Facile one-pot method for the synthesis of polysubstituted phthalide derivatives

Article abstract of DOI:10.1080/00397911.2013.871735

A new three-component cyclization method is described involving two starting materials, ethyl 4-chloroacetoacetate and aldehydes, catalyzed by piperidine, acid, and iodine. Ten corresponding polysubstituted phthalides are formed with good yields (44-78%). A mechanism of the reaction is also proposed.

Full text of DOI:10.1080/00397911.2013.871735

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Facile One-Pot Method for the Synthesis
of Polysubstituted Phthalide Derivatives
Xiu-Yan Yang a b , Xiao-Qian Xu a b , Xiao-Kui Wang b , Zhi-Bing Zheng
b , Guo-Ming Zhao b & Song Li a b
a Shenyang Pharmaceutical University , Shenyang , China
b Institute of Pharmacology and Toxicology, Academy of Military
Medical Sciences , Beijing , China
Published online: 14 May 2014.
To cite this article: Xiu-Yan Yang , Xiao-Qian Xu , Xiao-Kui Wang , Zhi-Bing Zheng , Guo-Ming Zhao
& Song Li (2014) Facile One-Pot Method for the Synthesis of Polysubstituted Phthalide Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:12, 1780-1785, DOI: 10.1080/00397911.2013.871735
To link to this article: http://dx.doi.org/10.1080/00397911.2013.871735
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Synthetic Communications1, 44: 1780–1785, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.871735
FACILE ONE-POT METHOD FOR THE SYNTHESIS OF
POLYSUBSTITUTED PHTHALIDE DERIVATIVES
Xiu-Yan Yang,1,2 Xiao-Qian Xu,1,2 Xiao-Kui Wang,2
Zhi-Bing Zheng,2 Guo-Ming Zhao,2 and Song Li1,2
1Shenyang Pharmaceutical University, Shenyang, China
2Institute of Pharmacology and Toxicology, Academy of Military Medical
Sciences, Beijing, China
GRAPHICAL ABSTRACT
Abstract A new three-component cyclization method is described involving two starting
materials, ethyl 4-chloroacetoacetate and aldehydes, catalyzed by piperidine, acid, and
iodine. Ten corresponding polysubstituted phthalides are formed with good yields (44–
78%). A mechanism of the reaction is also proposed.
Keywords Catalyst; cyclization; mechanism; phthalide
INTRODUCTION
Polysubstituted phthalides are common structural subunits in pharmaceutical
and natural products that have a wide range of biological activities, including
modulation of the central nervous system and protection against brain ischemia.[1–5]
Moreover, they have been used as key intermediates in the synthesis of biologically
active compounds such as nidulol and lactonamycin (Fig. 1).[6,7] As a result, the prep-
aration of polysubstituted phthalides in general has been a focused area in organic
synthesis.
Traditionally, synthetic methods for polysubstituted phthalide derivatives
have been mainly based on benzannulation of 4-methoxycarbonylbut-2-enoate with
methyl alkynoate or Diels–Alder reaction of methyl 2-(prop-1-en-2-yl)but-2-enoate
Received July 16, 2013.
Authors Xiu-Yan Yang and Xiao-Qian Xu contributed equally to this work.
Address correspondence to Guo-Ming Zhao, Institute of Pharmacology and Toxicology, Academy of
Military Medical Sciences, Beijing 100850, China. E-mail: zhaogm@bmi.ac.cn
1780

