Vilsmeier-type formylation

An unusual Vilsmeier-type formylation of a 2,4,6-triene is described on p. 301. Some novel steroidal-[10] annulenes have been prepared (p. 374). 

Phosphorus oxide chloride Ar. aldehydes from arylstannanes Vilsmeier-type formylation... 

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]. 

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). 

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-... 

Vilsmeier-Haack formylation of 2,5-diaryl-6a-thiathiophthens leads to the 3-formyl compounds, which are also obtainable from 3-aryl-l,2-dithiolium salts by treatment with triethylamine, and details have been given for the bromination of 2,5-disubstituted thiathiophthens. Nitration of 2-methylthio-5-phenyl-6a-thiathiophthen gives the 3-nitro-compound in poor yield, and attempted nitrosation experiments lead, in several examples, to rearranged structures of type (19), although the first stage of these reactions is presumed to be electrophilic attack on the 3-position. 

A-Formylation. When secondary amines were treated with TBDMSCl, DMAP, andEtsN in DMF the corresponding iV-formyl derivatives were formed (eq 23). It was found that the reaction proceeds through a Vilsmeier type reagent formed by the reaction of TBDMSCl and DMF. It is possible that other TBDMS alkylation reactions, such as protection of alcohols in DMF, may proceed through a similar DMF-derived Vilsmeier reagent. 

Tripodal tris-aldehyde ligand syntones, which have been prepared in [94] using Vilsmeier-Haack-type formylation of the corresponding tris-pyrroles by Scheme 2.82, gave the covalent capsules 124 and 125, the derivatives of ethylene-1,2- and butan-1,4-diamines, respectively. These macrobicyclic hgands encapsulate parent diamines during the template condensation with... 

Although in general azoles do not undergo Friedel-Crafts type alkylation or acylation, several isolated reactions of this general type are known. 3-Phenylsydnone (120) undergoes Friedel-Crafts acetylation and Vilsmeier formylation at the 4-position, and the 5-alkylation of thiazoles by carbonium ions is known. 

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. ... 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

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. 

V-Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position to give products of type (229) (82TL1201). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (230), thus examplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. 

An important class of cationic dyes, particularly for yellow to bluish-red hues, is derived from Fischer s base by condensation with 4-formyl-substituted anilines, or from Fischer s aldehyde (which may be prepared from Fischer s base via Vilsmeier formylation (B-71MI11205)) and an aromatic amine (Scheme 3). There are many examples of resonating charge dyes of this type which include a variety of aromatic amines and aldehydes. Of heterocyclic interest are the dyes formed by condensation of Fischer s aldehyde with... 

Tlie apparent ease with which certain of the sulfur-containing compounds undergo electrophilic substitution reactions has been considered significant in discussions of the aromaticity of these ring systems e.g. (66HC(21-2)1146). However, whilst this type of reactivity is normally associated with aromatic character it is important to note that the open-chain di(phenylthio)ethylene (52) is also smoothly formylated at the double bond under Vilsmeier conditions to give (53) (B-61MI22601). 

Protonation of lH-pyrrolizin-l-ones appears to take place on oxygen (see Sections III,A,2 and III,A,4). The other derivative of type 258 is the Vilsmeier formylation intermediate from l-chloro-3H-pyrrolizine, the perchlorate... 

Aminopyrimidine-5-carbaldehydes,24 prepared by Vilsmeier formylation, condense in a Friedlander-type reaction with a variety of active methylene partners such as ketones, j3-oxo esters, malonic add derivatives or arylacetonitriles, the latter preferably with electron-withdrawing substituents. 

An earlier investigation (23) demonstrated that the Vilsmeier-Haack reaction of the ArCOCHj type compounds gives the monoformylated compounds or the corresponding P-chloro-vinyl aldehydes. It was found, however, that in the case of o-hydroxyacetophenones, the methyl group was doubly formyl-ated by a Vilsmeier reagent to give our first target compounds, 4-oxo-4H-l-benzopyran-3-carboxaldehydes ( ) in one step ( 1, J ). The reason why double formylation took... 

A very similar type of benzochlorin 50 was also synthesized by Smith s group as a result of the cyclization of the product obtained after Vilsmeier formylation reaction of Ni or Cu(OEP) using dimethylaminoacrolein and phosphorous oxychloride.The utility of this class of compounds as photosensitizers for PDT was first shown by Morgan et Jn a mouse tumor model. With a few... 

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