Regioselective Suzuki-Miyaura cross-coupling reactions of 2,6-dichloroquinoxaline

Article abstract of DOI:10.1055/s-0031-1289754

A variety of mono- and diarylated quinoxaline derivatives were prepared by site-selective Suzuki-Miyaura cross-coupling reactions of 2,6- dichloroquinoxaline. The selectivity is controlled by electronic parameters. Georg Thieme Verlag Stuttgart · New York

Full text of DOI:10.1055/s-0031-1289754

PAPER
▌1637
paper
Regioselective Suzuki–Miyaura Cross-Coupling Reactions of
2,6-Dichloroquinoxaline
Cross-Coupling Reactions of 2,6-Dichloroquinoxaline
Iftikhar Ali,a Baraa Siyo,a Yaseen Al-Soud,a,b Alexander Villinger,a Peter Langer*a,c
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b
Department of Chemistry, Faculty of Science, Al al-Bayt University, 25115 Al-Mafraq, Jordan
c
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Received: 11.11.2011; Accepted after revision: 09.03.2012
2d,l,r,t, the yields were relatively low because of their
electron-poor character and low reactivity. In the case of
products 3d,k,l,n,q,r,t, a small amount of starting materi-
al could be recovered and a small amount of the corre-
sponding diarylated quinoxaline was formed (less than
5%). Due to the more difficult chromatographic separa-
tion, the yields were lower. The best yields were observed
using tetrahydrofuran as the solvent, Pd(PPh3)4 (5 mol%)
as the catalyst, and K3PO4 (2 equiv) as the base. The reac-
tions were carried out at 90 °C for 8 hours (see Table 2,
Abstract: A variety of mono- and diarylated quinoxaline deriva-
tives were prepared by site-selective Suzuki–Miyaura cross-
coupling reactions of 2,6-dichloroquinoxaline. The selectivity is
controlled by electronic parameters.
Key words: catalysis, palladium, Suzuki reaction, quinoxalines, re-
gioselectivity
Quinoxalines1 show a broad spectrum of biological activ-
ities, including antifungal,2 antihistaminic, antioxidant
and anti-inflammatory,3 antibacterial,4 antiamoebic,5 anti-
proliferative,6 fungicidal and algicidal,7 antimalarial and
antileishmanial,8 cytotoxic,9 anticancer,10 anti-HIV and
anti-HCV,11 and antituberculosis activity.12 In addition,
quinoxalines represent potent and selective class III tyro-
sine kinase inhibitors13 and potential influenza NS1A pro-
tein inhibitors.14 Certain quinoxalines containing an
octadepsipeptide substructure, such as echinomycin and
triostin A, have been reported as antibacterial and antitu-
mor agents, and as potent inhibitors of RNA synthesis.15
Quinoxaline-derived molecules have been also studied as
thermoplastics16 and, due to their bipolar character, as po-
tential emissive and electron-transport moieties and,
hence, as potential building blocks for the synthesis of
organic semiconductors.17 In recent years, site-selective
palladium-catalyzed cross-coupling reactions of polyha-
logenated heterocyclic substrates have been studied.18
Herein, we report what are, to the best of our knowledge,
the first Suzuki–Miyaura cross-coupling reactions of 2,6-
dichloroquinoxaline.19 These reactions proceed with ex-
cellent site selectivity, which is controlled by electronic
parameters, and provide a convenient approach to various
pharmacologically relevant quinoxaline derivatives.
Table 1 Synthesis of 3a–t
Yielda (%) of 3
2, 3
Ar
a
b
c
d
e
f
2-Tol
77
67
75
37
90
96
72
63
65
97
53
23
62
45
96
77
52
30
78
25
3-Tol
4-Tol
2,6-Me2C6H3
3,5-Me2C6H3
2,4,6-Me3C6H2
2-MeOC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
2,6-(MeO)2C6H3
2,3,4-(MeO)3C6H2
3-FC6H4
g
h
i
j
k
l
m
n
o
p
q
r
s
4-FC6H4
The reaction of commercially available 2,6-dichloroqui-
noxaline (1) with arylboronic acids 2a–t (1.3 equiv) af-
forded the 2-aryl-6-chloroquinoxalines 3a–t in 23–97%
yield (Scheme 1, Table 1). The reaction conditions were
systematically optimized for derivative 3c (Table 2) in or-
der to isolate the products in optimal yields. Both elec-
tron-poor and electron-rich arylboronic acids could be
successfully employed. In the case of arylboronic acids
2-thienyl
4-EtC6H4
4-t-BuC6H4
4-(F3C)C6H4
4-(H2C=CH)C6H4
2-ClC6H4
SYNTHESIS 2012, 44, 1637–1646
Advanced online publication: 10.05.2012
t
3-ClC6H4
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
a Yield of isolated product.
DOI: 10.1055/s-0031-1289754; Art ID: SS-2011-N1060-OP
© Georg Thieme Verlag Stuttgart · New York

1638
I. Ali et al.
PAPER
entry 6) to obtain the best yields. The reactions of (more lents of the arylboronic acid, Pd(PPh3)4 (5 mol%), and a 2
reactive) electron-rich arylboronic acids could be success- M aqueous solution of K2CO3 (1,4-dioxane, 120 °C, 12
fully carried out at slightly lower temperature and for a h).
shorter reaction time (85 °C, 4 h; Table 2, entry 3). When
the reactions were carried out in toluene or 1,4-dioxane, a
N
N
Cl
ArB(OH)2
N
N
Ar
2
higher temperature was necessary and the products were
isolated in lower yield than the reaction in tetrahydrofuran
(Table 2, entries 2 and 5). Thus, the optimized conditions
given in entry 6 allowed the preparation of the 2-aryl-6-
chloroquinoxalines 3a–t in optimal yields.
Cl
Ar
1
4a–f
Scheme 2 Synthesis of 4a–f. Reagents and conditions: 1 (1 equiv),
2 (2.5 equiv), Pd(PPh3)4 (5 mol%), 2 M K2CO3, 1,4-dioxane, 120 °C,
12 h.
ArB(OH)2
N
N
Cl
N
N
Ar
2
Table 3 Synthesis of 4a–f
Cl
Cl
Yielda (%) of 4
2
Ar
1
3a–t
Scheme 1 Synthesis of 3a–t. Reagents and conditions: 1 (1 equiv),
2 (1.3 equiv), Pd(PPh3)4 (5 mol%), K3PO4 (2 equiv), THF, 90 °C, 8 h.
a
c
2-Tol
4a: 64
4b: 51
4c: 94
4d: 49
4e: 47
4f: 26
4-Tol
Table 2 Optimization of the Reaction Conditions for the Synthesis
of 3c
e
3,5-Me2C6H3
2-MeOC6H4
4-EtC6H4
4-t-BuC6H4
g
o
p
Yielda
(%) of 3c
Entry Solvent
Catalyst
Temp
( °C)
Time
(h)
1
2
3
4
5
6
1,4-dioxane
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
85
110
85
3
6
4
4
6
8
0
69
71
29
66
75
a Yield of isolated product.
1,4-dioxane
THF
The Suzuki–Miyaura reactions of the 2-aryl-6-chloroqui-
noxalines 3c,h,m–o with 1.3 equivalents of the arylboron-
ic acids 2c,e,g,m,p afforded the disubstituted products
5a–g in good yields (Scheme 3, Table 4). The reactions
were carried out using Pd(PPh3)4 (5 mol%) and a 2 M
aqueous solution of K2CO3 (1,4-dioxane, 120 °C, 8 h).
toluene
toluene
THF
85
110
90
a Isolated yield; K3PO4 (2 equiv) was used as the base in all reactions.
Ar2B(OH)2
N
N
Ar1
N
N
Ar1
2
The structures of all products were established by spectro-
scopic methods. The structure of 3g (Figure 1) was inde-
pendently confirmed by X-ray crystal structure analysis.20
Cl
Ar2
3
5a–g
Scheme 3 Synthesis of 5a–g. Reagents and conditions: 3 (1 equiv),
2 (1.3 equiv), Pd(PPh3)4 (5 mol%), 2 M K2CO3, 1,4-dioxane, 120 °C,
8 h.
The structures of all products were established by spectro-
scopic methods. The structure of 5e (Figure 2) was inde-
pendently confirmed by X-ray crystal structure analysis.20
The syntheses of derivatives 3a–t, 4a–f, and 5a–g have
not, to the best of our knowledge, been previously report-
ed, except for 3c and 3h.21 Compound 3c has been recent-
ly prepared using a copper-catalyzed condensation of a
diazo ketone;21 however, this compound could only be ob-
tained as a 1:1 mixture of regioisomers. Thus, the method
reported herein is much better suited for the synthesis of
arylquinoxalines 3. Although a variety of quinoxaline de-
rivatives (including heterocyclic and functionalized com-
pounds) have been successfully prepared, the use of 4-
cyanophenylboronic acid, 4-formylphenylboronic acid, 4-
Figure 1 ORTEP view of the crystal structure of 3g
The Suzuki–Miyaura reactions of 2,6-dichloroquinoxa-
line (1) with the arylboronic acids 2a,c,e,g,o,p gave the
2,6-diarylquinoxalines 4a–f in good yields (Scheme 2,
Table 3). The best yields were obtained using 2.5 equiva-
Synthesis 2012, 44, 1637–1646
© Georg Thieme Verlag Stuttgart · New York

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Cross-Coupling Reactions of 2,6-Dichloroquinoxaline
1639
All solvents were dried by standard methods and all reactions were
carried out under an inert atmosphere. For 1H and 13C NMR spectra
the deuterated solvents indicated were used. Mass spectrometric
data (MS) were obtained by electron ionization (EI, 70 eV), chemi-
cal ionization (CI, isobutane) or electrospray ionization (ESI). For
preparative-scale chromatography silica gel 60 (0.063–0.200 mm,
70–230 mesh) was used.
