PhI(OAc)2 mediated an efficient Knoevenagel reaction and their synthetic application for coumarin derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.07.018

A phenyliododiacetate (PhI(OAc)₂) mediated an efficient and novel protocol for the Knoevenagel reaction has been successfully accomplished. A base free, simple and straightforward method afforded wide substrate scope and good functional group tolerance, having high yields (80–92%) under environmentally benign and mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2017.07.018

Accepted Manuscript
PhI(OAc)2 mediated an efficient Knoevenagel reaction and their synthetic ap-
plication for coumarin derivatives
Danish Khan, Sayeed Mukhtar, Meshari A Alsharif, Mohammed Issa Alahmdi,
Naseem Ahmed
PII:
S0040-4039(17)30857-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.018
TETL 49100
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 May 2017
24 June 2017
3 July 2017
Please cite this article as: Khan, D., Mukhtar, S., Alsharif, M.A., Alahmdi, M.I., Ahmed, N., PhI(OAc)2 mediated
an efficient Knoevenagel reaction and their synthetic application for coumarin derivatives, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.018
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PhI(OAc)2 mediated an efficient
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Knoevenagel reaction and their synthetic
application for coumarin derivatives
Danish Khan,a Sayeed Mukhtar,b Meshari A Alsharif,b
Mohammed Issa Alahmdib and Naseem Ahmeda*

1
Tetrahedron Letters
PhI(OAc)2 mediated an efficient Knoevenagel reaction and their synthetic
application for coumarin derivatives
Danish Khan,a Sayeed Mukhtar,b Meshari A Alsharif,b Mohammed Issa Alahmdib and Naseem Ahmeda*
aDepartment of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247 667, India
b Department of chemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
*Corresponding author. Fax and Tel.: +911332 285745
*E-mail: nasemfcy@iitr.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A phenyliododiacetate (PhI(OAc)2) mediated an efficient and novel protocol for the
Knoevenagel reaction has been successfully accomplished. A base free, simple and
straightforward method afforded wide substrate scope and good functional group
tolerance, having high yields (80-92%) under environmentally benign and mild
reaction conditions.
Available online
Keywords
Knoevenagel condensation
PhI(OAc) 2
2009 Elsevier Ltd. All rights reserved.
C-C bond formation
Coumarin derivatives
Introduction
The Knoevenagel condensation reaction is widely employed methods for the formation of C-C bonds1 with numerous applications in
the synthesis of fine chemicals,2 hetero Diels-Alder reactions3 and in the synthesis of heterocyclic4 as well as carbocyclic compounds of
various biological importance. Several active methylene compounds have been used as starting materials for the Knoevenagel
condensation that include malononitrile, cyano-ethylacetate, ethyl-acetoacetate and arylidene-malononitriles, etc. In general, the
Knoevenagel condensation is catalyzed by organic bases such as amines, pyridine, piperidine, a mixture of a secondary amine and
5
amino acids such as L-proline. The reaction also can be catalyzed by Lewis acids, including CdI2,6 ZnCl2,7 Al2O3,8 MgO, ZnO,9
TiCl4,10 KF-Al2O3,11 AlPO4-Al2O3,12 natural hydroxyapatite (Ca10(PO4)6(OH)2)13 and ammonium acetate (NH4OAc)-basic alumina.14
Because of the formation of undesirable side products the use of such bases/acids have led to environmental problems as to dispose
large amount of organic wastes. For the reactions, electrochemical, microwave and ultrasound activation methods have also been
reported.15 On the other hand, ionic liquids (ILs) are also well-known reaction media. In particular, “task-specific” ionic liquid catalysts
with basic and acidic functional groups have been reported for the Knoevenagel reactions.16
Coumarins are class of oxygen containing heterocycles, found in numerous natural products including edible vegetables and fruits, with
a benzopyrone skeletal framework.17 They are also used as additives in food and cosmetics, optical brightening agents and dispersed
fluorescent, laser dyes and used as ligand in Suzuki miyaura and Mizorokie-Heck cross coupling reaction.18 They also displayed
remarkable biological activity such as anti-HIV19, antifungal,20 anti-inflammatory,21 anticancer,22 antimicrobial, antioxidant,23 and
dyslipidemic24 activity. Derivatives obtained from 4-hydroxycoumarin protects liver cells from damage by peroxides.25 Among these
properties, cytotoxic effects were extensively studied.26 Synthesis of coumarin derivatives can be achieved by Perkin, Pechmann,
Wittig, Reformatsky, Claisen and Knoevenagel condensations.27 The classical methods for the synthesis of 3-acetylcoumarin, ethyl
coumarin-3-carbaoxylate and 3-cyanocoumarin is the Knoevenagel condensation using salicylaldehyde with ethyl acetoacetate, diethyl
malonate and α-cyano-ethylacetate compounds respectively, followed by intramolecular cyclization (Scheme 1).28 This traditional
methods generally required harsh reaction conditions and often resulted in low product yields. Therefore, in organic synthesis an
effective method for the straightforward synthesis of coumarins from simple, easily available and cheap starting materials is still in high
demand. Reddy et. al. in 2013 described Cu-catalyzed A3 coupling reaction to afford coumarins using ethoxyacetylene, pyrrolidine and
salicylaldehydes (Scheme 2).29 In 2015, X. He et. al. reported the reaction of salicylaldehydes with Meldrum’s acid in the presence of
catalytic amount of anhydrous FeCl3 in ethanol solvent for the synthesis of ethyl-coumarin-3-carboxylate (Scheme 3).30 Recently, S.
Fiorito et. al. successfully developed ytterbium triflate catalyzed and crop-derived products methods in the coumarins synthesis.31 In
the past few years, hypervalent iodine reagents, such as phenyliododiacetate (PIDA) have been used for the formation of C−C bonds,
without involvement of a toxic, transition-metal-containing reagent.32 There are few examples reported for the oxidative C-C bond

