Rh(III)-catalyzed C8 arylation of quinoline N-oxides with arylboronic acids

Article abstract of DOI:10.1016/j.cclet.2019.11.028

Herein, we report the first Rh^III-catalyzed regioselective C8 arylation of quinoline N-oxides with commercially available arylboronic acids as coupling partners. This procedure is simple, and the reaction shows perfect regioselectivity, a broad substrate scope, and isolated yields of up to 92percent. We demonstrate the utility of the reaction by using it for late-stage functionalization of a fungicide.

Full text of DOI:10.1016/j.cclet.2019.11.028

Journal Pre-proof
Lewis base catalyzed ring-expansion of isatin with
2,2,2-trifluorodiazoethane (CF3CHN2): An efficient route to
3-hydroxy-4-(trifluoromethyl)quinolinones
Shuipeng Lv, Yunfang Sun, Yue Xu, Shihai Yang, Lei Wang
PII:
S1001-8417(19)30675-8
https://doi.org/10.1016/j.cclet.2019.11.028
CCLET 5335
DOI:
Reference:
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Chinese Chemical Letters
Received Date:
Revised Date:
Accepted Date:
14 September 2019
16 November 2019
18 November 2019
Please cite this article as: Lv S, Sun Y, Xu Y, Yang S, Wang L, Lewis base catalyzed
ring-expansion of isatin with 2,2,2-trifluorodiazoethane (CF3CHN2): An efficient route to
3-hydroxy-4-(trifluoromethyl)quinolinones, Chinese Chemical Letters (2019),
doi: https://doi.org/10.1016/j.cclet.2019.11.028
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Communication
Lewis base catalyzed ring-expansion of isatin with 2,2,2-trifluorodiazoethane
(CF3CHN2): An efficient route to 3-hydroxy-4-(trifluoromethyl)quinolinones
Shuipeng Lva,b, Yunfang Sun b, Yue Xua, Shihai Yanga, *, Lei Wangb,*
a Department of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
b Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100193, China
 Corresponding authors.
E-mail addresses: siquanwl@gmail.com (S. Yang); lwang@implad.ac.cn (L. Wang)
ARTICLE INFO
Article history:
Received 14 September 2019
Received in revised form 12 November 2019
Accepted 13 November 2019
Available online
Graphical Abstract
ABSTRACT
A Lewis base catalyzed ring expansion of isatin with 2,2,2-trifluorodiazoethane (CF3CHN2) is developed. It
is characterized that the merge of tetramethylethylenediamine and CF3CHN2 generates reactive triazene
intermediates, which construct substituted 3-hydroxy-4-(trifluoromethyl)quinolinones with high efficiency.
Synthetic application of the procedure is broadened by 3-trifluormethylpyrazole fused 3-hydroxy-4-
(trifluoromethyl) quinolinone synthesis.
Keywords: Ring-expansion, Lewis base, Heterocycle, Quinolinones, Triazene
Quinolinone derivatives have received a great deal of interest in medicinal, bioorganic, and industrial chemistry due to as key
privileged scaffolds widely existed in many important biologically active molecules, agrochemicals and pharmaceuticals (Fig. 1) [1].
Trifluoromethyl (CF3)-containing quinolinone represents as one of the attractive heterocycles because embedding CF3 moiety could
extraordinarily affect their physiochemical, biological, and pharmacological properties [2]. Therefore, the development of new
protocols to construct such heterocycles persists as an important goal in medicinal and organic chemistry. Known methods for the
synthesis of 4-trifluoromethyl quinolinones involve the condensation of anilines with ethyl 4,4,4-trifluoroacetoacetate [3]. However,
these methods suffer from prefunctionalized starting materials and poor regioselectivities. In this context, the development of the
efficient methodologies for the synthesis of trifluoromethylated quinolinones is highly desirable in synthetic and medicinal chemistry.
Fig. 1. Selected bioactive molecules containing quinolinone scaffold.

