Cu(I)-Catalyzed 1 3 DipolarCu(I) Catalyzed 1,3 Dipolar Cycloadditions
Anne-Marie DechertAnne-Marie DechertFeb. 7, 2008
Outline
• Introduction to 1 3 Dipolar Cycloadditions• Introduction to 1,3 Dipolar Cycloadditions• Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and
Alkynes– Cascade Reactions– Extension of the Original Methodology
S th i f β L t• Synthesis of β−Lactams– Kinugasa Reaction
• 1 3 Dipolar Cycloadditions Between Azomethine Ylides and Activated1,3 Dipolar Cycloadditions Between Azomethine Ylides and Activated Alkenes
1, 3 Dipolar Cycloadditions
AB
C
D E
AB
C
D E
Typical 1,3 Dipoles
R2C N O R2C N O R2C O O R2C O ONitrones Carbonyl Oxide2R
2R
R2C NR
CHR2 R2C NR
CHR2
R2C O O R2C O ONitrones
Azomethine Ylide
Ca bo y O de
R2C N N R2C N N Diazoalkane
RC N O RC N O
RN N N RN N N
Nitrile Oxide
Azide
RC N CHR2 RC N CR2
RC N NR RC N NR
Nitrile Ylide
Nitrile Imine
Typical Dipolarophiles
R2C N R Imine
RC CR
R2C CR2
RN O
Alkyne
Alkene
Nitroso
Padwa, A.; ed., 1,3-Dipolar Cycloaddition Chemistry, John Wiley & Sons, New York, 1984.
RN NR Azo
Stereospecificity
HHPhH
PhC N N PhPh
H
Ph
H
H
Ph
Ph
HN
N PhPh
H Ph
NN PhPh
H H
- Stereospecific syn addition with respect to dipolarophile
Ph H Ph Ph
H CH3H NNPh
H NNH
Ph
N NHCPh
3
H3CO2C CO2CH3
N
CO2CH3H3CO2CCH3H
Ph N
CO2CH3H3CO2CCH3H
H
Huisgen, R.; Seidel, G.; Wallibillich, G.; Knupfer, H. Tetrahedron 1962, 17, 3.Huisgen, R.; Eberhard, P. Tetrahedron Lett. 1971, 4743.
Regioselectivity
- Dominated by Frontier Molecular Orbital (FMO) interactions- Sterics can also play a role
C C
E
AB
C
E
AB
D
E
D
E
HOMOdipole - LUMOdipolarophile LUMOdipole - HOMOdipolarophile
typical for an electron def icient dipolarophile typical f or an electron rich dipolarophile
If the energies of the two interactions are similar, both reactions can occur.
Houk, K.; Sims, J.; Due, B.; Strozier, R.; George, J. J. Am. Chem. Soc. 1973, 95, 7287.
g ,
1,3 Dipolar Cycloadditions of Azides and Alkynes
The Cu(I) Catalyzed 1,3 Dipolar Cycloadditions of Azides and Alkynes
C CHR1N N N R2
NN NR2cat. Cu(I)
R1
NOHNN
O
Ph
NPhN N
Ph
NN N
Ph
NN N
HOO
N NPh
NEt2
82% 84%88% 90%
NN N
SO
O
H2NN
N NPhHO N
NN
HOOH
NHNH
H2NHO HO
Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Tornoe, C.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
91% 84% 94%
Generation of The Cu(I) Catalyst
C CHR1N N N R2
NN NR2
Cu(I) salt1.0 eq. 2,6-lutidine
Formation of Byproducts
RR diacetylenesC CHR N N N R2 N N
R1
Cu(I) salt = CuOTf.C6H6, CuBr, CuI
1.0 eq. 2,6 lutidine
5- hydroxyltriazolesN
N NR1
HO R( ) 6 6
bistriazoles
Cu(II) salt (0 25 2 0 mol %)
NN
N
R1
R
N N
N
R1
R
Cu(II) salt (0.25-2.0 mol %)Na ascorbate and/orascorbic acid (5-10 mol %)C CHR1
N N N R2N
N N
R1
R2
Click Chemistry
NN NR2
- high yielding- wide in scope- stereospecific- inoffensive byproducts- simple reaction conditions
C CHR1 N N N R2 copper metalN
R1
simple reaction conditions
Rostovtsev, V.; Green, L.; Fokin, V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.Kolb, H.; Finn, M.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. J. Am. Chem. Soc. 2005, 127, 210.
