An efficient method for syntheses of functionalized 6-bulkysubstituted salicylates under microwave irradiation

Article abstract of DOI:10.1016/j.tet.2015.08.040

As an important fragment and synthetic intermediate, functionalized 6-arylsalicylate substructure widely exist in pharmacologically relevant natural products and bioactive compounds. In our recent works, we discovered two highly potent inhibitors for combating mutants of acetohydroxyacid synthase (AHAS), an important target for herbicide discovery. These two inhibitors contain 6-arylsalicylate skeleton. Previously, we have explored a new method to synthesize position-6 aryl substituted salicylic acid fragment. However, this method failed to synthesize 4-methyl-6-aryl salicylic acids. Herein, we developed a new efficient method for the synthesis of functionalized 4-methyl-6-bulkyarylsalicylates via a microwave-promoted Suzuki cross-coupling. This method has obvious advantages, such as a wide range of substrates, smooth and rapid reaction, moderate to excellent yields. Due to its superiority to the traditional available methods, this protocol could be utilized to synthesize pyrimidinyl(thio)salicylic acid and its derivatives.

Full text of DOI:10.1016/j.tet.2015.08.040

Tetrahedron 71 (2015) 8123e8130
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient method for syntheses of functionalized
6-bulkysubstituted salicylates under microwave irradiation
*
*
Ren-Yu Qu, Yu-Chao Liu, Qiong-You Wu, Qiong Chen , Guang-Fu Yang
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei 430079, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2015
Received in revised form 11 August 2015
Accepted 14 August 2015
Available online 29 August 2015
As an important fragment and synthetic intermediate, functionalized 6-arylsalicylate substructure
widely exist in pharmacologically relevant natural products and bioactive compounds. In our recent
works, we discovered two highly potent inhibitors for combating mutants of acetohydroxyacid synthase
(AHAS), an important target for herbicide discovery. These two inhibitors contain 6-arylsalicylate skel-
eton. Previously, we have explored a new method to synthesize position-6 aryl substituted salicylic acid
fragment. However, this method failed to synthesize 4-methyl-6-aryl salicylic acids. Herein, we de-
veloped a new efficient method for the synthesis of functionalized 4-methyl-6-bulkyarylsalicylates via
a microwave-promoted Suzuki cross-coupling. This method has obvious advantages, such as a wide
range of substrates, smooth and rapid reaction, moderate to excellent yields. Due to its superiority to the
traditional available methods, this protocol could be utilized to synthesize pyrimidinyl(thio)salicylic acid
and its derivatives.
Keywords:
AHAS inhibitors
Functionalized 6-arylsalicylates
Suzuki cross-coupling reactions
Electronic effect
Microwave irradiation
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Considerable attention has been paid to 6-bulkysubstituted sa-
licylates due to their ubiquity in natural products and their wide
range of valuable biological activities.1 Meanwhile, functionalized
6-substituted salicylates served as a kind of the key intermediate
have been widely applied in organic synthesis.2
Fig. 1. Structures of anti-resistance AHAS inhibitor Y10145 and Y10055.
In recent years, we focus our efforts on the discovery of novel
inhibitors targeting acetohydroxyacid synthase (AHAS), one of the
most important action targets for herbicide discovery, to combat
the resistance issues that could cause sharply reduce of sensitivity
toward the AHAS-inhibiting herbicide, and generate increased
challenges for the farmers to efficiently control agricultural weeds.3
Our continuous efforts have led to the discovery of several series of
lead-compounds, including pyrimidylsalicylate, sulfonylureas and
triazolopyrimidines.3 The AHAS inhibition results indicated that
those compounds showing good inhibition activity against wild-
type AHAS all contain 6-arylsubstituted salicylic acid fragment.4
However, the most promising compound (Y10145) with a Ki value
of 1.59ꢀ10ꢁ7 M against wild-type AHAS showed limited potency
toward W574L mutant AHAS (Ki, W574L¼1.63ꢂ0.33ꢀ10ꢁ4 M) (Fig. 1).
Interestingly, we found that the introduction of an additional
methyl group onto 4-position of salicylic acid moiety could result in
significant improvement of the inhibitory potency against W574L
mutant but the potency against wide type AHAS was almost
maintained as well (Fig. 1, Y10055).4a Thus, it is of great importance
to develop an efficient methodology to construct 4-methyl-6-
arylsalicylates containing library for screening novel inhibitors
with high potency against both W574L mutant and wide type
AHAS.
Not long ago, we have reported a highly efficient method to
synthesize 6-arylsubstituted salicylates (Fig. 2).5a This approach
overcame the limitation of traditional method such as [3þ3] cy-
clizations, transition-metal-catalyzed cyclization reactions.6 Un-
fortunately, we failed to apply this method for synthesis 4-methyl-
6-arylsubstituted salicylates (Fig. 2). Herein, as a continuation of
our research on the synthesis of structurally diverse heterocyclic
compounds,5be5e we report a new efficient method for the
* Corresponding authors. Tel.: þ86 27 67867800; fax: þ86 27 67867141; e-mail
addresses: qchen@mail.ccnu.edu.cn (Q. Chen), gfyang@ccnu.edu.cn (G.-F. Yang).
http://dx.doi.org/10.1016/j.tet.2015.08.040
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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R.-Y. Qu et al. / Tetrahedron 71 (2015) 8123e8130
Encouraged by these results, we next make use of this method to
synthesize 4-methyl-6-arylsubstituted salicylates. In the present
work, the key intermediate 5-hydroxy-2,2,7-trimethyl-4H-benzo
[d][1,3]dioxin-4-one 7 (Scheme 1) was prepared in a two-step
manner, starting from the carboxylation reaction of 3,5-
dihydroxytoluene to produce 2, 6-dihydroxy-4-methylbenzoic
acid 6,9 which underwent cyclization by treatment with acetone
in the presence of SOCl2 to afford the desired intermediate 7.
Subsequently, the reaction of compound 7 with trifluoroacetic an-
hydride was investigated with a view to synthesize 2,2,7-trimethyl-
4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethane-sulfonate 8.
As expected, under the optimized conditions, 2,2,7-trimethyl-4-
Fig. 2. Synthesis of 6-substituted salicylates and 6-substituted 4-methylsalicylates.
oxo-4H-benzo[d][1,3]dioxin-5-yl-trifluoromethane-sulfonate
8
reacted with phenylboronic acids to give the key intermediate 9a
with a yield of 92% smoothly (Scheme 1).
synthesis of the 6-arylsubstituted salicylates by using a microwave-
assisted methodology.7
2. Result and discussion
Palladium-catalyzed Suzuki cross-coupling reaction, one of the
most effective CeC bond construction methodology, usually need
a leaving group (such as OTf, I, Br, Cl) bearing aromatic ring as
substrate to react with arylboronic acid. Therefore, 2,2-dimethyl-4-
oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethanesu-lfonate (1)
was first prepared by using a previously reported synthetic strat-
egy.8 To optimize the palladium-catalyzed Suzuki cross-coupling
reaction, the reaction of aryl sulfonate (1) with phenylboronic
acids (2a) was selected as a model. As shown in Table 1, microwave
irradiation could dramatically accelerate the reaction efficiency and
increase the reaction yields. In addition, the reactant concentration,
the stoichiometric ratio of the catalyst, and the temperature were
proved to be important parameters that could significantly affect
the reaction yield. It was found that when the reaction temperature
increased from 100 ꢃC to 110 ꢃC, the yield increased sharply from
25% to 94%. However, further increasing the temperature to 120 ꢃC
led to a slight decrease of the yield to 85%. We also noted that the
reaction could not take place without Pd catalysis (entry 3). Reduce
the palladium loading was also unfavorable to the reaction and
a much lower yield was observed. Thus, the optimum reaction
condition should be 1 mol % Pd(PPh3)4, 2 equiv of NaHCO3, 110 ꢃC
under microwave irradiation with OTf as leaving group for sub-
strate I.
