Vilsmeier method

Synthesis of pyridines using Vilsmeier and inverse Vilsmeier methods 93H(35)539. 

The Vilsmeier method has been used to formylate 1,3,5-hexatrienes (56) yielding the aldehydes (57 and 58). It seems likely that suitable experimental conditions would make this a viable route to benzaldehydes.45... 

Aryltrifluoromethyl ketones are prepared by reaction of an aryl-lithium with a,a,a-trifluoro-N,N-dimethylacetamide. 2-Acyloxypyridines and N-acylimidazoles, " in conjunction with trifluoroacetic acid, acylate arenes in good yield without the need for a classical Friedel-Crafts catalyst or a preformed mixed anhydride. However, imidazole in trifluoroacetic anhydride is reported to form 2-aryl-Af,JV -diacyl-4-imidazolines with arenes reactive towards electrophilic attack. These adducts are readily hydrolysed by sodium hydroxide to the corresponding aldehyde [equation (14)]. This sequence may offer advantages over the Vilsmeier method of formylation, in that the aldehyde is introduced in a protected form. 

Acylthiophenes. Manufacturing methods introducing the carboxaldehyde group into the 2- or 5-positions of thiophene and alkylthiophenes utilise the Vilsmeier-Haack reaction. To synthesize 2-thiophenecarboxaldehyde (Table 5), a controlled addition of phosphoms oxychloride to thiophene in /V, /V- dim ethyl form am i de is carried out, causing the temperature to rise. Completion of the reaction is followed by an aqueous quench, neutralization, and solvent extraction to isolate the product. 

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). 

No significant amounts of diacylated products are obtained under Vilsmeier-Haack conditions an indirect method for preparing pyrrole-2,5-dicarbaldehydes is outlined in Scheme 16 (78S295, 82CJC383). 

Furan can also be acylated by the Vilsmeier-Haack method. Acylation of furans can also be carried out with acid anhydrides and acyl halides in the presence of Friedel-Crafts catalysts (BF3-Et20, SnCU or H3PO4). Reactive anhydrides such as trifluoroacetic anhydride, however, require no catalyst. Acetylation with acetyl p-toluenesulfonate gives high yields. 

Enamine acylations have been extended to include the Vilsmeier reaction (409) and thus provide a method for the generation of formyl ketones without the use of strong base. By this method an unsaturated potential trialdehyde could be formed as an intermediate in a pyridine-3-carboxaldehyde synthesis (410). 

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. ... 

The Vilsmeier cyclisation of acetanilides by the conventional methods described above often requires long reaction times and elevated temperatures. Moreover, only activated acetanilides react efficiently to afford 2-chloro-3-substituted-quinolines strongly deactivated systems afford mainly amidine 5 or acrylamide 6. ... 

Although limited to electron-rich aromatic compounds and alkenes, the Vilsmeier reaction is an important formylation method. When yV,A-dimethylformamide is used in excess, the use of an additional solvent is not necessary. In other cases toluene, dichlorobenzene or a chlorinated aliphatic hydrocarbon is used as solvent. ... 

Treatment of tricarbonylh4-1-(ethoxycarbonyl)-l//-azepine]iron(0) (30) with acetic anhydride and tetrafluoroboric acid at 0 C (Method A) yields the 3-acetyl derivative 31.226 The acetyl derivative is also formed, but in lower yield, by the action of acetic anhydride and tin(IV) chloride (Method B) on complex 30. The 3-propanoyl derivative (20% mp 95-96 C) can be prepared similarly, whereas formylation to give aldehyde 32 is successful under Vilsmeier conditions. 

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. 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

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>... 

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... 

Recently Bugge studied the reactivities of thienothiophenes 1 and 2 and thiophene by the competitive method, utilizing SnCl4-catalyzed acetylation with acetic anhydride, Vilsmeier formylation and chlorination with iV-chlorosuccinimide. Thienothiophenes 1 and 2 are always more reactive than thiophene. In acetylation the reactivities of 1 and 2 are similar, while in formylation and chlorination thienothiophene 2 is somewhat more reactive than isomer 1 (Table V). 

Kislyi et al. facilitated the formation of [l,2,3]triazolo[4,5-r lpyrimidin-7-ones from 5-amino-l,2,3-triazole-4-carbox-amides under Vilsmeier conditions (Scheme 47) or using triethyl orthoacetate and acetic anhydride (Scheme 48) <2003RCB1770>. These methods could be used to isolate the respective 5-formamidine 69 and 5-imidoate 70 reaction intermediates, if lower temperatures and shorter reaction times were employed. 

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. 

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