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Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013

1959 Born in Tokyo, Japan Publications 1983 B.Sc.; The University of Tokyo (UT); Prof. T. Mukaiyama >600 Publications (c.a 60 Reviews) 1988 Ph.D.; The University of Tokyo; Prof. T. Mukaiyama Science (1); JACS (66); Angew (34) 1987 Assistant Professor; Tokyo University of Science 1991 Lecturer; Tokyo University of Science Web of Knowledge data(03/2013): 1992 Associate Professor; Tokyo University of Science average citations: 52.32 1998 Professor; UT; Graduate School of Pharmaceutical Sciences H-index: 86 2007 Professor; UT; Department of , School of Science Most cited works: Important Honors and Awards Chem. Rev. 1999, 1069: 1061 times 1991 The Chemical Society of Japan Award for Young Synlett. 1994, 689: 601 times 1997 Springer Award in 2001 IBM Science Award Major Research Interests: 2002 Nagoya Silver Medal Novel Chiral 2005 Mitsui Chemical Catalysis Science Award Organic reaction in water 2006 Arthur C. Cope Scholar Awards Polymer supported catalysis Prof. Shu Kobayashi 2006 C.S. Hamilton Award Organic reaction in microreactors Doctoral years at UT with Prof. Mukaiyama

OBn OBn Lewis catalysts: TrClO4; TrCl-SnCl2, O + TrClO4 (stoichiometric) BnO O O 3β-Cholestanol BnO O SbCl4-Sn(OTf)2; SnCl4-Sn(OTf)2 BnO BnO (Tr = Ph3C) O Cholestanyl OBn OBn − for various catalytic C−C bond formations: CH2Br Aldol reactions, ... His first publication Chem. Lett. 1984, 907.

N Sn(OTf)2, TBAF, N Me Among the first examples of asymmetric OTMS (stoichiometric) OH O CHO + aldol reactions between prochiral silyl Ph SEt DCM, -78 oC; 78%, 82% ee Ph SEt and prochiral His first asymmetric reaction Chem. Lett. 1989, 297. JACS, 1991, 4247. First Independent publication

