meet the players...chodkiewicz w., cadiot p., willemart a.:. compt. rend. 1957, 245, 2061. 10 [cu]...

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1 Catalytic Dipolar Cycloadditions: Adventures with Copper, Ruthenium, and Rhodium Valery V. Fokin Associate Professor The Scripps Research Institute [email protected] http://www.scripps.edu/chem/fokin Meet the Players (H,R 2 ) R 1 N N N R 3 O N R 3 R 1 N N R 3 R 1 R 4 H N SO 2 R 3 R 1 O N N SO 2 R 3 R 1 R 4 R 1 N N N R 3 R 1 R 2 N N N R 3 R 1 O N R 3 R 2 O N R 3 R 1 R 1 HN N R 3 Cl R 3 N 3 HO N R 3 Cl R 3 SO 2 N 3 R 3 N 3 HO N R 3 Cl a. R 3 SO 2 N 3 R 4 N R 4 [Ru] [Cu] b. [Rh]

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  • 1

    Catalytic Dipolar Cycloadditions:Adventures with Copper, Ruthenium, and Rhodium

    Valery V. FokinAssociate Professor

    The Scripps Research Institute

    [email protected] http://www.scripps.edu/chem/fokin

    Meet the Players

    (H,R2)R1

    NN

    NR3

    O NR3

    R1

    N NR3

    R1

    R4

    HN

    SO2R3R1O

    NN SO2R3

    R1

    R4

    R1

    NN

    NR3

    R1R2

    NN

    NR3

    R1

    O NR3

    R2O N

    R3R1

    R1

    HN N

    R3Cl

    R3 N3 HO N

    R3Cl

    R3SO2N3

    R3 N3HO N

    R3Cl

    a. R3SO2N3

    R4

    NR4

    [Ru]

    [Cu]b. [Rh]

  • 2

    Organic Azides: Reactivity

    • Very energetic

    • Yet most are stable and can be handled safely if simple precautions are observed

    • Virtually inert to most other functionalities (certainly bio-orthogonal)

    Organic Azides: Reactivity

    • Very energetic

    • Yet most are stable and can be handled safely if simple precautions are observed

    • Virtually inert to most other functionalities (certainly bio-orthogonal)

  • 3

    Organic Azides: Reactivity

    • Very energetic

    • Yet most are stable and can be handled safely if simple precautions are observed

    • Virtually inert to most other functionalities (certainly bio-orthogonal)

    NNN

    RNu

    δ+δ−

    M, E+

    Organic Azides: Making Connections

    The Modified Staudinger Ligation

    Saxon E., Bertozzi C.R. Cell Surface Engineering by a Modified Staudinger Reaction.

    Science 2000, 287, 2007.

  • 4

    Organic Azides: Making Connections

    Kolb H.C., Finn M.G., Sharpless K.B. Click chemistry: Diverse chemical function from a few good reactions.

    Angew. Chem. Int. Ed. 2001, 40, 2004.

    “Click chemistry ideals are beautifully represented among cycloaddition reactions involving heteroatoms … especially 1,3-dipolar cycloadditions.

    OH

    N318

    CN

    Cl

    OH

    NNN

    CN19

    SN3

    N3 MeO2C CO2Me SN

    NNN

    N N

    MeO2C

    MeO2C

    CO2Me

    CO2Metoluene, 95°C, 5h90%

    16 17

    H2O, reflux85%

    Organic Azides: Making Connections

    “Click chemistry ideals are beautifully represented among cycloaddition reactions involving heteroatoms … especially 1,3-dipolar cycloadditions.

    OH

    N318

    CN

    Cl

    OH

    NNN

    CN19

    SN3

    N3 MeO2C CO2Me SN

    NNN

    N N

    MeO2C

    MeO2C

    CO2Me

    CO2Metoluene, 95°C, 5h90%

    16 17

    H2O, reflux85%

    However, the desired triazole-forming cycloaddition requires elevated temperatures or highly activated dipolarophiles, and usually results in a

    mixture of the 1,4- and 1,5-regioisomers.

