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Vy M. Dong, Jinquan Yu and their research work. Professional Experience University of Toronto: Associate Professor, July 2010 to present. Assistant Professor,

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Presentation on theme: "Vy M. Dong, Jinquan Yu and their research work. Professional Experience University of Toronto: Associate Professor, July 2010 to present. Assistant Professor,"— Presentation transcript:

1 Vy M. Dong, Jinquan Yu and their research work

2 Professional Experience University of Toronto: Associate Professor, July 2010 to present. Assistant Professor, July 2006 to June 2010. National Institutes of Health Postdoctoral Fellow at the University of California at Berkeley: December 2003 to May 2006. Organometallic and supramolecular chemistry with Robert Bergman and Kenneth Raymond Graduate Student at UC Berkeley and the California Institute of Technology: July 1998 to October 2003. Doctoral studies in organic synthesis with David MacMillan Undergraduate Research Assistant at the University of California at Irvine: June 1998. Undergraduate thesis on the tethered Biginelli condensation with Larry Overman. Vy M. Dong

3 Education experience: Harvard University - Cambridge, MA, USA Postdoctoral Fellow Supervisor: E. J. Corey February 2001 to May 2002 University of Cambridge - Cambridge, UK Junior Research Fellow (JRF) of St. John's College October 1999 to October 2003 University of Cambridge - Cambridge, UK Ph.D. in Chemistry Supervisor: Jonathan B. Spencer (also Mattew Gaunt’s PhD Supervisor) October 1994 to September 1999 Guangzhou Institute of Chemistry - Guangzhou, China M.Sc. in Chemistry Supervisor: S.-D. Xiao (萧树德 ) September 1988 to July 1990 Shanghai Institute of Organic Chemistry - Shanghai, China Coursework for M.Sc. degree September 1987 to July 1988 East China Normal University - Shanghai, China B.Sc. in Chemistry Top 5% on national examination for admission to SIOC Supervisors: L.-X. Dai and B.-Q. Wu September 1982 to July 1987 Jinquan Yu( 余金权 ) Jonathan B. Spencer (1960-2008).

4 Positions: The Scripps Research Institute - La Jolla, CA, USA Professor of Chemistry August 2010 to Present Associate Professor, Department of Chemistry July 2007 to August 2010 Brandeis University - Waltham, MA, USA Assistant Professor, Department of Chemistry March 2004 to June 2007 University of Cambridge - Cambridge, UK Royal Society Research Fellow October 2003 to February 2004 Guangzhou Institute of Chemistry - Guangzhou, China Teaching and Research Assistant in Organic Chemistry October 1990 to September 1994

5 Dong’s research work 1.Rh(I) complexes to activate the C-H bond of aldehydes History of Hydroacylation The reaction was discovered by Kiyoshi Sakai in 1972 as part in a synthetic route to certain prostanoids( 前列腺素 ). The first catalytic application was reported by Roy G. Miller in 1976 Tetrahedron Lett. 1972,13,1287-1290

6 Hydroacylation as an asymmetric reaction was first demonstrated by James and Young in 1983 (kinetic resolution) and by K. Sakai ( Kyushu Univ. ) (true asymmetric synthesis) in 1989 J. Am. Chem. Soc., 1976,98,1281–1283 Tetrahedron Lett., 1989,30,6349-6352 J. Chem. Soc., Chem. Commun., 1983, 1215-1216

7 Rh(I) planar square Rh(III) octahedron

8 Zengming Shen and Vy M. Dong* J. Am. Chem. Soc., 2008, 130, 2916-2917 conventional strategies such as Corey-Nicolaou’s PySSPy and Yamaguchi’s acid chloride Ketone Hydroacylation

9 The coordinating ability of the ether-oxygen can help suppress decarbonylation and facilitate hydroacylation. Through the screening of various chiral diphosphine ligands, they found that the relation between phosphine basicity and catalyst selectivity

10 Zengming Shen, Tom K. Wooand* Vy M. Dong* J. Am. Chem. Soc. 2009, 131, 1077 Mechanistic Insight

11 The turnover-limiting step: insertion of the ketone C=O bond to the rhodium hydride via TS A The ether oxygen is coordinated to Rh, and this coordination is critical for promoting insertion over competitive decarbonylation. But this protocol is limited in scope to ketoaldehydes bearing an ether linkage!

