Iodine-mediated oxidative annulation for one-pot synthesis of pyrazines and quinoxalines using a multipathway coupled domino strategy

Article abstract of DOI:10.1039/c4cc05844e

An efficient iodine-mediated oxidative annulation of aryl acetylenes-arylethenes-aromatic ketones with 1,2-diamines for the synthesis of pyrazines and regioselective synthesis of quinoxalines is presented. A multipathway coupled domino approach has been developed for the one-pot synthesis of 1,4-diazines with high functional group compatibility.

Full text of DOI:10.1039/c4cc05844e

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Iodine-mediated oxidative annulation for one-pot
synthesis of pyrazines and quinoxalines using a
multipathway coupled domino strategy†
K. K. Durga Rao Viswanadham,‡a Muktapuram Prathap Reddy,‡a
Pochampalli Sathyanarayana,b Owk Ravi,b Ruchir Kantc and
Surendar Reddy Bathula*ab
Cite this: Chem. Commun., 2014,
50, 13517
Received 28th July 2014,
Accepted 3rd September 2014
DOI: 10.1039/c4cc05844e
www.rsc.org/chemcomm
An efficient iodine-mediated oxidative annulation of aryl acetylenes– For instance, pyrazine derivatives have been reported with anti-
arylethenes–aromatic ketones with 1,2-diamines for the synthesis of fungal,6 antimycobacterial,7 and herbicidal activity.8 These deri-
pyrazines and regioselective synthesis of quinoxalines is presented. vatives are also used in the treatment of obesity, psychiatric and
A multipathway coupled domino approach has been developed for neurological disorders,9 and in the food industry as a flavoring
the one-pot synthesis of 1,4-diazines with high functional group agents.10 Recently, tetra-substituted pyrazines have been discovered
compatibility.
as semiochemicals in orchids.11
Quinoxaline also possess significant biological activities includ-
Unlike the conventional ‘stop and go’ synthesis, the domino ing antiviral,12 antibacterial,13 anticancer,14 and anti-inflammatory.15
strategy explores multiple bond-forming reactions under fixed Moreover, quinoxalines have displayed practical utility in the fields
reaction conditions, reducing the number of reagents or catalysts of organic semiconductor materials16 and organic synthons.17
needed.1a–d Because of the step economy and reduced purification
For the preparation of these six-membered heterocycles, different
burden, these reactions are gaining more prominence. Various type of reactions have been reported using 1,2-dicarbonyl
types of domino processes, including pericyclic,1e radical,1f photo- compounds,18,19 or epoxides,20,21 or hydroxy ketones,22,23 or their
chemical,1g and transition metal-mediated1h reactions, have been equivalents (Scheme 1).24,25 Recently, Chen et al.,26a Hashmi
reported. To make domino reactions more lucrative, recently, et al.26b and Minakata’s groups26c independently synthesized the
chemists have started coupling two or more domino processes quinoxalines from alkynes and 1,2-diamines in the presence of
in a one-pot operation.2 Across the globe several research groups, copper(II) or gold(I)26d,e or hypervalent iodine. Although such
including Wu’s group, have successfully utilized the multiplicative transformations are well developed, many of them require more
effect of a coupled domino strategy for the synthesis of various than one step and employ expensive metal oxidants; the substrate
different compounds.3 Apart from these reports, Wu et al. scope is also limited. In addition, most of the methods are not
demonstrated the significance of multi-pathway coupled domino applicable for pyrazines synthesis. Hence, developing a mild
(MPCD) strategies, a nature-inspired approach, for the synthesis and efficient method for the synthesis of both pyrazine and
of 2-acylbenzothiazoles.3b Inspired from these strategies, herein quinoxalines with a high substrate scope is highly challenging
we report an MPCD approach for the synthesis of both pyrazines and desirable. The iodine-mediated MPCD strategy reported by
and quinoxalines.
Wu et al.3 appears to be an advantageous method for the synthesis
Pyrazine and quinoxaline are prevalent heterocyclic units in of both pyrazine and quinoxalines with high substrate scope,
pharmaceuticals and bioactive natural products (Fig. S1, ESI†).4,5
a Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow-226 031,
India
b Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad-500007, India. E-mail: bsreddy@iict.res.in
c Molecular and structural biology Division, CSIR-Central Drug Research Institute,
Lucknow-226 031, India
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization data including X-ray crystal data for 5k. CCDC
975936. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cc05844e
‡ These authors contributed equally.
Scheme 1 Synthetic approaches to pyrazines and quinoxalines.
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Table 1 Optimization of iodine-mediated annulation of phenyl acetylene
and 1,2-diaminoethanea
Table
2
Synthesis of various pyrazines and quinoxalines from aryl
acetylenes and 1,2-diaminesa
Reagent
(equiv.)
Base
(1.2 equiv.)
Temp.
(1C)
Time
(h)
Yieldb
(%)
Entry
1
2
3
4
5
6
7
8
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.5)
I2 (2.0)
NIS (2.0)
—
80
80
90
12
12
12
12
12
12
12
12
12
12
12
12
12
12
24
12
n.r.
