A general synthesis of quinolinones and benzothiazine 1,1-dioxides via ring closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2008.03.144

A general synthesis of quinolinones and benzothiazine 1,1-dioxides is presented. A series of N-phenylacrylamides and N-phenylethylenesulfonamides were studied for their ability to undergo ring closing methathesis to yield the corresponding quinolinones and benzothiazine 1,1-dioxides, respectively. The reactions are general in scope and represents a mild method for the preparation of these heterocycles.

Full text of DOI:10.1016/j.tetlet.2008.03.144

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3677–3681
A general synthesis of quinolinones and benzothiazine
1,1-dioxides via ring closing metathesis
Joannie Minville, Jason Poulin, Claude Dufresne, Claudio F. Sturino *
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada,
16711 Trans Canada Hwy, Kirkland, Quebec, Canada H9H 3L1
Received 28 January 2008; revised 27 March 2008; accepted 27 March 2008
Available online 8 April 2008
Abstract
A general synthesis of quinolinones and benzothiazine 1,1-dioxides is presented. A series of N-phenylacrylamides and N-phenylethyl-
enesulfonamides were studied for their ability to undergo ring closing methathesis to yield the corresponding quinolinones and benzo-
thiazine 1,1-dioxides, respectively. The reactions are general in scope and represents a mild method for the preparation of these
heterocycles.
Ó 2008 Published by Elsevier Ltd.
Quinolinones are an interesting class of molecules pres-
ent in a number of biologically active natural products. For
example, this core is present in the antibiotics nybomycin
and deoxynybomycin,1 isolated from streptomycete cul-
tures. This structural core is also employed in medicinal
chemistry and is present in a number of medicinally valu-
able compounds. Figure 1 highlights several of these medic-
inally important compounds, and this figure also serves to
illustrate the variety of substitution patterns incorporated
in these molecules.2a–d
As part of our medicinal chemistry efforts, we had an
occasion to incorporate a quinolinone structural motif in
one of our target molecules. While several procedures have
been reported for the synthesis of quinolinones,3 they gen-
erally involve the use of strong bases and/or high tempera-
tures thus limiting the functional group compatibility of
these reactions. We envisioned that a ring closing metathe-
sis (RCM) reaction of a suitable functionalized diene, such
as 5 (Scheme 1), could represent a powerful method for the
formation of this ring system. If successful, the functional
group tolerability of this reaction would allow for a general
entry into this class of heterocycles. In addition, we were
also interested in exploiting this idea to prepare the corres-
ponding cyclic sulfonamide system (X = SO2 in Scheme 1).
Sulfonamides4 are an important functional group in medic-
inal chemistry, and these cyclic sulfonamides could poten-
tially represent interesting bioisostere replacements for
quinolinone ring systems. We wish to present in this Letter
an attractive method for the preparation of quinolinones
and benzothiazine dioxides via a RCM reaction.
Ring closing metathesis is widely used in synthetic
organic chemistry and has become the method of choice
for the formation of cyclic targets including heterocycles.5
Several reports have appeared in the literature describing
the use of RCM for the formation of lactams6 and cyclic
sulfonamides.7 These studies clearly establish the utility
of RCM for the synthesis of these ring systems. We envi-
sioned that a RCM approach would be amenable toward
the synthesis of quinolinones and benzothiazine 1,1-diox-
ides as outlined in Scheme 1. At the outset, the key ques-
tion we wished to address regarding our strategy was
whether N-phenylacrylamides and/or N-phenylethylene-
sulfonamides are viable substrates for RCM. Toward this
goal, we elected to employ diene 7 as a model substrate
*
Corresponding author at present address: Boehringer Ingelheim
Canada, Ltd, 2100 Rue Cunard, Laval, Quebec, Canada H7S 2G5. Tel.:
+1 450 682 4640.
E-mail address: csturino@lav.boehringer-ingelheim.com (C. F. Sturino).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.144

