Iron phthalocyanine as an efficient and versatile catalyst for N-alkylation of heterocyclic amines with alcohols: One-pot synthesis of 2-substituted benzimidazoles, benzothiazoles and benzoxazoles

Article abstract of DOI:10.1039/c3gc40137e

An efficient and versatile iron phthalocyanine catalyzed method has been developed for N-alkylation of various amines with alcohols. Readily available alcohols were used as alkylating agents for direct N-alkylation of aminobenzothiazoles, aminopyridines and aminopyrimidines. N-Alkylation of ortho-substituted anilines (-NH₂, -SH and -OH) led to the synthesis of 2-substituted benzimidazoles, benzothiazoles and benzoxazoles in one pot.

Full text of DOI:10.1039/c3gc40137e

View Article Online
View Journal
Green Chemistry
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
Volume 12 | Number 9 | September 2010 | Pages 1481–1676
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1463-9262
COMMUNICATION
CRITICAL REVIEW
Luque, Varma and Baruwati
Dumesic et al.
Magnetically seperable organocatalyst Catalytic conversion of biomass
for homocoupling of arylboronic acids to biofuels
1463-9262(2010)12:9;1-U
www.rsc.org/greenchem
Registered Charity Number 207890

Page 1 of 7
Green Chemistry
View Article Online
Iron Phthalocyanine as an Efficient and Versatile Catalyst for N-alkylation of Heterocyclic
Amines with Alcohols: One-pot Synthesis of 2-Substituted Benzimidazoles, Benzothiazoles
and Benzoxazoles
Manju Bala, Praveen Kumar Verma, Upendra Sharma, Neeraj Kumar and Bikram Singh*
R
NH2
NH
R1
R1
1 example
iolated yield 86 %
N
S
R1
NH2
NH2
N
R1
N
N
N
9 examples
isolated yield upto 90 %
8 examples
Fe
N
N
isolated yield upto 87 %
N
N
N
+
R
R
N
R1
NH
NH
R-CH2OH
S
R1
N
17 examples
isolated yield upto 94 %
NH2
N
R
X
X = NH, S, O
XH
An efficient and versatile method was developed for N-alkylation of various amines with alcohols by utilizing aboundently
available iron phthalocyanine as catalyst. Readily available alcohols were used as alkylating agents for direct N-alkylation of
aminobenzothiazoles, aminopyridines and aminopyrimidines. N-alkylation of ortho-substituted anilines (-NH2, -SH and –OH) led
to the synthesis of 2-substituted benzimidazoles, benzothiazoles and benzoxazoles in one-pot.

View Article Online
Green Chemistry
Page 2 of 7
Dynamic Article Links ►
Green Chemistry
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
PAPER
Iron Phthalocyanine as an Efficient and Versatile Catalyst for N-
alkylation of Heterocyclic Amines with Alcohols: One-pot Synthesis of 2-
Substituted Benzimidazoles, Benzothiazoles and Benzoxazoles†
Manju Bala,a,b Praveen Kumar Verma,a,b Upendra Sharma,b,c Neeraj Kumar b and Bikram Singh*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
Since the use of alcohols for N-alkylation reaction by Grigg3
An efficient and versatile iron phthalocyanine catalyzed
method has been developed for N-alkylation of various
amines with alcohols. Readily available alcohols were used
and Watanabe,4 different transition metals based methods have
been reported.5 Harsh reaction conditions, expensive metals,
40 toxic and capricious ligands limit the scope of these methods.
Inexpensive metals based environmentally benign catalytic
method are extremely desirable for the N-alkylation reactions
with alcohols.
10 as alkylating agents for direct N-alkylation of
aminobenzothiazoles,
aminopyridines
and
aminopyrimidines. N-alkylation of ortho-substituted
anilines (-NH2, -SH and –OH) led to the synthesis of 2-
Benzazoles such as benzimidazoles, benzothiazoles and
45 benzoxazoles are considered as privileged motifs in the field of
medicinal chemistry.6 The benzazole nucleus is pharmacophore
present in various modern drugs including omeprazole (proton-
pump inhibitor), candesartan and telmisartan (AT1 receptor
substituted
15 benzoxazoles in one-pot.
benzimidazoles,
benzothiazoles
and
Introduction
antagonist),
dabigatran
(direct
thrombin
inhibitor),
The N-alkylation of primary amines to higher amines is of
fundamental importance to academics as well as chemical
industries for the synthesis of dyes, additives, agrochemicals,
20 functional materials and pharmacophores in various bioactive
molecules.1 The conventional approaches for the synthesis of
secondary and tertiary amines involve alkylation of primary
amines with an alkylating agent having a good leaving group
such as alkyl halides, triflates, tosylates, and mesylates.2 These
25 conventional approaches are problematic due to the toxic
nature of reagents used, over alkylation and generation of
50 flunoxaprofen (NSAID), and riluzole (sodium channel
blocker).7 2-(N-alkylamino)benzothiazole is also present as
important structural unit in many biologically active
compounds such as fanetizole (anti-inflammatory agent), UDP-
galactopyranose mutase inhibitor, κ and µ opoid receptors, and
55 small molecule somatostatin receptor subtype 5 (SST5R)
antagonists (Scheme 2).8
S
O
N
stoichiometric
amount
of
waste.
