"All-water" one-pot diverse synthesis of 1,2-disubstituted benzimidazoles: Hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' by water

Article abstract of DOI:10.1039/c3gc37004f

A new "all-water" tandem arylaminoarylation/arylaminoalkylation- reduction-cyclisation route is reported for one-pot diversity oriented synthesis of regiodefined 1,2-disubstituted benzimidazoles. Water plays a crucial and indispensable role through hydrogen bond driven 'synergistic electrophile-nucleophile dual activation' in the formation of N-mono-aryl/aryl alkyl/alkyl/cycloalkyl o-nitroanilines under metal and base-free conditions to replace the transition metal-based C-N bond formation (aryl amination) chemistry and underlines the origin of regiodefined installation of the diverse selection of aryl, aryl alkyl, and alkyl/cycloalkyl groups as substituents on the benzimidazole scaffold to form the 1,2-disubstituted benzimidazoles. The influence of the hydrogen bond effect of water in promoting the arylaminoarylation reaction under base and metal-free conditions has been realized through observation of inferior yields in D₂O compared to that obtained in water during the reaction of o-fluoronitrobenzene with aniline separately performed in water and D₂O under similar experimental conditions. Water also provides assistance in promoting the subsequent nitro reduction and in the final cyclocondensation steps. The role of water in promoting the cyclocondensation reaction through hydrogen bonds is realized by the differential product yields during the reaction of mono-N-phenyl-o- phenylenediamine with benzaldehyde performed separately in water and D ₂O. The better hydrogen bond donor and hydrogen bond acceptor abilities of water compared to those of the organic solvents are the contributing/deciding factors for making the new water-assisted tandem arylaminoarylation/arylaminoalkylation-reduction-cyclisation strategy for the diversified synthesis of the regiodefined 1,2-disubstituted benzimidazoles effective in an aqueous medium, making it represent a true "all-water chemistry."

Full text of DOI:10.1039/c3gc37004f

Green Chemistry
View Article Online
View Journal
PAPER
“All-water” one-pot diverse synthesis of
1,2-disubstituted benzimidazoles: hydrogen
bond driven ‘synergistic electrophile–nucleophile
dual activation’ by water†
Cite this: DOI: 10.1039/c3gc37004f
Damodara N. Kommi, Pradeep S. Jadhavar, Dinesh Kumar and Asit K. Chakraborti*
A new “all-water” tandem arylaminoarylation/arylaminoalkylation–reduction–cyclisation route is reported
for one-pot diversity oriented synthesis of regiodefined 1,2-disubstituted benzimidazoles. Water plays a
crucial and indispensable role through hydrogen bond driven ‘synergistic electrophile–nucleophile dual
activation’ in the formation of N-mono-aryl/aryl alkyl/alkyl/cycloalkyl o-nitroanilines under metal and base-
free conditions to replace the transition metal-based C–N bond formation (aryl amination) chemistry and
underlines the origin of regiodefined installation of the diverse selection of aryl, aryl alkyl, and alkyl/
cycloalkyl groups as substituents on the benzimidazole scaffold to form the 1,2-disubstituted benz-
imidazoles. The influence of the hydrogen bond effect of water in promoting the arylaminoarylation reac-
tion under base and metal-free conditions has been realized through observation of inferior yields in D2O
compared to that obtained in water during the reaction of o-fluoronitrobenzene with aniline separately
performed in water and D2O under similar experimental conditions. Water also provides assistance in pro-
moting the subsequent nitro reduction and in the final cyclocondensation steps. The role of water in pro-
moting the cyclocondensation reaction through hydrogen bonds is realized by the differential product
yields during the reaction of mono-N-phenyl-o-phenylenediamine with benzaldehyde performed sepa-
rately in water and D2O. The better hydrogen bond donor and hydrogen bond acceptor abilities of water
compared to those of the organic solvents are the contributing/deciding factors for making the new
water-assisted tandem arylaminoarylation/arylaminoalkylation–reduction–cyclisation strategy for the diver-
sified synthesis of the regiodefined 1,2-disubstituted benzimidazoles effective in an aqueous medium,
making it represent a true “all-water chemistry.”
Received 11th December 2012,
Accepted 20th January 2013
DOI: 10.1039/c3gc37004f
www.rsc.org/greenchem
Introduction
The 1,2-disubstituted benzimidazole scaffold is a versatile
pharmacophore in drug discovery due to the wide range of bio-
logical activities exhibited by compounds bearing this struc-
tural unit. This has led to the development of antihypertensive
drug telmisartan (1) and the GABAA receptor agonist 2, HCV
NS5B RdRp inhibitors 3 and JTK-109 (4) as potent leads
(Fig. 1).1
The regiodefined 1,2-disubstitution on the benzimidazole
scaffold is a structural characteristic of these active com-
pounds. However, the synthesis of regiodefined 1,2-disubsti-
Fig. 1 Pharmaceutically important 1,2-disubstituted benzimidazoles.
tuted benzimidazoles is
a challenging task. The direct
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
E-mail: akchakraborti@niper.ac.in
cyclocondensation between o-phenylenediamine and aldehyde
often leads to competitive formation of the 1,2-disubstituted
and the 2-substituted benzimidazoles (Scheme 1).2
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3gc37004f
This journal is © The Royal Society of Chemistry 2013
Green Chem.

View Article Online
Paper
Green Chemistry
deficiencies in atom economy, cost effectiveness, safety, and
scalability.9 The use of water is the preferred non-conventional
reaction medium in the design of green chemical syntheses10
and signifiacant efforts hase been made in performing organic
synthesis in aqueous medium.11 Herein we demonstrate a new
“all-water” chemistry of N-arylation–eduction–ondensation for
diversified one-pot synthesis of regiodefined 1,2-disubstituted
benzimidazoles fulfilling the triple bottom line philosophy7 of
green chemistry.
Scheme 1 Competitive formation of 1,2-disubstituted and 2-substituted benz-
imidazoles during the direct cyclocondensation between o-phenylenediamine
and an aldehyde.
Although a few methods have been reported to control the
selectivity towards the formation of the 1,2-disubstituted benz-
imidazoles2 the pattern of the substituent at the N-1 position
of the 1,2-disubstituted benzimidazoles is dependent on the
aldehyde substrate that dictates the N-1 substituent to be the
one carbon homologue of the C-2 substituent. Thus, the con-
struction of the benzimidazole scaffold bearing a diverse range
of substituents at the N-1 and the C-2 positions of the 1,2-
disubstituted benzimidazole moiety poses a synthetic challenge.
The limited methodologies reported for the synthesis of regio-
defined 1,2-disubstituted benzimidazoles (Scheme 2) include
intermolecular coupling of o-iodo-N-alkylaniline with amide3
(Route A) or o-iodo/bromoanilides with alkyl/aryl amines4
(Route B), intramolecular coupling of Z-N′-(o-halophenyl)-N-
alkyl/phenyl)amidines5 (Route C), and the reductive cyclisation
of in situ formed o-nitroanilides from o-nitrochlorobenzenes
by palladium-catalyzed amidation (Route D).6
Results and discussion
In the reported procedures3–6 the aryl-amination step is critical
in inducting the substituents of the 1,2-disubstituted benzimi-
dazole scaffold and is achieved through transition-metal cata-
lysis, presumed12 to proceed through metalation of the Ar–
halogen bond (electrophilic activation) followed by abstraction
of the NH proton of the amine/amide (coordinated to the
metal centre) with a stronger base (nucleophilic activation) for
the final C–N bond formation (amination). Recently we
reported a metal and base-free route for the relevant C–N bond
forming step through water-assisted ‘electrophile–nucleophile
dual activation’13 for the synthesis of N-arylmethyl-2-substi-
tuted benzimidazoles (Scheme 3).14
The origin of the regiodefined disposition of the substitu-
ents on the benzimidazole scaffold under these reported
methods lies in the aryl-amination chemistry that necessitates
the use of transition metal catalysts in the presence of specific
and costly ligands and appropriate bases. The need of special
efforts to prepare the requisite starting materials further limits
the scope for diversity generation. There has been significant
influence of green chemistry tools on medicinal chemistry
research and chemistry based organisations advocate minimi-
sation of generation of metallic impurities7 and insist on the
use of green reaction media.8 A paradigm shift in the working
philosophy of medicinal chemistry research is visible to enrich
the medicinal chemist’s tool box suggesting further improve-
ments to the tried and tested methodologies that have
The crucial C–N bond forming step of this recent report is
based on the water-assisted N-alkylation of o-nitroanilines that
has the limitation of the use of benzylbromides as the alkylat-
ing agents for the N-alkylation step. However, the treatment of
o-nitroaniline with nBuBr, cyclohexyl bromide, allyl bromide,
and propargyl bromide in water under heating for 2 h did not
afford any significant amount of the respective N-alkylated-o-
nitroaniline. Thus, this new method is restricted to the gener-
ation of 1,2-disubstituted benzimidazoles with the N-1 substi-
tuent as aryl methyl group only.
This prompted us to adopt an alternative C–N bond for-
mation strategy for “all-water” N-arylation–reduction–conden-
sation for diversified one-pot synthesis of regiodefined 1,2-
disubstituted benzimidazoles (Scheme 4).
The new metal and base-free route for the relevant C–N
bond forming step involves water-assisted ‘synergistic electro-
phile–nucleophile dual activation’ (Scheme 5) for aromatic
nucleophilic substitution of o-nitrofluorobenzene with diverse
amines to form the intermediate N-arylated/alkylated-
o-nitroanilines.
In a model study o-fluoronitrobenzene (1a) was treated sepa-
rately with aniline (2a) and benzyl amine (2b) as representative
aromatic and aliphatic amines, respectively, in various
Scheme 2 Reported synthetic strategies for regiodefined 1,2-disubstituted
Scheme 3 Regiodefined synthesis of 1,2-disubstituted benzimidazoles via
tandem N-aryllmethylation–nitro reduction–cyclocondensation.
benzimidazoles.
