[CONTRIBUTION FROM
THE
KOYESCHEMICAL LABORATORY, UXIVERSITY OF ILLINOIS ]
SOME DECAMETHYLENE AND UNDECAMETHYLEKE DIAMINES' CHARLES C. PRICE; DAVID B. GUTHRIE, HARRY F. HERBRANDSON, ELIZABETH W. PEEL
AXD
Received February 4, 1946
In view of the antimalarial activity of 1,ll-undecane diamidine (1, 2) and the amoebicidal activity of long-chain aliphatic diamines (3), it was suggested3that a series of the latter type be prepared for assay as antimalarial drugs. The symmetrical decamethylene diamines were prepared by treating the appropriate secondary amine with decamethylene dibromide. Br(CH2)loBr
+ 2R2NH -+
R;N(CH~)IONR~
The products characterized are summarized in Table I. The unsymmetrical decamethylene diamines, summarized in Table 11, were prepared through decamethylene chlorohydrin (4).
1
HBr
~R'NH
HBr Distillation of 10-N-piperidyldecyl chloride was accompanied by partial dehydrohalogenation and some 10-N-piperidyl-l-decene was isolated from the distillate. The amino alcohol was prepared from morpholine as well as piperidine but was not further transformed to the corresponding diamines. The preparation of undecamethylene diamines was based on undecenyl alcohol, available by sodium and alcohol reduction of ethyl undecylenate (5). The acetate of the alcohol was converted to 11-bromoundecyl acetate by addition of hydrogen bromide (6) using benzoyl peroxide catalysis. The bromo ester was isolated and characterized, apparently for the first time.
+
( C € ~ ) ~ N ( C H ~ ) ~ I (() C HH ~ ) ~ ~ ( C H ~ ) I I O C O C H ~
* The work reported in this paper was carried out under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Illinois. 2 Present address: Department of Chemistry, University of Kotre Dame, Notre Dame, Indiana. 8 This suggestion was made by the malaria research group a t the National Institute of Health. 281
282
PRICE, GUTHRIE, HERBRANDSON, AND PEEL
Since treatment of the bromo ester with piperidine led not only to replacement of the bromine but partial aminolysis, it was found convenient to treat the mixed amino alcohol-amino ester with hydrochloric or hydrobromicacid to prepare the chloro- or bromo-amine which was then condensed with the desired secondary TABLE I SYMMETR:[CAL DECAMETHYLENE DIAMINES
-
R2N
0(CHzCHz)zN
B.P. OF AMINE
'c.
ANAL.
SALT
SNa
[.P.OC.
Calc'd
Found
(m.p. 49)b
li HBr
226
N.E. 237
N.E. 240
5001
205-207 (7mm.)
li HBr
275
N.E. 235
N.E. 235
5000
2OC-205 (8 mm.)
6931
193-203 (3 mm.)
8055
205-215 (3 mm.)
6932
173-183 (2 IIUII.)
8054
CzHs
\
N
/
n-CdHg
242-243 (2 m i . )
di P.S.* 188
288-292 (2 mi.)di HBr
149
C, 47.20 H, 4.76 N, 11.56
c, 47.44 H, 5.07 N, 11.18
89Op-Sa
C, 58.36 H, 8.21 N, 4.25
c, 58.50
8882
H, 8.37 N, 4.28
The Survey Number, designated SN, refers to the number assigned a drug by the Survey of Antimalarial Drugs. The activities of these compounds will be tabulated in a forthcoming monograph. b Anderson and Pollard, [ J . Am. Chem. Soc., 61,3440 (1939)l report 51.5'. e Adkins [ J . Am. Chem. Soc., 66, 2419 (1934)l reports 181-183' (2 mm.). P.S. = picrylsulfonate. 0
J
amine. When this secondary amine was low-boiling it was desirable to use the bromo amine since the chloro amine was too unreactive to condense readily a t the boiling point of the secondary amine. The properties of the diamines prepared are summarized in Table 111.
283
DECAMETHYLENE AND UNDECAMETHYLENE DIAMINES TABLE I1 10-N-PIPERIDYLDECYL AMINES
145-148 (2 mm.)
