Synthesis of substituted 1,2-dihydroquinolines and quinolines using ene-ene metathesis and ene-enol ether metathesis

Article abstract of DOI:10.1016/S0040-4039(01)01714-2

We describe a novel and convenient method for quinoline synthesis using ring-closing olefin metathesis (RCM), ene-ene metathesis, and ene-enol ether metathesis. We also report the first example of enol silyl ether-ene metathesis to produce cyclic enol silyl ether. Using this method, versatile substituted quinoline derivatives were readily prepared in excellent yield from anthranilic acid derivatives.

Full text of DOI:10.1016/S0040-4039(01)01714-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8029–8033
Synthesis of substituted 1,2-dihydroquinolines and quinolines
using ene–ene metathesis and ene–enol ether metathesis
Mitsuhiro Arisawa, Chumpol Theeraladanon, Atsushi Nishida and Masako Nakagawa*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 20 August 2001; revised 3 September 2001; accepted 7 September 2001
Abstract—We describe a novel and convenient method for quinoline synthesis using ring-closing olefin metathesis (RCM), ene–ene
metathesis, and ene–enol ether metathesis. We also report the first example of enol silyl ether–ene metathesis to produce cyclic
enol silyl ether. Using this method, versatile substituted quinoline derivatives were readily prepared in excellent yield from
anthranilic acid derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
The quinoline ring system is an important structural
unit in naturally occurring quinoline alkaloids, thera-
peutics, and synthetic analogues with interesting biolog-
ical activities. Therefore, the development of a new and
efficient synthetic route to the quinoline ring system is
of interest in both synthetic organic and medicinal
chemistry. Versatile methods for synthesis of the quino-
line ring system have been developed;1,2 however, the
reaction conditions have some drawbacks, such as the
need for high temperature and/or strongly acidic condi-
tions. Additionally, regioisomers are usually formed
during intramolecular electrophilic substitution of
unsymmetrically substituted aniline derivatives to the
quinoline ring, which is the most common method used
for synthesis of the quinoline ring system. Therefore,
synthesis of the quinoline ring with a variety of sub-
stituents remains to be resolved. In our continuing
study of the RCM reaction3–7 and in our approach to
the synthesis of novel anti-malarial agents,8 we were
intrigued by the possibility of exploiting an RCM reac-
tion of dienes, N-allyl-N-protected-o-aminostyrene, to
1,2-dihydroquinolines and quinolines (Scheme 1). We
synthesized the requisite diene, N-allyl-N-protected-o-
aminostyrene, from anthranilic acid derivatives as
shown in Schemes 2 and 3. This communication reports
a novel method for the synthesis of substituted 1,2-
dihydroquinolines and quinolines using RCM, includ-
ing enol silyl ether–ene metathesis.
We first examined the RCM reaction of 1, derived from
commercially available 2-isopropenylaniline, using 30
mol% of commercially available Grubbs’ catalyst (A).
Diene 1 readily reacted at rt for 3 h to give 1,2-dihy-
droquinoline 2 in 94% yield (Table 1, run 1). When the
amount of catalyst was reduced to 5 mol%, the yield of
2 decreased to 72% (run 2). The yield improved to 92%
when heated at 50°C for 1 h (run 3). General proce-
dure: Ru-benzylidene catalyst (5 mol%; A) was added
to a stirring solution of 1 in CH2Cl2 (0.01 M). The
mixture was degassed using the freeze–pump–thaw
(FPT) cycle method and stirred at 50°C for 1 h under
an Ar atmosphere. The reaction mixture was concen-
trated to give a crude residue that was subjected to
column chromatography (n-hexane:AcOEt=1:1) to
R
R
R
RCM
N
N
P
N
X
X
X
P
N-Allyl-N-protected-o-aminostyrene
1,2-Dihydroquinoline
Quinoline
Scheme 1. Our strategy for the synthesis of substituted 1,2-dihydroquinolines and quinolines.
Keywords: 1,2-dihydroquinoline; quinoline; quinoline alkaloid; ring-closing metathesis; ene–ene metathesis; enol silyl ether–ene metathesis;
ene–enol ether metathesis.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01714-2

