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Research areas
Natural product isolation and total synthesis.
Chemistry and biology of free radicals
Dr. Andrew ClarkAssociate Professor in Synthetic Chemistry
Development of synthetic methodology using copper, iron and ruthenium
Functional Genomics / Chemical Genetics / Interactomics
Use of plants in renewable plastics manufacture
Dr. Andrew ClarkChemistry Department, University of Warwick
Coventry, UK+44 24 76523242
msrir@csv.warwick.ac.uk
Atom Transfer Radical Cyclisation
OO
ClCl Cl
OO
ClCl30mol% CuCl
MeCN, 140oC Cl
OO
ClCl
CuCl2
CuCl
OO
ClCl
CuCl2
CuCl
H. Nagashima et al, Tetrahedron Lett., 1983, 24, 2395A. J. Clark, Chem. Soc. Rev., 2002, 31, 1
NN
BipyOO
Cl ClCl
30 mol% CuClLigand 1, 110 C, MeCN, 18 hrs, 98%
O
ClCl Cl
O
Ligand 1
NN
R
R
H. Nagashima et al, J. Org. Chem., 1993, 58, 464
NN
R
R
NN
NN
RR N
CHOR H2N R
NN
1 mol % CuCl
CH2Cl2, RT
NN
NTs
ClClCl
O NTs
ClCl
O
Cl
99%, 6 hrs
A. J. Clark, D. Duncalf, R. P. Filik, D. M. Haddleton, G. H. Thomas, H. Wongtap, Tet. Letts, 1999, 40, 3807
NTs
BrMeMe
O NTs
MeMe
O
BrCH2Cl2, RT
30 mol % CuBr
95%, 6 hrs
NTs
BrMeH
O NTs
MeH
O
Br30 mol % CuBr
CH2Cl2, 40 ºC
92%, 30 hrs, de 64%
05
101520253035404550
Ligand A Ligand B Ligand C Ligand D
de = 2% de = 34%
de = 44%
de = 54%
NN
NN
NN
NN
Ligand A Ligand B Ligand C Ligand D
NTs
Me Cl
O
Cl
NTs
Me Cl
O
Cl30 mol% CuCl30 mol% Ligand
0.12M in substrteNTs
Cl
O
Me
Cl
Steric Effect of N-Substituent
012345678
0.5 eq 1.0 eq 2.0 eq 3.0 eq
NTs
Me Cl
O
Cl
NTs
Me Cl
O
Cl30 mol% CuCl30 mol% Ligand
0.12M in substrteNTs
Cl
O
Me
Cl
Relative rate versus ligand equivalence
Toluene
CH2Cl2
NN
A. J. Clark, F. De Campo, R. J. Deeth, R. P. Filik, S. Gatard, N. A. Hunt, D. Lastecoueres, G. H. Thomas, J-B. Verlhac, H. Wongtap, J. Chem. Soc., Perkin 1, 2000, 671
N
N
CuN
N
D. M. Haddleton, A. J. Clark, D. J. Duncalf, A. M. Heming, D. Kukulj, A. J. Shooter , J. Chem.Soc., Dalton Trans, 1998, 381
D. M. Haddleton, D. J. Duncalf, D. Kukulj, M. C. Crossman, S. G. Jackson, S. A. F. Bon, A. J. Clark, A. J. Shooter, Eur. J. Inorg. Chem. 1998, 1799
NTs
BrMeMe
O NTs
MeMe
O
Br
Me2NN
NMe2
Me2N
CH2Cl2, RT
30 mol %
NN
95%, 6 hrs92%, <30 mins
NTs
BrMeH
O NTs
MeH
O
Br30 mol %
CH2Cl2, RT94%, 12 hrs, 66% d.e.