Green Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
(electrophilic activation). This is followed by HB formation of
the oxygen atom of the second molecule of the water dimer15
with the hydrogen atom of the amine 2a/2b (nucleophilic acti-
vation). Electrostatic attraction of the nitrogen atom of 2a/2b
and the carbon centre attached to the fluorine of 1a forms
intermediate Ia/Ib in which the nucleophile and the electro-
phile are brought in close proximity to facilitate the formation
of the Meisenheimer complex/adduct16 IIa/IIb (Scheme 5).
The various physico-chemical parameters of the solvent
such as acceptor/donor number, etc. often play pivotal roles in
organic reactions,17 and the formation of HB involving the
reactant and the solvent has significant influence on the
course of organic reactions.18 Therefore, the important/crucial
role of the reaction medium in making the N-arylation
effective can be visualised through formation of the HB
adducts IIa/IIb due to the hydrogen bond donor (HBD)
(α scale) and hydrogen bond acceptor (HBA) (β scale) proper-
ties of the solvent.19 While the α value is expected to be the
major/critical factor, the β value would also contribute to the
overall outcome of the reaction. Thus, despite having better α
values compared to that of water, inferior results are obtained
in HFIP and TFE due to their poor β values.
Scheme 4 “All-water” strategy for diversity oriented synthesis of regiodefined
1,2-disubstituted benzimidazoles.
Scheme 5 Hydrogen-bond driven ‘synergistic electrophile–nucleophile dual
activation’ by water for metal and base-free N-arylation.
Table 1 The reaction of 1a with 2a or 2b in water under different experimen-
tal conditionsa
The implication of HB formation of water with the fluorine
atom of 1a is demonstrated by the fact that the reaction of
o-chloronitrobenzene (1b) with 2a/2b gave 3a/3b in poor yields
(24/15%; entries 7/2) after 2.5/1 h and required longer periods
of time (15/10 h) to afford comparable yields (81/85%, entries
8/3) (Table 2). Due to the inferior β value of Cl, 1b does not
form a tightly H-bonded intermediate akin to Ia/Ib. This is
further demonstrated by the observation that the reaction of
o-bromonitrobenzene (1c) and o-iodonitrobenzene (1d) with
2a/2b did not produce any 3a/3b after 24 h as Br and I are poor
HB acceptors and do not facilitate the formation of the
relevant H-bonded intermediates akin to Ia/Ib or IIa/IIb
(Scheme 5). These results are in accord with the predictive
Yieldc (%)
Entry
Solvent
αb
βb
3a
3b
1
2
3
4
5
6
7
8
Tap water
Pure waterd
Ultrapuree
MeOH
EtOH
1.17
1.17
1.17
0.93
0.83
0.76
0.68
1.51
1.96
0.00
0.00
0.00
0.19
0.22
0.00
0.00
0.18
0.18
0.18
0.62
0.77
0.95
1.01
0.00
0.00
0.55
0.37
0.00
0.31
0.00
0.11
0.00
90
90
89
45
49
52
55
63
56
15
42
20
12
38
34
Trace
Trace
94
94
94
48
50
53
59
65
60
Trace
54
26
Trace
35
32
Trace
15
iPrOH
tBuOH
TFE
9
HFIP
THF
10
11
12
13
14
15
16
17
1,4-Dioxane
DCE
CH3CN
MeNO2
Toluene
Hexane
None
Table 2 Water-assisted N-arylation of different o-halonitrobenzene with 2b
and 2aa
a 1a (1 mmol) was treated with 2a or 2b (1 mmol, 1 equiv.) in the
appropriate solvent (2 mL), except for entry 22, under heating at
100 °C (oil bath) for 2 and 2.5 h, respectively. b Ref. 19. c Isolated yield.
d Pure water was obtained by purification of normal/tap water through
reverse osmosis and ionic/organic removal and has the resistivity of
15 MΩ at 25 °C. e Ultrapure water was obtained by further subjecting pure
water to UV treatment (185/254 nm), deionization and ultramembrane
filtration (0.01 μm under pressure up to 145 psi (10 bar) and has the
resistivity of 18.2 MΩ at 25 °C.
Entry
o-Halonitrobenzene
Amine
Time (h)
Yield of 3b (%)
1
2
3
4
5
6
7
8
9
1a: X = F
1b: X = Cl
1b: X = Cl
1c: X = Br
1d: X = I
1a: X = F
1b: X = Cl
1b: X = Cl
1c: X = Br
1d: X = I
2b
2b
2b
2b
2b
2a
2a
2a
2a
2a
1
1
94
15
85
0
10
24
24
2.5
2.5
12
24
24
0
solvents (Table 1). The o-N-phenylaminonitrobenzene 3a
and o-N-methylphenylaminonitrobenzene 3b were obtained in
excellent yields (89–96%) in tap, pure, and ultrapure water
(entries 1–3). These results indicate the specific assistance
rendered by water in promoting the N-arylation which is
envisaged through the following sequence of events. Water
90
24
81
0
10
0
a The o-halo nitrobenzene 1 (1 mmol) was treated with the amine 2a/
2b (1 mmol, 1 equiv.) in water (2 mL) at 100 °C (oil bath) for different
forms hydrogen bonds (HB) with the fluorine atom of 1a time intervals. b Isolated yield of the N-benzyl/phenyl-o-nitroaniline 3.
This journal is © The Royal Society of Chemistry 2013
Green Chem.

View Article Online
Paper
Green Chemistry
Table 3 Reaction of 1a with 2b or 2a in water under different experimental
conditionsa
Table 4 The influence/importance of the HB effect for the water-assisted
N-arylation of 1a with 2a performed separately with water and D2Oa
Entry
Amine
Water (mL)
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2a
2a
0.5
1
2
5
2
2
2
2
2
2
2
2
2
2
2
2
100
100
100
100
40
60
80
100
100
100
100
100
100
100
100
100
1
1
1
1
1
1
1
1
81
88
94
94
0
Yield of 3ab (%)
0
Entry
Time (min)
In water
In D2O
35
94
21
56
88
94
94
65
75
90
1
2
3
4
15
30
45
60
22
48
71
94
Trace
31
55
9
15 min
30 min
45 min
1
1.5
1
2
10
11
12
13
14
15
16
68
a 1a (1 mmol) was treated with amine 2a (1 mmol, 1 equiv.) in water or
D2O (2 mL) at 100 °C (oil bath) for different time intervals. b The
isolated yield of 3a.
2.5
a 1a (1 mmol) was treated with 2b/2a (1 mmol, 1 equiv.). b Isolated
yield of the o-N-benzyl/phenylnitroaniline.
periods (e.g. after 15, 30, 45, and 60 min) (Table 4). In each
occasion better yields of 3a were obtained for the reactions
performed in water compared to those obtained in D2O.
The differential isolated yields of 3a during the reactions in
water and in D2O after a specific time interval demonstrated
the distinct role/influence of the HB with water during the pro-
gress of the reaction (Fig. 2). The decrease in the product yield
in D2O compared to that obtained in water is due to less
effective formation of the hydrogen bonded assemblies Ia and
IIa (Scheme 5) due to the lesser HB affinity of F–D2O vs. F–H2O
and N–D2O vs. N–H2O. This is in agreement with the reported
results of weaker hydrogen bonding by deuterium with
oxygen23 and nitrogen24 acceptors.
It was observed that the reported procedures for the pre-
paration of N-mono-alkyl/arylamino-o-nitroanilines from 1a
involve the treatment of 1a with an excess of the amine under
sealed tube (heavy-walled reaction flask equipped with a gas-
tight Teflon cap) heating (∼115 °C) in THF–iPrOH for a pro-
longed period (∼48 h)25 or performing the reaction of 1a with
an excess (∼1.5 equiv.) of the amine in the presence of a base
(e.g., BuLi, Hinigs’s base, NaH, Et3N, K2CO3,) in THF–DMSO–
DMF at −78 °C to 100 °C for prolonged period
(∼16–48 h).25b,26 Thus, the water-assisted N-arylation strategy
HBA property of aromatically bound halogens (F ≫ Cl > Br >
I)20 and substantiate the implication of HB driven electrophilic
activation.21,2a
Although during the SNAr process the high electronegativity
of F would induce more electropositive character to the aryl
carbon bearing the F compared to that of carbons containing
other halogens (Cl, Br, I) and thereby would increase the rate
of the reaction for the fluoronitrobenzene,16 the complete lack
of reactivity of the bromo and the iodo compounds (1c and 1d,
respectively) indicates the significant influence of the HB
effect. The solvent study (Table 1) indicates that apart from the
classical effect of the polarity of the C–X bond (due to the
differential electronegativity of X) on the SNAr mechanism, the
HB provides further assistance in the stabilisation/facilitation
of the Meisenheimer complex/adduct.
The influence of the various reaction parameters such as
the amount of water, reaction temperature, and reaction time
was assessed during the water-assisted metal and base-free
reaction of 1a separately with 2b (entries 1–13, Table 3) and 2a
(entries 14–16, Table 3) to determine the best operative exper-
imental condition for the selective mono-N-arylation. The best
result was obtained during the treatment of 1a with an equi-
molar amount of 2b in water (2 mL per mmol of 1a) at 100 °C
for 1 h (entry 8, Table 3). On the other hand, the use of the aro-
matic amine 2a requires longer time (2.5 h) to afford compar-
able yield (entry 16, Table 3).
The substitution of deuterium for hydrogen affects the
strength of HB.22 Hence a decrease in the product yield would
occur when carrying out the reaction in D2O in place of water
and will be indicative of the HB effect in promoting the reac-
tion. To demonstrate/realise the influence/importance of the
HB effect of water on the base and metal/catalyst-free arylami-
noarylation process, 1a was treated with 2a separately in water
and heavy water (D2O) under similar experimental conditions
Fig. 2 Formation of 3a with different yields during the reaction of 1a with 2a
and the product (3a) was isolated after various reaction performed in water and D2O for a specific time period.
Green Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
developed under this study would form a sustainable and
clean synthesis of o-N-mono-alkyl/arylaminonitroanilines. The
generality of the water-assisted metal and base-free selective
mono-N-arylation is demonstrated through the reaction of a
few substituted o-fluoronitrobenzenes with a few representative
amines (Table 5). The protocol worked well for various substi-
tuted o-fluoronitrobenzenes during the reaction with aryl, aryl
alkyl, cycloalkyl, allylic, propargylic amines and amino alco-
hols. Excellent chemoselectivity was observed during the reac-
tion of o-fluoronitrobenzenes bearing chlorine without
competitive aromatic nucleophilic substitution of the chlorine
(Table 5, entries 4 and 6).
