Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes

Article abstract of DOI:10.1016/j.tetlet.2020.151854

The in-situ formed carbonylimidazole derivatives of Ar(alkyl)-CH₂COOH react at r.t. with substituted salicylaldehydes in [BMIM][PF₆] or [BMIM][BF₄] as solvent, and [PAIM][NTf₂] as basic-IL, to produce libraries of 3-aryl(alkyl)coumarins. Whereas these reactions can also be performed with similar efficiency in THF by employing DBU, the IL approach offers easier work-up and recycling of the IL solvent. An IL-mediated approach to the synthesis of novel coumarin-bearing diaryl-ethynes by the Sonogshira reaction is also reported, and the potential for recycling/reuse of the IL solvent is shown.

Full text of DOI:10.1016/j.tetlet.2020.151854

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile one-pot synthetic access to libraries of diversely substituted 3-aryl
(Alkyl)-coumarins using ionic liquid (IL) or conventional base/solvent,
and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes
Pavankumar Prabhala a, Hemantkumar M. Savanur a, Suraj M. Sutar a, Shruti S. Malunavar a,
Rajesh G. Kalkhambkar a, , Kenneth K. Laali b,
⇑
⇑
a Department of Chemistry, Karnatak University’s Karnatak Science College, Dharwad, Karnataka 580001, India
b Department of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The in-situ formed carbonylimidazole derivatives of Ar(alkyl)-CH2COOH react at r.t. with substituted sal-
icylaldehydes in [BMIM][PF6] or [BMIM][BF4] as solvent, and [PAIM][NTf2] as basic-IL, to produce libraries
of 3-aryl(alkyl)coumarins. Whereas these reactions can also be performed with similar efficiency in THF
by employing DBU, the IL approach offers easier work-up and recycling of the IL solvent. An IL-mediated
approach to the synthesis of novel coumarin-bearing diaryl-ethynes by the Sonogshira reaction is also
reported, and the potential for recycling/reuse of the IL solvent is shown.
Received 11 February 2020
Revised 13 March 2020
Accepted 16 March 2020
Available online xxxx
Keywords:
Ó 2020 Elsevier Ltd. All rights reserved.
3-aryl(alkyl)coumarins
Coumarin-bearing diaryl-ethynes
Salicylaldehydes and aryl(alkyl)-acetic acids
Carbonyldiimidazole
Ionic liquids
Coumarins are important constituents of biologically active nat-
ural products and valuable building blocks in synthetic and medic-
inal chemistry [1–4], that have also found application in materials
chemistry [5]. Substituted 3-arylcoumarins are of particular inter-
est due to their diverse biological activity notably as anti-Alzhei-
mer agents [6,7].
Drawbacks and limitations associated with the classical meth-
ods such as Pechman and Perkin reactions, have prompted the
development of newer strategies for the synthesis of 3-aryl-
coumarins. These methods include oxidative (KMnO4/AcOH) aryla-
tion of coumarins using arylboronic acids [8], Pd-catalyzed Suzuki
coupling starting with 3-chlorocoumarins in DMF/H2O/reflux [9],
decarboxylative coupling using N-hydroxyphthalimide esters with
Ir(ppy)3/DMSO/TFA [10], and condensation of allenes with phenols
and anisoles employing TfOH/DCE [11]. Among the methods that
employ salicylaldehydes as reaction partner are condensation of
salicylaldehydes with ynamides employing ZnBr2 [12], reaction
of N-acylbenzotriazoles with salicylaldehydes via acylation/
cyclization [13], reaction of salicylaldehydes with phenylacetic
acid using POCl3/pyridine to form the benzyl ester followed by a
base-catalyzed cyclization (KOH/pyridine) [14a], reaction of
salicylaldehydes with substituted phenylacetic acids using
cyanuric chloride/N-methylmorpholine/DMF/reflux [14b], and
condensation of salicylaldehydes with aryl-substituted 1,1-
dibromo-1-alkene [15].
In continuation of our studies on synthetic and catalytic chem-
istry in ILs [16], we sought to develop a simple IL-based one-pot
method using readily available low cost reagents that enables the
assembly of a library of 3-arylcoumarins under very mild condi-
tions. By using [PAIM][NTf2] as the basic-IL,[16e-g] and [BMIM]
[PF6] or [BMIM][BF4] as solvent, the in-situ formed carbonylimida-
zole derivatives of Ar(alkyl)-CH2COOH, formed by reaction with
carbonyl-diimidazole (CDI), smoothly reacted with salicylaldehyde
at r.t. to furnish 3-aryl(alkyl)coumarins (Fig. 1). Following an initial
feasibility study, the scope of the reaction was examined by
employing diversely substituted salicylaldehydes and substituted
phenylacetic acids, and the results are gathered in Table 1. Fig 2.
Further feasibility studies showed that this transformation
could also be achieved with similar efficiency at r.t. by using BDU
in THF; therefore the scope of the reaction was reexamined in
order to provide a broader side-by-side comparison (Table 2).
Whereas the IL-based method and the conventional base/
solvent method appear to have similar efficiency, the IL method
is advantageous from a practical point of view due to easier
⇑
Corresponding authors.
E-mail addresses: rgkalkhambkar@gmail.com (R.G. Kalkhambkar), Kenneth.
Laali@UNF.edu (K.K. Laali).
https://doi.org/10.1016/j.tetlet.2020.151854
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854

