4612 J . org. Chem., Vol. 44, No. 25, 1979
Leonard and Bryant
Regioselective Electrophilic Reactions on Substituted Purines. Predominant Intermediacy of 6- or 8-Purinyl Carbanions Nelson J . Leonard* and Jerry D. Bryant Roger Adams Laboratory, School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801 Received July 12, 1979
6-Ido-%(tetrahydropyran-2-y1)purine(1) was found to undergo reaction with n-butyllithium in THF to produce, depending ulpon the time and temperature of the reaction, either 6-lithio-or 8-lithio-9-(tetrahydropyran-2-yl)purine in predominance. Shorter reaction time and lower temperature were necessary for the utilization of the 6-lithio derivative, while longer reaction time and higher operating temperature favored the equilibration to the 8-lithio isomer. These carbanions were treated with a variety of electrophiles to produce the corresponding 6- or 8-substituted compounds (3 or 4). 6-Chloro-9-(tetrahydropyran-2-yl)purine (7) was treated similarly with nbutyllithiuni in THF at -78 "C and was then caused to react with various electrophiles to give 8-substituted 6-chloro-9-(ktrahydropyran-2-yl)purines (8). The chloro substituent in 8 was removed by hydrogenolysis or displaced with NH3 t o give the correspondingly substituted purines (4) or adenines (9).
T h e direct formatilon of 6-alkylpurines remains incompletely explored despite indications of the biological activity of some of these derivatives.',* To date, the methods of carbon-carbon bond formation at the 6 position of intact purines involve the reaction of suitable leaving groups with p h e n y l l i t h i ~ msodiomalonic ,~ ester^,^^^ cuprous cyanide,j and various alkylider~ephosphoranes.~~~ In addition, the Eschenmoser sulfide contraction8 has been applied to appropriately substituted purine^.^ Until recently, few effective methods have been reported for the direct formation from parent purines of 8-alkylpurines,loJ1 compounds which are produced in photoreactions of purines with alcohols, ethers, amines, and amino acids.12 As examples, 8-(2-hydroxy-2-propyl)adenine and 8-(2-hydroxy-2-propyl)guaninehave been obtained from the irradiation of DNA in the presence of 2-propanol with ultraviolet light,13J4 with acetone as a photosensitizer or organic peroxide as an initiator. 8Substituted purines may in fact be important consequences of protein-nucleic acid photo interaction^,'^ A promising approach, recently described,16 is the direct alkylation of protected adenosine derivatives a t the 8 position by lithiation followed by reaction with an alkyl halide. We describe here the use of a common purinyl precursor -(1) Henderson, 1'. R.: Frihart, C. R.; Leondard, N. J.; Schmitz, R. Y.;
Skoog, F. Phytochemistrq 1975, 14, 1687. (2) Frankland, B.; darvis, B. C.; Cherry, J. H. Planta 1971, 97, 39. (3) Lettr6, H.; Bdlwee, 13.; Maurer, H.; Rehberger, D. Naturwissenschaften 1963, 50, :!24. (4) Chaman, E. S.; Golovchinskaya, E. S. J . Gen. Chem. USSR (Engl. Trawl.) 1963, 33, 3269. (5) MacKay, L. B.; Hitchings, G. H. J . Am. Chem. SOC.1956, 78, 3511. (6) Taylor, E. C.; Marti:n, S. F. J . Am. Chem. Soc. 1974, 96, 8095. (7) Wanner, M. J.; Hageman, J. J. M.; Koomen, G. J.; Pandit, U. K. Reel. Truo. Chin. Pays-Bas 1978, 97, 211. (8) Roth, M.; Dubs. P.; G,mchi, E.; Eschenmoser, A. Helo. Chin. Acta 1971, 54, 710. (9) Vorbruggen, H.; Krolikiewicz, K. Angew. Chem., Int. Ed. Engl. 1976, 15, 689. (10) Typically, diethyl sodiomalonate is used in reaction with an 8chloropurine. See, e.g., Nikolaeva, L. A.; Golovchinskaya, E. S.J. Gen. Chem. USSR (Engl. Trans[.) 