Upload
polypeptide
View
32
Download
5
Tags:
Embed Size (px)
DESCRIPTION
chemistry notes
Citation preview
Pd Catalyzed
Functionalization of
Non-Acidic C(sp3)-H Bonds
Lindsey Cullen
Denmark Group Meeting
Oct. 26, 2010
C H
Pd cat.
C X
Carbon-Carbon Bond Formation in Organic
Molecules Traditional:
Functional Group Transformation
Alternative Approach:
C-H Functionalization
Why focus on C-H functionalization?
1. C-H bonds are common / could provide new disconnections
2. Atom economical
3. Cost effective
FG1 R
FG1 R
H R
H R
Challenges to C-H Functionalization
H FG
H FG
3. Regioselectivity
sp2 and sp3 C-H bonds are ubiquitous
1. Intrinsic low reactivity
Large kinetic barrier to cleave C-H bond (104 kcal/mol)
2. Chemoselectivity
Functionalized product may be more reactive
C-H Functionalization: A Definition
2. Inner-sphere mechanism:
Two general mechanisms:
1. Outer-sphere mechanism:
X
[M]
[M] X
[M] XH
C
[M] X CH
[M]
C X H
C H
[M]
C [M]
X
[M]
C X
C-H Functionalization - formation of a C-M bond by cleavage of
a C-H bond
Baudoin, O. et al. Chem. Eur. J. 2010, 16, 2654.
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
Reactivity of nonacidic sp3 C-H Bonds C-H functionalization of sp2 C-H bonds has been well studied:
H
R XMLn
R' FG
R X
MH
R'
R'
R X
C-H functionalization of non-acidic sp3 C-H bonds is less explored:
R1 R2
FG
1-2
H
MLn
-H+
R1 R2
FG
1-2
MLn
R' FG R1 R2
FG
1-2
R'
C(sp3)-H bonds lack orbitals to interact with metal center
Pd(II)/Pd(0) Systems for sp3 C-H Activation
PdII (OAc)2
Pd0
C-H
activation
R H
HOAc
PdIIR OAc
reoxidation
R' MR' R
transmetalation/reductive elimination
Pd(II)/Pd(0) Catalysis:
External oxidant is necessary to regenerate Pd(II) catalyst
Pd(II)/Pd(0) sp3 C-H Activation
Yu, J. -Q. et al. J. Am. Chem. Soc. 2008, 130, 7190.
Yu, J. -Q. et al. J. Am. Chem. Soc. 2006, 128, 12634.
NR
H
Pd(OAc)2 (10 mol%)
RB(OH)2
Ag2O, BQ, air
tAmOH, 100 C
R'N
R
R
R' 48-75%
H
NH
O
OMe
R1 R2
Pd(OAc)2 (10 mol%)
RB(OH)2
Ag2O, BQ, K2CO3tBuOH, 70 C
R
NH
O
OMe
R1 R2
41-85%
White, M. C. et al. J. Am. Chem. Soc. 2008, 130, 14090.
Pd(OAc)2 (10 mol%)
O2NCH2R
DMBQ, AcOH
dioxane/DMSO, 45 C
R
HSS PhPh
O O
R
R
NO2
50-70%
Pd(II)/Pd(IV) Systems for sp3 C-H Activation
Pd(IV)/Pd(II) Catalysis:
PdIILn C-H
activation
R H
PdIIR Ln
reductive
elimination
R' X
oxidative addition
PdIVR Ln
R'
X
R R'
Additional oxidative addition step leads to Pd(IV)
intermediates
Pd(II)/Pd(IV) sp3 C-H Activation
Sandford, M. S. et al. J. Am. Chem. Soc. 2005, 127, 7730.
NH
Pd(OAc)2 (5 mol%)
R-I
K2CO3, PivOH
tAmOH, 100-110 C
58-80%
NO H
NH
NO R
Daugulis, O. et al. J. Am. Chem. Soc. 2010, 132, 3965.
72%
N
H
Pd(OAc)2 (5 mol%)
[Ph2I]BF4
AcOH, 100 C N
Ph
Pd(0)/Pd(II) Systems for sp3 C-H Activation
LnPd0
oxidative
addition
R X
reductive
elimination
C-H Activation
R R'
LnPdII X
R
R' HX H
LnPdII R'
R
Pd(0)/Pd(II) Catalysis:
Oxidative addition to coupling partner gives Pd(II) intermediate
Most studied catalytic system for
non-acidic sp3 C-H functionalization
Many Possible Reaction Pathways
Dyker, G. Angew. Chem. Int. Ed. 1992, 31, 1023.
X
R
HPd(0), Base
HX
Pd
R
transmetalation
H
R
FG
Y-FG
Rreductive
elimination
-H
eliminationH
Two major challenges to sp3 C-H activation:
1. Selective sp3 C-H cleavage
2. Favoring one pathway over another
C-H Activation of a Methoxy Group
Dyker, G. Angew. Chem. Int. Ed. 1992, 31, 1023.
I
OCH3
Pd(OAc)2 (4 mol %)
K2CO3, nBu4NBr
DMF, 100 C, N23 d
O
H3CO
H3CO
90%
I
OCH3
Pd(OAc)2 (4 mol %)K2CO3, nBu4NBr
DMF, 100 C, N23 d
87%
OCH3
O
OCH3
H3CO
H3CO
Proposed Mechanism
Dyker, G. Angew. Chem. Int. Ed. 1992, 31, 1023.
LnPd0
-HII
OCH3
PdLn
OCH3
I
O
LnPd
I
OCH3
+
O
H3CO
PdLnI
-HI
O
H3CO
LnPd
+
I
OCH3
O
H3CO
H3CO
PdLnI
-HI
O
H3CO
H3CO
H3CO
H3CO PdLn
O-Pd0Ln
C-H Activation of a tert-Butyl Group
Dyker, G. Angew. Chem. Int. Ed. 1994, 33, 103.
IPd(OAc)2 (2.5 mol %)
K2CO3
nBu4NBr, DMF, 110 C
N2, 4 d
75%
I Pd(OAc)2 (2.5 mol %)
K2CO3
nBu4NBr, DMF, 110 C
N2, 4 d
59%
+
OMe
Br
OMe
(5 equiv)
Demonstrated cross coupling with electron rich aryl bromides:
C-H activation is not dependent on an adjacent heteroatom
C-H Activation of gem-Dialkyl Groups
Gives -Hydride Elimination
Baudoin, O. et. al. Angew. Chem. Int. Ed. 2003, 42, 5736.
Addition of bulky triaryl phosphine ligands promotes C-H
activation over protodehalogenation
Entry Base 1a (%)
1 Cs2CO3 19
Catalyst
Pd(OAc)2
1b (%) 1c (%)
55 6
1 Cs2CO3 0Pd(OAc)2 58 6
PR3
-
P(tBu)3
3 Pd(OAc)2 dppp Cs2CO3 0 32 10
4 Pd(OAc)2
1d (%)
Steric Differentiation in C-H Activation
Baudoin, O. et. al. Angew. Chem. Int. Ed. 2003, 42, 5736.
C-H activation occurs preferentially at the
less substituted alkyl group
Br
CO2Et
Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol %)
K2CO3DMF, 150 C, 30 min
CO2Et
83%
Br
Pd(OAc)2 (10 mol %)
P(o-Tol)3 (20 mol %)
K2CO3DMF, 150 C, 90 min 60%
CO2Et CO2Et
Br
Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol %)
K2CO3DMF, 150 C, 30 min 95
CO2Et CO2Et CO2Et+
: 571%
Steric Factors Prevail over Conjugation
Baudoin, O. et. al. Angew. Chem. Int. Ed. 2003, 42, 5736.
Steric factors prevail over formation of conjugated olefins
Br
CO2Et
Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol %)
K2CO3DMF, 150 C, 30 min
CO2Et
75%
+CO2Et CO2Et+
73 : 19 : 8
Br
Pd(OAc)2 (10 mol %)
P(o-Tol)3 (20 mol %)
K2CO3DMF, 150 C, 90 min 78%
CO2Et
CO2Et
Br
Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol %)
K2CO3DMF, 150 C, 30 min
80%
CO2Et +
86 : 14
CO2Et CO2Et
Possible Palladacycle Intermediates
Baudoin, O. et. al. Angew. Chem. Int. Ed. 2003, 42, 5736.
Olefin E could be formed through 5 or 6 membered palladcycle
Deuterium Labeling Studies
Baudoin, O. et. al. Angew. Chem. Int. Ed. 2003, 42, 5736.
Reaction proceeds through a 6-membered palladacycle
OTIPSD2C CD2
H3C CH3
Br
Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol%)
K2CO3, DMF, 150 C78%
OTIPSD2C
H3C
D
D
OTIPS
D3C CD3
Br
Pd(OAc)2 (10 mol %)P(o-Tol)3 (20 mol%)
K2CO3, DMF, 150 C86%
OTIPS
H
CD3
DD
via
PdLn
OTIPS
H
not
PdLn
OTIPS
H
Favoring Carbon-Carbon Bond Formation
Baudoin, O. et. al. Chem. Eur. J. 2009, 13, 792.
Trisubstituted substrates favor reductive elimination
Br
CN
Pd(OAc)2 (5 mol%)F-TOTP (20 mol %)
K2CO3 (2 equiv)DMF, 100 C
62%
CN
MeH
+CN
4 : 1
PdLn
CN
Me
H
Reductive
Elimination
-H
Elimination
Br
CN
Pd(OAc)2 (5 mol%)F-TOTP (20 mol %)
K2CO3 (2 equiv)DMF, 100 C
62%
NC
H
Intramolecular Arylation of Benzylic Methyl
Groups
Ren, H.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 3462.
Activation of benzylic methyl groups prevents
-hydride elimination
N
Br
R
Pd(OAc)2 (5 mol%)
P(p-Tol)3 (10 mol%)
Cs2CO3
NR
65-83%
Limited to R = EWG
R1
R2
Br
Br
+ MgBr
R3
Pd2(dba)3 (1.5 mol %)
tBu3P (6 mol %)
THF, rt, 20h
R1
R2
R3
78-99%
Dong, C. -G.; Hu, Q.-S. Angew. Chem. Int. Ed. 2006, 45, 2289.
Arylation of sp3 C-H of tert-Butyl Groups
Activation at quaternary carbons can also
Avoid -hydride elimination
Buchwald, S.L. et al. J. Am. Chem. Soc. 2005, 127, 4685.
PCy3
OMeMeO
SPhos
Br
ArB(OH)2 (2 equiv)
Pd2dba3 (1 mol %)
SPhos (4 mol %)
K3PO4 (3 equiv)
Tol
Ar
95-99%
Fagnou, K, et. al. J. Am. Chem. Soc. 2007, 129, 14570.
