Assembly of 3-substituted isocoumarins via a CuI-catalyzed domino coupling/addition/deacylation process

Article abstract of DOI:10.1021/jo2026433

An efficient strategy for the synthesis of a variety of 3-substituted isocoumarins has been developed. The reaction proceeded from o-halobenzoic acids and 1,3-diketones via a copper(I)-catalyzed domino reaction in DMF under the action of K₃PO₄ at 90-120 °C without a ligand to afford the corresponding 3-substituted isocoumarin derivatives in good to excellent yields. o-Halobenzoic acids could be o-iodobenzoic acid, o-bromobenzoic acid, and o-chlorobenzoic acid derivatives. 1,3-Diketones could be alkyl- and aryl-substituted 1,3-diketones.

Full text of DOI:10.1021/jo2026433

Article
pubs.acs.org/joc
Assembly of 3-Substituted Isocoumarins via a CuI-Catalyzed Domino
Coupling/Addition/Deacylation Process
Shangjun Cai,† Fei Wang,† and Chanjuan Xi*,†,‡
†Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An efficient strategy for the synthesis of a variety of 3-
substituted isocoumarins has been developed. The reaction proceeded
from o-halobenzoic acids and 1,3-diketones via a copper(I)-catalyzed
domino reaction in DMF under the action of K3PO4 at 90−120 °C
without a ligand to afford the corresponding 3-substituted isocoumarin
derivatives in good to excellent yields. o-Halobenzoic acids could be
o-iodobenzoic acid, o-bromobenzoic acid, and o-chlorobenzoic acid
derivatives. 1,3-Diketones could be alkyl- and aryl-substituted 1,3-diketones.
molecules involved multistep reaction sequences and harsh
conditions.9 In an attempt to circumvent these restrictions, a
metal-based formation of 2-alkenyl or 2-allylbenzoic acids and a
subsequent annulation toward the 3-substituted isocoumarins
were reported.10 These methods still suffered from either
multistep reactions or the requirement for a stoichiometric
amount of palladium. Later, palladium-catalyzed cyclization of
o-haloaromatic acids with π-components has been recognized
as an efficient method for synthesis of isocoumarins.11 How-
ever, in those reactions, a preactivated coupling partner, C-M
reagent, or an additive is used as a starting material to con-
struct isocoumarin derivatives. In some cases, the reaction
led to contamination by byproduct. Recently, the oxidative
cyclization of aromatic acids with alkynes in the presence of
rhodium catalyst provided an atom-economical method for
construction of 3,4-disubstituted isocoumarin derivatives.12
Herein, we would like to report a highly efficient domino process
for the construction of various 3-substituted isocoumarins by a
copper-catalyzed reaction of 2-halobenzoic acid and 1,3-diketones
in one pot.13
INTRODUCTION
■
Isocoumarins are an important class of heterocyclic scaffolds
that exhibit a wide range of biological activities, such as
antifungal, antibacterial, and antidiabetic effects.1 Among
various substituted isocoumarins, the 3-substituted isocoumar-
ins with no substituent at the 4-position have a great influence
on their biological activities.1d,e,2 For example, coriandrin (I),3
compound 185322 (II),4 thunberginol A (III),5 and
thunberginol B (IV)6 have been employed in the design of
pharmaceuticals and related compounds, such as inhibitor of
microtubule assembly anti-HIV, antiallergic, and antiviral agents
(Figure 1). In addition, 3-substituted isocoumarins are useful
A recent advance in Ullmann-type reactions provided the
opportunity for the development of new methodologies to
assemble heterocycles.14 For example, Ma et al and Fu et al had
developed useful Cu-catalyzed domino processes for elabo-
ration of heterocycles, such as indoles,14e,m isoquinolines,14p
and isoquinolin-1(2H)-one.14q Our group has recently established
some domino processes for the elaboration of heterocycles via Cu-
catalyzed addition/cyclization or coupling/cyclization reactions,
which included formation of 2-thioxo-2,3-dihydroquinazolin-4(1H)-
one,15 2-aminobenzimidazoles,16 thiophenes17 and pyrroles.18
Continuing our efforts in this area, we became interested in the
coupling reaction of 2-halobenzoic acids with 1,3-diketones, which
Figure 1. Structures of pharmacologically important 3-substituted
isocoumarins.
