Insight into the palladium-catalyzed oxidative arylation of benzofuran: Heteropoly acid oxidants evoke a Pd(II)/Pd(IV) mechanism

Article abstract of DOI:10.1016/j.tet.2013.02.061

The effects of oxidant and organic acid additives on the oxidative cross-coupling reactions of electron rich heterocycles, such as benzofuran with benzene were studied. Both regioselectivity and reaction rate could be controlled by varying the condition p

Full text of DOI:10.1016/j.tet.2013.02.061

Tetrahedron 69 (2013) 4429e4435
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Insight into the palladium-catalyzed oxidative arylation of
benzofuran: heteropoly acid oxidants evoke a Pd(II)/Pd(IV)
mechanism
,
b
Kyle C. Pereira a, Ashley L. Porter a, Shathaverdhan Potavathri a, Alexis P. LeBris a
,
,
Brenton DeBoef a
*
a University of Rhode Island, Department of Chemistry, 51 Lower College Road, Kingston, RI 02881, USA
b St. Luke’s School, 377 North Wilton Road, New Canaan, CT 06840, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The effects of oxidant and organic acid additives on the oxidative cross-coupling reactions of electron
rich heterocycles, such as benzofuran with benzene were studied. Both regioselectivity and reaction rate
could be controlled by varying the condition parameters. Furthermore, mechanistic insight was achieved
via kinetic studies, which indicate that reactions that are oxidized by the heteropoly acid H4PMo11VO40
operate via a Pd(II)/Pd(IV) mechanisms, while reactions oxidized by either AgOAc or Cu(OAc)2 operate by
a Pd(II)/Pd(0) mechanism.
Received 10 December 2012
Received in revised form 14 February 2013
Accepted 18 February 2013
Available online 26 February 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
CeH functionalization
Biaryl synthesis
Heteropoly acid
Palladium(IV)
1. Introduction
these reactions is an aryl iodide or bromide, and more than 1 equiv
of this pre-functionalized arene is often required.
A consortium of process chemists from major pharmaceutical
companies recently indicated that green coupling reactions in-
volving carbonehydrogen (CeH) bond activation for the formation
of carbonecarbon (CeC) bonds were the highest-priority ‘aspira-
tional’ research area for new reaction development.1 The current
best methods for forming biaryl CeC bonds are well known and
widely used, namely the Suzuki, Kumada, and Negishi coupling
reactions. Each of these processes are catalyzed by palladium and
involve one arene substrate that contains a halogen or pseudo-
halogen; the second substrate has been metalated or borylated. The
metal and halogen atoms of the substrates only serve to activate the
substrates for the palladium catalyzed coupling, as they are re-
moved during the course of the reaction and become part of the
waste stream. Particularly when heavy halogens are employed,
such as iodine, the waste associated with these coupling reactions
can become problematic. Numerous groups have disclosed
methods for direct arylation reactions that employ one unfunc-
tionalized arene, formally activating the CeH bond of one of the
substrates.2 Unfortunately, the other substrate for the majority of
The ideal process for synthesizing biaryls would be the oxidative
coupling of two unfunctionalized substrates (Scheme 1). We and
others have recently disclosed that such oxidative couplings are
possible, and are often regioselective.3 While it is tempting to view
these reactions as nearly ideal, in terms of atom economy, the
stoichiometric oxidants that are often required contribute to the
waste of the cross-coupling reaction. The best aspect of these re-
actions, in terms of green chemistry, is the fact that they do not
require pre-functionalized substrates, so oxidative couplings re-
duce the total number of synthetic steps required to form a CeC
Borylation
B(OH)2
R
H
R
Suzuki
Coupling
Halogenation
I
Direct
Arylation
Oxidative Coupling
H
R
* Corresponding author. Tel.: þ1 (401)874 9480; fax: þ1 (401)874 5072; e-mail
Scheme 1. Process economy of oxidative coupling.
address: bdeboef@chm.uri.edu (B. DeBoef).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.061

4430
K.C. Pereira et al. / Tetrahedron 69 (2013) 4429e4435
bond. This process economy has the potential to significantly
streamline the synthesis of biaryls both in terms of cost and
E-factor.
The most active conditions for the oxidative arylation of ben-
zofuran (Table 2, Class I) involve the use of a catalytic poly-
oxometalate oxidant, H4Mo11VO40 (HPMV), in an acidic medium.
We hypothesized that this high catalytic activity was correlated to
the acidic environment (no metal acetate oxidants).
1.1. Classification of oxidative coupling conditions
Acidic reactions that are buffered by superstoichiometric
amounts of AgOAc or Cu(OAc)2 (Class II) perform oxidative cou-
plings well, but are often complicated by the formation of by-
products, such as dimers and acetoxylated species. The use of the
same organometallic oxidants in a neutral solvent (dioxane) pro-
duces a relatively mild reaction medium (Class III). However, the
lack of a Brønstead acid in this system is accompanied by a signifi-
cant loss of catalytic activity. Higher catalyst loadings are often
required, and both longer reaction times and incomplete conver-
sions are often observed.
