Palladium-catalyzed ortho-arylation of O-phenylcarbamates with simple arenes and sodium persulfate

Article abstract of DOI:10.1021/ja100783c

By palladium catalysis, the C-H bond functionalization of O-phenylcarbamates with simple arenes has been achieved using sodium persulfate (Na₂S₂O₈), an inexpensive, easy-to-handle, and environmentally friendly oxidant. Thi

Full text of DOI:10.1021/ja100783c

Published on Web 04/01/2010
Palladium-Catalyzed Ortho-Arylation of O-Phenylcarbamates
with Simple Arenes and Sodium Persulfate
Xiaodan Zhao, Charles S. Yeung, and Vy M. Dong*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto,
Ontario, Canada M5S 3H6
Received January 28, 2010; E-mail: vdong@chem.utoronto.ca
Abstract: By palladium catalysis, the C-H bond functionalization of O-phenylcarbamates with simple arenes
has been achieved using sodium persulfate (Na2S2O8), an inexpensive, easy-to-handle, and environmentally
friendly oxidant. This oxidative cross-coupling involves two aromatic C-H bonds undergoing concomitant
oxidation to furnish a new biaryl C-C linkage. Excellent reaction efficiencies and regioselectivities were
observed with a range of electron-rich, electron-neutral, and electron-deficient arenes; minimal homocoupling
of either component was observed. When two reactive C-H bonds are present on the O-phenylcarbamate,
selective diarylation can be achieved via quadruple C-H bond functionalization. This work represents a
rare example of using O-carbamates as directing groups for catalytic C-H bond activation. Additionally, a
palladacycle obtained from an O-phenylcarbamate was prepared and fully characterized. This trifluoroac-
etate-bridged bimetallic Pd complex exhibits clean conversion to the ortho-arylation product upon treatment
with simple arenes. The addition of trifluoroacetic acid (TFA) was found to be critical for successful
cyclopalladation of O-phenylcarbamates. We propose this oxidative arene cross-coupling occurs via two
discrete C-H bond activations, namely cyclopalladation and electrophilic metalation, within a Pd(0/II) catalytic
cycle.
Introduction
The 2-arylphenol is a structural motif found in important
natural products, medicinal targets,1 and privileged ligands.2
Snieckus and co-workers have developed a widespread and
popular strategy for accessing elaborate phenol derivatives via
directed ortho-metalation (DoM) of O-phenylcarbamates.3
Notably, the O-carbamate not only serves as a useful protecting
group but also acts as a functional handle for further transforma-
tions, including anionic Fries rearrangements3,4 and cross-
couplings (Figure 1).5 Using DoM to form a C-C biaryl linkage,
however, requires multiple steps and valuable prefunctionalized
reagents involving distinct metalation, halogenation, and cross-
coupling steps (Figure 2).
Catalytic C-H bond functionalization of phenol derivatives
is a promising alternative synthetic strategy. Direct access to
(1) (a) He, X.; Alian, A.; Stroud, R.; Ortiz de Montellano, P. R. J. Med.
Chem. 2006, 49, 6308–6323. (b) Jeong, T.-S.; Kim, K. S.; An, S.-J.;
Cho, K.-H.; Lee, S.; Lee, W. S. Bioorg. Med. Chem. Lett. 2004, 14,
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Million, M.-E.; Boiziau, J.; Parker, F.; Tocque, B.; Roques, B. P.;
Garbay, C. J. Med. Chem. 1995, 38, 4693–4703.
Figure 1. O-Phenylcarbmates: A versatile functional group with unrealized
potential for catalytic C-H functionalization. C-X ) C-C, C-N, C-O,
C-S, C-F, C-Cl, C-Br, C-I.
(2) For reviews on BINOL, see: (a) Brunel, J. M. Chem. ReV. 2005, 105,
857–898. (b) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. ReV. 2003,
103, 3155–3212.
2-arylphenol derivatives has thus far been limited to oxidative
phenolic homo- and heterocoupling,6 anodic phenol/arene cross-
coupling,7 and transition metal-catalyzed arylation with aryl
iodides with either unprotected phenols8 in the presence of
phosphites or phosphoramidites,9 or benzodioxoles.10 Consider-
ing their synthetic utility, the use of O-phenylcarbamates in
catalytic C-H bond functionalization warrants further explora-
(3) For a review, see: Snieckus, V. Chem. ReV. 1990, 90, 879–933.
(4) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935–1937.
