A facile and convenient method for the synthesis of nitro phenols and chloropyridinols

Article abstract of DOI:10.1081/SCC-200026626

An efficient, simple, and practical method of preparation of nitro phenols and chloropyridinols has been reported by the active chlorine displacement of chloro nitro benzenes and poly chloro pyridines in the presence of alkali metal hydroxide in low polarity solvent with very good yields.

Full text of DOI:10.1081/SCC-200026626

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A Facile and Convenient
Method for the Synthesis
of Nitro Phenols and
Chloropyridinols
B. China Raju a , Parvathi Neelakantan a & U. T.
Bhalerao a
a Organic Chemistry Division , Indian Institute of
Chemical Technology , Hyderabad, 500 007, India
Published online: 06 Jan 2011.
To cite this article: B. China Raju , Parvathi Neelakantan & U. T. Bhalerao
(2004) A Facile and Convenient Method for the Synthesis of Nitro Phenols and
Chloropyridinols, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:16, 2903-2909, DOI: 10.1081/
SCC-200026626
To link to this article: http://dx.doi.org/10.1081/SCC-200026626
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 16, pp. 2903–2909, 2004
A Facile and Convenient Method for the
Synthesis of Nitro Phenols and
Chloropyridinols
#
*
B. China Raju, Parvathi Neelakantan, and U. T. Bhalerao
Organic Chemistry Division, Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
An efficient, simple, and practical method of preparation of nitro phenols
and chloropyridinols has been reported by the active chlorine displace-
ment of chloro nitro benzenes and poly chloro pyridines in the presence
of alkali metal hydroxide in low polarity solvent with very good yields.
Key Words: Nitro phenols; Chloropyridinols; Alkali metal hydroxide;
Tertiary butanol.
#Former Director, IICT, Hyderabad, 500 007, India.
*
Correspondence: B. China Raju, Organic Chemistry Division, Indian Institute of
Chemical Technology, Hyderabad 500 007, India; E-mail: chinaraju@iict.res.in.
2903
DOI: 10.1081/SCC-200026626
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2904
Raju, Neelakantan, and Bhalerao
INTRODUCTION
Nitro phenols and chloropyridinols are important intermediates in
organic synthesis for the preparation of various heterocyclic compounds
with applicational importance in pharmaceuticals and agrochemicals. Nitro
phenols are valuable intermediates in drugs,[1] adhesion inhibitors,[2]
adhesives,[3] and antineoplastic agents.[5] Dinitro phenols and chloro nitro
phenols are also valuable compounds as binding materials for glass fiber
reinforced plastics[6] and as sea lamprey larvicides.[6] Chloropyridinols are
most important intermediates for the synthesis of insecticides and herbi-
cides.[7] The general method for the preparation of nitro phenols are nitration
of phenols,[8] cleavage of phenolethers,[9] direct hydroxylation,[10] and
nucleophilic displacement.[11] Among these methods, the widely used
method is nucleophilic halogen displacement of chloro nitro benzenes and
chloropyridines. A few reagents are reported for the preparation of nitro
phenols and chloropyridinols by the nucleophilic displacement of chloro
nitro benzenes and chloro pyridines using aqueous metal hydroxides with
phase-transfer catalysts[11] and pressure reactions.[12] Our continuing interest
in the preparation of pesticides[13] and pesticide intermediates,[14] have led us
to report an efficient, simple, and practical method for the preparation of nitro
phenols (1b–3b), chloropyridinols (4b and 5b) from chloro nitro benzenes
(1a–3a) and chloropyridines (4a and 5a) in presence of potassium hydroxide
in tertiary butanol (Sch. 1). The common method reported for the preparation
of nitro aryl ethers are the nucleophilic aromatic substitution of chloro nitro
benzenes with alkoxides.[15] Basani et al.[16] reported the reaction of
4-chloro nitro benzene with various alkoxides in the parent alcohols, a sub-
stantial yield of substitution product obtained only with ethoxide, where as
dichloro azoxybenzene, dichloro azobenzene, and chloro anilines are the
main products in 2-propanol and tertiory butanol. Paradisi et al.[17] achieved
the substitution products and inhibited the formation of reduced products by
using the phase-transfer catalysts. Under similar conditions, no substitution
products was reported in tertiary butyl alcohol.
Scheme 1.

