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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 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
Do, H.Q.; Daugulis, O. J. Am. Chem. Soc., 2009, 131, 17052–17053.
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
Do, H.Q.; Daugulis, O. J. Am. Chem. Soc., 2009, 131, 17052–17053.
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 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
Ar-X + HSonogashira Reaction
R
[Cu] / O2+
Ar-H + X RDirect Alkynylation
Ar R[Cu] / O2
H RAr H Alkynylation withFunctionalized Alkynes
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
Ar-X + HSonogashira Reaction
R
[Cu] / O2+
Ar-H + X RDirect Alkynylation
Ar R[Cu] / O2
H RAr H Alkynylation withFunctionalized Alkynes
Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.
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
Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.
Proposed Mechanism of Cu-Catalyzed Direct Aerobic Alkynylation
28
Cross-Coupling Pathway
Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.
Proposed Mechanism of Cu-Catalyzed Direct Aerobic Alkynylation
29
Homo-Coupling and Cross-Coupling Pathway
Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.
Substrate Scope of Cu-Catalyzed Direct Aerobic Alkynylation
30
C6F5 C6F5N
C6 5
72%
6 5
69% Cl
Wei, Y.; Zhao, H.; Kan, J.; Su, W.; J. Am. Chem. Soc., 2010, 132, 2522–2523.
Substrate Scope of Cu-Catalyzed Direct Aerobic Alkynylation
31
H R+
CuCl21,10-phenanthroline
tBuOLi DDQArF RPolyfluroarene
tBuOLi, DDQDMSO, O2, 40 C1 2 3
Wei, Y.; Zhao, H.; Kan, J.; Su, W.; J. Am. Chem. Soc., 2010, 132, 2522–2523.
Substrate Scope of Cu-Catalyzed Direct Aerobic Alkynylation
32
Both tri- and difluoroarenes are unreactive.
Wei, Y.; Zhao, H.; Kan, J.; Su, W. J. Am. Chem. Soc., 2010, 132, 2522–2523.
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
Chu, L.; Qing, F. J. Am. Chem. Soc., 2010, 132, 7262–7263.
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
Chu, L.; Qing, F. J. Am. Chem. Soc., 2010, 132, 7262–7263.
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
Chu, L.; Qing, F. J. Am. Chem. Soc., 2010, 132, 7262–7263.
Substrate Scope of Aerobic Oxidative T ifl h l iTrifluoromethylation
38
Chu, L.; Qing, F. J. Am. Chem. Soc., 2010, 132, 7262–7263.
OutlineOu e
39
Cu-Catalyzed Oxidative Homo-Coupling Reaction
CuCu--Catalyzed Oxidative Catalyzed Oxidative HeteroHetero--Coupling Coupling ReactionReaction
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
( )
Hamada, T.; Ye, X.; Stahl, S. J. Am. Chem. Soc., 2008, 130, 833–835.
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
Hamada, T.; Ye, X.; Stahl, S. J. Am. Chem. Soc., 2008, 130, 833–835.
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
Cu-Catalyzed Oxidative Homo-Coupling Reaction
CuCu--Catalyzed Oxidative Catalyzed Oxidative HeteroHetero--Coupling Coupling ReactionReaction
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.
Cu Catalyzed Aerobic Phosphonation of sp C
47
Cu Ca a y ed e ob c osp o a o o sp C
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.
( )
Cu Catalyzed Aerobic Phosphonation of sp C
48
Cu Ca a y ed e ob c osp o a o o sp C
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
Gao, Y.; Zhao, Y.; Zhou, Y.; Han, L. J. Am. Chem. Soc., 2009, 131, 7956–7957.
Proposed Reaction Path Cu Catalyzed Aerobic Ph h i f C
50
Phosphonation of sp C
Yellowsuspensionsuspension
Phosphonate
Phosphite
Gao, Y.; Zhao, Y.; Zhou, Y.; Han, L. J. Am. Chem. Soc., 2009, 131, 7956–7957.
Substrate Scope for Cu Catalyzed Aerobic Ph h i f C
51
Phosphonation of sp C
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%)
% % % % % %
Gao, Y.; Zhao, Y.; Zhou, Y.; Han, L. J. Am. Chem. Soc., 2009, 131, 7956–7957.
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.
Basle, O.; Li, C-J. Chem. Comm., 2009, 4124-4126.
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.
Basle, O.; Li, C-J. Chem. Comm., 2009, 4124-4126.
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 =
Basle, O.; Li, C-J. Chem. Comm., 2009, 4124-4126.
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