(5) (a) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus,
V. J. Org. Chem. 1992, 57, 4066–4068. (b) Quasdorf, K. W.; Riener,
M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748–
17749. (c) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem.
Soc. 2009, 131, 17750–17752. (d) Xu, L.; Li, B.-J.; Wu, Z.-H.; Lu,
X.-Y.; Guan, B.-T.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Org. Lett.
2010, 12, 884–887.
9
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A R T I C L E S
Zhao et al.
Table 1. Screen of Known Direct Arylation Conditions to
O-Phenylcarbamates
entry
n
X
M
conditions
2aa (%)
1
5
I
I
Pd(OAc)2
Pd(OAc)2
AgOAc, AcOH,
130 °C16
0
2
3
4
5
5
Cs2CO3, xylene,
0
100 °C17
2.5 Br
2.5 Cl
[Ru(p-cymene)Cl2]2 PPh3, K2CO3, NMP,
120 °C18
[Ru(p-cymene)Cl2]2 ArCO2H, toluene,
0
0
Figure 2. Proposed catalytic arylation of O-phenylcarbamates.
tion.11 Arylation of O-phenylcarbamates with aryl iodides and
hypervalent iodonium salts (Ph2IOTf) has only recently been
achieved.12
120 °Cb19
5
IPhBF4 Pd(OAc)2
AcOH, 100 °C16
89
a GC yield with dodecane as an internal standard. b Ar
2,4,6-Me3C6H2.
)
Cross-coupling of simple arenes has emerged as a green
strategy for making biaryl linkages.13 This arylation involves
two aromatic C-H bonds (Ar-H and Ar′-H) undergoing
concomitant functionalization to form a new biaryl C-C bond
(Ar-Ar′). Despite recent advances, known oxidative arylations
remain limited to N-protected indoles,13a,b N-protected
pyrroles,13b pyridines,13c,d anilides,13e,f pyridine N-oxides,13g and
benzofurans.13h As such, developing oxidative cross-coupling
with broader substrate scope and studying the mechanistic
underpinning of these processes remains an important challenge
in catalysis.
benzene or o-dichlorobenzene) as coupling partners for the
formation of 2-arylphenol derivatives. In contrast to known
methods, our oxidative arene cross-coupling allows for direct
C-H bond arylation while avoiding the need for highly
functionalized coupling partners such as aryl iodides and
hypervalent iodine reagents.
Results and Discussion
Herein, we report a complementary Pd-catalyzed ortho-
arylation of O-phenylcarbamates using simple arenes (e.g.,
Initial Studies. We imagined that ortho-arylation would be
possible in a one-step process from an O-phenylcarbamate. On
the basis of known cyclopalladations,12,14 we proposed that
O-phenylcarbamates could undergo C-H bond activation with
Pd to produce a novel palladacycle that could be isolated and
characterized (Figure 2). In addition, we reasoned this palla-
dacycle intermediate could react with an arene coupling partner
(Ar-X) to produce 2-aryl and/or 2,6-diaryl O-phenylcarbamates.
Using o-tolyl dimethylcarbamate (1a), we considered various
arene coupling partners including aryl halides and hypervalent
iodonium salts (e.g., Ph2IBF4)15 (Table 1). Our preliminary
studies revealed that while aryl halides were ineffective oxidants
(entries 1-4), Ph2IBF4 showed promising results (entry 5), in
agreement with Fu and Liu’s recent report.12b Our results
demonstrated that O-carbamates are effective directing groups
for C-H activation in the presence of strong oxidants. With
these initial experiments, we concentrated our efforts on cross-
coupling with simple arenes to overcome the need for valuable
arylating agents.13
(6) (a) Grandbois, A.; Mayer, M.-E.; Be´dard, M.; Collins, S. K.; Michel,
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P. Tetrahedron Lett. 2007, 48, 8595–8598. (d) Temma, T.; Hatano,
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(11) For a related Boc-directed C-H bond activation, see: Wang, D.-H.;
Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8, 3387–3390.
(12) During preparation of this manuscript, the following accounts of ortho-
arylation of phenolic esters and O-phenylcarbamates with hypervalent
iodonium salts was reported: (a) Bedford, R. B.; Webster, R. L.;
Mitchell, C. J. Org. Biomol. Chem. 2009, 7, 4853–4857. (b) Xiao, B.;
Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem.
Soc. 2010, 132, 468–469.
