Synthesis of benzofused five-ring sultams via Rh-catalyzed C-H olefination directed by an N -Ac-substituted sulfonamide group

Article abstract of DOI:10.1021/jo502224d

A Rh-catalyzed N-Ac-sulfonamide group directed C-H olefination-cyclization to afford benzofused five-ring sultam is described with high yield and a wide range of substrate scope. The N-acetyl group is a key for this transformation implying that N-H acidit

Full text of DOI:10.1021/jo502224d

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Article
Synthesis of benzofused five-ring sultams via Rh-catalyzed C-
H olefination directed by an N-Ac substituted sulfonamide group
Xueyuan LI, Yi Dong, Fengyu Qu, and Gang Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502224d • Publication Date (Web): 16 Dec 2014
Downloaded from http://pubs.acs.org on December 18, 2014
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Synthesis of benzofused five-ring sultams via Rh-catalyzed C-H
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olefination directed by an N-Ac substituted sulfonamide group
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Xueyuan Lia, Yi Dongb,c , Fengyu Qua,* and Gang Liub,c,*
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a College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, PR
China
b
TsinghuaꢀPeking Center for Life Sciences, School of Medicine, Tsinghua University, Haidian Dist.,
Beijing 100084, PR China.
c
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua
University, Haidian Dist., Beijing 100084, PR China.
* Corresponding author. Eꢀmail addresses: gangliu27@tsinghua.edu.cn, qufengyu@hrbnu.edu.cn
Abstract
A Rhꢀcatalyzed NꢀAcꢀsulfonamide group directed CꢀH olefinationꢀcyclization to
afford benzofused fiveꢀring sultam is described with high yield and wide range of
substrate scope. NꢀAcetyl group is a key for this transformation implying that NꢀH
acidity is the major influence. The acetyl group is removed under mild conditions in
excellent yield to provide NHꢀfree sultam that can be transformed into various
benzofused fiveꢀring sultam analogs via acylation, nucleophilic substitution,
Mitsunobu alkylation.
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Introduction
In the process of drug research, a satisfactory protocol to look for lead compounds
was identified to be basic and essential for. In the further, to build up diverse drugꢀlike
compound libraries rapidly, an effective synthetic method of privilegedꢀstructures
combined with advanced highꢀthroughput screening will facilitate the new drug
discovery. Benzofused fiveꢀring sultam was found in many biologically active
compounds such as selective CRTh2 antagonists, human leukocyte elastase inhibitors,
active saccharin and 5ꢀHT2 receptor antagonists [1] (Figure 1), therefore, it acted as an
important privilegedꢀstructure in drug discovery. Synthetic methods of benzofused
fiveꢀring sultam were reported only in a few articles until recently. In 2008, Hanson
and coworkers reported a cascade reaction to synthesize benzofused fiveꢀring sultam
in a parallel approach from 2ꢀbromobenzenesulfonamide via a Heck reaction (Scheme
1. eq (1)). [2]
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O
S
O
S
O
O
O
S
O
N
NH
N
O
OH
CN
O
HN
N
N
CO2H
F
Inhibitor of HCV NS5b
Human leukocyte elastase inhibitors
Selective CRTh2 antagonists
RNA-dependent RNA-polymerase
O
O
S
N
O
O
S
NH
O
O
S
3
N
N
O
N
OH
O
Active saccharin
HIV-1 inhibitor
5-HT2 receptor antagonist
F
Figure 1. Active benzofused fiveꢀring sultam analogues
In previous study, we first reported a Rhꢀcatalyzed ortho CꢀH olefination of arenas
directed by a sulfonic acid group to afford olefinated products, and then the
corresponding benzofused fiveꢀring sultam was prepared smoothly via a multiꢀstep
[3]
approach from this 2ꢀolefinated benzenesulfonic acid (Scheme 1. eq (2)).
This
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method was limited by a difficult preparation of sulfonamide via sulfonyl chloride
imtermediate. In order to improve synthetic efficiency, we assumed that the synthesis
of benzofused fiveꢀring sultam could be achieved by a sulfonamide group’s direction
via an ortho CꢀH olefination in oneꢀpot. Herein, we described an effective
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[4]
[5]
Rhꢀcatalyzed ortho CꢀH olefination directed by an NꢀAcꢀsulfonamide group
to
afford benzofused fiveꢀring sultams directly with good yields and a range of substrate
scopes. [6,7]
Scheme 1. Synthetic methods of benzofused fiveꢀring sultams
Results and Discussion
Initially, 2ꢀNꢀAc substituted 2ꢀmethylbenzenesulfonamide was selected as a model
substrate for exploiting this Rhꢀcatalyzed CꢀH activation in DMF at 100 ℃.
Fortunately, 79% yield of desired product was gained as expected when Cu(OAc)2
was used as an oxidant (Table 1, entry 1). Investigation of solvents proved that
toluene was ideal that the isolated yield reached 90% in comparison to DMF,
1,4ꢀdioxane and xylene (Table 1, entry1ꢀ4). This Rhꢀcatalyzed reaction showed great
dependence on oxidants obviously. The use of AgOAc led to a slightly decrease yield
(Table 1, entry 5), and no desired sultam was detected by LCꢀMS analysis when O2 or
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BQ were used as oxidants (Table 1, entry 6 and 7). Catalysts screening showed that
only [RhCp*Cl2]2 gave a satisfactory result, [Rh(OAc)2]2, [Rh(CO)Cl]2 and
Rh(NH4)3Cl6 were not effective (Table 1, entry 8~10).
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Under optimal condition, we investigated the replacements (R1) of 2ꢀNꢀAc substituted
group considering acidic influence on NꢀH bond for CꢀH activation and further
cyclization (Table 1). A lower yield (31%) was received when R1 was hydrogen
substitution (Entry 14) implying that the NꢀH acidity was important. Further
Nꢀmethylated or Nꢀphenylated derivative resulted in no desired product completely.
These observations indicated that the NꢀH acidity (entry 15, 16) contributed
significantly. To further understand, acetyl (entry 3), methyloxycarbonyl (entry 12),
trifluoroacetyl (entry 13), and Boc group (entry 11) were introduced. The yields were
90%, 52%, 0%, and 0% respectively.
Table 1. Rhꢀcatalyzed CꢀH olefination of NꢀAc substituted benzenesulfonamide
analogues with butyl acrylate to afford benzofused fiveꢀring sultama
Entry
R
[Rh]
Oxidant
Solvent
Yield(%)b
79
1
2
3
4
5
6
7
8
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
[RhCp*Cl2]2 Cu(OAc)2 DMF
[RhCp*Cl2]2 Cu(OAc)2 1,4ꢀdioxane 71
[RhCp*Cl2]2 Cu(OAc)2 toluene
90
88
80
0
[RhCp*Cl2]2 Cu(OAc)2 xylene
[RhCp*Cl2]2 AgOAc
[RhCp*Cl2]2 O2
toluene
toluene
toluene
[RhCp*Cl2]2 BQ
0
[Rh(CO) Cl]2 Cu(OAc)2 toluene
5
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Ac
[Rh(OAc) 2]2 Cu(OAc)2 toluene
Rh(NH4)3Cl6 Cu(OAc)2 toluene
[RhCp*Cl2]2 Cu(OAc)2 toluene
0
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Ac
0
Boc
0
Methoxycarbonyl [RhCp*Cl2]2 Cu(OAc)2 toluene
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0
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Trifluoroacetyl
[RhCp*Cl2]2 Cu(OAc)2 toluene
[RhCp*Cl2]2 Cu(OAc)2 toluene
[RhCp*Cl2]2 Cu(OAc)2 toluene
[RhCp*Cl2]2 Cu(OAc)2 toluene
H
31
0
CH3
Ph
0
a Reaction condition: Nꢀsubstituted 2ꢀmethylbenzenesulfonamide (0.5 mmol), Butyl
acrylate (2.0 equiv), Rh catalyst (2.5 mol%), oxidant (2.0 equiv), solvent (2.0 mL),
100℃. b Isolated yield.
