472
F. J.
XtCCARTY,
c. H. TILFORD .4ND M. G. VAN C A M P E N , J R .
Anal. Calcd. for CIIHIIN~Cl:C, 62.70; H,7.18; N, 13.30; C1, 16.83. Found: C, 62.36; H, 6.97; N, 13.36; Cl, 16.98. Nitriles used were either commercially available or were prepared according to the method of Marxer.10 I-Aminoethylimidazolines (XVIII) (cf. Table 11). General Procedure.-The appropriate nitrile (0.2 mole) mas mixed with 0.22 mole of diethylenetriamine or h-,X-dimethyldiethylenetriamine, and 200-500 mg. of dry hydrogen sulfide was passed into this mixture. The resulting solution was heated in an oil-bath a t 90-120" until evolution of ammonia was complete, this taking sometimes only a few minutes and sometimes 7-8 hr. Usually a temperature of 100-105" was sufficient. The resulting imidazolines were usually distilled twice and the dihydrochlorides prepared. 1,l '-Bisimidazolinylethanes(XIX) (cf. Table 111) General Procedure: Bis- [2,p-chloroanilinomethylimidazolinyl-( 1)Iethane (XIX/S).-Dry hydrogen sulfide (400 mp.) was
__
(10) A. Marxer, Helo. Chim. Acta., 37, 166 (1954).
Vol. 79
passed into a mixture of 49.98 g. (0.3 mole) of p-chloroanilinoac,etonitrile and 21.93 g. (0.15 mole) of triethylenetetramine. This was heated in an oil-bath a t llOo, when a rapid evolution of ammonia occurred, lasting for 1 hr. and becoming very slow during the next 6 hr. The reaction product crystallized on addition of 200 ml. of ethyl acetate. Crystals of XIX/8 were isolated and washed with ethyl acetate, when they had m.p. 162" (slight sintering a t 149'). Since this base conformed to the expected analytical results, the hydrochloride was prepared without further purification, by dissolving in alcohol and adding 2 equivalents z f alcoholic hydrochloric acid; hydrochloride m.p. 228-231 . Generally, the bases of Table I11 decomposed on distillation, with the exception of XIX/1 and XIX/2. When they did not crystallize upon addition of ethyl acetate, the solution was evaporated, dissolved in dilute hydrochloric acid, the oil reprecipitated by dilute ammonia in the cold and taken up in ethyl acetate or alcohol to prepare the hydrochloride. BASEL,SWITZERLAND
[CONTRIBUTIONFROM THE DEPARTMENT OF ORGANIC CHEMISTRY, RESEARCH LABORATORIES, THEIVILLIAM s.hlERRELL CO.]
Central Stimulants. a,a-Disubstituted 2-Piperidinemethanols and 1,l-Disubstituted Heptahydrooxazolo[3,4-a]pyridines BY FREDERICK J. M C C A R T Y , CHARLES H. T~LFORD AND M. G. VAN CAMPEN, JR. RECEIVED JULY 19, 1956
A series of a,a-disubstituted-2-pyridinemethanols was prepared and converted to the corresponding 2-piperidinemethanols by hydrogenation. Heptahydrooxazolo[3,4-a]pyridinederivatives of some of the piperidinemethanols were also prepared. A number of the piperidinemethanols and heptahydrooxazolidines possess central stimulant activity.
This investigation was a continuation of the and other pyridinemethanols by reaction of lithio search for new therapeutic agents in the a,a-disub- agents with ketones have been carried out.1° A stituted-2-piperidinealkanolseries. A previous pa- ketone synthesis from ethyl picolinate and 2per' described the synthesis of a series of a,a- pyridyllithium has been reported to yield trG2disubstituted-2-piperidine-ethanols and the related pyridinemethanol as a b y - p r o d u ~ t . ~Preparation octahydropyrid [1,2-c]oxazines. A number of these compounds had diuretic and anti-fungal properties. The piperidinemethanols of the present investigation are analogs of a,a-diphenyl-2-piperidinemethano1 hydrochloride2vawhich possesses central stimulant a ~ t i v i t y Generally, .~ these piperidinemethanols were prepared by hydrogenation of the corresponding pyridinemethanols. Some of them were treated with formaldehyde to yield the oxazolidine derivaQ-C02Et 2RLi tives. The synthetic methods used for preparing the intermediate pyridinemethanols are shown. Previous examples of Grignard reactions in which other pyridyl ketones were substituted for benzoylpyridine have been described in the literature.6-7 The preparation of a-phenyl-a-(2I thienyl)-2-pyridinemethanol (Table I, 35A) was recently reported.* The synthesis of di- and tripyridinemethan~ls~
+
Q-LR
(1) C. H . Tilford and M. G. Van Campen, Jr., THISJOURNAL, 76, 2431 (1954). ( 2 ) C. H. Tilford, R . S. Shelton and M. G. Van Campen, Jr., i b i d . , 70, 4001 (1948). (3) H. W. Werner and C.H. Tilford, U.S. Patent 2,624,739 (1953). (4) B. B. Brown and H. W. Werner, J . Phormacol. E x p t l . ThcraP., 110, 180 (1954). (5) K. Schofield, J . Chcm. Soc., 2408 (1949). (6) K. Winterfeld and F. W. Holschneider, Aich. Pharm., 273, 315
(1935).
