2.2- Disubstituted 27/-pyrroles alkylation

A reaction of JV-alkyl-and N-phenyl-2,5-disubstituted pyrroles with complex 219 at 0 °C gave the best yields of the corresponding pentathiepins 221 under conditions which include treatment with non-premixed sulfur monochloride and DABCO and with complex 220 (2005OL5725 Scheme 117). 

An enantioselective radical substitition (termed SOMO activation ) involving pyrroles has been reported <07SCI582>. For example, treatment of pyrrole 58 with octanal 59 and chiral amine 60 in the presence of CAN gave chiral 2-alkylated pyrrole 61. The mechanism included the formation of an enamine radical. A radical alkylation of 3-substituted pyrroles with xanthates produced 2,3-disubstituted pyrroles regioselectively <07TL4515>. 

The final series of five procedures presents optimized preparations of a variety of useful organic compounds. The first procedure in this group describes the preparation of 3-BROMO-2(H)-PYRAN-2-ONE, a heterodiene useful for (4+2] cycloaddition reactions. An optimized large scale preparation of 1,3,5-CYCLOOCTATRIENE, another diene useful for [4+2] cycloaddition, is detailed from the readily available 1,5-cyclooctadiene. Previously, the availability of this material has depended on the commercial availability of cyclooctatetraene at reasonable cost. A simple large scale procedure for the preparation of 3-PYRROLINE is then presented via initial alkylation of hexamethylenetetramine with (Z)-1,4-dichloro-2-butene. This material serves as an intermediate for the preparation of 2,5-disubstituted pyrroles and pyrrolidines via heteroatom-directed metalation and alkylation of suitable derivatives. The preparation of extremely acid- and base-sensitive materials by use of the retro Diels-Alder reaction is illustrated in the preparation of 2-CYCLOHEXENE-1.4-DIONE, a useful reactive dienophile and substrate for photochemical [2+2] cycloadditions. Functionalized ferrocene derivatives... 

RegiocontroUed synthesis of 2,4-disubstituted pyrroles is achieved using the alkylation of a protected cyanohydrin with an alkynyl bromide (equation 15). ... 

Disubstituted pyrroles lacking substituents at the 3- and S-positions are often required in porphyrin synthesis, and these can now be prepared from pyrrole itself. Thus, trichloroacetylation or trifluoroacetylation of pyrrole affords the 2-trihaloacetylpyrrole 8, which can be converted into the corresponding esters 9, carboxylic acids, or amides. The amides have been acetylated, or formylated, at the 4-position specifically, and the resulting acyl pyrroles (10) have been reduced to the alkyl pyrroles (11). This general procedure has now been improved by direct Friedel-Crafts formylation of the trichloroacetylpyrrole (8a) with dichloromethyl methyl ether (aluminium chloride) to the diacylpyrroles... 

Less common 2-substituted indole derivatives can be prepared by Friedel-Crafts alkylation of 4,7-dihydroindoles with a,p-unsaturated aldehydes, followed by oxidation with p-benzoquinone [317]. 4,7-Dihydroindoles, which can be considered as 2,3-disubstituted pyrroles, react with a wide variety of aromatic and aliphatic enals... 

Kojima and co-workers [52] identified the major thermal decomposition products of plasma polymerised polypyrrole as nitriles with less than four carbons and alkyl pyrroles. Evolution of only monosubstituted alkyl pyrroles, such as 2-methylpyrrole and 2-ethylpyrrole, suggests that polypyrroles consist of monosubstituted pyrrole rings. This is also supported by the result that the IR spectrum of polypyrroles differs from that of the electrochemically polymerised pyrrole, which consists of disubstituted pyrrole rings. Evolution of linear nitriles shows evidence that a polypyrrole molecule has the main chain containing nitrogen atoms. The mechanism of polymerisation of pyrrole in the discharge is considered to be similar to that of aromatic hydrocarbons, which mechanism involves a process of production of acetylene. 

Whereas 2,4-dialkyl-phenols react readily with HCHO, the 2,6-analogues show little or no reactivity, depending on the size of the alkyl groups. The kinetics and mechanism of the reaction between 4-t-butylphenol and formaldehyde in the presence of alkaline hydroxide catalysts have been studied the efficiencies of catalysts are in the order Careaction between 3,4-disubstituted pyrroles and HCHO, with acid catalysis, in good yields. 

Padwa and coworkers realized the synthesis of 2,4-disubstituted pyrroles using rearrangements of 2-fiiranyl carbamates via 5-methoxy-3-pyrrolin-2-one intermediates. 2-Furanyl carbamate 593 was treated with iodine and sodium bicarbonate followed by methyl iodide and silver oxide to give the N-substituted 5-methoxy-3-pyrrolin-2-one 595 via the iodinated intermediate 594 (Scheme 173 20090L1233). Padwa employed this method to synthesize 5-methoxypyrrol-2-ones, which were then treated with alkyl hthiates to give tricycHc products (2009T6720). 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

Fig. 1 Schematic drawing showing the structure of tris(A/,AT-disubstituted-dithiocarbam-ato)iron(III). Substituents R1 and R2 represent various types of alkyl groups including those being part of the ring systems morpholine, pyrrolidine or pyrrole (Table 1)... 

Iodine has been reported to possess a mild Lewis acidity and can activate carbonyl groups. It can for example catalyze the addition of pyrroles to cf,]3-unsaturated ketones (Scheme 85) [224], A mixture of pyrrol and 3 equiv. of ketone gave disub-stituted products in up to 92% yield in 10 min with 10 mol% of iodine. In cases when only 1.1 equiv. of ketone was apphed in the reaction, mono- and disubstituted products were isolated in few minutes in up to 95% yield in a ratio between 1 1 and up to 1 5. A-Alkylated pyrroles also participated in the reaction in good yields. 

H- 1,2-Oxazines are stabilized as 4,4-disubstituted derivatives but 4H- and 6if-l,2-thiazines are almost unknown. Possibly the paucity of these compounds simply reflects a lack of interest, for 6if-l,2-oxazines are comparatively common, and 3,5-diphenyl-6if- 1,2-oxazine, for example, is a stable crystalline solid. Similarly, cyano-1,2-oxazines (6 R=alkyl) are formed by the photolysis of azidopyridine oxides (5). However in the case where R3 = H, these products rearrange to pyrroles (7) (81CC36). 

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