Synthesis of isocoumarin derivatives via the copper-catalyzed tandem sequential cyclization of 2- halo-N-phenyl benzamides and acyclic 1,3-diketones

Article abstract of DOI:10.1021/jo300501j

A facile and rapid synthesis of isocoumarin derivatives using a copper-catalyzed tandem C-C/C-O coupling strategy from readily available substrates is described. The reactions of a wide range of 2-iodo-N-phenyl benzamides and acyclic diketones as starting materials were investigated.

Full text of DOI:10.1021/jo300501j

Article
pubs.acs.org/joc
Synthesis of Isocoumarin Derivatives via the Copper-Catalyzed
Tandem Sequential Cyclization of 2- Halo-N-phenyl Benzamides and
Acyclic 1,3-Diketones
Veerababurao Kavala, Cheng-Chuan Wang, Deepak Kumar Barange, Chun-Wei Kuo, Po-Min Lei,
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: A facile and rapid synthesis of isocoumarin
derivatives using a copper-catalyzed tandem C−C/C−O
coupling strategy from readily available substrates is described.
The reactions of a wide range of 2-iodo-N-phenyl benzamides
and acyclic diketones as starting materials were investigated.
was completely consumed, and two products were produced.
Both products were isolated and characterized by 1H NMR, 13
INTRODUCTION
■
C
Copper-catalyzed tandem sequential cyclization reactions are
powerful tools for the construction of a wide variety of
heterocyclic frame works.1 A wide range of heterocycles
including indoles, benzofurans, quinolines, isoqunolines,
quinazalines, quinazolones, and many more heterocycles have
been synthesized using this approach.2 We also recently
reported on a copper-catalyzed tandem cyclization leading to
the synthesis of triazole fused sultum derivatives3 In a
continuation to our interest in copper-catalyzed tandem
cyclization reactions, we wish to investigate the synthesis of
isoquinolinone4 derivatives using 2-halo-N-alkyl/aryl-benza-
mides and 1,3-dicarbonyl as the starting compounds. In fact,
Wang et al. reported on the synthesis of isoquinolinone
derivatives from the 2-halobenzamides and with various
ketoesters (Scheme 1).5 They did not, however, investigate
the possibility of using 1,3-diketones as coupling partners with
N-substituted-2-halobenzamides.
NMR, and HRMS. From the analytical data, the first product
was determined to be 3-methylisocoumarin, and the second
was acetanilide. The structure of the 3-methylisocoumarin
product was further confirmed by single crystal X-ray analysis
(Supporting Information). No trace of isoquinolinone deriva-
tive was observed in this reaction. This interesting result
prompted us to investigate the reaction in more detail.
Isocoumarins are an important class of heterocyclic scaffolds
that exhibit a wide range of biological activities.6 In addition,
isocoumarin derivatives are useful precursors for the synthesis
of various natural products and isoquinoline derivatives.7 A
plethora of methods are available for the construction of
isocoumarin rings from various sources.8 However, most of the
reported procedures have drawbacks, which include the use of
expensive catalysts such as palladium or rhodium, the need for
complex starting materials, and drastic conditions. Therefore,
an easy and handy method for the synthesis of isocoumarin
derivatives would be highly desirable, considering the above
drawbacks. Given this situation, we now report a new
methodology for the rapid synthesis of isocoumarin derivatives
by a copper-catalyzed one-pot sequential cyclization. While our
manuscript was being prepared, we found two papers based on
a similar concept for the synthesis of isocoumarin derivatives
using 2-iodobenzoic acids9 and methyl-2-iodobenzoates10 as
starting compounds. However, the conditions described in
these protocols required quite long reaction times, and when
substrates containing electron-withdrawing groups were used,
the product yields were low.