(7) N. Sperber, D. Papa, E. Schwenk and M. Sherlock, THISJOUR71, 887 (1949). (8) J. Heer, E. Sury and K. Hoffmann, Hclo. Chim. Acta, 38, 134
NAL,
(1955). (9) J. P. Wibaut, A. P. de Jonge, H . G. P. Van der Voort and P . Ph. H . L. Otto, Rcc. 1rm. chim., 70, 1054 (1951).
R = alkyl, cycloalkyl, aralkyl, aryl or heterocyclic
of aIa-dimethyl-2-pyridinemethanolfrom ethyl picolinate and methylmagnesium iodide has been reported." A series of pyridinemethanols, mainly of the type in which one R group is alkyl, has been prepared2 by condensation of pyridine with the ap(10) A. J. Nunn and K. Schofield, J. Chcm. Soc., 589 (1952). (11) W. Sobccki, Bn.. 41,4103 (1908).
CY,CY-DISUBSTITUTED 2-PIPERIDINEMETHANOLS
Jan. 20, 1957
473
TABLE I SUBSTITUTED PYRIDINEMETHANOLS. PIPERIDJNEMETHANOLS AND HEPTAHYDRO~XAZOLOPYRIDINES R' +bR' I
OH (A)
I
I
OH (B)
IA 1B 1C 1D 1D ID 2A 2B 2C 3A 3B 3C 3D 4A 4B 4C 5A 5B 5C1 5C2 6A 6B 6C 6D 6D 7A 7B 7C SA 8B 8C 9A 9B 9C 9D 10A 10B lOCt lOC2 10D 11A 11B 11C 12A 12B 12C1 12C1 12C~ 12D 13A 13B 13C 13C 14B 14C 14D
R'
Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyi Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl p-Tolyl +Tolyl p-Tolyl o-Tolyl O-Tolyl o-Tolyl O-Tolyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl
R'
Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl O-Tolyl O-Tolyl 0 -T01y 1 m-Tolyl m-Tolyl m-Tolyl m-To1y 1 P-Tolyl p-Toiyl @-Tolyl p-Ethylphen yl p-Ethylphenyl P-Ethylphenyl p-Ethylphenyl' 2,5-Dimethylphenyl 2,5-Dimethylphenyl 2,5- Dimethylp hen yl 2,5-Dimethylphenyl 2,bDimethylphenyl Mesityl Mesityl Mesityl p-Tolyl p-Tolyl p-Tolyl O-Tolyl o-Tolyl O-Tolyl o-Tolyl Benzyl Benzyl Benzyl Benzyl' Benzyl' 1-n'aphthyl 1-Naphthyl 1-Naphthyl p-Chloropheny 1 p-Chlorophenyl p-Chlorophenyl' p-Chlorophenyl p - Chlorophenyl' p-Chlorop henyl/ o-Chlorophenyl o-Chlorophenyl o-Chlorophenyl o-Chlorophenyl m-Chlorophenyl' m-Chlorophenyl m-Chlorophenyl
'
H
OH (D)
%.P., No.
I
Metho d
A
G I K B
G I B
G I K A G I B
G I I B
G I K B
G I E G I D
G I K A
G I I
K B G I C G
J I
I K C
G
J I B
I K
C.
cor."
