Indian Journal of Chemistry Vol. 428, March 2003, pp. 621-626

Synthesis of biologically active thiazolo-benzopyranyl-s-triazine derivatives

V V Mulwad* & Jyoti M Shirodkar

The Institute of Science, Department of Chemistry, 15, Madam Cama Road, Mumbai - 400 032, India

Received 18 September 2001 ; accepted (revised) 30 October 2002

6-Amino-2-oxo-2H [I]-benzopyran on oxidative cyclisation with potassium thiaocynate, acetic acid and bromine at 0-5°C gives 2-amino-7H [6]- thiazolo [5,4-d] benzopyran-7-one 1, which on treatment with cyanuric chloride in alcohol gives 2-(2' -amino-7' -oxo-7' H [6']- thiazolo [5', 4' -d] benzopyranyl)-4-6-dichloro-s-triazine 2. 6-Amino-2-oxo-2H [I]-benzopyran on refluxing with ammonium thiocy nate in hydrochloric acid and ethanol gives 6-thioureido-2H [1]-benzopyran-2-one 3. Compound 2 on refluxing with 3 in alcohol gives 2-(2'-amino-7'-oxo-7'H [6']- thiazolo [5', 4'-d] benzopyranyl)-4-(6"-thioureido-2" H-[ I "]-2" -oxo-benzopyranyl)-6-chloro-s-triazine 4. The si milar reaction is repeated on 4 to give 2- (2' -amino-7' -oxo-7' H [6']- thiazolo [5 ', 4' -d] benzopyranyl)-4-(6" -thioureido-2" H [I "]-2"-oxo benzopyranyl)-6-(6'" -thioureido-2'" H-[I "']-2'" -oxo-benzopyranyl)-s-tri azine 5. The structures of all compounds are confirmed on the basis of analytical and spectral data. Some of the compounds show significant antibacterial activity.

Thiazoles' containing N=C-S moiety have been used as antipsychotics2, antimalerials3 and antibacterials4.5. Benzothiazoles6, s-triazines7 and 2,4-dichloro-6-tria-zinylthioureas8, exhibit various biological activities. The presence of thioamido group imparts a wide variety of physiological p:-operties to thioureas derivatives 9.

Coumarin moiety is widely distributed in nature. Coumarin and its derivatives are substances of much

. I I f h ' 10 II S' '1 I potentia va ue or synt etlc purposes . . Iml ar y, coumarin shows diverse biological activity such as antifungal'2, anticoagulant'3, active against psorasis'4, carcinogen'5, antibacterial '6 and insecticides'7. It also appears extensively in nature as photosensitizing agent' 8. The combined presence of thioamido group, thiazole system, s-triazine moiety in coumarin, may possess above biological activity.

With this observation we thought of synthesizing 2-amino-7 H [6]- thiazolo [5,4-d] benzopyran-7 -one and its s-triazine derivatives, which might possess some pharmacological activity . Some new thiazolo derivatives were synthesized from 6-aminocoumarins.

6-AminocouI1)arin on stirring with potassium thiocyanate, acetic acid and bromine at 0-5°C gave 2-amino-7 H [6]- thiazolo [5,4-d] benzopyran-7-one 1. 'H NMR (OMSO-d6) spectrum of Ib showed singlet at 0 2.1(s, 3H, CH3), 6.29-6.3 (d, IH, C8-H, 1=9.5 Hz), 7 (s, IH, C5-H), 7.87-7.88 (d, IH, C9-H, 1=9.5 Hz), 5 (s, 2H, NH2 - 0 20 exchangeable). '3C NMR (OMSO-d6) showed signals at 018.78 (carbon of methyl group), 115.2 (C9a-C), 127.7(C9b-c), 148.6

(C3a-C), 148.9 (C5a-C) and four aromatic carbons were observed between 0110-142. 160.4 (>C=O), 166 (C2-C). Mass spectrum showed molecular ion peak mlz at 232.

In case of oxidative condensation of unsubstituted 6-aminocoumarin there was possibility of two types of thiazolobenzopyran, one being the linear thiazolo benzopyran and the other as angular thiazolo-benzopyran. However the formation of the linear thia-zolobenzopyran was ruled out from the 'H NMR spectrum. It (OMSO-d6) showed doublet at 07 .25-7.27 (d, IH, C4-H, 1=8.5 Hz) and 7.54-07.56(d, IH, C5-H, 1=8.5 Hz) along with other signals.