Our preliminary work in the field of palladium-catalyzed oxi-
dative cross couplings was fruitful, but also perplexing, in that we
discovered four different reaction conditions, each optimized for
the regioselective production of a different arylated heterocycle.
Fagnou, Dong, Zhang and others have also discovered a variety of
other palladium-catalyzed oxidative coupling reactions; however,
the catalysts for the processes are often similar to those shown in
Table 1.4
Table 1
In addition to the activity of the catalyst varying, the selectivity
Comparison of conditions for oxidative cross coupling of arenes4aec
of the reaction also varies from Class
I to III, with 2-
H
H
phenylbenzofuran 2 being favored at high acid concentrations
(Class I) and 3-phenylbenzofuran 3 being favored in non-acidic
conditions (Class III). With this rubric in hand, we set out to de-
termine the exact role of the acidity of the solvent and the oxidant
in the oxidative cross-coupling reactions. The studies described
below indicate that the mechanism by which the reaction proceeds
is directly correlated to both the acidity of the reaction media and
the nature of the oxidant.
Oxidative Coupling
Conditions
H
X
X
cat. Pd(OAc)2
Oxidant, Solvent
+
+
120 o
C
H
(excess)
X
Entry Solvent Oxidant
Major product
Regioselectivity
1
2
3
AcOH
10 mol % H4PMo11VO40
(HPMV), O2
>99:1 (Ref. 4a)
2. Results and discussion
O
2.1. The relationship between acid additive and both activity
and regioselectivity
PivOH
AgOAc (3 equiv)
3:1 (Ref. 4c)
N
SEM
Our initial studies focused on the role of the acid in Class I and
Class II reactions. It should be noted that the HPMV oxidized re-
actions (Class I conditions) presumably operate by an oxidative
relay, as the vanadium-based oxidant, which is only present in
catalytic quantities, is constantly regenerated by the O2 atmo-
sphere.5 The 3 atm pressure that is used in these reactions is not
necessary; we have observed that reactions containing only 1 atm
of O2 proceed well, but they stall because under these conditions,
O2 becomes the limiting reagent. Consequently, we have found it to
be convenient to simply run the reactions at moderate pressures of
O2 to provide a sufficient supply of the terminal oxidant.
Dioxane AgOAc (4 equiv)
Dioxane Cu(OAc)2 (4 equiv)
N
3.6:1 (Ref. 4b)
O
Me
4
4:1 (Ref. 4b)
N
O
Me
We hypothesized that the variety of conditions shown in Table 1
can be classified into three categories based on their relative ac-
tivity with our standard substrate, benzofuran (Table 2). We pro-
posed that benzofuran was an excellent choice for comparing these
reactions because of its reactivity in all of the reaction conditions
and because it, unlike its indole counterparts, was not prone to
decomposition.
Reactions under both Class I and Class II conditions were per-
formed in parallel and stopped after 3 h. Each of the reactions
contained 3 equiv of a carboxylic acid in the presence of gross ex-
cess of benzene (solvent). The AgOAc and HPMV oxidized reactions
displayed opposite reactivity preferences with respect to the sterics
of the carboxylic acid additive (Table 3). The conversion of the Class
II reactions increased as the size of the carboxylic acid increased,
though it appeared to reach a maximum at isobutyric acid (entry 3).
Table 2
Classification of oxidative coupling conditions
H
H
Table 3
Oxidative Coupling
Percent conversion as a function of organic acid
Conditions
H
O
O
Entry
Organic acida
% Conversion, Ratio 2:3
(Time) with AgOAcb
% Conversion,
Ratio 2:3 (Time)
with HPMVc
2
10 mol % Pd(OAc)2
Oxidant, Solvent
1
+
+
120 o
C
H
(excess)
O
3
1
2
3
4
5
6
7
AcOH (3 equiv)
44%, 1.6:1 (40 min)
77%, 1.7:1 (40 min)
85%, 1.6:1 (40 min)
50%, 1.2:1 (40 min)
97%, 1.8:1 (40 min)
98%, 1.2:1 (120 min)d
42%, 69:1 (3 h)
43%, >99:1 (3 h)
25%, >99:1 (3 h)
30%, >99:1 (3 h)
EtCO2H (3 equiv)
i-BuCO2H (3 equiv)
PivOH (3 equiv)
PivOH (10 equiv)
PivOH (10 equiv)
PivOH (20 equiv)
Class
Increasing Activity
I (acidic)
II (buffered)
III (basic)
Oxidant
Solvent
% Yield (2:3)
Reaction time
HPMVþO2
AgOAc or Cu(OAc)2
AcOH or PivOH
84% (1:1)a,b
3 h
AgOAc or Cu(OAc)2
Dioxane
AcOH or PivOH
81% (>99:1)a
25 min
77%, >99:1 (6.5 h)
84% (1:6)b
12 h
a
1 equiv.
b
c
AgOAc (3 equiv ), 120 ꢀC (MW).
