Sustainable synthesis of 3-substituted phthalides via a catalytic one-pot cascade strategy from 2-formylbenzoic acid with β-keto acids in glycerol

Article abstract of DOI:10.3762/bjoc.13.139

Background: Phthalides are privileged constituents of numerous pharmaceuticals, natural products and agrochemicals and exhibit several biological and therapeutic activities. Therefore, the development of new, facile, and sustainable strategies for the construction of these moieties is highly desired. Results: A broad substrate scope for β-keto acids was found to be strongly compatible with this catalytic process, affording a wide variety of 3-substituted phthalides in good to excellent yields. Conclusion: A concise and efficient synthesis strategy of 3-substituted phthalides from 2-formylbenzoic acid and β-keto acids via a catalytic one-pot cascade reaction in glycerol has been accomplished.

Full text of DOI:10.3762/bjoc.13.139

Sustainable synthesis of 3-substituted phthalides via a
catalytic one-pot cascade strategy from 2-formylbenzoic acid
with β-keto acids in glycerol
Lina Jia* and Fuzhong Han
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1425–1429.
College of Chemistry and Chemical Engineering, Qiqihar University,
Qiqihar 161006, China
doi:10.3762/bjoc.13.139
Received: 09 March 2017
Accepted: 11 July 2017
Published: 19 July 2017
Email:
Lina Jia* - jialinachn@163.com
*
Corresponding author
Associate Editor: R. Sarpong
Keywords:
© 2017 Jia and Han; licensee Beilstein-Institut.
License and terms: see end of document.
β-keto acid; decarboxylation; glycerol; one-pot cascade reaction;
phthalide
Abstract
Background: Phthalides are privileged constituents of numerous pharmaceuticals, natural products and agrochemicals and exhibit
several biological and therapeutic activities. Therefore, the development of new, facile, and sustainable strategies for the construc-
tion of these moieties is highly desired.
Results: A broad substrate scope for β-keto acids was found to be strongly compatible with this catalytic process, affording a wide
variety of 3-substituted phthalides in good to excellent yields.
Conclusion: A concise and efficient synthesis strategy of 3-substituted phthalides from 2-formylbenzoic acid and β-keto acids via a
catalytic one-pot cascade reaction in glycerol has been accomplished.
Introduction
The phthalides, also known as isobenzofuran-1(3H)-ones, are the key step in organic syntheses because of its broad func-
an important class of heterocycles which are of continued tional group compatibility and ingenious construction of molec-
interest for chemists [1,2]. 3-Substituted phthalides, which are ular architectures [11-14]. Consequently, an efficient synthesis
recognized as versatile building blocks found in a large number of 3-substituted phthalides via a one-pot cascade reaction is still
of bioactive compounds [3-5], exhibit a broad spectrum of phar- in high demand.
macological activity, such as antibacterial, anti-HIV, antifungal,
antibiotic, antitumor and immunosuppressive effects [6-10]. In An analogous approach was described involving a catalytic se-
addition, the one-pot cascade transformation has proven to be quence of the aldol/cyclization reaction of 2-formylbenzoic acid
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Beilstein J. Org. Chem. 2017, 13, 1425–1429.
and substituted ketones catalyzed by strong acids [15-17], present annulation protocol. To our delight, the reaction
strong bases [18,19] and solid acid catalysts [20,21]. The proceeded smoothly to give the desired 3-phenacylphthalide
majority of these protocols generally suffer from one or more (3a) in 32% yield with Et3N (20 mol %) as a catalyst at 65 °C
drawbacks, such as the requirement of stoichiometric or excess (Table 1, entry 2). To improve the efficiency of the reaction, a
amounts of strong, corrosive and harmful acids or bases as cata- detailed optimization study was performed with various bases,
lyst, harsh conditions and low functional group tolerance when such as tertiary, secondary and primary amines. When tertiary
substituted ketones are used as nucleophiles. Therefore, the amines were used as the catalyst, very low yields of 3a were ob-
importance of phthalides and the increasing awareness of the tained (Table 1, entries 3–5). Unfortunately, a sluggish reaction
need for environmentally benign chemical production provide was observed in the presence of pyrrolidine (Table 1, entry 6).
the demand and potential for the development of a green one- Gratifyingly, the desired product was obtained in the presence
pot cascade aldol/cyclization strategy for these compounds [22]. of primary amines in good yields (Table 1, entries 7–9). In addi-
tion, the use of several inorganic bases delivered no catalytic
The use of β-keto acids as ketone enolate equivalents in metal- activation (Table 1, entries 10 and 11). Notably, a higher reac-
and organocatalytic decarboxylative aldol reactions has been tion temperature did not increase the yield of 3a (Table 1, entry
extensively studied and proven to be a valuable and straightfor- 12). Overall, the best result was achieved when 20 mol % of
ward method for the preparation of several biologically active p-anisidine was used as the catalyst in glycerol at 65 °C for
