Chemoselective synthesis of aryl carboxamido sulfonic acid derivatives

Article abstract of DOI:10.1016/j.tet.2013.01.028

A one-pot two-step synthetic strategy for the preparation of aryl carboxamido sulfonic acid derivatives was developed. The synthesis started from m-(chlorosulfonyl)benzoyl chloride, which was reacted with amines, alcohols, thiols, or sodium azide and cata

Full text of DOI:10.1016/j.tet.2013.01.028

Tetrahedron 69 (2013) 2640e2646
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoselective synthesis of aryl carboxamido sulfonic acid
derivatives
Yung-Lin Yang, Basker Rajagopal, Chien-Fu Liang, Chun-Chi Chen, Hsiu-Ping Lai,
Chih-Hung Chou, Yen-Pin Lee, Yen-Ling Yang, Jing-Wen Zeng, Chun-Lin Ou,
*
Po-Chiao Lin
Department of Chemistry, National Sun Yat-sen University, Kaohsiung 804, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot two-step synthetic strategy for the preparation of aryl carboxamido sulfonic acid derivatives
was developed. The synthesis started from m-(chlorosulfonyl)benzoyl chloride, which was reacted with
amines, alcohols, thiols, or sodium azide and catalytic activator at rt to give the corresponding sulfonic
acid derivatives in good yields. The short reaction times and the one-pot chemoselective nature of the
procedure diminished undesired side reactions and enhanced the efficiency of the reaction. In cases of
electron-donor and electron-deficient substituted carboxanilides, piperidine was successfully in-
corporated at sulfur to obtain the corresponding sulfonamides in yields of 46% (4-nitroaniline) to nearly
quantitative (4-methoxyaniline). The optimized conditions were applied to the preparation of diary-
lsulfonamides, sulfonic esters, thiosulfonates, and a sulfonyl azide, which are very important and key
structures in modern organic synthesis. Furthermore, the method has been successfully used in the
preparation of inhibitors of isocitrate dehydrogenase mutants, which are closely related to
tumorigenesis.
Received 24 December 2012
Accepted 11 January 2013
Available online 26 January 2013
Keywords:
Sulfonic acid derivatives
Sulfonamide
One-pot synthesis
Sulfonyl azide
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
a one-pot two-step oxidative method to convert methyl sulfinates
and a range of amines into the corresponding sulfonamides, using
Sulfonic acid derivatives are very useful pharmaceutical com-
pounds, exhibiting a wide range of biological activities such as anti-
microbial, anti-cancer, anti-inflammatory, and antiviral functions.1e3
The sulfonamide group is considered a transition-state mimic of
peptide hydrolysis and is therefore used in the design of potent and
irreversible protease inhibitors.4 A large number of structurally novel
sulfonamide derivatives showed remarkable inhibitory activities
against quite significant proteases such as matrix metalloproteases,
m-CPBA.11 Caddick and co-workers reported a synthesis of sulfon-
amides from various pyridinium sulfonates using the activating
reagent triphenylphosphine ditriflate.12 The last method provided
high yields and tolerated a variety of functional groups.
The sulfonylation of amines with sulfonyl chlorides in the
presence of base is one of the most important methods of sulfon-
amide preparation because of its high efficiency and simplicity.2,13
However, this method is limited by the formation of undesired
disulfonamides and by the hydrolytic decomposition of highly ac-
tive sulfonyl chlorides.14 Recently, the direct conversion of a sul-
fonic acid to a sulfonamide was achieved using 2,4,6-trichloro-
1,3,5-triazine to form the reactive sulfonyl chloride in-
termediate.15,16 Mersharm and co-workers used copper(II) oxide to
efficiently catalyze the transformation of sulfonyl chlorides to sul-
fonamides and sulfonic esters in the absence of base in good
yields.17 Although the moisture sensitivity, harsh preparative con-
ditions, and disulfonamide side reactions of sulfonyl chlorides
considerably restrict their use in sulfonamide syntheses, their high
reactivity with primary amines makes them attractive for the de-
velopment of new, mild, and straightforward synthetic methods.
m-(Chlorosulfonyl)benzoyl chloride (CSBC) bears two highly re-
active functional groups, an acyl chloride, and a sulfonyl chloride. It is
an ideal building block for the simple bi-directional expansion of the
tumor necrosis factor-a converting enzyme (TACE), and HIV protease,
and the resulting loss of protease activity invited research into small
molecule treatments for cancer, arthritis, and acquired immunode-
ficiency syndrome (AIDS).5 Recently, Hamachi and co-workers de-
scribed an application of sulfonic esters in site-specific protein
labeling and biofunctional imaging.6e9 The tremendous utility of
sulfonylated molecules necessitates their rapid and effective syn-
thesis, particularly with a view to synthesize molecular libraries.
Numerous sulfonamide syntheses have been developed. A one-
pot reaction of sulfinic acid salts (prepared by reacting organome-
tallic reagents and sulfur dioxide) with N-chlorobenzotriazole can be
used to synthesize sulfonamides.10 Ruano et al. recently reported
* Corresponding author. Tel./fax: þ886 7 5253913; e-mailaddresses:pochiao1002@
gmail.com, pclin@mail.nsysu.edu.tw (P.-C. Lin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.028

Y.-L. Yang et al. / Tetrahedron 69 (2013) 2640e2646
2641
Table 1
structural complexity of substituted arylsulfonyl compounds
Optimization of reaction conditions for the one-pot synthesis of sulfonamides
(Scheme 1). Owing to the differential reactivities of its acyl and sulfonyl
chlorides, CSBC chemoselectively reacts at the more reactive acyl
chloride, followed by sulfonyl coupling to give diverse carboxamido
sulfonic acid derivatives in two distinct steps.18 Even though the acyl
and sulfonyl chloride groups participate in two sequential coupling
reactions for the introduction of different substituents, the high re-
activity of each functional group can easily lead to decomposition in
the presence of base during the reaction. In addition, the subsequent
flash column chromatography leads to the decomposition of unreac-
ted sulfonyl chloride intermediates, and thereby, reduces the reaction
yield and contaminates the desired product with byproducts such as
sulfonic acids. Furthermore, the reactivity of CSBC with other nucleo-
philes such as alcohols, thiols, and azides has rarely been assessed.
Therefore, a concise synthetic strategy is needed to facilitate the con-
struction of structurally related molecular libraries. This report de-
scribes the development of a one-pot two-step strategy for the
synthesis of aryl carboxamido sulfonic acid derivatives that is shorter
and more efficient than currently known procedures.
O
H
N
O
Cl
(a.)
(b.)
