Mild and convenient synthesis of 1,2-dihydroquinolines from anilines and acetone catalyzed by ytterbium(III) triflate in ionic liquids

Article abstract of DOI:10.1080/00397910600775374

A mild, convenient, and efficient process has been developed for the synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines by the reaction of anilines with acetone catalyzed by ytterbium(III) triflate [Yb(OTf)₃] in ionic liquids. The catalyst and ionic liquids can be easily recovered and reused, making this method friendly and environmentally acceptable. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600775374

w
Synthetic Communications , 36: 3065–3073, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600775374
Mild and Convenient Synthesis of
,2-Dihydroquinolines from Anilines and
1
Acetone Catalyzed by Ytterbium(III)
Triflate in Ionic Liquids
Yongshu Li, Chunlei Wu, Jianliang Huang, and Weike Su
Zhejiang Key Laboratory of Pharmaceutical Engineering,
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, China
Abstract: A mild, convenient, and efficient process has been developed for the
synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines by the reaction of anilines with
3
acetone catalyzed by ytterbium(III) triflate [Yb(OTf) ] in ionic liquids. The catalyst
and ionic liquids can be easily recovered and reused, making this method friendly
and environmentally acceptable.
Keywords: Anilines, 1,2-dihydroquinolines, ionic liquids, Skraup reaction,
ytterbium(III) triflate
The utility of 2,2,4-trimethyl-1,2-dihydroquinolines as antioxidants for rubber
and polyolefins, feed additives, dyes, and pharmaceuticals is well documen-
[
1–8]
ted.
However, it requires a large amount of sulfuric acid at temperatures
The most classical method to this structure is the Skraup reaction.
higher than 1508C, and the reaction is often violent. A number of other
[
9–14]
methods
variety of Lewis acids such as hydrochloric acid, aluminium trichloride,
have been reported for the synthesis of quinolines involving a
[16]
[15]
[17]
hydrogen fluoride and boron trifluoride, and a strongly acidic sulfonic
acid. However, many of these procedures are not satisfactory because of
[18]
Received in Japan February 26, 2006
Address correspondence to Weike Su, Zhejiang Key Laboratory of Pharmaceutical
Engineering, College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, China. E-mail: suweike@zjut.edu.cn
3
065

3
066
Y. Li et al.
harsh reaction conditions, difficulties in workup, the use of stoichiometric or
excessive amounts of catalyst, and use of metal halides as catalysts.
Moreover, the main disadvantages of almost all existing methods are that the
catalysts are destroyed in the workup procedure and cannot be recovered or
reused. Therefore, it is necessary to develop a mild and convenient method
for the synthesis of this kind of compound. Herein, we report a simple and
efficient procedure for the synthesis of 1,2-dihydroquinolines from available
anilines and acetone catalyzed by Yb(OTf) in ionic liquids with good yields.
3
Yb(OTf) has been extensively investigated as a mild, neutral, and
3
[
19]
versatile Lewis acid catalyst in organic chemistry
[21]
such as Aldol
[22]
[
20]
reaction,
reactions,
Mannich-type reaction,
23–26]
Friedel–Crafts acylation,
Micheal reaction,
[27]
and so on. Compared with the
cyclization
[
conventional Lewis acids, the most characteristic features of Yb(OTf) are
3
stability in water and high efficiency. It can be recovered easily after
reactions and reused without loss of activity. Yb(OTf) -catalyzed reactions
3
are clean and environmentally friendly. The applications of Yb(OTf) in
3
organic synthesis have aroused general interest in recent decades.
Room-temperature ionic liquids are air and moisture stable, so they have
been received a good deal of attention as potentially cleaner solvents in recent
[
28,29]
years.
reactions allowed easy recovery and reuse of the catalysts.
Utilization of ionic liquids particularly in metal-catalyzed
Conse-
[30–32]
quently, our attention turned to Lewis acidic metal-ion catalyzed modification
of the Skraup reaction and the potential advantage of ionic liquids to immobi-
lize such catalysts and stabilize the intermediary cations.
When anilines 1 and acetone 2 were treated with a catalytic amount of
Yb(OTf) in ionic liquids for 30 min at room temperature, then 2,2,4-trisubsti-
3
tuted-1,2-dihydroquinolines 3 were obtained in moderate to good yields
(
Scheme 1).
Table 1 shows that the results of the reaction were affected by the amount
of Yb(OTf) and different solvents.
3
To examine the catalytic activity of Yb(OTf) , we explored a modifi-
3
cation of the Skraup reaction with the reaction of aniline and acetone in
ionic liquid in the presence of 20%, 10%, 5%, and no Yb(OTf) . The
3
results are shown in Table 1. According to Table 1, 10% of Yb(OTf) was
3
enough and efficient for this reaction, and an excessive amount of the
catalyst did not increase the yields (Table 1, Entries 1–4). In the absence of
Scheme 1.

