Caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors

Article abstract of DOI:10.1016/S0968-0896(03)00372-9

HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than L-chicoric acid (IC₅₀=11.8 μg/mL) and others were comparable to L-chicoric acid. Furthermore, the structure-activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.

Full text of DOI:10.1016/S0968-0896(03)00372-9

Bioorganic & Medicinal Chemistry 11 (2003) 3589–3593
Caffeoyl Naphthalenesulfonamide Derivatives as HIV
Integrase Inhibitors
Yu-Wen Xu,a Gui-Sen Zhao,a,* Cha-Gyun Shin,b
Heng-Chang Zang,a Chong-Kyo Leec and Yong Sup Leed
aCollege of Pharmacy, Shandong University, PO Box 111, 44# Wenhuaxi Road, Ji’nan 250012,
Shandong Province, PR China
bDepartment of Biotechnology, Chung Ang University, An-Sung 456-756, South Korea
cPharmaceutical Screening Center, Korea Research Institute of Chemical Technology, PO Box 107,
Yusong, Taejeon 305-600, South Korea
dDivision of Life Sciences, Korea Institute of Science & Technology, PO Box 131, Cheongryang,
Seoul 130-650, South Korea
Received 27 May 2003; accepted 31 May 2003
Abstract—HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS
drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV
integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were
more potent than l-chicoric acid (IC50=11.8 mg/mL) and others were comparable to l-chicoric acid. Furthermore, the structure–
activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development
and design of HIV-1 integrase inhibitors in the future.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
next to conserved cytosine-adenine sequence from each
30-end of the viral DNA. IN then attaches the processed
30-end of the viral DNA to the host cell DNA in the
strand transfer reaction. The essential role of IN has
been described in experiment where IN mutants with
defective catalytic capability are replication-incompe-
tent. As there is no known human counterpart of HIV
integrase, IN is an attractive target for antiviral drug
design.6
The occurrence of tolerance to single target-directed
anti-human immunodeficiency virus (HIV) therapies
can potentially be overcome by combination treatments,
which disrupt multiple points in the viral life cycle.1
Among the most effective combination regiments are
those employing reverse transcriptase and protease
inhibitors;2 however, emergence of resistant virus is also
a limiting factor to reverse transcriptase and protease
inhibitors. To further enhance the effectiveness of com-
bination drug therapy, drugs targeting other steps in the
life cycle of HIV are needed.
For the past few years, extensive efforts have been made
resulting in a discovery of large number of HIV IN
inhibitors. Recent studies showed that l-chicoric acid
(1) and diecaffeoyl quinic acids (2) display potent activ-
ity against HIV IN and can inhibit HIV replication with
moderate anti-HIV activity.7À12 Common structural
features of the reported synthetic analogues are caffeic
acid esters separated by aliphatic, alicyclic, or aromatic
linker.13,14 However, the synthesis of caffeic amides
connected with a naphthlaenesulfonamide as HIV IN
inhibitors has not been reported previously. In the
present study, we synthesized new caffeoyl derivatives
using functionalized naphthalenesulfonamides and tested
An essential step in the viral life cycle is integration of
the viral DNA into the host genome.3 This step is cata-
lyzed by the viral enzyme, HIV integrase (HIV IN).
Integrase catalyzes two separate but chemically similar
reactions, known as 30-processing and DNA strand
transfer.4,5 In 30-processing, IN removes a dinucleotide
*Corresponding author. Tel.: +86-531-838-2835; fax: +86-531-294-
2324; e-mail: guisenzhao@sdu.edu.cn
0968-0896/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00372-9

3590
Y.-W. Xu et al. / Bioorg. Med. Chem. 11 (2003) 3589–3593
HIV IN inhibitory activities to explore the structure and
activity relationships.
then refluxing with thionyl chloride (5 equivalents) in
benzene v/v=8:1).19
The inhibitory activity of l-choride acid has been
included for comparison. In general, all compounds III
showed moderate HIV IN inhibitory activities and are
comparable or more potent than that of l-chicoric acid.
The inhibitory activities of all compounds III were
remarkably increased when compared to those com-
pounds II20 which containing acetyl protecting group.
Among the synthesized compounds, compound III-3
containing N-phenethylsulfonamide substitution in side
chain showed the best inhibitory activity and the next
order are N-benzylsulfoneamide and N-phenylsulfona-
mide substitution (entry 2, 1). Substitution of p-fluoro
group (entry 4) in N-phenylsulfonamide derivative
increased the HIV IN inhibitory activity while substitu-
tion of p-chloro and p-bromo groups decreased the
inhibitory activity (entry 5, 6).
