Nitriles in Heterocyclic Synthesis: Novel Syntheses of Functionally Substituted Isoxazoles, Pyrazoles, Pyrazines and their Condensed Derivatives Said Ahmed Soliman Ghozlan, Fatma Abd El Maksoud Abd El Aal, Mona Hassan Mohamed, and Mohamed Hilmy Elnagdi* Department of Chemistry, Faculty of Science, Cairo University, A. R. Egypt Z. Naturforsch. 41b, 489—495 (1986); received July 26, 1985 a-Oximinonitriles, 13C NMR Spectra, Aminoisoxazole Novel syntheses of functionally substituted isoxazoles, pyrazoles and pyrazines have been re­ ported utilizing ethyl tosyloximinoglyoxalate (1) and the pyridinium salt 2 as starting materials. Functionally substituted nitriles are versatile reagents and their utility in heterocyclic synthesis has received considerable recent attention [3 — 7]. In previous work we have reported several new approaches for the synthesis of azoles, azines and azoloazines utilizing simple readily obtainable polyfunctional nitriles as starting materials [8—12]. Although 1 and 2 can be readily prepared from ethyl cyanoacetate, however, their utility in synthesis of heterocycles has received only very little attention [1, 2, 13—16]. HcC,OOC CN 2 \ / C n - o - s o 2 ^ O V CH3 1 2 Compound 1 reacted with cyanothioacetamide in the reaction product revealed a carbonyl band at ether in the presence of pyridine to yield the pyrazine 1680 cm-1. If the reaction product was 8 one would derivative 3 or its tautomers (4 and 5). The formation expect the ester carbonyl absorption at shorter wave of 3 is assumed to proceed via 6 . Since the IR spec­ length. 13C NMR also revealed that only one trum revealed the absence of a CO absorption, the tautomer predominates in DMSO solution and could reaction product was considered to exist mainly in be intelligably interpreted in terms of structure 8 . It the hydroxy form 4 or the hydroxymercapto form 5. was observed, however, that the o- and ra-carbons in Compound 1 reacted with benzoylacetonitrile to the benzoyl moiety are not magnetically identical yield a product of molecular formula C 14H 11N 3O 3 which may be rationalized in terms of existence of (M.Wt. 269, M+ = 269). This product was assumed electrostatic attraction between the cyano group n- to be formed through condensation of 1 with ben­ cloud and the positive charges on the benzoyl o-car- zoylacetonitrile via elimination of p-toluenesul- bons, a factor which slows down the rate of rotation phonic acid. Three tautomeric structures are possible of the phenyl group. Moreover, the two o-carbons for the reaction product (cf. structures 7—9). IR and were observed at much higher field than expected for 13C NMR revealed clearly that the enol form 9 does aroyl o-carbons. This again can be reationalized in not exist either in solid state or in solution. Thus, the terms of deshielding by CN group anisotropy. IR spectrum of the reaction product revealed the Assignment of 13C NMR of the signals was made absence of any absorption for the hydroxy group. utilizing the data tabulated by Breitmaier and Voel- Also it revealed absorptions for two cyano groups, ter [17], as well as comparison with data obtained for the carbonyl and azomethine functions. It appears model molecules [18]. from the IR spectrum that form 7 predominates as Compound 7 could be converted into the pyrazine derivative 10 or its tautomer 11 on treatment with hydrazine hydrate at 110 °C in the absence of sol­ * Reprint requests to Prof. Dr. M. H. Elnagdi. vents. 'H NMR spectrum revealed two signals at Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen b 2.7 ppm and b 2.8 ppm for one proton, indicating 0340-5087/86/0400-0489/$ 01.00/0 the presence of both tautomers. 490 S. A. S. Ghozlan et al. • Nitriles in Heterocyclic Synthesis NC ^NL CN NC .N . CN NC . N . CN NC .N ^ CN H5C2OOC H,N -O r N xSH - xHO N xS -HO x X .: N SH H 0 NCCH2C-NH2 0 II RhCCH2CN * * V 113.1 ^ ' 113.6 V \ 9\ 7 103 7/s NC ^N. CN NCA .Nx 1 CN NC „N^ CN 9 T X , An An 12 3' 7 CO C CO CO CU-l3LH,U-<- H ,C H ,0 -C = 0U C // ■*-130.0 / / \ h 5c 2o Ph / \ / o f Z H H5c 20 HO Ph 14.3 59.6 164.3 / / 127. 