intermediates7 for the synthesis of various natural products, such as
canesin, α- and β-sorigenin methyl ethers, and 3-alkylisocoumarins
as well as some isoquinoline alkaloids.8
Although the 3-substituted isocoumarins play an important
role from both the biological and the synthetic points of view,
the available synthetic strategies that lead to these compounds
are limited. The classical methods for the assembly of these
Received: December 22, 2011
Published: February 2, 2012
© 2012 American Chemical Society
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are inexpensive and available starting materials. We envisioned that,
if the copper-catalyzed coupling between aryl halides 1 and these
activated methylene compounds 2 proceeded smoothly,19a the
resulting coupling products 3 would undergo an intramolecular
addition, followed by deacylation14e to afford 3-substituted iso-
coumarins 4 (Scheme 1). This reaction includes new C−C and
We next tried to optimize the reaction conditions. It was
found that all bases examined, Cs2CO3, K3PO4, BuONa, 1,8-
t
diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazobicyclo-
[2.2.2]octane (DABCO), are effective. We chose less-expensive
and less-toxic K3PO4 as a base for this reaction. We next tested
the reaction in different solvents. DMF and DMSO were
superior to MeCN and toluene. We are pleased to find that the
reaction did not need addition of any ligand or additive. On
the basis of above investigations, the optimal condition involved
the following parameters: 10 mol % CuI as a catalyst, K3PO4 as
a base, DMF as a solvent, and a reaction temperature at 90 °C
and ligand-free.
Scheme 1. Design of Synthesis of 3-Substituted
Isocoumarins by a Domino Reaction
Encouraged by the above results, we examined the scope and
limitation of 2-halobenzoic acid derivatives and 1,3-diketones
for the synthesis of 3-substituted isocoumarins. First, reaction
of 2-iodobenzoic acid 1a with various 1,3-diketones was
investigated, and results are summarized in Table 1. When 2a
Table 1. Synthesis of 3-Substituted Isocoumarins from 2-
a
Iodobenzoic Acid
C−O bond-forming as well as C−C and C−O bond-cleaving
events to occur in one sequence, which greatly enhances the
synthetic efficiency.
RESULTS AND DISCUSSION
■
With the above idea in mind, we investigated the reaction of
2-iodobenzoic acid 1a and pentane-2,4-dione 2a under the
catalysis of 10 mol % CuI in N,N-dimethylformamide (DMF)
with Cs2CO3 as a base (Scheme 2). We are pleased to find that,
Scheme 2. CuI-Catalyzed Coupling of 1a and 2a
after 12 h at 70 °C, a mixture of 3a (isolated 8%) and 4a
(isolated 48%) was obtained. We then tried to transform 3a
into 4a in a one-pot reaction and found that 4a formed
exclusively when the coupling reaction mixture was heated at
90 °C for 12 h.
In addition, compound 3a, the coupling product of 1a and 2a
at 30 °C, was isolated and subsequently treated with Cs2CO3 in
DMF at 90 °C. It was found that, in the presence of 10 mol %
CuI, compound 4a had formed in 73% isolated yield, whereas
no 4a could be detected in the absence of CuI (Scheme 3).
Scheme 3. Transformation of the Intermediate
a
Unless otherwise noted, the reactions were performed in a sealed
tube with 2-iodobenzoic acid (0.5 mmol), 1,3-diketone (0.5 mmol),
b
c
and K3PO4 (1.0 mmol) in DMF (1 mL). Isolated yields. Combined
yield with a ratio of 4c/4a = 3.5/1.
This result demonstrated that copper as a catalyst in the
cyclization also plays a crucial role for transformation into 3-
methylisocoumarie.
or heptane-3,5-dione 2b was employed as the substrate, the
desired products were formed in excellent yield (entries 1 and 2).
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When 1,3-diphenylpropane-1,3-dione 2c or 1,3-bis(4-
methoxyphenyl)propane-1,3-dione 2d was employed, the
corresponding product formed in good yield (entries 3 and 4).