3678
J. Minville et al. / Tetrahedron Letters 49 (2008) 3677–3681
O
Cl
O
HO
N
N
N
H
NH2
N
H
O
Cl
N
OH
2 2b
1 2a
Long acting β2-adrenoceptor agonist
Farnesyltransferase inhibitor
N
S
N
Cl
OH
N
O
O
N
N
F
N
O
NH2
O
3 2c
4 2d
5-HT1B and 5-HT2A receptor antagonist
Immunomodulator
Fig. 1. Biologically active quinolinones.
catalyst loading. From these initial experiments, the condi-
tions of entry 2 were selected as the standard conditions for
future studies as it represents a compromise between cata-
lyst loading and reaction times.
R4
R3
RCM
R1
R4
X
R1
X
N
R2
N
Having established the viability of using N-phenyl-
acrylamide 7 in a RCM reaction, we next turned our atten-
tion at investigating the scope for this transformation. A
variety of analogs of 7 were prepared varying the substitu-
ents around the N-phenylacrylamides core in order to
explore the effects of the substituents on the reaction effi-
ciency. The results of these studies are presented in Table
2, and several points from this table are worthy of further
comment. Overall, the reaction is general in scope (with a
few notable exceptions discussed below) providing good
to excellent yields of the corresponding quinolinones. Sub-
stitution of the benzene ring (R1) is well tolerated and we
were pleased to observe high yields for the analogs incorpo-
rating bromine or the strongly electron-withdrawing CF3
substituent (Table 2, entries 1 and 2, respectively). An
added advantage of incorporating bromine as a substituent
on the benzene ring is that it could potentially serve as a
handle for further functionalization. Substitution at nitro-
gen (R2) is well tolerated and provides excellent yields of
the corresponding quinolinone (Table 2, entries 4–6). While
Me and phenyl substitution at the acrylamide position (R3)
provided excellent yields of the corresponding quinolinone,
the reaction completely failed when either a bromine or a
CF3 substituent was present. Vinyl bromides have been
reported to be poor substrates for RCM, and this is consis-
tent with our observation.8 While there are several litera-
ture examples of vinyl chlorides undergoing successful
RCM,9,8b the corresponding reaction with a-chloroacryl-
amide (Table 2, entry 11) was unresponsive to treatment
R2 R3
X = CO or SO2
5
6
Scheme 1. RCM approach to quinolinones and benthothiazine 1,1-
dioxides.
to investigate its reactivity in a RCM reaction. The results
of these studies are summarized in Table 1.
Treatment of 7 with 10 mol % of Grubbs 2nd generation
catalyst in dichloromethane cleanly yielded the desired
quinolinone in 95% isolated yield. The catalyst loading
could be reduced to either 5% or 2% without erosion in
the efficiency of the cyclization reaction; however, there
was a corresponding increase in reaction time with lower
Table 1
RCM of model N-phenylacrylamide
Grubbs 2nd,
O
CH2Cl2, 40 ºC
0.01 M
N
H
O
N
H
7
8
Entry
Catalyst loading (mol %)
Time (h)
Yielda (%)
1
2
3
a
10
5
2
2.5
7.5
96
95
88
91
Isolated yields.

J. Minville et al. / Tetrahedron Letters 49 (2008) 3677–3681
3679
Table 2
Table 3
RCM of substituted N-phenylacrylamides
Optimization studies
R4
R
1
1
10 mol% Grubbs 2nd
Solvent, T (ºC)
,
2
R3
O
5 mol% Grubbs 2nd
,
2
R
R4
R2
R1
3
R1
NH
N
R2
N
H
O
CH2Cl2, 40 ºC
0.01M
3
N
4
4
O
O
11
12
10
R3
9
Entry
Solvent
R
T (°C)
Yielda (%)
Entry
R1
R2
R3
R4
Yielda (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C6H6
Ph
Ph
Ph
Ph
Ph
Ph
Bu
22
40
40
22
80
22
22
17
38
38
16
36
53
11
2b
3c
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
4-CF3
2-Br
4-Me
H
H
H
H
H
H
H
H
H
H
Me
iPr
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
Br
CF3
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
Bu
86
82
99
98
95
99
98
99
5
6
7
C6H6
C6H6
a
Isolated yields.
Syringe pump addition.
Ethylene atmosphere.
b
c
b
NR
NR
NR
b
b
H
H
H
H
99
H
H
38c
NR
b
H
O O
S
Isolated yields.
NR: No reaction.
10% Grubbs catalyst.
1.
Cl
Cl
b
c
R3
R3
R1
R1
R2
N
pyr, CH2Cl2, -78 ºC
2.pryridine, 0 ºC to rt
R2
N
H
S
O
O
with Grubbs catalyst. Methyl substitution at the a-styrene
position (R4) of the molecule was well tolerated, giving
nearly quantitative yields of quinolinone (entry 12). How-
ever, the corresponding phenyl analog proved sluggish,
providing only a modest yield of the cyclized product
(38%, entry 13) even with a higher catalyst loading
(10%). Surprisingly, the n-butyl analog (entry 14) failed
to furnish any of the desired products. Thus, the present
reaction is sensitive to the steric demand of the R4 substi-
tuent, and this suggests that the styrene olefin is the site
of the initial reaction between the ruthenium catalyst and
the substrate.10
The low reactivity of the phenyl analog prompted us to
re-investigate the reaction conditions for this substrate. As
outlined in Table 3, several modifications of the reaction
conditions were evaluated, including modifying the solvent,
temperature, performing the reaction under an atmosphere
of ethylene, and delivery of the catalyst via syringe pump.
From this exercise, the optimal conditions identified
involved the use of benzene as the solvent with 10 mol %
of catalyst at room temperature. This provided a modest
yield of the desired heterocycle (53%). These conditions
were used with the butyl analog and, with this substrate,
only a low yield of the quinolinone was realized (11%).
Having established the scope of the quinolinones forma-
tion reaction, we then examined the applicability of this
chemistry toward the synthesis of benzothiazine 1,1-diox-
ides.11 The required N -phenylethylenesulfonamides were
prepared according to the reaction conditions described
in Scheme 2, which are based on modified literature proce-
dures.12 After some experimentation, the optimal reaction
13
14
40-66%
Scheme 2. Preparation of N-phenylethylenesulfonamides.
conditions identified were to treat the corresponding ani-
lines13 with 2-chloroethanesulfonyl chloride in the presence
of pyridine at À78 °C. The reaction mixture is then warmed
to 0 °C followed by the addition of a second equivalent of
pyridine, and then the reaction mixture is warmed to room
temperature. The corresponding unsaturated sulfonamides
were thus obtained in moderate to good yields following
standard work-up and purification. With the N-phenyleth-
Table 4
RCM of model N-phenylethylenesulfonamide
Grubbs 2nd
,
O
O
S
S
Solvent, T (ºC)
N
N
O
O
16
15
Entry
Solvent
Catalyst loading (mol %)
Yield (% conv)
1
2
3
a
CH2Cl2
CH2Cl2
C6H6
10
5
10
85a
(54)b
(0)b
Isolated yield.
b
Percent conversion estimated by 1H NMR analysis of the crude
reaction mixture.

