Vilsmeier-Haack reaction with

Heterocycles represented by the general structure (179) afford ring-expanded products (180) in the Vilsmeier-Haack reaction with chloromethyleneiminium salt (13). 

Methylbenzimidazole (492 R = Me) yields the benzimidazoline (506) in the Vilsmeier-Haack reaction with DMF-phosphorus oxychloride. Treatment of 2-amino-l-benzhydryl-benzimidazole with sodium in liquid ammonia affords a mixture of 2-nitrobenzimidazole and the azo-compound (507) by an autoxidation process. " The benzimidazole derivative (508), prepared by the action of diphenylamine-2,2 -dicarbonyl chloride on benzimidazole, is dearomatized on heating to give the condensed heterocycle (509). ... 

The reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

Another useful method for introducing formyl and acyl groups is the Vilsmeier-Haack reaction.67 /V.A-dialkylamidcs react with phosphorus oxychloride or oxalyl chloride68 to give a chloroiminium ion, which is the reactive electrophile. 

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>. 

In miscellaneous oxidative processes of indoles, two methods for the preparation of 3-hydroxyindoles have been reported. The first approach involves initial Vilsmeier-Haack reaction of indole-2-carboxylates 176 to afford the corresponding 3-formyl analogs 177. Activation of the aldehyde with p-toluenesulfonic acid (PTSA) and Baeyer-Villiger oxidation with m-chloroperoxybenzoic acid (wi-CPBA) then affords high yields of the 3-hydroxy compounds 178 <00TL8217>... 

The Vilsmeier-Haack reaction of 2,6-dimethylimidazo[2,T. ][l,3,4]thiadiazole 169 gives aldehyde 170, which after reduction with sodium borohydride affords 2,6-dimethyl-5-hydroxymethylimidazo[2,TA [l,3,4]thiadiazole 171 (Scheme 2) <2000AF550, 2006BMC3069, 2006TL2811>. 

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

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... 

When (190) was subjected to a Friedel-Crafts reaction with benzoyl chloride, the result was an analog of coralyne with a phenyl rather than a methyl group at position 8. Kametani et al. (74YZ478) have carried out a parallel study using the Vilsmeier-Haack reaction to produce norcoralyne. 

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). 

Acylpyrroles can also be prepared by using the Vilsmeier reaction with various amides. Excellent yields of 2-aroylpyrroles were obtained using morpholides instead of the more common N,N- dimethylamides (equation 178) (77JOC4248). Similarly, a variety of 3-acylin-doles have been prepared using the Vilsmeier-Haack reaction (79HC(25-3)357). 

The Vilsmeier-Haack reaction of ketones forms chlorovinyl aldehydes, which can add thiols readily. The reaction with a-tetralone gave the chlorovinyl aldehyde (230), and reaction with ethyl thioglycolate in ethanolic ethoxide solution formed the dihydro derivative (231), easily dehydrogenated to naphtho[l,2-6]thiophene-2-carboxylate (73JCS(P1)2956). 

Thenaldehyde (thiophene-2-carbaldehyde) is readily available via the Vilsmeier-Haack reaction of DMF with thiophene catalyzed by phosphorus oxychloride. The Sommelet reaction with 2-chloromethylthiophene also gives reasonable yields (63AHC(l)l). Likewise, thiophene is readily acylated with acyl anhydrides or acid chlorides (equation 14), using mild Friedel-Crafts catalysts, such as tin(IV) chloride, zinc chloride, boron trifluoride, titanium tetrachloride, mercury(II) chloride, iodine and even silica-alumina gels or low-calcium-content montmorillonite clays (52HC(3)l). 

A different approach to selective O-substitution involves preferential replacement of existing groups. When tris-0-(tert-butyldimethylsilyi)-D-glucal is treated with phosphorus oxychloride-dimethylformamide complex in pyridine, the 0-6 silyl ether is selectively and efficiently replaced by a formate ester (Vilsmeier-Haack reaction).85... 

The 1,3-ditelluretane 88 is obtained as a minor product along with the 1,3-ditellurafulvene 89 by the reaction of phenylacetylide with tellurium followed by acidification with trifluoroacetic acid (Scheme 27) <2003TL2397>. In the reaction of trimethylsilylethynyl tellurolate, use of tifluoroacetic acid in /-butyl alcohol at — 20°C leads to the formation of the 1,3-ditelluretane 90, presumably via the telluraketene 91. Vilsmeier-Haack reaction on the crude ditelluretane 90 furnishes dialdehydes 27 and 92 in 10% yield. 1,3-Ditelluretanes 27 and 92 can be transformed into other derivatives, as shown in Scheme 28. An /. // mixture of 27 and 92 condenses smoothly with phosphorane to give diester product 93. The reaction with diesterdithiole phosphonate or dithiole phosphonate affords 1,3-ditelluretane derivative 94 or 95, respectively. 

Pyridines have been synthesized from an unusual Vilsmeier-Haack reaction where POCl3 dehydrates the appropriate enol to give a diene which in turn reacts with the Vilsmeier reagent leading to an iminium salt which subsequently cyclizes (Scheme 104 Table 7) <2002TL2273>. 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

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