Abstract
Nucleophilic addition reactions of organometallic reagents to carbonyl compounds for carbon–carbon bond construction have played a pivotal role in modern chemistry. However, this reaction's reliance on petroleum-derived chemical feedstocks and a stoichiometric quantity of metal have prompted the development of many carbanion equivalents and catalytic metal alternatives. Here, we show that naturally occurring carbonyls can be used as latent alkyl carbanion equivalents for additions to carbonyl compounds, via reductive polarity reversal. Such ‘umpolung’ reactivity is facilitated by a ruthenium catalyst and diphosphine ligand under mild conditions, delivering synthetically valuable secondary and tertiary alcohols in up to 98% yield. The unique chemoselectivity exhibited by carbonyl-derived carbanion equivalents is demonstrated by their tolerance to protic reaction media and good functional group compatibility. Enantioenriched tertiary alcohols can also be accessed with the aid of chiral ligands, albeit with moderate stereocontrol. Such carbonyl-derived carbanion equivalents are anticipated to find broad utility in chemical bond formation.
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Change history
16 December 2016
In the version of this Article originally published, Z. Hearne was not acknowledged for proofreading the text. This has been corrected in all versions of the Article.
30 May 2017
In this Article we described a ruthenium-catalysed carbonyl addition method for alcohol production via simple unsubstituted hydrazone intermediates, but we inadvertently omitted the citation of two papers that had previously reported a similar carbanion reactivity1,2. In these papers, the authors illustrated a series of substituted hindered hydrazones (for example, tert-butyl-, trityl- and diphenyl-4-pyridylmethyl) for additions to carbonyl compounds; however, to yield the target alcohols under these circumstances, the lithium salts of these hydrazones had to be pre-formed, with subsequent C–C bond formation and removal of bulky substituents on azo-intermediates via radical decomposition. References 1. Baldwin, J. E. et al. Azo anions in synthesis: use of trityl- and diphenyl-4-pyridylmethylhydrazones for reductive C–C bond formation. Tetrahedron 42, 4235–4246 (1986). 2. Baldwin, J. E., Bottaro, J. C., Kolhe, J. N. & Adlington, R. M. Azo anions in synthesis. Use of trityl- and diphenyl-4-pyridylmethyl-hydrazones for reductive C–C bond formation from aldehydes and ketones. J. Chem. Soc. Chem. Commun. 22–23 (1984).
References
Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1989).
Noyori, R. & Kitamura, M. Enantioselective addition of organometallic reagents to carbonyl compounds: chirality transfer, multiplication, and amplification. Angew. Chem. Int. Ed. 30, 49−69 (1991).
Kobayashi, S. et al.. in Comprehensive Organometallic Chemistry III (eds Crabtree, R. H. & Mingos, D. M. P.) 403−491 (Elsevier, 2007).
Stowell, J. C. Carbanion Equivalents in Organic Synthesis (Wiley, 1979).
Kharasch, M. S. & Reinmuth, O. Grignard Reactions of Nonmetallic Substances (Prentice-Hall, 1954).
Wakefield, B. J. Organomagnesium Methods in Organic Chemistry (Academic, 1995).
Silverman, G. S. & Rakita, P. E. Handbook of Grignard Reagents (CRC, 1996).
Knochel, P. et al. Highly functionalized organomagnesium reagents prepared through halogen–metal exchange. Angew. Chem. Int. Ed. 42, 4302−4320 (2003).
Negishi, E.-i. Organometallics in Organic Synthesis (Wiley, 1980).
Pu, L. & Yu, H.-B. Catalytic asymmetric organozinc additions to carbonyl compounds. Chem. Rev. 101, 757−824 (2001).
Ashby, E. C. & Laemmle, J. T. Stereochemistry of organometallic compound addition to ketones. Chem. Rev. 75, 521−546 (1975).
Shibasaki, M. & Kanai, M. Asymmetric synthesis of tertiary alcohols and α-tertiary amines via Cu-catalyzed C−C bond formation to ketones and ketimines. Chem. Rev. 108, 2853−2873 (2008).
Duthaler, R. O. & Hafner, A. Chiral titanium complexes for enantioselective addition of nucleophiles to carbonyl groups. Chem. Rev. 108, 807−832 (1992).
Alonso, F., Beletskaya, I. P. & Yus, M. Metal-mediated reductive hydrodehalogenation of organic halides. Chem. Rev. 102, 4009−4092 (2002).
Jang, H.-Y. & Krische, M. J. Catalytic C−C bond formation via capture of hydrogenation intermediates. Acc. Chem. Res. 37, 653−661 (2004).
Skucas, E., Ngai, M. Y., Komanduri, V. & Krische, M. J. Enantiomerically enriched allylic alcohols and allylic amines via C−C bond-forming hydrogenation: asymmetric carbonyl and imine vinylation. Acc. Chem. Res. 40, 1394−1401 (2007).
Meng, F.-K., Haeffner, F. & Hoveyda, A. H. Diastereo- and enantioselective reactions of bis(pinacolato)diboron, 1,3-enynes, and aldehydes catalyzed by an easily accessible bisphosphine–Cu complex. J. Am. Chem. Soc. 136, 11304−11307 (2014).