Results and Discussion
The target compounds as typified by general structure
(III) were prepared by reacting different amines with
diacetyl caffeoyl chloride in acetone at room tempera-
ture followed by removal of diacetyl protecting groups
in MeOH–THF containing aqueous HCl15 as depicted
in Scheme 1. The structures and HIV IN inhibitory
activities of caffeoyl naphthalenesulfonamide derivatives
(III) are shown in Table 1.16,17
To further study the correlation of the structural fea-
tures and anti-HIV IN activities, methyl or nitro groups
were substituted at phenyl ring in N-phenylsulfonamide
derivative to result in lesser activity than that of l-chi-
coric acid. These results suggested that these com-
pounds with more potent inhibitory activities consisted
of two aryl units, one of which contains the 1,2-dihy-
droxy pattern (caffeoyl group) and the other contains
different electro-attracting groups as side chain, sepa-
rated by an appropriate linker segment. It was observed
that in the side chain, the compounds containing electro-
attracting groups on benzene ring have more potent
inhibitory activities than those containing electro-
donating groups. Furthermore, the presence of longer
span between benzene ring and sulfornamide caused the
more potent inhibitory activity. These activity differences
may probably be explained as the different interaction
The starting 5-amino-naphthalenesulfonamides (I) were
prepared from 1-naphthaleneamino-5-sulfonic acid as
depicted in Scheme 2. The compound 3 was purchased
from Shanghai chemical reagent company. The com-
pound 5 was prepared from compound 3 by reaction
with NaOH followed by protection of amino group in
ꢀ
Ac2O at 10 0C. The compound 6 was synthesized at
room temperature by substitution of sodium sulfonate
group in compound 5 to chlorosulfonyl group with
HOSO2Cl. 5-Amino-naphthalenesulfonamides (I)18
were synthesized from compound 7 by acylation of
compound 6 with different aromatic amines followed
by deprotection of acetyl groups. Ac2-caffeoyl-Cl was
prepared by treatment of 3,4-dihydroxycinnamic acid
with acetic anhydride (10equivalents) in pyridine
(v/v=5:1) in the dark overnight at room temperature,
Scheme 1.

Y.-W. Xu et al. / Bioorg. Med. Chem. 11 (2003) 3589–3593
Table 1. Structures and HIV IN inhibitory activities of target compounds
3591
Entry
1
Structure of II
IC50 (mg/mL)a of II
Structure of III
IC50 (mg/mL)a of III
12.2Æ1.1
>100
2
>100
11.9Æ2.2
24.6Æ6.3
>100
8.6Æ4.8
4.5Æ3.4
7.9Æ4.9
20.4Æ7.9
19.5Æ4.5
>100
3
4
5
6
>100
7
>100
8
>100
19.3Æ3.5
20.4Æ3.7
19.8Æ4.5
11.8
9
>100
10
>100
11
l-Chicoric acid(1)b
aEach value is average of at least two runs.
bl-Chicoric acid was prepared by known method.
Scheme 2.
between IN and the inhibitors containing different side
chain through van der Waals contact or hydrophobic
interaction. Although the caffeoyl compounds exhibited
good inhibition against isolated HIV IN, none of the
caffeoyl sulfonamide compounds could inhibit the
replication of HIV in cell bases assay at nontoxic con-
centration (data not shown) implicating the important
role of carboxylic acid in l-chicoric acid.
which have a naphthalenesulfonamide as a basic skele-
ton. This work is the first example on the synthesis of
caffeic acid amides joined a functional naphthanene-
sulfonamide for the development of HIV integrase
inhibitiors.
References and Notes
In conclusion, we have synthesized and tested the inhi-
bitory activities of a new type of HIV IN inhibitors,
1. DeClercq, E. J. Med. Chem. 1995, 38, 2491.
2. Zhang, X.; Neamati, N.; Lee, Y. K.; Orr, A.; Brown, R. D;

3592
Y.-W. Xu et al. / Bioorg. Med. Chem. 11 (2003) 3589–3593
Whitaker, N.; Pommier, Y.; Burke, T. R., Jr. Bioorg. and Med.
Chem. 2001, 9, 1649.
3. Boyer, P. L.; Tantillo, C.; Jacobo-Mmolina, A.; Nanni,
R. G.; Ding, J.; Arnold, E. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 4882.
4. Craigie, R.; Fujiwara, T.; Bushman, F. Cell 1990, 62, 829.
5. Katz, R. A.; Merkel, G.; Kulkosk, T.; Leis, J.; Salka, A. M.
Cell 1990, 63, 87.