Recently, 2,2,2-trifluorodiazoethane (CF3CHN2) has emerged as an attractive fluorine-containing building block based on its
different reactivities such as metal carbene precursors, 1,3-dipoles, C-nucleophiles/electrophiles and N-terminal electrophiles [4].
Compelling works have been reported according to these roles, especially ring formation protocols by [2+1] cycloaddition and [3+2]
cycloaddition. Since the pioneering work for trifluoromethyl cyclopropanes and cyclopropenes synthesis via [2+1] cycloaddition by
Carreira group [5], more methods by various catalytic strategy (Fe [4c, 5, 6], Cu [7], Rh [4c, 8], Ru [9], Co [4d], and myoglobin12 [10])
for trifluoromethylated three-membered rings symmetric and asymmetric synthesis have been promoted [5]. Also, versatile protocols
for trifluoromethylated five-membered heterocycles synthesis, such as pyrazoles, pyrazolines, 1,2,3-triazoles, and tetrazoles, was
established by [3+2] cycloaddition [4j, 11]. Despite huge advances in the trifluoromethylated three- and five- membered ring synthesis,
to some extent, these transformations are confined to the cycloaddition reactions. The trifluoromethylated six-membered heterocycles
formation via ring expansion using CF3CHN2 as a CF3 synthon still remains rarely exploited.
Scheme 1. Lewis base catalyzed ring expansion reactions.
Reported work indicated that the quinolinone ring could be assemble by ring expansion reaction of isatin with diazomethane and
Eistert ring expansion of isatin with ethyl diazocetate [12-14]. We have reported the combination of CF3CHN2 with Lewis base could
make sense in organic synthesis and medicinal chemistry via triazene intermediates formation [16]. Herein, as part of our ongoing
research, we demonstrate an efficient and facile ring expansion of isatin with CF3CHN2 catalyzed by Lewis base to assemble 3-
hydroxy-4-(trifluoromethyl) quinolinones with high efficiency (Scheme 1).
o
The plan study began with an evaluation of Lewis base in the model reactions of isatin 1a with CF3CHN2 2 in toluene at 60 C.
Notably, the reaction proceeded smoothly and yielded the desired ring expansion product in moderate yield with Dabco as the catalyst
(Table 1, entry 1). Next, we evaluated different Lewis bases (entries 2–7). Interestingly, we found that the TMEDA afforded an efficient
reaction (64%) (entry 7). To improve the yield of 3a, various stock solvents of CF3CHN2 were examined to indicate that toluene was
still essential for the high efficiency of this ring expansion protocol (entry 8-10). Further optimization of this transformation revealed
that the external solvent 1,4-dioxane could significantly enhance the reaction efficiency (entry 11 and 13-15). Attempts to increase the
yield of 3a were carried out with different reaction temperatures. Notably, this reaction afforded the trifluoromethylated quinolinone
heterocycle with excellent yield at 80 oC (entry 12).
Table 1
Condition optimization.a
Entry
Solvent
(0.4 mL)
--
--
--
--
--
--
--
--
--
--
1,4-Dioxane
1,4-Dioxane
THF
DCE
MeCN
T (oC)
Yield
(%)b
59
44
46
54
37
31
64
57
61
49
70
81
43
56
23
2 in solvent
Base
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Dabco
DMAP
Et3N
DIPEA
DBU
TMG
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
60
60
60
60
60
60
60
60
60
60
60
80
80
80
80
9
1,4-Dioxane
MeCN
10
11
12
13
14
15
Toluene
Toluene
Toluene
Toluene
Toluene
a Reaction conditions: isatin 1a (0.3 mmol, 1.0 equiv.) and CF3CHN2 2 (1.2 mmol, 4 equiv., 1.5 mol/L in stocked solvent), 20 mol% base (0.06
mmol, 0.2 equiv.), 12 h.
b Isolated yields after flash chromatography.