Ethanolic solution of compound 1 was added with stirring to ethanolic solution of cyanuric chloride at room temperature to give 2-(2'-amino-7' -oxo-7' H [6']- thiazolo[5',4' -d]benzopyranyl)-4-6-dichloro-s-triazine 2. It showed positive Beilstein and Lassignes sodium fusion tests, indicating presence of chlorine. 'H NMR (OMSO-d6) spectrum showed a singlet at 0 11.01 for one proton of -NH group, which was 0 20 exchangeable instead of two protons of - NH2 along with other peaks. I3C NMR (OMSO-d6) showed additional signals for C4-C, C6-C at 0169.7. Mass spectrum showed molecular ion M+ peak mlz at 379, M+2 peak mlz at 381and M+4 peak mlz at 383 indicating presence of two chlorine atoms.

Hydrochlorides of 6-aminocoumarin was on refluxing with ammonium thiocynate gave 6-thioureido-2H [l]-benzopyran-2-one 3 (Scheme I, Table I). 'H NMR (OMSO-d6) spectrum showed

622 INDIAN 1. CHEM. , SEC S, MARCH 2003

I KSCN RIWO

0

H2N ~ ~ Br2 R

~ 3"

6 5" 0

3 ~ N 9b 9 Ls R /2 I (I )

H2N (la-ld)

R

5' 6 ' 7 0 RI 4 '~ 50' 0 7 ' 0

Cyanuric CI I Y --'---.-;.~ 5 ~ I 3a' ~ ~J 8' chlondc 1'1 y N 3 ~t 9& 9" '~

C~ ~ ~Sl' (2) R N 3 NH (2a-2d)

RIWO 01

H2N-C-HN ~ I ~ M (3) I~ 5' 6 ' RI 4 '~ 50' 0 , 7' 0

6P 3a' ~ I ~ s' 5~ I 3' /9" '

N N N 90 9' ~ 4 1 11 2 \\ -SI ' R

/I NH-C-NW~ ~ r.r 3N NH

o 8a" (4) I" (4a-4d)

o

RI~°'i0 H2N-C-HN~

M (3) R 1

8/1

(5) (5a-5d)

-------------. 6 H2N-C-HN ~

II (3) 5 S (3a-3d)

R

Scheme I

singlet fo r -NH proton at 8 8. 15 and - NH2 proton at 89.2, which were 0 20 exchangeable. I3C NMR (OMSO-d6) showed signals for >C=S carbon at 8 182 in addi tion to >C=O carbon at 8160. Mass spectrum showed molecular ion peak mlz at 234.

Ethanolic solution of compounds 2 and 3 was refluxed on water bath to give 2-(2'-amino-7'-oxo-7' H

[6']-thiazolo [5', 4'-d] benzopyrany l)-4-(6"-thio-ureido-2" H [1"]-2"-oxo-benzopyranyl)-6-chloro-s-triazine 4 . It showed positive Beilstein and Lassignes sodium fusion tests, indicating presence of chlorine. IH NMR (OMSO-d6) showed signals at 88.9 (s , IB, NH, 0 20 exchangeable), 9.35 (s, 1 H, NH, 0 20 exchangeable) and 1O.8(s, 1 H, NB, 0 20 exchange

MULWAD el of.: SYNTHES IS OFTHIAZOLO-BENZOPYRANYL-S-TRIAZINES

Table I-Characterization data of compounds la-d, 2a-d, 3a-d, 4a-d and Sa-d .