compounds of medicinal and agrochemical interest [23-30]. 0.5 h, providing 3a in 80% yield (Table 1, entry 9).
Notably, the decarboxylative reaction of β-keto acids provides a
traceless means of activation with CO2 as the only byproduct.
Table 1: Optimization of the reaction conditionsa.
On the other hand, glycerol, as an environmentally friendly
reaction medium, has received increasing interest for organic
reactions because of its peculiar physical and chemical proper-
ties such as polarity, low toxicity, biodegradability, high boiling
point, and ready availability from renewable feed stocks [31].
Many organic transformations have been accomplished using
glycerol as a solvent [32-40]. Therefore, as part of our ongoing
Entry
Catalyst
Yield (%)b
research interest in exploring novel and sustainable transformat-
ions of β-keto acids [41,42], we envisioned that the direct
utilization of β-keto acids as nucleophilic species and glycerol
as a solvent will allow the establishment of an efficient catalyt-
ic one-pot cascade aldol/cyclization reaction. Herein, we present
a new method to provide a convenient, green and efficient alter-
native for rapidly accessing a variety of 3-substituted phthalides
1
2
3
4
5
6
7
8
9
10
none
–c
Et3N
32
iPr2NEt
11
N-methylmorpholine
DMAP
trace
–c
pyrrolidine
benzylamine
aniline
trace
56
(
Scheme 1).
67
p-anisidine
K2CO3
80
Results and Discussion
–c
1
1
2
NaOH
–c
To optimize the reaction conditions, 2-formylbenzoic acid (1a)
and benzoylacetic acid (2a) were chosen as model substrates.
As summarized in Table 1, the reaction did not occur without
the use of a base, indicating that a promoter is essential for an
effective transformation (Table 1, entry 1). We then turned our
attention to the examination of a series of base catalysts for the
1
p-anisidine
80d
aGeneral reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol) and base
0.1 mmol) in glycerol (3 mL) at 65 °C for 0.5 h. DMAP = 4-dimethyl-
aminopyridine. bThe yields indicated are the isolated yields after
column chromatography. cNo reaction. dThe reaction was carried out
at 90 °C.
(
Scheme 1: Synthesis of 3-substituted phthalides from substituted 2-formylbenzoic acids and β-keto acids.
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Beilstein J. Org. Chem. 2017, 13, 1425–1429.
With the optimal conditions in hand, we started to explore the (2j) turned out to be a good substrate, and the corresponding
scope and limitations of this one-pot cascade aldol/cyclization product was obtained in 76% yield. It is worth mentioning that
system. Typical results are shown in Scheme 2. The annulation even a β-keto acid bearing a heteroaromatic ring (2k) afforded
proceeded smoothly with β-keto acids 2 bearing diverse arene the desired product in 85% yield. Unfortunately, acetoacetic
substituents to provide the corresponding isobenzofuran-1(3H)- acid did not undergo the reaction due to its low reactivity.
ones in moderate to excellent yields. For para-substituted Finally, the substituted 2-formylbenzoic acid 1b (5,6-(OCH3)2)
β-keto acids 2b–f, both electron-donating and electron-with- was also tested for this transformation, and the target product 3l
drawing groups such as methyl (2b), methoxy (2c), and halo- was obtained with 67% yield.
gens (2d–f) afforded the products in relatively high reaction
yields. The use of meta-aryl substituted β-keto acids provided After investigating the scope of the synthesis of 3-substituted
the products in good yields, whereas β-keto acid 2i, bearing a phthalides, the recyclability of glycerol was investigated for the
methyl group at the ortho-position, was evaluated to produce reaction shown in Table 2. After completion of the condensa-
the desired compound 3i in moderate yield due to steric tion, the mixture was extracted with ethyl acetate. The glycerol
hindrance. Moreover, 3-(naphthalen-2-yl)-3-oxopropanoic acid phase was directly reused for further reactions. We were
Scheme 2: Substrate scope of the synthesis of 3-substituted phthalides. General reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol) and p-anisidine
(0.1 mmol) in glycerol (3 mL) at 65 °C for 0.5 h. The yields indicated are the isolated yields after column chromatography.
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Beilstein J. Org. Chem. 2017, 13, 1425–1429.
pleased to observe that the yield of 3a was almost consistent
Supporting Information
after four runs.
Supporting Information File 1
Experimental procedures, characterization data and copies
of NMR spectra.
Table 2: Reuse of glycerol in the synthesis of 3a.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-139-S1.pdf]
Acknowledgements
This work was supported by the grants of the National Natural
Science Foundation of China (no. 21402102), the Heilongjiang
Province Science Foundation for Youths (no. QC2016015) and
the Program Young Teachers Scientific Research in Qiqihar
University (no. 2014k-M02).
Run
Reaction time (h)
Yield (%)a
1b
2c
3c
4c
0.5
0.5
1.0
1.0
80
80
80
78
aThe yields indicated are the isolated yields after column chromatogra-
phy. bGeneral reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol) and
p-anisidine (0.1 mmol) in glycerol (3 mL) at 65 °C for 0.5 h.
cRecovered glycerol was used.
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