Catalytic Modification of Arenes
John F. Hartwig
Department of Chemistry
University of California, Berkeley
Approaches to Catalytic Modification of Arenes
By C-H Bond Functionalization?
R'
By Cross-Coupling Reactions
R'
X
R
X
R
R
O
R
XR'
X
NC
X
X
R
R
O
X
Br
R
R
R'
R
R
R'RN
R
X
R
R
X
RO
R
N
R'
R
O
R1
R''
Transition Metal Boryl Complexes
LnM
B
R
R
Potential Properties: •Lewis Acidic at BR2
•M-B pi-bonding
•Strong σ-Donation from BR2
These properties lead to selective functionalization of arenes and alkanes:
OR
R H + H B
OR
catalytic
LnM-B(OR)2
OR
+ H2
R B
OR
Transition Metal Boryl Complexes
LnM
B
R
R
Potential Properties: •Lewis Acidic at BR2
•M-B pi-bonding
•Strong σ-Donation from BR2
Topics
1. Discovery of C-H borylation of aliphatic C-H Bonds
2. A platform for practical aromatic C-H bond functionalization
3. Use of the mechanistic data to develop new functionalizations
4. Some new C-C coupling reactions
Initial Observations of C-H Bond
Functionalization with Metal-Boryl Complexes
O
Fe
B
hν
O
OC
OC
Bcat + CpFe(CO)2H
100%
[CpFe(CO)2]2 + H2
Hartwig, Waltz, He, Muhoro J. Am. Chem. Soc. 1995, 117, 11357.
Me
OC
OC
W B
O
O
CO
Me
hν, 20 min
Bcat* + Cp*W(CO)3H
85%, one isomer
Waltz, K.M.; Hartwig, J.F. Science, 1997, 227, 211.
For formation of two isomers of tolylboronate ester as trace side product from borylation of toluene solvent
when forming [Ir(arene)(Bcat)3], see Nguyen, P.; Blom, H. P.; Westcott, S. A.; Taylor, N. J.; Marder, T. B. J.
Am. Chem. Soc. 1993, 115, 9329.
Catalytic Functionalization of Primary C-H Bonds
Cp*
Cp*
pinBBpin
Rh
!4-
- C6Me6
(unreactive)
pinB
pinB
O
O
B B
O
O
pinBBpin=
Rh
catalytic intermediate
for C-H bond cleavage?
R
n
+ B2pin2
R = H,
O
O
2.5%[Cp*Rh(C6Me6)]
or 2.5%[Cp*RhCl2]2
R
150 °C
nBu
O
Bpin + HBpin
n
70-88%
O
R
N
F
R
Chen, Schlecht, Semple, Hartwig Science 2000, 287, 1995-8.
Lawrence, Takahashi, Bae, Hartwig J. Am. Chem. Soc, 2004, 126, 15334-15335.
For an the borylation of benzene catalyzed by Cp*Ir(PMe3)(Ph)(H) with three turnovers see,
Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 1999, 121, 7696.
Catalytic Functionalization of Arene C-H Bonds
Cp*
Cp*
pinBBpin
Rh
!4-
- C6Me6
(unreactive)
pinB
pinB
Rh
pinBBpin=
O
O
B B
O
O
catalytic intermediate
for C-H bond cleavage?
0.5%[Cp*Rh(C6Me6)]
+ B2pin2
150 °C
2
Bpin
+ H2
82%, 328 turnovers
Chen, Schlecht, Semple, Hartwig Science 2000, 287, 1995-8.
Lawrence, Takahashi, Bae, Hartwig J. Am. Chem. Soc, 2004, 126, 15334-15335.
For an the borylation of benzene catalyzed by Cp*Ir(PMe3)(Ph)(H) with three turnovers see,
Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 1999, 121, 7696.
Mechanism of the Rh-Catalyzed
Alkane Functionalization
•Isolated and observed in the catalytic system
•Kinetically and chemically competent
Cp*
pinB Rh X
H
Bpin
B2pin2
HBpin
X=H, Bpin
H
Cp*
Cp*
Rh
Rh
X
pinB
X
Trapped by
phosphine
during
mechanistic
studies
Cp*
RBpin
pinB Rh X
R
H
R-H
Evidence for this catalytic cycle
Cook,bond
Hapke,
Incarvito,
Fan,
Webster,
Hall
J. Am.of
Chem.
