Domino reaction to functionalized 2-hydroxybenzophenones from electron-deficient chromones and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo201384f

A base-promoted one-pot tandem reaction sequence has been developed to transform electron-deficient chromone-fused dienes 1 and 1,3-dicarbonyl compounds 2 to functionalized 2-hydroxybenzophenones 3 under mild conditions. This domino process, which involve

Full text of DOI:10.1021/jo201384f

NOTE
pubs.acs.org/joc
Domino Reaction to Functionalized 2-Hydroxybenzophenones from
Electron-Deficient Chromones and 1,3-Dicarbonyl Compounds
Hong Chen, Fuchun Xie, Jian Gong, and Youhong Hu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai, 201203, People's Republic of China
S Supporting Information
b
ABSTRACT: A base-promoted one-pot tandem reaction se-
quence has been developed to transform electron-deficient
chromone-fused dienes 1 and 1,3-dicarbonyl compounds 2 to
functionalized 2-hydroxybenzophenones 3 under mild condi-
tions. This domino process, which involves multiple reactions,
including Michael addition/cyclization/elimination, serves as
an efficient, economic, and eco-friendly method for the con-
struction of diversified 2-hydroxybenzophenone scaffolds with-
out a transition-metal catalyst and inert atmosphere.
he substituted 2-hydroxybenzophone framework is ubiqui-
tous in a wide variety of naturally occurring and synthetic
this transformation occurs by way of a tandem process involving
sequential Michael addition/intramolecular cyclization/elimination
(Scheme 1). In this pathway, the electron-deficient chromone
behaves as an acceptor in Michael addition of the nucleo-
philic 1,3-dicarbonyl compound to generate intermediate A.
This process is followed by chromone ring opening to form
intermediate B and a 5,1-hydrogen shift to give the highly
conjugated intermediate C. The resulting carbanion derived by
deprotonation of C then undergoes intramolecular cyclization at
the internal carbonyl group followed by elimination to afford the
functionalized 2-hydroxybenzophenone 3.
It is important to note that the participation of electron-
deficient chromones, containing multiple reactive centers, in
domino reactions has not been fully investigated or applied
to the synthesis of heterocycles.8aꢀh Only a few reports exist
describing inverse-electron-demand DielsꢀAlder reactions of
these substances, which afford xanthones and 2-hydroxybenzo-
phenones in low to moderate yields.9aꢀc Although many useful
methods have been developed, there are some inconveniences:
for example, use of a metal catalyst, lack of atom economy, in-
compatibility with substrate scopes, and inconvenient operation
under an inert atmosphere. Herein, we describe the results of a
recent investigation aiming at developing a mild, simple, efficient,
and catalyst-free method for the synthesis of polyfunctionalized
2-hydroxybenzophenones via cascade reactions of electron-
deficient chromones 1 with 1,3-dicarbonyl compounds 2.
At the beginning of the current study, we examined the
reaction of chromone-linked acrylonitrile 1a with acetylacetone
2a under a variety of conditions (Table 1). The results show that
reaction of these substrates in the presence of 1 equiv of DBU at
room temperature in THF leads to the formation of the desired
T
compounds that exhibit important biological activities.1aꢀh Clas-
sical approaches for the synthesis of these substances generally
involve addition of organometallic reagents, such as aryllithium
or -magnesium reagents, to aldehydes followed by oxidation
of the resulting alcohols.2aꢀc Recently, metal-catalyzed direct
CꢀH bond arylation reactions of aryl aldehydes with boronic
acids or aryl halides have been utilized for the generation of
benzophenones.3aꢀj In addition, attention has been paid to the
preparation of functionalized 2-hydroxybenzophones starting
with the corresponding chromones, especially 3-formylchro-
mone, which serves as a bis-electrophile. In this regard, Langer
and his co-workers developed a domino Michael/retro-Michael/
aldol process that takes place between 3-formylchromones and
1,3-bis-silyl enol ethers in the presence of catalytic trimethylsilyl
triflate to generate functionalized 2-hydroxybenzophenones, in
which aroyl and OH groups are present at the 3- and 4-positions
of the phenyl ring, respectively.4aꢀe 3-Formylchromones are
also known to undergo Michael addition and cyclization reac-
tions with bis-nucleophilic reagents under basic conditions to
produce similarly functionalized 2-hydroxybenzophenones5aꢀd
and (2-hydroxyphenyl)(heteroaryl)methanones.6aꢀd
In recent efforts, we have conducted investigations aimed at
the synthesis of natural productlike scaffolds through cascade