  • 5

    Azide-Alkyne Cycloaddition: Synthesis of 1,2,3-Triazoles

    A. Michael, J. Prakt Chem. 1893, 48, 94.

    EtOOC

    N N N NN

    N

    COOEtCOOEt EtOOC

    • Both are energetic, but sufficiently stable• Chemically inert to most other functionalities• React irreversibly forming 1,2,3-triazoles (ΔH = - 55 to -65 kcal/mol)

    NN

    N NN

    N

    Azide – Alkyne Cycloaddition:Making Connections

  • 6

    NN

    N NN

    N

    • Both are energetic, but sufficiently stable• Chemically inert to most other functionalities• React irreversibly forming 1,2,3-triazoles (ΔH = - 55 to -65 kcal/mol)

    BUT very slowly and not regioselectively

    Azide – Alkyne Cycloaddition:Making Connections

    1,2,3-Triazoles

    • Very stable to oxidation, reduction, and hydrolysis • High dipoles (ca. 4.7 – 5.2 Debye)• Weakly basic (N-2 and N-3 are H-bond acceptors)• Favorable metabolism and toxicology profiles

  • 7

    Properties of 1,2,3-Triazoles

    • Weakly basic hydrogen bond acceptors (at N2, N3)

    • Much less basic than next member in the series

    pKBH+ = 1.2pKa = 9.3

    pKBH+ = 0 pKBH+ = 1 pKBH+ = 5.2 pKBH+ = 7 pKBH+ = 9.3

    pKBH+ = 1.2pKa = 9.3

    pKBH+ = 3.6

    • Stable to severe reductive and oxidative conditions

    Properties of 1,2,3-Triazoles

  • 8

    • Two launched drugs and a number of compounds under investigation contain 1,2,3-triazoles

    Tazobactamß-lactamase inhibitor

    Substance P antagonist*Currently under investigation by Merck

    RufinamideAnti-epileptic

    131 MDDR hits on this general fragment

    1,2,3-Triazoles

    Organic Azides: Reactivity

    NNN

    RNu

    δ+δ−

    M, E+

  • 9

    Metal Acetylides: Reactivity

    G.S. Akimova, V.N. Chistokletov, A.A. Petrov, Zh.Obsh. Khim. 1965, 1, 2077.G.S. Akimova, V.N. Chistokletov, A.A. Petrov, Zh. Org. Khim. 1967, 3, 2241.

    [M] = Li, Mg

    Copper(I) Acetylides: Reactivity

    C. Glaser Ber. Dtsch. Chem. Ges. 1869, 2, 422.

    CuHNH4OH

    CuCl

    NH4OH

    O2

    CuCH3COOH

    Δ +

    F. Straus Justus Liebigs Ann. Chem. 1905, 190.

    HBr

    1. CuCl, NH2OH•HCl, EtNH2

    2.

    Chodkiewicz W., Cadiot P., Willemart A.:. Compt. Rend. 1957, 245, 2061.

  • 10

    [Cu]

    Cu

    CuCu

    Cu

    Cu

    Cu

    Structure of Copper(I) Acetylides

    [Cu]

    Structure of Copper(I) Acetylides

    Cu

    CuCu

    Cu

    Cu

    Cu

    Cu

    Cu

    Cu

    Cu

    CuCu

    Cu

    Cu

    Cu

    CuCu

    Cu

    Cu

    Cu

  • 11

    In situ Generation of ReactiveCopper(I) Acetylides

    R HCu(II), Ascorbate

    H2OR [Cu]

  • 12

    CuAAC:

    Copper-Catalyzed Azide-Alkyne Cycloaddition

    Not “click chemistry” and was not discovered when the 2001 Angewandte “Click Chemistry”paper was published.

    Surely a click reaction, but not click chemistry!

