Synthesis of 2-[2,4-diaminothiazol-5-oyl]benzothiazoles

Article abstract of DOI:10.1002/jhet.387

(Chemical Equation Presented) The synthesis of 2-(4-amino-2- alkylaminothiazol-5-oyl)benzothiazoles and 2-[2,4-bis(arylamino)thiazol-5-oyl] benzothiazoles as benzothiazoloylthiazole analogs of the cytotoxic marine alkaloid dendrodoine is reported. The highly decorated thiazole ring assembly was achieved using 2-bromoacetybenzothiazole to supply the C5 ring carbon and amidinothioureas of the type R¹NH-CS-NH-C(=NHR²)-(NHR ³) to provide the four ring atoms [C4-N3-C2-S1] in a [4+1] thiazole ring construction strategy. The antibacterial activity of these new analogs is reported.

Full text of DOI:10.1002/jhet.387

994
Synthesis of 2-[2,4-Diaminothiazol-5-oyl]benzothiazoles
T. F. Abbs Fen Rejia* and Kallikat N. Rajasekharanb
Vol 47
aDepartment of Chemistry, Nesamony Memorial Christian College, Marthandam,
Tamil Nadu 629165, India
bDepartment of Chemistry, University of Kerala, Trivandrum, Kerala 695 581, India
*E-mail: abbsfen@gmail.com
Received September 1, 2009
DOI 10.1002/jhet.387
Published online 18 June 2010 in Wiley InterScience (www.interscience.wiley.com).
The synthesis of 2-(4-amino-2-alkylaminothiazol-5-oyl)benzothiazoles and 2-[2,4-bis(arylamino)thia-
zol-5-oyl]benzothiazoles as benzothiazoloylthiazole analogs of the cytotoxic marine alkaloid dendro-
doine is reported. The highly decorated thiazole ring assembly was achieved using 2-
bromoacetybenzothiazole to supply the C5 ring carbon and amidinothioureas of the type
R1NHACSANHAC(¼¼NHR2)A(NHR3) to provide the four ring atoms [C4AN3AC2AS1] in a [4þ1]
thiazole ring construction strategy. The antibacterial activity of these new analogs is reported.
J. Heterocyclic Chem., 47, 994 (2010).
INTRODUCTION
the remarkable cytotoxic activity of benzothiazole deriv-
atives as reviewed recently [10,11], we decided to
extend our work on the synthesis and bioactivity screen-
ing of dendrodoine analogs to 2-(2,4-diaminothiazol-5-
oyl)benzothiazoles.
A recent review [1] on marine pigments highlights
the rich variety of colored molecules that can be found
in marine organisms. These pigments have structures
that in many instances have no counterpart in any terres-
trially derived molecules. Many among these are alka-
loidal pigments. One among these, the pale yellow, bish-
eterocyclic, cytotoxic alkaloid dendrodoine, 3-N,N-dime-
thylamino-5-indol-3-oyl-1,2,4-thiadiazole 1, isolated
from the tunicate Dendrodoa grossularia [2], is consid-
ered unique in being the first and only naturally occur-
ring 1,2,4-thiadiazole derivative [1]. It is reported to be
cytotoxic to lymphoma cells L1210 in culture [2,3].
RESULTS AND DISCUSSION
Several modifications of the classic Hantzsch 2-ami-
nothiazole synthesis have recently been developed for
the direct ring assembly of highly decorated thiazole
derivatives. Among such methods, the use cyanothiour-
eas [12,13] RNHACSANHACN, our reports [14–16] on
the use of amidinothioureas RNHACSANHAC(¼¼NH)
ANH2 and RNHACSANHAC(¼¼NH)ANHNO2, or the
recent use of S-alkyldithiobiurets [17] RNHACSANHA
C(SR)ANH2, as the source of the four [S1AC2A
N3AC4] ring atoms for the thiazole ring construction
are noteworthy. The remaining ring C5 atom could be
sourced from a-haloketones, which reacted with the
above thioureas to afford 4-amino-5-acyl-2-(substituted
amino)thiazoles. Nevertheless, our report [14,16] on the
use of amidinothioureas of the type R1NHACSANH
AC(¼¼NHR2)A(NHR3) seems to be the only direct ring
synthesis of 5-acyl-2,4-bis(substituted amino)thiazoles.
Based on these considerations, we have now chosen the reac-
tion between the amidinothiourea derivatives 2a–g and 2-(2-
bromoacetyl)benzothiazole 3 to access hitherto unreported
2-(4-amino-2-alkylaminothiazol-5-oyl)benzothiazoles and
2-[2,4-bis(arylamino)thiazol-5-oyl]benzothiazoles.
