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Diastereoselective addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones

Nature Chemistry volume 7, pages 10241027 (2015) | Download Citation

Abstract

The α-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. Here we describe how an umpolung strategy that involves the addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones—directed by the alkoxide of the 1-azo-3-alkoxy propenes formed in situ via base-induced ring opening of the epoxide—leads to the syn-selective production of α-alkyl-β-hydroxy N-sulfonyl hydrazones with α-quaternary centres. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary and tertiary alkyl, as well as alkenyl, aryl, allenyl and alkynyl groups. Subsequent hydrolysis of the β-hydroxy N-sulfonyl hydrazone products produces the corresponding β-hydroxy ketones. In addition to hydrolysis, the hydrazone products are poised to undergo numerous different known synthetic transformations via well-established chemistry, which would provide access to a wide array of useful structures.

  • Compound C14H18N2O3S

    4-methyl-N'-((1R,6S,E)-1-methyl-7-oxabicyclo[4.1.0]heptan-2-ylidene)benzenesulfonohydrazide

  • Compound C16H22N2O3S

    N'-((2R,3S)-3-hydroxy-2-methyl-2-vinylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C16H22N2O3S

    N'-((2S,3S,E)-3-hydroxy-2-methyl-2-vinylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C13H16N2O3S

    4-methyl-N'-((1R,5S,E)-1-methyl-6-oxabicyclo[3.1.0]hexan-2-ylidene)benzenesulfonohydrazide

  • Compound C16H24N2O3S

    N'-((2R,3S,E)-2-ethyl-3-hydroxy-2-methylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C18H26N2O3S

    N'-((2R,3S,E)-2-(but-3-en-1-yl)-3-hydroxy-2-methylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H26N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-isopropyl-2-methylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H24N2O3S

    N'-((2R,3S,E)-2-cyclopropyl-3-hydroxy-2-methylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H24N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-(prop-1-en-2-yl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C20H24N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-phenylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C21H26N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-(p-tolyl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H22N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-(prop-1-yn-1-yl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C15H22N2O3S

    N'-((2R,3S,E)-2-ethyl-3-hydroxy-2-methylcyclopentylidene)-4-methylbenzenesulfonohydrazide

  • Compound C16H24N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-isopropyl-2-methylcyclopentylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H26N2O3S

    N'-((2R,3S,E)-2-(tert-butyl)-3-hydroxy-2-methylcyclopentylidene)-4-methylbenzenesulfonohydrazide

  • Compound C15H20N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-vinylcyclopentylidene)-4-methylbenzenesulfonohydrazide

  • Compound C19H22N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-phenylcyclopentylidene)-4-methylbenzenesulfonohydrazide

  • Compound C16H20N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-methyl-2-(prop-1-yn-1-yl)cyclopentylidene)-4-methylbenzenesulfonohydrazide

  • Compound C13H16N2O3S

    (E)-N'-(7-oxabicyclo[4.1.0]heptan-2-ylidene)-4-methylbenzenesulfonohydrazide

  • Compound C14H18N2O3S

    (E)-4-methyl-N'-(6-methyl-7-oxabicyclo[4.1.0]heptan-2-ylidene)benzenesulfonohydrazide

  • Compound C15H22N2O3S

    N'-((2R,3S,E)-2-ethyl-3-hydroxycyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C16H24N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-isopropylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C15H20N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-vinylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C19H22N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-phenylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C16H20N2O3S

    N'-((2R,3S,E)-3-hydroxy-2-(prop-1-yn-1-yl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C16H22N2O3S

    N'-((2R,3S,E)-3-hydroxy-3-methyl-2-vinylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H24N2O3S

    N'-((2R,3S,E)-3-hydroxy-3-methyl-2-(prop-1-en-2-yl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C20H24N2O3S

    N'-((2R,3S,E)-3-hydroxy-3-methyl-2-phenylcyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H22N2O3S

    N'-((2R,3S,E)-3-hydroxy-3-methyl-2-(prop-1-yn-1-yl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H22N2O3S

    N'-((2R,3S,E)-3-hydroxy-3-methyl-2-(propa-1,2-dien-1-yl)cyclohexylidene)-4-methylbenzenesulfonohydrazide

  • Compound C17H21BrMgN2O3S

    magnesium (1S,E)-1-methyl-2-(propa-1,2-dien-1-yl)-3-(2-tosylhydrazono)cyclohexan-1-olate bromide

  • Compound C9H14O2

    (2S,3S)-3-hydroxy-2-methyl-2-vinylcyclohexan-1-one

  • Compound C9H16O2

    (2S,3S)-2-ethyl-3-hydroxy-2-methylcyclohexan-1-one

  • Compound C8H14O2

    (2S,3S)-2-ethyl-3-hydroxycyclohexan-1-one

  • Compound C12H14O2

    (2S,3S)-3-hydroxy-2-phenylcyclohexan-1-one

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References

  1. 1.

    in Modern Synthetic Methods Vol. 6 (ed. Scheffold, R.) 1–102 (Helvetica Chimica Acta, 1992).

