Base promoted regioselective aromatization for the preparation of substituted 3-hydroxybenzene dicarboxylate

Article abstract of DOI:10.1002/jhet.4024

A new convenient base promoted aromatization process has been developed to prepare substituted 3-hydroxybenzene dicarboxylate using commercially available materials. In particular, regioselectivity will occur for substrates with mono-substitution at 5- or

Full text of DOI:10.1002/jhet.4024

Received: 29 January 2020
DOI: 10.1002/jhet.4024
Revised: 3 May 2020
Accepted: 4 May 2020
A R T I C L E
Base promoted regioselective aromatization for the
preparation of substituted 3-hydroxybenzene dicarboxylate
Weihang Guo1 | Xianheng Wang1 | Changkuo Zhao1
| Yuhe Wang2
1Department of Medicinal Chemistry,
Abstract
Zunyi Medical University, Zunyi, China
2Department of Pharmacy, Zunyi Medical
University Affiliated Hospital, Zunyi,
China
A new convenient base promoted aromatization process has been developed to
prepare substituted 3-hydroxybenzene dicarboxylate using commercially avail-
able materials. In particular, regioselectivity will occur for substrates with
mono-substitution at 5- or 6-position. This new process provides less reaction
steps and moderate yields, and can be used extensively in the synthesis of
other substrates to functionalize phenol esters.
Correspondence
Changkuo Zhao, Department of Medicinal
Chemistry, Zunyi Medical University,
No. 06, Xuefu West Road, Zunyi 563003,
Guizhou, China.
Email: zck7103@hotmail.com
Yuhe Wang, Department of Pharmacy,
Zunyi Medical University Affiliated
Hospital, 139 Dalian Road, Zunyi, China.
Email: 1149076068@qq.com
Funding information
Doctoral Scientific Research Foundation
of Zunyi Medical University, Grant/Award
Numbers: [2013]F-633, [2014]F-697;
Guizhou Administration of Traditional
Chinese Medicine, Grant/Award Number:
QZYYZD-2019-05; Joint fund project of
Science and Technology Foundation of
Zunyi City, Grant/Award Number:
ZunyiKeHe HZ [2019]26; Public Bidding
Project Foundation of Zunyi Medical
University, Grant/Award Number: [2013]
F-680; Science and Technology
Foundation of Guizhou Province, Grant/
Award Number: QianKeHe ZhiCheng
[2019]2829
Phenolic acid is naturally found in different plants, mainly
including gallic acid, phloroglucinol compounds, Salvia
miltiorrhiza, chlorogenic acid, quinic acid derivatives, tea
polyphenol compounds, ellagic acid enamel, polyflavanol
polyphenols, and phenylpropanoids. Phenolic acids
have strong pharmacological effects in anti-oxidation,
antibacterial, anti-inflammatory, and hypolipidemic
effects, and have attracted many medicinal chemists to
participate in their total synthesis, structure activity rela-
tionship (SAR), and pharmacology research. However,
there is little literature to describe the synthesis of poly-
phenoic acids.[1–3]
Tilivalline is a metabolite from Klebsiella oxytoca that
has been shown to be a cytotoxin and is a key event caus-
ing antibiotic-associated hemorrhagic colitis. Tilivalline
shows cytotoxic to mouse leukemia L1210 cells owing to
its unique structure of pyrrolo[1,4]benzodiazepine and
indole framework.[4]
In 1998, Nagasaka et al first developed a new route
for the synthesis of tilivalline, which was obtained from
J Heterocyclic Chem. 2020;1–6.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
GUO ET AL.
commercial available diethyl acetylenedicarboxylate and
diethyl furan-3, 4-dicarboxylate.[5] As a key building block,
2, 3-dicarboxylate phenol plays an important role in this
overall synthesis. This scaffold can be easily prepared from
cycloaddition product (D-A cycloaddition) by Lewis acid
BF3 promoted rearrangement in a yield of up to 81%
(Scheme 1).
phenol (1), inspired by the successful synthesis of
2, 3-dicarboxylic phenol. We envisioned that Diels-Alder
cycloaddition reaction of diethyl but-2-ynedioate and
diethyl furan-3, 4-dicarboxylate (2) and continuous aro-
matization reaction promoted by Lewis acid could also
give the title compound. The proposed synthetic route is
shown in Scheme 3:
In order to expand the product pipeline of these com-
pounds, more tilivalline analogs are needed for the high
throughput screening (HTS). In the synthesis of these
derivatives, substituted 3-hydroxybenzene dicarboxylate
(1) (Figure 1) is highly desirable as an important building
block. In this article, we described a convenient method
to the synthesis of phenolic esters from the commercial
available material.
