1. Petasis-Borono Mannich Reaction (PBM Reaction)
Hua Wu
LSPN Seminar

2. Outline Background and Introduction General Protocols
Reaction Scope and Synthetic Application
Asymmetric Petasis Reaction
Summary

3. Background and Outline
B.S., 1978, Aristotelian University of Thessaloniki, Greece
Ph.D., 1983, University of Pennsylvania
 Research Associate and Adjunct Lecturer,
University of Pennsylvania,  
Working in University of Southern California (USC)
Prof. Nicos A. Petasis
Research Field: New Synthetic Methods and Strategies, organotitanium, organoboron
Petasis-Borono Mannich Reaction (Petasis Reaction)
Petasis-Ferrier Rearrangement Reaction
c. Petasis-Tebbe Olefination
Petasis, N. A. et al. Tetrahedron Lett. 1996, 37, 141.
Cp2TiCl2 + 2 CH3MgCl → Cp2Ti(CH3)2 + 2 MgCl2

4. Background and Introduction
What is the Petasis Reaction ?

5. Backgroud and Introduction
Discovery of Mannich Reaction

6. Backgroud and Introduction
First Example of Petasis Reaction
In 1993, Nicos A. Petasis (USC) described the preparation of tertiary allylic amines from paraformaldehyde, secondary amines,
and vinyl boronic acids under acid-free conditions. Yields ranged from 75-96%.
Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
Reaction of vinyl boronic acids with secondary amines and paraformaldehyde gives tertiary allylamines.
b. This 3-CR (3-component reaction) can also been described as a boronic acid Mannich.

7. Backgroud and Introduction
Mechanism Investigation
The precise mechanism of the first PBM is still disputed:
· Petasis noted that in the absence of acid, it was unlikely that significant amounts of the iminium salt would form.
Also, boronic acids did not readily add to preformed iminium salts, though they did react with diamines. Based on
these observations, Petasis proposed the formation of an intermediate ammonium borate complex followed by
internal delivery of the vinyl nucleophile.

8. General Protocols
However, the vast majority of cases in the literature employ an aldehyde substrate containing a directing group near the carbonyl, indicating a necessity for formation of two-center ionic complex.
Reviews:
Dömling, A. Chem. Rev. 2006, 106,
Multicomponent Reactions. Zhu, J.; Bienaymé, H., eds. Wiley-VCH; Weinheim, 2005.
Orru, R. V. A.; de Greef, M. Synthesis 2003, 10,
Ugi, I. Pure Appl. Chem. 2001, 73,
Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6,
Ugi, I. J. Prakt. Chem. 1997, 339,
Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18,

9. General Protocols Theoretical Study on the Mechanism：DFT Calculation
Highly stereocontrolled as anti-amino alcohols diastereomer.
Tao, J. C. Li, S. H. Chin. J. Chem. 2010, 28, 41

10. Aldehydes Used in Petasis Reaction
a. Order of reactivity: glycolaldehyde > glyoxylic acid > salicylaldehyde.
b. Vinyl boronic acids are in general more reactive than their aryl counterparts.

11. Effect of Esterification
Tetracoordinate boron intermediate is more difficult to form with sterically hindered boronate ester.
Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236.

12. Glyoxylic Acid Synthesis of Vinyl a-Amino Acids
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
The methodology was applied to primary and secondary amines, and bulky amines were also reported to react under these conditions.

13. Glyoxylic Acid Synthesis of Enantiopure a-Amino Acids
The Petasis reaction exhibits high degrees of stereocontrol when a chiral amine or aldehyde is used as a substrate. When certain chiral amines, such as (S)-2-phenylglycinol, are mixed with an α-keto acid and vinyl boronic acid at room temperature, the corresponding allylamine is formed as a single diastereomer.
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.

14. Glyoxylic Acid Synthesis of a-Amino Acids
Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5965
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53,
antiplatelet agent
Kalinski, C.; et al. Synthesis 2008, 4007.

15. Glyoxylic Acid Petasis-type Reaction
Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762.
Naskar, D.; Roy, A.; Seibel, W.L., Portlock, D.E. Tetrahedron Lett. 2003, 44,

16. Imino Amides Synthesis of a-Functionalized Glycine Derivatives
An efficient approach was developed for the α-arylation of imino amides with arylboronic acids.
Zhao, L.; Liao, X. H.; Li, C. J. Synlett 2009, 2953.

17. Glycolaldehyde Synthesis of Enantiopure a-Amino Alcohol
When a α-hydroxy aldehyde is used as a substrate in the synthesis of β-amino alcohols, a single diastereomer is generated. This reaction forms exclusively anti-product.
optically pure glyceraldehydes
Petasis, N. A.; Zavialov, I. A.  J. Am. Chem. Soc. 1998, 120, 11798–11799.
Unconventional aldehyde equivalent
a potent immunosuppressive agent
Sugiyama, S.; Arai, S.; Kiriyama, M.; Ishii, K. Chem. Pharm. Bull. 2005, 53, 100.

18. Glycolaldehyde Synthesis of amino polyols and amino sugars L-xylose
Ritthiwigrom, T.; Pyne, S. G. Org. Lett. 2008, 10, 2769.
Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. Org. Chem. 2010, 75, 815.
Synthesis of amino polyols and amino sugars
Petasis, N.A. (2005). Zhu, J.; Bienayme, H., ed. Multicomponent Reactions. Wiley-VCH. pp. 

19. Salicylaldehyde Synthesis of Alkylaminophenol
Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.

20. Salicylaldehyde Synthesis of 2H-Chromenes
Catalytic amount of dibenzyamine
Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.

21. 2-Pyridine Carbaldehydes
Mandai, H.; Murota, K.; Sakai, T. Tetrahedron Lett. 2010, 51, 4779.

22. Asymmetric PBM

23. Chiral Amine
The first report in the asymmetric version of this reaction was made by Petasis, using an enantiomerically pure amine with boronic acids.
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53,

24. Chiral Amine Chiral Benzoamines Chiral Pyrrolidines
Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545.
Chiral Pyrrolidines
Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46,

25. Chiral Aldehyde Chiral a-Hydroxyl Aldehyde
Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097.
This method has been applied to the synthesis of hyacinthacine B3 and purported hyacinthacine B7.
Batey, R.A.; Mackay, D.B. Tetrahedron Lett. 2000, 41, 9935–9938.

26. Chiral Boronic Ester
The chiral amine was observed to be responsible for the stereochemical outcome.
Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969.
Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236.

27. Asymmetric Catalytic PBM
Chiral Boronic Ester Ligand
Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129,
Not a real Petasis Reaction !

28. Asymmetric Catalytic PBM
Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

29. Mechanistic studies
Mechanistic studies using NMR and ESI-MS analysis of reaction mixtures at room temperature indicated single ligand exchange.
Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

30. Asymmetric Catalytic PBM
N-acylated quinoline salts
Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.

31. Asymmetric Catalytic PBM
Synthesis Chiral Aminophenols
Bifunctional Chiral Thiourea Catalyst
Yuan, W. C. et al. Org. Lett., 2012, 14, 976–979

32. Mechanistic Investigantion

33. Summary and Outlook
Petasis reaction 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.

34. THANKS !