Pyrroles, 2- - derivatives lithiation

Katritzky et al. <1997JOC4148> described the cyclization of pyrrole derivatives 133 via lithiation at the benzotriazol-1-ylmethyl group and subsequent intramolecular nucleophilic displacement of tosylate to give in good yields dihydropyrrolizines 65, which lead to 3/7-dihydropyrrolizines 68 under treatment with malonate anion (see Section 11.01.5.3). 

These authors also demonstrated that the outcome of analogous additions of lithiated alkoxyallenes 120 to isothiocyanates is highly dependent on the nature of the alkyl group in the isothiocyanates as depicted in Schemes 8.34and 8.35 [88, 91]. Whereas methyl isothiocyanate 134 leads to pyrrole derivative 135, the correspond-... 

When, instead of aldehydes, A-tosyl imine 196 is used as an electrophile in a reaction with lithiated methoxyallene 183, allenyl imines 197 result. As shown in Scheme 26, they can be converted into pyrrole derivatives 198 and 199"" . 

SCHEME 26. Addition of lithiated methoxyallene 183 to tosyhmine 196. Synthesis of pyrrole derivatives... 

Metal complexes of pyrrole have also been investigated as substrates for lithiation reactions, with both iron and rhenium Tj -pyrrole derivatives having been found to undergo a-lithiation [90H(31 )383]. Azaferrocene was the first derivative of this type to be studied [83JOM(25l)C41], but it was found that lithiation was not selective and occurred equally in both rings. However, notwithstanding this, it has recently been reported that isomer-ically clean products can be obtained in certain circumstances from reaction with certain carbonyl compounds (Scheme 12) (89MI2). 

The metallation of 1-methylpyrrole proceeds considerably less easily than that of thiophene and furan. With the butyllithium TMEDA complex in hexane, however, this pyrrole derivative can be lithiated in a short time. Since THF is attacked very readily by BuLi TMEDA, it cannot be used as a co-solvent during the metallation. It is added when the metallation in hexane is complete. 

The TV-protected pyrrole (212) can be palladated, but not lithiated, in the 3-position to give the stable complex (213) this is readily converted into the 3-methoxycarbonylpyrrole (214) (82JOM(234)l23). The use of palladium derivatives thus further increases the range of transformations made possible through the intermediacy of metallo groups. 

Two sequential lithiations and treatments with different bifunctional electrophiles make possible one-pot syntheses of relatively complex molecules. Thus, in the [1+2+2] annulation depicted in Scheme 69, alkylation of 1-benzylbenzotriazole 399 with 2-bromoacetaldehyde diethyl acetal to give intermediate 426 is followed by alkylation with W-benzylideneaniline to produce derivative 427. Following treatment with formic acid causes cyclization to ethoxypyrrolidine 428 that subsequently eliminates ethanol and benzotriazole to give pyrrole 429 <1997JHC1379>. 

Synthesis of 2-Substituted Pyrroles via a-LiTHiATiON of N-Protected Derivatives... 

As with pyrrole, the a-lithiation of N-substituted indoles occurs readily [790R1 84MI2], and reaction can also be performed in the presence of a number of reactive functional groups at C-3. Thus the 3-carboxylic acid, 3-diethylamide, and 3-aldehyde derivatives of N-methylindole (9,10, and 11) have all been a-lithiated (87JOC104 91M17), the latter via its a-(N-methylpiperazino) alkoxide 12. 

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

To exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, f-butylcarbamoyl, benzenesulfonyl, dimethylamino and dimethylaminomethyl have been used (81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (396) (81JOC3760). Another useful process involves the /V-lithiation, carbonation, and C-2 lithiation of indoles, which leads for example to 2-haloindoles in excellent yields (92JOC2495). 

N-Substituted pyrroles, furans and thiophenes can be 2-lithiated, and these lithio derivatives are important synthetic intermediates (Section 3.3.3.8). 2-Mercuri and 2-palladio derivatives are also important (Sections 3.3.3.8.8 and 3.3.3.8.9). 

V-Benzylthieno[3,2-6]pyrrole (18) was lithiated and upon treatment of the lithio derivative with methyl chloroformate, 2-methoxycarbonyl-lV-benzylthieno[3,2-f>]pyrrole (51) was obtained (Scheme 10). The a-proton in the thiophene ring is more reactive towards metal-hydrogen exchange compared to the proton at C-5. 

To exploit the reactions of the C-lithio derivatives of N-unsubstituted pyrroles and indoles, N-protecting/masking groups such as ferf-butoxycarbonyl, terZ-biitylcarbamoyl, benzenesulfonyl, dimethylamino, and dimethylaminomethyl must be used. This is illustrated by a route to G-acylated pyrroles 441. Another very useful process involves N-lithiation, N-carbonation, and lithiation of the resulting indol-l-ylcarboxylate at C(2) reaction with an electrophile and loss of carbon dioxide during work-up give N-unsubstituted 2-substituted indoles, for example, 2-haloindoles in excellent yields. 

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