    N

    NNHO

    O

    O

    PhHO

    O

    N

    NN

    O PhCuSO4 • 5H2O, 1 mol%

    sodium ascorbate, 5 mol%

    H2O, r.t., 6 h88%

    NN

    NNH

    N NN

    NH

    NH2

    HN

    NN

    N N

    N

    NN

    NH

    NH2

    H2N

    CuSO4 � 5H2O, 1 mol%sodium ascorbate, 5 mol%

    H2O/tBuOH, 4 : 1, r.t., 2 h

    88%

    CuAAC: Simple, Reliable, Tolerant

  • 13

    N NN

    O NH

    O COOH

    HNO

    HOOC

    NNN

    HN

    O

    COOH

    O

    NHO

    H3COOCNH

    HN

    COOHO

    NNN

    O O

    HN COOCH3

    NH

    HNCOOCH3

    OO

    NNN

    O

    HN

    OCOOH

    H3COOC

    HOOCHN

    NH

    O

    O

    O

    HNNH

    COOCH3O

    COOCH3O

    NNN

    NN

    N OHNAcHO

    O

    H3COOCS

    NH

    N NN O

    N

    O

    HNOH3COOC

    COOH

    S

    H3COOC SHN

    N

    O

    NN

    ONH

    OHOOC

    2, 90% 1, 96%

    4, 72%

    8, 90%

    6, 93%5, 84%

    7, 93%

    3, >99%

    CuAAC: Hydrolysis-Stable Amide Bond Surrogate

    O

    H

    H H

    OH H

    NHN

    O

    OO

    OH

    N3

    O

    H

    H H

    OHN

    NN

    NHN

    O

    O

    O

    OH

    5% CuSO410% Sodium ascorbate

    Dioxane/H2O45 oC, 8 h

    6 grams, 90%

    CuAAC: “Fusing” complex molecules

  • 14

    DendrimersDendrimers

    Complete control of size and shapeComplete control of size and shape

    Chemically addressable surfaceChemically addressable surface

    Multivalent, polyfunctionalMultivalent, polyfunctional

    O

    O

    NN

    N

    N NN

    R

    R

    O

    O

    NN

    N

    N NN

    O

    O

    NN

    N

    N NN

    R

    R

    OO

    NNNN

    NN

    R R

    OO

    NNNN

    NN

    OO

    NNNN

    NN

    R R

    O

    O

    NN

    N

    NN N

    OO

    NNNN

    NN

    R R

    OO

    NNNN

    NN

    OO

    NNNN

    NN

    R R

    O

    O

    NN

    N

    N NNR

    R

    O

    O

    NN

    N

    N NN

    O

    O

    NN

    N

    N NNR

    R

    O

    O NN

    N

    NN

    N

    O

    O

    NN N

    NNN

    R

    R

    O

    O

    NN N

    NNN

    O

    O

    NN N

    NNN

    R

    R

    O

    O

    NN N

    NNN

    R

    R

    O

    O

    NN N

    NNN

    O

    O

    NN N

    NNN

    R

    R

    O

    O

    NN N

    NNN

    O

    O

    NN N

    NNN

    O

    NN N

    1716

    NN

    NN

    OO

    OO

    N N

    N OO

    O

    NN

    O

    O

    OH

    HOH

    H

    O

    OO

    O

    OCl

    NO

    Cl

    Cl

    S OO

    N

    1

    2

    3

    4 5 6

    N3

    N3 MeOO

    N3

    9

    N3HO

    8

    N3HO

    O

    7

    NN3tBuO

    O

    H

    CuAAC: Synthesis of Dendrimers

  • 15

    • ca. quantitative yield for each step of the reaction sequence

    • only stoichiometric amounts of reagents

    • no byproducts: no chromatography up to the 4thgeneration

    Wu, P. et al. Angew. Chem. Int. Ed. 2004, 43, 3928.