In these cases, benzoic acid and 4-methoxybenzoic acid were
also obtained, respectively. The results indicated that
deacylation unambiguously occurred in the reaction. The
reaction of 1a with hexafluoropentane-2,4-dione 2e did not
proceed (entry 5). When unsymmetrical 1,3-diketone 2f was
engaged in the system, the reaction gave a mixture of two
isomeric products in a 3.5:1 ratio within a 73% combined
yield (entry 6). The 3-phenylisocoumarin 4c is major. When
3-methylpentane-2,4-dione 2g was used, the corresponding
product 4f was obtained in 36% yield (entry 7). When β-keto
ester 2h was employed as a substrate, the product was obtained in
low yield (entry 8), most of the β-keto ester remained.
Monoketones were also examined in the reaction. Unfortunately,
the reaction did not proceed and starting materials remained
(entries 9 and 10).
Table 2. Synthesis of 3-Substituted Isocoumarins from 2-
Bromobenzoic Acid Derivatives
a
2-Bromobenzoic acid 1b and its derivatives were then applied
under the optimized condition. To our delight, the reaction
with 2-bromobenzoic acid derivatives could proceed smoothly
and the products were obtained in satisfactory yields, as shown
in Table 2. However, in comparison with the aryl iodides,
slightly higher temperatures were required to complete the
reaction. For example, when 1b was treated with 2a under the
optimized condition, the desired product was obtained in 71%
yield at 100 °C (entry 1). The reaction of monosubstituted 2-
bromobenzoic acids with 2 proceeded always in good yields
regardless of electron-donating or electron-withdrawing groups
linked on the benzene ring (entries 2−12). In general, electron-
donating substituents on the 2-bromobenzoic acid ring (entries
2−7) are superior to electron-withdrawing substituents (entries
8−12) to afford 3-substituted isocoumarins. A substrate with
two substituents situated para and meta to the carboxyl group
also afforded an excellent yield of the corresponding 3-
substituted isocoumarin derivatives 4 (entries 13 and 14).
To further demonstrate the scope of this reaction, we
examined the reaction with 2-chlorobenzoic acids, and the
corresponding products were also obtained in moderate yield at
120 °C (Table 2, entries 15 and 16). Since chlorobenzene did
not couple with 1,3-diketones under the same reaction con-
dition, the formation of 4a and 4t in our reaction demonstrated
that the ortho-COOH group may promote the coupling
reaction. Subsequently, 2-fluorobenzoic acid was tested under
the optimized condition. In this case, the desired product was
not obtained even when the reaction temperature was raised to
140 °C. For the 2-halobenzoic acids, their relative reactivity was
in the order of aryl iodides > aryl bromides > aryl chlorides >
aryl fluorides.
On the basis of the above results, we propose the following
reaction mechanism for this cascade sequence (Scheme 4). After
initial formation of coupling compound 3′ by the Hurtley
reaction,19,20 the carboxylate ion could attack the carbonyl group
of the 1,3-diketone moiety to produce intermediate 5.21,19c
Next, the alkoxy anion in 5 would attack another keto moiety
to form an intermediate 6 with a four-membered ring,14e which
undergoes the C−C bond and the C−O bond disconnection to
yield 3-substituted isocoumarin 4.
a
Unless otherwise noted, the reactions were performed in a sealed
tube with 2-bromobenzoic acid (0.5 mmol), 1,3-diketones (0.5 mmol),
b
c
and K3PO4 (1.0 mmol) in DMF (1 mL). Isolated yields. In this
reaction, 27% of 6-(dimethylamino)-3-methyl-1H-isochromen-1-one
was isolated.
2-halobenzoic acids and 1,3-diketones. The efficiency and
functional group tolerance of this procedure have been fully
demonstrated by synthesizing a number of 3-alkylisocoumarins
and 3-arylisocoumarins. Considering the relatively inexpensive
catalytic system and the commercial availability of the starting
materials, it should be of great benefit for organic synthesis.
CONCLUSION
■
We have demonstrated a new method based on the CuI-
catalyzed domino coupling/addition/deacylation process for
the construction of 3-substituted isocoumarins from various
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120.6, 125.3, 126.1, 128.2, 128.9, 129.7, 130.0, 132.0, 134.9, 137.6,
153.7, 162.4; ESI-MS [M + H]+ m/z 223.4.
