Sodium sulfide: A sustainable solution for unbalanced redox condensation reaction between o -nitroanilines and alcohols catalyzed by an iron-sulfur system

Article abstract of DOI:10.1055/s-0034-1380134

Unbalanced redox condensation reaction between o-nitroanilines and alcohols, leading to benzimidazole and quinoxaline heterocycles can be efficiently promoted and catalyzed by sodium sulfide (40 mol%) in combination with iron(III) chloride hexahydrate (1 mol%). Beside the role as a precursor for the iron-sulfur (Fe/S) catalyst formation, hydrated sodium sulfide was shown to be an excellent noncompetitive, multi-electron reducing agent.

Full text of DOI:10.1055/s-0034-1380134

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 1741–1748
1741
paper
Synthesis
T. B. Nguyen et al.
Paper
Sodium Sulfide: A Sustainable Solution for Unbalanced Redox
Condensation Reaction between o-Nitroanilines and Alcohols
Catalyzed by an Iron–Sulfur System
Thanh Binh Nguyen*
Ludmila Ermolenko
Ali Al-Mourabit*
N
R1
HO
R3
R3
N
R2
NHR2
FeCl3•6H2O
1 mol%)
(
R1
+
+
2 2
Na S•nH O
HO
HO
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des
Substances Naturelles, CNRS, 91198, Gif-sur-Yvette Cedex,
France
nguyen@icsn.cnrs-gif.fr
ali.almourabit@cnrs.fr
NO2
4
0 mol%
N
N
R2 = H, Me
Ph
Ph
1.2 equiv
Received: 11.12.2014
Accepted: 07.01.2015
Published online: 10.02.2015
DOI: 10.1055/s-0034-1380134; Art ID: ss-2014-c0749-st
active sites of a wide range of enzymes, play a pivotal role
in promoting redox reactions in biological systems, their
use as redox catalyst remains limited. In the course of our
study focused on the development of new redox condensa-
tion reactions using this family of biomimetic and inexpen-
sive catalytic systems, we are particularly interested in the
use of oxidizing components bearing a nitro group, which
are readily available, capable of receiving up to six elec-
trons, and lead to a wide range of nitrogen-containing com-
pounds, including azaheterocycles.
Abstract Unbalanced redox condensation reaction between o-ni-
troanilines and alcohols, leading to benzimidazole and quinoxaline het-
erocycles can be efficiently promoted and catalyzed by sodium sulfide
(40 mol%) in combination with iron(III) chloride hexahydrate (1 mol%).
Beside the role as a precursor for the iron–sulfur (Fe/S) catalyst forma-
tion, hydrated sodium sulfide was shown to be an excellent noncom-
petitive, multi-electron reducing agent.
Ideally, in a self-balanced redox condensation (or redox-
neutral reaction) involving a nitro compound, the reducing
partner releases exactly six electrons to the nitro group.
The atom efficiency is thus maximized and the formation of
byproducts is minimized. For example, we reported recent-
ly two well-balanced six-electron exchange reactions of o-
nitroaniline (1a) as oxidizing components with 2-
phenethylamine (5) or 4-picoline (7) leading to quinoxaline
Key words redox condensation, iron–sulfur, benzimidazole, atom
economy, sodium sulfide
Redox condensation reactions are one of the most pow-
erful tools to enhance the efficiency of the synthesis of de-
sired motifs and functions from readily available and sim-
ple starting materials with better redox, step, and atom
economy. Although iron–sulfur clusters, ubiquitous in the
1
2
6 or benzimidazole 8 (Scheme 1).
previous work: unbalanced
N
N
H2N
no external electron donor
excess 2a: side-products
dppf,5a Au,3c Pd5c catalysts
Ph
Ph
5
Fe/S cat.
6
H
NH2
our previous work:
e– self-balanced
HO
Ph
N
Ph
6
2a
NO2
N
3aa
Me
N
1a
e–
2
H
7
N
Fe/S cat.
N
Fe/S cat.
N
this work: well-balanced
8
Na2S: multi-electron donor
Scheme 1 Synthesis of quinoxalines and benzimidazoles from o-nitroanilines
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T. B. Nguyen et al.
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The use of alcohols as reducing partners is highly inter-
esting because of their availability in a wide range of struc-
tures and their low prices. Indeed, alcohols have been used
well-balanced. The choice of this reducing agent is of vital
importance to the success of the global transformation.
Such an ideal reducing agent should fill the electron gap,
but should not be a competitive reducing agent with benzyl
alcohol or interfere with the main reaction pathway. As a
matter of fact, the redox condensation will stop when ei-
ther oxidizing or reducing agent is depleted.
