Iron(II) bromide-catalyzed oxidative coupling of benzylamines with ortho-substituted anilines: Synthesis of 1,3-benzazoles

Article abstract of DOI:10.1039/c4ra12490a

An iron(II) bromide-catalyzed oxidative coupling of benzylamines with 2-amino/hydroxy/mercapto-anilines has been developed, allowing the synthesis of a diversity of substituted 1,3-benzazoles in good to excellent yields. This transformation is compatible with a wide range of functional groups. The method is practical, economical and employs molecular oxygen as an oxidant.

Full text of DOI:10.1039/c4ra12490a

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Iron(II) Bromide-Catalyzed Oxidative Coupling of Benzylamines with
ortho-Substituted Anilines: Synthesis of 1,3-Benzazoles
Kovuru Gopalaiah* and Sankala Naga Chandrudu
Department of Chemistry, University of Delhi, Delhi 110007, India
ABSTRACT:
An iron(II) bromideꢀcatalyzed oxidative coupling of benzylamines with 2ꢀ
amino/hydroxy/mercaptoꢀanilines has been developed, allowing the synthesis of a
diversity of substituted 1,3ꢀbenzazoles in good to excellent yields. This transformation is
compatible with a wide range of functional groups. The method is practical, economical
and employs molecular oxygen as an oxidant.
______________________________________________________________________
* Corresponding Author
Eꢀmail: gopal@chemistry.du.ac.in
1

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INTRODUCTION
Nitrogenꢀcontaining ring systems are considered to be privileged structures because of
their occurrence in many natural products and synthetic compounds with interesting
biological activity.1 Specifically, benzimidazoles and its structural isosteres;
benzoxazoles and benzothiazoles (1,3ꢀbenzazoles) represent a medicinally and
pharmaceutically important class of heterocyclic motifs that are found as the core
structural skeletons in a variety of drug molecules such as pantoprazole,2 tafamidis,3 and
riluzole4 (Figure 1). They possess a wide range of biological and pharmacological
activities including antitumor,5 anticancer,6 antiparasitic,7 antiparkinson,8 and
antimicrobial9 properties. Therefore, the development of different synthetic methods for
the preparation of 1,3ꢀbenzazoles has received much attention. The conventional methods
for the synthesis of these important heteroaromatic compounds typically involve two
approaches. One consists of the condensation of orthoꢀsubstituted anilines having the
cyclizable groups (NH2, OH, SH) with carboxylic acids under harsh dehydrating
conditions10 or oxidative couplings with aldehydes11 (Scheme 1a). The other consists of
the
transition
metalꢀcatalyzed
intramolecular
crossꢀcoupling
of
orthoꢀ
haloanilides/analogues (Scheme 1b).12 Our literature survey revealed that 1,3ꢀbenzazoles
can also be synthesized from benzylamines/aliphatic amines13 or benzylalcohols14 by the
reaction of orthoꢀsubstituted anilines having the amine/hydroxyl/mercaptan groups.
However, there are only a few reports for these approaches. With respect to the amines as
substrates, the first oxidative coupling between primary amines and 2ꢀhydroxyanilines to
synthesize benzoxazoles using Shvo catalyst {[(η5ꢀPh4C4CO)]2HRu2(CO)4(ꢁꢀH)} and
2,6ꢀdimethoxybenzoquinone (DMBQ) as terminal oxidant was reported by Marsden and
2

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coꢀworkers (Scheme 1c).13a Endo and Bäckvall employed Shvo catalyst, Coꢀsalen
complex and DMBQ to prepare benzoxazoles from primary amines and 2ꢀ
hydroxyanilines.13b Taddei and coꢀworkers reported microwave assisted Pd/Cꢀcatalyzed
reaction between primary amines and 2ꢀamino/hydroxyanilines in the presence of acetic
acid and large amount of crotonitrile as hydrogen acceptor to obtain benzimidazoles and
benzoxazoles.13c Subsequently, Liu et al. modified the above microwave procedure to the
conventional heating and carried out the reaction with Pd/C catalyst in the absence of
oxidants and hydrogen acceptors.13d Narender et al.15a and Nguyen et al.15b,c
independently reported a few metalꢀfree procedures for synthesis of benzimidazoles and
benzothiazoles from benzylamines and 2ꢀamino/mercaptoanilines. Many of the above
methods have one or more shortcomings such as need of microwave radiation, precious
metal catalysts, complex ligands, stoichiometric amounts of reagents, additives and nonꢀ
renewable oxidants which adversely affect the economics as well as the ecofriendly
nature of the reaction.
