Weak Coordination Promoted Regioselective Oxidative Coupling Reaction for 2,2′-Difunctional Biaryl Synthesis in Hexafluoro-2-propanol

Article abstract of DOI:10.1021/acs.orglett.5b02115

An unprecedented weak coordination promoted dehydrogenative cross-coupling reaction has been developed by palladium catalysis, which provides a convenient access to a wide range of 2,2′-difunctional biaryls from easily accessible substrates. Both HFIP solvent and oxidants serve as the critical factors in this new reaction. A plausible mechanism involving Pd(II)/Pd(IV) is proposed. The reaction demonstrates excellent reactivity, broad functional-group tolerance and high yields.

Full text of DOI:10.1021/acs.orglett.5b02115

Letter
pubs.acs.org/OrgLett
Weak Coordination Promoted Regioselective Oxidative Coupling
Reaction for 2,2′-Difunctional Biaryl Synthesis in Hexafluoro-2-
propanol
Chao Zhang and Yu Rao*
MOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and
School of Life Sciences, Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: An unprecedented weak coordination pro-
moted dehydrogenative cross-coupling reaction has been
developed by palladium catalysis, which provides a convenient
access to a wide range of 2,2′-difunctional biaryls from easily
accessible substrates. Both HFIP solvent and oxidants serve as
the critical factors in this new reaction. A plausible mechanism
involving Pd(II)/Pd(IV) is proposed. The reaction demonstrates excellent reactivity, broad functional-group tolerance and high
yields.
Scheme 1. Oxidative C−H Dehydrogenative Coupling
he 2,2′-difunctional biaryl scaffold serves an important
T
structural motif in natural products and bioactive
compounds.1 Because of its significance, the development of
general, efficient, and mild methods for aryl−aryl bond formation
remains an area of tremendous research efforts. The most
common method for 2,2′-difunctional biaryl construction is
metal-catalyzed cross-coupling between two functionalized
arenes.2 Compared with classic cross-coupling with preinstalled
functional groups, direct dehydrogenative arene coupling3 by
activating two C−H bonds represents the most efficient method
for the formation of 2,2′-difunctional biaryls.
Over the past decade, direct C−H bond cleavage by weak
coordination4 of metal catalysts with nearby common functional
groups has been well studied by Yu and co-workers and has led to
the discovery of a number of powerful C−H functionalization
reactions. However, the application of this strategy in
dehydrogenative cross-coupling to access 2,2′-difunctional
biaryls is still surprisingly under-developed. Currently, the
majority of studies of 2,2′-difunctional biaryl synthesis by
dehydrogenative cross-coupling have relied on the use of strong
coordinating groups like pyridine,5 amide,6 oxazoline or
imidazole,7 etc.8 (Scheme 1). In contrast, the application of
ester, ketone, or carbamate functionality as the directing group in
transition-metal-catalyzed dehydrogenative cross-coupling has
not yet been achieved, despite ester, ketone, or carbamate
functional groups being readily available and also easily
converted to alcohols, amines, amides, and other carbonyl
compounds.
Here, we report the first example of Pd(II)-catalyzed
dehydrogenative cross-coupling assisted by weak coordination,
which can now readily provide a broad range of 2,2′-difunctional
biaryl compounds (Scheme 1). We envisioned that under proper
acidic conditions palladium(II) catalysts might promote o-C−H
bond cleavage by weak coordination with the carbonyl oxygen of
aromatic ketones or benzoates. Moreover, with suitable ligands
and co-oxidants, a Pd(II) complex can be converted into a
Pd(IV)9 intermediate stabilized by a potential dual-coordination
with two weakly coordinating groups. Finally, a C−C bond
formation would be made possible via a reductive elimination
from Pd(IV) to afford corresponding dehydrogenated cross-
coupling arenes. Our aim was to identify suitable weak
coordination-promoted dehydrogenative cross-coupling condi-
tions via a Pd(II)/Pd(IV) cycle for preparation of unique 2,2′-
difunctional biaryls (Scheme 2).
