Journal of Sciences Synthesis of Novel Compounds … of Novel Compounds Derived from Saccharin...

International Journal of Science and Technology Volume 3 No. 9, September, 2014

IJST © 2014– IJST Publications UK. All rights reserved. 521

Synthesis of Novel Compounds Derived from Saccharin

1Redha. I.H.AL-Bayati, 2Mazin.J.H, 3Athraa. H.Mekky Mustansiriya University -Department of Chemistry, College of Sciences, AL 1

University Mustansiriya -Department of Chemistry, College of Sciences, AL 2

University Qar-ThiDepartment of Chemistry, College of Sciences, 3

ABSRACT

This work involves synthesis and characterization of some new derivatives saccharin .five main compounds (1-5) were synthesized

via alkylation saccharin by reaction sodium saccharin with different halo compounds ,then compounds (6,7) were obtained from

reaction compound(1)with hydrazine or 2,4-dinitrophenylhydrazine respectively, also compound ( 8) was synthesized from reaction

compound (6) with ethyl acetoacetate, while indole compounds(9,10) have been synthesized by reaction compound (1) with

coumarin compounds(11,12,13,14) were obtained from the reaction compound (1) with phenol nediamine and its substituted . phenyle

with hydrazine hydrate. The )3( 15) was synthesized by reaction compound( ompoundC.eridineor pip 4SO2derivatives in con H

reaction compound(4) with sodium azide in the presence ammonium chloride to give tetrazole ring compound (16) . Schiff bases

(17,18,20) can be synthesized from compound 5 with hydrazine and dehydro acetic acid. compound has been synthesized by reaction

compound with phenyl isothiocyanate in the presence tri ethylamine . finally the reaction of compound( 5) with hydrazine in the

,IR ,nds characterized by UVcompou synthesized wereof s. All structure)19(produced presence sodium hydroxide or sodium acetate

.NMR-C13NMR,-H1

Keywords: sweetening agent ,saccharin, sulfonamide drivatives. .

INTRODUCTION

Saccharine is important compound, IUPC name is 1,1,3-trioxo-

1,3-dihydrobenzo [d]isothiazole figure (1) .It is the first

artificial sweetening agent 1,2.It has been used as a sweetening

agent ever since it was discovered in 1879.It is about 550 times

sweeter than cane sugar .It is excreted from the body in urine

unexchanged 3,4.

NH

S

O

OO

Fig(1) :chemical structure of saccharin.

Intensive research on human populations has established no

association between saccharin and cancer .In fact more than 30

human studies have been completed and support saccharin’s

safety at human level consumption5

This compound has been widely inserted into a variety of

biologically active compounds . its identified as an important

molecular component in various classes of 5HT1a

antagonists,6human leukocyte elastase (HLE) inhibitors,7

analgesics,8 human mast cell tryptase inhibitors,9 and

aldehyde dehydrogenase inhibitors10.

The1,1,3-trioxo-1,3- dihydrobenzo[d]isothiazol-2-yl fragment

has been used in medicinal chemistry and is present in several

drug molecules, e.g., Ipsapirone (A,B)11

Studies showed later saccharin is non-coloric sweeting agent

an oncariogenis opposite to sucrose ,which generally used in

liquid preparation such as syeups , oral solution ,drops

,suspension 12.

In its acid from saccharin is not water-soluble ,unstable when

heated but doesn’t react chemically with other food ingredient,

has effectively no food energy13,14.

MATERIALS AND METHODS

Melting points were determined on Gallen Kamp(MFB-600)

melting point apparatus and are uncorrected. IR spectra of the

compounds were recorded on ashimadzu FT-IR-3800

spectrometer as KBr disk. The UV spectra were performed on

Cintra-5-Gbes scientific equipment. Analytical thin layer

chromatography (TLC) was performed on plates precoated

with silica gel (Merck 60 F254, 0.25 mm) visualizing with

ultraviolate light .the 1H-NMR and 13C-NMR spectra ( solvent

DMSO) were recoreded on broker 300 MHZ spectrometerwith

TMS as internal standerd in chemistry department–AL-Byat

university /Jordon .

