CHAPTER- 4 SYNTHESIS OF 2-AMINO …shodhganga.inflibnet.ac.in/bitstream/10603/9231/9/09...CHAPTER-4 Development and Application of New Methodologies for Synthesis of Bioactive Molecules

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Development and Application of New Methodologies for Synthesis of Bioactive Molecules 216

4.1 INTRODUCTION:

4.1.1 Importance of benzothiazole nucleus:

4.1.2 Characteristics of nucleus:

4.2 LITERATURE SURVEY:

4.2.1 Synthesis of 2-amino benzothiazole (Reported methods)

4.2.2 Reactions of 2-amino benzothiazole:

4.3 APPLICATION:

4.4 OBJECTIVE OF THE WORK:

4.5 DESIGN AND DEVELOPMENT:

4.6 EXPERIMENTAL:

4.7 RESULT AND DISCUSSION:

4.7.1 Mechanism:

4.8 SUMMERY AND CONCLUSION:

4.9 REFERENCES:

4.10 SPECTRA:

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4.1 INTRODUCTION:

Antimicrobial agents, since their discovery have substantially reduced the threats

posed by infectious diseases. The use of these “wonder drugs” has led to a dramatic

drop in deaths from diseases that were previously widespread, untreatable and

frequently fatal. Over the years, antimicrobial have saved the lives and eased the

suffering of millions of people. But today’s main concern is the emergence and

spreads of microbes those are resistant to economical and effective first-line drugs.

The bacterial infections which contribute most to human diseases are also those in

which emerging and microbial resistance is most evident. Some important examples

include diarrhoeal diseases, respiratory tract infections, meningitis, penicillin-resistant

Streptococcus Pneumoniae, vancomycin-resistant entercocci, and multi-resistant

Mycobacterium Tuberculosis. When infections become resistant to first line

antimicrobials, treatment has to be switched to second or third line drugs which are

nearly always much more expensive and more toxic as well e.g. the drug needed to

treat multi drug-resistant form of tuberculosis are over 100 times more expensive than

the first line drugs used to treat non-resistant forms.

Most alarming of all are diseases where resistance is developing for all currently

available drugs; current trends suggest that some diseases will have no effective

therapies within the next ten years. So, there is a requirement to develop new

replacement drug immediately which is effective against resistant bacteria having

lesser toxicity as well as economical also.1 In view of the biological importance of the

benzothiazole nucleus containing compounds, in the present work, it is plan to

synthesize 2‐aminobenzothiazoles by developing novel methodology.

4.1.1 Importance of benzothiazole nucleus:

Benzothiazole is a privileged bicyclic ring system. It contains a benzene ring fused to

a thiazole ring. The small and simple benzothiazole nucleus is present in compounds

involved in research aimed at evaluating new products that possess interesting

biological activities like- antimicrobial, antitubercular, antitumour, antimalarial,

anticonvulsant, anthelmintic, analgesic and anti-inflammatory activity.2

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In addition, the benzothiazole ring is present in various marine or terrestrial natural

compounds, which have useful biological activities. Due to their importance in

pharmaceutical utilities, the synthesis of various benzothiazole derivatives is of

considerable interests.

4.1.2 Characteristics of nucleus:

Structure

IUPAC Name 1,3-Benzothiazole

Molecular Formula C6H4N2

Molecular Weight 139.19

Boiling Point 227-228

OC

Melting Point 2OC

Density 1.644 g/ml

Physical appearance colourless, slightly viscous liquid

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4.2 LITERATURE SURVEY:

Benzothiazoles are bicyclic ring system.3 A number of 2‐aminobenzothiazoles have

been studied as central muscle relaxants and found to interfere with glutamate

neurotransmission in biochemical, electrophysiological and behavioural experiments.4

Benzothiazole ring made from thiazole ring fused with benzene ring. Thiazole ring is

a five‐member ring consists of one nitrogen and one sulphur atom in the ring.

Benzothiazole derivatives have been studied and found to have various chemical

reactivity and biological activity. It was found to be possessing pharmacological

activities such as anti‐viral, anti‐bacterial, anti‐microbial and fungicidal activities.5

Benzothiazole nucleus containing molecules are also reported as anti‐allergic,6

anti‐diabetic,7 antitumor,

8 anti‐inflammatory, anti-helmintic, and anti‐HIV agents. 2-

aryl substituted benzothiazoles show antitumor activity while condensed pyrimido-

benzothiazoles and benzothiazolo-quinazolines showed anti‐viral activity.9-10

Substituted 6‐nitro and 6‐aminobenzothiazoles have been reported for antimicrobial

activity.

4.2.1 Synthesis of 2-amino benzothiazole (Reported methods)

1) One step process for synthesis of 2-aminobenzothiazole have been reported using

substituted aniline, potassium thiocyanate and bromine in acidic condition at low

temperature (0-5OC). For the acidic media acetic acid as solvent have been is used for

the synthesis of 2-aminobenzothiazole.11

Scheme 4.1: Synthetic scheme for 2-aminobenzthiazole from aniline and KSCN

2. Kim, S. et. al. have been reported the synthetic method for 2- alkyl benzothiazole.

In this method the thiobenzamides were cyclized to their corresponding

phenylbenzothiazoles by a Jacobsen synthesis using the oxidizing agent potassium

ferricyanide in aqueous sodium hydroxide (NaCN / K3Fe(CN)6) as cyclizing agents.

