Hybrids of privileged structures benzothiazoles and pyrrolo[2,1-c] [1,4]benzodiazepin-5-one, and diversity-oriented synthesis of benzothiazoles

Article abstract of DOI:10.1016/j.ejmech.2012.01.014

Privileged structures like Benzothiazole and Pyrrolobenzodiazepine offer wonderful opportunity to explore in anti-cancer drug discovery as a mean to counter drug-resistance problem. BT-PBD hybrids and diverse BT derivatives have been synthesized and their in vitro cytotoxic activities were screened against five cancer cell lines have been discussed. The novel compounds showed promising results as compared with the marketed drug etoposide and could well be used in future anti-cancer drug development studies.

Full text of DOI:10.1016/j.ejmech.2012.01.014

European Journal of Medicinal Chemistry 50 (2012) 27e38
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Hybrids of privileged structures benzothiazoles and pyrrolo[2,1-c] [1,4]
benzodiazepin-5-one, and diversity-oriented synthesis of benzothiazoles
,
a
a
b
b
D. Subhas Bose a , Mohd. Idrees , Ismail K. Todewale , N.M. Jakka , J. Venkateswara Rao
*
a Organic & Biomolecular Chemistry Division, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Biology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Privileged structures like Benzothiazole and Pyrrolobenzodiazepine offer wonderful opportunity to
explore in anti-cancer drug discovery as a mean to counter drug-resistance problem. BT-PBD hybrids and
diverse BT derivatives have been synthesized and their in vitro cytotoxic activities were screened against
five cancer cell lines have been discussed. The novel compounds showed promising results as compared
with the marketed drug etoposide and could well be used in future anti-cancer drug development
studies.
Received 3 October 2011
Received in revised form
21 December 2011
Accepted 7 January 2012
Available online 14 January 2012
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
Anti-cancer drugs
Privileged structures
Benzothiazoles
Pyrrolobenzodiazepines
Diversity-oriented synthesis
1. Introduction
as they are potent AhR (aryl hydrocarbon receptor) binders in
sensitive tumor cells leading to DNA damage by reactive interme-
Vast number of chemotherapeutic anti-cancer drugs are pres-
ently available for clinical use which are broadly classified into
three major groups based on their mode of action; genotoxic
agents, antimetabolites, and mitotic spindle inhibitors [1].
However, there is a continuous demand for the development of
new anti-cancer drugs due to the development of drug resistance
among cancer cells [2]. In this scenario, privileged structures [3] in
medicinal chemistry offer a hugely explorable platform in the
development of new chemical entities for future perspective.
Among several privileged structures known, we have been involved
in the development of expeditious synthetic methods and appli-
cations related to benzothiazoles (BT), pyrrolobenzodiazepines
(PBD), quinolines, dihydropyrimidinones and few others [4].
Noteworthy among them are BT and PBD for their recent anti-
cancer profile. Exploration of BT bicyclic system has resulted in
the successful generation of biologically active compounds across
a wide range of therapeutics [5]. Especially after the recognition of
DF 203 and 5F 203 (Phortess prodrug) [6] as novel anti-cancer drug
candidates (Fig. 1), attracted our interest to explore BT chemical
space. The mode of action of DF 203 and 5F 203 is unique in nature
diates generation through a sequence of complex processes. Simi-
larly, the anti-cancer profile of natural and synthetic PBDs due to
their inherent ability to bind DNA minor groove is well known and
explored in the field [7]. On the other hand, diversity-oriented
synthesis (DOS) has gained considerable interest to explore
chemical space in the discovery of new drugs and targets for
chemotherapy [8] and DOS around privileged structures have been
termed as ‘rationale DOS’ [9]. The present article describes molec-
ular hybridization of BT-PBD systems (Fig. 2) and diversity-oriented
synthesis of BT leading to the generation of few potent anti-cancer
candidates.
2. Results
2.1. Chemistry
Retrosynthetic analysis for molecules 1a, 1b, and 1c (Scheme 1)
reveals that the approach towards the key intermediate 4-(6-
substituted-1,3-benzothiazol-2-yl)-2-nitrobenzoic acids (2a, 2b and
2c) for A-ring and (2S)-2-[di(ethylsulfanyl)methyl]tetrahydro-1H-
pyrrole (3) another key intermediate for the construction of C-ring of
benzothiazolopyrrolo[2,1-c] [1,4]benzodiazepines (1a, 1b, and 1c).
We began our study on the preparation of key intermediates
benzothiazolyl-2-nitrobenzoic acids 2aec (Scheme 2) by the
* Corresponding author. Fax: þ91 40 27160387.
E-mail addresses: dsb@iict.res.in, bose_iict@yahoo.co.in (D. Subhas Bose).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.01.014

28
D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
A
B
Fig. 1. (A) Naturally occurring PBDs (B) BTA, anti-cancer drug candidates.
(2S)-2-[Di(ethylsulfanyl)methyl]tetrahydro-1H-pyrrole, 3 [13]
aliphatic skeleton was synthesized by a modified route to improve
the yield and optical purity. This route afforded maximum yields
with excellent optical purity (as it avoids reagents like DIBAL-H).
The synthesis of protected tetrahydro-1H-pyrrole (3) was started
with the treatment of (S)-proline with benzyl chloroformate in the
presence of aqueous sodium bicarbonate giving N-carbobenzoxy
derivative (7) in 97% yield as
a colorless sticky compound
(Scheme 3). Compound 7 was reacted with sodium borohydride and
iodine in dry THF [14] to give Cbz-(S)-prolinol 8 as a colorless
gummy liquid in 74% yield. Oxidation of primary alcohol present in
compound 8 led to aldehyde 9 within 1 h in 90% yield using cyanuric
chloride and stoichiometric dry DMSO in THF [15].
Fig. 2. BTA-PBD hybrids.
Aldehyde 9 was immediately converted to diethylthioacetal
derivative (10) by treating with ethanethiol in the presence of Lewis
acid trimethylsilyl chloride (TMSCl), in dry dichloromethane. Free
amine (3) was generated from the ethanethiol protected N-carbo-
benzoxy derivative (10) using TMSI (insitu generated from NaI and
TMSCl in CH3CN) in 85% yield. Coupling of nitro acids 2aec with (S)-
pyrrolidine-2-carbaldehyde diethyl dithioacetal 3 afforded the key
intermediate amides 11aec (Scheme 4). Reduction of nitro group in
compounds 11aec were carried out by treating with SnCl2$2H2O in
methanol for 1 h afforded the corresponding aminodiethylthioacetal
derivatives, 12aec around 50e55% yields. Finally, the crucial step of
deprotection of thioacetal group of compounds 12aec was per-
formed using HgCl2/CaCO3 in CH3CN/H2O (4:1) resulting in the insitu
formation of the intermediate amino-aldehyde which upon subse-
quent ring closure to afford target BTA-PBD compounds 1aec in
55e38% yields.
nitration of readily available p-toluic acid by using a modified
version of the method reported in the literature where trifluoro-
acetic anhydride was used along with ammonium nitrate [10].
Thus, p-toluic acid was treated with ammonium nitrate in the
presence of conc. H2SO4 in dichloromethane at 0 ꢀC to afford nitro
compound 4 in 92% yield as a light yellow solid. Compound 4 was
treated with thionyl chloride to obtain acid chloride, which was
coupled with p-anisidine in the presence of triethylamine to afford
amide 4a in 85% yield as light yellow crystals. Amide 4a was then
treated with Lawesson’s reagent [11] in dry toluene under reflux
conditions to afford thioamide 5a as pale yellow prism in 88% yield.
Intramolecular cyclization of thioamide 5a using Dess-Martin
periodinane (DMP) [4b], in CH2Cl2 at room temperature within
15 min resulted in the formation of 2-arylbenzothiazole 6a as
a light yellow solid in 90% yield. Compound 6a upon treatment with
tetrabutylammonium permanganate, TBAP [12] in dry pyridine at
room temperature afforded benzothiazolyl-2-nitrobenzoic acid 2a
as a free flowing light yellow solid in 87% yield. The rest of the
benzothiazolyl-2-nitrobenzoic acids 2b and 2c were synthesized by
using the same reaction sequences.
2.1.1. DOS of benzothiazoles
This diversity-oriented synthesis of benzothiazoles was classi-
fied into two series of forward synthetic schemes (i) synthesis of
Scheme 1. Retrosynthetic analysis of BTA-PBD hybrids.

D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
29
Scheme 2. (a) NH4NO3, conc. H2SO4, CH2Cl2, 0 ꢀC-R. T., 4e5 h (b) SOCl2, cat. DMF, benzene, reflux (c) 4-R-aniline, Et3N, dry THF, 0 ꢀC-R. T., 2 h (d) Lawesson’s reagent, toluene, reflux,
1e2 h (e) DMP, CH2Cl2, R.T., 15 min (f) tetrabutylammonium permanganate (TBAP), dry pyridine, R.T., 12 h.
Scheme 3. (a) Benzyl chloroformate, aq. NaHCO3, 16 h, 0 ꢀC-R. T. (b) NaBH4/I2, THF,
reflux, 18 h (c) cyanuric chloride/DMSO, THF, ꢁ30 ꢀC, 1 h (d) EtSH, TMSCl, CH2Cl2,
16e24 h, R. T. (e) TMSCl/NaI, CH3CN, 0 ꢀC-R.T.
Fig. 3. Substituted benzothiazole amines.
diverse benzothiazole amines (BTA amines, Fig. 3) (ii) diversifica-
tion of 6-fluoro-2-[4-methylphenyl]benzothiazole.
above, the other benzothiazole amines (13aec and 13e) were
synthesized.
A typical synthetic scheme of BTA-amine 13d was started with
the reaction between 3,4,5-trimethoxyaniline 14 and 2-methyl-3-
nitrobenzoyl chloride using triethylamine in THF to obtain amide
15 in 85% yield as colorless solid (Scheme 5). Amide 15 was con-
verted to thioamide 16 using Lawesson’s reagent in toluene under
reflux conditions in 85% yield. Thioamide 16 was reacted with Dess-
Martin periodinane in CH2Cl2 at room temperature leading to the
formation of 2-arylbenzothiazole 17 (BTA 17) in 90% yield as pale
yellow solid. BTA 17 was finally reduced with SnCl2$2H2O in
methanol under reflux conditions afforded the benzothiazole
amine 13d in 58% yield. By adopting the similar strategy described
Next, we turned our attention to diversify BTA-amine 13e in
three different ways (Scheme 6). Medicinally important guanidine
pharmacophore (found in a vast number of drugs, drug candidates
and antiproliferative natural products like lucentamycins AeD,
clethramycin, pyrronamycins A and B, Cimipronidine etc.) [16]
was incorporated in BTA-amine 13e by coupling primary amine
with N,N-1,3-dicyclohexylcarbodiimide in dry THF in the presence
of catalytic N-hydroxybenzotriazole for about 18 h at room
temperature. The guanidine-BTA derivative 18a was obtained as
a colorless solid upon column chromatography in 75% yield. BTA-
amine 13e was further diversified by the incorporation of urea
Scheme 4. (a) SOCl2, cat. DMF, benzene, 80 ꢀC, 2 h (b) (2S)-pyrrolidine-2-carboxaldehyde diethyl dithioacetal (3), Et3N, THF, 0 ꢀC-R.T., 2 h (c) SnCl2$2H2O, MeOH, 1 h, Reflux (d)
HgCl2, CaCO3, CH3CN/H2O (4:1), R.T., 12e24 h.

30
D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
Scheme 5. (a) 2-methyl-3-nitrobenzoyl chloride, Et3N, THF, 0 ꢀC-R.T. (b) Lawesson’s reagent, toluene, reflux, 2 h (c) DMP, CH2Cl2, 15 min, R.T. (d) SnCl2$2H2O, MeOH, reflux, 2 h.