1,2-Dihydroquinolines from Anilines and Acetone
3067
a
Table 1. Results of the modified Skraup reaction under different conditions
Catalyst
(equiv.)
Time
(min)
Reaction
temp (8C)
Yield
b
(%)
Entry
Solvent
c
1
2
3
4
5
6
7
8
9
None
Yb(OTf)
[bmim][BF
[bmim][BF
4
]
]
30
30
r.t.
r.t.
ND
3
/0.05
4
70
81
81
ND
40
67
63
Yb(OTf) /0.1
[bmim][BF4]
[bmim][BF4]
Acetone
30
30
r.t.
r.t.
3
Yb(OTf) /0.2
3
c
None
Yb(OTf)
600
600
30
Reflux
Reflux
r.t.
3
/0.1
Acetone
[bpy][BF4]
Yb(OTf) /0.1
3
Yb(OTf)
3
/0.1
[bmim][PF
[bmim][BF
[bmim][BF4]
[bmim][BF
6
]
30
60
r.t.
r.t.
TfOH/0.3
TfOH/0.3
Yb(OTf) /0.1
4
]
Trace
45
1
1
0
1
60
30
75
r.t.
d
3
4
]
81
a
Entries 1–4 and 7–12 were run with aniline (1 mmol), acetone (3 mmol), and 2 mL
ionic liquids, and 50 mmol of acetone was used for entries 5 and 6.
b
Isolated yield was based on aniline.
Not detected.
c
d
3 4
The recycling of Yb(OTf) and [bmim][BF ] was reused five times, and the yields
are 79%, 78%, 76%, 70%, and 59% respectively.
Yb(OTf) , no reaction was found (Table 1, Entries 1, 5). To investigate the
3
real catalyst species, Yb(OTf)3 or TfOH, the experiment using TfOH
(30 mol%) in place of Yb(OTf) has been tried. The product was obtained
3
with yield of 45% at 758C but a trace product was detected at r.t. (Table 1,
Entries 9, 10). Yb(OTf) should be the real catalyst species at r.t.
3
There are many kinds of ionic liquids, so an effective one needed to be
screened out for this reaction. The experiment was carried out in the
following ionic liquids: [bpy][BF ] (bpy ¼ 1-butylpyridine), [bmim][BF ]
4
4
(
bmim ¼ 1-butyl-3-methyl imidazolium), and [bmim][PF ], as the reaction
6
solvents. The results are listed in Table 1. The yield was very low (Table 1,
Entry 6, 40%) when acetone was used as the solvent even under reflux con-
ditions for 10 h. The reaction rate and yield were obviously improved when
ionic liquids were the solvent (Table 1, Entries 3, 7, 8). Especially in the
case of [bmim][BF ], the yield was the highest at 81% after 30 min at 258C
4
(
Table 1, Entry 3). [bmim][BF ] was chosen as the reaction’s solvent.
Recycling of catalyst and [bmim][BF ] were also investigated. During our
4
4
ongoing study on catalyst recycling, we have found that Yb(OTf) is effec-
3
tively immobilized in ionic liquids. To examine the catalytic activities of
both Yb(OTf)3 and recycled ionic liquid, the reaction of aniline with
acetone was chosen as a model one. In the presence of 10 mol% of
Yb(OTf) , when aniline and acetone in [bmin][PF ] were stirred at room
3
6
temperature for 0.5 h, it was always immobile for [bmim][BF ]. The recyclabil-
4
ity of the catalyst and solvent is important in the context of economic feasibility

