Convenient Access to meta-Substituted Phenols by Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling and Oxidation

Article abstract of DOI:10.1002/chem.201702651

We report a new approach to the synthesis of meta-substituted phenols in which a single palladium catalyst accomplishes a Suzuki–Miyaura cross-coupling between a β-chlorocyclohexenone and an arylboronic acid, and oxidation of the resulting cyclohexenone to the corresponding phenol upon introduction of a terminal oxidant and electron transfer mediator. Notably, this method also allows ready access to ortho, meta-disubstituted phenols, sterically congested biaryl phenols, and more highly substituted phenols.

Full text of DOI:10.1002/chem.201702651

A Journal of
Accepted Article
Title: Convenient Access to meta-Substituted Phenols by Palladium-
Catalyzed Suzuki-Miyaura Cross-Coupling and Oxidation.
Authors: Arturo Orellana and Zi Wang
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To be cited as: Chem. Eur. J. 10.1002/chem.201702651
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Supported by

10.1002/chem.201702651
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Convenient Access to meta-Substituted Phenols by Palladium-
Catalyzed Suzuki-Miyaura Cross-Coupling and Oxidation
Zi Wang and Arturo Orellana*a]
syn-β-hydride elimination would outcompete the difficult
endocyclic anti-β-hydride elimination[8] or palladium enolate
isomerization (not shown) required for subsequent endocyclic
syn-β-hydride elimination.
Abstract: We report a new approach to the synthesis of meta-
substituted phenols in which single palladium catalyst
accomplishes Suzuki-Miyaura cross-coupling between β-
a
a
a
chlorocyclohexenone and an arylboronic acid, and oxidation of the
resulting cyclohexenone to the corresponding phenol upon
introduction of a terminal oxidant and electron transfer mediator.
Notably, this method also allows ready access to ortho, meta-
disubstituted phenols, sterically congested biaryl phenols, and more
highly substituted phenols.
a) Substituted phenols by Susuki-Miyaura cross-coupling
OH
OH
Suzuki-Miyaura
cross-coupling
H
H
R
X
H
H
R
OH
B
+
X = I, Br
HO
R'
1
R'
H
H
meta-halophenols are widely available
and relatively inexpensive for R = H
numerous examples for R = H
very few examples for R = C
•
•
•
Introduction
b) Meta-substituted phenols by oxidative Heck reaction (Stahl)
Polysubstituted phenols are an important class of aromatic
compounds found in pharmaceuticals and natural products, or
as intermediates in the synthesis of complex molecules.[1] Their
preparation can be challenging or lengthy, particularly when the
final product includes a meta-substituent relative to the phenol
hydroxyl group. This is not surprising since the inherent
reactivity of phenols in electrophilic aromatic substitution
reactions provides ortho- and para-substituted products readily,
but does not allow access to meta-substituted products.
Similarly, directed ortho-metallation strategies have limited use
in the generation of meta-substituted phenols.[2] Palladium-
catalyzed cross-coupling reactions of meta-halophenols with
OH
O
H
N
N
H
H
OH
B
Me
5%
Me
+
HO
R'
1
Pd(MeCN)4•2BF4 (5%)
10% AMS, NMP, 50 °C
then, DMSO, 80 °C
R'
limited to H at ortho-position
•
O
H
H
O
H
O
H
Pd
R'
H
H
H
H
H
anti-β-hydride
elimination
syn-β-hydride
elimination
R'
organometallic reagents provide
a viable route to meta-
R'
substituted phenols, however this approach is limited by the
availability of these electrophilic partners. Indeed, while a large
number of Suzuki-Miyaura cross-coupling reactions using meta-
halophenols have been reported,[3] very few examples have a
carbon substituent at the ortho-position between the hydroxyl
group and the meta-substituent, and of these only four bear an
alkyl group at that position (Scheme 1a).[4] Furthermore, the
classic conversion of nitrobenzene to meta-halophenol is not
suitable when an alkyl substituent is desired at the ortho-position
relative to the nitro group.[5] Clearly, the challenging preparation
of these electrophilic partners severely limits the use of cross-
coupling strategies to access meta-substituted phenols.
