A rapid and modified approach for C-7 amination and amidation of 4-methyl-7-nonafluorobutylsulfonyloxy coumarins under microwave irradiation

Article abstract of DOI:10.1039/c4ra01720j

A facile, efficient and reliable access for the synthesis of an array of 4-methyl-7-(alkyl/aryl/heteroaryl) amino and amido coumarins has been developed by treating 4-methyl-7-nonafluorobutylsulfonyloxy coumarin with various amines and pyridones in presence of a catalyst combination of Pd₂(dba) ₃/xantphos under microwave irradiation. Nonaflates coupled efficiently to give the diaryl amines in acceptable to excellent yields whereas the corresponding triflate was unstable, yielding the detriflated product as well as the hydrolyzed product as competing side products along with the desired product. The wide bite angle (108°) of xantphos, employment of Cs ₂CO₃ as a mild base and the utilization of TBAF3H ₂O as an additive proved to be key for success of the reaction.

Full text of DOI:10.1039/c4ra01720j

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A rapid and modified approach for C-7 amination
and amidation of 4-methyl-7-
Cite this: RSC Adv., 2014, 4, 19766
nonafluorobutylsulfonyloxy coumarins under
microwave irradiation†
Received 27th February 2014
Accepted 14th April 2014
a
a
M. Nibin Joy, Yadav D. Bodke, K. K. Abdul Khader,b M. Syed Ali Padusha,b
*
DOI: 10.1039/c4ra01720j
Ayyiliyath M. Sajithc and A. Muralidharanc
www.rsc.org/advances
A facile, efficient and reliable access for the synthesis of an array of 4- assisted organic synthesis (MAOS) has indisputably became a
methyl-7-(alkyl/aryl/heteroaryl) amino and amido coumarins has been powerful tool in drug discovery laboratories these days for the
developed by treating 4-methyl-7-nonafluorobutylsulfonyloxy construction of versatile chemical entities due oen to superior
coumarin with various amines and pyridones in presence of a catalyst reaction rates, selectivity and product yields as compared to
combination of Pd2(dba)3/xantphos under microwave irradiation. standard thermal conditions.6 It is well documented that
Nonaflates coupled efficiently to give the diaryl amines in acceptable microwave assistance can lead to enormous rate enhancement
to excellent yields whereas the corresponding triflate was unstable, compared to conventional heating by signicantly shortening
yielding the detriflated product as well as the hydrolyzed product as the reaction times. Moreover, a better reproducibility, greater
competing side products along with the desired product. The wide yields and less side reactions have oen been observed when
bite angle (108ꢀ) of xantphos, employment of Cs2CO3 as a mild base compared to standard heating methodologies.7
and the utilization of TBAF$3H2O as an additive proved to be key for
Coumarins are an important class of benzopyrones that are
widely distributed throughout the plant kingdom either in free
or combined state.8 They represent one of the most active
classes of compounds and possess a wide spectrum of phar-
macological activities.9 Coumarin derivatives have various
therapeutic applications including photo chemotherapy, anti-
tumor, anti-HIV therapy,10 and are also active as anti-bacte-
rial,11,12 anti-inammatory13 and anti-viral agents.14 In addition,
coumarins are found to be lipid lowering agents with moderate
triglyceride lowering activity15 whereas hydroxycoumarins are
powerful chain breaking anti-oxidants which prevent free
radical injury.16,17 The diverse biological activities of coumarins
as anticoagulants and antithrombotics are extensively reported
in literature.18 The coumarin motif is present within the
chemical structure of pharmaceutical drugs such as warfarin,
acenocoumarol, carbochromen etc. and in antibiotics such as
novobiocin, clorobiocin and coumermycin A1.19 Coumarin
derivatives have also been used as luminescent probes, triplet
sensitizers and photostable laser dyes.20 For the past 20 years,
these varied applications of coumarins have encouraged many
researchers to synthesize and evaluate the pharmacological
prole of new coumarin derivatives.21
success of the reaction.
Introduction
The Buchwald–Hartwig cross-coupling reaction between
amines and organic halides or triates has emerged as one of
the foremost methods for the creation of C(sp2)–N bonds under
mild conditions.1 The reaction provides an efficient pathway to
a range of pharmaceuticals, natural products, dyes and poly-
mers and hence has signicantly extended its scope in recent
years.2 The development of more efficient ligands by Buchwald
and co-workers3 has considerably increased the extent of these
reactions and has found widespread use in pharmaceutical
industries.4 The metal catalyzed cross-coupling reactions are
considerably slow and usually take hours or days for complete
conversion of reactants which is too long for medicinal chem-
istry research programs in which large libraries of compounds
have to be made within a short period of time.5 The microwave
aDepartment of P.G studies and Research in Industrial Chemistry, Kuvempu University,
Jnana Sahyadri, Shankaraghatta, Shimoga, Karnataka, India-577451. E-mail:
ydbodke@gmail.com; Fax: +91-8282-256262; Tel: +91-8282 256228
bPost Graduate and Research Department of Chemistry, Jamal Mohamed College,
Bharathidasan University, Tiruchirapalli, India
The diverse applications of coumarins in various areas of
chemistry have been well reported in literature. Furthermore,
the structure activity relationship (SAR) studies of various het-
eroaryl/aryl coumarins have revealed that the presence of
substituted heteroaryl/aryl groups in the coumarin moiety is an
indispensable feature for their active pharmacological
cOrganic Chemistry Division, School of Chemical Sciences, Kasaragod Govt. College,
Kannur University, Kannur, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra01720j
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properties.22 However, the instability (lactone ring cleavage) of resorcinol 1 was treated with ethyl acetoacetate in 1-butyl-3-
the coumarin nuclei in basic as well as prolonged heating methylimidazolium chloroaluminate at 30 ꢀC for 20 min.26 The
conditions is broadly reported in literature.22,23 As a continua- obtained hydroxy coumarin 2 was then converted to corre-
tion of our ongoing research program in medicinal chemistry,24 sponding triate 3a by treating it with triuoromethane
ꢀ
we were interested in the synthesis of some substituted amino sulfonic anhydride in pyridine at ꢁ10 C for 2 h. The interme-
and amido coumarins which may possess signicant biological diate thus obtained was then subjected to Buchwald–Hartwig
activity. Continuing with our ongoing studies on microwave amination with the intention of synthesizing a series of novel 4-
assisted synthesis25 and considering the instability of coumarin methyl-7-(heteroaryl) amino/amidocoumarins of considerable
nuclei to prolonged heating conditions, we decided to utilize pharmacological relevance.