O Lanthanide trifluoromethanesulfonates OSiMe3 (CH O)aq, THF 2 as stable Lewis in aqueous Ph OH Ph Yb(OTf) (1 mol%) media. Recovery and reuse of catalysts 3 Me 90% from aqueous layer. Chem. Lett. 1991, 2187. Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013 OH Part 1. Chiral Catalysis HO OSiMe Catalysis for Activation of 3 catalyst (10 mol%) + NH O N OMe Catalyst: (CLAC synthesis: chiral Lewis acids controlled synthesis) NMI, DCM, −45 oC Ph OMe Ph H 70%, 87% ee Sn(OTf)2 OH O OH O OSiMe3 chiral NMI = N-methylimidazole (sub-stoichiometric) 1. MeI, K CO RCHO + + 2 3 R SEt R SEt Br Br 2. CAN TBSO SEt Bu2Sn(OAc)2 OTBS OTBS DCM, −78 oC 83% chiral amine = L1 chiral amine = L2 O O (stoichiometric) 86%, 98% ee Zr NH O 82%, 98% ee O O 2 syn:anti = 98:2 syn:anti = 99:1 Ph OMe N Br Br N R Me catalyst J. Am. Chem. Soc. 1997, 7153. L1 O H N Sn N Strecker reaction (dinuclear cat.): Angew. Chem. Int. Ed. 1998, 3186 Sn N N N Hetero D-A reaction: J. Am. Chem. Soc. 1999, 4220; J. Am. Chem. Soc. N Me O H Me 2003, 3793. Me : J. Am. Chem. Soc. 2002, 3292. L2 R [3+2] cycloadition: J. Am. Chem. Soc. 2004, 11279. Isolable, air-stable, storable Zr catalyst: J. Am. Chem. Soc. 2006, 11232. J. Am. Chem. Soc. 1994, 9805 HO 100 gram-scale synthesis of Vancomycin's building block using OH O O OH catalyst: Adv. Synth. Catal. 2006, 1831. H3C(H2C)9 O CO2H Yb catalysts for (aza)-Diels-Alder reactions: Synlett, 1994, 689. OH Nb catalysts for stereoselective ring opening of meso- and meso- khafrefungin : J. Am. Chem. Soc. 2007, 8103. application to enantioselective of D-erythro-Sphingosine (Tetrahedron Lett. 1994, 9573.); sphingofungin B (synlett 1996, 672.); Catalysts khafrefungin (J. Am. Chem. Soc. 2001, 1372)... O Nu O X Ph Ph Zirconium Catalysts for Addition to R R N Challenges in Lewis acids catalyzed enantioselective reaction with imines Cu cat. N NH HN X = OR; NHR - Lewis acids are trapped by the basic of EtO * R R Sc, Y, EtO CuL the starting materials/products => difficult to make it catalytic Ln, Zr, Nb O O diamine N-acyliminoesters O - Lewis acid - interaction is not regid => difficult to H Mannich type: Org. Lett. 2002, 143; make it enantioselective O n J. Am. Chem. Soc. 2003, 2507; C11H23 NH OH LA J. Am. Chem. Soc. 2004, 6558. R LA LA R HO Aldol-type: Angew. Chem. Int. Ed. 2004, 3258; Ph N N N Allylation: Angew. Chem. Int. Ed. 2006, 1615. Review: Acc. Chem. Res. 2008, 292. HPA-12 R1 R2 R1 R2 R1 R2 (3 steps, 82.9 % yield) Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013 O O Activation of Nucleophiles: "Catalytic Reaction" Ca(OAr)2 (10 mol%) O O (10 mol%) NO2 + MeO OMe + - OML* Ph O M B BH OH O MeO OMe toluene, −20 oC 1 NO2 H + R CHO 80%, 96% ee Ph OR OR R1 * OR BH M+B- + - Pyridinebisoxazoline (Pybox) Ligands: direct aldol reaction: M B = catalyst O N - neutral coordinative ligands: stronger Ph Ph Alkaline Earth Metal Catalysts N N Bronsted bacicity of the complexes Ca - three coordination number => more Ph Ph RO OR rigid complexes = high ee Pybox-calcium alkoxide complexes Angew. Chem. Int. Ed. 2009, 9117. : J. Org. Chem. 2010, 963. Michael reaction: J. Am. Chem. Soc. 2010, 7890. Strontium Catalysis: J. Am. Chem. Soc. 2008, 2430. Picture