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α-and β-Amino Ketones and Corresponding Secondary Alcohols
a!-
and @-AminoKetones and Corresponding Secondary Alcohols* By F. F. BLICKE a n d W. K. JOHNSONt
Basic ketones of the types RCOCH~CHZNR'~and RCOCHZNR'Z were prepared by the use of the Mannich reaction or from a pbenacyl halide. Some of the ketones were reduced to the corresponding secondary alcohols. A number of quaternary salts of the ketones and alcohols were synthesized.
of the types RCOCH2CH2NR'2 (I) and RCOCH2NR'2 (11), as well as their corresponding secondary alcohols, have either been shown to exhibit pharmacological activity or to be useful for the synthesis of pharmacologically active products. The preparation of a number of such compounds as bases, hydrochlorides, and quaternary salts has been described in this paper. Compounds of type I were obtained by the use of the Mannich reaction; those of type I1 were prepared from phenacyl halides. Mannich reactions were carried out by the use of acetovanillone, paraformaldehyde and the hydrochlorides of the following amines: dimethylamine, methylbenzylamine, hexamethylenimine, and heptamethylenimine. The products obtained are listed in Table I. The hydroASIC KETONES
We were unable to obtain Mannich bases when phenyl cyclohexyl ketone, isobutyrophenone or adrenalone hydrochloride was employed,' Three basic ketones were synthesized by interaction of phenacyl chloride with hexamethylenimine and heptamethylenimine, respectively, and by reaction between chloroacetylcatechol and hexamethylenimine. Each ketone hydrochloride was reduced to the corresponding secondary alcohol with the use of platinum oxide. Six quaternary salts of basic ketones (Table 11) were obtained by interaction of phenacyl bromide, 3,4-dimethoxyphenacyl bromide or chloroacetylcatechol with tertiary amines such as trimethylamine, N-methylhexamethylenimine and Nmethylheptamethylenimine. In two instances the quaternary salts of the basic ketones (compounds 3 and 5, Table 11) were reduced t o the
TABLEHYDROCHLORIDES
>
OF
MANNICH BASES
(4) HO
(3) CHaO R
1 Dimethylamino
OHCOCHzCHaR.HC1 M. p..
Yield,
OC.
%
Formula
Carbon Calcd. Found
.. .
...
Analyses, yo Hydrogen Chlorine Calcd. Found Calcd. Found
. . . .. .
184
73
CiiHi80aNCla
188-189
90
ClaHn08NCI 64.39 64.53 6.61 6.84 10.54 10.74
3 l-Hexamethyleniminob 166-168
60
CieHidOaNCl 61.24 61.53 7.71 7.86 11.30 11.63
4 1-Heptamethylenimino 163-165 46 (decompn.)
CnH2sOaNCl 62.16 62.27 8 . 1 4 7.99 10.82 10.97
2 Methylbenzylamino
(decompn.) (decompn.)
(decompn.)"
13.65 13.45
Calcd. % N, 5.39; found, 5.40. b The methobromide melted a t 164-165O (dec.) after recrystallization from methanol Anal.-Calcd. for ClrHaOiNBr: C. 54.85; H.,7.04; N. 3.76; Br, 21.47. Found: C. 54.65; H, 6.98; N. 3:83. Br. 21.40. This product precipitated from the reaction m:xture with one m4ecular equivalent of ethanol of crystallization which was last when the substance was heated at 110' for 3 hours. Compounds 1, 2, and 4 were recrystallized from absolute ethanol. (1
6
chlorides of the Mannich bases prepared from dimethylamine and hexamethylenimine hydrochlorides were reduced with the aid of platinum oxide to the corresponding secondary alcohols.