Scheme 6. (a) N,N-dicyclohexylcarbodiimide (DCC), HOBt, THF, R. T., 12 h (b) benzylisocyanate, Et3N, THF, R.T., 12 h (c) cyclopropane carbonylchloride, Et3N, THF, R.T.
pharmacophore by reacting it with benzylisocyanate in Et3N using
dry THF as the solvent at room temperature for 12 h to afford BTA-
urea compound 18b in 88% yield as colorless solid. Finally, a cyclo-
propyl amide 18c was prepared by the reaction between BTA-
amine 13e and cyclopropane carbonylchloride in the presence of
Et3N in dry THF for 1e2 h in 82% yield.
anhydrous ZnCl2 and catalytic H3PO4 at room temperature for 24 h)
using NaH in CH3CN to afford the benzothiazoles- -glucose diac-
etonide 23. Selective deprotection of acetonide group at 5,6 posi-
tion in compound 23 with 0.8% H2SO4 in methanol at room
D
temperature for 12
compound 24 in 80% yield. This approach of utilization of carbo-
hydrates especially -glucose is reported in literature (relating to
h to afford monodeprotected acetonide
Diversification of 6-fluoro-2-[4-methylphenyl]benzothiazole 21
D
was performed to synthesize benzothiazole-
D
-glucose and benzo-
the exploitation of Warburg effect in cancer cells) [18]. Compound
21 was further diversified by oxidizing the benzylic methyl group to
the corresponding carboxylic functionality followed by the amide
bond formation with S-proline methyl ester to produce a benzo-
thiazole-amino acid hybrid molecule (Scheme 9). We first exam-
ined the oxidation of compound 21 using periodic acid (H5IO6) and
catalytic chromic acid (CrO3) in CH3CN at room temperature [19] to
afford benzothiazole carboxylic acid 25 in 90% yield. Compound 25
thiazole-S-proline hybrid molecules. Initially, the parent molecule
6-fluoro-2-[4-methylphenyl]benzothiazole 21 was synthesized
(Scheme 7) by the method described for the synthesis of compound
6a. Bromination of compound 21 at benzylic position was carried
out by using NBS (N-bromosuccinimide) and catalytic amount of
benzoyl peroxide in CCl4 but resulted in bromination at an
unidentified position in the aromatic ring. Similarly, it was studied
with Br2/CHCl3 but the required monobromo compound was
formed in very little amount beside a number of byproducts.
However, side-chain bromination with NaBrO3 and NaHSO3
mixture in ethyl acetate/H2O solvent system at room temperature
for 4e5 h gave a good yield (92%) of the monobromo compound 22
exclusively without any side products (Scheme 8) [17].
Compound 22 was reacted with
D-glucose diacetonide
(prepared by the treatment of -glucose in dry acetone using
D
Scheme 7. (a) 4-methylbenzoyl chloride, Et3N, TH, 0 ꢀC-R. T. (b) Lawesson’s reagent,
toluene, reflux, 2 h (c) DMP, CH2Cl2, 15 min, R.T.
Scheme 8. (a) NaBrO3/NaHSO3, ethyl acetate/H2O, 4e5 h, R. T. (b) d-glucose diac-
etonide, NaH, CH3CN, R.T. (c) 0.8% H2SO4, MeOH, R.T.

D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
31
laboratory illumination. The percent inhibition of cell viability was
determined with reference to the control values (without test
compound). The data were subjected to linear regression analysis
and the regression lines were plotted for the best straight-line fit.
The IC50 (inhibition of cell viability) concentrations were calculated
using the respective regression equation. Among the 12
compounds tested in this series, only 6 compounds 1aec, 13d, 18a
and 24 showed significant cytotoxic activities (the remaining
Scheme 9. (a) H5IO6/cat. CrO3, CH3CN, 1e2 h, R. T (b) SOCl2, benzene, reflux (c) (S)-
compounds showed IC50 values more than 50 mM). Based on the
regression equation, IC50 values of the selected potent compounds
were calculated and the results are presented (Table 1).
proline methyl ester HCl, Et3N, THF, 2 h, 0 ꢀC-R.T.
was converted to acid chloride by reacting with SOCl2 in reflux
benzene for 1e2 h using catalytic DMF followed by the reaction
with (S)-proline methyl ester hydrochloride in dry THF and Et3N to
give the amide 26 in 82% yield.
3. Discussion and conclusions
In the present work, we have disclosed new anti-cancer
compounds having BT as core privileged sub-structure. Our
approach consisted syntheses of BT-PBD hybrids (combining two
privileged structures known to have different mechanism of action
for cytotoxicity) and diversity-oriented synthesis of benzothiazoles.
All the BT-PBD hybrids showed potent activities; however, the
fluoro analogue 1b showed better activities on an average and
specifically showed more potent activity on THP-1 cancer cell line.
Higher activity by the fluoro analogue 1b could be attributed to the
cell-permeability factor which is usually enhanced by fluoro
compounds. Among DOS generated BT molecules, noteworthy are
BT amine 13d and 5,6-deprotected BT-glucose derivative 24.
Interestingly, the diacetonide BT-glucose derivative 23 did not
2.2. Biological assay
Cytotoxic activities of the synthesized compounds (1aec,13aee,
18aec) have been evaluated in vitro against five tumor cell lines:
THP-1 (human acute monocytic leukemia), U-937 (human histio-
cytic lymphoma), HL-60 (human promyelocytic leukemia), Jurkat
(Human T-cell leukemia) and A-549 (lung carcinoma). All leukemia
cell lines (THP-1, U-937, HL-60, and Jurkat) were cultured in RPMI-
1640 and A-549 were cultured in DMEM. Both media were sup-
plemented with 10% heat-inactivated FCS, 1 mM NaHCO3, 2 mM L-
glutamine and penicillinestreptomycin in a humidified atmo-
sphere of 95%, 5% CO2 at 37 ꢀC. Initially, the stock concentrations
were prepared by dissolving 8 mg of each test compound in 1 mL of
DMSO and further diluted to obtain required experimental stock
solution from 0.1 to 100 ppm and obtained the final volume of
show any significant anti-cancer activity (more than 50 mM) in the
tested cancer cell lines. Here we assume that membrane penetra-
tion and accumulation is facilitated when 5,6-position of glucose
moiety is free and hence particularly compound 24 is showing anti-
cancer activity. The new BT compounds 13d and 23 provided
wonderful leads for further SAR studies and our future directions
could lead us into their optimization, mechanistic and modeling
studies.
In conclusion, we describe herein the coupling of two different
pharmacophores, each endowed with different biological proper-
ties, afforded the hybrid compound, whose biological profile was
markedly improved. In this initial study, our aim was to identify few
new anti-cancer leads having BT system which could be developed
further by SAR and optimization. Accordingly, novel BT-PBD
hybrids and diverse BT derivatives have been synthesized and
evaluated for their in vitro cytotoxic activities against five cancer
cell lines. Overall the activities are in the range of the marketed
drug etoposide and in the case of U-937 cell lines, few compounds
showed similar activities as camptothecin. We anticipate that the
hybrid BT-PBD synthesis and the DOS strategies described in the
manuscript could be explored further to have interesting implica-
tions in the fields of chemistry-driven drug discovery and combi-
natorial chemistry.
200 mL. In all the experiments, HL-60, THP-1, U-937, Jurkat and A-
549 cells were seeded at a final density of 2 ꢂ 104 cells per well in
96 well microtiter plates. The cells were treated with different test
concentrations of 1aec, 13aee, and 18aec and their cytotoxicities
were compared with the activity of positive controls, Camptothecin
and Etoposide at identical conditions with five replicates each.
Cytotoxicity was measured using the MTT (3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide) as described by Mosmann
[20]. In brief, the cells (2 ꢂ 104) were seeded in each well containing
0.1 mL of RPMI medium or DMEM in 96 well plates. After 24 h,
different test concentrations were added and cell viability was
assessed after 2 days, by adding 10 ml per well of MTT (3-(4, 5-
dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide; 5 mg/
mL; stock solution, Sigma). The plates were incubated at 37 ꢀC for
additional 4 h. The medium was discarded and the formazan blue,
formed in the cells, was dissolved with 100 mL of DMSO. The rate of
color production was measured at 570 nm in a spectrophotometer
(Spectra MAX Plus; Molecular Devices; supported by SOFT max
PRO-3.0). All experiments were conducted under the standard
Table 1
In vitro cytotoxicity data of compounds 1aec, 13d, 18a, and 24 on THP-1, A-549, HL-60, Jurkat and U-937 tumor cell lines.
Compound
IC50
(
m
M) ꢃ SE
THP-1
A-549
HL-60
Jurkat
U-937
1a
1b
1c
13d
18a
24
Etoposide
Camptothecin
2.14 ꢃ 0.18
0.49 ꢃ 0.11
3.09 ꢃ 0.26
3.56 ꢃ 0.48
3.1 ꢃ 0.26
N/T
N/T
N/T
4.56 ꢃ 0.38
3.23 ꢃ 0.27
5.01 ꢃ 0.42
9.51 ꢃ 1.33
0.008 ꢃ 0.006
6.39 ꢃ 2.12
4.13 ꢃ 1.57
7.27 ꢃ 3.15
5.63 ꢃ 0.35
7.15 ꢃ 0.60
22.28 ꢃ 5.68
1.83 ꢃ 0.20
0.600 ꢃ 0.03
11.27 ꢃ 1.40
6.58 ꢃ 1.05
9.43 ꢃ 1.56
9.75 ꢃ 0.85
2.23 ꢃ 0.12
3.20 ꢃ 0.27
5.35 ꢃ 0.63
0.026 ꢃ 0.002
6.03 ꢃ 0.51
3.44 ꢃ 0.29
5.41 ꢃ 0.44
N/T
N/T
N/T
3.0 ꢃ 0.22
2.16 ꢃ 0.15
0.071 ꢃ 0.0053
17.94 ꢃ 1.19
1.980 ꢃ 0.11
N/T¼Not Tested.

32
D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
4. Experimental section
(M þ Naþ, 50); Anal. Calcd. for C15H14N2O4: C, 62.93; H, 4.93; N,
9.79. Found: C, 63.10; H, 4.88; N, 9.62.
4.1. Chemistry
4.1.3. N-(4-Fluorophenyl)-4-methyl-3-nitrobenzamide (4b)
All reactions were monitored by analytical Thin Layer Chroma-
tography (TLC) performed on E-Merck 0.25 mm precoated silica gel
glass plates (60 F254). Visualization of the spots on TLC plates was
achieved either by exposure to UV light or iodine vapor or by dipping
the plates in ethanolic solution of phosphomolybdic acid (PMA) and
heating the plates at 120 ꢀC. Column chromatography was performed
using silica gel (Acme, 60e120 mesh). Solvents were dried according
to conventional methods and purified by distillation prior to use.
Solvents for chromatography (n-hexane and EtOAc) were distilled
prior to use. Evaporations were carried out under reduced pressure
on Buchi rotary evaporator below 40e44 ꢀC. Melting points were
obtained using a precision digital melting point Veego VMP-DS
apparatus and are uncorrected. IR spectra were obtained on a Per-
kineElmer 683 or 1310 spectrophotometer with sodium chloride
optics or KBr pellets.1H and 13C NMR spectra were recorded on either
a Bruker Avance 300 (300.132 MHz for 1H, 75.473 MHz for 13C), or
Varian FT-200 MHz (Gemini) spectrometer in CDCl3 or DMSO-d6.
