A room temperature one-pot Knoevenagel-Chan-Evans-Lam coupling reaction for synthesis of N-aryl-2-Iminocoumarins in bio-mass-derived green solvent 2-methylTHF

Article abstract of DOI:10.1016/j.tetlet.2019.07.031

An efficient approach for the synthesis of biologically interesting N-aryl-2-iminocoumarins by a copper-catalyzed one-pot procedure has been developed by the reaction of 2-hydroxybenzaldehydes, malononitrile and arylboronic acids using triethylamine as a base in a bio-mass-derived green solvent 2-MethylTHF at room temperature. This protocol allows access to several N-aryl-2-iminocoumarins in high yields in a relatively short period of time under mild reaction conditions. The procedure operates by a simple telescoped process wherein 2-imino-2H-chromene-3-carbonitriles are formed in situ by the reaction of 2-hydroxybenzaldehyde, malononitrile, and TEA. Further a subsequent one-pot reaction of imine with the arylboronic afforded the target compounds. To understand the reaction mechanism, MALDI-ESI studies were performed, which showed the in situ generated iminocoumarins to be in ligation cooper to form a copper-iminocoumarin complex thus facilitating the smooth formation of N-aryl-2-iminocoumarins in the reaction. Overall, this protocol is practically valuable, useful in organic synthesis, shows good functional group tolerance and provides access to a diverse array of N-aryl-2-iminocoumarins derivatives.

Full text of DOI:10.1016/j.tetlet.2019.07.031

Accepted Manuscript
A Room Temperature One-Pot Knoevenagel-Chan-Evans-Lam Coupling reac-
tion for Synthesis of N-Aryl-2-Iminocoumarins in Bio-mass-derived Green
Solvent 2-MethylTHF
Prashant S. Mandal, A. Vijay Kumar
PII:
S0040-4039(19)30692-6
https://doi.org/10.1016/j.tetlet.2019.07.031
TETL 50940
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 May 2019
10 July 2019
16 July 2019
Please cite this article as: Mandal, P.S., Vijay Kumar, A., A Room Temperature One-Pot Knoevenagel-Chan-Evans-
Lam Coupling reaction for Synthesis of N-Aryl-2-Iminocoumarins in Bio-mass-derived Green Solvent 2-
MethylTHF, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.07.031
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A Room Temperature One-Pot Knoevenagel-
Chan-Evans-Lam Coupling reaction for
Synthesis of N-Aryl-2-Iminocoumarins in
Bio-mass-derived Green Solvent 2-
MethylTHF
Leave this area blank for abstract info.
Prashant S. Mandal and A. Vijay Kumar*
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai, Maharashtra, India – 400019
HO
OH
B
R2
TEA
CN
CN
CN
N
O
R1
R1
+
Cu(OAc) .H O
OH
2
2
O
R2
CN
NH



green solvent
R1
 sequential synthesis
 gram scale synthesis
O
room temperature
mild condition
 readily available starting materials

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A Room Temperature One-Pot Knoevenagel-Chan-Evans-Lam Coupling reaction for
Synthesis of N-Aryl-2-Iminocoumarins in Bio-mass-derived Green Solvent 2-
MethylTHF
Prashant S. Mandal and A. Vijay Kumar*
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai, Maharashtra, India – 400019
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient approach for the synthesis of biologically interesting N-aryl-2-iminocoumarins by
a
copper-catalyzed one-pot procedure has been developed by the reaction of 2-
Received in revised form
Accepted
Available online
hydroxybenzaldehydes, malononitrile and arylboronic acids using triethylamine as a base in a
bio-mass-derived green solvent 2-MethylTHF at room temperature. This protocol allows access
to several N-aryl-2-iminocoumarins in high yields in a relatively short period of time under mild
reaction conditions. The procedure operates by a simple telescoped process wherein 2-imino-
2
H-chromene-3-carbonitriles are formed in situ by the reaction of 2-hydroxybenzaldehyde,
Keywords:
malononitrile, and TEA. Further a subsequent one-pot reaction of imine with the arylboronic
afforded the target compounds. To understand the reaction mechanism, MALDI-ESI studies
were performed, which showed the in situ generated iminocoumarins to be in ligation cooper to
form a copper-iminocoumarin complex thus facilitating the smooth formation of N-aryl-2-
iminocoumarins in the reaction. Overall, this protocol is practically valuable, useful in organic
synthesis, shows good functional group tolerance and provides access to a diverse array of N-
aryl-2-iminocoumarins derivatives.
Knoevenagel reaction
Chan-Lam Coupling
Copper Acetate
Iminocoumarin
Arylboronic Acid
Green Solvent
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
The N-arylation of imines is an active region of research in
found to show diverse biological properties such as antimalarial
1
7,18
19
20,21
and anticancer,
anti-inflammatory,
inhibition (MK-2), dynamins I and II GT Pase,
antiproliferative activity, antimicrobial,
2
2-24
organic synthesis. Transition metal catalyzed C-N bond
formation reactions are an important transformations that enables
the synthesis of valuable aryl imine products. Currently only two
processes are generally available for the C-N bond formation i.e.
Ullmann and Chan-Lam-Evan coupling reaction; both of these
methods are quite general and are commonly used for synthesis
mitogen-activated protein kinase
2
5
26
HIV-1
1
27
28-31
integrase inhibition, and cell imaging.
Additionally, they
3
2
33
are also useful as fluorescent dyes, and sensors for thiols and
2
3
34
2
H S.
4
of relevant nitrogen based compounds. Chan-Lam-Evan is a
O
O
O
robust copper-catalyzed reaction which involves the cross-
coupling of aryl boronic acids with heteroatom nucleophiles
such as amines, anilines, amides, imines, ureas, sulfoximines,
Ph
S
HN
H C)
N
HN
(H C)
R2
H
(
2
2
2
2
NH
NH
5
,6
R1
carbamates, carboxylic acids, phenols and thiols.
MeO
Coumarins and their derivatives are an important class of
oxygen based heteroaromatic structural units that are found in
several biologically active molecules and natural products. They
N
N
O
O
Antimalarial agents
OH
Anticancer agents
COOH
7
-9
10
are well-known for diverse applications in perfumery and as
OH
1
1
dyes in laser technology. These compounds are known to show
biological properties relevant for human health such as
NH
NH
HN
HN
1
2
13
14
15
antibacterial,
antifungal,
anti-HIV,
and anti-tumor
activities. Analogous to coumarins, iminocoumarins are a class
of coumarins that are of profound value due to their interesting
applications. A recently discovered fused core iminocoumarin
natural products i.e. Hyrtimomine A and B (Figure 1), which
have been isolated from an Okinawan marine sponge Hyrtios sp
and several other fused core iminocoumarin natural products are
N
N
O
O
Hyrtimomine A (1)
Hyrtimomine B (2)
Figure 1 Representative molecules having the N-Phenyl
iminocoumarin core structure
1
6

