Vilsmeier reagents

Vilsmeier reagent The reagent obtained from POCI3 mixed with either N,N-dimethyl-formamide or N-methylformanilide. Used for introducing the methanoyl (formyl) (-CHO) group into activated aromatic substrates. 

Typically, an acetanilide (1 mol. equiv.) was treated with the Vilsmeier reagent generated from POCI3 (7 mol. equiv.) and V,V-dimethylformamide (DMF, 2.5 mol. equiv.) at 75 °C for 4 - 20 h. The reaction products were readily obtained by filtration after pouring the reaction mixture onto ice-water minor reaction products were isolated after basification of the filtrate. A variety of acetanilides were studied under these optimised reaction conditions and some significant observations were noted. Activated acetanilides 3 [e.g. R = 4-Me (70%), 4-OMe (56%)] reacted faster and in better yield to give quinolines 4 than other strongly deactivated systems 3 [e.g. R = 4-Br (23%), 4-Cl (2%), 4-NO2 (0%)] — in these cases, formamidines 5 and acrylamides 6 were the major reaction products. 

In the Meth-Cohn quinoline synthesis, the acetanilide becomes a nucleophile and provides the framework of the quinoline (nitrogen and the 2,3-carbons) and the 4-carbon is derived from the Vilsmeier reagent. The reaction mechanism involves the initial conversion of an acylanilide 1 into an a-iminochloride 11 by the action of POCI3. The a-chloroenamine tautomer 12 is subsequently C-formylated by the Vilsmeier reagent 13 derived from POCI3 and DMF. In examples where acetanilides 1 (r = H) are employed, a second C-formylation of 14 occurs to afford 15 subsequent cyclisation and... 

In a useful extension to the Meth-Cohn quinoline synthesis, pyridoquinolin-2-ones 27 are readily prepared in a one-pot procedure by sequential treatment of an acetanilide 3, firstly with the Vilsmeier reagent from DMF and POCI3 to afford the intermediate 16, which is then further reacted in situ with another secondary amide. ... 

Treatment of 5,7-diamino-l,3,4-thiadiazolo[3,2-n]pyrimidinium ehloride (25) with Vilsmeier reagent gave the 7-formamido-l,2,4-triazolo[l,5-c]pyrimidin-5-one (27) (90JHC851) (Seheme 42). Compound 27 has presumably been formed via rupture of the 1,3,4-thiadiazole ring of 25 and... 

A new eonversion of an aetivated nitro group at furazan ring into halogen was reported by Sheremetev et al. (000MC67) (Seheme 92). When dinitrofurazans 165a-c were allowed to reaet with an exeess of Vilsmeier reagent in POCI3 on... 

Pyrrolo[ 1,2-b [l, 2,4[triazinium salt 30 was obtained (90CB2039) by the reaction of hydrazone 29 with the Vilsmeier reagent prepared from DMF and oxalylchloride (Scheme 9). 

Note The most common Vilsmeier reagent, (chloromethylene)dimethylammo-nium chloride (ClHC=+NMe2 CU), is usually made in situ from MesNCHO and POCI3, SOCI2, or COCI2. As well as chlorolysis of 0x0 substituents, these reagents are prone to react at other sites in the substrate molecule. 

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. 

In contrast to iV-disubstituted 3-hydroxyanilines which react with Vilsmeier reagent to give AWisubstituted salicylaldehydes, their heteroanalogous iV-disubstituted 2-amino-4-hydroxythiazoles (60) react with Vilsmeier reagent to give iV-disubstituted 2-amino-4-chlorothiazole-5-aldehydes (61) <96JPR51>. 

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... 

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. 

Luminol amidine 132, synthesized from luminol and the Vilsmeier reagent from DMF and thionyl chloride, has been proposed as a suitable luminol derivative for analytical purposes because, unlike luminol, it can be easily purified by recrystallization from water. 132 exhibits a chemiluminescence quantum yield of about 20% of luminol in ferricyanide-catalyzed oxidation by aqueous alkaline hydrogen peroxide Amax of the emission is 452 nm 196>. 

The efficient synthesis of 2-phenyl-l,3,4-oxadiazole and 2-(4-pyridyl)-l,3,4-oxadiazole as pure compounds in 95-98% yields from the respective A-aroylhydrazines and using a bentriazole-derived Vilsmeier reagent has been reported <2000JOC2246>. 

The reaction of compounds 161 with the Vilsmeier reagent affords 5-formyl-6-substituted imidazo[2,l- ][l,3,4]thia-diazole-2-iV-(dimethylaminomethino)sulfonamides 168 (Equation 7) <1999AF858>. 

Marson, C. M. Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994. (Book). 

The addition of C-4 or C-6 is not a common route to pyrimidines, although in an example of this approach, 4-aryl-2-chloropyrimidines 622 were prepared from acetophenone cyanoimines 621, where the C-6 carbon came from DMF via the Vilsmeier reagent <2002SC3011>. The starting acetophenone cyanoimines were readily prepared from the analogous acetophenones by successive treatment with titanium tetrachloride and bis(trimethylsilyl)carbodiimide <2002SC3011>. 

Other sources of C-4 include the Vilsmeier reagent formed from POCI3 and DMF, which gives 2,4-dichloroquin-azolines 839 with A -aryl-A -(phenoxycarbonyl)urea derivatives 838 <1998BML2891>. 

---