Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease

Article abstract of DOI:10.1016/j.ejmech.2017.07.008

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases

Full text of DOI:10.1016/j.ejmech.2017.07.008

Accepted Manuscript
Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual
inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of
Alzheimer's disease
Hua-Li Yang, Pei Cai, Qiao-Hong Liu, Xue-Lian Yang, Fan Li, Jin Wang, Jia-Jia Wu,
Xiao-Bing Wang, Ling-Yi Kong
PII:
S0223-5234(17)30530-5
10.1016/j.ejmech.2017.07.008
EJMECH 9571
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 16 April 2017
Revised Date: 20 June 2017
Accepted Date: 6 July 2017
Please cite this article as: H.-L. Yang, P. Cai, Q.-H. Liu, X.-L. Yang, F. Li, J. Wang, J.-J. Wu, X.-B.
Wang, L.-Y. Kong, Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual
inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease,
European Journal of Medicinal Chemistry (2017), doi: 10.1016/j.ejmech.2017.07.008.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual
inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment
of Alzheimer's disease
Hua-Li Yangab, Pei Caib, Qiao-Hong Liub, Xue-Lian Yangb, Fan Lib, Jin Wangb,
Jia-Jia Wub, Xiao-Bing Wangb and Ling-Yi Kongab*
a
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical
University, Shenyang 110016, China.
b
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key
Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, China.
* Corresponding author.
Tel/Fax: +86-25-83271405. E-mail: cpu_lykong@126.com.

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Abstract
A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and
evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the
compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and
monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory
activities against monoamine oxidases (IC50, 0.027±0.004 µM for MAO-B;
3.275±0.040 µM for MAO-A) and Aβ1-42 aggregation (54.0±1.1%, 25 µM). Moreover,
compound 4x showed low toxicity according to in vitro cell toxicity test. The results
of the parallel artificial membrane permeability assay for blood-brain barrier indicated
that compound 4x would be potent to cross the blood-brain barrier. Collectively, these
findings demonstrate that compound 4x was an effective and promising candidate for
AD therapy.
Keywords: Alzheimer’s disease, Coumarin, Pargyline, Monoamine oxidases, Aβ1-42
aggregation.
1. Introduction
Alzheimer’s disease (AD), the most ordinary form of dementia in the elderly, is
an age-related progressive neurodegenerative disorder characterized by memory loss,
decline in language skills and other cognitive impairments [1]. As reported by WHO,
more than 30 million people are suffering from AD worldwide, and the incidence of
AD will significantly rise to 100 million by 2050 [2]. Due to complex nature and
multitude of factors potentially involved in pathogenesis, many aspects of AD are not
yet fully known. Accordingly, some factors, such as low levels of neurotransmitter
acetylcholine (ACh), the aggregation of β-amyloid peptide, dyshomeostasis of
biometals, hyperphosphorylation of tau protein, and oxidative stress, are suggested to
play key roles in the pathogenesis of AD [3, 4]. Thus, the multi-target-directed ligand
(MTDL) strategy, aiming to this multifaceted disease, has drawn much attention as a
promising therapeutic approach [5, 6].

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Monoamine oxidases (MAOs), FAD-dependent enzymes responsible for the
regulation and metabolism of major monoamine neurotransmitters, were drawn much
attention in recent years [7-9]. By in vivo two-photon imaging, close correlation of
monoamine oxidase activity with progress of AD in mice was reported in 2016 [10].
MAOs exist as two isoforms, MAO-A and MAO-B, which exhibit different substrate
and inhibitor specificities. MAO-A, preferentially degrading serotonin, adrenaline and
noradrenaline, has a close correlation with depression, whereas MAO-B is specifically
responsible for the neurodegenerative disease such as AD [11]. High expression level
of MAO-B in neuronal tissue relates to the level of hydrogen peroxide, resulting in
oxidative damage and apoptotic signaling events [12, 13]. Thus, MAO-B inhibitors
are considered as potential candidates for anti-Alzheimer drugs.
Among the multiple factors that induce AD, Aβ plays a crucial role. The
aggregation of Aβ, especially Aβ1-42 in brain leads to the formation of senile plaques,
associated with neurodegeneration [14]. Recently, a study on amyloid-β oligomers
and plaques provided solid evidence for the view that the accumulation of Aβ is an
important mechanism underlying AD [15]. Therefore, inhibition of Aβ1-42
aggregation is a potential therapeutic strategy for AD treatment.
Many efforts have been addressed toward the design of MTDLs targeting
cholinesterase (ChE) inhibition, MAO inhibition, Aβ deposit inhibition, antioxidative
and metal chelating properties [5, 16-18]. In this study, a series of
coumarin-pargyline hybrids were designed, synthesized and evaluated for their
biological activity, including MAO-B inhibitory activity, inhibition of Aβ1-42
aggregation properties, and ability to cross the blood–brain barrier (BBB).
Meanwhile, computational studies were performed to predict their binding modes
in active pocket and illustrate their exceedingly high affinities.
2. Results and discussion
2.1. Design and synthesis of the target coumarin-pargyline hybrids
Coumarins are widely present in many plant species and have attracted
considerable attention in recent years because they display a wide range of

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biological properties associated with neurological disorders, especially for AD
[18-20]. Previous studies have shown that coumarin analogs exhibited potent
MAO-B inhibitory activity, especially for the 3-, 4-, and 7-substituted coumarin
analogs [21, 22]. Besides its MAO-B inhibition, quite a few studies reported that
coumarin analogs also exhibited Aβ anti-aggregation potency by functionalization
of their aromatic center [22, 23]. These results indicate that coumarin is a
noteworthy scaffold for the discovery and development of multifunctional drugs for
the treatment of AD.
Pargyline is an irreversible selective MAO-B inhibitor drug (IC50 for MAO-A
is 0.01152 µmol/L and for MAO-B is 0.00820 µmol/L) [24, 25]. The
propargylamine moiety derived from selective MAO-B inhibitor plays an important
role in neuroprotective properties [26, 27].
Considering the above mentioned, the privileged natural product coumarin and
the drug fragment of pargyline were combined to design and synthesize a series of
coumarin-pargyline hybrids which are expected to be selective MAO-B inhibitors,
as well as inhibitors of Aβ1-42 aggregation (Figure. 1).
The
synthetic
pathways
of
target
compounds
4a-x
with
7-hydroxy-2H-chromen-2-one 1 as staring material were summarized in Scheme 1.
Compounds 2a-c were obtained by alkylation of 1 with different α,
ω-dibromoalkanes in the presence of potassium carbonate. The obtained compounds
2a-c reacted with commercially available secondary amines in refluxing CH3CN for
10 h to give the key intermediates 3a-u. Finally, the reaction of compounds 3a-u
with 3-bromopropyne under basic conditions provided target compounds 4a-u. It
should be noted that the propargylation of amines had to be performed by
monitoring the reaction course at 65°C against the formation of dipropargylated
products at high temperature [28]. To explore the superiority of
N-benzylpropargylamine and N-methylpropargylamine moieties from pargyline,
target compounds 4v-x were synthesized by direct reaction of compounds 2a-c with
N-methylpropargylamine at the optimized conditions.
2.2. MAOs inhibitory activities of the target compounds

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The hMAO-A and hMAO-B inhibitory activities of coumarin-pargyline hybrids
were measured by a previously described fluorescence-based Amplex Red assay using
pargyline as reference compound [29]. The corresponding IC50 values and selectivity
index (SI) values are shown in Table 1. For compounds 4a-u, the substituents in the
phenoxy ring have no significant effect on hMAO-B inhibitory. Comparing the IC50
values of 4a-u and 4v-x, compounds with N-methylpropargylamine moiety
performed much better activities than that with N-benzylpropargylamine moiety in
hMAO-B inhibition. Besides, the linker length between coumarin and
propargylamine moiety played a significant role in determining the inhibitory activity
for hMAO-B inhibitory. Among them, 4x with a four-carbon spacer (hMAO-B,
IC50=0.027±0.004 µM; SI, 121.3) showed the most potent inhibitory activity and
selectivity for hMAO-B, which was stronger than the reference compound pargyline
(hMAO-B, IC50=0.194±0.030 µM; SI, 18.15).
The molecular modeling study based on MAO-B (PDB code: 2V60) was
performed using docking program, AutoDock 4.2 package with Discovery Studio 2.0.
As shown in the Figure 2, the size of compound 4x with a four-carbon spacer is better
suited to fill the binding cavity in hMAO-B.
2.3. Reversibility study of hMAO-B inhibition
The most promising compound 4x with a nanomolar hMAO-B inhibitory activity
was selected for further studies. To evaluate whether the target compound 4x is a
reversible hMAO-B inhibitor or not, a time-dependent inhibition assay was carried
out [30]. The irreversible inhibitor pargyline was tested as the reference compound.
As shown in Figure 3, 4x was an irreversible inhibitor of hMAO-B as evidenced by a
significant time-dependent increase of inhibitory activity. This result was consistent
with irreversible inhibitor pargyline. According to the studies, propargylamino group
present in the compound 4x may lead to the irreversible inhibition of the enzyme [28,
31].
2.4. Aβ1-42 self-aggregation inhibitory activity of the target compounds
With the above studies on the hMAO-B inhibitory activities of all the target
compounds, 4o-x presented a potential to inhibit hMAO-B, while the others had weak