Scheme 1. Synthesis route of 2,2,7-trimethyl-5-phenyl-4H-benzo[d][1,3]dioxin-4-one
under the optimal condition.
With the optimized conditions in hand, our attention turned to
the evaluation of the scope and limitations of this reaction (Table 2).
Thus, we investigated the scope of substrates by employing a vari-
ety of arylboronic acids substituted with electron-donating and
electron-withdrawing groups. As shown in Table 2, significant
structural variations in the arylboronic acid components were well
tolerated and afforded the corresponding functionalized 6-
substituted salicylates 3 and 4-methyl-6-substituted salicylates 9
in good yields. Both electron-rich and electron-poor aryl boronic
acids could be successfully utilized in this transformation. For in-
stance, methyl, methoxy, halogen, and trifluoromethyl derivatives
showed no significant effects on the transformation and afforded
good yields of products in this two reaction (Table 2, 3be3h,
9be9h). It is worth noting that potentially problematic but valuable
carbonyl and heterocycle substituted aryl boronic acid (Table 2, 3i,
3m, 3n, 9i, 9m, 9n), could also get considerable yields.
In addition, the position (ortho-, meta- or para-) and the number
(mono-, dis-, poly-) of substituents in arylboronic acids did not
retard the reaction. We also extended the substrates to alkenyl
boronic acids. Not surprisingly, the process showed good functional
group compatibility for the alkenyl reagents (Table 2, 3o, 9o). When
we explored the scope of alkyl reagents that could potentially react
with substrates 1 and 8 to study the generality of the reaction,
regrettably, this reaction did not happen.
Table 1
Optimization of the reaction conditionsa
Entry
Temp(ꢃC)
1:2a
Pd(PPh3)4
Base
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
c MW:120
MW:120
MW:120
MW:120
MW:120
MW:120
MW:120
MW:120
MW:110
MW:100
120d
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
5 mol %
5 mol %
0 mol %
2 mol %
1 mol %
0.5 mol %
0.5 mol %
0.2 mol %
1 mol %
1 mol %
1 mol %
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
6
8
6
6
6
73%
50%
0%
82%
85%
63%
60%
53%
94%
25%
77%
6
10
13
5
20
630
9
10
11
a
Unless otherwise noted, all the reactions were carried out at 1 mmol scale in the
solution of DME (3 mL) and H2O (0.6 mL) with 1 mol % of Pd(PPh3)4, 2 equiv of base,
protected by N2.
Finally, we removed the protecting groups of functionalized 6-
arylsalicylates (3) and (9) successfully to obtain the target com-
pounds 6-arylsalicylates 4 and 10. For almost all the substrates with
different substituents at 3 and 9, deprotection proceeded smoothly
and afforded moderate to excellent yields of products (Table 3).
b
Isolated yields.
Microwave irradiation.
Conventional heating method.
c
d

R.-Y. Qu et al. / Tetrahedron 71 (2015) 8123e8130
8125
Table 2
Table 3
The reaction with Aryl sulfonate (1), (8) and various arylboronic acids or alkenyl
The synthesis of functionalized 6-arylsalicylates(4) from functionalized 6-
boronic acidsa
arylsalicylates (3)a
3. Conclusion
1H NMR spectra were recorded on 400/600 (400/600 MHz)
spectrophotometers. Chemical shifts (d) are reported in ppm from
In summary, we have developed a convenient and efficient
method for the synthesis of functionalized 6-arylsalicylates (4) and
(10) using microwave-assisted Suzuki cross-coupling reactions. The
protocol is not only applicable to 4-unsubstituted salicylates (1),
but also 4-methyl-salicylates (8). At the same time, the reactions
possess a wide range of substrates and produce a variety of densely
functionalized 6-arylsalicylates (4) and (10) in good to excellent
yields within a very short time. These important intermediates will
provide a solid basis for the discovery of salicylate-containing drugs
and agrichemicals.
the solvent resonance as the internal standard (CDCl3: 7.26 ppm,
DMSO: 2.50 ppm). Data are reported as follows: chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, m¼multiplet,
q¼quaternary), coupling constants (Hz) and integration. 13C NMR
spectra were recorded on 400/600 (100/150 MHz) spectropho-
tometers (CDCl3: 77.0 ppm, DMSO: 39.5 ppm) with complete pro-
ton decoupling. Mass spectra were measured on a Trace MS
spectrometer. Elemental analysis was determined on an elemen-
tary analysis instrument. Microwave irradiation reactions were
carried out on a Smith synthesizerÔ instrument.
4. Experimental section
4.1. General information
4.2. General procedure of the synthesis of 7 and 8
4.2.1. 5-Hydroxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one
(7). A solution of the 2,6-dihydroxybenzoic acid (3.36 g,
20.0 mmol), and DMAP (126 mg, 1.03 mmol) in dry acetone (1.9 mL)
and DME (15 mL) was cooled to 0 ꢃC and treated with SOCl2 (3.4 g,
28.6 mmol) in DME (5 mL). The reaction mixture was stirred for 2 h,
maintaining the temperature at less than 30 ꢃC. The reaction mix-
ture was filtered through pad of silica gel, and the residue was
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification. All the
solvents were treated according to general methods. Flash column
chromatography (FC) was performed using 200e300 mesh silica
gel.

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R.-Y. Qu et al. / Tetrahedron 71 (2015) 8123e8130
recrystallized to give acetonide 7. (2.25 g, 54%). White solid,
mp:105e106 ꢃC 1H NMR (600 MHz, DMSO)
10.21 (s, 1H), 6.50 (s,
1H), 6.40 (s, 1H), 2.28 (s, 3H), 1.70 (s, 6H). 13C NMR (150 MHz, CDCl3)
7.32e7.27 (m, 2H), 7.09 (t, J¼7.6 Hz, 2H), 6.98 (d, J¼8.0 Hz, 2H), 1.79
(d, J¼2.4 Hz, 6H).
d
4.3.6. 2,2-Dimethyl-5-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one
d
165.22, 160.94, 155.16, 149.92, 111.05, 107.85, 106.90, 96.74, 25.45,
(3f). White solid, 90% yield; mp: 170e171 ꢃC. (Lit.: 168e169 ꢃC). 1H
22.34. EIMS: m/z¼208.00 (Mþ). Anal. Calcd for (C11H12O4): C, 63.45;
NMR (400 MHz, CDCl3)
d
7.50 (d, J¼8.0 Hz, 1H), 7.28e7.22 (m, 4H),
H, 5.81. Found: C, 63.66; H, 5.79.
7.00 (d, J¼8.0 Hz, 1H), 6.95 (d, J¼8.4 Hz, 1H), 2.40 (s, 3H), 1.80 (d,
J¼2.0 Hz, 6H).
4.2.2. 2,2,7-Trimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluorom
ethanesulfonate(8). To a solution of acetonide 7 (2.08 g, 10.0 mmol)
and pyridine (1.2 ml, 15.0 mmol) in dry CH2Cl2 (20 ml) was added
triflic anhydride (3.38 g, 12.0 mmol) at such a rate that the tem-
perature was maintained at 0 ꢃC. The temperature of the solution
was allowed to warm to 20 ꢃC during 1.5 h with stirring. To the
reaction mixture was added 1 M HCl (20 ml) and the organic and
the aqueous layers were separated. The later was extracted with
CH2Cl2 (3ꢀ10 mL). The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromatography using
petroleum ether/EtO2Ac (10/1) as eluent to give the 8. (3 g, 88%).