2005, 127,
2538-2552.
HowHartwig,
is the C-H
cleaved
and
what
is the
origin
highSoc.
terminal
regioselectivity?
Practical Arene Borylation Catalysts
B2pin2 +
1/2[IrCl(COD)]2/bpy
(3 mol%)
H Ar
(neat)
80 °C
N
2 Ar Bpin + H2
N
bpy
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig JACS 2002, 124, 390.
Practical Arene Borylation Catalysts
1/2[IrCl(COD)]2/bpy
1/2[IrCl(COD)]2/bpy
(3 mol%)
(3 mol%)
B2pin2 + H Ar
Ar Bpin + HBpin
Ar Bpin + H2
80
°C
80
°C
(neat)
H Ar
N
[PhBpin]
[B2pin2]
N
bpy
8 min
-1
3.5 10
Concentration mol L-1
3 10-1
Origins of the
induction period:
2.5 10-1
2 10
-1
1) Reduction of
COD to COE
-1
1.5 10
1 10
-1
2) Generation of
HBpin from B2pin2
5 10-2
0 10
0
0 100
3
1 10
2 103
3 103
t (s)
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig JACS 2002, 124, 390.
Practical Arene Borylation Catalysts
Cl
1/2[IrCl(COD)]2/dtbpy
(5 mol%)
Cl
cyclohexane
25 °C
B2pin2 +
2 Ar Bpin + H2
With 0.003 mol % Ir
24,800 turnovers
B2pin2 + Ar-H
+ 20% HBpin
Origins of the
induction period:
1) Reduction of
COD to COE
B2pin2 + Ar-H
2) Generation of
HBpin from B2pin2
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig JACS 2002, 124, 390.
Highly Active Arene Borylation Catalysts
1/2[Ir(OMe)(COD)]2/dtbpy
(3 mol%)
B2pin2 + 2 H Ar
2 Ar Bpin + H2
hexane
1.0 equiv/B
room temperature
Conversion of B2pin2
and HBpin
N
N
dtbpy
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig JACS 2002, 124, 390.
Ishiyama, Takagi, Hartwig, Miyaura Angew. Chem. Int. Ed. 2002, 41 , 3056.
Boller, Murphy, Hapke, Ishiyama, Miyaura, Hartwig, JACS 2005, 127, 14263.
see also with Ir-bisphosphine complexes as catalyst: Cho, J. Y.; Tse, M. K.; Holmes, D.;
Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305-308.
Highly Active Arene Borylation Catalysts
1/2[Ir(OMe)(COD)]2/dtbpy
(3 mol%)
B2pin2 + 2 H Ar
2 Ar Bpin + H2
hexane
1.0 equiv/B
room temperature
pinB
Cl
pinB
82%
Cl
53%
Cl
Cl
84%
Cl
CF3
pinB
I
84%
O
pinB
83%
CF3
91%
Br
Br
pinB
CN
83%
N
H 88%
CF3
pinB
pinB
pinB
pinB
82%
S
81%
Cl
Cl
pinB
pinB
81%
OMe
Cl
pinB
CN
80%
CO2Me
Ishiyama, Takagi, Hartwig, Miyaura Angew. Chem. Int. Ed. 2002, 41 , 3056.
Meta-Halogenation of Arenes
H Ar + 1/2 B2pin2
1) 1/2[Ir(OMe)(COD)]2/dtbpy (0.1 mol%)
THF, 80 oC,then removal of volatiles
Ar Br + 1/2 H2
2) CuBr2, MeOH/H2O (1:1), 80 oC,
4-6 h
MeO
Me
MeO
Br
Br
F3C
Me
65%
85%
MeO
Cl
77%
O
75%
Br
Me
65%
F3C
62%
65%
Br
Br
Br
F3C
Br
MeO
77%
Br
Br
MeO
Br
Cl
Me
H3C
NC
Me
N
72%
Me
N
Me
N
6 mol% Ir
61%
Murphy, J.M.; Liao, X, Hartwig, J.F. J. Am. Chem. Soc. 2007, 129, 15434-15435.