2
Tetrahedron Letters
HO
OH
Our Previous Work:
B
R2
R2
Cu(OAc) H O
2.
2
R1
R1
R3
+
EtOH, rt, 24 h
O
O
N
O
NH
Ar
This Work:
CN
1
. CNCH CN, Et N
2 3
O
R1
R1
2
. Cu(OAc) H O, ArB(OH)
2
2.
2
N
OH
2-MeTHF, 2 h, rt
Ar
Figure 2. Copper-catalyzed cascade reactions
Despite their importance, these derivatives are less explored in
Chan-Lam-Evans protocol. Our group was the first to report the
account of these advantages with a purpose to develop and
improve alternate methodologies for N-aryliminocoumarins
synthesis in a one-pot approach avoiding cumbersome steps of
intermediate syntheses, purification steps and that too from
readily available precursors. Thus in this context, we present
herein a simple one-pot Knoevenagel-Chan-Evans-Lam coupling
reaction for synthesis of N-aryl-2-iminocoumarins in bio-mass-
derived green solvent 2-methylTHF operable at room
temperature.
3
5
Chan-Lam-Evans reaction of iminocoumarin derivatives in
which we developed a simple and mild protocol for the reaction
of iminocoumarins with aryl boronic acids via a copper-catalyzed
reaction. In this present work we showcase a one-pot procedure
wherein one can easily synthesize N-aryl iminocoumarins using a
copper-catalyst through
a cascade/tandem reaction of 2-
hydroxybenzaldehyde, malononitrile, and arylboronic acids TEA
3
6
as base in greener solvent 2-MeTHF (Figure 2).
All these precursors are readily available starting materials
which are commercially accessible. Therefore, taking in to
Table 1. Optimization reaction condition
copper salts,
PhB(OH)2
CN
CN
CN
NH
O
base
R1
+
solvent, 30 min
rt, time
open air
O
N
OH
CN
2a
O
Ph
1
a
3a
4a
Sr. No.
copper Salts
CuBr
CuCl
CuSO
solvent
2-MeTHF
base
time
12 h
12 h
6 h
yieldb
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
.
2
TEA
36
.
2
.2H
2
O
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
TEA
65
.
4
.5H
2
O
TEA
69
.
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
TEA
3 h
72
.
.H
.H
.H
.H
.H
.H
.H
.H
.H
.H
.H
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
TEA
2 h
92
.
TEA
2 h
89c
90d
62e
88
.
TEA
2 h
.
TEA
2 h
.
TEA
3 h
0.
1.
2.
3.
4.
5.
THF
NaOH
KOH
DABCO
DABCO
DABCO
-
4 h
75
THF
4 h
63
MeCN
24 h
24 h
24 h
24 h
78
DCE
73
DMF
60
2-MeTHF
0
aReaction condition: 1a (0.81 mmol), 2a (0.81 mmol), base (0.081 mmol), PhB(OH)
(1.22 mmol), Copper salt (10 mol%) rt. isolated yield, Cu(OAc) .H O
b
c
2
2
2
d
e
(
2 2 2 2
20 mol %). Cu(OAc) .H O (30 mol %), Cu(OAc) .H O (5 mol%).
2
. Result and Discussion
Initially, the iminocoumarin intermediates 3a necessary for
(1a) malononitrile in presence of TEA (2a) in 2-MeTHF solvent
at room temperature (Table 1). The formed intermediate
iminocoumarin was further subjected to react with phenylboronic
N-aryliminocoumarin synthesis were prepared by the
Knoevenagel condensation reaction of 2-hydroxybenzaldehyde

