Transition-metal free C(sp2)-C(sp2) bond formation: Arylation of 4-aminocoumarins using arynes as an aryl source

Article abstract of DOI:10.1039/c9ob01919g

A mild, efficient and transition-metal free synthetic strategy has been developed for the α-arylation of 4-aminocoumarins. This synthetic strategy proceeds via C(sp²)-C(sp²) bond formation between 4-aminocoumarins and aryne precursors in a single step by simple treatment with a fluoride source in the absence of a metal-catalyst. Moreover, this methodology affords good yields of 4-amino-3-arylcoumarin derivatives bearing halide functionality.

Full text of DOI:10.1039/c9ob01919g

Organic &
Biomolecular Chemistry
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PAPER
Transition-metal free C(sp2)–C(sp2) bond
formation: arylation of 4-aminocoumarins
using arynes as an aryl source†
Cite this: Org. Biomol. Chem., 2019,
17, 9014
a,b
Abhilash Sharmaa,b and Pranjal Gogoi
*
A mild, efficient and transition-metal free synthetic strategy has been developed for the α-arylation
of 4-aminocoumarins. This synthetic strategy proceeds via C(sp2)–C(sp2) bond formation between
4-aminocoumarins and aryne precursors in a single step by simple treatment with a fluoride source in the
absence of a metal-catalyst. Moreover, this methodology affords good yields of 4-amino-3-arylcoumarin
derivatives bearing halide functionality.
Received 2nd September 2019,
Accepted 25th September 2019
DOI: 10.1039/c9ob01919g
rsc.li/obc
Grignard reagents for the construction of a C(sp2)–C(sp2)
Introduction
bond.6 Furthermore, Wang and co-workers have reported a
C–C bond formation reactions between two sp2 hybridized metal-free direct C–H arylation of quinones and naphtho-
carbon centers are one of the most fundamental reactions in quinones using diaryliodonium salts as an aryl source.7
organic synthesis which provide the foundation for the con- Later, Li et al. have developed a photocatalyst-free oxidative
struction of molecular frameworks and have been in the fore- C(sp2)–H thiocyanation of heteroarenes and arenes.8
front of research in organic synthesis.1 There are several estab- Similarly, Xie and his group have reported C-3 alkoxycarbo-
lished synthetic strategies where different functionalized nylation and C-3 alkylation of quinoxalin-2(1H)-ones.9a,b
carbon centers have been used for the construction of such Recently, Xie and co-workers have reported visible light-
C–C bonds.2 In this regard, transition-metal catalysts play a induced organic dye-catalyzed C-2 sulfonylation of quinoline
predominant role in the construction of C–C bonds.3
A
N-oxides.9c In addition to these, cross-dehydrogenative coup-
variety of metal catalysts such as Mn, Cu, Ni, Pd, Ag, Ru, Rh, ling (CDC) is another method which leads to the formation
Ir etc. have been extensively used for this task. Among the of C–C bonds directly between two unmodified C–H
numerous synthetic methods for the construction of C–C bonds.10 This CDC strategy is particularly applicable to an
bonds, transition-metal free reactions have gained predomi- sp3 hybridized carbon center which is adjacent to the carbo-
nance over others and are widely accepted in industrial prac- nyl group or heteroatom or at the allylic and benzylic posi-
tice due to their environmental friendliness. Additionally tions. Therefore, the development of new synthetic strat-
most of the transition metals are toxic in nature, and the egies for direct C–C bond formation between two sp2 hybri-
removal of trace amounts of such transition-metal residues dized carbon centers is highly desirable and necessary in
from the desired products is quite necessary and challen- organic synthesis.
ging in the pharmaceutical industries.4 To overcome such
On the other hand, arynes are versatile transient intermedi-
issues, metal-free strategies have been developed for C–C ates and have emerged as potent electrophiles for the atom
bond formation via direct C–H/C–H cross coupling. In this economical synthesis of various building blocks and natural
regard, Itami and co-workers have reported a base-promoted products.11 In this context, Kobayashi’s protocol using o-silyl
metal-free coupling reaction of aryl halides with arenes.5 aryl triflate12 as a versatile aryne precursor is widely accepted
Later, Shirakawa and Hayashi have reported a transition- in the synthetic community for the development of new-aryne
metal free coupling reaction between aryl halides and aryl based reactions which include muticomponent,13 cyclo-
addition,14 and insertion reactions.15 Interestingly, various
nucleophiles including N-heterocycles, urea and imines could
aApplied Organic Chemistry Group, Chemical Science and Technology Division,
be coupled with arynes to form their corresponding insertion
products.16 They also serve as key building blocks for the con-
CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India.
E-mail: gogoipranj@yahoo.co.uk
struction of transition-metal-free C–C bonds via coupling with
a suitable nucleophile. However, metal-free C-arylation reac-
tions using arynes as an aryl source are rare. In this regard,
bAcademy of Scientific and Innovative Research (AcSIR), CSIR-NEIST Campus, India
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR and HRMS spectra of all products. See DOI: 10.1039/c9ob01919g
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Chartrand and Ramtohul have reported a method for direct products were obtained when amines and sulphonamides
C-arylation of β-enamino esters and ketones employing react with arynes (Scheme 1b).23 These interesting reactions of
arynes.17 Also, Hu and co-workers have developed a nucleophi- N-arylation as well as C-arylation of aniline encouraged us to
lic fluoroalkylation of arynes using a nucleophilic fluoroalky- develop a new arylation strategy for 4-aminocoumarins. In our
lating agent.18 Recently, Mhaske and co-workers have reported investigation, it is interesting to note that when 4-aminocou-
a metal-free C-arylation of malonamide esters employing aryne marins were treated with an aryne precursor in the presence of
precursors.19 Furthermore, Rodriguez et al. have developed a a fluoride source, a C-arylated product was formed instead of
general method for C-arylation of β-ketoamides.20 Moreover, an N-arylated product without the protection of amine
arynes have also been used for direct C-arylation reactions functionality.
involving C(sp2)–C(sp2) bond formation. In this regard
In continuation of our research on the development of new
Greaney et al. have reported a transition-metal-free direct aryla- synthetic strategies involving aryne chemistry,24 we present
tion of anilines via C–H arylation instead of N–H arylation due here the α-arylation of 4-aminocoumarins under transition-
to steric hindrance around the nitrogen atom (Scheme 1a).21 metal-free conditions (Scheme 1c). 4-Amino-3-arylcoumarin
Later, they also developed a metal-free Truce–Smiles rearrange- was previously synthesized via acylation of 2-hydroxybenzoni-
ment for the synthesis of bis(hetero)aryls via coupling of two trile with α-ketoacid chlorides followed by treatment with
sp2-carbon centers.22 Another interesting chemistry was TiCl3 and Zn dust at refluxed temperature.25 Besides the use
reported by Larock’s group, where regioselective N-arylated of transition metals, this synthetic approach involves a multi-
step sequence. Therefore, a general and versatile synthetic
method for efficient synthesis of 4-amino-3-arylcoumarin
derivatives under mild conditions is highly desirable. To the
best of our knowledge, there is no such synthetic method-
ology involving direct arylation of 4-aminocoumarins with
arynes.
Results and discussion
We initiated our optimization studies by treating benzyne
derived in situ from 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate 1a (0.25 mmol) and CsF (0.5 mmol) with 4-amino-
coumarin 2a (0.25 mmol) in CH3CN at room temperature for
6 h. Under these reaction conditions, the desired product 3aa
Scheme 1 Scope of N- vs. C-arylation.
Table 1 Optimization studiesa
was obtained in 45% yield (Table 1, entry 1). To improve the
Entry
F− source (equiv.)
Additive (equiv.)
Solvent
Time (h)
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
CsF (2.0)
KF (2.0)
TBAF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (3.0)
KF (4.0)
KF (3.0)
KF (3.0)
—
—
—
—
CH3CN
CH3CN
CH3CN
CH3CN
THF
DCM
Dioxane
DMF
DMSO
CH3CN/THF (1 : 1)
THF
THF
THF
6
6
6
6
6
6
6
6
6
6
6
6
6
3
6
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
rt
45
50
Trace
65
70
ND
ND
ND
ND
52
72
70
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.0)
18-Crown-6 (1.5)
18-Crown-6 (1.5)
—
9
10
11
12
13
14
15
76
67
ND
THF
THF
a Conditions: o-Silyl aryl triflate 1a (0.25 mmol), 4-aminocoumarin 2a (0.25 mmol), fluoride source (2 to 4 equiv.), additive (1 to 2 equiv.), solvent
(3 mL) stirred at rt for 6 h. b Isolated yield. ND: not detected.