Meta-Halogenation of Arenes
H Ar + 1/2 B2pin2
1) 1/2[Ir(OMe)(COD)]2/dtbpy (0.1 mol%)
THF, 80 oC,then removal of volatiles
Ar Cl + 1/2 H2
2) CuCl2, MeOH/H2O (1:1), 80 oC,
4-6 h
MeO
Me
MeO
Cl
Cl
F3C
Me
61%
Cl
Me
MeO
Me
Cl
MeO
O
63%
Cl
79%
Cl
MeO
Cl
54%
Me
O
65%
MeO
Cl
77%
Me
Et2N
NC
TIPSO
56%
81%
61%
Cl
Cl
Cl
PivO
Cl
Me
N
72%
Me
Me
N
6 mol% Ir
46%
Murphy, J.M.; Liao, X, Hartwig, J.F. J. Am. Chem. Soc. 2007, 129, 15434-15435.
Meta-Amination of Arenes
1) 1/2 B2pin2 1/2[Ir(OMe)(COD)]2/dtbpy (0.1 mol%)
THF, 80 oC,then removal of volatiles
H Ar
Ar NHR
2) 2 equiv H2NR, 1 equiv KF,
10 mol % Cu(OAc)2.H2O,
MS 4 A, CH3CN, O2, 80 °C
H
N
H3CO
OCH3
Cl
H3CO
OCH3
OCH3
64%
H
N
Cl
56%
H
N
H
N
OCH3
OEt
OEt
H
N
Cl
OCH3
57%
OEt
OEt
57%
C8H17
O
47%
H
N
H3CO
CH3
OEt
OEt
66%
Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Org. Lett. 2007, 9, 761-764
Meta-Cyanation of Arenes
1) 1/2 B2pin2, 1/2[Ir(OMe)(COD)]2/dtbpy (0.1 mol%)
THF, 80 ºC, the removal of volatiles
Ar–CN
H–Ar
2) 1.5 equiv Cu(NO3)2•3H2O, 3 equiv Zn(CN)2,
1 equiv CsF
MeOH/H2O (5:1), 90 ºC
Me
Me
Me
Cl Me
CO2Me
OMe Me
MeO
OMOM
Me
CN
CN
CN
CN
CN
61%
65%
59%
53%
51%
NH2
Br
I Me
OMe Cl
N
Me Cl
N
CN
CN
CN
CN
58%
57%
46%
58%
Liskey, C.W.; Liao, X.; Hartwig, J.F.
J. Am. Chem. Soc. 2010, 132, 11389-11391
Cl NC
N
N
H
N
Me
Etravirine (HIV)
Br
O
Me
CN
A General meta-Functionalization
of 1,3, and 1,2,3-Substituted Arenes
R1
R1
B(OH)2
R2
BF3K
R2
R3
R1
R3
R2
dtbpy-Ir cat
B2pin2
HOAr
Cu(II)
OAr
R1
CF3
(Phen)CuCF3 R2
R2
ArB(OH)2
R3
CuX2
Bpin
R3
R3
R2
R3
X=Cl, Br
R1
KHF2
X
R2
KIO4
H+
R3
R1
R1
Zn(CN)2/
Cu(NO3)2
Cu(OAc)2
HNRR'
R1
R1
NRR'
CN
R2
R3
R2
R3
For fluorination, see
Furuya and Ritter Org. Lett. 2009, 11, 2860.
[Ir(COD)X]/dtbpy Catalyst in Total Synthesis
H
by borylation of
HN
Me3Si
Et
O
Cl
F3C HO
by borylation of
CF3
N
Boc
Bpin
O
H2N
N
N
H
Rhazinicine
O
NBoc2
O
SM-130686
Beck, E. M.; Hatley, R.; Gaunt, M. J.
Angew. Chem. Int. Ed. 2008, 47, 3004-3007.
Tomita, D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 6946-7.
Me
Me
by borylation of
N
N
NH
H
N
N
Complanadine A
Fischer and Sarpong,
JACS 2010, 5926
H
NBoc
H
Benzylic stereocenter set
by asymmetric !-arylation
by borylation/
OMe
HO
halogenation of
OMe
OH
H O
H
Me
NEt2•HCl
H
OMe
Liao, X.; Stanley, L. M.;
(-)-Taiwaniaquinol B
J. F. JACS
and Taiwaniaquinone D Hartwig,
2011, 133, 2088.
Intermediate in the Functionalization
of Arenes by Bpy-Ir
CH3
O
Ir
2
Ishiyama, Takagi,
Ishida, Miyaura,
Anastasi, Hartwig,
JACS 2002, 124,
390.
