Tetrahydropyrimidin-2 ( 1 H )-ones with three neighbouring phenyl groups . Synthesis and allylic strain effects

Favoured conformations of differently N-substituted cis,trans-4,5,6-triphenyltetrahydropyrimidin-2(1H)-ones and the allylic strain caused by different groups were studied. It was found that the diequatorial conformer is strongly preferred in equally N,N’-disubstituted products, where the effects of the two substituents negate each other. It was shown that a benzyl group gives rise to much stronger allylic strain than a methyl group. Additionally, unusual azetidine formation was observed upon acid hydrolysis of benzylideneamino azide via SN2 mechanism. It was suggested that N-substitution does not significantly influence the ring geometry angle, while quaternisation affords serious increase of puckering.


Introduction
Compounds with a 1,2,3-triphenylpropane skeleton are useful models for conformational relationship studies due to their symmetry and the limited number of allowed conformations.Heterocyclic systems of this type are of special interest due to the tendency of phenyl groups to adopt axial vs equatorial position in the conformations of the various isomers.The conformational behaviour of tetrahydrooxazinones 1 and tetrahydrothiazinethiones 2 with three neighbouring phenyl groups (Figure 1) has been investigated.It was found that an N-substituent shifts the conformational equilibrium towards the conformer with an axial substituent at the carbon next to the nitrogen, due to the partial double character of the N-CO bond.The latter brings the N-substituent close to the equatorial one at the adjacent carbon, thus giving rise to allylic strain, A (1,2) . 3It has been observed that the effect is most clearly revealed in the case of trans,cis diastereoisomers, 4 while with the rest of the isomers either the same conformer is favoured for unsubstituted compounds or an equilibrium between both allowed forms exists.
Oxazinones and thiazinethiones showed similar patterns of behaviour and only slight differences were observed, probably due to the difference in C-O and C-S bond lengths.However, it has been found that in both series all N-substituents shift the equilibrium towards the sterically unfavoured diaxial form.Thus, an explicit comparison between the conformational preferences for a given configuration and the role of allylic strain, caused by different substituents, cannot be performed.The determination of the effects in tetrahydropyrimidinones (Figure 1), where the carbon-heteroatom bond lengths are equal and the effects of the two Nsubstituents are in concurrence, could provide more complete information about the allylic strain of different groups in these systems.Tetrahydropyrimidinones are also useful as optically active chiral auxiliaries in a variety of organic reactions such as alkylation, aldol condensation, Michael addition and many others. 5mong the broad range of procedures for direct asymmetric C-C bond formation, which now plays a key role in the preparation of complex natural products and pharmaceuticals, 6,7 the use of chiral auxiliaries is also considered as a methodology of great practical relevance, 8 despite their stoichiometric application.Different heterocyclic compounds, tetrahydropyrimidinones, [9][10][11] as well as their O-analogues, 12,13 have been widely applied as auxiliaries and the stereochemistry of the final product was fully controlled by the auxiliary used.
A study on the synthesis and allylic strain effects in differently N-substituted cis,transtetrahydropyrimidin-2(1H)-ones with triphenylpropane skeleton, 14 is presented herein.

