Formation of certain substituted 5H-pyrrolo2,3-bpyrazines by thermal cyclisation of pyrazinylhydrazones and a route to 5H-pyrazino2,3-bindole; a synthesis of 5H-pyrrolo2,3-b pyrazine and some of its properties

摘要

1976 1361Formation of Certain Substituted 5H-Pyrrolo2,3-bpyrazines by ThermalCyclisation of Pyrazinylhydrazones and a Route to 5H-Pyrazino2,3-amp;in-dole ; a Synthesis of 5H-PyrroIo2,3-b pyrazine and Some of its PropertiesBy Bernard A. J. Clark, John Parrick," and (in part) Roderick J. J. Dorgan, School of Chemistry, BrunelThermal (non-catalytic) cyclisation of the pyrazinylhydrazones (6a-i) caused ring closure on to the carbon atomof the pyrazine nucleus to give the 3-substituted and 2.3-disubstituted 5H-pyrrolo2,3-6pyrazines (7a-g), (8).and (9), respectively. 6,7,8,9-Tetrahydro-5H-pyrazino2,3-6 indole (79) was dehydrogenated to the parentpyrazino2,3-6 indole (1 5 ) . Pyrrolo2,3-bpyrazine (7h) has been obtained from 2-amino-3-methylpyrazineand some of its properties have been investigated.University, Uxbridge, Middlesex UB8 3PHWE have shown that pyridylhydrazones may be cyclisedto yield pyrrolopyridines (azaindoles) .1*2 The presenceAr N H .N : CR .CH, R'( 1 ) Ar = 4-pyrimidyl L3-F: N NH( 3 )(2) Ar = 3-pyridylH 'H(4 1 ( 5 )of an additional nitrogen atom in the nuclei of pyrimi-dine, pyrazine, and pyridazine as compared with pyri-dine might be expected to reduce the ease of cyclisationof their heteroarylhydrazones as compared with thecorresponding pyridylhydrazones. There appeared tobe some evidence 3 to support this idea: although somesuccessful cyclisations of 4-pyrimidylhydrazones (1) topyrrolo2,3-amp;jpyrimidines (3) have been reported, theconversion was generally not as smooth as in the case ofthe corresponding 2-pyridylhydrazones.This findinghas recently been extended and ~onfirmed.~ Themechanism of the thermal cyclisation is not establishedbut it has been suggested that it may be a concertedpr0cess.~953-Pyridylhydrazones (2) give mainly pyrrolo3,2-b-pyridines (a), formed by cyclisation on to the 2-position,with only small quantities of pyrrolo2,3-cpyridines (5)produced by reaction at the 4-position. This indicatesthat cyclisation on to the position adjacent to a ringnitrogen atom is the favoured process and led us to thinkthat pyrazinylhydrazones (6a-i) might cyclise at the 3-position to give derivatives of pyrrolo2,3-bpyrazine.The pyrrolo2,3-bpyrazine nucleus had only once beenreported when this work was done.Hydrazinopyrazine was readily converted into a seriesof solid hydrazones (6a-i).Ammonia was evolvedwhen solutions of these pyrazinylhydrazones in diethyl-ene glycol were refluxed, and elemental analysis of theproducts was consistent with the presence of either theA. H. Kellyand J. Parrick, Canad. J . Chem., 1966,44, 2455.A. H. Kelly and J. Parrick, J . Chem. SOG. ( C ) , 1970, 303.P. A. Crooks and B. Robinson, Canad. J . Chern., 1969, 47,T. D. Duffy and D. G. Wibberley, J.C.S. Perkin I I , 1974,2061.1921.pyrrolo2,3-bpyrazine or the isomeric imidazol,2-a-pyrazine (10) ring system. However, the i.r. spectra ofall the isolated products showed absorption in the region3 125-3 200 cm-l attributable to NH.Also, the n.m.r.spectra showed only two remaining signals 'due toprotons of the pyrazine nucleus, and a low-field signalremovable on addition of D20, thus confirming theassignment of the pyrrolo2,3-bpyrazine structures (7a-i), (euro;9, and (9) to these new compounds.The parent pyrrolo2,3-bpyrazine (7h) was obtainedin 74 yield from 2-amino-3-methylpyrazine (1 1).Treatment with triethyl orthoformate