A Stepwise Mechanism is Proposed
Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. J. Am Chem. Soc. 2005, 127, 210.
The Unexpected Formation of Trisubstituted Triazoles
OMH
CuI, rt, 1h, air
OOH
N NN
OMeMeO
OOH
N3
OMeH
CuI, rt, 1h, airO
OHN N
N
OMe
OMe
Unexpected Result
OMe
p
Perhaps Glaser Coupling:
OOH
N3CuI, rt, 1h, air
MeO OH
OMeMeO
OH
OMe
MeO
Alternative Pathway:
O N NN
OOH
N NN
OMe
H
CuI, rt, 1h, air
OH
OMeMeO
Gerard, B.; Ryan, J.; Beeler, A.; Porco, J. Tetrahedron 2006, 62, 6405.
NOMe
H O N NN
Mechanistic Rational for the Formation of Trisubstituted Triazoles
N3Cu(CH3CN)4PF6(0.2 eq.)
ligand (0 2 eq )
MeMe
MeN
NH
Me
Me
Me
Me
HMe
ligand (0.2 eq.)DIEA (1 eq.)NMO (0.1 eq.)rt/air
NN
N NN
NN
NMe
Me
MeMe
Ligands
Proposed Mechanism:
Ligands
Proposed Mechanism:
R1LnCuR1L CHR1
HR1
DIEA R1L C
R1
II
NNN
R2
NNN
R2
RLnCu
B-H
HR DIEA
NNN
R2
RLnCu II
1.[O]2 red elimB H
BwithoutDIEA
R1H
2. red. elim
R1R1
Gerard, B.; Ryan, J.; Beeler, A.; Porco, J. Tetrahedron 2006, 62, 6405.
N NNR2
R1
NNN
R2
R
The Use of N-Sulfonyl Azides as 1,3 Dipoles
Finzi, P.; Grunanger, P. Tetrahedron Lett. 1963, 4, 1839.Yoo, E.; Ahlquist, M.; Kim, S.; Bae, I.; Fokin, V.; Sharpless, K. B.; Chang, S. Angew. Chem. Int. Ed. 2007, 46, 1730.Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
Proposed Route to Sulfonamides
Cu(I), 2 mol %TBTA, 2 mol %Na ascorbate 4 mol %HC C R1
BnN
NN NNNa ascorbate 4 mol %
NaHCO3, 1 eq
OR1
HN
SO2
R
N N N SO2R
N NBn
BnN NN
TBTA =
HC C R1
[Cu]N
N N SO2R-N2
R1 N[Cu]
SO2R
R1
N N N SO2R-H+
[Cu]R1
N
R1NSO2R•
H H2O ONH
O2SR
NSO2R
[Cu]
NN
R1
Cassidy, M.; Raushel, V.; Fokin, V. Angew. Chem. Int. Ed. 2006, 118, 3154.Cho S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16047.
A Cu(I) Catalyzed Cascade to Form Azetidinimines
Ligand t[h] trans-A: cis-A: B
2,6lutidine 3 80:13:7
HC C R1NPh
N N N SO2Tol
Cu(I), 10 mol %ligand (1 eq.)
N
NSO2Tol
R1 NN N SO2Tol
pyridine 3 95:5:0
TBTA <2 42:58:0
Ph MeCN, rt NPhPh HR1
NSO2R• N
Ph
Ph
A B
R1H Ph
via [2+2]BnN
NN
N NBnNN
TBTA =
Alkyne Scope
PhCu(I), 10 mol %
idi 2 NSO2Tol
R1
N
BnN NN
HC C R1NPh
PhN N N SO2Tol
pyridine, 2 eq.
