Auxiliary-Assisted Palladium-Catalyzed Direct C(sp3)-H Sulfonamidation to Afford 1,2-Amino Alcohol Derivatives

Article abstract of DOI:10.1021/acs.joc.6b02975

An auxiliary-assisted Pd-catalyzed C(sp³)-H sulfonamidation approach using NFSI as both nitrogen source and oxidant to afford 1,2-amino alcohol derivatives is described in this paper. This method is novel and attractive because of its high yiel

Full text of DOI:10.1021/acs.joc.6b02975

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Note
Auxiliary-assisted palladium-catalyzed direct C(sp3)-
H sulfonamidation to afford 1,2-amino alcohol derivatives
Yi Dong, and Gang Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02975 • Publication Date (Web): 06 Mar 2017
Downloaded from http://pubs.acs.org on March 6, 2017
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Auxiliary-assisted
palladium-catalyzed
direct
C(sp3)-H
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sulfonamidation to afford 1,2-amino alcohol derivatives
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Yi Dong and Gang Liu*
School of Pharmaceutical Sciences, Tsinghua University, Haidian Dist., Beijing, 100084, P. R. China
* Corresponding author. E-mail addresses: gangliu27@tsinghua.edu.cn
Abstract
An auxiliary-assisted Pd-catalyzed C(sp3)-H sulfonamidation approach using NFSI as
both nitrogen source and oxidant to afford 1,2-amino alcohol derivatives is described
in this paper. This method is novel and attractive because of its high yields, wide
range of substrate scopes and good tolerance for many functional groups. Oximido
and sulfonyl group can be removed with this method.
Transition-metal-catalyzed direct C-H bond functionalization has emerged as a
revolutionary synthetic technology to access target molecules during the
1
process of organic synthesis due to its high atom and step economy. Because
of the significance of C-N bond formation in the synthetic progress of natural
products and drug molecules, direct C-H amination or amidation catalyzed by
transition metals, including Pd, Rh, Ir, Ru, Co, and Cu, has been
2
well-established over the past several years. In these typical procedures, C-H
amination or amidation can work well to generate the new C-N bond through
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two major strategies: one requiring amines/amides and external oxidants3 and
another requiring pre-activated amine sources under oxidant-free conditions,
such as N-benzoate alkylamines,4 N-chloroamines,5 and nitrosobenzenes.6
9
Recently,
many
excellent
studies
have
shown
that
NFSI
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(N-Fluorobenzenesulfonimide), as both a nucleophilic nitrogen or nitrogen
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radical, is an effective nitrogen source for C-N bond formation, and very
recently, it was effectively applied in the benzylic C(sp3)-H sulfonamidation
catalyzed by palladium and copper catalysts to generate C-N bonds with high
efficiency. (Scheme 1, A and B).8
Scheme 1. Transition-metal-catalyzed direct C(sp3)-H sulfonamidation
In some classical examples of total synthetic procedures of natural products,
the skillful application of directed C(sp3)-H amination/amidation thoroughly
demonstrated the art of total synthesis of complicated compounds,2c, 9 causing
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more researchers to take note and try to exploit novel methods of C(sp3)-H
amination/amidation with high efficiency and effective application. Previous
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2b, 10
studies of C(sp3)-H amination mainly focused on intramolecular reactions,
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but the method was generally limited because of the dependence on the
substrate structure. Intermolecular C(sp3)-H amination/amidation has often
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occurred on allylic and benzylic C(sp3)-H bonds; however, activation on other
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unactivated groups, such as methyl, remains challenging.
Therefore, an
efficient method with strong stability over a wide range of functional groups is
an urgent need.
1,2-Amino alcohol is an important moiety in natural products and synthetic
pharmacologically active molecules.12 In the past few years, many small
molecules containing the structural fragment of 1,2-amino alcohol have been
successfully developed as drugs, such as a selective β2 acceptor agonist
(Salbutamol), an α-adrenergicreceptor blocker (Tamsulosin), and a calcium
channel blocker (Amlodipine), which shows that 1,2-amino alcohol is an
important “privileged structure” for the biological activity of drug molecules.
Recently, many intramolecular C-H amidation strategies have been developed
to prepare amino alcohol derivatives. 10 Most recently, Chang et al reported a
Cp*Ir(III)-catalyzed intermolecular C(sp3)-H sulfonamidation approach to
afford 1,2-amino alcohol by using sulfonyl azide as the nitrogen source via an
exo-iridacycle formed through coordination with the ketoximenitrogen.13 Given
the general applicability of Pd-catalyzed coupling reactions in synthesis and the
potent catalytic performance of Pd catalysts in the C(sp3)-H bond activation
process, 14 we propose to develop a Pd-catalyzed activation method to realize
C-H amidation on the β-position of the hydroxyl group in the alcohol
derivatives. In 2012, Álvarez and Muñiz et al (Scheme 1, B) reported that a
chelation-assisted 5-member palladacycle intermediate could benefit C(sp3)-H
bond activation, which showed that Pd-catalyzed C-H sulfonamidation strongly
relies on the stability of the palladium intermediate.8a In 2012 and 2015, Dong
et al revealed that the C-H bond on the β-position of the alcohol could be
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activated in a Pd-catalytic system by assembling an aldoxime group as an
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assisted directing group (Scheme 1, C).
Inspired by these results, we
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hypothesized that C-H sulfonamidation on the β-position of alcohol should be
feasible by using a suitably auxiliary-assisted aldoxime group to form a stable
exo-palladacycle intermediate (Scheme 1, D).
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To verify the hypothesis of Pd-catalyzed C(sp3)-H sulfonamidation of
alcohol derivatives, aldoxime-assembling quinolyl (DG1) on butan-2-ol was
chosen as a model substrate to test this reaction. By treating with 3.0 equivalent
of NFSI in the presence of 10 mol% Pd(OAc)2 in DCE at 100°C, this reaction
was completed and the desired C-H sulfonamidated product 2a was isolated in
52% yield (Table 1, entry 1). We then investigated the solvent effect on this
reaction and found that no desired compound was detected by LC-MS when the
reaction was performed in toluene or 1,4-dioxane (Table 1, entries 2 and 4).
Other solvents such as acetonitrile gave low conversion rate (50%) and isolated
yield (31%) at 100°C (Table 1, entry 3), whereas MeNO2 granted a slightly
raised yield of 67% (Table 1, entry 5). Pd(dba)2 was effective for this C(sp3)-H
sulfonamidation with 58% yield in MeNO2 (Table 1, entry 6), but Pd(acac)2 had
no catalytic performance under the same condition (Table 1, entry 7).
Subsequent directing group (DG) screening revealed that only DG1 was
effective for this Pd-catalyzed C(sp3)-H sulfonamidation (Table 1, entries 5 and
8~14). When the reaction of 1a was carried out in MeNO2 under Ar atmosphere,
the isolated yield further increased to 72% (Table 1, entry 15).