The
alternative
NH
S
N
environmentally benign approach is metal catalyzed
borrowing-hydrogen methodology by employing inexpensive
30 and readily available alcohols as alkylating agents (Scheme 1).
This approach is atom economic, thermodynamically favoured
and waste free as water is the only byproduct and follow a
cascade redox type pathway involving in-situ alcohol
oxidation/imine formation/imine hydrogenation steps.
N
N
H
Me
OMe
MeO
Me
Fanetizole
Omeprazole
O
H
N
N
S
N
N
R4
R3
R1
NH2
F3CO
H
R2O
H
SST5R antagonists
Riluzole
R'NH2
R'
Scheme 2 Bioactive molecules with benzazole and 2-N-
(alkylamino)azole moieties.
R
N
H
R
OH
Earlier workRef 3-5
M
M = Ir, Ru, Rh, Cu, Pd
60
Recently, our group has developed metal phthalocyanines
based inexpensive, ligand free, environmentally benign
methods for nitro reduction,9a-9c carbonyl reduction9d and
reductive amination.9e Herein, we report iron(II)phthalocyanine
as an efficient, inexpensive and versatile catalyst for N-
This work
Fe
MH2
R'
R
N
R
O
R'NH2
65 alkylation of heterocyclic amines and synthesis of 2-substituted
benzazoles.
35 Scheme 1 Transition metal catalyzed borrowing hydrogen
methodology for N-alkylation of amines.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

View Article Online
Page 3 of 7
Green Chemistry
provided the N-alkylation product but NaOtBu was
comparatively more effective (Table 3, entries 3 and 4).
Results and Discussion
Optimization of reaction conditions
30 Table
3 Screening of bases for N-alkylation of 2-
aminobenzothiazolea
The reaction of 2-aminobenzothiazole with benzyl alcohol was
selected as the model reaction for establishing the best reaction
conditions. Initially, the effect of various iron based catalysts
was investigated (Table 1). Reaction did not proceed without
any catalyst in the presence of NaOtBu, which excluded the
contribution of base itself as a catalyst (Table 1, entry 1). The
highest activity was observed with Fe(II)Pc followed by FeCl3
S
S
N
5
FePc (1 mol%)
Base, 100 o
Toluene, 12 h
HO
NH2
+
NH
C
N
Entry
Base
Yield (%)b
1
2
3
4
5
6
NaOH
K2CO3
Cs2CO3
NaOtBu
K3PO4
3
No Reaction
10 (Table 1, entries 5 and 6). Other iron salts as well as Fe(III)Pc
were found ineffective (Table 1 entries 2-4, 7).
72
92
32
1
Table
1
Catalyst screening for N-alkylation of 2-
DABCO
aminobenzothiazolea
a
Reaction conditions: 2-aminobenzothiazole (1 mmol), benzyl
alcohol (1 mmol), Fe(II)Pc (1 mol%), base (2 mmol), toluene (5 mL),
at 100 oC for 12 h. b GC-MS yield.
S
S
N
Catalyst (1 mol%)
NaOtBu, 100 o
Toluene, 12 h
HO
NH2
+
NH
C
N
Once the best reaction conditions were achieved, the scope
of the method was investigated for the N-alkylation of various
35 aminobenzothiazoles, aminopyridines and aminopyrimidines.
Entry
Catalyst
Yield (%)b
1
2
3
4
5
6
7
-
-
3
2
Iron metal
Fe2O3
FeSO4
FeCl3
Fe(II)Pc
Fe(III)Pc
Regioselective N-alkylation of aminobenzothiazoles
12
64
92
4
The N-alkylation of 2-aminobenzothiazoles with alkyl halides
occurs on the most basic endocyclic nitrogen, affording N-
endosubstituted 3-alkyl-2-iminobenzothiazolines as products
40 (Scheme 3).10 Various transition metal based catalytic methods
have been developed for the preparation of 2-(N-
alkylamino)benzothiazoles.11 However, use of expensive
metals and requirement of multiple steps, limit the scope of
these methods. Recently, Li et al. have applied copper based
45 catalyst for direct N-alkylation of 2-aminobenzothiazole with
benzyl alcohols to synthesize 2-(N-alkylamino)benzothiazoles
at high temperature.12
a
Reaction conditions: 2-aminobenzothiazole (1 mmol), benzyl
alcohol (1 mmol), catalyst (1 mol%), NaOtBu (2 mmol), toluene (5
mL) at 100 oC for 12 h. b GC-MS yield.
15
Toluene was found as the best solvent for N-alkylation
reaction (Table 2, entry 4). No reaction occurred in case of
water (Table 2 entry 2), while, DMF, 1,4-dioxane, PEG-400
and ethanol resulted in much lower yields (Table 2, entries 1, 3
5 and 6).
