Copper(II)-Catalyzed Four-Component Oxysulfonylation/Diazenylation: Synthesis of α-Arylhydrazo-β-keto Sulfones

Article abstract of DOI:10.1021/acs.joc.8b01843

A new and convenient method for one-pot synthesis of α-arylhydrazo-β-keto sulfones is developed via Cu (II)-catalyzed oxysulfonylation/diazenylation of alkenes. This four-component cascade reaction enables a series of α-arylhydrazo-β-keto sulfone derivatives accessed from readily available alkenes, sulfinates, and diazonium salts under aerobic conditions. Furthermore, the 3-sulfonyl cinnolin-4(1H)-one skeleton is successfully constructed from the corresponding α-arylhydrazo-β-keto sulfone product under basic conditions.

Full text of DOI:10.1021/acs.joc.8b01843

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Article
Copper (II)-Catalyzed Four-Component Oxysulfonylation/
Diazenylation: Synthesis of #-Arylhydrazo-#-keto Sulfones
Wen-Chao Gao, Yu-Fei Cheng, Yu-Zhu Shang, Hong-Hong
Chang, Xing Li, Rong Zhou, Yan Qiao, and Wen-Long Wei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01843 • Publication Date (Web): 05 Sep 2018
Downloaded from http://pubs.acs.org on September 5, 2018
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Copper (II)-Catalyzed Four-Component Oxysulfonylation/Diazenylation:
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Synthesis of α-Arylhydrazo-β-keto Sulfones
WenꢀChao Gao,a* YuꢀFei Cheng,a YuꢀZhu Shang,a HongꢀHong Chang,a Xing Li,a Rong Zhou,a* Yan
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Qiao,b and WenꢀLong Weib
a College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, P. R.
China
b State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences,
Taiyuan 030001, P. R. China
*Eꢀmail: gaowenchao@tyut.edu.cn; zhourong@tyut.edu.cn.
Abstract:
O
N2
BF4
R2
R2
O2 (air)
CuSO4 5H2O (20 mol%)
N
R1SO2Na
Ar
N
Ar
+
+
H
DMF, rt
SO2R1
Rapid construction of -arylhydrazo- -keto sulfones
Cu (II)-catalyzed four-component reaction
23 examples, up to 85% isolated yield
C-O, C-N, and C-S bond formation
A new and convenient method for oneꢀpot synthesis of αꢀarylhydrazoꢀβꢀketo sulfones
is developed via Cu (II)ꢀcatalyzed oxysulfonylation/diazenylation of alkenes. This
fourꢀcomponent cascade reaction enables a series of αꢀarylhydrazoꢀβꢀketo sulfone
derivatives accessed from readily available alkenes, sulfinates and diazonium salts under
aerobic conditions. Furthermore, 3ꢀsulfonyl cinnolinꢀ4(1H)ꢀone skeleton is successfully
constructed from the corresponding αꢀarylhydrazoꢀβꢀketo sulfone product under basic
conditions.
Introduction
As an important class of compounds in organic chemistry, hydrazone and its
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derivatives are usually encountered in both laboratories and industry to synthetic building
blocks,1 pharmaceutical agents,2 and chelating molecules towards metal ions.3 Traditionally,
hydrazones are prepared from the condensation of hydrazines with carbonyl compounds
under neutral or acidic conditions.4 Since αꢀhydrazo ketone derivatives are good candidates
for the construction of indoles (Fischer indole synthesis) as well as amino acids,5 another
frequently used method to construct hydrazones especially for αꢀhydrazo ketone derivatives
is the coupling of diazonium salts with 1,3ꢀdicarbonyl compounds, that was known as
Japp–Klingemann reaction (Scheme 1, eq. 1).6a Although Japp–Klingemannꢀtype coupling
for αꢀhydrazo ketones construction has been extensively studied for several decades,6bꢀe the
synthesis of αꢀhydrazo ketone derivatives from simple and unactivated alkenes would be
more convenient but unexplored.7
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Methods for mild and selective diversification of alkenes have elicited strong interest
in synthetic community since they provide a powerful platform to access structurally
complex molecules from common and simple starting materials.8 Specifically, radical
oxysulfonylation and oxyarylation of alkenes via direct aerobic oxidation offer facile and
efficient strategies for the synthesis of βꢀketo sulfones and αꢀaryl ketones (Scheme 1, eq. 2
and 3).9 Significant progress has been achieved for oxygenation of alkenes via Cuꢀcatalyzed
dioxygen activation, and examples of which include the noteworthy work of Lei,10 Jiang,11
Jiao,12 Wang,9a and Heinrich.9d We were therefore motivated to investigate if the
Cuꢀcatalyzed radical activation and oxygenation of alkenes could access αꢀarylꢀβꢀketo
sulfones with the utility of both sulfonyl and aryl radical precursors.13 However, the desired
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αꢀarylꢀβꢀketo sulfones through radical oxysulfonation/arylation were not detected, and
αꢀhydrazoꢀβꢀketo sulfones were isolated as the major products (scheme 1, eq. 4). Herein,
we would like to present this unexpected fourꢀcomponent reaction for oneꢀpot synthesis of
αꢀhydrazoꢀβꢀketo sulfones via Cu (II)ꢀcatalyzed radical oxysulfonylation of alkenes and
subsequent diazenylation of βꢀketo sulfones, by employing alkenes, diazonium salts and
sulfinates under aerobic conditions.