4.3.7. 5-(4-Methoxyphenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (3g). White solid, 94% yield; mp: 164e165 ꢃC. (Lit.:
165e166 ꢃC). 1H NMR (600 MHz, CDCl3)
d
7.50 (t, J¼7.8 Hz, 1H), 7.28
(d, J¼8.4 Hz, 2H), 7.00 (d, J¼7.8 Hz, 1H), 6.94 (dd, J¼8.4, 6.0 Hz, 3H),
3.85 (s, 3H), 1.79 (s, 6H).
4.3.8. 2,2-Dimethyl-5-(4-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]
dioxin-4-one (3h). White solid, 97% yield; mp: 177e178 ꢃC. (Lit.:
177e178 ꢃC). 1H NMR (600 MHz, CDCl3)
(t, J¼7.8 Hz,1H), 7.43 (d, J¼7.8 Hz, 2H), 7.03 (d, J¼8.4 Hz,1H), 6.98 (d,
J¼7.8 Hz, 1H), 1.80 (s, 6H).
d
7.66 (d, J¼7.8 Hz, 2H), 7.56
White solid, mp: 58e59 ꢃC. 1H NMR (600 MHz, CDCl3)
6.80 (s, 1H), 2.43 (s, 3H), 1.74 (s, 6H). 13C NMR (100 MHz, DMSO)
d 6.85 (s, 1H),
4.3.9. 5-(4-Acetylphenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (3i). White solid, 94% yield; mp: 158e159 ꢃC. (Lit.:
d
180.41, 156.87, 156.49,149.87, 147.54, 118.42, 117.63, 106.86,104.67,
157e158 ꢃC). 1H NMR (600 MHz, CDCl3)
d
8.01 (d, J¼8.4 Hz, 2H),
24.83, 21.35. EIMS: m/z¼304.01 (Mþ). Anal. Calcd for (C12H11F3O6S):
7.56 (t, J¼7.8 Hz, 1H), 7.43 (d, J¼8.4 Hz, 2H), 7.01 (dd, J¼18.0, 7.8 Hz,
C, 42.36; H, 3.26; S, 9.42. Found: C, 42.17; H, 3.44. S, 9.31.
2H), 2.65 (s, 3H), 1.81 (s, 6H).
4.3. General procedure of the synthesis of compounds
3ae3o5a and 9ae9o
4.3.10. 5-(3,5-Dichlorophenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-
4-one (3j). Yellow solid, 95% yield; mp: 139e140 ꢃC. (Lit.:
139e140 ꢃC). 1H NMR (600 MHz, CDCl3)
d
7.55 (t, J¼7.8 Hz, 1H), 7.37
Aryl salicylates 1 or 8 (0.5 mmol) and 2a (0.5 mmol) were dis-
solved in DME (3 mL) and H2O (0.6 mL) in a microwave vial under
a nitrogen atmosphere. Pd(PPh3)4 (0.005 mmol) and sodium bi-
carbonate (1 mmol) were added, and the reaction mixture was ir-
radiated in a microwave apparatus at 110 ꢃC for 4e10 min. After the
reaction mixture was cooled to ambient temperature, the product
was concentrated, and the crude mixture was purified by silica gel
column chromatography using petroleum ether/acetone (20/1 to
10/1) as eluent to give the title compound 3a in 94% yield and 9a in
92% yield.
(d, J¼1.8 Hz, 1H), 7.19 (d, J¼1.8 Hz, 2H), 7.03 (d, J¼8.4 Hz, 1H), 6.95
(d, J¼7.8 Hz, 1H), 1.80 (s, 6H).
4.3.11. 5-(3-Chloro-4-fluorophenyl)-2,2-dimethyl-4H-benzo[d][1,3]-
dioxin-4-one (3k). Yellow solid, 92% yield; mp: 153e154 ꢃC. (Lit.:
154e155 ꢃC). 1H NMR (600 MHz, CDCl3)
d
7.54 (t, J¼7.8 Hz, 1H),
7.38e7.33 (m, 1H), 7.20e7.13 (m, 2H), 7.01 (d, J¼8.4 Hz, 1H), 6.96 (d,
J¼7.8 Hz, 1H), 1.79 (s, 6H).
4.3.12. 2,2-Dimethyl-5-(3,4,5-trimethoxyphenyl)-4H-benzo[d][1,3]-
dioxin-4-one (3l). Yellow solid, 90% yield; mp: 158e159 ꢃC. (Lit.:
4.3.1. 2,2-Dimethyl-5-phenyl-4H-benzo[d][1,3]dioxin-4-one
156e157 ꢃC). 1H NMR (600 MHz, CDCl3)
d
7.52 (t, J¼7.8 Hz, 1H), 7.03
(3a). White solid, 94% yield; mp: 164e165 ꢃC. (Lit.: 164e165 ꢃC). 1H
(d, J¼7.8 Hz, 1H), 6.98 (d, J¼8.4 Hz, 1H), 6.52 (s, 2H), 3.91 (s, 3H),
NMR (600 MHz, CDCl3)
d
7.52 (t, J¼7.8 Hz,1H), 7.40 (dt, J¼7.2, 6.0 Hz,
3.87 (s, 6H), 1.80 (s, 6H).
3H), 7.35e7.30 (m, 2H), 7.01 (d, J¼7.8 Hz, 1H), 6.97 (d, J¼8.4 Hz, 1H),
1.79 (s, 6H).
4.3.13. 5-(Dibenzo[b,d]furan-4-yl)-2,2-dimethyl-4H-benzo[d][1,3]-
dioxin-4-one (3m). White solid, 93% yield; mp: 208e209 ꢃC. (Lit.:
4.3.2. 5-(4-Chlorophenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
210e211 ꢃC). 1H NMR (600 MHz, CDCl3)
d 8.00e7.93 (m, 2H),
one (3b). Yellow solid, 96% yield; mp: 174e175 ꢃC. (Lit.:
175e176 ꢃC). 1H NMR (600 MHz, CDCl3)
d
7.53 (t, J¼7.8 Hz, 1H), 7.37
7.65e7.60 (m, 1H), 7.49 (dd, J¼7.2 1.3 Hz, 1H), 7.44 (t, J¼7.8 Hz, 1H),
7.39 (dt, J¼9.0, 4.2 Hz, 2H), 7.34e7.30 (m, 1H), 7.19 (dd, J¼7.8, 1.2 Hz,
1H), 7.07 (dd, J¼8.4, 1.2 Hz, 1H), 1.91 (s, 6H).
(d, J¼8.4 Hz, 2H), 7.26 (t, J¼4.2 Hz, 4H), 6.98 (dd, J¼12.6, 7.8 Hz, 2H),
1.79 (s, 6H).
4.3.14. 5-(Benzofuran-2-yl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
4.3.3. 5-(3-Chlorophenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (3n). Yellow solid, 90% yield; mp: 145e146 ꢃC. (Lit.:
one (3c). White solid, 87% yield; mp: 157e158 ꢃC. (Lit.:
146e147 ꢃC). 1H NMR (600 MHz, CDCl3)
d
7.62 (d, J¼7.8 Hz, 1H), 7.58
157e158 ꢃC). 1H NMR (600 MHz, CDCl3)
7.37e7.32 (m, 2H), 7.31 (s, 1H), 7.20 (d, J¼7.2 Hz, 1H), 6.99 (dd,
J¼14.4, 7.8 Hz, 2H), 1.80 (s, 6H).
d
7.53 (d, J¼7.8 Hz, 1H),
(t, J¼7.8 Hz, 1H), 7.51 (d, J¼8.4 Hz, 1H), 7.45 (d, J¼7.8 Hz, 1H),
7.34e7.28 (m, 1H), 7.24 (t, J¼7.8 Hz, 1H), 7.13 (s, 1H), 7.03 (d,
J¼7.8 Hz, 1H), 1.82 (s, 6H).
