Synthesis of N-lactqsylated thiourea and benzothiazolyl thiourea

Article abstract of DOI:10.1002/hc.20207

Several N-lactosylated aryl thioureas and benzothiazolyl thioureas have been prepared by the condensation of hepta-O-acetyl-β-D-lactosyl isothiocyanate with aryl amines and 2-aminobenzothiazole/substituted benzothiazoles. Hepta-O-acetyl-β-D-lactosyl isoth

Full text of DOI:10.1002/hc.20207

Heteroatom Chemistry
Volume 17, Number 4, 2006
Synthesis of N -Lactosylated Thiourea
and Benzothiazolyl Thiourea
Prashant V. Tale and Shirish P. Deshmukh
P.G. Department of Chemistry, Shri Shivaji College, Akola 444 001, Maharashtra, India
Received 28 August 2005; revised 13 November 2005
which is essentially based on the reaction of isothio-
ABSTRACT: Several N-lactosylated aryl thioureas
cyanate and amines [10].
and benzothiazolyl thioureas have been pre-
Here, we report the synthesis of several 1-hepta-
pared by the condensation of hepta-O-acetyl-β-
O-acetyl-ꢀ-D-lactosyl-3-N-aryl thioureas 4a–g and 1-
D-lactosyl isothiocyanate with aryl amines and
hepta-O-acetyl-ꢀ-D-lactosyl-3-[2-N-substituted ben-
2-aminobenzothiazole/substituted
benzothiazoles.
zothiazolyl] thioureas 6a–g by the condensation
of hepta-O-acetyl-ꢀ-D-lactosyl isothiocyanate 2 with
aryl amines (3a–g) and 2-aminobenzothiazoles/
substituted benzothiazoles 5a–g. Required lactosyl
isothiocyanate was prepared by the reaction of
hepta-O-acetyl-ꢁ-D-lactosyl bromide 1 [11] with lead
thiocyanate [12] (Fig. 1). Required 2-aminobenzo-
thiazoles/substituted benzothiazoles were prepared
by the oxidative cyclization of 1-aryl thiourea with
the help of molecular bromine [13] and 1-aryl
thiourea was prepared by reaction of aryl amine hy-
drochlorides with ammonium thiocyanate [14].
Hepta-O-acetyl-β-D-lactosyl isothiocyanate was pre-
pared by the interaction of hepta-O-acetyl-α-D-lactosyl
bromide and lead thiocyanate. The structures of
these new N-lactosides have been established on
the basis of IR, NMR, and mass spectral stud-
ꢀ
C
ies.
2006 Wiley Periodicals, Inc. Heteroatom Chem
17:306–309, 2006; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20207
INTRODUCTION
Glycosyl thioureas, glycosyl guanidine, and glycosyl
derivatives of ꢀ-cyclodextrines have potential phar-
macological properties [1–4] (such as treatment of
AIDS, vectorized transport of drugs). The lactosyl
isothiocyanate has been studied as hexose trans-
porter inhibitor [5]. N-Lactosylated compounds and
their derivatives are reported to show various appli-
cations in medicinal chemistry [6,7] and 2-amino-
substituted benzothiazoles shows antitumor [8] and
antimalarial [9] activity. Looking at the importance
of these compounds, we plan to synthesize thioureas
and benzothiazolyl thiourea containing ꢀ-D-lactosyl
substituent on the nitrogen bond. For the synthe-
sis of thiourea, conventional method was reported
RESULT AND DISCUSSION
1-Hepta-O-acetyl-ꢀ-D-lactosyl-3-N-aryl thioureas 4a
–g (Fig. 2) and 1-hepta-O-acetyl-ꢀ-D-lactosyl-3-[2-N-
substituted benzothiazolyl] thioureas 6a–g (Fig. 3)
are prepared by the condensation of hepta-O-
acetyl-ꢀ-D-lactosyl isothiocyanate 2 with aryl amines
(3a–g) and 2-aminobenzothiazole/substituted ben-
zothiazoles 5a–g in benzene for 3 and 4 h, respec-
tively. Then, the solvent was distilled off and sticky
residue obtained was triturated with petroleum ether
(60–80◦C) to afford a white solid (4a–g) and (6a–g),
respectively. The products were found to be desulfur-
ized when boiled with alkaline lead acetate solution.
