Synthesis and antimicrobial activity of 5-aryl-6-[tetra(O-benzoyl)-β- D-glucopyranosylimino]-4-benzylthio-2-phenylimino-5,6-dihydro-2H-1,3, 5-thiadiazines

Article abstract of DOI:10.1007/s10593-005-0222-4

Certain 5-aryl-6-[tetra(O-benzoyl)-β-D-glucopyranosylimino]-4- benzylthio-2-phenylimino-5,6-dihydro-2H-1,3,5-thiadiazines have been prepared by interaction of N-[tetra(O-benzoyl)-β-D-glucopyranosyl] isocyanodichloride and 1-aryl-5-phenyl-2-(S-benzyl)-2,4-

Full text of DOI:10.1007/s10593-005-0222-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 6, 2005
SYNTHESIS AND ANTIMICROBIAL ACTIVITY
OF 5-ARYL-6-[TETRA(O-BENZOYL)-β-D-GLUCO-
PYRANOSYLIMINO]-4-BENZYLTHIO-2-PHENYLIMINO-
5,6-DIHYDRO-2H-1,3,5-THIADIAZINES
M. G. Dhonde1 and S. P. Deshmukh2
Certain
5-aryl-6-[tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-2-phenylimino-5,6-dihydro-
2H-1,3,5-thiadiazines have been prepared by interaction of N-[tetra(O-benzoyl)-β-D-glucopyranosyl]
isocyanodichloride and 1-aryl-5-phenyl-2-(S-benzyl)-2,4-isodithiobiurets. The products have been
characterized through the usual chemical transformations, IR, NMR and mass spectral analyses. The
compounds have been screened for their antibacterial activities against various bacteria.
Keywords: isodithiobiurets, isocyanodichlorides, 1,3,5-thiadiazines, synthesis.
Benzoylated glucosyl nucleoside analogs having 1,3,5-thiadiazine moieties as heterocyclic bases have
not been earlier synthesized. We now report the synthesis of 5-aryl-6-[tetra(O-benzoyl)-β-D-
glucopyranosylimino]-4-benzylthio-2-phenylimino-5,6-dihydro-2H-1,3,5-thiadiazines
using
N-[tetra(O-
benzoyl)-β-D-glucopyranosyl] isocyanodichloride (1) as a key reagent. The latter has been prepared in our
laboratory for the first time by interaction of N-[tetra(O-benzoyl)-β-D-glucopyranosyl] isothiocyanate with
excess of chlorine gas.
The reaction of compound 1 and 1-aryl-5-phenyl-2-(S-benzyl)-2,4-isodithiobiurets (2) was carried out in
cold dry chloroform for 24 h. The solvent was distilled off and sticky mass was isolated as a residue. When
triturated several times with petroleum ether it was converted to a granular yellow solid. This solid was dissolved
in ethanol and basified with cold ammonium hydroxide solution to give 5-aryl-6-[tetra(O-benzoyl)-β-D-
glucopyranosylimino]-4-benzylthio-2-phenylimino-5,6-dihydro-2H-1,3,5-thiadiazines 3 (Scheme). Compounds
3 were purified by recrystallization from ethanol, their purity was checked by TLC. The products were found to
be non-desulfurisable when boiled with alkaline plumbite solution (Scheme 1).
The compounds were screened for their antibacterial activities against various pathogenic bacteria such
as E. coli, S. aureus, Pr. mirabilis, S. typhi by disc method at concentration 10 µg·ml-1 in DMF. Amongst the
compounds tested for the antibacterial activity, compounds 3b,d,g, and 3i showed higher activity against E. coli,
S. typhi and S. aureus, compounds 3e,j, and 3k demonstrated higher activity against Pr. mirabilis, while other
compounds revealed good to moderate activity.
__________________________________________________________________________________________
1
2
Shri Mathuradas Mohota College of Science, Umrer Road, Nagpur, India. Shri Shivaji College,
Akola-444 001 (M. S.), India; e-mail:madhudash2001@yahoo.com. Published in Khimiya Geterotsiklicheskikh
Soedinenii, No. 6, pp. 910-913, June, 2005. Original article submitted September 26, 2003; revision submitted
January 23, 2005.