Compd Mol. formu la m. p. (0C)

(Rec. solvent)

la

2a

3a

4a

Sa

lb

2b

3b

4b

sb

Ie

2e

3e

4e

se

Id

2d

3d

4d

sd

CIOH6N20 2S 255 (Ethanol)

CI3HsNs0 2SC\2 >260 (Dich loromethane)

C IOHgN20 2S 120 (Ethanol)

C2)H '2N704S2C\ 200 (Dichloromethane)

C3) H'9N90 6S) 230 (Dichlorolllethane)

C II HgN20 2S 145 (Ethanol)

C'4H7NS0 2SC\2 2 10 (Dichl oromethane)

C II HION20 2S 155 (Ethanol)

C2sH '6N70 4S2C\ 180 (Dich lorolllethane)

C)6H2S N90 6S) 160 (Dichlorolllethane)

C' 2H ION20 3S 200 (Ethanol)

C,sH9NsO)SCI2 >260 (Dich loromethane)

C'2H12N20 )S 160 (Ethanol)

C27 H20N70 6S2C\ 245 (Dichloromethane)

C39H3,N90 9S3 >260 (Dich loromethane)

C '2H ION20 2S 176 (Ethanol)

C, sHgNs0 2SCI2 >260 (Dichlorolllethane)

C'2H'2N202S 180 (Ethanol)

C27H20N70 4S2C\ 245 (Dichloromethane)

C39H3,N90 6S3 230 (Dichloromethane)

Yield (Found/Calcd) % -----------------

(%) N S CI

79

82

80

72

68

73

80

77

70

62

66

77

78

69

58

68

75

77

69

58

14.14 ( 14.03

19.18 ( 19.34

12.73 ( 12.52

17.83 (17 .56

17.19 (17.10

12.07 (12.18

18.47 ( 18.69

11.97 (11.82

16.97 ( 16.26

16.26 (16.52

10.69 (10.1 6

17.11 ( 17.35

10.6 1 (10.26

15.37 ( 15.66

14.57 ( 14.28

11 .38 (11.54

17.8 1 (17.53

11.29 ( 11.23

16.1 8 ( 16.03

15.42 ( 15.22

16. 16 16.24

8.77 8.20

14.55 14.68

11.65 11 .92

13. 10 13.36

13.79 13.62

8.44 8.22

13.68 13.92

11.08 11.82

12.39 12.44

12.2 1 12.05

7.82 7.99

12.12 12.34

10.04 10.30

11.10 11.65

13.0 1 13 .28

8. 14 8.29

12.90 12.52

10.57 10.22

11.75 11 .38

-) 19. 18 19.25)

-)

6.46 6.54)

-)

- )

18.47 18.38)

-) 6. 15 6.29)

-)

-) 17.11 17.02)

-) 5.57 5.62)

-)

-)

17.81 17.94)

-) 5.86 5.72)

-)

C, H Analysis of all the compounds was found to be sati sfactory

623

able). I3C NMR (DMSO-d6) showed signals at 818 and 20 (carbons of methyl groups), 117 . 1 (C9a' -C, C4a" -C), 117-145 (aromatic 7 carbons), 126 (C9b'-C), 131 (C/-C, C/'-C), 142 (C6"-C), 143 .5 (C3a'-C), 152 (CSa'-C, Csa"-C), 155 (carbon of C=S), 159.8 (two >C=O), 165 (C2' -C), 167 (C2 and C4), 169 (C6) .

A similar reaction was repeated on compound 4 to give 2-(2'-amino-7'-oxo-7' H[6']-thiazolo[5',4'-d]benzo-pyranyl)-4-(6"-thioureido-2" H-[ 1"]-2"-oxo-benzopyr-anyl)-6-(6'"-thioureido-2''' H-[ 1''']-2'''-oxo-benzopyra-nyl)-s-triazine 5. It showed negative Beilstein and Lassignes sodium fussion tests, indicating absence of

624 INDIAN 1. CHEM., SEC B, MARCH 2003

chlorine. 'H NMR (DMSO-d6) spectrum showed singlets for two protons of 2xNH at 88.9 and 9.3 respectively, which were D20 exchangeable. Singlet for one proton of -NH at 8 11.9 which was D20 exchangeable. I3C NMR (DMSO-d6 ) showed signals at 8167 for C2. C4 and C6 carbons and absence of signal at 8169. for >C-Cl carbon.

Experimental Section General. Melting points were taken in open

capillaries and are uncorrected. The IR spectra were recorded on Perkin-Elmer 257 spectrophotometer using KBr. I3C NMR and 'H NMR were recorded on YXR-300 spectrometer (using TMS as internal standard). The homogeneity of the compounds was described by TLC on silica gel -G plates the spots were developed in iodine chamber.

