Studies of one-pot double couplings on dibromoquinolines

Article abstract of DOI:10.1016/j.tet.2011.04.052

In a series of studies, the regioselectivity of Suzuki couplings of dibromoquinolines has been investigated. In general, it is much harder to achieve high levels of regioselectivity in these systems compared to many of the other dibromoheteroaromatics that have been studied. Useful levels of selectivity could be achieved for both a 5,7-dibromoquinoline as well as 3,4-dibromoquinoline. Double Suzuki couplings could also be achieved on these two compounds.

Full text of DOI:10.1016/j.tet.2011.04.052

Tetrahedron 67 (2011) 4147e4154
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Tetrahedron
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Studies of one-pot double couplings on dibromoquinolines
*
Alexander Piala, Diyar Mayi, Scott T. Handy
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37130, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In a series of studies, the regioselectivity of Suzuki couplings of dibromoquinolines has been investigated.
In general, it is much harder to achieve high levels of regioselectivity in these systems compared to many
of the other dibromoheteroaromatics that have been studied. Useful levels of selectivity could be ach-
ieved for both a 5,7-dibromoquinoline as well as 3,4-dibromoquinoline. Double Suzuki couplings could
also be achieved on these two compounds.
Received 15 March 2011
Received in revised form 12 April 2011
Accepted 14 April 2011
Available online 21 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
reporting good selectivity for coupling at the 4 position.8 In one
case, the initial Suzuki coupling at C4 was the followed by a second
Highly substituted quinolines are valuable compounds, partic-
ularly in the pharmaceutical area. For example, both mefloquine
(an antimalerial)1 and talnetant (a potenial NK3 receptor antago-
nist)2 feature substituted quinoline cores (Fig. 1). Their importance
has certainly resulted in the development of a number of methods
for the synthesis of substituted quinolines.3 There are the classic
condensation-type approaches, including the Skraup, Doeb-
nerevon Miller, Friedlander, and Combes reactions.4 More recently,
though, there has been tremendous growth in the application of
cross-coupling chemistry to haloquinolines.5
Our interest has been the in the development of conditions for
rendering cross-coupling approaches more convergent by
employing one-pot, regioselective double couplings on dihalohe-
teroaromatics.6,7 Given the importance of substituted quinolines,
we were interested in applying this approach to them as well.
There have been several earlier reports of regioselectivity in the
cross-couplings of polyhaloquinolines (Scheme 1). 4,7-Dichloro-
quinoline has been studied by two different groups, with both
coupling reaction at C7 to afford product 1 in 69% yield over the two
steps.9
Cl
Ph
PhSi(OMe)3
POPd1
TBAF
Cl
Cl
Cl
N
Cl
Cl
Cl
N
88%
MeCN, reflux
Cl
Ph
N
PhSnMe3
POPd1
Cy2NMe
H2), 135 °C
N
76%
Cl
Ph
PhB(OH)2
Pd(OAc)2
TBAB
N
N
78%
Na2CO3
(12% dicoupled)
O
H2O, 135 °C
O
O
Cl
N
Ph
Et
NH
MeMgBr
B(OH)2
HO
O
N
H
Pd(Ph3P)4
Na2CO3
EtOH/Toluene, reflux
Ni(dppp)Cl2
Et2O
Cl
Cl
N
N
H
1
OH
Ph
75%
92%
N
CF3
Scheme 1. 4,6-Dichloroquinoline couplings.
CF3
mefloquine
talnetant
In the two reports on couplings of 8-alkoxy-5,7-dibromoqui-
nolines, the only one that studied regioselectivity reported good
selectivity for coupling at the 5 position10 (Scheme 2). The other
reported a symmetrical double coupling of both bromides under
standard Suzuki conditions.11
Fig. 1. Some biologically active quinolines.
* Corresponding author. E-mail address: shandy@mtsu.edu (S.T. Handy).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.052

4148
A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
Br
Ph
PhB(OH)2
Pd(Ph3P)4
Na2CO3
Br
Br
N
N
Br
N
OMe
Br
OMe
MeOH/Toluene, reflux
94%
TMS
OMe
TMS
Pd(Ph3P)2Cl2
CuI
Et3N, 50 C
Br
N
OMe
Scheme 4. Double couplings of polyhaloquinolines.
90%
Scheme 2. 8-Alkoxy-5,7-dibromoquinoline couplings.
p-TolylB(OH)2
NiCl2(dppm)
K3PO4
Cl
N
p-Tolyl
N
In the case of 2,4-dihaloquinones, there have been several
studies (Scheme 3). The earliest had initially been reported to
couple at the C4 position.12 This regioselectivity was later corrected
to be a Sonogashira coupling at C2.13 Similar regioselectivity has
also been reported for Stille, Heck, and Suzuki couplings of
2,4-dibromoquinoline.14 Interestingly, by employing 2-bromo-
4-iodoquinoline, the intrinsic regioselectivity of dihaloquinolines
can be overcome and Sonogashira coupling of this compound af-
fords the product of coupling at C4 with complete selectivity. Fi-
nally, a two-pot double coupling of dibromoquinoline 2 has also
been reported. In this case, the first coupling is a simple SNAr re-
action with an amine, which occurs at C2, followed by a Stille
coupling at the remaining bromide.15
Cl
p-MeOC6H4
dioxane, reflux, 3 h
then p-MeOC6H4B(OH)2
NiCl2(dppe)
78%
K3PO4
dioxane, reflux, 4 h
Scheme 5. 4,6-Dihaloquinoline double couplings.
and even mixed Suzuki/Sonogashira couplings and Suzuki/Buch-
waldeHartwig aminations. Regioselectivity for the dichloride fa-
vored reaction at the 4 position, but this regioselectivity could be
reversed by use of a more reactive halide (iodide or bromide) at the
6 position.
Cl
N
Cl
N
Hex
2. Results and discussion
Pd/C, Ph3P
CuI
Et3N, H2O 80 °C
Cl
Hex
Ph
2.1. Studies on 5,7-dibromo-2-methylquinoline
82%
Br
Br
Our studies in this area began with a 5,7-dibromoquinoline 3.