Boller, Murphy,
Hapke, Ishiyama,
Miyaura, Hartwig
JACS 2005, 127,
14263
1) HBpin, COE
2) dtbpy
40 oC
30 min
N
N
Ir
Bpin
95 %
Bpin
Bpin
Ir-N1=2.177 Å, IrN2=2.221 Å, IrB1=2.055 Å IrB2=2.057 Å, IrB3=2.027 Å, IrC1=2.308 Å IrC2=2.318 Å
Intermediate in the Functionalization
of Arenes by Bpy-Ir
CH3
Ir
2
Ishiyama, Takagi,
Ishida, Miyaura,
Anastasi, Hartwig,
JACS 2002, 124,
390.
Boller, Murphy,
Hapke, Ishiyama,
Miyaura, Hartwig
JACS 2005, 127,
14263
40 oC
1) HBpin, COE
30 min
2) dtbpy
N
N
Bpin
95 %
Bpin
Ir
Bpin
Recall that HBpin eliminated this induction period:
[PhBpin]
[B2pin2]
-1
3.5 10
3 10-1
Concentration mol L-1
O
Origins of the induction
period:
2.5 10-1
2 10
-1
1) Reduction of COD to
COE
-1
1.5 10
1 10
2) Generation of HBpin from
B2pin2
-1
5 10-2
0 10
0
0 100
3
1 10
2 103
t (s)
3 103
Mechanism for Arene Borylation
by Ir(III) Complexes
oxidative addition or
sigma bond metathesis
Bpin
But
N
N
But
Bpin -alkene
N
Bpin +alkene
Bpin
N
Ir
Ir
Bpin
Turnoverlimiting
Bpin
Bpin
HBPin
N
Ir
N
pinB
H
Bpin
B2pin2
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig, JACS 2002, 124, 390
Boller, Murphy, Hapke, Ishiyama, Miyaura, Hartwig JACS 2005, 127, 14263.
Electronic Effects on C-H Borylation
Effect of pinacolate or catecholate
on the electron density at Ir
N
Bpin
Ir
Bpin
N
Bpin
N
Bcat
Ir
Bcat
N
Bcat
C6D6
RT
5 min
C6D6
50 °C
120 min
Bpin
O
B
3
d5
O
>90%
Bpin
Bcat
3
O
R
B
d5
65%
O
Bcat
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig, JACS 2002, 124, 390.
Boller, Murphy, Hapke, Ishiyama, Miyaura, Hartwig JACS 2005, 127, 14263
Liskey, C.W.; Wei, C.S.; Pahls, D.R.; Hartwig, J.F. Chem. Commun., 2009, 5603
web theme issue: 'Selective Catalysis for Organic Synthesisʼ
Electronic Effects on C-H Borylation
N
Bpin
Ir
Bpin
N
Bpin
C6D6
RT
5 min
3
d5
Effect of pinacolate or catecholate
on the electron density at Ir
O
C
Bpin
N
Bpin
Ir
Bpin
N
Bpin
>90%
∂COE = 3.92
N
Bcat
Ir
Bcat
N
Bcat
∂COE = 4.77
µCO=1987 cm-1
C6D6
50 °C
120 min
Bcat
3
d5
65%
O
C
N
Bcat
Ir
N
Bcat
Bcat
µCO=2017 cm-1
Ishiyama, Takagi, Ishida, Miyaura, Anastasi, Hartwig, JACS 2002, 124, 390.
Boller, Murphy, Hapke, Ishiyama, Miyaura, Hartwig JACS 2005, 127, 14263
Liskey, C.W.; Wei, C.S.; Pahls, D.R.; Hartwig, J.F. Chem. Commun., 2009, 5603
web theme issue: 'Selective Catalysis for Organic Synthesisʼ
Electronic Effects on C-H Borylation
N
Bpin
Ir
Bpin
N
Bpin
C6D6
RT
5 min
3
d5
Effect of pinacolate or catecholate
on the electron density at Ir
O
C
Bpin
N
Bpin
Ir
Bpin
N
Bpin
>90%
∂COE = 3.92
N
Bcat
Ir
Bcat
N
Bcat
∂COE = 4.77
µCO=1987 cm-1
C6D6
50 °C
120 min
Bcat
3
d5
65%
O
C
N
Bcat
Ir
N
Bcat
Bcat
µCO=2017 cm-1
Therefore, although the C-H cleavage can occur by σ-bond metathesis...