The scope of benzene substitution (R2) is outlined in Table 2. All tested substituents
were tolerant in these transformations, i.e. all electronꢀrich or electronꢀpoor
substitutions on both ortho and meta positions gave good yields (compounds 1ꢀ10). It
should note that, regardless electronꢀrich or electronꢀpoor substitutions introduced,
paraꢀsubstituted benzenesulfonamide also resulted in a 2ꢀolefinated benzofused
fiveꢀring sultam in excellent yield when the amount of butyl acrylate was slightly
improved to 2.5 equivalents, such as compounds 11 and 12. To our delight,
multiꢀsubstituted substrates were able to offer the desired benzofused fiveꢀring
sultams (4-10) via this CꢀH activation by NꢀAcꢀsulfonamide direction. Some
electronꢀwithdrawing functional groups such as NO2, CN were investigated, but no
desired olefinationꢀMichael addition occurred.
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Table 2. The benzene ring’s scope (R2) for synthesis of benzofused fiveꢀring sultamsa
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O
O
O O
S
[RhCp*Cl2]2 (2.5 mol%)
Cu(OAc)2 (2.0 equiv)
OBun
S
Ac
R2
N Ac
O
N
R2
+
H
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toluene, 100 C
O
OBun
MeO
O
O
F
O
O
O
O
O
S
S
S
N Ac
O
N Ac
N Ac
O
O
OBun
OBun
OBun
1, 90%
2, 86%
OMe
3, 75%
OMe
O
O
O
O
O
O
S
S
S
N Ac
O
N Ac
O
N Ac
O
MeO
OBun
OBun
OBun
6, 95%
4, 88%
5, 90%
OMe
O
O
O
O
O
S
O
Cl
S
S
N Ac
N Ac
O
N Ac
O
O
F
OMe
OBun
OBun
OBun
7,92%
8, 86%
9, 77%
O
OBun
O
OBun
O
O
O
O
O
O
S
S
S
N Ac
O
N Ac
N Ac
O
MeO
Cl
O
O
OBun
11, 91%b
OBun
OBun
12, 86%b
10, 74%
aReaction condition: NꢀAcꢀbenzenesulfonamide derivatives (0.5 mmol), Butyl
acrylate (2.0 equiv), [RhCp*Cl2]2 (2.5 mol%), Cu(OAc)2 (2.0 equiv), toluene (2.0
mL), 100℃. b 2.5 equiv butyl acrylate was used. Isolated yield.
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Under the optimal condition, we continuously investigated various α, βꢀunsaturated
carbonyl reagents (R3). Acrylic acid esters were proved to be ideal substrates （Table
3）, whereby all esters used, including benzyl (13), tetrahydrofurfuryl (14), tertiary
butyl (15) and methyl (16) esters, were conveniently tolerated in these transformations.
The using of ethyl vinyl ketone (17) in this reaction gave a moderate yield because a
nonꢀcyclic olefinated side product (17’) was observed in 46% yield. Lastly,
acrylamides derivatives (18ꢀ21) worked well in this method. All above results
illustrated that this new NꢀAcꢀsulfonamideꢀdirected CꢀH activation were very
effective to synthesize benzofused fiveꢀring sultams with high substituent’s scopes.
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Table 3. The α, βꢀunsaturated carbonyl reagent scope (R3) for synthesis of benzofused
fiveꢀring sultams a
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O
O
O O
S
S
[RhCp*Cl2]2 (2.5 mol%)
Cu(OAc)2 (2.0 equiv)
R3
Ac
N Ac
O
N
+
H
7
O
toluene, 100 C
8
9
R3
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O
O
O
O
O
O
S
S
S
N Ac
N Ac
O
N Ac
O
O
O
O
O
O
13, 85%
14, 86%
15, 82%
O
O
S
O
O
O
O
O O
S
S
S
Ac
N Ac
O
N Ac
O
N
N Ac
O
H
O
N
O
17', 46%
18, 75%
17, 51%
16, 87%
O
O
O
S
O
O
S
O
S
N Ac
O
N Ac
N Ac
O
N
O
N
HN
O
O
19, 61%
20, 78%
21, 93%
aReaction condition: NꢀAc 2ꢀmethylbenzenesulfonamide (0.5 mmol), α, βꢀunsaturated
carbonyl reagents (2.0 equiv), [RhCp*Cl2]2 (2.5 mol%), Cu(OAc)2 (2.0 equiv),
toluene (2.0 mL), 100℃. Isolated yield.
As expected, NꢀAc group was easily removed under 1.1 equiv K2CO3 in a mixture
solvent of nꢀbutyl alcohol and water (v:v = 20:1) at 60℃ for 5 h that provided 22
(Scheme 2). Compound 22 was further carried out acylation, nucleophilic substitution,
and Mitsunobu alkylation (Table 4). Nꢀmethyl product (23), Nꢀbenzyl (24), Nꢀallyl (25)
were gained by nucleophilic substitution, respectively, with 80%, 86% and 85% yields
in DMF at room temperature when 1.5 equiv methyl iodide, benzyl bromide and allyl
bromide were used. When 4ꢀfluorobenzoyl chloride, 4ꢀ(trifluoromethyl)benzoyl
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chloride and methanesulfonyl chloride were employed for acylation, products of
acylation (26, 27 and 28) were prepared with 83%, 77%, 84% yields. Nꢀethyl (30) or
Nꢀbutyryl product (31) was obtained with excenllent yields via Mitsunobu reaction in
the present of DEAD, PPh3 and corresponding alcohol. Interestingly,
ethoxycarbonation occurred to afford compound 29 with an excellent yield without
alcohol. Compound 22 could also transform to Nꢀolefinated product (32) in 98% yield
via Michael addition with ethyl propiolate.
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Scheme 2. Removal of NꢀAc group
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Table 4 Diversity investigation of compound 22
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6
7
8
O
O
O
O
S
S
conditions a~e
NH
N R4
O
O
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17
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22
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OBun
OBun
O
O
O
O
O
O
S
S
Ph
S
N
N Allyl
N
nBuO2C
nBuO2C
nBuO2C
24, 86%, (a), X = Br
23,80%, (a), X = I
25, 85%, (a), X = Br
O
O
S
O
O
S
O
O
S
O
O
N
N
N Ms
nBuO2C
26, 83%, (b)
nBuO2C
nBuO2C
28, 84%, (b)
F
CF3
27, 77%, (b)
O
O
O
O
O
O
O
S
N
O
O
S
S
S
N
N
N
OEt
CO2Et
nBuO2C
30, 92%, (c)
nBuO2C
29, 98% (d)
nBuO2C
31, 90%, (c)
nBuO2C
32, 98% (E/Z = 2.9:1), (e)
Condition: a) K2CO3, RꢀX, DMF, r.t. b) Et3N, RCO(Cl) or MsCl, Dichloromethane r.t.
,
c) DEAD, PPh3, ROH, THF, r.t. d) DEAD, PPh3, THF, r.t. e) Nꢀmethyl morpholine,
Ethyl propiolate, Dichloromethane, r.t.
A proposed mechanism was described in Scheme 3. Introducing NꢀAc group
increased acidity of NꢀH bond, which promoted the formation of intermediate A
assisted by OAcꢀ. Then ortho deprotonation generated intermediate B. Subsequently
coordinated with alkene, followed by 1,2ꢀmigratory insertion occurred to give
intermediate C. βꢀH elimination of intermediate C gave the intermediate D, which
underwent reductive elimination to provided olefinated product E and Rh(I). In final,
Michael addition resulted in the desired sultam under current neutral condition and
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100 degree temperature,[8] and Rh (I) was oxidized to form Rh (III) by Cu(II) for next
catalytic cycle.
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Scheme 3. Proposed mechanism of benzofused fiveꢀring sultam formation
Conclusion
In summary, a new and efficient synthesis of benzofused fiveꢀring sultam was
described in this paper. A broad substrate scopes and good yields made this method
more effective to synthesize sultam analogues. This tandem process of ortho CꢀH
olefination/intramolecular Michael addition was very smooth that allowed introducing
various substituents of benzofused fiveꢀring sultam. Obviously, acetyl group was the
key of this transformation implying that NꢀH acidity played the major influence.
Acetyl group was removed easily under a mild condition to generate an Nꢀfree sultam.