In recent years, great advances have been made in the use of noble metals and
their compounds in organic synthesis. In view of their high cost, limited availability and
toxicity, researches were directed to find alternatives to the noble metal catalysts.16 In this
context, iron compounds are receiving full attention as ideal candidates on several
counts.17 Iron shows variable valences, cheap, environmentally benign, and suitable for
safe and large scale applications. Herein, we report a practical and efficient iron(II)
bromide
catalyzed
oxidative
coupling
of
benzylamines
with
2ꢀ
amino/hydroxy/mercaptoanilines to give synthetically valuable 1,3ꢀbenzazole compounds
using molecular oxygen as a sole oxidant (Scheme 1d).
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Figure 1. Representative drugs belonging to benzimidazole, benzoxazole and
benzothiazole skeletons.
Scheme 1
4

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RESULTS AND DISCUSSION
In our initial studies, the reaction of benzylamine (1a) with 2ꢀaminoaniline (2a) was
performed in the presence of 10 mol % of iron catalyst in chlorobenzene at 110 oC for 18
h under an air atmosphere. Firstly, various iron(II) and iron(III) salts were evaluated for
their ability to catalyze the reaction (Table 1). We found that FeBr2 was the best and
affording 2ꢀphenylbenzimidazole (3a) in 78% yield (Table 1, entry 7), whereas other iron
salts led to low yields (Table 1, entries 1ꢀ6). Encouraged by this promising result, we
further tested the catalytic activity under the atmosphere of molecular oxygen.
Gratifyingly, the reaction was accelerated and the yield of 3a was significantly increased
to 92% (Table 1, entry 8). The same yield of the product 3a was also obtained when the
iron catalyst loading was decreased from 10 to 5 mol % (Table 1, entry 9). However, a
further decrease of iron catalyst loading resulted in relatively low yield of 3a (Table 1,
entry 10). No product was observed in the absence of catalyst (Table 1, entry 11). When
the reaction performed in an inert atmosphere, only trace amount of product was noticed
(Table 1, entry 12). We also examined different solvents in addition to chlorobenzene for
the reaction (Table 1, entries 13ꢀ15). When toluene, N,Nꢀdimethylformamide (DMF), and
Nꢀmethylꢀ2ꢀpyrrolidone (NMP) were used as solvents, the yields of 3a were 68%, 83%,
and 79%, respectively. Performing the reaction without solvent (neat) resulted in low
yield (Table 1, entry 16). Finally, a lower reaction temperature resulted in low yield of
the desired product due to incomplete reaction (Table 1, entry 17). Thus, the optimal
catalytic conditions consist of 5 mol % FeBr2, chlorobenzene as the solvent, and the
reaction was carried out at 110 oC under the atmosphere of molecular oxygen.
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Table 1. Optimization of Reaction Conditions for the Synthesis of Benzimidazolesa
NH2
NH2
catalyst
N
NH2
+
N
H
1a
2a
3a
Entry
Catalyst
Solvent
Time
(h)
Yield
(%)b
FeSO4.7H2O
Fe(OAc)2
Fe(acac)3
FeCl3
1
2
3
4
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
18
18
18
18
17
31
12
43
5
6
7
FeCl2
FeBr3
FeBr2
chlorobenzene
chlorobenzene
chlorobenzene
18
18
18
56
70
78
8c
FeBr2
FeBr2
FeBr2
chlorobenzene
chlorobenzene
chlorobenzene
4
4
4
92
92
9c,d
10c,e
80
0
11c
chlorobenzene
chlorobenzene
toluene
4
12d,f
13c,d
14c,d
FeBr2
FeBr2
FeBr2
18
4
trace
68
83
DMF
4
15c,d
16c,d
17c,d,g
FeBr2
FeBr2
FeBr2
NMP
4
79
80
45
4
chlorobenzene
18
a Reaction conditions: 2a (2.0 mmol), 1a (2.4 mmol), catalyst (10 mol %), solvent (2 mL),
110 oC, air atmosphere unless otherwise noted. b Isolated yield. c Reaction was performed
d
e
under molecular oxygen (O2 balloon). Using 5 mol % of catalyst. Using 3 mol % of
catalyst. f Reaction was performed under argon atmosphere. g Reaction was performed at
90 oC.
