Ethylene glycol as hydrogen donor for the syntheses of thymol analogues via hydrolysis of 4-methylcoumarins

Article abstract of DOI:10.1016/j.tetlet.2012.09.122

Treatment of 4-methylcoumarins with potassium hydroxide in ethylene glycol resulted in the formation of the 'normal' 2-isopropenylphenols and/or the 'abnormal' 2-isopropylphenols depending on the nature of the substrates. The solvent ethylene glycol was b

Full text of DOI:10.1016/j.tetlet.2012.09.122

Tetrahedron Letters 53 (2012) 6755–6757
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Tetrahedron Letters
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Ethylene glycol as hydrogen donor for the syntheses of thymol analogues
via hydrolysis of 4-methylcoumarins
⇑
Junbiao Chang , Shuyang Wang, Zhenhua Shen, Gang Huang, Yueteng Zhang, Jing Zhao, Changwei Li,
⇑
Fangfang Fan, Chuanjun Song
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2012
Revised 20 September 2012
Accepted 26 September 2012
Available online 11 October 2012
Treatment of 4-methylcoumarins with potassium hydroxide in ethylene glycol resulted in the formation
of the ‘normal’ 2-isopropenylphenols and/or the ‘abnormal’ 2-isopropylphenols depending on the nature
of the substrates. The solvent ethylene glycol was believed to be the hydrogen donor for double-bonding
reduction where 2-isopropylphenol was produced.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Thymol
4-Methylcoumarin
Ethylene glycol
Double-bond reduction
Thymol 1 ( Fig. 1) is a naturally occurring phenolic terpene
which showed antiseptic, antioxidant, and antibacterial activ-
ity.1–6 Upon hydrogenation, thymol yields menthol, another
important natural terpenoid with analgesic, antiseptic, and antimi-
crobial properties.7–9 The most straightforward method for the
synthesis of thymol is a Lewis acid catalyzed isopropylation of
m-cresol with propylene or iso-propanol.10–17 Recently, an ionic li-
quid catalyzed18 or microwave-assisted19 process has also been de-
scribed. However, this approach is always associated with the
production of isomer 2 where the alkylation has occurred at the
position para to the hydroxy group, as well as the di-alkylated
by-products 3 and 4. In 2000, Rao20 and co-workers reported that
hydrolysis of 4,7-dimethylcoumarin, followed by hydrogenation of
the resulting double-bond, gave thymol regioselectively in 51%
overall yield. In a project searching for anti-obesity drug,21 we
need to get access to thymol and its analogues. This promoted us
to re-visit Rao’s route. We now disclose the full detail of our find-
ings during the hydrolysis of 4-methylcoumarin derivatives.
As shown in Scheme 1, we first studied the hydrolysis of 4,7-
dimethylcoumarin 5, which itself was obtained by Pechmann
condensation22 between m-cresol and ethyl acetoacetate. The reac-
tion was complete within 1 h by treatment of 5 with KOH in reflux-
ing ethylene glycol. Apart from 2-isopropenyl-5-methylphenol 6 in
90% yield, a minor product was also isolated. Surprisingly, the
structure was confirmed to be thymol 1 resulting from reduction
of the double-bond in 6.
Next, hydrolysis of other 4-methylcoumarins was explored and
the results were collected in Table 1.
As shown in Table 1, hydrolysis of 4,6-dimethylcoumarin gave
2-isopropenyl-4-methylphenol 7a in 87% isolated yield, together
with a small amount of p-cresol 7b, which probably was formed
by retro-Pechmann reaction (entry 1). When an extra methyl group
was introduced into the 7-position, that is, hydrolysis of 4,6,7-trim-
ethylcoumarin resulted in the formation of a mixture of 2-isopro-
penyl-4,5-dimethylphenol 8a and 4-methylthymol 8b in a ratio
of 0.56:1 according to 1H NMR integration of the crude products
(entry 2). 8a and 8b could be isolated in 20% and 34% yields, respec-
tively, after careful chromatography. On the other hand, hydrolysis
of 4,6,8-trimethylcoumarin mainly gave 2-isopropenyl-4,
6-dimethylphenol 9a (entry 3). Only a trace amount (3%) of
propylphenol 9b was obtained. Hydrolysis of other substituted
4-methylcoumarins revealed that the outcome of the products was
dependent on the substrates. In particular, an electron-donating
OH
OH
OH
OH
⇑
1
Corresponding authors.
E-mail addresses: changjunbiao@zzu.edu.cn (J. Chang), chjsong@zzu.edu.cn
2
3
4
(C. Song).
Figure 1. Possible products for the isopropylation of m-cresol.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.122