reactions that take advantage of the multiple reactivity of sub-
stituted chromones.7aꢀf In this study, we observed that tandem
reactions of 3-(1-alkynyl)chromones with 1,3-dicarbonyl com-
pounds lead to the formation of functionalized xanthones.7a
More recently, we observed that treatment of the electron-
deficient chromone-linked acrylonitrile derivative 1a with 1,3-
dicarbonyl compound 2a in the presence of DBU in THF at
room temperature leads to generation of a product mixture
containing 2-hydroxybenzophenone 3aa. We envisioned that
Received: July 8, 2011
Published: September 14, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201384f J. Org. Chem. 2011, 76, 8495–8500
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Proposed Mechanism
of the process (Table 2). The findings show that these reactions
lead to production of the corresponding functionalized benzo-
phenones 3 in moderate to excellent yields (Table 2). 1-Phenyl-
butane-1,3-dione (2c) (Table 2, entry 3) gave complicated
products, and 3ac was found to be the major product in 45%
yield. This means that the substitution of the carbonyl group at
phenyl is more active. Notably, the presence of bulky groups
leads to slightly decreased yields and prolonged reaction times as
a consequence of steric hindrance in the cyclization step
(Table 2, entries 9ꢀ12). It is clear that an electron-donating
group on the phenyl ring will decrease the reactivity of the
carbonyl group (Table 1, entry 11). Interestingly, reactions at
60 °C of β-ketone esters 2m and 2n containing α-substituents
that activate α-hydrogens are less efficient, perhaps a result of
formation and the ensuing reaction of bis-carbanions at high
temperature. However, reactions of the keto esters at room
temperature for 4 and 6 h yield the desired products 3am and 3an
in respective yields of 66% and 62%. Diethyl malonate (2g) and
malononitrile (2o) react under the optimized conditions to yield
complicated product mixtures. An exploration of this process led
to the finding that 3ao was generated in 54% yield by carrying out
the reaction in the presence of t-BuOK (2 equiv) in DMF at
120 °C for 30 min under microwave irradiation conditions.
Further studies showed that the tandem reaction can be
extended to other electron-deficient chromone-linked substrates,
which react with ethyl acetoacetate to form the corresponding
functionalized benzophenones 3 in 43ꢀ80% yield (Table 3).
The electronic effects of substituents on the aryl chromone ring
did not affect the reactions (Table 3, entries 1 and 2). Notably,
reactions of substrates 1i and 1j, which lack electron-withdrawing
groups, require prolonged reaction times to afford the desired
products, albeit in lower yields. Clearly, only electron-deficient
chromones serve as strong Michael acceptors in this process.
In conclusion, the investigation described above has led to the
development of an efficient method for the synthesis of func-
tionalized 2-hydroxybenzophenones starting with easily pre-
pared electron-deficient chromone-linked substrates and com-
mercially available 1,3-dicarbonyl compounds. The attractive
features of this procedure, which involves a tandem reaction
sequence with simplicity of execution, takes place under mild
conditions without a transition-metal catalyst and inert atmo-
sphere and tolerates a variety of functional groups to generate
complex 2-hydroxybenzophenones. Finally, the functionalized
Table 1. Optimization of the Reaction To Form Functional-
ized Benzophenone 3aaa
entry
solvent
vase
temp (°C)
time (h)
yield (%)
1
THF
DBU
room temp
2
24
2
<30c
60b
63b
<30c
64b
60b
<30c
<30c
57b
50b
39b
2
THF
DBU
room temp
3
THF
DBU
60
60
60
60
60
60
60
60
60
60
60
60
60
4
THF
Et3N
2
5
THF
t-BuOK
K2CO3
KOH
NaH
2
6
THF
2
7
THF
2
8
THF
2
9
CH3CN
DMF
DMSO
toluene
EtOH
EtOH
EtOH
DBU
2
10
11
12
13
14
15
DBU
2
DBU
2
DBU
2
<30c
77b
69b
DBU
2
t-BuOK
2
K2CO3
2
74b
a General conditions: substrate 1a (0.2 mmol), 2a (0.2 mmol), and base
(0.2 mmol, 1 equiv) in solvent (1 mL). b Isolated yield. c The yield was
evaluated by thin-layer chromatography (TLC), which determined the
remaining starting material 1.
hydroxyl benzophenonederivative3aa inyieldsthat vary withtime
(<30% yield in 2 h and 60% yield in 24 h). Incontrast, at 60 °C, the
process proceeds to completion, giving 3aa in 63% yield. Among
others, DBU, K2CO3, and t-BuOK perform as optimal bases for
promoting this reaction (Table 1, entries 3ꢀ8). In addition,
ethanol (EtOH) appears to be the best solvent for the reaction
(Table 1, entries 13ꢀ15). Thus, the optimized conditions, invol-
ving reaction of 1a with 2a in EtOH at 60 °C in the presence of 1
equiv of DBU, results in the formation of 3aa in 77% yield.