Scheme 1. Approach by Wang et al. to the Synthesis of
Isoquinolin-1(2H)-one Derivatives
RESULTS AND DISCUSSION
The reaction is presumably initiated with the reaction of
copper iodide and acetylacetone to produce a copper(I)
complex, and the oxidative addition of 2-iodo-N-phenyl-
■
To pursue our objective, we used 2-iodo- N-phenyl-benzamide
and acetylacetone as model substrates. The reaction of 2-iodo-
N-phenyl-benzamide and acetylacetone was conducted in the
presence copper(I) iodide (10 mol %) and cesium carbonate in
DMSO at 100 °C. After a 10 min reaction, the starting amide
Received: March 9, 2012
Published: April 18, 2012
© 2012 American Chemical Society
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benzamide to this copper(I) complex results in the formation
the Cu(III) intermediate (II). The base-mediated abstraction of
the amidic proton from the intermediate (II) followed by the
intramolecular nucleophilic addition of the amide nitrogen to
one of the carbonyl groups of intermediate (III) produces the
intermediate (IV). Since this intermediate (IV) is a charged
species, it is unstable. Hence, it undergoes a C−C bond
cleavage to furnish intermediate (V), which is further converted
to intermediate (VI) via reductive elimination. The attack of
acetylacetone on intermediate (VI) results in the regeneration
of the copper catalyst and the formation of intermediate (VII).
Intermediate (VII) then loses an acetanilide (4a) molecule to
produce the isocoumarin derivative 3a (Scheme 2). This
Table 1. Reactions of Various 2-Benzoic Acid Derivatives
with Acetylacetone
Scheme 2. Plausible Mechanistic Pathway
a
Reaction conditions: nitrogen atmosphere, 1 (0.5 mmol), 2a (1
b
mmol), Cs2CO3 (1 mmol), CuI (0.05 mmol), DMSO (3 mL). NMR
yield with CH2Br2 as internal standard.
reaction mechanism is very similar to the mechanism proposed
by Lei and co-workers for the reaction of aryl halides with
acetyl acetone.11 The difference here is the internal nucleophile
(amidic nitrogen) attack on one of the carbonyl carbons of the
Cu(III) complex, whereas in Lei’s proposed mechanism the
attack involves an external nucleophile (H2O).
attributed to the stronger ortho effect of N-phenylamides.12 It
is interesting to note that the reactions of methyl-2-
iodobenzoate and N,N-diethyl-2-iodobenzamide failed to give
the expected products. However, Fan et al.10 have obtained
moderate yield of the product with methyl-2-bromobenzoate
with the same catalyst in the presence of K2CO3 as base and
DMF as solvent. The reason for this failure may be due to the
absence of the nucleophilic oxygen or a nitrogen site in both
entry 5 and entry 6. From all of the experiments described in
Table 1, it is quite clear that 2-iodo-N-phenyl-benzamide
derivatives are superior for the generation of isocoumarin
derivatives. Hence, we then used a variety of substituted 2-iodo-
N-phenyl-benzamide derivatives for the synthesis of a
structurally diverse series of isocoumarin derivatives.
Encouraged by these initial observations, we first focused our
attention on optimizing the reaction conditions. In this regard,
we examined various solvents. The findings indicated that the
reaction proceeded well in polar aprotic solvents such as DMF
and DMSO, and moderate yields were obtained when
acetonitrile was used. The poor yields were obtained when a
nonpolar solvent, such as toluene, was used. The next screened
various copper sources. The reaction was equally efficient when
copper salts such as CuCl, CuBr, and CuI were used. We also
tested various inorganic bases in the reaction. Both cesium
To determine if other 2-iodobenzoic acid derivatives, such as
2-iodobenzoic acid, methyl-2-iodobenzoate, and N-alkyl-2-
iodobenzamide, could be used in this reaction, we examined
the reaction of all of these derivatives with acetylacetone in the
presence of the copper catalyst (CuI) and cesium carbonate in
DMSO at 100 °C. The results were summarized in Table 1. As
can be seen from the Table 1, when 2-iodo-benzoic acid was
used in the reaction, the desired product was produced in
moderate yield. In this case, however, the reaction time needed
to be extended, compared with the use of amide derivatives
such as 2-iodo-N-methyl-benzamide and N-benzyl-2-iodoben-
zamide. It should also be noted that the reaction of 2-iodo-N-
phenyl-benzamide resulted in the production of high yields of
the expected isocoumarin derivative within 10 min. When the
reaction was performed with 2-iodo-N-(4-nitrophenyl)-
benzamide under the present reaction conditions, the reaction
completed in 10 min but yield of the product was 85%. The
higher reactivity of 2-iodo-N-phenylbenzamides may be
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carbonate and potassium carbonate were found to be more
Table 3. Scope of the Reaction with Respect to Various 2-
Iodo-N-phenyl-benzamides
efficient for this reaction (Table 2).