MeCN, rt N
N
PhPh
N
NSO2Tol
PhPh
Ph
N
NSO2Tol
PhPh
Me Me
Cl
N
NSO2Tol
PhPh
TMS
Fokin, V.; Whiting, M. Angew. Chem. Int. Ed. 2006, 118, 3157.
yield = 90%trans: cis = 95:5
yield = 55%trans: cis = 95:5
yield = 48%trans: cis = 25:75
Reaction Scope: the Imine Component
SO2Tol
HC C PhNR2
R1N N N SO2Tol
Cu(I), 10 mol %pyridine, 2 eq.
MeCN, rt N
NSO2Tol
PhPh
R1
R1 R2 Yield(%) trans:cis
4-FC6H4 Ph 87 95:5
4-(MeO)C6H4 Ph 79 95:5
Ph SO2Ph 5 NR
CO2Et Ph 53 5:95
CO Et 4 (MeO)C H 63 5:95CO2Et 4-(MeO)C6H4 63 5:95
N N N S NO N N N S MO O O O
Fokin, V.; Whiting, M. Angew. Chem. Int. Ed. 2006, 118, 3157.
N N N S NO2 N N N S Br N N N S IN N N S MeO O O O
Synthesis of N-Sulfonyl-1,2,3-Triazoles
Yoo, E.; Ahlquist, M.; Kim, S.; Bae, I.; Fokin,V.; Sharpless, K. B.; Sukbo, C. Angew. Chem. Int. Ed. 2007, 46, 1730.
Fu’s Extension to Azomethine Imine Dipoles
Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.
Asymmetric Extension
NN
O
CO2Et
5% CuI0.5 eq. Cy2NMe
NN
O
CO2Et5.5% ligand A
PPh2
PPh2= A
H Ph 1.2 eq. Ph% g
<2%
N
O5% CuI0 5 eq Cy2NMe N
O
O
Me Me
O = BN
N
H PhCO2Et
1.2 eq.
0.5 eq. Cy2NMeNN
CO2Et
Ph5.5% ligand B
N N
iPr iPr
= B
O O
98%, 19% ee
MeO
NN
O
H PhCO2Et
1 2 eq
5% CuI0.5 eq. Cy2NMe
NN
O
CO2Et
Ph5.5% ligand C
= C
PMe
MeMe
Me
MeNiPr
Fe
Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.
1.2 eq.
98%, 90% ee
Asymmetric ExtensionO O
NN
O
H PhCO2Et
1 2
5% CuI0.5 eq. Cy2NMe
NN
O
CO2Et
Ph5.5% ligand A = A
PMeMe
MeMeO
NiPrFe
1.2 eq. Ph
98%, 90% ee
MeMe
O5% CuI
N
OP
MeMeO
NtBu
NN
H PhCO2Et
1.2 eq.
0.5 eq. Cy2NMeNN
CO2Et
Ph5.5% ligand B
= BMe
MeMe
MeN
Fe
100%, 58% ee
NN
O
H PhCO2Et
5% CuI0.5 eq. Cy2NMe
NN
O
CO2Et
Ph5.5% ligand C MeMe
P
MeMe
N
O
iPrFe= C
Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.
H Ph1.2 eq. Ph
MeMe
Me100%, 80% ee
Reaction Scope: The Azomethine Imine Component
Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.
Reaction Scope: The Alkyne Component
Me
NN
O
H PhR
5% CuI0.5 eq. Cy2NMe
NN
O
R
Ph5.5% ligand
PMe
Me
Me
MeMeO
NiPrFe
H Ph 1.2 eq. Ph Me
MeMe
O
NN
Ph CO2Et NN
O
NMe
Ph
77%, 88% ee
Ph
100%, 94% ee
O
NN
O
NN
O
Ph
73%, 88% ee
Ph
63%, 74% ee
Fu, G.; Shintani, R. J. Am. Chem. Soc. 2003, 125, 10778.- erosion of regioselectivity observed for electron rich alkynes
Application to Kinetic ResolutionApplication to Kinetic Resolution
Downey, W.; Fu, G.; Suarez, A. J. Am. Chem. Soc. 2005, 127, 11245.