Reactions of various 1,3-dicarbonyl compounds 2 with 1a
under the optimized conditions were explored to probe the scope
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NOTE
Table 2. Reactions of 1a with Various 1,3-Dicarbonyl Compounds 2a
a Reaction conditions: substrate 1a (0.2 mmol), 2 (0.2 mmol) and DBU (0.2 mmol) in EtOH (1 mL) at 60 °C. After complete conversion of the starting
material 1a as determined by TLC, the reactions were quenched. b Isolated yield. c The reaction was carried out at room temperature. d The reaction was
carried out at 120 °C on microwave for 30 min in the DMF/t-BuOK system (2 equiv).
2-hydroxybenzophenones prepared in this effort are currently
being subjected to biological evaluation.
plates. All of the reagents were used directly as obtained commercially or
synthesized according to literature procedures.
General Procedure. Representative Experimental Procedure for
the Synthesis of 3-Acetyl-5-(2-hydroxybenzoyl)-2-methylbenzonitrile
(3aa). DBU (1 equiv, 0.2 mmol, 30 mg) was added to a mixture of
compound 1a (1 equiv, 0.2 mmol, 39.4 mg) and compound 2a (1 equiv,
0.2 mmol, 20 mg) in dry EtOH (1 mL), and the resulting solution was
heated to 60 °C for 2 h. After complete conversion of the starting
material (TLC), the mixture was poured into water and extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated to give the
crude product, which was further purified by column chromatography to
afford the desired compound 3aa (77%, 42.9 mg) as a yellow solid: mp
143ꢀ145 °C. 1H NMR (300 MHz, CDCl3) δ 11.63 (s, 1 H), 8.12 (s, 1
H), 8.01 (s, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.12
(d, J = 8.4 Hz, 1 H), 6.94 (t, J = 7.7 Hz, 1 H), 2.79 (s, 3 H), 2.64 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 199.6, 197.8, 163.3, 145.2, 139.8, 137.4,
’ EXPERIMENTAL SECTION
General Methods. Melting points were measured on a Kofler hot
1
stage and are uncorrected. H NMR spectral data were recorded in
CDCl3 or DMSO-d6 solutions on a 300 or 400 MHz spectrometer, and
13C NMR were recorded in CDCl3 or (CD3)2CO on a 100 MHz spectro-
meter. Chemical shifts (δ) are reported in parts per million (ppm), and
the signals are described as br s (broad singlet), d (doublet), dd (doublet
of doublet), m (multiple), q (quartet), s (singlet), and t (triplet). Coupling
constants (J values) are given in Hz. Low-resolution mass spectra (MS)
and high-resolution mass spectra (HRMS) were recorded at an ionizing
voltage of 70 eV. Column chromatography was carried out on silica gel
(200ꢀ300 mesh). All reactions were monitored using TLC on silica gel
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NOTE
Table 3. Reactions of 2d with Various Dienes 1a
a Reaction conditions: substrate 1 (0.2 mmol), 2d (0.2 mmol) and DBU (0.2 mmol) in EtOH (1 mL) at 60 °C. After complete conversion of the starting
material 1 as determined by TLC, the reactions were quenched. b Isolated yield.
136.1, 135.2, 132.6, 132.5, 119.3, 118.9, 118.2, 116.7, 115.7, 29.9, 19.3;
HRMS calcd for C17H13NO3 279.0895, found 279.0902.
135.8, 134.6, 132.7, 132.2, 119.2, 118.8, 118.3, 116.7, 115.6, 62.0, 19.6,
14.2; HRMS calcd for C18H15NO4 309.1001, found 309.1006.
tert-Butyl 3-Cyano-5-(2-hydroxybenzoyl)-2-methylbenzoate (3ae):
Characterization of 3abꢀ3af, 3ahꢀ3ao, and 3bdꢀ3kd. 3-
Acetyl-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)benzonitrile (3ab):reac-
tion was run for 9 h; yellow solid; mp 155ꢀ156 °C; 1H NMR (300 MHz,
CDCl3) δ11.47 (s, 1H),8.13(s,1H), 7.80(s, 1H), 7.61 (t, J=7.8 Hz, 1H),
7.37 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H),
2.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.1, 196.6, 163.5, 143.1,
141.8, 138.1, 135.2, 132.4, 130.1, 119.6, 119.2, 117.8, 114.3, 112.0, 30.9;
HRMS calcd for C17H10F3NO3 333.0613, found 333.0616.
