Protection of pyrroles

Protection of pyrroles and indoles. These heterocycles undergo t-butoxycar-bonylation in 80-95% yield on reaction with 1 and a catalytic amount of DMAP in acetonitrile. The Boc group is cleaved almost instantaneously by TFA at 25°.1 The same conditions are useful for protection of the indole group of tryptophan.2 Primary amino acid esters can be converted into bis(Boc) derivatives, and amino groups of peptides also undergo t-butoxycarbonylation.3... 

The Tsc group was developed as a more soluble alternative to the Nsc group for the protection of pyrrole-imidazole polyamides. It is formed from the 4-nitrophenyl... 

A-Protection of Pyrroles. Pyrroles typically undergo electrophilic substitution at the a-(2)-position, but when protected as A-triisopropylsilylpyrroles, substitution occurs exclusively at the (3-(3)-position (eq 6). It has been shown that 3-bromo-l-(triisopropylsilyl)pyrrole undergoes rapid halogen-metal exchange with n-Butyllithium to generate the 3-lithiopyrrole, which... 

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. 

Variants on this theme can be seen in methods for the protection of amines (16), alcohols (17), including sugar hemiacetals (18), and pyrrole (19). 

Alkylation at nitrogen has been achieved by treating indole or pyrrole with alkyl halides in ionic solutions of potassium carbonate in l- -butyl-3-methylimidazolium tetrafluoroborate [bmim][BFJ <06TL2435>. Bis-protection of 3,3 -diiodo-2,2 -biindoles with Me, Boc, C02Et, or S02Ph has been described by Roy and Gribble <06SC3487>. 

A similar reaction of pyrroles 20 with acrylates provides the C-2 substituted a-alkenyl derivatives 21 in 24-91% yield [29]. The 2,6-dichlorobenzoyl protecting group is noteworthy as it prevents cyclization of the phenyl group onto the pyrrole ring (vide infra). 

Stille couplings on W-protected derivatives of 85 proceed well, as shown below for the synthesis of pyrroles 86 [70]. 

No deprotonation of carbon occurs with pyrroles unsubstituted on nitrogen, so in order for carbanion formation to occur, protection of the nitrogen is essential. However, once protected, the a-lithiation of N-substituted pyrroles occurs readily (790R1 84MI2), and in the case of AT-methylpyr-role, both 2-mono and 2,5-dilithiation can occur, depending upon the reaction conditions (Scheme 5) [79JCS(P1)2845 82SC231]. 

In addition to the protected pyrroles mentioned above, the 1-azafulvene dimer formed by Mannich reaction of pyrrole-2-carboxaldehyde with di-methylamine has also been successfully lithiated adjacent to both pyrrole nitrogens (Scheme 10). Reaction with electrophiles and subsequent hydrolysis leads to 5-substituted pyrrole-2-carboxaldehydes in good yield [88TL777 92JOM(423)173]. 

The 4- and 6-positions of pyrrolo[2,3-3]pyridines can be substituted via palladium-catalyzed cross-coupling reactions with the 4- or 6-halo-substituted derivatives (Scheme 3) <2001SL609>. Nucleophilic displacement of the 4-substituent of 6-chloro-4-nitro- and 4,6-dichloro-pyrrolo[2,3-/ ]pyridines takes place with phenols. Protection of the pyrrole nitrogen with a /3-trimethylsilylethoxymethyl (SEM) group affords good yields of the aryl ethers (Equation 3) <2006TL2069>. 

Anodic oxidation of pyrrole and N-substituted pyrroles results in the formation of polypyrroles in an oxidized state, which can be useful for the preparation of conducting organic polymers.185-188 Oxidation of 2,5-di-substituted pyrroles produces soluble products and no layer of polymers.187 One of the proposed applications of such a layer of conducting polymer is the protection of semiconductor electrodes from photocorrosion.189-191... 

The electrochemical polymerization of pyrrole or thiophene readily lends itself to formation of composites. Polypyrrole-acetylene laminates have been made by using polyacetylene as an electrode 295). The polypyrrole forms as a 5 pm skin on the polyacetylene. If the polyacetylene is first doped, the polypyrrole completely permeates the film. In both cases the conductivity of the composite reached 30-40 S cm-1 and was much less sensitive than that of pure polyacetylene to exposure to moist air or water, so that the polypyrrole protects the polyacetylene even in the case where it permeates the film. In this latter case, treatment with ammonia caused the conductivity to drop by 30 x whereas for the sandwich films the conductivity dropped by 4600 x through the film but only 17 x in the surface layers. 

---