HPMV (10 mol %), 3 atm O2, 120 ꢀC (oil bath).
AgOAc (3 equiv), 3 atm O2, 120 ꢀC (oil bath).
a
AcOH solvent.
AgOAc (4 equiv).
b
d

K.C. Pereira et al. / Tetrahedron 69 (2013) 4429e4435
4431
Class I reactions, oxidized by HPMV, tended to be more active with
smaller carboxylic acid additives (entries 1 and 2).
As shown in Fig. 3, the reactions that were oxidized by AgOAc
yielded the 3-phenyl product 3 when no acid was present in the
reaction, though very low conversions were observed (Class III
conditions). A nearly equal mixture of 2 and 3 was produced when
acid was introduced to the reaction (Class II conditions). As ob-
served with the Class I reactions, the AgOAc oxidized conditions
became more reactive as the organic acid concentration increased.
Consequently, there is no advantage to using any amount of acidic
additive beyond 3 equiv, as the rate of the reaction will be com-
parable and the selectivity of the process is not affected by acidic
additives. These data led us to optimize conditions for oxidatively
arylating acid-sensitive substrates, such as N-alkylindoles, the de-
tails of which were recently published.4c
Interestingly, the observed rates for reactions containing AgOAc
were 4.5 times faster than those containing HPMV, as they both
reached w40% conversion in 40 min and 3 h, respectively (Table 3,
entry 1). The rate enhancements for the AgOAc reactions (Class II
conditions) were not simply caused by the microwave heating, as
comparable reactions in an oil bath took only twice as long to
complete (Table 2, entries 5 and 6). When AgOAc was used with
10 equiv of PivOH, 40 min of microwave (MW) heating were re-
quired to achieve 97% conversion; whereas, HPMV with 20 equiv
PivOH required 6.5 h (3 atm O2) in an oil bath to achieve 77%
conversion (entries 6 and 7).
Though the activity of the catalysts was directly coupled to the
sterics of the organic acid additive, the selectivity of the reactions
was not. Reactions employing AgOAc as the oxidant provided ap-
proximately 1.5:1 ratios of the two regiomers, 2 and 3, while re-
actions oxidized by HPMV produced the 2-phenyl product 2 nearly
exclusively (Table 3).
H
H
10 mol % Pd(OAc)2
AgOAc (3 equiv)
H
O
O
2
PivOH (x equiv)
1
+
+
120 oC, 1.5 h
The correlation between the concentration of the organic acid
and the observed rate of the oxidative cross-couplings was con-
firmed for both Class I and Class II reaction conditions (Figs.1 and 2).
A series of identical reactions were performed where the only var-
iable was the amount of organic acid that was added to the reaction.
HPMV/O2 oxidized reactions were accelerated by the presence of
either acetic or pivalic acid. Only the 2-phenyl product 2 was ob-
served for all of the data points with the Class I reactions.
H
(excess)
O
3
H
10 mol % Pd(OAc)2
H
10 mol % HPMV
H
O
O
AcOH (x equiv)
1
+
2
120 oC, 1.5 h
Fig. 3. Class II conditions: effect of PivOH concentration.4c
only product
(excess)
2.2. Kinetic studies
We next investigated the role of oxidant and catalyst loading on
the rate of the reaction (Fig. 4). An ‘inverse-induction period’ for the
Class I conditions was observed. Induction periods are often ob-
served in catalytic reactions, and they are marked by slow con-
version at early reaction times while the active catalyst forms in
situ; this period is then followed by an increase in the reaction rate.
We observed the opposite trend: the first catalytic turnover was
rapid and regeneration via oxidation was then rate-limiting (Fig. 4).
Doubling the catalyst loading caused the conversion during the
Fig. 1. Class I conditions: effect of AcOH concentration.
H
x mol % Pd(OAc)2
y mol % HPMV
H
H
H
10 mol % Pd(OAc)2
10 mol % HPMV
O
H
O
PivOH (10 equiv)
120 oC, 1.5 h
H
1
+
2
O
O
PivOH (x equiv)
1
+
only product
(excess)
2
120 oC, 1.5 h
only product
(excess)
Fig. 2. Class I conditions: effect of PivOH concentration.
Fig. 4. Class I conditions: kinetic studies.