, DIEA (1 eq), solvent , 0°C, 30 min
aniline (1 eq)
Eq. 2
piperidine
(1.1 eq) , DIEA (1 eq) , activator (0.1 eq)
O
S
O
O
S
O
N
Cl
(1.1eq)
3
Entries
Solvent
Activator
Timea (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
DMF
DMF
DCM
DCM
ACN
ACN
THF
DMAP
TMA$HCl
DMAP
TMA$HCl
DMAP
TMA$HCl
DMAP
d
d
1
24
24
24
24
1
Decomposed
Decomposed
87
20
48
43
67
87
THF
TMA$HCl
TMA$HCl:trimethylamine hydrochloride.
DIEA: N,N-diispropylethylamine.
a
Reaction time in the second step.
O
O
S
O
O
S
R1
R2
R1-NH2, DIEA, 0°C
(2) R2-X, nucleophilic activator, DIEA
(1)
N
X
Cl
Cl
Eq. 1
O
H
and reaction efficiency, the use of a catalytic amount of DMAP in
dichloromethane promised general applicability in the synthesis of
diverse sulfonic acid derivatives.
O
X=NH, O, S, and N3
1
2
Scheme 1. General scheme for the one-pot synthesis of carboxamido sulfonic acid
derivatives.
2.2. R1-group substituent effects in the syntheses of
sulfonamides
2. Results and discussion
A series of substituted anilines bearing electron-withdrawing
and electron-donating groups (4ae4l, Table 2) were used to ex-
amine the reactivity in the first coupling step, after which the
corresponding sulfonamides were formed using piperidine. Ani-
lines substituted with chlorine, bromine, or iodine (at the ortho,
meta, and para positions in 4ae4e) did not obviously affect the
production of the desired products 5ae5e. Despite the presence of
electron-withdrawing nitro group, a moderate yield (77%) was
obtained with m-nitroaniline (4f), in which the amino group is
apparently less affected by resonance effect. However, in the case of
4-nitroaniline (4g), nitro substitution at the para position consid-
erably diminished the nucleophilicity of the amino group and
thereby lowered the reaction yield (46%, entry 7). In the case of 2,4-
dinitroaniline (4h), the yield of 5h after 20 h was 5%. The reaction
yield improved to 40% after the addition of a half equivalent of
pyridine (entry 8). The secondary amine N-ethyl-2,4-dinitroaniline
(4i) was expected to be more reactive than dinitroaniline 4h be-
cause of the electron-donating nature of the N-ethyl group; how-
ever, the steric hinderance due to the ethyl group diminished the
reactivity of the amine and resulted in no product formation (entry
9). As expected, the yields of 4-methoxyl (4j) and 2,4,6-trimethyl
(4k) substituted anilines were almost quantitative; these findings
are rationalized by consideration of the strongly electron-donating
group(s) (entries 10 and 11). The fused 2-aminonaphthalene could
also serve as a nucleophile in the reaction with 1, giving a moderate
yield (72%, entry 12). The applicability of diverse R1 substituents in
the developed one-pot synthetic strategy greatly expands the
structural variability possible in the synthesis of sulfonamides.
2.1. Optimization of a one-pot, two-step synthesis of car-
boxamido sulfonamides
Making use of the well-known difference in reactivity between
acyl chlorides and sulfonyl chlorides,18 CSBC 1 was reacted with two
different nucleophiles in a one-pot strategy to give the desired, di-
substituted products 2 (Scheme 1). In the presence of N,N-diiso-
propylethylamine (DIEA), primary amines reacted chemoselectively
with the more reactive acid chloride, leaving the sulfonyl chloride
untouched. Subsequently, without quenching or work-up processes,
the second nucleophile was added, along with a catalytic amount of
nucleophilic activator (4-dimethylaminopyridine (DMAP), trime-
thylamine, or pyridine) and 1 equiv of DIEA. Compared to the one-
pot synthesis, disubstituted sulfonamides could also be obtained
in two individual steps; however, the average yield of the two-step
procedure was generally about 60%.18 Carboxamido sulfonamides,
sulfonic esters, thiosulfonates, and sulfonic azides could also be
synthesized using this one-pot strategy.
A variety of solvent/nucleophilic activator combinations were
screened to optimize the reaction conditions (Scheme 1 and
Table 1). In the model study, aniline (1 equiv) was used as the initial
nucleophile to form the amide bond with the highly reactive acid
chloride; then, the resulting intermediate was treated with piper-
idine (1.1 equiv) in the presence of a nucleophilic activator
(0.1 equiv) to give the disubstituted product (Eq. 2 in Table 1). Using
N,N-dimethylformamide (DMF) as the reaction solvent resulted in
the decomposition of m-(chlorosulfonyl)benzoyl chloride (entries 1
and 2).19 The use of solvents such as dichloromethane (DCM),
acetonitrile (ACN), or tetrahydrofuran (THF) overcame this prob-
lem. In the preparation of sulfonic esters, the absence of catalytic
activator resulted in no distinguishable product formation after
24 h. Referring to Table 1, DMAP in DCM as well as TMA$HCl in THF
showed good catalytic ability in the formation of sulfonamide 2. By
contrast, the use of ACN instead of DCM or THF in the presence of
different catalysts resulted in lower yields and prolonged reaction
times (entries 5 and 6). Therefore, considering organic solubility
2.3. Applicability of the one-pot, two-step preparation for
carboxamido sulfonamides, sulfonic esters, thiosulfonates,
and a sulfonyl azide
To expand the utility of this method in organic synthesis, the
preparation of sulfonamides, sulfonic esters, thiosulfonates, and
sulfonyl azides was attempted. In addition to piperidine, primary
aliphatic amine 6a and pyrrolidine 6b were successfully employed

2642
Y.-L. Yang et al. / Tetrahedron 69 (2013) 2640e2646
Table 2
When highly nucleophilic thiols participated in the one-pot
synthesis, complete conversion to the newly formed thiosulfo-
nates was observed. But, in the case of thiocresol, the product 7d was
obtained in 48% yield owing to the decomposition during column
chromatography (entry 4). When tert-butyl thiol 6e was employed
in thiosulfonate formation, the desired product 7e was obtained in
good yield (72%). Oxygen nucleophiles result in sulfonic esters that
are valuable intermediates in organic synthesis and show important
pharmacological properties.23 However, the reaction of sulfonyl
Diversely substituted anilines in the synthesis of sulfonamides 5ae5l
O
H
N
O
R
(a.)
(b.)
Cl
4a-4l (1 eq)
, DIEA(1 eq), DCM , 0°C
Eq. 3
O
S
O
piperidine (1.1 eq.), DIEA(1 eq) ,
DMAP(0.1 eq), DCM , r.t.
O
S
O
N
Cl
5(a-l)
(1.1eq)
chlorides with alcohols may result in b-elimination byproducts in-
Entries
1
Substrate (4ae4l)
Product (5ae5l)
Isolated yield (%)
69
stead of the sulfonic esters.24 In order to expand the scope of our
method to the synthesis of sulfonic esters from sulfonyl chlorides
and alcohols, we investigated the reaction of the sulfonyl chloride
with an aliphatic alcohol tether bearing an alkyne functional group.