4.3.4. 5-(2-Chlorophenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (3d). White solid, 92% yield; mp: 181e182 ꢃC. (Lit.:
4.3.15. (E)-2,2-Dimethyl-5-(pent-1-en-1-yl)-4H-benzo[d][1,3]dioxin-
4-one (3o). Yellow oil, 96% yield. 1H NMR (600 MHz, CDCl3)
180e181 ꢃC). 1H NMR (600 MHz, CDCl3)
7.44e7.41 (m, 1H), 7.38e7.31 (m, 2H), 7.28 (dd, J¼7.2, 2.4 Hz, 1H),
7.03 (d, J¼8.4 Hz, 1H), 6.93 (d, J¼7.8 Hz, 1H), 1.78 (s, 3H), 1.77 (s, 3H).
d
7.57 (t, J¼7.8 Hz, 1H),
d
7.50e7.37 (m, 2H), 7.24 (d, J¼7.8 Hz, 1H), 6.82 (d, J¼8.4 Hz, 1H),
6.30e6.18 (m, 1H), 2.26 (q, J¼7.2 Hz, 2H), 1.71 (s, 6H), 1.53 (dd,
J¼15.0, 7.2 Hz, 2H), 0.97 (t, J¼7.2 Hz, 3H).
4.3.5. 5-(4-Fluorophenyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (3e). White solid, 96% yield; mp: 178e179 ꢃC. (Lit.:
4.3.16. 2,2,7-Trimethyl-5-phenyl-4H-benzo[d][1,3]dioxin-4-one
(9a). White solid, 92% yield; mp: 140e141 ꢃC. 1H NMR (600 MHz,
178e179 ꢃC). 1H NMR (400 MHz, CDCl3)
d
7.52 (t, J¼8.0 Hz, 1H),

R.-Y. Qu et al. / Tetrahedron 71 (2015) 8123e8130
8127
DMSO)
d
7.40e7.33 (m, 3H), 7.31 (d, J¼7.2 Hz, 2H), 6.96 (s, 1H), 6.88
164.23,
128.86, 126.76, 125.53, 124.70, 124.67, 122.83, 117.32, 108.96, 105.29,
25.46, 21.69. EIMS: m/z¼336.15 (Mþ). Anal. Calcd for (C18H15F3O3):
C, 64.28; H, 4.50. Found: C, 64.47; H, 4.77.
(s, 1H), 2.37 (s, 3H), 1.74 (s, 6H). 13C NMR (100 MHz, CDCl3)
d
159.36, 156.96, 145.92, 145.44, 143.96, 140.08, 128.36, 127.53,
126.84, 116.42, 109.05, 104.92, 25.44, 21.68. EIMS: m/z¼268.09
(Mþ). Anal. Calcd for (C17H16O3): C, 76.10; H, 6.01. Found: C, 76.35;
H, 5.94.
4.3.24. 5-(4-Acetylphenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-
4-one (9i). White solid, 97% yield; mp: 155e156 ꢃC. 1H NMR
(600 MHz, DMSO)
7.02 (s, 1H), 6.91 (s, 1H), 2.62 (s, 3H), 2.39 (s, 3H), 1.75 (s, 6H). 13
NMR (150 MHz, CDCl3) 197.65, 159.36, 157.07, 146.70, 145.12,
d
7.96 (d, J¼7.8 Hz, 2H), 7.47 (d, J¼7.8 Hz, 2H),
4.3.17. 5-(4-Chlorophenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-
C
4-one (9b). White solid, 93% yield; mp: 183e184 ꢃC. 1H NMR
d
(600 MHz, DMSO)
6.98 (s,1H), 6.89 (s, 1H), 2.37 (s, 3H),1.74 (s, 6H). 13C NMR (100 MHz,
CDCl3) 159.49, 157.12, 146.65, 144.28, 138.59, 133.50, 129.84,
d
7.44 (d, J¼8.4 Hz, 2H), 7.35 (d, J¼8.4 Hz, 2H),
144.26, 135.82, 128.72, 127.88, 126.56, 117.19, 108.93, 105.23, 26.58,
25.50, 21.75. EIMS: m/z¼310.15 (Mþ). Anal. Calcd for (C19H18O4): C,
73.53; H, 5.85. Found: C, 73.74; H, 5.73.
d
128.01, 126.80, 116.91, 108.98, 105.16, 25.53, 21.78. EIMS: m/
z¼302.07 (Mþ). Anal. Calcd for (C17H15ClO3): C, 67.44; H, 4.99.
Found: C, 67.61; H, 5.20.
4.3.25. 5-(3,4-Dichlorophenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]di-
oxin-4-one (9j). White solid, 94% yield; mp: 139e140 ꢃC. 1H NMR
(600 MHz, DMSO)
7.01 (s, 1H), 6.93 (s, 1H), 2.38 (s, 3H), 1.74 (s, 6H). 13C NMR (150 MHz,
CDCl3) 159.34, 157.14, 146.87, 142.85, 140.14, 131.82, 131.61, 130.22,
d
7.64 (d, J¼7.8 Hz, 2H), 7.32 (d, J¼8.4 Hz, 1H),
4.3.18. 5-(3-Chlorophenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-
4-one (9c). White solid, 89% yield; mp: 156e157 ꢃC. 1H NMR
d
(600 MHz, DMSO)
(s, 1H), 6.91 (s, 1H), 2.38 (s, 3H), 1.74 (s, 6H). 13C NMR (150 MHz,
CDCl3) 159.30, 157.06, 146.64, 143.97, 141.93, 133.55, 128.95,
d
7.45e7.38 (m, 3H), 7.28 (d, J¼6.6 Hz, 1H), 7.00
129.66, 128.17, 126.70, 117.40, 108.86, 105.32, 25.54, 21.78. EIMS: m/
z¼336.04 (Mþ). Anal. Calcd for (C17H14Cl2O3): C, 60.55; H, 4.18.
Found: C, 60.69; H, 4.34.
d
128.40, 127.50, 126.90, 126.78, 117.07, 109.01, 105.19, 25.54, 21.75.
EIMS: m/z¼302.05 (Mþ). Anal. Calcd for (C17H15ClO3): C, 67.44; H,
4.99. Found: C, 67.53; H, 5.01.
4.3.26. 5-(4-Chloro-2-fluorophenyl)-2,2,7-trimethyl-4H-benzo[d]
[1,3]dioxin-4-one (9k). White solid, 91% yield; mp: 161e162 ꢃC. 1H
NMR (600 MHz, DMSO)
1H), 7.05 (s, 1H), 6.94 (s, 1H), 2.39 (s, 3H), 1.73 (s, 3H), 1.70 (s, 3H).
13C NMR (150 MHz, CDCl3)
160.05, 159.57, 158.40, 156.60, 146.81,
d
7.47e7.41 (m, 2H), 7.36 (d, J¼8.4 Hz,
4.3.19. 5-(2-Chlorophenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-
4-one (9d). White solid, 88% yield; mp: 189e190 ꢃC. 1H NMR
d
(600 MHz, DMSO)
(m, 1H), 2.39 (s, 3H), 1.72 (s, 3H), 1.71 (s, 3H). 13C NMR (100 MHz,
CDCl3) 159.29, 156.32, 146.59, 141.82, 139.21, 132.25, 129.64,
128.91, 128.76, 126.68, 126.43, 117.26, 110.40, 105.29, 26.81, 24.25,
21.78. EIMS: m/z¼302.06 (Mþ). Anal. Calcd for (C17H15ClO3): C,
67.44; H, 4.99. Found: C, 67.60; H, 4.78.
d
7.49e7.45 (m,1H), 7.42e7.37 (m, 2H), 7.36e7.31
137.08, 134.45, 134.38, 130.47, 126.75, 124.43, 117.59, 115.93,
115.76, 110.29, 105.39, 26.83, 23.97, 21.78. EIMS: m/z¼320.11 (Mþ).
