Vilsmeier-type synthesis

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

Vilsmeier type reagent 160 was employed in the direct and efficient synthesis of dimethylformamidrazones from hydrazines . 2-Benzotriazolyl-13-dioxolane (161) has been utilized as a novel formyl cation equivalent . 1-... 

Applications of the Vilsmeier-type reaction to the synthesis of a variety of imine-substituted indoles have been reported. The scope appears to be very wide and further examples will undoubtedly be forthcoming. Perhaps the most important development is the use of triflic anhydride in combination with amides to generate highly reactive imino-triflate reagents in situ, and this general area of reagent modification is also likely to develop. 

The efficiency of a bis(disilyl)sulfide for thiolactam synthesis has been explored prior activation of the amide into a Vilsmeier type intermediate was necessary [32]. 

Vilsmeier-type reagent 749 reacted with imines 750 to afford enaminoimine hydrochlorides 751, which were transformed to pyrazoles 752 upon addition of hydrazine (Scheme 94) <2000JHC1309>. A variety of vinylogous iminium salts 753 were useful precursors for the regiocontrolled synthesis of heterocyclic appended pyrazoles 754 (Equation 161) <2002T5467>. 

In many cases synthesis of the fluorinated 1,3-CCC-bielectrophile precursors is the most difficult part of the syuthetic sequeuce and using classical methods is usually accomplished by the use of highly toxic fluoroacetic add derivatives in Claisen condensation with ethyl formiate [81], ethyl chloroformate [95,96], diethy-loxalate [82, 97], acetyl, benzoyl chlorides [82] or Vilsmeier-type formylation [98, 99] (Scheme 13). The product of Vilsmeier-type formylation is 3-dimethylamino-2-fluoroacrolein 54 which reacts with triethyloxonium tetrafluoroborate and dimeth-ylamine to give the vinamidinium salt 55 [91], which also can be used as 1,3-bielectrophile (see Scheme 19). Also Reformatsky-type synthesis of ethyl a-fluoroacetoacetate 52 starting from ethyl chlorofluoroacetate 56 was described in 20 % yield [82]. 

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. ... 

A type Ilbc approach to pyrroles was employed in the synthesis of pyrrolo[2,l-fc]thiazoles <06S1433>. The key step involved a formylation with the Vilsmeier-Haack reagent followed by a cyclocondensation of the putative iminium intermediate. 

The action of phosphorus halides on pyrrolinones and related compounds offers an alternative route to chloropyrroles. Yields of around 60% of 2,5-dichloropyrroles were obtained in this way from N-substituted succinimides (82ZC126). Vilsmeier reaction of N-alkylsuccinimidals formed chlorinated pyrrole aldehydes in modest yields (90CJC791), and there are other examples [66YZ158 81H(15)547]. A useful synthesis of chloropyrrole-2-carboxylates employed the action of phosphorus pentachloride on pyrrolidin-2-one-5-carboxylates (40) (87CB45) (Scheme 15), and in a Pummerer-type reaction pyrrol-3-yl sulfoxides were transformed by thionyl chloride into chloropyrroles. Yields were increased to >80% by the use of oxalyl chloride (88JOC2634) (Scheme 15). 

The 5//-pyrido[4,3-f ]benzo[/]indole ring system (e.g., 192) represents another type of isoellipticine, and its synthesis has been explored by Bisagni and co-workers (95) (Scheme 33). Azaindole 188 was elaborated by means of conventional lithiation methodology to alcohol 189. A sequence of dehydration, hydrogenation, and chlorination gave 190. Either Vilsmeier-Haack conversion to aldehyde 191 and polyphosphoric acid (PPA) cyclization to the desired ring system 192 or direct cyclization to 192 completed the synthesis. The side chain amines were introduced by heating the components neat to provide 193-195. The methoxyl derivatives 196 and 197 were also synthesized (95). 

Friedlander quinoline synthesis, cyclisations under Vilsmeier conditions, six-membered mesionic heterocycles of the m-quino-methane dianion type,2 the basic properties of 2,6-di-t-butyl-pyridine,2 and isotopic exchange in purines.22... 

The Bischler-Napieralski cyclization is a classic reaction for the synthesis of heterocycles such as quinolines and isoquinolines. Thus, early efforts were devoted to the application of this transformation within this series of compounds (via activation of a carbamate or an analogue), along with known variants (using Vilsmeier-like intermediates, isocyanates, or activated ami-dines). These types of cyclization would produce the desired 6-azaindole at the correct oxidation state. To our dismay, none of these approaches provided the desired target. Instead, they resulted in either no reaction, decomposition, or unproductive reaction. 

If the self-condensation of the iminium chlorides is minimized by suitable substitution, reaction with other reactive substrates is readily accomplished. Perhaps the best-known example of this type of reaction is the Vilsmeier-Haack aldehyde synthesis (121,285,286 general review of this reaction can be found in Houben-Weyl ( ). 

Vilsmeier-Haack-type reaction provided the C ring of the Aspidosperma skeleton, and elaboration of the E ring was achieved by the addition of a radical generated from the xanthate derivative of the primary alcohol to give nonacyclic compound 111. The final steps for the completion of the total synthesis consisted of the formation of a lactone ring, which was achieved by oxidation of the tertiary amine with potassium ferricyanide,... 

From Vllsmeier Salts (Type Q.—The Vilsmeier-Haak reaction has been applied to the synthesis of 2- (or 5-)substituted 4-cyanoisothiazoles (45). Thus, condensation of a Vilsmeier salt prepared from phosphorus oxy-... 

There are numerous multistep processes that generate electrophiles. As examples of these types of reactions, we will consider the diazotization of anilines and the formation of chloroiminium ions in the Vilsmeier-Haack reaction. Aryl diazonium ions are useful in the modification of arenes by the Sandmeyer reaction and as electrophilic intermediates in diazonium coupling reactions for the synthesis of dyes and pigments. Several types of synthetic methods have been developed for this chemistry, and the mechanism varies depending on the methodology [13]. Under some conditions, the nitrosonium ion (18) initiates the process (Scheme 1.5). NjOj and NOCl have also been proposed as intermediates in diazotization—both are considered as nitrosonium ion carriers. The aniline reacts... 

A novel synthesis of isoselenazoles (150), using bromoseleno-intermediates in the final cyclization stage, comprises the successive treatment, at -80 C, of selenoethers of type (148), e.g. cis-/3-methylseleno-2-propenal, with bromine and ammonia it generally affords the desired heterocycles in very good yield. The precursors (148) are ultimately derived from the appropriate ketones (146), which are first converted into the chloro-aldehydes (147) by the Vilsmeier-Haack reaction, and then treated with methaneselenol in pyridine-triethylamine. They arise as mixtures of cis- and trans-isomers, separable by spinning-band fractional distillation. The u.v. and n.m.r. spectra of the isoselenazoles were recorded and discussed. ... 

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