O
Br
Pd(OAc)2 (3 mol %)
PCy3-HBF4 (6 mol %)
Cs2CO3 (1.1 equiv)
tBuCO2H (30 mol %)Mesitylene, 135 C, 15h
OR R
77-92%
Use of Substrates without Quaternary
Carbons
Reductive elimination pathway can be competitive
with -H elimination
Fujii, N.; Ohno, H. et. al. Org. Lett. 2008, 10, 1759.
Pd(OAc)2 (3 mol %)
PCy3-HBF4 (6 mol %)
Cs2CO3 (1.4 equiv)
tBuCO2H (30 mol%)xylene, 140 C, 6-24 h
Br
N
CO2Me
R2 N
CO2Me
R1R1
R2R3 R3
N
CO2Me
98%
N
CO2Me
80%
H
N
CO2Me
76%
H
H
N
CO2Me
89%
N
CO2Me
38%
Site-Selective sp3 C-H Arylation
sp3 C-H activation is favored over sp2 C-H
and -hydride elimination
Fanou, K. et. al. J. Am. Chem. Soc. 2008, 130, 3266.
Pd(OAc)2 (5 mol %)P(tBu)3-HBF4 (5 mol %)
K2CO3 (1.5 equiv)PhCH3, 110 C
N
O-H
H+
Br
Me
(2.0 equiv)
N
O-
H
Me
89%Pd2(dba)3 (2.5 mol %)
X-Phos (5 mol %)
NaOtBu (3.0 equiv)
PhCH3, 110 C (W)N
O-H
H+
Br
Me
(1.5 equiv)
N
O-
77%
PCy2
iPr iPr
iPr
X-Phos
Amide Directed Intermolecular Arylation
sp3 C-H activation is favored over sp2 C-H activation
and -hydride elimination
Yu, J.-Q. et. al. J. Am. Chem. Soc. 2009, 131, 9886.
Pd(OAc)2 (10 mol %)
Cy-JohnPhos-HBF4 (20 mol %)
CsF (3.0 equiv), 3 M.SPhCH3, 100 C, N2, 24h
NHC6F5
O
R1
R2
H
+
(3.0 equiv)
NHC6F5
O
R1
R2
Ar
Ar I
NHC6F5
O
Me
H
Ph
30% mono
53% di
NHC6F5
OMe
p-Tol
78%
NHC6F5
OH
p-Tol
H
58%
NHC6F5
O
p-Tol
80%
H
sp3 C-H Functionalization Adjacent to
Nitrogen Atoms
NR
X
R'Pd(0) cat.
NR
Pd
R'
R' N R
Desired Product
NR
Pd
R'
H
Undesired
Byproducts
-Hydride elimination can lead to unproductive side
reactions including dehalogenation of the starting material
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Difficulty with Amine Substrates
Lewis basicity of nitrogen has dramatic effect on
the reaction outcome
N
Br H
Pd(OAc)2 (20 mol %)
PCy3-HBF4 (40 mol %)
CsCO3 (1.5 equiv)
PivOH (30 mol %)
Mes, 150 C, 16h
N
Not observed
Starting material recovered in 83% yield
31P NMR shows an unreactive Pd(II) intermediate
Pd
Cy2PBr
N
31P NMR signal
at 47 ppm
Amide substrates lead to desired product
N
Br H
O
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Importance of Base and Additives
Bulky pivalate additives greatly increase yield
Entry Base Additive Yield (%)
1 Cs2CO3 none 14
2 CsOPiv none 5
3 Cs2CO3 27AcOH (30 mol%)
4 Cs2CO3 83PivOH (30 mol%)
5 Cs2CO3 88CsOPiv (110 mol%)
N
Br H
Pd(OAc)2 (5 mol %)PCy3-HBF4 (10 mol %)
Base (1.5 equiv)Additive (x mol %)
Mes, 150 C, 16h
N
O O
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Counterion Effect
Rb2CO3 was optimal base for preventing
dehalogenation of the starting material
Entry Base Yield (%)
1 Na2CO3 0
2 K2CO3 31
3 Rb2CO3 56
4 Cs3CO3 48
N
Br H
Pd(OAc)2 (5 mol %)
PCy3-HBF4 (10 mol %)
Base (1.5 equiv)
PivOH (30 mol %)
Mes, 150 C, 16h
N
O OMeO MeO
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Amide Scope
Selective for methyl C(sp3)-H and deactivated by
electron rich aromatic rings
NR
Br H
Pd(OAc)2 (5 mol %)
PCy3-HBF4 (10 mol %)
Rb2CO3 (1.5 equiv)
PivOH (30 mol %)
Mes, 150 C, 16h
N R
O O
R' R'
N
O
N
O
N
O Ph
83% 68% 37%
N
O
MeO
N
O
MeO
MeO
N
O
F56% 44% 70%
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Sulfonamide Scope
Sulfonamides gave similar results
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
N
S
N
S
N
S
N
S
CH3 N
SMeO
MeO
OTIPS
N
S N
62% 82% 59%
52% 47% 71%
OO
O O O OO
O O O OO O
SN
R
Br H
Pd(OAc)2 (5 mol %)
PCy3-HBF4 (10 mol %)
Cs2CO3 (1.5 equiv)
PivOH (30 mol %)
Mes, 150 C, 16h
NS
RR'
O O OO
Reactivity of sp2 and sp3 C-H Bonds
Complete selectivity for sp2 C-H bond via a seven-membered
palladacycle
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
N
Br H
Pd(OAc)2 (5 mol %)
PCy3-HBF4 (10 mol %)
Rb2CO3 (1.5 equiv)
PivOH (30 mol %)
Mes, 150 C, 16h
H
N H
O O
88%
SN
Br H
Pd(OAc)2 (5 mol %)PCy3-HBF4 (10 mol %)
Cs2CO3 (1.5 equiv)PivOH (30 mol %)
Mes, 150 C, 16h
O O
H
NS
O O
H
83%
KIE Effects
The observed KIE shows the the C-H(D) bond is cleaved
in the rate determining step
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
N
Pd(OAc)2 (5 mol %)PCy3-HBF4 (10 mol %)
Rb2CO3 (1.5 equiv)PivOH (30 mol %)
Mes, 150 C, 16h
OBr
HDD
N
O
D(H)D
kH/kD = 3.4
N
CH3
O
CH3
Br
vs N
CD3
O
CD3
Br
kH = 3.2 10-6 M/s kD = 4.9 10
-7 M/s
kH/kD = 6.5
Simple Catalytic Cycle
What is a mechanism of C-H cleavage? What is the role
of the base additive?
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
PdLn
Br
O
N
LnPd
O
N
Br
PdLn
N
O
N
O
Oxidative Addition
C(sp3)-H bond cleavage
mechanism?
ReductiveElimination
Mechanism for sp3 C-H Activation
Concerted metalation-deprotonation (CMD) pathway shown
for sp2 C-H bond activation may be operative
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
LnPd0
oxidative
addition
R X
reductive
elimination
C-H Activation
R R'
LnPdII X
R
R' HX H
LnPdII R'
R
?
Isolation of Pd(II) Intermediate
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
N
O
Br
+ Pd(PCy3)2PhCH3, rt, 24h
Pd
CO2NMe2
Br
PCy3
Cy3P
70%
No significant
Interactions between
the amide and the Pd(II) center.
Isolation of Pd(II) Intermediate
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
N
O
Br
+ Pd(PCy3)2PhCH3, rt, 24h
Pd
CO2NMe2
Br
PCy3
Cy3P
70%
N
Br HRb2CO3 (1.5 equiv)
PivOH (30 mol %)
Mes, 150 C, 16h
N
O O
CO2NMe2
PdBr
PCy3
Cy3P (5 mol %)
67%(76% standard conditions)
Isolated Pd(II) complex is a catalyst precursor for the reaction
Stoichiometric Studies to Probe Role of
Base
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Z
Base (10 equiv)Additive (3 equiv)
Mes, 150 C, 4h NZ
PdBr
PCy3
Cy3P
N
Entry Base Additive Yield (%)
1 none none 0
2 Cs2CO3 none 0
3 CsOPiv none 28
4 Cs2CO3 96CsOPivPd
Br
PCy3
Cy3P
N
O
5 none none 0
6 Cs2CO3 none 6
7 CsOPiv none 35
8 Cs2CO3 80CsOPiv
SO2
PdBr
PCy3
Cy3P
N
Potential Pd(II) Intermediates
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
CONMe2
Pd
O
OMe3P
I
CONMe2
Pd
Br
Me3P
II
PMe3
Coordination of amide does not promote dissociation
of phosphine ligand
Pd
Br
Me3P
IV
NMe2
O
Pd
Br
Me3P
III
O
NMe2
Role of Pivalate and Base Additives
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Proposed concerted
metalation-deprotonation (CMD)
transition state:
Pivalate acts as the base
to promote C-H cleavage
Pivalate promotes phosphine
dissociation
Pivalate prevents catalyst
inhibition by excess phosphine
Carbonate is necessary for
irreversible deprotonation of
pivalate ligand after CMD
Proposed Catalytic Cycle
Rousseaux, S.; Fagnou, K. et. al. J. Am. Chem. Soc. 2010, 132, 10692.
Rate = k[Pd][PivO-]
Fast
Oxidative Addition
Fast
Ligand Exchange
Slow
Metalation-Deprotonation
N
Br
O
Pd
N
Br
O
Cy3P
PCy3
Pd
N
O
Cy3P O
O
N
O
Pd H
O
tBu
OCy3P
Pd
N
O
Cy3P O
tBu
OH
Pd
N
O
Cy3P O
tBu
O
N
O
LnPd(0)
CsOPiv
CsBr + PCy3CO3
2-
HCO3-
H
Irreversible
Deprotonation
Reductive
Elimination
Conclusions & Future Directions
Most substrates to date are designed to prevent -hydride elimination.
Selective intramolecular sp3 C-H functionalization can be achieved by
oxidative addition into an adjacent aryl halide
Further development using intermolecular coupling of aryl or alkyl halides
with an appropriate directing group could great increase the synthetic
utility of this process
X
R
Pd(0), Base
HX
Pd
RRreductive
elimination
H
O H X
I I
X=C, O, N
H Br
CN
H
Br
N
H
The reaction proceeds through a concerted metalation-deprotonation
mechanism with crucial involvement of base and additives.