4432
K.C. Pereira et al. / Tetrahedron 69 (2013) 4429e4435
inverse-induction period to also double. Furthermore, upon dou-
bling the oxidant, the rate of the first catalyst turnover remained
the same, however the rate of the reaction following the inverse-
induction period doubled. Following the inverse-induction period,
the HPMV catalyzed reaction displayed zeroth order kinetics, in-
dicating that the rate-determining step of the overall process was
the HPMV-mediated catalyst oxidation. If one of the two CeH
palladations were rate-limiting, an increase in the overall rate of
the reaction would be observed when the palladium loading was
increased. These data indicate that the reaction is first order in both
palladium and HPMV.
Quite different results were observed with AgOAc mediated
reactions (Fig. 5). The rate-limiting step of the overall reaction was
not catalyst regeneration. Unfortunately, it was difficult to perform
kinetic studies to ascertain the orders of each of the reactants, as
the AgOAc in these reactions is not completely dissolved. However,
when the oxidant loading was reduced by 50%, the initial reaction
rate remained nearly the same, indicating that the oxidant was
likely not involved in the rate-determining step, as opposed to the
HPMV-mediated reaction. Doubling of the palladium loading ap-
proximately doubled the initial reaction rate. These data lead us to
postulate a first order dependence on the palladium catalyst con-
centration and zero order dependence for oxidant loading.
classes produce different regioisomers of phenylbenzofuran, with
the acidic conditions favoring 2, the buffered conditions producing
a mixture of regiomers and the basic conditions favoring 3. In-
terestingly, the buffered Class II conditions employing AgOAc pro-
duced a near equal mixture of 2 and 3, while Class II conditions
employing Cu(OAc)2 yielded 3, as the major product. These data led
us to speculate that the oxidant was associated with or was influ-
encing the structure of the palladium catalyst during the benzo-
furan metalation step.4b,e,6
To assess whether the oxidant could also be influencing the
palladation of the benzene substrate, we performed two competi-
tion studies. Equimolar amounts of p-dimethoxybenzene and
p-xylene were reacted with benzofuran in reactions oxidized by
HPMV, AgOAc and Cu(OAc)2 (Class I and II conditions). Class III
conditions were not screened because HPMV is insoluble in non-
polar solvents like dioxane (Table 4).
Table 4
Competition reactions
R1
R1
10 mol % Pd(OAc)2
Oxidant
+
O
O
+
R2
1
+
R1
AcOH (1 equiv)
120 oC, 1.5 h
H
O
H
x mol % Pd(OAc)2
AgOAc (y equiv)
H
O
O
R1
R1
Oxidant
Major
Prod. Ratio
2
PivOH (x equiv)
1
product
+
+
120 oC, 1.5 h
H
MeO
(excess)
MeO
Me
O
3
1
2
10 mol %
HPMV, O2
3.5:1
2.9:1
OMe
OMe
OMe
OMe
OMe
OMe
Me
O
MeO
MeO
Me
AgOAc
(3 equiv)
Me
O
MeO
MeO
Me
Me
F
3
4
Cu(OAc)2
(3 equiv)
9:1
O
F
F
10 mol %
3.5:1
HPMV, O2
F
F
O
F
F
F
F
F
F
F
F
F
5
6
AgOAc
(3 equiv)
2.4:1
1.2:1
F
O
Fig. 5. Class II conditions: kinetic studies.
F
F
F
F
F
F
F
F
F
All of these data taken together indicate that reactions using
Class I, Class II, and Class III conditions are very different. Reactions
oxidized by HPMV are better facilitated by AcOH, whereas, AgOAc
performs better when used with sterically hindered organic acids,
such as i-BuCO2H or PivOH. This provides evidence that AgOAc and
HPMV likely oxidize palladium intermediates through orthogonal
mechanisms.
Cu(OAc)2
(3 equiv)
F
O
For competitions between the two electron-rich arenes (entries
1e3), all three of the oxidants favored the formation of the p-
dimethyoxybenzene adduct, despite the fact that this was the more
electron-rich, but more sterically hindered, substrate. When the
reaction was allowed to choose between benzene and the deacti-
vated arene, pentafluorobenzene, the Class II conditions preferred
to arylate the fluorinated substrate despite the fact that the ben-
zene substrate contained six times more CeH bonds. This chemo-
selectivity is consistent with a CMD palladation mechanism
involving a Pd(II) intermediate.4c,7 The Class I conditions, however,
selectively arylated the benzene (entries 4e6). This implies that the
Class I conditions may be evoking a unique mechanism. To date, all
proposed mechanisms for these oxidative couplings assume that
the intermediates are palladium complexes existing in either the
0 or þ2 oxidation state. Based on the data shown in Table 4 and on
the inverted preference for small carboxylic acid additives (Table 3),
2.3. Competition studies indicate Pd(II)/Pd(IV) mechanism
Both we and Fagnou have proposed mechanisms for the oxi-
dative arylations of indole and benzofuran substrates.4c,e We have
both assumed that these reactions proceed by two sequential CeH
palladation steps forming ArePdeAr intermediates, which undergo
reductive elimination to form the biaryl products, and it is now
generally accepted that these palladation steps occur via a con-
certed metalationedeprotonation (CMD) mechanism. The data
presented herein indicate that the regioselectivity of the pallada-
tion of the benzofuran substrate is primarily controlled by the ox-
idant, but the absence of a Brønstead acid also influences the
regioselectivity. As shown in Tables 1 and 2, the various reaction

K.C. Pereira et al. / Tetrahedron 69 (2013) 4429e4435
4433
we hypothesize that the Class I reaction conditions (HPMV in acid)
may promote a Pd(II)/Pd(IV) mechanism.8 This possibility is also
consistent with the fact that HPMV oxidized couplings do not
precipitate palladium blackdeven after 100% conversion of the
substratesdwhile the formation of palladium black is often evident
in reactions that employ Ag(I) and Cu(II) oxidants.
