Palladium-Catalyzed Chemoselective Activation of sp3 vs sp2 C-H Bonds: Oxidative Coupling to Form Quaternary Centers

Article abstract of DOI:10.1021/acscatal.9b00091

The oxidative activation of alkyl C-H bonds vs arene C-H bonds with Pd(OAc)₂ has been found to be generalizable to a number of nucleophilic substrates, allowing the formation of a range of hindered quaternary centers. The substrates share a common mechanistic path wherein Pd(II) initiates an oxidative dimerization. The resultant dimer modifies the palladium catalyst to favor activation of alkyl C-H bonds, in contrast to the trends typically observed via a concerted metalation-deprotonation mechanism. Notably, insertion occurs at the terminus of the alkyl arene for hindered substrates. Two different oxidant systems were discovered that turn over the process. Parameters have been identified that predict which substrates are productive in this reaction.

Full text of DOI:10.1021/acscatal.9b00091

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Article
Palladium Catalyzed Chemoselective Activation of sp3 vs sp2
C–H Bonds: Oxidative Coupling to Form Quaternary Centers
Gang Hong, PRADIP D NAHIDE, uday kumar neelam, Peter Amadeo, Arjun Vijeta,
John M. Curto, Charles E. Hendrick, Kelsey Faith VanGelder, and Marisa C Kozlowski
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00091 • Publication Date (Web): 08 Mar 2019
Downloaded from http://pubs.acs.org on March 8, 2019
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Page 1 of 10
ACS Catalysis
Palladium Catalyzed Chemoselective Activation of sp3 vs sp2 C–H Bonds: Oxidative
Coupling to Form Quaternary Centers
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Gang Hong, Pradip D. Nahide, Uday Kumar Neelam, Peter Amadeo, Arjun Vijeta, John M.
Curto, Charles E. Hendrick, Kelsey F. VanGelder, and Marisa C. Kozlowski*
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Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States.
Supporting Information Placeholder
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ABSTRACT: The oxidative activation of alkyl C–H bonds vs
arene C–H bonds with Pd(OAc)2 has been found to be
generalizable to a number of nucleophilic substrates allowing
the formation of a range of hindered quaternary centers. The
substrates share a common mechanistic path wherein Pd(II)
initiates an oxidative dimerization. The resultant dimer modifies
the palladium catalyst to favor activation of alkyl C–H bonds in
contrast to the trends typically observed via a concerted
metalation deprotonation mechanism.
Notably, insertion
occurs at the terminus of the alkyl arene for hindered substrates.
Two different oxidant systems were discovered that turn over the process. Parameters have been identified that predict,
which substrates are productive in this reaction.
KEY WORDS: cross dehydrogenative coupling; oxidative coupling; palladium; chemoselective activation; quaternary
Introduction
dehydrogenative coupling forms
a hindered bond
8
(Scheme 1, eq 5). One unique feature of this process is
the catalytic activation of benzylic C–H bonds under
oxidizing conditions with palladium that typically result in
sp2 C–H activation. Another unusual feature is that
coupling occurs at the terminus of the alkyl arene,
presumably via a migration of the palladium center. In this
article, we disclose our discovery of a range of acyclic and
cyclic substrates that can participate in this process to
generate hindered bonds selectively (eq 6). From the
studies undertaken, guidelines are now available to
predict which carbon nucleophiles will be effective.
The use of aromatic hydrocarbons as precursors to the
construction of more complex structures has many
intrinsic advantages. Aromatic hydrocarbons are
inexpensive building blocks readily available from
petroleum. Their direct functionalization to desired
targets avoids the introduction of functional groups such
as halides that require the use of hazardous materials or
generate
undesired
byproducts.
The
aromatic
hydrocarbons are also more stable than the
corresponding functionalized equivalents such as benzylic
halides. For example, naphthylic halide analogs are not
stable and are not readily amenable to SN2 displacement.