*
Received March 31,1958, from the College of Pharmacy. University of Michigan, Ann Arbor, Mich. Presented to the Scientific Section, A. Pa. A,. Detroit meeting, April 13, 1956. This paper represents part of a dissertation submitted by W. K . Johnson in partial fulfillment of the requirements for the Ph.D. degree in the University of Michigan, 1953. t The Upjohn Company Fellow. 1950-1953.
corresponding secondary alcohols by the use of platinum oxide. In order to obtain methyl-N,Nheptamethylene - (2 - hydroxy - 2 - phenylethy1)ammonium bromide it was necessary to allow methyl bromide to react with 1-(1-heptamethy1enimino)-2-hydroxy-2-pheny1ethane'
1 See W. K. Johnson, Doctoral Dissertation. University of Michigan. 1853.
July 1956
SCIENTIFIC EDITION EXPERIMENTAL
Mannich Reactions.-Hydrochlorides of the folowing secondary amines were used in the general procedure described below: dimethylamine, methylbenzylamine (l),hexamethylenimine (2),and heptamethylenimine (2). Acetovanillone' (0.1mole), 4.0Gm. of paraformaldehyde, 0.1 mole of the required amine hydrochloride and 200 cc. of absolute ethanol were refluxed for 24 hours. If the product did not separate from the cooled reaction mixture, the solvent was removed. The products are listed in Table I. In the following two instances, the basic ketone salt was reduced to the corresponding secondary alcohol. 1 (3 Methoxy 4 hydroxyphenyl) 3 dimethylaminopropanolHydrochloride.-The required basic ketone hydrochloride (10.0Gm.)was dissolved in 50 cc. of acetic acid and hydrogenated in the presence of 0.3 Gm. of platinum oxide catalyst under an initial pressure of 45 pounds. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The product melted at 171-172' (decompn.) after recrystallization from isopropyl alcohol; yield 4.0 Gm. (40%). And.-Calcd. for CI~H~OO~NCI: N, 5.35; C1, 13.24. Found: N, 5.26;C1, 13.36. 1 (3 Methoxy 4 hydroxyphenyl) 3 (1hexamethy1enimino)propanol Hydrochloride.-This compound was prepared in the manner described above in 87% yield; m. p. 148-150' (decompn.) after recrystallization from absolute ethanol. Anal.-Calcd. for C ~ ~ H ~ ~ O B N C,C60.96; I: H, 8.25; N, 4.44; C1, 11.23. Found: C, 61.03; H, 8.42; N, 4.55; C1, 11.05. Phenyl (1-hexamethy1enimino)ethyl Ketone Hydrochloride.-Phenacyl chloride (15.5 Gm., 0.1 mole), 9.9 Gm. (0.1mole) of hexamethylenimine, 6.0 Gm. of anhydrous sodium carbonate and 100 cc. of absolute ethanol were refhxed for 4 hours. The cold mixture was filtered and ethereal hydrogen chloride was added to the filtrate to precipitate the product; yield 11.7 Gm. (46%); m. p. 222-223' (decompn.) after recrystalliition from butanol. Ad.-Calcd. for ClrH2oONCI: N, 5.52; C1. 13.97. Found: N, 5.16; C1, 14.14. Phenyl ( 1-heptamethy1enimino)ethyl Ketone Hydrochloride.-This product was obtained in the manner described above by the use of heptamethylenimine; m. p. 220-221' (decompn.) after recrystallization from butanol; yield 43%. And-Calcd. for ClsHnONCI: N, 5.23; C1, 13.24. Found: N, 5.10; C1, 13.33. 3,4-Dihydroxyphenyl ( 1-hexamethy1enimino)methyl Ketone Hydrochloride.-This substance was prepared in the described manner with the use of chloroacetylcatechol~and hexamethylenimine except that the reaction mixture was not heated but was allowed to remain a t room temperature for 24 hours; m. p. 241-242' (decompn.) after recrystallization from methanol-ether; yield 47%. And-Calcd. for C~~H~OOSNCI: C, 58.75; H,
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* Obtained from the Marathon Corporation, Chemical Division, Rothschild, Wis. 8 Purchased from Winthrop-Steams.
441
7.06; N, 4.90; C1, 12.41. Found: C, 58.95; H, 7.30; N, 4.87; C1, 12.54.