92%, 30 hrs, 40ºC, de 64%
A. J. Clark, F. De Campo, R. J. Deeth, R. P. Filik, S. Gatard, N. A. Hunt, D. Lastecoueres, G. H. Thomas, J-B. Verlhac, H. Wongtap, J. Chem. Soc., Perkin 1, 2000, 671
N CHO NN
Si NNreflux, 24 hrs
SiCu
CuX
XMeCN
MeCN
ICP = 4.3% Cu
NH2
9 % functionalised
Si
NTs
BrH
O NTs
H
O
Br30 mol %
ClCH2CH2Cl,reflux
48 hours 72%
NTs
H
O
Br
A. J. Clark, J. V. Geden, and S. Thom. J. Org. Chem., 2006, 71, 1471
Ligand Acceleration
NN N
N
NN
N
NN
NN
N
N
NNR
NN
Tren-Me6 PMDETA TMEDA
TPA NPMI BiPy
Solid Supported Catalysts for ATRC
NN
NMe2
NMe2
N
N *
N *
N*
Me
Me
MeCuX
Me
CuX
PS-Me6-tren.CuX PS(CL)-Me6-tren.CuX
OO
O
N
Et2NNEt2
NN
NMe2
JJ
JJ-TEDETA.CuX1
CuX
Me
Me
PS-PMDETA.CuX
CuX
X=Cl, Br
A. J. Clark et al, J. Org. Chem., 1999, 64, 8954
0
0.5
1
1.5
2
2.5
3
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5
Run 2
Run 3
Run 4
Run 5
Run 6
Run 7
Time (hrs)
Kinetics to 80% Conversion (PS-PMDETA.CuCl)L
n([
Ao
]/[A
])
NTs
ClClCl
O NTs
ClCl
O
ClDCE, reflux
30 mol %
A. J. Clark, J. V. Geden, and S. Thom. J. Org. Chem., 2006, 71, 1471
N
Cl Cl
O
Bn
N
Cl Cl
O
Bn
N
Cl
Cl
O
Bn
N
Cl
Cl
O
Bn
CuCl, Ligand
RT, CH2Cl2
NN
?
F. Ghelfi et al, Tetrahedron., 1997, 41, 1403
N
Cl
O
Bn
N
Cl
O
BnN
Cl
O
Bn
Cl
N
MeCl Cl
OBoc
30 mol% Cu(A)Cl
N
Me
OBoc
ClCl
RT, CH2Cl250%
N
MeCl
OBoc
N
MeCl
OBoc
Cu(I)
N
MeCl
OBoc
ClCu(II)
AgNO3, THF:H2O
N
Me
OBoc
CHO
77%
N
Me
OBoc
ClCu(I)
NN
N
Me
OBoc
Cl
Cu(II)
A. J. Clark, G. M. Battle, A. Bridge, Tet. Letts., 2001, 42, 1999.
4-exo vs 5-endo
NBn
BrMe
Me
O
NBnO
Br
4-exo
NBn
OBr
5-endo
NBn
O NBn
ONBn
O
Br 30 mol% CuBr, 30 mol% ligand
CH2Cl2, 20 mins, RTn n n
n = 1 39% 43%n = 2 52% 10%n = 3 21% 60%n = 7 15% 40%
NN N
N
4-exo
NBn
MeMe
O 4
5
5-endo
NBn
MeMe
O
A. J. Clark, C. P. Dell, J. M. Ellard, N. A. Hunt, J. P. McDonagh, Tet. Letts., 1999, 40, 8619
Cu(I)
NBn
O n NBn
O n
NO Bn
4-exo
5-endo
A. J. Clark, C. P. Dell, J. M. Ellard, N. A. Hunt, J. P. McDonagh, Tet. Letts., 1999, 40, 8619
NBn
O NBn
ONBn
O
Br 30 mol% CuBr, 30 mol% ligand
CH2Cl2, 20 mins, RTn n n
Cu(II)
NBn
O n
H
H
N
OH
OMe
OMe
OMe
ERYTHRINITOL
N
Br
O
MeOOMe
NO
NO84% 1:1
ArAr
NO
MeOOMe
N
OMe
OMe
O30 mol% CuBr,
30 mol% tren-Me6CH2Cl2, 20 mins, RT
'Friedel-Crafts'N
OMe
OMe
O
-H
H2N
Br
O
OMe
OMe
O
Br, base
1)
2)
NO
Ph
Br
NO
Ph
toluene, 110ºC, 2 hrs
30 mol% CuBr, TPA
72%N
N
N
N
TPA
NO
Ph
Br30 mol% CuBr, TPA
NO
Ph
Me
1,2 DCE, 110 ºC, 2 hrs
42%
A. J. Clark, C. P. Dell, J. P. McDonagh, C. R. Acad. Sci. Ser IIc: Chim, 2001, 4, 575
NPMB
O
BrHH
H
NN
N
N
TPA
NPMB
OH
H H
CuBr, TPAtoluene, reflux2 hr, 69%
NPMB
OH
H H
CuBr, TPA1,2-DCE, reflux2 hr, 79%
Application to natural product synthesis
NH
O
HHO
O
H
Eremophilne lactam, Petasites hybridus.