Table 4 Synthesis of 5a–g
Ar1
Ar2
Yielda (%) of 5
3
2
c
e
4-Tol
3,5-Me2C6H3
4-t-BuC6H4
2-MeOC6H4
4-FC6H4
5a: 70
5b: 78
5c: 47
5d: 76
5e: 63
5f: 91
5g: 54
c
p
g
m
e
4-Tol
Synthesis of 3a–t; General Procedure
c
4-Tol
A THF soln (8 mL) of 2,6-dichloroquinoxaline (1, 1.0 mmol), an ar-
ylboronic acid 2 (1.3 equiv), K3PO4 (2 equiv), and Pd(PPh3)4 (5
mol%) was heated at 90 °C for 8 h. The reaction mixture was cooled
to r.t., then H2O (100 mL) was added and the mixture was extracted
with CH2Cl2 (100 mL). The organic layer was dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by column chromatography (gradient elution, n-heptane–
EtOAc).
h
m
n
o
4-MeOC6H4
4-FC6H4
2-thienyl
4-EtC6H4
3,5-Me2C6H3
3,5-Me2C6H3
4-Tol
e
c
a Yield of isolated product.
6-Chloro-2-(o-tolyl)quinoxaline (3a)
Starting with 1 (0.1 g, 0.5 mmol), 2a (0.088 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3a was isolated as a white solid; yield: 0.098 g (77%); mp 121–
123 °C.
IR (ATR): 3074 (w), 3043 (w), 2986 (w), 2930 (w), 2746 (w), 1606
(m), 1568 (w), 1539 (m), 1445 (w), 1417 (w), 1385 (w), 1335 (w),
1268 (w), 1175 (m), 1065 (m), 1037 (s), 960 (s), 901 (s), 870 (m),
827 (s), 785 (m), 754 (s), 726 (s), 701 (m), 579 (s), 553 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3), 7.25–7.36
(m, 3 H, ArH), 7.44–7.48 (m, 1 H, ArH), 7.65 (dd, J = 9.1, 2.3 Hz,
1 H, ArH), 7.98–8.06 (m, 2 H, ArH), 8.92 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 20.4 (CH3), 126.4 (CH), 128.1
(CH), 129.6 (CH), 129.9 (CH), 130.8 (CH), 131.2 (CH), 131.3
(CH), 135.5 (C), 136.6 (C), 136.7 (C), 140.5 (C), 141.3 (C), 146.7
(CH), 155.1 (C).
GC-MS (EI, 70 eV): m/z (%) = 254 (35) [M+], 253 (100).
HRMS (EI): m/z [M + H]+ calcd for C15H12ClN2: 255.06835; found:
255.06869.
Figure 2 ORTEP view of the crystal structure of 5e
6-Chloro-2-(m-tolyl)quinoxaline (3b)
nitrophenylboronic acid, 2-pyridylboronic acid, and 2-in-
dolylboronic acid resulted in the formation of complex
mixtures from which no pure compounds could be isolat-
ed.
Starting with 1 (0.1 g, 0.5 mmol), 2b (0.088 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3b was isolated as a white solid; yield: 0.085 g (67%); mp 125–
127 °C.
IR (ATR): 3024 (w), 2960 (w), 2856 (w), 1952 (w), 1841 (w), 1711
(w), 1606 (w), 1588 (m), 1537 (m), 1453 (m), 1330 (w), 1314 (m),
1169 (m), 1135 (m), 962 (s), 912 (s), 869 (m), 831 (s), 789 (s), 692
(s), 673 (m), 585 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 7.26 (d,
3J = 7.5 Hz, 1 H, ArH), 7.37 (t, J = 7.7 Hz, 1 H, ArH), 7.63 (dd,
J = 8.9, 2.3 Hz, 1 H, ArH), 7.87 (d, 3J = 7.5 Hz, 1 H, ArH), 7.92 (s,
1 H, ArH), 7.98–8.02 (m, 2 H, ArH), 9.22 (s, 1 H, ArH).
The monoarylated products 3a–t were synthesized by
Suzuki–Miyaura reactions of 2,6-dichloroquinoxaline (1)
in good yields. The site selectivity can be explained by the
fact that position 2 of 2,6-dichloroquinoxaline is more
electron deficient than position 6 (Figure 3).
less electron-deficient
13C NMR (75.46 MHz, CDCl3): δ = 20.5 (CH3), 123.6 (CH), 127.0
(CH), 127.1 (CH), 128.1 (CH), 129.8 (CH), 130.22 (CH), 130.23
(CH), 134.1 (C), 135.3 (C), 138.0 (C), 139.8 (C), 140.8 (C), 143.3
(CH), 151.1 (C).
N
N
Cl
Cl
GC-MS (EI, 70 eV): m/z (%) = 254 (100) [M+], 239 (4), 227 (18),
219 (5), 192 (10), 165 (11), 75 (12).
more electron-deficient
Figure 3 Possible explanation for the site selectivity in cross-
coupling reactions of 1
HRMS (EI): m/z [M+] calcd for C15H11ClN2: 254.06053; found:
254.06032.
6-Chloro-2-(p-tolyl)quinoxaline (3c)
In conclusion, a variety of mono- and diarylated quinoxa-
line derivatives were prepared by site-selective Suzuki–
Miyaura cross-coupling reactions of 2,6-dichloroquinox-
aline.
Starting with 1 (0.1 g, 0.5 mmol), 2c (0.088 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3c was isolated as a white solid; yield: 0.096 g (75%); mp 136 °C.
IR (ATR): 3063 (w), 2916 (w), 2854 (w), 2722 (w), 1607 (m), 1576
(w), 1536 (m), 1476 (m), 1413 (m), 1315 (m), 1170 (s), 1064 (m),
© Georg Thieme Verlag Stuttgart · New York
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1640
I. Ali et al.
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1044 (m), 1018 (w), 958 (m), 918 (m), 890 (m), 813 (s), 712 (m),
569 (s) cm–1.
(m), 1125 (m), 1042 (m), 964 (m), 892 (s), 846 (s), 828 (s), 788 (s),
688 (m), 588 (m), 572 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3), 7.29 (d,
3J = 7.9 Hz, 2 H, ArH), 7.63 (dd, J = 9.1, 2.1 Hz, 1 H, ArH), 7.97–
8.02 (m, 4 H, ArH), 9.22 (s, 1 H, ArH).
1H NMR (300.13 MHz, CDCl3): δ = 1.97 (s, 6 H, 2 CH3), 2.25 (s, 3
H, CH3), 6.90 (s, 2 H, ArH), 7.62 (dd, J = 8.9, 2.3 Hz, 1 H, ArH),
7.96–8.06 (m, 2 H, ArH), 8.70 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (CH3), 127.4 (2 CH),
128.0 (CH), 129.9 (2 CH), 130.7 (CH), 131.2 (CH), 133.5 (C),
134.9 (C), 140.7 (C), 140.8 (C), 141.7 (C), 144.1 (CH), 151.9 (C).
13C NMR (75.46 MHz, CDCl3): δ = 19.2 (2 CH3), 20.1 (CH3), 127.2
(CH), 127.8 (2 CH), 129.7 (CH), 130.1 (CH), 132.9 (C), 134.5 (C),
135.1 (2 C), 137.8 (C), 139.9 (C), 140.3 (C), 146.4 (CH), 154.8 (C).
GC-MS (EI, 70 eV): m/z (%) = 254 (100) [M+], 227 (20), 192 (10),
GC-MS (EI, 70 eV): m/z (%) = 282 (40) [M+], 281 (100), 267 (9),
165 (9), 116 (11).
246 (4), 128 (2), 115 (5).
HRMS (EI): m/z [M+] calcd for C15H11ClN2: 254.06053; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClN2: 283.09869;
254.06064.
found: 283.10003.
6-Chloro-2-(2,6-dimethylphenyl)quinoxaline (3d)
6-Chloro-2-(2-methoxyphenyl)quinoxaline (3g)
Starting with 1 (0.1 g, 0.5 mmol), 2d (0.097 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3d was isolated as a brownish, heavy oil; yield: 0.050 g (37%).
Starting with 1 (0.1 g, 0.5 mmol), 2g (0.099 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3g was isolated as a white solid; yield: 0.097 g (72%); mp 143 °C.
IR (ATR): 3063 (w), 3020 (w), 2919 (w), 2855 (w), 2735 (w), 2516
(w), 2392 (w), 2230 (w), 1932 (w), 1865 (w), 1748 (w), 1667 (w),
1602 (m), 1546 (m), 1505 (w), 1474 (s), 1451 (w), 1377 (w), 1293
(m), 1199 (w), 1169 (s), 1131 (w), 1091 (w), 1062 (m), 1042 (s),
1029 (w), 960 (m), 914 (w), 899 (s), 829 (s), 786 (w), 731 (m), 673
(m), 626 (m), 584 (s), 541 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.00 (s, 6 H, 2 CH3), 7.07–7.10
(m, 2 H, ArH), 7.17–7.23 (m, 1 H, ArH), 7.65 (dd, J = 8.9, 2.3 Hz,
1 H, ArH), 7.98–8.08 (m, 2 H, ArH), 8.72 (s, 1 H, ArH).
IR (ATR): 3069 (w), 2973 (w), 2838 (w), 1939 (w), 1754 (w), 1600
(s), 1544 (w), 1493 (m), 1459 (s), 1392 (w), 1296 (w), 1239 (s),
1173 (m), 1117 (m), 1060 (s), 1020 (m), 962 (m), 930 (m), 901 (m),
876 (m), 834 (s), 741 (s), 702 (m), 641 (m), 583 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 6.98 (d,
3J = 8.3 Hz, 1 H, ArH), 7.08 (dt, J = 7.5, 0.9 Hz, 1 H, ArH), 7.38–
7.44 (m, 1 H, ArH), 7.61 (dd, J = 8.9, 2.5 Hz, 1 H, ArH), 7.81 (dd,
J = 7.6, 1.7 Hz, 1 H, ArH), 7.98–8.03 (m, 2 H, ArH), 9.27 (s, 1 H,
ArH).