0009-3122/05/4106-0787©2005 Springer Science+Business Media, Inc.
787

Scheme 1
S
CH2OBz
Cl
Cl
CHCl3
EtOH/
N
C
C
N
NH
NH
C
Ph
R
O
+
S CH2
Ph
OBz
NH3
2
Bz
O
R
N
OBz
CH2OBz
1
N
CH2
S
Ph
O
N
S
Bz
O
N
Ph
OBz
OBz
3
a R = Ph, b R = o-Tol, c R = m-Tol, d R = p-Tol, e R = o-ClC6H4, f R = m-ClC6H4, g R = p-ClC6H4,
h R = m- O2NC6H4, i R = p-O2NC6H4, j R = o-MeOC6H4, k R = p-MeOC6H4; Bz = benzoyl
EXPERIMENTAL
Melting points are uncorrected, optical rotation was measured at 38°C. IR spectra [1-3] recorded for
1
4.0 cm-1 flat, smooth, abex in 4000-200 cm-1 range. H NMR spectra [2, 4, 5] (300 MHz) were obtained for
solutions in deuteriochloroform using traces of CHCl3 as internal standard, chemical shifts were given in δ scale
relative to TMS. The FAB mass spectra [6, 7] were recorded on JEOL SX 102/DA-6000 Mass
spectrometer/Data system using Argon/Xenon (6 kV, 10 mA) as the FAB gas. The accelerating voltage was
10 kV and the spectra were recorded at room temperature. m-Nitrobenzyl alcohol (NBA) was used as a matrix
unless specified otherwise. Thin layer chromatography was conducted on Merck TLC Aluminium sheet Silica
gel 60 F254
.
N-[Tetra(O-benzoyl)-β-D-glucopyranosyl] isocyanodichloride (1) was prepared from N-[tetra(O-
benzoyl)-β-D-glucopyranosyl] isothiocyanate with excess of chlorine gas similar to the synthesis of phenyl
isocyanodichloride [8]. 1-Aryl-5-phenyl-2-(S-benzyl)-2,4-isodithiobiurets 2 were prepared by the method [9].
N-[Tetra(O-benzoyl)-β-D-glucopyranosyl] Isocyanodichloride (1). Through a solution of N-[tetra(O-
benzoyl)-β-D-glucopyranosyl] isothiocyanate [10] (6.37 g) in chloroform (20 ml) excess chlorine gas (generated
from 10 g of KMnO4 and 70 ml of concentrated hydrochloric acid) was passed maintaining the temperature
below 10°C. After complete addition of chlorine, a pale yellow reaction mixture was diluted with dry petroleum
ether (40 ml) and filtered to remove suspended impurities. After vacuum evaporation a pale yellow solid was
obtained (6.3 g); mp 165-167°C. Found, %: C 61.88; H 3.75; N 2.11; Cl 10.53. C35H27Cl2NO9. Calculated, %:
C 62.10; H 3.99; N 2.07; Cl 10.50.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-phenyl-2-phenylimino-5,6-dihydro-
2H-1,3,5-thiadiazine (3a). The reaction of compound 1 (3.38 g, 0.005 mol; Rf 0.28; EtOAc–CCl4 = 1:2 as an
eluent) and 1,5-diphenyl-2-(S-benzyl)-2,4-isodithiobiuret (2a) (1.9 g, 0.005 mol) was carried out in cold dry
chloroform for 24 hr. The solvent was then removed to leave a sticky syrup which was triturated with petroleum
ether until a yellow solid resulted. The solid was dissolved in ethanol and basified with cold ammonium
38
hydroxide solution to give compound 3a (4.5 g, 91.8%); mp 140°C (ethanol), [α]D = -6.66° (c 0.0014 in
CHCl3). The purity of product was checked by TLC and Rf value 0.92 (EtOH–CHCl3–Me2CO = 1:2:3 as an
eluent) was recorded. IR spectrum, ν, cm-1: 3062.7 (Ar–H), 2893.0 (C–H, aliphatic), 1728.1 (C=O), 1596.9
(C=N), 1380.9 (C–N), 1265.2 (C–O), 856.3 (β-D-glucopyranosyl ring deformation), 756.0 (C–S), 709.8
788

1
(monosubstituted ring), 614.5 (C–S–C). H NMR spectrum (CDCl3), δ, ppm: 8.05-7.2 (35H, m, Ar–H); 5.3-4.2
(5H, m, β-D-glucopyranosyl ring); 4.5-4.0 (2H, br. d, CH2–O); 4.52-4.40 (2H, br. s, S–CH2–Ph). Mass spectrum,
m/z (I, %): 997 [M+ + OH]; 980 [M]+; 935 [M – C2H5O]; 907 [M – C4H9O]; 873 [M – PhCH2O]; 595 [TBG –
+
NH2 ]; 579 [TBG]+; 462 [TBG – C8H5O]; 401 [M – TBG]; 376 [M – TBGNC]; 361 [M – TBGNCN]; 286 [M –
TBGNCNC6H3]; 220 [M – TBGNCHPh2]; 105 [PhCO]+. Found, %: C 68.26; H 4.32; N 5.60; S 6.90.
