Intermolecular 1,3-dipolar cycloadditions of azomethine imines

Dipolar cycloadditions of azomethine imines, formed in situ from aldehydes and N 1 -alkyl- N 2 - acylhydrazines, with electron-deficient dipolarophiles produce pyrazolidines: mono-substituted dipolarophiles afford principally 4-substituted pyrazolidines


Introduction
As part of our research effort into the preparation of peptidomimetics containing 5-membered heterocyclic rings, 1 we wished to investigate the synthesis of pyrazolidines (tetrahydropyrazoles) 1, Scheme 1.
Our ultimate targets were constrained mimics of the types 3 and 4 as replacements for the dipeptide unit 5. 2 The incorporation of a cyclic moiety into a peptide backbone can restrict the conformational freedom of the peptide and these so-called peptidomimetics 3 can possess enhanced biological activity or increased selectivity towards specific receptor sites.The pyrazolidine ring is accessible via 1,3-dipolar cycloaddition reaction of an azomethine imine 2 with an appropriately substituted alkene (Scheme 1), 4 that has the potential to generate three new chiral centers at C-3, C-4 and C-5.It is perhaps not surprising that many of the reported examples of cycloadditions involving azomethine imines have been intramolecular, allowing some control to be exercised over the regio-and stereochemistry of the product. 5zomethine imines are available from the addition to an aldehyde, 6, of a 1,2-disubstituted hydrazine 7, 6 resulting in the formation of an aminol, 8 (Scheme 2) that loses the elements of water to form the dipole. 7Certain restrictions are placed on the hydrazine substituents; if R 2 = H, then the aminol eliminates water to form a stable hydrazone, and it is also usual for R 3 to be an electron-withdrawing group in order to stabilize the formal negative charge on the dipole 2.
In order to progress towards our long-term objective, and since intermolecular cycloadditions with azomethine imines had been relatively little studied, we have examined the scope and limitations of the reaction, investigating the effects of varying the nature of the different components: the aldehyde, hydrazine and dipolarophile.The results of this exploratory work are described herein: our report is prompted by recent related studies using rigid cyclic azomethine ylides. 8,9