Previous workRef 11, 12
Previous workRef 10
R
N
Cu, Ir
NH
R
20 Table
2
Solvent screening for N-alkylation of 2-
S
50
aminobenzothiazolea
N
S
N
RCH2OH
RCH2X
NH2
NH
S
R
N
S
S
S
N
FePc (1 mol%)
Fe
HO
NH
NH2
+
NH
NaOtBu, 100 o
C
N
Solvent, 12 h
This work
Entry
Solvent
Yield (%)b
55 Scheme
3
Regioselective
N-alkylation
of
2-
1
2
3
4
5
6
DMF
H2O
EtOH
1
aminobenzothiazoles with alkyl halides and alcohols.
no reaction
In contrast, Fe(II)Pc catalyzed regioselective N-alkylation of
aminobenzothiazoles with alcohols afforded N-exosubstituted
N-alkylaminobenzothiazoles under the optimal reaction
20
92
5
Toluene
1,4-dioxane
PEG-400
7
60 conditions
(Table
4).
The
N-alkylation
of
2-
a
Reaction conditions: 2-aminobenzothiazole (1 mmol), benzyl
aminobenzothiazole with benzyl alcohol (entry 4a) gave the
desired product in excellent yield. The halogen subsituted
benzyl alcohols (entries 4b and 4c) afforded the corresponding
products in good yields. 3-Methoxybenzyl alcohol (entry 4d)
65 and heteroaromatic alcohol such as 2-pyridylmethanol (entry
4e) were efficiently utilized to obtain the corresponding
desired product.
alcohol (1 mmol), Fe(II)Pc (1 mol%), NaOtBu (2 mmol), solvent (5
mL) at 100 oC for 12 h. b GC-MS yield.
The reaction conditions were further optimized through
variation of different bases (Table 3). Bases such as NaOH,
25 K2CO3 and DABCO were found ineffective whereas K3PO4
afforded only 32 % yield of the desired product (Table 3,
entries 1, 2 and 5, 6). Both Cs2CO3 and NaOtBu efficiently
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
Green Chemistry
Page 4 of 7
Table 4 N-alkylation of aminobenzothiazoles with alcohols.a,b
Table 5 N-alkylation of aminopyridines and aminopyrimidines
with alcohols.a,b
R2
FePc (1 mol%), Toluene, N2
NaOtBu (2 mmol), 100oC, 12 h
R1
OH
+
R2 NH2
N
R1
R2
H
FePc (1 mol%), Toluene, N2
NaOtBu (2 mmol), 100oC, 12 h
R1
OH
+
R2 NH2
N
R1
H
S
N
S
N
S
Cl
N
N
H
H
N
H
N
Br
N
N
N
N
N
N
N
H
H
H
4a, 92% (87%)
4b, 79% (74%)
4c, 55% (52%)
Br
Br
Br
Br
5c, 71% (68%)
5a, 72%
5b, 52%
S
N
S
N
S
Me
Me
Me
N
H
N
N
H
N
H
N
N
N
OMe
N
H
N
H
N
H
N
N
4d, 85% (81%)
4e, 88% (80%)
4f, 67% (63%)
Br
Me
Me
Me
Me
Me
Me
5d, 57% (52%)
S
5e, 80% (77%)
5f, 95% (90%)
N
HN
N
H
N
N
N
N
N
N
S
N
NH
N
OMe
4g, 86% (83%)
H
H
N
N
OCH3
Br
4h, 75% (72%)
Me
Me
Me
Me
a Reaction conditions: amine (1 mmol), alcohol (1 mmol), Fe(II)Pc (1
mol%), NaOtBu (2 mmol), toluene (5 mL) at 100 C for 12 h. b Isolated
5 yields are given in parenthesis.
Me
5h, 80% (76%)
5g, 92% (90%)
5i, 24% (20%)
N
H
The N-alkylation of 6-aminobenzothiazole with benzyl
alcohol and 3-methoxybenzyl alcohol afforded the desired
products in good yields (entries 4f and 4g). Furthermore, the N-
alkylation of 4-amino-2,1,3-benzothiadiazole with benzyl
10 alcohol also afforded the corresponding product in good yield
(entry 4h).
5j, (86%)c
a Reaction conditions: amine (1 mmol), alcohol (1 mmol), Fe(II)Pc (1
45 mol%), NaOtBu (2 mmol), toluene (5 mL) at 100 C for 12 h. b Isolated
yields are given in parenthesis. c Reaction temperature 140 C.