HPMV, and other heteropoly acids having Keggin structures,
have been classified as superacids and are strong oxidants.9a HPMV
has even been shown to efficiently oxidize methane in the presence
of H2O2. Previously reported redox potentials of HPMV, Agþ and
Cu2þ (0.65 V,9b 0.41 V,10 and 0.40 V,11 respectively) also indicate
that HPMV has the potential to evoke a Pd(II)/Pd(IV) mechanism in
oxidative reactions like the one described herein.
containing AgOAc were prone to explosions when a Biotage Initi-
ator microwave synthesizer was used because the silver mirror,
which inevitably formed on the sides of the reaction vessel, in-
terfered with the infrared sensor that was positioned perpendicular
to the reaction tube. CEM microwaves have an infrared sensor that
is placed directly under the reaction vessel. Serendipitously, the
action of the stir bar kept the bottom of the reaction tube clean,
thus allowing for accurate temperature control.
GC/MS analysis was performed using an Agilent Technologies
6890 GC System fixed with a 5973 Mass Selective Detector. Dodec-
ane was used as an internal standard. The GC method employed
a 25 mꢁ0.200 mm, 0.33
m, DB-1 column. The temperature program
started at 40 ꢀC for 0.50 min, which was followed by a ramp at a rate
of 20 ꢀC/min to 300 ꢀC. The flow rate of the UHP He carrier gas was
held constant at 0.8 mL/min. Retention times for benzofuran (1),
dodecane, 3-phenylbenzofuran (3), and 2-phenylbenzofuran (2)
were 4.88, 6.66, 9.93, and 10.33 min, respectively.
3. Conclusion
The classification system of reactions conditions of palladium-
catalyzed oxidative coupling reactions that is presented herein
explains the activity of reactions well, but does not necessarily
predict the regioselectivity of the reactions. The evidence suggests
that acid concentration plays a rather low role in mediating
regioselective C2 versus C3-arylation (2, 3). Conversely, oxidant
choice greatly affects regioselectivity. This is in line with our pre-
vious observations using N-acetylindole substrates, and both we
and Fagnou have hypothesized that this oxidant-controlled selec-
tivity is a consequence of the formation of heterometallic catalytic
clusters.4b,e,6 Furthermore, we have demonstrated that the rate-
limiting step for our HPMV/O2 conditions is regeneration of the
palladium catalyst, but for AgOAc oxidized reactions, it is likely one
of the CeH palladations.
4.2. Class I conditions: representative procedure
A
magnetically stirred solution of benzofuran (0.080 g,
0.677 mmol), palladium acetate (0.015 g, 0.068 mmol), H4PMo11VO40
(0.121 g, 0.068 mmol), and PivOH (0.690 g, 6.77 mmol) in 4 mL of
benzene was heated at 120 ꢀC in a Schlenk tube under 3 atm O2. An
aliquot was subjected to GC/MS analysis before the reaction and at
60 min intervals (Schlenk tube is recharged with 3 atm O2 after each
aliquot)to determinepercent conversionwithrespectto dodecaneas
the internal standard. Purification was achieved by flash chroma-
tography using 100% hexanes to yield pure 2 (106 mg, 81%). Spectral
data was consistent with that which was previously reported.4a
Furthermore, both the kinetic studies and the competition studies
presented herein indicate that reactions oxidized by HPMV (Class I
conditions) likely proceed by a different mechanism than those oxi-
dized by either AgOAc or Cu(OAc)2. We propose that this unique
mechanism involves Pd(IV) intermediates, while Class II and Class III
conditions operate by a more conventional Pd(II)/Pd(0) mechanism.
The reaction conditions for the oxidative arylation of benzofuran
are highly tunable in terms of overall starting material conversion
and product regioselectivity. This shows much promise toward
the extension of the scope of these conditions to other similar
substrates.