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Scheme 1. Different Methods for Synthesis of α-Hydrazo, -Aryl and -Sulfonyl Ketones
Japp-Klingemann reaction
O
O
R1
R2
N
O
O
R1
R3
N2
R4
N
O
N
R3
base
R2
N
H2O
R4
+
R3
R2
H
(1)
R4
-R1CO2H
X
Arylhydrazones
Oxygenation of alkenes
O
Cat.
O2
SO2R
(2)
(3)
+
+
RSO2NHNH2
Ar
Ar
Ar
Ar
O
R
R
Cat.
O2
N2
X
Synthesis of -arylhydrazo- -keto sulfones (this work)
α
β
O
O
R2
Ar
x
N2
X
SO2R1
[Cu]
O2
Ar
+
R1SO2Na
+
(4)
R2
R2
HN
N
Ar
SO2R1
Results and Discussion
Our investigation started with 4ꢀmethoxyphenyl diazonium salt (1a), sodium
toluenesulfinate (2a) and styrene (3a) as substrates under air atmosphere, and the
representative results are listed in Table 1. No product was detected in the absence of
catalysts in DMA (entry 1). When copper (II) catalysts were employed in the reaction
system, the desired αꢀhydrazoꢀβꢀketo sulfone 4a was obtained as the major product (entries
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3ꢀ6). To our delight, the yield of 4a was increased to 80% using CuSO4·5H2O as the catalyst
(entry 6). Attempt to increase or lower the reaction temperature resulted in the decrease on
the reaction efficiency (entries 7 and 8). Other solvents, such as CH2Cl2, DMF, CH3CN,
C2H5OH, H2O and DMSO were proved to be not effective (entries 9ꢀ14). Furthermore, two
sulfonylating reagents, sulfonylhydrazide 2b and sulfinic acid 2c, which were commonly
used in radical sulfonylation of alkenes,9a,10 were also examined in this transformation.
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Unfortunately,
the
desired
product
4a
was
not
detected,
whereas
1ꢀphenylꢀ2ꢀ(phenylsulfonyl)ethanone was isolated as the major product instead (entries 15
and 16).
Table 1. A Brief Survey on Reaction Conditionsa
Entry
Cat. (20 mol %) Solvent
Temp. (oC) Yield
(%)b
1
ꢀꢀ
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
45
0
0
2
AgOTf
52
61
66
76
80
64
54
57
0
3
Cu(OTf)2
4
Cu(Ac)2
5
CuSO4
6
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
7
8
9
r.t.
r.t.
r.t.
r.t.
r.t.
10
11
12
13
CH2Cl2
CH3CN
C2H5OH
H2O
0
0
0
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CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
DMSO
DMA
DMA
r.t.
r.t.
r.t.
20
0
15c
16d
0
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a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3a (1 mmol), catalyst (20 mol %), in 1 mL of
solvent, under air atmosphere for 6ꢀ8 h. b Isolated yield of 4a. c 2a was replaced by 2b. d 2a was replaced
by 2c.
With the optimal conditions in hand, the scope and limitations of this Cu (II)ꢀcatalyzed
fourꢀcomponent reaction was subsequently investigated using different alkenes, sulfinates
and diazonium salts (Table 2 and Table 3). A series of styrene derivatives with different
substituents were firstly subjected to the optimal reaction conditions. Both
electronꢀdonating groups, including 4ꢀmethyl (4b) and 4ꢀmethoxyl (4c), and
electronꢀwithdrawing group such as chloro (4d), bromo (4e and 4f), and fluoro (4gꢀi)
groups on the phenyl ring of alkenes were well tolerated, readily affording the
corresponding products in good yields. Moreover, the location of the substituents on the
phenyl ring only had slight influence on the reaction yields (4e vs 4f, and 4h vs 4i). To our
delight, the Xꢀray single crystal structure of 4d was obtained to further confirm the product
exclusively in the hydrazone form rather than azo form.7,14 Other aromatic ring like
naphthyalene was also suitable for this transformation, and the desired product 4j was
furnished in 67% yield. However, when hexꢀ1ꢀene or βꢀmethylstyrene was employed as the
substrate, the corresponding αꢀhydrazoꢀβꢀketo sulfone 4k or 4l was not detected.
Furthermore, two naturally derived alkenes from Lꢀtyrosine and coumarin also performed
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well under the standard conditions, giving the corresponding products in moderate to high
yields (4m and 4n).
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Table 2. Scope of Alkenes for One-pot Synthesis of α-Arylhydrazo-β-keto Sulfonesa
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N2BF4
SO2Na
+
OMe
O2 (air)
CuSO4•5H2O (20 mol%)
O
+
N
Ar
Ar
N
DMA, r.t.
H
Ts
OMe
Me
1a
2a
4
3
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3 (1 mmol), CuSO4·5H2O (20 mol %), in DMA (1
mL), stirred at room temperature under air atmosphere.
Next, the scope of sulfinates and diazonium salts were examined. As shown in Table 3,
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various sodium sulfinates bearing electronꢀdonating (OMe and tꢀBu) or withdrawing (F and
CF3) groups on the phenyl ring could be smoothly converted to the corresponding products
in moderate to good yields (4oꢀs). Other aromatic systems such as thienyl and naphthyl ring
could be also tolerated in this transformation, delivering the corresponding products in
moderate yields. Moreover, sodium methanesulfinate was good sulfonyl source for this
reaction, and the product 4v was obtained in 64% yield. In addition, several aryl diazonium
salts with different substituents on the phenyl ring also proceeded smoothly, and provided
the products 4wꢀy in moderate yields.
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Table 3. Scope of Sulfinates and Diazonium salts for One-pot Synthesis of α-Arylhydrazo-β-keto
Sulfonesa
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a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), 3a (1 mmol), CuSO4·5H2O (20 mol %), in DMA (1
mL), stirred at room temperature under air atmosphere.