104-106 181-182 312-324 117-121 158-159 182-183 95-96 190-192 296-297 90-91 193-195 290-291 134-136
83-85 193-195 316-318 59-61 156- 157 323-324 271-273 93-95 175-177 280-282 116-117 200-203 147-148 192-193 271-272 119-121 181-183 316-317 119-120 193- 194 255-256 224-226 104-105 188-190 235-236 284-286 114-116 148-149 186-188 283-284 110-111 215-216 124-1 25 320 276 99-100 125-127 208-209 172 276-277 194-196 304-305 83-85
Yield,
'$io Formula
79 92 92
82 56 86 69 33 89 69 62 47 20 72 45 70 77 39 68 74 74 92 60 58 79 10 46 44 83 68
22 68 74 42
94 24 83 64
Carbon, % Calcd. Found
Hydrogen, % Calcd. Found
CisHisOn'b
C ~ ~ H , ~ O N C I72.85 ~ 72.27 ClsH=ONClb 71.15 71.10 81.69 82.41 CIgHZiON CZ~HZLM'?~ 69.86 69.88 72.26 C~,H~~ONC ~ ~ 72.33 CipHiiON 82.89 83.16 73.21 73.19 CigHisOSCl 71.79 71.73 CioHzaONCl 82.89 82.90 CigHi7ON 73.21 73.22 CioHisONCl CigH240NCl 71.79 71.91 Cz4HnOiNC 70.40 70.55 CigHi70N 82.89 82.98 73.21 72.87 CioHisONCl CigHr40NCl 71.79 71.79 83.00 82.87 CzoHlpON 73.72 73.89 GHzoO X C1 Cz0Hz60NCl 72.40 71.74 CZoHHONC1 72.40 71.70 CzoHigON 83.00 83.09 73.72 73.43 CznHzoOSCl GoH16ONCl 72.40 72.25 82.05 82.01 GiHzsON 70.91 71.03 CzsH~sOsNc CzlHziO?; 83.14 83.23 Cz1HnONCl 74.20 74.21 72.91 72.80 CziHSONCl 83.01 82.83 GHlgON CmHzoONCl 73.72 73.77 72.40 72.57 GoHzsONCl 83.01 83.08 CzoHigON C,H2oOSCl 73.72 73.58 GHzsONCl 72.40 72.28 CzlHzsONCld 73.36 73.39 82.89 8 2 . 7 8 CigHi7On' 73.21 72.85 CisH180NC1 CigHz40NCl 71.79 71.44 ClgHaONCl 71.79 72.08 CuHnOsW 70.40 70.21 84.84 84.76 CZZHI~ON GH180r'jCl 75.96 75.74 CzzHz40NCl 74.66 74.44 CisHirONCl 73.09 72.84 65.08 64.99 Ci8Hi50NClz CisHzoOn'Cl" 71.64 71.57 CieHziONClz 63.90 64.26 63.90 64.38 CisHilONC12 CioHmONCl 72.73 72.76 CisHirONCl 73.09 72.96 CisHisOXCl~ 65.08 64.67 71.64 71.88 CisHzoONCP CisHziONClz 63.90 64.28 CieHisONCla 65.07 64.86 CisHniONClz 63.90 63.95 Ci,HmONCl 72.73 72.92
5.44 7.30 7.58 6.38 7.02 6.23 5.82 7.61 6.23 5.82 7.61 6.65 6.23 5.82 7.61 6.62 6.19 7.90 7.90 6.62 6.19 7.90 8.20 6.90 6.98 6.53 8.16 6.62 6.19 7.90 6.62 6.19 7.90 7.62 6.23 5.82 7.61 7.61 6.65 5.50 5.22 6.83 4.77 4.55 6.68 6.26 6.26 6.43 4.77 4.55 6.68 6.26 4.55 6.26 6.43
5.35 7.29 8.19 6.73 7.21 6.35 5.89 7.82 6.42 5.87 7.84 6.61 6.34 6.09 7.76 6.58 5.90 7.91 7.69 6.56 6.31 8.12 8.03 7.02 6.95 6.46 8.23 6.62 6.25 7.96 6.87 6.18 7.86 7.65 6.50 5.93 7.77 7.75 6.74 5.32 5.33 6.54 4.80 4.71 6.88 6.39 6.37 6.35 4.80 4.34 6.63 6.48 4.76 6.40 6.47
474
Vol. 79
F. J. MCCARTY, C. H. TILFORD AND M. G. VAN CAMPEN, JR. TABLE I (Continued) M.P.,
NO.