from Harder, S. Chem. Rev. 2010, 3852. Barium Catalysis: J. Am. Chem. Soc. 2006, 8704. Alkaline Earth Metal Compounds: Review for Alkaline Earth Metal Catalysis: Acc. Chem. Res. 2010, 58. - low = stronger Bronsted basicity of counter anion => Silver Catalysis: silver with phosphine ligand for [3+2] : based-catalyzed reactions Angew. Chem. Int. Ed. 2011, 4893. J. Am. Chem. Soc. 2012, 20049. - Highl nucleophilicity (as of group 1) - Significant Lewis Acidity (as of group 3) => substrate binding for high ee Modification of Nucleophiles - Large ionic radius (Ca2+, 1.00Å; Sr2+, 1.18Å; Ba2+, 1.35Å; ) => large number of coordination sites => challenges in chiral modification for high ee Fluorenone Schiff O R R Asymmetric Calcium Catalysis N N i O O Ca(O Pr)2 (10 mol%) Ph N base O ligand (10 mol%) Ph N OMe + Ph N OMe OMe o Ph OMe −30 C, THF Ph COOMe Ph quant., 83% ee Schiff base * N fluorenone imines 14π-e aromatic anions O O low pKa N Ca O Mannich-type reaction: (R = COOMe) Angew. Chem. Int. Ed. 2008, 5613. N N Ph N (R = alkyl, aryl) J. Am. Chem. Soc. 2010, 3244. OMe Ph Ph a Box ligand O O O O Ph Sulfonylimidates as Nucleophiles N N N N * Ca Ca N Ca(OR)2 Ph Ph Ph Ph Mannich-type reaction, Michael-type reaction: OR OR N Ca O (DBU) J. Am. Chem. Soc. 2008, 1804. (alkaline earth Ph N base). Angew. Chem. Int. Ed. 2009, 6041. Box-calcium alkoxide complexes OMe (organosuperbase). Angew. Chem. Int. Ed. 2012, Bisoxazoline (Box) Ligands: Ph 9525. Tsuji-Trost Reaction: Chem. Commun. 2008, 6354. pros: covalence/ionic bond = strong interaction Review: Chem. Eur. J. 2009, 10694. cons: decrease in Bronsted basicity of chiral calcium enolate the complexes J. Am. Chem. Soc. 2007, 5364 picture from Chem. Eur. J. 2009, 10694. Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013 Other Chiral Catalysis - Allylation Part 2. Organic Reaction in Aqueous Media Neutral Coordinate Organocatalysts (NCOs) Initial Finding O S Ln(OTf)3 and Sc(OTf)3 = Stable Lewis Acids in Aqueous Media Me ptolyl NHBz NHBz HN Aldol reaction N (3 equiv.) OSiMe3 OH O + SiCl3 Yb(OTf)3 (10 mol%) DCM, 78 oC Ph Ph H − PhCHO + Ph 73%, 93% ee THF-H2O (4:1) J. Am. Chem. Soc. 2003, 6610. Adv. Synth. Catal. 2004, 1023. 91% - HOTf (various pH): low conversions Both Yb and water Enantioselective Transfer Aminoallylation - In THF only or water only: low conversions are important OH Mannich-type reaction EtOH NH3 + OMe Yb(OTf)3 (10 mol%) O NH2 p HOOC OH rt, 5min OOC HCHO + ClC6H4NH2 + O p 72%, 87% ee Me THF-H2O (9:1) ClC6H4 Me 92% B(pin) J. Chem. Soc., Chem. Commun., 1995, 1379. NH3 first ex. in aqueous media: NH NH Michael reaction, allylation, Diels-Alder reaction: Synlett, 1994, 689 O COO COO O O Interesting finding: Cu(OTf) = Excellent Catalyst for Aldol Reaction and Allylation in Aqueous Media O 2 J. Am. Chem. Soc. 2006, 11038. Chem. Lett. 1997, 959. How about other metals? Transmetallation(TM) (In, Zn, Ag) Systematic Studies of Various in Water I NHBz In I(5 mol%) NHBz * HN Sc N B(pin) L (5 mol%) + 4.3 constant (pKh) PhMe, MeOH, 0 oC 7 Ph H Ph 4.8 10 inner-sphere water ligands 99%, 96% ee exchange rate constant (WERC) base CN L*−InI B(pin) O O Ph Ph N HN L*−InI transmetallation Ph Ph L* E

