DMAP-promoted in situ activation of bromoacetic acid as a 2-carbon synthon for facile synthesis of pyridines and fused pyridin-2-ones

Article abstract of DOI:10.1016/j.tet.2016.08.062

A general and simple synthesis of 2,4,6-trisubstituted pyridines and fused pyridine-2-ones from bromoacetic acid is developed via a DMAP-promoted in situ activation strategy. In this protocol, readily accessible bromoacetic acid has been effectively emplo

Full text of DOI:10.1016/j.tet.2016.08.062

Tetrahedron xxx (2016) 1e8
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DMAP-promoted in situ activation of bromoacetic acid as a 2-carbon
synthon for facile synthesis of pyridines and fused pyridin-2-ones
*
*
Lu Wang, Gaoyuan Zhu, Weifang Tang, Tao Lu , Ding Du
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2016
Received in revised form 18 August 2016
Accepted 22 August 2016
Available online xxx
A general and simple synthesis of 2,4,6-trisubstituted pyridines and fused pyridine-2-ones from bro-
moacetic acid is developed via a DMAP-promoted in situ activation strategy. In this protocol, readily
accessible bromoacetic acid has been effectively employed as a 2C synthon to undergo formal [2þ4]
cycloadditions with diverse acyclic and cyclic 1-azadienes. Low costs of the reagents and materials, mild
reaction conditions and broad functional-group tolerance make this protocol applicable for practical and
scalable synthesis.
Keywords:
Pyridine
Ó 2016 Elsevier Ltd. All rights reserved.
Fused pyridin-2-one
Bromoacetic acid
Heterocyclic synthesis
Annulation
GAP chemistry
1. Introduction
functionality by the reaction of (phenylthio)acetic acid with N-
sulfonyl-1-azadienes (Scheme 1, eq b). Chi and co-workers re-
6
Functionalized pyridines are recognized as attractive privileged
structures and important building blocks due to their prevalence in
numerous natural products, pharmaceuticals and functional ma-
ported DMAP-catalyzed facile synthesis of similar 2-sulfonate
functionalized trisubstituted pyridines from -chloro acetic ester
a
1
terials. Thus, they have become common synthetic targets among
2
organic community.
However, among exisiting synthetic
3
methods, relatively high reaction temperature is usually required
or toxic transition-metals are used as the catalysts. Besides, the
substrates applied for pyridine synthesis are sometimes not readily
accessible. Therefore, the development of more general and envi-
ronmentally benign (metal-free) methods that allow rapid access to
the pyridine motif from readily accessible starting materials is
highly desirable.
Recently, organocatalysis has been established as a powerful
tool for the synthesis of substituted pyridines owing to the non-
toxic nature and unique reactivity of organocatalysts. Loh and
4
co-workers reported a synthetic approach to functionalized pyr-
idines via an amine-catalyzed aza-RauhuteCurrier/cyclization/
desulfonation cascade reaction of 2,3-butadienoates with N-sul-
5
fonyl-1-azadienes (Scheme 1, eq a). Smith and co-workers de-
veloped an isothiourea-catalyzed one-pot synthesis of
polysubstituted pyridines bearing a readily derivatived 2-sulfonate
*
Corresponding authors. E-mail addresses: lut163@163.com (T. Lu), ddmn9999@
Scheme 1. Previous organocatalytic synthesis of pyridines from 1-azadienes.
cpu.edu.cn (D. Du).
http://dx.doi.org/10.1016/j.tet.2016.08.062
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
L. Wang et al. / Tetrahedron xxx (2016) 1e8
and N-sulfonyl-1-azadienes (Scheme 1, eq c). For these methods,
2. Results and discussion
N-sulfonyl-1-azadienes are used as the nitrogen source3
b,3f,7
to
combine with diverse 2-carbon synthon precursors for the con-
struction of the pyridine motif under different organocatalytic
conditions. However, there are still some limitations for these
methods, such as expensive or not commercially available sub-
strates or catalysts.
In order to develop simple and practical synthetic protocols
from readily accessible starting materials and catalysts for rapid
access to pyridines, we reason that bromoacetic acid, a low-cost
commercially available reagent ($0.1/g, Aldrich), may be used as
the potential 2-carbon synthon precursor to combine with N-sul-
fonyl-1-azadienes via an organocatalyst-promoted in situ activa-
tion strategy. Herein, we reported 4-dimethylaminopyridine
Our recent research focuses on the development of novel syn-
thetic methodologies for quick construction of diverse heterocyclic
10
frameworks with N-heterocyclic carbene (NHC) catalysis. Since
11
NHCs have been successfully applied to generate NHC-bound
12
enolates via in situ activation of carboxylic acids, several NHC
precursors were first employed to examine the reaction of bro-
moacetic acid 1 with 1-azadiene 2a in the presence of CDI ($1/g,
Aldrich), a low-cost commonly used peptide coupling reagent.
As result, precursor triazolium salt C was found effective for the
synthesis of pyridine 3a in 37% yield (Table 1, entry 2). As DMAP is
Table 1
(
DMAP)-promoted in situ activation of bromoacetic acid 1 for facile
synthesis of 2,4,6-trisubstituted pyridines 3 from 1-azadienes 2,
which can be easily prepared through the condensation of
a
Optimization of the reaction conditions
a,b-
8
unsaturated enones with 4-methylbenzenesulfonamide (Scheme
, path a). In addition, this protocol proved to be equally applica-
2
ble for the synthesis of fused pyridin-2-ones 7/8 from cyclic 1-
9
azadienes 5/6 (Scheme 2, path b). For these reactions,
imidazole-bound acyl intermediate I derived from in situ activa-
tion of bromoacetic acid by CDI/DIPEA is unreactive. So, the more
reactive DMAP-bound acyl intermediate II is formed by nucleo-
philic substitution of I with DMAP to facilitate the reaction. The
subsequent deprotonation of II with DIPEA affords the key DMAP-
bound enolate III, which undergoes formal [4þ2] cycloaddition
with acyclic 1-azadienes 2 or cyclic azadienes 5/6 to afford the
corresponding (fused) 2-bromo pyridin-2-one intermediates. For
acyclic 1-azadiene substrates, the 2-bromo pyridin-2-one in-
termediates undergo a tandem HBr elimination/N- to O- sulfonyl
transfer process to afford 2,4,6-trisubstituted pyridines 3. For cyclic
Entry
Promoter (y mol %)
Base
NEt3
Solvent
Yield (%)b
c
1
2
A/B (15)
C (15)
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
toluene
CH CN
3
1,4-dioxane
DME
1,2-DCE
1,2-DCE
Trace
37
64
28
43
82
78
49
24
14
18
62
41
c
NEt
NEt
3
3
4
5
6
7
8
9
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (120)
DMAP (80)
DMAP (40)
3
Cs
2
CO
3
NaH
DIPEA
DBU
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
1
-azadiene substrates, the fused 2-bromo pyridin-2-one in-
termediates only undergo HBr elimination to give fused pyridin-2-
ones 7/8.
1
1
1
1
0
1
2
3
Bold entry aims to highlight that this is the optimal reaction condition.
a
All reactions were performed in a 25 mL round-bottom flask on a 0.3 mmol scale
with 1.2 equiv of 1, 1.0 equiv of 2a, 1.2 equiv of CDI, 5.0 equiv of a base, in an an-
ꢀ
hydrous solvent (3 mL) at 70 C for 8e12 h in air.
b
Isolated yields based on 2a.