Anal. Calcd for (C17H14ClFO3): C, 63.66; H, 4.40. Found: C, 63.80;
H, 4.55.
d
4.3.27. 2,2,7-Trimethyl-5-(3,4,5-trimethoxyphenyl)-4H-benzo[d][1,3]
dioxin-4-one (9l). White solid, 90% yield; mp: 147e148 ꢃC. 1H NMR
4.3.20. 5-(4-Fluorophenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-
(600 MHz, DMSO)
d
6.94 (s, 2H), 6.58 (s, 2H), 3.76 (s, 6H), 3.70 (s,
159.28,
4-one (9e). White solid, 96% yield; mp: 184e185 ꢃC. 1H NMR
3H), 2.37 (s, 3H), 1.74 (s, 6H). 13C NMR (150 MHz, CDCl3)
d
(600 MHz, DMSO)
6.97 (s, 1H), 6.89 (s, 1H), 2.37 (s, 3H), 1.74 (s, 6H). 13C NMR (100 MHz,
CDCl3) 163.54, 161.10,159.59, 157.12,146.59, 144.54,136.09, 130.19,
130.12, 126.93, 116.74, 114.88, 114.67, 109.07, 105.12, 25.51, 21.74.
EIMS: m/z¼286.09 (Mþ). Anal. Calcd for (C17H15FO3): C, 71.32; H,
5.28. Found: C, 71.58; H, 5.17.
d
7.36 (dd, J¼6.6, 6.0 Hz, 2H), 7.24e7.18 (m, 2H),
157.04, 152.53, 146.39, 145.53, 137.38, 135.80, 126.89, 116.61,
109.00, 105.83, 104.98, 60.80, 55.96, 25.54, 21.75. EIMS: m/
z¼358.12 (Mþ). Anal. Calcd for (C20H22O6): C, 67.03; H, 6.19. Found:
C, 67.01; H, 6.04.
d
4.3.28. 5-(Dibenzo[b,d]furan-3-yl)-2,2,7-trimethyl-4H-benzo[d][1,3]
dioxin-4-one (9m). White solid, 94% yield; mp: 215e216 ꢃC. 1H
4.3.21. 2,2,7-Trimethyl-5-(p-tolyl)-4H-benzo[d][1,3]dioxin-4-one
NMR (600 MHz, DMSO)
d
8.19e8.13 (m, 2H), 7.54 (dd, J¼13.3, 4.6 Hz,
(9f). White solid, 92% yield; mp: 148e149 ꢃC. 1H NMR (600 MHz,
2H), 7.49 (dt, J¼15.0, 4.2 Hz, 2H), 7.41 (dd, J¼11.2, 4.1 Hz, 1H), 7.10 (s,
DMSO)
6.86 (s, 1H), 2.36 (s, 3H), 2.35 (s, 3H), 1.73 (s, 6H). 13C NMR
(100 MHz, CDCl3) 159.54, 157.05, 146.29, 145.67, 137.18, 128.59,
d
7.20 (d, J¼8.4 Hz, 2H), 7.18 (d, J¼8.4 Hz, 2H), 6.93 (s, 1H),
1H), 7.08 (s, 1H), 2.43 (s, 3H), 1.92 (s, 3H), 1.78 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d 159.58, 156.76, 155.86, 153.45, 146.64, 138.90,
d
126.83, 126.29, 124.94, 124.24, 123.75, 122.88, 122.60, 120.69,
120.30, 117.10, 111.35, 110.82, 105.27, 26.81, 24.22, 21.83. EIMS: m/
z¼358.11 (Mþ). Anal. Calcd for (C23H18O4): C, 77.08; H, 5.06. Found:
C, 76.98; H, 4.90.
128.33, 126.89, 116.25, 109.14, 104.93, 25.50, 21.74, 21.21. EIMS: m/
z¼282.11 (Mþ). Anal. Calcd for (C18H18O3): C, 76.57; H, 6.43. Found:
C, 76.83; H, 6.63.
4.3.22. 5-(4-Methoxyphenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]di-
4.3.29. 5-(Benzofuran-2-yl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-
oxin-4-one (9g). White solid, 89% yield; mp: 138e139 ꢃC. 1H NMR
4-one (9n). Yellow solid, 85% yield; mp: 179e180 ꢃC. 1H NMR
(600 MHz, DMSO)
6.91 (s, 1H), 6.86 (s, 1H), 3.79 (s, 3H), 2.36 (s, 3H), 1.73 (s, 6H). 13
NMR (100 MHz, CDCl3) 159.64, 159.04, 157.08, 146.29, 145.31,
d
7.25 (d, J¼8.4 Hz, 2H), 6.94 (d, J¼8.4 Hz, 2H),
(600 MHz, DMSO)
7.34 (dd, J¼13.8, 6.6 Hz, 2H), 7.28 (t, J¼7.2 Hz, 1H), 7.20 (s, 1H), 7.09
(s, 1H), 2.42 (s, 3H), 1.76 (s, 6H). 13C NMR (150 MHz, CDCl3)
159.01,
d
7.69 (d, J¼7.2 Hz, 1H), 7.60 (d, J¼8.4 Hz, 1H),
C
d
d
132.36, 129.69, 126.85, 116.07, 113.26, 109.00, 104.88, 55.07, 25.48,
21.74. EIMS: m/z¼298.10 (Mþ). Anal. Calcd for (C18H18O4): C, 72.47;
H, 6.08. Found: C, 72.61; H, 5.99.
157.26, 154.97, 153.56, 146.76, 132.97, 128.77, 125.95, 124.61, 122.72,
121.33, 117.98, 111.17, 109.10, 106.64, 105.28, 25.49, 21.82. EIMS: m/
z¼308.15 (Mþ). Anal. Calcd for (C19H16O4): C, 74.01; H, 5.23. Found:
C, 74.23; H, 5.11.
4.3.23. 2,2,7-Trimethyl-5-(4-(trifluoromethyl)phenyl)-4H-benzo[d]
[1,3]dioxin-4-one (9h). White solid, 92% yield; mp: 172e173 ꢃC. 1H
4.3.30. (E)-2,2,7-Trimethyl-5-(pent-1-en-1-yl)-4H-benzo[d][1,3]di-
NMR (400 MHz, DMSO)
2H), 7.03 (s, 1H), 6.92 (s, 1H), 2.39 (s, 3H), 1.75 (s, 6H). 13C NMR
(100 MHz, CDCl3) 159.40, 157.12, 146.83, 143.95, 129.47, 129.14,
d
7.74 (d, J¼8.0 Hz, 2H), 7.56 (d, J¼8.0 Hz,
oxin-4-one (9o). White solid, 98% yield; mp: 34e35 ꢃC. 1H NMR
(600 MHz, DMSO)
d
7.33 (d, J¼16.2 Hz, 1H), 7.20 (s, 1H), 6.80 (s, 1H),
d
6.35e6.25 (m, 1H), 2.33 (s, 3H), 2.22e2.16 (m, 2H), 1.64 (s, 6H),

8128
R.-Y. Qu et al. / Tetrahedron 71 (2015) 8123e8130
1.52e1.39 (m, 2H), 0.94 (t, J¼7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3)
NMR (600 MHz, CDCl3)
d
10.77 (s, 1H), 7.97 (d, J¼8.4 Hz, 2H), 7.44 (t,
d
160.42, 156.64, 146.23, 142.19, 135.00, 128.07, 122.08, 115.82,
J¼7.8 Hz, 1H), 7.33 (d, J¼8.4 Hz, 2H), 7.05 (d, J¼7.8 Hz, 1H), 6.78 (d,
107.85, 104.82, 35.15, 25.54, 22.32, 21.85, 13.72. EIMS: m/z¼260.11
(Mþ). Anal. Calcd for (C16H20O3): C, 73.82; H, 7.74. Found: C, 73.77;
H, 7.55.
