S-arylation of mercaptobenzimidazoles using Cu(I) catalysts - Experimental and theoretical observations

Article abstract of DOI:10.1016/j.tetlet.2011.04.078

Substituted 2-mercaptobenzimidazoles (MBI) are an important class of bio-active and industrially important organic compounds. In this Letter, a new synthetic method is presented for the selective S-arylation of MBI with substituted aryl iodides using low

Full text of DOI:10.1016/j.tetlet.2011.04.078

Tetrahedron Letters 52 (2011) 3347–3352
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
S-arylation of mercaptobenzimidazoles using Cu(I) catalysts—experimental
and theoretical observations
Ramkumar Sekar a, Marutheeswaran Srinivasan b, Antonius T. M. Marcelis c, Anandan Sambandam a,
⇑
a Department of Chemistry, National Institute of Technology, Trichy 620 015, India
b Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
c Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted 2-mercaptobenzimidazoles (MBI) are an important class of bio-active and industrially impor-
tant organic compounds. In this Letter, a new synthetic method is presented for the selective S-arylation
of MBI with substituted aryl iodides using low cost copper (I) iodide and 1,10-phenanthroline as a cata-
lytic system. The selective formation of S-arylated product was confirmed by several spectroscopic tech-
niques and the vibrational spectrum was found to be in very good agreement with the theoretical
spectrum calculated by density functional theory.
Received 14 March 2011
Revised 18 April 2011
Accepted 19 April 2011
Available online 27 April 2011
Keywords:
C–S cross coupling
MBI
Ó 2011 Elsevier Ltd. All rights reserved.
Copper (I) catalyst
Aryl iodide
DFT calculation
Substituted 2-mercaptobenzimidazole (MBI) molecules have
drawn the attention of many synthetic chemists mainly for their
wide range of biological activities (such as antiviral,1 antibacterial,2
antiulcerative,3 antifungal,4 and antitumor5) and industrial appli-
cations (such as corrosion inhibitor for copper,6 steel plating,7 anti-
oxidant for plating rubber compounds,8 and adsorbents for heavy
metal ions9). Especially, a difluoromethoxy-substituted 2-thioaryl-
benzimidazole is an interesting compound, since it is used as a gas-
tric acid secretion inhibitor.10
Several preparation methods are available in the literature for
2-thioarylbenzimidazoles.11 However, there is no facile synthetic
route for S-arylation of MBI. Generally, S-arylated benzimidazoles
may be prepared either by coupling of MBI with iodonium salts12
or by nucleophilic displacement of 2-(methylsulfonyl)-1H-benz-
imidazole with thiophenol in the presence of a base13 or by the
most often followed method, that is, reaction of N-protected
2-chlorobenzimidazoles with arylthiols.14 However, these methods
are rather unattractive, due to poor product yield (40–60%),
H
N
S
N
R
B
A
H
N
(I) CuI
SH
N
N
(II) 1,10-phenanthroline
R
SH
x
N
R = H, OCHF2
R
Scheme 1. S-arylation in MBI.
E-mail address: sanand@nitt.edu (A. Sambandam).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.078

3348
R. Sekar et al. / Tetrahedron Letters 52 (2011) 3347–3352
Table 1
CuI-catalyzed S-arylation of FMBI (entries 1–10) and MBI (entries 11–13)
Entry
Aryliodide
Producta
Time(h)
22
Yieldb (%)
H
N
I
F
S
1
84
N
F
O
H
N
I
F
S
N
F
2
24
87
O
CH
3
H
N
O
I
F
S
N
F
3
22
88
O
O
CH
3
H
N
I
F
S
N
F
O
4
5
6
24
24
22
88
89
83
CH
3
H C CH
3
3
H
N
I
I
F
S
N
F
O
I
H
N
HOOC
I
F
S
N
F
O
O
OH
H
N
I
I
F
S
N
F
O
7
24
81
I
COOH
O
N
N
8
24
72
I
F
S
F
O

R. Sekar et al. / Tetrahedron Letters 52 (2011) 3347–3352
3349
Table 1 (continued)
Entry
Aryliodide
Producta
Time(h)
30
Yieldb (%)
OH
H
N
F
S
OH
I
9
—
N
F
F
O
S
H
N
I
I
F
S
10
11
22
24
86
74
N
S
O
H
N
S
S
N
H
N
I
12
22
26
77
71
N
COOH
I
O
13
N
N
S
a
The reactions were carried out with 1.0 equiv MBI (or) FMBI, 1.0 equiv aryliodides, 5 mol % CuI, 10 mol % 1,10-phenanthroline and 2.0 equiv K2CO3.