1
reaction was run for 2 h; yellow solid; mp 75ꢀ76 °C; H NMR (300
MHz, CDCl3) δ 11.70 (s, 1 H), 8.26 (s, 1 H), 8.01 (s, 1 H), 7.57 (t, J =
7.8 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 7.9 Hz, 1 H), 6.93 (t,
J = 7.6 Hz, 1 H), 2.86 (s, 3 H), 1.61 (s, 9 H); 13C NMR (100 MHz,
CDCl3) δ 198.0, 164.7, 163.3, 146.1, 137.2, 135.9, 135.3, 134.3, 134.0,
132.7, 119.1, 118.8, 118.3, 116.8, 115.3, 83.2, 28.1, 19.6; HRMS calcd for
C20H19NO4 337.1314, found 337.1313.
Ethyl 3-Cyano-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)benzoate
1
3-Benzoyl-5-(2-hydroxybenzoyl)-2-methylbenzonitrile (3ac): reac-
tion was run for 6 h; yellow gum; 1H NMR (300 MHz, CDCl3) δ 11.65
(s, 1 H), 8.07 (s, 1 H), 7.81ꢀ7.78 (m, 3 H), 7.66 (t, J = 7.3 Hz, 1 H),
7.58ꢀ7.48(m, 4 H), 7.09 (d, J = 8.5 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H),
2.61 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 197.92, 195.34, 163.29,
144.02, 140.51, 137.28, 135.90, 134.47, 134.32, 132.68, 131.89, 130.09,
129.02, 119.23, 118.87, 118.28, 116.60, 115.12, 18.67; HRMS calcd for
C22H15NO3 341.1052, found 341.1043.
(3af): reaction was run for 3 h; yellow gum; H NMR (300 MHz,
CDCl3) δ 11.49 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.62 (t, J = 7.8 Hz,
1H), 7.39 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.97 (t, J = 7.6 Hz,
1H), 4.45 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 196.5, 165.2, 163.5, 141.4, 138.0, 135.9, 134.9, 132.7 (d,
J = 15.7 Hz), 122.8, 120.1, 119.6, 119.0, 117.8, 114.4, 112.0, 63.3, 13.7;
HRMS calcd for C18H12F3NO4 363.0718, found 363.0719.
Ethyl 3-Cyano-5-(2-hydroxybenzoyl)-2-propylbenzoate (3ah): reac-
tion was run for 2 h; yellow gum; 1H NMR (300 MHz, CDCl3) δ 11.68
(s, 1 H), 8.34 (d, J = 1.8 Hz, 1 H), 8.04 (d, J = 1.8 Hz, 1 H), 7.57 (t, J = 7.8
Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 1 H), 6.94 (t, J =
7.6 Hz, 1 H), 4.42 (q, J = 7.1 Hz, 2 H), 3.35ꢀ3.15 (m, 2 H), 1.74 (dd, J =
15.5, 7.6 Hz, 2 H), 1.41 (t, J = 7.7, 6.6 Hz, 3 H), 1.09 (t, J = 7.3 Hz,
Ethyl 3-Cyano-5-(2-hydroxybenzoyl)-2-methylbenzoate (3ad): re-
action was run for 2 h; yellow solid; mp 80ꢀ81 °C; 1H NMR (300 MHz,
CDCl3) δ 11.68 (s, 1 H), 8.38 (s, 1 H), 8.05 (s, 1 H), 7.58 (t, J = 8.1 Hz, 1
H), 7.46 (d, J = 8.1 Hz, 1 H), 7.11 (d, J = 8.1 Hz, 1 H), 6.93 (t, J = 8.1 Hz,
1 H), 4.42 (q, J = 7.1 Hz, 2 H), 2.91 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 197.9, 165.3, 163.3, 146.9, 137.3, 136.1,
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NOTE
3 H).13C NMR (100 MHz, CDCl3) δ 197.3, 164.8, 162.7, 150.7, 136.6,
135.5, 135.4, 134.3, 132.1, 131.4, 118.6, 118.2, 117.7, 116.2, 114.6, 61.4,
34.0, 24.1, 13.7, 13.6; HRMS calcd for C20H19NO4 337.1314, found
337.1305.
