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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 JIAZHEJIAZHEJIA

MICHIGAN STATE UNIVERSITYMICHIGANSTATEUNIVERSITYDEPARTMENT OFCHEMISTRY

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 earths 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, Franois 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, 25272536.

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

+

MnNu2 H

Mn

2H+

Mn+2Nu2

Nu1

Nu1 Nu2 H2O(H2O2)Mn+2

Nu2

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

+

MnNu2 H

Mn

2H+

Mn+2Nu2

Nu1

Nu1 Nu2 H2O(H2O2)Mn+2

Nu2

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, 833835.Zhang, C.; Jiao, N. J. Am. Chem. Soc., 2010, 132, 2829.

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. CuIPh Ph+ Ph Ph

cat. Cu+ 1/2 O2 + H2O

base

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, 1705217053.

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

Do, H.Q.; Daugulis, O. J. Am. Chem. Soc., 2009, 131, 1705217053.

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, 1705217053.

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 : iPrMgClLiCl : ZnCl2

iPrMgClLiCl : tetramethylpiperidine : ZnCl2

iPrMgClLiCl : 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

Do, H.Q.; Daugulis, O. J. Am. Chem. Soc., 2009, 131, 1705217053.

91% 71% 73%

OutlineOu e

21

Cu-Catalyzed Oxidative Homo-Coupling Reaction

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

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 polyfluroroar

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