Successive substitution of halogen atoms in 4,6-dihaloquinolines in palladium-catalyzed reactions with amines and arylboronic acids

Article abstract of DOI:10.1007/s11172-005-0239-y

A procedure was developed for the synthesis of 4,6-diamino- and 4,6- or 6,4-arylaminoquinolines by palladium-catalyzed C-N- and/or C-C-cross-coupling of 6-bromo-4-chloroquinoline.

Full text of DOI:10.1007/s11172-005-0239-y

Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 215—219, January, 2005
215
Successive substitution of halogen atoms in 4,6ꢀdihaloquinolines
in palladiumꢀcatalyzed reactions with amines and arylboronic acids
ꢀ
I. P. Beletskaya, A. V. Tsvetkov, P. V. Tsvetkov, G. V. Latyshev, and N. V. Lukashev
Department of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Еꢀmail: beletska@org.chem.msu.ru
A procedure was developed for the synthesis of 4,6ꢀdiaminoꢀ and 4,6ꢀ or 6,4ꢀarylaminoꢀ
quinolines by palladiumꢀcatalyzed C—Nꢀ and/or C—Cꢀcrossꢀcoupling of 6ꢀbromoꢀ4ꢀ
chloroquinoline.
Key words: catalytic amination, 6ꢀbromoꢀ4ꢀchloroquinoline, Suzuki reaction,
crossꢀcoupling.
Earlier,1 we have developed a convenient procedure
Scheme 1
for the synthesis of 4,6ꢀdiarylquinolines, 4,6ꢀ and 6,4ꢀarylꢀ
alkynylquinolines, and 4,6ꢀdialkynylquinolines by the
oneꢀpot crossꢀcoupling reaction of 4,6ꢀdihaloquinolines
with arylboronic acids and terminal acetylenes. In the
present study, this approach was used to prepare 4,6ꢀdiꢀ
aminoquinolines, 6ꢀaminoꢀ4ꢀarylquinolines, and 4ꢀamiꢀ
noꢀ6ꢀarylquinolines, which are potentially biologically
active compounds (certain aminoquinoline derivatives are
known to possess antimalarial2 and antimicrobial3 activiꢀ
ties and can inhibit kinase4). The regioselective introducꢀ
tion of only one group by the crossꢀcoupling reaction can
be controlled by the nature of both the halogen atom and
the ligand in a palladium complex.
Amination of 6ꢀbromoꢀ4ꢀchloroquinoline (1)5 with a
small excess of morpholine was carried out in refluxing
dioxane in the presence of sodium tertꢀbutoxide and a
Reagents and conditions: 2 mol.% [Pd], ButONa, dioxane,
100 °C, 7 h.
2 mol.% palladium catalyst (Scheme 1, Table 1).
stitution was unambiguously determined from the results
of elemental analysis of product 2 and the 1H NMR specꢀ
troscopic data. All catalysts provide high selectivity of this
process. However, the yield of 6ꢀaminoꢀ4ꢀchloroquinoline
2 and the selectivity of the reaction are somewhat higher
in the presence of complexes with the ligands L1 and L2.
The use of 4 equiv. of morpholine and an increase in the
reaction time to 24 h resulted in the formation of diaminoꢀ
quinoline 3 as the major product (91% yield).
The possibility of amination at the chlorine atom alꢀ
lows for performing the successive oneꢀpot replacement
of both halogen atoms in 6ꢀbromoꢀ4ꢀchloroquinoline with
different amines (see Scheme 2). The second amine was
added to the reaction mixture after completion of the
replacement of the bromine atom with the first amine
(TLC control). Both reactions afforded diaminoquinolines
4 and 5 in high yields.
We used DPPF and BINAP, which are most comꢀ
monly used in amination,6 as the ligands. We also used
the ligands L1 and L2 exhibiting high activity in amination
and Suzuki arylation of aryl bromides.*
We found that this substrate is subjected to amination
predominantly at the bromine atom. The position of subꢀ
* O. V. Gusev, T. A. Peganova, A. M. Kalsin, N. V. Vologdin,
P. V. Petrovskii, K. A. Lyssenko, A. V. Tsvetkov, and I. P.
Beletskaya, Organometallics, 2005, submitted for publication.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 210—214, January, 2005.
