Vilsmeier reaction mechanism

In the Meth-Cohn quinoline synthesis, the acetanilide becomes a nucleophile and provides the framework of the quinoline (nitrogen and the 2,3-carbons) and the 4-carbon is derived from the Vilsmeier reagent. The reaction mechanism involves the initial conversion of an acylanilide 1 into an a-iminochloride 11 by the action of POCI3. The a-chloroenamine tautomer 12 is subsequently C-formylated by the Vilsmeier reagent 13 derived from POCI3 and DMF. In examples where acetanilides 1 (r = H) are employed, a second C-formylation of 14 occurs to afford 15 subsequent cyclisation and... 

The mechanism of the Mannich reaction is similar to that of the Vilsmeier reaction as the electrophile is also a methyleniminium cation, formed this time from a condensation of dimethylamine and formaldehyde in acetic acid solution (Scheme 7.7a). This reacts with indole to yield 3-(A, 7V-dimethylaminomethyl)indole (although not shown, it is possible that initial attack occurs at N-1 and rearrangement of the side chain to C-3 takes place in a follow-up step) (Scheme 7.7b). Scheme 7.7... 

As Scheme 23 illustrates, DMF reacts with POCI3 to form Vilsmeier reagent 158. Aryl-Pd-I species 159, generated by the oxidative addition of iodotoluene 160 to Pd(0) species, reacts with the reagent 158 to yield chloroiminium ion 162 via an adduct 161 through a hetero-Heck-type reaction mechanism, and liberates H-Pd-I species. Finally, the hydrolysis of chloroiminium ion 162 gives amide 163. 

The first cycl[3,2,2]azine derivative prepared in this way was 20.22 Theoretical considerations concerning the mechanism of the reaction have been presented.2311 1-Azacycl[3,2,2]azines (21)24 and 5-azacycl[3,2,2]azines (22a)25 may be obtained by the same route. 5-Azacycl[3,2,2]azines (22b)26 have been obtained recently by Vilsmeier reaction of the corresponding 5,7-dimethyl-6-azaindolizines. 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

Heterocycle (427) gives naphthyridone (128) (69% yield) in a Vilsmeier reaction <83IJC(B)916>. Compound (428) and alkyne (429) yield product (430) (75% yield) in acetonitrile at 110°C and product (431) (58% yield) in toluene at 110°C <87CB1427>. Maleic anhydride reacts with enamine (432 R1 = Me, Et R2 = H, Me) giving pyranopyridtriones (433) (9-27% yield) <80S698>, and a mechanism has been proposed for this transformation. 

The reaction mechanism involves initial conversion of acylanilides in to a-iminochloride by the action of phosphorous oxychloride. The formed chloroenamine is treated with Vilsmeier reagent, providing the active iminium salt, which is readily cyclized to provide 2-chloro-3-alkyl quinolines. ... 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

A kinetic study of the Vilsmeier-Haak formylation of thiophene derivatives in dichloroethane solution has been recently reported.156 Reactions of thiophene and 2-methylthiophene follow third-order kinetics, first-order in substrate, dimethylformamide (DMF), and phosphorus oxychloride. These results are in agreement with a mechanism involving a rapid preequilibrium step leading to an... 

Figure 6.12 shows that carboxylic acids can also be converted into carboxylic chlorides without releasing HC1. This is possible when carboxylic acids are treated with the chloro-enamine A. First the carboxylic acid adds to the C=C double bond of this reagent electrophilically (mechanism Figure 3.40, see also Figure 3.42). Then, the addition product B dissociates completely to give the ion pair C it constitutes the isopropyl analog of the Vilsmeier-Haack intermediate B of the DMF-catalyzed carboxylic chloride synthesis of Figure 6.11. The new Vilsmeier-Haack intermediate reacts exactly like the old one (cf. previous discussion) The chloride ion undertakes an SN reaction at the carboxyl carbon. This produces the desired acid chloride and isobutyric N,N-dimethylamide.

In a related reaction, the Gattermann aldehyde synthesis, the carbon monoxide of the previous reaction is replaced by hydrogen cyanide (Scheme 6.6). This reaction gives poor yields with benzene itself, but is successful with activated species such as aryl ethers and phenols. The reaction proceeds via an aryl imine and the mechanism is not dissimilar to that of the Vilsmeier-Haack reaction. 

An unprecedented attack on an azide group by an iminium species, generated in situ under Vilsmeier conditions, furnishes a novel route to construct the imidazole ring. Thus, A -aryl-5-chloro-2-(dimethylamino)imidazole-4-carbox-aldehydes 1257 were obtained from the Vilsmeier cyclization of A -aryl-2-azidoacetamides 1256. The possible mechanism for the reaction is illustrated in Scheme 316 <1998JOC7136>. 

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