Pd-catalyzed C-H functionalizations of O-Methyl oximes with arylboronic acids

Article abstract of DOI:10.1021/ol902552v

"Chemical Equation Presented" Useful methods have been developed to construct orfto-arylated aryl aldoximes, aryl ketoximes, and fluorenones via Pd(ll)-catalyzed direct C-H arylation by using arylboronic acids as arylating reagents based on the analysis o

Full text of DOI:10.1021/ol902552v

ORGANIC
LETTERS
2010
Vol. 12, No. 1
184-187
Pd-Catalyzed C-H Functionalizations of
O-Methyl Oximes with Arylboronic Acids
Chang-Liang Sun,† Na Liu,† Bi-Jie Li,† Da-Gang Yu,† Yang Wang,† 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, and State Key Laboratory of Natural and Biomimetic Drugs, Peking
UniVersity, Beijing 100871, China
zshi@pku.edu.cn
Received November 9, 2009
ABSTRACT
Useful methods have been developed to construct ortho-arylated aryl aldoximes, aryl ketoximes, and fluorenones via Pd(II)-catalyzed direct
C-H arylation by using arylboronic acids as arylating reagents based on the analysis of the pathways of direct functionalization of aryl
aldoximes.
Direct C-H functionalization is the most straightforward
pathway to construct useful and complicated natural and
synthetic molecules. Recently, many efforts have been
made to pursue this goal.1 Among those methods, func-
tional group oriented ortho C-H activation is a common
strategy to address this problem.2 Actually, the O-methyl
oximyl group has been successfully applied for ortho
acetoxylation and amination.3 Very recently, arylation
followed by further transformation with aryl iodides to
synthesize fluorenones has also been successfully devel-
oped.4
Compared with direct arylation with arylboronic acids
directed by other anchoring groups, the arylation oriented
by CdX (X ) O, N) remains challenging.5 The major issue
(2) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 4156. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,
M. S. J. Am. Chem. Soc. 2005, 127, 7330. (d) Dick, A. R.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (e) Giri, R.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 4082. (f) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (g) Wang, C.; Piel,
I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194. (h) Ackermann, L. Org.
Lett. 2005, 7, 3123. (i) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano,
S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (j) Campeau, L.-C.; Parisien, M.;
Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (k) Shi, B.; Maugel,
N.; Zhang, Y.; Yu., J. Angew. Chem., Int. Ed. 2008, 47, 4. (l) Houlden,
C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-
Milburn., K. I. J. Am. Chem. Soc. 2008, 130, 10066.
† College of Chemistry.
‡ State Key Laboratory of Natural and Biomimetic Drugs.
(1) For recent reviews, see: (a) Godula, K.; Sames, D. Science 2006,
312, 67. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;
Lazareva, A. Synlett 2006, 3382. (c) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439. (d) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,
4, 4041. (e) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.
(f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (g) Ritleng, V.;
Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (h) Jia, C.; Kitamura,
T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (i) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1699. (j) Li, B.-J.; Yang, S.-D.; Shi., Z.-J. Synlett 2008,
7, 949.
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2004, 126, 9542. (b) Thu, H.; Yu, W.; Che, C. J. Am. Chem. Soc. 2006,
128, 9048.
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10.1021/ol902552v  2010 American Chemical Society
Published on Web 12/02/2009