Toward achieving a new oxidative cross-coupling, we focused
on identifying conditions for the arylation of O-phenylcarbamate
(14) For a review on palladacycles, see: Dupont, J.; Consorti, C. S.; Spencer,
J. Chem. ReV. 2005, 105, 2527–2572.
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11904–11905. (d) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 9651–9653. (e) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew.
Chem., Int. Ed. 2008, 47, 1115–1118. (f) Brasche, G.; Garc´ıa-Fortanet,
J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207–2210. (g) Cho, S. H.;
Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254–9256.
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Organometallics 2007, 26, 4869–4871.
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Chem. Soc. 2005, 127, 7330–7331. (b) Deprez, N. R.; Kalyani, D.;
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2302.
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Pd-Catalyzed Ortho-Arylation of O-Phenylcarbamates
A R T I C L E S
In contrast to anilide arylations,13e,f O-phenylcarbamate arylation
occurs with high efficiency using electron-deficient arenes,
including o-dichlorobenzene (2d-n) and o-difluorobenzene
(2o-s). With these simple o-disubstituted arenes, exclusive
functionalization was observed at the 4-position. Benzene
(2a,t,u, 71-98%) and electron-rich arenes, including o-dimeth-
yl- and o-dimethoxybenzene (2v-w, 47-76%), were also
suitable coupling partners.
Table 2. Optimization of Reaction Conditions for Selective Mono-
and Diarylation of O-Phenylcarbamatesa
Rather than consuming a valuable aryl halide or boronic acid
and producing stoichiometric amounts of waste byproducts in
the process, this approach uses an inexpensive arene as the
reagent and formally liberates one equivalent of H2. Furthermore,
while boronic acids are known to homocouple, the analogous
arene dimerization to form polyhalogenated biphenyls is minimal
under our conditions (i.e., only trace homocoupling products
could be observed with o-dichloro- and o-difluorobenzene). The
use of electron-rich arenes as coupling partners, however,
resulted in competitive homocoupling, thus reducing the reaction
efficiency (2w, 47%). Homocoupling with benzene also occurs,
but phenylation of 1a remains competitive; benzene generates
the corresponding biphenyl side product with a catalyst TON
) 8.5.
entry
oxidant/equiv
2bb (%)
2cb (%)
1
2
3
4
5
6
7
Cu(OAc)2/3
AgOAc/3
Ag2CO3/3
1 atm of O2, DMSO/0.2
Oxone/3
3
0
0
27
0
0
0
0
1
0
18
83 (76)
Na2S2O8/1.5
Na2S2O8/3
73 (62)
15
a Conditions: substrate, 0.2 mmol; o-dichlorobenzene,
1 mL; Pd
(OAc)2, 10 mol %; TFA, 5 equiv; 48 h. b GC yield with dodecane as an
internal standard; isolated yield in parentheses.
1b with electron-deficient arenes such as o-dichlorobenzene
(Table 2). This model system would help us probe issues of
both reactivity and selectivity, as competing mono- and diary-
lation can take place. We decided to focus on using electron-
deficient arenes because they represent a challenging class of
substrates for oxidative coupling. For example, related arylations
of anilides are relatively inefficient with electron-deficient
arenes.13f Neither biaryl 2b nor 2c was formed in the absence
of Pd catalysts; the presence of trifluoroacetic acid (TFA) was
also found to be critical.20 Oxidants reported for previous ortho-
arylations were not optimal: Cu(OAc)2, AgOAc, and Ag2CO3
were ineffective (Table 2, entries 1-3). The use of O2 as an
oxidant, which is known to be effective in related anilide
arylations,13f liberated product 2b in only a modest 27% yield
(entry 4). In comparison, when benzene was used as the simple
arene, O213e,f was sufficient in promoting the desired C-H bond
The 2,6-diarylphenol motif is found in molecules that have
demonstrated promising activities in various enzymatic
inhibition studies.1 Our work provides access to these
structures using simple arenes as coupling partners (Table
4, entries 2-5). Notably, we demonstrate rare examples of
oxidative diarylation and 4-fold C-H bond functionalization
with unprecedented efficiency.13b A range of 2,6-diaryl-O-
phenylcarbamates (2c,x-z) were prepared (68% to 78%). The
reaction tolerates electron-neutral and -donating substituents at
the para position. However, substitution with electron-
withdrawing groups resulted in selective monoarylation to yield
2-aryl-O-phenylcarbamates as the major products (2aa-ab,
66%).
