Chlorotrimethylsilane-mediated friedlaender synthesis of polysubstituted quinolines

Article abstract of DOI:10.1055/s-2007-966003

New convenient conditions for the Friedlander synthesis of quinolines are described. Polysubstituted quinolines were readily prepared using chlorotrimethylsilane as a promoter and water-acceptor agent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966003

1214
PAPER
Chlorotrimethylsilane-Mediated Friedländer Synthesis of Polysubstituted
Quinolines
C
hlorotrimeth
e
r
diated
F
g
r
iedländer
S
e
y
Polysubstitute
d
QuV
inolines . Ryabukhin,a,b Dmitriy M. Volochnyuk,*a,c Andrey S. Plaskon,b Vasiliy S. Naumchik,a
Andrei A. Tolmachevb
a
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kyiv-94, Ukraine
b
c
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
Received 12 December 2006; revised 29 January 2007
We now show that chlorotrimethylsilane in N,N-dimeth-
Abstract: New convenient conditions for the Friedländer synthesis
of quinolines are described. Polysubstituted quinolines were readily
prepared using chlorotrimethylsilane as a promoter and water-ac-
ceptor agent.
ylformamide can be used as a condensation agent in the
Friedländer annulation.18
Initially we sought a convenient preparative method for
Key words: quinolines, annulation, o-amino aromatic carbonyls, the synthesis of derivatives of quinolin-3-ylacetic acid19
chlorotrimethylsilane, parallel synthesis
without additional functional groups in the pyridine
ring.20 Several approaches have earlier been described for
this acid using 3-acetyl-21a (Willgerodt reaction) or 3-ha-
loquinolines as starting compounds.21b–d For this purpose
The quinoline scaffold plays an important role as a com-
we decided to use a Friedländer annulation based on 4-
oxo acids. 1-(2-Aminophenyl)ethanone (1a) and 4-oxo-
pentanoic acid (6) were chosen as model substrates for the
optimization of the reaction conditions (Scheme 1). The
best results were obtained when heating equivalent quan-
tities of 1-(2-aminophenyl)ethanone (1a) and 4-oxopen-
tanoic acid (6) in N,N-dimethylformamide in the presence
of chlorotrimethylsilane (5 equiv) at 95 °C (water bath)
for eight hours in an Ace pressure tube to keep the volatile
chlorotrimethylsilane and formed hydrogen chloride in
the reaction mixture.18g In this case using starting com-
pounds (2 mmol), N,N-dimethylformamide (2 mL) in an
8-mL Ace pressure tube, after simple dilution with three
volumes of water, filtration, and, if necessary, triturating
with water in an ultrasonic bath for several hours and then
washing with isopropyl alcohol, gave the desired product
13a as its hydrochloride salt in 91% yield with 97% puri-
ty. The reaction was scaled up to 0.25 mol of compound
1a using a 0.5-L autoclave and, in this case, the yield of
13a was 95%.
ponent of antimalarial, antibacterial, anti-asthmatic, anti-
hypertensive, and anti-inflammatory agents.1–3 Aryl-
substituted quinolines exhibit 5-lipoxygenase4 and ty-
rosine kinase PDGF-RTK5 inhibiting properties,
7
leucotriene6 and LTD4 antagonistical properties, and oth-
ers. Furthermore, polyquinolines derived from quinolines
undergo hierarchical self-assembly into a variety of nano-
structures with electronic and photonic functions.8
Although various methods have been developed for quin-
oline synthesis,9 such as the Skraup, Dobner von Miller,
Friedländer, and Combes syntheses, novel methods are
still desired.10 Of the available methods, the Friedländer
annulation is one of the most simple and straightforward
approaches to polysubstituted quinolines.11 Generally the
reaction is carried out either by refluxing an aqueous or al-
coholic solution of reactants in the presence of a base or
by heating the reactants at high temperatures in the ab-
sence of catalyst. Subsequent work has shown that acidic
catalysts are more effective than basic catalysts for the re-
action.11b,12 However, many of these classical methods re-
quire drastic conditions that result in lower yields due to
side reactions. In recent times, iodine,13 Lewis acids14
[e.g., NaAuCl4, Bi(OTf)3, Nd(NO3)3·6H2O], a combina-
tion of acidic catalysts and microwave irradiation,15 and
ionic liquids16 have all been found to be effective for this
conversion; effective methods based on the generation of
aminocarbonyl compounds in situ have also been elabo-
rated.17 Nevertheless, the majority of efficient reaction
procedures requires the use of expensive catalysts or spe-
cial equipment, thus limiting their wider use.
CO2H
TMSCl
DMF
O
CO2H
+
O
NH2
N
1a
6a
13a
Scheme 1
To demonstrate the generality of this method we investi-
gated the scope of this reaction under the optimized con-
ditions [DMF (5 equiv), TMSCl, 95 °C, Ace pressure
tube). The results are summarized in Table 1. As shown in
Table 1 this method is equally effective for both cyclic
and acyclic ketones. In particular, we draw attention to 4-
chloroacetoacetic ester (2c), ethyl pyruvate (5), deriva-
SYNTHESIS 2007, No. 8, pp 1214–1224
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.03.2007
DOI: 10.1055/s-2007-966003; Art ID: P14706SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chlorotrimethylsilane-Mediated Friedländer Synthesis of Polysubstituted Quinolines
1215
tives of piperidin-4-one 7c,i, and sterically hindered ke- literature only the tert-butyl analogue of 11g has been de-
tones 4g,h. It is worthwhile to note that, to our knowledge, scribed, which was obtained by cyclocondensation of 1-
sterically hindered ketones of type 4g,h have not previ- isocyano-2-(2-methoxy-1-phenylvinyl)benzene with tert-
ously been used in the Friedländer annulation. Thus, in the butyllithium.10h
Table 1 Chlorotrimethylsilane-Promoted Synthesis of Quinolines 9–18d,e
R2
R2
N
R4
R3
R4
R3
TMSCl
DMF
O
R1
+
R1
O
NH2
2–8
1
9–18
Entry Amino ketone
Carbonyl compound
Product
Yield
(%)a
Mp (°C)b
[lit.]c
Previously reported
results
1
O
84
199–200
[oil]22a
110 °C (60%);22a
NaAuCl4 (2.5
mol%), 40 °C
(54%);14a Bi(OTf)3
(5 mol%), r.t.