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With the optimized reaction conditions in hand, we next explored the scope of the
oxidative coupling reaction using various benzylamines (1) and 2ꢀaminoanilines (2)
(Table 2). First, the reaction between various amines (1b-1n) and 2ꢀaminoaniline (2a)
was investigated under standard conditions. The results disclosed that the reactions
proceeded smoothly and tolerated a wide range of functional groups, including methoxy,
fluoro, chloro, trifluoromethyl, acetal, thienyl, pyridyl and nitro groups. The electronic
properties of the substituents on the aryl ring of the benzylamines affected the yields of
the reaction to some extent. In general, the benzylamines bearing an electronꢀdonating
substituent (e.g., −Me and −OR) (Table 2, entries 2, 3, 8 and 9) produced a slightly
higher yield of cyclization products than those analogues bearing an electronꢀ
withdrawing substituent (e.g., −F and −Cl) (Table 2, entries 4ꢀ6). However, benzylamine
bearing a strong electronꢀwithdrawing substituent such as trifluoromethyl group at the
meta positions afforded slightly lower yield of product 3g (Table 2, entry 7). The steric
hindrance of ortho substituent had some influence on the oxidative coupling reaction. For
example, the reaction of 2a with pꢀ and oꢀmethoxybenzylamines resulted in the formation
of the corresponding 2ꢀpꢀanisylbenzimidazole (3c) and 2ꢀoꢀanisylbenzimidazole (3i) in
96% and 87% yields, respectively (Table 2, entries 3 and 9). Similarly, other sterically
hindered substrates such as oꢀchlorobenzylamine and 1ꢀnaphthylmethylamine gave the
corresponding 2ꢀ(oꢀchlorophenyl)benzimidazole (3e) and 2ꢀ(1ꢀnaphthyl)benzimidazole
(3j) in 81% and 83% yields, respectively (Table 2, entries 5 and 10). In addition,
heteroarylmethylamines such as 2ꢀthiophenemethylamine (1k) and 4ꢀpicolylamine (1l)
could also be used as substrates, leading to formation of the corresponding 2ꢀ(thiophenꢀ2ꢀ
yl)benzimidazole (3k) and 2ꢀ(pyridinꢀ4ꢀyl)benzimidazole (3l) in 81% and 65% yields,
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respectively (Table 2, entries 11ꢀ12). Gratifyingly, nonꢀbenzylic amine 1m and secondary
amine 1n were also good coupling partners for this oxidative coupling reaction, giving
the corresponding products in good yields (3m, 3a, 73%, 88%, respectively, Table 2,
entries 13ꢀ14).
Next, we studied the reactions between 4ꢀmethylbenzylamine (1b) and various
substituted 2ꢀaminoanilines (2b-2e) under standard conditions (Table 2, entries 15ꢀ18).
High yields (76ꢀ82%) of the desired products were obtained with both electronꢀrich and
electronꢀdeficient 2ꢀaminoanilines. Even the heteroaryl substrate 2,3ꢀdiaminopyridine
produced the corresponding cyclized product without any difficulty (Table 2, entry 18).
Evidently, electronic effect of the substituents on the aryl ring in 2ꢀaminoanilines has
very little influence.