Table 2. Screening for Reaction Conditions
temp
(°C)
time
(h)
yield
b
a
entry catalyst
base
solvent
(%)
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
toluene
dioxane
MeCN
DMF
90
100
60
40
12
19
0.5
7
50
26
95
81
85
93
98
85
92
79
16
90
87
2
3
4
100
60
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
80
2.5
0.16
0.5
1.5
3
7
100
100
100
100
100
100
100
8
9
10
11
12
13
Na2CO3
K3PO4
49
0.5
0.5
Cs2CO3
Cs2CO3
a
Reaction conditions:nitrogen atmosphere, 1a (0.5 mmol), 2a (1
b
mmol), Cs2CO3 (1 mmol), CuI (0.05 mmol), solvent (3 mL). NMR
yields with CH2Br2 as internal standard.
With the optimal conditions in hand, the scope of the
tandem sequential cyclization was then explored. The reaction
of a variety of 2-iodo-N-phenyl-substituted benzamide deriva-
tives with acetylacetone was initially examined, and the results
are summarized in Table 3. Reactions of 2-iodo-N-phenyl-
substituted benzamide derivatives containing electron-with-
drawing or electron-donating groups with acetylacetone were
performed under the optimized reaction conditions, and the
corresponding isocoumarin derivatives were produced in good
to excellent yields. It is noteworthy that when substrates that
contained electron-releasing groups were used, the reaction
required a longer time compared to reactions of substrates
possessing electron-withdrawing groups. The reaction is very
fast in the case of substrates with electron-withdrawing groups.
In particular, substrates containing nitro and dibromo func-
tional groups react rapidly to produce the corresponding
product. It is important to note that products containing
electron-withdrawing groups were very unstable under the
reaction conditions used, and it was necessary to quench the
reaction immediately after completion of the reaction. In the
case of substrates having nitro and fluoro groups, the reaction
was very rapid and the product also decomposed rapidly in the
reaction medium.
Next, the scope of this reaction was extended to various 1,3-
dicarbonyl compounds. When an unsymmetrical diketone such
as 1-phenylbutane-1,3-dione was used as the coupling partner
in the reaction with 1a, we observed the formation of two
isomeric products in which 3-phenylisocoumarin (56%) was
the major product and 3-methylisocoumarin the minor product
(10%). Reactions with symmetrical substituted diphenylpro-
pane-1,3-dione derivatives gave a single product in moderate
yields. Under the present reaction conditions, several
unidentified products were produced when 3-methylpentane-
a
Reaction conditions: nitrogen atmosphere, 1 (1 mmol), 2a (2 mmol),
b
Cs2CO3 (2 mmol), CuI (0.1 mmol), DMSO (3 mL). Isolated yields.
c
Reaction performed at 80 °C.
2,4-dione and ethylacetoacetate were employed as substrates
(Table 4).
To further demonstrate the generality of our methodology,
we utilized 2-bromo-N-phenyl-benzamide and 2-chloro-N-
phenyl-benzamide as substrates. To our delight, both substrates
gave the corresponding product within very short time
(Scheme 3). This reaction trend is also consistent with the
stronger ortho effect of N-phenylamides.13
Pyranoquinoline is one of the prominent structural motifs
found in alkaloids extracted from rutaceae plants.14 Derivatives
of pyranoquinoline compounds are known to exhibit a wide
range of pharmacological and biological activities and can have
antiallergic, anticoagulant, coronary constricting, and antihista-
mic effects.15 Considering the importance of the pyranoquino-
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Table 4. Scope of the Reaction with Respect to Various 1,3-Diketones
a
b
Reaction conditions: nitrogen atmosphere, 1 (1 mmol), 2 (1.2 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), DMSO (3 mL). Isolated yields.
