Decarboxylative sp C–N Couplings: Recent Progress...2 equiv BTMG dioxane (3 mL), r.t., 1 h 1 equiv...
Transcript of Decarboxylative sp C–N Couplings: Recent Progress...2 equiv BTMG dioxane (3 mL), r.t., 1 h 1 equiv...
Decarboxylative sp3 C–N Couplings: Recent ProgressSeptember, 2018
■ Outline
NH
X
MesI
OCOR
OCORN
XR
R
YY
Ir Cu
or Cu
■ Decarboxylative sp3 C–N coupling under non-photonic conditions
■ Decarboxylative sp3 C–N coupling using bicyclic tertiary acids
■ Decarboxylative sp3 C–N coupling using new N-heterocycles
■ General considerations
Initial publication: Liang, Y.; Zhang, X.; MacMillan, D. W. C. Nature 2018, 559, 83–88
Decarboxylative sp3 C–N Couplings: Recent ProgressSeptember, 2018
■ Outline
NH
X
MesI
OCOR
OCORN
XR
R
YY
Ir Cu
or Cu
■ Decarboxylative sp3 C–N coupling under non-photonic conditions
■ Decarboxylative sp3 C–N coupling using bicyclic tertiary acids
■ Decarboxylative sp3 C–N coupling using new N-heterocycles
■ General considerations
Decarboxylative sp3 C–N CouplingsSeptember, 2018
■ General considerations
NH
X
MesI
OCOR
OCOR NX
R
R
Y
YIr Cu
Ir Cu organic base
organic base
NN
IrN
N
t-Bu
t-Bu F
F
PF6−
Me
Me
Ir(F-Meppy)2(dtbbpy)PF6Strem 77-0320
NIrN
N
Ir(ppy)3Strem 77-7015
CuTCCAS 68986-76-5
N N
MeO OMe
dOMe-PhenCAS 92149-07-0
N N
Ph Ph
BPhenCAS 1662-01-7
N P N
Nt-Bu
N
N
N
N
t-Bu
Me
Me
Me
Me
N
N
BTMGCAS 29166-72-1
BTTPCAS 161118-67-8
DBUCAS 6674-22-2
Decarboxylative sp3 C–N Couplings: Recent ProgressSeptember, 2018
■ Outline
NH
X
MesI
OCOR
OCORN
XR
R
YY
Ir Cu
or Cu
■ Decarboxylative sp3 C–N coupling under non-photonic conditions
■ Decarboxylative sp3 C–N coupling using bicyclic tertiary acids
■ Decarboxylative sp3 C–N coupling using new N-heterocycles
■ General considerations
Unpublished Results
Decarboxylative sp3 C–N Couplings: Non-Photonic ConditionsSeptember, 2018
■ Non-photonic conditions: indole scope
NH Mes
IOCOCy
OCOCy N
20 mol% CuTC, 30 mol% dMe-Phen3 equiv BTMG
dioxane (3 mL), r.t., 1 h
1 equiv
58% yield
1 equiv0.1 mmol
R
R
N N N
N N N
ClBr Cl
Br Cl
Ac
50% yield 49% yield
50% yield 48% yield 49% yieldNMR yield
N N
Me Me
dMe-Phen
Decarboxylative sp3 C–N Couplings: Non-Photonic ConditionsSeptember, 2018
■ Non-photonic conditions: 7-azaindole scope, with BTMG
N NH Mes
IOCOCy
OCOCyN N
20 mol% CuTC, 30 mol% Me4-Phen2 equiv BTMG
dioxane (3 mL), r.t., 1 h
2 equiv
75% yield
1 equiv0.1 mmol
R
R
N N N N N N
N N N N N N
Cl
Ac
82% yield 94% yield
85% yield 59% yield 52% yieldNMR yield
N N
Me Me
Me4-Phen
Me Me
Cl
Br
BrCl
NC
Decarboxylative sp3 C–N Couplings: Non-Photonic ConditionsSeptember, 2018
■ Non-photonic conditions: 7-azaindole scope, with DBU
N NH Mes
IOCOCy
OCOCyN N
20 mol% CuTC, 30 mol% Me4-Phen4 equiv DBU
dioxane (3 mL), r.t., 1 h
2 equiv
69% yield
1 equiv0.1 mmol
R
R
N N N N N N
N N N N N N
Cl
Ac
67% yield 92% yield
71% yield 57% yield 60% yieldNMR yield
N N
Me Me
Me4-Phen
Me Me
Cl
Br
BrCl
NC