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Table 2. Synthesis of Benzimidazolesa
NH2
NH2
FeBr2 (5 mol%)
N
+
R
R
NH2
Chlorobenzene
110 oC, O2
N
H
1
2
3
Entry
Amine 1
Aniline 2
Time (h)
Benzimidazole 3
Yield (%)b
1
2
3
4
R1 = H
1a
1b
1c
1d
4
6
6
8
3a
3b
3c
3d
92
93
96
87
R1 = Me
N
NH2
NH2
R1
R1 = OMe
R1 = F
R1
NH2
N
H
2a
2a
N
N
NH2
5
6
1e
1f
6.5
7.5
3e
3f
81
84
Cl
H
Cl
N
N
NH2
Cl
2a
2a
Cl
H
Cl
Cl
CF3
F3C
N
NH2
7
1g
10.5
3g
80
N
H
CF3
CF3
O
O
N
NH2
8
9
1h
1i
5
7
3h
3i
89
87
2a
2a
O
N
H
O
N
NH2
OMe
NH2
N
H
MeO
N
10
9.5
83
1j
2a
3j
N
H
N
S
NH2
NH2
11
12
6
3k
3l
81
65
1k
1l
2a
2a
N
H
S
N
N
18
N
N
H
N
13
14
15
n-C7H15
NH2
1m
1n
1b
2a
2a
11.5
8
n-C7H15
3m
3a
73
88
79
N
H
N
Ph
Ph
N
Ph
H
N
H
NH2
NH2
N
NH2
Me
12
3n
N
H
Me
O2N
H3C
O2N
2b
NH2
NH2
N
NH2
NH2
NH2
Me
Me
Me
16
17
18
1b
1b
1b
4
8
6
3o
3p
3q
82
76
80
N
H
Me
Me
Me
H3C
2c
2d
2e
NH2
NH2
N
N
H
NH2
NH2
N
N
H
N
N
a Reaction conditions: diamine 2 (2.0 mmol), benzylamine 1 (2.4 mmol), FeBr2 (5 mol %), chlorobenzene (2 mL), O2 balloon, 110 oC.
b Isolated yield.
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Furthermore, this methodology could be extended to the preparation of
benzoxazole derivatives by using 2ꢀhydroxyꢀ5ꢀmethylaniline (4). When the substrate 4
was treated with benzylamine (1a) under the optimized conditions used for
benzimidazoles, the desired product 2ꢀphenylꢀ5ꢀmethylbenzoxazole (5a) was obtained in
58% yield and the small amount of starting materials were remained in the reaction
o
mixture after 30 h (Table 3, entry 1). However, performing the reaction at 120 C the
starting materials were completely consumed in 30 h and produced the desired product in
71% yield (Table 3, entry 2). We then applied these reaction conditions to explore the
generality of the reaction. A variety of benzylamines that were used previously for the
benzimidazoles syntheses, were reacted with 2ꢀhydroxyꢀ5ꢀmethylaniline (4) in the
presence of FeBr2 in chlorobenzene at 120 oC under the atmosphere of molecular oxygen
to provide benzoxazoles 5b-5k in moderate to good yields (Table 3, entries 3ꢀ12).
Unfortunately, 4ꢀpicolylamine, nꢀoctylamine and dibenzylamine failed to give the
benzoxazole products under the same reaction conditions, and starting materials were
recovered.
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Table 3. Synthesis of Benzoxazolesa
Me
+
NH2
OH
Me
FeBr2 (5 mol%)
N
O
R
R
NH2
Chlorobenzene
120 oC, O2
1
4
5
Entry
Amine 1
R1 = H
Time (h)
Benzoxazole 5
Yield (%)b
58
1c
2
30
30
30
30
30
1a
5a
R1 = H
71
74
80
69
1a
1b
1c
1d
5a
5b
5c
5d
R1 = Me
R1 = OMe
R1 = F
Me
3
N
O
NH2
R1
R1
4
5
Me
Me
N
NH2
6
7
28
28
1e
1f
5e
5f
65
67
O
Cl
Cl
N
NH2
Cl
O
Cl
Cl
Cl
CF3
F3C
Me
N
O
NH2
8
25
1g
5g
62
CF3
CF3
Me
Me
O
O
N
O
NH2
9
28
26
76
73
1h
1i
5h
5i
O
O
N
O
NH2
OMe
NH2
10
MeO
Me
Me
N
O
11
1j
24
71
5j
S
N
O
NH2
12
1k
26
67
5k
S
a Reaction conditions: 2-hydroxy-5-methylaniline 4 (2.0 mmol), benzylamine 1 (2.4 mmol), FeBr2 (5 mol %),
chlorobenzene (1 mL), O2 balloon, 120 oC unless otherwise noted. b Isolated yield. c Reaction was performed at
110 oC.