Isolated yield after column chromatographic purification.
b
method for the synthesis of heterocyclic compounds.16 Since
sulfur-containing compounds have long been known to act as poi-
sons of catalysts, the transition metal-catalyzed C–S cross coupling
reaction is much less studied than the corresponding C–N and C–O
coupling reactions.17 In 1980, Migita et al.18 first reported C–S bond
formation using a palladium-catalyzed reaction. After that, consid-
erable progress has been made in coupling of aryl halides with thi-
ols, using Pd(0) and Ni(0) catalysts.19 However, this approach is not
attractive from an industrial perspective because Pd and Ni are
expensive and toxic.20 Later, Venkataraman21 and Buchwald22 re-
ported C–S bond formation using the less expensive CuI catalyst.
Using this catalyst, it is possible to S-arylate 2-mercaptobenzo-
thiazoles (MBT)23 through an intermolecular mechanism. How-
ever, in the case of MBI, both S-arylation and N-arylation may
take place due to the existence of two tautomeric forms (thioketo
and thiol).24 Developing a catalytic system capable of selectively
arylating the sulfur in MBI with aryl iodides through a simple pro-
cedure is, therefore, the subject of our research efforts. Interest-
ingly, Reddy et al.25 recently did not succeed to S-arylate MBI
with aryl iodides using a nano-sized indium oxide catalyst.
In this Letter we describe our successful experiments to selec-
tively S-arylate MBI with aryl iodides, using copper (I) iodide as a
catalyst with 1,10-phenanthroline as a ligand (Scheme 1). The
compounds were fully characterized with different spectroscopic
techniques (IR, NMR, MS, etc.) to confirm the structures of the
formed products. We also used theoretical calculations (Density
Functional Theory; DFT) to obtain theoretical spectra (absorbance
and IR) and compared them with experimental spectra to discrim-
inate between N- and S-arylation. Modern computational chemis-
try methods offer a unique possibility for the synthetic organic
chemist to generate optimized structures and from the structural
and electronic properties make decisions as to which chemical
transformations have occurred in the reactions under
investigation.26
Figure 1. Normalized absorption and emission spectra of compound 8. (A)
Absorption spectrum in chloroform solution. (B) Emission spectrum in chloroform
solution (kexc = 265 nm). (C) Absorption spectrum obtained from time dependent-
DFT calculations. Inset: fluorescence of a solution of 8.
lengthy protocols, commercial unavailability and stench of thi-
ophenols. Instead of using 2-chlorobenzimidazole as a precursor,
Teague et al.15 used
a reaction of 2-mercaptobenzimidazole
(MBI) with activated aryl fluorides to obtain 2-arylthio-substituted
benzimidazoles. However, this approach usually requires aryl fluo-
rides activated by electron-withdrawing groups such as nitro
groups, which limits the scope of the reaction. These limitations
have led to an increased interest in developing a transition metal
catalytic system for S-arylation of MBI with aryl halides.
Transition metal-catalyzed C–S bond formation between aryl
halides and heterocyclic compounds has evolved as an important

3350
R. Sekar et al. / Tetrahedron Letters 52 (2011) 3347–3352
N
L
I
S
CuI
HN
I
(I)
(III)
L
I
I
CuIII
L
CuIII
S
I
N
(II)
HN
N
HS
HN
Scheme 2. Possible catalytic cycle.