45
53
58
55
n.r.
n.r.
n.r.
70
71
70
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
Pyridine
DIPEA
NaOH
KOH
Na2CO3
CS2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
110
100
100
100
100
100
100
100
100
100
100
100
a
9
Reaction conditions: 1 (1.0 mmol), I2 (2.0 mmol) and 2/K2CO3
10
11
12
13
14
15
16
(1.0/1.2 mmol) or 3 (1.0 mmol) in DMSO, open air at 100 1C. Isolated
yields provided.
69
72
71
71
Phenyl acetylenes with electron-donating groups at either ortho-,
meta- or para-positions on the phenyl ring all furnished the
corresponding products in good yields (71–76%). The presence
of an electron-withdrawing group on the phenyl acetylene was
also tolerated. However, the product was obtained in moderate
yield (65–68%).
38
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), I2 (2.0 mmol),
K2CO3 (1.2 mmol), heated in DMSO, open air at 100 1C for 12 h.
Isolated yield. n.r. = no reaction.
b
As a next step different ethylenediamines were employed in
because this reaction is metal free and generates 1,2-dicarbonyl this reaction. Propane-1,2-diamine reacts with both electron-
compounds under identical reaction conditions from multiple rich and -poor phenyl acetylenes, affording products in good
substrates (aryl acetylenes–arylethenes–aromatic ketones). To yields (72–76%). As expected, propane-1,2-diamine delivered
initiate our study aimed at developing an iodine-mediated MPCD two regioisomers (1 : 1).
strategy for the preparation of proposed heterocycles, the test
Encouraged by the above results, we turned our attention
reaction between phenyl acetylene (1a) and 1,2-diaminoethane towards the synthesis of quinoxalines using arylethenes 1 and
(2a) was carried out in the presence of iodine (1.1 mmol) and benzene-1,2-diamine 3 as our next substrates. After several
K2CO3 (1.2 mmol) in DMSO at 80 1C. As expected, the above experimental iterations, the optimal reaction conditions emerged
combination of reagents resulted in the desired product (4a), but with phenyl acetylene 1a (1.0 mmol), benzene-1,2-diamine 3a
in low yields (45%) (entry 2 in Table 1). But the above transforma- (1.0 mmol), and I2 (2.0 mmol) at 100 1C in DMSO. To probe the
tion in DMSO at 100 1C in the presence of iodine (2 mmol) and substrate scope for this reaction, a series of substituted phenyl
K2CO3 (1.2 mmol) afforded the corresponding pyrazine 4a in 72% acetylenes were subjected to the optimized reaction conditions
yield (entry 13 in Table 1). However, this reaction did not work in (Table 2). Arylethenes with different substituents, such as Me, Et,
the absence of inorganic base. Among various inorganic bases t-Bu and OMe, could all provide the corresponding products
tested, Na2CO3, KOH, NaOH and Cs2CO3 were all effective, with 74–80% yields (Table 2, 5b–f). Next, the reaction scope of
although affording the products with diminished yields, and o-phenylenediamine was studied (Table 2). The compounds
K2CO3 appeared the best among them (Table 1, entries 10–13). bearing an electron-donating group formed the products in good
Pyridine, triethylamine, and N,N-diisopropylethylamine (DIPEA) yields. Notably, mixtures of regioisomers (1 : 0.6) were formed in this
were also examined (Table 1, entries 6–8), but no product transformation (Table 2, 5g–i, 78–85%). Surprisingly, the reaction
formation was observed. The screening experiments also showed involving 3,4-diaminobenzophenone was found to be highly regio-
that increasing the amount of iodine did not enhance the yield selective to produce corresponding products 5j–l exclusively, in
(Table 1, entry 14) and even after prolonging the reaction time acceptable yields (69–76%). Uptill now, we do not know the reason
to 24 h (Table 1, entry 15). We have also replaced the I2 with for this selectivity. The structure of 5k was unambiguously
N-iodosuccinimide (NIS) and examined the reaction progress, but confirmed by X-ray crystallography (Fig. S2, ESI†).
it only inhibited the reaction. When the reaction was conducted
To expand the scope of the substrates, terminal aryl alkenes
at a lower temperature, it proceeded with a lower yield (Table 1, were investigated using the conditions optimized for aryl acetylene,
entries 1 and 2), and a higher reaction temperature did not but reaction did not occur. To identify suitable conditions for the
increase the yield (Table 1, entry 5).
reaction, a series of oxidants were screened. Initially, the desired
As depicted in Table 2, a broad variety of pyrazines could be product 4 was obtained in 23% yield in the presence of hydrogen
readily obtained under the optimized conditions. The annula- peroxide (H2O2) (Table 3, entry 3). The oxidants, such as tert-butyl
tion of 2a with various phenyl acetylenes was first examined. hydroperoxide (TBHP) and cumene hydroperoxide (CMHP),
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Table 3 Optimization of iodine mediated annulation of phenylethene and
1,2-diaminoethanea
Table 5 Synthesis of various pyrazines and quinoxalines from aromatic
ketones and 1,2-diaminesa
Reagent Base
Entry (equiv.) (1.2 equiv.) (equiv.)
