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

2. Neil Garg 2000 - B. S. Chem. at New York University
Ph.D. at Caltech (Pr. Brian Stoltz)
N.I.H. postdoctoral fellow at University of California (Ir. - Pr. Larry Overman)
Assistant Professor at U.C.L.A .
Associate Professor at U.C.L.A.
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

3. Garg’s 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

7. Aryne chemistry Roberts 1953
14C labeling experiment : proof of a symmetrical intermediate

8. Aryne chemistry Wittig and Levine 1955
First trapping of the benzyne intermediate
First postulation of Pyridyne

9. Aryne chemistry Kauffmann 1962
First trapping of the pyridyne intermediate

10. 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.

11. Benzyne preparation Kobayashi, Chem. Lett.1983, 1211. Kobayashi
Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.

12. Aryne distortion model
P character
Less elctronegative = more stabilize hybridisation : More p character = LUMO lower
Guitiàn. Synlett 1998, 157.
Angew. Chem. Int. Ed. 2010, 49,
 J. Am. Chem. Soc. 2010, 132,

13. Aryne distortion model
Prediction trick
Addition places negative charge close to electron withdrawing group
We have an urly T.S. so this tric is not the reality (would work for a late T.S.)
Guitiàn. Synlett 1998, 157.
Angew. Chem. Int. Ed. 2010, 49,
 J. Am. Chem. Soc. 2010, 132,

14. 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

15. 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.

16. Previous regioselective inductions
3,4 –pyridyne from Kobayashi’s precursor
Tsukazaki, M.; Snieckus, V. Heterocycles 1992, 33, 533.
Diaz,M. T.; Cobas, A.; Guitian, E.; Castedo, L. Synlett 1998, 157.

17. Garg’s predicted Effect of substituents
DFT calculations

18. Regioselectivity studies

19. Regioselectivity studies
Distortion model vs steric hindrance

20. Regioselectivity studies

21. Regioselectivity studies
Yoshihiro Sato

22. Derivatizations of pyridyne adducts
Reductive cleavage
SIPr-HCl : 1,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride / TMDSO : Tetramethyldisiloxane
First example of a reductive sulfamate cleavage

23. Derivatizations of pyridyne adducts
Using synthetic handles
Suzuki–Miyaura coupling / Buchwald–Hartwig amination / Ni Kumada–Corriu coupling / Ni Sulfamate amination

24. 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

25. Back-up
Benzyne
* Tokiwa, H.; Akai, s. et al. J. Org. Chem. 2013, 78, 2965.

26. Back-up precursor synthesis
Grignard: halogen exchange ? -> was done in a separate vial

27. Back-up
Comparison between a C5 Bromide and Chloride

28. Back-up
predicted Effect of substituents

29. 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.