1066ꢀ5285/05/5401ꢀ0215 © 2005 Springer Science+Business Media, Inc.

216
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Beletskaya et al.
Table 1. Ratio between monoꢀ and diamination products preꢀ
pared by catalytic amination of 6ꢀbromoꢀ4ꢀchloroquinoline with
morpholinea
Table 2. Catalytic arylation of 4ꢀchloroꢀ6ꢀ
morpholinoquinoline (2) with 4ꢀmethoxyꢀ
phenylboronic acid
Catalyst
Yieldb (%)
Catalyst
Yielda of 6 (%)
89 (86)b
2
3
Pd(dba)2 + BINAP
PdCl2(dppf)
PdCl2(L1)
PdCl2(L2)
Pd(PPh3)4
13
54
47
12
PdCl2(dppf)
PdCl2(L1)
PdCl2(L2)
85
93 (92)c
92
9
5
2
9
Pd(dba)2 + BINAP
84
1
a The H NMR spectroscopic data.
a
The ratio of 6ꢀbromoꢀ4ꢀchloroquinoline to morpholine
is 1 : 1.2.
b Preparative yield.
b The H NMR spectroscopic data.
1
c Preparative yield.
Scheme 3
Scheme 2
Reagents and conditions: 2 mol.% [Pd], K2CO3, dioxane, H2O,
100 °C, 24 h.
electronꢀdonating substituent. We succeeded in replacing
the chlorine atom in high yield only with the use of the
Pd(dba)2—BINAP catalytic system. It should be noted
that palladium complexes with BINAP are rarely used in
the Suzuki reaction.
Successive amination—arylation of 6ꢀbromoꢀ4ꢀ
chloroquinoline can be carried out in a oneꢀpot
fashion without isolation of an intermediate using the
Pd(dba)2/BINAP complex as the catalyst for both reacꢀ
tions (Scheme 4). For this purpose, it is necessary to add
arylboronic acid, water, and an additional amount of a
base to the reaction mixture after completion of the first
step (amination at the bromine atom). We used this
method for the synthesis of 4ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀ
morpholinoquinoline 6 and 6ꢀpiperidinoꢀ4ꢀ(4ꢀtolyl)ꢀ
quinoline 7 in rather high total yields (84 and 68%, reꢀ
spectively).
It is worthy of note that this approach makes it posꢀ
sible to exclude isolation of an intermediate and decreases
the consumption of the catalyst.
The halogen atoms in 6ꢀbromoꢀ4ꢀchloroquinoline (1)
can be replaced in another order, i.e., the aryl substituent
is initially introduced at position 6 by the Suzuki reaction
followed by the introduction of the amino group at posiꢀ
tion 4 (Scheme 5). The first step of this sequence, viz.,
Suzuki arylation, was carried out for two substrates, viz.,
Reagents and conditions: 2 mol.%, PdCl2(L1), ButONa, dioxane.
A combination of the C—Nꢀ and C—Cꢀcrossꢀcouꢀ
pling reactions of dihaloquinoline 1 is another example of
the synthetic potential of the methodology under considꢀ
eration. Its monoamination product 2 was used in the
Suzuki reaction with 4ꢀmethoxyphenylboronic acid in the
presence of palladium complexes (Scheme 3, Table 2).
Surprisingly, the Pd(PPh3)4 complex, which has been
earlier demonstrated1 to be an efficient catalyst for the
replacement of the chlorine atom in 6ꢀarylꢀ4ꢀchloroꢀ
quinolines by the Suzuki reaction, appeared to be essenꢀ
tially inactive in the case of 4ꢀchloroꢀ6ꢀmorpholinoꢀ
quinoline 2. A complex with DPPF also proved to be
inefficient, and even catalysts with the ligands L1 and L2
did not give satisfactory results. Apparently, this is associꢀ
ated with the deactivating effect of the amino group as an

Catalytic amination of dihaloquinolines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
217
Scheme 4
Reagents and conditions: 2 mol.%, Pd(dba)2/BINAP, dioxane.