2
Tetrahedron
formation by hypervalent iodine reagent.33 Herein, we report a facile methodology for Knoevenagel reaction and their application for
coumarins synthesis using salicylaldehyde with α-substituted ethylacetate and PhI(OAc)2 in ethanol.
Previous work:
Scheme 1.
Scheme 2.
Scheme 3.
Present work:
Scheme 4.
Results and discussion
In an initial study, aldehyde 1 and cyano-ethylacetate 2a were tested for the Knoevenagel reaction in the presence of PIDA, which
afforded 90% and 92% yield of product respectively (Table 1, entry 3). To verify the role of PIDA, we performed a comparative
experiment without PIDA. However, the reaction failed to afford the desired product 3a and 4g (Table 1, entry 1). It confirmed that
PIDA is necessary to promote the process. To optimize the product yield, we also found that treating with 20 mol% (0.2 equiv.) of
PIDA, generated trace amount of the desired product (Table 1, entry 2). When PIDA increased to 0.5 equiv., the product yield was
enhanced (Table 1, entry 10). Use of 1.0 equiv. of PIDA afforded maximum yield (Table 1, entry 3). Fuerthermore, increase of PIDA
2.0 equiv., the product yield was decreased (Table 1, entry 9). The effects of molecular iodine and other hypervalent iodine reagents
such as IBX, PhIO and Dess-Martin were investigated. In case of molecular iodine, no conversion was observed (Table 1, entry 5).
Dess-Martin
lower yields and longer reaction time (Table 1, entries 6, 7 and 8).
PIFA also gave the similar result (Table 1, entry 4). Similarly, other solvents including DMSO, THF, DCM, acetonitrile and DMF were
screened but poor yields were obtained (Table 1, entries 12-16). In addition, it was found that at high/refluxed temperature, no product
formation was observed (Table 1, entry 11). Therefore, this reaction could be best performed with 1.0 equiv. PhI(OAc)2 in ethanol at
35-40 oC for 0.5-1 h.
Table 1. Optimization of reaction conditions

3
aReaction condition: benzaldehyde/salicylaldehyde (1.0 mmol),
cyano-ethylacetate (1.0 mmol) and PIDA (1.0 mmol) in ethanol (5 mL)
at 35-40 oC. bPIDA (20 mol%). cPIDA (2.0 equiv). dPIDA (0.5 equiv).
eat 80oC. fIsolated yields.
Entry
Reagent
(1 equiv.)
-
Solvent
Time
(h)
1.0
1.0
1.0/0.5
1.5
1.0
1.0
12
8
Yieldf(%)
3a/4g
0/0
1
2b
3
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
DCM
PIDA
PIDA
PIFA
Trace
90/92
90/92
0/0
Table 2. Synthesis of alkenes
4
5
I2
6
IBX
67/70
40/44
58/63
68/72
46/52
0/0
7
PhIO
8
Dess martin
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
9c
10d
11e
12
13
14
15
16
1.0
1.0
2
6
30/30
63/62
37/38
49/49
66/64
DMSO
THF
3
8
ACN
6
DMF
3
Reaction condition. Benzaldehyde (1.0 mmol, 0.1061gm), cyano-ethylacetate (1.0 mmol, 0.1131gm) and PIDA (1.0 mmol, 0.3221gm) in
ethanol (5 ml) at 35-40 oC.
The substituent effects on the benzaldehyde ring were examined. Both electron-donating and electron withdrawing groups were well
tolerated, and good to excellent yields of the corresponding substituted ethyl-2-cyano-3-phenylacrylate were obtained (Table 2).
Replacing chloro in the 1a to other halogen, such as bromo, did not affect the yield to any significant degree (3d and 3e). We observed
that, yield was slightly higher for electron withdrawing group (3c and 3h). Similarly, the para-substituted hydroxyl substrates with
respect to aldehyde group slightly decreased the yield might be due to electron donating tendency via resonance (3f), which decreased
the electrophilic nature of the aldehyde group.
Table 3. Synthesis of coumarin derivatives

