Simultaneous exploration of TBAF·3H2O as a base as well as a solvating agent for the palladium catalyzed Suzuki cross-coupling of 4-methyl-7-nonafluorobutylsulfonyloxy coumarins under microwave irradiation

Article abstract of DOI:10.1016/j.jfluchem.2016.01.002

A concise, efficient and facile protocol for the synthesis of a variety of 4-methyl-7-aryl/heteroaryl coumarins has been developed by utilizing the palladium catalyzed Suzuki cross-coupling reaction of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin with a wide range of electronically diverse boronic acids under microwave irradiation. In the presence of a suitable catalyst, ligand and base, the coupling reaction proceeded smoothly to give the biaryls in satisfactory to exceptional yields. The dual role of TBAF·3H₂O as a base as well as a solvating agent and the utilization of dppp as a ligand with moderate bite angle (91°) were found to be instrumental for the success of the reaction. Prominent features of this optimization conditions include: shorter reaction times, good to excellent yield and exceptional tolerance to a wide variety of functional groups.

Full text of DOI:10.1016/j.jfluchem.2016.01.002

Accepted Manuscript
Title: Simultaneous exploration of TBAF·3H2O as a base as
well as a solvating agent for the palladium catalyzed Suzuki
cross-coupling of 4-methyl-7-nonafluorobutylsulfonyloxy
coumarins under microwave irradiation
Author: M. Nibin Joy Yadav D. Bodke K.K. Abdul Khader
Ayyiliyath M. Sajith Talavara Venkatesh A.K. Ajeesh Kumar
PII:
S0022-1139(16)30002-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.01.002
FLUOR 8711
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
20-7-2015
23-12-2015
4-1-2016
Please cite this article as: M.Nibin Joy, Yadav D.Bodke, K.K.Abdul Khader,
Ayyiliyath M.Sajith, Talavara Venkatesh, A.K.Ajeesh Kumar, Simultaneous
exploration of TBAFcdot3H2O as a base as well as a solvating agent for the
palladium catalyzed Suzuki cross-coupling of 4-methyl-7-nonafluorobutylsulfonyloxy
coumarins under microwave irradiation, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.01.002
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Simultaneous exploration of TBAF.3H2O as a base as well as a
solvating agent for the palladium catalyzed Suzuki cross-coupling of
4-methyl-7-nonafluorobutylsulfonyloxy coumarins under microwave
irradiation
M. Nibin Joya,b, Yadav D. Bodkea* ydbodke@gmail.com, K. K. Abdul Khaderc,
Ayyiliyath M. Sajithd, Talavara Venkatesha, A. K. Ajeesh Kumara,e
aDepartment of P.G studies and Research in Industrial Chemistry, Kuvempu
University, Jnana Sahyadri, Shankaraghatta, Shimoga, Karnataka, India- 577451.
bDepartment of Science and Humanities (Chemistry), Karpagam College of
Engineering, Othakkal Mandapam, Coimbatore, Tamil Nadu, India-641032.
cPost Graduate and Research Department of Chemistry, Jamal Mohamed College,
Bharathidasan University, Tiruchirapalli, India.
dPost Graduate and Research Department of Chemistry, Kasaragod Govt. College,
Kannur University, Kannur, India.
eAnthem Biosciences Pvt. Ltd., No. 49, Bommasandra Industrial Area, Bangalore,
Karnataka, India- 560099.
*Corresponding author at: Dept. of P.G studies and Research in Industrial Chemistry, Kuvempu
University, Jnana Sahyadri, Shankaraghatta, Shimoga, Karnataka. Tel.: +91-08282 256228.
1

GRAPHICAL ABSTRACT
R
B(OH)2
Pd (OAc)2
dppp
NfO
O
O
O
F
R
O
O
TBAF.3H2O
Microwave, 80 oC
R = Aryl/Heteroaryl
F
F
F
F
O
S
ONf =
dppp =
PPh2 PPh2
O
F
F
F
F
Bite angle= 91o
A concise, efficient and facile protocol for the synthesis of a variety of 4-methyl-7-
aryl/heteroaryl coumarins has been developed by utilizing the palladium catalyzed Suzuki cross-
coupling reaction of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin with a wide range of
electronically diverse boronic acids under microwave irradiation.
2

Highlights
1. An efficient protocol for the palladium catalyzed Suzuki coupling of 4-methyl-7-
nonafluorobutylsulfonyloxy coumarins has been achieved.
2. The dual role of TBAF.3H2O as a base and a solvating was found to be instrumental for
the success of the reaction.
3. An assortment of 4-methyl-7-aryl coumarins were successfully synthesized using the
optimized conditions.
3

Abstract
A concise, efficient and facile protocol for the synthesis of a variety of 4-methyl-7-
aryl/heteroaryl coumarins has been developed by utilizing the palladium catalyzed Suzuki cross-
coupling reaction of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin with a wide range of
electronically diverse boronic acids under microwave irradiation. In the presence of a suitable
catalyst, ligand and base, the coupling reaction proceeded smoothly to give the biaryls in
satisfactory to exceptional yields. The dual role of TBAF.3H2O as a base as well as a solvating
agent and the utilization of dppp as a ligand with moderate bite angle (91°) were found to be
instrumental for the success of the reaction. Prominent features of this optimization conditions
include: shorter reaction times, good to excellent yield and exceptional tolerance to a wide
variety of functional groups.
Keywords: Coumarin; Nonaflates; Suzuki coupling; Microwave.
4