  2. 2.

    & Stoichiometric Asymmetric Synthesis (Sheffield Academic Press, 2000).

  3. 3.

    & in Comprehensive Organic Synthesis Vol. 2 (eds Trost, B. M. & Fleming, I.) 99–131 (Pergamon Press, 1991).

  4. 4.

    in Asymmetric Synthesis Vol. 3 (ed. Morrison, J. D.) 1–110 (Academic Press, 1984).

  5. 5.

    & The asymmetric alkylation of dimethylhydrazones; intermolecular chirality transfer using sparteine as chiral ligand. Chem. Commun. 50, 14817–14819 (2014).

  6. 6.

    & Regioselective asymmetric α,α-bisalkylation of ketones via complex-induced syn-deprotonation of chiral N-amino cyclic carbamate hydrazones. J. Am. Chem. Soc. 133, 8741–8720 (2011).

  7. 7.

    & Origins of stereoselectivity in the α-alkylation of chiral hydrazones. J. Org. Chem. 75, 8578–8584 (2010).

  8. 8.

    & Simple and efficient asymmetric α-alkylation and α,α-bisalkylation of acyclic ketones by using chiral N-amino cyclic carbamate hydrazones. Angew. Chem. Int. Ed. 47, 5207–5210 (2008).

  9. 9.

    & Asymmetric syntheses via metalated chiral hydrazones: overall enantioselective α-alkylation of acyclic ketones. Tetrahedron 40, 1345–1359 (1984).

  10. 10.

    Asymmetric Synthesis 1st edn, Vol. 3 (ed. Morrison, J. D.) 275–339 (Academic Press, 1984).

  11. 11.

    & The SAMP-/RAMP-hydrazone methodology in asymmetric synthesis. Tetrahedron 58, 2253–2329 (2002).

  12. 12.

    & Enantioselective alkylation of cyclohexanone via chiral lithio-chelated enamines. J. Am. Chem. Soc. 98, 3032–3033 (1976).

  13. 13.

    & Asymmetric alkylation of acyclic ketones via chiral metallo enamines. effect of kinetic vs. thermodynamic metalations. J. Org. Chem. 43, 3245–3247 (1978).

  14. 14.

    & Enantioselective alkylation of ketones via chiral, nonracemic lithioenamines. An asymmetric synthesis of α-alkyl and α,α′-dialkyl cyclic ketones. J. Am. Chem. Soc. 103, 3081–3087 (1981).

  15. 15.

    & Asymmetric synthesis of α-alkylated cyclic ketones via chiral chelated lithioenamines. Tetrahedron Lett. 573–576 (1978).

  16. 16.

    & Stereoselective reactions 3. Highly efficient method for the asymmetric synthesis of 2-alkylcycloalkanones via chiral chelated lithioenamines. Chem. Pharm. Bull. 27, 2760–2766 (1979).

  17. 17.

    & Enantioselective 1,4-addition of aliphatic Grignard reagents to enones catalyzed by readily available copper(I) thiolates derived from TADDOL. Preliminary communication. Helv. Chim. Acta 80, 2515–2519 (1997).

  18. 18.

    in Handbook of Grignard Reagents (eds Silverman, G. S. & Rakita, P. E.) 9–21 (Marcel Dekker, Inc., 1996).

  19. 19.

    & The catalytic enantioselective construction of molecules with quaternary carbon stereocenters. Angew. Chem. Int. Ed. 37, 388–401 (1998).

  20. 20.

    & Carbonyl regeneration from p-toluenesulfonylhydrazones (tosylhydrazones). Synthesis 456–457 (1976).

  21. 21.

    & Recent applications of the Shapiro reaction. Acc. Chem. Res. 16, 55–59 (1983).

  22. 22.