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activity. From the view of MTDLs targeting both hMAO and Aβ1-42, hybrids 4o-x
with favorable hMAO-B inhibitory activities were chosen for their further bioassay to
inhibit self-induced Aβ1-42 aggregation by thioflavin-T based fluorescence assay [32,
33]. Curcumin and resveratrol were used as reference compounds [30, 33-34].
Inhibitory activities as inhibition ratios at a test concentration of 25 µM were
displayed in Figure 4. The result showed that hybrids 4o-x exhibited
moderate-to-good potencies (30.6-59.3% at 25 µM) compared to that of curcumin
(47.7% at 25 µM) and resveratrol (61.3% at 25 µM). The hybrids 4o and 4w-x had
better performance on anti-β-amyloid aggregation property.
A structure-activity relationship analysis indicated that the property and locality
of substituents in the phenoxy ring had significant impacts on Aβ1-42 inhibitory
activity. The F-substituted hybrid 4u (30.6% at 25 µM) exhibited lower inhibitory
activities than the corresponding CH3-substituted hybird 4p (50.0% at 25 µM). The
para-substituted compound 4r (49.1% at 25 µM) exhibited much higher inhibitory
activities than meta-substituted compound 4s (38.2% at 25 µM). From inhibition
ratios of compounds 4v-x (36.4%, 59.3%, 54.0% at 25 µM, respectively), 4w with a
three-carbon spacer and 4x with a four-carbon spacer had more potent inhibition of
self-induced Aβ1-42 aggregation than 4v with a three- carbon spacer.
The potent inhibitor 4x was selected with X-ray crystal structure of the protein
Aβ1-42 structure (PDB code 1IYT) for molecular docking studies because of its total
performance regarding hMAO-B inhibition and self-induced Aβ1-42 aggregation
inhibition. As shown in Figures 5A and 5B, the coumarin ring of compound 4x
interacted with the residue Phe20 via π-π stacking interaction. A hydrogen bond
interaction was formed between carbonyl group of compound 4x and the residue
Lys16. These results indicated that the π-π stacking interaction and hydrogen bond
interactions played important roles in the stability of the 4x-Aβ complex.
2.5. In vitro blood-brain barrier permeation assay
The blood-brain barrier (BBB) protects the brain from harmful chemicals, and
makes it difficult for drugs to reach the target cells. Thus, it is important to cross the
blood-brain barrier (BBB) for the drugs targeting central nervous system (CNS). On

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this basis, the parallel artificial membrane permeation assay (PAMPA)-BBB method
was used to evaluate the brain penetration ability of compound 4x [35]. Table 2
showed the permeability values of eight reference drugs with known CNS penetration
and compound 4x. The experimental and reported permeability values of eight
reference drugs provided a good linear correlation: Pe (exp) = 0.6022 Pe (Bibl) +
0.8073 (R2 =0.9749). From this equation and considering the limits established by Di
et al. for BBB permeation, we established that compound with Pe value above
3.22×10-6 cm s-1could penetrate into the CNS. Compound 4x showed a Pe value of
8.92×10-6 cm s-1, indicating that it could easily cross the BBB.
2.6. Cell toxicity
The safety is extraordinary important for the CNS drugs, so the potential toxicity
effect of 4x was investigated on 4x-treated PC12 cells. The cells were exposed to
compound 4x for 24 h and the cell viability was determined by the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay [36, 37]. As shown
in Figure 6, compound 4x showed little effect on the cell viability at 0-100 µM. The
data showed that compound 4x was nontoxic to PC12 and might be used to develop
promising drug candidates for the therapy of treating AD.
2.7. Acute Toxicity.
Fifteen KM mice (KM mice, which are common closed colony mice and most
widely used in biomedical research in China) were randomly allocated into 3 groups,
and the compound 4x, pargyline were given in a single oral dose of 2.4 mmol/kg
respectively. After administration of compounds, mice were monitored continuously
for the first 4 h for any abnormal behavior and mortality changes, intermittently for
the next 24 h, and occasionally thereafter for 14 days to monitor the onset of any
delayed effects. During the experimental period, no acute toxicity, such as mortality,
or significant abnormal changes in water or food consumption or body weight were
observed. Furthermore, all mice were sacrificed on the 14th day after drug
administration, and no damage to the heart, liver, or kidneys was macroscopically
detected.
Besides, the orbital blood was collected before decapitation, and the levels of

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aspartate aminotranferase (AST) and alanine aminotranferase (ALT) were evaluated
(Figure. 7) [38]. Compared with the control group, compound 4x and pargyline did
not significantly alter these parameters.
Overall, compound 4x was nontoxic and well tolerated at doses up to 2.4
mmol/kg.
3. Conclusions
In this study, a series of coumarin-pargyline hybrids were designed, synthesized
and evaluated as dual inhibitors of amyloid-β aggregation and monoamine oxidases
for the treatment of AD. Among the synthesized compounds, compound 4x exhibited
the most potent hMAO-B inhibitor activity, high selectivity for hMAO-B over
hMAO-A, as well as significant inhibition of Aβ1-42 aggregation. Meanwhile,
compound 4x could penetrate the blood-brain barrier (BBB) and showed low toxicity
according to in vitro cell toxicity test and in vivo acute toxicity test. In summary, these
results suggested that compound 4x is an effective and promising candidate for AD
therapy.
4. Methods
4.1. Chemistry
All chemicals (reagent grade) used were purchased from Sino pharm Chemical
Reagent Co., Ltd. (China). Reaction progress was monitored using analytical thin
layer chromatography (TLC) on precoated silica gel GF254 (Qingdao Haiyang
Chemical Plant, Qing-Dao, China) plates and the spots were detected under UV light
(254 nm). Column chromatography was performed on silica gel (90-150 µm; Qingdao
1
13
Marine Chemical Inc.). H NMR and C NMR spectra were measured on a Bruker
ACF-500 spectrometer at 25°C and referenced to TMS. Chemical shifts are reported
in ppm (δ) using the residual solvent line as internal standard. Splitting patterns are
designed as s, singlet; d, doublet; t, triplet; m, multiplet. Mass spectra were obtained
on a MS Agilent 1100 Series LC/MSD Trap mass spectrometer (ESI-MS) and a
Mariner ESI-TOF spectrometer (HRESIMS), respectively.
4.1.1.General procedures for the preparation of compounds 2a-c.

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To a solution of 7-hydroxy-2H-chromen-2-one 1 (4 mmol) and powdered K2CO3
(8 mmol) in acetone (20 mL), corresponding α,ω-dibromoalkane (24 mmol) was
added. The reaction mixture was refluxed for 10-12 h. Upon completion, K2CO3 was
removed by filtration and the solvent was concentrated under vacuum, the residue was
purified on silica gel chromatography with petroleum ether/ethyl acetate (7:1, v/v) as
elution solvent to give the desired product 2a-c [18, 38].
4.1.1.1. 7-(2-bromoethoxy)-2H-chromen-2-one (2a).
The general procedure described for 2a-c was used, starting from 1,
1,2-dibromoethane and powdered K2CO3, and 2a was obtained as a White solid (yield
75%); 1H NMR (500 MHz, DMSO) δ 8.00 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.65 (d,
J = 8.6 Hz, 1H, H5-coumarin), 7.03 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.99 (dd, J =
8.6, 2.5 Hz, 1H, H7-coumarin), 6.31 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.45 (t, J = 5.3
Hz, 2H,O-CH2-), 3.84 (t, J = 5.3 Hz, 2H, CH2Br). Analytical data of 2a were conform
to the literature [18, 38].
4.1.1.2. 7-(3-Bromopropoxy)-2H-chromen-2-one (2b).
The general procedure described for 2a-c was used, starting from 1,
1,3-dibromopropane and powdered K2CO3, and 2b was obtained as a White solid
1
(yield 79%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.62 (d, J = 8.7 Hz, 1H, H5-coumarin), 7.00 (d, J = 2.5 Hz, 1H,
H8-coumarin), 6.96 (dd, J = 8.6, 2.5 Hz, 1H, H7-coumarin), 6.29 (d, J = 9.5 Hz, 1H,
H3-coumarin), 4.18 (s, 2H, O-CH2-), 3.67 (t, J = 6.6 Hz, 2H, CH2Br), 2.27 (t, J =
6.3 Hz, 2H, OCH2-CH2). Analytical data of 2b were conform to the literature [18,
38].
4.1.1.3. 7-(4-Bromobutoxy)-2H-chromen-2-one (2c).
The general procedure described for 2a-c was used, starting from 1,
1,4-dibrombutan and powdered K2CO3, and 2c was obtained as a White solid (yield
83%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.4 Hz, 1H, H4-coumarin), 7.61
(d, J = 8.5 Hz, 1H, H5-coumarin), 6.98 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.94 (d, J =
8.7 Hz, 1H, H7-coumarin), 6.27 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.11 (s, 2H,
O-CH2-), 3.61 (s, 2H, CH2Br), 1.97 (dd, J = 8.5, 6.2 Hz, 2H, O(CH2)2-CH2), 1.86 (dd,

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J = 8.6, 5.9 Hz, 2H, OCH2-CH2). Analytical data of 2c were conform to the literature
[18, 38].
4.1.2. General procedures for the preparation of compounds 3a-u.
A mixture of compound 2a-c (1 mmol), benzylamine derivatives (3 mmol),
powdered K2CO3 (5 mmol) and a catalytic amount of KI in acetonitrile (20 mL) was
stirred at reflux for 10 hours. K2CO3 was removed by filtration and the solvent was
concentrated under vacuum, the residue was purified on silica gel chromatography
with DCM/MeOH (100:1, v/v) as elution solvent to give the desired product 3a-u [18,
38].
4.1.2.1. 7-[2-(benzylamino)ethoxy]-2H-chromen-2-one (3a).
The general procedure described for 3a-u was used, starting from 2a,
benzylamine, powdered K2CO3 and KI, and 3a was obtained as a Yellow oil (yield
91%); 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.6 Hz, 1H, H4-coumarin), 7.62
(d, J = 8.6 Hz, 1H, H5-coumarin), 7.32 (dt, J = 15.1, 7.5 Hz, 4H, Ph-H), 7.24 (m, 1H,
Ph-H), 6.99 (d, J = 2.5 Hz, 1H, H8-coumarin), 6.95 (dd, J = 8.6, 2.4 Hz, 1H,
H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.14 (t, J = 5.6 Hz, 2H,
O-CH2-), 3.76 (s, 2H, CH2Ph), 2.87 (t, J = 5.6 Hz, 2H, OCH2-CH2). HRMS: calcd for
C18H17NO3 [M + H]+ 296.1208, found 296.1281.
4.1.2.2. 7-{2-[(4-methylbenzyl)amino]ethoxy}-2H-chromen-2-one (3b)
The general procedure described for 3a-u was used, starting from 2a,
4-methylbenzylamine, powdered K2CO3 and KI, and 3b was obtained as a Yellow oil
(yield 89%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.4 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.21 (d, J = 7.8 Hz, 2H, Ph-H), 7.10 (d, J =
7.7 Hz, 2H, Ph-H), 6.97 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.94 (d, J = 8.6 Hz, 1H,
H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.13 (t, J = 5.6 Hz, 2H,
O-CH2-), 3.71 (s, 2H, CH2Ph), 2.85 (s, 2H, OCH2-CH2), 2.26 (s, 3H, CH3). HRMS:
calcd for C19H19NO3 [M + H]+ 310.1365 , found 310.1438.
4.1.2.3. 7-{2-[(4-isopropylbenzyl)amino]ethoxy}-2H-chromen-2-one (3c)
The general procedure described for 3a-u was used, starting from 2a,
4-isopropylbenzylamine, powdered K2CO3 and KI, and 3c was obtained as a Yellow

