Lombardo methylenation

The Lombardo reagent is usually prepared by addition of TiCU to a precooled suspension of zinc dust in a solution of dibromomethane in dry THF at very low temperature (e.g., -40°C), and aged for 2 days at 4°C before the methylenation." Different from the Wittig Reaction, the Lombardo methylenation is highly selective and occurs under nonbasic conditions. This reaction is especially valuable for the methylenation of keto ester, for which the Wittig Reaction fails, " and for the olefination of /3,y-unsaturated enones without enolization. Thus the Lombardo methylenation is an alternative olefination method when Wittig Reaction or Tebbe Olefination is not applicable. However, it also... 

It is plausible that the Lombardo methylenation proceeds via an analogous pathway of Tebbe Olefination, as illustrated below. 

Other references related to the Lombardo methylenation are cited in the literature. 

Lombardo methylenation (zinc-dibromomethane-titanium tetrachloride) of methyl 2-deoxy-5-0-(4-phenylbenzoyl)-P-D-g/ycero-pent-3-uloside, followed by dihydroxylation, gave the 3-C-hydroxymethyl derivative 7 (R = 4-phenylbenzoyl) exclusively. A ran of other 2-deoxypentuloses was also subjected to a similar course of reactions, but erally resulted in the formation of epimers during the dihydroxylation step. The hydroxymethyl group was further transformed first with tosyl chloride to the tosylate which was displaced with adenine or thymine to yield nucleoside analogues. ... 

Hydroboration occurred from the less hindered top face of rac-29 and resulted in the formation of alcohol rac-30. After a three-step sequence which included oxidation with tetrapropylammonium perruthenate (TPAP), methyl lithium addition and repeated oxidation with TPAP, ketone rac-31 was isolated. Finally, epimerization of the stereogenic center at C-7 to the correct configuration and methylenation with the Lombardo reagent led to the formation of racemic kelsoene (rac-1). 

The first progress was made by Takai and Lombardo, who developed an in situ entry to titanium-alkylidene chemistry starting from the reagent combinations 5 and 6 (Scheme 4) [9]. These reactions proceed via a gem-dizinc compound 7 (its formation is catalyzed by traces of lead or lead(II) salts), which is subsequently transmetalated with TiCl4 to the titanium-alkylidene species 8, the actual olefination reagent. To date, 8 has not been characterized in detail [10]. These in situ reagents exhibit chemoselectivities similar to those of the structurally defined methylenation reagents 1-3. 

Under special conditions (addition of lithium amide, phase-transfer catalysis), compounds with apparently unactivated methylene groups (e.g., 5-methoxy-l-tetra-lone, Lombardo and Mander, 1980) or even with a methyl group at an arylcarbonyl group (Sugihara et al., 1987) undergo diazo transfer with arenesulfonyl azides. This is also the case for esters of 4-arylbut-3-enoic acid and related compounds (Davies et al., 1989, and references therein). 

Nevertheless, phase-transfer catalysis is an advantageous method for diazo transfer reactions, as mentioned previously for cyclic a-diazo ketones (Lombardo and Mander, 1980) and shown also by Starks (1971) and Ledon (1974). Di( er -butyl) malonate reacts with 4-toluenesulfonyl azide in methylene chloride and in the presence of a small amount (2 mol- o) of methyl(trioctyl)ammonium chloride as phase-transfer catalyst. After workup with aqueous NaOH A tert-hviiy ) diazomalonate is obtained in 59-63% yield, whereas without phase-transfer catalysis the yield is only 47 % after a reaction time of 4 weeks The procedure is described in Organic Syntheses (Ledon, 1988). Diazo transfer to malonates and vinylogous malonates has also been investigated by Davies et al. (1985). 

Treatment of 44 with Lombardo s reagent (TiCl4/Zn/CH2Br2) (27) in CH2CI2 gave a mixture of the desired methylenation product 45 (24% yield)... 

Another reagent for the methylenation of aldehydes or ketones is the Oshima-Lombardo reagent TiCl4-Zn-CH2l2 (or CH2Br2). This reagent is non-basic and can therefore be advantageous for base-sensitive substrates (2.105). 

A drawback of the Tebbe and related reagents is that they are generally suitable only for methylenation and do not permit the formation of higher alkyl analogues. However, the alkenylation of esters (or amides) has been found possible using the Oshima-Lombardo conditions in the presence of TMEDA (tetramethylethylene-diamine) (2.106). This chemistry requires the prior formation of the alkyl gem-dibromide and a more-convenient method, using a dithioacetal, has been reported (2.107). ... 

Indeed, the reproducibility of this method was questioned by Lombardo in 1982 [14]. He attempted to apply Takai and Oshima s procedure to the methylenation of a gibberellin derivative with Zn (pure, without lead)-CH2Br2-TiCl4, but only decomposition of the substrate was observed. Lombardo later demonstrated an improved procedure. According to his report, the requisite ageing period for the preparation of the reagent was three days (Scheme 5.7). 

Scheme S.7. Methylenation of a gibberellin derivative by Lombardo s method.

An equimolar mixture of 4 and jS-TiCh generated reactive spedes for the methylenation, as shown in Table 5.2. As described above, the methylenation procedure due to Takai or Lombardo employed diiodomethane, zinc, and titanium(IV) chloride. In these procedures, the titanium(IV) chloride would be reduced to titanium(O), titanium(I), titanium(II), or titanium(III). The oxidation state of tita-... 

The problem about the aging period for preparation of reactive species 3, argued by Lombardo, should not be attributed only to the formation of gem-dizinc species. As titanium(IV) chloride is also reduced with zinc powder, [17] the titanium salt that works as a mediator would be the low-valent one. The reduction process of titanium(IV) may also sometimes cause the problem of reproducibility of methylenation reaction. In 1998, Matsubara and coworkers reported a general... 

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