1. Introduction
The Suzuki–Miyaura cross-coupling reaction between organoboranes and organic halides or
pseudohalides has emerged as one of the foremost methods for the creation of carbon–carbon
bonds under mild conditions [1]. The reaction provides an efficient pathway to a range of
pharmaceuticals, herbicides, natural products, polymers and liquid crystalline materials and
hence has significantly extended its scope in recent years [2]. Salient features of these reactions
are the availability, stability and non-toxicity of a variety of boronic acids, extensive functional
group tolerance and easy access for product isolation [3]. These features evidently reveal its
significance in synthetic chemistry and hence this reaction has found widespread use in
pharmaceutical industries. The microwave assisted organic synthesis (MAOS) has gained
remarkable importance in drug discovery laboratories these days mostly due to their superior
reaction rates, selectivity and product yields as compared to standard thermal conditions [4].
Transition metal catalyzed cross-coupling reactions usually take hours or days for completion by
conventional heating whereas the use of microwave irradiation will complete those reactions in
minutes with excellent reproducibility and lesser side-reactions [5].
Coumarins are an important class of benzopyrones that are essentially found in green plants
either in free or combined state [6]. They represent one of the most active classes of compounds
and possess a wide spectrum of biological activity [7]. Coumarin derivatives have numerous
therapeutic applications including photo chemotherapy, anti-tumor therapy, anti-HIV therapy [8],
and are also active as anti-bacterial [9], anti-inflammatory [10] and anti-coagulating agents [11].
In addition, coumarins are known to be lipid lowering agents with moderate triglyceride
lowering activity [12] whereas hydroxycoumarins are powerful chain breaking anti-oxidants and
can prevent free radical injury [13,14]. The coumarin core is present within the chemical
structure of several pharmaceutical drugs such as warfarin, acenocoumarol, carbochromen etc.
and in antibiotics such as novobiocin, clorobiocin and coumermycin A1 [15]. In view of these
varied applications, the investigation of facile and efficient methods for the synthesis of diversely
substituted coumarin derivatives has been the aim of many researchers for the past 20 years [16].
The diverse applications of coumarins in various fields of chemistry have been extensively
reported in the literature. Furthermore, the structure activity relationship (SAR) studies of
various aryl/heteroaryl coumarins have revealed the fact that the presence of substituted
5

heteroaryl/aryl groups in the coumarin moiety is an indispensable characteristic for their
pharmacological action [17]. Coumarin derivatives with substitution at 7th position are known to
possess various bioactive applications [18]. 4-Methyl-7-substituted coumarins are reported to
have diverse applications in the field of medicinal chemistry such as Monoamine Oxidase
Inhibitory Potency and DNA binding capacity [19]. Even though the synthesis of various 3,4,6,7
and 8 substituted coumarins have been extensively reported in the literature [20], the synthesis of
7-substituted coumarins require the conversion of its triflate to corresponding boronic ester
which took 17 hours for completion and the further biaryl coupling was quite unclear [21].
Furthermore, the methodology for the synthesis of 7-arylcoumarins was reported to be time
consuming over night reactions with relatively lower yields [22]. Moreover, the instability
(lactone ring cleavage) of the coumarin scaffold in basic as well as under prolonged heating
conditions was broadly reported in literatures [17,23]. These observations prompted us to utilize
the microwave irradiation for the synthesis of coumarin derivatives by considering the fact that
the reactions could reach to completion within minutes as compared to conventional heating
methodologies.
As a continuation of our ongoing research program in the synthesis of biologically active
molecules [24], we were interested in synthesizing some 7-substituted coumarins which may
possess considerable pharmacological activities. On continuation of our ongoing research on
palladium catalyzed cross-coupling reactions [25], it has been planned to apply the Suzuki
coupling reaction for the synthesis of various coumarin analogues under microwave irradiation.
Among the pseudohalides, the stability and reactivity of nonaflates over corresponding triflates
in the palladium catalyzed cross-coupling reactions has been recently reported from our
laboratory [26]. In this letter, we report a facile and reliable protocol for the synthesis of a variety
of 4-methyl-7-aryl/heteroaryl coumarins by utilizing the Suzuki cross-coupling reaction of 4-
methyl-7-nonafluorobutylsulfonyloxy coumarin with various aryl/heteroaryl boronic acids under
microwave irradiation. To the best of our knowledge, the exploration of the 7th position of
coumarins for direct arylation by Suzuki coupling under microwave irradiation is few.
6

2. Results and discussion
The parent 4-methyl-7-hydroxycoumarin molecule 2 was prepared by the modified
Pechmann cyclization of resorcinol 1 with ethyl acetoacetate in 1-butyl-3-methylimidazolium
chloroaluminate at 30 °C for 20 minutes [27] (Scheme 1). The obtained hydroxy coumarin 2 was
then converted to corresponding triflate 3a by treating it with trifluoromethanesulfonic anhydride
in dichloromethane (DCM) and pyridine at െ10 °C for 2 h. The intermediate thus obtained was
then subjected to Suzuki coupling with the intention of synthesizing an array of novel 4-methyl-
7-aryl/heteroaryl coumarins of considerable pharmacological relevance (Scheme 2).
As a model reaction, we selected the triflate 3a and phenylboronic acid in various solvents
under microwave irradiation for optimizing the reaction conditions. We decided to optimize the
reaction by employing TBAF.3H2O as a base as it has been reported to have significant effect in
suppressing the hydrolysis of pseudohalides by increasing its solvation in the reaction medium
[26,28]. To our disappointment, we obtained the detriflated product 5 as the major product in all
the explored conditions (Table 1). The triflate proved to be highly unstable in the reaction
conditions which could be presumably due to the unstable nature of the intermediate Pd(II)
complex that is expected to form during its preliminary oxidative addition to Pd(0).
Our subsequent efforts were to optimize the reaction conditions by changing the substrate to
corresponding nonaflates. The hydroxycoumarin intermediate 2 was converted to the
corresponding nonaflate by treating it with 1.5 equivalent of nonafluorobutanesulfonic anhydride
at െ10 °C in dichloromethane (DCM) and pyridine as base for 2 hours. The obtained nonaflate
intermediate 3b was found to be highly stable than the corresponding triflates and didn’t
decompose even after storing for a longer period of time. The intermediate 3b was then subjected
to Suzuki coupling with various boronic acids with the objective of synthesizing a variety of
novel 4-methyl-7-substituted coumarins (Scheme 3).
As a model reaction, we selected the nonaflate 3b and phenylboronic acid in order to
optimize the reaction conditions in view of the fact that the products and impurities could be
easily identified by TLC and LC-MS. A series of palladium catalysts like Pd2(dba)3, Pd(OAc)2,
Pd(dppf)Cl2, Pd(dppf)CH2Cl2, PdCl2.(CH3CN)2 etc. were screened at the initial stage with
TBAF.3H2O (2 equiv) in various solvents like DME, DMF and 1,4-dioxane at 100 °C for 30 min.
7

