Preparation and reactivity of 3-amino-2,4-dichloroquinoline

Article abstract of DOI:10.1055/s-0032-1316733

A simple and efficient synthesis of 2-substituted 3-amino-4- chloroquinolines and 2,4-disubstituted 3-aminoquinolines was carried out by reacting 3-amino-2,4-dichloroquinoline with various oxygen-, sulfur- and nitrogen-containing nucleophiles. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316733

LETTER
▌2205
letter
Preparation and Reactivity of 3-Amino-2,4-dichloroquinoline
3-Amino-2,4-dichloroquinoline
Adam Šimáček,a Martin Grepl,b Ludmila Hradilová,a,b Pavel Hradil*a,b
a
Department of Organic Chemistry, Palacky University, Tr. 17. Listopadu 12, 77146 Olomouc, Czech Republic
b
Farmak a.s., Na Vlčinci 16/3, 77117 Olomouc, Czech Republic
E-mail: ph.1@tiscali.cz; E-mail: hradil@farmak.cz
Received: 23.03.2012; Accepted after revision: 01.07.2012
opening reaction of the pyridinium salts is referred to as
Zincke cleavage and has been described earlier.7,8
Abstract: A simple and efficient synthesis of 2-substituted 3-ami-
no-4-chloroquinolines and 2,4-disubstituted 3-aminoquinolines
was carried out by reacting 3-amino-2,4-dichloroquinoline with
various oxygen-, sulfur- and nitrogen-containing nucleophiles.
After the recrystallization from methanol, compound 3, in
the form of a white powder, can be used for other reac-
Key words: heterocycles, quinolones, dichloroquinoline, amino- tions.
quinoline, substitution
O
Cl
+N
+N
Cl
POCl3
Quinoline derivatives are a class of heterocyclic com-
pounds that have importance in organic chemistry and
pharmaceutical chemistry; these compounds are also pre-
cursors for many biologically active compounds.1,2 The
best-known quinoline alkaloid is quinine, which has been
widely used to treat malaria.3 Some new thiazolo
[5,4-b]quinolines have recently been considered as poten-
tial anticancer drugs (1).4,5 The structurally related tacrine
(2) received notable importance for the development of
drugs against Alzheimer’s disease (Figure 1).6
DMA, reflux
N
H
4
OH
N
5
Cl
Cl
NH2
O
NH2
AcONH4
melting
HOCH2CH2NH2
EtOH, reflux
5
N
H
6
N
Cl
3
Scheme 1 Synthesis of compound 3
Et
Cl
NH2
Melted ammonium acetate was reacted with compound 3,
and product 6 was isolated as the main product.
N
Et
N
S
NH
Based on this reaction scheme, a series of 2-substituted 3-
amino-4-chloroquinolines was prepared by reacting com-
pound 3 with various oxygen-, sulfur- and nitrogen-
containing nucleophiles. Several 2,4-disubstituted 3-ami-
noquinolines were isolated when some thiophenols were
used (Scheme 2).
N
N
1
2
Figure 1 Structure of thiazolo[5,4-b]quinoline with anticancer
activity 1 and parasympathomimetic tacrine (2)
Our interest was in the synthesis of 3-amino-2,4-dichloro-
quinoline (3) from compound 4, which was chosen as a
simple and versatile starting material (Scheme 1).7 The re-
action of compound 4 with an excess of phosphorus oxy-
chloride and a catalytic amount of N,N-dimethylaniline
(DMA) gave compound 5 in good yield. The chlorination
of 4 using thionyl chloride or phosphorus oxychloride, in
the absence of a catalyst, was not successful.
Compounds 8–13 were prepared by reacting compound
3 with sodium alcoholate in the corresponding alcohol.
Crude products in the forms of white powders were ob-
tained after the addition of cold water to the reaction mix-
ture. The reactions of the phenols and thiols (or
thiophenols) were carried out in DMF solution containing
a two-molar excess of the corresponding nucleophile and
a four-molar excess of potassium carbonate as a base. Un-
der these conditions, crude products were isolated after
the evaporation of the DMF under reduced pressure and
extraction with ethyl acetate or diethyl ether from the re-
action mixture diluted with water. Both of the thiophenol
derivatives were separated using column chromatogra-
phy.
