Efficient and practical synthesis of dissymmetrical ethers of 4-nitrocatechol

Article abstract of DOI:10.1080/00397910802050949

An efficient and practical synthesis of dissymmetrical ethers of 4-nitrocatechol from 5-nitrosalicyladehyde and 2-hydroxy-5-nitroacetophenone via Baeyer-Villiger oxidation is described. These dissymmetrical ethers are useful in the synthesis of various coccidiostats and other important pharmaceutical intermediates. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802050949

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Efficient and Practical
Synthesis of Dissymmetrical
Ethers of 4-Nitrocatechol
Murugan Subashini a , Kalpattu K. Balasubramanian a
& Shanmugasundaram Bhagavathy a
a Shasun Research Centre, Chennai, India
Published online: 09 Sep 2008.
To cite this article: Murugan Subashini , Kalpattu K. Balasubramanian &
Shanmugasundaram Bhagavathy (2008): Efficient and Practical Synthesis of
Dissymmetrical Ethers of 4-Nitrocatechol, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:18, 3088-3106
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Synthetic Communications1, 38: 3088–3106, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802050949
Efficient and Practical Synthesis of
Dissymmetrical Ethers of 4-Nitrocatechol
Murugan Subashini, Kalpattu K. Balasubramanian, and
Shanmugasundaram Bhagavathy
Shasun Research Centre, Chennai, India
Abstract: An efficient and practical synthesis of dissymmetrical ethers of
4-nitrocatechol from 5-nitrosalicyladehyde and 2-hydroxy-5-nitroacetophenone
via Baeyer–Villiger oxidation is described. These dissymmetrical ethers are useful
in the synthesis of various coccidiostats and other important pharmaceutical
intermediates.
Keywords: Baeyer–Villiger oxidation, coccidiostats, 2-hydroxy-5-nitroacetophenone,
4-nitrocatechol, 5-nitrosalicyladehyde
INTRODUCTION
Coccidiostats are 4-hydroxy-6,7-substituted 3-carboalkoxyquinolines (1)
that are valuable agents in the control of coccidiosis in poultry.[1] Mizzoni
et al. report a detailed study on the structural requirements for anticocci-
dial activity for a series of quinates 1.[2] Some examples of well-known
coccidiostats (Fig. 1) are decoquinate (1a), iso-decoquinate (1b), buqui-
nolate (1c), methyl benzoquate (1d), and cyproquinidate (1e). These
quinolines also act as antimalarials[3] and serve as synthons for the syn-
thesis of complex natural products.[4,5]
The synthetic route often used for the preparation of these quino-
lines, as depicted in Scheme 1, employs the dissymmetrical ethers of
4-nitrocatechol as the starting material.[6,1f] There are also a few other
methods of synthesis of these quinolines, but these are not commercially
Received February 20, 2008.
Address correspondence to Shanmugasundaram Bhagavathy, Shasun Research
Centre, 27, Vandaloor Kelambakkam Road, Keelakottaiyur (Post), Chennai
600048, India. E-mail: bhagavathy@shasun.com
3088

Dissymmetrical Ethers of 4-Nitrocatechol
3089
Figure 1. 4-Hydroxyquinoline-3-carboxylate.
Scheme 1. Synthesis of decoquinate: (a) 10% Pd=C, H2, 6 bar, EtOH–EtOAc
(3:1), rt, 30 min, 97%, (b) diethylethoxy methylene malonate, 35–40 ꢀC, 4 h,
ꢀ
98%; (c) Dowtherm A, 250–260 C, 15 min, 57%.
significant.[3,7] The key starting material (viz., the dissymmetrical ethers
of 4-nitrocatechol 2), though structurally not complex, is not easy to
access by the regioselective mono-alkylation. Presently, there is no good
method for regioselective alkylation of electron-poor catechol. We report
an efficient and practical method for the synthesis of dissymmetrical
ethers of 4-nitrocatechol via Baeyer–Villiger oxidation.
RESULTS AND DISCUSSION
A variety of methods are known in literature for alkylation of bisphenols
in literature,[8] but there are only a few reports on regioselective alky-
lation of electron-poor bisphenols.[9–11] Initially, we explored the regiose-
lective alkylation of 4-nitrocatechol 4 using NaH (1.0 eq.) and alkyl
halide (1.0 eq.) in DMF. This yielded a mixture of three compounds,
the monoethers 5 and 6 and the bis-ether 7 (Scheme 2).
Scheme 2. Alkylation of 4-nitrocatechol.

3090
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
Cao et al.[10] reported the selective methylation of 4 using NaOH=
MeI catalyzed by solid–liquid phase-transfer catalyst PEG400. They
selectively obtained the monoether, and no bis-ethers were isolated.
The authors do not mention which monoether was obtained. Several
attempts of the same reaction in our hands afforded a mixture of the
monoethers 5 and 6 (no bisether 7), and the conversion was also very
poor (viz. 25%). Pfister et al.[11] claim that the 4-acyl catechol could be
regioselectively O-alkylated at the 1-position with alkylhalide in DMF
using Li2CO3 at 55 ꢀC. Similarly, when we attempted the reaction of
4-nitrocatechol 4 with decylbromide in dimethylformamide (DMF) under
Pfister’s condition, neither did we observe any regioselectivity nor did the
reaction go to completion even after 48 h.
With a view to find out if bases play any role in regioselectivity, we
studied the reaction of 4 with various alkylhalides (viz., decylbromide,
methyliodide, and ethyl p-toluenesulphonate) using different bases such
as Na2CO3, K2CO3, K3PO4, Na3PO4, Cs2CO3, Ba(OH)2, and Li2CO3
in DMF as solvent at 70–80 ꢀC. None of the reactions showed any regios-
electivity and afforded only a mixture of 5, 6, and 7 . Also, in none of the
cases did the reaction go to completion, although the degree of conver-
sion varied depending upon the amount of base used. Also, increasing
the equivalence of the alkylating agent or the base did not lead to any
selectivity.
Thus we turned our attention to developing a different approach
(via Baeyer–Villiger oxidation) for the synthesis of dissymmetrical
ethers of 4, bearing in mind the suitability of the method for large-scale
synthesis. A simple retrosynthetic analysis showed that 5-nitrosalicylal-
dehyde 8 and 2-hydroxy-5-nitroacetophenone 9, which are commercially
available, could be used as starting material. Etherification of 8 and 9
followed by Baeyer–Villiger oxidation of the respective ethers 10 and
12 and saponification of its esters 11 and 13 would lead without any
ambiguity to the monoether 5 (Scheme 3). This could subsequently be
etherified with an alkylating agent to obtain various dissymmetrical
ethers 2.
Etherification of the aldehyde 8 and ketone 9 with the alkylating
agent (decylbromide or ethyl p-toluenesulphonate) using Cs2CO3 in
DMF afforded the corresponding ethers 10a,b and 12a,b, respectively,
in very high yields.
There are many reports in the literature on the Baeyer–Villiger oxi-
dation of the ketones and aldehydes with different peracids to afford
the corresponding esters and formats[12] in very good yields, but there
are only a few reports on Baeyer–Villiger oxidation of electron-poor
aromatic systems using m-CPBA,[13a] peracetic acid,[13b,c] and sodium per-
carbonate,[13d] Baeyer–Villiger oxidation of 10 and 12 could be achieved