13C NMR (75.46 MHz, CDCl3): δ = 20.4 (2 CH3), 128.1 (2 CH),
128.3 (CH), 129.1 (CH), 130.8 (CH), 131.3 (CH), 135.7 (C), 136.3
(2 C), 136.7 (C), 140.9 (C), 141.5 (C), 147.2 (CH), 155.7 (C).
GC-MS (EI, 70 eV): m/z (%) = 268 (39) [M+], 267 (100), 253 (6),
232 (6), 190 (2), 133 (3).
HRMS (EI): m/z [M + H]+ calcd for C16H14ClN2: 269.08431; found:
269.08432.
13C NMR (75.46 MHz, CDCl3): δ = 54.6 (OCH3), 110.4 (CH),
120.5 (CH), 125.1 (C), 126.9 (CH), 129.7 (2 CH), 130.5 (CH),
130.7 (CH), 133.9 (C), 140.2 (C), 140.3 (C), 147.1 (CH), 151.3 (C),
156.4 (C).
GC-MS (EI, 70 eV): m/z (%) = 270 (100) [M+], 253 (55), 241 (48),
213 (17), 178 (14), 165 (27), 151 (8), 118 (11), 110 (14), 103 (9), 90
(11), 75 (24).
HRMS (ESI): m/z [M + H]+ calcd for C15H12ClN2O: 271.06327;
6-Chloro-2-(3,5-dimethylphenyl)quinoxaline (3e)
Starting with 1 (0.1 g, 0.5 mmol), 2e (0.097 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3e was isolated as a white solid; yield: 0.12 g (90%); mp 178–
179 °C.
found: 271.06367.
6-Chloro-2-(4-methoxyphenyl)quinoxaline (3h)
Starting with 1 (0.1 g, 0.5 mmol), 2h (0.099 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3h was isolated as a yellowish white solid; yield: 0.086 g (63%); mp
144–146 °C.
IR (ATR): 3042 (w), 3010 (w), 2916 (w), 2858 (w), 2735 (w), 1936
(w), 1880 (w), 1798 (w), 1755 (w), 1606 (m), 1573 (w), 1536 (m),
1494 (w), 1453 (w), 1416 (w), 1398 (w), 1371 (w), 1312 (m), 1258
(w), 1172 (s), 1088 (m), 997 (m), 966 (m), 867 (m), 828 (s), 782
(m), 706 (s), 674 (m), 626 (m), 590 (m), 542 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.35 (s, 6 H, 2 CH3), 7.06 (s, 1
H, ArH), 7.59 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.66 (s, 2 H, ArH),
7.95–7.99 (m, 2 H, ArH), 9.17 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (2 CH3), 125.3 (2 CH),
128.0 (CH), 130.7 (CH), 131.2 (CH), 132.1 (CH), 134.9 (C), 136.3
(C), 138.8 (2 C), 140.8 (C), 141.7 (C), 144.4 (CH), 152.2 (C).
GC-MS (EI, 70 eV): m/z (%) = 268 (100) [M+], 241 (13), 226 (4),
190 (6).
IR (ATR): 3048 (m), 3015 (w), 2930 (w), 2894 (w), 2039 (w), 1915
(w), 1882 (w), 1651 (w), 1604 (s), 1580 (w), 1519 (m), 1463 (w),
1398 (w), 1315 (s), 1269 (w), 1250 (s), 1183 (w), 1167 (s), 1114
(m), 1024 (s), 955 (m), 921 (m), 898 (m), 823 (s), 783 (m), 689 (m),
633 (m), 570 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 6.98 (d,
3J = 9.1 Hz, 2 H, ArH), 7.58 (dd, J = 9.1, 2.5 Hz, 1 H, ArH), 7.92–
3
7.98 (m, 2 H, ArH), 8.06 (d, J = 8.9 Hz, 2 H, ArH), 9.18 (s, 1 H,
ArH).
13C NMR (62.89 MHz, CDCl3): δ = 55.4 (OCH3), 114.6 (2 CH),
128.0 (CH), 128.8 (C), 128.9 (2 CH), 130.6 (CH), 131.1 (CH),
134.6 (C), 140.8 (C), 141.4 (C), 143.8 (CH), 151.5 (C), 161.6 (C).
GC-MS (EI, 70 eV): m/z (%) = 270 (100) [M+], 255 (17), 243 (10),
227 (8), 200 (7), 192 (4), 133 (11), 110 (5).
HRMS (EI): m/z [M+] calcd for C16H13ClN2: 268.07618; found:
268.07635.
HRMS (EI): m/z [M+] calcd for C15H11ClN2O: 270.05544; found:
270.05544.
6-Chloro-2-(2,4,6-trimethylphenyl)quinoxaline (3f)
Starting with 1 (0.12 g, 0.6 mmol), 2f (0.121 g, 1.3 equiv),
Pd(PPh3)4 (0.035 g, 0.05 equiv), K3PO4 (0.254 g, 2 equiv), and THF
(4 mL), 3f was isolated as a yellowish solid; yield: 0.163 g (96%);
mp 100 °C.
6-Chloro-2-(2,3-dimethoxyphenyl)quinoxaline (3i)
Starting with 1 (0.12 g, 0.6 mmol), 2i (0.142 g, 1.3 equiv),
Pd(PPh3)4 (0.035 g, 0.05 equiv), K3PO4 (0.254 g, 2 equiv), and THF
(4 mL), 3i was isolated as a white solid; yield: 0.118 g (65%); mp
124 °C.
IR (ATR): 3076 (w), 3042 (m), 2964 (w), 2916 (m), 2854 (w), 1818
(w), 1727 (w), 1610 (m), 1567 (w), 1539 (m), 1470 (w), 1446 (m),
1417 (w), 1373 (m), 1330 (w), 1317 (w), 1295 (m), 1266 (w), 1163
Synthesis 2012, 44, 1637–1646
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Cross-Coupling Reactions of 2,6-Dichloroquinoxaline
1641
IR (ATR): 2996 (w), 2951 (m), 2840 (m), 1582 (m), 1542 (m), 1484
(m), 1466 (s), 1428 (m), 1397 (w), 1320 (m), 1266 (s), 1234 (m),
1175 (m), 1110 (m), 1086 (m), 1041 (s), 994 (s), 934 (m), 918 (m),
850 (m), 834 (s), 783 (m), 765 (m), 741 (s), 690 (m), 679 (m), 623
(m), 597 (s), 534 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.69 (s, 3 H, OCH3), 3.86 (s, 3
H, OCH3), 7.00 (dd, J = 8.1, 1.5 Hz, 1 H, ArH), 7.15 (t, J = 7.9 Hz,
1 H, ArH), 7.38 (dd, J = 7.7, 1.5 Hz, 1 H, ArH), 7.62 (dd, J = 8.9,
2.3 Hz, 1 H, ArH), 7.98–8.04 (m, 2 H, ArH), 9.27 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 56.0 (OCH3), 61.4 (OCH3),
114.3 (CH), 122.7 (CH), 124.8 (CH), 128.0 (CH), 130.8 (CH),
130.9 (CH), 131.2 (C), 135.3 (C), 141.2 (C), 141.4 (C), 147.6 (C),
147.8 (CH), 151.9 (C), 153.1 (C).
GC-MS (EI, 70 eV): m/z (%) = 300 (100) [M+], 285 (47), 283 (91),
271 (34), 257 (23), 242 (13), 213 (11), 179 (18), 165 (26), 142 (6),
120 (7), 110 (13), 100 (7), 75 (20).
HRMS (EI): m/z [M+] calcd for C17H15ClN2O3: 330.07657; found:
330.07637.
6-Chloro-2-(3-fluorophenyl)quinoxaline (3l)
Starting with 1 (0.1 g, 0.5 mmol), 2l (0.09 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3l was isolated as a white solid; yield: 0.03 g (23%); mp 172–
173 °C.
IR (ATR): 3087 (w), 3065 (w), 2923 (w), 2850 (w), 1953 (w), 1815
(w), 1704 (w), 1590 (m), 1495 (w), 1435 (m), 1402 (w), 1314 (m),
1203 (m), 975 (s), 865 (s), 831 (s), 789 (s), 695 (s), 670 (s), 596 (m)
cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 7.13–7.19 (m, 1 H, ArH),
7.43–7.50 (m, 1 H, ArH), 7.67 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.85–
7.89 (m, 2 H, ArH), 8.00–8.05 (m, 2 H, ArH), 9.23 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 113.5 (d, 2JCF = 23.3 Hz, CH),
116.4 (d, 2JCF = 21.1 Hz, CH), 122.0 (d, 4JCF = 2.7 Hz, CH), 127.1
(CH), 129.8 (d, 3JCF = 8.2 Hz, CH), 129.9 (CH), 130.6 (CH), 134.7
(C), 137.6 (d, 3JCF = 7.8 Hz, C), 139.7 (C), 141.0 (C), 142.8 (CH),
149.5 (d, 4JCF = 2.7 Hz, C), 162.4 (d, 1JCF = 247.2 Hz, C).
