Cobalt complex catalyzed atom-economical synthesis of quinoxaline, quinoline and 2-alkylaminoquinoline derivatives

Article abstract of DOI:10.1039/c8cc02366b

A new phosphine-free Co(ii) complex-catalyzed synthesis of various quinoxalines via dehydrogenative coupling of vicinal diols with both o-phenylenediamines and 2-nitroanilines is reported. This complex was also effective for the synthesis of quinolines. The practical aspect of this catalytic system was revealed by the one-pot synthesis of 2-alkylaminoquinolines.

Full text of DOI:10.1039/c8cc02366b

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Reactivity differences of Sc
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Cobalt Complex Catalyzed Atom-Economical Synthesis of
Quinoxaline, Quinoline and 2-Alkylaminoquinoline Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
a
Sujan Shee, Kasturi Ganguli, Kalipada Jana and Sabuj Kundu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new phosphine free Co(II) complex catalyzed synthesis of alcohols, respectively are more attractive as it avoids pre-
various quinoxalines via dehydrogenative coupling of vicinal diols functionalized molecules, halogenated coupling partners or
with both the o-phenylenediamines and 2-nitroanilines is addition of excessive additives. Following these strategies for
reported. This complex was also effective for the synthesis of the synthesis of these molecules mostly precious and less-
quinolines. The practical aspect of this catalytic system was abundant 4d and 5d transition metals based catalysts are
[12]
reported.
revealed by one-pot synthesis of 2-alkylaminoquinolines.
Herein, we report phosphine free cobalt complex catalyzed
environmentally benign synthesis of quinoxaline and quinoline
derivatives as well as one-pot synthesis of 2-
alkylaminoquinolines. To the best of our knowledge cobalt
complex mediated atom-economical synthesis of quinoxalines
and 2-alkylaminoquinolines following dehydrogenative
coupling and borrowing hydrogen methodology is not
reported yet.
The development of catalysts based on abundant and
nonprecious 3d transition metals received significant attention
[1]
over the past few decades. Cobalt is one of the attractive
candidates among the 1st row transition metals and numerous
[2]
reactions using cobalt catalysts are known.
Recently,
following the borrowing hydrogen strategy cobalt complex
mediated some C-C and C-N bond forming reactions such as
[
3]
[4]
N‑alkylation of amines, C-alkylation of ketones, amides,
[5]
Inspired by the high reactivity of several tridentate ligand
[
6]
[13]
and alcohols,
and other dehydrogenative coupling
containing Co(II) complexes, we synthesized a new nitrogen
containing proton responsive ligand L1 and its corresponding
Co(NNN) complex was synthesized in good yield (89%) by
[7]
reactions were reported. These protocols have significant
advantages over the conventional methods as it employs
alcohol as a greener alkylating partner. It also does not require
precious metal catalysts and avoids the formation of
stoichiometric salt waste. However, most of these cobalt
complexes are based on expensive, air and moisture sensitive
reacting L1 and CoBr in methanol at room temperature (Fig.
2
1
). This paramagnetic complex was characterized by elemental
analysis, ESI-MS, X-ray crystallography, UV-Vis and IR
spectroscopy. The solid state structure of complex showed a
distorted square pyramidal structure with a dihedral angle of
A
[3d, 6, 8]
phosphine ligands which limits their applications.
Sustainable synthesis of quinoxaline, quinoline and 2-
alkylaminoquinoline derivatives remains an attractive target to
the organic chemists due its wide range of pharmacological
and biological activities including antibacterial, antiamoebic,
antidepressant, antiviral, anticancer, antitumor, antimalarial,
3
6.55 (3) ° between the benzimidazole and quinoline moiety.
[9]
and anti-inflammatory properties. Quinoxaline derivatives
also utilized as electroluminescent materials, organic
[10]
semiconductors, cavitands and fluorescent dyes. Compared
[11]
to the various conventional methods,
the synthesis of
quinoxaline and quinoline derivatives via dehydrogenative
coupling of biomass-derived vicinal diols with 1,2-diamines or
2-nitroanilines and coupling of amino alcohols with secondary
Complex A
Fig. 1 Synthesis of complex
A and its molecular structure.
Ellipsoids are drawn at 30% thermal probability level.
a
Table 1 Screening of the optimal conditions
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Journal Name
Entry
Co (II) Cat.
Base (equiv.)
Yield of 4a (%)
t
KO Bu (1.2)
1
2
3
4
5
6
CoBr
2
25
88
2
t
KO Bu (1.2)
A
-
t
KO Bu (1.2)
i
NaO Pr (1.2)
A
A
A
A
73
75
96
70
KOH (1.2)
CsOH.H
CsOH.H
2
2
O (1.2)
O (1.2)
b
7
a
Reaction conditions: o-phenylenediamine (0.5 mmol), 1,2-propanediol (2.5
°
mmol), toluene (2 mL), heated at 150 C for 24 h under closed condition; GC yield
b
n-dodecane as internal standard). refluxed at 140 C.
