Cooperative iridium complex-catalyzed synthesis of quinoxalines, benzimidazoles and quinazolines in water

Article abstract of DOI:10.1039/c8gc03744b

Herein, an efficient methodology for the synthesis of a diverse class of N-heterocyclic moieties, such as quinoxalines, benzimidazoles and quinazolines, was developed in water using bio-renewable alcohols. The quinoxalines were successfully synthesized from a wide range of diamines and nitroamines with diols in air. Interestingly, benzimidazoles and quinazolines were synthesized with excellent isolated yields without using any external base. Finally, the preparative scale synthesis of various N-heterocycles and pharmaceutically active quinoxalines established the practicability of this protocol. For this iridium system, a metal-ligand cooperative mechanism was proposed based on kinetic and DFT studies.

Full text of DOI:10.1039/c8gc03744b

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: K. Chakrabarti, M.
Maji and S. Kundu, Green Chem., 2019, DOI: 10.1039/C8GC03744B.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Page 1 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C8GC03744B
Journal Name
ARTICLE
Cooperative Iridium Complex Catalyzed Synthesis of Quinoxalines,
Benzimidazoles and Quinazolines in Water
Kaushik Chakrabarti, Milan Maji and Sabuj Kundu*
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient methodology for the synthesis of diverse class of N-heterocyclic moieties like quinoxaline, benzimidazole and
quinazolines was developed in water using bio-renewable alcohols. The quinoxalines were successfully synthesized from
wide range of diamines and nitroamines with diols under air. Interestingly, without using any external base benzimidazoles
and quinazolines were synthesized with excellent isolated yields. Finally, preparative scale synthesis of various N-
heterocycles and pharmaceutically active quinoxalines established the practicability of this protocol. For this iridium system,
a metal-ligand cooperative mechanism was proposed based on kinetic and DFT studies.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Development of environmental friendly catalytic processes is
one of the greatest challenge for the chemist now a days. In this
regard, carrying out reactions utilizing water as a green, non-
Introduction
Quinoxaline, benzimidazole and quinazoline derivatives are
important N-heterocyclic moieties which are considered as one
of the major building blocks in dyes, pharmaceutical,
agrochemical and material industries.1-5 These nitrogen
containing heterocycles were found in several antitumor,
antibacterial, antihelmintic, antiviral, anti-HIV and anticancer
related drugs.6-11 Traditional synthetic approach for these
derivatives are the condensation of 1,2-diamines with
toxic and non-flammable solvent become one of the prime goal
in sustainable chemistry which received significant attention in
last two decades.37 Several catalytic reactions such as
hydrogenation of CO2 and other unsaturated bonds,38-40
alcohols oxidation,41-44 alkylation of amines with alcohols,45-47
and oxidative cyclization48 were extensively explored in water
utilizing various transition metal catalysts. However, to the best
of our knowledge synthesis of quinoxaline, benzimidazole and
quinazoline derivatives from alcohols in water is not reported
yet.
aldehydes or 1,2-diketones.12, However, availability of the
13
expensive and reactive aldehydes or 1,2-diketones limits these
processes for broader scope. Commonly, benzimidazoles and
quinazolines are synthesized via coupling of 1,2-
diaminobenzene with acids (e.g. formic acid), acid chlorides or
anhydrides which suffers from low atom efficiency and requires
high temperature and strong acidic conditions.14,
X
R4
HO
R2
R3
N
R1
n = 0, X
N
N
R2
R3
X
= NH, S
Ir
[
HO
]/
R4CH2OH
and
NH2
Ir
[
H2O
], Base
()n
R1
15
R1
N
For the
R4
H2O
n = 0, X
= NH2, NO2
synthesis of substituted quinoxalines few other methods also
reported such as oxidation-trapping of α-hydroxy ketones with
1, 2-diamines, cyclization-oxidation of phenacyl bromides and
oxidative coupling of epoxides with ene-1,2-diamines.16-18 But,
all these synthetic procedures suffered from common
drawbacks such as formation of stoichiometric amount salt
wastes, limited functional group tolerance and in some cases
requirement of excess oxidants. After development of hydrogen
borrowing methodology19, 20, several heterogeneous and
homogeneous catalysts were reported for the synthesis of
quinoxaline,21-27 benzimidazole28-32 and quinazoline33-36
derivatives from the condensation of primary alcohols or vicinal
diols with diamines.
N
Water as a green solvent
Alcohols as renewable coupling partner
R1
n = 1, X
= NH
Scheme 1 Synthesis of diverse class of N-heterocyclic moieties
in water.
