Boronic Acids and Esters in the Petasis-Borono Mannich Multicomponent Reaction

1. Boronic Acids and Esters in the Petasis-Borono Mannich MulticomponentReaction Wu Hua 2010-9-25

2. B.S., 1978, Aristotelian University of Thessaloniki, GreecePh.D., 1983, University of Pennsylvania Research: • New chemistry of organotitanium compounds • New chemistry of organoboron compounds • New Synthetic Methods and Strategies • Lipoxins and other Lipids

3. Mechanism of the Mannich Reaction :

4. Major advantage of this MCR: a.Immense potential scaffold variability. b.Large variety of organoboronic acids are readily available. c.Most of these compounds are also air- and water-stable as well as low-toxic and environmentally friendly . d.boronic acids also tolerate many functional groups, thereby allowing the facile synthesis of multifunctional molecules without the excessive use of protecting groups.

5. Reaction of vinyl boronic acids with the adducts of secondary amines and paraformaldehyde gives tertiary allylamines. This simple and practical method was used for the synthesis of geometrically pure naftifine, a potent antifungal agent. This 3-CR (3-component reaction) can also been described as a boronic acid Mannich variant. N. A. Petasis, I. Akritopoulou, Tetrahedron Lett.1993, 34, 583.

6. General Mechanism:

7. a. A complete study of three different aldehydes demonstrated the following order of reactivity: glycolaldehyde > glyoxylic acid > salicylaldehyde. b. Regarding the nature of the boronic acids employed in the reaction, vinyl boronic acids are in general more reactive than their aryl counterparts.

8. A new, general, and practical method forthe synthesis of β,γ-unsaturated α-amino acids. Nicos A. Petasis. J. Am. Chem. Soc. 1997, 119, 445-446

9. Koolmeister, Scobie, M. Tetrahedron Lett. 2002, 43, 5965.

10. Jourdan, Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027.

11. Analogously to the condensation with phenyl boronic acid derivatives, heteroaryl amino acids were also obtained in good yields from heteroaryl boronic acids. More reactive than their aryl counterparts. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.

12. (a) microwave irradiation, 120 C, 10 min, DCM; (b)TMS–diazomethane, THF, rt, 3 h. (a) microwave irradiation, 120 C, 10 min, DCM Electron-poor (hetero-)anilines often gave unsatisfactory yields and conversions. However, Sanofi-Aventis chemists could show that even these problematic cases can be easily mastered under microwave conditions. N. J. McLean. Tetrahedron Letters,2004, 45, 993–995

13. The presence of a substituent in the nitrogen atom of the indole ring was observed to be crucial to success of the reaction. In the absence of such a substituent, low yields of the corresponding product were obtained. Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762.

14. Salicylaldehyde and Derivatives N. A. Petasis, Tetrahedron Letters, 42 (2001) 539–542

15. Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.

16. Water as the solvent Pedro M. P. Gois.Eur. J. Org. Chem. 2009, 1859–1863

17. Stas, S.; Tehrani, K. A. Tetrahedron 2007, 63, 8921.

18. Aza-cope rearragement Stas, S.; Abbaspour Tehrani, K.; Laus, G. Tetrahedron 2008, 64, 3457.

19. Asymmetric Petasis-Borono Mannich Reaction Petasis reaction has been tested for this proposal in three different approaches. • The first comprises the use of a stereogenic carbon in the amine that can induce some regioselectivity on the formation of the new carbon-nitrogen bond. • Enantiopure or enantioenriched boronic ester, resulting in the formation of an enantiomerically pure side product. • c. A more elegant process is the use of a chiral ligand that can complex • with the boronic ester.

20. The first report in the asymmetric version of this reaction was made by Petasis, using an enantiomerically pure aminewith two different boronic acids. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.

21. N-tosyl-3-indolylboronic acid reacted with glyoxylic acid using chiral methylbenzylamine as the chiral auxiliary and the secondary amines were obtained exclusively as one diastereoisomer in reasonable yields Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545.

22. Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.

23. The best enantioselectivities were reported by Takemoto and co-workers in the addition of boronic acids to N-acylated quinoline salts. Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.

25. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

27. Application

28. A new class of compounds for HIV therapy.

29. Summary a. Typically Pt-3CR works satisfactorily with secondary or hindered primary amines, hydrazines and anilines in solvents such as DCM at room temperature. Alkenyl, electron-rich and electron-neutral (hetero-)aryl boronic acids can be employed. b. The use of secondary amines is desirable when compared to primary ones, since the latter usually results in low yields because of the lower reactivity of the imine compared to the iminium formed from the former. c. As a result of this exquisite reactivity, the Petasis reaction (Scheme 1) has become an attractive method for the preparation of an assortment of compounds, among which amino acids, heterocycles and alkylaminophenols are the most easily accessible.

30. Problem a. Regarding the asymmetric version, no suitable chiral catalyst has been developed for the general reaction. b. One other aspect that seems to be prominent is the discovery of substitutes for each component of the reaction, particularly the discovery of new suitable aldehydes without the need of a hydroxyl group for the boron activation.