IR spectrum of the products show characteristics
absorption of lactose unit in the range of 900–910
and 1000–1100 cm−1 [15]. The coupling constants
Correspondence to: Shirish P. Deshmukh; e-mail: prashanttale@
rediffmail.com.
c
ꢀ
2006 Wiley Periodicals, Inc.
306

Synthesis of N-Lactosylated Thiourea and Benzothiazolyl Thiourea 307
FIGURE 1
4a. mp 169◦C; yield 83%, [ꢁ]2D8 +75.18◦ (c,
1.104); Rf 0.82 (CCl4:EtOAc, 3:1); IR (KBr): 3342
(NH), 3024 (Ar-H), 2942 (ali C H), 1760 (C O), 1538
(C N), 1372 (C N), 1230 (C O), 1048 (C S), 1048,
912 (characteristic of lactose), 698 (monosubstituted
of the anomeric proton of lactosyl thioureas and
benzothiazolyl thiourea ranged from 8 to 10 Hz,
which indicated that the linkage between lactose unit
and thioureas had the ꢀ-configuration [16,17]. Mass
spectra of acetolactose unit [18] show peak at m/z,
619, 331, 169, and 109.
1
benzene); H NMR (ppm): ꢂ 8.05 (1H, s, NH), 7.47–
7.15 (5H, m, Ar-H), 6.57 (1H, d, NH, J = 8.4 Hz), 5.77
(1H, t, H-1, J = 9.0 Hz), 5.34 (2H, m, H-3,4ꢁ), 5.13
(1H, t, H-2ꢁ, J = 9.6 Hz), 4.95 (1H, d, H-1ꢁ, J = 10.5
Hz), 4.85 (1H, m, H-2), 4.70 (2H, m, H-3ꢁ, 4), 4.17
(3H, m, H-6,6ꢁ,6ꢁ), 3.87 (1H, m, H-6), 3.76 (2H, m,
H-5,5ꢁ), 2.15–1.96 (21H, m, 7COCH3); FABMS (m/z):
771 (M + 1)+ (base peak), 711 (M−CH3COOH), 669
(M − CH3COOH, CH2CO), 619 (M − C7H7N2S), 559,
331, 169, 109. Anal. Calcd for C33H42O17N2S: C, 51.42;
H, 5.45; N, 3.63; S, 4.15; Found: C, 51.35; H, 5.41; N,
3.55; S, 4.03%.
EXPERIMENTAL
IR spectra were recorded in Nujol, KBr on a FT-
IR Perkin-Elmer RXI (4000–450 cm−1) spectropho-
tometer. 1H NMR spectra were obtained on a Bruker
DRX-300 (300 MHz FT NMR) NMR Spectrometer in
CDCl3 solution with TMS as internal reference. The
mass spectra FAB were recorded on a Jeol SX-102
mass spectrometer. Optical rotation [α]D measured
on a Equip-Tronics digital polarimeter EQ-800 for
sample in CHCl3.
4b. mp 149◦C; yield 62%; [ꢁ]2D8 +46.87◦ (c,
1.280); Rf 0.55 (CCl4:EtOAc, 3:1.5); Anal. Calcd for
C33H41O17N2SCl: C, 49.25; H, 5.09; N, 3.48; S, 3.97;
Found: C, 49.20; H, 5.01; N, 3.39, S, 3.78%.
Procedure: 1-Hepta-O-acetyl-β-D-lactosyl-3-N-aryl
Thioureas 4a–g (Fig. 2)
4c. mp 153◦C; yield 48%; [ꢁ]2D8 −111.11◦ (c,
1.080); Rf 0.56 (CCl4:EtOAc, 3:1.5); Anal. Calcd for
C33H41O17N2SCl: C, 49.25; H, 5.09; N, 3.48; S, 3.97;
Found: C, 49.17; H, 5.05; N, 3.47; S, 3.79%.