available on the synthesis of benzazoles directly from
alcohols.18 Recently, Ru/Xanthphos,19a Ru,18a IBX19b have been
applied for the synthesis of benzimidazole. Deng et al. reported
N-alkylation of aminopyridines and aminopyrimidines
50 dppf
[1,1’-bis(diphenylphosphino)ferrocene]
catalyzed
The selective N-alkylation of aminopyridines to the
corresponding secondary amines is a challenging task due to
15 the formation of amides as byproduct.13 Under present reaction
conditions the N-alkylation of substituted aminopyridines and
aminopyrimidines with alcohols proceeded smoothly with good
to excellent yields (Table 5). The reaction of 4-bromo-2-
aminopyridine with benzylic alcohols (entries 5a and 5b)
20 afforded the desired products in good yields. Also, the reaction
with 2-pyridylmethanol (entry 5c) did not distress the yield of
the corresponding secondary amine product. The N-alkylation
of 4,6-dimethyl-2-aminopyridine was successfully caried out
with benzylic alcohols (entries 5d and 5e) in good to high
25 yields. Interestingly, the reaction of 4,6-dimethyl-2-amino-
pyrimidines with benzylic alcohols (entries 5f-5h) afforded the
desired products in excellent yields. Low yield of the product
(24 %) was observed for the N-alkylation of 4,6-dimethyl-2-
amino-pyrimidine with isoamyl alcohol (entry 5i). The present
30 protocol also performed the N-alkylation of aniline with benzyl
alcohol in high yield (entry 5j).
synthesis of 2-arylbenzoxazoles directly from o-nitrophenols
and benzyl alcohols.20
The process involves N-alkylation of anilines to
corresponding imines, followed by in-situ cyclization and
55 oxidation to corresponding 2-arylbenzazoles (Scheme 4).
H
NH2
N
X
N
N-alkylation
HO
+
XH
XH
X = NH, S, O
oxidation
60
N
X
Scheme 4 N-alkylation of ortho-substituted anilines and in-situ
cyclization to 2-arylbenzazoles.
Although, the reaction conditions were similar as for the N-
alkylation, however, reaction took longer time for completion
65 at slightly high temperature. Various experiments were carried
out to optimize the N-alkylation of ortho-substituted anilines
(see supporting information, Table S1). In order to explore the
scope of the present method, the reactions of o-substituted (-
NH2 or -SH or -OH) anilines were successfully performed with
70 a variety of alcohols (Table 6, 7 and scheme 5).
N-alkylation of ortho-substituted anilines: synthesis of
benzimidazoles, benzothiazoles and benzoxazole
The reaction of o-phenylenediamine with benzyl alcohol
(entry 6a) afforded 2-phenylbenzimidazole in high yield. Good
yields were obtained with halide bearing benzyl alcohols
(entries 6b and 6c). The reaction of 3-methoxybenzyl alcohol,
75 3-methylbenzyl alcohol and 1-naphthyl alcohol proceeded
smoothly to give the desired products in good to excellent
yields (entries 6d-6f). Heteroaromatic alcohol, 2-
pyridylmethanol (entry 6g), gave the corresponding product in
The most commonly used methods for the synthesis of
35 benzazoles include the condensation of ortho-substituted (-NH2
or -SH or -OH) anilines with aldehydes,14 nitriles,15 carboxylic
acids,16 or acyl chlorides.17 Most of these methods are
associated with the limitations such as poor selectivity, side
reactions, tedious work-up procedures and requirement of
40 special oxidation process. Alternatively, few reports are also
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
Page 5 of 7
Green Chemistry
good yield (69%), however, low yield (41%) was obtained with
aliphatic alcohol, isoamyl alcohol (entry 6h).
phenylbenzoxazole by the reaction of 2-aminophenol with
55 benzyl alcohol in good yield (Scheme 5).
O
Table 6 N-alkylation of o-phenylenediamine with alcohols.a,b
NH2
OH
FePc (1 mol%), Toluene, N2
NaOtBu (2 mmol), 120 oC, 36 h
HO
+
N
H
GC-MS Yield = 89%
1 mmol
1.5 mmol
NH2
NH2
N
FePc (1 mol%), Toluene, N2
NaOtBu (2 mmol), 120 oC, 36 h
+
HO
R
R
5
10
15
Scheme 5 N-alkylation of 2-aminophenol with benzyl alcohol
and in-situ cyclization to 2-phenylbenzoxazole.
N
H
N
H
N
H
N
Cl
N
N
N
60 Mechanistic Study
Br
6c, (81%)
6a, 89% (84%)
6b, 79% (75%)
Based on the previously known hydrogen transfer
methodologies,18,21 it is expected that the present process
underwent the three steps of alcohol oxidation-imine
formation-imine hydrogenation. To confirm this, few
65 experiments were carried out. In the absence of amine,
oxidation of benzyl alcohol to benzaldehyde was observed
under present reaction conditions confirming the first step (Fig.
1 a). When the reaction was carried out at low temperature (70
oC) or stopped in-between, imine was observed as major
70 product which confirms the second step. The hydrogenation of
imine afforded corresponding amine under the present reaction
conditions, which further confirmed the second step (Fig. 1b).
H
N
H
N
H
N
N
N
N
H3C
OCH3
6d, 70%
6e, (94%)
6f, 92% (89%)
H
H
N
N
N
N
N
6h, 41%
6g, 69% (66%)
a
Reaction conditions: o-phenylenediamine (1 mmol), alcohol (1.5
20 mmol), Fe(II)Pc (1 mol%), NaOtBu (2 mmol), toluene (5 mL) at 120
C for 36 h. b Isolated yields are given in parenthesis.