Table 1. Optimization of reaction conditiona
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Entry
1
DG/substrate
DG1/1a
DG1/1a
DG1/1a
DG1/1a
DG1/1a
DG1/1a
DG1/1a
DG2/1b
DG3/1c
DG4/1d
DG5/1e
DG6/1f
DG7/1g
DG8/1h
DG1/1a
1
Pd catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
Solvent
DCE
Yield/%b
52
0
2
toluene
MeCN
3
31
0
4
1,4-dioxane
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
5
67
58
0
6
7
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
0
9
0
10
11
12
13
14
0
0
0
0
0
15c
72
a
Pd catalyst: 10 mo%, 1a~1h: 0.2 mmol, NFSI: 3.0 equiv, solvent: 1.0 mL,
under air. b Isolated yield. c Under Ar. DCE = Dichloroethane
Then, the substrate scope was investigated under the optimal conditions, and the
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representative results are summarized in Table 2. A variety of aliphatic aldoxime
derivatives can be utilized to afford the corresponding sulfonamides in good yields via
this C(sp3)-H activation, including different lengths of aliphatic chain substitution (2a,
3~6), sterically demanding substitutions on the β-position (5, 7 and 8) and aromatic
groups substituted on different positions (10 and 11). Additionally, a range of
functional groups are stable in these reaction conditions, such as ester (9, 12, 16~18,
20, 22 and 23), chloride (15), sulfonate ester (14 and21), amide (19), methoxyl (13),
furyl (18), alkenyl (17) and hydroxyl (23). It is notable that when alkenyl- and
furyl-containing substrates were applied in this method, the corresponding desired
sulfonamidated products could be obtained with an incomplete conversion in 45% and
52% isolated yields, respectively, and the yields based on the recovered starting
material could reach 66% and 78% (17 and 18). When the β-position was
pre-activated by Cl and OTs, this C(sp3)-H sulfonamidation also occurred well, and Cl
and OTs groups were tolerated under this palladium catalytic condition.
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Table 2. Palladium-catalyzed C(sp3)-H sulfonamidation to afford 1,2-amino alcohol
derivatives a
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a Pd(OAc)2: 10 mol%, oxime: 0.2 mmol, NFSI: 3.0 equiv, MeNO2: 1.0 mL, under Ar.
Isolated yield (brsm yield in the parentheses), brsm, based on the recovered starting
material.
Oximido and sulfonyl group can be removed with this method (Scheme 2). For the
product 10, the N-O bond of oximido is cleaved to give free hydroxyl group
compound (24) in 86% yield under Pd/C-catalyzed hydrogenation conditions.
Alternatively, treatment by con. H2SO4 at 0°C takes away one sulfonyl group to afford
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compound 25 in excellent yield. Further benzoylation and acidification by con. H2SO4
remove the last sulfonyl group to give benzoylated product (26).
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Scheme 2. Removal of oximido and sulfonyl group
The mechanism of the palladium-catalyzed C(sp3)-H sulfonamidation is
proposed (Scheme S1 in supporting information). Substrate 1a and the
palladium(II) salt coordinate to form palladacycle
activation, which was then oxidized by NFSI to the fluorinated high-oxidation
state intermediate II 16
Anionic bis(sulfonyl)imide and cationic fluorinated
I via auxiliary-assisted C-H
.
Pd(IV) intermediate II engage in direct nucleophilic substitution to form a new
C-N bond and afford the palladium(II) intermediate III, which then was
cleaved by HOAc to release the sulfonamidated product 2a and regenerate
Pd(OAc)2 for the next catalytic cycle.
In summary, a palladium-catalyzed C(sp3)-H sulfonamidation was developed
using NFSI as both nitrogen source and oxidant to afford 1,2-amino alcohol
derivatives in good yields with a wide range of substrate scopes. Oximido and
sulfonyl group are removed, respectively, in this method. Compared with
previous synthetic methods, this method is attractive for its highly efficient
catalytic performance and tolerance for many functional groups, which likely
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provides a potential application in the study of 1,2-amino alcohol fragment
drugs.
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Experimental Section
General information
The automatic LC-MS analysis was also performed on a Thermo Finnigan
LCQ Advantage mass spectrometer equipped with an Agilent HPLC system
and an eluent splitter (5% eluent was split into the MS system).
High-resolution LC-MS was carried out by Agilent LC/MSD TOF using a
column of Agilent ZORBAX SB-C18 (rapid resolution, 3.5 μm, 2.1 × 30 mm)
at a flow of 0.40 mL/min. The solvent was MeOH/water (75:25 (v/v)),
containing 5 mmol/L ammonium formate. The ion source is electrospray
ionization (ESI).
Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic
resonance (13C NMR) spectroscopy were performed on Bruker Advance 400,
1
spectrometer. Chemical shifts of H NMR spectra are reported as in units of
parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal
of chloroform-d (δ = 7.260, singlet) or dmso-d6 (δ = 2.500, quintet).
Multiplicities were given as: s (singlet); br s (broad singlet); d (doublet); t
(triplet); q (quartet); dd (doublet of doublets); m (multiplets), etc. The number
of protons (n) for a given resonance is indicated by nH. Carbon nuclear
magnetic resonance spectra (13C NMR) are reported as in units of parts per
million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of
chloroform-d (δ = 77.160, triplet) or dmso-d6 (δ = 39.510, septet).
Gerenal procedure for synthesis of oximes.15b Alcohol (20 mmol),
N-hydroxyphthalimide (24 mmol) and PPh3 (24 mmol) were dissolved in 30
mL THF. The mixture was cooled to 0°C, and DIAD (24 mmol) was added.
Then the reaction mixture was warmed to room temperature and stirred
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overnight. The reaction mixture was concentrated, and the residue was purified
with flash column chromatography to afford the PhthN protected alcohols. 2 mmol
PhthN protected alcohol was dissolved in 10 mL MeOH, and 120 μL hydrazine
hydrate was added. The reaction mixture was stirred at room temperature for 1h, then
2 mmol aldehyde was added. The reaction mixture was stirred at room temperature
for 30min and concentrated, and the residue was purified with flash column
chromatography to afford oxime.
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(E)-quinoline-8-carbaldehyde O-(sec-butyl) oxime. 1H NMR (400 MHz, CDCl3)
δ 9.39 (s, 1H), 8.95 (d, J = 3.0 Hz, 1H), 8.29 (d, J = 7.3 Hz, 1H), 8.17 (d, J =
8.2 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 8.2,
4.1 Hz, 1H), 4.41 – 4.28 (m, 1H), 1.89 – 1.72 (m, 1H), 1.71 – 1.55 (m, 1H),
1.33 (d, J = 6.3 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 150.0, 145.9, 145.5, 136.5, 130.7, 129.2, 128.4, 126.6, 126.3, 121.5, 81.0,
28.7, 19.5, 9.9.