9 186.1 143.1 7 n h 2 n h 2. h 2o N ^ ^COPh T HNx A HN. N N NH2 N X N NH, 10 11 * Can be interchanged. Compound 2 reacted with hydroxylamine vealed the signal at d 14.1 ppm as quartet, hydrochloride in refluxing ethanol in the presence of (7= 150.5) and the signal at d 60.6 ppm as triplet, sodium acetate to yield a product of molecular for­ (7 = 210.7) where other signals appeared as singlets. mula C 8H 12N 60 4 (M.Wt. 256, IVT = 256). Several Since the carbons other than those linked to the ester isomeric structures for the reaction product are pos­ function did not reveal any C—H coupling structures sible (c/. structures 12—17). 'H NMR spectrum of 12 and 14 were excluded as both have carbon linked the reaction product revealed a triplet at d 1.2 ppm to hydrogen atom. The presence of two signals at for three protons, two proton quartets at d 4.2 for <5 116.5 and d 111.0 ppm also excluded the pyrazines the ester group and three 2 proton singlets at d 5.9, 13 and 15 as pyrazine carbons as well as amidoxime d 7.7 and d 10.0 ppm. These data can be interpreted carbons are expected to appear at d values higher for any one of the structures 12—17. The IR spec­ than d 128 ppm. Thus, structure 16 was assigned for trum revealed bands for carbonyl, azomethine and the reaction product. The signal at d 150.5 ppm was amino functions but revealed no cyano group absorp­ assigned for the amidoxime carbons, the signals at ö tion. The 13C NMR revealed signals at d 14.1, 60.6, 116.5 and 147.0 ppm were assigned to the isoxazole 111.0, 116.5, 145.1, 147.0, 150.5 and 165.2 ppm. The C-4 and C-5, the signal at d 145.1 ppm was assigned signals at d 14.1, 60.6 and 165.2 ppm were assigned for isoxazole C-3 and d 111.0 ppm for the carbon for the ester CO — CH 2—CH> Proton coupling re­ linked to azomethine function [17], S. A. S. Ghozlan etal. • Nitriles in Heterocyclic Synthesis 491 165.2 60.6 U.1 16 NH, H,N NO COOC,H2 5 N NH, 17 Compound 16 reacted with hydrazine hydrate at into the isoxazolo[3,4:5',6']-isoxazolo[3,4-b]pyrazine 140 °C (bath temperature) to yield only the hy- derivative 20 when boiled in acetic anhydride for a drazide 18. Treatment of 16 with acetic acid-hydro- long period. Compound 19 in turn was converted chloric acid mixture afforded the isoxazolo[3,4-b]- into 20 on refluxing in acetic anhydride, pyrazine derivative 19. Compound 16 could be cyclized NOH H ,N 16 A c ,0 AcOH / HCl 0 o NOH II ii H,C-C-HN NH-C-CH 3 H C l• H2N NH2 A c ,0 0. •N N N N OH 20 19 492 S. A. S. Ghozlan et al. ■ Nitriles in Heterocyclic Synthesis Compound 2 reacted with thiourea to yield a pro­ tained as the only isolable product. 13C NMR spec­ duct which was formulated as pyrimidine derivative trum of the mixture revealed that it is a mixture of 21. the hvdrazinium salt 22 and the pyrazole derivative Compound 2 reacted with hydrazine hydrate in re- 23. Thus, 13C NMR revealed three signals for both fluxing ethanol to yield a mixture of two products CH3 and CH 2 carbons, both showed the correct non of which could be isolated in a pure state. coupling patterns. Also the signals for the CN band Although on TLC two different components could at d 113.0 ppm and 113.2 ppm were assigned for be observed, trials to chromatograph the reaction three CN groups. The ester C = 0 function appeared mixture were unsuccessful!. However, when this as two carbons at d 165 ppm and d 163 ppm for the mixture was refluxed for a short period in acetic acid- ester function of the hydrazinium salt 22 and the hydrochloric acid mixture the pyrazolo[3,4-b]- ester function of pyrazole derivative 23. Signal at pyrazine derivative 24 was obtained. Moreover, d 119.2 was assigned for C-4, and signal at when the mixture was treated with hydroxylamine d 149.4 ppm was assigned for C-5 and C-3 in the hydrochloride in refluxing ethanol in the presence of pyrazole component and the signal at d 96.0 ppm sodium acetate the isoxazole derivative 16 was ob­ was assigned for the azomethine linkage in the HCl • H ,N N . COOH I "N N ^ N H 2 • HCl 24 A c O H /H C l K5.5 U9.1 113.0 1 4 9 .4 5 113.2 NC H,N ■N. | CN <«— 113.0 NH 3 NH2 + |5' l3 2 1 2 1 HN. .c -o ch 2-c h , NC' 0=C-0CH7-CH, 2 (ft t t t t t t 165.0 60.6 14.3 113.2 163.2 59.8 14.2 NH 2 NH2 • H 20 22 23 N ,H — C — NH, 21 PhNHNH 2 Ph-HNHN N ^ C N P h -H N -N N ^ ,C N > COOC2 H 5 P h -N .