Regioselective palladium(0)-catalyzed cross-coupling reactions of 5,7-dichloro-1,6-naphthyridine

Article abstract of DOI:10.1055/s-0032-1316540

A variety of mono- and diarylated naphthyridine derivatives were prepared by site-selective Suzuki-Miyaura cross-coupling reactions of 5,7-dichloro-1,6-naphthyridine. The first attack occurs at position 5. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1316540

PAPER
▌2255
paper
Regioselective Palladium(0)-Catalyzed Cross-Coupling Reactions of
5,7-Dichloro-1,6-naphthyridine
Cross-Coupling Reactions of 5,7-Dichloro-1,6-naphthyridine
Iftikhar Ali,a Zahid Hassan,a Martin Hein,a Abiodun Falodun,a,b Tamás Patonay,c Alexander Villinger,a Peter Langer*a,d
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City 30001, Nigeria
c
Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
d
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Received: 05.02.2012; Accepted after revision: 15.05.2012
neuroprotective,10 anticonvulsant, and cardiac11 activities.
Abstract: A variety of mono- and diarylated naphthyridine deriva-
In addition, other naphthyridine derivatives exhibit inhibi-
tives were prepared by site-selective Suzuki–Miyaura cross-cou-
tion of protein kinase D (PKD),12 and acetylcholinesterase
pling reactions of 5,7-dichloro-1,6-naphthyridine. The first attack
occurs at position 5.
(AChE) and butyrylcholinesterase (BuChE),13 and some
naphthyridine moieties act as transient receptor potential
Key Words: catalysis, palladium, Suzuki reaction, naphthyridine,
regioselectivity
vanilloid (TRPV1) antagonist.14 1,6-Naphthyridine deriv-
atives also exhibit interesting biological properties, such
as activity as antinociceptive agents,15 HIV-1 integrase in-
hibitors,16 and as anti-human cytomegalovirus (HCMV)
Palladium-catalyzed cross-coupling reactions represent
agents.17 Some other compounds containing the 1,6-naph-
powerful synthetic tools for the formation of highly sub-
thyridine motif have been reported to show inhibition of
stituted heterocycles1 that play a key role in total synthe-
fibroblast growth factor receptors (FGFR). Fibroblast
sis.2 The regioselectivity of palladium-catalyzed cross-
growth factors are major factors for some tumors and an-
coupling reactions of polyhalogenated heterocycles has
giogenesis and are essential for the growth and survival of
been broadly studied and it can provide a versatile and
solid tumors. The inhibition of FGFR tyrosine kinases is
feasible way to design and synthesize libraries of various
considered to be an effective strategy to prevent this inap-
heterocyclic scaffolds.3 In this context, the Suzuki–
propriate vascularization18 (Figure 2).
Miyaura reaction plays an important role.4
Naphthyridines are nitrogen-containing heterocycles con-
OMe
N
taining two pyridine moieties (Figure 1). The first 1,8-
naphthyridines were prepared by Arnold Reissert in 1893.
In 1927, the syntheses of the parent 1,5- (A) and 1,8-naph-
N
O
O
N
OMe
thyridines (D) were described. The 1,6- (B), 1,7- (C), and
2,7-naphthyridines (F) were prepared in 1958 and 2,6-
naphthyridine (E) was synthesized in 1965.5
N
N
NH
H
HN
O
NH
FGFR inhibitor
antinociceptive agent
N
N
N
N
N
N
N
N
S
NH2
A
D
B
E
C
F
O
O
O
N
N
N
N
N
N
H
N
N
N
N
O
anti-HCMV agent
O
OH
Figure 1 Isomeric structures of naphthyridines
HIV-1 integrase inhibitor
Figure 2 Pharmacologically relevant 1,6-naphthyridine derivatives
Naphthyridines are of considerable pharmacological rele-
vance. They show activity for the treatment of cardiac
arrhythmia, hypertension, rheumatoid arthritis, hyperlip-
idemia, and myocardial infarction.6 1,8-Naphthyridines
have been reported to possess a wide range of biological
activity, such as antibacterial,7 antitumor,8 neurotoxic,9
Commercially available 5,7-dichloro-1,6-naphthyridine
(1) represents an interesting substrate for site-selective
Suzuki–Miyaura cross-coupling reactions which have, to
the best of our knowledge, not previously been reported.
The reaction of 1 with 4-methylphenylboronic acid (2a,
1.3 equiv) afforded 7-chloro-5-(p-tolyl)-1,6-naphthyri-
dine (3a) in up to 70% yield (Scheme 1, Tables 1 and 2);
the reaction conditions were systematically optimized for
this reaction (Table 1). The best yields were obtained
SYNTHESIS 2012, 44, 2255–2263
Advanced online publication: 26.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316540; Art ID: SS-2012-N0111-OP
© Georg Thieme Verlag Stuttgart · New York

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I. Ali et al.
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Table 1 Optimization of the Reaction Conditions for the Synthesis of 3a
Entry
Solvent
Base (equiv)
Temp (°C)
Time (h)
Yielda (%) of 3a Ratiob 1/3a/5b
c
1
2
1,4-dioxane
1,4-dioxane
THF
K3PO4 (2)
80
100
80
6
6
–
–
–
–
–
–
–
–
1:4:1
c
c
c
c
c
c
c
2 M K2CO3
2 M K2CO3
K3PO4 (2)
1:3:1.2
3
6
1:3.2:2.5
1:4:1.8
4
THF
80
6
5
toluene
K3PO4 (2)
70
6
1:4.2:2.1
1:3.1:1.3
1:3.1:1.3
1:3.2:1.3
6
toluene
2 M K2CO3
Cs2CO3 (2)
Cs2CO3 (2)
2 M K2CO3
2 M K2CO3
2 M K2CO3
2 M K2CO3
80
6
7
toluene
65
6
8
THF
70
6
c
9
DME
65
10
6
49
–
d
c
10
11
12
1,4-dioxane
DMF
65
–
–
c
100
70
6
–
1:3.1:1.1
c
1,4-dioxane–toluene (1:1)
8
70
–
a Yields of isolated products; Pd(PPh3)4 was used as the catalyst in all reactions.
b Ratio of 1, 3a, and of twofold arylated product 5b in the crude product mixture (by 1H NMR).
c Not determined.
d No conversion.
using the solvent system 1,4-dioxane–toluene (1:1),
Pd(PPh3)4 (5 mol%) as the catalyst, and 2 M potassium
carbonate solution as the base at 70 °C for eight hours (Ta-
ble 1, entry 12). Reactions carried out at temperatures
higher than 70 °C afforded a mixture of substrate 1, mono-
arylated product 3a and diarylated product 5b. The reac-
tions of 1 with electron-poor and electron-rich arylboronic
acids 2a–l (1.3 equiv), using the optimized conditions giv-
en in Table 1, entry 12, afforded the 5-aryl-7-chloronaph-
thyridines 3a–l in 33–96% yields (Scheme 1, Table 2).
Table 2 Synthesis of 5-Aryl-7-chloro-1,6-naphthyridines 3a–l
Entry
Boronic acid Ar1
Product Yielda (%)
1
2
2a
2b
2c
2d
2e
2f
4-MeC6H4
3a
3b
3c
3d
3e
3f
70b
80b
74
3,5-Me2C6H3
2-MeOC6H4
4-FC6H4
3
4
54
5
2,3,4-(MeO)3C6H2
2,3-(MeO)2C6H3
2-MeC6H4
67
6
96
Cl
N
Cl
N
Ar1B(OH)2
2
7
2g
2h
2i
3g
3h
3i
70
N
N
i
Ar1
8
4-ClC6H4
33
Cl
1
3a–l
9
4-F3CC6H4
65
Scheme 1 Synthesis of 3a–l. Reagents and conditions: (i) 1 (1
equiv), Ar1B(OH)2 (1.3 equiv), Pd(PPh3)4 (5 mol%), 2 M K2CO3 (1
mL), 1,4-dioxane–toluene (1:1, 8 mL), 70 °C, 8 h.