C56H44N4O9S2. Calculated, %: C 68.57; H 4.48; N 5.71; S 6.53.
The reaction of compound 1 was extended to several other 1-aryl-5-phenyl-2-(S-benzyl)-2,4-
isodithiobiurets and corresponding products 3b-k were prepared.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-2-phenylimino-5-(o-tolyl)-5,6-dihydro-
2H-1,3,5-thiadiazine (3b). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2b (1.95 g,
38
0.005 mol). Yield 4.1 g, 82.5%; mp 159°C; [α]D = -140.0° (c 0.0015 in CHCl3), Rf 0.52 (n-BuOH–CHCl3–
Me2CO = 1:2:3). Found, %: C 68.44; H 4.32; N 5.39; S 6.75. C57H46N4O9S2. Calculated, %: C 68.81; H 4.62;
N 5.63; S 6.43.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-2-phenylimino-5-(m-tolyl)-5,6-dihydro-
2H-1,3,5-thiadiazine (3c). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2c (1.95 g,
38
0.005 mol). Yield 3.2 g, 64.4%; mp 160°C; [α]D = -84.6° (c 0.0013 in CHCl3), Rf 0.68 (n-BuOH–CHCl3–
Me2CO = 1:2:3). Found, %: C 68.52; H 4.34; N 5.48; S 6.65. C57H46N4O9S2. Calculated, %: C 68.81; H 4.62;
N 5.63; S 6.43.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-2-phenylimino-5-(p-tolyl)-5,6-dihydro-
2H-1,3,5-thiadiazine (3d). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2d (1.95 g,
38
0.005 mol). Yield 4.0 g, 80.6%; mp 172°C; [α]D = -35.71° (c 0.0014 in CHCl3), Rf 0.72 (n-BuOH–CHCl3–
Me2CO = 1:2:3). IR spectrum, ν, cm-1: 3062.7 (Ar–H), 2977.9 (C–H, CH3), 2885.3 (C–H, CH2), 1728.1 (C=O),
1596.9 (C=N), 1404.1 (C–N), 1265.2 (C–O), 854.1 (β-D-glucopyranosyl ring deformation), 825.5
1
(1,4-disubstituted ring), 750 (C–S), 619.7 (C–S–C), 709.8 (monosubstituted ring). H NMR spectrum (CDCl3),
δ, ppm: 8.0-7.25 (34H, m, Ar–H); 5.3-4.2 (5H, m, β-D-glucopyranosyl ring); 4.49-4.30 (2H, br. s, S–CH2–Ph);
4.5-4.0 (2H, br. d, CH2O); 2.4-1.7 (3H, br. s, Ar–CH3). Mass spectrum, m/z (I, %): 994 [M]+; 967 [M – CHN];
923 [M – C4H7O]; 887 [M – PhCHOH]; 847 [M – C8H5NS]; 827 [M – C12H9N]; 805 [M – C12H13S]; 767 [M –
+
C15H15S]; 728 [M – C20H12N]; 639 [TBGNH–CHS]+; 596 [TBG – NH2 ]; 579 [TBG]+; 475 [TBG – C6H4CO];
+
+
300 [C17H16O5 ]; 231 [C13H11O4 ]; 105 [PhCO+]. Found, %: C 68.84; H 4.47; N 5.27; S 6.62. C57H46N4O9S2.
