2- Aryl -5-methylpyrroles

A review of aromatic substitution by the 5 rnI reaction has been published. The reactions of enolate ions of 2-acetyl-(147) and 3-acetyl-1-methylpyrroles (148) with aryl iodides and neopentyl iodides under irradiation conditions afforded good yields of substitution products by 5rn1 mechanisms, without the need for initiator. These... 

However, recently it has been shown (88ZOR2436) that 2-aryl-3-methylpyrroles (122) can be synthesized from aryl ethyl ketoximes (121) using vinyl chloride instead of acetylene in good preparative yields (45-51%). The yield of the corresponding N-vinyl derivatives (123) is 4-6% in this case (Scheme 59). 

A thermally induced rearrangement of arylhydrazones of furoxan-3-carbonyl compounds into 2-aryl-5-[(hydroximino)arylmethyl]-2//-l,2,3-triazole 1-oxides has been observed for the first time.156 2-(2,2-Dicyano-l-hydroxyethenyl)-l-methylpyrroles (192) are readily rearranged to their 3-isomers (193) in nearly quantitative yield when heated to 75-142 °C. The inter- or intra-molecular auto-protonation of a pyrrole ring... 

Photoreaction of 2-, 3- and 4-iodoquinolines with five-membered heterocycles (pyrrole, iV-methylpyrrole, furan and thiophene) affords the corresponding -(2-heteroaryl)quino-lines (n = 2, 3,4) in appreciable yields526. 3-Halo-1-methylquinolin-2-ones can be converted into 3-aryl-l-methylquinolin-2-ones by photochemical coupling with various aromatic or heteroaromatic compounds527,528. 

Carbonsulfur bonds can be formed by the reaction of elemental sulfur with a lithio derivative, as illustrated by the preparation of thiophene-2-thiol 446. If dialkyl or diaryl disulfides are used as reagents to introduce sulfur, then alkyl or aryl sulfides are formed sulfinic acids are available by reaction of lithium derivatives with sulfur dioxide. In the pyrrole series, a 2-thiol and the corresponding selenol can be prepared via reaction of 2-lithio-l-methylpyrrole with sulfur or selenium, then trapping with Me3SiCl leading to the 2-Me3SiX-substituted derivatives <1997T13079>. 

Heterocyclization of ketoximes with propyne or allene in superbase MOR-DMSO, leading to 2-alkyl(aryl, hetaryl)-5-methyl- 53 and 2,3-dialkyl-4-methylpyrroles 54 in yields of up to 63%, was accomplished (Equation (15)) (00S1585). 

In contrast, N-methylpyrrole underwent direct arylations atthe 3-position [93], and a comparable result was obtained in direct arylations of N-phenylpyrrole employing the electron-deficient rhodium complex 114, in combination with Ag2C03 under microwave irradiation [74b]. Selected examples of regioselective arylations of substituted five-membered heteroarenes are summarized in Table 9.3. 

Reactions of Pyrroles. 1,3-Di-t-butylpyrrole forms the first stable protonated pyrrole, the salt (104). Electrophilic substitution of pyrrole with MeaC or Me FC in the gas phase occurs mainly at the j3-position, as does nitration and Friedel-Crafts acylation of l-phenylsulphonylpyrrole2 Pyrrole-2,5-dialdehyde has been prepared by Vilsmeier-Haack formylation of the ester (105), followed by hydrolysis. A similar method has been used to convert the di-acetal (106) into pyrrole-2,3,5-tricarbaldehyde. AT-Benzoyl-pyrrole reacts with benzene in the presence of palladium(II) acetate to yield a mixture of l-benzoyl-2,5-diphenylpyrrole, the bipyrrolyl (107), and compound (108). Treating lithiated A-methylpyrrole with nickel(II) chloride results in the polypyrrolyls (109 = 0-4). 2-Aryl-1-methylpyrroles are obtained by cross-coupling of l-methylpyrrol-2-ylmagnesium bromide with aryl halides in the presence of palladium(0)-phosphine complexes. ... 

Pyrrole itself tends to give tars under radical conditions, probably by way of initial N-hydrogen abstraction, but some A -substituted derivatives will undergo preparatively useful arylations, with attack taking place predominantly at an a-position. More efficient routes to arylpyrroles depend on transition metal-mediated coupling processes (see section 2.7.2.2). A -Methylpyrrole is attacked by electrophilic benzoyloxy radicals at its a-positions. ... 

Similar conditions were used to prepare pyrroles from both t-butyl and benzyl isocyanoacetate. <94JHC255, 94S170> The reaction was also effective for preparing some rather hindered 3-aryl-4-methylpyrrole-2-carboxylates. Several p-methylnitrostyrenes were prepared by condensation of an aromatic aldehyde with nitroethane. These nitrostyrenes condensed with ethyl or methyl isocyanoacetate. Even o,o -disubstituted... 

Both l-methylpyrrol-2-ylmagnesium bromide and l-methyl-pyrrol-2-ylzinc chloride give good yields in cross coupling with aryl iodides (Scheme 128) <81TL5319>. 

The arene substrates are not limited to simple benzene derivatives. A variety of het-eroarenes can also participate in alkene arylations to generate the desired coupling products. Stoichiometric oxidative coupling of aromatic heterocycles such as furan, thiophene, selenophene, A-methylpyrrole, benzofiiran and benzothiophene with a variety of alkenes, including acrylonitrile, styrene and methyl acrylate, have been extensively studied by Fu-jiwara and coworkers [8]. Furan, thiophene, selenophene and A-methylpyrrole are easily alkenylated with alkenes to give 2-alkenylated and 2,5-dialkenylated heterocycles in relatively low yields (3 6%) [8a], while the reactions of benzofuran and benzothiophene with alkenes produced a mixture of 2- and 3-alkenylated products [8b]. 

Lautens and Hulcoop developed a Pd-catalyzed annula-tion of 3-aryl substituted pyrroles to yield indoles, following retro-Diels-Alder loss of cyclopentadiene (Scheme 2, equations 1 and 2) [4]. Miura, Satoh, and coworkers found that indoles were formed from Af-methylpyrrole-2 carboxylic acid and alkynes as catalyzed by palladium (equation 3) [5, 6]. The indoles themselves undergo this oxidative coupling with alkynes to form octa-substituted carbazoles, e.g.4[6]. 

The 2,5-diarylation of thiazole can be carried out effectively with a bulky phosphine ligand. In this case, no monoarylated product is observed, even in the early stage of the reaction, which suggests that the second arylation proceeds relatively rapidly (Equation 10.62) [95]. The selective 2-arylation of thiazole is accomplished by using Cul and BU4NF as cocatalyst and base, respectively (Equation 10.63) [96]. By using Pd(OH)2/C as catalyst, the 5-position can be arylated selectively (Equation 10.64) [97]. The palladium-catalyzed arylation of thiazole as well as 1-methylpyrrole with a polymer-Unked aryl iodide has been reported [98]. 

Borylated pyrrole 88 was prepared by Oestreich by treatment of the corresponding pyrrole with pinacolborane and a ruthenium(II) thiolate complex. The direct synthesis of 88 promises to find wide utility in medicinal chemistry and was applied to a variety of substituted indoles (13JA10978). N-Methylpyrrole was directly arylated at room temperature by photoredox catalysis with diaryliodonium salts to furnish 89 in 84% yield (13SL507). 

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