Substituent Effect on 66Ring-Chain Tautomerism of l12,3,4-tetrahydro-s-tetrazines

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1 Journal f. prakt. Chemie. Band 333, Heft 1, 1991, S J. A. Barth, Leipzig Substituent Effect on 66Ring-Chain Tautomerism of l12,3,4-tetrahydro-s-tetrazines M. M. EL-ABADELAH*, A. Q. HUSSEIN Chemistry Department, Faculty of Science, University of Jordan, Amman, Jordan A. S. ABUSHAMLEH Natural Science Department, Mutah University, Karak, Jordan Abstract. Methylhydrazones (111) of aromatic aldehydes and ketones react with nitrile imines (11) to give 1,2,3,4-tetrahydro-s-tetrazines IV (1-9) which exhibit ring-chain tautomerism in solution. The extent of this tautomerism is dependent both on steric and electronic effects of substituent groups at C-3 and C-6 ring carbons. In a previous paper we reported the synthesis of 1,2,3,4-tetrahydro-s-tetrazines via the reaction of nitrile imines (1,3-dipole) with a variety of methylhydrazones [I, 21. Tetrahydro-s-tetrazines derived from aromatic aldehydes exhibit ring-chain tautomerism in solution as shown by their n.m.r. spectra [I], the extent of this ring-chain tautomeric ratio depending on the nature of substituents at C-3. Therefore, we sought to undertake a systematic study to elucidate the influence of substituents onto this ringchain tautomeric equilibrium in these tetrahydro-s-tetrazines. Therefore, we synthesized several sets of the latter compounds following procedures described in literature [ 1, 21, (Scheme 1). The assignment of tetrahydro-s-tetrazine ring system (structure IV) to these compounds (Table 1) is based on spectral data. Thus, the i.r. spectra exhibit an N-H absorption in the range cm- (KBr pellets), cm-i (CHC1, solution), and a C = N bond stretching at ca cm-i. The E.I. mass spectra of compounds IV show the correct molecular ions as suggested by their molecular formulae. The I3C-n.m.r. spectra of compounds 1-7 exhibit a signal at ppm indicative of an sp3-carbon, flanked by two nitrogen atoms in a six-membered ring, and is assigned to the C-3 ring carbon in tautomer IV(A) [2]. In compounds 8 and 9 tautomer IV(B) predominates as indicated by the absence of the signal in the range ppm characteristic of the cyclic tautomer IV(A). The ring-chain, tautomeric ratio in these compounds is inferred from the relative intensities of the respective H-n.m.r. signals, in particular those of the N-Me protons; the latter give rise to two singlets of unequal intensities at ca and ppm, belonging to the cyclic IV(A) and acyclic IV(B) tautomers, respectively (Table 1). Signal doubling is also observed for the N-2 hydrogen and C-3 hydrogen as well as for the methyl protons of the R group. Their intensity ratios are in accord with the tauto-

2 62 J. prakt. Chem. 333 (1991) 1 Ph 9 - R' N -NHPh R-C N- N -NHPh [R-C= N-N -Ph] Nf 4 YAr -R R' I ( N- 1 &hfnh 1 Ar H-N-N=c.~~ I /R' Me Me m I CAI Ip Me OMe H CHMe, C1 H H Ph a: R = Ph, b: R = CO,Me, c: R = COMe Scheme 1 meric ratios of IV(A) and IV(B) as calculated utilizing the N-I methyl signals. This has been consistently observed in compounds 1-5, and is also valid for the C-3 methyl in compounds 6 as well as the C-3 ethyl in compounds 7. A similar trend of signal doubling is also observed in the '3C-n.m.r. spectra of compounds IV; the N-I methyl, for instance, appears at ca. 39 (tautomeric form A) and 43 ppm (form B). Electronic Effect The extent of tautomeric ratio is dependent on the nature of substituents at C-6. It can be seen from table 1 that the ratio of the acyclic tautomer IV(B) in compounds 1 increases on changing of the C-6 substituent in the following order: Ph(la), CO,Me(lb), COMe(1c). This pattern is consistently observed in the related sets of compounds 2a-c and 3 a-c. This may be explained on the basis of increased conjugative ability of the R- grouping in the acyclic tautomer relative to the cyclic tautomer in the order: COMe > C0,Me > Ph. It is worth noting that para-substituents on the aryl moiety (Ar) also tend to favour the acyclic tautomer IV(B) in the equilibrium. Thus, both p-ome and p-no, groups (in 2 and 3 respectively) electronically increase the population of the acyclic tautomer IV(B), the nitro-group being more pronounced. This trend of influence of para-substituents is consistently observed in the sets of compounds 2,3,4c and 5c in the following order: H > C1, Br > OMe > NO, (order of increasing ratio of the acyclic tautomer IV(B), Table 1).

