Pyrrole, alkylation rearrangement

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). 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

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. 

Although pyrrolyl halides are well-known compounds, their instability to acid, alkali, and heat precludes their commercial availability. Since pyrrole is a very reactive, Jt-excessive heterocycle, it undergoes halogenation extremely readily [6, 7], For example, the labile 2-bromopyrrole, which decomposes above room temperature, is a well-known compound, as are A-aIkyl-2-halopyrroles, readily prepared by direct halogenation, usually with NBS for the synthesis of bromopyrroles [8, 9], The 2-halopyrrole is usually the kinetic product but the 3-halopyrrole is often the thermodynamic product, and this property of halopyrroles can be exploited in synthesis. For example, A-benzylpyrrole (1) can be dibrominated to give 2 as the kinetic product, which rearranges to 3 upon treatment with acid [10, 11]. Other A-alkyl-2,5-dibromopyrroles are available in this fashion. 

In times past it was thought that indoles already bearing an alkyl substituent at C-3 were further alkylated by direct attack at C-2. However, although 2,3-dialkylindoles are readily formed the reaction still involves attack at C-3. This can be demonstrated by the example in Scheme 7.3, where 3-(4 -hydroxybutyl)indole, containing an isotopic label located at C-T, is treated with boron trifluoride in diethyl ether. Two 1,2,3,4-tetrahy-drocarbazoles (l,2,3,4-tetrahydrodibenzo[6,J)pyrroles) are formed in a ratio of 1 1. These differ only in the position of the label. This result indicates that a 3,3-spiroindoleninium intermediate is formed first, and this then undergoes rearrangement of either bond a or bond b to C-2. As the two bonds a and b are identical, equal amounts of the tetrahydrocarbazoles... 

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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