Photocatalysis by 3,6-disubstituted-s-tetrazine: Visible-light driven metal-free green synthesis of 2-substituted benzimidazole and benzothiazole

Article abstract of DOI:10.1021/jo401445j

s-Tetrazine based molecules were prepared for visible-light-driven organic transformations. The 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) derivative shows visible light absorption and reversible one-electron reduction behavior. In the presence of pytz and aerial oxygen, aldehyde reacts with o-phenylenediamine or o-aminothiophenol under visible light irradiation at ambient temperature to produce corresponding 2-substituted benzimidazoles and benzothiazoles, respectively. Pytz catalyst demonstrates excellent catalytic activity for alkyl, aryl, organo-metallic substituted aldehydes and reducing sugar. The reaction yield is high for both the electron-donating and electron withdrawing substituents in aromatic aldehydes. The use of a metal-free catalyst and visible light energy, along with the mild reaction conditions, makes this reaction an environmentally benign and energy-saving chemical process.

Full text of DOI:10.1021/jo401445j

Article
pubs.acs.org/joc
Photocatalysis by 3,6-Disubstituted‑s‑Tetrazine: Visible-Light Driven
Metal-Free Green Synthesis of 2‑Substituted Benzimidazole and
Benzothiazole
Suvendu Samanta, Sudipto Das, and Papu Biswas*
Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103, West Bengal, India
S
* Supporting Information
ABSTRACT: s-Tetrazine based molecules were prepared for visible-light-
driven organic transformations. The 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz)
derivative shows visible light absorption and reversible one-electron
reduction behavior. In the presence of pytz and aerial oxygen, aldehyde
reacts with o-phenylenediamine or o-aminothiophenol under visible light
irradiation at ambient temperature to produce corresponding 2-substituted
benzimidazoles and benzothiazoles, respectively. Pytz catalyst demonstrates
excellent catalytic activity for alkyl, aryl, organo-metallic substituted aldehydes
and reducing sugar. The reaction yield is high for both the electron-donating
and electron withdrawing substituents in aromatic aldehydes. The use of a
metal-free catalyst and visible light energy, along with the mild reaction
conditions, makes this reaction an environmentally benign and energy-
saving chemical process.
dabigatran, H1 receptor antagonist mizolastin, and anthelmintic
agent such as albendazole, mebendazole, etc. (Supporting
Information Figure S1). On the other hand, benzothiazole rings
are found in the sodium-channel blocker riluzole, aldol reductase
inhibitors IDD552, and cationic trypsin precursor RWJ-51084
(Supporting Information Figure S1). They are also showing
interesting utility in dyes,20 chemosensing,21 and corrosion
science22 as well as in advanced material science such as nonlinear
optics (NLO),23 organic light-emitting diodes (OLED),24 and
liquid crystals.25
INTRODUCTION
■
In recent times, energy issues have become so important that
many scientific investigations have sought the development
of new sustainable energy resources.1 The use of solar energy is
the most useful alternative sustainable energy source as its
abundance is “virtually unlimited” and free. It is also well
known that solar light contains 43% visible light.2 So, the use of
visible light to drive organic reactions provides an energetically
beneficial pathway for green synthesis.3 Although most com-
mon organic molecules do not absorb light in the visible region,
through photosynthesis, nature has shown us the use of various
visible light absorbing chromophores for conversion of the
solar energy to chemical energy. This inspires the scientific
communities to apply visible light in organic synthesis. The
recent works on photoredox catalysis by MacMillan and
Nicewicz,4 Yoon,5 and the Stephenson6 group have attracted
significant attention in this field. Numerous new exciting visible
light photochemical processes sensitized by polypyridyl metal
complexes, organic dye, or mpg-C3N4 photoredox catalysts
have been reported since then.7
Among N-containing heteroaromatic compounds, benzimi-
dazole, benzothiazole, and its derivatives are vital core struc-
tures used to create drugs and materials. They exhibit biological
activities such as anticancer,8 antiulcer,9 antihypertensive,10
antibacterial,11 enzyme inhibition,12 antitumor,13 antipara-
sitics,14 and anticonvulsive ones.15 Benzimidazole derivatives
also exhibit significant activity against several viruses such as
HIV,16 herpes (HSV-1),17 RNA,18 influenza,19 and human cyto-
megalovirus (HCMV).16 Drugs having a benzimidazole ring
include proton-pump inhibitors (omeprazole), AT1 receptor
antagonists (candesartan, telmisartan), direct thrombin inhibitor
Typically, the synthesis of these 1,3-benzazole scaffolds
involves the treatment of 1,2-phenylenediamine or o-amino-
thiophenols either with carboxylic acids under strongly acidic
conditions or with aldehydes under oxidative conditions.
