Pd-Catalyzed Site-Selective p-Hydroxyphenyloxylation of Benzylic α-C(sp3)-H Bonds with 1,4-Benzoquinone

Article abstract of DOI:10.1021/acs.orglett.6b02782

A Pd-catalyzed, site-selective p-hydroxyphenyloxylation of benzylic α-C(sp³)-H bonds with 1,4-benzoquinone using thioamide as a directing group is reported. 1,4-Benzoquinone is employed as the p-hydroxyphenyloxy source without extra oxidants. T

Full text of DOI:10.1021/acs.orglett.6b02782

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Site-Selective p‑Hydroxyphenyloxylation of Benzylic
α‑C(sp3)−H Bonds with 1,4-Benzoquinone
Guangjun Song, Ziwei Zheng, Yanhui Wang, and Xinhong Yu*
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, and State Key Laboratory of Bioengineering Reactors, East
China University of Science & Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed, site-selective p-hydroxypheny-
loxylation of benzylic α-C(sp3)−H bonds with 1,4-benzoqui-
none using thioamide as a directing group is reported. 1,4-
Benzoquinone is employed as the p-hydroxyphenyloxy source
without extra oxidants. This method exclusively gives site
selectivity at α-C(sp3)−H bonds rather than the usual β-
C(sp3)−H bonds through C−H activation mode. The
reactions proceed with high functional group tolerance in
yields of 42−93%.
hydroquinone derivatives is still rare. In 2006, Renaud et al.
developed a radical addition to 1,4-benzoquinones at the
oxygen atom when bulky secondary and tertiary alkyl radicals
were used (Scheme 1b).6 It is noteworthy that the products of
addition at oxygen and carbon are both found.
ince benzoquinone and its derivatives have wide application
Sin many fields and are ubiquitous in organic chemistry,
functionalization of benzoquinones is still highly desirable.1
Despite the significant progress achieved for the Pd-catalyzed
cross-coupling reactions, only scattered examples of Pd-
catalyzed coupling with benzoquinone have been attained.
Stille or Suzuki coupling is an indirect strategy to
functionalization of benzoquinones.2 This procedure requires
first installing a Br, I, or OTf group and suffers from chemo-
and regioselectivity during prefunctionalization. In 2014, Lee
first reported Pd-catalyzed direct C−H functionalization of
benzoquinone (Scheme 1a).3 The direct functionalization of
benzoquinones was so far mainly based on a radical pathway
such as Meerwein arylation,4 Ag-catalyzed C−H monofunc-
tionalization,5 and so on. However, the direct functionalization
of benzoquinone exclusively at the oxygen atom leading to
In fact, benzoquinones often play as an oxidant or ligand
instead of a substrate in Pd catalysis.7 An early report that
benzoquinone can coordinate with Pd(0), followed by a redox
process to regenerate Pd(II) and hydroquinone.8 However,
hydroquinone was usually released from the metal prior to act
as a coupling partner in the presence of other ligand,
nucleophile, and steric effect.8a To the best of our knowledge,
hydroquinones originated from benzoquinones couple with
other atoms has not been explored yet. Over the past decades,
chelation-assisted transition-metal-catalyzed direct functionali-
zation of C−H bonds has been well developed.9 However,
functionalization of C(sp3)−H bonds is still a fundamental and
ongoing challenge, especially in regioselectivity due to the
inertness of aliphatic C−H bonds.10
Scheme 1. Site-Selective Functionalization of Benzoquinone
Given these developments, we envisaged that benzoquinone
was reduced to hydroquinone through a Pd(0)/Pd(II) mode,
followed by Pd(II) activation of C−H bonds under assistance
of a directing group to form cyclometalated intermediate, which
would facilitate the subsequent coupling (Scheme 1c). This
method is different from previous C−H activation reactions.