Scheme 3. Reaction of Chloro and Bromo Benzamides with Acetylacetone
line derivatives, we attempted to synthesize these derivatives
using the present method. Starting materials such as 2-chloro-
N-phenylquinoline-3-carboxamide derivatives were synthesized
in four steps, starting from aniline, by following established
procedures.16 These 2-chloro-N-phenylquinoline-3-carboxa-
mide derivatives were treated with acetylacetone under the
optimized reaction conditions, and pyarnoquinolinone deriva-
tives were produced in good yields (Table 5). As can be seen in
Table 5, it is important to note that all of the 2-chloro-N-
phenylquinoline-3-carboxamide derivatives participated in the
reaction with equal ease to produce the corresponding
pyranoquinolinone derivatives. It should also be noted that
the present methodology can also be used in the synthesis of
benzopyranoquinolinone derivatives. The structure of the
newly synthesized pyranoquinolinone derivatives were con-
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Table 5. Synthesis of Pyranoquinolinone Derivatives
a
b
Reaction conditions: nitrogen atmosphere, 1 (1 mmol), 2a (2 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), DMSO (3 mL). Isolated yield.
firmed by the single crystal X-ray analysis of a representative
sample, namely, compound 3s (Figure 1).
Figure 2. Single crystal structure of compound 6a.
variety of different electronic properties and various 1,3-
Figure 1. Single crystal structure of compound 3s.
diketones could be successfully used to access structurally
diverse isocoumarin derivatives in good to excellent yields. In
addition, this methodology can also be utilized for the synthesis
Finally, we carried out the reaction of 2-iodo-N-phenyl-
benzamide with a cyclic diketone 1,3-cyclohexadione using the
of various pyranoquinolinone derivatives, which are important
present reaction conditions (Scheme 4). To our delight, an
constituents in many pharmaceutically active substances.
isoquinolinone derivative was produced (Figure 2). This
Interestingly, the reaction involving 1,3-cyclohexadione gave
outcome is very different from reactions involving acyclic
ketones.
In summary we report herein on the efficient rapid synthesis
an isoquinolinone derivative. Further investigations of the
scope of this reaction are currently underway in our laboratory.
of isocoumarin derivatives by employing copper-catalyzed
tandem C−C/C−O coupling transformation as the key step.
A remarkable number of 2-iodo-N-phenyl-benzamides with a
EXPERIMENTAL SECTION
All chemicals were purchased from various sources and used directly
without further purification. Analytical thin-layer chromatography was
■
performed using silica gel 60F glass plates and gel 60 (230−400 mesh)
Scheme 4. Reaction of 2-Iodo-N-phenyl-benzamide with 1,3-
Cyclohexadione
was used in flash chromatography separations. NMR spectra were
recorded in CDCl3 with tetramethylsilane as the internal standard for
1H NMR (400 MHz) and CDCl3 solvent as the internal standard for
13C NMR (100 MHz), and coupling constants are expressed in hertz.
HRMS spectra were recorded using ESI-TOF or EI+ mode. Melting
points were recorded using an electrothermal capillary melting point
apparatus and are uncorrected.
General Procedure. A 25 mL round-bottom flask was charged
with a magnetic stirrer and 3 mL of DMSO. Substituted N-pheny-2-
halobenzamide (1 mmol), 1,3-diketone (1.2 mmol), copper(I) iodide
(10 mol %), and cesium carbonate (2 mmol) were then added to the
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flask. The reaction solution was stirred at 100 °C under N2 until the
reaction was complete as evidenced by TLC. After completion of the
reaction, the resulting solution was transferred to a beaker containing
crushed ice, and the resulting solid was isolated on a filter. In most
cases, the isolated solid contained only the isocoumarin derivative (3)
and the amide remained in the solution (4). In a very few cases the
solid was a mixture of the products. In such cases, the crude product
was purified by column chromatography (ethylacetate/hexane) on
silica gel.
150 (100), 161 (12), 136 (6). HRMS (ESI) m/z calcd for C10H7ClO2
(M + H) 195.0213, found 195.0199.
3-Methyl-7-nitro-1H-isochromen-1-one (3i). Yellow solid;
1
156.6 mg (76%); mp 176−178 °C. H NMR (400 MHz, CDCl3) δ
9.08 (d, J = 2.12 Hz, 1H), 8.47 (dd, J = 8.72, 2.36 Hz, 1H), 7.49 (d, J =
8.64 Hz, 1H), 6.38 (s, 1H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.1, 159.0, 146.8, 142.7, 129.1, 126.4, 125.8, 120.4, 103.1,
20.1; MS (EI) m/z (relative intensity) 205 (M+, 100), 175 (26), 159
(16), 103 (13). HRMS (EI) m/z calcd for C10H7NO4 (M+) 205.0375,
found 205.0373.