Scheme 6 Hydrogen-bond driven ‘synergistic electrophile–nucleophile dual
activation’ by water for metal and base-free N-arylation.
This finding was extended for an ‘all-water’ one-pot tandem
N-arylation–reduction–condensation for the synthesis of
N-aryl/aryl alkyl/alkyl-2-aryl/heteroaryl/cycloalkyl benzimidazoles
(Scheme 6).
after 1 h. However, the use of HOAc instead of aq. HCl
afforded 12% yield of 4a (Scheme 7).
The tandem ‘all-water’ arylaminoarylation/arylaminoalkyla-
tion–reduction sequence gave 4a in 88% yield but when HOAc
was used instead of aq. HCL in the nitro reduction step 4a was
obtained in poor yield (42%) (Scheme 7). These findings high-
lighted the beneficial effect of using water in the reduction
step since the redox potential is influenced by the solvent28
and better solvation of the In3+ cation in water facilitates elec-
tron transfer from the In metal.
The preformed 4a was next treated with benzaldehyde 5a
under various conditions (Table 7). Although the condensation
takes place in water without any metal catalyst, the presence
(10 mol%) of In or InCl3 offers an advantage in that the con-
densation may be performed at reduced temperature (∼80 °C).
However, the use of aprotic solvents such as toluene, 1,4-
dioxane, THF, DMF, and DCE under similar conditions gave
lower yields in the presence or absence of In or InCl3 and
demonstrated the advantage of using water in the conden-
sation stage.
Thus, various substituted o-fluoronitrobenzenes 1 were sub-
jected to the treatment with different amines 2 in water at
100 °C and the in situ formed N-arylated products 3 treated
with In and aq. HCl27 to form the N-monoalkylated/arylated
o-phenylenediamines 4 which without isolation were treated
with various aldehydes 5 to afford the 1,2-disubstituted benzi-
midazoles 6 in a regiodefined manner. The excellent results
(Table 6) demonstrated the general applicability for the regio-
specific diversity-oriented synthesis of 1,2-disubstituted
benzimidazoles.
While the indispensable role of water in promoting the
N-arylation was clearly realised/demonstrated, it was decided
to further assess any advantage in using water in the
subsequent stages (e.g., reduction and condensation) of the
one-pot regiospecific synthesis of 1,2-disubstituted benzimida-
zoles. The treatment of 3a with In (2.5 equiv.) and aq. HCl
(5 equiv.) afforded o-N-phenylaminoaniline 4a in 92% yield
The inferior yields of 6a obtained during the reaction of 4a
with 5a in organic solvents that are poor HB donors (entries
6–10, Table 7) compared to that in water (entry 4, Table 1) indi-
cated the HB-assisted rate acceleration in water. To demon-
strate the influence of the HB effect the reaction of 4a with 5a
was performed separately in water and in D2O for different
sets of reaction periods under similar experimental conditions
and in each case the isolated yield of 6a was calculated
(Table 8).
The better yields obtained in water compared to those
obtained in D2O revealed the effect of HB-assisted rate accel-
eration (Fig. 3). The decrease of the product yield in D2O is the
result of lesser HB affinity of N–D2O vs. N–H2O and is in
accord with weaker hydrogen bonding by deuterium with
nitrogen.24
Table 5 The HB driven metal and base-free synthesis of N-mono-alkyl/aryl-
amino-o-nitroanilines in watera
Entry o-Fluoronitrobenzene Amine
Time (h) Yieldb (%)
1
2
3
4
5
6
1a: R1 = R2 = H
2a
2b
2b
2b
2b
2b
2.5
1
1
1
1
90
94
93
95
94
96
1a: R1 = R2 = H
1e: R1 = Me, R2 = H
1f: R1 = Cl, R2 = H
1g: R1 = H, R2 = Me
1h: R1 = H, R2 = Cl
1
7
1a
1
93
8
1a
1a
1a
1.5
2.5
2.5
95
88
90
9
10
Conclusions
In conclusion, a new ‘all-water’ strategy of tandem arylaminoary-
lation/arylaminoalkylation–reduction–cyclisation for diversity-
oriented one-pot synthesis of regiodefined 1,2-disubstituted
a The o-fluoronitrobenzene 1 (1 mmol) was treated with the amine
(1 mmol, 1 equiv.) in water (2 mL) at 100 °C (oil bath). b Isolated yield
of the N-arylated product.
This journal is © The Royal Society of Chemistry 2013
Green Chem.

View Article Online
Paper
Green Chemistry
Table 6 The ‘all-water’ one-pot tandem arylaminoarylation/arylaminoalkylation–reduction–cyclisation for diversity oriented synthesis of regiodefined 1,2-disubsti-
tuted benzimidazolesa
Entry
Substrate
Amine
Aldehyde
Timeb (h)
Yieldc Y(%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1e
1e
1e
1g
1g
1g
1f
1f
1f
1h
1h
1h
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
R = H
R = Me
R = Cl
R = OCH2Ph
R = H
R = Me
R = OCH2Ph
R = H
R = Me
R = OCH2Ph
R = H
R = Me
R = OCH2Ph
R = H
R = Me
R = OCH2Ph
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
89
88
89
88
88
86
88
87
85
86
85
84
88
86
84
88
9
10
11
12
13
14
15
16
17
1a
R = H
2
88
18
19
20
1a
1a
1a
R3 = H
R3 = Me
R3 = Br
R = H
R = H
R = H
5
5
5
84
85
86
21
1a
R = H
3
84
22
1a
R = H
4
88
23
24
1a
1a
R = H
R = H
5
5
80
83
25
1a
2b
2
85
26
27
1a
1a
2b
2b
2
2
87
86
a The o-fluoronitrobenzene 1 (1 mmol) was treated with the aromatic/aliphatic amine 2 (1 mmol, 1 equiv.) in water (2 mL) at 100 °C (oil bath) for
2.5/1 h (TLC) followed by In (2.5 equiv.) and HCl (5 equiv.), and after the reduction was completed (0.5–1 h, TLC) it was treated with the aldehyde
(1 mmol, 1 equiv.) in water (2 mL) at 100 °C (oil bath). b The total time required for the conversion of 1 to the final product. c Isolated yield of the
1,2-disubstituted benzimidazole.
benzimidazoles is reported. Water plays a crucial and indis- to the better hydrogen bond donor and hydrogen bond accep-
pensable role through hydrogen bond driven ‘synergistic tor ability of water compared to those of organic solvents. The
electrophile–nucleophile dual activation’ during the arylamino- role/influence of the HB effect of water during the arylamino-
arylation/arylaminoalkylation of o-fluoroanilines that forms arylation step is demonstrated by the inferior yields of
the basis of incorporation of the substituents on the benzimi- o-N-phenyl nitrobenzene obtained in D2O compared to those
dazole scaffold in a regiodefined manner and is realized due obtained in water during the reaction of o-fluoronitrobenzene
Green Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
Table 8 The influence of the HB effect for the water-assisted cyclocondensa-
tion of 4a with 5a to form 6a performed separately with water and D2Oa
Scheme 7 Demonstration of the beneficial effect of using water during the
nitro reduction and the tandem arylaminoarylation/arylaminoalkylation–
reduction processes.
Yield of 6ab (%)
Entry
Time (min)
In water
In D2O
1
2
3
4
5
6
15
30
45
60
90
Trace
20
43
56
78
Trace
11
30
48
69
Table 7 Influence of the reaction medium and the indium metal or InCl3
during the reaction of mono-N-phenylamino-o-phenylenediamine 4a with benz-
aldehyde 5a to form 6aa
120
90
82
a 4a (1 mmol) was treated with 5a (1 mmol, 1 equiv.) in water or D2O
(2 mL) at 100 °C (oil bath) for different time intervals. b The isolated
yield of 6a.
Temp
(°C)
Time
(h)
Yieldb
(%)
Entry
Solvent
Catalyst
1
2
3
4
5
6
7
8
Water
Water
Water
Water
None
None
None
None
None
None
None
None
rt
60
80
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Trace
35
83
90
87
61
56
43
62
48
40
72
92
91
90
70
58
75
71
64
45
75
92
93
79
76
65
75
71
100
Reflux
100
100
Reflux
100
Reflux
rt
60
80
80
80
80
Reflux
80
80
80
rt
60
80
80
EtOH
Toluene
1,4-Dioxane
THF
DMF
DCE
Water
Water
Water
Ethanol
Methanol
1,4-Dioxane
THF
Toluene
DMF
DCE
Water
Water
Water
9
None
None
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
In (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
InCl3 (10 mol%)
Fig. 3 Formation of 6a with different yields during the reaction of 4a with 5a
performed in water and D2O for a specific time period.
Experimental section
EtOH
Toluene
1,4-Dioxane
THF
DMF
DCE
80
80
Reflux
80
80
The glassware to be used in reactions was thoroughly washed
and dried in an oven and the experiments were carried out
with required precautions. Chemicals and all solvents were
commercially available and used without further purification.
1H and 13C NMR spectra were recorded on a 400 MHz NMR
spectrometer in CDCl3 with a residual undeuterated solvent
(CHCl3 at 7.26/77.0) using TMS as an internal standard.
Chemical shifts (δ) are given in ppm and J values are given in
Hz. 13C NMR spectra were fully decoupled and were referenced
a 4a (184 mg, 1 mmol) was treated with benzaldehyde 5a (106 mg,
1 mmol, 1 equiv.) in the appropriate solvent (2 mL) under different
reaction conditions for 2 h. b Isolated yield of 6a.
with aniline in water and D2O separately under similar exper- to the middle peak of the solvent CDCl3 at 77.00 ppm. Splitting
imental conditions. Water also exerts beneficial effects during patterns were designated as s, singlet; bs, broad singlet; d,
the nitro reduction and condensation steps that make this syn- doublet; dd, doublet of doublet; t, triplet; m, multiplet. Mass
thetic strategy a true example of ‘all-water chemistry’. The spectra were recorded under APCI mode of ionisation. Accurate
water-assisted arylaminoarylation/arylaminoalkylation chem- mass measurements were performed on a Q-TOF instrument
istry provides green procedures for novel base-free synthesis of calibrated internally with sodium formate. Infra-red (IR)
N-alkyl/aryl-o-nitroanilines, and a tandem arylaminoarylation/ spectra were recorded in the range 4000–600 cm−1 either as
arylaminoalkylation–reduction protocol for one-pot synthesis neat for liquid or KBr pellets for solid samples. The purity of
of mono-N-alkyl/aryl-o-phenylenediamines.
the compounds was checked on the silica gel GF-254 under UV
This journal is © The Royal Society of Chemistry 2013
Green Chem.