(E)-picolinaldehyde O-(sec-butyl) oxime. 1H NMR (400 MHz, CDCl3) δ 8.61 (d,
J = 3.5 Hz, 1H), 8.16 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.3 Hz, 1H),
7.25 (d, J = 8.8 Hz, 1H), 4.37 – 4.26 (m, 1H), 1.86 – 1.69 (m, 1H), 1.65 – 1.53
(m, 1H), 1.30 (d, J = 6.3 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 152.2, 149.4, 148.3, 136.7, 123.8, 121.0, 81.8, 28.6, 19.4, 9.8.
(E)-2-hydroxybenzaldehyde O-(sec-butyl) oxime. 1H NMR (400 MHz, CDCl3) δ
10.06 (s, 1H), 8.16 (s, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H),
6.98 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 4.30 – 4.16 (m, 1H), 1.82 –
1.67 (m, 1H), 1.68 – 1.53 (m, 1H), 1.30 (d, J = 6.3 Hz, 3H), 0.97 (t, J = 7.4 Hz,
13
3H). C NMR (100 MHz, CDCl3) δ 157.6, 151.0, 131.0, 130.7, 119.7, 116.9,
116.8, 81.6, 28.4, 19.1, 9.7.
1
(E)-2,6-dimethoxybenzaldehyde O-(sec-butyl) oxime. H NMR (400 MHz,
CDCl3) δ 8.39 (s, 1H), 7.25 (t, J = 6.8 Hz, 1H), 6.56 (d, J = 8.3 Hz, 2H), 4.41 –
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4.26 (m, 1H), 3.84 (s, 6H), 1.82 – 1.72 (m, 1H), 1.64 – 1.50 (m, 1H), 1.29 (d, J
5
6
13
= 6.3 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). C NMR (100 MHz, CDCl3) δ 159.2,
7
8
143.4, 130.7, 110.1, 104.3, 80.3, 56.2, 28.7, 19.3, 9.8.
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(E)-2,6-difluorobenzaldehyde O-(sec-butyl) oxime. 1H NMR (400 MHz, CDCl3)
δ 8.24 (s, 1H), 7.32 – 7.19 (m, 1H), 6.92 (t, J = 8.4 Hz, 2H), 4.35 – 4.25 (m,
1H), 1.81 –1.71 (m, 1H), 1.65 – 1.52 (m, 1H), 1.29 (d, J = 6.3 Hz, 3H), 0.96 (t,
J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.3(d, J = 6.8 Hz), 159.7 (d,
J = 6.8 Hz), 138.8, 130.4 (t, J = 10.5 Hz), 111.9 (m), 81.5, 28.6, 19.3, 9.8.
(E)-2-((methyl(oxo)(phenyl)-l6-sulfanylidene)amino)benzaldehyde O-(sec-butyl)
1
oxime. H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H),
7.78 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.05
– 6.95 (m, 2H), 6.86 (t, J = 7.3 Hz, 1H), 4.27 (q, J = 6.4 Hz, 1H), 3.26 (s, 3H),
1.84 – 1.74 (m, 1H), 1.70 – 1.52 (m, 1H), 1.35 – 1.29 (m, 3H), 1.04 – 0.95 (m,
13
3H). C NMR (100 MHz, CDCl3) δ 146.2, 143.8, 139.3, 133.5, 130.2, 129.7,
128.6, 126.3, 126.2, 122.4, 121.9, 80.7, 46.4, 28.7, 19.4, 9.9.
1
(E)-pyrido[3,2-g]quinoline-10-carbaldehyde O-(sec-butyl) oxime. H NMR
(400 MHz, CDCl3) δ 9.54 (s, 1H), 9.08 (d, J = 1.8 Hz, 2H), 8.33 (s, 1H), 8.28 (d,
J = 8.4 Hz, 2H), 7.41 (dd, J = 8.5, 3.7 Hz, 2H), 4.54 – 4.43 (m, 1H), 2.02 – 1.83
(m, 1H), 1.73 – 1.61 (m, 1H), 1.40 (d, J = 6.2 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 152.6, 145.8, 136.4, 134.3, 128.5, 126.6, 123.5,
121.2, 80.7, 28.8, 19.4, 9.9.
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(E)-1-(quinolin-8-yl)ethan-1-one O-(sec-butyl) oxime. H NMR (400 MHz,
CDCl3) δ 8.93 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz,
1H), 7.73 (d, J = 7.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.39 (dd, J = 8.2, 4.2 Hz,
1H), 4.35 – 4.25 (m, 1H), 2.47 (s, 3H), 1.88 – 1.75 (m, 1H), 1.68 – 1.55 (m,
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1H), 1.32 (d, J = 6.3 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H). C NMR (100 MHz,
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80.4, 28.8, 19.5, 17.7, 9.9.
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(E)-quinoline-8-carbaldehyde O-isopropyl oxime. H NMR (400 MHz, CDCl3)
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δ 9.39 (s, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.14 (d, J =
8.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.45 – 7.38 (m,
13
1H), 4.54 (dt, J = 12.4, 6.2 Hz, 1H), 1.36 (s, 3H), 1.35 (s, 3H). C NMR (100
MHz, CDCl3) δ 150.0, 146.0, 145.6, 136.3, 130.7, 129.3, 128.4, 126.5, 126.2,
121.4, 75.9, 21.9.
(E)-quinoline-8-carbaldehyde O-hexan-2-yl oxime. 1H NMR (400 MHz, CDCl3)
δ 9.39 (s, 1H), 8.94 (s, 1H), 8.28 (d, J = 7.3 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H),
7.84 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 8.0, 4.0 Hz, 1H),
4.52 – 4.27 (m, 1H), 1.96 – 1.69 (m, 1H), 1.61 – 1.51 (m, 1H), 1.52 – 1.27 (m,
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7H), 0.92 (t, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3) δ 150.0, 145.9,
145.4, 136.4, 130.7, 129.2, 128.4, 126.6, 126.2, 121.4, 79.9, 35.7, 27.9, 23.0,
20.1, 14.2.
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(E)-quinoline-8-carbaldehyde O-(3-methylbutan-2-yl) oxime. H NMR (400
MHz, CDCl3) δ 9.40 (s, 1H), 8.95 (s, 1H), 8.29 (d, J = 7.3 Hz, 1H), 8.17 (d, J =
8.2 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 7.8,
3.8 Hz, 1H), 4.21 (p, J = 6.1 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.28 (t, J = 6.8 Hz,
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3H), 1.00 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 149.9, 145.8, 145.2, 136.5, 130.7, 129.2, 128.4, 126.6, 126.2, 121.4,
84.3, 32.4, 18.8, 17.7, 16.2.
