A. WAYNERUDDY
4006 [CONTRIBUTION FROM
THE
~701.
m
STERLING-WINTHROP RESEARCH INSTITUTE]
Antispasmodics. 11. Substituted a-(6-Aminoethy1)-phenylacetonitriles and 3-Phenylpropylamines B Y A. WAYNE RUDDY' In a n attempt t o fmd antispasmodics with greater musculotropic properties a number of substituted 3-phenylpropylamines have been prepared. These amines were obtained from the corresponding substituted aminoalkylphenylacetonitriles by treatment with sodium amide. Hydrochlorides and methiodides were prepared of the basic nitriles and the resulting 3phenylpropylamines. The preliminary tests in vitro indicated that the most active compound against barium chloride induced spasms was N- (3-isobutyl-3-phenylpropyl)-piperidine.
R'
In a previous paper2 from these laboratories there was reported a number of substituted 3-phenylpropylamines which were found later to have principally a musculotropic type of activity. In an attempt to increase their musculotropic properties further study has been made in this series. Into the 3-position of the phenylpropylamines was introduced phenyl, cyclohexyl, cyclopentyl, nhexyl, isobutyl, o-methdyl and isobutenyl groups. The various basic substituents were pyrrolidine, 2methylpyrrolidine, dimethylamine, diethylamine and piperidine.
CBH~CRCN-CH~-CH~N/
\R'
f 2NaNH2
+
iently by stirring with sodium amide in refluxing benzene, but the aminoethylalkylphenylacetonitriles and cyclohexylphenylacetonitriles required the temperature of refluxing xylene for complete cleavage. The yields of amines from this reaction were very good with the exception of the P-rnethal-
TARLE I R I SUBSTITUTED ~-(~-AMINOETHYL)-PHENYLACETONITRILES C6H5-C-CH2-CH2-An~
I
CN Yield,
Base B.p., OC. Mm.
M.p. OC.
Phenyl
Am N CIH sf'
Phenyl Cyclohexyl
N C I H ~ C H ~ ~78 X(CH,ih 72
150-158
1
1.5248
Cyclohexyl
X:(C?H5:?
82
171-182
2
1.5188
Cyclohexyl Cyclohexyl Cyclopent~yl n-Hexyl Isobutyl
NCIHP NCsHioh N(C1lr)z N(CnHs)? N(CH3j2
PO 82
e
70 68
134-140 138-142 11?--110
1 0 2f 0.4
1 5208 1.4937 1..>012
Isohut>-l
NiC2115>2
81
114-118
0.05
1.4902
Isobutyl
NC~II~O"
7'2
136-142
0 0.;
1.3140
8-Methallyl Isoliutenyl
NC6Hia XC;H.o
72
141-160 13G-139
1 0 1
1 5258
R
"0
82
-
1n 0
..-
i.)
(cob
nz6D
207-208.3 170.8-171.6
11
Hydrochlorides and methiodides Nitrogen, % ' Chlorine, % Iodine, '% Formula Calcd. Found Calcd. Found Calcd. Found CwHzzNz.HC1 1 0 . 8 5 10.80 CziHz61Nzd 6.47 6 . 2 1 29.36 29.20
f
e
1 5272
228.8-229.8 200-202 156.8-158 168,s-169.6 194.6-105.8 230-233 184-18(5 103-105 242-242.8 150.B-l:i2.8 132.9-1R.t 165.5-156 9 193.4-183 .i 171.4-173 212.8-214.4 203-204.5 199.7-201
CiaHneNz.HC1 9 . 1 3 CioHaINz 6.79 CaHsoNz.HC1 8 . 3 7 CiiHasINr 0.36 CeoHsN2.HCI X.43 C~IHIONZ.HCI8 . 0 8 Ci11lrN2.HCl CeHa2N?.IlCI 8 . 3 1 CieHzrNz.HCI 7.25 CuNnIN~ C ~ ~ H Z ~ N Z . €9.07 ICI 8.76 CioHaiINz CigHzaNz.HC1 8 73 CzoHaiINz m ClsHzeNz.HC1 8 . 7 9 CioHzsNn.HC1 8 . 7 9 CzoHaINn 6.60
'
9.01 6.82 8.36
11..55 1 1 . 5 8
10.69
6.22
5.31 8.12 8 30
7.14 9.09 G.72 8.65
30.65
28.82
28.51
32.85
33.15
30.03
30.60
29.77
29.62
38.91
29.85
10.65 10.G1 10.22 9.96 12.11 13.08 10.62 10.70 12.G3 12.53
11.48
11.4?
