Convenient preparation of N-8-quinolinyl benzenesultams as novel NF-κB inhibitors

Article abstract of DOI:10.1016/j.tetlet.2008.01.136

An efficient synthesis of a series of N-8-quinolinyl benzenesultams as novel NF-κB inhibitors was described via diazotization-induced cyclization of easily accessible N-8-quinolinyl-2-aminobenzenesulfonamides.

Full text of DOI:10.1016/j.tetlet.2008.01.136

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2320–2323
Convenient preparation of N-8-quinolinyl benzenesultams
as novel NF-jB inhibitors
Yuli Xie a, Gangli Gong a, Yidong Liu a, Shixian Deng a, Alison Rinderspacher a,
Lars Branden b, Donald W. Landry a,*
a Department of Medicine, Columbia University, 630 W 168th Street, New York, NY 10032, USA
b Department of Physiology and Cellular Biophysics, Russ Berrie Med Sc Pav 1150 St Nicholas Ave 520, New York, NY 10032, USA
Received 5 September 2007; revised 28 January 2008; accepted 30 January 2008
Available online 6 February 2008
Abstract
An efficient synthesis of a series of N-8-quinolinyl benzenesultams as novel NF-jB inhibitors was described via diazotization-induced
cyclization of easily accessible N-8-quinolinyl-2-aminobenzenesulfonamides.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Benzenesultam; NF-jB; Diazotization; Cyclization
Nuclear factor kappaB (NF-jB) is a pivotal transcrip-
tion factor that regulates gene expression involved in
inflammation and immune responses. The NF-jB pathway
has provided a favorable target for pharmacological inter-
N
HN
S
vention of chronic inflammation, neurodegenerative dis-
1
O
O
eases, and certain types of cancer, where the pathway is
often constitutively or excessively active. Peptides, siRNA,
natural products, and small molecules that target one or
multiple steps of NF-jB signaling are under investigation
as potential therapeutics.2 Our NIH Molecular Libraries
Screening Centers Network (MLSCN) recently identified
sultam 1 (Fig. 1) as a novel NF-jB inhibitor in cell-based
high throughput screening assays.
NF-jB is normally sequestered in the cytoplasm
through an association with its inhibitory protein IjB.
Upon stimulation of the NF-jB pathway, IjB is rapidly
phosphorylated, ubiqutinated, and then degraded by pro-
teasomes. Freed from its inhibition, NF-jB translocates
to the nucleus where it binds to DNA regulatory sites
and activates specific gene expression.1 Preliminary results3
show that compound 1 stabilizes IjB and prevents NF-jB
Fig. 1. The structure of NF-jB inhibitor 1.
translocation in different types of cells with sub-micromo-
lar IC50s. In contrast to existing blockers of NF-jB trans-
location, compound 1 did not appear to inhibit IjB kinases
(IKKs) and proteasomes, the major components of the IjB
degradation machinery, and thus likely represents a struc-
turally and pharmacologically new class of modulators of
the NF-jB pathway. For structure–activity relationship
studies and further biological investigation, we sought an
easy synthetic access to the original hit 1 and its analogs.
The tetracyclic target 1 consists of a structurally con-
strained cyclic sulfonamide with the sultam bridging quinol-
inyl and phenyl moieties. This unique scaffold has rarely
been studied and lacks a general synthetic method. In this
Letter, we describe an efficient synthesis of this class of
compounds that allows a diverse substitution pattern.
*
Corresponding author. Tel.: +1 212 3055839; fax: +1 212 3053475.
E-mail address: dwl1@columbia.edu (D. W. Landry).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.136

