Synthesis of fused medium-ring heterocycles by the rearrangement of quaternary ammonium derivatives

摘要

The general aim of this study was to develop new modes of access to benzfusedudmedium-ring heterocycles. The approach adopted was to utilise theudrearrangements, with concurrent ring expansion, of heterocyclic quaternaryudammonium N-ylides and N-oxides. Of particular interest were new applications ofudthe [2,3] rearrangements of these systems. udBase promoted [2,3] sigmatropic rearrangement of 1-viny1-2-udethoxycarbonylmethyl-1,2,3,4-tetrahydroisoquinolinium salts at room temperature inudacetonitrile afforded functionalised 2,3,4,5-tetrahydro-1H-3-benzazonineudderivatives, as mixtures of the olefinic isomers, in high yields. This is the firstudapplication of this rearrangement to the synthesis of benz-fused aza-heterocycles. Audstereoselective preference for the formation of the E-benzazonines was observed. udThe E-benzazonines degraded to polar material on p.t.l.c. and acid-catalysedudtransannular interactions were proposed. The rearrangement reaction at highudtemperature also provided 1-vinyl-2,3,4,5-tetrahydro-1H-benzazepines, the productsudof [1,2] Stevens rearrangement. The mechanisms and product distributions of theseudrearrangements are discussed, with reference to models of the expected concertedudtransition states.udApplication of the [2,3] sigmatropic rearrangement to 1-vinyl-tetrahydroisoquinoliniumudsalts with nitrile or phenacyl ylide stabilising groupsudprovided the appropriate 4-substituted-2,3,4,5-tetrahydro-1H-3-benzazonineudderivatives in good yields. Successful [2,3] rearrangement of the phenacyl stabilisedudylide was limited to low temperatures, with Stevens rearrangement products beingudisolated selectively at high temperature. Rearrangement of an unstabilisedudmethylene ylide, generated by fluorodesilylation, gave a 4-unsubstituted 3-udbenzazonine in low yield. Base-promoted rearrangement of N-methyl-tetrahydroisoquinoliniumudsalts with no ylide stabilising group afforded Hofmann eliminationudproducts and demonstrated a limitation on the potential synthetic uses of the [2,3]udrearrangement. udRearrangement of vinyl substituted 2-ethoxycarbonylmethyl-tetrahydroisoquinoliniumudsalts gave, in most cases, 6- or 7-substituted-2,3,4,5-tetrahydro-1H3-udbenzazonine derivatives via the [2,3] rearrangement. A decrease in the Estereoselectivityudof the rearrangement was observed from C1'-substituted salts andudprobably reflected changes in the preferred concerted transition state geometry.udLimitations to the potential uses of the [2,3] rearrangement were exemplified by theudrearrangements of the 2',2'-dimethyl and trans-2'-dimethoxyphenyl salts at roomudtemperature. The former provided a mixture of the [1,2] and [2,3] rearrangementudproducts, indicative of steric interference by the cis-2'-methyl group with theudconcerted transition state, while the latter gave the Stevens rearrangement productudselectively, indicative of promotion of the [1,2] radical pathway by the radicaludstabilising group at C2'.udHydrogenation of the E -2,3,4,5-tetrahydro- 1H-3-benzazonines gaveud2,3,4,5,6,7-hexahydro-derivatives, while the Z-2,3,4,5-tetrahydro-1H-3-udbenzazonines were unaffected. Hydrogenation of a 6-methyl-2,3,4,5-tetrahydro-1H-ud3-benzazonine derivative was accompanied by a [1,3] hydrogen shift to anudendocyclic olefinic 3-benzazonine. Hydrogenolysis of an N-benzyl-tetrahydro-3-udbenzazonine could not be obtained preferentially without concurrent hydrogenation.udThe reaction afforded a secondary amine derivative of the 3-benzazonine system.udThe [2,3] rearrangement of a 2-(tetrahydro-2'-furanon-3'-y1)-1-vinyl-tetrahydroisoquinoliniumudsalt afforded the first example of the 2,3,4,5-tetrahydro-ud1H-3-benzazonine-4-spiro-3'-tetrahydro-T-furanone ring system in low yield.udAn effort to extend the [2,3] rearrangement to the synthesis of unsaturated 3-udbenzazonines from a 