Vilsmeier cyclization

An angular 5-deazapteridino-desazaflavin with similar oxidative behavior is made from two molecules of 6-chlorouracil and 1,4-diaminobenzene with subsequent Vilsmeier cyclization (89CC44). Another approach to such a 5-deazaflavin is achieved in one step by reaction of two moles of 6-chloro-5-formyluracil with 1,4-diaminobenzene [86CPB2653 88JCS(P1)1813 89JHC49] (Scheme 124). 

An unprecedented attack on an azide group by an iminium species, generated in situ under Vilsmeier conditions, furnishes a novel route to construct the imidazole ring. Thus, A -aryl-5-chloro-2-(dimethylamino)imidazole-4-carbox-aldehydes 1257 were obtained from the Vilsmeier cyclization of A -aryl-2-azidoacetamides 1256. The possible mechanism for the reaction is illustrated in Scheme 316 <1998JOC7136>. 

The well-known Bischler-Napieralski reaction, in effect an intramolecular Vilsmeier cyclization, is reviewed elsewhere.65... 

Some pyrazole derivatives play a vital role in biological fields because of their analgesic, antiinflammatory, antibacterial and hypoglycaemic activities. Microwave irradiations have been used in the preparation of pyrazoles (45-80%) from hydra-zones using the Vilsmeier cyclization method by treatment with POCI3 and DMF (Selvi and Perumal, 2002). The reaction is speeded up by factors of several hundred fold. 

Benzoisobacteriochlorin 14 can be prepared from nickel(II) chlorin 12 by vinylogous Vilsmeier reaction to give 13 and subsequent acid-induced cyclization.22 The chlorin 12 is, as expected, alkylated in a meso position adjacent to the reduced pyrrole ring. 

Acid-induced cyclization of the appropriate (hydroxypropenyl)pyrroles 30, which can be easily derived from a-unsubstituted pyrroles by vinylogous Vilsmeier reaction followed by reduction of the formyl function, yields the corresponding expanded porphyrinogens 31. The... 

TL9381, 96CC1395>. The reaction involves deprotonation of the Vilsmeier reagent, dimerization of the carbene formed and electrophilic cyclization of the dimer by bromonium ion action followed by aqueous hydrolysis. 

Formation of a pyridine ring onto bis-heterocycles is another route to these tricyclic systems. Reaction of 4-amino-2-morpholino-5-(2-morpholinothiazoM-yl)thiazolc 154 with the Vilsmeier reagent proceeds by direct cyclization to the bis-thiazolylpyridine 155 (Equation 36) <1997JHC1291>. 

The synthesis reported by Bonjoch and co-workers utilizes a Ni-mediated reductive cyclization of vinyl iodide 82 with concomitant reductive indolenine formation quenching of the presumed intermediate (dehydrotubifoline, 83) with the Vilsmeier reagent affords A-formyl derivative 84 [36b]. Photoisomerization gives norfluorocurarine (22) in low yield. Similarly, Rawal and He produce... 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

The reaction of 3-isonitrosopyrazolo[5,l-6]quinazolin-2,9-dione 453 with the Vilsmeier reagent gave the expected o-cyanoamidine derivative, which was cyclized [77IJC(B)335] by hydroxylamine to [l,2,4]triazino[6,l-b]quinazolin-10-one 454. 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

A multi-stage synthesis of azocino[4,5,6-cd]indoles has been suggested (03M13519). From 4-bromoindole (84) with the help of successive transformations (among them the Vilsmeier-Haack reaction, Henry nitroaldole condensation, lithium aluminum hydride reduction and insertion of an allyl fragment), indole 85 has been produced in 18% yield. The cyclization of the latter on palladium... 

Synthesis from quinazoline precursors was achieved by carrying out a Vilsmeier-Haack reaction on 3-amino-2-methyl-4-quinazolone (96) to give the intermediate diformyl derivative 97 that cyclized to 3-formylpyra-zolo[5,l-b]-quinazolin-9-one (98) [73IJC532 84IJC(B)161]. 

Performing a Vilsmeier-Haack reaction on 3-benzoyloxy-2-methyl-quinazolin-4-one (184) afforded the isoxazolo[3,2- ]quinazolinone (185) [86IJC(B)709]. This ring system (187) was also synthesized by cyclocondensation of anthranilic acids or isatoic anhydrides with the isoxazolin-3-ones (186) (77AF766 83MIP1), or by condensation of methyl anthrani-late with 3-chloropropanoyl chloride followed by cyclization with hydroxylamine hydrochloride (77AF766). 

Under controlled conditions, the acetylaminopyrazole 80 was converted by Vilsmeier-Haack reaction to a mixture of chloro derivatives (81 R2 = H, CHO) in poor and moderate yields, respectively. Cyclization is preceded by C-formylation and formation of the imidoyl chloro group.95... 

Thermal cyclization of l-(l-methyl-2-pyrrolyl)buta-l,3-diene yields l-methyl-4,5-dihy-droindole (77TL151) and several examples of the cyclization of substituted vinyl derivatives have been reported, e.g. (395) -> (396) <74JCS(Pl)153l), (397) -> (398) <80JCR(S)233>, whilst the 2-(2-indolyl)propenoic ester (399) cyclizes under Vilsmeier-Haack conditions to produce (400) (80T2125). 

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