Pyrroles directed lithiation

Direct lithiation of N-(dimethylamino)pyrrole (80) and subsequent quenching with trimethylstannyl chloride affords 81 in excellent yield [67], The N-dimethylamino group can be removed with Cr2(0Ac)4 2H20. 

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... 

Directed lithiation continues to be a versatile method for synthetic elaboration of pyrroles and indoles Conditions for lithiation of l-vinylpyrrole were explored. Lithiation with n-butyllithium with or without TMEDA or KO-f-Bu gave a mixture of C2 and o(-vinyl lithiation. Use of a catalytic amount of (/-Pr)2NH (12 mol %) with a stoichiometric amount of -butylIithium/KO-/-Bu at -60 to -80" leads to selective C2 lithiation. <95RTCl8> These conditions are believed to reflect a... 

A dramatic application was the asymmetric synthesis of epibatidine 70 by Simpkins.18 Diels-Alder reaction of the deactivated pyrrole 63 with the alkynyl sulfone 64 gave the bicyclic core 65 of epibatidine. Selective reduction gave the compound 66 needed for epibatidine, but in racemic form. A directed lithiation (chapter 7) and sulfonation led to achiral bis sulfone 67. 

In the synthesis of amino boronic acid dipeptides 7 (Scheme 11.37) as inhibitors of the serine protease dipeptidyl peptidase IV (DPPIV), Kelly and co-workers have reported an elegant preparation of the optically active proline boronic acid (boroPro) by a direct lithiation of N-Boc-pyrrolidine and a quench with B(OMe)3. The subsequent hydrolysis and resolution with (-1-)-pinanediol provided rapid access to a key chiral intermediate in the synthesis of these dipeptides. The direct a-functionalisation approach avoided a catal5Aic hydrogenation step required in their original synthesis starting from IV-Boc-pyrrole. ... 

Electron-rich heterocycles, snch as pyrrole and furan, bear more resemblance to car-bocyclic rings their side chains are mnch less acidic, and undergo lateral lithiation mnch less readily. Without a second directing group, methyl groups only at the 2-position of fnran, pyrrole or thiophene may be deprotonated. 

The usual directing groups such as secondary amides will also successfully direct lateral lithiation at the 2-methyl group of a pyrrole (Scheme 226/° . 

Halogen-metal exchange can also be used as a route to 2-lithiated pyrroles, and because this process can be achieved at much lower temperatures than direct metalation it is now possible to use the /-BOC protecting group with n-butyllithium (87TL6025). 2,5-dilithiation can also be achieved using this system, and the two bromine atoms in l-tcr/-butoxycarbonyl-2,5-dibromopyrrole can both be replaced to give symmetrical products. 

When considering the synthesis of phospholes, one has to forget most of the classical and powerful methods employed for the preparation of thiophenes and pyrroles. For example, Paal-Knorr condensation, direct ortho-lithiation, halogenation with NBS or I2/Hg2+ and Vilsmeier-Haack formylation are not operative in phosphole chemistry. Likewise, no chemical or electrochemical oxidative polymerization... 

Much effort has been directed toward synthesis of fluorine-containing heterocycles, owing to their biological activity <2004MI357>. A 2-fluoro-substituted pyrrole 304 has been synthesized (ca. 40%) by a treatment of the 5-lithiated l-methyl-2-octyl-l//-pyrrole with iV-fluoro-iV-(phenylsulfonyl)benzenesulfonamide (Equation 69) <2003JFC(124)159>. At room temperature pyrrole 304 slowly undergoes a dimerization process. 

Pyrrolopyridines can be lithiated at the 2-position, in direct analogy to pyrrole itself. The reaction is sufficiently mild that it has been applied to the functionalization of purine nucleosides, as illustrated by the examples in Scheme 22. ... 

It is a significant comment on the relative ease of a-lithiation in six- and five-membered systems that (iV-protected) pyrazoles lithiate at C-5, i.e. at the pyrrole-like a-position, though, again chelation assistance from the iV-protecting group also directs to C-5. ... 

Side chain lithiation is a major source of reactivity in terms of the elaboration of pyrroles and indoles, and new examples and developments continue to be reported. One major development has been the lithiation of 2-alkyl groups of 2-alkylindole-1 -carboxylate lithium salts. The carboxyl group protects the nitrogen atom, directs the lithiation, and can easily be removed after alkylation (Scheme 121) <86JA6808>. Similarly, lithiation of 2,3-dialkylindoles takes place at the 2-methylene position via the C,7V-dilithio derivative, using three equivalents of butyllithium <9UOC2256>. 

Several of the directing groups developed for benzenoid lithiation have also been employed with pyrroles and indoles. l-Methylpyrrole-2-(A-/-butyl)carhoxamide is lithiated at C3, although in modest yield (Equation (106)) <85JOC4362>. 

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