Acylation of a 6‐(Methylamino)‐5‐nitrosopyrimidine and 1,3‐Dipolar Cycloaddition of an 8‐Methylisoxanthopterin N(5)‐Oxide. Synthesis of C(6),N(8)‐Disubstituted Isoxanthopterins

Abstract

Acylation of 2-amino-4-(benzyloxy)-6-(methylamino)-5-nitrosopyrimidine (5) with acetic anhydride or chloroacetic anhydride in the presence of 4-(dimethylamino)pyridine (DMAP) led to the C(2)-acylamino derivatives 6 and 7, respectively. In the absence of a base, acetylation did not lead to a product, while chloroacetylation led to the 6-chloropteridine 11. Chloroacetylation in the presence of Hünigs base provided the pteridinone N(5)-oxide 10, suggesting that acylation of 5 is readily reversible, and that the unfavourable equilibrium must be displaced by a follow-up reaction to trap the acylation product. Acylation of 5 with hexadienoyl chloride, followed by intramolecular Diels -Alder reaction, provided the pteridinone 12. A high yielding 1,3-dipolar cycloaddition of the acylnitrone 10 to electron-poor and electron-rich dipolarophiles, followed by spontaneous N,O-bond cleavage, gave the C(6)-substituted pteridinones 19a -19e that were deprotected to the pteridine-4,7(3H,8H)-diones 20a -20e. Substitution of the 6-chloropterin 11 provided the 6-morpholinopteridine 25. Sonogashira coupling yielded the fluorescent [(pteridin-6-yl)ethynyl]-glucopyranoside 26, 6-ethynylpteridine 28, and 6,6'-(ethynediyl)-bispteridine 29. The alkyne 28 reacted with Me 3 SiCl and LiBr in MeCN to produce the bromoalkene 31.Introduction. -We described new routes to 6-substituted pteridines based on intramolecular Diels -Alder cycloadditions, ene-reactions, and condensations of N(6)-acylated or N(6)-alkylated 6-amino-5-nitrosopyrimidines [1 -4]. We also showed that the pteridinone N(5)-oxides, resulting from the condensation of 6-amino-5-nitrosopyrimidines with chloroacetic acid anhydride ((ClCH 2 CO) 2 O) react as acylnitrones. The course of their [3 þ 2] cycloaddition to acceptor-substituted dipolarophiles is illustrated in Scheme 1 by the addition of 1 to methyl acrylate. This reaction provides 2, resulting from a spontaneous eliminative cleavage of the N,O bond of the initially formed isoxazolidine, and thus constitutes a new, high-yielding access to isoxanthopterins 2 possessing a functionalised side chain at C(6) [5]. The poor solubility of these isoxanthopterins was assumed to result from a favourable intermolecular H-bonding of the DADA motif involving HN(2'), N(1'), HN(8') and O¼C(7') of the products of type 2. This hypothesis prompts to investigate the formation and 1,3-dipolar cycloaddition of N(8)-alkyl derivatives of 1. The simplest ones, N(8)-methylpteridinone N(5)-oxides, should be obtained by an intramolecular condensation of 6-[(chloroacetyl)(methyl)-amino]-5-nitrosopyrimidines. We were thus interested in the cycloaddition of N(8)-alkylated pteridinone N(5)-oxides and the solubility of the resulting products, in the formation of the pteridinone N-oxides by condensation of 6-[(alkyl)(chloroacetyl)-amino]-5-nitrosopyrimidines, and in the N-acylation leading to these amides. As we had

Synthesis of 4-alkylamino-6-arylamino-5-nitrosopyrimidines via intramolecular oxidation-reduction reactions of N-alkyl-N-(6-arylamino-5-nitropyrimidin-4-yl)glycinates

“…With the ethyl-N-alkyl-N-(6-arylamino-5-nitropyrimidin-4-yl)glycinates (11)(12)(13)(14) in hand, we investigated their intramolecular oxidation-reduction reactions by treatment with an equivalent of sodium methoxide in methanol at room temperature. 4-Alkylamino-6-arylamino-5-nitrosopyrimidines (15)(16)(17)(18) were the major products of these reactions (Table 1). In a number of cases, however, along with compounds 15-18, the formation of 5-hydroxypteridine-6,7-diones (19)(20)(21)(22) and/or trans-esterification methyl-esters products (23), were observed.…”

“…The synthesized products 15-23 were characterized by spectroscopic methods. In the NMR spectra of 5nitrosopyrimidines (15)(16)(17)(18), two sets of signals were observed. As is known from previous studies, 21,23 the nitroso-group in 5-nitrosopyrimidines with amino substituents in the neighboring 4-and 6-positions can form stable intramolecular hydrogen bonds; therefore, two rotamers (I and II) are possible (Scheme 4).…”

“…Table 2. Approximates ratios of rotamers I : II of 4-alkylamino-6-arylamino-5-nitrosopyrimidines (15)(16)(17)(18) in CDCl3 at room temperature (calculated from 1 H NMR spectra)…”

“…5-Nitrosopyrimidines with an electron-donating group at position 2 are usually prepared by direct nitrosation of the corresponding pyrimidines with sodium nitrite in aqueous acid or with isopentyl nitrite under neutral conditions. 7,13,[17][18][19][20] Some time ago, we found that 2-unsubstituted-5-nitrosopyrimidines (2) can be prepared also via intramolecular oxidation-reduction reactions of methyl-N-methyl-N-(5-nitro-6-substituted pyrimidin-4-yl)glycinates (1) in basic media. Some by-products (pteridines 3 and purine derivatives 4 and 5) can also be formed in these reactions as shown in Scheme 1.…”