Scheme 2. Scope of substrates. Reaction conditions: 1 (0.3 mmol, 1.0 equiv.) and CF3CHN2 (1.2 mmol, 4 equiv., 1.5 mol/L in toluene), 20 mol%
TMEDA (0.06 mmol, 0.2 equiv.), 1,4-dioxane (0.4 mL), 80 oC, 12-36 h. a produced 3r with 31% yield. b produced 3r with 37% yield.
With the optimized conditions in hand, we attempted to explore the generality of this ring expansion protocol to construct a range of
substituted 3-hydroxy-4-(trifluoromethyl) quinolinones. As indicated in Scheme 2, a number of substituted isatins 1 were suitable for
this transformation. Various substrates with both electron-rich (1b, 1c) and electron-deficient (1d-f) substituents at 5-position of isatin
scaffold were tolerated, yielding the corresponding quinolinones in very good to excellent yields. The trifluoromethoxy substrates 1g
formed the desired product in excellent yield under the standard conditions, thus affording an efficient route to multiple
trifluoromethylated compound. Notably, the halogen substituted substrates at different positions were all suitable for the transformation
with high efficiency (3h-l). Furthermore, this Lewis base-catalyzed ring expansion reaction was extended by variation of the N-
substituent R1 of the isatin 1, resulting in the construction of the corresponding trifluoromethylated products 3n, 3o in excellent yields
(R1 = Me, Ph) and 3p, 3q in poor yields (R1 = Ac, Boc). Also, unprotected isatin was also suitable for this transformation and assembled
3r with high efficiency. However, the iodine incorporated poly-substituted at 4,7-position of isatin could be employed for this protocol
without forming the ring-expansion product but affording the spiro-epoxyoxindole product 3s in 46% yield and leaving an additional
iodine group for further transformation.
Scheme 3. CF3-containing spiro-epoxyoxindole synthesis.
To further show the generality of the ring expansion procedure, we performed the reaction of alkyne protected isatin 1t with
CF3CHN2 in toluene under the standard conditions. This Lewis base catalytical strategy unlocked new routes for the straightforward and
efficient assembly of 3-trifluormethylpyrazole fused 3-hydroxy-4-(trifluoromethyl) quinolinone (Scheme 4). The configurations of
compounds 3t was structurally confirmed by X-ray diffraction analysis and the supplementary crystallographic data can be obtained
free of charge from the Cambridge Crystallographic Data Centre (CCDC No. 1886034).
Scheme 4. 3-Trifluormethylpyrazole fused quinolinone synthesis.

A postulated mechanism for this Lewis base catalysis via the triazene intermediate is proposed based on our previous work and
literature precedents (Scheme 5) [15]. Firstly, triazene intermediate I is generated from the N-electrophilicity of CF3CHN2 with
TMEDA. Then, this intermediate undergoes the 3+2 cycloaddition with isatin 1a to regenerate catalyst and afford spiroheterocycle
intermediate III. The subsequent ring expansion step takes place to generate the final product 3a with loss of nitrogen gas at high
temperature.
Scheme 5. Proposed mechanism for ring expansion reactions.
In conclusion, we have developed a Lewis base catalyzed ring expansion of isatins with CF3CHN2 via triazene formation procedure
to synthesize a series of 3-hydroxy-4-(trifluoromethyl) quinolinones in very good to excellent yields. Notably, this ring expansion
strategy also allows the synthesis of the 3-trifluormethylpyrazole fused 3-hydroxy-4-(trifluoromethyl) quinolinone. Further applications
of Lewis base catalysis with CF3CHN2 for the synthesis of related heterocycles will be reported in due course.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
We are grateful for financial support from the National Natural Science Foundation of China (No. 81602977), the CAMS
Innovation Fund for Medical Sciences (2019-RC-HL-010; 2017-I2M-1-013), the Science and Technology Development Project of Jilin
Province of China (No. 20190304050YY) and China Association of Chinese Medicine (No. 2017QNRC001).

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