One-pot synthesis of highly functionalizable 3-(phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones via a Cu-catalyzed aza-Michael addition/cyclization reaction

Article abstract of DOI:10.1246/cl.160772

A straightforward and mild one-pot method used for the synthesis of 3-(phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones via a Cu-catalyzed aza-Michael addition/base-mediated cyclization reaction is described. Addition of a range of readily available 2-aminobenzoates to phenyl vinyl sulfone was catalyzed by 5 mol% of a Cu complex at ambient temperature, followed by cyclization with KOt-Bu at 0°C to afford new versatile 3-sulfonyl-substituted-2,3-dihydro-4(1H)-quinolinones in good yield (53-99%).

Full text of DOI:10.1246/cl.160772

CL-160772
Received: August 24, 2016 | Accepted: September 11, 2016 | Web Released: November 5, 2016
One-pot Synthesis of Highly Functionalizable 3-(Phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones
via a Cu-catalyzed Aza-Michael Addition/Cyclization Reaction
Seongil Kang, Hongju Yoon, and Yunmi Lee*
Department of Chemistry, Kwangwoon University, Seoul 01897, Korea
(E-mail: ymlee@kw.ac.kr)
NH2
A straightforward and mild one-pot method used for the
H
H
N
cat. CuCl/DPEPhos
N
synthesis of 3-(phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones
via a Cu-catalyzed aza-Michael addition/base-mediated cyclization
reaction is described. Addition of a range of readily available 2-
aminobenzoates to phenyl vinyl sulfone was catalyzed by 5 mol %
of a Cu complex at ambient temperature, followed by cyclization
with KOt-Bu at 0 °C to afford new versatile 3-sulfonyl-substituted-
2,3-dihydro-4(1H)-quinolinones in good yield (53-99%).
SO2Ph
cat. KOt-Bu
base
CO2Me
1a
toluene, 22 °C
CO2Me
SO2Ph
+
O
3a
4a
SO2Ph
3-(phenylsulfonyl)-
2,3-dihydro-4(1H)-quinolinone
2
Scheme 1. The synthesis of 3-sulfonyl-substituted-2,3-dihydro-
4(1H)-quinolinone 4a.
Keywords: Quinolinone
| One-pot reaction | Copper catalyst
Table 1. Optimization of the one-pot reaction conditionsa
NH2
2,3-Dihydro-4(1H)-quinolinones serve as valuable building
blocks in medicinal chemistry and useful intermediates in
synthetic organic chemistry.1 Due to the importance of 2,3-
dihydro-4(1H)-quinolinones, various approaches towards their
synthesis have been studied.2 Commonly used methods are
Brønsted acid- or Lewis acid-catalyzed annulations including
the Friedel-Craft cyclization of N-aryl-substituted β-amino acid
derivatives,3 rearrangement of N-aryl-substituted β-lactams,4
intramolecular Michael addition of aniline derivatives,5 and
SNAr cyclization of fluoroaryl-substituted aminopropanones.6 In
addition, organocatalysis plays an important role in synthesizing
2,3-dihydro-4(1H)-quinolinones under mild reaction conditions;
for example, the cyclization of 2-aminoacetophenone and
aldehydes in the presence of chiral aminocyclodextrins or a
proline catalyst7 or intramolecular conjugate addition catalyzed
by a chiral thiourea or thiazolium salt.8 Another strategy uses
palladium catalysts to promote the intramolecular cyclocarbonyl-
ation of 2-iodoanilines with α,β-unsaturated olefins and CO gas to
afford highly functionalized 2,3-dihydro-4(1H)-quinolinones.9
Despite the above-mentioned advances, only a few examples of
the synthesis of functionalized 3-substituted-2,3-dihydro-4(1H)-
quinolinones have been reported and new synthetic approaches
are still required.