Results and Discussion
The triphenylated amino and methylamino propyl chlorides were obtained in our laboratory 15 as pairs of diastereoisomers, which differ in the relative configuration at C-1/C-2, that at C-2/C-3 being the same, TT/ET and EE/TE couples. 16Since nucleophilic substitution of the chlorine atom with an azide group and subsequent routine transformations provides a relatively short method for tetrahydropyrimidin-2(1H)-one construction, TT-chlorides represent good candidates as starting materials in the synthesis of the cis,trans-pyrimidinones 14 .
The transformation was first studied in the case of TT-amino chloride 1, where, surprisingly, instead of the expected amino azide, the corresponding ET benzylideneamino compound 2 was isolated, as shown in Scheme 1.The latter can be explained by a retroaldol cleavage of the starting chloride with elimination of benzylideneamine as a by-product, which hydrolyzes spontaneously to benzaldehyde and reacts with the free amino group.This suggestion is confirmed by the observed trans-stilbene formation.
As the retroaldol reaction requires a lone electron pair on nitrogen, the latter was inactivated as a Schiff base by performing the transformation in the presence of benzaldehyde as a coreagent.Thus, the retroaldol cleavage was precluded, affording the product in a much higher yield with no trans-stilbene formation.The assignment of the configuration of the product as ET is based on the observed coupling constants in the proton NMR spectra in comparison with those of a broad range of differently 1,3-bifunctionalysed compounds with triphenylpropane skeleton, as well as on the known fact that benzyl chlorides undergo similar reactions by S N 2 mechanism via inversion of the configuration. 17An additional proof for the ET configuration of the azide 2 is the cis,trans configuration of pyrimidinone 6, whose synthesis is described below (Scheme 2).Azide 2 represents a direct precursor of the target diamine.In an attempt to hydrolyze both the azido and benzylideneamino groups of 2 under acidic conditions azetidine 3 was isolated as an unexpected product of intramolecular cyclisation (Scheme 2).
The 1 H and 13 C NMR spectra of compounds 3 and 4 show common signals for H-2/H-4 and C-2/C-4 resonances, which is a direct proof for their trans,trans-configuration 18 (Table 1).Methylation of azetidine 3 and comparison of the physical and spectral data of the product with those of the known trans,trans-1-methyl-azetidine, 2 gave an additional confirmation of its structure and stereochemistry.The vicinal coupling values ( 3 J) in a series of cyclobutanes of known geometry have been correlated by Abraham et al. 19 with puckering angles.It was found that smaller couplings are observed for smaller puckering angles.Afterward, Kingsbury et al. 20 have applied these correlations to azetidines.The authors have found that very large 3 J are suggestive of axial hydrogens in a puckered ring.In a previous study in our laboratory, 2 N-methyl azetidines were investigated.It was shown that the conformations with e,e,e and e,a,e phenyls in puckered rings are preferred for trans,trans and cis,cis diastereoisomers, 21 respectively, while a planar ring is favoured for the cis,trans isomer.The coupling of 8.5 Hz, observed for the free base of 3 (Table 1) is suggestive of puckered ring.This value compared with 8.9 Hz for the corresponding Nmethyl derivative shows that N-methylation does not significantly influence the ring geometry.In contrast, the larger couplings observed for the ammonium salts, 10.4 Hz and 9.9 Hz for the hydrobromide and hydrochloride of 3, respectively (Table 1), and 10.9 Hz for the hydrochloride of N-methyl derivative, indicate that the quaternisation of nitrogen results in a strongly biased preferred conformation with e,e,e phenyls in a puckered ring.This suggestion could be tested by the conformational behaviour of the cis,trans-isomer, as it was assumed that a planar ring is favoured for its N-methyl derivative.Thus, the transformation was performed with a diastereoisomeric mixture of chlorides 1, TT/ET 4.7:1, and the hydrobromide of cis,transazetidine was obtained as an impurity.The latter shows very dissimilar couplings, J cis 2.8 Hz and J trans 11.0 Hz, which confirms that quaternisation affords a serious increase of the puckering angle.
Surprisingly, couplings of 8.4 Hz and 6.5 Hz were observed in the proton spectrum of the hydrobromide of cis,trans-azetidine in methanol-d 4 , instead of a large and a small one as in deuterochloroform.The former are very similar to the couplings of 8.7 Hz and 5.4 Hz for the Nmethyl derivative.It could be suggested that contrary to the trans,trans-isomer, where a puckered ring is favoured in deuteromethanol, the ring geometry in the case of the cis,transproduct depends on the solvent, and that protic solvents lead to a significant decrease of the puckering angle, while in aprotic the puckered ring is preferred.In the case of azetidine 4, the 3 J value of 6.4 Hz is suggestive of a planar or slightly puckered ring.The latter compared with the N-methyl derivative (8.9 Hz), shows that an adjacent C=O group affords a decrease of the puckering angle, probably due to the partial double bond character of C-N.
The trans,trans-configuration of the product, which is the result of inversion at C-1, C-2 in azetidine, respectively, gives an indication that the nitrogen originates from the benzilideneamino group.The latter hydrolyzes to an amine as a first step, which afterwards attacks the carbon bearing the azide functionality, leading to cyclisation with inversion of the configuration at C-1.It could be suggested that the reaction goes via S N 2 mechanism with inversion of the configuration at C-1, bearing the azide functionality, and S N 1 does not take place as a parallel mechanism, as no cis,trans-azetidine formation was detected when pure TT-chloride was used.
When starting from the N-methylamino chloride 8 (Scheme 3), no retroaldol cleavage was observed, which most probably is due to the increased basicity at the nitrogen due to the N-alkyl substituent or/and to a faster than retroaldol reaction nucleophilic substitution in this case.
ET-Diamines 5 and 10, easily obtained by hydrogenation of azides 2 and 9, represent direct precursors of tetrahydropyrimidinones 6 and 11, which after methylation gave the corresponding N,N'-disubstituted products 7 and 12, as shown in Scheme 2 and Scheme 3. Thus, we had four products for comparison, which differ in the position and the type of N-substitution, with cis,trans configuration, the most useful isomer for allylic strain effect investigations in these hindered systems, where 1,3-parallel interactions between bulky groups lead to a strong limitation of the allowed conformations.
N,N'-Dimethyl pyrimidinone 12, having equal N-substituents, the effects of which cancel each other, is a conformational analogue of the N-unsubstituted product, whose preparation by hydrolysis of 2 was unsuccessful.As can be seen on Table 2, small J cis (3.0 Hz) and large J trans (12.7 Hz) are observed for the dimethylated product 12.These data show that the conformation with a,e,e phenyls (B-12) is strongly preferred for this derivative, as well as for the N,N'-unsubstituted and the equally N,N'disubstituted compounds.This preferred conformation is in agreement with the classical stereochemical canons, as the diaxial form (e,a,a, A-12) is strongly disfavoured in the absence of other factors as a norm.An N-alkylation should give rise to allylic strain, which should shift the conformational equilibrium towards the form with e,a,a phenyls, thus avoiding the interaction between the Nsustituent and the equatorial one on the neighbouring carbon.As can be seen on Table 2 and Scheme 4, the e,a,a conformer is strongly preferred for Nbenzyl pyrimidinone 6 (A-6, Scheme 4) as a result of allylic strain.The effect of the latter is strong enough in this case to predominate over the steric restrictions for the diaxial conformer.Conversely, an N-methyl group does not change significantly the conformational preferences and the a,e,e form (B-11) is favoured again, while e,a,a (A-11) is very slightly populated, J trans 12.4 Hz in 11 vs J trans 12.7 Hz in 12.This could be due to a relatively small allylic strain of the methyl group, which cannot bias the conformational equilibrium towards the sterically unfavoured diaxial form, or/and to a very strong steric preference for a conformation with equatorial phenyl groups.However, a comparison between the N-benzyl (6) and N-benzyl-N'-methyl (7) products, where A-6 vs B-7 are favoured, gives an indication that the effect of the methyl group is strong enough to eliminate the effect of allylic strain, caused by the benzyl group.
When performing the transformation with a diastereoisomeric mixture of chlorides 1, TT/ET 4.7:1, trans,trans-pyrimidinone 22 13 was isolated as an impurity (Scheme 5).The observed relatively small couplings, 3.2 Hz and 4.3 Hz, show that the triequatorial conformer B-13 is favoured in this case, while the triaxial one (A-13) is only slightly populated.The latter demonstrates that even the allylic strain of a benzyl group is not strong enough to predominate over the forceful steric restrictions of a triaxial conformation.A comparison of the results, described herein, with those obtained for the corresponding pyrimidinones with two neighbouring phenyl groups, 23 where the effects are not clearly revealed, demonstrates the crucial role of the third phenyl in the conformational distribution in these highly hindered heterocyclic systems.The latter and the relative symmetry of triphenylated pyrimidinones make them explicit models for conformational relationship studies, allylic strain of different groups in particular.
It was found for tetrahydrooxazinones 1 and tetrahydrothiazinethiones 2 with three neighbouring phenyl groups, already studied in our laboratory, that the conformational preferences are strongly dependent on N-substitution as a result of allylic strain and that the effects are most clearly revealed in the case of the cis,trans diastereoisomer.When comparing the favoured conformations of pyrimidinones with those of oxazinones and thiazinethiones with the same configuration, it can be summarized that all heterocyclic compounds of these series have similar conformational behaviour and only slight differences are observed.Thus, while for N-unsubstituted, as judged from equally disubstituted pyrimidinones, the diequatorial conformer a,e,e (B-12) is strongly preferred, and for thiazinethiones e,a,a form is only slightly populated, in oxazinones both conformers are more or less equally populated, indicating a balance in the steric strain of the diaxial and diequatorial conformations.A possible explanation can be given by the shorter C-O bond in respect to C-N, which increases the steric interactions in the former fragment, thus making both forms almost equally allowed.N-Methylation in oxazinones and thiazinethiones leads to a strong preference for the diaxial conformer, e,a,a.This shows that the allylic strain of the methyl group is sufficient to fix the products in the sterically unfavoured diaxial conformations, especially in thiazinethiones, where the steric strain in both forms is not balanced as in the oxazinones.This observation is in agreement with the favoured e,a,a form for N-benzyl pyrimidinone (A-6), but is in contrast with the conformational preferences of the Nmethyl derivative (a,e,e, B-11).A possible reason could be the existence of a proton at the second nitrogen, which accomplishes some steric interactions, thus decreasing the effect of methyl group allylic strain, which is relatively small, as it was shown above.
The same vicinal couplings, observed for N-benzyl and N-methyl oxazinones, 1 suggest that both groups provoke similar allylic strain in these systems, where the two fragments of the