Several oxidative and catalytic reagents, 1,4-benzoquinone,26
PhI(OAc)2,27 heteropoly acids,28 thionyl chloride-treatment,29
H2O2/HCl,30 iodine,31 air/dioxane,32 sulfamic acid,33 FeCl3·
6H2O,34 In(OTf)3,35 Yb(OTf)3,36 Sc(OTf)3,37 Cu(OTf)2,38
KHSO4,39 ionic liquids,40 (bromo dimethyl) sulfoniumbro-
mide,41 ZrOCl2·8H2O,42 HfCl4,43 copper complex,44 polymer-
supported hypervalent iodine,45 TsOH/graphite and N,N-
dimethylaniline/graphite,46 cobalt(III) salen complex on
activated carbon,47 cobalt(II) chloride hexahydrate,48 VO-
(acac)2-CeCl3 combo catalyst,49 gold/CeO2,50 nanoporous
aluminosilicate AlKIT-5,51 Co(OH)2/CoO(II),52 and CuO-
53
np/SiO2 have been employed as catalysts for the synthesis
of benzimidazoles from various aldehydes. In the literature,
various reagents and catalysts have also been reported for the
Received: July 4, 2013
Published: October 17, 2013
© 2013 American Chemical Society
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synthesis of 2-substituted benzothiazoles involving the
condensation of o-aminothiophenols with substituted aldehydes
such as I2,54 TMSCl,55 H2O2,56 H2O2/Fe(NO3)3,57 Dowex
50W,58 ionic liquids59 under microwave irradiation, silica gel,60
Sc(OTf)3,61 PEG 400,62 H2O2/CAN,63 trichloroisocyanuric
acid (TCCA),64 and NH4Cl.65
(because of a low-lying π* orbital leading to a n−π* transition
in the visible region) and electroactive heterocycles that dis-
play a very high electron affinity,70 which makes them easily
reducible (actually they are the electron poorest C−N
heterocycles). These molecules have been widely used as
dienes in inverse electron demand Diels−Alder reactions,71 and
to develop nitrogen-rich energetic materials.72 Photophysical
properties of some substituted tetrazines with a high
fluorescence quantum yield and good chemical and photo-
chemical stability have also been thoroughly investigated.73−76
s-Tetrazines have a strong electron-deficient character. Thus, s-
tetrazines substituted by heteroatoms73,75,77 and aromatics78
can be reduced easily in organic solvents to accept one electron
to give an anion radical. This reducing nature of the s-tetrazines
is even more pronounced for the first excited state, which
therefore has a relatively strong oxidizing power. Consequently,
s-tetrazines interact with various electron donor substrates at an
excited state.
Considering the visible light absorption behavior and revers-
ible one-electron reduction properties, we have synthesized 3,6-
di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) and 3,6-diphenyl-
1,2,4,5-tetrazine (phtz)70a,78,79 and applied to the photo-
catalytic synthesis of 2-substituted benzimidazoles and
benzothiazoles from different aldehydes. The optical and
electrochemical properties of the pytz molecule were studied
by UV−vis absorption spectroscopy and cyclic voltammetry.
Pytz exhibits maximum absorption peaks at 535 nm (ε =
235 M−1 cm−1, Figure 2a) and a quasi-reversible reduction peak
(ΔE1/2 = 90 mV) at 160 mV in ethanol (Figure 2b). On the
other hand, phtz shows absorption maxima at 550 nm (ε =
660 M−1 cm−1, Supporting Information Figure S1a) and a
quasi-reversible reduction peak (ΔE1/2 = 225 mV, Supporting
Information Figure S1b) at −385 mV in ethanol. These results
clearly demonstrate that presence of two pyridine rings makes
tetrazine moiety highly electron deficient, hence, facilitating
easy reduction of tetrazine ring.
Although the reaction was efficiently carried out by the above
catalysts or reagents, some of these methods suffer from one or
more disadvantages, such as usage of stoichiometric or larger
quantity of reagent, high cost of the catalysts, prolonged reaction
times, occurrence of side reactions, severe reaction conditions,
and strong oxidizing nature of the reagents and the protocol often
involved metal salts, which are toxic toward our environment.
Especially, the preparation of substituted benzimidazole and
benzothiazoles under metal-free conditions is highly desirable
for pharmaceutical purposes due to the low threshold residual
tolerance of metals. Therefore, the investigation to search for mild
and practicable, stable, cheap, and eco-friendly green synthetic
methods of 2-substituted benzimidazoles and benzothiazoles
continues to attract the attention of researchers. Recently,
Nguyen et al. reported66 green synthesis of 2-substituted
benzimidazoles from benzylamines in the presence of O2 and
acetic acid. An efficient method for synthesis67 of the 2-substituted
benzothiazoles from variety of aldehydes has been developed in
presence of [Ru(bpy)3Cl2], O2, and visible light irradiation.
In our continuous effort to exploit visible light to synthesis
azole based heterocycles,68 herein we report simple, efficient,
and eco-friendly synthesis of 2-substituted benzimidazoles and
benzothiazoles at ambient temperature from various alkyl and
aryl aldehydes under visible light irradiation using 3,6-
di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) as catalyst (Figure 1).
Initial attempts to optimize the reaction conditions for the
synthesis of 2-substituted benzimidazoles, were performed with
benzaldehyde as a model substrate in the presence of pytz,
o-phenylenediamine and solvents (Table 1). In a typical experi-
ment, a mixture of o-phenylenediamine (1 mmol) and ben-
zaldehyde (1 mmol) in 20 mL ethanol (EtOH) was irradiated
under visible light in presence of 1 mg (0.0042 mol %) catalyst
for 1−3 h. The effect of reaction time, solvent and amount of
Figure 1. s-Tetrazines exploited for the synthesis of 2-substituted
benzimidazole and benzothiazole from various aldehydes.
RESULTS AND DISCUSSION
■
The first synthesis of the s-tetrazines was reported by Pinner69
at the end of the 19th century. s-Tetrazines are highly colored
Figure 2. UV−vis absorption spectra (a) and cyclic voltammogram (CV) (b) of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) in ethanol. Scan rate for
cyclic voltametic measurement is 50 mVs−1.
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ability of pytz to drive the selectivity toward 2-substituted
product.