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Table 2 One-pot synthesis of 4-amino-3-arylcoumarinsa
yield of the reaction product we used KF instead of CsF as the
fluoride source. Under these reaction conditions, the desired
product 3aa was isolated in 50% yield (Table 1, entry 2).
When TBAF was used only traces of 3aa were observed
(Table 1, entry 3). The use of KF in the presence of 18-crown-6
in CH3CN produced 3aa in 65% yield (Table 1, entry 4). During
our optimization studies, we also investigated the solvent
effect by screening some common solvents, such as THF,
DCM, dioxane, DMF, and DMSO and a solvent mixture of
CH3CN and THF. To our delight, a significantly improved yield
of 70% was observed when the reaction was performed in THF
(Table 1, entry 5). The use of a mixture of CH3CN and THF
gave 3aa in 52% yield (Table 1, entry 10). The desired product
3aa was not observed when DCM, dioxane, DMF and DMSO
were used as solvents (Table 1, entries 6–9). After optimizing
our fluoride source and reaction media, a few more experi-
ments were performed by changing the amount of KF and
18-crown-6 (Table 1, entries 11 to 13). Interestingly, an
improved yield of 76% was observed when the reaction was
performed using 3 equiv. of KF as a fluoride source and 1.5
equiv. of 18-crown-6 as an additive in THF for 6 h (Table 1,
entry 13), which were considered to be the optimized reaction
conditions. Moreover, increasing the reaction temperature and
decreasing the reaction time lowered the yield of product 3aa
(Table 1, entry 14). As a control experiment, when the reaction
was performed in the absence of fluoride, product 3aa was not
observed (Table 1, entry 15). The coupled product 3aa was
1
characterized by H NMR, 13C NMR and HRMS analyses and
compared with the reported data (see the ESI†).
With the optimized reaction conditions in hand, we next
generalized our transition-metal free C–C bond formation
strategy for the synthesis of our targeted 4-amino-3-arylcou-
marin derivatives (Table 2).
The cascade transition-metal free reactions of arynes with a
wide range of 4-aminocoumarins for the one-pot synthesis of
4-amino-3-arylcoumarin derivatives are presented in Table 2.
As shown in Table 2, o-silyl aryl triflate 1a was treated with a
variety of 4-aminocoumarins bearing methyl, fluoro, chloro,
a Conditions: o-Silyl aryl triflate 1 (0.25 mmol), 4-aminocoumarin 2
(0.25 mmol), KF (0.75 mmol), 18-crown-6 (0.37 mmol), THF (3 mL)
stirred at rt for 6 h.
bromo and methoxy substituents leading to our desired 3-aryl- variety of 4-aminocoumarins to obtain 4-amino-3-arylcoumar-
4-aminocoumarins being obtained in good yields (Table 2, ins in 72–66% yields (Table 2, 3ba–3ch). Moreover, symmetri-
3aa–3ah). It is noteworthy that both electron-rich and electron- cal aryne derived from 1d was also treated with 4-aminocou-
deficient 4-aminocoumarins efficiently participated in the one- marin to furnish the desired product 3da in good yield. In
pot metal-free coupling process to provide the corresponding addition, an aryne precursor bearing an electron-withdrawing
products (3ab–3ah) in good yields. This result confirms that group such as 4,5-difluoro-2-(trimethylsilyl)phenyl trifluoro-
the electronic effects of the substituents did not play any sig- methanesulfonate 1e was also used as a suitable aryne precur-
nificant role in our reaction. Importantly, the chloro- and sor, leading to our desired product 3ea in 67% yield.
bromo-substituents tolerated the reaction conditions and can
Moreover, secondary amine 2i was also used as a substrate
be used for further functionalization (Table 2, 3ad and 3ae). for our coupling process. In this investigation, o-silyl aryl tri-
Moreover, 6,7 disubstituted 4-aminocoumarin 2ag also pro- flate 1a is allowed to react with 2i under our optimized reac-
vided the desired product 3ag in good yield. Other symmetrical tion conditions to obtain the desired product 3-phenyl-4-(phe-
silyltriflates such as 4,5-dimethoxy-2-(trimethylsilyl)phenyl tri- nylamino)-2H-chromen-2-one in 62% yield (Scheme 2).
fluoromethanesulfonate 1b, 3-(trimethylsilyl)-2-naphthyl tri-
Similarly, secondary amine 2j was also examined for our
fluoromethanesulfonate 1c and 5-(trimethylsilyl)benzo[d][1,3] arylation process where N-protected iso-butyl aminocoumarin
dioxol-6-yl trifluoromethanesulphonate 1d were also explored 2j gives our desired product 4-(isobutylamino)-3-phenyl-2H-
as aryne precursors for our one-pot synthetic strategy. In this chromen-2-one in only 19% yield, which could be due to the
regard, symmetrical silyl triflates 1b and 1c were treated with a steric hindrance of the iso-butyl group (Scheme 3).
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Table 3 Synthesis of 4-amino-3-arylcoumarins from unsymmetrical
benzyne precursorsa
Scheme 2 Synthesis of 3-phenyl-4-(phenylamino)-2H-chromen-2-
one from aryne.
Benzyne
Entry precursors (1f–j)
4-Amino-3-arylcoumarins (3fa–3ja)
1
2
3
4
5
Scheme 3 Synthesis of 4-(isobutylamino)-3-phenyl-2H-chromen-2-
one from aryne.
However, the yield of the product obtained from secondary
aminocoumarins 2i and 2j is lower than that from primary
aminocoumarins. This suggests that 4-aminocoumarin 2a is a
better substrate than secondary aminocoumarins 2i and 2j.
In order to explore the substrate scope, unsymmetrical
benzyne precursors i.e. 4-methyl-2-(trimethylsilyl)phenyl tri-
fluoromethanesulfonate 1f and 4-methoxy-2-(trimethylsilyl)
phenyl trifluoromethanesulfonate 1g were treated with 4-ami-
nocoumarin 2a under our optimized reaction conditions
(Table 3).
a Conditions: o-Silyl aryl triflate 1 (0.25 mmol), 4-aminocoumarin 2
(0.25 mmol), KF (0.75 mmol), 18-crown-6 (0.37 mmol), THF (3 mL)
stirred at rt for 6 h.
Benzyne precursors 1f and 1g gave 4-amino-3-arylcoumarin
derivatives 3fa/3f′a and 3ga/3g′a as a mixture of regioisomers
in good yields (Table 3, entries 1 and 2). The regioisomers
were not separated into individual isomers and they are rep-
resented as mixtures. Interestingly, when unsymmetrical
arynes derived from 2-methyl-6-(trimethylsilyl)phenyl trifluoro-
methanesulfonate 1h, 3-methoxy-2-(trimethylsilyl)phenyl tri-
fluoromethanesulfonate 1i and 1-(trimethylsilyl)-2-naphthyl
trifluoromethanesulfonate 1j were treated with 2a, single regio-
isomers 3ha, 3ia and 3ja were obtained in 67%, 69% and 67%
yields, respectively, with excellent regioselectivities.
To gain insight into the reaction mechanism, a few deuter-
ium-labelling experiments were performed. As shown in
Scheme 4, when 4-aminocoumarin 2a was treated with o-silyl
aryl triflate 1a under the optimized conditions, no deuterium
incorporated product 3aa was observed. Another independent
experiment was performed using these two substrates in THF
(dry) in the presence of D2O as the fourth component under
Scheme 4 Deuterium labelling experiments.
the same reaction conditions. Interestingly, this experiment Scheme 5. As shown in Scheme 5, the carbon atom of the
gave the deuterium incorporated product 3aa-D in 72% yield enamine moiety of 2a undergoes direct nucleophilic addition
with quantitative incorporation of deuterium at the ortho-posi- to arynes generated in situ from aryne precursor 1a to form a
1
tion, which was characterized by H and 13C NMR and HRMS zwitterionic intermediate A. Subsequently, intermediate A
analyses (Scheme 4).
undergoes deprotonation at the activated methylene position
Based on our experiments, a plausible reaction mechanism followed by protonation at the aryl ring to form our desired
for the synthesis of 4-amino-3-arylcoumarin is proposed in product 3aa.