Spectral Data. 3-Methyl-1H-isochromen-1-one (3a). Pale
1
yellow solid; 144.2 mg (90%); mp 70−72 °C. H NMR (400 MHz,
7-Chloro-3-methyl-1H-isochromen-1-one (3j). Colorless solid;
1
CDCl3) δ 8.24 (d, J = 7.96 Hz, 1H), 7.66 (td, J = 7.60, 1.13 Hz, 1H),
7.46−7.42 (m, 1H), 7.33 (d, J = 7.84 Hz, 1H), 6.25 (s, 1H), 2.28 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 154.7, 137.8, 134.8,
129.6, 127.6, 125.0, 120.0, 103.6, 19.7; MS (ESI) m/z (relative
intensity) 161 (M + H, 100), 143 (18). HRMS (ESI) m/z calcd for
C10H8O2 (M + H) 161.0603, found 161.0603.
161.8 mg (83%); mp 148−150 °C. H NMR (400 MHz, CDCl3) δ
8.21 (d, J = 1.88 Hz, 1H), 7.61 (dd, J = 8.40, 2.14 Hz, 1H), 7.28 (d, J =
8.40 Hz, 1H), 6.23 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.9, 155.1, 136.1, 135.2, 133.3, 129.0, 126.6, 121.2, 103.0,
19.8; MS (EI) m/z (relative intensity) 194 (M+, 100), 152 (22), 123
(17), 102 (3). HRMS (EI) m/z calcd for C10H7ClO2 (M+) 194.0135,
found 194.0133.
3,7-Dimethyl-1H-isochromen-1-one (3b). White solid; 128.9
1
mg (74%); mp 122−124 °C. H NMR (400 MHz, CDCl3) δ 8.05 (s,
5,7-Dibromo-3-methyl-1H-isochromen-1-one (3k). Pale yel-
1
1H), 7.48 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 6.22 (s, 1H), 2.44
(s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.3, 153.8,
137.8, 136.2, 135.3, 129.3, 124.9, 119.9, 103.5, 21.4, 19.7; MS (ESI)
m/z (relative intensity) 175 (M + H, 100), 147 (2). HRMS (ESI) m/z
calcd for C11H10O2 (M + H) 175.0759, found 175.0747.
low solid; 270.7 mg (85%); mp 148−150 °C. H NMR (400 MHz,
CDCl3) δ 8.34 (d, J = 1.68 Hz, 1H), 8.02 (d, J = 2.00 Hz, 1H), 6.57 (s,
1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 156.5,
140.7, 136.0, 131.6, 122.4, 120.7, 120.3, 102.0, 20.2; MS (EI) m/z
(relative intensity) 320 (M+ + 4, 54), 318 (M+ + 2, 100), 315 (M+,
44), 275 (11), 239 (13), 237 (12), 170 (34), 102 (7). HRMS (EI) m/z
calcd for C10H6Br2O2 (M+) 315.8735, found 315.8737.
7-Methoxy-3-methyl-1H-isochromen-1-one (3c). White solid;
165.5 mg (87%); mp 96−98 °C. 1H NMR (400 MHz, CDCl3) δ 7.66
(s, 1H), 7.27 (d, J = 1.08 Hz, 2H), 6.22 (s, 1H), 3.89 (s, 3H), 2.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 163.2, 159.1, 152.4, 131.4,
126.5, 124.5, 121.0, 109.9, 103.2, 55.7, 19.5; MS (ESI) m/z (relative
intensity) 191 (M + H, 100), 173 (4), 145 (2). HRMS (ESI) m/z
calcd for C11H10O3 (M + H) 191.0708, found 191.0705.
6,7-Dimethoxy-3-methyl-1H-isochromen-1-one (3d). Blue
solid; 187.3 mg (85%); mp 126−128 °C. 1H NMR (400 MHz,
CDCl3) δ 7.61 (s, 1H), 6.70 (s, 1H), 6.18 (s, 1H), 3.97 (s, 3H), 3.95
(s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 155.3,
153.6, 149.4, 133.5, 113.1, 109.6, 105.7, 103.3, 56.4, 56.3, 19.7; MS
(EI) m/z (relative intensity) 220 (M+, 100), 171 (68), 170 (64), 149
(16), 115 (6). HRMS (EI) m/z calcd for C12H12O4 (M+) 220.0736,
found 220.0739.
