Facile conversion of para-benzoquinones to para-alkoxyphenols with primary/secondary alcohols and amberlyst-15: A process showing novel reducing property of such alcohols

Article abstract of DOI:10.1016/j.tetlet.2013.10.119

A new efficient methodology has been developed for the synthesis of para-alkoxyphenols, an important group of anti-melanoma compounds, by heating alcoholic solutions of para-benzoquinones in the presence of amberlyst-15. The most notable feature here is the behaviour of the used primary or secondary alcohol as an effective reducing agent.

Full text of DOI:10.1016/j.tetlet.2013.10.119

Tetrahedron Letters 55 (2014) 86–89
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile conversion of para-benzoquinones to para-alkoxyphenols
with primary/secondary alcohols and amberlyst-15: a process
showing novel reducing property of such alcohols
⇑
Rina Mondal, Chayan Guha, Asok K. Mallik
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2013
Revised 24 October 2013
Accepted 26 October 2013
Available online 5 November 2013
A new efficient methodology has been developed for the synthesis of para-alkoxyphenols, an important
group of anti-melanoma compounds, by heating alcoholic solutions of para-benzoquinones in the pres-
ence of amberlyst-15. The most notable feature here is the behaviour of the used primary or secondary
alcohol as an effective reducing agent.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
para-Alkoxyphenols
para-Benzoquinones
Amberlyst-15
Reducing property
Antimelanoma compounds
Melanoma is the most lethal cancer of the skin, and the incidence
of melanoma worldwide has doubled in the past 20 years.1 Once
malignant melanoma has progressed to the metastatic stage, it be-
comes refractory to treatment with currently available therapies.1
This necessitates development of newer chemotherapeutic agents
for the treatment of patients with disseminated malignant mela-
noma. It has been known that p-alkoxyphenols form an important
group of antimelanoma compounds.2 Two important approaches
in developing p-alkoxyphenols as anti-melanoma agents are based
on their (i) ribonucleotide reductase (RNR) inhibition activity3 and
(ii) tyrosinase dependent cytotoxicity.1,4 In the first approach, the
reduction of ribonucleotides, which provide the building blocks
for DNA replication and repair in all living cells, is inhibited by
quenching of a tyrosyl free radical through the interaction of p-alk-
oxyphenol with RNR protein R 2.3 In the second approach, p-alkoxy-
phenols and related phenol-based prodrugs are bioactivated to
catechols and then to quinones in melanoma cells as a result of their
oxidation by tyrosinase. The quinones so generated exert their cyto-
toxicity by causing intracellular glutathione depletion of melanoma
cells.1,4
that the deoxyribonucleic acid pools of HIV or HSV-infected cells
are exhausted by their action.3,5 All these biological activities along
with the general radical scavenging activities of p-alkoxyphenols6
make their laboratory synthesis important. The general routes fol-
lowed so far for the synthesis of p-alkoxyphenols are partial alkyl-
ation of quinol7,8 (by use of common alkylating agents like alkyl
sulphates7a or alkyl halides7b,7c as well as by use of alcohols in the
presence of different catalytic systems8), Baeyer–Villiger reaction
of p-alkoxybenzaldehydes or p-alkoxyketones9 or acid catalysed
hydrogen peroxide oxidation of p-alkoxybenzaldehydes,10 cycliza-
tion of suitable Fischer carbenes11 and controlled dealkylation of
12a
p-dialkoxybenzenes by substoichiometric amounts of AlI3
or
BBr3.12b Moreover, a two-step conversion of p-benzoquinone to
p-alkoxyphenols by reaction of the former with P(OR)3 followed
by alkaline hydrolysis of the intermediate is known.13
The routes involving alkylation of quinol by use of alcohols have
been reported in a number of patents.8 However, in none of them
the mechanistic aspects for the conversion have been discussed.
Two mechanistic possibilities for the conversion are (i) direct partial
alkylation of quinol, and (ii) an oxidation of quinol to p-benzoqui-
none followed by conversion of the latter to the p-alkoxyphenols.
In the second possibility the last step would require a reduction pro-
cess, and here quinol or alcohol is the reducing agent and that is an
important aspect requiring clarification. In a recent paper Yadav
et al.14 have reported the conversion of quinol to p-methoxyphenol
by the reaction of the former with methanol in the presence of 40%
dodecatungstophosphoric acid (DTP)/montmorillonite clay (K10) as
The RNR inhibition activity of p-alkoxyphenols mentioned above
not only develops their anti-melanoma property but also makes
them effective against bacteria and viruses, for example, it is known
⇑
Corresponding author. Tel.: +91 033 2414 6223; fax: +91 033 2414 6484.
E-mail address: mallikak52@yahoo.co.in (A.K. Mallik).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.119

