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Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model

Nature Chemistry volume 5, pages 54–60 (2013)Cite this article

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Abstract

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle.

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Figure 1: Pyridine-containing drugs, pyridyne isomers and previous examples of pyridynes.
Figure 2: Design of 3,4-pyridynes with controllable regioselectivity.
Figure 3: Synthesis of silyltriflates 20, 22 and 25.
Figure 4: Competition between steric interactions and electronic effects in transition states for nitrone cycloadditions.
Figure 5: Derivatization of adducts 26 and 30.

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References

  1. Pozharskii, A. F., Soldatenkov, A. & Katritzky, A. R. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry, and Applications 2nd edn (Wiley, 2011).

    Book  Google Scholar 

  2. Joule, J. A. & Mills, K. Heterocyclic Chemistry 5th edn (Wiley, 2010).

    Google Scholar 

  3. Colby, D. A., Bergman, R. G. & Ellman, J. A. Synthesis of dihydropyridines and pyridines from imines and alkynes via C–H activation. J. Am. Chem. Soc. 130, 3645–3651 (2008).

    Article  CAS  Google Scholar 

  4. Fischer, D. F. & Sarpong, R. Total synthesis of (+)-complanadine A using an iridium-catalyzed pyridine C–H functionalization. J. Am. Chem. Soc. 132, 5926–5927 (2010).

    Article  CAS  Google Scholar 

  5. Seiple, I. B. et al. Direct C–H arylation of electron-deficient heterocycles with arylboronic acids. J. Am. Chem. Soc. 132, 13194–13196 (2010).

    Article  CAS  Google Scholar 

  6. Ye, M. et al. Ligand-promoted C3-selective arylation of pyridines with Pd catalysts: gram-scale synthesis of (±)-preclamol. J. Am. Chem. Soc. 133, 19090–19093 (2011).

    Article  CAS  Google Scholar 

  7. Levine, R. & Leake, W. W. Rearrangement in the reaction of 3-bromopyridine with sodium amide and sodioacetophenone. Science 121, 780 (1955).

    Article  CAS  Google Scholar 

  8. Zoltewicz, J. A. & Nisi, C. Trapping of 3,4-pyridyne by thiomethoxide ion in ammonia. J. Org. Chem. 34, 765–766 (1969).

    Article  CAS  Google Scholar 

  9. May, C. & Moody, C. J. A concise synthesis of the antitumor alkaloid ellipticine. J. Chem. Soc. Chem. Commun. 926–927 (1984).

  10. Gribble, G. W., Saulnier, M. G., Sibi, M. P. & Obaza-Nutaitis, J. A. Synthesis and Diels–Alder reactions of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole. A new annulation strategy for the construction of ellipticine and isoellipticine. J. Org. Chem. 49, 4518–4523 (1984).

    Article  CAS  Google Scholar 

  11. May, C. & Moody, C. J. A new precursor to 3,4-didehydropyridine, and its use in the synthesis of the antitumor alkaloid ellipticine. J. Chem. Soc. Perkin Trans. 1 247–250 (1988).

  12. Díaz, M. T., Cobas, A., Guitián, E. & Castedo, L. Polar control of the regioselectivity of hetaryne cycloadditions. Synthesis of ellipticine. Synlett 157–158 (1998).

  13. Díaz, M. T., Cobas, A., Guitián, E. & Castedo, L. Synthesis of ellipticine by hetaryne cycloadditions – control of regioselectivity. Eur. J. Org. Chem. 4543–4549 (2001).

  14. Enamorado, M. F., Ondachi, P. W. & Comins, D. L. A five-step synthesis of (S)-macrostomine from (S)-nicotine. Org. Lett. 12, 4513–4515 (2010).

    Article  CAS  Google Scholar 

  15. Nam, H-H. & Leroi, G. E. First direct observation of pyridyne: matrix infrared study of the photolysis products of 3,4-pyridinedicarboxylic anhydride. J. Am. Chem. Soc. 110, 4096–4097 (1988).

    Article  CAS  Google Scholar 

  16. Jamart-Grégoire, B., Leger, C. & Caubère, P. New applications of complex bases: nucleophilic condensations of pyridyne. Tetrahedron Lett. 131, 7599–7602 (1990).