The subject of this study was the development of a novel, sim-
ple C–S cross-coupling methodology between mercaptobenzimida-
zole and substituted iodobenzenes using commercially available
low-cost copper catalysts. 5-Difluoromethoxy-2-mercapto-1H-
benzimidazole (FMBI) and substituted iodobenzenes were used
as the prototypical substrate combination for preliminary optimi-
zation of the reaction conditions. Among the various copper cata-
lysts available, CuI was chosen due to its good stability.22
Initially, we planned to perform the coupling reaction using CuI,
ethylene glycol and K2CO3 in isopropyl alcohol to generate the final
product, but due to the poor solubility of FMBI in isopropyl alcohol,
we replaced isopropyl alcohol by DMF. However, the yield was
very poor. Surprisingly, high yields were obtained by performing
the coupling reaction in pure DMF in the presence of CuI, K2CO3
and 1,10-phenanthroline (without ethylene glycol) at 130–140 °C
under a nitrogen atmosphere (see Table 1).27 1,10-Phenanthroline
has been found to be one of the best ligands for Cu in these kinds of
reactions.23 Its possible role is to prevent aggregation, decomposi-
tion of intermediate copper complexes, and to improve the solubil-
ity of the intermediate copper complexes.28
Using these optimized reaction conditions, the coupling reac-
tions were performed with various available substituted iodobenz-
enes and the observed product yields are generally good (>80%, see
entries 1–7). Furthermore, we found that S-arylation using 2-iodo-
benzoic acid gave a highly fluorescent cyclized compound 8 in good
yield. The structure was confirmed, among others, by the absence of
–NH peaks in its IR and 1H NMR spectra. For this cyclized compound
8, the observed experimental and theoretical absorbance spectra
are shown in Figure 1. The experimental (kmax = 268 nm) and theo-
retical (kmax = 270 nm) maxima match well. In addition, the exper-
imental emission spectrum (kem = 438 nm) for this compound is
also shown in Figure 1. S-arylation was not successful when 2-iodo-
phenol was used (see entry 9). This may be due to the nucleophilic-
ity of the –OH group29 or due to its electron-donating properties
which reduce its reactivity.23 The coupling reaction is also feasible
with 2-iodothiophene, a heterocyclic compound (see entry 10).
For comparison, we also performed the coupling reactions
with unsubstituted MBI. However, the yields of the correspond-
ing products were slightly lower (70–75%) than for the difluoro-
methoxy-substituted MBI’s (see entries 11–13). The reason for
the lower yields with unsubstituted MBI may lie in the absence
of the electron-withdrawing difluoromethoxy group at C-5.30 The
cyclized product obtained by the reaction of unsubstituted MBI
with 2-iodobenzoic acid (entry 13) also shows fluorescence
(kem = 438 nm; see also Supplementary data Fig. S1).
S- and N-arylated products. However, only the formation of S-ary-
lated products was observed. Even when the reaction time is
increased from 24 to 52 h no N-arylation of the initial S-arylated
product is observed. This can be understood from the mechanism
of the copper-assisted nucleophilic substitution reaction. This
mechanism follows three important steps; that is (I) an oxidative
addition, (II) an intermediate step in which the thiol adds to the
copper, and (III) the reductive elimination as shown in Scheme
2.31 In the intermediate step, the –SH group predominantly attacks
the copper complex as compared to the –NH, because sulfur is a
more powerful nucleophile than nitrogen due to its nature, that
is, large size, high polarizability and availability of more electron
lone pairs. Furthermore, according to Pearson’s Hard Soft Acid Base
(HSAB) principle,32 sulfur is softer as compared to nitrogen and
thus favors interaction with copper, which is a soft metal atom.
So, S-arylation will be preferred as compared to N-arylation.
