Synthesis of quinoxalines and pyrido[2,3-b]pyrazines by SuzukiMiyaura cross-coupling reaction

Article abstract of DOI:10.1007/s11164-015-2377-7

Abstract: Bromo-substituted quinoxalines and pyrido[2,3-b]pyrazines were synthesized by condensation reactions of aromatic 1,2-diamino and 1,2-diketone compounds. These compounds were used as common intermediates for postcondensation modification by SuzukiMiyaura coupling reaction to form aryl-substituted quinoxalines and pyrido[2,3-b]pyrazines. High-efficiency with improved product yield of aryl-substituted quinoxalines and pyrido[2,3-b]pyrazine derivatives was achieved by conducting a coupling reaction in presence of Pd(dppf)Cl₂·CH₂Cl₂ in tetrahydrofuran (THF) using K₂CO₃ as base at reflux temperature. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-015-2377-7

Res Chem Intermed
DOI 10.1007/s11164-015-2377-7
Synthesis of quinoxalines and pyrido[2,3-b]pyrazines
by Suzuki–Miyaura cross-coupling reaction
Arjun Kumbhar1 Sanjay Jadhav1 Rajashri Salunkhe1
•
•
Received: 4 October 2015 / Accepted: 24 November 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Bromo-substituted quinoxalines and pyrido[2,3-b]pyrazines were synthe-
sized by condensation reactions of aromatic 1,2-diamino and 1,2-diketone compounds.
These compounds were used as common intermediates for postcondensation modifica-
tion by Suzuki–Miyaura coupling reaction to form aryl-substituted quinoxalines and
pyrido[2,3-b]pyrazines. High-efficiency with improved product yield of aryl-substituted
quinoxalines and pyrido[2,3-b]pyrazine derivatives was achieved by conducting a cou-
pling reaction in presence of Pd(dppf)Cl2ÁCH2Cl2 in tetrahydrofuran (THF) using K2CO3
as base at reflux temperature.
Graphical abstract
Keywords Suzuki–Miyaura reaction Á Quinoxalines Á Pyrido[2,3-b]pyrazines Á
Pd(dppf)Cl2ÁCH2Cl2
&
Rajashri Salunkhe
rss234@rediffmail.com
1
Department of Chemistry, Shivaji University, Kolhapur, Maharashtra 416004, India
123

A. Kumbhar et al.
Introduction
The biological activity manifested by many polycyclic nitrogen-containing
heterocyclic compounds makes them attractive targets for organic chemists for
synthesis of pharmaceutical motifs [1–4]. Annulated pteridines such as quinoxaline
and pyrazine derivatives are versatile intermediates for preparation of various
nitrogen-containing compounds. They represent key structural motif in many
medicinally important compounds, including quinoxaline anticancer drugs such as
chloroquinoxaline sulfonamide (CQS) and XK469 [5, 6]. Both of these compounds
exhibit activity against solid tumors and are known to be antineoplastic quinoxaline
topoisomerase II poisons [7–10]. It is also noteworthy that, by virtue of their
thermal stability, intense luminescence, and other desirable properties, they have
been widely used in organic semiconductors, and electroluminescent materials for
manufacture of highly efficient organic light-emitting diodes (OLEDs) [11–14].
Pyrazines are also useful precursors utilized in a number of synthetic platforms and
starting materials for construction of heteroaromatic systems.
In recent years, transition-metal-catalyzed cross-coupling has been used as an
efficient process in the chemist’s toolbox for construction of many heterocyclic
compounds [15–17]. Among such approaches, palladium-catalyzed Suzuki–
Miyaura coupling is a powerful, versatile, and popular method for construction of
a variety of pharmaceutically active heterocyclic compounds [18–20].
In this work, synthesis of p-extended quinoxaline and pyrazine derivatives was
carried out in a two-step reaction. In the first step, as described in Scheme 1,
O
O
Br
N
N
N
Br
Br
1
O
O
O
O
Yield 92 %
Br
Br
R1
NH2
NH2
N
N
BAHC
R1=Br
X= N
Br
Br
N
BAHC
R1=H
X= C
X
N
N
Br
Br
O
2
4
Yield 93 %
Yield 91 %
O
Br
Br
N
N
N
3
Yield 92 %
Scheme 1 Synthesis of key precursors of quinoxaline and pyrido[2,3-b]pyrazines
123

