THE ACTION OF GRIGNARD REAGENTS ON OXIMES. I. THE

[CONTRIBUTION FROM TBF, DEPARTMENT OF CHEMISTRY, UNIVERSITY OF NOTRE DAME]

THE ACTION OF GRIGNARD REAGENTS ON OXIMES. I. THE ACTION OF PHENYLMAGNESIUM BROMIDE ON MIXED KETOXIMES KENNETH N. CAMPBELL AND JAMES F. McKENNA

Received February 17, 1939

Very few studies have been made on the reaction between Grignard reagents and oximes. Busch and Hobein' report the formation of diphenylanilinomethane instead of the expected hydroxylamine, when benzaldoxime was treated with phenylmagnesium bromide. Diels and ter Meer2 found that no reaction occurred when diacetyl monoxime was treated with methylmagnesium iodide, but that the 0-methyl ether reacted normally, through the carbonyl group, to give the corresponding carbinol. I n a study of the action of Grignard reagents on isonitrosoketones, Orekoff and TiffeneauSfound that the carbonyl group alone reacted. Angeli and his co-workers4 obtained the expected disubstituted hydroxylamine from the action of phenylmagnesium bromide on the N-phenylether of benzaldoxime. Hoch5in recent years has studied the action of Grignard reagents on various ketoximes. He reportedba that propiophenone oxime reacted with phenylmagnesium bromide to give a compound (I) of the formula C16I16N, and a second substance (11) of the formula CI~II,NO. He assigned to compound I the ethyleneimine structure, and to compound I1 the structure of a hydroxylamine. CHs-CH-C(CaHs)z \/

H

H I

CHsCHz--C-

(CB6)l

I &HOH

I1

According to Hoch, propiophenone oxime and ethylmagnesium bromide yielded solely an ethylene imine and no hydroxylamine. Later papers of Hoch's have dealt with the action of Grignard reagents on benzophenone oximesband alpha-trisubstituted acetophenone oximes.6c B U ~ CAND H HOBEIN,Ber., 40,2096 (1907). DIELSAND TER MEER,ibid., 42, 1940 (1909). 3 OREKOFF AND TIFFENEAU, Bull. 800. chim., 41, 839 (1927). 4 ANQBLI, ALLESSANDRI, AND AIAZZI-MANCINI, Chem. Zentr., 1911, 11, 606. 6 ( a ) , HOCH,Compt. rend., 196, 1865 (1934); ( a ) , ibid., aOS, 799 (1936); (e), ibid., 204, 358 (1937). 198 1 2

199

ACTION OF GRIGNARD REAGENTS ON OXIMES

Some years ago, when the late Professor Stieglitz was studying the rearrangements of substituted hydroxylamines, he and his students investigated the possibility of preparing them by the action of Grignard reagents on mixed ketoximes. This work resulted in the discovery of what was, apparently, a new type of rearrangement, the migration of a nitrogen atom from one carbon atom to another, for instead of the expected hydroxylamines, which would be formed in accordance with equation I, the products were beta-amino alcohols, formed in accordance with equation 11. The nitrogen atom which was originally attached to carbon atom 1 has migrated to carbon atom 2.

R (1)

RMgX

+

R’C-CH2R‘’

II

I I

R‘C-CHnR”

Ha >

NOH

NHOH R

(11)

RMgX

+

i

a

R’C-CHaR”

II

NOH

2

\1

Ha >

R’C-CHR”