5 mol % CuCl
5 mol % DPEPhos
5 mol % KOt-Bu
H
N
H
N
OMe
SO2Ph
base
O
1a
OMe
+
THF
0.5-2 h
toluene, 22 °C, 5 h
SO2Ph
SO2Ph
O
O
2
3a
4a
Temp Time
Yield
/%b
Entry Base (equiv)
Toluene:THF
/°C
/h
1
2
3
4
5
6
7
8
KOt-Bu (3.0)
KOt-Bu (3.0)
LiOt-Bu (3.0)
NaOt-Bu (3.0)
KOt-Bu (1.5)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
22
22
22
22
22
¹78
0
0.5
0.5
0.5
0.5
0.5
2
1:0
1:2
1:2
1:2
1:2
1:2
1:2
1:3.3
6
71
<2
34
52
48
75
93
1
1
0
aReaction conditions: Anthranilate 1a (0.36 mmol), vinyl
sulfone (0.30 mmol), CuCl (0.015 mmol), DPEPhos
2
(bis[(2-diphenylphosphino)phenyl] ether, 0.015 mmol), KOt-
b
Bu (0.015 mmol), toluene (1.5 mL) under N2. Determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an
internal standard.
We have recently investigated a mild and efficient synthesis
of N-aryl-substituted β-aminosulfones using a Cu-catalyzed aza-
Michael addition of aromatic amines to vinyl sulfones.10
Inspired by this recent discovery, we envisioned that β-amino-
sulfone 3a derived from the addition of methyl anthranilate (1a)
to phenyl vinyl sulfone (2) could be used as a precursor for the
preparation of 3-sulfonyl-substituted-2,3-dihydro-4(1H)-quino-
linone 4a via the cyclization of the in situ generated 3a with
base in a single vessel (Scheme 1). Herein, we describe a facile
and convenient approach to the synthesis of 3-sulfonyl-sub-
stituted-2,3-dihydro-4(1H)-quinolinones via a one-pot sequential
process that involves a Cu-catalyzed aza-Michael addition
reaction followed by cyclization of the resulting β-aminosulfone
under mild reaction conditions. A range of readily accessible
2-aminobenzoates and a vinyl sulfone can be used to obtain
a variety of synthetically useful 3-sulfonyl-substituted-2,3-
dihydro-4(1H)-quinolinones in good to excellent yield.
Our study commenced with the optimization of a one-pot
synthesis of 3-sulfonyl-substituted-2,3-dihydro-4(1H)-quinoli-
none 4a as summarized in Table 1. Guided by the conditions
previously optimized for the Cu-catalyzed aza-Michael addi-
tion,10 anthranilate 1a was treated with vinyl sulfone 2 in the
presence of 5 mol % of CuCl, DPEPhos, and KOt-Bu in toluene
at room temperature, generating β-aminosulfone 3a with
complete conversion. Then, it was directly reacted with KOt-
Bu to perform the base-mediated intramolecular cyclization to
afford a new type of 2,3-dihydro-4(1H)-quinolinone 4a. As a
result shown in Entry 1 of Table 1, the desired sequential
process proceeded, but a low yield of product 4a was obtained
due to the poor cyclization reaction observed using toluene as
the reaction solvent. When THF was added in the cyclization
step, the desired product 4a was obtained in 71% yield
1356 | Chem. Lett. 2016, 45, 1356–1358 | doi:10.1246/cl.160772
© 2016 The Chemical Society of Japan

Table 2. Substrate scope of 2-aminobenzoates 1a
are some exceptions, a new type of 3-sulfonyl-substituted-2,3-
dihydro-4(1H)-quinolinones 4 was obtained in good to excellent
yield. When 2-aminobenzoates 1b-1e including a methyl-,
fluoro-, chloro-, and bromo-substituent in the para-position were
used, the Cu-catalyzed conjugate addition reactions proceeded
efficiently to give complete conversion within 5 h and the
subsequent cyclization step afforded the desired dihydroquino-
linones 4b-4e in 64-84% yield. However, the reaction with
para-iodo-substituted aminobenzoate 1f was not efficient; a
longer reaction time (5 h vs. 12 h) for the catalytic amination
reaction was required and a moderate yield was obtained (60%
yield of 4f). The electron-donating methoxy group affected the
high reactivity, affording the 3-sulfonyl-substituted-2,3-dihydro-
4(1H)-quinolinones 4g and 4h in >99% yield within 3 h. The
use of the sterically demanding aminobenzoate 1i bearing a
methyl group in the ortho-position gave a poor yield of product
4i (24% yield) due to the sluggish amination reaction (40%
conversion). Methyl 2-aminobenzoates bearing a fluoro-, chloro-,
and bromo-substituent in the ortho- or meta-position were also
transformed to the corresponding dihydro-4(1H)-quinolinones
4j-4n in 53-73% yields. It was noted that catalytic conjugate
additions of ortho- or meta-halo-substituted starting materials to
alkene 2 did not undergo full conversion, although the reaction
time was prolonged (16-20 h vs. 3-5 h) or a higher catalyst
loading was used (10 mol % CuCl for 4m vs. 5 mol % CuCl).