in a 110 W microwave oven (Table 2). Disappointingly, under most of the reaction conditions
examined, the formation of product was not observed as only a trace amount of the required
biaryl was formed (Table 2, entries 1 to 7). However, we observed the formation of biaryls in
considerably better yield (45 %) when Pd(OAc)2 was used as a catalyst in DME as solvent
(Table 2, entry 8). On the basis of our assumption that the improvement of solubility of reagents
in the solvent system could facilitate the coupling more effectively, we added water and
methanol as a co-solvent with DME and the reaction was carried out at 100 °C for 30 min. in a
110 W microwave oven. The hypothesis proved to be true as we observed the formation of
desired product in reasonable yield when DME-MeOH in 3:1 ratio (Table 2, entry 10) was used
along with TBAF.3H2O and Pd(OAc)2. DME-H2O mixture yielded the biaryls in comparatively
lower yield (Table 2, entry 9) which could be rationalized by the fact that DME-MeOH improved
the overall solubility of the reagents when compared to that of DME-H2O [29]. A significant
improvement in the yield of the desired product could not be realized either by decreasing
reaction temperature and reaction time or by increasing the amount of the base (Table 2, entries
11,12 and 13).
In our continuous efforts to improve the yield of the desired product, we screened the
reaction by adding some diphosphine ligands (Figure 1) to the catalyst [Pd(OAc)2] which are
known to enhance the catalytic activity in the reaction system. The results are summarized in
Table 3. These catalytic systems generated in situ were treated with the nonaflate 3b,
phenylboronic acid and TBAF.3H2O in DME-MeOH (3:1) at 100 °C for 30 min. in a 110 W
microwave oven. We observed that the reaction conditions and the nature of the ligand have a
crucial influence in the formation of desired product. Ligands with moderate bite angle that
could accomplish chelation and form a cis complex in the reaction medium [30] were found to be
necessary for better conversions. To our delight, we obtained the biaryl coupled product in
satisfactory yield when 1,3-bis(diphenylphosphino)propane (dppp) was used as the ligand (Table
3, entry 3). Ligands with bite angle less than that of dppp (91°) furnished the product in lower
yields and the ligands with bite angle greater than that of dppp produced unwanted side products
which caused a decrease in the yield of the desired product (Table 3, entries 1, 2 and 4, 5).
Finally, addition of one more equivalent of base and decreasing the temperature to 80 °C
rendered the required biaryl in 98 % yield with 93 % of isolated yield (Table 3, entry 6).
8

In the present study, the ligand with moderate bite angle (dppp) is assumed to increase the
stability of the catalyst in the reaction medium [30]. Presumably, it could be accounted that the
dppp ligand with moderate bite angle immediately initiated the catalytic reaction without an
incubation period. This would bring about an increase in the electron density and hence the
stability of the catalyst by forming a divalent square planar complex which in turn enhanced the
reductive elimination and procured the biaryls as a major product rather than competitive side
products [31]. In the current study, it is speculated that the ligands with wider bite angles might
have involved in side reactions by β-hydride elimination or substitution reactions [32].
In order to investigate the effect of various bases in the developed strategy, the Suzuki
coupling reaction was carried out using a variety of bases while keeping all the other parameters
unchanged (Table 4). Among the various bases screened, TBAF.3H2O gave outstanding yield
and proved to be superior to K3PO4, CsF and Cs2CO3. The plausible reasons for this superiority
might be the moderate basicity of TBAF.3H2O and its increase in solvation in the reaction
medium when its stoichiometric equivalence was increased [28,33]. Moreover, it is assumed that
the presence of a nucleophilic activator like TBAF.3H2O facilitated the decomposition of
divalent Pd(OAc)2 to a catalytically active Pd(0) species and the stabilization of the oxidative
adduct complex thereby increasing the rate of the reaction to a greater extent [33,34]. The dual
role of TBAF.3H2O as a base as well as a solvating agent is greatly acknowledged in the present
study.
Next, we focused our attention to evaluate the generality of the developed protocol (Scheme
4). Keeping this in mind, we applied the optimized condition [1.5 equiv. boronic acid, 3 equiv.
TBAF.3H2O, 5 mol % Pd(OAc)2, 0.1 equiv. dppp, DME-MeOH (3:1), 80 °C, 30 min,
microwave] to a wide range of sterically and electronically different boronic acids (Table 5). All
the boronic acids furnished the required biaryls in acceptable to excellent yields. The
methodology showed exceptional functional group tolerance and almost all the reactions were
completed within 30 min. with a smaller amount of side products. Electron rich boronic acids
provided excellent yield (Table 5, entries 10 to 12 and 21 to 23), whereas electronically poor
boronic acids gave slightly lower yields (Table 5, entries 5 to 9) even after increasing the
reaction time to 1 hour. Furthermore, sterically hindered boronic acids gave moderate yields
(Table 5, entries 14 to 20).
9

A plausible mechanism of the Suzuki coupling reaction of nonaflates with boronic acids has
been proposed (Scheme 5). In the first step, coordination of dppp to divalent palladium acetate
results in the formation of a Pd(0) species which subsequently undergoes oxidative addition with
the nonaflate 3b to form an organo palladium complex. This oxidative adduct was stabilized by
TBAF.3H2O which subsequently facilitated transmetallation. Meanwhile, the boron atom of the
boronic acid also forms a borate complex with TBAF.3H2O which is assumed to have a crucial
role to facilitate the transmetallation step. Finally, it undergoes reductive elimination to give the
coupled product and completes the catalytic cycle.
3. Conclusion
In summary, a rapid, facile and modified approach for the synthesis of an array of 4-methyl-
7-aryl/heteroaryl coumarins has been developed under microwave irradiation. This method
paved the way for an assortment of pharmacologically relevant coumarins with exceptional
functional group tolerance, shorter reaction times and higher yields. The biological screening of
the synthesized molecules will be done in due course and will be communicated shortly.
4. Experimental
4.1. General information
All solvents and reagents were obtained from commercial suppliers and used without any
further purification unless otherwise noted. Analytical TLC was performed on pre-coated
aluminum sheets of silica (60 F254 nm) and visualized by short-wave UV light at λ 254. Melting
1
points were determined on an EZ - Melt automated melting point apparatus. H NMR spectra
were recorded at 400 MHz and 300 MHz using an internal deuterium lock. Chemical shifts were
measured in δ (ppm). Data is presented as follows: chemical shift, multiplicity, coupling constant
(J) in Hz, and integration. The following abbreviations were used for the splitting patterns: s for
singlet, d for doublet, t for triplet, m for multiplet and br for broad. 13C NMR spectra were
recorded at 100 MHz using an internal deuterium lock. LC-MS analyses were performed using
ESI/APCI, with an ATLANTIS C18 (50X4.6 mm - 5µm) column and a flow rate of 1.2 mL/min.
4.2. Procedure for the synthesis of 4-methyl-7-hydroxy coumarin intermediate 2
10

