J. Org. Chem., Vol. 44, No. 22.1979 3835
Imidazo[ 1,5-a]-1,3,5-triazinones
Guanine, Hypoxanthine, and Xanthine Analogues. Synthesis of Imidazo[ 1,5-a]-1,3,5-triazinonesvia Rearrangement (Joseph B. Holtwick, Boienna Golankiewicz, Brian N. Holmes, and Nelson J. Leonard* Roger Adams Laboratory, School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801 Received June 25, 1979
Syntheses of substituted imidazo[1,5-a]-1,3,5-triazinones, which are analogues of N(9)-substitutedguanines, hypoxanthines, and xanthines, have been accomplished by cyclization-rearrangement. Condensation of ethyl with urea, thiourea, guanidine, and 2-cyano-2-formamidopropionateand ethyl 2-acetamido-2-cyanopropionate N’,M-dimethylguanidine yielded substituted 4,5-dihydro-5-methylpyridin-4-ones.Treatment of these 4,5dihydro-5-methylpyrimidin-4-ones with chlorotrimethylsilane and hexamethyldisilazane in pyridine gave the correspondingly substituted imidazo[1,5-~]-1,3,5-triazinones. Structures were established in this series on the basis of precursors and routes of synthesis,‘Hand ’% NMR spectra, and mass spectra and by X-ray crystallographic analysis of one member among the interrelated compounds in the series. Scheme I
The synthesis and biological evaluation of analogues of the naturally occurring nucleic acid bases and their corresponding nucleosides, nucleotides, and coenzymes are directed toward defining those chemical interactions involved in the effecting or preventing of a specific biological response. In contrast to the successful syntheses of innumerable purine base analogues which contain a ringjuncture nitrogen,l the documentation of the syntheses of N-glycosyl nucleosides of this type has been limited to the cases of the imidazo[l,2-~]-1,3,5-triazine (e.g., 1),2,3 imi0
0
0 II
0 0
YHz NC-C-H
II II
NHCH
CH,COCH
F
I
NC-C-H
“90
EtO/c*O
NC-C-CH,
0
I NH,
EtO/C‘\O l l a , R = H ; b, R = C H ,
P
0
0
0 12’
5
8
1
Ii
R =Ribosyl
dazo [ 1,2-c]pyrimidine (e.g., 2),4,5 s-triazolo[1,5-u]pyrimidine (e.g., 3),677and s-triazolo[4,3-a]pyrimidine(e.g., 4)s ring systems. In addition, the syntheses of a few bridgehead-nitrogen bearing C-glycosyl nucleosides, derived from pyrazolo [ 1,5-a]- 1,3,5-triazines (e.g., 5),9 s-triazolo[4,3-a]pyridines (e.g., 6),1° and s-triazolo[4,3-a]pyrazines (e.g., 7),11 have recently been published. We have communicated an observed rearrangement which effectively leads to imidazo[ 1,5-~]-1,3,5-triazines, analogues of N(9)-substituted guanines, hypoxanthines, (1) Mosby, W. L. “The Chemistry of Heterocyclic Compounds”; Interscience: New York, 1961; Vol. XV, Part 2. (2) Prisbe, E. J.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1978, 43, 4774. (3) Prisbe, E. J.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1978, 43, 4784. (4) Bartholomew, D. G.; Huffman, J. H.; Matthews, T. R.; Robins, R. K.; Revankar, G. R. J . Med. Chem. 1976, 19, 814. (5) Bartholomew. D. G.; Dea, P.; Robins, R. K.; Revankar, G. R. J. Org. Chem. 1975, 40, 3708. (6) Winkley, M. W.; Judd, G. F.; Robins, R. K. J . Heterocycl. Chem. 1971, 8, 237. (7) Revankar, G. R.; Robins, R. K.; Tolman, R. L. J. Org. Chem. 1974, 39, 1256. (8) Barascut, J.-L.; Imbach, J.-L. Bull. Soc. Chim. Fr. 1975, 2561. (9) De Las Heras, F. G.; Chu, C. K.; Tam, S. Y.-K.; Klein, R. S.; Watanabe, K. A.; Fox, J. J. J . Heterocycl. Chem. 1976, 13, 175. (10)Huynh-Dinh. T.;Igolin, J.; Marquet, J.-P.; Bisagni, E.; Lhoste, J.-M. J . Org. Chem. 1976. 41, 3124. (11) Huynh-Dinh, T.; Sarfati, R. S.; Gouyette, C.; Igolen, J.; Bisagni, E.; Lhoste, J.-M.; Civier, A. J . Org. Chem. 1979, 44, 1028.