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1
oil (yield 88%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.24 (d, J = 7.8 Hz, 2H, Ph-H),
7.16 (d, J = 7.8 Hz, 2H, Ph-H), 6.98 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.94 (d, J =
8.6 Hz, 1H, H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.13 (t, J = 5.6 Hz,
2H, O-CH2-), 3.72 (s, 2H, CH2Ph), 2.87 (t, J = 5.6 Hz, 2H, OCH2-CH2), 2.85-2.80 (m,
1H, CH), 1.18 (d, J = 6.9 Hz, 6H, 2×CH3). HRMS: calcd for C21H23NO3 [M + H]+
338.1678, found 338.1751.
4.1.2.4. 7-{2-[(4-methoxybenzyl)amino]ethoxy}-2H-chromen-2-one (3d)
The general procedure described for 3a-u was used, starting from 2a,
4-methoxybenzylamine, powdered K2CO3 and KI, and 3d was obtained as a Yellow
1
oil (yield 80%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.25 (d, J = 8.2 Hz, 2H, Ph-H),
6.98 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.94 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin),
6.86 (d, J = 8.5 Hz, 2H, Ph-H), 6.28 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.13 (t, J = 5.7
Hz, 2H, O-CH2-), 3.72 (s, 3H, OCH3), 3.69 (s, 2H, CH2Ph), 2.85 (s, 2H, OCH2-CH2).
HRMS: calcd for C19H19NO4 [M + H]+ 326.1314, found 326.1387.
4.1.2.5. 7-{2-[(3-methoxybenzyl)amino]ethoxy}-2H-chromen-2-one (3e)
The general procedure described for 3a-u was used, starting from 2a,
3-methoxybenzylamine, powdered K2CO3 and KI, and 3e was obtained as a Yellow
1
oil (yield 81%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.62 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.22 (t, J = 7.8 Hz, 1H, Ph-H),
6.99 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.97-6.93 (m, 2H, Ph-H), 6.91 (d, J = 7.6 Hz,
1H, Ph-H), 6.78 (dd, J = 8.2, 2.6 Hz, 1H, H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H,
H3-coumarin), 4.14 (t, J = 5.6 Hz, 2H, O-CH2-), 3.73 (d, J = 4.2 Hz, 5H, CH2Ph+
OCH3), 2.87 (t, J = 5.6 Hz, 2H, OCH2-CH2). HRMS: calcd for C19H19NO4 [M + H]+
326.1314, found 326.1387.
4.1.2.6. 7-{2-[(3-fluorobenzyl)amino]ethoxy}-2H-chromen-2-one (3f)
The general procedure described for 3a-u was used, starting from 2a,
3-fluorobenzylamine, powdered K2CO3 and KI, and 3f was obtained as a Yellow oil
(yield 75%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin),

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7.62 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.34 (td, J = 8.0, 6.1 Hz, 1H, Ph-H), 7.26-7.10
(m, 2H, Ph-H), 7.03 (td, J = 8.0, 7.4, 2.2 Hz, 1H, Ph-H), 6.99 (d, J = 2.4 Hz, 1H,
H8-coumarin), 6.95 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H,
H3-coumarin), 4.14 (s, 2H, O-CH2-), 3.79 (s, 2H, CH2Ph), 2.87 (s, 2H, OCH2-CH2).
HRMS: calcd for C18H16FNO3 [M + H]+ 314.1114, found 314.1187.
4.1.2.7. 7-{2-[(3,4-difluorobenzyl)amino]ethoxy}-2H-chromen-2-one (3g)
The general procedure described for 3a-u was used, starting from 2a,
3,4-difluorobenzylamine, powdered K2CO3 and KI, and 3g was obtained as a Yellow
1
oil (yield 78%); H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J = 9.6 Hz, 1H,
H4-coumarin), 7.60 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.46-7.25 (m, 2H, Ph-H), 7.18
(dd, J = 4.3, 2.1 Hz, 1H, Ph-H), 7.05-6.86 (m, 2H, H8+ H7-coumarin), 6.27 (d, J =
9.6 Hz, 1H, H3-coumarin), 4.13 (t, J = 5.6 Hz, 2H, O-CH2-), 3.75 (s, 2H, CH2Ph),
2.85 (t, J = 5.6 Hz, 2H, OCH2-CH2). HRMS: calcd for C18H15F2NO3 [M + H]+
332.1020, found 332.1093.
4.1.2.8. 7-[3-(benzylamino)propoxy]-2H-chromen-2-one (3h)
The general procedure described for 3a-u was used, starting from 2b,
benzylamine, powdered K2CO3 and KI, and 3h was obtained as a Yellow oil (yield
91%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61
(d, J = 8.6 Hz, 1H, H5-coumarin), 7.33-7.27 (m, 4H, Ph-H), 7.21 (d, J = 6.8 Hz, 1H,
Ph-H), 6.97 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.93 (dd, J = 8.6, 2.4 Hz, 1H,
H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.15 (t, J = 6.4 Hz, 2H,
O-CH2-), 3.70 (s, 2H, CH2Ph), 2.64 (t, J = 6.9 Hz, 2H, O(CH2)2-CH2), 1.89 (p, J = 6.6
Hz, 2H, OCH2-CH2). HRMS: calcd for C19H19NO3 [M + H]+ 310.1365, found
310.1438.
4.1.2.9. 7-{3-[(4-methylbenzyl)amino]propoxy}-2H-chromen-2-one (3i)
The general procedure described for 3a-u was used, starting from 2b,
4-methylbenzylamine, powdered K2CO3 and KI, and 3i was obtained as a Yellow oil
(yield 89%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.20 (d, J = 7.7 Hz, 2H, Ph-H), 7.09 (d, J =
7.7 Hz, 2H, Ph-H), 6.96 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz,

ACCEPTED MANUSCRIPT
1H, H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.14 (t, J = 6.4 Hz, 2H,
O-CH2-), 3.65 (s, 2H, CH2Ph), 2.63 (t, J = 6.8 Hz, 2H, O(CH2)2-CH2), 2.26 (s, 3H,
CH3), 1.88 (p, J = 6.6 Hz, 2H, OCH2-CH2). HRMS: calcd for C20H21NO3 [M + H]+
324.1521, found 324.1594.
4.1.2.10. 7-{3-[(4-isopropylbenzyl)amino]propoxy}-2H-chromen-2-one (3j)
The general procedure described for 3a-u was used, starting from 2b,
4-isopropylbenzylamine, powdered K2CO3 and KI, and 3j was obtained as a Yellow
1
oil (yield 88%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.4 Hz, 1H,
H4-coumarin), 7.60 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.22 (d, J = 8.0 Hz, 2H，Ph-H),
7.14 (d, J = 7.8 Hz, 2H, Ph-H), 6.96 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.92 (dd, J =
8.6, 2.4 Hz, 1H, H7-coumarin), 6.27 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.14 (t, J = 6.4
Hz, 2H, O-CH2-), 3.65 (s, 2H, CH2Ph), 2.85-2.81 (m, 1H, CH), 2.63 (t, J = 6.8 Hz,
2H，O(CH2)2-CH2), 1.88 (p, J = 6.7 Hz, 2H, OCH2-CH2), 1.17 (d, J = 6.9 Hz, 6H, 2×
CH3). HRMS: calcd for C22H25NO3 [M + H]+ 352.1834, found 352.1907.
4.1.2.11. 7-{3-[(4-methoxybenzyl)amino]propoxy}-2H-chromen-2-one (3k)
The general procedure described for 3a-u was used, starting from 2b,
4-methoxybenzylamine, powdered K2CO3 and KI, and 3k was obtained as a Yellow
1
oil (yield 89%); H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.60 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.25-7.20 (m, 2H, Ph-H), 6.95
(d, J = 2.4 Hz, 1H, H8-coumarin), 6.91 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.84
(d, J = 8.6 Hz, 2H, Ph-H), 6.27 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.13 (t, J = 6.4 Hz,
2H, O-CH2-), 3.71 (s, 3H, OCH3), 3.62 (s, 2H, CH2Ph), 2.61 (t, J = 6.8 Hz, 2H,
O(CH2)2-CH2), 1.90-1.82 (m, 2H, OCH2-CH2). HRMS: calcd for C20H21NO4 [M +
H]+ 340.1471, found 340.1543.
4.1.2.12. 7-{3-[(3-methoxybenzyl)amino]propoxy}-2H-chromen-2-one (3l)
The general procedure described for 3a-u was used, starting from 2b,
3-methoxybenzylamine, powdered K2CO3 and KI, and 3l was obtained as a Yellow
1
oil (yield 82%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.19 (t, J = 7.8 Hz, 1H, Ph-H),
6.97 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.95-6.90 (m, 2H, Ph-H), 6.89 (d, J = 7.6 Hz,