As an important heterocycle, cinnoline skeleton is found in many drugs (eg. Cinoxacin)
and reported to have a wide range of pharmacological applications.15 With the product 4j
derived from 2ꢀfluorostyrene in hand, a baseꢀpromoted intramolecular cyclization could
smoothly proceed to afford the 3ꢀsulfonylated cinnolinꢀ4(1H)ꢀone 5 in 60% yield (Scheme
2). Therefore, our methodology has also offered an alternative way to 3ꢀsulfonylated
cinnoline derivatives.
Scheme 2. Synthesis of 3-Sulfonylated Cinnolin-4(1H)-one Skeleton from 4j
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Ts
Ts
HN
N
F
OMe
N
O
N
OMe
Na2CO3 (0.5M)
O
CH3CH2OH, 80oC
1 h
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4j
5, 60%
In order to gain insight into the reaction mechanism of the formation of compounds 4,
we performed several control experiments. Firstly, this transformation was completely
inhibited in the presence of a catalytic amount of the radical inhibitor
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) (Scheme 3, eq 1). Under the standard
reaction conditions but without diazonium salts, the reaction of 3a with 2a only gave
1ꢀphenylꢀ2ꢀ(phenylsulfonyl)ethanone (6) in 90% yield (Scheme 3, eq 2). However, βꢀketo
sulfone 6 failed to couple with diazonium salt 1a to give 4a in the absence of TsNa or
CuSO4•5H2O, whereas the desired αꢀarylhydrazoꢀβꢀketo sulfone 4a could be isolated in
71% yield when treating the mixture of 6 and 1a with 1.0 equiv of TsNa and 20 mol % of
CuSO4•5H2O (Scheme 3, eq. 3 and 4). These results indicated that βꢀketo sulfone 6 was a
key intermediate for the generation of 4a, and the combination of TsNa with CuSO4•5H2O
was necessary for the diazenylation step.
Scheme 3. Control Experiments
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According to these results and literature reports, a plausible mechanism was proposed
in Scheme 4. Initially, in the presence of Cu (II) catalyst, the sulfonyl anion 2 was oxidized
via single electron transfer (SET) process by dioxygen,16 affording the oxygen centered
radical I, which could resonate to sulfonyl radical II. The addition of sulfonyl radical II to
CꢀC double bond produced a benzyl radical III, which interacted with O2 to afford peroxy
radical IV. A Cu (II)ꢀperoxyl intermediate V was then generated via radical coupling,11,12
and it subsequently decomposed to the βꢀketo sulfone VI by elimination of [Cu(OH)]+.17
Thereafter, in the presence of CuSO4•5H2O and sodium sulfinates, βꢀketo sulfone VI was
continuously converted to an enol Cu (II) intermediate VII, which underwent diazenylation
by the coupling with diazonium salts to produce intermediate VIII. Finally, the
tautomerization of VIII led to the product 4.
Scheme 4. A Proposed Mechanism for the Formation of Compound 4
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O2
Cu (I)
O
Cu (II)
O
S
O
O
Ph
S Ar
O
Ar S
Ar
S
Ar
7
8
9
Ph
O
O
O
I
II
III
2
O2
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[Cu(II)-(OH)]+
OCu(II)
O
O
O
O
O
O
O
Cu(I)
Ph
S Ar
O
S Ar
S Ar
O
Ph
Ph
O
VI
V
IV
Cu(II)
O
ArSO2
O
O
O
H
O
Cu(II)
S Ar
R N2
S
Ar
O
Ph
Ph
O
tautomerization
O
S
Ar
N
N
Ph
N R
H
N R
O
VII
VIII
4
Conclusion
In summary, we have developed a copperꢀcatalyzed fourꢀcomponent reaction by
employing alkenes, sodium sulfinates, diazonium salts and dioxygen, through radical
oxysulfonylation and diazenylation to access αꢀarylhydrazoꢀβꢀketo sulfones. Notably, this
transformation exhibits a broad range of functionalꢀgroup tolerance and enables the
formation of CꢀO, CꢀS and CꢀN bonds in oneꢀpot. Furthermore, the conversion of the
αꢀarylhydrazoꢀβꢀketo sulfone 4j to a 3ꢀsulfonylated cinnolinꢀ4(1H)ꢀone is readily realized.
Efforts towards further mechanistic details and other synthetic applications are underway.
Experimental
General Information. NMR spectra were recorded using 400 MHz NMR
spectrometers with CDCl3 as the deuterated solvent, and the resonances of proton, carbon,
and fluorine were at 400, 100, and 376 MHz, respectively. Chemical shifts (δ) were
reported in ppm and referenced to the deuterated chloroform (1H: δ = 7.26 ppm, C: δ =
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77.00 ppm). Highꢀresolution mass spectrometry (HRMS) was carried out on a TOFꢀQ
spectrometer instrument with an ESI source. Melting points were measured with a RDꢀII
type melting point apparatus (uncorrected). Xꢀray structural analysis was obtained with an
Xꢀray singleꢀcrystal diffractometer. Solvents, unless otherwise noted, were purified
according to standard procedures before use. Column chromatography was performed on
silica gel (200ꢀ300 mesh) by using EtOAc and PE (Petroleum ether) as eluent. PE, where
used, has the boiling point range of 60ꢀ90 °C.