2-Methyl-4H-benzo[f ]isochromen-4-one (3l). Colorless solid;
1
197.8 mg (94%); mp 166−168 °C. H NMR (400 MHz, CDCl3) δ
8.30 (d, J = 8.36 Hz, 1H), 8.20 (d, J = 8.72 Hz, 1H), 7.92 (d, J = 8.44
Hz, 1H), 7.83 (d, J = 8.72 Hz, 1H), 7.72−7.64 (m, 2H), 7.04 (s, 1H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4, 156.3, 137.0,
136.1, 129.4, 128.9, 127.9, 127.4, 127.2, 124.2, 124.1, 116.8, 99.5, 20.3;
MS (ESI) m/z (relative intensity) 211 (M + H, 100), 195 (7), 122 (3).
HRMS (ESI) m/z calcd for C14H10O2 (M + H) 211.0759, found
211.0754.
3-Phenyl-1H-isochromen-1-one (3m). Pale yellow solid; 142.5
mg (64%); mp 89−91 °C; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J =
8.20 Hz, 1H), 7.90−7.88 (m, 2H), 7.72 (td, J = 7.60, 0.96 Hz, 1H),
7.52−7.43 (m, 5H), 6.96 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
162.3, 153.7, 137.6, 134.9, 132.0, 130.0, 129.7, 128.9, 128.2, 126.1,
125.3, 120.6, 101.9; MS (ESI) m/z (relative intensity) 223 (M + H,
100), 201 (10), 195 (5). HRMS (ESI) m/z calcd for C15H10O2 (M +
H) 223.0759, found 223.0734.
3-(p-Tolyl)-1H-isochromen-1-one (3n). White solid; 153.9 mg
(65%); mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J =
8.04 Hz, 1H), 7.78 (d, J = 8.08 Hz, 2H), 7.70 (t, J = 7.62 Hz, 1H),
7.50−7.46 (m, 2H), 7.27 (d, J = 8.08 Hz, 2H), 6.91 (s, 1H), 2.40 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 154.0, 140.4, 137.9,
134.9, 129.8, 129.7, 129.4, 128.0, 126.0, 125.3, 120.6, 101.2, 21.5; MS
(EI) m/z (relative intensity) 236 (M+, 100), 208 (74), 165 (22), 152
(3), 119 (4). HRMS (EI) m/z calcd for C16H12O2 (M+) 236.0837,
found 236.0838.
7,8-Dimethoxy-3-methyl-1H-isochromen-1-one (3e). Pale
1
yellow solid; 154.2 mg (72%); mp 93−95 °C. H NMR (400 MHz,
CDCl3) δ 7.29 (d,, J = 9.2 Hz, 1H), 7. 02 (d,, J = 9.2 Hz, 1H), 6.11(s,
1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.7, 152.6, 152.3, 151.2, 132.5, 120.7, 120.4, 114.6, 103.2,
61.7, 56.8, 19.5; MS (EI) m/z (relative intensity) 220 (M+, 100),
205(74), 191 (46), 147 (16). HRMS (EI) m/z calcd for C12H12O4
(M+) 220.0736, found 220.0740.
7-Methyl-5H-[1,3]dioxolo[4,5-g]isochromen-5-one (3f). Pale
1
pink solid; 147.4 mg (72%); mp 187−189 °C. H NMR (400 MHz,
CDCl3) δ 7.58 (s, 1H), 6.70 (s, 1H), 6.14 (s, 1H), 6.07 (s, 2H), 2.25
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 153.8, 153.7, 148.0,
135.5, 114.6, 107.5, 103.7, 103.6, 102.2, 19.6; MS (EI) m/z (relative
intensity) 204 (M+, 44), 162 (27), 133 (32). HRMS (EI) m/z calcd
for C11H8O4 (M+) 204.0423, found 204.0422.