O
O
Me
N
O
Me
NH2
Me
⋅HCl
2a
Me
(82%);14b I2 (1
mol%), r.t. (53%);13
PTSA (1 equiv),
MW (300 W)
9a
1a
1a
1a
1a
1a
(92%)15b
2
3
4
5
90
87
89
81
205–206
[oil]15b
I2 (1 mol%), r.t.
(68%);13 PTSA (1
equiv), MW (300
W) (91%)15b
Me
O
O
O
OEt
⋅HCl
OEt
O
2b
N
Me
O
9b
9c
9d
107–108
Friedländer conden-
sation using 4-chlo-
roacetoacetic ester23
O
Me
Cl
OEt
Cl
OEt
2c
N
243–244
[198]22b
Friedländer conden-
sation using b-
ketoamides24
O
O
O
O
Me
O
NH2
NH2
⋅HCl
2d
2e
N
Me
O
268–269
Cl
Cl
Me
N
N
H
H
⋅HCl
N
Me
O
9e
6
7
1a
1a
86
84
175–176
PTSA (1 equiv),
Me
[105–106]15b MW (300 W)
(95%)15b
O
O
N
2f
⋅HCl
9f
156–157
related cyclization25
O
Me
[166–167]22b using oxonitriles in
EtOAc–piperidine
system or in 18 M
H2SO4
CN
CN
Ph
Ph
3
N
10
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

1216
S. V. Ryabukhin et al.
PAPER
Table 1 Chlorotrimethylsilane-Promoted Synthesis of Quinolines 9–18d,e (continued)
R2
R2
N
R4
R3
R4
R3
TMSCl
DMF
O
R1
+
R1
O
NH2
2–8
1
9–18
Entry Amino ketone
Carbonyl compound
Product
Yield
(%)a
Mp (°C)b
[lit.]c
Previously reported
results
Me
8
1a
Me
86
167–168
DPP (0.5 equiv),
Ph
[108–110]15a 108 °C, MW
(76%)15a
O
⋅HCl
Ph
4a
N
11a
9
1a
83
184–185
Me
[120–121]22c
Me
S
O
N
4b
S
⋅HCl
11b
10
1a
79
195–196
Me
Me
N
H
O
O
N
4c
HN
⋅HCl
11c
12a
11
12
1a
1a
87
91
187–188
237–238
Friedländer conden-
Me
sation using deriva-
tives of pyruvic
acid25a,26
Me
OEt
O
N
CO2Et
5
6
O
Me
CO2H
CO2H
N
Me
O
⋅HCl
13a
13
14
15
1a
1a
1a
82
84
76
183–184
O
Me
N
Me
O
Me
⋅HCl
7a
7b
14a
71–72
O
Me
COOMe
COOMe
N
⋅HCl
14b
14c
211–212
HCl, 140 °C
Me
N
N
Ph
[104–105]22d (55%)22d
N
Ph
⋅HCl
O
7c
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

PAPER
Chlorotrimethylsilane-Mediated Friedländer Synthesis of Polysubstituted Quinolines
1217
Table 1 Chlorotrimethylsilane-Promoted Synthesis of Quinolines 9–18d,e (continued)
R2
R2
N
R4
R3
R4
R3
TMSCl
DMF
O
R1
+
R1
O
NH2
2–8
1
9–18
Entry Amino ketone
Carbonyl compound
Product
Yield
(%)a
Mp (°C)b
[lit.]c
Previously reported
results
16
1a
1a
96
158–159
[58–60]27a
[79]27b
70% H2SO4, heat,
30 min (92%);27a
HCl, 160 °C
Me
N
NH2
⋅HCl
(66%)27b
15
9g
17
18
2c
94
85
111–112
[75–76]23
AcOH–benzene, re-
flux (62%)23
Ph
O
O
OEt
Cl
Ph
NH2
N
1b
1b
140–141
[109–
Ph
Me
O
111]10h
.
O
N
4d
⋅HCl
O
11d
19
1b
96
191–192
[202.5]22f
HCl, 130 °C
(41%)22f
Me
Ph
O
O
4e
5
N
⋅HCl
O
11e
12b
20
21
1b
1b
88
97
90–91 [114–
115]26
Ph
Me
N
CO2Et
6
Ph
CO2H
N
Me
⋅HCl
13b
14d
22
23
1b
1b
92
89
186–187
HCl, 100–200 °C, 2
Ph
N
O
[128–130]22e h (47%);22e
NaAuCl4 (2.5
7d
mol%), 40 °C
(73%);14a Bi(OTf)3
⋅HCl
(5 mol%), r.t.
(90%)14b
215–216
NaAuCl4 (2.5
Ph
N
O
[118–120]14a mol%), 40 °C
(60%)14a
7e
⋅HCl
14e
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

