Recent Developments in Copper- Catalyzed Aerobic Oxidative ... · Recent Developments in Copper-Catalyzed Aerobic Oxidative Coupling Reactions Using Oxygen as Oxidant ZHE JIA MICHIGAN

Recent Developments in CopperRecent Developments in Copper--Recent Developments in CopperRecent Developments in CopperCatalyzed Aerobic Oxidative Coupling Catalyzed Aerobic Oxidative Coupling

Reactions Using Oxygen as OxidantReactions Using Oxygen as Oxidant

ZHE JIAZHE JIAZHE JIAZHE JIA

MICHIGAN STATE UNIVERSITYMICHIGAN STATE UNIVERSITYDEPARTMENT OF CHEMISTRY

2/16/2011

Transition Metal Catalyzed Aerobic Oxidative Coupling Reaction

2

Activate two different C-H bonds or H-Heteroatom bonds

Couple them via a transition metal catalyst

Carry out the reaction in air or O with O as the oxidant Carry out the reaction in air or O2, with O2 as the oxidant

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.Gligorich, K. M. Sigman, M. S. Angew. Chem. Int. Ed. 2006, 45, 6612-6615.Gligorich, K. M. Sigman, M. S. Chem. Commun., 2009, 3854-3867.

Copper Catalyzed Aerobic Oxidative Coupling ReactionCopper Catalyzed Aerobic Oxidative Coupling Reaction3

Why copper?

Copper is relatively abundant in the earth’s crust.

Copper can bind and activate dioxygen well that perform a variety of critical biological functionscritical biological functions.

Glaser Coupling (1869)

Gamez, P.; Aubel, P. G.; Driessen, W. L.; Reedijk, J. Chem. Soc. Rev., 2001, 30, 376-385. Lewis, E. A.; Tolman, W. B. Chem. Rev., 2004, 104, 1047-1076.Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.Glaser, C. Ann. Chem. Pharm. 1870, 154, 137.

Pros and Cons of Oxidative Coupling Reactionp g

4

Attractions:Attractions: Challenges:Challenges:

Direct C-H functionalizaton

Hi h t ffi i

Homocoupling of the two nucleophiles

High atom economy efficiency

H2O is generated as by-product environmentally friendly

p

Direct reaction of the nucleophiles with the oxidant

y y

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.Stahl, S. S. Science, 2005, 309, 1824-1826.Gligorich, K. M.; Sigman, M. S. Chem. Commun., 2009, 3854-3867.

Transition Metal Catalyzed Coupling Reaction PPattern

5

Oxidative

Preactivation

R'-XMLnR-R'

OxidativeAddition

15

Nucleophile Electrophile

LnMR'

LnMR'

ReductiveElimination

1

24XR

R

TransmetalationM = Fe, Co, Ni, Cu, Pd, Ru, Rh ... ...

m-Rm-X 3

Armin de Meijere, François Diederich, Metal-Catalyzed Cross-Coupling Reactions, 2nd, Completely Revised and Enlarged Edition, Wieley-VCH, Weinheim, 2004

Models for Coupling Reaction Bond ConstructionModels for Coupling Reaction Bond Construction6

Classic Coupling Model

Oxidative Coupling Model

Liu, C.; Jin, L.; Lei, A. Synlett., 2010, 17, 2527–2536.

To Combine Two Nucleophiles Togethero Co b e o uc eop es oge e

7

Nu1 H

2+

Mn+2X2[O] Nu1 H

+

Mn+2X2O2

Nu2 H

+

Mn Nu2 HMn

2H+

Mn+2Nu2

Nu1

Nu1 Nu2 H2O(H2O2)

Mn+2Nu2

Nu1

Nu1 Nu2

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.Gligorich, K. M.; Sigman, M. S. Angew. Chem. Int. Ed. 2006, 45, 6612-6615.

To Combine Two Nucleophiles Togethero Co b e o uc eop es oge e

8

Nu1 H

2+

Mn+2X2[O] Nu1 H

+

Mn+2X2O2

Nu2 H

+

Mn Nu2 HMn

2H+

Mn+2Nu2

Nu1

Nu1 Nu2 H2O(H2O2)

Mn+2Nu2

Nu1

Nu1 Nu2

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.Gligorich, K. M.; Sigman, M. S. Angew. Chem. Int. Ed. 2006, 45, 6612-6615.

