Efficient synthesis of 2H-chromene derivatives via a dual-organocatalytic reaction

Article abstract of DOI:10.1016/j.tetlet.2020.152402

An efficient synthetic method was developed for the selective construction of 2H-chromene derivatives from various salicylaldehydes and acetylenic diesters using a dual catalyst system (p-toluenesulfonic acid monohydrate and pyrrolidine). The advantages of this transformation include high selectivity, good functional group tolerance, operational simplicity, and mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2020.152402

Tetrahedron Letters 61 (2020) 152402
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of 2H-chromene derivatives via a
dual-organocatalytic reaction
⇑
Siriphong Somprasong, Watcharapon Prasitwatcharakorn, Torsak Luanphaisarnnont
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2020
Revised 14 August 2020
Accepted 21 August 2020
Available online 1 September 2020
An efficient synthetic method was developed for the selective construction of 2H-chromene derivatives
from various salicylaldehydes and acetylenic diesters using a dual catalyst system (p-toluenesulfonic acid
monohydrate and pyrrolidine). The advantages of this transformation include high selectivity, good func-
tional group tolerance, operational simplicity, and mild reaction conditions.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
2H-Chromenes
Catalysis
p-Toluenesulfonic acid
Pyrrolidine
Regioselective synthesis
2
H-Chromenes are an important structural motif in organic
due to its increased environmental friendliness, and organocat-
alytic reactions to synthesize 2H-chromene derivatives have been
developed using the oxa-Michael-aldol reaction [15], Petasis reac-
tion [16], Knoevenagel condensation [17], [4+2]-cycloaddition [18],
and formal [4+2]-cycloaddition reaction [19–20].
chemistry. Various substituted chromene derivatives can be found
as secondary metabolites in biosynthetic pathways. They are also
found in a wide range of natural products and synthetic com-
pounds with potent biological and pharmaceutical properties [1].
For example, (2S)-Candenatenin E is a flavonoid isolated from the
heartwood of Dalbergia candenatensis, which exhibits cytotoxicity
towards cancer cells [2]. Tuberatolide B, isolated from marine Sar-
gassum macrocarpum, acts as an efficient farnesoid X receptor
antagonist and an anticancer compound [3]. Rottlerin (mallotoxin),
extracted from the fruit glands of Mallotus philippensis, is used as a
protein kinase Cd (PKCd)-selective inhibitor for the analysis of pro-
tein content [4]. Iclaprim is a Gram-positive antibiotic candidate
for skin infections [5]. Acolbifene is a selective estrogen receptor
modulator that can potentially be used for breast cancer treatment
One important issue in the synthesis of 2H-chromene is the
selectivity between 2H-chromene, 4H-chromene and coumarin
products [21–22]. Previous reports have shown that the reaction
conditions and the electronic nature of the substrate play an
important role in the selectivity. The reactions of various salicy-
laldehydes and acetylenic diesters in the presence of a combination
of an organocatalyst and a Lewis acid catalyst were reported to
give coumarin products; however, when electron deficient salicy-
laldehydes were used, 2H-chromene products were instead
obtained in moderate yields [19,22]. Another report showed that
aniline could act as an efficient catalyst for the synthesis of 2H-
chromene derivatives, but the reaction required the use of lactic
acid as a solvent [20]. Although several synthetic methods for
2H-chromenes have been reported, limitations such as the require-
ment of an electron-withdrawing substituent in the substrates or
the use of acid as a solvent still exist. Herein, we have developed
an efficient method to synthesize 2H-chromene derivatives with
a broad substrate scope, high selectivity, and high yields using a
[
6]. In addition to their biological properties, 2H-chromene deriva-
tives have also been used as building blocks in the syntheses of
compounds with interesting optical properties such as pho-
tochromic compounds and fluorescence probes [7] (Fig. 1).
Various methods have been developed to synthesize 2H-chro-
mene scaffolds. Transition-metal catalysts such as Pd [8], Fe [9],
Co [10] Re [11], Yb [12], and Au [13] have been shown to be effec-
tive for the synthesis of 2H-chromene derivatives. Additionally, a
variety of inorganic base-mediated reactions have been reported
dual-organocatalytic combination (pTsOHÁH
2
O and pyrrolidine).
[
14]. Recently, organocatalysis has attracted significant attention
To optimize the reaction condition, the model reaction between
salicylaldehyde (1a) and dimethyl acetylenedicarboxylate (2a) in
the presence of a Brønsted acid and an amine base was chosen.
The optimization of various parameters including bases, solvents,
⇑
Corresponding author.
E-mail address: torsak.lua@mahidol.ac.th (T. Luanphaisarnnont).
https://doi.org/10.1016/j.tetlet.2020.152402
040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
0