1218
S. V. Ryabukhin et al.
PAPER
Table 1 Chlorotrimethylsilane-Promoted Synthesis of Quinolines 9–18d,e (continued)
R2
R2
N
R4
R3
R4
R3
TMSCl
DMF
O
R1
+
R1
O
NH2
2–8
1
9–18
Entry Amino ketone
Carbonyl compound
Product
Yield
(%)a
Mp (°C)b
[lit.]c
Previously reported
results
24
1b
83
123–124
O
Ph
[137–139]22g
S
S
N
7f
⋅HCl
14f
25
1b
85
212–213
O
Ph
O
S
F
O
S
N
O
O
⋅HCl
7g
F
14g
16
26
27
28
29
1b
1b
1b
87
92
76
81
89–90
NaAuCl4 (2.5
mol%), 60 °C
(50%);14a
O
O
Ph
O
[80–81]14a
CF3
CF3
bmimCl·ZnCl2, 80
8a
8b
N
Me
O
°C (55%)16c
147–148
79–80
Ph
O
O
S
CF3
S
N
CF3
O
17
O
O
Ph
CF3
CF3
CF3
CF3
8c
N
18
204–205
O
Me
O
O
O
N
Me
Me
NH2
O
O
N
4f
⋅HCl
1c
N
11f
30
31
1c
86
93
223–224
Me
O
O
O
N
⋅HCl
7h
14h
82–83
[oil]10h
Ph
O
Me
Cl
Cl
Ph
NH2
O
N
⋅HCl
4g
1c
11g
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

PAPER
Chlorotrimethylsilane-Mediated Friedländer Synthesis of Polysubstituted Quinolines
1219
Table 1 Chlorotrimethylsilane-Promoted Synthesis of Quinolines 9–18d,e (continued)
R2
R2
N
R4
R3
R4
R3
TMSCl
DMF
O
R1
+
R1
O
NH2
2–8
1
9–18
Entry Amino ketone
Carbonyl compound
Product
Yield
(%)a
Mp (°C)b
[lit.]c
Previously reported
results
32
1c
89
141–142
Ph
N
Cl
Me
O
4h
⋅HCl
11h
33
1c
85
177–178
Ph
O
Cl
Cl
Cl
N
F
⋅HCl
4i
F
11i
34
35
1c
94
84
185–186
254–255
O
Ph
Cl
N
Ph
4j
⋅HCl
11j
O
Ph
N
NH
O2N
O2N
⋅HCl
NH
Ph
NH2
O
7i
14i
1c
a Yields refer to pure isolated products.
b Melting points are uncorrected.
c Literature melting points refer to corresponding free base.
d Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
e The HCl content in compounds 9–18 was determined by elemental analysis and by titration using Mettler Toledo DL31 KF Titrator.
Table 2 1H NMRa and APCI MS Data of Quinolines 9–18
1H NMR d (DMSO-d6), J (Hz)
MS m/z
[M + H]+
9a
9b
9c
2.68 (s, 3 H, COCH3), 2.76 (s, 3 H, CH3), 2.81 (s, 3 H, CH3), 7.86 (t, 3J = 8.0, 1 H, 7-Qn), 8.11 (t, 3J = 8.0, 1 H, 6- 200
Qn), 8.38 (d, 3J = 8.0, 2 H, 5,8-Qn)
1.37 (t, 3J = 6.8, 3 H, CH2CH3), 2.75 (s, 6 H, 2 CH3), 4.47 (q, 3J = 6.8, 2 H, CH2CH3), 7.80 (t, 3J = 8.4, 1 H, 7-Qn), 230
7.95 (t, 3J = 8.4, 1 H, 6-Qn), 8.19 (d, 3J = 8.4, 1 H, 5-Qn), 8.28 (d, 3J = 8.4, 1 H, 8-Qn)
1.37 (t, 3J = 6.9, 3 H, CH2CH3), 2.71 (s, 3 H, CH3), 4.46 (q, 3J = 6.9, 2 H, CH2CH3), 4.96 (s, 2 H, CH2Cl), 7.74 (td, 264
3J = 8.4, 4J = 0.9, 1 H, 7-Qn), 7.88 (td, 3J = 8.4, 4J = 0.9, 1 H, 6-Qn), 8.06 (d, 3J = 8.4, 1 H, 5-Qn), 8.22 (d, 3J = 8.4,
1 H, 8-Qn)
9d
9e
9f
2.82 (s, 3 H, CH3), 2.90 (s, 3 H, CH3), 7.89 (t, 3J = 8.4, 1 H, 6-Qn), 8.07(t, 3J = 8.4, 1 H, 7-Qn), 8.19 (br s, 1 H, NH), 201
8.29 (br s, 1 H, NH), 8.39 (d, 3J = 8.4, 1 H, 8-Qn), 8.44 (d, 3J = 8.4, 1 H, 5-Qn)
2.85 (s, 3 H, CH3), 2.90 (s, 3 H, CH3), 7.47 (d, 3J = 8.7, 2 H, 2,6-Ar), 7.79 (d, 3J = 8.7, 2 H, 3,5-Ar), 7.92 (t, 3J = 8.4, 311
1 H, 7-Qn), 8.09 (t, 3J = 8.4, 1 H, 6-Qn), 8.42 (d, 3J = 8.4, 2 H, 5,8-Qn), 11.20 (s, 1 H, NH)
1.11 [s, 6 H, C(CH3)2], 2.75 (s, 2 H, COCH2), 3.18 (s, 3 H, CH3), 3.49 (s, 2 H, CH2), 7.91 (t, 3J = 8.4, 1 H, 7-Qn),
8.15 (t, 3J = 8.4, 1 H, 6-Qn), 8.47 (d, 3J = 8.4, 1 H, 5-Qn), 8.59 (d, 3J = 8.4, 1 H, 8-Qn)