A moderate yield of the product 7f in the one-pot reaction was ob-
NH2
Cl
5a
NH2
ꢀ
tained (65%). In the presence of 4 A molecular sieves, the yield of
2
5b
73
compound 7f was improved to 80% (entry 6), and similarly, a quan-
titative yield was obtained for sulfonyl isopropyl ester 7g (entry 7).
Cl
H2N
2.4. Preparation of sulfonamide-type inhibitors for isocitrate
dehydrogenase mutants
3
4
5
5c
5d
5e
72
70
78
Cl
H2N
The developed one-pot synthetic strategy provides a new
method for the preparation of the sulfonamide-type inhibitors of
isocitrate dehydrogenase isoform (IDH) mutants (IDH1m and
IDH2m). The association of IDH mutants and their abnormal
Br
H2N
product D-2-hydroxyglutarate is known to be closely related to
I
tumorigenesis.25 Sulfonamide analogues 10ae10d (Table 4) were
synthesized and their inhibition of IDH1m and IDH2m was further
evaluated via in vitro and ex vivo assays. Compounds 10a and 10b
are known to show the best inhibition activity against IDH1m,
NH2
6
5f
77
NO2
giving IC50 values below 1 m
M26
H2N
7
8
5g
5h
46
Table 3
NO2
One-pot synthesis of diverse benzanilido sulfonic acid derivatives
NO2
H2N
O
O
H
40a
N
Cl
NO2
Eq. 4
(a) aniline (1 eq), DIEA (1 eq), DCM, 0 °C
O
S
O
R
2 (1.1 eq), DIEA(1 eq) ,DMAP(0.1 eq),
DCM , r.t.
NO2
H
(b)
O
S
R2
O
Cl
N
Et
9
5i
db
(1.1eq)
7(a-g)
NO2
Entries
Substrate (R2)
Cl NH2
Product (7ae7g)
Isolated yield (%)
85
10
11
5j
Quant
90
H2N
OMe
1
2
3
4
5
6
7a
H
N
7b
7c
7d
7e
7f
90
80a
48a
72a
80b
H2N
5k
NaN3
H2N
12
5l
72
SH
a
Pyridine of 0.5 equiv instead of DMAP in the reaction.
No desired product obtained.
b
(CH3)3CeSH
in the preparation of substituted sulfonamides, providing the cor-
responding sulfonylbenzanilides 7a and 7b in excellent yields over
two steps (85e90%, entries 1 and 2). Considering the importance of
sulfonyl azides as building blocks in organic synthesis,20e22 the
weakly nucleophilic azido group was also successfully employed in
the formation of a substituted sulfonyl azide. Sodium azide
smoothly produced the benzanilido sulfonyl azide 7c in 80% yield in
the absence of a nucleophilic activator (entry 3).
OH
7
7g
99b
OH
No addition of DMAP.
a
b
ꢀ
Addition of 3 equiv in weight of 4 A molecular sieves at step (b).

Y.-L. Yang et al. / Tetrahedron 69 (2013) 2640e2646
2643
Table 4
functionalized sulfonyl azides can be easily prepared in one-pot
using our strategy by employing different nucleophiles in the initial
acyl chloride substitution stage, followed by sodium azide in the
sulfonyl chloride substitution stage. As shown in Table 5, the sul-
fonyl azide 7c (Table 3, entry 3), prepared by the one-pot method,
was treated with alkynes to afford the corresponding 1,4-sulfonyl
triazoles 12a and 12b via Cu(I)-catalyzed cycloaddition in the
presence of copper(I) thiophene-2-carboxylate (CuTC) catalyst.27
The reaction was carefully optimized and gave moderate yields
(78% and 87%). The 1,4-sulfonyl triazole products were relatively
unstable compared to their nonsulfonylated 1,4-triazole counter-
parts because of the presence of the strongly electron-withdrawing
sulfonyl group. Upon further treatment with Cu catalysts, these
sulfonyl triazoles could be converted into various synthetically
important compounds such as amides,21 amidines,28 and imi-
dates,29 via nucleophilic attacks on the resultant ketenimine in-
termediates. Here, the one-pot procedure could provide, with high
efficiency, variously substituted sulfonyl azides, which could sub-
sequently be converted to reactive sulfonyl triazoles from different
alkynes for advanced chemical transformations.
Preparation of various sulfonamide inhibitors of IDH mutants
R1
O
R2
NH
N
R2
N
R1
N
(a)
(b)
COCl
(1 eq),
DIEA (1 eq),
DCM, 0°C
O
S
O
NH
4-butylaniline
(1.2 eq),
DCM, rt
DIEA (1 eq),
SO2Cl
10 a-d
CH3
Entries
Substrate
(R1)
Substrate
(R2)
Product
Isolated
yield (%)
(10ae10d)
1
2
3
4
Me
Me
H
OMe
Cl
OMe
Cl
10a
10b
10c
10d
66a
64a
71
H
72
a
Overall yield for the four steps from 2-methyl benzoic acid.
Here, an efficient and concise strategy for the preparation of
compound 10 analogues was proposed, as shown in Scheme 2. 5-
(Chlorosulfonyl)-2-methylbenzoyl chloride (9) can be prepared by
the chlorosulfonation of 2-methyl benzoic acid with chlorosulfuric
acid and subsequent treatment with SOCl2. Compound 9 was ob-
tained without further purification beyond the removal of excess
SOCl2 under reduced pressure. Then, compounds 10a and 10b were
synthesized conveniently using the developed one-pot method, by
sequentially adding the first amine (NH2R1) with the second one
(NH2R2). The one-pot strategy described here afforded increased
overall yields (66% (10a) and 64% (10b) over four steps, Table 4)
with a reduced number of steps and reaction times compared to the
original sequence for the preparation of these anti-cancer agents.26
Further, CSBC without methyl substitution was also used to suc-
cessfully prepare 10c and 10d in 71% and 72% yields; these com-
pounds are known to exhibit moderate IDH1m inhibition activity at
Table 5
Cu(I)-catalyzed cycloadditions of a benzanilido sulfonyl azide derivative
O
O
H
N
H
N
R
, CuTC (10 mol %)
toluene, rt, 14 h
O
S O
N3
O
R
S
N
O
N
N
7c
12a-b
Entries
1
Substrate (R)
Product (12ae12c)
Isolated yield (%)
12a
78
87
IC50 between 1 and 50 m
M26
2
12b
OMe
CuTC: copper(I) thiophene-2-carboxylate.
Scheme 2. Preparation of sulfonamide inhibitors. (a) HSO3Cl, 50 ꢀC, 2 h, 93%; (b) SOCl2,
rt, 16 h, 100%; (c) R1NH2, R2NH2, DIPEA 0 ꢀC to rt for 3 h, 68e70%.