°
Scheme 1 Substrate scope for quinoxaline Synthesis. Reaction conditions:
(
diamine (0.5 mmol), vicinal diol (2.5 mmol), Cat.
A
(5 mol%), CsOH.H
mmol), toluene (2 mL), heated at 150 C for 24 h under closed condition; isolated
2
O (0.6
°
Initially, dehydrogenative coupling of 1,2-propanediol with yields.
o-phenylenediamine was selected as model reaction to
determine the optimum reaction conditions and the reaction
was carried in toluene for 24 h using Co(II) complexes (5 mol%)
coupling of diamine and diol. To our delight, in comparison to
the recently reported Zhang group’s system (3 mol%
t
[12a]
and 1.2 equiv. of KO Bu (Table 1). The yield of the desired 2-
Ru(II)/dppp), complex
A exhibited much higher activity.
methylquinoxaline (4a) product was significantly higher in
With this optimized conditions the coupling of various diols
with substituted nitroanilines was carried out to examine the
generality of this protocol (Scheme 2). At first verities of
quinoxaline were synthesized using different vicinal diols
keeping 2-nitroaniline as a fixed coupling partner. Similar
reaction with 3,4-dimethyl-2-nitroaniline also provided good to
presence of complex
Next, in the presence of complex
tested and CsOH.H O delivered the best results. The yield of 4a
A
compare to the metal precursor CoBr
2
.
A
, different bases were
2
was reduced by lowering the ratio of 1,2-diol to diamine and
also by decreasing the oil bath temperature (SI, Table S1).
Similar phenomenon was also reported for the Co(II) catalyzed
coupling of amino alcohols with secondary alcohols and the
excellent yields (71-93%) of the desired quinoxaline (4h, 4n).
However, yields were relatively lower with less substituted
unsymmetrical diols compare to the more substituted diols
[14]
reaction was carried out at high temperature (180 °C).
Next, different quinoxaline were synthesized from various
vicinal diols and diamines (Scheme 1). Reaction of o-
phenylenediamine with different mono substituted vicinal
diols provided good to excellent yields of the expected
under this reaction conditions (Scheme 2, 4a-4g). Zhang’s
[12a]
group also observed similar phenomenon.
Different
substituted nitroanilines were also smoothly converted to the
desired product with excellent yield (4i, 4k, 4m) whereas
pyridine containing nitroamine showed moderate reactivity
products (Scheme 1, 4a, 4c-4f). However, yields of the
quinoxalines was slightly lower with both disubstituted vicinal
diol and substituted aryl diamines under the same reaction
(
4o).
conditions
(4b
,
4g-4k). Notably, challenging pyridine
containing diamine also afforded 3-methylpyrido[2,3-
b]pyrazine (4l) in moderate yields under this reaction
conditions.
N
N
N
N
N
After establishing the potential of this system to catalyze
the coupling of diamines with diols, we sought out the
synthesis of quinoxaline from 2-nitroaniline and diol. In this
process the nitro group of 2-nitroanilines and the vicinal diols
serve as the hydrogen acceptor and donors respectively. This
eco-friendly strategy is attractive as it avoids the use of any
external reducing agents and produces only water as by
N
N
N
4b, 96%
4a, 75%
4c, 69%
4d, 66%
N
N
Ph
Ph
N
N
N
N
N
Cl
N
4
e, 62%
4g, 92%
4h, 71%
4i, 95%
[12a, 15]
product.
For this purpose 2-nitroaniline and 2,3-
N
N
N
N
N
N
butanediol were chosen as primary substrates for the
optimization of the reaction parameters. Interestingly,
N
Br
O
N
N
4k, 93%
4m, 90%
4n, 93%
4o, 48%
complex
A in presence of 0.5 equiv. of CsOH.H O delivered
2
96% yield for the desired product after 24 h. Notably, the
catalyst loading in this reaction was significantly lower (0.2 mol Scheme 2 Quinoxaline synthesis from 2-nitroanilines and vicinal diols. Reaction
conditions: 2-nitroaniline (0.5 mmol), vicinal diol (1.5 mmol), Cat. A (0.2 mol%),
%) compare to the
2
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°
2
CsOH.H O (0.25 mmol), toluene (2 mL), heated at 150 C for 24 h under closed
condition; isolated yields.
substituted 2-aminobenzyl alcohol provided good yield of 6h
under the same reaction conditions. The yield of the desired
Br
O
N
N
N
N
N
N
N
N
H
H
H
H
6
a, 94%
6b, 92%
6c, 81%
6d, 87%
O
O
Cl
Br
S
N
N
H
N
N
H
N
N
H
4
N
N
H
6
e, 63%
6f, 80%
6g, 55%a
6h, 84%
Scheme 3 Synthesis of quinoline derivatives. Reaction conditions: 2-aminoaryl
alcohol (0.5 mmol), secondary alcohol (0.6 mmol), Cat.