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acetate (20 equiv.) was stirred at 130 °C overnight. After com-
pletion of the reaction, water (50 ml) was added. The mixture
was stirred for 20 min, filtered and concentrated in vacuo. The
residue was successively washed with water and ethanol to give
Scheme 5 Probable reaction mechanism for the synthesis of 4-amino- 4-aminocoumarin 2a. Compounds 2b–h were prepared using
3-arylcoumarin.
the same method.
4-Amino-2H-chromen-2-one (2a).26 Applying the general
experimental procedure using 4-hydroxycoumarin (3 mmol,
1 equiv.) and ammonium acetate (60 mmol, 20 equiv.),
4-amino-2H-chromen-2-one 2a was obtained as a light brown
1
solid (0.430 g, 89% yield); mp 233–235 °C; H NMR (500 MHz,
DMSO-d6): δ 7.98 (dd, J1 = 1.0 Hz, J2 = 8.3 Hz, 1H), 7.56–7.59
(m, 1H), 7.40 (br s, 2H), 7.28–7.31 (m, 2H), 5.22 (s, 1H); 13C
NMR (126 MHz, DMSO-d6): δ 161.6, 155.5, 153.5, 132.0, 123.1,
Scheme 6 Gram scale experiment for 3aa.
122.8, 116.7, 114.3, 83.7; IR (CHCl3): 3376, 3212, 2917, 2850,
1638, 1549, 1219, 772 cm−1; HRMS (+ESI) calcd for C9H8NO2
[M + H]+: 162.0555; found: 162.0564.
4-Amino-6-methyl-2H-chromen-2-one (2b).26 Applying the
Furthermore, to explore the practical utility of our synthetic
strategy, the synthetic strategy was performed on a gram scale
(Scheme 6). In our experiment, 1a (6 mmol) was treated with
2a (6 mmol) under our optimized conditions to give our
desired product 3aa in 72% yield.
general experimental procedure using 4-hydroxy-6-methyl-
coumarin (2 mmol, equiv.) and ammonium acetate
1
(40 mmol, 20 equiv.), 4-amino-6-methyl-2H-chromen-2-one 2b
was obtained as a light brown solid (0.287 g, 82% yield); mp
266–268 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.80 (d, J =
0.9 Hz, 1H), 7.39 (dd, J1 = 1.8 Hz, J2 = 8.4 Hz, 1H), 7.32 (br s,
2H), 7.17 (d, J = 8.4 Hz, 1H), 5.19 (s, 1H), 2.35 (s, 3H); 13C NMR
(126 MHz, DMSO-d6): δ 161.8, 155.5, 151.7, 132.8, 132.4, 122.7,
116.5, 114.0, 83.8, 20.4; IR (CHCl3): 3376, 3207, 2922, 2845,
1621, 1570, 1218, 772 cm−1; HRMS (+ESI) calcd for C10H10NO2
[M + H]+: 176.0712; found: 176.0710.
Conclusion
In summary, we have developed a mild, efficient and tran-
sition-metal-free C(sp2)–C(sp2) bond forming strategy for the
direct synthesis of 4-amino-3-arylcoumarins using aryne as an
aryl source. A series of 4-amino-3-arylcoumarins have been syn-
thesized using this one-pot synthetic strategy in good yields
with excellent functional group compatibility including
halides. Remarkably, this synthetic strategy gave a C-arylated
product instead of an N-arylated product without protecting
amine functionality.
4-Amino-6-fluoro-2H-chromen-2-one (2c).26 Applying the
general experimental procedure using 6-fluoro-4-hydroxycou-
marin (1 mmol, 1 equiv.) and ammonium acetate (20 mmol,
20 equiv.), 4-amino-6-fluoro-2H-chromen-2-one 2c was
obtained as a light brown solid (0.145 g, 80% yield); mp
298–300 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.89 (dd, J1
=
2.9 Hz, J2 = 9.7 Hz, 1H), 7.44–7.49 (m, 1H), 7.41 (br s, 2H),
7.34–7.37 (m, 1H), 5.24 (s, 1H); 13C NMR (126 MHz, DMSO-d6):
δ 161.4, 157.6 (d, J = 239.3 Hz), 154.8, 149.9, 119.4 (d, J =
24.2 Hz), 118.7 (d, J = 8.6 Hz), 115.3 (d, J = 8.7 Hz), 108.8 (d, J =
25.3 Hz), 84.2; IR (CHCl3): 3368, 3203, 2922, 2835, 1635, 1551,
1220, 772 cm−1; HRMS (+ESI) calcd for C9H7FNO2 [M + H]+:
180.0461; found: 180.0461.
Experimental section
General
All reactions involving oxygen- or moisture-sensitive com-
pounds were carried out under an argon atmosphere using
oven-dried or flame-dried glassware. All other solvents and
reagents were purified according to the standard procedures or
were used as received from TCI, Aldrich, Merck and
Spectrochem. The reactions were monitored by thin-layer
chromatography (TLC) using aluminium-backed silica gel
plates (0.2 mm thickness); the chromatograms were visualized
with ultraviolet light (254 nm). Flash column chromatography
was performed with silica gel 60 (100–200 or 200–400 mesh).
HRMS data were recorded by electrospray ionization with a
Q-TOF mass analyzer.
4-Amino-6-chloro-2H-chromen-2-one (2d).26 Applying the
general experimental procedure using 6-chloro-4-hydroxycou-
marin (1 mmol, 1 equiv.) and ammonium acetate (20 mmol,
20 equiv.), 4-amino-6-chloro-2H-chromen-2-one 2d was
obtained as a light brown solid (0.158 g, 81% yield); mp
330–332 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.13 (d, J =
2.4 Hz, 1H), 7.61–7.63 (m, 1H), 7.46 (br s, 2H), 7.33 (d, J =
8.8 Hz, 1H), 5.23 (s, 1H); 13C NMR (126 MHz, DMSO-d6):
δ 161.1, 154.6, 152.3, 131.8, 127.4, 122.5, 118.8, 115.8, 84.2; IR
(CHCl3): 3367, 3198, 2917, 2845, 1626, 1570, 1219, 772 cm−1
;
HRMS (+ESI) calcd for C9H7ClNO2 [M + H]+: 196.0165; found:
196.0166.
Starting materials
General procedure for the synthesis of 4-aminocoumarin. A
4-Amino-6-bromo-2H-chromen-2-one (2e).26 Applying the
mixture of 4-hydroxycoumarin (1 equiv.) and ammonium general experimental procedure using 6-bromo-4-hydroxycou-
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marin (1 mmol, 1 equiv.) and ammonium acetate (20 mmol, amino)-2H-chromen-2-one 2i was obtained as a white solid
20 equiv.), 4-amino-6-bromo-2H-chromen-2-one 2e was (0.197 g, 83% yield); mp 258–260 °C; 1H NMR (500 MHz,
obtained as a light brown solid (0.197 g, 82% yield); mp DMSO-d6): δ 9.33 (s, 1H), 8.24 (dd, J1 = 1.2 Hz, J2 = 8.1 Hz, 1H),
1
305–307 °C; H NMR (500 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.72 7.63–7.64 (m, 1H), 7.27–7.50 (m, 7H), 5.31 (s, 1H); 13C NMR
(d, J = 8.3 Hz, 1H), 7.45 (br s, 2H), 7.26 (d, J = 8.8 Hz, 1H), 5.23 (126 MHz, DMSO-d6): δ 161.5, 153.3, 152.4, 138.1, 132.3, 129.5,
(s, 1H); 13C NMR (126 MHz, DMSO-d6): δ 161.1, 154.5, 152.7, 125.9, 125.0, 123.6, 122.7, 117.0, 114.4, 84.3; IR (CHCl3): 3391,
134.6, 125.5, 119.1, 116.2, 115.2, 84.2; IR (CHCl3): 3352, 3207, 3280, 2922, 2845, 1656, 1611, 1591, 1536, 1260, 1219,
2922, 2845, 1618, 1525, 1219, 772 cm−1; HRMS (+ESI) calcd for 772 cm−1; HRMS (+ESI) calcd for C15H12NO2 [M + H]+:
C9H7BrNO2 [M + H]+: 239.9660; found: 239.9669.
238.0868; found: 238.0880.