Different oxidants were explored in this system. Commonorganic oxidants, such as 1,4-quinone and PhI(OAc)2, were notefficient for this transformation (entries 2 and 3, Table 1). Othercopper salts, such as CuCl2, could be employed as an oxidantwith a very low efficiency (entry 5, Table 1). Dioxygen (O2)could not play a role as a direct oxidant; however, it can beused as a co-oxidant in the presence of a catalytic amount ofCu(OAc)2 with a relatively lower conversion (entry 9, Table1). This transformation is not sensitive to Pd(II) species.According to all these studies, relatively cheap PdCl2 wasemployed as a catalyst with 1 equiv of Cu(OAc)2 in the presenceof 16 equiv of AcOH in TEFol for this transformation.Evaluating the Reactivities of Different Alkenes. After
screening the reaction conditions, the different alkenes werefurther explored (Table 2). We found that different acrylic acidesters were suitable substrates, whether methyl, ethyl, n-butyl,or benzyl was the protecting group (entries 1-4, Table 2). Freeacrylamide and N,N-disubstituted amide could also be employedin this transformation to produce the desired ortho-olefinatedproducts in moderate to good yields (entries 5 and 6, Table 2).It is noteworthy that the dynamic !-hydride elimination productwas observed when the methyl group was present at the R-posi-tion of the acrylate (entry 7, Table 2). However, !-substitutedethyl acrylate was not suitable for this transformation (entry 8,Table 2). Furthermore, no desired product was obtained whenstyrene was subjected to these reaction conditions (entry 9, Table2). This may arise from the alkylation of arenes in a Friedel-Crafts manner under the relatively strong acidic conditions.Screening of Different Substituted Benzylamines.Different
benzylamine derivatives were screened under the standardconditions (Table 3). Two methyl groups on nitrogen werenecessary to complete this transformation (entry 1, Table 3).When either one methyl group or both of them were substitutedby a proton, this transformation was completely terminated
(entries 2 and 3, Table 3). When N-methyldibenzylamine wasemployed as a substrate, only one phenyl ring was olefinatedunder this condition in a moderate isolated yield, which mightbe controlled by steric effects (entry 4, Table 3). Moreover, theisolated yield for the cyclic amine derivative was very low (entry5, Table 3). An acetyl substituent on nitrogen instead of one ofthe methyl groups decreased the electron density of nitrogen;
Table 1. ortho Olefination of 1a under Various Conditionsa
a The reactions were carried out in 0.5 mmol scale of 1a in the presenceof 1.0 mmol of 2a and the proper catalyst in 2 mL of different solvents.b NMR yields with the use of CH2Br2 as internal standard. c The reactionswere carried out under balloon pressure of O2. d Isolated yields. e Theproducts were obtained as a mixture accompanied with some esterexchanging products. f This reaction was carried out in the absence ofpalladium catalyst.
Table 2. ortho Functionalization of N,N-Dimethylbenzylamine withDifferent Alkenesa
a All the reactions were carried out in the scale of 0.5 mmol of 1a and1.0 mmol of 2 in 2.5 mL of solvent. b Isolated yields. c The yield wasdetermined by 1H NMR with the use of CH2Br2 as an internal standard.Table 3. ortho Olefination of Different N-SubstitutedBenzylaminesa
a All the reactions were carried out in 0.5 mmol scale under standardconditions. b Isolated yields if without further notes. c NMR yield with theuse of CH2Br2 as an internal standard. d Only one benzyl was olefinated.
A R T I C L E S Cai et al.
7668 J. AM. CHEM. SOC. 9 VOL. 129, NO. 24, 2007
final product 3. The palladium hydride species was transformedto Pd(0) and further oxidized to Pd(II) by Cu(II) to finish thiscatalytic cycle.Application of Developed ortho Olefination-Hydrogena-
tion. 3-o-Tolylpropanoic acid and its derivatives have beenutilized as a key structural unit in bioactive molecules.17According to this developed process, the compound 4rd wassynthesized by this transformation in excellent yield with shortroutes (eq 9).17a This process also offers a new method to quicklyconstruct this type of compound in high efficiency and gooddiversity, which will be beneficial to further unveil new utilitiesof this unique scaffold.
ConclusionsStarting from the easily available N,N-dimethylbenzylamines,
we have developed a novel method to achieve a regioselectivefunctionalization via direct C-H functionalization by tuningthe acidity of the reaction conditions. Although the acid hasbeen applied to the C-H activation by electrophilic attackthrough enhancing the electrophilic ability of metal ions, theacid plays a much more important role to conduct thistransformation. The acidity and quantity of the Bronsted acidremarkably controlled the efficiency of this ortho olefination.Starting from the corresponding functionalized tertiary amines,highly selectively ortho-functionalized toluene and its deriva-tives were synthesized by simple reduction. These two trans-formations could be combined in one vessel to offer a muchmore environmentally benign process. Besides ortho-function-
alized N,N-dimethylbenzylamines,18 3-o-tolylpropanoic acid andits derivatives are also important units of synthetic moleculesand show some biological activity.17 Our development hereadvances a remarkable and useful method to construct both ofthese important scaffolds. Further study to apply these methodsto organic synthesis is underway in our laboratory.Experimental SectionGeneral Methods. All the reactions were carried out in a stoppered
Schlenk flask.19 All the solvents were freshly distilled before use exceptCF3CH2OH. CF3CH2OH, anhydrous Cu(OAc)2, Pd/C (5 wt % Pd), andPd(CH3CN)4(BF4)2 were purchased from Acros. PdCl2 was purchasedfrom Zealand Co. Ltd., and Pd/C (10 wt % Pd) and N,N-dimethylben-zylamine were purchased from Sinopharm Chemical Reagent Co., Ltd.N,N-Dimethylbenzylamine was distilled under reduced pressure andstored under N2 atmosphere. Other commercially available chemicalswere directly used without further purification.Physical Methods. 1H NMR (300 MHz) and 13C NMR (75 MHz)
were registered on Varian 300M spectrometers with CDCl3 as solventand tetramethylsilane (TMS) as an internal standard. Chemical shiftswere reported in units (ppm) by assigning the TMS resonance in the1H spectrum as 0.00 ppm and the CDCl3 resonance in the 13C spectrumas 77.0 ppm. All coupling constants (J values) are reported in hertz(Hz). Column chromatography was performed on silica gel 200-300mesh. IR, GC, and MS were performed by the State-authorizedAnalytical Center in Peking University.General Procedure for Preparation of Functionalized N,N-
Dimethylbenzylamines 1. Functionalized N,N-dimethylbenzylamineswere prepared by reductive amination according to the reportedprocedure.20 To a solution of NEt3 (4.2 mL, 30 mmol) in absolute EtOH(23 mL) was added dimethylamine hydrochloride (2.48 g, 30 mmol),Ti(i-PrO)4 (9.0 mL, 30 mmol), and the corresponding aldehyde (15mmol). The mixture was stirred at 25 C for 12 h, NaBH4 (0.86 g,22.5 mmol) was added, and the resulting mixture was further stirredfor 10 h at 25 C. The reaction was quenched by pouring the mixtureinto aqueous ammonia (25 mL, 2 N) and filtered through a Celite pad,and the resulting inorganic solid was washed with CH2Cl2 (100 mL).The filtrate was washed with CH2Cl2 (3 50 mL), concentrated toabout 30 mL, and washed with HCl (2 N, 3 10 mL). The solutionwas neutralized to pH ) 9 with 10% aqueous NaOH and extractedwith CH2Cl2 (3 50 mL). Additional NaOH was added to keep theinorganic phase basic. The organic phases were combined and driedover MgSO4 and then evaporated to give the corresponding N,N-dimethylbenzylamine 1 without further purification.General Procedure for the ortho Olefination of Tertiaryamines
with Acrylic Esters. In a typical experiment, PdCl2 (4.4 mg, 0.025mmol), Cu(OAc)2 (90.8 mg, 0.5 mmol), and CF3CH2OH (2 mL) wereadded into a Schlenk tube. Then N,N-dimethylbenzylamine 1 (0.5mmol) was added, followed by 2 (1.0 mmol) and HOAc (0.5 mL, 8.0mmol). The flask was stoppered and heated at 85 C in an oil bath for48 h. The mixture was made slightly alkaline with a saturated Na2CO3solution (3 mL), and a light blue precipitate appeared. The suspensionwas filtered through a Celite pad and extracted with CH2Cl2 three times.The combined organic layers were dried over anhydrous Na2SO4 andevaporated in vacuo. The desired products 3 were obtained in thecorresponding yields after purification by flash chromatography on silicagel with PE, EtOAc, and NEt3.
(17) (a) Bohacek, R.; Boosalis, M. S.; McMartin, C.; Faller, D. V.; Perrine, S.P. Chem. Biol. Drug Des. 2006, 67, 318. (b) Frankish, N.; Farrell, R.;Sheridan, H. J. Pharm. Pharmacol. 2004, 56, 1423. (c) Burlingame, R. P.;Wyman, L.; Chapman, J. P. J. Bacteriol. 1986, 168, 55. (d) Kuhler, T. C.;Swanson, M.; Christenson, B.; Klintenberg, A.-C.; Lamm, B.; Fagerhag,J.; Gatti, R.; Olwegard-Halvarsson, M.; Shcherbuchin,V.; Elebring,T.; Sjostrom, J.-E. J. Med. Chem. 2002, 45, 4282. (e) Conner, S. E.;Knobelsdorf, J. A.; Mantlo, N. B.; Schkeryantz, Jeffrey M.; Shen, Q.;Warshawsky, A. M.; Zhu, G. PCT Int. Appl. WO 2003072100 A1,2003.
(18) (a) Fevig, J. M.; Cacciola, J.; Buriak, J.; Rossi, K. A.; Knabb, R. M.;Luettgen, J. M.; Wong, P. C.; Bai, S. A.; Wexler, R. R.; Lam, P. Y. S.Bioorg. Med. Chem. Lett. 2006, 16, 3755. (b) Kung, H. F.; Newman, S.;Choi, S.-R.; Oya, S.; Hou, C.; Zhuang, Z.-P.; Acton, P. D.; Ploessl, K.;Winkler, J.; Kung, M.-P. J. Med. Chem. 2004, 47, 5258. (c) Hine, J.; Khan,M. N. J. Am. Chem. Soc. 1977, 99, 3847. (d) Nielsen, S. F.; Larsen, M.;Boesen, T.; Schonning, K.; Kromann, H. J. Med. Chem. 2005, 48, 2667.
(19) Safety note: CF3CH2OH is corrosive and H2 is explosive. Thus, greatcaution should be exercised when handling them.
(20) Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928.
Scheme 6. Proposed Mechanism of ortho Olefination ofN,N-Dimethylbenzylamine
A R T I C L E S Cai et al.