3
in redox condensations with o-nitrophenols, o-nitrobenz-
4
3c,5
amides, and o-nitroanilines
leading to the correspond-
ing azaheterocycles. Typically, such reactions required ei-
3a
ther very high reaction temperatures expensive catalysts
3
b,4,5b
3c
5c
(
such as dppf,
gold, or palladium ), or UV irradiation
Sulfide in combination with iron has been used by Na-
ture in primitive metabolism and it is responsible for the
5a
with titanium dioxide nanoparticles as a photocatalyst.
7
Beside all these drawbacks, such reactions necessitate
the theoretically use of excess alcohol. Indeed, because each
early evolution of life. Based on this idea and in continuing
our efforts in the development of new applications of iron–
3c,5a
1,2,8
molecule of benzyl alcohol (2a)
involved in the redox
sulfur catalysts for redox condensation reactions,
we
condensation leading to heterocycle 3aa releases only four
electrons while nitroarene 1a receives up to six electrons,
the global transformation is an unbalanced process. Alcohol
chose inexpensive and low-molecular-weight sodium sul-
fide for this study. This reagent should play a dual role as:
9
(i) a precursor for the formation of Fe/S redox catalyst, and
(ii) an external and complementary reducing agent.
The unbalanced redox condensation between o-ni-
troaniline (1a) and benzyl alcohol (2a) leading to 2-phenyl-
1H-benzimidazole (3aa) was chosen as a model reaction
(Table 1). Without an iron catalyst, heating a mixture of 1a
and 2a with sodium sulfide (1 equiv) resulted in the forma-
tion of 3aa (52%) along with phenylenediamine (4) (up to
48%) from the direct reduction of 1a. Although the conver-
sion to 3aa was low, this result demonstrated that sodium
sulfide could promote the redox condensation even in the
absence of a transition metal.
2
a must therefore be used in more than one equivalent6
along with the formation of aldehyde or carboxylic acid de-
rivatives as byproducts.
Although the global transformation can be always clas-
sified as redox and step economical, the atom efficiency is
poor. The yield is inevitably lowered due to difficulties in
separating the byproduct from the electron compensation
processes.
A direct solution to this unbalanced coupling is to add a
reducing agent to the reaction mixture to compensate for
the electron deficiency and to render the global process
Table 1 Optimization of Reaction Conditionsa
Na2S•nH2O
y equiv)
NH2
NO2
NH2
N
(
+
HO
Ph
Ph
+
FeCl3•6H2O
z mol%)
N
H
NH2
(
1
a
2a
(x equiv)
3aa
4
2
.5 mmol
b
Entry
2a (equiv)
Na
2
S·nH
2
O (equiv)
FeCl
3
·6H
2
O (mol%)
Temp (°C)
Yield (%)
aa
52
3
4
1
2
3
4
5
6
7
8
2
1
0
0
0
5
5
1
1
1
5
130
130
130
130
130
130
130
140
140
48
24
5
2
0.6
0.4
0.4
0.4
0.4
0.4
0.4
0
73
2
65
2
>95
0
1.5
1.5
1.2
1.2
2
>95
0
>95
0
>95 (90)c
>98 (95)c
0
0
0
9
0
a
Reaction conditions: 1a (2.5 mmol), 2a, Na
Determined by H NMR spectroscopy of the crude mixture, based on 1a unless otherwise indicated.
Isolated yield.
2
S·nH
2
2 3 2
O (40% H O, MW = 130 g/mol), FeCl ·6H O, argon atmosphere, 24 h.
b
c
1
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T. B. Nguyen et al.
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A possible explanation for this over-reduction of the ni-
tro group while only a smaller amount of 2a is oxidized is
that sodium sulfide might release more than two electrons
and might compete with 2a in reducing the nitro group of
Table 2 Scope of o-Nitroanilines 1 in the Reaction with 2a
Entry o-Nitroaniline 1
Benzimidazole 3
Yieldb
(
%)
1
a. To confirm this hypothesis, we lowered the quantities of
NH2
NO2
H
N
sodium sulfide. To our delight, this action not only reduced
the ratio of 4 but also increased the yield of condensed
product 3aa (entry 2). However, when the amount of sodi-
um sulfide was reduced to 0.4 equivalents (entry 3), the re-
action stagnated at 65% conversion into 3aa while 1a and
1
87
Me
N
Me
3ba
1
b
Me
Me
2
a remained unchanged despite prolonged heating (up to
H
N
NH2
NO2
72 h).