Results and Discussion
For these reasons, much research has focused on the
effective use of aromatic hydrocarbons as substrates and
metal catalyzed C–H activation chemistry has played a key
Our analysis of the reaction from eq 5 revealed the
intermediacy of a dimer from the azlactone, which readily
forms under a range of oxidative conditions. Notably,
others have found reactions that also proceed through
dimers similar to those that we reported. Reasoning that
9
1
role. The use of palladium, in particular, has proven highly
10
effective especially in the activation of sp2 C–H bonds of
2
arenes (e.g. Scheme 1, eq 1), even allowing C–H
other substrates which form similar dimeric intermediates
activation of two reaction partners where the only
might
be
subject
to
a
similar
reaction
3
byproduct is dihydrogen. On the other hand, the
activation of the sp3 C–H bonds of aromatic hydrocarbons
by palladium occurs much less readily to the point where
toluene derivatives can undergo selective sp2 C–H
functionalization in the presence of one or more benzylic
Scheme 1. Pd-Catalyzed Activation of Arenes and
Toluenes
4
centers. Strategies to achieve benzylic activation have
5
relied on directing groups (Scheme 1, eq 2), generation
6
of benzylic radicals (Scheme 1, eq 3) , or the lower acidity
7
of benzylic sites (Scheme 1, eq 4).
Recently, we have reported an alternative strategy to
activation
of
aromatic
hydrocarbons
wherein
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Typical Pd CDC via arene insertion
strongly affected by the batch of palladium used. Older
1
2
3
4
5
6
7
8
Pd(OAc)2
pyridine
batches of palladium were highly effective in the
stoichiometric conversion of dinitrile 1a to 3aa with
toluene (Scheme 2), while new batches were not. Different
sources of Pd(OAc)2 are known to give much different
results due to different composition arising from the
preparation, such as the red-brown [Pd3(OAc)5NO2].
[Pd3(OAc)6] is a dark purple solid whereas [Pd(OAc)2]n
(1)
(2)
AcOH/Ac2O
H
OAc
100 °C
Directed Pd CDC benzylic insertion
O
O
Pd(OAc)2, AgOAc
O2, Xylene
N
H
+
ArI
N
H
N
130 °C, 24 h
N
CH3
O
Ar
19
Radical Pd CDC benzylic insertion
polymer is a light grey-purple powder.
9
A
Pd(II)
CO
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CH3
CH2
+
(t-BuO)2
+
A
H
A
O
(3)
(4)
Scheme 3. Catalytic Palladium Oxidative Coupling of

A = NR2, NHR, OR
Malononitriles with Methylarenes (eq 8)
Deprotonative toluene arylation
CN
R2
Ar
NC CN
R2
A
B
or
NIXANTPHOS Pd G3
KN(SiMe3)2
CN
(8)
CH3
+
R1
R1
H3C
Ar Br
110 °C, 12 h
0.1 M
1
2
3
Previous work
A
B
100 mol % Pd(OAc)2, 95 °C, 24 h
20 mol % Pd(OAc)2, 1 equiv 2,6-DMBQ
1 equiv PivOH, charcoal, 115 °C, 48 h
Pd(OAc)2
2,6-DMBQ
PivOH
PMP
PMP
O
O
O
( )
(5)
R
n
O
H3C
Me
N
N
R
( )
NC CN
NC CN
+
NC CN
n
activated C
1,4-dioxane
95 °C, 45 h
H
Ph
Ph
Me
(~20 equiv)
n = 0, 1, 2, 3
MeO
MeO
MeO
This work
A = carbon Nu
3aa
3ab
, A: 36%
3ac
, A: 96%
B: 96%
, A: 59%
B: 65%
Pd(II)
oxidant
B: 27%
A
( )
( )
n
n
(6)
H3C
+
A
H
R
R
OMe

NC CN
NC CN
NC CN
Me
profile (eq 7), the literature was surveyed for compounds
that readily undergo oxidative dimerization. A surprisingly
large number of compounds with similar behavior was
MeO
MeO
Me
3ad
3ae
, A: 50%
B: 32%
, A: 55%
B: 97%
3ba
, A: 85%
11
12
identified
including
malonates,
malononitrile,
13
14
15
16
cyanoacetate, oxindoles, isooxindoles, benzofurans,
Proceeding with older batches of Pd(OAc)2, the para-
methoxyphenyl and para-methylphenyl malononitriles
were found to be effective partners in the coupling of
17
18
fluorenes, and hydroxycoumarins.
Pd(II)
H3C
A
oxidant
(7)
A
A
+
A
H
different toluenes (Scheme 3).
Further, the same

A = carbon Nu
stoichiometric oxidant discovered for the azlactones,
dimethylbenzoquinone (DMBQ), was found to be effective
in turning over the process with catalytic amounts of
Pd(OAc)2. In most cases, similar yields were obtained for
the catalytic vs stoichiometric palladium conditions.