gave the unstableethyl N-(3-methylpyrazin-2-yl)formimidate (12) (66)which, when heated with N-methylaniline at 180 "CH(6)a; R'=H, R2 =Mec; R' = R2=Med; R'= Ph, R2=Mee; R1= Me, R2=Phf ; R'= R2=Ph9; R' R2 = CHdch; R2CH2-CR1 = indan-l-ylidene h; R' = R2 = Hi ; R2CH2.CR1 =1,234-tetra-(7)a; R' = H, R2 =Mec; R' =R2 =Med; R' = Ph,R2 =Mee; R1 =Me,R2= Phf; R' = R 2 = Phg; R'and R2= CH24i; R' =H.R2=CH0j; R' = H,R2= NO2k; R' =H,R2=6rb; R'= H, R2 =Ph b; R' =H,R2 =Phhydro-1-naphthylidenereadily gave W-met hyl-N2- (3-me t hylpyrazin-2-yl) -N1-phenylformamidine (13).The amidine (13) was thentreated with sodium N-methylanilide at 180 "C. Re-cently, Yakhontov 7 has reported the preparation of (7h),ti T. L. Gilchrist and R. C . Storr, ' Organic Reactions andS. Klutchko, H. V. Hansen, and R. I. Meltzer, J . Org. Chem.,V. A. Azimov and L. N. Yakhontov, Khim. geterotsikl.Orbital Symmetry,' Cambridge University Press, 1972, p. 234.1965, 30, 3454.Soedinenii, 1973, 8581362 J.C.S. Perkin Iin unspecified yield, by a conventional Madelung synthe-sis from 2-fonnamido-3-methylpyrazine (14) and base.(111 R = NH,(12) R = N:CH.OEt(13 1 R = N: CH-NMePh(14) R = NH*CHOtWThe 1H n.m.r.spectrum of pyrrolo2,3-bpyrazine (7h)showed two pairs of doublets: one (J 2.6 Hz) at lowerfield attributed to the 5- and 6-H and one at higher field(J 3.5 Hz) from the 2- and 3-H. It seems likely that the3-H signal is at highest field 6 6.77 in (CD,),SQ and the2-H signal at 7.95, but assignment of the doubletscentred at 8.43 and 8.30 is uncertain. By analogy withindole it would be expected that the 5-H would show asthe higher field signal.8 All the pyrrolo2,3-bpyrazinesstudied gave a doublet in each of the ranges 8.234.53and 8.03-8.32 2.3-2.7 Hz) and showed a broadpeak (NH) in the range 11.57-12.60.The U.V.spectra of pyrrolopyrazine and the alkylderivatives show only two maxima, e.g. (7h) has maximaat 218 (log c 4.07) and 309 nm (3.80), corresponding tothe I and I11 bands of indole. The absorption maximumcorresponding to band I1 of indole is apparently absent,and this corresponds with the findings for pyrrolopyri-dines, for which it has been suggestedB that bands I1and I11 overlap.Pyrrolo2,3-bpyrazine-3-carbaldehyde (7i) was ob-tained by treatment of lH-pyrrolo2,3-bpyrazine (7h)with hexamethylenetetramine, and was identical withthe compound obtained by treatment of 2-amino-3-methylpyrazine with the Vilsmeier reagent.6 Mono-nitro- and -bromo-derivatives of (7h) were also obtained,and their lH n.m.r. spectra show the compounds to be2- or 3-substituted derivatives, but do not allow anunambiguous assignment of structure.On the evidencefrom the formylation experiment and more generalconsiderations, it is likely these products are the 3-substituted isomers (7j and k).The pyrazinoindole (15) was obtained by dehydrogen-ation of the tetrahydro-derivative (7g).EXPERIMENTAL1.r. and n.m.r. spectra were recorded as previouslydescribed.1deg; U.V. spectra were measured for ethanolicsolutions with a Unicam SP 800 spectrometer.* For details of Supplementary Publications see Notice t oAuthors No. 7 , J.C.S. Perkin I , 1975, Index issue.* P. J. Black and M. L. Heffernan, Austral. J . Chem., 1966,18, 353.Details of the pyrazinylhydrazones, their cyclisation, andthe properties of the pyrrol02,3-bpyrazines (7a-g) , (8),and (9) are given in Supplementary Publication No.SUP21746 (6 pp.).*Ethyl N- (3-Methy@yrazin-2-yZ) formimidate ( 12) .