HRMS (EI): m/z [M+] calcd for C16H13ClN2O2: 300.06601; found:
300.06569.
6-Chloro-2-(2,6-dimethoxyphenyl)quinoxaline (3j)
Starting with 1 (0.12 g, 0.6 mmol), 2j (0.142 g, 1.3 equiv),
Pd(PPh3)4 (0.035 g, 0.05 equiv), K3PO4 (0.254 g, 2 equiv), and THF
(4 mL), 3j was isolated as a yellow solid; yield: 0.175 g (97%); mp
135–137 °C.
19F NMR (282.40 MHz, CDCl3): δ = –111.56 (ArF).
GC-MS (EI, 70 eV): m/z (%) = 258 (100) [M+], 231 (31), 196 (21),
169 (4), 129 (4), 110 (15), 100 (4), 75 (23), 63 (1), 50 (4).
HRMS (EI): m/z [M+] calcd for C14H8ClFN2: 258.03546; found:
IR (ATR): 3079 (w), 2985 (w), 2831 (w), 1621 (w), 1586 (m), 1538
(m), 1497 (s), 1464 (w), 1425 (m), 1394 (w), 1336 (w), 1304 (s),
1259 (m), 1225 (m), 1208 (m), 1181 (s), 1154 (m), 1060 (m), 1021
(s), 965 (m), 883 (m), 832 (s), 795 (s), 786 (m), 732 (s), 700 (m)
cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.78 (s, 6 H, 2 OCH3), 6.93–
6.94 (m, 2 H, ArH), 7.40 (d, J = 2.8 Hz, 1 H, ArH), 7.61 (dd, J = 8.9,
2.3 Hz, 1 H, ArH), 7.98–8.02 (m, 2 H, ArH), 9.29 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 55.9 (OCH3), 56.3 (OCH3),
113.0 (CH), 115.9 (CH), 117.5 (CH), 126.6 (C), 127.9 (CH), 130.7
(2 CH), 135.1 (C), 141.1 (C), 141.3 (C), 148.0 (CH), 151.8 (C),
152.0 (C), 154.3 (C).
GC-MS (EI, 70 eV): m/z (%) = 300 (100) [M+], 285 (64), 283 (88),
269 (14), 257 (12), 242 (16), 214 (7), 179 (13), 165 (24), 148 (13),
120 (7), 110 (11), 100 (5), 75 (14).
258.03571.
6-Chloro-2-(4-fluorophenyl)quinoxaline (3m)
Starting with 1 (0.1 g, 0.5 mmol), 2m (0.09 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3m was isolated as a yellowish white solid; yield: 0.08 g (62%); mp
165–168 °C.
IR (ATR): 3054 (w), 3012 (w), 2914 (w), 1600 (s), 1558 (w), 1514
(m), 1478 (m), 1305 (m), 1237 (s), 1162 (m), 1047 (m), 957 (m),
901 (m), 872 (m), 828 (s), 790 (m), 720 (m), 691 (m), 571 (s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 7.13–7.21 (m, 2 H, ArH), 7.64
(dd, J = 9.1, 2.5 Hz, 1 H, ArH), 7.96–8.02 (m, 2 H, ArH), 8.07–8.14
(m, 2 H, ArH), 9.20 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 116.3 (d, 2JCF = 21.5 Hz, 2 CH),
3
128.1 (CH), 129.5 (d, JCF = 8.7 Hz, 2 CH), 130.7 (CH), 131.4
(CH), 132.5 (d, 4JCF = 3.2 Hz, C), 135.3 (C), 140.7 (C), 141.7 (C),
143.7 (CH), 150.8 (C), 164.4 (d, 1JCF = 251.31 Hz, C).
HRMS (EI): m/z [M+] calcd for C16H13ClN2O2: 300.06601; found:
300.06590.
19F NMR (282.40 MHz, CDCl3): δ = –110.01 (ArF).
GC-MS (EI, 70 eV): m/z (%) = 258 (100) [M+], 233 (11), 231 (33),
196 (20), 169 (5).
HRMS (EI): m/z [M+] calcd for C14H8ClFN2: 258.03546; found:
6-Chloro-2-(2,3,4-trimethoxyphenyl)quinoxaline (3k)
Starting with 1 (0.12 g, 0.6 mmol), 2k (0.165 g, 1.3 equiv),
Pd(PPh3)4 (0.035 g, 0.05 equiv), K3PO4 (0.254 g, 2 equiv), and THF
(4 mL), 3k was isolated as a yellowish solid; yield: 0.105 g (53%);
mp 106–108 °C.
258.03559.
IR (ATR): 3052 (w), 2943 (m), 2848 (w), 1601 (s), 1542 (m), 1494
(w), 1460 (m), 1433 (w), 1414 (s), 1335 (w), 1309 (m), 1280 (m),
1210 (m), 1171 (m), 1133 (w), 1106 (s), 1087 (m), 1014 (s), 969
(m), 949 (w), 928 (m), 902 (m), 853 (m), 823 (m), 774 (s), 597 (m),
544 (m) cm–1.
6-Chloro-2-(2-thienyl)quinoxaline (3n)
Starting with 1 (0.1 g, 0.5 mmol), 2n (0.082 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3n was isolated as a yellow solid; yield: 0.056 g (45%); mp 154–
156 °C.
1H NMR (300.13 MHz, CDCl3): δ = 3.79 (s, 3 H, OCH3), 3.86 (s, 3
IR (ATR): 3095 (w), 3064 (w), 3011 (w), 2007 (w), 1941 (w), 1887
(w), 1746 (w), 1693 (w), 1593 (m), 1541 (s), 1474 (m), 1433 (w),
1414 (m), 1369 (w), 1311 (m), 1269 (w), 1176 (s), 1131 (m), 1062
(s), 1002 (s), 942 (s), 872 (m), 832 (s), 789 (m), 709 (s), 588 (s), 558
(m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 7.11–7.14 (m, 1 H, ArH), 7.48
(dd, J = 5.1, 1.1 Hz, 1 H, ArH), 7.59 (dd, J = 8.9, 2.5 Hz, 1 H, ArH),
7.77 (dd, J = 3.8, 1.1 Hz, 1 H, ArH), 7.89–7.96 (m, 2 H, ArH), 9.13
(s, 1 H, ArH).
3
H, OCH3), 3.87 (s, 3 H, OCH3), 6.78 (d, J = 8.7 Hz, 1 H, ArH),
7.55–7.61 (m, 2 H, ArH), 7.94–8.00 (m, 2 H, ArH), 9.24 (s, 1 H,
ArH).
13C NMR (75.46 MHz, CDCl3): δ = 56.2 (OCH3), 61.0 (OCH3),
61.6 (OCH3), 108.2 (CH), 123.8 (C), 125.9 (CH), 128.0 (CH), 130.6
(CH), 130.8 (CH), 134.9 (C), 141.1 (C), 141.2 (C), 142.3 (C), 147.6
(CH), 151.7 (C), 152.5 (C), 155.7 (C).
GC-MS (EI, 70 eV): m/z (%) = 330 (100) [M+], 315 (51), 313 (40),
299 (12), 287 (14), 272 (15), 257 (13), 229 (12), 215 (15), 203 (10),
201 (26), 178 (10), 163 (14), 153 (11), 135 (8), 110 (6), 100 (7).
13C NMR (62.89 MHz, CDCl3): δ = 127.2 (CH), 128.1 (CH), 128.6
(CH), 130.2 (CH), 130.3 (CH), 131.4 (CH), 134.8 (C), 140.6 (C),
141.5 (C), 141.8 (C), 142.8 (CH), 147.5 (C).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1637–1646

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I. Ali et al.
PAPER
2
GC-MS (EI, 70 eV): m/z (%) = 246 (100) [M+], 219 (29), 184 (12),
130.2 (q, JCF = 32.46 Hz, C), 130.9 (CH), 131.7 (CH), 136.0 (C),
140 (10), 110 (11), 100 (3), 84 (2), 75 (12).
139.6 (C), 140.7 (C), 142.2 (C), 143.8 (CH), 150.3 (C).
HRMS (EI): m/z [M+] calcd for C12H7ClN2S: 246.00130; found:
19F NMR (282.40 MHz, CDCl3): δ = –62.81 (ArCF3).
246.00147.
GC-MS (EI, 70 eV): m/z (%) = 308 (100) [M+], 281 (24), 246 (9),
226 (8), 212 (2), 177 (4), 152 (6), 136 (2), 110 (17), 100 (4), 75 (20),
50 (3).
HRMS (EI): m/z [M+] calcd for C15H8ClF3N2: 308.03226; found:
308.03178.
6-Chloro-2-(4-ethylphenyl)quinoxaline (3o)
Starting with 1 (0.1 g, 0.5 mmol), 2o (0.098 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3o was isolated as a white solid; yield: 0.13 g (96%); mp 104 °C.
IR (ATR): 3068 (w), 3039 (w), 2955 (m), 2865 (w), 1607 (s), 1537
(s), 1504 (w), 1477 (s), 1445 (w), 1416 (m), 1334 (w), 1313 (s),
1281 (m), 1225 (w), 1173 (s), 1053 (s), 1014 (m), 957 (s), 922 (m),
908 (s), 871 (m), 825 (s), 720 (m), 689 (m), 628 (m), 582 (s), 569
(m), 540 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.21 (t, 3J = 7.7 Hz, 3 H, CH3),
2.65 (q, J = 7.5 Hz, 2 H, CH2), 7.29 (d, 3J = 8.5 Hz, 2 H, ArH), 7.59
(dd, J = 9.1, 2.3 Hz, 1 H, ArH), 7.94–8.02 (m, 4 H, ArH), 9.19 (s, 1
H, ArH).