12 J. Am. Chem. Soc. 2009, 131, 15608–15609 Counterion effects on reactivity: catalysts with more strongly coordinating counterions gave better selectivity for hydroacylation over decarbonylation

13 The reason of choosing AgNO3 as the optimal additive is that nitrate is less strongly coordinating than Cl (giving shorter reaction times) but coordinating enough to suppress decarbonylation and assist in enantioinduction The appropriate choice of counterion was crucial in suppressing decarbonylation and controlling enantioselectivity Counterions’ coordinating strengths: SbF6- < BF4- < -OTf <-OMs { "@context": "", "@type": "ImageObject", "contentUrl": "", "name": "The reason of choosing AgNO3 as the optimal additive is that nitrate is less strongly coordinating than Cl (giving shorter reaction times) but coordinating enough to suppress decarbonylation and assist in enantioinduction The appropriate choice of counterion was crucial in suppressing decarbonylation and controlling enantioselectivity Counterions’ coordinating strengths: SbF6- < BF4- < -OTf <-OMs

14 Chem. Sci. 2011, 2,407-410 The presence of a nitrogen atom not only promotes faster reactivity but also suppresses decarbonylation completely.

15 Rh-Catalyzed Intramolecular/ Intermolecular Olefin Hydroacylation J. Am. Chem. Soc. 2009, 131, 6932. Formation of medium-sized ring heterocyclic ketone Coordination of X to Rh helps promoting olefin hydroacylation over olefin isomerization, aldehyde decarbonylation, and catalyst decomposition Regioselectivity would depend on the catalyst choice and substrate structure (i.e. X, tether length, and olefin substitution) Challenge: regio-selectivity

16 If reductive elimination were turnover-limiting in our case, D would be scrambled into the α- position of 11-D. However, we observed that products 10-D and 11-D had D at only the β- position. This lack of D scrambling suggests that reductive elimination is not the turnover- limiting step in our catalytic system.

17 J. Am. Chem. Soc. 2010, 132, 16330–16333 Challenge was still in regiocontrol While reactive in Rh-catalyzed intermolecular hydroacylation,terminal olefins tend to give achiral, linear products or mixtures of regioisomers Bolm, C. Adv. Synth. Catal. 2007, 349, 1185. H. Suemune ( Kyushu Univ ), J. Org. Chem. 2004, 69, 1144- 1150

18 1a:salicylaldehyde

19 J. Am. Chem. Soc. 2010, 132, 16354–16355 Challenge: In general, intermolecular hydroacylation is difficult to achieve due to competing pathways such as decarbonylation and catalyst decomposition

20 2.Palladium-Catalyzed C–H Bond Functionalization first intermolecular palladium-catalyzed transformations of sp2C-H bonds to C-S J. Am. Chem. Soc. 2009, 131, 3466–3467 Chelation-assisted strategy Pervious work: sp2 C-H bonds to C-O, C-X, C-C, and C-N (Yu, Sanford and Ellman’s work)

21 Angew. Chem. Int. Ed. 2011, 50, 932 –934 The first direct observation of C-S bond-forming reductive elimination from Pd (IV) complexes; the first Pd (IV) complexes containing a Pd-SO2R bond These results support the feasibility of palladium-catalyzed sulfonylation and desulfitative C-C cross-coupling reactions through a Pd (II)- Pd (IV) catalytic cycle

22 Chem. Sci., 2010, 1, 331–336 Using sodium persulfate, a nontoxic, environmentally benign, and easy-to- handle oxidant Synlett. 2011, in press Invited contribution in honor of Xiyan Lu and Li-Xin Dai

23 Tetrahedron, 2009, 65, 3062–3068 Nitrosoalkene and vinylnitrene represent two important intermediates that have been relatively elusive and underutilized for C–N bond formation

24 3.Others a. Ru-catalyzed activation of sp3 C–O bonds Chem. Sci. 2011, 2,544 Direct insertion into electron-rich bonds such as typically insert ethereal C–O bonds

