Novel synthesis of anthelmintic drug 4-isothiocyanato-4′- nitrodiphenyl ether and its analogs

Article abstract of DOI:10.1080/00397910802448481

An efficient, mild, chemoselective, and convenient protocol for synthesis of isothiocyanate derivatives. This protocol was applied successfully in the novel synthesis of anthelmintic drug 4-isothiocyanato-4′-nitrodiphenyl ether and its analogs. Copyright Taylor & Francis Group, LLC.

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Novel Synthesis of Anthelmintic
Drug 4-Isothiocyanato-4′-
nitrodiphenyl Ether and Its
Analogs
A. C. Chaskar a , B. P. Bandgar b , R. K. Modhave a
A. B. Patil a & S. Yewale a
,
a C. K. Thakur Research Centre, Navi Mumbai,
Maharashtra, India
b Solapur University, Solapur, Maharashtra, India
Version of record first published: 25 Feb 2009.
To cite this article: A. C. Chaskar, B. P. Bandgar, R. K. Modhave, A. B. Patil & S.
Yewale (2009): Novel Synthesis of Anthelmintic Drug 4-Isothiocyanato-4′-nitrodiphenyl
Ether and Its Analogs, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:6, 992-1001
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Synthetic Communications1, 39: 992–1001, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802448481
Novel Synthesis of Anthelmintic Drug
4-Isothiocyanato-40-nitrodiphenyl Ether
and Its Analogs
A. C. Chaskar,1 B. P. Bandgar,2 R. K. Modhave,1
A. B. Patil,1 and S. Yewale1
1C. K. Thakur Research Centre, Navi Mumbai, Maharashtra, India
2Solapur University, Solapur, Maharashtra, India
Abstract: An efficient, mild, chemoselective, and convenient protocol for
synthesis of isothiocyanate derivatives. This protocol was applied successfully
in the novel synthesis of anthelmintic drug 4-isothiocyanato-40-nitrodiphenyl
ether and its analogs.
Keywords: Amines, carbon disulfide, ferrous sulfate, isothiocyanates, triethyl-
amine
INTRODUCTION
Isothiocyanates are key intermediates in the synthesis of various hetero-
cycles[1,2] and agrochemicals that have antifungal and anthelmintic
activities.[3–5] Isothiocyanates have exhibited antitumor and antiparasitic
activities[3,4] and are used in the preparation of irreversible inhibitors.[6] Iso-
thiocyanates[7] exist in nature as marine sesquiterpenes and play important
roles as antiproliferatives.[8] They are also used in the therapy of blood can-
cer as enzyme inhibitors for the HIV virus[9] and are used as herbicides.[10]
Various methods have been reported for the synthesis of isothiocya-
nates from amines,[11–16] isocyanides,[17,18] organic halides,[19,20] olefins,[21,22]
nitrile oxides,[23] and aldoximes.[24] To obtain isothiocyanate from
amines, the most widely used methods involve reaction of the amine with
Received June 21, 2008.
Address correspondence to A. C. Chaskar, C. K. Thakur Research Centre,
Navi Mumbai, Maharashtra, India 410206. E-mail: achaskar@rediffmail.com
992

4-Isothiocyanato-40-nitrodiphenyl Ether
993
an activated thiocarbonyl such as thiophosgene,[25] thiocarbonyl
diimidazole,[26] and di-2-pyridyl thiocarbonate.[27] However, most of the
reported literature methods suffered from one or more drawbacks such
as use of toxic reagents, long reaction times, low yields, and inconvenient
workup procedures. Therefore it is necessary to develop a facile synthetic
procedure for the preparation of isothiocyanates.
In the continuation of our ongoing program to develop efficient
reagents for the conversion of amines to isothiocyanates,[28] this article
describes ferrous sulfate as a novel catalyst for the synthesis of
isothiocyanates (Scheme 1).
RESULTS AND DISCUSSION
Amine, carbon disulfide, and acetone were stirred at room temperature
to form dithiocarbamate salt, which was subsequently treated with
triethyl amine and ferrous sulfate to secure isothiocyanates. This
reaction could not be completed without ferrous sulfate; therefore it
acts as a catalyst. The pure product was isolated using n-hexane. A
broad range of structurally diverse aromatic amines have been used
(Table 1).
This novel methodology is used for the synthesis of anthelmintic drug
4-Isothiocyanato-40-nitrodiphenyl ether (Scheme 2).
CONCLUSION
In conclusion, this is an efficient, simple, and novel methodology for
synthesis of isothiocyanates. Relatively short reaction times, utilization
of cheap and readily available reagents, and high yields of products are
some of the advantages of the present protocol. These advantages make
the present method useful for large-scale operations.
Scheme 1. Synthesis of isothiocyanate.