Recently, the palladium-catalyzed oxidation of cyclohexanone
derivatives to phenols has received considerable attention as a
method to access substituted phenols.[6,7] Stahl and co-workers
have demonstrated that the palladium-catalyzed oxidative Heck
reaction between boronic acids and cyclohexenone, and the
subsequent palladium-catalyzed oxidation of the coupled
product in the same pot provides access to meta-substituted
phenols (Scheme 1b).[7e] This route, however, does not allow
access to phenols substituted at both the ortho- and meta-
positions. Presumably this limitation arises because exocyclic
Scheme 1. Selected methods for the synthesis of meta-substituted phenols..
We have devised a new approach to the synthesis of poly-
substituted phenols that is complementary to the above methods
and exhibits broader scope with respect to the electrophilic
partner. We envisioned an assisted tandem catalysis[9] approach
to phenols that integrates the Suzuki-Miyaura[10] cross-coupling
of β-chlorocyclohexenones[11] with boronic acids, and the
palladium-catalyzed oxidation of the coupled products upon
introduction of an oxidative switch[12-13] (Equation 1). β-
chlorocyclohexenones are easily and quantitatively prepared
from the corresponding 1,3-cyclohexanediones by treatment
with oxalyl chloride (not shown).[14] Furthermore, 1,3-
cyclohexanediones are readily alkylated at the 2-position (not
shown), providing convenient access to ortho,meta-disubstituted
phenols.[15] Thus, our method complements the gold-catalyzed
synthesis of annelated ortho, meta-disubstituted phenols from
alkynes and furans.[16]
Assisted tandem
Suzuki-Miyaura
cross-coupling
OH
O
OH
B
R
R
(1)
+
[a]
Z. Wang and Professor A. Orellana*
Department of Chemistry
York University
& palladium-
HO
R'
1catalyzed oxidation
R'
Cl
β-chloro unsaturated ketones readily
available from 1,3-cyclohexanedione
works for H and C
at ortho-position
•
•
4700 Keele Street, Toronto, ON
M3J 1P3 CANADA
E-mail: aorellan@yorku.ca
Supporting information for this article is given via a link at the end of
the document.
Results and Discussion
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We chose to use β-chlorocyclohexenone and phenylboronic
acid as substrates for initial reaction development and to
optimize both steps of the tandem reaction at once. Because the
oxidative addition partner is a vinylogous acid chloride and
should therefore undergo facile oxidative addition, we
constrained ourselves to the use of a simple catalyst system
consisting of triphenylphosphine and palladium(II) salts. We also
chose solvent systems that are well-suited for oxidative
palladium chemistry,[17] and limited ourselves to oxygen or
hydrogen peroxide as terminal oxidants with the goal of
maintaining high atom economy. Table 1 shows selected results
from our optimization study. We quickly established that a
solvent mixture consisting of DMSO, which has long been used
in oxidative palladium chemistry,[18] and water was suitable for
cross-coupling using Pd(OAc)2 as the palladium source, and that
simply using a balloon of oxygen was insufficient for oxidation
(entry 1). We reasoned that liberating palladium from its
phosphine ligands after completion of the cross-coupling may
facilitate the oxidation and therefore added excess hydrogen
peroxide to oxidize triphenylphosphine to the phosphine oxide,
and to act as a terminal oxidant, however this was ineffective
(entry 2). Pyridines have proven to be effective ligands in
oxidative palladium reactions,[19] however the use of 2-
methoxypyridine in our reaction was not fruitful (entry 3). In
contrast, the use of excess HCl and 20% CuCl2 as an electron
transfer mediator[20] led to a significant improvement in yield, and
we chose this system for future oxidations (entry 4). The
beneficial effect of HCl may be due to acid-catalyzed formation
of the enol, which can in principle lead to a palladium enolate
and subsequent oxidation by β-hydride elimination. Other
solvent systems commonly used for Suzuki-Miyaura coupling did
not improve the reaction (entries 5-7). Changing the base to
more soluble Cs2CO3 provided a further improvement (entry 9).
We noted that the vinylogous acid chloride underwent some
decomposition upon storage. Reasoning that this may be a
problem during the reaction, we used a slight excess and
observed a corresponding improvement in yield (entry 9). Using
PdCl2 instead of Pd(OAc)2 led to a reduction in yield, however
using Pd(MeCN)4•2BF4 provided the phenol in 88% isolated
yield.