240
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1220
S. V. Ryabukhin et al.
PAPER
Table 2 1H NMRa and APCI MS Data of Quinolines 9–18 (continued)
1H NMR d (DMSO-d6), J (Hz)
MS m/z
[M + H]+
9g
0.82 (t, 3J = 6.8, 3 H, CH2CH3), 3.97 (q, 3J = 6.8, 2 H, CH2CH3), 5.01 (s, 2 H, CH2Cl), 7.35 (m, 2 H, Ph), 7.52 (m, 4 326
H, Ph, 5-Qn), 7.66 (t, 3J = 8.4, 1 H, 7-Qn), 7.90 (t, 3J = 8.4, 1 H, 6-Qn), 8.14 (d, 3J = 8.4, 1 H, 8-Qn)
10
2.99 (s, 3 H, CH3), 7.58 (m, 3 H, Ph), 7.77 (m, 1 H, 7-Qn), 7.87 (m, 2 H, Ph), 7.97 (m, 1 H, 6-Qn), 8.12 (d, 3J = 8.4, 245
1 H, 5-Qn), 8.30 (d, 3J = 8.4, 1 H, 8-Qn)
11a
11b
11c
2.95 (s, 3 H, CH3), 7.68 (m, 3 H, 3,4,5-Ph), 7.85 (t, 3J = 8.0, 1 H, 7-Qn), 8.05 (s, 1 H, 3-Qn), 8.30 (m, 4 H, 2,6-Ph, 220
5,6-Qn), 8.48 (m, 1 H, 8-Qn)
2.80 (s, 3 H, CH3), 7.30 (m, 1 H, 4-Th), 7.67 (m, 1 H, 7-Qn), 7.83–7.91 (m, 2 H, 6-Qn, 3-Th), 8.07 (s, 1 H, 3-Qn), 226
8.14 (dd, 3J = 8.4, 4J = 0.9, 1 H, 5-Qn), 8.26–8.30 (m, 2 H, 8-Qn, 5-Th)
2.82 (s, 3 H, CH3), 6.43 (dd, 3J1 = 4.2, 3J2 = 2.1, 1 H, 4-pyr), 7.45 (d, 3J = 2.1, 1 H, 3-pyr), 7.64 (d, 3J = 4.2, 1 H, 5- 209
pyr), 7.72 (t, 3J = 8.4, 1 H, 7-Qn), 7.94 (t, 3J = 8.4, 1 H, 6-Qn), 8.14 (d, 3J = 8.4, 1 H, 5-Qn), 8.24 (s, 1 H, 3-Qn), 8.63
(d, 3J = 8.4, 1 H, 8-Qn), 13.40 (br s, 1 H, NH)
11d
11e
11f
6.82 (dd, 3J = 3.6, 4J = 2.0, 1 H, 4-fur), 7.58–7.70 (m, 6 H), 7.94 (t, 3J = 8.0, 2 H), 8.04 (d, 3J = 6.8, 2 H), 8.18 (m, 1 272
H), 8.65 (m, 1 H, 8-Qn)
7.28 (t, 3J = 8.1, 1 H), 7.42 (t, 3J = 8.1, 1 H), 7.55–7.65 (m, 7 H,), 7.76 (d, 3J = 8.1, 1 H), 7.84 (t, 3J = 8.1, 1 H), 7.92 322
(d, 3J = 8.1, 1 H), 8.10 (m, 2 H), 8.39 (m, 1 H, 8-Qn)
2.69 (s, 3 H, CH3), 6.27 (s, 2 H, CH2), 7.48 (s, 1 H, 5-Qn), 7.52 (s, 1 H, 8-Qn), 7.87 (dd, 3J1 = 8.0, 3J2 = 5.2, 1 H, 5- 265
py), 8.05 (s, 1 H, 3-Qn), 8.82 (dd, 3J = 5.2, 4J = 1.2, 1 H, 6-py), 8.91 (dd, 3J = 8.0, 4J = 1.2, 1 H, 4-py), 9.47 (d,
4J = 1.2, 1 H, 2-py)
11g
1.50 (s, 9 H, CH3), 7.60 (m, 5 H), 7.71 (s, 1 H, 3-Qn), 7.77 (d, 4J = 2.4, 1 H, 5-Qn), 7.85 (dd, 3J = 8.6, 4J = 2.4, 1 H, 297
7-Qn), 8.36 (d, 3J = 8.6, 1 H, 8-Qn)
11h
11i
1.73 (s, 6 H), 2.05 (s, 9 H), 7.52 (m, 6 H), 7.71 (s, 1 H), 7.74 (d, 3J = 9.1, 1 H), 8.09 (m, 1 H)
375
3.04 (t, 3J = 7.85, 2 H), 3.25 (t, 3J = 7.85, 2 H), 7.17 (m, 1 H), 7.37 (t, 3J = 8.8, 2 H), 7.43 (d, 3J = 6.6, 2 H), 7.59 (m, 397
1 H), 7.63 (m, 2 H), 7.69 (m, 2 H), 7.77 (dd, 3J = 9.1, 4J = 2.5, 1 H), 8.08 (d, 3J = 9.1, 1 H)
11j
0.86 (d, 3J = 7.1, 6 H), 3.16 (m, 1 H), 6.98 (s, 1 H), 7.35 (d, 3J = 6.6, 2 H), 7.47 (m, 5 H), 7.55 (m, 3 H), 7.68 (d,
3J = 9.0, 1 H), 8.00 (d, 3J = 9.0, 1 H)
359
230
292
12a
12b
13a
13b
14a
1.38 (t, 3J = 6.9, 3 H, CH2CH3), 2.81 (s, 3 H, CH3), 2.85 (s, 3 H, CH3), 4.50 (q, 3J = 6.9, 2 H, CH2CH3), 7.86 (t,
3J = 8.7, 1 H, 7-Qn), 8.05 (t, 3J = 8.7, 1 H, 6-Qn), 8.36 (d, 3J = 8.7, 1 H, 5-Qn), 8.58 (d, 3J = 8.7, 1 H, 8-Qn)
0.88 (t, 3J = 7.2, 3 H, CH2CH3), 2.68 (s, 3 H, CH3), 4.02 (q, 3J = 7.2, 2 H, CH2CH3), 7.34 (m, 2 H, Ph), 7.54 (m, 5
H, Ph, 5,6-Qn), 7.81 (t, 3J = 8.3, 1 H, 7-Qn), 8.04 (d, 3J = 8.3, 1 H, 8-Qn)
2.74 (s, 3 H, CH3), 3.03 (s, 3 H, CH3), 3.98 (s, 2 H, CH2), 7.82 (t, 3J = 8.4, 1 H, 7-Qn), 7.98 (t, 3J = 8.4, 1 H, 6-Qn), 216
8.34 (d, 3J = 8.4, 1 H, 5-Qn), 8.66 (d, 3J = 8.4, 1 H, 8-Qn)
3.00 (s, 3 H, CH3), 3.71 (s, 2 H, CH2), 7.31 (m, 2 H, Ph), 7.45 (d, 3J = 8.4, 1 H, 5-Qn), 7.64 (m, 3 H, Ph), 7.77 (t,
3J = 8.4, 1 H, 7-Qn), 8.06 (t, 3J = 8.4, 1 H, 6-Qn), 8.49 (d, 3J = 8.4, 1 H, 8-Qn)