Dissymmetrical Ethers of 4-Nitrocatechol
3091
Scheme 3. Synthesis of monoethers of 4-nitrocatechol: (a) decylbromide, Cs2CO3,
ꢀ
ꢀ
DMF, 70–80 C, (b) Cs2CO3, ethyl p-toluenesulphonate, DMF, 60–70 C; (c)
ꢀ
(CF3CO)2O, 30% H2O2, CH2Cl2, 25–30 C, 20–30 min; and (d) NaOH, THF,
ꢀ
25–30 C.
with m-CPBA, CH3CO3H, CF3CO3H, and sodium percarbonate. We
found that only CF3CO3H could bring about the oxidation at ambient
temperature in high yields. In the case of sodium percarbonate, the reac-
tion did not proceed to completion, while m-CPBA and CH3CO3H
needed higher temperatures and longer durations for completion.
Scheme 4. Synthesis of dissymmetrical ethers of 4-nitrocatehol.

3092
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
Table 1. Synthesis of dissymmetrical ethers of 4-nitrocatechol
S.No.
Substrate
Product
Yielda (%)
Mp[Ref.]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
2a
2b
2c
2d
2e
2f
80
95
85
86
81
93
84
94
95
89
88
81
82
91
57–58[1f]
49–50[1f]
58–61[1f]
35–36[1f]
45–46[1f]
35–37[1f]
44–46
2g
2h
2i
85–87[14]
60–62
65–70
2j
2k
2l
59–60
55–60
40–42
101–102[6f]
2m
2n
aYields mentioned are isolated yields.
Thus, Baeyer–Villiger oxidation of the respective ethers 10a,b and
12a,b using trifluoroacetic anhydride and 30% hydrogen peroxide in
CH2Cl2 at rt afforded the corresponding formate 11a,b and ester 13a,b,
respectively, in good yields. The 1H NMR spectrum of the crude product
indicated the presence of minor amounts of the hydrolyzed product
(viz. 5). Thus, crude 11a,b and 13a,b, without further purification, were
hydrolyzed using NaOH in THF to afford the monoethers of 4-nitroca-
techol 5a,b (Scheme 3) in good yields and purity.
The monoethers 5a and 5b, when treated with the base Cs2CO3 and
its corresponding alkyl halides in DMF, yielded the dissymmetrical ethers
of 4-nitrocatechol 2a–n (Scheme 4, Table 1) in high purity and yields, and
all these compounds were thoroughly characterized. The dissymmetrical
ether 2a has been converted to the known decoquinate 1a (Scheme 1)
following the literature procedure.[1f]
CONCLUSION
We have developed an efficient and practical method for the synthesis
of dissymmetrical ethers of 4-nitrocatechol using the Baeyer–Villiger
oxidation strategy. Our approach provides an unambiguous route for
the synthesis of monoethers of 4-nitrocatechol at the 1-position. This
methodology can be easily exploited for commercial scale.

Dissymmetrical Ethers of 4-Nitrocatechol
EXPERIMENTAL
3093
For all the reactions, the commercially available laboratory grade (LR)
solvents and LR reagents were used directly without further purification.
1H and 13C NMR spectra were recorded on a Bruker Avance 300-MHz
spectrometer with tetramethylsilane (TMS) as reference. Column chroma-
tographic purification was performed using 60- to 120- mesh silica gel.
Melting points were taken in a Veego model VMP-PM apparatus and are
uncorrected. HRMS data were recorded on QTOF-Micromass-UK instru-
ment. Complete spectral data (1H NMR,13C NMR, IR, mass, and high
resolution mass spectroscopy [HRMS]) for all compounds are given here.
2-Decyloxy-5-nitrobenzaldehyde (10a)
A solution of 8 (5 g, 30 mmol), Cs2CO3 (10 g, 30 mmol), and iododecane
(7.6 mL, 36 mmol) in DMF (25 mL) was stirred at 70–80 ꢀC for about 3 h.
The resulting mixture was cooled to 0 ꢀC, water (50 mL) was added and it
was acidified with 20% HCl. A yellow solid was precipitated out. The
solid was filtered, washed with H2O (100 mL), and dried.
Yield: 9.1 g (99%), mp 39–41 ꢀC; 1H NMR (300 MHz, CDCl3):
d ¼ 0.88 (t, 3H, J ¼ 6.0 Hz, CH3), 1.28–1.40 (m, 12H, 6 ꢁ CH2), 1.48–
1.60 (m, 2H, CH2), 1.87–1.94 (m, 2H, CH2), 4.22 (t, 2H, J ¼ 6.0 Hz,
OCH2), 7.10 (d, 1H, J3,4 ¼ 9 Hz, H-3), 8.41 (dd, 1H, J3,4 ¼ 9.3 Hz,
J4,6 ¼ 3.0 Hz, H-4), 8.69 (d, 1H, J4,6 ¼ 2.7 Hz, H-6), 10.48 (s, 1H,
CHO); 13C NMR (75 MHz, CDCl3): d ¼ 14.12 (q, CH3), 22.68 (t,
CH2), 25.92 (t, CH2), 28.83, 29.27, 29.51 (3t, CH2), 31.88 (t, CH2),
69.92 (t, OCH2), 112.91 (d, C-3), 124.48 (d, C-6); 130.65 (d, C-4),
141.37, 165.30 (3s, C-1, C-2, C-3), 187.65 (d, -CHO), IR (KBr, cmꢂ1):
1591 (m), 1521 (s), 1390 (w), 1693 (s), 1657 (w), 1609 (s), 1591 (m);
mass (m=z): 308 [M þ H]þ . HRMS calcd. for [C17H25NO4Na]:
330.1681; found: 330.1681.
2-Ethoxy-5-nitrobenzaldehyde (10b)
A solution of 8 (5 g, 0.0299 mol) and Cs2CO3 (10.7 g, 0.0329 mol) in
DMF (20 mL) was added slowly (ꢃ20 min) to a mixture of ethyl
p-toluenesulphonate (EPTS) (7.9 g, 0.04 mol) in DMF (10 mL) and then
heated to 60–70 ꢀC under a nitrogen atmosphere for about 4 h. The result-
ing mixture was cooled to 0 ꢀC, quenched with water (20 mL), and acidi-
fied with 20% HCl. A yellow solid was precipitated. The solid was
filtered, washed with water (100 mL), and dried under high vaccum.

