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1
Catalytic Dipolar Cycloadditions:Adventures with Copper, Ruthenium, and Rhodium
Valery V. FokinAssociate Professor
The Scripps Research Institute
fokin@scripps.edu 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
R2
O NR3 R1
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
N3
18
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
N3
18
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 h 88%
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
COOCH3
O
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 NN
R
R
O
O
NN
N
N NN
O
O
NN
N
N NN
R
R
O
O NNN
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 4th
generation
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 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
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 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
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
Rx
N3
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 R2
CuL•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 R1
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 R2N N
N 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
N3N
N
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.Li
Ar
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)