S y n t h e s i s o f H e t a r y l -a n d A r y l s u l f o n y l -S u b s t i t u t e d P y r r o l o -a n d P y r i d o [ 1 , 2 -a ] q u i n o l i n e Abstract: 4-Hetaryl and 4-tosyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-4-carbonitriles were prepared in two steps by the condensation of 2-(1-pyrrolidinyl)benzaldehydes with substituted acetonitriles XCH 2 CN (X = hetaryl, tosyl), followed by the thermal cyclization of the corresponding arylidene derivatives. Similarly, starting from 2-(1-piperidinyl)benzaldehydes 5-hetaryl and 5-tosyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline-5-carbonitriles were obtained. For the hetaryl-substituted derivatives the cyclization step was found to be assisted by protons. In addition 4,5,5a,6,7,8-hexahydro-1H-pyrazolo[3,4-e]indolizine and 1, 4,5,5a,6,7,8,9-octahydro-pyrazolo[4,3-c]quinolizine derivatives were prepared by the same method starting from 5-(1-pyrrolidinyl)-and 5-(1-piperidinyl)-3-methyl-1-phenylpyrazole-4-carbaldehydes. The relative configuration between the bridgehead hydrogen and the cyano group was assigned as trans on the basis of x-ray crystallographic data.Pyrrolo[1,2-a]quinoline derivatives are attracting chemists' attention because their skeleton often appears in marine alkaloids (for reviews see 1 ). In particular, the derivatives with partially or completely hydrogenated heterocyclic rings are of great interest. Moreover, certain tetrahydropyrido[1,2-a]quinolines, 2 the homologues of pyrroloquinolines, have shown high biological activity. In the eighties Verboom and Reinhoudt developed an efficient method 3 for the preparation of hexahydropyrroloand pyrido[1,2-a]quinolines 2 (Scheme 1) using the so called tert-amino effect. (The term was coined 4 to describe this type and related cyclizations.) Thus upon heating cinnamonitriles 1 in high-boiling polar solvents the target derivatives 2 were isolated in good yields. 3 The starting materials 1 were obtained easily by condensation of the corresponding aminoaldehydes (R 1 = H) or ketones (R 1 =CH 3 , Ar) with malonodinitrile. Furthermore, the method was extended to the preparation of various heterocycles by varying widely the tert-amine framework. 5
Scheme 1The method of Verboom and Reinhoudt; n = 1, 2 Stereochemical and mechanistic aspects of the tert-amino effect were thoroughly investigated. 3c-f The authors assumed a sigmatropic hydrogen shift occurred from the canonic structure 3, this was the rate-determining step, a further fast cyclization of the bipolar intermediate 4 then occurred. The stereochemical studies on the cyclization of derivatives of type 1, with substituted and chiral tertamine moieties, revealed the high regio-and stereoselectivity of the reaction and revealed that the hydrogen shift occurred suprafacially. 3d-f However, kinetic measurements indicated that in fact it was not a sigmatropic rearrangement, but rather a hydride transfer, 3c so a mixed mechanism was suggested. 3c-e Also, it should be noted that all research on the tert-amino effect and its synthetic applications wa...
