Condensations at the Methyl Groups of N-Acetylbenzamide and

STEW4RT D. WORK, DAVID R. BRYANT, AND CHARLES R. HAUSER. Vol. 86. Bis-[( I-methylcyclopropyl)]methyl]-durene (VIIIa).-To a solution of 2.0 g. of VIIa ...
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STEW4RT

D.

WORK,

DAVIDR.BRYANT,A N D CHARLESR.HAUSER

Bis-[( I-methylcyclopropyl)]methyl]-durene(VIIIa).-To a solution of 2.0 g. of VIIa in 200 ml. of liquid ammonia and 200 ml. of ether was added in portions 0.3 g. of sodium until a blue color was observed. A4fter2 hr. the mixture was treated with 5 g . of ammonium chloride. ;\fter the ammonia had evaporated the usual work-up afforded 0.4 g. (SOTc) of VIIIa, m.p. 103-106" after recrystallization from ethanol and sublimation." 4 . mixture m.p. with VIa was depressed. When a solution of 1 g. of 1.IIa in 75 ml. of absolute alcohol was treated with 6 g. of W-2 Raney nickel'' a t reflux for 7 hr., there was obtained 0.2 g. of crude VIIIa, m.p. 100-107". The same product was obtained by lithium aluminum hydride reduction of VIIa in ether. Several recrystallizations and sublimation afforded pure VIIIa, m.p. 110.0-111.0". To a suspension of 4.2 g. of lithium aluminum hydride in 100 ml. of ether was added 19.0 g. of VIIa in 100 ml. of tetrahydrofuran. The mixture was held a t reflux for 5 hr. and worked up to yield 6.2 g. (93Yc) of a hydrocarbon, m.p. 109-111". Recrystallization from methanol and ethanol afforded the pure compound, m.p. 110-111", with little loss. At first this compound was believed to be I - I a , but mass spectrographic,14n.m.r.,14 and near infrared analyses29showed it to be pure \'IIIa. 4 n a l . Calcd. for C Z O H ~C, ~ : 88.8: H , 11.2. Found: C, 88.8; H , 11.2.

-____

(29) P Gassman, Chem Ind (London), 740 (1962), reports t h a t compounds having a methylene group in a cyclopropyl ring absorb in t h e 1.6251 650 p region; V I I I a ahsorbed a t I 638 p

[CONTRIBUTION FROM

THE

Vol. 86

Of the three methods for preparing pure VIIIa from VIIa, that involving reduction with lithium aluminum hydride appears superior. 3,3-Dimethylthietane.-The bismethanesulfonate of neopentyl glycol was prepared essentially as described above for compounds IVa,b,c, in over 90% yield. The purified sample melted a t 69-71 O after crystallization from methanol. Anal. Calcd. for CiH18OeS2: C, 32.3; H , 6.2. Found: C, 32.1; H , 6.1. The conversion of this methanesulfonate to thietane was carried out as described above for the preparation of compounds Va,b,c, except that the lower boiling thietane was distilled as formed from the reaction mixture and was isolated from the distillate. 3,3-Di1nethylthietane,~~ b.p. ll.?kllio, was obtained in 69T0 yield ( b u t more was present). 3-Benzhydrylthietane .-2-Benzhydryl-l,3-propanediol31 was converted into the b i s m e t h a n e ~ u l f o n a t eas ~ ~described31 in over 90yo yield. This compound was used to prepare 3-benzhydrylthietane, m.p. 105.0-107.5', in 65% yield as described earlier in this paper for compounds Va,b,c. The analytical sample melted a t 106.0-108.0" after recrystallization from ethanol. Anal. Calcd. for C16H&: C, 79.9; H , 6.6; S, 13.3. Found: C, 79.8; H , 6.6; S,13.5. (30) S Searles, Jr , and F Lutz, J . A m . Chem. Soc , 80, 3168 (1958). (31) MI. S Kewman and M Wolf, i b i d , 74, 3225 (1952). (32) This compound, colorless needles, m.p. lB2-133°, was first prepared b y >I. Okawara, 1956, in this Laboratory.