25 A selective intramolecular alkyl transfer process. This observation suggests that reversible sp3 C–H bond activation is taking place

26 b. Negishi cross-coupling between organozinc reagents and CO2 J. Am. Chem. Soc. 2008, 130, 7826–7827 J. Am. Chem. Soc. 2008, 130, 6058–6059

27 Work of Iwasawa (Tokyo Institute of Technology) J. Am. Chem. Soc. 2006, 128, 8706

28 基本原理: C-H 键直接与 Pd 发生氧化加成 (top) electrophilic metalation of the aromatic C–H bond pathway ( S Ar E ) (bottom) Concerted proton transfer metallation pathway 1. 杂原子的配位定位作用,同 时使 C-H 键更易活化 2.Various E+ K. Fagnou,Science , 2007,316,1172 Fujiwara-type reaction

29 早期研究 : 始于 C(sp2)-H 键的烯化 I Moritani; Y Fujiwara. Tetrahedron Lett. 1967, 8, 1119. Drawback: 1 使用大大过量的芳烃(一部分作为溶剂) 2 缺少区域选择性控制 Y. Fujiwara, I. Moritani, J. Am. Chem. Soc. 1969,91,7166

30 highly electrophilic cationic species: Pd(O2CCF3)+ Y Fujiwara,Science, 2000, 287, 1992

31 One vinyl H or D in all adducts was mainly from the solvent acid, which presumably results from the protonation of vinyl-Pd complex IMc by TFA-d1 or TFA The involvement of s-aryl-Pd complexes IMa has been confirmed by the 1H NMR spectrum from the disappearance of the aryl H of 1 in the reaction with l eq of Pd(OAc)2 in TFA in a few minutes at room temperature.

32 The fact that the hydroarylation reaction failed in other solvents such as acetic acid indicates the necessity of TFA for the formation of cationic Pd(II) species and for the protonation of a vinyl-Pd intermediate IMc to complete the catalytic cycle. X. Lu, G. Zhu, S. Ma, Tetrahedron Lett. 33, 7205 (1992). A possible mechanism would be the electrophilic attack of the aromatic C–H bond by cationic Pd(II) species to form IMa followed by coordination of alkyne to give IMb. A trans insertion of C–C triple bonds to the s-aryl- Pd bond (23–25) results in IMc, and 1/1 arene/alkyne adduct would be released from Pd(II) (24) upon protonation of IMc

33 后来通过引入导向基团,提高区域选择性 Masahiro Miura,J. Org. Chem.,1998,63,5211–5215 J. Am. Chem. Soc., 2002, 124, 1586-1587

34 C(sp2)-H 键和 C(sp3)-H 键的芳基化和烷基化

35 Organometallics, 2006, 25,5973-5975 Ar-H+Ar’-H→Ar’-Ar 比较困难 Ar-H 和 Ar’-H 很容易发生自身偶联,减 少交叉偶联产物 K. Fagnou, Science, 2007,316,1172 3 eq. Cu(OAc) 2 and arene (~30 eq) homo-coupling VS cross-coupling palladium(II) complexes can react via S Ar E with good selectivity for electron-rich arenes J. Am. Chem. Soc.,2006,128,1066–1067


37 Yu’s research work Metal-catalyzed carbon-carbon and carbon-heteroatom bond forming reactions based on C-H activation Pd(II)/Pd(IV), Pd(II)/Pd(0) and Cu(II)/Cu(0) redox systems 1.Activation of sp2 C-H bond 2.Activation of sp3 C-H Bonds

38 1.Activation of sp2 C-H bond Science, 2009, 323, 1593 Yuzo Fujiwara, Science 2000,287, 1992

39 2.Activation of sp3 C-H Bonds

40 J. Am. Chem. Soc. 2008, 130, 14082–14083 Pd(II)-Catalyzed Carboxylation of Aryl and Vinyl C-H Bond

41 X-ray crystallography of the first C-H insertion intermediate isolated from the cyclometalation of carboxylic acids.

42 Angew. Chem. Int. Ed. 2009, 48, 6097 –6100 Challenge: Pd(II)-catalyzed intermolecular alkylation of C-H bonds with alkyl halides 目前 C-H 活化多为形成 C(sp2)- C(sp2) 的反应,烷基化反应相 对较少