To the weighed quantity of phenol (1 equiv.) and ethyl acetoacetate (1.1 equiv.), the ionic
liquid [bmim]Cl·2AlCl3 (1.1 equiv.) was added and the reaction mixture was stirred at 30 °C for
20 min. All additions were carried out in an inert atmosphere. The reaction was quenched by
adding 6 M HCl in cold conditions. The resultant product was filtered and further purified by
column chromatography to obtain the titled compound 2 as off white solid in 88 % yield. MP :
1
70-72 °C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.68 Hz, 3H, CH3), 6.1 (s, 1H, ArH), 6.69
(d, J=2.32 Hz, 1H, ArH), 6.77-6.80 (dd, J1=2.24 Hz J2=8.6 Hz, 1H, ArH), 7.57 (d, J=8.68 Hz,
1H, ArH), 10.51 (s, 1H, OH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 112.3, 117.5, 130.5,
154.5, 161.1, 160.4 (CO); LC-MS: Calculated 176.2, Observed 177.2; Analysis calculated for
C10H8O3: C, 68.18, H, 4.58 %, found: C, 68.21, H, 4.57 %.
4.3.Procedure for the synthesis of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin 3b
To a solution of 4-methyl-7-hydroxy coumarin (2, 1 equiv.) in DCM, was added pyridine (2
equiv.) at െ10 °C, followed by the addition of nonafluorobutane sulfonic anhydride (1.5 equiv.)
drop wise. Reaction mixture was warmed to 0 °C and stirred for 2 h. Reaction mass was then
diluted with DCM, bi-phased with water and extracted, organic layer was washed with NaHCO3,
brine solution and dried over Na2SO4 and distilled under reduced pressure. The obtained crude
compound was purified by column chromatography packed with 60-120 silica gel and eluted
with 15 to 20 % ethyl acetate in petroleum ether to obtain the titled compound 3 as colorless
1
solid in 87 % yield. MP : 86-88 °C; H NMR (300 MHz, CDCl3): δ 2.47 (d, J=1.08 Hz, 3H,
CH3), 6.37 (d, J=1.08 Hz, 1H, ArH), 7.23-7.29 (m, 2H, ArH), 7.69 (d, J=8.67 Hz, 1H, ArH); 13C
NMR (100 MHz, CDCl3): δ 23.2 (CH3), 115.3, 116.5, 116.9 (m, CF2), 118.9 (m, CF2), 126.7 (m,
CF3), 132.2, 154.1-154.7 (2 peaks), 156.3 (m, SO2CF2), 160.6 (CO); 19F NMR (376.5 MHz,
CDCl3): δ െ125.32 to െ125.22 (m), െ120.77 to െ120.68 (m), െ112.97 to െ112.87 (m), െ80.59
to െ80.52 (m); LC-MS: Calculated 458.3, Observed 459.3; Analysis calculated for C14H7F9O5S:
C, 36.69, H, 1.54 %, found: C, 36.74, H, 1.51 %.
4.4.General procedure of the coupling reaction
To a solution of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin (3b, 1 equiv.) in DME-
MeOH (3:1), were added Pd(OAc)2 (0.05 equiv.) and dppp (0.1 equiv.). The solution was purged
with nitrogen and stirred at room temperature for 10 min, at which time boronic acid (1.5 equiv.)
and TBAF.3H2O (3 equiv.) was added. The reaction solution was purged again with nitrogen and
11

then placed in the microwave and heated for 20–30 min at 80 °C at 110 W. When TLC and LC-
MS showed full consumption of starting materials, the reaction mixture was diluted with ethyl
acetate, separated the organic layer, given water wash, brine wash and was dried over anhydrous
sodium sulfate and distilled under reduced pressure to get the crude material. The crude product
was further purified by column chromatography and eluted in varying polarities to obtain the
diaryls 4a-x.
1
4.4.1. 4-Methyl-7-(pyridin-3-yl)-2H-chromen-2-one (4a): White solid. MP : 88-90 °C; H NMR
(400 MHz, CDCl3): δ 2.49 (d, J=2.04 Hz, 3H, CH3), 6.31 (s, 1H, ArH), 7.43-7.51 (m, 3H, ArH),
8.22-8.25 (dd, J1=1.96 Hz J2=7.92 Hz, 1H, ArH), 8.42-8.45 (dd, J1=2.24 Hz J2=8.08 Hz, 1H,
ArH), 8.71-8.75 (dd, J1=1.76 Hz J2=7.84 Hz, 1H, ArH), 9.12 (d, J=8.92 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3): δ 23.2 (CH3), 115.3, 116.5, 117.1, 119.7, 136.2, 138.3, 145.1, 147.6, 154.1,
156.3, 157.6, 157.9, 160.6 (CO); LC-MS: Calculated 237.2, Observed 238.2; Analysis calculated
for C15H11NO2: C, 75.94, H, 4.67, N, 5.90 %, found: C, 75.91, H, 4.68, N, 5.93 %.
4.4.2. 7-(5-Chloropyridin-3-yl)-4-methyl-2H-chromen-2-one (4b): White solid. MP : 92-95 °C;
1H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.16 Hz, 3H, CH3), 6.31 (d, J=1.12 Hz, 1H, ArH),
7.43-7.49 (m, 3H, ArH), 8.44 (d, J=8.12 Hz, 1H, ArH), 9.08 (s, 1H, ArH), 9.14 (d, J=7.84 Hz,
1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 115.3, 120.5, 121.1, 123.7, 125.2, 135.3,
135.8, 138.1, 149.6, 150.5, 154.1, 156.3, 157.6, 160.6 (CO); LC-MS: Calculated 271.2,
Observed 272.2; Analysis calculated for C15H10ClNO2: C, 66.31, H, 3.71, N, 5.16 %, found: C,
66.35, H, 3.69, N, 5.14 %.
4.4.3. 4-Methyl-7-(2-methylpyridin-4-yl)-2H-chromen-2-one (4c): White solid. MP : 90-93 °C;
1H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.44 Hz, 3H, CH3), 3.34 (s, 3H, CH3), 6.31 (d, J=1.08
13
Hz, 1H, ArH), 7.38-7.46 (m, 5H, ArH), 9.08-9.11 (dd, J1=1.88 Hz J2=8.24 Hz, 1H, ArH); C
NMR (100 MHz, CDCl3): δ 23.2 (CH3), 27.1 (CH3), 111.3, 114.5 (2C), 116.8, 120.1, 123.4,
126.2, 129.3, 139.8, 143.4, 151.1 (2C), 152.6, 154.5, 160.4 (CO); LC-MS: Calculated 251.2,
Observed 252.2; Analysis calculated for C16H13NO2: C, 76.48, H, 5.21, N, 5.57 %, found: C,
76.52, H, 5.20, N, 5.55 %.
1
4.4.4. 4-Methyl-7-phenyl-2H-chromen-2-one (4d): Off white solid. MP : 78-80 °C; H NMR
(400 MHz, CDCl3): δ 2.49 (d, J=1.28 Hz, 3H, CH3), 6.49 (s, 1H, ArH), 7.59-7.61 (dd, J1=1.72
Hz J2=8.12 Hz, 1H, ArH), 7.64-7.67 (dd, J1=1.08 Hz J2=8.48 Hz, 2H, ArH), 7.71-7.73 (d, J=7.8
12