Based on the ligand promoted dehydrogenation concept,
water soluble Cp*Ir complexes bearing a 2-hydroxypyridine
functionalized ligands exhibited higher activity in several
alcohol dehydrogenation related reactions in water.42,
43, 48
Recently, Himeda et al. reported a series of new electron rich
iridium complexes containing both the 2-hydroxypyridine and
imidazoline functionality which efficiently catalysed the
hydrogenation of CO2 and the dehydrogenation of formic acid
in aqueous medium.39 Inspired by this, we synthesized several
water soluble Ir complexes and screened their potential in
synthesis of quinoxaline, benzimidazole and quinazoline
derivatives using cheaper bio-derived vicinal diols or alcohols as
coupling partner with diamines and 1,2-nitroamines (Scheme
1).
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016,
India. *E-mail: sabuj@iitk.ac.in
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 7
ARTICLE
Journal Name
c
heating). Under argon condition. dWithout KOH only catalyst 2 was
Result and Discussion
View Article Online
e
f
DOI: 10.1039/C8GC03744B
used. Without KOH only catalyst 2 was used in argon condition. 2.5 mol
% 1b was used.
The investigation of the above protocol was started by
selecting the coupling between benzene-1,2-diamine and
propane-1,2-diol as a benchmark reaction in presence of Cat. 1a
which yielded only 15% of the desired product (Table 1). After
that several Ir (III) complexes and as well as Ir-precursors were
screened, in which 2-hydroxy pyridine based complex 1b
offered the highest yield (72%) of 2-methylquinoxaline (Table
1). Different weak and strong bases were tested in which KOH
(1.5 equiv.) provided the optimum result (Table 1). Notably, the
yield of 2-methylquinoxaline was decreased by lowering the
amount of diol or changing the reaction atmosphere from air to
argon (Table 1, entries 9-10). Finally, 2.5 mol % Cat. 1b with 1.5
equiv. of KOH in 24 h under air furnished the best result (Table
1, entry 21). No product formation was detected in presence of
only Cat. 1b or KOH, indicating the combination effect of
catalyst and base in this transformation (Table 1, entries 19 and
20).
After establishing the optimum reaction conditions, this
protocol was applied to the wide range of vicinal diamines and
diols using complex 1b. Different symmetrical and
unsymmetrical diol derivatives were tested with benzene-1,2-
diamine which provided excellent to good isolated yields of the
desired products (Table 2, entries C1-C7). With unsymmetrical
diamines and diols two type of regioisomers were produced in
good yields (Table 2, entries C9-C11). The ratio of this
1
regioisomers was obtained from H NMR analysis of the crude
reaction mixtures. Afterward, diverse range of unsymmetrical
1,2-diamines derivatives were reacted with 2,3-butanidiol
which gave good isolated yields of the expected quinoxalines
(Table 2, entries C12-C14). Symmetrical 4,5-dimethylbenzene-
1,2-diamine,
4,5-dimethoxylbenzene-1,2-diamine
and
naphthalene-1,2-diamine derivatives were also responded well
in this condition (Table 2, entries C8, C15, C16 and C19).
Additionally, 2,3-diaminepyridine furnished the desired
quinoxaline derivatives with different diols in good isolated
yields (Table 2, entries C17-C18).
Table 1 Optimization for the synthesis of 2-methylquinoxaline.a
NH2
N
CH3
H O
CH3 Ir-Cat (2 mol %), KOH,
HO
2
+
reflux, 24 h, under Air
NH2
N
HO
A
C
B
Table 2 Synthesis of various quinoxalines from diamines and
nitroamines.a
Me
Cl
Cl
H
2OTf
H
N
N
R
N
N
R
N
Ir
HO
N
Ir
NH2
N
R2
N
R2
HO
1b
Cat. , KOH,
H O
2
N
N
Ir
+
reflux, 24 h, under Air
X
N
C
R3
HO
R3
R1
R1
Cl
X = NH2, NO2
Cl
OH2
A
B
1a
R
Cat
Cat
Cat
Cat
= OMe
= OH
= Me
= H
2
Cat.