General procedure for the synthesis of 4-(isobutylamino)-2H-
4-Amino-7-methoxy-2H-chromen-2-one (2f).26 Applying the
general experimental procedure using 7-methoxy-4-hydroxy- chromen-2-one (2j).26
A
mixture of 4-hydroxycoumarin
coumarin (2 mmol,
1 equiv.) and ammonium acetate (1 equiv.) and tert-butylamine (10 equiv.) was refluxed in acetic
(40 mmol, 20 equiv.), 4-amino-7-methoxy-2H-chromen-2-one 2f acid overnight. After completion of the reaction, water was
was obtained as a light brown solid (0.322 g, 84% yield); mp added until it precipitates. The mixture was stored in a fridge
299–301 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.89 (d, J = overnight and then filtered and concentrated in vacuo. The
8.9 Hz, 1H), 7.29 (br s, 2H), 6.89 (dd, J1 = 2.5 Hz, J2 = 8.9 Hz, residue was successively washed with water and ethyl acetate
1H), 6.84 (d, J = 2.5 Hz, 1H), 5.07 (s, 1H), 3.82 (s, 3H); 13C NMR to give 4-(isobutylamino)-2H-chromen-2-one (2j)26
(126 MHz, DMSO-d6): δ 162.3, 161.9, 155.9, 155.5, 124.1, 111.1,
4-(Isobutylamino)-2H-chromen-2-one (2j).26 Applying the
107.5, 100.7, 81.7, 55.7; IR (CHCl3): 3376, 3222, 2922, 2850, general experimental procedure using 4-hydroxycoumarin
1615, 1554, 1219, 772 cm−1; HRMS (+ESI) calcd for C10H10NO3 (1 mmol, 1 equiv.) and tert-butylamine (10 mmol, 10 equiv.), 4-
[M + H]+: 192.0661; found: 192.0675.
(isobutylamino)-2H-chromen-2-one 2j was obtained as a light
4-Amino-6,7-dimethyl-2H-chromen-2-one (2g).26 Applying brown solid (0.175 g, 80% yield); mp 144–146 °C; 1H NMR
the general experimental procedure using 4-hydroxy-6,7-di- (500 MHz, DMSO-d6): δ 8.08 (dd, J1 = 1.1 Hz, J2 = 8.0 Hz, 1H),
methylcoumarin (1 mmol, 1 equiv.) and ammonium acetate 7.71 (t, J = 5.6 Hz, 1H), 7.57 (m, 1H), 7.28–7.32 (m, 2H), 5.13 (s,
(20 mmol, 20 equiv.), 4-amino-6,7-dimethyl-2H-chromen-2-one 1H), 3.04 (m, 2H), 1.94–2.02 (m, 1H), 0.92 (d, J = 6.6 Hz,
2g was obtained as a light brown solid (0.162 g, 86% yield); 6H);13C NMR (126 MHz, DMSO-d6): δ 161.6, 153.2, 153.0,
1
mp 299–301 °C; H NMR (500 MHz, DMSO-d6): δ 7.73 (s, 1H), 131.9, 123.3, 122.4, 116.9, 114.4, 81.2, 49.7, 26.5, 20.2; IR
7.27 (br s, 2H), 7.07 (s, 1H), 5.12 (s, 1H), 2.27 (s, 3H), 2.24 (s, (CHCl3): 3328, 3095, 2959, 2871, 1617, 1558, 1249, 767 cm−1
;
3H); 13C NMR (126 MHz, DMSO-d6): δ 162.0, 155.7, 152.0, HRMS (+ESI) calcd for C13H16NO2 [M + H]+: 218.1181; found:
141.6, 131.5, 122.9, 117.1, 111.8, 83.2, 19.5, 18.9; IR (CHCl3): 218.1190.
3350, 3224, 2923, 2850, 1623, 1558, 1219, 772 cm−1; HRMS
General procedure for the synthesis of 4-amino-3-arylcou-
(+ESI) calcd for C11H12NO2 [M + H]+: 190.0868; found: marin derivatives from aryne precursors. An oven-dried round
190.0878. bottomed flask (50 mL) equipped with a magnetic stir bar was
4-Amino-7-methyl-2H-chromen-2-one (2h).26 Applying the evacuated and purged with argon. o-Silyl aryl triflate
general experimental procedure using 4-hydroxy-7-methyl- (0.25 mmol, equiv.), 4-aminocoumarin (0.25 mmol,
coumarin (2 mmol, equiv.) and ammonium acetate 1.0 equiv.), KF (0.75 mmol, 3 equiv.), 18-crown-6 (0.37 mmol,
1
1
(40 mmol, 20 equiv.), 4-amino-7-methyl-2H-chromen-2-one 2h 1.5 equiv.) and THF (3 mL) were successively added at room
was obtained as a light brown solid (0.290 g, 83% yield); mp temperature. The reaction mixture was stirred at rt for 6 h.
262–264 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.85 (d, J = Water (10 mL) was added to the reaction mixture and the
7.9 Hz, 1H), 7.33 (br s, 2H), 7.09–7.11 (m, 2H), 5.16 (s, 1H), organic layer was extracted with EtOAc (20 × 2 mL). The com-
2.36 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ 161.8, 155.7, bined organic phases were washed with brine and dried over
153.7, 142.7, 124.2, 122.7, 116.7, 111.9, 83.1, 20.9; IR (CHCl3): sodium sulfate. The solvent was removed, and the residue was
3367, 3217, 2927, 2850, 1618, 1539, 1219, 772 cm−1; HRMS purified by column chromatography on silica gel using
(+ESI) calcd for C10H10NO2 [M + H]+: 176.0712; found: hexanes/ethyl acetate as an eluent.
176.0710.
4-Amino-3-phenyl2H-chromen-2-one (3aa).25 Applying the
General procedure for the synthesis of 4-(phenylamino)-2H- general experimental procedure using 2-(trimethylsilyl)phenyl
chromen-2-one (2i). A mixture of 4-hydroxycoumarin (1 equiv.) trifluoromethanesulfonate (0.06 mL; 0.25 mmol, 1 equiv.),
and aniline (3 equiv.) was stirred at 160 °C for 20 min. After 4-aminocoumarin (0.04 g; 0.25 mmol, 1 equiv.), KF (0.043 g;
completion of the reaction, the reaction mixture was dissolved 0.75 mmol, 3 equiv.), and 18-crown-6 (0.100 g; 0.37 mmol,
in methanol (20 ml) and then aqueous NaOH solution was 1.5 equiv.) in THF (3 mL), 4-amino-3-phenyl-2H-chromen-2-
added dropwise. The mixture was stirred for 20 min. The pre- one 3aa was obtained as a white solid (0.045 g, 76% yield) after
cipitate so formed was washed with water and then with purification by flash chromatography on silica gel (40% EtOAc/
ethanol to obtain pure 2i.25
hexane); mp 180–182 °C; 1H NMR (500 MHz, CDCl3):
4-(Phenylamino)-2H-chromen-2-one (2i).27 Applying the δ 7.28–7.58 (m, 9H), 5.00 (br s, 2H); 13C NMR (126 MHz,
general experimental procedure using 4-hydroxycoumarin CDCl3): δ 161.9, 153.1, 149.7, 132.7, 131.9, 130.6, 129.2, 128.1,
(1 mmol, 1 equiv.) and aniline (3 mmol, 3 equiv.), 4-(phenyl- 123.6, 121.4, 117.5, 114.2, 101.0; 1H NMR (500 MHz, DMSO-
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d6): δ 8.15 (d, J = 7.8 Hz, 1H), 7.31–7.61 (m, 8H), 6.77 (br s, HRMS (+ESI) calcd for C15H11NO2Cl [M + H]+: 272.0478;
2H); 13C NMR (126 MHz, DMSO-d6): δ 160.8, 152.5, 150.8, found: 272.0474.
133.7, 131.9, 131.0, 128.6, 127.1, 123.5, 123.4, 116.5, 114.6,
4-Amino-6-bromo-3-phenyl-2H-chromen-2-one (3ae). Applying
97.4; IR (CHCl3): 3450, 3340, 2920, 2850, 1673, 1628, 1606, the general experimental procedure using 2-(trimethylsilyl)
1548, 1501, 1428, 1286, 1207, 752 cm−1; HRMS (+ESI) calcd for phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol,
C15H12NO2 [M + H]+: 238.0868; found: 238.0870.