Amongst the xylene isomers, para-xylene (27-36%) was
less effective than meta-xylene (59-65%) or ortho-xylene
(32-50%). In all cases, reactions were conducted until all
starting material was consumed and the mass balance is
decomposition with no specific byproducts being isolable.
Notably, higher yields were obtained under catalytic
conditions for para-methoxytoluene. We speculate that
stochiometric Pd(OAc)2 can cause direct oxidation of the
para-methoxytoluene, which was mitigated with lower
amounts of Pd(OAc)2 in the presence of the mild oxidant
DMBQ.
Acyclic Substrates: Malononitriles. A primary concern
was whether the reaction was restricted to cyclic
nucleophiles. Thus, the initial priority was to explore
acyclic substrates capable of oxidative dimerization.
Malononitriles are also well-known to undergo oxidative
dimerization.12 To probe the fundamental reactivity, trials
were first conducted with stoichiometric Pd(OAc)2 using
dinitrile 1a along with toluene (Scheme 2).
Scheme 2.
Coupling
Variable Yields in Dinitrile Toluene
100 mol % Pd(OAc)2
CN
CN
NC CN
toluene
95 °C, 24 h
19-100%
MeO
MeO
3aa
1a
For ethylbenzene, a divergence in behavior was seen
Good reactivity was observed, but the outcome was
2
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ACS Catalysis
R
relative to our prior report with azlactone (eq 5)8 where
exclusive functionalization of the terminal CH3 position
occurred. With the malononitrile, a mixture of the terminal
(methyl) vs internal (benzylic) products was observed (eq
9). The terminal product is proposed to arise from initial
CN
CO2Et
100 mol % Pd(OAc)2
0.3 M dioxane
EtO2C CN
R
1
2
3
4
5
6
(10)
+
95 °C, 24 h
H3C
Me
Me
4a, 1.0 equiv
EtO2C
2. 20 equiv
5
Me
EtO2C
CN
CN
EtO2C
CN
benzylic insertion followed by -hydride elimination and
Me
20
migratory insertion.
We hypothesize that the driving
7
8
9
Me
Me
Me
force for rearrangement to the terminal position is largely
controlled by formation of the less hindered alkyl
palladium species. However, these results indicate that the
nucleophile also plays a role, where sterically small
nucleophiles can react at either the - or  -positions.
Under stochiometric conditions, there is a preference for
the latter 3ag’, whereas the former 3ag predominates
under catalytic conditions. Under catalytic conditions, the
higher effective concentration of the nucleophile relative
to the palladium species may cause greater capture of the
benzylic intermediate prior to rearrangement.
5aa, 81%
5ab, 38%
5ac, 69%
OMe
Me
EtO2C CN
EtO2C CN
EtO2C
CN
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Me
Me
Me
5ad, 61%
5ae, 42%
5af, 67%
EtO2C
CN
Me
5ag, 33%
Initial trials using the same DMBQ oxidant as described
above for the malononitriles led to poor yields. On the
whole, the -cyanoacetates were less reactive than
malononitriles. As such, high throughput screening was
undertaken to identify an oxidant that would permit
turnover of the process. With varying amounts of
Pd(OAc)2, several oxidants were examined (Scheme 5a)
and K2S2O8 was found to be superior. Having observed
that carboxylic additives improved the yields with the
azlactone substrate,8 presumably by ligating the
palladium to prevent precipitation during the reduction,
both acetic acid and pivalic acid additives were examined.
Further, several solvents (DMF, NMP, 1,4-dioxane, 2-
butanol, diglyme, i-PrOAc) were screened to minimize the
amount of alkylarene employed (see SI). Overall acetic
acid in dioxane performed best. Further examination of
temperature (95, 110, 120 °C) revealed that higher
temperatures (120 °C) were well tolerated causing little
decomposition and higher yields (see SI).
NC CN
CN
CN
CH3
MeO
A or B
MeO
H3C
(9)
1a
3ag
+
NC CN
+
A: 75%, 3ag:3ag' = 1:3
B: 53%, 3ag:3ag' = 3:1
MeO
2g, 0.1 M
3ag'
Acyclic
Substrates:
-Cyanoacetates.
