Preparation of N-sulfonyl-2-quinolinone using ring-closing metathesis(RCM)

Article abstract of DOI:10.3987/COM-05-S(K)72

An efficient method for the preparation of N-sulfonyl-2-quinolinone using ring-closing metathesis (RCM) is described.

Full text of DOI:10.3987/COM-05-S(K)72

HETEROCYCLES, Vol. 66, 2005
683
HETEROCYCLES, Vol. 66, 2005, pp. 683 – 688. © The Japan Institute of Heterocyclic Chemistry
Received, 13th October, 2005, Accepted, 16th November, 2005, Published online, 18th November, 2005. COM-05-S(K)72
PREPARATION OF N-SULFONYL-2-QUINOLINONE USING
RING-CLOSING METATHESIS(RCM)
Mitsuhiro Arisawa,*# Chumpol Theeraladanon, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, JAPAN, fax: +81-43-290-2909, e-mail:
nishida@p.chiba-u.ac.jp, arisawa@pharm.hokudai.ac.jp
Abstract – An efficient method for the preparation of N-sulfonyl-2-quinolinone
using ring-closing metathesis (RCM) is described.
INTRODUCTION
It is still a challenge to develop more efficient methodologies and strategies for producing heterocycles
with the desired substituents and functional groups, despite the considerable amount of effort that has
been expended in this area.1
Metathesis has opened a new field of organic chemistry since it was introduced in the 1970s. Recent
ruthenium catalysts (A2, B3, C4, and D5 Figure), which were developed by Grubbs, Hoveyda, and their
respective co-workers, are compatible with a variety of functional groups, easy to handle and, now
commercially available.6
MesN
NMes
Ph
MesN
NMes
PCy3
Ru
PCy3
Ru
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
iPrO
Ru
Ru
Ph
PCy3
PCy3
iPrO
A
B
C
D
Figure. Ruthenium Carbene Catalysts.
We have been investigating the feasibility of using metathesis to prepare heterocyclic compounds and its
application to the synthesis of bioactive natural products. Recently, we found that N-allyl-o-vinylaniline
(1) gave 1,2-dihydroquinoline (2) by normal RCM, and developed silyl enol ether - ene metathesis for the
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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HETEROCYCLES, Vol. 66, 2005
novel synthesis of 4-silyloxy-1,2-dihydroquinoline, and thus demonstrated a convenient entry to
quinolines and 1,2,3,4-tetrahydroquinoline.7f,k We also found a novel selective isomerization of terminal
olefin and a cycloisomerization of 1,6-dienes, using ruthenium carbene catalyst and silyl enol ether,
which represented a new synthetic route to a series of substituted indoles (4) and
3-methylene-2,3-dihydroindoles (5) (Scheme 1).7h,l,n We now report our novel preparation of
N-sulfonyl-2-quinolinones using RCM.
a
RCM
N
N
X
X
1
2
Ts
Ts
Cycloisomerization
b Isomerization
d
N
X
N
X
Ts
Ts
3
5
c RCM
conditions
a: A or B (5 mol%), CH2Cl2, reflux, 1 h
b: B (5 mol%), CH2=CHOTMS (6a, 1 eq.),
reflux, 1.5 h, c: B (5-20 mol%), benzene or
toluene, reflux, d: B (10 mol%), 6a (1 eq.),
xylene, reflux, 2 h
N
X
4
Ts
Scheme 1. Synthesis of 2, 4, 5 from 1.
R2
O
O
R2
O
R2
P
P
P
X
D-A
N
OH
OMe
N
N
O
+
O
OTMS
R3
R3
OR1
dynemicin A core
OR1
OR1
Scheme 2. Diels-Alder Reaction for Dynemicin A Core.
2-Quinolones are valuable intermediates in organic synthesis8 and N-sulfonyl-2-quinolinones are difficult
to prepare by conventional methods because O-sulfonyl-2-quinolinones would be obtained preferentially
instead of N-sulfonylation. In our previous work on the synthesis of dynemicin A,9 we found that
N-protected-2-quinolinone derivatives are good dienophiles for the Diels-Alder reaction (Scheme 2).
Theoretically, N-sulfonyl-2-quinolinones should be better dienophiles than N-methoxycarbonyl or