SYNTHESIS OF PHTHALIDES
1781
Figure 1. Structures of nidulol and lactonamycin.
Scheme 1. Traditional synthesis of phthalide derivatives.
Scheme 2. Synthesis of substituted phthalide derivatives.
with furan-2,5-dione under appropriate conditions (Scheme 1).[8–12] However, these
approaches have some drawbacks such as high cost and tedious procedures.
Recently, methods that construct the aromatic backbone from acyclic precursors
have received growing interest because of their short synthetic steps.[13–17] Herein,
we describe an efficient method to synthesize polysubstituted phthalides from
ethyl 4-chloroacetoacetate and aldehydes in the presence of piperidine, acid, and
iodine (Scheme 2). Our method is simple and economical because no special
apparatus or chemical is required. It is also devoid of any toxic by-products during
the reaction.
RESULTS AND DISCUSSION
We initially conducted a preliminary study evaluating catalysis of acid and base
using ethyl 4-chloroacetoacetate (2 equiv) and ethanal (1 equiv) as the starting sub-
strates. The results are shown in Table 1. No product was found in the presence of
acid or base only (Table 1, entries 1–3). Addition of catalytic amounts of both acid
and base to the reaction yielded less product (Table 1, entry 4). Increasing the
amounts of acid and base (1 equiv) led to more products (Table 1, entry 5), but greater

1782
X.-Y. YANG ET AL.
Table 1. Optimization of reaction conditions for the synthesis of 1a
Entry
Catalysta
Yield (%)b
1
2
3
4
5
6
7
8
9
AcOH (1 equiv)
Piperidine (1 equiv)
0
0
Triethylamine (1 equiv)
Piperidine:AcOH (1:1) (cat)
0
5
Piperidine (1 equiv), AcOH (1 equiv)
Piperidine (2 equiv), AcOH (2 equiv)
Piperidine (1 equiv), AcOH (1 equiv), HCl (cat)
Piperidine (1 equiv), AcOH (1 equiv), I2 (1 equic), HCl (cat)b
Piperidine (1 equiv), AcOH (1 equiv), HCl (1 equiv)
18
14
39
63
18
a4-Chloroacetoacetate (2 equiv) and ethanal (1 equiv) in the presence of catalysts refluxed for 12 h in
ethanol.
bRefers to pure products separated by chromatography.
amounts of the catalysts did not result in greater yields (Table 1, entries 6). Addition
of 0.12 equiv concentrated hydrochloric acid and 1 equiv iodine gave the best result,
whereas other amounts completed the reaction in poor yields (Table 1, entries 7–9). In
many cases, the poor yields were a result of the formation of other by-products that
could not be isolated by column chromatography.
Table 2. Optimization of reaction solvents
Entry
Solventa
Yield (%)b
1
2
3c
4
5
6
7
Methanol
Ethanol
Ethanol
42
63
0
1,4-Dioxane
Acetic acid
DMF
24
15
0
DMSO
0
a4-Chloroacetoacetate (2 equiv) with ethanal (1 equiv) in the presence of piperidine (1 equiv), glacial
acetic acid (1 equiv), concentrated hydrochloric acid (0.12 equiv), and iodine (1 equiv) refluxed for 12 h
in different solvents (except entry 3).
bRefers to pure products separated by chromatography.
cReacted at 40 ꢀC in ethanol.

SYNTHESIS OF PHTHALIDES
1783
Table 3. Synthesis of substituted phthalides 1a–1j
Entry
R
Product
Yielda (%)
1
2
CH3
CH3CH2CH2
2-Br-C6H4
1a
1b
1c
1d
1e
1f
63
69
56
65
50
58
44
60
60
78
3
4
4-Cl-C6H4
5
2-OCH3-C6H4
3-Br-4-OH-C6H3
3-OCH3-4-OH-C6H3
3-Br-4-OH-5-OCH3-C6H2
2-Cl-4-F-C6H3
3-NO2-C6H4
6
7
1g
1h
1i
8
9
10
1j
aRefers to pure products separated by chromatography.
We continued to investigate the effect of solvents on the reaction, such as meth-
anol, 1,4-dioxane, acetic acid, dimethylformamide (DMF), and dimethylsulfoxide
(DMSO), but the yields were found no better than the yield of ethanol (Table 2).
Scheme 3. Possible mechanism of the reaction.