The synthetic scheme is given in Scheme 4.2.12

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Scheme 4.2: Synthetic scheme for preparation of 2-alkyl benzothiazole using thiobenzamides

3. Bradshaw, T. D. et al. have been reported another method for cyclisation of

thiobenzamides using sodium hydride in N-methylpyrrolidinone (NMP) as a cyclizing

agent at 140OC of reaction mixture temperature. The synthetic scheme is given in

Scheme 4.3.13

Scheme 4.3: Synthetic scheme for preparation of 2-alkyl benzothiazole using thiobenzamides and

sodium hydride in N-methylpyrrolidinone (NMP) as cyclizing agent

4. Qiuping, D. et al. have been disclosed the synthesis of 2-N-alkylbenzothiazole

using 2-iodobenzenamine and isothiocyanate as starting material. To catalyze the

reaction copper iodide in the presence of DABCO and solvent toluene at 50°C was

used.14

Scheme 4.4: Synthetic scheme for preparation of 2-N-alkyl benzothiazole

5. Tweit, R. C. et al. also have been reported the synthesis of 2-aminobenzothiazole

using alkyl isothiocyanate and 2-aminothiol as starting material in the presence of

alcohol as a solvent at reflux. The synthetic scheme is given in Scheme 4.5.15

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Scheme 4.5: Synthetic scheme for preparation of 2-amino benzothiazole

4.2.2 Reaction of 2-amino benzothiazole:

1. Catriona, G. M. et al. have been reported the hydrolysis of 2-aminobenzothiazole

was reported using strong base aqueous potassium hydroxide on reflux condition for

6-8 hrs. The synthetic scheme is given in Scheme 4.6.16

Scheme 4.6: Synthetic scheme for preparation of 2-amino thiol

2. Yaseen, A. A. et al. have been disclosed the sulphonation reaction of 2-

aminobenzthiazole with alkylthionyl chloride in presence of organic base and

dichloromethane (DCM) as a solvent of the reaction at room temperature (25).17

Scheme 4.7: Synthetic scheme for sulphonation reaction of 2-aminobenzthiazole

3. Alejandro, C. et al.

have been reported the reaction of amino group of 2-amino

benzothiazole with carbondisulphide and methyl iodide in the presence of basic

medium. Dimethylformamide (DMF) has used as a solvent in the reaction. The

synthetic scheme is given in Scheme 4.8.18

Scheme 4.8: Synthetic scheme for preparation of dithioimidocarbonate

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Reactions of 2-thiolaniline:

1. Ian, H. et al. have been reported the reaction of 2-thiolaniline with aromatic acid in

the presence of polyphosphoric acid at 110OC

for the synthesis of 2-

aminobenzthiazole derivatives. The synthetic scheme is given in Scheme 4.9.19

Scheme 4.9: Synthetic scheme for the 2-aminobenzthiazole derivatives

2. Rajeeva, B. et al. have been reported the synthesis of ethyl-2-benzothiazole

carboxylate using o-aminothiophenol and diethyl oxalate as a starting material at mild

reflux reaction condition for 4 hrs. The synthetic scheme is given in Scheme 4.10.20

Scheme 4.10: Synthetic scheme for ethyl-2-benzothiazole carboxylate

3. Reddy, P. V. G. et al. have been reported the synthesis of conjugated benzothiazole

using o-aminothiophenol and aromatic acid at mild reflux reaction condition for 4 hrs.

In the presence of POCl3. The synthetic scheme is given in Scheme 4.11.21

Scheme 4.11: Synthetic scheme for 2-(4-methylphenyl) vinyl]-1,3-benzothiazole

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4.3 APPLICATION:

1. Antimicrobial activity:

Microbes are the causative agents for various types of diseases like pneumonia,

ameobiasis, typhoid, malaria, common cough, cold and various infections and cause

some severe diseases like tuberculosis, influenza, syphilis, and AIDS etc.

Benzothiazoles show a chemotherapeutic activity and a considerable amount of work

has been done on the synthesis of new potent antibacterial and antifungal

benzothiazoles. 2‐(substitutedarylsulfonamido)‐6‐substituted (A, Scheme 4.12) have

reported for their anti‐bacterial activity against Bacillus subtilis, Salmonella typhi and

S. dysentery.22

Scheme 4.12: Anti‐bacterial benzothiazolotriazole derivatives

Another, derivative i.e. N-(2-amino-6-fluorobenzo[d]thiazol-7-yl)benzene

sulfonamide (B, Scheme 4.12) was synthesized and studied for their antibacterial and

anti-fungal activities and it showed moderate activity against S. aureus, S. albus and

C.ablicans. Various benzothiazolyl carboxamido pyrazoline derivatives (C, Scheme

4.12) were prepared and studied their anti-microbial activity.23

It was found that when

R=CH3 and R1 =o-OCH3C6H4, compound showed no activity and when R= Cl and R1

= p-OCH3C6H4, the compound was active against S. aureus and the compounds which

are left has showed activity against, S. aureus, E. coli, Pseudomonas aeruginosa,

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Klebsiella pneumoniae and Proteus mirabilis. In other words it can be stated that

benzothiazole moiety serves as a royal warrior against almost all types of microbes.