L*−In

the active

Angew. Chem. Int. Ed. 2010, 1838. Acc. Chem. Res. 2012, 1331. 6 -1 -1 pKh = 4.3−10.08; WERC > 3.2 10 M s J. Am. Chem. Soc. 1998, 8287. Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013 Catalytic Asymmetric Reaction in Aqueous Media Catalyzed by Ln(OTf) Hydrolysis constant 3 + + 2 - large ionic radius, large number of coordination sites = challenging 3+ + + [M(OH) ] [H ] M + 2H2O M(OH)2 + 2H Kh = [M2+] Challenges in designing a chiral ligand for Ln(OTf)3 : pKh = -logKh - too strong coordinating ability => reduction of Lewis acidity WERC: measured by NMR, sound absorption, or multidentate legand method - too weak coordinating ability => low ee due to achiral free L.A pathways Martell, A. E., Ed.; Coordination Chemistry, ACS Monograph 168; ACS: o Washignton, DC, 1978; Vol.2. - Pr(OTf)3 (10 mol%) Ligand 3 (12 mol%), 0 C: N (2R, 3R), 85%, 78% ee, syn:anti = 91:9. Study Objectives: Effect of Metal Salts in the Yields of Aldol Reaction O O - first example of Ln(OTf)3 in catalytic asymmetric OH O OSiMe3 MXn (0.2 eq.) aldol reactions in aqueous media (10 year for the O O asymmetric version vs. Chem. Lett. 1991, 2187.) PhCHO + Ph Ph Ph THF-H2O (9:1) N - ee and dr are highly dependent on the size of rt, 12h Me 6 -1 -1 lanthanides: size fitting effect of macrocyclic ligands Yields > 50%: pKh = 4.3−10.08; WERC > 3.2 10 M s Explanation: Ligand 3 Org. Lett. 2001, 165. J. Am. Chem. Soc. 2003, 2989. pKh < 4.3: fast hydrolysis, formation of proton => decomposition of enol Catalytic Asymmetric Reaction with Aqueous Formaldehyde pKh > 10.08: cation is too stable, low Lewis acidity Sc(OTf)3 (10 mol%) O Small WERC: slow reaction as Lewis acids need to coordinate with substrate OSiMe 3 Ligand 4 (12 mol%) + aq. HCHO Ph OH Catalytic Enantioselective Aldol Reaction Ph o (5 equiv.) H2O/DME = 1/9, − 20 C Me M(OTf)2 (x mol%) OH O 89%, 90% ee OSiMe3 PhCHO + Ligand (y mol%) Ph Ph N N - use commercial available formalin Ph H2O-EtOH (1/9), temp tBu tBu - high yields and enantioselectivities Me J. Am. Chem. Soc. 2004, 12236. Ininitial Finding with Cu(II) and Pb(II) (2S, 3S) OH HO Ligand 4 Cu(OTf) (20 mol%); Ligand 1 (20 mol%), −10 oC: O O 2 (2S, 3S), 74%, 67% ee, syn:anti = 3.2:1. Enantioselective Mannich-type Reaction NHBz N N first example of catalytic asymmetric aldol reaction in NHBz N Ph Ph aqueous media; Chem. Lett. 1999, 71. OSiMe ZnF2(100 mol%) HN O 3 ligand 5 (10 mol%) Ligand 1 EtO EtO H + p C H pMe H O, 0 oC C6H4 Me Pb(OTf) (20 mol%); Ligand 2 (24 mol%), 6 4 2 2 O 91%, 95%ee O o O 0 C: (2S, 3S), 62%, 55% ee, syn:anti = 9:1. acylhydrazono O O first example of chiral crown-based Lewis Ph Ph - additives such as cetyltrimethylammonium acid in catalytic asymmetric reactions ; bromide is needed in some cases O O J. Am. Chem. Soc. 2000, 11531. MeO NH HN OMe - first enantioselective Mannich-type reactions O the same level of reaction rate to Pb(OTf)2 in Water catalyzed achiral reaction J. Am. Chem. Soc. 2004, 7768. Ligand 2 Ligand 5 Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013

Other Organic Reaction in Aqueous Media Part 3. Surfactant-Type Catalyst Lewis Acid Surfactant Combined Catalysts (LASCs) Pd-Catalyzed Allylic Amination Using (aq.) NH3 for Primary Synthesis A New Idea for Catalysis in Water: Surfactants: for better solubility of sub. LASC for [PdCl(allyl)]2 (5 mol%) OAc NH (R)-BINAP (20 mol%) 2 Stable Lewis acids in water = catalysts in Water Ph Ph aq. NH /1,4-dioxane (1/2) Ph Ph ? 3 Synthesis of LASCs 1: Sc(O3SOC12H25)3 0.04M, rt, 18 h ScCl3 + 3RSO3H Sc(RSO3)3 NH3 gas: NR 71%, 87% ee 2: Sc(O3SC12H25)3 - Previous thinking "ammonia fails to act as an effective nucleophile for π-palladium" . Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U.K., 1991; Vol. 4, p 585: + amonia deactivates transition metal catalyts + overreaction to secondary/tertiary amines - Polar solvent, diluted conditions and an excess amount of ligands are critical