(
Scheme 4 One-pot synthesis of 2-alkylaminoquinolines. Reaction conditions: 2-
aminoaryl alcohol (0.5 mmol), nitrile (0.5 mmol), Cat. (5 mol%), and CsOH.H
0.5 mmol) in toluene (2 mL) at 150 C for 12 h followed by addition of Cat.
A
0.5 mmol), toluene (2 mL) at 150 C for 6 h; isolated yields. 12 h.
a(5 mol%), CsOH.H
2
O
°
A
2
O
(5
°
(
A
mol%), CsOH.H
isolated yields. second step: Cat. A (10 mol%).
2
O (0.5 mmol) and primary alcohol (2.5 mmol) heated for 24 h;
a
Next, complex
A mediated acceptorless dehydrogenative
coupling reaction between 2-aminoaryl alcohols and
secondary alcohols was explored. First row transition metal product with 1-hexanol was poor due to the lower reactivity
complex catalyzed similar reaction for the synthesis of for the coupling of 2-aminoquinoline with 1-hexanol (6g).
[
14, 16]
quinolines is less explored in literature.
For this purpose
To examine the practical applicability of this catalytic
all the reaction parameters was optimized and 93% isolated system, preparative scale reactions were carried out which
yield of 5a was observed for the cross coupling of 2- smoothly provided the corresponding products in 68-84%
aminobenzyl alcohol and 1-phenylethanol in presence of 5 isolated yields (SI, Scheme S1). Complex
A was found to be
mol% complex after 6 h of reflux in toluene. Afterwards, effective for the dehydrogenation of alcohol in presence of a
A
coupling of 2-aminobenzyl alcohol with various substituted 1- sacrificial hydrogen acceptor (SI, Scheme S2). Formation of H2
phenylethanol bearing electron donating and withdrawing during the quinoxaline synthesis from vicinal diols and
groups were carried out which produced the desired products diamines was confirmed by GC analysis. This catalytic system
in good to excellent yields (Scheme 3, 5b-5f). 1,2,3,4- showed the similar reactivity in presence of mercury that
Tetrahydro-1-naphthol showed 92% yield whereas straight suggested the homogeneity of the reaction (SI, S7). For the
chain 2-heptanol provided moderate yield. Interestingly, synthesis of quinoxaline from o-phenylenediamine when
following this protocol heteroaromatic 1-(pyridin-2-yl)ethanol complex
also delivered excellent results (5j, 5k).
A (5 mol%) was treated with 1.1 equiv. LiBEt H (5.5
3
mol%) it showed similar reactivity in presence of significantly
We were further interested to explore the one-pot lower amount of base (8 mol%) (SI, S6.2). This data suggested
synthesis of 2-alkylaminoquinolines encouraged by the recent that probably in situ generated paramagnetic (NNN)Co(I)Br
[8, 13c, 19]
[17]
Ru(II) catalyzed only two reports. These nitrogen containing complex is the active catalyst for the reaction.
heteroaromatics are important building block for the synthesis Unfortunately, we were unable to get the single crystal of this
of variety of organic molecules and also present in several Co(I) complex after numerous attempts. Undoubtedly, several
[
9b, 18]
biologically active compounds.
Gratifyingly, this cobalt kinetic experiments and theoretical calculations are needed to
system was also able to catalyze the same reaction in one-pot understand this mechanism clearly which is currently going on
manner and yielded 94% of 6a using 2-aminobenzyl alcohol, in our laboratory.
benzyl cyanide and benzyl alcohol (Scheme 4 and SI Table S3).
In summary, a new air and moisture-stable Co(NNN)
To the best of our knowledge, this is the first example of Co(II) complex catalyzed sustainable synthesis of variety of N-
catalyzed synthesis of 2-alkylaminoquinolines via acceptorless heterocyclic compounds (quinoxalines, quinolines and 2-
dehydrogenative annulation followed by N-alkylation reaction. alkylaminoquinolines) was developed. Following this protocol
Afterward,
a
range of 2-alkylaminoquinolines was several quinoxalines were synthesized from coupling of both
synthesized in good to excellent yields following the one-pot the diamines and 2-nitroanilines with the vicinal diols.
three component coupling of 2-aminobenzyl alcohols with a Additionally, this catalyst was also effective in one-pot
number of substituted 2-arylacetonitriles and primary alcohols synthesis of 2-alkylaminoquinolines. To the best of our
(
Scheme 4, 6a-6f). This system tolerated both the electron knowledge this is the first example of cobalt complex
donating and withdrawing as well as heteroatom-bearing 2- mediated atom-economical synthesis of quinoxalines and 2-
arylacetonitriles and primary alcohols. Likewise, chloro alkylaminoquinolines. Utilization of non-precious metal based
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catalyst and phosphine free ligand system makes this an
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Board (SERB) and Indian Institute of Technology, Kanpur for
financial support. S.S. thank CSIR India and K.G. thank IITK for
the fellowship.
3 (a) F. Kallmeier and R. Kempe, Angew. Chem. Int. Ed. 2018,
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