Palladium plays dual roles in this reaction, including reduction
of benzoquinone to the hydroquinone coupling partner via a
redox process and activation of the C−H bonds by the resulting
Pd(II) species. The protocol can allow for convenient synthesis
of aryl alkyl ethers, which are widely found in numerous
biologically molecules and natural products (Figure 1).11
Received: September 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02782
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Letter
coupling partners, the specific directing group and catalyst serve
a single reaction in most cases.14
Encouraged by achieving the desired promise, we attempted
to optimize the reaction conditions. When surveying the effect
of solvents, we found that the yield was improved to 88% in
CCl4 (Table 1, entry 8). PivOH and K2CO3 can promote the
reaction (Table 1, entries 8, 12, 13, and 18).This may be
attributed to both of them as promoters of proton abstraction
as reported by Echavarren and Fagnou.15 Using a Pd(0) instead
of Pd(OAc)2 precatalyst resulted in a lower yield (entries 10
and 11). A superior outcome was provided by 1,4-
benzoquinone (4.0 equiv), PivOH (5.0 equiv), and Pd(OAc)2
(0.1 equiv) at 100 °C (Table 1, entry 8). Argon is beneficial to
the coupling; this is probably because both oxygen and 1,4-
benzoquinone can oxidate Pd(0) to Pd(II).8
Figure 1. Drugs and natural products containing aryl alkyl ethers.
In recent years, amides have been developed to use as
directing groups in metal-catalyzed C−H activation.12 At the
outset of our studies, 2-phenylpropanamide was used as the
model substrate, and different Pd catalysts, additives, and
solvents were systematically examined (see the Supporting
Information). Although our initial efforts to achieve Pd-
catalyzed p-hydroxyphenyloxylation of C(sp3)−H bonds with
1,4-benzoquinone were generally unsuccessful, we were
inspired by a report by Yu in 2015 using thioamide as a
directing group.13 Fortunately, the desired product 3a was
achieved in 40% yield (Table 1, entry 1). To our surprise, it
gives regioselectivity at α-C(sp3)−H bonds rather than the
usual β-C(sp3)−H bonds. This result implies that coordination
behavior of thioamide is essential for the reaction to proceed.
While numerous transformations can be achieved with various
Under the optimized reaction conditions, we explored the
scope of thioamides (Scheme 2). First, we examined different
a,b
Scheme 2. Substrate Scope
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
solvent
DCE
additive (equiv)
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
PivOH (5.0)
none
40
0
2
HFIP
ACN
1,4-dioxane
DMF
PhMe
PhCl
CCl4
3
trace
0
4
5
trace
60
47
88
0
6
7
8
9
CCl4
10
11
12
13
14
15
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CCl4
31
22
55
72
43
0
CCl4
CCl4
CCl4
PivOH (3.0)
AcOH (5.0)
TFA (5.0)
CCl4
CCl4
a
Reaction conditions: 1 (0.2 mmol), 2a (0.8 mmol), Pd(OAc)2 (0.02
c
16
CCl4
PivOH (5.0)
NaOAc (2.0)
K2CO3 (2.0)
PivOH (5.0)
60
56
84
51
b
mmol), PivOH (1.0 mmol), Ar, 24 h at 100 °C. Isolated yield.
17
18
CCl4
CCl4
substitutions on the aryl using 1,4-benzoquinone as the partner.
Substrates containing all kinds of functional groups work well
to provide good to excellent yields in which electron-donating
groups are superior to withdrawing groups. When electron-rich
arenes are used, the methoxy- and para-substituted methyl are
much better groups than others. Among halogen-substituted
arenes, para-substituted chlorine is worse than meta-substituted
d
19
CCl4
a
Reaction conditions: 1a (0.2 mmol), 2a (0.8 mmol), additive, [Pd]
catalyst (0.02 mmol), and solvent (3.0 mL). The mixture was
b
c
conducted under a Ar atmosphere for 24h. Isolated yields. The
reaction was conducted under an air system. The reaction was
conducted on 80 °C. PivOH = trimethylacetic acid.
d
B
DOI: 10.1021/acs.orglett.6b02782
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bromine and fluorine. One important feature of this method is
that heteroaryls are also compatible with this system. Substrates
1q and 1r also proceed smoothly. It is evident that excellent
yields can be achieved from 1a, 1m, and 1n, which are probably
propitious to stabilize palladium intermediates. The structure of
the 3j was confirmed by X-ray crystallography (see the SI).