Mechanistic Proposal. Few mechanistic studies have been
reported for oxidative arene cross-coupling via tandem C-H
bond functionalization.13d Herein, we present studies that support
a distinct mechanistic proposal shown in Figure 3. Our oxidative
cross-coupling occurs via a Pd(0/II) catalytic cycle involving
(1) C-H bond activation by carbamate-assisted cyclopalladation,
(2) C-H bond functionalization by electrophilic metalation, (3)
reductive elimination, and finally, (4) reoxidation of Pd(0) to
an active Pd(II) catalyst with sodium persulfate.
15
arylation (cf. 85% GC yield for 1a). Because Ph2IBF4 was
found to be effective in preliminary studies, we chose to explore
stronger metal salt oxidants for our oxidative arene cross-
coupling. While we found that Oxone resulted in decreased
yields (entry 5), we discovered that Na2S2O8 was an efficient
oxidant (entries 6 and 7).21 Furthermore, by simply controlling
the stoichiometry of the oxidant, we could select for either the
2-arylated product 2b (62%, entry 6) or the 2,6-diarylated
product 2c (76%, entry 7).22
Synthetic Scope. With this protocol in hand, we were able to
rapidly access 21 different 2-arylcarbamates in 44-98% yields
(Table 3). O-Phenylcarbamates bearing substitution at the ortho
or meta positions underwent regioselective monoarylation to
form products 2d-w. Significant variation on the aromatic ring
of the masked phenol was tolerated, including electron-donating
groups (e.g., Me, Et, iPr, tBu, Ph, OMe) and electron-withdraw-
ing groups (e.g., F, Cl, COOMe). Substrates bearing a stronger
electron-withdrawing group (e.g., CF3), however, gave the
desired ortho-arylation product with poor efficiency (<20%).
Role of TFA and Na2S2O8. Both TFA and sodium persulfate
were found to be critical in achieving high efficiency for our
oxidative cross-coupling of O-phenylcarbamates. A recent
computational study by Davies and Macgregor suggests that
acetate anions can facilitate intramolecular H-transfer through
a six-membered transition state.23 In addition to this role, we
propose that TFA enhances the electrophilicity of the Pd center
and aids electrophilic metalation.20,24 Dissociation of a trifluo-
roacetate anion and concurrent generation of a cationic Pd
species has been proposed in the literature (Figure 4).24b,25
Substitution of TFA with the less acidic acids (e.g., trichloro-
(23) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
2005, 127, 13754–13755.
(20) Li, R.; Liang, L.; Lu, W. Organometallics 2006, 25, 5973–5975.
(21) (a) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org. Chem. 2008, 73,
4717–4720. (b) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett.
2006, 8, 1141–1144.
(24) TFA is known to facilitate the formation of Pd(II) σ-aryl intermediates.
Our results suggest that TFA can also promote direct C-H activation
by palladacycle formation. (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.;
Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–1995. (b) Jia,
C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara,
Y. J. Am. Chem. Soc. 2000, 122, 7252–7263.
(22) The use of phenol esters under our oxidative arylation conditions
yielded no desired product. See ref 12b.
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A R T I C L E S
Zhao et al.
Table 3. Pd-Catalyzed Oxidative Arylation of O-Phenylcarbamatesa
a Reaction conditions: substrate, 0.2 mmol; arene, 1 mL; Pd(OAc)2, 10 mol %; Na2S2O8, 3 equiv; TFA, 5 equiv; 30-68 h. b After 24 h, 5 mol % of Pd(OAc)2
was added. c With benzene, 0.5 mL, and o-dichlorobenzene, 0.5 mL, 90% of 2t was isolated. d o-Dimethoxybenzene, 0.5 mL.
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5840 J. AM. CHEM. SOC. VOL. 132, NO. 16, 2010

Pd-Catalyzed Ortho-Arylation of O-Phenylcarbamates
A R T I C L E S
Table 4. Pd-Catalyzed Oxidative Mono- and Diarylation of
O-Phenylcarbamatesa
Figure 3. Proposed mechanism for Pd-catalyzed oxidative arylation of
O-phenylcarbamates. X ) CO2CF3.
Figure 4. Proposed dissociation of trifluoroacetate anion from
Pd(TFA)2.24b,25
Figure 5. Preparation of dimeric Pd complex 3.
to be a useful additive in C-H bond activations,12b led to
decomposition products under our reaction conditions.
