6OGO
SEYMOUR L. SHAPIRO, HAROLD SOLOWAY AKD LOUISFREEDMAN
The authors wish to express their thanks and gratitude to Messrs P. Sadtler and Son, Inc., Research Laboratories, Philadelphia, U.S.A., for kindly carrying out the infrared spectrograms. The infrared
[ CONTRIBUTIOS FROM
THE
VOl.
so
measurements of Ia were also carried out by l l r , Nagib Doss, Chemistry Department, Ohio State University, E.S.A., t o whom we are highly indebted. ABBASSIA,
CAIRO,EGYPT
RESEARCH LABORATORIES O F THE
u.s.\'ITaMIS
CORPORATIOS]
Aminophenylethanols and Related Compounds BY SEYMOUR L. SHAPIRO, HAROLD SOLOWAY AND LOUISFREEDMAN RECEIVED MAY15, 1958 A\minophen>-lethanuls of the types I and 11, and the corresponding halides were required as svnthetic intermediates. The alcohols of the type I were prepared by condensation of styrene oxide and secondary amines, while the alcohols of the type I1 were prepared by amination of 2-bromo-2-phenylethanol. Treatment of the alcohols I or 11 with thionyl chloride in ether afforded the identical chloride which in the instance of the isomeric pyrrolidino alcohols proved to be 1-(2-chloro-2-phenJ-lethyl)-pyrrolidine hydrochloride.
I n connection with the broad study of the pharmacological activity of substituted u- and pphenylethylamines, we required a number of alcohols of the type represented by I and 11. R1>scH2yHoH R9
r:)h.Y€€CHIOII
RB I1
The groups RIand R? were varied as alkyl, aralkyl, aryl and cycloalkyl, and Ka was retained principally as phenyl but was also varied as p-chlorophenyl, p-tolyl, u-naphthyl and cyclohexyl. Reports of derivatives of the structures I and I1 in a variety of pharmacological categories such as methadon analogs, antihistamines, antispasmodics and anesthetics2 will be detailed in subsequent papers. Derivatives of this type have received but scant inspection. 3 , 4 The synthesis of the aminoalcohols of the type I was effected by condensation of the appropriate secondary amine with styrene oxide or the related oxide; the compounds prepared are described in Table 1. I t has been clearly established that with secondary styrene oxide forms only secondary alcohols of the type I. From Table I i t is seen that bulky groups attached to the secondary amine tend to give lower yields. "hen a steric effect was anticipated, the reaction was carried out a t a higher temperature and for a longer heating period. I t is of interest that controlled studies' of the reaction of diethylamine and styrene oxide a t 60' showed virtually no reaction a t 6 hours and about 70y0 of the reactants remained after 12 hours. These workers concluded that styrene oxide reacts only sluggishly with amines, although they noted vigorous interaction of diethanolamine with styrene ( I ) S . L. Shapiro, H. Soloway and I,. Freedman, Meeting-in-Miniature. Westchester Section, American Chemical Society, April 21, 3953. ( 2 ) S. L. Shapiro, H . Soloway, E. Chodos and L. Freedman, THIS Jounh.hL, in press. (3) G A . Alles and I' K. Enoefel. Arch. intern. pharmacodynamie, 47, W i (1834). (4) C. S. ?ilarvel and V. d u Vigneaud, THIS Jounh-a~,46. 2093 (1924). ( 5 ) W. Emerson, ihid., 67, 5 1 0 (1945). (I,) A . Funke and G. Benoit, Buii. SOL. c h i m . France, 30, 1021 (19Z3). ( 7 ) L. Shecter, J . a'ynstra and R. P. Kurkjy, I n d . E t i g . Chem., 49, I107 (1957).
oxide which was attributed to the catalytic effect of the hydroxyl groups of the reactant amine. In contrast to these observations, a 92% yield (conipound 14, Table I) with diethylamine was obtained after 16 hours reaction time. These data suggest that after the 6-hour induction period a catalytic effect is obtained from the formed aminoalcohol of the reaction. The amino alcohols represented by I1 and described in Table I1 were prepared from secondary amines and 2-bromo-2-phenylethanol using the method of King, et al.,g and Golumbic and Cottley with slight modification. The amino alcohols of the type I , as well as their hydrochlorides were readily converted to the corresponding chloride hydrochlorides (Table I11) by treatment with thionyl chloride in ether. IVhen the amino alcohol of the type I1 as the hydrochloride was treated similarly with thionyl chloride, the chloride obtained in 727, yield was identical with that obtained using the secondary alcohol I as the reactant. Using the isomeric amino alcohols (compound 25, Table I, and compound 3, Table 11),the series of reactions reflecting the rearrangement and the identity of the chloride formed is shown in Scheme
r.
