Alcohol mediated synthesis of 4-oxo-2-aryl-4H-chromene-3-carboxylate derivatives from 4-hydroxycoumarins

Article abstract of DOI:10.1021/jo301044y

The unusual alcohol mediated formation of 4-oxo-2-aryl-4H-chromene-3- carboxylate (flavone-3-carboxylate) derivatives from 4-hydroxycoumarins and β-nitroalkenes in an alcoholic medium is described. The transformation occurs via the in situ formation of a Michael adduct, followed by the alkoxide ion mediated rearrangement of the intermediate. The effect of the different alcohol and nonalcohol media on the reaction was investigated.

Full text of DOI:10.1021/jo301044y

Article
pubs.acs.org/joc
Alcohol Mediated Synthesis of 4‑Oxo-2-aryl‑4H‑chromene-3-
carboxylate Derivatives from 4‑Hydroxycoumarins
Manoj R. Zanwar, Mustafa J. Raihan, Sachin D. Gawande, Veerababurao Kavala, Donala Janreddy,
Chun-Wei Kuo, Ram Ambre, and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, R.O.C.
S
* Supporting Information
ABSTRACT: The unusual alcohol mediated formation of 4-
oxo-2-aryl-4H-chromene-3-carboxylate (flavone-3-carboxylate)
derivatives from 4-hydroxycoumarins and β-nitroalkenes in an
alcoholic medium is described. The transformation occurs via
the in situ formation of a Michael adduct, followed by the
alkoxide ion mediated rearrangement of the intermediate. The
effect of the different alcohol and nonalcohol media on the
reaction was investigated.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Flavones are an important class of oxygen heterocycles and are
useful intermediates in the fields of medicinal, pharmaceutical,
and synthetic chemistry (Figure 1).1−4 Several natural products
that contain this heterocyclic framework have antiviral,
anticancer, anti-inflammatory, and antioxidant properties.1
Among the members of the flavone family, 4-oxo-4H-
chromene-3-carboxylate derivatives are very interesting scaf-
folds, since they can act as both a Michael acceptor and a 1,3-
diketone, due to the presence of an ester functionality at C-
3.2−4 However, concerning the polysubstituted counterparts,
the chemistry of 2-alkyl substituted derivatives have been
explored much more extensively than the 2-aryl derivatives.3,4
This may be due to the absence of a convenient protocol for
preparing 2-aryl derivatives. In fact, all of the reported
methodologies for the synthesis of these esters consist of a
multistep process or involve the use of complex mixtures of
reagents.1−4 As a result, a demand exists for a more
straightforward and cost-effective procedure for the synthesis
of 4H-chromen-4-one moieties.
In addition to controlling the efficacy of a reaction, the
medium used also has a significant role in determining the
reaction pathway.5 The polarity of the solvent used in a reaction
is a major determinant of the fate of the reaction. The reaction
pathway is determined by the stability of a particular transition
state that is produced in a specific medium. Thus, the effect of
the medium on a chemical transformation is a very important
issue in the field of chemistry.5
In a recent publication, we reported on the synthesis of a series
of oximes, hydroxyiminodihydrofuroquinolinone derivatives,
from 4-hydroxy-1-methyl quinolin- 2(1H)-one and (E)-(2-
nitrovinyl)benzenes, using methanol as the solvent, in the
presence of a catalytic amount of diisopropylethylamine.6a We
proposed that the conversion occurred via the formation of a
Michael adduct. The Michael adduct underwent base mediated
C−O bond formation to produce an oxime. However, when we
examined the reactions of 4-hydroxycoumarin (a, Scheme 1)
and (E)-(2-nitrovinyl)benzenes (2) under the same conditions,
the reaction was sluggish. From these two experimental
outcomes, it appeared that the nitrogen heterocycle, 4-
hydroxy-1-methylquinolin-2(1H)-one, itself acts as a base and,
because of this, the basicity of the medium appears to be an
important factor in the formation of an oxime derivative.
Taking cues from these observations, we used 2 equiv of
diisopropylethylamine to synthesize an oxime derivative (2a′,
Scheme 1), from 4-hydroxycoumarin (a) and (E)-(2-
nitrovinyl)benzenes derivatives (2). At room temperature,
only the corresponding Michael adduct was observed. At this
point, with the desired oxime in mind, we carried out the
reaction at 70 °C. However, the desired oxime was not formed,
but the result was more exciting and interesting than our
1
expectation. H and 13C NMR, IR, mass, and single crystal X-
ray analysis data (Figure 2 and Supporting Information)
revealed that the product was methyl 4-oxo-2-p-tolyl-4H-
chromene-3-carboxylate (2a), which was formed in 33% yield.
The use of 4 equiv of diisopropylethylamine improved the yield
to 51%. This finding presents a novel and straightforward route
Our long-term goal is directed at exploring the utility of (E)-
(2-nitrovinyl)benzenes in organic synthesis.6 In a continuation
of our research dealing with nitro olefins, we wish to report,
herein, on the unprecedented alcohol mediated synthesis of 4-
oxo-2-aryl-4H-chromene-3-carboxylates from 4-hydroxycou-
marins and β-nitroalkenes.
Received: May 21, 2012
Published: July 18, 2012
© 2012 American Chemical Society
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Figure 1. Biologically active 4H-chromen-4-one derivatives.
Scheme 1. Reaction of 4-Hydroxycoumarin and (E)-1-Methyl-4-(2-nitrovinyl)benzene
Table 1. Effect of Different Bases
ab
,
Entry
Base
Yield
1
2
DIPEA
51
55






68
46

53
Pyridine
c
3
Diethyl Amine
d
4
Ammonium Acetate
d
5
DABCO
d
6
c
NaHCO3
7
Piperidine
c
8
Amberlyst A-25 Basic
Figure 2. X-ray crystal structure of 2a (ORTEP diagram).
9
TEA
10
KF
d
for the preparation of a relatively unexplored member of the
flavone family.
11
DBU
12
N, N′-Dimethylcyclohexylamine
a
b
In this context, recently, Balalaie and co-workers disclosed
that the treatment of 4-hydroxycoumarin with (E)-(2-
nitrovinyl)benzenes in acetonitrile, in the presence of
ammonium acetate, resulted in the formation of the (3E)-3-
[amino(aryl)methylidene]chromane-2,4-dione derivative
(Scheme 1).7 However, in our case, when methanol was used
as the solvent instead of acetonitrile, a flavone derivative was
produced as the major product. Hence, these results explain the
effect of the media in chemical transformations in a more
comprehensive fashion.
This exciting experimental outcome prompted us to
determine the optimal conditions for the conversion. To
pursue this goal, we first ran the reaction using different bases
(Table 1). No product was obtained with diethylamine (entry
3), piperidine (entry 7) and amberlyst A-25, a basic ion-
exchange resin (entry 8). However, the use of ammonium
acetate (entry 4), DABCO (entry 5), NaHCO3 (entry 6), and
All reactions were performed on a 2 mmol scale. Yield refers to the
isolated yield of the purified compound. No product was observed.
An inseparable mixture was formed.
c
d
DBU (entry 11) resulted in the formation of an inseparable
mixture. On the other hand, bases such as DIPEA (entry 1),
pyridine (entry 2), TEA (entry 9), KF (entry 10), and N,N-
dimethyl cyclohexyl amine (entry 12) were found to be more
effective. Among them, TEA was found to be superior to the
other bases used. When the reaction was carried out at room
temperature, only the Michael adduct was formed and no
evidence of the desired product was observed. However, at 70
°C the desired product (2a) was obtained in good yield and the
yield was not improved when the reaction was conducted at
higher temperatures. Hence, the substrate scope was explored
by carrying out the reaction at 70 °C with TEA as the base.
