Synthesis of Some New 2-Amino 5-Phenoxybenzenethiols

SYNTHESIS OF SOME NEW 2-AMINO 5-PHENOXYBENZENETHIOLS.

PHENOTHIAZINES, NITROPHENOTHIAZINES, BENZOTHIAZONES

AND THEIR SULPHONES

A

SUMMARY

Submitted to the

M.J.P. Rohilkhand University, Bareilly

For the Degree

Of

DOCTOR OF PHILOSOPHY

in

CHEMISTRY

2007

Supervision : Submitted By :

Dr. A.K. AGARWAL PINKESH KUMAR

Reader,

Department of Chemistry

Hindu College, Moradabad

Summary

Synthesis of some new 2-Amino 5-phenoxybenzene-thiols, phenothiazines, Nitrophenothiazines, benzo-thiazines and their sulphones

Submitted by :- Pinkesh Kumar Supervisor :- Dr. A.K. Agrawal

Introduction :-

Phenothiazines exhibit anticancer activities1-20 and reserches are being pursued to develop potent anticancer agents. Phenothiazines also find uses as heat stabilizers21, indicators22, antioxidants23-25, dyes26,27, photosensitizers28 and lubricants29. A fold along nitrogen suphur axis present in phenothiazines as well as 1, 4 benzothiazines is considered a structural specificity responsible to impart a wide spectrum of pharmacological and biological activities.

Structural resemblence of 1:4 benzothiazines to pheno-thiazines and their pharmacological30-35 and industrial applications36-40 have focussed our interest to explore their medicinal potential. They have been synthesised in the present work with slight modifications in the substitution pattern to get some unknown phenothiazines & benzothiazines. Heterocylic sulphones have also been reported to possess bioloical activity41-45 and it is considered worth while to synthesize benzothiazine sulphones to explore their biological potential.

In the present work we synthesize some new phenothiazines, 4H-1:4 benzothiazines and sulphones of benzothiazines to explore their medicinal potential.

EXPERIMENTAL :-

A. Synthesis of 2-Amino 5-Phenoxybenzene Thiol :-

Synthesis of 2-amino 5-phenoxybenzene thiol reqired in the synthesis of phenothiazines, 1:4 benzothiazines and 1:4 benzothiazine sulphones has been prepared by the following method :

a. Preparation of 4–phenoxyphenylthioura (II)

4–Phenoxyaniline (0.1 mole) and a mixture of hydrochloric acid (9 ml.) and water (25 ml.) were taken in a R.B. flask (250 ml.) fitted with condenser and was heated for about 30 minutes. The solution of 4–Phenoxyaniline hydrochloride (I) obtained was allowed to cool down to room temperature and ammonium thiocyanate (0.1 mole) was added. The reaction mixture was refluxed for 4 hours. The solid separated out on cooling was filtered, washed with water, dried and crystallized from ethanol. The prepared compound was found to be 4–phenoxy phenyl thiourea. The physical data are recorded in Table–1.

b. Preparation of 2–amino–6–phenoxybenzothiazole (III)

4–Phenoxyphenylthiourea (II; 0.1 mole) was taken in a two neck R.B. flask (500 ml.) containing chloroform (100ml.) equipped with a mechanical stirrer and dropping funnel. Bromine (0.1 mole) in chloroform (100 ml.) was added dropwise with stirring to the reaction mixture over a period of 1 hour. The temperature was maintained below 5°C. After complete addition of bromine the stirring was continued for a period of 3 hours. The reaction mixture was then refluxed till the evolution of hydrogen bromide vapours ceased (about 4 hours). Chloroform was removed by distillation and resulting solid was treated with sulphur dioxide water and filtered. The filterate was neutralised with aqueous ammonia and the precipitate obtained was filtered, washed well with water and crystallized from ethanol. The resulting compound was found to be 2-amino 6-phenoxy benzothiazole. The physical data are recorded in Table–1.

c. Preparation of 2–amino–5–phenoxybenzenethiol (IV)

2–Amino–6–Phenoxybenzothiazole (III), potassium hydroxide (5 times by weight of 2–aminobenzothiazole) and water (10 times by weight of 2–aminobenzothiazole) were refluxed until the evolution of ammonia gas ceased. The contents were filtered, diluted by addition of cold water and neutralised by 5N acetic acid with vigorous stirring. The temperature of the solution was not allowed to rise above room temperature (controlling by adding ice) otherwise a decomposed greenish mass is resulted instead of 2–aminobenzenethiol. The yellowish precipitate obtained was extracted 3 times with ether. Ether was evaporated and the yellow solid was recrystallized from ethanol. The physical data are recorded in Table–1.