2
69
Interestingly, adding iron(III) chloride hexahydrate (5
N
mol%) increased the conversion into 3aa (>95%) and sup-
pressed the formation of 4 (entry 4). At this stage, we
wished to further lower the quantities of 2a and iron salt
3ca
1
c
Me
Me
NH2
NO2
H
N
Me
(entries 5–7). A slight excess of 2a (1.2 equiv) is necessary
3
4
5
6
70
72
65
73
to compensate for its loss due to azeotropic evaporation
with water formed during the reaction. Finally, we found
that full conversion of 2a into 3aa could be achieved using
Me
3da
N
1d
MeO
NH2
H
10
MeO
only 1 mol% of iron salt. Benzimidazole 3aa could be iso-
lated in high yields by simple filtration and evaporation of
the methanolic extract of the crude reaction mixture (en-
tries 7 and 8). To confirm the synergy effect between iron
and sulfur, a control experiment was carried out between
N
NO2
N
1
e
3ea
NH2
H
N
1a and 2a using iron(III) chloride hexahydrate (5 mol%) (en-
try 9). No trace of either 3aa or 4 was observed, supporting
that the combination Fe/S is really efficient in promoting
this reaction.
We next investigated the scope of our reaction under
optimized conditions (Scheme 2). Substituted benzyl alco-
hols reacted smoothly to give the product in good to excel-
lent yields, regardless of the electronic properties of the
substituents. These substituents range from simple alkyl
Cl
NO2
N
Cl
3fa
1f
NH2
NO2
H
N
Br
N
Br
3ga
1
g
Me
N
NHMe
NO2
3ab–3ad, ether 3ae and 3af, halo 3ag–3aj, to trifluorometh-
7c
90
61
yl 3ak groups. When 2-methylbenzyl (2d) alcohol was
used, a higher reaction temperature was needed to afford a
high yield of 3ad. Most notably, a wide range of heteroaro-
matic products bearing a 2-furyl, 2-thienyl, or 3-pyridyl
substituent was readily obtained using these reaction con-
ditions 3al–3an. These structures could be useful for me-
dicinal chemistry applications.
N
1
1
h
3
ha
N
NH2
NO2
H
N
N
8
N
i
3ia
Next we expanded the range of o-nitroanilines in this
redox condensation protocol with benzyl alcohol (2a) (Ta-
ble 2). To our delight we found that a wide range of substi-
tuted o-nitroanilines (alkyl, halogen, ether) gave the de-
sired products in high yields (entries 1–6). With respect to
the N-unsubstituted o-nitroanilines, we found that N-
methyl derivative 1h required a higher reaction tempera-
ture (150 °C) (entry 7). Moreover, a heterocyclic nitro com-
pound, such as 3-nitro-2-aminopyridine (1i) is a useful
substrate, further demonstrating the versatility of this re-
dox condensation reaction (entry 9).
a
Reaction conditions: 1 (2.5 mmol), 2a (324 mg, 3 mmol, 1.2 equiv),
Na S·nH O (≥60%,130 mg, 1 mmol, 40 mol%), FeCl ·6H O (7 mg, 0.025
2
2
3
2
mmol, 1 mol%), argon atmosphere, 140 °C (unless otherwise noted), 24 h.
b
Isolated yield.
Reaction performed at 150 °C.
c
In order to further demonstrate the application of the
present Fe/S system, we switched to a different unbalanced
redox condensation reaction between 1a and vic-diols such
as 1-phenylethane-1,2-diol (5a), butane-2,3-diol (5b), and
ethylene glycol (5c) (Scheme 3).
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Na2S•nH2O
(40 mol%)
NH2
HO
+
N
R
FeCl3•6H2O
NO2
N
H
R
(1 mol%)
140 °C, 24 h
1a
2b–k
3ab–ak
2.5 mmol
(1.2 equiv)
H
N
Me
H
Me
Me
H
N
N
Me
N
N
N
3ab, 87%
3ac, 84%
3ad, 82%
F
N
N
N
OMe
O
N
N
H
H
N
H
O
3ae, 89%
3af, 79%
3ag, 80%
I
H
N
H
N
H
N
Cl
Br
N
N
N
3ah, 90%
3ai, 84%
3aj, 81%
H
N
H
N
H
N
O
S
N
CF3
N
N
N
3
ak, 76%
3
al, 44%
3am, 60%
H
N
N
3an, 84%
Scheme 2 Scope of benzyl alcohols in the reaction with 1a
With the same molar ratio between the starting materi-
NH2
NO2
HO
HO
N
FeCl3•6H2O (1 mol%)
Na2S•nH2O (40 mol%)
als and catalysts as for Scheme 2 and Table 2, the reaction
led to the condensed products 6aa and 6ab in high yields.
The reaction of 1a with 5c required however two equiva-
lents of the gem-diol to compensate the loss by its volatility.
In the three cases examined, the stabilizing effect of the
substituents on gem-diols is of vital importance for the suc-
cess of the condensation. Indeed, a higher yield was ob-
tained at lower reaction temperature for 5a (150 °C, 85%)
compared to 5b (170 °C, 75%) and 5c (180 °C, 67%).