7672 J. AM. CHEM. SOC. 9 VOL. 129, NO. 24, 2007
Indirect ortho Functionalization of Substituted Toluenesthrough ortho Olefination of N,N-Dimethylbenzylamines Tuned
by the Acidity of Reaction ConditionsGuixin Cai, Ye Fu, Yizhou Li, Xiaobing Wan, and Zhangjie Shi*
Contribution from Beijing National Laboratory of Molecular Sciences (BNLMS), PKU GreenChemistry Center and Key Laboratory of Bioorganic Chemistry and Molecular Engineering ofMinistry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, Peoples
Republic of China, and Shanghai Key Laboratory of Green Chemistry and Chemical Processes,East China Normal UniVersity, Shanghai 200062, Peoples Republic of China
Received January 26, 2007; E-mail: [email protected]
Abstract: Highly regioselective olefination of substituted N,N-dimethylbenzylamines was developed by tuningthe acidity of reaction conditions based on analysis of their features. The ortho-functionalized N,N-dimethylbenzylamines were further transformed into 3-(2-tolyl)propanoic acid and its derivatives undermild conditions. These two transformations could be combined into one pot, and 3-(2-tolyl)propanoic acidand its derivatives were obtained in moderate to good yields. Mechanistic studies indicated that electrophilicattack on the phenyl ring by the Pd(II) ion assisted by the N,N-dimethylaminomethyl group was a key stepduring this catalytic transformation, which was controlled by the acidity of the reaction conditions.
IntroductionIn the past several decades, many efforts have been made to
direct functionalization of a variety of C-H bonds.1 AromaticC-H activation through different chemical processes has beenstudied.2 Direct functionalization of aromatic C-H bonds byelectrophilic attack of metal ions is one of the most importantpathways.3 Functional groups containing heteroatoms, such as
acetamino, oxazolyl, pyridyl, and imino groups, have beenbroadly utilized to provide either stoichiometric or catalyticortho-metalation of aromatic rings to construct C-C4a-f andC-X (X ) halides, N, etc.) bonds.4g-jPrevious synthetic workon functionalization of N,N-dimethylbenzylamine generallyutilized n-BuLi to ortho lithiate the N,N-dimethylbenzylamine,which limited the tolerance of functional groups in the sub-strates.5 Although the N,N-dimethylaminomethyl group has beenused as a directing group to realize the ortho-metalation bytransition metal complexes to form metallocycles and furtherconstruct C-C bonds in a stoichiometric manner under basicconditions,6 the catalytic version of ortho functionalization ofan aromatic C-H bond directed by an N,N-dimethylaminom-ethyl group has rarely been reported, except one case reportedby Murai and co-workers, in which achieved ortho silylationcatalyzed by Ru(0) was initiated through oxidative addition.7
(1) (a) Murai, S. ActiVation of UnreactiVe Bonds and Organic Synthesis;Springer-Verlag: Berlin, 1999; pp 48-78. (b) Shilov, A. E.; Shulpin, G.B. Chem. ReV. 1997, 97, 2879. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.ReV. 2002, 102, 1731. (d) Arndtsen, B. A.; Bergman, R. G.; Mobley, T.A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (e) Cho, J.-Y.; Tse, M.K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305. (f)Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,2685. (g) Lail, M.; Arrowood, B. N.; Gunnoe, T. B. J. Am. Chem. Soc.2003, 125, 7506. (h) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.; Inoue,Y. J. Am. Chem. Soc. 2003, 125, 12102. (i) Davies, H. M. L.; Hansen, T.;Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (j) Crabtree, R. H. J.Organomet. Chem. 2004, 689, 4083. (k) Sen, A. Acc. Chem. Res. 1998,31, 550. (l) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (m) Stahl,S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37,2180. (n) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (o) Chen, H. Y.;Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995. (p)Brown, S. H.; Crabtree, R. H. J. Am. Chem. Soc. 1989, 111, 2935. (q)Solari, E.; Musso, F.; Ferguson, R.; Floriani, C.; Villa, A. C.; Rizzoli, C.Angew. Chem., Int. Ed. Engl. 1995, 34, 1510. (r) Dick, A. R.; Sanford, M.S. Tetrahedron 2006, 62, 2439.
(2) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,M.; Chatani, N. Nature 1993, 366, 529. (b) Shi, Z.; He, C. J. Am. Chem.Soc. 2004, 126, 13596. (c) Shabashov, D.; Daugulis, O. Org. Lett. 2005,7, 3657. (d) Ishiyama, T.; Sato, K.; Nishio, Y.; Miyaura, N. Angew. Chem.,Int. Ed. 2003, 42, 5346. (e) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem.2003, 3485. (f) Zhao, J.; Campo, M.; Larock, R. C. Angew. Chem., Int.Ed. 2005, 44, 1873. (g) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.;Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78.
(3) (a) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.; Kitamura, T.; Fujiwara,Y. Science 2000, 287, 1992. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.Chem. Res. 2001, 34, 633. (c) Hennessy, E.; Buchwald, S. L. J. Am. Chem.Soc. 2003, 125, 12084. (d) Hashmi, A. S. K.; Schwarz, L.; Choi, J. H.;Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (e) Wang, X.; Lane,B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (f) Alexakis, A.;Tomassini, A.; Andrey, O.; Bernardinelli, G. Eur. J. Org. Chem. 2005,1332.
(4) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (b) Boele, M. D.K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries,J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (c)Tremont, S. J.; ur Rahman, H. J. Am. Chem. Soc. 1984, 106, 5759. (d)Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156. (e) Kalyani,D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005,127, 7330. (f) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2004, 126, 2300. (g) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem.Soc. 2006, 128, 9048. (h) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int.Ed. 2005, 44, 2112. (i) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang,S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416. (j) Tsang, W. C. P.; Zheng,N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.
(5) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Saa, J. M.; Llobera, A.;Garcia-Raso, A.; Costa, A.; Deya, P. M. J. Org. Chem. 1988, 53, 4263.
(6) (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (b) Holton, R. A.; Davis, R. G.J. Am. Chem. Soc. 1977, 99, 4175. (c) Dunina, V. V.; Kuzmina, L. G.;Kazakova, M. Y.; Gorunova, O. N.; Grishin, Y. K.; Kazakova, E. I. Eur.J. Org. Chem. 1999, 1029. (d) Grove, D. M.; van Koten, G.; Ubbels, H. J.C. J. Am. Chem. Soc. 1982, 104, 4285. (e) Holton, R. A. Tetrahedron Lett.1977, 4, 355. (f) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A. K.J. Chem. Soc., Perkin Trans. 2 1983, 1511.
(7) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani, N.; Murai,S. Chem. Lett. 2002, 396.
Published on Web 05/27/2007
7666 9 J. AM. CHEM. SOC. 2007, 129, 7666-7673 10.1021/ja070588a CCC: $37.00 2007 American Chemical Society
activation[13] and by steric effects in the second C!Hactivation.[14] To further verify our prediction, the moresterically hindered p-xylene was subjected to this trans-formation, and ortho arylation was observed in very low yield,with most of the starting material 1a being recovered.
The scope of N-acetanilides was further investigated(Table 1). N-Alkylated and free anilines were not fit for thistransformation. Different derivatives of N-acetyl-1,2,3,4-tet-rahydroquinoline, regardless of substitution at the aliphatic oraromatic ring, were perfectly suitable substrates for thistransformation (entries 14, Table 1). However, N-methylacetanilide 1e did not serve well as a substrate and quicklydecomposed under cross dehydrogenative arylation (CDA)conditions (entry 5, Table 1). Additional studies indicatedthat acetanilide 1 f was a good substrate, and the N!H bondwas not functionalized (entry 6, Table 1). In this case, only theortho sp2 C!H bond was arylated efficiently.
Furthermore, different common arenes were tested forthis ortho arylation behavior (Table 2). We found: 1) Lesshindered ortho- and meta-dialkyl-substituted electron-richbenzene derivatives could be utilized as the arene source toperform the ortho arylation with excellent selectivities(entries 1 and 3, Table 2). With monoalkyl-substitutedarenes, two isomers (functionalized at the meta and parapositions) were isolated as a mixture (entries 4, 5, 7, and 8,Table 2). Thus, steric hindrance rather than electronic effectsplayed the vital role in controlling the selectivity of the secondC!H activation. 2) Different arenes with fused rings, evenwith heteroatoms, could serve as substrates to complete thistransformation at less hindered positions (entry 6, Table 2).3) Benzene could be employed as the arene source withexcellent efficiency (entry 6, Table 1; entry 2, Table 2). Evenelectron-deficient arenes, such as biphenyl and fluoroben-zene, were also good reagents for this arylation, but a highercatalyst loading was required (entries 7 and 8, Table 2). The
reactivity of these electron-deficient arenes seems to supportthe proton-abstraction pathway to activate the C!H bond of asecond arene to afford intermediate 6 via 5, as described inthe aforementioned catalytic cycle (Scheme 2).[15]
Carbazole and its derivatives further drew our attention,as they are the key structural units in many natural drugs andsynthetic optical materials.[16] On the basis of the newobservations, we aimed to construct the carbazole unitthrough a process free of halogenated and metal-containingreagents (Scheme 3). In our design, the C!N bond ofcarbazole could be constructed by PdII-catalyzed C!Hactivation, as demonstrated by Buchwald and co-workers.[17]
The ortho-arylated acetanilides could be constructed by ournew CDA reaction with commercially available acetanilidesand arenes. Building on the above developments, we envi-sioned that the regioselective ortho palladation of acetani-lides would give a palladacycle analogous to 4. This keyintermediate may undergo further C!H activation of a secondarene to construct biaryl C!C bonds, thereby furnishing theintermolecular cross-coupling product. Thus, the carbazolecore can be constructed through three C!H and one N!Hfunctionalization with a Pd catalyst in a highly chemo- andregioselective manner. Prefunctionalization of arenes with
Scheme 2. Proposed catalytic cycle for highly selective cross dehydro-genative arylation (CDA).
Table 1: Substrate scope of N-acetanilides for Pd-catalyzed crossdehydrogenative arylation.[a]
Entry 1 3 Yield [%][b]
17873[c]
2 71
3 86
4 64
5[d] 16
6[e] 66
[a] All reactions were performed using 1 (0.3 mmol), 2a (1.0 mL), andEtCOOH (1.5 mL) unless noted otherwise (see the SupportingInformation). [b] Yields of isolated product. [c] Yield of isolated producton a scale of 10.0 mmol. [d] Most of starting material 1e decomposedunder these conditions. [e] Benzene (1 mL) was used in place of 2a.
Communications
1116 www.angewandte.org ! 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 1115 1118
activation[13] and by steric effects in the second C!Hactivation.[14] To further verify our prediction, the moresterically hindered p-xylene was subjected to this trans-formation, and ortho arylation was observed in very low yield,with most of the starting material 1a being recovered.
The scope of N-acetanilides was further investigated(Table 1). N-Alkylated and free anilines were not fit for thistransformation. Different derivatives of N-acetyl-1,2,3,4-tet-rahydroquinoline, regardless of substitution at the aliphatic oraromatic ring, were perfectly suitable substrates for thistransformation (entries 14, Table 1). However, N-methylacetanilide 1e did not serve well as a substrate and quicklydecomposed under cross dehydrogenative arylation (CDA)conditions (entry 5, Table 1). Additional studies indicatedthat acetanilide 1 f was a good substrate, and the N!H bondwas not functionalized (entry 6, Table 1). In this case, only theortho sp2 C!H bond was arylated efficiently.