Synthesis of quinoxalines and pyrido[2,3-b]pyrazines…
appropriate quinoxaline and pyrazine derivatives containing one or more bromo
substituents were synthesized from corresponding 1,2-diamino and 1,2-diketone
compounds. Secondly, the classical Suzuki–Miyaura cross-coupling protocol
between bromo compounds and arylboronic acids was employed to obtain the
desired products in quantitative yield.
In continuation of our work related to heterogeneous Pd catalysis [21–24], we
report herein a concise synthesis of pyrazine and quinoxaline derivatives that further
demonstrates the synthetic power of coupling two or three nucleophiles to bromo
compounds as an extension. This methodology furnishes an elegant entry to diverse
pteridine analogues, using Suzuki–Miyaura cross-coupling based on readily
accessible, commercial starting materials.
Results and discussion
Our work began with the intention of developing general reaction conditions for
palladium-catalyzed arylation of pyrido[2,3-b]pyrazines and quinoxalines. As shown in
Scheme 1, four precursors used for Pd-catalyzed Suzuki–Miyaura coupling reactions
were synthesized following the literature procedure [25]. The key required starting
compounds 1, 2, and 3 were obtained from condensation reactions of commercially
available 5-bromo-2,3-diaminopyridine with benzil or 9,10-phenanthraquinone or 4,40-
dibromobenzil, respectively, in good to excellent yields using Brønsted acid hydrotrope
combined catalyst (BAHC) in water. Meanwhile, 4 was prepared from 1,2-
diaminobenzene and 4,40-dibromobenzil by adopting the same reaction procedure.
All compounds were solids and well soluble in chlorinated solvents and THF, but
insoluble in ethanol. Their chemical structures were confirmed by 1H and 13C nuclear
magnetic resonance spectroscopy (NMR), and mass-spectrometric analysis. The
spectral data are in harmony with data reported in literature [25].
It is known that uncatalyzed substitution at 7-position of 7-bromo-2,3-
diphenylpyrido[2,3-b]pyrazine (1) is problematic, because these reactions provide
low yield with the formation of a mixture of regioisomeric products due to the
elimination/addition mechanism, as addition often competes with substitution [26].
Considering these problems, palladium-catalyzed cross-coupling reaction can
expected to be one of the most advantageous alternatives to introduce functionalized
side-chains and other substituents into 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine
(1) without facing the problems found in uncatalyzed transformation as disclosed by
Liebscher and Yin [27]. To optimize the reaction conditions, we began our studies
by examining the coupling reaction of compound 1 with phenyl boronic acid, as
shown in Table 1. Initial studies were carried out at 1 mmol scale and reflux
temperature using different palladium sources such as Pd(OAc)2, PdCl2, and
Pd(dppf)Cl2ÁCH2Cl2 with K2CO3 as base in THF. We found that Pd(OAc)2 and
PdCl2 were less effective (Table 1, entries 2 and 3), while Pd(dppf)Cl2ÁCH2Cl2 [28]
gave 89 % yield of the desired product in 4 h at reflux temperature (Table 1,
entry 1). The next, important goal of our investigation was to identify an optimum
base. It was observed that organic bases such as triethylamine (TEA) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) did not work satisfactorily (Table 1,
123