During the course of these studies, we rationalized that
the overall reaction is very complex because reduction of
the nitro group, oxidation of sulfide and benzylic alcohol
are all multistep processes with a wide range of redox in-
termediates.
+
R
R
N
24 h
1a
5
6
1.2 equiv
N
N
N
N
Me
Me
N
N
Ph
6
aa, 150 °C, 85%
6ab, 170 °C, 75%
6ac, 180 °C, 67%
from 2 equiv of 5c
Scheme 3 Reaction of 1a with ethylene glycols 5a–c
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1
Each sulfide anion released more than four electrons,
suggesting that sulfide ion is oxidized into a mixture of var-
ious oxygenated anion species of sulfur in which sulfur has
positive oxidation states. Because of the similarities in their
H NMR (500 MHz, CD OD): δ = 8.10–8.08 (m, 2 H), 7.64–7.48 (m, 5
3
H), 7.27–7.24 (m, 2 H).
13
C NMR (75 MHz, DMSO-d ): δ = 151.2, 143.8, 135.0, 130.2, 129.8,
6
1
28.9, 126.4, 122.5, 121.7, 118.9, 111.3.
11
chemical and physical properties along with their com-
12
2-(p-Tolyl)-1H-benzimidazole (3ab)
plex redox and disproportionation behaviors, the qualita-
tive and quantitative studies of these anions are beyond the
scope of this paper.
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 4-methylbenzyl alcohol (2b, 366 mg, 3 mmol). Purifica-
tion according to the general procedure afforded a pale yellow solid;
In conclusion, we have demonstrated that the low atom
efficiency of an unbalanced redox condensation reaction
such as o-nitroanilines/benzyl alcohols could be resolved by
adding a complementary, non-competitive reducing agent:
hydrated sodium sulfide. In combination with iron (as low
as 1 mol% FeCl ·6H O), sodium sulfide is the reagent of
13
yield: 452 mg (87%); mp 282 °C (Lit. 275–277 °C).
1
H NMR (300 MHz, CD OD): δ = 7.98–7.95 (m, 2 H), 7.59–7.56 (m, 2
3
H), 7.35–7.32 (m, 2 H), 7.25–7.22 (m, 2 H), 2.40 (s, 3 H).
13
C NMR (75 MHz, CD OD): δ = 153.7, 152.5, 142.0, 130.9, 128.4,
3
1
27.9, 124.0, 115.8, 21.6.
3
2
choice to fulfill this task, underlined by its low cost, high
functional-group tolerance, low molecular weight, and that
it is a multi-electron donor. Further studies of the potential
of our iron–sulfur catalyst and exploration of related reac-
tion are currently ongoing.
2
-(4-Isopropylphenyl)-1H-benzimidazole (3ac)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 4-(isopropyl)benzyl alcohol (2c, 450 mg, 3 mmol). Purifi-
cation according to the general procedure afforded a pale yellow sol-
14
id; yield: 496 mg (84%); mp 254–255 °C (Lit. 225–226 °C).
H NMR (300 MHz, CD OD): δ = 8.01–7.99 (m, 2 H), 7.60–7.57 (m, 2 H),
3
7
1
.40–7.37 (m, 2 H), 7.26–7.21 (m, 2 H), 2.96 (septet, J = 6.9 Hz, 1 H),
.27 (d, J = 6.9 Hz, 6 H).
Commercially available starting materials were purchased from Sig-
ma-Aldrich and used without further purification. 1H and C NMR
spectra were acquired using Bruker (300 MHz) spectrometer. NMR
chemical shifts are reported relative to TMS with the residual solvent
13
13
C NMR (75 MHz, CD OD): δ = 153.7, 152.9, 140.3, 128.7, 128.3,
3
128.0, 123.9, 115.9, 35.5, 24.3.
1
13
as internal reference [CDCl , δ = 7.26 ( H) and δ = 77.0 ( C); DMSO-d6,
3
2-(o-Tolyl)-1H-benzimidazole (3ad)
1
13
1
δ = 2.50 ( H) and δ = 39.5 ( C); DMSO-d , δ = 3.31 ( H) and δ = 49.0
6
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 2-methylbenzyl alcohol (2d, 366 mg, 3 mmol). Purifica-
tion according to the general procedure afforded a pale yellow solid;
13
(
C)]. Reaction progress was monitored by TLC on precoated silica gel
plates (Kieselgel 60 F254). The spots were visualized under UV light
254 nm) or with vanillin stain. Flash column chromatography was
(
15
yield: 426 mg (82%); mp 222–223 °C (Lit. 223–224 °C).
conducted using silica gel (230–400 mesh) or alumina with different
mixtures of solvents as mobile phase (heptane–CH Cl , heptane–
1
H NMR (300 MHz, CD OD): δ = 7.64–7.58 (m, 3 H), 7.42–7.23 (m, 5
3
2
2
H), 2.49 (s, 3 H).
