Vilsmeier-Haack reagent

The stabilized phosphonium ylide (601) reacts with aromatic aldehydes to give N-phenacylpyrazoles (602) in good yields (73CC7). Ketone semicarbazones and ketazines react with two moles of phosphorus oxychloride-DMF, the Vilsmeier-Haack reagent, with the formation of 4-formylpyrazoles (603 R = H or PhC=CH2) (70JHC25, 70TL4215). 

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 reactions of isoxazolin-5-ones (1379) with 1 mol of phosphoryl chloride and DMF in boiling chloroform for 1.5 hr afforded 1,3-oxazin-6-ones (1381) in 69-74% yields via aminomethylenemalonate derivatives (1380) (87JOC3426). If 2 mols of Vilsmeier-Haack reagent were used in boiling carbon tetrachloride for 2 hr, then 1381 (R = H) and the amino-methylenemalonamate derivative (1382) were obtained in 8% and 76% yields, respectively, from 1379 (R = H). 

Keywords Benzothiazoles, Pyrazole, Acetophenone, Vilsmeier-Haack reagent, antibacterial and antifungal activity. 

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

Tasneem, Synlett 2003, 138. (Review of the Vilsmeier-Haack reagent). 

TABLE 7.34. SYNTHESIS OF UNSATURATED 5(4/f)-OXAZOLONES FROM A-ACYLAMINO ACID DERIVATIVES AND VILSMEIER-HAACK REAGENT... 

Reaction of A -acylamino acids with the Vilsmeier-Haack reagent leads to 2-alkyl-4-[(Af,Af-dimethylamino)methylene]-5(47i)-oxazolones 814. The reactivity of these compounds with various nucleophiles has been studied. Primary alkylamines undergo amine exchange with 814 to afford 2-alkyl-4-[(alkylamino)methylene]-5(4/i)-oxazolones 815 (Scheme 7.250). ° ... 

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). 

S)-Valine, 66, 153 Vilsmeier-Haack reagent, 66, 121 Vibro-mixer, 65, 52... 

Other reagents, such as sulfuryl chloride [60], the Vilsmeier-Haack reagent [(Me2N+= CHX)X ] [61] and, more recently, diethylaminosulfiir trifluoride (DAST) [11-13] are useful for the direct replacement of hydroxy groups by halogen atoms. 

Aryl acetones react with the Vilsmeier-Haack reagent to form conjugated iminium salts 726, which spontaneously cyclize upon basic aqueous work-up to afford 3-formyl-pyran-4-ones (Scheme 180) <2004T5069>. (1,3-Diphenylpropane-2,2-diyl)bis(butylsulfane) 727 also reacts with the Vilsmeier-Haack reagent to afford 3,5-diphenyl-4//-pyran-4-one upon basic aqueous workup (Equation 291) <2004T5069>. 

The conversion of carboxylic acids and SOCl2 into acid chlorides is frequently catalyzed by DMF. The mechanism of this catalysis is shown in Figure 6.11. It is likely that SOCI2 and DMF first react to give the Vilsmeier-Haack reagent A. It differs from the reactive interne-... 

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