the microwave irradiation for the synthesis of various amino
Initially, we carried out the reaction optimization by treating
and amido coumarins in view of the fact that the reaction triate 3a with aniline as the product formation could be easily
could reach to completion within minutes as compared to identied by TLC and LC-MS. The identication of an effective
classical heating. In this letter, we report a rapid and novel catalyst combination is a major task in Buchwald coupling since
access for the synthesis of a variety of 4-methyl-7-(alkyl/aryl/ a variety of catalysts in combination with various ligands have
heteroaryl) amino and amido coumarins 4a–t by utilizing been developed hitherto.3,27 An extensive literature survey
the palladium catalyzed cross-coupling of 4-methyl-7-non- revealed that the amination can be successfully carried out with
auorobutylsulfonyloxycoumarins 3b with various aryl/hetero- Pd2(dba)3 or Pd(OAc)2 in combination with various ligands like
aryl amines under microwave irradiation.
BINAP, dppf, xantphos, DPEphos etc.28 We started our initial
screening in Pd2(dba)3 since the obtained results could be easily
reproducible with quantitative yields and are more efficient
even though it is a little time consuming.4a,d,29 Various in situ
generated catalyst combinations and bases were tried in
dioxane and the reaction was carried out at 120 ꢀC for 30 min at
110 W in a microwave oven (Table 1). To our disappointment, in
most of the cases we found the detriated product 5 as the
major product (>50%) with only traces of required product 4a
(Scheme 2).
Results and discussions
The parent coumarin scaffold 2 was synthesized using the
modied Pechmann cyclization condition (Scheme 1) in which
The triate 3a was proved to be unstable and subsequent C–
O bond cleavage occurred even within 30 min. of the
Scheme
coumarin intermediate.
1 Synthesis of 4-methyl-7-trifluoromethylsulfonyloxy commencement of the reaction. Even though we could see a
little amount of product mass (15%) when xantphos was used as
Table 1 Effect of various ligands and bases in the coupling of triflate 3a with anilinea
Entry
Catalyst
Ligand
Base
Solvent
Yield 5 (%)
Yield 2 (%)
Yield 4a (%)
1
2
3
4
5
6
7
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
BINAP
dppf
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
85
76
28
50
35
Traces
Traces
Traces
<10
45
32
23
Nil
Traces
15
Xantphos
DPEphos
Xantphos
Xantphos
Xantphos
Traces
30b
20
18
40b,c
45b,d
a
Reaction conditions: 4-methyl-7-triuoromethylsulfonyloxy coumarin 3a (1 mmol), aniline (1.3 mmol), Pd2(dba)3 (5 mol%), ligand (0.1 mmol),
b
c
base (2 mmol), dioxane, microwave irradiated at 110 W at 120 ꢀC for 30 min. 1 mmol of TBAF$3H2O used as an additive. Reaction carried
out for 15 min. d Reaction carried out at 100 ꢀC.
Scheme 2 Buchwald coupling of 4-methyl-7-trifluoromethylsulfonyloxy coumarin intermediate with aniline.
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a ligand and Cs2CO3 as base in dioxane, the saponied product dramatically enhances the reactivity of nonaates and hence is
2 of the triate was obtained as a major product (Table 1, entry an ideal tool for creating a good leaving group.34 Moreover, it
3). Although the use of hydrated tetrabutyl ammonium uoride has been reported that the nonaates are less prone to O–S
(TBAF$3H2O) as an additive with Cs2CO3 and xantphos sup- bond cleavage than corresponding triates which subsequently
pressed the triate saponication to some extent, the detriated causes the hydrolysis.35 Owing to these observations, we treated
product 5 prevailed as a major competitor (Table 1, entry 5). the nonaate 3b with aniline in different Pd2(dba)3/ligand
Neither decreasing the reaction time nor the temperature gave combinations and Cs2CO3 as base in various solvents and the
acceptable conversion (Table 1, entries 6 and 7). Among the reaction was carried out in a microwave oven at 120 ꢀC at 110 W
various bases screened (Cs2CO3, K3PO4, NaOtBu, NaOH), for 30 min (Table 2).
Cs2CO3, albeit in low yield, gave better conversions. The
We observed that the reaction conditions and nature of
observed decomposition of aryl triate could be plausibly due to catalyst have a determining inuence on this coupling reaction.
the unstable nature of intermediate Pd(II) complex that is Pd2(dba)3/xantphos catalytic system were found to be essential
expected to arise from initial oxidative addition of the triate to for better conversions and polar solvents like DMF, NMP were
Pd(0).30 It is presumed that the base promoted nucleophilic found to be ineffective (Table 2, entries 1–6). To our delight, we
attack at the sulfur atom is too high in triates which apparently could see the product in considerably better yield when Cs2CO3
caused the undesired phenol formation and resulted in lower was used as a base along with the catalytic system in dioxane
yields of desired product.31
but still the hydrolyzed compound 2 remained as a competitive
In order to circumvent the problems caused by instability side-product (Table 2, entry 4). Fortunately, we obtained the
and saponication of triate, we tried the reaction optimization product in an acceptable yield when TBAF$3H2O (1 equiv.) was
with corresponding
nonaates. The 4-methyl-7-non- used as an additive along with Cs2CO3 in dioxane which
auorobutylsulfonyloxy coumarin intermediate 3b was synthe- signicantly reduced the hydrolysis of the nonaate (Table 2,
sized by the reaction of hydroxy intermediate
2
with entry 7). Finally, addition of one more equivalent of TBAF$3H2O
nonauorobutane sulfonic anhydride in pyridine at ꢁ10 ꢀC for and reducing the reaction temperature to 100 C procured the
1 h (Scheme 3). Nonaates are reported to be more stable than required diaryl amine 4a in 96% yield with 92% of isolated yield
corresponding triates and hence can be stored for longer (Table 2, entry 8).