Scheme 4. Proposed Reaction Pathway
3-(4-Methoxyphenyl)-1H-isochromen-1-one (4d):23 White solid,
81 mg (65% yield), mp 110−112 °C; 1H NMR (CDCl3, 600 MHz) δ
3.82 (s, 3H), 6.77 (s, 1H), 6.92 (d, JH−H = 8.8 Hz, 2H), 7.41 (dd, JH−H
=
7.6, 4.3 Hz, 2H), 7.64 (t, JH−H = 7.4 Hz, 1H), 7.76 (d, JH−H = 8.7 Hz,
2H), 8.23 (d, JH−H = 8.1 Hz, 1H); 13C NMR (CDCl3, 150 MHz)
δ 55.4, 100.2, 114.2, 120.1, 124.5, 125.8, 126.8, 127.6, 129.6, 134.8,
137.9, 153.7, 161.1, 162.5; ESI-MS [M + H]+ m/z 253.6.
3,4-Dimethyl-1H-isochromen-1-one (4f):10b White solid, 31 mg
(36% yield), mp 133−134 °C; 1H NMR (CDCl3, 300 MHz) δ 2.15 (s,
3H), δ 2.29 (s, 3H), δ 7.41−7.48 (m, 2H), δ 7.71 (t, JH−H = 6.6 Hz,
1H), δ 8.27 (d, JH−H = 7.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
12.3, 17.4, 107.8, 120.5, 122.5, 127.2, 129.7, 134.7, 138.7, 150.2, 162.9;
ESI-MS [M + H]+ m/z 175.3.
3,6-Dimethyl-1H-isochromen-1-one (4g): White solid, 72 mg
(83% yield), mp 61−62 °C; 1H NMR (DMSO-d6, 300 MHz) δ
2.20 (s, 3H), δ 2.39 (s, 3H), δ 6.41 (s, 1H), δ 7.27 (t, JH−H = 8.3 Hz,
2H), δ 7.93 (d, JH−H = 8.3 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz) δ
19.1, 21.4, 103.1, 116.7, 125.0, 128.6, 128.9, 137.4, 145.8, 154.4, 161.8;
ESI-MS [M + H]+ m/z 175.3. HRMS calcd for C11H10O2, 174.0681;
found, 174.0685.
7-Methoxy-3-methyl-1H-isochromen-1-one (4h):13 White solid,
66 mg (70% yield), mp 101−103 °C; 1H NMR (DMSO-d6, 300 MHz)
δ 2.19 (d, JH−H = 1.0 Hz, 3H), δ 3.83 (s, 3H), δ 6.43 (s, 1H), δ 7.32−
7.36 (m, 1H), δ 7.40−7.45 (m, 2H); 13C NMR (DMSO-d6, 75 MHz)
δ 18.8, 55.5, 102.8, 109.6, 120.2, 123.9, 127.0, 131.0, 152.0, 158.5,
161.9; ESI-MS [M + H]+ m/z 191.3. HRMS calcd for C11H10O3,
190.0630; found, 190.0626.
EXPERIMENTAL SECTION
■
General Comments. All the reactions were carried out in a
predried screwcapped tube with a Teflon-lined septum under a N2
atmosphere. Unless otherwise indicated, all materials were obtained
from commercial sources and used as received. DMF, toluene,
CH3CN, and DMSO were freshly distilled. Column chromatography
3-Ethyl-6-methyl-1H-isochromen-1-one (4i): White solid, 74 mg
1
1
was performed on silica gel. H NMR and 13C NMR spectra were
(79% yield), mp 62−63 °C; H NMR (CDCl3, 600 MHz) δ 125
(t, JH−H = 8.4, 3H), 2.44 (s, 3H), 2.54 (q, JH−H = 7.5 Hz, 2H), 6.17 (s,
1H), 7.13 (s, 1H), 7.24 (d, JH−H = 8.1 Hz, 1H), 8.11 (d, JH−H = 8.0 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 11.2, 21.9, 26.6, 101.9, 117.6,