Decarboxylative sp3 C–N Couplings: Non-Photonic ConditionsSeptember, 2018
■ Non-photonic conditions: pyrazole scope
NMR yield
NH
N
MesI
OCOCy
OCOCy NN20 mol% CuTC, 30 mol% BPhen
no exogenous base
dioxane (3 mL), r.t., 1 h
2 equiv
95% yield
1 equiv0.1 mmol
R
R
NN
82% yield 65% yield
75% yield 91% yield 97% yield 61% yield
Br
94% yield
NN
CF3
NN
CONH2
NN
Ph
NN
Ar
Ar = para-Cl-C6H4
NN
Ar
Ar = para-Br-C6H4
NN
CF3EtO2C
NN
Br
single regioisomer
Decarboxylative sp3 C–N Couplings: Non-Photonic ConditionsSeptember, 2018
■ Non-photonic conditions: other N-heterocycles scope
NMR yield
NH
X
MesI
OCOCy
OCOCy NX40 mol% CuTC, 60 mol% BPhen
no exogenous base
dioxane (3 mL), r.t., 1 h
2 equiv1 equiv0.1 mmol
R
R
single regioisomer
Y
Y
73% yield
N
N
34% yield
82% yield 85% yield
48% yield
N
N
N
N
N NN
NN
N
Br
ClN
N
Decarboxylative sp3 C–N Couplings: Non-Photonic ConditionsSeptember, 2018
■ Non-photonic conditions: experimental procedure
N NH
MesI
OCOCy
OCOCy
N N
20 mol% CuTC, 30 mol% Me4-Phen2 equiv BTMG
dioxane (3 mL), r.t., 1 h
2 equiv1 equiv0.1 mmol
N N
Me Me
Me4-Phen
Me Me
Cl
Cl
75% NMR yield
Procedure:To an 8 mL vial equipped with a stir bar was added N-nucleophile, copper salt, ligand, and iodomesitylene dicarboxylate.Dioxane was added and the solution was degassed immediately by sparging with N2 for 3–5 minutes. If necessary, exogenous base (such as BTMG or DBU) was added under the atmosphere of N2. The reaction was stirred for 1 hour at room temperature. An internal standard (mesitylene) was added and the crude reaction mixture was analyzed by 1H NMR.
Notes:1. If the iodomesitylene dicarboxylate or the N-nucleophile is a liquid, its solution in dioxane was used instead.2. Pre-mixing the copper salt and the ligand in solution is not necessary. If a stock solution of copper catalyst is needed, the ligation step (such as stirring or sonification the solution) should be performed under the atmosphere of N2.
Decarboxylative sp3 C–N Couplings: Recent ProgressSeptember, 2018
■ Outline
NH
X
MesI
OCOR
OCORN
XR
R
YY
Ir Cu
or Cu
■ Decarboxylative sp3 C–N coupling under non-photonic conditions
■ Decarboxylative sp3 C–N coupling using bicyclic tertiary acids
■ Decarboxylative sp3 C–N coupling using new N-heterocycles
■ General considerations
Unpublished Results
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[1.1.1]pentane acid: 7-azaindole scope, non-photonic
NMR yield
N N
Me Me
Me4-Phen
Me Me
60 mol% CuTC, 90 mol% Me4-Phen4 equiv DBU
dioxane (1.5 mL), r.t., 1 hCO2Me
NNN N
H MesI
OCOR
OCOR
1 equiv0.05 mmol
1 equiv
RR
CO2Me
N N
Cl
49% yield
CO2Me
N N
54% yield
Cl
CO2Me
N N
40% yield
Br
CO2Me
N N
45% yield
BrCl
CO2Me
N N
35% yield
Ac
CO2Me
N N
55% yield
NC
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[1.1.1]pentane acid: indole scope, non-photonic
NMR yield
60 mol% CuTC, 90 mol% BPhen4 equiv DBU
dioxane (1.5 mL), r.t., 1 hCO2Me
NNH Mes
IOCOR
OCOR
