Diapositive 1

1
Regioselective reactions of 3,4-pyridynes
enabled by the aryne distortion model February
5th 2014 Patrick Cyr
Adam E. Goetz and Neil K. Garg. Nat. Chem. 2013,
5, 54
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Neil Garg

• 2000 - B. S. Chem. at New York University
• 2000-2005 - Ph.D. at Caltech (Pr. Brian Stoltz)
• 2005-2007 - N.I.H. postdoctoral fellow at
  University of California (Ir. - Pr. Larry
  Overman)
• 2007 - Assistant Professor at U.C.L.A .
• 2012 - Associate Professor at U.C.L.A.
• 2013 - Professor at U.C.L.A.
• Awards UCLA Faculty Career Development Award /
  UCLA Faculty Research Grant NSF CAREER Award /
  Thieme Chemistry Journal Award / Dupont Young
  Professor Award Boehringer Ingelheim New
  Investigator Award .
• 41 publications in 7 years

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Gargs research interest
4
Aryne chemistry
Stoermer Kahlert
1902

• First (possible) suggestion of Aryne

5
Aryne chemistry
Wittig
1942

• First suggestion of Benzyne
• Switterionic intermediate

6
Aryne chemistry
Gilman
1945

• First strong indication for a Benzyne
  intermediate

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Aryne chemistry
Roberts
1953

• 14C labeling experiment proof of a symmetrical
  intermediate

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Aryne chemistry
Wittig and Levine
1955

• First trapping of the benzyne intermediate

• First postulation of Pyridyne

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Aryne chemistry
Kauffmann
1962

• First trapping of the pyridyne intermediate

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Characteristic feature of Arynes

• Electrophilic specie

• Biradical character

• Gampe, C. M. Carreira, E. M. Angew. Chem. Int.
  Ed. 2012, 51, 3766.
• Wenk, H. H. Winkler, M. Sander, W. Angew.
  Chem. Int. Ed. 2003, 42, 502.

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Benzyne preparation
Kobayashi, Chem. Lett.1983, 1211.
Tadross, P. M. Stoltz, B. M. Chem. Rev. 2012,
112, 3550.
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Aryne distortion model
P character

• Guitiàn. Synlett 1998, 157.
• Angew. Chem. Int. Ed. 2010, 49, 9132-9135.
•  J. Am. Chem. Soc. 2010, 132, 1267-1269.

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Aryne distortion model
Prediction trick

• Addition places negative charge close to
  electron withdrawing group

• Guitiàn. Synlett 1998, 157.
• Angew. Chem. Int. Ed. 2010, 49, 9132-9135.
•  J. Am. Chem. Soc. 2010, 132, 1267-1269.

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Hetarynes regioselectivity prediction

• Goetz, A. E. Bronner, S. M. Cisneros, J. D.
  Melamed, J. M. Paton, R. S. Houk, K. N.
  Garg, N. K. Angew. Chem. Int. Ed. 2012, 51, 2758
  2762

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Previous regioselective inductions
3,4 pyridyne from 3-halo

• Mal, D. Senapati, B. K. Pahari, P. Synlett
  2005, No. 6, 994.
• Vinter-Pasquier, K. Jamart-Grégoire, B.
  Caubère, P. Heterocycles 1997, 45, 2113.

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Previous regioselective inductions
3,4 pyridyne from Kobayashis precursor

• Tsukazaki, M. Snieckus, V. Heterocycles 1992,
  33, 533.
• Diaz,M. T. Cobas, A. Guitian, E. Castedo, L.
  Synlett 1998, 157.

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Gargs predicted Effect of substituents

• DFT calculations

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Regioselectivity studies
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Regioselectivity studies
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Regioselectivity studies
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Regioselectivity studies
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Derivatizations of pyridyne adducts
Reductive cleavage

• First example of a reductive sulfamate cleavage

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Derivatizations of pyridyne adducts
Using synthetic handles
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Conclusion

• First general method to control the 3,4-pyridyne
  regioselectivity
• Versatile synthetic handles were used as
  directing groups
• Improvement of the post-transformation of the
  sulfamate moiety needed
• Further validation of the aryne distortion model
  as a predictive tools for the
• regioselectivity on hetaryne
• This work should promote the use of pyridyne in
  total synthesis and
• in pharmaceutical industries

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Back-up
Benzyne
Tokiwa, H. Akai, s. et al. J. Org. Chem. 2013,
78, 2965.
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Back-up
precursor synthesis
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Back-up
Comparison between a C5 Bromide and Chloride
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Back-up
predicted Effect of substituents
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Back-up
3,4 -pyridyne
Tsukazaki, M. Snieckus, V. Heterocycles 1992,
33, 533.
Vinter-Pasquier, K. Jamart-Grégoire, B.
Caubère, P. Heterocycles 1997, 45, 2113.
Diaz,M. T. Cobas, A. Guitian, E. Castedo, L.
Synlett 1998, 157.