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Finally, oxidative coupling of benzylamines with 2ꢀmercaptoaniline was
conducted to prepare 2ꢀsubstituted benzothiazoles. The effective conditions for the
reaction of 2ꢀaminoaniline (2a) were found to be not suitable in this case. Treatment of 2ꢀ
mercaptoaniline (6) with benzylamine (1a) in the presence of FeBr2 (5 mol %) in
chlorobenzene under the atmosphere of molecular oxygen gave 2ꢀphenylbenzothiazole
(7a) in 53% yield (Table 4, entry 1). However, a good yield of benzothiazole 7a was
obtained under solventꢀfree condition (Table 4, entry 2). In this way, 2ꢀmercaptoaniline
(6) was reacted with various benzylamines 1b-1l under solventꢀfree condition to afford
benzothiazoles 7b-7l in good to high yields (Table 4, entries 3ꢀ13). A secondary amine
1n was also underwent the oxidative coupling with 2ꢀmercaptoaniline (6) to give the 2ꢀ
phenylbenzothiazole (7a) in 59% yield (Table 4, entry 14).
The synthetic utility of the ironꢀcatalyzed oxidative coupling reaction has been
demonstrated by the synthesis of some important biologically active molecules namely 2ꢀ
(thiophenꢀ2ꢀyl)ꢀ1Hꢀbenzo[d]imidazole (3k)18 (Table 2, entry 11), and 5ꢀmethylꢀ2ꢀ(pꢀ
substituted phenyl)benzoxazoles 5b-d19 (Table 3, entries 3ꢀ5), which exhibits
antileishmanial and antibacterial activities, respectively.
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Table 4. Synthesis of Benzothiazolesa
NH2
SH
FeBr2 (5 mol%)
110 oC, O2
N
S
+
R
R
NH2
1
6
7
Entry
Amine 1
Time (h)
Benzothiazole 7
Yield (%)b
1c
2
R1 = H
R1 = H
18
11
7a
7a
7b
7c
7d
53
78
80
85
83
1a
1a
3
R1 = Me 1b
9.5
9.5
18
N
NH2
R1
R1
S
4
R1 = OMe
1c
5
R1 = F
1d
N
S
NH2
6
7
1e
20
19
7e
7f
75
73
Cl
Cl
N
S
NH2
Cl
1f
Cl
Cl
Cl
CF3
F3C
N
S
NH2
8
1g
20
7g
67
CF3
CF3
O
O
N
S
NH2
9
10
19
76
72
1h
1i
7h
7i
O
O
N
S
NH2
OMe
NH2
10
MeO
N
S
11
1j
12
7j
75
N
S
S
NH2
NH2
12
13
14
20
18
24
7k
7l
69
56
59
1k
1l
S
N
S
N
N
N
S
Ph
N
Ph
1n
Ph
7a
H
a Reaction conditions: 2-mercaptoaniline 6 (2.0 mmol), benzylamine 1 (2.4 mmol), FeBr2 (5 mol %), O2 balloon, 110 oC.
b Isolated yield. c Reaction was performed in chlorobenzene.
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To gain some understanding of the mechanism of these oxidative coupling
reactions, a few control experiments were performed under standard conditions as shown
in Scheme 2. Treatment of benzylamine (1a) with iron(II) bromide under standard
conditions but in the absence of 2ꢀamino/hydroxy/mercaptoanilines (2a, 4 and 6)
furnished the homoꢀcoupling product Nꢀbenzylbenzaldimine (10) in 90% yield (Scheme
2a). Gratifyingly, the desired products 3a, 5a and 7a were obtained smoothly in 94, 67
and 75% yields respectively, when the imine 10 treated with 2ꢀ
amino/hydroxy/mercaptoanilines separately under standard conditions (Scheme 2b).
Next, we carried out a reaction between benzylamine (1a) and 2ꢀaminoaniline (2a) under
standard conditions, and analyzed the reaction mixture by GCꢀMS at different time
intervals to identify the possible intermediates (cf. Supporting Information). We detected
the formation of Nꢀbenzylbenzaldimine (10) and Nꢀbenzylidenebenzeneꢀ1,2ꢀdiamine (11)
intermediates in the reaction. In a separate experiment, the intermediate 11 prepared from
2ꢀaminoaniline and benzaldehyde, was treated with iron(II) bromide in chlorobenzene at
o
110 C under the atmosphere of molecular oxygen, furnished the 2ꢀphenylbenzimidazole
(3a) in 95% yield (Scheme 2c).