Fe(II)Pc (1 mol%)
NaOtBu (2 equiv.), 100 oC, 12 h
HO
O
Reaction of substituted benzyl alcohols with 2-
...
a
aminothiophenol
afforded
the
desired
2-substituted
S
S
25 benzothiazoles in excellent yields (Table 7). In case of benzyl
alcohol (entry 7a), 2-bromobenzyl alcohol (entry 7b), 4-
bromobenzyl alcohol (entry 7c), 3-methoxybenzyl alcohol
(entry 7d), and 2-methylbenzyl alcohol (entry 7e) good to
excellent yields were observed. Heteroaromatic alcohols such
30 as 2-pyridylmethanol (entry 7f) and 4-pyridylmethanol (entry
7g) also gave the corresponding benzothiazole products in
excellent yields. The reaction of aliphatic isoamyl alcohol
(entry 7h) afforded the desired product in low yield.
Fe(II)Pc (1 mol%)
NaOtBu (2 equiv.), 100 oC, 12 h
HO
...
b
+
NH
N
N
N
1 mmol
1 mmol
75
Figure 1 Oxidation of alcohol (a) and hydrogenation of imine
(b).
The synthesis of 2-arylbenzazoles from ortho-substituted
anilines and alcohols involves in-situ alcohol oxidation to
80 aldehyde/imine formation/cyclization and finally oxidation of
cyclized product (Scheme 4)18. We propose that FePc promote
the oxidation of alcohols to aldehydes. Aldehydes react with 2-
arylbenzazoles to form imine, which remain in equilibrium
with cyclized product. The cyclized product is then oxidized
85 either by base or oxygen22 to final product. To confirm this,
controlled experiments were carried out with and without FePc
(entries 1 and 6 respectively, Scheme 6 left, Table S1). Yield of
desired product decreased drastically without FePc. On the
other hand reaction of 2-aminothiophenol with benzaldehyde
90 instead of alcohol in the absence of catalyst gave 83% of 2-
phenylbenzothiazole (entry 18, Table S1). This confirmed that
FePc is mainly involved in oxidation of alcohols to aldehydes.
Table 7 N-alkylation of 2-aminothiophenol with alcohols.a,b
35
SH
S
N
FePc (1 mol%), Toluene, N2
NaOtBu (2 mmol), 120 oC, 36 h
+
HO
R
R
NH2
S
N
S
S
N
Br
N
Br
7c, 99% (96%)
7a, 94% (90%)
7b, 96% (90%)
40
45
50
S
S
S
N
N
N
N
H3C
OCH3
7d, 99% (92%)
7e, 73% (70%)
7f, 99%
FePc
S
S
S
S
FePc
N
N
N
N
N
NH2
SH
N
yield = 92%
GC-MS yield >99%
C6H5CH2OH
C6H5CHO
SH
7h, 44%
7g, 99%
S
S
isolated
without
FePc
without
FePc
N
N
a
GC-MS yield >99%
yield = 7%
Reaction conditions: 2-aminothiophenol (1 mmol), alcohol (1.5
mmol), Fe(II)Pc (1 mol%), NaOtBu (2 mmol), toluene (5 mL) at 120
C for 36 h. b Isolated yields are given in parenthesis.
Scheme
6
Controlled experiments for elucidation of
95 mechanism.
The present protocol was also applied for the synthesis of 2-
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
Green Chemistry
Page 6 of 7
As, no effect of FePc was observed when controlled
experiments were performed with isolated imine intermediate
(Scheme 6, right), further confirmed the involvement of FePc
in the oxidation of alcohols to aldehydes.
To a stirred suspension of FePc (1 mol%) and NaOtBu (2 mmol)
55 in toluene (5 mL) were added alcohol (1.5 mmol), o-substituted
aniline (1.0 mmol) at room temperature and then temperature
was raised to 120 oC for 36 h. On completion of the reaction (as
monitored by TLC), reaction mixture was filtered and passed
through anhydrous Na2SO4 and dried under vacuum. The crude
60 product was analysed by GC-MS or purified by column
chromatography over silica-gel (60-120 mesh) with appropriate
mixture of n-hexane and ethyl acetate. The GC-MS yields of
products were calculated on the basis of amine reactants.
5
Experimental
General Information
Metal salts used were purchased from Merck, Germany. Iron
phthalocyanines, amines, alcohols, and benzothiazoles were
purchased from Sigma-Aldrich, USA. Silica gel (60-120 mesh)
Conclusion
10 used for column chromatography was purchased from Sisco
Research Laboratories Pvt. Ltd., India and all other chemicals
were purchased from Spectrochem, India, Merck, Germany and
Sigma-Aldrich, USA and were used without further
purification. NMR spectra were recorded on a Bruker Avance-
15 300 spectrometer. Mass spectra were recorded on QTOF-Micro
of Waters Micromass. The GC-MS analysis was carried out on
Shimadzu (QP 2010) series Gas Chromatogram-Mass
Spectrometer (Tokyo, Japan), AOC-20i auto-sampler coupled,
and a DB-5MS capillary column, (30 m x 0.25 mm i.d.,
20 0.25µm). The initial temperature of column was 70 °C held for
4 min. and was programmed to 230 °C at 4 °C/min., then held
for 15 min. at 230 °C; the sample injection volume was 2 µL in
GC grade dichloromethane. Helium was used as carrier gas at a
flow rate of 1.1 mL min-1 on split mode (1: 50). Melting points
25 were determined on a Barnstead Electrothermal 9100.
