1,3-vs. 1,5-Cyclization of azomethine ylides derived from 1-azabuta-1,3-dienes and difluoro-and dichlorocarbenes. Experimental and quantum-chemical study

1,3-vs. 1,5-Cyclization of azomethine ylides derived from 1-azabuta-1,3-dienes and difluoro-and dichlorocarbenes, leading to halogenosubstituted aziridine or pyrrole derivatives, was investigated. Calculations of the reaction profiles were carried out at the B3LYP/6-31G* level to evaluate factors responsible for the predominant transformation pathways of the ylides.


Scheme 1 ISSN 1557-7012
Reactions of carbenes and carbenoids with 1-azabuta-1,3-dienes have been studied poorly and only on an example of halosubstituted carbenes. 1,2The reaction of N-phenylimine of cinnamic aldehyde with dichlorocarbene resulted in the preparation of 2,2-dichloro-1-phenyl-3styrylaziridine (yield 64%) formed by 1,3-cyclization of the corresponding azomethine ylide. 3y contrast, azomethine ylides generated from N-alkyl-1-azabuta-1,3-dienes and aryl(chloro)carbenes undergo 1,5-cyclization to give 1,2,3-trisubstituted pyrroles in 15-65% yields. 46][7] At the same time, the products of the 1,5-cyclization of difluoroazomethine ylides, involving the C=C bond of the furan ring, have been obtained in good yields in the reaction of difluorocarbene with N-(5-R-furan-2-ylmethylidene)anilines. 6Since the formation of difluoroazomethine ylides in the reaction of difluorocarbene with imines have also been evidenced by the 1,3-dipolar cycloaddition to activated acetylenes and ethylenes, 2,[5][6][7] difluoroaziridines can be obtained by intramolecular nucleophilic substitution and are fairly stable, 8 the reason why these compounds do not form in the reaction of difluorocarbene with the C=N bond is unclear.The aim of the present experimental and theoretical research was to find out factors responsible for the nature of products of the reactions of difluoro-and dichlorocarbenes with 1-azabuta-1,3-dienes and for the direction of cyclization of halosubstituted azomethine ylide intermediates.

Results and Discussion
We studied the reactions of difluoro-and dichlorocarbenes with 1-azabuta-1,3-dienes 1a-d (Scheme 2).Difluorocarbene was generated by reduction of dibromodifluoromethane with active lead (obtained by reduction of aqueous lead acetate with sodium borohydride) in dichloromethane in the presence of tetrabutylammonium bromide under ultrasound irradiation.Dichlorocarbene was generated by thermal decomposition of sodium trichloroacetate in chloroform in the presence of benzyltriethylammonium chloride (TEBA).
It was found that the result of the reaction of azadiene 1а with difluorocarbene depends on the quantity of the source of difluorocarbene introduced in reaction.With 1.2 eq of the source of difluorocarbene, we isolated as the major product fluoropyrrole 2 (yield 23%).This product probably arises via intermediate formation of difluoroazomethine ylide 3, 1,5-cyclization of the latter into difluoropyrroline 4, and subsequent HF elimination (Scheme 3).

Scheme 3
The reaction with a double excess of the source of difluorocarbene gave, along with fluoropyrrole 2 (17%), trifluoromethylpyrrole 5 (13%) whose structure was proved by X-ray diffraction (Figure 1).With a triple excess of the source of difluorocarbene, trifluoromethylpyrrole 5 formed as a single product and was isolated in 34% yield (Scheme 4).
The reaction of azadiene 1a with dichlorocarbene resulted in preparation of compound 7 in 35% yield (Scheme 6).The structure of the product 7 was proved by 1 H, 13 C NMR spectroscopy and elemental analysis.The probable route to compound 7 involves formation of ylide 8, subsequent 1,3-cyclization of the latter into aziridine 9, and, finally, conversion of this unstable product into imidoyl chloride 10 (cf. 9