The strong oxidant Na2S2O8 promotes reoxidation of Pd(0)
to Pd(II). Because both strong oxidants such as Na2S2O821 and
hypervalent iodonium salts (Ph2IBF4)15 are effective in our
oxidative ortho-arylation, alternative mechanistic proposals
involving Pd(II/III)26 and/or Pd(II/IV)27 catalytic cycles are also
reasonable to consider. Based on the studies described below,
however, we favor a mechanism involving two discrete C-H
bond activations via Pd(0/II) catalysis.
Support for the First C-H Bond Activation by Cyclopalla-
dation. As previously mentioned, directed C-H bond activation
of O-phenylcarbamates was unknown until recently.12 Fu and
Liu demonstrated that monomeric Pd ·HOTf complexes were
competent catalysts for the ortho-arylations of phenylcarboxy-
lates with hypervalent iodine reagents.12b However, isolation
and characterization by X-ray crystallography of the proposed
palladacycle intermediate derived from an O-phenylcarbamate
had not been achieved. We prepared Pd complex 3 by combining
m-tolyl dimethylcarbamate with Pd(OAc)2 in the presence of
1
TFA as characterized by H, 13C, and 19F NMR spectroscopy
(Figure 5); following recrystallization, we were able to deduce
the molecular geometry of 3 by X-ray crystallography (Figure
6). The O-phenylcarbamate ligands are oriented in a head-to-
a Reaction conditions: substrate, 0.2 mmol; arene, 1 mL; Pd(OAc)2, 10
mol %; Na2S2O8, 3 equiv; TFA, 5 equiv; 48-72 h.
(25) (a) Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24, 6440–
6444. (b) Swang, O.; Blom, R.; Ryan, O. B.; Fægri, K., Jr. J. Phys.
Chem. 1996, 100, 17334–17336.
acetic acid, tribromoacetic acid, or acetic acid) leads to a
decrease in reaction efficiencies. Triflic acid, which is known
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A R T I C L E S
Zhao et al.
Figure 8. Competition study between electron-rich and electron-neutral
arenes for oxidative arylation.
Figure 6. ORTEP plot of dimeric Pd complex 3. All H atoms have been
omitted for clarity. Anisotropic displacement ellipsoids are shown at the
50% probability level. Selected bond lengths (Å) and angles (deg) for 3:
Pd(1)-Pd(2) ) 2.9163(10), Pd(1)-O(1) ) 2.012(6), Pd(1)-C(1) )
1.957(8), C(2)-O(1) ) 1.249(10), C(2)-N(1) ) 1.338(11), O(2)-C(2) )
1.320(10), Pd(1)-O(3) ) 2.072(6), Pd(1)-O(4) ) 2.160(6), N(1)-C(2)-O(1)
) 120.1(8), O(2)-C(2)-N(1) ) 114.3(8), O(2)-C(2)-O(1) ) 125.1(7),
C(1)-Pd(1)-O(1) ) 83.3(3), C(1)-Pd(1)-O(3) ) 94.8(3), O(3)-Pd(1)-
O(4) ) 87.5(2), O(4)-Pd(1)-O(1) ) 89.3(2), O(3)-C(3)-O(5) ) 133.2(9).
Figure 9. Competition study between electron-neutral and electron-deficient
arenes for oxidative arylation.
With palladacycle 3 in hand, we performed a series of
competition experiments to study the second C-H bond
activation step in our oxidative cross-coupling. Treatment of 3
with a 1:1 mixture of benzene and o-dimethoxybenzene resulted
in 96% conversion to the o-3,4-dimethoxyphenyl product (2ac)
(Figure 8). In comparison, the phenylation product with benzene
(2t) was observed in <2% yield. Thus, more electron-rich arenes
appear to undergo arylation at a faster reaction rate than less
electron-rich arenes. Indeed, a second competition study between
benzene and o-dichlorobenzene supports this reactivity trend
(Figure 9). Our earlier experiments, however, revealed that
oxidative ortho-arylation of 3-methoxyphenyl dimethylcarbam-
ate (1m) with benzene (2u, 71%) was more efficient than
o-dimethoxybenzene (2w, 47%) (see Table 2, entries 20, 21).