-2-Ami-no-3-methylpyrazine l1 (8.0 g), triethyl orthoformate (22 g),and ethanolic hydrogen chloride ( 6 ~ ; 0.76 ml) were heatedslowly to 145 OC, and ethanol was collected as the tempera-ture rose from 115 to 145 "C over 5 h. The excess of triethylorthoformate was distilled off and the residue distilledunder reduced pressure to give ethyl N-(3-methylpyrazin-2-y1)formimidate (8.0 g, 66), b.p. 106-108deg; a t 8 mmHg,vwx. (liq.) 1 636 cm-l (CZN), 6(CC14) 8.12 (1 H, d, J 2.0 Hz,(2 H, q, J 7.0 Hz, CH,), 2.52 (3 H, s, 3-CH3), and 1.40 (3 H,t, J 7.0 Hz, CH,). The formimidate was unstable and noelemental analysis was obtained.N1-Methyl-N2-( 3-metlayZpyrazin-2-yl) -N1-phenyZformami-dine (13).-The formimidate (12) (8.0 g) and N-methylani-line (10.4 g) were heated slowly a t 180 "C.Ethanol beganto distil off a t 110 "C and was collected over 2 h. Theexcess of methylaniline was distilled off (b.p. 88" a t 14mmHg). The residue solidified on cooling and was tritur-ated with petroleum (b.p. 40-60") to give the ainidine (13)(9.9 g, 91 yo), which crystallised from benzene-petroleum(b.p. 40-60") as needles, m.p. 83-83.5" (Found: C, 69.3;H, 6.2; N, 24.5. Cl3HI4N4 requires C, 69.0; H, 6.2; N,24.8), G(CDC1,) 8.94 (1 H, s, CH), 8.07 (2 H, s, 5- and G-H),7.30 (5 H, m, Ph), 3.58 (3 H, s, NCH,), 2.67 (3 H, s, 3-CH3).euro;iH-PyrroZo2,3-bpyrazi~e (7h) .-Freshly prepared soda-mide (3.2 g) was added to dry N-methylaniline (17.8 g) withstirring under a stream of nitrogen, and the suspension wasbrought slowly t o boiling.The mixture was refluxed for40 min and then a warm solution of the amidine (13) (9.0 g)in methylaniline (10 ml) was added over 15 min. The excessof methylaniline was distilled off a t atmospheric pressure.Water was added to the cooled residue and the mixturestirred for 1 h. After filtration, the solution was continu-ously extracted with ether overnight. The dried extractwas evaporated and a small quantity of N-methylanilinedistilled off under reduced pressure. The residue crystal-lised from benzene to give BH-~~rroZo2,3-bJ~yrazine (3.52 g,74), m.p.155-156' (sublimes) (Found: C, 60.2; H,4.2; N, 35.3; M , 119. C,H,N, requires C, 60.5; H, 4.20;N, 35.3; amp;I, 119), vmX. (KBr) 3 180 cm-l (NH), A,, 218(log E 4.07) and 309 nm (3.80), s(CD,),SO 12.13 (1 H, s,exchanged in D,O, NH), 8.43 (1 H, d, J 2.6 Hz, 5- or 6-H),8.30 (1 H, d, J 2.6 Hz, 5- or 6-H), 7.95 (1 H, d, J 3.5 Hz,2-H), and 6.77 (1 H, d, J 3.5 Hz, 3-H).Details of the 3-formyl-, 3-nitro-, and 3-bromo-5N-pyrrolo2,3-bpyrazines are given in the SupplementaryPublication.5H-Pyrazino2,3-bindoZe (15).-6,7,8,9-Tetrahydro-5H-pyrazino2,3-bindole ( 1.7 g), chloranil (4.9 g), and xylene(160 ml) were refluxed for 10 h. The solution was cooledand the precipitate collected and dissolved in dilute sodiumhydroxide solution. Extraction of this solution with etheryielded 5H-pyruzino2,3-bindoZe (0.44 g). A furtherquantity (0.2 g) was obtained when the xylene filtrate wasdiluted with ether, washed with alkali, and then water, andevaporated. The combined solids (40) were crystallised* R. E. Willette, Adv. Heterocyclic Chem., 1968, 9, 27.lo B. A. J. Clark, M. M. S. El-Bakoush, and J. Parrick, J.C.S.11 H. Gainer, amp;I. Kokorudz, and W. K. Langdon, J . Org.5-H), 7.98 (1 H, d, J 2.0 Hz, 6-H), 8.37 (1 H, S, N:CH), 4.40Perkin I , 1974, 1531.Chem., 1961, 26, 23601976 1363from benzene; m.p. 241-243" (Found: C, 70.6; H, 4.2;N, 24.6; M , 169. C,,H,N, requires C, 71.0; H, 4.1;N, 24.8; M , 169), Amax. 214 (log E 4.36), 244 (3.951, 261(4.00), and 319 nm (3.92), 8(CD3),S0 12.20 (1 H, s, ex-changed in D,O, NH), 8.50 (1 H, d, J 2.6 Hz, 2- or 3-H),8.37 (2 H, m, 2- or 3-H and 9-H), and 7.40 (3 H, m, 6-, 7-,and 8-euro;-I).6/ 1940 Received, 6th October, 1976