J¼7.2 Hz, 1H), 3.49 (s, 3H), 2.66 (s, 3H).
4.4.10. Methyl 30,50-dichloro-3-hydroxy-[1,10-biphenyl]-2-
carboxylate (4j). Yellow solid, 92% yield; mp: 65e66 ꢃC. (Lit.:
66e67 ꢃC). 1H NMR (600 MHz, CDCl3)
d 10.85 (s, 1H), 7.43 (t,
4.4. General procedure of the synthesis of compounds
J¼7.8 Hz, 1H), 7.34 (s, 1H), 7.13 (s, 2H), 7.05 (d, J¼8.4 Hz, 1H), 6.74 (d,
4ae4o5a and 10ae10o
J¼7.2 Hz, 1H), 3.58 (s, 3H).
To a stirred solution of 3a or 9a (1 mmol) in MeOH (10 ml) was
added K2CO3 (1.1 mmol) at room temperature. The resulting mix-
ture was stirred at 50 ꢃC for 4e10 h and then allowed to cool to
room temperature. The solvent was evaporated in vacuo. The
mixture was quenched with saturated aqueous NH4Cl and 1 N
aqueous HCl, and extracted with Et2O. The organic layer was
washed with brine, dried over Na2SO4 and concentrated. Purifica-
tion of the residue by flash column chromatography (hexane/
acetone¼5/1) gave 4a in 94% yield and 10a in 93% yield.
4.4.11. Methyl 30-chloro-40-fluoro-3-hydroxy-[1,10-biphenyl]-2-
carboxylate (4k). Yellow solid, 97% yield; mp: 63e64 ꢃC. (Lit.:
64e65 ꢃC). 1H NMR (600 MHz, CDCl3)
d 10.80 (s, 1H), 7.42
(t, J¼7.8 Hz, 1H), 7.30e7.27 (m, 1H), 7.13 (t, J¼8.4 Hz, 1H),
7.11e7.06 (m, 1H), 7.04 (d, J¼8.4 Hz, 1H), 6.75 (d, J¼7.2 Hz, 1H),
3.56 (s, 3H).
4.4.12. Methyl 3-hydroxy-30,40,50-trimethoxy-[1,10-biphenyl]-2-
carboxylate (4l). Yellow solid, 89% yield; mp: 103e104 ꢃC. (Lit.:
103e104 ꢃC). 1H NMR (600 MHz, CDCl3)
d 10.52 (s, 1H), 7.41 (t,
4.4.1. Methyl 3-hydroxy-[1,10-biphenyl]-2-carboxylate
J¼7.8 Hz, 1H), 7.01 (d, J¼8.4 Hz, 1H), 6.84 (d, J¼7.2 Hz, 1H), 6.45 (s,
(4a). Colorless oil, 94% yield. 1H NMR (600 MHz, CDCl3)
d
10.64
2H), 3.90 (s, 3H), 3.85 (s, 6H), 3.56 (s, 3H).
(s, 1H), 7.42 (t, J¼8.4 Hz, 1H), 7.36 (t, J¼7.2 Hz, 2H), 7.33 (d, J¼7.2 Hz,
1H), 7.23 (d, J¼7.2 Hz, 2H), 7.01 (d, J¼8.4 Hz, 1H), 6.81 (d, J¼7.2 Hz,
1H), 3.49 (s, 3H).
4.4.13. Methyl 2-(dibenzo[b,d]furan-4-yl)-6-hydroxybenzoate
(4m). Yellow solid, 91% yield; mp: 106e107 ꢃC. (Lit.: 105e106 ꢃC).
1H NMR (600 MHz, CDCl3)
d
10.88 (s, 1H), 7.97 (d, J¼7.8 Hz, 1H),
4.4.2. Methyl 40-chloro-3-hydroxy-[1,10-biphenyl]-2-carboxylate
7.96e7.90 (m, 1H), 7.51 (dd, J¼12.0, 6.6 Hz, 2H), 7.43 (t, J¼7.8 Hz,
1H), 7.39 (d, J¼3.0 Hz, 2H), 7.35 (t, J¼7.2 Hz, 1H), 7.11 (d, J¼8.4 Hz,
1H), 6.98 (d, J¼7.2 Hz, 1H), 3.21 (s, 3H).
(4b). Yellow oil, 90% yield. 1H NMR (400 MHz, CDCl3)
d 10.73 (s,
1H), 7.40 (t, J¼8.0 Hz, 1H), 7.36e7.30 (m, 2H), 7.18e7.12 (m, 2H),
7.04e6.99 (m, 1H), 6.75 (dd, J¼7.6, 0.8 Hz, 1H), 3.52 (s, 3H).
4.4.14. Methyl 2-(benzofuran-2-yl)-6-hydroxybenzoate (4n). Yellow
solid, 87% yield; mp: 69e70 ꢃC. (Lit.: 69e70 ꢃC). 1H NMR (600 MHz,
4.4.3. Methyl 30-chloro-3-hydroxy-[1,10-biphenyl]-2-carboxylate
(4c). Yellow oil, 92% yield. 1H NMR (400 MHz, CDCl3)
d
10.75 (s,
CDCl3)
d
10.39 (s, 1H), 7.62 (d, J¼7.8 Hz, 1H), 7.50e7.44 (m, 2H), 7.30
1H), 7.41 (t, J¼8.0 Hz, 1H), 7.28 (dt, J¼10.0, 2.0 Hz, 2H), 7.24 (s, 1H),
7.09 (dt, J¼6.8, 2.0 Hz, 1H), 7.02 (d, J¼8.4 Hz, 1H), 6.76 (d, J¼7.6 Hz,
1H), 3.52 (s, 3H).
(t, J¼7.2 Hz, 1H), 7.28e7.23 (m, 1H), 7.10 (dd, J¼12.0, 7.8 Hz, 2H),
6.81 (s, 1H), 3.63 (s, 3H).
4.4.15. (E)-Methyl
2-hydroxy-6-(pent-1-en-1-yl)benzoate
11.11 (s, 1H),
4.4.4. Methyl 20-chloro-3-hydroxy-[1,10-biphenyl]-2-carboxylate
(4y). Yellow oil, 97% yield. 1H NMR (600 MHz, CDCl3)
d
(4d). Yellow oil, 95% yield. 1H NMR (600 MHz, CDCl3)
d
11.11 (s,
7.33 (t, J¼7.8 Hz, 1H), 6.94e6.86 (m, 3H), 6.05e5.79 (m, 1H), 3.95 (s,
3H), 2.20 (d, J¼7.2 Hz, 2H), 1.51 (dd, J¼14.4, 7.2 Hz, 2H), 0.97 (t,
J¼7.2 Hz, 3H).
1H), 7.46 (t, J¼7.8 Hz, 1H), 7.39 (d, J¼8.4 Hz, 1H), 7.31e7.24 (m, 2H),
7.21 (dd, J¼6.6, 1.8 Hz, 1H), 7.06 (d, J¼8.4 Hz, 1H), 6.71 (d, J¼7.2 Hz,
1H), 3.51 (s, 3H).
4.4.16. Methyl 3-hydroxy-5-methyl-[1,10-biphenyl]-2-carboxylate
4.4.5. Methyl 40-fluoro-3-hydroxy-[1,10-biphenyl]-2-carboxylate
(10a). White solid, 93% yield; mp: 87e88 ꢃC. 1H NMR (600 MHz,
(4e). Yellow oil, 94% yield. 1H NMR (400 MHz, CDCl3)
d
10.70 (s,
DMSO)
d
9.95 (s, 1H), 7.40 (d, J¼7.2 Hz, 1H), 7.39 (d, J¼7.8 Hz, 1H),
1H), 7.44e7.33 (m, 1H), 7.23e7.10 (m, 2H), 7.08e7.02 (m, 2H),
7.02e6.98 (m, 1H), 6.79e6.73 (m, 1H), 3.51 (s, 3H).