EtOAc or hexane–Et O).
2
13
C NMR (75 MHz, CD OD): δ = 138.5, 132.1, 131.6, 131.0, 127.1,
3
Redox Condensation Reaction of o-Nitroanilines 1 with Benzyl Al-
cohols 2 or vic-Diols 5; General Procedure
123.7, 115.8, 20.5.
A 20-mL test-tube equipped with a magnetic stirring bar was charged
with o-nitroaniline 1 (2.5 mmol, 1 equiv), alcohol 2 or 5 (3 mmol, 1.2
equiv), Na S·nH O (≥60%, 130 mg, 1 mmol, 40 mol%) and FeCl ·6H O
2-(4-Methoxyphenyl)-1H-benzimidazole (3ae)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 4-methoxybenzyl alcohol (2e, 414 mg, 3 mmol). Purifica-
2
2
3
2
(7 mg, 0.025 mmol, 1 mol%). The resulting mixture was stirred for 24
tion according to the general procedure afforded a pale yellow solid;
h under an argon atmosphere at the indicated temperature (see
Schemes 2 and 3 and Table 2). After cooling to r.t., the mixture was
purified in different ways. (i) For NH benzimidazole products, the
mixture was washed with CH Cl (3 × 2 mL) then dissolved in MeOH.
yield: 498 mg (89%); mp 242–245 °C (Lit.13 222–225 °C).
1
H NMR (300 MHz, CD OD): δ = 8.04–7.99 (m, 2 H), 7.58–7.54 (m, 2
3
H), 7.25–7.19 (m, 2 H), 7.09–7.04 (m, 2 H), 3.85 (s, 3 H).
2
2
13
C NMR (75 MHz, DMSO-d ): δ = 160.6, 151.3, 143.9, 135.0, 128.0,
The MeOH solution was filtered through a short pad of silica gel. The
filtrate was concentrated in vacuo to afford the NH benzimidazole
product. Further purification by column or recrystallization was car-
ried out if necessary. (ii) For N-methyl-2-phenylbenzimidazole 3ha
and quinoxalines 5, the crude mixture was dissolved in a minimum
volume of CH Cl and purified by column chromatography (silica gel
6
122.7, 122.1, 121.4, 118.5, 114.4, 111.0, 55.3.
2-(1,3-Benzodioxol-5-yl)-1H-benzimidazole (3af)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 1,3-benzodioxol-5-ylmethanol (2f, 456 mg, 3 mmol). Pu-
rification according to the general procedure afforded a grey solid;
2
2
or alumina, heptane–EtOAc, EtOAc, EtOAc–MeOH, hexane–Et O). We
2
13
16
noted that some C NMR signals of NH-benzimidazoles are missing
or difficult to observe.
yield: 471 mg (79%); mp 252–253 °C (Lit. 239–240 °C).
1
H NMR (300 MHz, CD OD): δ = 7.60–7.52 (m, 4 H), 7.26–7.17 (m, 2
3
H), 6.93 (d, J = 6.9 Hz, 1 H), 6.01 (s, 2 H).
2
-Phenyl-1H-benzimidazole (3aa)
13
C NMR (75 MHz, CD OD): δ = 151.9, 149.5, 148.5, 138.8, 123.6,
3
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification accord-
ing to the general procedure afforded a white solid; yield: 461 mg
122.3, 120.9, 114.3, 108.3, 106.4, 101.7.
13
(95%); mp 293–294 °C (Lit. 292–294 °C).
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2-(3-Fluorophenyl)-1H-benzimidazole (3ag)
2-(Furan-2-yl)-1H-benzimidazole (3al)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 3-fluorobenzyl alcohol (2g, 378 mg, 3 mmol). Purification
according to the general procedure afforded a pale yellow solid; yield:
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and furan-2-ylmethanol (2l, 294 mg, 3 mmol). Purification
according to the general procedure afforded a grey solid; yield: 202
17
14
424 mg (80%); mp 255–256 °C (Lit. 258 °C).
mg (44%); mp 285–286 °C (Lit. 287 °C).
1
1
H NMR (300 MHz, CD OD): δ = 7.90–7.79 (m, 2 H), 7.62–7.49 (m, 3
H NMR (300 MHz, DMSO-d ): δ = 12.94 (s, 1 H), 7.94 (dd, J = 1.8, 0.7
3
6
H), 7.28–7.18 (m, 3 H).
Hz, 1 H), 7.66–7.49 (m, 2 H), 7.23–7.17 (m, 3 H), 6.73 (dd, J = 3.5, 1.8
1
3
Hz, 1 H).