3094
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
Yield: 5.1 g (88%); mp 70–72 ꢀC (lit.[15] ¼ 71–72 ꢀC); 1H NMR
(300 MHz, CDCl3): d ¼ 1.57 (t, 3H, J ¼ 6 Hz, CH3), 4.33 (q, 2H,
J ¼ 9 Hz OCH2), 7.13 (d, 1H, J3,4 ¼ 9 Hz, H-3), 8.41 (dd, 1H,
J3,4 ¼ 9 Hz, J4,6 ¼ 3 Hz, H-4), 8.69 (d, 1H, J4,6 ¼ 3 Hz, H-6), 10.48
(s, 1H, CHO).
2-Decyloxy-5-nitroacetophenone (12a)
A solution of 9 (3 g, 0.017 mol), Cs2CO3 (5.4 g, 0.017 mol), and iodode-
cane (4.2 mL, 0.02 mol) in DMF (15 mL) was stirred at 70–80 ꢀC for
about 1 h. The resulting mixture was cooled to 0 ꢀC, water (50 mL) was
added, and it was acidified with 20% HCl. The aqueous solution was
extracted with CH2Cl2 (2 ꢁ 30 mL), and the organic layer was washed
with H2O (100 mL), dried over Na2SO4, and concentrated. The crude
product (5.4 g) was purified by column chromatography.
Yield: 5 g (94%); mp 35–36.6 ꢀC; 1H NMR (300 MHz, CDCl3):
d ¼ 0.88 (t, 3H, J ¼ 6.9 Hz, CH3), 1.28–1.55 (m, 12H, 6 ꢁ CH2), 1.56–
1.62 (m, 2H, CH2), 1.86–1.96 (m, 2H, CH2), 2.66 (s, 3H, COCH3), 4.19
(t, 2H, J ¼ 6.6 Hz, OCH2), 7.07 (d, 1H, J3,4 ¼ 9 Hz, H-3), 8.33 (dd,
1H, J3,4 ¼ 9.0 Hz, J4,6 ¼ 3.0 Hz, H-4), 8.63 (d, 1H, J3,4 ¼ 3 Hz, H-6),
13C NMR (75 MHz, CDCl3): d ¼ 14.11 (q, CH3), 22.68, 26.08, 28.95,
29.26, 29.28, 29.49, 31.80 (7t, 7 ꢁ CH2), 31.88 (q, COCH3), 69.93 (t,
OCH2), 112.53, 126.63 (2d, arom. CH), 128.42 (s, C-1), 141.22, 162.70
(2s, C-2, C-3), 197.28 (s, CO); IR (KBr, cmꢂ1): 1852 (w), 1765 (m),
1683 (s), 1607 (s), 1585 (s), 1520 (s), 1487 (s), 1466 (s); mass (m=z):
322 [M þ H]þ . HRMS calcd. for [C18H27NO4Na]: 344.1838; found:
344.1837.
2-Ethoxy-5-nitroacetophenone[16] (12b)
A solution of 9 (4 g, 0.022 mol), Cs2CO3 (7.9 g, 0.024 mol), and EPTS
(5.3 g, 0.026 mol) in DMF (20 mL) was stirred at 70–80 ꢀC under a nitro-
gen atmosphere for about 5 h. The resulting mixture was cooled to 0 ꢀC,
quenched with water (50 mL), and neutralized with 20% dilute HCl. The
aqueous solution was extracted with ether (2 ꢁ 50 mL), and the organic
layer was washed with water (2 ꢁ 100 mL), dried over Na2SO4, and con-
centrated. The crude product (4 g) was purified by column chromato-
graphy using 90:10 (hex.–EtOAc).
1
Yield: 3.4 g (74%); H NMR(300 MHz, CDCl3): d ¼ 1.56 (t, 3H,
J ¼ 6.9 Hz, CH3), 2.66 (s, 3H, COCH3), 4.28 (q, 2H, J ¼ 6.9 Hz,
OCH2), 7.06 (d, 1H, J3,4 ¼ 9 Hz, H-3), 8.31–8.35 (dd, 1H, J3,4 ¼ 9 Hz,
J4,6 ¼ 3 Hz, H-4), 8.63 (d, 1H, J4,6 ¼ 3 Hz, H-6).

Dissymmetrical Ethers of 4-Nitrocatechol
3095
General Procedure for Baeyer–Villiger Oxidation
Trifluoroacetic anhydride (0.21 mol) was cooled to ꢂ10 ꢀC for about
10–20 min, and 30% H2O2 (0.05 mol) was added dropwise (maintaining
the temperature between 0 and ꢂ10 ꢀC) and stirred for about 10 min.
To this mixture, 10a=10b=12a=12b (0.016 mol) in CH2Cl2 (25 mL) was
added slowly and stirred at rt for 10–30 min. After reaction completion,
the mixture was cooled to 0 ꢀC, diluted with CH2Cl2 (20 mL), and
quenched with water (50 mL). The product was extracted with CH2Cl2
(10 mL), and the organic layer was washed with 10% Na2CO3 solution
(2 ꢁ 50 mL) until the pH was neutral and then washed with water
(2 ꢁ 100 mL). The organic layer was dried over Na2SO4 and concentra-
ted. This crude product was taken directly to the next stage without
further purification.
Formic Acid-2-Decyloxy-5-nitrophenyl Ester (11a)
1
Yield: 89%; H NMR (300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 9 Hz,
CH3), 1.27–1.38 (m, 12H, 6 ꢁ CH2), 1.38–1.42 (m, 2H, CH2), 1.76–1.86
(m, 2H, CH2), 4.10 (t, 2H, J ¼ 6.0 Hz, OCH2), 7.04 (d, 1H,
J3,4 ¼ 9.0 Hz, H-3), 8.03 (d, 1H, J4,6 ¼ 3 Hz, H-6), 8.17–8.21 (dd, 1H,
J3,4 ¼ 9 Hz, J4,6 ¼ 3 Hz, H-4), 8.27 (s, 1H, OCHO), 13C NMR (75 MHz,
CDCl3): d ¼ 14.13 (q, CH3), 22.69, 25.76 (2t, CH2), 28.77, 28.92, 29.22,
29.30, 29.51 (5t, CH2), 31.89 (t, CH2), 69.75 (t, OCH2), 112.17, 118.99,
123.68 (3d, C-3, C-4, C-6), 138.28, 140.72 (3s, C-1, C-2, C-3), 157.69
(d, CHO).
Formic Acid 2-Ethoxy-5-nitrophenyl Ester (11b)
1
Yield: 97%; H NMR (300 MHz, CDCl3): d ¼ 1.46 (t, 3H, J ¼ 6.9 Hz,
CH3), 4.21 (q, 2H, J ¼ 6.9 Hz OCH2), 7.06 (d, 1H, J3,4 ¼ 9 Hz, H-3),
8.03 (d, 1H, J4,6 ¼ 2.8 Hz, H-6), 8.19 (dd, 1H, J3,4 ¼ 9 Hz,
J4,6 ¼ 2.8 Hz, H-4), 8.28 (s, 1H, OCHO).
Acetic Acid-2-decyloxy-5-nitrophenyl Ester (13a)
Yield: 96%; mp 59–59.4 ꢀC; 1H NMR(300 MHz, CDCl3): d ¼ 0.88 (t, 3H,
J ¼ 6.9 Hz, CH3), 1.28–1.44 (m, 14H, 7 ꢁ CH2), 1.78–1.83 (m, 2H, CH2),
2.33 (s, 3H, OCOCH3), 4.08 (t, 2H, J ¼ 6.3 Hz, OCH2), 7.01 (d, 1H,
J3,4 ¼ 9 Hz, H-3), 7.97 (d, 1H, J4,6 ¼ 3 Hz, H-6), 8.15 (dd, 1H, J3,4 ¼ 9.0
Hz, J4,6 ¼ 3.0 Hz, H-4); 13C NMR (75 MHz, CDCl3): d ¼ 14.12, 20.40