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Scheme 2. Control Experiments
On the basis of the above experimental results and previous reports in the
literature,13a,16b,20 we propose a tentative mechanism for the formation of 1,3ꢀbenzazoles
as outlined in Scheme 3. The first step may involve the oxidative addition of iron to the
benzylamine forming the complex 8. Benzylimine (9) and iron(II) bromide are generated
by further oxidation of complex 8. The reaction of imine 9 with another molecule of
benzylamine generates Nꢀbenzylbenzaldimine (10) with the liberation of ammonia. The
imine 10 could be easily transformed into 2ꢀ(benzylideneamino)aniline/phenol/
thiophenol (11) by the transimination with 2ꢀamino/hydroxy/mercaptoanilines. In
parallel, the imine 11 could be formed directly from benzylimine (9) by transimination
with 2ꢀamino/hydroxy/mercaptoanilines. Afterwards, the imine 11 may undergo
intramolecular
cyclization
gives
the
2ꢀphenylꢀ2,3ꢀdihydroꢀ1Hꢀ
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benzo[d]imidazole/oxazole/thiazole (12). Oxidation of resulting intermediates 12 in the
presence of iron(II) bromide and molecular oxygen gives the 2ꢀsubstituted
benzimidazoles, benzoxazoles and benzothiazoles, through the formation of iron complex
13.
Scheme 3. Proposed Reaction Mechanism
CONCLUSIONS
We have developed a simple, novel, and efficient method for the synthesis of 2ꢀ
substituted 1,3ꢀbenzazoles from benzylamines and 2ꢀamino/hydroxy/mercaptoanilines in
a oneꢀpot process. The inexpensive and nonꢀtoxic iron(II) bromide as catalyst, and
environmentally friendly molecular oxygen as oxidant were used in this procedure, which
makes the transformation very practical and economical. Further studies on the scope of
the reaction using benzylamines are currently underway in our laboratory.
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EXPERIMENTAL SECTION
General Information:
Melting points were determined on a Büchi melting point apparatus and were
uncorrected. NMR spectra were recorded on a 400 MHz spectrometer (1H at 400 MHz,
13C at 100 MHz), using DMSOꢀd6 or CDCl3 or CD3OD as the solvent with
tetramethylsilane (TMS) as the internal standard at room temperature. Highꢀresolution
mass spectra (HRMS) were obtained using an electrospray quadrupole timeꢀofꢀflight
(ESIꢀQꢀTOF) mass spectrometer. IR spectra were recorded on a FTꢀIR spectrometer. GCꢀ
MS analysis were performed on a gas chromatograph mass spectrometer operating at 70
eV, connected to a gas chromatograph fitted with a HPꢀ5 column. Standard GCꢀMS
o
programme: split mode (split ratio 400:1), injector temperature 300 C, MS source 230
o
oC, MS quadrupole 150 C, column flow 1 mL minꢀ1, total flow 404 mL minꢀ1. All
commercially obtained materials and solvents were used directly without further
purification unless otherwise noted. Chlorobenzene was dried over P2O5 and distilled
before use. Reactions were carried out in ovenꢀdried Schlenk tube or roundꢀbottom flask.
General Procedure for Iron-Catalyzed Synthesis of Benzimidazoles 3:
To a Schlenk tube were added diamine 2 (1 equiv, 2.0 mmol), benzylamine 1 (1.2 equiv,
2.4 mmol), FeBr2 (5 mol %), and chlorobenzene (2 mL). Next the tube was equipped
with O2 balloon, and the reaction mixture was stirred constantly at 110 °C until complete
consumption of diamine as monitored by TLC. Upon completion of the reaction, the
mixture was cooled to room temperature, diluted with EtOAc, and filtered over neutral
alumina. The solvent was evaporated under reduced pressure and the residue was purified
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by column chromatography over silica gel (100−200 mesh) using hexane/ethyl acetate
mixture as eluent to afford the desired products 3.