We have recently been interested in synthesizing [4]
and cytotoxicity screening [5] of thiazole analogs of
dendrodoine in the light of its reported cytotoxicity and
the difficulty in its synthesis [6]. Two approaches were
adopted by us; in the first, to overcome the limited op-
portunity for substitution positions in the 1,2,4-thiadia-
zole ring, it was replaced by a 1,3-thiazole ring [4a]. In
the second, the indoloyl unit was varied to other benzo-
fused heterobicyclic rings [7]. This allowed us to intro-
duce much structural diversity leading to a large portfo-
lio of dendrodoine analogs. We were also enthused by
the recently reported in vitro cytotoxicity of bis(indo-
lyl)thiazoles [8] and indolylthiazoles [9]. Further, noting
Accordingly, the reaction of 1-ethyl-3-(N-nitroamidi-
no)thiourea 2a in N,N-dimethylformamide (DMF) with
2-(2-bromoacetyl)benzothiazole 3 afforded a yellow
C
V
2010 HeteroCorporation

July 2010
Synthesis of 2-[2,4-Diaminothiazol-5-oyl]benzothiazoles
995
Scheme 1
Figure 1. Energy minimized structure of 4a.
is presented in Scheme 1. Three other thiazoloylbenzo-
thiazoles 4b–d were also synthesized. An interesting
feature of the 1H NMR spectrum of 4a–d was the
appearance of the two hydrogens of the 4-amino group
as two well separated broad singlets. For example, in
the case of 4a, these hydrogens were seen at d 8.78 and
8.94. The results of energy minimized computations on
4a obtained using MOPAC by the AM1 method are
shown in Figure 1. These computed structures showed
that one of the two hydrogens of the amino group could
be strongly hydrogen bonded to the ring nitrogen of the
benzothiazole unit. In addition, the 4-amino group in 4a
could also be amide like as it could be viewed as a vi-
nylogous amide ACOAC5¼¼C4ANH2, which would also
impede the rotation of the C4AN bond.
Next, 1-phenyl-3(N,N0-diphenylamidino)thiourea 2e
was reacted with 3 to obtain a deep yellow compound
with molecular composition C23H16N4OS2. Based on the
1
FAB-MS, H and 13C NMR spectra, the structure of the
compound was assigned as 2-[2,4-bis(phenylamino)thia-
zol-5-oyl]benzothiazole 4e. In a similar reaction, two
other 2-[2,4-diarylaminothiazol-5-oyl]benzothiazoles 4f–
g were also obtained.
To assess the bioactivity, the benzothiazoles 4a–g
were screened against the bacterial strains Escherichia
coli, Salomonella typhi, Staphylococcus aureus, and Ba-
cillus subtilis and the results are shown in Table 1.
crystalline compound which showed in the thin layer
chromatogram a single fluorescent yellow spot. Based
on the elemental analysis, the molecular composition of
the compound was found to be C13H12N4OS2. The IR
spectrum shows distinct bands at 3467, 3285, 3233, and
3175 cmꢀ1, which are ascribed to mNAH vibrations. The
aliphatic CAH stretching bands were seen at 2972,
2928, and 2850 cmꢀ1 and a strong band at 1623 cmꢀ1
indicated the presence of a conjugated carbonyl group.
The 1H NMR spectrum consisted of a three-hydrogen
triplet at d 1.18, due to methyl hydrogens. The peak due
to the methylene hydrogens could not be seen as it
appeared to be submerged in the broad solvent-based
peak. The multiplet at d 7.45–7.62 was assignable to the
H-5 and H-6 of the benzothiazole ring. The two one-
hydrogen doublets at d 8.07 and 8.16 were attributed to
H-4 and H-7 of the benzothiazole ring, respectively. The
broad peak at d 8.39 was due to the NH hydrogen of
the NHR group. The FAB MS showed a strong MHþ
peak at m/z 305. Based on these, the compound was for-
mulated as 2-(4-amino-2-ethylaminothiazol-5-oyl)benzo-
thiazole 4a; the reaction steps involved in its formation
Table 1
Antibacterial activity of benzothiazoloylthiazoles 4a–g.
Compound
E. coli
S. typhii
S. aureus
B. subtilis
4a
4b
4c
4d
4e
4f
4g
9
7
8
7
7
7
NA
NA
NA
6
NA
NA
NA
NA
10
7
8
10
8
10
7
8
6
12
8
8
12
10
NA
13
NA
12
Penicillin G
Values are in diameter of zone of inhibition (mm) and average of three
replicates.