Oxidant
Temp. Time Yieldb
(1C)
(h)
(%)
1
2
3
4
5
6
7
8
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.5)
I2 (2.0)
—
—
—
80
80
80
100
110
100
12
12
12
12
12
12
12
12
12
12
12
12
12
24
n.r.
Trace
23
33
29
26
27
56
53
61
72
68
69
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
H2O2 (1.5)
H2O2 (1.5)
H2O2 (1.5)
TBHP (1.5)
a
CMHP (1.5) 100
Reaction conditions: 7 (1.0 mmol), I2 (2.0 mmol) in DMSO at 100 1C
IBX (1.5)
IBX (1.5)
IBX (1.5)
IBX (2.0)
IBX (2.5)
IBX (2.0)
IBX (2.0)
100
100
100
100
100
100
100
for 2–3 h, and then added 2/K2CO3 (1.0/1.2 mmol) or 3 (1.2 mmol) in
DMSO, open air at 100 1C. Isolated yields provided.
9
10
11
12
13
14
68
a
Reaction conditions: 6 (1.0 mmol), I2 (2.0 mmol), IBX (2.0 mmol) in
DMSO at 100 1C for 2–3 h, and then added 2/K2CO3 (1.0/1.2 mmol) or 3
b
(1.2 mmol) in DMSO, open air at 100 1C. Isolated yields.
were screened. In all the reactions, product 4 was obtained but in
lower yields (Table 3, entries 6 and 7). To our delight, the yield
was increased to 56% when 2-iodoxybenzoic acid (IBX) was
selected as an oxidant (Table 3, entry 8). After extensive optimiza-
tion, it was found that the desired product could be obtained in
72% yield when 1a (1 mmol) and I2/IBX (2.0/2.0 mmol) were
mixed and heated at 100 1C for 1.5 h, with the subsequent
addition of 1,2-diaminoethane/K2CO3 to the mixture for another
Scheme 2 Proposed mechanism.
10 h at 100 1C (Table 3, entry 11). This optimal condition (absence (2a)/K2CO3 or benzene-1,2-diamine (3a) to afford the corre-
of base) is also used to synthesize quinoxalines. Then, the scope sponding products in one-pot. The electron withdrawing or
of both terminal aryl alkenes (6) and 1,2-diamines (2/3) was also donating groups present on aromatic ketones were well tolerated
explored (Table 4). The results demonstrated that the electronic to produce 4 and 5 in good yields (Table 5).
nature of the aryl alkenes (6 and 2/3) had little influence on the
reaction efficiency, as all the desired products were obtained in this domino reaction is as follows, using phenyl acetylene 1a, or
moderate to good yields (Table 4, 65–80%).
styrene 6a, or acetophenone 7a, and 1,2-diaminoethane 2a, or
As presented in Scheme 2, a possible reaction mechanism for
To further expand the substrate scope, substituted aceto- benzene-1,2-diamine 3a as examples: initially, phenyl acetylene
phenones 7 were also investigated. Furthermore, acetophenone (1a) or styrene (6a) or acetophenone (7a) was converted into
7a in the presence of I2 in DMSO could easily be transformed phenacyl iodide27 (A) through consecutive iodination and oxidation
to arylglyoxals, which then reacted with 1,2-diaminoethane with I2 or I2/IBX. Subsequently, phenacyl iodide (A) was further
converted into phenylglyoxal (B) in DMSO.3b Finally, phenylglyoxal
(B) reacted with 2a/K2CO3 or 3a via a condensation, and oxidative
dehydrogenation sequence to afford the desired products 4a
and 5a, respectively.
Table 4 Synthesis of various pyrazines and quinoxalines from arylethenes
and 1,2-diaminesa
In summary, an I2 promoted domino protocol has been
developed to construct pyrazines and quinoxalines from simple
and readily available aryl acetylenes–arylethenes–aromatic ketones
and 1,2-diaminoethane–benzene-1,2-diamine, which could be use-
ful for generation of a related compound library. The overall process
involves three different reactions (iodination, Kornblum oxidation,
and condensation) that were self-sequentially assembled in a single
reactor. In addition, the protocol could exclusively provide single-
regioisomer in the case of 3,4-diaminobenzophenone with different
a
Reaction conditions: 6 (1.0 mmol), IBX (2.0 mmol) I2 (2.0 mmol) in
DMSO at 100 1C for 2–3 h, and then added 2/K2CO3 (1.0/1.2 mmol) or 3
(1.2 mmol) in DMSO, open air at 100 1C. Isolated yields provided.
aryl acetylenes. Further studies on the application of this strategy for
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and quinoxalines synthesis via MPCD strategy, the following control
experiment was performed. Intermediate ‘A’ was obtained in 82% yield
via reaction of 1a with I2 (2.0 mmol) in DMSO, open air conditions in the
absence of 1,2-diaminoethane where the reaction is slow enough to
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