3 M. M. EL-ABADELAH et al., 112,3,4-Tetrahydro-s-tetrazines 63 Table 1 Data for compounds prepared Coum- m.p.[ C] Yield Tautomer Molecular Formula Analysis Vo pound ) [VoIb) Ratio [Yo] (M? CalcdJFound C H N lb lc 2a 2b 2c 3a 3b 3c 4c 5c 6b 6c 7a 7c 8a 8b 8c 9b 9c H I an4 2 (310) C17H18N40 (294) C22H22N40 (358) (31iOY (ii4i C21Hl,N,O2 (373) C,,H NO (355)17 C,,H NO (339)17 C,,H,,ClN,O ( ) C17H17BrN40 ( ) (31i4Y 1 8H20N40 (308) C23H24N4 (356) (31i2Y C22H26N4 (370) (3;02? (3%6? C23H22N40 (370) oo ) Data for compound l a are given in ref. [l]. ) Yields refer to crystallized products. Steric Effect Introducing an alkyl group at C-3 is expected to hinder, sterically, intracyclization with the result that the acyclic tautomeric ratio will increase. This has been realized in this study whereby compounds 6 (R = Me) exhibit an increased ratio of the acyclic tautomer, compared to their counterpart compounds 1 (R = H). This steric effect is also evident in compounds 7 (R = Et), and is overwhelming in compounds 8 (R = CHMe,)

4 64 J. prakt. Chem. 333 (1991) 1 where the acyclic tautomer predominates (> 99%, Table 1). In compounds 9 (R = Ph), both electronic and steric factors are operative, and disfavour intracyclization leading to the preponderance of the acyclic tautomer (9c = > 99%). Acetylation of each of compounds 1 b, 2 b, and 3 b produces the respective N-2 acetyl derivatives (10, Scheme 2). These derivatives exist in the cyclic form and are incapable of exhibiting ring-chain tautomerism. Ph 10 a-c p-meoc,h, Scheme 2 Ac k now 1 e d g em e n t. The authors wish to thank Mutah University, Karak, Jordan, for financial support and Professor D. H. Busch, University of Kansas, Lawrence, Kansas, U.S.A., for providing the facilities of i.r. and n.m.r. measurements. Experimental Melting points were determined on an electrothermal melt-temp. apparatus and are uncorrected. 1.r. spectra (KBr pellets) were recorded on a Perkin-Elmer 283B Infrared Spectrophotometer, and i.r. spectra (CHC1, solution) were recorded with a Perkin-Elmer 1600 Series FTIR. H-n.m.r. spectra (in CDCI,) were recorded with a Varian XL300 NMR Spectrometer. Mass spectra were obtained with a Finnigan MAT 112 at 70 ev. Microanalyses were performed at M.H.W. Laboratories, Phoenix, Arizona, U.S.A. The hydrazonoyl chlorides (I), precursors of nitrile imines (11), have been prepared following literature described procedures [l, 21. Monomethylhydrazones (111) of benzaldehyde [3], p-nitrobenzaldehyde [4], p-methoxybenzaldehyde [4], p-chlorobenzaldehyde [5], p-bromobenzaldehyde [5], benzophenone [6], acetophenone [7], propiophenone [7], and isobutyrophenone [7] have been prepared according to literature methods. 3,6-Disubs t i tu ted- 1,2,3,4- tetra hydro-s- te trazines (1-9) A solution of the appropriate hydrazonoyl chloride (I), (0.02 mol) and the partner monomethylhydrazone (111), (0.02 mol) in dry tetrahydrofuran (60 ml) was treated with triethylamine (0.10 mol). The resulting solution was kept at room temperature for two days. The precipitated triethylammoniurn chloride was filtered off, and the organic solvent was removed in vacuo from the filtrate. The oily residue was triturated with ethanol (10 ml), and the solidified product was collected and recrystallized from 95% ethanol.

5 M. M. EL-ABADELAH et al., 1,2,3,4-Tetrahydro-s-tetrazines 65 2-Ace t y 1-1,2,3,4- t e t ra hydro -s - te t razi nes (1Oa-c) Compound 1 b (0.01 mol) in acetic anhydride (10 ml) was refluxed for 2 h. The resulting reaction mixture was then cooled to room temperature, and water (50 ml) was added dropwise with constant stifring. The precipitated product (10 a), was collected, and recrystallized from chloroform/petroleum ether (40-60 "C). Yield, 72%; m.p., "C; analysis, C,,H2,N,0, req.: C, 64.74; H, 5.72; N, Found: C, 64.58; H, 5.81; N, 16.03%. The 2-acetyl derivatives (lob, 1Oc) were prepared similarly from the respective parent compounds (2 b, 3 b). lob: Yield, 65%; m.p "C; analysis: C,,H,,N,O, req.: C, 62.80; H, 5.80; N, Found: C, 62.88; H, 5.66; N, 14.90%. 1Oc: Yield, 75%; m.p "C; analysis: C,,H,,N,O, req.: C, 57.41; H, 4.82; N, Found: C, 57.62; H, 4.59; N, 17.71%. References HUSSEIN, A. Q.; EL-ABADELAH, M. M.; AL-ADHAMI, K. H.; ABUSHAMLEH, A. S.: Heterocycles 29 (1989) EL-ABADELAH, M. M.; HUSSEIN, A. Q.; KAMAL, M. A.; AL-ADHAMI, K. H.: Heterocycles 27 (1988) 917. TODD, D.: J. Am. Chem. SOC. 71 (1949) SUCROW, W.; SIDPIANKA, M.; NEOPHYTOU, A.: Chem. Ber. 105 (1972) SUCROW, W.; MENTZEL, C.; SLOPIANKA, M.: Chem. Ber. 106 (1973) 450. SZMANT, H. H.; MCGINNIS, C.: J. Am. Chem. SOC. 72 (1950) IOFFE, B. V.; STOPSKII, V. S.; SERGEEVA, Z. I.: Zh. Org. Chem. 4 (1968) 986. Received April 18th, Authors' addresses: Prof. Dr. M. M. EL-ABADELAH University of Jordan, Faculty of Science, Chemistry Department Amman, Jordan A. S. ABUSHAMLEH, Mutah University, Natural Science Department Karak, Jordan