3096
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
(2q, 2 ꢁ CH3), 20.40, 22.68, 25.76, 28.83, 29.23, 29.31, 29.53, 31.89 (8t,
8 ꢁ CH2), 69.93 (t, OCH2), 111.97, 119.10, 123.25 (3d, arom. CH),
139.53, 140.73, 156.26 (3s, C-1, C-2, C-3), 168.27 (s, CO), IR (KBr,
cmꢂ1): 2085 (w),1894 (w), 1774 (s), 1690 (w), 1598 (s), 1510 (s), 1466 (s),
1343 (s), 1330 (m); mass (m=z): 338 [M þ H]þþ . HRMS calcd. for
[C18H27NO5Na]: 360.1787; found: 360.1788.
Acetic Acid 2-Ethoxy-5-nitrophenyl Ester (13b)
Yield : 93%, mp: 72.8–73.7 ꢀC; 1H NMR (300 MHz, CDCl3): d ¼ 1.45 (t,
3H, J ¼ 6.9 Hz, CH3), 2.34 (s, 3H, OCOCH3), 4.16 (q, 2H, J ¼ 6.9 Hz,
OCH2), 7.00 (d, 1H, J3,4 ¼ 9 Hz, H-3), 7.97 (d, 1H, J4,6 ¼ 3 Hz, H-6),
8.15 (dd, 1H, J3,4 ¼ 9 Hz, J4,6 ¼ 3 Hz, H-4). 13C NMR (75 MHz, CDCl3):
d ¼ 14.43, 20.42 (2q, 2 ꢁ CH3), 65.20 (t, OCH2), 112.01, 119.17, 123.24
(3d, arom. CH), 139.53, 140.79, 156.10 (3s, C-1, C-2, C-3), 168.27
(s, CO); IR (KBr, cmꢂ1): 1760 (s), 1600 (s), 1519 (s), 1472 (s), 1348 (s),
1295 (s), 1223 (s); mass (m=z): 226 [M þ H]þ . HRMS calcd. for
[C10H11NO5Na]: 248.0535; found: 248.0528.
2-Decyloxy-5-nitrophenol (5a)
NaOH (672 mg, 0.017 mol) was added to a solution of crude 11a in THF
(25 mL) and stirred at rt for about 1 h. After the reaction was complete
it was quenched with water (50 mL) and neutralized with 20% HCl.
The product was extracted with ether (2 ꢁ 30 mL) and washed with water
(2 ꢁ 50 mL). The organic layer was dried over Na2SO4, concentrated, and
dried.
Yield: 4 g (83%); mp 46–49 ꢀC (lit.[1f] 46–49 ꢀC), 1H NMR (300
¼
MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6 Hz, CH3), 1.28–1.60 (m, 14H,
7 ꢁ CH2), 1.82–1.91 (m, 2H, CH2), 4.15 (t, 2H, J ¼ 6 Hz, OCH2),
5.84 (s, 1H, OH), 6.87 (d, 1H, J3,4 ¼ 9.0 Hz, H-3), 7.79–7.84 (m, 2H,
H-4, H-6).
2-Ethoxy-5-nitrophenol (5b)
NaOH (473 mg, 0.01 mol) was added to a solution of crude 11b in THF
(13 mL) and stirred at rt for about 1 h. After the reaction was complete, it
was quenched with water (30 mL) and neutralized with 20% HCl. The
aqueous solution was extracted with ether (2 ꢁ 20 mL), and the organic
layer was washed with water (2 ꢁ 50 mL), dried over Na2SO4, and
concentrated.