3
068
Y. Li et al.
and sustainable development. Thus, the recovered catalyst and ionic liquid,
which were immobilized, were reused in the next run. The catalytic activity
of Yb(OTf) and solvent was basically stable for four times. The yields of
3
the product were 82%, 81%, 79%, and 79%, respectively (Table 1, Entry
12). However, the yields obviously decreased after the fifth turn.
To extend the scope of this method, the substituted anilines were tested to
react with acetone catalyzed by Yb(OTf) in ionic liquid, and the results are
3
summarized in Table 2.
From Table 2, we can see that the reactions need less time because
Yb(OTf) is a homogeneous catalyst in ionic liquids. The great advantage
3
of homogeneous catalysis over heterogeneous one is that all Yb(OTf) is
3
available to the reagents and so it is inherently more efficient. The faster
rates associated with Yb(OTf) could result from enhanced Lewis acidity of
3
Yb(III) and easier generation of charged cations in the ionic liquid because
the reaction mixtures were homogeneous. The major drawback is that it can
be difficult to separate the catalyst from the products of the reaction. Fortu-
nately, we need not do this, because the catalyst in ionic liquids can be
recycled and reused without loss of its catalytic activity.
Several aromatic anilines with either electron-releasing or electron-
withdrawing groups afforded high yields of products. The results shown in
Table 2 clearly indicate the scope and generality of the reaction with
respect to different aromatic anilines. The experimental procedure is mild
and has the ability to tolerate a variety of functional groups such as halide,
alkyl, and methoxycarbonyl groups.
In conclusion, the present procedure provides an efficient and improved
modified Skraup reaction for the synthesis of 2,2,4-trimethyl-1,2-dihydro qui-
nolines catalyzed by Yb(OTf) in ionic liquids. Yb(OTf) has more catalytic
3
3
Table 2. Synthesis of 1,2-dihydroquinolines in ionic liquids
a
using Yb(OTf) as the catalyst
3
b
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
-H
3a
3b
3c
3d
3e
3f
81
75
79
62
68
79
80
74
72
o-CH
m-CH
3
3
p-CH3
o-Cl
p-Cl
o-Et
p-Br
3g
3h
3i
o-COOCH
3
a
All reactions were run with anilines (1 mmol), acetone
(0.1 mmol), and 2 mL of [bmim][BF ] in
0 min at room temperature.
(
3 mmol), Yb(OTf)
3
4
3
b
Isolated yields based on anilines.

1,2-Dihydroquinolines from Anilines and Acetone
3069
activity than conventional molecular solvent. The work described herein
provides an efficient method for the preparation of 1,2-dihydroquinolines.
Good yields, recyclability of the catalyst and solvent, ease of workup, mild
and neutral reaction conditions, and short reaction times are some of the
important features of this method. Studies on the application of Yb(OTf)3
and ionic liquids in organic synthesis are now in progress.
EXPERIMENTAL
Melting points were determined on a digital melting-point apparatus WRS-1B
and are uncorrected. Infrared spectra were recorded on Nicolet Aviatar-370
1
13
infrared spectrophotometer. H NMR spectra (400 MHz) and C NMR
100 MHz) spectra were determined on Varian 400 instrument using CDCl3
(
as the solvent with TMS as an internal standard. Mass spectra were recoded
on Thermo Finnigan LQC-Advantage (ESI) and Finnigan Truce DSQ (EI).
[33,34]
The three ionic liquids were prepared according to the literature.
the chemicals used are commercially available.
All
General procedure for the synthesis of 2,2,4-trimethyl-1,2-dihydroquino-
lines was as follows: acetone (0.22 mL, 3 mmol) and aniline (0.098 g,
1
0
mmol) were added to [bmim][BF ] (2 mL) with Yb(OTf)3 (0.062 g,
4
.1 mmol) at room temperature. The reaction was stirred for 30 min. The
mixture was then extracted with ethyl acetate (10 mL ꢀ 2), and the
combined organic layer was washed with brine and dried over anhydrous
Na SO . After evaporation, the crude product was obtained and purified by
2
4
preparative TLC on silica gel using ethyl acetate–cyclohexane (1:4) as
eluent. When recycling the solvent/catalyst system, fresh aniline and
acetone were added, and ether was used as extracting solvent after drying
of the solvent/catalyst for 4 h at 808C under vacuum.
2
,2,4-Trimethyl-1,2-dihydroquinoline (3a)
[35]
21
1
Oil,
IR (film, n, cm ): 3372 (N-H); H NMR (CDCl ) ppm d: 7.05 (dd,
3
J ¼ 1.6, 6.0 Hz, 1H), 6.96 (dt, J ¼ 1.2, 6.4 Hz, 1H), 6.62 (dt, J ¼ 1.2,
6
.4 Hz, 1H), 6.41 (dd, J ¼ 0.8, 6.8 Hz, 1H), 5.29 (s, 1H), 3.57 (brs, 1H),
1
3
1
.97 (d, J ¼ 1.6 Hz, 3H), 1.25 (s, 6H); C NMR: d 142.9, 128.1, 128.0
(
2 ꢀ CH), 123.2, 121.1, 116.7, 112.5, 51.4, 30.6 (2 ꢀ CH ), 18.2; MS
3
þ
(
ESI): m/z 174 (M þ 1).
2
,2,4,8-Tetramethyl-1,2-dihydroquinoline (3b)
[35]
Oil,
21
1
IR (film, n, cm ): 3369 (N-H); H NMR (CDCl ) ppm d: 6.93
3
(d, J ¼ 7.6 Hz, 1H), 6.43 (dd, J ¼ 0.8, 2.8 Hz, 1H), 6.21 (s, 1H), 5.21