A. Kumbhar et al.
Table 1 Optimization of reaction conditions for Pd-catalyzed arylation of 1 with phenyl boronic acida
+
solvent, base, heat
1
5
Entry Catalyst (1 mol%)
Ligand (3 mol%) Base
Solvent
Time (h) Yieldb (%)
1
Pd(dppf)Cl2ÁCH2Cl2
Pd(OAc)2
–
K2CO3
THF
THF
THF
4
14
14
5
89
62
2
PPh3
K2CO3
K2CO3
3
PdCl2
PPh3
58
4
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
Pd(dppf)Cl2ÁCH2Cl2
–
–
–
–
–
–
–
–
Na2CO3 THF
84
5
K3PO4
TEA
THF
10
15
15
16
9
59
6
THF
51
7
DBU
THF
53
8
K2CO3
K2CO3
K2CO3
K2CO3
EtOH
37
9
DMF
70c
69c
66c
10
11
a
1,4-Dioxane
Toluene
9
10
Reaction conditions: compound 1 (1.0 mmol), phenyl boronic acid (1.2 mmol), Pd catalyst (1 mol%),
PPh3 (3 mmol), base (2.0 mmol), solvent (5 ml), reflux under aerobic conditions
b
Isolated yields after purification
c
Reactions at 80 °C
entries 6 and 7). Upon screening commonly used inorganic bases, it was found that
K2CO3 played a crucial role (Table 1, entry 1), while K3PO4 was considerably less
effective (Table 1, entry 5). Comparable conversion was obtained using Na2CO3 or
K2CO3 (Table 1, entry 4). Having determined the best base, the effect of various
solvents on the reaction were surveyed. Among the various solvents used, we found
that THF provided the optimal yield of the desired product (Table 1, entry 1) as
compared with other solvents (Table 1, entries 8–11), similar to our previously
reported Pd-DABCO@SiO2 catalyst [29].
To probe the generality of the method, the reaction of 7-bromo-2,3-
diphenylpyrido[2,3-b]pyrazine (1) with different substituted arylboronic acids were
conducted (Table 2). It was observed that the reactions of compound 1 with phenyl,
4-acetylphenyl, and (3,5-dimethyl-4-methoxy)phenyl boronic acids afforded the
desired products in good yields (78–89 %) in 4–17 h (Table 2, entries 1–3). The
reaction of sterically hindered naphthyl boronic acid with compound 1 could also be
effected in 84 % yield in 14 h (Table 2, entry 4). Similarly, compound 2 was also
reactive against phenyl and 4-methylphenyl boronic acids with good product yield
(Table 2, entries 5 and 6).
Encouraged by these findings, we sought to ascertain the coupling of tribromo-
substituted pyrazine (3) with phenyl boronic acid under the same optimized
123

Synthesis of quinoxalines and pyrido[2,3-b]pyrazines…
Table 2 Suzuki–Miyaura coupling of pyrido[2,3-b]pyrazines with arylboronic acidsa
B(OH)2
PPh2
Cl
Cl
Catalyst
Pyrazines
Pyrazines
1/2/3
+
Fe
CH2Cl2
Pd
5a-5d/6a-6b/7a-7b
THF, K2CO3, reflux
PPh2
R
Catalyst
Entry Pyrazine
Product
Time
(h)
4
Yieldb
(%)
1
1
1
89[27]
5a
2
17
78[27]
5b
3
1
12
89[29]
5c
4
1
14
84[29]
5d
6a
5
2
18
72
123

A. Kumbhar et al.
Table 2 continued
Entry Pyrazine
Product
Time
(h)
Yieldb
(%)
6
2
10
66
6b
7
3
14
81c
7a
8
3
14
78c
7b
a
Reaction conditions: compound 1 or 2 (1.0 mmol), arylboronic acid (1.2 mmol), Pd(dppf)Cl2ÁCH2Cl2
(1 mol%), K2CO3 (2.0 mmol), THF (5 ml), reflux under aerobic conditions
b
Isolated yields after purification
c
Reaction conditions: compound 3 (1.0 mmol), phenyl boronic acid (3.2 mmol), Pd(dppf)Cl2ÁCH2Cl2
(3 mol%), K2CO3 (6.0 mmol), THF (5 ml), reflux under aerobic conditions
conditions; For example, we were also able to couple tribromide with phenyl and
4-methylphenyl boronic acid, which proceeded with good yields (Table 2, entries 7
and 8) using 3 mol% catalyst.
As an expansion of this study, we next explored preparation of structurally
related quinoxaline derivatives. For this study, precursor compound 4 was applied
for Suzuki–Miyaura coupling under conditions similar to those used for pyrazines;
the reactions are detailed in Table 3. Three different arylboronic acids were
successfully coupled with compound 4 using 2 mol% catalyst. In all cases
123