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Table 2. Reaction of 4-Hydroxycoumarin with Different Nitroalkene Derivatives
a
Yields refer to isolated and purified compounds. Parentheses indicate the yield calculated by 1H NMR spectroscopy of the crude reaction mixture
b
using CH2Br2 as an internal standard. All reactions were performed on a 2 mmol scale.
The scope of the methodology was examined, first, by
treating 4-hydroxycoumarin with a series of β-nitroalkene
derivatives. To accomplish this, we used several o-, m-, p- as
well as unsubstituted (E)-(2-nitrovinyl)benzenes, containing
both electron-donating and -withdrawing groups (Table 2). We
also tested a variety of 4-hydroxycoumarin derivatives (Scheme
2) and alcohols (Table 3) to elaborate the chemistry further.
In the case of 4-hydroxycoumarin, the yields of the desired
products were found to be dependent on the electronic nature
of the substituents on the phenyl moiety of (E)-(2-nitrovinyl)-
benzene (Table 2). With the unsubstituted (E)-(2-nitrovinyl)-
benzene the expected product was obtained in 72% yield (entry
1). The desired products were obtained in moderate to good
yields when electron-donating groups were present on the
phenyl ring (entries 2−7). However, the introduction of an
electron-withdrawing group (such as a nitro group) resulted in
a lower product yield (entry 10). Halide substituted (E)-(2-
nitrovinyl)benzenes (entries 8 and 9) also produced lower
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Scheme 2. Reaction of Substituted 4-Hydroxycoumarin and
Table 3. Reaction in Different Alcoholic Medium
(E)-1-Methyl-4-(2-nitrovinyl) Benzene
a
Yields refer to isolated and purified compound. Parentheses indicate
1
the yield calculated by H NMR spectroscopy of the crude reaction
mixture using CH2Br2 as the internal standard. All reactions were
b
performed on a 2 mmol scale.
product yields than the (E)-(2-nitrovinyl)benzenes with
methoxy, methyl, ethyl, and amine functionalities; presumably,
the electron-withdrawing inductive effect of the halide
functionality makes the phenyl ring electron deficient. The
effect of steric factors on product yields was quite interesting.
When more sterically hindered (E)-(2-nitrovinyl)benzenes
were used, the yields were improved. The presence of an o-
substituent resulted in good to excellent yields of the desired
products (entries 11 and 12). (E)-(2-Nitrovinyl)benzenes,
derived from 2-napthaldehyde, produced the expected product
in good yield (entry 13). However, a low product yield was
obtained in the case of (E)-2-(2-nitrovinyl)thiophene (entry
14). With other heterocyclic nitroalkenes, such as pyridine,
pyrrole, indole, and furan, we did not observe the desired
product and an inseparable mixture of products were obtained
in all the cases.
Next, to explore the diversity of our protocol further, we
treated halo (1b, Scheme 2) and methyl (1c, Scheme 2)
substituted 4-hydroxycoumarin derivatives with (E)-1-methyl-
4-(2-nitrovinyl)benzene. Presumably, due to the electron-
donating inductive effect of the methyl functionality, the latter
produced a higher product yield (1c) than the former (1b).
The presence of a strong electron-withdrawing group, such as
4-hydroxy-6-nitro-2H-chromen-2-one, the desired product (1d)
was obtained in poor yield. However, with 6-(dimethylamino)-
4-hydroxy-2H-chromen-2-one, the expected flavone derivative
(1e) was obtained in good yield.
After studying the different reactions of (E)-(2-nitrovinyl)-
benzenes and 4-hydroxycoumarins, we focused our attention on
determining the effect of the medium used in the reaction
(Table 3). To pursue this goal, the reaction of (E)-1-methyl-4-
(2-nitrovinyl)benzene and 4-hydroxycoumarin were performed
in different alcoholic media. We observed that the presence of
an sp2 carbon α to the C−O bond resulted in a higher yield of
the flavone derivative than bulkier sp3 counterparts. Hence,
benzyl alcohol (entry 3, Table 3) and allylic alcohol (entry 4)
were more productive than ethanol (entry 1), n-propyl alcohol
(entry 2), and ethylene glycol (entry 5). The low yields of the
desired products with thiophene methanol (entry 6) and
furfuryl alcohol (entry 7) are probably due to the instability of
the sulfur and oxygen heterocycles at the high temperature
used.
a
Yields refer to isolated and purified compounds. Parentheses indicate
1
the yield calculated by H NMR spectroscopy of the crude reaction
mixture using CH2Br2 as the internal standard. All reactions were
performed on a 2 mmol scale.
b
Scheme 3. Reaction in Nonalcoholic Medium
To further explore the effect of the medium, we used
methylamine and ethylmercaptan as solvents (Scheme 3). In
these cases, no expected product (2b and 2c) was obtained.
However, compounds 2d and 2e were formed as the primary
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Scheme 4. Use of Different Michael Acceptors
Scheme 5. Plausible Mechanism for the Formation of Methyl 4-Oxo-2-phenyl-4H-chromene-3-carboxylate Derivatives
amine and the thio nucleophiles underwent a faster Michael
addition with (E)-(2-nitrovinyl)benzene than the C-nucleo-
phile, 4-hydroxycoumarin, in the presence of a base. However,
with less activated nitrogen containing nucleophiles, such as
aniline and N-methylaniline, a complex mixture of products was
obtained.
of the product, G. The driving force behind this thermal
dehydrogenation is the extensive conjugation, which is achieved
by the product, due to the formation of multiple bonds.
Presumably, the presence of an electron-withdrawing ester
group drives the intermediate, F, toward this dehydrogenation.
The possible alternative route (Pathway c) for this conversion
would involve the SN2 type attack of the phenolic OH at the
benzylic carbon which, upon elimination of nitromethane,
would produce intermediate F. However, it is likely an SN2
attack would be controlled by steric factors.
The proposed mechanism of the reaction (Scheme 5)
indicates that the elimination of nitromethane in an
intermediate step leads to the formation of the final product
and, hence, the likely active reactants are 4-hydroxycoumarin
and benzaldehyde. Based on this assumption, we examined the
reaction of 4-hydroxycoumarin and benzaldehyde in the
presence triethylamine (Scheme 6). However, 3,3′-(phenyl-
methylene) bis(4-hydroxy-2H-chromen-2-one) (1x) was pro-
duced as the sole product. This result can be explained by
considering the formation of intermediate M (Scheme 5) from
4-hydroxycoumarin and benzaldehyde. The attack of the
second molecule of 4-hydroxycoumarin at intermediate M
results in the formation of 1x. On the other hand, the desired
product (1a) was obtained along with traces of an inseparable
mixture of byproducts, when the same reaction was carried out
To study the efficacy of other Michael acceptors in this
transformation, we used cinnamylnitrile (i, Scheme 4) and
cinnamyl gemdicarboxylate (ii). However, no Michael adduct
was formed and only the starting materials were recovered.