In the rearrangement of the product from the amino alcohol 11, liberation from its saltlo was not required for conversion to Ia. With no noted formation of sulfur dioxide during the thionyl chloride treatment of 11, and evolution of sulfur dioxide upon subsequent handling of this initial reaction chloroproduct IIb, the 2-pyrrolidino-2-phenethyl sulfite hydrochloride could form I a directly or yield Ia through the ethylenimonium chloride IIa.'O (8) L. C . King, S . \V. Berst and F. S.Hayes, THISJ O U K N A L , 71, 3498 (1949). (9) C. Golumbic and D . L. Cuttle, i b z d . , 61, 990 (lY39). (10) (a) E. h l . Schultz and J . A I , Sprague, i b i d . , 7 0 , 48 ( 1 9 4 8 ) ; (13) R. C. Fuson and C . L . Zirkle, ibid., 70, 2700 (1948); ( c ) J . Hinc, "Physical Organic Chemistry," McGrair.-Hill Book Co., Inc., Kew r o r k , N. Y., 1 9 j 6 , p p , 121-124; (d) in ref. loa, 2-dimethylamino-lchloropropane did not rearrange immediately when liberated from its hydrochloride a t room temperature, h u t did change t o t h e isomeric I-dimethylamino-9-chloropropane upon distillation, b.p. 64-67' (97 100 mm.). I n t u r n , ref. 10b reported t h a t when I-ethyl-2-chloromethylpyrrolidine is liberated from its hydrochloride Salt, it rearranges a t ruom temperature t o 1-ethyl-3-chloropiperidine.
Nov. 20, 1958
AMINOPHEKYLETHANOLS
6061
TABLE I Ri WPHENYLAMINOETHANOLS AND SALTS R3CHCH2P;(- .R4Xa
I
OH Compounds
1 2f 3 4
5 6
I
8 9 10 11 12 13 14' 15 16"" 1-ad
18"" 19 20 21 22 23 24 25 26 27 28 29"" 30"b 31 32 33 34 35" 36 37 38 39 40 41 42
Ri
CHICHICHaCH,r CHICHICHr CHICH3CHr CHICH3CHsC2HsC~HICzHjCzHr C2H5n-C3H7n-CsH7i-C3H7i-C3H7n-C4H9C,Hg-"
R4X
M.p., 'C.,b+ or b.p. (mm.)
Yield,d
m,
116-117 (19) 142-144ca 133-135 115-116 (4) 104 (0.2) 117-120 (0.06) 160-162'b HCl 130-132 (0.06) 132-133" HC1 168-169 (0.03) 146-148 (0.06) H C1 156-l5icb 142-143 (0.1) 112 (2.5) CH3Br 154-156ca 110-112 (0.15) 102-104 (0.2) 152-154 (0.4) 104-106 (0.22) 91-92'" HC1 135-139 (0.12) 142-143"" HCl 114-115 (0.5) 190 (0.11) 57-5gcd HC1 162-164'* €IPic.Q 150-162 CH3Br 167-168"" 76-77"* 112 (2.4) 65-67cf HC1 201-203 117-119 (0.05) HCI 148-15OCb 82-83"' HCl 192-193ca 141-143 (1.5) HC1 187-1 88'" 102-103 (0.05) 172-174 (0.2) 95-96cf 2.HC1 198-20 1 HCl HPic.'
Formula
Analyses, Yo6 Carbon Hydrogen hTitrogen Calcd. Found Calcd. Found Calcd. Found
96 61 91 84 i8 68 80 70 27 75 31 47 92 32 94 80 74
88 52 78 79 86 21 70 79 61 60 73 72 63 86 40 70 93 95 35 65 85 33 43
48.7 74.6 75.3 -ii.2 66.8 '79.6 69.2 i5.0 79.3 68.3 80.0
54.2 63.3 '75.3 79.0 76.0 65.2 80.3 i0.i
49.1 4.6 4 . 5 14.2 1 4 . 3 i4.6 9 . 9 10.0 7 5 . 0 1 0 . 2 10.1 6 . 8 6.9 ii.2 9 . 9 10.2 6 . 0 5.6 67.0 9 . 0 9 . 2 5 . 2 5 . 0 79.5 7.9 8.1 5 . 8 5.8 69.2 7.3 7.2 5.0 5.1 74.7 7.9 7 . 8 10.9 1 1 . 3 79.2 7.5 7.9 6.2 6.4 68.3 6 . 9 6.8 80.0 8.3 8 . 7 5.5 5.1
54.4 7.7 7.8 63.4 8 . 0 8 . 2 76.1 1 0 . 2 10.3 79.2 8 . 7 8.6 76.0 1 0 . 5 1 0 . 4 65.2 9.4 8.8 80.6 8.6 8.7 71.1 7.9 7.9 -n 1 1 . 1 i i . 2 10.9 10.6 83.4 8 3 . 2 7.9 8.2 75.4 10.3 9 . 0 9 . 2
-..