-
Cyanoacetates are also well known to undergo such
dimerizations, although somewhat more slowly.11 To
probe the fundamental reactivity, trials were first
conducted
with
stoichiometric
Pd(OAc)2
using
cyanoacetate 4a along with 20 equivalents of alkylarene
in dioxane (eq 10, Scheme 4). At 95 °C, the reaction with
toluene proceed well (81% yield). Again, para-xylene
(38%) was less effective than meta-xylene (69%) or ortho-
xylene (61%). Substrates with electron-donating groups
(para-methoxytoluene) proceeded with moderate
conversion (42%), but those with electron-withdrawing
groups, such as para-trifluorotoluene or para-
cyanotoluene gave no product. 2-Methylnaphthalene
proceeded well (67%), whereas the more hindered 1-
methylnaphthalene did not work (<10%). In contrast to
the malononitriles, ethylbenzene gave the product arising
exclusively from functionalization of the terminal position
of the alkyl (5ag)
Scheme 5. Optimization of Oxidant for Cyanoacetates
with Alkylarenes.a,b
30 mol %
20 mol %
10 mol %
5 mol %
Pd(OAc)2
e
u
2
O 8
S 2
K 2
)
n
o
Q
B
c
O
-
B
M
t
A
n
g 2
i
O
O
O
u
(
A
q
D
u
o
z
n
u
C
Scheme 4.
Stoichiometric Palladium Oxidative
B
-
t
e
b
Coupling of Cyanoacetates with Alkylarenes (eq 10)
aSubstrate 4a, Pd(OAc)2, 0.1 M toluene, 95 °C, 15 h.
bSphere size correlates with conversion vs an internal
standard (see SI for quantitative values).
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OMe
O
MeS
S
Cl
1
2
3
4
5
6
7
8
S
N
Applying the optimized conditions (eq 11) to a range of
HO
N
SMe
H
toluene substrates (top of Scheme 6) provided results as
good as for the stoichiometric transformation with the
exception of para-methoxytoluene, which likely
undergoes an oxidation side reaction with the K2S2O8. Yet
again, para-xylene (48%) was less effective than meta-
xylene (68%) or ortho-xylene (62%). Further, the catalytic
conditions performed well for several different
cyanoacetates (bottom of Scheme 6) including those
bearing electron-withdrawing groups (5ba) or electron-
donating groups (5da).
O
O
N
N
H
N
H
Cl
H
anti-cancer agent
(Hoffmann-LaRoche)
spirobrassinin
dioxibrassinin
Very good initial results were obtained in the coupling
9
of 3-phenyloxindole (6a) with toluene (eq 13) with
stoichiometric Pd(OAc)2 (see SI). A survey of oxidants
revealed K2S2O8 as highly effective while minimizing
byproduct formation (see SI). In this case, using dioxane
as a solvent was not as effective (see SI), so reactions were
conducted in 0.1 M alkylarene. Further optimization (Table
1) revealed that the palladium catalyst loading could be
lower when a pivalic acid additive and activated charcoal
were employed (entry 6).
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Scheme 6. Catalytic Palladium Oxidative Coupling of
Cyanoacetates with Alkylarenes (eq 11)
20 mol % Pd(OAc)2
CN
1 equiv K2S2O8
1 equiv HOAc
EtO2C
CN
( )n
( )n
(11)
R2
CO2Et
H3C
+
charcoal
0.3 M Dioxane
120 °C, 45 h
R1
R2
R1
n = 0-1
2, 20 equiv
4, 1.0 equiv
EtO2C
5
Me
Table 1. Optimization of 3-Phenyloxindole Toluene
Coupling (eq 12)
EtO2C
CN
CN
EtO2C
CN
Me
Me
Me
Me
Ph
Ph
Pd(OAc)2 (X equiv)
K2S2O8 (Y equiv)
5aa
5ab
, 79%
, 48%
5ac
, 68%
Ph
O
O
+
OMe
(12)
EtO2C
EtO2C
N
N
CN
CN
EtO2C
CN
additive
120 °C, 24 h
H3C
Me
Me
2a. 0.1 M
6, 0.15 mmol
7
Me
Me
Me
Me
5ad
5ae
, 9%
, 62%
5af
, 66%
additive
(equiv)
entry
X
Y
yield (%)b
EtO2C
CN
1
2
3
4
5
6
7
8
9
0.3
0.3
0.2
0.2
0.3
0.2
0.3
0.2
0.2
2
1
2
2
2
2
2
2
2
98 (97)c
76
Me
5ag
, 14%
64
EtO2C
CN
EtO2C
CN
, R1 = CF3, 69%
5ba
, R1 = H,
58%
5ca
5da
PivOH (1)
AcOH (1)
PivOH (1)
AcOH (1)
K2CO3 (1)
NaOAc (1)
72
, R1 = OMe, 62%
R1
80
5ea
, 63%
96d
77d
51
Cyclic Substrates: Oxindoles. Moving away from acyclic
substrates, oxindoles are another class of compounds that
readily dimerize.14 In addition, oxindoles bearing two
substituents at the 3-position are found in natural
products and pharmaceutical targets (Scheme 7).21
Notably, 3-aryl-3-benzyl motif that maps onto this
method has been utilized by Hoffmann-LaRoche.21c
Functionalization of oxindoles has been the focus of much
work, including oxidative methods.22
44
aReaction conditions: 6a (0.15 mmol), 2a (0.1 M),
o
Pd(OAc)2 (X mol %), K2S2O8 (Y equiv) at 120 C for 24 h
under argon. bIsolated yield.