The reactions were carried out under
c
0
N
2
.
CDI¼N,N -Carbonyldiimidazole;
DBU¼1,8-diazabicyclo[5.4.0]-undec-7-ene; Mes¼2,4,6-(CH
3
)
3
C
6
H
2
;
DIPEA¼N,N-
diisopropylethylamine.
frequently used for facilitating the peptide coupling reactions, we
then used stoichiometric amount of DMAP to promote this reaction.
It was found that product 3a was obtained in 64% yield when the
ꢀ
reaction was heated at 70 C in the presence of 1.2 equiv of DMAP
(entry 3). Notably, unlike the NHC-catalyzed reaction usually car-
ried out under inert gas shielding, this reaction is not air-sensitive
which makes it more simple and practical. Then, an array of bases
and solvents were used to further optimize the reaction conditions
using DMAP as the promoter. DIPEA and 1,2-DCE were finally
established as the optimal base and solvent, respectively (entry 6).
Unfortunately, lowering DMAP loading resulted in significantly
decreased yield (entries 12 and 13). Considering the low cost of
DMAP ($0.5/g, Aldrich), the optimal reaction conditions were
established as that in entry 6 affording 3a in 82% yield. Notably, N-
0
Ts pyridin-2-one intermediate 3a was observed under lower
ꢀ
temperature (40 C), and it was converted to products 3a under
higher temperature with prolonged reaction time.
With the optimized conditions established, the substrate scope
and generality of the reaction were probed (Scheme 3). Generally,
Scheme 2. Our pyridine and fused pyridine-2-one synthesis starting from bromoacetic
acid.
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L. Wang et al. / Tetrahedron xxx (2016) 1e8
3
Scheme 3. The substrate scope of the reaction between bromoacetic acid and 1-azadienes.
substituted 1-azadienes worked well under the optimized reaction
conditions. When R groups of 1-azadienes were substituted phe-
are substituted phenyls, 2-naphthyl or 2-furyl reacted smoothly to
give the pyridine products 3mer in good to high yields. It is
noteworthy that aliphatic 1-azadiene was also suitable for this
protocol; product 3s was obtained in 76% yield.
Given the low costs of reagents and materials used as well as the
tolerance of air, this protocol is expected to be practical for larger
scales. Therefore, a gram-scale preparation of 3a was demonstrated
under the standard conditions with two different purification
methods (Scheme 4a). Column chromatography purification
1
nyls, a wide range of functional groups at diverse positions on the
benzene ring like halos (3bec, 3g and 3i), methoxy (3d, 3h and 3j),
trifluoromethyl (3e) and nitro (3f) groups were well tolerated,
affording the corresponding products 3bej in good to high yields.
More steric hindered 2-naphthyl 1-azadiene and 2-furyl
substituted 1-azadiene also furnished the desired product 3k and
2
3
l in good yields. On the other hand, 1-azadienes whose R groups
Scheme 4. Synthetic applications.
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4
L. Wang et al. / Tetrahedron xxx (2016) 1e8
afforded 3a in comparable yield to the small scale, while purifica-
tion by recrystallization afforded 3a in 63% yield. Although the
latter method resulted in decreased isolated yield, it is more su-
perior to the former one in terms of application in organic process
research and development. The utility of products 3 has been well
illustrated by the chemical transformations of the tosylate unit,
which is widely applied in cross-coupling reactions for diverse CeC
3. Conclusion
In conclusion, we have described a DMAP-promoted facile
synthesis of 2,4,6-trisubstituted pyridines and fused pyridine-2-
ones from bromoacetic acid via a in situ activation strategy. The
advantages of this protocol include: a) easily accessible and low
costs of the reagents and materials; b) mild reaction conditions; c)
wide reaction scope; d) simple separation and purification of the
products; e) practical and scalable synthesis. In addition, the syn-
thesized 2-sulfonate pyridines are amenable to diverse chemical
transformations to access other pyridine derivatives. In this pro-
tocol, bromoacetic acid has been effectively employed as a 2C
synthon to undergo formal [2þ4] cycloadditions with both acyclic
and cyclic 1-azadienes. Further investigation of bromoacetic acid as
a 2C synthon for other formal [2þm] cycloadditions is currently
underway in our laboratory.
2
b,5e6,13
or CeN bond formations.
Another useful application is
demonstrated in the synthesis of 4,6-diphenylpyridin-2(1H)-one 4
14
from 3a in high yield by treatment with LiHMDS (Scheme 4b).
We next turn our attention to investigate the reaction of cyclic
1
-azadienes 5 or 6 containing a 1,2-benzoisothiazole-1,1-dioxide or
1,2,3-benzoxathiazine-2,2-dioxide motif with bromoacetic acid in
the presence of DMAP (Scheme 5). Gratifyingly, the conditions used
in above pyridine synthesis were also applicable to this reaction.
The desired fused pyridin-2-ones 7a-l and 8a-c were obtained in
moderate to high yields. This reaction could tolerate a broad array
3
of R groups including substituted phenyls, 2-naphthyl, styryl and
4. Experimental
heteroaromatic groups. Notably, there are several other advantages
for this reaction. The reaction of cyclic 1-azadienes is faster than the
reaction of acyclic 1-azadienes. On the other hand, products 7 and 8
can precipitate from the solution owing to their low solubility in the
solvent. The precipitate was filtered and subsequently washed with
DCM to get the pure products. So, the separation and purification of
products 7 and 8 are simpler and practical, and thus matches the
GAP (Group-Assisted Purification) chemistry/technology concept
which avoids traditional chromatography to substantially minimize
the use of silica gels and solvents.15
4.1. General information
All reactions were carried out in dry glassware, and were moni-
tored by analytical thin-layer chromatography (TLC), which was vi-
sualized by ultraviolet light (254 nm). All solvents were obtained
from commercial sources and were purified according to standard
procedures. Bromoacetic acid is obtained from commercial source
8
9
without further purification prior to use. Substrates 2 and 5/6 can
be prepared according to known procedures. Purification of the
products 3 was accomplished by flash chromatography using silica
gel (200e300 mesh). Purification of the products 7 and 8 was ac-
complished by filtration followed by azeotrope from DCM. All NMR
spectrawere recorded on Bruker spectrometers, running at 300 MHz
1
13
or 500 MHz for H and 75 MHz or 125 MHz for C, respectively.
Chemical shifts ( ) and coupling constants (J) are reported in ppm
and Hz, respectively. The solvent signals were used as references
residual CHCl in CDCl ¼77.0 ppm; residual DMSO
¼7.26 ppm,
in DMSO-d
¼2.50 ppm,
d
(
3
3
:
d
H
d
c
6
:
d
H
d
c
¼39.5 ppm). The following abbrevia-
tions are used to indicate the multiplicity in NMR spectra: s (singlet);
d (doublet); t (triplet); q (quartet); m (multiplet). High resolution
þ
mass spectrometry (HRMS) was recorded on TOF perimer for ESI .