The phenomenon could be explained by considering the role
of the methoxide ion in the reaction, which is formed from the
solvent methanol in the presence of a base (Scheme 5). The
initially formed Michael adduct (A) either is attacked by a
methoxide ion to form intermediate B via C−O bond cleavage
(Pathway a, Scheme 5) or undergoes elimination of nitro-
methane, resulting in the formation of intermediate M
(Pathway b). Intermediate B (Pathway a) undergoes
tautomerism and C−C bond rotation to form intermediate
D. The base mediated elimination of nitromethane from
intermediate D results in the formation of E. The intermediate
E could also be formed from intermediate M via the
participation of the solvent. E then undergoes cyclization via
an intramolecular Michael addition of the phenolic OH to form
F. The thermal dehydrogenation of F results in the formation
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Scheme 6. Reactions in the Presence and Absence of
Nitromethane
Table 4. Multicomponent Protocol for the Synthesis of
Flavone Derivatives
in the presence of nitromethane. The probable explanation for
this outcome is that the nitromethane attacks intermediate M
faster than the second molecule of 4-hydroxycoumarin to form
the Michael adduct A, which was observed during the reaction.
This provides convincing evidence to support that the
elimination of nitromethane actually occurred after cleavage
of the C−O bond (Pathway a, Scheme 5). This finding rules
out the possibility that pathway b is operative. To confirm this,
we examined the reaction between 4-hydroxycoumarin and
(E)-(2-nitrovinyl)benzene in a 2:1 ratio. No biscoumarin
product (1x) was detected. Moreover, to determine whether
the reaction occurs via the intermediate formation of 1x, we
carried out a reaction between biscoumarin (1x) and
nitromethane in the presence of TEA in methanol at 70 °C.
However, the desired product (1a) was not produced, even
after 48 h, and the starting material was recovered.
Besides elaborating the reaction mechanism, this experiment
revealed the possibility that our desired flavone could be
synthesized via a three component reaction (Table 4). Hence,
we focused our attention toward the possibility of such a
multicomponent protocol. This goal was pursued by the
treatment of 4-hydroxycoumarin and nitromethane with
different aldehydes in the presence of TEA in methanol. In
all the cases, the products were obtained in moderate yields
(entries 1, 2, 4, and 5); however, the expected flavone was
obtained in poor yield in the case of 4-chlorobenzaldehyde
(entry 3).
In this context, to determine whether the medium
participates in this step via the in situ generation of alkoxide
ions, we isolated the Michael adduct and carried out the
reaction in methanol in the presence and absence of a base
(Scheme 7). The reaction clearly proceeded more efficiently in
the presence of a base than in the absence of base. Hence, in
the presence of base the alcohol produces alkoxide ions in situ.
The alkoxide ion plays a key role in the formation of the final
product from the Michael adducts.
We next carried out a reaction between 4-hydroxycoumarin
and (E)-1-methyl-4-(2-nitrovinyl)benzene at room temperature
in the presence of sodium methoxide to determine whether the
direct use of sodium methoxide would enhance the efficiency of
the reaction (Scheme 8). Only the Michael adduct was detected
in the reaction mixture, and no expected product was produced
in 48 h. However, the desired product was formed on heating,
but the yield was low. Although, this experiment did not result
in an increase in the yield of the desired product, it explains the
a
b
Yields refer to isolated and purified compounds. The reaction was
performed on a 2 mmol scale.
role of temperature and base in a more comprehensive manner.
The former is required to excite the methoxide ion to
participate in a nucleophilic attack at the carbonyl carbon of
the Michael adduct, and the latter mediates the formation of a
Michael adduct by the abstraction of an alcoholic proton of the
4-hydroxycoumarins as well generating a methoxide ion in situ.
CONCLUSIONS
■
In conclusion, we demonstrate, here, a simple and cost-effective
method for the synthesis of a wide variety of 4-oxo-2-aryl-4H-
chromene-3-carboxylate derivatives. The method, which
permits the synthesis of many new 4-oxo-2-aryl-4H-chro-
mene-3-carboxylate derivatives, overcomes many of the
previous limitations and provides a route to producing these
moieties for use in the fields of medicinal and synthetic
chemistry. The reaction occurs through the in situ generation of
a Michael adduct, followed by the C−O bond cleavage of the
coumarin moiety of the Michael adduct via participation by the
alcoholic medium. The most plausible pathway for the
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Scheme 7. Role of Base in the Formation of Flavone Derivatives from a Michael Adduct
Scheme 8. Reaction in the Presence of Methoxide Ion
(ppm) 8.27 (d, J = 8.0 Hz, 1H), 7.76−7.70 (m, 3H), 7.57−7.50 (m,
4H), 7.45 (t, J = 7.6 Hz, 1H), 3.80 (s, 3H) ; 13C NMR (100 MHz,
CDCl3) δ 175.2, 165.8, 163.3, 156.0, 134.5, 132.2, 131.9, 129, 128.2,
126.4, 125.9, 123.4, 118.3, 118.3, 52.9; LRMS (FAB) (m/z) (relative
intensity) 281 (M+ + 1, 88), 273 (9); HRMS (FAB) calcd for
C17H13O4 (M + H)+: 281.0814, found 281.0810.
conversion was explored by examining a wide variety of
reaction conditions.
EXPERIMENTAL SECTION
■
General Information. All chemicals were purchased from various
sources and were used directly without further purification. Analytical
thin-layer chromatography was performed using silica gel 60F glass
plates, and silica gel 60 (230−400 mesh) was used in flash
chromatographic separations. NMR spectra were recorded in CDCl3
with tetramethylsilane and Chloroform as the internal standards for 1H
Methyl 4-Oxo-2-p-tolyl-4H-chromene-3-carboxylate (2a).
Compound 2a was eluted with 15% EtOAc/Hex as a brown solid
(402 mg, 68%); mp: 126−128 °C; FT-IR (KBr) ν/cm−1 1737, 1644,
1
1619, 1564, 1466, 1383, 1091, 762; H NMR (400 MHz, CDCl3) δ
(ppm) 8.24 (dd, J = 8.0, 1.5 Hz, 1H), 7.72−7.68 (m, 1H), 7.63 (d, J =
8.2 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.45−7.41 (m, 1H), 7.30 (d, J =
8.0 Hz, 2H), 3.81 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 175.2, 166.0, 163.4, 156.0, 142.6, 134.4, 129.8, 129.3, 128.1, 126.3,
125.8, 123.3, 118.2, 117.9, 52.9, 21.8; LRMS (EI) (m/z) (relative
intensity) 294 (M+, 100), 279 (30), 276 (20); HRMS (EI) calcd for
C18H14O4 (M+): 294.0892, found 294.0893.
NMR (400 MHz) and CDCl3 solvent as the internal standard for 13
C
NMR (100 MHz). Coupling constants were expressed in hertz. HRMS
spectra were recorded using FAB-TOF, ESI, or EI+ mode. Melting
points were recorded using an electrothermal capillary melting point
apparatus and are uncorrected.
General Procedure for Preparation of 4-Oxo-2-aryl-4H-
chromene-3-carboxylate Derivatives (Tables 2 and 3). To a
stirred solution of 4-hydroxycoumarin (0.32 g, 2 mmol) and (E)-1-
methyl-4-(2-nitrovinyl)benzene (0.65 g, 4 mmol) in alcohol (6 mL)
was added triethylamine (1.10 mL, 4 equiv). The reaction mixture was
heated at 70−80 °C, and the progress of the reaction was monitored
by TLC. After completion of the reaction, the solvent was evaporated
in vacuum. The resulting residue was further purified by flash column
chromatography (ethyl acetate/hexane) on silica gel.
General Procedure for the One-Pot Preparation of 4-Oxo-2-
aryl-4H-chromene-3-carboxylate Derivatives via a Three
Component Reaction (Table 4). To a stirred solution of 4-
hydroxycoumarin (0.32 g, 2 mmol), benzaldehyde (0.42 g, 4 mmol),
and nitromethane (0.42 mL, 8 mmol) in alcohol (6 mL) was added
triethylamine (1.10 mL, 4 equiv). The reaction mixture was heated at
70 °C, and the progress of the reaction was monitored by TLC. After
completion of the reaction, the solvent was evaporated in vacuum. The
resulting residue was further purified by flash column chromatography
(ethyl acetate/hexane) on silica gel.