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated to give the crude product, which was further purified by
column chromatography (4/1 petroleum ether/ethyl acetate) to afford
compound 3ao (54%, 56.8 mg) as a yellow solid: 1H NMR (300 MHz,
DMSO-d6) δ 10.25 (s, 1 H), 8.02 (s, 2 H), 7.68 (s, 2 H), 7.43 (t, J =
7.8 Hz, 1 H), 7.33 (d, J = 7.7 Hz, 1 H), 7.04ꢀ 6.89 (m, 2 H); 13C NMR
(100 MHz, (CD3)2CO) δ 196.3, 162.3, 155.0, 140.5, 136.8, 133.3,
127.2, 120.7, 120.1, 118.7, 115.8, 97.8; HRMS calcd for C15H9N3O2
263.0695, found 263.0704.
Ethyl 3-Cyano-5-(2-hydroxy-5-methoxybenzoyl)-2-methylbenzo-
ate (3bd): reaction was run for 2 h; yellow solid; mp 105ꢀ106 °C; 1H
NMR (300 MHz, CDCl3) δ 11.25 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H),
7.20 (dd, J = 9.1, 3.0 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 6.88 (d, J = 3.0 Hz,
1H), 4.42 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 2.90 (s, 3H), 1.40 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.4, 165.3, 157.7, 151.7,
147.0, 136.1, 135.7, 134.6, 132.1, 125.3, 119.8, 117.8, 116.7, 115.7, 114.9,
62.0, 55.9, 19.6, 14.2; HRMS calcd for C19H17NO5 339.1107, found
339.1105.
Ethyl 3-Cyano-5-(5-fluoro-2-hydroxybenzoyl)-2-methylbenzoate (3cd):
reaction was run for 2 h; yellow solid; mp 149ꢀ151 °C; 1H NMR (400
MHz, CDCl3) δ 11.40 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.06 (d, J =
1.6 Hz, 1H), 7.33 (ddd, J = 9.2, 7.7, 3.1 Hz, 1H), 7.15 (dd, J = 8.6, 3.0 Hz,
1H), 7.09 (dd, J = 9.2, 4.4 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.92 (s, 3H),
1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.2, 165.3,
159.7, 156.0, 153.6, 147.5, 135.7 (d, J = 3.9 Hz), 134.6, 132.5, 125.3,
125.0, 120.5 (d, J = 7.2 Hz), 118.0 (d, J = 6.3 Hz), 117.6, 117.3, 116.8,
116.1, 62.3, 19.8, 14.4; HRMS calcd for C18H14FNO4 327.0907, found;
327.0914.
Ethyl 3-Acetyl-5-(2-hydroxybenzoyl)-2-methylbenzoate (3dd): re-
action was run for 2 h; yellow solid; mp 65ꢀ66 °C; 1H NMR (300 MHz,
CDCl3) δ 11.82 (s, 1 H), 8.15 (s, 1 H), 7.90 (s, 1 H), 7.58ꢀ7.52 (m, 2
H), 7.11 (d, J = 8.3 Hz, 1 H), 6.92 (t, J = 7.5 Hz, 1 H), 4.41 (q, J = 7.2 Hz,
2 H), 2.68 (s, 3 H), 2.62 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 202.2, 199.4, 166.8, 163.2, 141.8, 141.1, 136.8,
135.1, 133.2, 133.0, 132.3, 130.3, 119.0, 118.7, 61.7, 30.7, 18.1, 14.2;
HRMS calcd for C19H18O5 326.1154, found 326.1151.
Ethyl 3-Cyano-5-(2-hydroxybenzoyl)-2-isopropylbenzoate (3ai): re-
1
action was run for 8 h; yellow gum; H NMR (300 MHz, CDCl3) δ
11.67 (s, 1 H), 8.03 (s, 2 H), 7.57 (s, 1 H), 7.49 (dd, J = 8.0, 1.7 Hz, 1 H),
7.11 (dd, J = 8.4, 1.1 Hz, 1 H), 6.94 (t, J = 0.9 Hz, 1 H), 4.41 (q, J = 7.1
Hz, 2 H), 3.77ꢀ3.65 (m, 1 H), 1.54 (d, J = 7.2 Hz, 6 H), 1.40 (t, J = 7.1
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 197.8, 167.0, 163.3, 154.4,
137.2, 136.9, 136.0, 134.2, 133.4, 132.7, 119.2, 118.8, 118.3, 117.6, 112.7,
62.3, 31.6, 21.1, 14.1; HRMS calcd for C20H19NO4 337.1314, found
337.1306.