3
070
Y. Li et al.
1
3
(
d, J ¼ 1.2 Hz, 1H), 3.49 (brs, 1H), 2.20 (s, 3H), 2.00 (s, 3H), 1.21 (s, 6H);
C
NMR: d 141.5, 130.2, 129.3, 128.0 (2 ꢀ CH), 121.2, 116.7, 96.8, 52.2, 31.9
þ
þ
(
2 ꢀ CH ), 19.3, 17.4; MS (EI): m/z 188 (M þ 1, 30), 187 (M , 75), 172 (100).
3
2,2,4,5-Tetramethyl-1,2-dihydroquinoline (3c)
[36]
Oil,
21
1
IR (film, n, cm ): 3368 (N-H): H NMR (CDCl ) ppm d: 6.98
3
(
d, J ¼ 7.6 Hz, 1H), 6.90 (d, J ¼ 7.2 Hz, 1H), 6.57 (dd, J ¼ 7.6 Hz,
J ¼ 7.2 Hz, 1H), 5.31 (s, 1H), 3.55 (s, 1H), 2.09 (s, 3H), 1.99 (s, 3H), 1.29
1
3
s, 6H); C NMR: d 143.6, 128.7, 127.8, 123.9, 119.6, 118.4, 113.9, 110.3,
(
þ
þ
5
2.3, 31.4 (2 ꢀ CH ), 21.7, 18.3; MS (EI): m/z 188 (M þ 1, 18), 187 (M ,
3
6
8), 172 (100).
2,2,4,6-Tetramethyl-1,2-dihydroquinoline (3d)
[
35]
21
1
Oil, IR (film, n, cm ): 3367 (N-H); H NMR (CDCl ) ppm d: 6.88 (s, 1H),
3
6
.80 (dd, J ¼ 2.4, 7.8 Hz, 1H), 6.38 (d, J ¼ 7.8 Hz, 1H), 5.30 (s, 1H), 3.20
1
3
(
s, 1H), 2.22 (s, 3H), 1.97 (s, 3H), 1.22 (s, 6H); C NMR: d 141.4, 129.3,
28.8, 129.1, 125.9, 125.0, 113.5, 96.6, 52.0, 31.1 (2 ꢀ CH ), 21.0, 19.0;
1
3
þ
þ
MS (EI): m/z 188 (M þ 1, 28), 187 (M , 100).
8-Chloro-2,2,4-trimethyl-1,2-dihydroquinioline (3e)
[
37]
21
1
Oil,
IR (film, n, cm ): 3396 (N-H); H NMR (CDCl ) ppm d: 7.07 (dd,
3
J ¼ 0.8, 7.2 Hz, 1H), 6.96 (d, J ¼ 7.2 Hz, 1H), 6.54 (t, J ¼ 7.6 Hz, 1H),
1
3
5
.34 (s, 1H), 4.30 (s, 1H), 1.98 (d, J ¼ 1.2 Hz, 3H), 1.31 (s, 6H); C NMR:
d 139.4, 128.9, 128.2, 128.0, 122.6, 122.0, 117.0, 116.5, 52.0, 31.5, 29.7,
8.7; MS (EI): m/z 210 ( M þ 1, 11), 208 ( M , 34), 191 (100).
3
7
35
þ
1
6-Chloro-2,2,4-trimethyl-1,2-dihydroquinoline (3f)
[
35]
21
1
Oil,
(
IR (film, n, cm ): 3381 (N-H); H NMR (CDCl ) ppm d: 6.99
3
d, J ¼ 2.0 Hz, 1H), 6.91 (dd, J ¼ 2.0 Hz, 8.0 Hz, 1H), 6.35 (d, J ¼ 8.8 Hz,
1
H), 5.35 (s, 1H), 1.95 (s, 3H), 1.26 (s, 6H); C NMR: d 141.8, 129.5,
3
1
1
27.8, 127.7, 123.4, 122.9, 121.6, 113.8, 52.0, 30.9 (2 ꢀ CH ), 18.5; MS
3
3
7
35
þ
(
EI): m/z 210 ( M þ 1, 10), 208 ( M þ 1, 34), 191 (100).
8-Ethyl-2,2,4-trimethyl-1,2-dihydroquinoline (3g)
[
38]
21
1
Oil,
(
IR (film, n, cm ): 3414 (N-H); H NMR (CDCl ) ppm d: 6.99
3
d, J ¼ 8.0 Hz, 1H), 6.92 (d, J ¼ 7.2 Hz, 1H), 6.62 (t, J ¼ 7.2 Hz, 1H), 5.32