3
acid in presence CuBr
2
which successfully afforded the target
92%, where 4-Me and 4-OMe also formed the respective
compound only in lower yield 36% (entry 1).
products in high yields 4b, 4c 90 and 88%. The halo derivatives
also worked well to form the corresponding product with
excellent yield such as fluoro, (4d, 86%), chloro (4e, 84%) and
2 2
After screening the different copper salts such as CuCl .2H O
the yield was increased up to 65% (entry 2), while using of
CuSO .5H O and Cu(OAc) reaction work and give the
corresponding product in 69 to 72% yields (entry 3 & 4). The use
of Cu(OAc).H O drastically increased the yield up to 92% (entry
). Screening of commonly used bases and solvents such as,
4
2
2
bromo (4f, 80%). The electron withdrawing group such as 4-CF
(4g, 78%), and for 4-NO (4h, 55%) also worked well to form the
3
2
2
desired product in moderate yield. The meta substituted
derivatives 3-Me and 3-OMe also reacted smoothly to form the
products in good to moderate yield (4i, 75% and 4j, 78%)
respectively. The sterically hindered naphthalene derivative also
formed the desired product in good yield (4k, 70%).
5
NaOH, KOH, DABCO THF, acetonitrile, DCE, DMF, and 2-
MeTHF, suggested that TEA and 2-MeTHF is the most effective
combination for this reaction. Notably, this method is insensitive
to air and moisture, providing an operationally simple approach
for the synthesis of N-aryliminocoumarin heterocycles.
Next, the reactivity of different salicylaldehydes (1a-e) and
malononitrile with phenylboronic acid was investigated, and the
results are summarized in Table 3. It was observed that aldehyde
containing electron-donating groups and electron-withdrawing
groups reacted well and successfully formed the corresponding
product in excellent yield. The reaction with substituted aldehyde
showed excellent result such as 4-OMe group gives (4aa, 85%)
yield and the N, N-diethyl group (4ab, 82%) yield. Both these
reactions worked and formed the products in excellent yield. The
electron-withdrawing group such as -Cl and -Br successfully
afforded products in high yield (4ac, 80%) and (4ad, 75%)
respectively. The sterically hindered group i.e. tert-Butyl groups
also afforded the desired product (4ae, 65%) in good yield.
Having established the optimum reaction conditions i.e.
TEA/Cu(OAc)
substrate scope and the generality of this synthetic approach.
Table 2). All the substrates reacted smoothly and converted to
2 2
.H O/2-MeTHF, we sought to examine the
(
the corresponding N-aryliminocoumarin in moderate to excellent
yield.
Table 2. Substrate scope with different arylboronic acid
a,b
derivatives
CN
1
. CNCH2CN , TEA
. Cu(OAc)2.H2O, ArB(OH)2
-MeTHF, 5 mL, 2 h, rt
O
2
O
N
OH
2
Table 3 Scope of 2-hydroxybenzaldehyde derivatives with
Ar
a,b
phenylboronic acid
1a
4a
CN
1
.
CNCH2CN , TEA
2. Cu(OAc)2.H2O, PhB(OH)2
-MeTHF, 5 mL, 2 h, rt
R1
R1
O
CN
N
CN
CN
O
N
OH
a-e
2
Ph
1
4a-e
O
O
N
O
N
CN
HO
HO
OH
OH
B
B
CN
O
O
O
N
4
aa, 85%
ab, 82%
CH3
OMe
O
OH
CN
4a, 92%
4b, 90%
4c, 88%
CN
O
CN
CN
CN
N
CN
N
CN
N
N
O
N
4
N
OH
O
O
O
Cl
CN
N
HO
HO
HO
OH
OH
OH
B
B
B
CN
CN
Cl
F
Cl
Br
O
O
4ac, 80%
4d, 86%
4e, 84%
4f, 80%
OH
CN
N
CN
N
CN
Br
CN
N
Br
CN
CN
O
O
O
O
O
N
4ad, 75%
4ae, 65%
Br
OH
Br
CH3
CF3
NO2
CN
N
O
CN
CN
4
g, 78%
4h, 55%
4i, 75%
O
OH
CN
N
CN
N
aReaction condition: 1a (0.81 mmol), CNCH
2
mmol), PhB(OH) (1.22 mmol), Cu(OAc) .H O (10 mol %) rt. isolated yield.
O
O
2
CN (0.81 mmol), TEA (0.081
b
2
2
OCH3
To test the efficacy of our protocol we performed some control
experiments (Scheme 1), wherein a copper-free synthesis of 2-
4j, 78%
4k, 70%
(phenylimino)-2H-chromene-3-carbonitrile was tried wherein the
aReaction condition: 1a (0.81 mmol), CNCH
2-imino-2H-chromene-3-carbonitrile 2a was reacted with
2
CN (0.81 mmol), TEA (0.081
O (10 mol %) rt. isolated yield.
b
differently substituted aniline derivatives with NH OAc as a base
mmol), ArB(OH)
2
(1.22 mmol), Cu(OAc)
2
.H
2
4
in presence of glacial acetic acid as solvent under reflux
The scope of N-arylation reaction was examined with various
aromatic boronic acids, the phenyl group gave excellent yield 4a,
conditions, which formed the expected product in lower yield
(4aa 55%). Similarly we tried the reaction of 2a with 4-OMe and