278
2.49 (s, 3 H, CH3), 2.96 (s, 3 H, CH3), 3.15 (t, 3J = 6.9, 2 H, CH2), 4.55 (t, 3J = 6.9, 2 H, OCH2), 7.11 (d, 3J = 8.1, 1 276
H, 6-Ar), 7.41 (d, 3J = 8.1, 1 H, 5-Ar), 7.83 (t, 3J = 8.4, 1 H, 7-Qn), 7.89 (s, 1 H, 3-Ar), 7.94 (t, 3J = 8.4, 1 H, 6-Qn),
8.35 (d, 3J = 8.4, 1 H, 5-Qn), 8.76 (d, 3J = 8.4, 1 H, 8-Qn)
14b
14c
1.73 (m, 4 H, CH2CH2CH2CH2CH), 1.89 (m, 2 H, CH2CH2CH2CH2CH), 2.62 (s, 3 H, CH3), 3.00 (m, 2 H,
CH2CH2CH2CH2CH), 3.07 (s, 3 H, OCH3), 3.15 (m, 1 H, CH2CH2CH2CH2CH), 7.44 (t, 3J = 8.4, 1 H, 7-Qn), 7.55
(t, 3J = 8.4, 1 H, 6-Qn), 7.81 (d, 3J = 8.4, 1 H, 5-Qn), 7.94 (d, 3J = 8.4, 1 H, 8-Qn)
270
2.72 (s, 3 H, CH3), 2.94 (m, 2 H, CH2CH2N), 3.55 (m, 2 H, CH2CH2N), 3.72 (s, 2 H, CH2N), 4.56 (m, 2 H, NCH2Ph), 289
7.45 (m, 3 H, Ph), 7.81 (m, 3 H, Ph, 7-Qn), 7.91 (t, 3J = 8.1, 1 H, 6-Qn), 8.29 (d, 3J = 8.1, 1 H, 5-Qn), 8.36 (d, 3J = 8.1,
1 H)
14d
14e
2.17 (qt, 3J = 6.9, 2 H, CH2CH2CH2), 2.89 (t, 3J = 6.9, 2 H, CH2), 3.17 (t, 3J = 6.9, 2 H, CH2), 7.64 (d, 3J = 8.4, 2 H, 246
Ph), 7.40–7.54 (m, 6 H, Ph, 5,6,7-Qn), 7.93 (d, 3J = 8.4, 1 H, 8-Qn)
1.35 (m, 2 H), 1.48 (m, 4 H), 1.95 (m, 2 H), 2.80 (t, 3J = 6.0, 2 H), 3.49 (t, 3J = 6.0, 2 H), 7.32 (d, 3J = 8.4, 1 H, 5- 288
Qn), 7.37 (d, 3J = 8.0, 2 H, Ph), 7.82 (m, 3 H, Ph), 7.86 (t, 3J = 8.4, 1 H, 7-Qn), 8.05 (t, 3J = 8.4, 1 H, 6-Qn), 8.51 (d,
3J = 8.4, 1 H, 8-Qn)
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

PAPER
Chlorotrimethylsilane-Mediated Friedländer Synthesis of Polysubstituted Quinolines
1221
Table 2 1H NMRa and APCI MS Data of Quinolines 9–18 (continued)
1H NMR d (DMSO-d6), J (Hz)
MS m/z
[M + H]+
14f
14g
14h
14i
15
3.90 (s, 2 H, CH2S), 7.41 (m, 6 H), 7.52 (t, J = 8.2, 1 H), 7.61 (m, 3 H), 7.76 (t, 3J = 8.2, 1 H), 8.14 (d, 3J = 8.2, 1 H), 326
8.58 (m, 1 H)
4.68 (s, 2 H, CH2), 7.39 (d, 3J = 6.6, 2 H), 7.46 (d, 3J = 8.3, 1 H), 7.68 (m, 5 H), 7.91 (t, 3J = 8.3, 1 H), 8.11 (dd,
3J1 = 6.6, 3J2 = 5.3, 1 H), 8.26 (d, 3J = 8, 1 H), 8.45 (dd, 3J = 9.7, 4J = 2.7, 1 H)
376
1.40–1.70 (m, 12 H), 1.91 (m, 2 H), 2.77 (s, 3 H, CH3), 2.92 (m, 2 H), 3.24 (m, 4 H), 6.33 (s, 2 H, OCH2O), 7.68 (s, 326
1 H, 5-Qn), 7.92 (s, 1 H, 8-Qn)
3.52 (m, 4 H, CH2CH2N), 4.15 (s, 2 H, CH2N), 7.42 (m, 2 H, Ph), 7.67 (m, 3 H, Ph), 8.23 (m, 2 H), 8.43 (d, 3J = 8.8, 306
1 H), 10.31 (br s, 1 H, NH)
2.89 (s, 3 H, CH3), 5.10 (br s, 2 H, NH2), 7.19 (t, 3J = 7.8, 1 H, 5-Ar), 7.33 (d, 3J = 7.8, 1 H, 3-Ar), 7.50 (td, 3J = 7.8, 235
4J = 1.5, 1 H, 4-Ar), 7.77 (dd, 3J = 7.8, 4J = 1.5, 1 H, 6-Ar), 7.86 (t, 3J = 8.4, 1 H, 7-Qn), 8.02 (t, 3J = 8.4, 1 H, 6-Qn),
8.15 (s, 1 H, 3-Qn), 8.32 (d, 3J = 8.4, 1 H, 5-Qn), 8.40 (d, 3J = 8.4, 1 H, 8-Qn)
16
17
2.62 (s, 3 H, CH3), 7.38 (m, 2 H, Ph), 7.56–7.67 (m, 5 H, Ph, 5,7-Qn), 7.92 (m, 1 H, 6-Qn), 8.11 (d, 3J = 8.4, 1 H, 8- 316
Qn)
7.03 (dd, 3J = 4.8, 4J = 3.2, 1 H, 4-Th), 7.24 (d, 3J = 8.4, 1 H), 7.28–7.47 (m, 4 H), 7.56 (d, 3J = 4.8, 1 H, 3-Th), 7.59 384
(d, 3J = 8.4, 1 H, 5-Qn), 7.82 (t, 3J = 8.4, 1 H, 7-Qn), 7.98 (d, 3J = 3.2, 1 H, 5-Th), 8.03 (t, 3J = 8.4, 1 H, 6-Qn), 8.33
(d, 3J = 8.4, 1 H, 8-Qn)
18
7.37–7.48 (m, 2 H, 3,5-Ph), 7.57–7.64 (m, 3 H, 2,4,6-Ph), 7.68 (d, 3JHH = 8.3, 1 H, 8-Qn), 7.88 (t, 3JHH = 8.3, 1 H, 7- 370
Qn), 8.10 (t, 3JHH = 8.3, 1 H, 6-Qn), 8.35 (d, 3JHH = 8.3, 1 H, 5-Qn)
Ph
Unexpected results were obtained in the Friedländer an-
nulation with trifluoromethyl-containing diketones 8a–c.