Conclusions
Differently N-substituted cis,trans-pyrimidin-2(1H)-ones were prepared and the effects of allylic strain caused by different N-substituents were studied in these systems, where the classical stereochemical factors and the effects of N-substituents are clearly revealed due to the equality of the two carbon-hetero atom bond lengths and the relative symmetry of the molecule.It was observed that in the symmetrically N,N'-disubstituted compound 12, which is a conformational analogue of the unsubstituted derivative, as the effects of the two groups cancel each other, the a,e,e conformation is strongly preferred.It was shown that a benzyl substituent shifts the conformational equilibrium towards the sterically unfavoured diaxial form (e,a,a-6), while the effect of a methyl group is relatively small and the e,a,a form is only very slightly populated.However, the latter effect is strong enough to eliminate that of the benzyl group in the N-benzyl-N'-methyl derivative 7, where the a,e,e conformer is preferred again.Thus, a benzyl group gives rise to much stronger allylic strain than a methyl group.However, the former is not strong enough to predominate over the forceful steric restrictions of a triaxial conformation in trans,trans-pyrimidinone 13.Unusual azetidine formation was observed upon acid hydrolysis of benzylideneamino azide 2, instead of the expected diamine.It was shown that the nitrogen originates from the benzylideneamino group and that the reaction goes via S N 2 mechanism.It was suggested for the trans,trans-isomer, based on NMR data analysis and on a comparison with known triphenylated N-methyl azetidines, that N-substitution does not significantly influence the ring geometry angle, while quaternisation affords a serious increase of puckering and strongly biases the equilibrium towards the conformer with e,e,e phenyls.It was observed in the case of cis,trans-azetidine, where a planar ring is assumed to be favoured for the N-methyl derivative, that the ring geometry of the hydrobromide depends on the solvent, and that a protic solvent leads to a significant decrease of the puckering angle, while in aprotic the puckered ring is preferred.