A

n

N

N

N

S

O

OO

N

NN

N

S

O

OO

N N

N

N

B

International Journal of Science and Technology (IJST) – Volume 3 No. 9, September, 2014


General procedure for the synthesis of compounds

1. Synthesis of compounds (1-4)

(0.01mol,2.41gm) sodium saccharin hydrate was dissolved in

20 ml dry DMF then the flask fitted with dropping funnel

containing (0.0175 mol, 2.87gm) of ethyl-4-chloroacetoacetate

or 0.02mol from chloro proponylnitrile , chloro acetone ,

chloropropogel was added dropwise with stirring then the

mixture was refluxed for 6 hours into water bath . the reaction

mixture was cooled to room temperature and poured into ice

water with stirring . The obtained ppt was filtered off , washed

with water, drized and recrystallized from appropriate solvent.

Table (1) shows some physical properties of the compounds.

2. SYNTHESIS OF COMPOUND 5

This compound was prepared by two steps .

Step1:

Synthesis of N-1,3-benzothiazol-2-yl-2-chloroacetamide-2-

mimobezothiazol (0.01mol ,1.5 gm) of 2-aminobezothiazol

was dissolved in dry benzene20ml(0.05mol,5.6gm)

chloroacetyl chloride was added dropwise with stirring at room

temperature overnight. reaction mixture was poured into ice

water .the solid precipitation was formed ,filter off, washing

with D.W and dried , recrystallized from ethanol . Table (1)

shows some physical properties of the compounds.

Step 2:

A mixture of sodium saccharin (0.1mol,2.41gm) in dry DMF

was added to (0.01mol,2.26gm) of compound was prepared in

step1, then the mixture was heated under refluxed for 6 hr.

cooled and poured into ice-water .the precipitated was formed

collected and washed with water ,the solid was recrystallized

from dioxin:water (8:2) , Table (1) shows some physical

properties of the compound.

3. Synthesis of compound 6

A solution of hydrazine hydrate (0.005mol, 0.25gm) in

ethanol was added drop wise to the solution of compound 1

(0.0025mol,0.78gm) with stirring then the mixture was

refluxed for 6 hr . Acrystalline deposit was separated then the

mixture was cooled in ice bath to complete the crystallization

. Tthe solid filtered and recrystallized from methanol ,Table

(1) shows some physical properties of the compound.


Amixtureof2,4-dinitrophenylhydrazine (0.002mole ,0.396gm)

and compound 1 (0.002mole,0.622gm) were taken in absolute

ethanol (30ml).The mixture was refluxed for 12 hr ,excess

solvent was distilled off and resultant residue was poured on

crushed ice water to obtained the yellow solid precipitated

were filtered and recrystallized from ethanol- water. Table (1)

shows some physical properties of the compound.


Ethyl acetoacetate 2ml was added to compound 6 (0.2gm), then

the mixture was heated at 170C -180C in oil bath for 8hr ,the

progress of the reaction was monitored by TLC hexane : ethyl

acetate (1:1) ,after compelate the reaction excess ethyl

acetoacetate was evaporated . The solid was formed filtered off

and recrystallized from ethanol . Physical properties listed in

table (1)

.

6. Synthesis of compound (9,10)

(0.002mol,0.622gm) of compound 1 ,(0.002mol) of

phenylenediamine or 3,4-diamine toluene and catalyst amount

of PTSA 20ml toluene with 1oml propanol ,then the mixture

refluxed for 12hr.after solvent evaporated under reduce

pressure ,ethanol 20ml was added with stirring off white solid

obtained Physical properties listed in table (1).