1,2-Dihydroquinolines from Anilines and Acetone
3071
(
s, 1H), 3.65 (s, 1H), 2.44 (q, J ¼ 7.2 Hz, 2H), 1.99 (s, 3H), 1.28 (s, 6H), 1.23
1
3
(
t, J ¼ 3.6 Hz, 3H); C NMR: d 140.5, 129.0, 127.9, 127.7, 125.6, 121.6,
þ
1
21.2, 116.5, 51.6, 31.1, 29.7, 23.6, 18.9, 13.1; MS (ESI): m/z 202 (M þ 1).
6
-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (3h)
[
35]
21
1
Mp: 76–778C (lit.,
788C); IR (KBr, n, cm ): 3375 (N-H); H NMR
(
CDCl ) ppm d: 7.12 (d, J ¼ 2.4 Hz, 1H), 7.04 (dd, J ¼ 2.4, 8.4 Hz, 1H),
3
6
.30 (d, J ¼ 8.4 Hz, 1H), 5.33 (d, J ¼ 1.2 Hz, 1H), 1.94 (s, 3H), 1.26
1
s, 6H); C NMR: d 142.6, 131.1, 129.6, 128.1, 126.7, 123.8, 114.7, 109.1,
3
(
8
1
þ
79
þ
5
2.4, 31.4 (2 ꢀ CH ), 18.9; MS (EI): m/z 253 ( M , 61), 251 ( M , 63),
3
2
34 (100).
8
-Carbomethoxy-2,2,4-trimethyl-1,2-dihydroquinoline (3i)
[
35]
21
1
Oil,
1
IR (film, n, cm ): 3328 (N-H); H NMR (CDCl ) ppm d: 7.90 (br,
3
H), 7.66 (d, J ¼ 8.4 Hz, 1H), 7.10 (d, J ¼ 7.2 Hz, 1H), 6.43 (t, J ¼ 7.2 Hz,
1
H), 5.32 (s, 1H), 3.83 (s, 3H), 1.96 (s, 3H), 1.33 (s, 6H); C NMR:
3
1
d 169.5, 147.7, 131.0, 128.8, 128.5, 127.9, 122.3, 114.2, 96.6, 52.2, 51.7,
þ
3
2.8 (2 ꢀ CH ), 19.4; MS (ESI): m/z 232 (M þ 1).
3
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (Nos.
2
0276072 and 20476098).
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1
2
3
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