Exploiting azafulvenium methides chemistry

The synthesis of heterocycles via reactive intermediates, ( e


Introduction
1,3-Thiazolidine-4-carboxylic acids have proven to be useful building blocks in organic synthesis.The most interesting aspect of their reactivity is the possibility of carrying out diastereoselective reactions thus allowing the development of synthetic routes to chiral heterocycles.Of particular interest is also the use of 1,3-thiazolidine-4-carboxylic acids as precursors of reactive intermediates (e.g.azadienes or dipoles), which widen the type of structures that can be made available from these heterocycles.In the recent past, we have explored both approaches to new heterocyclic compounds and some illustrative examples of this chemistry will be presented in this paper.Particular emphasis will be given to our more recent research work, the generation and reactivity of azafulvenium methide systems.
The Diels-Alder reaction of acyclic 2-azadienes is a useful method for the preparation of pyridines, dihydropyridines and tetrahydropyridines.N-Arylidenedehydroalanine methyl esters had already been prepared in 1979 by Öhler and Schmidt, by the reaction of thiazolidine esters with silver carbonate and DBU. 1 This synthetic strategy for the generation of the 2-azadienes 2a-2f from the corresponding thiazolidines 1a-1f was further explored (Scheme 1).These intermediates can participate as 2-azadienes in Diels-Alder reactions with a range of dienophiles.The azadiene 2a show a particular reactivity pattern since it reacts with both electron deficient and electron rich dienophiles.

Scheme 1
In fact, the azadiene 2a, generated in situ from the thiazolidine 1a in the presence of a large excess of but-3-en-2-one, leads to the formation of three compounds in an overall yield of 76%.On the other hand, the same azadiene reacts with N-cyclohex-1-enylpyrrolidine with the formation of the cycloadducts 6 (37%) and 7 (20%) (Scheme 2). 2

Scheme 2
The unusual reactivity of azadiene 2a, characterized by the participation in both the normal and inverse Diels-Alder reaction, can be attributed to the fact that the HOMO and LUMO energy levels are rather close as indicate by AM1 calculations.The AM1 calculated polarization of the relevant frontier orbitals of azadiene 2a shows a higher contour value at C-4 than at C-1 in both LUMO and HOMO orbitals.This polarization explains the observed regioselectivity in the normal and inverse Diels-Alder reactions of this compound.On the other hand, the calculations predict both orbitals to be nearly symmetrical with respect to the C=N-C=C plane, a result which is in agreement with the fact that no endo/exo selectivity has been experimentally observed. 3he azadienes (1a and 8) exclusively act as dienophiles in the reaction with cyclopentadiene and these compounds then undergo an aza Cope rearrangement (a 2-aza- [3,3]sigmatropic shift) at room temperature, followed by prototropy to give 11.The cycloadditions of 1-(benzylideneamino)acrylates 2a with cyclopentadiene gives two products the norbornene ester 10a and the tetrahydropyridine ester 11a.When allowed to stand in solution at room temperature for 10 days the product was found to consist of only a single component, compound 11a.A similar result was obtained starting from thiazolidine 8.In fact, compound 11b was also prepared by heating a solution of the Schiff base 10b in toluene (Scheme 3). 4

Scheme 3
Thiazolidines 12 react with silver carbonate and DBU to give isolable cross-conjugated bis(enamines) 14, the more stable tautomers of the azadienes 13 (Scheme 4). 5 The diester 14a has been also prepared from methyl β-halo-α-aminopropionate hydrohalides by reaction with bases. 6Other cross-conjugated bis(enamines) of this type have been produced by thermal rearrangement of vinylaziridines. 7These compounds undergo an interesting photocyclization to 3,4-dihydropyrroles which can be intercepted, as 1,3-dipoles, in cycloaddition reactions with alkenes and alkynes. 6,7,8Compound 14a is also reported to react as an electrophile with hydrazines 9 and with primary amines, 10 giving hydrazones and imines of methyl pyruvate as products.The diester 14a reacts with DDQ to give a single product in high yield, a 1:1 adduct of the diester and DDQ (15), which structure was established by X-ray crystallography.Reaction of the diester 14a with methyl vinyl ketone gives the tetrahydropyridine 16 in moderate yield.The ARKAT formation of this product can be rationalized as a conjugate addition-cyclization sequence, somewhat analogous to the Hantzsch dihydropyridine synthesis (Scheme 4). 5 a