Dissymmetrical Ethers of 4-Nitrocatechol
3097
Yield:2.2 g(98%); mp 113–114 ꢀC (lit.[17] ¼ 113–114 ꢀC), 1H NMR
(300 MHz, CDCl3): d ¼ 1.52 (t, 3H, J ¼ 6 Hz, CH3), 4.25 (q, 2H, J
¼ 6.9 Hz, OCH2), 5.87 (s, 1H, OH), 6.88 (d, 1H, J3,4 ¼ 9 Hz, H-3),
7.80–7.85 (m, 2H, H-4, H-6).
1-Decyloxy-2-ethoxy-4-nitrobenzene (2a)
A solution of 5a (200 mg, 0.67 mmol), and Cs2CO3 (221 mg, 0.67 mmol),
and EPTS (148 mg, 0.74 mmol) in DMF (2.5 mL) was stirred at 70–80 ꢀC
under a nitrogen atmosphere for about 1.5 h. The resulting mixture was
cooled to 0 ꢀC, water (20 mL) was added, and it was neutralized with
20% HCl. The aqueous solution was extracted with ether (2 ꢁ 10 mL)
and the organic layer was washed with water (2 ꢁ 50 mL), dried over
Na2SO4 and concentrated.
ꢀ
ꢀ
1
Yield: 0.44 g (80%); mp 57–58 C (lit.[1f] ¼ 57.5–58.5 C); H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6.9 Hz, CH3), 1.27–1.46 (m,
14H, 7 ꢁ CH2), 1.49 (t, 3H, J ¼ 6.9 Hz, CH2), 1.82–1.91 (m, 2H, CH2),
4.07–4.19 (m, 4H, 2 ꢁ OCH2), 6.86 (d, 1H, J5,6 ¼ 9.0 Hz, H-6), 7.72
(d, 1H, J3,5 ¼ 3 Hz, H-3), 7.87 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5).
1-Decyloxy-2-methoxy-4-nitrobenzene (2b)
A solution of 5a (500 mg, 1.69 mmol), Cs2CO3 (606 mg, 1.85 mmol), and
methyl iodide (0.1 mL, 2.03 mmol) in DMF (2.5 mL) was stirred at rt
under a nitrogen atmosphere for about 1 h. The resulting mixture was
cooled to 0 ꢀC, water (20 mL) was added, and it was neutralized with
20% HCl. The aqueous solution was extracted with ether (2 ꢁ 10 mL),
and the organic layer was washed with water (2 ꢁ 50 mL), dried over
Na2SO4, and concentrated.
Yield: 502 mg (95%); mp 48–50 ꢀC (lit.[1f] ¼ 49–50 ꢀC); 1H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6.9 Hz, CH3), 1.27–1.48 (m,
14H, 7 ꢁ CH2), 1.83–1.93 (m, 2H, CH2), 3.95 (s, 3H, OCH3), 4.10 (t,
2H, J ¼ 6 Hz, OCH2), 6.90 (d, 1H, J5,6 ¼ 9.0 Hz, H-6), 7.75 (d, 1H,
J3,5 ¼ 3 Hz, H-3), 7.90 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5).
1-Decyloxy-2-propyloxy-4-nitrobenzene (2c)
A solution of 5a (2 g, 6.77 mmol), Cs2CO3 (2.4 g, 7.48 mmol), and n-pro-
pylbromide (0.74 mL, 8.1 mmol) in DMF (20 mL) was stirred at 70–80 ꢀC
under a nitrogen atmosphere for about 4 h. The resulting mixture was
cooled to 0 ꢀC, water (50 mL) was added, and it was neutralized with

3098
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
20% HCl. The aqueous solution was extracted with ether (2 ꢁ 100 mL),
and the organic layer was washed with water (2 ꢁ 100 mL), dried over
Na2SO4, and concentrated.
Yield: 1.95 g (85%); mp 58–61 ꢀC (lit.[1f] ¼ 59–61 ꢀC); 1H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6 Hz, CH3), 1.07 (t, 3H,
J ¼ 6 Hz, CH3), 1.27–1.55 (m, 14H, 7 ꢁ CH2), 1.82–1.92 (m, 4H, 2 ꢁ
CH2), 4.01–4.11 (m, 4H, 2 ꢁ OCH2), 6.87 (d, 1H, J5,6 ¼ 9.0 Hz, H-6),
7.73 (d, 1H, J3,5 ¼ 2.4 Hz, H-3), 7.87 (dd, 1H, J5,6 ¼ 9 Hz,
J3,5 ¼ 2.7 Hz, H-5).
1-Decyloxy-2-butyloxy-4-nitrobenzene (2d)
A solution of 5a (2 g, 6.77 mmol), Cs2CO3 (2.4 g, 7.48 mmol), and n-
butylbromide (0.88 mL, 8.13 mmol) in DMF (20 mL) was stirred at 70–
80 ꢀC under a nitrogen atmosphere for about 4 h. The resulting mixture
was cooled to 0 ꢀC, water (50 mL), was added and it was neutralized with
20% HCl. The aqueous solution was extracted with ether (2 ꢁ 100 mL),
and the organic layer was washed with water (2 ꢁ 100 mL), dried over
Na2SO4, and concentrated.
ꢀ
ꢀ
1
Yield: 2.0 g (86%); mp 35–36 C (lit.[1f] ¼ 35–37 C), H NMR(300
MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6 Hz, CH3), 1.0 (t, 3H, J ¼ 7.5 Hz,
CH3), 1.27–1.38 (m, 12H, 6 ꢁ CH2), 1.43–1.56 (m, 4H, 2 ꢁ CH2), 1.80–
1.91 (m, 4H, 2 ꢁ CH2), 4.05–4.11 (m, 4H, 2 ꢁ OCH2),6.89 (d, 1H,
J5,6 ¼ 9 Hz, H-6), 7.73 (d, 1H, J3,5 ¼ 2.6 Hz, H-3), 7.86–7.89 (dd, 1H,
J5,6 ¼ 8.7 Hz, J3,5 ¼ 2.7 Hz, H-5).
1-Decyloxy-2-isopropyloxy-4-nitrobenzene (2e)
A solution of 5a (500 mg, 1.69 mmol), Cs2CO3(660 mg, 1.94 mmol), and
isopropyl bromide (0.5 mL, 0.0042 mol) in DMF (2.5 mL) was stirred at
70–80 ꢀC under a nitrogen atmosphere for about 9 h. The resulting mix-
ture was cooled to 0 ꢀC, water (50 mL) was added, and it was neutralized
with 20% HCl. The aqueous solution was extracted with ether
(2 ꢁ 20 mL), and the organic layer was washed with water (2 ꢁ 50 mL),
dried over Na2SO4, and concentrated.
ꢀ
ꢀ
1
Yield: 0.46 g (81%); mp 45–46 C (lit.[1f] ¼ 45.5–47.5 C); H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6.9 Hz, CH3) 1.27–1.35 (m,
12H, 6 ꢁ CH2), 1.38 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.45–1.47 (m, 2H,
CH2), 1.81–1.90 (m, 2H, CH2), 4.08 (t, 2H, J ¼ 9 Hz, OCH2), 4.53–4.61
(m, 1H, OCH), 6.87 (d, 1H, J5,6 ¼ 9.0 Hz, H-6), 7.77 (d, 1H,
J3,5 ¼ 3 Hz, H-3), 7.87 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5).