S

NH2HCl NH – C – NH2

NH4SCN

C6H5O in HCl C6H5O

4–Phenoxy Aniline 4–Phenoxy Phenyl

Hydro Chloride Thio Urea

(I) (II)

Br2 in CHCl3

N N

C – NH2 Liq.NH3 C–NH2 HBr

S –NH4Br S

C6H5O C6H5O

2–Amino 6 – Phenoxy benzothiazole

(III)

Hydrolysis KOH + H2O

NH2 NH2

Glacial CH3 COOH

SK –CH3 COOK SH

C6H5O C6H5O

2–Amino 5- Phenoxy benzene thiol

(iv)

The purity of the synthesized compounds has been checked by thin layer chromatography and the structures have been assigned by their elemented analysis and spectrum data.

The physical data of the compound (II), (III) and (IV) are given in the Table – 1.

Table – 1 : Physical Data of Compounds (ii), (iii) and (iv)

Infra-red spectra of 2-amino 5-phenoxybenzene thiol shows two sharp bands at 3460 cm–1 and 3370 cm–1 due to primary amino group and a weak band at 2340 cm–1 due to SH stretching vibrations. The bands at 1255 cm–1 and 1065 cm–1 are attributed to C – O – C asymmetric and symmetric stretching vibrations. The H’NMR spectra of 2-amino 5-phenoxy benzene thiol exhibits a multiplet in the region Ö 7.63 – 6.56 due to aromatic protons and a broad signal due to primary amino group at Ö4.34. A singlet observed at Ö1.58 is assigned to SH proton.

B. Synthesis and Spectral Studies of Phenothiazines and Nitrophenothiazines :-

a. Synthesis of Phenothiazines and their spectral studies :-

Phenothiazines have been synthesised by Smiles rearrangement. 2-Amino 5-Phenoxybenzene thiol (i) was condensed with halonitro-benzenes (ii) (e.g. 4-Chloro 3-nitrobenzoic acid, 0-chloronitrobenzene, 2, 5-dichloronitrobenzene, 2-nitro 4-tri fluoromethyl chlorobenzene, 2,5-dibromonitrobenzene, 1-chloro 2, 4 dinitrobenzene and 4-chloro 3-nitroanisole) to prepare diphenyl sulphides (iii) which on formylation with 90% formic acid and subsequent treatment with alcoholic potassium hydroxide underwent Smiles rearrangement yielding substituted phenothiazines (v).

NH2HCl O2N R

+ CH3COONa

C6H5O SH X Et. OH

(i) (ii) – H X

2-Amino 5-phenoxy Halonitro benzene

benzene thiol NH2 O2N R

C6H5O S

2-amino 2 -nitro (iii)

diphenyl sulphides

90% formylation

HCOOH – H2O

H – C = O H – C = O

N+ Acetone N H O2N R

KOH + C2H5OH

S– O2N R Smiles S

C6H5O Rearran- C6H5O (iv)

-gement 2- formamide 2-nitro

diphenyl sulphides

H – C = O

H

N –HNO2 N

KOH

SH O2N R S

C6H5O (i) C6H5O R

substituted phenothiazines

(v)

where X = Cl, Br

R = H, –COOH, NO2, Cl, Br, –OCH3, CF3

Table–2: Physical Data of the substituted Phenothiazines

The purety of the compounds was checked by Molecular weight determination and TLC. The structures of compounds was prooved by I.R., H. NMR and Mass spectra.

The synthesized phenothiazines are :

a. 7–Carboxy–3–phenoxyphenothiazine

b. 3–Phenoxyphenothiazine

c. 7–Chloro–3–phenoxyphenothiazine

d. 7–Trifluoromethyl–3–phenoxyphenothiazine

e. 7–Bromo–3–phenoxyphenothiazine

f. 7–Nitro–3–phenoxyphenothiazine

g. 7–Methoxy–3–phenoxyphenothiazine

(b). Synthesis of Nitrophenothaizines and their spectral studies :-

To a stirred suspention of 2-amino 5-phenoxybenzene thiol (0.01 mol.), ethanol (20ml.) and sodium hydroxide (0.01 mole) contained in (50 ml.) R.B. flask fitted with a reflux condenser, was added an alcoholic solution of the reactive halonitrobenzene (0.01mole). The colour of the solution was darkened immediately. The contents were then refluxed for 2 hours, concentrated, cooled and filtered. The solid seperated out was washed with hot water followed by 30% ethanol. Crystallisation from methanol or acetone afforded pure compounds. The physical data are tabulated in the Table – 3.

