Berman et al.
JOCArticle
relative to the N-bound rhodium complex 2. These results
are consistent with reports on the preparation and charac-
terization of (2-substituted)-pyridine- and quinoline-based
Os and Ir-NHC complexes wherein ortho-substitution was
necessary for obtaining the complexes.16 The requirement
for ortho-substitution is also consistent with our observa-
tions that the Rh-catalyzed intermolecular alkylation of
pyridines with alkenes only occurs when the pyridine sub-
strates are substituted at the ortho position.8a
neck in a silicone oil bath, heated at 165 °C for 24 h, and then
cooled to room temperature. The reaction mixture was transferred
to a 60 mL separatory funnel using 3 Â 5.0 mL of CH2Cl2 and -
2.5 mL of MeOH. The resulting solution was washed with satu-
rated NaHCO3 (1 Â 20 mL), and the aqueous layer was extracted
with CH2Cl2 (3 Â 10 mL). The organic extracts were combined,
washed with saturated NaCl (1 Â 20 mL), dried over Na2SO4,
filtered through glass wool, and concentrated to dryness under
reduced pressure. The crude product mixture was loaded onto a
Biotage samplet using a minimal amount of CH2Cl2 and MeOH
(ca. 0.5 mL). This solvent was removed by placing the samplet
under reduced pressure in a vacuum desiccator for ca. 15 min, and
the samplet was loaded into a Biotage SP1 system. Eluting with a
methanol/dichloromethane gradient calculated by the Biotage
instrument provided 0.0133 g, 49% yield of 1k as a pale yellow
powder: Rf (5% methanol/dichloromethane) 0.45; mp 275 °C
(decomp); 1H NMR (400.13 MHz, DMSO-d6) δ 11.87 (br s,
1 H), 8.48 (s, 1 H), 8.14-8.10 (m, 3 H), 8.06-8.03 (m, 1 H),
7.96-7.94 (m, 1 H), 7.83-7.81 (m, 1 H), 7.73-7.64 (m, 3 H),
7.38-7.35 (m, 1 H), 6.50 (s, 1 H); 13C {1H} NMR (100.61 MHz,
DMSO-d6) δ 176.7, 150.3, 141.1, 134.0, 133.0, 132.3, 132.0, 129.1,
129.1, 128.2, 128.0, 127.6, 127.5, 125.4, 125.2, 125.0, 123.8, 119.2,
108.2; HRMS-EI (m/z) calcd for C19H14NO 272.1070, observed
272.1072.
Conclusion
In summary, we have developed a Rh(I)-catalyzed strat-
egy for the direct arylation of azines. A variety of differen-
tially substituted aryl bromides and aroyl chlorides can be
used in this protocol, including chloro, fluoro, trifluoro-
methyl, ether, and ketone functionality. The heterocycle is
used directly without requiring any prefunctionalization.
This strategy represents an expeditious route to an important
class of arylated azines and for appropriate substrates should
be of broad utility.
Experimental Section
1-Methyl-3-(2-naphthyl)isoquinoline (1l). The reaction was
conducted with 1-methylisoquinoline (0.3432 g, 2.400 mmol),
2-bromonaphthalene (0.0828 g, 0.400 mmol), and 1.00 mL of
1,4-dioxane at 175 °C for 24 h. The crude mixture was purified
by flash chromatography using an ethyl acetate/hexanes gradi-
ent to provide 0.0236 g, 22% yield of 1l as a white powder:
Rf (10% ethyl acetate/hexanes) 0.50; mp 128 - 130 °C; 1H NMR
(400.13 MHz, CDCl3) δ 8.72 (s, 1 H), 8.33-8.30 (m, 1 H),
8.21-8.19 (m, 1 H), 8.12 (s, 1 H), 8.05-8.00 (m, 2 H), 7.95-7.92
(m, 2 H), 7.76-7.72 (m, 1 H), 7.66-7.61 (m, 1 H), 7.58-7.52
(m, 2 H), 3.14 (s, 3 H); 13C {1H} NMR (100.61 MHz, CDCl3) δ
158.7, 149.8, 137.1, 136.9, 133.7, 133.4, 130.1, 128.7, 128.4,
127.7, 127.7, 126.9, 126.7, 126.2, 126.2, 125.7, 124.8, 115.6,
22.8; HRMS-EI (m/z) calcd for C20H16N 270.1277, observed
270.1286.
2-(2-Naphthyl)-5,6-dimethylpyrazine (1m). The reaction was
conducted with 2,3-dimethylpyrazine (0.2594 g, 2.400 mmol),
2-bromonaphthalene (0.0828 g, 0.400 mmol), and 1.10 mL of
1,4-dioxane at 175 °C for 24 h. The crude mixture was purified
by flash chromatography using an ethyl acetate/hexanes gradi-
ent to provide 0.0153 g, 16% yield of 1m as a pale yellow powder:
Rf (10% ethyl acetate/hexanes) 0.20; mp 111-112 °C; 1H NMR
(400.13 MHz, CDCl3) δ 8.90 (s, 1 H), 8.52 (s, 1 H), 8.18-8.16
(m, 1 H), 8.01-7.92 (m, 3 H), 7.57-7.56 (m, 2 H), 2.70 (s, 3 H),
2.65 (s, 3 H); 13C {1H} NMR (100.61 MHz, CDCl3) δ 151.9,
150.6, 149.3, 138.5, 134.2, 133.7, 133.5, 128.7 (2 carbons), 127.7,
126.7, 126.5, 126.1, 124.1, 22.3, 21.8; HRMS-EI (m/z) calcd for
C16H15N2 235.1230, observed 235.1233.