ꢀ
periods.31a,32 They are slightly more reactive than corresponding
In the present study, the ligands having bite angle less than
triates and are considered as a practical alternative to tri- that of xantphos (108ꢀ) proved to be inefficient (Table 2, entries
ates.33 The strong electron-withdrawing property of the per- 1–3). The superiority of xantphos to other ligands might be
uorinated alkyl chain in combination with the SO2 moiety attributed to the wide bite angle characteristic (Fig. 1) of
Scheme 3 Synthesis of 4-methyl-7-nonafluorobutylsulfonyloxycoumarin intermediate and its Buchwald coupling with various amines.
Table 2 Effect of various ligands and bases in the coupling of nonaflate 3b with anilinea
Entry
Catalyst
Ligand
Base
Solvent
Yield 5 (%)
Yield 2 (%)
Yield 4a (%)
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
BINAP
dppf
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Dioxane
Dioxane
Dioxane
Dioxane
NMP
DMF
Dioxane
Dioxane
28
15
24
Traces
15
Traces
15
Traces
18
76
20
35
35
44
Traces
Traces
48
Traces
35
60
42
DPEphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
30
75b
96c,d
a
Reaction conditions: 4-methyl-7-nonauorobutylsulfonyloxy coumarin 3b (1 mmol), aniline (1.3 mmol), Pd2(dba)3 (5 mol%), ligand (0.1 mmol),
Cs2CO3 (2 mmol), solvent, microwave irradiated at 110 W at 120 ꢀC for 30 min. b 1 mmol of TBAF$3H2O used as an additive. c Reaction carried out at
100 ꢀC. d 2 mmol of TBAF$3H2O used.
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Fig. 1 Structure of various ligands screened and their bite angles.
Table 3 Effect of various bases in the Buchwald coupling reactiona
Aliphatic primary amines didn't furnish any coupled product
with the nonaate in the optimized conditions and was proved
to be inert.
Entry
Base
Yieldb (%)
Our next attention was to elaborate the substrate scope by
extending the reaction for the synthesis of cyclic amides.
Keeping this in mind, we applied the optimized condition to a
variety of heteroannulated pyridones (Scheme 4) and our results
are depicted in Table 5.
Gratifyingly, under these conditions, all the pyridones
coupled well enough to procure the cyclic amides at C-7 position
of coumarins. Sterically hindered pyridones rendered the lac-
tams in comparatively smaller yields than that of other pyr-
idones as expected (Table 5, entries 4 & 6).
A plausible mechanism37 of the coupling reaction of pyr-
idone with nonaate has been proposed (Scheme 5). The rst
step in the catalytic cycle is the formation of a true catalytic
species (a coordinatively unsaturated electron rich palladium
complex) which undergoes oxidative addition with coumarin
nonate to yield oxidative adduct complex 3. The subsequent
step involves the complexation of pyridone with this palladium
complex which increases the acidity of pyridone proton result-
ing in its deprotonation by Cs2CO3 to yield the complex 6.
Finally, it undergoes reductive elimination to form the coupled
diaryl amines and completes the catalytic cycle.
Although the effect of TBAF in these reactions is quite
unclear, it is speculated that TBAF possess some critical bene-
cial roles such as the stabilization of low-coordinated Pd(II)
species 3 and 6 that are expected to form during the coupling
process and acts as a phase-transfer catalyst in order to enhance
the desired product formation.38
1
2
3
4
5
6
7
8
K2CO3
18
25
20
Traces
Traces
48
78
92
NaHCO3
Na2CO3
NaOH
NaOtBu
K3PO4
CsOAc
Cs2CO3
a
Reaction
conditions:
4-methyl-7-nonauorobutylsulfonyloxy
coumarin 3b (1 mmol), aniline (1.3 mmol), Pd2(dba)3 (5 mol%),
xantphos (0.1 mmol), base (2 mmol), TBAF$3H2O (2 mmol), dioxane,
microwave irradiated at 110 W at 100 ꢀC for 30 min. b Isolated yield.
the ligand which increased the steric bulk and enhanced the
reductive elimination step by forming a cis complex in
the catalytic cycle.36 Increase in the solvation of TBAF$3H2O
in the reaction medium when its stoichiometric ratio was
increased could be the prominent feature for the complete
suppression of hydrolysis of the nonaate.31b,c In the current
work, hydrated TBAF considerably reduced the saponication
of the nonaates when compared to triates which is in
agreement with earlier observations.31b,c
Our subsequent efforts were to study the effect of the base in
the reaction system. Keeping this in mind, we explored the
reaction by varying the bases and by keeping all the other
parameters constant (Table 3). Among the various bases
screened, Cs2CO3 gave excellent conversions which could be
attributed to the unique properties of cesium cation like high
ionic radius, low charge density and high polarizibility.25c The
usage of strong bases like NaOtBu and NaOH caused the
substantial cleavage of the lactone ring (Table 3, entries 4, 5).