1 equiv0.05 mmol
1 equiv
RR
CO2Me
N
46% yield
CO2Me
N
47% yield
CO2Me
N
61% yield
CO2Me
N
54% yield
CO2Me
N
52% yield
CO2Me
N
52% yield
CO2Me
N
58% yield
Br Cl
Br Cl
ClBr CN
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[1.1.1]pentane acid: other N-heterocycles, non-photonic
NMR yield
H-acac
CO2Me
NX
N
NH
XN
MesI
OCOR
OCOR60 mol% CuTC
90 mol% BPhen + 60 mol% H-acac
60 mol% DBUdioxane (1.5 mL), r.t., 1 h
1 equiv 1 equiv0.05 mmol
Me
O O
Me
CO2Me
N
NBr
CO2Me
N
NCl
CO2Me
NN
N
CO2Me
N
NN
N
CO2Me
N NN
42% yield 42% yield 63% yield
24% yield26% yield
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[1.1.1]pentane acid: aniline, photoredox
NMR yield
diketone
MesI
OCOR
OCOR
2 mol% Ir(F-Meppy)2(dtbbpy)PF660 mol% CuTC, 90 mol% diketone
2 equiv BTTP
dioxane (1.0 mL)blue LEDs, fan, r.t., 1 h
2 equiv1 equiv0.05 mmol
NH2
RR
CO2Me
HN
OMe
Me
O
CAS 39207-65-3
Br CN
F3C
F3C
F3C
94% yield 92% yield
29% yield 33% yield
CO2Me
HN
CO2Me
HN
CO2Me
HN
CO2Me
HN
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[2.2.2]octane acid: pyrazole, non-photonic
NMR yield
60 mol% CuTCno exogenous ligandno exogenous base
dioxane (1.5 mL), r.t., 1 hNH
N
MesI
OCOR
OCOR
2 equiv1 equiv0.05 mmol
R
n-pentyl
NNR
n-pentyl
NN
Br
n-pentyl
NN
n-pentyl
NN
Me
n-pentyl
NN
Me
Me
56% yield60% yield 50% yield 40% yield
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[2.2.2]octane acid: aniline, photoredox
NMR yield
diketone
MesI
OCOR
OCOR
2 mol% Ir(F-Meppy)2(dtbbpy)PF660 mol% CuTC, 90 mol% diketone
2 equiv BTTP
dioxane (1.0 mL)blue LEDs, fan, r.t., 1 h
2 equiv1 equiv0.05 mmol
NH2
R
OMe
Me
O
CAS 39207-65-3
n-pentyl
HN
R
n-pentyl
HN
n-pentyl
HN
n-pentyl
HN
n-pentyl
HN
n-pentyl
HN
Br CN
Cl
F3C
F3C
F3C
62% yield 46% yield 85% yield
72% yield 54% yield
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Bicyclo[2.2.2]octane acid: aniline, photoredox
NMR yield
diketone
MesI
OCOR
OCOR
2 mol% Ir(F-Meppy)2(dtbbpy)PF660 mol% CuTC, 90 mol% diketone
2 equiv BTTP
dioxane (1.0 mL)blue LEDs, fan, r.t., 1 h
2 equiv1 equiv0.05 mmol
NH2
R
OMe
Me
O
CAS 39207-65-3
CO2Me
HN
R
CO2Me
HN
CO2Me
HN
CO2Me
HN
CO2Me
HN
CO2Me
HN
Br CN
Cl
F3C
F3C
F3C
44% yield 40% yield 77% yield
60% yield 62% yield
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Experimental procedure: photoredox conditions
Procedure:To an 8 mL vial equipped with a stir bar was added photocatalyst, N-nucleophile, copper salt, ligand, and iodomesitylene dicarboxylate. Dioxane was added and then base was added to the mixture. Next, the solution was degassed by sparging with N2 for 3–5 minutes. The reaction was stirred and irradiated using 34 W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 hour. An internal standard (mesitylene) was added and the crude reaction mixture was analyzed by 1H NMR.
Notes:1. If the iodomesitylene dicarboxylate or the N-nucleophile or the ligand is a liquid, its solution in dioxane was used instead.