- First example of Pd-catalyzed allylic amination using aqueous NH3 for synthesis of primary amines. J. Am. Chem. Soc. 2009, 4200. LASC and organic substrates in water: LASC 2 :PhCHO formation of the colloidal particles = 1 :20 (16.7mM) Catalytic Asymmetric Allylation of Aldehydes in Aqueous Media Catalytic Aldol Reaction water OSiMe Zn(OH) (10 mol%) 3 1 (10 mol%) OH O O 2 OH Ligand 4 (12 mol%) PhCHO + PhCHO + B Ph H O, rt, 4h Ph Ph LASCs O 2 H O/MeOH = 3:7 Ph 1.0 equiv. 1.5 equiv. 92% Me Me 2 0 oC, 1h Me DCM, DMF, MeOH, neat.: low yields products Ligand 4 (see previous page) 92%, 81% ee inital rate in water = 1.3 102 times in DCM centrifugation syn:anti = 10:1 - in organic solvents: uncatalyzed reaction of allylboronate and aldehydes - in aqueous solvents: the uncatalyzed reaction is suppressed, transmetallation mechanism is proposed: E ZnL reaction occurs active species at the interface Zn(II)L base O fast B O ZnL Me with and without stirring Zn catalysts: Angew. Chem. Int. Ed. 2011, 12262. Mannich-type reaction, allylation: J. Am. Chem. Soc. 2000, 7202. Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013 Bronsted Acid Surfactant Combined Catalysts (BASCs) Chiral LASCs for Catalytic Asymmetric Reaction with a The concept for dehydrative esterification in water Hydrophobic Substrates

Sc(DS)3 (10 mol%) OSiMe3 Ligand (12 mol%) OH H2O (0.5M) + aq. HCHO (5 equiv.) then reduction with Pt cat./H2 artificial odorant 56%, 91% ee N N t t Merging between chiral Lewis acid Screening of Catalysts Bu Bu in water and LASCs concepts catalyst OH HO (10 mol%) ngew. Chem. Int. Ed. 2008, 6909. CH3(CH2)10CO2H +HO(CH2)3Ph CH3(CH2)10CO2(CH2)3Ph Ligand A H O, 40 oC, 24 h (1:1) 2 Surfactants for Reactions in supercritical Dioxide DBSA-substrates catalysts yields (%) (scCO2) Sc[O S(CH ) CH ] 15 Yb(OTf)3 (5 mol%) 3 2 10 3 3 OSiMe3 NHBnO NBn additive (4g/L) Yb[O3S(CH2)10CH3]3 4 + OMe Ph OMe Ph scCO2 C12H25C6H4SO3H (DBSA) 60 50 oC, 15MPa, 3h low solubitities in scCO2 C8H17C6H4SO3H (OBSA) 39 none: 10%; poly(ethylene glycol) = surfactant: 72% H2SO4, TfOH <5

C12H25C6H4SO3Na 2 Aldol reactions, Fridedel-Crafts reactions: J. Org. Chem. 2004, 680. Part 4. Polymer-supported Catalysis the reaction in neat conditions is faster but the same equilibrium is obtained Why Immobilize the Catalysts Selective Esterification - : less waste, reuse of catalyst DBSA CH3(CH2)10CO2(CH2)11CH3 (A) CH3(CH2)10CO2H (10 mol%) - high-throughput synthesis: simple work-up and separation + CH3(CH2)11OH + procedure = fast access to large number of compounds CH3CO2H 40 oC, 48 h (1:1:1) CH3CO2(CH2)11CH3 (B) Initial Works: Polymer-Supported Sc = Lewis Acid Catalysts neat: A = 63%; B = 35%; in H O: A = 81%; B = 4% 2 H F2 H2 H 2 H Transesterification C O C C C C CH (CH ) CO Me S 3 2 10 2 DBSA (10 mol%) CN n CH2NTf n O OScX2 + CH3(CH2)10CO2(CH2)11CH3 o Sc(OTf) CH3(CH2)11OH 40 C, 48 h, 90% Nafion-Sc polyacryronitrile derivative 2 dehydration, Mannich-type, Substitution: Synlett. 1999, 1401. J. Org. Chem. 1996, 2256. J. Am. Chem. Soc. 1996, 8977. J. Am. Chem. Soc. 2002, 11971. Org. Lett. 2007, 311. Lewis acids for : (aza)-Diels-Alder, Friedel-Crafts reactions Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013