A mixture of hepta-O-acetyl-ꢀ-D-lactosyl isothio-
cyanate 2 0.005 and 0.005 mol of aryl amines (3a–g)
in 20 mL of benzene was refluxed at 90◦C for 3 h
while monitoring by TLC. After completion of the
reaction, the solvent was distilled off and the sticky
residue obtained was triturated with petroleum ether
(60–80◦C) to afford a white solid (4a–g). The prod-
ucts were recrystallized from ethanol–water.
4d. mp 139◦C; yield 86%; [ꢁ]2D8 +130.66◦ (c,
1.148); Rf 0.82 (CCl4:EtOAc, 3:0.6); IR (KBr): 3340
(NH), 3024 (Ar-H), 2980 (ali C H), 1754 (C O), 1530
R = phenyl, b) o-Cl-phenyl, c) m-Cl-phenyl, d) p-Cl-phenyl, e) o-tolyl, f) m-tolyl, g) p-tolyl
FIGURE 2
Heteroatom Chemistry DOI 10.1002/hc

308 Tale and Deshmukh
R = a)H, b) 4-Cl, c) 5-Cl, d) 6-Cl, e) 4-Me, f) 5-Me, g) 6-Me.
FIGURE 3
C34H44O17N2S: C, 52.04; H, 5.61; N, 3.57; S, 4.08;
Found: C, 51.98; H, 5.50; N, 3.53; S, 4.01%.
(C N), 1370 (C N), 1232 (C O), 1048 (C S), 1048,
912 (characteristic of lactose), 832 (1,4-disubstituted
benzene), 602 (C–Cl); H NMR (ppm): ꢂ 7.78 (1H,
1
s, NH), 7.12–7.39 (4H, m, Ar-H), 6.52 (1H, d, NH,
J = 7.8 Hz), 5.73 (1H, t, H-1, J = 9.0 Hz), 5.34 (2H,
m, H-3,4ꢁ), 5.14 (1H, t, H-2ꢁ), 4.95 (1H, d, H-1ꢁ, J =
10.5 Hz), 4.85 (1H, m, H-2), 4.76 (2H, m, H-3ꢁ,4),
4.18 (3H, m, H-6,6ꢁ,6ꢁ), 3.87 (3H, m, H-5,5ꢁ,6), 2.16–
1.96 (21H, m, 7COCH3); FABMS (m/z): 805 (M + 1)+
(base peak), 769 (M − Cl), 709 (M − CH3COOH, Cl),
619 (M − C7H6N2SCl), 559, 331, 169, 109. Anal. Calcd
for C33H41O17N2SCl: C, 49.25; H, 5.09; N, 3.48; S, 3.97;
Found: C, 49.20; H, 5.00; N, 3.29; S, 3.72%.
1-Hepta-O-acetyl-β-D- lactosyl-3-[2-N-substituted
benzothiazolyl] Thioureas 6a–g (Fig. 3)
A mixture of hepta-O-acetyl-ꢀ-D-lactosyl isothio-
cyanate 2 0.005 and 0.005 mol 2-aminobenzo-
thiazoles/substituted benzothiazoles 5a–g in 20 mL
of benzene was refluxed at 90◦C for 4 h while moni-
toring by TLC. After completion of the reaction, the
solvent was distilled off and the sticky residue ob-
tained was triturated with petroleum ether (60–80◦C)
to afford white solid (6a–g). The products were re-
crystallized from ethanol–water.
4e. mp 148◦C; yield 79%; [ꢁ]2D8 +61.61◦ (c,
1.136); Rf 0.58 (CCl4:EtOAc, 3:1); Anal. Calcd for
C34H44O17N2S: C, 52.04; H, 5.61; N, 3.57; S, 4.08;
Found: C, 52.00; H, 5.53; N, 3.56; S, 3.75%.
