A Simple Introduction of the Mizoroki-Heck Reaction

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1 A Simple Introduction of the Mizoroki-Heck Reaction Reporter: Supervisor: Zhe Niu Prof. Yang Prof. Chen Prof. Tang 2016/2/3

2 Content Introduction Intermolecular Mizoroki-Heck Reaction Intramolecular Mizoroki-Heck Reaction Tandem Mizoroki-Heck Reaction Summary Acknowledgement 2

3 Content Introduction Intermolecular Mizoroki-Heck Reaction Intramolecular Mizoroki-Heck Reaction Tandem Mizoroki-Heck Reaction Summary Acknowledgement 3

4 Introduction 1968 Heck, R. F. JACS, 1968, 90, History: Bull. Chem. Soc. Jpn. 1971, 44, 581 (Mizoroki) J. Org. Chem. 1972, 37, 2320 (Heck)

5 Introduction Books: In Metal-catalyzed Cross-coupling Reactions, Wiley-VCH: New York, The Mizoroki-Heck Reaction, Wiley-VCH: New York,

6 Content Introduction Intermolecular Mizoroki-Heck Reaction Intramolecular Mizoroki-Heck Reaction Summary Acknowledgement 6

7 Intermolecular Brief Mechanism: 7

8 Intermolecular Regioselectivity? Eur. J. Org. Chem., 2001, Org. Lett. 2006, 8,

9 Intermolecular Regioselectivity Neutral condition: Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2 7. Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57,

10 Intermolecular Regioselectivity Cationic condition: Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2 7. Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57,

11 Intermolecular Cationic Conditions Strongly coordinating bidentate ligands: J. Org. Chem. 1993, 58, Increasing polarity of reaction system: J. Org. Chem. 2001, 66, J. Org. Chem

12 Intermolecular Cationic Conditions Silver effect: J. Med. Chem. 1999, 42, J. Org. Chem. 1988, 53,

13 Intermolecular Cationic Conditions Silver effect: Synthesis, 1997, J. Org. Chem. 1987, 52,

14 Intermolecular Regioselectivity Additive LiCl: Influence of Pt-Bu 3 : J. Org. Chem. 1988, 53, J. Org. Chem. 2006, 71,

15 Content Introduction Intermolecular Mizoroki-Heck Reaction Intramolecular Mizoroki-Heck Reaction Tandem Mizoroki-Heck Reaction Summary Acknowledgement 15

16 Intramolecular First intramolecular Mizoroki-Heck reaction (1977): Tetrahedron, 1977, 12, 1037 Important differences between inter- and intra Heck reaction: Inter- Only mono- and disubstituted olefins Not very efficient Difficult regiocontrol for electronic neutral olefins Rare reports of asymmetric examples Intra- Tri- or tetrasubstituted olefins Generally more efficient Generally giving high regioselectivity Have been well developed for a wide variety of substrates 16

17 Intramolecular Migratory Insertion The reaction is considered to be a concerted process The elimination of entropic factors in the intramolecular Heck allows insertion into trisubstituted and tetrasubstituted olefins, which is not possible in the bimolecular process The regiochemistry of the intermolecular Heck insertion step is highly sensitive to the electronics of the substrate Does the intramolecular Mizoroki-Heck reaction suffer from the same lack of regiocontrol? 17

18 Intramolecular Regioselectivity in the Intramolecular Heck Reaction Formation of medium-sized-rings : Formation of Macrorings : Tetrahedron, 1981, 37,

19 Intramolecular Probing the Transition State of the Migratory Insertion Step J. Am. Chem. Soc., 1990, 112,

20 Intramolecular Exo-selectivity in the formation of small rings J. Org. Chem. 1987, 52, Angew. Chem., Int. Ed. 1995, 34,

21 Intramolecular Endo-selectivity in the formation of small rings Tetrahedron Lett., 29, J. Org. Chem., 62, J. Am. Chem. Soc., 114,

22 Intramolecular Endo-selectivity in the formation of small rings J. Am. Chem. Soc., 114,

23 Content Introduction Intermolecular Mizoroki-Heck Reaction Intramolecular Mizoroki-Heck Reaction Tandem Mizoroki-Heck Reaction Summary Acknowledgement 23

24 Tandem-Heck Advantages of the Heck Reaction in C-C Bond Formation Palladium is extraordinarliy tolerant of nearly all types of organic functionality and is highly chemoselective J. Am. Chem. Soc. 1993,115, 6094 Intramolecular Heck reaction can form very sterically hindered carboncarbon bonds under reasonably mild conditions Angew. Chem., Int. Ed. 1995, 34, Ability to form quarternary carbon stereocenters with high levels of asymmetric induction...more on this to come 24

25 Tandem-Heck Tandem reactions: Additional reaction pathways become available when the initial Pd C species does not (or can not) decompose via β-hydride elimination 25

26 Tandem-Heck Tandem Heck reactions: Tandem carbonylation sequences: Scopadulcic acid A J. Am. Chem. Soc. 1999, 121, High CO pressure makes final carbonylation faster than β-hydride elimination ACIEE, 1996, 35,

27 Tandem-Heck Tandem Heck Reactions with Alkynes: Tandem Heck-Electrocyclization: Alkynes insert more rapidly than alkenes Chem Rev., 1996, 96, % Tetrahedron 1996, 52,

28 Tandem-Heck Tandem Heck-π-Allyl Reactions: Tandem C-H activition: Tetrahedron Lett. 1994, 35, Angew. Chem. Int. Ed. 2009, 48,

29 Content Introduction Intermolecular Mizoroki-Heck Reaction Intramolecular Mizoroki-Heck Reaction Tandem Mizoroki-Heck Reaction Summary Acknowledgement 29

30 Summary Regioselectivity 30

31 Summary Regioselectivity 31

32 Summary Tandem Mizoroki-Heck reaction Additional reaction pathways become available when the initial Pd C species does not (or can not) decompose via β-hydride elimination 32

33 Summary Conclusions, Limitations, and Future Directions Powerful method for the construction of polycyclic structures and quarternary carbon stereocenters The incredible functional group tolerance of palladium make Heck reactions possible on even the most sensitive of substrates Extensive optimization studies are often required to develop optimal conditions for every new substrate Reactions are easily poisoned by molecular oxygen Further investigation of tandem reactions involving the intramolecular Heck and application in complex molecule synthesis Finding milder reaction conditions that also allow for lower catalyst loadings 33

34 Prof. Yang, Prof. Chen & Prof. Tang Mr. Han Yixin Members of Laboratory Everyone here Thank you for your attention!