4
Tetrahedron Letters
4
-NO
2
aniline derivatives, reaction worked but afforded only
iminocoumarin ligands similarly to the monomeric complexes
5aa either via an imino N and nitrile CN functional group or
imino N and O-bond are also possible. Peaks corresponding to
acetate bridged Cu-dimeric-complex was also observed in the
MALDI-ESI spectra. This evidence indicated the formation of
various pre iminochromene – copper complexes during the
reaction. We hypothesize that this association of the substrate
with copper metal enables a more facile reaction.
lesser yields i.e. (4ab 62% and 4ac 34%) respectively. It was
observed that, the reaction work in presence of glacial acetic acid
and NH OAc does not form the expected product in significantly
4
good yields as compared to the Chan-Evans-Lam coupling
reaction. These experiments endorse our one-pot sequential
copper catalyzed protocol to be a superior methodology when
compared to the existing methods to achieve the target
compounds in excellent yields under mild reaction conditions.
CN
NH2
CN
CN
O
O
glacial AcOH (15 mL)
Cu
3a
2-MeTHF
H2O
+
Copper(I)/(II) Complex
+
NH4OAc
O
N
4aa, 55%
O
O
O
NH
24 h, rt
O
NH
reflux, 12h
2a
MALDI of reaction mixture
(
1 equiv)
(1 equiv)
2a
3b
NH2
CN
N
(a) Monomeric Cu(I)-imino complexes
CN
NH
N
H
N
glacial AcOH (15 mL)
NH4OAc
+
O
5a
or
Cu
H2O
O
4ab, 62%
reflux, 12h
O
N
O
N
H
Cu
O
2
H O
Theoretical
Observed
250.9882
250.0382
250.9882
250.0382
O
2a
3c
NH2
CN
CN
NH
(b) Dimeric Cu(II)-imino complexes
glacial AcOH (15 mL)
NH4OAc
+
O
N
N
N
O
H
reflux, 12h
4ac, 34%
H
N
O
N
O
Cu
N
NO2
3d
5aa
Cu
N
N
H
O
2a
O
NO2
or
H
N
Scheme 1: Control Experiments
4
03.0256
403.0256
Theoretical
Observed
403.1326
403.1326
CN
(c) Dimeric Cu(II)-imino complexes
HO
OH
B
CN
CN
H
N
O
N
H
N
O
N
O
O
+
+
Cu(OAc)2.H2O (10 mol%)
O
N
O
Cu
O
O
O
Cu
OH
Cu
O
2-MeTHF, rt, 2 h, rt
5ab
Cu
O
O
O
N
H
N
O
N
H
1a
2a
3a
4a
1.7 g
N
or
1.0 g
541 mg
2.0 g
Theoretical
Observed
605.5530
605.3947
605.5530
605.3947
Scheme 2 Gram Scale (Z)-2-(phenylimino)-2H-chromene-3-
carbonitrile
Figure 3. Proposed structure of mass fragment ions detected by
MALDI-ESI analysis of 2-imino-2H-chromene-3-carbonitrile
and Cu(OAc) .H O reaction mixture
2 2
To demonstrate the methods practicality, we checked a gram-
scale (Z)-2-(phenylimino)-2H-chromene-3-carbonitrile synthesis
in which reaction was carried out by employing 2-
hydroxybenzaldehyde 1a (8.19 mmol, 1.0 g), malononitrile 2a
3
. Conclusion
In conclusion, we report on the development of an efficient
(8.19 mmol, 541 mg) and phenylboronic acid 3a (12.23 mmol,
1
.49 g) under the standard reaction conditions (Scheme 1). This
copper-catalyzed one-pot tandem protocol for the synthesis
of N-arylated iminochromenes under Chan-Evans Lam reaction
conditions in 2-MeTHF green solvent. To the best of our
knowledge, this is the first strategy for preparing the N-arylated
iminochromenes by a sequential synthetic method which is
operationally simple and requires no isolation of the
iminocoumarin intermediates. The broad substrate scope and
good to excellent product yields suggest that this methodology
would be synthetically useful. Further, the environmental and
economic advantages derived from the use of such a benign
solvent are clear in terms of safety, cost and innocuousness.
transformation proceeded smoothly to afford 1.7 g (84%) of the
product 3a. Thus, this result vouches for the scalability of the
developed protocol.
Based on the previous reports of Chan-Lam-Evan coupling
reaction and substrate study, we propose a plausible mechanistic
pathway for N-aryliminocoumarin under copper-catalyzed
reaction condition. Initially, Knoevenagel condensation reaction
of 2-hydroxybenzaldehyde and malononitrile in presence of base
takes place to form the iminocoumarin intermediate, which reacts
with copper to form a copper acetate-iminocoumarin complex
(see the supporting information) (Scheme 2). The evidence for
the formation of this complex was proved by subjecting the
reaction mixtures to MALDI analysis before the addition of aryl
boronic acid. The MALDI-ESI spectra showed mass ions
consistent with several proposed reaction-relevant complexes
(Figure 3). The imino-ligand Cu-monomeric-complex, 5a (Figure
3
), were identified in comparatively high abundance. Monomeric
and dimeric copper-complexes were clearly observed (see SI).
Possibly Cu monomeric complex can be either with imino N and
O bond or imino N-bond and CN functional groups, preferably a
imino N-bond and CN mode due to the favoured chelation
possibility. A tetragonal-complex of Cu-iminochromene with two

5
2 2
Figure 4. MALDI-ESI mass spectra (2, 4-Dihydroxybenzoic acid as the matrix) of Cu(OAc) .H O and 2-imino-2H-chromene-3-
carbonitrile stirred at room temperature in 2-MeTHF solvent for 24 h.

6
Tetrahedron Letters
H
N
N
N
O
O
N
N
CN
H
N
CN
OH
OH
H
NC
NC
HO
CN
N
CN
O
O
NH
NC
Cu(OAc)2
AcO
Ar B(OH)2
Oxidation of (CuI
CuII)
II
L
AcO B(OH)2
Transmetallation
Cu
L
AcO
II
I
L
L
Ar
AcO Cu
Cu
L
AcO
L
CN
O
N
II
Cu
L
AcO
AcO
L
III
L
L
Ar
Reductive elimination
C-N bond formation
Cu
Oxidation of (CuII
CuIII
)
I
L
AcO
AcO
Cu
L
O
N
CN
Scheme 2. Plausible mechanistic pathway.
. Experimental
.1. General information
Experimental Procedure for synthesis of (Z)-2-(phenylimino)-2H-
chromene-3-carbonitrile: 4aa
To a solution of 2-imino-2H-chromene-3-carbonitrile 2a (0.81
4
4
mmol) with phenylboronic acid (1.22 mmol) and Cu(OAc)
2 2
.H O
NMR spectra were recorded with tetramethylsilane as the internal
standard. TLC was performed on glass-backed silica plates.
(
10 mol%) in 2-MeTHF solvent. The reaction mixture was stirred
for 1h and then the solvent was removed and crude crude residue
was purified by column chromatography with ethyl
acetate/petroleum ether (5:95) to give the compound 4aa with
Column chromatography was performed using silica gel (200-
1
3
00 mesh) eluting with ethyl acetate and petroleum ether. H-
1
3
NMR spectra were recorded at 400 MHz, and C- NMR spectra
9
5% yield.
were recorded at 100 MHz. Chemical shifts (δ) are reported in
Experimental Procedure for synthesis of N-Arylimino derivative
from different aniline derivatives: 4ab-4ac
To a solution of 2-imino-2H-chromene-3-carbonitrile 2a (0.81
ppm downfield from CDCl
3
(δ = 7.26 ppm) or DMSO-D
6
(δ =
1
2
.49 ppm) for H-NMR and relative to the central CDCl
3
resonance (δ = 77.0 ppm) or DMSO-D
6
(δ = 39.5 ppm) for 13C-
4
mmol), aniline derivatives (0.81 mmol) and base NH OAc (0.81
NMR spectroscopy. Coupling constants (J) are given in Hz.
Commercial grade solvents were dried and purified by standard
procedures as specified in Purification of Laboratory Chemicals.
mmol) in glacial acetic acid and the reaction mixture was reflux
for 12h. After completion of the reaction, the organic phase was
concentrated under reduced pressure and the crude residue was
purified by column chromatography with ethyl acetate/petroleum
ether (5:95) to give the compound.
4
.2. General procedure for the synthesis of Iminochromene
derivatives.
A solution of aldehyde (0.81 mmol), base (0.081), malononitrile
4
4
.2.1 (Z)-2-(Phenylimino)-2H-chromene-3-carbonitrile 4a, 4aa,
ab
(0.81 mmol) in 2-MeTHF (3 mL) was stirred for 30 min. The
34
progress of reaction was monitored by TLC analysis. After
complete conversion of both the starting material, the arylboronic
Yield 92%, 95%, 55% (yellow solid, 184 mg, 137 mg, 80 mg);
1
H-NMR (400 MHz, CDCl ) δ 7.89 (s, 1H), 7.59 (t, J = 7.8 Hz,
3
acid derivatives (1.22 mmol) and Cu(OAc)
2
.H
2
O (10 mol%) was
1H), 7.49 (t, J = 8.6 Hz, 3H), 7.41 – 7.27 (m, 4H), 7.19 (d, J =
1
3
8
1
1
3
.3 Hz, 1H); C-NMR (101 MHz, CDCl ) δ 153.69, 144.75,
44.68, 144.58, 134.07, 128.84, 128.80, 125.02, 124.86, 123.18,
17.73, 116.44, 114.76, 107.40.
added. The reaction completed within 2h. After completion of the
reaction, the organic phase was concentrated under reduced
pressure and the crude residue was purified by column
chromatography with ethyl acetate/petroleum ether (5:95) to give
the compound.