Dissymmetrical Ethers of 4-Nitrocatechol
3099
2-Allyloxy-1-decyloxy-4-nitrobenzene (2f)
A solution of 5a (500 mg, 1.69 mmol), Cs2CO3 (683 mg, 2.0 mmol), and
allylbromide (0.4 mL, 4.6 mol) in DMF (2.5 mL) was stirred at 60–70 ꢀC
under a nitrogen atmosphere for about 5 h. The resulting mixture was
cooled to 0 ꢀC, water (50 mL) was added, and it was neutralized with
20% HCl. The aqueous solution was extracted with ether (2 ꢁ 20 mL),
and the organic layer was washed with water (2 ꢁ 50 mL), dried over
Na2SO4, and concentrated.
Yield: 0.53 g (93%); mp 36–37 ꢀC (lit.[1f] ¼ 36–38 ꢀC), 1H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6 Hz, CH3), 1.27–1.42 (m,
12H, 6 ꢁ CH2), 1.43–1.54 (m, 2H, CH2), 1.83–1.92 (m,2H, CH2), 4.10
(t, 2H, J ¼ 6 Hz, OCH2), 4.67 (dt, 2H, J ¼ 5.2 Hz, OCH2), 5.34 (dq,
1H, J ¼ 1.5, 9.0 Hz, H-A), 5.47 (dq, 1H, J ¼ 1.5, 18 Hz, H-B), 6.01–
6.14 (m, 1H, H-C), 6.91 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.75 (d, 1H,
J3,5 ¼ 3 Hz, H-3), 7.89 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5).
2-Benzyloxy-1-decyloxy-4-nitrobenzene (2g)
A solution of 5a (500 mg, 1.69 mmol), Cs2CO3 (606 mg, 1.86 mmol), and
benzyl chloride (0.2 mL, 0.0202 mole) in DMF (2.5 mL) was stirred at
60–70 ꢀC under N2 atm for about 1 h. The reaction mixture was cooled
to 0 ꢀC, water (50 mL) was added, and it was neutralized with 20%
HCl and worked up as usual.
Yield: 0.55 g (84%); mp 39–42 ꢀC; 1H NMR (300 MHz, CDCl3):
d ¼ 0.88 (t, 3H, J ¼ 6 Hz, CH3), 1.27–1.42 (m, 12H, 6 ꢁ CH2), 1.44–
1.55 (m, 2H, CH2), 1.83–1.92 (m, 2H, CH2), 4.11 (t, 2H, J ¼ 6 Hz,
OCH2), 5.19 (s, 2H, PhCH2), 6.92 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.33–7.48
(m, 5H, arom. CH), 7.81 (d, 1H, J3,5 ¼ 3 Hz, H-3), 7.90 (dd, 1H,
J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5); 13C NMR (75 MHz, CDCl3): d ¼ 14.13
(q, CH3), 22.70, 25.95 (2t, CH2), 28.92, 29.33, 29.53, 29.58 (4t, CH2),
31.90 (t, CH2), 69.45 (t, OCH2), 71.18 (t, PhCH2), 109.25, 111.13,
118.30, 127.27, 128.18, 128.63 (6d, arom. CH), 136.06, 141.02, 147.98,
155.00 (4s, arom. C); IR (KBr, cmꢂ1): 2940( s), 2917 (s), 2851 (s), 1590
(m), 1516 (s), 1504 (s), 1388 (w), 1352 (s); mass (m=z): 385 [M þ H]þ ;
HRMS: calcd. for [C23H31NO4Na]: 408.2151; found: 408.2157.
1-Ethoxy-2-methoxy-4-nitrobenzene (2h)
A solution of 5b (0.2 g, 1.09 mmol), Cs2CO3 (0.355 g, 0.01 mol), and
methyl iodide (0.3 mL, 4.81 mmol) in DMF (1 mL) was stirred at rt under
a nitrogen atmosphere for about 3 h. The resulting mixture was cooled to

3100
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
0 ꢀC, quenched with water (50 mL), and neutralized with 20% HCl.
The aqueous solution was extracted with ether (2 ꢁ 20 mL), and the
organic layer was washed with water (2 ꢁ 50 mL), dried over Na2SO4,
and concentrated.
ꢀ
ꢀ
1
Yield: 0.2 g (94%), mp 85–87 C (lit.[14] ¼ 85–88 C); H NMR (300
MHz, CDCl3): d ¼ 1.52 (t, 3H, J ¼ 9 Hz, CH3), 3.96 (s, 3H, OCH3),
4.22 (q, 2H, J ¼ 9 Hz, OCH2), 6.91 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.75 (d,
1H, J3,5 ¼ 3 Hz, H-3), 7.90 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5).
2-Decyloxy-1-ethoxy-4-nitrobenzene (2i)
A solution of 5b (0.3 g, 1.63 mmol), Cs2CO3 (587 mg, 1.86 mmol), and
decylbromide (0.4 mL, 1.95 mmol) in DMF (3 mL) was stirred at 60–
70 ꢀC under N2 atm for about 30 min. The resulting mixture was cooled
to 0 ꢀC, quenched with H2O (50 mL), and neutralized with 20% HCl, then
worked up as usual. The crude was crystallized with methanol (5 mL) and
ꢀ
1
dried. Yield: 502 mg (95%); mp 60–62 C; H NMR (300 MHz, CDCl3):
d ¼ 0.88 (t, 3H, J ¼ 6 Hz, CH3) 1.28 (m, 12H, 6 ꢁ CH2), 1.48–1.54 (m,
5H, J ¼ 6 Hz, CH3, CH2), 1.84–1.89 (m, 2H, CH2), 4.07 (t, 2H, J ¼ 6 Hz,
Hz, OCH2), 4.19 (q, 2H, J ¼ 6 Hz, OCH2), 6.90 (d, 1H, J5,6 ¼ 9 Hz, H-6),
7.74 (d, 1H, J3,5 ¼ 3 Hz, H-3), 7.89 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz,
H-5); 13C NMR (75 MHz, CDCl3): d ¼ 14.33, 14.55 (2q, 2 ꢁ CH3),
22.69 (t, CH2), 25.90 (t, CH2), 28.88 (t, CH2), 29.33, 29.54 (4t, 2 ꢁ 2CH2),
), 64.97 (t, OCH2) 64.53 (t, OCH2), 107.95, 110.96, 117.65 (3d, 3 ꢁ arom.
CH), IR (KBr, cmꢂ1): 2853 (m), 2274 (m), 1584 (m), 1513 (s), 1344 (s),
1279 (s), 1232 (s); mass (m=z): 323 [M þ H]þ . HRMS calcd. for
[C18H30NO4]: 324.2175; found: 324.2182.
1-Ethoxy-4-nitro-2-propyloxybenzene (2j)
A solution of 5b (0.3 g, 1.63 mmol), Cs2CO3 (587 mg, 1.86 mmol), and
n-propyl bromide (0.18 mL, 1.95 mmol) in DMF (3 mL) was stirred at
60–70 ꢀC under N2 atm for about 3 h. The resulting mixture was cooled
to 0 ꢀC, quenched with H2O (50 mL), and neutralized with 20% HCl, then
worked up as usual.
Yield:0.32 g (89%); mp 65–67 ꢀC; 1H NMR (300 MHz, CDCl3):
d ¼ 1.07 (t, 3H, J ¼ 7.5 Hz, CH3), 1.50 (t, 3H, J ¼ 7.2 Hz, CH3), 1.91
(sexet, 2H, J ¼ 7.2 Hz, CH2), 4.04 (t, 2H, J ¼ 6 Hz, OCH2), 4.20 (q,
2H, J ¼ 6 Hz, OCH2), 6.90 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.73 (d, 1H,
J3,5 ¼ 3 Hz, H-3), 7.89 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5); 13C
NMR (75 MHz, CDCl3): d ¼ 10.39 (q, CH3), 14.55 (q, CH3), 22.30
(t, CH2), 64.98, 70.92 (2t, 2 ꢁ CH2), 108.01, 111.00, 117.68 (3d, 3 ꢁ arom.