Limitations to the Kinetic Resolution of Azomethine Imine Dipoles
Downey, W.; Fu, G.; Suarez, A. J. Am. Chem. Soc. 2005, 127, 11245.
Other Cu(I) Catalyzed 1,3 Dipolar Cycloadditions
Synthesis of Pyrazoles: A Direct Approach
i TsNHNH2 NN
2R1
O
HR1
i. TsNHNH2MeCN, rt, 3h
ii. 5M NaOH
N
R1
R2
NNH
R250 oC
1
20 mol % InCl
R1 = EDGR2 = EWG
OR1
O
R1
N2
R2
20 mol % InCl3H2O, rt
NNH
R2
R1 OE
R
O
R1 = OEtR2 = EWG
OR1
O
R1
N2
R2
R1 = OEt
NNH
R2
Aggarwal, V.; Bonnert, R.; Vicente, J. J. Org. Chem. 2003, 68, 5381.Jiang, N.; Li, C. Chem. Commun. 2004, 394.Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.
R2 = aryl, alkyl
Initial Attempts to Form Pyrazoles Using
Cu(I) as a PromoterCu(I) as a Promoter
Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.
Reaction Scope: The Alkyne Component
R H i) nBuLi -78 oC
ii) Cu (I), -17 oC
O
BnON2
NNH
R
O
BnO BnOH
) ( ), O
F3CCH3
NNBnO
CF3
NNBnO O
Diazocarbonyl Compounds
ONH
O
75% yield
NH
O
72% yield
BnON2
EtON2
O
Cl
O
t-BuON2
O
NN2Me
MeON
NNH
O
BnO NNH
O
BnO NNH
O
BnO
Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.
60% yield 74% yield 74% yield
A Concerted Mechanism
R CuLn
OR1
N NN R1
O
H
HN
N R1
ON
O
R1
N2
[3+2] R CuLn R
- EWGs slow reaction
R CuLn
EWGs slow reaction
- Similar rates in THF, ether, and toluene
- Observed regioselectivity
consistent witha concerted mechanism
- Observed regioselectivity
L b li St diLabeling Studies
HN OBn
O
Ph LiCuCN.6LiCl
O
BnON2
D
NN
Ph D
73 % D
BnOH Ph H/D
16% D
Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.
N2
An Unexplained Side Product
O
BnON2
DHN
NOBn
O
BnOH Ph H/DPh Li
CuCN.6LiCl Ph D
73 % D
BnOH Ph H/D
16% D
n 2 n 4 9 2
major product:BnOH
Non-deuterated 6.0:1deuterated
Deuterated 6.2:1
Ready, J.; Qi, X. Angew. Chem. Int. Ed. 2007, 46, 3242.
Outline
I d i 1 3 Di l C l ddi i• Introduction to 1,3 Dipolar Cycloadditions• Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and
Alkynesy– Cascade Reactions– Extension of the Original Methodology
• Synthesis of β−Lactams– Kinugasa Reaction
• 1 3 Dipolar Cycloadditions Between Azomethine Ylides and• 1,3 Dipolar Cycloadditions Between Azomethine Ylides and Activated Alkenes
Synthesis of β−Lactams
NO
S
COOH
R
OO• N
X NX O
The Staudinger Synthesis
COOH•
RR HR R RR
Staudinger, H. Liebigs. Ann. Chem. 1908, 356, 51.
Penicillin Core
Ullmann Type Coupling
Cl
Ph
NHTs CuIDMEDA
Cs2CO2
NTs
Ph
O3 NTsO
Ph
Lu H ; Li C Org Lett 2006 8 5365Lu, H.; Li, C. Org. Lett. 2006, 8, 5365.