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1 (1 Hexamethylenimino) 2 hydroxy 2phenylethane Hydrochloride.-The required basic ketone hydrochloride (10.2 Gm., 0.04 mole) was dissolved in 100 cc. of water and hydrogenated in the presence of 0.3 Gm. of platinum oxide catalyst under an initial pressure of 50 pounds; m. p. 173174" (decompn.) after recrystallization from ethanolether; yield 9.1Gm. (880Jo). Anal.-Calcd. for Cl,HnONCl: N, 5.48; C1, 13.86. Found: N, 5.38;C1, 13.96. 1 (1 Hexamethylenimino) 2 hydroxy 2(3,4-dihydrorpphenyl)ethane Hydrochloride.-The required basic ketone hydrochloride was reduced in the described manner; m. p. 161-163' (decompn.) after recrystallization from butanol; yield 86%. And-Calcd. for Cl,Hz,OaNC1: C, 58.42; H, 7.71; N, 4.87; C1, 12.32. Found: C, 58.72; H, 7.85; N, 4.22; C1, 12.36. 1 (1 Heptamethylenimino) 2 hydroxy 2phenylethane Hydrochloride.-By the described process, this compound was obtained in 65y0 yield from the required ketone salt; m. p. 152153' (decompn.)after recrystallizationfrom isopropyl alcoh01. And-Calcd. for ClsH2rONCl: N, 5.19; C1, 13.14. Found: N, 5.13; C1, 13.21.
N
- Methylhexamethy1enimine.-Hexamethylen-
imine (2)(29.7Gm., 0.3 mole), 46.5 Gm. of 35% formaldehyde, and 76.5 Gm. of 90% formic acid were heated on a steam bath for 12 hours. After the addition of 35 cc. of concentrated hydrochloric acid to the cold mixture, the solution was evaporated to dryness on a steam bath. The residue was dissolved in a minimum amount of water, sodium hyoxide was added to the solution and the amine was extracted with ether. From the dried extract, 27.7 Gm. (81.5%) of product was obtained; b. p. 137-139' (740mm.).l For characterization, the base was converted into the hydrochloride; m. p. 182-183' (decompn.). N-Methylheptamethy1enimine.-By the method described above, 113.0Gm. of heptamethylenimine (2)yielded 97.3 Gm. (78.5%) of product; b. p. 159-161" (734mm.). The hydrochloride melted a t 162-163' (decompn.). Thereported m. p. is 163-164' (2). 3,4-Dimethoxyacetophenone.-A mixture of 166 Gm. of acetovanillone and 450 cc. of water was stirred and heated on a steam bath. A solution was prepared from 150 Gm. of sodium hydroxide and 750 cc. of water, and 360 cc. of this solution was added to the mixture. Methyl sulfate (142 cc.) was then added at such a rate that the mixture refluxed. The mixture was refluxed for 45 minutes. An additional 30 cc. of methyl sulfate was added, followed shortly by 60 cc. of sodium hydroxide solution. After the last mentioned operation had been repeated two more times, the mixture was made strongly alkaline, extracted with ether. and then the extract was dried with magnesium sulfate. The product boiled a t 158-160" (8 mm.); m. p. 52-53'; yield 155 Gm. (86%). The reported b. p. is 158' (9mm.) (3)and the m. p. is 51' (corr.) (4). The quaternary salts of the basic ketones (Table 11)were obtained in the following manner. 4 G. R . Toy, (Doctoral Dissertation, University of Michigan 1951) prepared the base by a diEerent method; b. p . 1391140'; m. p. of the hydrochloride, 181.5-183.5".
442
JOURNAL OF THE
AMERICANPHARBIACEUTICAL ASSOCIATION
Compounds 1 and 2.-Phenacyl bromide (0.1 mole), 0.1 mole of N-methylhexamethylenimine (or N-methylheptamethylenimine) and 150 cc. of absolute ethanol were refluxed for 4 hours, and ether was then added to the cold mixture to precipitate the product. Compound 3.-Chloroacetylcatechol (10.8 Gm.), 4.8 Gm. of triniethylamine and 100 cc. of absolute
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Vol. XLV, No. 7
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Methyl N,N hexamethylene (2 hydroxy 2phenylethy1)ammonium Bromide.-The quaternary bromide (compound 5, Table 11) was hydrogenated in the manner described above; m. p . . 173-174' (decompn.); yield 66y0. And-Calcd. for ClsHuONBr: C, 57.31; H, 7.92; N, 4.46; Br, 25.42. Found: C, 57.44; H. 7.70; N, 4.19; Br, 25.64.
TABLE 11.-QUATERNARYSALTS OF BASICKETONES
RCOCHA' x+ R'
R
1 2 3 4 5
6
CsHs CsHs 3,4-(H0)zCsHa 3,4-(HO)zCeHa 3,4-(CH30)2CsH:< 3,4-( CH30)tCsHa Formula
1 2 3 4 5 6
ClsHnONBr ClsHlrONBr CiiHi6OOaNCI C2iH240ioN1 C17H2aOaNBr ClaHzsOaNBr
Yield.