4.3. Class II conditions: representative procedure
A
magnetically stirred solution of benzofuran (0.080 g,
0.677 mmol), palladium acetate (0.015 g, 0.068 mmol), AgOAc
(0.339 g, 2.03 mmol), and PivOH (0.690 g, 6.77 mmol) in 4 mL of
benzene and was heated at 120 ꢀC in a closed vial. An aliquot was
subjected to GC/MS analysis before the reaction and at 20 min in-
tervals to determine percent conversion with respect to dodecane
as the internal standard. Purification was achieved by flash chro-
matography using 100% hexanes to yield a 1:1 mixture of 2 and 3
(110 mg, 84%). Spectral data was consistent with that which was
previously reported.4a
4. Experimental section
4.1. General considerations
4.4. Class III conditions: representative procedure
Substrates, including benzofuran, propionic acid, isobutyric acid,
trimethylacetic acid, and dodecane were purchased from Acros
Chemicals. All the oxidants used, with the exception of
H4PMo11VO40, were purchased from Acros Chemicals. Benzene was
purchased from SigmaeAldrich. All reagents were stored under an
inert atmosphere before use. Pd(OAc)2 was obtained from Precious
Metals Online (http://www.precmet.com.au/). Upon receipt, it was
then dried under vacuum at 100 ꢀC for approximately 2 h.
H4PMo11VO40 was synthesized via a slight modification of the
published procedure.9a This modification involved further drying by
heating under vacuum at 135 ꢀC for approximately 16 h, producing
a golden brown powder. Vanadium(V) oxide and phosphoric acid
were purchased from Acros Chemicals. Molybdic trioxide was pur-
chased from Wayne Pigment Corp. AcOH was purchased from Alfa
Aesar. Upon receipt, the AcOH was distilled over acetic anhydride
(2:3 v/v) at 145 ꢀC using a short path distillation apparatus.
A magnetically stirred solution of benzofuran (0.080 g,
0.677 mmol), palladium acetate (0.015 g, 0.068 mmol), AgOAc
(0.339 g, 2.03 mmol), and PivOH (0.690 g, 6.77 mmol) in 4 mL of
benzene and was heated at 120 ꢀC in a closed vial. An aliquot was
subjected to GC/MS analysis before the reaction and at 2 h intervals
to determine percent conversion with respect to dodecane as the
internal standard. Purification was achieved by flash chromatog-
raphy using 100% hexanes to yield a 1:6 mixture of 2 and 3 (110 mg,
84%). Spectral data was consistent with that which was previously
reported.4a
4.5. Effect of acid sterics (Table 3)
A
magnetically stirred solution of benzofuran (0.080 g,
0.677 mmol), palladium acetate (0.015 g, 0.068 mmol), AgOAc
(0.318 g, 1.91 mmol), and 3 equiv of varying organic acids in 4 mL of
benzene was heated at 120 ꢀC for 40 min (MW). An aliquot was
subjected to GC/MS analysis before and after the reaction to de-
termine percent conversion with respect to dodecane as the in-
ternal standard.
Reactions that were heated in conventional oil baths were per-
formed in Schlenk vacuum tubes that were purchased from Kontes
(218710-0025). Microwave reactions were performed using either
a CEM Explorer or Discover microwave synthesizer. Reactions

4434
K.C. Pereira et al. / Tetrahedron 69 (2013) 4429e4435
A magnetically stirred solution of benzofuran (0.080 g, 0.677
(0.015 g, 0.068 mmol), AgOAc (0.339 g, 2.03 mmol), and PivOH
(0.690 g, 6.77 mmol) in 4 mL of benzene was heated at 120 ꢀC in
a closed vial. An aliquot was subjected to GC/MS analysis before the
reaction and at 20 min intervals to determine percent conversion
with respect to dodecane as the internal standard.
mmol), palladium acetate (0.015 g, 0.068 mmol), H4PMo11VO40
(0.121 g, 0.068 mmol), and 3 equiv of varying organic acids in 4 mL
of benzene was heated at 120 ꢀC for 3 h in a Schlenk vacuum tube
under 3 atm O2. An aliquot was subjected to GC/MS analysis before
and after the reaction to determine percent conversion with respect
to dodecane as the internal standard.
4.7.5. Pd(OAc)2 (20 mol %), 3 equiv AgOAc. A solution of benzofuran
(0.160 g, 1.354 mmol), palladium acetate (0.060 g, 0.272 mmol), and
PivOH (1.38 g, 13.54 mmol) in 8 mL of benzene. Two magnetically
stirred solutions were created from the reaction material. AgOAc
(0.339 g, 2.03 mmol) was then added to each vial and heated at
120 ꢀC in a closed vial. An aliquot was subjected to GC/MS analysis
before the reaction (for each vial) and at 20 min intervals (offset by
10 min, i.e., A: 10 min, 30 min, etc.; B: 20 min, 40 min, etc.) to
determine percent conversion with respect to dodecane as the in-
ternal standard.