Although compound 5 is considered to be a pyridinium
salt, it was not isolated in crystalline form, and it was used
in the crude form in the subsequent reaction steps. The
transformation of compound 5 into 3 was performed using
an amine base in an ethanolic solution. Many aliphatic
amines were tested in this reaction, and 2-aminoethanol
was favored because of its higher boiling point. This ring-
Reactions of compound 3 with excess amounts of amines
were carried out without solvent, and the crude products
were isolated after the evaporation of the amine and/or ex-
traction with diethyl ether. Compound 7 was prepared by
the reaction of 3 with sodium azide in DMF and isolated
SYNLETT 2012, 23, 2205–2208
Advanced online publication: 31.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316733; Art ID: ST-2012-D0272-L
© Georg Thieme Verlag Stuttgart · New York

2206
A. Šimáček et al.
LETTER
Cl
N
than position 4. Only very strong nucleophiles (e.g. thio-
phenolate ions) attack both positions and yield two prod-
ucts. The higher reactivity of the C-2 position was
concluded from 2D NMR of molecules 8 and 32. Their
structure was proved by the HMBC experiment. The in-
teraction between hydrogens of the methyl group in com-
pound 8 with carbon C-2 (δ = 153 ppm) is seen as the
cross-peak. This carbon has no cross-peak interaction
with any aromatic hydrogen. This cross-peak interaction
from hydrogen (δ = 7.78 ppm) on C-5 must be present if
C-4 is substituted by methoxy group. The same situation
is valid for hydrogen of NH group and hydrogen on C-11
of compound 32. The reactivity of positions 2 and 4 are
the opposite of the reactivity of these positions in 2,4-di-
chloro-3-substituted quinolines when the substituent in
position 3 is an electron-withdrawing group such as a cy-
ano group.9
NH2
R1
N
R2
Cl
N
NH2
HNR1R2
R1SH
R1
Cl
N
S
R1OH
NH2
3
DMF, K2CO3
R1
O
R1
S
N
NaN3
DMF
NH2
R1
S
Cl
Cl
N
NH2
NH2
The chemical structure and regioselectivity were con-
firmed with mass spectrometry (CIMS) and NMR10–17
(one- and two-dimensional NMR spectra are available as
Supporting Information). The numbering of carbons for
NMR purposes is shown on the structure in Table 1.
N
N3
N
7a
N
7b
N
Scheme 2 Reaction of compound 3 with various nucleophiles
after addition of water (extraction to ethyl acetate is pos-
sible).
Acknowledgment
This project was supported in part by the Ministry of Education,
Youth and Sport of the Czech Republic (grants IGA
453103071/31).
All prepared compounds are listed in Table 1.
We concluded that position 2 on the quinoline ring is
much more reactive in nucleophilic replacement reactions
Table 1 Chemical Structures of the Prepared Compounds
R2
4
5
8
NH2
6
7
3
R1
2
N
1
Compound R1
R2
Yield (%) Mp (°C)
Compound R1
4-FC6H4S
R2
Yield (%) Mp (°C)
8
9
MeO
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
90
80
78
75
79
70
50
43
25
50
55
50
77
45
89– 92
89– 90
74– 75
70– 72
129–132
76– 79
111–114
123–125
104–107
131–133
143–145
150–152
83– 86
94– 97
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Cl
43
33
45
44
40
40
25
40
40
68
85
49
35
25
122–124
147–150
156–158
86– 89
EtO
4-ClC6H4S
4-BrC6H4S
4-MeOC6H4S
PhS
Cl
10
11
12
13
14
15
16
17
18
19
20
21
MeOCH2CH2O
EtOCH2CH2O
HOCH2CH2O
(Me)2NCH2CH2O
PhO
Cl
Cl
PhS
120–122
99–102
4-FC6H4S
4-ClC6H4S
4-BrC6H4S
4-MeOC6H4S
EtNH
4-FC6H4S
4-ClC6H4S
120–123
148–150
128–130
140–143
59– 62
2-MeC6H4O
4-MeC6H4O
4-ClC6H4O
4-BrC6H4O
4-IC6H4O
4-BrC6H4S
4-MeOC6H4S
Cl
Cl
Cl
Cl
Cl
n-BuNH
Et2N
gel form
149–152
169–171
MeO(O)CCH2S
PhS
BnNH
PhNH
Synlett 2012, 23, 2205–2208
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Amino-2,4-dichloroquinoline
2207
oxychloride removal in the previous step. The end of the
reaction was determined using TLC and HPLC. EtOH was
removed by distillation under reduced pressure. To a
sufficiently concentrated reaction mixture (170 g), H2O was
added, and compound 3 solidified in the form of a white
solid. The product was washed with H2O and dried (8.4 g;
47% yield calculated on compound 4).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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References and Notes
(1) Kouznetsov, V. V.; Méndez, L. Y. V.; Gómez, C. M. M.