N
N
N
N
1e
R
= H
Cat
N
N
N
Me
N
N
Me
Me
1b
1c
1d
R
R
R
()2
N
C5
[
]
68% 80%
C4
[
]
C3
73% 83%
C1
C6
[
]
C2
[
]
70%
86% 87%
89% 90%
Entry
1
2
3
4
5
6
7
8
9b
10c
11d
12e
13
14
15
16
17
18
19
20
21f
Catalyst (2 mol %)
Base (equiv.)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
-
Yield (%)
N
N
R2
R3
Me
N
N
Me
N
Ph
Ph
N
Ph
1a
1b
1c
1d
1e
2
15
72
19
18
12
55
3
Me
Me
N
N
C9
76% (9a:9b 2:1)
9a R2 =Me & R3 =H
9b R2 =H & R3 =Me
C8 [ ]
72% 83%
C7
[
]
77% 83%
[
]
85% 92%
N
R2
R3
N
R2
R3
N
N
Me
Me
N
Me
MeO
N
Me
C10
N
C11
86% (11a:11b 3.4:1)
90% (11a:11b 4.1:1)
11a R2 =Ph & R3 =H
11b R2 =H & R3 =Ph
82% (10a:10b 3:2)
Me
MeO
Ph
N
Me
]
[
]
10a R2 =Ph & R3 =H
10b R2 =H & R3 =Ph
[Cp*IrCl2]2
[Cp*Ir(H2O)3](OTf)2
C13
N
[
C12
84% 89%
77%
7
N
N
N
Me
Me
N
Me
Me
1b
1b
2
42 (68)
14
6
N
Me
N
N
Br
N
C17
65%
C16
69%
C15
62%
C14
73%
N
R2
2
-
7
MeO
MeO
N
N
Ph
Me
Me
N
N
N
N
Me
Me
1b
1b
1b
1b
1b
1b
1b
-
NaOH (1.5)
K2CO3 (1.5)
Cs2CO3 (1.5)
KOH (2.0)
KOH (1)
KOH (0.75)
No base
KOH (1.5)
KOH (1.5)
62
30
27
74
56
34
2
Cl
[C20
N
R3
N
]
87% (20a:20b 1.7:1)
20a R2 =Ph & R3 =H
20b R2 =H & R3 =Ph
[C21
]
84%
C19
Br
C18
88%
70%
N
N
Me
N
N
Ph
Ph
N
N
Ph
Ph
Br
Me
Me
N
N
Ph
N
Me
]
Me
[C23
Me
[C24
[C22
]
90%
[C25
]
70%
78%
]
73%
0
92
aReaction Conditions: Diamine or Nitroamine (0.5 mmol), Diol (2.5
mmol), KOH (0.75 mmol), cat. 1b (2.5 mol %), H2O (3.0 mL), 120 °C (oil
bath temperature), 24 h. Isolated Yields. Reaction yields from
nitroamines are in bracket.
1b
aReaction Conditions: Amine (0.3 mmol), Diol (1.5 mmol), KOH (0.45
mmol), Ir cat. (2 mol %), H2O (2.0 mL), 120 °C (oil bath temperature), 24
h. Yield determined by GC analysis. b2 equiv. Diol was used (48 h
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 7
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Subsequently, we expanded this methodology by using 2-nitro using complex 2. Both electron withdrawing and donating group
View Article Online
DOI: 10.1039/C8GC03744B
aniline derivatives with vicinal diols in synthesis of various containing benzyl alcohol derivatives provided moderate to
quinoxaline moiety using complex 1b. In this transfer good yields of the desired benzimidazoles (Table 4, entries E2-
hydrogenative coupling conditions, 2-nitroaniline was reacted E5). Furthermore, heteroatom containing primary alcohols such
with different diols which furnished excellent isolated yields of as piperonyl alcohol, 2-thiophenemethanol and furfuryl alcohol
various quinoxaline derivatives (Table 2, entries C1, C2, C4-C7). also responded well in this condition (Table 4, entries E6-E8).
Several substituted nitroamines and diols were efficiently cross Aliphatic alcohol like 1-hexanol, 2-Aminothiophenol and methyl
coupled which disclosed the greater applicability of this 3,4-diaminobenzoate furnished moderate yield of the
procedure (Table 2, entries C8, C13 and C20-C24). In this case respective products (Table 4, entries E9, E13 and E14). Good to
also both unsymmetrical nitroamines and diols produced two excellent isolated yields of the respective benzimidazole
type of regioisomers in good yields (Table 2, entries C11 and products were observed from coupling of various substituted
C20) and these isomers were isolated individually by column diamines with benzyl alcohol (Table 4, entries E10-E12).
chromatography.
