APRIL
1961
REACTIONS OF a-&ACETYLENIC-f-Ak€INJZS
[CONTBIBUTION FROM
THE CHEMICAL LABOIUTORIES OF THE
1073
UNIVERSITYOF NOTREDAME]
Some Reactions of a-t-Acetylenic-t-amines' G. F. HENNION
R&
AND
ALBERT C. PERRINO'
August 9,1960
The reactions of two atacetylenicdsmines, (CH&C(N&)-C=CH, were studied in detail. These compounds, 3dimethylamino-3-methyl-1-butyneand 3-pyrrolidino-%methyl-l-butyne, were found to undergo the typical reactions of the triple bond and of the ethynyl hydrogen. From the two model compounds, twenty-six new substances of the following classes were prepared: scetylenic-1,4-amino alcohols, C-alkylated acetylenic amines, acetylenic-l,4diamines, 2,74aminc3,5dia1xtylenes, 2-amino-7-hydroxy-3,5diacetylenea,l,%amino ketones, l,%amho alcohols, acetylenic amino acids, allylic amines, and saturated arninea. These compoundswere characterized by the formation of methiodide and hydrochloride salts.
A previous papers described the synthesis of acetylenic secondary and tertiary amines through the interaction of acetylenic chlorides of the type RR'C(Cl)-CdH with primary and secondary amines. Recently14 this method was studied in detail and shown to constitute a valuable new synthetic technique. Furthermore, it has been found5 earlier that the acetylenic primary amines underwent alkylation, acylation, hydrogenation, and addition to carbonyl compounds in the expected manner. Since the properties of the tertiary amines had not been studied systematically and since these compounds constitute a new class of sterically hindered amines, an investigation of the reactions of a-t-acetylenic-t-amines for possible exploitation of the products as pharmaceutical agents' was considered to be of interest. The transformations discussed below are shown in Fig. 1. Each of the acetylenic-t-amines, 3dimethylamino-3-methyl-1-butyne (11), and 3-pyrrolidino3-methyl-1-butyne (111), gave with ammoniacal silver nitrate solution, curdy white precipitates typical of compounds possessing a terminal ethynyl group. Treatment of I1 and I11 with ethylmagnesium bromide gave the Grignard but with somewhat surprising results. The rate of formation of the organometallic was much slower than anticipated and several hours of reflux were generally needed for complete reaction (stoichiometric evolution of ethane). It had been reported716that the addition of amines increased the rate of reaction between alkylacetylenes and ethylmagnesium bromide. The (1) Paper no. 74 on substituted acetylenes; previous paper, G. F. Hennion and A. P. Boisselle, J. Org. C h . , 26, 725 (1961). (2) Eli Lilly Company Fellow, 1957-1959. Abstracted from the Ph.D. Dissertation of A. C. P., 1960. (3) G. F. Hennion and K. W. Nelson, J. Am. Chem. Soc., 79,2142 (1957). (4) G. F. Hennion and R. S. Hanael, J. Am. Chem.Soc., 82,4908 (1960). (5) G. F. Hennion and E. G. Teach, J. Am. Chem. Soc., 75,4297 (1953). (0) Pharmacological teating ia in progress in the Lilly Research Laboratories, Indianapolis, Indiana.
decreased basicitys of the amine function coupled with a decrease in the acidity of the ethynyl hydrogen may explain the pronounced decrease in rate exhibited by I1 and 111. Additions of carbonyl compounds (aldehyde or ketone) to an ethereal suspension of the Grignards of I1 and 111, followed by hydrolysis, resulted, in several cases, in the formation of acetylenic-l,4amino alcohols (IV, V, VI, VII). The Grignard reagents were sensitive to enolizable ketones and when cyclohexanone, desoxybenzoin, acetophenone or propiophenone was employed, no amino alcohol was isolated. When the lithium salt of I11 was condensed with acetophenone in liquid ammonia,lo however, VI11 could be obtained in low yield. Esterification of IV with acetic anhydride or propionic anhydride and pyridine failed. This is in agreement with Huggil and Rose." The reaction between the sodium salts of I1 and 111, in liquid ammonia, and ethyl and butyl bromides gave the C-alkylated derivatives,12 IX, X, XI and XI. By employing the Mannich reactionla with formaldehyde and diethylamine or pyrrolidine on I1 and 111, the acetylenic 1,4-diamines XIII, XIV, XV and XVI were prepared in good to excellent yields. Oxidative coupling of I1 and I11 to 2,7-bis(dimethylamino) - 2,7 - dimethyl - 3,5 - octadiyne (XVII) and 2,7-bis (pyrr olidino)-2,7dimet h yl-3,5octadiyne (XVIII), respectively, was accomplished by two techniques. In one method the reaction mixture was heated a t 50-55' a t atmospheric pres(7) J. H. Wotiz, C. A. Holliingsworth, and R. Dessy, J . Am. Chem. Soc., 77, 103 (1955). (8) J. H. Wotir, C. A. Hollingsworth, and A. W. Simon, J . Oig. chem., 24, 1202 (1959). (9) K. N. Campbell, F. C. Fatora, and B. K. Campbell, J. Org. Chem.,17,1141 (1952). (10) G. F. Hennion and J. M. Campbell, J . Org. Chem., 21,761 (1950). (11) H. P. W. Huggil and J. D. Rose, J. Chem. Soc., 335 (1950). (12) R. F. Parcell and C. B. Pollard, J. Am. Chem. SOO, 72,2385 (1950). (13) J. D. Rose and B. C. L. Weedon, J. Chem. Sa.,783 (1949).
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EENNION AND PEBRINO
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