10
11
12
2j
4-MeOC6H4
4-EtC6H4
3j
79
2k
2l
3k
3l
79c
67b
4-t-BuC6H4
The Suzuki–Miyaura reactions of 1 with arylboronic acids
4a–i (2.5 equiv) gave 5,7-diaryl-1,6-naphthyridines 5a–i
in good yields. The best yields were obtained using aryl-
boronic acid 4a–i (2.5 equiv), Pd(PPh3)4 (5 mol%), and 2
M potassium carbonate solution (2 mL) as the base (1,4-
dioxane, 110 °C, 12 h). The reactions could be successful-
ly carried out with both electron-rich and electron-poor ar-
ylboronic acids. The reaction of 1 with arylboronic acid 4c
afforded product 5c in an excellent 94% yield (Scheme 2,
Table 3).
a Yields of isolated products.
b Contained 5% of 1 (by 1H NMR) that could not be separated.
c Contained 10% of 1 (by 1H NMR) that could not be separated.
The Suzuki–Miyaura reactions of 5-aryl-7-chloronaph-
thyridines 3e,f with arylboronic acids 6a–d (1.3 equiv) af-
forded the disubstituted products 7a–d in good yields. The
reaction of 3e with arylboronic acid 6a afforded product
7a in an excellent 89% yield (Scheme 3, Table 4). The
mono- and diarylations to give 3, 5, and 7 were all at-
Synthesis 2012, 44, 2255–2263
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Cross-Coupling Reactions of 5,7-Dichloro-1,6-naphthyridine
2257
Ar1B(OH)2
Ar2B(OH)2
Ar1
Cl
N
Ar2
N
Cl
N
N
4
6
N
N
N
N
i
i
Ar1
3
Ar1
7a–d
Ar1
Cl
1
5a–i
Scheme 3 Synthesis of 7a–d. Reagents and conditions: (i) 3 (1
mmol), Ar2B(OH)2 (1.3 equiv), Pd(PPh3)4 (5 mol%), 2 M K2CO3 (1
mL), 1,4-dioxane (8 mL), 110 °C, 8 h.
Scheme 2 Synthesis of 5a–i. Reagents and conditions: (i) 1 (1 mmol),
Ar1B(OH)2 (2.5 equiv), Pd(PPh3)4 (5 mol%), 2 M K2CO3 (2 mL), 1,4-
dioxane (8 mL), 110 °C, 12 h.
The structures of all products were established by NMR,
MS, and IR data. The structures of 3f (Figure 3) and 5c
(Figure 4) were independently confirmed by X-ray crys-
tallography.19
Table 3 Synthesis of 5,7-Diaryl-1,6-naphthyridines 5a–i
Entry
Boronic acid Ar1
Product Yielda (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
2-MeOC6H4
5a
5b
5c
5d
5e
71
74b
94
67
79
49
64
74
73
4-MeC6H4
3,5-Me2C6H3
4-EtC6H4
4-t-BuC6H4
2,3,4-(MeO)3C6H2 5f
4g
4h
4i
4-F3CC6H4
3-FC6H4
5g
5h
5i
4-MeOC6H4
a Yields of isolated products.
b Contained 5% of 1 (by 1H NMR) that could not be separated.
tempted using alkyl- and vinylboronic acids instead of ar-
ylboronic acids, however, the reactions were unsuccessful
due to the formation of complex mixtures (decomposi-
tion). Likewise the use of heteroarylboronic acids, such as
2-thienylboronic acid, was also studied, but did not result
in pure products (formation of complex mixtures that
could not be separated). For some derivatives, only low or
moderate yields were obtained. This can be explained by
practical problems during the chromatographic separation
(similar Rf values). The products had to be separated from
diarylated products (in the case of 3d,e), from monoaryl-
ated products (in the case of 5f) and from mono- and dia-
rylated products (in the case of 7c,d). In addition, a small
amount of starting material and some unknown impurities
(maybe biaryls formed by dimerization of the arylboronic
acids) had to be separated.
Figure 3 ORTEP view of the crystal structure of 3f
The first attack of site-selective palladium-catalyzed reac-
tions usually occurs at the electronically more deficient
and sterically less hindered position. The site-selective
synthesis of 3a–l can be explained on the basis of elec-
1
tronic effects (Figure 5). The H NMR chemical shift of
the molecules in which the halide is replaced by a hydro-
gen usually gives a good estimate of the electronic char-
acter and the site-selectivity of palladium-catalyzed cross-
coupling reactions of polyhalogenated substrates.20 The
position C5 (1H NMR, δ = 9.15) is more electron-deficient
compared to position C7 (1H NMR, δ = 8.45). Therefore,
the first attack takes place at position C5.
Table 4 Synthesis of 5-Aryl1-7-aryl2-1,6-naphthyridines 7a–d
Entry Substrates Ar1
Ar2
Product Yielda
(%)
1
2
3
4
6a 3e 2,3,4-(MeO)3C6H2 3,5-Me2C6H3 7a
6b 3e 2,3,4-(MeO)3C6H2 4-MeC6H4 7b
6c 3e 2,3,4-(MeO)3C6H2 4-t-BuC6H4 7c
6d 3f 2,3-(MeO)2C6H3 2-MeC6H4 7d
89
We have successfully synthesized arylated naphthyridine
derivatives by site-selective Suzuki–Miyaura cross-
coupling reactions of 5,7-dichloro-1,6-naphthyridine. The
first attack occurred at position 5, which is more electron-
deficient compared to position 7.
64b
54b
47b
a Yields of isolated products.
b Contained 5% of 1 (by 1H NMR) that could not be separated.
© Georg Thieme Verlag Stuttgart · New York
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I. Ali et al.
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858 (s), 828 (s), 813 (s), 782 (s), 768 (m), 725 (m), 603 (m), 588
cm–1 (m).
1H NMR (250.13 MHz, CDCl3): δ = 2.36 (s, 3 H, CH3), 7.25 (d, 3J =
8.3 Hz, 2 H, HAr), 7.37 (dd, J = 8.7, 4.2 Hz, 1 H, HAr), 7.48 (d, 3J =
8.1 Hz, 2 H, HAr), 7.84 (s, 1 H, HAr), 8.31–8.35 (m, 1 H, HAr), 8.95
(dd, J = 4.3, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (CH3), 120.2 (CH), 120.8
(C), 122.2 (CH), 129.3 (2 CH), 130.0 (2 CH), 134.3 (C), 136.2
(CH), 139.8 (C), 148.3 (C), 152.9 (C), 155.2 (CH), 162.1 (C).
GC-MS (EI, 70 eV): m/z (%) = 254 (M+, 100), 253 (73), 239 (87),
217 (42), 203 (30), 190 (23), 177 (8), 127 (8), 108 (11), 96 (13).
HRMS (ESI): m/z [M + H]+ calcd for C15H12ClN2: 255.06835;
found: 255.06841.
7-Chloro-5-(3,5-dimethylphenyl)-1,6-naphthyridine (3b)
Following GP1 using 1 (0.199 g, 1 mmol), 2b (0.194 g, 1.3 equiv),
Pd(PPh3)4 (0.058 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 8 mL) gave 3b (0.214 g, 80%) as a light-yellow
solid; mp 155–159 °C.
IR (ATR): 3073 (w), 2953 (w), 2860 (w), 2726 (w), 1597 (m), 1552
(s), 1519 (w), 1494 (w), 1462 (m), 1429 (m), 1343 (m), 1298 (s),
1240 (w), 1164 (m), 1096 (w), 1076 (s), 975 (m), 904 (m), 879 (m),
849 (s), 822 (m), 772 (m), 709 (m), 601 cm–1 (m).