Curr. Org. Chem. 2005, 9, 141.
(2) Kategaonkar, A. H.; Pokalwar, R. U.; Sonar, S. S.; Gawali,
V. U.; Shingate, B. B.; Shingare, M. S. Eur. J. Med. Chem.
2010, 45, 1128.
(3) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew.
Chem. Int. Ed. 2003, 43, 5274.
(4) Loza-Mejía, M. A.; Maldonado-Hernández, K.; Rodríguéz-
Hernández, F.; Rodríguéz-Sotres, R.; González-Sánchez, I.;
Quintero, A.; Solano, J. D.; Lira-Rocha, A. Bioorg. Med.
Chem. 2008, 16, 1142.
(5) Loza-Mejía, M. A.; Olvera-Vázquez, S.; Maldonado-
Hernández, K.; Guadarrama-Salgado, T.; González-
Sánchez, I.; Rodríguéz-Hernández, F.; Solano, J. D.;
Rodríguez-Sotres, R.; Lira-Rocha, A. Bioorg. Med. Chem.
2009, 17, 3266.
(6) Elsinghorst, P. W.; Härtig, W.; Gündisch, D.; Mohr, K.;
Tränkle, C.; Gütschow, M. Curr. Top. Med. Chem. 2011, 11,
2731.
(7) Rehwald, M.; Bellmann, P.; Jeschke, T.; Gewald, K.
J. Prakt. Chem. 2000, 342, 371.
(8) Hewawasam, P.; Chen, N.; Ding, M.; Natale, J. T.; Boissard,
C. G.; Yeola, S.; Gribkoff, V. K.; Starrett, J.; Dworetzky,
S. I. Bioorg. Med. Chem. 2004, 14, 1615.
Note: Ethylamine and aq methylamine were both
successfully used for this reaction instead of ethanolamine.
When using these compounds, the reactions were carried out
in pressure tubes; C9H6Cl2N2 (211.99); mp 115–119 °C. MS:
m/z (%) = 213.2 (100) [M(35Cl) + H]+, 215.2 (60), 217.1
(10).
1H NMR (400 MHz, DMSO-d6):  = 7.90 (ddd, 1 H, J = 8.4,
1.4, 0.6 Hz, H-5), 7.82 (ddd, 1 H, J = 8.3, 1.2, 0.6 Hz, H-8),
7.62 (ddd, 1 H, J = 8.4, 6.9, 1.3 Hz, H-6), 7.52 (ddd, 1 H, J
= 8.3, 6.9, 1.4 Hz, H-7), 6.13 (s, 2 H, NH2). 13C NMR (100
MHz, DMSO-d6):  = 140.4, 139.6, 136.4, 128.8, 128.6,
126.7, 126.6, 122.1, 118.0.
(12) Procedure for the Preparation of 3-Amino-4-
chloroquinolin-2(1H)-one (6): Compound 3 (0.4 g, 1.87
mmol) and ammonium acetate (3.45 g, 44.75 mmol) were
mixed and the reaction mixture was stirred in an oil bath in
the melted state (160 °C) for 6 h. The end of the reaction was
determined using TLC. The reaction mixture was diluted
with H2O and extracted with EtOAc. The combined organic
layer was dried and concentrated. A white crystalline
powder was obtained with a yield of 0.1 g (yield: 28%);
C9H7ClN2O (194.02); mp 227–233 °C. MS: m/z (%) = 195.1
(100) [M(35Cl) + H]+, 197.1 (35).
(9) Mekheimer, R. A. J. Chem. Soc., Perkin Trans. 1999, 2183.