2
P. Prabhala et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Facile one-pot synthesis of a library of 3-arylcoumarins
Table 1
Synthesis of 3-aryl(alkyl)coumarins in IL
Run#
1
Ar(alkyl)CH2CO2H
Salicylaldehyde
Producta
IL
Timeb[h]
1
Yieldc [%]
76d
[BMIM][PF6]
2
3
[BMIM][PF6]
[BMIM][BF4]
1
2
68e
78d
4
5
[BMIM][PF6]
[BMIM][BF4]
1
2
68f
67e
6
7
[BMIM][BF4]
[BMIM][BF4]
1
2
77d
69d
8
[BMIM][PF6]
[BMIM][BF4]
[BMIM][BF4]
[BMIM][PF6]
12
16
6
54e
55e
61e
86d
9
10
11
1
Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854

P. Prabhala et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1 (continued)
Run#
12
Ar(alkyl)CH2CO2H
Salicylaldehyde
Producta
IL
Timeb[h]
6
Yieldc [%]
72d
[BMIM][PF6]
13
[BMIM][BF4]
1
69d
14
15
16
[BMIM][BF4]
[BMIM][BF4]
[BMIM][BF4]
1
2
1
65e
68e
60e
17
18
19
20
[BMIM][PF6]
[BMIM][PF6]
[BMIM][BF4]
[BMIM][PF6]
3
2
4
2
66e
74d
70d
72d
Reaction conditions: Ar(R)CH2COOH (1 mmol), CDI (1.1 mmol), [BMIM][X] (10 -12 mL), Salicylaldehyde (1 mmol), [PAIM][NTf2] (1.4 mmol); broom temperature; c Isolated
a
yield of pure product; dYield employing fresh IL; eYield using recycled IL (2nd cycle); Yield using recycled IL (3rd cycle).
f
Fig. 2. IL-mediated one-pot sequential synthesis of coumarin-bearing diaryl-ethynes
Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854

4
P. Prabhala et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Synthesis of 3-aryl(alkyl)coumarins in conventional base and solvent
Run #
21
Ar(R)CH2CO2H
Salicylaldehyde
Producta
Solvent
Timeb[h]
Yieldc [%]
THF
2
72
22
23
THF
THF
1
2
64
75
24
25
THF
THF
1
2
63
60
26
27
THF
THF
2
1
73
66
28
29
30
31
THF
THF
THF
THF
12
22
8
55
51
60
82
2
32
33
THF
THF
12
3
65
66
34
THF
4
55
Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854

P. Prabhala et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Table 2 (continued)
Run #
35
Ar(R)CH2CO2H
Salicylaldehyde
Producta
Solvent
Timeb[h]
Yieldc [%]
THF
1
61
36
37
38
39
40
THF
THF
THF
THF
THF
1
2
1
2
1
68
69
74
68
61
a
Reaction conditions: Acid (1 mmol), Salicylaldehyde (1 mmol), CDI (1.1 mmol), DBU (1.5 mmol), THF (10 mL); broom temperature; cIsolated Yield of pure products.
Table 3
Sequential IL-mediated synthesis of coumarin-bearing diaryl-ethynes
Run #
1
Coumarin
Aryl-ethyne
Producta
IL
Timeb [h]
Yieldc [%]
[BMIM][PF6]
9
63
2
[BMIM][PF6]
7
66
3
[BMIM][PF6]
7
63
4
[BMIM][BF4]
5
54
(continued on next page)
Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854