2-Amino-7 H[6]-thiazolo[5,4-d]benzopyran-7 -one I:General procedure. A solution of bromine (0.01 mole) in 95 % acetic acid (4mL) was added dropwise to a mixture of aminocoumarin (0.00862 mole) in 95% acetic acid (15 mL) and potassium thiocyanate (0.04 mole) in 95% acetic acid (15 mL) . During the addition and after the addition the reaction mixture was maintained at ODe. After stirring the mixture for 5 hr it was poured into water (50 mL) and neutralized with ammonium hydroxide. A solid separated out which was filtered and recrystalli sed from ethanol.

la: IR (KBr): 3195 (-NH2), 1691 (>C=O), 1639 em-I; 'H NMR (OMSO-d6): 86.49-86.51 (d, IH, Cs-H, 1=9.5 Hz) , 7.25-87.27 (d, IH, C4-H, 1=8.5 Hz), 7.54-87 .56(d, lH , Cs-H, 1=8.5 Hz), 8-88.02 (d, IH, C9-H, 1=9.5 Hz), 7.66 (s, 2H, NH2 -D20 exchangeable); I3C NMR (DMSO-d6): 8112 (Cs-C), 114(Cs-C), 116.3 (C9a-C), 120.79(C4-C), 128.5 (C9b -C), 142 (C9-C), 148.6(C3a -C), 149.5 (CSa-C), 159 (>C=O), 166.3(C2-C).

Ib: IR (KBr): 3309, 3348 (NH2), 2938 (CH-stretching), 1683(>C=0), 1624, 1551 , 1455, 1387 em-I; 'H NMR (DMSO-d6): 8 2.1(s, 3H, CH3), 6.29-6.3 (d, IH, Cs-H, 1=9.5 Hz), 7 (s, IH , Cs-H), 7.87-7.88 (d, IH , C9-H, 1=9.5 Hz), 5 (s, 2H, NH2 -020 exchangeable); '3C NMR (DMSO-d6): 818.78 (carbon of methyl group), 110.6 (Cs-C), 114.6(Cs-C), 115.2 (C9a-C), 127.7(C9b -C), 132 (C4-C), 142 (C9 -C), 148.6 (C3a-C), 148.9 (CSa-C), 160.4 (>C=O), 166 (CrC); M+ peak mlz at 232 (8l.62%), 203(23.32%), 176(3.l8%), 330(2.08%), 162 (2.12%), 149 (4.24%), 134(3.18%), 116(5.3%), 102(8.48%), 84(19.08%), 75(5 .3%), 64(3.18%),40(100%).

lc: IR (KBr): 3420 (-NH2)' 2920 (CH-stretching), 1699(>C=0), 1618 cm-'.

Id: IR (KBr): 3394 (NH2), 2925 (CH-stretching), 1742(>C=0), 1624 cm-'.

2-(2'-Amino-7'-oxo-7' H[6']-thiazolo [5', 4'-d]-benzopyranyl)-4-6-dichloro-s-triazine 2: General procedure. A solution of compound 1 (0.0 I mole) in ethanol was added with stirring to a ethanolic solution of cyanuric chloride. The reaction mixture was stirred for 30 min . at room temp and neutral pH was maintained by adding ag. sodium bicarbonate solution . It was then poured over crushed ice and resulting solid was filtered, dried and recrystalli sed from dichloromethane.

2a: IR (KEr): 3167, 3313(-NH), 1701 (>C=O), 1649 cm-'.

2b: IR (KBr) : 3281, 3453 (NH), 2943 (CH-stretching), 1707(>C=0), 1624 cm-' ; 'H NMR (DMSO-d6): 8 2.29(s, 3H, CH3), 6.41-6.43 (d, IH, Cs'-H, 1=9.5 Hz), 7.15(s, IH, Cs'-H), 7 .99-8 .01(d, IH, C9'-H, 1=9.5 Hz), 1l.01(s, IH, NH -D20 exchangeable); I3C NMR (OMSO-d6) : 818 (carbon of methyl groups), 115.8 (Cs'-C), 116.9(C9a'-C), 117.8 (Cs'-C), 126(C9b'-C) , 139 (C4'-C), 142 (C9' -C), 143(C3a'-C), 152 (Cs/-C), 159 (>C=O), 165(C2' -C), 169.08 (Cr C) , 169.7 (C4-C, C6-C); M+ peak mlz at 379(100%), M+2 peak mlz at 381(66.35%), M+4 peak mlz at 383(10.90%), 302(34.8%), 275(27.84%), 196(l6.24%},115(13 .92%).