Scheme 5
Reagents and conditions: a. 4ꢀMeOC6H4B(OH)2, Pd(PPh3)4, dioxane, H2O, K2CO3, 100 °C, 30 min; b. 4ꢀClC6H4B(OH)2, Pd(PPh3)4,
dioxane, H2O, K2CO3, 100 °C, 30 min; c. morpholine, [Pd] (see Table 3), ButONa, dioxane, 100 °C, 24 h; d. piperidine, PdCl2(L2),
ButONa, dioxane, 100 °C, 24 h.
4ꢀmethoxyphenylboronic acid and 4ꢀchlorophenylboronic
acid. The reactions were performed according to our proꢀ
cedure1 with the use of Pd(PPh3)4 and gave the products
in high yields.
Study of the influence of the nature of the catalyst on
amination of 4ꢀchloroꢀ6ꢀ(4ꢀmethoxyphenyl)quinoline 8
with morpholine demonstrated (Table 3) that the reacꢀ
tion involves amination to give product 9 along with reꢀ
duction of the C—Cl bond to form product 10. The perꢀ
centage of the latter increases in the reaction with the use
of a DPPF complex. The best results were obtained in the
reaction performed in the presence of a complex with the

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Beletskaya et al.
Table 3. Ratio between amination and reduction products of 4ꢀ
chloroꢀ6ꢀ(4ꢀmethoxyphenyl)quinoline 8 prepared by the reacꢀ
tion with morpholine
9.38 Hz, J = 2.64 Hz); 7.34 (d, 1 H, J = 4.69 Hz); 7.34 (d, 1 H,
J = 2.64 Hz); 3.91 and 3.33 (both m, 4 H each).
4,6ꢀBis(morpholino)quinoline (3). 6ꢀBromoꢀ4ꢀchloroquinoꢀ
line (50.0 mg, 0.206 mmol), morpholine (72 mg, 0.824 mmol,
4 equiv.), ButONa (60 mg, 0.619 mmol), PdCl2(L1) (3.6 mg,
0.004 mmol), and dioxane (2.5 mL) were mixed under argon in
a flask equipped with a reflux condenser. The reaction mixture
was refluxed for 24 h (TLC control), cooled, diluted with
CH2Cl2, and filtered through a 3ꢀcm silica gel layer. The solvent
was removed under reduced pressure. The product was purified
by column chromatography on silica gel (Et3N—CH2Cl2, 1 : 50,
as the eluent). 4,6ꢀBis(morpholino)quinoline (3) was obtained
in a yield of 56 mg (91%), m.p. 140—141 °C. Found (%):
C, 68.04; H, 7.20; N, 14.09. C17H21N3O2. Calculated (%):
Catalyst
Conversion (%)
Yielda (%)
9
10
PdCl2dppf
PdCl2(L1)
PdCl2(L2)
Pd(dba)2 + BINAP
91
94
100
99
60
91
98 (95)b
95
18
3
2
4
a 1H NMR spectroscopic data.
b Preparative yield.
1
C, 68.20; H, 7.07; N, 14.04. H NMR, δ: 8.59 (d, 1 H, J =
4.98 Hz); 7.96 (d, 1 H, J = 9.38 Hz); 7.42 (dd, 1 H, J = 9.38 Hz,
J = 2.83 Hz); 7.23 (d, 1 H, J = 2.83 Hz); 6.82 (d, 1 H, J =
4.99 Hz); 3.97, 3.92, 3.26, and 3.19 (all m, 4 H each).
ligand L2, which afforded compound 9 in virtually quanꢀ
titative yield.
