ROBERTE. LYLEAND GLORIA G. LYLE
3536
Vol. 76
[CONTRIBUTION FROM THE DEPARTMENT O F CHEMISTRY OF THE UNIVBRSlT\’ O F NEIV IIAMPSIIIRE]
Molecular Rearrangements. V. 4-Hydroxy-1-methylisonipecotonitrileas an Intermediate in the Synthesis of Substituted Piperidines1 BY ROBERT E. LYLEAND GLORIAG. LYLE RECEIVED NOVEMBER 30, 1953 The preparation and reactions of 4-hydroxy-1-methylisonipccotoiiitrile( I ) are described. The product of the piiinco! rearrangement of 4-hydroxy- 1-methyl-4-piperidyldiphenylcarbinol ( V ) , derived from I, is showii t o depend on t h e reaction conditions. The anomalous rewtion of bromine water with l-tnethyl-l-piperidylidenediphcn).lmethane ( X I I ) is discussed.
Because of the interest in substituted piperidines solvents and thus was not readily separated from as pharmaceuticals and the availability of l-methyl- the magnesium hydroxide produced in the basic 4-piperidone,2the preparation and reactions of the reaction mixture. cyanohydrin of I-methyl-4-piperidone (4-hydroxyBy analogy to l-hydroxy-l-cyclolicxyldiphcn~l1-methylisonipecotonitrile) (I) as a possible inter- carbino1,j V would be expected t o undergo the pinaniediate in the synthesis of more highly Substituted col rearrangement with ring expansion on treatliiciit piperidines ha\-e been studied. with sulfuric acid to form l - m e t h y l - ~ , ~ ~ - d i p l i e ~ i y l - l Although the preparation and some of the reac- aza-4-cycloheptanone (VI) and with iiiigratioii of a tions of I have been reported p r e v i ~ u s l ythe , ~ refer- phenyl group to give l-methyl-4-phenyl-4-piperidyl ence is obscure and the details given in available phenyl ketone (VII) with zinc chloricle in acetic periodicals are inadequate. For this reason 4- anhydride. The rearrangement of V under the hydroxy-] -niethylisonipecotonitrile (I) was pre- former conditions gave a product to which the strucpared from 1-iiiethyl--l.-piperidoiie or its hydrochlo- ture V I was assigned, for this product exhibited an ride using the procedure of Tarboureich4 for the ultraviolet spectum (Ama, 239 mp, log enlax 2.93s and synthesis of cyclohexanone cyanohydrin. 1Vith , , ,A 294.5 mp, log cmax 2.646) very closely related this method an S35, yield of I could be obtained; to that of 2,2-diphenylcycloheptanone, ’ foriiictl ail however, the isolation of I from the aqueous reac- oxime, and was reduced to an alcohol, l-nietliyl-.S,.5tion mixture was complicated by its water solubility diphenyl-1-aza-4-cycloheptanol (VIII), with lithand ether insdubility indicating the polar nature of ium aluminum hydride. the compound. T h e rearrangement of 4-hydroxy- l-inethyl-4piperidyldiphenylcarbiriol (V) with zinc chloride iii acetic anhydride also was found to proceed in a manner analogous to that of 1-hydroxy-1-c>clo11, R = OAc; R’ = C?;;hydrochloride hexyldiphenylcarbinol. If the frce base of I’ were II,C, ,CELIII. R = O H ; R’ COOEt used in the rearrangement, however, a complex ‘A“ Il., R = OBz; R’ = COOEt; hydrochloride mixture of products was obtained from which only a I sinall amount of l-methyl--l--phe~i~l--l--piperidyl CK phenyl ketone (1‘11)could be isolated as the oxime. The cyanohydrin I on reaction with acetic anhy- The use of the hydrochloride of 1- gave, with no dride gave a normal alcohol derivative, 4-acetoxy- complications, V I I , identified by coniparisoii with 1-methylisonipecotonitrile, characterized as the an authentic sample of IT1 preparcd by the iiicthod hydrochloride 11. The free base of this ester, in of Eisleb.6 contrast to many piperidine compounds, could be distilled a t atmospheric pressure a t a temperature of 250’ with no apparent decomposition. Hydrolysis of the nitrile I and esterification of the resulting acid gave a ‘70% yield of ethyl 4-hydroxy11-methylisonipecotate (111). Comparable yields of the ester could be obtained directly from l/--\/I’ll CH,S/ ’ phR1gUr CH:jS methyl-&piperidone hydrochloride without isola\---/ C--I’h +-\~~ ./‘CS tion of the intermediate compounds. The ester II I11 readily formed a benzoate IV, isolated as a 0 hydrochloride, on treatment with benzoyl chlo\‘I1 ride. The reaction of phenylmagnesiuni bromide or I n an effort to extend the information concerning pheiiyllithium with I11 gave 4-hydroxy-l-methyl-4- these pinacol rearrangements, the synthesis of conipiperidyldiphenylcarbinol (17). The use of phenyl pounds related to V was attempted. I n this alterGrignard for the preparation of V was less satisfac- nate method isonicotinic acid was converted to tory, however, for V is relatively insoluble in organic methyl 1-methylisonipecotate (IX) by the method ( I ) Presented in p a r t before t h e Division of Organic Chemistry a t of Supniewski and Serafinowna.7 The reaction of t h e 122nd Meeting of t h e American Chemical Society a t Atlantic IX with phenyllithium gave l-nleth7.l-~-piperid~ldi~
=z
-.-.\