This substrate was selected since regiocontrol is difficult in the
synthesis of 5 and/or 7 substituted quinolines when using most
condensation approaches. The synthesis of the desired starting
material is outlined in Scheme 6 and follows standard literature
procedures. Thus, 3,5-dibromoaniline was prepared according to
the procedure of Tour and was then condensed with crotonalde-
hyde in a conventional Dobnerevon Miller synthesis to afford 3.18
Ph
Pd(Ph3P)2Cl2
CuI
Hunigs base
Dioxane, RT
N
Br
Br
N
44%
I
Ph
Ph
Pd(Ph3P)2Cl2
CuI
Hunigs base
Dioxane, RT
N
N
Br
44%
1. Br2, HOAc
Br
Br
Br
N
2. NaNO2
HN
NCHO
SnBu3
O2N
O2N
O2N
O2N
H2SO4, EtOH
3. SnCl2, H2O
DMF, 120 °C
Pd(Ph3P)4
Dioxane, reflux
N
R
N
R
Br
NH2
71%
84%
Br
N
NH2
2
N
R =
CHO
NCHO
Br
Scheme 3. 2,4-Dihaloquinoline couplings.
conc HCl
27% over 4 steps
Br
Other examples of regioselectivity as well as two-pot double
couplings have been reported as well (Scheme 4). For the most part,
these reactions feature a standard SNAr reaction with either an
amine or a phenol for the first ‘coupling’ and then a Suzuki coupling
at the remaining halide.16
3
Scheme 6. Synthesis of 5,7-dibromoquinoline 3.
Initial attempts at regioselectively coupling this material were
not entirely satisfactory as a mixture of both isomers 4 and 5 was
obtained (Scheme 7). Fortunately, 4 was the major isomer (2:1
ratio) and could be isolated by means of preparative TLC. Its identity
Finally, there have been reports of one-pot double couplings as
well (Scheme 5). In a series of papers, Beletskaya has studied 4,6-
dihaloquinolines.17 Very good overall yields could be achieved for
double Suzuki couplings as well as double Sonogashira couplings

A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
4149
Br
Br
Ph
O
1.
Br
PhB(OH)2
COEt
Br
Pd(Ph3P)4
K3PO4
Ph
N
Br
N
Br
N
NH2
Toluene
Pyridine
reflux
H2SO4
heat
N
OH
5
3
4
Dioxane/H2O
reflux
9
56%
2:1 4:5
2.
Scheme 7. Dibromoquinoline 3 regioselectivity.
1. MeI, NaH
Br
Br
OMe
was confirmed by dehalogenation of the remaining bromine atom
under standard hydrogenation conditions. The resulting product
exhibited the expected pattern of four doublets and one triplet in
the aromatic region as opposed to the pattern of four doublets and
one very narrow doublet for the regioisomer with coupling at C7. As
a result, the 1H NMR was consistent with coupling at the C5 bro-
mine, rendering our results consistent with those reported by
Trecourt.10
2. NBS
NH4OAc
N
8
Scheme 8. Synthesis of dibromoquinoline 8.
Several other sets of reaction conditions were explored, in-
cluding variations in catalyst, base, and solvent, none of which
significantly altered the isomeric ratio, but it was eventually noted
that the conditions in Table 1 afforded the cleanest reaction mix-
ture (as analyzed by TLC) and could successfully afford the dicou-
pled products as separable mixtures of isomers.
p-MeOC6H4
Br
N
10
OMe
p-MeOC6H4B(OH)2
Br
Br
Br
C6H4OMe
OMe
Pd(Ph3P)4
Na2CO3
Dioxane/H2O
90 °C, 24 h
N
OMe
Table 1
N
8
Dibromoquinoline 3 double couplings
11
RB(OH)2 (1.1 equiv.)
Pd(OAc)2
p-MeOC6H4
C6H4OMe
OMe
Cs2CO3
R'
Br
R
NMP/H2O (6:1 v/v)
90 °C, 12 h
N
12
2:2:1 (10:11:12), 58% recovered SM
then
R'B(OH)2 (1.6 equiv.)
Cs2CO3
R
N
Br
N
R'
N
7
3
6
Scheme 9. Dibromoquinoline 8 regioselectivity.
90 °C, 12 h
Entry
R
R0
Yield 6
Yield 7
Unfortunately a highly complex and poorly separable mixture was
produced, containing three products as well as considerable re-
covered starting material. Regioselectivity was effectively non-
existent, with both the products of coupling at C3 and C6 being
formed in nearly equal amounts. The third product was eventually
determined to be the product of dicoupling. Some attempts at
optimization did lead to conditions that afforded better selectivity
for coupling at C6 over C3, but larger amounts of dicoupling were
formed and significant amounts of starting material still remained.
It was suspected that the introduction of a larger ether group at
C2 might improve the selectivity of the coupling for steric reasons.
Unfortunately, these larger ethers (such as isopropyl or benzyl)
were resistant to bromination at C3. Further efforts in this series
were discontinued at this point.
The identity of the coupling products was determined by careful
separation of the three products. NMR spectroscopy clearly iden-
tified 10 and 11 as regioisomers, while 12 contained two sets of
distinctive doublets for the para substituted aromatic substituents.
The regioselectivity of compound 11 was assigned on the basis of an
NOE experiment that clearly showed an interaction between the
protons on the aryl substituent ortho to the biaryl linkage and the
protons on the C4 methyl group on the quinoline. This same in-
teraction was not present in regioisomer 10.
1
2
3
4
5
6
7
8
9
p-MeOC6H4
Ph
p-FC6H4
Ph
37
53
96
43.6
30
35
52
51
55
17
18
0
25.5
23
17
46
47
28
p-MeOC6H4
Ph
p-FC6H4
trans-Heptenyl
p-MeOC6H4
3,4-diMeOC6H3
Ph
Ph
p-MeOC6H4
trans-Heptenyl
Ph
3,4-diMeOC6H3
3,4,5-triMeOC6H2
3,4-diMeOC6H3
Curiously, there was one set of coupling partners that did not af-
ford regioisomeric mixturedthe coupling with p-fluo-
a
rophenylboronic acid, followed by phenylboronic acid (Table 1, entry
3). The reason for this different behavior is not clear, but it was re-
producible. All other coupling partners afforded roughly 2:1 regioi-
someric mixtures in generally good yield. The regioisomers could be
separatedbycareful column chromatography to afford pure products.
2.2. Studies on 3,6-dibromo-4-methyl-2-methoxyquinoline
Another quinoline that was explored was dibromoquinoline
8. This compound was synthesized in fairly standard fashion
using a LimpacheKnorr approach starting with p-bromoaniline
(Scheme 8). Condensation with ethyl acetoacetate, followed by acid
catalyzed cyclization afforded bromoquinoline 9.19 For ease of
handling, the hydroxy group was methylated and was then bro-
minated at C3 using NBS. Dibromoquinoline was thus formed in
31% yield over the four steps.
2.3. Studies on 3,4-dibromoquinoline
Another dibromoquinoline that was studied was 3,4-dibromo-
quinoline 13. This compound was readily prepared in two steps
(68% yield overall) from 4-hydroxyquinoline via bromination with
NBS, followed by conversion of the hydroxyl into a bromide using
PBr320 (Scheme 10).