Furthermore, different common arenes were tested forthis ortho arylation behavior (Table 2). We found: 1) Lesshindered ortho- and meta-dialkyl-substituted electron-richbenzene derivatives could be utilized as the arene source toperform the ortho arylation with excellent selectivities(entries 1 and 3, Table 2). With monoalkyl-substitutedarenes, two isomers (functionalized at the meta and parapositions) were isolated as a mixture (entries 4, 5, 7, and 8,Table 2). Thus, steric hindrance rather than electronic effectsplayed the vital role in controlling the selectivity of the secondC!H activation. 2) Different arenes with fused rings, evenwith heteroatoms, could serve as substrates to complete thistransformation at less hindered positions (entry 6, Table 2).3) Benzene could be employed as the arene source withexcellent efficiency (entry 6, Table 1; entry 2, Table 2). Evenelectron-deficient arenes, such as biphenyl and fluoroben-zene, were also good reagents for this arylation, but a highercatalyst loading was required (entries 7 and 8, Table 2). The
reactivity of these electron-deficient arenes seems to supportthe proton-abstraction pathway to activate the C!H bond of asecond arene to afford intermediate 6 via 5, as described inthe aforementioned catalytic cycle (Scheme 2).[15]
Carbazole and its derivatives further drew our attention,as they are the key structural units in many natural drugs andsynthetic optical materials.[16] On the basis of the newobservations, we aimed to construct the carbazole unitthrough a process free of halogenated and metal-containingreagents (Scheme 3). In our design, the C!N bond ofcarbazole could be constructed by PdII-catalyzed C!Hactivation, as demonstrated by Buchwald and co-workers.[17]
The ortho-arylated acetanilides could be constructed by ournew CDA reaction with commercially available acetanilidesand arenes. Building on the above developments, we envi-sioned that the regioselective ortho palladation of acetani-lides would give a palladacycle analogous to 4. This keyintermediate may undergo further C!H activation of a secondarene to construct biaryl C!C bonds, thereby furnishing theintermolecular cross-coupling product. Thus, the carbazolecore can be constructed through three C!H and one N!Hfunctionalization with a Pd catalyst in a highly chemo- andregioselective manner. Prefunctionalization of arenes with
Scheme 2. Proposed catalytic cycle for highly selective cross dehydro-genative arylation (CDA).
Table 1: Substrate scope of N-acetanilides for Pd-catalyzed crossdehydrogenative arylation.[a]
Entry 1 3 Yield [%][b]
17873[c]
2 71
3 86
4 64
5[d] 16
6[e] 66
[a] All reactions were performed using 1 (0.3 mmol), 2a (1.0 mL), andEtCOOH (1.5 mL) unless noted otherwise (see the SupportingInformation). [b] Yields of isolated product. [c] Yield of isolated producton a scale of 10.0 mmol. [d] Most of starting material 1e decomposedunder these conditions. [e] Benzene (1 mL) was used in place of 2a.
Communications
1116 www.angewandte.org ! 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 1115 1118
activation[13] and by steric effects in the second C!Hactivation.[14] To further verify our prediction, the moresterically hindered p-xylene was subjected to this trans-formation, and ortho arylation was observed in very low yield,with most of the starting material 1a being recovered.
The scope of N-acetanilides was further investigated(Table 1). N-Alkylated and free anilines were not fit for thistransformation. Different derivatives of N-acetyl-1,2,3,4-tet-rahydroquinoline, regardless of substitution at the aliphatic oraromatic ring, were perfectly suitable substrates for thistransformation (entries 14, Table 1). However, N-methylacetanilide 1e did not serve well as a substrate and quicklydecomposed under cross dehydrogenative arylation (CDA)conditions (entry 5, Table 1). Additional studies indicatedthat acetanilide 1 f was a good substrate, and the N!H bondwas not functionalized (entry 6, Table 1). In this case, only theortho sp2 C!H bond was arylated efficiently.
Furthermore, different common arenes were tested forthis ortho arylation behavior (Table 2). We found: 1) Lesshindered ortho- and meta-dialkyl-substituted electron-richbenzene derivatives could be utilized as the arene source toperform the ortho arylation with excellent selectivities(entries 1 and 3, Table 2). With monoalkyl-substitutedarenes, two isomers (functionalized at the meta and parapositions) were isolated as a mixture (entries 4, 5, 7, and 8,Table 2). Thus, steric hindrance rather than electronic effectsplayed the vital role in controlling the selectivity of the secondC!H activation. 2) Different arenes with fused rings, evenwith heteroatoms, could serve as substrates to complete thistransformation at less hindered positions (entry 6, Table 2).3) Benzene could be employed as the arene source withexcellent efficiency (entry 6, Table 1; entry 2, Table 2). Evenelectron-deficient arenes, such as biphenyl and fluoroben-zene, were also good reagents for this arylation, but a highercatalyst loading was required (entries 7 and 8, Table 2). The
reactivity of these electron-deficient arenes seems to supportthe proton-abstraction pathway to activate the C!H bond of asecond arene to afford intermediate 6 via 5, as described inthe aforementioned catalytic cycle (Scheme 2).[15]
Carbazole and its derivatives further drew our attention,as they are the key structural units in many natural drugs andsynthetic optical materials.[16] On the basis of the newobservations, we aimed to construct the carbazole unitthrough a process free of halogenated and metal-containingreagents (Scheme 3). In our design, the C!N bond ofcarbazole could be constructed by PdII-catalyzed C!Hactivation, as demonstrated by Buchwald and co-workers.[17]
The ortho-arylated acetanilides could be constructed by ournew CDA reaction with commercially available acetanilidesand arenes. Building on the above developments, we envi-sioned that the regioselective ortho palladation of acetani-lides would give a palladacycle analogous to 4. This keyintermediate may undergo further C!H activation of a secondarene to construct biaryl C!C bonds, thereby furnishing theintermolecular cross-coupling product. Thus, the carbazolecore can be constructed through three C!H and one N!Hfunctionalization with a Pd catalyst in a highly chemo- andregioselective manner. Prefunctionalization of arenes with
Scheme 2. Proposed catalytic cycle for highly selective cross dehydro-genative arylation (CDA).
Table 1: Substrate scope of N-acetanilides for Pd-catalyzed crossdehydrogenative arylation.[a]
Entry 1 3 Yield [%][b]
17873[c]
2 71
3 86
4 64
5[d] 16
6[e] 66
[a] All reactions were performed using 1 (0.3 mmol), 2a (1.0 mL), andEtCOOH (1.5 mL) unless noted otherwise (see the SupportingInformation). [b] Yields of isolated product. [c] Yield of isolated producton a scale of 10.0 mmol. [d] Most of starting material 1e decomposedunder these conditions. [e] Benzene (1 mL) was used in place of 2a.
Communications
1116 www.angewandte.org ! 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 1115 1118
halide and boronic acids can thus be avoided in this efficientsynthetic scheme.
We tested the synthesis of the carbazole scaffold withmultiple C!H activation steps, as envisioned. Under thestandard arylation conditions, ortho-phenylated acetanilide
3 fb was produced in a good yield (Scheme 4). This compoundcould be directly transformed into carbazole 8a (isolated in91% yield) under Buchwald conditions. Starting from 1 f, theortho position of the newly installed phenyl ring of 3 fb could
be further phenylated to produce acetanilide 7 through asecond CDA reaction by simply increasing the catalystloading under the same conditions. Carbazole 8b was easilyobtained from 7 through the PdII-catalyzed C!N bondformation in an excellent yield and high selectivity andcould undergo a third cross-coupling to yield derivatives.
With simple processes completely free of halogenated andorganometallic reagents, 4-deoxycarbazomycin B, a degrada-tion product of the natural product carbazomycin B, wassynthesized in few simple steps (Scheme 5).[18] This method-ology allowed the swift development of a diverse library ofcarbazoles with different functionalities from commerciallyavailable acetanilides and common arenes.
In conclusion, our new concept was realized to conducthighly selective cross-coupling of arenes controlled bydirecting groups, and a practical method was developed to
Table 2: Cross dehydrogenative arylation of 1,2,3,4-N-acetyltetrahydro-quinoline 1a with different arenes.[a]
Entry Arene 2 3 Yield [%][b]
17873[c]
2 66
3 46
4[d] 78 (1.1:1)
5[d] 69 (2.5:1)
6[e] 63
7[d,f ] 43 (1:1)
8[g,h] 48 (2.3:1)
[a] All reactions were carried out using 1a (0.3 mmol), 2 (1.0 mL),EtCOOH (1.5 mL), and the appropriate amount of of Cu(OTf)2 (see theSupporting Information for details). [b] Yield of isolated product. Theratios given in parenthesis refer to the relative yield of para- to meta-substituted product. [c] Yield of isolated product on a scale of10.0 mmol. [d] The ratio of the two isomers was determined by GC.[e] Some by-products (less than 10%) were observed, but theirstructures could not be determined. [f ] 5.0 equiv biphenyl was used.[g] 20 mol% Pd(OAc)2 was used. [h] The ratio of the two isomers wasdetermined by 1H NMR spectroscopy.
Scheme 3. A rational design on construction of carbozoles throughmultiple C!H activations by Pd catalysis avoiding organohalides andorganometallic reagents.
Scheme 4. Pathways completely free of halogenated and organometal-lic reagents for the synthesis of polysubstituted carbozoles throughmultiple C!H activations. a) Benzene (1 mL), 1 f (0.3 mmol), Pd(OAc)2(10 mol%), and Cu(OTf)2 (1 equiv) in propionic acid (1.5 mL), 46 h.b) Benzene (1.0 mL), 1 f (0.3 mmol), Pd(OAc)2 (20 mol%), and Cu-(OTf)2 (1 equiv) in propionic acid (1.5 mL), 6 h.
Scheme 5. Synthesis of 4-deoxycarbazomycin B from substituted acet-anilide and benzene through sequential C!H activation.
AngewandteChemie
1117Angew. Chem. Int. Ed. 2008, 47, 1115 1118 ! 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org
Mechanistically, the transformation was initiated fromortho cyclopalladation directed by O-methyl oxime togenerate cyclopalladium species A, which underwent trans-metalation with arylboronic acids to produce diaryl Pdspecies B (Scheme 3).10 Reductive elimination of B producedthe desired ortho arylated product 4. Pd(0) was furtherreoxidized to Pd(II) by Cu(II) species and/or co-oxidant tofulfill the catalytic cycle. In the presence of proper DMOPfor the arylation of aryl aldoximes, the transformation wasterminated at this stage. With the addition of TfOH, thisarylated product was further transformed to product 6.Furthermore, 6 was hydrolyzed to give 9H-fluoren-9-one 7under strongly acidic conditions. Thus, starting from the samereagents, different pathways have been developed to ap-proach different scaffolds by tuning the reaction conditions.