ACCEPTED MANUSCRIPT
1H, Ph-H), 6.77 (dd, J = 8.2, 2.6 Hz, 1H, H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H,
H3-coumarin), 4.15 (t, J = 6.4 Hz, 2H, O-CH2-), 3.72 (s, 3H, OCH3), 3.67 (s, 2H,
CH2Ph), 2.63 (t, J = 6.8 Hz, 2H, O(CH2)2-CH2), 2.31 (s, 1H, NH), 1.89 (t, J = 6.6 Hz,
2H, OCH2-CH2). HRMS: calcd for C20H21NO4 [M + H]+ 340.1471, found 340.1543.
4.1.2.13. 7-{3-[(3-fluorobenzyl)amino]propoxy}-2H-chromen-2-one (3m)
The general procedure described for 3a-u was used, starting from 2b,
3-fluorobenzylamine, powdered K2CO3 and KI, and 3m was obtained as a Yellow oil
(yield 91%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.60 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.32 (q, J = 7.4 Hz, 1H, Ph-H), 7.19-7.12 (m,
2H, Ph-H), 7.01 (td, J = 8.9, 2.2 Hz, 1H, Ph-H), 6.96 (d, J = 2.3 Hz, 1H H8-coumarin),
6.92 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.27 (d, J = 9.4 Hz, 1H, H3-coumarin),
4.14 (t, J = 6.4 Hz, 2H, O-CH2-), 3.71 (s, 2H, CH2Ph), 2.62 (t, J = 6.7 Hz, 2H,
O(CH2)2-CH2), 2.32 (s, 1H, NH), 1.89 (p, J = 6.6 Hz, 2H, OCH2-CH2). HRMS: calcd
for C19H18FNO3 [M + H]+ 328.1271, found 328.1343.
4.1.2.14. 7-{3-[(3,4-difluorobenzyl)amino]propoxy}-2H-chromen-2-one (3n)
The general procedure described for 3a-u was used, starting from 2b,
3,4-difluorobenzylamine, powdered K2CO3 and KI, and 3n was obtained as a Yellow
1
oil (yield 93%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.39-7.28 (m, 2H, Ph-H), 7.15
(dd, J = 8.3, 4.9 Hz, 1H, Ph-H), 6.96 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.91 (dd, J =
8.6, 2.4 Hz, 1H, H7-coumarin), 6.27 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.14 (t, J = 6.4
Hz, 2H, O-CH2-), 3.68 (s, 2H, CH2Ph), 2.61 (t, J = 6.8 Hz, 2H, O(CH2)2-CH2), 2.31 (s,
1H, NH), 1.88 (t, J = 6.5 Hz, 2H, OCH2-CH2). HRMS: calcd for C19H17F2NO3 [M +
H]+ 346.1176, found 346.1249.
4.1.2.15. 7-[4-(benzylamino)butoxy]-2H-chromen-2-one (3o)
The general procedure described for 3a-u was used, starting from 2c,
benzylamine, powdered K2CO3 and KI, and 3o was obtained as a Yellow oil (yield
95%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61
(d, J = 8.6 Hz, 1H, H5-coumarin), 7.34-7.26 (m, 4H, Ph-H), 7.23-7.17 (m, 1H, Ph-H),
6.96 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin),

ACCEPTED MANUSCRIPT
6.27 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.07 (t, J = 6.5 Hz, 2H, O-CH2-), 3.68 (s, 2H,
CH2Ph), 2.53 (t, J = 7.0 Hz, 2H, O(CH2)3-CH2), 2.12 (s, 1H, NH), 1.77 (p, J = 6.7 Hz,
2H, OCH2-CH2), 1.57 (p, J = 7.2 Hz, 2H, O(CH2)2-CH2). HRMS: calcd for
C20H21NO3 [M + H]+ 324.1521, found 324.1594.
4.1.2.16. 7-{4-[(4-methylbenzyl)amino]butoxy}-2H-chromen-2-one (3p)
The general procedure described for 3a-u was used, starting from 2c,
4-methylbenzylamine, powdered K2CO3 and KI, and 3p was obtained as a Yellow oil
(yield 94%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.19 (d, J = 7.7 Hz, 2H, Ph-H), 7.09 (d, J =
7.7 Hz, 2H, Ph-H), 6.95 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz,
1H, H7-coumarin), 6.27 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.06 (t, J = 6.5 Hz, 2H,
O-CH2-), 3.63 (s, 2H, CH2Ph), 2.52 (d, J = 7.0 Hz, 2H, O(CH2)3-CH2), 2.26 (s, 3H,
CH3), 1.83-1.70 (m, 2H, OCH2-CH2), 1.60-1.50 (m, 2H, O(CH2)2-CH2). HRMS: calcd
for C21H23NO3 [M + H]+ 338.1678, found 338.1751.
4.1.2.17. 7-{4-[(4-isopropylbenzyl)amino]butoxy}-2H-chromen-2-one (3q)
The general procedure described for 3a-u was used, starting from 2c,
4-isopropylbenzylamine, powdered K2CO3 and KI, and 3q was obtained as a Yellow
1
oil (yield 94%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.22 (d, J = 7.6 Hz, 2H, Ph-H),
7.14 (d, J = 7.9 Hz, 2H, Ph-H), 6.96 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.93 (s, 1H,
H7-coumarin), 6.27 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.06 (t, J = 6.5 Hz, 2H,
O-CH2-), 3.63 (s, 2H, CH2Ph), 2.84 (d, J = 6.8 Hz, 1H, CH), 2.53 (t, J = 7.0 Hz, 2H,
O(CH2)3-CH2), 1.77 (p, J = 6.8 Hz, 2H, OCH2-CH2), 1.56 (q, J = 7.1 Hz, 2H,
O(CH2)2-CH2), 1.17 (d, J = 6.9 Hz, 6H, 2×CH3). HRMS: calcd for C23H27NO3 [M +
H]+ 366.1991, found 366.2064.
4.1.2.18. 7-{4-[(4-methoxybenzyl)amino]butoxy}-2H-chromen-2-one (3r)
The general procedure described for 3a-u was used, starting from 2c,
4-methoxybenzylamine, powdered K2CO3 and KI, and 3r was obtained as a Yellow
1
oil (yield 87%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.23 (d, J = 8.6 Hz, 2H, Ph-H),

ACCEPTED MANUSCRIPT
6.96 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin),
6.85 (d, J = 8.6 Hz, 2H, Ph-H), 6.28 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.06 (t, J = 6.5
Hz, 2H, O-CH2-), 3.72 (s, 3H, OCH3), 3.62 (s, 2H, CH2Ph), 2.53 (d, J = 7.0 Hz, 2H,
O(CH2)3-CH2), 1.77 (p, J = 6.7 Hz, 2H, OCH2-CH2), 1.57 (p, J = 7.1 Hz, 2H,
O(CH2)2-CH2). HRMS: calcd for C21H23NO4 [M + H]+ 354.1627, found 354.1700.
4.1.2.19. 7-{4-[(3-methoxybenzyl)amino]butoxy}-2H-chromen-2-one (3s)
The general procedure described for 3a-u was used, starting from 2c,
3-methoxybenzylamine, powdered K2CO3 and KI, and 3s was obtained as a Yellow
1
oil (yield 89%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H,
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.19 (t, J = 7.8 Hz, 1H, Ph-H),
6.95 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.94-6.89 (m, 2H, Ph-H), 6.88 (d, J = 7.6 Hz,
1H), 6.76 (dd, J = 8.2, 2.6 Hz, 1H, H7-coumarin), 6.27 (d, J = 9.5 Hz, 1H,
H3-coumarin), 4.07 (t, J = 6.5 Hz, 2H, O-CH2-), 3.72 (s, 3H, OCH3), 3.66 (s, 2H,
CH2Ph), 2.53 (t, J = 7.0 Hz, 2H, O(CH2)3-CH2), 2.28 (s, 1H, NH), 1.77 (p, J = 6.7 Hz,
2H, OCH2-CH2), 1.57 (p, J = 7.2 Hz, 2H, O(CH2)2-CH2). HRMS: calcd for
C21H23NO4 [M + H]+ 354.1627, found 354.1700.
4.1.2.20. 7-{4-[(3-fluorobenzyl)amino]butoxy}-2H-chromen-2-one (3t)
The general procedure described for 3a-u was used, starting from 2c,
3-fluorobenzylamine, powdered K2CO3 and KI, and 3t was obtained as a Yellow oil
(yield 93%); 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.60 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.36-7.29 (m, 1H, Ph-H), 7.19-7.11 (m, 2H,
Ph-H), 7.04-6.98 (m, 1H, Ph-H), 6.96 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.92 (dd, J =
8.6, 2.4 Hz, 1H, H7-coumarin), 6.27 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.07 (t, J = 6.5
Hz, 2H, O-CH2-), 3.70 (s, 2H, CH2Ph), 2.53 (t, J = 7.1 Hz, 2H, O(CH2)3-CH2), 2.32 (s,
1H, NH), 1.77 (p, J = 6.7 Hz, 2H, OCH2-CH2), 1.57 (p, J = 7.2 Hz, 2H，
O(CH2)2-CH2). HRMS: calcd for C20H20FNO3 [M + H]+ 342.1427, found 342.1500.
4.1.2.21. 7-{4-[(3,4-difluorobenzyl)amino]butoxy}-2H-chromen-2-one (3u)
The general procedure described for 3a-u was used, starting from 2c,
3,4-difluorobenzylamine, powdered K2CO3 and KI, and 3u was obtained as a Yellow

