1- Methylpyrrole, chlorination

Polysubstituted 2- or 5-methylpyrroles can be laterally chlorinated through a two-stage process that involves initial i/wo-chlorination in the )3-position, followed by rearrangement into the side chain. Migration is also possible from the vinylogous a -position (80JA1377). 

Chlorination with /V-chlorosuccinimide is less selective (81JOC2221). 1-Methylpyrrole reacts with N-chloroimides to give (69) in which the imidyl group is attached to C-2 the 2-chloro compound is proposed as an intermediate (Equation 2) (89JOC5347,93CC1757). 

A kinetic and product study of the dichloroacetic acid (DCA) catalyzed chlorination of 1-methylpyrrole with a series of 3- and 4-substituted A -chlorobenzamides 325 under nitrogen, at 40 °C was carried out (Scheme 73) <2003T2125>. Chlorination at C-2 of the pyrrole ring leads to the formation of 2-chloro-l-methylpyrrole 326 and subsequently 2,5-dichloro-l-methylpyrrole 327. The total yield of attack at C-2 is therefore the sum of the yields of pyrroles 326 and 327. The yields of 2-chlorination (ca. 84%) and 3-chlorination (ca. 2.6%) were essentially constant as... 

The addition sequence may determine the primary reaction course or influence impurity formation. For example, condensation of diethyl 3-oxoglutarate 33 with chloroacetone and methylamine is expected to give the 5-methylpyrrole 34, the Hantzch pyrrole product (Figure 5.14). The isomeric 4-methylpyrrole 35 (a precursor to zomepirac sodium) was prepared in good yield by first treating 33 with methylamine, then adding chloroacetone [22]. The addition sequence was also important for the chlorination of the sulfinate anion 36 The dimer 37 was produced when N-chlorosuccinimide was added to the reaction, but when 36 was added slowly to excess Cl2, the desired sulfonyl chloride 38 was produced (Figure 5.14) [23], The course of these reactions may be predicted if one takes a mental snapshot of them. 

A chlorine in the electrophilic 4-position can be replaced by hydroxymethyl (173) (Scheme 25) <89T993>. Coupling of the t-butyl ether of 5-bromouracil (174) with A-methylpyrrol-2-yl(trimethyl)-stannane gave the 5-coupled product (175) in low yield. Modest yields of coupling products were also obtained in reactions with 2-thienyl- and 2-selenylstannanes and unprotected iodouracil. Sily-lation of 5-bromouracil is recommended before the coupling reaction. Silyl-protected 5-bromouracil... 

Chlorination of Aromatic Compounds. NCS has also been used for the chlorination of pyrroles and indoles however, the reaction is less straightforward than when NBS and N-Iodosuccinimide are used. In the chlorination of 1-methylpyrrole, it has been demonstrated that basic conditions (NaHCOs, CHCI3) lead to the formation of 1-methyl-2-succinimidylpyrrole (eq 11). In the presence of catalytic amounts of perchloric acid, thiophenes and other electron-rich aromatic compounds have been chlorinated with NCS. (N-Chlorosuccinimide-Dimethyl Sulfide is used for the selective -substitution of phenols.)... 

Under conditions of acid catalysis 1-methylpyrrole was largely chlorinated by A -chlorobenzamide (Scheme 14). There was evidence of an amplified isotope effect kmko = 19.10 at 40°C), which points to deprotonation of the sigma-complex being rate-determining. Thus, the chlorination process should be reversible (89CC1466). The observed instability of 2-chloropyrrole in acidic medium supports this (75JOC3161). (See also 3,b and 3,c for reactions of W-bromo- and N-iodo-imides.)... 

In the pyrrole series h ogenated azides can be prepared by direct halogenation. 2,4r-Dimethyl-3-ethylpyiTole-5-carbonyl azide has been brominated to 2-bromomethyl-3-ethyl-4-methylpyrrol n5-car-bonyl azide and 2-methyl-3,4-diethylpyrrole-5-carbonyl azide (XXIX) has been chlorinated with sulfuryl chloride to 2-trichloro-methyl-3,4-diethylpyrrole-5-carbonyl azide, which on treatment with methanol yields 3,4-diethyl-2-carbomethoxy-5-carbomethoxyaminopyr-role (XXX). Dichlorination is also successful 2,4-dimethyl-3-bromo-... 

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