[CONTRIBUTION FROM THE CHEMISTRY DEPARTMENT OF
THE
UNIVEBSITY OF MISSOURI]
THE BECKMANN REARRANGEMENT OF CERTAIN CYCLOHEXANONE OXIMES HERBERT E. UNGNADE
AND
A. DOUGLAS McLARENl
Received August 26, 1944
The Beckmann rearrangement of a-dkylcyclohexanone and cyclopentanone oximes may lead to two possible structural isomers. In all such rearrangements reported in the literature, single substances were obtained in which the nitrogen was attached to the alkyl substituted carbon (1,2). In the present investigation mono-, di- and tri-alkylcyclohexanone oximes have been rearranged. The cyclohexanone oximes with one a-alkyl group gave single products which had the 2-keto-7-alkylhexamethyleniminestructure, even when other alkyl groups were present on other ring carbons. Wallach's rearrangements of menthone oxime (3) and tetrahydrocarvone oxime (4) represent additional cases of this kind. The only known exception is the rearrangement of 2,4,4-trimethylcyclohexanone oxime which gives a mixture of the two possible products (5). Unsymmetrical alkylcyclohexanone oximes without a-substituents have been found to give mixtures of isomers upon rearrangement (6). Two new examples have been investigated. Under identical conditions all cyclohexanone oximes gave essentially the same yield of lactams. The type of alkyl group had apparently no effect on the rearrangement and the reaction took place readily with a 2,6-dialkylcyclohexanone oxime. The st,ructures of the lactams (I) were established by hydrolysis t o the amino acid hydrochlorides (11)and degradation of the latter by means of the haloform reaction. ( CHR)r -C=O
I
CHa CH-NH I
1
-
( CHR)*-CO OH
I CHa CH--NHZ
HC1
I1 R = H or methyl
- 1
(CHR)r-COOH COOH
+ CKIa
I11
The yield of iodoform and the dibasic acids (111) was low. The degradation of the known 6-aminoheptanoic acid (11, R = H), on the other hand, gave an equally small yield of iodoform and adipic acid. In view of the low yields of iodoform, 6-amino-3,5-dimethylheptanoicacid was first converted to the 6-keto acid by the action of nitrous acid and subsequent oxidation of the hydroxy acid with chromic acid, and then oxidized with hypoiodite. The yield of iodoform was no larger than in the previous case. In order to eliminate the possibility that branched chain acids without the requisite grouping-CH(NH-JCHa might give iodoform due to side reactions, 6-amino-4-methylhexanoic acid was treated with sodium hypoiodite under identical conditions, but no iodoform was found. From the Ph.D. thesis of A. Douglas MoLaren, 1943. 29
30
H. E. UNGNADE AND A. D. MCLAREN
The structure of 6-amino-2,7,7-trimethyloctanoiclactain has been established by degradation with nitrous acid and oxidation t o the keto acid. The isomeric rearrangement product cannot form a keto acid in this manner. Eight pure lactams have been converted to the amino acids. The results are reported at this time since this work mill have to be discontinued for the duration of the war. TABLE I ALHYWYCLOHEXANONES CYCLOHEXANONE
4-Methyl 3-Ethyl cis-3,5-Dimethyl ttans-2,5-Dimethyl trans-2,4-Dimethyla 3,4-Dimethyl 2-t-Butyl-4-methyl 2,4,6-Trimethyl
"y'i
B.P.,
"L'.
168-168.2 189-191.5 178-179.3 174-175.8 80 176.8-177 77 186.4-188 30-86 213.5-215.3 187-1881 70 74 84 65 90
70
193-194h
1 1 9 S g
SEYICARBAZONE M.P., OC.
1
.._I OXIME
B.p.,"C.
I Mm.
____-
1.4448 192-193 1.4511 181-182 1.4417 197.5-198 1.4452 167-168 1.4461 192-193 1.4513 184-185 1.4562 159-16od 1.4451 216.5-217.5 dec 1.4472 173-174'
.
104-110 110-112.5 142-143
5 3 4
109-114*
5
125-127
21
M.p., "C.