1964,34, 1127. (11) An anomalous C(8) alkylation has been reported in the reaction of sodium theophyllinate with crotyl bromide: Donat, J.; Carstens, E. Chem. Ber. 1959, 92, 1500. (12) Elad. D. In "Photochemistry and Photobiology of Nucleic Acids"; Wang, S.Y., Ed.; Academic Press: New York, 1976; Vol. I, Chapter 7. (13) Ben-Ishai, R.; Green, M.; Graff, E.; Steinmaus, H.; Salomon, J. Photochem. Photobtloi. 1973, 17, 155. (14) Salomon. J.; Elad, D. Biochem. Biophys. Res. Commun. 1974,58, 890. (15) Sperling, J.; Havron. A. Photochern. Photobiol. 1977, 26, 661. (16) Barton, D. H.R.: Hedgecock, C. J. R.; Lederer, E.; Motherwell, W. B. Tetrahedron L e t t . 1979, 279. See also: Cbng-Dahn, N; Beaucourt, 300 "C; NMR ((CD3)2SO)d 7.45-7.60 (m, 2, ArH), 7.81-7.98 (m, 2, ArH), 8.95 (s, 1,purine CH), 9.20 (s, 1, purine CH); MS m / e 237 (B, M'). Anal. Calcd for C12H7NjO:C, 60.75; H, 2.97; N, 29.53. Found: C, 61.01; H, 3.19; N, 29.44. 6-Chloro-8-(2-hydroxy-2-propyl)-9-( tetrahydropyran-2y1)purine (8a). A solution of 6-chloro-9-(tetrahydropyran-2y1)purine (7)18 (100 mg, 0.42 mmol) in THF (25 mL) was cooled to -78 "C under a positive argon atmosphere, n-butyllithium (2.1 M in hexane, 0.21 mL, 0.44 mmol) was added, and the solution was stirred for 1 h. Acetone (175 mg, 3 mmol) was added, and the solution was stirred an additional 30 min and was then quenched and worked up in the usual manner. The residue was chromatographed on silica gel (7.5 g) by using CHC1, as an eluent. The combination of the appropriate fractions gave 7 (9 mg, 9% recovery) and the product 8a (87 mg, 70% yield): mp 220 "C dec; NMR (CDCl,) 6 1.5-2.2 (m, 6, CH,'s), 1.78 (s, 3, CH,), 1.82 (s, 3, CH3),3.55-3.9 (m, I, OCH2),4.13-4.37 (m, 1, OCH2),6.22 (d of d, J = 2 and 11 Hz, 1, N-CH-O), 8.67 (s, 1, 2-CH); MS m / e (re1 intensity) 296 (5.5), 298 (1.9, M'), 213 (33). 215 (10, M' CjH,O), 85 (B, CjHgO'). Anal. Calcd for C1JHllC1N402: C, 52.61; H, 5.78; N, 18.88. Found: C, 52.60; H, 5.83; N, 18.50.
4616 J . Org. @hem.,Vol. 44, No. 25, 1979
6-Chloro-&(%-hydroxy-2-propyl)purine.A solution of 8a was hydrolyzed as described above to remove the 9-protecting group (95% yield): mp 201-203 "C dec; NMR ((CD3),CO)6 1.73 (s, 6, CHJ, 8.59 Is, 1, 2-CH); MS m / e (re1intensity) 212 (60), 214 (17, M'), 197 (loo), 199 (42, M' - CH3), 169 (la), 171 (7, M' CzH3O), 155 (57), 157 (22, M' - C3H50). Anal. Calcd for C&IgC1N40:C, 45.18; H, 4.27; N, 26.35. Found C, 45.29; H, 4.45; N, 26.05. 6-Chloro-84hydroxydiphenylmethyl)-9-(tetrahydropyran-2-y1)purine (8b). A solution of 7 (240 mg, 1 mmol) in THF (40 mL) was treated with n-butyllithium (2.6 M in hexane, 0.5 mL, 1.3 mmol) as before. After an analogous workup and chromatography, the product was obtained as a colorless solid (260 mg, 62% yield): mp 224 "C dec; NMR (CDClJ 6 1.5-2.0 (m, 6, CH,'s), 3.14 (m, 1,OCHz),3.98 (m, 1, OCH,), 5.17 (s, I,OH), 5.29 (d of d, J = 2 and 11 Hz, 1, N-CH-0), 7.30 (s, 5, ArH), 7.36 (s, 5, ArH), 8.67 {s, 1, purine CH); MS m / e (re1 intensity) 420 (2), 422 (0.9, M'), 336 (lOCI), 338 (34, M' - Dhp). Anal. Calcd for C23H21C1N402: C, 65.63; H, 5.03; N, 13.31. Found: C, 65.39; H, 4.95; N, 13.52. 6-Chloro-8-(hydrox:ydiphenylmethyl)purine,A solution of 8b was hydrolyzed 150 remove the 9-protecting group (88% yield): mp 233-236 "C dec; NMR ((CD3)&O) 6 7.30 (m, 6, ArH), 7.54 (m, 4, ArH), 8.61 ( 9 , 1, purine CH); MS m / e (re1 intensity) 336 (loo), 338 (34, M'1, 318 (151, 320 (6, M' - HzO), 259 (28), 261 (10, M+ - CSH,). Anal. Calcd for CI8Hl3C1N40: C, 64.19; H, 3.89; N, 16.64. Found: C, 64.40; H, 3.69; N, 16.69. 