6ꢀMorpholinoꢀ4ꢀpiperidinoquinoline (4). 6ꢀBromoꢀ4ꢀchloroꢀ
quinoline (50 mg, 0.206 mmol), morpholine (19 mg,
0.216 mmol), ButONa (59 mg, 0.618 mmol), PdCl2(L1) (3.6 mg,
0.004 mmol) and dioxane (2.5 mL) were mixed under argon in a
flask equipped with a reflux condenser. The reaction mixture
was refluxed for 7 h (TLC control). Then piperidine (53 mg,
0.624 mmol) was added, after which the reaction mixture was
refluxed for 24 h (TLC control), cooled, diluted with CH2Cl2,
and filtered through a 3ꢀcm silica gel layer. The solvent was
removed under reduced pressure. The product was purified by
column chromatography on silica gel (Et3N—CH2Cl2, 1 : 50, as
the eluent). 6ꢀMorpholinoꢀ4ꢀpiperidinoquinoline (4) was obꢀ
tained in a yield of 52 mg (85%), m.p. 120—121 °C. Found (%):
C, 72.68; H, 7.79; N, 14.34. C18H23N3O. Calculated (%):
C, 72.70; H, 7.80; N, 14.13. 1H NMR, δ: 8.54 (d, 1 H, J =
4.98 Hz); 7.93 (d, 1 H, J = 9.09 Hz); 7.39 (dd, 1 H, J = 9.09 Hz,
J = 2.64 Hz); 7.23 (d, 1 H, J = 2.64 Hz); 6.78 (d, 1 H,
J = 4.98 Hz); 3.91, 3.26, 3.14, and 1.83 (all m, 4 H each);
1.70 (m, 2 H).
Analogously, the reaction in the presence of a catalyst
with the ligand L2 results in amination of 4ꢀchloroꢀ
quinoline 11 piperidine to form compound 12 in high
yield.
It should be noted that the second chlorine atom in
the benzene ring of product 12 is not replaced even with a
twofold excess of piperidine.
To summarize, we have demonstrated that various
types of compounds can be prepared from 6ꢀbromoꢀ
4ꢀchloroquinoline by the oneꢀpot combination of
crossꢀcoupling reactions. The results of our study may be
of interest for combinatorial chemistry.
Experimental
The reactions were monitored by TLC on Silufolꢀ254 plates
and 1H NMR spectroscopy. The yields of amination products of
6ꢀbromoꢀ4ꢀchloroquinoline were determined by 1H NMR specꢀ
troscopy (except for experiments, in which the products were
4ꢀMorpholinoꢀ6ꢀpiperidinoquinoline (5) was prepared analoꢀ
gously from 6ꢀbromoꢀ4ꢀchloroquinoline (50 mg) in a yield of
1
48 mg (78%), oil. H NMR, δ: 8.55 (d, 1 H, J = 4.86 Hz); 7.91
1
isolated preparatively). The H NMR spectra were recorded in
(d, 1 H, J = 9.37 Hz); 7.44 (dd, 1 H, J = 9.37 Hz, J = 2.71 Hz);
7.21 (d, 1 H, J = 2.71 Hz); 6.79 (d, 1 H, J = 4.86 Hz); 3.97, 3.25,
3.17, and 1.76 (all m, 4 H each); 1.63 (m, 2 H). MS (70 eV,
m/z): 297 [M]+ (100); 181 (17); 238 (18); 207 (33); 183 (21); 155
(15); 91 (9); 49 (10).
CDCl3 on a Varian VXR 400 instrument operating at 400 MHz.
The chemical shifts are given on the δ scale relative to (Me3Si)2O.
The mass spectra (EI, 70 eV) were measured on a Thermo
Finnigan SSQ 7000 mass spectrometer. 6ꢀBromoꢀ4ꢀchloroꢀ
quinoline (1) was prepared according to a procedure described
earlier.5
4ꢀChloroꢀ6ꢀmorpholinoquinoline (2). 6ꢀBromoꢀ4ꢀchloroꢀ
quinoline (50 mg, 0.206 mmol), morpholine (22 mg, 0.247 mmol,
1.2 equiv.), ButONa (24 mg, 0.247 mmol), a palladium catalyst
(0.004 mmol, 2 mol.%) (see Table 1), and dioxane (2.5 mL)
were mixed under argon. The reaction mixture was refluxed for
7 h (TLC control), cooled, diluted with CH2Cl2, and filtered
through a 3ꢀcm silica gel layer. The solution was concentrated
under reduced pressure. The product was purified by column
chromatography on silica gel (light petroleum—Et2O, 1 : 1, as the
eluent). 4ꢀChloroꢀ6ꢀmorpholinoquinoline 2 was obtained in a
yield of 47 mg (92% in the case of the ligand L1), m.p. 98—100 °C.