13C NMR (75.46 MHz, CDCl3): δ = 15.4 (CH3), 28.8 (CH2), 127.5
(2 CH), 128.1 (CH), 128.8 (2 CH), 130.8 (CH), 131.2 (CH), 133.8
(C), 134.9 (C), 140.8 (C), 141.7 (C), 144.1 (CH), 147.1 (C), 151.9
(C).
6-Chloro-2-(4-vinylphenyl)quinoxaline (3r)
Starting with 1 (0.1 g, 0.5 mmol), 2r (0.096 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3r was isolated as a yellow solid; yield: 0.04 g (30%); mp 113–
115 °C.
IR (ATR): 3046 (w), 2921 (m), 2851 (w), 1606 (m), 1568 (w), 1536
(m), 1475 (m), 1445 (w), 1411 (m), 1333 (w), 1314 (m), 1210 (w),
1172 (s), 1047 (m), 957 (m), 899 (m), 825 (s), 782 (w), 731 (m), 572
(s) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 5.29 (d, J = 11.3 Hz, 1 H,
=CH2), 5.79 (d, J = 17.6 Hz, 1 H, =CH2), 6.65–6.75 (m, 1 H, =CH),
7.49 (d, 3J = 8.3 Hz, 2 H, ArH), 7.61 (dd, J = 8.9, 2.3 Hz, 1 H, ArH),
7.95–8.00 (m, 2 H, ArH), 8.06 (d, 3J = 8.5 Hz, 2 H, ArH), 9.21 (s, 1
H, ArH).
GC-MS (EI, 70 eV): m/z (%) = 268 (100) [M+], 255 (26), 253 (79),
226 (4), 190 (7), 163 (2), 116 (18), 110 (8), 89 (7), 84 (1), 75 (11).
HRMS (EI): m/z [M+] calcd for C16H13ClN2: 268.07618; found:
268.07642.
13C NMR (75.46 MHz, CDCl3): δ = 114.6 (=CH2), 125.9 (2 CH),
126.6 (2 CH), 127.0 (CH), 129.7 (CH), 130.3 (CH), 134.1 (C),
134.5 (C), 135.1 (CH), 138.6 (C), 139.8 (C), 140.7 (C), 142.9 (CH),
150.3 (C).
2-(4-tert-Butylphenyl)-6-chloroquinoxaline (3p)
Starting with 1 (0.1 g, 0.5 mmol), 2p (0.106 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3p was isolated as a white solid; yield: 0.115 g (77%); mp 99–
102 °C.
GC-MS (EI, 70 eV): m/z (%) = 266 (100) [M+], 238 (14), 204 (10),
177 (3), 129 (12).
HRMS (EI): m/z [M+] calcd for C16H11ClN2: 266.06053; found:
266.06088.
IR (ATR): 3093 (w), 3063 (w), 2955 (m), 2867 (w), 1601 (m), 1569
(w), 1537 (m), 1504 (w), 1474 (m), 1455 (w), 1404 (m), 1392 (w),
1360 (m), 1333 (w), 1316 (m), 1270 (m), 1200 (m), 1174 (m), 1147
(w), 1093 (m), 1045 (m), 1012 (m), 957 (s), 920 (s), 897 (s), 879
(m), 841 (s), 826 (s), 739 (m), 694 (w), 672 (m), 577 (s), 539 (m)
cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.30 (s, 9 H, 3 CH3), 7.50 (d,
3J = 8.7 Hz, 2 H, ArH), 7.60 (dd, J = 9.1, 2.5 Hz, 1 H, ArH), 7.95–
8.04 (m, 4 H, ArH), 9.21 (s, 1 H, ArH).
13C NMR (75.46 MHz, CDCl3): δ = 31.2 (3 CH3), 34.9 (C), 126.2 (2
CH), 127.3 (2 CH), 128.1 (CH), 130.8 (CH), 131.2 (CH), 133.6 (C),
134.9 (C), 140.9 (C), 141.7 (C), 144.1 (CH), 151.9 (C), 153.9 (C).
GC-MS (EI, 70 eV): m/z (%) = 296 (31) [M+], 281 (100), 265 (5),
253 (11), 218 (1), 203 (1), 163 (4), 140 (2), 116 (7), 110 (4), 75 (5),
39 (1).
6-Chloro-2-(2-chlorophenyl)quinoxaline (3s)
Starting with 1 (0.12 g, 0.6 mmol), 2s (0.121 g, 1.3 equiv),
Pd(PPh3)4 (0.035 g, 0.05 equiv), K3PO4 (0.254 g, 2 equiv), and THF
(4 mL), 3s was isolated as a white solid; yield: 0.129 g (78%); mp
177 °C.
IR (ATR): 3091 (w), 3047 (m), 2982 (w), 1921 (w), 1807 (w), 1621
(w), 1598 (s), 1543 (m), 1504 (w), 1476 (s), 1447 (w), 1429 (m),
1397 (w), 1356 (w), 1324 (w), 1311 (m), 1265 (w), 1248 (m), 1176
(s), 1147 (w), 1137 (m), 1093 (w), 1075 (m), 1040 (s), 961 (s), 935
(s), 921 (w), 898 (s), 833 (s), 791 (m), 748 (s), 723 (m), 686 (m),
676 (m), 579 (m), 538 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 7.34–7.40 (m, 2 H, ArH),
7.44–7.49 (m, 1 H, ArH), 7.62–7.68 (m, 2 H, ArH), 8.00–8.07 (m,
2 H, ArH), 9.13 (s, 1 H, ArH).
13C NMR (75.46 MHz, CDCl3): δ = 126.5 (CH), 127.2 (CH), 129.3
(CH), 129.8 (CH), 129.9 (CH), 130.3 (CH), 130.9 (CH), 131.5 (C),
134.9 (C), 135.1 (C), 139.8 (C), 140.6 (C), 145.9 (CH), 151.5 (C).
HRMS (EI): m/z [M+] calcd for C18H17ClN2: 296.10748; found:
296.10752.
GC-MS (EI, 70 eV): m/z (%) = 274 (100) [M+], 247 (20), 241 (30),
239 (93), 212 (21), 177 (31), 137 (18), 110 (20), 102 (12), 100 (9).
HRMS (EI): m/z [M+] calcd for C14H8Cl2N2: 274.00591; found:
274.00546.
6-Chloro-2-[4-(trifluoromethyl)phenyl]quinoxaline (3q)
Starting with 1 (0.1 g, 0.5 mmol), 2q (0.123 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3q was isolated as a white solid; yield: 0.081 g (52%); mp 128–
130 °C.
6-Chloro-2-(3-chlorophenyl)quinoxaline (3t)
IR (ATR): 3043 (w), 1928 (w), 1809 (w), 1617 (w), 1604 (m), 1538
(m), 1519 (w), 1478 (m), 1414 (m), 1326 (s), 1260 (w), 1195 (w),
1174 (w), 1157 (m), 1107 (s), 1068 (s), 1015 (m), 960 (m), 927 (m),
899 (m), 850 (m), 832 (s), 800 (w), 651 (m), 598 (s), 568 (m) cm–1.
Starting with 1 (0.1 g, 0.5 mmol), 2t (0.1 g, 1.3 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), K3PO4 (0.212 g, 2 equiv), and THF (4 mL),
3t was isolated as a white solid; yield: 0.035 g (25%); mp 167 °C.
IR (ATR): 3080 (w), 3048 (m), 1937 (w), 1822 (w), 1712 (w), 1602
(w), 1537 (m), 1475 (m), 1371 (w), 1311 (s), 1258 (w), 1175 (m),
1106 (w), 1065 (m), 1048 (w), 966 (s), 940 (m), 904 (m), 831 (m),
791 (s), 755 (m), 700 (s), 671 (m), 638 (w), 586 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 7.67 (dd, J = 8.9, 2.3 Hz, 1 H,
3
ArH), 7.75 (d, J = 8.1 Hz, 2 H, ArH), 8.01–8.06 (m, 2 H, ArH),
8.23 (d, 3J = 8.1 Hz, 2 H, ArH), 9.26 (s, 1 H, ArH).
1
13C NMR (75.46 MHz, CDCl3): δ = 123.9 (q, JCF = 272.35 Hz,
3
CF3), 126.1 (q, JCF = 3.30 Hz, 2 CH), 127.8 (2 CH), 128.2 (CH),
Synthesis 2012, 44, 1637–1646
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Cross-Coupling Reactions of 2,6-Dichloroquinoxaline
1643
1H NMR (300.13 MHz, CDCl3): δ = 7.41–7.43 (m, 2 H, ArH), 7.65
(dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.93–8.04 (m, 3 H, ArH), 8.13–8.14
(m, 1 H, ArH), 9.20 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 125.4 (CH), 127.6 (CH), 128.1
(CH), 130.4 (2 CH), 130.9 (CH), 131.6 (CH), 135.4 (C), 135.7 (C),
138.1 (C), 140.7 (C), 142.0 (C), 143.7 (CH), 150.4 (C).
GC-MS (EI, 70 eV): m/z (%) = 275 (17), 274 (100) [M+], 247 (18),
239 (26), 212 (21), 177 (23), 137 (14), 110 (18), 100 (6), 84 (2), 75
(28), 63 (2), 50 (6).
HRMS (EI): m/z [M+] calcd for C22H18N2: 310.14645; found:
310.14679.
2,6-Bis(3,5-dimethylphenyl)quinoxaline (4c)
Starting with 1 (0.1 g, 0.5 mmol), 2e (0.186 g, 2.5 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-dioxane (4 mL),
4c was isolated as a yellow solid; yield: 0.16 g (94%); mp 190–
192 °C.