Conclusion
We have achieved an efficient, modied and concise protocol
With the optimized condition in hands, we shied our for C-7 amination and amidation of 4-methyl-7-non-
attention to evaluate the generality of the developed protocol. A auorobutylsulfonyloxy coumarins by the in situ generation of a
series of primary and secondary amines with various electronic Pd/xantphos catalyst system in presence of Cs2CO3 and
and steric characteristics were effectively coupled with the TBAF$3H2O under microwave irradiation. The nonaates
nonaate and our results are summarized in Table 4. Electron proved to be superior than corresponding triates in terms of
withdrawing amines gave slightly lesser yields even aer 1 h reactivity and stability to hydrolysis. The use of Cs2CO3 as a mild
whereas electron donating amines gave exceptional yields to base which broadened the substrate scope and utilization of
produce the corresponding diaryl amines (Table 4, entries 4–8). hydrated TBAF as an additive which signicantly suppressed
The presence of electron-withdrawing groups might have the nonaate hydrolysis were proved to be the key for success of
reduced the nucleophilicity of the nitrogen in amines which the reaction. This method provided a facile and reliable access
considerably decreased the formation of coupled product. to a variety of pharmacologically relevant coumarins and could
Sterically hindered amines gave slightly lesser yields even aer be extended for the coupling of other densely functionalized
continuing the reaction for 1 h. (Table 4, entries 12–14). heterocycles. The biological screening of the newly synthesized
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Table 4 Buchwald coupling of the nonaflate intermediate with various aminesa
Entry
Nonaate (3)
Amine (2)
Product
Yieldb (%)
1
3b
92
2
3
3b
3b
94
91
4
3b
82
5
3b
79
6
7
3b
3b
76
87
8
3b
90
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Table 4 (Contd.)
Entry
Nonaate (3)
Amine (2)
Product
Yieldb (%)
9
3b
92
10
3b
88
82
11
3b
12
3b
79
13
3b
80
14
3b
82
a
Reaction conditions: 4-methyl-7-nonauorobutylsulfonyloxy coumarin 3b (1 mmol), amine (1.3 mmol), Pd2(dba)3 (5 mol%), xantphos (0.1 mmol),
Cs2CO3 (2 mmol), TBAF$3H2O (2 mmol), dioxane, microwave irradiated at 110 W at 100 ꢀC for 30 min. b Isolated yield.
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Scheme 4 Buchwald coupling of 4-methyl-7-nonafluorobutylsulfonyloxycoumarin intermediate with various pyridones.
molecules will be done in due course and will be communicated ꢁ120.77 to ꢁ120.68, m; d ꢁ112.97 to ꢁ112.87, m; d ꢁ80.59 to
shortly as a continuation of the current work.
ꢁ80.52, m; LC-MS: calculated 394.2, observed 395.2.
General procedure for the synthesis of substituted diaryl
amines
4a–t.
To
a
solution
of
4-methyl-7-non-
auorobutylsulfonyloxy coumarin (3b, 1 equiv.) in dioxane,
were added a premixed solution of Pd2(dba)3 (5 mol%) and
xantphos (0.1 equiv.) in dioxane. The solution was purged with
argon and stirred at room temperature for 10 min, at which
time the amine/pyridone (1.3 equiv.), Cs2CO3 (2 equiv.) and
TBAF$3H2O (2 equiv.) were added. The reaction solution was
purged again with argon and then placed in the microwave and
heated for 20–30 min. at 100 ꢀC at 110 W. When TLC and LC-MS
showed full consumption of starting materials, the reaction
mixture was ltered, diluted with ethyl acetate, separated the
ethyl acetate layer, given water wash, brine wash, dried over
anhydrous sodium sulfate and distilled in vacuo to get the crude
material. The crude product was puried by column chroma-
tography and eluted in varying polarities to obtain the
substituted diaryl amines 4a–t.
Experimental
General information
All solvents and reagents were obtained from commercial
suppliers and used without any further purication unless
otherwise noted. All the reactions were carried out under the
inert atmosphere of argon. Analytical TLC was performed on
pre-coated aluminum sheets of silica (60 F254 nm) and visual-
ized by short-wave UV light at l 254. Melting points were
determined on an EZ-melt automated melting point apparatus.
1H NMR spectra were recorded at 400 MHz and 300 MHz using
an internal deuterium lock. Chemical shis were measured in d
(ppm). Data is presented as follows: chemical shi, multiplicity,
coupling constant (J) in Hz, and integration. The following
abbreviations are 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. 19F NMR spectra were recorded at 376.5 MHz in
CFCl3 using an internal deuterium lock. LC-MS analyses were
performed using ESI/APCI, with an ATLANTIS C18 (50 ꢂ 4.6
4-Methyl-7-(phenylamino)-2H-chromen-2-one (4a). MP: 78–
1
ꢀ
80 C; H NMR (400 MHz, CDCl3): d 2.49, d, J ¼ 1.28 Hz, 3H,
CH3; d 3.94, br, 1H, NH; d 6.49, s, 1H, ArH; d 7.59–7.61, dd, J1 ¼
1.72 Hz J2 ¼ 8.12 Hz, 2H, ArH; d 7.64–7.67, dd, J1 ¼ 1.00 Hz J2 ¼
8.48 Hz, 2H, ArH; d 7.71–7.73, d, J ¼ 7.8 Hz, 1H, ArH; d 7.82–
7.86, m, 1H, ArH; d 7.92–8.05, m, 2H, ArH; 13C NMR (100 MHz,
CDCl3): d 24.7, CH3; d 107.7, d 110.5, d 113.5, d 117.9, d 124.7, d
125.6, d 131.4, d 132.7, d 140.8, d 141.7, d 144.4, d 148.3, d 158.1,
CO; LC-MS: calculated 251.1, observed 252.1; anal. calcd for
mm to 5 mm) column and a ow rate of 1.2 mL minꢁ1
.
Procedure for the synthesis of 4-methyl-7-non-
auorobutylsulfonyloxy 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 nonauorobutane
sulfonic anhydride (1.2 equiv.) drop wise. Reaction mixture was
warmed to 0 ꢀC and stirred for 1 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. Crude compound
was puried 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 3b as colorless solid in 87%
C
16H13NO2: C, 76.48; H, 5.21; N, 5.57%, found: C, 76.39; H, 5.26;
N, 5.53%.
4-Methyl-7-(pyridine-4-ylamino)-2H-chromen-2-one
(4b).