4.2. General procedure for the synthesis of pyridines 3 via
DMAP-promoted reaction of bromoacetic acid 1 with 1-
azadienes 2
To an oven-dried 25 mL round-bottom flask was charged with
bromoacetic acid 1 (50 mg, 0.36 mmol), 1-azadienes 2 (0.3 mmol),
CDI (58 mg, 0.36 mmol) and DIPEA (194 mg, 1.5 mmol). Then an-
hydrous 1,2-DCE (3 mL) was added to the flask and the resulting
ꢀ
mixture was heated at 70 C in air for a period time until the
completion of the reaction as monitored by TLC. The mixture was
cooled to room temperature. 20 mL of 1,2-DCE was added to the
solution which was washed with saturated aqueous NaHCO
4
SO ,
3
(
15 mLꢁ2). The organic phase was dried over anhydrous Na
2
filtered and evaporated under reduced pressure. The residue was
purified by chromatography on silica gel to using hexane/EtOAc
(10:1) as the eluent afford products 3.
4
.2.1. 4,6-Diphenylpyridin-2-yl 4-methylbenzenesulfonate
2
b,6
ꢀ
1
(3a). Known compound,
white solid, mp: 121e123 C.
H
NMR (300 MHz, CDCl
3
):
d
7.98 (d, J¼8.2 Hz, 2H), 7.83 (s, 1H),
7.79e7.72 (m, 2H), 7.65 (d, J¼6.0 Hz, 2H), 7.52e7.49 (m, 3H),
7.44e7.33 (m, 5H), 7.25 (s, 1H), 2.48 (s, 3H).
4
. 2 . 2 . 4 - ( 4 - C h l o r o p h e n y l ) - 6 - p h e n y l p y r i d i n - 2 - y l 4 -
Scheme 5. The reaction between bromoacetic acid and cyclic 1-azadienes.
ꢀ
1
methylbenzenesulfonate (3b). White solid, mp: 141e143 C.
H
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L. Wang et al. / Tetrahedron xxx (2016) 1e8
5
NMR (300 MHz, CDCl
H), 7.74 (dd, J¼6.6, 2.9 Hz, 2H), 7.59 (d, J¼8.5 Hz, 2H), 7.48 (d,
J¼8.5 Hz, 2H), 7.44e7.34 (m, 5H), 7.21 (d, J¼0.8 Hz, 1H), 2.48 (s, 3H).
3
):
d
7.97 (d, J¼8.3 Hz, 2H), 7.78 (d, J¼0.8 Hz,
127.26, 126.99, 119.60, 114.16, 21.65. HRMS (ESI) calcd for
þ
1
C
24
H
19ClNO
3
S (MþH) : 436.0769, found 436.0768.
13
C NMR (125 MHz, CDCl
3
):
d
157.69, 156.70, 152.37, 145.04, 137.27,
4.2.10. 4-(2-Methoxyphenyl)-6-phenylpyridin-2-yl 4-
ꢀ
1
135.84, 135.68, 134.38, 129.64, 129.54, 129.36, 128.73, 128.56,
methylbenzenesulfonate (3j). White solid, mp: 129e131 C.
NMR (300 MHz, CDCl ):
7.99 (d, J¼8.3 Hz, 2H), 7.82 (s, 1H), 7.73
(dd, J¼6.5, 3.0 Hz, 2H), 7.46e7.36 (m, 7H), 7.28 (d, J¼0.6 Hz, 1H),
H
1
C
28.33, 126.90, 116.58, 111.30, 21.59. HRMS (ESI) calcd for
3
d
þ
24
H
19ClNO
3
S (MþH) : 436.0769, found 436.0763.
13
7
.10e7.02 (m, 2H), 3.86 (s, 3H), 2.48 (s, 3H). C NMR (125 MHz,
4
.2.3. 4-(4-Bromophenyl)-6-phenylpyridin-2-yl 4-methylbenz-
CDCl ): 157.08, 156.55, 155.64, 151.48, 144.84, 137.86, 134.68,
130.66, 130.35, 129.50, 129.28, 128.82, 128.50, 126.94, 126.82,
3
d
6
enesulfonate (3c). Known compound,
white solid, mp:
7.97 (d, J¼8.1 Hz, 2H), 7.78
ꢀ
1
157e159 C. H NMR (300 MHz, CDCl
3
):
d
121.09, 119.59, 114.23, 111.54, 55.60, 21.64. HRMS (ESI) calcd for
þ
(
2
s, 1H), 7.77e7.70 (m, 2H), 7.63 (d, J¼8.4 Hz, 2H), 7.51 (d, J¼8.4 Hz,
C
25
H22NO
4
S (MþH) : 432.1264, found 432.1264.
H), 7.45e7.33 (m, 5H), 7.20 (s, 1H), 2.48 (s, 3H).
4
. 2.11. 4- (Naphthal en -2-yl) -6-phenylpyridin-2-yl 4 -
6
4
.2.4. 4-(4-Methoxyphenyl)-6-phenylpyridin-2-yl 4-methylb-
methylbenzenesulfonate (3k). Known compound, white solid,
mp: 106e108 C. H NMR (300 MHz, CDCl ): d 8.23 (s, 1H),
6
ꢀ
1
enzenesulfonate (3d). Known compound, white solid, mp:
3
ꢀ
1
153e155 C. H NMR (300 MHz, CDCl
3
):
d
7.98 (d, J¼8.2 Hz, 2H), 7.80
8.03e7.98 (m, 3H), 7.91e7.83 (m, 4H), 7.70 (dd, J¼7.8, 1.6 Hz, 2H),
7.58e7.49 (m, 5H), 7.40 (d, J¼8.1 Hz, 2H), 7.29 (d, J¼0.9 Hz, 1H), 2.51
(s, 3H).
(
s, 1H), 7.74 (dd, J¼6.4, 2.9 Hz, 2H), 7.62 (d, J¼8.7 Hz, 2H), 7.40 (dd,
J¼6.0, 2.6 Hz, 4H), 7.36 (s, 1H), 7.21 (s, 1H), 7.02 (d, J¼8.7 Hz, 2H),
3
.88 (s, 3H), 2.48 (s, 3H).
4
.2.12. 4-(Furan-2-yl)-6-phenylpyridin-2-yl 4-methylbenzenesulfonate
2
b,6
ꢀ
1
4
.2.5. 6-Phenyl-4-(4-(trifluoromethyl)phenyl)pyridin-2-yl 4-
(3l). Known compound,
(300 MHz, CDCl ):
2.9 Hz, 2H), 7.57 (d, J¼1.1 Hz, 1H), 7.44e7.32 (m, 5H), 7.26 (s, 1H), 6.95
(d, J¼3.4 Hz, 1H), 6.56 (dd, J¼3.3, 1.7 Hz, 1H), 2.47 (s, 3H).
white solid, mp: 118e120 C. H NMR
ꢀ
1
methylbenzenesulfonate (3e). White solid, mp: 163e165 C.
NMR (300 MHz, CDCl ):
H), 7.80e7.73 (m, 6H), 7.46e7.34 (m, 5H), 7.25 (d, J¼0.7 Hz, 1H),
.49 (s, 3H). 13C NMR (125 MHz, CDCl
): 157.78, 156.99, 152.27,
45.15, 140.93, 137.23, 134.43, 131.58 (q, JCeF¼32.6 Hz, 1C), 129.82,
29.61, 128.81, 128.67, 127.60, 126.99, 126.16, 123.86 (q,
H
3
d
7.96 (d, J¼8.3 Hz, 2H), 7.86 (s,1H), 7.73 (dd, J¼6.6,
3
d
7.98 (d, J¼8.3 Hz, 2H), 7.82 (d, J¼0.7 Hz,
1
2
1
3
d
4.2.13. 6-(4-Methoxyphenyl)-4-phenylpyridin-2-yl 4-methylb-
6
1
enzenesulfonate (3m). Known compound, white solid, mp:
ꢀ
1
J
C
CeF¼271.0 Hz, 1C), 116.98, 111.80, 21.65. HRMS (ESI) calcd for
119e121 C. H NMR (300 MHz, CDCl
3
):
d
7.97 (d, J¼8.3 Hz, 2H),
þ
H
25 19
F
3
NO
3
S (MþH) : 470.1032, found 470.1037.