View Article Online
Paper
Green Chemistry
1
at 254 nm. Melting points were measured using a melting Brown solid; mp = 90–92 °C; H NMR (400 MHz, CDCl3): δ =
point apparatus and were uncorrected. Evaporation of solvents 7.26–7.22 (m, 2H), 7.15 (d, J = 7.72 Hz, 1H), 7.07–7.03 (m, 1H),
was performed under reduced pressure, using a rotary vacuum 6.87–6.77 (m, 5H), 5.21 (brs, 1H), 3.79 (brs, 2H); MS (APCI)
evaporator.
m/z: 185.2 (M + H)+.31
Typical procedure for ‘all-water’ one-pot tandem N-arylation–
reduction–condensation for synthesis of regiodefined
1,2-disubstituted benzimidazole. 1-Benzyl-2-phenyl-1H-
benzimidazole 6b
Typical procedure for water-assisted tandem N-arylation–
reduction for one-pot synthesis of o-N-phenylaminoaniline 4a
from 1a using In/HCl as the reduction agent
The mixture of o-fluoronitrobenzene 1a (141 mg, 1 mmol) and
aniline 2a (93 mg, 1 mmol, 1 equiv.) in water (4 mL) was
stirred magnetically at 100 °C (oil-bath) for 2.5 h (TLC) followed
by addition of In (287 mg, 2.5 mmol, 2.5 equiv.), HCl (2.5 mL,
2 N aq. HCl, 5 mmol, 5 equiv.) and stirring was continued for a
further 1 h (TLC). The reaction mixture was cooled to room
temperature, neutralized (till effervescence ceases) with solid
NaHCO3 (∼140 mg) and extracted with EtOAc (2 × 5 mL). The
combined EtOAc extracts were washed with water (5 mL), dried
(MgSO4) and concentrated under rotary vacuum evaporation.
The crude product was adsorbed on silica gel (230–400, 500 mg)
and purified by flash chromatography (hexane–EtOAc, 90 : 10)
to obtain analytically pure product 4a (162 mg, 88%).31
The mixture of 1a (141 mg, 1 mmol) and 2b (107 mg, 1 mmol,
1 equiv.) in water (2 mL) was stirred magnetically at 100 °C
(oil-bath) for 1 h (TLC) followed by addition of In (287 mg,
2.5 mmol, 2.5 equiv.), HCl (2.5 mL of 2 N aq. HCl, 5 mmol,
5 equiv.) and stirring for a further 0.5 h. The resultant mixture
was treated with 5a (106 mg, 1 mmol, 1 equiv.) for 0.5 h. The
reaction mixture was cooled to room temperature, neutralized
(till effervescence ceases) with solid NaHCO3 (∼140 mg) and
extracted with EtOAc (2 × 5 mL). The combined EtOAc extracts
were washed with water (5 mL), dried (MgSO4) and concen-
trated under rotary vacuum evaporation. The crude product
was adsorbed on silica gel (230–400, 500 mg) and purified by
flash chromatography (hexane–EtOAc, 85 : 15) to obtain ana-
lytically pure 6b as a white solid (252 mg, 89%).29
Typical procedure for water-assisted tandem N-arylation–
reduction for one-pot synthesis of o-N-phenylaminoaniline 4a
from 1a using In/HOAc as the reducing agent
Typical procedure for the selective N-arylation
(o-N-phenylaminonitrobenzene 3a; entry 1, Table 5)
The mixture of o-fluoronitrobenzene 1a (141 mg, 1 mmol) and
aniline 2a (93 mg, 1 mmol, 1 equiv.) in water (4 mL) was
stirred magnetically at 100 °C (oil-bath) for 2.5 h (TLC) fol-
lowed by addition of In (287 mg, 2.5 mmol, 2.5 equiv.), HOAc
(0.3 mL, 5 mmol, 5 equiv.) and stirring was continued for a
further 1 h. The reaction mixture was cooled to room temp-
erature, neutralized (till effervescence ceases) with solid
NaHCO3 (∼312 mg) and extracted with EtOAc (2 × 5 mL). The
combined EtOAc extracts were washed with water (5 mL), dried
(MgSO4) and concentrated under rotary vacuum evaporation.
The crude product was adsorbed on silica gel (230–400,
500 mg) and purified by flash chromatography (hexane–EtOAc,
90 : 10) to obtain analytically pure product 4a (77 mg, 42%).31
The mixture of o-fluoronitrobenzene 1a (141 mg, 1 mmol) and
aniline 2a (93 mg, 1 mmol, 1 equiv.) in water (2 mL) was
stirred magnetically at 100 °C (oil-bath) for 2.5 h (TLC). The
reaction mixture was cooled to room temperature and treated
with NaHCO3 (∼170 mg) and extracted with EtOAc (2 × 5 mL).
The combined EtOAc extracts were washed with water (5 mL),
dried (MgSO4) and concentrated under rotary vacuum evapo-
ration. The crude product was adsorbed on silica gel (230–400,
500 mg) and purified by flash chromatography (hexane–EtOAc,
95 : 5) to obtain analytically pure product 3a (192 mg, 90%);
Brown solid; mp = 73–75 °C; IR (Neat) ν: 3390, 1610, 1595,
1
1555, 1499, 1353, 1255, 1148 cm−1; H NMR (CDCl3, 400 MHz)
δ: 9.49 (brs, 1H), 8.20 (dd, J = 8.60 and 1.56 Hz, 1H), 7.44–7.42
(m, 2H), 7.40–7.38 (m, 1H), 7.37–7.36 (m, 1H), 7.25–7.21
(m, 2H), 6.79–6.75 (m, 1H); MS (APCI) m/z: 215.2 (M + H)+.30
Experimental procedure for demonstrating
Typical procedure for the synthesis of o-N-phenylaminoaniline the influence of the HB effect during the
4a
water-assisted arylaminoarylation and the
penultimate cyclocondensation steps
Typical procedure for the reaction of 1a with 2a in water to
form 3a after different time intervals to demonstrate the
influence of the HB effect for the water-assisted
arylaminoarylation (N-arylation of 1a with 2a in water: Table 4)
To the mixture of o-N-phenylaminonitrobenzene 3a (214 mg,
1 mmol) in water (4 mL) was added In (287 mg, 2.5 mmol,
2.5 equiv.) and HCl (2.5 mL 2 N aq. HCl, 5 mmol, 5 equiv.),
and the mixture was stirred magnetically at 100 °C (oil-bath)
for 1 h (TLC). The reaction mixture was cooled to room temp-
erature, neutralized (till effervescence ceases) with solid
NaHCO3 (∼140 mg) and extracted with EtOAc (2 × 5 mL). The The mixture of o-fluoronitrobenzene 1a (141 mg, 1 mmol) and
combined EtOAc extracts were washed with water (5 mL), dried aniline 2a (93 mg, 1 mmol, 1 equiv.) in water (2 mL) was
(MgSO4) and concentrated under rotary vacuum evaporation. stirred magnetically at 100 °C (oil-bath) separately for 15, 30,
The crude product was adsorbed on silica gel (230–400, 45, and 60 min. In each case the reaction mixture was cooled
500 mg) and purified by flash chromatography (hexane–EtOAc, to room temperature and treated with NaHCO3 (∼170 mg) and
90 : 10) to obtain analytically pure product 4a (169 mg, 92%); extracted with EtOAc (2 × 5 mL). The combined EtOAc extracts
Green Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
were washed with water (5 mL), dried (MgSO4) and concen-
The physical data (IR, NMR and MS) of new compounds are
trated under rotary vacuum evaporation. The crude product provided below.