Drawbacks of Coordinate Bonds Polymers: Microencapsylated [MC OsO4]: - Low stability initial catalyst: screening: - Preparation can be troublesome - Lower reactivity (vs. monomer catalysts) x y z n CN Alternative Idea of Immobilized Catalysts: Microcapsules Instead of Using Coordinate poly(acryronitryl-co-butadiene-co-styrene) - coating and isolating substances Bonds, Why not (used for coating medicine) in food and pharmaceutical [PS-MC OsO ] Immobilize Catalysts 4 [ABS-MC OsO4] industry in Microcapsules ? - many techniques have been developed - first polymer-supported Os cat. - good yield and high ee with NMO -good recovery and reuse - olefin moiety of butadiene was oxidized to - not good for asymmetric form hydrophilic polymer: effetive in Borrow the idea form coacervation-phase separation teachniques (a transformation asymmetric reaction physio-chemical method in microcapsule), general procedure: - leaching of OsO4 when K3Fe(CN)6 is used design: (hydrophilic solvents and of polymer) I II incoporate less polar groups to the polymer

OPh x y NaO x y

interaction between π−electron of and vacant orbitals of metal THF, 80 oC, 12h 1. polymers are dissolved in appropriate solvent at high temp. quant. OPh 2. catalysts are added and stirred Cl x = 0.05 O 3. cool down for coaservation (I: phase separation) y = 0.95 4. wash and dry (II) poly(4-phenoxyethoxymethylstyrene-co-styrene) [PEM-MC OsO4] J. Am. Chem. Soc. 1998, 2985. Chem. Commun. 2003, 449 and related references - good yields and high ee for asymmetric hydroxylation with K3Fe(CN)6 - no leaching of OsO4 Microencapsulated Sc(OTf)3 [PS-MC Sc(OTf)3]: - aldol, imino-aldol, Diels-Alder, Friedel-Crafts, Mannich, Strecker... reactions PEM-MC OsO (5 mol%) K Fe(CN) (2 equiv.), 4 3 6 OH - reactivity is as good or better (imino-aldol) than monomer (DHQD) PHAL (5 mol%) K CO (2 equiv) - both in batch and flow system 2 2 3 Ph OH H2O- (1/1) Ph - Control experiments for the amount of immobilized Sc(OTf)3 : polystyrene 3h K Fe(CN) (2 equiv.), 100%; polybutadiene 43%; polyethylene 0% : π-electron-Metal interaction 3 6 OsO4: quant. recovery K CO (2 equiv), 30 oC, 5 h MC Sc(OTf) Ph 2 3 ligand: >95% recovery OSiMe 3 NH O 3 (ca. 0.5 equiv.) 1st: 85%, 78% ee; 2nd: 66%, 78% ee; 3rd: 84%, 78% ee PhCHO + PhNH + Me 2 Ph MeCN, rt, 3h Ph Ph high yield Me [MC Pd(PPh3)] for cross coupling and other [MC metal]: Chem. Commun. flow system: reuse 3 times, >90% 2003, 449 and related references Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013

Second Generation: Polymer Incarcerated (PI) [PI OsO4] catalyst Properties - stable for several months in air without sublimation MC catalyst Polymer Incarcerated (PI) - mice experiments: no acute toxicity MC catalysts are dissolved or swelled cross-linking between MC: after reactions => leaching of metals more robust catalysts [PI OsO4] for synthesis of 1mol scale of campothecin precursor

Chem. Rev. 2009, 594.