7.70e7.75 (m, 3H), 7.62e7.65 (m, 2H), 7.46e7.53 (m, 3H), 7.37 (d,
J¼8.1 Hz, 2H), 7.17 (d, J¼1.0 Hz, 1H), 6.91 (d, J¼8.9 Hz, 2H), 3.86 (s,
3H), 2.47 (s, 3H).
4
.2.6. 4-(4-Nitrophenyl)-6-phenylpyridin-2-yl 4-methylb-
ꢀ
1
enzenesulfonate (3f). White solid, mp: 172e174 C. H NMR
300 MHz, CDCl ):
(
7
1
1
3
d
8.26 (d, J¼8.8 Hz, 2H), 7.99e7.91 (m, 5H),
4 . 2 .14 . 6 - ( 4 - B r o m o p h e n yl ) - 4 - p h e n yl p y r i d i n - 2 - yl 4 -
6
.68e7.65 (m, 2H), 7.57e7.52 (m, 3H), 7.40 (d, J¼8.1 Hz, 2H), 7.34 (s,
methylbenzenesulfonate (3n). Known compound, white solid,
H), 2.50 (s, 3H). 13C NMR (125 MHz, CDCl
d
157.96, 154.50,
mp: 112e114 C. H NMR (300 MHz, CDCl
ꢀ
1
):
d
7.96 (d, J¼8.2 Hz, 2H),
3
):
3
53.91,148.48,145.35,143.43,136.85,134.45,130.04,129.68,129.39,
7.79 (s, 1H), 7.69e7.58 (m, 4H), 7.57e7.44 (m, 5H), 7.38 (d, J¼8.1 Hz,
1
28.75, 127.79, 127.14, 123.87, 117.85, 113.18, 21.73. HRMS (ESI) calcd
2H), 7.25 (s, 1H), 2.49 (s, 3H).
þ
for C24
19
H N
2
O
5
S (MþH) : 447.1009, found 447.1002.
4
.2.15. 6-(4-Nitrophenyl)-4-phenylpyridin-2-yl 4-methylb-
ꢀ
1
4
. 2 . 7 . 4 - ( 3 - C h l o r o p h e n y l ) - 6 - p h e n y l p y r i d i n - 2 - y l 4 -
enzenesulfonate (3o). White solid, mp: 169e171 C. H NMR
(300 MHz, CDCl ):
8.26 (d, J¼8.8 Hz, 2H), 7.91e7.99 (m, 5H),
7.65e7.68 (m, 2H), 7.52e7.54 (m, 3H), 7.41 (d, J¼8.1 Hz, 2H), 7.34 (s,
ꢀ
1
methylbenzenesulfonate (3g). White solid, mp: 96e98 C. H NMR
300 MHz, CDCl ):
7.97 (d, J¼8.3 Hz, 2H), 7.79 (d, J¼0.9 Hz, 1H),
.76 (dd, J¼6.6, 2.9 Hz, 2H), 7.62 (s, 1H), 7.56e7.50 (m, 1H),
3
d
(
7
7
(
1
1
(
3
d
13
3
1H), 2.51 (s, 3H). C NMR (125 MHz, CDCl ): d 157.92, 154.45,
13
.47e7.35 (m, 7H), 7.20 (d, J¼0.9 Hz, 1H), 2.49 (s, 3H). C NMR
125 MHz, CDCl ): 157.74, 156.89, 152.33, 145.11, 139.24, 137.33,
35.27, 134.43, 130.50, 129.75, 129.61, 128.84, 128.65, 127.29, 127.00,
153.87, 148.44,145.35, 143.38,136.78,134.40,130.02, 129.67, 129.36,
128.71, 127.76, 127.12, 123.83, 117.82, 113.1, 21.71. HRMS (ESI) calcd
3
d
þ
for C24
H
19
N
2
O
5
S (MþH) : 447.1009, found 447.1014.
25.33, 116.86, 111.66, 21.68. HRMS (ESI) calcd for C24
MþH) : 436.0769, found 436.0769.
H19ClNO
3
S
þ
4 . 2 .16 . 6 - ( 3 - N i t r o p h e n y l ) - 4 - p h e n y l p y r i d i n - 2 - y l 4 -
methylbenzenesulfonate (3p). Known compound, white solid,
mp: 140e142 C. H NMR (300 MHz, CDCl
8.26 (dd, J¼8.1, 1.4 Hz, 1H), 8.13 (d, J¼7.8 Hz, 1H), 7.99 (d, J¼8.3 Hz,
2H), 7.89 (d, J¼0.9 Hz, 1H), 7.67 (dd, J¼7.5, 2.0 Hz, 2H), 7.60 (t,
J¼8.0 Hz, 1H), 7.56e7.51 (m, 3H), 7.43 (d, J¼8.1 Hz, 2H), 7.34 (d,
J¼0.9 Hz, 1H), 2.49 (s, 3H).
6
ꢀ
1
4
. 2. 8. 4-(3 -Methox yp henyl) -6-phenyl pyridin -2-yl 4-
3
):
d
8.59 (t, J¼1.8 Hz, 1H),
ꢀ
1
methylbenzenesulfonate (3h). White solid, mp: 100e102 C.
NMR (300 MHz, CDCl ):
7
1
(
1
1
C
H
3
d
7.82 (d, J¼8.3 Hz, 2H), 7.65 (s, 1H),
.63e7.55 (m, 2H), 7.25e7.18 (m, 6H), 7.04 (d, J¼6.1 Hz, 2H), 6.98 (s,
13
H), 6.83 (dd, J¼8.2, 2.0 Hz, 1H), 3.69 (s, 3H), 2.30 (s, 3H). C NMR
): 160.03, 157.49, 156.32, 153.43, 144.90, 138.46,
37.26, 134.31, 130.74, 130.10, 129.43, 128.58, 128.41, 126.78, 119.26,
125 MHz, CDCl
3
d
4.2.17. 6-(Naphthalen-2-yl)-4-phenylpyridin-2-yl 4-methylb-
6
16.75, 114.73, 112.73, 111.36, 55.19, 21.43. HRMS (ESI) calcd for
enzenesulfonate (3q). Known compound, white solid, mp:
þ
ꢀ
1
25
H
22NO
4
S (MþH) : 432.1264, found 432.1269.
152e154 C. H NMR (300 MHz, CDCl ): d 8.24 (s, 1H), 8.02 (d,
3
J¼8.3 Hz, 2H), 7.98 (d, J¼1.0 Hz, 1H), 7.90e7.85 (m, 4H), 7.70 (dd,
J¼7.8, 1.6 Hz, 2H), 7.57e7.49 (m, 5H), 7.40 (d, J¼8.1 Hz, 2H), 7.29 (d,
J¼0.9 Hz, 1H), 2.51 (s, 3H).