Why O2 as Oxidant?y O2 as O da ?

9

O2 is the quintessential oxidant for chemical synthesis!synthesis!

Huge abundance in nature Huge abundance in nature

Available at virtually no cost

Produces no environmentally hazardous by-products

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.Stahl, S. S. Science 2005, 309, 1824-1826.

Metalloenzyme-catalyzed Aerobic Oxidationy y

10

a) a) OxygenaseOxygenase PathwayPathway b) b) OxidaseOxidase PathwayPathway

In the oxygenase pathway (a) the substrate oxidation involves oxygen-atom transfer In the oxygenase pathway (a), the substrate oxidation involves oxygen atom transfer from molecular oxygen.

The oxidase pathway (b), utilizes molecular oxygen as a electron/proton acceptor in the oxidation of the substrate

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.Stahl, S. S. Science 2005, 309, 1824-1826.

oxidation of the substrate.

Examples of Oxygenase and Oxidasea p es o O yge ase a d O dase

11

C-N Functionalization of Terminal Alkynes

Stahl – Oxidase Pathway

O H

Jiao – Dioxygenase Pathway

R H + H NR1

H O2 ActivationR

O HN

R1

O

[Cu]

Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc., 2008, 130, 833–835.Zhang, C.; Jiao, N. J. Am. Chem. Soc., 2010, 132, 28–29.

Metal Catalyzed Oxidase Reactionse a Ca a y ed O dase eac o s

12

(n+2)+Stage A:Substrate Oxidation

2

n(n+2)+

2

2

Substrate Oxidation

n+

ox

+2

nn

Stage B:Metal Oxidation

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.http://www.chem.wisc.edu/content/investigation-fundamental-reactions-between-palladium-and-molecular-oxygen

Metal Catalyzed Oxidase Reactionse a Ca a y ed O dase eac o s

13

(n+2)+Stage A:Substrate Oxidation

2

n(n+2)+

2

2

Substrate Oxidation

n+

ox

+2

nn

Stage B:Metal Oxidation

Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420.http://www.chem.wisc.edu/content/investigation-fundamental-reactions-between-palladium-and-molecular-oxygen

OutlineOu e

14

CuCu--Catalyzed Oxidative Catalyzed Oxidative HomoHomo--Coupling Coupling ReactionReaction

CuCu--Catalyzed Oxidative Catalyzed Oxidative HeteroHetero--Coupling Coupling ReactionReaction

C C B d F ti C-C Bond Formation

C-N Bond FormationC N Bond Formation

C-P Bond Formation

Cu Catalyzed Aerobic Oxidative C-C Bond H li R i Homocoupling Reaction

15

Glaser Coupling (1869)

cat. CuI

Ph Ph+ Ph Phcat. Cu

+ 1/2 O2 + H2Obase

Ph + CuClbase

Ph Cu(I)

One Possible Mechanism Pathway:

H ( )

O2

Ph Ph Cu(II)Ph Cu(I)+

Ph Phdimerization

Ph Ph

Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422.Glaser, C. Ann. Chem. Pharm. 1870, 154, 137.

Ph Ph Ph Ph

Arene Dimerizatione e e a o

16

Aromatic Glaser-Hay Reaction

Ar Hcat. CuCl2, O2

THF baseAr Ar

THF, base

C t l d d t ti di i ti f b l i OCopper-catalyzed, deprotonative dimerization of arenes by employing O2as the terminal oxidant.

FF F

F

F

F

HF

F H

F+

cat. CuCl2, O2

THF, base+ H2O

Do, H.Q.; Daugulis, O. J. Am. Chem. Soc., 2009, 131, 17052–17053.

FF

Aromatic Glaser-Hay Reactiono a c G ase ay eac o

17

Previous Work

Cu-Catalyzed Arylationy yof Arene C-H Bond

Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404-12405.Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.-1129Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185-15192.

Aromatic Glaser-Hay Reactiono a c G ase ay eac o

18

Inspiration from Previous Work

Cu-Catalyzed Oxidative yArene Dimerization


Initial Study on Aromatic Gl H R iGlaser-Hay Reaction

19

FF

FOMe F

F OHF

F H

FF

F

F

F

MeO

+F

MeO

OH

FF

F

MeO FF

cat. CuCl2, O2

DMF, tBuOLi

H

F56% 38%Methoxytetrafluorobenzene

A less polarized C-metal Formed by ArLi intermediateSolutionA less polarized C-metal bond in the intermediate is needed!