    Article  Google Scholar 

  17. Sha, C-K. & Yang, J-F. Total syntheses of ellipticine alkaloids and their amino analogues. Tetrahedron 48, 10645–10654 (1992).

    Article  CAS  Google Scholar 

  18. Tsukazaki, M. & Snieckus, V. Synthetic connections to the directed ortho metalation reaction. 3,4-Pyridynes from 4-trialkylsilyl-3-pyridyl triflates. Heterocycles 33, 533–536 (1992).

    Article  CAS  Google Scholar 

  19. Vinter-Pasquier, K., Jamart-Grégoire, B. & Caubère, P. Complex base-induced generation of 3,4-didehydropyridine derivatives: new access to aminopyridines or pyridones. Heterocycles 45, 2113–2129 (1997).

    Article  CAS  Google Scholar 

  20. Walters, M. A. & Shay, J. J. 2,3-Pyridyne formation by fluoride-induced desilylation-elimination. Synth. Commun. 27, 3573–3579 (1997).

    Article  CAS  Google Scholar 

  21. Carroll, F. I. et al. Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine. J. Med. Chem. 50, 6383–6391 (2007).

    Article  CAS  Google Scholar 

  22. Lin, W., Chen, L. & Knochel, P. Preparation of functionalized 3,4-pyridynes via 2-magnesiated diaryl sulfonates. Tetrahedron 63, 2787–2797 (2007).

    Article  CAS  Google Scholar 

  23. Jiang, L., Yu, X., Fang, B. & Wu, J. Silver triflate-catalyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with pyridyne. Org. Biomol. Chem. 10, 8102–8107 (2012).

    Article  CAS  Google Scholar 

  24. Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).

    Article  CAS  Google Scholar 

  25. Reinecke, M. G. Hetarynes. Tetrahedron 38, 427–498 (1982).

    Article  CAS  Google Scholar 

  26. Cheong, P. H-Y. et al. Indolyne and aryne distortions and nucleophilic regioselectivities. J. Am. Chem. Soc. 132, 1267–1269 (2010).

    Article  CAS  Google Scholar 

  27. Im, G-Y. J. et al. Indolyne experimental and computational studies: synthetic applications and origins of selectivities of nucleophilic additions. J. Am. Chem. Soc. 132, 17933–17944 (2010).

    Article  CAS  Google Scholar 

  28. Goetz, A. E. et al. An efficient computational model to predict the synthetic utility of heterocyclic arynes. Angew. Chem. Int. Ed. 51, 2758–2762 (2012).

    Article  CAS  Google Scholar 

  29. Spartan 06 (Wavefunction Inc., Irvine, California, 2006).

  30. Bronner, S. M., Goetz, A. E. & Garg, N. K. Overturning indolyne regioselectivities and synthesis of indolactam V. J. Am. Chem. Soc. 133, 3832–3835 (2011).

    Article  CAS  Google Scholar 

  31. Rau, N. J. & Wenthold, P. G. Experimental investigation of the absolute enthalpies of formation of 2,3-, 2,4-, and 3,4-pyridynes. J. Phys. Chem. A 115, 10353–10362 (2011).

    Article  CAS  Google Scholar 

  32. Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions Chem. Lett. 12, 1211–1214 (1983).

    Article  Google Scholar 

  33. Rosen, B. M. et al. Nickel-catalyzed cross-couplings involving carbon–oxygen bonds. Chem. Rev. 111, 1346–1416 (2011).

    Article  CAS  Google Scholar 

  34. Quintana, I., Boersma, A. J., Peña, D., Pérez, D., & Guitián, E. Metal-catalyzed cotrimerization of arynes and alkenes. Org. Lett. 8, 3347–3349 (2006).

    Article  CAS  Google Scholar 

  35. Gerfaud, T., Neuville, L. & Zhu, J. Palladium-catalyzed annulation of acyloximes with arynes (or alkynes): synthesis of phenanthridines and isoquinolines. Angew. Chem. Int. Ed. 48, 572–577 (2009).

    Article  CAS  Google Scholar 

  36. Yoshida, H., Shirakawa, E., Honda, Y. & Hiyama, T. Addition of ureas to arynes: straightforward synthesis of benzodiazepine and benzodiazocine derivatives. Angew. Chem. Int. Ed. 41, 3247–3249 (2002).