I

I

HO NH2

Stieglitz and his students confined their studies to the reaction between phenylmagnesium bromide and the oximes of acetophenone,6 propiophenone,’ desoxybenzoin,8and benz~phenone.~We are continuing the work on this problem, and have under investigation the action of aliphatic and aromatic Grignard reagents on alkyl, aryl, and mixed ketoximes. 1n.this paper we are reporting the results of a study of the reaction between phenylmagnesium bromide and mixed ketoximes. 6 J. E. COLE,Doctoral Dissertation, University of Chicago, 1929. Acetophenone oxime reacted with a concentrated solution of phenylmagnesium bromide to yield l,l-diphenyl-l-hydroxy-2-aminoethane. 7 (a) W.E. STUBGEON, Doctoral Dissertation, Chicago, 1929. (b) G. H. LOVINS, Maater’s Dissertation, Chicago, 1934. Propiophenone oxime reacted with a concentrated solution of phenylmagnesium bromide to give l,l-diphenyl-l-hydroxy-2aminopropane. Since the structure of this compound waa not unequivocally established, and since Hoch reported that the reaction yielded a hydroxylamine, we have reinvestigated the reaction. 8 K. N. CAMPBELL, Doctoral Dissertation, Chicago, 1932. Desoxybeneoin oxime reacted with phenylmagnesium bromide to give the expected 1,1,2-triphenyl-lhydroxy-2-aminoethane, but the yields were very poor, and a variety of by-products were isolated. 9 CAMPBELL, Zoc. cit. In this case, since there is no alpha hydrogen atom, an amino alcohol wm not obtained. The product waa identified as o-phenylbenzhydrylaniline by means of analyses, hydrolysis to aniline and 9-phenylfluorene, and by comparison with an authentic sample which waa kindly supplied by Professor Henry Gilman. This work confirms t h a t of Hoch,@which appeared later.

200

KENNETH N. CAMPBELL AND JAMES F. MCKENNA

As stated earlier, HochSareported that propiophenone oxime and phenylmagnesium bromide gave a hydroxylamine and an ethylene imine. The physical constants given by Hoch for the hydroxylamine and its derivatives are identical with those reported by Sturgeon7" and by L ~ v i n for s ~ the ~ compound they assumed to be 1,1-diphenyl-1-hydroxy-2-aminopropane and its derivatives. We have prepared the compound by the procedure of Sturgeon (Hoch gave very meagre experimental data) and have also synthesized it from alanine ester hydrochloride and phenylmagnesium bromide.I0 The product from both methods was identical, and hence the substance must be 1,l-diphenyl-l-hydroxy-2-aminopropane,and not a hydroxylamine, as erroneously assumed by Hoch. We have not obtained any product corresponding to the ethyleneimine of Hoch under the conditions we used. We have also studied the action of phenylmagnesium bromide on the oximes of p-methylacetophenone, p-chloroacetophenone, and methyl a-naphthyl ketone. The expected amino alcohol was obtained in each case, and its identity was established by direct comparison with a sample synthesized in another way. The ketoximes do not react readily with phenylmagnesium bromide*, and it is necessary to use a large excess of Grignard reagent, to concentrate the Grignard reagent, and to add the oxime at an elevated temperaturet. When the Grignard reagent is sufficiently concentrated, a definite color change takes place. Calculations made from the amount of ether originally used and that recovered on concentration indicate that the color change occurs when about one mole of ether remains per mole of Grignard reagent. Instead of concentrating the Grignard reagent, about half of the diethyl ether may be replaced by diiioamyl ether, and the reaction may be run at the same temperature as with the concentrated reagent. The amino alcohol is obtained in about the same yields, and the method presents no advantages. When, however, part of the diethyl ether is replaced by toluene, the reaction seems to take a different course, but the products have not yet been identified. EXPERIMENTAL

1,I-Diphenyl-I-hydroxy-I-aminopropane

Propiophenone oxime.-This was prepared by a method similar to that of L ~ v i n s . ' ~ Forty grams of ketone, 24 g. of hydroxylamine hydrochloride, 25 g. of sodium hydroxide and 150 cc. of 95% alcohol were refluxed for one hour and allowed to stand over10

THOMAS AND BETTZIECHE, 2. physiol. Chew., 140, 251 (1924).

* Unpublished results of Campbell and Hess show that the ketoximes react much more readily with aliphatic Grignard reagents, but that in this case the reaction does not seem to take the same course. f The optimum temperature of an oil-bath surrounding the reaction flaskis about 160-165', although this varies somewhat with the different oximes.


