Programmed selective sp2 C-O bond activation toward multiarylated benzenes

Article abstract of DOI:10.1021/ol4011757

A variety of important multiarylated benzenes were efficiently synthesized from phloroglucinol derivatives 1 through sequential cross-couplings via Pd-catalyzed C-OTs, Ni-catalyzed C-OC(O)NEt₂, and C-OMe bond activation. High selectivity was achieved based on the rational design and inherent diversity in the reactivity of different C-O bonds.

Full text of DOI:10.1021/ol4011757

ORGANIC
LETTERS
Programmed Selective sp2 CÀO Bond
2013
Vol. 15, No. 13
3230–3233
Activation toward Multiarylated Benzenes
Fei Zhao,† Yun-Fei Zhang,§ Jing Wen, Da-Gang Yu,† Jiang-Bo Wei,† Zhenfeng Xi,*,†,‡
and Zhang-Jie Shi*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China, State Key Laboratory of
Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China,
Department of Chemistry, China Agricultural University, Beijing 100094, China, and
College of Chemistry and Chemical Engineering, Lanzhou University, Gansu 730000, China
zshi@pku.edu.cn; zfxi@pku.edu.cn
Received April 26, 2013
ABSTRACT
A variety of important multiarylated benzenes were efficiently synthesized from phloroglucinol derivatives 1 through sequential cross-couplings
via Pd-catalyzed CÀOTs, Ni-catalyzed CÀOC(O)NEt2, and CÀOMe bond activation. High selectivity was achieved based on the rational design and
inherent diversity in the reactivity of different CÀO bonds.
Multiarylated arenes are important motifs in materials
science1 and drug discovery.2 Much attention has been
paid by chemists to developing synthetic methods toward
this motif for a long time. To achieve the multiarylated
structures bearing different substituted aryl groups, vari-
ous kinds of strategies have been established during the last
several decades.3 Among those, transition-metal-catalyzed
cross-coupling reactions have been proven to be one of the
most powerful tools to construct such structures.4À7
The sequentialselective cross-coupling reaction isaquite
useful method to construct multiarylated arenes. There are
mainly two strategies to realize high selectivity. One is
† Peking University.
§ China Agricultural University.
Lanzhou University.
‡ Chinese Academy of Sciences.
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r
10.1021/ol4011757
Published on Web 06/21/2013
2013 American Chemical Society

chemoselective activation of different CÀX bonds, and
another is regioselective activation of one kind of CÀX
bond. Using the former strategy, our group reported an
example to synthesize triarylated benzene with sequential
transition-metal-catalyzed activation of CÀCl, CÀCN,
and CÀOMe bonds.4 With the latter strategy, several
groups have developed various methods to synthesize
multiarylated arenes and heteroarenes. For example, Miller
and co-workers reported a regioselective CÀBr bond
activation and cross-coupling to construct enantiomerically
enriched multiarylated poly arenes.5
Due to the high step-economy and atom-economy,
direct arylation of aryl CÀH bonds became more powerful
to synthesize various biaryls. Moreover, multiarylation of
aryl CÀH bonds has been also realized by many groups.
For example, Gaunt and co-workers realized one example
of synthesis of multiarylated aniline derivative through
copper-catalyzed sequential CÀH bond activation.6 Itami
and co-workers developed a sequential palladium-catalyzed
cross-coupling to synthesize multiarylated thiophenes via
CÀH activation.7 Recently, a sequential Pd-catalyzed
arylation of imidazoles and thiazoles has also been
reported by Murai and Shibahara.8
On the other hand, CÀO bond activation has recently
drawn much attention due to the easy availability, low
toxicity, and environmental friendliness of oxygen-con-
taining compounds.9 Different types of CÀO bonds, in-
cluding those in sulfates,10 phosphates,11 esters,12 ethers,13
and even alcohols and phenols,14 have been readily used as
coupling partners. In these reports, the activities of various
CÀO bonds have been systematically studied. It is found
that the reactivity of CÀO bonds could be very different
and largely depends on the nature of the O-containing
leaving group. On the basis of this feature, a substrate
containing several different CÀO bonds with distinguish-
able reactivities could be selectively applied to construct
multiarylated arenes. Moreover, polyphenols exist widely in
nature and are one of the most important structures in
biomass. To our knowledge, the synthesis of important
multiarylated arenes using commercially available and in-
expensive polyphenols as the starting materials has never
been reported. Herein, we report a programmed synthesis of
multiarylated benzenes via selective and sequential CÀO
bond activation of phloroglucinol derivatives (Scheme 1).
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Scheme 1. Programmed Synthesis of Multiarylated Benzenes
through Transition-Metal-Catalyzed Sequential sp2 CÀO Bond
Activation
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Org. Lett., Vol. 15, No. 13, 2013
3231