DEPARTMENT OF CHEMISTRY, DUKEUNIVERSITY, DURHAM, N. C ]

Condensations at the Methyl Groups of N-Acetylbenzamide and Diacetylimide by Means of Potassium Amide in Liquid Ammonia1" BY STEWART D. WORK,DAVIDR . BRYANT,'~ AND CHARLES R. HAUSER RECEIVED AUGUST21, 1963 Condensations a t the methyl groups of S-acetylbenzamide and diacetylimide were accomplished through their dipotassio salts IIa-b, which were prepared by means of two molecular equivalents of potassium amide in liquid ammonia. The condensations involved benzylation, benzoylation, and an aldol-type condensation with benzyl chloride, meth) 1 benzoate, and benzophenone, respectively. The benzplations of IIa-b were realized in good yields, although special conditions were required with I I b because of the tendency of its benzyl derivative to cleave. The benzoylations of IIa-b afforded the corresponding benzoyl derivatives, which were cyclized with hydrazine to form 3-phenylpyrazolone-5 ( X I I ) accompanied by elimination of benzamide and acetamide, respectively. The aldol condensation of IIa afforded the corresponding monohydroxyimide XI11 in good yield, but that of IIb produced not only monohydroxyimide X I X but also dihydroxyimide X X I and cleavage product XX These products were dehydrated to give corresponding aJ-unsaturated compounds

This paper describes three types of condensations a t the methyl groups of N-acetylbenzamide (Ia) and diacetylimide (Ib) through their dipotassio salts I I a and I I b , respectively. These salts were prepared by means of two molecular equivalents of potassium amide in liquid ammonia (eq. 1). PKNHz

RCOXHCOCHI

___f

K RCONCOCHzK

= =

C6Hs CH3

IIa, R b, R

= =

Va, R b, R

CeHsCHz

C6Hs CH3

= =

CsH6 CHB

RCOXCOCH3

These reactions are similar to those observed with benzoylacetone and acetylacetone, to which imides Ia-b are related as nitrogen analogs. Condensations a t the or-carbon of succinimide also have been r e p ~ r t e d . ~ Beiizylations of dipotassio salts IIa and IIb were effected with benzyl chloride to form the C-benzyl derivatives IVa and I l r b in yields of 64 and 6370, respectively (eq. 2). That the alkylation products were IVa-b and not the possible N-benzyl derivatives Va-b was indicated b y their solubility in 57c sodium hydroxide solution and by bands in their infrared spectra for the N-H group a t (1) (a) Supported in part by the Xational Institutes of H e a l t h ;

(2)

3.05 and 3.14 p , respectively.

(1)

liq. NHs

Ia, R b, R

RCONHCOCHlCHlCeHj IVa, R = CeH6 b , R = CHI

(b)

Kational Science Foundation Predoctoral Fellow (1958-1961) ( 2 ) See especially C R Hauser and T 11 Harris, J A m Chem. S O L , 80, 6360 ( 1 9 5 8 ) , R . B ?Ifeyer and C R Hauser, J Org Chem , 26, 158 (1960); R J Light and C . R Hauser, ibid , S6, 1716 (1961). (3) D . R Bryant and C. R . Hauser, J A m . C h e m Soc , 83, 3468 (1961).

Structure IVa was confirmed by alkaline hydrolysis to form, besides benzoic acid and ammonia, hydrocinnamic acid, which was employed in an independent synthesis of IVa5 (Scheme A ) . SCHEME 4 1, N a O H

IVa

i

C~H~CHXHZCOOH 2 , HC1 CeHsCONCO

!

-coz

Structure IVb was confirmed by independent syntheses from hydrocinnamamide (VI) and acetic anhy(4) See L . J . Bellamy, "The Infra-red Spectra of Complex Molecules," 2nd E d , John Wiley and Sons, Inc , New York, K Y . , 1958, p. 221 ( 5 ) 4 . J Hill and W M Degnan, J . A m . Chem. S o c , 61, I595 11940); T . B. Johnson and I*. H . Chernoff, ibid., 33, 517 (1911).

CONDENSATIONS AT METHYL GROUPS OF N-ACETYLBENZAMIDE

March 5 , 1964

-

SCHEME D

dride and from acetamide and hydrocinnamoyl chloride (Scheme B) ; IVb appears to have been obtained previously only as side reaction product (2% yield) .6