Meng, F.-K., Jang, H., Jung, B. & Hoveyda, A. H. Cu-catalyzed chemoselective preparation of 2-(pinacolato)boron-substituted allylcopper complexes and their in situ site-, diastereo-, and enantioselective additions to aldehydes and ketones. Angew. Chem. Int. Ed. 52, 5046−5051 (2013).
Chaulagain, M. R., Sormunen, G. J. & Montgomery, J. New N-heterocyclic carbene ligand and its application in asymmetric nickel-catalyzed aldehyde/alkyne reductive couplings. J. Am. Chem. Soc. 129, 9568−9569 (2007).
Jackson, E. P. et al. Mechanistic basis for regioselection and regiodivergence in nickel-catalyzed reductive couplings. Acc. Chem. Res. 48, 1736−1745 (2015).
Miller, K. M., Huang, W.-S. & Jamison, T. F. Catalytic asymmetric reductive coupling of alkynes and aldehydes: enantioselective synthesis of allylic alcohols and α-hydroxy ketones. J. Am. Chem. Soc. 125, 3442−3443 (2003).
Yang, Y., Perry, I. B., Lu, G., Liu, P. & Buchwald, S. L. Copper-catalyzed asymmetric addition of olefin-derived nucleophiles to ketones. Science. 353, 144−150 (2016).
Anastas, P. T. & Warner, J. C. Green Chemistry: Theory and Practice (Oxford Univ. Press, 2000).
Li, C.-J. & Trost, B. M. Green chemistry for chemical synthesis. Proc. Natl Acad. Sci. USA 105, 13197−13202 (2008).
Breslow, R. On the mechanism of thiamine action. IV.1 evidence from studies on model systems. J. Am. Chem. Soc. 80, 3719−3726 (1958).
Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Ed. 18, 239−258 (1979).
Wu, Y., Hu, L., Li, Z. & Deng, L. Catalytic asymmetric umpolung reactions of imines. Nature 523, 445−450 (2015).
Brehme, R., Enders, D., Fernandez, R. & Lassaletta, J. M. Aldehyde N,N-dialkylhydrazones as neutral acyl anion equivalents: umpolung of the imine reactivity. Eur. J. Org. Chem. 2007, 5629−5660 (2007).
Flanigan, D. M., Romanov-Michailidis, F., White, N. A. & Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem. Rev. 115, 9307−9387 (2015).
Bruneau, C. & Dixneuf, P. H. (eds) Ruthenium Catalysts and Fine Chemistry (Springer, 2004).
Dai, X.-J. & Li, C.-J. En route to a practical primary alcohol deoxygenation. J. Am. Chem. Soc. 138, 5433−5440 (2016).
Huang, J.-L., Dai, X.-J. & Li, C.-J. Iridium-catalyzed direct dehydroxylation of alcohols. Eur. J. Org. Chem. 2013, 6496−6500 (2013).
Zimmerman, H. E. & Traxler, M. D. The stereochemistry of the Ivanov and Reformatsky reactions. I. J. Am. Chem. Soc. 79, 1920−1923 (1957).
Wright, S. W., Hageman, D. L. & McClure, L. D. Fluoride-mediated boronic acid coupling reactions. J. Org. Chem. 59, 6095−6097 (1994).
Littke, A. F. & Fu, G. C. The first general method for Stille cross-couplings of aryl chlorides. Angew. Chem. Int. Ed. 38, 2411−2413 (1999).
Burns, T. P. & Rieke, R. D. Highly reactive magnesium and its application to organic syntheses. J. Org. Chem. 52, 3674−3680 (1987).
Krasovskiy, A. & Knochel, P. A LiCl-mediated Br/Mg exchange reaction for the preparation of functionalized aryl- and heteroarylmagnesium compounds from organic bromides. Angew. Chem. Int. Ed. 43, 3333−3336 (2004).
Kitanosono, T., Xu, P. & Kobayashi, S. Heterogeneous versus homogeneous copper(II) catalysis in enantioselective conjugate-addition reactions of boron in water. Chem. Asian. J. 9, 179−188 (2014).
Acknowledgements
The authors acknowledge the Canada Research Chair Foundation (to C.J.L.), the CFI, FQRNT Center for Green Chemistry and Catalysis, NSERC and McGill University for financial support. The authors thank Z. Hearne for proofreading. The authors thank P. Querard and Z. Huang for their donation of compound 6a and chiral (S,S)-DPEN ligand, respectively. X.J.D. thanks the chemistry department for a Heather Munroe-Blum fellowship.
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H.W. and X.-J.D. are co-first authors responsible for this work, regardless of the listed name order. H.W. discovered the reaction. X.-J.D. conceived the concept. X.-J.D. and H.W. designed and performed the experiments, and analysed the data. X.-J.D. and H.W. co-wrote the paper with feedback and guidance from C.-J.L. C.-J.L. directed the project. All authors discussed the experimental results and commented on the manuscript.
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Wang, H., Dai, XJ. & Li, CJ. Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds. Nature Chem 9, 374–378 (2017). https://doi.org/10.1038/nchem.2677
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DOI: https://doi.org/10.1038/nchem.2677
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