Reactions of 1,3-diazabuta-1,3-dienes with ketenes: how crucial are the steric factors/conformational preferences in influencing reaction pathways?

The [4+2] cycloaddition reactions of 2-methylthio substituted 1,3-diazabuta-1,3-dienes with monophenyl and diphenyl ketenes and the reliance of the cycloaddition pathways on the conformational preferences of 1,3-diazabuta-1,3-dienes are described.


Introduction
Ketenes have received extensive consideration owing to their ability to selectively participate as facile 2π components in the commonly encountered [2+2] cycloaddition reactions with alkenes 1 as well as carbon-nitrogen double bonds of imines 2 and azadienes. 3It offers an entrenched route to the synthesis of four-membered carbocyclic 3 and heterocyclic systems including imperative intermediates for various antibiotics and natural products. 4he cycloadditions of 1,3-diazabuta-1,3-dienes with ketenes have been reported to form [4+2] or [2+2] cycloadducts 5,6 and their formation have purely been explicated on steric grounds. 5It was observed that the reactions of 1,3-diazabuta-1,3-dienes (1a-1c) with diphenyl ketene led exclusively to the formation of azetidinones 3 and the formation of [4+2] cycloadducts were thought to be inhibited by the proximity of bulky substituents in the corresponding six-membered ring 4. Similarly, the preferred formation of pyrimidinone 4 and exclusion of 3 in reactions of 1d with diphenylketene was also attributed to steric reasons 5 (Scheme 1).These reactions were believed to proceed through a stepwise mechanism involving a zwitterionic intermediate 2 and the theoretical calculations suggested that the formation of azetidinone is a kinetically governed process and is much higher in energy than the corresponding [4+2] cycloadduct.5c,5d Earlier disclosures from our laboratory have shown that the reactions of polarized 1,3-diazabuta-1,3-dienes (1b,1e-1f) with monosubstituted ketenes resulted exclusively in the formation of [4+2] cycloadducts 6 and a number of speculative mechanistic possibilities were invoked to explain their formation.6d Recently, it has been reported that the size of substituents at N-1 plays a significant role in controlling the periselectivity observed in electrocyclisation of the zwitterionic intermediate 2 and it has been experimentally established that the reactions of 1,3-diazabuta-1,3-dienes 1 with ketenes involve reversible and irreversible formation of azetidinones 3 and pyrimidinones 4, respectively.5d For example, the reactions of 1-p-tolyl-2,4-diphenyl-1,3-diazabuta-1,3-diene 1g with ketenes led to the peri-/stereoselective formation of pyrimidinones 4, while the reactions of 1-benzyl-2,4-diphenyl-1,3-diazabuta-1,3-diene 1h with ketenes resulted in the isolation of corresponding azetidinones 3. On the basis of calculated potential energies it has been shown that in the former case, the pyrimidinones 4g are more stable than the hypothetical azetidinones 3g, with two phenyl substituents in vicinal positions (N-1 and C-4), while in the latter case, azetidinones 3h are relatively more stable and easily isolable because N-1 phenyl is moved away from the β-lactam ring by the insertion of the methylenic group.5d In view of the arguments presented above it was felt that the [2+2] cycloaddition observed in reactions of 1b with diphenylketene may possibly be altered to a [4+2] cycloaddition by carrying out reactions with 1,3-diazabutadienes having bulkier N-1 substituents.Such 1,3-diazabutadienes (1i and 1j), 7 having o-tolyl and 1-naphthyl substituents at N-1, have been prepared by the usual procedure and their reactions with monophenyl or diphenylketene have been found to follow the envisaged [4+2] route leading to the synthesis of corresponding pyrimidinones 4i and 4j.The formation of pyrimidinone 4 in these cases is possibly preferred due to the enhanced steric interaction between N-1 aryl (o-tolyl or 1-naphthyl) and vicinal C-4 phenyl substituent in the corresponding hypothetical azetidinone 3i and 3j 7 (Scheme 1).However, in a number of the reported reactions of 1,3-diazabuta-1,3-dienes with ketenes, the observed cycloaddition mode appears to be at variance with the expectations on steric grounds.For example, the reactions of diazadienes 1e with diphenylketene and 1f with phthalimidoketene have been observed to follow a [4+2] cycloaddition route leading to the formation of pyrimidinones 4e and 4f, respectively, while the reaction of 1b with diphenylketene led to the isolation of azetidinone 3b (Scheme 2).6d