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(E)-quinoline-8-carbaldehyde O-(5-methylhexan-2-yl) oxime. H NMR (400
MHz, CDCl3) δ 9.39 (s, 1H), 8.97 – 8.90 (m, 1H), 8.28 (d, J = 6.8 Hz, 1H), 8.16
(dd, J = 8.3, 1.2 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43
(dd, J = 8.3, 4.2 Hz, 1H), 4.48 – 4.24 (m, 1H), 1.88 – 1.69 (m, 1H), 1.64 – 1.47
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(m, 2H), 1.44 – 1.23 (m, 5H), 0.92 (s, 3H), 0.90 (s, 3H). C NMR (100 MHz,
CDCl3) δ 150.0, 145.9, 145.4, 136.4, 130.7, 129.2, 128.4, 126.5, 126.2, 121.5,
80.1, 34.8, 33.8, 28.3, 22.8, 22.7, 20.1.
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(E)-quinoline-8-carbaldehyde O-(1-cyclopentylethyl) oxime. H NMR (400
MHz, CDCl3) δ 9.38 (s, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 7.3 Hz, 1H),
8.16 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43
(dd, J = 8.3, 4.2 Hz, 1H), 4.28 – 4.17 (m, 1H), 2.11 (dd, J = 16.5, 8.2 Hz, 1H),
1.90 – 1.82 (m, 1H), 1.79 – 1.71 (m, 1H), 1.68 – 1.60 (m, 2H), 1.58 – 1.50 (m,
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2H), 1.35 (d, J = 6.3 Hz, 3H). C NMR (100MHz, CDCl3) δ 149.9, 145.8,
145.1, 136.5, 130.7, 129.2, 128.4, 126.6, 126.2, 121.4, 83.9, 45.3, 29.4, 29.2,
25.8(×2), 19.1.
(E)-quinoline-8-carbaldehyde O-(1-cyclohexylethyl) oxime. 1H NMR (400 MHz,
CDCl3) δ 9.39 (s, 1H), 8.99 – 8.89 (m, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.20 –
8.11 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (dd, J =
8.3, 4.2 Hz, 1H), 4.20 (p, J = 6.3 Hz, 1H), 1.91 (d, J = 12.7 Hz, 1H), 1.80 –
1.60 (m, 5H), 1.37 – 1.05 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 149.9, 145.8,
145.2, 136.4, 130.7, 129.2, 128.4, 126.6, 126.2, 121.4, 83.9, 42.6, 29.2, 28.4,
26.8, 26.5, 26.4, 17.0.
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(E)-2-(((quinolin-8-ylmethylene)amino)oxy)propyl benzoate. H NMR (400
MHz, CDCl3) δ 9.44 (s, 1H), 8.94 (dd, J = 4.1, 1.6 Hz, 1H), 8.25 (dd, J = 7.3,
1.3 Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 8.12 – 8.04 (m, 2H), 7.85 (dd, J =
8.2, 1.3 Hz, 1H), 7.56 –7.51 (m, 2H), 7.46 – 7.36 (m, 3H), 4.90 – 4.73 (m, 1H),
4.55 (d, J = 5.0 Hz, 2H), 1.47 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 166.7, 150.1, 146.6, 145.9, 136.6, 133.1, 130.4, 130.2, 130.0, 129.6, 128.5
(×2), 126.6, 126.5, 121.6, 77.4, 67.2, 16.9.
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(E)-quinoline-8-carbaldehyde O-(1-phenylpropan-2-yl) oxime. H NMR (400
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MHz, CDCl3) δ 9.41 (s, 1H), 8.95 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.16 (d, J =
8.2 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (dd, J = 8.1,
4.0 Hz, 1H), 7.35 – 7.16 (m, 5H), 4.74 – 4.53 (m, 1H), 3.19 (dd, J = 13.6, 5.7
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Hz, 1H), 2.85 (dd, J = 13.6, 7.0 Hz, 1H), 1.31 (d, J = 6.3 Hz, 3H). C NMR
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(100 MHz, CDCl3) δ 150.0, 145.9 (×2), 138.8, 136.5, 130.5, 129.8, 129.4,
128.4, 128.3, 126.6, 126.3, 126.2, 121.5, 80.4, 42.3, 19.4.
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(E)-quinoline-8-carbaldehyde O-(4-phenylbutan-2-yl) oxime. H NMR (400
MHz, CDCl3) δ 9.43 (s, 1H), 8.95 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H),
8.16 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43
(dd, J = 8.1, 4.1 Hz, 1H), 7.31 – 7.21 (m, 4H), 7.18 (t, J = 7.0 Hz, 1H), 4.49 –
4.38 (m, 1H), 2.98 – 2.65 (m, 2H), 2.16 – 2.05 (m, 1H), 1.95 – 1.84 (m, 1H),
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1.38 (d, J = 6.3 Hz, 3H). C NMR (100 MHz, CDCl3) δ 150.0, 145.8, 145.6,
142.5, 136.5, 130.6, 129.3, 128.6, 128.5, 128.4, 126.6, 126.3, 125.8, 121.5, 79.0,
37.7, 31.9, 20.2.
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methyl (E)-4-(((quinolin-8-ylmethylene)amino)oxy)pentanoate. H NMR (400
MHz, CDCl3) δ 9.37 (s, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H),
8.16 (dd, J = 8.2, 1.0 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H),
7.43 (dd, J = 8.3, 4.2 Hz, 1H), 4.49 – 4.38 (m, 1H), 3.68 (s, 3H), 2.58 – 2.43 (m,
2H), 2.10 – 1.95 (m, 2H), 1.36 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 174.3, 150.0, 145.8 (×2), 136.5, 130.4, 129.4, 128.4, 126.5, 126.3, 121.5, 78.6,
51.7, 31.0, 30.3, 20.0.
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(E)-quinoline-8-carbaldehyde O-(1-methoxypropan-2-yl) oxime. H NMR (400
MHz, CDCl3) δ 9.43 (s, 1H), 8.94 (dd, J = 4.1, 1.6 Hz, 1H), 8.27 (dd, J = 7.3,
1.3 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.85 (dd, J = 8.2, 1.3 Hz, 1H), 7.56
(t, J = 7.7 Hz, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 4.64 – 4.54 (m, 1H), 3.65 (dd,
J = 10.4, 5.7 Hz, 1H), 3.55 (dd, J = 10.4, 4.4 Hz, 1H), 3.43 (s, 3H), 1.37 (d, J =
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6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 150.0, 146.4, 145.8, 136.5, 130.3,
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MHz, CDCl3) δ 9.44 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 7.3 Hz, 1H),
8.16 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43
(dd, J = 8.2, 4.1 Hz, 1H), 4.65 –4.55 (m, 1H), 3.83 (dd, J = 11.0, 3.9 Hz, 1H),
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3.70 (dd, J = 10.9, 6.2 Hz, 1H), 1.46 (d, J = 6.3 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 150.1, 147.0, 145.9, 136.4, 130.0, 129.7, 128.4, 126.5, 126.4, 121.5,
78.7, 47.2, 17.4.