Ethyl 6-Cyano-4-(2-hydroxybenzoyl)-[1,10-biphenyl]-2-carboxylate
(3aj): reaction was run for 6 h; yellow solid; mp 105ꢀ106 °C; 1H NMR
(300 MHz, CDCl3) δ 11.67 (s, 1 H), 8.32 (s, 1 H), 8.15 (s, 1 H),
7.65ꢀ7.44 (m, 5 H), 7.38 (d, J = 3.0 Hz, 2 H), 7.13 (d, J = 8.3 Hz, 1 H),
6.97 (t, J = 7.6 Hz, 1 H), 4.07 (q, J = 7.3 Hz, 2 H), 0.96 (t, J = 7.1 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 197.7, 166.0, 163.3, 148.2, 137.4,
137.4, 136.2, 135.5, 133.7, 133.7, 132.8, 129.2, 128.4, 128.3, 119.3, 118.9,
118.2, 116.6, 114.8, 61.9, 13.5; HRMS calcd for C23H17NO4 371.1158,
found 371.1163.
Ethyl 6-Cyano-4-(2-hydroxybenzoyl)-40-methoxy-[1,10-biphenyl]-2-
carboxylate (3ak): reaction was run for 6 h; yellow solid; mp
1
129ꢀ130 °C; H NMR (300 MHz, CDCl3) δ 11.68 (s, 1H), 8.27 (s,
1H), 8.13 (s, 1H), 7.68ꢀ7.47 (m, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.13 (d,
J = 8.6 Hz, 1H), 7.07ꢀ6.90 (m, 3H), 4.12 (q, J = 7.6 Hz, 2H), 3.88
(s, 3H), 1.04 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.8,
166.3, 163.3, 160.4, 148.0, 137.3, 137.1, 135.5, 134.0, 133.6, 132.8, 129.9,
128.2, 119.3, 118.9, 118.3, 116.8, 114.9, 114.0, 61.92, 55.31, 13.67;
HRMS calcd for C24H19NO5 401.1263, found 401.1269.
Ethyl 6-Cyano-40-fluoro-4-(2-hydroxybenzoyl)-[1,10-biphenyl]-
2-carboxylate (3al): reaction was run for 5 h; yellow solid; mp
1
97ꢀ99 °C; H NMR (300 MHz, CDCl3) δ 11.66 (s, 1H), 8.33 (d,
J = 1.8 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.65ꢀ7.55 (m, 1H), 7.53 (dd,
J = 8.1, 1.5 Hz, 1H), 7.41ꢀ7.31 (m, 2H), 7.25ꢀ 7.16 (m, 2H), 7.13 (dd,
J = 8.5, 0.9 Hz, 1H), 6.96 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 4.11 (q, J =
7.1 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
197.6, 165.7, 164.5, 163.4, 162.0, 147.2, 137.7, 137.5, 135.5, 133.8 (d, J =
17.6 Hz), 132.7, 132.2, 130.4 (d, J = 8.4 Hz), 119.3, 119.0, 118.2, 116.4,
115.8, 115.6, 115.1, 62.05, 13.62; HRMS calcd for C23H16FNO4
389.1063, found 389.1062.
Diethyl 5-(2-Hydroxybenzoyl)-2-methylisophthalate (3ed):5d reac-
tion was run for 2 h; yellow solid; mp 55ꢀ57 °C; 1H NMR (300 MHz,
CDCl3) δ 11.84 (s, 1 H), 8.16 (s, 2 H), 7.57ꢀ7.52 (m, 2 H), 7.09 (d, J =
9.0 Hz, 1 H), 6.91 (t, J = 7.6 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 4 H), 2.79 (s, 3
H), 1.40 (t, J = 7.1 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 198.7,
166.3, 162.6, 142.7, 136.1, 134.4, 132.7, 132.5, 132.2, 118.3, 118.1, 118.0,
61.0, 17.7, 13.6; HRMS calcd for C20H20O6 356.1260, found 356.1257.