To explain this apparent contradiction, we propose that electron-
Figure 7. Direct phenylation of dimeric Pd complex 3.
tail fashion. Notably, the formed Pd complex 3 is dimeric in
nature, exhibiting bridging trifluoroacetate ligands and a weak
interaction between two Pd nuclei.28
(27) Arylation at Pd(IV) has been proposed: (a) Rosewall, C. F.; Sibbald,
P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131,
9488–9489. (b) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael,
F. E. J. Am. Chem. Soc. 2009, 131, 15945–15951.
This molecular structure confirms that O-carbamate is a
suitable directing group for C-H bond activation. Furthermore,
this structure supports the feasibility of a palladacycle inter-
mediate in our proposed mechanism. Indeed, subjecting Pd
complex 3 to benzene resulted in smooth conversion to the
phenylated product 2t in excellent yield at elevated temperatures
(Figure 7). Moreover, an oxidant or external additives is not
required to promote the desired ortho-arylation of complex 3.
Thus, the second C-H bond activation can occur via a Pd(II)
intermediate.
(28) The internuclear distance between the two Pd atoms was determined
to be 2.9163(10) Å, slightly longer than known bimetallic complexes
containing acetate bridging ligands.26a In comparison to other Pd
complexes bearing bridging trifluoroacetate ligands, our bimetallic Pd
complex 3 exhibits slightly shorter Pd-Pd bonds: (a) Ruddock, P. L.;
Williams, D. J.; Reese, P. B. Steroids 2004, 69, 193–199. (b)
Stromnova, T. A.; Paschenko, D. V.; Boganova, L. I.; Daineko, M. V.;
Katser, S. B.; Chukarov, A. V.; Kuz’mina, L. G.; Howard, J. A. K.
Inorg. Chim. Acta 2003, 350, 283–288. (c) Schwarz, I.; Rust, J.;
Lehmann, C. W.; Braun, M. J. Organomet. Chem. 2000, 605, 109–
116. (d) Goddard, R.; Kru¨ger, C.; Mynott, R.; Neumann, M.; Wilke,
G. J. Organomet. Chem. 1993, 454, C20-C25. For a Pd ·TFA complex
exhibiting a similar Pd-Pd bond distance, see: (e) Stromnova, T. A.;
Orlova, S. T.; Kazyul’kin, D. N.; Stolyarov, I. P.; Eremenko, I. L.
Russ. Chem. Bull. 2000, 49, 150–153.
Support for Second C-H Bond Activation by Electrophilic
Metalation via Pd(II). A number of mechanisms can be
considered for the second C-H bond activation, including
Fagnou’s concerted metalation deprotonation29 or Sanford’s
proposed σ-bond metathesis.13d Our experimental results sug-
gest, however, that arene activation occurs by a variant of the
classical electrophilic aromatic substitution mechanism (SEAr),30
namely electrophilic metalation.31
(29) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 8754–8756. (b) Gorelsky, S. I.; Lapointe, D.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
(30) For a discussion on classical SEAr, see: Carey, F. A.; Sundberg, R. J.
AdVanced Organic Chemistry, Part B: Reactions and Synthesis, 5th
ed.; Springer: New York, 2007; pp 1004-1025.
(31) For a discussion on electrophilic metalation, see: (a) Carey, F. A.;
Sundberg, R. J. AdVanced Organic Chemistry, Part B: Reactions and
Synthesis, 5th ed.; Springer: New York, 2007; p 1026. (b) Ryabov,
A. D. Chem. ReV. 1990, 90, 403–424. (c) Davidson, J. M.; Triggs, C.
J. Chem. Soc. A 1968, 1324–1330.
(26) For seminal work on catalytic oxidations involving Pd(III) intermedi-
ates, see: (a) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302–309.
(b) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T.
J. Am. Chem. Soc. 2009, 131, 17050–17051.
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Pd-Catalyzed Ortho-Arylation of O-Phenylcarbamates
A R T I C L E S
Figure 10. Transition state for a concerted metalation deprotonation
mechanism supported by Fagnou and Woo’s computational and mechanistic
studies.29
Figure 12. Proposed electrophilc metalation mechanism for functional-
ization of the second arene.
noalkylations.32 Moreover, in electrophilic metalations using
stoichiometric amounts of Hg and Pd complexes,31 kinetic
isotope effects were also observed.20,31 Thus, our results are
consistent with an SEAr mechanism via two elementary steps:
electrophilic attack of Pd on the simple arene to yield a Wheland
intermediate followed by rate-limiting proton abstraction to form
the aryl Pd σ-complex (Figure 12).31 However, both concerted
metalation deprotonation29 and σ-bond metathesis13d remain
viable pathways and further mechanistic studies are underway.