Run twice dActivated
c
charcoal (10x weight of Pd) was added.
Additional 3-substituted oxindoles were synthesized
following literature protocols and were examined in the
coupling with toluene (eq 13, Scheme 8). Different 3-aryl
Scheme 7. Bioactive Oxindole Structures
23
groups
with
both
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Scheme 8. Palladium Oxidative Coupling of Oxindoles
to the oxidative coupling method reported by Li and
workers wherein selective coupling of the oxindole
1
2
3
4
5
6
7
8
24
with Toluene (eq 13)
R1
R1
occurs via
a
Friedel-Crafts reaction results in
A: 150 mol% Pd(OAc)2
B: 20 mol % Pd(OAc)2,
2 equiv K2S2O8,
1 equiv PivOH,
A or B
Ph
functionalization of the arene C–H of toluene rather than
the benzylic C–H. The 2-naphthyl substrate formed
product (7ma) in high yield whereas the hindered 1-
naphthyl substrate reacted poorly.
O
O
(13)
0.1 M toluene
120 °C, 24 h
N
Me
N
Me
charcoal
6
7
Me
Me
Heterocyclic groups could also be employed at the 3-
position including a case with a nitrogen substituent (7na-
7pa). The oxindole could also be employed directly
without protection of the nitrogen (7qa) or with other
protecting groups (7ra, 7sa); however, the Boc group was
somewhat unstable at the high reaction temperatures.
Me
Ph
9
Ph
O
Ph
Ph
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
O
O
N
Me
N
Me
N
Me
N
Me
7aa, A: 98%
7ba, A: 93%
7ca, A: 88%
7da, A: 45%
B: 96%
B: 93%
B: 67%
B: 32%
Similar trends were observed again with different
arylalkanes with improved outcomes for ethylbenzene (eq
14, Scheme 9). Varying toluene, poor reactivity was again
observed for substrates with electron-withdrawing groups
such as para-methylbenzonitrile and para-chlorotoluene.
The reaction was also unsuccessful for 2-methylfuran. To
probe the -hydride elimination and rearrangement,
isobutylbenzene was examined. As expected, the addition
of steric hindrance abrogated reactivity.
F
Me2N
MeO
Ph
Ph
Ph
Ph
Ph
O
N
O
O
O
N
N
N
Me
Me
Me
7fa, A: 97%
B: 73%
Me
7ga, A: 98%
B: 80%
F3C
7ea, A: 50%
7ha, A: 98%
B: 6%
B: 65%
NC
Cl
F
Ph
Ph
Ph
Ph
Scheme 9. Palladium Oxidative Coupling of Parent
O
O
O
O
Oxindole with Alkylarenes (eq 14)
N
N
N
N
R2
Me
7ka, A: 91%
B: 63%
Me
Me
Me
Ph
R2
7la, A: 75%
7ia, A: 95%
7ja, A: 87%
Ph
A or B
B:89%
B: 98%
B: 88%
( )n
O
(14)
O
+
120 °C
24 h
H3C
( )n
2, 0.1M
N
N
Me
S
Me
Me
Me
6a
7
O
N
Me
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
O
O
O
O
Me
N
N
N
O
O
O
N
Me
Me
Me
N
Me
N
N
Me
Me
Me
7ma, A: 99%
7na, A: 9%
7oa, A: 41%
7pa, A: 58%
7ac, A: 61%
7ad, A: 62%
B: 83%
B: 34%
7ab, A: 37%
B: 48%
B:36%
Ph
Ph
Ph
Ph
Ph
O
Ph
O
OMe
O
N
O
N
O
O
N
N
N
N
Me
Me
7ag, A: 68%
B: 46%
Me
7af, A: 11%
H
Boc
Bn
7ae, A: 41%
7qa, A: 92%
7ra, A: 68% (95 oC)
7sa, A: 99%
B: 39% (95 oC)
B:94%
B: 98%
Cyclic Substrates: Benzofuranones. Benzofuranones
are isoelectronic with oxindoles and also exhibit oxidative
dimerization behavior.16 They are found in a number of
natural products and pharmaceutical targets (Scheme
electron-donating and electron-withdrawing substituents
were well tolerated leading to high yields under both
stoichiometric and catalytic conditions (7aa-7ma). For
example, generation of the oxindole cation initiates a
Friedel-Crafts reaction with arenes; such a pathway cannot
incorporate toluene at the benzylic carbon. Notably, this
approach to 7ba, 7fa and similar structures is orthogonal
25
10).
