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


■ Outline

NH

X

MesI

OCOR

OCORN

XR

R

YY

Ir Cu

or Cu





Decarboxylative sp3 C–N CouplingsSeptember, 2018


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


■ Outline

NH

X

MesI

OCOR

OCORN

XR

R

YY

Ir Cu

or Cu





Unpublished Results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


■ Non-photonic conditions: 7-azaindole scope, with BTMG

N NH Mes

IOCOCy

OCOCyN N

20 mol% CuTC, 30 mol% Me4-Phen2 equiv BTMG


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


N N

Me Me

Me4-Phen

Me Me

Cl

Br

BrCl

NC


■ Non-photonic conditions: 7-azaindole scope, with DBU

N NH Mes

IOCOCy

OCOCyN N

20 mol% CuTC, 30 mol% Me4-Phen4 equiv DBU


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


N N

Me Me

Me4-Phen

Me Me

Cl

Br

BrCl

NC


■ Non-photonic conditions: pyrazole scope

NMR yield

NH

N

MesI

OCOCy

OCOCy NN20 mol% CuTC, 30 mol% BPhen

no exogenous base


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


■ Non-photonic conditions: other N-heterocycles scope

NMR yield

NH

X

MesI

OCOCy

OCOCy NX40 mol% CuTC, 60 mol% BPhen

no exogenous base


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


■ Non-photonic conditions: experimental procedure

N NH

MesI

OCOCy

OCOCy

N N

20 mol% CuTC, 30 mol% Me4-Phen2 equiv BTMG



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.


■ Outline

NH

X

MesI

OCOR

OCORN

XR

R

YY

Ir Cu

or Cu





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


■ Bicyclo[1.1.1]pentane acid: indole scope, non-photonic

NMR yield

60 mol% CuTC, 90 mol% BPhen4 equiv DBU


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


■ 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


■ 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


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


■ 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


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


■ Bicyclo[2.2.2]octane acid: aniline, photoredox

NMR yield

diketone

MesI

OCOR

OCOR


2 equiv BTTP



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


72% yield 54% yield


■ Bicyclo[2.2.2]octane acid: aniline, photoredox

NMR yield

diketone

MesI

OCOR

OCOR


2 equiv BTTP



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


60% yield 62% yield


■ 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 equiv BTTP



NH2

n-pentyl

HN

Br

Br

62% NMR yield

diketone

OMe

Me

O


■ Experimental procedure: non-photonic conditions

60 mol% CuTC, 90 mol% BPhen4 equiv DBU


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.


■ Outline

NH

X

MesI

OCOR

OCORN

XR

R

YY

Ir Cu

or Cu





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


■ 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(ppy)3BPhen, BTMG

Ir(F-Meppy)2(dtbbpy)BPhen, no base

N

N

NH

N

Ir(ppy)3BPhen, BTMG


■ 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


2 equiv1 equiv0.10 mmol 77% NMR yield

N NN

N NH

N

Decarboxylative sp C–N Couplings: Recent Progress...2 equiv BTMG dioxane (3 mL), r.t., 1 h 1 equiv...

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