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Typical Procedure for the Preparation of Diazonium Salts
To BF3•Et2O (1.06 g, 7.50 mmol, 1.50 equiv) contained in a threeꢀneck round bottom flask
fitted with two addition funnels was slowly added 5.0 mmol of the aromatic amine in 10.0
mL of anhydrous THF at 0°C in an iceꢀwater bath. tꢀBuONO (0.618 g, 6.00 mmol, 1.20
equiv) in 5.00 mL of anhydrous THF was then added dropwise to the above rapidly stirred
reaction solution. The reaction mixture was stirred for 30 min, and then nꢀhexane (40 mL)
was added. The formed precipitate was suction filtered, washed with cold ether (10 mL×2)
and dried under reduced pressure at room temperature to give the desired diazonium salt.
Typical Procedure for the Synthesis of α-Arylhydrazo-β-keto Sulfones
To a mixture of styrene (1.0 mmol), sodium toluenesulfinate (0.4 mmol), 4ꢀmethoxyphenyl
diazonium salt (0.2 mmol), CuSO4•5H2O (0.04 mmol, 20 mol%), and DMA (1 mL) in a 10
mL roundꢀbottomed flack at room temperature under air atmosphere. The reaction vessel
was allowed to stir at room temperature until the starting material was consumed. After the
reaction, the resulting mixture was diluted by EtOAc (30 mL), washed by H2O (10 mL×3),
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dried by Na2SO4 and concentrated under vacuum. The residue was purified by column
chromatography (eluent: PE/EtOAc = 4:1) to give the desired 4a.
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(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-1-phenyl-2-tosylethanone (4a)
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o
Yield: 64.0 mg (80%); time: 7 h; yellow solid; m.p. 184ꢀ186 C; TLC, Rf = 0.34 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.45 (s, 1H), 8.04 (d, 2H, J = 8.4 Hz), 7.77 (d, 2H,
J = 8.4 Hz), 7.52 (t, 1H, J = 7.2 Hz), 7.43ꢀ7.34 (m, 4H), 7.12 (d, 2H, J = 8.8 Hz), 6.89 (d,
13
2H, J = 9.2 Hz), 3.81 (s, 3H), 2.44 (s, 3H); C NMR (CDCl3, 100 MHz): δ 186.5, 157.4,
145.2, 137.6, 137.4, 135.0, 131.9, 130.1, 129.6, 128.6, 127.7, 116.9, 114.9, 55.6, 21.7;
HRMS (ESI) m/z calcd for C22H21N2O4S [M + H]+: 409.1216, found: 409.1218.
(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-1-(p-tolyl)-2-tosylethanone (4b)
o
Yield: 64.2 mg (76%); time: 7 h; yellow solid; m.p. 182ꢀ184 C; TLC, Rf = 0.32 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.43 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz), 7.71 (d, 2H,
J = 8.0 Hz), 7.36 (d, 2H, J = 8.0 Hz), 7.20 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 9.2 Hz), 6.90
(d, 2H, J = 8.8 Hz), 3.81 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ
186.0, 157.3, 145.1, 142.7, 137.7, 135.1, 134.6, 130.3, 129.6, 128.53, 128.47, 116.8, 114.9,
55.6, 21.7, 21.6; HRMS (ESI) m/z calcd for C23H23N2O4S [M + H]+: 423.1373, found:
423.1375.
(Z)-1-(4-Methoxyphenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4c)
Yield: 63.0 mg (72%); time: 6 h; yellow solid; m.p. 235ꢀ237 oC; TLC, Rf = 0.33 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.35 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H,
J = 8.8 Hz), 7.36 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.90 (dd, 4H, J = 8.8 Hz, J =
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2.4 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 2.43 (s, 3H); C NMR (CDCl3, 100 MHz): δ 184.9,
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162.9, 157.3, 145.1, 137.8, 135.2, 132.5, 129.6, 128.5, 116.7, 115.0, 113.1, 55.6, 55.4, 21.7;
HRMS (ESI) m/z calcd for C23H23N2O5S [M + H]+: 439.1322, found: 439.1335.
(Z)-1-(4-Chlorophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4d)
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o
Yield: 60.0 mg (68%); time: 8 h; yellow solid; m.p. 158ꢀ160 C; TLC, Rf = 0.35 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.48 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz), 7.72 (d, 2H,
J = 8.4 Hz), 7.37 (t, 4H, J = 8.4 Hz), 7.12 (d, 2H, J = 9.2 Hz), 6.92 (d, 2H, J = 8.8 Hz), 3.82
13
(s, 3H), 2.44 (s, 3H); C NMR (CDCl3, 100 MHz): δ 185.2, 157.6, 145.4, 138.3, 137.5,
135.7, 134.9, 131.5, 129.6, 128.6, 128.1, 116.9, 115.0, 55.6, 21.7; HRMS (ESI) m/z calcd
for C22H20ClN2O4S [M + H]+: 443.0826, found: 443.0831.
(Z)-1-(4-Bromophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4e)
o
Yield: 68.0 mg (70%); time: 10 h; yellow solid; m.p. 202ꢀ204 C; TLC, Rf = 0.30
1
(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.49 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz),
7.65 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 5.2 Hz), 7.12 (d, 2H, J =
9.2 Hz), 6.92 (d, 2H, J = 8.8 Hz), 3.82 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ
185.3, 157.6, 145.4, 137.4, 136.2, 134.8, 131.6, 131.0, 129.6, 128.6, 127.9, 126.9, 116.9,
115.0, 55.6, 21.7; HRMS (ESI) m/z calcd for C22H20BrN2O4S [M + H]+: 487.0322,
489.0302, found: 487.0328, 489.0308.