Brownish solid; Yield 83.5%; m.p: 140e141 ꢀC; IR (KBr): v 3463,
3014, 2970, 2946, 1740, 1438, 1368, 1215, 1093, 900, 830, 734 cmꢁ1
;
1HNMR (300 MHz, DMSO- d6):
d 2.65 (s, 3H, Ar-CH3), 7.05e7.10 (m,
2H, Ar-H), 7.5 (d, 1H, J ¼ 8.1, Ar-H), 7.74e7.83 (m, 2H, Ar-H), 8.21 (dd,
1H, J1 ¼ 8.1 Hz, J2 ¼ 1.7Hz, Ar-H), 8.65 (d, 1H, J ¼ 1.7, Ar-H), 10.4 (br s,
1H, CONH); 13C NMR (300 MHz, DMSO-d6):
d 19.5, 115.05, 115.3,
122.3, 123.5, 132.0, 133.1, 133.5, 135.0, 136.3, 148.7, 156.8, 160.0, 162.9;
MS( ESI): m/z (%) ¼ 274 (M þ H, 100); Anal. Calcd. for C14H11N2O4: C,
61.31; H, 4.04; N, 6.93. Found: C, 61.38; H, 4.98; N, 6.88.
4.1.4. 4-Methyl-3-nitro-N-phenylbenzamide (4c)
Colourless solid; Yield 86.1%; m.p.135e136 ꢀC; IR (KBr): v 3460,
3013, 2970, 2946, 1740, 1438, 1368, 1215, 1092, 901 cmꢁ1 1HNMR
(300 MHz, DMSO- d6): d 2.65 (s, 3H, Ar-CH3), 7.1 (m,1H, Ar-H), 7.3 (t,
2H, J ¼ 7.9Hz, Ar-H), 7.5 (d, 1H, J ¼ 7.8, Ar-H), 7.7 (d, 2H, J ¼ 7.8 Hz,
Ar-H), 8.2 (d, 1H, J ¼ 7.8 Hz, Ar-H), 8.6 (s, 1H, Ar-H), 10.2 (br s, 1H,
NH); 13C NMR (300 MHz, DMSO- d6):
d 19.5, 120.5, 123.5, 124.0,
Chemical shifts have been expressed in parts per million (
d
) relative
128.6, 132.0, 133.0, 133.7, 136.2, 138.7, 148.7, 163.1; MS (ESI): m/z
(%) ¼ 257 (M þ H, 100).
to tetramethylsilane (
d
¼ 0.0) as an internal standard and coupling
constants (J) in Hertz. Optical rotations were measured using JASCO
DIP-370 digital polarimeter at 20 ꢀC. Elemental analyses were per-
formed using an Elementar Vario EL microanalyzer. Microanalysis of
all the synthesized compounds agreed within ꢃ0.3% of calculated
values. Low-resolution mass spectra (ESI-MS) and HRMS were
recorded on Quattro LC, Micromass and Q STAR XL, Applied Bio-
systems respectively.
4.1.5. N1-(4-Methoxylphenyl)-4-methyl-3-nitro-1-
benzenecarbothioamide (5a)
Lawesson’s reagent (5.07 g, 12.55 mmol) was added to the
stirred solution of amide 4a (7.15 g, 25.00 mmol) in dry toluene
(50 mL) at 60 ꢀC. The mixture was then refluxed for 1e2 h till TLC
showed the completion of the reaction. After the completion of
the reaction, solvent toluene was evaporated under reduced
pressure. The resulting residue was quenched with 5 mL of
Sodium hypochlorite solution (available approx. 4% chlorine).
Ice-cubes were added to it to get dark yellow colored crude solid
which was filtered through Buchner funnel. Recrystallization
(using acetone: water mixture) followed by column chromatog-
raphy using EtOAc: petroleum ether (2:5) afforded pure pale
yellow colored prisms 5a (6.64 g) in 88% yield. m.p. 132e134 ꢀC;
4.1.1. 4-Methyl-3-nitrobenzoic acid (4)
To a stirred solution of 4-methylbenzoic acid (13.61 g, 0.1 mol) in
CH2Cl2 (100 mL) was added NH4NO3 (7.60 g, 0.1 mol) and stirred for
10 min. To the above mixture conc. H2SO4 (18.5 mL, 0.35 mol) was
added drop wise at 0 ꢀC for a period of 15 min while stirring. Stir-
ring was continued at room temperature for a period of 2e5 h till
TLC showed the completion of the reaction. The reaction mixture
was quenched with cold water (200 mL) and then allowed to return
to room temperature. The organic layer was washed several times
with water to remove acidic impurities and evaporated under
reduced pressure to afford crude solid. Recrystallization using
EtOAc: petroleum ether mixture to give 4 as light yellow prisms
(16.66 g) in 92% yield. m.p. 178e180 ꢀC (lit. 184e185 ꢀC [21]); 1H
1H NMR (200 MHz, CDCl3):
d 2.67 (s, 3H, Ar-CH3), 3.84 (s, 3H, Ar-
OCH3), 6.88e6.99 (d, 2H, J ¼ 8.81 Hz, Ar-H), 7.36e7.47 (d, 1H,
J ¼ 7.35 Hz, Ar-H), 7.56e7.69 (d, 2H, J ¼ 8.08 Hz, Ar-H), 8.03e8.13
(d, 2H, J ¼ 7.35 Hz, Ar-H), 8.33 (s, 1H, Ar-H), 8.97 (br s, 1H,
CONH); MS (ESI): m/z (%) 303 (M
C15H14N2O3S: C, 59.59; H, 4.67; N, 9.27. Found: C, 59.39; H, 4.55;
N, 9.35.
þ
H); Anal. Calcd. for
NMR (300 MHz, CDCl3):
d 2.65 (s, 3H, Ar-CH3), 7.41e7.49 (d, 1H,
J ¼ 7.73 Hz, Ar-H), 8.08e8.16 (dd, 1H, J1 ¼ 8.50 Hz, J2 ¼ 1.55 Hz, Ar-
H), 8.51e8.54 (d, 1H, J ¼ 1.55 Hz, Ar-H).
4.1.6. N-(4-Fluorophenyl)-4-methyl-3-nitrothiobenzanilide (5b)
pale yellow solid; Yield 85.2%; m.p.138e139 ꢀC; IR (KBr): v 3462,
3346, 2970, 1740, 1509, 1439, 1367, 1215, 1094, 1076, 910, 833, 800,
4.1.2. N1-(4-Methoxyphenyl)-4-methyl-3-nitrobenzamide (4a)
Nitro acid 4 (5.5 g, 30.38 mmol) was converted to 4-methyl-3-
nitrobenzoyl chloride (6.06 g, 30.38 mmol) using SOCl2 and dry
benzene at 80 ꢀC in the presence of catalytic amount of DMF (2
drops). Freshly prepared acid chloride was added drop wise to
a stirred solution of p-anisidine (3.816 g, 31.00 mmol) and Et3N
(10 mL) in dry THF (35 mL) at 0 ꢀC and the stirring was continued at
room temperature for a period of 2e3 h. Solvent THF was evapo-
rated under reduced pressure. The crude solid was washed with
a saturated solution of NaHCO3, 1N HCl and cold water to remove if
any unreacted starting materials were present. The crude solid was
filtered through Buchner funnel and recrystallized using MeOH to
afford 4a (7.30 g) as a light yellow crystalline solid in 85% yield. m.p.
732, 694, 608 cmꢁ1; 1HNMR (500 MHz, DMSO-d6):
d 2.53 (s, 3H, Ar-
CH3), 7.14 (t, 2H, J ¼ 8.89 Hz, Ar-H), 7.36 (d, 1H, J ¼ 7.91 Hz, Ar-H),
7.68e7.73 (m, 2H, Ar-H), 8.02 (d, 1H, J ¼ 7.91, Ar-H), 8.38 (d, 1H,
J ¼ 1.7 Hz, Ar-H), 11.61(br s, 1H, NH); 13C NMR (300 MHz, DMSO-d6),
19.4, 115.1, 115.4, 123.1, 126.5, 131.7, 132.5, 135.3, 136.0, 140.7, 148.2,
158.2, 161.5, 194.4; MS (ESI): m/z (%) ¼ 291 (M þ H, 100).
4.1.7. 4-Methyl-3-nitro-N-phenylthiobenanilide (5c)
Bright yellow crystal; Yield 87.4%; m.p. 124.5e126.0 ꢀC; IR (KBr):
v 3450, 3308, 3070, 2928, 1617, 1521, 1444, 1398, 1346, 1209, 1069,
1022, 994, 895, 817, 762, 689, 662, 578, 497, 415; 1HNMR (300 MHz,
DMSO-d6): d 2.63(s, 3H, Ar-CH3),7.26e7.30 (m, 1H, Ar-H), 7.40e7.46
150e152 ꢀC; 1H NMR (300 MHz, CDCl3):
d
2.69 (s, 3H, Ar-CH3), 3.81
(m, 3H, Ar-H), 7.80 (d, 2H, J ¼ 7.9 Hz, Ar-H), 8.12 (d,1H, J ¼ 7.9 Hz, Ar-
H), 8.49 (s, 1H, Ar-H), 11.68 (br s, 1H, NH); 13C NMR (300 MHz,
DMSO- d6), 19.3, 123.1, 124.1, 126.5, 128.5, 131.7, 132.5, 135.2, 139.6,
140.9, 148.2, 194.2. MS (ESI) : m/z (%) ¼ 273 (M þ H, 100).
(s, 3H, Ar-OCH3), 6.82e6.90 (d, 2H, J ¼ 9.06 Hz, Ar-H), 7.42e7.53 (m,
3H, Ar-H), 7.66e7.72 (br s, CONH), 8.00e8.07 (d, 2H, J ¼ 7.55 Hz, Ar-
H), 8.38 (s, 1H, Ar-H); MS (ESI): m/z (%) ¼ 287 (M þ H, 100), 309

D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
33
4.1.8. 6-Methoxy-2-(4-methyl-3-nitrophenyl)-1,3-benzothiazole4e
(6a)
Dess-Martin periodinane (4.66 g, 11.00 mmol) was added to
4.1.12. Procedure for the preparation of tetrabutylammonium
permanganate (TBAP) reagent
KMnO4 (4.00 g, 25.32 mmol) dissolved in minimum amount of
water was added with stirring to an aqueous solution 150 mL of
tetrabutylammonium bromide (9.38 g, 29.10 mmol).12 Upon stir-
ring for 10e15 min a purple colored precipitate formed in the
reaction mixture, which was filtered using Buchner funnel and
dried in calcium chloride desiccator for 10e12 h to obtain a purple
solid TBAP reagent (8.68 g) in 95% yield.
a stirred solution of thioformanilide 5a (3.00 g, 10 mmol) in CH2Cl2
(50 mL) at room temperature. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was
quenched with H2O (2 ꢂ 10 mL) and the reaction mixture was
extracted with CH2Cl2 (3 ꢂ 10 mL). The combined organic phase was
initially dried with anhydrous Na2SO4 and the solvent evaporated
under reduced pressure, to afford the crude product which was
purified by column chromatography on silica gel using EtOAc:
petroleum ether (1:3) as eluent to give the 2-arylbenzothiazole 6a
as a light yellow solid (2.682 g) in 90% yield. m.p. 141e142 ꢀC; 1H
4.1.13. 4-(6-Fluoro-1,3-benzothiazol-2-yl)-2-nitrobenzoic acid (2b)
m.p. 218e220 ꢀC; IR (KBr): v 3376, 2923, 1725, 1602, 1542, 1367,
1251, 1200, 818, 793 cmꢁ1
;
1H NMR (200 MHz, DMSO-d6):
NMR (300 MHz, CDCl3):
d
2.68 (s, 3H, Ar-CH3), 3.90 (s, 3H, Ar-OCH3),
d
7.24e7.36 (dt, 1H, J1 ¼ 8.98 Hz, J2 ¼ 2.76 Hz, Ar-H), 7.70e7.78 (m,
7.06e7.11 (dd, 1H, J1 ¼ 9.06 Hz, J2 ¼ 3.02 Hz, Ar-H), 7.31e7.33 (d, 1H,
J ¼ 2.26 Hz, Ar-H), 7.41e7.46 (d,1H, J ¼ 8.30 Hz, Ar-H), 7.90e7.94 (dd,
1H, J ¼ 9.06 Hz, Ar-H), 8.12e8.17 (d,1H, J ¼ 7.55 Hz, Ar-H), 8.58 (s,1H,
1H, Ar-H), 7.86e8.09 (m, 2H, Ar-H), 8.26e8.32 (m,1H, Ar-H), 8.48 (s,
1H, Ar-H); MS (ESI): m/z (%) ¼ 319 (M þ H, 10); Anal. Calcd. for
C14H7FN2O4S: C, 52.83; H, 2.22; N, 8.80. Found: C, 53.08; H, 2.40; N,
9.01.