Nꢀfree sultam derivations were performed via acylation, nucleophilic substitution, and
Mitsunobu alkylation. Impressively, diverse library of benzofused fiveꢀring sultam
analogues could be built rapidly by this new method, which would benefit from
pharmacological activity screening in sultams drug discovery.
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Experimental Section
General procedure for Rh-Catalyzed olefination of N-Ac substituted
benzenesulfonamide and butyl acrylate: a 10 mL sealed tube equipped with a
magnetic stir bar was charged with [RhCp*Cl2]2 (7.7 mg, 2.5 mol%), Cu(OAc)2 (181
mg, 1.0 mmol), NꢀAc substituted 2ꢀmethylbenzenesulfonamide (107 mg, 0.5 mmol)
and 2.0 mL toluene. The mixture was stirred, and then butyl acrylate (1 mmol) was
added. The reaction tube was capped and stirred at 100 °C. The reaction was
monitored by LC–MS. When the starting material was consumed completely, solvent
was removed under vacuum. The reaction mixture was diluted with ethyl acetate, then
washed with 2 N HCl aqueous solution (2 × 20 mL). Subsequently, the mixture was
extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed
with brine (20 mL) and then dried over anhydrous sodium sulfate. The organic solvent
was removed on a rotary evaporator in vacuo. The residue was purified by preparative
TLC on silica gel (EtOAc: Petroleum ether = 1:5, Rf = 0.3) to afford 1 153 mg (90%
yield) as a white powder.
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Compound 1 (153 mg, 90% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz,
1H), 7.35 (t, J = 7.4 Hz, 2H), 5.68 (dd, J = 7.7 Hz, 3.2 Hz, 1H), 4.08 (t, J = 6.7 Hz,
2H), 3.15 (dd, J = 15.9 Hz, 3.3 Hz, 1H), 2.92 (dd, J = 15.9 Hz, 7.8 Hz, 1H), 2.66 (s,
3H), 2.62 (s, 3H), 1.58 – 1.51 (m, 2H), 1.33 – 1.24 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ 169.8, 167.7, 135.4, 135.0, 134.3, 132.3, 131.6, 122.2,
65.1, 55.1, 39.4, 30.6, 23.8, 19.2, 17.1, 13.8. HRMS (ESI): m/z (M + Na+) calcd for
C16H21O5NNaS, 362.1033, found: 362.1024.
Compound 2 ~ 21 were synthesized according to synthesis of compound 1.
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Compound 2 (165 mg, 86% yield):: 1H NMR (400 MHz, CDCl3) δ 8.24ꢀ8.22 (m, 1H),
7.81 (dt, J = 15.3 Hz, 7.5 Hz, 2H), 5.73 (dd, J = 7.9 Hz, 3.1 Hz, 1H), 4.08 (t, J = 6.7
Hz, 2H), 4.05 (s, 3H), 3.18 (dd, J = 16.1 Hz, 3.2 Hz, 1H), 2.94 (dd, J = 16.1 Hz, 7.9
Hz, 1H), 2.64 (s, 3H), 1.58 – 1.51 (m, 2H), 1.34 – 1.23 (m, 2H), 0.89 (t, J = 7.4 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 169.8, 167.9, 163.1, 137.5, 134.2 (2xC), 132.2,
129.7, 126.9, 65.2, 54.2, 53.3, 39.3, 30.5, 23.8, 19.1, 13.8. HRMS (ESI): m/z (M + H+)
calcd for C17H22O7NS, 384.1111, found: 384.1105.
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Compound 3 (129 mg, 75% yield): 1H NMR (400 MHz, CDCl3) δ 7.69 (td, J = 8.1 Hz,
5.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.29 – 7.24 (m, 1H), 5.74 (dd, J = 8.0 Hz, 3.0
Hz, 1H), 4.09 (t, J = 6.7 Hz, 2H), 3.18 (dd, J = 16.2 Hz, 3.2 Hz, 1H), 2.95 (dd, J =
16.2 Hz, 8.1 Hz, 1H), 2.61 (s, 3H), 1.59 – 1.52 (m, 2H), 1.34 – 1.25 (m, 2H), 0.90 (t, J
= 7.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.6, 167.3, 156.6 (d , J = 259.1 Hz)
138.0, 136.8 (d, J = 7.4 Hz), 122.1 (d, J = 17.9 Hz), 120.8 (d, J = 3.9 Hz), 116.9 (d, J
= 17.7 Hz), 65.3, 55.6, 39.1, 30.6, 23.8, 19.2, 13.8. HRMS (ESI): m/z (M + H+) calcd
for C15H19O5FNS, 344.0968, found: 344.0971.
Compound 4 (155 mg, 88% yield): 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 2.2 Hz,
2H), 5.62 (dd, J = 7.7 Hz, 3.3 Hz, 1H), 4.09 (td, J = 6.7 Hz, 1.7 Hz, 2H), 3.13 (dd, J =
15.9 Hz, 3.4 Hz, 1H), 2.91 (dd, J = 15.9 Hz, 7.7 Hz, 1H), 2.61 (s, 6H), 2.41 (s, 3H),
1.59 – 1.52 (m, 2H), 1.34 – 1.25 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 169.9, 167.7, 145.5, 135.7, 134.7, 132.6, 129.6, 122.4, 65.1, 55.0,
39.5, 30.6, 23.7, 21.9, 19.2, 17.0, 13.8. HRMS (ESI): m/z (M + H+) calcd for
C17H24O5NS, 354.1370, found: 354.1366.
Compound 5 (166 mg, 90% yield): 1H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 6.78
(s, 1H), 5.61 (dd, J = 7.8 Hz, 3.3 Hz, 1H), 4.10 (td, J = 6.6 Hz, 1.8 Hz, 2H), 3.99 (s,
3H), 3.12 (dd, J = 15.9 Hz, 3.4 Hz, 1H), 2.89 (dd, J = 15.9 Hz, 7.8 Hz, 1H), 2.59 (s,
3H), 2.44 (s, 3H), 1.60 – 1.50 (m, 2H), 1.36 – 1.26 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 169.9, 167.8, 155.4, 148.1, 137.5, 118.9, 116.6, 112.4,
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65.1, 56.4, 55.0, 39.4, 30.6, 23.7, 22.6, 19.2, 13.8. HRMS (ESI): m/z (M + H+) calcd
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for C17H24O6NS, 370.1319, found: 370.1315.
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Compound 6 (183 mg, 95% yield): 1H NMR (400 MHz, CDCl3) δ 6.54 (d, J = 1.3 Hz,
1H), 6.47 (d, J = 1.7 Hz, 1H), 5.60 (dd, J = 8.1 Hz, 3.3 Hz, 1H), 4.10 (t, J = 6.7 Hz,
2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.15 (dd, J = 16.1 Hz, 3.3 Hz, 1H), 2.85 (dd, J = 16.1
Hz, 8.2 Hz, 1H), 2.58 (s, 3H), 1.61 – 1.54 (m, 2H), 1.36 – 1.23 (m, 2H), 0.90 (t, J =
7.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.9, 167.5, 166.4, 156.6, 139.2, 114.0,
99.7, 99.5, 65.0, 56.4, 56.0, 54.9, 39.3, 30.5, 23.5, 19.0, 13.6. HRMS (ESI): m/z (M +
H+) calcd for C17H24O7NS, 386.1268, found: 386.1263.