challenges: low reactivity of CÀO bonds and poor selectivity
in CÀO activation. Because of the strong electron-donating
ability of most oxygen-containing groups, the CÀO bond in
polyphenol derivatives will be deactivated by other oxygen-
containing substituents. The higher electron density on
arenes also hampers the coordination with electron-rich
low-valent transition-metal catalysts, which is proposed to
lead to oxidative addition of CÀO bond in many cases.12k
Moreover, how to selectively cleave one CÀO bond in the
presence of other similar CÀO bonds is also a big issue.
As is known, a variety of functional groups have been
used to protect the aryl CÀOH bond. According to the
leaving ability of leaving groups and the bond strength,
the aryl CÀO bonds could be mainly categorized in three
parts: (a) relatively less inert CÀO bonds, including those
in aryl triflates, arenesulfonates, phosphates, and mesylates;
(b) inert CÀO bonds, including those in carboxylates,
carbonates, and carbamates; (c) highly inert CÀO bonds,
including those in aryl ethers and phenols themselves. Our
design is to make use of the different reactivity of the diverse
CÀO bonds with diverse leaving groups in order to realize
high selectivity. Moreover, the introduction of oxygen with
electron-withdrawing groups, which always in accordance
with the leaving group, would increase its own reactivity and
reduce the inhibition to other CÀO bonds. Furthermore,
different kinds of coupling partners should be carefully
chosen to reduce overcouplings.
Scheme 2. First Step of Arylation via Pd-Catalyzed CÀOTs
Bond Cleavage
a All of the reactions were carried out on a scale of 0.2 mmol of 1 and
0.4 mmol of 2. b Isolated yields.
Scheme 3. Second Step of Arylation via Ni-Catalyzed
CÀOC(O)NEt2 Bond Cleavagea,b
Based on the rational design, we synthesized phloroglu-
cinol derivative 1 with three kinds of CÀO bonds from
commercially available phloroglucinol dihydrate (see the
Supporting Information).15 With substrate 1 in hand, we
tried the first arylation via CÀOTs bond activation. Under
the palladium-catalyzed SuzukiÀMiyaura cross-coupling
conditions, the tosyloxy group could perform as a good
leaving group. The CÀO bond of aryl carbamates as well
as pivalates has been proven to be inactivate under
Pd-catalyzed condition.12k,n,o The CÀO bond of aryl ethers
is tolerated under Pd conditions, too.13i After systematic
optimization based on Buchwald’s pioneering report,16
t
we found that the reaction proceeded in BuOH with
Pd(OAc)2 as catalyst and XPhos as ligand. In this case,
anhydrous K3PO4 performed as the best base.17 Both
electron-deficient and electron-rich arylboronic acids gave
excellent yields. The carbamoyloxy and methoxy group
remained in the first arylation, and the cleavage of these
two CÀO bonds was not observed (Scheme 2). However, due
to the deactivation of the C-OTs bond by other two CÀO
bonds, a little bit higher temperature and longer reaction time
were needed in contrast with previous work.16
The CÀO bond of the carbamate moiety in compound 3was
further selectively activated and underwent SuzukiÀMiyaura
cross-coupling via nickel catalysis (Scheme 3). Several
(15) (a) Thomsen, I.; Torssell, K. B. G. Acta Chem. Scand. 1991, 45,
539. (b) Lipshutz, B. H.; Buzard, D. J.; Olsson, C.; Noson, K. Tetra-
hedron 2004, 60, 4443. (c) Sengupta, S.; Leite, M.; Raslan, D. S.;
Quenelle, C.; Snieckus, V. J. Org. Chem. 1992, 57, 4066.
(16) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818.
a All of the reactions were carried out on a scale of 0.2 mmol of 3 and
0.24 mmol of 4. b Isolated yields. c Conditions: 10 mol % of Ni(PCy3)2-
Cl2, 20 mol % of PCy3, 48 h.
(17) For a review on roles of bases in transition-metal-catalyzed
coupling reactions, see: Ouyang, K.; Xi, Z. Acta Chim. Sin. 2013, 71, 13.
3232
Org. Lett., Vol. 15, No. 13, 2013