In order to further confirm S-arylation, the vibrational proper-
ties of the products were investigated by a combined approach of
FTIR measurements and density functional theory (DFT) calcula-
tions, since DFT has been successfully applied earlier to the
description of the vibrational properties of many heterocyclic mol-
ecules.33 Full geometry optimization of the S- and N-arylated prod-
ucts, together with the vibrational analysis of all possible isomers
(Fig. 2) were carried out at the B3LYP/6-31G(d) level of theory
using the GAUSSIAN 03 program.34 It is important to mention here
that calculation of the selected parameters of the neutral mole-
cules in the gas phase requires much less calculation time than
in the presence of solvent molecules; however, this did not result
in significant differences between the calculated and experimental
vibrational spectra.35
The substrates FMBI and MBI may exist in two tautomeric forms
(thiol ꢀ thionine) and hence upon coupling with aryl iodides may
yield either S- or N-arylated products as shown in Scheme 1. The
calculated energies for 5- and 6-substituted S-arylated products
are ꢀ1322.1090 and ꢀ1322.1094 a.u. whereas the calculated en-
ergy for N-arylated product is ꢀ1322.1102 a.u. Generally, vibra-
tions above 3000 cmꢀ1 are assigned to –NH and aromatic –CH
stretching and vibrations at 645 and 621 cmꢀ1 are assigned to
symmetric and antisymmetric N–H out of plane bending modes.
These peaks are easily recognized in the calculated vibrational
spectra of the 5- and 6-substituted S-arylated product (Fig. 2B
and C). However, the calculated spectrum of the N-arylated prod-
uct does not show such peaks (Fig. 2A).
The calculated theoretical spectrum of the S-arylated product
matches well with the experimental vibrational spectrum (com-
pound 1). Together with the results from 1H-NMR spectra, this
clearly indicates that N-arylation is negligible and only S-arylated
We next investigated if increasing the amount of aryl iodide
from 1 to 3 equiv using the same protocol would yield both

R. Sekar et al. / Tetrahedron Letters 52 (2011) 3347–3352
3351
13. Lan, P.; Romero, F. A.; Malcolm, T. S.; Stevens, B. D.; Wodka, D.; Makara, G. M.
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16. (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (b)
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338–340.
18. Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-I.; Kato, Y.; Kosugi, M. Bull. Chem.
Soc. Jpn 1980, 53, 1385–1389.
19. (a) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D., III; Volante, R. P. J.
Org. Chem. 1998, 63, 9606–9607; (b) Zhang, Y.; Ngeow, K. N.; Ying, J. Y. Org. Lett.
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3000 3500 4000
23. Murru, S.; Ghosh, H.; Sahoo, S. K.; Patel, B. K. Org. Lett. 2009, 11, 4254–4257.
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11346–11352.
-1
Wavenumber(cm )
Figure 2. Vibrational spectra of arylated 2-mercaptobenzimidazole (entry 1): (A)
calculated infrared absorption spectrum of N-arylated product; (B and C) calculated
infrared absorption spectrum for 5- and 6-substituted S-arylated product; (D)
experimental infrared absorption spectrum. (see inserts for DFT-optimized struc-
tures of the S and N-arylated product).
25. Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697–1700.
26. Alcolea Palafox, M.; Rastogi, V. K.; Tanwar, R. P.; Mittal, L. Spectrochim. Acta,
Part A 2003, 59, 2473–2486.
27. General procedure for CuI-catalyzed coupling of aryl iodides with (F)MBI: CuI
(0.05 equiv), 1,10-phenanthroline (0.1 equiv) and K2CO3 (2 equiv) were placed
in an oven-dried screw-capped test tube with Teflon-lined septum that was
filled with nitrogen. About 2.5 mL of dry DMF was then added at room
temperature. Now the corresponding aryl iodide (1.0 mmol) was added
followed by MBI or FMBI (1.0 equiv) and the tube was placed in the
preheated oil bath at 140 °C and the reaction mixture was magnetically
stirred for 22 h. After complete disappearance of iodobenzene (the progress of
the reaction was followed by TLC), the reaction mixture was allowed to cool to
room temperature. Then water was added and the reaction mixture was
extracted with ethyl acetate. After removal of the solvent in vacuum, the crude
residue was purified by column chromatography.
product is formed and isolated in the CuI-catalyzed coupling of
(F)MBI with aryl iodides.