IR (ATR): 3012 (w), 2913 (m), 2854 (w), 2734 (w), 1597 (m), 1538
(w), 1435 (w), 1373 (w), 1316 (m), 1286 (w), 1217 (w), 1164 (m),
1087 (m), 1037 (m), 967 (m), 938 (w), 842 (s), 788 (m), 771 (w),
711 (m), 681 (s), 628 (m), 569 (w), 544 (w) cm–1.
HRMS (EI): m/z [M+] calcd for C14H8Cl2N2: 274.00591; found:
274.00535.
1H NMR (300.13 MHz, CDCl3): δ = 2.33 (s, 6 H, 2 CH3), 2.36 (s, 6
H, 2 CH3), 6.97 (s, 1 H, ArH), 7.05 (s, 1 H, ArH), 7.29 (s, 2 H, ArH),
7.70 (s, 2 H, ArH), 7.93 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.01–8.19
(m, 2 H, ArH), 9.20 (s, 1 H, ArH).
13C NMR (75.46 MHz, CDCl3): δ = 20.4 (4 CH3), 124.3 (2 CH),
124.4 (2 CH), 125.4 (CH), 128.6 (CH), 128.7 (CH), 128.9 (CH),
130.8 (CH), 135.7 (C), 137.6 (2 C), 137.7 (2 C), 138.6 (C), 140.5
(C), 140.7 (C), 141.3 (C), 142.9 (CH), 150.8 (C).
Synthesis of 4a–f; General Procedure
A 1,4-dioxane soln (8 mL) of 2,6-dichloroquinoxaline (1, 1.0
equiv), an arylboronic acid 2 (2.5 equiv), 2 M K2CO3 (2 mL), and
Pd(PPh3)4 (5 mol%) was heated at 120 °C for 12 h. The reaction
mixture was cooled to r.t., then H2O (100 mL) was added and the
mixture was extracted with CH2Cl2 (100 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The residue was purified by column chromatography (gradient
elution, n-heptane–EtOAc).
GC-MS (EI, 70 eV): m/z (%) = 338 (100) [M+], 311 (2), 296 (1),
180 (7), 154 (2), 130 (8), 115 (4), 77 (1).
HRMS (EI): m/z [M+] calcd for C24H22N2: 338.17775; found:
338.17749.
2,6-Di(o-tolyl)quinoxaline (4a)
Starting with 1 (0.1 g, 0.5 mmol), 2a (0.169 g, 2.5 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-dioxane (4 mL),
4a was isolated as a white solid; yield: 0.1 g (64%); mp 139 °C.
2,6-Bis(2-methoxyphenyl)quinoxaline (4d)
IR (ATR): 3092 (w), 3019 (w), 2921 (w), 2854 (w), 2735 (w), 1954
(w), 1822 (w), 1539 (m), 1494 (w), 1481 (m), 1434 (m), 1349 (w),
1314 (m), 1268 (w), 1164 (m), 1060 (m), 1029 (m), 977 (w), 961
(m), 848 (s), 791 (w), 757 (s), 728 (s), 705 (w), 666 (m), 626 (m),
600 (w), 564 (w), 546 (w), 535 (w) cm–1.
Starting with 1 (0.1 g, 0.5 mmol), 2g (0.19 g, 2.5 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-dioxane (4 mL),
4d was isolated as a yellow solid; yield: 0.085 g (49%); mp 128–
129 °C.
IR (ATR): 3066 (w), 3024 (w), 2938 (w), 2838 (w), 1599 (m), 1489
(m), 1440 (w), 1336 (w), 1268 (m), 1233 (s), 1163 (m), 1116 (m),
1060 (m), 1039 (w), 1016 (s), 960 (m), 904 (m), 842 (w), 828 (m),
784 (m), 741 (s), 695 (w), 666 (m), 617 (m), 576 (m), 562 (w), 541
(w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.75 (s, 3 H, OCH3), 3.80 (s, 3
H, OCH3), 6.93–6.97 (m, 2 H, ArH), 6.99–7.09 (m, 2 H, ArH),
7.26–7.40 (m, 3 H, ArH), 7.82 (dd, J = 7.5, 1.7 Hz, 1 H, ArH), 7.89
(dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.05–8.18 (m, 2 H, ArH), 9.25 (s, 1
H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 55.5 (OCH3), 55.6 (OCH3),
111.4 (CH), 111.5 (CH), 121.1 (CH), 121.5 (CH), 126.7 (C), 128.6
(CH), 129.0 (CH), 129.4 (C), 129.5 (CH), 131.1 (CH), 131.3 (CH),
131.6 (CH), 132.1 (CH), 140.0 (C), 140.9 (C), 141.8 (C), 147.3
(CH), 151.8 (C), 156.6 (C), 157.4 (C).
GC-MS (EI, 70 eV): m/z (%) = 342 (100) [M+], 341 (58), 325 (48),
313 (29), 297 (10), 270 (4), 237 (19), 207 (3), 193 (4), 164 (6), 139
(15), 131 (7), 118 (8), 90 (4), 77 (3), 63 (3), 39 (1).
1H NMR (300.13 MHz, CDCl3): δ = 2.28 (s, 3 H, CH3), 2.41 (s, 3
H, CH3), 7.22–7.33 (m, 7 H, ArH), 7.47–7.50 (m, 1 H, ArH), 7.71
(dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.02–8.12 (m, 2 H, ArH), 8.95 (s, 1
H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 20.4 (CH3), 20.6 (CH3), 126.1
(CH), 126.4 (CH), 128.0 (CH), 128.9 (CH), 129.1 (CH), 129.4
(CH), 129.9 (CH), 130.0 (CH), 130.6 (CH), 131.3 (CH), 132.2
(CH), 135.4 (C), 136.6 (C), 137.2 (C), 140.5 (C), 140.9 (C), 141.0
(C), 143.7 (C), 146.2 (CH), 154.9 (C).
GC-MS (EI, 70 eV): m/z (%) = 310 (48) [M+], 309 (100), 190 (2),
165 (8), 153 (4), 115 (10), 89 (3), 75 (1), 65 (2), 51 (1), 39 (1).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.15428; found:
311.15435.
2,6-Di(p-tolyl)quinoxaline (4b)
Starting with 1 (0.1 g, 0.5 mmol), 2c (0.169 g, 2.5 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-dioxane (4 mL),
4b was isolated as a white solid; yield: 0.08 g (51%); mp 203–
205 °C.
HRMS (EI): m/z [M+] calcd for C22H18N2O2: 342.13628; found:
342.13586.
IR (ATR): 3020 (w), 2913 (w), 2856 (w), 2726 (w), 1614 (m), 1503
(w), 1402 (w), 1322 (w), 1275 (w), 1186 (w), 1167 (m), 1118 (w),
1054 (m), 975 (w), 931 (m), 849 (w), 816 (s), 723 (m), 691 (w), 606
(m), 587 (w), 554 (w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 2.37 (s, 3
H, CH3), 7.25 (d, 3J = 7.9 Hz, 2 H, ArH), 7.29 (d, 3J = 7.9 Hz, 2 H,
ArH), 7.60 (d, 3J = 8.1 Hz, 2 H, ArH), 7.95 (dd, J = 8.7, 1.9 Hz, 1
H, ArH), 8.03 (d, 3J = 8.1 Hz, 2 H, ArH), 8.08–8.21 (m, 2 H, ArH),
9.24 (s, 1 H, ArH).
13C NMR (75.46 MHz, CDCl3): δ = 21.2 (CH3), 21.5 (CH3), 126.1
(CH), 127.3 (2 CH), 127.4 (2 CH), 129.7 (CH), 129.80 (CH),
129.83 (2 CH), 129.9 (2 CH), 134.1 (C), 136.9 (C), 137.5 (C), 138.1
(C), 140.5 (C), 141.7 (C), 142.0 (C), 143.6 (CH), 151.5 (C).
2,6-Bis(4-ethylphenyl)quinoxaline (4e)
Starting with 1 (0.1 g, 0.5 mmol), 2o (0.188 g, 2.5 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-dioxane (4 mL),
4e was isolated as a white solid; yield: 0.08 g (47%); mp 150 °C.
IR (ATR): 3025 (w), 2931 (w), 2874 (w), 1614 (m), 1513 (w), 1452
(m), 1300 (w), 1203 (w), 1165 (m), 1121 (w), 1057 (m), 1015 (m),
960 (m), 914 (w), 829 (s), 798 (w), 684 (w), 633 (w), 609 (m), 590
(w), 553 (w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.22 (t, 3J = 7.2 Hz, 3 H, CH3),
1.24 (t, 3J = 7.5 Hz, 3 H, CH3), 2.65 (q, J = 7.5 Hz, 2 H, CH2), 2.67
(q, J = 7.5 Hz, 2 H, CH2), 7.27 (d, 3J = 8.5 Hz, 2 H, ArH), 7.32 (d,
3J = 8.5 Hz, 2 H, ArH), 7.62 (d, J = 8.3 Hz, 2 H, ArH), 7.95 (dd,
3
GC-MS (EI, 70 eV): m/z (%) = 310 (100) [M+], 295 (2), 268 (1),
J = 8.7, 2.1 Hz, 1 H, ArH), 8.05 (d, 3J = 8.3 Hz, 2 H, ArH), 8.08–
166 (14), 139 (1), 116 (15), 91 (1), 63 (1).
8.21 (m, 2 H, ArH), 9.23 (s, 1 H, ArH).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1637–1646

1644
I. Ali et al.
PAPER
13C NMR (62.89 MHz, CDCl3): δ = 15.4 (CH3), 15.5 (CH3), 28.6
(CH2), 28.8 (CH2), 126.1 (CH), 127.4 (2 CH), 127.5 (2 CH), 128.6
(2 CH), 128.7 (2 CH), 129.7 (CH), 129.8 (CH), 134.3 (C), 137.1
(C), 141.6 (C), 141.7 (C), 142.0 (C), 143.7 (CH), 144.4 (C), 146.7
(C), 151.5 (C).