201

night. The product, which weighed 37 g., was purified by conversion t o the sodium salt and subsequent liberation by dilute sulfuric acid. The purified oxime melted

at 53-55'. Effect of temperature on reaction of propiophenone oxime with phenylmagneaium bromide.-Since the temperature at which the reaction is carried out greatly affects the course of the reaction, a preliminary study was made to determine a suitable temperature. Ether was distilled from an ethereal solution of phenylmagnesium bromide until the color changed from brown t o grey-green. This color change occurred when the temperature within the reaction flask reached about 135" (the oilbath temperature was 160'). Dry propiophenone oxime was then added at different temperatures. At 115" there was little reaction, at 125" the reaction was mild, while at 135" (inside temperature) the reaction was vigorous and exothermic, and a dense white smoke was evolved. At this point the temperature of the oil-bath was 160-165".

3

Reaction of propiophenone oxime with phenylmagnesium bromide.'-Phenylmagnesium bromide was prepared in the usual way from 20.4 g. (0.84 mole) of magnesium turnings, 350 cc. of ether and 131.5 g. of phenylbromide, in a 1-liter, 3-necked flask. The water in the reflux condenser was turned off, and the flask was heated in an oil bath until the latter reached 160", and the Grignard color change took place. This occurred when about 270 cc. of ether had been recovered, and about 78 cc. (0.74 mole) remained in the flask. Water was again allowed to circulate in the reflux condenser, and 25 g. (0.167 mole) of dry, finely powdered propiophenone oxime was added in portions t o the concentrated Grignard reagent while the oil bath temperature was maintained at 155-165". Heating and stirring were continued for thirty minutes after the addition of the last portion of oxime, and the mixture was then allowed to cool somewhat. It was hydrolyzed by slow addition t o a mixture of 200 cc. of concentrated hydrochloric acid and 800 g. of ice. The acid solution was extracted with several portions of ether t o remove unreacted oxime and other nonbasic impurities. These extracts were discarded. The acid solution was filtered to remove material not extracted by the ether. The solid so obtained weighed 21 g., and on recrystallization from absolute alcohol-ether yielded 3.8 g. of 1, l-diphenyl1-hydroxy-2-aminopropanehydrochloride. The rest was tar. The aqueous acid filtrate was treated with a few grams of ammonium chloride and made basic with ammonium hydroxide. The alkaline solution was extracted several times with ether; the ether extracts were dried over potassium carbonate and refluxed to remove dissolved ammonia. Hydrogen chloride gas was then passed in until no more precipitate appeared. There was obtained 8.3 g. of alkamine hydrochloride, m.p. 246-247". The total yield of the amino alcohol hydrochloride was 12.1 g., or 27% of the theoretical amount. The free base was prepared by shaking 1.0 g. of the hydrochloride with 20 cc. of 10% sodium hydroxide solution and taking the product up in ether. The material remaining after evaporation of the ether was recrystallized from benzene and ligroin and then melted at 103-104". The benzamide was prepared by treatment of the hydrochloride with 10% sodium hydroxide and benzoyl chloride. It melted a t 189.5-190.5". Preparation of 1,l-diphenyl-1-hydroxy-3-aminopropanefrom alanine eater hydrochloride.-The procedure of Thomas and Bettzieche,lo was used. A Grignard reagent $ CAMPBELL,loc. cit., observed t h a t desoxybenzoin oxime reacted with phenylmagnesium bromide when the oil bath temperature was 160-165", and Bloch (Doctoral Dissertation, Chicago, 1936) found the same temperature most satisfactory for the reaction of acetophenone oxime with the Grignard reagent.

