a number of iV-methylcarboxanilides in this
way; Kuhn and Morris 779 converted ethyl /?-ionylideneacetate into the corresponding
o-toluidide in 80% yield. The general directions below for the
Boudroux reaction have been applied to, inter alia, iV,JV-diphenylacetamide
(85%), JV^-diphenylbenzamide (88%), iV-hexanoylaniline (87%), and dodecananilide
(80%). 777
A solution of the amine (0.1 mole) in ether (30 ml) is added slowly to methylmagnesium
iodide (0.1 mole) in dry ether (50 ml). When the violent reaction is ended, the ester (0.05 mole)
in ether (about 20 ml) is added and the whole is warmed for 2 h on the water-bath. The product
is then decomposed cautiously with water (50 ml), the basic magnesium compounds are
dissolved in 2N-hydrochloric acid, and the ethereal layer is separated, dried, and freed from
ether and unchanged amine by distillation. The residual anilide is purified by recrystallization.
777
Birkhofer and Frankus 780 similarly converted /?-amino esters into the TV-(aminoacyl)
derivatives of iV-methylaniline, carbazole, and indole.
The rate of reaction of carboxylic esters with amines can often be increased
by using as acylating agents esters that exchange their alcohol residues with
particular ease. With this in mind Schwyzer 781 recommends the use of cyanomethyl
esters, RCOOCH2CN. The cyanomethyl esters of N-protected amino
acids react readily even at room temperature with amino esters and are thus
particularly suitable for peptide synthesis. Also, phenyl trifluoroacetate has
been recommended for trifluoroacetylation of amino acids and peptides. 782
The possibilities offered by such activated esters for peptide synthesis are
reviewed in the monograph by Schroder and Liibke. 783
Isopropenyl acetate, obtained from ketene and acetone, reacts as an activated
ester of acetic acid and, like its generator ketene, acetylates amides highly
exothermally at room temperature. 784 Even 1-acetylimidazole, which is difficult
to prepare in other ways, is thus obtained from imidazole in 94% yield. 785
776 E. S. Stern, Chem. & Ind. (London), 1956, 277.
777 H. L. Bassett and C. R. Thomas, /. Chem. Soc, 1954, 1188.
778 F. Weygand and co-workers, Angew. Chem., 65, 530 (1953).
779 R. Kuhn and C. J. O. R. Morris, Ber. Deut. Chem. Ges., 70, 853 (1937).
780 L. Birkhofer and E. Frankus, Chem. Ber., 94, 216 (1961).
781 R. Schwyzer and co-workers, Helv. Chim. Acta, 38, 69, 80, 83 (1955).
782 F. Weygand and A. Ropsch, Chem. Ber., 92, 2095 (1959).
783 E. Schroder and K. Liibke, "The Peptides," Academic Press, New York-London,
Vol.1, 1965; Vol.2, 1966.
784 H. J. Hagemeyer Jr., and D. C. Hull, Ind. Eng. Chem., 41, 2920 (1949).
785 J. H. Boyer, /. Amer. Chem. Soc, 74, 6274 (1952).