Results and Discussion
As an orienting cycloaddition, benzaldehyde (lacking α-hydrogen atoms), N 1 -acetyl-N 2methylhydrazine 9 (selected as meeting the criteria outlined earlier, and prepared simply from ethyl acetate and methylhydrazine 10 ) and methyl propenoate (a simple mono-substituted dipolarophile) were reacted together (Scheme 3) in toluene at reflux for 72 h under Dean-Stark water removal. 11Whereas the syn-isomer 10 was obtained pure following column chromatography, preparative HPLC was necessary to separate the anti-isomer 11 from a trace impurity.Although it was not possible to isolate this latter material in pure form, it was tentatively assigned as the 5methoxycarbonylpyrazolidine 12 based on its signals in the 1 H NMR spectrum of the mixture.Also isolated from the reaction mixture were the trisubstituted hydrazine 13 (33%; incompletely characterized), formed by conjugate addition of the hydrazine to methyl propenoate, 8 and the hexahydrotetrazine 14 (27%) presumably arising from dimerization of the dipole, a reaction that has been observed by others. 6,7,12In an attempt to improve the efficiency of the reaction and minimize the formation of these unwanted by-products, the effect of altering the reaction conditions was investigated.
Although the use of a Dean-Stark trap would appear necessary to promote formation of the dipole, cycloadditions of azomethine imines have been carried out in the presence of a molar equivalent of water. 8When the reaction was attempted either without water removal or with one molar equivalent of water added, a reduction in yield of the cycloadducts 10 and 11 and the hexahydrotetrazine 14 was observed, suggesting that dipole formation had been inhibited.A significant proportion of the azomethine imine dimerizes to form 14 in preference to cycloaddition.Triethylamine has been reported as an effective suppressant of dipole dimerization during the cycloaddition of azomethine imines; 13 however, a reaction performed in the presence of 3 molar equivalents of base did not result in a significant drop in the quantity of dimer 14 formed.Lowering the reaction temperature to that of benzene at reflux, or to ambient temperature (using 4Å molecular sieves to remove water), gave reduced yields of 10 and 11.To minimize the conjugate addition (to form 13) that competes with dipole formation, an extra molar equivalent of aldehyde was used but this resulted in only a slight increase in the yields of 10 and 11.Increasing the amount of hydrazine present so that complete conversion of the aldehyde to the dipole could take place despite any conjugate addition likewise produced a similar, marginal improvement.We were thus unable to improve significantly upon the initial yield, and so turned our attention towards the reaction of the azomethine imine with other dipolarophiles (Scheme 4).
Cycloaddition of the azomethine imine with acrylonitrile gave the syn-and anti-4cyanotetrahydropyrazoles 15 (15%) and 16 (10%) respectively.The regiochemistry of the products was again determined by 2D NMR spectroscopy.The relative stereochemistry was assigned by comparison with the 1 H NMR spectra of the 4-methoxycarbonyltetrahydropyrazoles 10 and 11, for which C-4(H) resonates at δ 3.94 for the syn-isomer 10 and δ 3.45 for 11.The corresponding values for cycloadducts 15 and 16 are δ 3.78 and δ 3.44, respectively.In addition, the coupling constant 3 J 3,4 is larger in isomer 15 than in 16 (6.6Hz compared to 6.0 Hz) which compares favorably with the values for 10 and 11 (7.7 Hz and 5.9 Hz, respectively).The antiisomer 16 was not isolated in pure form as it contained traces of an impurity (assigned from the 1 H NMR spectrum of the mixture as the 5-substituted pyrazolidine) inseparable by chromatography.
When the symmetrical 1,2-disubstituted dipolarophile, dimethyl fumarate was used, the anti, anti-product 17 (38%; stereochemistry determined by n.O.e.experiments) was isolated along with an inseparable mixture of further 17 (21%) and an isomer tentatively assigned from the 1 H NMR spectrum as the syn, anti-product 18 (6%).Dimethyl maleate as dipolarophile afforded only one pure isolated product (11%), all-syn 19, assigned on the basis of n.O.e.experiments.A mixture of further unidentified cycloaddition products (22%) was also obtained.Only two diastereoisomers, the all-syn 19 and the anti, syn-isomer (having both ester substituents anti-to the phenyl substituent) can arise from concerted cycloaddition.However, since at least three different cycloadducts appeared to be formed, this suggests some conversion of dimethyl maleate into the more stable fumarate before cycloaddition.Reaction of the dipole with Nphenylmaleimide, usually a very reactive dipolarophile, resulted in isolation of one cycloadduct, the anti, syn-isomer 20 (stereochemistry again determined by n.O.e.studies) in a disappointing yield of 4%.We next examined the effect of altering the aldehyde.Replacing benzaldehyde by 2methylpropanal (heating only for 16 h) gave the 4-substituted pyrazolidines 21 and 22, in 25% and 11% yield, respectively (Scheme 5).The regiochemistry was determined by 2D NMR spectroscopy, the stereochemistry by comparison with data for 10 and 11. 14 Also isolated was the 5-substituted isomer 23 in 1% yield (stereochemistry undetermined).Cycloaddition is thus possible when the aldehyde bears a simple alkyl or aryl group.Next we examined the use of more functionalized aldehydes, particularly those that would offer the exocyclic amino functionality present in the tetrahydropyrazoles 3 and 4. Subjecting the Bocprotected α-amino aldehyde 24 (synthesized from S-alanine 1a,15 ) to the normal cycloaddition conditions with methyl acrylate did not give the expected adducts, but instead gave cyclization involving the carbamate functionality to afford the dihydrooxazole 25 (27%) (Scheme 6).The N,N-dibenzylated aldehyde 26 (prepared by tribenzylation of S-alanine with PhCH 2 Br-K 2 CO 3 , reduction of the benzyl ester using LiAlH 4 , and Swern oxidation of the resulting 2dibenzylaminopropan-1-ol 16 ) was employed to prevent this, but instead gave rise to the 2,3dihydro-1,3,4-oxadiazole 27 from an alternative cyclization involving the hydrazine N-acetyl group (Scheme 6).2-Benzyloxypropanal 28 (prepared by benzylation of ethyl lactate using PhCH 2 Br-NaH and reduction of the ester with DIBAL at -50˚C) gave the analogous product 29.Products 25, 27, and 29 were incompletely characterized.The presence of an electronegative atom αto the dipole carbon atom thus seems to encourage formation of charge-neutral molecules 27 and 29 over reaction with the dipolarophile; this may be because of a destabilization of the dipole.Attempts to carry out cycloadditions using 2-oxopropanal (methyl glyoxal) or ethyl glyoxylate as aldehyde component were unsuccessful, the only product isolated in each case being the conjugate addition product 13 (see above).
We next turned our attention to two further hydrazines.The N 1 -acetyl-N 2 -benzylhydrazine 30, formed via reductive alkylation of N-acetylhydrazine using benzaldehyde, 17 afforded cycloadduct 31 in only 4% yield upon reaction with 2-methylpropanal and methyl propenoate (Scheme 7) in a sealed tube for 72 h, with molecular sieves being used to remove water.The increased steric bulk of the hydrazine substituent seemed to hinder the cycloaddition.We assume this adduct to be a 4-methoxycarbonylpyrazolidine 31, based on the precedent above, although it proved impossible to determine unequivocally either the regio-or stereo-chemistry of this product as the C-4 and C-5 methine protons were indistinguishable by NMR spectroscopy.Similarly, N 1 -tert-butoxycarbonyl-N 2 -methylhydrazine 32 18 afforded the tetrahydropyrazole 33 (18%) as the only cycloadduct from reaction with benzaldehyde and methyl propenoate (Scheme 8).Once again the structure of this product is assumed to be that shown, although the signals for C-4(H) and one of the methylene protons could not be distinguished by NMR spectroscopy, hindering elucidation of the regio-and stereochemistry.