In summary, we have developed a useful and efficient proce-
dure for the preparation of S-arylated 2-mercapto-benzimidazoles
in good yield by a catalytic coupling reaction between (F)MBI and
substituted aryl iodides using commercially available low cost cop-
per (I) iodide with 1,10-phenanthroline as ligand. In addition to
spectroscopic evidence, DFT calculations confirmed the formation
of only S-arylated product. The synthetic method developed here
efficiently yields new compounds that may find many applications
in the fields of pharmaceutics, agrochemicals, and industrial
science.
5- (or 6-) (Difluoromethoxy)-2-(phenylsulfanyl)-1H-benzimidazole (1). Light
yellow colored solid product. 1H NMR (300 MHz, CDCl3/TMS; ppm) d 6.21 (d,
1H, J = 1.8 Hz), 6.45 (d, 1H, J = 1.5 Hz), 6.70 (d, 1H, J = 1.5 Hz), 6.97–7.00 (m,
2H); 7.12–7.25 (m, 2H), 7.35–7.42 (m, 1H); 7.45–7.48 (m, 2H); 10–13 (br s,
1H). 13C NMR (300 MHz, CDCl3; ppm) d 113.6, 115.6, 116.2, 119.7, 128.9, 129.5,
129.6, 133.0, 138.0, 146.7, 150.6. IR (KBr disc, cmꢀ1) 3438, 3062, 2984, 2888,
2786, 1879, 1628, 1427, 1383, 1280, 1176, 1124, 1041, 976, 806, 749, 688, 621,
540, 493, 443. GC–MS (EI, m/z): 293.1 [M+]. Anal. Calcd for C14H10F2N2OS: C,
57.53; H, 3.45; N, 9.58; S, 10.97. Found: C, 57.27; H, 3.52; N, 9.62; S, 10.88.
5- (or 6-) (Difluoromethoxy)-2-[(4-methylphenyl)sulfanyl]-1H-benzimidazole (2).
Brown colored oily product. 1H NMR (400 MHz, CDCl3/TMS; ppm) d 1.97 (s, 3H)
6.17 (s, 1H), 6.36 (s, 1H), 6.55 (s, 1H), 6.8–6.9 (m, 2H), 7.07 (s, 1H), 7.23 (d, 1H,
J = 8.8 Hz), 7.29 (d, 2H, J = 8.0 Hz), 9.89 (br s, 1H). 13C NMR (400 MHz, CDCl3;
ppm) d 21.46, 105.0, 112.2, 119.4, 125.2, 130.5, 130.8, 134.2, 155.3, 164.2. IR
(KBr disc, cmꢀ1) 3446, 3038, 2959, 2918, 2791, 2688, 1614, 1507, 1487, 1440,
1411, 1336, 1278, 1232, 989, 812, 736, 639, 621, 532, 488, 430. GC–MS (EI, m/
z): 307.3 [M+]. Anal. Calcd for C15H12F2N2OS: C, 58.82; H, 3.95; N, 9.14; S 10.47.
Found: C, 58.80; H, 3.88; N, 9.18; S, 10.50.
Acknowledgments
Authors thank DST, New Delhi for the major research project
(SR/S1/PC-49/2009) and also thank Dr. M. M. Balakrishnarajan for
extending support in the theoretical calculations.
5- (or 6-) (Difluoromethoxy)-2-[(4methoxyphenyl)sulfanyl]-1H-benzimidazole (3).