(E)-2-(((quinolin-8-ylmethylene)amino)oxy)propyl 4-phenylbutanoate. 1H NMR
(400 MHz, CDCl3) δ 9.46 (s, 1H), 8.94 (dd, J = 4.1, 1.7 Hz, 1H), 8.29 (dd, J =
7.3, 1.1 Hz, 1H), 8.18 (dd, J = 8.3, 1.7 Hz, 1H), 7.88 (dd, J = 8.1, 1.2 Hz, 1H),
7.58 (t, J = 7.7 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 7.30 – 7.25 (m, 2H),
7.22 – 7.16 (m, 3H), 4.69 – 4.615 (m, 1H), 4.33 (dd, J = 5.0, 1.8 Hz, 2H), 2.68
(t, J = 7.4 Hz, 2H), 2.41 (t, J = 7.4 Hz, 2H), 2.05 – 1.95 (m, 2H), 1.41 (d, J =
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6.6 Hz, 3H). C NMR (100 MHz, CDCl3) δ 173.6, 150.1, 146.6, 146.0, 141.5,
136.4, 130.2, 129.6, 128.6, 128.5, 128.4, 126.5, 126.3, 126.0, 121.5, 77.2, 66.4,
35.3, 33.7, 26.7, 16.7.
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(E)-2-(((quinolin-8-ylmethylene)amino)oxy)propyl acetate. H NMR (400 MHz,
CDCl3) δ 9.42 (s, 1H), 8.97 (d, J = 2.7 Hz, 1H), 8.27 (dd, J = 7.3, 1.3 Hz, 1H),
8.19 (dd, J = 8.3, 1.5 Hz, 1H), 7.87 (dd, J = 8.2, 1.3 Hz, 1H), 7.58 (t, J = 7.7 Hz,
1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 4.72 – 4.58 (m, 1H), 4.30 (dd, J = 5.0, 1.5
Hz, 2H), 2.10 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
171.3, 150.1, 146.6, 145.7, 136.8, 130.1, 129.7, 128.5, 126.7 (×2), 121.6, 77.3,
66.6, 21.1, 16.8.
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(E)-quinoline-8-carbaldehyde
O-(1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)
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oxime. H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.90 (d, J = 3.9 Hz, 1H),
8.12 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.89 – 7.85 (m, 1H), 7.80 –
7.73 (m, 2H), 7.65 – 7.60 (m, 2H), 7.44 – 7.33 (m, 2H), 4.88 – 4.76 (m, 1H),
4.09 (dd, J = 14.0, 8.3 Hz, 1H), 3.82 (dd, J = 14.0, 4.1 Hz, 1H), 1.41 (d, J = 6.5
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Hz, 3H). C NMR (100 MHz, CDCl3) δ 168.6, 150.0, 146.4, 136.5, 134.5,
133.9, 132.9, 132.5, 129.4, 128.4, 126.4, 123.8, 123.4, 121.5, 76.6, 42.9, 17.9.
(E)-2-(((quinolin-8-ylmethylene)amino)oxy)propyl pent-4-enoate. 1H NMR
(400 MHz, CDCl3) δ 9.42 (s, 1H), 8.95 (dd, J = 4.1, 1.6 Hz, 1H), 8.27 (dd, J =
7.3, 1.3 Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 7.86 (dd, J = 8.2, 1.3 Hz, 1H),
7.57 (t, J = 7.7 Hz, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 5.88 – 5.76 (m, 1H),
5.02 (ddq, J = 22.3, 10.2, 1.4 Hz, 2H), 4.72 – 4.56 (m, 1H), 4.31 (d, J = 2.7 Hz,
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2H), 2.54 – 2.44 (m, 2H), 2.44 – 2.35 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H). C
NMR (100 MHz, CDCl3) δ 173.2, 150.1, 146.6, 145.9, 136.9, 136.6, 130.2,
129.7, 128.5, 126.6, 126.6, 121.6, 115.7, 77.3, 66.5, 33.7, 29.1, 16.8.
(E)-2-(((quinolin-8-ylmethylene)amino)oxy)propyl furan-2-carboxylate. 1H
NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.93 (dd, J = 4.1, 1.7 Hz, 1H), 8.24 (dd,
J = 7.3, 1.2 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.85 (dd, J = 8.2, 1.3 Hz,
1H), 7.59 – 7.52 (m, 2H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.21 (dd, J = 3.5, 0.7
Hz, 1H), 6.48 (dd, J = 3.5, 1.7 Hz, 1H), 4.79 – 4.69 (m, 1H), 4.52 (dd, J = 5.0,
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2.0 Hz, 2H), 1.44 (d, J = 6.6 Hz, 3H). C NMR (100 MHz, CDCl3) δ 158.8,
150.1, 146.7, 146.5, 146.0, 144.8, 136.5, 130.3, 129.6, 128.5, 126.6, 126.5,
121.6, 118.3, 112.0, 77.2, 66.9, 16.8.
2-((((E)-quinolin-8-ylmethylene)amino)oxy)propyl
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2-((3r,5r,7r)-adamantan-1-yl)acetate. H NMR (400 MHz, CDCl3) δ 9.41 (s,
1H), 8.93 (dd, J = 4.1, 1.7 Hz, 1H), 8.27 (dd, J = 7.3, 1.3 Hz, 1H), 8.17 (dd, J =
8.3, 1.7 Hz, 1H), 7.85 (dd, J = 8.2, 1.3 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43
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(dd, J = 8.3, 4.2 Hz, 1H), 4.68 – 4.57 (m, 1H), 4.28 (d, J = 5.0 Hz, 2H), 2.12 (s,
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2H), 2.00 – 1.90 (m, 3H), 1.68 – 1.56 (m, 12H), 1.39 (d, J = 6.5 Hz, 3H). C
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128.5, 126.6, 126.5, 121.6, 77.3, 66.1, 49.2, 42.6, 36.9, 33.0, 28.8, 16.9.
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2-((E)-(quinolin-8-ylimino)methoxy)propyl
(4R)-4-((3R,10S,12S,13R,17R)-3,12-dihydroxy-10,13-dimethylhexadecahydro-1
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H-cyclopenta[a]phenanthren-17-yl)pentanoate. H NMR (400 MHz, CDCl3) δ
9.43 (s, 1H), 8.98 (d, J = 2.7 Hz, 1H), 8.30 (dd, J = 7.3, 1.1 Hz, 1H), 8.25 –
8.19 (m, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.78 – 7.66 (m, 1H), 7.66 – 7.57 (m, 1H),
7.52 – 7.44 (m, 2H), 4.70 –4.62 (m, 1H), 4.35 – 4.27 (m, 2H), 3.97 –3.93 (m,
1H), 3.69 – 3.57 (m, 1H), 2.48 – 2.38 (m, 1H), 2.35 –2.26 (m, 1H), 1.92 – 1.72
(m, 8H), 1.72 – 1.61 (m, 2H), 1.55 –1.45 (m, 3H), 1.45 –1.35 (m, 8H), 1.31 –
1.24 (m, 2H), 1.15 – 1.05 (m, 2H), 1.03 – 0.95 (m, 4H), 0.90 (s, 3H), 0.65 (s,
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3H). C NMR (100 MHz, CDCl3) δ 174.4, 150.1, 146.5, 145.8, 136.7, 130.2,
129.7, 128.6, 126.7, 121.6, 73.3, 72.0, 66.4, 48.4, 47.6, 46.7, 42.3, 36.7, 36.2,
35.4, 35.3, 34.3, 33.9, 31.6, 31.1, 30.7, 28.8, 27.6, 27.3, 26.3, 23.8, 23.4, 17.5,
16.8, 12.9.