Hz, 1H, ArH), 7.82-7.86 (m, 1H, ArH), 7.92-8.05 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ
23.2 (CH3), 107.7, 110.5, 113.5, 117.9, 124.7, 125.6, 131.4, 132.7, 140.8, 142.7, 146.4, 151.3,
160.4 (CO); LC-MS: Calculated 236.2, Observed 237.2; Analysis calculated for C16H12O2: C,
81.34, H, 5.12 %, found: C, 81.36, H, 5.11 %.
4.4.5. 4-(4-Methyl-2-oxo-2H-chromen-7-yl)benzonitrile (4e): Brown solid. MP : 101-103 °C; 1H
NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.36 Hz, 3H, CH3), 6.47 (s, 1H, ArH), 7.56-7.64 (m, 2H,
ArH), 7.71 (d, J=7.44 Hz, 1H, ArH), 7.77-7.82 (m, 2H, ArH), 7.91 (d, J=8.04 Hz, 1H, ArH),
7.99 (d, J=7.52, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 114.2, 115.1, 118.6
(CN), 121.5, 123.1, 127.2, 130.4, 131.7, 132.0, 136.1, 137.2, 140.3, 146.3, 154.5, 156.1, 160.4
(CO); LC-MS: Calculated 261.2, Observed 262.2; Analysis calculated for C17H11NO2: C, 78.15,
H, 4.24, N, 5.36 %, found: C, 78.19, H, 4.22, N, 5.32 %.
1
4.4.6. 7-(4-Fluorophenyl)-4-methyl-2H-chromen-2-one (4f): White solid. MP : 85-88 °C; H
NMR (400 MHz, CDCl3): δ 2.47 (d, J=1.56 Hz, 3H, CH3), 6.33 (d, J=1.16 Hz, 1H, ArH), 7.24-
7.29 (m, 2H, ArH), 7.44-7.47 (m, 2H, ArH), 7.76-7.80 (m, 2H, ArH), 8.04 (d, J=8.20 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): δ 24.7 (CH3), 110.6, 113.8, 118.0, 121.5, 125.8, 131.7,
134.2, 138.6, 141.9, 143.7, 146.5, 148.5, 154.9 (m, CF), 160.4 (CO); 19F NMR (376.5 MHz,
CDCl3): δ െ 121.7; LC-MS: Calculated 254.2, Observed 255.2; Analysis calculated for
C16H11FO2: C, 75.58, H, 4.36 %, found: C, 75.61, H, 4.35 %.
4.4.7. Methyl 4-(4-methyl-2-oxo-2H-chromen-7-yl)benzoate (4g): Brown solid. MP : 98-100 °C;
1H NMR (300 MHz, CDCl3): δ 2.49 (d, J=1.17 Hz, 3H, CH3), 3.9 (s, 3H, OCH3), 6.34 (d, J=1.14
Hz, 1H, ArH), 7.47-7.56 (m, 2H, ArH), 7.64-7.72 (m, 3H, ArH), 8.14-8.17 (dd, J1=1.68 Hz
13
J2=6.51 Hz, 2H, ArH); C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 53.8 (OCH3), 115.3, 122.5,
123.7, 127.1, 128.2, 131.1, 131.8 (2C), 132.1, 133.3 (2C), 139.1, 143.6, 153.1, 155.3, 163.1
(CO), 165.3 (CO, Ester); LC-MS: Calculated 294.3, Observed 295.3; Analysis calculated for
C18H14O4: C, 73.46, H, 4.79 %, found: C, 73.49, H, 4.78 %.
4.4.8. 2-(4-Methyl-2-oxo-2H-chromen-7-yl)benzonitrile (4h): Brown solid. MP : 102-104 °C; 1H
NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.52 Hz, 3H, CH3), 6.49 (s, 1H, ArH), 7.59-7.67 (m, 2H,
ArH), 7.73 (d, J=7.8 Hz, 1H, ArH), 7.82-7.86 (m, 2H, ArH), 7.94 (d, J=8.16 Hz, 1H, ArH), 8.01
(d, J=7.76, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 114.4, 115.3, 118.7 (CN),
13

