TIPS-protected pyrrole

It is well known that TIPS-protected pyrrole (48) can be selectively haloge-nated at the P-position by the reaction of MBS in tetrahydrofuran (THF). Also, P-substituted pyrroles 50 can be brominated in the a-position under identical reaction conditions (140L6334). 

In 2006, Gaunt and co-workers described a regioselective alkenylation of pyrroles under mild aerobic oxidative conditions. A catalytic amount of palladium acetate was able to selectively functionalize tert-butojycarbamate (BOC)-protected pyrrole at the C2-position while a C3-selectivity was achieved with triisopropylsilyl (TIPS)-protected pyrroles (Scheme 9.4). The aerobic conditions worked well for reactive alkenes such as acrylate derivatives, nevertheless the use of peroxide ( BuOOBz) appeared necessary in order to achieve good yields with more challenging substrates [i.e., methyl vinyl sul-fone). Interestingly, intermolecular alkenylation of pyrrole can also be effected with complete selectivity and good yields. 

A more versatile A-protection strategy is seen in Muchowski s A-TIPS-pyrrole (6) [17-19]. Whereas bromination of IV-trimethylsilylpyrrole gives almost exclusively C-2 attack, the NBS bromination of 6 affords the C-3 product 7 in a 96 4 ratio (C-3/C-2) in 93% yield. Deprotection... 

Pyrroles are lithiated at the 2-position whether or not the A-protecting group has the ability to coordinate (Scheme 131) . 3-Lithiopyrroles are best obtained by halogen-metal exchange on 3-bromo-A-TIPS pyrrole 275 (Scheme 132). ... 

Various iodinated pyrroles have been prepared by direct iodination or via initial thallation. For example, 3-iodo-V-TIPS-pyrrole is prepared in 83% yield from V-TIPS-pyrrole. And 3,4-diiodo-2-formyl-l-methylpyrrole is available in 54% yield via a bis-thallation reaction.Although V-protected 2-lithiopyrroles are readily generated and many types are known, these intermediates have not generally been employed to synthesize halogenated pyrroles. 

Pyrroles almost exclusively add to acetylenes as Ai-centered nucleophiles however, when the acetylene is activated by a strong electron-withdrawing substituent, pyrrole can add to the triple bond as a C-centered nucleophile. " In their gold-catalyzed alkynylation of pyrrole with silyl-protected alkynyl benziodoxolone hypervalent iodine reagent 6, members of the Waser laboratory only saw C-alkynylated products (Scheme 10.2). Using this method, 1/f-pyrrole (1) could be C2-funtionalized to afford 7 in 62% yield, whereas Ai-TIPS pyrrole (8) was selectively transformed into C3-product 9 in 79% yield. In both cases, auration of the heterocycle led to an organogold(III) intermediate that reductively eliminated to afford the alkynylated products. 

It has been previously shown that the regioselectivity of pyrrole borylation can be switched from C2 to C3 if the nitrogen is TIPS or Boc protected. More recently, however, Maleczka and Smith described a very useful method that circumvents the installation and removal steps required for pyrrole protection (Scheme 10.8). The researchers demonstrated that 177-pyrrole (1) could be exclusively borylated at the C3 position (29) when Bpin was employed as a traceless directing group. As the AH of pyrrole is not particnlarly acidic, triethylamine was added to the reaction mixture to make the B—H bond in HBpin more hydridic and ensure successful A-borylation. 

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