(Z)-1-(3-Bromophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4f)
o
Yield: 69.2 mg (71%); time: 7 h; yellow solid; m.p. 149ꢀ151 C; TLC, Rf = 0.33 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.52 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz), 7.94 (s, 1H),
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7.70ꢀ7.61 (m, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.15 (d, 2H, J = 9.2
6
7
13
Hz), 6.92 (d, 2H, J = 9.2 Hz), 3.82 (s, 3H), 2.44 (s, 3H); C NMR (CDCl3, 100 MHz): δ
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184.7, 157.7, 145.4, 139.2, 137.3, 134.8, 134.6, 133.2, 129.6, 129.4, 128.63, 128.53, 121.7,
117.0, 115.0, 55.6, 21.7; HRMS (ESI) m/z calcd for C22H20BrN2O4S [M + H]+: 487.0322,
489.0302, found: 487.0328, 489.0306.
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(Z)-1-(4-Fluorophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4g)
o
Yield: 59.6 mg (70%); time: 5.5 h; yellow solid; m.p. 187ꢀ189 C; TLC, Rf = 0.36
1
(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.45 (s, 1H), 8.03 (d, 2H, J = 8.4 Hz),
7.85ꢀ7.78 (m, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.15ꢀ7.05 (m, 4H), 6.91 (d, 2H, J = 9.2 Hz),
13
3.81 (s, 3H), 2.44 (s, 3H); C NMR (CDCl3, 100 MHz): δ 185.0, 165.0 (d, J = 272.0 Hz),
157.6, 145.3, 137.6, 134.9, 133.5 (d, J = 3.1 Hz), 132.6 (d, J = 8.9 Hz), 129.6, 128.6, 116.9,
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115.0, 114.8, 55.6, 21.7; F NMR (CDCl3, 376 MHz): δ ꢀ102.65; HRMS (ESI) m/z calcd
for C22H20FN2O4S [M + H]+: 427.1122, found: 427.1120.
(Z)-1-(3-Fluorophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4h)
o
Yield: 61.4 mg (72%); time: 6 h; yellow solid; m.p. 131ꢀ133 C; TLC, Rf = 0.33 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.51 (s, 1H), 8.04 (d, 2H, J = 8.4 Hz), 7.56 (d, 1H,
J = 7.6 Hz), 7.49ꢀ7.45 (m, 1H), 7.42ꢀ7.35 (m, 3H), 7.25ꢀ7.18 (m, 1H), 7.13 (d, 2H, J = 8.8
13
Hz), 6.91 (d, 2H, J = 9.2 Hz), 3.82 (s, 3H), 2.45 (s, 3H); C NMR (CDCl3, 100 MHz): δ
185.0, 157.7, 145.4, 136.1 (d, J = 256.3 Hz), 129.6, 129.3 (d, J = 7.5 Hz), 128.6, 125.8 (d, J
= 2.9 Hz), 118.8 (d, J = 21.0 Hz), 117.0, 116.9 (d, J = 22.9 Hz), 115.0, 55.6, 21.8; 19F NMR
(CDCl3, 376 MHz): δ ꢀ112.95; HRMS (ESI) m/z calcd for C22H20FN2O4S [M + H]+:
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427.1122, found: 427.1117.
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(Z)-1-(2-Fluorophenyl)-2-(2-(4-methoxyphenyl)hydrazono)-2-tosylethanone (4i)
8
9
o
Yield: 62.2 mg (73%); time: 11 h; yellow solid; m.p. 153ꢀ155 C; TLC, Rf = 0.31
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(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.47 (s, 1H), 8.03(d, 2H, J = 8.4 Hz),
7.47ꢀ7.41 (m, 2H), 7.37 (d, 2H, J = 8.4 Hz), 7.18 (t, 1H, J = 7.6 Hz ), 7.08 (d, 1H, J = 8.8
Hz), 7.02 (d, 2H, J = 8.8 Hz), 6.85 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 2.44 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ 185.1, 159.6 (d, J = 249.4 Hz), 157.7, 145.3, 137.1, 134.8, 132.6 (d, J
= 8.2 Hz), 130.4 (d, J = 3.1 Hz), 129.6, 128.6, 123.9, 116.9, 115.6, 115.4 (d, J = 22.2 Hz),
55.6, 21.7; 19F NMR (CDCl3, 376 MHz): δ ꢀ110.22; HRMS (ESI) m/z calcd for
C22H20FN2O4S [M + H]+: 427.1122, found: 427.1105.
(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-1-(naphthalen-2-yl)-2-tosylethanone (4j)
o
Yield: 61.4 mg (67%); time: 9 h; yellow solid; m.p. 186ꢀ188 C; TLC, Rf = 0.35 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.49 (s, 1H), 8.37 (s, 1H), 8.08 (d, 2H, J = 8.0 Hz),
7.90ꢀ7.84 (m, 4H), 7.62ꢀ7.50 (m, 2H), 7.38 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 8.8 Hz),
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6.86 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 2.45 (s, 3H); C NMR (CDCl3, 100 MHz): δ 186.2,
157.4, 145.3, 137.7, 135.1, 135.0, 134.6, 132.3, 131.8, 129.6, 129.3, 128.6, 128.2, 128.1,
127.7, 127.4, 126.6, 126.1, 116.8, 115.0, 55.6, 21.7; HRMS (ESI) m/z calcd for
C26H23N2O4S [M + H]+: 459.1373, found: 459.1387.