2. Antitumor activity:

The benzothiazole moiety with various substitutions has shown antitumor activity.

The aminomethylphenyl derivatives (A, Scheme 4.13) and 4, 7-dimethoxy

benzothiazole (B, Scheme 4.13) shows selective growth inhibitory properties against

human cancer cell lines and proliferation of cells respectively. Chlorinated and

fluorinated derivatives of this moiety exhibit good in vitro as well as in vivo antitumor

activity. Substituted 2‐(4‐aminophenyl) benzothiazoles examined, in vitro , shows

antitumor activity in ovarian, breast, lung, renal and colon carcinoma human cell line

2‐(4‐aminophenyl)-benzothiazoles consists of a novel mechanistic class of antitumor

agents.24

Pyrimido benzothiazole and benzothiazolo quinoline derivatives, imidazo

benzothiazoles and polymerized benzothiazoles have posses anti‐tumour activity.

Some fluorinated analogues of 2‐(4‐aminophenyl)-benzothiazoles were reported to

block the C‐oxidation. The 2‐cyano derivatives of benzothiazole exhibit interesting in

vitro anti‐tumour activity.

Scheme 4.13: Some antitumor benzothiazolotriazole derivatives

3. Anthelmintic activity:

Benzimidazoles recent reports of resistance have been forced the researchers to

develop new drugs with anthelmintic activity, to fight against helminthiasis, which is

causing untold misery to the infected individuals. Benzothiazole derivatives have been

synthesized, which is sulphur isostere of benzimidazole, reported for better

anthelmintic activity. A 8‐fluoro‐9‐substituted benzothiazolo 1,3,4‐triazoles (A,

Scheme 4.14) compounds have been studied for their anthelmintic activity against

earthworm, Perituma posthuma and showed a good activity.25

A compound with R=

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o‐nitro anilino substituent was found to possess excellent anthelmintic activity, than

the other compounds, Some substituted imidazo benzothiazoles were examined in vivo

anthelmintic activity against H. nana infection and were found to show good to

moderate activity.

Scheme 4.14: Structure of reported anthelmintic substituted‐2‐benzothiazolamine

4. Anticonvulsant activity:

For anticonvulsant activity a large number of benzothiazole derivatives were

evaluated and found to possess significant activity against various types of seizures. In

the search of new anticonvulsant agents having benzothiazole nucleus, Amit, B. N. et

al synthesized a lot of substituted‐2‐benzothiazolamines (Scheme 4.15).26

Benzothiazoles were first observed in 1978 as anticonvulsive agents against

pentylenetetrazole induced convulsions on 2‐(‐4‐arylthiosemicarbazidocarbonylthio)

benzothiazoles and then several benzothiazoles containing sulphonamide derivatives

(Scheme 4.16), benzothiazolamines were synthesized and evaluated for their activity

against electroshock and pentylenetetrazole induced seizures. This review revealed

that benzothiazole moiety as a dynamic agent against convulsive seizures.

Sulphonamide derivatives having benzothiazole nucleus is synthesized by treating

2‐(4‐aminophenylsulphonamido)‐6‐halo/alkyl benzothiazoles with alkyl

isothiocyanate and were evaluated for their anticonvulsant activity. A

2‐(4‐arylthiosemicarbazidocarbonylthio) benzothiazoles were screened for their

anticonvulsant activity against pentylenetetrazole induced convulsions in mice and

found that all the compounds possess measurable anticonvulsant activity. A large

number of 2‐(3H)‐benzothiazolo derivatives have been synthesized and evaluated for

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their anticonvulsant activity in mice and were found to be significantly anticonvulsant

activity.

Scheme 4.15: Structure of reported anticonvulsant substituted‐2‐benzothiazolamines

Scheme 4.16: Structure of reported anticonvulsant substituted‐2‐benzothiazolamines

sulphonamide

5. Anti-inflammatory activity:

Pyrazolones and pyrazolinones are more valuable non‐steroidal anti‐inflammatory

agents. Phenylbutazone and its congeners incorporating a pyrazoline‐3, 5‐dione

structure are more potent anti‐inflammatory agents. In the recent years a number of

benzothiazole derivatives have been synthesized and found to possess

anti‐inflammatory activity. Some new 2‐(4'‐butyl‐3',5’‐dimethylpyrazol‐1'‐yl)‐6‐

substitutedbenzothiazole were found to posses significant anti‐inflammatory activity

reported by Singh, S. P. et al.27

A series of 2‐(2‐alkoxy ‐6‐pentadecylphenyl)

methylthio‐1H‐ Benzimidazoles / benzothiazoles and benzoxazoles from an anacardic

acid and investigated by Paramashivappa, R. et al. for their ability to inhibit human

cycloxygenase‐2‐enzyme (COX‐2).28

Scheme 4.17: Structure benzothiazol-pyrazolone derivatives

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Other report showed that, replacement of the urea moiety by benzothiazoles

sulfonamide showed inhibitors of HIV‐1 protease with improved potency and

anti‐viral activities.