NA, Not active.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

996
T. F. Abbs Fen Reji and K. N. Rajasekharan
Vol 47
EXPERIMENTAL
2H, CH2), 1.51(quintet, J ¼ 7.1 Hz, 2H, CH2), 3.33(br, 2H,
CH2), 7.45–7.64(m, 2H, H-5, H-6), 8.06(d, J ¼ 7.8 Hz, 1H, H-
4), 8.17(d, J ¼ 7.5 Hz, 1H, H-7), 8.42(br, 1H, NH), 8.92(br,
1H, NH), 9.00(br, 1H, NH); FABMS: 333 (MHþ).
Melting points are uncorrected and were determined by
open capillary method using an immersion bath of silicon oil.
Thin layer chromatography was performed using silica gel-G
(E. Merck, India) coated on glass plates. The spots were
visualized in iodine vapour or under UV light. The spectra
were recorded on: JEOL DRX 300 or DPX 300 NMR spec-
2-[2-Allylamino-4-aminothiazol-5-oyl]benzothiazole
(4d).
Yield: 63%, m.p. 254–255ꢁC; Anal. found: C, 53.29: H, 3.91:
N, 17.57%; calcd. for C14H12N4OS2 (316.40): C, 53.14: H,
3.82: N, 17.71%; IR (KBr) m: 3486, 3299, 3238, 3083, 3050,
2967, 2933, 2894, 2842, 1626, 1599, 1565, 1506, 1458, 1322,
1
trometer (300 MHz for H and 75 MHz for 13C NMR spectra),
1094, 1013, 958, 891, 825, 764, 729cmꢀ1 1H NMR: (300
;
JEOL SX 102/DA-6000 mass spectrometer (using Argon/Xe-
non, 6 KV, 10 mA as the FAB gas and m-nitrobenzyl alcohol
as the matrix) for FAB mass spectra, and Nicolet 400D FTIR
spectrometer fot IR spectra. Reagents and solvents were from
Merck India and Fluka. Elemental analysis was done at Cen-
tral Drug Research Institute, India. The antibacterial acticity
was evaluated by the Kirby-Baur method [18].
MHz, DMSO-d6) d: 4.02(m, 2H, CH2), 5.11–5.32(m, 2H,
CH2), 5.82–6.00(m, 1H, CH), 7.45–7.64(m, 2H, H-5, H-6),
8.07(d, J ¼ 7.8 Hz, 1H, H-4), 8.17(d, J ¼ 7.5 Hz, 1H, H-7),
8.43(br, 1H, NH), 8.77(br, 1H, NH), 9.09(br, 1H, NH);
FABMS: 317 (MHþ).
2-[2,4-Bis(phenylamino)thiazol-5-oyl]benzothiazole,
(4e).
Yield: 65%, m.p. 235–238ꢁC; Anal. found: C, 64.31: H, 3.85:
N, 13.25%; calcd. for C23H16N4OS2 (428.52): C, 64.46: H,
3.76: N, 13.08%; IR (KBr) m: 3433, 3272, 3198, 3048, 1626,
1600, 1562, 1485, 1445, 1414, 1324, 1268, 912, 757,
General procedure for the synthesis of 2-(2,4-diamino-
thiazol-5-oyl)benzothiazoles (4a–g). A solution of 2-(2-bro-
moacetyl)benzothiazole 3 (0.254 g, 1 mmol), obtained from
2-(1-hydroxyethyl)benzothiazole [19,20], in DMF (2mL)
was added to 1-alkyl-3-(N-nitroamidino)thiourea (2a–d) or
1-aryl-3-(N,N0-diarylamidino)thiourea (2e–g) (1 mmol) in
DMF (2 mL). The reaction mixture was stirred well and
triethylamine (0.3 mL, 2 mmol) was added and warmed at
50–60ꢁC for 15 min. It was then cooled and poured into
ice-cold water with constant stirring. The yellow precipitate
thus obtained was filtered, washed with water, and dried.
The crude product was purified by crystallization from
methanol–water (2:1), then from benzene–petroleum ether
(1:1) in the case of 4a–d, and from ethanol–water (3:1) in
the case of 4e–g.
690cmꢀ1 1H NMR: (300 MHz, DMSO-d6) d: 7.11–7.23(m,
;
2H, 2ArH), 7.38–7.50(m, 4H, 4ArH), 7.53–7.72(m, 4H, H-5,
H-6, 2ArH), 7.77(d, J ¼ 8.1 Hz, 2H, 2ArH), 8.12(d, J ¼ 7.8
Hz, 1H, H-4), 8.23(d, J ¼ 7.8 Hz, 1H, H-7), 11.85(s, 1H,
NH); 13C NMR: (75 MHz, , DMSO-d6) d: 91.1, 119.7, 120.1,
122.8, 123.7, 123.9, 124.3, 126.8, 127.0, 129.0, 129.2, 135.9,
138.7, 138.9, 152.8, 163.6, 169.6, 170.6, 172.1; FABMS: 429
(MHþ).