7
8
DMAc/DMSO/H2O instead of DMSO/H2O
26%
64%
83%
73%
88%
Cs2CO3 instead of Na2CO3
10% excess A
9
10
11
10% excess A, PdCl2 instead of Pd(OAc)2
10% excess A, Pd(MeCN)4(BF4)2 instead of Pd(OAc)2
Concerned that the vinyloguos acid chloride may be
decomposing at 90 °C, we optimized the temperature of the
cross-coupling step and determined that when conducted at 60
°C, the first step yields 89% isolated yield of the coupled product
in the simplest case possible (Scheme 2). We therefore
implemented this slight change in substrate scope studies (see
below). In a separate control experiment we also verified that the
oxidation step is indeed catalyzed by palladium (Scheme 2).
This experiment also confirms that CuCl2 acts as an electron
transfer mediator and is not directly responsible for the
oxidation[21] of the cyclohexenone to the phenol.
O
OH
O
PhB(OH)2 (1 equiv.)
Pd(MeCN)4•2BF4 (5%)
PPh3 (15%)
O2, HCl (3 equiv)
CuCl2 (20%)
no Pd
DMSO/H2O
100 °C, 16 h
DMSO/H2O
60 °C, 3 h
Ph
Ph
not formed
Cl
1.2 equiv
89%
Scheme 2. Optimized temperature for cross-coupling and control experiment
verifying palladium-catalyzed oxidation to phenol.
We next explored the scope of the tandem reaction by using
the β-chlorocyclohexenone and a variety of boronic acids (Table
2). The phenol synthesis (yields in bold) works equally well when
electron-deficient (entries a and b) or electron-rich arylboronic
acids are used (entry c). Similarly, ortho-tolylboronic acid gives
the coupled product in good yield (entry d), however, the use of
more sterically demanding 2,6-xylylboronic acid gave the
coupled product in significantly lower yield (entry e). 4-
Vinylphenyl boronic acid gave a relatively low yield (entry f),
which may be the result of side reactions with the vinyl group.
trans-2-Phenyl vinylboronic acid (entry g) and electron-rich
heterocyclic boronic acids (entries h and i) all provided the
coupled products in moderate yields. In some cases (entries a,
b, c, g and h) we conducted parallel reactions that were stopped
after the coupling step and compared the isolated yields of the
coupled product (in italics) with the yields of the corresponding
phenol. The close agreement between these two values
suggests that the overall yield is largely determined by the
success of the coupling step.
Table 1. Optimization of meta-phenol synthesis by tandem Suzuki-Miyaura
cross-coupling and oxidation.
OH
Pd(OAc)2 (5%), PPh3 (15%)
Na2CO3 (2 equiv)
DMSO/H2O (4:1)
90 °C, 2 h
O
OH
B
HO
+
Cl
A 1 equiv
O2 (balloon), HCl (3 equiv.)
CuCl2 (20%), 100 °C, 16 h
B 1 equiv
entry
change from above
yield
Table 2. Synthesis of meta-substituted phenols by Suzuki-Miyaura cross-
coupling and oxidation.
1
2
3
4
5
6
no HCl, no CuCl2
0%
<10%
0%
no HCl, no CuCl2, 5 equiv. H2O2 added
no HCl, no CuCl2, 20% 2-methoxypyridine
none
53%
0%
PhMe/EtOH/H2O instead of DMSO/H2O
PhMe/DMSO/H2O instead of DMSO/H2O
20%
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10.1002/chem.201702651
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Pd(MeCN)4•2BF4 (5%)
Pd(MeCN)4•2BF4 (5%)
O
OH
O
OH
PPh3 (15%), Cs2CO3 (2 equiv)
DMSO/H2O (4:1)
60 °C, 2 h
PPh3 (15%), Cs2CO3 (2 equiv)
DMSO/H2O (4:1)
90 °C, 2 h
OH
B
OH
B
H
H
R
R
+
+
HO
R'
HO
R'
then:
O2 (balloon), HCl (3 equiv.)
