The successive substitution of halogens in 4-chloro-6-iodoquinoline by aryl groups in cross-coupling reactions with arylboronic acids

Article abstract of DOI:10.1016/S0040-4039(02)01516-2

The conditions for selective stepwise substitution of iodine and chlorine atoms in 4-chloro-6-iodoquinoline which allow the synthesis of the corresponding diarylquinolines with different aryl groups in the 4- and 6-positions, in a one-pot procedure, in hi

Full text of DOI:10.1016/S0040-4039(02)01516-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7267–7270
The successive substitution of halogens in
4-chloro-6-iodoquinoline by aryl groups in cross-coupling
reactions with arylboronic acids
Alexey V. Tsvetkov, Gennadij V. Latyshev, Nikolai V. Lukashev* and Irina P. Beletskaya
Department of Chemistry, Moscow State Lomonosov University, Vorobyevy Gory, Moscow 119992, Russia
Received 22 May 2002; revised 12 July 2002; accepted 19 July 2002
Abstract—The conditions for selective stepwise substitution of iodine and chlorine atoms in 4-chloro-6-iodoquinoline which allow
the synthesis of the corresponding diarylquinolines with different aryl groups in the 4- and 6-positions, in a one-pot procedure,
in high yields are reported. A significant effect of the addition of water or Bu4NBr on the rate and yield of both stages was
discovered. © 2002 Elsevier Science Ltd. All rights reserved.
Over the past 5 years the elaboration of strategies for
regioselective Pd-catalyzed CꢀC bond forming reactions
in dihaloheteroarenes has attracted considerable atten-
tion.1 We used 4-chloro-6-iodoquinoline 12 as a model
compound for the study of selective cross-coupling
reactions as polysubstituted quinolines are known to
possess versatile biological activity.3 A priori it was
difficult to predict how different the reactivity of the
two Csp2ꢀHal bonds in 1 would be during Suzuki-cou-
pling, taking into consideration that the CꢀCl bond in
the pyridine ring is activated. The search for a catalyst
was performed in the reaction of 1 with 4-anisylboronic
acid in the ratio 1:1 in THF–H2O (3:1) using K2CO3 as
(Scheme 1). The structure and purity of the isolated
product 2 was proved by H NMR spectroscopy and
elemental analysis.
1
On the contrary for the second step, substitution of
chlorine (Scheme 2), the best result was achieved with
Pd(PPh3)4 as the catalyst. After 48 h, the yield of diaryl
substituted product was 82%. Other Pd catalysts
showed unsatisfactory results.
We have found that the two-step reaction can be per-
formed in a one-pot manner with Pd(PPh3)4 (Scheme
3). The second arylboronic acid was added to the
reaction mixture after the first reaction was complete.
a
base. In all cases we observed only iodine
replacement.
Using Pd(PPh3)4 (2 mol%) as catalyst in the reaction
(Scheme 3), we studied the influence of solvent, temper-
ature, bases, addition of water and Bu4NBr (Table 1).
The best results were obtained either with phosphine-
free catalyst precursor Pd(OAc)2 or PdCl2(dppf)
Cl
O
Cl
N
O
B(OH)2
I
N
1
THF - H2O - 3 : 1
64 0C (reflux)
"Pd" 2 mol %
K2CO3
100%
2
PdCl2(dppf)
Pd(OAc)2
Pd(PPh3)4
PdCl2(PPh3)2
4 h
4 h
15 h
5 h
Scheme 1.
Keywords: palladium; Suzuki reaction; successive cross-coupling; diarylquinolines.
* Corresponding author. Tel.: +7-095-939-53-10; e-mail: nvluk@org.chem.msu.su
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01516-2