Table 4 Synthesis of benzimidazoles from diamines.a
H
N
NH2
After successfully synthesizing various quinoxalines in
presence of complex 1b, next we extended this sustainable
methodology in formation of benzimidazole derivatives in
water. However, the yield of 1-phenylbenimidazole was
significantly low (14%) under the previously mentioned
optimized conditions (Table 3, entry 3). Hence, the coupling of
benzene-1,2-diamine with benzyl alcohol was optimized and it
was found that complex 2 (2.5 mol %) under argon condition
without any external base offered maximum 92% yield of 1-
phenylbenzimidazole (Table 3, entry 7).
2
H O
Cat.
, , reflux
2
+
Ar
Ar
OH
Argon, 24 h
NH2
N
R1
R1
D
E
A
H
N
H
N
H
N
H
N
R'
N
N
N
N
E4 78%
E1
E2 R'
E3 R'
Cl
E5
Me
87%
= OMe 84%
56%
= Cl
75%
H
N
H
H
N
H
N
H
N
O
N
S
4
O
N
N
N
N
N
Me
O
41%b,c
E6
E7
80%
72%
E10
81%
E9
E8
64%
H
H
N
H
N
Me
Me
S
N
N
N
N
N
MeO2
C
MeO
E14
64%
E12
E11
82%
52%b
E13
80%
Table 3 Optimization for the synthesis of benzimidazole.a
aReaction Conditions: Amine (0.3 mmol), benzyl alcohol (0.45 equiv.),
cat. 2 (2.5 mol %), H2O (2.0 mL), 120 °C (oil bath temperature), 24 h,
under argon. Isolated Yields. b3 mol % cat. 2 was used and heated for 36
h. c5 equiv. hexanol was used.
NH2
NH2
H
N
°
H O
, 120 C
Ir-Cat,
2
+
Ph
OH
Ph
Argon, 24 h
N
D
N
A
E
Cl
2OTf
H
N
H
As quinazolines are one of the exciting class of heterocyclic
compounds, we applied our catalytic system for the sustainable
synthesis of these derivatives. Interestingly, it was found that
the coupling of 2-aminobenzyl amine with benzyl alcohol using
complex 2 (2.0 mol %) under argon condition without any
external base offered maximum 94% isolated yield of 2-
phenylquinazoline within 24 h (Table 5, entry G1).
N
R
N
Ir
HO
N
Ir
N
OH2
2
Cl
1a
1b
R
R
Cat.
Cat.
= OMe
= OH
Cat.
Entry
1
Catalyst (2 mol %)
Yield (%)
Table 5 Synthesis of quinazolines from diamine.a
1b
2
1b
1b
1a
2
2
2
2
2
27
77
14
4
0
9
92
68
58
42
2
NH2
N
2
H O
Cat.
, , reflux
2
3b,c
4b
+
Ar
OH
Argon, 24 h
NH2
N
Ar
D
F
G
5b,c
6c
N
N
N
N
N
N
N
N
7e
OMe
Cl
Me
G4
N
85%
G2
G6
G3
88%
G1
90%
94%
N
8f
N
N
9g
N
N
N
N
10h
CO2Me
N
O
G7
G8
83%
87%
G5
60%
88%
O
OMe
aReaction Conditions: Amine (0.3 mmol), benzyl alcohol (0.45 equiv.), Ir cat.
(2 mol %), H2O (2.0 mL), 120 °C (oil bath temperature), 24 h. Yield determined
by GC analysis. bKOH (0.45 equiv.) was used. cIn open air. eCat. 2 (2.5 mol %)
was used. fBenzyl alcohol (2 equiv.), 18% N-alkylation happened on E. gBenzyl
alcohol (1.2 equiv.). hBenzyl alcohol (1 equiv.)
N
N
O
S
N
N
N
N
G9
74%
G10
78%
G11
68%
aReaction Conditions: Amine (0.3 mmol), benzyl alcohol (0.45 equiv.),
cat. 2 (2 mol %), H2O (2.0 mL), 120 °C (oil bath temperature), 24 h, under
argon. Isolated Yields.
Afterward, this optimised conditions was applied for the
coupling of different benzyl alcohols with benzene-1,2-diamine
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 7
ARTICLE
Journal Name
Next, several electron withdrawing and donating group cooperativity also can’t be ruled out. So, we synthesised cat. 1e
View Article Online
DOI: 10.1039/C8GC03744B
containing benzyl alcohol derivatives were tested which gave and employed it in the standard reaction condition which gave
excellent yields to moderate of the products (Table 5, entries 13% yield of 2-methylquioxaline (SI, Scheme S3). This result
G2-G6). Additionally, 1-naphthalenemethanol, heteroatom indicated compare to the N-H group, O-H functionality played
containing primary alcohols such as piperonyl alcohol, furfuryl more significant role in the enhancement of the catalytic
alcohol, 2-thiophenemethanol and nicotinyl alcohol were activity.
responded well in this condition (Table 5, entries G7-G11).