With the required dibromide in hand, regioselective couplings
were undertaken. Using some standard conditions from earlier
work on thiophenes, the test reaction in Scheme 9 was undertaken.

4150
A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
1.
NBS
OH
N
Br
Br
DMSO, H2O
N
2. PBr3
68% overall
13
Scheme 10. Synthesis of 3,4-dibromoquinoline.
In general, excellent regioselectivity for coupling at C4 was
obtained, regardless of reaction conditions (catalyst, base, and
solvent). The most significant problem was discriminating between
mono- and dicoupling. Considerable optimization of the cat-
alyst, base, and solvent, eventually led to the combination of
tetrakis(triphenylphosphine) palladium(0) with potassium hydro-
xide in a 6:1 (v/v) mixture of dioxane and water as the best option.
Using these conditions, roughly 35% of the starting material
remained, but dicoupling was kept to a minimum (Table 2, entry 1).
The use of a greater excess of boronic acid did result in greater
consumption of starting material, but only at the cost of the for-
mation of greater amounts of dicoupled product 15.
Fig. 2. Determination of regioselectivity on 14.
difficulty using radial chromatography (Chromatotron) to afford good
yields of the dicoupled products (Table 3).
Table 2
Dibromoquinoline 13 monocouplings
C6H4OMe
Br
C6H4OMe
C6H4OMe
Br
pMeOC6H4B(OH)2
Pd(Ph3P)4
Br
Table 3
Dibromoquinoline 13 double couplings
KOH
N
N
N
Diox/H2O
60 °C, 24 h
RB(OH)2
Pd(Ph3P)4
14
15
13
KOH
Product ratio (13/14/15)a
R
Entry
Equivalents of boronic acid
Br
N
R
Dioxane/H2O (6:1 v/v)
90 °C, 24 h
Br
R'
1
2
3
1.2
1.4
1.6
1.8
1.6
1.8
35:52:3
17:63:14
15:70:10
12:55:32
15:61:23
10:61:23
then
R'B(OH)2
90 °C, 24 h
N
4
5b
6b
16
13
Ratio determined by 1H NMR.
Reaction at 90 ꢀC.
a
Entry
R0
% Yielda
b
1
2
3
4
5
6
7
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
m-NO2C6H4
2-Thiophenyl
trans-Heptenyl
Ph
70
68
68
0b
52
33
68
m-NO2C6H4
2-Thiophenyl
trans-Heptenyl
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
The regioselectivity of this initial coupling was determined by
means of extensive 2D NMR techniques. After assigning each pro-
ton and carbon signal in the NMR spectrum of 14, HMBC was
employed to determine connectivity between the aryl substituent
and the quinoline ring. In particular, the observation of cross peaks
in the HMBC spectrum of 14 between H2 and C3, H2 and C4, and
H20 and C4 were sufficient to rule out the product of coupling at C3
(Fig. 2). As it turns out this regioselectivity is also in agreement with
that predicted using the 1H NMR guidelines reported earlier by this
group.21 Thus, the chemical shift values for the 3 and 4 positions of
quinoline are 7.26 and 8.00, respectively, thereby indicating that C4
should be the more reactive site for cross-couplings. It is also in
agreement with the regioselectivity predicted by the bond disso-
ciation energy calculations reported by Houk and co-workers for
the corresponding chloroquinolines (96.2 kcal/mol for C4 and
97.5 kcal/mol for C3).22
a
Isolated yields.
b
Yield (72%) of the product of double coupling of dibromoquinoline 13 with the
first boronic acid was the only product isolated.
Interestingly, numerous attempts to obtain the mixed coupling
product with p-methoxyphenylboronic acid and trans-hepte-
nylboronic acid failed completely and only afforded the dicoupling
product with p-methoxyphenylboronic acid (Table 3, entry 4). The
problem is clearly not the p-methoxyphenylboronic acid, as other
couplings employing it proceeded normally. Similarly, the reversed
order of addition worked well to afford the mixed product in good
yield (Table 3, entry 7).
Giventheimperfectcontrolovermonoversusdicoupling,attempts
to perform dicouplings on quinoline 13 were expected to afford highly
complex mixtures of products. In an effort to simplify these mixtures,
the initial coupling was conducted using an excess (1.6 equiv) of the
boronic acid. This excess was expected to reduce the amount of
starting material remaining and thereby simplify the product mixture
after the second coupling to be largely one of dicoupling with the first
boronic acid and regioselective mixed coupling with the two boronic
acids. In practice, these mixtures could be separated with minimal
3. Conclusions
Given the importance of substituted quinolines, the ability to
regioselectively coupling dihaloquinolines is of clear utility. The
present research, in combination with prior studies clearly dem-
onstrates that regioselectivity is often achievable. As 5,7-dibromo-
quinoline 3 shows, though, regioselectivity is not always complete.
Further, both 3,6-dibromoquinoline 8 and 3,4-dibromoquinoline 13

A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
4151
demonstrate that selectivity between mono- and dicoupling can be
a more formidable challenge. Rather interestingly, using the 1H NMR
chemical shift method, the comparatively poor regioselectivity in
the coupling of 3 relative to 13 can be appreciated as the chemical
shift difference between C5 and C7 is only 0.07 ppm, compared to
one of 0.74 ppm for C3 and C4.23 Using Houk’s model (for the cor-
responding chloroquinolines), a more significant difference of
1.3 kcal/mol for the bond dissociation energies at C3 and C4 versus
only 0.6 kcal/mol for C5 versus C6 can be noted.22 As a result, both
models support the observed results.
With respect to halting the reaction at one coupling, although it
might seem that a reduction in reaction temperature would be
sufficient to enable control, that has not been the case in the
present work and the reason for the difference in behavior of
quinoline 3 and 13 is not yet clear. Hopefully, the present results
will encourage the study of further dihaloquinoline isomers and
lead to the establishment of reliable reaction conditions for the
regioselective functionalization of these compounds as well.
7.54e7.45 (m, 5H), 7.71 (d, J¼3 Hz, 1H), 7.74 (d, J¼9 Hz, 1H), 8.10
(d, J¼9 Hz, 1H), 8.23 (s, 1H); 13C NMR (125 MHz, CDCl3) 25.3, 55.6,
113.1, 114.7, 120.4, 122.1, 123.5, 127.6, 127.8, 127.9, 128.9, 129.2,
136.3, 135.5, 137.0, 143.6, 147.6, 158.6, 159.4; IR: 3100, 3080, 1630,
1550, 1430, 1420, 1370, 1140, 1110, 1080, 960, 820, 780 cmꢁ1
.
HRMS (EI) calcd for C23H19NO: 325.1467; observed: 325.1465.