4
Tetrahedron
Reaction condition. salicylaldehyde (1.0 mmol, 0.1221gm), α-substuted ethylacetate (1.0 mmol) and PIDA (1.0 mmol, 0.3221gm) in ethanol
(5 ml) at 35-40oC.
Salicylaldehyde 1a bearing a variety of substituents on the benzene ring reacted very smoothly to afford the corresponding coumarins
(4a-r) in 80-92% yield, indicated that the substituents on the aromatic ring of 1a did not have significant influence on the reaction.
Salicylaldehydes possessing several functional groups such as methoxy, hydroxyl, chloro, bromo and 2-hydroxy-1-naphthaldehyde
were also tolerated in this reaction, and good yields of corresponding products were obtained. When ethyl-acetoacetate was subjected to
the reaction, the corresponding product (4a) was obtained in 92% yield. Under the optimum conditions, cyano-ethylacetate and diethyl
malonate were smoothly converted to 3-cyano-coumarin (4g) and ethyl coumarin 3-carboxylate (4m) in 92% and 90% yield,
respectively (Table 3). However, some reactants required more reaction time. In addition, it was found that electron donating group at
para position to aldehyde group converted slowly, the corresponding product (4c, 4i and 4o) was obtained in 82%, 80% and 84% yield
respectively. While more conjugated system converted more smoothly and required less reaction time. The respective product (4f, 4l
and 4r) was obtained in 91%, 91% and 92% yield respectively.
The structure elucidation of 3b and 4b was done on the basis of the collective information obtained from various spectroscopic
1
1
techniques such as H-NMR, 13C-NMR and GC-MS. Disappearance of aldehyde proton in H NMR spectrum of 3b and 4b and
appearance of singlet at δ 8.14 and δ 8.47 ppm respectively confirmed the formation of product 3b and 4b. In 13C-NMR spectrum of 3b
and 4b showed eleven and twelve signals respectively. Further the structure of the product 3b and 4b was confirmed by HRMS. The
m/z molecular ion peak of compound 3b and 4b appears as [M + Na]+ at 254.0746 and 242.0504.
In order to understand the reaction mechanism, we examined the reaction of salicylaldehyde 1a with α-substituted ethylacetate A
promoted by PhI(OAc)2 B at room temperature. On the basis of literature report,34 a possible reaction mechanism is proposed (Scheme
5). First, salicylaldehyde 1a reacted with PhI(OAc)2 B to form the reactive species C. Further, C reacted with α-substituted ethylacetate
(enol form) A and converted into E. Then, adduct E converted into F by the elimination of PhIO, ethyl alcohol, acetic acid and
intramolecular cyclisation.
Scheme 5. Proposed mechanism
Conclusion
In conclusion, we have developed a highly efficient and environmental friendly method for Knoevenagel reaction and their synthetic
application for coumarin derivatives using PhI(OAc)2 in good to excellent yield under mild reaction conditions. This method tolerated a
wide range of functional groups.
Acknowledgments
DK is thankful to MHRD for financial support. We sincerely thank Instrumentation center and department of chemistry IITR for
various facilities. The reviewer’s comments are appreciated.

5
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35. General procedure: α-substituted ethylacetate (1.0 mmol) and Phenyliododiacetate (1.0 mmol) was dissolved in ethanol (5 ml) with constant
stirring. After 10 minutes benzaldehyde /salicylaldehyde (1.0 mmol), was added and the mixture was allowed to stir for appropriate time. Then the
progress of the reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, ethanol was evaporated
under reduce pressure. The product was extracted with ethyl acetate, dried over Na2SO4 and solvent was evaporated under reduce pressure. The
residue obtained was recrystallized by ethyl acetate and hexane to product 3a-3h and 4a-4r. Characterization data: Compound 3b, White solid;
1
Yield: 86%; H NMR (CDCl3, 400 MHz) δ ppm 8.14 (s, 1H), 7.97 (d, J = 8.88 Hz, 2H), 6.97 (d, J = 8.88 Hz, 2H), 4.34 (q, J = 7.13, 2H), 3.87 (s,
1H), 1.36 (t, J = 7.12 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ ppm 163.86, 163.19, 154.45, 133.71, 124.45, 116.29, 114.84, 99.44, 62.49, 55.69,
14.23; Compound 4a, White solid; Yield: 92%; 1H NMR (CDCl3, 400 MHz) δ ppm 8.49 (s, 1H), 7.65-7.61 (m, 2H), 7.35 (d, J = 9.28 Hz, 1H), 7.31
(d, J = 7.56 Hz, 1H), 2.70 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ ppm 195.54, 159.24, 155.28, 147.45, 134.39, 130.20, 124.96, 124.45, 118.21,
116.63, 30.50; GC-MS (m/z): 188 [M+., C11H8O3].

6
Tetrahedron
Highlight
 Highly efficient method for Knoevenagel reaction.
 Excellent yield under mild reaction condition.
 Less reaction time.
 Tolerated different functional groups.
 Synthesis of biological active compounds.