7.35 (d, J¼7.2 Hz, 1H), 7.34 (d, J¼7.2 Hz, 1H), 7.29 (d, J¼7.2 Hz, 2H),
6.73 (s, 1H), 6.66 (s, 1H), 3.51 (s, 3H), 2.28 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d 171.29, 161.58, 144.73, 144.62, 142.76, 127.97,
4.4.6. Methyl 3-hydroxy-40-methyl-[1,10-biphenyl]-2-carboxylate
127.41, 126.62, 123.87, 116.77, 109.16, 51.42, 21.54. EIMS: m/
z¼242.06 (Mþ). Anal. Calcd for (C15H14O3): C, 74.36; H, 5.82. Found:
C, 74.47; H, 5.67.
(4f). Yellow oil, 90% yield. 1H NMR (400 MHz, CDCl3)
d 10.55 (s,
1H), 7.38 (dd, J¼12.0, 4.4 Hz, 1H), 7.14 (dd, J¼18.8, 8.0 Hz, 4H),
7.02e6.92 (m, 1H), 6.84e6.72 (m, 1H), 3.50 (s, 3H), 2.39 (s, 3H).
4.4.17. Methyl 40-chloro-3-hydroxy-5-methyl-[1,10-biphenyl]-2-
4.4.7. Methyl 3-hydroxy-40-methoxy-[1,10-biphenyl]-2-carboxylate
carboxylate (10b). White solid, 93% yield; mp: 89e90 ꢃC. 1H NMR
(4g). Yellow oil, 97% yield. 1H NMR (400 MHz, CDCl3)
d
10.56 (s,
(600 MHz, DMSO)
d
10.02 (s, 1H), 7.46 (d, J¼8.4 Hz, 2H), 7.30 (d,
1H), 7.38 (t, J¼8.0 Hz, 1H), 7.19e7.13 (m, 2H), 6.97 (d, J¼8.4 Hz, 1H),
6.90 (t, J¼5.6 Hz, 2H), 6.79 (d, J¼7.6 Hz, 1H), 3.84 (s, 3H), 3.52 (s,
3H).
J¼8.4 Hz, 2H), 6.75 (s, 1H), 6.66 (s, 1H), 3.54 (s, 3H), 2.28 (s, 3H). 13
C
NMR (100 MHz, CDCl3)
d 170.49, 162.09, 149.78, 146.59, 145.33,
142.08, 128.94, 123.43, 122.69, 118.06, 108.44, 51.67, 21.54. EIMS: m/
z¼276.10 (Mþ). Anal. Calcd for (C15H13ClO3): C, 65.11; H, 4.74.
Found: C, 64.83; H, 4.99.
4.4.8. Methyl 3-hydroxy-40-(trifluoromethyl)-[1,10-biphenyl]-2-
carboxylate (4h). Yellow oil, 91% yield. 1H NMR (600 MHz, CDCl3)
d
10.81 (s, 1H), 7.63 (d, J¼7.8 Hz, 2H), 7.44 (t, J¼7.8 Hz, 1H), 7.35 (d,
4.4.18. Methyl 30-chloro-3-hydroxy-5-methyl-[1,10-biphenyl]-2-
J¼7.8 Hz, 2H), 7.06 (d, J¼8.4 Hz,1H), 6.76 (d, J¼7.2 Hz,1H), 3.49 (s, 3H).
carboxylate (10c). White solid, 90% yield; mp: 73e74 ꢃC. 1H NMR
(600 MHz, DMSO)
d 10.05 (s, 1H), 7.43 (s, 1H), 7.43 (s, 1H), 7.33 (s,
4.4.9. Methyl 40-acetyl-3-hydroxy-[1,10-biphenyl]-2-carboxylate
1H), 7.24 (dd, J¼4.98, 1.8 Hz, 1H), 3.54 (s, 3H), 2.29 (s, 3H). 13C NMR
(4i). Yellow solid, 95% yield; mp: 96e97 ꢃC. (Lit.: 98e99 ꢃC). 1H
(100 MHz, CDCl3) d 170.94, 161.80, 144.98, 144.52, 142.95, 133.21,

R.-Y. Qu et al. / Tetrahedron 71 (2015) 8123e8130
8129
128.60, 128.02, 126.69, 126.36, 123.71, 117.35, 108.83, 51.58, 21.54.
EIMS: m/z¼276.02 (Mþ). Anal. Calcd for (C15H13ClO3): C, 65.11; H,
4.74. Found: C, 65.22; H, 4.64.
(Mþ). Anal. Calcd for (C15H12Cl2O3): C, 57.90; H, 3.89. Found: C,
58.18; H, 3.79.
4.4.26. Methyl 40-chloro-20-fluoro-3-hydroxy-5-methyl-[1,10-biphen
yl]-2-carboxylate (10k). White solid, 93% yield; mp: 63e64 ꢃC. 1H
4.4.19. Methyl 20-chloro-3-hydroxy-5-methyl-[1,10-biphenyl]-2-
carboxylate (10d). White solid, 91% yield; mp: 74e75 ꢃC. 1H NMR
NMR (600 MHz, DMSO)
7.35e7.31 (m, 1H), 7.31e7.25 (m, 1H), 6.81 (s, 1H), 6.63 (s, 1H), 3.52
(s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3)
170.69, 161.99,
d
10.15 (s, 1H), 7.48 (d, J¼10.2 Hz, 1H),
(600 MHz, DMSO)
2H), 7.23e7.18 (m, 1H), 6.80 (s, 1H), 6.54 (s, 1H), 3.42 (s, 3H), 2.29 (s,
3H). 13C NMR (100 MHz, CDCl3)
170.85, 161.85, 145.27, 141.63,
d 10.19 (s, 1H), 7.51e7.45 (m, 1H), 7.39e7.31 (m,
d
d
160.27, 157.80, 145.36, 136.40, 133.56, 133.46, 130.58, 129.27, 129.11,
124.07, 123.95, 118.09, 115.33, 115.07, 109.37, 51.75, 21.49. EIMS: m/
z¼294.04 (Mþ). Anal. Calcd for (C15H12ClFO3): C, 61.13; H, 4.10.
Found: C, 61.35; H, 4.03.
141.25, 132.46, 129.62, 128.43, 128.04, 126.17, 123.62, 117.64, 109.36,
51.80, 21.57. EIMS: m/z¼276.01 (Mþ). Anal. Calcd for (C15H13ClO3):
C, 65.11; H, 4.74. Found: C, 64.96; H, 4.66.
4.4.20. Methyl 40-fluoro-3-hydroxy-5-methyl-[1,10-biphenyl]-2-
carboxylate (10e). White solid, 96% yield; mp: 52e53 ꢃC. 1H NMR
4.4.27. Methyl 3-hydroxy-30,40,50-trimethoxy-5-methyl-[1,10-biphen
yl]-2-carboxylate (10l). White solid, 92% yield; mp: 124e125 ꢃC. 1H
(600 MHz, DMSO)
7.27e7.20 (m, 2H), 6.73 (s, 1H), 6.65 (s, 1H), 3.53 (s, 3H), 2.28 (s, 3H).
13C NMR (100 MHz, CDCl3)
171.16, 163.05, 161.76, 160.61, 144.87,
d
9.99 (s, 1H), 7.32 (dd, J¼8.4, 5.4 Hz, 2H),
NMR (600 MHz, DMSO)
(s, 2H), 3.77 (s, 6H), 3.68 (s, 3H), 3.60 (s, 3H), 2.28 (s, 3H). 13C NMR
(100 MHz, CDCl3) 171.06, 161.20, 152.24, 144.50, 144.18, 138.30,
d 9.92 (s, 1H), 6.72 (s, 1H), 6.71 (s, 1H), 6.58
d
d
143.51, 138.77, 129.58, 129.51, 123.93, 117.03, 114.41, 114.20, 109.13,
51.53, 21.52. EIMS: m/z¼260.04 (Mþ). Anal. Calcd for (C15H13FO3): C,
69.22; H, 5.03. Found: C, 69.26; H, 4.93.