4.2.3. 6-(40-Fluorophenyl)-2-methyl-8-phenylquinoline. Elution
from silica using 20% ethyl acetate in hexanes afforded the title
compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) 2.79
(s, 3H), 6.98 (s, 1H), 7.28e7.16 (m, 4H), 7.54e7.42 (m, 4H), 7.64
(d, J¼3 Hz, 1H), 7.81e7.68 (m, 3H), 8.06 (d, J¼9 Hz, 1H), 8.23 (s,
1H); 13C NMR (125 MHz, CDCl3) 25.2, 111.3, 120.4, 122.0, 123.7,
127.7, 127.9, 129.3, 116.0 (d, JC,F¼3 Hz), 129.5 (d, JC,F¼9 Hz), 132.0
(d, JC,F¼21 Hz), 136.4, 137.0, 143.6, 147.7, 158.8, 161.8 (d,
JC,F¼240 Hz); IR: 3120, 3080, 1640, 1550, 1420, 1380, 1140, 1120,
1080, 940, 820, 770 cmꢁ1. HRMS (EI) calcd for C22H16FN:
313.1267; observed: 313.1268.
4. Experimental
4.1. General
4.2.4. 8-(40-Fluorophenyl)-2-methyl-6-phenylquinoline. Elution from
silica using 20% ethyl acetate in hexanes afforded the title compound
as a pale yellow oil. 1H NMR (500 MHz, CDCl3) 2.77 (s, 3H), 6.97 (s,
1H), 6.90 (t, J¼7 Hz, 2H), 7.25 (d, J¼7 Hz, 2H), 7.41 (d, J¼9 Hz, 1H),
7.54e7.46 (m, 4H), 7.76 (dt, J¼2, 7 Hz, 2H), 8.14 (d, J¼9 Hz, 1H), 8.28 (s,
1H); 13C NMR (125 MHz, CDCl3) 25.2, 111.1, 116.0 (d, JC,F¼3 Hz), 120.3,
122.1, 123.7, 127.6, 127.9, 129.1, 129.2 (d, JC,F¼9 Hz), 132.0, 132.1 (d,
JC,F¼22 Hz), 136.3, 137.1, 143.4, 147.8, 158.6, 161.4 (d, JC,F¼230 Hz); IR:
3110, 3070, 1630, 1540, 1430, 1410, 1380, 1150, 1120, 1080, 960, 810,
780 cmꢁ1. HRMS (EI) calcd for C22H16FN: 313.1267; observed: 313.1266.
Melting points were measured on a Mel-Temp Capillary melting-
point apparatus and are uncorrected.1H NMR spectrawere recorded
using aJEOL 500 MHzspectrometer, and chemical shifts arereported
in
a JEOL 500 MHz spectrometer, reported in
d
(ppm) relative to TMS. 13C NMR spectra were recorded using
d
(ppm) and referenced to
the CHCl3 signal. Infrared spectrawere measure bya Varian 7000 FT-
IR spectrometer with an SPECAC golden-gate ATR.
4.2.5. 6-(trans-Heptenyl)-8-(40-methoxyphenyl)-2-methyl-
quinoline. Elution from silica using 25% ethyl acetate in hexanes
afforded the title compound as a light brown oil. 1H NMR
(500 MHz, CDCl3) 1.04 (t, J¼7 Hz, 3H), 2.01 (quintet, J¼7 Hz, 2H),
2.25 (quintet, J¼7 Hz, 2H), 2.36 (t, J¼7 Hz, 2H), 2.71 (s, 3H), 3.37 (t,
J¼7 Hz, 2H), 3.88 (s, 3H), 6.45 (dt, J¼7, 15 Hz, 1H), 6.57 (d, J¼15 Hz,
1H), 7.02 (d, J¼8 Hz, 2H), 7.14 (d, J¼9 Hz, 1H), 7.37 (d, J¼8 Hz, 2H),
7.48 (d, J¼3 Hz, 1H), 7.86 (s, 1H), 8.03 (d, J¼9 Hz, 1H); 13C NMR
(125 MHz, CDCl3) 14.1, 22.8, 25.2, 29.6, 31.9, 33.3, 120.9, 121.3,
121.8, 125.7, 125.8, 127.7, 127.9, 129.0, 129.3, 135.2, 136.6, 138.4,
147.0, 159.0; IR: 3110, 3060, 1640, 1550, 1410, 1380, 1150, 1110,
4.2. General conditions for the double coupling of quinoline
To a solution of 50.0 mg (0.167 mmol) of dibromoquinoline 3 in
2 mL of a 6:1 v/v mixture of NMP and water was added 1.9 mg
(0.0084 mmol) of palladium acetate, 22.8 mg (0.187 mmol) of
phenylboronic acid, and 108.3 mg (0.332 mmol) of cesium car-
bonate. The mixture was degassed by bubbling through argon for
5 min, then sealed and heated to 90 ꢀC for 20 h. At this point, the
reaction was cooled and 38.2 mg (0.273 mmol) of p-methoxy-
phenylboronic acid and 119.2 mg (0.366 mmol) of cesium carbon-
ate were added. The reaction was once again heated to 90 ꢀC for
24 h. The reaction was then cooled and partitioned between water
and ether (20 mL of each). The organic layer was dried over mag-
nesium sulfate, filtered, and concentrated in vacuo to afford a crude
mixture of products. These were separated on silica gel using flash
column chromatography (20% ethyl acetate/hexanes as eluent) to
afford 52.4 mg (53%) of 6-(40-methoxyphenyl)-2-methyl-8-phe-
nylquinoline and 18.1 mg (18%) of 8-(40-methoxyphenyl)-2-methyl-
6-phenylquinoline, both as light yellow oils.
1080, 950, 810, 790 cmꢁ1
345.2093; observed: 345.2091.
. HRMS (EI) calcd for C24H27NO:
4.2.6. 6-(trans-Heptenyl)-8-(40-methoxyphenyl)-2-methyl-
quinoline. Elution from silica using 25% ethyl acetate in hexanes
afforded the title compound as a light brown oil. 1H NMR (500 MHz,
CDCl3) 1.04 (t, J¼7 Hz, 3H), 2.01 (quintet, J¼7 Hz, 2H), 2.25 (quintet,
J¼7 Hz, 2H), 2.36 (t, J¼7 Hz, 2H), 3.87 (s, 3H), 6.39e6.28 (m, 2H),
7.02 (d, J¼8 Hz, 2H), 7.27 (d, J¼9 Hz,1H), 7.69 (d, J¼3 Hz,1H), 7.75 (d,
J¼8 Hz, 2H), 8.09 (s, 1H), 8.32 (d, J¼9 Hz, 1H); 13C NMR (125 MHz,
CDCl3) 14.0, 22.9, 25.2, 29.4, 31.9, 33.1, 120.8, 121.1, 121.6, 125.5,
125.8, 127.7, 129.6, 129.7, 135.1, 136.6, 138.1, 147.2, 159.1; IR: 3110,
3060, 1650, 1540, 1420, 1410, 1370, 1140, 1110, 1080, 960, 820,
780 cmꢁ1. HRMS (EI) calcd for C24H27NO: 345.2093; observed:
345.2095.