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12a, R = H . X = N H , b, R = H , X = S H c, R = H , X = O H d, R CH,, X = NH, e, R = CH,, X =ICH,I,N f, R=CH,,X=SH g, R = CH,, X = OH
13a, R = H , X = N H , b, R = H , X = S H c , R=CH,, X = N H z d, R = CH,, X -(CH,),N e, P= CH,, X = SH f , R=H, X = H g , R=CH,, X = H h, 3-CH3-13f i , 3-cH3-13g
The listings o f R and X conveniently indicate substitution but do not necessarily indicate the favored tautomeric form.
and xanthines,I2 and we now supply details indicative of the generality of this cyclization-rearrangement. Earlier reference to this heterocyclic system is limited to the reported preparation of compound 8 by Biltz,13 in extension of Fischer’s exploratory investigation of the chemical properties and reactivity of the0br0mine.l~ 5-Acetamido-6-amino-4,5-dihydro-5-methyl-2(3~-thiopyrimidin-4-one (12f)was a pivotal intermediate in our synthesis (Scheme I). The closure to an imidazo ring, on the basis of the work of Vorbruggen involving the amination of 0-trimethylsilylated heterocycle^,'^ resulted in 13e as a the corresponding imidazo[l,5-~]-1,3,5-triazine result of quaternary-carbon bond cleavage16 and rear(12) Golankiewicz, B.; Holtwick, J. B.; Holmes, B. N.; Duelser, E. N.; Leonard, N. J. J . Org. Chem. 1979,44, 1740. (13) Biltz, H. Ber. Dtsch. Chem. Ges. E 1934, 67, 1856. (14) Fischer, E.; Frank, F. Ber. Dtsch. Chem. Ges. 1897, 30, 2604. (15) Vorbriiggen,H.; Krolikiewin, K.; Niedballa, U. Justus Liebigs Ann. Chem. 1975, 988. (16) Holmes, B. N. Ph.D. Thesis, University of Illinois, 1977.
0 1979 American Chemical Society
Holtwick et al.