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J. Minville et al. / Tetrahedron Letters 49 (2008) 3677–3681
ylenesulfonamide in hand, we next turned our attention at
exploring the ability of these compounds to undergo RCM
reactions. The first reaction parameter examined was the
effect of catalyst loading on the RCM reaction of substrate
15 as shown in Table 4. We were pleased to see that an
exposure of diene 15 to 10 mol % of Grubbs catalyst pro-
videdan 85% isolated yield of the benzothiazine 1,1-dioxide
product 16. Lowering the catalyst loading to 5 mol % was
found to have a significant negative impact on the product
yield, in contrast to what was observed in the quinolinone
series. When benzene was employed as the reaction solvent,
the reaction mixture turned black within 15 min (a sign of
catalyst decomposition) and none of the expected product
was detected. From these initial studies, the conditions of
entry 1 from Table 4 were selected as the standard condi-
tions for further studies.
The scope of the N-phenylethylenesulfonamide RCM
chemistry presented in Table 5, in general, mirrors the
results with the quinolinone system. As illustrated in this
table, benzene substitution (R1) is well tolerated as both
electron-withdrawing and electron-donating substituents
give excellent yields of the desired product (Table 5, entries
1–6). Similar to the quinolinone findings, substitution on
nitrogen (R2) with alkyl, benzyl, and substituted benzyl
derivatives smoothly proceeded to give excellent yields of
the corresponding benzothiazine 1,1-dioxide products.
While a methyl substituent at the a-styryl position (R3)
allows for the smooth conversion to the cyclized product
(92%), a phenyl substituent at this position completely
shuts down the RCM reaction (Table 5, entry 14), similar
to what was observed with the quinolinone series (Table
2, entries 13 and 14).
In summary, we have presented an efficient RCM
approach for the synthesis of highly functionalized quinoli-
nones and benzothiazine 1,1-dioxides. The method is gen-
eral in scope and offers the opportunity for the
convenient synthesis of functionalized systems. The gener-
ality and scope of the method presented herein should find
application in the synthesis of these ring systems. To date,
the main limitation in the RCM of these substrates is the
narrow scope at substitution at the a-styryl and a-acrylam-
ide positions of the molecule. Studies aimed at overcoming
these limitations are in progress and will be disclosed in due
course.
Acknowledgment
J.M. and J.P. wish to thank the Natural Science and
Engineering Council of Canada (NSERC) for undergradu-
ate fellowships.
References and notes
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RCM of substituted N-phenylethylenesulfonamides
R3
1
1
10 mol% Grubbs 2nd,
2
2
R3
R2
R1
O
R1
S
CH2Cl2, 40 ºC
0.01 M
3
N
R2
N
O S
O
3
O
4
4
17
18
Entry
R1
R2
R3
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
2-Me
4-Me
2-Cl
4-OMe
4-CF3
2,4-Cl
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
87
95
82
Quant.
85
75
Quant.
86
85
82
Bn
4-CN–Bn
4-Br–Bn
4-CF3–Bn
H
96
94
92
NRb
H
H
H
H
6. For leading references in the use of RCM for the synthesis of lactams
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O. C.; Blechert, S. Synlett 1996, 65; (c) Lim, S. H.; Ma, S.; Beak, P. J.
Isolated yields.
NR: No reaction.
b

J. Minville et al. / Tetrahedron Letters 49 (2008) 3677–3681
3681
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