6. Chen, I. J.; Neamati, N.; Nicklaus, M. C.; Orr, A.; Ander-
son, L.; Barchi, J. J., Jr; Kelley, J. A.; Pommier, Y.; Mac-
Kerell, A. D., Jr Bioorg. and Med. Chem. 2000, 8, 2385.
7. Robinson, W. E., Jr. Infect. Med. 1998, 15, 129.
8. Robinson, W. E., Jr.; Reinecke, G.; Abdel-Malek, S.; Jia,
Q.; Chow, S. A. Natl. Acad. Sci. U.S.A. 1996, 93, 6326.
9. Robinson, W. E.; Codeiro, M.; Abdel-Malek, S.; Jia, Q.;
Chow, S. A.; Reinecke, G.; Mitchell, W. M. Mol. Pharmacol.
1996, 50, 846.
10. McDougall, B. R.; King, P. J.; Wu, B. W.; Hostomsk, Z.;
Reinecke, M. G.; Robinson, W. E., Jr. Antimicrob. Agent
Chemother. 1998, 42, 140.
11. Neamiati, N.; Hong, H.; Mazumder, A.; Wang, S.; Sun-
der, S.; Nicklaus, N. C.; Milne, G. W. A.; Proska, B.; Pom-
mier, Y. J. Med. Chem. 1997, 40, 942.
MS calcd for C25H19N2O5FS (MÀH+) 477.50, found 477.5.
III-5: Yield 77%, mp: 234–236 ꢀC, Rf=0.35 (EtOAc/petro-
leum ether 1:1); IR (KBr, cmÀ1): 450, 3330, 3057, 1656, 1603,
1516, 1490, 1285, 1148, 926–714; 1H NMR (DMSO, 400 MHz)
d 10.91 (s, 1H), 10.21 (s, 1H), 9.57 (s, 1H), 9.27 (s, 1H), 8.56
(d, 1H, J=8.5 Hz), 8.40(d, 1H, J=8.2 Hz), 8.25 (d, 1H,
J=7.2 Hz), 7.97 (d, 1H, J=7.4 Hz), 7.76 (t, 1H, J=7.2 Hz),
7.67 (t, 1H, J=8.3 Hz), 7.47 (d, 1H, J=15.7 Hz), 7.23 (d, 2H,
J=8.2 Hz), 7.05 (t, 3H, J=6.3 Hz), 6.97 (d, 1H, J=7.9 Hz),
6.80(t, 2H,
J=6.9 Hz) MS calcd for C25H19N2O5ClS
(MÀH+)493.96, found 493.5. III-6: Yield 62%, mp: 162–
166 ꢀC, Rf=0.4 (EtOAc/petroleum ether 3:2); IR (KBr, cmÀ1):
3346, 3246, 3027, 1656, 1597, 1516, 1488, 1270, 1150, 974–709;
1H NMR (DMSO, 400 MHz) d 10.88 (s, 1H), 10.18 (s, 1H),
9.52 (s, 1H), 8.56 (d, 1H, J=8.8 Hz), 8.41 (d, 1H, J=8.5 Hz),
8.25 (d, 1H, J=7.4 Hz), 7.96 (t, 1H, J=7.1 Hz), 7.75 (t, 1H,
J=7.7 Hz), 7.67 (t, 1H, J=8.2 Hz), 7.47 (d, 1H, J=15.6 Hz),
7.35 (d, 2H, J=7.1 Hz), 7.07 (s, 1H), 6.96 (t, 3H, J=10.1 Hz),
6.80(t, 2H,
J=7.9 Hz) MS calcd for C25H19N2O5BrS
(MÀH+) 539.41, found 539.5. III-7: Yield 78%, mp: 156–
160 ꢀC, Rf=0.5 (EtOAc/petroleum ether 3:2); IR (KBr, cmÀ1):
3400, 3249, 3047, 1659, 1599, 1513, 1496, 1283, 1148, 974–701;
1H NMR (DMSO, 400 MHz) d 10.52 (s, 1H), 10.16 (s, 1H),
9.52 (s, 1H), 9.22 (s, 1H), 8.59 (d, 1H, J=8.5 Hz), 8.37 (d, 1H,
J=8.5 Hz), 8.19 (d, 1H, J=7.2 Hz), 7.94 (t, 1H, J=6.6 Hz),
7.73 (t, 1H, J=7.7 Hz), 7.63 (t, 1H, J=7.7 Hz), 7.47 (d, 1H,
J=15.7 Hz), 7.06 (s, 1H), 6.97–6.89 (m, 5H), 6.80 (t, 2H,
J=7.7 Hz), 2.11 (s, 3H) MS calcd for C26H22N2O5S (MÀH+)
473.54, found 473.5. III-8: Yield 82%, mp: 166–170 ꢀC,
Rf=0.5 (EtOAc/petroleum ether 3:2); IR (KBr, cmÀ1): 3346,
12. Neamati, N.; Hong, H.; Sunder, S.; Milne, G. W. A.;
Pommier, Y. Mol. Pharmacol. 1997, 52, 1041.
