Practical route to 2-quinolinones via a Pd-catalyzed C-H bond activation/C-C bond formation/cyclization cascade reaction

Article abstract of DOI:10.1021/ol503292p

Quinolinone derivatives were constructed via a Pd-catalyzed C-H bond activation/C-C bond formation/cyclization cascade process with simple anilines as the substrates. This finding provides a practical procedure for the synthesis of quinolinone-containing alkaloids and drug molecules. The utility of this method was demonstrated by a formal synthesis of Tipifarnib.

Full text of DOI:10.1021/ol503292p

Letter
pubs.acs.org/OrgLett
Practical Route to 2‑Quinolinones via a Pd-Catalyzed C−H Bond
Activation/C−C Bond Formation/Cyclization Cascade Reaction
Junliang Wu, Shaohua Xiang, Jing Zeng, Minli Leow, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, 21
Nanyang Link, Singapore 637371
S
* Supporting Information
ABSTRACT: Quinolinone derivatives were constructed via a
Pd-catalyzed C−H bond activation/C−C bond formation/
cyclization cascade process with simple anilines as the
substrates. This finding provides a practical procedure for
the synthesis of quinolinone-containing alkaloids and drug
molecules. The utility of this method was demonstrated by a
formal synthesis of Tipifarnib.
We began our reaction by employing Pd(OAc)2 as the
catalyst and Na2S2O8 as the oxidant. This relationship has been
verified as an effective combination for catalytic functionaliza-
tion of C−H bond involving a Pd(II)−Pd(0) catalyst cycle.13
However, upon heating 5 mol % of Pd(OAc)2 with aniline 1a,
ethyl acrylate 2a, and Na2S2O8 in toluene, no desired product
3a was detected. Considering the difficulties associated with the
formation of 4-membered ring transition state in the proposed
mechanism, acetic anhydride was added as an additive to form
an amide in situ. To our delight, a trace amount of 3a was
observed (entry 1). Efforts were made to optimize the reaction
conditions, and a range of additives were examined. As shown
in Table 1, when 2 equiv of TFA was used, 3a was obtained in
50% yield (entry 2) while the addition of camphorsulfonic acid
(CSA) gave a yield of 30% for this reaction (entry 5). Under
the same reaction conditions, we were pleased to find that
when p-toluenesulfonic acid monohydrate (TsOH·H2O) was
used as the additive, 83% yield of 3a could be achieved (entry
6). On the other hand, utilization of acetic acid, benzoic acid, or
an alkaline such as triethylamine as the additive could not
improve the yield (entries 3 and 4). We went on to screen a
number of solvents, and toluene was found to be the most
effective solvent for this reaction as compared to DCE,
chloroform, DMF, DMSO, and DMA (entries 10−14). It
should be noted that a trace amount of product was observed
when the reaction was performed at a lower temperature of 80
°C (entry 15). Hence, we concluded that 1 equiv of TsOH·
H2O in toluene was the optimum condition for this catalytic
C−H bond activation reaction (entry 8).
uinolinones are an important class of molecules present
Q in a number of biologically active natural products and
medicinally valuable compounds and have therefore attracted
considerable attention from medicinal and synthetic organic
chemists.1 Several synthetic methodologies for the construction
of such structures have been developed in the past several
decades.2 However, these procedures generally involve the use
of preactivated substrates and multistep strategy and/or harsh
reaction conditions which limit the functional group compat-
ibility of these reactions.
In the past few decades, transition-metal-catalyzed function-
alization of the C−H bond has emerged as a versatile strategy
for chemical synthesis.3 This synthetic strategy is intriguing for
chemical and pharmaceutical industries because it may not only
significantly simplify and shorten the synthetic route for various
types of organic compounds but also allow the utilization of
readily available, cheap and environmentally benign starting
materials. Recently, there has been much progress in terms of
synthesis efficiency and atom economy in highly selective
functionalization of C−H bonds involving directing groups.