4.2.1. 6-(40-Methoxyphenyl)-2-methyl-8-phenylquinoline. Elution
from silica using 25% ethyl acetate in hexanes afforded the title
compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) 2.77 (s,
3H), 3.91 (s, 3H), 7.06 (d, J¼9 Hz, 2H), 7.23 (d, J¼9 Hz, 2H),
7.53e7.37 (m, 6H), 7.71 (d, J¼3 Hz, 1H), 7.79 (d, J¼9 Hz, 1H), 8.15
(d, J¼9 Hz, 1H), 8.26 (s, 1H); 13C NMR (125 MHz, CDCl3) 25.2, 55.8,
113.3, 114.8, 120.4, 122.0, 123.7, 127.6, 127.7, 127.9, 128.9, 129.3,
136.4, 135.6, 137.0, 143.6, 147.7, 158.8, 159.5; IR: 3110, 3070, 1650,
4. 2. 7. 6-(20, 30-Dimethoxyphenyl)-2-methyl-8-phenyl-
quinoline. Elution from silica using 25% ethyl acetate in hexanes
afforded the title compound as a clear oil. 1H NMR (500 MHz,
CDCl3) 2.76 (s, 3H), 3.95 (s, 3H), 3.98 (s, 3H), 6.99 (d, J¼8 Hz, 1H),
7.21 (d, J¼8 Hz, 1H), 7.34 (s, 1H), 7.53e7.46 (m, 6H), 7.71 (d, J¼3 Hz,
1H), 8.09 (d, J¼9 Hz, 1H), 8.24 (s, 1H); 13C NMR (125 MHz, CDC13)
25.2, 56.0, 56.1, 111.3, 112.2, 115.8, 120.4, 121.2, 123.7, 127.7, 127.9,
129.3, 129.7, 136.4, 137.0, 135.6, 143.6, 147.7, 148.7, 150.2, 150.3,
158.8; IR: 3100, 3080, 1640, 1540, 1430, 1420, 1380, 1150, 1120, 1080,
1540, 1420, 1410, 1380, 1160, 1120, 1080, 960, 810, 790 cmꢁ1
HRMS (EI) calcd for C23H19NO: 325.1467; observed: 325.1466.
.
4.2.2. 8-(40-Methoxyphenyl)-2-methyl-6-phenylquinoline. Elution
from silica using 25% ethyl acetate in hexanes afforded the title
compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) 2.76 (s,
3H), 3.87 (s, 3H), 7.03 (d, J¼8 Hz, 2H), 7.21 (d, J¼8 Hz, 2H),

4152
A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
940, 810, 780 cmꢁ1. HRMS (EI) calcd for C24H21NO2: 355.1572; ob-
served: 355.1570.
methyl-2-methoxyquinoline (309 mg, 1.25 mmol) and 14 mg am-
monium acetate in 20 mL acetonitrile. The reaction was allowed to
proceed for 24 h, after which the acetonitrile was removed via
rotary evaporation and the crude product was purified using silica
gel flash chromatography (hexanes/ethyl acetate 10:1) to afford
295 mg (72%) of the product as a white solid. Mp: 170e172 ꢀC; 1H
NMR (500 MHz, CDCl3) 2.67 (s, 3H), 3.79 (s, 3H), 7.27 (d, J¼9.1 Hz,
1H), 7.77 (d, J¼9.1 Hz, 1H), 7.89 (s, 1H); 13C NMR (125 MHz, CDCL3)
19.3, 30.4, 115.0, 115.5, 120.7, 121.5, 127.5, 132.5, 136.5, 143.8, 157.1;
IR: 3120, 3060, 1650, 1550, 1430, 1410, 1370, 1160, 1110, 1080, 960,
820, 790 cmꢁ1. HRMS (EI) calcd for C11H9NOBr2: 328.9051; ob-
served: 328.9054.
4. 2. 8. 8-(20, 30-Dimethoxyphenyl)-2-methyl-6-phenyl-
quinoline. Elution from silica using 25% ethyl acetate in hexanes
afforded the title compound as a clear oil. 1H NMR (500 MHz,
CDCl3) 2.78 (s, 3H), 3.91 (s, 3H), 3.98 (s, 3H), 7.06e7.00 (m, 2H), 7.42
(d, J¼8 Hz, 1H), 7.50 (t, J¼7 Hz, 2H), 7.74 (, J¼3 Hz, 1H), 7.80 (d,
J¼3 Hz, 1H), 7.78 (s, 1h), 8.18 (d, J¼9 Hz, 1H), 8.28 (s, 1H); 13C NMR
(125 MHz, CDCl3) 25.3, 56.1, 56.4, 111.3, 123.1, 115.6, 120.4, 121.1,
123.5, 127.7, 127.8, 129.2, 129.5, 135.4, 136.3, 127.0, 143.6, 147.8,
148.8, 150.1, 150.2, 158.6; IR: 3100, 3060, 1650, 1550, 1430, 1380,
1140, 1110, 1080, 950, 820, 790 cmꢁ1. HRMS (EI) calcd for
C24H21NO2: 355.1572; observed: 355.1575.
4.2.15. 3-Bromo-4-hydroxyquinoline. N-Bromosuccinimide (135 mg,
0.76 mmol) was added to a solution of 4-hydroxyquinoline (100 mg,
0.69 mmol) in 5 mL dimethylsulfoxide and 0.5 mL water. The re-
action was allowed to continue for 24 h after which the DMSO was
removed via rotary evaporation to afford 150 mg (97%) of the
product as a yellow solid. Product was used without further
purification.20
4.2.9. 2-Methyl-6-phenyl-8-(20,30,40-trimethoxyphenyl)quinoline. Elution
from silica using 30% ethyl acetate in hexanes afforded the title
compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) 2.75 (s,
3H), 3.89 (s, 6H), 3.91 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 6.70 (s, 2H),
6.97 (d, J¼9 Hz, 1H), 7.02 (s, 1H), 7.25 (dd, J¼9, 2 Hz, 1H), 7.34 (s, 1H),
7.72 (d, J¼2 Hz, 1H), 8.15 (d, J¼9 Hz, 1H), 8.24 (s, 1H); 13C NMR
(125 MHz, CDCl3) 25.2, 56.0, 56.1, 56.2, 56.4, 104.9, 111.3, 112.6,
115.8, 120.4, 121.2, 122.0, 123.7, 130.7, 139.7, 135.6, 137.0, 138.1, 143.6,
147.7, 148.7, 150.3, 151.3, 158.8; IR: 3110, 3080, 1640, 1550, 1430,
1410,1380,1140, 1120,1080, 960, 810, 790 cmꢁ1. HRMS (EI) calcd for
C27H27NO5: 345.2064; observed: 345.2064.