202


prepared from 8 g. of magnesium, 326 cc. of ether and 80 g. of bromobenzene w m treated with 10.2 g. of alanine ethyl ester hydrochloride, t o yield 15.1 g. of 1,l-diphenyl-1-hydroxy-2-aminopropane(99% of the theoretical). Portions of the alkamine were converted to the hydrochloride and benzamide. For a comparison of these products with those obtained above, see Table 1. I-Phenyl-1-p-tolyl-I-hydrozyJ-arninoethane p-MethyEacetophenone.-The procedure of Adams and Noller11 was used. From 540 g. of toluene, 375 g. of aluminum chloride, and 102 g. of acetic anhydride there was obtained 114 g. of p-methylacetophenone, b.p. 101"/15mm. p-Methylacetophenone ozime.-A mixture of 30 g. of ketone, 100 cc. of 95% alcohol, a saturated aqueous solution of 19 g. of hydroxylamine hydrochloride and a saturated aqueous solution of 43 g. of sodium hydroxide was boiled under B reflux condenser for three hours. The cooled mixture was poured into an equal volume of water and neutralized with dilute sulfuric acid. The mixture was allowed to stand for fifteen minutes, the oxime was then collected and washed with about 700 cc. of water. The dried crude material weighed 32 g., a 95% yield. After recrystallization from lowboiling petroleum ether i t melted at 85-87'.

COMPOUND

F B o ~ 8 T ~ ~ NFBOY ' OnUD

MIXl'U~

IIOCH'B 8TUBHIDBOXOEON'B YLACOMPOUND

-~ 103-104 103-104 Free base .................... 103-104 246-247 246-247 Hydrochloride.. . . . . . . . . . . . . . 246-247 Benzamide. . . . . . . . . . . . . . . . . . 190.5-191.5 189.5-190.5 189.5-191

103 258

189

103-104 246-247 191

Reaction of p-methylacetophenone oxime with phenylmagnesium brmnide.-A Grignard reagent was prepared from 30.4 g. (1.25 mole) of magnesium, 450 cc. of ether and 210 g. of bromobenzene. Ether was distilled off until the color change occurred. A t this point 333 cc. of ether had been recovered, leaving 117 cc. (1.13 mole) in the flask. p-Methylacetophenone oxime (36.7g., 0.25 mole) was added in small portions to the concentrated Grignard reagent, while the oil bath was kept a t 155-160". Stirring and heating were continued for ten minutes after the last portion of oxime was added. The somewhat cool reaction product was poured onto 800 g. of ice, and the mixture made slightly acid with concentrated hydrochloric acid and extracted three times with ether. Distillation of this ether extract yielded 2.0 g. of biphenyl and a considerable amount of tar. The aqueous acid solution was then made basic with ammonium hydroxide and was again extracted with ether. This extract, after drying over potassium carbonate, was evaporated to dryness to yield 17.0 g. of amino alcohol, a 30.4% yield. After recrystallization from absolute alcohol the substance melted a t 107-108". The hydrochloride was prepared and repeatedly recrystallized from absolute alcohol-ether mixture. The benzamide was prepared by the Schotten-Baumann reaction and purified by recrystallization from benzene and petroleum ether. The alkamine nitrate was made by dissolving a portion of the alkamine in 8% hydro11

NOLLER AND ADAMS,J . Am. Chem. SOC., 46,1889 (1924).

203


chloric acid, and adding ammonium nitrate. After several hours the nitrate precipitated, and was recrystallized from absolute alcohol-ether mixture. Preparation of 1-phenyl-1-p-tolyl-1-hydroxy-9-aminoethane from a-aminoacetophenone hydrochloride and p-tolylmagnesium bromide.-The procedure of McKenzie, Mills and Myleslz was used, with double quantities. A 43% yield of amino alcohol was obtained. This substance, after recrystallization from benzene and petroleum ether, melted a t 107-108". Portions of i t were converted t o the hydrochloride, nitrate, and benaamide. For a comparison of these substances with those obtaiwd from the oxime reaction, see Table 11. 1-Phenyl-l-cY-naphthyl-l-hydrozy-9-aminoethane

Methyl or-naphthyl hetotime.-Methyl a-naphthyl ketone was prepared from naphthalene by the procedure of St. Pfau and Ofnerls and separated from the p-isomer by means of the picrate. Thirty grams of methyl a-naphthyl ketone (b.p. 166167"/12 mm.), 125 cc. of 95% alcohol, B saturated aqueous solution of 24 g. of hydroxylamine hydrochloride, and a saturated aqueous solution of 28 g. of sodium hydroxide were boiled under reflux for five hours. The solution was allowed t o stand for several hours, and was then diluted with an equal volume of water and acidified with TABLE 11 MELTINGP O I N T S OF 1-PHENYL-1-P-TOLYL-1-HYDROXY-2-AMINOETHANE AND DERIVATIVES A.Y1No KETONR

COMPOUND

Free base.. . . . . . . . . . . . . . . . . . . . . . . . . Hydrochloride ..................... Nitrate.. .......................... Benaamide. .......................