Calculated, %: C 68.81; H 4.62; N 5.63; S 6.43.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(o-chlorophenyl)-2-phenylimino-
5,6-dihydro-2H-1,3,5-thiadiazine (3e). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2e
(2.04 g, 0.005 mol). Yield 4.0 g, 80%; mp 141°C; [α]D38 = -141.66° (c 0.0012 in CHCl3), Rf 0.82 (EtOH–CHCl3–
Me2CO = 1:2:3). Found, %: C 65.95; H 3.93; Cl 3.00; N 5.16; S 6.34. C56H43ClN4O9S2. Calculated, %: C 66.27;
H 4.24; Cl 3.50; N 5.52; S 6.31.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(m-chlorophenyl)-2-phenylimino-
5,6-dihydro-2H-1,3,5-thiadiazine (3f). Obtained from compound 1 (3.38 g, 0.005 mol) and of compound 2f
(2.04 g, 0.005 mol). Yield 4.4 g, 88%; mp 145°C; [α]D38 = -77.77° (c 0.0018 in CHCl3), Rf 0.79 (EtOH–CHCl3–
Me2CO = 1:2:3). IR spectrum, ν, cm-1: 3065.5 (Ar–H), 2916.2 (C–H, aliphatic), 1728.1 (C=O), 1596.9 (C=N),
1380.9 (C–N), 1265.2 (C–O), 854.1 (β-D-glucopyranosyl ring deformation), 802.0 (1,3-disubstituted ring),
1
755.2 (C–S), 709.8 (monosubstituted ring), 625 (C–S–C), 578 (C–Cl). H NMR spectrum (CDCl3), δ, ppm:
8.0-7.0 (34H, m, Ar–H); 5.25-4.38 (5H, m, β-D-glucopyranosyl ring); 4.52-4.35 (2H, br. s, S–CH2–Ph);
4.44-4.05 (2H, br.d, CH2O). Mass spectrum, m/z (I, %): 1014 [M]+; 986 [M – CO]; 941 [M – C3H5O2]; 909 [M –
PhCO]; 895 [M – PhCOCH2]; 867 [M – PhCOOC2H2]; 850 [M – PhNHC(=S)N=CH2]; 639 [TBG–NH–CH=S]+;
604 [TBGCN]+; 579 [TBG]+; 231 [C14H15O3]+; 149 [PhCOOCH2H4]; 106 [PhCHO]+. Found, %: C 66.05;
H 4.23; Cl 3.21; N 5.36; S 6.00. C56H43ClN4O9S2. Calculated, %: C 66.27; H 4.24; Cl 3.50; N 5.52; S 6.31.
789

6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(p-chlorophenyl)-2-phenylimino-
5,6-dihydro-2H-1,3,5-thiadiazine (3g). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2g
38
(2.04 g, 0.005 mol). Yield 4.2 g, 84%; mp 165°C; [α]D = -111.76° (c 0.0017 in CHCl3), Rf, 0.70 (EtOH–
CHCl3–Me2CO = 1:2:3). Found, %: C 66.09; H 4.01; Cl 2.97; N 5.28; S 5.95. C56H43ClN4O9S2. Calculated, %:
C 66.27; H 4.24; Cl 3.50; N 5.52; S 6.31.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(m-nitrophenyl)-2-phenylimino-5,6-
dihydro-2H-1,3,5-thiadiazine (3h). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2h (2.1 g,
38
0.005 mol). Yield 4.1 g, 79.9%; mp 156°C; [α]D = 166.66° (c 0.0009 in CHCl3), Rf 0.42 (EtOH–CHCl3–
Me2CO = 1:1:2). IR spectrum, ν, cm-1: 3028.8 (Ar–H), 2900.1 (C–H, aliphatic), 1728.1 (C=O), 1596.9 (C=N),
1527.5 (C–NO2), 1373.2 (C–N), 1265.2 (C–O), 852 (β-D-glucopyranosyl ring deformation), 801
1
(1,3-disubstituted ring), 780 (C–S), 709.8 (monosubstituted ring), 625 (C–S–C). H NMR spectrum (CDCl3),
δ, ppm: 7.95-7.15 (34H, m, Ar–H); 5.31-4.25 (5H, m, β-D-glucopyranosyl ring); 4.52-4.0 (2H, br. s, S–CH2–