13. King, P. J.; Ma, G.; Miao, W.; Jia, Q.; McDougall, B. R.
J. Med. Chem. 1999, 42, 497.
14. Lin, Z.; Neamati, N.; Zhao, H.; Kiyru, Y.; Turpin, B. R.;
DeClercq, E.; Rice, W. G.; Pmmier, Y.; Burke, T. R., Jr.
J. Med. Chem. 1999, 42, 1401.
15. Omuna, Hitoshi. Patent: WO. Patent 9,112,237,1991;
Chem. Abstr. 1991, 128, 365d.
1
3237, 3057, 1659, 1597, 1529, 1491, 1272, 1152, 972–696; H
NMR (DMSO, 400 MHz) d 11.40(s, 1H), 10.19 (s, 1H), 8.57
(d, 1H, J=8.5 Hz), 8.43 (d, 1H, J=8.8 Hz), 8.36 (d, 1H,
J=6.6 Hz), 7.96 (t, 1H, J=7.1 Hz), 7.89 (s, 1H), 7.81–7.70(m,
3H), 7.49–7.45 (m, 3H), 9.07 (s, 1H), 6.95 (d, 1H, J=6.3 Hz),
6.82–6.80(m, 2H) MS calcd for C 25H19N3O7S (MÀH+)
504.51, found 504.5. III-9: Yield, 70%, mp: 172–176 ꢀC,
Rf=0.45 (EtOAc/petroleum ether 3:2); IR(KBr, cmÀ1): 3331,
16. The enzyme inhibition assay of compounds against HIV-1
integrase was carried out as described previously: Oh, J.-W.;
Shin, C.-G. Mol. Cells 1996, 6, 96.
17. III-1: Yield 75%, mp: 256–258 ꢀC, Rf=0.5 (EtOAc/petroleu
mether 2:1); IR (KBr, cmÀ1): 3346, 3250, 3037, 1664, 1598,
1516, 1493, 1284, 1147, 927–687; 1H NMR (DMSO, 400 MHz)
d 10.69 (s, 1H), 10.16 (s, 1H), 9.53 (s, 1H), 9.23 (s, 1H), 8.59
(d, 1H, J=8.8 Hz), 8.39 (d, 1H, J=8.5 Hz), 8.24 (d, 1H,
J=6.3 Hz), 7.95 (d, 1H, J=6.9 Hz), 7.74 (t, 1H, J=7.7 Hz),
7.67 (t, 1H, J=8.3 Hz), 7.47 (d, 1H, J=15.7 Hz), 7.15 (t, 2H,
J=6.6 Hz), 7.07–6.90(m, 5H), 6.80 (t, 2H, J=8.2 Hz). MS
calcd for C25H20N2O5S (MÀH+) 459.51, found 459.6. III-2:
Yield 78%, mp: 242–244 ꢀC, Rf=0.4 (EtOAc/petroleum ether
1:1); IR (KBr, cmÀ1): 3476, 3373, 3288, 3053, 1667, 1626,
1600, 1516, 1493, 1262, 1150, 915–699; 1H NMR (DMSO,
400 MHz) d 10.19 (s, 1H), 9.53 (s, 1H), 9.23 (s, 1H),8.53 (d,
1H, J=8.8 Hz), 8.38 (d, 1H, J=8.5 Hz), 8.16 (d, 1H, J=7.1
Hz), 7.95 (d, 1H, J=7.4 Hz), 7.73–7.64 (m, 4H), 7.50(d, 1H,
J=15.7 Hz), 7.22–7.16 (m, 5H), 7.08 (s, 1H), 6.96 (d, 1H,
J=6.9 Hz), 6.83 (m, 2H), 4.04 (s, 2H) MS calcd for
C26H22N2O5S (MÀH+) 473.54, found 473.5. III-3: Yield 75%,
mp: 244–248 ꢀC, Rf=0.45 (EtOAc/petroleum ether 1:1); IR
(KBr, cmÀ1): 3364, 3280, 3026, 1666, 1629, 1603, 1516, 1492,
1