MP: 79–81 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.40, d, J ¼ 2.08 Hz,
3H, CH3; d 3.94, br, 1H, NH; d 7.15–7.18, dd, J1 ¼ 2.96 Hz J2 ¼
7.92 Hz, 1H, ArH; d 7.25–7.28, m, 2H, ArH; d 7.35–7.37, d, J ¼
8.24 Hz, 1H, ArH; d 7.83–7.90, m, 2H, ArH; d 8.26–8.28, dd, J1 ¼
1.4 Hz J2 ¼ 8.16 Hz, 1H, ArH; d 8.40–8.42, d, J ¼ 8.92 Hz, 1H,
ArH; 13C NMR (100 MHz, CDCl3): d 24.7, CH3; d 110.2, d 117.9, d
118.8, d 118.7, d 125.8, d 129.9, d 132.9, d 136.2, d 141.8, d 146.6, d
155.4, d 157.6, CO; LC-MS: calculated 252.2, observed 253.2;
anal. calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10%, found:
C, 71.36; H, 4.87; N, 11.08%.
1
ꢀ
yield. MP: 86–88 C; H NMR (300 MHz, CDCl3): d 2.47, d, J ¼
1.08 Hz, 3H, CH3; d 6.37, 1H, ArH; d 7.23–7.29, m, 2H, ArH; d
7.69, d, J ¼ 8.67 Hz, 1H, ArH; 13C NMR (100 MHz, CDCl3): d 23.2,
CH3; d 115.3, d 116.5, d 116.9, m, CF2; d 118.9, m, CF2; d 126.7, m,
CF3; d 132.2, d 154.1–154.7 (2 peaks), d 156.3, m, SO2CF2; d 163.4,
CO; 19F NMR (376.5 MHz, CDCl3): d ꢁ125.32 to ꢁ125.22, m; d
4-Methyl-7-(pyrimidin-2-ylamino)-2H-chromen-2-one (4c).
MP: 81–84 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.36, d, J ¼ 1.16 Hz,
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Table 5 Buchwald coupling of the nonaflate intermediate with various pyridonesa
Entry
Nonaate (3)
Pyridones (2)
Product
Yieldb (%)
1
3b
91
2
3
4
3b
3b
3b
90
87
82
5
3b
93
6
3b
77
a
Reaction conditions: 4-methyl-7-nonauorobutylsulfonyloxy coumarin 3b (1 mmol), pyridone (1.3 mmol), Pd2(dba)3 (5 mol%), xantphos (0.1
mmol), TBAF$3H2O (2 mmol), Cs2CO3 (2 mmol), dioxane, microwave irradiated at 110 W at 100 ꢀC for 30 min. b Isolated yield.
3H, CH3; d 3.83, br, 1H, NH; d 6.38, s, 1H, ArH; d 6.64–6.66, dd, J1 146.5, d 154.9, d 159.1, CO; d 160.6; LC-MS: calculated 253.1,
¼ 1.76 Hz J2 ¼ 7.84 Hz, 1H, ArH; d 6.83–6.84, d, J ¼ 3.36 Hz, 1H, observed 254.1; anal. calcd for C14H11N3O2: C, 66.40; H, 4.38; N,
Ar H; d 7.27–7.29, m, 2H, ArH; d 7.87–7.89, dd, J1 ¼ 1.44 Hz J2 ¼ 16.59%, found: C, 66.48; H, 4.38; N, 16.54%.
8.48 Hz, 2H, ArH; 13C NMR (100 MHz, CDCl3): d 24.7, CH3; d
7-(4-Fluorophenylamino)-4-methyl-2H-chromen-2-one (4d).
110.7, d 113.8, d 118.0, d 121.5, d 125.8, d 132.7, d 140.1, d 141.9, d MP: 83–85 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.47, d, J ¼ 1.56 Hz,
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7.78, d, J ¼ 7.76 Hz, 1H, ArH; 13C NMR (100 MHz, CDCl3): d 23.4,
CH3; d 26.2, CH3; d 111.1, d 112.2, d 114.3, d 117.8, d 121.8, d
129.7, d 131.1, d 133.2, d 139.6, d 142.4, d 154.3, d 155.8, d 159.5,
CO; LC-MS: calculated 265.1, observed 266.1; anal. calcd for
C
17H15NO2: C, 76.96; H, 5.70; N, 5.28%, found: C, 77.02; H, 5.68;
N, 5.22%.
7-(4-Methoxyphenylamino)-4-methyl-2H-chromen-2-one
1
ꢀ
(4h). MP: 88–90 C; H NMR (400 MHz, CDCl3): d 2.49, d, J ¼
1.56 Hz, 3H, CH3; d 3.88, br, 1H, NH; d 3.93, s, 3H, OCH3; d 6.34,
s, 1H, ArH; d 7.54–7.59, m, 3H, ArH; d 7.64–7.72, m, 3H, ArH; d
8.14–8.17, dd, J1 ¼ 2.24 Hz J2 ¼ 8.68 Hz, 1H, ArH; 13C NMR (100
MHz, CDCl3): d 21.1, CH3; d 55.8, OCH3; d 110.2, d 117.9, d 118.8,
d 125.9, d 129.8, d 132.9, d 136.8, d 141.6, d 141.8, d 146.0, d 146.6,
d 155.5, d 156.3, d 159.5, CO; LC-MS: calculated 281.2, observed
282.2; anal. calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98%,
found: C, 72.71; H, 5.28; N, 4.94%.
4-Methyl-7-(thiophen-3-ylamino)-2H-chromen-2-one
(4i).
