ABNORMAL KE.ACTION OP
Peb. 20, 1(33(5
[CONTRIBUTION FROM THE
DEPARTMENT OF
AN
ORGANOCADIIIUM IIEAGENT
967
CHEMISTRY, UNIVERSITY O F CALIFORNIA]
An Abnormal Reaction of an Organocadmium Reagent: para-Acylation of rnMethoxythenylcadmium Reagent BY WILLIAMG. DAUBEN AND
JOHN
W. COLLETTB’
RECEIVED AUGUST21, 1958 1Vhen the cadmium reagent prepared from m-methoxybromobenzene was allowed to react with an acid chloride, acylation occurred on the carbon atom adjacent to that originally holding the halogen atom. The amount of this abnormal reaction varied with the acyl halide used b u t was always the major pathway, the normal reaction being less favored. The abnormal acylation reaction was found to occur with no other aryl halides. The mechanism of the reaction was investigated and it was found that no rearrangement of the cadmium reagent itself had occurred, since upon reaction with diacetyl the expected m-substituted product resulted. The mechanism was shown to be that of an electrophilic aromatic substitution where the organocadmium reagent acts as an internal Lewis acid. A similar abnormal substitution was found to occur with acid anhydrides and from these studies it was shown that the process was intramolecular.
Previously, the synthesis of tetrahydrobenzophenones has been achieved by one of two methods, the reaction of an aroyl chloride with cyclohexene in the presence of aluminum chloride (Darzens’ reaction) and the reaction of cyclohexenyllithium with an aromatic a ~ i d . ~In, ~ both of these methods the potential carbonyl group finds its source in the carbonyl of the aromatic acid. An alternate procedure which would allow for a more ready preparation of tetrahydrobenzophenones containing substituents in the tetrahydro ring is the reaction of a cyclohexenyl-1-carbonyl chloride with an aromatic organocadmium reagent. Such a reaction system utilizing the unsaturated acid deriva-
the expected band a t 6.09 j t and this material upon ring closure with formic acid yielded 2-methoxy4b,5,6,7,8,8a-hexahydrofluorenone (IVb) which showed only the band a t 5.92 p . Li
I
0 I1
R1
r
IT
a, RI = RZ = H ;
0
I11 b, R1 = OCH3, Rz = H; Rz = OCHa
RI
IV c, R, =H,
When the ultraviolet spectra of I I I b and 1Vb were examined, i t was found that the former had a Xmax 248 mp ( E 11,500) and the latter had a Xmax / ~ -, 250 mjt ( E 9400). The comparison of these values with those obtained with the product from the tive, cinnamoyl chloride, and diphenylcadmiuni cadmium reaction (Amax 268 mp, E 11,100) clearly has been reported by Nightingale4 to yield the showed that this material was more complex than simply having ring closed material present. The expected benzalacetophenone in 44% yield. When cyclohexenyl-1-carbonyl chloride was spectral data indicated that an isomerization had allowed t o react with the cadmium reagent derived occurred since by examination of the ultraviolet from m-bromoanisole, an 18% yield of analytically spectral values of the methoxyl-substituted acetopure material was obtained, but the product p h e n o n e ~ ,a~ similar bathochromic shift is obshowed unexpected spectral properties. The ultra- tained in going from the m- to the p-isomer. violet spectrum showed a maximum a t 268 mp That isomerization had occurred was established in two ways. First, the authentic 4-methoxy(E 11,100) with a shoulder a t 285 mp ( E 9000) and the infrared spectrum possessed carbonyl bands 3’,4’,5’,6’-tetrahydrobenzophenone(IIIc) and its a t 5.92 and 6.09 p. Looking first a t the doublet ring closed derivative IVc were prepared v i a the in the infrared, Zimmerman3 has reported that the cyclohexenyllithium procedure followed by ring 3,4,5,6-tetrahydrobenzophenone- closure. I t was found that IIIc possessed Xmax unsubstituted (IIIa), prepared by the reaction of cyclohexenyl- 281 mp (E 11,600) and 6.09 p while IVc possessed lithium and lithium benzoate, possesses only a Amax 268 mk ( E 14,600) and 5.92 p with a shoulder single carbonyl absorption a t 6.09 p . Although a t 287 mp (E 10,000). Second, by fractional the band a t lower wave length in the previous crystallization of the 2,4-dinitrophenylhydrazones material might be due to abnormal transannular prepared from the cadmium reaction product, the effects on the chromophore, it seemed more likely derivative of IIIc and IVc was isolated. Upon that the first formed unsaturated ketone, due to chromatography of the reaction mixture directly, the presence of the rnethoxyl group, had undergone the fluorenone IVc was obtained. By examination cyclization to a fluorenone. Such was found to of the infrared spectrum of the cadmium reaction be the case since 3-methoxy-3’,4’,5‘,6‘-tetrahydro-product it was found that approximately 40y0 of the benzophenone (IIIb), prepared from cyclohexenyl- fluorenone and 60% of the uncyclized tetrahydrolithium and lithium m-methoxybenzoate, possessed benzophenone were present. Furthermore, the spectrum also indicated that in the uncyclized (1) Abraham Rosenberg Fellow, 1956-1957; General Electric Co. Fellow, 1057-1958. fraction some of the m-isomer was present to the (2) E. A. Braude a n d J. A. Coles, J . Chem. SOC.,2014 (1950); 1430 extent of about 10% of that fraction.