3. Conclusion
The method proposed here can be easily used to prepare scaf-
folds that may be utilized in combinatorial chemistry approaches
for the preparation of derivatives and chemical libraries of com-
pounds. Such derivatives and compound libraries may display bi-
ological activities and be useful for identifying and designing
compounds that possess particular activities. It is noteworthy that
this strategy can be extended to substituted chlorosulfonyl benzoyl
chlorides; no significant change in the reactivity or yield was ob-
served in these transformations.
An efficient and convenient one-pot two-step procedure for the
synthesis of carboxamido sulfonic acid derivatives was developed.
The procedure tolerated various functional groups and obviated
purification of highly moisture-sensitive sulfonyl chloride in-
termediates. Although the electronic and steric characteristics of
the participating nucleophiles R1 and R2 affected the coupling ef-
ficiency, the desired coupling products were obtained in moderate
to high yields by using base and a nucleophilic activator. In this
study, nucleophilic substitution occurred selectively at the carbonyl
group; no products from bis-addition were observed. Furthermore,
alcohols, thiols, and sodium azide were also used as nucleophiles to
give the corresponding sulfonic esters, thiosulfonates, and sulfonyl
azide in good to excellent yields. The developed one-pot method
has been demonstrated as a concise and efficient route to prepare
bioactive inhibitors of IDH mutants. To evaluate the applicability of
this method in expanding the structural complexity of resultant
disubstituted sulfonic derivatives, via Cu(I)-catalyzed cycloaddi-
tion, the substituted sulfonyl azide 7c has been used to give im-
portant compound 12, which can be further converted into various
2.5. Substituted sulfonyl azides in the preparation of sulfonyl
triazole derivatives via Cu(I)-catalyzed cycloaddition
To evaluate the utility of the sulfonic acid derivatives obtained
by our one-pot strategy in advanced chemical reactions, azido
compound 7c provided a unique opportunity for the preparation of
1,4-sulfonyl triazoles using Cu(I)-catalyzed cycloaddition reactions.
These 1,4-sulfonyl triazoles have received significant attention in
click chemistry owing to their synthetic versatility. A wide range of

2644
Y.-L. Yang et al. / Tetrahedron 69 (2013) 2640e2646
organic compounds. The one-pot synthetic strategy developed here
successfully prevented undesired decomposition and side reactions
(d, J¼9 Hz, 2H), 3.02 (t, J¼5.4 Hz, 4H), 1.68e1.60 (m, 4H),1.47e1.43
(m, 2H); 13C NMR (75 MHz, CDCl3):
164.6, 137.1, 136.5, 136.1, 132.3,
d
(such as
b
-elimination) during the synthesis of sulfonic acid de-
130.7, 130.2, 129.9, 129.3, 125.9, 122.2, 47.2, 25.3, 23.5; HRMS (ESI):
calcd for C18H18N2O3SCl [M]þ: 377.0727, found: 377.0733.
rivatives and is expected to be applied in the construction of sul-
fonic acid-based molecular libraries.
4.2.5. Compound 5d. White solid; mp: 204 ꢀC; 1H NMR (300 MHz,
4. Experimental section
4.1. General methods
CDCl3):
d
8.17 (s, 1H), 8.14 (d, J¼7.8 Hz, 1H), 8.04 (s, 1H), 7.92 (d,
J¼7.8 Hz, 1H), 7.68 (t, J¼7.8 Hz, 1H), 7.59 (d, J¼8.7 Hz, 2H), 7.50 (d,
J¼8.7 Hz, 2H), 3.02 (t, J¼5.4 Hz, 4H), 1.64 (quin, J¼5.4 Hz, 1H), 1.43
(quin, J¼5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 164.6, 137.2, 137.0,
1H and 13C NMR spectra were acquired at 300 MHz and 75 MHz,
respectively (unless other indicated), related to CDCl3 (calibrated at
7.26 ppm in 1H NMR and at 77.0 ppm in 13C NMR) and methanol-d4
(calibrated at 4.87, 3.31 ppm in 1H NMR and at 49.15 ppm in 13C
NMR). Melting points were determined in open capillary tubes. Flash
136.1, 132.3, 130.7, 130.0, 125.9, 122.4, 117.9, 47.2, 25.3, 23.6; HRMS
(ESI): calcd for [MꢁH]ꢁ: 421.0222, found: 421.0215; IR (CH2Cl2):
1655, 1591, 1529, 578, 507.
4.2.6. Compound 5e. White solid; mp: 206.4 ꢀC; 1H NMR
chromatography was performed using silica gel (43e60
m
m, Merck).
(300 MHz, DMSO-d6):
d
10.58 (s, 1H), 8.27 (d, J¼9.0 Hz, 2H), 7.94
(d, J¼7.8 Hz, 1H), 7.80 (t, J¼7.8 Hz, 1H), 7.72 (d, J¼8.7 Hz, 2H), 7.62
(d, J¼8.7 Hz, 2H), 2.93 (t, J¼5.4 Hz, 4H), 1.55e1.53 (m, 4H),
4.2. Representative procedure for the one-pot synthesis of
sulfonamides
1.37e1.36 (m, 2H); 13C NMR (75 MHz, DMSO-d6):
d 164.1, 138.6,
137.3, 136.1, 135.6, 132.0, 130.2, 129.7, 126.3, 122.7, 46.6, 24.6, 22.8;
HRMS (ESI): calcd for [MꢁH]ꢁ: 469.0083, found: 469.0083; IR
(CH2Cl2): 1652, 1601, 1527, 499.
The procedure for the preparation of compound 3 is represen-
tative for all sulfonamides prepared from m-(chlorosulfonyl)ben-
zoyl chloride. Aniline (62.9 mg, 0.675 mmol) was dissolved in
CH2Cl2 (1 mL), followed by addition of DIEA (117
mL, 0.675 mmol) at
4.2.7. Compound 5f. White solid; mp: 143e144 ꢀC; 1H NMR
(300 MHz, DMSO-d6): d 10.93 (s, 1H), 8.78e8.77 (m, 1H), 8.33e8.31
0
ꢀC. Then, m-(chlorosulfonyl)benzoyl chloride (113.36
mL,
0.743 mmol) in a solution of CH2Cl2 (1 mL) was added to the re-
action mixture by syringe, drop-wise. After reacting for 30 min, the
(m, 2H), 8.21 (dd, 1H, J¼3.0, 6.0 Hz), 8.01e7.96 (m, 2H), 7.87e7.82
(m, 1H), 7.71e8.66 (m, 1H), 2.96e2.92 (t, 4H, J¼6.0 Hz), 1.59e1.52
ice bath was removed. DIEA (117
m
L, 0.675 mmol), DMAP (6.81 mg,
(m, 4H), 1.40e1.32 (m, 2H); 13C NMR (75 MHz, DMSO-d6):
d 164.6,
0.0675 mmol), piperidine (66 L, 0.675 mmol) were added to the
m
147.9,140.0, 136.2,135.2,132.2,130.6,130.1,129.8,126.5,118.5,114.7,
47.3, 25.3, 23.6; HRMS (ESI): calcd for C18H19N3O5S [MꢁH]ꢁ:
388.0967, found: 388.0958; IR (neat): 3273, 3084, 2922, 2839, 1658,
1598, 1523, 1341, 1168, 576.
solution at 25 ꢀC. The reaction was checked by TLC until the starting
material was completely converted to product (1 h). After removal
of CH2Cl2 under reduced pressure, the crude mixture was purified
by column chromatography to obtain the desired product.