Ar-H); 13C NMR (75 MHz, CDCl3):
d 20.5, 55.8, 104.0, 116.2, 123.0,
124.0, 130.8, 132.9, 133.4, 135.4, 136.4, 148.4, 149.5, 158.1, 162.3; MS
(ESI): m/z (%) ¼ 301 (MþþH, 100); Anal. Calcd. for C15H12N2O3S: C,
59.99; H, 4.03; N, 9.33. Found: C, 60.12; H, 3.98; N, 9.21.
4.1.14. 4-(1,3-Benzothiazol-2-yl)-2-nitrobenzoic acid (2c)
m.p. 179e181 ꢀC; IR (KBr): v 3377, 2924, 1716, 1611, 1539, 1239,
1150, 756 cmꢁ1; 1H NMR (200 MHz, DMSO-d6):
d 7.36e7.60 (m, 2H,
4.1.9. 6-Fluoro-2-(4-methyl-3-nitrophenyl)-1,3-benzothiazole4e
Ar-H), 7.93e8.14 (m, 3H, Ar-H), 8.27e8.34 (m, 1H, Ar-H), 8.50 (s, 1H,
Ar-H); MS (ESI): m/z (%) ¼ 301 (M þ H, 8), 271 (45), 242 (100); Anal.
Calcd. for C14H8N2O4S: C, 56.00; H, 2.69; N, 9.33. Found: C, 55.85; H,
2.60; N, 9.27.
(6b)
m.p. 154e156 ꢀC; 1H NMR (200 MHz, CDCl3):
d 2.70 (s, 3H, Ar-
CH3), 7.19e7.30 (m, 1H, Ar-H), 7.44e7.49 (d, 1H, J ¼ 8.6 Hz, Ar-H),
7.56e7.62 (dd, 1H, J1 ¼ 2.34 Hz, J2 ¼ 7.81 Hz, Ar-H), 7.97e8.04 (m,
1H, Ar-H), 8.13e8.19 (dd, 1H, J1 ¼ 1.56 Hz, J2 ¼ 7.81 Hz, Ar-H),
8.60e8.62 (d, 1H, J ¼ 1.56 Hz, Ar-H); 13C NMR (75 MHz, CDCl3):
4.1.15. (2S)-1-[(Benzyloxy)carbonyl]tetrahydro-1H-2-
pyrrolecarboxylic acid (7)
d
20.5, 107.8, 108.1, 115.3, 115.6, 123.3, 124.6, 127.0, 129.5, 131.0,
To a stirred aqueous solution of S-proline (5.0 g, 43.48 mmol, 1.0
equiv) and NaHCO3 (18.26 g, 217.40 mmol, 2.5 equiv) was added
drop wise benzylchloroformate (8.16 g, 47.82 mmol, 1.1 equiv) at
133.6, 136.0, 150.6, 162.4; MS (EI): m/z (%) ¼ 288 (Mþ 100), 271 (98),
243 (95), 227 (10), 216 (25), 69 (30), 63 (30), 45 (20); Anal. Calcd. for
C14H9FN2O2S: C, 58.33; H, 3.15; N, 9.72. Found: C, 58.53; H, 3.22; N,
9.66.
0
ꢀC and stirred overnight at room temperature. The reaction
mixture was quenched with 1N HCl till pH 2. This solution was
extracted with EtOAc (3 ꢂ 15 mL) treated with brine and dried over
Na2SO4. Upon column chromatography using EtOAc: petroleum
ether (1:3) afforded a colorless gummy compound 7 (10.5 g, 97%
4.1.10. 2-(4-Methyl-3-nitrophenyl)-1,3-benzothiazole4e (6c)
m.p. 169e171 ꢀC; 1H NMR (300 MHz, CDCl3):
d 2.69 (s, 3H, Ar-
CH3), 7.37e7.56 (m, 3H, Ar-H), 7.88e7.93 (d, 1H, J ¼ 7.55 Hz, Ar-H),
8.03e8.08 (d, 1H, J ¼ 8.30 Hz, Ar-H), 8.18e8.22 (dd, 1H, J ¼ 1.51 Hz,
J ¼ 8.30 Hz, Ar-H) 8.63e8.65 (m, 1H, Ar-H); MS (EI): m/z (%) ¼ 271
(MþþH, 40); Anal. Calcd. for C14H10N2O2S: C, 62.21; H, 3.73; N,
10.36. Found: C, 62.45; H, 3.80; N, 10.22.
yield). [
a
]
D
ꢁ73.57ꢀ (c 1.4, CHCl3); IR (Neat): v 2959, 2887, 1706,
1426, 1358, 1180, 1124, 1089, 765, 698 cmꢁ1 1H NMR (300 MHz,
;
CDCl3):
d 1.85e2.33 (m, 4H, CH2), 3.42e3.66 (m, 2H, CH2),
4.31e4.42 (m,1H, CH), 5.08e5.17 (m, 2H, Ar-CH2), 7.20e7.36 (m, 5H,
Ar-H); MS (ESI): m/z (%) ¼ 250 (M þ H, 55), (M þ NHþ4 , 100).
4.1.11. 4-(6-Methoxy-1,3-benzothiazol-2-yl)-2-nitrobenzoic acid
(2a)
4.1.16. Benzyl (2S)-2-(hydroxymethyl)tetrahydro-1H-1-
pyrrolecarboxylate (8)
Freshly prepared (see procedure below) tetrabutylammonium
permanganate, TBAP (6.31 g, 16.66 mmol) was added to a solution
of 2-arylbenzothiazole 6a (2.50 g, 8.33 mmol) in dry pyridine
(50 mL) at room temperature. The reaction mixture became
exothermic after stirring for 5 min. The reaction was continued at
room temperature for a period of 12 h till TLC showed the
completion of the reaction. The reaction mixture was poured into
a mixture of NaHSO3 and cold dilute HCl. The yellow solid product
resulted was extracted with ethyl acetate (3 ꢂ 10 mL). The organic
layer was evaporated under reduced pressure to get crude acid.
Recrystallization using EtOAc: petroleum ether afforded 2a (2.39 g)
as a pale yellow solid in 87% yield. m.p. 221e222 ꢀC; IR (KBr): v
To a solution of Cbz-(S)-proline 7 (10.5 g, 46.25 mmol) in dry
THF (100 mL) in a two necked round bottom flask was added
NaBH4 (3.98 g, 105.3 mmol) in three portions at 0 ꢀC. After stirring
the reaction mixture at 0 ꢀC for ½ hour, I2 (10.70 g, 42.16 mmol)
dissolved in dry THF (25 mL) was added drop wise over a period of
30 min. This solution was refluxed for a period of 18 h till the TLC
showed complete disappearance of the starting material. The
milky reaction mixture was stirred further for 30 min at room
temperature followed by the addition of methanol (50 mL) till
a clear solution appears. A white paste was obtained after evap-
oration under reduced pressure. It was further quenched with 1N
HCl and extracted with CH2Cl2 (3 ꢂ 20 mL). Column chromatog-
raphy afforded a colorless gummy liquid Cbz-(S)-prolinol 8 (7.55 g,
2925, 1715, 1601, 1538, 1369, 1225, 1143, 1025, 826, 792 cmꢁ1
;
1H
NMR (200 MHz, DMSO-d6): 3.91 (s, 3H, Ar-OCH3), 7.06e7.15 (dd,
d
74% yield). [
a]
ꢁ41.6ꢀ (c 1.73, CHCl3) (lit. ꢁ41.8ꢀ (c 1.4, CHCl3)
D
1H, J1 ¼ 8.85 Hz, J2 ¼ 2.72 Hz, Ar-H), 7.41e7.45 (m, 1H, Ar-H),
7.90e7.98 (m, 2H, Ar-H), 8.20e8.27 (d, 1H, J ¼ 8.17 Hz, AR-H),
8.42 (s, 1H, AR-H); MS (ESI): m/z (%) ¼ 331 (10); Anal. Calcd. for
C15H10N2O5S: C, 54.54; H, 3.05; N, 8.48. Found: C, 55.02; H, 3.22; N,
8.66. The same procedure was followed for the syntheses of
compounds 2b and 2c.
[22]); IR (Neat): v 3430, 3033, 2953, 2880, 1680, 1418, 1357, 1192,
1105, 1049, 747, 698 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 1.60e1.72
(m, 1H), 1.77e2.10 (m, 3H), 3.36e3.45 (m, 1H), 3.50e3.66 (m, 3H),
3.91e4.01 (m, 1H), 4.15e4.27 (br s, 1H), 5.11e5.15 (d, 2H,
J ¼ 3.77 Hz), 7.25e7.37 (m, 5H); MS (ESI): m/z (%) ¼ 236
(M þ H, 100).

34
D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
4.1.17. Benzyl (2S)-2-formyltetrahydro-1H-1-pyrrolecarboxylate
(9)
CHCl3) [23a]); IR (Neat): v 3447, 2964, 2926, 2868, 1614, 1448, 1378,
1338, 1263, 1183, 1110, 1050, 973, 754, 588 cmꢁ1; 1H NMR (300 MHz,
In a 100 mL two-necked round bottom flask was taken cyanuric
chloride (5.65 g, 30.62 mmol, 1.2 equiv), and dissolved in dry THF. To
thissolutionwasadded dry DMSO(10.86mL,153.14 mmol, 6.0 equiv),
slowly at ꢁ30 ꢀC. After 30 min was added Cbz-(S)-prolinol 8 (6.0 g,
25.53 mmol, 1.0 equiv) dissolved in dry THF (60 mL) at ꢁ30 ꢀC and
stirring was continued for further 30 min at ꢁ30 ꢀC. Et3N (21.32 mL,
153.14 mmol, 6.0 equiv), was added to the reaction mixture and the
temperature was maintained for further 30 min at ꢁ30 ꢀC. Slowly it
wasallowed towarm-upfor roomtemperature and stirred for further
15 min. The organic solvents were evaporated under reduced pres-
sure to get a white solid. To this was added Et2O and the suspension
was treated with 1N HCl till two clear layers develop. The organic
layer was separated and treated with saturated solution of NaHCO3,
brine and Na2SO4. Flash chromatography using EtOAc: petroleum
ether (1:2) afforded a colorless liquid Cbz-(S)-prolinal 9 (5.35 g, 90%
CDCl3): d 1.19e1.31 (m, 6H, SCCH3), 1.59e2.16 (m, 4H, CH2),
2.54e2.79 (m, 4H, CH2), 2.86e2.96 (m, 1H, CH), 3.01e3.11 (m, 1H,
CH), 3.22e3.31 (q, 1H, J ¼ 7.55 Hz, CH), 3.70e3.75 (d, 1H, J ¼ 8.3 Hz,
CH); 13C NMR (75 MHz, CDCl3):
d 14.5, 24.2, 24.9e25.0, 29.9, 46.1,
57.0, 62.1; MS (ESI): m/z (%) ¼ 206 (M þ H, 100), 144 (30), 101 (10);
HRMS (ESI) calcd. for C9H19NS2 205.1037 [M þ H]þ, found 205.1040.