125.1, 128.9, 129.3, 137.7, 145.7, 159.5, 163.1; ESI-MS [M + H]+ m/z
189.3. HRMS calcd for C12H12O2, 188.0837; found, 188.0839.
6-Methyl-3-phenyl-1H-isochromen-1-one (4j):24 White solid, 100
recorded on 300 and 600 MHz spectrometers at ambient tempera-
ture with CDCl3 or DMSO-d6 as the solvent. Chemical shifts (δ) were
given in parts per million, referenced to the residual proton resonance
of CDCl3 (7.26) or DMSO (2.5), and to the carbon resonance of
CDCl3 (77.16) or DMSO-d6 (39.52). Coupling constants (J) were
given in hertz (Hz). The terms m, d, and s refer to multiplet, doublet,
and singlet. The melting points were measured on an X-4 digital
melting point apparatus and were uncorrected. The reaction progress
was monitored by 1H NMR. 1H NMR yields, using trichloroethene as
an internal standard, were obtained in proportion to the integral area
of the trichloroethene signal.
1
mg (85% yield), mp 107−108 °C; H NMR (CDCl3, 300 MHz) δ
2.41 (s, 3H), 6.80 (s, 1H), 7.19−7.23 (m, 2H), 7.34−7.43 (m, 3H),
7.80 (dd, JH−H = 7.7, 1.7 Hz, 2H), 8.10 (d, JH−H = 8.0 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 21.9, 101.7, 118.1, 125.1, 126.0, 128.8,
129.5, 129.5, 129.8, 132.0, 137.5, 146.0, 153.5, 162.3; ESI-MS [M +
H]+ m/z 237.2.
General Procedure for the Synthesis of 3-Substituted
Isocoumarins 4. A sealed tube was charged with the mixture of
o-halobenzoic acid 1 (0.5 mmol), 1,3-diketone 2 (0.5 mmol), CuI
(0.05 mmol, 10 mg), and K3PO4 (1.0 mmol, 212 mg), and the mixture
was then stirred in DMF (1 mL) at room temperature under a nitrogen
atmosphere. Half an hour later, the tube was sealed and the mixture
was allowed to stir at 90−120 °C for an indicated time. After
completion, the mixture was cooled to room temperature. H2O
(5 mL) was then added, and the mixture was extracted with EtOAc
(5 mL × 3) and dried by anhydrous Na2SO4. Evaporation of the
solvent, followed by purification on silica gel (petroleum ether/ethyl
acetate = 5/1), provided the corresponding product 4.
7-Methoxy-3-phenyl-1H-isochromen-1-one (4k):24 Yellow solid,
94 mg (75% yield), mp 167−168 °C; 1H NMR (CDCl3, 300 MHz) δ
3.86 (s, 3H), 6.85 (s, 1H), 7.24 (dd, JH−H = 8.6, 2.6 Hz, 1H), 7.27−
7.43 (m, 4H), 7.65 (d, JH−H = 2.4 Hz, 1H), 7.79 (d, JH−H = 7.1 Hz,
2H); 13C NMR (CDCl3, 75 MHz) δ 55.8, 101.6, 110.0, 121.6, 124.7,
124.9, 127.6, 128.8, 129.6, 131.2, 132.1, 151.6, 159.6, 162.5; ESI-MS
[M + H]+ m/z 253.7.
7-Methoxy-3-(4-methoxyphenyl)-1H-isochromen-1-one (4l):24
1
Light yellow solid, 67 mg (48% yield), mp 139−141 °C; H NMR
(CDCl3, 600 MHz) δ 3.86 (s, 3H), 3.91 (s, 3H), 6.80 (s, 1H), 6.95 (d,
JH−H = 8.8 Hz, 2H), 7.29 (dd, JH−H = 8.6, 2.5 Hz, 1H), 7.39 (d, JH−H
=
3-Methyl-1H-isochromen-1-one (4a):22 White solid, 60 mg (76%
yield), mp 72−73 °C; 1H NMR (DMSO-d6, 300 MHz) δ 2.22 (s, 3H),
δ 6.52 (s, 1H), δ 7.48−7.52 (m, 2H), δ 7.74−7.79 (m, 1H), δ 8.07 (d,
JH−H = 8.2 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 19.1, 103.2,
119.1, 125.3, 127.8, 128.7, 135.1, 137.4, 154.4, 161.9; ESI-MS [M +
H]+ m/z 161.3.