4.4 OBJECTIVE OF THE WORK:

Sodium dichloroiodate (I) is commercially available iodine reagent (not a hypervalent

iodine reagent) in a 50% water solution and reported for the iodination of the aromatic

ring29

at 40–70OC for 72 h, more recently we used this reagent for the transformation

of alcohol to aldehyde and aldehyde to corresponding nitriles.30

Iodine and iodine reagents have attracted increasing interest during the last decade

because of their selective, mild, and environmentally friendly properties as oxidizing

agents in organic synthesis. Investigation from our laboratories have revealed a series

of new paradigm for iodine reagent mediated reactions under mild conditions

While working on this reagent, we found that it can be used for the regioselective C-S

bond forming reaction. We observed that in the presence of aqueous solution of

sodium dichloroiodate, 4-chloroaniline will react with potassium thiocyanate to

produce 2-aminobenzthiozole.

NaICl2 = {Na+

Cl-…..

I+

Cl-}

Figure 1– Structure of sodium dichloroiodate (I)

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4.5 DESIGN AND DEVELOPMENT:

Though there are many methods reported for synthesis of 2-aminobenzthiozole, but

most of the methods are having limitations like use of acids, starting material not

easily available, and also use of costly starting material as shown in literature

methods. Therefore still there is broad scope for development of new method for

synthesis of 2-aminobenzthiozole, so to overcome above mentioned drawbacks.

Efforts has been done to develop a new method for direct synthesis of substituted 2-

aminobenzthiozole from substituted aniline by using sodium dichloroiodate, i.e.

NaICl2, which can overcome some of the limitations of existing methods in terms of

safety, reaction time, yield, availability of starting materials and cost of reagents.

In the literature it has been found that for direct synthesis of 2-aminobenzthiozole

scaffold, many methods are reported which uses metals as catalyst. While using such

metals required harsh reaction condition. In the literature it was also found that for the

synthesis of 2-aminobenzthiozole required 2-3 steps and hence takes more time with

fewer yields.

Hypervalent iodine reagents are very well known for its oxidizing properties. We have

tried to extend these oxidizing properties of hypervalent iodine reagents for the

synthesis of 2-aminobenzthiozole.

Based on this aspect the model reaction was carried out by using 4-chloroaniline and

potassium thiocyanate, silica (catalytic) with combination of iodine (I) reagent such as

NaICl2 (sodium dichloroiodate), and reaction was monitored by TLC.

Reaction went to completion within 4 h. After completion of reaction and work up,

products containing a mixture of compounds were isolated. These compounds were

separated by column chromatography & characterizations were carried out by using

IR and NMR techniques and their structure were elucidated as 6-chloro-2-

aminobenzthiozole. The isolated yield was 99% as shown in Scheme 4.18

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Scheme 4.18

So in our preliminary study, we had successfully developed a simple method for

synthesis of 2-aminobenzthiozole. In proposed intensified method all the reaction

conditions are feasible and mild from industrial point of view. In this route less

number of steps will be required and all the reagents commercially available and

conditions are easy to handle.

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4.6 EXPERIMENTAL:

General procedure for synthesis of 6-chloro-2-aminobenzthiazole derivative:

Table 4, Entry 1: 6-chloro-2-aminobenzthiazole derivative

To a stirred solution of 4-chloro-aniline (0.1g, 1 equiv., 0.78 mmol.), and potassium

thiocyanate (0.53g, 7 equiv., 5.4 mmol.) in DMSO:H2O (9:1 mL) was added a NaICl2

(2M, 0.52 g, 3 equiv., 2.3 mmol). The reaction mixture was stirred vigorously at room

temperature for 5 min. Then reaction was shifted to reflux temperature at 50Oc

followed by addition of catalytic amount of silica (90:120 mesh).The progress of the

reaction was monitored by TLC. The reaction was quenched with water (10 mL) and

extracted with ethyl acetate (3 X 10 mL). The organic layer was separated and washed

successively with 10% aqueous solution of Na2S2O4 (2 x 10 mL), 10% aqueous

solution of NaHCO3 (2 x 15 mL), and finally with H2O (2 x 20 mL). The organic layer

was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give

crude product. Pure 4-chloro-2-aminobenzthiozole as a yellow solid was obtained

after silica gel column chromatography (EtOAc: hexane).