"
8.64 8 . 6 0 11.12
6.48
30.78 10 60
11.12
NCIHs = 1-pyrrolidyl. * Base m.p. 73-74'. Ref. 4 reported m.p. 71.5-72.5'. Anal. Calcd.: C, 73.49; H, 7.09. Found: C, 73.76; H, 7.22. Methiodides were recrystallized from ethyl acetate containing a small amount of methanol. e Where no boiling point is given the basic nitrile was used without distillation. f Hydrochloride would not crystallize. NCdHvCHs = 2-methyl-1-pyrrolidyl. NCbHlo = 1-piperidyl. p' Anal. Calcd.: C, 69.72; H, 8.61, Found: C,69.55; H, 8.68. i Ref. 6 reported b.p. 180-185' (4 mm.). Anal. Calcd.: C, 68.43; N, 8.97. Found: C, 68.56; H, 9.07. I Anal. Calcd.: C, 71.11; H,9.11. Found: C, 71.16; H, 9.00. ln Anal. Calcd.: C, 56.33; H, 7.33. Found: C, 56.55; H, 7.33. 1 Annl. Calcd.: C, 71.56; H, 8.54. Found: C, 71 65; H,8 j l . a
I t was found most convenient to prepare these 3phenylpropylamines by alkylating the appropriate phenylacetonitrile with an aminoethyl chloride with the aid of sodium amide. The basic nitriles were then treated with excess sodium amide in order to replace the cyano group by hydrogen. The aminoethyldiphenylacetonitriles were cleaved conven(1) Chilcott Laboratories, Division of The Maltine Company, Morris Plains, N. J. (2) A. IT. Ruddy and J. S. Buckley, Jr., THISJOURNAL, 72, 718 (1950). ( 3 ) Report 0. 1'. B. 981, Office of the Publication Hoard, Dept. of Commerce, pp. 41- $2.
lyl and isobutenylphenylacetonitriles which gave 48 and 58%, respectively. Four of the basic nitriles needed as intermediates, 4-dimethylamino-2,2-diphenylbutanenitrile, 2,Z-diphenyl-4-N-piperidylb~tanenitrile,~ 2,2-diphenyl-4N-pyrr~lidylbutanenitrile~ and 4-diethylamino-Z-nhexyl-2-phenylbutanenitrile6have been prepared previously* (4) D. J. Dupr6, J. Elks, B. A. Hems, K, N. Speyer and R. 11. Evans, J. Chcm. Sac., 500 (1949). ( 5 ) M. nockmiihl and G . Ehrhart (to U'inthrop Chemical Co., Inc ) U. S. Patent 2,230,774, Feb. 4, 1941. (li) 0. Eisleb, B o . , 7 0 , 1443 (1911).
Scpt., 1951
a-(~-AMINOETIIYL)-PHRNYLACETONITRILES .\ND ~-PIIENYI,PROPYI,AMINRS 4097
After this work was begun an example of the 3alkyl - 3 - phenylpropylamines was described by Bergel, et 4' who prepared a-phenylpentyldimethylamine from the corresponding nitrile by treatment with sodium and alcohol. In addition to the diphenyl- and cyclohex ylp henylpropylamines previously described2there was recently reported8 a number of diphenylpropylamines prepared by hydrogenation of the corresponding diphenylallylamines. Since it is possible that the double bond might migrate in the conversion of 2-isobutenyl-2-phenyl4-N-piperidylbutanenitrile into N - (5 - methyl - 3phenyl - 4 - hexenyl) -piperidine the structure of the compound was proven in the following way. The ultraviolet absorption spectrum of the product was examined and no absorption indicative of a conjugated system was found.g Mild oxidation with potassium permanganate gave a volatile fragment which was identified as acetone by isolation as the insoluble dibenzal derivative. The corresponding 3-hexenylamine would be conjugated with the benzene ring and would produce isobu tyraldehyde with a mild oxidizing agent. All of the amine hydrochlorides and methiodides reported in Tables I and I1 were given a preliminary screening by Dr. -4. M. Lands and his staff of our Pharmacology Department. The compounds were tested for their spasmolytic activity in vitro against spasms induced in isolated rabbit ileum by acetylcholine and (7) F. Bergel, .I. W. Haworth, A. L. Morrison and H. Rinderknecht, J. Chem. SOL, 261 (1944). (8) D. W. Adamson, i b i d . . S 145 (1949). (9) The author is grateful to Dr. F. C. Nachod and his staff for this
information.