We then first attempt to synthesize tetraethyl
norcantharidinate 3a (R1 = R2 = CO2Et) from diethyl
but-2-ynedioate and diethyl furan-3, 4-dicarboxylate (2a,
R1 = R2 = CO2Et) by D-A [4 + 2] cycloaddition
reaction.[7–9] Several solvents, temperature, and times
have been optimized. The optimum reaction results
showed that the reaction was carried out at 124ꢀC for
20 hours in a sealed tube using toluene as solvent, and
the optimum reaction yield is 51.4% (Table 1).
1 | RESULTS AND DISCUSSION
Br
NBS
Na, CH3OH
In 2016, Kenta Kanosue et al developed a four-step syn-
thesis route for the preparation of 3-hydroxypyromellitic
acid from 1,2,4-trimethylbenzene[6] (Scheme 2). After
methylation in Na/CH3OH and bromination with NBS,
bromodurene was obtained smoothly in a low yield (30%).
In the following, bromodurene was oxidized with potas-
sium permanganate in water to give 3-bromopyromellitic
acid, which was finally treated with catalytic copper pow-
der under the condition of sodium hydrate and sodium
acetate in water to afford 3-hydroxypyromellitic acid in a
yield of 74% for the last two steps. However, the tedious
reaction steps, low yields (22% in total) and harsh reaction
conditions limit their further use in industrial production.
Based on of this study, a same synthetic strategy can
also be employed for the substituted 2, 3-dicarboxylic
30% (for two steps)
OH
Br
HOOC
HOOC
COOH
COOH
HOOC
HOOC
COOH
COOH
AcONa
KMnO4, H2O
pyridine
Cu
74% (for two steps)
SCHEME 2 Original route to synthesis of phenolic acid
OH
R1
R2
COOEt
COOEt
1
FIGURE 1 Chemical structure of the building block 1
O
OH
OBn
CO2Et
CO2Et
O
BF3.Et2O
CO2Et
EtO2C
EtO2C
CO2Et
CO2Et
BnBr, K2CO3
toluene, 80oC, 3d
83%
60oC, 4h, 81%
CO2Et
OBn
OBn
OBn
OBn
H
N
O
O
1) LiOH.H2O, rt, 17h
2) KOH,50oC, 15h
CO2H
CO2H
1) TMSN3
Ac2O, 19h
O
2) EtOH, 10 min
O
72%(over 3 steps)
O
O
OBn
Cbz
OH
H
H
N
O
H
OBn
Cbz
N
O
H
N
1) LiHMDS, 90min
2) CbzCl, 2h, 92%
NaBH4
82%
L-proline, DMSO
81%(over 2steps)
N
N
N
O
H
N
O
O
H
N
OBn
Cbz
OBn
indole, AcOH
78%
Pd/C, H2
38%
N
H
H
N
H
(Tilivalline)
N
SCHEME 1 Total synthesis
N
O
of tilivalline

GUO ET AL.
3
OH
SCHEME 3 Synthetic strategy of
phenolic acid
O
O
R1
R2
O
CO2Et
CO2Et
R1
R1
R2
COOEt
COOEt
O
R2
2
O
1
3
O
TABLE 1
Optimization of Diels-Alder reaction
TABLE 3
Condition optimization for base promoted
O
aromatization reaction
O
O
O
EtOOC
COOEt
CO2Et
OH
EtOOC
EtOOC
COOEt
EtOOC
EtOOC
COOEt
COOEt
O
2a
O
base
O
3a
O
O
CO2Et
O
COOEt
Entry
Solvent
T/ꢀC
Time (h)
Yield/%
Condition
LiOH
Solvent
C2H5OH
H2O
T/ꢀC
RT
Time/h
48
Yield
39.3
1
2
3
4
5
6
DCM
RT
24
24
24
24
24
20
Trace
<5%
Trace
28.9
DCM
Reflux
LiOH
RT
48
Destroyed
40.7
Toluene
Toluene
Toluene
Toluene
RT
LiOH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
40
48
Reflux
NaOH
NaOH
NaOH
K2CO3
K2CO3
RT
24
45.3
Sealed tube, 100
Sealed tube, 124
41.6
40
24
58.7
51.4
Reflux
RT
24
Destroyed
40.6
48
TABLE 2
Aromatization rearrangement under acid condition
40
48
38.9
O
O
OH
O
EtOOC
EtOOC
COOEt
COOEt
O
BF3.Et2O
X
O
60oC-reflux
O
1a
3a
O
O
58.7%. The detailed optimization results were shown in
Table 3:
Condition
BF3.Et2O
BF3.Et2O
TFA
Solvent
DCM
DCM
DCM
H2O
T/ꢀC
Time/h
Yield
The same methodology was further explored to syn-
thesize phenol derivatives containing different functional
group 1a-d in a moderate to good yield (Table 4). How-
ever, only 2-furancarboxylic acid gives no desired product
1e in the same condition.