65 The use of abundantly available and low toxic iron based
catalyst is an attractive catalytic alternative to other costly and
toxic transition metals. In the present study, an efficient iron
phthalocyanine catalyzed method has been developed for the
N-alkylation of aminobenzothiazoles, aminopyridines and
70 aminopyrimidines. The present process is also applicable for
the efficient synthesis of 2-substituted benzimidazoles,
benzothiazoles and benzoxazole by the N-alkylation of ortho-
substituted anilines with readily available alcohols.
Acknowledgments
75 The authors are grateful to the Director of the Institute for
providing necessary facilities. Mr. P. K. V. and Mr. U. S. are
thankful to CSIR for Senior Rresearch Fellowship. We are also
thankful to Mr. Shiv Awasthi and Ms. Vijayalata Pathania for
technical assistance.
General experimental procedure for N-alkylation of
aminobenzothiazoles
80
aAcademy of Scientific & Innovative Research; CSIR-Institute of
Himalayan Bioresource Technology, Palampur, Himachal Pradesh-
176 061, INDIA
To a stirred suspension of FePc (1 mol%) and NaOtBu (2 mmol)
in toluene (5 mL) were added alcohol (1.0 mmol),
30 aminobenzothiazole (1.0 mmol) at room temperature and then
bNatural Plant Products Division, CSIR-Institute of Himalayan
85 Bioresource Technology, Palampur, Himachal Pradesh-176 061,
INDIA
o
temperature was raised to 100 C for 12 h. On completion of
cPresent address: Indian Institute of Technology Bombay, Powai, 400
076, India.
E-mail: bikram_npp@rediffmail.com
the reaction (as monitored by TLC), reaction mixture was
filtered and passed through anhydrous Na2SO4 and dried under
vacuum. The crude product was analysed by GC-MS or
35 purified by column chromatography over silica-gel (60-120
mesh) with appropriate mixture of n-hexane and ethyl acetate.
The GC-MS yields of products were calculated on the basis of
aminobenzothiazole reactants.
90 †IHBT communication no. 3464
†Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
Notes and references
General experimental procedure for N-alkylation of
40 aminopyridines and aminopyrimidines
95
100
105
110
1
(a) S. A. Lawerencem, Amines: Synthesis Properties and
Applications, Cambridge University, Cambridge, 2004; (b)
K. P. C. Vollhardt, N. E. Schore, Organic Chemistry:
Structure and Function, 3rd ed., W. H. Freeman, New York,
1999, p. 936; (c) A. A. Nunez Magro, G. R. Eastham and D.
J. Cole-Hamilton, Chem. Commun., 2007, 3154-3156; (d)
A. Seayad, M. Ahmed, H. Klein, R. Jackstell, T. Gross and
M. Beller, Science, 2002, 297, 1676-1678.
To a stirred suspension of FePc (1 mol%) and NaOtBu (2 mmol)
in toluene (5 mL) were added alcohol (1.0 mmol), pyridine or
pyrimidine (1.0 mmol) at room temperature and then
o
temperature was raised to 100 C for 12 h. On completion of
45 the reaction (as monitored by TLC), reaction mixture was
filtered and passed through anhydrous Na2SO4 and dried under
vacuum. The crude product was analysed by GC-MS or
purified by column chromatography over silica-gel (60-120
mesh) with appropriate mixture of n-hexane and ethyl acetate.
50 The GC-MS yields of products were calculated on the basis of
amine reactants.
2
3
(a) J. S. Bradshaw, K. E. Krakowiak and R. M. Izatt,
Tetrahedron, 1992, 48, 4475-4515; (b) R. N. Salvatore, C.
H. Yoon and K. W. Jung, Tetrahedron, 2001, 57, 7785-
7811; (c) J. F. Hartwig, Synlett, 2006, 1283-1294; (d) S. L.
Buchwald, C. Mauger, G. Mignani and U. Scholz, Adv.
Synth. Catal., 2006, 348, 23-39.
R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N.
Tongpenyai, J. Chem. Soc., Chem. Commun., 1981, 611-
612.
General experimental procedure for the synthesis of ortho-
substituted benzazoles
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

View Article Online
Page 7 of 7
Green Chemistry
4
5
Y. Watanabe, Y. Tsuji, H. Ige, Y. Ohsugi and T. Ohta, J.
Org. Chem.,1984, 49, 3359-3363.