Ethyl 3-Benzoyl-5-(2-hydroxybenzoyl)-2-methylbenzoate (3fd): re-
action was run for 2 h; yellow solid; mp 69ꢀ70 °C; 1H NMR (300 MHz,
CDCl3) δ 11.82 (s, 1 H), 8.28 (s, 1 H), 7.81 (d, J = 7.2 Hz, 2 H), 7.69 (s,
1 H), 7.65ꢀ7.46 (m, 5 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.89 (t, J = 7.6 Hz, 1
H), 4.41 (q, J = 7.1 Hz, 2 H), 2.55 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 199.4, 197.1, 166.6, 163.2, 141.3, 141.2,
136.8, 136.4, 135.0, 134.1, 133.1, 132.3, 132.0, 130.6, 130.1, 128.8, 119.0, 118.6,
118.6, 61.6, 18.4, 14.2; HRMS calcd for C24H20O5 388.1311, found 388.1318.
Ethyl 5-(2-Hydroxybenzoyl)-3-(4-methoxybenzoyl)-2-methylbenzo-
ate (3gd): reaction was run for 4 h; yellow solid; mp 111ꢀ113 °C; 1H
NMR (300 MHz, CDCl3) δ 11.83 (s, 1 H), 8.26 (s, 1 H), 7.78 (d, J = 8.7
Hz, 2 H), 7.67 (s, 1 H), 7.58ꢀ7.49 (m, 2 H), 7.07 (d, J = 8.4 Hz, 1 H),
6.96ꢀ6.86 (m, 3 H), 4.41 (q, J = 7.1 Hz, 2 H), 3.88 (s, 3 H), 2.54 (s, 3 H),
1.41 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.6, 195.6,
166.6, 164.4, 163.2, 141.8, 141.0, 136.8, 135.0, 133.1, 132.5, 132.1, 131.7,
130.3, 129.4, 119.0, 118.7, 118.6, 114.1, 61.6, 55.6, 18.3, 14.2; HRMS
calcd for C25H22O6 418.1416, found 418.1419.
Ethyl 2-(Chloromethyl)-3-cyano-5-(2-hydroxybenzoyl)benzoate (3am):
reactionwas run for6 h;yellowsolid; mp83ꢀ84°C;1H NMR(300 MHz,
CDCl3) δ 11.60 (s, 1 H), 8.44 (s, 1 H), 8.10 (s, 1 H), 7.59 (t, J = 7.9 Hz, 1
H), 7.44 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 6.95 (t, J = 7.7 Hz, 1
H), 5.27 (s, 2 H), 4.47 (q, J = 7.2 Hz, 2 H), 1.44 (t, J = 7.1 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 196.8, 163.7, 162.8, 143.8, 138.0, 137.0,
135.5, 134.6, 132.0, 131.4, 118.8, 118.4, 117.5, 114.9, 62.1, 39.0, 13.5;
HRMS calcd for C18H14ClNO4 343.0611, found 343.0613.
Ethyl 2-Benzyl-3-cyano-5-(2-hydroxybenzoyl)benzoate (3an): reac-
tion was run for 6 h; yellow solid; mp 67ꢀ68 °C; 1H NMR (300 MHz,
CDCl3) δ 11.94 (s, 1 H), 7.54 (m, 3 H), 7.49 (s, 1 H), 7.48ꢀ7.35 (m, 5
H), 7.09 (d, J = 8.4 Hz, 1 H), 6.88 (t, J = 7.6 Hz, 1 H), 4.62 (q, J = 7.1 Hz,
2 H), 4.05 (s, 2 H), 1.56 (t, J = 7.3 Hz, 3 H) ; 13C NMR (100 MHz,
CDCl3) δ 201.0, 169.6, 163.0, 161.2, 137.1, 134.9, 134.5, 132.7, 130.4,
130.3, 129.4, 128.7, 127.7, 127.6, 119.0, 118.8, 118.1, 116.9, 112.7, 63.0,
21.0, 13.3; HRMS calcd for C24H19NO4 385.1314, found 385.1295.
General Procedure for Synthesis of 2-Amino-5-(2-hydro-
xybenzoyl)isophthalonitrile (3ao). t-BuOK (0.8 mmol, 89.6 mg)
was added to a mixture of compound 1a (0.4 mmol, 78.8 mg) and 2o
(0.4 mmol, 26.5 mg) in dry DMF (2 mL), and the resulting solution was
reacted at 120 °C for 30 min under microwave irradiation. Then the
mixture was extracted with ethyl acetate. The combined organic layers
Ethyl 5-(2-Hydroxybenzoyl)-2-methyl-3-(4-(trifluoromethyl)benzoyl)-
benzoate (3hd): reaction was run for 2 h; yellow solid; mp 85ꢀ
1
86 °C; H NMR (300 MHz, CDCl3) δ 11.78 (s, 1 H), 8.30 (s, 1 H),
7.93 (d, J = 8.1 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.69 (s, 1 H),
8499
dx.doi.org/10.1021/jo201384f |J. Org. Chem. 2011, 76, 8495–8500

The Journal of Organic Chemistry
NOTE
7.56ꢀ7.51 (m, 2 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.90 (t, J = 7.4 Hz, 1 H), 4.42
(q, J = 7.2 Hz, 2 H), 2.56 (s, 3 H), 1.42 (t, J = 7.1 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 199.2, 195.9, 166.4, 163.2, 141.3, 140.5, 139.2, 136.9,
135.3, 132.9, 132.5, 132.4, 130.6, 130.3, 125.9, 125.9, 119.0, 118.7, 118.6,
61.7, 18.4, 14.2; HRMS calcd for C25H19F3O5 456.1185, found 456.1192.