Procedure for Preparation of 3,3′-(Phenylmethylene)bis(4-
hydroxy-2H-chromen- 2-one) (Scheme 6). To a stirred solution of
4-hydroxycoumarin (0.32 g, 2 mmol) and benzaldehyde (0.42 g, 4
mmol) in alcohol (6 mL) was added triethylamine (1.10 mL, 4 equiv).
The reaction mixture was heated at 70 °C, and the progress of the
reaction was monitored by TLC. After the completion of the reaction,
the solvent was evaporated in vacuum. The resulting residue was
further purified by flash column chromatography (ethyl acetate/
hexane) on silica gel.
Methyl 2-(4-Methoxyphenyl)-4-oxo-4H-chromene-3-carbox-
ylate (3a). Compound 3a was eluted with 15% EtOAc/Hex as a
brown solid (411 mg, 66%); mp: 103−105 °C; FT-IR (KBr) ν/cm−1
1
1735, 1638, 1606, 1560, 1466, 1382, 1091, 760; H NMR (400 MHz,
CDCl3) δ (ppm) 8.23 (dd, J = 7.9, 1.6 Hz, 1H), 7.71−7.66 (m, 3H),
7.50 (d, J = 8.4 Hz, 1H), 7.43−7.39 (m, 1H), 7.01−6.97 (m, 2H), 3.87
(s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 166.2,
163.0, 162.5, 155.9, 134.3, 130.0, 126.2, 125.7, 124.2, 123.2, 118.1,
117.3, 114.5, 55.7, 52.9; LRMS (FAB) (m/z) (relative intensity) 311
(M+ + 1, 100), 289 (28), 279 (75), 273 (6); HRMS (FAB) calcd for
C18H15O5 (M + H)+: 311.0919, found 311.0919.
Methyl 2-(3-Methoxy-4-methylphenyl)-4-oxo-4H-chromene-
3-carboxylate (4a). Compound 4a was eluted with 20% EtOAc/Hex
as a brown solid (415 mg, 64%); mp: 106−108 °C; FT-IR (KBr) ν/
1
cm−1 1733, 1638, 1517, 1466, 1379, 1091, 760; H NMR (400 MHz,
CDCl3) δ (ppm) 8.25 (dd, J = 7.9, 1.6 Hz, 1H), 7.73−7.69 (m, 1H),
7.53 (d, J = 8.4 Hz, 1H), 7.46−7.42 (m, 1H), 7.38 (dd, J = 8.4, 2.2 Hz,
1H), 7.27 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H),
3.94 (s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2,
166.3, 162.9, 156.0, 152.2, 149.3, 134.4, 126.3, 125.8, 124.4, 123.3,
122.0, 118.2, 117.6, 111.2, 111.0, 56.3, 56.3, 53.0; LRMS (FAB) (m/z)
(relative intensity) 324 (M+, 13), 309 (100), 307 (20), 289 (12), 281
(6), 279 (5); HRMS (FAB) calcd for C19H16O5 (M+): 324.0998,
found 324.0994.
Methyl 2-(4-Ethyl-2,5-dimethoxyphenyl)-4-oxo-4H-chro-
mene-3-carboxylate (5a). Compound 5a was eluted with 20%
EtOAc/Hex as an off-white solid (463 mg, 63%); mp: 156−158 °C;
1
FT-IR (KBr) ν/cm−1 1739, 1647, 1506, 1466, 1376, 1086, 760; H
SPECTRAL DATA
NMR (400 MHz, CDCl3) δ (ppm) 8.26 (dd, J = 8.0, 1.6 Hz, 1H),
7.70−7.65 (m, 1H), 7.48−7.40 (m, 2H), 7.01 (s, 1H), 6.81 (s, 1H),
3.83 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 2.69 (q, J = 7.5 Hz, 2H), 1.23
(t, J = 7.5 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 174.9, 165.5,
163.4, 156.2, 151.5, 151.3, 138.2, 134.2, 126.4, 125.7, 123.8, 119.3,
■
Methyl 4-Oxo-2-phenyl-4H-chromene-3-carboxylate (1a).
Compound 1a was eluted with 15% EtOAc/Hex as an off-white
solid (407 mg, 72%); m.p.: 100−102 °C; FT-IR (KBr) ν/cm−1 1736,
1
1643, 1569, 1466, 1384, 1092, 760; H NMR (400 MHz, CDCl3) δ
6501
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118.9, 118.2, 113.1, 111.9, 77.5, 77.2, 76.9, 24.0, 14.1; LRMS (FAB)
(m/z) (relative intensity) 369 (M+ + 1, 100), 368 (M+, 67), 337 (87),
322 (7), 307 (10); HRMS (FAB) calcd for C21H21O6 (M+H)+:
369.1338, found 369.1335.
119.4, 118.3, 111.4, 55.7, 52.3; LRMS (FAB) (m/z) (relative intensity)
311 (M+ + 1, 95), 307 (12), 280 (19), 279 (100); HRMS (FAB) calcd
for C18H15O5 (M + H)+: 311.0919, found 311.0923.
Methyl 2-(2-Bromophenyl)-4-oxo-4H-chromene-3-carboxy-
late (12a). Compound 12a was eluted with 15% EtOAc/Hex as a
white solid (614 mg, 85%); mp: 103−105 °C; FT-IR (KBr) ν/cm−1
Methyl 2-(4-(Diethylamino)phenyl)-4-oxo-4H-chromene-3-
carboxylate (6a). Compound 6a was eluted with 20% EtOAc/Hex
as a green solid (466 mg, 66%); mp: 147−149 °C; FT-IR (KBr) ν/
cm−1 1735, 1654, 1601, 1560, 1474, 1376, 1086; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.22 (d, J = 7.9 Hz, 1H), 7.67−7.61 (m, 3H), 7.48
(d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 9.1 Hz, 2H),
3.87 (s, 3H), 3.42 (q, J = 7.0 Hz, 4H), 1.21 (t, J = 7.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 175.1, 166.9, 163.4, 155.7, 150.3, 133.7,
129.8, 126.0, 125.1, 123.2, 117.8, 117.2, 115.0, 110.9, 52.7, 44.5, 12.5;
LRMS (FAB) (m/z) (relative intensity) 352 (M+ + 1, 100), 351 (M+,
82), 320 (66), 307 (45); HRMS (FAB) calcd for C21H22O4N (M +
H)+: 352.1549, found 352.1552.
1
1736, 1648, 1462, 1384, 1096, 760; H NMR (400 MHz, CDCl3) δ
(ppm) 8.29−8.28 (m, 1H), 7.74−7.70 (m, 2H), 7.49−7.37 (m, 5H),
3.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.7, 164.4, 164.4,
156.0, 134.7, 133.6, 133.4, 132.3, 130.6, 127.5, 126.4, 126.1, 123.8,
122.3, 119.6, 118.4, 52.7; LRMS (FAB) (m/z) (relative intensity) 359
(M+ + 1, 100), 327 (46), 307 (58); HRMS (FAB) calcd for
C17H12O4Br (M + H)+: 358.9919, found 358.9926.