994
A. C. Chaskar et al.
Scheme 2. Synthesis of 4-isothiocyanato-40-nitrodiphenyl ether.
EXPERIMENTAL
Melting points were taken in open capillaries. The IR spectra were
recorded on a Perkin-Elmer 257 spectrometer using KBr discs. 1H
NMR and 13C NMR spectra in CDCl3 were recorded on a VXR 300-
MHz instrument using TMS as internal standard, and mass spectra were
recorded on Shimadzu GC-MS. The homogeneity of the compounds was
described by thin-layer chromatography (TLC) on silica-gel plates. The
spots were developed in an iodine chamber.
4-Acetamindo-40-nitrodiphenyl Ether (3)
4-Acetamidophenol (1.51 g, 0.01 mol; 1), p-nitrochlorobenzene (1.57 g,
0.01 mol; 2), potassium carbonate (3.2 g), and dimethylformamide
(10.0 ml) were charged in a round-bottom flask under stirring. The reac-
ꢀ
tion mass was heated at 153 C for 5 h. The progress of the reaction was

4-Isothiocyanato-40-nitrodiphenyl Ether
995
Table 1. Synthesis of various isothiocyanates using ferrous sulfate
Sr.
No.
Time Yield
(h) (%)
Substrate
Product
1
2
95
2
3
4
2
94
2.5 72
2.5 78
5
2
2
84
76
6
7
8
3.5 84
3
79
(Continued )

996
A. C. Chaskar et al.
Table 1. Continued
Sr.
No.
Time Yield
(h) (%)
Substrate
Product
9
3
80
10
11
3
69
3
68
12
3.5 65
monitored by TLC. The reaction mass was quenched in 40.0 ml deionized
water. The product was isolated by filtration and dried in an air oven at
ꢀ
50 C. Purification of crude product was done using ethanol and acti-
ꢀ
vated charcoal. Yield: 120% w=w; melting point: 151 to 153 C.
1H NMR (CDCl3) (d ppm): 8.4 (s, 1H), 8.17 (d, 2H, J ¼ 7.8 Hz), 7.2 (d,
2H, J ¼ 7.8 Hz), 7.3 (d, 2H, J ¼ 7.0 Hz), 7.6 (d, 2H, J ¼ 7.0 Hz), 2.22 (s, 3H).
4-Amino-40-nitrodiphenyl Ether (4)
4-Acetamindo-40-nitrodiphenyl ether (2.72 g 0.01 mol) was treated with
concentrated hydrochloride (8.0 ml) and deionized water (4.0 ml) in a
round-bottom flask and slowly heated to reflux temperature for 3 h.
The reaction was monitored by TLC using a dichloromethane–methanol
(9:1) solvent system. The reaction mass was filtered through a Buckner

4-Isothiocyanato-40-nitrodiphenyl Ether
997
ꢀ
filter and cooled at 40 to 50 C. The reaction mass was basified slowly
under stirring with 50% sodium hydroxide solution. The precipitate
was isolated and purified by uꢀsing charcoal treatment. Yield: 63.54%
w=w; melting point: 135 to 137 C.
1H NMR (CDCl3) (d ppm): 8.10 (d, 2H, J ¼ 7.6 Hz), 6.9 (d, 2H,
J ¼ 7.6 Hz), 7.1 (d, 2H, J ¼ 7.1 Hz), 6.7 (d, 2H, J ¼ 7.1 Hz), 3.71 (s, 2H).
4-Isothiocyanato-40-nitrodiphenyl Ether (5)
4-Amino-40-nitrodiphenyl ether (2.30 g, 0.01mol), carbon disulfide (0.6 ml),
triethylamine (7 ml), and acetone (10 ml) was charged into a round-bottom
flask. The reaction mixture was stirred at room temperature for 1 h. to
achieve triethylammonium dithiocarbamate salt. Then a pinch of ferrous
sulfate and triethyl amine was added in triethylammonium dithiocarbamate
salt, and the stirring was continued for 2 h. The reaction progress was mon-
itored by TLC. After completion of the reaction, excess carbon disulfide
was removed by distillation. The reaction mass was quenched in 50ml
ice-cold water with constant stirring. The product was isolated by filtration
and dried under vacuum. The product was purified using n-hexane. Yield:
68% w=w; HPLC purity: 99%; melting point 122 to 124 ꢀC.
1
IR (KBr): 2087, 1660, 1585, 1540, 1370, 1100, 870, 792. H NMR
(CDCl3) (d ppm): 8.13 (d, 2H, J ¼ 7.8 Hz), 6.9 (d, 2H, J ¼ 7.8 Hz), 7.02
(d, 2H, J ¼ 7.4 Hz), 7.30 (d, 2H, J ¼ 7.4 Hz). 13C NMR (CDCl3)
(d ppm): 162.9, 155.7, 140.8, 136, 125.2, 124, 120.6, 118.8, 118.1. Elem.
anal. calcd.: C, 57.35; H, 2.96; N, 10.29; O, 17.63; S, 11.78. Found: C,
57.13; H, 2.98; N, 10.17; O, 17.68; S, 12.10.
Compound 10
IR (KBr): 2087, 1640, 1560, 1536, 1372, 1109, 868, 790. 1H NMR
(CDCl3) (d ppm): 7.3 (s, 1H), 7.18 (d, 1H, J ¼ 6.8 Hz), 6.9 (d, 1H,
J ¼ 6.8 Hz), 7.0 (d, 2H, J ¼ 7.0 Hz), 7.32 (d, 2H, J ¼ 7.0 Hz). 13C NMR
(CDCl3) (d ppm): 157.08, 152, 136.03, 131.32, 128.70, 128.67, 127.03,
125.92, 125, 120.78, 120.43. Elem. anal. calcd.: C, 52.72; H, 2.38; Cl,
23.94; N, 4.73; O, 5.40; S, 10.83. Found: C, 52.87; H, 2.37; Cl, 24.03;
N, 3.98; O, 6.32; S, 11.14.
Compound 11
1
IR (KBr): 2082, 1651, 1520, 1107, 873, 798. H NMR (CDCl3) (d ppm):
7.1 (s, 1H), 7.19 (d, 1H, J ¼ 6.8 Hz), 7.0 (d, 1H, J ¼ 6.8 Hz), 6.85 (d, 2H,