1 equiv.), 4-amino-6-bromocoumarin (0.060 g; 0.25 mmol,
4-Amino-6-methyl-3-phenyl-2H-chromen-2-one (3ab). Applying 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6
the general experimental procedure using 2-(trimethylsilyl) (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-6-
phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol, bromo-3-phenyl-2H-chromen-2-one 3ae was obtained as a
1 equiv.), 4-amino-6-methylcoumarin (0.044 g; 0.25 mmol, white solid (0.051 g, 64% yield) after purification by flash
1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 chromatography on silica gel (40% EtOAc/hexane); mp
(0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-6- 270–272 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.45 (d, J =
methyl-3-phenyl-2H-chromen-2-one 3ab was obtained as a 2.3 Hz, 1H), 7.76 (dd, J1 = 2.2 Hz, J2 = 8.8 Hz, 1H), 7.44–7.47
white solid (0.043 g, 68% yield) after purification by flash (m, 2H), 7.30–7.47 (m, 4H), 6.82 (br s, 2H); 13C NMR
chromatography on silica gel (40% EtOAc/hexane); mp (126 MHz, DMSO-d6): δ 160.5, 151.6, 149.8, 134.4, 133.4, 130.9,
277–279 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.99 (s, 1H), 128.7, 127.3, 126.1, 118.8, 116.5, 115.4, 98.0; IR (CHCl3): 3454,
7.41–7.46 (m, 3H), 7.30–7.35 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 3332, 2922, 2850, 1672, 1628, 1601, 1545, 1496, 1428, 1398,
6.78 (br s, 2H), 2.38 (s, 3H); 13C NMR (126 MHz, DMSO-d6): 1219, 773 cm−1; HRMS (+ESI) calcd for C15H11NO2Br [M + H]+:
δ 160.9, 150.7, 150.6, 133.8, 132.6, 132.5, 130.9, 128.6, 127.0, 315.9973; found: 315.9974.
123.3, 116.2, 114.1, 97.4, 20.4; IR (CHCl3): 3468, 3348, 2917,
4-Amino-7-methoxy-3-phenyl-2H-chromen-2-one (3af). Applying
2855, 1663, 1633, 1610, 1556, 1508, 1429, 1280, 1218, the general experimental procedure using 2-(trimethylsilyl)
771 cm−1; HRMS (+ESI) calcd for C16H14NO2 [M + H]+: phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol,
252.1025; found: 252.1024.
1 equiv.), 4-amino-7-methoxycoumarin (0.048 g; 0.25 mmol,
4-Amino-6-fluoro-3-phenyl-2H-chromen-2-one (3ac). Applying 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6
the general experimental procedure using 2-(trimethylsilyl) (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-7-
phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol, methoxy-3-phenyl-2H-chromen-2-one 3af was obtained as a
1 equiv.), 4-amino-6-fluorocoumarin (0.045 g; 0.25 mmol, white solid (0.048 g, 72% yield) after purification by flash
1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 chromatography on silica gel (40% EtOAc/hexane); mp
(0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino- 210–212 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.07 (d, J =
6-fluoro-3-phenyl-2H-chromen-2-one 3ac was obtained as a 8.8 Hz, 1H), 7.30–7.45 (m, 5H), 6.89–6.93 (m, 2H), 6.87 (brs,
white solid (0.041 g, 64% yield) after purification by flash 2H), 3.85 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ 162.1,
chromatography on silica gel (40% EtOAc/hexane); mp 161.0, 154.2, 151.0, 133.9, 131.0, 128.5, 126.9, 124.8, 111.2,
282–284 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.08 (dd, J1
2.9 Hz, J2 = 10.0 Hz, 1H), 7.31–7.51 (m, 7H), 6.85 (brs, 2H); 13
=
C
107.7, 100.4, 95.4, 55.7; IR (CHCl3): 3454, 3342, 2922, 2850,
1638, 1602, 1546, 1513, 1431, 1272, 1219, 772 cm−1; HRMS
NMR (126 MHz, DMSO-d6): δ 160.6, 157.7 (d, J = 239.0 Hz), (+ESI) calcd for C16H14NO3 [M + H]+: 268.0974; found:
150.1 (d, J = 1.9 Hz), 148.9, 133.4, 130.8, 128.6, 127.2, 119.1 (d, 268.0974.
J = 23.3 Hz), 118.5 (d, J = 8.7 Hz), 115.6 (d, J = 8.9 Hz), 109.4 (d,
4-Amino-6,7-dimethyl-3-phenyl-2H-chromen-2-one
(3ag).
J = 25.7 Hz), 97.9; IR (CHCl3): 3468, 3337, 2915, 2847, 1669, Applying the general experimental procedure using 2-(tri-
1633, 1610, 1556, 1504, 1435, 1410, 1212, 771 cm−1; HRMS methylsilyl)phenyl trifluoromethanesulfonate (0.06 mL;
(+ESI) calcd for C15H11NO2F [M + H]+: 256.0774; found: 0.25 mmol, 1 equiv.), 4-amino-6,7-dimethylcoumarin (0.047 g;
256.0770.
0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and
4-Amino-6-chloro-3-phenyl-2H-chromen-2-one (3ad). Applying 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL),
the general experimental procedure using 2-(trimethylsilyl) 4-amino-6,7-dimethyl-3-phenyl-2H-chromen-2-one 3ag was
phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol, obtained as a white solid (0.046 g, 69% yield) after purification
1 equiv.), 4-amino-6-chlorocoumarin (0.049 g; 0.25 mmol, by flash chromatography on silica gel (40% EtOAc/hexane); mp
1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 220–222 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.94 (s, 1H),
(0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-6- 7.29–7.44 (m, 5H), 7.13 (s, 1H), 6.54 (br s, 2H), 2.31 (s, 3H),
chloro-3-phenyl-2H-chromen-2-one 3ad was obtained as a 2.28 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ 161.0, 150.8 (d,
white solid (0.047 g, 69% yield) after purification by flash J = 1.7 Hz), 141.2, 133.9, 131.7, 130.9, 128.5, 126.9, 123.5,
chromatography on silica gel (40% EtOAc/hexane); mp 116.7, 111.9, 96.8, 19.4, 18.4; IR (CHCl3): 3458, 3342, 2922,
292–294 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.33 (d, J = 2845, 1664, 1613, 1546, 1431, 1216, 772 cm−1; HRMS (+ESI)
2.4 Hz, 1H), 7.65 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 7.30–7.47 calcd for C17H16NO2[M + H]+: 266.1181; found: 266.1178.
(m, 6H), 6.96 (br s, 2H); 13C NMR (126 MHz, DMSO-d6):
4-Amino-7-methyl-3-phenyl-2H-chromen-2-one (3ah). Applying
δ 160.5, 151.2, 149.9, 133.4, 131.6, 130.9, 128.6, 127.7, 127.3, the general experimental procedure using 2-(trimethylsilyl)
123.2, 118.6, 116.1, 97.9; IR (CHCl3): 3444, 3323, 2927, 2845, phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol,
1674, 1626, 1605, 1552, 1498, 1428, 1399, 1219, 772 cm−1
;
1 equiv.), 4-amino-7-methylcoumarin (0.044 g; 0.25 mmol,
9020 | Org. Biomol. Chem., 2019, 17, 9014–9025
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1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 THF (3 mL), 4-amino-3-(3,4-dimethoxyphenyl)-7-methoxy-2H-
(0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-7- chromen-2-one 3bf was obtained as a white solid (0.057 g, 69%
methyl-3-phenyl-2H-chromen-2-one 3ah was obtained as a yield) after purification by flash chromatography on silica gel
white solid (0.044 g, 70% yield) after purification by flash (60% EtOAc/hexane); mp 250–252 °C; 1H NMR (500 MHz,
chromatography on silica gel (40% EtOAc/hexane); mp DMSO-d6): δ 8.04 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H),
223–225 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.04 (d, J = 6.89–6.92 (m, 2H), 6.80–6.85 (m, 2H), 6.78 (br s, 2H), 3.84 (s,
8.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.33–7.35 (m, 3H), 3H), 3.78 (s, 3H), 3.74 (s, 3H); 13C NMR (126 MHz, DMSO-d6):
7.13–7.15 (m, 2H), 6.88 (brs, 2H), 2.40 (s, 3H); 13C NMR δ 162.0, 161.2, 154.3, 151.3, 148.6, 147.7, 126.1, 124.7, 123.3,
(126 MHz, DMSO-d6): δ 161.0, 152.6, 150.9, 142.4, 133.9, 131.0, 114.5, 111.9, 111.2, 107.8, 100.4, 95.4, 55.7, 55.4, 55.3; IR
128.6, 127.0, 124.5, 123.4, 116.5, 112.1, 96.8, 20.9; IR (CHCl3): (CHCl3): 3409, 3338, 2923, 2850, 1633, 1597, 1539, 1510, 1219,
3414, 3344, 2922, 2850, 1636, 1615, 1598, 1544, 1514, 1435, 1025, 994, 770 cm−1
1218, 770 cm−1; HRMS (+ESI) calcd for C16H14NO2 [M + H]+: C18H18NO5[M + H]+: 328.1185; found: 328.1182.