7
4
.2.2 (Z)-2-(p-Tolylimino)-2H-chromene-3-carbonitrile 4b
Hz, 3H); 13C-NMR (101 MHz, CDCl
) δ 153.37, 147.90,
3
-1
Yield 90% (yellow solid, 192 mg); m.p. 130-131ºC; IR (ν/cm ):
145.33, 134.27, 128.86, 125.93, 125.89, 125.07, 122.78, 117.51,
2
1
8
231, 1650, 1595, 1566, 1455, 1380, 1291, 1218, 1193, 1044,
116.36, 114.30, 106.76; HRMS Mass Chemical Formula:
1
+
017. H-NMR (400 MHz, CDCl
.4, 7.5, 1.6 Hz, 1H), 7.38 (dd, J = 7.7, 1.6 Hz, 1H), 7.22 (ddd, J
4.8, 3.8, 1.5 Hz, 3H), 7.18 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.3
3
) δ 7.75 (s, 1H), 7.48 (ddd, J =
C
17
H
10
F
3
N
2
O [M + H] : 315.0740; Found: 315.0719.
=
4.2.8 (Z)-2-((4-Nitrophenyl)imino)-2H-chromene-3-carbonitrile
4h
1
3
Hz, 1H), 2.37 (s, 3H). C-NMR (101 MHz, CDCl
1
1
3
) δ 153.69,
44.25, 144.16, 141.73, 134.80, 133.86, 129.31, 128.69, 124.69,
23.39, 117.73, 116.32, 114.75, 107.60, 21.11; HRMS Mass
Yield 55%, 34% (yellow solid, 132 mg, 59 mg); m.p. 204-205ºC;
-1
IR (ν/cm ): 2235, 1657, 1605, 1582, 1506, 1488, 1464, 1366,
+
1
Chemical Formula: C17
H
13
N
2
O [M + H] : 261.1022; Found:
1337, 1256, 1185, 1111, 1051; H-NMR (400 MHz, CDCl
3
) δ
2
61.1005.
8.27 (s, 1H), 8.15 (d, J = 8.3 Hz, 3H), 7.65 (d, J = 51.6 Hz, 1H),
1
3
7
.40 (s, 1H), 6.90 (d, J = 7.4 Hz, 3H); C-NMR (101 MHz,
CDCl ) δ 156.45, 154.61, 151.85, 135.58, 134.64, 129.30,
125.73, 125.43, 124.74, 123.04, 117.47, 117.15, 113.53, 103.37;
4
.2.3 (Z)-2-((4-Methoxyphenyl)imino)-2H-chromene-3-
3
carbonitrile 4c and 4ac
Yield 88%, 62% (yellow solid, 198 mg, 102 mg); m.p. 150-
+
HRMS Mass Chemical Formula: C16
292.0717; Found: 292.0727.
10 3 3
H N O [M + H] :
-1
1
1
7
7
51ºC; IR (ν/cm ): 2231, 1651, 1604, 1504, 1379, 1293, 1218,
192, 1168, 1033; H-NMR (400 MHz, CDCl ) δ 7.69 (s, 1H),
3
.46 (s, 1H), 7.35 (t, J = 7.5 Hz, 3H), 7.19 (d, J = 7.5 Hz, 1H),
.11 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H);
1
4.2.9 (Z)-2-(m-Tolylimino)-2H-chromene-3-carbonitrile 4i
Yield 75% (yellow solid, 160 mg); m.p. 120-121ºC; IR (ν/cm ):
-1
1
3
C-NMR (101 MHz, CDCl
33.66, 128.54, 125.41, 124.57, 117.80, 116.21, 114.70, 113.83,
07.94, 55.39; HRMS Mass Chemical Formula: C17 [M
3
) δ 157.23, 153.68, 143.45, 137.26,
2230, 1725, 1644, 1604, 1508, 1488, 1447, 1369, 1337, 1257,
1
1
1
+
1186, 1050; H-NMR (400 MHz, CDCl
3
) δ 8.27 (d, J = 4.1 Hz,
H
13
N
2
O
2
1H), 8.26 (d, J = 9.1 Hz, 1H), 7.73 (ddd, J = 8.5, 7.4, 1.6 Hz,
1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 – 7.53 (m, 1H), 7.44 –
+
H] : 277.0972; Found: 277.0965.
7
.39 (m, 2H), 7.32 – 7.26 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 1.60
1
3
4
4
.2.4 (Z)-2-((4-Fluorophenyl)imino)-2H-chromene-3-carbonitrile
d
3
(s, 3H); C-NMR (101 MHz, CDCl ) δ 154.62, 151.79, 143.89,
135.55, 129.27, 125.70, 124.73, 123.03, 117.47, 117.15, 116.48,
-1
Yield 86% (yellow solid, 185 mg); m.p. 137-138ºC; IR (ν/cm ):
2
1
114.46, 113.51, 103.40, 20.47; HRMS Mass Chemical Formula:
+
231, 1651, 1605, 1563, 1454, 1382, 1223, 1194, 1123, 1095,
C
17
H
13
N
2
O [M + H] : 261.1022; Found: 261.1005.
1
3
051; H-NMR (500 MHz, CDCl ) δ 7.82 (s, 1H), 7.57 – 7.50
(
m, 1H), 7.43 (dd, J = 7.7, 1.5 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.26
4.2.10 (Z)-2-((3-Methoxyphenyl)imino)-2H-chromene-3-
carbonitrile 4j
(td, J = 7.6, 0.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.11 – 7.05 (m,
1
3
2
1
1
H); C-NMR (126 MHz, CDCl
3
) δ 161.12, 159.18, 153.54,
Yield 78% (yellow solid, 177 mg); m.p. 151-153ºC;