Intramolecular C-H insertion
Rh2(S-PTA)4(5 mol %)ON
M O C
N2
ON
HHMeO2C
OMeO2C ON
O
Ananda, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 9063.
The Kinugasa Reaction
CHN
R1
N
O
R1
Ph
R2
R2
CC CuLnPh pyridine
O OPhR2
H OH
O
CC CuLnPh
[3+2]Ph CuLn
OH
H
CuLnPh
H OPh
H
CH
NR1 OR2
[3+2]
NO
R1
HR2
N OPh
R1
H R2N
Ph
R1
H R2
OPh
OPhOPh
H
NR1
H R2
NR1
H R2NR1
H R2
Kinugasa, M.; Hashimoto, S. J. Chem. Soc. Chem. Commun. 1972, 466-467.Ding, L.; Irwin, W. J. Chem. Soc. Perkin Trans. 1. 1976, 2382.Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.
Pioneering Efforts by Miura
Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.
Attempts at Asymmetric Induction in the Kinugasa Reaction
OPh CuI (10 mol %)N
OPhHPh N
O
Ph
Ph
H
ligand A (1 eq.) N
Ph PhK2CO3/DMF
O
N N
OMe Me
iP
Ligand A =
45% yield40% ee
iPr iPr
HPh NO
Ph
Ph
H
CuI (1 eq.)ligand A (1 eq.) N
OPh
K2CO3/DMFPhHPh Ph
K2CO3/DMF
54% yield68% ee68% ee
Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.
A Chiral Auxiliary Based Approach
PhRH
R1 Ph R1R H33
O
N
O
Ph
ON
[Cu]
R1
O
N
O
Ph
ON
[Cu]
R134
34
lower in energy:substituents on opposite faces
higher in energy:substituents on the same face
B Bn BnOMeOMeMeO
NO
O
Bn
NPhO
HNO
O
Bn
NO Ph
NO
O NO Ph
CuI, Et3N
O Ph Ph
5:3
Basak, A.; Ghoh, S.; Bhowmick, T.; Das, A.; Bertolasi, V. Tetrahedron Lett. 2002, 43, 5501.
5:3
70% combined yield
Fu’s Use of a Chiral Ligand to Induce Asymmetry
R1 NO R3
R2 H
1-2.5%CuCl, ligand A
Cy2NMe2 NO
R2R1
R3 NFe MeM
Me NMe
FeMeMe
MeMeMe
= AMeMe
MeMeMe
up to 93% ee
Alkyne Scope
R1NO 1-2.5%CuCl, ligand A
CyR1OMe
RN
Cy H
g
Cy2NMe2N
O
OMe
R1 cis:trans %ee,cis
isolatedyield %(cisisomer)
4 CF C H 95 5 92 654-CF3C6H4 >95:5 92 65
4-OMeC6H4 >95:5 93 57
CH2Ph 71:29 73 43
Lo, M.; Fu, G. J. Am. Chem. Soc. 2002, 124, 4572.
2
1-cyclohexenyl 90:10 91 45
Variation of the Nitrone Component
Lo, M.; Fu, G. J. Am. Chem. Soc. 2002, 124, 4572.
Intramolecular Attempts With the Kinugasa Reaction
MMe
O
CuBr (5%)ligand A (5.5%)
Cy2NMe (0.5 eq) NAr NMe N
Me
FeMeMe
MeMeMe
= A
NO
ArO Fe Me
MeMe
MeMeMe Me
30% yield6% ee
NO
CuBr (5%)ligand B (5.5%)
Cy2NMe (0.5 eq)N
Ar PPh N
OMe
Me
= BAr OAr
74% yield
PFe Me
MeMe
MeMePh N iPr = B
Shintani, R.; Fu, G. Angew. Chem. Int. Ed. 2003, 42, 4082.