•This C-H bond cleavage is favored for more electron-rich Ir centers.
•Strong σ-donation by the boryl group is important for C-H bond cleavage.
Developing More Active Catalysts
Electronic properties of ligands used for Ir-catalyzed arene boryation:
ν(CO) Values for L2M(CO)m complexes:
L2
ν(CO) for L2Ni(CO)2
reference
for L2Mo(CO)4
2 PPh3
2000
1940
a,b,c
highest ν = 2023
2 PMe3
1990
1926
c
2019
bpy
1978
1904
a,c
2017
phen
1977-1980
1897-1915
a,c
-
4,4ʼ-Me2py
1973
1893
d
2014
1875-1993
predicted
-
3,4,7,8-Me4-phen 1967-1970
a Plankey,
B. J.; Rund, J. V. Inorg. Chem. 1979, 18, 957. b. Meriwether, L. S.; Fiene, M. L. J. Am. Chem. Soc. 1959, 81, 4200. b
Tolman, C. A. J. Am. Chem. Soc. 1970, 92, 2956. c Christensen, P. A.; Hamnett, A.; Higgins, S. J.; Timney, J. A. J. Electroanal.
Chem. 1995, 395, 195. d Sieler, J.; Than, N.-N.; Benedix, R.; Dinjus, E.; Walther, D. Z. Anorg. Allg. Chem. 1985, 522, 131.
Among this series, tetramethylphenanthroline is the most donating...
and the one to generate a catalyst for alkane borylation.
Developing More Active Catalysts
The arene borylation catalyst does not functionalize aliphatic C-H bonds
+ B2pin2
5 mol % [Ir(COD)OMe]2
10 mol % dtbpy
neat, 24 h
150 °C
Bpin
<5%
But the catalysts containing substituted phenanthrolines do...
+ B2pin2
5 mol % [Ir(COD)OMe]2
10 mol % substituted-phen
neat, 24 h
120 °C
Carl Liskey, unpublished
Bpin
70-85%
Intramolecular Silylation of
Aromatic C-H Bonds
O
[Ir]/phen (1.0 mol %),
Me Et Et
norbornene
Si
H THF, 80 °C
O
Et2SiH2, [Ir(cod)OMe]2
Me (0.05 mol %), THF, rt
Me
F
MeO
O
Si
Et2
58%
>20:1 selectivity
O
Si
Et2
88%
>20:1 selectivity
Me
O
Si
Et2
F3C
O
Si
Et2
O
Si
Et2
73%
1:1 selectivity
55%
>20:1 selectivity
Regioselectivity appears to be controlled by steric effects.
Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 17092.
Intramolecular Silylation of
Aromatic C-H Bonds
R
Me
O
Si
Et2
O
Si
Et2
R=Et, 63%
R=Pr, 65%
X
O
Si
Et2
R=H, X=I, 86%
R=Me, X=Br, 75%
O
Si
Et2
O
SiEt2
70%
R
Me
S
Me
71%
61%
Me
Me
Me2N
RO
O
Si
Et2
R=TBS, 86%
R=Piv, 83%
O
Si
Et2
82%
Regioselectivity appears to be controlled by steric effects.
...and functional group tolerance looks high.
Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 17092.
Transformations of the Siloles
from Directed Silylation
Cross coupling and oxidation can be conducted on the oxasiloles
OH
Me
3-iodopyridine,
R
Pd(OAc)2, dcpe,
2 M aq. NaOH,
dioxane, 65 °C
N
Me
OAc
1) KHCO3, H2O2,
THF/MeOH, rt TBSO
Me
O
Si 2) Ac O, Et N,
2
3
Et2
CH2Cl2, rt
OAc
70%
72%
Orthogonal Coupling of Halogen-Containing Oxasiloles
OH
Me
Br
O
Si
Et2
1) Ar-B(OH)2, K2CO3,
Pd(PCy3)2Cl2
Me
Me
2) Ar-I, NaOH,
Pd(OAc)2, dcpe
OMe
Me
56% overall
Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 17092.
Why C-H Activation with Boron Reagents?