3836 J Org C m m , Vol 44, N o . 22, 1979 rangement. Raney nickel desulfurization in aqueous ammonia yielded 6,8-dimethylimidazo[ 1,5-~]-1,3,5-triazin-4(3H)-one (13g), the structure of which was established by single-crystal X-ray analysis inter alia as a representative of the entire series. Results a n d Discussion ‘The condensation (of disubstituted cyanoacetic esters with guanidine was shown very early to provide derivatives A synthetic of 2,6-diamino-4,5-dihydropyrimidin-4-0nes.’~ route based on this precedent was adapted to the preparation of the 4,5-dihydropyrimidin-4-ones 12a,b,d-g as shown in Scheme I. Ethyl 2-amino-2-cyanoacetate (9), prepared according t o the method of Domkin and Kur’yanovich,18was formylated by treatment with acetic formic anhydride to give ethyl 2-cyano-2-formamidoacetate (10). Subsequent reaction of an ethanolic solution of 10 with methyl iodide in the presence of sodium ethoxide gave ethyl 2-cyano-2-formamidopropionate (Ila). Condensation of l l a or ethyl 2-acetamido-2-cyanopropionate (llb)I9with guanidine, W,”-dimethylguanidine, or thiourea in ethanol containing 1-3 molar equiv of sodium ethoxide, followed by the addition of acetic acid to pH 5 . 5 , yielded the corresponding 3,5-dihydropyrimidin-4-one derivatives 12a,b,d-f. The condensation of 1l b with urea requires conditions different from those c>mployedin the cyclizations with guanidine, N’,N’ -dimethylguanidine, and thiourea. Examination of the literature reveals that condensations of substituted a-cyano esters with urea in the presence of sodium ethoxide afford the acyclic cyanoacetylureas.20 In the present case, N-(~!-acetamido-2-cyanopropionyl)urea (14) was first formed and could be isolated and charac-
electrocyclically) than would be provided before cyclization of the five-membered ring. One possible route of 12 to 13 would then result, e.g., from an electrocyclic conversionz1 of 15 to 16 (X is trimethylsilylated in all but 12e) and
15
16
rotation about the original N ( 1 ) 4 ( 6 ) bond (see numbering in 12) to place the isocyanate grouping in juxtaposition to the original N6 for closure to the resonance-stabilized ring system of 13. Whatever the detailed mechanistic pathway, the structures of the resulting rearrangement products (13) were firmly established by interconversion, analogy, spectroscopic data, and X-ray analysis. For example, Raney nickel desulfurization of compound 13e in aqueous ammonia gave 13g. A single crystal of 13g of suitable dimensions for X-ray analysisl2 was obtained by slow crystallization from 2-propanol. The crystal structure determination of compound 13g (see Experimental Section) also confirmed the structure of the 8-methylimidazo[1,5-~]-1,3,5-triazin-4(3H)-one (13f) product of Raney nickel disulfurization of 13b. The ‘H NMR spectra of the dimethyl (13g) and monomethyl (13f) compounds showed parallel chemical shifts for the 8-CH3 and 2-H resonances, differing in the 6-CH3 chemical shift, 6 2.65, for 13g and the 6-H shift, 6 8.18, for 13f. The structures of the dimethyl and monomethyl thio compounds, 13e and 13b, respectively, were thus established since they were the precursors of 13g and 13f. The 13C NMR spectra of 0 II 13e and 13g were confirmatory for the lack of any tetNHCCH, rasubstituted carbon in this set of compounds. This was NC-C-CH, also true for 13a and 13d (see below), which, along with I H,C* 13c, are structurally related, substituted imidazo[l,5-a]H,NCN 0 I1 1,3,5-triazin-4(3H)-ones, as supported by other spectro0 scopic criteria. 