Coordination groups such as hydroxyls,4 carbonyls,5 amides,6
N-heterocycles,7 imines,8 pyridine N-oxides,9 and carboxyls10
are commonly used as the directing group for performing C−H
bond functionalization. Although catalyzed C−H functionaliza-
tion of nitrogen-containing substrates is well-known, employing
anilines as substrates for C−H activation is much less
common.11 Acyls are usually introduced on the amino group
to assist in the C−H bond functionalization of anilines
substrates;6a,12 therefore, the free amino group could be
obtained by deacylation of acyls after the C−H bond activation
process for further synthesis. The direct employment of anilines
as the substrates for C−H bond activation still remains very
challenging. Herein, we report our preliminary results on the
synthesis quinolinone derivatives by employing simple and
readily available anilines as the substrates involving C−H
activation catalyzed by Pd(OAc)2 via an in situ acylation and
deacylation process.
Evaluation of substituted anilines revealed that both electron-
poor and -rich derivatives are effective in cyclization, and the
reaction is compatible with fluoro, chloro, bromo, methyl,
alkoxy, and trifluoromethyl functional groups (3a−l) as
summarized in Scheme 1. The good tolerance of substrate-
Received: November 13, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503292p
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Palladium-Catalyzed Direct Ring Construction of
Anilines 1 with Acrylates 2
ab
,
b
entry
additive/loading
solvent
yield (%)
1
acetic acid/2
TFA/2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
trace
50
2
3
benzoic acid/2
Et3N/2
trace
NR
30
4
5
CSA/2
6
TsOH·H2O/2
TsOH·H2O/3
TsOH·H2O/1
TsOH·H2O/0.5
TsOH·H2O/1
TsOH·H2O/1
TsOH·H2O/1
TsOH·H2O/1
TsOH·H2O/1
TsOH·H2O/1
83
7
72
8
95 (92)
67
9
10
11
12
13
14
72
CHCl3
DMF
trace
NR
NR
NR
trace
DMSO
DMA
c
15
Toluene
a
Reaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), Pd(OAc)2 (5
mol %), Na2S2O8 (1.5 mmol), acetic anhydride (1 mmol), additives,
b
1
solvent, 2 mL, 100 °C, 36 h. Yields were determined by H NMR
with 1,3,5-trimethoxybenzene as the internal standard; the number in
parentheses refers to the yield of isolated product. Reaction was
c
conducted at 80 °C.
bearing Cl and Br provides a convenient platform for further
elaboration via conventional Pd(0)-catalyzed cross-coupling
(3j, 3k). For m-toluidine and 3-trifluoromethylaniline, C−H
bond activation occurred solely para to the methyl or
trifluoromethyl group to provide the corresponding products
3c and 3l in 96% and 53% yields, respectively. In addition, 4-(4-
methylphenyl)aniline was also a suitable substrate to provide 6-
(4-methylphenyl)quinol-2-one 3h in 88% yield. However, the
reactions with anilines bearing electron-withdrawing groups,
such as trifluoromethyl, nitro, or carboxyl at the para position,
cannot give the desired quinolinone products. The substrate
scope was further extended to a broad variety of substituted
cinnamates. Substitutions at the ortho, meta, and para positions
of phenyl group were all well tolerated. The results revealed
that this procedure exhibited electronic dependence. The
substituents on the aryl influenced the efficiency of the
cyclization significantly. Electron-rich functional groups on
the aryl moiety displayed higher reactivity than those with
electron-deficient groups. For cinnamates substituted with
electron-donating groups on the aryl moiety such as methyl
and methoxy, their corresponding products 3n and 3o were
obtained in 95% and 96% yields, respectively, while moderate
to good yields of the desired products were obtained for
electron-deficient cinnamates substituted with fluoro or chloro
(3p, 3q, 3r, and 3s). No desired products were observed when
ethyl (2E)-3-(2-trifluoromethylphenyl)propenoate were em-
ployed as the substrate. In addition, heterocyclic substituents
containing propenoate could also be subjected to the reaction
conditions, with 3t obtained in good yield by employing ethyl
(2E)-3-(3-thienyl)propenoate as the substrate. It should be
noted that alkyl-substituted propenoates could also be used in
this reaction, and 3u and 3v were obtained in 37% and 58%
yields by employing ethyl crotonate and ethyl methacrylate as
the substrates, respectively. The reactions are not limited to the
a
Reaction conditions: 1 (0.5 mmol), 2 (2.5 mmol), Pd(OAc)2 (5 mol
%), Na2S2O8 (1.5 mmol), acetic anhydride (1 mmol), TsOH·H2O (0.5
b
mmol), toluene, 2 mL, 100 °C, 36 h. Isolated yields.