Sesquiterpenic lactone, Ligularia species.
O
Br
NPMB
O
O
Br
NPMB
(a) CuBr.TPA, toluene,
110oC, 2h
(b) CAN, MeCN, H2O
89%
NH
O
R
Mn+
Mn+1
X R
Traditional Radical Polar Crossover Reaction
N
O
R
N
O
R
Br
Mn+1
Mn
RN
O
R
OMe
O
Cl
ClOMe
O
O
MeO
OMe
O
2 eq CuCl, DMSO
R
Mn+
Mn+1
X R
Radical CarbeneCrossover Reaction
Mn
Mn+1
R
N
ClCl
Cl
O
R
N
Cl
Cl
O
R O
R
30 mol%CuBrTPA
NOR O
Br
NOR O
OMe OMe
toluene reflux
R = Boc, yield 54%R = PMB, yield 83%
A. J. Clark, J. V. Geden, S. Thom, J. Org. Chem., 2006, in preparation
Cl
NPMB
O
OMe
O
Cl
Cl
CuCl/TPA
NPMB
O
O
PMBN
O
O
toluene, reflux5 h, 35%
Ar
Ar
NH
O
HN
O
HO
OH
N
O
MeN
O
Me
Trikendiol
Indigoid
Cl
NPMB
Ar
O
O
Cl
ClCu(I) NPMB
Ar
O
O
Cl
ClNPMB
Ar
O
O
Cl
Cl
R XMn+
Mn+1
RMn+
Mn+1
X R
NPMB
Ar
O
O
Cl
ClCu(II)
Mn+
Mn+1
Mn+1
Mn
R R-H
-H
NPMB
Ar
O
O
Cl
Cl
Cu(I)NPMB
Ar
O
O
Cl
Mn+
Mn+1
Mn+
Mn+1
R
Cu(I)NPMB
Ar
O
O
Mn+
Mn+1
Mn+
Mn+1
R
observed dimer
Formal radical/polar/carbene triple crossover reaction
NR
O
Br
30 mol% CuBr30 mol% TPACH2Cl2, RT 1hr N
O
Br
R
R Yield (%) Time (hr)
Bn 96 1
PMB 98 1
i-Bu 98 2
t-Bu 0 24
A. J. Clark, G.M. Battle, A. Bridge, Tetrahedron Letts., 2001, 42, 4409
NBn
O
Br
30 mol% CuBr30 mol% TPAtoluene, reflux24hrs, 82%
NO Bn
3:1
NO R
DBU, CH2Cl2,
12 hrs
R
NR
O
Br
R
5-endo
4
5 R
NR
O
Br
?
R
NR
O
Br
?
R 55
44
NO
Br30 mol% CuBr/TPA,
DCM, RT, 20 mins, 98%
4-exo vs 5-exo
4
5
NO
Br
PMB
30 mol% CuBr / TPAtoluene, reflux, 1 hr
NO PMB
Br
60%
NO
Cl
ClCl
PMB
30 mol% CuCl / TPAtoluene, reflux, 18 hrs
NO PMB
Cl
NO PMB
CHO
23% 12%
NO
4.25
Br
NO
Br
: 1
NPMB
O
30 mol% CuCl / TPA
toluenereflux, 5 h
BrN
O PMB
26%
NPMB
O
30 mol% CuCl / TPA
toluenereflux, 6 DAYS
ClCl
H
NO PMB
Cl
NPMB
OClCl
H
10%2%
N
O
Br
PMB30 mol% CuCl / TPA
toluenereflux, 3 h
5-exo5-endo
N
Br
O
PMB N
Br
O
PMB
52% 20%
N
OCl
ClCl
PMB30 mol% CuCl / TPA
toluenereflux, 3 h
N
Cl
ClCl O
PMB N
Cl
ClCl O
PMB
13% 7%
N
ClCl O
PMB
5%
N
OCl PMB
N
OCl PMB
Cl
29% 21%
6-endo
30 mol%CuCl(TPA)
DCM
NN
N
N
TPA
NO
Cl
Pmb
ClCl
NO
Cl
Pmb
NO
Cl
Pmb
NucNO
Cl
Pmb
Nuc
30 mol%CuCl(TPA)
DCMNO
Cl
Pmb
ClCl
NO
Cl
PmbMeOH
OMe
67%
NHOR
OO
N
OX
PGCu
NHOH
O
OO
NHOMe
OO
OH
L-755,807Bradykinin inhibitor
Microsphaeropsis sp. MF6057
PI-091Platelet aggregation inhibitor
Paecilomyces sp. F-3430
NHOH
O
OO
MeO2C
EpolactaeneNeuritogenic agent
Penicillium sp. BM1689-P
NHN
OO
HOMe
