l-Proline catalyzed facile and efficient synthesis of functionalized indol-3-yl pyran derivatives by multi-component reactions

Article abstract of DOI:10.1007/s11164-017-2897-4

A simple and green synthetic method for preparation of functionalized indol-3-yl pyran derivatives was developed. The reactions were carried out by one-pot three-component synthesis of 3-cyanoacetyl indoles, malononitrile/cyanoacetate and various aldehydes/isatins/acenaphthenequinone in the presence of catalytic amount of l-proline. The advantages of this method included straightforward processing, excellent yields, broad substrate scope and environmental friendliness.

Full text of DOI:10.1007/s11164-017-2897-4

Res Chem Intermed
DOI 10.1007/s11164-017-2897-4
L-Proline catalyzed facile and efficient synthesis
of functionalized indol-3-yl pyran derivatives
by multi-component reactions
Jing Wang1 Hongzhi Liu1 Ren Wen1
•
•
•
Zexin Zhu2 Jie Li3 Songlei Zhu1
•
•
Received: 28 November 2016 / Accepted: 2 February 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract A simple and green synthetic method for preparation of functionalized
indol-3-yl pyran derivatives was developed. The reactions were carried out by one-
pot three-component synthesis of 3-cyanoacetyl indoles, malononitrile/cyanoacetate
and various aldehydes/isatins/acenaphthenequinone in the presence of catalytic
amount of L-proline. The advantages of this method included straightforward pro-
cessing, excellent yields, broad substrate scope and environmental friendliness.
Keywords Indol-3-yl pyran Á L-Proline catalyst Á Multi-component reactions
Introduction
Multi-component reactions (MCRs) has been developed as one of the most powerful
tools for the synthesis of structurally complex, biologically active and drug-like
compounds [1–3], for their convergence, productivity, easy execution, excellent
yields and atom economy characters [4–7].
Jing Wang, Hongzhi Liu and Ren Wen have contributed equally to this work.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2897-4)
contains supplementary material, which is available to authorized users.
&
Songlei Zhu
songleizhu@xzhmu.edu.cn
1
Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004,
China
2
3
Shenzhen College of International Education, Shenzhen 518048, China
Zhengda Tianqing Pharmaceutical Group Co. LTD, Lianyungang 222062, China
123

J. Wang et al.
Pyran frame is an example of the ‘privileged scaffolds’ existing in numerous
natural and synthetic products [8–15]. Compounds containing the pyran ring system
exhibit important biological or pharmacological activities as hypertensive agents
[16], anti-coagulants [17], anticancer agents [18, 19], inhibitors of matrix
metalloproteinases [20] and analgesic agents [21]. Another example of the
‘privileged scaffolds’ is indole framework [22–24]. Among indole derivatives, the
3-substituted indole nucleus are prevalent in numerous natural products which show
prominent anticancer, anti-tumour, anti-inflammatory, hypoglycemic, analgesic and
anti-pyretic activities [25–30]. Some biologically active 3-substituted indole
representatives [31–33] are shown in Fig. 1.
Although a number of methods for the construction of indol-3-yl pyran
derivatives have been reported, many of them suffer from some drawbacks, for
example, the use of metal catalyst InCl3 [34], relative toxic organic catalyst Et3N
[35] or piperidine under ultrasonic irradiation [36]. Thus, it is still necessary to
develop an efficient and relatively low toxic method to construct this type of
meaningful heterocyclic compounds.
In recent years, L-proline catalyzed organic reaction has drawn much attentions
because of its commercially available, ease of handing and excellent solubility in
water and organic solvents characters [37–41]. L-Proline has been proved to be an
efficient catalyst in different organic reactions such as asymmetric aldol conden-
sations [42, 43], Mannich reactions [44, 45], Diels–Alder reactions [46], Michael
additions [47] and many multicomponent reactions [48–52].
As continuation of our interest in developing new methodologies for the
preparation of highly functionalized heterocyclic compounds [53–56], as well as the
research for L-proline catalyzed reactions [57], herein we report a simple and
Fig. 1 Representative structure of biologically 3-substituted indoles
123