Scheme 7
The latter takes up trichloroacetyl chloride formed by thermolysis of the source of dichlorocarbene (sodium trichloroacetate) to give adduct 11.The adduct undergoes halophilic attack with trichloromethide to form anion 12 which cyclizes into pyrrolidone 13 whose subsequent hydrolysis gives rise to final reaction product 7 (Scheme 7).Similar processes were earlier observed in the hydrodechlorination of trichloroacetamides under the conditions of thermocatalytic decomposition of sodium trichloroacetate in chloroform. 10he reactions of azadienes 1b,c with dichlorocarbene afforded both 1:1 adducts, chloropyrroles 14a,b, and pyridine derivatives 15a and 16a,b formed from one molecule of azadiene and two molecules of dichlorocarbene (Scheme 8).The structures of all compounds were proved by 1 H, 13 C NMR spectroscopy and elemental analysis.The structure of compound 16a was further elucidated by X-ray diffraction (Figure 2).Chloropyrroles 14a,b are formed via 1,5-cyclization of dichloroazomethine ylides 17a,b, arising by the reaction of the starting azadienes with dichlorocarbene, into dichloropyrrolines 18a,b, followed by dehydrochlorination.Pyridone 15a is likely to be formed by the following mechanism.An electrophilic dichlorocarbene readily adds to a nucleophilic enamine C=C bond of pyrroline 18а to give cyclopropapyrrole 19a.Further, which is characteristic of aminosubstituted dichlorocyclopropanes, the three-membered ring undergoes cleavage by a bond opposite to the dichloromethylene group, yielding tetrahydropyridine derivative 20a (Scheme 9).Hydrolysis of the latter on silica during chromatographic treatment of the reaction mixture gives rise to pyridone 15a.Alternatively, the latter can arise via hydrolysis of salt 22а formed by dehydrochlorination of compound 20а.Thus, dichloroylides 17a,b formed by the reaction of azadienes 1b,c with dichlorocarbene, unlike dichloroylide 8 from azadiene 1a and dichloroylide from azadiene 1d, 3 undergo 1,5rather than 1,3-cyclization.
To find out reasons for the different behavior of difluoro-and dichlorosubstituted azomethine ylides and reveal factors responsible for the preferential cyclization pathway, we performed computations of reaction profiles using the Gaussian suite of quantum-chemical programs. 11Geometry optimizations of intermediates, transition states, reactants, and products in the gas phase were performed at the B3LYP/6-31G* level.For the sake of simplicity, as models for approximation of the chemical behavior of ylides from azadienes 1a-d we took azadienes 23a-c, 24a-c, in view of the expectation that the phenyl groups eliminated on passing from 1a-d to 23a-c,24a-c would not strongly affect both 1,3-and 1,5-cyclization of the corresponding ylides.Energy parameters of the reactions shown in Scheme 11 were obtained.