Found (%): C, 62.55; H, 5.45; N, 10.98. C13H13ClN2O. Calcuꢀ
lated (%): C, 62.78; H, 5.27; N, 11.26. 1H NMR, δ: 8.55 (d, 1 H,
J = 4.69 Hz); 7.98 (d, 1 H, J = 9.38 Hz); 7.49 (dd, 1 H, J =
4ꢀ(4ꢀMethoxyphenyl)ꢀ6ꢀmorpholinoquinoline (6). А. 4ꢀChloꢀ
roꢀ6ꢀmorpholinoquinoline (2) (15 mg, 0.06 mmol), 4ꢀmethoxyꢀ
phenylboronic acid (14 mg, 0.09 mmol, 1.5 equiv.), K2CO3
(25 mg, 0.18 mmol), a palladium catalyst (0.001 mmol, 2 mol.%)
(see Table 2), and dioxane (2.5 mL, 0.5 mL) were mixed under
argon. The reaction mixture was refluxed for 24 h (TLC conꢀ
trol), cooled, diluted with CH2Cl2, and filtered through a 3ꢀcm
silica gel layer. The solution was concentrated under reduced
pressure. Column chromatography on silica gel (light petroꢀ
leum—Et2O, 1 : 1, as the eluent) afforded 4ꢀ(4ꢀmethoxyphenyl)ꢀ
6ꢀmorpholinoquinoline (6) in a yield of 17 mg (86% for the
1
BINAP catalyst), oil. H NMR, δ: 8.71 (d, 1 H, J = 4.40 Hz);
8.04 (d, 1 H, J = 9.38 Hz); 7.45 (dd, 1 H, J = 9.38 Hz, J =
2.64 Hz); 7.21 (d, 1 H, J = 4.40 Hz); 7.17 (d, 1 H, J = 2.64 Hz);
7.44 and 7.04 (both m, 2H each); 3.89 (s, 3 H); 3.84 and
3.16 (both m, 4 H each). MS (70 eV, m/z): 320 [M]+ (100);

Catalytic amination of dihaloquinolines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
219
289 (6); 281 (6); 262 (78); 234 (5); 218 (7); 207 (13); 191 (25);
109 (7); 96 (9).
leum—Et2O, 1 : 1, as the eluent) afforded 6ꢀ(4ꢀmethoxyphenyl)ꢀ
4ꢀmorpholinoquinoline 9 in a yield of 56 mg (95% in the case of
the ligand L2), m.p. 155—156 °C. Found (%): C, 74.68; H, 6.32;
N, 8.52. C20H20N2O2. Calculated (%): C, 74.98; H, 6.29;
B. 6ꢀBromoꢀ4ꢀchloroquinoline (50 mg, 0.206 mmol),
morpholine (21 mg, 0.237 mmol), ButONa (23 mg, 0.237 mmol),
Pd(dba)2 (2.3 mg, 0.004 mmol), BINAP (2.5 mg, 0.004 mmol),
and dioxane (2.5 mL) were mixed under argon. The reaction
mixture was refluxed for 7 h until 6ꢀbromoꢀ4ꢀchloroquinoline
disappeared (TLC control). Then 4ꢀmethoxyphenylboronic acid
(63 mg, 0.412 mmol), K2CO3 (115 mg, 0.824 mmol), and water
(0.5 mL) were added, and the mixture was refluxed until the
reaction was completed (24 h, TLC control). Product 6 was
isolated as described in the method А. The yield was 55 mg (84%).