X-
M p..
162-163 183-185 234-235 169-1 7 1 203-204 167-168
Br Br
hT(CH2)dCHa) N(CH2)dCHa) N(CH3h N(CHz)e(CHa) N(C&)s(CH3) N(CH2)7(CHs)
c1 Picratc Br Br
O C .
(decompn.) (decompn.) (decompn.) (decompn. ) (decompn.) (decompn.)
Carbon Calcd. Found
Analyses, Yo Hydrogen Nitrogen Calcd. Found Calcd. Found
57.68 58.90
7.10 7.41
7.41 7.66
7.04 7.32
... 7.12 7.52
...
&:85 55.97
57.90 58.73
...
54:82 55.63
... ...
4.49 4.29 5.70 11.38 3.76 3.63
...
4.45 4.07 5.66 11.56 3.69 3.37
5% 64 91 85 86 73 64
Halogen Calcd. Found
25.60 24.50 14.43
25.65 24.40 14.37
21:47 20.69
21:38 20.53
Compound 1 was recrystallized from ethanol-ether; 3 from methanol; 5 from ethanol; 6 from isopropyl alcohol.
ethanol were allowed to react at room temperature for 24 hours whereupon the product precipitated. Compound 4.-Chloroacetylcatechol (5.6 Gm.), 3.4 Gm.of N-methylhexamethylenimineand 50 cc. of absolute ethanol were allowed t o react at room temperature for 24 hours. The solvent was removed, the residue was dissolved in 2 liters of boiling water, and 10 Gm. of picric acid was added. The picrate precipitated from the cold solution. Compounds 5 and 6.-A mixture of 10.4 Gm. of 3,4-dimethoxyphenacyI bromide, 4.5 Gm. of Nmethylhexamethylenimine (or N-methylheptamethylenimine) and 50 cc. of absolute ethanol was refluxed for 4 hours. Ether was added t o the cold mixture t o precipitate the product. Trimethyl [2 hydroxy 2 (3,4 dihydroxyphenyl )ethyl] ammonium Chloride.-Trimethyl-3,4dihydroxyphenacylammonium chloride (compound 3, Table 11) (12.6 Gm., 0.06 mole), dissolved in 50 cc. of water, was hydrogenated under an initial pressure of 50 pounds in the presence of 0.3 Gm. of platinum oxide catalyst. The catalyst was removed by filtration and the solvent was removed under reduced pressure; m. p. 172-173' (decompn.) after recrystallization from methanol-ether; yield 5.0 Gm. (40%). Anal.-Calcd. for CllH1503NC1: N. 5.66; CI. 14.32. Found: N, 5.60; C1, 14.19.
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Methyl N,N heptamethylene (2 hydroxy 2phenylethy1)ammonium Bromide.-When the quaternary bromide (compound 6, Table 11) was hydrogenated as described above, a mixture of products was obtained from which methylphenylcarbinol was isolated in 55% yield. The carbinol was identified as the a-naphthylurethane; m. p. and mixed m. p. 105". The reported m. p. is 106' (5). The desired compound was prepared by the addition of a slight excess of methyl bromide to a n ethereal solution of 1- ( 1-heptamethylenimino)-2hydroxy-2-phenylethane. After a week the salt had precipitated in 45% yield; m. p. 167-169' (decompn. ) after recrystallization from butanol-ether. And-Calcd. for ClsHtaONBr: C, 58.53; H, 7.98; N, 4.27; Br, 24.35. Found: C, 58.27; H, 8.04; N, 4.23; Br, 24.18.