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M. Arisawa et al. / Tetrahedron Letters 42 (2001) 8029–8033
and 14 were subjected to the above conditions using
catalysts A and B (Table 3). When catalyst A was used
for RCM of 13 and 14, only the corresponding dimeric
compounds 15 and 17 were obtained. In sharp contrast,
the expected cyclization occurred to give benzoazepine
16 and benzoazocine 18, respectively, using catalyst B.
1) TsCl, pyridine
NH2
N
2) allyl bromide
K2CO3
Ts
1
We also examined the effect of protective groups on
nitrogen. Dienes 19–21 were prepared in essentially the
same manner (Scheme 3) and treated with catalysts A
and B. The reaction of the N-benzyl derivative 19 using
catalyst A gave 22 quantitatively (Table 4, run 1). The
N-acetyl derivative 20 did not give any product in the
presence of catalyst A (run 2), whereas the N-Boc
derivative 21 cyclized to quinoline 24 under similar
conditions in moderate yield (run 4). Catalyst A proba-
bly coordinated with the terminal double bond of 20 to
form a chelated intermediate 25, which could not con-
vert to 23. On the other hand, the higher reactivity of
catalyst B overcame this problem, and 23 was obtained
in 98% yield (run 3). Protective groups on products
22–24 were readily removed by silica gel column chro-
matography followed by spontaneous air oxidation to
give quinoline 26 quantitatively.
Scheme 2. Preparation of RCM precursor 1.
give 2 (92%) as a colorless oil.9 Various dienes 3–7,
prepared from anthranilic acid (Scheme 3), were sub-
jected to the above optimal reaction conditions to
investigate the scope and limitations of the system. The
results are summarized in Table 2. Substrates with an
electron-donating group such as -OMe (runs 2 and 3) as
well as those with a weak electron-withdrawing group
(-Cl, runs 4–6), gave the corresponding quinolines 8–11
in excellent yield. Diene 7 was also successfully trans-
formed to benzoquinoline (run 7). In the reaction of 6,
catalyst B proved to be superior to the classical Grubbs
catalyst A, and gives 11 in quantitative yield, consistent
with recent reports (runs 5 and 6).10 In the present
method, since o-aminostyrene is the RCM precursor,
no regioisomers were formed. In addition, a diene such
as 3, with a sterically hindered substituent at the posi-
tion ortho to aniline, also gave the corresponding 1,2-
dihydroquinoline (run 2).2
We also investigated the synthesis of 4-methoxy- and
4-siloxy-1,2-dihydroquinolines by ene–enol metathesis
of diene (27 and 28) from o-aminoacetophenone, since
4-substituted quinolines are key intermediates for the
synthesis of quinoline derivatives, such as chloroquine
and quinine (Table 5). Enol methyl ether (27)11 and
enol tert-butyldimethylsilyl (TBDMS) ether (28) were
prepared by standard methods and treated with ruthe-
nium catalysts A and B, respectively, under similar
These results prompted us to screen similar RCM reac-
tions of dienes such as 13 and 14 to construct other
related heterocycles such as benzoazepine and benzoa-
zocine. Dramatic differences were observed when 13
Table 1. Synthesis of 1,2-dihydroquinoline 2 using the RCM method
PCy3
Cl
Ph
Ru
Cl
PCy3
(A)
N
N
CH2Cl2
1
Ts
2
Ts
(0.01 M)
Run
Catalyst
(mol%)
Temp.
Reaction
Time (h)
Product
(%)
(˚C)
1
2
3
30
5
rt
rt
3
3
1
94
72
92
5
50
O
O
H
1) Me2C(OMe)2
1) allyl bromide
K2CO3
1) DIBAH
2) MnO2
cat. HCl
OH
OMe
O
2) TsCl, pyridine
NH2
NH
Ts
NH
Ts
N
X
2) Ph3P=CH2
X
X
X
Ts
3 - 7
Scheme 3. Preparation of RCM precursors 3–7.

