Palladium-catalyzed C(sp3)-H activation: A facile method for the synthesis of 3,4-dihydroquinolinone derivatives

Article abstract of DOI:10.1002/anie.201402562

3,4-Dihydroquinolinones were synthesized by the palladium-catalyzed, oxidative-addition-initiated activation and arylation of inert C(sp ³)-H bonds. Pd(OAc)₂ and P(o-tol)₃ were used as the catalyst and ligand, respectively, to improve the efficiency of the reaction. A further advantage of this reaction is that it could be performed in air. A relatively rare seven-membered palladacycle was proposed as a key intermediate of the catalytic cycle.

Full text of DOI:10.1002/anie.201402562

Angewandte
Chemie
DOI: 10.1002/anie.201402562
3
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C(sp ) H Activation
Hot Paper
3
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Palladium-Catalyzed C(sp ) H Activation: A Facile Method for the
Synthesis of 3,4-Dihydroquinolinone Derivatives**
Jia-Xuan Yan, Hu Li, Xiang-Wei Liu, Jiang-Ling Shi, Xin Wang, and Zhang-Jie Shi*
Abstract: 3,4-Dihydroquinolinones were synthesized by the
intramolecular[8] and intermolecular[9] activation reactions
palladium-catalyzed, oxidative-addition-initiated activation
have been reported and have thus been confirmed to be
3
3
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and arylation of inert C(sp ) H bonds. Pd(OAc)2 and P(o-
efficient processes. Notably, for intramolecular C(sp ) H
tol)3 were used as the catalyst and ligand, respectively, to
improve the efficiency of the reaction. A further advantage of
this reaction is that it could be performed in air. A relatively
rare seven-membered palladacycle was proposed as a key
intermediate of the catalytic cycle.
activation reactions, the formation of either four-member-
ed[8a,c–e] or five-membered[8f–i] rings has been particularly
successful, whereas the synthesis of six-membered or larger
rings has still rarely been reported (Figure 1).[10] Obviously,
I
n bioactive molecules, pharmaceutics, natural products, and
À
industrial materials, C H bonds are ubiquitous. For years,
chemists have been considering the direct functionalization of
À
C H bonds for the synthesis of important molecules to avoid
tedious and sluggish synthetic procedures.[1] In recent years,
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C H bond activation reactions have experienced great
developments, and among all of these progresses, palla-
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dium-catalyzed C H bond activation has shown its great
advantages.[2] However, most of the current research mainly
2
[2e,h–j]
À
focuses on the activation of C(sp ) H bonds,
as such
transformations benefit substantially from the interactions
between the catalyst and the p electrons,[2a,e] which enables
2
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catalyst–substrate binding and C(sp ) H bond cleavage
through electrophilic metalation,[3] a concerted metalation–
deprotonation (CMD) process,[4] or other pathways.[5] The
aforementioned methods could also be applied to some
3
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C(sp ) H bond activation reactions. For example, several
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beautiful examples of the activation of benzylic C(sp ) H
bonds and allylic C(sp ) H bonds have been described.
However, the activation of common C(sp ) H bonds has
remained more challenging[7] because of a lack of p electrons
and high steric hindrance. Fortunately, chemists have devel-
3
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Figure 1. C(sp ) H activation reactions that are initiated by oxidative
3
[6]
À
addition.
3
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the formation of seven-membered or even larger palladacycle
intermediates during the catalytic process is more difficult
than that of five- or six-membered palladacycles.[4f,10] Herein,
we reported a successful method to synthesize 3,3-disubsti-
tuted 3,4-dihydroquinolinone derivatives by an oxidative-
oped another strategy as an alternative method to the direct
3
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activation of C(sp ) H bonds that is initiated by the oxidative
addition of organohalides to Pd0 precatalysts. In fact, both
addition-initiated strategy that features seven-membered
[*] J.-X. Yan, Dr. H. Li, Dr. X.-W. Liu, J.-L. Shi, X. Wang, Prof. Dr. Z.-J. Shi
Beijing National Laboratory of Molecular Sciences (BNLMS)
PKU Green Chemistry Centre and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry
3
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palladacycles as key intermediates through direct C(sp ) H
bond activation.