CuCl2 (20%), 100 °C, 16 h
Cl
then:
O2 (balloon), HCl (3 equiv)
CuCl2 (20%), 100 °C, 16 h
R'
Cl
R'
1.2 equiv
1 equiv
1.0 equiv
1.2 equiv
(HO)2B
(HO)2B
(HO)2B
OMe
OH
OH
OH
O
O
H
Me
Me
S
O
a 80%
80%b
b 75%
79%b
c 79%
79%b
OMe
Me
Me
OMe
Me
Me
(HO)2B
(HO)2B
(HO)2B
88%
k 54%
j 70%
OH
OH
OH
OMe
Ph
f 40%a
e 50%a
d 81%
Me
Me
Ph
h 63% 68%b
(HO)2B
(HO)2B
i 57%a
(HO)2B
Me
m 66%a
80%b
n 62%a
73%b
l 48%a
g 65%
69%b
S
O
OH
O
OH
OH
Me
a) Using Pd(OAc)2 instead of Pd(MeCN)4•2BF4. b) Isolated yield of cross-
coupled product in a parallel reaction.
o 39%
Me
Me
Me
S
p 0%
57%c
q 0%
52%c
We then progressed to the more challenging synthesis of
ortho,meta-disubstituted phenols. The required β-chlorocyclo-
hexenones were readily prepared by alkylation of the 1,3-
diketone and chlorination with oxalyl chloride. These substrates
proved more robust than the parent chloride and were therefore
used as the limiting reagent in all future experiments. Table 3
shows that substitution at the α-position of the cyclohexenone
renders the coupling step more challenging and the overall
process lower yielding (entries j-n). In two instances (entries l
and n) parallel reactions were stopped after the cross-coupling
step, and comparison of the yield of isolated coupled product (in
red italics) with the isolated yield of phenol revealed a significant
difference, suggesting that the oxidation step may be more
challenging for these substrates. A significant drop in yield was
also observed when benzo[b]thien-3-ylboronic is used (entry o),
which may reflect the increased steric environment or the
electron-rich nature of this system. The cross-coupling reaction
fails completely under standard conditions when it involves two
sterically demanding partners (entries p and q). Fortunately, this
limitation can be addressed by using more sophisticated
catalysts (yields in blue italics, see discussion below). Finally,
entries r and s demonstrate that this simple catalytic system
enables the synthesis of biaryl systems bearing medicinally-
relevant functional group content.
Me
Me
OH
OH
Ph
Me
O
O
O
O
S
S
Me
Me
r 51%a
s 52%a
N
N
a) Using Pd(OAc)2 instead of Pd(MeCN)4•2BF4. b) Isolated yield of cross-
coupled product in
reported in table 4.
a parallel reaction. c) Using re-optimized conditions
Given the simple catalyst system used in our initial work, it is
not surprising that the isolated yields of ortho,meta-disubstituted
phenol are, in general, lower than those of meta-phenols, and
we attribute these lower yields to the more challenging cross-
coupling step. A wealth of more sophisticated phosphine ligands
have been developed to address challenging cross-coupling
reactions leading to congested biaryls. We therefore reasoned
that one of these reactions should provide the desired
congested phenol after some optimization, and re-investigated
the cross-coupling step in the tandem reaction using the most
challenging example (Table 3, entry q) using dppe, DPEPhos
and SPhos as ligands on palladium since they are known to
provide highly hindered biaryls by Suzuki-Miyaura cross-
coupling (Table 4).[22] Changing the base from Cs2CO3 to KOH
had a significant improvement in yield (entry 1). Using DPEPhos
did not provide the desired product (entry 2), and changing the
ligand to SPhos gave marginally better results (entry 3). In
contrast, using Pd(dppf)Cl2•CH2Cl2 as the catalyst provided the
disubstituted phenol in 52% yield, which is significant given the
congested nature of this product and the fact that palladium
catalyzes both steps. The same conditions also provided
product p (Table 3) in 57% yield.
Table 3. Synthesis of ortho,meta-disubstituted phenols by Suzuki-Miyaura
cross-coupling and oxidation.
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Table 4. Re-optimization of catalyst system for the synthesis of sterically
congested meta-phenols.
Acknowledgements
This work was supported by a Discovery grant from the Natural
Sciences and Engineering Council of Canada (NSERC). We
thank Professor Michael Organ for generous sharing of
resources.
