A New Synthesis of Pteridines Substituted with Branched and Linear Alkenyl Groups at C(6). The Nitroso‐Ene Reaction of 4‐(Alkenoylamino)‐5‐nitrosopyrimidines

Abstract

Pteridines substituted with a 1,1‐, 1,2‐, or 1,1,3‐substituted alkenyl group (mostly (E)‐configured) at C(6) were synthesized in high yields by the intramolecular nitroso‐ene reaction of 4‐(alkenoylamino)‐2‐amino‐6‐benzyloxy‐5‐nitroso‐ and 4‐(alkenoylamino)‐2,6‐diamino‐5‐nitrosopyrimidines. Thus, the N‐alkenoyl nitrosopyrimidines 4 and 5 provided the pteridines 6 and 7, respectively, characterized by a 1,2‐disubstituted (E)‐alkenyl substituent, the C(4)‐(E)‐geranoyl amide 13 led regio‐ and stereoselectively to the (E)‐1,1,2‐trisubstituted alkenyl‐pteridine 16, and the C(4)‐(Z) isomer 14 led to 17 possessing a 1,1‐disubstituted alkenyl group. The trifluoromethylated butenoyl amide 15 possessing a less highly nucleophilic alkenoyl group reacted more slowly to give the trifluoromethylated vinylpteridine 18. Also the 4‐(alkenoylamino)‐2,6‐diamino‐5‐nitrosopyrimidine 20 reacted more slowly than 4 and 5, and provided the pteridines 23; introduction of additional N‐acyl groups as in 21 and 22 led to a considerably faster ene reaction.The X‐ray crystal structure analysis of the nitroso amide 15 shows eight symmetrically independent molecules in the unit cell. In the crystalline state, the N,N‐dimethylformamidine derivative 9 of 6 forms a centrosymmetric dimer with the 7,8‐lactam group connected by intermolecular hydrogen bonds.

Diels–Alder Additions, Ene Reactions, and Condensations of 4‐(Acylamino)‐5‐nitrosopyrimidines – Synthesis of 8‐Substituted Guanines and of 6‐Substituted Pteridinones

“…In the HMBC spectrum of 21b, the formamidinyl H-atoms show crosspeaks with C(2') and C(3) at 163.58 and 156.52 ppm, indicating that the assignment of C(2) and C(8a) in [3] and [4] has to be reversed. Treating the N-crotonoyl-nitrosopyrimidine 19 with Ph 3 P in boiling o-xylene yielded 80% of the purine 22 that was debenzylated with in situ generated Me 3 SiBr to yield 92% of the poorly soluble 8-(prop-1-enyl)guanine (23).…”

“…We found that N-(alka-2,4-dienoyl)-4-amino-5-nitrosopyrimidines 4 undergo a facile, high-yielding intramolecular Diels -Alder cycloaddition to 5, followed by a spontaneous elimination, leading to pteridinones 6 possessing a (Z)-3-hydroxyalk-1-enyl group at C(6) [3]. Pteridinones 9 possessing an (E)-configured alkenyl substituent at C(6) result from a stereoselective nitroso-ene reaction of N-alk-2-enoyl derivatives 7 [4]. Similarly as for the cycloaddition of 4, the initial product of the ene reaction is a hydroxylamine derivative 8 that could not be observed.…”

“…First, we synthesized the known 8-(trifluoromethyl)-purines 26 and 27. 8-(Trifluoromethyl)guanine (27) had been obtained in a yield of 77% by heating pyrimidine-5,6-diamine with a mixture of (CF 3 CO) 2 O and CF 3 COOH to 2608 [20], or in a yield of 46% by treating guanine with CF 3 I, FeSO 4 , and H 2 O 2 in a H 2 O/DMSO mixture [21]. The O-benzyl derivative 26 had been obtained in 29% overall yield by chlorinating 27 with phosphorous oxychloride followed by treatment with benzyl alcohol and NaH [22].…”

A New Synthesis of Ciliapterin and Dictyopterin. Ene Reactions of (Alkenylamino)‐nitroso‐pyrimidines

“…-We already described the synthesis of pteridinone 11 [1]. It was obtained in almost quantitative yield by nitroso-ene reaction of the pent-2-enamide 10 that was obtained in 60 to 65% yield from the known diamino-nitrosopyrimidine 9 and (E)-pent-2-enoyl chloride.…”

“…The stronger interaction could be reflected in the relative bond lengths, and the N¼O, CÀNO, C¼C, and CÀNH bond lengths of the crystalline (acylamino)- nitroso-pyrimidines I [19], II [20], and III [1] that are similar to 10 were compared to those of 17, as listed in the Table 2 ).…”