,

107-108 183-184 175-176 145-146

FROM OXIMR

107-108 182-183 174-175 143-145

MIXTURI

107-108 182-182.5 176 143-145

dilute sulfuric acid. The oxime obtained weighed 32 g., a 98% yield. After recrystallization from 50% alcohol it melted at 136.5-137.5'. Reaction of methyl a-naphthyl ketozime with phenylmagnesium bromide.-The Grignard reagent was prepared from 20.4 g. (0.84 mole) of magnesium, 142 g. of bromobenzene and 300 cc. of ether. The color change occurred when 190 cc. of ether had been recovered, leaving 1.0 mole in the flask. The oil bath was maintained at about 170" while 21.1 g. (0.114 mole) of methyl a-naphthyl ketoxime was added. Heating and stirring were continued for an additional ten minutes. The product was poured onto 700 g. of ice and made faintly acid with hydrochloric acid. Most of the amino alcohol hydrochloride, mixed with tar, separated at this point. The acid aqueous solution was extracted with ether, and was then adjusted t o a pH of about 5. Ammonium nitrate was added, and the solution was allowed t o stand for several hours, when a precipitate of alkamine nitrate (2.2 9 . ) separated. The total yield of alkamine salts was 35.5%. The free base and the benzamide were prepared by the usual methods. Preparation of I-phenyl-la-naphthyl-1-hydroxy-9-aminoethanefrom a-amino~~~~

MCKENZIE,MILLS,AND MYLES,Ber., 63, 904 (1930). 13 ST.PFAU AND OFNER,Helv. Chim. Acta., 9, 669 (1926).

12

204


acetophenone hydrochloride and a-naphthylmagnesium bromide.-The method of LuceI4 was used. Ten grams of the amino ketone hydrochloride was added t o CL. Grignctrd reagent prepared from 8.5 g. of magnesium, 91 g. of a-bromonaphthalene and 350 cc. of ether. A 99% yield of amino alcohol hydrochloride (19.0 g.) was obtained. The free base, nitrate, and benzamide were made. For a comparison of these derivatives with those obtained above, see Table 111. 1-Phenyl-i-p-chlorophenyl-1-hydroxy-8-aminoethane

p-Chloroacetophenone oxime.-This was made from p-chloroacetophenonels in a manner similar to that described for methyl a-naphthyl ketoxime. Thirty grams of ketone, 43 g. of sodium hydroxide and 19 g. of hydroxylamine hydrochloride TABLE 111 MELTINGP O I N T S

O F 1-pHENYL-1-a-NAPHTHYL-1-HYDROXY-2-AMINOETHANEA N D

DERIVATIVES COMPOUND

Free base .......................... Hydrochloride. .................... Nitrate. ........................... Benzamide ........................

FROM AMINO KETONE

162-163 237 202 194-195

FROM O X I M D

MIXTURE

161-162 237 203.5

161 236.5 204

TABLE IV MELTINGPOINTS

O F 1-PHENYL-1-P-CHLOROPHENYL-l-HYDROXY-2-AMINOETHANE AND

DERIVATIVES COMPOUND

Free base.. ........................ Hydrochloride ..................... Nitrate. ........................... Benzamide. .......................

