Highly Efficient Methodology for the Reductive Coupling of Aldehyde Tosylhydrazones with Alkyllithium Reagents

Aldehyde tosylhydrazones are nearly ideal synthetic intermediates; they are readily available, stable, and frequently crystalline compounds that can be stored indefinitely, whereas the parent aldehydes cannot, being susceptible to autoxidation, selfcondensation, and hydration.1 In this work, we describe a new and efficient process for the construction of C-C σ bonds by the reductive coupling of aldehyde tosylhydrazones with alkyllithium reagents. In an earlier study we reported that aldehyde tosylhydrazones are readily N-tert-butyldimethylsilylated, in quantitative yield, and that the resultant derivatives undergo 1,2-addition of vinyllithium reagents to form olefinic products in a process involving, ultimately, [3,3]-sigmatropic elimination of dinitrogen from an allylic diazene intermediate.2 In this work, we show that saturated (sp3-hybridized) alkyllithium reagents (typically, 1.2 equiv) add to N-tert-butyldimethylsilyl aldehyde tosylhydrazones at -78 °C and that the resultant adducts can be made to extrude dinitrogen in a free-radical process,3 leading to a net reductive coupling reaction that often proceeds with remarkable overall efficiency (Scheme 1, Table 1). These features distinguish the present methodology from the important precedents of Vedejs et al., who reported the reductive coupling of (nonsilylated) aldehyde tosylhydrazones with alkyllithium reagents (g3 equiv, 20-61% yield) by an anionic fragmentation pathway,4a and of Bertz, who described the coupling of nonepimerizable aldehyde tosylhydrazones with cuprate reagents, also by anionic fragmentation.4b Sequential treatment of aldehyde tosylhydrazones (0.2 M in tetrahydrofuran, THF) with triethylamine (1.3 equiv) and tertbutyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 1.2 equiv) at -78 °C followed by the addition of methanol (1.3 equiv), dilution with hexanes, and immediate washing of the cold reaction solution with saturated aqueous sodium bicarbonate solution, and then brine, drying over magnesium sulfate, and concentration affords the silylated tosylhydrazones in quantitative yield.2 Because of their propensity to hydrolyze upon exposure to silica gel, these intermediates are used directly in the coupling reactions, without purification. Entry 8 (Table 1) is illustrative of a typical coupling protocol: a solution of (2S)-1-lithio-2-methyl-3-phenylpropane (0.378 mmol, 1.2 equiv) in diethyl ether (1.0 mL) at -78 °C was added to a solution of N-tert-butyldimethylsilyl (2S)3-(tert-butyldiphenylsilyloxy)-2-methylpropanal tosylhydrazone (147 mg, 0.315 mmol) in THF (1.5 mL) at -78 °C. After 15 min, acetic acid (1.25 equiv) was added, followed by trifluoroethanol (TFE, 5.0 mL), and the resulting solution was warmed to 23 °C to induce diazene formation and elimination of dinitrogen. The reaction was complete within 8 h at 23 °C. After extractive isolation and chromatography on silica gel, the coupled product was obtained as a colorless oil (133 mg, 95%). 1H and 13C NMR analysis showed that the coupled product was a single diastereomer, demonstrating that epimerization of the aldehydederived stereocenter did not occur throughout the sequence of tosylhydrazone formation, silylation, and coupling. Entries 6, 7, and 9-12 of Table 1 were also shown to proceed without detectable epimerization, reinforcing the potential utility of the method for asymmetric synthesis using “R-chiral” aldehydes.5 Recent advances in the preparation of (stereochemically) complex primary alkyllithium reagents further extend the potential of the method in asymmetric synthesis, as illustrated by entries 6, 8, and 10.6 Prior studies support the pathway shown in Scheme 1 as the likely sequence for the present coupling chemistry: 1,2-addition of the alkyllithium reagent and protonation of the adduct followed by elimination of p-toluenesulfinic acid, protodesilylation, and loss of dinitrogen.2 That the latter step proceeds by a radical pathway was established unequivocally by trapping of the intermediate free radical with TEMPO, by intramolecular radical cyclization experiments (see the Supporting Information), and by the observation of fragmentation within the substrate of entry 13.7 A particularly noteworthy feature of the coupling chemistry described is the overall efficiency of the process (Table 1), a sequence initiated by 1,2-addition of the alkyllithium reagent. The latter step is no doubt facilitated relative to additions to the anionic intermediates formed from nonsilylated tosylhydrazones4 by the fact that the silylated tosylhydrazone is a neutral species; however, the X-ray crystal structure of N-tert-butyldimethylsilyl 1-naphthaldehyde tosylhydrazone (Figure 1) suggests that there may be other beneficial factors associated with N-silylation as well. The sulfonamide nitrogen is found to be nearly planar, a common feature within silylated amines but not within sulfonylhydrazones.8 The bulky tert-butyldimethylsilyl group is adjacent to the imino lone pair, while the arenesulfonyl group is syn coplanar with the aldimine hydrogen atom. This places one of the sulfonyl oxygens in a nearly ideal orientation to direct the addition of an organolithium reagent to the imine group. The least basic organometallic reagent observed to add efficiently to a silylated tosylhydrazone is the amide enolate of entry 5 (addition at -20