The tert-Amino Effect in the Synthesis of Hetaryl- and Arylsulfonyl-Substituted Pyrrolo- and Pyrido[1,2-a]quinoline Derivatives and their Pyrazolo Annulated Analogues

Abstract

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...

tert‐Amino effect at a coumarin and a 2‐quinolone system: Synthesis of 1,2 fused 5H‐chromeno[4,3‐b]pyridin‐5‐ones and a 6H‐benzo[h][1,6]naphthyridin‐5‐one

“…On the grounds of the similarity between the substrates 4 and 6 as well as the analogy with the occurring chemical transformations, it could be assumed that both reactions most probably follow analogous mechanistic sequences. Sigmatropic rearrangement, hydride transfer or a mixed mechanism has been suggested till now for the tert-amino cyclization reactions [5]. The mechanism of the lower oxidation-reduction reaction in Scheme 2 may be regarded as a variant of the tert-amino effect, that is, a tert-amino effect working in a sec-amino compound.…”

Green synthesis of pyrimido‐isoquinolines and pyrimido‐quinoline using ZnO nanorods as an efficient catalyst: Study of antioxidant activity

“…[21] In spite of this wide range of applications, only a few members of this family of compounds have been reported. [22,23] Performing reaction under solvent-free conditions has some advantages such as simple synthesis, energy saving, freedom from solvent waste, and avoidance of the use of dangerous and toxic chemicals. Also, in recent years, there has been increasing interest in nanomaterials as catalysts.…”

“…For example, many of pyrimidoquinoline and pyrimidoisoquinoline derivatives show biological activities such as anticancer, anti‐inflammatory, antiallergic, antimicrobial, antibacterial, antifungal, antimalarial and antifolate . In spite of this wide range of applications, only a few members of this family of compounds have been reported …”

tert-Amino effect: the Meth-Cohn and Reinhoudt reactions (Review)

“…Tverdokhlebov [27] and Ryabukhin [28] studied the cyclization of benzothiazoles 33a and benzimidazoles 33b. It was found that the reaction was facilitated by acid catalysis.…”