(10) Preparation of 1-(2,4-Dichloroquinolin-3-yl)pyridinium
Salt (5):
1H NMR (400 MHz, DMSO-d6): d = 12.1 (bs, 1 H, NH), 7.59
(dd, 1 H, J = 7.6, 1.0 Hz, H-5), 7.29-7.27 (m, 2 H, H-7, H-8),
7.22 (t, 1 H, J = 7.8 Hz, H-6), 5.76 (s, 2 H, NH2). 13C NMR
(100 MHz, DMSO-d6): d = 157.0, 135.4, 131.3, 125.9,
123.1, 121.6, 119.8, 115.5, 111.1.
Compound 4 (20 g, 83.6 mmol) and N,N-dimethylaniline
(1.26 g, 10.4 mmol) were mixed and phosphorus
oxychloride (200 mL, 2.14 mol) was added all at once.
The reaction mixture was stirred vigorously and heated.
Compound 4 gradually dissolved yielding a yellow solution
that was heated to boiling for 3 h. The end of the reaction was
determined using TLC. After the reaction was complete, the
phosphorus oxychloride was removed by distillation under
reduced pressure, and the crude product was mixed with
toluene (2 × 40 mL). Toluene was properly removed by
distillation under reduced pressure. Compound 5 was
isolated in the form of a brown gel, which immediately
solidified to form a brown resin.
(13) Procedure for the Preparation of 5-Chlorotetrazolo[1,5-
a]quinolin-4-amine (7): Compound 3 (1 g, 4.7 mmol) was
dissolved in DMF (4.6 g). To this solution was added a
suspension of sodium azide (0.5 g, 7.7 mmol) in DMF (15.8
g). The reaction mixture was stirred vigorously and heated to
100 °C for 5.5 h. During this time, another portion of DMF
(10.5 g) was added. The end of the reaction was determined
using TLC. DMF was removed by distillation under reduced
pressure, and the reaction mixture was extracted with
EtOAc. The organic layer was dried and concentrated. The
product was obtained in the form of almost white powder
(0.75 g, 73%); C9H6ClN5 (219.03); mp 243–244 °C. MS: m/z
(%) = 220.1 (100) [M(35Cl) + H]+, 222.1 (30).
1H NMR (400 MHz, DMSO-d6):  = 9.53 (dd, 2 H, J = 6.7,
1.3 Hz, py), 9.10 (tt, 1 H, J = 7.9, 1.4 Hz, py), 8.63 (dd, 2 H,
J = 7.9, 6.8 Hz, py), 8.40 (ddd, 1 H, J = 8.4, 1.3, 0.6 Hz, H-
5), 8.28 (ddd, 1 H, J = 8.5, 1.2, 0.6 Hz, H-8), 8.19 (ddd, 1 H,
J = 8.4, 7.0, 1.4 Hz, H-7), 8.03 (ddd, 1 H, J = 8.3, 7.0, 1.3
Hz, H-6). 13C NMR (100 MHz, DMSO-d6):  = 150.6, 147.4,
147.3, 144.5, 141.7, 134.9, 131.8, 130.9, 125.8, 124.9,
130.1, 129.3.
1H NMR (400 MHz, DMSO-d6):  = 8.39 (dd, 1 H, J = 8.2,
1.0 Hz, H-8), 7.92 (dd, 1 H, J = 8.3, 1.0 Hz, H-5), 7.66 (ddd,
1 H, J = 8.4, 7.3, 1.3 Hz, H-6), 7.57 (ddd, 1 H, J = 8.4, 7.3,
1.3 Hz, H-7), 6.84 (s, 2 H, NH2). 13C NMR (100 MHz,
DMSO-d6):  = 143.6, 130.5, 129.1, 126.5, 124.6, 123.9,
123.3, 116.6, 106.4.
(11) Procedure for the Preparation of 3-Amino-2,4-
dichloroquinoline (3): Crude product 5 isolated in the
previous reaction step was dissolved in EtOH (600 mL). The
solution was heated to boiling, and ethanolamine (40 g, 0.65
mol) was added over a period of 20 min. The reaction
mixture changed color from yellow to purple. The reaction
mixture was heated to boiling for 16 h with vigorous stirring.