was adsorbed on silica gel (230–400, 500 mg) and purified by
N-Benzyl-2-nitroaniline (entry 2, Table 5). Red solid
flash chromatography (hexane–EtOAc, 95 : 5) to obtain ana- (214 mg, 94%); mp = 91–93 °C; IR (Neat) ν: 3444, 2896, 1610,
lytically pure 3a in 22 (47 mg), 48 (102 mg), 71 (152 mg), and 1575, 1525, 1359, 1165 cm−1 1H NMR (CDCl3, 400 MHz)
;
94% (201 mg) yields respectively.30
δ: 8.43 (brs, 1H), 8.20 (d, J = 8.60 Hz, 1H), 7.40–7.30 (m, 6H),
6.81 (d, J = 8.60 Hz, 1H), 6.66 (t, J = 7.76 Hz, 1H), 4.55 (d, J =
5.60 Hz, 2H); MS (APCI) m/z: 229.1 (M + H)+.33
Typical procedure for the reaction of 1a with 2a in D2O to form
3a after different time intervals to demonstrate the influence
of the HB effect for the water-assisted arylaminoarylation
(N-arylation of 1a with 2a in D2O: Table 4)
N-Benzyl-5-methyl-2-nitroaniline (entry 3, Table 5). Red
solid (214 mg, 93%); mp = 100–102 °C; IR (Neat) ν: 3445,
2887, 1609, 1578, 1529, 1365, 1172 cm−1 1H NMR (CDCl3,
;
The mixture of o-fluoronitrobenzene 1a (141 mg, 1 mmol) and 400 MHz) δ: 8.44 (brs, 1H), 8.07 (d, J = 8.76 Hz, 1H), 7.39–7.30
aniline 2a (93 mg, 1 mmol, 1 equiv.) in D2O (2 mL) was stirred (m, 5H), 6.61 (s, 1H), 6.48 (dd, J = 9.12 and 2.12 Hz, 1H),
magnetically at 100 °C (oil-bath) separately for 15, 30, 45, and 4.53 (d, J = 5.60 Hz, 2H), 2.29 (s, 3H); MS (APCI) m/z: 243.2
60 min. In each case, the reaction mixture was cooled to room (M + H)+.34
temperature and treated with NaHCO3 (∼170 mg) and
N-Benzyl-5-chloro-2-nitroaniline (entry 4, Table 5). Red solid
extracted with EtOAc (2 × 5 mL). The combined EtOAc extracts (249 mg, 95%); mp = 89–91 °C; IR (Neat) ν: 3427, 2936, 1617,
1
were washed with water (5 mL), dried (MgSO4) and concen- 1573, 1522, 1353, 1270, 1165 cm−1; H NMR (CDCl3, 400 MHz)
trated under rotary vacuum evaporation. The crude product δ: 8.44 (brs, 1H), 8.14 (d, J = 9.16 Hz, 1H), 7.41–7.31 (m, 5H),
was adsorbed on silica gel (230–400, 500 mg) and purified by 6.83 (d, J = 2.08 Hz, 1H), 6.65 (dd, J = 10.8 and 3.64 Hz, 1H),
flash chromatography (hexane–EtOAc, 95 : 5) to obtain 3a in 0, 4.53 (d, J = 5.60 Hz, 2H); MS (APCI) m/z: 263.2 (M + H)+.33
31 (66 mg), 55 (117 mg), and 68% (145 mg) yields,
respectively.30
N-Benzyl-4-methyl-2-nitroaniline (entry 5, Table 5). Red
solid (227 mg, 94%); mp = 90–93 °C; IR (Neat) ν: 3446, 2898,
1
1610, 1571, 1522, 1360, 1161 cm−1; H NMR (CDCl3, 400 MHz)
Typical procedure for the reaction of 4a with 5a in water to
form 6a after different time intervals to demonstrate the
influence of the HB effect for the water-assisted
cyclocondensation step (reaction of 4a with 5a in water:
Table 8)
δ: 8.33 (brs, 1H), 7.99 (s, 1H), 7.38–7.19 (m, 6H), 6.72 (d, J =
8.68 Hz, 1H), 4.53 (d, J = 5.68 Hz, 2H), 2.25 (s, 3H); MS (APCI)
m/z: 243.1 (M + H)+.34
N-Benzyl-4-chloro-2-nitroaniline (entry 6, Table 5). Red solid
(251 mg, 96%); mp = 69–71 °C; IR (Neat) ν: 3429, 2938, 1620,
The mixture of mono-N-phenyl-o-phenylenediamine 4a 1573, 1519, 1360, 1163 cm−1 1H NMR (CDCl3, 400 MHz) δ:
;
(184 mg, 1 mmol) and benzaldehyde 5a (106 mg, 1 mmol) in 8.40 (brs, 1H), 8.16 (d, J = 2.12 Hz, 1H), 7.36–7.31 (m, 6H),
water (2 mL) was stirred magnetically at 100 °C (oil-bath) for 6.77–6.74 (m, 1H), 4.53 (d, J = 5.20 Hz, 2H); MS (APCI) m/z:
15, 30, 45, 60, 90, and 120 min. The reaction mixture was 263.3 (M + H)+.34
cooled to room temperature and extracted with EtOAc
(2 × 5 mL). The combined EtOAc extracts were washed with (204 mg, 93%); IR (Neat) ν: 3418, 2975, 1616, 1545, 1402, 1326,
water (5 mL), dried (MgSO4) and concentrated under rotary 1258, 1149 cm−1 1H NMR (CDCl3, 400 MHz) δ: 8.17–8.15
N-Cyclohexyl-2-nitroaniline (entry 7, Table 5). Yellow solid
;
vacuum evaporation. The crude product was adsorbed on (m, 2H), 7.41–7.37 (m, 1H), 6.86 (d, J = 8.68 Hz, 1H), 6.61–6.56
silica gel (230–400, 500 mg) and purified by flash chromato- (m, 1H), 3.54–3.50 (m, 1H), 2.07–2.04 (m, 2H), 1.82–1.79
graphy (hexane–EtOAc, 85 : 15) to obtain 6a in 0, 20 (54 mg), (m, 2H), 1.68–1.64 (m, 1H), 1.45–1.32 (m, 5H); 13C NMR
43 (116 mg), 56 (151 mg), 78 (210 mg), and 90% (243 mg) (CDCl3, 100 MHz) δ: 146.1, 144.8, 136.0, 127.1, 114.8, 114.2,
yields, respectively.32
Typical procedure for the reaction of 4a with 5a in D2O to [M + H+], 221.1290; Found 221.1292.
50.9, 32.7, 25.6, 24.6. HRMS (ESI) m/z calcd for C12H17N2O2
form 6a after different time intervals to demonstrate the influ-
2-(2-Nitrophenylamino)ethanol (entry 8, Table 5). Brown
ence of the HB effect for the water-assisted cyclocondensation solid (173 mg, 95%); mp = 75–76 °C; IR (Neat) ν: 3416, 2939,
step (reaction of 4a with 5a in D2O: Table 8)The mixture of 2886, 1605, 1572, 1509, 1355, 1259, 1162 cm−1 1H NMR
;
mono-N-phenyl-o-phenylenediamine 4a (141 mg, 1 mmol) and (CDCl3, 400 MHz) δ: 8.23 (brs, 1H), 8.14 (dd, J = 8.56 and
benzaldehyde 5a (141 mg, 1 mmol) in D2O (2 mL) was stirred 1.32 Hz, 1H), 7.43 (t, J = 7.96 Hz, 1H), 6.88 (d, J = 8.60 Hz, 1H),
magnetically at 100 °C (oil-bath) for 15, 30, 45, 60, 90, and 6.64 (t, J = 8.48 Hz, 1H), 3.94 (d, J = 5.48 Hz, 2H), 3.50 (q, J =
120 min. In each case the reaction mixture was cooled to room 5.36 Hz, 2H), 2.02 (brs, 1H); MS (APCI) m/z: 183.2 (M + H)+.34
temperature and extracted with EtOAc (2 × 5 mL). The com-
N-Allyl-2-nitroaniline (entry 9, Table 5). Brown solid
bined EtOAc extracts were washed with water (5 mL), dried (156 mg, 88%); mp = 52–54 °C; IR (Neat) ν: 3442, 2985, 1638,
1
(MgSO4) and concentrated under rotary vacuum evaporation. 1605, 1405, 1302, 1268, 1140 cm−1; H NMR (CDCl3, 400 MHz)
The crude product was adsorbed on silica gel (230–400, δ: 8.17 (dd, J = 8.56 and 1.52 Hz, 2H), 7.40–7.44 (m, 1H),
500 mg) and purified by flash chromatography (hexane–EtOAc, 6.82 (d, J = 7.96 Hz, 1H), 6.68–6.63 (m, 1H), 6.00–5.90 (m, 1H),
85 : 15) to obtain 6a in 0, 11 (30 mg), 30 (81 mg), 48 (130 mg), 5.34–5.23 (m, 2H), 4.00–3.96 (m, 2H); MS (APCI) m/z: 179.1
69 (186 mg), and 82% (221 mg) yields respectively.32
(M + H)+.35
This journal is © The Royal Society of Chemistry 2013
Green Chem.

View Article Online
Paper
2-Nitro-N-(prop-2-ynyl)aniline (entry 10, Table 5). Low
Green Chemistry
1-Benzyl-2-(4-(benzyloxy)phenyl)-6-methyl-1H-benzimidazole
melting solid (158 mg, 90%); IR (Neat) ν: 3410, 2948, 2119, (entry 7, Table 6). White solid (352 mg, 88%); mp
=
1
1611, 1549, 1409, 1256, 1143 cm−1; H NMR (CDCl3, 400 MHz) 215–217 °C; IR (Neat) ν: 3035, 2986, 1614, 1495, 1458, 1439,
1
δ: 8.22 (dd, J = 8.56 and 1.52 Hz, 1H), 8.14 (brs, 1H), 7.55–7.51 1383, 1272, 1175 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.71 (d,
(m, 1H), 6.99 (d, J = 8.60 Hz, 1H), 6.79–6.75 (m, 1H), 4.16 J = 8.20 Hz, 1H), 7.60 (d, J = 8.64 Hz, 2H), 7.43–7.30 (m, 8H),
(d, J = 2.44 Hz, 2H), 2.31 (s, 1H); 13C NMR (CDCl3, 100 MHz) 7.11 (d, J = 7.52 Hz, 3H), 7.02–6.98 (m, 3H), 5.41 (s, 2H), 5.10
δ: 144.1, 136.3, 136.2, 126.9, 116.5, 113.9, 78.9, 72.3, 32.6; (s, 2H), 2.43 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 160.0,
HRMS (ESI) m/z calcd for C9H8N2NaO2 [M + Na+], 199.0483; 153.7, 141.3, 136.7, 136.5, 136.4, 132.8, 130.6, 129.1, 128.6,
Found 199.0479.
128.1, 127.7, 127.5, 125.9, 124.2, 122.8, 119.3, 115.1, 110.2,
1-Benzyl-2-phenyl-1H-benzimidazole (entry 1, Table 6). 70.1, 48.2, 21.8. HRMS (ESI) m/z calcd for C28H25N2O [M + H+],
White solid (252 mg, 89%); mp = 130–131 °C; IR (Neat) ν: 405.1967; Found 405.1967.