    Article  CAS  Google Scholar 

  37. Yoshida, H., Fukushima, H., Ohshita, J. & Kunai, A. Arynes in a three-component coupling reaction: straightforward synthesis of benzoannulated iminofurans. Angew. Chem. Int. Ed. 43, 3935–3938 (2004).

    Article  CAS  Google Scholar 

  38. Toledo, F. T., Comasseto, J. V. & Raminelli, C. Selenostannylation of arynes produced by silylaryl triflates under mild reaction conditions. J. Braz. Chem. Soc. 21, 2164–2168 (2010).

    Article  CAS  Google Scholar 

  39. Effenberger, F. & Daub, W. Darstellung von didehydropyridinen aus (trimethylsilyl)pyridinen. Chem. Ber. 124, 2119–2125 (1991).

    Article  CAS  Google Scholar 

  40. Vorbrüggen, H. & Krolikiewicz, K. Silylation-amination of hydroxy N-heterocycles. Chem. Ber. 117, 1523–1541 (1984).

    Article  Google Scholar 

  41. Kaye, H. & Chang, S-H. N-Vinylation of heteroaromatic O-trimethylsilyl lactims. Tetrahedron 26, 1369–1376 (1970).

    Article  CAS  Google Scholar 

  42. Liu, Z. & Larock, R. C. Facile N-arylation of amines and sulfonamides and O-arylation of phenols and arenecarboxylic acids. J. Org. Chem. 71, 3198–3209 (2006).

    Article  CAS  Google Scholar 

  43. Matsumoto, T., Sohma, T., Hatazaki, S. & Suzuki, K. On the regiochemistry of cycloaddition of unsymmetrical aryne with nitrone. Remarkable effect of trialkylsilyl substituent. Synlett 843–846 (1993).

  44. Dai, M., Wang, Z. & Danishefsky, S. J. A novel α,β-unsaturated nitrone-aryne [3+2] cycloaddition and its application in the synthesis of the cortistatin core. Tetrahedron Lett. 49, 6613–6616 (2008).

    Article  CAS  Google Scholar 

  45. Hadjipavlou–Litina, D. & Hansch, C. Quantitative structure–activity relationships of the benzodiazepines. A review and reevaluation. Chem. Rev. 94, 1483–1505 (1994).

    Article  Google Scholar 

  46. Ramgren, S. D., Silberstein, A. L., Yang, Y. & Garg, N. K. Nickel-catalyzed amination of aryl sulfamates. Angew. Chem. Int. Ed. 50, 2171–2173 (2011).

    Article  CAS  Google Scholar 

  47. Macklin, T. K. & Snieckus, V. Directed ortho-metalation methodology. The N,N-dialkyl aryl O-sulfamate as a new directed metalation group and cross-coupling partner for Grignard reagents. Org. Lett. 7, 2519–2522 (2005).

    Article  CAS  Google Scholar 

  48. Sergeev, A. G. & Hartwig, J. F. Selective, nickel-catalyzed hydrogenolysis of aryl ethers. Science 332, 439–443 (2011).

    Article  CAS  Google Scholar 

  49. Mesganaw, T., Fine Nathel, N. F. & Garg, N. K. Cine substitution of arenes using the aryl carbamate as a removable directing group. Org. Lett. 14, 2918–2921 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Boehringer Ingelheim, DuPont, Eli Lilly, Amgen, AstraZeneca, Roche, the A. P. Sloan Foundation, the University of California, Los Angeles, the ACS Division of Organic Chemistry (fellowship to A.E.G.) and the Foote Family (fellowship to A.E.G.) for financial support. Jordan Cisneros (University of California, Los Angeles) is acknowledged for experimental assistance and thanks Pfizer for financial support. These studies were supported by shared instrumentation grants from the National Science Foundation (CHE-1048804) and the National Center for Research Resources (S10RR025631).

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  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, 90095, California, USA

    Adam E. Goetz & Neil K. Garg

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A.E.G. planned and carried out the experimental work. A.E.G. and N.K.G. conceived the project, co-wrote the manuscript and commented on the manuscript.

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Correspondence to Neil K. Garg.

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Goetz, A., Garg, N. Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model. Nature Chem 5, 54–60 (2013). https://doi.org/10.1038/nchem.1504

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