3331, 3057, 1655, 1596, 1522, 1494, 1270, 1151, 923–710; H
NMR (DMSO, 400 MHz) d 10.19 (s, 1H), 9.90 (s, 1H), 9.52 (s,
1H), 9.23 (s, 1H), 8.58 (d, 1H, J=8.8 Hz), 8.41 (d, 1H, J=8.6
Hz), 8.04 (d, 1H, J=7.2 Hz), 7.96 (t, 1H, J=6.9 Hz), 7.69 (t,
1H, J=7.7 Hz), 7.61 (t, 1H, J=7.4 Hz), 7.48 (d, 1H, J=15.4
Hz), 7.07–6.89 (m, 6H), 6.82 (m, 2H), 1.91 (s, 3H) MS calcd
for C26H22N2O5S (MÀH+) 473.54, found 473.5. III-10: Yield
77%, mp: 232–235 ꢀC, Rf=0.5 (EtOAc/petroleum ether 3:2);
IR (KBr, cmÀ1): 3356, 3356, 3065, 1663, 1598, 1515, 1491,
1
1267, 1151, 935–735; H NMR (DMSO, 400 MHz) d 10.22 (s,
1H), 9.89 (s, 1H), 9.55 (s, 1H), 9.26 (s, 1H), 8.57 (d, 1H, J=8.8
Hz), 8.40(d, 1H, J=8.5 Hz), 8.01–7.98 (m, 2H), 7.70 (t, 1H,
J=7.9 Hz), 7.61 (t, 1H, J=8.3 Hz), 7.48 (d, 1H, J=15.4H),
7.07 (s, 1H), 6.95 (d, 1H, J=7.5 Hz), 6.89–6.80(m, 3H), 6.62
(d, 1H, J=7.7 Hz), 2.10(s, 3H), 1.86 (s, 3H) MS calcd for
C27H24N2O5S (MÀH+) 487.57, found 487.6.
18. I-1 yellow crystal, yield 72%. mp: 170–172 ꢀC. Rf=0.65
(petroleum ether/Et2O 1:1). IR (KBr, cmÀ1): nNH: 3489, 3400,
3260, n=CH: 3076, 3023, bNH: 1633, 1613, nC=C: 1572, 1595,
1
1263, 1162, 916–699; H NMR (DMSO, 400 MHz) d 10.19 (s,
1H), 9.51 (s, 1H), 9.22 (s, 1H), 8.49 (d, 1H, J=8.8 Hz), 8.39 (d,
1H, J=8.5 Hz), 8.15 (d, 1H, J=7.2 Hz), 7.94 (d, 1H, J=7.4
Hz), 7.71–7.66 (dd, 2H, J=7.9, 8.3 Hz), 7.48 (d, 1H, J=15.7
Hz), 7.20–6.95 (m, 8H), 6.82 (t, 2H, J=7.9 Hz), 3.03 (t, 2H,
1494, nSO2N
: 1322, 1155, gCH: 918–695. MS calcd for
C16H14N2O2S (MÀH+) 298.37, found 297.75. I-2 Yellow
solid, yield 72%, mp: 176–178 ꢀC, Rf=0.6 (petroleum ether/
Et2O 1:1), IR(KBr, cmÀ1): nNH: 3451, 3375, 3288, n=CH: 3081,
3063, 3027, bNH: 1633, 1614, nC=C: 1586, 1573, 1512, 1495,
J=7.7 Hz), 2.60(t, 2H,
J=7.7 Hz) MS calcd for
C27H24N2O5S (MÀH+) 487.57, found 487.8. III-4: Yield 75%,
mp: 146–150 ꢀC, Rf=0.6 (EtOAc/petroleum ether 1:1); IR
(KBr, cmÀ1): 3410, 3342, 3043, 1659, 1599, 1506, 1285, 1148,
n
SO N: 1301, 1154, gCH: 924–697, MS calcd for C17H16N2O2S
2
(MÀH+) 312.39, found 311.57. I-3: Brown crystal, yield 90%,
mp: 116–118 ꢀC, Rf=0.4 (petroleum ether/Et2O 1:1), IR (KBr,