1784
X.-Y. YANG ET AL.
To see the scope of this method, two aliphatic aldehydes and eight aromatic
aldehydes were examined under the optimized conditions, and the corresponding
results were summarized in Table 3. The substitutes on the aromatic aldehydes
exhibited an effect on the yields of the reactions. The electron-withdrawing groups
gave better yields than the electron-donating groups. For example, 3-nitrobenzalde-
hyde afforded the desired product 1j as a white crystalline solid in 78% yield (Table 3,
entry 10). By comparison, 2-methoxy benzaldehyde, 3-bromo-4-hydroxy-5-methoxy
benzaldehyde, 3-bromo-4-hydroxybenzaldehyde, and 3-methoxy-4-hydroxybenzal-
dehyde gave lower yields.
To further the scope the present synthesis, a plausible mechanism of the reaction
is proposed (Scheme 3). It involes the Knoevenagel reaction of aldehydes with
4-chloroacetoacetate to give a Konevenagel product 2, which undergoes both
Michael-type addition and intramolecular aldol condensation in the presence of
piperidine to give a 1,3-dicarbonyl derivative 4, which can form the enol 5 by
isomerazation. It is possible to generate the stable aromatization product 6 after
the dehydrohalogenation of allyl halide catalyzed by base. Then hydrolyzation of 6
give the intermediate 7. Finally, the desired phthalide derivatives 1 is easily obtained
by internal esterification in the presence of acid. In this process iodine is possible to
promote elimination and hydrolyzation through an exchange of chlorine.
In summary, we have identified and studied a new and facile reaction of
4-chloroacetoacetate with aldehydes to produce corresponding substituted phtha-
lides in moderate yields. The proposed procedure leads to building blocks, potential
intermediates of organic materials, and new substituted phthalides. It holds potential
for use in organic synthesis.
EXPERIMENTAL
1H NMR and13C NMR spectra were recorded at 400 MHz and 100 MHz on a
JNM-ECA-400 instrument with tetramethylsilane (TMS) as an internal standard in
the DMSO. Infrared (IR) spectra were recorded in KBr disk using a Nicolet
6700 FT-IR spectrophotometer. Electrospray ionization–mass spectrometry (ESI-MS,
high resolution) was done using a Waters Xevo G2 Qtof (ESI) mass spectrometer.
Melting points were determined using a RY-1 apparatus and were uncorrected.
Ethyl 4-chloroacetoacetate (2 mmol) and ethanal (1 mmol) were placed in a
flask under an atmosphere of nitrogen. Piperidine (1 mmol), glacial acetic acid
(1 mmol), iodine (1 mmol), concentrated hydrochloric acid (0.01 mL), and ethanol
(10 mL) were added. The resulting mixture was heated at 80 ꢀC for 12 h. After cooling
to room temperature, the solvent was removed by evaporation. The residue was
poured into 50 mL of water and extracted with ether. The organic layer was separated
and was washed with saturated sodium chloride solution. The solvent was removed
after dried over sodium sulfate and the residue was purified by column chromato-
graphy on silica gel to give the product 1a (0.15 g, white powder) in 63% yield, mp
1
138.3–139.1 ꢀC. H NMR (DMSO-d6, 400 MHz): d ppm, 11.12 (s, 1H, OH), 6.91
(s, 1H, Ph-H), 5.24 (s, 2H, CH2), 4.3 (q, 2H, CH2, J ¼ 8 Hz), 2.45 (s, 3H, CH3),
1.29 (t, 3H, CH3, J ¼ 8 Hz); 13C NMR (DMSO-d6, 100 MHz), d, ppm, 170.2,
166.7, 159.5, 150.9, 136.9, 124.2, 123.6, 113.3, 106.6, 68.3, 61.0, 14.0, 13.6. HRMS:
calc. for C12 H11O5 235.0612; found 235.0612.

SYNTHESIS OF PHTHALIDES
1785
FUNDING
This study was supported by the National Nature Science Foundation of
China (Grant No. 21172263).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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