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Compound 7 (177 mg, 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.9 Hz,
1H), 6.93 (d, J = 8.9 Hz, 1H), 5.55 (t, J = 4.2 Hz, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.91 (s,
2H), 3.85 (s, 2H), 3.22 (dd, J = 14.8 Hz, 4.8 Hz, 1H), 3.07 (dd, J = 14.8 Hz, 3.7 Hz,
1H), 2.56 (s, 3H), 1.48 – 1.38 (m, 2H), 1.24 – 1.15 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 169.3, 167.6, 148.7, 148.3, 124.4, 122.6, 116.7, 112.5,
64.7, 56.6, 56.3, 54.0, 36.2, 30.4, 23.5, 19.0, 13.7. HRMS (ESI): m/z (M + Na+) calcd
for C17H23NNaO7S, 408.1093, found: 408.1093
Compound 8 (160 mg, 86% yield): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz,
1H), 7.35 (d, J = 8.3 Hz, 1H), 5.63 (dd, J = 7.9 Hz, 3.2 Hz, 1H), 4.08 (t, J = 6.7 Hz,
2H), 3.14 (dd, J = 16.1 Hz, 3.3 Hz, 1H), 2.91 (dd, J = 16.1 Hz, 7.9 Hz, 1H), 2.67 (s,
3H), 2.61 (s, 3H), 1.58 – 1.51 (m, 3H), 1.33 – 1.24 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 169.6, 167.4, 136.5, 134.9, 134.0, 133.9, 132.9, 123.3,
65.2, 54.4, 39.0, 30.5, 23.7, 19.1, 14.7, 13.7. HRMS (ESI): m/z (M + Na+) calcd for
C16H20ClNNaO5S, 396.0648, found: 396.0649
Compound 9 (137 mg, 77% yield): 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 8.3
Hz, 4.3 Hz, 1H), 7.19 (t, J = 8.7 Hz, 1H), 5.58 (d, J = 4.0 Hz, 1H), 5.14 – 5.10 (m,
1H), 4.16 (t, J = 6.7 Hz, 2H), 3.12 (dd, J = 17.0 Hz, 2.5 Hz, 1H), 2.74 (dd, J = 17.0 Hz,
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10.6 Hz, 1H), 2.60 (s, 3H), 1.67 – 1.60 (m, 2H), 1.43 – 1.33 (m, 2H), 0.94 (t, J = 7.4
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 168.9, 167.6, 155.9 (d, J = 250.2 Hz), 134.1
(d, J = 3.9 Hz), 133.6 (d, J = 6.5 Hz), 130.7 (d, J = 4.4 Hz), 122.5 (d, J = 19.1 Hz),
120.7 (d, J = 19.7 Hz), 65.1, 53.0, 36.9, 30.4, 23.6, 19.1, 16.4, 13.8. HRMS (ESI): m/z
(M + Na+) calcd for C16H20FNNaO5S, 380.0944, found: 380.0934
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Compound 10 (143 mg, 74% yield): 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 5.72
– 5.70 (m, 1H), 4.04 (td, J = 6.7 Hz, 1.8 Hz, 2H), 3.08 (dd, J = 15.3 Hz, 3.5 Hz, 1H),
2.80 (dd, J = 15.3 Hz, 5.2 Hz, 1H), 2.60 (s, 6H), 2.40 (s, 3H), 1.58 – 1.48 (m, 2H),
1.33 – 1.24 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.3,
167.5, 141.0, 135.1, 133.4, 132.5, 131.4, 130.0, 65.3, 55.2, 38.8, 30.5, 23.7, 19.2, 16.5,
15.5, 13.8. HRMS (ESI): m/z (M + Na+) calcd for C17H22ClNNaO5S, 410.0805, found:
410.0804
Compound 11 (212 mg, 91% yield):1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 15.9
Hz, 1H), 7.56 (s, 1H), 7.35 (s, 1H), 6.63 (d, J = 15.9 Hz, 1H), 5.66 (dd, J = 7.7 Hz, 3.2
Hz, 1H), 4.24 (t, J = 6.7 Hz, 2H), 4.09 (t, J = 6.6 Hz, 2H), 3.15 (dd, J = 16.0 Hz, 3.3
Hz, 1H), 2.94 (dd, J = 16.0 Hz, 7.8 Hz, 1H), 2.61 (s, 3H), 2.48 (s, 3H), 1.75 – 1.68 (m,
2H), 1.60 – 1.50 (m, 2H), 1.48 – 1.40 (m, 2H), 1.33 – 1.26 (m, 2H), 0.97 (t, J = 7.4 Hz,
3H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.8, 167.5, 165.7,
145.7, 136.4, 135.8, 131.1, 129.8, 128.9, 126.2, 124.7, 65.2, 65.1, 54.9, 39.3, 30.8,
30.6, 23.8, 22.0, 19.3, 19.2, 13.9, 13.8. HRMS (ESI): m/z (M + H+) calcd for
C23H32O7NS, 466.1894, found: 466.1890.
Compound 12 (219 mg, 86% yield): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.17
(s, 1H), 8.07 (d, J = 15.9 Hz, 1H), 7.26 (s, 1H), 6.74 (d, J = 15.9 Hz, 1H), 5.73 (d, J =
4.4 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.08 (t, J = 6.7 Hz, 2H), 4.00 (s, 3H), 3.17 (dd, J
= 15.9 Hz, 2.8 Hz, 1H), 3.03 (dd, J = 16.1 Hz, 7.5 Hz, 1H), 2.63 (s, 3H), 1.75 – 1.68
(m, 2H), 1.56 – 1.51 (m, 2H), 1.48 – 1.40 (m, 2H), 1.32 – 1.25 (m, 2H), 0.97 (t, J =
7.4 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.4, 167.3,
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165.4, 164.7, 136.6, 136.0, 135.5, 134.7, 131.9, 129.0, 126.6, 126.0, 65.4, 65.3, 55.1,
53.3, 38.9, 30.8, 30.6, 23.9, 19.3, 19.2, 13.9, 13.8. HRMS (ESI): m/z (M + H+) calcd
for C24H32O9NS, 510.1792, found: 510.1789.
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Compound 13 (159 mg, 85% yield): 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 7.7 Hz,
1H), 7.36 – 7.30 (m, 3H), 7.28 – 7.22 (m, 4H), 5.68 (dd, J = 7.6 Hz, 3.4 Hz, 1H), 5.14
– 5.07 (m, 2H), 3.19 (dd, J = 15.8 Hz, 3.5 Hz, 1H), 2.98 (dd, J = 15.8 Hz, 7.7 Hz, 1H),
2.63 (s, 3H), 2.59 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 169.5, 167.7, 135.4, 135.2,
135.0, 134.3, 132.2, 131.7, 128.7 (2xC), 128.6 (2xC), 128.5, 122.1, 67.1, 55.1, 39.4,
23.7, 17.1. HRMS (ESI): m/z (M + H+) calcd for C19H20O5NS, 374.1057, found:
374.1053.
Compound 14 (158 mg, 86% yield):1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.7 Hz,
1H), 7.39 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 5.69 (dd, J = 7.7 Hz, 3.3 Hz,
1H), 4.18 – 4.15 (m, 1H), 4.11 – 4.00 (m, 2H), 3.88 – 3.73 (m, 2H), 3.20 (dt, J = 16.0
Hz, 3.4 Hz, 1H), 2.99 – 2.91 (m, 1H), 2.66 (s, 3H), 2.62 (s, 3H), 2.00 – 1.84 (m, 3H),
1.59 – 1.51 (m, 1H). 13C NMR (150 MHz, CDCl3) δ 169.8, 167.7, 135.3, 135.0, 134.4,
132.2, 131.7, 122.3, 76.3, 68.5, 67.2, 55.0, 39.4, 28.1, 25.8, 23.8, 17.1. HRMS (ESI):
m/z (M + H+) calcd for C17H22O6NS, 368.1162, found: 368.1160.
Compound 15 (139 mg, 82% yield): 1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.7 Hz,
1H), 7.40 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 5.66 (dd, J = 8.2 Hz, 3.2 Hz,
1H), 3.12 (dd, J = 15.9 Hz, 3.3 Hz, 1H), 2.77 (dd, J = 15.9 Hz, 8.2 Hz, 1H), 2.66 (s,
3H), 2.62 (s, 3H), 1.40 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 169.1, 167.6, 135.7,
135.0, 134.2, 132.2, 131.5, 122.3, 81.9, 55.2, 40.5, 28.1 (3xC), 23.8, 17.0. HRMS
(ESI): m/z (M + Na+) calcd for C16H21O5NNaS, 362.1033, found: 362.1027.