is to avoid the direct addition of arylboronic acids to the
CdX group in the presence of Pd(II) species, which has been
well studied (Scheme 1).6 On the other hand, arylboronic
amount of 7a. Interestingly, the corresponding aldehyde 5
could not be transformed into 7a directly under the same
condition. Ketone 7a could be produced from 6 by hydrolysis
with excellent efficiency. Further studies indicated that 5
could not be obtained from 3 by direct arylation. Thus, 7a
was obtained through the pathway from the intermediates
4a and 6. During these transformations, Pd(II), Cu(II), and
the in situ generated acid might play vital roles to promote
different transformations. Thus, we envisioned that these
complicated transformations could be selectively controlled
at different stages to afford the desired products by tuning
the reaction parameters.
Scheme 1
.
Competition of Arylation of CdX and the ortho sp2
C-H Bond
With this idea in mind, we conducted many trials to
approach our goals (Table S1, Supporting Information). After
the systematic screening, we found that, when 2 6-dimethoxy-
pyridine (DMOP) was used as a base, the arylation occurred
in high efficiency, and the desired ortho phenylated product
4a was isolated in an 86% yield. The proper steric hindrance
and basicity of DMOP might trap the proton generated in
situ and at the same time did not inhibit the cyclopalladation
of O-methyl aldoxime.
acid and the in situ generated proton may lead to the
decomposition of oxime groups. Herein we demonstrated
systematic investigations of various transformations between
aldoximes/ketoximes and arylboronic acids.
We initially tested our idea with O-methyl (E)-2-methyl-
benzaldoxime 1a with phenylboronic acid 2a in the presence
of Pd(OAc)2 and Cu(OTf)2. The reaction produced a
complicated mixture. After careful analysis of this mixture,
we found six compounds, accompanied by small amounts
of biphenyl and benzene generated from 2a (Scheme 2).
The substrate scope was further surveyed (Figure 1).
Various boronic acids 2 were tested. We found that: (1) the
Scheme 2
.
Complication of Arylation of 1a with Boronic Acid
2a via Pd(II) Catalysis
Besides the recovery of 1a, the desired ortho phenylated
product 4a was observed in a moderate yield. As predicted,
both 1a and 4a were partially hydrolyzed to the correspond-
ing aldehydes 3 and 5. Unexpectedly, annulated product 6
and its hydrolyzed 9H-fluoren-9-one 7a were also observed
in low yields. It is very important to note that the arylation
of CdX (X ) O or N) was completely inhibited during this
process.
Further efforts have been made to unveil the relationships
among all those compounds. Compound 4a was first
synthesized through traditional Suzuki-Miyaura coupling
from the corresponding halide.7 When 4a was submitted to
the same condition for ortho C-H arylation, the desired
annulated product 6 was observed, accompanied by a small
Figure 1. Direct arylation of benzaldoximes via Pd-catalyzed C-H
activation. All the reactions were carried out in 0.2 mmol scale.
Islolated yields.
electronic property of different substituents on the aryl rings
did not affect this transformation very much, and arylboronic
acids bearing both electron-donating groups and electron-
withdrawing groups worked well; (2) the survival of the
halogen substituents, such as C-Br and C-Cl, offered a
great opportunity to functionalize the products further (4e,
4i); (3) arylboronic acids with various substituents at both
(6) (a) Liu, G.; Lu, X. J. Am. Chem. Soc. 2006, 128, 16504. (b)
Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153. (c) Zhou, C.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302. (d) Zhou, C.; Larock,
R. C. J. Org. Chem. 2006, 71, 3551.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
Org. Lett., Vol. 12, No. 1, 2010
185