Thus, the yields of products 4j-4n were moderate.
The resulting 3-sulfonyl-substituted-2,3-dihydro-4(1H)-
quinolinones can be transformed to other valuable synthetic
building blocks. For example, the phenylsulfonyl group on the
product was easily cleaved under radical reduction conditions
to form 2,3-dihydro-4(1H)-quinolinones as illustrated in
Scheme 2.11 Treatment of 4a or 4h with n-Bu3SnH and
azobisisobutyronitrile (AIBN) provided the corresponding de-
sulfonylated products 5 and 6 in 90-92% yield.
The synthetic utility of this methodology was demonstrated
by the synthesis of the 5,6-dihydrophenanthridine derivative 8,
which is a useful structural motif found in biologically active
molecules and natural products (Scheme 3).12 After N-Boc-
protection of 4h, conjugate addition of β-keto sulfone to methyl
vinyl ketone in the presence of triethylamine afforded the
desired Michael addition product 7 in 86% yield. An intra-
molecular aldol reaction of 7 was then carried out under
pyrrolidine and acetic acid conditions, followed by the elimi-
nation of water and phenylsulfonic acid using p-TsOH to give
pyrrolidine-substituted 5,6-dihydrophenanthridine 8 in 50%
yield.13
5 mol % CuCl
H
N
5 mol % DPEPhos
5 mol % KOt-Bu
toluene, 22 °C, 3−20 h;
NH2
OMe
+
SO2Ph
SO2Ph
R
3.0 equiv KOt-Bu
THF, 0 °C, 1 h
R
O
O
1
2
4
H
N
H
N
H
N
SO2Ph
Me
SO2Ph
O
F
SO2Ph
O
O
4a (89%, 5 h)
4b (84%, 5 h)
4c (75%, 5 h)
H
N
H
N
H
N
Br
SO2Ph
O
I
SO2Ph
Cl
SO2Ph
O
O
(60%, 12 h)
4d (74%, 5 h)
4f
4e (64%, 5 h)
Me
H
N
H
N
H
N
MeO
MeO
SO2Ph MeO
SO2Ph
O
SO2Ph
O
O
4h (>99%, 3 h)
4g (>99%, 3 h)
4i (24%, 16 h)
F
Br
H
H
H
N
N
N
Cl
SO2Ph
SO2Ph
O
SO2Ph
O
O
4j (64%, 20 h)
4k (73%, 16 h)
4l (53%, 16 h)
H
N
H
N
Br
SO2Ph
SO2Ph
F
O
O
4m (65%, 16 h)b
4n (60%, 16 h)
aReaction conditions: 2-Aminobenzoate 1 (0.36 mmol), vinyl
sulfone 2 (0.30 mmol), CuCl (0.015 mmol), DPEPhos (bis[(2-
diphenylphosphino)phenyl] ether, 0.015 mmol), KOt-Bu
(0.015 mmol), toluene (1.5 mL) under N2. In the cyclization
step, KOt-Bu (0.9 mmol) and THF (5 mL) were added. The
values in parenthesis show the yields after purification and
reaction times for the aza-Michael addition, respectively.
b10 mol % CuCl was used.