cmÀ1): nNH: 3449, 3375, 3280, n=CH: 3084, 3057, bNH: 1624,
1
975–701; H NMR (DMSO, 400 MHz) d 10.66 (s, 1H), 10.18
(s, 1H), 9.53 (s, 1H), 9.24 (s, 1H), 8.57 (d, 1H, J=8.8 Hz), 8.40
(d, 1H, J=8.6 Hz), 8.20(d, 1H, J=7.2 Hz), 7.96 (t, 1H, J=7.1
Hz), 7.75 (t, 1H, J=8.3 Hz), 7.65 (t, 1H, J=8.3 Hz), 7.48 (d,
1H, J=15.7 Hz), 7.07–6.96 (m, 6H), 6.81 (t, 2H, J=7.9 Hz)
1588, nC=C: 1573, 1512, 1496, nSO N: 1321, 1153, gCH: 933–
2
699, MS calcd for C18H18N2O2S (MÀH+)326.42, found
325.62. I-4 Yellow crystal, yield 76%, mp: 168–170 ꢀC,

Y.-W. Xu et al. / Bioorg. Med. Chem. 11 (2003) 3589–3593
3593
Rf=0.64 (petroleum ether/Et2O 1:1), IR(KBr, cmÀ1): nNH
:
(KBr, cmÀ1): 3318, 3061, 1771, 1668, 1629, 1596, 1532, 1499,
1205, 1150, 900–700; H NMR (DMSO, 400 MHz) d 10.34 (s,
1
3394, 3323, 3252, n¼CH: 3059, 3106, bNH: 1621, nC=C: 1593,
1573, 1508, nSO N: 1314, 1139, gCH: 937–702, MS calcd for
1H), 8.52 (d, 1H, J=8.5 Hz), 8.41 (d, 1H, J=9.5 Hz), 8.16 (d,
1H, J=7.4 Hz), 7.87 (d, 1H, J=8.3 Hz), 7.73–7.61 (m, 5H)
7.39 (d, 1H, J=8.2 Hz), 7.20–7.04 (m, 6H), 3.04 (t, 2H, J=7.1
Hz), 2.60(t, 2H, J=7.4 Hz), 2.32 (s, 6H) MS calcd for
C29H23N2O7FS (MÀH+) 561.57, found 561.0. II-5: Yield 72%,
mp: 190–192 ꢀC, Rf=0.45 (EtOAc/petroleum ether 1:1); IR
(KBr, cmÀ1): 3254, 3047, 1770, 1667, 1630, 1596, 1532, 1496,
2
C16H13N2O2FS (MÀH+) 316.36, found 315.41. I-5: Yellow
solid, yield 75%, mp: 202–204 ꢀC, Rf=0.65 (petroleum ether/
Et2O 1:1), IR (KBr, cmÀ1): nNH: 3390, 3322, 3102, n=CH
:
3047, bNH: 1622, nC=C: 1596, 1573, 1512, 1491, nSO N: 1316,
2
1139, gCH: 934–681, MS calcd for C16H13N2O2ClS (M–H+)
332.81, found 331.49. I-6: Yellow solid, yield 34%, mp: 212-
214 ꢀC, Rf=0.7 (petroleum ether/Et2O 1:1), IR (KBr, cmÀ1):
1
1224, 1185, 898–715; H NMR (DMSO, 400 MHz) d 10.91 (s,
n
NH: 3451, 3391, 3312, n=CH: 3102, 3042, bNH: 1621, nC=C
:
1H), 10.35 (s, 1H), 8.58 (d, 1H, J=8.8 Hz), 8.41 (d, 1H, J=8.8
Hz), 8.25 (d, 1H, J=7.4 Hz), 7.97 (t, 1H, J=7.5 Hz), 7.77 (t,
1H, J=8.5 Hz), 7.68–7.59 (m, 4H), 7.37 (d, 1H, J=8.2 Hz),
7.22 (d, 2H, J=4.9 Hz), 7.04 (t, 3H, J=6.9 Hz), 2.32 (s, 6H)
Ms calcd for C29H23N2O7ClS (MÀH+) 578.03, found 577.6.