•Strong B-C bond makes the C-H bond functionalization favored thermodynamically
+ XBpin
Bpin
+ XH
21 kcal/mol exothermic for B2pin2
2-4 kcal/mol exothermic for HBpin
•Participation of the p-orbital and the strong σ-donation by an “anionic” boryl ligand
leads to a low barrier for C-H bond cleavage
Cp*
pinB
pinB
Rh
Cp*
RH
pinB
pinB
Cp*
R
Rh
H
pinB
pinB
Rh
R
H
•Reversal of bond polarity leads to rapid formation of B-C bonds by
metathesis or reductive elimination
Ph
(bpy)(pinB)2(H)Ir
ΔG‡=3-4 kcal/mol
Bpin
PhBpin
R-Bpin
Electronic Effect on
C-C Reductive Elimination
Ph2
P
Ar
Pd
R
P
Ph2
PPh3
C6D6
Ar-R + LnPd(0)
Taft parameter
σ* krel(110 °C)
R=
Me
0.00
>600
0.22
>250
CH2Ph
31
CH2C(O)Ar 0.60
0.92
1.7
CH2CF3
1.30
1
CH2CN
2.60
no rxn
CF3
no rxn
CH(CO2Me)2
Culkin, D.A.; Hartwig, J.F. J. Am. Chem. Soc. 2001, 123, 5816-5817.
Culkin, D.A.; Hartwig, J.F. J. Am. Chem. Soc. 2002, 124; 9330-9331.
Culkin, D.A., Hartwig, J.F. Organometallics, 2004, 23, 3398-3416.
Reductive Elimination of Trifluoroarenes
MeO
Pri
Pr
Me
O
CF3
Pd
P Ar
Cy2
i
Cho, E. J.; Senecal, T. D.; Kinzel,
T.; Zhang, Y.; Watson, D. A.;
Ar-CF3 Buchwald, S. L. Science 2010,
328, 1679.
For Xantphos-Pd see:
Grushin, V. V.; Marshall, W. J. J.
Am. Chem. Soc. 2006, 128, 12644.
tBu
Ar
N
Pri
N
tBu
N
Cu CF3
ArI
Pd
OTf
F
Ar-CF3
CF3
Ball, N. D.; Kampf, J. W.;
Sanford, M. S.
J. Am. Chem. Soc. 2010,
132, 2878.
Ar-CF3
N
Dubinina, G. G.; Furutachi, H.; Vicic, D. A.
J. Am. Chem. Soc. 2008, 130, 8600.
Can reductive elimination of trifluoroarenes occur
with an inexpensive metal, ligand and reagent?
Synthesis and Reactivity of (phen)CuCF3
1) phen (1.0 equiv.)
benzene or Et2O, rt
CuOtBu
2) TMSCF3 (1.0 equiv.)
rt, O/N
N
N
Cu
CF3
90%
red solid
If an aryl-Cu(III) intermediate is generated, reductive elimination should be faster
than from palladium(II).
ArI
N
N
Cu
CF3
CF3
N
Cu
N
I
Ar
Ar-CF3 +
N
N
Cu
Cu(III)
I
Reductive elimination from Cu(III) occurs with a low barrier:
Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 9971.
Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics 2007, 26, 4546.
Tye, Jesse W.; Weng, Z.; Giri, R.; Hartwig, John F. Angew. Chem. Int. Ed. 2010, 49, 2185.
Synthesis and Reactivity of (phen)CuCF3
CuOtBu
1) phen (1.0 equiv.)
benzene or Et2O, rt
N
2) TMSCF3 (1.0 equiv.)
rt, O/N
N
Cu
CF3
90%
red solid
In the lab...
ArI
(10 equiv.)
N
N
Cu
CF3
Ar-CF3
DMF (0.050 M)
rt, 19 h
(Ar = 4-nBuC6H4-)
77%
+
N
N
Cu
I
68%
What is the stability of (phen)Cu-CF3 and what is the scope of its reactions with ArX?