C NMR (75 MHz, CD OD): δ = 164.7 (d, J = 245 Hz), 152.1 (d, J = 26
3
13
Hz), 133.4 (d, J = 7.0 Hz), 132.2 (d, J = 8.6 Hz), 124.4, 123.7 (d, J = 3.0
Hz), 118.1 (d, J = 21.5 Hz), 114.7 (d, J =23.4 Hz) (1 C missing due to
overlap).
C NMR (75 MHz, DMSO-d ): δ = 145.6, 144.6, 143.6, 134.2, 122.6,
6
121.9, 118.8, 112.3, 111.3, 110.5 (1 C missing due to overlap).
2-(Thiophen-2-yl)-1H-benzimidazole (3am)
2
-(4-Chlorophenyl)-1H-benzimidazole (3ah)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and thiophen-2-ylmethanol (2m, 342 mg, 3 mmol). Purifica-
tion by column chromatography (alumina, heptane–EtOAc, 2:1) af-
forded a pale yellow solid; yield: 421 mg (84%); mp 300–301 °C (Lit.16
285–287 °C).
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 4-chlorobenzyl alcohol (2h, 428 mg, 3 mmol). Purifica-
tion according to the general procedure afforded a pale yellow solid;
13
yield: 515 mg (90%); mp 305 °C (Lit. 289−291 °C).
1
1
H NMR (300 MHz, DMSO-d ): δ = 13.02 (br s, 1 H), 8.20 (d, J = 8.7 Hz,
H NMR (500 MHz, DMSO-d ): δ = 12.93 (s, 1 H), 7.84 (d, J = 3.5 Hz, 1
6
6
2
H), 7.63–7.59 (m, 4 H), 7.23–7.19 (m, 2 H).
H), 7.72 (d, J = 5.0 Hz, 1 H), 7.61–7.51 (m, 2 H), 7.23 (dd, J = 5.0, 3.5 Hz,
1
3
1 H), 7.20–7.18 (m, 2 H).
C NMR (75 MHz, DMSO-d ): δ = 150.1, 134.4, 129.0, 128.1, 122.2,
6
13
1
15.1.
C NMR (125 MHz, DMSO-d ): δ = 146.9, 143.6, 134.7, 133.6, 128.7,
6
128.2, 126.7, 122.4, 122.0, 118.5, 111.0.
2-(4-Bromophenyl)-1H-benzimidazole (3ai)
2
-(Pyridin-3-yl)-1H-benzimidazole (3an)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 4-bromobenzyl alcohol (2i, 645 mg, 3 mmol). Purification
according to the general procedure afforded a pale yellow solid; yield:
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and pyridin-3-ylmethanol (2n, 327 mg, 3 mmol). Purification
according to the general procedure afforded a grey solid; yield: 293
18
570 mg (84%); mp 300 °C (Lit. 299 °C).
14
1
mg (60%); mp 250 °C (Lit. 247 °C).
H NMR (300 MHz, DMSO-d ): δ = 13.01 (s, 1 H), 8.13 (d, J = 8.5 Hz, 2
6
1
H), 7.76 (d, J = 8.5 Hz, 2 H), 7.62–7.59 (m, 2 H), 7.25–7.19 (m, 2 H).
H NMR (300 MHz, CD OD): δ = 9.23–9.21 (m, 1 H), 8.62–8.60 (m, 1
3
1
3
H), 8.44–8.42, (m, 1 H), 7.61–7.53 (m, 3 H), 7.27–7.24 (m, 2 H).
C NMR (75 MHz, DMSO-d ): δ = 150.2, 131.9, 129.4, 128.4, 123.2,
6
13
1
22.3, 115.4.
C NMR (75 MHz, CD OD): δ = 151.4, 150.3, 148.5, 140.6, 136.0,
3
128.0, 125.7, 124.5, 116.3.
2-(2-Iodophenyl)-1H-benzimidazole (3aj)
5
-Methyl-2-phenyl-1H-benzimidazole (3ba)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 2-iodobenzyl alcohol (2j, 702 mg, 3 mmol). Purification
according to the general procedure and an additional recrystallization
Prepared according to the general procedure using 1b (380 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification accord-
ing to the general procedure afforded a pale yellow solid; yield: 451
(
MeOH) afforded a pale yellow solid; yield: 650 mg (81%); mp 255–
17
20
256 °C (Lit. 258 °C).
mg (87%); mp 244–245 °C (Lit. 244–246 °C).
1
1
H NMR (300 MHz, DMSO-d ): δ = 12.74 (br s, 1 H), 8.06 (d, J = 7.9 Hz,
H NMR (300 MHz, CD OD): δ = 8.07 (m, 2 H), 7.52 (m, 4 H), 7.40 (s, 1
6
3
1
H), 7.71–7.52 (m, 3 H), 7.30–7.23 (m, 4 H).