-1
44.69, 144.44, 140.42, 134.02, 128.77, 125.01, 124.95, 124.89,
IR (ν/cm ): 2232, 1733, 1655, 1606, 1590, 1566, 1480, 1387,
1
17.68, 116.32, 115.50, 115.32, 114.58, 107.42; HRMS Mass
3
1289, 1255, 1217, 1150, 1048; H-NMR (400 MHz, CDCl ) δ
+
Chemical Formula: C
2
1
H
10FN
2
O [M + H] : 265.0772; Found:
8.26 (s, 1H), 7.71 (t, J = 7.1 Hz, 1H), 7.64 – 7.56 (m, 1H), 7.51 –
7.34 (m, 3H), 7.24 (dd, J = 15.6, 8.4 Hz, 1H), 7.08 (d, J = 8.2 Hz,
65.0744.
1
3
1
H), 6.90 – 6.67 (m, 1H), 3.80 (s, 3H); C-NMR (101 MHz,
CDCl ) δ 156.38, 154.56, 151.79, 144.59, 135.51, 133.95,
129.26, 128.69, 125.67, 124.75, 117.40, 115.29, 113.49, 110.85,
4
.2.5 (Z)-2-((4-Chlorophenyl)imino)-2H-chromene-3-
3
carbonitrile 4e
Yield 84% (yellow solid, 193 mg); m.p. 148-149ºC; IR (ν/cm ):
-1
108.62, 55.27; HRMS Mass Chemical Formula: C17
+ H] : 277.0972; Found: 277.0965.
H
13
N
2
O
2
[M
+
2
1
7
7
1
1
1
231, 1647, 1604, 1580, 1567, 1482, 1454, 1382, 1290, 1215,
1
3
122, 1010; H-NMR (500 MHz, CDCl ) δ 7.84 (s, 1H), 7.57 –
.52 (m, 1H), 7.52 – 7.48 (m, 2H), 7.43 (dd, J = 7.7, 1.3 Hz, 1H),
.29 – 7.26 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.3 Hz,
4.2.11 (Z)-2-(Naphthalen-1-ylimino)-2H-chromene-3-
carbonitrile 4k
Yield 70% (yellow solid, 169 mg); m.p. 135-136ºC; IR (ν/cm ):
1
3
-1
H); C-NMR (126 MHz, CDCl
3
) δ 153.49, 145.17, 144.81,
43.55, 134.16, 131.77, 128.82, 124.99, 124.92, 118.00, 117.63,
2230, 1650, 1614, 1563, 1502, 1453, 1395, 1341, 1288, 1214,
1
16.36, 114.47, 107.19; HRMS Mass Chemical Formula:
1191, 1059; H-NMR (500 MHz, CDCl
3
) δ 8.32 (dd, J = 5.4, 4.3
+
C
16
H
10ClN
2
O [M + H] : 281.0476; Found: 281.0468.
Hz, 1H), 7.90 – 7.85 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.54 –
.42 (m, 6H), 7.24 (td, J = 7.6, 1.0 Hz, 1H), 7.06 (d, J = 8.3 Hz,
7
1
3
4
4
.2.6 (Z)-2-((4-Bromophenyl)imino)-2H-chromene-3-carbonitrile
f
3
1H); C-NMR (101 MHz, CDCl ) δ 153.65, 145.04, 144.48,
140.60, 134.20, 133.98, 128.71, 127.72, 126.47, 126.15, 125.80,
-1
Yield 80% (yellow solid, 152 mg); m.p. 160-161ºC; IR (ν/cm ):
2
1
125.46, 125.09, 124.79, 124.18, 117.73, 117.08, 116.47; HRMS
+
231, 1644, 1602, 1567, 1455, 1380, 1290, 1196, 1121, 1072,
Mass Chemical Formula: C20
Found: 297.1008.
H
13
N
2
O [M + H] : 297.1022;
1
3
045; H-NMR (400 MHz, CDCl ) δ 7.80 (s, 1H), 7.56 – 7.35
(
m, 4H), 7.23 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 19.8, 8.0 Hz, 3H).
1
3
C-NMR (101 MHz, CDCl
34.09, 131.71, 128.77, 124.93, 124.87, 117.95, 117.59, 116.30,
14.42, 107.14; HRMS Mass Chemical Formula: C16
3
) δ 153.44, 145.10, 144.74, 143.50,
4.2.12 (Z)-7-Methoxy-2-(phenylimino)-2H-chromene-3-
3
4
1
1
carbonitrile 4aa
Yield 85% (yellow solid, 155 mg); H NMR (400 MHz, CDCl
7.75 (s, 1H), 7.43 – 7.37 (m, 2H), 7.29 (d, J = 5.3 Hz, 1H), 7.28 –
.23 (m, 2H), 7.21 – 7.15 (m, 1H), 6.79 (dd, J = 8.6, 2.4 Hz, 1H),
1
H
10BrN
2
O
3
) δ
+
[M + H] : 324.9971; Found: 324.9952.
7
1
3
4
.2.7 (Z)-2-((4-(Trifluoromethyl)phenyl)imino)-2H-chromene-3-
6.59 (d, J = 2.3 Hz, 1H), 3.86 (s, 3H); C NMR (101 MHz,
CDCl ) δ 164.69, 155.59, 144.82, 144.52, 135.65, 129.75,
carbonitrile 4g
Yield 78% (yellow solid, 200 mg); m.p. 162-163ºC; IR (ν/cm ):
233, 1656, 1600, 1567, 1510, 1455, 1321, 1218, 1155, 1061;
3
-1
128.71, 128.01, 124.61, 122.91, 112.52, 111.20, 103.39, 100.95,
56.03.
2
1
H- NMR (400 MHz, CDCl
3
) δ 7.86 (s, 3H), 7.60 (d, J = 8.2 Hz,
6
H), 7.55 – 7.38 (m, 7H), 7.31 – 7.24 (m, 8H), 7.08 (d, J = 8.2