1H NMR (250.13 MHz, CDCl3): δ = 2.30 (s, 6 H, 2 CH3), 7.05 (s, 1
H, HAr), 7.16 (s, 2 H, HAr), 7.34 (dd, J = 8.5, 4.1 Hz, 1 H, HAr), 7.84
(s, 1 H, HAr), 8.29–8.34 (m, 1 H, HAr), 8.94 (dd, J = 4.3, 1.7 Hz, 1
H, HAr).
Figure 4 ORTEP view of the crystal structure of 5c
less electron-deficient
13C NMR (62.89 MHz, CDCl3): δ = 21.3 (2 CH3), 120.3 (CH), 120.8
(C), 122.2 (CH), 127.8 (2 CH), 131.2 (CH), 136.3 (CH), 136.9 (C),
138.2 (2 C), 148.2 (C), 152.8 (C), 155.2 (CH), 162.5 (C).
Cl
N
N
GC-MS (EI, 70 eV): m/z (%) = 268 (M+, 75), 255 (32), 253 (100),
231 (19), 217 (26), 190 (13), 163 (4), 139 (3).
HRMS (ESI): m/z [M + H]+ calcd for C16H14ClN2: 269.084; found:
269.08434.
Cl
more electron-deficient
Figure 5 Possible explanation for the site-selectivity of cross-cou-
pling reactions of 1
7-Chloro-5-(2-methoxyphenyl)-1,6-naphthyridine (3c)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2c (0.099 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3c (0.100 g, 74%) as a white solid; mp
159–161 °C.
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. Chemicals were purchased from Aldrich.
IR (ATR): 3322 (br), 2989 (w), 2830 (w), 1603 (m), 1582 (w), 1553
(m), 1492 (w), 1432 (m), 1372 (m), 1347 (w), 1303 (m), 1238 (m),
1110 (m), 1020 (s), 858 (m), 746 (s), (m), 601 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 3.62 (s, 3 H, OCH3), 6.97 (d,
3J = 8.5 Hz, 1 H, HAr), 7.05 (dt, J = 7.6, 0.9 Hz, 1 H, HAr), 7.31–7.37
(m, 2 H, HAr), 7.39–7.45 (m, 1 H, HAr), 7.91–7.97 (m, 2 H, HAr),
8.97 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 55.5 (OCH3), 111.1 (CH), 120.8
(CH), 121.1 (CH), 122.0 (C), 122.1 (CH), 126.3 (C), 131.1 (CH),
131.5 (CH), 136.7 (CH), 148.4 (C), 152.0 (C), 155.2 (CH), 156.8
(C), 160.5 (C).
GC-MS (EI, 70 eV): m/z (%) = 270 (M+, 70), 269 (76), 253 (69), 241
(36), 234 (100), 203 (62), 191 (17), 176 (24), 165 (62), 151 (16),
102 (28).
5-Aryl-7-chloro-1,6-naphthyridines 3a–l; General Procedure 1
A soln of 1 (1.0 mmol), arylboronic acid 2 (1.3 equiv), 2 M K2CO3
(1 mL per cross coupling), and Pd(PPh3)4 (5 mol%) in 1,4-dioxane–
toluene (1:1, 8 mL) was heated at 70 °C for 8 h. After cooling to r.t.,
H2O was added and the mixture was extracted with CH2Cl2. The or-
ganic layer was dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by column chromatography (gradient n-
heptane–EtOAc).
HRMS (ESI): m/z [M + H]+ calcd for C15H12ClN2O: 271.06327;
found: 271.06347.
7-Chloro-5-(p-tolyl)-1,6-naphthyridine (3a)
Following GP1 using 1 (0.199 g, 1 mmol), 2a (0.176 g, 1.3 equiv),
Pd(PPh3)4 (0.058 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 8 mL) gave 3a (0.178 g, 70%) as a white solid; mp
138–141 °C.
7-Chloro-5-(4-fluorophenyl)-1,6-naphthyridine (3d)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2d (0.09 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3d (0.07 g, 54%) as a white solid; mp
162–164 °C.
IR (ATR): 3129 (w), 3021 (w), 2862 (w), 1914 (w), 1738 (w), 1610
(w), 1549 (s), 1466 (w), 1378 (w), 1340 (m), 1294 (m), 1182 (m),
1163 (m), 1112 (m), 1068 (s), 1043 (m), 970 (m), 880 (m), 867 (s),
IR (ATR): 3116 (w), 3054 (w), 1895 (w), 1597 (m), 1577 (w), 1562
(m), 1507 (s), 1434 (w), 1381 (w), 1367 (m), 1327 (m), 1220 (s),
Synthesis 2012, 44, 2255–2263
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Cross-Coupling Reactions of 5,7-Dichloro-1,6-naphthyridine
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1155 (m), 968 (m), 881 (m), 833 (s), 771 (m), 729 (m), 575 (m), 528
cm–1 (s).
ane–toluene (1:1, 8 mL) gave 3g (0.18 g, 70%) as a brown solid; mp
105–107 °C.
1H NMR (300.13 MHz, CDCl3): δ = 7.16–7.21 (m, 2 H, HAr), 7.41
(dd, J = 8.7, 4.3 Hz, 1 H, HAr), 7.60–7.65 (m, 2 H, HAr), 7.92 (s, 1
H, HAr), 8.30–8.34 (m, 1 H, HAr), 9.02 (dd, J = 4.2, 1.5 Hz, 1 H, HAr).
IR (ATR): 3066 (w), 2992 (w), 2858 (w), 1600 (m), 1556 (s), 1479
(w), 1368 (m), 1303 (s), 1063 (m), 1034 (m), 972 (m), 864 (s), 768
(s), 736 (m), 603 cm–1 (m).
13C NMR (75.46 MHz, CDCl3): δ = 115.9 (d, 2JCF = 22.0 Hz, 2 CH),
120.7 (CH), 122.5 (CH), 122.6 (C), 132.1 (d, 3JCF = 8.3 Hz, 2 CH),
133.2 (d, 4JCF = 3.3 Hz, C), 135.8 (CH), 148.4 (C), 152.9 (C), 155.4
(CH), 160.8 (C), 163.7 (d, 1JCF = 250.3 Hz, C).
19F NMR (282.40 MHz, CDCl3): δ = –111.04 (ArF).
GC-MS (EI, 70 eV): m/z (%) = 258 (M+, 100), 257 (89), 221 (55),
195 (22), 169 (12), 144 (3), 131 (4), 111 (12), 98 (10).
HRMS (ESI): m/z [M + H]+ calcd for C14H9ClFN2: 259.04328;
found: 259.04323.
1H NMR (250.13 MHz, CDCl3): δ = 1.99 (s, 3 H, CH3), 7.19–7.34
(m, 5 H, HAr), 7.81–7.90 (m, 2 H, HAr), 8.96 (dd, J = 4.3, 1.9 Hz, 1
H, HAr).
13C NMR (250.13 MHz, CDCl3): δ = 19.8 (CH3), 120.7 (CH), 121.6
(C), 122.5 (CH), 125.8 (CH), 129.3 (CH), 129.7 (CH), 130.6 (CH),
135.9 (CH), 136.3 (C), 148.2 (C), 152.3 (C), 155.5 (CH), 156.3 (C),
162.8 (C).
GC-MS (EI, 70 eV): m/z (%) = 254 (M+, 30), 253 (100), 217 (21),
190 (14), 108 (9).
HRMS (ESI): m/z [M + H]+ calcd for C15H12ClN2: 255.06835;
7-Chloro-5-(2,3,4-trimethoxyphenyl)-1,6-naphthyridine (3e)
Following GP1 using 1 (0.199 g, 1 mmol), 2e (0.276 g, 1.3 equiv),
Pd(PPh3)4 (0.058 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 8 mL) gave 3e (0.221 g, 67%) as a white solid; mp
140 °C.
found: 255.06796.
7-Chloro-5-(4-chlorophenyl)-1,6-naphthyridine (3h)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2h (0.1 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3h (0.045 g, 33%) as a light-yellow
solid; mp 150–152 °C.