Cl
H
Cl
H
N
KOtBu
HO
N
Ir
N
HO
N
The practical applicability of this methodology was further
extended by preparative scale synthesis of several quinoxalines,
benzimidazoles and quinazolines (Fig. 1, 1a-1d). Furthermore,
synthesis of biologically active quinoxaline derivatives was
carried out efficiently by this methodology which furnished
anti-HIV derivative (E7), EGFR Tyrosine Kinase inhibitor (C16 and
C22) and Tyrphostin AG 1296 (C19) with good to excellent yields
(Fig. 1, 1e and SI, Scheme S1).49-51 Starting from substituted 1,2-
N
2-propanol
, 80 °C
N
Ir
*Cp
H
*Cp
Cl
1bH (Ir-H, = -13.23 ppm)

1b
NH2
N
CH3
HO
HO
CH3 Cat. 1bH (2.5 mol %), KOH,
+
H O
, reflux, 24 h, under Air
2
NH2
N
84%
yield
A
C
B
diamine derivatives versatile quinoxaline moieties C7, C16 and Scheme 2 Synthesis of Ir-H and its reactivity.
C19 were synthesized in good isolated yield. Following this
methodology 2-nitroaniline derivatives were smoothly
In alcohol dehydrogenation reaction metal hydride is
converted to C7 and C22 in excellent yields. After that we tested considered as one of the key intermediates.48 Thus Ir-H species
reusability of this aqueous catalytic system for the synthesis of (cat 1bH) was synthesized from the cat. 1b in KOtBu/2-propanol
quinoxaline from diamine in water by simple phase separation which showed a singlet peak (Ir-H) at -13.23 ppm in H NMR
1
technique. The recovered aqueous solution containing the spectrum (SI Fig. S2). To test our hypothesis, this Ir-H species
catalyst could be recycled up to third run (SI, Table S2).
was employed for the quinoxaline synthesis under the standard
catalytic conditions which furnished 84% yield of 2-
methylquinoxaline (Scheme 2). This experiment undoubtedly
suggested that the Ir-H is one of the active intermediate in this
catalytic process.
1a) From diamines
N
N
N
N
Me
Me
N
Me
Me
N
N
Me
Br
N
N
68% (0.483 g)
64% (0.358 g)
58% (0.362 g)
61% (0.266 g)
1b) From nitroamines
path b
N
N
Me
Me
Br
N
Me
Me
N
N
N
Ph
Ph
1b,
NH2
NH2
Ir Cat
KOH
NH2
HO
HO
R1
R2
N
MeO
N
Me
Me
N
Me
-[2H2O]
NO2
83% (0.468 g)
66% (0.561 g)
79% (0.508 g)
73% (0.550 g)
1c) From diamines
nIr]
O
R1
R2
L
[
H
-[H2O]
N
H
N
H
path a
Me
Me
N
N
S
H O
2
-
L Ir H
]
2
[
-
n
O
O
N
N
N
O
OH
R2
O
L Ir H
]
2
[
-
n
N
N
R1
R2
75% (0.500 g)
76% (0.543 g)
67% (0.402 g)
N
-[H2O]
R2
1d) From diamines
N
R1
NO2
R1
NH2
X
L Ir
[
]
n
N
N
N
N
-2H2O
W
O
N
N
79% (0.607 g)
71% (0.418 g)
63% (0.392 g)
1e)
N
Ph
N
N
Ph
Ph
MeO
MeO
N
Ph
Me
N
Ph
N
N
Me
N
C16
C22
C7
DPQ Anti-HIV derivative
61%
80% [84%]
69% [77%]
C19
82%
Tyrphostin AG 1296
EGFR Tyrosine Kinase inhibitor
Fig. 1 Preparative scale synthesis of several quinoxalines,
benzimidazoles and quinazolines (Fig. 1a-1d), Synthesis of
biologically active quinoxaline derivatives (Fig. 1e).