H), 7.10 (d, J = 7.8 Hz, 1 H), 2.48 (s, 3 H).
13
13
C NMR (75 MHz, DMSO-d ): δ = 152.6, 143.1, 139.6, 136.6, 134.4,
C NMR (75 MHz, CD OD): δ = 151.6, 132.5, 129.9, 129.1, 128.8,
6
3
131.3, 131.2, 128.1, 122.4, 121.7, 119.1, 111.5, 97.4.
126.3, 124.1, 117.3, 111.1, 20.4 (2 C missing due to overlap).
2-[4-(Trifluoromethyl)phenyl]-1H-benzimidazole (3ak)
7-Methyl-2-phenyl-1H-benzimidazole (3ca)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 4-(trifluoromethyl)benzyl alcohol (2k, 528 mg, 3 mmol).
Purification according to the general procedure afforded a white sol-
Prepared according to the general procedure using 1c (380 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification accord-
ing to the general procedure afforded a pale yellow solid; yield: 358
19
21
id; yield: 501 mg (76%); mp 263–265 °C (Lit. 265–266 °C).
mg (69%); mp 244–246 °C (Lit. 246–248 °C).
1
1
H NMR (300 MHz, CD OD): δ = 8.23 (d, J = 7.8 Hz, 2 H), 7.82 (d, J = 7.8
H NMR (300 MHz, CD OD): δ = 8.14 (d, J = 7.8, 1.8 Hz, 2 H), 7.55 (m, 3
3
3
Hz, 2 H), 7.70–7.54 (m, 2 H), 7.31–7.26 (m, 2 H).
H), 7.45 (s, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 2.64 (s,
1
3
3 H).
C NMR (75 MHz, CD OD): δ = 150.2, 143.5, 134.9, 133.3, 131.3 (q, J =
3
13
3
2 Hz), 126.9, 125.7 (q, J = 3.8 Hz), 124.0 (q, J = 270 Hz), 118.1, 111.5.
C NMR (75 MHz, CD OD): δ = 153.1, 131.3, 131.2, 130.3, 130.0,
3
128.2, 128.1, 128.0, 124.5, 123.9, 113.7, 17.1.
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1
747
Synthesis
T. B. Nguyen et al.
Paper
5,6-Dimethyl-2-phenyl-1H-benzimidazole (3da)
2-Phenyl-3H-imidazo[4,5-b]pyridine (3ia)
Prepared according to the general procedure using 1d (415 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification by col-
umn chromatography (silica gel, heptane–EtOAc, 4:1) afforded a pale
Prepared according to the general procedure using 1i (348 mg, 2.5
mmol), and benzyl alcohol (2a, 327 mg, 3 mmol). Reaction was per-
formed at 150 °C. Purification by flash chromatography (EtOAc–
MeOH, 1:0 to 9:1) afforded a white solid; yield: 297 mg (61%); mp
22
yellow solid; yield: 390 mg (70%); mp 251–253 °C (Lit. 249–251 °C).
27
1
289–290 °C (Lit. 289–291 °C).
H NMR (300 MHz, CD OD): δ = 8.04 (m, 2 H), 7.49 (m, 3 H), 7.35 (m, 2
3
1
H), 2.37 (s, 6 H).
H NMR (500 MHz, DMSO-d ): δ = 8.34 (dd, J = 4.8, 1.3 Hz, 1 H), 8.25–
6
1
3
8.24 (m, 2 H), 8.01 (dd, J = 7.9, 1.2 Hz, 1 H), 7.59–7.51 (m, 3 H), 7.24
C NMR (75 MHz, CD OD): δ = 152.5, 133.0, 131.3, 130.2, 130.0 (2 C),
3
(dd, J = 7.9, 4.8 Hz, 1 H).
1
27.6, 116.0, 20.5.
13
C NMR (125 MHz, DMSO-d ): δ = 150.2, 131.9, 129.4, 128.3, 123.2,
6
122.3, 117.5, 113.2.
6-Methoxy-2-phenyl-1H-benzimidazole (3ea)
Prepared according to the general procedure using 1e (420 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification by col-
umn chromatography (silica gel, heptane–EtOAc, 4:1) afforded a pale
2
-Phenylquinoxaline (6aa)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and 1-phenylethane-1,2-diol (5a, 414 mg, 3 mmol). Purifica-
23
yellow solid; yield: 403 mg (72%); mp 147–149 °C (Lit. 148–150 °C).