IR (ATR): 3005 (w), 2955 (w), 2839 (w), 1601 (m), 1555 (s), 1494
(m), 1469 (m), 1435 (w), 1373 (m), 1300 (s), 1225 (m), 1100 (s),
1072 (s), 1023 (m), 976 (m), 877 (m), 770 (m), 597 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 3.53 (s, 3 H, OCH3), 3.87 (s, 3
H, OCH3), 3.88 (s, 3 H, OCH3), 6.77 (d, J = 8.5 Hz, 1 H, HAr), 7.09
(d, J = 8.5 Hz, 1 H, HAr), 7.35 (dd, J = 8.5, 4.2 Hz, 1 H, HAr), 7.91
(s, 1 H, HAr), 8.03–8.07 (m, 1 H, HAr), 8.97 (dd, J = 4.2, 1.7 Hz, 1
H, HAr).
IR (ATR): 3076 (w), 2923 (w), 2852 (w), 1602 (m), 1563 (w), 1551
(m), 1464 (m), 1402 (w), 1304 (m), 1264 (m), 1074 (s), 1013 (m),
966 (m), 875 (m), 835 (s), 771 (s), 745 (m), 603 (m), 586 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 7.39–7.48 (m, 3 H, HAr), 7.55–
7.59 (m, 2 H, HAr), 7.92 (s, 1 H, HAr), 8.28–8.32 (m, 1 H, HAr), 9.01
(dd, J = 4.0, 1.3 Hz, 1 H, HAr).
13C NMR (75.46 MHz, CDCl3): δ = 56.2 (OCH3), 61.1 (OCH3), 61.6
(OCH3), 107.8 (CH), 120.7 (CH), 121.9 (C), 122.2 (CH), 124.3 (C),
125.9 (CH), 136.8 (CH), 142.1 (C), 148.3 (C), 151.6 (C), 152.2 (C),
155.1 (C), 155.3 (CH), 159.9 (C).
GC-MS (EI, 70 eV): m/z (%) = 330 (M+, 100), 329 (49), 313 (53),
294 (90), 279 (84), 268 (28), 257 (22), 251 (21), 241 (12), 229 (54),
215 (40), 165 (50), 139 (27).
13C NMR (75.46 MHz, CDCl3): δ = 120.7 (C), 120.9 (CH), 122.6
(CH), 128.9 (2 CH), 131.4 (2 CH), 135.5 (C), 135.6 (CH), 136.1
(C), 148.5 (C), 152.9 (C), 155.5 (CH), 160.6 (C).
GC-MS (EI, 70 eV): m/z (%) = 274 (M+, 100), 273 (69), 239 (74),
203 (43), 176 (22), 150 (11), 119 (10).
HRMS (ESI): m/z [M + H]+ calcd for C14H9Cl2N2: 275.01373;
found: 275.01322.
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClN2O3: 331.0844;
7-Chloro-5-[4-(trifluoromethyl)phenyl]-1,6-naphthyridine (3i)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2i (0.123 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3i (0.100 g, 65%) as a white solid; mp
151–153 °C.
found: 331.08454.
7-Chloro-5-(2,3-dimethoxyphenyl)-1,6-naphthyridine (3f)
Following GP1 using 1 (0.199 g, 1 mmol), 2f (0.24 g, 1.3 equiv),
Pd(PPh3)4 (0.058 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 8 mL) gave 3f (0.288 g, 96%) as a white solid; mp
133–135 °C.
IR (ATR): 3118 (w), 3053 (m), 2931 (w), 2849 (w), 1603 (m), 1555
(s), 1519 (w), 1470 (m), 1410 (m), 1322 (s), 1176 (m), 1165 (m),
1107 (s), 1062 (s), 1016 (m), 971 (m), 880 (m), 841 (m), 771 (m),
618 (m), 606 cm–1 (m).
1H NMR (300.13 MHz, CDCl3):δ = 7.41 (dd, J = 8.7, 4.3 Hz, 1 H,
HAr), 7.73 (s, 4 H, HAr), 7.93 (s, 1 H, HAr), 8.26 (d, J = 8.5 Hz, 1 H,
HAr), 9.02 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
IR (ATR): 3345 (m), 3333 (m), 2999 (w), 2838 (w), 1603 (w), 1556
(m), 1468 (s), 1427 (m), 1370 (w), 1259 (s), 1209 (m), 1087 (s),
1031 (m), 982 (s), 859 (m), 795 (m), 749 (s), 696 cm–1 (m).
1H NMR (250.13 MHz, CDCl3): δ = 3.52 (s, 3 H, OCH3), 3.92 (s, 3
H, OCH3), 6.98–7.08 (m, 2 H, HAr), 7.16–7.26 (m, 1 H, HAr), 7.37
(dd, J = 8.5, 4.1 Hz, 1 H, HAr), 7.97 (s, 1 H, HAr), 8.05–8.10 (m, 1
H, HAr), 9.01 (dd, J = 4.3, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 55.9 (OCH3), 61.4 (OCH3),
113.6 (CH), 120.9 (CH), 121.8 (C), 122.3 (CH), 122.8 (CH), 124.6
(CH), 131.7 (C), 136.8 (CH), 146.8 (C), 148.1 (C), 151.9 (C), 152.7
(C), 155.4 (CH), 159.9 (C).
MS GC-MS (EI, 70 eV): m/z (%) = 300 (M+, 76), 299 (64), 285 (62),
283 (100), 271 (33), 264 (30), 257 (20), 246 (14), 239 (33), 229
(14), 221 (26), 213 (29), 193 (22), 177 (25), 165 (67), 152 (27), 125
(12), 102 (14).
13C NMR (75.46 MHz, CDCl3): δ = 120.7 (C), 121.4 (CH), 122.7
1
3
(CH), 123.9 (q, JCF = 271.3 Hz, CF3), 125.7 (q, JCF = 3.8 Hz, 2
CH), 130.5 (2 CH), 131.6 (q, 2JCF = 32.5 Hz, C), 135.3 (CH), 140.5
(C), 148.5 (C), 152.8 (C), 155.6 (CH), 160.2 (C).
19F NMR (282.40 MHz, CDCl3): δ = –62.74 (ArCF3).
GC-MS (EI, 70 eV): m/z (%) = 308 (M+, 100), 307 (67), 271 (43),
239 (48), 203 (26), 177 (10), 126 (4), 102 (5), 88 (4), 75 (13), 51 (5),
39 (1).
HRMS (ESI): m/z [M + H]+ calcd for C15H9ClF3N2: 309.04009;
found: 309.03998.
HRMS (ESI): m/z [M + H]+ calcd for C16H14ClN2O2: 301.07383;
found: 301.07366.
7-Chloro-5-(4-methoxyphenyl)-1,6-naphthyridine (3j)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2j (0.099 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3j (0.106 g, 79%) as a white solid; mp
144–146 °C.
7-Chloro-5-(o-tolyl)-1,6-naphthyridine (3g)
Following GP1 using 1 (0.199 g, 1 mmol), 2g (0.176 g, 1.3 equiv),
Pd(PPh3)4 (0.058 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
© Georg Thieme Verlag Stuttgart · New York
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2260
I. Ali et al.
PAPER
IR (ATR): 3088 (w), 2974 (w), 2844 (w), 1600 (s), 1574 (w), 1513
(s), 1488 (w), 1467 (m), 1380 (m), 1339 (m), 1250 (s), 1174 (m),
1068 (m), 1021 (s), 866 (m), 834 (s), 784 (m), 577 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 6.98 (d,
3J = 8.9 Hz, 2 H, HAr), 7.36 (dd, J = 8.7, 4.2 Hz, 1 H, HAr), 7.56 (d,
3J = 8.9 Hz, 2 H, HAr), 7.84 (s, 1 H, HAr), 8.35–8.38 (m, 1 H, HAr),
8.97 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 55.5 (OCH3), 114.1 (2 CH),
119.9 (CH), 120.7 (C), 122.2 (CH), 129.6 (C), 131.6 (2 CH), 136.2
(CH), 148.3 (C), 152.9 (C), 155.1 (CH), 160.9 (C), 161.6 (C).
added and the mixture was extracted with CH2Cl2. The organic lay-
er was dried (Na2SO4), filtered, and concentrated in vacuo. The res-
idue was purified by column chromatography (gradient n-heptane–
EtOAc).