Scheme 10. Bioactive Benzofuranone Structures
5
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O
R2
R1
OH
R3
O
R2
O
R1
1
2
3
4
5
6
7
8
HO
A or B
R3
( )n
O
O
O
(15)
OH
OH
O
OHC
120 °C
24 h
H3C
O
( )n
2, 0.1M
A 100 mol % Pd(OAc)2
O
OH
O
NH
HO
HO
O
8
9
O
O
O
OHC
B
20 mol % Pd(OAc)2, 2 equiv K2S2O8, 1 equiv PivOH, charcoal
OH
(+)-Hopeahainol A
Ph
Ph Ph
Rosmadial
(R)-Fumimycin
Me
Et
O
O
O
Using the same conditions developed for the oxindoles,
toluene coupled very well with the parent 3-
O
O
O
9
9aa, A: 94%
9ba, A: 97%
9ca, A: 94%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
B: 91%
B: 95%
B: 90%
phenylbenzofuranone
to
generate
9aa
under
Ph
Ph
Ph
O
stoichiometric or catalytic conditions in 94% and 91%
yield, respectively. Substrates varying the core ring
system substituents (top Scheme 11) or the 3-aryl group
i-Pr
t-Bu
MeO
O
O
O
O
O
9da, A: 95%
9ea, A: 93%
9fa, A: 98%
26
(middle Scheme 11) were generated and were found to
B: 90%
B: 89%
B: 93%
couple with toluene very well. Electron-donating (9fa, 9ja-
9la) and electron-withdrawing groups (9ga, 9ha) could be
employed. Notably, chloro groups could be employed
providing an opportunity for further derivatization (9ha).
Lower catalyst loadings could also be employed, but
required longer reaction or resulted in lower yields (for
9ba with 5 mol % Pd(OAc)2, 59% and 75% product were
obtained at reaction times of 24 h and 48 h, respectively).
Ph
Ph
Ph
F
Cl
O
O
O
O
O
O
Me
Me
9ia, A: 93%
9ga, A: 96%
9ha, A: 97%
B: 98%
B: 97%
B: 89%
O
MeO
MeO
O
i-Pr
t-Bu
t-Bu
A similar scope was seen with different alkylarenes as
had been observed in the cases above (bottom, Scheme
11).
O
O
O
O
O
9la, A: 93%
O
9ja, A: 92%
9ka, A: 94%
B: 86%
B: 90%
B: 89%
Scheme 11.
Palladium Oxdiative Coupling of
Me
Ph
Benzofuranones with Alkylarenes (eq 15)a
Ph
Me
O
O
O
O
Me
9ac, A: 76%
B: 54%
9ab, A: 67%
Ph
Ph
B: 41%
Me
O
O
O
O
9ad, A: 72%
9be, A: 43%
B: 58%
B: 34%
aFor 9ba, using conditions B with 5 mol % Pd(OAc)2, 59% and
75% product were obtained at reaction times of 24 h and 48 h,
respectively.
Substrate Properties Correlated with Reactivity. In
our prior report, the dimer of the azlactone (eq 5) was
found to form under reaction conditions. When isolated
and resubjected to the reaction conditions, this dimer also
converted to product. The corresponding dimers were
observed in the conversion of substrates 1, 4, 6, and 8
although very little of the dimer built up during the
conversion of oxindoles 6 or benzofuranones 8. The dimer
(10) of -cyanoacetate 4a was readily formed with
oxidants and was independently synthesized (Scheme 12)
with Cu(TMEDA)ClOH. Resubjection of dimer 10 to the
reaction conditions with Pd(OAc)2 and toluene again
afforded the product 5aa (Scheme 12).