1.4681
160-161
168-170 (2 mm.)
1.4657
173-174
C, 42.17 H, 5.25 N, 12.69
C, 42.52 H , 5.36 N, 12.69
C, 43.51
C, 43.84 H, 5.67
H, 5.53 176-178 (1 mm.)
1.4659
167-170
N, 11.93
C, 44.83 H, 5.59 N, 11.53
C, 44.77
H, 5.80 198-200 (2 mm.)
1.4661
166-167
C, 45.95 H, 6.05 N, 11.59
C, 46.23 H, 6.23 N, 11.32
180-182 (2 mm.)
1.4799
188-190
C, 41.51 H, 4.94 N, 12.50
H, 4.84 N, 12.90
C, 41.45
This product has been reported (4) to boil a t 235-240" (6 mm.) and to form a dihydrochloride melting a t 133". T-4BLE 111 I~-N-PIPERIDYLUNDECYL AMINES RZN
B.P. OF M N E ,
P . P . OF DIPICRYLJILF:NATE,
"c. --
190 (3 mm.)
1.4703
C.
176-178
ANAL.
Calc'd
Found
C, 44.15 H, 5.67
8874
N, 12.12
C, 44.46 H , 5.94 N, 11.95
210 (3.5 mm.) 200 (2.5 mm.)
1.4678 1.4682
168-171
c, 45.37 H, 5.92 N, 11.76
C, 45.46 H, 5.85 N, 11.22
8875
215 (2.5 mm.)
1.4678
165-167
C, 46.52 H, 6.16 N, 11.42
C, 46.47 H, 6.00 N, 11.55
8876
195 (3.5 mm.)
1.4791
186-188
C, 42.19 H, 5.09 N, 12.30
C, 42.66 H, 5.58 N, 12.05
9518
a The Survey Number, designated SN, refers to the number assigned a drug by the Survey of Antimalarial Drugs. The activities of these compounds will be tabulated in a forthcoming monograph.
284
PRICE, GUTHRIE, HERBRANDSON, AND PEEL EXPERIMENTAL4
Symmetrical decamethylene diamines (D. B. G.). Decamethylene glycol was converted t o the dibromide by treatment with hydrobromic-sulfuric acid in 67% yield, b.p. 127-130" (4 mm.); m.p. 27' [lit. (7), b.p. 162' (9 mm.); m.p. 27.4'1. The dibromide was converted t o the diamine by heating at 90-100' with the desired secondary amine for twenty-four hours. The properties of products, obtained in 55-80% yield, are summarized in Table I. Unsymmetrical decamethylene diamines (H. F. H.) . Decamethylene glycol was converted t o the chlorohydrin essentially according to the directions of Bennett and Mosses (4). The product, obtained in 55% yield, boiled at 126128" (2 mm.); m.p. 12-13'; ng 1.4578. A forerun, b.p. 104-110" (2 mm.), map. 10-12", was evidently decamethylene dichloride. A mixture with the chlorohydrin melted from 1"to 7". Treatment of the chlorohydrin with piperidine a t 140-160" for twelve hours yielded the piperidyl alcohol in 91% yield, b.p. 159-164" (3 mm.). It crystallized from 30-60" petroleum The hydrochloride crystallized from chloroformether as flat, white platelets, m.p. fi0-61'.6 ethyl acetate as fine, white needles, m.p. 170-171". IO-N-Morpholino-f -decanol was obtained in a similar fashion in 82% yield, b.p. 163-170" (2 mm.). On recrystallization from 30-60"petroleum ether i t melted at 40-40.5". Its hydrobromide, prepared in hot, dilute hydrobromic acid, recrystallized from chloroform as white needles, m.p. 164-165". Anal. Calc'd for ClrHsoBrNOzC, 51.85; H, 9.32; N, 4.32. Found: C, 52.33; H, 9.60; N, 4.32. IO-N-Piperidyl-f -decy1 chloride hydrochloride was prepared in 82% yield by treatment of the alcohol with thionyl chloride in benzene. After recrystallization from ethyl acetate it melted at 135-136" [lit. (3), 127-128'1. The amino chloride distilled under vacuum only with considerable dehydrohalogenation. From the forerun, b.p. 109-116" (2 mm.), 