5,7-Bis(2-methoxyphenyl)-1,6-naphthyridine (5a)
Following GP2 using 1 (0.1 g, 0.5 mmol), 4a (0.19 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5a (0.122 g, 71%) as a light-yellow solid; mp 156–158
°C.
IR (ATR): 3067 (w), 2922 (w), 2834 (w), 1597 (m), 1571 (m), 1518
(w), 1488 (m), 1330 (m), 1281 (s), 1235 (s), 1164 (m), 1015 (s), 966
(m), 771 (m), 751 (s), 655 cm–1 (m).
GC-MS (EI, 70 eV): m/z (%) = 270 (M+, 100), 255 (16), 239 (46),
227 (34), 203 (14), 192 (27), 164 (26).
1H NMR (300.13 MHz, CDCl3): δ = 3.62 (s, 3 H, OCH3), 3.87 (s, 3
H, OCH3), 6.95–7.09 (m, 4 H, HAr), 7.27–7.33 (m, 2 H, HAr), 7.37–
7.46 (m, 2 H, HAr), 7.92–7.96 (m, 1 H, HAr), 8.01 (dd, J = 7.6, 1.7
Hz, 1 H, HAr), 8.50 (s, 1 H, HAr), 8.97 (dd, J = 4.3, 1.9 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 55.4 (OCH3), 55.5 (OCH3),
111.1 (CH), 111.3 (CH), 120.9 (CH), 121.1 (CH), 121.5 (CH),
121.6 (C), 121.9 (CH), 128.1 (C), 128.5 (C), 129.8 (CH), 130.4
(CH), 131.7 (CH), 131.8 (CH), 136.3 (CH), 150.9 (C), 152.1 (C),
154.2 (CH), 157.1 (C), 157.4 (C), 158.9 (C).
GC-MS (EI, 70 eV): m/z (%) = 342 (M+, 100), 341 (79), 311 (27),
297 (25), 281 (26), 237 (17), 180 (14).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O2: 343.1441; found:
343.1446.
HRMS (ESI): m/z [M + H]+ calcd for C15H12ClN2O: 271.06327;
found: 271.06363.
7-Chloro-5-(4-ethylphenyl)-1,6-naphthyridine (3k)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2k (0.097 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3k (0.107 g, 79%) as a light-brown
heavy oil.
IR (ATR): 3028 (w), 2962 (m), 2870 (w), 1914 (w), 1726 (w), 1599
(s), 1548 (s), 1513 (w), 1467 (m), 1427 (w), 1366 (m), 1342 (m),
1300 (m), 1179 (m), 1074 (s), 970 (s), 879 (s), 857 (m), 838 (s), 769
(m), 618 (m), 602 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 1.19 (t, J = 7.6 Hz, 3 H, CH3),
2.64 (q, J = 7.4, 14.9 Hz, 2 H, CH2), 7.26 (d, 3J = 7.9 Hz, 2 H, HAr),
7.32 (dd, J = 8.7, 4.2 Hz, 1 H, HAr), 7.49 (d, 3J = 8.3 Hz, 2 H, HAr),
7.83 (s, 1 H, HAr), 8.32–8.35 (m, 1 H, HAr), 8.93 (dd, J = 4.2, 1.7 Hz,
1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 15.5 (CH3), 28.8 (CH2), 120.2
(CH), 120.7 (C), 122.2 (CH), 128.2 (2 CH), 130.1 (2 CH), 134.5
(C), 136.2 (CH), 146.1 (C), 148.4 (C), 152.9 (C), 155.2 (CH), 162.1
(C).
5,7-Di(p-tolyl)-1,6-naphthyridine (5b)
Following GP2 using 1 (0.1 g, 0.5 mmol), 4b (0.169 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5b (0.115 g, 74%) as a light-yellow solid; mp 112–114
°C.
IR (ATR): 3128 (w), 3014 (w), 2917 (w), 2857 (w), 2730 (w), 1911
(w), 1599 (m), 1656 (s), 1513 (m), 1453 (w), 1365 (m), 1181 (m),
968 (m), 877 (m), 817 (s), 766 (s), 721 cm–1 (s).
GC-MS (EI, 70 eV): m/z (%) = 268 (M+, 83), 267 (48), 253 (23), 239
1H NMR (250.13 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 2.37 (s, 3
H, CH3), 7.21 (d, 3J = 8.1 Hz, 2 H, HAr), 7.25–7.29 (m, 3 H, HAr),
7.58 (d, 3J = 8.1 Hz, 2 H, HAr), 8.07 (d, 3J = 8.3 Hz, 2 H, HAr), 8.19
(s, 1 H, HAr), 8.30–8.34 (m, 1 H, HAr), 8.92 (dd, J = 4.2, 1.7 Hz, 1
H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 21.3 (CH3), 21.4 (CH3), 115.9
(CH), 120.7 (C), 121.5 (CH), 127.2 (2 CH), 129.2 (2 CH), 129.5 (2
CH), 130.2 (2 CH), 135.9 (CH), 136.0 (C), 139.0 (C), 139.1 (2 C),
152.5 (C), 153.9 (C), 154.3 (CH), 160.9 (C).
(100), 216 (15), 190 (14), 151 (5).
HRMS (ESI): m/z [M + H]+ calcd for C16H14ClN2: 269.084; found:
269.08427.
5-(4-tert-Butylphenyl)-7-chloro-1,6-naphthyridine (3l)
Following GP1 using 1 (0.1 g, 0.5 mmol), 2l (0.116 g, 1.3 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (1 mL), and 1,4-diox-
ane–toluene (1:1, 4 mL) gave 3l (0.1 g, 67%) as a white solid; mp
116–118 °C.
IR (ATR): 3069 (w), 2962 (m), 2867 (w), 1731 (w), 1600 (s), 1562
(s), 1548 (s), 1514 (w), 1467 (s), 1404 (w), 1362 (m), 1299 (m),
1264 (m), 1122 (m), 1070 (s), 971 (m), 880 (m), 865 (m), 836 (s),
774 (m), 617 (m), 601 (s), 539 cm–1 (m).
GC-MS (EI, 70 eV): m/z (%) = 310 (M+, 100), 309 (89), 295 (59),
266 (3), 217 (5), 190 (7), 147 (11).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.15482; found:
311.15442.
1H NMR (300.13 MHz, CDCl3): δ = 1.30 (s, 9 H, 3 CH3), 7.36 (dd,
J = 8.7, 4.2 Hz, 1 H, HAr), 7.47 (d, 3J = 8.7 Hz, 2 H, HAr), 7.53 (d,
3J = 8.7 Hz, 2 H, HAr), 7.86 (s, 1 H, HAr), 8.37–8.41 (m, 1 H, HAr),
8.97 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 31.3 (3 CH3), 34.8 (C), 120.2
(CH), 120.8 (C), 122.2 (CH), 125.7 (2 CH), 129.9 (2 CH), 134.3
(C), 136.3 (CH), 148.4 (C), 152.8 (C), 152.9 (C), 155.2 (CH), 162.1
(C).
GC-MS (EI, 70 eV): m/z (%) = 296 (M+, 32), 281 (100), 239 (12),
205 (6), 177 (4), 127 (4), 108 (7).
HRMS (ESI): m/z [M + H]+ calcd for C18H18ClN2: 297.1153; found:
5,7-Bis(3,5-dimethylphenyl)-1,6-naphthyridine (5c)
Following GP2 using 1 (0.1 g, 0.5 mmol), 4c (0.186 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5c (0.16 g, 94%) as a light-yellow solid; mp 174–176 °C.