Dissymmetrical Ethers of 4-Nitrocatechol
3101
om. CH), 141.22, 148.54, 154.42 (3s, 3 ꢁ arom. C), IR (KBr, cmꢂ1): 2939
(m), 2879 (m), 1586 (m), 1500 (s), 1347 (s), 1289 (s), 1231 (s), 1140 (w);
mass (m=z): 225 [M þ H]þ . HRMS calcd. for [C11H16NO4]: 226.1079;
found: 226.1073.
2-Butoxy-1-ethoxy-4-nitrobenzene (2k)
A solution of 5b (0.3 g, 1.63 mmol), Cs2CO3 (587 mg, 1.86 mmol), and
n-butylbromide (0.2 mL, 1.96 mmol) in DMF (3 mL) was stirred at 70–
80 ꢀC under N2 atm for about 0.5 h. The resulting mixture was cooled
to 0 ꢀC, quenched with H2O (50 mL), and neutralized with 20% HCl, then
worked up as usual.
Yield: 0.35 g (88%); mp 59–60 ꢀC; 1H NMR (300 MHz, CDCl3):
d ¼ 1.00 (t, 3H, J ¼ 7.5 Hz, CH3), 1.46–1.56 (m, 5H, CH3, CH2), 1.86
(m, 2H, CH2), 4.08 (t, 2H, J ¼ 6 Hz, OCH2), 4.19 (q, 2H, J ¼ 6 Hz,
OCH2), 6.90 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.74 (d, 1H, J3,5 ¼ 3 Hz, H-3),
7.88 (dd, 1H, J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5), 13C NMR (75 MHz, CDCl3):
d ¼ 13.85, 14.55 (2q, 2 ꢁ CH3), 19.18, 30.95 (2t, 2 ꢁ CH2), 64.98, 69.23
(2t, 2 ꢁ OCH3), 107.98, 110.99, 117.66 (3d, 3 ꢁ arom. CH), 141.23,
148.58, 154.42 (3s, 3 ꢁ arom. C); IR (KBr, cmꢂ1): 2935 (m), 2874 (m),
1587 (m), 1522 (s), 1504 (s), 1476 (w), 1396 (w), 1341 (s), 1282 (s); mass
(m=z): 239 [M þ H]þ . HRMS calcd. for [C12H18NO4]: 240.1236; found:
240.1237.
1-Ethoxy-2-isopropoxy-4-nitrobenzene (2l)
A solution of 5b (0.5 g, 2.7 mmol), Cs2CO3 (890 mg, 2.7 mmol), and iso-
propylbromide (0.3 mL, 3.2 mmol) in DMF (2.5 mL) was stirred at 70–
80 ꢀC under N2 atm for about 5 h. The resulting mixture was cooled to
0 ꢀC, quenched with H2O (50 mL), and neutralized with 20% HCl, then
worked up as usual.
Yield: 0.5 g (81%); mp 55–57 ꢀC; 1H NMR (300 MHz, CDCl3):
d ¼ 1.39, 1.41 (2s, 6H, 2 ꢁ CH3), 1.49 (t, 3H, J ¼ 9 Hz, CH3), 4.16
(q, 2H, J ¼ 9 Hz, OCH2), 4.59 (septet, 1H, J ¼ 6 Hz, OCH), 6.89 (d,
1H, J5,6 ¼ 9 Hz, H-6), 7.76 (d, 1H, J3,5 ¼ 3 Hz, H-3), 7.88 (dd, 1H,
J5,6 ¼ 9 Hz, J3,5 ¼ 3 Hz, H-5); 13C NMR (75 MHz, CDCl3): d ¼ 14.55
(q, CH3), 21.92 (q, CH3), 64.96 (t, OCH2), 72.52 (d, OCH), 111.12,
111.44, 118.06 (3d, 3 ꢁ arom. C-H), 141.10, 147.30, 155.50 (3s, 3 ꢁ arom.
om. C), IR (KBr, cmꢂ1): 2896 (m), 2636 (w), 1852 (w), 1583 (m), 1504 (s),
1474 (m), 1340 (s), 1260 (s), 1229 (s), 1109 (m); mass (m=z): 225
[M þ H]þ . HRMS calcd. for [C11H16NO4]: 226.1079; found: 226.1081.