(S,Z)-Methyl-2-benzamido-3-(4-(2-(2-(4-methoxyphenyl)hydrazono)-2-tosylacetyl)phe
nyl)propanoate (4m)
o
Yield: 77.2 mg (63%); time: 14 h; yellow solid; m.p. 155ꢀ157 C; TLC, Rf = 0.27
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(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.43 (s, 1H), 8.03 (d, 2H, J = 8.0 Hz),
7.73ꢀ7.69 (m, 4H), 7.50 (t, 1H, J = 7.2 Hz), 7.42ꢀ7.34 (m, 4H), 7.17 (d, 2H, J = 8.0 Hz),
7.09 (d, 2H, J = 9.2 Hz), 6.87 (d, 2H, J = 9.2 Hz), 6.63 (d, 1H, J = 7.6 Hz), 3.79 (s, 3H),
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3.76 (s, 3H), 3.37ꢀ3.29 (m, 2H), 2.43 (s, 3H); C NMR (CDCl3, 100 MHz): δ 186.1, 171.7,
166.8, 157.5, 145.3, 140.2, 137.5, 136.3, 134.9, 133.6,131.9, 130.3, 129.6, 128.74, 128.67,
128.6, 126.9, 116.8, 115.0, 55.6, 53.4, 52.5, 37.8, 21.7; HRMS (ESI) m/z calcd for
C33H32N3O7S [M + H]+: 614.1996, found: 614.2009.
(Z)-7-(2-(2-(4-Methoxyphenyl)hydrazono)-2-tosylacetyl)-2H-chromen-2-one (4n) Yield:
o
80.8 mg (85%); time: 20 h; yellow solid; m.p. 175ꢀ177 C; TLC, Rf = 0.23 (PE:EtOAc =
1
9:1); H NMR (CDCl3, 400 MHz): δ 12.58 (s, 1H), 8.05 (d, 2H, J = 8.4 Hz), 7.75ꢀ7.71 (m,
2H), 7.64 (dd, 1H, J = 8.0 Hz and 1.6 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.4 Hz),
7.11 (d, 2H, J = 9.2 Hz), 6.90 (d, 2H, J = 8.4 Hz), 6.51 (d, 1H, J = 9.6 Hz), 3.80 (s, 3H),
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2.45 (s, 3H); C NMR (CDCl3, 100 MHz): δ 184.6, 160.2, 157.8, 153.2, 145.5, 142.6,
140.4, 137.3, 134.6,129.7, 128.6, 128.6, 127.2, 125.7, 121.1, 118.52, 118.47, 117.1, 115.1,
55.6, 21.8; HRMS (ESI) m/z calcd for C25H21N2O6S [M + H]+: 477.1115, found: 477.1091.
(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-1-phenyl-2-(phenylsulfonyl)ethanone (4o)
o
Yield: 53.6 mg (68%); time: 6 h; yellow solid; m.p. 195ꢀ197 C; TLC, Rf = 0.34 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.47 (s, 1H), 8.16 (d, 2H, J = 7.6 Hz), 7.7 (d, 2H, J
= 6.8 Hz), 7.66 (t, 1H, J = 7.6 Hz), 7.58 (t, 2H, J = 8.0 Hz), 7.52 (t, 1H, J = 7.2 Hz), 7.41 (t,
13
2H, J = 8.0 Hz), 7.13 (d, 2H, J = 9.2 Hz), 6.90 (d, 2H, J = 8.8 Hz), 3.81 (s, 3H); C NMR
(CDCl3, 100 MHz): δ 186.4, 157.5, 140.6, 137.3, 135.0, 134.0, 132.0, 130.1, 128.9, 128.5,
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127.8, 127.7, 116.9, 115.0, 55.6; HRMS (ESI) m/z calcd for C21H19N2O4S [M + H]+:
395.1060, found: 395.1062.
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ne (4p)
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Yield: 59.2 mg (70%); time: 6 h; yellow solid; m.p. 171ꢀ173 oC; TLC, Rf = 0.30 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.42 (s, 1H), 8.11 (d, 2H, J = 8.4 Hz), 7.76 (d, 2H, J
= 7.6 Hz), 7.51 (t, 1H, J = 7.2 Hz), 7.41 (t, 2H, J = 7.2 Hz), 7.11(d, 2H, J = 8.8 Hz), 7.03 (d,
2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.8 Hz), 3.88 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 186.6, 164.1, 157.4, 137.5, 135.0, 131.9, 131.8, 131.1, 130.1, 128.3, 127.7, 55.7,
55.6; HRMS (ESI) m/z calcd for C22H21N2O5S [M + H]+: 425.1165, found: 425.1172.
(Z)-2-((4-(tert-Butyl)phenyl)sulfonyl)-2-(2-(4-methoxyphenyl)hydrazono)-1-phenyletha
none (4q)
o
Yield: 54.8 mg (61%); time: 6.5 h; yellow solid; m.p. 147ꢀ149 C; TLC, Rf = 0.24
1
(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.45 (s, 1H), 8.08 (d, 2H, J = 7.2 Hz),
7.78 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J = 7.2 Hz), 7.52 (t, 1H, J = 6.8 Hz), 7.41 (t, 2H, J =
13
7.2 Hz), 7.13 (d, 2H, J = 8.0 Hz), 6.89 (d, 2H, J = 8.0 Hz), 3.81 (s, 3H), 1.34 (s, 9H); C
NMR (CDCl3, 100 MHz): δ 186.5, 157.9, 157.3, 137.3, 134.9, 131.8, 130.1, 130.0, 128.4,
128.3, 128.0, 127.7, 127.6, 126.0, 125.9, 116.9, 116.7, , 55.5, 35.2, 31.0; HRMS (ESI) m/z
calcd for C25H27N2O4S [M + H]+: 451.1686, found: 451.1688.