Table 1. Optimization of Reaction Conditions for the
Synthesis of 2-Substituted Benzimidazole
a
This reaction meets many of the requirements of green
chemistry: (a) a very low E-factor80 was achieved because
minimal waste is generated; (b) high atom-economy is
achieved; (c) the reaction is driven by visible light and occurs
at ambient temperature; (d) the reaction uses molecular oxygen
from air as the oxidant; (d) a nonmetal, cheap, and a relatively
small quantity of s-tetrazine is used as the catalyst; (f) the
reaction uses environmentally benign ethanol as the solvent
that is easily recycled during workup.
time
(h)
amount of catalyst
(mg)
yield
(%)
b
c
entry catalyst solvent
TON
1
pytz
pytz
pytz
pytz
pytz
pytz
pytz
pytz
pytz
pytz
pytz
pytz
phtz
pytz
EtOH
EtOH
EtOH
EtOH
EtOH
2.0
2.0
2.0
1.0
3.0
2.0
2.5
2.5
2.0
2.5
3.0
2.0
2.0
2.0
2.0
2.0
1.0
2.0
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
90
90
90
60
90
80
30
30
60
30
10
40
40
00
212
106
70
2
3
4
141
212
189
71
With the optimized protocol, we next set out to explore the
scope and limitation of the reaction (Table 2). In order to get
an insight into the effect of starting materials on the yield of
2-substituted benzimidazole, several substituted aldehydes
including aromatic, heteroaromatic, and aliphatic groups were
used as the starting materials; the results are listed in the
Table 2. Most of the aldehydes gave excellent yields over 80%
and the highest yield of 95% was obtained in the case of
salicyldehyde as a starting material (entry 2), while the rela-
tively lower yield of 60% was obtained in the case of hetero-
cyclic aldehyde, 2-pyridine carboxaldehyde (entry 9). Other
heterocyclic aldehydes such as 2-thiophene-carboxaldehyde,
furfuraldehyde, and 3H-imidazole-4-carbaldehyde exhibit even
poorer yields. The reaction was also investigated for both the
electron-donating or electron-withdrawing substituents in the
aromatic ring. The experimental results show that reaction
yield is excellent (>90%) for both the electron-donating and
electron-withdrawing aromatic substituents. This protocol is
also highly efficient for the ferrocenecaboxaldehyde (entry 14).
The catalytic TONs and TOFs obtained in the synthesis of
different benzimidazole were found to be moderately high.
Encouraged by these results, we further studied to expand
the synthetic scope of this protocol and carried out the reaction
using o-aminothiophenol for the synthesis of 2-substituted
benzothiazole. The effect of reaction time, solvent, and amount
of catalyst on the reaction was again evaluated thoroughly.
Interestingly, solvent and amount of catalyst for the reaction
remain same but reaction proceeds within much lower time
(20−30 min).
To study the generality of this protocol for the synthesis of
2-substituted benzothiazole, a variety of aromatic, heterocyclic,
and aliphatic aldehydes with various substitution patterns were
reacted with o-aminothiophenol under the optimized con-
ditions to give 2-substituted benzothiazole. As can be seen from
Table 3, most of the substrates afforded good yields of the
corresponding 2-substituted benzothiazole. In general, the
aromatic aldehydes containing electron-donating as well as
electron-withdrawing substituent exhibit excellent yield as well
as TON, and TOF (Table 3, entries 1−8 and 10−12). Pyridine
2-carboxaldehyde (Table 3, entry 9) was not very suitable for
this transformation, giving low yield. Further investigation
indicates that aliphatic aldehydes are also suitable for this
reaction (Table 3, entries 13−15). Interestingly, the tereph-
thalaldehyde selectively gave the 4-benzothiazole-yl-benzalde-
hyde (entry 11) as product in excellent yield and selectivity
when the reaction was carried out in ethanol medium irrespec-
tive of ratio of aldehyde and o-aminothiophenol due to lower
solubility of 4-benzothiazole-yl-benzaldehyde in ethanol. On
the other hand, when the reaction was carried out in tetra-
hydrofuran medium, exclusively phenyl-1,4-dibenzothiazole
(entry 12) was formed. So, this protocol might be useful for
5
6
MeOH
THF
7
8
CH3Cl
CH2Cl2
CH3CN
DMF
71
9
141
71
10
11
12
13
14
15
16
24
DMSO
EtOH
EtOH
EtOH
EtOH
94
94
d
e
f
00
pytz
1.0
90
212
a
Reaction Conditions: benzaldehyde (1 mmol), o-phenylenediamine
(1 mmol). 20 mL of solvent used for all reactions. The moles of 2-
substituted benzimidazole formed per mol catalyst. Reaction carried
out in absence of visible-light (dark). Reaction carried out without
any catalyst but in presence of visible-light. Reaction Conditions:
benzaldehyde (2 mmol), o-phenylenediamine (1 mmol).
b
c
d
e
f
catalyst on the reaction was evaluated thoroughly. The op-
timum reaction conditions are 2 h and in presence of 1 mg
catalyst in ethanol. Further prolonging the reaction time or
increasing the amount of catalyst will not improve the yield of
the reaction. The solvent has a prominent influence on the
yield (Table 1). The experimental results show that ethanol is a
good solvent with above 90% yield. (Table 1, entries 1−5).
However, tetrahydrofuran (entry 7), chloroform (entry 8),
dichloromethane (entry 9), acetonitrile (entry 10), dimethyl
formamide (entry 11), and dimethyl sulfoxide (entry 12) are
not suitable for the reaction and methanol (entry 6) show
moderately high yield. To ascertain that visible light is
necessary (as shown in proposed mechanism later on) for the
reaction to proceed, a control reaction was carried out in the
dark in presence of pytz. In absence of visible light, pytz shows
no catalytic activity (entry 14), which clearly demonstrates the
role of visible light in this reaction. Similarly, a control reaction
in the absence of pytz did not proceed under identical condi-
tions (entry 15). To compare catalytic activity of the 3,6-
di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) with the 3,6-diphenyl-
1,2,4,5-tetrazine (phtz), we have also investigated the catalytic
activity of phtz under identical conditions (entry 13). Phtz
shows much inferior activity.