Scheme 9
The reaction of (p-methoxyphenyl)glyoxal and L-cysteine methyl ester gives as expected a thiazolidine as a mixture of the (2S,4R)-and (2R,4R)-diastereoisomers.However, in this case the two diastereoisomers of methyl 2-(p-methoxyphenyl)thiazolidine-4-carboxylate can be separated by selective crystallisation proving that the interconversion of these isomers through a reversible ring opening mechanism is difficult.The reaction of each thiazolidine with prop-2-ynyloxyacetic acid chloride in presence of potassium carbonate leads to the corresponding N-acylthiazolidines (33 and 36) with retention of configuration at C-2.Using our synthetic strategy the chiral 5-(p-methoxyphenyl)-1H-pyrrolo [ Scheme 10

Scheme 11
The study was extended to other 3-alkyl pyrrolo[1,2-c]thiazole-2,2-dioxide derivatives. 24n the case of pyrrolo[1,2-c]thiazole 45c bearing an isopropyl group at C-3, the sealed tube ARKAT thermolysis leads to pyrrole 49 in moderate yield.The two substituents at the terminus of the double bond of 49 preclude its conversion into a pyrrolizine.Thus, under FVP reactions conditions two products are obtained, the N-vinylpyrrole 49 and 6-oxo-cyclopenta[b]pyrrole 50, which structure was determined by X-ray crystallography (Scheme 12).

Scheme 14
The mechanism for the formation of 56 is shown in Scheme 15.The styryl-1H-pyrrole 55 generates pyrrol-3-ylketene 57 on eliminating methanol.c]thiazole-2,2-dioxide 45f by solution-phase thermolysis (300 ºC). 22Storr et al. considering that this unsuccessful result was due to the high thermal stability of this sulfone, characterized by low bond order of the 3,4-bond of the sulfolene moiety, attempted the flash vacuum pyrolysis. 21lthough sulfur dioxide was eliminated from sulfone 45f no identifiable products were detected.However, we observed that under our FVP conditions two products are obtained from pyrrolo [1,2-c]

Scheme 16
The 1-azafulvenium methide (62) does not have a proton in the appropriate position to allow the suprafacial [1,8]H shift of the type described in Scheme 11 for the synthesis of Nvinylpyrroles.Therefore, the process occurs via an alternative route, an 1,7-electrocyclic reaction gives 63 which undergoes a rearrangement to pyrrole 60.This is in fact, a mechanism pathway similar to the one described for the phenyl derivatives 55.The mechanistic interpretation for the synthesis of 5-oxo-5H-pyrrolizine 61 from 60 is also outlined in Scheme 17.

Scheme 17
It has been reported that pyrazole derivative 68 undergoes SO 2 extrusion in solution and the corresponding 1,2-diazafulvenium methide 69 does not react with N-phenylmaleimide or dimethyl acetylenedicarboxylate but can be intercepted in 8π+2π cycloaddition with silylated acetylenes giving adducts resulting from the addition across the 1,7-position. 21We also observed that 1,2-diazafulvenium methide 69 can be trapped by reacting with bis(trimethylsilyl)acetylene, confirming the reported result.However, the dipolar system 69 also participates in the cycloaddition with N-phenylmaleimide giving the corresponding cycloadduct in 87% yield (Scheme 18).

2
b R = p-Me 2 NC 6 H 4 c R = p-NO 2 C 6 H 4 d R = 4-pyridyl e R = COPh f R = CO 2 Et