Developing the Saegusa–Ito Cyclisation for the Synthesis of Difluorinated Cyclohexenones

Abstract

Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile gave the turnover of the initial palladium(II) salt, whereas the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products, in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry.

Atom Efficient Synthesis of Selectively Difluorinated Carbocycles through a Gold(I)-Catalyzed Cyclization

“…% acetone in dichloromethane) to afford an inseparable mixture of 1, 3-trans, 1, 9a-trans-4b and 1, 3-cis, 1, 9a-trans-4b as a colourless solid (0.162 g, 69 %, 4.9:1). Rf (4aS*,5R*,7R*,8aR*)-6,6-Difluoro- 7-methyloctahydro-4aH-isochromene-4a,5-diol (4a, 5-trans, 5, 7-trans-4c), (4aS*,5R*,7S*,8aR*)-6,6-difluoro- 5, and (4aS*,5S*,7R*,8aR*)-6,6-difluoro -7methyloctahydro-4aH-isochromene-4a,5-diol (4a, 5-cis, 5, 7-cis-4c). Prepared according to general procedure B from trans-3c and cis-3c (0.308 g, 1.00 mmol) with 1,3-bis (2 tert-Butyl (4aS*,5R*,7R*,8aR*)-6,6-difluoro-4a,5-dihydroxy-7methyloctahydroisoquinoline-2(1H)-carboxylate (4a, 5-trans, 5, 7-trans-4d), tert-butyl (4aS*,5R*,7S*,8aR*)-6,6-difluoro-4a,5-dihydroxy-7-methyloctahydroisoquinoline-2(1H)-carboxylate (4a, 5-trans, 5, 7-cis-4d) and tert-butyl (4aS*,5S*,7R*,8aR*)-6,6-difluoro-4a,5-dihydroxy-7-methyloctahydroisoquinoline-2(1H)-carboxylate (4a, 5-cis, 5, 7-cis-4d).…”

“…The material was further purified by flash column chromatography (40 g silica, 6 % acetone in dichloromethane) to afford an inseparable mixture of 6, 7-trans, 7, 9-trans-4i, and 6, 7-cis, 7, 9-trans-4i (0.108 g, 44 %, 3.8:1). Rf = 0.7 (8 % acetone in dichloromethane); The following signals were attributed to both the minor 6, 7-cis, 7, 9-trans-diastereoisomer 4i and major 6, 4a,5,6,7, and trans-methyl (3R*,4aR*)-3-methoxy-3-methyl-4,4a,5,6,7,8hexahydro-3H-isochromene-1-carboxylate (3, 4a-trans-5). 2, 132.7, 128.7, 97.1, 51.2, 48.6, 40.2, 33.3, 31.7, 27.1, 26.2, 25.1, 22.2 ppm; The following signals were attributed to the minor 3, 4a-trans-diastereoisomer 5 (assigned on the basis of δ and intensity); 1 H NMR (400 MHz, CDCl3): δ = 3.31 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ = 164.…”

“…4 In our efforts towards the development of new methods for the synthesis of selectively difluorinated carbocycles we recently reported the Saegusa-Ito cyclization as a concise and efficient protocol for the construction of selectively difluorinated cyclohexenones (Scheme 2). 5 Scheme 2. Context of the current study.…”

“…Hz), 68.6, 66.7, 62.9, 58.4, 40.5 (d,4 JC-F = 5.1 Hz), 36.6, 30.4 ppm;19 F NMR (376 MHz, 12.0 Hz), 116.0, 70.9, 68.2, 63.6, 62.5 (d,, 41 7,. 40.0, 31.7 ppm; F NMR (376 MHz, CDCl3): δ = -96.7 (d, 2 J = 66.4 Hz, 1F), 104.5 (dt, 2 J = 68.6,5 JF-H = 4.9 Hz, 1F) ppm; ν ̅/(neat) = 3443, 2928, 1736, 1100, 1056 cm-1 ; HRMS (APCI): calcd for C14H26F2O5N, 326.1774 [M+NH4] + , found: 326.1772; MS (CI): m/z (%): 326(100)[M+NH4] + ; tR (GC) = 13.73 minutes (major trans-diastereoisomer), 13.66 minutes (minor cisdiastereoisomer). *this is by comparison with compounds from the Saegusa-Ito series.…”

“…5 ** the cis-and trans-stereoisomers appeared as one peak by GC. .98 M solution in hexanes, 16 mmol), diisopropylamine (2.38 mL, 17 mmol) and 1-(1-allylcyclopropyl)ethan-1-one5 (1.00 g, 8 mmol) in THF (8 mL). The crude product (1.41 g) was purified by Kugelrohr distillation to afford 3h (0.730 g, 31 %) as a pale yellow oil.b.p.…”