Although the reaction of o-phenylenediamine with aldehydes
in the presence of various catalysts has been exploited to build
the benzimidazole scaffold, the issue of selectivity still remains
critical due to the competitive formation of 1,2-disubstituted
and 2-substituted benzimidazoles. It can be observed that
current protocol is completely selective toward formation of
2-substituted benzimidazole with excellent yield. The use of
2 equiv of benzaldehyde also afforded 2-substituted benzimi-
dazole (Table 1, entry 15) as the sole product and indicated the
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a
Table 2. Scope of the 3,6-Di(pyridin-2-yl)-1,2,4,5-s-tetrazine Catalyzed Synthesis of the 2-Substituted Benzimidazoles
a
b
c
Reaction Conditions: aldehyde (1 mmol), o-phenylenediamine (1 mmol), 1 mg catalyst, ethanol 20−30 mL. Isolated yield after purification. The
d
moles of 2-substituted benzimidazole formed per mol catalyst. Rate of the formation of 2-substituted benzimidazole per mol catalyst per unit time.
e
o-Phenylenediamine (2 mmol).
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a
Table 3. Scope of the 3,6-Di(pyridin-2-yl)-1,2,4,5-s-tetrazine Catalyzed Synthesis of the 2-Substituted Benzothiazoles
a
b
c
Reaction Conditions: aldehyde (1 mmol), o-aminothiophenol (1 mmol), 1 mg catalyst, ethanol 20−30 mL. Isolated yield after purification. The
d
moles of 2-substituted benzothiazole formed per mol catalyst. Rate of the formation of 2-substituted benzothiazole per mol catalyst per unit time.
e
Solvent: Tetrahydrofuran, o-aminothiophenol (2 mmol).
the selective synthesis of mono- or di-benzothiazole from
dialdehyde.
Another interesting aspect of our protocol is the synthesis of
2-[(D-gluco-1,2,3,4,5-pentahydroxyl)pentyl]-1H-benzimidazole
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Scheme 1. Synthesis of 2-[(D-Gluco-1,2,3,4,5-pentahydroxyl)pentyl]-1H-benzimidazole and 2-[(D-Gluco-1,2,3,4,5-
pentahydroxyl)pentyl]-benzothiazole from D-Glucose
(entry 15, Table 2) or benzothiazole (entry 16, Table 3) from
D-glucose. Synthesis of sugar-based benzimidazoles was first
reported more than one hundred years ago by Griess and
Harrow through condensation of D-glucose and o-phenylenedi-
amine in the presence of hydrochloric acid to afford the open
chain sugar derivative as the minor product, and in fact it was
the first report for synthesis of benzimidazoles.81 Several syn-
thetic routes for the preparation of various aldo-benzimidazoles
have been achieved in the intervening years.82 We describe
herein an improved protocol for the synthesis of benzimidazole
and benzothiazole by direct condensation of D-glucose, with
o-phenylenediamine in the presence visible light and pytz
catalyst in neutral medium (Scheme 1). We are also currently
exploring the scope of this protocol for the synthesis of various
aldo-benzimidazoles by direct oxidative condensation of aldoses,
including mono-, di-, and trisaccharides, with o-phenylenediamines
in the presence of pytz and visible light.
under the same condition and found that the efficiency of the
catalyst remains the same. It can also be seen that for those
aldehydes that formed imine readily, the reaction time is
shorter and the yield is relatively much higher (Table 2 and
Table 3). On the other hand, for aldehydes that do not form
imine easily, (heterocyclic and aliphatic aldehydes), the reac-
tion time is relatively longer with moderate yield. Now, upon
irradiation, pytz gets excited to pytz*, which is reductively
quenched by imine intermediate 1 to produce pytz radical
anion and monoaldimine radical cation 2 via single electron
transfer oxidation. The radical cation 2 then yields another
radical species 3 after deprotonation. Now, intramolecular
nucleophilic attack on CN carbon atom takes place, followed
by regeneration of the catalyst pytz through oxidation. Sub-
sequent proton uptake produces hydrogenated cyclized inter-
mediate 5. Then, oxidative dehydrogenation by air leads to
desired benzimidazoles or benzothiazoles.
To confirm the role of O2 (air) in this process, a reaction was
run with benzaldehyde and o-aminothiophenol under inert
atmosphere in the presence of pytz and visible light. The
compound that got isolated under inert atmosphere is highly
unstable84 in the presence of air, even in the solid state, and
quickly got converted into the corresponding benzothiazole.
The FT-IR spectrum of this compound was obtained within a
very short time (to avoid interaction with O2) and compared
with the spectrum of pure 2-phenyl benzothiazole. From the
FT-IR spectrum (Supporting Information Figure S2) it is
evident that the product isolated under inert atmosphere
exhibits a strong peak at around 2950 cm−1 due to N−H
stretching.84 This peak is absent in pure 2-phenyl benzothiazole
(Supporting Information Figure S2).
To obtain more insight into the reaction process, we move
toward the mechanism of the pytz-catalyzed synthesis of
2-substituted benzimidazole or benzothiazole and Scheme 2
Scheme 2. Proposed Reaction Mechanism
To prove the radical intermediate, we have carried out the
same reaction in the presence of the radical inhibitor TEMPO
(Table 2, entry 1 and Table 3, entry 1). It results in a drastic
decrease in the yield of the corresponding benzimidazole or
benzothiazole, suggesting the possibility of a radical inter-
mediate. Scheme 2 shows the plausible reaction mechanism.
