Bridged [2.2.1] bicyclic phosphine oxide facilitates catalytic γ-umpolung addition-Wittig olefination.

Chemical Science View Article Online Open Access Article. Published on 18 January 2018. Downloaded on 20/04/2018 13:07:25. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. EDGE ARTICLE Cite this: Chem. Sci., 2018, 9, 1867 View Journal | View Issue Bridged [2.2.1] bicyclic phosphine oxide facilitates catalytic g-umpolung addition–Wittig olefination† Kui Zhang,‡ Lingchao Cai,‡ Zhongyue Yang, K. N. Houk and Ohyun Kwon * A novel bridged [2.2.1] bicyclic phosphine oxide, devised to circumvent the waste generation and burdens of purification that are typical of reactions driven by the generation of phosphine oxides, has been prepared in three steps from commercially available cyclopent-3-ene-1-carboxylic acid. The performance of this novel phosphine oxide was superior to those of current best-in-class counterparts, as verified experimentally Received 9th October 2017 Accepted 2nd January 2018 through kinetic analysis of its silane-mediated reduction. It has been applied successfully in halide-/ base-free catalytic g-umpolung addition–Wittig olefinations of allenoates and 2-amidobenzaldehydes to DOI: 10.1039/c7sc04381c produce 1,2-dihydroquinolines with good efficiency. One of the 1,2-dihydroquinoline products was rsc.li/chemical-science converted to known antitubercular furanoquinolines. Introduction The classic Wittig reaction has been adopted widely for the construction of carbon–carbon double bonds since its discovery in 1953.1 The reaction is, however, far from ideal in terms of its environmental impact, requiring stoichiometric amounts of organic halide, base, and tertiary phosphine and producing stoichiometric amounts of base–halide salt and phosphine oxide wastes.2 Typically, the latter is not water-soluble, co-elutes with the olen product during chromatographic separation, and (for a solid product) readily precipitates with the product, impeding its purication, particularly in large-scale processes (e.g., those conducted on industrial scale).3 Traditionally, phosphorus ylides are prepared from corresponding phosphonium halides using stoichiometric amounts of base. Although less prevalent, ylides can also be prepared by simply mixing activated alkenes, acetylenes, and allenes with tertiary phosphines.4 In fact, halogen- and base-free Wittig olenations between activated alkenes and aldehydes predate the venerable Morita–Baylis–Hillman reaction by several years.4a More recently, Werner, Lin, and Voituriez each reported halogen- and base-free catalytic Wittig olenations.5 We also envisioned a halide- and base-free g-umpolung–Wittig process.6 In our reaction, phosphine adds to the allenoate 1a to form the zwitterionic intermediate A (Scheme 1). Deprotonation of the sulfonamide 2a and g-addition produces the ylide B, which, through a Wittig reaction, generates the 1,2-dihydroquinoline 3a and produces the phosphine oxide (condition 1; steps I / II / III). To minimize the generation of the phosphine oxide byproduct, we turned our attention to the recently developed catalytic Wittig conditions. In 2009, O'Brien and coworkers reported the rst phosphine oxide-catalyzed Wittig reaction for the synthesis of alkenes, with the phosphine oxide byproduct reduced by a silane in situ back to the phosphine.7a This strategy has since been employed to promote Wittig, Appel, Staudinger, and Mitsunobu reactions, as well as other reactions that are thermodynamically driven by virtue of the formation of phosphine oxide.7–9 When we applied catalytic Bu3P5b or phospholane oxide 4 7a under the reported reaction conditions, the desired dihydroquinoline was obtained in less than 5% yield (conditions 2 and 3; steps I / II / III / IV). Presumably, the allenoate 1a oligomerized under the high temperatures. Consequently, we directed our study to the development of new phosphine oxides that can be reduced Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, USA. E-mail: † Electronic supplementary information (ESI) available. CCDC 1489646. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc04381c ‡ K. Z. and L. C. contributed equally to this work. This journal is © The Royal Society of Chemistry 2018 Scheme 1 g-Umpolung–Wittig reaction. Chem. Sci., 2018, 9, 1867–1872 | 1867 View Article Online Chemical Science under milder conditions to realize the g-umpolung–Wittig reaction in a catalytic mode. Open Access Article. Published on 18 January 2018. Downloaded on 20/04/2018 13:07:25. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Results and discussion Recently reported catalytic Wittig reactions have been mainly promoted by phospholane oxide 4 and dibenzophosphole oxide 5 (Fig. 1), which are reduced faster than larger-ring phosphacycloalkane oxides or acyclic counterparts.7,8 The currently accepted mechanism for silane-mediated reduction of phosphine oxides to phosphines is based on the studies of Horner and Mislow (Scheme 2).10 Krenske demonstrated computationally that the rate-determining step (RDS) of the reduction is an intramolecular hydride transfer from silicon to phosphorus aer coordination of the phosphine oxide to the silane.11 The transition state (TS) for the hydride transfer features a fourmembered P–O–Si–H ring, in which both the P and Si atoms are centers of two trigonal bipyramids bridged by O and H atoms. Consequently, we surmised that a phosphine oxide with an a–P–b angle close to 90
may undergo facile silane-mediated reduction, due to minimal structural deformation upon proceeding to the TS.12 Previously, we reported the invention of the [2.2.1] bicyclic phosphine oxide 6, whose C–P–C angle in the X-ray structure was 93.3
(Fig. 1).13 Relative to the phospholane oxide 4 and the dibenzophosphole oxide 5, compound 6 is reduced faster by a silane (vide infra). Accordingly, we designed the [2.2.1] bicyclic phosphine oxide 7, which possesses a scaffold similar to that of 6.14 Computational modeling predicted Edge Article a C–P–C angle of 92.6
—much closer to 90
than the corresponding value (95.4
) of its non-bridged counterpart 4.15,16 Despite its smaller endocyclic C–P–C angle (91.5
), the triarylphosphine oxide 5 is reduced at a rate similar to that of the dialkylarylphosphine oxide 4, because more electron rich alkylsubstituted phosphine oxides are reduced faster than their arylsubstituted counterparts.5b To test our hypothesis, we synthesized the phosphine oxide 7. As depicted in Scheme 3, reduction, hydroboration, and oxidation of commercially available cyclopent-3-ene-1carboxylic acid, followed by bismesylation, produced the dimesylate 8 with 2.8 : 1 trans-to-cis selectivity, in 70% yield over two steps. A 2.4 : 1 mixture of the exo- and endo-P-phenylphosphine oxides 7 (dP ¼ 55.8) and 70 (dP ¼ 57.4) was obtained in 68% isolated yield aer bisalkylation with dilithium phenylphosphide and subsequ (...truncated)