Reactions of triene-conjugated diazo-compounds containing thiophene

Triene-conjugated diazo-compounds 12a,b which have a thiophene ring as the α,β double bond and olefinic groups at the γ,δ and ε,ζ positions react via intramolecular (3+2) cycloaddition to the ε,ζ bond to give the methano-bridged thieno[2,3-d ]diazocines 21a,b in high yield. This is wholly different reaction path to that followed by their analogues 6/11 that have a benzene ring at the α,β position. The latter react via an intramolecular 1,1-cycloaddition process followed by rearrangment to give the pyrrolo[2,1-a ]phthalazines 8 .


Introduction
Recent work 2 on the chemistry of triene-conjugated diazo-compounds of the general type 1 has shown that they can react via a variety of routes, and that the preferred reaction path depends strongly on both the nature of the substituents attached to the pendant diene system, and the stereochemistry about the γ,δ double bond.Systems in which the triene system includes a cyclopentene ring at the γ,δ position, e.g. 2 (Scheme 1), react rapidly at room temperature by an intramolecular (3+2) cycloaddition reaction to give the bridged benzodiazocine systems 3 (70-80%), accompanied in some cases by the hydrocarbon 4 in low yield.The occurrence of this cycloaddition reaction seems to be uniquely dependent on the presence of the 5-membered ring.Its inclusion apparently results in a highly favourable stereochemical disposition of the two reacting groups as illustrated in structure 5, which leads to the dominance of this reaction path.In the absence of the cyclopentene ring, e.g. in the γ,δ-cis systems 6 (Scheme 2), the diazo-compounds are much longer-lived and react on heating by an entirely different path leading predominantly to the carbene-derived hydrocarbons 7 (ca.75%) and the phthalazines 8 (ca.25%).The latter are thought to be formed via a 1,1cycloaddition to the γ,δ bond to give 9 followed by ring cleavage and ring expansion as shown.In a similar reaction of 11, the trans analogues of 6, the phthalazines 8 are formed as the exclusive products in ca.75% yield. 3  1,1-Cycloaddition reactions are relatively rare in diazo-compound chemistry 4a-c and this reaction provided the first example in conjugated systems of this type.It was therefore of interest to study its possible extension to the related systems 12/13 in which the benzene ring is replaced by thiophene, which, if they should react in the same way, would lead to the formation of 14.

Results
The diazo-compounds studied were the cis and trans isomers 12a,b and 13a,b.They were generated, as in earlier work 2 , by the thermal decomposition of the sodium salts of the corresponding tosylhydrazones 18 and 20 under aprotic conditions in 1,2-dimethoxyethane (DME) as solvent.

Scheme 2
The synthesis of the tosylhydrazones is illustrated for the γ,δ cis isomers 18a,b in Scheme 3.The aldehydes 17 were prepared by Suzuki coupling reactions of 2-formylthiophene-3-boronic acid with the appropriate bromodiene 16.The bromodienes were prepared by Wittig or Wadsworth-Emmons olefination reactions of (Z)-3-bromo-2-phenylbut-2-enal 15.The latter and its (E) isomer were prepared as a mixture from benzyl methyl ketone via Arnold's bromoformylation reaction 5a,b and were separated by chromatography.The γ,δ trans isomers 19a,b were prepared by a parallel route.The tosylhydrazones were all single isomers except for 19a (Ar = Ph) which was obtained as a mixture of E / Z isomers at the terminal double bond which could not be separated.
The γ,δ cis diazo-compound 12a (Ar = Ph) was first generated by heating its precursor tosylhydrazone salt at reflux in DME (ca.80 °C) and gave two products, the methano-bridged thienodiazocine 21a (38%), and the cyclopropabenzothiophene 22 (56%) as shown in Scheme 4. They were identified by comparison of their mass and NMR spectra with the corresponding benzo analogues 3 and 4. For example, the 1 H NMR spectrum of 21a showed three singlets at δ 3.56, 5.38, and 5.70 for the methine protons at the 1, 9, and 12 positions which corresponded to the absorptions at 3.28, 5.26, and 5.71 for the equivalent protons in 3 (R 4 = Ph).The lack of spin coupling between H-12 and its adjacent protons, due to their nearly orthogonal orientation, was also observed in 3. The reaction was then repeated under milder conditions -room temperature for 2 days followed by heating at 50 °C for 4 hours.Scheme 3. Reagents: i, ArCH 2 P + Ph 3 X -or ArCH 2 P(O)(OEt) 2 / base; ii, 2-formylthiophene-3boronic acid / Pd(PPh 3 ) 4 / NaHCO 3 ; iii, TsNHNH 2 / H + , iv, Na salt in DME In this case the only product was the diazocine 21a, isolated in 70% yield.This suggests that, at the higher reaction temperature, 22 was formed primarily by extrusion of nitrogen from 21a.This reaction path was confirmed by heating an NMR sample of 21a.However, it is possible that 22 was also formed directly via 23, the carbene generated by the loss of nitrogen from 12a.The second example of this type of reactant, 12b (Ar = C 6 F 5 ), under the milder reaction conditions, reacted in the same way to give the thienodiazocine 21b (Ar = C 6 F 5 ) (63%).This product also showed the three characteristic 1 H NMR absorptions at δ 4.00, 5.34, and 5.85.
The γ,δ trans diazo-compound 13a (Ar = Ph), generated by heating its precursor tosylhydrazone salt at reflux in DME, failed to react via any intramolecular reaction path and gave as the major product the 'carbene dimer' 25 (54%) and the azine 24 (40%), both presumably formed, as shown in Scheme 5, by reaction of the carbene 23a (Ar = C 6 H 5 ) with its diazocompound precursor.The azine had the expected spectroscopic properties and its identity was confirmed by comparison with a sample prepared directly by reaction of the corresponding aldehyde with hydrazine.The 'carbene dimer' 25 had a mass spectrum consistent with its proposed structure with a parent (M+1) + ion at m/z 629 and a major fragment at m/z 314.However further characterisation was impossible as the compound could not be obtained in a pure state due to further reaction or polymerisation which gave products with very similar TLC retention characteristics.A similar reaction was carried out under higher dilution and milder conditions (room temperature for 7 days) in an effort to favour an intramolecular reaction path.This gave only a complex mixture of products.The other trans reactant 13b (Ar = C 6 F 5 ) also gave a complex mixture of products that were not separated or identified.However, the primary product mixture and several components separated by chromatography were examined by 1 H NMR spectroscopy and it was clear that a product of the type 14, analogous to 8, had not been formed.