14D 15-4 15B 15c1 15c* 16X 16B 16C 17A 17B 17C 17c 17D 17D 18-4 1813 18C1 18C2 19.4 19c 20B 20c 21A 21B 21c 22A 22c1 22c2 23A 23B 23 C 24% 24B 24 C 25.1 25B 25c 26A 26B 26C 27.4 27C 28A 28C 29A 29C 30x
:mu 3oc 31A 31B 31C :31c :32B 32B 32c 32Ci 32cz 33'4 33C n4a 3 $I3
R
R'
Phenyl m-Chlorophenyl Phenyl p-Bromophenyl Phenyl p-Bromophenyl Phenyl @-Bromophenyl Phenyl p-Bromophenyle Phenyl p-Fluorophenyl Phenyl 9-Fluorophenyl Phenyl p-Fluorophenyl p-Chlorophenyl P-Chlorophenyl p-Chlorophenyl p-Chlorophenyl p-Chlorophenyl p-Chlorophenyl 9-Chlorophenyl p-Chlorophenyl p-Chlorophenyl p-Chlorophenyl p - Ch lorophenyl p-Ch lorophenyl p-Chlorophenyl o-Chlorophenyl p-Chlorop henyl o-Chlorophenyl p-Chlorophen yl o-Chlorophenyl p-Chlorophenyl o-Chlorophenyl' @-Bromophenyl p-Bromophenyl' p-Bromophen yl $-Bromophenyl Phenyl p-Hydroxyp henylh Phenyl $-Hydroxyphenyl Phenyl p-Anisyl Phenyl p -Anisyl Phenyl p-Anisyl Phenyl p-Phenetyl' Phenyl p-Phenetyl Phenyl p-Phenetyr Phenyl 3,4-Methylenedioxyphenyl Phenyl 3,4-Methylenedioxyphenyl Phenyl 3,4-Methylenedioxyphenyl Phenyl 2-Methoxy-1-naphthyl Phenyl 2-Methoxy- 1-naphthyl Phenyl 2-Methoxy-1-naphthyl $-Benzyloxyphenyl #-Benzyloxyphenyl p-Benzyloxyphenyl p-Benzyloxyphenyl p-Hydroxyphenyl $-Hydroxyphenyl p - Anisyl p-ilnisyl p-Anisyl p-ilnisyl p -Anisyl p-ilnisyl p-Phenet yl' p-Phenetyl p-Phenetyl p-Phenetyl Phenyl p-Aminophenyl Phenyl p-9minophenylk Phenyl 9-Dimethylaminophenyl' Phenyl 9-Dimethylaminophenyl p-Dimethylaminop-Dimethylaminophenyl phenyl p-Dimethylaminop-Dimethylaminophenyl phenyl Phenyl 9-TriniethylsilylPhenyl phenyl Phenyl p-TrimethylsilylPhenyl phenyl Phenyl 2-Pyridyl" Phenyl 2-Pyridyl Phenyl 2-Pyridyl Phenyl 2 Piperidyl Phenyl 2 Piperidyl' Phenyl @-Indolyli Phenyl 8-Indolyl Phenyl 2-Fury1 Phenyl 2. Fury1
'"2;
Method
C
G I I C G I C G
J I K C G I I C I
C I A
G 1 A I I C G I C
G I C
G I C
G I
D I C' I B I D
G I 1B \G
IJ 11 G G I
I I .4 I c 9
G
cor.
126-128 96 203-204 314-315 275-276 83-85 187-189 288-289 88-89 187- 193 83-84 309-310 169-171 132-134 110-112 182-192 273-275 306-307 102-103 306-307 165-167 213-214 120-122 158- 160 285-286 110-112 276-277 235 112-114 190-192 259-260 103-105 142-144 256 123-126 146-147 229-230 90-91 154-156 261-262 93-94 219 73-75 188-190 152-153 233-234 148-151
256-258 74-76 171-173 100-102 347-348 171-172 180- 193 201-202 340 282 178-179 156-159 60-62 164-166
Yield,
%
68
20 22 40 67 24 97 80 81 33
68 13 27 61 16 40 80 33 45 25 36 52 74 72 20 62 20
85 72 19 77 1.5 19 62 11 61
63 65
35
75 29 45 6 29 40
Formula
Carbon, % Calcd. Found
64.26 63.53 57.39 56.48 56.48 77.40 68.45 67.17 63.46 58.95 64.29 58.01 65.52 59.50 65.46 58.95 58.01 58.01 Sl.58 46.82 69.01 67.60 78.33 69.61 68.35 78.6,5 69.06 69.06 74.75 66.76 65.62 80.92 73.11 71.97 81.15 75.35 6+.39 i4.76 67.13 66.01 7