ACCEPTED MANUSCRIPT
1
oil (yield 90%); H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.6 Hz, 1H，
H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.37-7.30 (m, 2H, Ph-H), 7.16
(s, 1H, Ph-H), 7.01-6.90 (m, 2H，H7+H8-coumarin), 6.28 (d, J = 9.4 Hz, 1H，
H3-coumarin), 4.07 (t, J = 6.5 Hz, 2H, O-CH2-), 3.67 (s, 2H, CH2Ph), 2.52 (s, 2H,
O(CH2)3-CH2), 2.44 (s, 1H, NH), 1.78 (p, J = 6.7 Hz, 2H, OCH2-CH2), 1.57 (p, J =
7.1 Hz, 2H, O(CH2)2-CH2). HRMS: calcd for C20H19F2NO3 [M + H]+ 360.1333, found
360.1406.
4.1.3. General procedures for the preparation of compounds 4a-u.
To a solution of compound 3a-u (1 mmol), powdered K2CO3 (1.1 mmol) and a
catalytic amount of KI in acetonitrile (15 mL), 3-bromopropyne (1.1 mmol) was
added. The reaction mixture was heated for 1-2 hours at 65 °C. Upon completion,
K2CO3was removed by filtration and the solvent was concentrated under vacuum, the
residue was purified on silica gel chromatography with petroleum ether/ethyl acetate
(10:1, v/v) as elution solvent to give the desired product 4a-u [39].
4.1.3.1. 7-{2-[benzyl(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one (4a)
The general procedure described for 4a-u was used, starting from 3a, powdered
K2CO3, 3-bromopropyne and KI, and 4a was obtained as a Yellow solid (yield 56%);
m.p. 102-104 °C; IR (KBr) ν 3214, 2920, 1727, 1610, 1508, 1283, 1130, 1031, 845
cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H，H4-coumarin), 7.62
(d, J = 8.6 Hz, 1H, H5-coumarin), 7.36-7.29 (m, 4H, Ph-H), 7.29-7.20 (m, 1H, Ph-H),
7.00 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.94 (d, J = 8.6 Hz, 1H, H7-coumarin), 6.29
(d, J = 9.5 Hz, 1H, H3-coumarin), 4.21 (t, J = 5.8 Hz, 2H, O-CH2-), 3.70 (s, 2H,
CH2Ph), 3.40 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.22 (s, 1H, C≡CH), 2.88 (t, J = 5.8 Hz,
2H, OCH2-CH2). 13C NMR (125 MHz, DMSO-d6) δ 162.08 (C2-coumarin), 160.77
(C7-coumarin), 155.84 (C8a-coumarin), 144.80 (C4-coumarin), 138.93 (C-Ph),
129.92 (C4a-coumarin), 129.19 (2×CH-Ph), 128.69 (2×CH-Ph), 127.55 (CH-Ph),
113.27 (C3-coumarin), 112.91 (C5-coumarin), 112.80 (C6-coumarin), 101.68
(C8-coumarin), 79.26 (-C≡), 76.61 (≡CH), 67.09 (O-CH2-), 57.98 (N-CH2-), 51.59
(OCH2-CH2), 42.34 (CH2-C≡). HRMS: calcd for C21H19NO3 [M + H]+ 334.1365,
found 334.1438.

ACCEPTED MANUSCRIPT
4.1.3.2. 7-{2-[(4-methylbenzyl)(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one (4b)
The general procedure described for 4a-u was used, starting from 3b, powdered
K2CO3, 3-bromopropyne and KI, and 4b was obtained as a Yellow solid (yield 84%);
m.p. 71-73 °C; IR (KBr) ν 3281, 2921, 1726, 1626, 1510, 1294, 1129, 1043, 829 cm-1;
1H NMR (500 MHz, DMSO-d6) δ 8.00 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.62 (d, J =
8.6 Hz, 1H, H5-coumarin), 7.25-7.09 (m, 4H, Ph-H), 6.99 (d, J = 2.4 Hz, 1H,
H8-coumarin), 6.94 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.30 (d, J = 9.5 Hz, 1H,
H3-coumarin), 4.20 (t, J = 5.9 Hz, 2H, O-CH2-), 3.65 (s, 2H, CH2Ph), 3.40 (d, J = 2.4
Hz, 2H, CH2-C≡), 3.20 (t, J = 2.3 Hz, 1H, C≡CH), 2.87 (t, J = 5.9 Hz, 2H,
OCH2-CH2), 2.28 (s, 3H, CH3). 13C NMR (125 MHz, DMSO-d6) δ 162.07
(C2-coumarin), 160.77 (C7-coumarin), 155.84(C8a-coumarin), 144.81(C4-coumarin),
136.59 (C-Ph), 135.79 (C-Ph), 129.91 (C4a-coumarin), 129.25 (2×CH-Ph), 129.18 (2
×CH-Ph), 113.29 (C3-coumarin), 112.90 (C5-coumarin), 112.79 (C6-coumarin),
101.67 (C8-coumarin), 79.30 (-C≡), 76.57 (≡CH), 67.08 (O-CH2-), 57.71 (N-CH2-),
51.45 (OCH2-CH2), 42.26 (CH2-C≡), 21.17 (CH3). HRMS: calcd for C22H21NO3 [M +
H]+ 348.1521, found 348.1594.
4.1.3.3. 7-{2-[(4-isopropylbenzyl)(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one
(4c)
The general procedure described for 4a-u was used, starting from 3c, powdered
K2CO3, 3-bromopropyne and KI, and 4c was obtained as a Yellow solid (yield 51%);
m.p. 58-59 °C; IR (KBr) ν 3246, 2959, 1706, 1626, 1509, 1298, 1133, 1030, 829 cm-1;
1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61 (d, J =
8.6 Hz, 1H, H5-coumarin), 7.26-7.12 (m, 4H, Ph-H), 6.98 (d, J = 2.4 Hz, 1H,
H8-coumarin), 6.93 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H,
H3-coumarin), 4.19 (t, J = 5.8 Hz, 2H, O-CH2-), 3.65 (s, 2H, CH2Ph), 3.40 (d, J = 2.4
Hz, 2H, CH2-C≡), 3.19 (s, 1H, C≡CH), 2.91-2.79 (m, 3H, OCH2-CH2+CH), 1.17 (d, J
= 6.9 Hz, 6H, 2×CH3). 13C NMR (125 MHz, DMSO-d6) δ 162.06 (C2-coumarin),
160.76 (C7-coumarin), 155.83 (C8a-coumarin), 147.59 (C-Ph), 144.81(C4-coumarin),
136.25 (C-Ph), 129.91 (C4a-coumarin), 129.12 (2×CH-Ph), 126.56 (2×CH-Ph),
113.30 (C3-coumarin), 112.89 (C5-coumarin), 112.79 (C6-coumarin), 101.67

ACCEPTED MANUSCRIPT
(C8-coumarin), 79.31 (-C≡), 76.59 (≡CH), 67.05 (O-CH2-), 57.77 (N-CH2-), 51.47
(OCH2-CH2), 42.39 (CH2-C≡), 33.55 (CH), 24.37 (2×CH3). HRMS: calcd for
C24H25NO3 [M + H]+ 376.1834, found 376.1907.
4.1.3.4. 7-{2-[(4-methoxybenzyl)(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one
(4d)
The general procedure described for 4a-u was used, starting from 3d, powdered
K2CO3, 3-bromopropyne and KI, and 4d was obtained as a Light yellow solid (yield
49%); m.p. 79-81 °C; IR (KBr) ν 3307, 2836, 1721, 1615, 1510, 1240, 1127, 1035,
835 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.22 (d, J = 8.5 Hz, 2H, Ph-H), 6.99 (d, J =
2.4 Hz, 1H, H8-coumarin), 6.93 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.87 (d, J =
8.6 Hz, 2H, Ph-H), 6.29 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.19 (t, J = 5.9 Hz, 2H,
O-CH2-), 3.72 (s, 3H, OCH3), 3.61 (s, 2H, CH2Ph), 3.38 (d, J = 2.4 Hz, 2H, CH2-C≡),
3.19 (s, 1H, C≡CH), 2.86 (t, J = 5.9 Hz, 2H, OCH2-CH2). 13C NMR (125 MHz,
DMSO-d6) δ 162.07 (C2-coumarin), 160.77 (C7-coumarin), 158.81 (C-Ph), 155.84
(C8a-coumarin), 144.81(C4-coumarin), 130.65 (C-Ph), 130.41 (2×CH-Ph), 129.91
(C4a-coumarin), 114.06 (2×CH-Ph), 113.28 (C3-coumarin), 112.90 (C5-coumarin),
112.79 (C6-coumarin), 101.69 (C8-coumarin), 79.32 (-C≡), 76.56 (≡CH), 67.10
(O-CH2-), 57.35 (N-CH2-), 55.45 (OCH3), 51.37 (OCH2-CH2), 42.16 (CH2-C≡).
HRMS: calcd for C22H21NO4 [M + H]+ 364.1471, found 364.1543.
4.1.3.5.
7-{2-[(3-methoxybenzyl)(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one
(4e)
The general procedure described for 4a-u was used, starting from 3e, powdered
K2CO3, 3-bromopropyne and KI, and 4e was obtained as a Light yellow solid (yield
62%); m.p. 73-74 °C; IR (KBr) ν 3251, 2954, 1713, 1602, 1485, 1272, 1131, 1038,
837 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.4 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.22 (dd, J = 8.6, 7.1 Hz, 1H, Ph-H), 6.99 (d, J
= 2.4 Hz, 1H, H8-coumarin), 6.94 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.92-6.86
(m, 2H, Ph-H), 6.81 (dt, J = 8.2, 2.0 Hz, 1H, Ph-H), 6.29 (d, J = 9.4 Hz, 1H,
H3-coumarin), 4.20 (t, J = 5.8 Hz, 2H, O-CH2-), 3.72 (s, 3H, OCH3), 3.67 (s, 2H,