In conclusion, we have developed novel methods toconstruct ortho arylated aryl aldoximes and ketoximes viaPd(II)-catalyzed direct C-H arylation by using arylboronicacids. On the basis of the analysis of ortho arylation of arylaldoximes, cascade transformations toward interesting fluo-renone scaffold were conducted by switching the reactionpathways through changing the reaction parameters. Thesestudies showed various transformations to functionalize arylcarbonyl compounds starting from simple chemicals.
Acknowledgment. Support of this work by the grant fromNSFC (No. 20672006, 20821062, 20925207, and GZ419)and the973programfromMOSTofChina (2009CB825300)is gratefully acknowledged.
Supporting Information Available: Brief experimentaldetail and other spectral data for products. This material isavailable free of charge via the Internet at http://pubs.acs.org.
OL902552V(10) Motoyama, T.; Shimazaki, Y.; Yajima, T.; Nakabayashi, Y.; Naruta,
Y.; Yamauchi, O. J. Am. Chem. Soc. 2004, 126, 7378.
Figure 3. Cascade reaction to produce polysubstituted 9H-fluoren-9-ones 7 via Pd-catalyzed C-H activation. All the reactions werecarried out in 0.2 mmol scale. Isolated yields.
Scheme 3. Proposed Mechanism for Pd(II)-Catalyzed Arylationand Cascade Transformation to Fluorenone
Org. Lett., Vol. 12, No. 1, 2010 187
Pd-Catalyzed C-H Functionalizations ofO-Methyl Oximes with Arylboronic AcidsChang-Liang Sun, Na Liu, Bi-Jie Li, Da-Gang Yu, YangWang, andZhang-Jie Shi*,,
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory ofBioorganic Chemistry and Molecular Engineering of Ministry of Education, College ofChemistry, and State Key Laboratory of Natural and Biomimetic Drugs, PekingUniVersity, Beijing 100871, [email protected]
Received November 9, 2009
ABSTRACT
Useful methods have been developed to construct ortho-arylated aryl aldoximes, aryl ketoximes, and fluorenones via Pd(II)-catalyzed directC-H arylation by using arylboronic acids as arylating reagents based on the analysis of the pathways of direct functionalization of arylaldoximes.
Direct C-H functionalization is the most straightforwardpathway to construct useful and complicated natural andsynthetic molecules. Recently, many efforts have beenmade to pursue this goal.1 Among those methods, func-tional group oriented ortho C-H activation is a commonstrategy to address this problem.2 Actually, the O-methyloximyl group has been successfully applied for orthoacetoxylation and amination.3 Very recently, arylationfollowed by further transformation with aryl iodides tosynthesize fluorenones has also been successfully devel-oped.4
Compared with direct arylation with arylboronic acidsdirected by other anchoring groups, the arylation orientedby CdX (X ) O, N) remains challenging.5 The major issue
College of Chemistry. State Key Laboratory of Natural and Biomimetic Drugs.(1) For recent reviews, see: (a) Godula, K.; Sames, D. Science 2006,
312, 67. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;Lazareva, A. Synlett 2006, 3382. (c) Dick, A. R.; Sanford, M. S. Tetrahedron2006, 62, 2439. (d) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,4, 4041. (e) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.(f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (g) Ritleng, V.;Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (h) Jia, C.; Kitamura,T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (i) Dyker, G. Angew. Chem.,Int. Ed. 1999, 38, 1699. (j) Li, B.-J.; Yang, S.-D.; Shi., Z.-J. Synlett 2008,7, 949.
(2) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.Soc. 2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.2005, 127, 4156. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,M. S. J. Am. Chem. Soc. 2005, 127, 7330. (d) Dick, A. R.; Hull, K. L.;Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (e) Giri, R.; Yu, J.-Q.J. Am. Chem. Soc. 2008, 130, 4082. (f) Tsang, W. C. P.; Zheng, N.;Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (g) Wang, C.; Piel,I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (h) Ackermann, L. Org.Lett. 2005, 7, 3123. (i) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano,S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (j) Campeau, L.-C.; Parisien, M.;Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (k) Shi, B.; Maugel,N.; Zhang, Y.; Yu., J. Angew. Chem., Int. Ed. 2008, 47, 4. (l) Houlden,C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn., K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(3) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2004, 126, 9542. (b) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006,128, 9048.
(4) (a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. Angew.Chem., Int. Ed. 2008, 47, 9462. (b) Shabashov, D.; Maldonado, J. R. M.;Daugulis, O. J. Org. Chem. 2008, 73, 7818.
(5) Gurbuz, N.; ozdemir, I.; Cetinkaya, B. Tetrahedron Lett. 2005, 46,2273.
ORGANICLETTERS
2010Vol. 12, No. 1
184-187
10.1021/ol902552v 2010 American Chemical SocietyPublished onWeb 12/02/2009
Pd-Catalyzed C-H Functionalizations ofO-Methyl Oximes with Arylboronic AcidsChang-Liang Sun, Na Liu, Bi-Jie Li, Da-Gang Yu, YangWang, andZhang-Jie Shi*,,
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory ofBioorganic Chemistry and Molecular Engineering of Ministry of Education, College ofChemistry, and State Key Laboratory of Natural and Biomimetic Drugs, PekingUniVersity, Beijing 100871, [email protected]
Received November 9, 2009
ABSTRACT
Useful methods have been developed to construct ortho-arylated aryl aldoximes, aryl ketoximes, and fluorenones via Pd(II)-catalyzed directC-H arylation by using arylboronic acids as arylating reagents based on the analysis of the pathways of direct functionalization of arylaldoximes.
Direct C-H functionalization is the most straightforwardpathway to construct useful and complicated natural andsynthetic molecules. Recently, many efforts have beenmade to pursue this goal.1 Among those methods, func-tional group oriented ortho C-H activation is a commonstrategy to address this problem.2 Actually, the O-methyloximyl group has been successfully applied for orthoacetoxylation and amination.3 Very recently, arylationfollowed by further transformation with aryl iodides tosynthesize fluorenones has also been successfully devel-oped.4
Compared with direct arylation with arylboronic acidsdirected by other anchoring groups, the arylation orientedby CdX (X ) O, N) remains challenging.5 The major issue
College of Chemistry. State Key Laboratory of Natural and Biomimetic Drugs.(1) For recent reviews, see: (a) Godula, K.; Sames, D. Science 2006,
312, 67. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;Lazareva, A. Synlett 2006, 3382. (c) Dick, A. R.; Sanford, M. S. Tetrahedron2006, 62, 2439. (d) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,4, 4041. (e) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.(f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (g) Ritleng, V.;Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (h) Jia, C.; Kitamura,T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (i) Dyker, G. Angew. Chem.,Int. Ed. 1999, 38, 1699. (j) Li, B.-J.; Yang, S.-D.; Shi., Z.-J. Synlett 2008,7, 949.
(2) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.Soc. 2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.2005, 127, 4156. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,M. S. J. Am. Chem. Soc. 2005, 127, 7330. (d) Dick, A. R.; Hull, K. L.;Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (e) Giri, R.; Yu, J.-Q.J. Am. Chem. Soc. 2008, 130, 4082. (f) Tsang, W. C. P.; Zheng, N.;Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (g) Wang, C.; Piel,I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (h) Ackermann, L. Org.Lett. 2005, 7, 3123. (i) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano,S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (j) Campeau, L.-C.; Parisien, M.;Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (k) Shi, B.; Maugel,N.; Zhang, Y.; Yu., J. Angew. Chem., Int. Ed. 2008, 47, 4. (l) Houlden,C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn., K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(3) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.2004, 126, 9542. (b) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006,128, 9048.
(4) (a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. Angew.Chem., Int. Ed. 2008, 47, 9462. (b) Shabashov, D.; Maldonado, J. R. M.;Daugulis, O. J. Org. Chem. 2008, 73, 7818.
(5) Gurbuz, N.; ozdemir, I.; Cetinkaya, B. Tetrahedron Lett. 2005, 46,2273.
ORGANICLETTERS
2010Vol. 12, No. 1
184-187
10.1021/ol902552v 2010 American Chemical SocietyPublished onWeb 12/02/2009
Org. Lett., Vol. 15, No. 22, 2013 5777
(Scheme 3).Under the optimal reaction conditions, phenyliodide could couple with thiazole but in only 18% yield,whereas the yield can be improved to 47%by elevating thereaction temperature from 100 to 140 !C. In comparison,the p-fluorophenyl iodide and p-methoxyphenyl iodidewere compatible under standard conditions, affording the5-arylated thiazole derivatives in moderate yields (54%and 39%, respectively). However, we failed to improvethe reaction efficiency further at an even higher reactiontemperature (140 !C). Unexpectedly, the sterically hinderedortho-methyl phenyl iodide coupled more efficiently withthiazole specifically at theC-5position inup to60%isolatedyield. Futher studies to promote the efficacy is underway.To further illustrate the regioselective control of our cur-
rent metholodogy, an experiment using 2-phenylthiazole 6as the substrate was carried out (Scheme 4). As expected,the corresponding 5-phenylatedproduct 710was exclusivelyobtained in 44% isolated yield and the otho-phenylatedproduct 8 on the phenyl ring was not observed.
Based on our investigations and previous theoreticalcalculations by Gorelsky,6a,11 the catalytic pathway isconsidered to proceed as shown in Figure 2. After thereduction of the Pd(II) species to aPd(0) species (thismightbe stabilized by the starting thiazole moiety or the corre-sponding product), arylpalladium species 9 is generatedthrough the oxidative addition by aryl iodide (bromide).After the regioselective C!H activation of thioazole toform biaryl Pd(II) species 10, reductive elimination occursto afford the desired biaryl product 3 by releasing the Pd(0)species to complete the catalytic cycle.12
In conclusion, we have developed an efficient, ligand-free, and highly regioselective Pd(II)-catalyzed arylation ofthiazole derivatives. The broad substrate scope and ligand-free conditions made this method synthetically useful.Further investigations to gain insight into the reactionmechanism, to promote the efficacy for other thioazlederivatives, and to apply this methodology to the synthesisof biologically active molecules are underway.
Acknowledgment. Support of this work by the 973Project from the MOST of China (2009CB825300) andNSFC (No. 21072010) is gratefully acknowledged.
Supporting Information Available. Experimental pro-cedures and spectral data for all compounds. This mate-rial is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Substrate Scope of Regioselective Arylation of4-Methylthiazole Using Aryl Bromidesa
aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.