Scheme 11
According to the computation results, the most populated are ylides s-trans-23a-с (Figures 3, 8, 13).These results are consistent with the NMR spectra of 1-azabuta-1,3-dienes 1a-d.Compounds 1a-d were prepared by condensation of the corresponding aldehyde and amine.Therewith, a single (Е)-isomer of azadienes 1b-d and a mixture of the (Е) -and (Z)-isomers of azadiene 1a are formed. 12In the latter case, the major (Z)-isomer 1a was the only isolated in the crystalline state, and it was reacted with carbenes.
The computation results are presented in Figures 3-15.The resulting data show that the barriers to the formation of difluorosubstituted azomethine ylides in the reactions of difluorocarbene with azadienes 23-24a-c are 6.4-12.4kcal mol -1 , whereas the formation of dichlorosubstituted azomethine ylides in the reactions of dichlorocarbene with azadienes is barrierless.The lack of barriers to ylide formation in the case of dichlorocarbene is associated with the much higher energy of the latter, and is consistent with available reactivity data for these two species.Even if we assume that more advanced quantum-chemical approaches or an augmented basis set will reveal a low barrier (the fact that DFT B3LYP/6-31G(d) does not reveal this barrier suggests that it is very low), this by no means will affect conclusions given below.As follows from Figures 4-7, 9-12, 14, 15, there is a radical difference in the reactions of difluoroand dichlorocarbenes, leading to difluoro-and dichlorosubstituted azomethine ylides.This difference consists in that the barriers to 1,3-cyclizations leading to aziridines or 1,5-cyclizations leading to pyrrolines are always lower than the barriers to dissociation of these intermediates to the starting dichlorocarbene and azadiene, whereas the barriers to the corresponding cyclization reactions of difluorosubstituted azomethine ylides are mostly higher than the barriers to dissociation of these intermediates to the starting difluorocarbene and azadiene.In other words, dichlorocarbene reactions with azadienes are irreversible, whereas difluorocarbene reactions with azadienes are reversible.
Analysis of the computation results for the reaction of difluorocarbene with azadienes 23a, 24a shows that the barriers to the 1,3-cyclization of ylides 25 F a, 27 F a, 28 F a, 30 F a into the corresponding aziridines are higher than the barriers to dissociation of these intermediates into the starting materials.Pyrrole 31 F a can be formed only by 1,5-cyclization of ylide 28 F a which can result from either the reaction of difluorocarbene with azadiene s-cis-23a or s-trans s-cisisomerization of ylide 25 F a. Since azadiene s-trans-23a the most populated (Figure 3) and more reactive than azadiene s-cis-23a (Figure 4), ylide 25 F a is preferentially formed.However, the latter prefers to dissociate rather than to izomerize into ylide 28 F a. As a result, difluorocarbene is consumed in reactions whose barriers are lower than the barrier to the isomerization 25 F a → 28 F a, equal to 10.5 kcal mol -1 , for example, in dimerization leading to tetrafluoroethene. 13These computational results explain the absence of both 1,3-and 1,5-cyclization products in difluorocarbene reactions of azadienes 1b,c.
A different picture is observed in dichlorocarbene reactions.The reaction of dichlorocarbene with the most populated azadiene s-trans-23a (Figure 6) gives rise to ylide 25 Cl a whose barrier to cyclization into aziridine 26 Cl a (10.2 kcal mol -1 ) is higher than the barrier to conversion into ylide 28 Cl a (9.4 kcal mol -1 ).The latter may also be formed by the reaction of dichlorocarbene with the second most populated azadiene s-cis-23a (Figure 6).Ylide 28 Cl a has a much lower barrier to 1,5-cyclization into pyrroline 31 Cl a (2.8 kcal mol -1 ) than that to 1,3-cyclization into aziridine 29 Cl а (14.2 kcal mol -1 ).These data fit experimental results, namely, the formation of pyrrole derivatives 14a,b and their subsequent reaction products, compounds 15a and 16a,b, in the reactions of dichlorocarbene with azadienes 1b,c.2-Phenyl substitution in azadienes 23, 24 produces considerable changes in the energy characteristics of both their reactions with carbenes and reactions of the corresponding ylides.Moreover, an appreciable change in the relative population of azadienes themselves is observed (Figure 8).The reaction of difluorocarbene with the most populated azadiene s-trans-23b results in formation of ylide 25 F b whose barrier to isomerization into ylide 28 F b (6.6 kcal mol -1 ) lower than the barrier to dissociation into the starting molecules (7.1 kcal mol -1 ) and 1,3-cyclization into aziridine 26 F b (7.8 kcal mol -1 ) (Figure 9).Ylide 28 F b has a low barrier to 1,5-cyclization into pyrroline 31 F b (4.3 kcal mol -1 ), which is much lower than the barrier to its dissociation into the starting azadiene and difluorocarbene (10.5 kcal mol -1 ) (Figure 9).By contrast, the barriers to dissociation of ylide 27 F b, 30 F b is lower than the barriers to their 1,3-cyclization into aziridines 26 F b, 29 F b (Figure 10).Thus, the fact that we obtained pyrrole 2 in the reaction of azadiene 1a with difluorocarbene completely agrees with computation results, and the formation of this product is most likely to occur via addition of difluorocarbene to s-trans-azadiene 1а, isomerization of s-trans-isomer ylide 2а to s-cis-isomer, and cyclization of the latter.In going from N-methylazadienes 23a, 24a to N-phenylazadienes 23c, 24c, the relative stability of azadiene isomers changes only slightly, but the energy profiles for formation and reactions of the corresponding difluoro-and dichloroylides are affected considerably (Figures 3,  13-15).The reaction of difluorocarbene with the most populated azadiene s-trans-23c (Figure 13) gives rise to ylide 25 F c. Compared to ylide 25 F b, ylide 25 F c has a lower barrier to 1,3cyclization into aziridine and higher barrier to transformation into ylide 28 F c which might further transform into pyrroline 31 F c (Figure 14).Therewith, the barrier to dissociation into the starting molecules decreases and becomes lower by 5.2 kcal mol -1 lower than the barrier to 1,3cyclization into aziridine.As a result, difluorocarbene is consumed in side reactions with barriers lower than 11.9 kcal mol -1 .These results explain the absence of both 1,3-and 1,5-cyclization products in the reaction of difluorocarbene with azadiene 1d.
In the reaction of this azadiene with dichlorocarbene, replacement of the N-methyl substituents by N-phenyl, too, decreases the barrier to 1,3-cyclization into aziridine and increases the barrier of the isomerization 27 Cl с → 28 Cl c (Figure 15).Therewith, the barrier to 1,3cyclization of ylide 27 Cl с turns to be 4.9 kcal mol -1 lower than the barrier to isomerization into ylide 28 Cl c which might further transform into pyrrolidine 30 Cl c.There results are consistent with experimental data, 3 namely, the formation of dichloroaziridine from azadiene 1d in the reaction with dichlorocarbene and the absence of the corresponding pyrrole derivatives from the reaction products.Thus, our experiments gave evidence to show that the reactions of 1-azabuta-1,3-dienes with difluoro-and dichlorocarbenes are quite sensitive to substituents in the azadiene and to the nature of the halogen.As follows from computations, the reactions of dichlorocarbene with azadienes are generally irreversible, whereas the reactions of difluorocarbene with azadienes are reversible.Reaction result is also strongly dependent on the geometry of the azadiene, since it predetermines the geometry of the primary azomethine ylide intermediate.Kinetic ylides formed from the most stable s-trans-azadienes are incapable to 1,5-cyclization into pyrrolines, and the latter can arise exclusively via s-trans → s-cis-isomerization of the primary ylide.As shown by computations and experiments, this process is made possible by a certain structural modification of the ylide, i.e. introduction of substituents.With difluoroylides whose 1,3-cyclization is unfavored by energy and does not compete with other processes, the s-trans-ylide → s-cis-ylide isomerization is facilitated by introduction of a bulky (Ph) substituent in the 2-position of the parent azadiene.By contrast, with dichloroylides the s-trans → s-cis isomerization leading eventually to pyrroline formation is realized only in the absence of Ph substituents in the 1 and 2 positions.Phenyl substitution in one of these positions produces such a strong decrease in the 1,3-cyclization barrier that aziridine formation becomes the major reaction.The observed difference in the effects of substituents in the azadiene on the structure and behavior of difluoroand dichloroylides is associated not only with the difference in the van der Waals radii of chlorine and fluorine, but also with the pyramidalization of the NCHlg 2 fragment on replacement of chlorine by the more electronegative fluorine.
Comparison of the experimental and computational results for dihalocarbene reactions with azadienes leads us to conclude that DFT methods at the simple B3LYP/6-31G* level of theory which allows profound computations without severe simplification of real structures can be used for selecting substrates for purposeful synthesis of 1,3-or 1,5-cyclization products.