Formed by ArLi intermediate with O2 or ArCu with hydroxide derived from water.

King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044-5045.Do, H.Q.; Daugulis, O. J. Am. Chem. Soc., 2009, 131, 17052–17053.

Substrate Scope of Aromatic Glaser-Hay ReactionSubs a e Scope o o a c G ase ay eac o

20

Hindered Zn and Mg amide bases were used

Less acidic the arene H the stronger base was needed

BaseDicyclohexylamine : iPrMgCl•LiCl : ZnCl2

iPrMgCl•LiCl : tetramethylpiperidine : ZnCl2

iPrMgCl•LiCl : tetramethylpiperidine

Less acidic the arene H, the stronger base was needed

g 2 (1.1 : 1 : 0.25)

y p p 2(1 : 1.1 : 0.5)

y p p(1.1 : 1)

Product

%

N

N

N

N

NN

BuBu


91% 71% 73%

OutlineOu e

21

Cu-Catalyzed Oxidative Homo-Coupling Reaction


C-C Bond Formation

C-N Bond Formation

C-P Bond Formation

Cu-Catalyzed Direct Aerobic Alkynylation of Arenes with Terminal Alkynes

22

Direct Alkynylation

The first example of direct alkynylation of an aromatic C-H bond with terminal alkynes.

…but limited to polyfluroroarenes!

Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.

Alkynylation of Arenes with Terminal Alkynes

23

y y a o o e es e a y es

Ar-X + HSonogashira Reaction

R

[Cu] / O2+

Ar-H + X RDirect Alkynylation

Ar R[Cu] / O2

H RAr H Alkynylation withFunctionalized Alkynes

Armin de Meijere, François Diederich, Metal-Catalyzed Cross-Coupling Reactions, 2nd, Completely Revised and Enlarged Edition, Wieley-VCH, Weinheim, 2004Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.

Alkynylation of Arenes with Terminal Alkynesy y a o o e es e a y es

24


R

[Cu] / O2+


Ar R[Cu] / O2


OH

Cl SiEt3+GaCl3 (10mol%), BuLi (30mol%)

OH SiEt3

2,6-di(tert-butyl)-4-methylpyridine(10mol%)

80-90%

NHR

Cl SiEt3+

NHR SiEt3

X X(10mol%)

GaCl3 (10mol%), BuLi (30mol%)

o Dichlorobenzene55-85%

+

XX

N H Br R NPdCl2(PPh3)2 (3-5mol%)

R

o-Dichlorobenzene

KOAc56-98%

Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc. 2002, 124, 8528-8529.Amemiya, R.; Fujii, A.; Yamaguchi, M. Tetrahedron Lett. 2004, 45, 4333-4335.Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,129, 7742-7744.

RKOAc

Cu-Catalyzed Direct Aerobic Alkynylation of A i h T i l AlkArenes with Terminal Alkynes

25


R

[Cu] / O2+


Ar R[Cu] / O2



Cu-Catalyzed Aerobic Alkynylation of P fl b i h Ph l l

F F F F

Pentafluorobenzene with Phenylacetylene26

F F

H

FF

F H Ph+[Cu], ligand

base (2equiv.)O2, 40 C, 12h

F F

FF

F Ph + +Ph2

C6F5 C6F5

2, ,3 4 51 2

Entry Reaction Condition (equiv. of reagents) Solvent % Yield 3 (4/5)

1 CuCl (20 mol% ) O (1atm) DMSO undetectable1 CuCl2 (20 mol%.), O2 (1atm), NaHCO3/K3PO4 (2equiv.)

DMSO, 70°C

undetectable(>90/-)

2 CuCl2 (20 mol%), O2 (1atm), tBuOLi (2equiv.)

DMSO, 40°C

11 (57/5)( q )

3 CuCl2 (20 mol%), O2 (1atm), tBuOLi (2equiv.), 1,10-phenanthroline (0.2equiv.)

DMSO, 40°C

49 (38/4)

CuCl (20 mol%) O (1atm)4

CuCl2 (20 mol%), O2 (1atm), tBuOLi (2equiv.), 1,10-phenanthroline (0.2equiv.)