OH
O
OH Me
B
coupling conditions
DMSO/H2O (4:1)
90 °C, 2 h
Me
Me
Me
HO
then:
O2 (balloon), HCl (3 equiv)
CuCl2 (20%), 100 °C, 16h
Cl
Me
1.2 equiv
Keywords: Phenols • Palladium • Cross-coupling • Oxidation •
1.0 equiv
Me
Tandem Catalysis
entry
coupling conditions
yield
21%
0%
[1]
[2]
Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: Amsterdam,
1996; Vol. 52.
1
2
3
4
5% Pd(OAc)2, 15% PPh3, 200% KOH
5% Pd(OAc)2, 15% DPEPhos, 200% KOH
5% Pd(OAc)2, 15% SPhos, 200% KOH
5% Pd(dppf)Cl2•CH2Cl2, 200% KOH
(a) E. J.-G. Anctil, V. Snieckus, in Metal-Catalyzed Cross-Coupling
Reactions, 2nd Edition. Vol 2. (Eds.: De Meijere, A; Diederich, F.) Wiley-
VCH, Chichester, 2004, pp.761-813. (b) V. Snieckus Chem. Rev. 1990,
90, 879-993. For an ingenuous use of carboxylate as a traceless meta-
directing group for in the synthesis of meta-phenols, see: (c) J. Luo, S.
Araromi, S. Preciado, I. Larrosa Chem. Asian. J. 2016, 11, 347. (d) J.
Luo, S. Preciado, I. Larrosa Chem. Commun. 2015, 51, 3127. (e) J. Luo,
S. Araromi, S. Preciado, I. Larrosa J. Am. Chem. Soc. 2014, 136, 4189.
A recent SciFinder search yielded nearly 500 examples of this reaction.
For recent reports, see: (a) J. Wen, Z. Huang, S. Hu, S. Li, W. Li, X.
Wang J. Hazard. Mater. 2016, 318, 363. (b) X. Duan, H. Wang, Z. Ji, Y.
Cui, Y. Yang, G. Qian J. Solid State Chem. 2016, 241, 152.
<10%
52%
Ph
P
[3]
[4]
Ph
Ph Ph
O
Ph
MeO
P
P
Ph
Fe
PdCl2•CH2Cl2
OMe
P
Ph
A recent SciFinder search yielded only 34 examples Suzuki-Miyaura
cross-coupling of meta-halogenated, ortho-substituted phenol. Of these,
only four used an ortho-alkyl, meta-halophenol. All remaining examples
utilized meta-halophenols bearing a formyl, carboxylate or nitrile group
at the meta-position. For recent examples, see: (a) J. G. Varnes, T.
Gero, S. Huang, R. B. Diebold, C. Ogoe, P. T. Grover, M. Su, P.
Mukherjee, J. C. Saeh, T. Macintyre, G. Repik, K. Dillman, K. Byth, D.
J. Russel, S. Ioannidis Bioorg. Med. Chem. Lett. 2014, 24, 3026. (b) K.
Seth, P. Purohit, A. K. Chakraborti Org. Lett. 2014, 16, 2334. (c) O.
Saku, M. Saki, M. Kurokawa, K. Ikeda, T. Takizawa, N. Uesaka Bioorg.
Med. Chem. Lett. 2010, 20, 1090.
PCy2
SPhos
Ph
Pd(dppf)Cl2•CH2Cl2
DPEPhos
Equation 2 demonstrates that this tandem reaction constitutes
a convenient approach to polysubstituted phenols. Alkylation of
the α-position of the vinylogous chloride proceeds as expected
by simple enolate formation with LDA and introduction of an
alkyl electrophile. This is preferable to alkylation of the 2-methyl-
1,3-cyclohexanedione followed by treatment with oxalyl chloride
since this latter approach leads to mixtures of vinyloguous
chlorides (not shown). Tandem cross-coupling and oxidation
using standard conditions leads to the trisubstituted phenol in
66% yield.
[5]
A recent Scifinder search yielded no examples of conversion of
nitrobenzenes with a carbon substituent at the ortho-position to the
corresponding meta-halo, ortho-alkyl phenol. Presumably this
transformation would result in mixtures of positional isomers. For
conversion of meta-halophenols to ortho,meta-dihalophenols by
directed ortho-metallation and subsequent Sonogashira cross-coupling
at the ortho-position see: R. Sanz, M. P. Castroviejo, Y. Fernández, F.