Scheme 3. Substrate Scope ofRegioselectiveArylation ofThiazolea
aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.
Scheme 4. Evaluation of the Regioselective Arylation versusDirected ortho-C!H Functionalization of 2-Phenylthiazole
Figure 2. Proposed mechanism for regioselective arylation ofthiazole derivatives.
(10) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int.Ed. 2007, 46, 7996.
(11) (a) Gorelsky, S. I.Organometallics 2012, 31, 4631. (b) Gorelsky,S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658.
(12) To investigate whether the reaction was catalyzed homo- orheterogeneously, a further Hg drop test was performed. It was foundthat, in the presence of an additional 400 mgHg, the reaction proceededalso smoothly, affording the desired product in 50% isolated yield. Thisresult umbiguously demonstrated that this catalytic process was homo-geneous. Refer to: Whitesides, G. M.; Hackett, M.; Brainard, R. L.;Lavalleye, J. P. P. M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.;Brown, D. W.; Staudt, E. M. Organometallics 1985, 4, 1819. The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013 5777
(Scheme 3).Under the optimal reaction conditions, phenyliodide could couple with thiazole but in only 18% yield,whereas the yield can be improved to 47%by elevating thereaction temperature from 100 to 140 !C. In comparison,the p-fluorophenyl iodide and p-methoxyphenyl iodidewere compatible under standard conditions, affording the5-arylated thiazole derivatives in moderate yields (54%and 39%, respectively). However, we failed to improvethe reaction efficiency further at an even higher reactiontemperature (140 !C). Unexpectedly, the sterically hinderedortho-methyl phenyl iodide coupled more efficiently withthiazole specifically at theC-5position inup to60%isolatedyield. Futher studies to promote the efficacy is underway.To further illustrate the regioselective control of our cur-
rent metholodogy, an experiment using 2-phenylthiazole 6as the substrate was carried out (Scheme 4). As expected,the corresponding 5-phenylatedproduct 710was exclusivelyobtained in 44% isolated yield and the otho-phenylatedproduct 8 on the phenyl ring was not observed.
Based on our investigations and previous theoreticalcalculations by Gorelsky,6a,11 the catalytic pathway isconsidered to proceed as shown in Figure 2. After thereduction of the Pd(II) species to aPd(0) species (thismightbe stabilized by the starting thiazole moiety or the corre-sponding product), arylpalladium species 9 is generatedthrough the oxidative addition by aryl iodide (bromide).After the regioselective C!H activation of thioazole toform biaryl Pd(II) species 10, reductive elimination occursto afford the desired biaryl product 3 by releasing the Pd(0)species to complete the catalytic cycle.12
In conclusion, we have developed an efficient, ligand-free, and highly regioselective Pd(II)-catalyzed arylation ofthiazole derivatives. The broad substrate scope and ligand-free conditions made this method synthetically useful.Further investigations to gain insight into the reactionmechanism, to promote the efficacy for other thioazlederivatives, and to apply this methodology to the synthesisof biologically active molecules are underway.
Acknowledgment. Support of this work by the 973Project from the MOST of China (2009CB825300) andNSFC (No. 21072010) is gratefully acknowledged.
Supporting Information Available. Experimental pro-cedures and spectral data for all compounds. This mate-rial is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Substrate Scope of Regioselective Arylation of4-Methylthiazole Using Aryl Bromidesa
aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.
Scheme 3. Substrate Scope ofRegioselectiveArylation ofThiazolea
aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.
Scheme 4. Evaluation of the Regioselective Arylation versusDirected ortho-C!H Functionalization of 2-Phenylthiazole
Figure 2. Proposed mechanism for regioselective arylation ofthiazole derivatives.
(10) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int.Ed. 2007, 46, 7996.
(11) (a) Gorelsky, S. I.Organometallics 2012, 31, 4631. (b) Gorelsky,S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658.
(12) To investigate whether the reaction was catalyzed homo- orheterogeneously, a further Hg drop test was performed. It was foundthat, in the presence of an additional 400 mgHg, the reaction proceededalso smoothly, affording the desired product in 50% isolated yield. Thisresult umbiguously demonstrated that this catalytic process was homo-geneous. Refer to: Whitesides, G. M.; Hackett, M.; Brainard, R. L.;Lavalleye, J. P. P. M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.;Brown, D. W.; Staudt, E. M. Organometallics 1985, 4, 1819. The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013 5777
(Scheme 3).Under the optimal reaction conditions, phenyliodide could couple with thiazole but in only 18% yield,whereas the yield can be improved to 47%by elevating thereaction temperature from 100 to 140 !C. In comparison,the p-fluorophenyl iodide and p-methoxyphenyl iodidewere compatible under standard conditions, affording the5-arylated thiazole derivatives in moderate yields (54%and 39%, respectively). However, we failed to improvethe reaction efficiency further at an even higher reactiontemperature (140 !C). Unexpectedly, the sterically hinderedortho-methyl phenyl iodide coupled more efficiently withthiazole specifically at theC-5position inup to60%isolatedyield. Futher studies to promote the efficacy is underway.To further illustrate the regioselective control of our cur-
rent metholodogy, an experiment using 2-phenylthiazole 6as the substrate was carried out (Scheme 4). As expected,the corresponding 5-phenylatedproduct 710was exclusivelyobtained in 44% isolated yield and the otho-phenylatedproduct 8 on the phenyl ring was not observed.
Based on our investigations and previous theoreticalcalculations by Gorelsky,6a,11 the catalytic pathway isconsidered to proceed as shown in Figure 2. After thereduction of the Pd(II) species to aPd(0) species (thismightbe stabilized by the starting thiazole moiety or the corre-sponding product), arylpalladium species 9 is generatedthrough the oxidative addition by aryl iodide (bromide).After the regioselective C!H activation of thioazole toform biaryl Pd(II) species 10, reductive elimination occursto afford the desired biaryl product 3 by releasing the Pd(0)species to complete the catalytic cycle.12
In conclusion, we have developed an efficient, ligand-free, and highly regioselective Pd(II)-catalyzed arylation ofthiazole derivatives. The broad substrate scope and ligand-free conditions made this method synthetically useful.Further investigations to gain insight into the reactionmechanism, to promote the efficacy for other thioazlederivatives, and to apply this methodology to the synthesisof biologically active molecules are underway.
Acknowledgment. Support of this work by the 973Project from the MOST of China (2009CB825300) andNSFC (No. 21072010) is gratefully acknowledged.
Supporting Information Available. Experimental pro-cedures and spectral data for all compounds. This mate-rial is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Substrate Scope of Regioselective Arylation of4-Methylthiazole Using Aryl Bromidesa
aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.
Scheme 3. Substrate Scope ofRegioselectiveArylation ofThiazolea
aUnless otherwise noted, all reactions were carried out in 0.2 mmolscale in 2 mL of solvent at 100 !C. Isolated yields are given.
Scheme 4. Evaluation of the Regioselective Arylation versusDirected ortho-C!H Functionalization of 2-Phenylthiazole
Figure 2. Proposed mechanism for regioselective arylation ofthiazole derivatives.
(10) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int.Ed. 2007, 46, 7996.
(11) (a) Gorelsky, S. I.Organometallics 2012, 31, 4631. (b) Gorelsky,S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658.
(12) To investigate whether the reaction was catalyzed homo- orheterogeneously, a further Hg drop test was performed. It was foundthat, in the presence of an additional 400 mgHg, the reaction proceededalso smoothly, affording the desired product in 50% isolated yield. Thisresult umbiguously demonstrated that this catalytic process was homo-geneous. Refer to: Whitesides, G. M.; Hackett, M.; Brainard, R. L.;Lavalleye, J. P. P. M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.;Brown, D. W.; Staudt, E. M. Organometallics 1985, 4, 1819. The authors declare no competing financial interest.
10.1021/ol4027073 r 2013 American Chemical SocietyPublished on Web 10/31/2013
ORGANICLETTERS
2013Vol. 15, No. 2257745777
Reigoselective Arylation of ThiazoleDerivatives at 5Position via Pd Catalysisunder Ligand-Free Conditions
Xiang-Wei Liu,, Jiang-Ling Shi, Jia-Xuan Yan,, Jiang-Bo Wei,, Kun Peng, )Le Dai, ) Chen-Guang Li, ) Bi-Qin Wang, and Zhang-Jie Shi*,,
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory ofBioorganic Chemistry and Molecular Engineering of Ministry of Education, College ofChemistry, Peking University, Beijing 100871, China, State Key Laboratory ofOrganometallic Chemistry, ChineseAcademy of Sciences, Shanghai 200032,China, Collegeof Chemistry andMaterial Chemistry, Sichuan Normal University, Sichuan 610066, China,andDSMNutritional Products,DSMNutritionCenter,DSM(China) Limited,No. 476LiBing Road, Zhangjiang Hi-tech Park, Pudong new area, Shanghai, 201203, China
Received September 28, 2013
ABSTRACT
An efficient regioselective arylation of thiazole derivatives via Pd-catalyzed C!H activation is reported. The transformation was hypothesized through aPd(0/II) catalytic cycle in the absence of special ligand sets. This method provided an efficient process to direct arylation of thiazoles at the 5-position.
Selectivity is one of the perpetual research topics inorganic synthesis.1Direct functionalization ofC!Hbondsvia transition-metal catalysis has recently emerged as apowerful and practical alternative to the well-applied Pd-catalyzed cross-coupling reactions (e.g., Suzuki!Miyaura,Stille, and Negishi couplings) owing to the ubiquity ofC!H bonds and the avoidance of prefunctionalization of
the starting materials; thus, considerable interest has beeninstigated in the synthetic community.2 To realize theselective functionalization among multiple C!H bondsthat exist in the substrates and products, current solutionsinvolved either a certain directing group2d,j,3 or an inherentdistinguishedC!Hbond exerted by the electronic nature.4Especially, the directing group strategy has exhibited itsadvantages in the past decades. However, the directinggroups are not always desirable in the target molecule, andthe removal of them is usually indispensible, thus obviouslylimiting their synthetic utility.5 Alternatively, the use ofelectronically activated substrates to enable the selectiveC!H bond activation/functionalizaiton was preferable,especially for the derivatization of heterocyclic aromatics.A thiazole-containing structural motif is frequently
found in biologically active molecules, organic materials,and pharmaceuticals (Figure 1).4o In fact, the elaborationof thiazole has been well documented.6 Recently, signifi-cant developments to carry out C!H activations haveenabled direct arylation of heterocyclics and some beautiful
Peking University.Chinese Academy of Sciences. Sichuan Normal University.
)DSM Nutritional Products, DSM Nutrition Center, DSM (China)Limited.
(1) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.(2) (a)Alberico,D.; Scott,M.E.;Lautens,M.Chem.Rev.2007,107, 174.