IR (ATR): 3034 (w), 2913 (w), 2859 (w), 1596 (m), 1562 (m), 1494
(w), 1039 (m), 860 (m), 848 (s), 775 (m), 712 (m), 688 cm–1 (s).
1H NMR (300.13 MHz, CDCl3): δ = 2.32 (s, 6 H, 2 CH3), 2.33 (s, 6
H, 2 CH3), 6.96 (s, 1 H, HAr), 7.06 (s, 1 H, HAr), 7.25–7.29 (m, 3 H,
HAr), 7.76 (s, 2 H, HAr), 8.19 (s, 1 H, HAr), 8.26–8.30 (m, 1 H, HAr),
8.94 (dd, J = 4.3, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 21.4 (2 CH3), 21.5 (2 CH3),
116.7 (CH), 120.9 (C), 121.6 (CH), 125.2 (2 CH), 127.9 (2 CH),
130.7 (CH), 130.8 (CH), 135.9 (CH), 138.1 (2 C), 138.3 (2 C),
138.7 (C), 138.9 (2 C), 154.3 (C), 154.4 (CH), 161.4 (C).
297.11525.
5,7-Diaryl-1,6-naphthyridines 5a–i; General Procedure 2
A soln of 1 (1.0 mmol), arylboronic acid 4 (2.5 equiv), 2 M K2CO3
(2 mL), and Pd(PPh3)4 (5 mol%) in 1,4-dioxane (8 mL) was heated
at 110 °C for 12 h in a pressure tube. After cooling to r.t., H2O was
Synthesis 2012, 44, 2255–2263
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Cross-Coupling Reactions of 5,7-Dichloro-1,6-naphthyridine
2261
GC-MS (EI, 70 eV): m/z (%) = 338 (M+, 100), 337 (83), 323 (76),
307 (6), 292 (3), 231 (3).
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2: 339.18558; found:
339.18594.
13C NMR (75.46 MHz, CDCl3): δ = 56.1 (OCH3), 56.2 (OCH3), 60.9
(OCH3), 61.1 (2 OCH3), 61.5 (OCH3), 107.6 (CH), 107.7 (CH),
120.7 (CH), 121.5 (C), 121.6 (CH), 125.8 (CH), 125.9 (C), 126.0
(CH), 126.6 (C), 136.3 (CH), 142.1 (C), 142.6 (C), 151.5 (C), 151.8
(C), 152.0 (C), 152.5 (C), 154.3 (C), 154.4 (CH), 154.5 (C), 158.4
(C).
5,7-Bis(4-ethylphenyl)-1,6-naphthyridine (5d)
GC-MS (EI, 70 eV): m/z (%) = 462 (M+, 100), 447 (54), 431 (23),
415 (11), 401 (15), 387 (12), 331 (6), 255 (8), 224 (24), 194 (20),
165 (15), 151 (20).
Following GP2 using 1 (0.1 g, 0.5 mmol), 4d (0.188 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5d (0.114 g, 67%) as a brown solid; mp 90–92 °C.
HRMS (ESI): m/z [M + H]+ calcd for C26H27N2O6: 463.18636;
found: 463.18707.
IR (ATR): 3069 (w), 3011 (w), 2961 (m), 2870 (w), 1914 (w), 1599
(s), 1582 (w), 1555 (s), 1513 (m), 1440 (w), 1365 (m), 1327 (m),
1181 (m), 971 (m), 833 (s), 767 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 1.19 (t, J = 4.5 Hz, 3 H, CH3),
1.23 (t, J = 4.3 Hz, 3 H, CH3), 2.59–2.71 (m, 4 H, CH2), 7.24 (d, 3J =
8.3 Hz, 2 H, HAr), 7.27–7.31 (m, 3 H, HAr), 7.61 (d, 3J = 8.3 Hz, 2
H, HAr), 8.10 (d, 3J = 8.3 Hz, 2 H, HAr), 8.21 (s, 1 H, HAr), 8.32–8.36
(m, 1 H, HAr), 8.93 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 15.5 (CH3), 15.6 (CH3), 28.7
(CH2), 28.8 (CH2), 115.9 (CH), 120.7 (C), 121.5 (CH), 127.3 (2
CH), 128.0 (2 CH), 128.3 (2 CH), 130.3 (2 CH), 135.9 (CH), 136.3
(C), 136.4 (C), 145.3 (C), 145.5 (C), 152.5 (C), 153.9 (C), 154.3
(CH), 160.9 (C).
5,7-Bis[4-(trifluoromethyl)phenyl]-1,6-naphthyridine (5g)
Following GP2 using 1 (0.100 g, 0.5 mmol), 4g (0.236 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5g (0.135 g, 64%) as a white solid; mp 180 °C.
IR (ATR): 3045 (w), 1931 (w), 1606 (m), 1566 (m), 1519 (w), 1320
(s), 1312 (s), 1156 (m), 1102 (s), 1065 (s), 1013 (m), 843 (s), 770
(m), 619 (m), 589 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 7.38 (dd, J = 8.5, 4.2 Hz, 1 H,
HAr), 7.64 (d, J = 8.1 Hz, 2 H, HAr), 7.73–7.81 (m, 4 H, HAr), 8.22–
8.27 (m, 3 H, HAr), 8.31 (s, 1 H, HAr), 9.01 (d, J = 2.3 Hz, 1 H, HAr).
GC-MS (EI, 70 eV): m/z (%) = 338 (M+, 100), 337 (63), 309 (70),
293 (10), 255 (1), 217 (3), 154 (16), 115 (2), 89 (2), 77 (2), 51 (1),
39 (1).
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2: 339.18558; found:
339.18577.
13C NMR (62.89 MHz, CDCl3): δ = 118.2 (CH), 121.2 (C), 122.7
1
1
(CH), 124.0 (q, JCF = 272.4 Hz, CF3), 124.2 (q, JCF = 271.9 Hz,
CF3), 125.6 (q, 3JCF = 4.1 Hz, 2 CH), 125.8 (q, 3JCF = 3.7 Hz, 2 CH),
127.4 (2 CH), 130.5 (2 CH), 131.0 (q, 2JCF = 32.5 Hz, C), 131.3 (q,
2JCF = 32.9 Hz, C), 135.0 (CH), 141.8 (q, 5JCF = 1.8 Hz, 2 C), 152.2
(2 C), 154.9 (CH), 159.7 (C).
19F NMR (282.40 MHz, CDCl3): δ = –62.59 (ArCF3), –62.64
(ArCF3).
GC-MS (EI, 70 eV): m/z (%) = 418 (M+, 100), 417 (76), 350 (10).
HRMS (ESI): m/z [M + H]+ calcd for C22H13F6N2: 419.09774;
5,7-Bis(4-tert-butylphenyl)-1,6-naphthyridine (5e)
Following GP2 using 1 (0.1 g, 0.5 mmol), 4e (0.222 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5e (0.156 g, 79%) as a light-yellow solid; mp 125–127 °C.
IR (ATR): 3037 (w), 2957 (s), 2865 (w), 1918 (w), 1602 (s), 1514
(w), 1468 (m), 1363 (m), 971 (m), 882 (m), 842 (s), 772 (m), 725
(m), 559 cm–1 (s).
1H NMR (300.13 MHz, CDCl3): δ = 1.28 (s, 9 H, 3 CH3), 1.32 (s, 9
H, 3 CH3), 7.28 (dd, J = 8.5, 4.3 Hz, 1 H, HAr), 7.44 (d, 3J = 8.7 Hz,
2 H, HAr), 7.49 (d, 3J = 8.5 Hz, 2 H, HAr), 7.64 (d, 3J = 8.7 Hz, 2 H,
HAr), 8.11 (d, 3J = 8.7 Hz, 2 H, HAr), 8.21 (s, 1 H, HAr), 8.36–8.39
(m, 1 H, HAr), 8.94 (dd, J = 4.3, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 31.3 (3 CH3), 31.4 (3 CH3), 34.7
(C), 34.8 (C), 115.9 (CH), 120.7 (C), 121.5 (CH), 125.5 (2 CH),
125.8 (2 CH), 127.1 (2 CH), 129.9 (2 CH), 135.9 (CH), 136.2 (2 C),
152.2 (C), 152.3 (C), 152.5 (C), 153.9 (C), 154.3 (CH), 160.9 (C).
found: 419.0984.