ACCEPTED MANUSCRIPT
CH2Ph), 3.42 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.20 (s, 1H, C≡CH), 2.88 (t, J = 5.8 Hz,
13
2H, OCH2-CH2). C NMR (125 MHz, DMSO-d6) δ 162.09 (C2-coumarin), 160.77
(C7-coumarin), 159.72 (C-Ph), 155.84 (C8a-coumarin), 144.81 (C4-coumarin),
140.62 (C-Ph), 129.92 (C4a-coumarin), 129.71 (CH-Ph), 121.31 (CH-Ph), 114.58
(CH-Ph), 113.25 (C3-coumarin), 112.94 (CH-Ph), 112.91 (C5-coumarin), 112.80
(C6-coumarin), 101.69 (C8-coumarin), 79.31 (-C≡), 76.62 (≡CH), 67.07 (O-CH2-),
57.98 (N-CH2-), 55.37 (OCH3), 51.54 (OCH2-CH2), 42.47 (CH2-C≡). HRMS: calcd
for C22H21NO4 [M + H]+ 364.1471, found 364.1543.
4.1.3.6. 7-{2-[(3-fluorobenzyl)(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one (4f)
The general procedure described for 4a-u was used, starting from 3f, powdered
K2CO3, 3-bromopropyne and KI, and 4f was obtained as a Light yellow solid (yield
55%); m.p. 58-59 °C; IR (KBr) ν 3267, 2927, 1713, 1625, 1509, 1292, 1133, 1044,
831 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.4 Hz, 1H, H4-coumarin),
7.62 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.35 (td, J = 7.9, 6.2 Hz, 1H, Ph-H), 7.22-7.11
(m, 2H, Ph-H), 7.11-7.02 (m, 1H, Ph-H), 6.99 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.94
(dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.29 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.21
(t, J = 5.7 Hz, 2H, O-CH2-), 3.72 (s, 2H, CH2Ph), 3.44 (d, J = 2.4 Hz, 2H, CH2-C≡),
3.22 (s, 1H, C≡CH), 2.88 (t, J = 5.7 Hz, 2H, OCH2-CH2). 13C NMR (125 MHz,
DMSO-d6) δ 163.51 (C-Ph), 162.06 (C2-coumarin), 161.90 (C-Ph), 160.77
(C7-coumarin), 155.84 (C8a-coumarin), 144.81 (C4-coumarin), 142.20 (CH-Ph),
130.59 (CH-Ph), 129.92 (C4a-coumarin), 125.01 (CH-Ph), 115.61 (CH-Ph), 114.37
(C6-coumarin), 113.24(C3-coumarin), 112.91 (C5-coumarin), 101.67 (C8-coumarin),
79.24 (-C≡), 76.67 (≡CH), 66.94 (O-CH2-), 57.40 (N-CH2-), 51.58 (OCH2-CH2),
42.51 (CH2-C≡). HRMS: calcd for C21H18FNO3 [M + H]+ 352.1271, found 352.1343.
4.1.3.7.
7-{2-[(3,4-difluorobenzyl)(prop-2-yn-1-yl)amino]ethoxy}-2H-chromen-2-one(4g)
The general procedure described for 4a-u was used, starting from 3g, powdered
K2CO3, 3-bromopropyne and KI, and 4g was obtained as a Light yellow solid (yield
61%); m.p. 75-76 °C; IR (KBr) ν 3297, 2827, 1721, 1612, 1516, 1284, 1131, 1027,
839 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),

ACCEPTED MANUSCRIPT
7.62 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.40-7.30 (m, 2H, Ph-H), 7.18 (d, J = 4.2 Hz,
1H, Ph-H), 6.98 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.94 (d, J = 8.6 Hz, 1H,
H7-coumarin), 6.29 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.21 (t, J = 5.7 Hz, 2H,
O-CH2-), 3.70 (s, 2H, CH2Ph), 3.45 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.22 (s, 1H, C≡CH),
2.89 (t, J = 5.7 Hz, 2H, OCH2-CH2). 13C NMR (125 MHz, DMSO-d6) δ 162.01
(C2-coumarin), 160.75 (C7-coumarin), 155.81 (C8a-coumarin), 150.61 (C-Ph),
149.77 (C-Ph), 148.99 (CH-Ph), 148.15 (CH-Ph), 144.76 (C4-coumarin), 137.02
(C-Ph), 129.88 (C4a-coumarin), 125.52 (CH-Ph), 117.58 (C6-coumarin), 113.20
(C3-coumarin), 112.89 (C5-coumarin), 101.64 (C8-coumarin), 79.21 (-C≡), 76.64
(≡CH), 66.85 (O-CH2-), 56.86 (N-CH2-), 51.44 (OCH2-CH2), 42.49 (CH2-C≡).
HRMS: calcd for C21H17F2NO3 [M + H]+ 370.1176, found 370.1249.
4.1.3.8. 7-{3-[benzyl(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one (4h)
The general procedure described for 4a-u was used, starting from 3h, powdered
K2CO3, 3-bromopropyne and KI, and 4h was obtained as a Light yellow solid (yield
78%); m.p. 80-82 °C; IR (KBr) ν 3240, 2919, 1721, 1611, 1465, 1281, 1119, 1048,
842 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.31-7.25 (m, 4H, Ph-H), 7.23 (s, 1H, Ph-H),
6.94 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.89 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin),
6.29 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.11 (t, J = 6.2 Hz, 2H, O-CH2-), 3.60 (s, 2H,
CH2Ph), 3.32 (d, J = 2.4 Hz, 2H，CH2-C≡), 3.17 (t, J = 2.3 Hz, 1H, C≡CH), 2.63 (t, J
13
= 6.9 Hz, 2H, O(CH2)2-CH2), 1.91 (t, J = 6.6 Hz, 2H, OCH2-CH2). C NMR (125
MHz, DMSO-d6) δ 162.29 (C2-coumarin), 160.79 (C7-coumarin), 155.85
(C8a-coumarin), 144.83 (C4-coumarin), 139.11 (C-Ph), 129.92 (C4a-coumarin),
129.11 (2×CH-Ph), 128.65 (2×CH-Ph), 127.45 (CH-Ph), 113.16 (C3-coumarin),
112.85 (C5-coumarin), 112.73 (C6-coumarin), 101.59 (C8-coumarin), 79.09 (-C≡),
76.50 (≡CH), 66.86 (O-CH2-), 57.77 (N-CH2-), 49.36 (O(CH2)2-CH2), 41.59
(CH2-C≡), 26.91 (OCH2-CH2). HRMS: calcd for C22H21NO3 [M + H]+ 348.1521,
found 348.1594.
4.1.3.9. 7-{3-[(4-methylbenzyl)(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one
(4i)

ACCEPTED MANUSCRIPT
The general procedure described for 4a-u was used, starting from 3i, powdered
K2CO3, 3-bromopropyne and KI, and 4i was obtained as a Light yellow solid (yield
72%); m.p. 71-73 °C; IR (KBr) ν 3263, 2918, 1707, 1627, 1511, 1299, 1140, 1049,
837 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.15 (d, J = 7.7 Hz, 2H, Ph-H), 7.05 (d, J =
7.7 Hz, 2H, Ph-H), 6.90 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.88 (d, J = 8.6 Hz, 1H,
H3-coumarin), 6.28 (d, J = 9.5 Hz, 1H，H7-coumarin), 4.08 (t, J = 6.3 Hz, 2H,
O-CH2-), 3.54 (s, 2H, CH2Ph), 3.30 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.15 (s, 1H, C≡CH),
2.59 (d, J = 6.8 Hz, 2H, O(CH2)2-CH2), 2.23 (s, 3H, CH3), 1.89 (t, J = 6.5 Hz, 2H,
OCH2-CH2). 13C NMR (125 MHz, DMSO-d6) δ 162.30 (C2-coumarin), 160.79
(C7-coumarin), 155.84 (C8a-coumarin), 144.84 (C4-coumarin), 136.44 (C-Ph),
135.99 (C-Ph), 129.88 (C4a-coumarin), 129.20 (2×CH-Ph), 129.11 (2×CH-Ph),
113.12 (C3-coumarin), 112.83 (C5-coumarin), 112.70 (C6-coumarin), 101.59
(C8-coumarin), 79.18 (-C≡), 76.41 (≡CH), 66.81 (O-CH2-), 57.53 (N-CH2-), 49.14
(O(CH2)2-CH2), 41.59 (CH2-C≡), 26.90 (OCH2-CH2), 21.15 (CH3). HRMS: calcd for
C23H23NO3 [M + H]+ 362.1678, found 362.1751.
4.1.3.10.
7-{3-[(4-isopropylbenzyl)(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one (4j)
The general procedure described for 4a-u was used, starting from 3j, powdered
K2CO3, 3-bromopropyne and KI, and 4j was obtained as a Yellow solid (yield 69%);
m.p. 77-78 °C; IR (KBr) ν 3258, 2960, 1720, 1624, 1511, 1296, 1139, 1047, 838 cm-1;
1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61 (d, J =
8.6 Hz, 1H, H5-coumarin), 7.19 (d, J = 7.9 Hz, 2H, Ph-H), 7.12 (d, J = 7.9 Hz, 2H,
Ph-H), 6.92 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.89 (dd, J = 8.5, 2.4 Hz, 1H,
H3-coumarin), 6.29 (d, J = 9.5 Hz, 1H, H7-coumarin), 4.10 (t, J = 6.2 Hz, 2H,
O-CH2-), 3.56 (s, 2H, CH2Ph), 3.32 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.15 (s, 1H，C≡CH),
2.82 (p, J = 6.9 Hz, 1H, CH), 2.62 (t, J = 6.8 Hz, 2H，O(CH2)2-CH2), 1.91 (p, J = 6.5
Hz, 2H，OCH2-CH2), 1.16 (d, J = 6.9 Hz, 6H, 2×CH3). 13C NMR (125 MHz,
DMSO-d6) δ 162.30 (C2-coumarin), 160.77 (C7-coumarin), 155.84 (C8a-coumarin),
147.45 (C-Ph), 144.80 (C4-coumarin), 136.40 (C-Ph), 129.88 (C4a-coumarin), 129.07