small scale described above (0.5 mmol). Quilolinone 3a was
successfully prepared on a 5 mmol scale in 80% yield, which is
lower than that on a small scale (92%).
A plausible mechanism for this direct ring construction of
anilines with acrylates is shown in Scheme 2. First, aryl-Pd
complex II is formed via C−H activation at the 2-position
carbon atom of the substrate assisted by an in situ formed
acetyl on N atom. Next, Heck-type coupling of II with acrylate
through Pd complex III forms intermediate IV and releases the
Pd(0) species. This was followed by oxidation of Pd(0) by
Na2S2O8 to Pd(II) to complete the metal catalytic cycle. Under
acidic conditions, the intermediate IV could be transferred to
intermediate V and followed the ammonolysis of the ester with
the amide to give the intermediate VI. Lastly, the quinolinone
product was afforded by hydrolysis of intermediate VI. In order
to get evidence for our proposed mechanism, a control reaction
was carried out with intermediate IV in the presence of 1 equiv
of TsOH·H2O at 100 °C for 36 h. Gratifyingly, the desired
product could be obtained quantitatively.
Tipifarnib (Figure 1) is a potent, orally active inhibitor of
farnesyl protein transferase which has been found to exhibit
potent activity against neoplastic diseases, antineoplastic activity
in solid tumors, such as breast cancer, as well as in
B
DOI: 10.1021/ol503292p
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Letter
material, quinolinone 5 was generated in 95% yield. Treatment
of intermediate 5 with tert-butyl hydroperoxide in the presence
of a catalytic amount of pyridine and iodine afforded
quinolinone 6 in 98% yield, which can be subsequently
converted to Tipifarnib in three steps according to reported
literatures.14b,15
Scheme 2. Plausible Mechanism for the Cyclization Reaction
In summary, we have developed a concise and general
strategy for the construction of quinolinone by a one-pot Pd-
catalyzed cascade C−H bond activation reaction. This strategy
includes ammonolysis, C−H bond activation, and a cyclization
reaction successively in one pot. A broad range of quinolinone
derivatives have been prepared in good to excellent yields. The
utility of this method was demonstrated by a formal synthesis
of Tipifarnib.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xuewei@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Figure 1. Tipifarnib.
■
We gratefully acknowledge Nanyang Technological University
(RG6/13) and Ministry of Education (MOE2009-T2-1-030)
Singapore for financial support.
hematological malignancies, found in leukemia.The key feature
of Tipifarnib is the quinolinone-containing ring A and ring B at
the 4 and 6 positions, respectively. To date, several strategies
for the synthesis of Tipifarnib have been developed.14 However,
these procedures generally involved multisteps construction of
quinolonine core and sequentially introduction of ring A and
ring B on quinolinone, which resulted in more chemical waste
and overall low total yield.
As a utility of our method, we provide a concise route for the
formal synthesis of Tipifarnib, as shown in Scheme 3. We first
tried to utilize 4-amino-4′-chlorobenzophenone as the starting
material for the Tipifarnib synthesis. However, no desired
product was detected from the reaction mixture, and this
indicates that the C−H bond activation was obstructed by the
lower electron density of the substrate. To our delight, when 4-
amino-4′-chlorodiphenylmethane 4 was used as the starting
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