C-H sulfonamidation procedure for synthesis of 2a:
A 5 mL round-bottom flask was charged with Pd(OAc)2 (10 mol%, 4.6 mg), NFSI
(3.0 equiv, 189.2 mg), oxime 1a (0.2 mmol, 45.6 mg) and 1.0 mL MeNO2. The
mixture was stirred at 100ºC under Ar atmosphere, and the reaction was monitored by
UPLC-MS. When the starting material was consumed completely, the reaction
mixture was cooled to room temperature, then 1,10-phenanthroline (8 mg) and
Na2CO3 (180 mg) were added to quench the reaction, and the mixture was further
stirred at room temperature for 24h. Then the mixture was filtered through a pad of
Celite and washed with DCM. The filtrate was concentrated, and the residue was
purified with flash column chromatography (Petroleum ether/ethyl acetate/DCM =
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20:1:5) to afford the amidated product 2a as a colorless oil (75 mg, 72% yield), Rf =
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0.4 (Petroleum ether/EtOAc/DCM = 20:1:5). H NMR (400 MHz, CDCl3) δ 9.23 (s,
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1H), 8.91 (d, J = 22.6 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 6.5 Hz, 5H), 7.83
(d, J = 8.0 Hz, 1H), 7.56 – 7.38 (m, 8H), 4.70 –4.62 (m, 1H), 4.28 (dd, J = 15.6, 8.2
Hz, 1H), 3.79 (dd, J = 15.5, 2.6 Hz, 1H), 1.83 – 1.64 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 149.9, 146.2, 145.7, 139.8, 136.3, 133.7, 130.0, 129.5,
129.0, 128.5, 128.2, 126.4, 126.2, 121.5, 83.3, 51.5, 25.2, 9.5. HRMS (ESI): m/z (M +
H+) calcd for C26H26O5N3S2, 524.1308, found: 524.1300.
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(E)-N-(phenylsulfonyl)-N-(2-(((quinolin-8-ylmethylene)amino)oxy)propyl)
benzenesulfonamide (3), a colorless oil (53 mg, 52% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.23 (d, J = 26.9 Hz, 1H),
8.97 – 8.94 (m, 1H), 8.27 – 8.07 (m, 6H), 7.86 (d, J = 8.1 Hz, 1H), 7.65 – 7.40 (m,
8H), 4.94 – 4.75 (m, 1H), 4.24 (dd, J = 15.6, 8.1 Hz, 1H), 3.74 (dd, J = 15.6, 3.9 Hz,
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1H), 1.33 (d, J = 6.4 Hz, 3H). C NMR (100 MHz, CDCl3) δ 150.0, 146.5, 145.9,
139.9, 136.3, 133.8, 130.1, 129.6, 129.1, 128.6, 128.3, 126.5, 126.3, 121.5, 78.5, 52.8,
18.0. HRMS (ESI): m/z (M + H+) calcd for C25H24O5N3S2, 510.1152, found:
510.1143.
(E)-N-(phenylsulfonyl)-N-(2-(((quinolin-8-ylmethylene)amino)oxy)hexyl)
benzenesulfonamide (4), a colorless oil (77 mg, 70% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.96 (d, J =
2.1 Hz, 1H), 8.18 (d, J = 6.7 Hz, 2H), 8.11 (d, J = 6.9 Hz, 4H), 7.86 (d, J = 8.0 Hz,
1H), 7.62 – 7.41 (m, 8H), 4.72 – 4.63 (m, 1H), 4.26 (dd, J = 15.6, 8.2 Hz, 1H), 3.77
(dd, J = 15.5, 3.2 Hz, 1H), 1.78 – 1.67 (m 1H), 1.65 – 1.55 (m, 1H), 1.52 – 1.41 (m,
13
1H), 1.38 – 1.27 (m, 3H), 0.88 (t, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3) δ
150.0, 146.1, 145.8, 140.0, 136.5, 133.8, 130.2, 129.5, 129.1, 128.6, 128.4, 126.5,
126.4, 121.5, 82.3, 51.9, 31.9, 27.4, 22.8, 14.1. HRMS (ESI): m/z (M + H+) calcd for
C28H30O5N3S2, 552.1621, found: 552.1610.
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(E)-N-(3-methyl-2-(((quinolin-8-ylmethylene)amino)oxy)butyl)-N-(phenylsulfonyl)
benzenesulfonamide (5), a colorless oil (65 mg, 61% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.98 (s, 1H),
8.20 (d, J = 7.0 Hz, 1H), 8.19 – 8.04 (m, 5H), 7.87 (d, J = 8.0 Hz, 1H), 7.51 – 7.44 (m,
1H), 7.47 (d, J = 1.6 Hz, 7H), 4.63 – 4.57 (m, 1H), 4.24 (dd, J = 15.8, 9.2 Hz, 1H),
3.76 (d, J = 15.8 Hz, 1H), 2.16 – 2.05 (m, 1H), 1.04 (d, J = 6.9 Hz, 3H), 0.99 (d, J =
6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 149.8, 145.7, 145.3, 139.9, 136.9, 133.7,
129.9, 129.5, 129.0, 128.6, 128.4, 126.7 (×2), 121.5, 86.8, 49.71, 30.6, 18.0, 17.9.
HRMS (ESI): m/z (M + H+) calcd for C27H28O5N3S2, 538.1465, found: 538.1455.
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(E)-N-(5-methyl-2-(((quinolin-8-ylmethylene)amino)oxy)hexyl)-N-(phenylsulfonyl)
benzenesulfonamide (6), a colorless oil (76 mg, 67% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 9.02 – 8.90
(m, 1H), 8.18 (t, J = 7.6 Hz, 2H), 8.12 (d, J = 6.9 Hz, 4H), 7.85 (d, J = 8.1 Hz, 1H),
7.63 – 7.39 (m, 8H), 4.71 – 4.61 (m, 1H), 4.26 (dd, J = 15.6, 8.1 Hz, 1H), 3.78 (dd, J
= 15.6, 3.6 Hz, 1H), 1.85 – 1.47 (m, 3H), 1.43 –1.33 (m, 1H), 1.28 – 1.18 (m, 1H),
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0.88 (d, J = 1.6 Hz, 3H), 0.86 (d, J = 1.6 Hz, 3H). C NMR (100 MHz, CDCl3) δ
150.0, 146.2, 145.8, 140.0, 136.3, 133.8, 130.2, 129.5, 129.0, 128.6, 128.4, 126.5,
126.3, 121.5, 82.4, 51.9, 34.2, 30.1, 28.1, 22.7, 22.6. HRMS (ESI): m/z (M + H+)
calcd for C29H32O5N3S2, 566.1778, found: 566.1767.