GC-MS (EI, 70 eV): m/z (%) = 338 (100) [M+], 323 (55), 308 (13),
190 (2), 154 (13), 115 (5), 102 (1), 90 (1), 51 (1).
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2: 325.16993; found:
325.17059.
6-(4-tert-Butylphenyl)-2-(p-tolyl)quinoxaline (5b)
Starting with 3c (0.05 g, 0.2 mmol), 2p (0.046 g, 1.3 equiv),
Pd(PPh3)4 (0.012 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5b was isolated as a light yellow solid; yield: 0.054 g
(78%); mp 185–187 °C.
HRMS (EI): m/z [M+] calcd for C24H22N2: 338.17775; found:
338.17782.
IR (ATR): 3061 (w), 3032 (w), 2902 (w), 2865 (w), 1916 (w), 1614
(m), 1514 (w), 1450 (m), 1397 (w), 1362 (m), 1269 (w), 1186 (w),
1166 (m), 1143 (w), 1109 (w), 1048 (w), 1009 (w), 958 (m), 925
(m), 889 (w), 842 (w), 819 (s), 740 (w), 718 (m), 687 (w), 672 (w),
628 (w), 606 (m), 564 (w), 558 (m), 547 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.31 (s, 9 H, 3 CH3), 2.37 (s, 3
H, CH3), 7.28 (d, 3J = 7.9 Hz, 2 H, ArH), 7.46 (d, 3J = 8.7 Hz, 2 H,
ArH), 7.65 (d, 3J = 8.5 Hz, 2 H, ArH), 7.95 (dd, J = 8.9, 1.9 Hz, 1
H, ArH), 8.03 (d, 3J = 8.3 Hz, 2 H, ArH), 8.09 (d, J = 8.7 Hz, 1 H,
ArH), 8.22 (d, J = 1.5 Hz, 1 H, ArH), 9.23 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (CH3), 31.3 (3 CH3), 34.7
(C), 126.0 (2 CH), 126.1 (CH), 127.1 (2 CH), 127.4 (2 CH), 129.7
(CH), 129.8 (CH), 129.9 (2 CH), 134.0 (C), 136.7 (2 C), 140.4 (2
C), 141.7 (C), 141.9 (C), 143.6 (CH), 151.3 (C).
2,6-Bis(4-tert-butylphenyl)quinoxaline (4f)
Starting with 1 (0.1 g, 0.5 mmol), 2p (0.223 g, 2.5 equiv), Pd(PPh3)4
(0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-dioxane (4 mL),
4f was isolated as a white solid; yield: 0.052 g (26%); mp 265–
267 °C.
IR (ATR): 3062 (w), 2964 (m), 2863 (w), 2707 (w), 1614 (m), 1504
(w), 1455 (m), 1361 (m), 1301 (w), 1265 (m), 1202 (w), 1138 (w),
1047 (m), 976 (w), 930 (m), 890 (m), 823 (s), 742 (w), 694 (w), 640
(w), 610 (m), 566 (s), 545 (w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 1.32 (s, 18 H, 6 CH3), 7.47 (d,
3
3J = 8.5 Hz, 2 H, ArH), 7.52 (d, J = 8.7 Hz, 2 H, ArH), 7.65 (d,
3J = 8.5 Hz, 2 H, ArH), 7.97 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.06
(d, 3J = 8.5 Hz, 2 H, ArH), 8.09–8.23 (m, 2 H, ArH), 9.25 (s, 1 H,
ArH).
GC-MS (EI, 70 eV): m/z (%) = 352 (100) [M+], 309 (25), 297 (9),
178 (10), 152 (7), 141 (15), 65 (1), 39 (1).
13C NMR (62.89 MHz, CDCl3): δ = 31.2 (3 CH3), 31.3 (3 CH3),
34.7 (C), 34.9 (C), 126.0 (2 CH), 126.1 (CH), 126.2 (2 CH), 127.1
(2 CH), 127.2 (2 CH), 129.7 (CH), 129.8 (CH), 134.1 (C), 136.8
(C), 141.6 (C), 141.7 (C), 141.9 (C), 143.7 (CH), 151.3 (C), 151.5
(C), 153.5 (C).
GC-MS (EI, 70 eV): m/z (%) = 394 (63) [M+], 380 (31), 379 (100),
363 (10), 335 (3), 295 (2), 182 (11), 154 (10), 102 (1), 41 (3).
HRMS (ESI): m/z [M + H]+ calcd for C25H25N2: 353.20123; found:
353.20151.
6-(2-Methoxyphenyl)-2-(p-tolyl)quinoxaline (5c)
Starting with 3c (0.05 g, 0.2 mmol), 2g (0.04 g, 1.3 equiv),
Pd(PPh3)4 (0.012 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5c was isolated as a light yellow solid; yield: 0.03 g
(47%); mp 125–127 °C.
HRMS (EI): m/z [M+] calcd for C28H30N2: 394.24035; found:
394.24046.
IR (ATR): 3063 (w), 3002 (w), 1916 (w), 2834 (w), 1613 (w), 1567
(w), 1518 (w), 1464 (m), 1415 (w), 1322 (w), 1283 (w), 1243 (m),
1182 (w), 1119 (m), 1059 (w), 1025 (m), 977 (w), 932 (m), 900 (m),
833 (s), 823 (s), 754 (s), 716 (w), 636 (w), 616 (w), 609 (m), 576
(w), 543 (w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 3.77 (s, 3
H, OCH3), 6.94–7.04 (m, 2 H, ArH), 7.26–7.33 (m, 3 H, ArH), 7.39
(dd, J = 7.5, 1.7 Hz, 1 H, ArH), 7.91 (dd, J = 8.7, 1.9 Hz, 1 H, ArH),
8.01–8.17 (m, 4 H, ArH), 9.21 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (CH3), 55.6 (OCH3), 111.4
(CH), 121.1 (CH), 127.4 (2 CH), 128.6 (CH), 129.0 (CH), 129.3
(C), 129.5 (CH), 129.9 (2 CH), 131.1 (CH), 132.6 (CH), 134.1 (C),
139.9 (C), 140.4 (C), 141.4 (C), 141.5 (C), 143.3 (CH), 151.5 (C),
156.6 (C).
Synthesis of 5a–g; General Procedure
A 1,4-dioxane soln (8 mL) of a 2-aryl-6-chloroquinoxaline 3 (1.0
equiv), an arylboronic acid 2 (1.3 equiv), 2 M K2CO3 (2 mL), and
Pd(PPh3)4 (5 mol%) was heated at 120 °C for 8 h. The reaction mix-
ture was cooled to r.t., then H2O (100 mL) was added and the mix-
ture was extracted with CH2Cl2 (100 mL). The organic layer was
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (gradient elu-
tion, n-heptane–EtOAc).
6-(3,5-Dimethylphenyl)-2-(p-tolyl)quinoxaline (5a)
Starting with 3c (0.05 g, 0.2 mmol), 2e (0.039 g, 1.3 equiv),
Pd(PPh3)4 (0.012 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5a was isolated as a light yellow solid; yield: 0.045 g
(70%); mp 168 °C.
GC-MS (EI, 70 eV): m/z (%) = 326 (100) [M+], 311 (20), 284 (20),
182 (9), 163 (12), 139 (12), 131 (5), 115 (2), 102 (1), 63 (1), 39 (1).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.14919;
found: 327.15004.
IR (ATR): 3030 (w), 2913 (m), 2727 (w), 1601 (m), 1555 (w), 1463
(w), 1427 (w), 1370 (w), 1276 (w), 1184 (w), 1164 (w), 1075 (w),
1049 (m), 960 (m), 929 (w), 881 (w), 818 (s), 776 (w), 717 (m), 682
(m), 640 (w), 624 (w), 614 (s), 569 (w), 555 (w), 536 (w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.34 (s, 6 H, 2 CH3), 2.37 (s, 3
H, CH3), 6.99 (s, 1 H, ArH), 7.28 (s, 1 H, ArH), 7.30 (s, 3 H, ArH),
7.95 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.03 (d, 3J = 8.1 Hz, 2 H, ArH),
8.08 (d, 3J = 8.7 Hz, 1 H, ArH), 8.20 (d, J = 2.1 Hz, 1 H, ArH), 9.23
(s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (3 CH3), 125.4 (2 CH),
126.4 (CH), 127.4 (2 CH), 129.6 (CH), 129.7 (CH), 129.8 (2 CH),
129.9 (CH), 134.0 (C), 138.6 (2 C), 139.7 (C), 140.4 (C), 141.6 (C),
141.7 (C), 142.3 (C), 143.6 (CH), 151.5 (C).
6-(4-Fluorophenyl)-2-(4-methoxyphenyl)quinoxaline (5d)
Starting with 3h (0.08 g, 0.3 mmol), 2m (0.054 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5d was isolated as a white solid; yield: 0.074 g (76%);
mp 187–189 °C.
IR (ATR): 3062 (w), 3014 (w), 2970 (w), 2843 (w), 1600 (m), 1545
(w), 1510 (m), 1454 (w), 1401 (w), 1306 (w), 1253 (m), 1226 (m),
1178 (w), 1115 (w), 1100 (w), 1027 (m), 960 (m), 902 (w), 890 (w),
826 (s), 785 (w), 720 (w), 696 (w), 640 (m), 631 (w), 589 (m), 554
(w), 534 (m) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 7.02 (d,
3J = 9.1 Hz, 2 H, ArH), 7.13 (t, J = 8.7 Hz, 2 H, ArH), 7.62–7.69 (m,
2 H, ArH), 7.90 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.07–8.16 (m, 4 H,
ArH), 9.23 (s, 1 H, ArH).