Table – 3 : Physical Data of substituted nitrophenothiazines

H R3

N R2

C6H5O S R1

R

Synthesised nitrophenothiazines are 1:3 dinitro 7–phenoxy phenothiazines, 2,4 dibromo 1–nitro 7–phenoxy phenothiazine, 3–chloro 1–nitro 7–phenoxyphenothiazine and 1–chloro–3–nitro– 7–phenoxyphenothiazine.

All nitrophenothiazines exhibits two sharp and intense bands in the region 1580 – 1550 cm–1 and 1345 – 1330 cm–1 due to vibrations of aromatic nitro group. The sharp bands at 740 and 760 cm–1 are due to C–Cl streching vibrations in halogen substituted compounds.

In N.M.R. spectral data of 3-nitro phenothiazines shows a singlet at Ö9.74 due to N–H proton which is shifted to Ö10.30 – 9.81 in 1-nitrophenothiazines. This shifting towards downfield in 1-nitro phenothiazines is ascribed to intramolecular hydrogen bonding as –NH -----O = N.

H O

N O

N

H5C6O S

C. Synthesis and Spectral studies of 4–H–1, 4 Benzothiazines :-

To a stirred suspention of b - diketone/ b-ketoester (0.01 mole) in D.M.S.O. (6 ml.) was added 2 amino–5–phenoxybenzine thiol (0.01 mole) and the resulting mixture was refluxed for 30–40 minutes, concentrated and cooled down to room temperature. The solid seperated out was filtered, washed with petroleum ether and crystallized from methanol. The physical data of the compounds prepared are tabulated in Table – 4.

Table – 4 : Physical Data of substituted 4H-1, 4-benzothiazines

O

H5C6O S C R1

N R

H

All 4–H–1, 4 benzothiazines exhibit a single sharp peak in the region 3395 – 3270 cm–1 due to N–H stretching vibrations. The bands in the region 1680–1580 cm–1 are observed due to C=O stretching vibrations of carbonyl group. All benzothiazines exhibit two bonds in the region 1260–1220 cm–1 and 1040–1005 cm–1 due to C–O–C asymmetric and symmetric vibrations respectively. In H–NMR spectra all benzothiazines exhibit a single sharp peak in the region Ö 9.51 – 8.84 due to N–H proton. The multiplets in the region Ö8.30 – 6.40 can be attributed to aromatic ring protons.

The Synthesized subsituted 4H–1, 4–benzothiazines are :

a. 2–(4–Chlorobenzoyl)–3–methyl–7–phenoxy–4H–1, 4–benzothiazine

b. 2–Acetyl–3–methyl–7–phenoxy–4H–1, 4–benzothiazine

c. Ethyl 3–methyl–7–phenoxy–4H–1, 4–benzothiazine–2–carboxylate

d. Methyl 3–methyl–7–phenoxy–4H–1, 4–benzothiazine–2–carboxylate

e. 2–(4–Bromobenzoyl)–3–methyl–7–phenoxy–4H–1, 4–benzothiazine

f. 2–Benzoyl–3–methyl–7–phenoxy–4H–1, 4–benzothiazine

g. 2–(4–Methylbenzoyl)–3–methyl–7–phenoxy–4H–1, 4–benzothiazine

h. 3–Methyl–2–(2–methoxybenzoyl)-7–phenoxy–4H–1,4–benzothiazine

i. 3–Methyl–2–(4–methoxybenzoyl)-7–phenoxy–4H–1,4–benzothiazine

j. 2-(3,4-Dichlorobenzoyl)-3–methyl-7–phenoxy–4H–1,4-benzothiazine

k. 2–Trifluoroacetyl–3–methyl–7–phenoxy–4H–1,4–benzothiazine

l. 3–Methyl–2–(3–methoxybenzoyl)-7–phenoxy–4H–1,4–benzothiazine

m. 2–(4–Fluorobenzoyl)–3–methyl–7–phenoxy–4H–1,4–benzothiazine

n. 2–Benzoyl–3–phenyl–7–phenoxy–4H–1,4–benzothiazine