4.1.20. (2S)-2-[Di(ethylsulfanyl)methyl]tetrahydro-1H-1-pyrrolyl
[4-(6-methoxy-1,3-benzothiazol-2-yl)-2-nitrophenyl]methanone
(11a)
N,N-Dimethylformamide (2 drops) was added to a stirred
suspension of the nitro acid 2a (1.5 g, 4.5 mmol,1.0 equiv) and thionyl
chloride (0.80 g, 6.78 mmol, 1.5 equiv) in dry benzene (20 mL) and
refluxed for a period of 4e5 h till a transparent solution obtained.
After evaporation of benzene under reduced pressure, the resultant
yellow solid was dissolved in THF (15 mL) and added drop wise for
a period of 10 min to a vigorously stirred mixture of (S)-pyrrolidine-
2-carbaldehyde diethyl thioacetal 3 (0.93 g, 4.5 mmol,1.0 equiv), Et3N
(3 mL), and ice/water (4-5 drops) at 0 ꢀC. The reaction mixture was
stirred at room temperature for a period of 1.5 h. After removal of the
THF by evaporation under reduced pressure, the residue was diluted
with water (20 mL) and extracted with EtOAc (3 ꢂ 10 mL). The
combined organic phase was washed with water (2 ꢂ 10 mL), brine,
dried (Na2SO4), and the solvent was removed by evaporation under
reduced pressure to afford dark red oil. Purification of the crude
product by column chromatography using EtOAc: petroleum ether,
(1:2) to afford the corresponding amide as a low melting solid 11a
yield). [
a
]D ꢁ66.58ꢀ (c 1.06, CHCl3) (lit. ꢁ74.42ꢀ (c 0.1384 CHCl3) [23]);
IR (Neat): v 3450, 3033, 2955, 2884,1705,1415,1355,1204,1173,1120,
766, 699 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 1.73e2.27 (m, 4H, CH2),
3.35e3.76 (m, 3H, CH2, CH), 4.10e4.38 (m, 1H, CH), 5.08e5.16 (d, 1H,
J ¼ 6.61 Hz, CH), 7.23e7.38 (m, 5H, Ar-H), 9.47 and 9.57 (s, 1H, rota-
meric CHO). Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00.
Found: C, 66.88; H, 6.42; N, 5.96.
4.1.18. Benzyl (2S)-2-[di(ethylsulfanyl)methyl]tetrahydro-1H-1-
pyrrolecarboxylate (10)
Ethanethiol (2.93 g, 47.18 mmol, 2.2 equiv) was added to a stirred
solution of Cbz-(S)-prolinal 9 (5.0 g, 21.46 mmol, 1.0 equiv) in dry
CHCl3 (50 mL) under nitrogen atmosphere. After stirring for a period
of 30 min trimethylsilyl chloride (6.75 mL, 53.66 mmol, 2.5 equiv)
was added to it at room temperature. The reactionwas continued for
further 12e24 h till TLC showed the completion of the reaction. The
reaction mixture was carefully neutralized using saturated solution
of NaHCO3, extracted with CHCl3 (3 ꢂ 20 mL) treated with brine and
dried over Na2SO4. The crude diethyl thioacetal was purified by
column chromatography on silica gel using EtOAc: petroleum ether
(1.175 g, 50% yield). [
NMR (200 MHz, CDCl3):
a
]
ꢁ84.2ꢀ (c 0.5, CHCl3); m.p. 83e85 ꢀC; 1H
1.32e1.43 (dt, 6H, J1 ¼7.35 Hz, J2 ¼ 2.20 Hz,
D
d
SCCH3), 1.78e2.43 (m, 4H, CH2), 2.65e2.91 (m, 4H, CH2), 3.28e3.38
(m, 2H, CH2), 3.91 (s, 3H, Ar-OCH3), 4.64e4.75 (m, 1H, CH),
4.79e4.83 (d, 1H, J ¼ 3.67 Hz, CH), 7.08e7.15 (dd, 1H, J1 ¼ 8.81 Hz,
J2 ¼ 2.20 Hz, Ar-H), 7.32e7.36 (d, 1H, J ¼ 2.20 Hz, Ar-H), 7.51e7.56 (d,
1H, J ¼ 8.08 Hz, Ar-H), 7.93e7.99 (d, 1H, J ¼ 8.81 Hz, Ar-H), 8.30e8.36
(dd,1H, J1 ¼8.08 Hz, J2 ¼ 2.20 Hz, Ar-H), 8.75e8.77 (d,1H, J ¼ 1.47 Hz,
(1:5) to afford a pale yellow liquid 10 (7.27 g,100% yield). [
a
]D ꢁ48.5ꢀ
Ar-H); 13C NMR (75 MHz, CDCl3):
d 15.0, 24.7, 26.3, 27.2, 29.7, 50.4,
(c 1.05, CHCl3) (lit. ꢁ50.9ꢀ (c 0.2104 CHCl3) [23a]); 1H NMR
52.8, 55.8, 61.2, 104.0, 116.5, 122.9, 124.4, 128.8, 132.2, 135.7, 136.7,
145.7, 148.5, 158.5, 161.2, 165.8; MS (ESI): m/z (%) ¼ 518 (M þ H, 20),
540 (M þ Naþ, 25), 556 (M þ Kþ,100); Anal. Calcd. for C24H27N3O4S3:
C, 55.68; H, 5.26; N, 8.12. Found: C, 55.45; H, 5.12; N, 8.43. The same
procedure was used for the preparation of compound 11b (1.14 g, 48%
yield) and compound 11c (1.26 g, 52% yield).
(200 MHz, CDCl3): d 1.05e1.39 (m, 6H, SCCH3),1.70e1.84 (m,1H, CH),
1.98e2.11 (m, 3H, CH2, CH), 2.37e2.73 (m, 4H, CH2), 3.38e3.48 (m,
1H, CH), 3.55e3.70 (m,1H, CH), 4.16e4.27 (m,1H, CH), 4.55e4.60 (d,
1H, J ¼ 3.77 Hz, CH), 4.96e5.27 (m, 2H, Ar-CH2), 7.23e7.38 (m, 5H,
Ar-H); MS (ESI): m/z (%) ¼ 340 (M þ H, 10), 362 (M þ Na, 80), 377
(M þ K, 15); Anal. Calcd. for C17H25NO2S2: C, 60.14; H, 7.42; N, 4.13.
Found: C, 60.09; H, 7.22; N, 4.24.
4.1.21. (2S)-2-[Di(ethylsulfanyl)methyl]tetrahydro-1H-1-pyrrolyl
[4-(6-fluoro-1,3-benzothiazol-2-yl)-2-nitrophenyl]methanone (11b)
4.1.19. (2S)-2-[Di(ethylsulfanyl)methyl]tetrahydro-1H-pyrrole (3)
To a solution of TMSCl (3.47 mL, 27.44 mmol, 2.0 equiv) in dry
CH3CN (60 mL) containing molecular sieves at 0 ꢀC was added
sodium iodide (4.93 g, 32.89 mmol, 2.4 equiv) in portions over
10 min. Stirring was continued for a period of 1e2 h at room
temperature till a brick red color of TMSI persisted. To this solution
was added drop wise Cbz-(S)-proline diethyl thioacetal 10 (4.65 g,
13.71 mmol, 1.0 equiv) dissolved in dry acetonitrile (40 mL) over
a period of 30 min. Stirring is continued for further approximately
1e2 h till the TLC (EtOAc: petroleum ether, 1:1) showed the
completion of the reaction. After quenching with methanol (15 mL)
and evaporation at 35 ꢀC under reduced pressure, the resulting oil
was dissolved in ether (50 mL) and extracted with 0.5 N HCl
(3 ꢂ 20 mL). The combined aqueous layers, after adjusting to pH 8
with 2N NaOH, were back-extracted with ether (3 ꢂ 15 mL), and the
combined organic phase was washed with brine, dried over Na2SO4
and evaporated under reduced pressure to afford a pale yellow liquid
[
a
]
D ꢁ98.0ꢀ (c 0.5, CHCl3); m.p. 150e152 ꢀC; IR (Neat): v 3430.14,
2963.46, 2922.42, 2869.58, 1633.49, 1547.41, 1512.06, 1431.89,
1351.42, 1249.19, 1203.00, 856.37, 815.75 cmꢁ1; 1H NMR (200 MHz,
CDCl3, TMS):
d
1.32e1.43 (dt, 6H, J1 ¼ 7.31 Hz, J2 ¼ 2.19 Hz, SCCH3),
1.81e2.41 (m, 4H, CH2), 2.66e2.89 (m, 4H, CH2), 3.28e3.39 (m, 2H,
CH2), 3.91 (s, 3H, Ar-OCH3), 4.64e4.75 (m, 1H, CH), 4.79e4.84 (d,
1H, J ¼ 3.66 Hz, CH), 7.22e7.34 (dt, 1H, J1 ¼ 8.77 Hz, J2 ¼ 2.19 Hz, Ar-
H), 7.54e7.65 (m, 2H, Ar-H), 8.01e8.10 (m, 1H, Ar-H), 8.31e8.38 (dd,
1H, J1 ¼ 8.04 Hz, J2 ¼ 1.46 Hz, Ar-H), 8.78e8.80 (d, 1H, J ¼ 1.46 Hz,
Ar-H); 13C NMR (75 MHz, CDCl3):
d 14.9, 24.7, 26.3, 26.6, 27.2, 29.6,
50.4, 52.8, 61.2, 107.9, 108.2, 115.6, 115.9, 123.2, 124.9, 129.0, 132.4,
135.2, 145.7, 150.5, 159.3, 162.6, 165.6; MS (ESI): m/z (%) ¼ 505
(M þ H, 5), 528 (M þ Naþ, 22), 544 (M þ Kþ, 6).
4.1.22. [4-(1,3-Benzothiazol-2-yl)-2-nitrophenyl](2S)-2-
[di(ethylsulfanyl)methyl]tetrahydro-1H-1-pyrrolylmethanone (11c)
[
a
]
D
ꢁ87.6ꢀ (c 0.5, CHCl3); m.p. 139e142 ꢀC; IR (Neat): v 3430,
3 (2.39 g, 85% yield). [
a]
D ꢁ32.5ꢀ (c 0.66, CHCl3) (lit. ꢁ31.8ꢀ (c 0.434
2961, 2923, 2859, 1632, 1545, 1512, 1430, 1350, 756 cmꢁ1; 1H NMR

D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
35
(300 MHz, CDCl3):
d
1.33e1.42 (dt, 6H, J1 ¼ 7.55 Hz, J2 ¼ 3.02 Hz,
was washed with ethyl acetate (5 mL). The filtrate was dried by
using Na2SO4 and directly poured on silica gel column. Column
chromatography (EtOAc: petroleum ether, 3:1) afforded a pale
SCCH3), 1.81e2.18 (m, 3H, CH2, CH), 2.27e2.39 (m, 1H, CH),
2.67e2.87 (m, 4H, CH2), 3.30e3.37 (m, 2H, CH2), 4.66e4.74 (m, 1H,
CH), 4.80e4.83 (d, 1H, J ¼ 3.77 Hz, CH), 7.40e7.59 (m, 3H, Ar-H),
7.91e7.96 (d, 1H, J ¼ 7.55 Hz, Ar-H), 8.08e8.12 (d, 1H, J ¼ 7.55 Hz,
Ar-H), 8.37e8.41 (dd, 1H, J1 ¼7.55 Hz, J2 ¼ 1.51 Hz, Ar-H), 8.82e8.84
yellow gummy syrup 1a (0.184 g, 55% yield). [
a]
45.4ꢀ (c 0.36,
D
acetone); 1H NMR (300 MHz, CDCl3):
d
2.00e2.25 (m, 3H, CH2, CH),
2.31e2.41 (m, 1H, CH), 3.54e3.92 (m, 3H, CH2, CH), 3.89 (s, 3H, Ar-
OCH3), 7.04e7.10 (dd, 1H, J1 ¼ 9.06 Hz, J2 ¼ 3.02 Hz, Ar-H), 7.31e7.34
(d, 1H, J ¼ 2.26 Hz, Ar-H), 7.78e7.82 (d, 1H, J ¼ 4.53 Hz, N]CH),
7.91e7.96 (m, 2H, Ar-H), 8.00e8.04 (m, 1H, Ar-H), 8.09e8.14 (d, 1H,
(d, 1H, J ¼ 1.51 Hz, Ar-H); 13C NMR (75 MHz, CDCl3):
d 15.0, 24.7,
26.3, 26.5, 27.2, 29.6, 50.4, 52.8, 61.2,121.8,123.3, 123.8,126.2,126.9,
128.9, 132.5, 135.1, 135.5, 145.6, 153.8, 163.9, 165.7; MS (ESI): m/z
(%) ¼ 487 (M þ H, 5), 510 (M þ Naþ, 15), 526 (M þ Kþ, 4).