DDQ (0.15equiv.)DMSO, 40°C

72 (24/7)

CuCl2 (30 mol%), O2 (1atm),

Wei, Y.; Zhao, H.; Kan, J.; Su, W.; J. Am. Chem. Soc., 2010, 132, 2522–2523.

52 ( ), 2 ( ),

tBuOLi (3equiv.), 1,10-phenanthroline (0.3 equiv.)DDQ (0.15equiv.)

DMSO, 40°C

85 (14/13)

Proposed Mechanism of Cu-Catalyzed Direct Aerobic Alkynylation

27

R HArF H

Cross-Coupling Pathway

LnCuIIX2

ArF

+base

+base

LnCuII

R

R HLnCuII

R

LnCuIIArF

XRArF H

baseLnCuII

ArF

AR

XX

O2

baseArF CB

R2LnCuII

ArF

R

ArF ArF

ArF H+

baseR H

+base

A RA



28

Cross-Coupling Pathway



29

Homo-Coupling and Cross-Coupling Pathway


Substrate Scope of Cu-Catalyzed Direct Aerobic Alkynylation

30

C6F5 C6F5N

C6 5

72%

6 5

69% Cl



31

H R+

CuCl21,10-phenanthroline

tBuOLi DDQArF RPolyfluroarene

tBuOLi, DDQDMSO, O2, 40 C1 2 3



32

Both tri- and difluoroarenes are unreactive.


Cu Mediated Aerobic Oxidative Trifluoromethylation of Terminal Alkynes

33

The first example of a copper-mediated oxidative trifluoromethylation.

In situ generated CuCF3

Direct oxidative coupling of terminal alkynes

Chu, L.; Qing, F. J. Am. Chem. Soc., 2010, 132, 7262–7263.

Initial Study on Aerobic Oxidative T ifl h l iTrifluoromethylation

34


Initial Study on Aerobic Oxidative T ifl h l iTrifluoromethylation

35

Under dry air

Under O2

Reactive CuCF3was quenched by

CuI, KF,1,10-phenantrolineMe3SiCF3 (5 equiv.) was quenched by

high concentration of O2

Ph100 C, DMF

Ph Ph3 3 ( q )

O2exclusively

Chu, L.; Qing, F. J. Am. Chem. Soc., 2010, 132, 7262–7263.Wiemers, D. M. Burton, D. J. J. Am. Chem. Soc., 1986, 108, 832–834.

Plausible Reaction Pathways for Aerobic O id i T ifl h l iOxidative Trifluoromethylation

36

CuI-IN

NCF3

R H+

base

NN O2 NPath APath B R

CuI

N

NCuI

N

NCF3 R

O2Cu

N

N

R

CuN CF3

O2O2 CF3

R HR

CuN

R

2

R CF3


Plausible Reaction Pathways for Aerobic O id i T ifl h l iOxidative Trifluoromethylation

37

CuI-IN

NCF3

R H+

base

NN O2 NPath APath B R

CuI

N

NCuI

N

NCF3 R

O2Cu

N

N

R

CuN CF3

O2O2 CF3

R HR

CuN

R

2

R CF3


Substrate Scope of Aerobic Oxidative T ifl h l iTrifluoromethylation

38


OutlineOu e

39



C-C Bond Formation

C N B d F ti C-N Bond Formation

R1 H H NRR'+O

R1 NRR' + H2O[Cu]

C-P Bond Formation

O2

Amidation of Terminal AlkynesAmidation of Terminal Alkynes40

HalogenationR X [C ] R1R2NH

Coupling via Alkynyl Halide

R H

R X

X = halide

[Cu], R1R2NHbase

NR

R1

R H

[Cu], R1R2NH, base, O2

RR2

Direct Coupling of Terminal Alkynes

Hamada, T.; Ye, X.; Stahl, S. J. Am. Chem. Soc., 2008, 130, 833–835.DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064–5106.

Cu Catalyzed Aerobic Oxidative Amidation of T i l Alk

O OO

Terminal Alkynes41

Ph

HHN O

O

+[Cu], base (2 equiv.)