6a. mp 127◦C; yield 93%; [ꢁ]2D8 +15.97◦ (c,
1.252); Rf 0.61 (CCl4:EtOAc, 3:2); IR (KBr): 3342
(NH), 3020 (Ar-H), 2945 (ali C H), 1763 (C O), 1532
(C N), 1377 (C N), 1236 (C O), 1055 (C S), 1055,
4f. mp 109◦C; yield 76%; [ꢁ]2D8 +68.96◦ (c,
1.160); Rf 0.84 (CCl4:EtOAc, 3:2); IR (KBr): 3353
(NH), 3020 (Ar-H), 2934 (ali C H), 1747 (C O),
1538 (C N), 1377 (C N), 1232 (C O), 1055 (C S),
1055, 904 (characteristics of lactose), 762 (1,3-
1
915 (characteristic of lactose), 743 (C S); H NMR
(ppm): δ 7.82 (1H, s, NH), 7.71–7.26 (4H, m, Ar-
H), 5.70 (1H, t, H-1, J = 8.7 Hz), 5.41 (3H, m,
H-3,4ꢁ, NH), 5.20 (1H, m, H-2ꢁ), 4.87 (1H, d, H-1ꢁ,
J = 8.7 Hz), 4.50 (2H, m, H-2,3ꢁ), 4.23 (4H, m, H-
4,6,6ꢁ,6ꢁ), 3.89 (3H, m, H-5,5ꢁ,6), 2.17–1.65 (21H, m,
7COCH3); FABMS (m/z): 828 (M + 1)+ (base peak),
768 (M + 1 −CH3COOH), 708 (M + 1 − 2CH3COOH),
619 (M − C8H6N3S2), 559, 331, 169, 109. Anal. Calcd
for C34H41O17N3S2: C, 49.33; H, 4.95; N, 5.07; S, 7.73;
Found: C, 49.25; H, 4.88; N, 4.97; S, 7.68%.
1
disubstituted benzene); H NMR (ppm): δ 7.86 (1H,
s, NH), 7.35–6.93 (4H, m, Ar-H), 6.54 (1H, d, NH,
J = 8.7 Hz), 5.77 (1H, t, H-1, J = 9 Hz), 5.34 (2H,
d, H-3,4ꢁ), 5.13 (1H, t, H-2ꢁ, J = 9.3 Hz), 4.94 (1H,
d, H-1ꢁ, J = 10.5 Hz), 4.86 (1H, m, H-2), 4.66 (2H,
m, H-3ꢁ,4), 4.17 (3H, m, H-6,6ꢁ,6ꢁ), 3.87 (1H, m, H-
6), 3.76 (2H, m, H5,5ꢁ), 2.38 (3H, s, Ar-CH3), 2.15–
1.16 (21H, m, 7COCH3); FABMS (m/z): 784 (M +
1)+ (base peak), 768 (M − CH3), 708 (M − CH3COOH,
CH3), 619 (M − C8H9N2S), 559, 331, 169, 109. Anal.
Calcd for C34H44O17N2S: C, 52.04; H, 5.61; N, 3.57; S,
4.08; Found: C, 52.01; H, 5.59; N, 3.52; S, 3.81%.
6b. mp 165◦C; yield 65%; [ꢁ]2D8 +112.45◦ (c,
1.156); Rf 0.86 (CCl4:EtOAc, 3:2), Anal. Calcd for
C34H40O17N3S2Cl: C, 47.38; H, 4.64; N, 4.87; S, 7.42;
Found: C, 47.31; H, 4.60; N, 4.75; S, 7.33%.
4g. mp 124◦C; yield 64%; [ꢁ]2D8 +248.01◦ (c,
1.008); Rf 0.64 (CCl4:EtOAc, 3:0.9); Anal. Calcd for
6c. mp 198◦C; yield 70%; [ꢁ]2D8 +55.55◦ (c,
1.080); Rf 0.82 (CCl4:EtOAc, 3:2), Anal. Calcd for
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of N-Lactosylated Thiourea and Benzothiazolyl Thiourea 309
C34H40O17N3S2Cl: C, 47.38; H, 4.64; N, 4.87; S, 7.42;
Found: C, 47.28; H, 4.57; N, 4.72; S, 7.35%.
ACKNOWLEDGMENTS
The authors acknowledge the help of R.S.I.C.,
C.D.R.I., Lucknow, for providing spectral data. They
are also thankful to Principal Dr. S. G. Bhadange for
encouragement and necessary facilities.