Ph); 4.40-4.0 (2H, br. d, CH2O). Mass spectrum, m/z (I, %): 1025 [M]+; 932 [M – PhNH2]; 886 [M – Ph–NH–
CH2–SH]; 638 [TBGNH=C=S]+; 579 [TBG]+; 475 [TBG – C6H4CO]; 424 [TBG – C12H11]; 335 [TBG –
2PhCOOH]; 105 [PhCO]+. Found, %: C 65.21; H 3.98; N 6.52; S 6.15. C56H43N5O11S2. Calculated, %: C 65.56;
H 4.19; N 6.82; S 6.24.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(p-nitrophenyl)-2-phenylimino-5,6-
dihydro-2H-1,3,5-thiadiazine (3i). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2i (2.1 g,
0.005 mol). Yield 4.6 g, 89.7%; mp 125°C; [α]D38 = 100.00° (c 0.0012 in CHCl3), Rf 0.54 (EtOH–CHCl3–Me2CO
= 1:1:2). Found, %: C 65.41; H 4.00; N 6.69; S 6.45. C56H43N5O11S2. Calculated, %: C 65.56; H 4.19; N 6.82; S
6.24.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(o-methoxyphenyl)-2-phenylimino-
5,6-dihydro-2H-1,3,5-thiadiazine (3j). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2j
38
(1.97 g, 0.005 mol). Yield 4.6 g, 85.1%; mp 154°C (decomp.); [α]D = -76.92° (c 0.0013 in CHCl3), Rf 0.59
(n-BuOH–CHCl3–Me2CO = 1:2:3). IR spectrum, ν, cm-1: 3062.7 (Ar–H), 2977.9 (C–H, OCH3), 2885.3 (C–H,
CH2), 1728.1 (C=O), 1596.9 (C=N), 1373.2 (C–N), 1265.2 (C–O), 848.6 (β-D-glucopyranosyl ring
deformation), 802.0 (C–S), 749.0 (1,2-disubstituted ring), 709.8 (monosubstituted ring), 635.4 (C–S–C).
1H NMR spectrum (CDCl3), δ, ppm: 8.0-7. 15 (34H, m, Ar–H); 5.3-4.0 (5H, m, β-D-glucopyranosyl ring);
4.45-4.1 (2H, br. s, S–CH2–Ph); 4.25-4.12 (2H, br. d, CH2–O); 3.7-3.65 (3H, br. s, CH3–O–Ar). Mass spectrum,
m/z (I, %): 1010 [M]+; 937 [M – C4H9O]; 914 [M – C6H8O]; 843 [M – C13H11]; 831 [M – C14H11]; 744 [M –
C15H12N3S]; 664 [M – C21H20N3S]; 648 [M – C21H20N3OS]; 579 [TBG]+; 350 [TBG – C14H13O3]; 333 [TBG –
C14H14O4]; 231 [C14H15O3]+; 106 [PhCHO]+. Found, %: C 67.54; H 4.29; N 5.55; S 6.67. C57H46N4O10S2.
Calculated, %: C 67.72; H 4.55; N 5.54; S 6.33.
6-[Tetra(O-benzoyl)-β-D-glucopyranosylimino]-4-benzylthio-5-(p-methoxyphenyl)-2-phenylimino-
5,6-dihydro-2H-1,3,5-thiadiazine (3k). Obtained from compound 1 (3.38 g, 0.005 mol) and compound 2k (1.97
38
g, 0.005 mol). Yield 4.5 g, 87.7%; mp 240°C (decomp.); [α]D = 60.00° (c 0015 in CHCl3), Rf 0.48 (n-BuOH–
CHCl3–Me2CO = 1:2:3). Found, %: C 67.49; H 3.99; N 5.33; S 6.43. C57H46N4O10S2. Calculated, %: C 67.72; H
4.55; N 5.54; S 6.33.
The authors acknowledge the help of R. S. I. C., C. D. R. I., Lucknow for providing the spectral data.
They are also thankful to Prof. R. N. Kale, Head Department of Chemistry and Principal Dr. V. B. Wagh for
encouragement and necessary facilities.
790

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