2c: IR (KBr): 3437 (NH), 2922 (CH-stretching), 1703(>C=0), 1660, cm-'.

2d: IR (KBr): 3443 (NH), 2927 {CH-stretching), 1741(>C=0), 1624 cm-'.

6-Thioureido-2H-[I]benzopyran-2-one 3: General procedure. Amjnocoumarin (O.Olmole) was dis-solved in mixture of conc . HCI (2mL) and water (5mL) by heating. Solution of amine hydrochloride was cooled and ammonium thiocynate (0.01 mole) in ethanol was added to it. Mixture was heated on water bath for 7 hr. On cooling, a solid separated out which was filtered, washed with water, dried and recrystallised from ethanol.

3a: IR (KBr): 3441(-NH2), 1742 (>C=O), 1624 crn-'. 3b: IR (KBr): 3340, 3408 (NH, -I\H2), 2934 (CH-

stretching), 1716 (>C=O), 1685, 1626 crn-'. 'H NMR (OMSO-d6): 8 2.3 (s, 3H, CH3), 6.6 1- 8 6.63(d, IH, C3-H, 1=9.5 Hz) , 7.56(s, IH, Cs-H), 8.15-8 8.l7(d, 2H, C4-H, NH D20 exchangeable), 8.5(s, 1 H, Cs-H, 1=9.5 Hz), 9.2 (s, 2H, NH2 -D20 exchangeable); I3C NMR (DMSO-d6) : 818.2 (carbon of methyl group) ,

MULWAD et al.: SYNTHESIS OF THIAZOLO-BENZOPYRANYL-S-TRIAZINES 625

110 (C3-C), 115 (Cg-C), 117.2 (C4a-C) , 128 (Cs-C), 134 (CrC), 140.8 (C4-C), 143 (C6-C), 152(Csa-C), 160 (>C=O), 182 (carbon of C=S); M+ peak m/z at 234 (3.18%), 217(13.78%), 205(38.16%), 188 (100%), 174(19.08%), 160 (16.96%), 147(14.84%), 132(30.74%), 119(5.3%), 103 (41.34%), 91(15.9%), 77(66.78%).

3c: IR (KBr): 3427 (NH, -NH2), 2927(CH-stretching), 1702 (>C=O), 1621 cm· l.

3d: lR (KBr): 3424 (-NH), 2930 (CH-stretching), 1742(>C=0), 1624 cm·l.

2-(2' -Amino-7'-oxo-7' H [6']-thiazolo [5' ,4' -d]-benzopyranyl) -4-(6/1 -thioureido-2/1 H _[l/l]_2/1_oxo_ benzopyranyl)-6-chloro-s-triazine 4: General procedure. A solution of compound 1 (O.Olmole) in ethanol was added to a solution of compound 3 (0.01 mole) in ethanol. The resultant reaction mixture was refluxed on water-bath over a period of 2 hr and neutral pH was maintained by adding aq. sodium bicarbonate solution. It was then poured over crushed ice and resulting solid was filtered, dried and recrystallised from dichloromethane.

4a: lR (KBr): 3441 (-NH), 1733 (>C=O), 1652, 1615 cm· l.

4b: IR (KBr): 3247 (NH), 2963 (CH-stretching), 1736(>C=0), 1625 cm· l; IH NMR (OMSO-d6): 82.25 (s, 6H, 2xCH3), 6.3-8 8.5 (mu ltiplete, 7H, Ar-H), 8.9 (s, I H, NH, 0 20 exchangeable), 9.35 (s, IH, NH, 0 20 exchangeable), 1O.8(s, 1 H, NH, 0 20 exchangeable); I3C NMR (OMSO-d6): 818 and 20 (carbons of methyl groups), 117.1(C9a'-C, C4a/l_C),

117-/45 (aromatic 7 carbons), 126 (C9b'-C), 131 (C/-C, C/' -C), 142 (C6/1-C ), 143.5 (C3a'-C), 152 (CSa'-C, CSa/l-C ), 155 (carbon of C=S) , 159.8 ( two >C=O), 165 (C2'-C), 167 (C2 and C4), 169 (C6 ).