37-39 liq. 77-77.5 108.5-109.5 96-97 liq. 84.6-86* 40-41a 139.5-140.5i
* The trans configuration was arrived a t by application of v. Auwers-Skita rule t o the dimethylcyclohexanes (9). The same rule applied to the isomeric ketones would lead t o the opposite configuration (10). The configuration of the 2,5-isomer is subject t o the same uncertainty. b Anal. Calc'd for C8HlaNO: C, 68.08; H, 10.64. Found: C, 67.76; H, 10.94. c d: 0.8941; M, (calc'd) 50.81; M, (found) 50.95. Anal. Calc'd for CllHtOO: C, 78.55; H, 11.90. Found: C, 78.81; H, 12.27. *Anal. Calc'd for CItHtaNOa: C, 64.05; H , 10.02. Found: C, 64.24; H , 10.03. Both the solid and liquid isomers of the cyclohexanol gave this same ketone on oxidation. The mixture of the semicarbaaones did not show a melting point depression. Calc'd for CllHtlNO: C, 72.13; H, 11.42. Found: C, 72.30; H, 11.87. e Anal. The constants reported are for the ketone obtained by oxidation of the solid isomer. The ketone derived from the liquid isomer boiled at 184-188', n z 1.4453. Anal. Calc'd for CpHt,NO: C, 69.85; H, 10.97. Found: C, 69.69; H , 11.15. h d: 0.8906; M, (calc'd) 41.57; M, (found) 41.86. Anal. Calc'd for CoHlaO: C, 77.18; H , 11.41. Found: C, 76.76; H, 11.56. Calc'd for CloHleNOs: C, 60.91; H, 9.64. Found: C, 60.69; H, 9.50. 3 Anal. i Anal. Calc'd for CoHlrNO: C, 69.85; H, 10.97. Found: C, 69.66; H, 10.88.
Acknowledgment : The authors wish to thank the University Research Council for funds to purchase chemicals used in this investigation. EXPERIMENTAL*,
The starting materials for this investigation, a series of alkylcyclohexanols, have beeu described in a previous communication from this laboratory (7). The corresponding cyclohexanones were obtained in good yields by oxidation with sodium dichromate and sulfuric P
a
Analyses by A. D. McLaren, J. R. Janes, and A. Ludutsky. All melting points uncorrected.
31
REARRANGEMENT OF CYCLOHEXANONE OXIMES
acid essentially as described for the preparation of menthone from menthol (8). The temperature wm kept at 5" during the addition of the calculated amount of sodium dichromate dissolved in one half of the aqueous sulfuric acid, to the cyclohexanol mixed with the other half of the acid solution. The mixture was then warmed t o 60" on a water-bath and allowed to cool overnight with stirring. The cyclohexanones were isolated by extraction with benzene and distillation under atmospheric pressure. Purification by way of the bisulfite addition compounds was unnecessary. The structure of the cyclohexanols had no apparent influence on the yield of the ketones. The constants of the cyclohexanones, their semicarbazones and oximes are given in Table I. TABLE I1 BECICMANN REARRANGEMENT -
% CARBON CSCLOBEXANONE
OXIME
2-RETOHEXAMETHYLENINIINE
se
8-
M.P.,
% HYDROGEN
"C.
s ___ 2-Methyl
7-Methyl
67
+Methyl
5-Met hyl
62
9.590.5O *41-42b
cis-3,5-I>imethyl
4,6-Dimethyl
45
122-123
traits-2,-l-I)imethyl 5,7-Dimethyl
53
trans-2,5-I)imethyl 4,7-Dimethyl
71
183.5134.5 135-126
67 73 57 77 69
3,4-Dimethyl 2,3,5-Trimethyl 2,4,6-Trimethyl 3-Ethyl 2-t-Butyl-4methyl
4,5- and 5,6Dimethylo 4,6,7-Trimethyl 3,5,7-Trimethyl 4- and 6-Ethylc 5-Methyl-7-tbutyl
I 1
1453.5' 148.5 142-149 8 68.1068.0210.91 10.62 153
21
67.73 68.02 10.94 10.62 68.1768.0210.7810.62
liq.
