Substitution, electrophilic Vilsmeier reaction

These compounds are less common than indole (benzo[ ]pyrrole). In the case of benzo[i>]furan the aromaticity of the heterocycle is weaker than in indole, and this ring is easily cleaved by reduction or oxidation. Electrophilic reagents tend to react with benzo[Z ]furan at C-2 in preference to C-3 (Scheme 7.21), reflecting the reduced ability of the heteroatom to stabilize the intermediate for 3-substitution. Attack in the heterocycle is often accompanied by substitution in the benzenoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzo[Z ]furan, plus the 4-, 6- and 7-isomers. When the reagent is in benzene maintained at 10 °C, both 3- and 2-nitro[ ]furans are formed in the ratio 4 1. Under Vilsmeier reaction conditions (see Section 6.1.2), benzo[Z ]furan gives 2-formylbenzo[6]furan in ca. 40% yield. 

Examples of electrophilic substitution (other than protonation) at the heterocyclic ring of benz- and dibenz-azepines appear to be confined to a few Vilsmeier reactions. 8-Chloro-l//-l-benzazepin-2-one with a mixture of DMF and POCl3 yields the 2,8-dichloro aldehyde (106) (72CPB1325). Under similar conditions Ar-mesyl-4,5-dihydro-3//-3-benzazepine formylates at the 1-position (107 R1 = CHO, R2 = H) (71BSF3985). In contrast, (V-mesyl-1,2,4,5-tetrahydro-3/7-3 -benzazepin-1 -one yields a mixture of the 1-chloro dihydro compound (107 R1 = Cl, R2 = H) and the chloro aldehyde (107 R1 = Cl, R2 = CHO). 

N, A -dimethylformamide (DMF). This reaction proceeds by formation of the electrophilic Vilsmeier complex, followed by electrophilic substitution of the heterocycle. The formyl group is generated in the hydrolytic workup. 

Shkurko and Mamaev50,408 have studied the l//-benzothieno[3,2-6]-pyrrole system 391 extensively. Electrophilic substitution (e.g., Mannich reaction, acetylation, diazonium coupling) takes place at C-2, as predicted by MO calculations.4080 If position 2 is occupied, substitution occurs at C-3.44 The Vilsmeier reaction on the 2-aryl derivative gave the expected product, but bromination of the parent system 391 failed. A 3-bromo derivative was successfully obtained from the N-methyl compound 392 with bromine in chloroform.44... 

The cyclazine monoester (265a) is more stable than the parent compound but electrophilic substitution is still accompanied by extensive tar formation. The 3-formyl derivative (265b) was formed in a Vilsmeier reaction. 

A high density of electrons associated with atoms C(3) and C(5) of 1,4-dihydropyridines and 1,4-dihydropyrimidines is also observed when these heterocycles undergo electrophilic substitutions such as Friedel-Crafts [315, 316, 317, 318, 319, 320] and Vilsmeier [297, 321] reactions (Scheme 3.99). In [315] it was shown that treatment of dihydropyridines 371 with aroyl or acyl chlorides 372 in the presence of SnCl4 leads to acylation of the heterocycle at position 3 (compounds 373). Dihydropyridines 374 and dihydroazolopyrimidines 376 undergo Vilsmeier reaction with the formation of the corresponding derivatives 375 and 377. It is interesting that imine heterocycle 376 after Vilsmeier reaction exists in the enamine tautomeric form. The tautomerism of dihydroazines and factors influencing it will be discussed in detail in Sect. 3.8. 

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-... 

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.)... 

A systematic study of substitution reactions of oxazole itself has not been reported. Bromination of 2-methyl-4-phenyloxazole or 4-methyl-2-phenyloxazole with either bromine or NBS gave in each case the 5-bromo derivative, while 2-methyl-5-phenyloxazole was brominated at C(4). Mercuration of oxazoles with mercury(II) acetate in acetic acid likewise occurs at C(4) or C(5), depending on which position is unsubstituted 4,5-di-phenyloxazole yields the 2-acetoxymercurio derivative. These mercury compounds react with bromine or iodine to afford the corresponding halogenooxazoles in an electrophilic replacement reaction (81JHC885). Vilsmeier-Haack formylation of 5-methyl-2-phenyloxazole with the DMF-phosphoryl chloride complex yields the 4-aldehyde. 

The dibenzo derivatives (103 R2 = H) similarly undergo electrophilic substitution and cycloaddition reactions. Typically, under Vilsmeier-Haack conditions the 7-formyl (103 R2 = CHO) and the 7-acetyl (103 R2 = COMe) derivatives are formed from the unsubstituted compounds (103 R2 = H). With strong acids the dibenzo compounds (103) form salts (73CL175). 

Some reactions can be controlled to give good yields of monosubstituted products. One is the Vilsmeier reaction in which a combination of an N, N- d imet hyla mide and POCI3 is used to make a carbon electrophile in the absence of strong acid or Lewis acid. It is a substitute for the Friede 1-Crafts acylation, and works with aromatic compounds at the more reactive end of the scale (where pyrrole is). 

In 4-ethoxyimidazoles the 5-position becomes more reactive towards electrophiles than the annular nitrogen, allowing 5-benzylation with benzyl chloride in the presence of potassium carbonate (Equation (25)). The Vilsmeier reaction gives the 5-carbaldehyde in 86% yield, and a number of unsaturated reagents also substitute at that site <88CPB1669>. 

Reactions with electrophilic reagents take place with substitution at C-3 or by addition at the pyridine nitrogen. All the aza-indoles are much more stable to acid than indole (cf. 20.1.1.9), no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards other electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Maniuch and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quatemisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. Acylation at C-3 in all four systems can be carried out at room temperature in the presence of excess aluminium chloride. ... 

The electrophilic Vilsmeier reagent (Me2N=CHOPOCl2), which readily formylates enolic ethers/ has now been found to react under more vigorous conditions with suitable dienes, or even with a 17-methylene-androstane (175) (Scheme 10), to give formyl derivatives e.g. 176). The over-all reaction is one of substitution, via electrophilic addition followed by deprotonation, which is favoured by conjugation in the final product (Scheme 10). A most significant... 

Mild electrophilic reagents240,241 afford only monosubstituted derivatives for example, nitrosation, azo coupling, acylation with trifluoro-acetic anhyride or a Vilsmeier reaction on 217 give 7-substituted derivatives (224) (E= -NO, —N=NAr,CF3CO, or -CHO [Eq. (83)1. 

An example of electrophilic substitution has been provided, however, in the formylation of 6,6-diphenylfulvene by a Vilsmeier reaction [36], while an acetylation has been achieved in a two-phase system with a phase transfer agent, using methyl iodide, carbon monoxide, sodium hydroxide and dicobaltoctacarbonyl [241]. 

The diester (XXXIV) undergoes a range of electrophilic substitution reactions at the 2-position, to wit diazo-coupling, nitration (by benzoyl nitrate), and formylation by means of a Vilsmeier reaction [263], Acetyl chloride in the presence of tin(IV) chloride gives the 2,5-diacetyl derivative. 

The coordinated cyclobutadiene readily undergoes electrophilic substitution. It can be acylated under Friedel-Crafts conditions, sulphonated and mer-curated. Like ferrocene (p. 284) it performs the Vilsmeier reaction with PhN(Me)CHO/POClj giving the aldehyde (f -C H3CHO)Fe(CO)3 and the Mannich condensation with GHjO/Me NH giving (f/ -C H3CHjNMe3)Fe(CO), which occur... 

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