4.6. Kinetic studies: effect of acid concentration (Figs. 1e3)
A
magnetically stirred solution of benzofuran (0.075 g,
0.635 mmol), palladium acetate (0.014 g, 0.064 mmol), AgOAc
(0.318 g, 1.91 mmol), and varying amounts of PivOH in 3 mL of
benzene was heated at 120 ꢀC for 40 min (MW). An aliquot was
subjected to GC/MS analysis before and after the reaction to de-
termine percent conversion with respect to dodecane as the in-
ternal standard.
A magnetically stirred solution of benzofuran (0.080 g, 0.677
mmol), palladium acetate (0.015 g, 0.068 mmol), H4PMo11VO40
(0.121 g, 0.068 mmol), and varying amounts of PivOH in 3 mL of
benzene was heated at 120 ꢀC for 6.5 h in a Schlenk vacuum tube
under 3 atm O2. An aliquot was subjected to GC/MS analysis before
and after the reaction to determine percent conversion with respect
to dodecane as the internal standard.
4.7.6. Pd(OAc)2 (10 mol %), 1.5 equiv AgOAc. A magnetically stirred
solution of benzofuran (0.080 g, 0.677 mmol), palladium acetate
(0.015 g, 0.068 mmol), AgOAc (0.170 g, 1.01 mmol), and PivOH
(0.690 g, 6.77 mmol) in 4 mL of benzene was heated at 120 ꢀC in
a closed vial. An aliquot was subjected to GC/MS analysis before the
reaction and at 20 min intervals to determine percent conversion
with respect to dodecane as the internal standard.
A magnetically stirred solution of benzofuran (0.080 g, 0.677
mmol), palladium acetate (0.015 g, 0.068 mmol), H4PMo11VO40
(0.121 g, 0.068 mmol), and varying amounts of AcOH in 3 mL of
benzene was heated at 120 ꢀC for 1.5 h in a Schlenk vacuum tube
under 3 atm O2. An aliquot was subjected to GC/MS analysis before
and after the reaction to determine percent conversion with respect
to dodecane as the internal standard.
4.8. Competition studies (Table 4)
A magnetically stirred solution of benzofuran (0.050 g, 0.423
mmol), palladium acetate (0.010 g, 0.042 mmol), H4PMo11VO40
(0.075 g, 0.085 mmol), benzene (1.33 mL, 14.9 mmol), peta-
fluorobenzene (1.66 mL, 14.9 mmol), and 2 mL acetic acid was
heated at 120 ꢀC for 1 h in a Schlenk vacuum tube under 3 atm O2.
An aliquot was subjected to GC/MS analysis after the reaction to
determine product ratios.
4.7. Kinetic studies: effect of catalyst and oxidant concentra-
tion (Figs. 4 and 5)
A magnetically stirred solution of benzofuran (0.050 g, 0.423
mmol), palladium acetate (0.010 g, 0.042 mmol), silver acetate
(0.212 g, 1.27 mmol), benzene (1.33 mL, 14.9 mmol), 1.66 mL peta-
fluorobenzene (1.66 mL, 14.9 mmol), and 2 mL acetic acid was
heated at 120 ꢀC for 1 h in a Teflon capped vial. An aliquot was
subjected to GC/MS analysis after the reaction to determine product
ratios.
A magnetically stirred solution of benzofuran (0.050 g, 0.423
mmol), palladium acetate (0.010 g, 0.042 mmol), copper(II) acetate
(0.230 g, 1.27 mmol), benzene (1.33 mL, 14.9 mmol), 1.66 mL
petafluorobenzene (1.66 mL, 14.9 mmol), and 2 mL acetic acid was
heated at 120 ꢀC for 1 h in a Teflon capped vial. An aliquot was
subjected to GC/MS analysis after the reaction to determine product
ratios.
A magnetically stirred solution of benzofuran (0.050 g, 0.423
mmol), palladium acetate (0.010 g, 0.042 mmol), H4PMo11VO40
(0.075 g, 0.085 mmol), p-xylene (1.40 mL, 11.4 mmol), 1,4-
dimethoxybenzene (1.57 g, 11.4 mmol), and 2 mL acetic acid was
heated at 120 ꢀC for 1 h in a Schlenk vacuum tube under 3 atm O2.
An aliquot was subjected to GC/MS analysis after the reaction to
determine product ratios.
4.7.1. Pd(OAc)2 (10 mol %), 10 mol % H4PMo11VO40. A magnetically
stirred solution of benzofuran (0.080 g, 0.677 mmol), palladium
acetate (0.015 g, 0.068 mmol), H4PMo11VO40 (0.121 g, 0.068 mmol),
and PivOH (0.690 g, 6.77 mmol) in 4 mL of benzene was heated at
120 ꢀC in a Schlenk vacuum tube under 3 atm O2. An aliquot was
subjected to GC/MS analysis before the reaction and at 60 min in-
tervals (Schlenk tube was recharged with 3 atm O2 after each ali-
quot) to determine percent conversion with respect to dodecane as
the internal standard.