Herein, as briefly shown in Table 1, a model investigation was
initiated with benzophenone 1, which contains a carbonyl group
as the weakly coordinating group to test our idea. We evaluated
numerous conditions that varied combinations of Pd(II)
catalysts, external oxidants, and acid additives. After many
Received: July 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02115
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Letter
(trifluoroethanol) provided 2 in a moderate yield of 40%, which
is similar to that of DCE (entry 5). Gratifyingly and interestingly,
in the presence of HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol),12
the yield was significantly improved to 70% (entry 8). We think
that HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol) may work as an
effective ligand for palladium to promote this reaction.
Compared with other solvents, HFIP could serve not only as a
solvent system but also as a suitable ligand because of its acidity
(pKa = 9.3), which might account for its critical role in this
reaction. Notably, it was found that optimizations with the
combination of K2S2O8 and NaIO4 could increase the yield up to
89% (entry 10). Further investigations confirmed that both a
palladium catalyst and an oxidant were essential for the reaction
(entries 11−12). Other oxidants such as PhI(OAc)2, oxone, and
metal catalysts including Cu, Ru, and Rh, etc., cannot promote
the transformation under the reaction conditions (entries 13−
15).
Scheme 2. Proposed Reaction Process
Having identified these optimal conditions, we set out to
explore the scope for this new reaction. As displayed in Table 2, a
Table 1. Optimization of the Reaction Conditions
Table 2. Homo-dehydrogenative Cross Coupling of Aryl
a
Ketones, Esters, and Carbamates
a
yield
(%)
entry
1
conditions
Pd(OAc)2, K2S2O8 (1.1 equiv), AgOTf (1.0 equiv), TfOH 30
(1.0 equiv), DCE 70 °C
2
Pd(OAc)2, K2S2O8 (1.1 equiv), TfOH (2.0 equiv), DCE
48
11
70 °C
3
Pd(OAc)2, NaIO4 (1.1 equiv), TfOH (2.0 equiv), DCE
70 °C
b
4
Pd(OAc)2, NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH 50 (41)
(2.0 equiv), DCE 70 °C
5
Pd(OAc)2, NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH 25
(2.0 equiv), TFE 70 °C
6
Pd(OAc)2, NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH NR
(2.0 equiv), ethanol 70 °C
7
Pd(OAc)2, NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH NR
(2.0 equiv), 2-propanol 70 °C
b
8
Pd(OAc)2, K2S2O8 (1.1 equiv), TfOH (2.0 equiv), HFIP
70
70 °C
b
b
9
Pd(OAc)2, NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH 86 (83)
(2.0 equiv), HFIP 70 °C
10
11
Pd(OAc)2, NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH 93 (89)
(2.0 equiv), HFIP 50 °C
NaIO4 (0.6 equiv), K2S2O8 (0.5 equiv), TfOH (2.0 equiv), NR
HFIP 70 °C
12
13
Pd(OAc)2, TfOH (2.0 equiv), HFIP 70 °C
Pd(OAc)2, PhI(OAc)2 (1.1 equiv), TfOH (2.0 equiv),
HFIP 70 °C
NR
10
a
b
c
14
15
Pd(OAc)2, Oxone (1.1 equiv), TfOH (2.0 equiv), HFIP
18
Isolated yield. DCE as solvent; only NaIO4 used as oxidant. Overall
70 °C
yield of three regioisomers.
other metals [Ru(II), Rh(III), Cu(II)], NaIO4 (0.6 equiv), NR or
K2S2O8 (0.5 equiv), TfOH (2.0 equiv), HFIP 70 °C trace
variety of substituted benzophenones were surveyed. The scope
of the benzophenone was found to be broad, and various
benzophenones were smoothly converted into the correspond-
ing dimers (3a−o) in moderate to excellent yields. Different
substituted aryl groups, as well as the electron-rich (3a,b,f) and
electron-deficient (3c,d,h) aryl groups, were well tolerated. For
unsymmetrical diaryl ketone substrates, the more electron-rich
or less sterically hindered parts coupled preferentially (3e,g).
