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 x SH- xHO N x S - 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 . P h -N ^ C ° 0C 2H5 N 'N H 2 'N NH 2 25a 25b

Ph-HNHN ^Nv^/COOC2H5

P h -N , CN 'NH, 25c S. A. S. Ghozlan et al. ■ Nitriles in Heterocyclic Synthesis 493

pyrazole component. The signals at ö 145.5 and formed by Microanalytical data Center at Cairo Uni­ d 149.1 ppm were assigned for the two carbons versity. linked the nitrogen bridge in the hydrazinium salt. Compounds 1 and 2 were prepared following liter­ In contrast to the behaviour of hydrazine hydrate, ature procedures [ 1 , 2 ]. phenylhydrazine reacted with 2 to yield a product of molecular formula C 2oH 19N 70 2 (M.Wt. 389, M+ = Reaction of 1 with cyanothioacetamide (3) 389), (cf. 25a—c). 13C NMR revealed that compound To a cold solution of cyanothioacetamide 25 exists as an equilibrium mixture of forms 25 a—c as (0.01 mol) in a mixture of pyridine (2 ml) and ether it revealed more than one signal for every carbon in (5 ml) was added dropwise a solution of 1 (0.01 mol) the molecule. in ether (100 ml). The reaction mixture was left over­ night, diluted with water and then acidified with con­ Experimental centrated hydrochloric acid. The solid product, so formed, was collected by filtration, washed with All melting points are uncorrected. IR spectra water till the filtrate become neutral to litmus and were recorded (KBr) on a Pye Unicam SP-1000 spec­ the product was crystallized from the proper solvent trophotometer. 'H NMR spectra were recorded on a (cf. Table I). Varian EM 390-90 MHz spectrometer using DMSO as solvent and TMS as internal reference. Chemical Reaction of 1 with benzoylacetonitrile (7) shifts are expressed in values. 13C NMR were meas­ ured on a Varian EM 390-90 MHz in the Institut für The same experimental procedure described Organische Chemie, Technische Hochschule Darm­ above for preparation of 3 was adopted, and the re­ stadt, Bundesrepublik Deutschland. Mass spectra sulting mixture was diluted with water. The product were recorded on a Mass spectrometer Ms 30 and was filtered off and crystallized from the proper sol­ Ms 9 (AEI) 70 eV. Microanalytical data were per­ vent (cf. Table I).

Table I. Compounds 3, Compound Cryst. M.p. Yield Molecular Analysis (%) 10, 16, 18-25. (colour) solvent (°C) (%) formulae found/(required) (M .W t.) C H N S

3 EtOH 140 80 q h ,n 4o s 40.6 1.4 31.6 18.0 (brown) (178) (40.4 1.1 31.5 17.9) 7 EtOH 108 80 C 14H 22N3O3 62.6 4.1 15.7 (yellow) (269) (62.5 4.1 15.6) 10 EtOH >300 60 CpH.NsO, 56.2 3.2 27.9 (yellowish brown) (255) (56.5 3.5 27.4) 16 EtOH 272 90 c 8h 12n 6o 4 37.5 4.7 32.9 (yellow) (256) (37.5 4.7 32.8) 18 AcOH >300 60 C6H 10N8O3 29.4 4.0 46.5 (reddish brown) (242) (29.7 4.1 46.3) 19 AcOH >300 60 c 6h 7n 6o 3ci 29.4 2.6 33.6 (brown) (246.5) (29.2 2.8 34.1) 20 AcOH >300 70 c„)H 8n 6o 4 43.1 3.5 (brown) (276) (43.4 3.4) 21 d m f -h 2o >300 60 c 9h 10n 6o 2s 40.2 3.6 11.8 (yellow) (266) (40.6 3.7 12. 1) 22 and 23 EtOH 182 85 c 8h 1(1n 6o 2 43.1 4.5 37.8 (orange) (222) (43.2 4.5 37.8) 24 AcOH >300 60 C6H8Nft0 2Cl2 27.4 2.6 32.0 (brown) (266) (27.1 2.7 31.6) 25 EtOH 142 80 C,nH 19N70 , 61.8 5.0 25.1 (red) (389) (61.6 4.9 25.0) 494 S. A. S. Ghozlan et al. • Nitriles in Heterocyclic Synthesis