J. Fañanas J. Org. Chem. 2005, 70, 6548.
O
OH
O
LDA; MeI
54%
Me
Me
Me
(2)
Ph
Me
Me
PhB(OH)2
[6]
For early examples of this transformation, see: (a) L. Ruzicka, E.
Morgeli Helvetica Chimica Acta 1936, 19, 377. (b) E. Mosettig, H. M.
Duvall J. Am. Chem. Soc. 1937, 59, 367. (c) R. P. Linstead, K. O. A.
Michaelis J. Chem. Soc. 1940, 1134. (d) R. P. Linstead, K. O. A.
Michaelis, S. L. S. Thomas J. Chem. Soc. 1940, 1139. (e) J. W. Cook,
R. Schoental J. Chem. Soc. 1945, 288. (f) C. D. Gutsche, W. S.
Johnson J. Am. Chem. Soc. 1946, 68, 2239. (g) E. C. Kornfeld, E. J.
Fornefeld, G. B. Kline, M. J. Mann, D. E. Morrison, R. G. Jones, R. B.
Woodward J. Am. Chem. Soc. 1956, 78, 3087. (h) R. B. Turner, D. E.
Nettleton, R. Ferebee J. Am. Chem. Soc. 1956, 78, 5923. (i) R. N.
Lacey J. Chem. Soc. 1960, 1625. (j) Z. Horii, S. Yamamura, H. Hakusui,
T. Nishikado, T. Momose Chem. Pharm. Bull. 1968, 16, 2456. (k) T. T.
Wenzel J. Chem. Soc., Chem. Commun. 1989, 932.
as in Table 3
66%
t
(unoptimized)
Cl
Cl
Conclusions
We have demonstrated a new method for the synthesis of
meta-substituted phenols in which palladium catalyzes both a
Suzuki-Miyaura cross-coupling and the oxidation of the coupled
product to the corresponding phenol. This tandem reaction can
also be used to prepare ortho,meta-disubstituted sterically
congested phenols, as well as trisubstituted phenols, and avoids
many limitations inherent in more traditional approaches to these
valuable intermediates. Lastly, the modular nature of this
approach to the synthesis of polysubstituted phenols makes it
well-suited for the synthesis of small molecule libraries.
[7]
For recent examples of palladium-catalyzed oxidations of
cyclohexanones to phenols, see: (a) M. F. Oldfield, L. Chen, N. P.
Botting Tetrahedron 2004, 60, 1887. (b) Y. Izawa, D. Pun. S. S. Stahl
Science, 2011, 333, 209-213. (c) T. Diao, T. J. Wadzinski, S. S. Stahl,
Chem. Sci. 2012, 3, 887-891. (d) M. T. Kessler, M. H. G. Prechtl Chem.
Cat. Chem. 2012, 4, 326. (e) Y. Izawa, C. Zheng, S. S. Stahl Angew.
Chem. Int. Ed. 2013, 52, 3672-3675. (f) T. Diao, D. Pun, S. S. Stahl J.
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10.1002/chem.201702651
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FULL PAPER
Am. Chem. Soc. 2013, 135, 8205-8212. (g) T. Diao, D. Pun, S. S. Stahl
J. Am. Chem. Soc. 2013, 135, 8213-8221. (h) J. H. Park, C. Y. Park, M.
J. Kim, M. U. Kim, Y. J. Kim, G.-H. Kim, C. P. Park Org. Process. Res.
Dev. 2015, 19, 812. (i) J. Zhang, Q. Jiang, D. Yang, X. Zhao, Y. Dong,
R. Liu Chem. Sci. 2015, 6, 4674.
vinylogous esters. The need to use strongly basic enolates or
organometallic reagents in the penultimate step of this sequence limits
the functional group compatibility of this methodology. G. Yu, D. L. J.
Clive. J. Org. Chem. 2016, 81, 8470.
[16] (a) S. Tsupova, F. Rominger, M. Rudolph, A. S. K. Hashmi Green
Chem. 2016, 18, 5800. (b) A. Zeiler, M. J. Ziegler, M. Rudolph, F.
Rominger, A. S. K Hashmi Adv. Synth. Catal. 2015, 357, 1507. (c) A. S.
K. Hashmi, M. Wölfle, J. H. Teles, W. Frey Synlett, 2007, 1747. A. S. K.
Hashmi, T. M. Frost, J. W. Bats J. Am. Chem. Soc. 2000, 122, 11553.