Methyl 2-(Naphthalen-1-yl)-4-oxo-4H-chromene-3-carboxy-
late (13a). Compound 13a was eluted with 20% EtOAc/Hex as a
yellow solid (537 mg, 81%); mp: 184−186 °C; FT-IR (KBr) ν/cm−1
1736, 1648, 1458; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.34 (dd, J =
8.0, 1.6 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.95−7.93 (m, 1H), 7.88−
7.85 (m, 1H), 7.75−7.68 (m, 2H), 7.57−7.46 (m, 5H), 3.53 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 174.7, 164.9, 164.8, 156.0, 134.5,
Methyl 2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-4H-chromene-3-
carboxylate (7a). Compound 7a was eluted with 15% EtOAc/Hex
as a red solid (406 mg, 62%); mp: 161−163 °C; FT-IR (KBr) ν/cm−1
1
1730, 1641, 1448, 1383, 1082, 760; H NMR (400 MHz, CDCl3) δ
(ppm) 8.22 (dd, J = 8.0, 1.5 Hz, 1H), 7.71−7.67 (m, 1H), 7.49 (d, J =
8.2 Hz, 1H), 7.43−7.39 (m, 1H), 7.27 (dd, J = 8.2, 1.8 Hz, 1H), 7.19
(d, J = 1.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.06 (s, 2H), 3.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 166.0, 162.6, 155.9,
150.8, 148.4, 134.4, 126.2, 125.8, 125.7, 123.5, 123.2, 118.1, 117.6,
108.8, 108.2, 102.2, 53.0; LRMS (FAB) (m/z) (relative intensity) 325
(M+ + 1, 100), 324 (M+, 37), 293 (70), 289 (12); HRMS (FAB) calcd
for C18H13O6 (M + H)+: 325.0712, found 325.0719.
133.5, 131.6, 130.6, 129.6, 128.6, 127.8, 127.5, 126.7, 126.3, 125.9,
124.8, 124.8, 123.6, 120.7, 118.2, 52.5; LRMS (FAB) (m/z) (relative
intensity) 331 (M+ + 1, 100), 307 (16), 300 (18); HRMS (FAB) calcd
for C21H15O4 (M + H)+: 331.0970, found 331.0976.
Methyl 4-Oxo-2-(thiophen-2-yl)-4H-chromene-3-carboxy-
late (14a). Compound 14a was eluted with 15% EtOAc/Hex as a
brown solid (157 mg, 27%); mp: 99−101 °C; FT-IR (KBr) ν/cm−1
1735, 1637,1569, 1466, 1387, 1091, 759; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.21 (dd, J = 7.6, 1.6 Hz, 1H), 7.72−7.68 (m, 1H), 7.66−7.65
(m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.44−7.40 (m, 1H), 7.18−7.16 (m,
1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 165.8,
156.3, 155.7, 134.6, 133.4, 131.8, 131.0, 128.6, 126.2, 125.9, 123.2,
118.1, 116.0, 53.3; LRMS (FAB) (m/z) (relative intensity) 287 (M+ +
1, 100), 271 (9); HRMS (FAB) calcd for C15H11O4S (M + H)+:
287.0378, found 287.0382.
Methyl 2-(4-Fluorophenyl)-4-oxo-4H-chromene-3-carboxy-
late (8a). Compound 8a was eluted with 20% EtOAc/Hex as a
brown solid (320 mg, 53%); mp: 111−113 °C; FT-IR (KBr) ν/cm−1
1
1737, 1647, 1621, 1605, 1570, 1466, 1383, 1092, 761; H NMR (400
MHz, CDCl3) δ (ppm) 8.25 (dd, J = 7.9, 1.5 Hz, 1H), 7.77−7.69 (m,
3H), 7.51 (d, J = 8.3 Hz, 1H), 7.46−7.42 (m, 1H), 7.22−7.17 (m,
2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.0, 164.8 (J =
252.0 Hz), 165.7, 162.2, 156.0, 134.6, 130.5 (J = 9.0 Hz), 128.3 (J =
4.0 Hz), 126.3, 126.0, 123.3, 118.3, 118.2, 116.3 (J = 22.0 Hz), 53.0 ;
LRMS (FAB) (m/z) (relative intensity) 299 (M+ + 1, 100), 273 (4);
HRMS (FAB) calcd for C17H12O4F (M + H)+: 299.0720, found
299.072.
Methyl 5-Chloro-4-oxo-2-p-tolyl-4H-chromene-3-carboxy-
late (1b). Compound 1b was eluted with 20% EtOAc/Hex as a
yellow solid (313 mg, 48%); mp: 160−162 °C; FT-IR (KBr) ν/cm−1
1
1738, 1644, 1557, 1436, 1368, 1090; H NMR (400 MHz, CDCl3) δ
(ppm) 8.20 (d, J = 2.3 Hz, 1H), 7.76−7.61 (m, 3H), 7.48 (d, J = 8.8
Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 3.81 (s, 3H), 2.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 174.0, 165.7, 163.7, 154.3, 142.9, 134.7,
131.8, 129.8, 128.9, 128.1, 125.6, 124.3, 120.0, 117.8, 53.0, 21.8; LRMS
(FAB) (m/z) (relative intensity) 329 (M+ + 1, 100), 307 (27); HRMS
(FAB) calcd for C18H14O4Cl (M + H)+: 329.0581, found 329.0581.
Methyl 5-Methyl-4-oxo-2-p-tolyl-4H-chromene-3-carboxy-
late (1c). Compound 1c was eluted with 20% EtOAc/Hex as a
pink solid (401 mg, 65%); mp: 129−131 °C; FT-IR (KBr) ν/cm−1
1738, 1645, 1486, 1368, 1091; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.02 (d, J = 0.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.5, 2.1
Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 3.8 (s,
3H), 2.46 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
175.3, 166.2, 163.3, 154.3, 142.4, 135.9, 135.7, 129.7, 129.4, 128.1,
125.6, 123.0, 118.0, 117.7, 52.9, 21.7, 21.2; LRMS (EI) (m/z) (relative
intensity) 308 (M+, 74), 293 (15), 277 (100); HRMS (EI) calcd for
C19H16O4 (M+): 308.1049, found 308.1050.
Methyl 6-Nitro-4-oxo-2-(p-tolyl)-4H-chromene-3-carboxy-
late (1d). Compound 1d was eluted with 15% EtOAc/Hex as an
off-white solid (178 mg, 26%); mp: 158−160 °C; FT-IR (KBr) ν/
cm−1 1737, 1650, 1623, 1533, 1499, 1344, 1090; 1H NMR (400 MHz,
CDCl3) δ (ppm) 9.10 (d, J = 2.5 Hz, 1H), 8.55−8.52 (m, 1H), 7.68
(d, J = 9.2 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H),
3.82 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7,
165.0, 164.0, 158.7, 145.3, 143.5, 130.0, 128.8, 128.3, 128.2, 123.5,
123.0, 120.1, 118.2, 53.2, 21.8; LRMS (ESI) (m/z) (relative intensity)
341 (M+ + 1, 100), 295 (23); HRMS (ESI) calcd for C18H14NO6 (M +
H)+: 340.0821, found 340.0814.
Methyl 2-(4-Chlorophenyl)-4-oxo-4H-chromene-3-carboxy-
late (9a). Compound 9a was eluted with 15% EtOAc/Hex as a
white solid (320 mg, 51%); mp: 134−136 °C; FT-IR (KBr) ν/cm−1
1
1735, 1647, 1618, 1560, 1466, 1380, 1088, 759; H NMR (400 MHz,
CDCl3) δ (ppm) 8.25 (dd, J = 7.9, 1.4 Hz, 1H), 7.75−7.67 (m, 3H),
7.53−7.43 (m, 4H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
175.0, 165.6, 162.0, 156.0, 138.3, 134.7, 130.6, 129.6, 129.4, 126.4,
126.0, 123.3, 118.4, 118.2, 53.1; LRMS (FAB) (m/z) (relative
intensity) 315 (M+ + 1, 100), 307 (26), 285 (19), 283 (55); HRMS
(FAB) calcd for C17H12O4 Cl (M + H)+: 315.0424, found 315.0423.