REFERENCES ( 1 ) Blicke, F. P.. and Lu, Chi-Jung. J . Am. Chem. Soc., 74 3933(1952) ?2) Blicke, F. F., and Doorenbos. N. J . , ibid.. 76, 2317
(1954). (3) Mannich. C.. and Neumann, P., Arch. Pharm., 248. 127(1910) (4) Finnemore H. J . Chcm. Soc 93 1515(1908). (5) Bickel, V. k., knd French, H.'E.,'J. Am. Chcm. Soc., 48. 749(1926).
and @-AminoKetones and Corresponding Secondary Alcohols* By F. F. BLICKE a n d W. K. JOHNSONt
Basic ketones of the types RCOCH~CHZNR'~and RCOCHZNR'Z were prepared by the use of the Mannich reaction or from a pbenacyl halide. Some of the ketones were reduced to the corresponding secondary alcohols. A number of quaternary salts of the ketones and alcohols were synthesized.
of the types RCOCH2CH2NR'2 (I) and RCOCH2NR'2 (11), as well as their corresponding secondary alcohols, have either been shown to exhibit pharmacological activity or to be useful for the synthesis of pharmacologically active products. The preparation of a number of such compounds as bases, hydrochlorides, and quaternary salts has been described in this paper. Compounds of type I were obtained by the use of the Mannich reaction; those of type I1 were prepared from phenacyl halides. Mannich reactions were carried out by the use of acetovanillone, paraformaldehyde and the hydrochlorides of the following amines: dimethylamine, methylbenzylamine, hexamethylenimine, and heptamethylenimine. The products obtained are listed in Table I. The hydroASIC KETONES
We were unable to obtain Mannich bases when phenyl cyclohexyl ketone, isobutyrophenone or adrenalone hydrochloride was employed,' Three basic ketones were synthesized by interaction of phenacyl chloride with hexamethylenimine and heptamethylenimine, respectively, and by reaction between chloroacetylcatechol and hexamethylenimine. Each ketone hydrochloride was reduced to the corresponding secondary alcohol with the use of platinum oxide. Six quaternary salts of basic ketones (Table 11) were obtained by interaction of phenacyl bromide, 3,4-dimethoxyphenacyl bromide or chloroacetylcatechol with tertiary amines such as trimethylamine, N-methylhexamethylenimine and Nmethylheptamethylenimine. In two instances the quaternary salts of the basic ketones (compounds 3 and 5, Table 11) were reduced t o the
TABLEHYDROCHLORIDES
>
OF
MANNICH BASES
(4) HO
(3) CHaO R
1 Dimethylamino
OHCOCHzCHaR.HC1 M. p..
Yield,
OC.
%
Formula
Carbon Calcd. Found
.. .
...
Analyses, yo Hydrogen Chlorine Calcd. Found Calcd. Found
. . . .. .
184
73
CiiHi80aNCla
188-189
90
ClaHn08NCI 64.39 64.53 6.61 6.84 10.54 10.74
3 l-Hexamethyleniminob 166-168
60
CieHidOaNCl 61.24 61.53 7.71 7.86 11.30 11.63
4 1-Heptamethylenimino 163-165 46 (decompn.)
CnH2sOaNCl 62.16 62.27 8 . 1 4 7.99 10.82 10.97
2 Methylbenzylamino
(decompn.) (decompn.)
(decompn.)"
13.65 13.45
Calcd. % N, 5.39; found, 5.40. b The methobromide melted a t 164-165O (dec.) after recrystallization from methanol Anal.-Calcd. for ClrHaOiNBr: C. 54.85; H.,7.04; N. 3.76; Br, 21.47. Found: C. 54.65; H, 6.98; N. 3:83. Br. 21.40. This product precipitated from the reaction m:xture with one m4ecular equivalent of ethanol of crystallization which was last when the substance was heated at 110' for 3 hours. Compounds 1, 2, and 4 were recrystallized from absolute ethanol. (1
6
chlorides of the Mannich bases prepared from dimethylamine and hexamethylenimine hydrochlorides were reduced with the aid of platinum oxide to the corresponding secondary alcohols.
*
Received March 31,1958, from the College of Pharmacy. University of Michigan, Ann Arbor, Mich. Presented to the Scientific Section, A. Pa. A,. Detroit meeting, April 13, 1956. This paper represents part of a dissertation submitted by W. K . Johnson in partial fulfillment of the requirements for the Ph.D. degree in the University of Michigan, 1953. t The Upjohn Company Fellow. 1950-1953.
