A-amino alkoxides

Pyrroles and indoles have one further unique mode of lateral lithiation—deprotonation of an Af-methyl group (also an a lithiation). The reaction works particularly weU with an aldehyde director, temporarily protected as the a-amino alkoxide 565 (Scheme 228)°° . 

In addition to the parent heterocycle, both AT,N-diethyl-l-methylpyr-role-3-carboxamide and l-methylpyrrole-3-carboxaldehyde have been selectively a-lithiated in the 2-position (85TL6213 87JOC104), the latter compound via the intermediacy of an a-(Af-methylpiperazino) alkoxide (Scheme 6). The a-amino alkoxide is formed in situ, via the addition of... 

Comins and Killpack have also investigated the lithiation of a small number of N-protected indole-3-carboxaldehydes, using lithium N-methyl-piperazide to form the a-amino alkoxide, and found that decomposition occurred with the A -benzenesulfonyl, N-ter/-butoxycarbonyl, and A -di-methylcarbamyl derivatives (87JOC104). Success was achieved with the N-methoxymethyl derivative 19, although no attempt was made to subsequently remove the normally difficult to hydrolyze methoxymethyl protecting group. Therefore the real viability of this method as a route to... 

N-Methylindole-2-carboxaldehyde also undergoes /8-lithiation, after in situ conversion to its a-amino alkoxide with lithium A-methylpiperazide, and the resulting 3-lithio species has been successfully alkylated with methyl iodide (Scheme 22)(87JOC104). However, when the same reaction was repeated using N,A(,A -trimethylethylenediamine as the amine com-... 

Addition of A/ -forrnyl-/V,/V,/V -trimethylethylenediamine to 21 yields a-amino alkoxide 22. A further directed ortho metalation takes place by coordination of nBuLi to the ethylenediamine moiety and subsequent deprotonation. As result intermediate 6 is formed. 

An interesting protection of an aldehyde group in a lithiation reaction is to convert it to a-amino alkoxide. The alkoxide, here, is the ortho directing group... 

A three-step synthesis of cerpegin (118) was described by Hong and Comina (235). Lithiation of 2-methoxypyridine (361) with mesityllithium followed by the addition of N-formyl-A/,lV, 7V -trimethylethylenediamine (362) gave an a-amino alkoxide which was treated with n-butyl lithium. The resulting dianion 363 was reacted with cerium chloride followed by acetone to yield, after acidification, the lactol 364. Oxidation with PCC gave 365, which was treated with methyl iodide at 145°C to afford 118 (Scheme 43) (235). The overall yield was 34%. 

Reaction in THP at 50 kHz followed by lithiation of the intermediate a-amino-alkoxide on its ortho position and quenching with electrophiles provide ortho-substituted benzaldehydes in a one-step protocol. 

The tertiary amide group (CONR2) is a widely used DMG but it usually requires further derivatisation ° to convert it to a reactive functional group however, it readily participates in intramolecular cyclisation reactions to form lactones/ Tertiary amides have also been converted to ketones through an intermediary a-amino alkoxide that plays the role of the DMG (Scheme 11.3). 

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