Dark brown colored oily product. 1H NMR (400 MHz, CDCl3/TMS; ppm) d 3.50
(s, 3H), 6.29 (s, 1H), 6.47 (s, 1H), 6.58 (d, 1H, J = 8.0 Hz), 6.93–6.96 (m, 1H), 7.17
(d, 1H, J = 4.0 Hz),7.33 (d, 1H, J = 8.0 Hz), 7.44 (d, 2H, J = 8.0 Hz), 10.49 (br s,
1H). 13C NMR (400 MHz, CDCl3; ppm) d 55.04, 105.9, 115.0, 116.5, 118.5, 136.7,
137.0, 139.6, 146.5, 153.2, 160.6. IR (KBr disc, cmꢀ1) 3420, 3075, 2943, 2780,
1888, 1670, 1628, 1591, 1492, 1443, 1402, 1343, 1289, 1255, 1176, 1130, 1029,
987, 829, 772, 646, 617, 534, 499, 439. GC–MS (EI, m/z): 323.3 [M+]. Anal. Calcd
for C15H12F2N2O2S: C, 55.89; H, 3.75; N, 8.69; S, 9.95. Found: C, 55.93; H, 3.78;
N, 8.67; S, 9.92.
2-[(4-tert-Butylphenyl)sulfanyl]-5-(or 6-) (difluoromethoxy)-1H-benzimidazole
(4). Colorless solid product. 1H NMR (300 MHz, CDCl3/TMS; ppm) d 1.26 (s,
9H), 6.21 (s, 1H), 6.46 (s, 1H), 6.71 (s, 1H), 6.96 (d, 1H, J = 1.8 Hz), 6.99 (d, 1H,
J = 1.8 Hz), 7.263 (s, 1H), 7.39 (d, 1H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz); 9.9 (br
s,1H). 13C NMR (300 MHz, CDCl3; ppm) d 31.05, 34.7, 99.6, 99.8, 103.7, 116.6,
119.7, 127.1, 128.0, 129.5, 133.0, 146.7, 150.6, 153.2. IR (KBr disc, cmꢀ1) 3436,
3028, 2960, 2862, 2796, 2695, 2358, 1624, 1465, 1428, 1389, 1352, 1267, 1183,
1127, 1034, 821, 651, 622, 556. Anal. Calcd for C18H18F2N2OS: C, 62.05; H, 5.21;
N, 8.04; S, 9.20. Found: C, 62.11; H, 5.18; N, 8.01; S, 9.15.
5- (or 6-) (Difluoromethoxy)-2-[(4-iodophenyl)sulfanyl]-1H-benzimidazole (5).
Light yellow colored solid product (yield: 89%). 1H NMR (300 MHz, CDCl3/TMS;
ppm) d 6.26 (s, 1H), 6.51 (s, 1H), 6.76 (s, 1H), 7.01–7.04 (m, 1H), 7.12–7.15 (m,
1H), 7.26 (d, 1H, J = 2.1 Hz), 7.38–7.43 (m, 1H), 7.55 (s, 1H), 9.5–11.5 (br s, 1H).
13C NMR (300 MHz, CDCl3; ppm) d 93.9, 115.7, 116.2, 119.9, 128.0, 128.6,
133.7, 137.9, 138.9, 140.9, 150.3. IR (KBr disc, cmꢀ1) 3438, 3042, 2776, 1627,
1594, 1564, 1445, 1361, 1346, 1276, 1123, 1040, 997, 948, 857, 805, 720, 668,
632, 532, 476, 432. GC–MS (EI, m/z): 418 [M+]. Anal. Calcd for C14H9F2IN2OS: C,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.078.
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40.19; H, 2.17; N, 6.70; S, 7.67. Found: C, 40.17; H, 2.20; N, 6.66; S, 7.69.
981, 850, 807, 713, 669, 646, 624, 571, 474. Anal. Calcd for C12H8F2N2OS2: C,
48.31; H, 2.70; N, 9.39; S, 21.50. Found: C, 48.29; H, 2.72; N, 9.42; S, 21.49.
4-{[5- (or 6-) (Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl}benzoic acid (6).