HETEROCYCLES, Vol. 66, 2005
685
N-methoxymethyl derivatives. However, we could not prepare N-sulfonyl-2-quinolinones using
conventional methods.
RESULTS AND DISCUSSION
Dienes (7) were prepared by condensation of the corresponding N-protected aniline and acid chloride.
When catalyst B was used for RCM of 7a under the standard conditions, no cyclized product was
obtained and the starting material was recovered (Entry 1). Thus, instead of catalyst B, catalyst C was
used under the same reaction conditions. The N-tosyl-2-quinolinone (8a) was obtained in trace amounts.
o
When the reaction temperature was raised to 100 C, N-tosyl-2-quinolinone (8a) was obtained in 56%
yield, while rearranged product (9) was also obtained in 32% yield (Entry 3). In Entry 4, the reaction
o
temperature was reduced to 80 C, the reaction mixture was stirred for 4 h, and the desired
N-tosyl-2-quinolinone (8a) was obtained in quantitative yield. Thermal rearrangement of 8 to 9
occurred at 100 °C quantitatively without any catalyst. Compound (9) should be a useful substrate for
the synthesis of 2-substituted quinolines by a coupling reaction.
R
100 oC
B
C
or
5 mol%
+
N
P
O
N
P
O
N
OP
Rearranged Product
7a
7b
7c
8a : P = Ts
8b : P = Bs
9
Entry
Substrate
Catalyst
Conditions
Product (%)
Remark
Temp. (oC)
R
P
Solvent
Time (h)
-
-
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
7a
7a
7a
7a
7b
7c
50
50
H
1
2
3
4
5
6
Ts
Ts
Ts
Ts
Ts
Bs
B
C
C
C
C
C
NR
1
1
4
4
4
5
H
8a (trace)
rearrange 32 %
100
80
H
8a (56)
8a (95)
8a (74)
8b (90)
-
H
STM 20%
-
80
Me
H
80
Table. Preparation of N-Sulfonyl-2-quinolinone.
N-Crotonoyl-N-tosylaminostyrene (7b) was subjected to the same reaction conditions as in Entry 4 and
gave N-tosyl-2-quinolinone (8a) in 74% yield (Entry 5). RCM of 7c was accomplished within 5 h using
catalyst C, and N-benzenesulfonyl-2-quinolinone (8b) was obtained in 90% yield (Entry 6).

