Vilsmeier procedure

A very talented collaborator, Dr S. W. McCombie, quickly developed an improved Vilsmeier procedure for the synthesis of the desired thionobenzoate 11 and then showed that 11 was smoothly reduced to the desired deoxy-compound 15 at 80° under reflux in benzene using a suitable initiator. Our first example was with cholesterol, but a further example with the glucose derivative 16 showed the power of the new reaction. Derivative 16 gave the thionobenzoate 17 without difficulty. Reduction with tributyltin hydride under the same conditions as above gave a high yield of the desired deoxy-compound 18. 

The Friedel-Crafts acetylation of 3-phenylsydnone was accomplished with boron trifluoride etherate as catalyst. Formylation at C-4 by the Vilsmeier procedure occurred with 3-phenylsydnone. Mercuration is easily afforded with mercury(II) acetate or mer-cury(13) chloride and thioethers can be made directly with DMSO in acetyl chloride (74T409). At least one fused ring as in compound (35) has been made by a coupling reaction on the sydnone (34) at C-4 (79JCS(P2)175l). 

A new synthesis of olivacine 1138) (Scheme 24) and guatarabuine takes advantage of the stabilization of dihydropyridine derivatives by complexation with tricarbonylchromium(o). Thus, the readily prepared intermediate (139) gives a tricarfaonylchromiun complex (140), which can be formylated by the Vilsmeier procedure and dehydrogenated to demethylolivacine (141) this can be readily converted into olivacine and its N-methyl tetrahydro derivative, gua tambuine. ... 

Both substances yielded the 3-sulfonic acid (15% fuming sulfuric acid) and the 3-nitro compound (fuming nitric-sulfuric acid) neither 56 nor 57 could be formylated by the Vilsmeier procedure. 

Application of the Vilsmeier procedure to A,A-disubstituted 2-aminothiophenes and work-up with perchloric acid gave isolable iminium salts in high yields (Scheme 93) [141]. The same kind of product was obtained from W,W-disubstituted 2-aminothiophene 5-carboxylic acids with yields of 62-85%, thus showing that ipso-displacement of the carboxylic acid group had occurred (Scheme 93) [141]. Work-up in the usual way with aq NaOH gave the aldehydes. 

For aromatic hydrocarbons some very efficient formytation and acylation procedures are known (e.g. Friedel-Crafts, Vilsmeier, Gattermann-Koch), They are treated in introductory text books. 

The most useful general method for the C-acylation of pyrroles is the Vilsmeier-Haack procedure in which pyrrole is treated with the phosphoryl chloride complex (55a, b) of an AiA-dialkylamide (54). The intermediate imine salt (56) is hydrolyzed subsequently under mildly alkaline conditions to give the acylated pyrrole (57). On treatment of the imminium salt (56 R =H) with hydroxylamine hydrochloride and one equivalent of pyridine and heating in DMF, 2-cyanopyrrole (58) is formed (80CJC409). 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

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. ... 

An interesting variation of this procedure relies upon the formation of malondialdehyde precursors in situ. Vinylogs of Vilsmeier-Haack intermediates (60), formed from dimethylaminoacroleins (59) and phosgene, undergo reaction with 2,4,6-triaminopyrimidine to yield 6-alkyl- and 6-aryl-substitutcd 2,4-diaminopyrido[2,3-d]-pyri-midines (61). Dimethylaminoacroleins were found to be unsatisfactory. ... 

Scheme 11.5 gives some examples of these acylation reactions. Entry 1 is an example of a chloromethylation reaction. Entry 2 is a formylation using carbon monoxide. Entry 3 is an example of formylation via to-chloromethyl ether. A cautionary note on this procedure is the potent carcinogenicity of this reagent. Entries 4 and 5 are examples of formylation and acetylation, using HCN and acetonitrile, respectively. Entries 6 to 8 are examples of Vilsmeier-Haack reactions, all of which are conducted on strongly activated aromatics. 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vilsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

The authors of this review have developed a straightforward procedure for the synthesis of unsubstituted and alkyl-substituted thieno-thiophenes 1, 2, and 3 the method involves intramolecular condensation of ortho-bifunctional thiophene derivatives. Vilsmeier formylation of an alkyl (5-ethyl-2-thienylthio)acetate (53) furnishes the (5-ethyl-3-formyl-. 2-thienylthio)acetate (54) which when heated with alcoholic sodium... 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Brassilexin 48 and sinalexin 49 are among the most potent phytoalexins produced by economically important cruciferous plants. The most efficient preparation of brassilexin 48, sinalexin 49, and analogues 52 reported uses a Vilsmeier formylation-amination of readily available indoline-2-thiones 50 followed by an aqueous ammonia work-up procedure with subsequent oxidation of the 3-(amino)methyleneindoline-2-thione intermediates 51 using iodine in pyridine (Scheme 10) <20010L1213, 2005JOC1828>. The reaction yields are dictated by the efficiency of the... 

Reaction of 3-methyl-6-methylaminouracil 494 with 495, obtained by the Vilsmeier reaction of ethyl acetoacetate and ethyl benzoylacetate, or with vinyl ketones 496 under a modified procedure previously described <1984CPB1699, 2002H(57)491>, afforded the pyrido[2,3-,71pyrimidine derivatives 497-500 (Scheme 21) <2004H(63)1393>. 

The Vilsmeier-Haack formylation procedure (Scheme 24) provides the most effective synthesis of formylpyrroles and indoles. Reaction of the heterocycles with the immonium cation (72), derived from DMF or (V-methylformanilide with an acid chloride, such as phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, benzoyl chloride or bromotriphenylphosphonium bromide, yields the intermediate heteroarylimmonium salt (73). Under suitable reaction conditions, this salt may be isolated from the reaction involving phosphorus oxychloride as an impure chlorophosphate (78TH30500) or precipitated from the reaction system as the thermally unstable perchlorate by the addition of sodium... 

Acyl-2-alkyl-2,3-dihydro-4( 1 //)-pyridones A are readily available heterocycles in both racemic and chiral form. l-Acyl-2-alkyl-l,2-dihydropyridines B are much less readily accessible, especially enantiopure, but are much sought after building blocks for alkaloid synthesis. A very efficient (83-96%) and simple procedure has now been developed for the A — B transformation, illustrated as follows treatment of l-allyloxycarbonyl-2-cyclohexyl-2,3-dihydro-4-pyridone with one equivalent of the Vilsmeier reagent in trichloroethylene at room temperature gave l-allyloxycarbonyl-4-chloro-2-cyclohexyl-l,2-dihydropyridine in 92% yield. 

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