    CuAAC: Synthesis of Dendrimers

    O

    OO

    OO

    O

    O

    OOO

    OHOH

    O

    HOHO

    OO

    O

    OHO

    HO

    OHO

    HO

    O

    OO

    O

    O

    OOO

    OHOH

    O

    HOHO

    OO

    O

    OHO

    HO

    OHO

    HO

    CuAAC: Polyfunctional Dendritic Probes

  • 16

    NNN

    O

    O O

    OO

    O

    NHO

    O

    O

    N

    NN

    N

    NH

    O OO

    N

    NN

    N

    O

    OO

    OO

    O

    O

    OOO

    OHOH

    O

    HOHO

    OO

    O

    OHO

    HO

    OHO

    HO

    O

    OO

    O

    O

    OOO

    OHOH

    O

    HOHO

    OO

    O

    OHO

    HO

    OHO

    HO

    CuAAC: Polyfunctional Dendritic Probes

    NNN

    O

    O O

    OO

    O

    NHO

    O

    O

    N

    NN

    N

    NH

    O OO

    N

    NN

    N

    O

    OO

    OO

    O

    O

    OOO

    OO

    O

    OO

    OO

    O

    OO

    O

    OO

    O

    O

    O

    O

    OO

    OO O

    O

    OO

    O

    O

    OOO

    OO

    O

    OO

    OO

    O

    OO

    O

    OO

    O

    O

    O

    O

    OO

    OO O

    CuAAC: Polyfunctional Dendritic Probes

  • 17

    NNN

    O

    O O

    OO

    O

    NHO

    O

    O

    N

    NN

    N

    NH

    O OO

    N

    NN

    N

    O

    OO

    OO

    O

    O

    OOO

    OO

    O

    OO

    OO

    O

    OO

    O

    OO

    O

    O

    O

    O

    OO

    OO O

    OHO

    HOHO

    HO

    O N NN

    OOH

    HOHO

    HO

    O NN N

    OOHHO

    HO

    HO

    ON

    N N

    OOHHO

    HO

    HO

    O

    NN N

    OOHHOHO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NNN

    OOH

    HOHO

    HO

    O

    NN

    N

    O

    OO

    O

    O

    OOO

    OO

    O

    OO

    OO

    O

    OO

    O

    OO

    O

    O

    O

    O

    OO

    OO O

    OHO

    HOHO

    HO

    O NN

    N

    OOH

    HOHO

    HO

    O NN N

    OOHHO

    HO

    HO

    ON

    N N

    OOHHO

    HO

    HO

    O

    NN N

    OOHHO

    HO

    HO

    O

    NN N

    OHHO

    HO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NN

    N

    CuAAC: Polyfunctional Dendritic Probes

    NNN

    O

    O O

    OO

    O

    NHO

    O

    O

    N

    NN

    N

    NH

    O OO

    N

    NN

    N

    O

    OO

    OO

    O

    O

    OOO

    OO

    O

    OO

    OO

    O

    OO

    O

    OO

    O

    O

    O

    O

    OO

    OO O

    OHO

    HOHO

    HO

    O N NN

    OOH

    HOHO

    HO

    O NN N

    OOHHO

    HO

    HO

    ON

    N N

    OOHHO

    HO

    HO

    O

    NN N

    OOHHOHO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NNN

    OOH

    HOHO

    HO

    O

    NN

    N

    O

    OO

    O

    O

    OOO

    OO

    O

    OO

    OO

    O

    OO

    O

    OO

    O

    O

    O

    O

    OO

    OO O

    OHO

    HOHO

    HO

    O NN

    N

    OOH

    HOHO

    HO

    O NN N

    OOHHO

    HO

    HO

    ON

    N N

    OOHHO

    HO

    HO

    O

    NN N

    OOHHO

    HO

    HO

    O

    NN N

    OHHO

    HO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NN N

    OOH

    HOHO

    HO

    O

    NN

    N

    P. Wu, M. Malkoch, J.N. Hunt, R. Vestberg, E. Kaltgrad, M.G. Finn, V.V. Fokin, K.B. Sharpless, and C.J. Hawker, Chem. Comm. 2005, 5775-5777

    240-fold more potentthan mannose inhemagglutination

    CuAAC: Polyfunctional Dendritic Probes

  • 18

    CuAAC: One Pot Synthesis of 1,2,3-Triazoles

    OPh

    Cl

    NNN

    PhO

    CuSO4 • 5H2O, 1 mol%sodium ascorbate, 5 mol%

    H2O/DMSO, 10 : 1, 60 oC, 12 h

    96%

    NaN3 3 eq.

    Cl

    N NN

    OPh

    Feldman A.K., Colasson B., Fokin V.V. Org. Lett. 2004, 6, 3897.

    R Br NaN3Cu(0), CuSO4, MW

    tBuOH, H2O, 10-15 min125 oC

    NN

    N

    R1

    R1

    H

    R

    CuAAC: One Pot Synthesis of 1,2,3-Triazoles

    P.Appukkuttan, W.Dehaen, V.V. Fokin, E. Van der Eycken Org. Lett. 2004, 6, 4223.

  • 19

    NN

    N

    Ph HCN

    NN

    N

    Ph HO

    O

    O

    NN

    N

    Ph

    Me

    HN

    NN

    HHO

    84% 91%

    89% 81%

    R Br NaN3Cu(0), CuSO4, MW

    tBuOH, H2O, 10-15 min125 oC

    NN

    N

    R1

    R1

    H

    R

    CuAAC: One Pot Synthesis of Triazoles

    P.Appukkuttan, W.Dehaen, V.V. Fokin, E. Van der Eycken Org. Lett. 2004, 6, 4223.

