Treatment of cyclic tert-trihalomethylcarbinols with CrCl 2 in THF/HMPA in the presence of aryl or aliphatic aldehydes initiates a cascade sequence of one carbon ring expansion-olefination affording conjugated exo-cyclic ketones. Acyclic tert-trihalomethylcarbinols undergo a comparable cascade of one carbon homologation-olefination.Trihalomethylcarbinols and their derivatives are a diverse 1 and readily accessible class of functionalized alcohols. 2 Their reduction, inter alia, electrochemical, 3 zero-valent metals/ metal salts, 4 or aqueous Cr(II), 5 principally induces elimination to the corresponding 1,1-dihaloölefin. However, our laboratories recently observed that sec-trihalomethylcarbinol derivatives follow a different reaction manifold when reduced with Cr(II) salts in THF leading stereoselectively to (Z)-α-haloenol esters and (Z)-β-haloenol ethers. 6 We consequently examined the behavior under similar conditions of tert-trihalomethylcarbinols in the presence of aldehydes and report herein a cascade sequence 7 of one carbon ring expansion/ homologation-olefination affording conjugated ketones. 8The cascade sequence was optimized using carbinol 1 9 (X = Cl) and benzaldehyde 2 as the test system. The best yield of adduct 3 10 was obtained using CrCl 2 (6 equiv) in THF/HMPA (2:1) at 40 °C (Table 1, entry 1). Using the tribromo-version of 1 (X = Br), the results were identical, except the reaction only required 2 h instead of the 4 h when X = Cl. The output of j.falck@utsouthwestern.edu; mioskow@aspirine.u-strasbg.fr. † University of Texas Southwestern. ‡ Université Louis Pasteur.Supporting Information Available Synthetic procedures, analytical data, X-ray files, and 1 H/ 13 C spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 3 did not improve using a lower THF/HMPA ratio (i.e., 1:1) and it decreased linearly as the ratio increased in favor of THF. Other solvents or their combinations, e.g., THF only, DMF, EtOAc, dioxane, and HMPA, were not satisfactory. There was also a strict dependence on the amount of CrCl 2 ; 5 and 4 equivalents gave 3 in 51% and 30% yield, accordingly. Efforts to use fewer equivalents of CrCl 2 by coupling the reaction to a regeneration system showed promise, but clearly need further improvement. For instance, under otherwise identical conditions as entry 1, CrCl 2 (1 equiv)/Mn powder (8 equiv) and CrCl 2 (1 equiv)/Fe powder (10 equiv) gave rise to 3 in 58% and 42% yield, respectively.We were gratified to find that the cascade was also applicable to aliphatic (entry 2, 4→ 5 10 ), α,β-unsaturated (entry 3, 6 → 7 10 ), and electron rich (entry 4, 8 → 9 10 and entry 5, 10 → 11 11 ) aldehydes. In all, only exo-cyclic olefins were generated including 5, the thermodynamically less stable positional isomer. Notably, the yield of adduct, as demonstrated in the condensation of 1 with 10 (entry 5), could be ameliorated utilizing a mod...