Methyl 2-(3-Nitrophenyl)-4-oxo-4H-chromene-3-carboxy-
late (10a). Compound 10a was eluted with 20% EtOAc/Hex as a
yellow solid (140 mg, 21%); mp: 170−172 °C; FT-IR (KBr) ν/cm−1
1735, 1648, 1534, 1466, 1380, 1094, 761; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.64−8.63 (m, 1H), 8.42−8.39 (m, 1H), 8.26 (dd, J
= 7.9, 1.3 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.78−7.70 (m, 2H), 7.56
(d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 3.85 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 174.8, 165.2, 160.3, 155.9, 148.6, 135.0, 133.9,
133.7, 130.3, 126.4, 126.4, 126.3, 123.4, 123.3, 119.2, 118.3, 53.3;
LRMS (FAB) (m/z) (relative intensity) 326 (M+ + 1, 100), 310 (8),
294 (46), 289 (17), 278 (6); HRMS (FAB) calcd for C17H12O6N (M
+H)+: 326.0665, found 326.0664.
Methyl 2-(2-Methoxyphenyl)-4-oxo-4H-chromene-3-carbox-
ylate (11a). Compound 11a was eluted with 15% EtOAc/Hex as a
brown solid (498 mg, 80%); mp: 130−132 °C; FT-IR (KBr) ν/cm−1
1740, 1647,1618, 1466, 1382, 1088, 759; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.26 (dd, J = 8.0, 1.5 Hz, 1H), 7.70−7.66 (m, 1H), 7.54−7.40
(m, 4H), 7.09−7.05 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H),
3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.9, 165.2, 163.6,
157.1, 156.2, 134.2, 132.9, 130.2, 126.4, 125.7, 123.8, 121.8, 120.8,
Methyl 6-(Dimethylamino)-4-oxo-2-(p-tolyl)-4H-chromene-
3-carboxylate (1e). Compound 1e was eluted with 15% EtOAc/
Hex as a yellow solid (567 mg, 84%); mp: 187−189 °C; FT-IR (KBr)
6502
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Article
ν/cm−1 1730, 1612, 1502, 1435, 1373, 1233, 1185, 1093, 901; H
NMR (400 MHz, CDCl3) δ (ppm) 7.61 (d, J = 8.0 Hz, 2H), 7.40 (d, J
= 9.1 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.13
(dd, J = 9.2, 3.1 Hz, 1H), 3.79 (s, 3H), 3.03 (s, 6H), 2.42 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.4, 166.6, 162.7, 148.6, 148.6, 142.0,
129.8, 129.6, 128.0, 123.9, 120.1, 118.8, 116.9, 105.4, 52.8, 40.9, 21.7;
LRMS (ESI) (m/z) (relative intensity) 338 (M+ + 1, 100); HRMS
(ESI) calcd for C20H20NO4 (M + H)+: 338.1392, found 338.1385.
Ethyl 4-Oxo-2-p-tolyl-4H-chromene-3-carboxylate (1f). Com-
pound 1f was eluted with 15% EtOAc/Hex as a white solid (210 mg,
34%); mp: 106−108 °C; FT-IR (KBr) ν/cm−1 1733, 1645, 1465,
(dd, J = 8.0, 1.5 Hz, 1H), 7.71−7.67 (m, 1H), 7.52−7.48 (m, 3H),
7.43 (t, J = 7.6 Hz, 1H), 7.30 (dd, J = 5.0, 0.7 Hz, 1H), 7.14 (d, J = 8.0
Hz, 2H), 7.04 (d, J = 3.3 Hz, 1H), 6.96 (dd, J = 5.0, 3.4 Hz, 1H), 5.41
(s, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 165.0,
163.9, 156.0, 142.4, 137.0, 134.4, 129.6, 129.2, 129.0, 128.1, 127.3,
127.0, 126.3, 125.8, 123.4, 118.2, 117.6, 61.6, 21.8; LRMS (FAB) (m/
z) (relative intensity) 377 (M+ + 1, 100), 376 (M+, 4); HRMS (FAB)
calcd for C22H17O4S (M + H)+: 377.0848, found 377.0840.
1
(Furan-2-yl)methyl 4-Oxo-2-p-tolyl-4H-chromene-3-carbox-
ylate (1l). Compound 1l was eluted with 15% EtOAc/Hex as an off-
white solid (211 mg, 29%); mp: 148−150 °C; FT-IR (KBr) ν/cm−1
1
1
1731, 1643, 1385, 1085; H NMR (400 MHz, CDCl3) δ (ppm) 8.24
1380, 1088; H NMR (400 MHz, CDCl3) δ (ppm) 8.25 (dd, J = 8.0,
(dd, J = 8.0, 1.4 Hz, 1H), 7.71−7.67 (m, 1H), 7.54−7.48 (m, 3H),
7.43 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 0.7 Hz, 1H), 7.18 (d, J = 8.0 Hz,
2H), 6.39 (d, J = 3.2 Hz, 1H), 6.35−6.34 (m, 1H), 5.24 (s, 2H), 2.41
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 165.0, 163.7, 156.0,
149.0, 143.4, 142.3, 134.4, 129.6, 129.0, 128.1, 126.3, 125.8, 123.3,
118.2, 117.6, 111.5, 110.7, 59.2, 21.8; LRMS (FAB) (m/z) (relative
intensity) 361 (M+ + 1, 100), 360 (M+, 5), 307 (3); HRMS (FAB)
calcd for C22H17O5 (M + H)+: 361.1076, found 361.1074.
1.5 Hz, 1H), 7.72−7.64 (m, 3H), 7.50 (d, J = 8.3 Hz, 1H), 7.44−7.40
(m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 2.43 (s,
3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2,
165.4, 163.2, 156.0, 142.4, 134.3, 129.6, 129.7, 128.2, 126.2, 125.7,
123.3, 118.2, 118.1, 62.0, 21.7, 14.0; LRMS (FAB) (m/z) (relative
intensity) 309 (M+ + 1, 100), 308 (M+, 6), 279 (4); HRMS (FAB)
calcd for C19H17O4 (M + H)+: 309.1127, found 309.1122.
Propyl 4-Oxo-2-p-tolyl-4H-chromene-3-carboxylate (1g).
Compound 1g was eluted with 15% EtOAc/Hex as a brown gummy
solid (221 mg, 34%); FT-IR (KBr) ν/cm−1 1732, 1645, 1619, 1465,
1379, 1088, 759; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.25 (dd, J =
8.0, 1.6 Hz, 1H), 7.72−7.64 (m, 3H), 7.51 (d, J = 8.4 Hz, 1H), 7.45−
7.41 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 4.17 (t, J = 6.6 Hz, 2H), 2.43
(s, 3H), 1.63−1.55 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 175.2, 165.6, 163.3, 156.0, 142.4, 134.4, 129.7, 129.4,
128.2, 126.3, 125.8, 123.4, 118.3, 118.2, 67.7, 21.9, 21.7, 10.4; LRMS
(FAB) (m/z) (relative intensity) 323 (M+ + 1, 100), 322 (M+, 6), 279
(5); HRMS (FAB) calcd for C20H19O4 (M + H)+: 323.1283, found
323.1281.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data of compound 2a and H and 13C NMR
1
copies of all the compounds are available in Supporting
Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
cheyaocf@ntnu.edu.tw
■
Benzyl 4-Oxo-2-p-tolyl-4H-chromene-3-carboxylate (1h).