1
tion by flash chromatography (hexane–Et
2
O, 9:1 to 8:2) afforded a
H NMR (300 MHz, CDCl ): δ = 8.10 (m, 2 H), 7.49 (d, J = 8.8 Hz, 1 H),
.40 (m, 3 H), 7.03 (d, J = 2.3 Hz, 1 H), 6.88 (dd, J = 8.8, 2.3 Hz, 1 H),
.78 (m, 3 H).
3
pale yellow oil which solidified on standing; yield: 438 mg (85%); mp
7
3
28
7
7–78 °C (Lit. 78–79 °C).
1H NMR (300 MHz, CDCl
): δ = 9.30 (s, 1 H), 8.19–8.10 (m, 4 H), 7.79–
.69 (m, 2 H), 7.57–7.47 (m, 3 H).
13
3
C NMR (75 MHz, CDCl ): δ = 156.7, 151.7, 139.2, 136.3, 134.2, 129.9,
3
7
1
29.0, 126.5, 116.2, 112.6, 97.6, 55.7.
13
C NMR (75 MHz, CDCl ): δ = 152.0, 143.5, 142.5, 141.7, 136.9, 130.5,
3
130.4, 129.8, 129.8, 129.3, 129.3, 127.8.
5-Chloro-2-phenyl-1H-benzimidazole (3fa)
Prepared according to the general procedure using 1f (432 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification accord-
ing to the general procedure afforded a pale yellow solid; yield: 371
2
,3-Dimethylquinoxaline (6ab)
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and butane-2,3-diol (5b, 270 mg, 3 mmol). Purification by
24
mg (65%); mp 211–212 °C (Lit. 212 °C).
1
flash chromatography (hexane–Et
low solid: 296 mg (75%); mp 105–106 °C (Lit. 106 °C).
1H NMR (300 MHz, CDCl
): δ = 7.96–7.91 (m, 2 H), 7.65–7.59 (m, 2 H),
.69 (s, 6 H).
2
O, 9:1 to 8:2) afforded a pale yel-
H NMR (300 MHz, CD OD): δ = 8.06 (m, 2 H), 7.57 (m, 5 H), 7.22 (m, 1
3
29
H).
13
3
C NMR (75 MHz, CD OD): δ = 154.7, 132.5, 131.8, 131.7, 130.7,
3
2
1
30.3, 129.4, 128.0,127.9, 124.4, 116.5.
13
C NMR (75 MHz, CDCl ): δ = 153.6, 141.2, 129.0, 128.5, 23.4.
3
5-Bromo-2-phenyl-1H-benzimidazole (3ga)
Quinoxaline (6ac)
Prepared according to the general procedure using 1g (543 mg, 2.5
mmol), and benzyl alcohol (2a, 324 mg, 3 mmol). Purification accord-
ing to the general procedure afforded a pale yellow solid; yield: 492
Prepared according to the general procedure using 1a (345 mg, 2.5
mmol), and ethylene glycol (5c, 310 mg, 5 mmol). Purification by
flash chromatography (hexane–Et O, 9:1 to 8:2) afforded a pale yel-
25
mg (73%); mp 204–205 °C (Lit. 206–207 °C).
2
1
low oil which solidified on standing; yield: 218 mg (67%).
H NMR (300 MHz, CD OD): δ = 8.05 (m, 2 H), 7.73 (s, 1 H), 7.51 (m, 4
3
1
H), 7.36 (m, 1 H).
H NMR (300 MHz, CDCl ): δ = 8.83 (s, 2 H), 8.11–8.08 (m, 2 H), 7.78–
3
1
3
7.74 (m, 2 H).
C NMR (75 MHz, CD OD): δ = 154.5, 132.0, 131.9, 130.6, 130.3,
3
13
1
30.2, 128.0, 127.4, 127.0, 126.9, 116.5.
C NMR (75 MHz, CDCl ): δ = 144.9, 143.0, 130.0, 129.5.
3
1-Methyl-2-phenyl-1H-benzimidazole (3ha)
Supporting Information
Prepared according to the general procedure using 1h (380 mg, 2.5
mmol), and benzyl alcohol (2a, 327 mg, 3 mmol). Reaction was per-
formed at 150 °C. Purification by flash chromatography (heptane–
EtOAc, 19:2 to 8:2) afforded a white solid; yield: 468 mg (90%); mp
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380134.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
26
95–96 °C (Lit. 97–99 °C).
1
H NMR (300 MHz, CDCl ): δ = 7.84–7.80 (m, 1 H), 7.75–7.73 (m, 2 H),
.52–7.46 (m, 3 H), 7.37–7.34 (m, 1 H), 7.31–7.28 (m, 2 H), 3.82 (s, 3
3
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3
(
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(
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1741–1748

1
748
Synthesis
T. B. Nguyen et al.
Paper
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(
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(
(
(
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2
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7
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1741–1748