4.2.16. 3,4-Dibromoquinoline. Phosphorus tribromide (80.7 mg,
0.3 mmol) was added drop-wise to a solution of 3-bromo-4-
hydroxyquinoline (67 mg, 0.3 mmol) in 2 mL dimethyl formamide.
The reaction was allowed to proceed for 24 h, after which the
mixture was poured onto ice. Filtration afforded 51 mg (60%) of the
product as a white solid. Mp: 75e80 ꢀC; 1H NMR (500 MHz, CDCl3)
7.67 (t, J¼8.0 Hz, 1H), 7.78 (t, J¼8.0 Hz, 1H), 8.09 (d, J¼8.0 Hz, IH),
8.24 (d, J¼8.0 Hz, 1H), 8.89 (s, 1H); 13C NMR (125 MHz, CDCl3) 121.2,
127.4, 128.9, 129.1, 129.8, 130.3, 135.3, 146.6, 151.3; IR: 3060, 2920,
1560, 1480, 1330, 1100, 750 cmꢁ1. HRMS (EI) calcd for C9H5NBr2:
284.8789; observed: 284.8791.
4.2.10. 2-Methyl-8-phenyl-6-(20,30,40-trimethoxyphenyl)quinoline. Elution
from silica using 30% ethyl acetate in hexanes afforded the title
compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) 2.77 (s,
3H), 3.88 (s, 6H), 3.92 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 6.72 (s, 2H),
6.99 (d, J¼9 Hz,1H), 7.00 (s, 1H), 7.26 (dd, J¼9, 2 Hz, 1H), 7.33 (s, 1H),
7.71 (d, J¼2 Hz, 1H), 8.14 (d, J¼9 Hz, 1H), 8.23 (s, 1H); 13C NMR
(125 MHz, CDCL3) 26.2, 56.3, 56.4, 56.6, 56.7, 103.9, 112.4, 112.7,
115.6, 120.3, 121.2, 122.1, 122.7, 130.6, 139.3, 135.7, 137.0, 137.8, 143.4,
147.6, 148.9, 150.0, 151.2, 158.6; IR: 3120, 3080, 1650, 1550, 1430,
1410, 1370, 1160, 1110, 1080, 940, 810, 780 cmꢁ1. HRMS (EI) calcd for
C27H27NO5: 345.2064; observed: 345.2062.
4.2.17. 3-Bromo-2-methoxy-6-(40-methoxyphenyl)-4-methyl-
quinoline. To a solution of 55.6 mg (0.168 mmol) of 8 in 2 mL of
a
6:1 (v/v) mixture of dioxanes/water was added 9.7 mg
(0.0084 mmol) of tetrakis(triphenylphosphine) palladium(0),
28.3 mg (0.202 mmol) of para-methoxyphenylboronic acid, and
18.8 mg (0.336 mmol) of potassium hydroxide. The solution was
degassed by bubbling argon through it for 5 min and then heated to
90 ꢀC for 24 h. The cooled reaction was then quenched with water
(20 mL) and extracted with ethyl acetate (3ꢂ10 mL). Concentration
in vacuo afforded a crude product that was purified using rotary
chromatography (10% ethyl acetate in hexanes as eluent) to afford
the title product as a white solid. Mp: 155e182 ꢀC; 1H NMR
(500 MHz, CDCl3); 13C NMR (125 MHz, CDCl3) 20.07, 31.01, 55.48,
114.54, 115.06, 120.46, 121.15, 123.45, 128.20, 129.44, 132.48, 135.48,
137.30, 145.63, 158.02, 159.07. HRMS (EI) calcd for C18H16NO2Br:
357.0364; observed: 357.0364.
4.2.11. 40-Bromoacetoacetanilide. Ethyl acetoacetate (1.7 g, 13 mmol)
was added to a mixture of p-bromoaniline (2 g, 11.6 mmol), 25 mL of
xylenes, and 0.1 mL of pyridine. This solution was heated to reflux for
3 h, after which 20 mL of xylenes was removed via rotary evapora-
tion. Hexanes (25 mL) was added, and the mixture was chilled to 0 ꢀC
for 24 h. Filtration afforded 2.7 (92%) of the crude product as a purple
solid.19
4.2.12. 6-Bromo-4-methyl-2-quinolone. A solution of 40-bromoace-
toacetanilide (2.8 g, 11 mmol) and 13 mL sulfuric acid was heated to
120 ꢀC for 90 min, after which it was poured onto ice. Filtration
afforded 1.8 g (70%) of the crude product as a white powder.19
4.2.18. 3-Bromo-4-(40-methoxyphenyl)quinoline. To a solution of
48.5 mg (0.168 mmol) of 13 in 2 mL of a 6:1 (v/v) mixture of di-
oxanes/water was added 9.7 mg (0.0084 mmol) of tetrakis(tri-
phenylphosphine) palladium(0), 28.3 mg (0.202 mmol) of
para-methoxyphenylboronic acid, and 18.8 mg (0.336 mmol)
of potassium hydroxide. The solution was degassed by bubbling
argon through it for 5 min and then heated to 90 ꢀC for 24 h. The
cooled reaction was then quenched with water (20 mL) and
extracted with ethyl acetate (3ꢂ10 mL). Concentration in vacuo
afforded a crude product that was purified using rotary chroma-
tography (15% ethyl acetate in hexanes as eluent) to afford the title
product as a white solid. Mp: 88e105 ꢀC; 1H NMR (500 MHz, CDCl3)
3.904 (s, 3H), 7.071 (d, J¼8.6 Hz, 2H), 7.257 (d, J¼8.59, 2H), 7.450 (t,
J¼7.9 Hz, 1H), 7.555 (d, J¼7.4 Hz, 1H), 7.702 (t, J¼7.4), 8.117 (d,
J¼8.6 Hz, 1H), 9.032 (s, 1H); 13C NMR (125 MHz, CDCl3) 55.43,
114.04, 119.01, 126.51, 127.53, 128.91, 129.24, 129.49, 129.64, 130.80,
4.2.13. 6-Bromo-4-methyl-2-methoxyquinoline. Sodium hydride
(132 mg, 5.5 mmol) was added to a solution of 6-bromo-4-
methyl-2-quinoline (1.18 g, 5 mmol) in 2.5 mL dimethyl form-
amide and allowed to react for 10 min. Iodomethane (705 mg,
5 mmol) was then added to the solution and allowed to react for
1 h, after which the reaction was monitored via TLC. Upon
completion, the reaction was quenched with water and the
product extracted with ethyl acetate. Concentration via rotary
evaporation yielded the crude product, which was purified using
silica gel flash chromatography (hexanes/ethyl acetate 10:1) to
afford 0.8 g (66%) of the product as a yellow solid that was used
directly in the next reaction.