ACCEPTED MANUSCRIPT
(2×CH-Ph), 126.51 (2×CH-Ph), 113.08 (C3-coumarin), 112.83 (C5-coumarin),
112.71 (C6-coumarin), 101.59 (C8-coumarin), 79.13 (-C≡), 76.43 (≡CH), 66.77
(O-CH2-), 57.54 (N-CH2-), 49.13 (O(CH2)2-CH2), 41.57 (CH2-C≡), 33.52(CH), 26.88
(OCH2-CH2), 24.33 (2×CH3). HRMS: calcd for C25H27NO3 [M + H]+ 390.1991,
found 390.2064.
4.1.3.11.
7-{3-[(4-methoxybenzyl)(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one (4k)
The general procedure described for 4a-u was used, starting from 3k, powdered
K2CO3, 3-bromopropyne and KI, and 4k was obtained as a Yellow solid (yield 75%);
m.p. 82-84 °C; IR (KBr) ν 3258, 2949, 1710, 1631, 1510, 1301, 1147, 1031, 836 cm-1;
1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61 (d, J =
8.5 Hz, 1H, H5-coumarin), 7.19 (d, J = 8.5 Hz, 2H, Ph-H), 6.91 (d, J = 2.3 Hz, 1H,
H8-coumarin), 6.89 (d, J = 8.5 Hz, 1H, H7-coumarin), 6.82 (d, J = 8.5 Hz, 2H, Ph-H),
6.29 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.09 (t, J = 6.2 Hz, 2H, O-CH2-), 3.70 (s, 3H,
OCH3), 3.53 (s, 2H, CH2Ph), 3.30 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.15 (d, J = 2.3 Hz,
1H, C≡CH), 2.61 (t, J = 6.8 Hz, 2H, O(CH2)2-CH2), 1.90 (p, J = 6.6 Hz, 2H,
OCH2-CH2). 13C NMR (125 MHz, DMSO-d6) δ 162.29 (C2-coumarin), 160.79
(C7-coumarin), 158.72 (C-Ph), 155.83 (C8a-coumarin), 144.80 (C4-coumarin),
130.84 (C-Ph), 130.32 (2×CH-Ph), 129.86 (C4a-coumarin), 113.97 (2×CH-Ph),
113.08 (C3-coumarin), 112.82 (C5-coumarin), 112.71 (C6-coumarin), 101.56
(C8-coumarin), 79.19 (-C≡), 76.37 (≡CH), 66.80 (O-CH2-), 57.16 (N-CH2-), 55.36
(OCH3), 49.04 (O(CH2)2-CH2), 41.47 (CH2-C≡), 26.91 (OCH2-CH2). HRMS: calcd
for C23H23NO4 [M + H]+ 378.1627, found 378.1700.
4.1.3.12.
7-{3-[(3-methoxybenzyl)(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one (4l)
The general procedure described for 4a-u was used, starting from 3l, powdered
K2CO3, 3-bromopropyne and KI, and 4l was obtained as a Light yellow solid (yield
83%); m.p. 65-67 °C; IR (KBr) ν 3264, 2941, 1707, 1629, 1487, 1296, 1140, 1042,
840 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.60 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.19 (t, J = 7.8 Hz, 1H, Ph-H), 6.92 (d, J = 2.4

ACCEPTED MANUSCRIPT
Hz, 1H, H8-coumarin), 6.90 – 6.82 (m, 3H, Ph-H), 6.78 (dd, J = 8.2, 2.5 Hz, 1H,
H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.10 (t, J = 6.2 Hz, 2H,
O-CH2-), 3.69 (s, 3H, OCH3), 3.58 (s, 2H, CH2Ph), 3.34 (d, J = 2.5 Hz, 2H，CH2-C≡),
3.16 (s, 1H，C≡CH), 2.63 (t, J = 6.9 Hz, 2H，O(CH2)2-CH2), 1.91 (p, J = 6.6 Hz, 2H，
OCH2-CH2).
13C NMR (125 MHz, DMSO-d6) δ 162.29 (C2-coumarin), 160.78
(C7-coumarin), 159.68 (C-Ph), 155.84 (C8a-coumarin), 144.80 (C4-coumarin),
140.80 (C-Ph), 129.89 (C4a-coumarin), 129.65 (CH-Ph), 121.25(CH-Ph), 114.49
(CH-Ph), 113.10 (C3-coumarin), 112.86 (CH-Ph), 112.83 (C5-coumarin), 112.72
(C6-coumarin), 101.55 (C8-coumarin), 79.15 (-C≡), 76.46 (≡CH), 66.85 (O-CH2-),
57.84 (N-CH2-), 55.27 (OCH3), 49.23 (O(CH2)2-CH2), 41.69 (CH2-C≡), 26.88
(OCH2-CH2). HRMS: calcd for C23H23NO4 [M + H]+ 378.1627, found 378.1700.
4.1.3.13. 7-{3-[(3-fluorobenzyl)(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one
(4m)
The general procedure described for 4a-u was used, starting from 3m, powdered
K2CO3, 3-bromopropyne and KI, and 4m was obtained as a Light yellow solid (yield
69%); m.p. 46-48 °C; IR (KBr) ν 3269, 2920, 1708, 1629, 1486, 1297, 1139, 1050,
840 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.31 (q, J = 7.6 Hz, 1H, Ph-H), 7.13 (d, J =
7.6 Hz, 1H, Ph-H), 7.08 (d, J = 10.1 Hz, 1H, Ph-H), 7.03 (td, J = 8.7, 2.6 Hz, 1H,
Ph-H), 6.93 (d, J = 2.4 Hz, 1H, H8-coumarin), 6.88 (dd, J = 8.6, 2.4 Hz, 1H,
H7-coumarin), 6.29 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.11 (t, J = 6.2 Hz, 2H,
O-CH2-), 3.63 (s, 2H, CH2Ph), 3.35 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.19 (s, 1H, C≡CH),
2.63 (t, J = 6.8 Hz, 2H, O(CH2)2-CH2), 1.91 (p, J = 6.6 Hz, 2H, OCH2-CH2). 13C
NMR (125 MHz, DMSO-d6) δ 163.48 (C-Ph), 162.27 (C2-coumarin), 161.87 (C-Ph),
160.79 (C7-coumarin), 155.85 (C8a-coumarin), 144.82 (C4-coumarin), 142.38
(CH-Ph), 130.55 (CH-Ph), 129.90 (C4a-coumarin), 124.97 (CH-Ph), 115.54 (CH-Ph),
114.30 (C6-coumarin), 113.11 (C3-coumarin), 112.84 (C5-coumarin), 101.56
(C8-coumarin), 79.03 (-C≡), 76.57 (≡CH), 66.77 (O-CH2-), 57.31 (N-CH2-), 49.23
(O(CH2)2-CH2), 41.76 (CH2-C≡), 26.84 (OCH2-CH2). HRMS: calcd for C22H20FNO3
[M + H]+ 366.1427, found 366.1500.

ACCEPTED MANUSCRIPT
4.1.3.14.
7-{3-[(3,4-difluorobenzyl)(prop-2-yn-1-yl)amino]propoxy}-2H-chromen-2-one (4n)
The general procedure described for 4a-u was used, starting from 3n, powdered
K2CO3, 3-bromopropyne and KI, and 4n was obtained as a White solid (yield 70%);
m.p. 64-65°C; IR (KBr) ν 3253, 2950, 1704, 1625, 1517, 1296, 1138, 1048, 841 cm-1;
1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61 (d, J =
8.6 Hz, 1H, H5-coumarin), 7.35-7.20 (m, 2H, Ph-H), 7.12 (s, 1H, Ph-H), 6.91 (d, J =
2.3 Hz, 1H, H8-coumarin), 6.86 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.29 (d, J =
9.4 Hz, 1H，H3-coumarin), 4.09 (t, J = 6.1 Hz, 2H, O-CH2-), 3.59 (s, 2H, CH2Ph),
3.37 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.19 (s, 1H, C≡CH), 2.62 (t, J = 6.8 Hz, 2H,
O(CH2)2-CH2), 1.90 (p, J = 6.5 Hz, 2H, OCH2-CH2). 13C NMR (125 MHz, DMSO-d6)
δ 162.23 (C2-coumarin), 160.79 (C7-coumarin), 155.83 (C8a-coumarin), 150.59
(C-Ph), 149.72 (C-Ph), 148.96 (CH-Ph), 148.10 (CH-Ph), 144.80 (C4-coumarin),
137.19 (C-Ph), 129.85 (C4a-coumarin), 125.57 (CH-Ph), 117.61 (C6-coumarin),
113.01 (C3-coumarin), 112.81 (C5-coumarin), 101.48 (C8-coumarin), 79.05 (-C≡),
76.54 (≡CH), 66.60 (O-CH2-), 56.86 (N-CH2-), 48.83 (O(CH2)2-CH2), 41.77
(CH2-C≡), 26.77 (OCH2-CH2). HRMS: calcd for C22H19F2NO3 [M + H]+ 384.1333,
found 384.1406.
4.1.3.15. 7-{4-[benzyl(prop-2-yn-1-yl)amino]butoxy}-2H-chromen-2-one (4o)
The general procedure described for 4a-u was used, starting from 3o, powdered
K2CO3, 3-bromopropyne and KI, and 4o was obtained as a White solid (yield 81%);
m.p. 49-51°C; IR (KBr) ν 3198, 2955, 1711, 1621, 1508, 1284, 1132, 1019, 833 cm-1;
1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61 (d, J =
8.6 Hz, 1H, H5-coumarin), 7.30 (d, J = 6.6 Hz, 4H, Ph-H), 7.24 (dt, J = 6.5, 2.8 Hz,
1H, Ph-H), 6.95 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.5, 2.4 Hz, 1H,
H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H, H3-coumarin), 4.06 (t, J = 6.5 Hz, 2H,
O-CH2-), 3.58 (s, 2H, CH2Ph), 3.28 (d, J = 2.4 Hz, 2H, CH2-C≡), 3.14 (t, J = 2.3 Hz,
1H, C≡CH), 2.53 (d, J = 6.9 Hz, 2H, O(CH2)3-CH2), 1.76 (p, J = 6.6 Hz, 2H,
OCH2-CH2), 1.60 (p, J = 6.6, 6.1 Hz, 2H, O(CH2)2-CH2). 13C NMR (125 MHz,
DMSO-d6) δ 162.29 (C2-coumarin), 160.79 (C7-coumarin), 155.87 (C8a-coumarin),