Reaction of 7 with hydrazine hydrate and sodium acetate (1 g). The reaction mixture was then heated under reflux for 30 min. The product Compound 7 (0.01 mol) was treated with hy­ was filtered off and crystallized from the proper sol­ drazine hydrate ( 0.01 mol) and the mixture was vent ( c f Table I). heated on a water bath for 2 h. The precipitated product was triturated with ethanol, collected by filtration and crystallized from the proper solvent Reaction of 16 with hydrazine hydrate (cf. Table I). A mixture of compound 16 (0.01 mol) and hydrazine hydrate ( 0.01 mol) was heated for 2 h at Reaction of 2 with hydroxylamine hydrochloride 140 °C (bath temperature). The solid product so To a solution of 2 (0.01 mol) in ethanol (100 ml) formed, was triturated with ethanol, filtered off and was added hydroxylamine hydrochloride ( 0.01 mol) crystallized from the proper solvent (cf. Table I).

Table II. IR and l3C NMR data for compounds listed in Table I.

Compound Amax/crn 1 (selected bands) 13C NMR (<3) ppm (M +)

3 3160-3340 (NH. OH); 2200, 2185 (CN); 1610-1630 (C=N) and NH) 7 2180, 2190 (two CN); 1685 (benzoyl CO); 14.3 (C -l, t, CH,); 59.6 (C-2, q. CH,); 164.3 (C-3); (269) 1675 (ester CO); 1460-1650 (C=N) 103.7, 143.1 (C-4); 91.7, 144.5 (C-6); 186.1 (C-7); 113.6. 113.1 (C-8. C-9); 127.1. 127.9. 130.0, 138.2. 145.0. 143.1 (Ph carbons) 10a 3400-3460 (OH and NH,); 1660-1680 (CO); 1620-1640 (C = N ); 1600 (<5NH) 16b 3455, 3420, 3340, 3240 (NH, and OH); 1690 (CO); 14.1 (C-l, t, CH3); 60.6 (C-2. q. CH,); 165.2 (C-3); 1650 und 1620 (C =N and dNH) 111.0 (C-4); 150.5 (C-5); 116.5 (C-4 isoxazole); 145.1 (C-3 isoxazole); 147.0 (C-5 isoxazole) 18 3440, 3380. 3290 (OH, NH,); 1640 (CO, C=N) 19 3100-3400 (NH, and OH); 1620-1640 (6NH; and C=N) 20 br 3100-3480 (NH); 1710 (CO); 1640 (C =N and NH) 21 br 3300-3400 (NH,); 2210 (CN); 1650 (CO); 1640 (C =N and NH,) 22 and 23 br 3300-3380 (NH,); 2210. 2190 (two CN); 14.2. 14.3 (t, CH3); 59.8, 60.6 (q. CH,); (222) 1680 (CO); 1650 (C =N and <5NH,) 96.0 (azomethine linkage in pvrazole); 113.0. 113.2 (three CN); 119.2 (C-4 pyrazole); 149.4 (C-3, C-5 pyrazole); 145.5, 149.1 (C-4, C-6. in hydrazinium salt); 163.2, 165.0 (CO), in hydrazinium salt and pyrazole) 24 3140-3380 (NH, and OH); 1650 (CO); 1620 (C =N ) 25 a—c 3150-3400 (NH and NH,); 2200 (CN); 14.2, 14.3 (C -l, t, / - 270.9, C H 3); 1670 (CO); 1650 (NH, and C =N ) 60.9. 59.7 (C-2, q. J = 301. C H ,); 160.1. 165.1 (C-3); 112.1. 113.4 (C-4). 113.5, 133.9' (C-5): 148.5, 149.9, 149.3 (C-3 pyrazole); 118.3 118.6 (C-4 pyrazole); 144.7, 145.9 (C-5 pyrazole); 112.0. 120.6, 121.4. 121.5. 121.6. 129.1. 129.2. 129.4. 129.5, 129.6, 129.7. 146.3. 146.8. 152.1, 154.3 (Ph car­ bons)

a 'H NMR (d ppm): 2.7, 2.8 (s, 1H); 5.7 (pyrazole H-4); 5.9 (s. 2H. NH,); 7.4-7.9 (m, 5H. Ph); h 'H NMR (d ppm): 1.2 (t. 3H. CH3); 4.3 (q. 2H, CH,); 5.8 (s, 2H. NH,); 7.7 (s, 2H, NH,); 10.0 (s, 1H. OH). S. A. S. Ghozlan etal. • Nitriles in Heterocyclic Synthesis 495