Inspired by the pioneering works from the groups of
Cramer,[4f,10b] Baudoin,[8d,e] Kꢀndig,[8j,k] Martin,[11a,b] Su[11c,d]
and others,[8a,b,h] we initially chose amide 1a as a standard
Peking University, Beijing, 100871 (China)
E-mail: zshi@pku.edu.cn
3
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substrate to test the feasibility of intramolecular C(sp ) H
Prof. Dr. Z.-J. Shi
bond activation to form six-membered rings. The blocked a-
position of the carbonyl group, the nine chemically equal
hydrogen atoms, and the gem-dimethyl structure of this
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (China)
À
molecule should support the desired C H bond activation
[**] Support from the NSFC (J1030413, 20925207, and 20821062) and
the “973” Project from the MOST of China (2009CB825300) is
gratefully acknowledged.
and cyclopalladation process.[12,13] Fortunately, the desired
product was obtained in 30% yield (as determined by
1H NMR spectroscopy) in the presence of Pd(OAc)2 as the
catalyst, PCy3 as the ligand, and PivOH as an additive
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402562.
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Table 1: Optimization of the intramolecular C(sp ) H activation of 1a.
product was isolated in a reduced, but still reasonable yield
(entry 13), which indicates that PivOH does not greatly
enhance the efficiency of this transformation. As expected,
when the palladium catalyst is not included in the reaction
system, the desired product was not detected (entry 14). This
observation revealed the crucial role of Pd(OAc)2 for this
reaction.
Entry[a] Catalyst
Ligand
PCy3
PtBu3·HBF4 PivOH
P(o-tol)3
XPhos
P(4-FC6H4)3 PivOH
Additive Solvent
Yield[b] [%]
With the optimized reaction conditions in hand, the
substrate scope of this reaction was studied (Scheme 1). First,
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PivOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
mesitylene <5
toluene
NMP
30
25
43
40
21
27
28
PivOH
PivOH
5
6
Pd(OTFA)2 P(o-tol)3
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
–
7
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
8
9
<5
(63)
21
10
11
12[c]
13[c]
14[c]
DMAc
NMP
NMP
(72)
(64)
[d]
PivOH
NMP
–
[a] General reaction conditions: Substrate 1a (0.2 mmol) in the solvent
(2.0 mL) at 1408C for 24 h in air; 10 mol% of the catalyst, 20 mol% of
the ligand, 30 mol% of the additive, and 2.0 equiv of Cs2CO3 were used.
[b] Determined by 1H NMR analysis using CH2Br2 as an internal
standard. Yields of isolated products are given in parentheses. [c] 48 h.
[d] not determined. Cy=cyclohexyl, DMAc=N,N-dimethylacetamide,
DMF=N,N-dimethylformamide, NMP=N-methyl-2-pyrrolidinone,
OTFA=trifluoroacetate, Piv=pivaloyl, XPhos=2-dicyclohexylphos-
phino-2’,4’,6’-triisopropylbiphenyl.
(Table 1, entry 1). Further explorations showed that electron-
rich phosphine ligands gave similar results (entries 2–4),
whereas the use of electron-deficient phosphine ligands
resulted in much lower yields (entry 5). In comparison,
phosphine ligands with substantial steric hindrance enhanced
the efficiency, and P(o-tol)3 seemed to work best (entries 3
and 4).[8c] P(o-tol)3 might give the best results as this bulky
phosphine ligand easily dissociates from the palladium center
to form coordinatively unsaturated palladium centers, which
3
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are crucial for the C(sp ) H bond activation process. The
catalytic ability of the palladium species was also examined.