Experimental Section
General Procedures.All reagents were purchased from Aldrich, Merck and Fluka and were used without any further purification.Diethyl ether and toluene were dried over sodium wire, THF over LiAlH 4 .Merck Silica gel 60 (0.040-0.063 mm) was used for the column chromatography isolation of the products.The melting points were determined in capillary tubes without corrections.The IR spectra were taken on a Bruker IFS 113v as solutions in chloroform and were quoted in cm -1 .The NMR spectra were recorded on a Bruker DRX 250 spectrometer in deuterochloroform, the chemical shifts were quoted in ppm in δ-values against tetramethylsilane (TMS) as an internal standard and the coupling constants were calculated in Hz.The microanalyses were carried out by the microanalyses service of the Institute of Organic Chemistry, Bulgarian Academy of Sciences.
Preparation of azides 2 and 9. To a solution of chloride hydrochloride 1 or 8 (1 mmol) in dry DMF (5 ml), NaN 3 (3 mmol, 195 mg) was added and the mixture was stirred at 70 o C for 3-5 h.The solvent was removed in vacuo and the residue was extracted with dichloromethane-water.The organic layer was washed with brine, dried over MgSO 4 and evaporated to dryness.The crude product was dissolved in dry ether and 5% HCl in Et 2 O (1 mmol HCl) was added to precipitate the hydrochloride of the corresponding azide 2 or 9.The latter were not stable enough to be purified by chromatography or recrystallization and thus no analytical data are given.

General procedure for N-methylation
To an oil-free suspension of NaH (3 mmol, 114 mg 55-60% in oil) in dry THF (10 ml) heterocyclic compound 3, 6 or 11 (1.5 mmol) was added.The mixture was stirred at room temperature 15 min and methyl iodide (15 mmol, 0.8 ml) was then added.After 1 h stirring at room temperature the excess of NaH was quenched with water and the solvent was removed in vacuo.The residue formed was extracted with dichloromethane-water.The organic layer was washed with brine, dried over MgSO 4 and evaporated to dryness to afford the corresponding methylated product in quantitative conversion.trans,trans-1-Methyl-2,3,4-triphenylazetidine was prepared from hydrobromide or hydrochloride of trans,trans-2,3,4-triphenylazetidine 3; identical physical and spectral data with those of the known product.

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, C-N and C-O, are not equivalent.In contrast, the conformational preferences of equivalently built pyrimidinones show that a benzyl group gives rise to much stronger allylic strain than a methyl group.