CONCLUSION
■
In conclusion, the present procedure using an easily available
s-tetrazine, pytz provides a very simple and efficient methodology
for the synthesis of 2-substituted benzimidazoles or benzothia-
zoles from aldehydes under visible light irradiation. This pro-
cedure also shows excellent yields, selectivity toward 2-substituted
benzimidazoles, and does not produce unnecessary waste. Most
importantly, the use of renewable resources, such as visible
light, air, and an environmentally benign solvent in a highly
atom-economical and energy-efficient manner, adheres well to
the principles of green chemistry. 3,6-Di(pyridin-2-yl)-1,2,4,5-
tetrazine (pytz) absorbs visible light and undergoes one elec-
tron quasi-reversible reduction at a positive potential. After
considering these results, a possible mechanism of this catalytic
system is provided. We believe that the strategy of using
illustrates a plausible reaction pathway for this reaction. Audebert
and others have reported that s-tetrazines have a strong oxidizing
power in their ground state which is more pronounced in their
first excited state.70 They even demonstrated that fluorescence of
the fluorescent tetrazines are quenched by various electron
donors. They also utilized this phenomenon for the fluorimetric
sensing of amines by silica nanoparticles grafted on their surface
with tetrazine dyes.83
Primarily, we investigated whether the imine intermediate is
formed prior to formation of benzimidazole or benzothiazole.
We have carried out the reaction with preformed imine (mono-
aldimine intermediate in case of benzimidazole) compound
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2-(1H-Benzoimidazol-2-yl)-5-chlorophenol (Table 2, Entry 6). Off-
white solid (219 mg, 90%), mp 305−306 °C. H NMR (500 MHz,
DMSO-d6) δH 13.275 (s, 2H), 8.173 (d, 1H, J = 8.5 Hz), 7.685 (s,
1H), 7.416 (dd, 1H, J = 2.5, 6.5, and 2.5 Hz), 7.309 (d, 2H, J = 8.5
Hz), 7.078 (d, 1H, J = 8.5 Hz).
organic molecules that absorb visible light can be expanded to
the utilization of solar energy in various metal-free catalytic
methodologies in organic synthesis and chemical industry.
1
EXPERIMENTAL SECTION
2-(1H-Benzo[d]imidazol-2-yl)-5-bromophenol (Table 2, Entry 7).
Off-white solid (249 mg, 87%), mp 300−302 °C. 1H NMR (500 MHz,
DMSO-d6) δH 13.28 (s, 2H), 8.28 (t, 1H, J = 1 and 2 Hz), 7.71 (s,
2H), 7.61 (d, 1H), 7.52−7.50 (m, 2H), 7.28 (d, 2H, J = 10 Hz), 7.01
(dd, 1H, J = 1.5, 9.5, and 1 Hz).
2-{4-[2-(4-tert-Butyl-phenyl)-vinyl]-phenyl}-1H benzimidazole
(Table 2, Entry 8). White solid (323 mg, 92%), mp 375−377 °C.
Anal. Calcd for C215H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.23;
H, 6.89; N, 7.92. H NMR (300 MHz, DMSO-d6) δH 12.83 (s, 1H),
8.09 (d, 2H, J = 8.1 Hz), 7.68 (d, 2H, J = 8.4 Hz), 7.47 (d, 3H, J =
8.4), 7.32 (d, 2H, J = 8.4 Hz), 7.26 (s, 1H), 7.21 (s, 1H), 7.14−7.10
(m, 3H), 1.20 (s, 9H). 13C NMR (75 MHz, DMSO-d6) δC 151.5,
151.0, 139.1, 134.5, 129.9, 129.3, 127.3, 127.2, 126.8, 126.0, 34.8, 31.5.
LC−MS (ESI+): m/z = 353.00, [100%, MH+]; Calcd for C25H25N2:
353.20.
■
General Methods. Solvents were purified according to standard
methods prior to use, while all other substances and reagents used
were commercially available and used as received. The synthesis of 3,6-
di(pyridin-2-yl)-1,2,4,5-s-tetrazine (pytz) and 3,6-diphenyl-1,2,4,5-
tetrazine (phtz) were carried out following the method reported
earlier.70a,78,79 A Xenon lamp with a power of 300 W equipped with a
cutoff filter (λ > 420 nm) was used as a visible light source. The
reaction was carried out in a 100 mL double-walled quartz beaker flask
having water inlet and outlet to maintain the room temperature of the
1
reaction vessel. H NMR spectra were recorded using 300, 400, and
500 MHz NMR spectrometers, and 13C NMR spectra were measured
1
using a 75 MHz spectrometer. All H data were reported in parts per
million (ppm) relative to tetramethylsilane (δH = 0) in the deuterated
solvents. LC−MS were obtained from a liquid chromatography instru-
ment equipped with a mass-selective detector. All GC analyses were
performed on a GC system with an FID detector using a J & W HP−5
column (30 m, 0.32 mm internal diameter) and n-decane as the
internal standard. High-resolution mass spectra were recorded using
ESI ionization method with quadrupole time-of-flight MS systems.
Cyclic voltammetric (CV) measurement was carried out with a three-
electrode assembly comprising glassy carbon working electrode, a
platinum auxiliary electrode, and an aqueous Ag/AgCl reference elec-
trode. The concentration of the supporting electrolyte tetramethy-
lammonium perchlorate (TEAP) was 0.1 M, while that of the complex
was 1 mM. Under the given experimental conditions, the potential of
the external standard ferrocene/ferrocenium (Fc/Fc+) couple was
measured at +0.400 V vs Ag/AgCl. Elemental (C, H, N, and S)
analyses were performed on an elemental analyzer (Perkin−Elmer
2400 II). Melting points were determined in open capillaries and are
uncorrected.