Among all of the common PdII and Pd0 species, Pd(OAc)2
gave the best results (entries 3, 6, and 7). Next, different
solvents were screened to enhance the efficiency of this
reaction. In previous reports, similar reactions were mainly
carried out in two kinds of solvents, namely polar aprotic
solvents[8a–c,e] or non-polar solvents with p-conjugated system-
s.[8f–i] Some representative solvents were chosen for our
studies, and it was confirmed that polar solvents are a better
choice for this transformation (entries 3, 10, and 11). Only
a trace amount of the desired product could be obtained in
non-polar solvents (entries 8 and 9). Among all of the tested
polar solvents, NMP gave the best results, and the desired
product 2a could be isolated in 63% yield (entry 10). When
the reaction time was extended to 48 hours, the desired
product was obtained in 72% yield (entry 12). In the absence
of the additive PivOH, which has been shown to have
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Scheme 1. Substrate scope of the intramolecular C(sp ) H bond
activation of amides 1. Reaction conditions: 1a–t (0.2 mmol),
Pd(OAc)2 (0.02 mmol), P(o-tol)3 (0.04 mmol), PivOH (0.06 mmol),
Cs2CO3 (0.40 mmol) in NMP (2.0 mL), air atmosphere, 1408C, 48 h. If
not otherwise noted, X=Br.
À
the reactivity of different C X bonds was investigated. The 2-
chloro-substituted substrate 1b showed a low reactivity, which
possibly arises from the lower reactivity of the carbon–
chlorine bond. 2-Iodo-substituted compound 1c also gave
a lower yield than the 2-bromo-substituted compound 1a. In
this reaction, we observed that more protonated side product
was produced. Moreover, different bromo-substituted amides
were used to test whether different functional groups are
tolerated under the reaction conditions. When the amide
significant effects on many C H activation reactions,[8f–i,14] the
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contains alkyl substituents on the 4- or 5-position, the reaction
proceeded well and offered the desired products in good
yields (2d–f). The 4-phenyl-substituted substrate 1n and
a substrate containing a methoxy group (1h) also gave the
corresponding products in moderate yields. Fluoro, trifluoro-
methyl, and cyano groups were tolerated under the reaction
conditions, and the corresponding products could be isolated
in good yields (2i, 2k–m, 2o), indicating the compatibility of
this transformation with electron-deficient substituents. How-
ever, when there are substituents at the 3- or 6-position, the
cyclized products were obtained in low yields (2g, 2j), which
indicates that steric hindrance plays a key role in influencing
the efficiency of this reaction. Notably, the 4-chloro-substi-
tuted substrate 1p could give the 4-chloro-substituted product
2p in good yield, which provides another opportunity for
further transformations through orthogonal cross-couplings.
Unfortunately, a substrate with several fluoro substituents
gave a much worse result (2q), and the amount of protonated
side product substantially increased. Furthermore, some
sensitive functional groups, such as nitro, ester, and acyl
groups, were not tolerated. When changing the acyl group
from the pivaloyl group to a 1-methylcyclopentanecarbonyl
or a 1-methylcyclohexanecarbonyl group, the corresponding
products could also be obtained in a moderate yield (2r and
2s), which indicates that this reaction could also be applied to
the syntheses of polycyclic compounds with spiro centers.
2
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However, in the presence of a C(sp ) H bond that is located
À
at a suitable position for intramolecular C H activation, the
desired product of C(sp ) H activation could not be observed
(2t). It was thus confirmed that C(sp ) H bonds of aromatic
rings are easier to activate than inert C(sp ) H bonds.
3
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3
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Scheme 2. Mechanistic studies for the intramolecular C(sp ) H bond
2
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activation.
3
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To gain insight into the mechanistic pathway of this
transformation, we conducted mechanistic studies to deter-
3
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mine the kinetic isotope effect (KIE) of this C(sp ) H
activation process (Scheme 2).[15] The results obtained further
supported our initial hypothesis, and the intramolecular KIE
3
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value of kH/kD = 6.2 indicates that the C(sp ) H bond
activation step is involved in the rate-determining step of
the catalytic cycle. We then tried to isolate the possible active
intermediate. To our delight, complex 3,[16] which contains
a six-membered palladacycle, could be synthesized and used
as the reactant in a stoichiometric reaction under the standard
conditions. Unfortunately, the desired product could not be
detected, and only the protonated product 4 was observed.