(Z)-2-((4-Fluorophenyl)sulfonyl)-2-(2-(4-methoxyphenyl)hydrazono)-1-phenylethanone
(4r)
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o
Yield: 62.6 mg (76%); time: 5 h; yellow solid; m.p. 158ꢀ160 C; TLC, Rf = 0.29 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.43 (s, 1H), 8.20 (s, 2H), 7.77 (d, 2H, J = 6.8 Hz),
7.55ꢀ7.35 (m, 4H), 7.23 (d, 1H, J = 8.4 Hz), 7.13 (d, 2H, J = 8.0 Hz), 6.89 (d, 2H, J = 8.0
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Hz), 3.78 (s, 3H); C NMR (CDCl3, 100 MHz): δ 186.5, 166.1 (d, J = 255.4 Hz), 157.6,
137.2, 134.8, 132.1, 131.6 (d, J = 9.7 Hz), 130.1, 127.8, 117.0, 116.3 (d, J = 22.6 Hz), 115.0,
55.6; 19F NMR (CDCl3, 376 MHz): δ ꢀ63.17; HRMS (ESI) m/z calcd for C21H18FN2O4S [M
+ H]+: 413.0965, found: 413.0968.
(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-1-phenyl-2-((4-(trifluoromethyl)phenyl)sulfony
l)ethanone (4s)
o
Yield: 59.0 mg (64%); time: 10 h; yellow solid; m.p. 124ꢀ126 C; TLC, Rf = 0.36
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(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.47 (s, 1H), 8.30 (d, 2H, J = 8.4 Hz),
7.84 (d, 2H, J = 8.4 Hz), 7.77 (d, 2H, J = 7.2 Hz), 7.54 (t, 1H, J = 7.2 Hz), 7.43 (t, 2H, J =
7.2 Hz), 7.15 (d, 2H, J = 8.4 Hz), 6.91 (d, 2H, J = 8.4 Hz), 3.82 (s, 3H); 13C NMR (CDCl3,
100 MHz): δ 186.4, 157.8, 144.2, 137.0, 135.3 (q, J = 33.0 Hz), 134.7, 132.2, 130.1, 129.1,
19
127.9, 127.0 (q, J = 253.4 Hz), 126.1 (q, J = 3.6 Hz), 117.1, 115.0, 55.6; F NMR (CDCl3,
376 MHz): δ ꢀ63.18; HRMS (ESI) m/z calcd for C22H18F3N2O4S [M + H]+: 463.0934, found:
463.0939.
(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-1-phenyl-2-(thiophen-2-ylsulfonyl)ethanone
(4t)
o
Yield: 45.6 mg (57%); time: 8 h; yellow solid; m.p. 209ꢀ211 C; TLC, Rf = 0.22 (PE:EtOAc
1
= 9:1); H NMR (CDCl3, 400 MHz): δ 12.2 (s, 1H), 8.06 (dd, 1H, J = 3.6 Hz, J = 1.2 Hz),
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7.82 (s, 1H), 7.81 (s, 1H), 7.76 (dd, 1H, J = 4.8 Hz, J = 1.2 Hz), 7.54 (t, 1H, J = 7.2 Hz),
7.43 (t, 2H, J = 7.2 Hz), 7.17 (t, 1H, J = 9.2 Hz), 7.11 (d, 2H, J = 8.0 Hz), 6.89 (d, 2H, J =
8
9
13
8.8 Hz), 3.80 (s, 3H); C NMR (CDCl3, 100 MHz): δ 186.5, 157.6, 137.3, 135.7, 135.2,
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134.9, 132.1, 130.1, 127.8, 117.0, 115.0, 55.6; HRMS (ESI) m/z calcd for C19H17N2O4S2[M
+ H]+: 401.0624, found: 401.0613.
(Z)-2-(2-(4-Methoxyphenyl)hydrazono)-2-(naphthalen-2-ylsulfonyl)-1-phenylethanone
(4u)
o
Yield: 57.6 mg (65%); time: 8.5 h; yellow solid; m.p. 181ꢀ183 C; TLC, Rf = 0.33
(PE:EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.56 (s, 1H), 8.73 (s, 1H), 8.13 (dd, 1H,
J = 8.8 Hz, J = 1.6 Hz), 8.03 (q, 2H, J = 8.8 Hz), 7.92 (d, 1H, J = 8.0 Hz), 7.76 (d, 2H, J =
7.2 Hz), 7.68ꢀ7.60 (m, 2H), 7.50 (t, 1H, J = 7.2 Hz), 7.39 (t, 2H, J = 8.0 Hz), 7.16 (d, 2H, J
13
= 8.8 Hz), 6.91 (d, 2H, J = 8.8 Hz), 3.82 (s, 3H); C NMR (CDCl3, 100 MHz): δ 186.5,
157.6, 137.50, 137.36, 135.6, 135.0, 132.1, 132.0, 130.5, 130.1, 130.0, 129.8, 129.4, 129.1,
127.9, 127.7, 127.5, 123.1, 117.0, 115.0, 55.6; HRMS (ESI) m/z calcd for C25H21N2O4S [M
+ H]+: 445.1216, found: 445.1223.
(Z)-2-(Methylsulfonyl)-1-phenyl-2-(2-phenylhydrazono)ethanone (4v)
o
Yield: 38.8 mg (64%); time: 11 h; yellow solid; m.p. 153ꢀ155 C; TLC, Rf = 0.28
1
(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.28 (s, 1H), 7.90 (d, 2H, J = 8.8 Hz),
7.60 (t, 1H, J = 7.2 Hz), 7.49 (t, 2H, J = 7.2 Hz), 7.37ꢀ7.32 (m, 3H), 7.16ꢀ7.12 (m, 2H), 3.48
13
(s, 3H); C NMR (CDCl3, 100 MHz): δ 187.7, 141.0, 136.9, 132.5, 130.3, 129.7, 128.0,
125.5, 115.6, 45.6; HRMS (ESI) m/z calcd for C15H15N2O3S [M + H]+: 303.0798, found:
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303.0794.