corresponding secondary alcohols by the use of platinum oxide. In order to obtain methyl-N,Nheptamethylene - (2 - hydroxy - 2 - phenylethy1)ammonium bromide it was necessary to allow methyl bromide to react with 1-(1-heptamethy1enimino)-2-hydroxy-2-pheny1ethane'
1 See W. K. Johnson, Doctoral Dissertation. University of Michigan. 1853.
July 1956
SCIENTIFIC EDITION EXPERIMENTAL
Mannich Reactions.-Hydrochlorides of the folowing secondary amines were used in the general procedure described below: dimethylamine, methylbenzylamine (l),hexamethylenimine (2),and heptamethylenimine (2). Acetovanillone' (0.1mole), 4.0Gm. of paraformaldehyde, 0.1 mole of the required amine hydrochloride and 200 cc. of absolute ethanol were refluxed for 24 hours. If the product did not separate from the cooled reaction mixture, the solvent was removed. The products are listed in Table I. In the following two instances, the basic ketone salt was reduced to the corresponding secondary alcohol. 1 (3 Methoxy 4 hydroxyphenyl) 3 dimethylaminopropanolHydrochloride.-The required basic ketone hydrochloride (10.0Gm.)was dissolved in 50 cc. of acetic acid and hydrogenated in the presence of 0.3 Gm. of platinum oxide catalyst under an initial pressure of 45 pounds. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The product melted at 171-172' (decompn.) after recrystallization from isopropyl alcohol; yield 4.0 Gm. (40%). And.-Calcd. for CI~H~OO~NCI: N, 5.35; C1, 13.24. Found: N, 5.26;C1, 13.36. 1 (3 Methoxy 4 hydroxyphenyl) 3 (1hexamethy1enimino)propanol Hydrochloride.-This compound was prepared in the manner described above in 87% yield; m. p. 148-150' (decompn.) after recrystallization from absolute ethanol. Anal.-Calcd. for C ~ ~ H ~ ~ O B N C,C60.96; I: H, 8.25; N, 4.44; C1, 11.23. Found: C, 61.03; H, 8.42; N, 4.55; C1, 11.05. Phenyl (1-hexamethy1enimino)ethyl Ketone Hydrochloride.-Phenacyl chloride (15.5 Gm., 0.1 mole), 9.9 Gm. (0.1mole) of hexamethylenimine, 6.0 Gm. of anhydrous sodium carbonate and 100 cc. of absolute ethanol were refhxed for 4 hours. The cold mixture was filtered and ethereal hydrogen chloride was added to the filtrate to precipitate the product; yield 11.7 Gm. (46%); m. p. 222-223' (decompn.) after recrystalliition from butanol. Ad.-Calcd. for ClrH2oONCI: N, 5.52; C1. 13.97. Found: N, 5.16; C1, 14.14. Phenyl ( 1-heptamethy1enimino)ethyl Ketone Hydrochloride.-This product was obtained in the manner described above by the use of heptamethylenimine; m. p. 220-221' (decompn.) after recrystallization from butanol; yield 43%. And-Calcd. for ClsHnONCI: N, 5.23; C1, 13.24. Found: N, 5.10; C1, 13.33. 3,4-Dihydroxyphenyl ( 1-hexamethy1enimino)methyl Ketone Hydrochloride.-This substance was prepared in the described manner with the use of chloroacetylcatechol~and hexamethylenimine except that the reaction mixture was not heated but was allowed to remain a t room temperature for 24 hours; m. p. 241-242' (decompn.) after recrystallization from methanol-ether; yield 47%. And-Calcd. for C~~H~OOSNCI: C, 58.75; H,
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* Obtained from the Marathon Corporation, Chemical Division, Rothschild, Wis. 8 Purchased from Winthrop-Steams.
441
7.06; N, 4.90; C1, 12.41. Found: C, 58.95; H, 7.30; N, 4.87; C1, 12.54.