Experimental Section
General Procedures.The melting points were determined on a Boetius melting point apparatus (uncorrected values are given). 1H (300 MHz) and 13 C (75 MHz) NMR spectra were measured with a Bruker DPX 300 spectrometer and 19 F NMR (235 MHz) with Brucker Avance 250 spectrometer.13C NMR assignments were made using DEPT spectra.Microanalyses were performed on a EuroEA3000 (Eurovector).The mass spectra were run on MAT-731 and MAT CH-7 instruments.X-Ray crystallography data were collected with a STOE IPDS II instrument, using graphite monochromatized MoKα radiation (λ = 0.71073 Å).Complete crystallographic data, as a CIF file, have been deposited with the Cambridge Crystallographic Data Centre (CCDC Nos 670514 & 670515).Copies can be obtained free of charge from: CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. (e-mail: deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk/deposit).
The reaction mixtures were separated by column chromatography on Merck-60 silica gel.Methylene chloride and chloroform were dried by distillation over P 2 O 5 .Commercial tetrabutylammonium bromide was dried in a dessicator over Р 2 O 5 .Compounds 1a-d were prepared by condensation of the corresponding aldehyde and amine.Active lead was prepared as described earlier.7a

Figure 2 .
Figure 2. Perspective view of the X-ray crystal structure of 16a.