2
S. Somprasong et al. / Tetrahedron Letters 61 (2020) 152402
temperature, and time was investigated in order to improve the
yield. The results are summarized in Table 1.
When the reaction was carried out with no acid and no base, the
desired product 3aa was not obtained (Entry 1). In the absence of
an amine base, the desired product was also not obtained (Entry 2).
In the absence of an acid, only a trace amount of the product was
obtained (Entry 3).
Various Brønsted acids were subsequently examined (Entries
4
2
–8). pTsOHÁH O was found to be the optimal acid catalyst to pro-
mote the cyclization between 1a and 2a, giving the desired 2H-
chromene 3aa in 69% yield (Entry 8). Interestingly, only the 2H-
chromene product was obtained in high selectivity—no 4H-chro-
mene or coumarin products were obtained. Different organic bases
were also investigated (Entries 8–13). Pyrrolidine was found to be
the most effective base and gave the highest yield (Entry 8). Other
cyclic secondary amines (piperazine and piperidine) gave slightly
lower yields (Entries 9 and 10). Benzylamine, pyridine, and DABCO
were less effective or ineffective in the reaction (Entries 11–13).
Upon increasing the amount of pTsOHÁH
2
O from 10 mol% to
0 mol%, the yield of the reaction decreased to 45% (Entry 14).
2
When the acid was used in a stoichiometric amount, no desired
product was obtained (Entry 15). Decreasing the pyrrolidine load-
ing to 10 mol% and 20 mol% had a negative effect on the yield of the
reaction (Entries 16 and 17). Using a stoichiometric amount of
pyrrolidine also decreased the yield (Entry 18). This result sug-
Figure 1. Representative examples of 2H-chromene scaffolds in natural products
and synthetic compounds with biological, pharmaceutical, and optical properties.
2
gested that the ratio of pTsOHÁH O and pyrrolidine played a crucial
role in the catalytic process.
Table 1
Reaction optimization.a
Entry
Brønsted acid (mol%)
none
Amine base (mol%)
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
none
none
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
30
60
75
75
75
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
16
24
24
0
0
pTsOHÁH
2
O (10)
none
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Piperazine (30)
Piperidine (30)
Benzylamine (30)
Pyridine (30)
< 5
17
25
18
47
69
53
61
12
0
PhOH (10)
AcOH (10)
PhCOOH (10)
pNO
2
-PhCOOH (10)
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
pTsOHÁH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (20)
O (100)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
DABCO (30)
0
45
0
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (10)
Pyrrolidine (20)
Pyrrolidine (100)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
Pyrrolidine (30)
0
18
35
62
52
13
12
< 5
< 5
14
12
40
72
75
90 (86)
i
PrOH
BuOH
n
2
H O
2
CH Cl
2
PhMe
THF
EtOH
EtOH
EtOH
EtOH
EtOH
c
pTsOHÁH
2
O (10)
a
b
c
2
Reagents and conditions: 1a (0.25 mmol), 2a (0.3 mmol), pTsOHÁH O, amine base, solvent (0.5 mL), 75 °C, 8 h.
NMR yield. Value in parenthesis is the isolated yield.
1
2
a (0.25 mmol), 2a (0.375 mmol), pTsOHÁH O (0.025 mmol)