(Entry 2). In order to improve the efficiency of the one-pot
synthesis, different alkoxide bases, equivalents of base, and
reaction temperatures for the cyclization were screened (Entries
3-8). It was found that a lower reaction temperature in the
second step (0 °C vs. 22 °C) was more effective in decreasing
the formation of unidentified by-products, and KOt-Bu was
identified as the optimal base. Finally, when the cyclization was
performed with 3 equiv of KOt-Bu in a 1:3.3 ratio of toluene
and THF as solvent at 0 °C for 1 h, the one-pot sequential Cu-
catalyzed conjugate addition-cyclization provided 3-sulfonyl-
substituted-2,3-dihydro-4(1H)-quinolinone 4a with high effi-
ciency (93% yield, Entry 8).
Under the optimized reaction conditions used for the one-
pot process, the substrate scope of 2-aminobenzoates 1 was
examined as shown in Table 2. A variety of readily available
2-aminobenzoates were reacted with vinyl sulfone 2 using the
catalytic system of 5 mol % Cu complex in toluene at room
temperature to generate the intermediate β-aminosulfones, which
were cyclized using 3 equiv of KOt-Bu in THF. Although there
H
N
H
N
n-Bu3SnH, AIBN
toluene, 130 °C, 4 h
SO2Ph
O
O
4a
5 (90%)
H
N
H
N
MeO
MeO
MeO
MeO
n-Bu3SnH, AIBN
SO2Ph
toluene, 130 °C, 4 h
O
O
4h
6 (92%)
Scheme 2. Desulfonylation of 3-sulfonyl-substituted-2,3-dihydro-
4(1H)-quinolinones.
Chem. Lett. 2016, 45, 1356–1358 | doi:10.1246/cl.160772
© 2016 The Chemical Society of Japan | 1357

H
N
1. Boc2O, Et3N, DMAP
Boc
N
Supporting Information is available on http://dx.doi.org/
10.1246/cl.160772.
MeO
MeO
MeO
MeO
O
THF, 22 °C, 4 h, 95%
SO2Ph 2. methyl vinyl ketone, Et3N
SO2Ph
CH2Cl2, 22 °C,16 h, 86%
O
O
7
References and Notes
4h
Boc
1
a) N. S. Gill, A. Kaur, R. Arora, V. Dhawan, M. Bali, Curr.
Res. Chem. 2012, 4, 88. b) S. Chandrasekhar, S. N. C. V. L.
Pushpavalli, S. Chatla, D. Mukhopadhyay, B. Ganganna,
K. Vijeender, P. Srihari, C. R. Reddy, M. J. Ramaiah, U.
Bhadra, Bioorg. Med. Chem. Lett. 2012, 22, 645. c) Y. Xia,
Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E.
Hamel, T. Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155.
For a review, see: B. Nammalwar, R. A. Bunce, Molecules
2014, 19, 204.
a) M. Layek, M. A. Reddy, A. V. D. Rao, M. Alvala, M. K.
Arunasree, A. Islam, K. Mukkanti, J. Iqbal, M. Pal, Org.
Biomol. Chem. 2011, 9, 1004. b) Y. Gong, K. Kato, J.
Fluorine Chem. 2004, 125, 767. c) V. Y. Mitskyavichyus,
Chem. Heterocycl. Compd. 1996, 32, 456.
MeO
MeO
N
pyrrolidine, AcOH
CH2Cl2, 22 °C, 16 h;
p-TsOH, toluene
120 °C, 1 h, 50%
N
8
Scheme 3. Aromatization via Michael addition and aldol reactions.
2
3
H
N
N
I2, DMSO
N
Ref. 14
120 °C, 12 h;
SO2Ph
SO2Ph
SO2Ph
POCl3, 80 °C
0.5 h, 65%
Cl
NHMe
O
4a
9
10
5-HT6 receptor antagonist
4
a) J. Lange, A. C. Bissember, M. G. Banwell, I. A. Cade,
Aust. J. Chem. 2011, 64, 454. b) K. W. Anderson, J. J. Tepe,
Org. Lett. 2002, 4, 459. c) K. W. Anderson, J. J. Tepe,
Tetrahedron 2002, 58, 8475.
Scheme 4. The synthesis of 4-chloro-3-(phenylsulfonyl)quinolone.