Conclusions
7][8] A variety of mono-and 1,2-disubstituted dipolarophiles can be used, but the cycloaddition is more sensitive to structural variations in the hydrazine and aldehyde.No cycloadditions were observed with an aldehyde bearing an α-heteroatom functional group, so the only pyrazolidines accessible using this approach are those with alkyl or aryl substituents at the C-3.

Experimental Section
General Procedures.Melting points were determined using a Kofler hot-stage apparatus and are uncorrected.Combustion analyses were performed by MEDAC Ltd. (Englefield Green, Surrey).Accurate mass measurements were carried out by the EPSRC National Mass Spectrometry Service Centre (University of Wales Swansea).Infrared spectra were recorded using a Perkin-Elmer 1710 FT-IR spectrometer. 1 H NMR spectra were obtained at 400 MHz on a JEOL JNM-EX400 or at 300 MHz on a JEOL JNM-LA300 spectrometer. 13C NMR spectra were recorded at 100 MHz or at 75 MHz, respectively, on the same instruments.Low resolution mass spectra were recorded on a VG Micromass VG20-250 spectrometer or by the EPSRC National Mass Spectrometry Service Centre (University of Wales Swansea).Crystallographic measurements were carried out by the EPSRC X-Ray Crystallography Service (University of Southampton).All reagents were purified by distillation or recrystallization where appropriate, or according to standard procedures. 19Anhydrous toluene was obtained commercially.Column chromatography was carried out using Fluka Silica Gel 60 (220-440 mesh).Preparative HPLC was performed using a Waters Delta Prep 3000 instrument fitted with a Jones Apex 2 silica column (5 micron, 25cm x 21mm i.d.).