J ¼ 8.30 Hz, Ar-H); 13C NMR (75 MHz, CDCl3):
d 24.1, 29.2, 46.8, 53.6,
55.8, 84.0, 103.4, 104.0, 115.6, 116.1, 123.4, 123.6, 124.0, 124.7, 125.5,
131.1, 133.0, 136.4, 143.2, 165.2; MS (ESI): m/z (%) ¼ 364 (M þ H, 35),
396 (M þ MeOH, 100); HRMS (ESI) calcd. for C20H18N3O2S 364.1119
[M þ H]þ, found 364.1118; Anal. Calcd. for C20H17N3O2S: C, 66.10; H,
4.71; N, 11.56. Found: C, 65.96; H, 4.66; N, 11.23. The same proce-
dure was followed for the preparation of compound 1b (0.127 g,
43% yield) and compound 1c (0.110 g, 38% yield).
4.1.23. [2-Amino-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl](2S)-
2-[di(ethylsulfanyl)methyl]tetrahydro-1H-1-pyrrolylmethanone (12a)
A solution of the thioacetal protected nitro amide 11a (1.0 g,
1.93 mmol,1.0 equiv) and SnCl2$2H2O (1.30 g, 5.76 mmol, 3.0 equiv)
in methanol (20 mL) was refluxed for 1 h until TLC (EtOAc: petro-
leum ether, 1:1) indicated that reaction was complete. The solvent
was evaporated under reduced pressure and the residue was dis-
solved in ethyl acetate (20 mL) and then treated with saturated
solution of NaHCO3. The mixture was stirred for a period of 2 h and
the suspension was filtered through a short bed of celite. The
combined organic phases were evaporated under reduced pressure
to afford the corresponding amino thioacetal as dark yellow foam.
Purification of the resulting residue by column chromatography
(EtOAc) resulted a yellow sticky liquid 12a (0.518 g, 55% yield). IR
(Neat): v 3449, 3354, 2926, 2857, 1719, 1603, 1433, 1263, 1225, 1059,
4.1.27. (11aS)-8-(6-Fluoro-1,3-benzothiazol-2-yl)-1,2,3,11a-
tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (1b)
1H NMR (200 MHz, CDCl3):
d 1.96e2.42 (m, 4H, CH2), 3.51e3.96
(m, 3H, CH2, CH), 7.20e7.37 (m, 2H, Ar-H), 7.57e7.64 (dd, 1H,
J1 ¼8.08 Hz, J2 ¼ 2.20 Hz, Ar-H), 7.85e7.90 (d,1H, J ¼ 4.40 Hz, N]CH),
7.98e8.09 (m, 2H, Ar-H), 8.15e8.20 (d, 1H, J ¼ 8.81 Hz, Ar-H); MS
(ESI): m/z (%) ¼ 352 (M þ H, 10), 384 (M þ MeOH, 75); HRMS (ESI)
calcd. for C20H18FN3O2S (methyl ether of carbinolamine generated in
ESI mass spectrometer due to the reaction with methanol) 384.1140
[M þ H]þ, found 384.1143; Anal. Calcd. for C19H14FN3OS: C, 64.94; H,
4.02; N, 11.96. Found: C, 65.11; H, 3.89; N, 11.77.
1027, 831, 760 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.19e1.31 (m, 6H,
SCCH3), 1.58e2.07 (m, 3H, CH2, CH), 2.21e2.33 (m, 1H, CH),
2.58e2.84 (m, 4H, CH2), 3.57e3.69 (m, 2H, CH2), 3.89 (s, 3H, Ar-
OCH3), 4.62e4.76 (m, 2H, CH2), 4.90 (br s, Ar-NH2), 7.02e7.08 (dd,
1H, J1 ¼ 9.06 Hz, J2 ¼ 3.02 Hz, Ar-H), 7.28e7.41 (m, 4H, Ar-H),
7.88e7.93 (d, 1H, J ¼ 9.06 Hz, Ar-H); MS (ESI): m/z (%) ¼ 488
(M þ H, 10), 510 (M þ Naþ, 20), 526 (M þ Kþ, 4). The same proce-
dure was followed for the preparation of compound 12b (0.470 g,
50% yield) and compound 12c (0.488 g, 52% yield).
4.1.28. (11aS)-8-(1,3-Benzothiazol-2-yl)-1,2,3,11a-tetrahydro-5H-
pyrrolo[2,1-c][1,4]benzodiazepin-5-one (1c)
[a
]
61.538ꢀ (c 0.23, acetone); 1H NMR (200 MHz, CDCl3):
D
d
1.98e2.42 (m, 4H, CH2), 3.50e3.96 (m, 3H, CH2, CH), 7.30e7.66 (m,
4H, Ar-H), 7.85e7.90 (d, 1H, J ¼ 4.40 Hz, N]CH), 7.91e8.21 (m, 3H,
Ar-H). MS (ESI): m/z (%) ¼ 334 (M þ H, 10), 366 (M þ MeOH, 100);
HRMS (ESI) calcd. for C19H16N3OS (imine) 334.1014 [M þ H]þ, found
334.1010 and HRMS (ESI) calcd. for C20H19N3O2S (methyl ether of
carbinolamine generated in ESI mass spectrometer due to the
reaction with methanol) 366.120 [M þ H]þ, found 366.115; Anal.
Calcd. for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60. Found: C, 68.20;
H, 4.67; N, 12.44.
4.1.24. [2-Amino-4-(6-fluoro-1,3-benzothiazol-2-yl)phenyl](2S)-2-
[di(ethylsulfanyl)methyl]tetrahydro-1H-1-pyrrolylmethanone (12b)
IR (Neat): v 3446, 3345, 2925, 2852, 1736, 1616, 1450, 1330, 1253,
1155, 928, 817 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.19e1.31 (m, 6H,
SCCH3),1.56e2.09 (m, 3H, CH2, CH), 2.20e2.34(m,1H, CH), 2.56e2.81
(m, 4H, CH2), 3.54e3.70 (m, 2H, CH2), 3.89 (s, 3H, Ar-OCH3), 4.61e4.76
(m, 2H, CH2), 7.17e7.25 (m, 2H, Ar-H), 7.26e7.41 (m, 2H, Ar-H),
7.54e7.58 (dd, 1H, J1 ¼ 7.55 Hz, J2 ¼ 2.26 Hz, Ar-H), 7.95e8.01 (m,
1H, Ar-H); MS (ESI): m/z (%) ¼ 476 (M þ H, 5), 498 (M þ Naþ, 20).
4.1.29. 2-Methyl-3-nitro-N-(3,4,5-trimethoxyphenyl)benzamide
(15)
Brown solid; m.p. 168e169 ꢀC; IR (KBr): v 3463, 2970, 1740,
4.1.25. [2-Amino-4-(1,3-benzothiazol-2-yl)phenyl](2S)-2-
1439, 1368, 1215, 1117, 1006, 900 cmꢁ1; 1HNMR (300 MHz, DMSO-
[di(ethylsulfanyl)methyl]tetrahydro-1H-1-pyrrolylmethanone (12c)
IR (Neat): v 3437, 3344, 2925, 2855, 1739, 1618, 1431, 1329, 1157,
d6): d 2.51(s, 3H, Ar-CH3), 3.81(s, 3H, Ar-OCH3), 3.86( s, 6H, Ar-
OCH3), 7.42(t, 1H, J ¼ 7.93 Hz, Ar-H), 7.53 (s, 2H, Ar-H), 7.59e7.65(m,
760 cmꢁ1 1H NMR (300 MHz, CDCl3, TMS):
; d 1.19e1.45 (m, 6H,
1H, Ar-H), 7.79(d, 1H, J ¼ 7.93, Ar-H); 13C NMR (300 MHz, DMSO-
SCCH3), 1.67e2.12 (m, 3H, CH2, CH), 2.20e2.34 (m, 1H, CH),
2.59e2.85 (m, 4H, CH2), 3.56e3.70 (m, 2H), 3.89 (s, 3H, Ar-OCH3),
4.62e4.77 (m, 2H, CH2), 4.86 (br s, Ar-NH2), 7.27e7.50 (m, 5H, Ar-
H), 7.84e7.90 (d, 1H, J ¼ 7.55 Hz, Ar-H), 8.00e8.06 (d, 1H,
J ¼ 8.31 Hz, Ar-H); MS (ESI): m/z (%) ¼ 458 (M þ H, 5).
d6): d 15.0, 55.8, 60.0, 100.1, 123.4, 126.2, 126.9, 130.7, 135.0, 146.9,
150.1, 152.4, 194.7; MS (ESI): m/z (%) ¼ 347 (M þ H, 100).
4.1.30. N1-(3,4,5-Trimethoxyphenyl)-2-methyl-3-nitro-1-
benzenecarbothioamide (16)
m.p. 165e167 ꢀC; 1H NMR (200 MHz, CDCl3, TMS):
d 2.55 (s, 3H,
4.1.26. (11aS)-8-(6-Methoxy-1,3-benzothiazol-2-yl)-1,2,3,11a-
tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (1a)
Ar-CH3), 3.82 (s, 3H, Ar-OCH3), 3.86 (s, 6H, Ar-OCH3), 7.24e7.41 (m,
3H, Ar-H), 7.53 (m, 1H, Ar-H), 7.76 (m, 1H, Ar-H), 8.85 (br s, CONH);
MS (ESI): m/z (%) 363 (M þ H, 100); Anal. Calcd. for C17H18N2O5S: C,
56.34; H, 5.01; N, 7.73. Found: C, 56.43; H, 4.87; N, 7.55.
A suspension of the amino thioacetal 12a (0.45 g, 0.92 mmol, 1.0
equiv), HgCl2 (0.55 g, 2.04 mmol, 2.2 equiv), and CaCO3 (0.230 g,
2.3 mmol, 2.5 equiv) in CH3CN/H2O (4:1, 15 mL) was stirred slowly
at room temperature for a period of 18e24 h until TLC (ethyl
acetate) indicated the complete disappearance of the starting
material. The reaction mixture was diluted with ethyl acetate
(10 mL) and filtered through a short bed of celite and the filter cake
4.1.31. 5,6,7-Trimetoxy-2[2-methyl-3-nitrophenyl]benzothiazole
(17)
m.p.163e165 ꢀC; 1H NMR (300 MHz, CDCl3, TMS):
d
2.68 (s, 3H, Ar-
CH3), 3.92 (s, 3H, Ar-OCH3), 3.98 (s, 3H, Ar-OCH3), 4.11 (s, 3H, Ar-OCH3),

36
D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
7.33 (s,1H, Ar-H), 7.41e7.47 (m,1H, Ar-H), 7.82e7.88 (m, 2H, Ar-H); 13
NMR (75 MHz, CDCl3): 16.7, 56.3, 60.7, 61.5, 100.9, 125.2, 126.6,131.6,
C
4.1.38. N-Benzyl-N0-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]
urea (18b)
d
134.2, 136.1, 140.1, 146.6, 150.0, 151.8, 154.3, 165.1; MS (ESI): m/z
(%) ¼ 361 (Mþ, 100), 101 (80), 79 (35); Anal. Calcd for C17H16N2O5S: C,
56.66; H, 4.47; N, 7.77. Found: C, 56.59; H, 4.42; N, 7.73.