Y. Xie et al. / Tetrahedron Letters 49 (2008) 2320–2323
2321
Br
SO2Cl
Pd(OAc)2, PCy3•HBF4,
1.
Py, 74%
N
K2CO3, DMA, 130 °C
N
Br
O
S
N
N
N
2. (Boc)2O, DMAP,
THF, 40%
Boc
NH2
Boc
S
2
O
O
O
3
4
NBS, LiClO 4
SiO2, CH 2Cl2
99%
Br
Br
Br
Br
SO2Cl
Cu(0), DMF, 100 °C
N
Br
Py, 70%
Br
N
O
S
HN
N
Br
or Pd(OAc)2, K2CO3,
PEG-4000, 130 °C
HN
S
O
NH2
5
7
O
O
6
Scheme 1. The attempts of intermolecular arylation.
Our synthetic strategy was to construct the sultam
skeleton through the cyclization of easily accessible N-8-
quinolinyl benzenesulfonamides. We first attempted
metal-mediated intermolecular arylation. As shown in
Scheme 1, 8-aminoquinoline 2 was treated with 2-bromo-
benzenesulfonyl chloride in pyridine followed by the
protection of the nitrogen on sulfonamide with Boc2O to
give precursor 3. Unfortunately, palladium-catalyzed direct
intramolecular arylation4 of bromide 3 failed to effect cycli-
zation. Bromination of 8-aminoquinoline 2 provided dibro-
mide,5 and subsequent sulfonamidation yielded tribromide
6. However, neither Ullmann reaction nor palladium-cata-
lyzed intramolecular coupling6 of aryl bromide 6 afforded
the desired product 7.
Ultimately, diazotization-induced cyclization was
employed to synthesize the target compound (Scheme 2).
Sulfonamide 8 was prepared, as above, from 2-nitro-
benzenesulfonyl chloride and 8-aminoquinoline 2 in pyri-
dine. The nitro group was reduced with SnCl2 to provide
amine 9, and subsequent diazotization afforded triazine
10 in good yield. A literature procedure employing Cu(0)
and NaOH7 failed to yield the desired product, but we
found that thermolysis in a variety of solvents (EtOH,
H2O, DMSO, or HOAc) or neat afforded product 1 in
moderately poor yield. The best result (41% yield) was
obtained by heating in glacial acetic acid at 120 °C for
10 min. Beyond low yield, thermolysis in acid generated
large amounts of intractable tar and required multiple
rounds of chromatography on silica gel.
In the course of improving the synthesis of the triazine
intermediates, we attempted a mild non-aqueous diazoti-
zation-induced by tert-butyl nitrite (t-BuONO). This led
to our discovery of a convenient one-pot synthesis of N-
8-quinolinyl benzenesultams from N-8-quinolinyl-2-amino-
benzenesulfonamides. In a typical reaction, as shown in
Scheme 3, 2-aminobenzenesulfonamide 9a prepared from
6-methoxy-2-methylquinolin-8-amine 2a8 was dissolved in
HOAc and treated with 1.5 equiv of t-BuONO at 10 °C.
The reaction was allowed to warm to room temperature
over 10 min and smoothly afforded sultam 1a in good yield
(78%) without the isolation of the triazine intermediate.9
To investigate the scope of this one-pot protocol, a
selection of N-8-quinolinyl-2-aminobenzenesulfonamides
(9a–p) was prepared and subsequently cyclized in one-pot
reactions to give sultams (1a–p). In each case, the
NO2
NO2
O
O
SO2Cl
SO2Cl
Py, rt,
SnCl2,
EtOH,
N
N
NH2
reflux, 2 h
NO2
1.
Py, 79%
O
O
S
HN
HN
2
H2N
S
95%
88%
N
O
2. SnCl2, EtOH,
reflux, 2 h, 92%
O
8
2a
9a
NaNO2,
H2SO4,
0 °C,1 h
HOAc,
120 °C,
10 min
O
N
N
O
O
S
t
-BuONO, HOAc,
N
NH
1
S
N
N
10 °C -rt,10 min
78%
O
O
N
80%
41%
NH2
HN
S
10
1a
9
O
O
Scheme 2. Synthesis of sultam 1 via triazine intermediate.
Scheme 3. The one-pot synthesis of compound 1a.