7. Synthesis of compound (11,12)

(0.001mol ) of m-substituted phenol was added to

(0.001mol,0.311gm) of compound 1 and the mixture was

cooled down below 15 (15ml) of con . H2So4 was added drop

wise over a period of 30 min,and the mixture was brought to

room temperature the ice water was added under stirring .the

precipitate obtained was filtered and recrystallized from

ethanol .physical properties shown in table (1).

8. Synthesis of compound (13,14) Amixture of salicyldehyde (0.001mol,0.122gm) and

compound 1(0.001mol,0.311gm) and 5 drops of pip in ethanol

15ml was heated under refluxed for 2hr ,after cooling %10 HCl

was added.the solid product was filter off dried and

recrystallized from diut ethanol , Table (1) shows some

physical properties of the compound.

9. Synthesis of compound (15)

To solution of compound 5 (0.001mol , 0.373gm) in

absolute ethanol(0.005mol,0.25gm) hydrazine hydrate was

added drop wise,the mixture was heated for 24hr ,then cooled

the yellowish precipitate filtered off, recrystallized from, Table

(1) shows some physical properties of the compound.


A mixture of compound 4 (10mmole,

2.36gm)sodiumazide12mmol,0.78gm)dimethylformid 15ml

and ammonium chloride (10 mmol,0.53gm) was heated in oil

bath for 7hr at 125˚C. the solvent was removed under reduced

pressure . The residue was dissolved in 25ml of water and

carefully acidified with concentrated hydrochloric acid to PH

2 .The solution was cooled to 5˚C in ice bath .the solid

separated out ,filtered and crystallized from ethanol , Physical

properties listed in table (1).

11. Synthesis of compound (17,18,20)

To solution of compound 5 (0.005mol,1.195gm) in absolute

ethanol 20ml,5ml hydrazine hydrate for compound 17 ,0.006

mol for compound 18 and 0.005 mol of dehydro acetic acid for

compound 20 ,the mixture was refluxed for (6-12) hr ,then

cooled the solid formed filter off and dried ,crystallized from

appropriate solvent.




The mixture of compound 15 (0.005mol,0.47gm),hydrazine

hydrate 0.5gm and %5 methanolic (CH3COONa)5ml was

stirring overnight and the separated solid filtered and

recrystallized from ethanol, Physical properties listed in table

(1).

13.Synthesis of compound (21)

(0.001mol,267gm) of compound 17 and (0.002mol,0.27gm)

phenyl isothiocyanate in absolute ethanol ,three drops Et3N

was added then the mixture heated under refluxed for 7 hr

,white precipitate formed after cooled filtered ,dried

recrystallized from ethanol : Dioxan, Table (1) shows some

physical properties of the compound.

3. RESULTS AND DISCUSSION 15,16,17

The first five compounds were synthesized from reaction

sodium saccharin with different halo compounds using DMF

as solvent (scheme 1)

The structure of synthesized compound have been identified

using UV, FTIR ,and 1H-NMR,13C-NMR.

The FTIR spectrum of compounds (1-5) proved absorption

bands at (1735-1745cm-1) due to stretching vibration of C O

saccharin ring and compound 1 showed a new bands at 1755

cm-1,1720 cm-1 due to stretching vibration of 2 C Ogroups (

ester ,ketone ) respectively,while compound 2 exhibited band

at 2125 cm-1 due to stretching band vibrating of terminal triple

band (C CH)group ,also compound 4 shows anther band

at 2256 cm-1 responsible confirmed C N moiety .

The FTIR of compound 5 demonstrated new band at 1730 cm-

1 indicating the presence of ketone C O group.

The 1H-NMR spectrum of compound 1 in DMSO as solvent

displayed the following data in ppm ( 1.06-1.11(t,3H,CH3) ,

3.39 (s,2H, CO CH2CO) ,3.92-3.95( q, 2H,O-CH2-CH3)

,4.6(s,2H, N-CH2) ,8-8.3(m,4H, aromatic ring)

In addition for above , the 13C-NMR spectrum of the compound

appears the following data .