Reaction of 16 with acetic acid-hydrochloric Reaction of 2 with hydrazine hydrate acid mixture A solution of 2 (0.01 mol) in ethanol (100 ml) was To compound 16 (0.01 mol) was added glacial ace­ treated with hydrazine hydrate (0.01 mol, 0.5 ml) tic acid (150 ml) and hydrochloric acid (5 ml). The and the reaction mixture was then refluxed for 2 h. reaction mixture was refluxed for 3 h. The solvent The solvent was evaporated in vacuo and the solid was then evaporated in vacuo and the solid product, product was filtered off and crystallized from the so formed, was collected by filtration, washed with proper solvent (cf. Table I). water and then crystallized from the proper solvent (cf. Table I). Action of acetic acid-hydrochloric acid mixture on the reaction product of 2 with hydrazine hydrate The solid product isolated from the reaction of 2 Reaction of 16 with acetic anhydride with hydrazine hydrate was dissolved in a mixture of glacial acetic acid (50 ml) and hydrochloric acid To compound 16 (0.01 mol) was added acetic (15 ml) and the reaction mixture was then refluxed anhydride (30 ml) and the reaction mixture was re­ for 3 h. The solvent was evaporated in vacuo, the fluxed for 5 h. The solvent was evaporated in vacuo solid product, so formed was collected by filtration and the oily product was poured onto water. The and crystallized from the proper solvent. solid product, so formed, was collected by filtration, washed with water and crystallized from the proper Reaction of 2 with phenylhydrazine solvent (cf. Table I). To compound 2 (0.01 mol) was added phenyl­ hydrazine ( 0.01 mol), and the reaction mixture was heated on a water bath for 2 h. The precipitated solid Reaction of 2 with thiourea was triturated with ethanol, filtered off and crystal­ To a solution of 2 (0.01 mol) in glacial acetic acid lized from the proper solvent (cf. Table I). (1 0 0 ml) was added thiourea ( 0.01 mol) and the reaction mixture was refluxed for 3 h. The solvent The authors are grateful to Prof. Dr. K. Hafner was evaporated in vacuo and the solid product was and his group for conducting the 13C NMR measure­ filtered off and crystallized from the proper solvent ments. M. H. Elnagdi is grateful to the AvH for (cf. Table I). granting a fellowship.

[1] G. Kinast, Liebigs Ann. Chem. 1981, 1961. 11] G. E. H. Elgemeie, H. A. Elfahham, S. M. Hassan, [2] J. Perchais and J. P. Fleury, Tetrahedron 30, 999 and M. H. Elnagdi, Z. Naturforsch. 38b, 781 (1982). (1972). 12] H. A. F. Daboun. S. Abdou, M. M. Hussein, and [3] C. G. Overberger and W. Gavid, J. Org. Chem. 46, M. H. Elnagdi, Synthesis 1982, 502. 2757 (1981). 13] M. R. H. Elmoghayar, M. K. A. Ibraheim, A. H. H. [4] M. H. Elnagdi, D. H. Fleita, and M. R. H. Elmog- Elghandour. and M. H. Elnagdi, Synthesis 1981, 635. hayar. Tetrahedron 31, 63 (1975). 14] S. Abdou, S. M. Fahmy, and M. H. Elnagdi, [5] S. Ibraheim, B. Y. Riad, H. A. Elfahham, and M. H. Heterocycles 16, 2177 (1981). Elnagdi, Heterocycles 19, 2251 (1982). 15] M. H. Elnagdi and H. Wamhoff, J. Heterocycl. Chem. [6] G. E. H. Elgemeie, E. A. A. Hafez, and M. H. El­ 18, 1287 (1981). nagdi, Heterocycles 22, 2829 (1984). 16] G. E. H. Elgemeie, H. A. Elfahham. S. A. S. Ghoz­ [7] M. H. Elnagdi, H. A. Elfahham, and G. E. H. lan, and M. H. Elnagdi, Bull. Chem. Soc. Jpn. 57, Elgemeie, Heterocycles 20, 519 (1983). 1650 (1984). [8] M. H. Elnagdi, M. R. H. Elmoghayar, and G. E. H. 17] E. Breitmaier and H. Voelter, l3C NMR Spectro­ Elgemeie, Synthesis 1984, 1. scopy, Verlag Chemie, Weinheim 1978. [9] G. E. H. Elgemeie, S. A. Elees, I. Elsakka. and M. H. 18] M. H. Elnagdi, unpublished data. Elnagdi, Z. Naturforsch. 38b, 639 (1982). [10] M. H. Elnagdi, E. M. Kandeel, and K. U. Sadek, Z. Naturforsch. 32b, 311 (1977).