The formation of 3 from 1 is most likely via a SN2'
mechanism (Scheme 4). Thus, the ring opening is taking
place by the attack the OH group to form an oxygen
anion. Oxygen anion will rapidly capture proton to form
hydroxyl group. Finally, H2O was lost to complete the
aromatization.
In particular, when only one position was occupied in
5- or 6-position, regioisomers will theoretically occur.
However, for this rearrangement reaction, only one reg-
ioisomer was obtained (Scheme 5). According to 1H NMR
spectrum of compound 1c (Figure 2), the coupling con-
stants of the two protons in 7.68 (d, J = 8.1 Hz, 1H) and
6.84 (d, J = 8.1 Hz, 1H) clearly indicate that the two pro-
tons are in the ortho position instead of the meta position.
RT
48
48
24
24
24
No reaction
No reaction
No reaction
No product
Decomposed
Reflux
Reflux
RT
HCl (36%)
HCl (36%)
H2O
Reflux
With the intermediate 3a in hand, we then proceed to
the Lewis acid-catalyzed aromatization reaction.[2,10,11]
Unfortunately, no reaction occurred when the intermedi-
ate 3a was treated with BF3.Et2O under reflux condition
(Table 2). Other acids, such as TFA and HCl have been
tried, but no desired product (1a) was obtained.
Considering the presence of epoxide moiety in the
structure which could undergo a ring opening reaction
not only in the acid but also under the base condition,
we therefore intend to use a base to promote the aro-
matization. Thus, different bases, solvents and tempera-
ture conditions have been tried for this step. To our
surprise, the aromatization reaction proceeds well
under all basic conditions and the desired compound
can be obtained smoothly in a moderate yield. In par-
ticular, when NaOH was used as the base and EtOH as
solvent, the yield of aromatization can be as high as
2 | SUMMARY
We developed a new convenient base promoted aromati-
zation protocol to prepare different phenol derivatives

4
GUO ET AL.
TABLE 4
Data for base promoted aromatization reaction
OH
O
O
R1
R2
O
CO2Et
R1
R1
R2
COOEt
COOEt
O
R2
NaOH
EtOH
2
O
CO2Et
1
3
O
Entry
R1
R2
Yield (3)
51.4% (3a)
84% (3b)
66% (3c)
44.7% (3d)
46% (3e)
Yield (1)
1
2
3
4
5
CO2Et
CO2Et
58.7% (1a)
90% (1b)
82% (1c)
50% (1d)
— (1e)
H
H
H
H
H
Br
CH2OH
CO2H
SCHEME 4 Proposed aromatization
mechanism
OH
O
O
O
OH
O
O
O
O
O
O
O
O
OH
R
H
O
R
R
O
OH
3
O
OH
O
O
OH
O
-H2O
O
O
O
O
R
R
1
OH
O
OH
Mass spectra were run on a Waters UPLC-MS instru-
ment. TLC plates (GF 254) were bought from Branch
Qingdao Haiyang Chemical Plant.