4c: lR (KBr): 3488 (NH), 2925 (CH-stretching), 1705(>C=0), 1614 cm· l.

4d: IR (KBr): 3423 (NH), 2961 (CH-stretching), 1742(>C=0), 1624 cm· l.

2- (2'-Amino-7'-oxo-7'H [6']- thiazolo[5', 4'-d]-benzopyranyl)-4-(6/1-thioureido-2/1 H-[l/l]-2/1-oxo-benzopyranyl)-6-(6/1'-thioureido-2'" H-[l'/I]-2"'-oxo-benzopyranyl)-s-triazine 5: General procedure. A mixture of 4 (O.Olmole) and 3 (0.01 mole) in dimethyl formamide (15 mL) was refluxed for 3 hr. It was then poured over crushed ice and the resulting solid was filtered, dried and recrystallised from dichloro-methane.

Sa: IR (KBr): 3314 (-NH), 1715 (>C=O), 1623, 1557 cm·l.

5b: IR (KBr): 3278 (NH), 2961 (CH-stretching), 1733(>C=0), 1625 cm·l; IH NMR (OMSO-d6): 8

2.3(s, 9H, 3xCH3), 6.3-8.6 (multiplete, IIH, Ar-H), 8.9 (s, 2H, 2xNH, 0 20 exchangeable), 9.3(s, 2H, 2xNH, 0 20 exchangeable), 11.9(s, lH, NH, 0 20 exchangeable); I3C NMR (OMSO-d6): 818 and 20 (carbons of methyl groups), 116.8(C9a' -C, C4a"-C, C4a"'-C), 116-145 (aromatic 11 c), 126.8 (C9b'-C), 137 (C/-C, C/'-C, C/"-C), 143 (C6/1-C, C6'/I_C), 144

(C3a'-C), 152 (Csa'-C, CSa/l-C, CSa/l'-C), 155 (two carbons of C=S), 159.8 (three >C=O), 165 (C/ -C), 167(C2. C4 and C6) .

5c: IR (KBr): 3358(NH), 2923 (CH-stretching) , 1719 (>C=O), 1627 cm·l.

5d: IR (KBr): 3433 (NH), 2925 (CH-stretching), 1724(>C=0), 1624 cm·l.

Biological screening The compounds Id, 2d, 4d, 5d were screened for

their antibacterial activity against both gram-positive and gram-negative bacteria and found to be active as shown in Table II. Minimum inhibitory concentration (MIC) of these compounds was determined by tube dilution method l9 by using sodium penicillin , trimethoprim as a standard and OMF solvent.

Tube dilution method: In the tube dilution method, equal volumes of nutrient broth were taken up in six tubes. Same volume of sample was added to the first tube and therein decreasing dilutions were prepared (1 :2, 1:4, 1 :8, 1: 16, 1 :32). A sample control and a solvent control were also maintained. Finally same volumes of a 24 hrs . old culture (106 cjUlmL) were added to all tubes and then incubated at 37°C for 24 hr. Next day a loopful of the mixture was streaked on to a fresh nutrient agar plate to find out the minimum inhibitory concentration.

From data it could appeared that when all three chlorine atoms of cyanuric ch loride was replaced by -NH or thioamido group with heterocyclic ring was more active against S. typhi.

Table 11- Minimum inhibitory concentration

SI. No . RJ, R S. typhi S. aureus

Id R= R1=CH) + + 2d R= R1=CH) + + 4d R= R1=CH) + + Sd R= R1=CH ) ++ +

Note: ++ =100 ).lg/mL, + =200 ).lg/mL

626 INDIAN J . CHEM., SEC B, MARCH 2003

Acknowledgement We are thankful to Mr S V Chiplunkar, U D C T,

Mumbai for elemental analysis, Director R SIC, I I T Mumbai and T IF R, Mumbai for 13C NMR, IH NMR and mass spectra, Haffkine Institute, Parel for studies in microbial activities and to Government of Ma-harashtra and Lady Tata Memoriable Trust for schol-arship.

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