3-(4-Methoxyphenyl)-1H-isochromen-1-one (3o). White solid;
1
201.8 mg (80%); mp 120−122 °C; H NMR (400 MHz, CDCl3) δ
6-Fluoro-3-methyl-1H-isochromen-1-one (3g). Colorless solid;
8.29 (d, J = 7.36 Hz, 1H), 7.83 (d, J = 9.00 Hz, 2H), 7.72−7.67 (m,
1H), 7.48−7.44 (m, 2H), 6.98 (d, J = 8.88 Hz, 2H), 6.84 (s, 1H), 3.87
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 161.3, 153.9, 138.1,
135.0, 129.8, 127.8, 127.0, 125.9, 124.7, 120.3, 114.4, 100.4, 55.6; MS
(EI) m/z (relative intensity) 252 (M+, 100), 224 (60), 181 (17), 152
(9), 112 (5). HRMS (EI) m/z calcd for C16H12O3 (M+) 252.0786,
found 252.0780.
1
123.2 mg (69%); mp 96−98 °C. H NMR (400 MHz, CDCl3) δ
8.25−8.22 (m, 1H), 7.11 (td, J = 8.62, 2.33 Hz, 1H), 6.96 (dd, J =
8.92, 2.30 Hz, 1H), 6.20 (s, 1H), 2.26 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.8 (d, JC−F = 255 Hz), 162.1, 156.2, 140.5 (d, JC−F = 10
Hz), 133.0 (d, JC−F = 11 Hz), 116.6, 115.9 (d, JC−F = 23 Hz), 110.6 (d,
JC−F = 22 Hz), 103.2 (d, JC−F = 3 Hz), 19.8; MS (EI) m/z (relative
intensity) 178 (M+, 100), 136 (23), 107 (23). HRMS (EI) m/z calcd
for C10H7FO2 (M+) 178.0430, found 178.0435.
6-Chloro-3-phenyl-1H-isochromen-1-one (3p). White solid;
1
175.2 mg (68%); mp 212−214 °C; H NMR (400 MHz, CDCl3) δ
6-Chloro-3-methyl-1H-isochromen-1-one (3h). White solid;
8.24 (d, J = 8.44 Hz, 1H), 7.88−7.86 (m, 2H), 7.48−7.43 (m, 5H),
6.88(s, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7, 155.2, 141.7,
139.1, 131.8, 131.5, 130.6, 129.1, 128.8, 125.6, 119.0, 101.0; MS (EI)
m/z (relative intensity) 256 (M+, 60), 211 (84), 193 (15), 165 (21),
119 (100). HRMS (EI) m/z calcd for C15H9ClO2 (M+) 256.0291,
found 256.0297.
1
134.3 mg (70%); mp 152−154 °C. H NMR (400 MHz, CDCl3) δ
8.17 (d, J = 8.44 Hz, 1H), 7.39 (dd, J = 8.52, 1.98 Hz, 1H), 7.32 (d, J =
1.88 Hz, 1H), 6.18 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.2, 156.2, 141.5, 139.1, 131.3, 128.2, 124.5, 118.4, 102.8,
19.9; MS (ESI) m/z (relative intensity) 195 (M + H, 26), 172 (21),
5027
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Article
5,7-Dibromo-3-(p-tolyl)-1H-isochromen-1-one (3q). Greenish
yellow solid; 275.8 mg (70%); mp 216−218 °C. 1H NMR (400 MHz,
CDCl3) δ 8.40 (s, 1H), 8.06 (d, J = 1.84 Hz, 1H), 7.80 (d, J = 8.28 Hz,
2H), 7.29 (d, J = 8.24 Hz, 2H), 7.19 (s, 1H), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.5, 155.5, 141.4, 141.0, 136.3, 131.9, 129.9,
128.8, 125.7, 122.9, 121.3, 121.0, 99.4, 21.7; MS (EI) m/z (relative
intensity) 396 (M+ + 4, 58), 394 (M+ + 2, 100), 391 (M+, 58), 366
(55), 178 (10), 119 (12). HRMS (EI) m/z calcd for C16H10Br2O2
(M+) 391.9048, found 391.9054.
6,8-Dichloro-3-methyl-1H-isochromen-1-one (3r). Colorless
solid; 158.7 mg (70%); mp 163−165 °C. 1H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 1.72 Hz, 1H), 7.20 (d, J = 1.68 Hz, 1H), 6.14 (s,
1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 157.0,
141.6, 138.4, 130.4, 123.6, 115.6, 102.9, 19.7; MS (EI) m/z (relative
intensity) 228 (M+, 100), 213 (38), 157 (30). HRMS (EI) m/z calcd
for C10H6Cl2O2 (M+) 227.9745, found 227.9743.