136.56, 123.39, 116.64, 109.15, 105.11, 60.65, 55.84, 51.50, 21.34.
EIMS: m/z¼332.12 (Mþ). Anal. Calcd for (C18H20O6): C, 65.05; H,
6.07. Found: C, 65.05; H, 6.03.
4.4.21. Methyl 3-hydroxy-40,5-dimethyl-[1,10-biphenyl]-2-
4.4.28. Methyl 2-(dibenzo[b,d]furan-3-yl)-6-hydroxy-4-
carboxylate (10f). White solid, 95% yield; mp: 126e127 ꢃC. 1H
methylbenzoate (10m). White solid, 94% yield; mp: 131e132 ꢃC.
NMR (600 MHz, DMSO)
J¼8.4 Hz, 2H), 6.70 (s, 1H), 6.63 (s, 1H), 3.53 (s, 3H), 2.32 (s, 3H), 2.27
(s, 3H). 13C NMR (100 MHz, CDCl3)
171.39, 161.47, 144.65, 144.62,
d
9.91 (s, 1H), 7.20 (d, J¼8.4 Hz, 2H), 7.18 (d,
1H NMR (600 MHz, DMSO)
d
10.09 (s, 1H), 8.18 (d, J¼7.2 Hz,1H), 8.13
(d, J¼7.8 Hz, 1H), 7.66 (d, J¼7.8 Hz, 1H), 7.51 (d, J¼8.4 Hz, 1H), 7.43
(dd, J¼16.2, 7.8 Hz, 2H), 7.36 (d, J¼6.6 Hz, 1H), 6.85 (s, 2H), 3.34 (s,
d
139.77, 136.23, 128.15, 127.89, 123.98, 116.56, 109.22, 51.45, 21.55,
21.09. EIMS: m/z¼256.12 (Mþ). Anal. Calcd for (C16H16O3): C, 74.98;
H, 6.29. Found: C, 74.72; H, 6.07.
3H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 171.11, 161.71, 155.87,
153.25, 145.24, 138.16, 127.13, 126.99, 126.62, 124.31, 123.99, 123.28,
122.64, 122.54, 120.51, 119.43, 117.69, 111.53, 109.89, 51.48, 21.56.
EIMS: m/z¼332.07 (Mþ). Anal. Calcd for (C21H16O4): C, 75.89; H,
4.85. Found: C, 75.73; H, 4.74.
4.4.22. Methyl 3-hydroxy-40-methoxy-5-methyl-[1,10-biphenyl]-2-
carboxylate (10g). White solid, 90% yield; mp: 77e78 ꢃC. 1H NMR
(600 MHz, DMSO)
J¼8.4 Hz, 2H), 6.68 (s, 1H), 6.62 (s, 1H), 3.77 (s, 3H), 3.54 (s, 3H), 2.27
(s, 3H). 13C NMR (100 MHz, CDCl3)
171.43, 161.48, 158.47, 144.62,
144.22, 135.11, 129.11, 123.98, 116.44, 112.85, 109.24, 55.11, 51.52,
21.52. EIMS: m/z¼272.08 (Mþ). Anal. Calcd for (C16H16O4): C, 70.57;
H, 5.92. Found: C, 70.34; H, 5.71.
d
9.88 (s, 1H), 7.22 (d, J¼8.4 Hz, 2H), 6.95 (d,
4.4.29. Methyl 2-(benzofuran-2-yl)-6-hydroxy-4-methylbenzoate
(10n). Yellow solid, 88% yield; mp: 80e81 ꢃC. 1H NMR (600 MHz,
d
DMSO)
d
10.11 (s, 1H), 7.67 (d, J¼7.8 Hz, 1H), 7.58 (d, J¼8.4 Hz, 1H),
7.33 (t, J¼7.2 Hz, 1H), 7.27 (t, J¼7.2 Hz, 1H), 7.20 (s, 1H), 7.15 (s, 1H),
6.79 (s, 1H), 3.81 (s, 3H), 2.32 (s, 3H). 13C NMR (150 MHz, CDCl3)
d
170.58, 161.24, 156.40, 154.87, 145.02, 132.02, 128.69, 124.07,
123.81, 122.66, 120.88, 118.80, 110.74, 109.35, 103.67, 52.23, 21.44.
EIMS: m/z¼282.10 (Mþ). Anal. Calcd for (C17H14O4): C, 72.33; H,
5.00. Found: C, 72.49; H, 4.89.
4.4.23. Methyl 3-hydroxy-5-methyl-40-(trifluoromethyl)-[1,10-biphen
yl]-2-carboxylate (10h). White solid, 97% yield; mp: 112e113 ꢃC. 1H
NMR (600 MHz, DMSO)
(d, J¼7.8 Hz, 2H), 6.79 (s, 1H), 6.71 (s, 1H), 3.54 (s, 3H), 2.30 (s, 3H).
13C NMR (100 MHz, CDCl3)
170.87, 162.00, 146.64, 145.18, 143.10,
d
10.09 (s, 1H), 7.77 (d, J¼8.4 Hz, 2H), 7.50
4.4.30. (E)-Methyl 2-hydroxy-4-methyl-6-(pent-1-en-1-yl)benzoate
d
(10o). Colorless oil, 91% yield. 1H NMR (600 MHz, DMSO)
d 9.82 (s,
128.99, 128.67, 128.40, 125.63, 124.37, 124.34, 123.71, 122.93,
117.60, 108.80, 51.56, 21.52. EIMS: m/z¼310.06 (Mþ). Anal. Calcd for
(C16H13F3O3): C, 61.94; H, 4.22. Found: C, 62.07; H, 4.09.
1H), 6.84 (s, 1H), 6.56 (s, 1H), 6.23 (d, J¼16.1 Hz, 1H), 6.20e6.14 (m,
1H), 3.76 (s, 3H), 2.22 (s, 3H), 2.11 (q, J¼7.2 Hz, 2H), 1.46e1.34 (m,
2H), 0.89 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 171.70,
162.21, 145.15, 141.56, 132.44, 131.00, 121.02, 116.39, 107.77, 51.88,
34.95, 22.21, 21.51, 13.55. EIMS: m/z¼234.13 (Mþ). Anal. Calcd for
(C14H18O3): C, 71.77; H, 7.74. Found: C, 71.69; H, 7.63.
4.4.24. Methyl 40-acetyl-3-hydroxy-5-methyl-[1,10-biphenyl]-2-
carboxylate (10i). White solid, 96% yield; mp: 115e116 ꢃC. 1H
NMR (600 MHz, DMSO)
(d, J¼8.4 Hz, 2H), 6.78 (s, 1H), 6.70 (s, 1H), 3.54 (s, 3H), 2.60 (s, 3H),
2.30 (s, 3H). 13C NMR (100 MHz, CDCl3)
197.66, 170.76, 161.73,
d
10.06 (s, 1H), 7.99 (d, J¼8.4 Hz, 2H), 7.43
Acknowledgements
d
147.78, 144.95, 143.26, 135.26, 128.21, 127.50, 123.48, 117.40, 108.69,
51.48, 26.48, 21.47. EIMS: m/z¼284.09 (Mþ). Anal. Calcd for
(C17H16O4): C, 71.82; H, 5.67. Found: C, 71.89; H, 5.72.
The research was supported in part by the National Natural
Science Foundation of China (No. 21172091, 21272091, 21372093).
References and notes
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