4
.2.9. 4-(2-Chlorophenyl)-6-phenylpyridin-2-yl 4-methylb-
ꢀ
1
enzenesulfonate (3i). White solid, mp: 113e115 C.
300 MHz, CDCl ):
7.99 (d, J¼8.3 Hz, 2H), 7.77e7.73 (m, 3H),
.54e7.49 (m, 1H), 7.46e7.33 (m, 8H), 7.13 (s, 1H), 2.48 (s, 3H).
NMR (125 MHz, CDCl ): 157.00, 156.00, 152.03, 145.03, 137.38,
36.96, 134.46, 132.08, 130.76, 130.37, 130.19, 129.58, 128.80, 128.59,
H NMR
(
7
3
d
13
C
4 . 2 . 1 8 . 6 - ( F u r a n - 2 - y l ) - 4 - p h e n y l p y r i d i n - 2 - y l 4 -
6
3
d
methylbenzenesulfonate (3r). Known compound, white solid, mp:
ꢀ
1
1
143e145 C. H NMR (300 MHz, CDCl
3
): d 8.00 (s, 1H), 7.97 (s, 1H),
Please cite this article in press as: Wang, L.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.062

6
L. Wang et al. / Tetrahedron xxx (2016) 1e8
þ
7
1
.78 (d, J¼1.1 Hz, 1H), 7.63e7.66 (m, 2H), 7.46e7.52 (m, 4H), 7.39 (s,
118.10, 101.71. HRMS (ESI) calcd for C17
found 310.0533.
H
12NO
3
S (MþH) : 310.0532,
H), 7.36 (s, 1H), 7.15 (d, J¼1.1 Hz, 1H), 6.77 (d, J¼3.3 Hz, 1H), 6.50
(
dd, J¼3.3 Hz, J¼1.7 Hz, 1H), 2.47 (s, 3H).
4
.5.2. 9-(4-Chlorophenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-
ꢀ
1
4
(
.2.19. 6-Isobutyl-4-phenylpyridin-2-yl 4-methylbenzenesulfonate
one 5,5-dioxide (7b). White solid, mp: >300 C. H NMR (300 MHz,
DMSO-d ):
8.47 (d, J¼7.9 Hz, 1H), 8.28 (d, J¼7.8 Hz, 1H), 8.06e7.91
(m, 3H), 7.87 (t, J¼7.6 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J¼8.5 Hz, 2H),
3s). Colorless liquid. 1H NMR (300 MHz, CDCl
): 7.89 (d,
d
d
3
6
J¼8.3 Hz, 2H), 7.58 (dd, J¼7.7, 1.8 Hz, 2H), 7.51e7.42 (m, 3H), 7.32 (d,
13
J¼8.1 Hz, 2H), 7.21 (s, 1H), 7.17 (s, 1H), 2.52 (d, J¼7.2 Hz, 2H), 2.43 (s,
3
6.97 (s, 1H). C NMR (125 MHz, CDCl ): d 158.23, 151.82, 135.56,
13
3
CDCl
H), 1.86 (sep, 1H), 0.82 (d, J¼6.6 Hz, 6H). C NMR (125 MHz,
135.42, 134.14, 132.94, 131.69, 129.06, 124.99, 123.79, 122.20, 118.33,
þ
3
):
d
161.39, 157.19, 152.78, 144.94, 137.30, 134.03, 129.44,
101.42. HRMS (ESI) calcd for C17
found 344.0140.
H11ClNO
3
S (MþH) : 344.0143,
129.09, 128.76, 127.05, 120.31, 110.51, 46.75, 28.69, 22.27, 21.59.
þ
HRMS (ESI) calcd for C22
H24NO
3
S
(MþH) : 382.1471, found
3
82.1474.
4.5.3. 9-(4-Bromophenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-
ꢀ
1
one 5,5-dioxide (7c). White solid, mp: >300 C. H NMR (300 MHz,
DMSO-d ):
8.47 (d, J¼7.7 Hz, 1H), 8.29 (d, J¼7.7 Hz, 1H), 8.01 (t,
J¼7.5 Hz, 1H), 7.92e7.84 (m, 3H), 7.80e7.74 (m, 3H), 6.97 (s, 1H).
NMR (75 MHz, CDCl ): 158.25, 151.94, 135.61, 135.44, 134.55,
4
.3. Procedure for the scalable synthesis of pyridine 3a from 1
6
d
13
and 2a
C
3
d
To an oven-dried 250 mL round-bottom flask was charged with
bromoacetic acid 1 (1.82 g, 13.2 mmol), 1-azadiene 2a (3.97 g,
1.0 mmol), CDI (2.13 g, 13.2 mmol) and DIPEA (7.10 g, 55 mmol).
132.97, 132.03, 131.76, 129.30, 125.02, 124.39, 123.83, 122.23, 118.35,
þ
101.38. HRMS (ESI) calcd for C17
found 387.9636.
H
11BrNO
3
S (MþH) : 387.9638,
1
Then anhydrous 1,2-DCE (80 mL) was added to the flask and the
ꢀ
resulting mixture was heated at 70 C in air for a period time until
4.5.4. 9-(4-Methoxyphenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-
ꢀ
1
the completion of the reaction as monitored by TLC. The mixture
was cooled to room temperature. Then, the solution was washed
7-one 5,5-dioxide (7d). White solid, mp: >300 C. H NMR
(300 MHz, DMSO-d ):
8.48 (d, J¼7.8 Hz, 1H), 8.26 (d, J¼7.8 Hz, 1H),
7.99 (t, J¼7.5 Hz, 1H), 7.91 (d, J¼8.8 Hz, 2H), 7.85 (t, J¼7.6 Hz, 1H),
6
d
with water (50 mLꢁ2) and saturated aqueous NaHCO
3
(50 mLꢁ2).
13
The organic phase was dried over anhydrous Na SO , filtered and
2
4
7.74 (s, 1H), 7.09 (d, J¼8.8 Hz, 2H), 6.87 (s, 1H), 3.84 (s, 3H). C NMR
evaporated under reduced pressure. The residue was recrystallized
(75 MHz, CDCl ): 161.44, 158.43, 152.49, 135.33, 135.29, 132.80,
3
d
from hexane/EtOAc to afford 2.78 g of product 3a.
131.83, 128.89, 127.25, 125.17, 123.77, 122.14, 116.15, 114.53, 101.35,
þ
5
5.45. HRMS (ESI) calcd for C18
H
14NO
4
S (MþH) : 340.0638, found
4
.4. Procedure for the transformation of 3a to pyridin-2-one 4
340.0638.
To an oven-dried 25 mL round-bottom flask was charged with
a (120 mg, 0.3 mmol) and anhydrous THF (3 mL). Then LiHMDS
1 M in THF, 0.9 mL, 0.9 mmol) was added to the flask and the
4.5.5. 9-(4-(Trifluoromethyl)phenyl)-7H-benzo[4,5]isothiazolo[2,3-a]
ꢀ
1
3
(
pyridin-7-one 5,5-dioxide (7e). White solid, mp: >300 C. H NMR
(300 MHz, DMSO-d ):
8.48 (d, J¼7.7 Hz, 1H), 8.30 (d, J¼7.8 Hz, 1H),
8.12 (d, J¼8.0 Hz, 2H), 8.02 (t, J¼7.6 Hz, 1H), 7.94e7.85 (m, 3H), 7.80
6
d
resulting mixture was stirred at rt for 3 h. The reaction was
quenched with water (10 mL) and the resulting mixture was
extracted with EtOAc (15 mLꢁ3). The organic phase was dried over
13
(s, 1H), 7.04 (s, 1H). C NMR (75 MHz, CDCl
3
): d 158.17, 151.74,
139.50, 135.76, 135.49, 133.04, 131.74, 128.19, 125.90, 125.85, 124.97,
anhydrous Na
SO
2 4
, filtered and evaporated under reduced pressure.