Compound 16 (129 mg, 87% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz,
1H), 7.34 (d, J = 7.9 Hz, 2H), 5.68 (dd, J = 7.7 Hz, 3.5 Hz, 1H), 3.68 (s, 3H), 3.15 (dd,
J = 16.0 Hz, 3.5 Hz, 1H), 2.92 (dd, J = 16.0 Hz, 7.7 Hz, 1H), 2.66 (s, 3H), 2.62 (s,
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3H). 13C NMR (150 MHz, CDCl3) δ 170.2, 167.7, 135.3, 135.1, 134.3, 132.3, 131.7,
122.1, 55.0, 52.2, 39.2, 23.8, 17.1. HRMS (ESI): m/z (M + Na+) calcd for
C13H15O5NNaS, 320.0563, found: 320.0558.
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Compound 17 (75 mg, 51% yield): 1H NMR (400 MHz, CDCl3) δ 7.52 (t, J = 7.7 Hz,
1H), 7.35 – 7.31 (m, 2H), 5.78 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 3.33 (dd, J = 17.6 Hz, 2.7
Hz, 1H), 2.87 (dd, J = 17.6 Hz, 8.7 Hz, 1H), 2.65 (s, 3H), 2.61 (s, 3H), 2.53 – 2.43 (m,
1H), 2.40 – 2.30 (m, 1H), 1.07 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
208.0, 167.5, 136.4, 134.9, 134.4, 132.0, 131.5, 122.7, 54.3, 47.4, 36.6, 23.8, 17.1, 7.7.
HRMS (ESI): m/z (M + H+) calcd for C14H18O4NS, 296.0951, found: 296.0948.
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Compound 18 (116 mg, 75% yield): H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.9
Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 5.87 (dd, J = 9.5 Hz, 2.3
Hz, 1H), 3.24 (dd, J = 16.0 Hz, 2.4 Hz, 1H), 2.97 (s, 3H), 2.91 (s, 3H), 2.70 – 2.63 (m,
4H), 2.61 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 169.1, 167.4, 136.6, 134.6, 134.3,
132.0, 131.4, 123.6, 55.5, 39.0, 37.3, 35.6, 23.9, 17.1. HRMS (ESI): m/z (M + H+)
calcd for C14H19O4N2S, 311.1060, found: 311.1056.
Compound 19 (112 mg, 61% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz,
1H), 7.43 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 6.28ꢀ6.07 (m, 1H), 5.70 (td, J
= 8.6 Hz, 2.9 Hz, 1H), 4.63ꢀ4.56 (m, 1H), 3.80 – 3.71 (m, 3H), 3.19ꢀ3.11 (m, 1H),
2.77 – 2.59 (m, 6H), 1.39 (dd, J = 7.2 Hz, 1.6 Hz, 3H). 13C NMR (150 MHz, CDCl3)
173.3, 168.3, 167.9, 135.6, 134.9, 134.4, 132.8, 131.6, 122.8, 55.7, 52.7, 48.3, 41.5,
23.8, 18.5, 17.1. HRMS (ESI): m/z (M + H+) calcd for C16H21O6N2S, 369.1115, found:
369.1114.
Compound 20 (151 mg, 78% yield): 1H NMR (400 MHz, CDCl3) δ 7.67ꢀ7.59 (m, 1H),
7.57ꢀ7.47 (m, 1H), 7.35ꢀ7.20 (m, 5H), 7.06ꢀ7.01 (m, 1H), 5.97ꢀ5.90 (m, 1H),
4.71ꢀ4.37 (m, 2H), 3.37ꢀ3.29 (m, 1H), 2.99ꢀ2.58 (m, 10H), 13C NMR (150 MHz,
CDCl3) δ 167.1, 166.6, 137.2, 136.7, 129.0, 128.7, 128.3(2xC), 128.2, 128.1,
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127.7(2xC), 127.4, 126.5, 53.5, 51.1, 40.0, 34.9, 34.1, 29.8. HRMS (ESI): m/z (M +
H+) calcd for C20H23O4N2S, 387.1373, found: 387.1370.
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Compound 21(215 mg, 93% yield): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz,
1H), 7.52 (t, J = 7.7 Hz, 1H), 7.34 – 7.24 (m, 7H), 7.21 (d, J = 6.6 Hz, 2H), 7.00 (d, J
= 6.3 Hz, 2H), 5.98 (dd, J = 9.2 Hz, 2.2 Hz, 1H), 4.62 (s, 2H), 4.34 (s, 2H), 3.38 (dd, J
= 15.9 Hz, 2.6 Hz, 1H), 2.80 (dd, J = 15.9 Hz, 9.4 Hz, 1H), 2.63 (s, 3H), 2.57 (s,
3H).13C NMR (150 MHz, CDCl3) δ 169.8, 167.4, 137.0, 136.5, 135.8, 134.8, 134.2,
132.1, 131.5, 129.1 (2xC), 128.8 (2xC), 128.5 (2xC), 127.9, 127.7, 126.5 (2xC), 123.4,
55.6, 50.0, 48.4, 38.8, 23.9, 17.1. HRMS (ESI): m/z (M + H+) calcd for C26H27O4N2S,
463.1686, found: 463.1682.
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Synthesis of compound 22:
K2CO3 (1.1 equiv, 46 mg) was added to a solution of compound 1 (0.3 mmol, 80 mg)
n
in 5 mL BuOH/H2O(v/v = 20/1), and the reaction mixture was heated to 60℃ and
monitored by LCꢀMS until all of the starting material was consumed completely.
Solvent was removed in vacuo, and the residue was diluted with 10 mL ethyl acetate,
washed with 10 mL water, and extracted with ethyl acetate for two times. Then the
organic phase was combined, washed with brine and dried over anhydrous Na2SO4.
The organic layer was concentrated, and purified with column chromatography on
silica gel to afford 63 mg white solid (94% yield).
Compound 22 (63 mg, 94% yield): 1H NMR (400 MHz, CDCl3) δ 7.51 (t, J = 7.6 Hz,
1H), 7.30 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 5.44 (s, 1H), 5.04 (d, J = 9.9
Hz, 1H), 4.16 (t, J = 6.7 Hz, 3H), 2.96 (dd, J = 16.9 Hz, 3.4 Hz, 1H), 2.77 (dd, J =
16.9 Hz, 10.0 Hz, 1H), 2.65 (s, 3H), 1.66 – 1.59 (m, 2H), 1.42 – 1.33 (m, 2H), 0.94 (t,
J = 7.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 171.0, 138.4, 134.9, 134.2, 133.4,
131.3, 121.2, 65.5, 53.2, 40.6, 30.7, 19.2, 17.1, 13.8. HRMS (ESI): m/z (M + H+)
calcd for C14H20O4NS, 298.1108, found: 298.1105.
Synthesis of compound 23~25:
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General synthetic procedure of compound 23~25: K2CO3 (2.0 equiv, 27.6 mg) and
RꢀX (1.5 equiv) was added to a solution of compound 22 (0.1 mmol, 30 mg) in 1 mL
DMF, the reaction mixture was stirred at room temperature and monitored by LCꢀMS
until all of the starting material was consumed completely. Solvent was removed in
vacuo, and the residue was diluted with 10 mL ethyl acetate, washed with 10 mL
water, and extracted with ethyl acetate for two times. Then the organic phase was
combined, washed with brine and dried over anhydrous Na2SO4. The organic layer
was concentrated, and purified with column chromatography on silica gel (EtOAc/
petroleum ether) to afford colorless oil.