4.2.8. Compound 5g. Yellow solid; mp: 227e228 ꢀC; 1H NMR
4.2.1. Compound 3. White solid; mp: 150e151 ꢀC; 1H NMR
(300 MHz, CDCl3):
3H), 7.69 (t, 1H, J¼9 Hz), 2.99 (t, 4H, J¼6 Hz), 1.66e1.58 (m, 4H),
1.45e1.42 (m, 2H); 13C NMR (75 MHz, CDCl3):
164.8, 144.3, 143.9,
d 8.78 (s, 1H), 8.29e8.18 (m, 4H), 7.96e7.88 (m,
(300 MHz, DMSO-d6):
d
10.52 (s, 1H), 8.29 (d, J¼6 Hz, 2H), 7.93 (d,
J¼9 Hz), 7.84e7.77 (m, 3H), 7.38 (t, J¼6 Hz, 2H), 7.13 (t, J¼6 Hz, 1H),
d
2.93 (t, J¼6 Hz, 4H), 1.58e1.50 (m, 4H), 1.37e1.32 (m, 2H); 13C NMR
137.4, 135.6, 132.6, 131.2, 130.2, 125.9, 125.3, 120.7; HRMS (ESI):
calcd for C18H19N3O5S [MꢁH]ꢁ: 388.0967, found: 388.0958; IR
(neat): 2923, 2853, 1660, 1531, 1342, 1168, 577.
(75 MHz, DMSO-d6):
d 164.0, 138.7, 136.0, 135.9, 132.0, 130.1, 129.6,
128.6, 126.4, 124.0, 120.6, 46.6, 24.6, 22.8; HRMS (ESI): calcd for
C18H20N2O3S [MꢁH]ꢁ: 343.1116, found: 343.1108; IR (neat): 2941,
2853, 1654, 1599, 1541, 1442, 1324, 1668, 932, 579.
4.2.9. Compound 5h. Yellow solid; mixture, product; 1H NMR
(300 MHz, CDCl3):
d
11.71 (s, 1H), 9.277 (d, J¼9.6 Hz, 1H), 9.22 (d,
4.2.2. Compound 5a. White solid; mp: 152 ꢀC; 1H NMR (300 MHz,
J¼2.7 Hz, 1H), 8.58 (dd, J¼9.3, 2.7 Hz, 1H), 8.56 (d, J¼2.7 Hz, 1H),
8.38 (s, 1H), 8.05 (d, J¼7.8 Hz, 1H), 7.776 (t, J¼7.8 Hz, 1H), 3.085 (t,
J¼5.4 Hz, 4H), 1.685e1.499 (m, 4H), 1.478e1.421 (m, 2H); 2,4-
CDCl3):
d
8.49 (dd, J¼8.1, 0.9 Hz, 1H), 8.43 (s, 1H), 8.28 (s, 1H), 8.12
(d, J¼7.8 Hz, 1H), 7.96 (d, J¼8.1 Hz, 1H), 7.70 (t, J¼7.8 Hz, 1H), 7.43
(dd, J¼7.9, 0.9 Hz, 1H), 7.35 (td, J¼8.1, 0.9 Hz, 1H), 7.12 (td, J¼7.8,
0.9 Hz, 1H), 3.05 (t, J¼5.4 Hz, 4H), 1.70e1.62 (m, 4H), 1.48e1.40 (m,
dinitroaniline: 1H NMR (300 MHz, CDCl3):
d
9.115 (d, J¼2.4 Hz,
1H), 8.22 (dd, J¼2.7 Hz,1H), 6.9 (d, J¼9.3 Hz, 1H): 13C NMR (75 MHz,
2H); 13C NMR (75 MHz, CDCl3):
d
163.9, 138.1, 135.9, 134.4, 131.1,
CDCl3): d 164.9, 149.7, 149.6, 141.6, 136.4, 132.4, 130.9, 130.0, 129.2,
130.0, 129.4, 128.2, 126.4, 125.6, 123.6, 122.0, 47.2, 25.4, 23.6; HRMS
(ESI): calcd for C18H18N2O3SCl [MꢁH]ꢁ: 377.0727, found: 377.0721;
IR (CH2Cl2): 2941, 2853, 1668, 1480, 1440, 1341, 1313, 1170.
126.6, 125.9, 121.0, 119.7, 46.6, 24.7, 22.8; 2,4-dinitroaniline: 13C
NMR (75 MHz, CDCl3):
d 149.8, 135.1, 128.6, 128.2, 123.3, 119.8;
HRMS (ESI): calcd for C18H17N4O7S [M]þ: 433.0818, found:
433.0813.
4.2.3. Compound 5b. White solid; mp: 150 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
8.42 (s, 1H), 8.20 (s, 1H), 8.14 (d, J¼7.8 Hz, 1H), 7.87 (dt,
4.2.10. Compound 5j. White solid; mp: 178.9 ꢀC; 1H NMR
(300 MHz, CDCl3):
J¼6, 1.2 Hz, 1H), 7.82 (t, J¼1.8 Hz, 1H), 7.65 (t, J¼7.8 Hz, 1H), 7.55 (t,
J¼7.8 Hz, 1H), 7.30 (t, J¼8.1 Hz, 1H), 7.15 (dd, J¼7.8, 1.2 Hz, 1H), 2.99
(t, J¼5.4 Hz, 4H), 1.64e1.56 (m, 4H), 1.45e1.37 (m, 2H); 13C NMR
d
8.18 (s, 1H), 8.13 (d, J¼7.8 Hz, 1H), 8.10 (s, 1H),
7.88 (d, J¼7.8 Hz, 1H), 7.65 (t, J¼7.8 Hz, 1H), 7.57 (d, J¼8.6 Hz, 2H),
6.91 (d, J¼8.9 Hz, 2H), 3.82 (s, 3H), 3.00 (t, J¼5.3 Hz, 4H), 1.62
(quintet, J¼5.6 Hz, 4H), 1.47e1.35 (m, 2H); 13C NMR (300 MHz,
(75 MHz, CDCl3):
d 164.7, 139.1, 137.3, 136.1, 135.0, 132.3, 130.9,
130.3, 130.1, 125.9, 125.3, 121.0, 118.9, 47.3, 25.3, 23.6; HRMS (ESI):
calcd for C18H18N2O3SCl [MꢁH]ꢁ: 377.0727, found: 377.0725; IR
(CH2Cl2): 2924, 2852, 1659, 1482, 1423, 1339, 1314, 1169.