;
HRMS (+ESI) calcd for
252.1025; found: 252.1024.
4-Amino-3-(3,4-dimethoxyphenyl)-7-methyl-2H-chromen-2-one
4-Amino-3-(3,4-dimethoxyphenyl)-2H-chromen-2-one (3ba). (3bh). Applying the general experimental procedure using 4,5-
Applying the general experimental procedure using 4,5- dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate
dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.07 mL; 0.25 mmol, 1 equiv.), 4-amino-7-methylcoumarin
(0.07 mL; 0.25 mmol, 1 equiv.), 4-aminocoumarin (0.040 g; (0.044 g; 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol,
0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 3 equiv.), and 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in
18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), THF (3 mL), 4-amino-3-(3,4-dimethoxyphenyl)-7-methyl-2H-
4-amino-3-(3,4-dimethoxyphenyl)-2H-chromen-2-one 3ba was chromen-2-one 3bh was obtained as a white solid (0.052 g,
obtained as a white solid (0.054 g, 72% yield) after purification 67% yield) after purification by flash chromatography on silica
1
by flash chromatography on silica gel (60% EtOAc/hexane); mp gel (60% EtOAc/hexane); mp 247–249 °C; H NMR (500 MHz,
256–258 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.14 (d, J = DMSO-d6): δ 8.01 (d, J = 8.1 Hz, 1H), 7.00–7.15 (m, 3H),
7.7 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.30–7.32 (m, 2H), 7.02 (d, 6.81–6.85 (m, 2H), 6.74 (br s, 2H), 3.78 (s, 3H), 3.74 (s, 3H),
J = 8.2 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.84 (dd, J1 = 1.8 Hz, 2.40 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ 161.0, 152.5,
J2 = 8.2 Hz, 1H), 6.74 (br s, 2H), 3.80 (s, 3H), 3.75 (s, 3H); 13C 151.0, 148.6, 147.8, 142.2, 126.0, 124.4, 123.3, 123.2, 116.4,
NMR (126 MHz, DMSO-d6): δ 160.8, 152.4, 150.8, 148.7, 147.8, 114.4, 112.1, 111.9, 96.7, 55.4, 55.3, 20.9; IR (CHCl3): 3450,
131.6, 125.9, 123.4, 123.3, 123.2, 116.4, 114.6, 114.4, 111.9, 3338, 2923, 2850, 1636, 1616, 1541, 1512, 1220, 1025, 992,
97.4, 55.4, 55.3; IR (CHCl3): 3423, 3342, 2921, 2849, 1674, 772 cm−1
1623, 1605, 1546, 1511, 1241, 1023, 751 cm−1; HRMS (+ESI) 312.1236; found: 312.1240.
calcd for C17H16NO4 [M + H]+: 298.1079; found: 298.1080.
4-Amino-3-(naphthalen-2-yl)-2H-chromen-2-one (3ca). Applying
; HRMS (+ESI) calcd for C18H18NO4[M +
H]+:
4-Amino-3-(3,4-dimethoxyphenyl)-6-methyl-2H-chromen-2-one the general experimental procedure using 3-(trimethylsilyl)-2-
(3bb). Applying the general experimental procedure using 4,5- naphthyl trifluoromethanesulfonate (0.07 mL; 0.25 mmol,
dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 1 equiv.), 4-aminocoumarin (0.040 g; 0.25 mmol, 1 equiv.), KF
(0.07 mL; 0.25 mmol, 1 equiv.), 4-amino-6-methylcoumarin (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 (0.100 g;
(0.044 g; 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-3-(naphthalen-
equiv.), and 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in 2-yl)-2H-chromen-2-one 3ca was obtained as a white solid
THF (3 mL), 4-amino-3-(3,4-dimethoxyphenyl)-6-methyl-2H- (0.049 g, 68% yield) after purification by flash chromatography
chromen-2-one 3bb was obtained as a white solid (0.055 g, on silica gel (40% EtOAc/hexane); mp 252–254 °C; 1H NMR
70% yield) after purification by flash chromatography on silica (500 MHz, DMSO-d6): δ 8.19 (d, J = 7.7 Hz, 1H), 7.94–7.96 (m,
1
gel (60% EtOAc/hexane); mp 248–250 °C; H NMR (500 MHz, 3H), 7.87 (s, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.52–7.54 (m, 2H),
DMSO-d6): δ 7.97 (s, 1H), 7.40 (dd, J1 = 1.5 Hz, J2 = 8.4 Hz, 1H), 7.44 (dd, J1 = 1.3 Hz, J2 = 8.4 Hz, 1H), 7.35–7.38 (m, 2H), 6.92
7.21 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.81–6.85 (m, (br s, 2H); 13C NMR (126 MHz, DMSO-d6): δ 160.9, 152.6,
2H), 6.76 (br s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 2.37 (s, 3H); 13C 151.1, 133.3, 133.2, 131.8, 131.4, 129.8, 129.2, 127.9, 127.8,
NMR (126 MHz, DMSO-d6): δ 161.2, 150.9, 150.7, 148.8, 147.9, 127.4, 125.9, 125.7, 123.6, 123.4, 116.6, 114.6, 97.3; IR (CHCl3):
132.6, 132.5, 126.1, 123.4, 123.3, 116.3, 114.5, 114.4, 112.0, 3391, 3227, 2917, 2845, 1633, 1597, 1538, 1493, 1425, 1218,
97.5, 55.5, 55.4, 20.6; IR (CHCl3): 3421, 3340, 2922, 2855, 1667, 1110, 768 cm−1; HRMS (+ESI) calcd for C19H14NO2[M + H]+:
1638, 1603, 1549, 1510, 1219, 1025, 992, 771 cm−1; HRMS 288.1025; found: 288.1023.
(+ESI) calcd for C18H18NO4 [M + H]+: 312.1236; found:
312.1239.
4-Amino-7-methoxy-3-(naphthalen-2-yl)-2H-chromen-2-one
(3cf). Applying the general experimental procedure using 3-(tri-
4-Amino-3-(3,4-dimethoxyphenyl)-7-methoxy-2H-chromen-2-one methylsilyl)-2-naphthyl trifluoromethanesulfonate (0.07 mL;
(3bf). Applying the general experimental procedure using 4,5- 0.25 mmol, 1 equiv.), 4-amino-7-methoxycoumarin (0.048 g;
dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and
(0.07 mL; 0.25 mmol, 1 equiv.), 4-amino-7-methoxycoumarin 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL),
(0.048 g; 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 4-amino-7-methoxy-3-(naphthalen-2-yl)-2H-chromen-2-one 3cf
3 equiv.), and 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in was obtained as a white solid (0.051 g, 64% yield) after purifi-
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cation by flash chromatography on silica gel (40% EtOAc/ Hz, J2 = 8.4 Hz, 1H), 7.60–7.64 (m, 2H), 7.48 (dt, J1 = 8.6 Hz, J2
hexane); mp 281–283 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.11 = 11.0 Hz, 1H), 7.32–7.39 (m, 2H), 7.14–7.15 (m, 1H), 6.98 (br
(d, J = 9.6 Hz, 1H), 7.92–7.96 (m, 3H), 7.86 (s, 1H), 7.50–7.54 s, 2H); 13C NMR (126 MHz, DMSO-d6): δ 160.6, 151.9 (d, J =
(m, 2H), 7.44 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 6.94–6.96 (m, 142.4 Hz), 150.5 (d, J = 12.7 Hz), 149.6 (d, J = 12.5 Hz), 148.5
2H), 6.92 (br s, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, DMSO- (d, J = 12.7 Hz), 147.7 (d, J = 12.7 Hz), 132.1, 131.4 (dd, J1
=
d6): δ 162.2, 161.2, 154.4, 151.5, 133.3, 132.1, 131.6, 129.9, 3.7 Hz, J2 = 6.5 Hz), 128.3 (dd, J1 = 2.9 Hz, J2 = 6.3 Hz), 123.5
129.5, 127.9, 127.8, 127.4, 125.9, 125.8, 124.8, 111.3, 107.8, (d, J = 11.8 Hz), 120.3 (d, J = 16.4 Hz), 117.5 (d, J = 17.0 Hz),
100.5, 95.2, 55.8; IR (CHCl3): 3318, 3178, 2922, 2855, 1672, 116.6, 114.5, 95.6; IR (CHCl3): 3405, 3357, 2922, 2850, 1633,
1635, 1593, 1535, 1509, 1423, 1219, 772 cm−1; HRMS (+ESI) 1607, 1549, 1515, 751 cm−1
; HRMS (+ESI) calcd for
calcd for C20H16NO3[M + H]+: 318.1130; found: 318.1131.
