Vilsmeier adduct

Formylation of alcohols formate esters.2 The Vilsmeier adduct 1 of DMF and benzoyl chloride reacts with alcohols to give stable imidate ester chlorides (2). These are hydrolyzed by dilute acid to formate esters (3). 

The Vilsmeier adduct is a versatile intermediate it reacts with hydroxylamine and phenylhydrazine to give the isoxazole (33) and the pyrazole (34) and with ureas and amidines to give pyrimidine derivatives. 2-Methylpyrazine has been condensed with benzaldehyde in the presence of zinc chloride to give 2-styrylpyrazine in good yield.185... 

Having assembled the pyrrole core, we endeavored to attach the oxindole side chain and complete the synthesis of 2. Decarboxylation of 12 was achieved in quantitative yield by reaction with H2SO4 in methanol. The a-free pyrrole thus obtained (13) was treated with chloromethylene-dimethylammonium chloride in acetonitrile to form the Vilsmeier adduct 14 in situJ Addition of... 

Chlorosulfonic acid reacts with DMF 123 at low temperature (< 5 °C) yielding a mesomelic salt 124 which, by heating at 60 C, was converted into a new Vilsmeier adduct 125 (Scheme 9). ° ... 

There are several schemes for the synthesis of cellulose formates (slow) reaction of the polymer with formic acid faster reaction in the presence of a mineral acid catalyst, e.g., sulfuric or phosphoric acid. The latter route is usually associated with extensive degradation of the polymer chain. Reaction of SOCI2 with DMF produces the Vilsmeier-Haack adduct (HC(Cl) = N (CH3)2C1 ) [145]. In the presence of base, cellulose reacts with this adduct to form the unstable intermediate (Cell - O - CH = N" (CH3)2C1 ) from which cellulose formate is obtained by hydrolysis. The DS ranges from 1.2 to 2.5 and the order of reactivity is 5 > C2 > C3 [140-143,146]. 

A comment on the properties of the base employed in reactions that involve the formation of the Vilsmeier-Haack adduct is in order, because several derivatives of cellulose are obtained by this route. Preparation of Cell-Tos has been attempted in LiCl/DMAc, by reacting the polymer with TosCl/base. Whereas the desired product was obtained by employing triethy-lamine, use of pyridine (Py) resulted in the formation of chlorodeoxycellu-lose. In order to explain these results, the following reaction pathways have been suggested [147] ... 

That is, the difference between the mechanisms of action of the two bases lies in the ability of EtsN to add to the Vilsmeier-Haack adduct to form a tetrahedral intermediate, susceptible to Sn2 attack by (at least partially de-protonated) cellulose. This leads to formation of the desired Cell - Tos. 

The Vilsmeier-Haack type adduct, formed by the reaction of oxalyl chloride with DMF can be also be employed for the activation of carboxylic acids, as shown in Fig. 8 [200]. 

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. 

In another synthesis, the Vilsmeier salt (63) with aqueous methyl-amine gave the aza compound (64). The methyl iodide adduct of 64 was afterward reacted with methylamine, forming the diaza derivative (65).83... 

Several classes of carbon nucleophiles have been successfully used in these systems, reflecting the utility of Reissert chemistry for derivatizing azines via carbon-carbon bond formation. Apart from cyanide anion, other classes of carbon nucleophiles have been explored. For instance, addition of indole (51) to A-acyla-zinium salts proceeds selectively at the a-position (Scheme 9). Pyrrole, quinolines and isoquinolines all behave similarly [73-76]. A related reaction, yielding adduct 70 (Scheme 12b) has also been described. In this case, azine activation is promoted by Vilsmeier reagents (generated by reaction of amides with POCI3) [77]. p-Dicarbonyls are reactive inputs in this chemistry, and dialkyl malonates 53... 

Well known compounds of this type are Vilsmeier-Haack adducts, imino esters, amidines, carboxylic orthoesters, orthoamides etc., which have proven their synthetic utility in thousands of reactions. As a consequence of the synthetic importance of these compounds, more or less extensive reviews are available for all of them. 

For instance, treatment of indole with bromine gives exclusively 3-bromoindole. In the same vein, Michael addition with nitroethene, ethyl acrylate, and the Vilsmeier reagent all take place at C3. The adduct between indole and the Vilsmeier reagent can be hydrolyzed under basic conditions to give 1//-indole-3-carbaldehyde. Meanwhile, nitration and treatment with oxalyl chloride all give rise to the C3 electrophilic substitution products. 

Aryltrifluoromethyl ketones are prepared by reaction of an aryl-lithium with a,a,a-trifluoro-N,N-dimethylacetamide. 2-Acyloxypyridines and N-acylimidazoles, " in conjunction with trifluoroacetic acid, acylate arenes in good yield without the need for a classical Friedel-Crafts catalyst or a preformed mixed anhydride. However, imidazole in trifluoroacetic anhydride is reported to form 2-aryl-Af,JV -diacyl-4-imidazolines with arenes reactive towards electrophilic attack. These adducts are readily hydrolysed by sodium hydroxide to the corresponding aldehyde [equation (14)]. This sequence may offer advantages over the Vilsmeier method of formylation, in that the aldehyde is introduced in a protected form. 

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