Thus, 1,1,1-trifluoropentane-2,4-dione (8a) gave 3-(tri-
fluoroacetyl)quinoline 16, the same results as previously
reported in the literature (NaAuCl4 or bmimCl·ZnCl2 as a
catalyst). Meanwhile, 4,4,4-trifluoro-1-(2-thienyl)butane-
1,3-dione (8b) afforded 2-(trifluoromethyl)quinoline 17
in high yield as the sole product of the reaction. The struc-
ture of these compounds was confirmed by 13C and 19F
NMR spectroscopy as well as by comparison with model
compound 18 obtained from symmetrical 1,1,1,5,5,5-
hexafluoropentane-2,4-dione (8c). It is thought that the
differing regioselectivity is due to different reaction
mechanisms. In the case of 1,1,1-trifluoropentane-2,4-di-
one (8a) the reaction proceeds via the corresponding
R = Me
O
16
NH
O
O
CF3
19
CF3
O
+
1b
O
R
Ph
8a or 8b
S
17
CF3
R = 2-thienyl
O
NH2
20
Scheme 2
19
enaminone 19,14a which was detected by F NMR spec-
Ph
O
troscopy in the reaction mixture. In the case of 4,4,4-tri-
fluoro-1-(2-thienyl)butane-1,3-dione (8b) no interme-
diates were detected by 19F NMR spectroscopy. The first
step of the reaction is considered to be a crotonic conden-
sation between a ketone fragment and a CH-acidic group
of the diketone affording intermediate 20, followed by cy-
clization with participation of the more active trifluoro-
acetyl group, with the stage of formation of the
intermediate 20 being limiting (Scheme 2).
Cl
1d
11g
NH2
21
Ph
Ph
N
Cl
Cl
O
O
NH
23
22
With sterically hindered ketones of type 4g,h the reaction
can occur via an intermediate of type 21 that cyclizes in-
termolecularly to give the corresponding quinolines.28 In
this case an alternative reaction is almost impossible, so
that formation of intermediates of type 22 is hampered by
steric hindrance (Scheme 3).
Scheme 3
16, 17, 18, which contain acceptor substituents such as
ethoxycarbonyl, cyano, and trifluoroacetyl in the quino-
line ring, these precipitates were obtained as the monohy-
drochloride of the corresponding quinolines 3 with 80–
The general procedure for the synthesis of compounds 9–
18 was used. In all the cases except 9c, 9g, 10, 12a, 12b,
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

1222
S. V. Ryabukhin et al.
PAPER
11c
95% purity. The purification of these compounds can be
achieved by simple washing with acetonitrile. Com-
pounds 9c, 9g, 10, 12a, 12b, 16, 17, 18 precipitate as the
free base and can be purified by recrystallization from
methanol. H NMR and mass spectra data are given in
Table 2.
13C NMR (125 MHz): d = 19.8, 113.0, 119.2, 119.9, 120.1, 123.7,
125.7, 125.9, 128.1, 129.6, 133.9, 137.5, 144.7, 154.8.
11g
1
13C NMR (125 MHz): d = 30.1, 38.4, 120.4, 124.5, 126.0, 128.9,
129.5, 129.8, 130.0, 131.6, 132.1, 136.9, 143.8, 150.5, 168.9.
Nevertheless, some limitations were found in the course
of this work. In the case of sterically hindered ketones
4g,h,j, 1-(2-aminophenyl)ethanone (1a) undergoes self-
condensation affording compound 15 as the major prod-
uct.
11h
13C NMR (125 MHz): d = 28.6, 36.6, 40.0, 41.5, 119.5, 124.2,
125.8, 129.3, 129.4, 129.9, 130.0, 130.5, 131.3, 131.5, 137.5, 148.0,
169.0.
11i
In conclusion, we described an efficient route for the syn-
thesis of quinolines and polycyclic quinolines using chlo-
rotrimethylsilane as a promoter and water scavenger via
Friedländer annulation. The methodology is applicable to
a wide variety of a-methylene ketones and delivers the
target products in good yields, excellent homogeneity and
often in analytically pure form. The procedure is very sim-
ple and could be easily adapted to semi-automated solu-
tion-phase parallel synthesis of quinoline libraries. Over
1000 analogues have been synthesized in our
laboratories29 by parallel synthesis methods. This proce-
dure can be easily scaled up as illustrated by two examples
(see experimental) and can be used for the synthesis of
building blocks based on functionalized quinolines.
13C NMR (125 MHz): d = 33.7, 42.8, 115.8 (d, 2J = 25.2 Hz), 124.8,
127.9, 128.4, 129.2, 129.4, 129.7, 130.6, 131.3, 131.4, 131.8, 132.0,
135.8, 137.3, 144.9, 160.3, 162.6 (d, 1J = 245.7 Hz).