Besides aromatic groups, alkyl groups (3i−m) were also
compatible with the reaction conditions. Notably, when ketones
containing easily oxidizable α-protons were attempted, we found
that these ketones could be effectively transformed into the
desired products (3j,k) with excellent chemoselectivity. The
a
b
Conversion. Isolated yield.
fruitless attempts, to our delight, the desired 2,2′-dibenzoyl biaryl
compound 2 was observed in 30% yield after stirring for 6 h at 70
°C in the presence of Pd(OAc)2, potassium persulfate,10 triflic
acid (TfOH), and AgOTf (entry 1). The following study
revealed that AgOTf was not necessary for the reaction (entry 2).
It also was found that NaIO4 could be used as the oxidant to
promote the reaction as effectively as potassium persulfate (entry
3). Different solvent systems were screened as well. Among
them, no products were observed with other common solvents
such as DMSO, DMF, and ethanol, etc. In contrast, TFE11
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DOI: 10.1021/acs.orglett.5b02115
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Letter
sterically demanding cross-coupling product 3o could be formed
in a good yield of 76%. It was notable to find that a substrate with
a heteroaryl functional group was suitable for providing the
corresponding dimer product, 3n, which contained a 2-thienyl
group. As shown in Table 2, besides aromatic ketones, the
optimized conditions were further applied to other types of
substrates including benzyl acetates (4a−d), ethyl benzoates
(4e−f), and phenyl carbamates (4g−l), etc. To our delight, the
new reaction demonstrated the compatibility of all these
functional groups by generating the desired dimer products in
good yields.
Scheme 3. Applications of the CDC reaction
As illustrated in Table 3, after our study of this reaction for
homo-dimer synthesis, we tried to apply the conditions to
Table 3. Hetero-dehydrogenative Cross-Coupling of Ketones,
a
Esters, and Carbamates.
propylphenol 6b. This new strategy can serve as a highly
efficient way of preparing 6c and related structural analogues.
Interestingly, a novel drug dimer 6d was also synthesized from
ibuprofen,15 which is a representative nonsteroidal anti-
inflammatory drug (NSAID) used for relieving pain, helping
with fever, and reducing inflammation. Our procotol can be
employed to build up a variety of profen drug dimers, which can
be screened for early drug discovery.
In conclusion, we have developed a unique Pd(II)-catalyzed
ortho to ortho dehydrogenative cross-coupling reaction. The
method provides a novel and convenient access to a broad range
of highly valuble 2,2′-difunctional biaryls from readily accessible
substrates. Both the oxidants and HFIP solvent play critical roles
in this reaction. A possible Pd(II)/Pd(IV) mechanism may be
involved. The reaction demonstrates broad functional group
tolerance, excellent reactivity, and high yields. Further studies
into the scope, mechanism, and synthetic applications of this
reaction are in progress in our laboratory.
a
Isolated yield. The red part represented the substrate excess, while
the blue showed the substrate is 1 equiv.
prepare hetero-dimers, and for the reaction of systems with two
different weak coordinating functional groups as well. To our
delight, two types of hetero-dimer products (5a−c) and (5d−k)
could be obtained in good yield by using an excess of one
substrate, with excess starting material usually being readily
recovered (for details, see the Supporting Information). It is
noteworthy to point out that these results represent an
unprecedented mechanistic example of weak coordination
promoted hetero-dehydrogenative cross-coupling reactions.
Additionally, in comparison with traditional methods which
normally need three or more steps with relatively low overall
yields (20−30%), our new method can arrive at the target
products in only one step in higher yield.
The synthetic utility of this reaction can be further
demonstrated by preparation of a variety of biologically
important compounds and synthons, which is shown in Scheme
3. For instance, 2,2′-dibenzoyl biaryl 2 can be efficiently
converted into 6a13 via reduction by a mixture of magnesium
and magnesium iodide in 69% yield. Tetrahydromagnolol 6g14 is
a potent cannabinoid (CB) receptor agonist. Delightfully, we
found 6c could be easily constructed by a three-step chemical
manipulation in an overall yield of 62% from simple 4-
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02115.
Material and methods, general procedures, and additional
data (PDF)
NMR spectra of obtained compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yrao@mail.tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National “973” Foundation
(Grant No. 2011CB965300), the National Natural Science
Foundation of China (Grant No. 21302106), and the Tsinghua
University Initiative Scientific Research Program.
C
DOI: 10.1021/acs.orglett.5b02115
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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