Formylation Vilsmeier

The pyridine-like nitrogen of the 2H-pyrrol-2-yiidene unit tends to withdraw electrons from the conjugated system and deactivates it in reactions with electrophiles. The add-catalyzed condensations described above for pyrroles and dipyrromethanes therefore do not occur with dipyrromethenes. Vilsmeier formylation, for example, is only successful with pyrroles and dipyrromethanes but not with dipyrromethenes. 

Alkyl substituents. The steric effect of 1-alkyl substituents in the pyrrole series has been demonstrated in, for example, Vilsmeier formylation reactions. Thus as the bulk of the alkyl substituent on nitrogen is increased e.g. from Me to Bu ) so does the proportion of /3 substitution (70JCS(C)2573). A similar trend has been observed in a series of experiments on the trifiuoroacetylation of A-alkylpyrroles with trifluoroacetic anhydride (80JCR(S)42). 

The benzo[6] heterocycles are generally less reactive than their monocyclic counterparts. Thus benzo[6]thiophene unlike thiophene does not undergo Vilsmeier formylation or the Mannich reaction. 

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

Although in general azoles do not undergo Friedel-Crafts type alkylation or acylation, several isolated reactions of this general type are known. 3-Phenylsydnone (120) undergoes Friedel-Crafts acetylation and Vilsmeier formylation at the 4-position, and the 5-alkylation of thiazoles by carbonium ions is known. 

H- 1-Benzazepine, lV-benzyl-2,3,4,5-tetrahydro-Vilsmeier formylation, 7, 527 IH-l-Benzazepine, 2,3-dihydro-synthesis, 7, 541 IH-l-Benzazepine, 2,5-dihydro-synthesis, 7, 540... 

The introduction of the cheap and commercially available N,N-dimethylformamide, instead of A-methylformanilide in the POCI3 catalyzed Vilsmeier formylation of thiophene, has made 2-thio-... 

Vilsmeier formylation of praziquantel (9) with DMF-POCI3 at 60 °C for 5 h gave 2-cyclohexylcarbonyl-3-dimethyliminiummethylene-4-chloro-1,6,7,116-tetrahydro-2//-pyrazino[2,l-u]isoquinoline salt (01PHA146). 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Of great importance for porphyrin chemistry is the introduction of carbon substituents by Vilsmeier formylation100 or Friedel-Crafts acylation.100 The introduced substituents allow further carbon-chain elongations and other transformations so that interesting porphyrin derivatives can be synthesized. The Vilsmeier formylation of copper octaethylporphyrin (5) takes place at themethine position. The copper can then be easily removed by treatment with acid.105... 

The Vilsmeier formylation of copper deuteroporphyrin dimethyl ester (6) in which unsubstituted /3-positions are present yields a complex mixture of mono- and disubstituted formylation products which can be partially separated by chromatography on neutral alumina.106... 

In contrast to the Vilsmeier formylation the formylation with trimethyl orthoformate in trifluoroacetic acid proceeds with high selectivity so that only the /3-monoformylated deuteroporphyrin derivatives 8 are formed without any methinc substituted or diformylated products.1073 6... 

Both Friedel-Crafts acetylation and Vilsmeier formylation of the 2,3-dihydrooxazole 5 occur at C-5, indicating that the A-acyliminium ion is more stable than the oxonium ion17. This is corroborated by ab initio calculations, which show that 3-formyl-2,5-dihydro-3-oxazolium 7 is ca. 46 kJ mol 1 more stable than 3-formyl-2,4-dihydro-l-oxazolium 817. 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

Formylation of alkenes can be accomplished with N-disubstituted formamides and POCl3. ° This is an aliphatic Vilsmeier reaction (see 11-15). Vilsmeier formylation can also be performed on the ot position of acetals and ketals, so that hydrolysis of the products gives keto aldehydes or dialdehydes ... 

Vilsmeier formylation of 38 is possible with 65% yield (71). The 5-phenyl analog 39 with MeCOCl/AsCl3 also affords a 2-acetyl derivative the 5-phenyl group is not attacked under these conditions (71). 

The dihydro compound 122 has been reacted with a variety of electrophiles (Scheme 3) <2005CHE492>. Oxidation with bromine results in the fully aromatized product 124. Vilsmeier formylation, Michael addition, and nitrosation all occur at C-6, giving products 125-127. 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

The authors of this review have developed a straightforward procedure for the synthesis of unsubstituted and alkyl-substituted thieno-thiophenes 1, 2, and 3 the method involves intramolecular condensation of ortho-bifunctional thiophene derivatives. Vilsmeier formylation of an alkyl (5-ethyl-2-thienylthio)acetate (53) furnishes the (5-ethyl-3-formyl-. 2-thienylthio)acetate (54) which when heated with alcoholic sodium... 

Substituted 3-hydroxythiophenes are convenient starting-points for the synthesis of the thieno[3,2-Mthiophene system. Shvedov et obtained 50% of 3-chloro-3-ethoxycarbonyl-5-methylthiophene-2-aldehyde (110) from 3-ethoxycarbonyl-4-hydroxy-2-methylthiophene (109) by Vilsmeier formylation at 100°. Reaction with thioglycolic ter formed 3-ethoxycarbonyl-5-methoxycarbonyl-2-methylthieno[3,2-6]-thiophene (111) [. (36)]. 

Recently Bugge studied the reactivities of thienothiophenes 1 and 2 and thiophene by the competitive method, utilizing SnCl4-catalyzed acetylation with acetic anhydride, Vilsmeier formylation and chlorination with iV-chlorosuccinimide. Thienothiophenes 1 and 2 are always more reactive than thiophene. In acetylation the reactivities of 1 and 2 are similar, while in formylation and chlorination thienothiophene 2 is somewhat more reactive than isomer 1 (Table V). 

Gol dfarb and Litvinov first formylated a thienothiophene. In Vilsmeier formylation of 2-ethylthieno[2,3- ]thiophene (20) the formyl group enters the vacant a-position, producing 5-ethyl-2-formylthieno-[2,3- ]thiophene 16%). Oxidation of the latter with silver oxide gives 5-ethylthieno[2,3-6]thiophene-2-carboxylic acid (55) identical with that formed by cydizing the ester of (5-ethyl-3-formyl-2-thienylthio)acetic... 

Extending their earlier work on Vilsmeier formylation (c/. Vol. 7, p. 36), Traas et al. have formylated the a/S-unsaturated ketone isophorone almost exclusively at the more favoured exocyclic position to yield (190), which may be selectively... 

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