MP: 74–76 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.47, d, J ¼ 1.12 Hz,
3H, CH3; d 3.82, br, 1H, NH; d 6.27, s, 1H, ArH; d 6.52–6.55, dd,
J1 ¼ 1.72 Hz J2 ¼ 3.32 Hz, 1H, ArH; d 6.81, d, J ¼ 3.32 Hz, 2H,
ArH; d 7.23–7.26, m, 1H, ArH; d 7.54–7.59, m, 2H, ArH; 13C NMR
(100 MHz, CDCl3): d 23.2, CH3; d 105.6, d 108.7, d 113.6, d 114.9,
d 115.4, d 123.6, d 127.8, d 129.5, d 129.9, d 144.7, d 153.6, d 155.5,
d 159.4, CO; LC-MS: calculated 257.1, observed 258.1; anal.
calcd for C14H11NO2S: C, 65.35; H, 4.31; N, 5.44%, found: C,
65.38; H, 4.31; N, 5.41%.
7-(Furan-3-ylamino)-4-methyl-2H-chromen-2-one (4j). MP:
77–79 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.47, d, J ¼ 1.16 Hz, 3H,
CH3; d 3.84, br, 1H, NH; d 6.29, s, 1H, ArH; d 6.54-6.56, dd, J1 ¼
1.76 Hz J2 ¼ 3.36 Hz, 1H, ArH; d 6.83, d, J ¼ 3.36 Hz, 2H, ArH; d
7.27–7.29, m, 1H, ArH; d 7.57–7.61, m, 2H, ArH; 13C NMR (100
MHz, CDCl3): d 24.8, CH3; d 110.7, d 116.5, d 118.4, d 126.9, d
127.8, d 127.6, d 129.1, d 131.9, d 135.4, d 143.4, d 148.3, d 148.9, d
158.1, CO; LC-MS: calculated 241.2, observed 242.2; anal. calcd
for C14H11NO3: C, 69.70; H, 4.60; N, 5.81%, found: C, 69.84; H,
4.52; N, 5.77%.
7-(N-(4-Fluorophenyl)-N-methylamino)-4-methyl-2H-chromen-
2-one (4k). MP: 87–89 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.49, d, J ¼
1.68 Hz, 3H, CH3; d 3.55, s, 3H, NCH3; d 6.33, s, 1H, ArH; d 7.24–
7.29, m, 2H, ArH; d 6.71–6.73, dd, J1 ¼ 1.48 Hz J2 ¼ 8.56 Hz, 2H,
ArH; d 7.05–7.08, dd, J1 ¼ 1.76 Hz J2 ¼ 7.96 Hz, 2H, ArH; d 7.26, d,
J ¼ 8.72 Hz, 1H, ArH; 13C NMR (100 MHz, CDCl3): d 23.4, CH3; d
43.9, NCH3; d 111.7, d 112.8, d 114.8, d 118.1, d 118.7, d 123.1, d
130.1, d 147.2, d 150.9, d 153.6, d 154.9, m, CF; d 155.8, d 159.8, CO;
LC-MS: calculated 283.1, observed 284.1; anal. calcd for
C17H14FNO2: C, 72.07; H, 4.98; N, 4.94%, found: C, 72.12; H, 4.96;
N, 4.92%.
tert-Butyl 4-(4-methyl-2-oxo-2H-chromen-7-yl)piperazine-1-
carboxylate (4l). MP: 112–114 ꢀC; 1H NMR (400 MHz, CDCl3): d
1.53, s, 9H, t-Bu; d 2.49, d, J ¼ 1.08 Hz, 3H, CH3; d 3.61–3.69, m,
4H, CH2; d 3.69–3.73, m, 4H, CH2; d 6.79, s, 1H, ArH; d 7.22–7.28,
m, 2H, ArH; d 7.46, d, J ¼ 8.84 Hz, 1H, ArH; 13C NMR (100 MHz,
CDCl3): d 23.2, CH3; d 30.7, Boc CH3; d 50.8, CH2; d 51.7, CH2; d
81.9, Boc C; d 106.9, d 112.8, d 113.3, d 114.7, d 129.9, d 151.5, d
153.4, d 154.9, d 156.4, Boc CO; d 159.5, CO; LC-MS: calculated
334.2, observed 245.2; anal. calcd for C19H24N2O4: C, 66.26; H,
7.02; N, 8.13%, found: C, 66.38; H, 7.12; N, 8.17%.
Scheme 5 Proposed mechanism of the coupling reaction.
3H, CH3; d 3.96, br, 1H, NH; d 6.33, s, 1H, ArH; d 7.27–7.29, m,
2H, ArH; d 7.44–7.47, m, 2H, ArH; d 7.76–7.80, m, 2H, ArH; d
8.04, d, J ¼ 8.20 Hz, 1H, ArH; 13C NMR (100 MHz, CDCl3): d 24.7,
CH3; d 110.6, d 113.8, d 118.0, d 121.5, d 125.8, d 132.7, d 140.2, d
141.9, d 146.5, d 148.5, d 154.9, m, CF; d 160.1, CO; LC-MS:
calculated 269.2, observed 270.2; anal. calcd for C16H12FNO2: C,
71.37; H, 4.49; N, 5.20%, found: C, 71.49; H, 4.41; N, 5.17%.
Methyl 4-(4-methyl-2-oxo-2H-chromen-7-ylamino)benzoate
(4e). MP: 96–98 ꢀC; 1H NMR (300 MHz, CDCl3): d 2.49, d, J ¼ 1.17
Hz, 3H, CH3; d 3.88, br, 1H, NH; d 3.96, s, 3H, OCH3; d 6.34, s,
1H, ArH; d 7.47–7.51, m, 3H, ArH; d 7.64–7.72, m, 3H, ArH; d
8.14–8.17, dd, J1 ¼ 1.68 Hz J2 ¼ 6.51 Hz, 1H, ArH; 13C NMR (100
MHz, CDCl3): d 23.2, CH3; d 54.3, CH3(ester); d 111.4, d 112.6, d
114.5, d 117.8, d 121.1, d 121.8, d 129.8, d 133.1, d 142.2, d 146.4, d
154.2, d 156.1, d 159.8, CO; 165.4, CO(ester); LC-MS: calculated
309.1, observed 310.1; anal. calcd for C18H15NO4: C, 69.89; H,
4.89; N, 4.53%, found: C, 69.94; H, 4.86; N, 4.51%.