1
3032, 2955, 1610, 1466, 1455, 1364, 1256, 1161 cm−1; H NMR
1-Benzyl-5-methyl-2-phenyl-1H-benzimidazole
(entry
8,
(DMSO, 400 MHz) δ: 7.91–7.89 (m, 1H), 7.74–7.70 (m, 2H), Table 6). White solid (259 mg, 87%); mp = 133–135 °C; IR
7.53–7.45 (m, 3H), 7.38–7.33 (m, 3H), 7.32–7.30 (m, 1H), (KBr) νmax = 3255, 1644, 1616, 1472, 1286 cm−1 1H NMR
7.26–7.23 (m, 2H), 5.49 (s, 2H); MS (APCI) m/z: 285.2 (400 MHz, CDCl3): δ = 7.71–7.68 (m, 3H), 7.48–7.44 (m, 3 H),
(M + H)+.29
7.36–7.30 (m, 3 H), 7.13–7.07 (m, 4 H), 5.46 (s, 2 H), 2.52
1-Benzyl-2-(4-methylphenyl)-1H-benzimidazole (entry 2, (s, 3 H); MS (APCI) m/z: 299.4 (M + H+).38
Table 6). White solid (262 mg, 88%); mp = 267–269 °C; IR 1-Benzyl-5-methyl-2-(4-methylphenyl)-1H-benzimidazole
(Neat) ν: 3035, 2946, 1612, 1465, 1452, 1366, 1255, 1165 cm−1
(entry 9, Table 6). White solid (274 mg, 88%); mp =
1H NMR (DMSO, 400 MHz) δ: 7.80 (d, J = 8.0 Hz, 1H), 7.60 (d, 181–183 °C; IR (Neat) ν: 3032, 2925, 2855, 1616, 1475, 1453,
J = 6.96 Hz, 2H), 7.37–7.31 (m, 4H), 7.29–7.21 (m, 4H), 7.14 (d, 1383, 1325, 1253, 1163 cm−1 1H NMR (DMSO, 400 MHz) δ:
;
;
;
J = 7.24 Hz, 2H), 5.49 (s, 2H), 2.43 (s, 3H). MS (APCI) m/z: 299.3 7.66 (s, 1H), 7.59 (d, J = 8.12 Hz, 2H), 7.37–7.32 (m, 3H),
(M + H)+.29
7.29–7.26 (m, 2H), 7.13–7.11 (s, 2H), 7.08–7.05 (s, 2H), 5.44 (s,
3, 2H), 2.51 (s, 3H), 2.42 (s, 3H); MS (APCI) m/z: 313.4 (M + H)+.36
1-Benzyl-2-(4-(benzyloxy)phenyl)-5-methyl-1H-benzimidazole
1-Benzyl-2-(4-chlorophenyl)-1H-benzimidazole
Table 6). White solid (283 mg, 89%); IR (Neat) ν: 2994, 1635,
(entry
1475, 1386, 1278, 1016 cm−1; 1H NMR (CDCl3, 400 MHz) δ: 7.86 (entry 10, Table 6). White solid (347 mg, 86%); mp =
(d, J = 7.96 Hz, 1H), 7.63–7.60 (m, 2H), 7.43–7.21 (m, 8H), 186–187 °C; IR (Neat) ν: 3035, 2976, 1615, 1489, 1460, 1425,
7.11–7.07 (m, 2H), 5.38 (s, 2H); MS (APCI) m/z: 319.1 (M + H)+.36 1396, 1285, 1259, 1175 cm−1 1H NMR (CDCl3, 400 MHz) δ:
;
1-Benzyl-2-(4-(benzyloxy)phenyl)-1H-benzimidazole (entry 4, 7.65–7.63 (m, 3H), 7.47–7.40 (m, 4H), 7.37–7.33 (m, 4H),
Table 6). White solid (343 mg, 88%); mp = 165–167 °C; IR 7.14–7.05 (m, 6H), 5.44 (s, 2H), 5.13 (s, 2H), 2.52 (s, 3H); 13C
(Neat) ν: 3030, 2975, 1608, 1478, 1458, 1422, 1386, 1279, 1255, NMR (CDCl3, 100 MHz) δ: 160.0, 143.5, 136.6, 136.5, 134.2,
1
1175 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.84 (d, J = 7.92 Hz, 132.2, 130.7, 129.0, 128.7, 128.1, 127.7, 127.5, 125.9, 124.2,
1H), 7.61 (d, J = 8.52 Hz, 2H),7.42–7.39 (m, 4H), 7.37–7.29 (m, 119.6, 115.1, 110.6, 109.9, 109.8, 70.1, 48.4, 21.6; HRMS (ESI)
5H), 7.23–7.19 (m, 2H), 7.17–7.09 (m, 2H), 7.08–7.00 (m, 2H), m/z calcd for C28H25N2O [M + H+], 405.1967; Found 405.1966.
5.41 (s, 2H), 5.08 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 160.1,
1-Benzyl-6-chloro-2-phenyl-1H-benzimidazole (entry 11,
154.1, 143.2, 136.5, 136.4, 136.1, 130.7, 129.1, 128.1, 128.5, Table 6). White solid (270 mg, 85%); mp = 232–233 °C; IR
128.1, 127.8, 127.5, 125.9, 122.8, 122.6, 119.8, 115.1, 110.4, (KBr) νmax = 3240, 1645, 1609, 1486, 1275 cm−1 1H NMR
70.1, 48.4. HRMS (ESI) m/z calcd for C27H23N2O [M + H+], (400 MHz, CDCl3): δ = 7.79 (d, J = 8.56 Hz, 1H), 7.71–7.69 (m,
;
391.1810; Found 391.1810.
2H), 7.52–7.46 (m, 3H), 7.40–7.35 (m, 4H), 7.20 (d, J = 1.80 Hz,
5, 1H), 7.11 (d, J = 6.68 Hz, 2H), 5.45 (s, 2 H); MS (APCI) m/z:
1-Benzyl-6-methyl-2-phenyl-1H-benzimidazole
(entry
Table 6). White solid (262 mg, 88%); mp = 196–197 °C; IR 319.7 (M + H)+.39
(KBr) νmax = 3262, 1642, 1613, 1489, 1279 cm−1
;
1H NMR
1-Benzyl-6-chloro-2-(4-methylphenyl)-1H-benzimidazole
(400 MHz, CDCl3): δ = 7.76 (d, J = 5.40 Hz, 1H), 7.70–7.68 (m, (entry 12, Table 6). White solid (279 mg, 84%); mp =
2H), 7.48–7.45 (m, 3H), 7.39–7.32 (m, 3H), 7.16–7.12 (m, 3 H), 145–148 °C; IR (Neat) ν: 2990, 1633, 1608, 1456, 1382,
1
7.03 (s, 1H), 5.45 (s, 2 H), 2.46 (s, 3 H); MS (APCI) m/z: 299.3 1248 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.55 (d, J = 8.12 Hz,
(M + H)+.37
2H), 7.34–7.24 (m, 5H), 7.18 (d, J = 1.92 Hz, 1H) 7.15 (d, J =
1-Benzyl-6-methyl-2-(4-methylphenyl)-1H-benzimidazole (entry 8.60 Hz, 1H), 7.08 (d, J = 8.00 Hz, 2H), 5.40 (s, 2H); 13C NMR
6, Table 6). White solid (262 mg, 86%); mp = 194–196 °C; IR (CDCl3, 100 MHz) δ: 155.2, 141.8, 140.4, 136.7, 135.9, 129.5,
(Neat) ν: 3033, 2956, 1613, 1455, 1443, 1370, 1265, 1145 cm−1
;
129.2, 129.1, 128.5, 127.9, 126.7, 125.9, 123.3, 120.7, 110.5,
1H NMR (CDCl3, 400 MHz) δ: 7.73 (d, J = 8.24 Hz, 1H), 48.5, 21.42. HRMS (ESI) m/z calcd for C21H17ClN2Na [M + H+],
7.56–7.53 (m, 2H), 7.36–7.22 (m, 5H), 7.13–7.10 (m, 3H), 6.98 355.0978; Found 355.0977.
(s, 1H), 5.40 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H); 13C NMR (CDCl3,
1-Benzyl-2-(4-(benzyloxy)phenyl)-6-chloro-1H-benzimidazole
100 MHz) δ: 153.9, 141.3, 139.9, 136.7, 136.4, 132.9, 129.1, (entry 13, Table 6). White solid (373 mg, 88%); mp =
129.0, 129.0, 127.7, 127.3, 125.9, 124.2, 119.4, 110.2, 48.2, 21.9, 137–139 °C; IR (Neat) ν: 2995, 1633, 1624, 1457, 1366, 1218,
1
21.4. HRMS (ESI) m/z calcd for C22H21N2 [M + H+], 313.1705; 1157 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.74 (d, J = 8.0 Hz,
Found 313.1670.
1H), 7.61–7.59 (m, 2H), 7.43–7.01 (m, 14H), 5.39 (s, 2H), 5.10
Green Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
(s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 160.2, 154.9, 141.7, (m, 1H), 7.20 (d, J = 8.08 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
136.7, 136.4, 125.9, 130.7, 129.2, 128.6, 128.5, 128.2, 127.9, δ: 136.5, 135.7, 133.3, 130.1, 129.9, 129.6, 129.0, 128.9, 128.6,
127.5, 125.8, 123.3, 122.1, 120.6, 115.2, 110.4, 70.1, 48.5. 128.4, 123.9, 123.6, 122.6, 119.9, 110.3; HRMS (ESI) m/z calcd
HRMS (ESI) m/z calcd for C27H22ClN2O [M + H+], 425.1421; for C19H14BrN2 [M + H]+, 349.0340; Found 349.0342.
Found 425.1420.