4-Amino-7-methyl-3-(naphthalen-2-yl)-2H-chromen-2-one (3ch).
C15H10NO2F2[M + H]+: 274.0680; found: 274.0680.
3-Phenyl-4-(phenylamino)-2H-chromen-2-one (3ai). Applying
Applying the general experimental procedure using 3-(tri- the general experimental procedure using 2-(trimethylsilyl)
methylsilyl)-2-naphthyl trifluoromethanesulfonate (0.07 mL; phenyl trifluoromethanesulphonate (0.06 mL; 0.25 mmol,
0.25 mmol, 1 equiv.), 4-amino-7-methylcoumarin (0.044 g;
1
equiv.), 4-(phenylamino)-2H-chromen-2-one (0.059 g;
0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and
18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL),
4-amino-7-methyl-3-(naphthalen-2-yl)-2H-chromen-2-one 3ch 3-phenyl-4-(phenylamino)-2H-chromen-2-one 3ai was obtained
was obtained as a white solid (0.050 g, 66% yield) after purifi- as a white solid (0.049 g, 62% yield) after purification by flash
cation by flash chromatography on silica gel (40% EtOAc/ chromatography on silica gel (30% EtOAc/hexane); mp
1
hexane); mp 229–231 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.08 206–208 °C; H NMR (500 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.03
(d, J = 8.2 Hz, 1H), 7.93–7.97 (m, 3H), 7.87 (s, 1H), 7.50–7.54 (dd, J1 = 1.1 Hz, J2 = 8.1 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.43
(m, 2H), 7.45 (dd, J1 = 1.7 Hz, J2 = 8.4 Hz, 1H), 7.16–7.19 (m, (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 6.93–7.16 (m, 7H),
2H), 6.92 (br s, 2H), 2.43 (s, 3H); 13C NMR (126 MHz, DMSO- 6.72–6.77 (m, 3H); 13C NMR (126 MHz, DMSO-d6): δ 161.4,
d6): δ 161.1, 152.7, 151.3, 142.4, 133.3, 132.2, 131.6, 129.9, 152.3, 146.8, 140.7, 134.1, 131.7, 130.5, 127.9, 127.2, 126.6,
129.4, 127.9, 127.8, 127.4, 125.9, 125.7, 124.5, 123.4, 116.5, 124.3, 123.6, 122.1, 120.9, 116.9, 116.6, 106.8; IR (CHCl3):
112.2, 96.6, 20.9; IR (CHCl3): 3454, 3346, 2922, 2845, 1633, 3322, 2922, 2850, 1673, 1594, 1560, 1524, 1495, 1439, 1380,
1612, 1541, 1515, 1488, 1436, 1218, 772 cm−1; HRMS (+ESI) 1170, 761 cm−1; HRMS (+ESI) calcd for C21H16NO2[M + H]+:
calcd for C20H16NO2[M + H]+: 302.1181; found: 302.1178.
4-Amino-3-(benzo[d][1,3]dioxol-5-yl)-2H-chromen-2-one (3da).
314.1181; found: 314.1180.
4-(Isobutylamino)-3-phenyl-2H-chromen-2-one (3aj). Applying
Applying the general experimental procedure using 5-(tri- the general experimental procedure using 2-(trimethylsilyl)
methylsilyl)benzo[d][1,3]dioxol-6-yl trifluoromethanesulpho- phenyl trifluoromethanesulphonate (0.06 mL; 0.25 mmol,
nate (0.05 mL; 0.25 mmol, equiv.), 4-aminocoumarin equiv.), 4-(isobutylamino)-2H-chromen-2-one (0.054 g;
1
1
(0.040 g; 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and
3 equiv.), and 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in 18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-
THF (3 mL), 4-amino-3-(benzo[d][1,3]dioxol-5-yl)-2H-chromen- (isobutylamino)-3-phenyl-2H-chromen-2-one 3aj was obtained
2-one 3da was obtained as a white solid (0.051 g, 72% yield) as a yellow solid (0.014 g, 19% yield) after purification by flash
after purification by flash chromatography on silica gel (40% chromatography on silica gel (20% EtOAc/hexane); mp
EtOAc/hexane); mp 252–254 °C; 1H NMR (500 MHz, DMSO-d6): 196–198 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.25 (d, J =
δ 8.10 (dd, J1 = 1.2 Hz, J2 = 8.3 Hz, 1H), 7.57–760 (m, 1H), 7.3 Hz, 1H), 8.14(d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H),
7.29–7.32 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.82 (d, J = 1.5 Hz, 7.36–7.66 (m, 7H), 4.63 (d, J = 7.6 Hz, 2H), 2.19–2.27 (m, 1H),
1H), 6.46 (dd, J1 = 1.6 Hz, J2 = 7.9 Hz, 1H), 6.73 (br s, 2H), 6.02 0.94 (d, J = 6.6 Hz, 6H); 13C NMR (126 MHz, DMSO-d6):
(s, 2H); 13C NMR (126 MHz, DMSO-d6): δ 161.1, 152.6, 151.3, δ 157.7, 152.8, 140.0, 139.8, 130.7, 124.9, 124.6, 123.4, 123.3,
147.5, 146.4, 131.9, 127.2, 124.4, 123.6, 123.5, 116.6, 114.7, 122.8, 120.3, 117.9, 113.4, 111.8, 101.1, 51.4, 29.4, 19.5; IR
111.4, 108.7, 100.9, 97.4; IR (CHCl3): 3422, 3340, 2923, 2850, (CHCl3): 3399, 2958, 2924, 1648, 1590, 1524, 1460, 1219, 1025,
1634, 1601, 1550, 1502, 1442, 1220, 772 cm−1; HRMS (+ESI) 772 cm−1
;
HRMS (+ESI) calcd for C19H20NO2[M
294.1494; found: 294.1503.
4-Amino-3-(p-tolyl)-2H-chromen-2-one & 4-amino-3-(m-tolyl)-
+
H]+:
calcd for C16H12NO4[M + H]+: 282.0766; found: 282.0765.
4-Amino-3-(3,4-difluorophenyl)-2H-chromen-2-one (3ea).
Applying the general experimental procedure using 4,5- 2H-chromen-2-one (3fa) & (3f′a). Applying the general experi-
difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate mental procedure using 4-methyl-2-(trimethylsilyl)phenyl tri-
(0.06 mL; 0.25 mmol, 1 equiv.), 4-aminocoumarin (0.040 g; fluoromethanesulphonate (0.06 mL; 0.25 mmol, 1 equiv.),
0.25 mmol, 1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 4-aminocoumarin (0.040 g; 0.25 mmol, 1 equiv.), KF (0.043 g;
18-crown-6 (0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 0.75 mmol, 3 equiv.), and 18-crown-6 (0.100 g; 0.37 mmol,
4-amino-3-(3,4-difluorophenyl)-2H-chromen-2-one 3ea was 1.5 equiv.) in THF (3 mL), 4-amino-3-(p-tolyl)-2H-chromen-2-
obtained as a white solid (0.046 g, 67% yield) after purification one & 4-amino-3-(m-tolyl)-2H-chromen-2-one 3fa & 3f′a were
by flash chromatography on silica gel (40% EtOAc/hexane); mp obtained as a white solid (0.044 g, 70% yield) after purification
1
287–289 °C; H NMR (500 MHz, DMSO-d6): δ 8.16 (dd, J1 = 1.4 by flash chromatography on silica gel (40% EtOAc/hexane); mp
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202–204 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.15 (dd, J1
=
1.4 Hz, J2 = 8.4 Hz, 1H), 7.59–7.62 (m, 1H), 7.31–7.37 (m, 3H),
3.2 Hz, J2 = 7.8 Hz, 1H), 7.58–7.62 (m, 1H), 7.10–7.35 (m, 6H), 6.85–6.92 (m, 3H), 6.82 (br s, 2H), 3.76 (s, 3H); 13C NMR
6.91 (br s, 2H), 2.34 (s, 3H); 13C NMR (126 MHz, DMSO-d6): (126 MHz, DMSO-d6): δ 160.9, 159.5, 152.6, 151.0, 135.0, 132.0,
δ 160.9, 160.8, 152.6, 152.5, 150.8, 150.7, 137.6, 136.2, 133.6, 129.8, 123.6, 123.5, 123.2, 116.7, 116.4, 114.6, 113.0, 97.5, 55.0;
131.8, 131.7, 131.5, 130.8, 130.7, 129.2, 128.5, 127.9, 127.8, IR (CHCl3): 3398, 3340, 2927, 2850, 1664, 1625, 1597, 1259,
123.5, 123.4, 116.6, 116.5, 114.7, 114.6, 97.6, 97.4, 21.0, 20.9; 1219, 1025, 989, 772 cm−1
;
HRMS (+ESI) calcd for
IR (CHCl3): 3458, 3342, 2922, 2850, 1672, 1627, 1605, 1548, C16H14NO3[M + H]+: 268.0974; found: 268.0974.