Results and Discussion
In order to have a deeper insight into the mechanistic aspects and to ascertain the significance of steric factors in dictating the course of 1,3-diazabuta-1,3-diene-ketene cycloadditions, it was thought worthwhile to examine these reactions with 1,3-diazabuta-1,3-dienes bearing bulky phenyl groups at C-4 and a methylthio group at C-2 position.The desired 2-methylthio-1phenyl/benzyl-4,4 / -diphenyl-1,3-diazabuta-1,3-dienes (1k-1l) have been obtained by the treatment of diphenylmethanimine with phenyl/benzylisothiocyanate, methylation of the thioamide so obtained with methyl iodide and basification of the resulting hydroiodide salt with triethylamine.The treatment of 1k with phenylketene, generated insitu from phenylacetyl chloride and triethylamine, has been found to result in the formation of previously unknown [4+2] cycloadduct which has been characterized as 2-methylthio-3,5,6,6 / -tetraphenyl-3,4,5,6tetrahydropyrimidin-4-one (5a) on the basis of analytical and spectral evidences.Its IR (KBr) showed a strong absorption at 1708 cm -1 characteristic of a six-membered amide carbonyl group.Its 1 H NMR and 13 C NMR signals are also in agreement with the assigned structure.Clearly, the pyrimidinone 5a having three phenyl groups in close proximity to each other must encounter severe steric interactions as compared to the alternative azetidinone 6a.Further, the reaction of 1k with diphenylketene, generated insitu from diphenylacetyl chloride and triethylamine, also resulted in the exclusive formation of [4+2] cycloadduct which was characterized as pyrimidinone 5b.It is striking to note that the severe steric interaction expected due to the proximity of four phenyl groups was also not inhibitive for the formation of pyrimidinone 5b.In continuation of the present investigations, it was felt that the reactions of 2-methylthio-substituted 1,3-diazabuta-1,3-dienes having N-1 benzyl, instead of a phenyl, with ketenes may result in the isolation of [2+2] cycloadducts due possibly to the reduced steric interaction between N-1 benzyl and C-4 substituents.Accordingly, the reactions of 1l with monophenyl and diphenylketenes have been examined and interestingly, these reactions also resulted in the exclusive formation of [4+2] cycloadducts 7a and 7b respectively, instead of azetidinones 8a and 8b expected on steric grounds (Scheme 3).These cycloadducts were assigned the structures 7a and 7b with the help of spectral evidences.The formation of pyrimidinones 6 and 7 in these reactions are clearly at odds with steric arguments advanced by Rossi and coworkers 5d and by Wurthwein et al. 5b The [4+2] cycloaddition pathway followed in these reactions is not exclusively controlled by the steric factors and the observed difference in reactivity of C-2 phenyl and C-2 methylthio substituted 1,3-diazabuta-1,3-dienes with ketenes may probably be due to the difference in their conformational preferences, which in turn depend on the varied electronic influence of the substituents at various positions of the diazadienes.
To support the arguments presented above, ab initio 8a and density functional studies (DFT calculations) 8b,8c have been performed on the conformational preferences of 1,3-diazadiene at HF/6-21, MP2/6-31G*, MP2/6-31+//HF/6-31+G*, B3LYP/6-31+G**//B3LYP/6-31G* levels using Gaussian 94W series of programs.Absolute energies and relative energies on including ZPE corrections 9 reveal that s-cisoid is the preferred conformation on the PE surface of E-isomer and s-trans is the preferred conformation on the PE surface of Z-isomer.10a (Figure 1) The presence of hyperconjugatively polar donating groups (NH 2 , SH, Me) at C-2 position of 1,3-diazadiene have been found to strongly destabilize s-trans arrangement and increase the propensity of s-cisoid conformation both in gas phase as well as in solvent media.10a However, the preference for E-cisoid geometry has been observed to diminish under solvent conditions due to relatively less pronounced electron delocalisations in solvents.On the basis of the optimized structures of the transition states observed on the PE surface at various theory levels, it has been deduced that 1E s-cisoid 1,3-diazabuta-1,3-diene-ketene cycloaddition reaction proceed through asynchronously concerted Diels-Alder type pathway leading to the formation of pyrimidinone, whereas the formation of [2+2] cycloadduct, azetidinone originates from the 1Z s-trans The experimental observations supported by theoretical studies blatantly reflect that the reactions of C-2-methylthio substituted 1,3-diazabuta-1,3-dienes with ketenes proceed stereoselectively through asynchronously concerted Diels-Alder type cycloaddition (path 1).The possibility of the initial formation of [2+2] cycloadduct could be ruled out, as it is less likely for the sterically less demanding [2+2] cycloadducts to transform to sterically more crowded [4+2] cycloadducts.On the other hand, the reactions of C-2 phenyl substituted 1,3-diazabuta-1,3dienes with ketenes proceed through the initial formation of zwitterionic intermediate which exists in two interconvertible forms 2a and 2b due to smaller barrier across C-N bond (Scheme 4).The conrotatory ring closure (path 2) of the intermediate 2a results in azetidinone 3 as isolable products provided the substituents at N-1, C-3 and C-4 do not impose severe steric constraints.In case of demanding steric constrictions between these substituents, azetidinone 3 opens up to the sterically less demanding intermediate 2b via 2a which undergoes disrotatory ring closure (path 3) to stereoselectively form pyrimidinone 4. The above arguements also reasonably explain the till date dubious query about the remarkable stereoselectivity observed in the formation of pyrimidinones in 1,3-diazabuta-1,3-diene-ketene cycloadditions involving a zwitterionic intermediate.Thus, the conformational preferences of 1,3-diazabuta-1,3-dienes appear to be discernible in controlling the cycloaddition reaction pathways between 1,3diazabuta-1,3-dienes with ketenes.