Benzyl isocyanate (0.066 g, 0.5 mmol) was added to a mixture
of compound 13e (0.128 g, 0.5 mmol) and Et3N (0.055 g,
0.55 mmol) in dry THF (5 mL) under N2 atmosphere at room
temperature. The reaction was stirred for 12 h at the same
temperature until the starting material had been consumed
(monitored by TLC). The solution was poured onto hexane and
filtered to get crude solid, which upon column chromatography
using EtOAc: petroleum ether, (1:2) afforded a colorless solid 18b
(0.170 g, 88% yield). m.p. 241e243 ꢀC; 1H NMR (200 MHz, DMSO-
4.1.32. 2-Methyl-3-(5,6,7-trimethoxy-1,3-benzothiazol-2-yl)aniline
(13d)
Procedure described for the synthesis of compound 12a was fol-
lowed for the syntheses of amines 13aee. m.p. 125e127 ꢀC; 1H NMR
(300 MHz, CDCl3, TMS): d 2.02 (s,1H, Ar-CH3), 2.14 (br s, NH2), 3.91 (s,
3H, Ar-OCH3), 3.96 (s, 3H, Ar-OCH3), 4.08 (s, 3H, Ar-OCH3), 6.71e6.76
(d,1H, J¼ 7.55 Hz, Ar-H), 7.01e7.11 (m, 2H, Ar-H), 7.32 (s,1H, Ar-H);MS
(ESI): m/z (%) ¼ 331 (M þ H, 100); Anal. Calcd. for C17H18N2O3S: C,
61.80; H, 5.49; N, 8.48. Found: C, 62.02; H, 5.32; N, 8.34.
d6):
d
3.88 (s, 3H, Ar-OCH3), 4.36e4.41 (d, 2H, J ¼ 5.85 Hz, Ar-CH2),
6.40e6.49 (t, 1H, J ¼ 5.85 Hz, CNHCO), 6.97e7.04 (dd, 1H, J1 ¼ 8.77,
J2 ¼ 2.19 Hz, Ar-H), 7.21e7.37 (m, 5H, Ar-H), 7.51e7.58 (d, 2H,
J ¼ 8.77 Hz, Ar-H), 7.71e7.92 (m, 4H, Ar-H), 8.52 (s, NH, Ar-NHCO);
13C NMR (75 MHz, DMSO-d6):
d 41.6, 54.0, 102.8, 113.7, 116.1, 121.3,
4.1.33. 5-(6-Methoxy-1,3-benzothiazol-2-yl)-2-methylaniline (13a)
124.6, 125.2, 125.6, 126.0, 126.7, 134.2, 138.2, 141.4, 146.7, 153.5,
155.7, 163.3; MS (ESI): m/z (%) ¼ 390 (M þ H, 85); Anal. Calcd. for
C22H19N3O2S: C, 67.84; H, 4.92; N, 10.79. Found: C, 67.76; H, 5.01;
N, 10.84.
m.p. 148e149 ꢀC; 1H NMR (300 MHz, CDCl3, TMS):
d 2.20 (s, 3H,
Ar-CH3), 3.67 (br s, NH2), 3.87 (s, 3H, Ar-OCH3), 6.99e7.09 (m, 2H,
Ar-H), 7.24e7.37 (m, 3H, Ar-H), 7.84e7.88 (d, 1H, J ¼ 9.06 Hz, Ar-H);
MS (ESI): m/z (%) ¼ 271 (M þ H,100); Anal. Calcd. for C15H14N2OS: C,
66.64; H, 5.22; N, 10.36. Found: C, 66.34; H, 5.38; N, 10.67.
4.1.39. N1-[4-(6-Methoxy-1,3-benzothiazol-2-yl)phenyl]-1-
cyclopropanecarboxamide (18c)
4.1.34. 5-(6-Fluoro-1,3-benzothiazol-2-yl)-2-methylaniline (13b)
Freshly prepared cyclopropyl carbonyl chloride (0.104 g,
1.0 mmol) dissolved in dry THF (3 mL) was slowly added to
a solution of compound 13e (0.256 g, 1.0 mmol) in dry THF (5 mL) at
0 ꢀC. The reaction was continued at room temperature for 1e2 h till
TLC showed the completion of the reaction. Solvent was evaporated
under reduced pressure and the residue was washed with water,
saturated solution of NaHCO3 and 1N HCl solution to remove the
excess unreacted starting materials. Column chromatography
afforded a pure colorless solid 18c (0.265 g, 82% yield). m.p.
m.p. 126e128 ꢀC; 1H NMR (200 MHz, CDCl3, TMS):
d 2.22 (s, 3H,
Ar-CH3), 3.70 (br s, NH2), 7.07e7.39 (m, 4H, Ar-H), 7.49e7.57 (dd,
1H, J1 ¼ 7.81, J2 ¼ 2.34 Hz, Ar-H), 7.89e7.97 (m, 1H, Ar-H). MS (ESI):
m/z (%) ¼ 259 (M þ H, 100); Anal. Calcd. for C14H11FN2S: C, 65.10; H,
4.29; N, 10.84. Found: C, 64.93; H, 4.34; N, 10.95.
4.1.35. 5-(1,3-Benzothiazol-2-yl)-2-methylaniline (13c)
m.p. 164e166 ꢀC; 1H NMR (200 MHz, CDCl3, TMS):
d 2.22 (s, 3H,
Ar-CH3), 3.72 (br s, NH2), 7.07e7.13 (d, 1H, J ¼ 7.57 Hz, Ar-H),
7.27e7.48 (m, 4H, Ar-H), 7.81e7.87 (m, 1H, Ar-H), 7.96e8.02 (d,
1H, J ¼ 7.57 Hz, Ar-H); MS (ESI): m/z (%) ¼ 241 (M þ H, 100); Anal.
Calcd. for C14H12N2S: C, 69.97; H, 5.03; N, 11.66. Found: C, 70.10; H,
5.22; N, 11.59.
249e251 ꢀC; 1H NMR (200 MHz, DMSO-d6, TMS):
d 0.74e0.85 (m,
2H, CH2), 0.95e1.06 (m, 2H, CH2), 1.69e1.84 (m, 1H, CH), 3.86 (s, 3H,
Ar-OCH3), 7.00e7.08 (dd,1H, J1 ¼8.85, J2 ¼ 2.21 Hz, Ar-H), 7.32e7.37
(d, 1H, J ¼ 2.21 Hz, Ar-H), 7.71e7.97 (m, 5H, Ar-H), 9.91 (s, 1H,
CONH); 13C NMR (75 MHz, DMSO-d6):
d 6.60, 13.8, 54.6, 103.2, 114.3,
118.3, 122.0, 126.4, 127.0, 134.9, 140.6, 147.4, 156.4, 163.8, 171.4; MS
(ESI): m/z (%) ¼ 325 (M þ H, 100); Anal. Calcd. for C18H16N2O2S: C,
66.64; H, 4.97; N, 8.64. Found: C, 66.35; H, 5.03; N, 8.75.
4.1.36. 4-(6-Methoxy-1,3-benzothiazol-2-yl)aniline (13e)
m.p. 186e188 ꢀC; 1H NMR (200 MHz, CDCl3, TMS):
d 3.88 (s, 3H,
Ar-OCH3), 6.67e6.74 (d, 1H, J ¼ 8.19 Hz, Ar-H), 6.98e7.06 (dd, 1H,
J1 ¼8.94 Hz, J2 ¼ 2.98 Hz, Ar-H), 7.28e7.32 (d, 1H, J ¼ 2.98 Hz, Ar-H),
7.79e7.89 (m, 3H, Ar-H); MS (ESI): m/z (%) ¼ 257 (Mþ1, 100); Anal.
Calcd. for C14H12N2OS: C, 65.60; H, 4.72; N, 10.93. Found: C, 65.72;
H, 4.62; N, 10.88.
4.1.40. N-(4-Fluorophenyl)-4-methylbenzanilide (19)
colourless solid; m.p. 180.5e181.5 ꢀC; IR (Neat): v 2969, 1740,
1652, 1609, 1441, 1368, 1215, 1093, 896, 826, 747, 624 cmꢁ1; 1HNMR
(300 MHz, DMSO- d6):
d 2.43 (s, 3H, Ar-CH3), 7.02 (m, 2H, Ar-H),
7.27 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.75e7.8 (m, 2H, Ar-H), 7.87 (d, 2H,
4.1.37. N,N0-Dicyclohexyl-N0’-[4-(6-methoxy-1,3-benzothiazol-2-yl)
phenyl]guanidine (18a)
J ¼ 8.87 Hz, Ar-H), 9.95 (br s, 1H, NH); 13C NMR (300 MHz, DMSO-
d6):
d 21.0, 115.0, 115.3, 122.1, 122.2, 127.6, 128.9, 131.8, 135.6, 141.6,
To a stirred solution of compound 13e (0.256 g, 1.0 mmol) in dry
THF (10 mL) (0.206 g, 1.0 mmol) 1,3-dicyclohexylcarbodiimide
(DCC), and (0.0135 g, 0.1 mmol) N-hydroxybenzotriazole (HOBt)
were added and stirred at room temperature for a period of 12 h.
TLC (5% MeOH in ethyl acetate) showed the completion of the
reaction. THF was evaporated under reduced pressure and the
residue was extracted with ethyl acetate (2 ꢂ 10 mL). The combined
organic layers were washed with brine (1 ꢂ 5 mL), dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified
by column chromatography to give a colorless solid 18a (0.346 g,
156.6, 159.8, 165.3; MS (ESI): m/z (%) ¼ 230 (M þ H, 100).
4.1.41. N-(4-Fluorophenyl)-4-methylbenzothioamide (20)
pale yellow; m.p. 166e167 ꢀC; IR (Neat): v 2970, 1738, 1435,
1366, 1216, 1093, 993, 822, 760 cmꢁ1 1HNMR (300 MHz, DMSO-
;
d6):
3’,50-Ar-H), 7.77e7.84 (m, 4H, 3,5, 2’,6’-Ar-H), 11.29 (br s, 1H, NH);
13C NMR (300 MHz, DMSO- d6):
20.8, 114.4, 114.7, 125.8, 125.9,
d
2.39 (s, 3H, CH3), 7.09 (m, 2H, 2,6-Ar-H), 7.22 (d, 2H, J ¼ 7.9Hz,
d
127.2, 128.0, 136.0, 139.5, 140.6, 157.9, 161.2, 197.6; MS (ESI) : m/z
(%) ¼ 246 (M þ H, 100)
75% yield). m.p.126e128 ꢀC; 1H NMR (200 MHz, CDCl3):
d 1.02e1.98
(m, 20H, CH2), 3.38e3.59 (m, 2H, CH), 3.89 (s, 3H, Ar-OCH3),
7.01e7.09 (dd, 1H, J1 ¼ 9.37, J2 ¼ 2.34 Hz, Ar-H), 7.22e7.30 (d, 1H,
J ¼ 8.59 Hz, Ar-H), 7.34e7.39 (d, 1H, J ¼ 2.34 Hz, Ar-H), 7.82e8.05
(m, 4H, Ar-H); MS (ESI): m/z (%) ¼ 463 (M þ H, 100); Anal. Calcd.
for C27H34N4OS: C, 70.09; H, 7.41; N, 12.11. Found: C, 69.96; H, 7.49;
N, 12.32.