6756
J. Chang et al. / Tetrahedron Letters 53 (2012) 6755–6757
O
O
OH
OH
OH
O
O
KOH
KOH
+
DMSO-H2O
reflux, 1 h
100%
ethylene glycol
reflux, 1 h
6
5
5
6
1
, 8%
, 90%
Scheme 2.
Scheme 1. Hydrolysis of 4,7-dimethylcoumarin.
group at the 7-position of the coumarin precursor will facilitate the
formation of 2-isopropylphenol derivatives. While hydrolysis of
7-methoxy-4-methylcoumarin (entry 4) and 6,7-methylenedioxy-
4-methylcoumarin (entry 6) gave the corresponding 2-isopropyl-
phenols (10a and 12a), hydrolysis of 6-methoxy-4-methyl-couma-
rin (entry 5) resulted mainly in the formation of 2-isopropenyl-4-
methoxyphenol 11a. In the former cases, the only other products
(10b and 12b) were those resulting from retro-Pechmann reaction.
Hydrolysis of 4-methyl-7-nitrocoumarin gave a variety of prod-
ucts. The 1H NMR of the crude products clearly indicated the for-
mation of 2-isopropenyl-5-nitrophenol 13 which could be
isolated in low yield (10%), while no trace of 2-isopropyl-5-nitro-
phenol could be identified.
OH
OH
KOH
ethylene glycol
reflux, 2 h
80%
6
1
KOH
ethylene glycol
reflux, 2 h
14
15
Scheme 3.
(10:1) was used as a solvent, isopropenylphenol 6 was obtained
exclusively (Scheme 2), which indicated that ethylene glycol was
the hydrogen donor for double-bond reduction.
Finally, it was found that treatment of 2-isopropenylphenol 6
with KOH in refluxing ethylene glycol for 2 h also resulted in the
formation of thymol 1 in 80% isolated yield (Scheme 3). However,
The reasons for double-bond reduction were then explored,
using hydrolysis of 4,7-dimethylcoumarin as an example. The
results persist running the reaction either under strict argon atmo-
sphere or open to air, which always gave a mixture of isopropenyl-
phenol 6 and thymol 1. However, when a mixture of DMSO/H2O
Table 1
Hydrolysis of 4-methylcoumarins in ethylene glycol
Entry
4-Methylcoumarins
Product(s)/Yield
O
O
OH
OH
+
1
a
a
7a
7b
, 8%
, 87%
O
O
OH
OH
2
3
8b, 64%b
OH
8a, 36%b
OH
O
O
b
9a, 97%b
, 3%
9b
MeO
MeO
O
O
O
O
MeO
OH
MeO
OH
+
4
5
6
10a, 34%a
10b, 37%a
OH
OH
+
MeO
MeO
b
11b,5%b
OH
11a,
95%
O
O
OH
O
O
O
O
O
O
+
12a, 17%a
O2N
OH
12b, 53%a
O2N
O
O
7
13, 10%a
aIsolated yields.
bYields were determined based on integrations of the 1H NMR of the crude products. No other products were evident by 1H
NMR.

J. Chang et al. / Tetrahedron Letters 53 (2012) 6755–6757
6757
O-
O
O
O
O
I
O
HO-
R
R
R
R
O-
O-
OH
II
OH
O
O
HO-
III
IV
R
O-
O-
O-
O
R
R
H
OR'
R
H
H
V
VI
VII
VIII
HO-
OH
HO-
O-
O
H
R
OH
OH
IX
Scheme 4. Proposed mechanism.
under identical conditions, 2-isopropyltoluene 15 could not be ob-
tained from 2-isopropenyltoluene 14.
References and notes
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in equilibrium through enol–keto tautomerization. This equilib-
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In conclusion, we have disclosed that hydrolysis of coumarin
derivative will give 2-isopropenylphenol or 2-isopropylphenol
depending on the nature of the substrate. The solvent ethylene gly-
col was believed to be the hydrogen donor where 2-isopropylphe-
nol was produced.
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Outstanding Young Scholarship to J.C., #30825043; Young
Scholarship to C.S., #20902085) for the financial support.
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