4ꢀ(4ꢀMethylphenyl)ꢀ6ꢀpiperidinoquinoline (7) was prepared
analogously to compound 6 (method B) from 6ꢀbromoꢀ4ꢀ
chloroquinoline (50 mg, 0.206 mmol), piperidine (20 mg,
0.237 mmol), and 4ꢀmethylphenylboronic acid (56 mg,
0.412 mmol). The yield was 42 mg (68%), oil. 1H NMR, δ: 8.68
(d, 1 H, J = 4.39 Hz); 7.98 (d, 1 H, J = 9.08 Hz); 7.49 (dd, 1 H,
J = 9.08 Hz, J = 2.63 Hz); 7.18 (d, 1 H, J = 4.39 Hz); 7.16 (d,
1 H, J = 2.63 Hz); 7.40 and 7.31 (both m, 2 H each); 3.15 (m,
4 H); 2.45 (s, 3 H); 1.68 (m, 4 H); 1.57 (m, 2 H). MS (70 eV,
m/z): 302 [M]+ (100); 287 (4); 246 (7); 217 (12); 189 (4); 123 (7);
109 (8); 32 (3).
1
N, 8.74. H NMR, δ: 8.70 (d, 1 H, J = 4.98 Hz); 8.12 (d, 1 H,
J = 2.05 Hz); 8.09 (d, 1 H, J = 8.79 Hz); 7.87 (dd, 1 H, J =
8.79 Hz, J = 2.05 Hz); 7.61 and 7.02 (both m, 2 H each);
6.84 (d, 1 H, J = 4.98 Hz); 8.97 (m, 4 H); 3.85 (s, 3 H);
3.22 (m, 4 H).
6ꢀ(4ꢀChlorophenyl)ꢀ4ꢀpiperidinoquinoline (12) was prepared
analogously to compound 9 (catalyst with the ligand L2) starting
from 4ꢀchloroꢀ6ꢀ(4ꢀchlorophenyl)quinoline 11 (50 mg) and piꢀ
1
peridine in a yield of 57 mg (97%), oil. H NMR, δ: 8.68 (d,
1 H, J = 4.98 Hz); 8.13 (d, 1 H, J = 2.05 Hz); 8.10 (d, 1 H,
J = 8.79 Hz); 7.83 (dd, 1 H, J = 8.79 Hz, J = 2.05 Hz);
7.60, 7.40 (both m, 2 H each); 6.82 (d, 1 H, J = 4.98 Hz); 3.23,
1.85 (both m, 4 H each); 1.71 (m, 2 H). MS (70 eV, m/z):
322 [M]+ (100); 265 (12); 239 (5); 204 (7); 176 (24); 119 (8);
102 (9); 88 (13).
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos 01ꢀ03ꢀ33144
and 04ꢀ03ꢀ32995).
4ꢀChloroꢀ6ꢀ(4ꢀmethoxyphenyl)quinoline (8). 6ꢀBromoꢀ4ꢀ
chloroquinoline (50 mg, 0.206 mmol), 4ꢀmethoxyphenylboronic
acid (31 mg, 0.206 mmol), K2CO3 (85 mg, 0.618 mmol),
Pd(PPh3)4 (4.7 mg, 0.004 mmol), dioxane (2.5 mL), and water
(0.5 mL) were mixed under argon in a flask equipped with a
reflux condenser. The reaction mixture was refluxed for 30 min
(TLC control), cooled, diluted with CH2Cl2, and filtered through
a 3ꢀcm silica gel layer. The solution was concentrated unꢀ
der reduced pressure. Column chromatography (light petroꢀ
leum—Et2O, 1 : 1, as the eluent) afforded 4ꢀchloroꢀ6ꢀ
(4ꢀmethoxyphenyl)quinoline (8) in a yield of 55 mg (99%),
m.p. 112—113 °C. Found (%): C, 71.44; H, 4.39; N, 4.98.
C16H12ClNO. Calculated (%): C, 71.25; H, 4.48; N, 5.19.
1H NMR, δ: 8.73 (d, 1 H, J = 4.7 Hz); 8.33 (d, 1 H, J = 2.1 Hz);
8.15 (d, 1 H, J = 8.8 Hz); 7.98 (dd, 1 H, J = 8.8 Hz, J = 2.1 Hz);
7.66 (m, 2 H); 7.47 (d, 1 H, J = 4.7 Hz); 7.02 (m, 2 H);
3.86 (s, 3 H).
4ꢀChloroꢀ6ꢀ(4ꢀchlorophenyl)quinoline (11) was prepared
analogously to compound 8 from 6ꢀbromoꢀ4ꢀchloroquinoline
(50 mg, 0.206 mmol) and 4ꢀchlorophenylboronic acid (32 mg,
0.206 mmol) in a yield of 56 mg (99%), m.p. 115—116 °C.