15321 153.8 164-166 21
137-138 3 5-75 liq. 105-106
162-163 21 149-151 21 166-16821 168-17021
69.71 69.85 10.79 10.97 69.5769.85 11.04 10.97 67.7968.02 11.07 10.62 72.2872.1311.71 11.42
68.02 68.02 11.03 10.62
-
Hildebrand and Bogert (1) give the m.p. as 90-91". b Wallach (13) reported this compound as a liquid which failed to crystallize. c A similar mixture from 3-methylcyclohexanone oxime was separated by Wallach (6) by fractional crystallization. A mixture of isomers is t o be expected from an unsymmetrical cyclohexanone without &ha-substituents. Attempted separations were, however, unsuccessful. (1
The oximes were prepared by stirring a solution of two moles of the cyclohexanone with water (IO00 cc.), ethyl alcohol (500 cc.), and hydroxylamine sulfate (2.5 moles).' The mixture was brought to pH 6.8 by slow addition of 35% aqueous sodium carbonate and stirred for two hours. When the oximes did not crystallize from the reaction mixture they were extracted with ether and distilled under reduced pressure through a two-foot column packed with Pyrex helices. The average yield was 8070. The oximes of 2-t-butyl-4-methylcyclohexanone and 2,4,6-trimethylcyclohexanonecould not be obtained by this method. They were prepmed by refluxing the ketone, hydroxylamine hydrochloride, methanol, and powdered potassium carbonate for a period of a t least six hours. The oximes crystallized 4 The authors are indebted t o the Commercisl Solvents Co. for a generous sample of this compound.
32
H. E. UNGNADE AND A. D . MCLAREN
after addition of water. The semicarbazones of these two ketones were prepared similarly by using semicarbazide hydrochloride in the place of hydroxylamine hydrochloride. The Beckmann rearrangements were carried out by the procedure of Marvel and Eck (11). The experimental data and the constants for the 2-ketohexamethyleniminesare listed in Table 11. The substituted +caprolactams were then hydrolyzed t o the amino acid hydrochlorides, which were analyzed unless they were too hygroscopic for this purpose. When the hydrochlorides were not tractable they were converted t o the free amino acids according t o the procedure of Eck (12). The melting points and analyses of the amino acids and their hydrochlorides are given in Table 111. Haloform degradation. The best results were obtained when the amino acids or their hydrochlorides were oxidized with sodium hypoiodite in aqueous dioxane (14). Results (yield of isolated iodoform) : 6-amino-4-methylheptanoic acid 9.8%, 6-amino-3-methylhepTABLE I11 AMINOACIDS ACID, 6-AMINO
M2.F
CARBON,
"c.
%
HYDROGEN,
%
NITROGEN,
%
Found Calc'd 'Found Calc'd Found Calc'd _
Heptanoio 4-Met hylhexanoic 3,5-Dimethylhexanoic 4-Methylheptanoic 3-Met hyl heptanoic 3,5-Dimethylheptanoic 2,4-Dimethylheptanoic 4,7,7-Trimethyloc tanoic
_
193-195b 170-172.5157.65 160-164 i60.18 194-195.51 208-210 60.18 189-190.559.36 171-173.5 190-191 62.87
_
_
_
_
_
_
_
_
.
HYDROCH~OBIDE, X.P.,
c.
~
57.93 11.00 10.34 60.38 10.47 10.69 8.49 8.81 60.38 10.84 10.69 59.34f 11.07 10.98f 7.78 7.69 7.84 8.10 62.88' 11.36 11.42'1
131.5-132.8c 100-103d liq. 141.5-143' liq. 142.2-144.10 gummy 192-195'
0 All melting-points in this table were determined with a 4' rise in temperature per minute. b Hildebrand and Bogert (1) report m.p. 196-197.5' (con.). Calc'd for CTHlaClNOZ: C, 46.28; H , 8.81. Found: C, 46.04; H, 9.02. c Anal. * Hygroscopic. Calc'd for CgHlgClN02: C, 49.10; H, 9.22. Found: C, 48.81; H, 9.47. a Anal. f Calc'd for COHISO~N.QH~O. Calc'd for CsH&INOz: C, 51.55; H, 9.55. Found: C, 51.36; H, 9.61. 0 Anal. h Calc'd. for C11H*sN02+QH*O. i Anal. Calc'd for ClIH2&1N02: C, 55.60; H, 10.11. Found: C, 55.61; H, 10.39.