Experimental Section
General Procedures.Melting points were determined by open capillary method using Veego Precision Digital Melting Point apparatus (MP-D) and are uncorrected.IR spectra were recorded on a Shimadzu D-8001 spectrophotometer. 1 H NMR were recorded in deuteriochloroform with Brucker AC-E 200 (200 MHz) spectrometer using TMS as an internal standard.Chemical shifts are expressed as δ-(ppm) downfield from TMS and J values are in Hz. 13 C NMR spectra were also recorded on a Brucker AC-E 200 (50.4MHz) spectrometer in deuteriochloroform using TMS as an internal standard.Mass spectra were recorded on SHIMADZU GCMS-QP-2000 mass spectrometer.
Starting materials.Phenyl/benzyl isothiocyanate 11 and diphenylmethanimine 12 were prepared by the following reported procedures.

Reactions of 1,3-diazabuta-1,3-dienes (1k and 1l) with ketene. General procedure
To a well-stirred solution of 1,3-diazabuta-1,3-dienes (4 mmol) and dry triethylamine (1.4 ml, 10 mmol) in dry dichloromethane (30 ml), was added dropwise a solution of phenylacetyl chloride (6 mmol) in dry dichloromethane (30 ml) over a period of 1h.The mixture was further stirred at room temperature for a period of about 2 hr till the completion of the reaction (tlc).The reaction mixture was then washed with water (3×20 ml) and sodium bicarbonate solution (2×20 ml) and finally dried over anhydrous sodium sulphate.Removal of the solvent under reduced pressure yielded crude product which was purified through silica gel column chromatography and recrystallized from a mixture (1:2) of chloroform and hexane.

Table 1 .
The different products formed from the variously substituted 1,3-diazabuta-1,3dienes and ketenes and the yields of the reactions