11j
13C NMR (125 MHz): d = 23.1, 31.0, 124.6, 128.1, 128.2, 128.4,
128.6, 128.7, 128.8, 129.1, 130.0, 130.3, 131.5, 136.9, 137.6, 142.2,
143.5, 146.7, 162.1.
14a
13C NMR (125 MHz): d = 16.0, 20.9, 28.0, 76.9, 122.8, 123.7,
126.0, 127.4, 128.2, 129.0, 130.9, 132.0, 132.7, 134.3, 134.7, 139.5,
151.0, 153.1, 154.6.
14g
13C NMR (125 MHz): d = 52.5, 115.3 (d, J = 25.2 Hz), 118.9 (d,
2
2J = 25.2 Hz), 121.1, 126.6, 126.7, 127.0, 129.0, 129.6, 129.7,
129.9, 131.2, 133.8, 134.4, 138.6, 138.7, 147.2, 147.3, 148.9, 165.5
(d, 1J = 251.7 Hz).
All chemicals were obtained from commercially available sources
(Aldrich, Fluka, Enamine Ltd) and used without further purifica-
tion. DMF was freshly distilled and dried by standard methods,
monitoring of water concentration in solvents (the solvent con-
tained <0.05%, usually 0.02% of H2O) were performed using Mett-
ler Toledo DL31 KF Titrator. All solvents for the crystallization
were used without additional purification.
14i
13C NMR (125 MHz): d = 30.1, 40.0, 43.2, 122.7, 123.7, 123.9,
125.2, 129.4, 129.9, 130.0, 130.9, 133.4, 145.5, 147.9, 148.6, 158.3.
16
Melting points were measured with a Buchi melting points appara-
13C NMR (125 MHz): d = 23.8, 115.0 (q, J = 293.3 Hz), 124.1,
1
1
tus and are uncorrected. The H, 13C and 19F NMR spectra (500
126.4, 127.0, 128.2, 129.25, 129.27, 130.2, 130.7, 132.4, 133.6,
MHz, 125 MHz and 470 MHz, respectively) were recorded on a
Bruker Avance DRX 500 with DMSO-d6 as a solvent, TMS (1H and
13C) and CFCl3 (19F) were used as internal standards. LC/MS spec-
tra were recorded using chromatography/mass spectrometric sys-
tem that consists of HPLC Agilent 1100 Series equipped with
diode-matrix and mass-selective detector Agilent LC\MSD SL. Ac-
cording to HPLC MS data all the synthesized compounds have pu-
rity >95%. BRANSON 2510E-MT ultrasonic bath and autoclave
BERGHOF HR-500 were used.
147.8, 148.3, 153.1, 189.3 (q, 2J = 37.3 Hz).
19F NMR: d = –75.3.
17
13C NMR (125 MHz): d = 121.8 (q, J = 276.5 Hz), 126.9, 127.8,
1
128.3, 128.9, 129.1, 129.3, 129.4, 130.3, 130.4, 130.5, 130.7, 132.5,
3
133.8, 137.6, 137.9, 142.8 (q, J = 33.9 Hz), 144.1, 146.5, 149.0,
186.0.
19F NMR: d = –62.9.
Quinolines 9–18; General Procedure
An appropriate o-aminocarbonyl compound 1a–e (1 mmol) and an
appropriate carbonyl component 2–8 (1 mmol) were placed in an 8-
mL Ace pressure tube and dissolved in DMF (2 mL). TMSCl (4
mmol) was added dropwise to the soln. The tube was thoroughly
sealed and heated on a water bath for 4–10 h. After cooling, the
flask was opened (CAUTION: excessive pressure inside) and the
mixture was poured into H2O (5 mL) and allowed to stand at 20 °C
in an ultrasonic bath for 1 h. The thus-formed precipitate was fil-
tered and washed with small amount of MeOH (or MeCN). Recrys-
tallization from an appropriate solvent yielded the target compound.
18
13C NMR (125 MHz): d = 111.4 (3J = 19.2 Hz), 114.7 (1J = 292.3
Hz), 121.2 (1J = 275.9 Hz), 123.5, 127.0, 128.6, 129.0, 129.3,
130.3, 130.6, 130.7, 131.6, 132.3, 134.0, 142.0 (2J = 34.1 Hz),
147.0, 150.7, 186.3 (2J = 38.8 Hz).
19F NMR: d = –64.2 (3 F), –76.8 (3 F).
Ethyl 2-(Chloromethyl)-4-methylquinoline-3-carboxylate (9c)
1-(2-Aminophenyl)ethanone (1a, 25.6 g, 0.19 mol) was dissolved in
DMF (150 mL). To the soln thus obtained, ethyl 4-chloro-3-oxobu-
tanoate (2c, 31.2 g, 0.19 mol) was added and TMSCl (82.4 g, 0.76
mol) was carefully added dropwise. The autoclave was sealed and
heated at 100 °C for 8 h. After cooling the autoclave was opened and
the mixture was poured into H2O (1 L) and the mixture thus ob-
tained was allowed to stand at r.t. in ultrasonic bath for 1 h. The pre-
9d
13C NMR (125 MHz): d = 16.8, 20.11, 122.9, 126.0, 126.6, 128.9,
133.2, 133.3, 139.4, 148.7, 154.0, 167.6.
Synthesis 2007, No. 8, 1214–1224 © Thieme Stuttgart · New York

PAPER
Chlorotrimethylsilane-Mediated Friedländer Synthesis of Polysubstituted Quinolines
1223
cipitate formed was filtered and washed with i-PrOH (3 × 10 mL).
The mother liquor was evaporated in vacuo and the residue was
washed with i-PrOH (10 mL). The two portions were combined and
recrystallized (EtOH), affording the target compound; yield: 46.4 g
(93%).
13C NMR: d = 14.4, 16.4, 46.0, 62.6, 125.6, 126.8, 126.9, 128.8,
129.0, 129.1, 132.1, 145.6, 152.6, 167.4.