However, when 3 was submitted to the standard conditions as
the catalyst instead of Pd(OAc)2, the desired product 2a and
product 2 f, which bears a tert-butyl group in the 4-position,
were isolated in 53% and 75% yield, respectively. Notably,
when 1 f and 3 were mixed in a ratio of 2:1, product 2 f was
obtained in 63% yield, whereas product 2a could not be
observed.
Based on these preliminary results and the mechanisms
previously proposed by other groups,[8f,g,10a] we propose
a plausible mechanism (Scheme 3). First, the Pd0 species is
generated by the in situ reduction of the PdII species. Then,
oxidative addition of the carbon–halogen bond to the
Pd0 species affords intermediate A. Subsequently, intermedi-
ate A is transformed into intermediate B with the assistance
of pivalic acid.[17] Intermediate B undergoes concerted metal-
Scheme 3. Plausible reaction mechanism.
ation–deprotonation (CMD) to give intermediate C, which
features a seven-membered palladacycle. According to our
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Zhang, K. Chen, G.-H. Chen, B.-J. Li, S. Luo, Q.-Y. Guo, J.-B.
Wei, Z.-J. Shi, Org. Lett. 2013, 15, 10.
prediction, this step is the key rate-determining step of the
whole reaction. Finally, reductive elimination of intermediate
C could give the desired product and regenerate the Pd0
species.
[4] For selected references that support a concerted metalation–
deprotonation process, see: a) M. Lafrance, C. N. Rowley, T. K.
Woo, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 8754; b) D.
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In conclusion, we have achieved the activation of an inert
3
À
C(sp ) H bond and developed a facile method for the
synthesis of 3,3-disubstituted 3,4-dihydroquinolinone deriva-
tives from easily available ortho-halogenated acetilide deriv-
atives under mild conditions. A relatively rare seven-mem-
bered palladacycle was proposed as a key intermediate of the
catalytic cycle. Further investigations for a clearer under-
standing of the reaction pathway and to explore similar
3
À
activation reactions of other inert C(sp ) H bonds are under
way in our laboratory.
1987, 109, 203.
Experimental Section
3
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[6] For selected examples of allylic and benzylic C(sp ) H activa-
Pd(OAc)2 (4.5 mg, 0.02 mmol), P(o-tol)3 (12.2 mg, 0.04 mmol),
Cs2CO3 (130.3 mg, 0.40 mmol), and amides 1a–t (0.20 mmol; 1g–
i and 1r were added by syringe) were added to a Schlenk tube
(25 mL). Then, PivOH (6.1 mg, 0.06 mmol, ca. 6.7 mL) was added to
the tube with a microinjector. NMP (2.0 mL) was added by syringe,
and the reaction was performed on a parallel reactor for 48 hours in
air and at 1408C. After the reaction was finished, the reaction mixture
was cooled to room temperature and filtered through a celite pad
using EtOAc as the eluent. The reaction mixture was concentrated
under reduced pressure, and the resulting mixture was purified by
column chromatography on silica gel using petroleum ether/ethyl
acetate (3:1) as the eluent.
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Received: February 18, 2014
Published online: && &&, &&&&
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À
Keywords: C H activation · dihydroquinolinones ·
palladacycles · palladium · synthetic methods
3
À
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[13] a) F. Chen, S. Zhao, F. Hu, K. Chen, Q. Zhang, S. Zhang, B. Shi,
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
3
À
C(sp ) H Activation
J.-X. Yan, H. Li, X.-W. Liu, J.-L. Shi,
X. Wang, Z.-J. Shi*
&&&& — &&&&
3
À
Palladium-Catalyzed C(sp ) H
Activation: A Facile Method for the
Synthesis of 3,4-Dihydroquinolinone
Derivatives
3,4-Dihydroquinolinones were synthe-
sized by the palladium-catalyzed, oxida-
and ligand, respectively, to improve the
efficiency of the reaction. A further
advantage of this reaction is that it could
be performed in air.
tive-addition-initiated activation and ary-
3
À
lation of inert C(sp ) H bonds. Pd(OAc)2
and P(o-tol)3 were used as the catalyst
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!