    CuAAC: a Closer Look at the Catalyst

    Cu(II)

    Cu(I)

    Cu(0)

    Oxidation Disproportionation

    Cu+ + 1e- Cu0 Eo = 0.52 V

    Cu2+ + 1e- Cu+ Eo = 0.16 V

    Cu+ + Cu+ Cu0 + Cu2+ K ~ 106

  • 20

    Ph H

    HO

    N

    OH

    N

    NN PhNN

    Ph

    +

    Cu0 (on a stirbar)

    H2O/t-BuOH, 2 : 1

    RT, 24 hrs

    MW, 150 oC, 5 min

    99%

    N

    HO

    N

    OH

    N N

    NN

    CuAAC: Copper Metal Catalyzes the Reaction

    Rx N3

    Ry

    +H

    Rx

    N3

    RxN3

    Ry

    H

    Ry

    H

    24 - 48 hDMSO, water, tBuOH ...

    RxN

    NN

    H

    Ry Rx

    NN

    NH

    Ry

    RxN

    NN

    H

    Ry

  • 21

    Azide: 100 μL of 20 mmol solution in tBuOH (final conc. 5 mM)

    Alkyne: 100 μL of 24 mmol solution in tBuOH (final conc. 6 mM)

    CuSO4 200 μL of 0.05 mmol aq. solution (final conc. 0.025 mM)

    Added to a small piece of copper turning in a sealed mictrotiter plate and shaken at 40 ºC for 36 hrs. Completion determined by disappearance of azide using LCMS.

    Reactions initially diluted to 0.5 mM with DMSO, then to 10 μM with aq. buffer into 96 well plates

    Analysed for HIV-1 protease inhibition using a fluorescence assay

    Active compounds further diluted and re-assayed

    CuAAC: HIV-1 Protease InhibitorsSynthesis of the screening libraries

    R2

    HN

    N3

    R3

    O

    R1 1.1 eq.alkyne, 5 mol % CuSO4, Cu wire,1:1 tBuOH/H20, 50 ºC, 36 hrs

    R2

    HN

    N

    R3

    O

    R1

    NN

    R4

    + R4

    R1 = Various, R2, R3 = iBu, Bn, R4 = Various

    4 azides 70 alkynes280 triazoles

    Without the triazole ring all compounds were essentially inactive

    Further functionalisation of the triazole ring at the 5 position is OK and leads to more potent analogs

    PhPh

    HN

    HN

    O

    O

    O

    N

    PhPh

    HN

    HN

    O

    O

    O

    N NN

    PhPh

    HN

    HN

    O

    O

    NN

    HO

    PhPh

    HN

    N

    O

    O

    NN

    N N

    1) 2.2 eq. n-BuLi, -78 ºC, THF2) Electrophile

    PhPh

    HN

    N

    O

    O

    NN

    N N

    E

    E = HTMSCH2OHCH(CH3)OH

    IC50 = 134 nM10 µM56 nM43 nM

    CuAAC: HIV-1 Protease InhibitorsFunctionalization of the triazole

    Whiting M., Tripp J., Lin Y.-C., Lindstrom W., Olson A.J., Sharpless K.B., Elder J.H., Fokin V.V.J. Med. Chem. 2006, 49, 7697.

  • 22

    PhPh

    HN

    N

    O

    O

    NN

    N N

    ClOH

    Ki = 8 nM

    Ph PhHN

    N

    O

    O

    NN

    N N

    ClOH

    Ki = 20 nM

    CuAAC: HIV-1 Protease InhibitorsFunctionalization of the triazole

    Whiting M., Tripp J., Lin Y.-C., Lindstrom W., Olson A.J., Sharpless K.B., Elder J.H., Fokin V.V.J. Med. Chem. 2006, 49, 7697.

    CuAAC: a Closer Look at the Catalyst

    Cu(II)

    Cu(I)

    Cu(0)

    Oxidation Disproportionation

    Cu+ + 1e- Cu0 Eo = 0.52 V

    Cu2+ + 1e- Cu+ Eo = 0.16 V

    Cu+ + Cu+ Cu0 + Cu2+ K ~ 106

  • 23

    N

    "Cu"

    N

    N

    N

    Ph

    NN

    N

    PhN N

    NPh

    CuAAC: Accelerating/Stabilizing Ligand,TBTA

    NN

    NN

    N NN

    N

    NN

    Ph

    PhPh

    85%

    T.R. Chan et al, Org. Lett. 2004, 6, 2853.