L-Proline catalyzed facile and efficient synthesis of…
efficient protocol for the synthesis of 3-pyranyl indole derivatives catalyzed by L-
proline.
Results and discussion
Initially, the three-component reaction of 3-cyanoacetyl indole 1 (1), benzaldehyde
2 (1), and malononitrile 3 (1) (Scheme 1) was studied as a model reaction. As
shown in Table 1, different solvents (entries 1–6) were employed to find the optimal
O
CHO
NC
CN
CN
CN
CN
solvent, L-proline
reflux
+
+
O
NH2
N
H
N
H
2 a
3 a
1 a
4 a
Scheme 1 The model reaction
Table 1 Optimization of reaction conditions for the synthesis of 4 (1, 1, 1)
Entry
Solvent
Catalyst (mol%)
Temp (°C)
Yielda,b (%)
1
DMF
L-Proline (20)
L-Proline (20)
L-Proline (20)
L-Proline (20)
L-Proline (20)
L-Proline (20)
None
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
60
61
2
Dichloromethane
Acetonitrile
Water
40
3
63
4
20
5
Methanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
82
6
88
7
Trace
52
8
L-Proline (5)
L-Proline (10)
L-Proline (50)
L-Proline (20)
L-Proline (20)
L-Proline (50)
Piperidine(20)
Et3N(20)
9
76
10
11
12
13
14
15
16
17
18
19
a
88
72
40
58
20
35
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
83
InCl3(20)
87 [34]
43
Glycine
Alanine
38
Sarcosine
33
Isolated yields
b
All the reactions were carried out for 1 h
123

J. Wang et al.
reaction media. The results indicated that ethanol was found to be the ideal solvent
for this domino reaction which afforded maximum yield (entry 6). We also
evaluated the amount of L-proline required for this reaction. It was shown that
20 mol% L-proline was necessary to complete the reaction and provided the highest
yield (88%); while 5 or 10 mol% L-proline was not enough (52 or 76% yield
respectively), and 50 mol% L-proline did not lead to much more increase in terms of
the reaction yield (entries 6–10). Moreover, the reaction was carried out under
different temperatures, as showed in Table 1, with the temperature dropping, the
yields of products were decreased (entries 11–13).
Compared to some reported catalysts, such as InCl3 [34], Et3N [35] and
piperidine [36], although the model reaction could be catalyzed under the optimal
condition and good yields (80–87%) were obtained (Table 1, entries 14–16), L-
proline employed in this work manifested the advantages of higher yield (88%),
Ar
O
O
NC
CN
CN
CN
CN
L-proline (20 mol %)
ArCHO
+
+
NH2
N
H
ethanol, reflux, 1-2 h
R
N
R
H
1
2
3a
4
Scheme 2 The synthesis of 3-pyranyl indole derivatives 4 (entries 1–17)
Table 2 The synthesis of 3-pyranyl indole derivatives 4
Entry
Compound
1(R)
Product
Time (h)
Yielda (%)
2(Ar)
1
H
C6H5
4a
4b
4c
4d
4e
4f
1.0
1.0
1.5
1.5
2.0
1.5
1.0
1.5
1.5
2.0
1.5
1.0
1.5
1.0
1.5
1.5
2.0
88
80
77
75
79
70
85
84
74
71
77
79
77
78
73
74
71
2
H
4-Cl-C6H4
3
H
2-Cl-C6H4
4
H
2-Br-C6H4
5
H
2,4-(Cl)2-C6H3
3-NO2-C6H4
4-CH3-C6H4
4-OCH3-C6H4
2-OCH3-C6H4
2,3-(OCH3)2-C6H3
2-Naphthyl
4-Cl-C6H4
6
H
7
H
4g
4h
4i
8
H
9
H
10
11
12
13
14
15
16
17
a
H
4j
H
4k
4l
5-Br
5-Br
4-OCH3-C6H4
4-Cl-C6H4
4m
4n
4o
4p
4q
2-CH3
2-CH3
4-OCH3-C6H4
4-Cl-C6H4
1-CH3-2-C6H5
1-CH3-2-C6H5
4-OCH3-C6H4
Isolated yield
123