6d. mp 156◦C, yield 80.89%; [ꢁ]2D8 +84.17◦ (c,
1.188); Rf 0.60 (CCl4:EtOAc, 3:2); IR (KBr): 3342
(NH), 3020 (Ar-H), 2945 (ali C H), 1753 (C O),
1538 (C N), 1377 (C N), 1055 (C S), 1055, 915
(characteristic of lactose), 738 (C S), 604 (C–Cl);
1H NMR (ppm): δ 7.73 (1H, s, NH), 7.41–7.08 (3H,
m, Ar-H), 5.67 (1H, t, H-1, J = 8.4 Hz), 5.30 (3H,
m, H-3,4ꢁ, NH), 5.14 (1H, t, H-2ꢁ, J = 8.2 Hz), 5.02
(1H, d, H-1ꢁ, J = 9.9 Hz), 4.87 (1H, m, H-2), 4.49
(2H, m, H-3ꢁ,4), 4.22 (3H, m, H-6,6ꢁ,6ꢁ), 3.89 (3H,
m, H-5,5ꢁ,6), 2.16–1.63 (21H, m, 7COCH3); FABMS
(m/z): 862 (M + 1)+, 788 (M − C6H3), 724 (M − Cl,
CH2CO, CH3COOH), 678 (M + 1 − C7H5N2SCl), 619
(M − C8H5N3S2Cl), 331 (base peak), 169, 109. Anal.
Calcd for C34H40O17N3S2Cl: C, 47.38; H, 4.64; N,
4.87; S, 7.42; Found: C, 47.30; H, 4.58; N, 4.80;
S, 7.30%.
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6e. mp 116◦C; yield 82%; [ꢁ]2D8 +29.67◦ (c,
1.008), Rf 0.74 (CCl4:EtOAc, 3:2), Anal. Calcd for
C35H43O17N3S2: C, 49.94; H, 5.11; N, 4.99; S, 7.60;
Found: C, 49.88; H, 5.03; N, 4.84; S, 7.58%.
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6f. mp 184◦C; yield 64%; [ꢁ]2D8 +99.63◦ (c,
1.104); Rf 0.84 (CCl4:EtOAc, 3:2); IR (KBr): 3331
(NH), 2966 (ali C H), 1758 (C O), 1527 (C N), 1382
(C N), 1237 (C O), 1049 (C S), 1049, 920 (charac-
teristic of lactose); 1H NMR (ppm): δ 7.58 (1H, s, NH),
7.26 (3H, m, Ar-H), 5.71 (1H, t, H-1, J = 7.8 Hz), 5.41
(3H, m, H-3,4ꢁ, NH), 5.14 (1H, m, H-2ꢁ), 4.97 (1H, d,
H-1ꢁ, J = 9 Hz), 4.50 (2H, m, H-2,3ꢁ), 4.21 (4H, m, H-
4,6,6ꢁ,6ꢁ), 3.89 (3H, m, H-5,5ꢁ,6), 2.50 (3H, s, Ar-CH3),
2.17–1.66 (21H, m, 7COCH3); FABMS (m/z): 842
(M + 1)+, 826 (M − CH3), 782 (M + 1 − CH3COOH),
766 (M − C6H3), 695 (M − CS, CH2CO, CH3COOH),
619 (M − C9H8N3S2), 559, 331 (base peak), 169, 109.
Anal. Calcd for C35H43O17N3S2: C, 49.94; H, 5.11; N,
4.99; S, 7.60; Found: C, 49.85; H, 5.03; N, 4.89; S,
7.51%.
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6g. mp 169◦C; yield 76%; [ꢁ]2D8 +75.18◦ (c,
1.064); Rf 0.73 (CCl4:EtOAc, 3:2); Anal. Calcd
for C35H43O17N3S2: C, 49.94; H, 5.11; N, 4.99;
S, 7.60; Found: C, 49.81; H, 5.00; N, 4.87; S,
7.48%.
Heteroatom Chemistry DOI 10.1002/hc