4.2.14. 3,6-Dibromo-4-methyl-2-methoxyquinoline. N-Bromosucci-
nimide (222 mg, 1.25 mmol) was added to a solution of 6-bromo-4-

A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
4153
147.00,147.56,152.10,159.85; IR: 3040, 2940,1720,1640,1510,1490,
1240, 1160, 1020, 810 cmꢁ1. HRMS (EI) calcd for C16H12NOBr:
313.0137; observed: 313.0135.
3H), 6.873 (d, J¼10.02 Hz, 2H), 7.108 (d, J¼8.59 Hz, 2H), 7.181e7.161
(m, 2H), 7.269e7.201 (m, 3H), 7.468 (t, J¼8.02 Hz, 1H), 7.701 (t,
J¼7.73 Hz, 1H), 7.743 (d, J¼8.59 Hz, 1H), 8.171 (d, J¼8.59 Hz, 1H),
8.982 (s, 1H); 13C NMR (125 MHz, CDCl3) 55.23, 113.65, 126.63,
126.77, 126.96, 128.12, 128.36, 129.03, 129.53, 130.18, 131.28, 131.78,
133.27, 138.36, 145.25, 147.65, 151.89, 159.09; IR: 3050, 2920, 2840,
1730, 1610, 1520, 1480, 1380, 1240, 1170, 1040, 760 cmꢁ1. HRMS (EI)
calcd for C22H17NO: 311.1310; observed: 311.1308.
4.2.19. 2-Methoxy-3,6-bis(40-methoxyphenyl)-4-methylquinoline. To
a solution of 50.0 mg (0.167 mmol) of dibromoquinoline 8 in 2 mL of
a 6:1 v/v mixture of dioxane and water was added 9.7 mg
(0.0084 mmol) of tetrakis(triphenylphosphine) palladium(0),
61.4 mg (0.404 mmol) of p-methoxyphenylboronic acid, and 0.5 mL
of 2-M aqueous sodium carbonate. The mixture was degassed by
bubbling through argon for 5 min, then sealed and heated to 90 ꢀC
for 24 h. The reaction was then cooled and partitioned between
water and ether (20 mL of each). The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford
a crude mixture of products. Elution from silica using 20% ethyl
acetate in hexanes afforded the title compound as a white solid.
Mp: 160e185 ꢀC; 1H NMR (500 MHz, CDCl3) 2.396 (s, 3H), 3.788 (s,
3H), 3.851 (s, 3H), 3.867 (s, 3H), 6.985 (d, J¼8.6 Hz, 2H), 7.018 (d,
J¼8.6 Hz, 2H), 7.221 (d, J¼8.6 Hz, 2H), 7.442 (d, J¼8.6 Hz, 1H), 7.575
(d, J¼9.2, Hz, 2H), 7.759 (d, J¼8.6 Hz, 1H), 7.924 (s, 1H); 13C NMR
(125 MHz, CDCl3) 16.11, 29.02, 54.36, 54.47, 112.75, 113.48, 113.73,
120.99, 122.47, 127.14, 127.73, 128.04, 130.38, 131.44, 131.93, 133.78,
137.03, 141.39, 157.97, 158.30, 160.88; IR: 3040, 3020, 2850, 1640,
1600, 1560, 1500, 1470, 1440, 1280, 1240, 1030, 800 cmꢁ1. HRMS (EI)
calcd for C25H23NO3: 385.1678; observed: 385.1675.
4.3.2. 3-(40-Methoxyphenyl)-4-(trans-heptenyl)quinoline. Elution
from silica using 15% ethyl acetate in hexanes afforded the title
compound as a yellow oil. 1H NMR (500 MHz, CDCl3) 0.904 (t, J¼6.8,
3H), 1.345e1.242 (m, 4H), 1.435 (quintet, 2H), 2.236 (quartet, 2H),
3.872 (s, 3H), 5.957 (m, 1H), 6.519 (d, J¼17.7 Hz, 1H), 6.987
(d, J¼8.6 Hz, 2H), 7.362 (d, J¼8.6 Hz, 2H), 7.552 (t, J¼7.45 Hz, 1H),
7.693 (t, J¼7.45 Hz, 1H), 8.123 (d, J¼7.45, 1H), 8.238 (d, J¼7.45, 1H),
8.822 (s, 1H); 13C NMR (125 MHz, CDCl3) 14.23, 22.71, 28.79, 31.57,
33.75, 55.49, 113.90, 124.57, 125.86, 126.69, 126.73, 128.92, 129.87,
131.00, 131.64, 132.07, 141.31, 141.85, 147.72, 152.02, 159.16; IR: 3080,
2930, 2860, 1610, 1520, 1290, 1250, 1170, 840 cmꢁ1. HRMS (EI) calcd
for C23H25NO: 331.1936; observed: 331.1937.
4.3.3. 3-(40-Methoxyphenyl)-4-(20-thiophenyl)quinoline. Elution
from silica using 15% ethyl acetate in hexanes afforded the title
compound as
a
yellow solid. Mp: 108e138 ꢀC; 1H NMR
(500 MHz, CDCl3) 3.807 (s, 3H), 6.846 (d, J¼9.16 Hz, 2H), 7.032
(d, J¼4.58 Hz, 1H), 7.092 (d, J¼5.15 Hz, 1H), 7.186 (d, J¼9.16 Hz, 2H),
7.410 (d, J¼5.15 Hz, 1H), 7.535 (t, J¼7.45, 1H), 7.726 (t, J¼7.45, 1H),
7.936 (d, J¼8.02, 1H), 8.182 (d, J¼8.02, 1H), 8.973 (s, 1H); 13C NMR
(125 MHz, CDCl3) 55.18, 113.66, 114.78, 126.24, 126.92, 127.22, 127.28,
127.88, 128.41, 129.19, 129.28, 129.74, 130.23, 130.84, 134.20, 136.56,
147.06, 151.60, 158.96; IR: 3080, 2950, 2840, 1730, 1620, 1520, 1480,
1240, 1170, 1040, 830, 770 cmꢁ1. HRMS (EI) calcd for C20H15NOS:
289.0874; observed: 289.0873.