2,4-Bis(4-chlorophenylamino)thiazol-5-oylbenzothiazole, (4f).
Yield: 65%, m.p. 258–259ꢁC; Anal. found: C, 55.69: H, 2.99:
N, 11.41%; calcd. for C23H14Cl2N4OS2 (497.42): C, 55.53: H,
2.84: N, 11.26%; IR (KBr) m: 3428, 3275, 3207, 3066, 1631,
1572, 1497, 1424, 1324, 1269, 1221, 1186, 1095, 1021, 923,
2-(4-Amino-2-ethylaminothiazol-5-oyl)benzothiazole (4a).
Yield: 65%, m.p. 255–256ꢁC; Anal. found: C, 51.41: H, 3.90:
N, 18.55%; calcd. for C13H12N4OS2 (304.39): C, 51.29: H,
3.97: N, 18.41%; IR (KBr) m: 3467, 3285, 3233, 3175, 3067,
2972, 2928, 2850, 1623, 1592, 1558, 1450, 1351, 1093, 882,
1
826, 756, 628cmꢀ1; H NMR: (300 MHz, DMSO-d6) d: 7.41-
7.79(m, 10H, H-5, H-6, 8ArH), 8.08(d, J ¼ 9 Hz, 1H, H-4),
8.20(d, J ¼ 9 Hz, 1H, H-7), 11.76(s, 1H, NH); FABMS: 497
(MHþ).
1
818, 757, 722cmꢀ1; H NMR (300 MHz, DMSO-d6) d: 1.18(t,
J ¼ 7.0 Hz, 3H, CH3), 3.35(br, 2H, CH2), 7.45–7.62(m, 2H,
H-5, H-6), 8.07(d, J ¼ 7.8 Hz, 1H, H-4), 8.16(d, J ¼ 7.8 Hz,
1H, H-7), 8.39(br, 1H, NH), 8.78(br, 1H, NH), 8.94(br, 1H,
NH); FABMS: 305 (MHþ).
2,4-Bis(4-methylphenylamino)thiazol-5-oylbenzothiazole, (4g).
Yield: 63%, m.p. 221–224ꢁC; Anal. found: C, 65.51: H, 4.58:
N, 12.53%; calcd. for C25H20N4OS2 (456.57): C, 65.76: H,
4.42: N, 12.27%; IR (KBr) m: 3400, 3266, 3200, 3117, 3062,
2928, 2840, 1617, 1607, 1572, 1490, 1434, 1324, 1221, 1021,
2-[4-Amino-2-n-propylaminothiazol-5-oyl]benzothiazole (4b).
Yield: 63%, m.p. 211–213ꢁC; Anal. found: C, 52.95: H, 4.58:
N, 17.45%; calcd. for C14H14N4OS2 (318.42): C, 52.80: H,
4.43: N, 17.60%; IR (KBr) m: 3360, 3218, 3134, 3067, 2967,
2933, 2867, 1639, 1592, 1552, 1506, 1472, 1357, 1155, 1093,
1
923, 828, 764, 731, 620cmꢀ1; H NMR: (300 MHz, CDCl3) d:
2.30(s, 6H, 2CH3), 7.02–7.75(m, 10H, H-5, H-6, 8ArH),
8.10(d, J ¼ 7.8 Hz, 1H, H-4), 8.21(d, J ¼ 7.5 Hz, 1H, H-7),
11.86(s, 1H, NH); FABMS: 457 (MHþ).
891, 823, 778, 683, 622cmꢀ1 1H NMR: (300 MHz, DMSO-
;
d6) d: 0.91(t, J ¼ 7.4 Hz, 3H, CH3), 1.58(sextet, J ¼ 6.7 Hz,
2H, CH2), 3.38(br, 2H, CH2), 7.45–7.63(m, 2H, H-5, H-6),
8.06(d, J ¼ 6.9 Hz, 1H, H-4), 8.16(d, J ¼ 7.5 Hz, 1H, H-7),
8.40(br, 1H, NH), 8.79(br, 1H, NH), 8.95(br, 1H, NH); 13C
NMR: (75 MHz, , DMSO-d6) d: 11.3, 21.9, 39.2, 91.1, 122.8,
123.8, 126.4, 126.8, 135.8, 139.3, 153.1, 169.5, 170.6, 171.3;
FABMS: 319 (MHþ).
Acknowledgments. T.F.A.F.R.
acknowledges
University
Grants Commission, Govt. of India, New Delhi for financial sup-
port. The authors thank NIIST (RRL), Thiruvananthapuram and
CDRI, Lucknow for spectral and analytical data.
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