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Compound 23 (25 mg, 80% yield): 1H NMR (400 MHz, CDCl3) δ 7.48 (t, J = 7.7 Hz,
1H), 7.28 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 4.73 (t, J = 5.9 Hz, 1H), 4.14 (t,
J = 6.7 Hz, 2H), 2.96 – 2.90 (m, 4H), 2.80 (dd, J = 16.3 Hz, 6.0 Hz, 1H), 2.66 (s, 3H),
1.60 (dt, J = 14.6, 6.8 Hz, 2H), 1.33 (dq, J = 14.7 Hz, 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 170.7, 137.6, 134.6, 133.0 (2xC), 131.1, 121.3,
65.3, 59.4, 39.3, 30.6, 29.5, 19.2, 17.1, 13.8. HRMS (ESI): m/z (M + Na+) calcd for
C15H21NNaO4S, 334.1089, found: 334.1088
Compound 24 (33 mg, 86% yield): 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.9 Hz,
3H), 7.34 – 7.27 (m, 4H), 7.15 (d, J = 7.7 Hz, 1H), 4.78 (t, J = 5.9 Hz, 1H), 4.63 (d,
15.7 Hz, 1H), 4.51 (d, 15.7 Hz, 1H), 4.04 – 3.93 (m, 2H), 2.85 (dd, J = 16.1 Hz, 5.2
Hz, 1H), 2.73 – 2.64 (m, 4H), 1.52 – 1.45 (m, 2H), 1.24 – 1.21 (m, 2H), 0.88 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 137.6, 135.6, 134.4, 133.2, 132.9,
131.0, 128.8 (2xC), 128.6 (2xC), 128.1, 121.4, 65.1, 56.7, 46.5, 39.3, 30.5, 19.1, 17.1,
13.7. HRMS (ESI): m/z (M + Na+) calcd for C21H25NNaO4S, 410.1402, found:
410.1397
Compound 25 (29 mg, 85% yield): 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 7.7 Hz,
1H), 7.28 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 5.97ꢀ5.87 (m, 1H), 5.39 (d, J =
13.6 Hz, 1H), 5.29 (d, J = 13.6 Hz, 1H), 4.89 (t, J = 6.0 Hz, 1H), 4.13 – 4.07 (m, 3H),
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3.91 (dd, J = 15.8 Hz, 7.7 Hz, 1H), 2.95 (dd, J = 16.2 Hz, 5.6 Hz, 1H), 2.79 – 2.74 (m,
1H), 2.65 (s, 3H), 1.61 – 1.54 (m, 2H), 1.30 (dt, J = 14.9 Hz, 7.5 Hz, 2H), 0.91 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.5, 137.9, 134.4, 133.5, 133.0, 132.7,
131.0, 121.4, 120.0, 65.2, 56.7, 46.5, 39.8, 30.6, 19.2, 17.0, 13.8. HRMS (ESI): m/z
(M + Na+) calcd for C17H23NNaO4S, 360.1245, found: 360.1253
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Synthesis of compound 26~28:
General synthetic procedure of compound 26~28: Et3N (3.0 equiv, 41 mg) and
RCO(Cl) or MsCl (1.5 equiv) was added to a solution of compound 22 (0.1 mmol, 30
mg) in 1 mL DCM, the reaction mixture was stirred at room temperature and
monitored by LCꢀMS until all of the starting material was consumed completely.
Solvent was removed in vacuo, and the residue was diluted with 10 mL ethyl acetate,
washed with 10 ml water, and extracted with ethyl acetate for two times. Then the
organic phase was combined, washed with brine and dried over anhydrous Na2SO4.
The organic layer was concentrated, and purified with column chromatography on
silica gel (EtOAc/ petroleum ether) to afford colorless oil.
Compound 26 (35 mg, 83% yield): 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 8.5 Hz,
5.3 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.5 Hz,
1H), 7.19 (t, J = 8.6 Hz, 2H), 6.14 (t, J = 5.7 Hz, 1H), 4.08 (t, J = 6.7 Hz, 2H), 3.05 (d,
J = 5.8 Hz, 2H), 2.56 (s, 3H), 1.55 – 1.48 (m, 2H), 1.28 – 1.22 (m, 2H), 0.86 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.5, 167.5, 165.6 (d, J = 252.3 Hz),
135.3, 134.9, 134.2, 132.7, 131.6, 131.4 (d, J = 9.1 Hz), 130.8 (d, J = 3.2 Hz, 2xC),
122.1, 115.8 (d, J= 22 Hz, 2xC), 65.3, 54.9, 40.1, 30.5, 19.1, 16.9, 13.7. HRMS (ESI):
m/z (M + Na+) calcd for C21H22FNNaO5S, 442.1100, found:442.1093
Compound 27 (36 mg, 77% yield): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz,
2H), 7.77 (d, J = 8.2 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.34
(d, J = 7.5 Hz, 1H), 6.12 (t, J = 5.7 Hz, 1H), 4.09 (t, J = 6.7 Hz, 2H), 3.08 (d, J = 5.7
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Hz, 2H), 2.55 (s, 3H), 1.54 – 1.50 (m, 2H), 1.28 – 1.23 (m, 2H), 0.87 (t, J = 7.4 Hz,
3H). 13C NMR (100 MHz, CDCl3) 169.4, 167.4, 137.8, 135.2, 135.0, 134.3, 134.0,
132.5, 131.7, 129.1 (2xC), 125.6 (q, J = 3.6 Hz), 125.1 (2xC), 122.1, 65.3, 55.0, 39.9,
30.5, 19.1, 16.9, 13.7.HRMS (ESI): m/z (M + Na+) calcd for C22H22F3NNaO5S,
492.1068, found:492.1073.
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Compound 28 (32 mg, 84% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz,
1H), 7.37 (d, J = 7.7 Hz, 2H), 5.49 (dd, J = 8.7 Hz, 3.3 Hz, 1H), 4.13 (t, J = 6.7 Hz,
2H), 3.40 (dd, J = 16.7 Hz, 3.4 Hz, 1H), 3.27 (s, 3H), 2.98 (dd, J = 16.7 Hz, 8.7 Hz,
1H), 2.66 (s, 3H), 1.62 – 1.55 (m, 2H), 1.33 (dd, J = 15.0 Hz, 7.5 Hz, 2H), 0.91 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.1, 135.5, 135.1, 134.3, 132.8, 132.0,
122.3, 65.4, 57.9, 42.4, 40.4, 30.6, 19.2, 17.1, 13.8. HRMS (ESI): m/z (M + Na+)
calcd for C15H21NNaO6S2, 398.0708, found:398.0710.
Synthesis of compound 29
DEAD (2.0 equiv, 31ꢁL), PPh3 (2.0 equiv, 52 mg) was added to a solution of
compound 22 (0.1 mmol, 30 mg) in 1 mL THF, the reaction mixture was stirred at
room temperature and monitored by LCꢀMS until all of the starting material was
consumed completely. Solvent was removed in vacuo, and the residue was diluted
with 10 mL ethyl acetate, washed with 10 mL water, and extracted with ethyl acetate
for two times. Then the organic phase was combined, washed with brine and dried
over anhydrous Na2SO4. The organic layer was concentrated, and purified with
column chromatography on silica gel (EtOAc/ petroleum ether) to afford colorless oil.
Compound 29 (36 mg, 98% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.7 Hz,
1H), 7.34 (dd, J = 7.6 Hz, 2.9 Hz, 2H), 5.53 (dd, J = 7.7 Hz, 3.2 Hz, 1H), 4.52 – 4.40
(m, 2H), 4.10 (tt, J = 6.1 Hz, 3.2 Hz, 2H), 3.20 (dd, J = 16.0 Hz, 3.3 Hz, 1H), 2.97 (dd,
J = 16.0 Hz, 7.7 Hz, 1H), 2.67 (s, 3H), 1.60 – 1.53 (m, 2H), 1.45 (t, J = 7.1 Hz, 3H),
1.32 (dd, J = 16.5 Hz, 7.5 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 169.7, 150.8, 134.9, 134.8, 133.9, 132.5, 131.6, 121.8, 65.1, 64.0, 55.4, 39.6,
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30.5, 19.1, 17.0, 14.3, 13.7. HRMS (ESI): m/z (M + Na+) calcd for C17H23NNaO6S,
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392.1144, found:392.1140.
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Synthesis of compound 30 and 31
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General synthetic procedure of compound 30 and 31: DEAD (2.0 equiv, 31ꢁL), PPh3
(2.0 equiv, 52 mg) and ROH (2.0 equiv) was added to a solution of compound 22 (0.1
mmol, 30mg) in 1 mL THF, the reaction mixture was stirred at room temperature and
monitored by LCꢀMS until all of the starting material was consumed completely.
Solvent was removed in vacuo, and the residue was diluted with 10 mL ethyl acetate,
washed with 10 mL water, and extracted with ethyl acetate for two times. Then the
organic phase was combined, washed with brine and dried over anhydrous Na2SO4.
The organic layer was concentrated, and purified with column chromatography on
silica gel (EtOAc/ petroleum ether) to afford colorless oil.