(Z)-1-Phenyl-2-(2-phenylhydrazono)-2-tosylethanone (4w)
8
9
o
Yield: 53.0 mg (70%); time: 6 h; yellow solid; m.p. 183ꢀ185 C; TLC, Rf = 0.35 (PE:EtOAc
= 9:1); 1H NMR (CDCl3, 400 MHz): δ 12.43 (s, 1H), 8.05 (d, 2H, J = 6.8 Hz), 7.79 (d, 2H,
J = 8.0 Hz), 7.53 (t, 1H, J = 7.2 Hz), 7.43 (d, 2H, J = 6.8 Hz), 7.39ꢀ7.33(m, 4H), 7.17 (d, 3H,
J = 7.6 Hz), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 186.5, 145.4, 141.2, 137.3, 137.1,
132.1, 130.1, 129.66, 129.64, 129.0, 128.6, 127.8, 125.2, 115.5, 21.7; HRMS (ESI) m/z
calcd for C21H19N2O3S [M + H]+: 379.1110, found: 379.1118.
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(Z)-2-(2-(4-Chlorophenyl)hydrazono)-1-phenyl-2-tosylethanone (4x)
o
Yield: 51.0 mg (62%); time: 11 h; yellow solid; m.p. 187ꢀ189 C; TLC, Rf = 0.38
1
(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.38 (s, 1H), 8.04 (d, 2H, J = 8.0 Hz),
7.76 (d, 2H, J = 8.4 Hz), 7.54 (t, 1H, J = 7.6 Hz), 7.40 (q, 4H, J = 7.6 Hz), 7.32 (d, 2H, J =
8.8 Hz), 7.10 (d, 2H, J = 8.8 Hz), 2.45 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ 186.5, 145.6,
139.9, 137.1, 137.0, 132.3,130.3, 130.1, 129.7, 129.5, 128.9, 128.7, 127.9, 116.6, 21.8;
HRMS (ESI) m/z calcd for C21H18ClN2O3S [M + H]+: 413.0721, found: 413.0726.
(Z)-1-Phenyl-2-(2-(o-tolyl)hydrazono)-2-tosylethanone (4y)
o
Yield: 52.6 mg (67%); time: 7.5 h; yellow solid; m.p. 141ꢀ143 C; TLC, Rf = 0.32
1
(PE:EtOAc = 9:1); H NMR (CDCl3, 400 MHz): δ 12.63 (s, 1H), 8.06 (d, 2H, J = 8.4 Hz),
7.81 (d, 2H, J = 7.2 Hz), 7.56ꢀ7.49 (m, 1H), 7.45ꢀ7.35 (m, 4H), 7.22(t, 2H, J = 8.4 Hz), 7.17
13
(t, 1H, J = 7.6 Hz), 7.06 (t, 1H, J = 7.6 Hz), 2.46 (s, 3H), 2.45 (s, 3H); C NMR (CDCl3,
100 MHz): δ 186.6, 145.4, 139.4, 137.4, 137.2 132.1, 131.1, 130.2, 129.6, 129.4, 128.5,
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128.4, 128.1, 127.8, 127.5, 124.9, 124.6, 114.3, 21.7, 16.9; HRMS (ESI) m/z calcd for
C22H21N2O3S [M + H]+: 393.1267, found: 393.1269.
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Synthesis of 3-Sulfonylated Cinnolin-4(1H)-one 5 via Base-promoted Intramolecular
Cyclization
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To a solution of 4j (0.2 mmol, ) in 1 mL of EtOH was added 0.5 mL of 0.5 M aqueous
sodium carbonate (1.25 eq, 0.25 mmol) dropwise. The resulting mixture was then stirred at
reflux for 1 h. After completion of the reaction, EtOH was removed under vacuum, and the
residue was extracted by EtOAc (10 mL× 3), dried, concentrated and purified by column
chromatography (eluent: PE/EtOAc = 3:1) to afford 5.
o
Yield: 48.6 mg (60%); time: 1 h; yellow solid; m.p. 189ꢀ191 C; TLC, Rf = 0.37 (PE:EtOAc
1
= 7:3); H NMR (CDCl3, 400 MHz): δ 8.36 (d, 1H, J = 7.6 Hz), 8.15 (d, 2H, J = 8.4 Hz),
7.65 (t, 1H, J = 7.6 Hz), 7.50 (t, 1H, J = 7.6 Hz), 7.43 (d, 2H, J = 8.8 Hz), 7.35 (d, 2H, J =
8.0 Hz), 7.28 (s, 1H), 7.10 (d, 2H, J = 8.8 Hz), 3.93 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl3,
100 MHz): δ 165.9, 160.6, 144.8, 142.2, 136.4, 134.2, 134.1, 129.5, 129.4, 128.0, 127.3,
127.0, 126.0, 117.9, 115.1, 55.8, 21.7; HRMS (ESI) m/z calcd for C22H19N2O4S [M + H]+:
407.1060, found: 407.1063.
Supporting Information
Xꢀray crystallography data of 4d, Copies of 1H, and 13C NMR spectra.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No.
21502135) and Natural Science Foundation of Shanxi Province (No. 2015021037).
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(14) It was probably because the sulfonyl group is more electronꢀwithdrawing than carbonyl group,
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