During this time, another portion of ethanolamine (40 g, 0.65
mol) was added in small parts to the reaction mixture to
bring the pH of the solution into the alkaline range (the
fumes evolving from the reaction mixture must give a blue
color on moistened pH paper). It is necessary to note that the
amount of ethanolamine used for this reaction step and the
reaction time depends on the quality of the phosphorus
(14) Representative Procedure for the Preparation of 3-
Amino-4-chloro-2-methoxyquinoline (8): Compound 3
(0.13 g, 0.61 mmol) was dissolved in hot MeOH (2 mL). Into
this solution a solution of sodium methoxide (0.2 g, 3.7
mmol) in MeOH (4 mL) was added, and the reaction mixture
was heated to boiling for 2 h. The end of the reaction was
determined using TLC. The addition of H2O to the reaction
mixture led to the solidification of the product in the form of
a white solid (yield: 0.11 g, 90%); C10H9ClN2O (208.04); mp
89–92 °C. MS: m/z (%) = 208.9 (100) [M(35Cl) + H]+, 210.9
(33).
1H NMR (400 MHz, DMSO-d6):  = 7.78 (dd, 1 H, J = 7.6,
1.9 Hz, H-5), 7.68 (dd, 1 H, J = 7.5, 1.8 Hz, H-8), 7.43- 7.36
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2205–2208

2208
A. Šimáček et al.
LETTER
(m, 2 H, H-6, H-7), 5.72 (s, 2 H, NH2), 4.04 (s, 3 H, Me). 13
NMR (100 MHz, DMSO-d6):  = 153.3, 138.2, 130.4, 127.1,
125.6, 125.6, 124.7, 121.4, 114.8, 54.3.
C
(and the corresponding disulfide that was observed as a by-
product) were separated using liquid column chromatog-
raphy (stationary phase: silica gel; mobile phase: toluene).
Compound 23: yield: 0.25 g, 33%; compound 28: yield: 0.25
g, 25%. Compound 23: C15H10Cl2N2S (319.99); mp 147–150
°C. MS: m/z (%) = 320.9 (100) [M(35Cl) + H]+, 322.8 (65),
324.8 (15). 1H NMR (400 MHz, DMSO-d6):  = 7.88 (dd, 1
H, J = 8.2, 1.3 Hz, H-5), 7.56 (d, 2 H, J = 8,6 Hz, ArH), 7.56–
7.54 (m, 1 H, H- 8), 7.52 (d, 2 H, J = 8,6 Hz, ArH), 7.52–7.50
(m, 1 H, H- 6), 7.41 (dt, 1 H, J = 7.6, 1.2 Hz, H-7), 5.86 (s, 2
H, NH2). 13C NMR (100 MHz, DMSO-d6):  = 148.0, 141.1,
136.8, 135.8, 134.0, 129.7, 129.4, 128.6, 127.9, 126.1,
125.9, 122.0, 117.2. Compound 28: C21H14Cl2N2S2 (427.99);
mp 120–123 °C. MS: m/z (%) = 428.9 (100) [M(35Cl) + H]+,
430.8 (70), 431.8 (25)1H NMR (400 MHz, DMSO-d6): d =
7.95 (dd, 1 H, J = 8.3, 0.8 Hz, H-5), 7.57 (d, 2 H, J = 8.8 Hz,
ArH), 7.56– 7.53 (m, 1 H, H-8), 7.53 (d, 2 H, J = 8.7 Hz,
ArH), 7.42 (dt, 1 H, J = 7.6, 1.2 Hz, H-6), 7.34 (dt, 1 H, J =
7.5, 1.3 Hz, H-7), 7.29 (d, 2 H, J = 8.6 Hz, ArH), 7.04 (d, 2
H, J = 8.6 Hz, ArH), 6.03 (s, 2 H, NH2). 13C NMR (100 MHz,
DMSO-d6): d = 148.4, 143.0, 141.4, 135.9, 134.2, 134.0,
131.0, 129.7, 129.4, 129.4, 129.3, 128.9, 128.7, 128.0,
125.6, 123.7, 110.8.