N

S

O

OO

O O

O CH3

158

166194

13

60

45

46136.9

136

135

126121

125

The reaction compound 6 with ethyl acetoacetate produced

compound 8, FT-IR spectrum of it proved an absorption bands

at 1716 cm-1 and 1616 cm-1 due to C=O group and C=C of

lactone ring and disappearance band at 1687 cm-1 which

indicated to C=O of pyrazolone ring , also 1H-NMR spectrum

in DMSO as solvent illustrated the following values in ppm:

2.476(s, 3H,CH3 ),5.322(s,2H, N-CH2)

,5.95(s,1H,C=CH),13.4(s,1H,NH), 8-8.35(m,4H,aromatic

ring) .

In additional 13C-NMR spectra show the following data in

ppm. ,19,33,100,108,121,125,126,133,135 ,135.7,136,

151,158,159,160.7

On the other side ,compound 1 were cyclized with o-

phenylenediamine or its sub in presence of PTSA as catalyst

produce indole (9,10) respectively .Which their FTIR spectra

confirmed the disappearance of band at 1755 cm-1,1720 cm-1

for two C=O group of ester and ketone and demonstrated anew

bands at1627 cm-1 ,3276 cm-1 due to C=N,NH respectively of

indole ring .Beside that H-NMR spectra for compound 10 in

DMSO as solvent illustratedthe following data in ppm .

2.39(s, 3H,CH3),5.1(s,2H,N-CH2) 6.7-7.7(m,3H,aromatic),8-

8.6(m,4H,aromatic ring of saacharin),12-12.4(broad,1H,NH).

Intertingly 13C-NMR gave the following data.

,35,117,121,123,125126,128,131,135,135.8136,147,158.

Where as ,the compounds(11-14) were synthesized from

compound 1 with sub phenol in presence of H2SO4 or

piperidine .

The FTIR spectrum of compounds (11,12) showed anew band

at 1701 cm-1,1715 cm-1 owing to stretching vibration of C=O

lactone ring and 1616 cm-1 1624 cm-1 due to C=C band and dis

appearance bands at 1755 cm-1,172o cm-1 of ester and ketone

group.

It's worth to mention that compound 4 reaction with sodium

azide in the presence ammonium chloride to produce

compound 16 , the success of reaction confirmed by the

disappearance of the band at 2256 cm-1 which responsible for C N and appearance anew band at 3400 cm-1refer to

presence NH and absorption band at1257 cm-1,1296 cm-1

indicated to N=N-NH of tetrazol ring.

Schiff base (15,17,18,20) were synthesized by reaction of

compound (3 or 5) with hydrazine hydrate in presence few

drops of G.A.A as catalyst .FTIR spectra confirmed the

disappearance of bands at 1720 cm-1-1745 cm-1 for carbonyl

and demonstrated new bands at(1645 cm-1,1624 cm-1) indicated

the presence of azo methene group.

When Schiff base (17) react with phenylisothiocyanate in the

presence of Et3N to produce compound 21 FTIR spectra

showed anew band at1251,1230 cm-1 due to stretching

vibration of C=S group , and 3360 cm-1,3315 cm-1,3256 cm-1

,3147 cm-1 NH respectively and disappearance absorption

band at 3360 cm-1,3290 cm-1,3229 cm-1of NH2 ,while reaction

with dehydroacetic acid gave Compound (20). FTIR spectra

of it showed absorption band reveal to azomethen group and

important band at due to C=O of lacton ring of dehydroacetic

acid .



Table (1): physical properties of the synthesized compounds

H*= Hexane

E**=Ethylacetate

Comp.