Yield 0.139g, (99%), M.P. 196-199OC; IR (KBr): Vmax cm

-1 3457.8, 3261, 3081, 1633,

1533, 1445, 1303, 1276, 763. 1H NMR (60 MHz, CDCl3, δ ppm): δ7.55-7.31(m, 3H,

Ar-H), 5.39-5.31(S, 2H,-C-NH2); D2O exchange NMR (60 MHz, CDCl3, δ ppm):

δ7.53-7.27(m, 3H, Ar-H), 4.6 (s, D2O)

Table 4, Entry 2: 6-bromo-1,3-benzothiazol-2-amine

To a stirred solution of 4-bromo-aniline (0.1g, 1 equiv., 0.58 mmol.), and potassium

thiocyanate (0.39g, 7 equiv., 4.0 mmol.) in DMSO:H2O (9:1 mL) was added a NaICl2,

and same as treated by general procedure (2M, 0.38g, 1.7 mmol) to gave the product

with 0.129 g, as yellow solid, (99%), m.p. 82-84OC; IR (KBr): Vmax cm

-1 3456.9, 3263,

3083, 1636, 1540, 1448, 1308, 1280, 766, 1H NMR (60 MHz, CDCl3, δ ppm): δ 8.71

(s, 1H, Ar-H), 7.72-7.64 (m, 2H, Ar-H), 6.91-6.18 (S,2H,-C-NH2)

Table 4, Entry 3: 6-nitro-1,3-benzothiazol-2-amine

To a stirred solution of 4-nitro-aniline (0.1g, 1 equiv., 0.72 mmol.), and potassium

thiocyanate (0.49g, 7 equiv., 0.50 mmol.) in DMSO:H2O (9:1 mL) was added a

NaICl2, and same as treated by general procedure (2M, 0.48g, 2.1 mmol) to gave the

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yellow powder product with 0.140g, (99%), m.p. 247-249OC; IR (KBr): Vmax cm

-1

3451.5, 3297.5, 3047.4, 1652, 1566, 1527.7, 1494.1, 1325, 1H NMR (60 MHz, CDCl3,

δ ppm): δ8.50-8.12(m, 3H, Ar-H), 5.90-5.86 (s, 2H,-C-NH2)

Table 4, Entry 4: 1,3-benzothiazol-2-amine



and same as treated by general procedure (2M, 0.73g, 3.2 mmol) to gave the light

brown solid product with 0.140g, (87%), m.p. 128-130OC; IR (KBr): Vmax cm

-1 3402,

3265.9, 3052.1, 1636.8, 1525, 1442, 1306.3, 1102, 1H NMR (60 MHz, CDCl3, δ ppm):

δ7.73-7.50(m, 4H, Ar-H), 5.70-5.63 (S,2H,-C-NH2)

Table 4, Entry 5: 6-(trifluoromethyl)-1,3-benzothiazol-2-amine

To a stirred solution of 4-(trifluoromethyl) aniline (0.1g, 1 equiv., 0.60 mmol.), and

potassium thiocyanate (0.42g, 7 equiv., 4.3 mmol.) in DMSO:H2O (9:1 mL) was

added a NaICl2, and same as treated by general procedure (2M, 0.41g, 1.8 mmol) to

gave the product with 0.134g, (99%), m.p. 121-124OC; IR (KBr): Vmax cm

-1 3461.1,

3220.6, 1633.6, 1599.9, 1479.6, 1441.1, 1340.1, 1263,1166.9, 1128.4, 1H NMR (60

MHz, CDCl3, δ ppm): δ7.70-7.62(m, 3H, Ar-H), 4.32-4.29 (S,2H,-C-NH2)

Table 4, Entry 6: 6-methyl-1,3-benzothiazol-2-amine

To a stirred solution of 4-methyl-aniline (0.1g, 1 equiv., 0.93 mmol.), and potassium


and same as treated by general procedure (2M, 0.62 g, 2.8 mmol) to gave the product

with 0.149g, yellow powder, (97%), m.p.135-137OC (Lit.

1 132-133

OC); IR (KBr):

Vmax cm-1

3372.8, 3285.4, 3071.6, 2933.5, 1636.8, 1534.7, 1457.7, 1374.4, 1301.5,

1107.1. 1H NMR (60 MHz, CDCl3, δ ppm): δ7.63-7.30(m, 3H, Ar-H), 5.73-5.46

(S,2H,-C-NH2), 2.51 (S,3H, CH3)

Table 4, Entry 7: 6-methoxy-1,3-benzothiazol-2-amine

To a stirred solution of 4-methoxy-aniline (0.1g, 1 equiv., 0.81 mmol.), and potassium


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with 0.144g, (98%), m.p.165-167OC; IR (KBr): Vmax cm

-1 3379.3, 3283.1, 3090.6,

2936.7, 1636, 1544.6, 1457.9, 1332.9, 1270.3, 1049, 1H NMR (60 MHz, CDCl3, δ

ppm): δ7.53-7.12(m, 3H, Ar-H), 5.10-5.08 (bs,2H,-C-NH2), 3.82 (s,3H, -OCH3)