Compound 30 (30 mg, 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 7.6 Hz,
1H), 7.27 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 4.91 (t, J = 6.0 Hz, 1H), 4.13 (t,
J = 6.7 Hz, 2H), 3.52 – 3.38 (m, 2H), 2.97 – 2.91 (m, 1H), 2.77 (dd, J = 16.2 Hz, 6.4
Hz, 1H), 2.64 (s, 3H), 1.62 – 1.55 (m, 2H), 1.36 – 1.32 (m, 5H), 0.91 (t, J = 7.4 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 170.6, 137.7, 134.2, 133.4, 132.7, 130.9, 121.2,
65.1, 56.5, 39.7, 38.3, 30.5, 19.0, 16.8, 13.6, 13.6. HRMS (ESI): m/z (M + Na+) calcd
for C16H23NNaO4S, 348.1245, found: 348.1249
Compound 31 (32 mg, 90% yield): 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 7.7 Hz,
1H), 7.27 (d, J = 7.4 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 4.88 (t, J = 6.0 Hz, 1H), 4.13 (t,
J = 6.7 Hz, 2H), 3.35 – 3.31 (m, 2H), 2.95 (dd, J = 16.2 Hz, 5.5 Hz, 1H), 2.75 (dd, J =
16.2 Hz, 6.6 Hz, 1H), 2.64 (s, 3H), 1.76 – 1.69 (m, 2H), 1.62 – 1.55 (m, 2H), 1.42 (td,
J = 14.2 Hz, 7.1 Hz, 2H), 1.32 (dt, J = 12.2 Hz, 6.2 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H),
0.91 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.7, 137.8, 134.3, 133.4,
132.8, 131.1, 121.3, 65.2, 57.2, 43.4, 39.7, 30.6, 30.3, 20.2, 19.1, 17.0, 13.8, 13.7.
HRMS (ESI): m/z (M + Na+) calcd for C18H27NNaO4S, 376.1558, found: 376.1555
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Synthesis compound 32:
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Nꢀmethyl morpholine (1.5 equiv, 16 ꢁL) and ethyl propiolate (1.5 equiv, 15 ꢁL) was
added to a solution of compound 22 (0.1 mmol, 30mg) in 1 mL DCM, the reaction
mixture was stirred at room temperature and monitored by LCꢀMS until all of the
starting material was consumed completely. Solvent was removed in vacuo, and the
residue was diluted with 10 mL ethyl acetate, washed with 10 mL water, and extracted
with ethyl acetate for two times. Then the organic phase was combined, washed with
brine and dried over anhydrous Na2SO4. The organic layer was concentrated, and
purified with column chromatography on silica gel (EtOAc/ petroleum ether = 1:5) to
afford 29.1 mg colorless (E)ꢀ32 and 10 mg colorless (Z)ꢀ32.
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Compound (E)-32 (29 mg, 73% yield): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J =
14.1 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.36 – 7.32 (m, 2H), 5.37 (d, J = 14.1 Hz, 1H),
5.28 (dd, J = 9.1 Hz, 3.0 Hz, 1H), 4.23 (qd, J = 7.2 Hz, 3.0 Hz, 2H), 4.17 (t, J = 6.7
Hz, 2H), 3.18 (dd, J = 16.6 Hz, 3.1 Hz, 1H), 2.72 (dd, J = 16.6 Hz, 9.2 Hz, 1H), 2.67
(s, 3H), 1.65 – 1.58 (m, 2H), 1.38 – 1.26 (m, 5H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 170.0, 166.6, 136.2, 135.5, 134.8, 134.0, 131.8, 131.7, 122.0,
99.3, 65.5, 60.5, 55.1, 38.3, 30.6, 19.1, 17.2, 14.5, 13.7. HRMS (ESI): m/z (M + Na+)
calcd for C19H25NNaO6S, 418.1300, found: 418.1298
Compound (Z)-32 (10 mg, 25% yield): 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 7.6
Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 10.6 Hz, 1H),
6.35 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 5.30 (d, J = 10.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H),
4.06 (t, J = 6.7 Hz, 2H), 3.15 (dd, J = 16.3 Hz, 2.9 Hz, 1H), 2.70 (dd, J = 16.8 Hz, 8.9
Hz, 1H), 2.66 (s, 2H), 1.53 (dq, J = 13.7 Hz, 6.7 Hz, 2H), 1.31 – 1.26 (m, 5H), 0.89 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.0, 165.3, 137.4, 134.4, 133.8,
131.2, 131.1, 130.7, 122.4, 99.7, 64.9, 60.5, 57.6, 38.3, 30.6, 19.1, 17.2, 14.4, 13.8.
HRMS (ESI): m/z (M + Na+) calcd for C19H25NNaO6S, 418.1300, found: 418.1303
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Synthesis of Nꢀ(oꢀtolylsulfonyl)acetamide (1a):
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ZnCl2 (68 mg, 10 mmol%) was added to a mixture of 2ꢀmethylbenzenesulfonamide (5
mmol, 855 mg) in Ac2O (10 mL), then the reaction mixture was stirred at 50°C until
all the starting material was consumed completely, the residue was diluted with 30
mL ethyl acetate, washed with 30 mL water, and extracted with ethyl acetate for two
times. Then the organic phase was combined, washed with brine and dried over
anhydrous Na2SO4. The organic phase was concentrated to give crude product 1a,
which was recrystallised from toluene to give the Nꢀ(oꢀtolylsulfonyl)acetamide 1a
(873 mg, 82% yield). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.31 – 8.29 (m, 1H),
7.84 – 7.81 (m, 1H), 7.71 – 7.69 (m, 2H), 3.99 (s, 3H), 2.14 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 168.2, 137.8, 136.8, 134.3, 132.9, 131.0, 126.6, 23.4, 20.5.
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Other NꢀAcꢀsubstituted benzenesulfonamides were synthesized according to synthesis
of Nꢀ(oꢀtolylsulfonyl)acetamide.
Nꢀ((2,4ꢀdimethoxyphenyl)sulfonyl)acetamide (6a) (987 mg, 87% yield):
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.8
Hz, 2.1 Hz, 1H), 6.52 (d, J = 2.0 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 2.08 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 169.0, 166.0, 158.6, 133.4, 118.4, 104.8, 99.7, 56.4, 56.0,
23.3.
Nꢀ((4ꢀchloroꢀ2,5ꢀdimethylphenyl)sulfonyl)acetamide (10a) (1.1 g, 85% yield):
1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 8.00 (s, 1H), 7.32 (s, 1H), 2.59 (s, 3H),
2.42 (s, 3H), 2.09 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 167.8, 140.7, 136.5, 134.9,
134.8, 133.3, 133.0, 23.6, 19.9, 19.8.
Nꢀ((2ꢀfluorophenyl)sulfonyl)acetamide (3a) (922 mg, 85% yield):
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1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.08 (t, J = 7.3 Hz, 1H), 7.69 – 7.64 (m,
1H), 7.35 (t, J = 7.7 Hz, 1H), 7.27 – 7.22 (m, 1H), 2.11 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 168.5, 159.1 (d, J = 255.5 Hz), 136.6 (d, J = 8.6 Hz), 131.9, 126.7 (d, J =
12.2 Hz), 124.7 (d, J = 3.8 Hz), 117.3 (d, J = 20.6 Hz), 23.5
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Nꢀ((2,4ꢀdimethylphenyl)sulfonyl)acetamide (4a) (885 mg, 78% yield):
1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.2
Hz, 1H), 7.14 (s, 1H), 2.62 (s, 3H), 2.39 (s, 3H), 2.07 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 168.4, 145.3, 137.7, 133.8, 133.6, 131.2, 127.2, 23.4, 21.6, 20.4.