4.2.20. 3,4-Bis(40-methoxyphenyl)quinoline. To a solution of 48.5 mg
(0.168 mmol) of 13 in 2 mL of a 6:1 (v/v) mixture of dioxanes/water
was added 9.7 mg (0.0084 mmol) of tetrakis(triphenylphosphine)
palladium(0), 61.4 mg (0.404 mmol) of p-methoxyphenylboronic
acid, and 37.6 mg (0.672 mmol) of potassium hydroxide. The solution
was degassed by bubbling argon through it for 5 min and then
heated to 90 ꢀC for 24 h. After cooling, 0.336 mmol of the second
boronic acid was added and the reaction mixture heated once again
to 90 ꢀC for 24 h. The cooled reaction was then quenched with water
(20 mL) and extracted with ethyl acetate (3ꢂ10 mL). Concentration
in vacuo afforded a crude product that was purified on silica using
20% ethyl acetate in hexanes as eluent afforded the title compound
as a white solid. Mp: 100e111 ꢀC; 1H NMR (500 MHz, CDCl3) 3.79 (s,
3H), 3.847 (s, 3H), 6.80 (d, J¼8.59 Hz, 2H), 6.90 (d, J¼8.59 Hz, 2H), 7.10
(d, J¼8.59 Hz, 2H), 7.12 (d, J¼8.6 Hz, 2H), 7.73e7.68 (m, 2H), 8.16 (d,
J¼7.45 Hz, 2H), 8.97 (s, 1H); 13C NMR (125 MHz, CDCl3) 55.21, 56.03,
113.67, 113.74, 126.56, 126.72, 127.66, 128.61, 128.84, 129.52, 130.64,
131.30, 131.77, 132.89, 144.94, 147.48, 152.11, 158.60, 159.04; IR: 3080,
2920, 2840, 1720, 1620, 1590, 1500, 1470, 1280, 1240, 1160, 1050, 820,
760 cmꢁ1. HRMS (EI) calcd for C23H19NO3: 357.1365; observed:
357.1364.
4.3.4. 4-(40-Methoxyphenyl)-3-(20-thiophenyl)quinoline. Elution
from silica using 15% ethyl acetate in hexanes afforded the title
compound as a yellow solid. Mp: 109e118 ꢀC; 1H NMR (500 MHz,
CDCl3) 3.800 (s, 3H), 6.880e6.630 (m, 1H), 6.938e6.904 (m, 3H),
7.107 (d, J¼8.59 Hz, 2H), 7.164 (d, J¼5.73 Hz, 1H), 7.366 (t, J¼8.02 Hz,
1H), 7.516 (d, J¼8.59 Hz, 1H), 7.600 (t, J¼7.92 Hz, 1H), 8.065
(d, J¼8.02 Hz, 1H), 9.088 (s, 3H); 13C NMR (125 MHz, CDCl3) 55.27,
114.08, 114.78, 126.46, 126.74, 126.91, 126.98, 127.20, 127.46, 127.91,
128.18, 129.18, 131.42, 139.88, 144.74, 147.01, 150.84, 159.71; IR: 3080,
3040, 2930, 2840, 1610, 1520, 1500, 1280, 1240, 1170, 1030, 830,760,
700 cmꢁ1. HRMS (EI) calcd for C20H15NOS: 289.0874; observed:
289.0872.
4.3. General procedure for the double couplings of
dibromoquinoline 13
4.3.5. 3-(40-Methoxyphenyl)-4-(30-nitrophenyl)quinoline. Elution
from silica using 20% ethyl acetate in hexanes afforded the title
compound as a yellow solid. Mp: 120e132 ꢀC; 1H NMR (500 MHz,
CDCl3) 3.779 (s, 3H), 6.797 (d, J¼9.2 Hz, 2H), 7.060 (d, J¼9.2 Hz, 2H),
7.577e7.052 (m, 4H), 7.755 (m,1H), 8.143 (s,1H), 8.232 (m, 2H), 9.022
(s, 1H); 13C NMR (125 MHz, CDCl3) 55.25, 113.97, 122.83, 125.48,
126.51, 127.55, 129.36, 129.44, 129.92, 131.33, 131.68, 133.15, 136.67,
138.47, 142.32, 147.39, 148.13, 151.99, 159.01; IR: 3080, 2980, 2950,
2840, 1610, 1510, 1350, 1240, 1170, 1040, 830, 700 cmꢁ1. HRMS (EI)
calcd for C22H16N2O3: 356.1161; observed: 3556.1160.
To a solution of 48.5 mg (0.168 mmol) of 13 in 2 mL of a 6:1 (v/v)
mixture of dioxanes/water was added 9.7 mg (0.0084 mmol) of
tetrakis(triphenylphosphine) palladium(0), 0.202 mmol of boronic
acid, and 18.8 mg (0.336 mmol) of potassium hydroxide. The so-
lution was degassed by bubbling argon through it for 5 min and
then heated to 90 ꢀC for 24 h. After cooling, 0.336 mmol of the
second boronic acid was added and the reaction mixture heated
once again to 90 ꢀC for 24 h. The cooled reaction was then quenched
with water (20 mL) and extracted with ethyl acetate (3ꢂ10 mL).
Concentration in vacuo afforded a crude product that was purified
using rotary chromatography.
4.3.6. 4-(40-Methoxyphenyl)-3-(30-nitrophenyl)quinoline. Elution from
silica using 20% ethyl acetate in hexanes afforded the title compound
as a yellow solid. Mp: 124e131 ꢀC; 1H NMR (500 MHz, CDCl3) 3.834 (s,
3H), 6.907 (d, J¼8.59 Hz, 2H), 7.114 (d, J¼8.59 Hz, 2H), 7.549e7.422 (m,
3H), 7.789e7.744 (m, 2H), 8.119e8.081 (m, 2H), 8.212 (d, J¼8.59, 1H),
8.977 (s, 1H); 13C NMR (125 MHz, CDCl3) 55.27, 114.00, 122.00, 124.94,
126.68, 127.23, 127.31, 127.34, 129.09, 129.61, 129.76, 130.91, 131.63,
4.3.1. 3-(40-Methoxyphenyl)-4-phenylquinoline. Elution from silica
using 15% ethyl acetate in hexanes afforded the title compound as
a white solid. Mp: 124e130 ꢀC; 1H NMR (500 MHz, CDCl3) 3.813 (s,

4154
A. Piala et al. / Tetrahedron 67 (2011) 4147e4154
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136.09, 140.17, 146.12, 148.00, 148.06, 150.70, 159.43; IR: 3100, 3040,
2960, 2840, 1620, 1530, 1500, 1350, 1250, 1170, 1030, 850, 770,
730 cmꢁ1. HRMS (EI) calcd for C22H16N2O3: 356.1161; observed:
356.1159.
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