[17] For the use of dimethyl acetamide (DMAc) in oxidative palladium-
catalyzed reactions, see: T. Mitsudome, K. Mizumoto, T. Mizugaki, K.
Jitsukawa, K. Kaneda Angew. Chem. Int. Ed. 2010, 49, 1238. For
discussion on the use of dimethylsulfoxide in oxidative palladium
chemistry see reference 18a.
[8]
[9]
For a review of Heck reactions proceeding through anti-β-hydride
elimination, see: M. Ikeda, S. A. A. El Bialy, T. Yakura Heterocycles
1999, 51, 1957. For an apparent anti-β-hydride elimination leading to
cyclohexenones, see: T. Daisuke, A. G. Myers Org. Lett. 2004, 6, 433.
This type of catalysis is termed ‘Assisted Tandem Catalysis’. D. Fogg,
E. N. Dos Santos Coord. Chem. Rev. 2004, 248, 2365-2379.
[10] (a) N. Miyaura, K. Yamada, A. Suzuki Tetrahedron Lett. 1979, 20, 3437.
(b) N. Miyaura, A. Suzuki Chem. Rev. 1995, 95, 2457.
[11] We could find no examples of β-chlorocyclohexenones used in Suzuki-
Miyaura cross-coupling reactions in the primary literature and only one
report in the patent literature: F. Marion, F. Lieby-Muller, S. Grisoni, N.
Rahier, M. Perez, I. Sartori WO 2014020101. The analogous coupling
reaction with β-bromo- and β-iodoketones is known. For recent
examples, see: (a) J. Khalaf, M. E. Estrella-Jimenez, M. J. Shashack, S.
S. Phatak, S. Zhang, S. R. Gilbertson ACS Comb. Sci. 2011, 13, 351.
(b) L. Chapman, J. C. Beck, L. Wu, S. E. Reisman J. Am. Chem. Soc.
2016, 138, 9803.
[18] Reviews on aerobic oxidations with Pd: (a) S. S. Stahl Angew. Chem.
Int. Ed. 2004, 43, 3400-3420. (b) S. S. Stahl Science, 2005, 309, 1824-
1826. (c) K. M. Gligorich, M. S. Sigman Chem. Commun. 2009, 3854-
3867. (d) A. N. Campbell, S. S. Stahl Acc. Chem. Res. 2012, 45, 851-
853.
[19] (a) S. R. Fix, J. L. Brice, S. S. Stahl Angew. Chem. Int. Ed. 2002, 41,
164. (b) K. M. Engle, J.-Q. Yu J. Org. Chem. 2013, 78, 8927. See also
reference 18.
[12] For an example of quinones as the oxidative trigger in assisted tandem
catalysis with palladium, see: B. M. Trost, D. A. Thaisrivongs, M. M.
Hansmann Angew. Chem. Int. Ed. 2012, 51, 11522-11526.
[13] For a previous example of assisted tandem palladium catalysis in
phenol synthesis, see: S. Samadi, A. Orellana Chem.Cat.Chem. 2016,
8, 2472.
[20] For a review on the use of electron transfer mediators (ETMs), see: J.
Piera, J.-E. Bäckvall Angew. Chem. Int. Ed. 2008, 47, 3506-3523.
[21] K. Kikushima, Y. Nishina. RSC Adv. 2013, 3, 20150.
[22] For the use of SPhos, see: S. D. Walker, T. E. Barder, J. R. Martinelli,
S. L. Buchwald Angew. Chem. Int. Ed. 2004, 43, 1871. For the use of
DPEPhos, see: Y. Jingjun, M. P. Rainka, X.-X. Zhang, S. L. Buchwald,
J. Am. Chem. Soc. 2002, 124, 1162.
[14] C. H. Heathcock, E. F. Kleinmann, E. S. Binkley J. Am. Chem. Soc.
1982, 104, 1054.
[15] Clive has reported the use of 1,3-cyclohexanediones in a four-step
synthesis of phenols that proceeds through the corresponding α-bromo
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Catalytic two-step: The tandem
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b-chlorocyclohexenones and
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oxidation provide access to meta-
substituted and ortho,meta-
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disubstituted phenols.
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