    Cu+ + 1e- Cu0 Eo = 0.52 V

    Cu2+ + 1e- Cu+ Eo = 0.16 V

    Cu2+ + 1e- Cu+ Eo ~ 0.45VTBTA

    CuAAC: Resin-Supported TBTA

    TBTATris(BenzylTriazolyl)Amine

    TG-TBTATentaGel resin

    • Solution-phase ligand capable of supporting copper(I) catalysis

    • Avoids the use of reducing agents and large loeading of copper

    • Solid-phase catalyst facilitates separation of copper and ligand from products

    • TentaGel resin exhibits excellent swelling properties in a wide variety of solvents

    N

    NNN

    NN

    NN

    N N

    Bn

    Bn

    Bn N

    NNN

    NN

    NN

    N N

    Bn

    Bn

    Linker

    T.R. Chan, V.V. Fokin, QSAR and Comb. Sc. 2007, 1274.

  • 24

    Copper wash

    (e.g. Cu(MeCN)4PF6, CH2Cl2)

    NHTBTA

    O

    NHTBTA

    OCuPF6

    • Copper loading determined by leaching resin with pyridine (24 h), and the resulting solution analyzed by ICP-AA

    • Copper loading measured to be 0.19 mmol/g

    • loading is quantitative (TBTA:Cu stoichiometry determined to be 1.01:1)

    T.R. Chan, V.V. Fokin, QSAR and Comb. Sc. 2007, 1274.

    CuAAC: Resin-Supported TBTA

    Reactions performed at 50ºC, at 0.10 M concentration in MeOH with 3-4 mol% of catalyst (4 mg), purity determined by HPLC.

    CuAAC: Resin-Supported TBTA

  • 25

    CuLx•R1

    N NN R2

    NN

    N R2

    CuLxR1

    CuLxR1N

    NNR2

    R1 CuLx

    NNN R2

    R1 H

    NN

    N R2

    HR1[CuLx]

    H+H+Step A

    Step B

    Step C

    Step D

    Step E

    CuAAC: Not a Concerted Process

    F. Himo et al. J. Am. Chem. Soc. 2005, 127, 210-216

    DFT CalculationsUncatalyzed cycloaddition Ea = 25.4-26 kcal/molCopper-catalyzed cycloaddition Ea = 14.5 kcal/mol

    KineticsRate = [Azide]1[Alkyne]1.3-1.6[Cu]2

    Ea = 11 kcal/mol

    F. Himo et al. J. Am. Chem. Soc. 2005, 127, 210-216V. Rodionov et al. Angew. Chem. Int. Ed. 2005, 44, 2210-15

    M. Ahlquist et al. Organometallics 2007, 26, 4389-93

    CuAAC: Key Mechanistic Parameters

    [Cu]CuLR1

    NNN

    R2CuL•

    R1

    N NN R2

    [Cu]

  • 26

    CuAAC: An Isolated Example or a New Reactivity Manifold of Cu acetylides ?

    CuAAC: An Isolated Example or a New Reactivity Manifold of Cu acetylides ?

  • 27

    R1 H

    O

    1. H2NOH·HCl, NaOH

    t-BuOH:H2O (1:1)

    2. TsNClNa·3H2O

    R1

    ON3.Cu0/CuSO4 (cat.) R2

    R2

    Copper-Catalyzed Synthesis of Isoxazoles

    Hannsen, T., Wu, P., Fokin, V.V. J. Org. Chem. 2005, 70, 7761.

    R1 H

    O

    1. H2NOH·HCl, NaOH

    t-BuOH:H2O (1:1)

    2. TsNClNa·3H2O

    R1

    ON3.Cu0/CuSO4 (cat.) R2

    R2

    R1 H

    NR1 N

    R2H2NOH

    TsNClNa·3H2OO

    Cu0/CuSO4 (cat.)

    OH

    Copper-Catalyzed Synthesis of Isoxazoles

    Hannsen, T., Wu, P., Fokin, V.V. J. Org. Chem. 2005, 70, 7761.