~
0
L
d‘yo 0
(1952); 2209 (1953). (3) H. E. Zimmerman, J . Ora. Chem., 40, 549 (1955). ( 4 ) D. Nightingale and F. Wadsworth, THIS JOURNAL, 67, 417 (1045).
~
(5) T h e spectral d a t a for t h e methoxyacetophenones were found t o be: ortho, Anlax 247 mp ( e 8750); ntela, Amax 249 mp ( c 8800); para, Amnl 271 mp ( a 6600).
(365:
~'ILLIAM
G. DAUBEN AND JOHN W. COLLETTE
These results clearly demonstrated that in the reaction of the acid chloride with the cadmium reagent derived from m-bromoanisole, the carbonyl group is placed on the carbon atom adjacent to the position of the starting bromide. It next was of interest to investigate the generality of the abnormal cadmium reaction and the reaction of acetyl chloride with the cadmium reagents derived from the three isomeric bronioanisoles was examined. It was found that with o-bromoanisole, a mixture containing 96Y0 of o-methoxyacetophenone and 47, of the p-isomer was obtained. itlith m-bromoanisole, a mixture containing 337, m- and 65yG p-methoxyacetophenone was isolated. The pbromoanisole yielded only p-methoxyacetophenotie. Thus, the abnormal reaction occurs to an appreciable extent only with the m-methoxy derivative. The small amount of p-isomer derived from the ornethoxy derivative was formed in the reaction since the starting o-bromoanisole was shown to contain less than 0.57,of the p-isomer. The pathway for the formation of this sinal1 amount of pisomer will be discussed later. Turning attention to other substituted broniobenzenes, the products obtained in an earlier study6 were examined. Previously, the three isomeric broniotoluenes, 0- and p-bromochlorobenzene, and 1- and 2-bromonaphthalene in the form of their cadmium reagents were allowed to react with P-carbomethoxypropionyl chloride. The resulting methyl @-aroylpropionates from all of these materials were shown to be of the expected normal structure. When the same acid chloride was allowed to react with the three isomeric methoxyphenylcadmium derivatives, again only the mrnethoxy isomer showed the abnormal reaction, i.e., from nz-bromoanisole only methyl &(p-methoxybenzoyl)-propionate was ~ b t a i n e d . This ~ finding of the abnormal reaction only with the mrnethoxyphenylcadmium reagent8 establishes the requirement of a highly activated position adjacent to the carbon atom originally holding the bromine atom if the abnormal course is to be followed. Furthermore, the finding of different isomer composition with different acid chlorides shows the tlc'petidence of the reaction upon the nature of this rcactrtti t . Considcration of thc over-all reaction shows thew arc' three steps where the abnormal reaction could occur: the foriiiatiori of the Grignard reagent, its ArX -+ A r i l I g S +.ArCdS -+ ArCOI< (1,) 11' C;, Iiatil,cii and 11 'f11Ics. .I OTR ( h f i i i . . 1 5 , i8.5 (1R50). ( 7 ) I n the earlier work,B the product from the ni-methoxpphenyl cadrniiiin reagent had heen assigned the expected inela structure even Ilicnigh the m . p o f the acid (olitaineu after saponification) was about . I O " higher than t h a t reported in t h e literature. Such an assignment wa, made since t h e semicarhazone derivative possessed t h e m . p reimrted for the in-isomer and since aroylpropionic acids often are polymorphic. Subsequently, the semicarbazones of t h e In- and prwmers have been prepared in this Laboratory and shown t o possess the same m.p. and a m.p. of a mixture of t h e two isomers melted only 1' lou-er t h a n t h e pure components Thus, this correction of t h e erroneous structure assignment in the earlier work should be noted. (8) Klemm, Mann and Lind hindly informed us previous t o publication of their results ( J . Oug. C ' i z e i i z . , 23, 349 (1958)). t h a t \hey had foiind t h e product formed in the reaction of the n-methoxyphenylcadmium derivative with vi-methoxybenzuyl chloride was a mixture