998
A. C. Chaskar et al.
J ¼ 7.4 Hz), 7.28 (d, 2H, J ¼ 7.4 Hz). 13C NMR (CDCl3) (d ppm): 157.82,
156.13, 135.43, 130.12, 129.80, 128.68, 127.15, 125.97, 120.05, 119.15,
118.90. Elem. anal. calcd.: C, 52.72; H, 2.38; Cl, 23.94; N, 4.73; O, 5.40;
S, 10.83. Found: C, 53.10; H, 2.45; Cl, 23.57; N, 4.87; O, 5.13; S, 10.68.
Compound 12
1
IR (KBr): 2085, 1648, 1522, 1110, 868, 790. H NMR (CDCl3) (d ppm):
7.9 (s, 1H), 8.3 (d, 1H, J ¼ 7.6 Hz), 7.3 (d, 1H, J ¼ 7.6 Hz), 7.1 (d, 2H,
J ¼ 7.2 Hz), 7.30 (d, 2H, J ¼ 7.2 Hz). 13C NMR (CDCl3) (d ppm):
161.30, 158.20, 141.45, 137.12, 134.80, 129.81, 125.60, 119.12, 117.90,
112.60. Elem. anal. calcd.: C, 49.21; H, 2.22; N, 13.24; O, 25.21; S,
10.11. Found: C, 50.43; H, 2.90; N, 14.01; O, 24.85; S, 11.04.
Calculation for the Purity of 4-Isothiocyanato-40-nitrodiphenyl Ether
Preparation of Solutions
(a) n-Butyl amine (10 g) was dissolved in 500 ml 1,4-dioxane; (b) 0.4 g of
sodium hydroxide was dissolved in 100 ml distilled water; (c) 2.72 ml of
concentrated sulfuric acid (98%) was diluted to 1000 ml with distilled
water.
Blank Titration
n-Butyl amine solution 25 ml and 50 ml distilled water were taken in a
conical flask, and 2–3 drops of phenolphthalein indicator were added.
This solution was titrated against 0.1 N sulfuric acid solution. The read-
ing was noted at the endpoint (color changes from pink to colorless and
stable for 10 to 15 min).
Back Titration Reading
Product 5 (0.272 g) was weighed, and 25 ml n-butyl amine solution were
added to it. The mixture was stirred for 15 min. Then 50 ml distilled water
and 2–3 drops of phenolphthalein indicator were added. This solution
was titrated against 0.1 N sulfuric acid solution. The reading was noted
at the endpoint (color changes from pink to colorless and is stable for
10 to 15 min).

4-Isothiocyanato-40-nitrodiphenyl Ether
999
Calculation for Purity of 4-Isothiocyanato-40-nitrodiphenyl Ether
ðBlank reading ꢁ Back readingÞ ꢂ Normality of sulfuric acid
ꢂMolecular weight of product 5 ꢂ 100
Weight of product 5 ꢂ 1000
% Purity ¼
ACKNOWLEDGMENT
The authors gratefully acknowledge for the financial support from the
University Grants Commission, New Delhi. The authors are thankful
to Dr. S. T. Gadade, principal, C. K. Thakur College, for providing
laboratory and other facilities. The authors are also thankful to Cipla
Ltd. for help with the analytical analysis.
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