Synthesis of quinoxalines and pyrido[2,3-b]pyrazines…
Table 3 Suzuki–Miyaura coupling of quinoxaline with arylboronic acidsa
Br
B(OH)2
N
PPh2
Pd
Cl
Cl
Catalyst
K2CO3, THF, reLlux
+
CH2Cl2
Quinoxalines
8a-8c
Fe
N
R
PPh2
Br
4
Catalyst
Entry Quinoxaline
1
4
Product
Time (h)
16
Yieldb (%)
90
N
N
8a
F
2
4
20
88
N
N
F
8b
3
16
90
N
N
8c
a
Reaction conditions: compound 4 (1.0 mmol), arylboronic acid (2.2 mmol), Pd(dppf)Cl2ÁCH2Cl2
(2 mol%), K2CO3 (4.0 mmol), THF (5 ml), reflux under aerobic conditions
b
Isolated yields after purification
123

A. Kumbhar et al.
examined, compound 4 was efficiently transformed into the desired coupling
products with good yields (88–90 %) in 16–20 h.
Conclusions
In conclusion, bromo-substituted quinoxalines and pyrido[2,3-b]pyrazines gener-
ated from condensation reactions of aromatic 1,2-diamino and 1,2-diketone
compounds were efficiently obtained using green BAHC catalyst in water at room
temperature. These compounds were used as common intermediates for postcon-
densation modification by Suzuki–Miyaura cross-coupling reaction. The highly
active Pd(dppf)Cl2ÁCH2Cl2 catalyst was used for synthesis of novel pyrido[2,3-
b]pyrazine and quinoxaline derivatives with a variety of arylboronic acids in good
yields.
Experimental
General remarks
1H and 13C NMR spectra were recorded on a Bruker AC spectrometer at 300 and
75 MHz, respectively, using CDCl3 as solvent and tetramethylsilane (TMS) as
internal standard. Melting points were determined with a DBK melting point
apparatus and are uncorrected. All chemicals were obtained from Aldrich and
Spectrochem and used without further purification.
General procedure for Suzuki–Miyaura coupling reaction of pyrido[2,3-
b]pyrazine and quinoxaline derivatives
An oven-dried Schlenk flask, equipped with a magnetic stir bar, septum, and
condenser, was charged with compound 1/2/3/4 (1.0 mmol), arylboronic acid (1.2/
2.2/3.2 mmol), K2CO3 (2/4/6 mmol), Pd(dppf)Cl2ÁCH2Cl2 (1/2/3 mol%), and 5 ml
THF. The reaction mixture was refluxed, and after complete consumption of starting
materials as determined by thin-layer chromatography (TLC) analysis, the reaction
mixture was filtered and water (20 ml) was added. The filtrate was extracted with
diethyl ether (3 9 10 ml). The combined organic layers were collected, dried over
anhydrous Na2SO4, and concentrated in vacuum to afford product, which was purified
by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9/1).
Physical and spectroscopic data for selected compounds
Compound 6a; Yellow solid, m.p. 255–256 °C; 1H NMR (300 MHz, CDCl3): dH
(ppm) 7.49–7.63 (m, 3H), 7.74–7.90 (m, 6H), 8.57–8.60 (m, 2H), 8.82 (d, 1H,
J = 2.4 Hz), 9.37 (d, 1H, J = 7.8 Hz), 9.56 (d, 2H, J = 9.3 Hz); 13C NMR
(75 MHz, CDCl3): dC (ppm) 120.5, 123.0, 127.5, 128.1, 128.9, 129.1, 129.6, 131.3,
132.5, 137.3, 143.9, 154.8; ESI–MS (M.F. = C25H15N3; M? = 357.12).
123