Quinolactacin Tumor necrosis factor inhibitor
Penicillium sp. EPF-6
O
X
I
O
Bu3Sn OEt
Pd(0)
Bu3SnCO2Et
1) DIBAL-H2) TPAP3) BuLi, (EtO)2P(O)CH2CO2Et
40%
Bu3SnCO2Et
NHOH
O
OO
O
X
NO
OY
PGPG
NHOMe
OO
OH
O
OPGX
I
Bu3SnCO2Et
PdCl2(MeCN)2DMF, RT, 53%
O
MeOEt
H
H H
5.4%
3.7%
Me
CO2Et
H
2.4%
O
OEt
23
21
24
C21 C23 C24
29.5 19.4 20.5
O
OEt 30.3 19.0 21.3
NHOH
O
OO
30.4 19.2 21.4
NH
O
O
MeOCl
Cl
NH
O
O
MeO
OHCuCl, ligand
H2O
NHOH
O
OO
NO
O
OMe
PMB
4 eq CAN, MeOH, RT
20 mins 67% NO
MeO2C
PMB
OMe
NO
4 eq CAN, MeCN
wet20 mins 94%
O
OMe
PMB
NO
MeO2C
PMB
OH
A. J. Clark, C. P. Dell, J. M. McDonagh, J. Geden, P. Mawdsley, Org. Letts., 2003, 5, 2063
Stuart RookeJoanne PeacockAwh WongtapRobert FilikJohn EllardNicola HuntGary BattleJohn McDonaghJoanne GeddenNicholas MurphyLina YahyahTracey ThompsonTracey Li
EPSRCEPSRC Thailand GovernmentKnoll PharmaceuticalUniversity of WarwickEPSRC Project StudentshipAventis (Industrial CASE)Lilly Research CentreAstraZeneca (Industrial CASE)EPSRCSelf fundedAstraZenecaSelf funded
Triethyl Borane Initiated Radical ReactionsNitrogen Centered RadicalsAmidyl Radicals, Macrocyclisations ATRCLigand Testings for ATRCSynthesis of L-755,807 via ATRCAsymmetric ATRCBeta Lctam Synthesis via ATRC5-Endo cyclisation ATRC ReactionsSolid Supported and Dienamide ATRCCopper Mediated Rearrangements6-Exo ReactionsATRC5-Endo ATRCATRC in Ionic Liquids
RADICAL CHEMISTRY
POLYMER CHEMISTRYDr. Tom StrawDr. L. MwaikamboDr. David DuncalfDr. John Sherringham
OTHER PROJECTSDr. Suzanne DillyIsmail KasujeeKaren WorsfoldDivya PatelYasair Al-Faiyz
BBSRC GENOMICSUniversity of WarwickEPSRC/DTI/ HypersilRoche PharmaceuticalsSaudi Government
cDNA Viral Display, Ligand ImmobilisationEnantioselective AllyzirconationChiral FLASH Colum ChromatographyHydroxamic Acid ChemistryHydroxamic Acid Chemistry
EPSRC polymer initiativeDEFRAEPSRCHome Grown Cereals Authority
Dendrimer SynthesisPolymers from Renewable ResourcesCopper Mediated ATRPPolymers from Renewable Rsources
Cyclisation in ionic liquids
N
Br
TsO
N
NPF6
30 mol% CuBr30 mol% tren-Me6
NTs
O
Br
Run 1 20min 99%
Run 2 1hr 99%
Run 3 2hr 99%
Run 4 6hr 90%
Run 5 12hr 14%
Run 6 36hr No reaction
Work-up add toluene decant off ionic liquid
Further Application of Solid Supported Catalysts
PMBN
O
Cl
ClCl
N O
ClCl
PMB
Toluene, 0.12 M