R. Mondal et al. / Tetrahedron Letters 55 (2014) 86–89
87
Table 2
catalyst and benzoquinone as cocatalyst. Regarding the mechanistic
Results of amberlyst-15 catalysed reactions of 1 with alcohols
aspect of the conversion, they suggested that protonated quinone is
first methylated and then the resulting species is reduced with pro-
tonated quinol and a chain process is set up, which continues up to
the end.
Entry Quinone Alcohola,b
Time (h) Product (2)
Yield
(%)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
MeOH
EtOH
4
4
5
5
5
6
2a
72
69
64
68
63
69
(R1 = H, R2 = Me)
Amberlyst-15 is a sulfonated polystyrene resin. It possesses un-
ique properties such as environmental compatibility, nontoxicity,
reusability, noncorrosiveness, chemical and physical stability, and
can be used over a prolonged period. Owing to the numerous
advantages associated with this cheap catalyst, amberlyst-15 has
been explored as a powerful catalyst for various organic reac-
tions.15a Applicability of this resin in organic synthesis is being
studied currently in our laboratory.15b–e In continuation of recent
studies with amberlyst-15 in the laboratory we investigated the ef-
fect of heating of p-benzoquinones in an alcoholic medium in the
presence of this resin. We noted with much pleasure that in these
processes p-alkoxyphenols were obtained in good to very good
yields when the alcohol was primary or secondary. The outcome
of this study is presented herein.
Thus, when p-benzoquinone (1a) was refluxed, or heated at
100 °C in an alcohol, for 4–7 h in the presence of amberlyst-15 as
catalyst, it was found that 1a changed to a p-alkoxyphenol in cases
of use of primary and secondary alcohols (Scheme 1). The amount
of catalyst and reaction time were optimized for the reaction of 1a
in methanol (Table 1, which also contains the results of recycling of
the catalyst). However, that optimized time could not be followed
for use of other alcohols and also for use of 1b as substrate. When a
tertiary alcohol was used, no such reaction took place. The results
are given in Table 2.
2b
(R1 = H, R2 = Et)
n-PrOH
i-PrOH
n-BuOH
i-BuOH
2c
(R1 = H, R2 = n-Pr)
2d
(R1 = H, R2 = i-Pr)
2e
