Vilsmeier salts

Marson, C. M. Reactions of carbonyl compounds with (monohalo) methyleniminium salts (Vilsmeier reagents). Tetrahedron 1992,48, 3659-3726. 

Hexamethylphosphoramide, (MejN)3P=0, reacts with phosgene to give an interesting chlorophosphonium salt, in a manner similar to the formation of chloroiminium salts (Vilsmeier reagents) cf. Sections 10.2.2.3 and 10.2.7 [1638] ... 

Chlorocarbenium salts (Vilsmeier-Arnold type) are reported to react with silylated cyanurate... 

Iminium salts (Vilsmeier reagents) can be readily prepared from DMF and phthaloyl chloride. Stirring in dioxane solution for 3h at 40°C results in precipitation of the product in 78% yield (Eq. 6.49) [77]. Because of the hygroscopic nature of the product, it has also been used in situ (Eq. 6.50). The Vilsmeier reagent can be used to convert alcohols to alkyl chlorides, or aldehydes to dichlorides [77]. 

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

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 Reverse Vilsmeier Approach to the synthesis of quinolinium salts is discussed in Meth-Cohn, O. Taylor, D.L. Tetrahedron 1995, 51, 12869. 

Vilsmeier formylation of praziquantel (9) with DMF-POCI3 at 60 °C for 5 h gave 2-cyclohexylcarbonyl-3-dimethyliminiummethylene-4-chloro-1,6,7,116-tetrahydro-2//-pyrazino[2,l-u]isoquinoline salt (01PHA146). 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

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). 

Nucleophilic processes that generate chloroindoles are largely confined to the displacements of oxy functions and Sandmeyer reactions of diazo-nium salts [81 H( 15)547]. A low yield of 2-chloroindole was obtained by a reaction sequence that involved treatment of oxindole with phosphoryl chloride, and then treatment of the Vilsmeier salt with sodium bicarbonate [66JOC2627 86H(24)2879]. It is, however, much better to prepare this compound from 2-lithioindole (92JOC2495). With phosphoryl chloride and dimethylformamide ethyl l-hydroxyindole-2-carboxylate failed to give the expected 3-formyl derivative. Instead there was a 50% yield of the 3-chloro derivative (84CPB3678). Diazonium salts have been used as precursors in... 

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. 

The Vilsmeier-Haack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier-Haack reaction works better with electron-rich carbocycles and heterocycles. 

Treatment of the imine (47) with phosphoryl chloride in dimethylformamide gives the Vilsmeier salt (48) which when reacted with sodium hydrogen sulfide gives the thio compound (49) (Scheme 12) <81AX(B)1449>. 

Calculations by the Pariser-Parr-Pople method on the quinoneimine obtained by Fremy s salt oxidation of dibenz[6,/]azepine indicate that the carbon adjacent to the carbonyl group is the most nucleophilic center. This is confirmed by nitration [Cu(N03)2-Ac0H] and bromination [NBS-(PhC0)202] studies, in which the 1-substituted derivatives are obtained. However, acylation by Vilsmeier or Friedel-Crafts reaction fails, extensive decomposition of the ring system taking place. 

Synthesis The pyrazole-4-carbaldehyde synthesized according to Vilsmeier is reduced to the alcohol, which is chlorinated. The chloro derivative is reacted with sodium cyanide to give the nitrile, which is hydrolyzed to Lonazolac. The calcium salt, slightly soluble in water, is formed by adding calcium chloride to the free acid (Rainer et al., 1981 Unterhalt, 1982 Rainer et al. (Byk Gulden), 1969 1982 Kleemann et al., 1999). 

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