FROM AMINO KETONE

121.5-122 203 183 147-148

FROM OXIME

121.5-122 203 182-182.5 147-148

1

MIXTURE

121.5-122 203 182.5 147-148

yielded 31 g. of oxime, a 93.5% yield. After recrystallization from 50% alcohol the product melted a t 97.5-98'. Reaction of p-chloroacetophenone oxime with phenylmagnesium bromide.-A Grignard reagent made from 20.4 g. (0.84 mole) of magnesium, 142 g. of bromobenzene and 300 cc. of ether was concentrated until the color change occurred. There was recovered 206 cc. of ether, leaving 94 cc. (0.91mole) in the flask. The Grignard reagent was treated with 25 g. (0.15 mole) of p-chloroacetophenone oxime, while the oil bath was maintained at 160'. Heating and stirring were continued for an additional thirty minutes. The product was poured onto 700 g. of ice, acidified with hydrochloric acid and extracted with ether. The pH of the aqueous layer was then adjusted to about 5 by the addition of ammonium hydroxide. About 50 g. of am~~~

~

LUCE, Compt. rend., 180, 145 (1925). 1 6 Organic Syntheses, V, 17 (1925). l4


205

monium nitrate was added, and the solution was kept cold for thirty minutes. The precipitated alkamine nitrate was collected and dried. It weighed 9.5 g., a 21% yield. The benzamide, hydrochloride, and free base were made and purified as in earlier cases. p-Chloro-or-aminoacetophenone hydrochloride.-p-Chlorophenacyl bromide was made in 90% yield from p-chloroacetophenone by the method of Collet.l6 An addition product was formed from 96.8 g. of p-chlorophenacyl bromide and 61.3 g. of hexamethylenetramine in chloroform solution, by the general procedure of Slotta.” It was hydrolyzed by means of alcoholic hydrochloric acid to yield 35 g. of amino ketone hydrochloride, a 41% yield. i-Phenyl-i-p-chlorophenyl-i-hydroxy-d-aminoethanefrom p-chloro-a-aminoacetophenone hydrochloride and phenylmagnesium bromide.-This amino alcohol, which has not been described before, was made as follows. Phenylmagnesium bromide was made from 6 g. of magnesium, 42 g. of bromobenzene and 105 cc. of ether. T o this was added 10 g. of amino ketone hydrochloride over a period of twenty minutes. The mixture was warmed on a hot plate for one hour, and was then cooled and poured onto a mixture of 500 g. of ice and 55 cc. of 8% hydrochloric acid. The acid solution was extracted with ether, and was then made basic with ammonium hydroxide and again extracted with ether. The latter extracts were dried, and the ether was removed, leaving 3.5g. of amino alcohol, a 29% yield. The alkamine, which is soluble in alcohol and benzene, slightly eoluble in ether, and insoluble in ligroin, was obtained as very fine white plates on recrystallization from a mixture of benzene and ligroin. Anal. Calc’d for C1dHraCINO: C, 67.91;H, 5.70;N, 5.66;C1, 14.32. Found: C, 67.99;H, 6.09;N, 5.89; C1, 14.57. The hydrochloride was obtained as fine needles, soluble in water and alcohol, insoluble in ether and benzene. Anal. Calc’d for C14HlsClzN0, C1, 24.98. Found: C1, 25.03. The benzamide formed fine needles which were soluble in benzene and insoluble in ligroin. Anal. Calc’d for C21Hl8C1NO2:N, 3.98. Found: N, 3.66. The nitrate was obtained as a very fine crystalline powder, slightly soluble in water, soluble in alcohol, insoluble in benzene and ether. For a comparison of these substances with those obtained from the oxime reaction, see Table IV. SUMMARY

1. It has been shown that mixed ketoximes react with phenylmagnesium bromide in a concentrated solution at elevated temperatures. 2. The product of the reaction is not a hydroxylamine, as might be expected, but a beta amino alcohol, which results from the migration of a nitrogen atom from one carbon atom to another. 3. The reaction has been carried out with the oximes of pmethylacetophenone, p-chloroacetophenone, propiophenone, and methyl a-naphthyl ketone, and the amino alcohol obtained in each case has been compared with a sample synthesized in another way. l6

COLLET, Bull. SOC. chim., [3], 21, 69 (1899). SLOTTAA N D HELLER,Ber., 63, 1027 (1930).

THE ACTION OF GRIGNARD REAGENTS ON OXIMES. I. THE

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