Nitrosative cyclization

Later, a completely different and more convenient synthesis of riboflavin and analogues was developed (34). It consists of the nitrosative cyclization of 6-(A/-D-ribityl-3,4-xyhdino)uracil (18), obtained from the condensation of A/-D-ribityl-3,4-xyhdine (11) and 6-chlorouracil (19), with excess sodium nitrite in acetic acid, or the cyclization of (18) with potassium nitrate in acetic in the presence of sulfuric acid, to give riboflavin-5-oxide (20) in high yield. Reduction with sodium dithionite gives (1). In another synthesis, 5-nitro-6-(A/-D-ribityl-3,4-xyhdino) uracil (21), prepared in situ from the condensation of 6-chloro-5-nitrouracil (22) with A/-D-ribityl-3,4-xyhdine (11), was hydrogenated over palladium on charcoal in acetic acid. The filtrate included 5-amino-6-(A/-D-ribityl-3,4-xyhdino)uracil (23) and was maintained at room temperature to precipitate (1) by autoxidation (35). These two pathways are suitable for the preparation of riboflavin analogues possessing several substituents (Fig. 4). 

Nitrosative cyclization. Toxoflavin (2), an antibiotic isolated from Psu-domonas cocovenenans, has been synthesized recently by reaction of the aldehyde hydrazone (1) with a shght excess of sodium nitrite in acetic acid at 5°. This reaction was discovered by Goldner et al. and has been used for synthesis... 

Nitrosative cyclization, 547 Nitroso compounds, 97-98 Nitrosolysis, 422 N-Ni tro so-N-methylurea, 159 /3-Nitrostyrene, 422 Nitrosyl chloride, 422-423 Nitrosyl tetrafluoroborate, 226 cr-Nitrotriphenylmethane, 272 Nitroxides, 455-456 Nitroxyl radicals, 110 Nonactic acid, 106,107 Nonactin, 106, 625... 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Alkylaminofurazans of type 202 were nitrosated to give the corresponding ni-trosoamino derivatives, which were cyclized to fused 1,2,3-triazole 2-oxides 203 in 70-92% yields (96TL8577) (Scheme 133). 

Starting from the known isothiocyanate 351 <1998JHC29>, the cyclization of the semicarbazide 352, obtained from compound 351, by condensation with hydrazine hydrate, gives thione 353, whose nitrosation and reduction... 

Oxidative cyclization, substituted stil-benes to phenanthrenes, 46, 91 Oximes, reduction with lithium aluminum hydride, 48, 23 Oximinomalononitrile, from nitrosation of malononitrile, 48,1 reduction with aluminum amalgam, 48,2 ... 

The 1,2,3-triazine ring was constructed from o-aminophenyl oximes in the conditions of nitrosation (NaN02/HCl) , while hydrazinooximes were used for the synthesis of the 1,2,4-triazine ring Thus, cyclization of a-hydrazinooxime 342 with Pb304 in the presence of acetic acid afforded 1,2,4-triazines 343 in 44-54% yields (equation 149) . Interaction of oxime 344 with hydrazine leads to the spiro compound product 345 in 73% yield (equation 150) °. 

Meso-ionic 3-alkyl-l,2,3,4-oxatriazol-5-ones (271) are obtained by the nitrosation of 1-alkyl semicarbazides, RNHNHCONHj. At low temperatures, the intermediate A-nitroso derivatives (272) can be isolated, which cyclize on heating. An alternative synthetic route is illustrated by the formation of meso-ionic 3-methyl-l,2,3,4-oxatriazol-5-one (271, R = Me) from A-nitroso-iV-methylhydrazine (273) and phosgene. ... 

Since nicotine is the major precursor to NNN in tobacco and tobacco smoke, the reaction of nicotine with sodium nitrite was studied to provide information on formation of other tobacco specific nitrosamines, especially NNK and NNA, which could arise by oxidative cleavage of the l -2 bonds or l -5 bond of nicotine followed by nitrosation (26). The reaction was investigated under a variety of conditions as summarized in Table I. All three nitrosamines were formed when the reaction was done under relatively mild conditions (17 hrs, 20 ). The yields are typical of the formation of nitrosamines from tertiary amines (27). At 90 , with a five fold excess of nitrite, only NNN and NNK were detected. Under these conditions, both NNK and NNA gave secondary products. NNK was nitrosated a to the carbonyl to yield 4-(N-methyl-N-nitrosamino)-2-oximino-l-(3-pyridyl)-1-butanone while NNA underwent cyclization followed by oxidation, decarboxylation and dehydration to give l-methyl-5-(3-pyridyl)pyrazole, as shown in Figure 4. Extensive fragmentation and oxidation of the pyrrolidine ring was also observed under these conditions. The products of the reaction of nicotine and nitrite at 90 are summarized in Table II. 

The fused triazole ring is most commonly prepared by nitrosation followed by cyclization involving treatment of diaminopyrimidines with either sodium or potassium nitrite in dilute acid <1996CHEC-II(7)489, 2003JC0653>, as shown in the examples in Schemes 66 <1999JME833> and 67 <2004JHC575>. 

Gucky et al. prepared oximes 91 by nitrosation of the activated methylene group of 87 using nitrosylsulfuric acid and sodium nitrite in concentrated sulfuric acid (Scheme 68) <2002HC0613>. Oximes 91 were treated with hot POCI3 to induce a five-membered cyclization to provide the fused isoxazole ring in 92. The overall yields for transforming 87 to 92 are shown in Table 5. 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

The chloromethylpyrimido[5,4-( ]-l,2,4-triazine 86 is an extremely versatile starting material (see Section 10.20.7.2, Equation 12) and was synthesized from the commercially available thiol 151 as shown in Scheme 25. Thus, 6 -methylation of compound 151 gave the sulfide 152, which was nitrosated to allow access to the nitroso-thiomethyl derivative 153. Nucleophilic substitution of the thiomethyl group by hydrazine gave the cyclization precursor 154, which underwent cyclization with chloroacetaldehyde diethyl acetal under acidic conditions to give the chloro-methylpyrimido[5,4-( ]-l,2,4-triazine 86 after workup with aqueous ammonia <2003BML2895>. 

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