--
4.9 6.2 6.8 5.8 6.2
4.8 5.7 6.2 5.9 6.0
5.2
4.8
5.6 4.1
6.0 4.1
6 2 6.0 4.8 4 . 4 1 3 . 3 13.2 7.0 i . 3 4.9 4.8 7.2 7.1 6.2 5.7 1 1 . 8 12.2 7.1 6.8 9.3 9.3 6 . 8 6.7 5.8 5.4 i 7 . 7 7 7 . 9 1 0 . 2 10.2 5 . 7 5.7 67.7 67.7 9 . 2 8 . 8
51.4 54.6 63.9 i3.0 76.1
51.5 54.8 64.2 73.0 76.0
6 1 . 9 62.1 76.7 76.8 80.3 80.4 70.9 70.9
8.2 9.i i.2 9.2
5 . 8 6.7 6.0 0.2 8.1 5 . 2 5.2 9.6 6.4 6.2 (5.9 5 . 9 5.8 9 . 1 12.7 12.8 9.6 9.4
R3 = phenyl unless otherwise specified: R3 = p-chlorophenyl; a b Ra = cyclohexyl; Ra = a-naphthyl; a d RS = p-tolyl. Melting points are not corrected. Recrystallization solvent is ethanol unless otherwise specified ; ca isopropyl alcohol; cb methyl ethyl ketone: cc methyl ethyl ketone-isopropyl ether; cd heptane; ce acetonitrile; hexane; cg isopropyl alcohol-isopropyl ether; ch acetone. Yields are based on distilled or recrystallized product. e Analyses by LVeiler and Straws, Oxford, England. f H. Bretschneider, Monatsh., 78, 82 (1948), reports m.p. 139-142'. g HPic. = picric acid derivative. C4Hg = sec-butyl. s C6HII = cyclohexyl. C7H8N = 2-(4-pyridine@thyl). C8Hg = 2,6-dimethylphenyl. Ref. 6 reports b.p. 143-145' a t 14 mm. C8Hg = a-phenethyl. -c8Hl6- with attached nitrogen is 2-methyl-5-ethylpiperidyl. Ref. 6 reports m.p. 80-81'. p -C6H120- with attached nitrogen is 2,6-dimethylmorpholinyl. * -C8H8- with attached nitrogen is 1-indolinyl. -C5H11hT- with attached nitrogen is 4-methylpiperazyl.
'
The identity of the chloride Ia was established by conversion to 1-phenethylpyrrolidine by reductive dehalogenation with palladium-on-calcium carbonate, and the identity of the hydrochloride and picrate with these salts of authentic 1-phenethylpyrrolidine prepared from (2-bromoethy1)benzene and pyrrolidine. The isomeric salts prepared from 1-(a-phenyl-
ethyl)-pyrrolidine also were prepared for reference. The compounds concerned with this phase of our investigation are shown in Table IV. Treatment of the 2-pyrrolidino-2-phenylethanol with 48% hydrobromic acid'l in an attempt to ob(11) W. Pearlman, Tms JOURNAL, T O , 871 (1948),converted Kphenylethanolamine to N-8-bromoethylaniline hydrobromide in 85'G yield.
GO62
Vol. SO
._____
Ciim~inund?
RI
R?
.
RtX
C?H,C2H C2H,C.H CHrBr - (CH>)4--(CHz)aHC1 3 - ICH?)(HPic ' 0 -(CH*) >7 -(CH*)zO(CHz)JHC1 Footnotes have same significance as
1 2 :3 4
S?.p., O C . , h , c or b.p. ( m m )
Yield,o
128-132 (21) 152-154'O 99-102 (21 174-1 77 103-105 127-136 (21 154-156"" in Table I
55 13
:39 .'3 9 44 40
tain the primary bromide resulted only in isolation of the reactant alcohol recovered in Yc5% yield a3 the hydrobromide. SCHEMEI
OH FNCH&C,H; L/ I 1
n 1
Carbim, Calcri. Found
'6
NCH,CH>CnH,
d
Analyses. 5; e .~ Hydrogen, "b Nitrogen, G > Calcd. F o u n d Calcd Found
74.6 34.2
74,.5 9 9 9.9 ,%I,:{ 7.7 7 7
63.4 51.4
63.4
8.0
31.7
76.1 59.1
7K4 59.2
4.8 9.3 7.1
8.0 4.8 9.1 7.3
7.3 4 9 7.3 13.3 (7.8
5.8
7.0 4.7 ti.9
12.9 6.9 5.8
a hydrocarbon, m.p. 99-102', in %SI, yield, which proved to be 2-phenylnaphthalene.14-16 Treatment of the isomeric acetate (compound 9, Table IV) under comparable conditions indicated initial hydrolysis of the acetate, and ultimate isolation of 2-pyrrolidino-2-phenylethanolhydrobroinide in 947, yield.