(E)-N-(2-cyclopentyl-2-(((quinolin-8-ylmethylene)amino)oxy)ethyl)-N-(phenylsulfonyl)
benzenesulfonamide (7), a colorless oil (73 mg, 65% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.97 (d, J =
2.7 Hz, 1H), 8.18 (dd, J = 14.9, 7.7 Hz, 2H), 8.14 – 8.04 (m, 4H), 7.86 (d, J = 8.1 Hz,
1H), 7.55 (t, J = 7.7 Hz, 1H), 7.50 –7.44 (m, 7H), 4.64 (t, J = 7.4 Hz, 1H), 4.32 (dd, J
= 15.7, 9.2 Hz, 1H), 3.75 (dd, J = 15.7, 2.0 Hz, 1H), 2.31 – 2.04 (m, 1H), 1.88 – 1.40
(m, 8H). 13C NMR (100 MHz, CDCl3) δ 149.9, 145.5 (×2), 140.0, 136.7, 133.7, 130.2,
129.4, 129.0, 128.6, 128.4, 126.6, 126.6, 121.5, 86.2, 51.4, 42.6, 29.1, 28.7, 25.7, 25.6.
HRMS (ESI): m/z (M + H+) calcd for C29H30O5N3S2, 564.1621, found: 564.1608.
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(E)-N-(2-cyclohexyl-2-(((quinolin-8-ylmethylene)amino)oxy)ethyl)-N-(phenylsulfonyl)
benzenesulfonamide (8), a colorless oil (68 mg, 59% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.99 (s, 1H),
8.28 – 8.00 (m, 6H), 7.87 (s, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.47 (s, 7H), 4.59 (s, 1H),
4.36 – 4.19 (m, 1H), 3.81 (d, J = 15.6 Hz, 1H), 1.86 (d, J = 11.2 Hz, 1H), 1.81– 1.61
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(d, J = 32.9 Hz, 5H), 1.19 (s, 5H). C NMR (100 MHz, CDCl3) δ 150.0, 145.7 (×2),
140.1, 136.7, 133.8, 130.2, 129.5, 129.1, 128.7, 128.5, 128.5, 126.7, 126.5, 121.6,
86.5, 50.2, 40.8, 28.8, 28.4, 26.7, 26.5, 26.4. HRMS (ESI): m/z (M + H+) calcd for
C30H32O5N3S2, 578.1778, found: 578.1766.
(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl benzoate (9), a colorless oil (82 mg, 65% yield). Rf = 0.3 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.96 (dd, J
= 4.1, 1.6 Hz, 1H), 8.21 –8.16 (m, 2H), 8.16 – 8.12 (m, 4H), 8.11 –8.07 (m, 2H), 7.88
(dd, J = 8.1, 1.2 Hz, 1H), 7.59 – 7.41 (m, 11H), 5.09 –5.03 (m, 1H), 4.67 – 4.53 (m,
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2H), 4.44 (dd, J = 16.0, 8.6 Hz, 1H), 3.94 (dd, J = 16.0, 3.2 Hz, 1H). C NMR (100
MHz, CDCl3) δ 166.3, 150.1, 147.5, 145.8, 139.7, 136.5, 134.0, 133.3, 130.0, 129.9,
129.6, 129.1, 128.7, 128.5(×2), 128.4, 126.6, 126.5, 121.6, 80.6, 64.0, 49.2. HRMS
(ESI): m/z (M + H+) calcd for C32H28O7N3S2, 630.1363, found: 630.1346.
(E)-N-(3-phenyl-2-(((quinolin-8-ylmethylene)amino)oxy)propyl)-N-(phenylsulfonyl)be
nzenesulfonamide (10), a colorless oil (53 mg, 45% yield). Rf = 0.3 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.98 (d, J =
2.8 Hz, 1H), 8.22 (t, J = 8.9 Hz, 2H), 7.95 (d, J = 7.6 Hz, 4H), 7.88 (d, J = 8.0 Hz,
1H), 7.58 (t, J = 7.7 Hz, 1H), 7.54 – 7.40 (m, 7H), 7.34 (t, J = 7.2 Hz, 2H), 7.26 (t, J =
6.5 Hz, 3H), 5.03 (td, J = 8.7, 2.7 Hz, 1H), 4.29 (dd, J = 16.0, 8.9 Hz, 1H), 3.57 (dd, J
= 16.0, 2.7 Hz, 1H), 3.26 (dd, J = 14.0, 6.1 Hz, 1H), 2.85 (dd, J = 14.0, 7.9 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 150.0, 146.8, 145.7, 139.6, 137.5, 136.7, 133.8, 130.0,
129.8, 129.7, 129.0, 129.0, 128.7, 128.6, 128.5, 128.4, 126.6, 126.6, 121.6, 83.2, 50.4,
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38.9. HRMS (ESI): m/z (M + H+) calcd for C31H28O5N3S2, 586.1465, found:
586.1451.
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(E)-N-(4-phenyl-2-(((quinolin-8-ylmethylene)amino)oxy)butyl)-N-(phenylsulfonyl)ben
zenesulfonamide (11), a colorless oil (74 mg, 62% yield). Rf = 0.3 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.98 (d, J =
2.2 Hz, 1H), 8.20 (d, J = 7.4 Hz, 2H), 8.07 (d, J = 7.8 Hz, 4H), 7.88 (d, J = 8.1 Hz,
1H), 7.60 – 7.44 (m, 8H), 7.26 (d, J = 6.3 Hz, 2H), 7.18 (d, J = 7.5 Hz, 3H), 4.77
–4.69 (m, 1H), 4.29 (dd, J = 15.6, 7.7 Hz, 1H), 3.79 (dd, J = 15.5, 3.9 Hz, 1H), 2.94 –
2.76 (m, 1H), 2.75 – 2.63 (m, 1H), 2.16 – 2.00 (m, 1H), 1.99 – 1.89 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 150.0, 146.5, 145.6, 141.9, 139.9, 136.7, 133.8, 130.0,
129.6, 129.1, 128.7 (×2), 128.6, 128.5 (×2), 126.6, 126.0, 121.5, 81.5, 51.8, 33.9, 31.5.
HRMS (ESI): m/z (M + H+) calcd for C32H30O5N3S2, 600.1621, found: 600.1609.