Table 1. Third Step of Arylation via Ni-Catalyzed CÀOMe Bond Cleavagea,b
product
entry
substrate
Ar1
Ar2
Ar3
Ph (6a)
and yield
1
5aa
Ph
Ph
Ph
Ph
7aaa (72%)
7aab (76%)
7aac (77%)
7aba (66%)
7abb (77%)
7abc (70%)
7aca (41%)
7acb (49%)
7acc (47%)
7baa (51%)
7bab (79%)
7bac (65%)
7bba (68%)
7bbc (67%)
7caa (74%)
7cab (82%)
7cac (80%)
7cba (56%)
7cbb (71%)
7cbc (57%)
2
4-nBuC6H4 (6b)
4-Me2NC6H4 (6c)
Ph
4-nBuC6H4
4-Me2NC6H4
Ph
4-nBuC6H4
4-Me2NC6H4
Ph
4-nBuC6H4
4-Me2NC6H4
Ph
3
4
5ab
5ac
5ba
4-MeC6H4
1-naphthyl
Ph
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4-tBuC6H4
5bb
5ca
4-tBuC6H4
4-PhC6H4
4-MeC6H4
Ph
4-Me2NC6H4
Ph
4-nBuC6H4
4-Me2NC6H4
Ph
5cb
4-PhC6H4
4-MeC6H4
4-nBuC6H4
4-Me2NC6H4
a All of the reactions were carried out on a scale of 0.2 mmol of 5 and 0.6 mmol of 6. b Isolated yields.
different conditions, which were developed by Garg,
Snieckus, and our group, were tested.18 It was found that
our method18b gave the best results for this step with slight
modification. This method showed good selectivity for the
aryl carbamate moiety while keeping ether CÀO bonds
untouched.12nÀp,18a,18b Starting from the biphenyl com-
pounds 3aÀd, a variety of terphenyl derivatives 5 were
synthesized in moderate to good yields. The substrates 3
with electron-withdrawing groups showed better reactivity
than those with electron-donating groups. However, the
electronic effect on arylboroxines is not significant. Apply-
ing 1-naphthylboroxine 4c to the reaction would only give
the corresponding product 5ac in low yield, which may arise
from low solubility.
Finally, the CÀOMe bonds were cleaved and coupled
with different aryl Grignard reagents 6aÀc in the presence
of catalytic Ni(PCy3)2Cl2 (Table 1).19 Using this method, a
variety of triarylated benzenes 7 with different functional
groups were obtained in moderate to good yields. Due to
the low reactivity, poor yields were often obtained for simple
anisole substrates. In our reaction, diarylated anisoles 5
performed better due to the electron-withdrawing nature of
aryl substituent. The existence of a naphthyl group would
decrease the reactivity as well, probably because of the steric
hindrance of naphthyl group.
In conclusion, we have developed a general strategy
toward multiarylated benzenes via sequential sp2 CÀO
bond activation of phloroglucinol derivatives. Based on
therationaldesignandanalysisofthereactivityofdifferent
kinds of CÀO bonds, the fully protected phloroglucinol 1
with CÀOTs, CÀOC(O)NEt2, and CÀOMe bonds was
synthesized and successfully applied in sequential cross-
couplings. It is noteworthy that all of the three cross-
couplingstook place inhigh selectivity and goodefficiency.
Further utilization of this method to functionalize the
polyphenol motif in natural products and drugs selectively
is ongoing in this laboratory.
Acknowledgment. This work was supported by NSFC
(No. 20925207, 21072010, 20821062) and the“973” Project
from the MOST of China (2009CB825300).
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Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352. (b) 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.
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Zhao, F.; Yu, D.-G.; Zhu, R.-Y.; Xi, Z.; Shi, Z.-J. Chem. Lett. 2011, 40,
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Supporting Information Available. Experimental details
and NMR spectra of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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