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A. V. Ts6etko6 et al. / Tetrahedron Letters 43 (2002) 7267–7270
O
Cl
O
B(OH)2
N
2
"Pd" 2 mol %
K2CO3
THF - H2O - 3 : 1
64 0C (reflux), 48 h
N
3
PdCl2(dppf)
Pd(OAc)2
Pd(PPh3)4
PdCl2(PPh3)2
11 %
4 %
82 %
21 %
Scheme 2.
Cl
N
O
O
B(OH)2
2)
1)
B(OH)2
I
"Pd" 2 mol % THF - H2O - 3 : 1
N
1
64 0C (reflux)
K2CO3
3
first step time*
second step time
yield of 3
69 %
19 %
2.5 %
<1 %
Pd(PPh3)4
15 h
5 h
4 h
4 h
48 h
48 h
48 h
48 h
PdCl2(PPh3)2
PdCl2(dppf)
Pd(OAc)2
*The yield of the reaction after the first step is quantitative.
Scheme 3.
simple cross-coupling reaction of 4-iodotoluene with
4-anisylboronic acid. The addition of Bu4NBr into
dioxane–H2O (3:1) does not influence the rate or yields
of the products of the first and second steps (entry 13).
In a benzene–H2O mixture the result was practically the
same as in aqueous THF but in aqueous MeCN and
particularly in aqueous dioxane the reaction proceeds
much faster (100% in 0.5 h for the first step and 97% in
4 h for the second step) (entries 1–4). However, this
difference is mainly accounted for by the difference in
the reflux temperature, because in aqueous dioxane at
64°C the first step is faster than in aqueous THF while
the second step does not proceed at all. At room
temperature even the first step of the reaction is very
slow (entries 9 and 10).
Under the optimal conditions chosen above we have
synthesized several diarylquinolines with the same or
different aryl substituents in very high yields (Scheme
4).4
The substituent on the phenyl ring in the product
forming at the first stage influences the rate of the
second step. Thus the substitution of chlorine in 4-
chloro-6-(4-chlorophenyl)quinoline proceeds faster then
in 4-chloro-6-(4-tolyl)quinoline or 4-chloro-6-(4-
anisyl)quinoline.
The nature of base is also an important factor. The best
result was obtained with K3PO4. The activity of the
bases decreases in the order K3PO4>K2CO3>Ba(OH)2>
CsF, but the general yield is high in all cases (entries
5–8). The presence of water significantly accelerates the
reaction. In anhydrous dioxane, the reaction requires 4
h for completion of the first step and after the second
step only 7% of product was obtained after 48 h (entry
11). The addition of the phase-transfer agent Bu4NBr
(0.5 equiv.) to the reaction in anhydrous dioxane
resulted in an increase in yield of the second reaction to
37% after 48 h, while the effect of this agent on the first
reaction was negative, essentially leading to retardation
(entry 12). The deleterious effect of Bu4NBr on the
cross-coupling at iodine is unexpected. In a separate
experiment this effect was confirmed to take place in a
All compounds obtained were characterized by 1H
NMR spectroscopy5 and elemental analyses.
Acknowledgements
We are grateful to Russian Foundation for Basic
Research (Grant No. 00-15-97406 and 01-03-33144)
and the foundation ‘Integration of High School and
Academy of Sciences’ (Grant AO-115) for financial
support.