Nꢀ((2ꢀmethoxyꢀ4ꢀmethylphenyl)sulfonyl)acetamide (5a) (984 mg, 81% yield):
1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0
Hz, 1H), 6.85 (s, 1H), 3.98 (s, 3H), 2.43 (s, 3H), 2.10 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 169.0, 156.9, 147.7, 131.3, 123.6, 121.5, 113.2, 56.4, 23.3, 22.2.
methyl 2ꢀ(Nꢀacetylsulfamoyl)benzoate (2a) (1.1 g, 86% yield):
1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.32 – 8.28 (m, 1H), 7.86 – 7.81 (m, 1H),
7.72 – 7.68 (m, 2H), 3.99 (s, 3H), 2.14 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.4,
167.5, 137.9, 133.7, 131.8, 131.5, 131.1, 130.7, 53.6, 24.1.
Nꢀ((3ꢀchloroꢀ2ꢀmethylphenyl)sulfonyl)acetamide (8a) (988 mg, 80% yield):
1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.9
Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 2.70 (s, 3H), 2.10 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 168.5, 138.7, 137.2, 135.7, 135.2, 130.0, 127.0, 23.6, 17.0.
Nꢀtosylacetamide (11a) (937 mg, 88% yield):
1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 2.45
(s, 3H), 2.07 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.4, 145.4, 135.6, 129.8, 128.5,
23.6, 21.8.
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Nꢀ((5ꢀfluoroꢀ2ꢀmethylphenyl)sulfonyl)acetamide (9a) (820 mg, 71% yield):
1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.86 (dd, J = 8.4 Hz, 2.7 Hz, 1H), 7.32
(dd, J = 8.4 Hz, 5.3 Hz, 1H), 7.25 (dt, J = 8.3 Hz, 2.6 Hz, 1H), 2.63 (s, 3H), 2.11 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 168.19, 160.5 (d, J = 248.0 Hz), 138.0 (d, J = 6.9
Hz), 134.4 (d, J = 7.1 Hz), 133.4 (d, J = 3.8 Hz), 121.3 (d, J = 20.7 Hz), 118.3(d, J =
25.2 Hz), 23.52, 19.70.
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methyl 4ꢀ(Nꢀacetylsulfamoyl)benzoate (12a) (1.13 mg, 88% yield):
1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.21 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 8.5
Hz, 2H), 3.97 (s, 3H), 2.09 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 167.5, 165.5,
142.3, 135.3, 130.4, 128.6, 52.9, 23.8.
(R)ꢀmethyl 2ꢀacrylamidopropanoate (19a) (549 mg, 70% yield):
1H NMR (400 MHz, CDCl3) δ 6.31 (dd, J = 17.0 Hz, 1.5 Hz, 1H), 6.18 (dd, J = 17.0
Hz, 10.1 Hz, 1H), 5.66 (dd, J = 10.1 Hz, 1.5 Hz, 1H), 4.68 (p, J = 7.2 Hz, 1H), 3.76 (s,
3H), 1.44 (d, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 173.6, 165.1, 130.5,
127.1, 52.6, 48.1, 18.4.
N,Nꢀdibenzylacrylamide (21a) (815 mg, 65% yield):
1H NMR (400 MHz, CDCl3) δ 7.32 (ddd, J = 27.6 Hz, 14.2 Hz, 6.6 Hz, 8H), 7.19 (t, J
= 12.3 Hz, 2H), 6.61 (dd, J = 16.7 Hz, 10.2 Hz, 1H), 6.49 (dd, J = 16.6 Hz, 2.1 Hz,
1H), 5.73 (dd, J = 10.2 Hz, 2.1 Hz, 1H), 4.66 (s, 2H), 4.51 (s, 2H). 13C NMR (100
MHz, CDCl3) δ 167.1, 137.3, 136.6, 129.1, 129.0, 128.7, 128.5, 127.8, 127.7, 127.6,
126.6, 50.0, 48.7, 40.2, 36.3, 29.8.
Synthesis of methyl oꢀtolylsulfonylcarbamate (12b):
2ꢀmethylbenzenesulfonamide (5 mmol, 855 mg) was added to a mixture of Et3N (3.0
equiv, 2 mL) in CH3CN (100 mL), then methyl chloroformate (1.5 equiv，588 µL) was
added slowly, the mixture was stirred at room temperature and monitored by LCꢀMS
and TLC until all the starting material was consumed completely, then evaporated
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CH3CN in vacuo. The residue was dissolved in ethyl acetate (30 mL) and then
aqueous NaHCO3 (30 mL) was added. The water phase was separated and dropwise
added concentrated HCl with a mixture of ice and to give a granular precipitate which
slowly crystallized upon standing. The crystals were collected by filtration, washed
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with water, and dried to give methyl oꢀtolylsulfonylcarbamate (458 mg, 40%). H
NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.0 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.39 (t, J =
7.7 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 3.68 (s, 3H), 2.67 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 150.8, 137.9, 136.4, 134.2, 132.7, 131.5, 126.5, 53.8, 20.5.
Synthesis of NꢀBoc substituted 2ꢀmethylbenzenesulfonamide (11b):
2ꢀmethylbenzenesulfonamide (5 mmol, 855 mg) was added to a mixture of DMAP
(10 mmol%, 62 mg) in CH2Cl2 (10 mL), then Et3N (1.1 equiv, 765 µL) and Boc2O
(1.15 equiv, 1.32 mL ) was added, the reaction mixture was stirred at room
temperature and monitored by LCꢀMS until all of the starting material was consumed
completely. The reaction mixture was washed with water (50 mL x 2) and extracted
by CH2Cl2 for two times, then the organic phase was combined and washed with brine
and dried over anhydrous Na2SO4. The organic layer was concentrated, and purified
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with silica gel column chromatography to afford white solid (1.016g, 75%). H NMR
(400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 1H), 7.54 – 7.50 (m, 2H), 7.38 – 7.33 (m,
2H), 2.67 (s, 3H), 1.33 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 149.4, 137.6, 137.0,
133.9, 132.6, 131.3, 126.2, 84.4, 27.9, 20.3.
Synthesis of Nꢀ trifluoroacetyl 2ꢀmethylbenzenesulfonamide (13b):
2ꢀmethylbenzenesulfonamide (5mmol, 885 mg) was added a mixture of TFA (1.3
equiv, 910 µL) in toluene (15 mL), the reaction mixture was heated to reflux and
monitored by LCꢀMS until all of the starting material was consumed completely.
Solvent was removed in vacuo, and the residue was diluted with 30 mL ethyl acetate,
washed with 30 mL water, then the organic phase was washed with brine and dried
over anhydrous Na2SO4. The organic layer was concentrated to afford white solid
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without further purification (1.268 g, 95%). H NMR (400 MHz, CDCl3) δ 8.81 (s,
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1H), 8.21 (d, J = 8.0 Hz, 1H), 7.62 – 7.58 (m, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.38 (d, J
= 7.7 Hz, 1H), 2.68 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 138.4, 135.3, 135.0, 133.0,
132.1, 126.9, 58.7, 20.5, 18.6.
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Synthesis of Nꢀmethyl 2ꢀmethylbenzenesulfonamide (15b):
The mixture of 2ꢀmethylbenzenesulfonamide (5mmol, 885 mg) and K2CO3 (1.1 equiv,
1.38 g) in CH3OH was stirred for 5 min at room temperature, then MeI (1.1 equiv, 342
µL) was added, the reaction mixture was monitored by LCꢀMS until all the starting
material was consumed completely. CH3OH was evaporated in vacuo, the residue was
diluted with 30 mL ethyl acetate, washed with 30 mL water, the organic phase was
washed with brine and dried over anhydrous Na2SO4. The organic layer was
concentrated, and purified with silica gel column chromatography to afford white
solid (276 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.96 (m, 1H), 7.47 (t, J =
7.5 Hz, 1H), 7.33 (t, J = 6.5 Hz, 2H), 4.41 (s, 1H), 2.65 (s, 6H). 13C NMR (150 MHz,
CDCl3) δ 137.2, 136.9, 133.0, 132.7, 130.0, 126.3, 29.2, 20.5.
Author Information
Corresponding author: Gang Liu, Fengyu Qu
Eꢀmail: gangliu27@tsinghua.edu.cn; qufengyu@hrbnu.edu.cn
Acknowledgments
This work was supported by grants from the National Natural Science
Foundation of China (No. 81273364, 91213303) and National 863 Program of
China (No. 2012AA020303) for support.
Supporting information:
Copies of NMR spectra of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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