Hiroyuki Morimoto
Stability of (phen)CuCF3
CuOtBu
1) phen (1.0 equiv.)
benzene or Et2O, rt
2) TMSCF3 (1.0 equiv.)
rt, O/N
Stability:
N
N
Cu
90%
CF3 red solid
Available from Aldrich
(agreement with Catylix)
conditions
solid state
in solution
(0.05 M in DMF)
under
N2
stable at rt
> 1 month
stable at rt for 1 day
decomposed at 50 °C
in air
decomposed
< 1 day
not examined
Hiroyuki Morimoto
Trifluoromethylation with (phen)CuCF3
N
N
+ Ar-I
Ar CF3
DMF (0.050 M), rt, 18 h
Cu
CF3
CF3
CF3
nBu
88%
CF3
Me2N
MeO
>95%
CF3
86%
CF3
75%
O
92%
CF3
92%
92%
OMe
CF3
CF3
CF3
CF3
CF3
Me
OMe
Cl
Me
OMe
90%
89%
87%
CF3
O2N
92%
Me
88%
88%
NC
O
87%
CF3
Br
CF3
H
HO
CF3
96%
CF3
N
92%
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 3793.
Scope of the Reactions of (phen)CuCF3
Reactions with 1:1 ArI to copper
(phen)Cu-CF3
Ar-I
Ar-CF3
DMF, rt–50 °C, 18 h
CF3
MeO
CF3
Ph
BnO
96%
CF3
89%
92%
CF3
Br
OMOM
97%
OMOM
CF3
O
89%
CF3
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 3793.
Scope of the Reactions of (phen)CuCF3
Reactions with 1:1 ArI to copper
Ar-I
(phen)Cu-CF3
DMF, rt–50 °C, 18 h
94%
Cl
CF3
CF3
CO2Et
69%
Cl
OHC
CF3
Me
EtO2C
85%
CF3
CF3
CF3
AcHN
Ar-CF3
Me
O
93%
OMe
O
F3C
F3C
N
Boc
N
92%
68%
99%
N
BOM
N
O
78% BOM
Trifluoromethylthymidine
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 3793.
Scope of the Reactions of (phen)CuCF3
Reactions of aryl bromides
Br
1.5 equiv [(phen)CuCF3]
DMF (0.25 M), 50 °C, 18 h
CF3
R
R
CF3
NC
78%
CF3
O 2N
CF3
EtO2C
50%
81%
CF3
F3C
81%
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 3793.
Trifluoroalkylation by (phen)CuRf
[(phen)CuCF2CF2CF3]
(1.5 equiv)
Ar-I
(0.50 mmol)
DMF (0.25 M)
50 °C, 18 h
CF2CF2CF3
CF2CF2CF3
BnO
O 2N
Ph
99% (79%)a
91%
N
CF2CF2CF3
88%
99%
CF2CF2CF3
Cl
Ar CF2CF2CF3
CF3CF2CF2
92%
N
Boc
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 3793.
Organometallic Chemistry of
Metal-Heteroatom vs Metal-Carbon Bonds
Underlying Principles
comparison of the properties of "anionic" ligands
Ln M R
vs
LnM NR2
more polar bond
non-polar
kinetically abasic
basic e- pair
vs
LnM BR2
vs
electrophilic
coordination to the
non-bonding orbital
Pauling Electronegativities: Pd: 2.20
C: 2.55
N: 3.04
B: 2.04
LnM CH2-FG
more polar
but lacks a
non-bonding orbital
Acknowledgments
C-H Bond Functionalization
Karen Waltz
Shell:
Huiyuan Chen
Tom Semple (Shell)
Sabine Schlecht
Minnesota:
Kazumori Kawamura
Marc Hillmyer
Kevin Cook
Nicole Wagner, Nicole Boaen
Natia Anstasi
Hokkaido:
Makato Takahashi
Tatsuo Ishiyama
Domingo Garcia
Norio Miyaura
Yuichiro Kondo
Jun Takagi, Yusuke Nobuta
Chulsung Bae
Texas A&M:
Doris Kunz
Mike Hall
Joshua Lawrence
C. Edwin Webster, Yubo Fan
Timothy Boller
Charles Harris
Naofumi Tsukada (Si)
Karma Sawyer et al.
Jaclyn Murphy
Christoph Tzschucke
NSF, NIH, Shell
Carolyn Wei
Johnson-Matthey
Tim Boebel
Frontier Science
Dan Robbins
Allychem, BASF
Carl Liskey
Eric Simmons
Now available:
Cu-Mediated
Trifluoromethylation
Hiroyuki Morimoto
Tetsu Tsubogo
Nichole Litvinas
NIH NIGMS