II-6: Yield 80%, mp: 192–194 ꢀC, Rf=0.4 (EtOAc/petroleum-
ether 1:1); IR (KBr, cmÀ1): 3258, 3037, 1770, 1667, 1628, 1594,
1533, 1491, 1207, 1153, 901–709; 1H NMR (DMSO, 400 MHz)
d 10.89 (s, 1H), 10.32 (s, 1H), 8.58 (d, 1H J=8.5 Hz), 8.42 (s,
1H, J=8.5 Hz), 8.26 (d, 1H, J=7.4 Hz), 7.98 (t, 1H, J=7.4
Hz), 7.77 (t, 1H, J=8.5 Hz), 7.70–7.66 (m, 4H), 7.39–7.34 (m,
3H), 7.10–6.98 (m, 3H), 2.32 (s, 6H) MS calcd for
C29H23N2O7BrS (MÀH+) 623.48, found 623.5. II-7: Yield
70%, mp: 170–174 ꢀC, Rf=0.5 (EtOAc/petroleum ether 1:1);
IR (KBr, cmÀ1): 3278, 3067, 1772, 1668, 1627, 1596, 1532,
1503, 1206, 1152, 902–704; 1H NMR (DMSO, 400 MHz) d
10.55 (s, 1H), 10.33 (s, 1H), 8.61 (d, 1H, J=8.5 Hz), 8.37 (d,
1H, J=8.6 Hz), 7.97 (t, 1H, J=6.8 Hz), 7.75 (t, 1H, J=8.2
Hz), 7.66–7.609 (m, 4H), 7.37 (t, 1H, J=8.2 Hz), 7.06 (d, 1H,
J=15.7 Hz), 6.96–6.89 (dd, 4H, J=9.9, J=8.5 Hz), 2.31 (s,
6H), 2.11 (s, 3H) MS calcd for C30H26N2O7S (MÀH+) 557.61,
found 557.5. II-8: Yield 56%, mp: 138–140 ꢀC, Rf=0.5
(EtOAc/petroleum ether 1:1); IR (KBr, cmÀ1): 3266, 3067,
1589, 1573, 1512, 1489, nSO N: 1315, 1139, gCH: 935–701, MS
2
calcd for C16H13N2O2BrS (MÀH+) 376.26, found 375.45. I-7:
Yellow crystal, yield 65%, mp: 194–196 ꢀC, Rf=0.6 (petro-
leum ether/Et2O 1:1), IR (KBr, cmÀ1): nNH: 3447, 3393, 272,
n
¼CH: 3104, 3025, bNH: 1632, nC=C: 1589, 1573, 1510, nSO N
:
2
1298, 1153, gCH: 926–703, MS calcd for C17H16N2O2S
(MÀH+) 312.39, found 311.64. I-8 Red crystal, yield 47%,
mp: 196–198 ꢀC, Rf=0.7 (petroleum ether/Et2O 1:1), IR (KBr,
cmÀ1): nNH: 3470, 3387, 3283, n¼CH: 3095, bNH: 1643, 1613,
n
C=C: 1583, 1570, 1529, nSO N: 1343, 1160 gCH: 949–735, MS
2
calcd for C16H13N3O4S (MÀH+) 343.37, found 342.45. I-9:
Brown crystal, yield 75%, mp: 178–180 ꢀC, Rf=0.5 (petroleum
ether/Et2O 1:1), IR(KBr, cmÀ1): nNH: 3447, 3374, 3272, n
:
¼CH
3059, 3024, bNH: 1634, 1616, nC=C: 1587, 1573, 1513, 1492,
n
SO N: 1303, 1150, gCH: 921–721, MS calcd for C17H16N2O2S
2
(MÀH+) 312.39, found 311.50. I-10 Yellow solid, yield 70%,
mp: 198–200 ꢀC, Rf=0.6 (petroleum ether/Et2O 1:1), IR (KBr,
cmÀ1): nNH: 3414, 3347, n¼CH: 3168, bNH: 1632, nC=C: 1589,
1574, 1513, 1486, nSO N: 1311, 1156, gCH: 936–703, MS calcd
2
for C18H18N2O2S (MÀH+)326.42, found 325.61.