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1 (1 Hexamethylenimino) 2 hydroxy 2phenylethane Hydrochloride.-The required basic ketone hydrochloride (10.2 Gm., 0.04 mole) was dissolved in 100 cc. of water and hydrogenated in the presence of 0.3 Gm. of platinum oxide catalyst under an initial pressure of 50 pounds; m. p. 173174" (decompn.) after recrystallization from ethanolether; yield 9.1Gm. (880Jo). Anal.-Calcd. for Cl,HnONCl: N, 5.48; C1, 13.86. Found: N, 5.38;C1, 13.96. 1 (1 Hexamethylenimino) 2 hydroxy 2(3,4-dihydrorpphenyl)ethane Hydrochloride.-The required basic ketone hydrochloride was reduced in the described manner; m. p. 161-163' (decompn.) after recrystallization from butanol; yield 86%. And-Calcd. for Cl,Hz,OaNC1: C, 58.42; H, 7.71; N, 4.87; C1, 12.32. Found: C, 58.72; H, 7.85; N, 4.22; C1, 12.36. 1 (1 Heptamethylenimino) 2 hydroxy 2phenylethane Hydrochloride.-By the described process, this compound was obtained in 65y0 yield from the required ketone salt; m. p. 152153' (decompn.)after recrystallizationfrom isopropyl alcoh01. And-Calcd. for ClsH2rONCl: N, 5.19; C1, 13.14. Found: N, 5.13; C1, 13.21.
N
- Methylhexamethy1enimine.-Hexamethylen-
imine (2)(29.7Gm., 0.3 mole), 46.5 Gm. of 35% formaldehyde, and 76.5 Gm. of 90% formic acid were heated on a steam bath for 12 hours. After the addition of 35 cc. of concentrated hydrochloric acid to the cold mixture, the solution was evaporated to dryness on a steam bath. The residue was dissolved in a minimum amount of water, sodium hyoxide was added to the solution and the amine was extracted with ether. From the dried extract, 27.7 Gm. (81.5%) of product was obtained; b. p. 137-139' (740mm.).l For characterization, the base was converted into the hydrochloride; m. p. 182-183' (decompn.). N-Methylheptamethy1enimine.-By the method described above, 113.0Gm. of heptamethylenimine (2)yielded 97.3 Gm. (78.5%) of product; b. p. 159-161" (734mm.). The hydrochloride melted a t 162-163' (decompn.). Thereported m. p. is 163-164' (2). 3,4-Dimethoxyacetophenone.-A mixture of 166 Gm. of acetovanillone and 450 cc. of water was stirred and heated on a steam bath. A solution was prepared from 150 Gm. of sodium hydroxide and 750 cc. of water, and 360 cc. of this solution was added to the mixture. Methyl sulfate (142 cc.) was then added at such a rate that the mixture refluxed. The mixture was refluxed for 45 minutes. An additional 30 cc. of methyl sulfate was added, followed shortly by 60 cc. of sodium hydroxide solution. After the last mentioned operation had been repeated two more times, the mixture was made strongly alkaline, extracted with ether. and then the extract was dried with magnesium sulfate. The product boiled a t 158-160" (8 mm.); m. p. 52-53'; yield 155 Gm. (86%). The reported b. p. is 158' (9mm.) (3)and the m. p. is 51' (corr.) (4). The quaternary salts of the basic ketones (Table 11)were obtained in the following manner. 4 G. R . Toy, (Doctoral Dissertation, University of Michigan 1951) prepared the base by a diEerent method; b. p . 1391140'; m. p. of the hydrochloride, 181.5-183.5".
442
JOURNAL OF THE
AMERICANPHARBIACEUTICAL ASSOCIATION
Compounds 1 and 2.-Phenacyl bromide (0.1 mole), 0.1 mole of N-methylhexamethylenimine (or N-methylheptamethylenimine) and 150 cc. of absolute ethanol were refluxed for 4 hours, and ether was then added to the cold mixture to precipitate the product. Compound 3.-Chloroacetylcatechol (10.8 Gm.), 4.8 Gm. of triniethylamine and 100 cc. of absolute
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Vol. XLV, No. 7
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Methyl N,N hexamethylene (2 hydroxy 2phenylethy1)ammonium Bromide.-The quaternary bromide (compound 5, Table 11) was hydrogenated in the manner described above; m. p . . 173-174' (decompn.); yield 66y0. And-Calcd. for ClsHuONBr: C, 57.31; H, 7.92; N, 4.46; Br, 25.42. Found: C, 57.44; H. 7.70; N, 4.19; Br, 25.64.
TABLE 11.-QUATERNARYSALTS OF BASICKETONES
RCOCHA' x+ R'
R
1 2 3 4 5
6
CsHs CsHs 3,4-(H0)zCsHa 3,4-(HO)zCeHa 3,4-(CH30)2CsH:< 3,4-( CH30)tCsHa Formula
1 2 3 4 5 6
ClsHnONBr ClsHlrONBr CiiHi6OOaNCI C2iH240ioN1 C17H2aOaNBr ClaHzsOaNBr
Yield.