1500, 1423, 1286, 1215, 970, 753 cm−1; HRMS (+ESI) calcd for
C16H14NO2[M + H]+: 252.1025; found: 252.1022.
4-Amino-3-(naphthalen-2-yl)-2H-chromen-2-one (3ja). Applying
the general experimental procedure using 1-(trimethylsilyl)-2-
4-Amino-3-(4-methoxyphenyl)-2H-chromen-2-one & 4-amino- naphthyl trifluoromethanesulfonate (0.07 mL; 0.25 mmol,
3-(3-methoxyphenyl)-2H-chromen-2-one (3ga) (3g′a). 1 equiv.), 4-aminocoumarin (0.040 g; 0.25 mmol, 1equiv), KF
&
Applying the general experimental procedure using 4-methoxy- (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 (0.100 g;
2-(trimethylsilyl)phenyl trifluoromethanesulphonate (0.06 mL; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-3-(naphthalen-
0.25 mmol, 1 equiv.), 4-aminocoumarin (0.040 g; 0.25 mmol, 2-yl)-2H-chromen-2-one 3ja was obtained as a white solid
1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 (0.048 g, 67% yield) after purification by flash chromatography
(0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-3-(4- on silica gel (40% EtOAc/hexane); mp 274–276 °C; 1H NMR
methoxyphenyl)-2H-chromen-2-one
& 4-amino-3-(3-methoxy- (500 MHz, DMSO-d6): δ 8.18 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H),
phenyl)-2H-chromen-2-one 3ga & 3g′a were obtained as a white 7.93–7.97 (m, 3H), 7.88 (s, 1H), 7.61–7.65 (m, 1H), 7.44 (dd,
solid (0.044 g, 65% yield) after purification by flash chromato- J1 = 1.7 Hz, J2 = 8.4 Hz, 2H), 7.33–7.38 (m, 3H), 6.97 (br s, 2H);
1
graphy on silica gel (60% EtOAc/hexane); mp 208–210 °C; H 13C NMR (126 MHz, DMSO-d6): δ 161.2, 152.7, 151.3, 133.4,
NMR (500 MHz, DMSO-d6): δ 8.15 (t, J = 8.1 Hz, 1H), 7.56–7.62 132.7, 132.1, 131.5, 129.9, 129.3, 128.1, 128.0, 127.6, 126.1,
(m, 1H), 7.23–7.38 (m, 3H), 6.87–7.01 (m, 3H), 6.85 (br s, 2H), 125.9, 123.7, 123.6, 116.7, 114.7, 97.5; IR (CHCl3): 3463, 3352,
3.79 (s, 3H); 13C NMR (126 MHz, DMSO-d6): δ 161.0, 160.7, 2922, 2850, 1632, 1602, 1549, 1501, 1219, 772 cm−1; HRMS
159.4, 158.3, 152.5, 152.4, 150.9, 150.8, 135.0, 132.0, 131.9, (+ESI) calcd for C19H14NO2[M
+
H]+: 288.1025; found:
131.7, 129.6, 125.6, 123.6, 123.5, 123.4, 123.3, 123.1, 116.5, 288.1025.
116.4, 116.3, 114.7, 114.6, 114.0, 112.8, 97.4, 97.2, 55.0, 54.3;
IR (CHCl3): 3454, 3342, 2922, 2855, 1674, 1626, 1603, 1547, the general experimental procedure using 2-(trimethylsilyl)
1281, 1219, 956, 773 cm−1
HRMS (+ESI) calcd for phenyl trifluoromethanesulfonate (0.06 mL; 0.25 mmol,
C16H14NO3[M + H]+: 268.0974; found: 268.0972.
1 equiv.), 4-aminocoumarin (0.040 g; 0.25 mmol, 1equiv), KF
4-Amino-3-(phenyl-2-d)-2H-chromen-2-one {3aa-(D)}. Applying
;
4-Amino-3-(o-tolyl)-2H-chromen-2-one (3ha). Applying the (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 (0.100 g;
general experimental procedure using 2-methyl-6-(trimethyl- 0.37 mmol, 1.5 equiv.) in THF (3 mL) and D2O (5.0 µL,
silyl)phenyl trifluoromethanesulphonate (0.06 mL; 0.25 mmol, 0.25 mmol), 4-amino-3-(phenyl-2-d)-2H-chromen-2-one 3aa-D
1 equiv.), 4-aminocoumarin (0.040 g; 0.25 mmol, 1 equiv.), KF was obtained as a white solid (0.043 g, 72% yield) after purifi-
(0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6 (0.100 g; cation by flash chromatography on silica gel (40% EtOAc/
0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-3-(o-tolyl)-2H- hexane); mp 208–210 °C; 1H NMR (500 MHz, CDCl3): δ 8.17 (d,
chromen-2-one 3ha was obtained as a white solid (0.042 g, J = 8.0 Hz, 1H), 7.59–7.62 (m, 1H), 7.44–7.47 (m, 2H), 7.31–7.36
67% yield) after purification by flash chromatography on silica (m, 4H), 6.78 (br s, 2H); 13C NMR (126 MHz, CDCl3): δ 160.9,
1
gel (40% EtOAc/hexane); mp 204–206 °C; H NMR (500 MHz, 152.5, 150.8, 133.7 (d, J = 11.7 Hz), 131.9, 130.9, 128.6, 128.5,
DMSO-d6): δ 8.15 (d, J = 8.4 Hz, 1H), 7.58–7.62 (m, 1H), 127.1, 123.5 (d, J = 21.8 Hz), 116.5, 114.6, 97.4 (d, J = 4.1 Hz);
7.31–7.35 (m, 3H), 7.10–7.16 (m, 3H), 6.87 (br s, 2H), 2.34 (s, IR (CHCl3): 3468, 3342, 2917, 2855, 1672, 1628, 1607, 1548,
3H); 13C NMR (126 MHz, DMSO-d6): δ 160.8, 152.5, 150.8, 1500, 1427, 967, 771 cm−1; HRMS (+ESI) calcd for C15H11DNO2
137.6, 133.6, 131.8, 131.5, 128.5, 127.9, 127.8, 123.5, 123.4, [M + H]+: 239.0931; found: 239.0925.
116.5, 114.6, 97.6, 21.0; IR (CHCl3): 3391, 3338, 2922, 2850,
1631, 1601, 1540, 1498, 1430, 1216, 1117, 773 cm−1; HRMS
(+ESI) calcd for C16H14NO2[M
+
H]+: 252.1025; found:
252.1027.
Conflicts of interest
4-Amino-3-(3-methoxyphenyl)-2H-chromen-2-one
(3ia).
Applying the general experimental procedure using 3-methoxy- There are no conflicts to declare.
2-(trimethylsilyl)phenyl trifluoromethanesulphonate (0.06 mL;
0.25 mmol, 1 equiv.), 4-aminocoumarin (0.040 g; 0.25 mmol,
1 equiv.), KF (0.043 g; 0.75 mmol, 3 equiv.), and 18-crown-6
(0.100 g; 0.37 mmol, 1.5 equiv.) in THF (3 mL), 4-amino-3-(3-
methoxyphenyl)-2H-chromen-2-one 3ia was obtained as a
Acknowledgements
white solid (0.046 g, 69% yield) after purification by flash We are grateful to the Director, CSIR-NEIST, Jorhat, India, for
chromatography on silica gel (60% EtOAc/hexane); mp his interest in this work and facilities. AS acknowledges the
214–216 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.13 (dd, J1
=
DST, New Delhi, India, for DST-Inspire fellowship grants.
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