Conclusion
In conclusion, we have developed an ortho-arylation of
O-phenylcarbamates using simple arenes as the cross-coupling
partner and sodium persulfate as a convenient oxidant. Further,
we demonstrate a rare use of O-carbamates in directing group
assisted catalytic C-H bond activation. The first cyclopalladate
derived from an O-phenylcarbamate as a bimetallic Pd species
containing a weak Pd-Pd interaction has been isolated and
characterized. Arylation of this Pd(II) complex is demonstrated
in the absence of external oxidants and/or additives. Based on
data obtained from competition experiments, we propose a
mechanism whereby two C-H bond activations occur via
cyclopalladation and electrophilic metalation, respectively,
within a Pd(0/II) catalytic cycle. We expect that insights gained
from our present study will aid future advances in oxidative
cross-coupling, including developing new coupling partners,
oxidants, catalysts, and strategies for controlling chemoselec-
tivity.
Figure 11. Competition study between deuterated and undeuterated arenes
for oxidative arylation.
rich arenes undergo competitive homodimerization, leading to
lower yields of the desired 2-phenylcarbamate products. (At-
tempted arylation of m-tolyl dimethylcarbamate (1i) with
o-dimethoxybenzene resulted in homocoupling of the simple
arene solely to generate the corresponding biaryl byproduct with
a catalyst TON ) 7.8; no desired 2-aryl-O-phenylcarbamate
product was produced.)
The significant differences in arene reactivity observed (i.e.,
o-dichlorobenzene , benzene , o-dimethoxybenzene) leads
us to favor an SEAr mechanism30,31 over both concerted
metalation deprotonation29 and the σ-bond metathesis13d path-
ways. In a concerted metalation deprotonation mechanism,
electron-deficient arenes usually undergo arylation faster due
to enhanced acidity (see Figure 10).29a However, recent
computational studies reveal that acidity is not the only critical
parameter.29b In Sanford’s oxidative coupling involving σ-bond
metathesis, electron-rich arenes (e.g., ArOMe) and electron-
deficient arenes (e.g., ArNO2) showed comparable reactivity
(1.3:1).13d
Next, we investigated the relative reactivity of isotopically
labeled arenes under catalytic conditions. Based on a competition
experiment, the observed product distributions suggest that both
benzene (2t:2t-d5 ) 3.9:1) and o-dichlorobenzene (2k:2k-d5 )
3.1:1) undergo the second C-H bond activation faster than their
deuterated analogues (Figure 11). Although most aromatic
substitutions involve a rate-limiting electrophilic attack, primary
kinetic isotope effects suggesting slow H-abstraction have been
reported for acylations, sulfonations, nitrosations, and ami-
Experimental Section
General Procedure for Oxidative Arylation. To a 1-dram vial
equipped with a Teflon cap were added the O-phenylcarbamate (0.2
mmol), Pd(OAc)2 (0.02 mmol, 10 mol %), Na2S2O8 (0.6 mmol),
and the simple arene (1 mL). Subsequently, trifluoroacetic acid (1
mmol) was added. The vial was stirred on a heating block at 70 °C
for the indicated length of time. The reaction mixture was cooled
to room temperature, diluted in EtOAc, and washed with satd
NaHCO3. The aqueous phase was re-extracted with EtOAc. The
combined organic extracts were dried over Na2SO4 and concentrated
in vacuo, and the resulting residue was purified by silica gel column
chromatography or preparative thin-layer chromatography (eluent:
hexanes/EtOAc) to afford the pure arylation products as single
regioisomers. For more details, see the Supporting Information.
Synthesis of Bimetallic Palladacycle 3 with m-Tolyl Dimeth-
ylcarbamate (1i). To a 1-dram vial were added m-tolyl dimeth-
ylcarbamate (1i) (21.5 mg, 0.12 mmol), Pd(OAc)2 (22.4 mg, 0.1
mmol), and dichloromethane (1 mL). Trifluoroacetic acid (11.4 mg,
0.1 mmol) was subsequently added into the vial, and the resulting
solution was heated at 40 °C for 30 min. After being cooled to
ambient temperature, the reaction mixture was concentrated in
(32) (a) Vougioukalakis, G. C.; Chronakis, N.; Orfanopoulos, M. Org. Lett.
2003, 5, 4603–4606. (b) Challis, B. C.; Higgins, R. J.; Lawson, A. J.
J. Chem. Soc., Perkin Trans. 2 1972, 1831–1836. (c) Olah, G. A.;
Lukas, J.; Lukas, E. J. Am. Chem. Soc. 1969, 91, 5319–5323. (d)
Zollinger, H. AdV. Phys. Org. Chem. 1964, 2, 163–200.