7.84 Hz, 2H), 7.16−7.12 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.9, 142.5, 138.2, 132.3, 129.5, 129.2, 127.2, 124.6, 120.4,
21.6; MS (EI) m/z (relative intensity) 211 (M+, 65), 167 (1), 119
(100); HRMS (EI) m/z calcd for C14H13NO (M+) 211.0997, found
211.0994.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data of compound 3a, 3l, 3q, and 6a in CIF
1
format and copies of H and 13C NMR spectra of all the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cheyaocf@ntnu.edu.tw.
■
3-Methyl-1H-pyrano[4,3-b]quinolin-1-one (3s). Yellow solid;
1
143.9 mg (68%); mp 198−200 °C; H NMR (400 MHz, CDCl3) δ
9.11 (s, 1H), 8.09 (d, J = 8.96 Hz, 1H), 7.98 (d, J = 8.20 Hz, 1H),
7.90−7.85 (m, 1H), 7.61−7.57 (m, 1H), 6.61 (s, 1H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 162.6, 158.6, 152.7, 151.6, 140.5,
133.4, 129.6, 129.1, 127.0, 126.9, 115.1, 106.0, 20.2; HRMS (ESI) m/z
calcd for C13H9NO2 (M + H) 212.0711, found 212.0703; MS (ESI)
m/z (relative intensity) 212 (M + H, 100), 202 (20), 184 (55), 156
(15).
8-Methoxy-3-methyl-1H-pyrano[4,3-b]quinolin-1-one (3t).
Yellow solid; 161.6 mg (67%); mp 232−234 °C. 1H NMR (400
MHz, CDCl3) δ 8.96 (s, 1H), 7.98 (d, J = 9.32 Hz, 1H), 7.52 (dd, J =
9.28, 2.66 Hz, 1H), 7.17 (d, J = 2.56 Hz, 1H), 6.57 (s, 1H), 3.96 (s,
3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.0, 158.1,
157.5, 150.8, 148.2, 138.5, 130.5, 128.1, 127.2, 115.3, 106.0, 105.8,
55.9, 20.2; HRMS (EI) m/z calcd for C14H11NO3 (M+) 241.0739,
found 241.0744; MS (EI) m/z (relative intensity) 241 (M+, 100), 226
(35), 198 (22), 170 (12), 119 (22).
3,6-Dimethyl-1H-pyrano[4,3-b]quinolin-1-one (3u). Pale
brown solid; 168.6 mg (75%); mp 188−190 °C. 1H NMR (400
MHz, CDCl3) δ 9.05 (s, 1H), 7.80 (d, J = 8.24 Hz, 1H), 7.70 (d, J =
6.6 Hz, 1H), 7.46 (t, J = 7.50 Hz, 1H), 6.66 (s, 1H), 2.81 (s, 3H), 2.37
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.0, 158.0, 151.7, 150.8,
140.5, 137.3, 133.2, 127.5, 126.9, 126.6, 114.8, 106.6, 20.2, 18.2;
HRMS (EI) m/z calcd for C14H11NO2 (M+) 225.0790, found
225.0793; MS (EI) m/z (relative intensity) 225 (M+, 100), 182
(11), 154 (13), 127 (3).
10-Methyl-8H-benzo[h]pyrano[4,3-b]quinolin-8-one (3v).
Yellow solid; 156.7 mg (60%); mp 262−264 °C. 1H NMR (400
MHz, CDCl3) δ 9.34−9.32 (m, 1H), 9.00 (s, 1H), 7.92−7.90 (m, 1H),
7.81−7.73 (m, 4H), 6.76 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.1, 158.4, 152.4, 151.3, 138.7, 135.3, 130.9, 130.2, 128.4,
128.2, 127.6, 125.9, 125.7, 125.5, 115.1, 106.6, 20.2; HRMS (EI) m/z
calcd for C17H11NO2 (M+) 261.0790, found 261.0795; MS (EI) m/z
(relative intensity) 261 (M+, 100), 246 (10), 219 (7), 190 (17), 171
(7), 163 (3), 127(3), 111 (3).
Notes
The authors declare no competing financial interest.
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.
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Pale yellow solid; 130.3 mg (45%); mp 187−189 °C. H NMR (400
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1
142−144 °C. H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.12 Hz,
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