[PI Pd] catalyst O O H 4 no solvent 120 oC, 2h x y z cross linking [MC Pd] [PI Pd] filtration washing O drying O Reduction with Hydrogen Gas [PI Pd] (5 mol%) yield (%) Ph Me st nd rd th th H2 (1 atm) Ph Me 1 2 3 4 5 O THF, rt, 1h O 85 80 87 91 90 Cross Coupling [PI Pd] (x mol%) B(OH)2 o P( MeOPh)3

+ (x mol%) MeO2C Br MeO2C K3PO4 H2O-toluene x = 0.01: quant; x = 0.001: 54% (TON = 53600) Other reactions with [PI Pd], other PI catalysts: Chem. Rev. 2009, 594. RCS Adv. 2012, 7456. and related references Baran Group Meeting Hai Dao Shu Kobayashi 04/20/2013

[PI Pd] vs. [PMI Pd] in Heck Reaction Nanoclusters in PI Catalysts I CO2Et [PI Au] for Oxidation Using Molecular Pd cat. (0.001 mol%) + CO2Et NaBH4 K CO (2 eq.), solvent cross linking 2 3 AuClPPh3 NMR, 120 oC, 24 h copolymer [MC Au] [PI Au] formation of [PI Pd] (hexane/THF): 52% (TON = 52300) gold nanocluster [PMI Pd] (MeOH/DCM): 83% (TON = 82500) O "Three-phase tests": OH [PI Au] (1 mol%), air Pd cat. cleavage Ar I Heck-adducts Ph Me K2CO3 (3 equiv), rt, PhCF3/H2O Ph Me Heck conditions 5h, 88% Angew. Chem. 2007, 4229. no or low level of active Pd(PPh3)4: 48 %; Pd/C: 10%; [PMI Pd]: 2% species in solutions

[PI/CB Au]: incoporate carbon black (CB) into microencapsulated Au to Pd polymer micelles = nano reactors J. Am. Chem. Soc. 2005, 2125. enhance stability of goldnanoclusters Bimetallic Effect in PI catalysts PI Catalysts Variation: Polymer-Micelle Incarcerated (PMI) Bimetallic nanoclusters: (reactivity of nanoclusters can be tunned by combination with other metals) PI catalysts PMI catalysts control size of clusters through - "ligand effect": donating and accepting electron btw two metals structure of metal clusters are formation of polymer micelles - "ensemble effect": independent activations of substrates not well regulated during formation of MC Roucoux, A; Patin, H. et al. Chem. Rev. 2002, 3757. Chiral Rh/Ag Nanoparticles for Asymmetric 1,4 Additions: Synthesis of [PMI Pd] O PI/CB cat. (0.75 mol% as Ph) Ph O iPr Me + Ligand (1 mol%) iPr Me toluene/H O, 100 oC, 6 h * PhB(OH)2 2 [PI/CB Rh]: 18% (-ee) vs. [PI/CB Rh/Ag(1/3)] 77% (92% ee) One-pot Reaction PI/CB Au(0.5 mol%) PI/CB Rh/Ag (1.5 mol%) change in structure of OH Ph O K2CO3 (0.5 eq) Ligand (2 mol% ) copolymers for micellar formation Pr Ph toluene/H O Pr * Ph 2 PhB(OH)2 (2 eq) o O2, 60 C, 16h Ar, 100 oC, 18h 88% (94% ee) iPr J. Am. Chem. Soc. 2012, 16963. Ligand OH

Application of PI Catalysts to Microchannel Reactor, Science 2004, 1305. Hai Dao Baran Group Meeting Shu Kobayashi 11/03/2012 Part 5. Other Works

Microreactor: Science 2004, 1305. : Chem. Soc. Rev., 1999, 1.