The Vilsmeier-Haack Reaction

The mechanism of the FePc-mediated oxidation step is outside the scope of this book. It s a fascinating one, however, and may be similar to the famous rebound mechanism of the iron-containing enzyme cytochrome P450 feel free to look it up in a book on bioinorganic chemistry or on the Internet. 

Would you describe the Mitsunobu reaction as mechanistically similar to the Appel reaction Explain. 

As our final example of the use of phosphorus in organic synthesis, we will choose the Vilsmeier-Haack reaction, the classic method for electrophilic formylation (addition of an aldehyde functionality) of aromatic rings with POCI3 and dimethylformamide (DMF, HCONMc2). 

Although DMF is commonly used as a solvent, it is used as a reactant here. Its two main resonance forms are as follows  

Chloride then attacks the iminium (C=N ) carbon, forming a chloroiminium cation and the P02Cl2 anion. The chloroiminium cation (shown in a box below) is the Vilsmeier reagent, the electrophile that reacts with the aromatic rings. 

---

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 reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

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. 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

The Vilsmeier-Haack reaction of 2,6-dimethylimidazo[2,T. ][l,3,4]thiadiazole 169 gives aldehyde 170, which after reduction with sodium borohydride affords 2,6-dimethyl-5-hydroxymethylimidazo[2,TA [l,3,4]thiadiazole 171 (Scheme 2) <2000AF550, 2006BMC3069, 2006TL2811>. 

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

A multi-stage synthesis of azocino[4,5,6-cd]indoles has been suggested (03M13519). From 4-bromoindole (84) with the help of successive transformations (among them the Vilsmeier-Haack reaction, Henry nitroaldole condensation, lithium aluminum hydride reduction and insertion of an allyl fragment), indole 85 has been produced in 18% yield. The cyclization of the latter on palladium... 

When (190) was subjected to a Friedel-Crafts reaction with benzoyl chloride, the result was an analog of coralyne with a phenyl rather than a methyl group at position 8. Kametani et al. (74YZ478) have carried out a parallel study using the Vilsmeier-Haack reaction to produce norcoralyne. 

In structural and synthetic chemistry, we also find instances of reconsideration 3-(3-methoxyphenoxy)-2-butanone gives by ringclosing dehydration a mixture of 2,3-dimethyl-4-methoxybenzofuran and 2,3-dimethyl-6-methoxybenzofuran,101 not just the 6-derivative.102 2-Ethyl-7-methoxybenzofuran is not formylated in position 3 by the Vilsmeier-Haack reaction, but in position 4.10,103... 

Acylpyrroles can also be prepared by using the Vilsmeier reaction with various amides. Excellent yields of 2-aroylpyrroles were obtained using morpholides instead of the more common N,N- dimethylamides (equation 178) (77JOC4248). Similarly, a variety of 3-acylin-doles have been prepared using the Vilsmeier-Haack reaction (79HC(25-3)357). 

The Vilsmeier-Haack reaction of ketones forms chlorovinyl aldehydes, which can add thiols readily. The reaction with a-tetralone gave the chlorovinyl aldehyde (230), and reaction with ethyl thioglycolate in ethanolic ethoxide solution formed the dihydro derivative (231), easily dehydrogenated to naphtho[l,2-6]thiophene-2-carboxylate (73JCS(P1)2956). 

Thenaldehyde (thiophene-2-carbaldehyde) is readily available via the Vilsmeier-Haack reaction of DMF with thiophene catalyzed by phosphorus oxychloride. The Sommelet reaction with 2-chloromethylthiophene also gives reasonable yields (63AHC(l)l). Likewise, thiophene is readily acylated with acyl anhydrides or acid chlorides (equation 14), using mild Friedel-Crafts catalysts, such as tin(IV) chloride, zinc chloride, boron trifluoride, titanium tetrachloride, mercury(II) chloride, iodine and even silica-alumina gels or low-calcium-content montmorillonite clays (52HC(3)l). 

The C(2)-C(3) bond formation provides the basis for the construction of t h i e n o [ 3,2 - A ] pyrid i nes according to method N. Scarce examples were, as a rule, based on nontrivial synthetic approaches. For example, thienopyridazines 164 undergo an unusual cyclization to give pyridothienopyridazines 165 under the conditions of the Vilsmeier-Haack reaction (2001T5413). 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

O. Meth-Cohn, S. P. Stanforth, The Vilsmeier-Haack Reaction, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 2, 111, Peigamon Press, Oxford, 1991. 

The salts of methylene derivatives of 2H- and 3//-pyrroles and -indoles are produced in the Ehrlich reaction (Scheme 32, Section 3.05.1.2.8) and they are also intermediates in the Vilsmeier-Haack reaction (Scheme 24, Section 3.05.2.1.6). Although 6-fV,fV-dimethyl-amino-l-azafulvene, i.e. 2-(Ar,Ar-dimethylaminomethylene)-2//-pyrrole, dimerizes spontaneously (see Section 3.05.2.5), the 6-aryl-6-Ar)Ar-dimethylamino-l-azafulvenes (514 R = aryl) can be isolated (71JCS(B)1405) but, curiously, they are more susceptible to reactions with nucleophiles at the 6-position than are the corresponding salts (B-77MI30508). The benzo[6 ]-1 -azafulvenes, obtained from the reaction of 2-formylindoles with dialkylamines, also dimerize spontaneously, but the isomeric benzo[c]-2-azaf ulvenes, derived from 3-formylindoles, are thermally more stable, although they are extremely moisture sensitive... 

Dimethyl-2,4-diphenyl-3-azapyrylium perchlorate 381 is converted under the Vilsmeier-Haack reaction conditions into the N,jV-dimethylaminovinyl derivative 382. By refluxing 382 in acetic acid mixed with either ammonium acetate or / -toluidine, compound 383 was obtained by an unusual recyclization via elimination of the iV,A-dimethylaminovinyl group (equation 109). 

---