4.7.2. Pd(OAc)2 (20 mol %), 10 mol % H4PMo11VO40. A magnetically
stirred solution of benzofuran (0.080 g, 0.677 mmol), palladium
acetate (0.030 g, 0.134 mmol), H4PMo11VO40 (0.121 g, 0.068 mmol),
and PivOH (0.690 g, 6.77 mmol) in 4 mL of benzene was heated at
120 ꢀC in a Schlenk vacuum tube under 3 atm O2. An aliquot was
subjected to GC/MS analysis before the reaction and at 60 min in-
tervals (Schlenk tube was recharged with 3 atm O2 each time) to
determine percent conversion with respect to dodecane as the in-
ternal standard.
4.7.3. Pd(OAc)2 (10 mol %), 20 mol % H4PMo11VO40. A magnetically
stirred solution of benzofuran (0.080 g, 0.677 mmol), palladium ac-
etate (0.015 g, 0.068 mmol), H4PMo11VO40 (0.242 g, 0.134 mmol), and
PivOH (0.690 g, 6.77 mmol) in 4 mL of benzene was heated at 120 ꢀC
ina Schlenk vacuumtube under3 atmO2. Analiquot was subjectedto
GC/MS analysis before the reaction and at 60 min intervals (Schlenk
tube was recharged with 3 atm O2 each time) to determine percent
conversion with respect to dodecane as the internal standard.
A magnetically stirred solution of benzofuran (0.050 g, 0.423
mmol), palladium acetate (0.010 g, 0.042 mmol), silver acetate
(0.212 g, 1.27 mmol), p-xylene (1.40 mL, 11.4 mmol), 1,4-
dimethoxybenzene (1.57 g, 11.4 mmol), and 2 mL acetic acid was
heated at 120 ꢀC for 1 h in a Teflon capped vial. An aliquot was
subjected to GC/MS analysis after the reaction to determine product
ratios.
A
magnetically stirred solution of benzofuran (0.050 g,
0.423 mmol), palladium acetate (0.010 g, 0.042 mmol), copper(II)
acetate (0.230 g, 1.27 mmol), p-xylene (1.40 mL, 11.4 mmol), 1,4-
dimethoxybenzene (1.57 g, 11.4 mmol), and 2 mL acetic acid was
4.7.4. Pd(OAc)2 (10 mol %), 3 equiv AgOAc. A magnetically stirred
solution of benzofuran (0.080 g, 0.677 mmol), palladium acetate

K.C. Pereira et al. / Tetrahedron 69 (2013) 4429e4435
4435
heated at 120 ꢀC for 1 h in a Teflon capped vial. An aliquot was
subjected to GC/MS analysis after the reaction to determine product
ratios.
2. The field has been reviewed extensively. For examples, see: (a) Dyker, G.
Handbook of CeH Transformations: Applications in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2005; (b) Godula, K.; Sames, D. Science 2006,
312, 67; (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 17; (d)
Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269; (e) Chen, X.; Engle, K. M.;
Wang, D.; Yu, J. Angew. Chem., Int. Ed. 2009, 48, 5094; (f) Joucla, L.; Djakovitch, L.
Adv. Synth. Catal. 2009, 351, 673.
Acknowledgements
3. Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
4. For selected examples, see: (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;
DeBoef, B. Org. Lett. 2007, 9, 3137; (b) Potavathri, S.; Dumas, A. S.; Dwight, T. A.;
Naumiec, G. R.; Hammann, J. M.; DeBoef, B. Tetrahedron Lett. 2008, 49, 4050; (c)
Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am.
Chem. Soc. 2010, 132, 14676; (d) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172;
(e) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072; (f)
The DeBoef group is supported by the National Science Foun-
dation (CAREER 0847222), and the National Institutes of Health
(NIGMS, 1R15GM097708-01). B.D.B. is a recipient of a Green
Chemistry Award from Pfizer, Inc.
ꢀ
Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73,
5022; (g) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904; (h) Hull,
K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651; (i) Rong, Y.; Li, R.; Lu, W.
Organometallics 2007, 26, 4376; (j) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am.
Chem. Soc. 2010, 132, 5837; (k) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc.
2007, 129, 6066; (l) Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
13864.
Supplementary data
Complete descriptions of all procedures for kinetic and com-
petition experiments as well as analytical methods. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.02.061.
5. Obora, Y.; Ishii, Y. Molecules 2010, 15, 1487.
6. (a) Brandon, R. W.; Claridge, D. V. Chem. Commun. 1968, 677; (b) Sloan, O. D.;
Thornton, P. Inorg. Chim. Acta 1986, 120, 173.
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8. Ling-Min Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712.
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