1-ethynyl-tetrahydroisoquinolinium salt gave only the Stevensudrearrangement product in poor yield.udThermolysis of 1-vinylic-tetrahydroisoquinolinium N-oxides unsubstituted atudCl' failed to provide [2,3] rearrangement and afforded 1-vinylic-1,3,4,5-tetrahydro- ud2,3-benzoxazepines in good yield by the Meisenheimer rearrangement. Neatudpyrolysis of the 1-vinyl-benzoxazepines gave an unexpected isomerisation toud1,3,3a,4,9,9a-hexahydroisoxazolo[3,4-b]naphthalene derivatives. This isomerisationudmay involve the formation and reaction of a nitrone intermediate.udThermolysis of 1'-substituted-l-vinylic-tetrahydroisoquinolinium N-oxidesudgave the first representatives of the 4,3-benzoxazonine system in mixtures with theudMeisenheimer rearrangement products. The Z-olefinic 1,2,3,5-tetrahydro-4,3-udbenzoxazonines were formed selectively. A stereoselective concerted [2,3]udrearrangement of the cis-N-oxides was indicated as thermolysis in refluxinguddichloromethane gave the 4,3-benzoxazonines with unchanged trans-N-oxides. Theudstructure of a 4,3-benzoxazonine was unequivocally established by X-ray structuraludanalysis. The 4,3-benzoxazonines were thermally labile and in refluxing xyleneudgave equilibrium mixtures with, and favouring, the less-strained 1-vinylic-2,3-udbenzoxazepines.udMeisenheimer rearrangement of a 5,6-dihydro-4H-s-triazolo[4,3-a]-1,4-udbenzodiazepine N-oxide afforded a 4,5-dihydro-7H-s-triazolo[4,3-a]-5,1,4-udbenzoxadiazocine, the first representative of this ring system, with structuraludsimilarities to the CNS active agent 'Alprazolam'. udFurther extension of the Meisenheimer rearrangement to tricyclic bridgeheadudN-oxides of the 10b-vinyl-pyrrolo[2,1-a]isoquinoline and 11b-vinyl-benzo[a]quinolizineudsystems gave, in low yield, the first examples of the 3,7-epoxy-ud3-benzazonine and 2H-3,8-epoxy-3-benzazecine ring systems.udModification of the Meisenheimer and Stevens rearrangement to give a fourudatom ring expansion by the inclusion of an a-cyclopropyl substituent was alsoudinvestigated. Thermolysis of a 1-cyclopropyltetrahydroisoquinoline N-oxide gaveudthe 2,3-benzoxazepine product of the Meisenheimer rearrangement. Thermolysis ofuda 1-(2'-phenylcyclopropyl)tetrahydroisoquinoline N-oxide derivative gave theudMeisenheimer rearrangement product and, in low yield, a 2,3,5,6-tetrahydro-5-udphenyl-1H-4,3-benzoxazecine derivative. Formation of the 4,3-benzoxazecine udsystem, the first example of this ring system, confirmed the plausibility of audmodified rearrangement pathway. The 4,3-benzoxazecine structure was confirmedudby X-ray crystallography. Base promoted rearrangement of the analogous 1-udcyclopropyl or 1-(2'-phenylcyclopropyl)-N-ethoxycarbonylmethyl salts affordedudonly 3-benzazepine derivatives by the Stevens rearrangement.udN-Alkylation of a 1-(2'-phenylcyclopropyl)-3,4-dihydroisoquinoline atudmoderate temperatures with iodometharte gave an unexpected Cloke rearrangementudand a new route to the pyrrolo[2,1-a]isoquinoline system. The structure of the Nmethyl-2,3,5ud,6-tetrahydropyrrolo[2,1-a]isoquinolinium iodide product wasudunequivocally established by X-ray structural analysis. udThe global minima and low energy conformations of the 2,3,4,5-tetrahydro-ud1H-3-benzazonine, 1,2,3,5-tetrahydro-4,3-benzoxazonine, and 2,3,5,6-tetrahydro-ud1H-4,3-benzoxazecine systems were determined with the molecular mechanics-basedudprogram PCModel and, where possible, compared with X-ray crystallographicudresults. The implications of the conformers found for the properties of theseudcompounds are discussed. It is envisaged that these studies may allow the futureudassessment of the potential of these compounds as CNS active agents.udThe present study has provided the synthesis of many novel isoquinolineudderivatives necessary for the investigations described above and has established newudsynthetic routes to five known and six new benz-fused medium ring heterocyclicudsystems.