tanoic acid IO%, 6-amino-3,5-dimethylheptanoicacid %I%, 6-amino-2,4-dimethylheptanoic acid 2.6%' 6-aminoheptanoic acid 11.O%, and 6-amino-4-methylhexanoicacid 0.0%. The dibasic acids were isolated in three representative cases by acidifying the filtrate with sulfur dioxide, saturating with ammonium sulfate and extracting. The first chloroform extract containing traces of oily material waa discarded. Subsequent repeated extractions with ether gave the adipic acids. 6-Aminoheptanoic acid gave adipic acid, m.p.147.5149" (crystallized from nitric acid). Mixed with an authentic specimen i t melted a t 147.5151'. From 6-amino-3-methylheptanoic acid was obtained dl-3-methyladipic acid, m.p. 91-92" (from benzene and petroleum ether). Mixed melting-point with synthetic material (m.p. 95-96') m.p. 91-93". 2,4-Dimethyladipic acid was obtained from 6-amino-3,5dimethylheptanoic acid as an oil. No derivatives of the liquid racemate have been described. dl-5-Methyladipic acid. trans-4-Methylcyclohexanol(20 g.) was dehydrated by refluxing with p-toluenesulfonic acid (2 g,). A mixture of hydrocarbon and water distilled at 80.5" (749 mm.). It was separated, the hydrocarbon dried and distilled; b.p. 102-102.5" (749 mm.).
REARRANGEMENT OF CYCLOHEXANONE OXIMES
33
Oxidation of this hydrocarbon (3.7 9.) with potassium permanganate (14.8 g.) in water (93 cc.) at 0' gave 0.5 g. of 3-methyladipic acid melting a t 95-96" (from benzene). Stepwise degradation. 6-Amino-3,B-dimet hylheptanoic acid hydrochloride (2.0 g.) was dissolved in water (10 cc.) and treated with an equivalent amount of sodium nitrite a t 5". After stirring for one hour, one equivalent of acetic acid was added and the mixture allowed to warm t o room temperature. The product separated as an oil. It was brought into solution by addition of dioxane. The hydroxy :kcid was oxidized with equivalent amounts of 20y0 aqueous sodium dichromate and sulfuric acid. The reagents were added with stirring while the temperature of the mixture was held below 15". Then the mixture was slowly heated on a water-bath. a f t e r cooling, the mixture was poured into water and the resulting solution csxtracted with chloroform. The eitract left an oil on evaporation which boiled a t 145-157" (21 mm.). The main portion boiled a t 145-147" (21 mm.); yield0.6 g . Oxidation of this product with sodium hypoiodite gave 100 mg. (7%) of iodoform. SUXMIRY
A series of alkylcyclohexanone oximes has been prepared and rearranged. The resulting lactams have been converted to amino acids and their structures established. In the rearrangement of alkylcyclohexanone oximes with one alpha substituent the nitrogen becomes preferentially attached to the substituted alpha carbon. COLUMBIA, Mo. REFERENCES (1) HILDEBRAND, JR.,AND BOGERT, J . A m . Chem. Soc., 68,650 (1936) (2) WALLACH, Ann., 389, 169 (1912). (3) WALLACH,Ann., 278, 304 (1894). (4) WALLACH, Ann., 323, 324 (1902). (5) WALLACH, Ann., 346,258 (1906). ( 6 ) WALI~ACH, A m . , 346, 253 (1906). (7) UNGNADE AND MCLAREN, J . A m . Chem. Soc., 66, 118 (1944). (8) SANDBORN, Org. Syntheses, Coll. Vol. I, p. 333 (1932). (9) SKITA,Ann., 427, 275 (1922), Ber., 66, 2234 (1923). (10) GODCHOT AND BEDOS, Compt. rend., 180, 751 (1925). (11) MARVEL AND ECK,Org. Syntheses, 17, 60 (1937). (12) ECK,Org. Syntheses, 17, 7 (1937). (13) WALLACH, Ann., 346,252 (1906). (14) FCSONAND TULLOCK, J . A m . Chem. Soc., 66, 1638 (1934).