Compound 1h was eluted with 4% EtOAc/Hex as a white solid
(506 mg, 68%); mp: 158−160 °C; FT-IR (KBr) ν/cm−1 1731, 1645,
Notes
The authors declare no competing financial interest.
1
1386, 1089; H NMR (400 MHz, CDCl3) δ (ppm) 8.26 (dd, J = 7.9,
1.4 Hz, 1H), 7.72−7.67 (m, 1H), 7.56−7.49 (m, 3H), 7.43 (t, J = 7.6
Hz, 1H), 7.29−7.27 (m, 3H), 7.20−7.14 (m, 4H), 5.25 (s, 2H), 2.40
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.1, 165.2, 163.8, 156.0,
142.4, 135.3, 134.4, 129.6, 129.2, 128.9, 128.6, 128.4, 128.2, 126.3,
125.8, 123.4, 118.2, 117.9, 67.7, 21.7; LRMS (FAB) (m/z) (relative
intensity) 371 (M+ + 1, 100), 370 (M+, 4), 307 (7); HRMS (FAB)
calcd for C24H19O4 (M + H)+: 371.1283, found 371.1285.
ACKNOWLEDGMENTS
■
Financial support for this work by the National Science Council
of the Republic of China (NSC 100-2113-M-003-008-MY3)
and National Taiwan Normal University (99T3030-2, 99-D,
100-D-06) is gratefully acknowledged.
Allyl 4-Oxo-2-p-tolyl-4H-chromene-3-carboxylate (1i). Com-
pound 1i was eluted with 20% EtOAc/Hex as a brown gummy solid
(370 mg, 58%); FT-IR (KBr) ν/cm−1 1732, 1644, 1620, 1464, 1385,
REFERENCES
(1) (a) Mijangos, M. V.; Gonzal
Vincent-Ruz, P.; Lujan-Montelongo, A.; Olivera-Díaz, D.; Bautista, E.;
Ortega, A.; Campos- Gonzalez, M. D. L. L.; Gamez-Montano, R. Org.
■
́
ez-Marrero, J.; Miranda, L. D.;
1
1088, 760; H NMR (400 MHz, CDCl3) δ (ppm) 8.25 (dd, J = 8.0,
́
̃
1.6 Hz, 1H), 7.73−7.66 (m, 1H), 7.64 (d, J = 6.5 Hz, 2H), 7.52 (d, J =
8.1 Hz, 1H), 7.46−7.42 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 5.87−5.79
(m, 1H), 5.30−5.18 (m, 2H), 4.73−4.71 (m, 2H), 2.37 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.2, 165.2, 163.5, 156.0, 142.5, 134.4,
131.6, 129.7, 129.3, 128.3, 126.3, 125.8, 123.4, 119.2, 118.2, 118.0,
66.6, 21.8; LRMS (FAB) (m/z) (relative intensity) 321 (M+ + 1, 100),
320 (M+, 3), 279 (8); HRMS (FAB) calcd for C20H17O4 (M + H)+:
321.1127, found 321.1125.
Biomol. Chem. 2012, 10, 2946−2949. (b) Gong, J.; Xie, F.; Ren, W.;
Chen, H.; Hu, Y. Org. Biomol. Chem. 2012, 10, 486−489. (c) Zhao, J.;
Zhao, Y.; Fu, H. Angew. Chem., Int. Ed. 2011, 50, 3769−3773. (d) Wu,
C.; Liu, Y.; Zeng, H.; Liu, L.; Wang, D.; Chen, Y. Org. Biomol. Chem.
2011, 9, 253−256. (e) Gaspar, A.; Silva, T.; Yanez, M.; Vina, D.;
Orallo, F.; Ortuso, F.; Uriarte, E.; Alcaro, S.; Borges, F. J. Med. Chem.
2011, 54, 5165−5173. (f) Wu, C.; Zeng, H.; Liu, L.; Wang, D.; Chen,
Y. Tetrahedron 2011, 67, 1231−1237. (g) Vedachalam, S.; Wong, Q.-
L.; Maji, B.; Zeng, J.; Ma, J.; Liu, X.-W. Adv. Synth. Catal. 2011, 353,
219−225. (h) Chai, G.; Qiu, Y.; Fu, C.; Ma, S. Org. Lett. 2011, 13,
5196−5199. (i) Gong, J.; Xie, F.; Chen, H.; Hu, Y. Org. Lett. 2010, 12,
3848−3851. (j) Sakamoto, M.; Yagishita, F.; Kanehero, M.; Kasashima,
Y.; Mino, T.; Fujita, T. Org. Lett. 2010, 12, 4435−4437. (k) Saxin, M.
F-.; Pemberton, N.; Andersson, K. D. S.; Dyrager, C.; Friberg, A.;
Grotli, M.; Luthman, K. J. Org. Chem. 2009, 74, 2755−2759. (l) Mal,
D.; De, S. R. Org. Lett. 2009, 11, 4398−4401. (m) Shimizu, M.;
Tsurugi, H.; Satoh, T.; Miura, M. Chem.Asian J. 2008, 3, 881−886.
(n) Abe, I.; Utsumi, Y.; Oguro, S.; Morita, H.; Sano, Y.; Noguchi, H. J.
Am. Chem. Soc. 2005, 127, 1362−1363. (o) Dao, T. T.; Chi, Y. S.;
Kim, J.; Kim, H. P.; Kim, S.; Park, H. Bioorg. Med. Chem. Lett. 2004,
14, 1165−1167. (p) Recanatin, M. i.; Bisi, A.; Cavalli, A.; Belluti, F.;
Gobbi, S.; Rampa, A.; Valenti, P.; Palzer, M.; Palusczak, A.; Hartmann,
R. W. J. Med. Chem. 2001, 44, 672−680 and references therein.
2-Hydroxyethyl 4-Oxo-2-p-tolyl-4H-chromene-3-carboxy-
late (1j). Compound 1j was eluted with 15% EtOAc/Hex as a
brown solid (210 mg, 32%); mp: 119−121 °C; FT-IR (KBr) ν/cm−1
1
1731, 1621, 1466, 1388, 1091, 761; H NMR (400 MHz, CDCl3) δ
(ppm) 8.25 (dd, J = 8.0, 1.5 Hz, 1H), 7.75−7.71 (m, 1H), 7.67 (d, J =
8.2 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.32 (d,
J = 8.0 Hz, 2H), 4.48 (t, J = 4.5 Hz, 2H), 3.84 (m, 2H), 3.59 (t, J = 6.3
Hz, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.9, 165.5,
164.3, 156.1, 142.9, 134.7, 129.9, 128.9, 128.4, 126.3, 126.0, 123.2,
118.3, 117.6, 67.7, 60.7, 21.8; LRMS (FAB) (m/z) (relative intensity)
325 (M+ + 1, 100), 289 (43), 273 (8); HRMS (FAB) calcd for
C19H17O5 (M + H)+: 325.1076, found 325.1076.
