Specific para-hydroxylation of nitronaphthalenes with cumene hydroperoxide in basic aqueous media

Article abstract of DOI:10.1016/S0040-4039(00)00415-9

A synthetic method for specific para-hydroxylation of nitroarenes has been developed. The reaction of nitronaphthalenes with cumeme hydroperoxide in basic aqueous media produces exclusively para-hydroxy nitronaphthalenes in good yield. The selectivity of ortho and para hydroxylation is mediated by water content. The rationale for water-controlled orientation of hydroxylation has been briefly discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00415-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3519–3522
Specific para-hydroxylation of nitronaphthalenes with cumene
hydroperoxide in basic aqueous media
Lei Zhu and Lin-hua Zhang ∗
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA
Received 28 February 2000; accepted 8 March 2000
Abstract
A synthetic method for specific para-hydroxylation of nitroarenes has been developed. The reaction of nitro-
naphthalenes with cumeme hydroperoxide in basic aqueous media produces exclusively para-hydroxy nitronaph-
thalenes in good yield. The selectivity of ortho and para hydroxylation is mediated by water content. The rationale
for water-controlled orientation of hydroxylation has been briefly discussed. © 2000 Elsevier Science Ltd. All
rights reserved.
Interest in the nucleophilic substitution of hydrogen in nitroarenes has grown significantly in recent
years.1 The hydroxylation of nitroarenes with potassium peroxide (K2O2) in liquid ammonia yielded
mono- or dinitronaphthols. The product ratio of ortho- and para-substitution is temperature dependent.2
The hydroxylation of nitroarenes with alkyl hydroperoxide was also reported in which the position
of hydroxylation depended on what base was selected.3 It was reported that the hydroxylation of
nitronaphthalene with organic peroxides in DMSO generated only para-isomer although the isolation
was not described.4,5 However, in our hands the reported procedure3–5 resulted in a complex mixture, and
the ratio of para-nitronaphthol to ortho-nitronaphthol was about 87 to 13 in DMSO by HPLC analysis.
The separation of the para-isomer from the ortho is very tedious and needs chromatography. Another
way of making para-alkoxynitronaphthalenes by a nitration of naphthalene was reported, but the reaction
yielded a mixture of regioisomers that was not easy to purify.6 Apparently, there is a need to develop a
reproducible and scaleable method to prepare the para-hydroxy isomer from the nitroarenes. The present
study reports a synthetic route, amenable to large scale, to para-hydroxylation of 1-nitro or 1,5-dinitro
naphthalene through the nucleophilic substitution of the hydrogen.
We first studied the hydroxylation of nitronaphthalene with organic peroxides in DMSO and DMF.
The results were not satisfactory in our hands due to the formation of para- and ortho-isomers. We
then examined the reactivity difference between cumene hydroperoxide and hydrogen peroxide as the
hydroxylation agents. The technical grade of cumene hydroperoxide works well in our hands without
further purification. However, hydroxylation of nitroarenes with hydrogen peroxide did not proceed as
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00415-9
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smoothly as with cumene hydroperoxide due to the precipitation of starting material from the reaction
mixture. In an attempt to achieve a homogeneous reaction condition, a small amount of water was
introduced into the DMSO solution. To our surprise, the hydroxylation of nitroarenes proceeds much
better than in DMSO alone. Apparently, this reaction does not need strictly controlled anhydrous
conditions as previously reported.2
On the basis of this discovery, we started our research on hydroxylation of nitroarenes in a mixture
of water and DMSO. As shown in Table 1, the reaction took place very slowly in water due to the
insolubility of the starting materials. When the reaction was carried out in anhydrous DMSO, a mixture
of para- and ortho- regioisomers was formed which was contradictory to previous reports. However, in
a mixture of water (25%) and DMSO (75%), this nucleophilic substitution gave exclusively the product
of para-hydroxylation in 62–82% yield as illustrated in Table 1.
Table 1
Hydroxylation of 1-nitronaphthalene
These reaction conditions were also tested on 1,5-dinitronaphthalene, which was reported among the
most unsuccessful ones to achieve para substitution due to steric hindrance by the substituent at position
5.1,7 It was also illustrated that the regio-preference varies with the base. Interestingly, under our aqueous
conditions hydroxylation predominantly took place at the para-position of 1,5-dinitro naphthalene
showing strong evidence of stereo- and base-independence (Table 2). When the water content increased
to 25%, the para-isomer became the sole product. Further studies revealed that water played an important
role in controlling the regiochemistry, and also improved the reaction yield as shown in Table 2.
The nucleophilic substitution of nitroarenes in aqueous media provides an economic and scaleable
route to para-isomers, which also sheds some light on the reaction mechanism. It is generally accepted
that ortho-addition is kinetically more favorable than para-addition in nitroarenes, but the para-adduct

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Table 2
Hydroxylation of 1,5-dinitronaphthalene
intermediate is thermodynamically more stable than ortho-isomer.7 However, the conditions for conver-
ting ortho-adduct to para-adduct through thermodynamic equilibrium have not been reported. Our results
revealed that the ortho- to para-adduct conversion could be facilitated by water content possibly through
a reversible process (Scheme 1). Another possible explanation is that water solvates change the reaction
kinetics, and make the para-substitution kinetically more favorable.
Scheme 1.
In summary, in basic aqueous media the nucleophilic hydroxylation of nitroarenes leads exclusively
to the para-isomer, which provides an economical and scaleable route to these series of compounds
that are not easily available through aromatic electrophilic substitution. The mechanism that directs the
regiochemistry is worthy of further study.
General procedure: 1-nitronaphthalen (1.0 mol) was dissolved in DMSO (1.5 L). Under cooling, KOH
(4.0 mol) in H2O (0.5 L) was added. With stirring, a solution of cumene hydroperoxide (tech. Grade, 1.0
mol) in DMSO (0.25 L) was added, and the pot temperature was controlled below 30°C. After addition
the reaction was stirred at room temperature for 2 h, and the aqueous solution of Na2S2O3 (30 g in 120

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g water) was added. After 1 h, H2O (1.5 L) and EtOAc (1.2 L) was added. The pH of the solution was
adjusted to about 4 with HCl (c) while keeping the solution below 5°C. The layer was separated, and
the aqueous layer was extracted with EtOAc (0.5 L). The combined EtOAc layers were washed with
10% NaCl solution (2×0.5 L). Sufficient 20% aqueous NaOH was added to adjust the pH to about 10
at low temperature. The aqueous layer was separated and washed with EtOAc (2×0.5 L). With cooling
and stirring, hydrochloric acid (c) was slowly added to aqueous solution until about pH 4. The solid was
collected and dried under vacuum to a constant weight. The structures of the products were confirmed by
comparison to authentic samples.1
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