General Procedure for Iron-Catalyzed Synthesis of Benzoxazoles 5:
To a Schlenk tube were added 2ꢀhydroxyꢀ5ꢀmethylaniline (4, 1 equiv, 2.0 mmol),
benzylamine 1 (1.2 equiv, 2.4 mmol), FeBr2 (5 mol %), and chlorobenzene (1 mL). Next
the tube was equipped with O2 balloon, and the reaction mixture was stirred constantly at
120 °C until complete consumption of 2ꢀhydroxyꢀ5ꢀmethylaniline as monitored by TLC.
Upon completion of the reaction, the mixture was cooled to room temperature, diluted
with CH2Cl2, and filtered over neutral alumina. The solvent was removed under reduced
pressure and the residue was purified by column chromatography over silica gel
(100−200 mesh) using hexane/ethyl acetate mixture as eluent to furnish the benzoxazoles
5.
General Procedure for Iron-Catalyzed Synthesis of Benzothiazoles 7:
To a Schlenk tube were added 2ꢀmercaptoaniline (6, 1 equiv, 2.0 mmol), benzylamine 1
(1.2 equiv, 2.4 mmol), and FeBr2 (5 mol %). Next the tube was equipped with O2 balloon,
and the reaction mixture was stirred constantly at 110 °C until complete consumption of
2ꢀmercaptoaniline as monitored by TLC. Upon completion of the reaction, the mixture
was cooled to room temperature, diluted with CH2Cl2, and filtered over neutral alumina.
The solvent was evaporated under reduced pressure and the residue was purified by
column chromatography over silica gel (100−200 mesh) using hexane/ethyl acetate
mixture as eluent to afford the benzothiazoles 7.
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Synthesis of N-benzylbenzaldimine (10):
To a Schlenk tube were added benzylamine (1a, 258 mg, 2.4 mmol), FeBr2 (26 mg, 5 mol
%), and chlorobenzene (1 mL). Next the tube was equipped with O2 balloon, and the
reaction mixture was stirred constantly at 110 °C for 2.5 h. The mixture was cooled to
room temperature, adsorbed on basic alumina and purified by column chromatography
over basic alumina using hexane/ethyl acetate mixture as eluent to afford the Nꢀ
benzylbenzaldimine 10 (423 mg, 90% yield) as a clear, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.40 (s, 1H), 7.80ꢀ7.78 (m, 2H), 7.43ꢀ7.40 (m, 3H), 7.35ꢀ7.34 (m, 4H), 7.29ꢀ
13
7.25 (m, 1H), 4.83 (s, 2H); C NMR (100 MHz, CDCl3) δ 161.9, 139.2, 136.1, 130.7,
128.6, 128.5, 128.2, 127.9, 126.9, 65.0.
Synthesis of N-benzylidenebenzene-1,2-diamine (11):
To a stirred solution of 2ꢀaminoaniline (2a, 400 mg, 3.70 mmol) in chlorobenzene (2 mL)
was added a solution of benzaldehyde (197 mg, 1.85 mmol) in chlorobenzene (1 mL) by
dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30
minutes at 0 °C and then warmed to room temperature. The crude mixture was purified
by column chromatography over basic alumina using hexane/ethyl acetate mixture as
eluent. Concentration of the relevant fractions (Rf = 0.43 in 0.2/9.8 v/v ethyl
1
acetate/hexane) afforded compound 11 (127 mg, 35%) as a clear, yellow oil; H NMR
(400 MHz, CDCl3) δ 8.46 (s, 1H), 7.85ꢀ7.82 (m, 2H), 7.40ꢀ7.38 (m, 3H), 7.02ꢀ6.98 (m,
2H), 6.71ꢀ6.66 (m, 2H), 4.15 (brs, 2H); 13C NMR (100 MHz, CDCl3) δ 157.5, 142.2,
137.1, 136.4, 131.1, 128.9, 128.7, 128.6, 127.7, 118.4, 117.1, 115.4; HRMS (ESI) m/z
calcd for C13H12N2 [M + H]+ 197.1073, found 197.1069.
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ACKNOWLEDGEMENTS
The authors sincerely thank and acknowledge DUꢀR&D Grant and University of Delhi
for financial support to carry out this work, and DUꢀDST mass spectrometry facility.
S.N.C thanks the Council of Scientific and Industrial Research, New Delhi, India, for a
research fellowship. We are grateful to Prof. M. L. N. Rao, Indian Institute of
Technology Kanpur, for helping the GCꢀMS analysis of samples.
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