8.7 Hz, 1H), 7.70 (d, JH−H = 2.3 Hz, 1H), 7.79 (d, JH−H = 8.8 Hz, 2H);
13C NMR (CDCl3, 150 MHz) δ 55.5, 55.9, 100.2, 110.1, 114.4, 121.3,
124.9, 126.6, 127.4, 131.8, 152.0, 159.4, 160.9, 162.8; ESI-MS [M +
H]+ m/z 283.7.
6-Fluoro-3-methyl-1H-isochromen-1-one (4m): White solid,
1
48 mg (54% yield), mp 96−97 °C; H NMR (CDCl3, 300 MHz) δ
3-Ethyl-1H-isochromen-1-one (4b):22 White solid, 65 mg (75%
2.26 (s, 3H), δ 6.20 (s, 1H), δ 6.94−6.98 (m, 1H), δ 7.07−7.14
yield), mp 73−74 °C; 1H NMR (CDCl3, 300 MHz) δ 1.24 (t, JH−H
=
(m, 1H), δ 8.21−8.26 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.8,
7.6 Hz, 3H), δ 2.49−2.57 (m, 2H), δ 6.21 (s, 1H), δ 7.30−7.42
(m, 2H), δ 7.63 (t, JH−H = 7.6 Hz, 1H), δ 8.20 (d, JH−H = 7.9 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 11.3, 26.7, 102.0, 120.2, 125.1, 127.6,
129.5, 134.7, 137.7, 159.5, 163.1; ESI-MS [M + H]+ m/z 175.3.
3-Phenyl-1H-isochromen-1-one (4c):22 White solid, 75 mg (68%
yield), mp 81−82 °C; 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 1H), δ
7.37−7.49 (m, 5H), δ 7.66−7.71 (m, 1H), δ 7.84−7.87 (m, 2H), δ
8.28 (d, JH−H = 7.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 101.9,
103.2 (d, JF−C = 2.2 Hz), 110.6 (d, JF−C = 22.2 Hz), 115.9 (d, JF−C
=
23.7 Hz), 116.5 (d, JF−C = 2.2 Hz), 132.9 (d, JF−C = 10.8 Hz), 140.4
(d, JF−C = 10.8 Hz), 156.1, 162.0, 166.8 (d, JF−C = 255.8 Hz); ESI-MS
[M + H]+ m/z 179.3. HRMS calcd for C10H7FO2, 178.0430; found,
178.0434.
7-Chloro-3-methyl-1H-isochromen-1-one (4n):13 White solid, 42
1
mg (44% yield), mp 165−167 °C; H NMR (CDCl3, 300 MHz) δ
2.26 (s, 3H), δ 6.22 (s, 1H), δ 7.19−7.26 (m, 1H), δ 7.73−7.75
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(m, 1H), δ 8.35 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.8, 103.1,
120.9, 121.5, 126.7, 132.1, 136.5, 137.9, 155.3, 161.7; ESI-MS
[M + H]+ m/z 194.3. HRMS calcd for C10H7ClO2, 194.0135;
found, 194.0131.
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7-Chloro-3-ethyl-1H-isochromen-1-one (4o): White solid, 50 mg
1
(48% yield), mp 73−75 °C; H NMR (CDCl3, 600 MHz) δ 1.26
(t, JH−H = 7.5 Hz, 3H), 2.55 (q, JH−H = 7.5 Hz, 2H), 6.21 (s, 1H), 7.23
(d, JH−H = 8.4 Hz, 1H), 7.73 (dd, JH−H = 8.4, 1.9 Hz, 1H), 8.35 (s,
1H); 13C NMR (CDCl3, 150 MHz) δ 11.2, 26.8, 101.5, 120.9, 121.6,
126.8, 132.1, 136.5, 137.9, 160.2, 161.8; ESI-MS [M + H]+ m/z 208.3.
HRMS calcd for C11H9ClO2, 208.0291; found, 208.0292.
6-Fluoro-3-phenyl-1H-isochromen-1-one (4p): White solid, 72 mg
(60% yield), mp 162−163 °C; 1H NMR (CDCl3, 300 MHz) δ 6.88 (s,
1H), 7.11−7.22 (m, 2H), 7.43−7.49 (m, 3H), 7.84−7.87 (m, 2H),
8.30 (dd, JH−H = 8.7, 5.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
(3) Hudson, J. B.; Graham, E. A.; Harris, L.; Ashwood-Smith, M.