V. N. IPATIEFF, c.J. CZAJKOWSKI '4ND HERMAN PINES
3098
1701.
73
acetonitrile in benzene with the aid of sodium amide and distilling the product through a 30-cm. column packed with glass helices. 0-Methallylphenylacetonitrile was obtained h 3 4 % yield, b.p. 124-128' (smm.), #D 1.6183. Anal. Calcd. for C12H13N: C, 84.17; H, 7.65; iT,8.18. Found: C, 84.29; H , 7.67; S ,8.07. The reaction also produced a 29% yield of dimethallylphenylacetonitrile, b.p. 146-148' (5 mm.), n 2 5 ~1.5228. Anal. Calcd. for CleHleN: C, 85.28; H, 8.49; h',6.22. Found: C, 85.32; H, 8-48; N,6.29. Substituted a-(P-Aminoethy1)-phenylacetonitriles .-Diphenylacetonitrile was alkylated with the appropriate aminoethyl chloride by a published procedure.3 Chloroethylamine Hydrochlorides.-Dimethylaminoethyl The alkyl- and cycloalkylphenylacetonitriles were prechloride and diethylaminoethyl chloride hydrochlorides are pared in the following manner. A mixture of 0.15 mole of commercially available. 2-( N-Pyrrolidy1)-ethyl chloride, lo aminoethyl chloride hydrochloride, 0.15 mole of alkylphenand 2-(N-piperidyl)-ethyl chloride" hydrochlorides were ylacetonitrile and 0.3 mole of sodium amide in 200 ml. of dry prepared by published procedures. 2-( N-2-Methylpyrroliwas stirred and gradually heated to about 60". dyl)-ethyl chloride hydrochloride was prepared by treating benzene exothermic reaction was then controlled by occasional 2-(N-2-methylpyrrolidy1)-ethano112 with thionyl chloride The cooling with an ice-bath. When the ammonia evolution in chloroform and recrystallized from isopropyl alcohol- had diminished the reaction was heated a t 65' for about two ethvl acetate. hours. To the cooled mixture water was added and the Anal. Calcd. for C7H14ClN.HCl: S , 7.61; C1, 38.52. benzene layer separated and washed with water. The prodFound: X, 7.84; C1,38.40. uct was then extracted with diluted hydrochloric acid, converted back to the base, extracted with ether and dried over The base distilled at 60-62' (8 mm.), #D 1.4622. Nitriles .-Diphenylacetonitrile is commercially available. sodium hydroxide pellets. After removing the solvent the Cyclohexylphenylacetonitrile,13 cyclopentylphenylacetoni- product was distilled under reduced pressure. The yields of trile,14 n-hexylphenylacetonitrile,6 isobutylphenylacetoni- basic nitriles were generally good ranging from 68 to 90%. trileu and isobutylidenephenylacetonitrilelewere prepared They are described in Table I. by published procedures. 6-Methallylphenylacetonitrile 3-Phenylpropylamines.-To a well stirred mixture of was prepared by treating P-methallyl chloride with phenyl- about 0.4 mole of sodium amide in 100 ml. of refluxing xylene was added, dropwise, a solution of 0.1 mole of a basic (10) J. B. Wright, H. G. Kolloff and J. H. Hunter, THIS J O U R N A L . nitrile in 100 ml. of xylene. The reaction was vigorously 70, 3098 (1948). stirred and refluxed for ten hours. The excess sodium amide (11) F. F. Blicke a n d C. E. Maxwell, ibid., 64, 428 (1942). was decomposed by the careful addition of water to the (12) R. 0. Clinton, U. J. Salvador and S. C. Laskowski, ibid., 71, stirred mixture. The xylene layer was separated, washed 3366 (1949). with water and then extracted with diluted hydrochloric (13) W.E.Bachman, "Organic Syntheses," Vol. 25, John Wiley and acid. The acid layer was made strongly basic with 35% Sons, Inc., New York, N. Y., 1945, p. 25. sodium hydroxide, extracted with ether and the ether solu(14) G.Vasiliu, V. Dumitrascu and H. Vulcan, Soc. Chim. R o m h i a tion dried over sodium hydroxide pellets. The solvent was Sect. romane Stiinte, Bul. chim. pur5 apl. (2) SA, 54 (1941-1942), removed and the amine distilled under reduced pressure. C. A , , 38, 5493 (1944). The substituted 3-phenylpropylamines, obtained in yields (1s) F. Rodroux and P. Taboury, Bull. soc. chim.Frnwcc, [1]7, 668 of 18 to 95%, are described in Table 11.