Synthesis of Nitro Phenols and Chloropyridinols
2905
The attempted reaction of 2-chloro nitro benzene in the presence of alkali
metal hydroxides in parent alcohols under reflux conditions gave substitution
product 2-nitro anisole (74%) with methanol. Where as 2-ethoxy nitro
benzene (30.6%), dichloro azobenzene (0.63%), and chloro aniline (8%) are
the main products with ethanol. Dichloro azobenzene (10%) and chloro
aniline (38%) are the only products with 2-propanol. Interestingly, under
similar conditions, tertiary butanol gave only nitro phenol (74%) in good
yield. This interesting reaction with potassium hydroxide in presence of
tertiary butanol (Bottle grade) prompted us to study and explore the feasibility
of this method to prepare industrially important intermediates such as 2-nitro
phenol (1b), 2,4-dinitro phenol (2b), 5-chloro-2-nitro phenol (3b), 3,5,6-tri-
chloro-2-pyridinol (4b), 3,4,5,6-tetrachloro-2-pyridinol, and 2,3,5,6-tetra-
chloro-4-pyridinol (5b).
In a typical procedure which involves the condensation of chloro nitro
benzenes/chloropyridines with potassium hydroxide in the presence of
tertiary butanol gave nitro phenols/chloropyridinols. The pentachloro pyri-
dine (5a) yielded two isomeric products 3,4,5,6-tetrachloro-2-pyridinol and
2,3,5,6-tetrachloro-4-pyridinol (5b) was confirmed by its 13C NMR, which
agrees very well with that of reported values.[12a] These isomers were methyl-
ated with methyl iodide and the obtained products were confirmed by
1H NMR. Two methoxyl groups appeared as separate singlets in the region
of 3.80 and 4.04 in the ratio of 60 : 40.[18] Under similar conditions 2-chloro-
5-methylpyridine[14d] (6a) and 2-chloropyridine (7a) failed to react. The
important factor to be considering here is the presence of water in tertiary
butanol (catalytic quantity). The rate of reaction has a direct effect on the
water content in the medium. The presence of water more than the required
amount decreases the yield of the alcohol formed. The results summarized
in Table 1 clearly indicating the nucleophilic displacement of halogens with
hydroxy group under reflux conditions. All the products were well character-
ized by its 1H NMR, IR, and mass and compared with authentic samples.
In conclusion, potassium hydroxide in tertiary butanol was found to be
mild and highly efficient for the synthesis of nitro phenols and chloropyridi-
nols through the nucleophilic displacement reaction of chloro nitro benzenes
and chloropyridines in good yields. The present method offers several advan-
tages such as mild reaction conditions, cleaner reactions, and simple experi-
mental procedures make this an attractive alternative to currently available
methods.
EXPERIMENTAL
The 1H NMR spectra were recorded on Gemini 200 MHz spectrometer in
CDCl3 and DMSO-d6 with TMS as internal standard. IR spectra were recorded

2906
Raju, Neelakantan, and Bhalerao

Synthesis of Nitro Phenols and Chloropyridinols
2907
on a Nicolet 740 FT IR spectrometer and Mass spectra obtained on VG Micro
mass 7070H. Melting points were obtained on a Toshniwal melting point
apparatus and are uncorrected.
Typical Experimental Procedure
2,4-Dichloro nitro benzene (6.06 g, 0.032 mol) and potassium hydroxide
(4.4 g, 0.078 mol) were refluxed in tertiary butanol (25 mL) for 10 hr.
The reaction mixture was cooled, solvent removed under reduced pressure.
The residue was dissolved in water (20 mL) and extracted with dichloro-
methane to remove the unreacted product. The aqueous layer was acidified
with conc. hydrochloric acid and extracted with dichloromethane. The
organic layer dried over sodium sulfate, concentrated and on flash chromato-
graphy afforded the 2-nitro-5-chloro phenol (3b, 4.23 g, 77%), m.p. 41.58C,
1
lit. 42–438C. H NMR (CDCl3, 200MHz): d 6.94 (d, 1H, aromatic), 7.18
(s, 1H, aromatic), 8.02 (d, 1H, aromatic), 10.62 (s, 1H, OH, D2O exchangeable).
IR (KBr): 3200, 1610, 1580, 1320, 1240 and 1180 cm21 MS: m/e 173, 175 Mþ.
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Received in India April 12, 2004