2322
Y. Xie et al. / Tetrahedron Letters 49 (2008) 2320–2323
Table 1
The one-pot synthesis of N-8-quinolinyl benzenesultams
R3 R4
R3
N
R4
R2
R1
R5
R2
R1
R5
R9
R6
t
-BuONO,HOAc,
N
R8
R7
10 °C - rt, 10 min
NH2
R7
O
HN
S
R9
R8
HN
O
S
O
O
R6
1a-p
9a-p
Comp
R1
R2
H
R3
R4
H
R5
R6
H
R7
R8
R9
H
Yield (%)
78
1a
CH3
H
OCH3
CH3
H
1b
1c
1d
1e
1f
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
CF3
Cl
CH3
F
OCH3
CF3
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
76
81
79
95
75
70
91
90
77
79
73
84
80
72
75
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
H
H
H
H
O
R3
N
O
S
O
R1
R3
R2
R1
O
R2
Cl
N
O
1. 6M HCl, toluene,
H
O
NO2
130 °C, 2 h
HN
NH2
O
S
N
H
HN
O
90%
S
2. SnCl2, EtOH,
reflux, 2 h
NH2
O
NO2
12
11
90%, 2 steps
9i R1 = CH3, R2 = H, R3 = H
9j R1 = H, R2 = CH3, R3 = H
9k R1 = H, R2 = H, R3 = CH3
Scheme 4. Synthesis of quinazolines of 9i–k by Skraup reaction.
product was isolated in good yield without tedious purifica-
tion (Table 1). Aminobenzenesulfonamides (9b–h and 9l–p)
were synthesized in a similar manner described in Scheme
3. Intermediates 9i–k were prepared from aniline 11 as out-
lined in Scheme 4: Sulfonamidation of aniline 11 with 2-
nitrobenzenesulfonyl chloride provided sulfonamide 12.
Skraup reaction under modified conditions10 followed by
the reduction of nitro group readily afforded the N-quinol-
inyl sulfonamides (9i–k).
inhibitors. Its potential as a general method to prepare
other biologically interesting biaryls is under investigation.
References and notes
1. Hayden, M. S.; West, A. P.; Ghosh, S. Oncogene 2006, 25, 6758.
2. Gilmore, T. D.; Herscovitch, M. Oncogene 2006, 25, 6887.
3. Unpublished data from Columbia and NCGC MLSCN Center.
4. Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581.
In summary, a highly efficient one-pot reaction for the
conversion of N-8-quinolinyl-2-aminobenzenesulfonamides
into their corresponding sultams under very mild condi-
tions has been described. This procedure offered a conve-
nient access to a unique class of heterocyclic compounds
that have shown therapeutic potential as novel NF-jB
5. Bagheri, M.; Azizi, N.; Saidi, M. Can. J. Chem. 2005, 83, 146.
6. Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. J. Org. Chem. 2006, 71, 1284.
7. Ullmann, F.; Gross, C. Ber. Dtsch. Chem. Ges. 1911, 43, 2694.
8. Qiu, L.; Jiang, P.; He, W.; Tu, C.; Lin, J.; Li, Y.; Gao, X.; Gu, Z.
Inorg. Chim. Acta 2007, 360, 431.
9. A typical synthesis: Compound 9a: To a solution of 6-methoxy-2-
methylquinolin-8-amine 2a (0.19 g, 1.0 mmol) in pyridine (5 ml) was

Y. Xie et al. / Tetrahedron Letters 49 (2008) 2320–2323
2323
added 4-methyl-2-nitrobenzenesulfonyl chloride (0.24 g, 1.0 mmol).
The mixture was stirred at room temperature overnight and preci-
pitated with H2O. The crude product was filtered and recrystallized
from EtOH to afford nitrobenzenesulfonamide (0.31 g, 79%) as red
crystal. 1H NMR (300 MHz, CDCl3) d 10.1 (br, 1H); 8.04 (d, 1H),
7.86 (d, 1H), 7.62 (m, 2H), 7.39 (d, 1H), 7.24 (d, 1H), 6.73 (s, 1H), 3.88
(s, 3H), 2.66 (s, 3H), 2.41 (s, 3H); ESI-MS (M++1): 388.0. To a
suspension of above nitro compound (0.20 g, 0.56 mmol) in EtOH
(5 ml) SnCl2 (0.32 g, 1.7 mmol) was slowly added. The mixture was
refluxed for 2 h. After the removal of EtOH, the residue was treated
with 1 M NaOH. The aqueous solution was extracted with CH2Cl2.
The combined organic phases were washed by brine, dried over
Na2SO4, and concentrated to yield 9a (0.18 g, 92%) as a white solid.
1H NMR (300 MHz, CDCl3) d 9.42 (br, 1H); 7.83 (d, 1H), 7.65 (d,
1H), 7.30 (s, 1H), 7.23 (d, 1H), 6.64 (s, 1H), 6.48 (d, 1H), 6.42 (s, 1H),
3.80 (s, 3H), 2.61 (s, 3H), 2.17 (s, 3H); ESI-MS (M++1): 358.1.
Compound 1a: To a solution of 9a (0.1 g, 0.28 mmol) in HOAc (1 ml)
at 10 °C was added t-BuONO (0.05 ml, 0.42 mmol). The reaction was
slowly warmed to room temperature over 10 min and quenched with
H2O. The mixture was extracted with EtOAc. The combined organic
phases were washed with saturated NaHCO3, dried over Na2SO4, and
concentrated. Flash chromatography (EtOAc/CH2Cl2 1:10 v/v) gave
1a (74 mg, 78%) as a yellow solid. 1H NMR (300 MHz, CDCl3) d 8.49
(s, 1H), 7.98 (d, 1H), 7.92 (d, 1H), 7.37 (d, 1H), 7.25 (d, 1H), 6.87 (s,
1H), 4.00 (s, 3H), 2.69 (s, 3H), 2.52 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 156.2, 155.2, 142.2, 134.8, 134.5, 134.1, 132.2, 131.4, 130.1,
129.0, 126.8, 124.4, 122.0, 112.5, 100.0, 56.2, 25.2, 22.6; ESI-MS
(M++1): 341.2.
10. Matsugi, M.; Tabusa, F.; Minamikawa, J. Tetrahedron Lett. 2000, 41,
8523.