123.86, 122.27, 119.63, 101.60. HRMS (ESI) calcd for C18
(MþH) : 378.0406, found 378.0401.
H F
11 3
NO
3
S
þ
The residue was purified by chromatography on silica gel to using
hexane/EtOAc (5:1) as the eluent afford 69 mg of compound 4.
4
.5.6. 9-(3-Chlorophenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-
ꢀ
1
4
.4.1. 4,6-Diphenylpyridin-2(1H)-one (4). Known compound,2b
one 5,5-dioxide (7f). White solid, mp: >300 C. H NMR (300 MHz,
DMSO-d ):
8.50 (d, J¼7.8 Hz, 1H), 8.30 (d, J¼7.8 Hz, 1H), 8.04e7.99
(m, 2H), 7.91e7.86 (m, 2H), 7.79 (d, J¼1.4 Hz,1H), 7.64e7.56 (m, 2H),
ꢀ
1
brown solid, mp: 209e211 C. H NMR (300 MHz, DMSO-d
d
6
):
6
d
11.83 (br s, 1H), 7.93 (d, J¼5.9 Hz, 2H), 7.83 (d, J¼6.3 Hz, 2H),
13
7.52e7.50 (m, 6H), 7.02 (s, 1H), 6.70 (s, 1H).
7.02 (d, J¼1.4 Hz, 1H). C NMR (125 MHz, CDCl
3
): d 158.15, 151.55,
137.42, 135.55, 135.37, 133.95, 132.91, 131.68, 130.82, 130.28, 127.00,
4
.5. General procedure for the synthesis of fused pyridine-2-
125.88, 124.97, 123.83, 122.16, 118.88, 101.47. HRMS (ESI) calcd for
þ
ones 7 or 8 via DMAP-promoted reaction of bromoacetic acid
1
C
17
H
11ClNO
3
S (MþH) : 344.0143, found 344.0138.
with cyclic 1-azadienes 5 or 6
4
.5.7. 9-(3-Methoxyphenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-
ꢀ
1
To an oven-dried 25 mL round-bottom flask was charged with
7-one 5,5-dioxide (7g). White solid, mp: >300 C. H NMR
(300 MHz, DMSO-d ):
8.51 (d, J¼7.8 Hz, 1H), 8.29 (d, J¼7.7 Hz, 1H),
8.01 (t, J¼7.5 Hz, 1H), 7.87 (t, J¼7.7 Hz, 1H), 7.76 (s, 1H), 7.49e7.45
bromoacetic acid 1 (50 mg, 0.36 mmol), cyclic 1-azadienes 5 or 6
0.3 mmol), CDI (58 mg, 0.36 mmol) and DIPEA (194 mg, 1.5 mmol).
6
d
(
13
Then anhydrous 1,2-DCE (3 mL) was added to the flask and the
(m, 3H), 7.15e7.13 (m, 1H), 6.98 (s, 1H), 3.87 (s, 3H). C NMR
(125 MHz, CDCl ): 159.73, 158.29, 153.00, 136.75, 135.36, 132.84,
ꢀ
resulting mixture was heated at 70 C in air for 3e5 h. The mixture
3
d
was cooled to room temperature and the products will precipitate
from the solution due to their low solubility in 1,2-DCE. The pre-
cipitate was filtered and washed with DCM to give the pure
products.
131.73, 130.14, 126.53, 125.04, 123.82, 122.14, 119.45, 118.26, 116.30,
þ
112.59, 101.75, 55.35. HRMS (ESI) calcd for C18
340.0638, found 340.0633.
4
H14NO S (MþH) :
4
.5.8. 9-(2-Chlorophenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-
ꢀ
1
4
.5.1. 9-Phenyl-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-one 5,5-
one 5,5-dioxide (7h). White solid, mp: >300 C. H NMR (300 MHz,
DMSO-d ):
8.39 (d, J¼7.7 Hz, 1H), 8.32 (d, J¼7.7 Hz, 1H), 7.98 (t,
J¼7.4 Hz, 1H), 7.88 (t, J¼7.4 Hz, 1H), 7.68e7.65 (m, 1H), 7.60e7.52
ꢀ
1
dioxide (7a). White solid, mp: >300 C. H NMR (300 MHz,
DMSO-d ):
8.49 (d, J¼7.8 Hz, 1H), 8.28 (d, J¼7.8 Hz, 1H), 8.00 (t,
J¼7.4 Hz,1H), 7.95e7.83 (m, 3H), 7.76 (s,1H), 7.61e7.53 (m, 3H), 6.93
6
d
6
d
13
(m, 3H), 7.49 (s, 1H), 6.67 (s, 1H). C NMR (125 MHz, CDCl
157.80, 152.73, 135.93, 135.49, 134.79, 132.95, 131.60, 131.05,
130.72, 130.39, 129.94, 127.66, 124.73, 123.68, 122.27, 122.24, 104.11.
3
):
13
(
s, 1H). C NMR (75 MHz, CDCl
3
):
d
158.35, 153.21, 135.30, 135.43,
d
135.38, 132.91, 131.79, 130.64, 129.10, 127.23, 125.09, 123.38, 122.20,
Please cite this article in press as: Wang, L.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.062

L. Wang et al. / Tetrahedron xxx (2016) 1e8
7
þ
(MþH)þ: 316.0274, found
HRMS (ESI) calcd for C17
H11ClNO
3
S (MþH) : 344.0143, found
HRMS (ESI) calcd for
316.0269.
15 5
C H10NO S
3
44.0140.
4
7
.5.9. 9-(2-Methoxyphenyl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-
ꢀ
1
Acknowledgements
-one 5,5-dioxide (7i). White solid, mp: >300 C.
):
8.39 (d, J¼7.8 Hz, 1H), 8.29 (d, J¼7.7 Hz, 1H),
.97 (t, J¼7.6 Hz, 1H), 7.86 (t, J¼7.7 Hz, 1H), 7.53e7.48 (m, 3H),
.22e7.20 (m, 1H), 7.11 (t, J¼7.6 Hz, 1H), 6.70 (d, J¼1.2 Hz, 1H), 3.86
s, 3H). 13C NMR (125 MHz, CDCl
): 158.11, 156.43, 152.23, 135.37,
34.18, 132.71, 131.62, 131.47, 129.72, 125.30, 125.00, 123.54, 122.15,
H NMR
(
300 MHz, DMSO-d
6
d
This work is funded by the National Natural Science Foundation
of China (No. 21572270 and 81172933), Jiangsu Provincial Natural
Science Foundation of China (No. BK20131305), the Qinglan Project
of Jiangsu Province, and the Priority Academic Program De-
velopment of Jiangsu Higher Education Institutions.
7
7
(
1
3
d
121.20, 120.78, 112.04, 104.38, 55.77. HRMS (ESI) calcd for
þ
C
18
H
14NO
4
S (MþH) : 340.0638, found 340.0633.