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A R T I C L E S
Zhao et al.
vacuo, and the resulting residue was redissolved in hexanes (2 mL).
After 2 h, precipitation of the desired complex occurred. The
suspension was filtered through Celite and washed with 2 × 0.3
mL hexanes. The residue was washed with dichloromethane, and
the wash solution was subsequently collected and concentrated in
vacuo to afford the bimetallic palladacycle 3 as a yellow solid (33.2
in 2% and 98% GC yields, respectively. The reaction mixture was
concentrated in vacuo, and the resulting residue was purified by
preparative thin-layer chromatography (eluent: hexanes/EtOAc )
3:1, v/v) to afford the product arising from arylation with o-
dimethoxybenzene 2ac as a yellow viscious oil (96%). 3′,4′-
Dimethoxy-4-methylbiphenyl-2-yl dimethylcarbamate (2ac): 1H
NMR (400 MHz, CDCl3) δ 7.25 (d, J ) 7. Hz, 1H), 7.07 (d, J )
7.7 Hz, 1H), 7.01 (s, 1H), 6.96 (m, 2H), 6.90 (d, J ) 8.7 Hz, 1H),
3.91 (s, 3H), 3.87 (s, 3H), 2.92 (s, 3H), 2.91 (s, 3H), 2.38 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 148.3, 148.1, 148.1,
138.2, 131.7, 130.7, 130.3, 126.5, 123.9, 121.3, 112.3, 110.8, 55.8,
55.7, 36.6, 36.3, 21.0; HRMS (ESI) m/z calcd for C18H22NO4 [M
+ H]+ 316.1543, found 316.1543.
1
mg, 84%): H NMR (400 MHz, CDCl3) δ 6.86 (d, J ) 8.1 Hz,
1H), 6.78 (d, J ) 8.0 Hz, 1H), 6.51 (s, 1H), 2.70 (s, 3H), 2.32 (s,
3H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0 (q, J
) 38.1 Hz), 154.4, 148.27, 135.8, 132.7, 124.7, 115.3, 115.0 (q, J
) 287.5 Hz), 107.5, 36.5, 36.4, 20.4; 19F NMR (376 MHz, CDCl3)
δ -74.5. Recrystallization from dichloromethane and hexanes gave
a single crystal suitable for X-ray analysis. For crystallographic
data, see the Supporting Information.
Acknowledgment. Dedicated to the memory of Professor Keith
Fagnou for his contributions to C-H bond functionalization.
Funding is provided by the University of Toronto, Canada Founda-
tion for Innovation, Ontario Research Fund, Boehringer Ingelheim
Ltd. Canada, and the Natural Sciences and Engineering Research
Council (NSERC) of Canada. V.M.D. is grateful for an Alfred P.
Sloan Fellowship and C.S.Y. for an NSERC Andre´ Hamer Award
and a Canada Graduate Scholarship. We thank Mengzhou Li for
helpful experiments and Yang Li and Serge Gorelsky for helpful
discussions.
Reaction of Bimetallic Palladacycle 3 with Benzene. In a
1-dram vial was stirred a solution of palladacycle 3 (33.2 mg, 0.042
mmol) and benzene (0.5 mL) on a heating block at 70 °C for 18 h.
After the solution was cooled to ambient temperature, GC-FID
analysis was conducted using dodecane (23 µL, 0.1 mmol) as an
internal standard. Target product 2t was afforded in >99% GC yield.
The reaction mixture was concentrated in vacuo, and the resulting
residue was purified by preparative thin-layer chromatography
(eluent: hexanes/EtOAc ) 3:1, v/v) to afford the phenylated product
2t as a colorless oil (20.3 mg, 95%).
Competitive Arylation of Bimetallic Palladacycle 3 with
Benzene and o-Dimethoxybenzene. In a 1-dram vial was stirred
a solution of palladacycle 3 (31.6 mg, 0.040 mmol), benzene (0.25
mL), and o-dimethoxybenzene (0.25 mL) on a heating block at 70
°C for 18 h. After the solution was cooled to ambient temperature,
GC-FID analysis was conducted using dodecane (23 µL, 0.1 mmol)
as an internal standard. The target products 2t and 2ac were afforded
Supporting Information Available: Experimental procedures
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA100783C
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5844 J. AM. CHEM. SOC. VOL. 132, NO. 16, 2010