121.7, 123.1, 127.2, 130.6, 131.9, 132.1, 136.3, 137.1, 140.6, 146.5, 154.7, 156.1, 160.6 (CO);
LC-MS: Calculated 261.2, Observed 262.2; Analysis calculated for C17H11NO2: C, 78.15, H,
4.24, N, 5.36 %, found: C, 78.19, H, 4.22, N, 5.32 %.
1
4.4.9. 4-Methyl-7-(4-nitrophenyl)-2H-chromen-2-one (4i): Yellow solid. MP : 95-97 °C; H
NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.60 Hz, 3H, CH3), 6.36 (d, J=1.24 Hz, 1H, ArH), 7.28-
7.33 (m, 2H, ArH), 7.48-7.53 (m, 2H, ArH), 7.81-7.85 (m, 2H, ArH), 8.16 (d, J=8.32 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): δ 25.1 (CH3), 111.6, 114.9, 118.0, 121.7, 125.8, 132.7,
135.4, 138.9, 142.4, 144.2, 146.5, 148.7, 160.4 (CO); LC-MS: Calculated 281.0, Observed
282.0; Analysis calculated for C16H11NO4: C, 68.32, H, 3.94, N, 4.98 %, found: C, 68.36, H,
3.93, N, 4.97 %.
4.4.10. 7-(4-Methoxyphenyl)-4-methyl-2H-chromen-2-one (4j): Light yellow solid. MP : 89-91
1
°C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.56 Hz, 3H, CH3), 3.93 (s, 3H, OCH3), 6.34 (s,
1H, ArH), 7.54-7.59 (m, 3H, ArH), 7.64-7.72 (m, 3H, ArH), 8.14-8.17 (dd, J1=2.24 Hz J2=8.68
13
Hz, 1H, ArH); C NMR (100 MHz, CDCl3): δ 22.6 (CH3), 55.8 (OCH3), 110.2, 117.9, 118.8,
125.9, 129.8, 132.9, 136.8, 141.6, 141.8, 146.0, 146.6, 155.5, 156.3, 160.4 (CO); LC-MS:
Calculated 266.3, Observed 267.3; Analysis calculated for C17H14O3: C, 76.68, H, 5.30 %, found:
C, 76.71, H, 5.28 %.
1
4.4.11. 4-Methyl-7-p-tolyl-2H-chromen-2-one (4k): White solid. MP : 85-87 °C; H NMR (400
MHz, CDCl3): δ 2.49 (d, J=1.64 Hz, 3H, CH3), 3.14 (s, 3H, CH3), 6.49 (s, 1H, ArH), 6.84-6.89
(m, 2H, ArH), 6.96-6.99 (dd, J1=1.24 Hz J2=7.76 Hz, 2H, ArH), 7.46-7.49 (dd, J1=1.36 Hz
J2=7.92 Hz, 2H, ArH), 7.78 (d, J=7.76 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.4
(CH3), 26.2 (CH3), 111.1, 112.2, 114.3, 117.8, 121.8, 129.7 (2C), 131.1, 133.2, 139.6, 142.4,
154.3, 155.8, 160.6 (CO); LC-MS: Calculated 250.3, Observed 251.3; Analysis calculated for
C17H14O2: C, 81.58, H, 5.64 %, found: C, 81.62, H, 5.63 %.
1
4.4.12. 7-(4-Ethylphenyl)-4-methyl-2H-chromen-2-one (4l): White solid. MP : 88-91 °C; H
NMR (400 MHz, CDCl3): δ 1.82-1.86 (m, 3H, CH3), 2.47 (d, J=1.24 Hz, 3H, CH3), 2.85-2.90
(m, 2H, CH2), 6.31 (s, 1H, ArH), 7.46-7.51 (m, 4H, ArH), 7.67 (d, J=7.64 Hz, 1H, ArH), 7.78-
7.81 (dd, J1=1.92 Hz J2=8.36 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.4 (CH3), 23.2
(CH3), 34.4 (CH2), 115.3, 121.6, 125.7, 129.7, 130.1 (2C), 130.6 (2C), 135.6, 138.1, 140.3,
14

152.1, 154.3, 160.4 (CO); LC-MS: Calculated 264.3, Observed 265.3; Analysis calculated for
C18H16O2: C, 81.79, H, 6.10 %, found: C, 81.82, H, 6.08 %.
4.4.13. 7-(Furan-3-yl)-4-methyl-2H-chromen-2-one (4m): Brown solid. MP : 87-89 °C; 1H NMR
(400 MHz, CDCl3): δ 2.46 (d, J=1.16 Hz, 3H, CH3), 6.29 (d, J=1.16 Hz, 1H, ArH), 6.54-6.56
(dd, J1=1.76 Hz J2=3.36 Hz, 1H, ArH), 6.84 (d, J=3.36 Hz, 1H, ArH), 7.27-7.29 (m, 2H, ArH),
7.56-7.61 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 111.2, 115.3, 121.5, 124.6,
127.7, 130.8, 132.3, 139.1, 140.1, 141.3, 146.4, 154.3, 158.9, 160.6 (CO); LC-MS: Calculated
226.2, Observed 227.2; Analysis calculated for C14H10O3: C, 74.33, H, 4.46 %, found: C, 74.37,
H, 4.44 %.
4.4.14. 7-(3-(Dimethylamino)phenyl)-4-methyl-2H-chromen-2-one (4n): Light yellow solid. MP :
1
102-104 °C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.32 Hz, 3H, CH3), 3.44 (s, 6H, NMe2),
6.31 (s, 1H, ArH), 6.82 (d, J=7.48 Hz, 1H, ArH), 7.03-7.07 (m, 2H, ArH), 7.29-7.34 (m, 3H,
13
ArH), 7.64-7.67 (dd, J1=1.84 Hz J2=8.32 Hz, 1H, ArH); C NMR (100 MHz, CDCl3): δ 23.2
(CH3), 43.6 (NMe2), 115.3, 115.5, 120.6, 122.7, 124.7, 129.3, 132.1, 134.3, 140.1, 141.8, 151.8,
156.1, 156.9, 160.4 (CO); LC-MS: Calculated 279.3, Observed 280.3; Analysis calculated for
C18H17NO2: C, 77.4, H, 6.13, N, 5.01 %, found: C, 77.43, H, 6.12, N, 4.99 %.
4.4.15. 7-(3,5-Difluorophenyl)-4-methyl-2H-chromen-2-one (4o): White solid. MP : 92-94 °C;
1H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.36 Hz, 3H, CH3), 6.31 (d, J=1.04 Hz, 1H, ArH),
7.06-7.10 (m, 1H, ArH), 7.54-7.59 (m, 2H, ArH), 7.77-7.81 (m, 2H, ArH), 7.92-7.95 (dd,
J1=1.68 Hz J2=8.08 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 105.3, 114.6,
19
115.3, 121.6, 125.7, 129.7, 132.1, 141.3, 144.1, 155.8, 157.5, 160.6 (CO), 165.5 (m, CF); F
NMR (376.5 MHz, CDCl3): δ െ109.2; LC-MS: Calculated 272.2, Observed 273.2; Analysis
calculated for C16H10F2O2: C, 70.59, H, 3.70 %, found: C, 70.63, H, 3.68 %.
4.4.16. 4-Methyl-7-(1-methyl-1H-indol-5-yl)-2H-chromen-2-one (4p): Light green solid. MP :
120-122 °C; 1H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.08 Hz, 3H, CH3), 3.86 (s, 3H, NCH3),
6.30 (d, J=1.08 Hz, 1H, ArH), 6.60 (d, J=3.12 Hz, 1H, ArH), 7.14 (d, J=3.08 Hz, 1H, ArH), 7.28
(s, 1H, ArH), 7.45 (s, 1H, ArH), 7.52-7.55 (dd, J1=1.72 Hz J2=8.52 Hz, 1H, ArH), 7.62-7.68 (m,
13
2H, ArH), 7.93 (s, 1H, ArH); C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 46.2 (NCH3), 106.3,
114.5, 115.3, 120.1, 122.3, 122.9, 129.3, 130.1, 134.5, 137.6, 139.1 (2C), 146.4, 147.2, 153.8,
15