CDCl3): d 164.3, 157.1, 137.3, 136.5, 132.0, 130.8, 130.5, 129.8, 125.8,
122.6, 114.5, 55.7, 47.2, 25.3, 23.6; HRMS (ESI): calcd for
C19H22N2O4S [MþNa]þ: 397.1198, found: 397.1181; IR (CH2Cl2):
2936, 1633, 1604, 1543, 1508, 1447, 1409, 1339, 1166.
4.2.4. Compound 5c. White solid; mp: 142e143 ꢀC; 1H NMR
(300 MHz, CDCl3):
7.92 (d, J¼7.8 Hz,1H), 7.69 (d, J¼7.8 Hz,1H), 7.64 (d, J¼9 Hz, 3H), 7.36
d
8.18 (s, 1H), 8.14 (d, J¼8.1 Hz, 1H), 8.05 (s, 1H),
4.2.11. Compound 5k. White solid; mp: 153 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
8.27 (s, 1H), 8.12 (d, J¼7.8 Hz, 1H), 7.86 (d, J¼7.8 Hz, 2H),

Y.-L. Yang et al. / Tetrahedron 69 (2013) 2640e2646
2645
7.60 (t, J¼7.8 Hz, 1H), 6.90 (s, 2H), 2.99 (t, J¼5.1 Hz, 4H), 2.28 (s, 3H),
2.20 (s, 6H), 1.63e1.56 (m, 4H), 1.45e1.38 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 164.8, 137.2, 137.1, 135.8, 135.4, 131.8, 131.1, 130.2,
129.5, 129.0, 126.3, 47.0, 25.2, 23.4, 21.1, 18.3; HRMS (ESI): calcd for
C21H26N2O3S [MꢁH]ꢁ: 385.1586, found: 385.1579; IR (CH2Cl2):
1574, 1610, 1651.
135.84, 132.96, 130.56, 129.98, 129.45, 129.07, 128.79, 125.83,
125.72, 124.71, 120.21, 21.04; HRMS (ESI) calcd for C20H17NO3S2
[MþH]þ: 384.0728, found: 383.1179; IR (neat): 3302, 3064, 2925,
2855, 1652, 1601, 1541, 1489, 1445, 1325, 1261, 805, 752, 691.
4.3.5. Compound 7e. Syrup; 1H NMR (400 MHz, CDCl3): 1H NMR
(400 MHz, CDCl3)
d 8.52 (s, 1H, eNH), 8.37 (s, 1H, Ha), 8.08 (d,
4.2.12. Compound 5l. White solid; mp: 124e126 ꢀC; 1H NMR
J¼7.7 Hz, 1H, Hd), 8.00 (d, J¼7.7 Hz, 1H, Hd), 7.63 (d, J¼7.9 Hz, 2H,
Hb), 7.55 (t, J¼7.9 Hz, 1H, Hc), 7.30 (t, J¼7.7 Hz, 2H, He), 7.12 (t,
J¼7.7 Hz, 1H, Hf), 1.38 (s, 9H, Hg), 13C NMR (100 MHz, CDCl3)
(300 MHz, DMSO-d6):
d
10.78 (s, 1H, NH), 8.46 (d, J¼5.7 Hz, 2H),
8.06e7.97 (m, 3H), 7.91e7.83 (m, 2H), 7.66 (d, J¼6.9 Hz, 1H),
7.61e7.54 (m, 3H), 2.98 (s, 4H), 1.62e1.52 (m, 4H), 1.44e1.34 (m,
d
163.97, 147.13, 137.46, 136.18, 132.14, 129.66, 30.74, 129.57, 129.00,
2H); 13C NMR (75 MHz, DMSO-d6):
d
164.8, 136.2, 135.4, 133.8,
125.10, 124.97, 120.64, 56.02; HRMS (ESI) calcd C17H19NO3S2 for
[MꢁH]ꢁ: 348.0728, found: 348.0720; IR (neat): 3340, 3074, 2971,
1656, 1601, 1546, 1445, 1332, 1264, 1147, 914, 761, 693, 613.
133.5, 132.2, 130.3, 129.8, 129.2, 128.1, 126.6, 126.1, 126.1, 125.5,
124.1, 123.3, 46.6, 24.7, 22.8; HRMS (ESI): calcd for C22H21N2O3S
[MꢁH]ꢁ: 393.1273, found: 393.1274; IR (CH2Cl2): 1652, 1599, 1526,
851, 754, 725, 701.
4.3.6. Compound 7f. White solid; mp: 121e123 ꢀC; 1H NMR
(300 MHz, MeOD):
d
8.42 (s, 1H), 8.23 (d, J¼7.8 Hz, 1H), 8.06 (d,
4.3. General procedure for the synthesis of sulfonyl azide,
sulfonic esters and thiosulfonates
J¼7.5 Hz,1H), 7.74 (t, J¼8.4, 7.5 Hz,1H), 7.65 (d, J¼8.1 Hz, 2H), 7.32 (t,
J¼7.5 Hz, 1H), 7.12 (t, J¼7.5 Hz, 1H), 4.18 (t, J¼6.0 Hz, 2H), 2.19 (dt,
J¼2.4, 4.5 Hz, 2H), 2.12 (d, J¼5.1 Hz, 1H), 1.84e1.74 (m, 2H). 13C NMR
The procedure for the preparation of compound 7g is repre-
sentative for sulfonic acid derivatives prepared from m-(chlor-
osulfonyl)benzoyl chloride. Aniline (244 mg, 2.62 mmol) was
(75 MHz, MeOD): d 166.7, 139.7, 138.2, 137.9, 134.1, 131.9, 131.2,
130.0, 128.4, 126.1, 122.6, 83.1, 71.1, 70.8, 29.1, 15.4; HRMS (ESI):
calcd for C18H18NO4S [MþH]þ: 344.0957, found: 344.0948; IR
(CH2Cl2): 2123, 1652, 1600, 1539, 787, 858, 755, 692.
dissolved in CH2Cl2 (2 mL), followed by addition of DIEA (456
m
L,
2.62 mmol) and 4 A molecular sieves (786 mg) at 0 ꢀC. Then, m-
(chlorosulfonyl)benzoyl chloride (440 L, 2.88 mmol) in a solution
ꢀ
m
4.3.7. Compound 7g. White solid; mp: 137e138 ꢀC. 1H NMR
of CH2Cl2 (1 mL) was added to the reaction mixture by syringe,
drop-wise. After reacting for 30 min, the ice bath was removed.