2-(Pyridin-2-yl)-1H-benzo[d]imidazole (Table 2, Entry 982). White
solid (117 mg, 60%), mp 220−222 °C. 1H NMR (400 MHz, DMSO-
d6) δH 8.679 (d, 1H, J = 4.4 Hz), 8.862 (d, 2H, J = 8.0 Hz), 7.964 (t,
1H, J = 8.0 and 7.6 Hz), 7.628 (dd, 2H, J = 3.2, 2.4, and 3.2 Hz), 7.484
(t, 1H, J = 5.6 and 6.4 Hz), 7.235 (dd, 1H, J = 3.2, 2.8, and 3.2 Hz).
2-(Anthracen-9-yl)-1H-benzo[d]imidazole (Table 2, Entry 1040).
Off-white solid (264 mg, 90%), mp 262−263 °C. 1H NMR (500 MHz,
DMSO-d6) δH 8.825 (s, 1H), 8.51 (d, 2H, J = 10.5 Hz), 7.70 (s, 2H),
7.62 (d, 2H, J = 11 Hz), 7.55 (t, 2H, J = 8 and10 Hz), 7.50 (t, 2H, J =
9 and 9.5 Hz), 7.31 (dd, 2H, J = 3.55 and 4 Hz).
1H-Benzo[d]imidazole (Table 2, Entry 1285). White solid (88.5 mg,
1
75%), mp 170−172 °C. H NMR (300 MHz, DMSO-d6) δH 12.52
(br, 1H), 8.25 (s, 1H), 7.64−7.58 (m, 2H), 7.22−7.26 (m, 2H). LC−
MS (ESI+): m/z = 119.10, [100%, MH+]; Calcd for C7H7N2: 119.06.
2-Methyl-1H-benzo[d]imidazole (Table 2, Entry 1386). White solid
1
(102 mg, 78%), mp 174−176 °C. H NMR (400 MHz, CDCl3) δH
General Experimental Procedure for the Synthesis of
2-Substituted Benzimidazole. A mixture of aldehyde (1 mmol,
1 equiv), o-phenylenediamine (1 mmol, 1 equiv), and catalyst
(0.00423 mmol, 1 mg) was taken in a 100 mL double-walled quartz
beaker having water inlet and outlet to maintain the temperature of the
reaction vessel in ethanol (20 mL). The beaker was exposed to visible
light under stirring condition and was allowed to proceed for 2−3 h.
The progress of the reaction was monitored by TLC or gas chro-
matography. After completion of the reaction, solvent was evaporated
at reduced pressure and the product was dissolved in minimum
volume of ethyl acetate. The solvent was concentrated in vacuo and
purified by column chromatography using silica gel (hexane/EtOAc)
to get the desired product.
9.82 (s, 1H), 7.60 (s, 2H), 7.26 (s, 2H), 2.70 (s, 3H).
Ferrocene Benzimidazole (Table 2, Entry 1487). Yellow solid (256
1
mg 85%). H NMR (500 MHz, DMSO-d6) δH 12.38 (s, 1H), 7.53−
7.44 (m, 2H), 7.12 (s, 2H), 5.03 (s, 2H), 4.45 (s, 2H), 4.09 (s, 5H).
LC−MS (ESI+): m/z = 303.00, [100%, MH+]; Calcd for C17H15N2Fe:
303.168.
2-[(D-Gluco-1,2,3,4,5-pentahydroxyl)pentyl]-1H-benzimidazole
(Table 2, Entry 1582a). Brown solid81 (243 mg, 91%), mp 213−
1
215 °C. H NMR (500 MHz, DMSO-d6) δH 12.26 (br, 1H), 7.48 (d,
2H, J = 4.5 Hz), 7.14−7.09 (m, 2H), 4.89 (d, 1H, J = 3.5 Hz), 5.07−
4.24 (m, 5H), 3.66−3.32 (m, 6H). LC−MS (ESI+): m/z = 269.00,
[100%, MH+]; Calcd for C12H17N2O5: 269.118.
1,4-Di(1H-benzo[d]imidazol-2-yl)benzene (Table 2, Entry 1148).
This compound was synthesized following the method described for
others benzimidazole using 2 equiv of o-phenylenediamine. Brown
2-Phenyl-1H-benzo[d]imidazole (Table 2, Entry 164). White solid
(174 mg, 90%) mp, 291−293 °C. 1H NMR (400 MHz, DMSO-d6) δH
12.92 (s, 1H), 8.17 (d, 2H, J = 6.0 Hz), 7.66 (d, 1H, J = 5.2 Hz), 7.56−
7.48 (m, 4H), 7.20 (s, 2H).
1
solid (248 mg, 80%), mp 112 °C. H NMR (400 MHz, DMSO-d6)
2-(1H-Benzo[d]imidazol-2-yl)phenol (Table 2, Entry 264). White
solid (199 mg, 95%), mp 240−242 °C. 1H NMR (500 MHz, DMSO-
d6) δH 13.16 (s, 1H), 8.04 (d, 1H, J = 10 Hz), 7.70−7.60 (m, 1H), 7.37
(t, 2H, J = 10 and 9 Hz), 7.27 (s, 2H), 7.03−6.99 (m, 2H).
2-(4-Chlorophenyl)-1H-benzo[d]imidazole (Table 2, Entry 364).
White solid (205 mg, 90%), mp 290 °C. 1H NMR (500 MHz, DMSO-
d6) δH 12.99 (s, 1H), 8.18(d, 2H, J = 10.5 Hz), 7.64 (qt, 3H, J = 9.5,
12, and 11 Hz), 7.52 (d, 1H), 7.24−7.16 (m, 2H).
13.05 (s, 2H), 8.35 (s, 4H), 7.70 (d, 2H, J = 7.6 Hz), 7.57 (d, 2H, J =
7.6 Hz), 7.19−7.26 (m, 4H). HRMS (ESI+): m/z = 311.2011, [100%,
MH+]; Calcd for C20H15N4: 311.3665.