156.4, 157.1, 160.4 (CO); LC-MS: Calculated 289.2, Observed 290.2; Analysis calculated for
C19H15NO2: C, 78.87, H, 5.23, N, 4.84 %, found: C, 78.91, H, 5.21, N, 4.83 %.
4.4.17. 7-(4-(Dimethylamino)phenyl)-4-methyl-2H-chromen-2-one (4q): Light yellow solid. MP :
1
103-105 °C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.36 Hz, 3H, CH3), 3.52 (s, 6H, NMe2),
6.33 (s, 1H, ArH), 6.82 (d, J=7.52 Hz, 2H, ArH), 7.73-7.84 (m, 5H, ArH); 13C NMR (100 MHz,
CDCl3): δ 23.6 (CH3), 43.6 (NMe2), 115.6, 115.9, 119.7, 122.8, 124.9, 129.8, 132.5, 134.7,
140.3, 151.8, 156.3, 156.9, 160.6 (CO); LC-MS: Calculated 279.3, Observed 280.3; Analysis
calculated for C18H17NO2: C, 77.4, H, 6.13, N, 5.01 %, found: C, 77.44, H, 6.11, N, 4.99 %.
4.4.18. 7-(3,5-Dichlorophenyl)-4-methyl-2H-chromen-2-one (4r): White solid. MP : 99-101 °C;
1H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.36 Hz, 3H, CH3), 6.29 (d, J=1.00 Hz, 1H, ArH),
7.03-7.07 (m, 1H, ArH), 7.50-7.54 (m, 2H, ArH), 7.71-7.76 (m, 2H, ArH) 7.86-7.89 (dd, J1=1.52
Hz J2=7.96 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 105.1, 114.2, 115.3,
121.6, 125.4, 129.7, 132.1, 137.9, 138.1, 141.0, 155.4, 157.3, 160.4 (CO); LC-MS: Calculated
304.0, Observed 305.0; Analysis calculated for C16H10Cl2O2: C, 62.97, H, 3.30 %, found: C,
62.99, H, 3.31 %.
4.4.19. 7-(3,5-bis(Trifluoromethyl)phenyl)-4-methyl-2H-chromen-2-one (4s): White solid. MP :
1
110-112 °C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.48 Hz, 3H, CH3), 6.34 (d, J=1.08 Hz,
1H, ArH), 7.13-7.17 (m, 1H, ArH), 7.58-7.62 (m, 2H, ArH), 7.75-7.79 (m, 2H, ArH), 7.96-7.99
(dd, J1=1.64 Hz J2=8.08 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 105.6,
114.6, 115.7, 121.9, 125.6, 126.9 (m, CF3), 129.8, 132.6, 138.3, 138.5, 141.2, 155.5, 157.6,
160.6 (CO); 19F NMR (376.5 MHz, CDCl3): δ െ58.6; LC-MS: Calculated 372.2, Observed
373.2; Analysis calculated for C18H10F6O2: C, 58.08, H, 2.71 %, found: C, 58.13, H, 2.69 %.
4.4.20. tert-Butyl-4-(4-methyl-2-oxo-2H-chromen-7-yl)phenylcarbamate (4t): Off white solid.
1
MP : 106-108 °C; H NMR (400 MHz, CDCl3): δ 1.56 (s, 9H, t-Bu), 2.49 (d, J=1.52 Hz, 3H,
CH3), 6.31 (s, 1H, ArH), 7.51-7.55 (m, 3H, ArH), 7.68-7.73 (m, 3H, ArH), 8.08-8.11 (dd,
J1=2.08 Hz J2=8.56 Hz, 1H, ArH), 8.31 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): δ 22.6 (CH3),
30.7 (Boc CH3), 81.9 (Boc C), 109.8, 117.5, 118.4, 125.3, 129.5, 132.1, 136.7, 141.2, 141.5,
145.8, 146.4, 155.2, 155.9, 160.2 (CO); LC-MS: Calculated 351.2, Observed 252.2; Analysis
calculated for C21H21NO4: C, 71.78, H, 6.02, N, 3.99 %, found: C, 71.84, H, 5.99, N, 3.97 %.
16