Dehydrogenation of alcohols was the key step in these Fig. 2 Probable mechanism with nitroamine.
reactions. Notably, Cat. 1a and 1b in Table 1 disclosed that
complexes bearing ortho-OH group containing ligand exhibited In case of 2-nitroaniline derivative the reaction was monitored
significantly higher activity than those having ortho-OMe at initial time and formation of 1,2-diamine was not detected in
substituents. This result clearly indicated that metal-ligand GC (Fig. 2). This observation indicated that probably the
cooperativity played significant role in this process which is well imination of the amino group of 2-nitroanilines (path a) was
documented in literature with similar 2-hydroxy pyridine based occurred before the reduction of the nitro group however
systems.39, 48, 52-54 However, for these systems, the effect of involvement
proton responsive N-H functionality in metal-ligand intermediate (path b) can’t be ruled out (Fig. 2).21 We also
of
1,2-phenylenediamine
as
transient
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 7
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
tested the catalytic efficiency of cat 1b and 2 in benzyl alcohol diamines and nitroamines with diols in water. Furthermore,
View Article Online
DOI: 10.1039/C8GC03744B
dehydrogenation under argon and aerobic condition where cat. base free synthesis of benzimidazoles and quinazolines from
1b in air and 2 in argon displayed superior activity (SI, Table S1). diverse range of primary alcohols and diamines was established.
This considerable reactivity differences of complexes 1b and 2 Preparative scale synthesis of these derivatives demonstrated
under these two conditions is not clear at this moment.
the generality of this protocol. Additionally, few
pharmaceutically active quinoxaline derivatives were
To shed more light on the alcohol dehydrogenation synthesized efficiently by this methodology. Kinetic studies and
mechanism, DFT calculations using benzyl alcohol as a model DFT calculations confirmed metal-ligand cooperative
substrate was performed. First, treatment of precatalyst 1b mechanism for the alcohol dehydrogenation. Finally, phosphine
with externally added KOH or with 2 by triflate anion would free bifunctional catalysts were found to be highly efficient in
generate a 2-pyridonate-based iridium intermediate I1 (Fig. 3, synthesis of various important N-heterocyclic moieties in water.
SI, Scheme S7).41 Afterwards, I1 mediated benzyl alcohol
dehydrogenation reaction can follow two probable pathways
(outer-sphere and inner-sphere).53 In outer-sphere pathways
benzyl alcohol was dehydrogenated via transition state TS1outer
(20.03 kcal/mol), and Ir-H intermediate (I3) was formed (Fig.
3).55, 56 Where as in case of inner-sphere pathway an alcohol
coordinate species I2 (0.23 kcal/mol) was generated from I1
which underwent β-hydride elimination by four membered
transition state TS1inner (60.61 kcal/mol) and formed
intermediate (I3) (Fig. 3).56 Finally ligand promoted hydrogen
elimination from I3 (1.6 kcal/mol) through TS2 (31.3 kcal/mol)
regenerated the intermediate I1 by an activation barrier 29.7
kcal/mol. Considerably higher activation barrier for the alcohol
dehydrogenation by inner-sphere route(60.38 kcal/mol) made
it less favoured over the outer-sphere pathway (20.03
kcal/mol).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the Science and Engineering Research Board
(SERB), India for financial support. KC thank UGC-India, MM
thank CSIR-India for fellowship.
Notes and references
1.
2.
K.-H. Lee, J. Med. Chem., 2005, 48, 6166-6166.
R. Sarges, H. R. Howard, R. G. Browne, L. A. Lebel, P. A.
Seymour and B. K. Koe, J. Med. Chem., 1990, 33, 2240-
2254.
H
H
H
N
N
3.
4.
P. Erk, in High Performance Pigments, eds. E. B. Faulkner
and R. J. Schwartz, Wiley-VCH, 2009, vol. 8.
B. D. Lindner, Y. Zhang, S. Höfle, N. Berger, C. Teusch, M.
Jesper, K. I. Hardcastle, X. Qian, U. Lemmer, A. Colsmann,
U. H. F. Bunz and M. Hamburger, J. Mater. Chem. C, 2013,
1, 5718-5724.
HO
N
O
H
N
N
O
N
H
N
N
Gsol
N
Ir
kcal/mol
Ir
H
O
O
Ir
Cp*
H
Cp*
H
H
Ph
Cp*
Ph
H
TS1inner
TS1outer
TS2
TS1inner
60.61
H
5.
R. Iemura, T. Kawashima, T. Fukuda, K. Ito and G.
Tsukamoto, J. Med. Chem., 1986, 29, 1178-1183.