Found (%): C, 66.12; H, 3.57; N, 5.00. C15H29Cl2N. Calcuꢀ
lated (%): C, 65.72; H, 3.31; N, 5.11. 1H NMR, δ: 8.89 (d, 1 H,
J = 4.4 Hz); 8.41 (d, 1 H, J = 2.4 Hz); 8.20 (d, 1 H, J = 9.1 Hz);
7.95 (dd, 1 H, J = 9.1 Hz, J = 2.4 Hz); 7.47 (m, 2 H); 7.40 (d,
1 H, J = 4.4 Hz); 7.36 (m, 2 H).
References
1. (a) I. P. Beletskaya, A. V. Tsvetkov, G. V. Latyshev, and N. V.
Lukashev, Zh. Org. Khim., 2003, 39, 1660 [Russ. J. Org. Chem.,
2003, 39 (Engl. Transl.)]; (b) A. V. Tsvetkov, G. V. Latyshev,
N. V. Lukashev, and I. P. Beletskaya, Tetrahedron Lett., 2002,
43, 7267; (c) I. P. Beletskaya, G. V. Latyshev, A. V. Tsvetkov,
and N. V. Lukashev, Izv. Akad. Nauk, Ser. Khim., 2004, 181
[Russ. Chem. Bull., Int. Ed., 2004, 53, 189].
2. (a) C. C. Price and R. M. Roberts, J. Am. Chem. Soc., 1946,
68, 1204; (b) D. E. Pearson, W. H. Jones, and A. C. Cope,
J. Am. Chem. Soc., 1946, 68, 1225.
3. (a) M. Ya. Uritskaya, O. S. Anisimova, I. S. Tubina, T. Yu.
Vinokurova, G. N. Permin, N. Yu. Moskolenko, T. L.
Gus´kova, S. N. Kutchak, L. F. Setevaev, N. D. Sokolova,
S. A. Shareva, L. A. Checherina, and L. N. Yakhontov,
Khim.ꢀfarm. Zh., 1983, 17, 1334 [Pharm. Chem. J., 1983, 17
(Engl. Transl.)]; (b) M. V. Rubtsov, C. N. Pershin, N. A.
Yanbukin, L. A. Pelenitsina, T. J. Gurevich, N. A. Novitskaya,
S. N. Milovanova, and S. A. Vichkanova, J. Med. Pharm.
Chem., 1960, 2, 113.
4. D. H. Boshelli, Ye Fei, Y. D. Wang, M. Dutia, S. L. Johnson,
Wu Bigi, K. Muller, D. W. Powell, D. Yaczko, M. Young,
M. Tischer, K. Arndt, C. Diseafani, C. Etienne, J. Cibbons,
J. Crod, J. Lucas, J. M. Weber, and F. Boschelli, J. Med.
Chem., 2001, 44, 3965.
6ꢀ(4ꢀMethoxyphenyl)ꢀ4ꢀmorpholinoquinoline (9). 4ꢀChloroꢀ
6ꢀ(4ꢀmethoxyphenyl)quinoline (8) (50 mg, 0.186 mmol),
morpholine (20 mg, 0.233 mmol, 1.25 equiv.), ButONa (22 mg,
0.233 mmol), a 2 mol.% palladium catalyst (see Table 3), and
dioxane (2.5 mL) were mixed under argon in a flask equipped
with a reflux condenser. The reaction mixture was refluxed for
24 h (TLC control), cooled, diluted with CH2Cl2, and filtered
through a 3ꢀcm silica gel layer. The solution was concentrated
under reduced pressure. Column chromatography (light petroꢀ
5. N. J. Leonard and S. N. Boyd, Jr., J. Org. Chem., 1946,
11, 419.
6. (a) B. H. Yang and S. L. Buchwald, J. Organomet. Chem.,
1999, 576, 125; (b) J. F. Hartwig, Angew. Chem., Int. Ed.,
1998, 37, 2046.
Received November 19, 2004