Scheme 12. Dimer Intermediate from Cyanoacetate
Substrate
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CN
CO2Et
Me
or above 15 kcal/mol did not form product. That
CN
EtO2C
Cu(TMEDA)Cl(OH)
MeOH
1
2
3
4
5
6
7
8
9
compounds with stronger dimer BDE values did not
generate product, even when the dimer was preformed
(see Scheme 13) indicates that the oxidizing power of the
dimer is not the most important factor. Furthermore, the
relative reactivity of the substrates in entries 3-11 followed
the order of the dimer BDE values as judged by TLC
monitoring.
CO2Et
NC
Me
rt
Me
4a
EtO2C
10, 51%
CN
50 mol % Pd(OAc)2
0.1 M toluene
Me
95 °C, 15 h
5aa, 66%
(26% SM, 8% dimer)
Heating the dimer with toluene alone did not form the
product. Similarly, subjection of substrate under the
catalytic conditions without Pd(OAc)2 did not form the
product. For example, when oxindole 6a was treated with
2 equiv K2S2O8, 1 equiv PivOH, charcoal, in 0.1 M toluene
for 24 h at 120 °C, the outcome was 73% unreacted 6a,
25% dimer, and 0% product. Thus, it appears that
Pd(OAc)2 plays a role in the C–H activation event of the
toluene as well as in dimerization of the nucleophilic
substrate.
Competition experiments between substrates were
performed to probe the role of BDE values (Scheme 14).
Reaction from the monomer and dimer gave different
outcomes, consistent with two separate steps
contributing to the overall rate: dimerization by palladium
and reaction of the dimer with a palladium alkyl. For all
pairs, the substrates with the stronger BDE values were
less reactive.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 14. Competition Experiments
Calculations of the bond dissociation energy (BDE)
values for a range of potential nucleophilic substrates was
undertaken (Table 2).
PMP
O
PMP
Ph
O
NC CN
PMP
NC CN
PMP
1 equiv
Pd(OAc)2
O
O
Ph
+
N
N
R
R
If the ability to undergo
Ph
+
Ph
toluene
95 °C, 18 h
1a
1 equiv
13
3aa
18
dimerization via nonionic processes is the most important
factor in determining reactivity, then the substrate C–H
bond dissociation energy should correlate with reactivity
in the overall process. A survey of all the substrates in
Table 2, revealed that only entries 3-11, possessing C–H
bond dissociation energies in the range of 61.0-71.6
kcal/mol, were effective in the transformation. Substrates
with similarly weak C–H bonds (entries 1-2, and to a lesser
extent, entries 12, 14), were found to be unreactive. All of
these compounds have weaker bond dissociation
energies than toluene (90 kcal/mol),27 which accounts for
why dimer alone (see above) is unable to activate toluene.
1 equiv
65.1 kcal/mol > 60.8 kcal/mol R = H
35%
19%
54%
13%
>
5.3 kcal/mol
2.4 kcal/mol R = dimer
1 equiv
NC CN
EtO2C CN
Pd(OAc)2
NC CN
EtO2C CN
Ph
Ph
+
PMP
R
R
PMP
+
toluene
95 °C, 18 h
Me
Me
1a
1 equiv
4a
3aa
5aa
1 equiv
65.1 kcal/mol < 70.7 kcal/mol R = H
84%
43%
trace
trace
5.3 kcal/mol < 13.0 kcal/mol R = dimer
1
aYields from H NMR using 4,4‘-di-t-Bubiphenyl as an
internal standard.
