Condensation of 4-chloro-2H-chromene-3-carbaldehydes and ethyl-3-aminocrotonates with p-TsOH: a facile approach for the synthesis of chromenyldihydropyridines

Article abstract of DOI:10.1080/00397911.2019.1631850

The investigated reaction of 4-chloro-2H-chromene-3-carbaldehyde 1a with ethyl 3-oxobutanoate 2a in the presence of ammonium acetate provided two compounds, 2H-chromenyldihydropyridine dicarboxylate 3a and chromenopyridine carboxylate 4a. However, the reaction of 1a with ethyl-3-aminocrotonate 5a in the presence of p-TsOH provided selectively 2H-chromenyldihydropyridine dicarboxylate 3a with very good yield. The established method was applied for the preparation of series of 2H-chromenyldihydropyridine dicarboxylates 3a–q.

Full text of DOI:10.1080/00397911.2019.1631850

Synthetic Communications
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Condensation of 4-chloro-2H-chromene-3-
carbaldehydes and ethyl-3-aminocrotonates with
p-TsOH: a facile approach for the synthesis of
chromenyldihydropyridines
Shravani Madhunala, Siva Hariprasad Kurma, Varsha Reddy Etikala & China
Raju Bhimapaka
To cite this article: Shravani Madhunala, Siva Hariprasad Kurma, Varsha Reddy Etikala & China
Raju Bhimapaka (2019): Condensation of 4-chloro-2H-chromene-3-carbaldehydes and ethyl-3-
aminocrotonates with p-TsOH: a facile approach for the synthesis of chromenyldihydropyridines,
Synthetic Communications, DOI: 10.1080/00397911.2019.1631850
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https://doi.org/10.1080/00397911.2019.1631850
Condensation of 4-chloro-2H-chromene-3-carbaldehydes
and ethyl-3-aminocrotonates with p-TsOH: a facile
approach for the synthesis of chromenyldihydropyridines
Shravani Madhunala, Siva Hariprasad Kurma, Varsha Reddy Etikala, and
China Raju Bhimapaka
Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 28 March 2019
The investigated reaction of 4-chloro-2H-chromene-3-carbaldehyde
1a with ethyl 3-oxobutanoate 2a in the presence of ammonium
acetate provided two compounds, 2H-chromenyldihydropyridine
dicarboxylate 3a and chromenopyridine carboxylate 4a. However,
the reaction of 1a with ethyl-3-aminocrotonate 5a in the presence
of p-TsOH provided selectively 2H-chromenyldihydropyridine dicar-
boxylate 3a with very good yield. The established method was
applied for the preparation of series of 2H-chromenyldihydropyridine
dicarboxylates 3a–q.
KEYWORDS
4-Chloro-2H-chromene-3-
carbaldehydes; ethyl-3-
aminocrotonates; 2H-
chromenyldihydropyridine
dicarboxylates; p-TsOH
GRAPHICAL ABSTRACT
Introduction
Dihydropyridines[1–4] are biologically important heterocyclic compounds and structural
motif present in various natural products and pharmaceuticals. 4-Chloro-2H-chromene-3-
carbaldehydes are useful chemical substrates[5] having two reactive sites at C-3
(Conjugated carbonyl group) and C-4 (Chloro functional group) and have been prepared
various heterocyclic compounds which are well documented in the literature.[6–10] As
part of our ongoing research work on 4-chloro-2H-chromene-3-carbaldehydes, author
group prepared 2H-chromenylacrylates,[11] 2H-chromenylmethylene benzohydrizides[12]
and 2H-chromenyl azlactones,[13] by chemical modification of 2H-chromene-3-carbalde-
hydes. Generally, condensation of carbaldehyde compounds with ethyl-3-aminocrotonate
gives dihydropyridines. However, David and his research group reported
CONTACT Bhimapaka China Raju
chinaraju@iict.res.in
Organic Synthesis and Process Chemistry Division, CSIR-
Indian Institute of Chemical Technology, Hyderabad 500007, India.
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC

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S. MADHUNALA ET AL.
Scheme 1. Reaction of 1a with 2a in presence of ammonium acetate.
5H-chromenopyridines[5] by the condensation of 4-chloro-2H-chromene-3-carbaldehyde
with ethyl-3-aminocrotonate in methanol under reflux conditions. Michael addition of
ethyl-3-aminocrotonate to the reactant of 4-chloro-2H-chromene-3-carbaldehyde provided
the dihydropyridyl moiety with the elimination of HCl. We were delighted this
observation and the reaction of 4-chloro-2H-chromene-3-carbaldehydes have been rein-
vestigated with various ethyl-3-aminocrotonates in the presence of various catalysts.
Interestingly, these reactions provided 2H-chromenyldihydropyridines instead of
5H-chromenopyridines. The observations about these reactions and results obtained were
presented below.
Results and discussions
In an initial experiment, we have conducted three-component, one-pot reaction of
4-chloro-2H-chromene-3-carbaldehyde 1a (1 mmol) with ethyl 3-oxo-butanoate 2a
(2 mmol) in the presence of ammonium acetate (4 mmol) in methanol at room tempera-
ture (Scheme 1). This reaction yielded two compounds, 2H-chromenyldihydropyridine
3a (65%) and 5H-chromenopyridine 4a (20%).[5] We also observed the formation of
ethyl-3-aminocrotonate 5a in minor quantity (10%). This probably formed between
ethyl 3-oxo-butanoate and ammonium acetate during the reaction. These compounds
were isolated and characterized by spectral data.
In order to obtain the compound 3a selectively, next, the reaction of 1a with 2a has
been tested with various ammonium salts and the results are tabulated in Table 1. We
observed the formation of compound 3a in major quantity and 4a in minor quantity
with NH4F (3a 62%, 4a 22% yield) and (NH4)2CO3 (3a 70%, 4a 15% yield, Table 1,
entry 2, 8). NH4Cl, NH4Br, (NH4)2NO3 and (NH4)2SO4 did not work (Table 1, entry
3–5 and 7) under these conditions. We believe that these ammonium salts are less react-
ive with 2a to form 5a to precede the reaction to give the final compound 3a. Next, we
have tested this reaction with various catalysts in the presence of (NH4)2CO3 (Table 1,
entry 9–22) in order to get the compound 3a with selectively. Among such catalysts,
AcOH, CaCl2, SnCl2, CuCl2, ZnCl2, CeCl3 and I2 produced both the compounds (3a
40–70%) and (4a 26–38% yield, Table 1, entry 10, 12–16, 18). Interestingly, NH2SO3H
and H3PW12O40 selectively provided only compound 3a with poor yields and longer
reaction time (Table 1, entry 19–20). The remaining catalysts p-TSA, TFA, BiCl3,
ZrOCl2 and Bi(OTf)3 did not work (Table 1, entry 9, 11, 17, 21–22) under
these conditions.
The above reactions produced mixture of compounds 3a and 4a. In order to obtained
compound 3a, we have next planned the reaction of 1a with ethyl-3-aminocrotonate.
The required ethyl-3-aminocrotonate 5a was prepared by the reaction of ethyl

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Table 1. Reaction of 1a and 2a with various ammonium salts.
CH3
NH
CH3
CO2C2H5
3a
CH3
C2H5O2C
C2H5O2C
Cl
Cl
N
O
O
CHO
+
NH4X
+
CH3OH, rt
OC2H5
H3C
O
1a
O
O
2a
4a
3a (%)a
4a (%)a
Entry
Catalyst
Time (h)
NH4X
1
2
3
4
---
---
---
---
24
28
24
60
66
62
---
---
28
22
---
---
NH4OH
NH4F
NH4Cl
NH4Br
5
6
7
8
NH4NO3
NH4OAc
---
---
---
---
72
72
---
65
---
70
---
28
---
15
NH4(SO4)2
(NH4)2CO3
51
8
9
p-TsOH
24
22
48
48
---
40
---
50
---
26
---
32
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
10
11
12
AcOH
TFA
CaCl2
SnCl2
13
14
15
8
8
8
50
66
50
30
29
31
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
CuCl2.H2O
ZnCl2
CeCl3
BiCl3
I2
16
17
18
8
24
8
60
---
70
38
---
18
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
NH2SO3H
19
20
24
24
30
20
---
---
(NH4)2CO3
(NH4)2CO3
H3PW12O40
ZrOCl2.6H2O
Bi(OTf)3
21
22
24
24
---
---
---
---
(NH4)2CO3
(NH4)2CO3
aIsolated yields.
3-oxobutanoate 2a with ammonium hydroxide.[5] Initially, the reaction of 1a (1 mmol)
with 5a (2 mmol) carried out in methanol at room temperature without using any cata-
lyst. Interestingly, this reaction was provided compound 3a selectively in 48% yield
(60 h, Scheme 2).
Next, we have carried out the reaction of 1a (1 mmol) with 5a (2 mmol) in the pres-
ence of various catalysts such as CaCl2, SnCl2, CuCl2, I2, ZnCl2, H3PW12O40, BiCl3,
NH2SO3H, ZrOCl2 and Bi(OTf)3 AcOH, CeCl3.7H2O (Table 2, entry 2–14) in methanol
at room temperature. All these catalysts provided the compound 3a in moderate to
good yields except AcOH and CeCl3.7H2O. However, we found p-TsOH is the best
catalyst and provided compound 3a in very good yield (75%, Table 2, entry 2). The
plausible mechanism for the formation of compound 3a is depicted in Scheme 3.
The result was encouraged us to establish the present protocol with various 4-chloro-2H-
chromene-3-carboxaldehydes with ethyl-3-aminocrotonates to prepare series of