The scope of 1,4-benzoquinone derivatives were investigated
next (see the SI). Unfortunately, all the substituted
benzoquinones are not transformed to the product under
optimal conditions. Among many oxidants, 1,4-benzoquinone is
most frequently used to recover Pd(II) from Pd(0).8e
Benzoquinone is a electron-deficient olefin that can coordinate
with Pd(0) intermediates then form Pd(II)/hydroquinone.8
The Pd(0)−alkene complexes proceed via an associative
addition/substitution pathway to remove of electron density
from the palladium(0).8b When stoichiometric palladium is
used, the tested benzoquinones are not converted to the
desired products and corresponding hydroquinones except
DDQ, which can oxidate thioamides. It demonstrates that
Pd(0) can not be oxidated by the tested benzoquinone
derivatives.
Scheme 4. Deuterium Labeling and Radical-Trapping
Experiments
However, this protocol can be readily scaled up, and when it
was performed on a gram scale of 1a, the product 3a was
achieved in 74% yield (Scheme 3).
Scheme 3. Large-Scale Synthesis of 3a on a Gram Scale
By combining these results, a plausible mechanism is
depicted in Scheme 5. First, Pd(0) coordinates with thioamide
Scheme 5. Proposed Mechanism
With the aim of gaining mechanistic insights into this
reaction, several radical-trapping and deuterium-labeling experi-
ments were performed (Scheme 4). The addition of 2 equiv or
4 equiv of 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) as a
radical scavenger does not inhibit the reaction (60% and 50%
yields, respectively). The addition of 4 equiv of 2,6-
dibutylhydroxytoluene (BHT) or 1,1-diphenylethene also has
a negligible effect on the yield (63%). A radical pathway was
ruled out. The intermolecular competition kinetic isotope effect
for C(sp3)−H of β-methyl is 0.9, and the result indicates that
the cleavage C−H bond of β-methyl is a not a rate-determining
step. It seems that β-methyls stabilize palladium intermedi-
ates.16 The KIE from two parallel reactions is 3.5, which
demonstrates that the cleavage of the α-C(sp3)−H bond is a
rate-determining step. Analysis by 1H NMR showed no
hydrogen shift in both experiments (see the SI). β-H
elimination of the five-membered metallacycle, followed by
bond rotation/insertion to form the four-membered pallada-
cycle, is not involved in this reaction. Pd-catalyzed α-C(sp3)−H
arylation and allylic alkylation of thioamides through an enolate
intermediate have been reported.17 However, this mechanism is
probably not suitable to this reaction because acid can promote
this coupling reaction, which also proceeds well at neutral
conditions. In 2014, Gaunt reported a Pd-catalyzed C−H
activation of aliphatic amines through a unique four-membered-
ring cyclopalladation for the first time.16 Zhang then achieved
α-C(sp3)−H bond activation/acetoxylation via a [4,6]-bcyclic
metallacycle.18
to serve as a directing group to form intermediate A, followed
by coordination with 1,4-benzoquinone and then in the
presence of PivOH to achieve C. The rate-determining step
is from C to D via a concerted metalation−deprotonation
mechanism.19 Subsequent reductive elimination from D
delivers the product 3a and releases Pd(0) for the next
catalytic cycle.
C
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Letter
́
2013, 49, 4558. (e) Molina, M. T.; Navarro, C.; Moreno, A.; Csaky, A.
̈
In conclusion, we have developed a Pd-catalyzed site-
selective p-hydroxyphenyloxylation of benzylic α-C(sp3)−H
bonds with 1,4-benzoquinone. The reaction proceeds with high
functional group tolerance and provides products exclusively at
the α-C(sp3)−H of thioamides rather than β-C(sp3)−H. This
strategy opens a new avenue for the rapid and efficient
synthesis of aryl alkyl ethers from readily available materials.
The preliminary reaction mechanism studies demonstrate that
this new method is probably through an unusual four-
membered palladacycle. Further study of the reaction
mechanism, chiral synthesis, and new organic transformations
are underway in our laboratories.
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ASSOCIATED CONTENT
■
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* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02782.
Experimental procedures and spectral data for all new
compounds (PDF)
Crystal data and structure for 3j (ZIP)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xhyu@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
(13) Spangler, J. E.; Kobayashi, Y.; Verma, P.; Wang, D.-H.; Yu, J.-Q.
J. Am. Chem. Soc. 2015, 137, 11876.
(14) Zhang, J. T.; Chen, H.; Wang, B. J.; Liu, Z. X.; Zhang, Y. H. Org.
Lett. 2015, 17, 2768.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (21476078) and the
Science and Technology Commission of Shanghai Municipality
(No. 12431900902).
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