2-(2-Naphthyl)-4,6-dimethylpyrimidine (1n). The reaction was
conducted with 4,6-dimethylpyrimidine (0.2594 g, 2.400 mmol),
2-bromonaphthalene (0.0828 g, 0.400 mmol), and 1.10 mL of
1,4-dioxane at 175 °C for 24 h. The crude mixture was purified
by flash chromatography using an ethyl acetate/hexanes gradi-
ent to provide 0.0205 g, 22% yield of 1n as a white powder:
Rf (10% ethyl acetate/hexanes) 0.40; mp 116-117 °C; 1H NMR
(400.13 MHz, CDCl3) δ 9.02 (s, 1 H), 8.61-8.59 (m, 1 H),
8.06-7.91 (m, 3 H), 7.57-7.54 (m, 2 H), 7.00 (s, 1 H), 2.63
(s, 6 H); 13C {1H} NMR (100.61 MHz, CDCl3) δ 166.9, 135.5,
134.6, 133.4, 129.2, 128.3, 128.1, 127.7, 126.9, 126.1, 125.4,
118.1, 24.3; HRMS-EI (m/z) calcd for C16H15N2 235.1230,
observed 235.1234.
General Procedure for the Catalytic Direct Arylation of Azines
with Aryl Bromides. To a 15 or 25 mL sealable flame- or oven-
dried Schlenk tube (Kontes No. 218710-0015 or 218710-0025)
containing a stir bar were added [RhCl(CO)2]2 (0.0078 g,
0.0200 mmol), the heterocycle (2.400 mmol), the aryl bromide
(0.400 mmol), and 1,4-dioxane (reaction solution diluted to a total
concentration of 0.30-0.80 M). The volume of the heterocycle is
not negligible at the concentrations used and must therefore be
included in the concentration calculation. The reaction vessel was
sealed, removed from the glovebox, submerged to the neck in a
silicone oil bath, heated at the indicated temperature with stirring
for 24 h, and then cooled to room temperature. The reaction
mixture was transferred to a 60 mL separatory funnel using 3 Â
5.0 mL of CH2Cl2 and 2.5 mL of MeOH. The resulting solution
was washed with saturated NaHCO3 (1Â 20 mL), and the aqueous
layer was extracted with CH2Cl2 (3 Â 10 mL). The organic extracts
were combined, washed with saturated NaCl (1 Â 20 mL), dried
over Na2SO4, filtered through glass wool, and concentrated to
dryness under reduced pressure. The crude product mixture was
loaded onto a Biotage samplet using a minimal amount of CH2Cl2
(ca. 0.5 mL). This solvent was removed by placing the samplet
under reduced pressure in a vacuum desiccator for ca. 15 min, and
the samplet was loaded into a Biotage SP1 system. Eluting with an
ethyl acetate/hexanes gradient calculated by the instrument from
the Rf of the product in a specified ethyl acetate/hexanes mixture
provided the desired product.
2-(3,5-Dimethylphenyl)quinoline (1h). The reaction was con-
ducted with quinoline (0.3100 g, 2.400 mmol), 1-bromo-3,5-
dimethylbenzene (0.0740 g, 0.400 mmol), and 1.0 mL of 1,4-
dioxane at 175 °C for 24 h. The crude mixture was purified by
flash chromatography using an ethyl acetate/hexanes gradient to
provide 0.0800 g, 86% yield of 1h as a clear, colorless oil: 1H NMR
(400.13 MHz, CDCl3) δ 8.34-8.12 (m, 2 H), 7.91-7.67 (m, 5 H),
7.49-7.45 (m, 1 H), 7.08 (br s, 1 H), 2.41 (s, 6 H); 13C {1H} NMR
(100.61 MHz, CDCl3) δ 157.9, 148.4, 139.8, 138.5, 136.7, 131.2,
129.8, 129.7, 127.6, 127.3, 126.3, 125.6, 119.4, 21.6; HRMS-EI
(m/z) calcd for C17H15N 233.1205, observed 233.1203.
2-(2-Naphthyl)-4-hydroxyquinoline (1k). To a 15 mL sealable
flame-dried Schlenk tube (Kontes No. 218710-0015) containing
a stir bar were added [RhCl(CO)2]2 (0.0038 g, 0.0100 mmol),
4-hydroxyquinoline (0.0436 g, 0.300 mmol), 2-bromonaphthalene
(0.0207 g, 0.100 mmol), and 0.33 mL of 1,4-dioxane. The reaction
vessel was sealed, removed from the glovebox, submerged to the
General Procedure for the Catalytic Direct Arylation of Azines
with Aroyl Chlorides. To a 15 or 25 mL sealable flame- or oven-
dried Schlenk tube (Kontes No. 218710-0015 or 218710-0025)
J. Org. Chem. Vol. 75, No. 22, 2010 7867