Supplementary data
4
7
.5.10. 9-(Naphthalen-2-yl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-
ꢀ
1
-one 5,5-dioxide (7j). White solid, mp: >300 C.
):
8.64e8.46 (m, 2H), 8.30 (d, J¼7.0 Hz, 1H),
.10e7.97 (m, 5H), 7.95e7.83 (m, 2H), 7.63 (s, 2H), 7.09 (s, 1H).
): 158.38, 152.89, 135.50, 135.40, 133.70,
32.91, 132.75, 132.55, 131.82, 128.74, 127.62, 127.38, 126.94, 125.15,
H
NMR
Supplementary data (The copies of 1H NMR, 13NMR charts of all
products) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2016.08.062.
(
300 MHz, DMSO-d
6
d
13
8
C
NMR (75 MHz, CDCl
1
3
d
1
C
24.15, 123.82, 122.23, 118.28, 101.67. HRMS (ESI) calcd for
References and notes
þ
21
H14NO
3
S (MþH) : 360.0689, found 360.0687.
1. For selected examples, see: (a) Guan, A.-Y.; Liu, C.-L.; Sun, X.-F.; Xie, Y.; Wang, M.-
A. Biorg. Med. Chem. 2016, 24, 342; (b) Roughley, S. D.; Jordan, A. M. J. Med. Chem.
4
5
.5.11. 9-(Furan-2-yl)-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-one
2
011, 54, 3451; (c) Wu, F.; Zhou, C.; Yao, Y.; Wei, L.; Feng, Z.;Deng, L.; Song, Y. J. Med.
ꢀ
1
,5-dioxide (7k). White solid, mp: >300 C. H NMR (300 MHz,
):
8.40 (d, J¼7.8 Hz, 1H), 8.27 (d, J¼7.8 Hz, 1H), 8.12e7.95
m, 2H), 7.86 (t, J¼7.6 Hz,1H), 7.70 (s,1H), 7.51 (d, J¼3.2 Hz,1H), 6.80
Chem. 2016, 59, 253; (d) Slavik, R.; Grether, U.; M u€ ller Herde, A.; Gobbi, L.; Fin-
a€ mer, S. D.; Schibli, R.; Mu, L.; Ametamey, S. M. J. Med. Chem.
DMSO-d
6
d
gerle, J.; Ullmer, C.; Kr
2015, 58, 4266; (e) Zheng, S.; Zhong, Q.; Mottamal, M.; Zhang, Q.; Zhang, C.; Le-
(
(
Melle, E.; McFerrin, H.; Wang, G. J. Med. Chem. 2014, 57, 3369; (f) Shin, Y.; Fryxell,
G. E.; Johnson Ii, C. A.; Haley, M. M. Chem. Mater. 2008, 20, 981; (g) Francisco, W.;
Pivatto, M.; Danuello, A.; Regasini, L. O.; Baccini, L. R.; Young, M. C. M.; Lopes, N. P.;
Lopes, J. L. C.; Bolzani, V. S. J. Nat. Prod. 2012, 75, 408.
13
s, 1H), 6.72 (s, 1H). C NMR (75 MHz, CDCl
3
): d 158.29, 149.06,
146.88, 141.64, 135.85, 135.38, 132.97, 131.78, 124.88, 123.61, 122.16,
114.31, 113.20, 112.29, 98.75. HRMS (ESI) calcd for C15
4
H10NO S
2
. (a) Huang, H.; Cai, J.; Tang, L.; Wang, Z.; Li, F.; Deng, G.-J. J. Org. Chem. 2016, 81,
þ
(
MþH) : 300.0325, found 300.0326.
1499; (b) Khajuria, R.; Kannaboina, P.; Kapoor, K. K.; Gupta, A.; Raina, G.; Jassal,
A. K.; Rana, L. K.; Hundald, M. S.; Das, P. Org. Biomol. Chem. 2015, 13, 5944; (c)
Sharma, R.; Patel, N.; Vishwakarma, R. A.; Bharatam, P. V.; Bharate, S. B. Chem.
Commun. 2016, 1009.
. For selected examples, see: (a) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Con-
stantieux, T. Chem. Rev. 2014, 114, 10829; (b) Neely, J. M.; Rovis, T. Org. Chem.
Front. 2014, 1, 1010; (c) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642; (d) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.;
Gevorgyan, V. Chem. Rev. 2013, 113, 3084; (e) Hill, M. D. Chem.dEur. J. 2010, 16,
12052; (f) Groenendaal, B.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008, 5474;
4
5
.5.12. (E)-9-Styryl-7H-benzo[4,5]isothiazolo[2,3-a]pyridin-7-one
ꢀ
1
,5-dioxide (7l). White solid, mp: >300 C. H NMR (300 MHz,
8.41 (d, J¼7.8 Hz, 1H), 8.28 (d, J¼7.8 Hz, 1H), 8.02 (t,
J¼7.5 Hz, 1H), 7.87 (t, J¼7.6 Hz, 1H), 7.79 (s, 1H), 7.75e7.67 (m, 3H),
3
6
DMSO-d ) d
13
7
.38e7.50 (m, 3H), 7.27 (d, J¼16.5 Hz, 1H), 6.63 (s, 1H). C NMR
(
125 MHz, DMSO-d ): 158.52, 150.44, 136.79, 135.57, 135.28,
6
d
(g) Wu, J.; Xu, W.; Yu, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015, 137, 9489.
134.96, 132.73, 131.80, 129.39, 128.93, 127.40, 125.14, 125.05, 123.39,
þ
4. Shi, Z.; Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52, 8584.
122.10, 119.23, 99.21. HRMS (ESI) calcd for C19
H14NO
3
S (MþH) :
5
. (a) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M. Z.; O’Riordan, T. J. C.; Smith,
A. D. Angew. Chem., Int. Ed. 2013, 52, 11642; (b) Stark, D. G.; O’Riordan, T. J. C.;
Smith, A. D. Org. Lett. 2014, 16, 6496.
3
36.0689, found 336.0684.
6
. Hao, L.; Chen, X.; Chen, S.; Jiang, K.; Torres, J.; Chi, Y. R. Org. Chem. Front. 2014, 1,
4
6
.5.13. 10-Phenyl-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazin-8-one
148.
ꢀ
1
,6-dioxide (8a). White solid, mp: >300 C. H NMR (300 MHz,
):
8.38 (d, J¼6.9 Hz,1H), 8.02e7.91 (m, 2H), 7.73e7.71 (m,
H), 7.65e7.61 (m, 2H), 7.59e7.51 (m, 4H), 7.00 (s, 1H). C NMR
125 MHz, DMSO-d ): 159.79, 152.42, 146.89, 138.57, 135.51,
7. (a) Coffinier, D.; Kaim, L. E.; Grimaud, L.; Ruijter, E.; Orru, R. V. A. Tetrahedron
DMSO-d
1
(
6
d
Lett. 2011, 52, 3023; (b) Lu, J.-Y.; Arndt, H.-D. J. Org. Chem. 2007, 72, 4205.
8. Ram, R. N.; Khan, A. A. Synth. Commun. 2001, 31, 841.
9
13
. Feng, X.; Zhou, Z.; Ma, C.; Yin, X.; Li, R.; Dong, L.; Chen, Y.-C. Angew. Chem., Int.