10-Npiperidyl-f -decene was isolated and identified as its hydrochloride, which crystallized from ethyl acetate as white plates, m.p. 166.5-167'. Anal. Calc'd for CISH&lN: C, 69.33; H, 11.64; N, 5.39. Found: C, 69.96; H, 11.88; N, 5.12. Conversion of the piperidyl alcohol to the diamines was accomplished most conveniently by refluxing in 427, hydrobromic acid to form the bromo amine hydrobromide. This was not isolated but treated in solution with an excess of the desired secondary amine and boiled overnight. The properties of the diamines, obtained in 32-63% yield, are listed in Table 11. Undecamethylene diamines (E. W. P.). Undecenyl acetate was obtained in W 9 2 % yield by the pyridine-catalyzed reaction of the alcohol with acetic anhydride, b.p. 142-152" (18 mm.); n: 1.4390. Addition of hydrogen bromide was accomplished in ice-cold benzene solution using benzoyl peroxide as catalyst. The bromo ester was obtained in 82% yield, b.p. 183-197' (16 mm.); n: 1.4648. The position of the bromine atom on the terminal carbon mas established by hydrolysis to 1,Il-undecamethylene glycol, m.p. 61-61.5' [lit. (6), 61-62°]. Treatment of the bromo ester with piperidine by boiling for ten hours gave a liquid mixture, boiling a t 172-186" (3 mm.), in about 80% yield. On standing, some crystals separated, which were identified as 11-Ii-piperidyl-l-undecanol, m.p. 63-65'. Anal. Calc'd for C M H ~ ~ YC, O :75.23; H, 13.02; N, 5.48. Found: C, 75.48; H, 1320; N, 5.65. Its hydrochloride, crystallized from absolute ethanol, melted a t 156-158". Anal. Calc'd for C 1 & & 1 ~ 0 : C, 65.83; H, 11.74. Found: C, 65.75; H, 11.84. ii-K-Piperid&l -undecyE chloride was prepared from the alcohol by boiling with con4 6
Microanalyses by Miss Theta ,Spoor and Miss Lillian Hruda. 10-X-Piperidyldecanol is repori,ed (3) to melt a t 55-56' and to boil at 210-211" (25 mm.).
DECAMETHYLENE AND UNDECAMETHYLENE DIAMINES
28 5
centrated hydrochloric acid for lifty-four hours. The chloride, obtained in 56% yield, boiled a t 164-168" (2.5 rnm.);n t 1.4739; m.p. -7" to -5". The corresponding bromide, prepared similarly, was not isolated but was used directly in reactions with secondary amines. The properties of the diamines, obtained in about 70-80% yield, are summarized in Table 111. The dipicrylsulfonates were prepared by treating the diamines, in aqueous solution as the hydrochlorides, with an aqueous solution of sodium picrylsulfonate. The salts could be purified by recrystallization from ethanol. SUMMARY
The preparation and properties of a number of decamethylene and undecamethylene di-tertiary amines has been reported. URBANA,ILL.
REFERENCES (1) GLYN-HUGHES, LOURIE, AND YORKE, Ann. Trop. Med., 32, 103 (1938). AND FULTON, Ann. Trop. Med., 32,257 (1938). (2) CHRISTOPHER (3) PYMANAND LEVENE,Brit. Pat. 433,086 (1935); Chem. Abstr., 30, 8241 (1936). See also, Brit. Pat. 456,916;U. S. Pat. 2,056,867. (4) BENNETTAND MOSSES,J . Chem. SOC.,1697 (1931). (5) GRUNAND WIRTH,Ber., 55, 2206 (1922). AND SMITH, J . Chem. Soc., 1308 (1934);SMITH,J . SOC.Chem. Id.,57,461 (1938). (6) AS:KTON (7) CHUIT,Helv. Chim. Acta, 9, 266 (1926).