Table 4, Entry 8: 2-amino-1,3-benzothiazole-6-carboxylic acid

To a stirred solution of 4-aminobenzoic acid (0.1g, 1 equiv., 0.70 mmol.), and




-1 3457.8,

3261, 3085, 1740, 1650, 1540, 1450, 1315, 1280, 768, 1H NMR (60 MHz, CDCl3, δ

ppm): δ10.92 (m, 1H, -OH), 8.58 (s, 1H, Ar-H), 8.10-7.68 (m, 2H,-Ar-H), 5.92-5.58

(bs, 2H,-C-NH2)

Table 4, Entry 9: ethyl 2-amino-1,3-benzothiazole-6-carboxylate

To a stirred solution of ethyl-4-aminobenzoate (0.1g, 1 equiv., 0.60 mmol.), and




-1 3459.5,

3263, 3090, 1775, 1660, 1545, 1453, 1318, 1282, 770, 1

H NMR (60 MHz, CDCl3, δ

ppm): δ8.42-7.58(m, 3H, Ar-H), 6.99-6.42 (bs,2H,-C-NH2), 4.20-4.31 (qa, 2H, -CH2),

1.29 (t, 3H, -CH3)

Table 4, Entry 10: 4-methyl-1,3-benzothiazol-2-amine

To a stirred solution of 2-methyl-aniline (0.1g, 1 equiv., 0.93 mmol.), and potassium



with 0.140g, (91%) as white powder, m.p.136-138OC; IR (KBr): Vmax cm

-1 3441.9,

3355.3, 3239.8, 2912.6, 1633.6, 1585.5, 1561.4, 1489.2, 1397, 1296, 1H NMR (60

MHz, CDCl3, δ ppm): δ7.82-7.32, (m, 3H, Ar-H), 5.79-5.38 (S,2H,-C-NH2), 2.40

(S,3H, CH3)

Table 4, Entry 11: 4-nitro-1,3-benzothiazol-2-amine

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with 0.140g, (99%), m.p. 250-252OC; IR (KBr): Vmax cm

-1 3326.4, 3085.8, 1619.2,

1587.5, 1505.9, 1351.2, 1259.3, 1H NMR (60 MHz, CDCl3, δ ppm): δ8.31-7.40(m,

3H, Ar-H), 6.90-6.86 (S,2H,-C-NH2)

Table 4, Entry 12: 4-chloro-1,3-benzothiazol-2-amine

To a stirred solution of 2-chloro-aniline (0.1g, 1 equiv., 0.78 mmol.), and potassium



with 0.138g, (95%), m.p. 203-205OC;IR (KBr): Vmax cm

-1 3431.5, 3325.7, 3200.6,

1614, 1575.5, 1484.1, 1397.5, 1301.2, 820.1, 704.6. 1H NMR (60 MHz, CDCl3, δ

ppm): δ7.91-7.39(m, 3H, Ar-H), 4.77-4.72(S,2H,-C-NH2)

Table 4, Entry 13: 4-bromo-1,3-benzothiazol-2-amine

To a stirred solution of 2-bromo-aniline (0.1g, 1 equiv., 0.58 mmol.), and potassium




-1 3458.1, 3260, 3083, 1636,

1541, 1446, 1305, 1275, 761, 1

H NMR (60 MHz, CDCl3, δ ppm): δ7.95-7.72(m, 3H,

Ar-H), 7.23-6.99 (bs, 2H,-C-NH2)

Table 4, Entry 14: 4-methoxy-1,3-benzothiazol-2-amine

To a stirred solution of 2-methoxy-aniline (0.1g, 1 equiv., 0.80 mmol.), and potassium




-1 3379.3, 3283.1, 3090.6,

2936.7, 1636, 1544.6, 1457.9, 1332.9, 1270.3, 1049, 1H NMR (60 MHz, CDCl3):

δ7.57-7.00(m, 3H, Ar-H), 5.45-5.10 (bs,2H,-C-NH2), 3.84 (s,3H, -OCH3)

Table 4, Entry 15: 4,5-dichloro-1,3-benzothiazol-2-amine

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To a stirred solution of 2, 3-diclhoro-aniline (0.1g, 1 equiv., 0.61 mmol.), and




-1 3403.4,

3326.4, 3220.6, 1628.8, 1571, 1460.4, 1380.2, 810, 579.9. 1H NMR (60 MHz, CDCl3,

δ ppm): δ7.48-7.25 (m, 2H, Ar-H), 6.78-6.64 (S,2H, NH2)

Table 4, Entry 16: 2-amino-6-nitro-1,3-benzothiazol-4-ol

To a stirred solution of 2-amino-5-nitrophenol (0.1g, 1 equiv., 0.64 mmol.), and

potassium thiocyanate (0.44 g, 7 equiv., 4.5 mmol.) in DMSO:H2O (9:1 mL) was



-1 3408.5,

3326.4, 3316.3, 1618.9, 1586.5, 1505.1, 1350.9, 1260.1, 1H NMR (60 MHz, CDCl3, δ

ppm): δ7.79-7.21(m, 5H, Ar-H, C-NH2, CDCl3), 2.85 (S, 1H, OH)

Table 4, Entry 17: 4,6-dimethyl-1,3-benzothiazol-2-amine

To a stirred solution of 2, 4-dimethylaniline (0.1g, 1 equiv., 0.82 mmol.), and




-1 3403.4,

3336, 3239.8, 2960.8, 1638.4, 1580.7, 1470, 1436.3, 1373, 1H NMR (60 MHz, CDCl3,

δ ppm): δ7.26-7.19(m, 2H, Ar-H), 3.90-3.79 (S,2H,-C-NH2), 2.17-1.84 (S,6H, CH3).

