Reactivities and electronic aspects of nucleic acid heterocycles. 7. Regiospecific substituent effects in 6-substituted purines as measured by proton magnetic resonance

Abstract

The 'H NMR spectra showed the H-2 signal at lower field than that of H-8 for purines 1-13, but a crossover of the two proton peaks was observed for the 6-phenoxypurines 14-16. Correlations of 6(H-2) and li(H-8) with substituent constants u,, up, up+ (calcd), F, and R were determined for 1-14, and with Brown's up+ and Taft's U R O and UI for fewer compounds. For correlation with both 6(H-2) and 6(H-8), the up set is the best, yielding correlation coefficients of 0.931 and 0.933, respectively. These ~( H ) -u correlations are impractical for predicting proton chemical shifts of 6-substituted purines. However, they are useful in sorting out the regiospecific effects and proportions of the field and resonance components of the 6-substituent, Le., 65% resonance and 35% field for H-2,44% resonance and 56% field for H-8, as derived from the polynomial equations 2 and 3, respectively. These observations are rationalized by considering contributions of the mesomeric structures a-e. Furthermore, because of the uniquely large resonance and field effects of the phenoxy group, the apparent crossover of H-2 and H-8 in 14-16 can be accounted for in the same manner using structures f and g Coburn et aL2 reported the first linear correlation of the chemical shifts of the 8and 2-hydrogen of eight 6-substituted purines plus purine itself with Brown's up+ and Taft's UR substituent constant, respectively. They also reported3 similar relations for the 13C chemical shifts of carbons 8 and 5 but not for the carbons a t other positions for a variety of 6-and 2,6substituted purines. In the course of our studies4 of the electronic aspects and reactivities of purines and pyrimidines, we have examined the relationship between the proton chemical shifts (6(H)) of 16 6-substituted purines and various sets of substituent constants (a). We have found: (1) the ~( H ) -u correlations are impractical for predicting proton chemical shifts of 6-substituted purines; (2) the correlation coefficients ( r ) obtained are useful in sorting out the regiospecific effects and proportions of the field and resonance components of the 6-substituent; and (3) these effects are consistent with certain mesomeric contributions to the purine structure. Results and DiscussionThe chemical shifts of H-2 and H-8 of 16 purine compounds at 0.1-0.2 M in dimethyl sulfoxide are shown in Table I. The 1H NMR peak assignments were made by virtue of partially 8-deuterated samples. The 6-phenoxypurines 14,15, and 16, and trimethylpurin-6-yl ammonium chloride 13 were prepared by nucleophilic substitution of 50% 8-deuterated 6-chloropurine (8), whereas other 6-substituted purines were partially deuterated selectively at the 8-position upon heating in D20.5 The relative order of H-8 at high field and H-2 at low field was obtained for purines 1-13, but a crossover of the two proton peaks was shown by the phenoxypurines 14-16.Correlation of the proton chemical shifts with the substituent constants was accomplished by means of the regression equationThe lH NMR chemical shift 6(H) reflect...

Structure–metabolism relationships in human- AOX: Chemical insights from a large database of aza-aromatic and amide compounds

“…Chloro compounds 12a-b were obtained upon alkylation of purine with benzyl bromide and propargyl bromide in the presence of K 2 CO 3 . The nucleophilic substitution of 6-chloroderivative with phenol, aniline, or cyclohexylamine according to literature procedures (23,24) afforded compounds 13a-d. In turn, bromination of 13b and 13c with Br 2 saturated aqueous Na 2 HPO 4 solution gave 14 and 15 (25).…”

Synthesis and Biological Testing of Purine Derivatives as Potential ATP-Competitive Kinase Inhibitors

“…The compound was prepared from 6-chloropurine 23 6-Phenoxy-9H-purine (3). 40 The compound was prepared from 6-chloropurine 23 (9-Methyl-9H-purin-6-yl)phenylamine (5). 41 The compound was prepared from 6-chloro-9-methyl-9H-purine 24 (7), 77 (14).…”

“…6-Phenoxy-9H-purine (3). 40 The compound was prepared from 6-chloropurine 23 (8), 158 (7), 119 (10), 94 (10), 77 (9).…”

“…6-Benzylsulfanyl-9H-purine (13). 43 The compound was prepared from 6-mercaptopurine (0.61 g, 3.6 mmol) and benzyl chloride (0.5 g, 3,96 mmol) according to general procedure C to yield 13 (640 mg; 73%): mp 195 °C; 1 H NMR δ 4.66 (s, 2H, CH2), 7.24-7.50 (m, 5H, Ph), 8.47 (s, 1H), 8.75 (s, 2H), 13.52 (s, 1H, N-H, exchangeable); GC (temperature program B) 15.2 min; MS m/z (%) 242 (100, M + ), 227 (3), 209 (98), 164 (20), 121 (22), 107 (39), 107 (40), 91 (90), 77 (54).…”

“…. 42 The compound was prepared from 6-mercaptopurine (0.61 g, 3.6 mmol) and 4-fluorobenzyl chloride (0.57 g, 3,96 mmol) according to general procedure C and to yield 14 (250 mg; 27%): mp 228 °C; 1 (12), 123 (40), 123 (40), 109 (100), 95 (39), 83 (26).…”