Discussion
These results show that the replacement of the benzene ring in the α,β position of 6 (and 11) with a thiophene ring resulted in a complete change in the preferred reaction path.Whereas the former gave the phthalazines 8 via a 1,1-cycloaddition reaction with the γ,δ bond and the subsequent rearrangement shown in Scheme 2, the latter completely failed to follow that reaction path.Instead the cis isomers 12a,b reacted predominantly to give 21a,b (Scheme 4) via a path analogous to that taken by the cyclopentene containing species 2 (Scheme 1).The trans isomers 13a,b reacted only via intermolecular paths (Scheme 5).Their failure to react via a 1,1 cycloaddition process (Scheme 6) leading to 14 is even more notable since this was the dominant high-yielding path for their benzo analogues 11 (Scheme 2).

Scheme 6
It seems likely that these results stem from the effect of the thiophene ring in compounds 12/13a,b on their molecular geometry.Firstly, the exocyclic bond angles at the α and β positions in these compounds will be greater than in the benzene analogues 6/11 (72° cf.60°, assuming symmetrical rings) resulting in an increase in the distance separating the terminal N atom of the diazo-group from the γ,δ bond.This would increase the activation energy for the 1,1cycloadition process for both 12 and 13 and make these processes less competitive with the many other reactions paths possible for these systems.Secondly, for the cis isomers, it would appear that the transition state for the intramolecular (3+2) reaction, 28, is strongly favoured by the presence of the thiophene ring, in the same way that the benzene analogue, 27, is favoured by the presence of the cyclopentene ring.The sum of the included bond angles is much the same in each case leading to a similar spatial disposition of the reacting groups.
The 1,1-cycloaddition shown in Scheme 2 thus remains the only example yet observed in the reactions of diene-or triene-conjugated diazo-compounds 2 and these results highlight the fine balance between competing reaction paths in these systems.
A methanolic solution of sodium methoxide (1 cm 3 , 0.480 M, 0.480 mmol) was added to a solution of (Z,E)-2-formyl-3-(4-perfluorophenyl-1-methyl-2-phenylbuta-1,3-dienyl)thiophene p- tosylhydrazone (0.300 g, 0.510 mmol) in anhydrous methanol (5 cm 3 ).The reaction mixture was stirred for 1 h at room temperature, then the solvent was removed in vacuo at room temperature to leave the sodium salt.The latter was dried in the evaporation flask at room temperature under high vacuum over phosphorus pentoxide in a desiccator for 12 h.Dry DME (20 cm 3 ) was added to the flask and the mixture heated at reflux for 3 h.After cooling to room temperature the reaction mixture was filtered through a pad of Celite and the solvent removed in vacuo to give a yellow oil.Dry-column flash chromatography (silica, hexane → 50% ether/hexane) gave several components, none of which showed, in their 1 H NMR spectra, any indication of the presence of the thiadiazatricyclododecatetraene, thiacyclopropaindene or phthalazine 21b, 22b , 14b (Ar = C 6 F 5 ) respectively.
,3-dienyl)thiophene (0.51 g, 1.2 mmol) in ethanol (10 cm 3 ).The reaction mixture was heated at 40 °C for 1 h, cooled to room temperature and stirred overnight.The solvent was removed in vacuo to give a pale yellow oil.