  • 28

    ON O

    ONON

    70%

    73%72%

    ON

    61%

    OO

    OH

    H

    H

    ON

    MeO OH

    H

    66%

    ON

    OH

    76%

    Copper-Catalyzed Synthesis of Isoxazoles

    Hannsen, T., Wu, P., Fokin, V.V. J. Org. Chem. 2005, 70, 7761.

    CuSO4Ascorbic acid

    NaOAc 45 oC, 4-8hNH2

    i) 1.0 equiv. NaNO2 2.0 equiv. HBr

    ii) 1.0 equiv.

    H2O+(Methanol or MeCN)

    NHN

    ClEtO

    O

    R2

    NN R2

    EtOO

    1.0 equiv.

    O

    Cl

    O

    OEt

    R1 = H, Cl, Br, NO2, SO2NH2

    R1R1 R

    1

    Copper-Catalyzed Synthesis of Pyrazoles

    NN

    EtO2C

    Br

    81%

    Cl

    NN

    EtO2C

    Ph

    SO2NH2

    79%

    NN

    EtO2C

    Ph

    83%

    CN

    X. Wang, V.V. Fokin 2008, unpublished

  • 29

    CuLx•R1

    N NN R2

    NN

    N R2

    CuLxR1

    CuLxR1N

    NNR2

    R1 CuLx

    NNN R2

    R1 H

    NN

    N R2

    HR1[CuLx]

    H+H+Step A

    Step B

    Step C

    Step D

    Step E

    CuAAC: Not a Concerted Process

    F. Himo et al. J. Am. Chem. Soc. 2005, 127, 210.

    CuLxR1N

    NNR2

    M

    NNN

    R2

    H

    R1

    CuLxR1

    NNN R2 N NN R2

    R1

    N NN R2

    R1M

    NNN

    H

    R1

    R2

    Can other metals do the trick?

  • 30

    RuAAC: the 1,5-Regioisomer

    Zhang, L. et al. J. Am. Chem. Soc. 2005, 127:15998.

    R1 HNN

    N R2

    H+Step A

    Step BStep C

    Step D

    RuCl NN

    N

    R2

    R1

    RuCl NN

    N

    R2

    R1

    RuCl LL

    NNN R2

    RuCl N

    NN

    R2

    R1

    R1

    RuAAC: Mechanism

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

  • 31

    RuAAC: Terminal Alkynes

    93%

    N3

    N

    NN

    NH2

    N

    NN

    H2N

    OH HO

    83%

    N3

    Cp*RuCl(PPh3)2, 2 mol%

    Dioxane, 60 oC, 1h

    Cp*RuCl(PPh3)2, 2 mol%

    Dioxane, 80 oC, 18h

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

    very stable,catalytically inactive

    RuAAC: Catalyst Deactivation

    Hursthouse J. Chem. Soc. Dalton Trans. 1996, 3771

    RuClL

    L

    N N NR2

    RuClN

    NN

    N R2

    , 3 eq

    r.t., toluene R2RuCl

    NR2

    N N NR2

    Ru

    N N

    NN

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

  • 32

    RuAAC: Terminal Alkynes/Aryl Azides

    L.K. Rasmussen, B.C. Boren, V.V. Fokin, Org. Lett. 2007, 5337.