Ph

N

OO

Ph2+ +

Ph

Cl

1 2 3 4 5

O2 (1 atm)solvent

1phenylacetylene

22-oxazolidinone

3 4 5

Entry Reaction Condition(equiv. of reagents)

Solvent % Yield3 (4/5)( q g ) ( )

1 CuCl2 (2), Cs2CO3 (2), 1 equiv. of 2

DMSO70°C

26 (42/17)

2 CuCl (2) Cs CO (2) DMSO 89 (4/ )2 CuCl2 (2), Cs2CO3 (2), 5 equiv. of 2

DMSO70°C

89 (4/-)

3 CuCl2 (0.2), Cs2CO3 (2), 5 equiv of 2

DMSO70°C

Trace (19/-), 5 equiv. of 2 70 C

4 CuCl2 (0.2), Na2CO3 (2), Pyridine (2), 5 equiv. of 2

DMSO70°C

90 (4/-)

5 CuCl2 (0.2), Na2CO3 (2), Pyridine (2), 1 equiv. of 2

Toluene70°C

69 (16/4)

Hamada, T.; Ye, X.; Stahl, S. J. Am. Chem. Soc., 2008, 130, 833–835.

Mechanistic Study of Cu Catalyzed Aerobic Oxidative Amidation of Terminal Alkynes

42

HHN O

O

+ N

OO

2+ +Clstandard condition

PhHN O+

(5 equiv.) Ph

NPh

2+ +Ph

1phenylacetylene

22 oxazolidinone

3 4 5phenylacetylene 2-oxazolidinone

ClO

standard condition

Ph

Cl+ HN O

(5 equiv.)

standard condition

( )


Proposed Mechanism of Cu Catalyzed Aerobic Oxidative Amidation of Terminal Alkynes

43

R H+ B:

BH+X-

RR

LnCuII

R

R HLnCuII

XLnCuIIX2

A BR

H-NR'Z+ B:

R NR'Z

R2

LnCuII

R

NR'Z

BH+X-+ B: + H2O

1/2 O2

2 BH+X+ 2 BH+X- C


Cu Catalyzed Direct Amination of Benzothiazolesd B land Benzoxazoles

44

N MeCu(OAc)2 (20 mol%)

PPh3 (40 mol%) NaOAc N Me

S

NH + H N

Ph

Me PPh3 (40 mol%), NaOAc

O2 (1atm)xylene, 140 C, 20h

S

NN

Me

Ph+ H2O

81%Benzothiazole N-Methylaniline

O

NH +

Cu(OAc)2 (20 mol%)PPh3 (40 mol%), NaOAc

O2 (1atm) O

NN + H2ONH

xylene, 140 C, 20hO

72%Benzoxazole Piperidine

Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett., 2009, 11, 1607-1610.

OutlineOu e

45



C C B d F ti C-C Bond Formation

C-N Bond Formation

C-P Bond Formation

Cu Catalyzed Aerobic Phosphonation of sp C

46

Cu Ca a y ed e ob c osp o a o o sp C

A new methodology for catalytically constructing C-P bonds:

H-phosphonate Alkynylphosphonate

Gao, Y.; Zhao, Y.; Zhou, Y.; Han, L. J. Am. Chem. Soc., 2009, 131, 7956–7957.


47


YellowUnder dry air

(i P O) P(O)H (0 5 l) Yellowsuspension

Ph

(i-PrO)2P(O)H (0.5 mmol)K2CO3 (0.05 mmol)

CuI (0 05 mmol)CuPhH

0.6 mmol CuI (0.05 mmol)DMSO, air

50 Covernight

PhPO

R'O PhP

91% (NMR Yield)

R'O

Gao, Y.; Zhao, Y.; Zhou, Y.; Han, L. J. Am. Chem. Soc., 2009, 131, 7956–7957.\Nakamura, E.; Mori, S. Angew. Chem. Int. Ed. 2000, 39,3750-3771.

( )


48


Under N2

Yellowsuspension

Gao, Y.; Zhao, Y.; Zhou, Y.; Han, L. J. Am. Chem. Soc., 2009, 131, 7956–7957.Nakamura, E.; Mori, S. Angew. Chem. Int. Ed. 2000, 39, 3750-3771.Niu, M.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun. 2007, 272-274.