X-
M p..
162-163 183-185 234-235 169-1 7 1 203-204 167-168
Br Br
hT(CH2)dCHa) N(CH2)dCHa) N(CH3h N(CHz)e(CHa) N(C&)s(CH3) N(CH2)7(CHs)
c1 Picratc Br Br
O C .
(decompn.) (decompn.) (decompn.) (decompn. ) (decompn.) (decompn.)
Carbon Calcd. Found
Analyses, Yo Hydrogen Nitrogen Calcd. Found Calcd. Found
57.68 58.90
7.10 7.41
7.41 7.66
7.04 7.32
... 7.12 7.52
...
&:85 55.97
57.90 58.73
...
54:82 55.63
... ...
4.49 4.29 5.70 11.38 3.76 3.63
...
4.45 4.07 5.66 11.56 3.69 3.37
5% 64 91 85 86 73 64
Halogen Calcd. Found
25.60 24.50 14.43
25.65 24.40 14.37
21:47 20.69
21:38 20.53
Compound 1 was recrystallized from ethanol-ether; 3 from methanol; 5 from ethanol; 6 from isopropyl alcohol.
ethanol were allowed to react at room temperature for 24 hours whereupon the product precipitated. Compound 4.-Chloroacetylcatechol (5.6 Gm.), 3.4 Gm.of N-methylhexamethylenimineand 50 cc. of absolute ethanol were allowed t o react at room temperature for 24 hours. The solvent was removed, the residue was dissolved in 2 liters of boiling water, and 10 Gm. of picric acid was added. The picrate precipitated from the cold solution. Compounds 5 and 6.-A mixture of 10.4 Gm. of 3,4-dimethoxyphenacyI bromide, 4.5 Gm. of Nmethylhexamethylenimine (or N-methylheptamethylenimine) and 50 cc. of absolute ethanol was refluxed for 4 hours. Ether was added t o the cold mixture t o precipitate the product. Trimethyl [2 hydroxy 2 (3,4 dihydroxyphenyl )ethyl] ammonium Chloride.-Trimethyl-3,4dihydroxyphenacylammonium chloride (compound 3, Table 11) (12.6 Gm., 0.06 mole), dissolved in 50 cc. of water, was hydrogenated under an initial pressure of 50 pounds in the presence of 0.3 Gm. of platinum oxide catalyst. The catalyst was removed by filtration and the solvent was removed under reduced pressure; m. p. 172-173' (decompn.) after recrystallization from methanol-ether; yield 5.0 Gm. (40%). Anal.-Calcd. for CllH1503NC1: N. 5.66; CI. 14.32. Found: N, 5.60; C1, 14.19.
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Methyl N,N heptamethylene (2 hydroxy 2phenylethy1)ammonium Bromide.-When the quaternary bromide (compound 6, Table 11) was hydrogenated as described above, a mixture of products was obtained from which methylphenylcarbinol was isolated in 55% yield. The carbinol was identified as the a-naphthylurethane; m. p. and mixed m. p. 105". The reported m. p. is 106' (5). The desired compound was prepared by the addition of a slight excess of methyl bromide to a n ethereal solution of 1- ( 1-heptamethylenimino)-2hydroxy-2-phenylethane. After a week the salt had precipitated in 45% yield; m. p. 167-169' (decompn. ) after recrystallization from butanol-ether. And-Calcd. for ClsHtaONBr: C, 58.53; H, 7.98; N, 4.27; Br, 24.35. Found: C, 58.27; H, 8.04; N, 4.23; Br, 24.18.
REFERENCES ( 1 ) Blicke, F. P.. and Lu, Chi-Jung. J . Am. Chem. Soc., 74 3933(1952) ?2) Blicke, F. F., and Doorenbos. N. J . , ibid.. 76, 2317
(1954). (3) Mannich. C.. and Neumann, P., Arch. Pharm., 248. 127(1910) (4) Finnemore H. J . Chcm. Soc 93 1515(1908). (5) Bickel, V. k., knd French, H.'E.,'J. Am. Chcm. Soc., 48. 749(1926).