O. O. Ajani, Eur. J. Med. Chem., 2014, 85, 688-715.
S. D. Undevia, F. Innocenti, J. Ramirez, L. House, A. A. Desai,
L. A. Skoog, D. A. Singh, T. Karrison, H. L. Kindler and M. J.
Ratain, Eur. J. Cancer, 2008, 44, 1684-1692.
V. G. Ugale and S. B. Bari, Eur. J. Med. Chem., 2014, 80, 447-
501.
N
O
N
TS2
31.3
N
H
H
N
Ir
6.
7.
O
HO
N
TS1outer
20.03
Cp*
N
Ph
Ir
H
I2
Cp*
0.23
8.
I3
1.6
H
N
H
I1
0
I1
0
N
O
N
O
N
9.
G. Grover and S. G. Kini, Eur. J. Med. Chem., 2006, 41, 256-
262.
N
N
Ir
Ir
Cp*
H2 elimination
Cp*
10.
11.
12.
A. K. Tiwari, V. K. Singh, A. Bajpai, G. Shukla, S. Singh and A.
K. Mishra, Eur. J. Med. Chem., 2007, 42, 1234-1238.
B. Santanu and C. Padmaparna, Curr. Med. Chem., 2008,
15, 1762-1777.
M. Ayaz, Z. Xu and C. Hulme, Tetrahedron Lett., 2014, 55,
3406-3409.
Alcohol dehydrogenation
Fig. 3 DFT study: free energy profile for dehydrogenation of benzyl
alcohol (Hybrid functional, M062X was used with the LANL2DZ basis
set for Ir and 6-31G** basis set for non-metal elements).
13.
14.
15.
J. B. Wright, Chem. Rev., 1951, 48, 397-541.
E. C. Wagner and W. H. Millett, Org. Synth., 1939, 19, 12.
C. Xu, F.-C. Jia, Z.-W. Zhou, S.-J. Zheng, H. Li and A.-X. Wu,
J. Org. Chem., 2016, 81, 3000-3006.
R. S. Robinson and R. J. K. Taylor, Synlett, 2005, 2005, 1003-
1005.
Conclusions
In summary, a straightforward synthesis of quinoxaline,
benzimidazole and quinazoline derivatives was developed for
the first time in water using alcohols. For the synthesis of
quinoxalines this methodology was successfully applied for the
dehydrogenative coupling of wide range of substituted
16.
17.
M. M. Ibrahim, D. Grau, F. Hampel and S. B. Tsogoeva, Eur.
J. Org. Chem., 2014, 2014, 1401-1405.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 7
ARTICLE
18.
Journal Name
K. Kumar, S. R. Mudshinge, S. Goyal, M. Gangar and V. A. 48.
Nair, Tetrahedron Lett., 2015, 56, 1266-1271.
A. Corma, J. Navas and M. J. Sabater, Chem. Rev., 2018, 49.
118, 1410-1459.
R. H. Crabtree, Chem. Rev., 2017, 117, 9228-9246.
F. Xie, M. Zhang, H. Jiang, M. Chen, W. Lv, A. Zheng and X. 50.
Jian, Green Chem., 2015, 17, 279-284.
S. Shee, K. Ganguli, K. Jana and S. Kundu, Chem. Commun., 51.
2018, 54, 6883-6886.
R. Zhang, Y. Qin, L. Zhang and S. Luo, Org. Lett., 2017, 19,
R. Wang, H. Fan, W. Zhao and F. Li, Org. Lett., 2016, 18,
View Article Online
3558-3561.
DOI: 10.1039/C8GC03744B
19.
C. Kumar Shahi, S. Pradhan, A. Bhattacharyya, R. Kumar
and M. K. Ghorai, Eur. J. Org. Chem., 2017, 2017, 3487-
3495.
A. Irfan, O. A. Tahir, M. Umer, S. Ahmad and H. Kousar,
World J. Pharm. Pharm. Sci., 2016, 6, 11-30.
M. J. Waring, T. Ben-Hadda, A. T. Kotchevar, A. Ramdani, R.
Touzani, S. Elkadiri, A. Hakkou, M. Bouakka and T. Ellis,
Molecules, 2002, 7, 641-656.
M. Z. Ertem, Y. Himeda, E. Fujita and J. T. Muckerman, ACS
Catal., 2016, 6, 600-609.
G. Zeng, S. Sakaki, K.-i. Fujita, H. Sano and R. Yamaguchi,
ACS Catal., 2014, 4, 1010-1020.
K.-i. Fujita, Y. Tanaka, M. Kobayashi and R. Yamaguchi, J.
Am. Chem. Soc., 2014, 136, 4829-4832.