6-Amino-8-(2-hydroxy-2-propyl)-9-( tetrahydropyran-2y1)purine (9a). A solution of 8a (50 mg, 0.16 mmol) in methanol (5.5 mL) was saturated with NH3 at 0 "C in a sealable tube. The reaction tube wa3 sealed and heated for 12 h at 90 "C. The tube was cooled and opened, the solvent was removed in vacuo, and the residue was extracled with hot acetone. The acetone was removed in vacuo, and the compound was applied to a column of neutral alumina (activity grade I, ICN Pharmaceuticals) and eluted with a gradient of CHC1, (300 mL) to 8% EtOH/CHC13 (300 mL). The combination of the appropriate fractions provided 9a (35 mg, 75% yield): mp 162-164 "C; NMR ((CD3),SO) 6 1.35-2.05 (m, 6, CHz's), 1.52 (s, 3, CH,), 1.62 (s, 3, CH,), 2.85-3.1 (m, 1,OCHz),3.75-4.15 (m, 1, OCHz), 5.68 (br, NH or OH), 6.25 (br d, J = 11 Hz, 1, N-CH-0), 6.88 (br, NH or OH), 8.02 (s, 1, purine CH); MS m / e 277 (M'), 193 (B, M' - Dhp), 178 (M' Dhp - CHB), 175 (M+ Dhp - H20). Anal. Calcd for C13H1BN502~1/3H20: C, 55.11; H, 7.00; N, 24.70. Found: C, 55.12; H, 6.82; N, 24.30. 6-Amino-8-(2.hydroxy-2-propy1)purine. A solution of 9a was hydrolyzed to remove the 9-protecting group: mp 244-245 "C dec (lit.25mp 249-251 "C dec); NMR ((CD,),SO) 6 1.55 (s, 6,
Leonard and Bryant CH,), 5.55 (br, NH or OH), 6.82 (br, NH or OH), 8.05 (s, 1,purine CH); MS m/e 193 (B, M'), 178 (M' - CH,), 175 (M' - H20),150 (M' - C,H,O), 136 (M' - C,H50). Anal. Calcd for C6HllN50: C, 49.73; H, 5.74; N, 36.25. Found C, 49.56; H, 5.64; N, 36.09. 6-Amino-8-(hydroxydiphenylmethy1)-9-(tetrahydropyran-2-y1)purine (9b). A solution of 8b (102 mg, 0.24 mmol) in methanol (4.5 mL) was saturated with NH3at 0 "C in a sealable tube. The reaction tube was sealed, heated at 90 "C for 12 h, cooled, and opened, and the contents were filtered. The filtrate was evaporated in vacuo, and the residue was extracted with hot CHC13. The addition of CCll to the chloroform layer effected the precipitation of 9b (60 mg, 60% yield): mp 253-255 "C dec; NMR ((CD3),SO)6 1.0-2.0 (m, 6, CHis), 2.653.0 (m, 1, OCH2),3.55-3.9 (m, 1, OCH,), 5.56 (br d, J = 11 Hz, 1,N-CH-0), 6.81 (br, NH or OH), 7.29 (s, 10, ArH), 8.05 (s, 1, purine CH); MS m / e 401 (M'), 317 (M' - Dhp), 299 (M' - Dhp - H2O). Anal. Calcd for C23H23N502: C, 68.81; H, 5.77; N, 17.45. Found C, 68.47; H, 5.67; N, 17.30. 6-Amino-8-(hydroxydiphenylmethyl)purine. A solution of 9b was hydrolyzed to remove the 9-protecting group: mp 270-271 "C dec; NMR ((CD,),SO) 6.83 (br, NH or OH), 7.1c7.55 (m, 10, ArH), 8.09 (9, 1, purine CH); MS m / e 317 (B, M'), 299 (M' H20),240 (M' - C6H5),212 (M' - C7H50). Anal. Calcd for Cl8Hl5N50: C, 68.12; H, 4.76; N, 22.07. Found C, 67.98; H, 4.74; N, 22.00.
Acknowledgment. This work was supported by Research Grant No. CHE76-23543 from the National Science Foundation. J.D.B. has held a Proctor and Gamble fellowship. The mass spectral data processing equipment employed in the present study was provided by NIH Grant No. CA 11388 and GM 16864, from the National Cancer Institute and the National Institute of General Medical Sciences, respectively. Registry No. 1, 71819-06-2; 2, 16347-32-3;3a, 71819-07-3; 3b, 71819-08-4; 3c, 71819-09-5; 4a, 71819-10-8; 4b, 71819-11-9; 5, 71819-12-0; 6, 71819-13-1; 7, 7306-68-5; 8a, 71819-14-2; 8b, 7181915-3;9a, 71819-16-4;9b, 71819-17-5; acetone, 67-64-1; 6-(2-hydroxy718192-propyl)purine, 71819-18-6; 8-(2-hydroxy-2-propyl)purine, 19-7; benzaldehyde, 100-52-7;phenylacetaldehyde, 122-78-1;6-(ahydroxybenzyl)purine, 71819-20-0; 6-(l-hydroxy-2-phenylethyl)purine, 71819-21-1; benzophenone, 119-61-9;8-(hydroxydiphenylmethyl)purine, 71819-22-2; 2-chlorobenzoxazole,615-18-9; 8-(benzoxazol-2-yl)purine, 71819-23-3; 6-chloro-8-(2-hydroxy-2-propyl)purine, 71819-24-4; 6-chloro-8-(hydroxydiphenylmethyl)purine, 71819-25-5; 6-amino-8-(2-hydroxy-2-propyl)purine, 23865-41-0; 6amino-8-(hydroxydiphenylmethyl)purine, 71819-26-6.
