G Model
CCLET 3626 1–4
Chinese Chemical Letters
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Original article
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A nucleophilic 1,3-rearrangement leading to 3,4-disubstituted
3,4-dihydroquinolines
a
a
b
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Q1 Chun-Xian He , Zhi-Bo Jiang , Hua-Qing Cui , Da-Li Yin *
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State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese
Academy of Medical Sciences, Beijing 100050, China
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Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A new nucleophilic 1,3-rearrangement is observed when treating 2-methoxyquinolino-3-lithium
Received 9 December 2015
Received in revised form 3 February 2016
Accepted 18 February 2016
Available online xxx
with an
a
-C substituted deoxybenzoin, and this rearrangement yielded an unusual 3,4-disubstituted
,4-dihydroquinoline. Several similar reactions were designed and executed to investigate this novel
,3-rearrangement, and mechanism involving nucleophilic addition and following 1,3-
3
1
a
a
a
rearrangement with an unusual dearomatization on the quinoline ring is proposed.
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Keywords:
Published by Elsevier B.V. All rights reserved.
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,3-Rearrangement
Dihydroquinoline derivatives
Reaction mechanism
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1. Introduction
2. Experimental
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Rearrangement is one of the most useful reactions applied in
organic synthesis, and it can be used to produce structures that are
not easily accessed by conventional transformations. Most of the
rearrangements are 1,2-rearrangement that are exemplified by
Hofmann rearrangement [1,2], Curtius reaction [3,4], Beckmann
reaction [5,6], Pinacol rearrangement [7,8], Favorskii rearrange-
ment [9,10] etc. In contrast, 1,3-carbon and longer rearrangements
are relatively rare. Herein, we disclose an unexpected 1,3-carbon
rearrangement with an unusual dearomatization on the quinoline
ring that was observed in one reaction.
Bedaquiline (TMC-207), a diarylquinoline (DARQ) derivative
[11,12], was the first one in this class launched for the treatment of
tuberculosis [13]. In searching for new anti-tuberculosis drugs
[14], we have designed conformationally restricted diarylquinoline
analogues to study if a rigid structural motif has impact on anti-
tubercular activity of the molecules. Compound 1 was one of our
designed molecules for this study (Fig. 1), and we proposed it could
be quickly accessed from 2-methoxyquinolino-3-lithium (2) and
N-methyl-4-phenyl-4-benzoylpiperidine (3) (Scheme 1).
The H NMR, C NMR, HMBC, HMQC, H–H COSY, DEPT were 32
recorded on Mercury-300, Mercury-400 or Bruker-AV600 33
spectrometer in acetone-d . Chemical shifts are reported as 34
a
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d
values using tetramethylsilane (TMS) as the internal standard. 35
HR–ESI–MS data were measured on a Micromas AutoSpec Ultima- 36
TOF spectrometer.
The starting material, 3-bromo-2-methoxyquinoline was pre- 38
pared using 3-bromo-2-chloroquinoline [15] with sodium meth- 39
ylate in methanol.
2-Methoxy-4-(1-methyl-4-phenylpiperidin-4-yl)-3,4-dihydro- 41
quinolin-3-yl)(phenyl)methanone (4): To a solution of n-butyl- 42
lithium (2.5 mol/L in hexane; 0.30 mL, 0.75 mmol) (1.4 equiv.) in 43
anhydrous tetrahydrofuran (2 mL) at ꢀ70 8C was added 3-bromo- 44
2-methoxyquinoline (170 mg, 0.71 mmol, in 2 mL anhydrous 45
tetrahydrofuran) (1.3 equiv.) dropwise via syringe under an 46
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atmosphere of N . After stirring for 1 h, a solution of ketone 47
(0.54 mmol) (1.0 equiv.) in anhydrous tetrahydrofuran (2 mL) was 48
added, the stirring continued at ꢀ70 8C for 30 min followed by 49
another 30 min of stirring at the room temperature. The reaction 50
was quenched by 10 mL of water, extracted with CH
3 ꢁ 10 mL). The combined organic layers were dried over 52
anhydrous Na SO , filtered and concentrated. The residue was 53
purified by flash column chromatography to afford the corre- 54
sponding product. 55
2
Cl
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(
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*
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001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.