Ethyl 5-(2-Hydroxybenzoyl)-2-methyl-[1,10-biphenyl]-3-carboxylate
(3id): reaction was run for 10 h; yellow solid; mp 87ꢀ89 °C; 1H NMR
(300 MHz, CDCl3) δ 11.95 (s, 1 H), 8.12 (s, 1 H), 7.68 (s, 1 H), 7.63 (d,
J = 8.3 Hz, 1 H), 7.57ꢀ7.39 (m, 4 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.08 (d, J
= 8.4 Hz, 1 H), 6.90 (t, J = 7.6 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 2.51 (s,
3 H), 1.41 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 200.3,
167.5, 163.2, 144.0, 141.0, 140.3, 136.5, 134.9, 133.3, 133.2, 132.1, 129.7,
129.2, 128.4, 127.6, 119.0, 118.8, 118.5, 61.4, 18.8, 14.3; HRMS calcd for
C23H20O4 360.1362, found 360.1362.
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Ethyl 5-(2-Hydroxybenzoyl)-40-methoxy-2-methyl-[1,10-biphenyl]-
3-carboxylate (3jd): reaction was run for 10 h; yellow gum; 1H NMR
(300 MHz, CDCl3) δ 11.95 (s, 1 H), 8.09 (s, 1 H), 7.66ꢀ7.61 (m, 2 H),
7.51 (t, J = 8.1 Hz, 1 H), 7.24 (d, J = 9.5 Hz, 2 H), 7.07 (d, J = 8.3 Hz, 1
H), 6.97 (d, J = 8.4 Hz, 2 H), 6.89 (t, J = 7.6 Hz, 1 H), 4.40 (q, J = 7.1 Hz,
2 H), 3.86 (s, 3 H), 2.51 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 200.2, 167.4, 162.9, 158.8, 143.5, 140.9, 136.2,
134.7, 133.1, 133.1, 132.4, 131.9, 130.2, 129.2, 118.8, 118.6, 118.3, 113.5, 61.2,
55.1, 18.6, 14.1; HRMS calcd for C24H22O5 390.1467, found 390.1456.
Ethyl 5-(2-Hydroxybenzoyl)-2-methyl-40-nitro-[1,10-biphenyl]-3-carbo-
xylate (3kd): reaction was run for 8 h; yellow solid; mp 97ꢀ98 °C; 1H
NMR (300 MHz, CDCl3) δ 11.85 (s, 1 H), 8.32 (d, J = 8.5 Hz, 2 H), 8.18
(s, 1 H), 7.72ꢀ7.46 (m, 5 H), 7.09 (d, J = 8.6 Hz, 1 H), 6.91 (d, J = 7.5
Hz, 1 H),4.43 (q, J = 7.8 Hz, 2 H), 2.50 (s, 3 H), 1.41 (t, J = 7.1 Hz,
3 H).13C NMR (100 MHz, CDCl3) δ 199.7, 167.0, 163.2, 147.3, 147.0,
141.8, 140.5, 136.7, 135.3, 133.0, 132.6, 132.3, 130.7, 123.7, 118.9, 118.8,
118.6, 61.6, 18.8, 14.2; HRMS calcd for C23H19NO6 405.1212, found
405.1208.
’ ASSOCIATED CONTENT
1
Supporting Information. Figures giving H NMR, 13C
S
b
NMR, and HRMS spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: yhhu@mail.shcnc.ac.cn.
’ ACKNOWLEDGMENT
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Commun. 2008, 1211–1213. (b) Gong, J.; Xie, F.; Chen, H.; Hu, Y.
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Financial support of this research provided by the State Key
Laboratory of Drug Research (SIMM1004KF-18) and National
Natural Science Foundation of China (30873142) is gratefully
acknowledged.
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