Experimental''
Materials.-Unless otherwise specified all materials were commercially available. l y e are grateful to the -1merican Cyanamid Co. for a sample of p-methylstyrene oxide. The vther oxides were synthesized as described below. p-Chlorostyrene oxide was prepared by the method of Bergkvist18 in 84y0 yield, b.p. 82-86" (4.1 mm.). 1-( 1,Z-Epoxyethy1)-naphthalene.--Using the same reaction sequence,l8 2-chloro-I-(a-naphthyl)-ethanolwas prepared in 36% yield, b . p . 132-133' (O.l5mm.), and converted in 68c/0 yield t o the product, b.p. 90-96" (0.10-0.13 mm.1. 1,Z-Epoxyethylcyclohexane.-The same procedure as directly above was used, cyclohexylmagnesium bromide being prepared by the technique of Gilman and Zoellner .I9 IIb .I 36V0 yield of 2-chloro-1-cyclohexylethanoln a s obtained, b . p . 83-86" (3.3 mm.), and was converted (70%) to (1,2LVhen 2-pyrrolidino-2-phenylethanol was treated epoxyethyl)-cyclohexane, b.p. 116-119' (151 mm.). with acetyl chloride, two products were isolated, .InaZ. Calcd. for CxH140: C , 76.1; H, 11.7. Found: the expected 2-pyrrolidino-2-phenylethylacetate in C , 76.3; H , 11.1. mixCompounds of Table I. General Procedures.--rl .i870 yield and 1.5% of the acetate which was idenof 1.0 equivalent of styrene oxide (or equivalent oxide) tical with that obtained in quantitative yield from ture and 1.5 equivalents of the secondary amine was maintained the 2-pyrr0lidino-l-phenylethanol.~~ under reflux. n'hen steric effects were anticipated the The isomeric acetates (compounds 7 and I), heating period was prolonged. The product was then isoTable IV) were next considered as reactants for lated by distillation. The heating period varied: 1 hour, compound 25; 2-3 conversion to the bromides following the procedure hours, compounds 1, 29, 30, 31. 35, 39, 11; 12-16 hours, of Stempel and Buzzi.I3 In the instance of 2- compounds 14,16, 18; 20-21 hours, compounds 5 , 6, 17, 19, pyrrolidino-I-phenylethyl acetate (compound 7 , 3 3 ; 30 hours, compound 1. In certain instances, a solvent (about 4 vol. so1vetit:l Table IV), the only isolable product obtained was vol. reactant) was used to modif)- the reaction. Compounds (1'2) (a) W. H. Saunders, J r . , S. Asperger and D. H. Edison, T H I S 11, 13, 23, 34 and 37 (ethanol) and compound 24 (butanol) J O U R N A L , 80, 2421 ( l Q j S ) ,in B study of rates of solvolpsis of deuterated were prepared in this manner using a 3-hour reflux period. 2-phenylethyi p-toluenesulfonates have shown t h a t about 10% phenyl For the synthesis of compounds 8, 10 and 21, the external migration occurs in acetolysis, and in contrast about 4570 phenyl migratemperature was controlled for 2 hours by use of an oil-bath tion had occurred in formolysis, and concluded t h a t phenyl participamaintained at 125-135". T h e preparation of compound 40 tion predominates in formolysis b u t is unutilized heating on a steam-bath for 15 hours. CH, important in acetolysis; (b) in t h e rearrange Exothermic reactions were noted in mixing the reactants I ment we have noted i t is not likely t h a t phenyl which involved the less hindered secondary amines yielding participation occurs a s shown in ref. 12a, compounds 1, 8, 11, 25, 29, 39 and 41. T h e influence of since under these conditions t h e anticipated steric factors is also manifest in comparable yields obtained rearranged product would be 2-phenyl-lwith the pyrrolidino products (compounds 25, 29,30) with a
rcQ A