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4.7 RESULT AND DISCUSSION:

For our preliminary study, 4-chloroaniline was used as a model substrate and a

catalytic amount of Silica (mesh 120) was used in all the reactions using a mixture of

Acetic acid: H2O (80:20) as reaction solvent and carried out at reflux temperature for

more than 24 h. The previous reports on the synthesis of 2-aminobenzthiazole guided

us towards the use of acetic acid: water as a reaction media.

As shown in table 1, varied reagents were tried to synthesise 2-aminobenzthiazole,

including DIB, DMP, IBX, ICl, I2, NBS and NaICl2. However, none except NaICl2

afforded the desired 2-aminobenzthiazole product (Table 1, entry 5).

TABLE 1. Reagent study for reaction at room temperature as well as reflux

Entry Reagent Reaction condition Time

(h)

Yielda

(%)

1. Iodobenzene Diacetate Acetic acid:H2O

rt/reflux 24 NR

b

2. o-Iodoxybenzoic acid Acetic acid:H2O

rt/reflux 24 NR

3. Iodine monochloried Acetic acid:H2O

rt/reflux 24 NR

4. Sodium metaperiodate Acetic acid:H2O

rt/reflux 24 NR

5. Sodium dichloroiodate Acetic acid:H2O

rt/reflux 18 30

6. Iodine Acetic acid:H2O

rt/reflux 24 NR

7. Dess-Martin

Periodinane

Acetic acid:H2O

rt/reflux 24 NR

8. N-Iodosuccinamide Acetic acid:H2O

rt/reflux 24 NR

aIsolated yields after silica gel column chromatography. NR= no reaction

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Further to optimise the reaction condition with NaICl2, different solvent systems were

tried (Table 2) and a mixture of DMSO: H2O (90:10) was found to be the most

suitable reaction media giving a high reaction rate and good yield of the product

(Table 2, entry 8). To further enhance the yield of the product, different molar ratio

of the reagents were used (Table 3), thus NaICl2 in 3 equivalent quantity and 7

equivalent of potassium thiocyanate (Table 3, entry 8) were found to be the best for

the reaction rate resulting in excellent yield of the product. Also, the reaction

completes within 4 h.

TABLE 2. Solvent study of the reaction.

Entry Solvent Reaction

condition

Time

(h)

Yield

(%)

1. Acetic acid: H2O Reflux 18 30

2. CH3CN: H2O Reflux 6 40

3. MeOH: H2O Reflux 6 NR

4. THF: H2O Reflux 5 45

5. EtOH: H2O Reflux 6 NR

6. IPA: H2O Reflux 24 NR

7. CHCl3 Reflux 12 NR

8. DMSO: H2O Reflux 4 50

9. Glycerol: H2O Reflux 12 NR

10. Acetone: H2O Reflux 12 NR

TABLE 3. Optimization of the reaction.

Entry NaICl2

(equiv.)

KSCN

(equiv.)

Time

(h)

Yield

(%)

1. 0.5 0.5 8 40

2. 0.5 1 8 40

3. 1 1 7 50

4. 1 1.5 7 58

5. 2 3 6 75

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6. 3 4 5 85

7. 3 5 4 90

8. 3 7 4 99.9

9. 4 7 4 99

10. 5 7 4 99

Further, the optimised reaction conditions were used for the synthesis of 2-

aminobenzthiazole using various substituted anilines containing electron withdrawing

and/or electron donating substituents. In all cases, excellent yield of the desired

product was obtained. The reaction rate was higher for anilines containing an electron

donating substituent (Table 4, entries 6, 7, 10, 18) as compared to the presence of

electron withdrawing substituent on the aniline ring (Table 4, entries 3, 8, 9, 17).

Whereas o-substituted anilines also not at the back of the reaction (Table 4, entries

11-14). It was remarkably that, reaction of disubstituted aniline also goes well (Table

4, entries 15, 16, 17).

Table 4. Reaction of substituted anilines with potassium thiocyanatea

Entry Substrate Product Time

(h)

Yieldb

(%)

1.

2 99

2.

2 99

3.

7 99

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4.

3 87

5.

2 99

6.

2 97

7.

3 98

8.

10 98

9.

6 98

10.

2 91

11.

1.5 99

12.

0.5 95

13.

0.5 97

14.

4 95

15.

0.5 98

16.

5 72

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17.