(300 MHz, CDCl3):
d
8.77 (s, 1H), 8.38 (s, 1H), 8.14 (d, J¼7.8 Hz,
1H), 8.00 (d, J¼7.5 Hz, 1H), 7.65 (d, J¼7.8 Hz, 2H), 7.57 (t, J¼7.8 Hz,
1H), 7.31 (t, J¼7.5 Hz, 2H), 7.14 (t, J¼7.2 Hz, 1H), 4.79e4.70 (m,
DIEA (456
m
L, 2.62 mmol), DMAP (160 mg, 1.31 mmol), and dis-
L, 13.078 mmol) were added to the
tillated isopropanol (1000
m
4H), 1.23 (d, J¼6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d 164.4,
solution at 25 ꢀC. The reaction was checked by TLC until the starting
material was completely converted to product (12 h). After removal
of CH2Cl2 under reduced pressure, the crude mixture was purified
by column chromatography to obtain the desired product.
138.0, 137.7, 136.3, 132.8, 130.3, 129.8, 129.1, 126.3, 125.1, 121.0,
78.5, 22.8 HRMS (ESI): calcd for C16H17NO4S [MꢁH]ꢁ: 318.0800,
found: 318.0795; IR (CH2Cl2): 3301, 2986, 1656, 1540, 1443,
1182, 913.
4.3.1. Compound 7a. White solid; mp: 140e141 ꢀC; 1H NMR
4.4. General procedure for the synthesis of sulfonamide-type
inhibitors
(300 MHz, DMSO-d6):
d
10.50(s,1H), 8.36(s,1H), 8.23(d, J¼7.8Hz,1H),
7.99 (d, J¼8.1 Hz,1H), 7.84 (t, J¼6 Hz,1H), 7.78 (m, 3H), 7.37 (t, J¼7.8 Hz,
2H), 7.12 (t, J¼7.5 Hz, 1H), 3.62 (t, J¼6.3 Hz, 2H), 2.91 (q, J¼6.6 Hz, 2H),
The procedure for the preparation of compound 10a: to a stirred
solution of 5-chlorosulfonyl-2-methyl-benzoylchloride (65 mg;
0.258 mmol) in DCM (1.3 mL) was added DIEA (0.045 mL;
0.258 mmol) followed by 1-(2-methylphenyl) piperazine
(49.56 mg) and stirred at 0 ꢀC for 30 min and at rt for 30 min under
nitrogen atmosphere. To the reaction mixture was added 4-
butylaniline (46.16 mg; 0.309 mmol) followed by DIEA (0.045 mL;
0.258 mmol) and stirred for 2 h at rt under nitrogen atmosphere.
TLC indicated completion of the reaction. The reaction mixture was
diluted with DCM (20 mL), washed with H2O (2ꢂ5 mL), dried over
MgSO4, filtered, and concentrated to afford the crude compound,
which was purified by silica gel flash column chromatography us-
ing 20e25% ethyl acetate in hexane as an eluent to afford the de-
sired product as a syrup (95.16 mg; 70.8%).
1.83 (q, J¼6.6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6):
d 164.2, 140.7,
138.8, 135.9, 131.4, 129.6, 129.3, 128.7, 125.9, 124.0, 120.6, 42.3, 32.0;
HRMS (ESI): calcd for C16H17N2O3NaSCl [MþNa]þ: 375.0546, found:
375.0529; IR (neat): 3286, 2924, 1656, 1598, 1496, 1442, 1323.
4.3.2. Compound 7b. White solid; mp: 135e136 ꢀC; 1H NMR
(300 MHz, DMSO-d6):
d
10.51 (s, 1H), 8.33 (s, 1H), 8.27 (d, J¼7.8 Hz,
1H), 8.01 (d, J¼8.1 Hz, 1H), 7.83e7.75 (m, 3H), 7.38 (t, J¼7.5 Hz, 2H),
7.13 (t, J¼7.5, 1H), 3.19 (t, J¼6.6 Hz, 4H), 1.69e1.64 (m, 4H); 13C NMR
(75 MHz, DMSO-d6):
d 164.0, 138.7, 136.7, 135.8, 131.9, 129.9, 129.7,
128.6, 126.2, 124.0, 120.6, 47.8, 24.7. HRMS (ESI): calcd for
C17H18N2O3NaS [MþNa]þ: 353.0936, found: 353.0920; IR (MeOH):
3333, 2958, 1650, 1600, 1538, 1443, 1328, 1198.
4.3.3. Compound 7c. White solid; mp: 157e158 ꢀC; 1H NMR
4.4.1. Compound 10a. Syrup; 1H NMR (300 MHz, MeOD):
d 7.73 (d,
(300 MHz, DMSO-d6):
d
10.61 (s, 1H), 8.56 (s, 1H), 8.44 (d, J¼7.8 Hz,
J¼8.1 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J¼8.1 Hz, 1H), 7.18e6.88 (m, 8H),
3.91e3.85 (m, 5H), 3.31e3.04 (m, 4H), 2.79e2.75 (m, 2H), 2.42 (t,
J¼36, 2H), 2.32 (s, 3H), 1.51e1.41 (m, 2H), 1.30e1.20 (m, 2H), 0.84 (t,
1H), 8.24 (d, J¼8.1 Hz, 1H), 7.92 (t, J¼7.8 Hz, 1H), 7.78 (d, J¼8.1 Hz,
2H), 7.38 (t, J¼7.8 Hz, 2H), 7.14 (t, J¼7.5 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6):
d
163.3, 138.6, 137.9, 136.5, 134.5, 130.6, 130.0, 128.7,
J¼14.7, 3H); 13C NMR (75 MHz, MeOD):
d 170.09, 153.91, 141.69,
126.2, 124.2, 120.7; HRMS (ESI): calcd for C13H10N4O3S [MꢁH]ꢁ:
141.25, 141.02, 138.72, 137.39, 136.23, 132.56, 130.11, 128.93, 125.88,
125.14, 122.99, 122.22, 119.95, 112.93, 56.10, 52.40, 51.69, 43.01,
35.88, 34.71, 23.28, 19.24, 14.24; HRMS (ESI) calcd for C29H36N3O4S
[MþH]þ: 522.2431, found: 522.2427.
301.0395, found: 301.0396; IR (neat): 2142, 1643, 1440, 1375, 1168.