    & Star-shaped D-π-A conjugated molecules: synthesis and broad absorption bands. Org. Lett. 11, 4732–4735 (2009).

  23. 23.

    & Metal-free carbon–carbon bond-forming reductive coupling between boronic acids and tosylhydrazones. Nature Chem. 1, 494–499 (2009).

  24. 24.

    et al. Cultivating the passion to build heterocycles from 1,2-diaza-1,3-dienes: the force of imagination. Eur. J. Org. Chem. 3109–3127 (2009).

  25. 25.

    & Working twenty years on conjugated azo-alkenes (and environs) to find new entries in organic synthesis. Synlett 1128–1140 (1997).

  26. 26.

    & Catalytic asymmetric addition of thiols to nitrosoalkenes leading to chiral non-racemic α-sulfenyl ketones. Org. Lett. 13, 3810–3813 (2011).

  27. 27.

    & Copper(I)-catalyzed addition of Grignard reagents to in situ-derived N-sulfonyl azoalkenes: an umpolung alkylation procedure applicable to the formation of up to three contiguous quaternary centers. J. Am. Chem. Soc. 132, 4546–4547 (2010).

  28. 28.

    & New fragmentation reaction of α,β-unsaturated carbonyls. Synthesis of exaltone and rac-muscane from cyclododecanone. Helv. Chim. Acta 50, 708–713 (1967).

  29. 29.

    & Novel fragmentation reaction of α,β-epoxyketones. Synthesis of acetylenic ketones. Tetrahedron Lett. 3943–3946 (1967).

  30. 30.

    & in Comprehensive Organic Synthesis Vol. 6 (eds Trost, B. M. & Fleming, I.) 1041–1070 (Pergamon Press, 1991).

  31. 31.

    & in Comprehensive Organic Synthesis 2nd edn, Vol. 6 (eds Molander, G. & Knochel, P.) 842–860 (Elsevier, 2014).

  32. 32.

    α-Arylation of α,β-unsaturated ketones: utilization of the α-epoxytosylhydrazone functional group as a D2-enonium synthon. J. Org. Chem. 41, 2935–2937 (1976).

  33. 33.

    & A novel α-alkylation of α,β-epoxy ketones. Tetrahedron Lett. 16, 3117–3120 (1975).

  34. 34.

    & α-Alkylation and arylation of α,β-unsaturated ketones. J. Org. Chem. 41, 2937–2139 (1976).

  35. 35.

    & . Enantioselective total synthesis of epothilone A using multifunctional asymmetric catalyses. Angew. Chem. Int. Ed. 39, 209–213 (2000).

  36. 36.

    . in Handbook of Grignard Reagents (eds Silverman, G. S. & Rakita, P. E.) 441–453 (Marcel Dekker 1996).

  37. 37.

    & Beyond thermodynamic acidity: a perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions. Angew. Chem. Int. Ed. 43, 2206–2225 (2004).

  38. 38.

    & Evolving organic synthesis fostered by the pluripotent phenylsulfone moiety. Chem. Rev. 109, 2315–2349 (2009).

  39. 39.

    & Catalytic asymmetric epoxidation of α,β-unsaturated ketones promoted by lanthanoid complexes. J. Am. Chem. Soc. 119, 2329–2330 (1997).

  40. 40.

    et al. Water vs. desiccant. Improvement of Yb-BINOL complex catalyzed enantioselective epoxidation of enones. Tetrahedron Lett. 39, 7353–7356 (1998).

  41. 41.

    & The first catalytic enantioselective synthesis of cis-epoxyketones from cis-enones. J. Org. Chem. 63, 8090–8091 (1998).

  42. 42.

    & Remarkable ligand effect on the enantioselectivity of the chiral lanthanum complex-catalyzed asymmetric epoxidation of enones. Tetrahedron Lett. 39, 7321–7322 (1998).

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Acknowledgements

We are grateful to J. M. Hatcher for conducting the preliminary experiments related to this work. We also thank J. Korp (University of Houston) for the X-ray structure determination and the National Sciences Foundation (NSF 1012287) and Welch Foundation (E-0806) for support.

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  1. Department of Chemistry, University of Houston, Houston, Texas 77204, USA

    • Maulen M. Uteuliyev
    • , Thien T. Nguyen
    •  & Don M. Coltart

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Contributions

All authors conceived and designed the experiments and analysed the data. M.M.U. and T.T.N. performed the experiments. D.M.C. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Don M. Coltart.

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https://doi.org/10.1038/nchem.2364