ACCEPTED MANUSCRIPT
144.83 (C4-coumarin), 139.21 (C-Ph), 129.93 (C4a-coumarin), 129.14 (2×CH-Ph),
128.68 (2×CH-Ph), 127.46 (CH-Ph), 113.21 (C3-coumarin), 112.83 (C5-coumarin),
112.70 (C6-coumarin), 101.58 (C8-coumarin), 79.11 (-C≡), 76.41 (≡CH), 68.53
(O-CH2-), 57.62 (N-CH2-), 52.30 (O(CH2)3-CH2), 41.34 (CH2-C≡), 26.57
(OCH2-CH2), 23.55 (O(CH2)2-CH2). HRMS: calcd for C23H23NO3 [M + H]+ 362.1678,
found 362.1751.
4.1.3.16. 7-{4-[(4-methylbenzyl)(prop-2-yn-1-yl)amino]butoxy}-2H-chromen-2-one
(4p)
The general procedure described for 4a-u was used, starting from 3p, powdered
K2CO3, 3-bromopropyne and KI, and 4p was obtained as a Light yellow solid (yield
76%); m.p. 69-70 °C; IR (KBr) ν 3213, 2954, 1711, 1621, 1509, 1285, 1131, 1020,
835 cm-1;1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.17 (d, J = 7.8 Hz, 2H, Ph-H), 7.10 (d, J =
7.7 Hz, 2H, Ph-H), 6.95-6.90 (m, 2H, H8+H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H,
H3-coumarin), 4.04 (t, J = 6.5 Hz, 2H, O-CH2-), 3.52 (s, 2H, CH2Ph), 3.27 (d, J = 2.4
Hz, 2H, CH2-C≡), 3.13 (s, 1H, C≡CH), 2.53-2.50 (m, 2H, O(CH2)3-CH2), 2.26 (s, 3H,
CH3), 1.75 (p, J = 6.5 Hz, 2H, OCH2-CH2), 1.59 (p, J = 7.1 Hz, 2H, O(CH2)2-CH2).
13C NMR (125 MHz, DMSO-d6) δ 162.30 (C2-coumarin), 160.78 (C7-coumarin),
155.87 (C8a-coumarin), 144.82 (C4-coumarin), 136.47 (C-Ph), 136.08 (C-Ph), 129.91
(C4a-coumarin), 129.25 (2×CH-Ph), 129.12 (2×CH-Ph), 113.21 (C3-coumarin),
112.82 (C5-coumarin), 112.69 (C6-coumarin), 101.56 (C8-coumarin), 79.16 (-C≡),
76.35 (≡CH), 68.48 (O-CH2-), 57.36 (N-CH2-), 52.09 (O(CH2)3-CH2), 41.28
(CH2-C≡), 26.52 (OCH2-CH2), 23.49 (O(CH2)2-CH2), 21.16 (CH3). HRMS: calcd for
C24H25NO3 [M + H]+ 376.1834, found 376.1907.
4.1.3.17. 7-{4-[(4-isopropylbenzyl)(prop-2-yn-1-yl)amino]butoxy}-2H-chromen-2-one
(4q)
The general procedure described for 4a-u was used, starting from 3q, powdered
K2CO3, 3-bromopropyne and KI, and 4q was obtained as a Yellow solid (yield 84%);
IR (KBr) ν 3262, 2957, 1711, 1620, 1509, 1285, 1130, 1019, 834 cm-1; 1H NMR (500
MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin), 7.61 (d, J = 8.6 Hz, 1H,

ACCEPTED MANUSCRIPT
H5-coumarin), 7.19 (d, J = 8.0 Hz, 2H, (2×CH-Ph)), 7.15 (d, J = 7.8 Hz, 2H, (2×
CH-Ph)), 6.95 (d, J = 2.3 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz, 1H,
H7-coumarin), 6.28 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.06 (t, J = 6.6 Hz, 2H,
O-CH2-), 3.53 (s, 2H, CH2Ph), 3.27 (d, J = 2.3 Hz, 2H, CH2-C≡), 3.13 (t, J = 2.3 Hz,
1H, C≡CH), 2.84 (p, J = 6.9 Hz, 1H, CH), 2.52 (s, 2H, O(CH2)3-CH2), 1.77 (p, J = 6.5
Hz, 2H, OCH2-CH2), 1.60 (p, J = 7.1 Hz, 2H, O(CH2)2-CH2), 1.17 (d, J = 7.0 Hz, 6H,
2 ×CH3).
13C NMR (125 MHz, DMSO-d6) δ 162.30 (C2-coumarin), 160.77
(C7-coumarin), 155.88 (C8a-coumarin), 147.49 (C-Ph), 144.81 (C4-coumarin),
136.50 (C-Ph), 129.91 (C4a-coumarin), 129.09 (2×CH-Ph), 126.55 (2×CH-Ph),
113.23 (C3-coumarin), 112.82 (C5-coumarin), 112.69 (C6-coumarin), 101.55
(C8-coumarin), 79.14 (-C≡), 76.36 (≡CH), 68.48 (O-CH2-), 57.33 (N-CH2-), 52.16
(O(CH2)3-CH2), 41.31 (CH2-C≡), 33.54 (CH), 26.52 (OCH2-CH2), 24.35
(O(CH2)2-CH2), 23.48 (2×CH3). HRMS: calcd for C26H29NO3 [M + H]+ 404.2147,
found 404.2220.
4.1.3.18. 7-{4-[(4-methoxybenzyl)(prop-2-yn-1-yl)amino]butoxy}-2H-chromen-2-one
(4r)
The general procedure described for 4a-u was used, starting from 3r, powdered
K2CO3, 3-bromopropyne and KI, and 4r was obtained as a Light yellow solid (yield
81%); m.p. 60-61°C; IR (KBr) ν 3191, 2921, 1711, 1615, 1512, 1249, 1131, 1036,
833 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.5 Hz, 1H, H5-coumarin), 7.19 (d, J = 8.6 Hz, 2H, Ph-H), 6.94 (d, J =
2.4 Hz, 1H, H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.86 (d, J =
8.6 Hz, 2H, Ph-H), 6.28 (d, J = 9.5 Hz, 1H, H3-coumarin), 4.05 (t, J = 6.5 Hz, 2H,
O-CH2-), 3.71 (s, 3H, OCH3), 3.50 (s, 2H, CH2Ph), 3.25 (s, 2H, CH2-C≡), 3.12 (s, 1H,
C≡CH), 2.51 (s, 2H, O(CH2)3-CH2), 1.75 (p, J = 6.4 Hz, 2H, OCH2-CH2), 1.59 (p, J =
7.2 Hz, 2H, O(CH2)2-CH2). 13C NMR (125 MHz, DMSO-d6) δ 162.29 (C2-coumarin),
160.79 (C7-coumarin), 158.74 (C8a-coumarin), 155.88 (C-Ph), 144.83 (C4-coumarin),
130.93 (C-Ph), 130.35 (2×CH-Ph), 129.92 (C4a-coumarin), 114.03 (2×CH-Ph),
113.22 (C3-coumarin), 112.82 (C5-coumarin), 112.69 (C6-coumarin), 101.56
(C8-coumarin), 79.18 (-C≡), 76.33 (≡CH), 68.49 (O-CH2-), 56.97 (N-CH2-), 55.42

ACCEPTED MANUSCRIPT
(OCH3), 52.03 (O(CH2)3-CH2), 41.16 (CH2-C≡), 26.54 (OCH2-CH2), 23.49
(O(CH2)2-CH2) . HRMS: calcd for C24H25NO4 [M + H]+ 392.1784, found 392.1856.
4.1.3.19. 7-{4-[(3-methoxybenzyl)(prop-2-yn-1-yl)amino]butoxy}-2H-chromen-2-one
(4s)
The general procedure described for 4a-u was used, starting from 3s, powdered
K2CO3, 3-bromopropyne and KI, and 4s was obtained as a Yellow oil (yield 77%); IR
(KBr) ν 3288, 2833, 1733, 1614, 1509, 1281, 1123, 1047, 836 cm-1; 1H NMR (500
MHz, DMSO-d6) δ 7.98 (d, J = 9.4 Hz, 1H, H4-coumarin), 7.61 (d, J = 8.5 Hz, 1H,
H5-coumarin), 7.22 (t, J = 7.8 Hz, 1H, Ph-H), 6.94 (d, J = 2.3 Hz, 1H, H8-coumarin),
6.92 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.88 – 6.84 (m, 2H, Ph-H), 6.80 (dd, J =
8.1, 2.5 Hz, 1H, Ph-H), 6.28 (d, J = 9.5 Hz, 1H, H4-coumarin), 4.06 (t, J = 6.5 Hz, 2H,
O-CH2-), 3.72 (s, 3H, OCH3), 3.55 (s, 2H, CH2Ph), 3.30 (d, J = 2.4 Hz, 2H, CH2-C≡),
3.14 (d, J = 2.3 Hz, 1H, C≡CH), 2.53 (s, 2H, O(CH2)3-CH2), 1.76 (p, J = 7.0, 6.6 Hz,
13
2H, OCH2-CH2), 1.60 (p, J = 6.6, 6.2 Hz, 2H, O(CH2)2-CH2). C NMR (125 MHz,
DMSO-d6) δ 162.29 (C2-coumarin), 160.78 (C7-coumarin), 159.69 (C8a-coumarin),
155.87 (C-Ph), 144.81 (C4-coumarin), 140.91 (C-Ph), 129.91 (C4a-coumarin), 129.70
(CH-Ph), 121.26 (CH-Ph), 114.54 (CH-Ph), 113.19 (C3-coumarin), 112.83
(C5-coumarin), 112.79 (CH-Ph), 112.69 (C6-coumarin), 101.56 (C8-coumarin), 79.16
(-C≡), 76.39 (≡CH), 68.52 (O-CH2-), 57.66 (N-CH2-), 55.33 (OCH3), 52.21
(O(CH2)3-CH2), 41.46 (CH2-C≡), 26.57 (OCH2-CH2), 23.54 (O(CH2)2-CH2). HRMS:
calcd for C24H25NO4 [M + H]+ 392.1784, found 392.1856.
4.1.3.20.
7-{4-[(3-fluorobenzyl)(prop-2-yn-1-yl)amino]butoxy}-2H-chromen-2-one
(4t)
The general procedure described for 4a-u was used, starting from 3t, powdered
K2CO3, 3-bromopropyne and KI, and 4t was obtained as a Light yellow solid (yield
69%); m.p. 45-46 °C; IR (KBr) ν 3196, 2957, 1711, 1620, 1508, 1285, 1131, 1019,
832 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 9.5 Hz, 1H, H4-coumarin),
7.61 (d, J = 8.6 Hz, 1H, H5-coumarin), 7.35 (q, J = 7.7 Hz, 1H, Ph-H), 7.14 (d, J =
7.6 Hz, 1H, Ph-H), 7.08 (t, J = 8.8 Hz, 2H, Ph-H), 6.95 (d, J = 2.2 Hz, 1H,
H8-coumarin), 6.92 (dd, J = 8.6, 2.4 Hz, 1H, H7-coumarin), 6.28 (d, J = 9.4 Hz, 1H,