43 Although the oxidation of the arylpalladium(II) intermediate by MeI to Pd(IV) was previously proposed (intermediate 8), in light of previous discoveries that arylpalladium species react with electrophiles such as aldehydes and ketones,direct s-bond metathesis between the aryl– Pd bond and the alkyl halide cannot be ruled out (intermediate 9) not a Friedel–Crafts-type reaction

44 Science,2010,327,315-319 Angew. Chem. Int. Ed. 2010, 49, 6169–6173 Pd-catalyzed arene C–H olefination Challenge: 1. the substrates that are typically effective in palladium-catalyzed C–H activation are synthetically restrictive, either because they are limited to electron-rich arenes or heterocycles, or because they possess impractical chelating functional groups to promote metalation. These directing groups include those thatare irremovable and recalcitrant to undergo further synthetic elaboration, such as Py, and those that are removable but require several steps for installation and detachment, such as oxazoline. 2. methods for effecting position-selective C–H activation on multiply substituted arenes, particularly via ligand control, remain underdeveloped


46 No traditional Mizoroki-Heck reaction product



49 J. Am. Chem. Soc. 2009, 131, 5072–5074 Meta-olefination of highly electron-deficient arene Fujiwara-type reactions using electrondeficient arenes using electrondeficient arenes under various reported conditions have two problems : 1.electron-deficient arenes were unreactive due to their poor coordination with Pd(OAc)2 2.reoxidation of Pd(0) by O2 was not possible in the absence of electron-rich arenes, external ligands, or co-oxidants

50 Py: the most efficient ligands to promote the reoxidation of Pd(0) by oxygen Yu hypothesized that, in these systems,displacement of the pyridyl ligand by the electron-deficient arene substrate is energetically disfavored due to the strength of the Pd-N bond. Even upon prior loss of acetate and formation of the corresponding Py2Pd(OAc)+, the resulting complex remained insufficiently electrophilic for C-H activation to take place increase in steric bulk at the 2 and 6 positions of the pyridine ring to weak Pd- N bond strength

51 the bond length of Pd-N is 0.05 Å longer than that of (Pyridine)2Pd(OAc)2 Py2Pd(OAc)2 complexes are highly stable under the same conditions

52 This paper was featured in: Perspectives in Science: Copper Puts Arenes in a Hard Position RSC Chemistry World: Copper catalysts give meta aromatics Research Highlights in Nature Chemistry: Electrophilic arylation: Substitution success Chemical and Engineering News: Dodging The Substitution Laws Science News: Helping Molecules Reach Meta Angewandte Chemie: Meta-Selective Transition-Metal Catalyzed Arene C-H Bond Functionalization This paper was voted as one of the top 12 papers of 2009 by Chemical and Engineering News Chemical Year in Review 2009 Science, 2009, 323, 1593

53 How to access the isomer that is not anticipated by these rules? Solutions to this problem often require numerous FG additions or manipulations in order to tailor the directing electronic properties of the precursor to furnish the desired product

54 吲哚能发生亲电取代反应,多取代于 3 号位 J. Am. Chem. Soc. 130, 8172 Sanford, J. Am. Chem. Soc. 128, 4972

55 We cannot rule out coordination of the Cu(III) species at the ortho position, followed by a migration to the meta site and arylation. However, we do not see any sign of ortho-arylation that may be expected through this pathway Although we cannot be certain of the precise mechanism of the reaction at this stage, a possible rationalization could involve the highly electrophilic Cu(III)-aryl species activating the aromatic ring sufficiently to permit an anti–oxy-cupration of the carbonyl group of an acetamide across the 2,3 positions on the arene ring

56 Christina White (UIUC) Melanie Sanford (UMichigan) Keith Fagnou(U Ottwa) Passed away in Nov. 2009 Matthew Gaunt (Cambridge) Yuzo Fujiwara (Kyushu University) Masahiro Miura (Osaka Univ.)

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