4.3.4. Compound 7d. Syrup; 1H NMR (400 MHz, CDCl3):
d 7.93 (s,
1H), 7.79 (s, 1H), 7.67 (d, J¼7.6 Hz, 1H), 7.64 (d, J¼7.6 Hz, 1H), 7.58 (d,
J¼8.0 Hz, 2H), 7.38 (t, J¼7.6 Hz, 2H), 7.36 (d, J¼8.2 Hz, 2H), 7.34 (t,
J¼8.0 Hz, 1H), 2.30 (s, 3H), 7.09 (d, J¼8.2 Hz, 2H), 7.14 (t, J¼7.6 Hz,
4.4.2. Compound 10b. Syrup; 1H NMR (300 MHz, MeOD):
d 7.78
(d, J¼6.6 Hz, 1H), 7.77 (s, 1H), 7.52e7.39 (m, 2H), 7.30 (t, J¼14.4,
1H); 13C NMR (100 MHz, CDCl3)
d 164.93, 138.59, 138.01, 137.86,
1H), 7.15e7.02 (m, 6H), 3.94e3.92 (m, 2H), 3.14e3.09 (m, 4H),

2646
Y.-L. Yang et al. / Tetrahedron 69 (2013) 2640e2646
2.80 (m, 2H), 2.44 (t, J¼29.7, 2H), 2.37 (s, 3H), 1.54e1.43 (m, 2H),
1.33e1.23 (m, 2H), 0.87 (t, J¼14.4, 3H); 13C NMR (75 MHz, MeOD):
126.81, 125.31, 121.01, 120.58, 118.10, 114.47, 55.35 HRMS (ESI) calcd
for C22H18N4O4S [MþNa]þ: 457.0946, found: 457.0941.
d
170.17, 149.88, 141.24, 140.99, 138.74, 137.36, 136.26, 132.59,
131.63, 130.08, 129.05, 128.91, 125.90, 125.70, 122.97, 122.14, 52.91,
49.59, 43.12, 35.89, 34.69, 23.33, 19.25, 14.22; HRMS (ESI) calcd
for C30H31N3O3SCl [MþNa]þ: 548.1775, found: 548.1712.
Acknowledgements
This work is supported by grants from National Science Council
(NSC 99-2113-M-110-007-MY2 and NSC 101-2113-M-110-007-
MY2) and National Sun Yat-sen University (01C030703 and
01A06802). We also thank for the support from the center of
emerging contaminants research at National Sun Yat-sen
University.
4.4.3. Compound 10c. Syrup; 1H NMR (300 MHz, MeOD):
d 7.91 (d,
J¼7.5 Hz, 1H), 7.74 (s, 1H), 7.67e7.59 (m, 2H), 7.09e6.91 (m, 8H),
3.88 (m, 5H), 3.31 (m, 2H), 3.08 (m, 2H), 2.88e2.86 (m, 2H), 2.48 (t,
J¼15.3, 2H), 1.55e1.48 (m, 2H), 1.34e1.24 (m, 2H), 0.88 (t, J¼14.4,
3H); 13C NMR (75 MHz, MeOD):
d 170.37, 153.88, 141.62, 141.35,
141.15, 137.44, 136.14, 132.45, 130.88, 130.15, 129.56, 126.65, 125.14,
123.14, 122.23, 119.92, 112.95, 56.11, 52.26, 51.67, 43.55, 35.90, 34.71,
23.29, 14.26; HRMS (ESI) calcd for C28H34N3O4S [MþH]þ: 508.2270,
found: 508.2276.
Supplementary data
1H NMR and 13C NMR of compounds. Supplementary data as-
sociated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2013.01.028.
4.4.4. Compound 10d. Syrup; 1H NMR (300 MHz, MeOD):
d 7.93 (d,
J¼1.8 Hz, 1H), 7.90 (s, 1H), 7.71e7.64 (m, 2H), 7.41 (d, J¼7.8 Hz, 1H),
7.34 (t, J¼14.4, 1H), 7.30e6.99 (m, 5H), 3.91 (br, 2H), 3.34e3.33 (m,
4H), 3.01 (br, 2H), 2.85 (b, 2H), 2.47 (t, J¼15.6 Hz, 2H), 1.54e1.34
(m, 2H), 1.31e1.21 (m, 2H), 0.87 (t, J¼14.7 Hz, 3H); 13C NMR
References and notes
1. Navia, M. A. Science 2000, 288, 2132.
2. Hansch, C. S.; Sammes, P. G.; Taylor, J. B. Comprehensive Medicinal Chemistry;
Pergamon Press: Oxford, 1990; Vol. 4.
3. Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40,
4761.
4. Roush, W. R.; Gwaltney, S. L.; Cheng, J.; Scheidt, K. A.; McKerrow, J. H.; Hansell,
(75 MHz, MeOD):
d 170.52, 149.92, 141.33, 141.17, 137.41, 136.14,
132.43, 131.61, 130.91, 130.10, 130.02, 129.54, 129.02, 126.59,
125.66, 123.13, 122.12, 52.68, 51.98, 43.70, 35.89, 34.68, 23.30,
14.17; HRMS (ESI) calcd for C27H29N3O3SCl [MꢁH]þ: 510.1618,
found: 510.1626.
E. J. Am. Chem. Soc. 1998, 120, 10994.
5. Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535.
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4.5. General procedure for the synthesis of 1,4-triazoles
The procedure for the preparation of compound 11a: to a stirred
solution of phenyl acetylene (25.33 mg; 0.248 mmol) in toluene
(0.82 mL) was added CuTC (3.14 mg; 0.0165 mmol) and stirred for
10 min at rt. To the resultant mixture was added compound 7c
(50 mg, 0.165 mmol) and stirred for 14 h at rt. The progress of the
reaction was monitored by TLC. The reaction mixture was diluted
with ethyl acetate (25 mL), stirred with cuprisorb resin (100 mg) for
30 min to remove Cu, filtered, washed with H2O (2ꢂ5 mL), dried
over anhyd MgSO4, filtered, and concentrated to afford the desired
product as a syrup (53 mg; 79.3%).
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4.5.1. Compound 12a. Syrup; 1H NMR (500 MHz, CDCl3):
d 8.63 (s,
1H), 8.36 (s, 1H), 8.31e8.26 (m, 2H), 8.13 (s, 1H), 7.82 (d, J¼4.2 Hz,
2H), 7.75 (t, J¼9.6 Hz, 1H), 7.64 (d, J¼4.8 Hz, 2H), 7.46e7.38 (m,
5H), 7.20 (t, J¼9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d 162.97,
147.69, 137.17, 136.99, 136.80, 134.62, 131.37, 130.61, 129.35,
129.21, 129.06, 128.43, 126.89, 126.12, 125.32, 120.60, 119.10
HRMS (ESI) calcd for C21H16N4O3S [MþNa]þ: 427.0841, found:
427.0835.
21. Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16046.
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€
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4.5.2. Compound 12b. Syrup; 1H NMR (500 MHz, CDCl3):
d 8.62 (s,
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1H), 8.31e8.27 (m, 3H), 8.08 (s, 1H), 7.76e7.73 (m, 3H), 7.64 (d,
J¼4.5 Hz, 2H), 7.40 (t, J¼9.0 Hz, 2H), 7.20 (t, J¼8.7 Hz, 1H), 6.96 (d,
J¼5.1 Hz, 2H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3): 162.97,
160.46, 137.17, 136.96, 136.93, 134.56, 131.33, 130.59, 129.21, 127.51,