1-Benzyl-5-chloro-2-phenyl-1H-benzimidazole (entry 14, Table 6). (232 mg, 84%); IR (Neat) ν: 2942, 2885, 1603, 1343,
Table 6). White solid (273 mg, 86%); mp = 181–182 °C; IR 1265, 1226, 1185, 1089 cm−1 1H NMR (CDCl3, 400 MHz)
(KBr) νmax = 3245, 1646, 1605, 1490, 1276 cm−1 1H NMR δ: 7.83–7.80 (m, 1H), 7.68–7.62 (m, 3H), 7.53–7.50 (m, 3H),
1-Cyclohexyl-2-phenyl-1H-benzimidazole
(entry
21,
;
;
(400 MHz, CDCl3): δ = 7.86 (d, J = 1.72 Hz, 1H), 7.71–7.69 (m, 7.29–7.23 (m, 2H), 4.39–4.32 (m, 1H), 2.38–2.30 (m, 2H),
2H), 7.54–7.47 (m, 3H), 7.38–7.35 (m, 3H), 7.23–7.20 (m, 1H), 1.98–1.64 (m, 6H), 1.42–1.27 (m, 2H); MS (APCI) m/z: 277.2
7.14–7.09 (m, 3H), 5.47 (s, 2H); MS (APCI) m/z: 319.2 (M + H)+.40
(M + H)+.38
2-(2-Phenyl-1H-benzimidazol-1-yl)ethanol
(entry
22,
1-Benzyl-5-chloro-2-(4-methylphenyl)-1H-benzimidazole (entry Table 6). (209 mg, 88%); IR (Neat) ν: 3396, 2985, 2876, 1606,
1
15, Table 6). White solid (279 mg, 84%); mp = 128–130 °C; IR 1346, 1265, 1245, 1186, 1059 cm−1; H NMR (CDCl3, 400 MHz)
(Neat) ν: 2996, 2912, 1625, 1605, 1455, 1430, 1381, 1382, 1248, δ: 7.74 (d, J = 6.12 Hz, 2H), 7.54 (d, J = 6.12 Hz, 1H), 7.39–7.17
1
1059 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.81 (s, 1H), 7.55 (d, (m, 6H), 4.33 (s, 2H), 4.06 (s, 2H); 13C NMR (CDCl3, 100 MHz)
J = 7.8 Hz, 2H), 7.34–7.06 (m, 9H), 5.41 (s, 2H), 2.40 (s, 3H); MS δ: 154.1, 142.5, 135.3, 129.8, 129.7, 128.5, 122.8, 122.6, 119.5,
(APCI) m/z: 333.5 (M + H)+.39
110.1, 60.8, 46.8; HRMS (ESI) m/z calcd for C15H14NaN2O
1-Benzyl-2-(4-(benzyloxy)phenyl)-5-chloro-1H-benzimidazole [M + Na+], 261.1004; Found 261.1003.
(entry 16, Table 6). White solid (373 mg, 88%); mp =
1-Allyl-2-phenyl-1H-benzimidazole (entry 23, Table 6). White
172–174 °C; IR (Neat) ν: 2939, 2923, 1610, 1455, 1386, 1253, solid (187 mg, 80%); mp = 86–88 °C; IR (Neat) ν: 2939, 1620,
1
1
1170 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.80 (d, J = 1.88 Hz, 1357,1253, 1161 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.90–7.85
1H), 7.62–7.59 (m, 2H), 7.44–7.37 (m, 4H), 7.36–7.30 (m, 4H), (m, 3H), 7.61–7.56 (m, 4H), 7.40–7.34 (m, 2H), 4.96 (s, 2H),
7.17 (dd, J = 1.92 and 8.56 Hz, 1H), 7.08–7.06 (m, 3H), 2.49 (s, 1H); MS (APCI) m/z: 235.2 (M + H)+.5b
7.05–7.04 (m, 1H), 7.03–7.02 (m, 1H), 5.43 (s, 2H), 5.11 (s, 2H);
2-Phenyl-1-(prop-2-yn-1-yl)-1H-benzimidazole (entry 24,
13C NMR (CDCl3, 100 MHz) δ: 160.3, 155.3, 144.0, 136.4, 136.0, Table 6). (182 mg, 83%); IR (Neat) ν: 2949, 2110, 1616, 1405,
134.7, 130.7, 129.2, 128.7, 128.2, 128.1, 127.9, 127.5, 125.9, 1259, 1150 cm−1; H NMR (CDCl3, 400 MHz) δ: 7.90–7.85 (m,
1
123.2, 122.5, 119.5, 115.2, 111.4, 70.1, 48.5. HRMS (ESI) m/z 3H), 7.61–7.56 (m, 4H), 7.40–7.34 (m, 2H), 4.96 (s, 2H), 2.49
calcd for C27H22ClN2O [M + H+], 425.1421; Found 425.1420.
(s, 1H); MS (APCI) m/z: 233.1 (M + H)+.32
1-(Furan-2-ylmethyl)-2-phenyl-1H-benzimidazole (entry 17,
1-Benzyl-2-(1H-indol-3-yl)-1H-benzimidazole
(entry
25,
Table 6). White solid (241 mg, 88%); mp = 130–132 °C; IR Table 6). White solid (274 mg, 85%); mp = 230–232 °C; IR
(Neat) ν: 3029, 2986, 2876, 1603, 1486, 1366, 1281, 1262, (Neat) ν: 3342, 3026, 2986, 2858, 1616, 1605, 1496, 1466, 1352,
1145 cm−1 1H NMR (CDCl3, 400 MHz) δ: 7.84–7.81 (m, 3H), 1265, 1263, 1156 cm−1 1H NMR (DMSO, 400 MHz) δ: 11.63
; ;
7.54–7.53 (m, 3H), 7.52 (d, J = 2.84 Hz, 1H),7.47–7.39 (m, 1H), (s, 1 H), 8.35 (d, J = 7.68 Hz, 1H), 7.71 (d, J = 7.68 Hz, 1H), 7.66
7.33–7.29 (m, 2H), 6.35 (d, J = 1.88 Hz, 1H), 6.34 (d, J = (s, 1H), 7.45 (t, J = 8.68 Hz, 2H), 7.29 (t, J = 7.48 Hz, 2H),
1.88 Hz, 1H), 5.34 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 149.4, 7.23–7.15 (m, 5H), 7.05 (d, J = 1.887.56 Hz, 2H), 5.72 (s, 2H);
143.1, 142.9, 135.9, 130.1, 129.9, 129.6, 128.7, 123.0, 122.7, 13C NMR, DMSO, 100 MHz) δ: 149.6, 143.1, 137.2, 135.9, 135.6,
119.9, 110.6, 110.4, 108.5, 42.2. HRMS (ESI) m/z calcd for 128.8, 127.4, 126.3, 125.9, 125.8, 122.4, 121.8, 121.7, 121.4,
C18H14N2NaO [M + Na]+, 297.1004; Found 297.0997.
1,2-Diphenyl-1H-benzimidazole (entry 18, Table 6). (227 mg, for C22H17KN3 [M + K+], 362.1060; Found 362.1062.
84%); IR (Neat) ν: 3034, 2931, 2853, 1614, 1497, 1454, 1418, 1-Benzyl-2-(thiophen-3-yl)-1H-benzimidazole (entry
1354, 1281, 1250, 1155 cm−1 1H NMR (CDCl3, 400 MHz) Table 6). White solid (252 mg, 87%); mp = 166–167 °C; IR
δ: 7.90 (d, J = 7.30 Hz, 1H), 7.59–7.50 (m, 5H), 7.34–7.27 (Neat) ν: 3035, 2966, 2878, 1618, 1486, 1369, 1289, 1259,
120.3, 118.4, 117.3, 110.0, 104.6, 46.97. HRMS (ESI) m/z calcd
26,
;
1
(m, 8H); MS (APCI) m/z: 271.2 (M + H)+.32
1158 cm−1; H NMR (DMSO, 400 MHz) δ: 7.85 (d, J = 7.64 Hz,
2-Phenyl-1-(4-methylphenyl)-1H-benzimidazole (entry 19, 1H), 7.60 (s, 1H), 7.52 (d, J = 4.92 Hz, 1H), 7.42–7.24 (m, 7H),
Table 6). (241 mg, 85%); IR (Neat) ν: 3031, 2935, 2856, 1610, 7.12 (d, J = 7.04 Hz, 2H), 5.53 (s, 2H); 13C NMR (CDCl3,
1495, 1456, 1359, 1283, 1253, 1185 cm−1 1H NMR (CDCl3, 100 MHz) δ: 149.7, 143.0, 136.2, 136.0, 130.9, 129.2, 128.2,
;
400 MHz) δ: 7.88 (d, J = 7.96 Hz, 1H), 7.57–7.55 (m, 2H), 127.9, 126.5, 126.3, 125.6, 123.1, 122.8, 119.8, 110.1, 48.1.
7.35–7.20 (m, 10H), 2.44 (s, 3H); MS (APCI) m/z: 285.5 HRMS (ESI) m/z calcd for C18H15N2S [M + H+], 291.0956;
(M + H)+.5b
Found 291.0953.
1-(4-Bromophenyl)-2-phenyl-1H-benzimidazole (entry 20,
1-Benzyl-2-cyclohexyl-1H-benzimidazole
(entry
27,
Table 6). White solid (299 mg, 86%); mp = 89–91 °C; IR (Neat) Table 6). (249 mg, 86%); IR (Neat) ν: 3035, 2932, 2855, 1613,
ν: 3032, 2933, 2853, 1608, 1498, 1453, 1362, 1275, 1258, 1189, 1499, 1455, 14183, 1355, 1282, 1255, 1156 cm−1
;
1H NMR
1
1068 cm−1; H NMR (CDCl3, 400 MHz) δ: 8.17 (d, J = 7.52 Hz, (CDCl3, 400 MHz) δ: 7.81 (d, J = 7.88 Hz, 1H), 7.31–7.24 (m,
2H), 8.03 (d, J = 8.0 Hz, 1H), 7.66–7.63 (m, 1H), 7.60–7.58 4H), 7.23–7.18 (m, 2H), 7.05 (d, J = 6.48 Hz, 2H), 5.37 (s, 2H),
(m, 2H), 7.48 (d, J = 7.52 Hz, 2H), 7.42–7.37 (m, 2H), 7.37–7.32 2.84–2.79 (m, 1H). 1.87 (s, 6H), 1.73 (m, 1H), 1.35–1.27
This journal is © The Royal Society of Chemistry 2013
Green Chem.

View Article Online
Paper
Green Chemistry
(m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 159.3, 136.3, 135.0, 12 S. Shekhar, P. Rydberg, J. F. Hartwig, J. S. Mathew,
128.9, 127.8, 126.1, 122.2, 122.0, 119.3, 109.6, 46.7, 36.5, 31.9,
26.3, 25.7. HRMS (ESI) m/z calcd for C20H23N2 [M + H+],
291.1861; Found 291.1862.
D. G. Blackmond, E. R. Strieter and S. L. Buchwald, J. Am.
Chem. Soc., 2006, 128, 3584.