Finally, the result displayed in Scheme 4 shows that the
3-(phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones can be used
as building-blocks used to prepare a serotonin 5-HT6 receptor
antagonist.14 When 2,3-dihydro-4(1H)-quinolinone 4a was
treated with I2 in DMSO, a dehydrogenation reaction occurred
to generate 3-(phenylsulfonyl)-4-quinolinol, which was subse-
quently transformed to 4-chloro-3-(phenylsulfonyl)quinoline (9)
using POCl3 at 80 °C in 65% yield. Chloro-substituted quinoline
9 could serve as a precursor for amine-substituted quinoline 10,
which showed higher antagonist activity against 5-HT6 receptors
than compound 9.
In summary, we have investigated a facile and mild
synthetic protocol used to prepare new versatile 3-sulfonyl-
substituted-2,3-dihydro-4(1H)-quinolinones. The synthesis in-
volves a one-pot Cu-catalyzed aza-Michael addition and base-
mediated intramolecular cyclization reaction sequence. The use
of readily available methyl 2-aminobenzoates and vinyl sulfone,
the use of an inexpensive Cu catalyst system and the synthetic
utility of the products make this new methodology attractive.
Further study towards the expansion of substrate scope to other
types of olefins is in progress.
5
6
7
a) R. Dhiman, S. Sharma, G. Singh, K. Nepali, P. M. S. Bedi,
Arch. Pharm. 2013, 346, 7. b) R. A. Bunce, B. Nammalwar,
J. Heterocycl. Chem. 2011, 48, 613.
a) R. A. Bunce, J. E. Schammerhorn, J. Sigle, J. Heterocycl.
Chem. 2013, 50, 373. b) R. A. Bunce, T. Nago, J.
Heterocycl. Chem. 2009, 46, 623.
a) K. Kanagaraj, K. Pitchumani, J. Org. Chem. 2013, 78,
744. b) S. Chandrasekhar, K. Vijeender, C. Sridhar,
Tetrahedron Lett. 2007, 48, 4935.
a) X. Liu, Y. Lu, Org. Lett. 2010, 12, 5592. b) T. Nemoto, T.
Fukuda, Y. Hamada, Tetrahedron Lett. 2006, 47, 4365.
a) K. Okuro, H. Alper, J. Org. Chem. 2012, 77, 4420. b) R.
Grigg, A. Liu, D. Shaw, S. Suganthan, D. E. Woodall, G.
Yoganathan, Tetrahedron Lett. 2000, 41, 7125.
8
9
10 S. Kim, S. Kang, G. Kim, Y. Lee, J. Org. Chem. 2016, 81,
4048.
11 M. S. Wilson, A. Padwa, J. Org. Chem. 2008, 73, 9601.
12 a) W.-I. Lee, J.-W. Jung, J. Jang, H. Yun, Y.-G. Suh,
Tetrahedron Lett. 2013, 54, 5167. b) J. Éles, G. Beke, I.
Vágó, É. Bozó, J. Huszár, Á. Tarcsay, S. Kolok, É. Schmidt,
M. Vastag, K. Hornok, S. Farkas, G. Domány, G. M. Keserű,
Bioorg. Med. Chem. Lett. 2012, 22, 3095. c) X.-J. Yang, F.
Miao, Y. Yao, F.-J. Cao, R. Yang, Y.-N. Ma, B.-F. Qin, L.
Zhou, Molecules 2012, 17, 13026.
13 a) S. Kiren, A. Padwa, J. Org. Chem. 2009, 74, 7781. b) C. J.
Stearman, M. Wilson, A. Padwa, J. Org. Chem. 2009, 74,
3491.
14 A. V. Ivachtchenko, E. S. Golovina, M. G. Kadieva, O. D.
Mitkin, I. M. Okun, Pharm. Chem. J. 2015, 48, 646.
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Science, ICT & Future
Planning (No. NRF-2014R1A1A1003650) and partially sup-
ported by the Research Grant of Kwangwoon University in
2015. The authors thank the Korea Basic Science Institute for
technical assistance in MS spectrometry.
1358 | Chem. Lett. 2016, 45, 1356–1358 | doi:10.1246/cl.160772
© 2016 The Chemical Society of Japan