(R1 = H, R2 = n-Bu)
2f
(R1 = H, R2 = i-Bu)
7
8
1a
1a
t-BuOH
i-AmOH
7
5
—
2g
—
67
(R1 = H, R2 = i-am)
9
1a
Allyl
6
6
6
7
2h
70
52
64
72
Alcohol
Propargyl
Alcohol
BnOH
(R1 = H, R2 = allyl)
10 1a
11 1a
12 1a
2i
(R1 = H, R2 = propargyl)
2j
(R1 = H, R2 = Bn)
Cinnamyl
alcohol
2k
(R1 = H,
R2 = PhCH = CHCH2)
13 1a
14 1a
15 1a
16 1a
17 1a
18 1a
19d 1b
20d 1b
21d 1b
PhCH2CH2OH
ClCH2CH2OH
7
6
5
4
4
4
4
5
6
2l
76
63
62
64
68
74
71
69
68
(R1 = H, R2 = PhCH2CH2)
2m
(R1 = H, R2 = ClCH2CH2)
i-PrOH/t-BuOH
(1:10, v/v)
EtOH/i-PrOH
(1:1, v/v)
EtOH/i-PrOH
(1:2, v/v)
EtOH/i-PrOH
(1:4, v/v)
MeOH
2d
2b + 2d
A plausible mechanism for the formation of p-alkoxyphenols in
the above reaction is given in Scheme 2. The present reaction ap-
pears to be an example where a primary or secondary alcohol is
reducing a stabilized carbocation. The failure of the reaction to oc-
cur in t-BuOH is obviously due to lack of reducing property of this
(5:1)c
2b + 2d
(2:1)c
2b + 2d
(1:3)c
2n + 2n0
(R1 = R2 = Me)
2o + 2o0
EtOH
(R1 = Me, R2 = Et)
2p + 2p0
OH
O
i-PrOH
(R1 = Me, R2 = i-Pr)
R1
Amberlyst-15
R2OH
R1
+
a
Amount of alcohol = 4.0 mL/mmole of 1.
Reflux temperature for use of MeOH, EtOH, n-PrOH and i-PrOH, while 100 °C for
Reflux / heat at 100 °C
4-7 h
b
OR2
O
the other alcohols.
c
Approx. (from 1H NMR).
For these entries 2n–p are 4-alkoxy-2-methylphenols, 2n0–p0 are 4-alkoxy-3-
d
1a: R1 = H
b: R1 = Me
2
methylphenols.
[R2= p-alkyl or s-alkyl]
O
O
O
Scheme 1. Conversion of 1 to 2.
ROH
SO3H
+
H
Table 1
Optimization of the reaction of 1a in MeOH
O
R
HO
O
OH
Sl.
no.
Amount (mg) of Amberlyst-15 per mmol
of 1a
Timea
(h)
Yield of 2a
(%)
1a
O
O
O
1
2
3
4
5
6
7
10
10
10
20
20
30
40
40
40
50
1
2
17
27
43
29
54
66
59
72
70
69
H
H
R'
R"
C
H
2
4.5
2
4.5
4.5
2
4
4.5
4
O
-H2O
OR
H
H2O
OR
OR
[ ROH = R'R"CHOH ]
Scheme 2. Plausible mechanism for formation of 2 from 1a.
8b,c
9b
10b
a
b
c
At reflux temperature.
Reaction was complete in these cases.
Yields of 2a in three consecutive recycling of the catalyst were 69%, 62% and
alcohol. It may be pointed out here that in the reaction of
p-benzoquinone with P(OR)3, P(III) acts as the reducing agent.13
Another feature to be mentioned is that the attack of t-BuOH to a
54%.