13 (a) S. V. Chankeshwara and A. K. Chakraborti, Org. Lett.,
2006, 8, 3259; (b) G. L. Khatik, R. Kumar and
A. K. Chakraborti, Org. Lett., 2006, 8, 2433;
(c) A. K. Chakraborti, S. Rudrawar, K. B. Jadhav, G. Kaur
and S. V. Chankeshwara, Green Chem., 2007, 9, 1335;
(d) N. Parikh, D. Kumar, S. Raha Roy and
A. K. Chakraborti, J. Chem. Soc., Chem. Commun., 2011, 47,
1797.
Acknowledgements
DNK and DK thank CSIR, New Delhi, India for a senior
research fellowship and research associateship, respectively.
14 D. N. Kommi, D. Kumar, R. Bansal, R. Chebolu and
A. K. Chakraborti, Green Chem., 2012, 14, 3329.
15 The involvement of a water dimer through HB formation
with reactants has been projected in water promoted
epoxide ring opening by alcohol [I. Vilotijevic and
T. F. Jamison, Science, 2007, 317, 1189].
References
1 (a) M. Sharpe, B. Jarvis and K. L. Goa, Drugs, 2001, 61,
1501; (b) J. L. Falcó, M. Piqué, M. González, I. Buria,
E. Méndez, J. Terencio, C. Pérez, M. Príncep, A. Palomer 16 J. March, in Advanced Organic Chemistry: Reactions, Mechan-
and A. Guglietta, Eur. J. Med. Chem., 2006, 41, 985;
(c) T. Ishida, T. Suzuki, S. Hirashima, K. Mizutani,
isms, and Structure, Wiley India (P) Ltd., New Delhi, 2006,
ch. 13, p. 643.
A. Yoshida, I. Ando, S. Ikeda, T. Adahi and H. Hashimoto, 17 (a) A. K. Chakraborti, S. Rudrawar, L. Sharma and G. Kaur,
Bioorg. Med. Chem. Lett., 2006, 16, 1859; (d) S. Hirashima,
T. Suzuki, T. Ishida, S. Noji, S. Yata, I. Ando, M. Komatsu,
S. Ikeda and H. Hashimoto, J. Med. Chem., 2006, 49, 4721.
2 (a) R. Chebolu, D. N. Kommi, D. Kumar, N. Bollineni and
A. K. Chakraborti, J. Org. Chem., 2012, 77, 10158;
(b) D. Kumar, D. N. Kommi, R. Chebolu, S. K. Garg,
R. Kumar and A. K. Chakraborti, RSC Adv., 2013, 3, 91;
Synlett, 2004, 1533; (b) A. K. Chakraborti, L. Sharma
and M. K. Nayak, J. Org. Chem., 2002, 67, 6406;
(c) A. K. Chakraborti, M. K. Nayak and L. Sharma, J. Org.
Chem., 1999, 64, 8027; (d) L. Sharma, M. K. Nayak and
A. K. Chakraborti, Tetrahedron, 1999, 55, 9595;
(e) M. K. Nayak and A. K. Chakraborti, Tetrahedron Lett.,
1997, 38, 8749.
(c) J.-P. Wan, S.-F. Gan, J.-M. Wu and Y. Pan, Green Chem., 18 (a) A. K. Chakraborti, L. Sharma and M. K. Nayak, J. Org.
2009, 11, 1633; (d) K. Bahrami, M. M. Khodaei and
A. Nejati, Green Chem., 2010, 12, 1237.
Chem., 2002, 67, 2541; (b) M. K. Nayak and
A. K. Chakraborti, Chem. Lett., 1998, 297.
3 B. Zou, Q. Yuan and D. Ma, Angew. Chem., Int. Ed., 2007, 19 M. J. Kamlet, J.-M. Abboud, M. H. Abraham and R. W. Taft,
46, 2598. J. Org. Chem., 1983, 48, 2877.
4 (a) N. Zheng and S. L. Buchwald, Org. Lett., 2007, 9, 4749; 20 J. Schwöbel, R.-U. Ebert, R. Kühne and G. Schüürmann,
(b) N. Zheng, K. W. Anderson, X. Huang, N. H. Nguyen and
S. L. Buchwald, Angew. Chem., Int. Ed., 2007, 46, 7509.
5 (a) C. T. Brain and J. T. Steer, J. Org. Chem., 2003, 68, 6814;
(b) P. Saha, M. A. Ali, P. Ghosh and T. Punniyamurthy, Org.
Biomol. Chem., 2010, 8, 5692.
6 J. Alonso, N. Halland, M. Nazaré, O. R’kyek, M. Urmann
and A. Lindenschmidt, Eur. J. Org. Chem., 2011, 234.
7 P. Tundo, P. Anastas, D. S. Black, J. Breen, T. Collins,
S. Memoli, J. Miyamoto, M. Polyakoff and W. Tumas, Pure
Appl. Chem., 2000, 72, 1207.
J. Phys. Chem. A, 2009, 113, 10104.
21 HB driven electrophilic activations by other systems
(CH moiety) for various organic transformations have been
reported: (a) A. K. Chakraborti, S. Raha Roy, D. Kumar
and P. Chopra, Green Chem., 2008, 10, 1111;
(b) A. K. Chakraborti and S. Raha Roy, J. Am. Chem. Soc.,
2009, 131, 6902; (c) S. Raha Roy and A. K. Chakraborti, Org.
Lett., 2010, 12, 3866; (d) A. Sarkar, S. Raha Roy and
A. K. Chakraborti, Chem. Commun., 2011, 47, 4538;
(e) S. Raha Roy, P. S. Jadhavar, K. Seth, K. K. Sharma and
A. K. Chakraborti, Synthesis, 2011, 2261; (f) A. Sarkar,
S. Raha Roy, N. Parikh and A. K. Chakraborti, J. Org. Chem.,
2011, 76, 7132.
8 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings,
T. A. Johnson, H. P. Kleine, C. Knight, M. A. Nagy,
D. A. Perry and M. Stefaniakc, Green Chem., 2008, 10, 31.
9 S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54, 22 M. Calvin, J. Hermans, Jr. and H. A. Scheraga, J. Am. Chem.
3451.
Soc., 1959, 81, 5048.
10 H. C. Hailes, Org. Process Res. Dev., 2007, 11, 114.
11 For organic reactions in water please see: (a) C.-J. Li, Chem.
23 G. Dahlgren, Jr. and F. A. Long, J. Am. Chem. Soc., 1960, 82,
1303.
Rev., 2005, 105, 3095; (b) R. N. Butler and A. G. Coyne, 24 A. Grimison, J. Phys. Chem. Soc., 1963, 67, 962.
Chem. Rev., 2010, 110, 6302; (c) S. Minakata and 25 (a) A. G. Tennyson, E. L. Rosen, M. S. Collins, V. M. Lynch
M. Komatsu, Chem. Rev., 2009, 109, 711; (d) A. Chanda and
V. V. Fokin, Chem. Rev., 2009, 109, 725;
(e) U. M. Lindström, Chem. Rev., 2002, 102, 2751.
and C. W. Bielawski, Inorg. Chem., 2009, 48, 6924;
(b) P. Zhang, E. A. Terefenko, C. C. McComas,
P. E. Mahaney, A. Vu, E. Trybulski, E. Koury, G. Johnson,
Green Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
J. Bray and D. Deecher, Bioorg. Med. Chem. Lett., 2008, 18, 29 R. Varala, A. Nasreen, R. Enugala and S. R. T. Adapa, Tetra-
6067. hedron Lett., 2007, 48, 69.
26 (a) T. M. Kirrane, S. J. Boyer, J. Burke, X. Guo, R. J. Snow, 30 K. W. Anderson, M. Mendez-Perez, J. Priego and
L. Soleymanzadeh, A. Swinamer, Y. Zhang, J. B. Madwed, S. L. Buchwald, J. Org. Chem., 2003, 68, 9563.
M. Kashem, S. Kugler and M. M. O’Neill, Bioorg. Med. 31 A. Spencer, J. Organomet. Chem., 1985, 295, 199.
Chem. Lett., 2012, 22, 738; (b) D. J. O’Neill, A. Adeodoyin, 32 D. B. Ramachary and G. B. Reddy, Org. Biomol. Chem.,
P. D. Alfinito, J. A. Bray, S. Cosmic, D. C. Deecher,
A. Fensome, J. Harrison, L. Leventhal, C. Mann, 33 J. W. Hubbard, A. M. Piegols and B. C. G. Söderberg, Tetra-
C. C. McComas, N. R. Sullivan, T. B. Spangler, A. J. Uvegas, hedron, 2007, 63, 7077.
E. J. Trybulski, G. T. Whiteside and P. Zhang, J. Med. 34 S. A. Brown and C. J. Rizzo, Synth. Commun., 2002, 32,
Chem., 2010, 53, 4511; (c) J. C. Bressi, R. de Jong, Y. Wu, 2657.
2006, 4, 4463.
A. J. Jennings, J. W. Brown, S. O’Connell, L. W. Tari, 35 W. K. Anderson and G. Lai, Synthesis, 1995, 1287.
R. J. Skene, P. Vu, M. Navre, X. Cao and A. R. Gangloff, 36 M. M. Guru, M. A. Ali and T. Punniyamurthy, J. Org. Chem.,
Bioorg. Med. Chem. Lett., 2010, 20, 3138; (d) M. Frohn,
2011, 76, 5295.
H. Xu, X. Zou, C. Chang, M. McElvaine, M. H. Plant, 37 X. Deng and N. S. Mani, Eur. J. Org. Chem., 2010, 4, 680.
M. Wong, P. Tagari, R. Hungate and R. W. Bürli, Bioorg. 38 C. V. C. Rao, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Med. Chem. Lett., 2007, 17, 6633.
Chem., 1979, 18, 229.
27 J. G. Lee, K. I. Choi, H. Y. Koh, Y. Kim, Y. Kang and 39 B. Qin, Yaoxue Xuebao, 2009, 44, 1233.
Y. S. Cho, Synthesis, 2001, 81.
28 N. G. Connelly and W. E. Geiger, Chem. Rev., 1996, 96, 877.
40 D. Zhao, J. Hu, N. Wu, X. Huang, X. Qin, J. Lan and J. You,
Org. Lett., 2011, 13, 6516.
This journal is © The Royal Society of Chemistry 2013
Green Chem.