Pyrrole protection

The attraction of the rhenium system is that deprotection of the pyrrole can readily be achieved by treatment with acid and DMSO, which replaces the kinetically labile i7- -pyrrole ligand on the metal [87JOM(326)C17 90H(31)383]. However, the relatively high cost of rhenium will almost certainly preclude its synthetic use as a pyrrole protecting group, especially when compared with the alternative methods discussed above. 

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. 

Synthesis of optically active PF-04634817 (271) based on commercially available (-)-Vince Lactam as chirality source. Starting from (-)-Vince Lactam the chiral key 4-amino-2-cyclopentene-l-carboxylic acid derivative 286 was synthesized. The componnd 286 is dimethyl pyrrole protected form of corresponding aminoacid, which was subjected to amide coupling with Boc-protected diamine 287 to give... 

Pyrrole Carboxylic Acids and Esters. The acids are considerably less stable than benzoic acid and often decarboxylate readily on heating. However, electron-withdrawing substituents tend to stabilize them toward decarboxylation. The pyrrole esters are important synthetically because they stabilize the ring and may also act as protecting groups. Thus, the esters can be utilized synthetically and then hydrolyzed to the acid, which can be decarboxylated by heating. Often P-esters are hydrolyzed more easily than the a-esters. 

In order to exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, benzenesulfonyl and dimethyl-amino have been used 81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (211) (8UOC3760). 

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. 

PROTECTION FOR IMIDAZOLES, PYRROLES, AND INDOLES A -Sulfonyl Derivatives... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

CF3CO2H, Me2S, 40-60 min, 100% yield, [Imidazole = His(Tos)]." The related phenylsulfonyl group has been used to protect pyrroles and indoles, and is cleaved with NaOH/H20/dioxane, it, 2 h. " ... 

A series of substituted benzimidazoles and pyrroles was protected and deprotected using this methodology. 

Pyrroles and indoles can be protected with the r-butyldimethylsilyl group by treatment with TBDMSCl and n-BuLi or NaH. Triisopropylsilyl chloride (NaH, DMF, 0°-rt, 73% yield) has been used to protect the pyrrole nitrogen in order to direct electrophilic attack to the 3-position.It has also been used to protect an indole.This derivative can be prepared from the silyl chloride and The silyl protective group is cleaved with Bu4N F , THF, rt or with CF3COOH. 

Two new sections on the protection for indoles, imidazoles, and pyrroles, and protection for the amide — NH are included. They are separated from the regular amines because their chemical properties are sufficienth different to affect the chemistry of protection and deprotection. The Reactivity Charts in Chapter 8 are identical to those in the first edition. The chart number appears beside the name of each protective group when it is first discussed. 

An important extension of the Knorr pyrrole synthesis developed by Cushman utilizes ketone enolates and BOC-protected a-amino aldehydes and ketones. Two examples (37, 38) are shown. 

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