19. Zhao, H.; Burke, T. R. Synth. Commun. 1998, 28, 737.
20. II-1: Yield 63%, mp: 206–208 ꢀC, Rf=0.4 (EtOAc/petro-
leum ether 1:1); IR (KBr, cmÀ1): 3314, 3070, 1763, 1738, 1658,
1597, 1531, 1497, 1216, 1153, 906–693; 1H NMR (DMSO,
400 MHz) d 10.74 (s, 1H), 10.34 (s, 1H), 8.61 (d, 1H, J=8.6
Hz), 8.39 (d, 1H, J=8.5 Hz), 8.26 (d, 1H, J=7.2 Hz), 7.97 (t,
1H, J=6.9 Hz), 7.76 (t, 1H, J=8.2 Hz), 7.68–7.59 (m, 4H),
737 (d, 1H, J=8.2 Hz), 7.17–7.02 (m, 5H), 6.93 (t, 1H, J=7.4
Hz), 2.31 (s, 6H) Ms calcd for C29H24N2O7S (MÀH+) 543.58,
found 543.7. II-2: Yield 67%, mp: 188–190 ꢀC, Rf=0.5
(EtOAc/petroleum ether 1:1); IR (KBr, cmÀ1): 3288, 3031,
1
1771, 1666, 1622, 1531, 1501, 1206, 1154, 900–696; H NMR
(DMSO, 400 MHz) d 11.43 (s, 1H), 10.35 (s, 1H), 8.58 (d, 1H,
J=8.5 Hz), 8.43 (d, 1H, J=8.6 Hz), 8.36 (d, 1H, J=7.2 Hz),
7.97 (d, 1H, J=7.7 Hz), 7.88 (s, 1H), 7.82–7.59 (m, 6H), 7.47
(d, 2H, J=5.1 Hz), 7.37 (d, 1H, J=8.2 Hz), 7.06 (d, 1H,
J=15.7 Hz), 2.31 (s, 6H) MS calcd for C29H23N3O9S
(MÀH+) 588.58, found 588.5. II-9: Yield 55%, mp: 196–
198 ꢀC, Rf=0.5 (EtOAc/petroleum ether 1:1); IR (KBr,
cmÀ1): 3266, 3060, 1773, 1662, 1628, 1533, 1497, 1208, 1151,
1
1
1770, 1665, 1622, 1595, 1527, 1500, 1207, 1151, 899–699; H
900–712; H NMR (DMSO, 400 MHz) d 10.34 (s, 1H), 9.91
NMR (DMSO, 400 MHz) d 10.33 (s, 1H), 8.55 (d, 1H, J=8.3
Hz), 8.38 (d, 1H, J=8.8 Hz), 8.16 (d, 1H, J=7.2 Hz), 7.96 (t,
1H, J=7.29 Hz), 7.74–7.60(m, 5H), 7.37 (d, 1H, J=8.3 Hz),
7.19–7.15 (m, 6H), 4.04 (s, 2H), 2.32 (s, 6H) MS calcd for
C30H26N2O7S (MÀH+) 557.61, found 557.5. II-3: Yield 65%,
mp: 212–216 ꢀC, Rf=0.6 (EtOAc/petroleum ether 1:1); IR
(KBr, cmÀ1): 3318, 3061, 1771, 1668, 1629, 1596, 1532, 1499,
(s, 1H), 8.60(d, 1H, J=8.5 Hz), 8.41 (d, 1H, J=8.5 Hz), 8.05
(d, 1H, J=6.6 Hz), 7.99 (t, 1H, J=7.4 Hz), 7.71–7.55 (m,
5H), 7.37 (d, 1H, J=8.2 Hz), 7.36–6.99 (m, 4H), 6.90(m,
1H), 2.31 (s, 6H), 1.91 (s, 3H) MS calcd for C30H26N2O7S
(MÀH+) 557.61, found 557.5. II-10: Yield 60%, mp: 200–
204 ꢀC, Rf=0.6 (EtOAc/petroleum ether 3:2); IR (KBr,
cmÀ1): 3285, 3075, 1754, 1664, 1625, 1587, 1524, 1505, 1219,
1
1
1205, 1150, 900–700; H NMR (DMSO, 400 MHz) d 10.34 (s,
1149, 901–737; H NMR (DMSO, 400 MHz) d 10.35 (s, 1H),
1H), 8.52 (d, 1H, J=8.5 Hz), 8.41 (d, 1H, J=9.5 Hz), 8.16 (d,
1H, J=7.4 Hz), 7.87 (d, 1H, J=8.3 Hz), 7.73–7.61 (m, 5H)
7.39 (d, 1H, J=8.2 Hz), 7.20–7.04 (m, 6H), 3.04 (t, 2H, J=7.1
Hz), 2.60(t, 2H, J=7.4 Hz), 2.32 (s, 6H) MS calcd for
C31H28N2O7S (MÀH+) 571.64, found 571.7. II-4: Yield 57%,
mp: 186–188 ꢀC, Rf=0.6 (EtOAc/petroleum ether 3:2); IR
9.87(s, 1H), 8.59 (d, 1H, J=8.8 Hz), 8.41(d, 1H, J=8.5 Hz),
8.01 (t, 2H, J=6.4 Hz), 7.72–7.60(m, 5H), 7.38 (d, 1H,
J=8.3 Hz), 7.10(d, 1H, J=8.5 Hz), 6.96 (d, 1H, J=7.4 Hz),
6.87 (t, 1H, J=7.4 Hz), 6.61 (d, 1H, J=7.9 Hz), 2.31 (s, 6H),
2.10(s, 3H), 1.86 (d, 3H) MS calcd for C 31H28N2O7S
(MÀH+) 571.64, found 571.7.