(b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,1013. (c) Amii, H.; Uneyama, K.Chem. Rev. 2009, 109, 2119. (d) Chen, X.;Engle,K.M.;Wang,D.-H.;Yu, J.-Q.Angew.Chem., Int. Ed.2009,48, 5094.(e) Colby, D. A.; Bergman, R. G.; Ellman, J. A.Chem. Rev. 2009, 110, 624.(f) Daugulis, O.; Do, H.-Q.; Shabashov, D.Acc. Chem. Res. 2009, 42, 1074.(g)Mkhalid, I.A. I.; Barnard, J.H.;Marder,T.B.;Murphy, J.M.;Hartwig,J.F.Chem.Rev.2009,110, 890. (h)Lyons,T.W.; Sanford,M.S.Chem.Rev.2010, 110, 1147. (i) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010, 111,1293. (j) Ackermann, L.Chem. Rev. 2011, 111, 1315. (k) Engle, K.M.;Mei,T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2011, 45, 788. (l) Yeung, C. S.;Dong,V.M.Chem.Rev. 2011, 111, 1215. (m)Arockiam,P.B.; Bruneau,C.;Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (3) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.
Org. Lett., Vol. 15, No. 18, 2013 4761
electron-withdrawing or electron-donating groups, werecompatiblewith this arylation.However, the electron-pooraryl groups performed better (3na vs 3ne, 3ni vs 3nm).Notably, the reaction exhibited excellent tolerance offunctional group. For example, fluoro (3na, 3nh, 3nm),chloro (3nb), bromo (3nc, 3nk), iodo (3no), trifluoromethyl(3nd, 3nl), and ester (3nn) groups are tolerated, and thedesired products were obtained in moderate to goodyields.14 The ortho-substituted diarylhyperiodonium tri-flates (3nh) were also suitable with a little decrease ofreactivity, which indicated that the considerable effect ofsteric hindrance. It is important to note that the electron-rich heterocyclic group (3np) could be also transferred in agood yield, which highly expanded the substrate scope.To understand the pathway of this arylation better,
we performed KIE experiments. Both intermolecularKIE (3.8) and intramolecular KIE (3.9) indicated theinvolvement of C!H bond cleavage into the rate deter-mining step (see the Supporting Information, eqs 2 and 3).Most importantly, the H/D exchange was examined bysimply heating the substrate 1b in the presence of thecatalyst in the mixed solvent of AcOD/ClCH2CH2Cl.After 24 h at 120 !C, 46% of deuterium incorporationwas observed at position, thus implying the C!Hcleavage in the absence of diarylhyperiodonium triflates
(see the Supporting Information, eq 1). On the basis ofthese preliminary results, a proposed mechanism is shownin Scheme 3. The coordination of the amide 1b withpalladiumcatalyst formed complex 8, which further under-went the C!H activation to produce 9. Diarylhyperiodo-nium salts oxidized the complex 9 to form Pd(IV) complex10. Following by the reductive elimination, the desiredproduct 3abwas generated, releasing the Pd(II) catalyst tofulfill the catalytic cycle.15
In summary, we reported a successful example of Pd-catalyzed primary and secondary sp3 C!H arylation byfirst using diarylhyperiodonium salts as arylation reagents.Various acid derivatives and different diarylhyperiodo-nium reagents were compatible with this arylation. Thismethod could be applied to direct arylation of naturallyimportant structural units, such as the derivatives of aminoacids and oleic acid. Preliminary mechanistic studies in-dicated the possible Pd(II)/Pd(IV) catalytic cycle of thistransformation. These studies provided a new method foran efficient functionalization of unreactive sp3 C!Hbonds and an alternative way to process direct arylationof primary and secondary sp3 C!H bonds under mildconditions. Further efforts to extend the applications ofthis method are underway.
Acknowledgment. We acknowledge financial supportfrom the National Basic Research Program of China(973 Program, 2009CB825300) and the national NSF ofChina (nos. 20925207 and 21002001).
Supporting Information Available. Experimental pro-cedures and NMR spectra analysis of the products. Thismaterial is available free of charge via the Internet athttp://pubs.acs.org.
Scheme 2. Pd-Catalyzed Direct Arylation of sp3 C!H Bondswith Different Diarylhyperiodonium Saltsa
aThe reactions were conducted with 0.20 mmol of 1a, 0.24 mmol of2a, 0.01mmol of Pd(SIMes)(OAc)2, 0.24mmol ofK2CO3, and 2.0mLofClCH2CH2Cl and stirred for 24 h at 120 !C unless otherwise noted.
Scheme 3. Proposed Mechanism (L = SIMes)
(14) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.(15) For selected reviews about Pd(IV) chemistry, see: (a) Mu!niz, K.
Angew. Chem., Int. Ed. 2009, 48, 9412. (b) Xu, L.-M.; Li, B.-J.; Yang, Z.;Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (c) Hickman, A. J.; Sanford,M. S. Nature 2012, 484, 177. The authors declare no competing financial interest.
4760 Org. Lett., Vol. 15, No. 18, 2013
such arylation conditions, arylation on either the aromaticring or biarylated products was not observed.
Subsequently, we examined the effects of the counter-anion of diarylhyperiodonium salts (Table 2). We foundthat tetrafluoroborates (BF4
!), hexafluorophosphates(PF6
!), p-toluenesulfonates (OTs!), or bromides (Br!)could be applied as counterions, and 3aa was obtainedwith lower efficacy (comparing entry 1 to entries 2!5). Thelow yields can be explained by the solubility of each salt inClCH2CH2Cl. Alternatively, the anion may be participatein the rate-limiting proton-abstraction step. To determinethe reactivity of the corresponding ArI from Ar2IOTf,we also tested PhI as an electrophile. The reaction indeedtook place but the efficiency was much lower. This resultindicated that the reactivity of diarylhyperiodonium tri-flates is much higher than that of ArI under the sameconditions (entry 6).With the optimized conditions in hand, we investigated
the scope of amide derivatives (Scheme 1). We found that(1) various substituents with different electronic featuresat the para- position of phenyl showed good to excellentreactivity (3aa!ae), (2) the steric effectweakly affected thistransformation (3ah), and (3) Other 3-heteroaryl substi-tuted amides, such as thiophenyl and furanyl, could also betolerated and the desired arylation products were obtainedin good to excellent yields (3af and 3ag). Thus, startingfrom different amides and diarylhyperiodonium triflates,there are two alternative routes to approach the sameproducts, which might be the complementary methodsfor each other.Since common sp3 C!H bonds, especially secondary
C!H bonds other than the benzylic position, exhibit poorreactivity, we turned to explore the potential reactivitywith aliphatic carboxylic amides (Scheme 1). We firsttested the cyclic substrates and found that 3-membered,4-membered, and 5-membered ring substrates are arylated
smoothly. However, only the double arylations at bothortho positions were observed (3aj!al). The primary sp3C!H bonds of propionyl derivatives also performed well,while only mono- and diarylated products were isolatedas a mixture at a nearly 1:1 ratio (3am). To extend theapplication of this arylation further, different aliphaticcarboxylic acid derivatives were tested. We found that, ingeneral, the length of the chain did not affect the efficacy(3an!aq), unless a very long chain was involved. Thebenzyl and sterically hindered cyclopentyl and isopropylgroups were compatible, which extended the substratescope (3ai, 3ar, and 3as). We further tested the derivativesof protected amino acids. To our delight, direct arylationtook place, and 3at was isolated in a 69% yield. Thenatural oleic acid derivative was also arylated in goodyield, leaving the double bond and allylic C!H bondsuntouched under these oxidative conditions (3au).13
Considering that different substituents with distinctelectronic and steric features may influence the reactivityof the diarylhyperiodonium salts, we then surveyed differ-ent functional groups of diarylhyperiodonium triflates(Scheme 2). Gratifyingly, a variety of symmetrical or un-symmetrical diarylhyperiodonium triflates successfullycoupled with 1n. Different functional groups on the arylgroup of diarylhyperiodonium triflates, nomatter whether
Table 2. Effects of Counteranions.a
entry X yieldb (%)
1 OTf 86
2 BF4 31
3 PF6 30
4 OTs 12
5 Br 13
6 c 37
aThe reactions were conducted with 0.10 mmol of 1a, 0.12 mmol of2a, 0.005mmol of catalyst, 0.12mmol of base, and 1.0mLof solvent andstirred for 24 h unless otherwise noted. bDetermined by crude 1HNMRspectroscopy. cUsing iodobenzene as arylation reagent.
Scheme 1. Pd-Catalyzed Direct Arylation of sp3 C!H Bondswith Different 8-Aminoquinoline Amidesa
aThe reactions were conducted with 0.20 mmol of 1a, 0.24 mmol of2a, 0.01mmol of Pd(SIMes)(OAc)2, 0.24mmol ofK2CO3, and 2.0mLofClCH2CH2C1 and stirred for 24 h at 120 !C unless otherwise noted.
(13) (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (b) Li, H.; Li, B.-J.; Shi,Z.-J. Catal. Sci. Technol. 2011, 1, 191.
Org. Lett., Vol. 15, No. 18, 2013 4761
electron-withdrawing or electron-donating groups, werecompatiblewith this arylation.However, the electron-pooraryl groups performed better (3na vs 3ne, 3ni vs 3nm).Notably, the reaction exhibited excellent tolerance offunctional group. For example, fluoro (3na, 3nh, 3nm),chloro (3nb), bromo (3nc, 3nk), iodo (3no), trifluoromethyl(3nd, 3nl), and ester (3nn) groups are tolerated, and thedesired products were obtained in moderate to goodyields.14 The ortho-substituted diarylhyperiodonium tri-flates (3nh) were also suitable with a little decrease ofreactivity, which indicated that the considerable effect ofsteric hindrance. It is important to note that the electron-rich heterocyclic group (3np) could be also transferred in agood yield, which highly expanded the substrate scope.To understand the pathway of this arylation better,
we performed KIE experiments. Both intermolecularKIE (3.8) and intramolecular KIE (3.9) indicated theinvolvement of C!H bond cleavage into the rate deter-mining step (see the Supporting Information, eqs 2 and 3).Most importantly, the H/D exchange was examined bysimply heating the substrate 1b in the presence of thecatalyst in the mixed solvent of AcOD/ClCH2CH2Cl.After 24 h at 120 !C, 46% of deuterium incorporationwas observed at position, thus implying the C!Hcleavage in the absence of diarylhyperiodonium triflates
(see the Supporting Information, eq 1). On the basis ofthese preliminary results, a proposed mechanism is shownin Scheme 3. The coordination of the amide 1b withpalladiumcatalyst formed complex 8, which further under-went the C!H activation to produce 9. Diarylhyperiodo-nium salts oxidized the complex 9 to form Pd(IV) complex10. Following by the reductive elimination, the desiredproduct 3abwa