A. V. Ts6etko6 et al. / Tetrahedron Letters 43 (2002) 7267–7270
7269
Table 1.
No.
Solvent, additives
Base
T (°C)
Time of first
stage (h)
Yield of first
stage (%)
Time of second
stage (h)
Yield of second
stage (%)
1
2
3
4
THF/H2O–3/1
K2CO3
K2CO3
K2CO3
K2CO3
64
100
69
15
0.5
15
2
100
100
100
100
48
4
48
14
69
97
50
83
Dioxane/H2O–3/1
Benzene/H2O–3/1
MeCN/H2O–3/1
76
5
6
7
8
Dioxane/H2O–3/1
Dioxane/H2O–3/1
Dioxane/H2O–3/1
Dioxane/H2O–3/1
K2CO3
K3PO4
CsF
100
100
100
100
0.5
0.25
7
100
100
100
100
4
4
12
4
97
97
97
88
Ba(OH)2
0.25
9
10
Dioxane/H2O–3/1
Dioxane/H2O–3/1
K2CO3
K2CO3
64
20
5
48
100
44
48
48
0
0
11
12
13
Dioxane
K2CO3
K2CO3
K2CO3
100
100
100
4
15
0.5
100
100
100
48
48
4
7
37
93
Dioxane+0.5 equiv. Bu4NBr
Dioxane/H2O–3/1+0.5 equiv.
Bu4NBr
Ar'
N
Cl
N
Ar
I
Ar'B(OH)
2)
ArB(OH)
1)
2
2
Pd(PPh3)4 2 mol % dioxane - H2O - 3 : 1
100 0C (reflux)
K2CO3
Cl
N
O
Cl
Cl
4
5
6
3
N
N
N
0.5
2.5
89 (87)
first step time, h
3
0.5
4
97 (96)
0.5
4
97 (96)
second step time, h
yield of product, %
(isolated)
100 (99)
Scheme 4.
4. Typical experiment: 4-Chloro-6-iodoquinoline (50 mg,
0.172 mmol), 0.172 mmol of first the boronic acid, 144 mg
of K2CO3 (1.032 mmol), 1.5 ml of dioxane and 0.5 ml of
water were refluxed under argon with 3.4 mmol (2 mol%)
of catalyst. The reaction was monitored by TLC. After the
reaction was finished, the second boronic acid (0.224
mmol, 1.3 equiv.) was added to the reaction mixture. After
the second reaction was finished the reaction mixture was
diluted with ether, filtered through silica gel, evaporated in
vacuo, and purified by column chromatography using
silica gel (ether–hexane 1:1).
References
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5. 1H NMR data (CDCl3, 400 MHz) of coupling products.
Compound 2: l 3.86 (s, 3H), 7.02 (m, 2H), 7.47 (d, J
(H,H)=4.7 Hz, 1H), 7.66 (m, 2H), 7.98 (dd, J (H,H)=8.8
Hz, J (H,H)=2.1 Hz, 1H), 8.15 (d, J (H,H)=8.8 Hz, 1H),
8.33 (d, J (H,H)=2.1 Hz, 1H), 8.73 (d, J (H,H)=4.7 Hz,
1H). Compound 3: l 2.44 (s, 3H), 3.81 (s, 3H), 6.95 (m,
2H), 7.31 (m, 3H), 7.42 (m, 2H), 7.52 (m, 2H), 7.92 (dd, J
(H,H)=8.8 Hz, J (H,H)=2.1 Hz, 1H), 8.06 (d, J (H,H)=
2.1 Hz, 1H), 8.20 (d, J (H,H)=8.8 Hz, 1H), 8.87 (d, J
(H,H)=4.7 Hz, 1H). Compound 4: l 2.35 (s, 3H), 2.43 (s,
3H), 7.21 (m, 2H), 7.29 (m, 3H), 7.42 (m, 2H), 7.47 (m,

7270
A. V. Ts6etko6 et al. / Tetrahedron Letters 43 (2002) 7267–7270
(d, J (H,H)=8.8 Hz, 1H), 8.91 (d, J (H,H)=4.4 Hz, 1H).
2H), 7.93 (dd, J (H,H)=8.8 Hz, J (H,H)=2.1 Hz, 1H), 8.09
Compound 6: l 7.29 (d, J (H,H)=4.4, 1H), 7.36 (m, 2H),
7.43 (m, 2H), 7.48 (m, 4H), 7.91 (dd, J (H,H)=8.8 Hz, J
(H,H)=2.1 Hz, 1H), 7.96 (d, J (H,H)=2.1 Hz, 1H), 8.24
(d, J (H,H)=8.8 Hz, 1H), 8.92 (d, J (H,H)=4.4 Hz, 1H).
(d, J (H,H)=2.1 Hz, 1H), 8.19 (d, J (H,H)=8.8 Hz, 1H),
8.86 (d, J (H,H)=4.7 Hz, 1H). Compound 5: l 2.46 (s, 3H),
7.36 (m, 7H), 7.50 (m, 2H), 7.90 (dd, J (H,H)=8.8 Hz, J
(H,H)=2.1 Hz, 1H), 8.07 (d, J (H,H)=2.1 Hz, 1H), 8.21