No

m.p.◦C Yield% color Recryst . Solvent Rf Mobile phase

1 110-111 72 white Ethanol %70 0.27 [H*:E**] 6:4

2 124-126 90 = Ethanol%70 0.36 [H:E] 5:5

3 263-265 75 Off white ethanol 0.53 [H:E] 5:5

4 143-145 53 white Ethanol%70 0.58 [H:E] 5:5

5 143-144 95 = Ethanol%80 0.49 [H:E] 5:5

6 150-152 31 Off white methanol 0.27 [H:E] 5:5

7 170-172 73 yellow Ethanol%70 0.25 [H:E]5:5

8 258-260 20 yellowish Ethanol [H:E]5:5

9 182-184 22 Off white Ethanol 0.48 [H:E]6:4

10 188-189 21 = Ethanol [H:E]5:5

11 228-230 30 = Methanol:Dioxan 0.64 [H:E ] 6:4

12 214-215 31 white Ethanol 0.66 [H:E]5:5

13 200-202 54 yellow [H:E]5:5

14 163-165 51 = dioxin 0.53 [Methnol:chloroform]

3:7

15 150-153 63 white methanol 0.43 [H:E]5:5

16 222-224 45 Off white Ethanol%70 0.42 [H:E]5:5

17 183-184 67 white methanol 0.46 [Methnol:chloroform]

3:7

18 199-201 70 yellow Methanol:Dioxan 0.38 [H:E]3:7

19 189-190 35 yellow 0.6 [Methnol:chloroform]

3:5

20 278-277 60 yellow Methanol:Dioxan [Methnol:chloroform]

5:5

21 188-190 83 White Methanol:Dioxan 0.53 [Methnol:chloroform]

5:5



Table (2) :FT-IR and UV spectral data of compounds (1-5)

Table (3):1H-NMR and 13C-NMR spectrum data of selected compounds

Comp.No Characteristic bands of 1H- NMR (ppm ,DMSO) Characteristic bands of 13C-NMR (ppm , DMSO)

1 1.06-1.11(t,3H,CH3) , 3.39 (s,2H, CO CH2CO) ,3.92-3.95(q,

2H,O-CH2-CH3) ,4.6(S,2H, N-CH2) ,8-8.3(m,4H, aromatic

ring)

2 3.4 ( S, 2H, N-CH2), 4.5(S,1H, C CH) ,7.7-8.3(m,4H,

aromatic ring)

27,75,76,121,125.2,125.9,135,136,136.9,157.8

4 2.73-3.01(t,2H,CH2-CN),4-4.29(t,2H,N-CH38-

8.5(m,4H,aromatic)

17,34,117,121,125,126,135,137,158

Comp

. No.

UV

Ethanol

Characteristic bands of FT-IR spectrum (cm⁻¹,KBr)

λ max

nm C-H

aromatic

C-H

alph.

C=O

Saccharine

ring

2SO C=C

ar.

Others

1 349

205

3089 2981

2943

2900

1735 1369(as)

1188(s)

1593

1465

1755 for C=O of ester

1720for C=O of ketone

3500(OH) tou

2 351

210

3093 2966

2940

1739 1338(as)

1184(s)

1589

1462 2125 for C CH

3275 for C-H alkyne (st),

667 bending

3 - 3090

3016

2029 1741 1348(as)

1193(s)

1558

1450

1705 for C=O amid

4 226

208

3089 2980 1739 1342(as)

1184(s)

1597

1462 2255 for C N

5 351

208

3091 2947

2912

1745 1323(as)

2284(s)

1593

1466

1730 for C=O ketone



Table (4): show the UV and FT-IR spectra data of compounds (6,7)

Table (5):1H-NMR and 13C-NMR spectra of compounds (6,7)

Figure (2) :FT-IR spectra of compound (1)

Comp.NO UV λ max

nm

Characteristic bands of FT-IR spectrum (cm⁻¹,KBr)

C-H aromatic

C-H alph.