8
Tetrahedron Letters
4
.2.13 (Z)-7-(Diethylamino)-2-(phenylimino)-2H-chromene-3-
Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan,
D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941; (c)
Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
3
4
carbonitrile 4ab
Yield 82% (yellow solid, 135 mg); H-NMR (400 MHz, CDCl
δ 7.63 (s, 1H), 7.44 – 7.36 (m, 2H), 7.27 – 7.22 (m, 2H), 7.19 –
7
1
1
3
)
1
998, 39, 2937.
4
5
.
.
Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.;
Sproules, S.; Watson, A. J. J. Am. Chem. Soc. 2017, 139,
.12 (m, 2H), 6.48 (dd, J = 8.9, 2.5 Hz, 1H), 6.20 (d, J = 2.3 Hz,
H), 3.41 (q, J = 7.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H); 13C-NMR
4
769.
3
(101 MHz, CDCl ) δ 156.30, 152.38, 146.46, 145.58, 144.68,
(a) Qiao, Y.; Li, G.; Liu, S.; Yangkai, Y.; Tu, J.; Xu, F.
Synthesis 2017, 49, 1834; (b) Vantourout, J. C.; Law, R.
P.; Isidro-Llobet, A.; Atkinson, S. J.; Watson, A. J. J. Org.
Chem. 2016, 81, 3942; (c) Qi, C.; Guo, T.; Xiong, W.
Synlett 2016, 27, 2626; (d) Jacobson, C. E.; Martinez-
Muñoz, N.; Gorin, D. J. J. Org. Chem. 2015, 80, 7305; (e)
Moon, S.-Y.; Kim, U. B.; Sung, D.-B.; Kim, W.-S. J. Org.
Chem. 2015, 80, 1856; (f) Jiang, Y.; Huang, S. Synlett
1
9
29.96, 128.64, 123.91, 122.96, 116.40, 108.47, 106.86, 98.01,
7.15, 44.85, 12.53.
4
.2.14 (Z)-6-Chloro-2-(phenylimino)-2H-chromene-3-
3
4
carbonitrile 4ac
Yield 80% (yellow solid, 145 mg); H-NMR (400 MHz, CDCl
δ 7.89 – 7.77 (m, 1H), 7.61 – 7.44 (m, 4H), 7.43 – 7.27 (m, 3H),
7
1
1
1
3
)
.22 – 7.09 (m, 1H); 13C-NMR (101 MHz, CDCl
) δ 152.04,
3
44.17, 143.22, 133.64, 130.03, 128.84, 127.94, 125.30, 123.17,
18.79, 117.80, 114.32, 108.73.
2
014, 25, 407; (g) Gao, J.; Shao, Y.; Zhu, J.; Zhu, J.; Mao,
H.; Wang, X.; Lv, X. J. Org. Chem. 2014, 79, 9000; (h)
Nasrollahzadeh, M.; Ehsani, A.; Maham, M. Synlett 2014,
2
5, 505; (i) Moon, S.-Y.; Nam, J.; Rathwell, K.; Kim, W.-
4
.2.15 (Z)-6,8-Dibromo-2-(phenylimino)-2H-chromene-3-
S. Org. Lett. 2014, 16, 338; (j) Sueki, S.; Kuninobu, Y.
Org. Lett. 2013, 15, 1544; (k) Rossi, S. A.; Shimkin, K.
W.; Xu, Q.; Mori-Quiroz, L. M.; Watson, D. A. Org. Lett.
2013, 15, 2314; (l) Srivastava, V. P.; Yadav, D. K.; Yadav,
A. K.; Watal, G.; Yadav, L. D. S. Synlett 2013, 24, 1423;
carbonitrile 4ad
Yield 75% (yellow solid, 108 mg); m.p. 210-211ºC IR (ν/cm ):
-
1
1
2
238, 1653, 1582, 1548, 1486, 1410, 1230, 1199, 1046; H -
NMR (500 MHz, CDCl ) δ 7.84 (d, J = 2.2 Hz, 1H), 7.66 (s, 1H),
.53 (dd, J = 8.4, 1.0 Hz, 2H), 7.49 (d, J = 2.2 Hz, 1H), 7.45 –
3
(m) Huang, F.; Quach, T. D.; Batey, R. A. Org. Lett. 2013,
7
7
.39 (m, 2H), 7.26 – 7.21 (m, 1H); 1 C-NMR (101 MHz, CDCl
3
15, 3150; (n) Sun, N.; Zhang, H.; Mo, W.; Hu, B.; Shen,
Z.; Hu, X. Synlett 2013, 24, 1443; (o) Raghuvanshi, D. S.;
Gupta, A. K.; Singh, K. N. Org. Lett. 2012, 14, 4326. (p)
Xu, H.-J.; Zhao, Y.-Q.; Feng, T.; Feng, Y.-S. J. Org.
Chem. 2012, 77, 2878; (q) Wang, L.; Zhou, W.-Y.; Chen,
S.-C.; He, M.-Y.; Chen, Q. Synlett 2011, 2011, 3041; (r)
Zhuang, R.; Xu, J.; Cai, Z.; Tang, G.; Fang, M.; Zhao, Y.
Org. Lett. 2011, 13, 2110.
(a) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A.
J. Am. Chem. Soc. 2010, 132, 1202; (b) Larrosa, M.;
Guerrero, C.; Rodríguez, R.; Cruces, J. Synlett 2010, 2010,
2101; (c) Grimes, K. D.; Gupte, A.; Aldrich, C. C.
Synthesis 2010, 2010, 1441; (d) Zhang, L.; Zhang, G.;
Zhang, M.; Cheng, J. J. Org. Chem. 2010, 75, 7472; (e)