74% yield88% ee
Intercepted Intermediate
Shintani, R.; Fu, G. Angew. Chem. Int. Ed. 2003, 42, 4082.
Other Attempts to Induce Asymmetry in the Kinugasa Reaction
Coyne, A.; Muller-Bunz, H.; Guiry, P. Tetrahedron: Asymmetry. 2007, 18, 199.
Outline
I d i 1 3 Di l C l ddi i• Introduction to 1,3 Dipolar Cycloadditions• Cu(I)-catalyzed 1,3 Dipolar Cycloaddition Between Azides and
Alkynesy– Cascade Reactions– Extension of the Original Methodology
• Synthesis of β−Lactams– Kinugasa Reaction
• 1 3 Dipolar Cycloadditions Between Azomethine Ylides and• 1,3 Dipolar Cycloadditions Between Azomethine Ylides and Activated Alkenes
1,3 Dipolar Cycloadditions of Azomethine Ylides Catalyzed by Chiral Metal Complexes
Highly Endo Selective Cycloadditions of Azomethine Ylides
1O
Cu(CH3CN)4ClO4(3 mol %)ligand A (3 mol %)
PhN OO
F
StBuPPh2 = AN CO2MeR1
R2 R3NPh
O
ligand A (3 mol %)Et3N, -10 oC
NH
CO2MeR1
R3R2
Fe 2 = A
endo
Ph
N
O
OPh
OMeO
N[Cu]
PhN OO
CO MeF
PhN OO
CO MeMeO
PhN OO
CO Me
PhN OO
CO MeNH
CO2MeHH N
H
CO2MeHH N
H
CO2MeHMeN
H
CO2MeMeH
Cabrera, S.; Arrayas, R.; Carretero, J. J. Am. Chem. Soc. 2005, 127, 16394.
endo:exo = >98:2yield(%) = 82ee(%) = >99
endo:exo = >98:2yield(%) = 81ee(%) = >99
endo:exo = >98:2yield(%) = 78ee(%) = 94
endo:exo = >98:2yield(%) = 50ee(%) = 80
Endo Selectivity Scope Continued
N CO2MePh
CO2Me
CO2Me
Cu(CH3CN)4ClO4(3 mol %)ligand (3 mol %)Et3N, -10 oC N
HCO2Me
PhFe
S-t-BuPPh2CO2MeMeO2C
= Ligand
CO2Me H 2
endo
47% yield94% eeendo/exo = 67:33
N CO2MePh CO2Me
Cu(CH3CN)4ClO4(3 mol %)ligand (3 mol %)
Ph
CO2MeMeO2C
Et3N, -10 oC NH
CO2MePh
endo
MeO2C
89% yield>99% ee
d / 90 10endo/exo = 90:10
Cu(CH3CN)4ClO4(3 mol %) OHC
N CO2MePhCHO (3 mol %)
ligand (3 mol %)Et3N, -10 oC N
HCO2Me
Ph
endo
Me Me
Cabrera, S.; Arrayas, R.; Carretero, J. J. Am. Chem. Soc. 2005, 127, 16394.
48% yield69% eeendo/exo = >98:<2
Highly Exo-selective and Enantioselective Cycloadditions of Azomethine Ylides
Ot BCuI (5 mol %) Ht B O C Ht B O C
Fe PAr2N t-Bu
N CO2MeAr
H
CO2t-BuCuI (5 mol %)ligand (5.5 mol %)
base (10 mol%)-25 oC N
HCO2MeAr
Ht-BuO2C
NH
CO2MeAr
d
Ht-BuO2C
exo endo
Ar base exo/endo yield (exo, %) ee ofexo
o-ClPh Et3N 76/24 76 98
p-MePh DBU 97/3 61 89
OM Ph 97/3 82 91p-OMePh DBU 97/3 82 91
Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241.