para and meta positions were good substrates (4d, 4g);
however, an ortho substituted arylboronic acid was not a
suitable substrate, which may arise from the steric hindrance;
(4) polysubstituted arylboronic acids were also suitable
substrates despite the lower reaction efficiency due to the
protonation of boronic acid. Different substituents on the aryl
oxime scaffold were also examined. O-Substituents of oximes
were of great importance for this transformation. Besides
O-methyl oxime, O-benzyl oxime also worked well (4c).
However, the unprotected oxime is not a suitable substrate
for this transformation. On the other hand, ortho substituents
of the O-methyl oximes showed good reactivity and selectiv-
ity for monoarylation. An increase of the electron density
with the o-methoxyl group seemed to make the reaction
messy and decreased the isolated yield substantially (4m).
However, 2,4-dimethyl substituents did not affect the ef-
ficiency (4n).
The condition of direct ortho arylation of aldoximes could
not be directly applied to aryl ketoximes. The ortho arylated
product formed but with incomplete conversion and low
yield, which may arise from the relatively high steric
hindrance. To our delight, the desired ortho arylated product
was obtained in an excellent yield in the absence of DMOP
(Figure 2, 10a). Similarly, different O-substituents of ac-
standard condition (10b). However, O-phenyl or O-acyl 2′-
methyl acetophenone oximes completely decomposed under
the same conditions (10c-10f).
The reactions of various O-methyl aryl ketoximes with
phenylboronic acid were carried out (Figure 2). Moreover,
O-methyl 2′-methoxy acetophenone oxime gave moderate
yields (10i). To our delight, the benzyl group facilitated ortho
arylation of the substrate and inhibited the generation of the
diarylation product (10g). However, the O-methyl ketoxime
derived from tert-butyl phenyl ketone provided arylated
products in low yields due to a steric effect (10h). Arylbo-
ronic acids bearing alkyl and electron-withdrawing groups
gave the corresponding ortho arylated products in good to
excellent yields (10j, 10k, and 10m-10r). However, aryl-
boronic acids bearing electron-donating groups afforded the
desired products in relatively lower efficiencies (10l).
Similarly, the survival of the halogen substituents, even the
C-Br group, on the boronic acids offered the possibility for
further functionalizations (10m-10o and 10q-10r). More-
over, six-membered cyclic aryl ketoxime gave desired
products in moderate yields (10s), while five-membered
cyclic aryl ketoxime did not undergo this process (10t).
In analyzing the pathways, we proposed that the desired
7a could become the major product by tuning the reaction
parameters if hydrolysis of 1a and 4a could be inhibited.
Since 9H-fluoren-9-one is an important structural scaffold,
existing in many natural products and synthetic drugs8 as
well as intermediates in materials chemistry,9 our attention
was further drawn into a one-pot method to access poly-
functionalized 9H-fluoren-9-ones.
To prove our assumption, we added different acids after
the first step (Table S2, Supporting Information). To our
delight, after adding 1.0 equiv of HOTf and lengthening the
reaction time at 90 °C for another 24 h, 4a was converted
completely, and cyclization products 6 and 7a were obtained
in 26% and 61% yield, respectively (entry 5, Table S2,
Supporting Information). To obtain the sole desired product
7a, hydrochloric acid was required to reach complete
hydrolysis of 6. Finally, 7a was isolated in 62% yield after
three steps in one pot. Under the same conditions, polysub-
stituted 9H-fluoren-9-ones 7a-7h were obtained in moderate
to good yields (Figure 3). In this transformation, steric
hindrance did not affect the reaction efficiency. In contrast,
the electronic effect played a key role. Alkyl groups were
beneficial for this transformation; however, the alkoxy group
promoted the reaction rate, while the yield of 7 decreased,
which might arise from the instability of the intermediates
and the final products under this acidic and oxidative
condition. Moreover, the substrates bearing an electron-
withdrawing group were not conducive to this transformation
to produce the final 9H-fluoren-9-one perhaps due to the
diminished electron density of arylated intermediates.
Figure 2. Direct ortho arylation of acetophenone oxime derivatives
with various arylboronic acids. All the reactions were carried out
in 0.2 mmol scale. Isolated yields. The corresponding arylboronic
acids were added in batches by 0.5 equiv every 2 h.
(8) (a) Greenlee, M. L.; Laub, J. B.; Rouen, G. P.; DiNinno, F.;
Hammond, M. L.; Huber, J. L.; Sundelof, J. G.; Hammond, G. G. Bioorg.
Med. Chem. Lett. 1999, 9, 3225. (b) Perry, P. J.; Read, M. A.; Davies,
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etophenone oximes were tested. O-Benzyl 2′-methyl ac-
etophenone oximes conducted the same arylation under the
(9) Gross, M.; Muller, D. C.; Nothofer, H.-G.; Scherf, U.; Neher, D.;
Brauchle, C.; Meerholz, K. Nature (London) 2000, 405, 661.
186
Org. Lett., Vol. 12, No. 1, 2010

Scheme 3
.
Proposed Mechanism for Pd(II)-Catalyzed Arylation
and Cascade Transformation to Fluorenone
Figure 3. Cascade reaction to produce polysubstituted 9H-fluoren-
In conclusion, we have developed novel methods to
construct ortho arylated aryl aldoximes and ketoximes via
Pd(II)-catalyzed direct C-H arylation by using arylboronic
acids. On the basis of the analysis of ortho arylation of aryl
aldoximes, cascade transformations toward interesting fluo-
renone scaffold were conducted by switching the reaction
pathways through changing the reaction parameters. These
studies showed various transformations to functionalize aryl
carbonyl compounds starting from simple chemicals.
9-ones 7 via Pd-catalyzed C-H activation. All the reactions were
carried out in 0.2 mmol scale. Isolated yields.
Mechanistically, the transformation was initiated from
ortho cyclopalladation directed by O-methyl oxime to
generate cyclopalladium species A, which underwent trans-
metalation with arylboronic acids to produce diaryl Pd
species B (Scheme 3).10 Reductive elimination of B produced
the desired ortho arylated product 4. Pd(0) was further
reoxidized to Pd(II) by Cu(II) species and/or co-oxidant to
fulfill the catalytic cycle. In the presence of proper DMOP
for the arylation of aryl aldoximes, the transformation was
terminated at this stage. With the addition of TfOH, this
arylated product was further transformed to product 6.
Furthermore, 6 was hydrolyzed to give 9H-fluoren-9-one 7
under strongly acidic conditions. Thus, starting from the same
reagents, different pathways have been developed to ap-
proach different scaffolds by tuning the reaction conditions.
Acknowledgment. Support of this work by the grant from
NSFC (No. 20672006, 20821062, 20925207, and GZ419)
andthe“973”programfromMOSTofChina(2009CB825300)
is gratefully acknowledged.
Supporting Information Available: Brief experimental
detail and other spectral data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Motoyama, T.; Shimazaki, Y.; Yajima, T.; Nakabayashi, Y.; Naruta,
Y.; Yamauchi, O. J. Am. Chem. Soc. 2004, 126, 7378.
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