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Alternatives to Bu3SnH in Radical Cyclisations: Copper Mediated 4-Exo and 5-Endo Radical Polar-Crossover
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Dr. Andrew Clark
Associate Professor of Synthetic ChemistryDirector Of Undergraduate Studies
University of Warwick
+44 24 [email protected]
New Trends in Applied Chemistry, Ovidius University of Constanta, 2012
• Stoichiometric
• Reductive Cyclisation
• Toxic Reagents
• Purification Issues
• Relatively expensive
(10g, £25)
Classical Radical Cyclisation
NR
Br
O
R1 R2
R3
Bu3SnH, AIBN
heat NRO
R3
R1
R2
NR
R1
R2
R3O
4-exo 5-endo
NR
O
R1 R2
R3
Bu3Sn
4-exo
NRO
R3
R1
R2
5-endo
NR
R1
R2
R3O
Bu3SnH
CuCl
CuCl2
O
Cl
O
Cl
O
ClCl
O
Cl
OO
ClCl
Cl30 mol% CuCl
MeCN, 140oC
Nagashima, Tet. Lett., 1983, 24, 2395.
CuCl
CuCl2
OO
ClCl
Atom Transfer Radical Cyclisation
A. J. Clark, Chem. Soc. Rev, 2002, 1
NTs
Br
O
30 mol% CuBr
DCM, RT, 6 h95%
NTs
O
Br
N
N
Me2NN
NMe2
NMe2
N
N
N N
TPA
0
0.5
1
1.5
2
2.5
3
Run 2Run 3Run 4Run 5Run 6Run 7
NTs
ClClCl
O NTs
ClCl
O
Cl30 mol %
Me2N
MeN
NMe PS
Solid supported catalysts can be re-used
CuCl
Interesting stereochemical reversal
NTs
Br
O
NTs
O
Br
30 mol% CuBr
72% de 94%
NTs
O
Br
70% de 90%
homogenous heterogenous
A. J. Clark, J. V. Geden, and S. Thom. J. Org. Chem., 2006, 71, 1471
NR
Br
O
30 mol% Cu[TPA]Br
DCM, RT,
Applications to lactams
NRO
Br
R Yield Time
Bn 96% 1 h
Pmb 98% 1 h
i-Bu 98% 2 h
t-Bu 0% 24 h
JJ O
O
O
NNEt2
NEt2
NPMB
Br
O
CCl3
NPMB
O
NPMBO
Br
NPMBO
50 mol% Cu[TPA]Br
toluene, 110°C
50 mol% Cu[TPA]Br
toluene, 110°C
NPMB
O
30 mol%Cu[TPA]Br
toluene, 110°C 82%
NPMBO
Br
3:1
A. J. Clark, J. V. Geden, S. Thom, and P. Wilson, J. Org. Chem., 2007, 72, 5923
NBn
O
Br30 mol%
Cu[TPA]BrDCM, RT
NBn
O NBn
O
NBn
ONBn
O
Cu(I)
Cu(II)
88%
5-Endo Cyclisations
NBn
O
Cu(II) Cu(I)
H
H
-H
-H
NBn
OOMe
MeOH
NBn
Br
O
74°
Radical-polar crossover reaction
HNPmb
O
Br
H H
H
H HNPmb
O
Cu[TPA]Br 79%
H
H HNPmb
O
69%
toluene
Cu[TPA]Brdichloroethane
Effect of solvent
NHOH
O
OO
NHOMe
OO
OH
L-755,807Bradykinin inhibitor
Microsphaeropsis sp. MF6057
PI-091Platelet aggregation inhibitor
Paecilomyces sp. F-3430
CCl3
NPmb
O
30 mol% Cu[TPA]Cl
DCM,MeOHNPMbO
Cl OMe
Trapping with nucleophiles
CCl3
NPmb
O
O
OMe 2 eq Cu[TPA]Cltoluene, 110 °C
O
NPmb
O
Ar
O
NPmb
O
Ar Purple solid
Unprecedented radical-polar-carbene triple crossover reaction
O
NPmb
Cl Cl
OAr
O
NPmb
Cl Cl
OAr
radical-polarcrossover
O
NPmb
OAr
carbene dimerisation
Cu(I)
NMe
O
MeN
O
Indigoid Skeleton
NH
O
HN
O
HO
OHTrikendiol
HIV-inhibitor
Improving catalysis
CuCl
CuCl2
O
Cl
O
Cl
O
ClCl
O
Cl
OO
ClCl
Cl30 mol% CuCl
MeCN, 140oC
CuCl2
OO
ClCl
?
atom transfer or redox from starting
material CN
CN
Cl
CN
Cl
CN
CN
Cl
NBn
Br
O NBn
O
Br
Temp AIBN CuBr Conv. Massmol% mol%
CH2Cl2
RT - 1.0 5% 98%
24 hr
TPA
50oC - 1.0 14% 99%
50oC 10.0 1.0 100% 84%
50oC 10.0 - 0% 98%
50oC 5.0 1.0 95% 99%
50oC 10.0 0.1 40% 89%
NBn
Br
O NBn
O
Br
10 mol% AIBN, CH2Cl224 hr, 97%
1 mol% CuBr2/TPA
A. J. Clark, P. Wilson. Tetrahedron Letts., 2008, 49, 4848
Addition of AIBN
Applications
NTs
Br
O
NTs
Br
O
Ph
NTs
Br
O
NTs
Br
O
1 mol% Cu[TPA]Br2, 10 mol% AIBN, 50°C
NTs
O
Br
NTs
O
Ph
Br
NTs
O
Br
NTs
O
Br
NTs
O70%
1:1
75%
90% 4:1 mixture
6:1 mixture
*
*
99%
NBn
Br
O NBn
O
Br
Time NaBH4 Cu Conv. Massmol% mol%
MeOH
10 min 10.0 1.0 Cu(I) 100% 91%
Cu[TPA]Br
10 min 5.0 1.0 Cu(I) 100% 90%
5 min 5.0 0.1 Cu(II) 100% 97%
5 min 2.5 0.1 Cu(II) 40% 88%
CuCl
CuCl2reducing agent
oxidised
Other reducing agents
Acknowledgements
PhD studentsGary BattleJohn McDonaghJoanna GedenPaul Wilson
Post DoctoralAlana Collis
FundingAventisLilly Research CentreAstraZenecaEngineering and Physical Sciences Research Council EPSRC
New Materials and Analytical extension£24M, 5 storeys, 4656 sq m. opened November 2011
New synthetic labOpened Nov 2010 by Prof. Grubbs
New 700 MHz NMR
New teaching lab, October 2012!
