Novel 14-Membered Hexaaza Macrocycles

An efficient method for the stereoselective synthesis of novel 14-membered cyclic bis-semicarbazones based on acid-catalyzed cyclization of the hydrazones of 3-(3-oxobutyl)semicarbazides has been developed. The starting semicarbazides were prepared according to a four-step strategy involving amidoalkylation of the sodium enolate of acetylacetone with N-(α-tosylbenzyl)carbamates followed by base-promoted retro-Claisen reaction and treatment of the obtained N-(3-oxobutyl)carbamates with hydrazine.

Compounds 5 can be synthesized by aza-Michael addition of carbamates to enones, 15 Mannich condensation of aldehydes with methyl ketones and carbamates, 16 reactions of N-alkoxycarbonylimines with ketones, 17 etc.The main drawbacks of the reported syntheses that strongly reduce their preparative value are small-scale preparations and the use of chromatography for isolation of the target products.
We supposed that compounds 5 could be obtained by retro-Claisen reaction of carbamates 6, which could be readily synthesized following our previousely reported approach based on amidoalkylation reactions. 18re we report the three-step synthesis of two examples of carbamates 5 on multigram scale via the preparation of carbamates 6 followed by retro-Claisen condensation, and the reaction of compounds 5 with hydrazine to provide the hydrazones of semicarbazides 4. The results of the acid-catalyzed heterocyclizations of 4, which unexpectedly gave 14-membered cyclic bis-semicarbazones instead of seven-membered cyclic semicarbazones 3, are described.

Results and discussion
The starting amidoalkylation reagents, ethyl N-(α-tosylbenzyl)carbamates 7a,b, were obtained by our convenient modification 18 of Engberts method 19 using p-toluenesulfinic acid (8) instead of sodium ptoluenesulfinate in the presence of formic acid.The three-component condensation of ethyl carbamate Next, we studied the reaction of carbamate 12a with hydrazine under various conditions using 1 H NMR spectroscopy.This reaction was found to proceed in two sequential steps involving a relatively fast formation of hydrazone 13a followed by slow substitution of the ethoxy group resulting in the target hydrazone of semicarbazide 14a (Scheme 3, Table 1).The latter could be readily isolated from the reaction mixtures after evaporation of all the volatiles under reduced pressure and treatment of the residues with ether in which compound 14a was poorly soluble.e Compound 14a was isolated in a 31% yield after evaporation of the reaction mixture in vacuo to dryness followed by treatment with Et 2 O and filtration.f Unidentified products were observed in the 1 H NMR spectrum along with 14a and 17. g Compound 14a was isolated in a 52% yield after evaporation of the reaction mixture in vacuo to dryness followed by treatment with Et 2 O and filtration.
The reaction of 12a with hydrazine hydrate or hydrazine in different solvents (EtOH, n-BuOH, Py) at room temperature or at reflux gave mixtures of hydrazone 13a and azine 16 (Table 1; entries 1-6, 11 and 12).The amount of azine 16 decreased with an increase in the reaction time (entry 1 vs entry 2), the use of an excess of N 2 H 4 (entry 2 vs entry 3), and when alcohols were used as solvents instead of pyridine (entries 3-6 vs entry 12).According to 1 H NMR spectroscopic data, hydrazone 13a was formed as a mixture of E-and Z-isomers, and azine 16 was a mixture of stereoisomers (up to 8) with significant predominance of two of them (Table 1).
Since the formation of semicarbazide 14a in the reaction of 12a with hydrazine in EtOH, n-BuOH and Py did not proceed, refluxing hydrazine or hydrazine hydrate was used as the solvent and reagent to induce the substitution of the ethoxy group.Under these conditions formation of azine 16 was completely suppressed, and gradual transformation of the intermediate hydrazone 13a into semicarbazide 14a (a mixture of E-and Z-isomers) was observed (Table 1; entries 7-9, 13).This transformation was practically complete in 24 hours.Dihydropyrazole 17 resulting from elimination of semicarbazide in 13a followed by ring closure was the major by-product formed in the reaction with hydrazine hydrate.Refluxing hydrazine gave the best results.Only 6% of dihydropyrazole 17 was observed after 20 hours (entry 13), and semicarbazide 14a was isolated in 52% yield.Under optimal conditions (N 2 H 4 , reflux, 23.5 h), compound 14a was obtained in 60% yield.Similarly, compound 14b was prepared in 65% yield from carbamate 12b.
The crude semicarbazides 14a,b were isolated as mixtures of E-and Z-isomers with significant predominance of one of them (up to 90%).Their configuration could not be determined unambiguously using a 1 H-1 H NOESY experiment in DMSO-d 6 .However, comparison of the experimental carbon chemical shifts for the CH 2 and CH 3 groups of the CH 2 C(=NNH 2 )CH 3 moiety in 14a with those calculated by the GIAO method at the RHF/6-311+G(2d,p) level using the DFT-B3LYP/6-31+G(d,p) optimized geometries for both (E)-14a and (Z)-14a clearly demonstrated that the major isomer of 14a had the (E)-configuration.The DFT calculations at the B3LYP/6-31+G(d,p) level also showed that the (E)-isomer of 14a was more stable (1.91 kcal/mol in DMSO) than the (Z)-isomer.Since the 1 H and 13 C NMR spectra of the major isomers of 14a and 14b were similar, we concluded that the major isomer of 14b also had the (E)-configuration.Since macrocycle 19a has two distant chiral centers, we expected it to form as a mixture of two diastereomers in approximately equal amounts.However, according to NMR spectra and X-ray analysis, only a single diastereomer of 19a with trans-orientation of the phenyl groups was obtained.Thus, formation of 19a via intermediate 20a could be excluded (Scheme 5).According to powder X-ray analysis, the crystallized macrocycle 19b was also a single diastereomer with trans-orientation of the aryl groups.Because of the extremely low solubility of analytically pure 19b, attempts to record its NMR spectra in solutions failed.However, the 1 H NMR spectrum (8489 scans) of a saturated solution of crude 19b in DMSO-d 6 showed two sets of signals of trans-and cis-isomers in a ratio of 91:9.Therefore, we suppose that compound 19b was similarly formed with high stereoselectivity according to the pathway shown in Scheme 5.

Conclusion
We have demonstrated that the acid-catalyzed cyclization of the hydrazones of 3-(3-oxobutyl)semicarbazides involving two molecules of the starting material provides an efficient stereoselective access to novel 14-membered cyclic bis-semicarbazones.The starting semicarbazides were readily prepared according to our original four-step approach involving amidoalkylation of the sodium enolate of acetylacetone with N-(α-tosylbenzyl)carbamates followed by base-promoted retro-Claisen reaction and treatment of the obtained N-(3-oxobutyl)carbamates with hydrazine.We hope that the obtained class of heterocycles could be of interest from various viewpoints, in particular, as new polyaza macrocyclic ligands for metal complexes.

Scheme 5 .
Scheme 5. A plausible pathway for the transformation of 14a,b into macrocycles 19a,b.

Table 1 .
Product distribution upon reaction of carbamate 12a with hydrazine.a In all cases the starting material was completely consumed.b According to the 1 H NMR spectra of the crude products obtained after evaporation of the reaction mixtures in vacuo to dryness, co-evaporation of the residues with toluene (2-4 times) and drying in vacuo.The amounts of azine 16 in mixtures with 13a were determined by comparision of the integral intensities of the NH 2 signals for 13a with those of the OCH 2 or CH 3 signals for 13a plus 16.
a c E/Z isomer ratios are given in parentheses.d Mixtures of stereoisomers.