Ed. 2013, 52, 14173.
6
d
1
33.94, 131.16, 129.51, 128.76, 128.16, 127.82, 119.67, 118.91, 116.93,
10. (a) Jiang, D.; Dong, S.; Tang, W.; Lu, T.; Du, D. J. Org. Chem. 2015, 80, 11593; (b)
Xu, J.; Hu, S.; Lu, Y.; Dong, Y.; Tang, W.; Lu, T.; Du, D. Adv. Synth. Catal. 2015, 357,
þ
105.15. HRMS (ESI) calcd for C17
H12NO
4
S (MþH) : 326.0482, found
923; (c) Hu, S.; Wang, B.; Zhang, Y.; Tang, W.; Fang, M.; Lu, T.; Du, D. Org. Biomol.
3
26.0472.
Chem. 2015, 13, 4661; (d) Zhang, Y.; Lu, Y.; Tang, W.; Lu, T.; Du, D. Org. Biomol.
Chem. 2014, 12, 3009; (e) Lu, Y.; Tang, W.; Zhang, Y.; Du, D.; Lu, T. Adv. Synth.
Catal. 2013, 355, 321; (f) Du, D.; Hu, Z.; Jin, J.; Lu, Y.; Tang, W.; Wang, B.; Lu, T.
Org. Lett. 2012, 14, 1274; (g) Du, D.; Hu, Z.; Tang, W.; Wang, B.; Lu, T. Tetrahedron
Lett. 2012, 53, 453; (h) Du, D.; Lu, Y.; Jin, J.; Tang, W.; Lu, T. Tetrahedron 2011, 67,
7557; (i) Xu, J.; Zhang, W.; Liu, Y.; Zhu, S.; Liu, M.; Hua, X.; Chen, S.; Lu, T.; Du, D.
RSC Adv. 2016, 6, 18601; (j) Dong, S.; Fang, C.; Tang, W.; Lu, T.; Du, D. Org. Lett.
2016, 18, 3882.
4
.5.14. 10-(4-Methoxyphenyl)-8H-benzo[e]pyrido[1,2-c][1,2,3]ox-
ꢀ
1
athiazin-8-one 6,6-dioxide (8b). White solid, mp: >300 C. H NMR
300 MHz, DMSO-d ):
8.49 (d, J¼7.8 Hz, 1H), 8.27 (d, J¼7.8 Hz, 1H),
(
6
d
7
2
.98e8.03 (m, 1H), 7.84e7.94 (m, 3H), 7.75 (s, 1H), 7.10 (d, J¼8.8 Hz,
13
H), 6.88 (s, 1H), 3.85 (s, 3H)$ C NMR (125 MHz, DMSO-d
6
):
11. For selected reviews, see: (a) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res.
d
161.49, 159.37, 151.28, 146.42, 137.85, 133.36, 129.04, 128.22,
2014, 47, 696; (b) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44, 5040;
(c) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev.
127.64, 126.91, 119.17, 118.49, 114.57, 114.47, 104.33, 55.41. HRMS
þ
2015, 115, 9307; (d) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Na-
ture 2014, 510, 485; (e) Chauhan, P.; Enders, D. Angew. Chem., Int. Ed. 2014, 53,
(
ESI) calcd for C18
H14NO
5
S (MþH) : 356.0587, found 356.0581.
1485; (f) Albanese, D. C. M.; Gaggero, N. Eur. J. Org. Chem. 2014, 5631; (g) Ryan,
4
.5.15. 10-(Furan-2-yl)-8H-benzo[e]pyrido[1,2-c][1,2,3]oxathiazin-8-
S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906; (h) De Sarkar, S.;
Biswas, A.; Samanta, R. C.; Studer, A. Chem.dEur. J. 2013, 19, 4664; (i) Chen, X.-
Y.; Ye, S. Org. Biomol. Chem. 2013, 11, 7991; (j) Izquierdo, J.; Hutson, G. E.; Cohen,
D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686; (k) Grossmann, A.;
Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314; (l) Douglas, J.; Churchill, G.;
Smith, A. D. Synthesis 2012, 44, 2295; (m) Tang, W.; Du, D. Chem. Rec. 2016, 16,
ꢀ
1
one 6,6-dioxide (8c). White solid, mp: >300 C. H NMR (300 MHz,
DMSO-d ):
6
d
8.33e8.24 (m, 1H), 8.04 (d, J¼1.2 Hz, 1H), 7.77e7.70
(
1
(
1
m, 1H), 7.68 (d, J¼3.5 Hz, 1H), 7.66e7.58 (m, 2H), 7.51 (d, J¼1.4 Hz,
13
H), 6.81 (dd, J¼3.5, 1.7 Hz, 1H), 6.76 (d, J¼1.2 Hz, 1H). C NMR
): 159.24, 148.65, 147.14, 146.50, 140.51, 138.66,
33.59, 128.29, 127.51, 119.28, 118.31, 114.98, 113.26, 110.64, 101.66.
1
489.
2. Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. J. Am.
Chem. Soc. 2014, 136, 10589.
75 MHz, CDCl
3
d
1
Please cite this article in press as: Wang, L.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.062

8
L. Wang et al. / Tetrahedron xxx (2016) 1e8
13. (a) Yang, J.; Liu, S.; Zheng, J.-F.; Zhou, J. Eur. J. Org. Chem. 2012, 2012, 6248; (b) Tetrahedron 2015, 71, 663; (e) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org.
Gao, C.-Y.; Yang, L.-M. J. Org. Chem. 2008, 73, 1624; (c) Gøgsig, T. M.; Lindhardt,
A. T.; Dekhane, M.; Grouleff, J.; Skrydstrup, T. Chem.dEur. J. 2009, 15, 5950.
Chem. 1999, 64, 8648.
15. For selected examples, see: (a) An, G.; Seifert, C.; Li, G. Org. Biomol. Chem. 2015,
13, 1600; (b) Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. Chem. Commun. 2010,
4330; (c) Seifert, C. W.; Paniagua, A.; White, G. A.; Cai, L.; Li, G. Eur. J. Org. Chem.
2016, 2016, 1714; (d) Wu, J.; An, G.; Lin, S.; Xie, J.; Zhou, W.; Sun, H.; Pan, Y.; Li,
G. Chem. Commun. 2014, 1259; (e) Yang, B.; Ji, X.; Xue, Y.; Zhang, H.; Shen, M.;
Jiang, B.; Li, G. Org. Biomol. Chem. 2016, 14, 6024; (f) Yang, B.; Shen, M.; Ji, X.; Xu,
Z.; Sun, H.; Jiang, B.; Li, G. J. Org. Chem. 2016, 81, 2488.
1
4. For selected examples for the synthesis of pyridin-2-ones, see: (a) Smith, C.
L.; Hirschh €a user, C.; Malcolm, G. K.; Nasrallah, D. J.; Gallagher, T. Synlett
014, 1904; (b) Alberola, A.; Calvo, L. A.; Ortega, A. G.; Sa n~ udo Ruíz, M. C.;
2
Yustos, P.; Granda, S. G.; García-Rodriguez, E. J. Org. Chem. 1999, 64, 9493; (c)
Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q. Org. Lett.
2
007, 9, 2421; (d) Liu, Z.-Q.; Hu, Y.-J.; Chen, X.-Y.; Wu, Q.; Lin, X.-F.
Please cite this article in press as: Wang, L.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.062