CzHsOH

CeHaCOCHzCN

H Br

SCHEME B

CBHSCOCHZC=NH~BI XI dCZH5

(CHaC0)zO

RCOCl

CeHsCHzCHzCONHz re5ux VI

acid

I X a or I X b

f--

I

reflux

1 , K N H e ; 2 , CeHsCHeCHeCOCI

1

It should be pointed out that the 63% yield of IVb mentioned above was obtained when the benzylation of I I b was effected in the presence of some potassium amide and the reaction mixture neutralized inversely (see eq. 2 and Experimental). When the benzylation was effected in the absence of potassium amide and the reaction mixture neutralized directly (conditions used for IVa), IVb was isolated in only 15% yield after 5 min., and none of IVb was isolated after 1 hr. Under the latter conditions, hydrocinnamamide (VI) was obtained. Presumably VI arose through cleavage of intermediate monopotassio salt IIIb, or of IVb present in equilibrium.' Jlonopotassio salt IIIb, prepared from IVb and potassium amide, underwent cleavage in the absence of, but not in the presence of, some potassium amide under similar conditions (see Experimental). Benzoylations of dipotassio salts IIa and IIb were effected with methyl benzoate in the presence of an extra equivalent of potassium amide to form the Cbenzoyl derivatives IXa and I X b in yields of 28 and 1370, respectively (Scheme C). IIa or IIb

SCHEME C K +RCOKCOCOCH~COC~HS XHt) VI1

CeHsCOOCHa (liq.

We employed the hydrobromide X I because it has been prepared in better yield than the h y d r o ~ h l o r i d e . ~ Compounds IXa-b have also been obtained by hydrogenation of the appropriate 6- (acylamino) -isooxazole followed by acidic hydrolysis. Io In the benzoylations of dipotassio salts IIa-b (Scheme C), the extra equivalent of potassium amide was used to effect the conversion of the resulting monopotassio salt VI1 t o its dipotassio salt VIII. Although the excess potassium amide probably converted some of the ester to benzamide, the yield of I X a based on the imide Ia was better (28%) than that (10%) isolated when the dipotassio salt I I a was treated with one-half of a molecular equivalent of methyl benzoate." The latter method, in which no excess potassium amide was used, still afforded much benzamide (35y0)and also benzoic acid (43%). In this case the benzamide apparently arose through cleavage of the monopotassio salt of imide Ia, which would be generated from IIa in the last step of the condensation reaction.ll This cleavage would be analogous to that of I I I b mentioned above. Interestingly, benzoylation products IXa-b underwent cyclization with hydrazine to form 3-phenylpyrazolone-5 (XII) and benzamide or acetamide, respectively (eq. 4). 1Xa-b-

HINNHp heat

II

RCONHCOCHzCOC6Ha IXa, R = C6H5 b, R CHB

f-

T h a t the products were IXa-b, not the possible Nbenzoyl derivatives Xa-b, was indicated by their solubility in 5% sodium hydroxide solution, by positive enol tests with ethanolic ferric chloride, and by their infrared spectra, which gave bands for the N-H group a t 3.07 and 3.04 p , r e ~ p e c t i v e l y . ~ CeH5C=0

Xa, R b, R

= =

C6H5 CH3

RCO~COCH~

IXa-b -----+ heat

CBHSCOCH~COOH +C ~ H S C O C H(3) ~ heat

Structures IXa-b were confirmed by independent syntheses from benzoylacetonitrile and the corresponding acid chloride through imino-ester hydrobromide X I (Scheme D). This method is analogous to that employed previously with the corresponding imino-ester hydrochloride.8 (6) H . Burton a n d D . A . M u n d a y , J . Chem. Soc., 1718 (1957). (7) By analogy with t h e alkaline cleavage of P-diketones (see E. S. Gould, "Mechanism and S t r u c t u r e in Organic Chemistry," H e n r y H o l t and Co., I n c . , S e w York, N Y., 1959, p 337) t h e present cleavage might involve t h e free imide I V b , a n d only a catalytic a m o u n t of base would be required. However, such imides appear t o undergo cleavage much more readily t h a n corresponding 0-diketones.

(4)

CH2

XI1

These cyclizations appear to be the first such examples involving the elimination of an acid amide, although the corresponding cyclization of ethyl benzoylacetate with hydrazine involving the elimination of ethanol is well known.12 Aldol Condensations of Dipotassio Salts IIa-b.-Dipotassio salt IIa underwent an addition reaction with benzophenone to form hydroxyimide XI11 in 75% yield (eq. 5 ) . K

(CsHs)zC=O (liq.

NHiCl

+ CeHsCOKCOCHzC( C6H5)z -+

IIa

Structures IXa-b were supported by acid-catalyzed hydrolysis to form, besides the corresponding carboxylic acid, acetophenone, which presumably arose through decarboxylation of intermediate benzoylacetic acid (eq. 3). 6 N HCl - coe

RCONHz

1 ,C=O

C&&,

i

K K RCO~cOCHCOC6I