5,7-Bis(3-fluorophenyl)-1,6-naphthyridine (5h)
Following GP2 using 1 (0.100 g, 0.5 mmol), 4h (0.174 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5h (0.119 g, 74%) as a white solid; mp 162–164 °C.
IR (ATR): 3071 (w), 2975 (w), 1926 (w), 1852 (w), 1765 (w), 1589
(m), 1561 (s), 1488 (m), 1442 (w), 1368 (m), 1217 (m), 1138 (m),
940 (m), 872 (s), 812 (m), 773 (s), 717 (m), 678 (m), 661 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 6.98–7.04 (m, 1 H, HAr), 7.09–
7.17 (m, 1 H, HAr), 7.32–7.45 (m, 5 H, HAr), 7.85–7.89 (m, 2 H,
HAr), 8.22 (s, 1 H, HAr), 8.27–8.31 (m, 1 H, HAr), 8.97 (dd, J = 4.2,
1.5 Hz, 1 H, HAr).
GC-MS (EI, 70 eV): m/z (%) = 394 (M+, 64), 379 (100), 363 (21),
337 (16), 323 (4).
HRMS (ESI): m/z [M + H]+ calcd for C28H31N2: 395.24818; found:
395.24873.
13C NMR (62.89 MHz, CDCl3): δ = 114.2 (d, 2JCF = 22.9 Hz, CH),
116.0 (d, 2JCF = 21.1 Hz, CH), 116.2 (d, 2JCF = 21.1 Hz, CH), 117.2
(d, 2JCF = 22.4 Hz, CH), 117.4 (CH), 120.9 (C), 122.3 (CH), 122.6
(d, 4JCF = 2.7 Hz, CH), 125.9 (d, 4JCF = 2.7 Hz, CH), 130.1 (d, 3JCF
=
3
5,7-Bis(2,3,4-trimethoxyphenyl)-1,6-naphthyridine (5f)
Following GP2 using 1 (0.1 g, 0.5 mmol), 4f (0.265 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5f (0.114 g, 49%) as a brown heavy oil.
8.2 Hz, CH), 130.3 (d, JCF = 8.2 Hz, CH), 135.3 (CH), 140.6 (d,
3JCF = 7.3 Hz, C), 140.9 (d, 3JCF = 7.3 Hz, C), 152.3 (C), 152.4 (d,
4JCF = 2.3 Hz, C), 154.8 (CH), 159.5 (d, 4JCF = 2.3 Hz, C), 162.8 (d,
1JCF = 247.2 Hz, C), 163.4 (d, 1JCF = 245.4 Hz, C).
19F NMR (282.40 MHz, CDCl3): δ = –112.32 (ArF), –112.64 (ArF).
GC-MS (EI, 70 eV): m/z (%) = 318 (M+, 95), 317 (100), 290 (6), 269
IR (ATR): 2934 (w), 2836 (w), 2568 (w), 2248 (w), 1594 (s), 1563
(m), 1494 (m), 1460 (s), 1410 (m), 1366 (m), 1332 (m), 1287 (s),
1275 (m), 1224 (m), 1094 (s), 1080 (s), 1010 (m), 904 (m), 800 (m),
725 (s), 532 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 3.51 (s, 3 H, OCH3), 3.82 (s, 3
H, OCH3), 3.84 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H,
OCH3), 3.88 (s, 3 H, OCH3), 6.72 (d, J = 8.9 Hz, 1 H, HAr), 6.75 (d,
J = 8.7 Hz, 1 H, HAr), 7.14 (d, J = 8.5 Hz, 1 H, HAr), 7.29 (dd, J =
8.3, 4.2 Hz, 1 H, HAr), 7.69 (d, J = 8.7 Hz, 1 H, HAr), 8.01–8.04 (m,
1 H, HAr), 8.39 (s, 1 H, HAr), 8.95 (dd, J = 4.3, 1.89 Hz, 1 H, HAr).
(4), 221 (7).
HRMS (ESI): m/z [M + H]+ calcd for C20H13F2N2: 319.10413;
found: 319.10403.
5,7-Bis(4-methoxyphenyl)-1,6-naphthyridine (5i)
Following GP2 using 1 (0.1 g, 0.5 mmol), 4i (0.19 g, 2.5 equiv),
Pd(PPh3)4 (0.029 g, 0.05 equiv), 2 M K2CO3 (2 mL), 1,4-dioxane (4
mL) gave 5i (0.126 g, 73%) as a light-yellow solid; mp 125–127 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2255–2263

2262
I. Ali et al.
PAPER
IR (ATR): 3065 (w), 2959 (w), 2916 (m), 2838 (w), 2551 (w), 2038
(w), 1727 (w), 1600 (s), 1579 (w), 1561 (w), 1511 (s), 1465 (m),
1368 (m), 1244 (s), 1173 (s), 1023 (s), 969 (m), 826 (s), 787 (m),
765 (m), 581 (m), 552 (m), 529 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 3.79 (s, 3 H, OCH3), 3.83 (s, 3
H, OCH3), 6.95 (d, 3J = 8.9 Hz, 2 H, HAr), 7.01 (d, 3J = 8.9 Hz, 2 H,
HAr), 7.29 (dd, J = 8.5, 4.2 Hz, 1 H, HAr), 7.66 (d, 3J = 8.9 Hz, 2 H,
HAr), 8.13–8.16 (m, 3 H, HAr), 8.34–8.37 (m, 1 H, HAr), 8.93 (dd, J =
4.0, 1.3 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 55.3 (OCH3), 55.4 (OCH3),
113.9 (2 CH), 114.2 (2 CH), 115.0 (CH), 120.4 (C), 121.3 (CH),
128.6 (2 CH), 131.4 (C), 131.6 (2 CH), 135.9 (CH), 152.6 (2 C),
153.5 (2 C), 154.3 (CH), 160.4 (C), 160.6 (C).
13C NMR (75.46 MHz, CDCl3): δ = 21.3 (CH3), 56.2 (OCH3), 61.2
(OCH3), 61.7 (OCH3), 107.7 (CH), 116.4 (CH), 121.5 (CH), 121.9
(C), 125.9 (C), 126.0 (CH), 127.2 (2 CH), 129.5 (2 CH), 136.3 (C),
136.5 (CH), 139.0 (C), 142.2 (C), 151.7 (C), 151.9 (C), 154.1 (C),
154.5 (CH), 154.6 (C), 158.9 (C).
GC-MS (EI, 70 eV): m/z (%) = 386 (M+, 73), 385 (55), 371 (100),
355 (27), 339 (18), 325 (24), 295 (7), 269 (14), 221 (25), 186 (11),
142 (13), 128 (28), 91 (3), 75 (1), 51 (2), 39 (3).
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O3: 387.17032;
found: 387.17041.
7-(4-tert-Butylphenyl)-5-(2,3,4-trimethoxyphenyl)-1,6-naph-
thyridine (7c)
Following GP3 using 3e (0.1 g, 0.3 mmol), 6c (0.069 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), 1,4-dioxane (4
mL) gave 7c (0.07 g, 54%) as a light-yellow heavy oil.
GC-MS (EI, 70 eV): m/z (%) = 342 (M+, 100), 341 (61), 311 (21),
299 (15), 255 (16).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O2: 343.1441; found:
343.1441.