4.4.21. 7-(4-Hydroxyphenyl)-4-methyl-2H-chromen-2-one (4u): Brown solid. MP : 86-88 °C; 1H
NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.68 Hz, 3H, CH3), 5.23 (s, 1H, OH), 6.31 (s, 1H, ArH),
7.01-7.04 (dd, J1=1.96 Hz J2=8.44 Hz, 2H, ArH), 7.68-7.77 (m, 5H, ArH); 13C NMR (100 MHz,
CDCl3): δ 22.6 (CH3), 110.2, 117.9, 118.8, 125.9, 129.8, 130.1 (2C), 132.9, 136.6, 137.8, 152.5,
155.3, 158.6, 160.4 (CO); LC-MS: Calculated 252.1, Observed 253.1; Analysis calculated for
C16H12O3: C, 76.18, H, 4.79 %, found: C, 76.23, H, 4.77 %.
4.4.22. 4-Methyl-7-(4-(methylamino)phenyl)-2H-chromen-2-one (4v): Yellow solid. MP : 93-95
1
°C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.28 Hz, 3H, CH3), 3.02 (s, 3H, NCH3), 6.31 (s,
1H, ArH), 6.77 (d, J=7.24 Hz, 2H, ArH), 7.66-7.72 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3):
δ 23.6 (CH3), 31.6 (NCH3), 115.5, 115.7, 119.7, 122.8, 124.7, 127.8 (2C), 132.3, 134.2, 140.1,
151.4, 156.3, 156.5, 160.4 (CO); LC-MS: Calculated 265.1, Observed 266.1; Analysis calculated
for C17H15NO2: C, 76.96, H, 5.70, N, 5.28 %, found: C, 76.99, H, 5.69, N, 5.27 %.
4.4.23. 7-(6-Methoxypyridin-3-yl)-4-methyl-2H-chromen-2-one (4w): White solid. MP : 92-94
1
°C; H NMR (400 MHz, CDCl3): δ 2.49 (d, J=1.32 Hz, 3H, CH3), 4.08 (s, 3H, OCH3), 6.29 (s,
1H, ArH), 7.03-7.06 (dd, J1=2.04 Hz J2=8.52 Hz, 1H, ArH), 7.61-7.66 (m, 3H, ArH), 8.24-8.29
(m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 22.8 (CH3), 57.5 (OCH3), 112.2, 114.9, 120.4,
122.9, 124.8, 125.9, 129.8, 136.6, 138.8, 143.0, 151.6, 154.5, 160.6 (CO), 162.1; LC-MS:
Calculated 267.1, Observed 268.1; Analysis calculated for C16H13NO3: C, 71.90, H, 4.90, N, 5.24
%, found: C, 71.94, H, 4.89, N, 5.22 %.
1
4.4.24. 4-Methyl-7-(thiophen-3-yl)-2H-chromen-2-one (4x): Off white solid. MP : 90-92 °C; H
NMR (400 MHz, CDCl3): δ 2.47 (d, J=1.08 Hz, 3H, CH3), 6.31 (d, J=1.08 Hz, 1H, ArH), 6.42-
6.44 (dd, J1=1.68 Hz J2=3.24 Hz, 1H, ArH), 6.78 (d, J=3.28 Hz, 1H, ArH), 7.19-7.33 (m, 2H,
ArH), 7.44-7.48 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 23.2 (CH3), 111.2, 117.3, 120.5
(2C), 124.6, 127.7, 128.3, 129.3 (2C), 137.4, 151.3, 154.6, 160.4,CO; LC-MS: Calculated 242.3,
Observed 243.3; Analysis calculated for C14H10O2S: C, 69.40, H, 4.16 %, found: C, 69.44, H,
4.15 %.
17

Acknowledgements
The authors are thankful to the Department of Industrial Chemistry, Kuvempu University for
rendering all the facilities to carry out the experiments. The authors are also thankful to SAIF,
Indian Institute of Technology, Madras for providing all the analytical data and spectra.
18

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22

Figure Captions
Figure 1: Structure of various ligands used and their bite angles
23

Tf2O, -10oC
Pyridine
HO
OH
[bmim]Cl.2AlCl3
CH3COCH2COOEt
30oC, 20 min.
TfO
O
O
HO
O
O
2h.
1
2
3a
Scheme 1: Synthesis of 4-methyl-7-trifluoromethylsulfonyloxy coumarin intermediate
24

B(OH)2
Catalyst/Solvent
O
O
O
O
TfO
O
O
TBAF.3H2O
Microwave/ 100oC
5
4d
3a
Trace
Major
O
O
S
O
F
OTf =
F
F
Scheme 2: Suzuki coupling of 4-methyl-7-trifluoromethylsulfonyloxy coumarin intermediate
with phenylboronic acid
25

B(OH)2
Nf2O, -10oC
Pyridine
O
O
Catalyst/Solvent
O
O
NfO
O
F
O
HO
O
O
TBAF.3H2O
2h.
Microwave/ 100oC
5
4d
2
3b
Minor
Trace
O
S
O
F
O
F
F
ONf =
F
F
F
F
F
Scheme 3: Synthesis of 4-methyl-7-nonafluorobutylsulfonyloxycoumarin intermediate and its
Suzuki coupling with phenylboronic acid
26

RB(OH)2
Pd (OAc)2, dppp
TBAF.3H2O
NfO
O
O
DME/MeOH (3:1)
Microwave, 80oC
R
O
O
3
4a-x
R = Aryl/Heteroaryl
F
O F F
S
O
F
F
ONf =
O
F F F F
Scheme 4: Synthesis of 4-methyl-7-aryl/heteroaryl coumarins
27

Pd(OAc)2
Ligand
ONf
O
O
O
O
R
Pd(0)- L2
1
3
L
ONf
Pd
L
O
O
(II)
L
R
O
O
Pd
(II)
L
[ArPd(II)(ONf)3]2-2Bu4N+
16e- complex
2
(-)
B(OH)2
F
R-B(OH)2
F
R-B(OH) +
TBAF
2
Scheme 5: Proposed mechanism of the coupling reaction
28

Tables
Table 1: Effect of various catalysts and solvents in the Suzuki coupling of 3a with phenylboronic acid
Yield 5 (%)
Entry
Catalyst
Pd2(dba)3
Base
Solvent
DMF
DMF
DMF
DMF
Yield 4d (%)
1
2
3
4
5
6
7
8
TBAF.3H2O
TBAF.3H2O
TBAF.3H2O
TBAF.3H2O
TBAF.3H2O
TBAF.3H2O
TBAF.3H2O
TBAF.3H2O
trace
trace
trace
trace
trace
4
90
88
90
92
87
82
80
75
Pd(dppf)Cl2
PdCl2.(CH3CN)2
Pd(dppf)CH2Cl2
PdCl2(PCy3)2
Pd(OAc)2
DMF
DMF
1,4- Dioxane
DME
Pd(OAc)2
Pd(OAc)2
5
8
Reaction conditions: 4-methyl-7-trifluoromethylsulfonyloxy coumarin (1 mmol), phenylboronic
acid (1.5 mmol), catalyst (0.05 mmol), TBAF.3H2O (2 mmol), solvent, microwave irradiated at
110 W at 100 °C for 30 min.
29