(Thiophen-2-yl)methyl 4-Oxo-2-p-tolyl-4H-chromene-3-car-
boxylate (1k). Compound 1k was eluted with 15% EtOAc/Hex as a
brown solid (179 mg, 24%); mp: 136−138 °C; FT-IR (KBr) ν/cm−1
1
1730, 1642, 1386, 1082; H NMR (400 MHz, CDCl3) δ (ppm) 8.25
6503
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The Journal of Organic Chemistry
Article
(2) (a) Cai, S.; Shen, Y.; Lu, P.; Wang, Y. Tetrahedron Lett. 2011, 52,
4164−4167. (b) Jana, R.; Trivedi, R.; Tunge, J. A. Org. Lett. 2009, 11,
3434−3436. (c) Budzisz, E.; Keppler, B. K.; Giester, G.; Wozniczka,
M.; Kufelnicki, A.; Nawrot, B. Eur. J. Inorg. Chem. 2004, 4412−4419.
(d) Ishizuka, N.; Matsumura, K.-i.; Sakai, K.; Fujimoto, M.; Mihara, S.-
I.; Yamamori, T. J. Med. Chem. 2002, 45, 2041−2055. (e) Seth, P. P.;
Totah, N. I. Org. Lett. 1999, 1, 1411−1414. (f) Lee, Y.-G.; Ishimaru,
K.; Iwasaki, H.; Ohkata, K.; Akiba, K.-Y. J. Org. Chem. 1991, 56, 2058−
2066. (g) Cremins, P. J.; Saengchantara, S. T.; Wallace, T. W.
Tetrahedron 1987, 43, 3075−3082 and references therein.
(3) (a) Budzisz, E.; Miernicka, M.; Lorenz, I.-P.; Mayer, P.;
Balcerczak, E.; Krajewska, U.; Rozalski, M. Eur. J. Med. Chem. 2010,
45, 2613−2621. (b) Budzisz, E.; Malecka, M.; Nawrot, B. Tetrahedron
2004, 60, 1749−1759. (c) Crombie, B. S.; Smith, C.; Varnavas, C. Z.;
Wallace, T. W. J. Chem. Soc., Perkin Trans. 1 2001, 206−215.
(d) Crombie, B. S.; Redhouse, A. D.; Smith, C.; Wallace, T. W. J.
Chem. Soc., Chem. Commun. 1995, 403−404. (e) Cremins, P. J.; Hayes,
R.; Wallace, T. W. Tetrahedron 1993, 49, 3211−3220. (f) Cremins, P.
J.; Hayes, R.; Wallace, T. W. Tetrahedron 1991, 47, 9431−9438.
(g) Saengchantara, S. T.; Wallace, T. W. Tetrahedron 1990, 46, 3029−
3036. (h) Cremins, P. J.; Wallace, T. W. J. Chem. Soc., Chem. Commun.
1986, 1602−1603. (i) Chantegrel, B.; Nadi, A. I.; Gelin, S. J. Org.
Chem. 1984, 49, 4419−4424. (j) Wallace, T. W. Tetrahedron Lett.
1984, 25, 4299−4302. (k) Nixon, N. S.; Scheinmann, F.; Suschitzky, J.
L. Tetrahedron Lett. 1983, 24, 597−600. (l) Klutchko, S.; Shavel, J., Jr.;
Strandtmann, M. V. J. Org. Chem. 1974, 39, 2436−2437 and references
therein.
(4) (a) Cushman, M.; Nagarathnam, D.; Burg, D. L.; Geahlen, R. L. J.
Med. Chem. 1991, 34, 798−806. (b) O. Hormi, E. O.; Moisio, M. R.;
Sund, B. C. J. Org. Chem. 1987, 52, 5272−5274. (c) Costa, A. M. B. S.
R. C. S.; Dean, F. M.; Jones, M. A.; Varma, R. S. J. Chem. Soc., Perkin
Trans. 1 1985, 799−808. (d) Chantegrel, B.; Nadi, A. I.; Gelin, S. J.
Org. Chem. 1984, 49, 4419−4424. (e) Bapin, P.; Dunogues, J.;
Petraud, M. Tetrahedron 1981, 37, 1131−1139. (f) Coppola, G. M.;
Dodsworth, R. W. Synthesis 1981, 523−524. (g) Costa, A. M. B. S. R.
C. S.; Dean, F. M.; Jones, M. A.; Smith, D. A.; Varma, R. S. J. Chem.
Soc., Chem. Commun. 1980, 1224−1226.
(5) (a) Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Fares, C.;
Klussmann, M. J. Am. Chem. Soc. 2011, 133, 8106−8109. (b) Ghandi,
M.; Bozcheloei, A. H.; Nazari, S. H.; Sadeghzadeh, M. J. Org. Chem.
2011, 76, 9975−9982. (c) Liu, H.; Chen, C.; Wang, L.; Tong, X. Org.
Lett. 2011, 13, 5072−5075. (d) Verma, A. K.; Rustagi, V.; Aggarwal,
T.; Singh, A. P. J. Org. Chem. 2010, 75, 7691−7703. (e) Zhao, Y.;
Yeung, Y.-Y. Org. Lett. 2010, 12, 2128−2131. (f) Zhang, J.; Chang, C.-
W. T. J. Org. Chem. 2009, 74, 685−695. (g) Minegishi, S.; Kobayashi,
S.; Mayr, H. J. Am. Chem. Soc. 2004, 126, 5174−5181 and references
therein.
(6) (a) Barange, D. K.; Kavala, V.; Kuo, C.-W.; Lei, P.-M.; Yao, C.-F.
Tetrahedron 2011, 67, 2870−2877. (b) Habib, P. M.; Kavala, V.; Kuo,
C.-W.; Raihan, M. J.; Yao, C.-F. Tetrahedron 2010, 66, 7050−7056.
(c) Barange, D. K.; Raju, B. R.; Kavala, V.; Kuo, C. -W.; Tu, Y.-C.; Yao,
C.-F. Tetrahedron 2010, 66, 3754−3760. (d) Gao, S.; Tu, Z.; Kuo, C.-
W.; Liu, J.-T.; Chu, C.-M.; Yao, C.-F. Org. Biomol. Chem. 2006, 4,
2851−2857. (e) Jang, Y.-J.; Yan, M.-C.; Lin, Y.-F.; Yao, C.-F. J. Org.
Chem. 2004, 69, 3961−3963. (f) Jang, Y.-J.; Shih, Y.-K.; Kuo, W.-Y.;
Yao, C.-F. Chem.Eur. J. 2003, 9, 2123−2128. (g) Chu, C.-M.; Liu, J.-
T.; Lin, W.-W.; Yao, C.-F. J. Chem. Soc., Perkin Trans. 1 1999, 47−52.
(h) Yao, C.-F.; Chu, C.-M.; Liu, J.-T. J. Org. Chem. 1998, 63, 719−722.
(7) Ghabraie, E.; Bararjanian, M.; Balalaie, S.; Rominger, F.;
Bijanzadeh, H. R. Helv. Chim. Acta 2011, 94, 1440−1446.
(8) (a) Singh, P.; Kumar, P.; Chandra, R.; Katyal, A.; Kalra, R.; Dass,
S. K.; Prakash, S. Catal. Lett. 2010, 134, 303−308. (b) Khurana, J. M.;
Kumar, S. Tetrahedron Lett. 2009, 50, 4125−4127. (c) Heravi, M. M.;
Nahavandi, F.; Sadjadi, S.; Oskooie, H. A.; Bamoharram, F. F. Synth.
Commun. 2010, 40, 498−503. (d) Sangshetti, J. N.; Kokare, N. D.;
Shinde, D. B. Green Chem. Lett. Rev. 2009, 2, 233−235.
6504
dx.doi.org/10.1021/jo301044y | J. Org. Chem. 2012, 77, 6495−6504