General Experimental Procedure for the Synthesis of 2-
Substituted Benzothiazole. A mixture of aldehyde (1 mmol,
1 equiv), o-aminothiophenol (1 mmol, 1 equiv) and catalyst (0.00423
mmol, 1 mg) was taken in ethanol (25 mL) in a 100 mL double-walled
quartz beaker. The quartz beaker was exposed to visible light under
stirring condition and was allowed to proceed for 30−60 min. The
progress of the reaction was monitored by TLC or gas chroma-
tography. After completion of the reaction, ethanol was evaporated at
reduced pressure and the product was dissolved in a minimum volume
of dichloromethane. The organic layer was dried over dehydrated
Na2SO4, concentrated in vacuo, and purified by column chromatog-
raphy using silica gel (hexane/EtOAc) to give the desired product.
2-Phenyl Benzothaizole (Table 3, Entry 168). Yellow solid (203 mg,
2-(4-Nitrophenyl)-1H-benzo[d]imidazole (Table 2, Entry 440). Off-
white solid (203 mg, 85%), mp 260 °C. 1H NMR (500 MHz, DMSO-
d6) δH 13.28 (s, 1H), 8.38(m, 4H), 7.71 (d, 1H, J = 9.5 Hz), 7.57 (d,
1H, J = 9.5), 7.25 (dd, 2H, J = 10.5, 3 and 10.5). LC−MS (ESI+):
m/z = 240.00, [100%, MH+]; Calcd for C13H10N3O2: 240.07.
4-(1H-Benzo[d]imidazol-2-yl)-N,N-dimethylaniline (Table 2, Entry
64
1
5 ). White solid (215 mg, 91%), mp 272−274 °C. H NMR (500
MHz, DMSO-d6) δH 7.96 (d, 2H, J = 8.5 Hz), 7.50(s, 2H), 7.13
(s, 2H), 6.80 (d, 2H, J = 8.5 Hz).
1
96%), mp 112 °C. H NMR (400 MHz, CDCl3) δH 8.140−8.100
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Article
(m, 3H), 7.849 (d, 1H, J = 6.4 Hz), 7.508−7.453 (m, 4H), 7.358 (t,
1H, J = 5.6 Hz).
60 min. The insoluble product was collected through filtration and
washed thoroughly with ethanol and tetrahydrofuran. The solubility of
the isolated 1,4-dibenzothiazole is poor in almost all common solvents,
so it was characterized by its C, H, N and S analysis, IR spectrum and
melting point. Off-white solid (0.330 mg, 96%), mp 196 °C. FT-IR
(KBr, ν/cm−1) 1482 w, 1432 w, 1387 s, 1310w, 1230 w, 970 m, 842 w,
762 m, 724 w, 686 w, 624 w. Anal. Calcd for C20H12N2S2: C, 69.74; H,
3.51; N, 8.13; S, 18.62. Found: C, 69.80; H, 3.48; N, 8.15; S, 18.60.
LC−MS (ESI+): m/z = 345.50, [100%, MH+]. Calcd for C20H12N2S2:
345.47.
2-Benzothiazol-2-yl-phenol (Table 3, Entry 268). White crystalline
1
solid (223 mg, 98%), mp 122 °C. H NMR (400 MHz, CDCl3) δH
12.546 (s, 1H), 7.97 (d, 1H, J = 8 Hz), 7.86 (d, 1H, J = 8 Hz), 7.668
(d, 1H, J = 7.6 Hz), 7.492 (t, 1H, J = 7.6 Hz), 7.389 (t, 2H, J = 7.2
Hz), 7.125 (d, 1H, J = 8.4 Hz), 6.94 (t, 1H, J = 7.2 Hz).
2-(4-Chloro-phenyl)-benzothiazole (Table 3, Entry 368). White
1
solid (226 mg, 92%), mp 112 °C. H NMR (400 MHz, CDCl3) δH
8.073 (d, 1H, J = 8 Hz), 8.018 (d, 2H, J = 8.4 Hz), 7.896 (d, 1H, J = 8
Hz), 7.516 (d, 1H, J = 7.6 Hz), 7.488 (t, 2H, J = 7.6 Hz), 7.398 (t, 1H,
J = 8 Hz).
ASSOCIATED CONTENT
* Supporting Information
■
2-(4-Fluoro-phenyl)-benzothiazole (Table 3, Entry 468). White
S
1
solid (206 mg, 90%), mp 102 °C. H NMR (400 MHz, CDCl3) δH
Figure S1, UV−vis spectrum and cyclic voltammogram of the
3,6-diphenyl-1,2,4,5-tetrazine (phtz), FT-IR spectra of 2-
phenyl-2,3-dihydrobenzothiazole and 2-phenylbenzothiazole,
1H, and 13C NMR spectra (for selected compounds). This
material is available free of charge via the Internet at http://
pubs.acs.org.
8.072−8.029 (m, 3H), 7.851 (d, 1H, J = 10.60 Hz), 7.468 (t, 1H, J =
9.87 Hz), 7.352 (t, 1H, J = 9.81 Hz), 7.327−7.118 (m, 2H).
2-(4-Nitro-phenyl)-benzothiazole (Table 3, Entry 568). Yellow
1
solid (243 mg, 95%), mp 233 °C. H NMR (400 MHz, CDCl3) δH
8.362 (d, 2H, J = 9.2 Hz), 8.274 (d, 2H, J = 9.2 Hz), 8.139 (d, 1H, J =
8.4 Hz), 7.969 (d, 1H, J = 8 Hz), 7.566 (t, 1H, J = 7.8 Hz), 7.474 (t,
1H, J = 8 Hz).
