Protection for Imidazoles, Pyrroles, and Indoles

PROTECTION FOR IMIDAZOLES, PYRROLES, INDOLES, AND OTHER AROMATIC HETEROCYCLES 

The protective group chemistry of these amines has been separated from that of the simple amines because, chemically, the two classes behave quite differently with respect to protective group cleavage. The increased acidity of these aromatic amines makes it easier to cleave the various amide, carbamate, and sulfonamide groups that are used to protect this class. A similar situation arises in the deprotection of nucleoside bases (e.g., the isobutanamide is cleaved with methanolic ammonia), again, because of the increased acidity of the NH group. 

2% KOH, H2O, reflux, 12 h, 64-92% yield. This group is more stable to n-BuLi than is the benzyl group in the protection of imidazoles 

BuLi and MtsCl (84% yield) can also be used to protect an indole.  

The Mts group is stable to CF3COOH, 1 N NaOH, hydrazine, 4 N HCl, 25% HBr-AcOH, and H2-Pd, but is cleaved with 1 M CF3S03H/CF3COOH/thioanisole or CH3S03H/CF3COOH/thioanisole. Thioanisole is required to obtain clean conversions. The Mts group is not efficiently cleaved by HR 

Like the trifluoromethylsulfonamides, phenacylsulfonamides are used to prevent dialkylation of primary amines. Phenacylsulfonamides are prepared in 91-94% yield from the sulfonyl chloride and cleaved in 66-77% yield by Zn/AcOH/trace HCl.  

CF3COOH, Mc2S, 40-60 min, 100% [Imidazole f= His(Mps)]. This group is also cleaved with hydrazine, 1 NNaOH, HOBT, and HF. The Mps group on histidine is stable to CF3COOH/anisole and to 25% HBr/AcOH. 

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Protection for Imidazoles, Pyrroles, Indoles, and Other Aromatic Heterocycles 872... 

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. 

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. 

MO-Acetals afford robust protection for indoles and pyrroles with SEM and BOM ethers being particular favourites. A SEM group has also been used to protect imidazole.534 They are introduced in much the same way as already discussed for amines and amides in section 8.6. L Hence treatment of Indolelactam derivative 274.1 with SEMC and sodium hydride in THF at —15 °C afforded the M 0-acetal 274 in >80% yield 535... 

C-arylations of azoles proceed smoothly when N-protected azoles (pyrrole, indole, and imidazole) are used. N-free pyrrole, imidazole, and indole are poor substrates for C-arylation. However, Sezen and Sames reported an interesting effect of MgO as an additive [10], 2-Phenylpyrrole was obtained cleanly in 86% yield by the reaction of unprotected pyrrole with iodobenzene in the presence of MgO (1.2 equiv.). No N-arylation occurred. MgO seems to be bound to nitrogen strongly, and not only protects the nitrogen, but also increases the nucleophilicity of heteroarene nucleus. 

Reagent for the Protection of Secondary Amines. SEM-Cl can be used to protect secondary aromatic amines (eq 13), and is an ideal reagent for the protection of imidazoles, indoles, and pyrroles (eqs 14-16). Many functional groups are compatible with the introduction and cleavage of SEM amines, and the SEM substituent is unusually stable to further functionahzation of the molecule. " Recently, a one-pot method for protection and alkylation of imidazoles employing w-butyllithium and SEM-Cl has been developed (eq 17). ... 

The cesium hydroxide-promoted addition of benzimidazole to phenylacetylene proceeded with exclusive anti-Markovnikov regioselectivity and complete stereoselectivity for the formation of the Z-isomer (Scheme 3.132) [142]. Similar reactivity was obtained for pyrrole and imidazole however, acyclic secondary amines such as diphenylamine or phenytmethylamine afforded mixtures of the stereoisomers. It should be noted that these additions were still regioselective for the anti-Markovnikov product. In related work, the base-assisted synthesis of enamines through the addition of indole derivatives to TMS-protected alkynes has been achieved using KOH as the promoter (Scheme 3.133) [143]. 

In 2005, Sames [50] developed a C-H arylation of N-alkyl indoles (indoles with a free NH can also be used) and pyrroles with aryl iodides using a rhodium catalyst. They demonstrated that CsOPiv activates the rhodium catalyst to form Rh(OPiv)2(Ph)L2 (L = P[p-(CF3)CgH4]j). In 2006, Sames [51] also developed a palladium NHC catalyst 53 for the C-H arylation of N-protected indoles, pyrroles, imidazoles, and imidazo[l,2-a]pyridines (Section 17.2.4.5) with aryl iodides. 

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