M. Arisawa et al. / Tetrahedron Letters 42 (2001) 8029–8033
Table 2. RCM of dienes 1–7 using catalysts A and Ba
8031
Ru-catalystb)
Yield (%)c)
Substrate
Product
Run
A
A
A
A
1
92
90
95
90
N
N
2
1
Ts
Ts
MeO
MeO
MeO
MeO
2
N
N
8
9
3
4
5
6
OMe Ts
OMe Ts
MeO
Cl
MeO
Cl
3
N
N
Ts
Ts
4
N
N
10
11
Ts
Ts
A
B
5
6
74
100
Cl
N
Cl
N
Ts
Ts
A
7
98
N
N
12
Ts
Ts
7
a) All reactions are carried out at 50 °C, 1 h, using 5 mol% of ruthenium catalyst, in CH2Cl2 (0.01 M).
b)
PCy3
Mes
N
N
Mes
Ph
Cl
Cl
Ph
Catalyst A:
Catalyst B:
Ru
PCy3
Cl
Ru
Cl
PCy3
c) Isolated yields.
conditions. When catalyst A was used, the RCM reac-
tion of 27 gave no cyclized product at all and the
starting material was recovered unchanged. On the
other hand, treatment of 27 with catalyst B gave the
corresponding 1,2-dihydro-4-methoxyquinoline 29 in
excellent yield (run 1 and 2).
To the best of our knowledge, this is the first report of
the synthesis of 4-hydroxyquinoline derivatives using an
enol silyl ether–ene metathesis methodology.12 This
novel method is currently being applied to the total
synthesis of natural products in our laboratory.
We next investigated the enol silyl ether–ene RCM and
found that the enol TBDMS ether 28 was an excellent
substrate for RCM. Enol TBDMS ether 28 successfully
underwent cyclization to give the expected 4-siloxy-1,2-
dihydroquinoline 30 in excellent yield through enol silyl
ether–ene metathesis with catalyst B, while catalyst A
was not effective (run 3 and 4). These results can be
applied to significantly enhance the utility of the RCM
reaction for the synthesis of heterocyclic compounds.
Acknowledgements
This research was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry
of Education, Culture, Sports, Science, and Technol-
ogy, Japan. We also thank Ms. R. Hara at the Analyt-
ical Center, Chiba University, for performing the mass
spectroscopy.

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M. Arisawa et al. / Tetrahedron Letters 42 (2001) 8029–8033
Table 3. Synthesis of 2,3-dihydro-1H-benzo[b]azepine and 1,2,3,4,5,6-hexahydrobenzo[b]azocine using RCMa
Ru-catalystb)
Substrate
Product
Run
1
Yield (%)c)
Ts
N
A
B
100
N
Ts
N
15
13
Ts
2
100
7
16
N
Ts
Ts
N
A
B
3
4
95
99
N
Ts
N
17
14
Ts
8
N
18
Ts
a) All reactions are carried out at 50 °C, 1 h, using 5 mol% of ruthenium catalyst, in CH2Cl2 (0.01 M).
b)
PCy3
Mes
N
N
Mes
Ph
Cl
Cl
Ph
Catalyst A:
Catalyst B:
Ru
PCy3
Cl
Ru
Cl
PCy3
c) Isolated yields.
Table 4. Effect of protective groups on nitrogen
Mes
N
N
Mes
Ph
PCy3
Cl
Cl
Ph
Cl
Ru
PCy3
Ru
Cl
or
(5 mol%)
PCy3
(A)
(B)
1) H+
2) air oxidation
N
N
P
N
P
CH2Cl2
(0.01 M)
26
22 - 24
19 - 21
50 ˚C, 1 h
Substrate
P
Product
P
Run
Catalyst
%
1
2
3
4
5
19
20
20
21
21
A
A
B
A
B
22
99
0
Bn
Bn
23
23
24
24
Ac
Ac
N
98
63
97
Ac
Ac
Ru
O
Boc
Boc
Boc
Boc
25

M. Arisawa et al. / Tetrahedron Letters 42 (2001) 8029–8033
8033
Table 5. Ene–enol metathesis to 4-methoxy- and 4-siloxy-1,2-dihydroquinolines
Mes
N
N
Mes
Ph
PCy3
Ru
Cl
Cl
Ph
Cl
Ru
Cl
OR
OR
or
PCy3
PCy3
(A)
(B)
(5 mol%)
N
N
Ts
Ts
CH2Cl2
(0.01 M)
29 - 30
27 -28
50 ˚C, 1 h
Substrate
R
Product
R
Run
Catalyst
%
1
2
3
4
27
27
28
28
A
B
A
B
-
0
95
0
Me
-
29
-
Me
Me
-
TBS
TBS
30
95
TBS
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