88
R. Mondal et al. / Tetrahedron Letters 55 (2014) 86–89
OH
OH
O
OCOCH3
D
O
CD3OD
Ac2O/Py
Amberlyst-15
100 oC , 6 h
OH
1a
D
+
HO
Amberlyst-15
O
OCD3
OCD3
O
H
Scheme 3. Formation of deuterium incorporated analogue of 2.
1a
H
O
O
5
-H2O
HO
protonated quinone is not favoured sterically, which was ascer-
tained from the observation that the reaction in a 1:10 mixture
of i-PrOH and t-BuOH (v/v) gave only p-i-propoxyphenol (entry
15). The results of the reactions done in mixtures of EtOH and i-
PrOH of three different compositions (entries 16–18) further clar-
ified the role of the said steric effect.
OH
H2O
O
O
Scheme 5. Formation of 5 from 1a in ethylene glycol.
The above mechanism was strongly supported by the following
results obtained by carrying out the same reaction of 1a in CD3OD.
In this experiment a product (mp 55–57 °C) was obtained which
did not show any 1H NMR signal for OMe. Acetylation of this prod-
uct gave an O-acetyl derivative, the ratio of acetoxy proton integra-
tion to aromatic proton integration (approx. 1:1) of this derivative
indicated deuterium incorporation in its aromatic ring (Scheme 3).
Alcohols are commonly known to act as reducing agent for or-
ganic substrates in the presence of bases (e.g., in MPV reduction,16
alkylation of 2,4,5-trimethylpyrrole with alcohol–alkoxide mix-
ture,17 conversion of chromone-3-aldehydes to 3-(hydroxy-
methyl)chromones with i-PrOH in the presence of basic
alumina,18 enone reduction with i-PrOH vapour and MgO19 etc.)
and in the presence of transition metal catalysts (by transfer
hydrogen reactions, also known as borrowing hydrogen methodol-
ogy).20 The novel feature in our case is that reduction by alcohol is
taking place in the presence of an acid.
When an unsymmetrical p-benzoquinone 1b was used as sub-
strate (entries 19–21), it was observed that both the isomeric prod-
ucts were formed (approx. ratio 15:1, 1H NMR), which could not be
separated by column chromatography over silica gel. Attempted
isolation of the major product by fractional crystallization was suc-
cessful only in case of the products obtained by use of methanol.
This product was found to be 4-methoxy-2-methylphenol (2n)
from comparison of its 1H NMR spectrum with that of its acetate
and finally from its mp.21 The formation of a 4-alkoxy-2-methyl-
phenol as the major product is quite expected for the use of other
alcohols (primary or secondary) also.
and then they underwent oxidative coupling in air22 to yield 4
(Scheme 4). It may be mentioned here that the formation of 4 could
not be avoided even by carrying out the reaction in argon atmo-
sphere and performing the work-up in the usual way. In the second
case, the reaction yielded 2,3-dihydrobenzo[b][1,4]-dioxin-6-ol (5)
(49%), the plausible mechanism of this transformation (which does
not involve any oxidation–reduction process) is delineated in
Scheme 5.
Thus, an efficient method for conversion of p-benzoquinones to
p-alkoxyphenols has been developed by us.23 Only one such con-
version is known so far,13 though the opposite process is more
common.24 Here a primary or secondary alcohol acts as a reducing
agent in an intermediate stage, and it may be mentioned that the
recent literature shows a growing trend for utilization of the reduc-
ing property of alcohols for transformation of various organic sub-
strates.18,20,25 On the other hand, though quinones are known to be
used for dehydrogenation of some classes of organic compounds,26
to the best of our knowledge, report of their use for dehydrogena-
tion of p- and s-alcohols is very rare.26f–h Furthermore, our result is
totally different from the long known result for the reaction of 1a
with primary alcohols in the presence of a Lewis acid,27 and the
method being reported appears to be a good addition to the current
important applications of amberlyst-15.15d–f,28
Acknowledgments
Two other variations in our experiments were done by (i)
replacement of p-benzoquinone (1) with 1,4-naphthoquinone
and (ii) replacement of monohydric alcohols with the dihydric
alcohol ethylene glycol. In the first case, 4,40-dialkoxy-2,20-bi(1H-
naphthylidene)-1,10-diones (4) (53–58%) were obtained. Possibly,
the expected products, 4-alkoxy-1-naphthols (3) were formed first
Financial assistance from UGC-CAS and DST-PURSE programs,
Department of Chemistry is gratefully acknowledged. The authors
also acknowledge the DST-FIST program to the Department of
Chemistry, Jadavpur University for providing NMR spectral data.
R.M. and C.G. are thankful to UGC, New Delhi for their Research
fellowships.
OR2
O
O
Amberlyst-15
R2OH
+
Reflux / heat at 100 o
4-7 h
O
C
OR2
O
OH
4
a: R2 = Me
b: R2 = Et
OR2
3
Scheme 4. Outcome of the reaction using 1,4-naphthoquinone.

R. Mondal et al. / Tetrahedron Letters 55 (2014) 86–89
89
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Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2013.10.119.
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a mixture of a
p-benzoquinone (1 mmol) (1) and an alcohol [or alcohol mixture] (4.0 mL),
amberlyst-15 (40 mg) was added and the mixture was refluxed, or heated at
100 °C for 4–7 h until the p-benzoquinone reacted completely (monitored by
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6.85(2H, d, J = 9.0 Hz); 13C NMR (75 MHz, CDCl3): d 56.85, 75.60, 78.90, 116.22,
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