C=O Saccharine ring

C=O pyrazole

C=N Others

6 206 309 2981

2920

2781

2723

1728 1687 1651

1627

3375 for NH and OH

7

-

3105

2981

2890

1732

1732 1616 1530,1338 for NO2

Comp.NO 1H-NMR 13C-NMR

6 3.618(s,2H,CH2),4.601(s,2H,N-

CH2),8-8.33(m,4H,amrotic ring)

34, 40.7, 114, 121, 125, 126, 135, 135.8 ,136 ,152 ,158 ,167

7 3.8(s,2H,CH2),4.6(s , 2H , N-CH2),

7.6-8.8(m,7H, aromatic

,11.33(S,1H,OH ,totaumeric

34.8 ,43 109 ,115 ,121 , 121.8 ,122,125 , 126 ,130 135, 136.6,

136.8 ,137.7 ,144.4 ,146.7 , 149 .4

158.6 ,166.9



NMR spectra of compound (1)-H1): 3Figure (

of compound(1) spectra NMR-C13): 4Figure (




NMR spectra of compound (8)-H1): 6Figure (

NMR spectra of compound(8)-C13): 7Figure (






compound(7)NMR spectra of -H1Figure (11 ):



)9NMR spectra of compound(-H1Figure (12 ):

NMR spectra of compound(2)-C13Figure (13 ):

Table (6) : FTIR spectrum of compounds(11-14)

Comp.

NO

C-H

aromatic

C-H

alph.

C=O

Saccharine

ring

C=O

Lactone

C=C other

11

3093

2971

2819

1739 1701 1616 3236 for OH

12

3088

3077

2968

2930

1743 1715 1558,1462,1516,

13

3082

3064

2937

2860

1726 1676 1610 1660 for C=O α,β unsaturated

14 3072 2985

2941

2862

1728 1678 1616 1668 for C=O α,β unsaturated



Table (7 ): FTIR bands of compound ( 9,15,17,18,20).

Scheme (1)

NS

O

O O

O

NH

N

S

DMF

Cl

O

O

CH3

O

NH2NH2

NH NH2

NO2

O2N

OH

N

S

O

O O N NH

O

CH3

O

O

CH3

O

N

S

O

O O N N

O

NO2

NO2

R

N

S

O

O O N NH

O

OCH3

S

N

NH

O

Cl

N

S

O

OO

Na .H2O

NH2 NH2

NS

N

O O

O

NH

N

S

NH2

Cl

N

DMF

DMF

S

O

OO

N

N

R

OH

OH

S

O

OO

N

N

N NNH

16

DMFNH4Cl

S

O

OO

N

O O

O

Br

N

S

O

O O O

R

O

N

S

O

O O

O

O CH3

O

NH2 NH2

R

PTSA

pip

S

O

O

O

N

N

NH

R

1

Cl CH

S

O

OO

N

CH

2

3

15

6

7

8

9R=CH39R=CH310R=H

11R=OH

12R=C2H5

13R=H

14R=Br

Comp.NO C-H

aromatic

C-H

alph.

C=O

Saccharine

ring

C=N C=C Others

15

3091

3074

2976

2926

- 1660

1645

1591

1572

3290 ,3263for NH2, OH,NH

17 3070 2960 - 1662

1624

1591,1471 3342,3319,3290,3229 for NH2

18 3097 2960

2918

1735 1687

1660

1639

20 3090 2972

2929

- 1651

1639

3358 for OH of DHA

1705 for C=O of DHA



Scheme (2)

O

N

S

OO

Na .2H2O+

DMF

Cl

O

CH3

N

S

O

O O

O

CH3

5

NH2 NH2

G.A.A NSO

O

O

N

CH3

N

N

S

O

O O

CH3

18

NS

N

OO

N

CH3

NH2

NH2

N

S

N

OO

NCH3

19

17

dehydroacetic acetic

NS

N

OO

N

CH3

NH

NH

S

NH Ph

S

NH Ph

NH2 NH2

NH2 NH2

20

21

O O

O

N

S

N

OO

N

CH3

N

N

CH3

O

OO

CH3

N

S

N

OO

NHCH3

Et3N

N

S

N

S

O

O O

N

CH3

N

SN

OO

CH3



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Journal of Sciences Synthesis of Novel Compounds … of Novel Compounds Derived from Saccharin...

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