GC-MS (EI, 70 eV): m/z (%) = 324 (100) [M+], 309 (5), 297 (5),
180 (42), 162 (20), 130 (27), 115 (11), 77 (1), 65 (1), 63 (1).
Synthesis 2012, 44, 1637–1646
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cross-Coupling Reactions of 2,6-Dichloroquinoxaline
1645
13C NMR (75.46 MHz, CDCl3): δ = 55.5 (OCH3), 114.6 (2 CH),
IR (ATR): 3021 (w), 2962 (m), 2854 (w), 2729 (w), 1915 (w), 1822
(w), 1727 (w), 1613 (m), 1513 (w), 1452 (m), 1336 (w), 1276 (w),
1209 (w), 1165 (m), 1080 (w), 1015 (w), 960 (m), 932 (m), 894 (w),
835 (m), 817 (s), 788 (w), 722 (w), 665 (w), 608 (m), 588 (w), 554
(w), 542 (w) cm–1.
2
116.0 (d, JCF = 22.0 Hz, 2 CH), 126.4 (CH), 128.9 (2 CH), 129.1
(d, 3JCF = 8.3 Hz, 2 CH), 129.3 (C), 129.6 (CH), 129.8 (CH), 135.9
(d, 4JCF = 3.3 Hz, C), 140.8 (C), 141.4 (C), 141.6 (C), 143.6 (CH),
151.3 (C), 161.5 (C), 163.0 (d, 1JCF = 247.59 Hz, C).
19F NMR (282.40 MHz, CDCl3): δ = –114.27 (ArF).
1H NMR (300.13 MHz, CDCl3): δ = 1.21 (t, 3J = 7.5 Hz, 3 H, CH3),
2.33 (s, 3 H, CH3), 2.65 (q, J = 7.7 Hz, 2 H, CH2), 7.22 (d, 3J = 7.7
Hz, 2 H, ArH), 7.29 (d, 3J = 8.3 Hz, 2 H, ArH), 7.57 (d, 3J = 8.1 Hz,
2 H, ArH), 7.92 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.02–8.18 (m, 4 H,
ArH), 9.21 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 15.4 (CH3), 21.2 (CH3), 28.8
(CH2), 126.1 (CH), 127.3 (2 CH), 127.5 (2 CH), 128.7 (2 CH),
129.7 (2 CH), 129.8 (2 CH), 134.3 (C), 136.8 (C), 138.1 (C), 141.6
(C), 141.7 (C), 141.9 (C), 143.7 (CH), 146.7 (C), 151.5 (C).
GC-MS (EI, 70 eV): m/z (%) = 324 (100) [M+], 309 (36), 254 (1),
166 (8), 154 (7), 116 (11), 103 (1), 91 (2), 77 (1), 51 (1).
HRMS (EI): m/z [M+] calcd for C23H20N2: 324.16210; found:
324.16206.
GC-MS (EI, 70 eV): m/z (%) = 330 (100) [M+], 315 (14), 287 (10),
260 (2), 195 (2), 170 (12), 120 (20), 103 (1), 90 (1), 75 (1), 65 (1),
63 (1).
HRMS (EI): m/z [M+] calcd for C21H15FN2O: 330.11629; found:
330.11615.
6-(3,5-Dimethylphenyl)-2-(4-fluorophenyl)quinoxaline (5e)
Starting with 3m (0.07 g, 0.3 mmol), 2e (0.058 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5e was isolated as a white solid; yield: 0.055 g (63%);
mp 163–165 °C.
IR (ATR): 3339 (s), 2919 (w), 2859 (w), 2735 (w), 1599 (m), 1538
(w), 1469 (w), 1410 (w), 1343 (w), 1298 (w), 1264 (w), 1225 (m),
1142 (w), 1048 (m), 960 (m), 911 (w), 839 (m), 827 (s), 789 (w),
722 (m), 684 (m), 634 (w), 612 (s), 573 (w), 552 (w), 541 (w) cm–1.
1H NMR (300.13 MHz, CDCl3): δ = 2.34 (s, 6 H, 2 CH3), 6.99 (s, 1
H, ArH), 7.16 (t, J = 8.7 Hz, 2 H, ArH), 7.29 (s, 2 H, ArH), 7.95 (dd,
J = 8.7, 1.9 Hz, 1 H, ArH), 8.04–8.20 (m, 4 H, ArH), 9.19 (s, 1 H,
ArH).
References
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13C NMR (62.89 MHz, CDCl3): δ = 20.4 (2 CH3), 115.2 (d,
2JCF = 21.97 Hz, 2 CH), 124.4 (2 CH), 125.4 (CH), 128.3 (CH),
3
128.5 (d, JCF = 8.2 Hz, 2 CH), 128.8 (CH), 129.2 (CH), 131.9 (d,
4JCF = 3.2 Hz, C), 137.6 (2 C), 138.6 (C), 140.5 (C), 140.7 (C),
141.6 (C), 142.2 (CH), 149.3 (C), 163.2 (d, 1JCF = 250.8 Hz, C).
19F NMR (282.40 MHz, CDCl3): δ = –110.61 (ArF).
GC-MS (EI, 70 eV): m/z (%) = 328 (100) [M+], 313 (3), 180 (13),
164 (3), 130 (9), 115 (5), 94 (1), 75 (1).
HRMS (EI): m/z [M+] calcd for C22H17FN2: 328.13703; found:
328.13668.
6-(3,5-Dimethylphenyl)-2-(2-thienyl)quinoxaline (5f)
Starting with 3n (0.05 g, 0.2 mmol), 2e (0.039 g, 1.3 equiv),
Pd(PPh3)4 (0.012 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5f was isolated as a yellow solid; yield: 0.058 g (91%);
mp 152 °C.
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K. H.; Lee, S. K.; Ryu, C. K. Bioorg. Med. Chem. Lett. 2005,
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IR (ATR): 3106 (w), 3012 (w), 2913 (m), 2858 (w), 2722 (w), 1602
(m), 1573 (w), 1539 (m), 1454 (w), 1417 (m), 1371 (w), 1321 (m),
1238 (w), 1161 (w), 1132 (m), 1064 (w), 1006 (m), 935 (w), 919
(m), 891 (w), 819 (s), 786 (w), 775 (m), 750 (w), 703 (m), 682 (s),
625 (w), 615 (s), 606 (w), 561 (w), 537 (w) cm–1.
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I.; Desplat, V.; Fabre, S. B.; Pinaud, N.; Ravanello, F.; Le-
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1H NMR (300.13 MHz, CDCl3): δ = 2.33 (s, 3 H, CH3), 2.34 (s, 3
H, CH3), 6.98 (s, 1 H, ArH), 7.10–7.13 (m, 1 H, ArH), 7.29 (s, 2 H,
ArH), 7.46 (dd, J = 5.1, 1.1 Hz, 1 H, ArH), 7.77 (dd, J = 3.8, 1.1 Hz,
1 H, ArH), 7.90–8.16 (m, 3 H, ArH), 9.15 (s, 1 H, ArH).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (2 CH3), 125.3 (2 CH),
126.4 (CH), 126.8 (CH), 128.5 (CH), 129.2 (CH), 129.7 (CH),
129.8 (CH), 130.2 (CH), 138.6 (3 C), 139.6 (C), 141.4 (C), 141.6
(C), 142.2 (C), 142.4 (CH), 147.0 (C).
GC-MS (EI, 70 eV): m/z (%) = 316 (100) [M+], 301 (4), 180 (19),
158 (7), 130 (14), 115 (5), 69 (1), 63 (1), 57 (1).
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2S: 317.11070; found:
317.11119.
2-(4-Ethylphenyl)-6-(p-tolyl)quinoxaline (5g)
Starting with 3o (0.07 g, 0.3 mmol), 2c (0.053 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane (4 mL), 5g was isolated as a yellowish solid; yield: 0.046 g
(54%); mp 152–154 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1637–1646

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I. Ali et al.
PAPER
(12) Vicente, E.; Silanes, S. P.; Lima, L. M.; Ancizu, S.;
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(19) The Suzuki cross-coupling reaction of 2,6-dichloro-
quinoxaline with one Boc-protected pyrazolylboronic acid
pinacol ester has been reported in a patent. Surprisingly, the
authors state the opposite regioselectivity for this reaction;
see: (a) Boyle, R. G.; Walker, D. W. WO 2010136755 (A1),
2010. For other palladium-catalyzed reactions of 2,6-
dichloroquinoxaline (Sonogashira reaction), see:
(b) Armengol, M.; Joule, J. A. J. Chem. Soc., Perkin Trans.
1 2001, 154. (c) Armengol, M.; Joule, J. A. J. Chem. Soc.,
Perkin Trans. 1 2001, 978.
(20) CCDC 865782 (3g) and 865783 (5e) contain all
crystallographic details for this publication. The data are
available, free of charge, at
(16) Baek, J. B.; Harris, F. W. J. Polym. Sci., Part A: Polym.
Chem. 2005, 43, 78.
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www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk].
(21) Martin, L. J.; Marzinzik, A. L.; Ley, S. V.; Baxendale, I. R.
Org. Lett. 2011, 13, 320.
(18) For reviews of site-selective palladium(0)-catalyzed cross-
coupling reactions, see: (a) Schröter, S.; Stock, C.; Bach, T.
Synthesis 2012, 44, 1637–1646
© Georg Thieme Verlag Stuttgart · New York