barium chloride. The most active compound was N- (3 -isobutyl - 3 - phenylpropyl) -piperidine hydrochloride which was 69 times as effective as papaverine against barium induced spasms and 9.5% as effective as atropine sulfate as an acetylcholine antagonist. Acknowledgment.-The author is indebted to hIr. M, E. Auerbach and Mr. K. D. Fleischer and staff for the analytical data. Experimental
(1910).
(16) J. V. Murray and J. B. Cloke, THISJOURNAL. 88, 2016 119.76).
[CONTRIBUTIOU
FROM THE IPATIEI'F
RENSSELAER, N. 1 ' .
RECEIVED FEBRUARY 28, 1951
HIGH PRESSURE
AND CATALYTIC LABORATORY, DEPARTMEST OF SORTWVESTERN cSIVERSITY1
CHEMISTRY,
Study in Terpene Series. XI.1 The Dehydroxymethylation of Bicyclic Primary Terpenic Alcohols by Hydrogenolysis in the Presence of Nickel Catalysts2 BY IT. N. IPATIEFF, G. J. CZAJKOWSKI AND HERMAN PINES The dehydroxymethylation of primary bicyclic alcohols to hydrocarbons containing one carbon atom less than the original alcohols has been studied. The catalysts used were nickel-Kieselguhr, Raney nickel and nickelalumina. The alcohols investigated were: hydronopol, nopol, myrtanol and 2-methyl-5-hydroxymethylbicyclo [3.2.lloctane. The hydrogenolysis proceeded in most cases in good yields a t 160-180" and 65-100 atmospheres of pressure. 2,2-Dimethylnorpinane formed from the hydrogenolysis of myrtanol, yielded isopropylbenzene on the dehydrogenation over platinum-alumina catalyst,
In previous papers1s3it was shown that, in the presence of nickel catalysts, primary alcohols yield hydrocarbons having one less carbon atom. The extensive isomerization that occurs during many reactions in the terpene series made it of interest to ascertain if the cleavage of primary bicyclic terpene alcohols is accompanied by isomerization. Nickelkie~elguhr,~nickelalumina' (77% Ni0-23% (1) For paper X of this series, see V. N. Ipatieff, W. W. Thompson and H. Pines, THISJOURNAL, 73, 553 (1951). (2) This work was made possible through the financial assistance of IJniversal Oil Products Company, Chicago, Illinois. (3) V. N.Ipatieff, G. S. Monroe, L. E. Fischer and E. E. Meisinger, I?id. E n g . Chcm., 41, 1802 (1949). (4) I., N. Ipatieff and R. R. Corson, ibid., 30, 1029 (1931).
&03)and m'-6 Raney nicke1,j containing alumina,6 were used as catalysts. The following alcohols n o p ~ l myrtanol ,~ were investigated : hydron~pol,~ and 2 - methyl - 5 - hydroxymethyl-bicyclo [3.2.l]octane.8 The latter compound was prepared by hydrogenating the unsaturated aldehyde obtained from the selenium dioxide oxidation of 2,6-dimethyl-2-bicyclo [3.2.1Ioctene. (6) H. Adkins and H. R. Billica, TEIS JOURNAL, 70, 695 (1848). (6) V. N. Ipatieff and H. Pines, ibid., 78, 5320 (1950). (7) J. P. Bain, ibid.,68, 638 (1946). (8) V. X. Ipatieff, J. E. Germain, W. W. Thompson and H. Pines, unpublished results. (9) V. N. Ipatieff, H. Pines, V. Dvorkovitz, R. C. Olberg and M. Savoy, .l. Or?.