C. D. Huu, M. H. Donat, J. M. Duchesne, P. Ganil, C.
Gueremy, E. Honore, B. Just, R. Kerphirique, S. Gontier, P.
Hubert, P. M. Laduron, J. L. Blevec, M. Meunier, J. M.
Miquet, C. Nemecek, M. Pasquet, O. Piot, J. Pratt, J.
Rataud, M. Reibaud, J. M. Stutzmann and S. Mignani, J.
Med. Chem., 1999, 42, 2828-2843.
(a) B. Blank, M. Madalska and R. Kempe, Adv. Synth.
Catal., 2008, 350, 749-758; (b) K. Fujita, Z. Li and
R.Yamaguchi, Tetrahedron Lett., 2003, 44, 2687-2690; (c)
K. I. Fujita, Y. Enoki and R. Yamaguchi, Tetrahedron,
2008, 64, 1943-1954; (d) R. Yamaguchi, S. Kawagoe, C.
Asai and K. I. Fujita, Org. Lett., 2008, 10, 181-184; (e) G.
Cami-Kobeci and J. M. J. Williams, Chem. Commun.,
2004, 1072-1073; (f) D. Hollmann, A. Tillack, D. Michalik,
R. Jackstell and M. Beller, Chem. Asian J., 2007, 2, 403-
410; (g) A. Tillack, D. Hollmann, D. Michalik and M.
Beller, Tetrahedron Lett., 2006, 47, 8881-8885; (h) A. J. A.
Watson and J. M. J. Williams, Science, 2010, 329, 635-636;
(i) G. E. Dobereiner and R. H. Crabtree, Chem. Rev., 2010,
110, 681-703; (j) R. H. Crabtree, Organometallics, 2011,
30, 17-19; (k) T. D. Nixon, M. K. Whittlesey and J. M. J.
Williams, Dalton Trans., 2009, 753-762; (l) T. Suzuki,
Chem. Rev., 2011, 111, 1825-1845; (m) G. Guillena, D. J.
Ramónand and M. Yus, Chem. Rev., 2010, 110, 1611–1641.
(a) A. A. Weekes and A. D. Westwell, Curr. Med. Chem.,
2009, 16, 2430-2440; (b) D. A. Horton, G. T. Bourne and
M. L. Smythe, Chem. Rev., 2003, 103, 893-930; (c) T. C.
Kuhler, M. Swanson, V. Shcherbuchin, H. Larsson, B.
Mellgard and J. E. Sjostrom, J. Med. Chem., 1998, 41,
1777-1788.
70
75
80
5
11 (a) L. L. Joyce, G. Evindar and R. A. Batey, Chem.
Commun., 2004, 446-447; (b) P. Saha, T. Ramana, N.
Purkait, M. A. Ali, R. Paul and T. Punniyamurthy, J. Org.
Chem., 2009, 74, 8719-8725; (c) Q. Ding, X. He and J. Wu,
J. Comb. Chem., 2009, 11, 587-591; (d) K. Inamoto, C.
Hasegawa, K. Hiroya and T. Doi, Org. Lett., 2008, 10,
5147-5150; (e) L. L. Joyce and R. A. Batey, Org. Lett.,
2009, 11, 2792-2795; (f) S. H. Cho, J. Y. Kim, S. Y. Lee
and S. Chang, Angew. Chem., Int. Ed., 2009, 48, 9127-
9130.
10
15
12 F. Li, H. Shan, Q. Kang and L. Chen, Chem. Commun.,
2011, 47, 5058-5060.
85 13 (a) C. Gunanathan, Y. Ben-David and D. Milstein, Science,
2007, 317, 790-792; (b) M. Haniti, S. A. Hamid, C. Liana
Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A.
Watson and J. M. J. Williams, J. Am. Chem. Soc., 2009,
131, 1766-1774.
90 14 (a) Y. Riadi, R. Mamouni, R. Azzalou, M. El Hadded, S.
Routier, G. Guillaumet and S. Lazar, Tetrahedron Lett.,
2011, 52, 3492-3495; (b) H. M. Bacchav, S. B. Bhagat and
V. N. Telvekar, Tetrahedron Lett., 2011, 52, 5697-5701.
15 D. F. Shi, T. D. Bradshaw, S. Wrigley, C. J. McCall, P.
Lelieveld, I. Fichtner and M. F. Stevens, J. Med. Chem.,
1996, 39, 3375-3384.
16 (a) J. Charton, S. Girault-Mizzi and C. Sergheraert, Chem.
Pharm. Bull., 2005, 53, 492-497; (b) J. A. Seijas, T,
Vazquez, M. Pilar, R. Carballido, M. Raquel, C. J. Crecente
and L. Romar-Lopez, Synlett, 2007, 313-317.
20
6
25
7
(a) F. Kallashi, D. Kim, J. Kowalchick, Y. J. Park, J. A.
Hunt, A. Ali, C. J. Smith, M. L. Hammond, J. V. Pivnichny,
X. Tong, S. S. Xu, M. S. Anderson, Y. Chen, S. S. Eveland,
Q. Guo, S. A. Hyland, D. P. Milot, A. M. Curniskey, M.
Latham, L. B. Peterson, R. Rosa, C. P. Sparrow, S. D.