4
S. MADHUNALA ET AL.
Scheme 2. Preparation of 3a by the reaction of 1a with ethyl-3-aminocrotonate 5a.
Table 2. Preparation of 2H-chromenyldihydropyridine 3a.
CH3
NH
CH3
CO2C2H5
C2H5O2C
Cl
Cl
CHO
+
NH2
O
CH3OH
H3C
OC2H5
Catalyst, rt
O
1a
O
5a
3a
Yield (%)a
Entry
Catalyst
Time (h)
1
2
3
4
---
60
4
48
75
---
45
p-TsOH
AcOH
CaCl2
6
24
5
SnCl2
24
24
42
40
42
46
---
55
6
CuCl2.H2O
I2
7
24
24
24
24
8
ZnCl2
9
CeCl3.7H2O
H3PW12O40
10
11
12
24
24
50
60
BiCl3
NH2SO3H
ZrOCl2.6H2O
Bi(OTf)3
13
14
24
24
48
57
aIsolated yields.
2H-chromenyldihydropyridines. Accordingly, the starting materials 4-chloro-2H-chromene-
3-carbaldehydes 1b–e were prepared from chroman-4-ones under Vilsmeier
reaction conditions.[5] Similarly, various aminocrotonates such as methyl 3-aminobut-2-
enoate 5b, ethyl 3-amino-3-phenylacrylate 5c and ethyl 3-amino-4,4,4-trifluorobut-2-enoate
5d, ethyl 3-(phenylamino)but-2-enoate 5e, ethyl 3-(benzylamino)but-2-enoate 5f and 4-ami-
nopent-3-en-2-one (amino ketone) 5h were prepared starting from corresponding b-ketoest-
ers and 1,3-diketone as per the literature procedures.[14–24] Thus prepared carbaldehydes
1b–e were reacted with 5a–h in the presence of p-TsOH under optimized conditions. The
carbaldehydes 1b–e were preceded smoothly with 5a–c and provided the series of 2H-chro-
menyldihydropyridines 3b–q in moderate to very good yields (Table 3). The electron donat-
ing groups provided good yields when compared to withdrawing groups. However,

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5
Scheme 3. Plausible mechanism.
Table 3. Preparation of 2H-chromenyldihydropyridines 3a–q.

6
S. MADHUNALA ET AL.
aminocrotonates 5d–h did not provided the corresponding compounds. All the compounds
3a–q are unknown and well characterized by spectral data (see SI).
Conclusion
In conclusion, we have developed a convenient approach for the preparation of 2H-
chromenyldihydropyridines by the reaction of 4-chloro-2H-chromene-3-carbaldehydes
with ethyl-3-aminocrotonates in the presence of p-TsOH in methanol at room tempera-
ture. The mild reaction conditions and commercially available reagents are the notable
points. The prepared compounds are medicinally and pharmaceutically important
heterocycles.
Experimental
General procedure for the preparation of diethyl-4-(4-chloro-2H-chromen-3-yl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3a)
Ethyl-3-aminocrotonate (5a, 2 mmol) was added to a stirred solution of 4-chloro-2H-
chromene-3-carbaldehyde (1a, 1 mmol), p-TsOH (1 mmol) in methanol at room tem-
perature. The contents were stirred until completion of the reaction (TLC, 4 h). The
solvent was removed under reduced pressure and the reaction mass diluted with ethyl
acetate and washed with water. Layers were separated and the organic layer was dried
over sodium sulfate. The crude product was purified by column chromatography
(60:120 silica gel, 1:9 ethyl acetate: hexane) afforded 2H-chromenyldihydropyridine 3a
as colorless solid. The remaining compounds 3b–q were prepared from corresponding
2H-chromene-3-carbaldehydes 1b–e with ethyl-3-aminocrotonates 5a–c under optimized
reaction conditions.
Spectral data for the synthesized compounds can be accessed on the publish-
er’s website.
Acknowledgment
The authors thank Director, CSIR-IICT for constant encouragement and support.
Funding
B. China Raju acknowledges SERB, New Delhi for financial support [EEQ/2017/000314]. IICT
manuscript communication no. IICT/Pubs./2018/265.
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