Synthesis of quinoxalines and pyrido[2,3-b]pyrazines…
Compound 6b; Yellow solid, m.p. 296–298 °C; 1H NMR (300 MHz, CDCl3): dH
(ppm) 1.26 (s, 3H), 7.19–7.35 (m, 2H), 7.75–7.90 (m, 6H), 8.56–8.60 (m, 2H), 8.86
(d, 1H, J = 2.4 Hz), 9.35 (d, 1H, J = 7.8 Hz), 9.55 (d, 2H, J = 9.3 Hz); 13C NMR
(75 MHz, CDCl3): dC (ppm) 29.6, 120.4, 124.1, 126.5, 128.0, 128.6, 129.1, 130.9,
132.4, 137.1, 143.9, 154.5; ESI–MS (M.F. = C26H17N3; M? = 371.14).
1
Compound 7a; Yellow solid, m.p. 333 °C; H NMR (300 MHz, CDCl3): dH
(ppm) 7.34–7.82 (m, 23H), 8.66 (d, 1H, J = 7.8 Hz), 9.45 (d, 1H, J = 3.6 Hz); 13
C
NMR (75 MHz, CDCl3): dC (ppm) 127.1, 128.7, 129.4, 130.3, 130.8, 134.4, 136.0,
136.6, 137.0, 137.5, 138.0, 140.2, 142.1, 142.3, 153.3, 154.5, 155.3; ESI–MS
(M.F. = C37H25N3; M? = 511.20).
1
Compound 7b; Yellow solid, m.p. [300 °C; H NMR (300 MHz, CDCl3): dH
(ppm) 2.48 (s, 9H), 7.24–7.34 (m, 4H), 7.37 (d, 2H, J = 7.5 Hz), 7.50–7.80 9 m,
14H), 8.65 (d, 1H, J = 3.0 Hz), 9.44 (d, 1H, J = 2.4 Hz); 13C NMR (75 MHz,
CDCl3): dC (ppm) 29.6, 126.6. 126.8, 126.9, 127.3, 129.4, 129.5, 130.1, 130.5,
130.7, 131.7, 133.6, 134.2, 137.3, 139.0, 142.0, 142.3, 153.3, 154.7, 155.1; ESI–MS
(M.F. = C40H31N3; M? = 553.16).
Compound 8a; Yellow solid, m.p. 235–237 °C; 1H NMR (300 MHz, CDCl3): dH
(ppm) 7.31–7.36 (m, 2H), 7.41–7.45 (m, 4H), 7.59–7.63 (m, 8H), 7.67–7.70 (m,
4H), 7.79 (dd, 2H, J = 3.3 and 6.3 Hz), 8.21 (dd, 2H, J = 3.6 and 6.3 Hz); 13C
NMR (75 MHz, CDCl3): dC (ppm) 126.9, 127.0, 127.5, 128.7, 129.1, 129.8, 130.4,
132.6, 137.9, 140.4, 141.2, 141.8, 152.7; ESI–MS (M.F. = C32H22N2;
M? = 434.17).
Compound 8b; Yellow solid, m.p. 217–219 °C; 1H NMR (300 MHz, CDCl3): dH
(ppm) 7.10–7.15 (m, 4H), 7.53–7.60 (m, 8H), 7.65 (d, 4H, J = 8.1 Hz), 7.78 (dd,
2H, J = 3.3 and 6.3 Hz), 8.18 (dd, 2H, J = 3.3 and 6.3 Hz); 13C NMR (75 MHz,
CDCl3): dC (ppm) 126.7, 127.1, 127.7, 129.0, 129.5, 130.6, 133.0, 138.1, 140.4,
141.9, 154.0, 160.0); ESI–MS (M.F. = C32H20F2N2; M? = 471.16).
Compound 8c; Yellow solid, m.p. 249–151 °C; 1H NMR (300 MHz, CDCl3): dH
(ppm) 2.42 (s, 6H), 7.10–7.13 (m, 4H), 7.55–7.62 (m, 6H), 7.66 (m, 4H), 7.76 (d,
2H, J = 3.3 Hz), 8.10 (d, 2H, J = 3.3 Hz); 13C NMR (75 MHz, CDCl3): dC (ppm)
28.2, 126.5, 127.0, 128.0, 129.3, 129.5, 130.5, 132.9, 138.1, 140.3, 142.0, 154.1,
159.7; ESI–MS (M.F. = C34H26N2; M? = 462.20).
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