S. Somprasong et al. / Tetrahedron Letters 61 (2020) 152402
3
Table 2
Substrates scope.a
Entry
R
R’
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
H
5-F
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ab
3bb
3cb
3db
3eb
3fb
3gb
82
92
86
92
98
80
93
95
99
99
99
99
96
99
5-Cl
5-Br
5-NO
5-OMe
3-OMe
H
5-F
5-Cl
5-Br
2
0
1
2
3
4
5-NO
5-OMe
3-OMe
2
Et
Et
a
Reagents and conditions: salicylaldehyde (1a–1g) (1.0 mmol), dialkyl acetylenedicarboxylate (2a and 2b) (1.5 mmol), pyrrolidine (0.3 mmol), pTsOHÁH
2
O (0.1 mmol),
EtOH (2.0 mL), 75 °C, 24 h.
Subsequently, different solvents were screened. Most alcoholic
solvents such as ethanol, methanol, and isopropanol were found
to be suitable for the reaction, giving the product in moderate to
good yields (Entries 8, 19 and 20). However, n-butanol and water
gave the product in significantly lower yields (Entries 21 and 22).
Aprotic solvents such as dichloromethane, toluene, and tetrahy-
drofuran were found to be less effective in the reaction (Entries
under the optimized reaction condition to provide the desired pro-
duct 3aa in 94% yield (Scheme 1c). These results suggested that
enamino ester 6 could be an intermediate in the reaction. 4H-Chro-
mene (7) could isomerize to the desired product 3aa under the
reaction conditions (Scheme 1d), suggesting that it could possibly
be an intermediate in the reaction. However, when aldehyde 8
was subjected to the optimized reaction conditions, no desired
product was obtained (Scheme 1e), suggesting that it was not an
intermediate in the reaction.
2
3–25). The best yield was obtained when ethanol was used as
the solvent.
To further optimize the reaction, the effects of reaction temper-
From these experimental results, a plausible mechanism for the
selective synthesis of 2H-chromenes was proposed (Scheme 2). The
ature and time were investigated. Decreasing the temperature led
to lower yields (Entries 26 and 27). Prolonging the reaction time
provided slightly higher yields (Entries 28 and 29). The yield of
the product significantly increased when the amount of 2a was
increased to 1.5 equivalents (Entry 30).
With the optimized conditions in hand, the substrate scope of
the reaction was investigated (Table 2). Salicylaldehydes with
halogen substituents such as fluoro, chloro, and bromo afforded
the corresponding 2H-chromene derivatives 3ba, 3ca, and 3da in
9
2%, 86%, and 92% yield, respectively (Entries 2–4). Salicylaldehy-
des with an electron-deficient nitro group gave product 3ea in
8% yield (Entry 5). A substrate with an electron-donating meth-
oxy group gave the corresponding product 3fa in 80% yield (Entry
9
6
). 3-Methoxysalicyladehyde also gave the corresponding product
3
ga in high yield (95%, Entry 7). Therefore, both electron-rich and
electron-deficient substituents on the salicylaldehydes were well-
tolerated in the reaction, giving their corresponding products in
good to excellent yields. When diethyl acetylenedicarboxylate
(2b) was used instead of 2a, the reactions gave product 3ab–3gb
in excellent yields (95–99%, Entries 8–14). Based on the substrate
scope study, this method was found to be useful and practical for
the synthesis of 2H-chromene derivatives with various
substituents.
Control experiments were performed in order to better under-
stand the reaction mechanism (Scheme 1). When salicylaldehyde
(1a) was reacted with pyrrolidine in deuterated methanol in the
presence or absence of pTsOHÁH
2
O, iminium product 4 and o-
quinomethide 5 were not observed which is not surprising as they
are highly reactive intermediates (Scheme 1a). Subsequently, we
investigated the possibility of enamino ester 6 as an intermediate
in the reaction. Ester 6 formed readily from pyrrolidine and 2a
(Scheme 1b) and could be used in a catalytic amount (30 mol%)
Scheme 1. Control experiments.

4
S. Somprasong et al. / Tetrahedron Letters 61 (2020) 152402
Institute for the Promotion of Teaching Science and Technology
IPST). Financial support from the Center of Excellence for Innova-
(
tion in Chemistry (PERCH–CIC), Thailand, Ministry of Higher Edu-
cation, Science, Research and Innovation is gratefully
acknowledged. We are also grateful for the support from the
Department of Chemistry and the Central Instrumental Facility
(
CIF), Faculty of Science, Mahidol University for research facilities.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152402.
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In summary, we have successfully developed a simple and effi-
cient method for the synthesis of 2H-chromene derivatives using a
[
[
1
2
dual-organocatalyst system (pTsOHÁH O and pyrrolidine). A vari-
ety of functionalized 2H-chromenes with electron-withdrawing
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Declaration of Competing Interest
(
2
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
(
(
7
(
1
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This research was supported by the Thailand Research Fund
MRG6180248), Thailand; S.S. is grateful for the scholarship from
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8