Colorless solid product. 1H NMR (300 MHz, CDCl3/TMS; ppm) d 6.45 (s, 1H),
6.70 (s, 1H), 6.95–7.04 (m, 1H), 7.34–7.47 (m, 2H), 7.75 (s, 1H), 7.96 (d, 2H,
J = 8.1 Hz). 13C NMR (300 MHz, CDCl3; ppm) d 94.6, 106.1, 112.8, 115.3, 115.7,
116.2, 119.7, 129.8, 134.0, 137.0, 138.4, 139.2, 146.8, 149.5, 162.6. IR (KBr disc,
cmꢀ1) 3445, 3181, 2921, 2441, 1881, 1646, 1594, 1492, 1390, 1357, 1273,
1172, 1114, 1100, 1041, 854, 803, 762, 646, 628, 513, 448. Anal. Calcd for
2-[(4-Methylphenyl)sulfanyl]-1H-benzimidazole (12). Colorless solid product. 1
H
NMR (400 MHz, CDCl3/TMS; ppm) d 2.34 (s, 3H), 7.17–7.19 (m, 4H), 7.26 (s,
2H), 7.44–7.51 (m, 2H), 10.5 (br s, 1H). 13C NMR (400 MHz, CDCl3; ppm) d 21.2,
122.4, 125.7, 130.7, 134.0, 139.9, 149.7. IR (KBr disc, cmꢀ1) 3441, 3040, 2953,
2920, 2860, 2789, 2695, 1619, 1510, 1491, 1441, 1406, 1349, 1268, 1235, 980,
804, 736, 636, 616, 527, 480, 432. Anal. Calcd for C14H12N2S: C, 69.97; H, 5.03;
N, 11.66; S, 13.34. Found: C, 69.95; H, 5.03; N, 11.69; S, 13.33.
12H-Benzo[e]benzo[4,5]imidazo[2,1-b][1,3]thiazin-12-one (13). Colorless solid
product. 1H NMR (400 MHz, CDCl3/TMS; ppm) d 7.26 (s, 1H), 7.42–7.58 (m,
3H), 7.69–7.78 (m, 2H), 8.63 (t, 2H, J = 8.0 Hz). 13C NMR (400 MHz, CDCl3; ppm)
d 116.1, 118.5, 122.7, 124.2, 125.9, 127.1, 131.4, 131.9, 132.4, 133.9, 142.5,
146.3, 171.0. IR (KBr disc, cmꢀ1) 3241, 2922, 2852, 1693, 1627, 1595, 1545,
1513, 1474, 1445, 1351, 1335, 1307, 1279, 1257, 1208, 956, 886, 745, 680, 620,
584, 557, 485, 445, 418. Anal. Calcd for C14H8N2OS: C, 66.65; H, 3.20; N, 11.10;
S, 12.71. Found: C, 66.68; H, 3.18; N, 11.14; S, 12.69.
C15H10F2N2O3S: C, 53.57; H, 3.00; N, 8.33; S, 9.53. Found: C, 53.55; H, 3.00; N,
8.37; S, 9.56.
5- (or 6-) (Difluoromethoxy)-2-[(40-iodobiphenyl-4-yl)sulfanyl]-1H-benzimidazole
(7). Colorless solid product. 1H NMR (400 MHz, DMSO-d6/TMS; ppm) d 7.05–
7.09 (m, 1H), 7.2–7.23 (m, 1H),7.35 (s, 1H), 7.42–7.58 (m, 3H), 7.62–7.65 (m,
2H), 7.73–7.8 (m, 2H), 7.84–7.9 (m, 2H), 13 (br s, 1H). 13C NMR (400 MHz,
DMSO-d6; ppm) d 94.2, 94.3, 114.2, 116.8, 119.3, 127.6, 128.6, 128.7, 132.1,
137.7, 137.8, 138.4, 138.9, 168.9. IR (KBr disc, cmꢀ1) 3437, 3061, 2788, 2705,
2598, 1902, 1590, 1470, 1385, 1287, 1175, 1114, 1042, 996, 802, 641, 622, 540,
484. GC–MS (EI, m/z): 368.4 [MꢀI]+. Anal. Calcd for C20H13F2IN2OS: C, 48.60; H,
2.65; N, 5.67; S, 6.49. Found: C, 48.56; H, 2.64; N, 5.69; S, 6.47.
28. Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657–
2660.
8- (or 9-) (Difluoromethoxy)-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]thiazin-
12-one (8). Light brown colored solid product. 1H NMR (400 MHz, CDCl3/TMS;
ppm) d 6.41 (d, 1H, J = 8.8 Hz), 6.59 (d, 1H, J = 8.0 Hz), 6.78 (d, 1H, J = 8.0 Hz),
7.20–7.30 (m, 1H), 7.50–7.58 (m, 1H), 7.69–7.74 (m, 1H), 8.43 (s, 1H), 8.56–
8.63 (m, 1H). 13C NMR (300 MHz, CDCl3; ppm) d 109.5, 116.7, 118.8, 119.1,
122.4, 126.0, 127.3, 131.4, 131.5, 132.0, 132.3, 132.4, 134.1, 159.5, 165.9. IR
(KBr disc, cmꢀ1) 3196, 2964, 2920, 2851, 1694, 1593, 1465, 1436, 1391, 1350,
1259, 1161, 1107, 1041, 804, 734, 680, 649, 612, 482, 465. GC–MS (EI, m/z):
318 [M+]. Anal. Calcd for C15H8F2N2O2S: C, 56.60; H, 2.53; N, 8.80; S, 10.07.
Found: C, 56.62; H, 2.54; N, 8.81; S, 10.10.
29. Guy, C. S.; Jones, T. C. Synlett 2009, 2253–2256.
30. Shin, J. M.; Cho, Y. M.; Sachs, G. J. Am. Chem. Soc. 2004, 126, 7800–7811.
31. (a) Cohen, T.; La, J. W.; Dietz, A. G. Tetrahedron Lett. 1974, 40, 3555–3558; (b)
Lindley, J. Tetrahedron 1984, 40, 1433–1456; (c) Rout, L.; Saha, P.; Jammi, S.;
Punniyamurthy, T. Eur. J. Org. Chem. 2008, 4, 640–643.
32. Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533–3539.
33. Bohlig, H.; Ackermann, M.; Billes, F.; Kudra, M. Spectrochim. Acta, Part A 1999,
55, 2635–2646.
34. (a) GAUSSIAN 03. Frisch, M. J. et al. Gaussian, Inc., Pittsburgh, PA, 2003. (a) B3LYP
is Becke’s three parameter hybrid method with LYP correlation functional.; (c)
Stevens, P. J.; Devlin, F. J.; Chablowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98,
11623–11627; (d) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B. 1988, 37, 785–789;
(e) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211.
35. Rodriguez-Valdez, L. M.; Villamisar, W.; Casales, M.; Gonzalez-Rodriguez, J. G.;
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4053–4064.
5- (or 6-) (Difluoromethoxy)-2-(thiophen-2-ylsulfanyl)-1H-benzimidazole (10).
Colorless solid product. 1H NMR (400 MHz, CDCl3/TMS; ppm) d 6.48 (s, 1H),
6.66 (s, 1H), 6.85–6.88 (m, 1H), 6.99–7.02 (m, 1H), 7.22–7.26 (m, 1H), 7.34–7.4
(m, 2H), 9.83 (br s, 1H). 13C NMR (400 MHz, CDCl3; ppm) d 106.2, 115.0, 115.6,
116.3, 118.9, 124.7, 128.2, 132.9, 136.9, 137.7, 146.7, 151.6. IR (KBr disc, cmꢀ1
)
3440, 3080, 2850, 2789, 1626, 1588, 1486, 1398, 1352, 1284, 1176, 1125, 1041,