To further probe the importance of the initial oxidation
to the dimer, the dimer of 6u was independently
28
synthesized and resubjected to the reaction conditions
Table 2. Bond Dissociation Energies of A-H and A-A
in a similar manner as outlined in Scheme 8. Similar to
monomer 6u, the dimer of 6u did not convert to the
product in the presence of Pd(OAc)2 (Scheme 13)
indicating that dimerization is necessary, but not sufficient
in order for the process to occur.
dimer
monomer
Entr
y
BDEa,b
(kcal/mol
)
A–H
BDEa
(kcal/mol)
Scheme 13. 3-Benzyloxindole Dimer with Pd(OAc)2
Ph
H
N
Me
N
Me
1
71.9
0.8
O
A or B
No Reaction
O
Ph
11
0.1 M toluene
120 °C, 24 h
Ph
O
Ph
H
N
A: 150 mol% Pd(OAc)2
Me
6u-dimer
2
3
71.0
60.8
1.4
2.4
B: 20 mol % Pd(OAc)2, 2 equiv K2S2O8,
1 equiv PivOH, charcoal
12
13
PMP
O
The dimer BDE values were also computed and
correlated more strongly with reactivity (Table 2).
Substrates with dimers BDE values either below 2 kcal/mol
O
N
H
Ph
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Page 8 of 10
NC CN
H
The discovery of a range of nucleophilic substrates that
1
2
3
4
5
6
7
8
can engage in the oxidative activation of alkyl C-H bonds
vs arene C–H bonds with Pd(OAc)2 has been described.
This process uses inexpensive alkylarene precursors
derived from petroleum and allows the formation of a
range of hindered quaternary centers. All of the substrates
react by an initial oxidative dimerization initiated by the
Pd(OAc)2 and/or the terminal oxidant. A number of
terminal oxidants are compatible with the process with
DMBQ or K2S2O8 being the most effective to date. The
resultant dimer modifies the palladium catalyst to favor
activation of alkyl C-H bonds in contrast to the trends
4
5
65.1
67.9
5.3
7.4
MeO
1a
8a
H
O
O
R
6f, R =
OMe
6
7
68.1
69.0
69.5
69.6
69.8
8.7
9
6b, R =
Me
10.0
10.5
10.8
11.4
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
8
6a, R = H
N
Me
9
6l, R = CN
typically observed via
a
concerted metalation
6k, R =
CF3
10
deprotonation mechanism. Notably, insertion occurs at
the terminus of the alkyl arene for hindered substrates via
-hydride elimination/migratory insertion, a pathway that
is not typically seen in oxidative palladium chemistry. The
bond dissociation energies of the dimeric intermediates
have been identified that predict which substrates are
productive in this reaction. These guidelines allow
rationale selection of substrates to employ in this method
and further mechanistic studies are underway to
understand the discrete steps of this unusual and complex
mechanism.
NC CO2Et
H
11
12
70.7
71.7
13.0
22.6
Me
MeO2C
4a
H
O
O
14
MeO2C
H
O
13
14
72.1
79.1
22.7
24.1
N
Ac
15
16
EtO2C CO2Et
H
ASSOCIATED CONTENT
Supporting Information. Experimental procedures for all
experiments and characterization data. This material is
available free of charge via the Internet at
http://pubs.acs.org.
Ph
H
O
15
74.7
26.3
N
Me
6u
O2N CO2Et
H
AUTHOR INFORMATION
16
17
81.9
78.2
27.9
38.6
Corresponding Authors
17
marisa@sas.upenn.edu
H
H
O
ACKNOWLEDGMENT
O
8m
We are grateful to the NSF (CHE1464778, CHE1764298) and
the NIH (GM-08765) for financial support of this research.
Partial instrumentation support was provided by the NIH and
NSF (1S10RR023444, 1S10RR022442, CHE-0840438, CHE-
0848460, 1S10OD011980) and computational support by was
provided by XSEDE (TG-CHE120052). G.H., P.N., U.N.K., and
A.V. thank the Chinese Scholarship Council, the University of
Guanajuato and CONACyT, Dr. Reddy’s Laboratories (Dr.
Rakeshwar Bandichhor), and the S. N. Bose Scholarship
Program of India, respectively, for financial support. Drs.
Rakesh Kohli and Charles W. Ross III are acknowledged for
obtaining accurate mass data.
aComputed at uB3LYP/6-31G*. bMeso diastereomer.
All told, it appears that the dimer must be able to
fragment readily, hence the poor results with compounds
with higher dimer BDE (Table 2, entries 12-17). The poor
results with dimers that cleave very readily (entries 1-2)
are consistent with two scenarios. The dimer may play a
partial role in assisting the palladium activation of toluene,
in which case a modest oxidizing power is needed which
the dimers of 11 and 12 lack. Alternately, the captodative
radical from homolysis of the dimer must engage the
palladium alkyl intermediate and cannot do so if it is too
stable, as manifested in very low dimer BDE values.
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