Alkoxides, amino<?-lithiated

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-... 

A practical six-step synthesis of (S)-camptothecin was developed by D.L. Comins and co-workers." In order to prepare the DE ring fragment, 2-methoxypyridine was Iithiated at C3 with mesityllithium and treated with A/-formyl-A/,A/, A/ -trimethyl ethylenediamine to form an -amino alkoxide in situ. In the same pot, the addition of n-BuLi brought about a directed lithiation at C4 to afford a dianion, which was trapped with iodine and treated with NaBHVCeCIs to give the desired 4-iodo-2-methoxy-3-hydroxymethyl pyridine in 46% yield. 

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%. 

Trialkylsilicon, germanium or tin derivatives have been introduced at position 5 of thiophene-2-carbaldehyde via lithiation <92S954>. The first step is the protection of the aldehyde as the amino-alkoxide by reaction with lithium A(-methylpiperazide (LNMP). Subsequent treatment with BuLi followed by R MCl and hydrolysis by cold brine gave the desired products. 

Apparently, the unreactive species formed after 50% conversion contains one equivalent of the product alcoholate of 27, one equivalent of the remaining lithium acetylide 25 and two equivalents of the chiral alkoxide 26, forming a mixed 3 1 alkoxide-acetylide tetramer, which shows a similar reactivity as 29. The product alcoholate of 27 was suggested to exhibit chelating abilities similar to the amino alcoholate 26. Then 26 and lithiated 27 could block via chelation the lithiums close to the acetylide moiety and cause the observed low reactivity, which is also apparent in 29. However, lithiated [ ketoaniline 27 did not show... 

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. 

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