(15) Representative Procedure for the Preparation of 3-
Amino-4-chloro-2-(4-methylphenoxy)quinoline (16):
K2CO3 (1.29 g, 9.33 mmol) and 4-methylphenol (0.5 g, 4.62
mmol) were mixed with DMF (6 mL). Into this suspension a
solution of compound 3 (0.5 g, 2.35 mmol) dissolved in
DMF (5 mL) was added. The reaction mixture was heated to
120 °C for 4.5 h. The end of the reaction was determined
using TLC. After the reaction was complete, the K2CO3 was
filtered off, and the solution was concentrated under reduced
pressure. The crude product was mixed with an aqueous
solution of K2CO3 (10%) and extracted with Et2O. The
organic layers were separated and dried. The evaporation of
Et2O under reduced pressure and the addition of MeOH led
to the solidification of the product in the form of a white
powder (yield: 0.17 g, 25%); C16H13ClN2O (284.07); mp
104–107 °C. MS: m/z (%) = 285.2 (100) [M(35Cl) + H]+,
287.1 (32).
1H NMR (400 MHz, DMSO-d6): d = 7.82 (ddd, 1 H, J = 8.2,
1.4, 0.5 Hz, H-5), 7.47 (ddd, 1 H, J = 8.2, 1.3, 0.5 Hz, H-8),
7.45-7.30 (m, 2 H, H-6, H-7), 7.26 (dd, 2 H, J = 8.7, 0.6 Hz,
ArH), 7.17 (d, 2 H, J = 8.5 Hz, ArH), 6.01 (s, 2 H, NH2), 2.35
(s, 3 H, Me). 13C NMR (100 MHz, DMSO-d6): d = 152.7,
151.3, 137.7, 134.5, 130.7, 130.3, 127.4, 126.2, 125.7,
125.2, 122.1, 121.4, 116.0, 20.9.
(17) Representative Procedure for the Preparation of N2-
Butyl-4-chloroquinoline-2,3-diamine (32): Compound 3
(0.5 g, 2.35 mmol) was dissolved in n-butylamine (6.8 g,
93 mmol). The reaction mixture was stirred and heated to
boiling for 13 h. Then, the excess of n-butylamine was
removed by distillation under reduced pressure. The addition
of MeOH–H2O (1:1) yielded the product in the form of a
white solid (yield 0.5 g, 85%); C13H16ClN3 (249.10); mp 59–
62 °C. MS: m/z (%) = 250.1 (75) [M(35Cl) + H]+, 252.1 (24)
1H NMR (400 MHz, DMSO-d6):  = 8.46 (dd, 1 H, J = 8.2,
0.9 Hz, H-8), 7.64 (dd, 1 H, J = 8.1, 1.2 Hz, H-5), 7.26 (ddd,
1 H, J = 8.3, 7.0, 1.5 Hz, H-7), 7.18 (ddd, 1 H, J = 8.2, 7.0,
1.3 Hz, H-6), 6.60 (t, 1 H, J = 4.9 Hz, NH), 5.63 (s, 2 H,
NH2), 3.49 (dt, 2 H, J = 7.0, 5.1 Hz, CH2), 1.63 (tt, 2 H, J =
11.1, 7.5 Hz, CH2), 1.41 (qt, 2 H, J = 14.4, 7.3 Hz, CH2),
0.94 (t, 3 H, J = 7.4 Hz, Me). 13C NMR (100 MHz, DMSO-
d6):  = 148.6, 141.1, 128.8, 125.8, 125.2, 122.5, 122.3,
121.2, 114.2, 41.3, 31.3, 20.3, 14.3.
(16) Representative Procedure for the Preparation of 3-
Amino-4-chloro-2-(4-chlorophenylthio)quinoline (23)
and 3-Amino-2,4-bis(4-chlorophenylthio)quinoline (28):
K2CO3 (1.29 g, 9.33 mmol) and 4-chlorothiophenol (0.67 g,
4.63 mmol) were mixed with DMF (6 mL). Into this
suspension a solution of compound 3 (0.5 g, 2.35 mmol)
dissolved in DMF (5 mL) was added. The reaction mixture
was heated to 120 °C for 30 min. The end of the reaction was
determined using TLC. After the reaction was complete, the
K2CO3 was filtered off, and the solution was concentrated
under reduced pressure. The crude product was mixed with
H2O and extracted with Et2O. The organic layers were
separated and dried. The Et2O was removed by distillation
under reduced pressure and the crude product was dissolved
in toluene. Both of 4-chlorothiophenol derivatives (23, 28)
Synlett 2012, 23, 2205–2208
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