J. Photochem. Photobiol. 1993, 57, 491.
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Cancer Chemother. Pharmacol. 2007, 59, 329.
101.3 (d, JF−C = 2.6 Hz), 111.6 (d, JF−C = 22.6 Hz), 116.5 (d, JF−C
=
23.4 Hz), 117.1, 125.5, 129.0, 130.5, 131.6, 133.1 (d, JF−C = 10.5 Hz),
140.3 (d, JF−C = 10.9 Hz), 155.0, 161.4, 166.8 (d, JF−C = 256.5 Hz);
ESI-MS [M + H]+ m/z 241.3. HRMS calcd for C15H9FO2, 240.0587;
found, 240.0586.
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H.; Shimoda, H.; Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1994,
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Abarbri, M. J. Org. Chem. 2005, 70, 6669.
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(14) For selected examples of the synthesis of heterocycles via a
copper-catalyzed one-pot process, see: (a) Zhu, J.; Xie, H.; Chen, Z.;
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Kesharwani, T.; Singh, J.; Tandom, V.; Larock, R. C. Angew. Chem., Int.
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Zhao, Y. J. Org. Chem. 2008, 73, 7841. (g) Yuan, Q.; Ma, D. J. Org.
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7-Chloro-3-phenyl-1H-isochromen-1-one (4q):24 Yellow solid, 66
1
mg (52% yield), mp 183−185 °C; H NMR (CDCl3, 300 MHz) δ
6.89 (s, 1H), 7.34−7.44 (m, 4H), 7.76−7.85 (m, 3H), 8.40 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 101.2, 121.6, 121.9, 125.4, 127.7, 129.0,
130.4, 131.7, 132.3, 136.3, 138.1, 154.2, 161.1; ESI-MS [M + H]+ m/z
257.1.
6,7-Dimethoxy-3-methyl-1H-isochromen-1-one (4r):10a White
1
solid, 90 mg (82% yield), mp 141−142 °C; H NMR (CDCl3, 300
MHz) δ 2.20 (s, 1H), 3.90 (s, 3H), 3.92 (s, 3H), 6.11 (s, 1H), 6.65 (s,
1H), 7.53 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.6, 56.2, 103.2,
105.6, 109.3, 112.8, 133.4, 149.2, 153.5, 155.1, 162.9; ESI-MS [M +
H]+ m/z 221.2.
6,7-Dimethoxy-3-phenyl-1H-isochromen-1-one (4s):24 White
solid, 124 mg (88% yield), mp 168−170 °C; 1H NMR (CDCl3,
600 MHz) δ 3.98 (s, 3H), 4.00 (s, 3H), 6.87 (d, JH−H = 12.0 Hz, 2H),
7.39−7.43 (m, 3H), 7.65 (s, 1H), 7.84 (d, JH−H = 8.2 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) δ 56.3, 101.6, 106.6, 109.5, 113.7, 125.0,
128.8, 129.7, 132.1, 133.2, 149.8, 152.7, 155.2, 162.3; ESI-MS [M +
H]+ m/z 283.9.
7-Chloro-8-methoxy-3-methyl-1H-isochromen-1-one (4t): White
solid, 48 mg (43% yield), mp 115−117 °C; 1H NMR (CDCl3,
300 MHz) δ 2.24 (s, 3H), 3.98 (s, 3H), 6.17 (s, 1H), 7.01 (d, JH−H
=
8.4 Hz, 1H), 7.64 (d, JH−H = 8.4 Hz, 1H); 13C NMR (CDCl3,
150 MHz) δ 19.6, 61.8, 103.1, 115.0, 121.5, 127.6, 136.5, 139.1, 155.4,
157.9, 158.7; ESI-MS [M + H]+ m/z 225.1. HRMS calcd for
C11H9ClO3, 224.0240; found, 224.0243.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of spectra for compounds 4a−4d and 4f−4t. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cjxi@tsinghua.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (20972085 and 21032004) and the
National Basic Research Program of China (2012CB933402).
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