3102
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
2-Allyloxy-1-ethoxy-4-nitrobenzene (2m)
A solution of 5b (0.5 g, 2.7 mmol), Cs2CO3 (889 mg, 2.7 mmol), and allyl-
bromide (0.27 mL, 3.2 mmol) in DMF (2.5 mL) was stirred at 70–80 ꢀC
under N2 atm for about 1 h. The resulting mixture was cooled to 0 ꢀC,
quenched with H2O (50 mL), and neutralized with 20% HCl, then
worked up as usual. The crude solid (580 mg) ꢀwas purified by column
1
chromatography. Yield: 0.5 g (82%); mp 40–42 C; H NMR (300 MHz,
CDCl3): d ¼ 1.51 (t, 3H, J ¼ 6.9 Hz, CH3), 4.20 (q, 2H, J ¼ 6.9 Hz
OCH2), 4.68 (dt, 2H, J ¼ 1.5, 6.0 Hz, OCH2), 5.35 (dq, 1H, J ¼ 1.5,
9.0 Hz, H-A), 5.47 (dq, 1H, J ¼ 1.5, 18 Hz, H-B), 6.02–6.16 (m, 1H, H-
C), 6.90 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.75 (d, 1H, J3,5 ¼ 2.6 Hz, H-3), 7.91
(dd, 1H, J5,6 ¼ 8.8 Hz, J3,5 ¼ 2.6 Hz, H-5); 13C NMR(75 MHz, CDCl3):
d ¼ 14.54 (q, CH3), 64.99 (t, OCH2), 70.05 (t, OCH2), 108.54 (d, C-3),
110.95 (d, C-6), 118.02 (d, C-5), 118.58 (t ¼ CH2), 132.22 (d, CH),
141.08, 147.83, 154.44 (3s, arom. C), IR (KBr, cmꢂ1): 2932 (m), 2937
(w), 1586 (w), 1514 (s), 1345 (s), 1277 (s), 1232 (s), 1137 (w), 1093 (m).
mass (m=z): 223 [M þ H]þ . HRMS calcd. for [C11H13NO4Na]:
246.0742; found: 246.0745.
2-Benzyloxy-1-ethoxy-4-nitrobenzene (2n)
A solution of 5b (0.2 g, 1.09 mmol), Cs2CO3 (355 mg, 1.09 mmol), and
benzylchloride (0.15 mL, 1.3 mmol) in DMF (1 mL) was stirred at 60–
70 ꢀC under a nitrogen atmosphere for about 2 h. The resulting mixture
was cooled to 0 ꢀC, quenched with water (30 mL), and neutralized with
20% HCl. The aqueous solution was extracted with ether (2 ꢁ 30 mL),
and the organic layer was washed with water (2 ꢁ 40 mL), dried over
Na2SO4, concentrated, and dried. Yield: 0.27 g (91%); mp 101-102 ꢀC
(lit.[6f] ¼ 101–102 ꢀC); 1H NMR (300 MHz, CDCl3): d ¼ 1.53 (t, 3H,
J ¼ 7.2 Hz, CH3), 4.21 (q, 2H, J ¼ 7.2 Hz OCH2), 5.20 (s, 2H, OCH2Ph),
6.92 (d, 1H, J5,6 ¼ 9 Hz, H-6), 7.31–7.48 (m, 5H, arom. CH), 7.80 (d, 1H,
J3,5 ¼ 3 Hz, H-3), 7.90 (dd, 1H, J3,5 ¼ 9 Hz, J5,6 ¼ 3 Hz, H-5).
4-Decyloxy-3-ethoxy-phenylamine[1f] (3)
To a solution of 2a (50 g, 0.156 mol) dissolved in ethyl acetate (300 mL)
and ethanol (100 mL) 10% Pd=C was added and kept under 6 bar of
hydrogen for 30 min. The solution was filtered over Celite1 and washed
with ethyl acetate (50 mL). The filtrate was concentrated and dried.
Yield: 44.2 g (97%), 1H NMR (300 MHz, CDCl3): d ¼ 0.88 (t, 3H,
J ¼ 6.9 Hz, CH3), 1.27 (s, 12H, 6 ꢁ CH2), 1.39–1.44 (m, 5H, J ¼ 6.9 Hz,

Dissymmetrical Ethers of 4-Nitrocatechol
3103
CH3, CH2), 1.70–1.80 (m, 2H, J ¼ 7.5 Hz, CH2), 3.39 (s, 2H, NH2), 3.90
(t, 2H, J ¼ 6.9 Hz, OCH2), 4.02 (q, 2H, J ¼ 6.9 Hz, OCH2), 6.20 (dd, 1H,
J5,6 ¼ 9.0 Hz, J6,2 ¼ 3.0 Hz, H-6), 6.30 (d, 1H, J2,6 ¼ 3.0 Hz, H-2), 6.74
(d, 1H, J5,6 ¼ 9.0 Hz, H-5).
6-Decyloxy-7-ethoxy-4-hydroxy-quinoline-3-carboxylic Acid Ethyl
Ester (1a)
Synthesis of Intermediate 2-[(4-Decyloxy-3-ethoxy-phenylamino)-meth-
lylene]-malonic acid diethyl ester
Diethylethoxy methylenemalonate (6.3 g, 0.029 mol) to 3 (8.6 g,
0.029 mol) was added, and stirred at 35–40 ꢀC for about 4 h. Reaction
was monitored by thin-layer chromatography (TLC). After reaction com-
pletion, the reaction mixture was concꢀentrated to remove ethanol.
Yield: 13.2 g (98%); mp 38– 40 C (lit.[1f] ¼ 38–40 ꢀC); 1H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6.0 Hz, CH3), 1.22–1.40 (m,
20H, 10 ꢁ CH2), 1.43–1.48 (m, 5H, CH2, CH3), 1.76–1.86 (m, 2H,
CH2), 3.98 (t, 2H, J ¼ 6.0 Hz, OCH2), 4.09 (q, 2H, J ¼ 6.0 Hz, OCH2),
4.21–4.34 (m, 4H, 2 ꢁ OCH2), 6.66–6.69 (m, 2H, H-5, H-2), 6.88 (d,
1H, J5,6 ¼ 9.0 Hz, H-6), 8.41 (d, 1H, J ¼ 15.0 Hz, ¼ CH), 10.99 (d, 1H,
J ¼ 12.0 Hz, NH).
Synthesis of 1a from 2-[(4-Decyloxy-3-ethoxy-phenylamino)methylene]-
malonic acid diethyl ester
A solution of 2-[(4-decyloxy-3-ethoxy-phenylamino)-methlylene]-malonic
acid diethyl ester (5 g) in Dowtherm A (20 mL) was heated to 260–270 ꢀC
for about 15 min. The reaction mixture was cooled and diluted with
hexane (300 mL). A white solid was precipitated. The solid was filtered
and washed with hexane, then dried at high vacuum.
ꢀ
ꢀ
1
Yield: 2.6 g (57%); mp 246–248 C (lit.[1f] ¼ 244–246 C); H NMR
(300 MHz, CDCl3): d ¼ 0.88 (t, 3H, J ¼ 6.9 Hz, CH3), 1.27–1.36 (m,
11H, CH3, 4 ꢁ CH2), 1.45–1.57 (m, 9H, CH3, 3 ꢁ CH2), 1.87–1.97 (m,
2H, CH2), 4.15 (t, 2H, J ¼ 6.9 Hz, OCH2), 4.26 (q, 2H, J ¼ 6.9 Hz,
OCH2), 4.48 (q, 2H, J ¼ 6.9 Hz, OCH2), 7.33, 7.50 (2s, 2H,H-5, H-8),
8.95 (s, 1H, H-2), 12.14 (s, 1H, OH).
ACKNOWLEDGMENTS
We are grateful to Shasun Research Centre (SRC) for providing the
facility to do this work and for the encouragement. Our thanks are due

3104
M. Subashini, K. K. Balasubramanian, and S. Bhagavathy
to the SRC-QC for analytical data. We also thank M. Kathiresan for
some laboratory assistance and K. Manikandan for literature assistance.
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