0.5 99

aReaction conditions: anilines (1 equiv), and potassium thiocyanate (7 equiv) and NaICl2 (3 equiv).

bIsolated yields after column chromatography and structures were confirmed by NMR , IR and

comparison of melting point with reported data.

As part of our studies on the development of novel methodology, herein we now

describe a new approach for the synthesis of 2-aminobenzthiazole in a single step with

an excellent yield and shorter reaction time without the use of any unstable or toxic

reagents.

4.7.1 MECHANISM:

Two possible mechanisms of this Reaction are shown below:

a) In this mechanism (Figure 1) of the reaction, initial attack of aniline loan pair

on electrophilic carbon centre of potassium thiocyanate took place. In second

step, iodination to ortho to amine took place, which was subsequent cyclisation

in situ gave desired product.

Figure 1

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b) In this mechanism, (Figure 2) roll of both DMSO as well as reagent is

explained. By same way amine will attack on electrophilic carbon centre of

potassium thiocyanate in presence of DMSO. Then formation of adduct, which

was iodinate at ortho position of amine. Subsequent attack of water on sulphur

and by concerted way cyclisation in final step take place, giving desired

product.

Figure 2

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4.8 SUMMERY AND CONCLUSION:

Form literature survey it was found that, till date no method for such an efficient

synthesis of 2-aminobenzthiazole from aniline as starting material has been reported.

The small and simple benzothiazole nucleus is present in compounds involved in

research aimed at evaluating new products that possess interesting biological activities

like- antimicrobial, anti-tubercular, anti-tumour, anti-malarial, anti-convulsant, anti-

helmintic, analgesic and anti-inflammatory activity. Benzothiazole nucleus containing

molecules are also reported as anti‐allergic, anti‐diabetic, anti-tumor,

anti‐inflammatory, anti-helmintic, and anti‐HIV agents. Owing to their importance in

pharmaceutical utilities, the synthesis of various benzothiazole derivatives has

charming considerable interests.

In summary, we have described an efficient protocol for preparing 2-

aminobenzthiazole derivatives using NaICl2 as a catalyst. The advantages of the

present method lie in using benign catalyst, mild reaction conditions, and excellent

yields.

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4.9 REFERENCES:

1. http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_D

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http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_DRS_2001

http://www.articlesbase.com/medicine-articles/importance-of-benzothiazole-nucleus-in-medicinal-531934.html

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Structure-Activity Relationship (QSAR); Analysis Journal of Medicinal

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Alzheimer’s Disease; Journal of Medicinal Chemistry, 2009, 52, 1428

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Isothiocyanate; Journal of combinatorial chemistry, 2009, 11, 587

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Malcolm, F. G. S.; Westwell, A. D. Antitumor Benzothiazoles. 2-(3,4-

Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a Simple

Fluorinated 2-Arylbenzothiazole, Shows Potent and Selective Inhibitory

Activity against Lung, Colon, and Breast Cancer Cell Lines; Journal of

Medicinal Chemistry, 2006, 49, 179

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Al-Masoudi, N. A.; Kadir, T. A.; Colla P. L.; Bernardetta, B.; Sanna, T.;

Loddo, R. Synthesis and in vitro antiproliferative activity of new benzothiazole

derivatives, ARKIVOC, 2008 (xv), 225

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aryl and -N-alkyl)isothioureas derived from 2-aminobenzothiazole , ARKIVOC,

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A. D.; Malcolm, F. G. S. Antitumor Benzothiazoles. Synthesis and in Vitro

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Biological Properties of Fluorinated 2-(4-Aminophenyl)benzothiazoles;

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Activity of Some New 2-Substituted Benzothiazole Derivatives, E-Journal of

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compounds with an extended conjugated system.; ARKIVOC, 2007, 16,113

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Chem. 1998, 8, 23

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V. G. Gurupadaiah, B. M.; Indian J. Heterocyclic. Chem., 2001, 11, 39

24. Trapani, V.; Patel, V.; Leong, C. O.; Ciolino, H. P.; Yeh, G. C.; Hose, C.;

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and Biological Evaluation of Benzimidazole/ Benzothiazole & Benzoxazole

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Bernstein, J.; Kathryn, A. L. US3,666,799, 1972. c) Tour, J. M.; Kosynkin, D.

V.; Org. Lett., 2001, 3, 991 d) Hajipour, A. R.; Arbabian, M.; Ruoho, A. E.; J.

Org. Chem. 2002, 67, 8622

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30. a) Telvekar, V. N.; Jadhav, N. C.; Syn. Comm. 2008, 38, 3107 b) Telvekar, V.

N.; Patel, K. N.; Kundaikar, H. S.; Chaudhari, H. K.; Tetrahedron Lett. 2008,

49, 2179

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4.10 SPECTRA: Table 4, entry 1

CHAPTER-4


Table 4, entry 1

CHAPTER-4


Table 4, entry 1(D2O exchange NMR)

CHAPTER-4


Table 4, entry 6

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Table 4, entry 17

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Table 4, entry 17

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Table 4, entry 4

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Table 4, entry 15

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Table 4, entry 15

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Table 4, entry 5

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