6
P. Prabhala et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 3 (continued)
Run #
5
Coumarin
Aryl-ethyne
Producta
IL
Timeb [h]
Yieldc [%]
[BMIM][PF6]
6
58
6
7
[BMIM][PF6]
7
8
62
70
[BMIM][PF6]
8
9
[BMIM][PF6]
[BMIM][BF4]]
6
8
72
61
10
[BMIM][BF4]
7
64
a
Reaction conditions: Step1: Aryl-acetic acid (1 mmol), CDI (1.1 mmol), [PAIM][NTf2] (1.5 mmol), [BMIM][X] (10-12 mL), Salicylaldehyde (1 mmol), r.t., 1-2 h; Step-2:
Alkyne (1.2 mmol), [PAIM][NTf2] (1 mmol), CuI (5 mol%), Pd(OAc)2 (10 mol%), 60 °C; bTime; cIsolated Yield of pure products.
work-up and product isolation, and recovery/reuse of the IL solvent
(see further).
arylacetylenes with Pd(OAc)2 as catalyst, and CuI as additive, and
the coupling products were isolated in acceptable yields. Similarly,
in representative cases, 6-bromo-3-aryl-coumarins underwent
Sonogashira reaction to form coupling products (Table 3). By
employing this method it is possible to install highly conjugated
Focusing on a wider range of substituents on the salicylalde-
hyde, and a variety of other aryl/heteroaryl- and alkyl/cycloalkyl-
substituted acetic acids, we found a number of cases where no
reaction occurred at r.t. in the IL solvent by using basic-IL
(Table S1), and similar observations were made when basic-IL
was replaced with DBU, while raising temperature resulted in
the formation unknown tarry materials. The observed trends sug-
gest that strongly electron withdrawing substituents (e.g. NO2,
and Cl) on salicylaldehyde (as in runs 2-5 and 8; Table S1), and
–SH on PhCH2CO2H (run 10; Table S1) and bulky ortho substitu-
tents (as in run 1; Table S1) should be avoided. Overall, aryl-acetic
acid is superior toalkyl/cycloalkyl-acetic acid for this reaction.
Facile access to 3-(p-bromo)phenylcoumarins by this method
prompted the development of an IL-mediated approach to the syn-
thesis of novel coumarin-bearing diaryl-ethynes by the Sonogshira
reaction (Table 3) in a one-pot sequential approach. Thus the 3-(p-
bromo)phenylcoumarins formed by the earlier described method
(Fig. 1) were subsequently allowed to react with representative
electron-rich/electron-poor pi-decks on
a coumarin platform.
These types of compounds may find utility as functional materials.
Finally, focusing on the recycling/reuse of the BMIM-IL solvent,
examples 11 and 18 in Table 1 were selected and they were
repeated four consecutive times in [BMIM][PF6] and in [BMIM]
[BF4] solvent. The results presented in graphical format in the SI file
(charts 1-2), indicate a fairly consistent trend, and in line with our
findings from a previous studies,[16g,h] [BMIM][PF6] exhibited a
somewhat better recovery/reuse profile as compared to [BMIM]
[BF4].
In summary, we have reported a facile IL-based one-pot method
that enables the assembly of a library of 3-arylcoumarins under
very mild conditions by using readily available low cost reagents.
An IL-mediated one-pot sequential approach provided access to
new coumarin-bearing diaryl-ethynes that may find application
Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854

P. Prabhala et al. / Tetrahedron Letters xxx (xxxx) xxx
7
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Please cite this article as: P. Prabhala, H. M. Savanur, S. M. Sutar et al., Facile one-pot synthetic access to libraries of diversely substituted 3-aryl (Alkyl)-
coumarins using ionic liquid (IL) or conventional base/solvent, and an IL-mediated approach to novel coumarin-bearing diaryl-ethynes, Tetrahedron Let-
ters, https://doi.org/10.1016/j.tetlet.2020.151854