Proposed Reaction Path Cu Catalyzed Aerobic Ph h i f C

49

Phosphonation of sp C

Yellowsuspensionsuspension

Phosphonate

Phosphite


Proposed Reaction Path Cu Catalyzed Aerobic Ph h i f C

50


Yellowsuspensionsuspension

Phosphonate

Phosphite


Substrate Scope for Cu Catalyzed Aerobic Ph h i f C

51


R H (R'O)2P(O)H+

CuI (0.05mmol)Et3N (0.1 mmol)

DMSO 55 CPh(R'O)2P(O) + H2O

0.6 mmol 0.5 mmolDMSO, 55 C

air

(iPrO)2P(O)

Cl

93% (83%) 95% (83%) 94% (82%)

% % % % % %


85% (72%) 98% (82%) 99% (88%)

Cu Catalyzed Aerobic Phosphonation of sp3 CCu Ca a y ed e ob c osp o a o o sp C

52

Basle, O.; Li, C-J. Chem. Comm., 2009, 4124-4126.

Mechanistic Study of Cu Catalyzed Aerobic Ph h i f 3 CPhosphonation of sp3 C

53

+ P(OR)2H CuBr (5 mol%)

+ H2ONAr

H( )2

O NAr

P(OR)2O

1 2 3

O2 (1 atm)60 C, 16h

MeOH(2 equiv.)

1 2 3

Aryl-protected amines is an important featurefeature.


Aryl group can stabilize the oxidized form of the tertiary amine.

Mechanistic Study of Cu Catalyzed Aerobic Ph h i f 3 CPhosphonation of sp3 C

54

+ P(OR)2H CuBr (5 mol%)

+ H2ONAr

H( )2

O NAr

P(OR)2O

1 2 3

O2 (1 atm)60 C, 16h

MeOH(2 equiv.)

A molecular oxygen uptake experiment shows i t t l ti f 1 i f O f th ti f 1 i f

1 2 3

i. a total consumption of 1 equiv. of O2 for the generation of 1 equiv. of desired product 3;

ii. 1 equiv. of 1 and 1 equiv. of 2 consumes 0.5 equiv. of O2.


O2 is involved in the oxidation of excess 2 to methyl phosphate

Possible Mechanism Pathway for Cu Catalyzed A bi Ph h i f 3 CAerobic Phosphonation of sp3 C

55

N H+ 1/2 O2

14

Iminium type intermediate

Ar NAr [Cu]-OH

[Cu]Cycle 1

1

NAr

P(OR)2O

+ H2Ophosphite form

(reactive)phosphonate form

(unreactive)

P(OR)2HP(OR)2

3

P(OR)2O

P(OR)2OH

[Cu]P(OR)2O

MeOH2O +

2

Basle, O.; Li, C-J. Chem. Comm., 2009, 4124-4126.MeOH + 1/2 O2

Cycle 2O 5

Substrate Scope of Cu Catalyzed Aerobic Ph h i f 3 CPhosphonation of sp3 C

56

Entry Amine Phosphite Product % Yield

1 79 (95)

NPh

P(OEt)2O

2 73 (75)P(OiPr)2O

HPMP = p-methoxyphenyl

3 69 (85)

Op methoxyphenyl

OMP =


o-methoxyphenyl

SummarySu a y

57

Copper-catalyzed aerobic oxidative coupling reactions enable direct C-H functionalization, and can be a powerful tool for constructing C-, p gC bonds and C-heteroatom bonds.

Reactions are conducted in air or an O2 atmosphere with O2 as a Reactions are conducted in air or an O2 atmosphere, with O2 as a stoichiometric oxidant. H2O or H2O2 is generated as a by-product.

However this chemistry is still in its infancy The substrate scope is However, this chemistry is still in its infancy. The substrate scope is very limited for some reactions.

Acknowledgementc o edge e

58

Dr. Baker

Dr Maleczka Dr. Maleczka

Dr. Smith, Dr. Wulff

Baker’s Group: Gina, Hui, Heyi, Quanxuan, Wen, Yiding, Greg, Salinda, Cat and KaylaYiding, Greg, Salinda, Cat and Kayla

Li, Hong, Yong, Chunjuan and Hao

Xin, Ipek, Herbert, Wenjun and Jason

THANK YOU!THANK YOU!

Recent Developments in Copper- Catalyzed Aerobic Oxidative ... · Recent Developments in Copper-Catalyzed Aerobic Oxidative Coupling Reactions Using Oxygen as Oxidant ZHE JIA MICHIGAN

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