González, I.; Mosquera, J.; Guerrero, C.; Rodriguez, R.;
Cruces, J. Org. Lett. 2009, 11, 1677; (f) Sreedhar, B.;
Venkanna, G. T.; Kumar, K. B. S.; Balasubrahmanyam, V.
Synthesis 2008, 2008, 795; (g) Kantam, M. L.; Venkanna,
G. T.; Sridhar, C.; Sreedhar, B.; Choudary, B. M. J. Org.
Chem. 2006, 71, 9522; (h) Hügel, H. M.; Rix, C. J.; Fleck,
K. Synlett 2006, 2006, 2290; (i) Quach, T. D.; Batey, R. A.
Org. Lett. 2003, 5, 4397; (j) Quach, T. D.; Batey, R. A.
Org. Lett. 2003, 5, 1381.
3
)
δ 153.37, 147.90, 145.33, 134.27, 128.86, 125.93, 125.89,
25.07, 122.78, 117.51, 116.36, 114.30, 106.76; HRMS Mass
1
+
9 2 2
Chemical Formula: C16H Br NO O [M + H] : 402.9076; Found:
4
02.9049.
4
.2.16 (Z)-6,8-Di-tert-butyl-2-(phenylimino)-2H-chromene-3-
3
4
carbonitrile 4ae
6
.
1
Yield 65% (yellow solid, 199 mg); H-NMR (400 MHz, CDCl
δ 7.82 (s, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.37 – 7.30 (m, 2H), 7.18
d, J = 2.3 Hz, 1H), 7.13 – 7.06 (m, 1H), 7.00 – 6.95 (m, 2H),
3
)
(
1
1
1
2
.31 (s, 9H), 1.04 (s, 9H). 13C-NMR (101 MHz, CDCl
3
) δ 150.50,
47.08, 146.69, 146.61, 146.05, 137.40, 129.57, 128.82, 123.86,
23.63, 121.14, 117.37, 114.86, 105.12, 34.61, 34.55, 31.24,
9.21.
Acknowledgments
PSM is grateful to UGC-BSR, Department of Chemistry, and
Institute of Chemical Technology (ICT) for the research
fellowship. AVK is thankful to DST, Govt. of India for the
INSPIRE Faculty Award [IFA12- CH-40] and research funding.
AVK is also thankful to DST-SERB, Govt. of India for the
research grant YSS/2015/002064. We also thank the Department
of Pharmaceutical Sciences and Technology, ICT, for the NMR
analysis and Prof. H. S. P. Rao, Pondicherry University for
HRMS analysis.
7
8
.
.
Keating, G.; O’kennedy, R. Coumarins: biology,
applications and mode of action. John Wiley & Sons, Inc.,
New York, NY 1997, 348.
Yu, D.; Suzuki, M.; Xie, L.; Morris‐Natschke, S. L.; Lee,
K. H. Med. Res. Rev. 2003, 23, 322.
9. Murray, R. D. H.; Méndez, J.; Brown, S. A. The natural
coumarins; John Wiley, Chichester, 1982.
1
1
1
0. Clark, G. Perfum. Flavor 1995, 20, 23.
1. Sekar, N. Colourage 2003, 50, 55.
2. Singh, I.; Kaur, H.; Kumar, S.; Kumar, A.; Lata, S.;
Kumar, A. Int J ChemTech Res 2010, 2, 1745.
3. Sardari, S.; Mori, Y.; Horita, K.; Micetich, R. G.; Nishibe,
S.; Daneshtalab, M. Bioorg. Med. Chem. 1999, 7, 1933.
4. Kirkiacharian, S.; Thuy, D. T.; Sicsic, S.; Bakhchinian, R.;
Kurkjian, R.; Tonnaire, T. Il Farmaco 2002, 57, 703.
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References and notes
1
2
3
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Org. Chem. 2005, 70, 6904.
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1
1
1
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994, 120, 502.
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359−1470; (b) Sambiagio, C.; Marsden, S. P.; Blacker, A.
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M. P. Tetrahedron Lett. 1998, 39, 2933; (b) Lam, P. Y. S.;
1
1

9
1
2
2
9. Peng, W.; Świtalska, M.; Wang, L.; Mei, Z.-W.; Edazawa,
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Supplementary Material
1H and 13C-NMR of all the compounds

1
0
Tetrahedron Letters
Highlights



One-pot Aryliminocoumarins synthesis without
isolating intermediates is showcased
Use
of
bio-mass-derived
solvent
2-
methyltetrahydrofuran is more environ-friendly
Mass spectrometry studies reveal formation of
iminocoumarin-copper complex