R1
COOEt
COOEt
O
O
O
R1
NaOH
EtOH
1
OH
O
3
3.1 | A typical synthesis for tetraethyl
7-oxabicyclo[2.2.1]hepta-2,5-diene-
2,3,5,6-tetracarboxylate (3a)
O
COOEt
COOEt
R1
X
4
A suspension of diethyl acetylenedicarboxylate (15.0 g,
14.1 mL, 88 mmol), Diethyl furan-3, 4-dicarboxylate
(6.84 g, 7.3 mL, 100 mmol, 1.2 eq) and 50 mL dry toluene
was charged in a sealed tube. The light-yellow reaction
mixture was heated to 120ꢀC for 4 hours. After being
cooled to the room temperature, the solvent was removed
completely under vacuum and the crude product was
purified by column chromatography, eluting with PE:
EA = 10:1 to give the title compound (17.4 g, 51.4%) as a
white solid. M.p. 114.8ꢀC-115.6ꢀC; Rf = 0.26 (PE:
SCHEME 5 Regioselectivity in aromatization reaction
using the commercial available material. In particular,
this new process provides a less reaction step and a better
yield verse the original synthetic approach and will be
extend to other substrate for the functional phenol ester.
3 | EXPERIMENTAL SECTION
1
EA = 10:1). H NMR (400 MHz, CDCl3) δ = 5.91 (d,
Melting points were determined by a Mettler Toledo
FP62 melting point apparatus and are uncorrected. H
NMR spectra were recorded at 400 MHz on a Varian
Unity nova 400 NMR spectrometer using tetra-
methylsilane (TMS) as an internal standard, and 13C
NMR spectra were recorded at 100 MHz respectively.
J = 1.1 Hz, 2H), 4.31-4.25 (m, 9H), 1.31 (t, J = 7.1 Hz,
12H). 13C NMR (100 MHz, CDCl3) δ = 161.71, 151.27,
87.15, 61.74, 14.02.
1
Compound 3b[5] (84%) as a yellow liquid, Rf = 0.32
1
(PE: EA = 1:1); H NMR (400 MHz, CDCl3) δ = 7.16 (s,
2H), 5.62 (s, 2H), 4.21 (q, J = 7.1 Hz, 4H), 1.26 (t,

GUO ET AL.
5
FIGURE 2 1H NMR spectrum for
compound 1c
J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ = 163.01,
152.62, 143.17, 109.99, 85.01, 61.39, 14.05.
using CH2Cl2: CH3OH = 5:1 as eluent to afford the title
compound (117.5 mg, 58.7%) as a red solid. m.p.124.6ꢀC-
1
Compound 3c (66%) as a yellow oil, Rf = 0.52(PE:
EA = 4:1); 1H NMR (400 MHz, CDCl3) δ = 7.09 (s, 1H), 5.63
(s, 1H), 5.47 (s, 1H), 4.31-4.25 (m, 4H), 1.31 (t, J = 6.9 Hz,
6H).13C NMR (100 MHz, CDCl3) δ =162.57, 162.11, 152.25,
151.19, 139.02, 137.05, 89.60, 87.00, 62.99, 61.65, 14.07.
Compound 3d (44.7%) as a clear oil. Rf = 0.26 (PE:
126.4ꢀC. Rf = 6.4 (CH2Cl2: CH3OH = 10:1). H NMR
(400 MHz, DMSO-d6) δ = 6.61 (s, 1H), 3.97 (dtt, J = 8.3,
5.2, 1.3 Hz, 8H), 1.22-1.07 (m, 12H). 13C NMR (100 MHz,
DMSO-d6) δ = 167.58, 165.33, 120.18, 119.76, 112.24,
59.03, 58.18, 14.95, 14.58. IR (KBr) ν (cm−1) = 3414, 3237,
2971, 2934, 2848, 1634, 1618, 1505, 1417, 1379, 1360,
1232, 1176, 1119, 1026, 941, 820.
1
EA = 2:1); H NMR (400 MHz, CDCl3) δ = 7.24 (s, 1H),
4.55-4.28 (m, 2H), 4.28-4.18 (m, 2H), 4.13-4.05 (m, 2H), 3.73
(dt, J = 14.2, 7.4 Hz, 1H), 3.52 (dd, J = 14.6, 7.3 Hz, 1H),
1.29 (t, J = 6.9 Hz, 3H), 1.23 (t, J = 5.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ = 164.12, 162.63, 158.38, 152.49,
152.18, 135.74, 86.09, 85.44, 61.81, 61.49, 59.33, 14.07.
Compound 3e (46%) as a white solid, Rf = 0.61 (PE:
EA = 3:1); m.p. 95.6.2ꢀC-96.8ꢀC; 1H NMR (400 MHz,
CDCl3) δ = 5.91 (s,1H), 4.48-4.06 (m,3H), 1.30 (t,
J = 7.1 Hz,3H); 13C NMR (100 MHz, CDCl3) δ = 161.69,
151.25, 87.13, 61.72, 14.01.