30 mol% Cu (I) catalyst
Catalyst Time (hrs) Yield (%)
30 mol% TPA, CuCl 3 71
JJ-NPMI.CuCl 1 61
JJ-TEDETA.CuCl 2 60
PS-Me6-tren.CuCl 5 62
PS(CL)-Me6-tren.CuCl 4 64
Si-NPMI.CuCl 9 63
PS-PMDETA.CuCl 23 33
0 2000 4000 6000 8000
0.0
0.5
1.0
1.5
2.0
2.5
0 2000 4000 6000 8000
0.0
0.5
1.0
1.5
2.0
2.5
ln[M
]o/[M
]
2,6-Di-tert-butyl-4-methylphenol4-Methoxyphenol 2,6-Diisopropylphenol Phenol Control
time/seconds
Polymerisation of MMAin presence of various phenols
Control
Ortho substitutedhindered phenol
Unhindered phenols
N
N
CuO
O
Br
CuN
NBr
A. J. Clark, M. C. Crossman, D.Duncalf, D. M. Haddleton,S. R. Morsley, A. J.Shooter, J. Chem.Soc., Chem Commun., 1997, 1734
a
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
a + eb c
df
g
hWater
t = 0
t = 10h
N N CH2 CH2 CH3
a
b
c d
e
f g h
Catalyst complex in water 25°C (Cu : ligand = 1 : 3)
N N1
2
3 4
5
6
7 8
Catalyst Complex in water at 50°C
NHOH
O
OO
NHOMe
OO
OH
L-755,807Bradykinin inhibitor
Microsphaeropsis sp. MF6057
PI-091Platelet aggregation inhibitor
Paecilomyces sp. F-3430
NHOH
O
OO
MeO2CEpolactaene
Neuritogenic agentPenicillium sp. BM1689-P
NHN
OO
HOMe
J. Antibiotics, 2000, 1247
NH
O
Me
OMe
O
H
Phytochemistry 1999, 1507
NH
O
O OMe
H
H
J. Org. Chem., 2000, 6412
N
O
Cl
ClCl
PMBO
i) PMBNH2, ZnCl2,
Benzene, Dean-Stark, 4 hrs
ii) Cl3CCOCl, DCM, 0oC, DEA, 31%
5-Exo Cyclisation
N O
Cl
PMB
Cl N O
PMB
ClCl
N O
PMB
ClCl
Cl
Cu(I)Cl
5-exo Cu(II)Cl
-HCl
N O
ClCl
PMB
71%
CuCl, TPA (30 mol%)
Toluene, 0.12 M, 3 hrs
NPMBCl
O
NPMBCl
O
Cl
NPMB
OClCl
Cl
NPMB
OClCl
Cl
NPMB
OClCl
+
A (29%) B (21%)
+
C (13%) D (7%)
++
E (5%)
• Five cyclisation products isolated; 6-endo (A and B) and 5-exo (C, D and E)
• Ratio A : B : C : D : E = 6.5 : 4.5 : 4.5 : 1.8 : 1.0 : (crude 1H NMR)
• NMR experiments have confirmed relative stereochemistry of C and D
• Ratio 6-endo : 5-exo = 1.5 : 1 (crude 1H NMR) = 2 : 1 (isolated)
NPMB
O
Cl
Cl
Cl CuCl, TPA (30 mol%)
Toluene, 0.12 M, 5 hrs
6-Endo Cyclisation
NPMBCl
O
Cl
NPMB
O
ClCl
NPMB
O
ClCl
NPMB
O
ClCl
Cl
NPMB
O
ClCl
NPMB
O
ClNPMB
Cl
O
NPMB
O
Cl
ClNPMB
Cl
O
NPMB
O
Cl
Cl
Cl
A
B
6-endo Cu(II)Cl -HCl
Cu(I)Cl
Cu(II)Cl
-HCl
H -HCl
Cu(II)Cl
H
NPMB
O
Br
NPMB
O
Br
52% 20%
+
de=44%
NPMB
O
Br
CuBr, TPA (30 mol%)
Toluene, 0.12 M, 2.5 hrs
NPMB
O
Cl
ClCuCl, TPA (30 mol%)
Toluene, 0.12 M, 5 hrs
NPMB
O