(10) A subset of recent work in this area includes: (a)Lindeman,
R. J.; Kirollos, S. K. Tetrahedron Lett. 1990, 31, 2689.
(b) Strekowski, L.; Lin, S. Y.; Lee, H.; Zhang, Z. Q.; Mason,
J. C. Tetrahedron 1998, 54, 7947. (c) Crouse, B.; Begue, J.
P.; Daniele, B. D. J. Org. Chem. 2000, 65, 5009. (d) Cho,
S. C.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Chem. Commun.
2001, 2576; and references therein. (e) Amii, H.; Kishkava,
Y.; Uneyama, K. Org. Lett. 2001, 3, 1109. (f) Jiang, B.;
Yui-Gui, S. J. Org. Chem. 2002, 67, 9449. (g) Yadav, J. S.;
Reddy, B. V. S.; Srinivasa Rao, R.; Navenkumar, V.;
Nagaiah, K. Synthesis 2003, 1610. (h) Du, W.; Curran, D. P.
Org. Lett. 2003, 5, 1765. (i) Ishkawa, T.; Manabe, S.;
Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004, 6, 2361.
(j) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2004, 6,
353. (k) Kobayashi, K.; Yoneda, K.; Miyamoto, K.;
Morikawa, O.; Konishi, H. Tetrahedron 2004, 60, 11639.
For recent reviews see: (l) Kouznetsov, V. V.; Vargaz
Mendez, L. Y.; Melendez Gomez, C. M. Curr. Org. Chem.
2005, 9, 141.
(2,4-Dimethylquinolin-3-yl)acetic Acid (13a)
1-(2-Aminophenyl)ethanone (1a, 31.4 g, 0.232 mol) was dissolved
in DMF (150 mL). To the soln thus obtained 4-oxopentanoic acid
(6, 29.7 g, 0.256 mol) was added and TMSCl (126.2 g, 1.161 mol)
was carefully added dropwise. The autoclave was sealed and heated
at 100 °C for 8 h. After cooling the autoclave was opened and the
mixture was poured into H2O (1 L) and the mixture thus obtained
was allowed to stand at r.t. in ultrasonic bath for 1 h. The precipitate
formed was filtered and washed with i-PrOH (3 × 10 mL). The
mother liquor was evaporated in vacuo and the residue was washed
with i-PrOH (10 mL). The two portions were combined and recrys-
tallized (EtOH) affording the target compound 13a as the hydro-
chloride salt; yield: 55.5 g (95%).
(11) (a) Friedländer, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572.
(b) Cheng, C. C.; Yan, S.-J. Org. React. 1982, 28, 37; and
references therein. (c) Glaiali, S.; Chelussi, G.; Mudadu, M.
S.; Gastuat, M. A.; Thumel, R. P. J. Org. Chem. 2001, 66,
4000.
13C NMR: d = 16.5, 20.1, 34.9, 121.5, 126.1, 127.0, 128.8, 129.2,
133.5, 137.2, 157.1, 171.5.
(12) (a) Strekowski, L.; Czamy, A. J. Fluor. Chem. 2000, 104,
281. (b) Hu, Y.-Z.; Zang, G.; Thummel, R. P. Org. Lett.
2003, 5, 2251.
Acknowledgment
(13) Wu, J.; Xia, H. G.; Gao, K. Org. Biomol. Chem. 2006, 4,
The authors acknowledge V. V. Polovinko (Enamine Ltd.) for spec-
tral measurements, Dr. A. N. Kostyuk and D. Dontsova (Institute of
Organic Chemistry, National Academy of Sciences of Ukraine) for
helpful discussions and suggestions upon preparation of the manus-
cript.
126.
(14) (a) Arcadi, A.; Chiarini, M.; Di Guespe, S.; Marinelly, F.
Synlett 2003, 203. (b) Yadav, J. S.; Reddy, B. V. S.;
Premalatha, K. Synlett 2004, 963. (c) Varala, R.; Enugala,
R.; Adapa, S. R. Synthesis 2006, 3825.
(15) (a) Song, S. J.; Cho, S. J.; Park, D. K.; Kwon, T. W.;
Jenekhe, S. A. Tetrahedron Lett. 2003, 44, 255. (b) Jia, C.
S.; Zhang, Z.; Tu, S. J.; Wang, G. W. Org. Biomol. Chem.
2006, 4, 104.
(16) (a) Wang, J.; Fan, X.; Zhang, X.; Han Can, L. Can. J. Chem.
2004, 82, 1192. (b) Palimkar, S. S.; Siddiqui, S. A.; Daniel,
T.; Lahoti, R. J.; Srinivasan, J. V. J. Org. Chem. 2003, 68,
9371. (c) Karthikeyan, G.; Perumal, P. T. J. Heterocycl.
Chem. 2004, 41, 1039.
(17) For recent examples see: (a) McNaughton, B. R.; Miller, B.
L. Org. Lett. 2003, 5, 4257. (b) Motokura, K.; Mizugaki,
K.; Ebitani, K.; Kiyotomi, K. Tetrahedron Lett. 2004, 45,
6029.
(18) For the use of TMSCl as a condensation agent, see:
(a) Ryabukhin, S. V.; Plaskon, A. S.; Tverdokhlebov, A. V.;
Tolmachev, A. A. Synth. Commun. 2004, 34, 1483.
(b) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synlett 2004, 2287. (c) Heaney, H.;
Papageorgeogu, G.; Wilkins, R. F. Tetrahedron 1997, 53,
2941. For the use of TMSI as a condensation agent, see:
(d) Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Yadav, J.
S. Synthesis 2004, 263. (e) Sabitha, G.; Reddy, G. S. K. K.;
Reddy, C. S.; Yadav, J. S. Synlett 2003, 858. (f) Sabitha,
G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2003, 44, 4129. (g) Ryabukhin, S. V.;
Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A.
Synthesis 2006, 3715. (h) Ryabukhin, S. V.; Plaskon, A. S.;
Ostapchuk, E. N.; Volochnyuk, D. M.; Tolmachev, A. A.
Synthesis 2007, 417.
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