L-Proline catalyzed facile and efficient synthesis of…
easy handling and green procedure characters. Furthermore, some other amino
acids, for example, glycine, alanine and sarcosine were also tested as a catalyst in
the experiment, the reaction performed to some extent with lower to moderate yields
(Table 1, entries 17–19).
Under the optimal conditions, the generality of the reaction was investigated with
3-cyanoacetyl indoles 1, various aldehydes 2 and malononitrile 3a in ethanol with
catalyst L-proline (20 mol%) (Scheme 2). The results were summarized in Table 2
(entries 1–11). It was shown that, the method was not only suitable to aromatic
aldehydes with electron-withdrawing groups (entries 2–6), but also to the aromatic
aldehydes with electron-donating groups (entries 7–10), as well as 2-naphthalde-
hyde (entry 11). Moreover, when different substituted 3-cyanoacetyl indoles 1 were
employed in the reaction under the optimized reaction conditions, the desired
3-pyranyl indole derivatives 4 (entries 12–17) were also obtained with satisfied
yields.
Ar
Ar
O
O
CN
CN
NC
CN
N
NC
3a
O
CN
H
COOH
N
H
+
O
H
Ar
H
N
H
N
N
H
H
6a
2
1
5
COOH
Ar
N
H
Ar
O
Ar
O
NC
CN
CN
NC
CN
NC
H
COOH
O
H
N
H
O
N
H
NH2
NH
N
N
H
N
H
H
N
O
4
6c
6b
Scheme 3 Proposed mechanism for the formation of compounds 4
Scheme 4 The synthesis of spiro-pyran derivatives 8 and 9 (entries 18–27)
123

J. Wang et al.
Based on the above results, a plausible mechanism for the formation of
compound 4 was proposed (Scheme 3). It was suggested that L-proline may catalyze
the Knoevenage condensation reaction of 3-cyanoacetyl indole 1 and aldehydes 2 to
Table 3 The synthesis of spiro-3-pyranyl indole derivatives 5 and 6
Entry
Compound
Product
Time (h)
Yielda (%)
1(-R)
7(-R0)
8
3(-X)
18
19
20
21
22
23
24
25
26
27
H
H
–
–
–
–
–
–
8
8
8
8
CN
9a
2
85
84
79
83
76
79
75
83
71
75
H
5-F
CN
9b
2
H
5-Br
CN
9c
2
H
5-CH3
CN
9d
2
H
H
H
–
CO2Me
CO2Et
CN
9e
1.5
1.5
3
H
9f
H
10a
10b
10c
10d
5-Br
2-CH3
–
CN
2
–
CN
3
1-CH3-2-
C6H5
–
CN
3
a
Isolated yield
Fig. 2 The crystal structure of 4q with DMF solvent molecule
123

L-Proline catalyzed facile and efficient synthesis of…
form the intermediate 5 which could be observed during the experiment procedure.
Then, the Michael addition was taken place between 5 and malononitrile 3a to give
the intermediate 6a. Finally, with the catalysis of L-proline, the O-atom of the
intermediate 6a attacked the nitrile group, which followed by intramolecular
cyclization and a subsequent H-atom shift, leaded to the final product 4.
To further explore the potential of this protocol for diverse heterocycle synthesis,
we replaced aldehydes and malononitrile by isatins 7/acenaphthenequinone 8 and
cyanoacetate 3 (2–3), respectively (Scheme 4). The corresponding spiro-3-pyranyl
derivatives 9 and 10 were synthesized smoothly, and the results are summarized in
Table 3 (entries 18–27). As illustrated in Table 3, this method is not only suitable to
different substituted isatins, but also applicable to acenaphthenequinone. Moreover,
the reaction could proceed smoothly when the malononitrile was replaced by
cyanoacetate.
1
All the products were characterized by melting points, IR, H NMR, 13C NMR
and HRMS spectral determination. Furthermore, the structure of 4q was established
by X-ray crystallographic analysis (Fig. 2). The detailed experimental procedure
and characterization data can be found in the supplementary file in the online
version.
Conclusion
In conclusion, we have developed an efficient and relatively low toxic protocol for
the synthesis of 3-pyranyl indole derivatives via the three-component reaction of
3-cyanoacetyl indoles, aldehydes/isatins/acenaphthenequinone and malononi-
trile/cyanoacetate in the presence of catalytic amount of L-proline (20 mol%). In
view of the additive effect that incorporating two biologically potential moieties
into a single molecule may enhance the biological activity of the compounds,
further biomedical screening work is in progress in our laboratories.
Acknowledgements This work was partially supported by Innovation Project of Xuzhou Medical
College; Collaborative Innovation Center of Tumor Biological Treatment; Key Laboratory of Organic
Synthesis of Jiangsu Province (KJS1010).
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