Br
CuBr, TPA (30 mol%)
Toluene, 0.12 M, 3 hrs
NPMB
O
NPMB
O
Br
NPMB
O
Br
45% 22%
+ +
7%de=34%
NPMB
O
Cl
Cl
NPMB
O
Cl
Cl
27% 2%
+
de=86%
NRO
Ph
PhO
OMe2 eq CAN, MeOH
NRO
Ph
PhO
OMeOMe
NRO
OO
Ph
Ph
NRO
Ph
PhO
OMe
NRO
Ph
PhO
OMe
NRO
Ph
PhO
OMe
A. D'Annibale et al, Tetrahedron Letts., 1997, 38, 1829
NRO
Ph
PhO
OMe
NRO
Ph
PhO
OMe
CAN
NHOH
OO
NO
MeO2C
PMB
OH CAN or TFA
N-Deprotection
NH
O
MeO2C
86-95%
NO
MeO2COH
NHOMe
OO
4 eq CAN MeCN
5-exo verses 5-endo
20 min, 75%NO
MeO2C
NO
4 eq CAN, MeOH, RT
65% NO
MeO2C
5-Endo cyclisation
O
OMe
PMB PMBOMe
NPMB
O
MeO2C
CAN
CAN
NPMB
O
MeO2C
NPMB
O
MeO2C
MeOH
NO
MeO2C
PMBNO
MeO2C
PMB
NO
MeO2C
PMB
CAN
CAN
NH
O
Me
OMe
O
H
NO
4 eq CAN, MeOH, RT
65% NO
MeO2C
5-Endo cyclisation
O
OMe
PMB PMBOMe
NH
O
Me
OMe
O
H
6-Endo Cyclisation
NPMBCl
O
Cl
NPMB
O
ClCl
NPMB
O
ClCl
NPMB
O
ClCl
Cl
NPMB
O
ClCl
NPMB
O
ClNPMB
Cl
O
NPMB
O
Cl
ClNPMB
Cl
O
NPMB
O
Cl
Cl
Cl
A
B
6-endo Cu(II)Cl -HCl
Cu(I)Cl
Cu(II)Cl
-HCl
H -HCl
Cu(II)Cl
H
NHOH
O
OO
O
X
NO
OY
PGPG
O
X
I
O
Bu3Sn OEt
Pd(0)
Bu3SnCO2Et
1) DIBAL-H2) TPAP3) BuLi, (EtO)2P(O)CH2CO2Et
40%
Bu3SnCO2Et
N
OOH
1) LDA, 4:1 THF:HMPA-78 C 5 hrs, RT 24 hrs
I
2) 10% HCl, reflux3) CH2N24) LiAlH4,
OH
9:1 mixture of diastereomers
34%
TPAPCHO
OPEtO
EtO CO2Et
Me NaH, THF
Me
CO2Et
CO2Et
Me
PhSSPh
1) DIBAl2) TPAP3) CrCl2, CHI3
I
I
I
I
Bu3SnCO2Et
PdCl2(MeCN)2DMF, RT, 53%
O
MeOEt
H
H H
5.4%
3.7%
Me
CO2Et
H
2.4%
NO
MeO2C
PMB
OH 2 eq MeMgBr
37%
NHOMe
OO
HO
NO
MeO2C
PMB
O
HN
HH
CO2Me
O
NO
MeO2C
PMB
OH H2, Pd/C, EtOAc
NO
MeO2C
97%PMB
OH
NHOH
OO
NOH
O
MeO
O
PMB
NO
MeO2COH4 eq CAN MeCN
20 min, 75%NO
MeO2C
Cyclisation in ionic liquids
N
Br
TsO
N
NPF6
30 mol% CuBr30 mol% tren-Me6
NTs
O
Br
Run 1 20min 99%
Run 2 1hr 99%
Run 3 2hr 99%
Run 4 6hr 90%
Run 5 12hr 14%
Run 6 36hr No reaction
Work-up add toluene decant off ionic liquid
N
N
CuO
O
Br
CuN
NBr
A. J. Clark, M. C. Crossman, D.Duncalf, D. M. Haddleton,S. R. Morsley, A. J.Shooter, J. Chem.Soc., Chem Commun., 1997, 1734
a
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
a + eb c
df
g
hWater
t = 0
t = 10h
N N CH2 CH2 CH3
a
b
c d
e
f g h
Catalyst complex in water 25°C (Cu : ligand = 1 : 3)
N N1
2
3 4
5
6
7 8
Catalyst Complex in water at 50°C
NHOH
OO
NO
MeO2C
PMB
OH CAN or TFA
N-Deprotection
NH
O
MeO2C
86-95%
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