Mechanism
NOMe
OAr
LnCuX
NOMe
OAr
CuLL
X Base
OMe
L
Ar
CO2R2
R1HH
NOMe
OAr
CuLL
CO2R2R1
OMeO
N[Cu]18 electron
tetrahedralcomplex
NOMe
R1R2O2C
ArBase.HX
NOMe
R1R2O2C
Ar
Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241.
OCuLL
NH O
Varying the Electronic Nature of the Ligand to Change Stereoselectivityy
Yan, X.; Peng, Z.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.; Wu, Y. Angew. Chem. Int. Ed. 2006, 45, 1979.
Proposed Mechanism
RMLn, Et3N
OMLn OMLn
N
CO2Me
R
Et3NH
NRO
OMe
n
NRO
OMe
n
R2NO2
CO2Me 3
MLR2O2N
NRO
OMe
MLn
R2 NO2
NRO
OMe
R2 NO2
H+
NH
R CO2Me
RO2N
R R2
Yan, X.; Peng, Z.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.; Wu, Y. Angew. Chem. Int. Ed. 2006, 45, 1979.
Summary of Cu(I)-Catalyzed Processes
Regioselective formation of 1,4 disubstituted triazoles
R1 N N N R2 NN N
R1
R2 1
4
cat. Cu(I)
1, 4 regioisomer obtained exclusively
Cascade reactions
HC C R1
N N N SO R
CuI (0.1 eq), base
R1HNR2R H O
NSO2R
NR1 R3
R1
HN
SR N
SO2TolR1
N N N SO2RN
R2
R1
R3
HNR2R, H2O, or NR2 O
R1 SO2 N
PhPh
amidines sulfonamides azetidinimines
Summary of Cu(I)-Catalyzed ProcessesReactions of other 1,3 dipoles
OO
Ph Cu
BnON2
HN
NOBn
O
Ph H
Kinugasa reaction
C NR1
N
O
R1
Ph
R2
O
CC CuLnPh
CH
NR OR2
Lewis acid activation
O LnCuX CuLL
X CO2R2R1 R1R2O2C
NOMe
ArN
OMe
OAr N
H O
OMeArBase
Acknowledgements
Dr Michael T CrimminsDr. Michael T. Crimmins
The Crimmins’ GroupDr. Anita Mattson Dr. Christie StaufferDee Jacobs Lizzie O’BryanMariam Shamszad Colin HughesMatt Haley Mark MansJay Stevens Tim MartinAdam Azman Philip WilliamsAdam Azman Philip WilliamsDr. Luke Zuccarello Dr. Michael EllisDr. Yan Zhang
Byproduct FormationByproduct Formation
Azide-Acetylide MechanismR2 H
CuLn (CuLn)2 R2 HCumLn
B BH
R2 Cu2Ln R2 Cu2Ln
2
R1N3
CuLL
Cu
R2
NN
R1
N
N
• CuL L
Cu
R2
NNR1
NN
NR1
R2LnCu2
NN
NR1
R2LnCu2
RR2
B BHN
NNR1
R2H
Kinetic Studies:Process is 2nd Order in Cu when process is catalytic in Cu.
- Increasing [Cu] causes less reactive metal aggregates to form ->Increasing [Cu] causes less reactive metal aggregates to form >indicate that Cu1 acetylide species is changing in solution.
- complexation may play a role.- 2nd Cu atom is likely is to activate the azide functionality, or complex with the acetylide
(causing a reduction in alkyne electron density, favoring cyclization)
Overall, little is known about the copper acetylide complex.
Bock, V.; Hiemsra, H.; van Maarseveen, J. Eur. J. Org. Chem. 2007, 51.
An Explanation for the Stereochemical Outcome
LnCu
NPhO
OMe
LnCu
CC
Yan, X.; Peng, Z.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.; Wu, Y. Angew. Chem. Int. Ed. 2006, 45, 1979.
C1C4
Stereochemical Explanation Continued
Yan, X.; Peng, Z.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.; Wu, Y. Angew. Chem. Int. Ed. 2006, 45, 1979.
Mechanism Support
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