4.1.42. 6-Fluoro-2-(4-methylphenyl)-1,3-benzothiazole4e (21)
Procedure described for the synthesis of compound 6a was
followed. m.p. 128e129 ꢀC; 1H NMR (300 MHz, CDCl3):
d 2.44 (s,
3H, Ar-CH3), 7.15e7.22 (m, 1H, Ar-H), 7.24e7.29 (d, 2H, J ¼ 7.55 Hz,
Ar-H), 7.52e7.56 (dd, 1H, J1 ¼ 7.55, J2 ¼ 2.26 Hz, Ar-H), 7.89e7.98
(m, 3H, Ar-H); 13C NMR (75 MHz, CDCl3):
d 21.4, 107.5, 107.9,

D. Subhas Bose et al. / European Journal of Medicinal Chemistry 50 (2012) 27e38
37
114.6, 114.9, 123.9, 127.3, 129.7, 130.6, 141.4, 150.7, 158.7, 161.9,
167.9; MS (ESI): m/z (%) ¼ 244 (M þ H, 100); Anal. Calcd for
C14H10FNS: C, 69.11; H, 4.14; N, 5.76. Found: C, 69.07; H, 4.08; N,
5.72.
6H, CH3), 2.88 (s, OH), 2.96 (s, OH), 3.70e3.87 (m, 2H, CH), 3.96e4.14
(m, 3H, CH2, CH), 4.57e4.60 (d,1H, J ¼ 3.78 Hz, CH), 4.64e4.81 (m, 2H,
Ar-CH2), 5.87e5.90 (d, 1H, J ¼ 3.78 Hz, CH), 7.17e7.25 (m, 1H, Ar-H),
7.42e7.49 (d, 2H, J ¼ 8.31 Hz, Ar-H), 7.54e7.59 (dd, 1H, J1 ¼ 7.55,
J2 ¼ 2.26 Hz, Ar-H), 7.95e8.06 (m, 3H, Ar-H); 13C NMR (75 MHz,
4.1.43. 2-[4-(Bromomethyl)phenyl]-6-fluoro-1,3-benzothiazole (22)
To a mixture of compound 21 (0.486 g, 2.0 mmol) dissolved in
ethyl acetate (15 mL) and NaBrO3 (0.60 g, 4.0 mmol) dissolved in
water (10 mL) was added drop wise a solution of NaHSO3 (0.41 g,
4.0 mmol) dissolved in water (5 mL) during a period of 15 min at
room temperature. Stirring was continued at room temperature for
a period of 4e6 h till the TLC (EtOAc: petroleum ether, 1:9) showed
completion of the reaction. Organic layer was evaporated under
reduced pressure and the solid formed in aqueous layer was back
extracted with CH2Cl2 (2 ꢂ 20 mL) treated with brine, dried over
Na2SO4 and column purified (using EtOAc: petroleum ether, 1:5) to
get a cream colored solid compound 22 (0.59 g, 92% yield). m.p.
CDCl3): d 26.2, 26.7, 64.4, 69.0, 80.0, 82.1, 82.4,105.1,107.6,108.0,111.9,
114.8,124.0,127.6,128.1,132.9,140.5,150.6,158.8,167.3; MS (ESI): m/z
(%) ¼ 462 (M þ H,100); Anal. Calcd for C23H24FNO6S: C, 59.86; H, 5.24;
N, 3.04. Found: C, 59.76; H, 5.31; N, 3.11.
4.1.46. 4-(6-Fluoro-1,3-benzothiazol-2-yl)benzoic acid (25)
H5IO6, periodic acid (1.596 g, 7.0 mmol) was dissolved in CH3CN
(15 mL) by vigorous stirring for 15e20 min at room temperature.
After complete dissolution of periodic acid, CrO3 (0.04 g,
0.0004 mmol) was added to it and stirred for 5 min. Now
compound 21 (0.486 g, 2 mmol) dissolved in CH3CN was added to
the above mixture slowly and stirring continued for 1e2 h till TLC
(ethyl acetate) showed the completion of the reaction. Organic
solvent was evaporated under reduced pressure and the resulting
solid was washed with water (2 ꢂ 10 mL) and extracted with ethyl
acetate to afford 25 as a colorless solid (0.491 g, 90% yield). m.p.
243e244 ꢀC; IR (KBr): v 2923, 2851,1681, 1292, 852 cmꢁ1; 1H NMR
115e116 ꢀC; 1H NMR (300 MHz, CDCl3):
d 4.50 (s, 2H, Ar-CH2Br),
7.16e7.30 (m, 1H, Ar-H), 7.46e7.60 (m, 3H, Ar-H), 7.89e8.06 (m, 3H,
Ar-H); MS (ESI): m/z (%) ¼ 322 (M þ H, 20), 324 (Mþ3, 20); Anal.
Calcd for C14H9BrFNS: C, 52.19; H, 2.82; N, 4.35. Found: C, 52.33; H,
3.00; N, 4.22.
(200 MHz, DMSO-d6):
d 7.24e7.36 (m, 1H, Ar-H), 7.70e7.78 (m, 1H,
4.1.44. 2-(4e(((3aR,5S,6aS)-5e((R)-2,2-Dimethyl-1,3-dioxolan-4-
yl)-2,2-dimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-6-yloxy)
methyl)phenyl)-6-fluorobenzo[d]thiazole (23)
Ar-H), 7.86e8.10 (m, 2H, Ar-H), 8.26e8.32 (m, 1H, Ar-H), 8.48 (s, 1H,
Ar-H); Anal. Calcd for C14H8FNO2S: C, 61.53; H, 2.95; N, 5.13. Found:
C, 61.59; H, 2.78; N, 5.23.
To a solution of d-glucose diacetonide (0.26 g, 1.0 mmol) in
dry CH3CN (10 mL) was added NaH 60% w/w (0.060 g, 1.5 mmol)
in portions at 0 ꢀC. After stirring for 30 min compound 22
(0.321 g, 1.0 mmol) was added and stirring was continued for
further 2e4 h at room temperature till TLC showed complete
disappearance of the starting materials. The reaction mixture
was then diluted with EtOAc (30 mL) and washed with H2O
(2 ꢂ 5 mL) and brine (1 ꢂ 10 mL). The organic layer was dried
over Na2SO4, and the solvent was evaporated under reduced
pressure. The crude product was passed through a thin layer of
silica gel chromatography using EtOAc: petroleum ether (1:3) as
eluent to afford a colorless gummy material 23 (0.446 g, 89%
4.1.47. Methyl (2S)-1-[4-(6-fluoro-1,3-benzothiazol-2-yl)benzoyl]
tetrahydro-1H-2-pyrrolecarboxylate (26)
N,N-dimethylformamide (1-2 drops) was added to a stirred
suspension of the fluoro benzothiazole acid 25 (0.273 g, 1.0 mmol)
and SOCl2 (0.177 g, 1.5 mmol) in benzene (10 mL) and the mixture
was refluxed 1e2 h till a transparent solution obtained. After
evaporation of benzene under reduced pressure, the resultant
yellow solid was dissolved in THF (10 mL) and added drop wise for
a period of 10 min to a stirred mixture of (S)-proline methyl ester
hydrochloride (0.165 g, 1.0 mmol), and Et3N (3 mL) at 0 ꢀC. The
reaction mixture was stirred at room temperature for a period of
1e2 h. After removal of the THF by evaporation under reduced
pressure, the residue was diluted with water (10 mL) and extracted
with EtOAc (3 ꢂ 5 mL). The combined organic phases were washed
with water (2 ꢂ 10 mL), sat. brine (5 mL), dried over Na2SO4 and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (ethyl acetate/hexane, 1:3; TLC:
EtOAc/hexane, 1:2) to afford the corresponding amide 26 as a low
melting colorless solid (0.315 g, 82% yield). m.p. 163e165 ꢀC;
yield). [
a
]
32.4ꢀ (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
1.24e1.53 (m, 12H, CH3), 3.94e4.14 (m, 4H, CH2, CH),
4.29e4.40 (m, 1H, CH), 4.54e4.57 (d, 1H, J ¼ 3.78 Hz, CH),
4.71e4.74 (d, 2H, J ¼ 3.02 Hz, Ar-CH2), 5.84e5.86 (d, 1H,
J ¼ 3.78 Hz, CH), 7.17e7.25 (m, 1H, Ar-H), 7.42e7.49 (d, 2H,
J ¼ 8.31 Hz, Ar-H), 7.54e7.59 (dd, 1H, J1 ¼ 7.55, J2 ¼ 2.26 Hz, Ar-
H), 7.95e8.06 (m, 3H, Ar-H); 13C NMR (75 MHz, CDCl3):
d 25.4,
26.2, 26.8, 67.5, 71.8, 72.4, 81.3, 82.0, 105.3, 107.6, 108.0, 109.1,
111.9, 114.8, 115.1, 124.0, 127.5, 128.0, 132.8, 140.9, 150.7, 162.1,
167.3; MS (ESI): m/z (%) ¼ 502 (M þ H, 100), 242 (20); Anal.
Calcd for C26H28FNO6S: C, 62.26; H, 5.63; N, 2.79. Found: C,
62.14; H, 5.34; N, 2.99.
[
d
a
]
ꢁ10.66ꢀ (c 0.2, CHCl3); 1H NMR (200 MHz, CDCl3):
D
1.77e2.43 (m, 4H, CH2), 3.50e3.73 (m, 2H, CH2), 3.81 (s, 3H,
COOCH3), 4.65e4.75 (m, 1H, CH), 7.19e7.30 (dt, 1H, J1 ¼ 8.31,
J2 ¼ 2.49 Hz, Ar-H), 7.47e7.64 (m, 1H, Ar-H), 7.67e7.76 (d, 1H,
J ¼ 8.31 Hz, Ar-H), 7.98e8.14 (m, 3H, Ar-H); 13C NMR (75 MHz,
4.1.45. (R)-1e((3aR,5S,6aS)-6-(4-(6-Fluorobenzo[d]thiazol-2-yl)
benzyloxy)-2,2-dimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-5-yl)
ethane-1,2-diol (24)
CDCl3): d 25.4, 29.3, 49.9, 52.3, 59.2, 107.7, 108.1, 115.0, 115.4, 124.3,
127.3, 128.1, 134.9, 138.4, 150.7, 159.7, 162.3, 172.6; MS (ESI): m/z
(%) ¼ 385 (M þ H, 100); Anal. Calcd for C20H17FN2O3S: C, 59.86; H,
5.24; N, 3.04. Found: C, 60.02; H, 5.22; N, 3.21.
To a stirred solution of benzothiazole glucose diacetonide 23
(0.25 g, 0.5 mmol) in excessofMeOH(15 mL) wasadded aqueous 0.8%
H2SO4 solution and stirred for overnight. TLC (EtOAc: petroleum
ether, 1:1) showed the completion of the reaction. The reaction was
quenched with triethyl amine. Methanol was evaporated under
reduced pressure and the resulting residue was washed with satu-
rated solution of NaHCO3 and extracted with ethyl acetate (3 ꢂ 5 mL).
Column chromatography using EtOAc: petroleum ether (1:2) affor-
Acknowledgments
Three of the authors (M.I., I.K.T., and N.M.J.) thank CSIR, New
Delhi, for financial support.
References
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22.9ꢀ (c 1.0, CHCl3); IR (Neat): v 2970, 1739, 1605, 1568, 1453, 1370,
1216,1072, 903, 811 cmꢁ1; 1H NMR (300 MHz, CDCl3):
1.22e1.31 (m,
a]
D
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