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Thus, the development of a novel method for preparing N-sulfonyl-2-quinolinone was achieved by RCM
using a well-defined Hoveyda catalyst (C) and dienes at 80 °C. The reaction proceeded efficiently under
mild conditions. Further studies of the D-A reaction using N-sulfonyl-2-quinolinone are currently in
progress in our laboratory.
EXPERIMENTAL
All melting points are uncorrected. IR spectra (cm-1) were recorded using a KBr or NaCl pellet. 1H
13
NMR and C NMR spectra were recorded in CDCl3 , CD3OD, and DMSO-d6 unless otherwise noted, at
400 MHz, with TMS as an internal standard. E. Merck silica gel 60 was used for column
chromatography, and E. Merck precoated TLC plates, silica gel F254, were used for preparative thin layer
chromatography. The organic layers were dried with anhydrous MgSO4 or Na2SO4.
N-p-Toluenesulfonyl-2-quinolinone (8a).
To a solution of N-p-toluenesulfonyl-2-aminostyrene (100 mg, 0.37 mmol) and Et3N (0.07 mL, 0.55
mmol) in 10 mL of CH2Cl2 under an Ar atmosphere, was added acryloyl chloride (0.03 mL, 0.40 mmol).
The solution was stirred at rt for 1 h and the reaction was quenched by the addition of saturated aqueous
NaHCO3. The mixture was extracted with AcOEt and the combined organic layers were washed with
brine and dried over Na2SO4. After removal of the solvent, the residue was purified by column
chromatography on silica gel (n-hexane:Acetone
N-acryloyl-N-p-toluenesulfonyl-2-aminostyrene as
=
3:1) to give 110 mg (92%) of
white solid. To solution of
a
a
N-acryloyl-N-p-toluenesulfonyl-2- aminostyrene (60 mg, 0.18 mmol) in 18 mL of toluene under an Ar
atmosphere, was added catalyst C (6.4 mg, 0.008 mmol). The mixture was stirred at 80 oC for 4 h. After
removal of the solvent, the residue was purified by column chromatography on silica gel
(n-hexane:AcOEt = 3:1) followed by recrystallization from AcOEt to give 49 mg (95%) of 8a as colorless
crystals. mp 165 oC; 1H NMR (CDCl3) δ 8.64 (1H, d, J = 8.8 Hz), 8.00 (2H, d, J = 8.4 Hz), 7. 75 (2H, d, J
13
= 9.5 Hz), 7.50 (1H, d, J = 7.7 Hz), 7.33 (3H, d, J = 7.9 Hz), 6.38 (1H, d, J = 9.3 Hz), 2.43 (3H, s); C
NMR (CDCl3) δ 161.9, 145.3, 141.8, 137.5, 136.6, 130.4, 129.4, 128.8, 128.7, 124.5, 122.2, 121.7, 119.2,
21.7; IR (KBr) 3451, 3051, 2921, 1681, 1591, 1360; LRMS (EI) m/z 341 [100].
N-Benzenesulfonyl-2-quinolinone (8b).
To a solution of N-benzenesulfonyl-2-aminostyrene (300 mg, 1.14 mmol) and Et3N (0.24 mL, 1.71 mmol)
in 10 mL of CH2Cl2 under an Ar atmosphere, was added acryloyl chloride (0.10 mL, 1.25 mmol). The
solution was stirred at rt for 1 h and the reaction was quenched by the addition of saturated aqueous
NaHCO3. The mixture was extracted with AcOEt and the combined organic layers were washed with
brine and dried over Na2SO4. After removal of the solvent, the residue was purified by column
chromatography on silica gel (n-hexane:Acetone
=
3:1) to give 335 mg (95%) of

HETEROCYCLES, Vol. 66, 2005
687
N-acryloyl-N-benzenesulfonyl-2-aminostyrene
as
a
white
solid.
To
a
solution
of
N-acryloyl-N-benzenesulfonyl-2-aminostyrene (90 mg, 0.27 mmol) in 27 mL of toluene under an Ar
atmosphere, was added catalyst C (8.6 mg, 0.014 mmol). The mixture was stirred at 80 oC for 5 h. After
removal of the solvent, the residue was purified by column chromatography on silica gel
(n-hexane:AcOEt = 3:1) followed by recrystallization from AcOEt to give 73 mg (90%) of 8b as colorless
crystals. mp 144 oC; 1H NMR (CDCl3) δ 8.47 (1H, d, J = 8.8 Hz), 8.12 (2H, d, J = 8.3 Hz), 7.65 (1H, dd,
13
J = 7.1, 7.8 Hz), 7.50-7.59 (5H, m), 7.33 (1H, dd, J = 7.3, 7.6 Hz), 6.38 (1H, d, J = 9.7 Hz); C NMR
(CDCl3) δ 161.9, 141.9, 139.7, 137.5, 134.1, 135.0, 128.9, 128.8, 128.7, 124.7, 122.2, 121.7, 119.2; IR
(KBr) 3451, 3060, 2921, 1666, 1591, 1448, 1363; LRMS (EI) m/z 285 [100].
ACKNOWLEDGEMENTS
This research was supported by Grants-in-Aid for the Encouragement of Young Scientists (A), for
Scientific Research (B), for Priority Area (A)(#17035014) and for Exploratory Research from the
Ministry of Education, Culture, Sports, Science and Technology, Japan. We also thank the Naito
Foundation and the Fujisawa Foundation for financial support.
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