4-(4-Methyl-2-oxo-2H-chromen-7-ylamino)benzonotrile (4f).
MP: 85–87 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.49, d, J ¼ 1.52 Hz,
3H, CH3; d 3.95, br, 1H, NH; d 6.49, s, 1H, ArH; d 7.59–7.64, m,
2H, ArH; d 7.71, d, J ¼ 7.8 Hz, 1H, ArH; d 7.82–7.86, dd, J1 ¼
1.24 Hz J2 ¼ 7.72 Hz, 2H, ArH; d 8.02, d, J ¼ 7.76 Hz, 2H, ArH;
13C NMR (100 MHz, CDCl3): d 24.7, CH3; d 108.5, d 109.8, d
117.9, d 118.8, d 125.9, d 129.8, CN; d 132.9, d 136.2, d 141.6, d
141.8, d 146.3, d 146.6, d 155.4, d 156.6, d 159.5, CO; LC-MS:
calculated 276.2, observed 277.2; anal. calcd for C17H12N2O2:
C, 73.90; H, 4.38; N, 10.14%, found: C, 73.99; H, 4.34; N,
10.11%.
7-(p-Tolylamino)-4-methyl-2H-chromen-2-one (4g). MP: 84–
1
ꢀ
86 C; H NMR (400 MHz, CDCl3): d 2.49, d, J ¼ 1.64 Hz, 3H,
CH3; d 3.14, s, 3H, CH3; d 3.76, br, 1H, NH; d 6.49, s, 1H, ArH; d
6.84–6.89, m, 2H, ArH; d 6.96–6.99, dd, J1 ¼ 1.24 Hz J2 ¼ 7.76 Hz,
2H, ArH; d 7.46–7.49, dd, J1 ¼ 1.36 Hz J2 ¼ 7.92 Hz, 2H, ArH; d
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d, J ¼ 7.24 Hz, 1H, ArH; d 7.52, d, J ¼ 7.64 Hz, 1H, ArH; d 7.80–
7.82, dd, J1 ¼ 1.12 Hz J2 ¼ 7.88 Hz, 2H, ArH; d 8.20–8.28, d, J ¼
6.84 Hz, 1H, ArH; 13C NMR (100 MHz, CDCl3): d 24.7, CH3; d
30.5, OCH3; d 110.2, d 117.9, d 118.8, d 125.9, d 129.8, d 132.9, d
136.2, d 141.6, d 141.8, d 146.4, d 146.6, d 154.7, d 155.4, d 156.6,
CO (pyridone); d 159.5, CO; LC-MS: calculated 334.2, observed
335.2; anal. calcd for C19H14N2O4: C, 68.26; H, 4.22; N, 8.38%,
found: C, 68.38; H, 4.18; N, 8.32%.
5-Methyl-1-(4-methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-
one (4s). MP: 82–84 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.40, d, J ¼
2.24 Hz, 3H, CH3; d 2.41, s, 3H, CH3; d 6.41, s, 1H, ArH; d 7.13–
7.16, dd, J1 ¼ 1.36 Hz J2 ¼ 7.92 Hz, 1H, ArH; d 7.22–7.27, m, 1H,
ArH; d 7.66–7.69, dd, J1 ¼ 2.04 Hz J2 ¼ 8.12 Hz, 1H, ArH; d 7.81–
7.83, dd, J1 ¼ 1.4 Hz J2 ¼ 7.88 Hz, 1H, ArH; d 8.20–8.25, m, 2H,
ArH; 13C NMR (100 MHz, CDCl3): d 18.5, CH3; d 24.7, CH3; d
110.2, d 117.9, d 118.8, d 125.9, d 129.8, d 132.9, d 136.2, d 141.6, d
141.8, d 146.3, d 146.6, d 155.4, d 156.6, CO (pyridone); d 159.5,
CO; LC-MS: calculated 267.3, observed 268.3; anal. calcd for
7-(4-Hydroxy-4-phenylpiperidin-1-yl)-4-methyl-2H-chromen-
2-one (4m). MP: 106–108 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.49,
d, J ¼ 1.64 Hz, 3H, CH3; d 2.51–2.54, m, 4H, CH2; d 2.62, s, 1H,
OH; d 3.363.41, m, 4H, CH2; 6.39, s, 1H, ArH; d 6.85–6.89, m, 2H,
ArH; d 7.57, d, J ¼ 8.84 Hz, 1H, ArH; d 7.72–7.74, m, 5H, ArH; 13
C
NMR (100 MHz, CDCl3): d 24.7, CH3; d 40.3, d 45.8, d 76.6, d
106.9, d 112.8, d 113.3, d 114.7, d 128.4, d 129.9, d 130.5, d 131.2, d
142.3, d 151.4, d 153.3, d 155.1, d 159.6, CO; LC-MS: calculated
335.2, observed 336.2; anal. calcd for C21H21NO3: C, 75.20; H,
6.31; N, 4.18%, found: C, 75.34; H, 6.27; N, 4.12%.
4-Methyl-7-(4-(2-methylpyridin-4-yl)piperazin-1-yl)-2H-chro-
men-2-one (4n). MP: 112–114 ꢀC; 1H NMR (400 MHz, CDCl3): d
2.18, d, J ¼ 2.4 Hz, 3H, CH3; d 2.48, s, 3H, CH3; d 3.40–3.52, m,
8H, CH2; d 6.91, s, 1H, ArH; d 7.00–7.02, d, J ¼ 7.6 Hz, 1H, ArH; d
7.10–7.14, dd, J1 ¼ 2.8 Hz J2 ¼ 7.6 Hz, 1H, ArH; d 8.20–8.21, d, J ¼
6.8 Hz, 1H, ArH; d 7.27–7.34, m, 2H, ArH; d 8.46, d, J ¼ 7.2 Hz,
1H, ArH; 13C NMR (100 MHz, CDCl3): d 23.4, CH3; d 27.3, CH3; d
31.7, d 44.6, d 51.7, d 106.9, d 113.5, d 113.7, d 115.4, d 122.6,
d 124.7, d 129.8, d 151.2, d 151.4, d 153.2, d 154.9, d 159.5, d 160.4,
d 163.3, CO; LC-MS: calculated 335.1, observed 336.1; anal.
calcd for C20H21N3O2: C, 71.62; H, 6.31; N, 12.53%, found: C,
71.68; H, 6.27; N, 12.51%.