Compound 1b[5] (90%) as a yellow liquid, Rf = 0.47
1
(PE: EA = 5:1); H NMR (400 MHz, CDCl3) δ = 10.72 (s,
1H), 7.40 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.89
(d, J = 7.4 Hz, 1H), 4.33 (dt, J = 17.7, 7.2 Hz, 4H), 1.33 (t,
J = 7.2 Hz, 8H). 13C NMR (101 MHz, CDCl3) δ = 168.78,
161.08, 161.05, 139.68, 134.30, 134.21, 119.39, 118.73,
62.01, 61.44, 13.94, 13.68.
Compound 1c (82%) as a yellow liquid, Rf = 0.47 (PE:
1
EA = 5:1); H NMR (400 MHz, CDCl3) δ = 11.16 (s, 1H),
7.68 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.37 (q,
J = 7.1 Hz, 2H), 4.33-4.27 (m, 2H), 1.32 (dt, J = 7.1,
3.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ = 168.61,
167.96, 157.41, 148.49, 137.43, 134.79, 119.61, 113.64,
62.77, 61.81, 14.08, 13.78.
3.2 | A typical synthesis for tetraethyl
2,3,5,6-tetracarboxylate phenol (1a)
Compound 1d (50%) as a yellow liquid, Rf = 0.47 (PE:
1
To a 25 mL round flask, a mixture of compound 3a
(200 mg, 0.52 mmol) and NaOH (102 mg, 4.24 mmol) in
ethanol (10 mL) was added in sequence. The reaction
mixture was stirred and heated at 40ꢀC. After the con-
sumption of starting material (by TLC), the reaction was
then cooled to room temperature. After removal of the
solvent, the residue was diluted in DCM and neutralized
with 1 N HCl. The organic layer was separated and the
aqueous layer was extracted with DCM (20 mL × 2). The
combined organic layers were dried over MgSO4. The sol-
vent was distilled completely under reduced pressure,
and the residue was purified by column chromatography
EA = 5:1); H NMR (400 MHz, CDCl3) δ = 10.74 (s, 1H),
7.16 (s, 1H), 6.83, 6.96 (s, 1H), 5.21 (s, 1H), 4.60 (s, 1H), 4.26
(dd, J = 17.2, 7.7 Hz, 2H), 4.17 (t, J = 6.7 Hz, 2H), 1.26 (t,
J = 7.3 Hz, 3H), 1.22 (t, J = 5.3 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ = 162.63, 161.60, 145.72, 144.60, 142.13, 116.68,
111.09, 87.88, 83.40, 71.34, 61.60, 29.67, 14.11.
ACKNOWLEDGMENTS
The authors would like to thank for the NMR and MS anal-
ysis from Dr Jianyong Zhang. Financial support came from
Joint fund project of Science and Technology Foundation of
Zunyi City (ZunyiKeHe HZ [2019]26), Guizhou

6
GUO ET AL.
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Administration of Traditional Chinese Medicine (QZYYZD-
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cal University ([2013]F-680), Doctoral Scientific Research
Foundation of Zunyi Medical University ([2013]F-633 and
[2014]F-697), Science and Technology Foundation of Gui-
zhou Province (QianKeHe ZhiCheng [2019]2829).
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The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
Changkuo Zhao designed the study. Weihang Guo prepared
the sample together. Xianheng Wang was responsible for
the test in vitro. Yuhe Wang collected and analyzed the
data. All authors gave the approval for the final submission.
[10] H. S. I. Chao, G. A. Berchtold, J. Am. Chem. Soc. 1981,
103, 898.
[11] P. Holy, P. Sehnal, M. Tichy, J. Zavada, I. Cisarova, Tetrahe-
dron Asymmetry 2004, 15, 3805.
DATA AVAILABILITY STATEMENT
Data are available as part of the electronic supplementary
material.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
ETHICS STATEMENT
No need for the animal ethics permission from local
agent. Since no animal was used in this project.
ORCID
How to cite this article: Guo W, Wang X,
Zhao C, Wang Y. Base promoted regioselective
aromatization for the preparation of substituted 3-
hydroxybenzene dicarboxylate. J Heterocyclic
Chem. 2020;1–6. https://doi.org/10.1002/jhet.4024
Changkuo Zhao https://orcid.org/0000-0001-7973-6333
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