(4-Benzothiazol-2-yl-phenyl)-dimethyl-amine (Table 3, Entry
AUTHOR INFORMATION
Corresponding Author
*E-mail: papubiswas_besus@yahoo.com. Tel.: +91-33-2668-4561.
Fax: +91-33-2668 7575.
Notes
68
1
■
6 ). Light yellow solid (240 mg, 95%), mp 162 °C. H NMR (400
MHz, CDCl3) δH 7.981 (m, 3H), 7.845 (d, 1H, J = 8 Hz), 7.443 (t,
1H, J = 7.6 Hz), 7.328−7.264 (m, 1H), 6.748 (d, 2H, J = 8.8 Hz),
3.053 (s, 6H).
2-Benzothiazol-2-yl-5-bromo-phenol (Table 3, Entry 768). White
1
solid (290 mg, 95%), mp 170 °C. H NMR (400 MHz, CDCl3) δH
The authors declare no competing financial interest.
11.746 (s, 1H), 8.347 (d, 1H, J = 2.4 Hz), 8.108 (d, 1H, J = 7.6 Hz),
8.047 (d, 1H, J = 8), 7.542−7.503 (m, 2H), 7.444−7.404 (m, 1H),
7.039 (d, 1H, J = 8).
ACKNOWLEDGMENTS
■
2-p-Tolyl-benzothiazole (Table 3, Entry 868). Yellow solid (206 mg,
S.D. and S.S. are indebted to CSIR, India for their JRF [08/
003(0072)/2010-EMR-I] and [08/003(0083)/2011-EMR-1],
respectively. P.B. acknowledges CSIR-India for the Project
(Sanction letter no. 01(2459)/11/EMR-II dated 16/05/2011).
The authors also acknowledge the facility developed in the
Department of Chemistry, BESUS through MHRD, India and
UGC-SAP.
1
92%), mp 86 °C. H NMR (400 MHz, CDCl3) δH 7.956 (d, 1H,
J = 6.4 Hz), 7.836 (d, 2H, J = 6.8 Hz), 7.703 (d,1H, J = 6.4 Hz), 7.328
(t, 1H, J = 6 Hz), 7.202 (t, H, J = 6 Hz), 7.119 (d, 2H, J = 6.4 Hz),
2.248 (s, 3H).
2-Pyridine-2-yl-benzothiazole (Table 3, Entry 968). White solid
1
(193 mg, 92%), mp 138 °C. H NMR (400 MHz, CDCl3) δH 8.688
(d, 1H, J = 4.8 Hz), 8.289 (d, 1H, J = 8 Hz), 8.117 (d, 1H, J = 8 Hz),
8.066 (d, 1H, J = 8 Hz), 8.010−7.968 (m, 1H), 7.534 (q, 2H, J = 5.2,
7.2, and 7.6 Hz), 7.453 (t, 1H, J = 7.6).
REFERENCES
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■
2-Anthracen-9-yl-benzothiazole (Table 3, Entry 1068). Yellow
1
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solid (216 mg, 70%). H NMR (400 MHz, CDCl3) δH 8.643 (s,1H),
8.277 (d, 1H, J = 8 Hz), 8.074 (t, 3H, J = 8.8 Hz), 7.84 (d, 2H, J = 8.8
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1
solid (226 mg, 95%), mp 138 °C. H NMR (400 MHz, CDCl3) δH
10.09(s, 1H), 8.308 (d, 2H, J = 8.4 Hz), 8.194 (d, 1H, J = 8.8 Hz),
8.128−8.070 (m, 3H), 7.587 (m, 1H), 7.511 (m, 1H).
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Benzothiazole (Table 3, Entry 1368). Light-yellow liquid (106 mg,
1
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80%). H NMR (400 MHz, CDCl3) δH 8.885 (s, 1H), 8.072−8.029
(m, 1H), 7.852 (d, 1H, J = 10.2 Hz), 7.466 (t, 1H, J = 9.8 Hz), 7.352
(t, 1H, J = 9.8 Hz).
2-Methyl-benzothiazole (Table 3, Entry 1468). Pale-yellow liquid
1
(123 mg, 84%). H NMR (400 MHz, CDCl3) δH 7.880 (d, 1H, J =
10.8 Hz), 7.752 (d, 1H, J = 10.8 Hz), 7.359 (t, 1H, J = 9.6 Hz), 7.23 (t,
1H, J = 10.8 Hz), 2.769 (s, 3H).
2-[(D-Gluco-1,2,3,4,5-pentahydroxyl)pentyl]-benzothiazole (Table
3, Entry 15). White solid (280 mg, 95%), mp 75−77 °C. Anal. Calcd
for C12H15NO5S: C, 50.52; H, 5.30; N, 4.91; S, 11.24. Found: C,
1
50.55; H, 5.32; N, 4.92; S, 11.27. H NMR (300 MHz, CD3OD) δH
6.96 (d, 1H, J = 10 Hz), 6.86−6.80 (m, 1H), 6.65−6.58 (m, 2H), 4.84
(s, 5H), 3.79−3.58(m, 6H). 13C NMR (75 MHz, DMSO-d6) δC 152.7,
136.2, 125.6, 124.5, 122.0, 121.5, 71.6, 71.4, 68.7, 68.3, 63.2. LC−MS
(ESI+): m/z = 285.90, [100%, MH+]; Calcd for C12H16NO5S: 286.08.
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(0.13 g, 1 mmol), 2-amino thiophenol (0.25 g, 2 mmol) and catalyst
(0.00423 mmol, 1 mg) was taken in tetrahydrofuran (20 mL). The
reaction mixture was then exposed to visible light and stirred for
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