4-(Triuoromethyl)-1-(4-methyl-2-oxo-2H-chromen-7-yl)pyridin-
2(1H)-one (4o). MP: 92–94 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.49,
d, J ¼ 1.76 Hz, 3H, CH3; d 6.21, d, J ¼ 7.80 Hz, 1H, ArH; d 6.33, s,
1H, ArH; d 7.34, s, 1H, ArH; d 7.46–7.49, m, 4H, ArH; 13C NMR
(100 MHz, CDCl3): d 24.7, CH3; d 108.5, d 110.8, d 113.8, d 117.6,
d 121.5, d 125.8, d 132.7, d 140.2, d 141.9, m, CF3; d 146.5, d 148.5,
d 154.9, d 160.7, CO (pyridone); d 163.1, CO; LC-MS: calculated
321.2, observed 322.2; anal. calcd for C16H10F3NO3: C, 59.82; H,
3.14; N, 4.36%, found: C, 59.96; H, 3.04; N, 4.34%.
C
16H13NO3: C, 71.90; H, 4.90; N, 5.24%, found: C, 71.95; H, 4.90;
N, 5.20%.
3-Chloro-7-(4-methyl-2-oxo-2H-chromen-7-yl)-1,7-naphthyr-
idin-8(7H)-one (4t). MP: 116–118 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.49, d, J ¼ 2.36 Hz, 3H, CH3; d 6.34, s, 1H, ArH; d 6.47–6.53, m,
2H, ArH; d 7.37–7.41, m, 2H, ArH; d 7.54–7.56, dd, J1 ¼ 2.24 Hz
J2 ¼ 8.04 Hz, 1H, ArH; d 8.72, s, 1H, ArH; d 9.21, s, 1H, ArH; 13
C
NMR (100 MHz, CDCl3): d 23.4, CH3; d 109.9, d 114.3, d 114.5, d
119.0, d 120.5, d 129.3, d 133.2, d 134.7, d 136.2, d 139.1, d 141.3, d
149.7, d 152.2, d 152.7, d 155.1, d 162.8, CO (pyridone); d 163.6,
CO; LC-MS: calculated 338.2, observed 339.2 & 341.2; anal. calcd
for C18H11ClN2O3: C, 63.82; H, 3.27; N, 8.27%, found: C, 63.94;
H, 3.23; N, 8.21%.
1-(4-Methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-one (4p).
MP: 79–82 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.41, d, J ¼ 2.08 Hz,
3H, CH3; d 7.15–7.18, dd, J1 ¼ 1.76 Hz J2 ¼ 7.92 Hz, 1H, ArH; d
7.27, s, 1H, ArH; d 7.35, d, J ¼ 8.24 Hz, 2H, ArH; d 7.83–7.90, m,
2H, ArH; d 8.26–8.28, m, 2H, ArH; 13C NMR (100 MHz, CDCl3): d
24.7, CH3; d 110.0, d 116.6, d 117.9, d 125.6, d 131.4, d 132.7, d
140.5, d 140.8, d 141.7, d 144.4, d 146.6, d 149.9, d 158.0, CO
(pyridone); d 160.6, CO; LC-MS: calculated 253.2, observed
254.2; anal. calcd for C15H11NO3: C, 71.14; H, 4.38; N, 5.53%,
found: C, 71.24; H, 4.36; N, 5.47%.
Acknowledgements
The authors are thankful to the Chairman, Department of
Industrial Chemistry, Kuvempu University for providing all the
facilities to carry out the research work. The authors are also
thankful to SAIF, Indian Institute of Technology, Madras for
rendering the analytical data and SIF, Indian Institute of
Science, Bangalore for providing the spectra.
3-Methyl-1-(4-methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-
one (4q). MP: 82–84 ꢀC; 1H NMR (400 MHz, CDCl3): d 2.43, d, J ¼
2.16 Hz, 3H, CH3; d 2.47, s, 3H, CH3; d 6.43, s, 1H, ArH; d 7.15, d,
J ¼ 8.04 Hz, 1H, ArH; d 7.25–7.29, m, 1H, ArH; d 7.68–7.71, dd,
J1 ¼ 1.96 Hz J2 ¼ 8.04 Hz, 1H, ArH; d 7.83–7.86, dd, J1 ¼ 2.12 Hz
J2 ¼ 8.28 Hz, 1H, ArH; d 8.19–8.25, m, 2H, ArH; 13C NMR (100
MHz, CDCl3): d 18.2, CH3; d 24.7, CH3; d 107.7, d 109.2, d 123.6, d
127.3, d 135.7, d 137.1, d 143.8, d 148.3, d 148.9, d 149.7, d 155.1, d
160.8, CO (pyridone); d 162.9, CO; LC-MS: calculated 267.3,
observed 268.3; anal. calcd for C16H13NO3: C, 71.90; H, 4.90; N,
5.24%, found: C, 71.98; H, 4.86; N, 5.22%.
References
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3-Methoxy-7-(4-methyl-2-oxo-2H-chromen-7-yl)-1,7-naphthyr-
idin-8(7H)-one (4r). MP: 120–122 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.49, d, J ¼ 2.24 Hz, 3H, CH3; d 4.11, s, 3H, OCH3; d 7.14–7.17,
dd, J1 ¼ 2.96 Hz J2 ¼ 7.92 Hz, 2H, ArH; d 7.27, s, 1H, ArH; d 7.36,
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