K. Chakrabarti, M. Maji, D. Panja, B. Paul, S. Shee, G. K. Das
and S. Kundu, Org. Lett., 2017, 19, 4750-4753.
H. Li, G. Lu, J. Jiang, F. Huang and Z.-X. Wang,
Organometallics, 2011, 30, 2349-2363.
20.
21.
22.
23.
24.
25.
26.
27.
5629-5632.
52.
53.
54.
55.
T. Hille, T. Irrgang and R. Kempe, Chem. Eur. J., 2014, 20,
5569-5572.
C. S. Cho and S. G. Oh, Tetrahedron Lett., 2006, 47, 5633-
5636.
K. Das, A. Mondal and D. Srimani, Chem. Commun., 2018,
54, 10582-10585.
P. Daw, A. Kumar, N. A. Espinosa-Jalapa, Y. Diskin-Posner,
Y. Ben-David and D. Milstein, ACS Catal., 2018, 8, 7734- 56.
7741.
28.
29.
30.
31.
32.
33.
Y. Shiraishi, Y. Sugano, S. Tanaka and T. Hirai, Angew.
Chem. Int. Ed., 2010, 49, 1656-1660.
T. B. Nguyen, J. Le Bescont, L. Ermolenko and A. Al-
Mourabit, Org. Lett., 2013, 15, 6218-6221.
P. Daw, Y. Ben-David and D. Milstein, ACS Catal., 2017, 7,
7456-7460.
K. Das, A. Mondal and D. Srimani, J. Org. Chem., 2018, 83,
9553-9560.
L. Li, Q. Luo, H. Cui, R. Li, J. Zhang and T. Peng,
ChemCatChem, 2018, 10, 1607-1613.
M. Chen, M. Zhang, B. Xiong, Z. Tan, W. Lv and H. Jiang,
Org. Lett., 2014, 16, 6028-6031.
34.
35.
J. Fang, J. Zhou and Z. Fang, RSC Adv., 2013, 3, 334-336.
S. Parua, R. Sikari, S. Sinha, G. Chakraborty, R. Mondal and
N. D. Paul, J. Org. Chem., 2018, 83, 11154-11166.
H. Fan, W. Zhang, W. Zhao and F. Li, ChemistrySelect, 2017,
2, 5735-5739.
Metal-Catalyzed Reactions in Water, eds. P. H. Dixneuf and
V. Cadierno, Wiley-VCH, 2013.
N. Onishi, S. Xu, Y. Manaka, Y. Suna, W.-H. Wang, J. T.
Muckerman, E. Fujita and Y. Himeda, Inorg. Chem., 2015,
54, 5114-5123.
36.
37.
38.
39.
L. Wang, N. Onishi, K. Murata, T. Hirose, J. T. Muckerman,
E. Fujita and Y. Himeda, ChemSusChem, 2017, 10, 1035-
1035.
40.
41.
42.
43.
44.
45.
46.
47.
Á. Vivancos, M. Beller and M. Albrecht, ACS Catal., 2018, 8,
17-21.
K.-i. Fujita, R. Tamura, Y. Tanaka, M. Yoshida, M. Onoda and
R. Yamaguchi, ACS Catal., 2017, 7, 7226-7230.
R. Kawahara, K.-i. Fujita and R. Yamaguchi, Angew. Chem.
Int. Ed., 2012, 51, 12790-12794.
R. Kawahara, K.-i. Fujita and R. Yamaguchi, J. Am. Chem.
Soc., 2012, 134, 3643-3646.
L. Rakers, F. Schäfers and F. Glorius, Chem. Eur. J., 2018, 24,
15529-15532.
O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden and J. M.
J. Williams, Chem. Commun., 2010, 46, 1541-1543.
J. Norinder and A. Börner, ChemCatChem, 2011, 3, 1407-
1409.
A. Fernandes and B. Royo, ChemCatChem, 2017, 9, 3912-
3917.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C8GC03744B
Table of Contents
HO
R2
R4CH2OH
HO
R3
X
Ir
H2O
[
]
Ir
H2O
[
]
NH2
()n
R1
N
N
R2
R3
X
N
N
R4
R4
and
R1
n = 1, X
N
R1
R1
n = 0, X
= NH, S
n = 0, X
= NH2, NO2
= NH
A sustainable protocol for the synthesis of various pharmaceutically relevant N-heterocyclic moieties was
developed in water. Based on kinetic and DFT studies a metal-ligand cooperative mechanism was proposed for
this system.