IR (ATR): 3053 (w), 2958 (m), 2866 (w), 1737 (w), 1601 (s), 1564
(m), 1513 (w), 1497 (m), 1462 (s), 1409 (m), 1366 (m), 1270 (m),
1233 (m), 1094 (s), 982 (m), 840 (m), 692 cm–1 (m).
1H NMR (250.13 MHz, CDCl3): δ = 1.29 (s, 9 H, 3 CH3), 3.53 (s, 3
H, OCH3), 3.88 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 6.77 (d, J = 8.7
Hz, 1 H, HAr), 7.15 (d, J = 8.5 Hz, 1 H, HAr), 7.27–7.32 (m, 1 H,
HAr), 7.45 (d, J = 8.5 Hz, 2 H, HAr), 8.01–8.05 (m, 1 H, HAr), 8.09
(d, J = 8.4 Hz, 2 H, HAr), 8.25 (s, 1 H, HAr), 8.95 (dd, J = 4.3, 1.7
Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 31.3 (3 CH3), 34.7 (C), 56.2
(OCH3), 61.1 (OCH3), 61.7 (OCH3), 107.7 (CH), 116.4 (CH), 121.5
(CH), 121.8 (C), 125.8 (2 CH), 125.9 (C), 126.0 (CH), 127.0 (2
CH), 136.2 (C), 136.5 (CH), 142.1 (C), 151.7 (C), 151.8 (C), 152.2
(C), 154.1 (C), 154.4 (CH), 154.6 (C), 158.9 (C).
5-Aryl1-7-aryl2-1,6-naphthyridines 7a–d; General Procedure 3
A soln of 3e,f (1.0 mmol), arylboronic acid 6 (1.3 equiv), 2 M
K2CO3 (1 mL), and Pd(PPh3)4 (5 mol%) in 1,4-dioxane (8 mL) was
heated at 110 °C for 8 h in a pressure tube. After cooling to r.t., H2O
was added and the mixture was extracted with CH2Cl2. The organic
layer was dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by column chromatography (gradient n-hep-
tane–EtOAc).
7-(3,5-Dimethylphenyl)-5-(2,3,4-trimethoxyphenyl)-1,6-naph-
thyridine (7a)
Following GP3 using 3e (0.1 g, 0.3 mmol), 6a (0.058 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), 1,4-dioxane (4
mL) gave 7a (0.108 g, 89%) as a light-yellow solid; mp 141–143
°C.
GC-MS (EI, 70 eV): m/z (%) = 428 (M+, 62), 413 (100), 397 (25),
367 (20).
HRMS (ESI): m/z [M + H]+ calcd for C27H29N2O3: 429.21727;
found: 429.21749.
IR (ATR): 2916 (w), 2839 (w), 1598 (m), 1562 (m), 1494 (w), 1460
(m), 1366 (m), 1279 (m), 1225 (m), 1094 (s), 1034 (m), 980 (m),
875 (m), 850 (m), 771 (m), 674 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 2.34 (s, 6 H, 2 CH3), 3.52 (s, 3
H, OCH3), 3.89 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 6.80 (d, J = 8.5
Hz, 1 H, HAr), 6.99 (s, 1 H, HAr), 7.18 (d, J = 8.5 Hz, 1 H, HAr), 7.31
(dd, J = 8.5, 4.2 Hz, 1 H, HAr), 7.76 (s, 2 H, HAr), 8.02–8.05 (m, 1
H, HAr), 8.24 (s, 1 H, HAr), 8.96 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
13C NMR (75.46 MHz, CDCl3): δ = 21.5 (2 CH3), 56.2 (OCH3), 61.1
(OCH3), 61.6 (OCH3), 107.8 (CH), 117.1 (CH), 121.6 (CH), 121.9
(C), 125.2 (2 CH), 125.9 (C), 126.1 (CH), 130.7 (CH), 136.5 (CH),
138.3 (2 C), 139.1 (C), 142.1 (C), 151.7 (C), 151.8 (C), 154.4 (CH),
154.5 (C), 154.6 (C), 158.9 (C).
5-(2,3-Dimethoxyphenyl)-7-(o-tolyl)-1,6-naphthyridine (7d)
Following GP3 using 3f (0.1 g, 0.3 mmol), 6d (0.053 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), 1,4-dioxane (4
mL) gave 7d (0.06 g, 47%) as a light-yellow heavy oil.
IR (ATR): 3056 (w), 2929 (m), 2835 (w), 1601 (m), 1567 (s), 1463
(s), 1425 (m), 1366 (m), 1260 (m), 1075 (s), 984 (m), 884 (m), 766
(s), 728 (s), 587 cm–1 (m).
1H NMR (250.13 MHz, CDCl3): δ = 2.40 (s, 3 H, CH3), 3.43 (s, 3
H, OCH3), 3.87 (s, 3 H, OCH3), 6.98–7.04 (m, 2 H, HAr), 7.13 (d,
J = 7.9 Hz, 1 H, HAr), 7.22–7.25 (m, 3 H, HAr), 7.34 (dd, J = 8.5, 4.3
Hz, 1 H, HAr), 7.49–7.53 (m, 1 H, HAr), 7.97 (s, 1 H, HAr), 8.05–8.09
(m, 1 H, HAr), 8.98 (dd, J = 4.3, 1.7 Hz, 1 H, HAr).
13C NMR (62.89 MHz, CDCl3): δ = 20.6 (CH3), 55.9 (OCH3), 61.3
(OCH3), 113.1 (CH), 120.9 (CH), 121.4 (C), 122.0 (CH), 123.2
(CH), 124.5 (CH), 125.9 (CH), 128.4 (CH), 130.1 (CH), 130.8
(CH), 133.1 (C), 136.2 (C), 136.7 (CH), 140.1 (C), 146.9 (C), 150.9
(C), 152.7 (C), 154.6 (CH), 156.8 (C), 158.7 (C).
GC-MS (EI, 70 eV): m/z (%) = 400 (M+, 74), 399 (60), 385 (100),
383 (36), 353 (23), 339 (25), 283 (8), 255 (15), 235 (23), 192 (9).
HRMS (ESI): m/z [M + H]+ calcd for C25H25N2O3: 401.18597;
found: 401.18604.
7-(p-Tolyl)-5-(2,3,4-trimethoxyphenyl)-1,6-naphthyridine (7b)
Following GP3 using 3e (0.1 g, 0.3 mmol), 6b (0.053 g, 1.3 equiv),
Pd(PPh3)4 (0.017 g, 0.05 equiv), 2 M K2CO3 (1 mL), 1,4-dioxane (4
mL) gave 7b (0.109 g, 64%) as a light-brown solid; mp 137–139 °C.
GC-MS (EI, 70 eV): m/z (%) = 356 (M+, 98), 355 (100), 339 (18),
325 (21), 309 (17), 269 (9), 242 (13), 219 (16).
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2O2: 357.161; found:
357.16088.
IR (ATR): 3076 (w), 3016 (w), 2970 (w), 2839 (w), 1597 (m), 1513
(w), 1465 (m), 1408 (m), 1291 (m), 1234 (m), 1093 (s), 1053 (m),
1012 (m), 986 (m), 871 (m), 819 (s), 686 cm–1 (m).
1H NMR (300.13 MHz, CDCl3): δ = 2.34 (s, 3 H, CH3), 3.53 (s, 3
H, OCH3), 3.88 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 6.77 (d, J = 8.7
Hz, 1 H, HAr), 7.15 (d, J = 8.5 Hz, 1 H, HAr), 7.23 (d, J = 7.9 Hz, 2
H, HAr), 7.29 (dd, J = 8.5, 4.3 Hz, 1 H, HAr), 8.01–8.07 (m, 3 H, HAr),
8.23 (s, 1 H, HAr), 8.95 (dd, J = 4.2, 1.7 Hz, 1 H, HAr).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2012, 44, 2255–2263
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cross-Coupling Reactions of 5,7-Dichloro-1,6-naphthyridine
2263
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Synthesis 2012, 44, 2255–2263