Wright and P. Sinclair, J. Bioorg. Med. Chem. Lett., 2011,
21, 558-561; (b) C. G. Mortimer, G. Wells, J. P. Crochard,
E. L. Stone, T. D. Bradshaw, M. F. Stevens and A. D.
Westwell, J. Med. Chem., 2006, 49, 179-185.
95
100
105
110
115
30
35
17 V. K. Tondon and M. Kumar, Tetrahedron Lett., 2004, 45,
4185-4187.
8
(a) B. Cavalleri, M. Turconi, G. Tamborini, E. Occelli, G.
Cietto, R. Pallanza, R. Scotti, M. Berti, G. Roman and F.
Parenti, J. Med. Chem., 1990, 33, 1470-1476; (b) J. Das, R.
V. Moquin, J. Lin, C. Liu, A. M. Doweyko, H. F. Defex, Q.
Fang, S. Pang, S. Pitt, D. R. Shen, G. L. Schieven, J. C.
Barrish and J. Wityak, Bioorg. Med. Chem. Lett., 2003, 13,
2587-2590; (c) Z. Y. Sun, Z. Zhu, Y. Ye, B. McKittrick, M.
Czarniecki, W. Greenlee, D. Mullins and M. Guzzi, Bioorg.
Med. Chem. Lett., 2009, 19, 6801-6805; (d) I. D. Linney, I.
M. Buck, E. A. Harper, S. B. Kalindjian, M. J. Pether, N. P.
Shankley, G. F. Watt and P. T. Wright, J. Med. Chem., 2000,
43, 2362-2370; (e) U. S. Sorensen, D. Strobaek, P.
Christophersen, C. Hougaard, M. L. Jensen, E. Nielsen, D.
Peters, L. Teuber, U. S. Sorensen, D. Stroaek, P.
Christophersen, C. Hougaard, M. L. Jensen, E. Nielsen, D.
Peters and L. Teuber, J. Med. Chem., 2008, 51, 7625-7624;
(f) S. N. Manjula, N. M. Noolvi, K. V. Parihar, S. A. M.
Reddy, V. Ramani, A. K. Gadad, G. Singh, N. G. Kutty and
C. M. Rao, Eur. J. Med. Chem., 2009, 44, 2923-2929.
(a) U. Sharma, N. Kumar, P. K. Verma, V. Kumar and B.
Singh, Green Chem., 2012, 14, 2289-2293; (b) U. Sharma,
P. K. Verma, N. Kumar, V. Kumar, M. Bala and B. Singh,
Chem. Eur. J., 2011, 17, 5903-5907; (c) U. Sharma, P.
Kumar, N. Kumar, V. Kumar and B. Singh, Adv. Synth.
Catal., 2010, 352, 1834-1840; (d) P. K. Verma, U. Sharma,
N. Kumar, M. Bala, V. Kumar and B. Singh, Catal. Lett.,
2012, 142, 907-913; (e) V. Kumar, U. Sharma, P. K. Verma,
N. Kumar and B. Singh, Adv. Synth. Catal. 2012, 354, 870-
878.
18 (a) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, O.
Saidi and J. M. J. Williams, Org. Lett., 2009, 11, 2039-
2042; (b) C. D. Wilfred and R. J. K. Taylor, Synlett, 2004,
1628-1630; (c) V. R. Ruiz, A. Corma and M. I. Sabater,
Tetrahedron Lett., 2010, 66, 730-735.
19 (a) G. M. Raghavendra, A. B. Ramesha, C. N. Revanna, K.
N. Nandeesh, K. Mantelingu and K. S. Rangappa,
Tetrahedron Lett., 2011, 52, 5571-5574; (b) J. N. Moorthy
and I. Neogi, Tetrahedron Lett., 2011, 52, 3868-3871.
20 M. Wu, X. Hu, J. Liu, Y. Liao and G. J. Deng, Org. Lett.,
2012, 14, 2722-2725.
21 (a) K. Shimizu, K. Sugino and A. Satsuma, Chem. Eur. J.,
2009, 15, 2341-2351; (b) K. Shimizu, R. Sato and A.
Satsuma, Angew. Chem. Int. Ed., 2009, 48, 3982-3986; (c)
G. E. Dobereiner and R. H. Crabtree, Chem. Rev., 2010,
110, 681-703; (d) G. Guillena, D. J. Ramon and M. Yus,
Chem. Rev., 2010, 110, 1611-1641.
40
45
50
120 22 The possibility of oxygen acting as oxidant for the
conversion of cyclized product into final product can not be
ruled out at this stage. However, all reactions were carried
out under nitrogen atmosphere so there is less possibilities
of oxygen acting as the sole oxidant.
55
9
125
60
65 10 P. Jimonet, F. Audiau, M. Barreau, J. C. Blanchard, A.
Boireau, Y. Bour, M. A. Coleno, A. Doble, G. Doerflinger,
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]