MesI
OCOR
OCOR
2 mol% Ir(F-Meppy)2(dtbbpy)PF660 mol% CuTC, 90 mol% diketone
2 equiv BTTP
dioxane (1.0 mL)blue LEDs, fan, r.t., 1 h
2 equiv1 equiv0.05 mmol
NH2
n-pentyl
HN
Br
Br
62% NMR yield
diketone
OMe
Me
O
Decarboxylative sp3 C–N Couplings: Bicyclic Tertiary AcidsSeptember, 2018
■ Experimental procedure: non-photonic conditions
60 mol% CuTC, 90 mol% BPhen4 equiv DBU
dioxane (1.5 mL), r.t., 1 hCO2Me
NNH Mes
IOCOR
OCOR
1 equiv0.05 mmol
1 equiv
BrBr
61% NMR yield
Procedure:To an 8 mL vial equipped with a stir bar was added N-nucleophile, copper salt, ligand, and iodomesitylene dicarboxylate.Dioxane was added and the solution was degassed immediately by sparging with N2 for 3–5 minutes. If necessary, exogenous base (such as BTMG or DBU) was added under the atmosphere of N2. The reaction was stirred for 1 hour at room temperature. An internal standard (mesitylene) was added and the crude reaction mixture was analyzed by 1H NMR.
Notes:1. If the iodomesitylene dicarboxylate or the N-nucleophile is a liquid, its solution in dioxane was used instead.2. Pre-mixing the copper salt and the ligand in solution is not necessary. If a stock solution of copper catalyst is needed, the ligation step (such as stirring or sonification the solution) should be performed under the atmosphere of N2.
Decarboxylative sp3 C–N Couplings: Recent ProgressSeptember, 2018
■ Outline
NH
X
MesI
OCOR
OCORN
XR
R
YY
Ir Cu
or Cu
■ Decarboxylative sp3 C–N coupling under non-photonic conditions
■ Decarboxylative sp3 C–N coupling using bicyclic tertiary acids
■ Decarboxylative sp3 C–N coupling using new N-heterocycles
■ General considerations
Unpublished Results
Decarboxylative sp3 C–N Couplings: New N-HeterocyclesSeptember, 2018
■ New N-heterocycles: summary of results
NMR yield
NH
X
MesI
OCOCy
OCOCy NX
RR
YY
Ir Cu
N NN
75% yield
Cl
N NN
77% yield
N NN
76% yield
N
NN
85% yield
ClN
NN
69% yield
Br
N
N N
86% yield
Cl
N
N N
54% yield
Cl
N
N N
60% yield
Cl Br
N
N
N
66% yield
BrN
N N
N
82% yield
Cl
N
N N
N
75% yield
Cl
Cl
N
N
NN
54% yield
Br
0.10 mmol1 equiv
2 equivdioxane, r.t., 1 h
single regioisomer
Decarboxylative sp3 C–N Couplings: New N-HeterocyclesSeptember, 2018
■ New N-heterocycles: summary of conditions
NMR yield
NH
X
MesI
OCOCy
OCOCyN
XR R
Y Y
0.10 mmol1 equiv
2 equiv
1 mol% photocatalyst20 mol% CuTC, 30 mol% ligand
2 equiv base
dioxane (3.0 mL), r.t., 1 h
N
N NHN
N
NHN N
H
N
N NH
NN
NH
NN
NH
NN
N NH
N
Ir(F-Meppy)2(dtbbpy)dOMe-Phen, BTMG
Ir(ppy)3BPhen, BTMG
Ir(F-Meppy)2(dtbbpy)BPhen, no base
Ir(F-Meppy)2(dtbbpy)dOMe-Phen, BTMG
Ir(F-Meppy)2(dtbbpy)dOMe-Phen, BTMG
Ir(ppy)3BPhen, BTMG
Ir(F-Meppy)2(dtbbpy)BPhen, no base
N
N
NH
N
Ir(ppy)3BPhen, BTMG
Decarboxylative sp3 C–N Couplings: New N-HeterocyclesSeptember, 2018
■ Experimental procedure: photoredox conditions
Procedure:To an 8 mL vial equipped with a stir bar was added photocatalyst, N-nucleophile, copper salt, ligand, and iodomesitylene dicarboxylate. Dioxane was added and then base was added to the mixture. Next, the solution was degassed by sparging with N2 for 3–5 minutes. The reaction was stirred and irradiated using 34 W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 hour. An internal standard (mesitylene) was added and the crude reaction mixture was analyzed by 1H NMR.
Notes:1. If the iodomesitylene dicarboxylate or the N-nucleophile is a liquid, its solution in dioxane was used instead.
MesI
OCOCy
OCOCy
1 mol% Ir(ppy)320 mol% CuTC, 30 mol% BPhen
2 equiv BTMG
dioxane (3.0 mL)blue LEDs, fan, r.t., 1 h
2 equiv1 equiv0.10 mmol 77% NMR yield
N NN
N NH
N