Tetrahedron Letters
Stereoselective synthesis of (Z)-3-ylidenephthalides via AlCl -mediated
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cyclization with 2-acylbenzoic acids
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Xujie Wang, Gangsheng Li, Xu Zhang, Ziming Feng, Jianshuang Jiang, Yanan Yang, Peicheng Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical
College, Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of (Z)-3-ylidenephthalides is reported in moderate to high yield
Received 26 December 2019
Revised 8 February 2020
Accepted 11 February 2020
Available online xxxx
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with AlCl as catalyst. Different substrates of the 2-acylbenzoic acids are well performed in the Z/E selec-
tivity. This method is highlighted by the gram-scale synthesis of the natural product (Z)-3-butylidene-5-
hydroxyphthalide with anti-inflammatory activity.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
AlCl
Stereoselective synthesis
Z)-3-ylidenephthalides
-Acylbenzoic acids
3
-mediated cyclization
(
2
Introduction
denephthalides, they still have limitations such as harsh reaction
conditions, generation of side products and high toxicity of
The (Z)-3-ylidenephthalide moiety is an important structure
group of both naturally occurring products [1] and synthetic prod-
ucts [2] exhibiting a wide range of biological activities (Fig. 1). For
examples, the natural product (Z)-3-butylidene-5-hydroxyph-
thalide (3a) possesses anti-inflammatory activity [3]. The Chinese
angelica ingredient (Z)-3-butylidenephthalide (2b) possesses
anti-diabetic [4] and anti-coagulant effects [5], and (Z)-3-(2-
chlorobenzylidene)phthalide exhibits anti-HIV activity [2c]. In
reagents. Although Takaishi and co-workers have reported the syn-
thesis of 3-phenacylidenephthalides by treating 2-(3-oxo-3-
2
phenylpropanoyl)benzoic acid with SOCl (Scheme 1a) [14], it
was limited by the poor stereoselectivity of the Z- and E-isomers.
In 2014, Xue and co-workers reported the TSTU-mediated
intramolecular cyclization of 2-acylbenzoic acids (Scheme 1b)
[15]. However, the high price of the coupling reagent restricts
the amplification of this method. Therefore, the development of
an economical and efficient protocol for the stereoselective synthe-
sis of (Z)-3-ylidenephthalides is still highly desirable. In this paper,
addition, (Z)-3-ylidenephthalides have been exploited as
a
versatile building block that can easily transform into other
biologically heterocyclic compounds [6].
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we describe the AlCl -mediated stereoselective cyclization of 2-
Many methods have been developed for the synthesis of (Z)-3-
ylidenephthalides, such as (a) the modified Perkin or Julia reaction
on anhydrides; [7] (b) the cyclization of 2-alkenyl or 2-allyl ben-
zoic acid derivatives; [8] (c) transition-metal-catalysed coupling–
cyclization reactions of 2-halobenzoic acids with alkynes; [9] (d)
oxidative cyclization of 2-alkynylbenzaldehydes; [10] (e) Pd-catal-
ysed CO insertion-cyclization reactions of 2-halo or 2-triflyloxy-
acetophenones; [11] (f) Rh- or Pd-catalysed oxidative coupling of
benzoic acids with terminal alkynes or alkenes; [12] (g)
acylbenzoic acids for the preparation of the (Z)-3-ylideneph-
thalides with satisfactory yield and a broad substrate scope.
Results and discussion
The substrate 4-methoxy-2-pentanoylbenzoic acid (1a) was
selected as model for the development of catalyst system. We
found 1a and its cyclized isomer 1a’was
a
mixture
0
(
1a:1a = 1:2.5) after isolated by column chromatograph, which
Au-catalysed tandem cyclization and hydrolysis of 2-alkynyl-N-
methoxylbenzamides [13]. While each of these methods repre-
sents an important advance towards the synthesis of (Z)-3-yli-
was presented in the NMR spectrum. Considering the cyclized iso-
mer 1a’ may undergo the elimination process and transform into
the 3-ylidenephthalide under acidic conditions, we screened vari-
ous organic and lewis acids. As shown in Table 1, sulfinylchloride
and p-toluensulfonic acid both generated the (Z)-3-butylidene-5-
methoxyphthalide 2a with relatively low Z/E stereoselectivity (en-
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040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
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