    O O

    OH

    N3OH

    OH

    OH

    OH NOH

    HOOH

    HO

    NN

    OH

    75%

    N3

    N

    NNH

    O

    N NN

    N

    N

    NH

    O

    81%

    NN

    OO

    N3 NN

    OO

    N NN

    Cp*RuCl(PPh3)2, 2 mol%

    Dioxane, 60 oC, 2h

    90%

    O O

    Cp*RuCl(PPh3)2, 2 mol%

    Dioxane, 60 oC, 8h

    Cp*RuCl(PPh3)2, 2 mol%

    Dioxane, 60 oC, 8h

    RuAAC: Terminal Alkynes

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

  • 33

    RuAAC: Internal Alkynes

    PhN3 Ph

    N

    NN

    [Ru], 4 mol%

    r.t., toluene, 4h

    83%, 0.48 g

    +Ph

    Ph

    PhN

    NN

    76%, 0 42g

    + [Ru], 4 mol%

    r.t., toluene, 4h

    2.4 mmol

    PhN3

    2 mmol

    2.4 mmol

    2 mmol

    [Ru] = RuCl

    RuCl

    Ph3PPh3P

    OR

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

    RuAAC: Internal Alkynes

    PhN3

    PhN

    NN

    HOHO

    83%

    + Ph

    Ph

    EtON3

    EtON

    NN

    HOHO

    72%

    +

    O

    OH

    OHO

    Cp*RuCl(COD), 2 mol%RT, 1,2-DCE, 2h

    Cp*RuCl(COD), 2 mol%RT, 1,2-DCE, 2h

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

  • 34

    RuAAC: Internal Alkynes

    PhOH

    N3 NNN

    Ph

    OH

    Ph NO

    O

    N3

    NN N

    PhN

    O

    O

    Cp*RuCl(COD), 2 mol%RT, 1,2-DCE, 2h

    +

    + Cp*RuCl(COD), 2 mol%RT, 1,2-DCE, 30 min

    93%

    95%

    Boren, B.C. et al, J. Am. Chem. Soc. 2008, 8923.

    Ru-Catalyzed Synthesis of Isoxazoles

    Grecian, S., Fokin, V.V. Angew. Chem. Int. Ed. 2008, in press.

    Cl

    NOH

    +

    NO

    Cl

    PhCl

    Cp*RuCl(COD), 2 mol%

    NO

    O

    MeMe

    Ac

    Cl

    NOH

    O

    MeMeAc

    + Cp*RuCl(COD), 2 mol%

    89%

    93%

    Et3N, 1.1 eq, 1,2-DCE, RT

    Et3N, 1.1 eq, 1,2-DCE, RT

    NO

    OMeMe

    AcCl

    NOH

    O

    MeMeAc

    +

    21%

  • 35

    Ru-Catalyzed Synthesis of Isoxazoles

    Grecian, S., Fokin, V.V. Angew. Chem. Int. Ed. 2008, in press.

    1,2,3-Triazoles are very stable, except ...

    O. Dimroth, Lieb. Ann. 1909, 364, 183

    NN

    N Ar

    Ar Li

    N

    RAr

    LiN

    Ar.LiAr

    R. Raap, Can. J. Chem. 1971, 49, 1792-1798

  • 36

    Ph[Cu]

    SO2TolN

    NN

    NSO2Tol

    Ph

    N

    N

    [Cu]Ph

    Ph

    NSO2Tol

    TolO2SNH

    HPh

    NNSO2TolN

    NSO2TolPh

    TolO2SN Ph

    [Cu]

    H+

    - H+

    -[Cu], -N2

    Ph

    NSO2Tol

    [Cu]

    -N2 H+, -[Cu]

    Ph

    H

    NSO2Tol

    Sulfonyl Azides – Mild Route to Keteneimines

    CuAAC: Reactions of Keteneimines

    Chang S. et al., JACS, 2005M. Cassidy, J. Raushel, V.V. FokinAngew. Chem. Int. Ed. 2005

    M. Whiting, V.V. FokinAngew. Chem. Int. Ed. 2005

  • 37

    CuAAC: One Pot Synthesis of Azetidinimines

    N

    NSO2R'R

    PhPhHR

    SO2N3

    Ph NPh

    +

    CuI, 10 mol%pyridine, 2 equiv

    CH3CN, 0.5Mr.t., 16h

    N

    NSO2R'R

    PhN

    NSO2R'R

    PhN

    NSO2R'R

    Ph

    NF3C

    Cl

    81% 65%79%

    M. Whiting, V.V. Fokin Angew. Chem. Int. Ed. 2005

    • Mårten Ahlquist• Michael Cassidy• Timothy Chan• Stepan Chuprakov• Scott Grecian• Luke Green• Jason Hein• Tony Horneff• Jason Kwok

    • Jarek Kalisiak• Larisa Krasnova• Ying-Chuan Lin• Suresh Pitram• Jessica Raushel• Jon Tripp• Mat Whiting• Timo Weide• Peng Wu

    NIH (NIGMS)Pfizer, Inc.

    The Skaggs Institutefor Chemical Biology

    Prof. Guochen Jia (Hong Kong UST)Prof. Vladimir Gevorgyan (UIC)Prof. K. Barry Sharpless (TSRI)Prof. Craig J. Hawker (UCSB)