14 Further structural verification resulted from a chemical terized by its ‘13 NMR spectrum. Cyclization to the direaction thaJ was diagnostic of the 3,4-amide unit in 13g hydropyrimidinone 12g was accomplished by addition of and 13f. ZemliEkaZ2has shown that 1,l-dimethoxyacetic acid to pH 8.5. We assume that the lower homoN,N-dimethylmethanamine, or N,N-dimethylformamide logue 1212 would also be obtainable from lla by a similar dimethyl acetal, alkylates heterocyclic bases at amide sequence. nitrogens when no free amino groups are present. With An efficient proceduxe for the closure to the imidazo ring this reagent, it was possible to convert compound 13g to 13a-e was based to yield the imidazo[l,5-a]-1,3,5-triazines 3,6,8-trimethylimidao[1,5-~]-1,3,5-triazin-4-one (13i), with on the amination of 0-trimethylsilylated heterocycles as ‘H NMR 6 3.43 for the new NCH3 protons, and 13f to reported by Vorbruggen et al.15 Treatment of the com3,8-dimethylimidazo[1,5-~]-1,3,5-triazin-4-one (13h), with pounds 12a,b,tl-f in pyridine with 2 molar equiv of 6 3.50 for the new NCH3 protons. chlorotrimethylsilane and excess hexamethyldisilazane at The 13C NMR spectra of compounds 12a,d-f and reflux under nitrogen gave the imidaz0[1,5-~]-1,3,5-tri- l%a,d,e,gare consistent with the structures as illustrated. azines 13a-e. ‘The formamido derivatives 12a and 12b Positions of appropriate chemical shift values clearly demonstrated a marked tendency toward this imidazole demonstrate the presence of a tetrasubstituted carbon ring closure and rearrangement in contrast to the acetprior to conversion of the substituted 4,5-dihydroamido derivatives 12d--f,which required prolonged heating pyrimidin-4-ones to the corresponding imidazo[ 1,5-u]at reflux to effect complete product formation. The se1,3,5-triazin-4(3H)-ones. For example, 5-acetamido-6quence of events has not been established, but initial amino-4,5-dihydro-2-(dimethylamino)-5-methylpyrimicyclization of a trimethylsilylated 12 to add an appended din-4-one (12e) shows four signals between 164 and 179 imidazole-type ring would thereby provide better stabippm corresponding to C(2), C(4), C(6), and the acetyl lization for C(4) C(51 cleavage (either heterolytically or carbonyl carbon; signals at 22.4, 26.0, and 36.9 ppm are due to the 5-CH3, COCH,, and (CH3)zNmethyl groups, respectively; and the crucial resonance at 53.4 ppm es(17) Merck, E. Fr,edlundws Fortschr. Teerfarbenfabnk. Verwandterind. 1073, 1077. (18) Domkin, V. D.; Kur’yanovich, L. A. Zh. Org. Khim. 1976, 12,908. (19) Albertson, PJ. F. J . Am. Chem. Soc. 1946, 68, 450. (20) Brown, D. J. “The Chemistry of Heterocyclic Compounds”; Interscience: New York. 1962; Vol. XVI, p 68 and references cited therein. 1906,8,
(21) Woodward, R. B.; Hoffmann, R. “The Conservation of Orbital Symmetry”, Verlag Chemie: Weinheim/Bergstr., Germany, 1970; pp 3 8 6 4 . (22) iemliEka, J. Collect. Czech. Chem. Commun. 1970, 35, 3572.
Imidazo[1,5-a]-1,3,5-triazinones
J . Org. Chem., V o l . 44. A;o. 22, 1979 3837
0.2-mm silica gel was used for column chromatography. tablishes the presence of the tetrasubstituted C(5).23 By Ethyl 2-Cyano-2-formamidoacetate(10). Ethyl isonitrocontrast, the I3C NMR spectrum of compound 13d, the socyanoacetate (20.0 g, 141 mmol) was reduced to 9 with sodium cyclization-rearrangement product of 12e, confirms the dithionite according to the method of Domkin and Kur'yanovich.*8 absence of a tetrasubstituted carbon. Similarly, the I3C Acetic formic anhydridez4 (13.6 g, 155 mmol) was added dropwise NMR spectra of compounds 12a,d,f possess resonances to a cooled (5 "C) solution of the aminocyano ester in ether (100 characteristic of carbon tetrasubstitution (54.4-62.6 ppm) mL), the solution was stirred magnetically at room temperature while compounds 13a,e,glack resonances indicative of the for 2 h, solvent was removed in vacuo, and excess acid was presence of a quaternary carbon. coevaporated with toluene under reduced pressure to give a yellow Analysis of the major fragment ions in the mass spectra oil which crystallized on scratching. Two recrystallizations from determined at 10 eV for the 4,5-dihydropyrimidin-4-one ether gave 10 as fine, long, colorless needles (8.3 g, 38%): mp 6 1 4 2 "C; 'H NMR (CDClJ 6 1.36 (t, 3, J = 6 Hz, CH,), 4.33 (9, 2, J and imidazo[1,5-~]-1,3,5-triazin-4-one derivatives revealed = 6 Hz, CHZ), 5.50 (d, 1,