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methyl
(E)-5-(N-(phenylsulfonyl)phenylsulfonamido)-4-(((quinolin-8-ylmethylene)
amino)oxy)pentanoate (12), a colorless oil (56 mg, 48% yield). Rf = 0.3 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.98 (d, J =
2.4 Hz, 1H), 8.24 – 8.16 (m, 2H), 8.11 (d, J = 6.8 Hz, 4H), 7.88 (d, J = 8.0 Hz, 1H),
7.64 – 7.42 (m, 8H), 4.77 – 4.69 (m, 1H), 4.28 (dd, J = 18.2, 10.5 Hz, 1H), 3.75 (dd, J
= 15.7, 3.6 Hz, 1H), 3.66 (s, 3H), 2.61 – 2.40 (m, 2H), 2.08 – 2.00 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 173.5, 149.5, 146.4, 144.3, 139.6, 137.8, 133.8, 130.9, 129.7,
129.0, 128.5, 128.4, 127.4, 126.9, 121.5, 81.4, 51.7, 51.4, 29.8, 27.5. HRMS (ESI):
m/z (M + H+) calcd for C28H28O7N3S2, 582.1363, found: 582.1347.
(E)-N-(3-methoxy-2-(((quinolin-8-ylmethylene)amino)oxy)propyl)-N-(phenylsulfonyl)
benzenesulfonamide (13), a colorless oil (73 mg, 68% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.94 (dd, J
= 4.1, 1.7 Hz, 1H), 8.20 – 8.10 (m, 6H), 7.86 (dd, J = 8.1, 1.2 Hz, 1H), 7.58 – 7.46 (m,
7H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 4.85 (td, J = 8.3, 4.5 Hz, 1H), 4.34 (dd, J = 16.0,
8.6 Hz, 1H), 3.93 (dd, J = 16.0, 3.4 Hz, 1H), 3.67 (qd, J = 10.8, 4.7 Hz, 2H), 3.39 (s,
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3H). C NMR (100 MHz, CDCl3) δ 150.1, 147.1, 145.9, 139.8, 136.3, 133.8, 129.8,
129.7, 129.0, 128.6, 128.3, 126.4, 126.3, 121.5, 81.3, 72.0, 59.5, 49.6. HRMS (ESI):
m/z (M + H+) calcd for C26H26O6N3S2, 540.1257, found: 540.1245.
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(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl 4-methylbenzenesulfonate (14), a colorless oil (91 mg, 67% yield). Rf = 0.4
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(Petroleum ether/EtOAc/DCM = 4:1:1). H NMR (400 MHz, CDCl3) δ 9.02 (s, 2H),
8.22 (d, J = 8.0 Hz, 1H), 8.09 (dd, J = 8.0, 1.6 Hz, 4H), 7.98 (dd, J = 7.2, 1.1 Hz, 1H),
7.92 – 7.86 (m, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.60 – 7.48 (m, 8H), 7.16 (d, J = 8.0 Hz,
2H), 4.82 – 4.76 (m, 1H), 4.38 – 4.26 (m, 3H), 3.81 (dd, J = 16.2, 3.0 Hz, 1H), 2.08 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 150.1, 147.7, 145.0, 139.6, 134.1, 134.1, 132.6,
130.2, 130.0, 129.3, 128.9, 128.7, 128.6, 128.5, 128.3, 126.9, 126.2, 121.9, 80.2, 68.8,
48.8, 21.5. HRMS (ESI): m/z (M + H+) calcd for C32H30O8N3S3, 680.1189, found:
680.1174.
(E)-N-(3-chloro-2-(((quinolin-8-ylmethylene)amino)oxy)propyl)-N-(phenylsulfonyl)be
nzenesulfonamide (15), a colorless oil (75 mg, 69% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 9.00 (d, J =
2.6 Hz, 1H), 8.27 – 8.06 (m, 6H), 7.90 (d, J = 8.1 Hz, 1H), 7.64 – 7.45 (m, 8H), 4.88
–4.92 (m, 1H), 4.37 (dd, J = 16.0, 8.5 Hz, 1H), 3.93 (dd, J = 16.1, 2.8 Hz, 1H), 3.84
(dd, J = 11.7, 3.9 Hz, 1H), 3.77 (dd, J = 11.8, 5.9 Hz, 1H). 13C NMR (100MHz,
CDCl3) δ 150.2, 148.0, 145.6, 139.7, 136.8, 134.1, 130.2, 129.4, 129.2, 128.7, 128.5,
126.9, 126.6, 121.8, 81.6, 49.7, 44.0. HRMS (ESI): m/z (M + H+) calcd for
C25H23ClO5N3S2, 544.0762, found: 544.0755.
(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl acetate (16), a colorless oil (47 mg, 41% yield). Rf = 0.3 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 9.00 (dd, J
= 4.1, 1.5 Hz, 1H), 8.26 – 8.18 (m, 2H), 8.15 (dd, J = 7.8, 1.8 Hz, 4H), 7.91 (dd, J =
8.1, 1.1 Hz, 1H), 7.63 – 7.47 (m, 8H), 4.91 (dd, J = 8.2, 3.7 Hz, 1H), 4.41 – 4.32 (m,
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3H), 3.89 (dd, J = 16.0, 3.4 Hz, 1H), 2.12 (s, 3H). 13C NMR (10 MHz, CDCl3) δ
171.0, 150.2, 147.6, 145.8, 139.7, 136.6, 134.1, 130.0, 129.6, 129.2, 128.7, 128.5,
126.6 (×2), 121.7, 80.4, 63.6, 49.3, 21.1. HRMS (ESI): m/z (M + H+) calcd for
C27H26O7N3S2, 568.1207, found: 568.1193.
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(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl pent-4-enoate (17), a colorless oil (55 mg, 45% yield). Rf = 0.4 (Petroleum
ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.98 – 8.93
(m, 1H), 8.21 – 8.10 (m, 6H), 7.88 (d, J = 8.1 Hz, 1H), 7.60 – 7.45 (m, 8H), 5.90 –
5.73 (m, 1H), 5.10 – 4.94 (m, 2H), 4.93 –4.86 (m, 1H), 4.40 – 4.36 (m, 2H), 4.35 –
4.30 (m, 1H), 3.86 (dd, J = 16.0, 3.2 Hz, 1H), 2.50 – 2.42 (m, 2H), 2.42 –2.36 (dd, J =
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13.3, 6.4 Hz, 2H). C NMR (100 MHz, CDCl3) δ 172.9, 150.5, 147.5, 145.8, 139.8,
136.8, 136.6, 134.0, 130.0, 129.6, 129.2, 128.7, 128.5, 126.6, 126.6, 121.7, 115.8,
80.4, 63.5, 49.3, 33.6, 29.0. HRMS (ESI): m/z (M + H+) calcd for C30H30O7N3S2,
608.1520, found: 608.1508.
(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl furan-2-carboxylate (18), a colorless oil (64 mg, 52% yield). Rf = 0.3
(Petroleum ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H),
8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.22 – 8.14 (m, 6H), 7.90 (dd, J = 8.1, 1.3 Hz, 1H),
7.62 (dd, J = 1.6, 0.8 Hz, 1H), 7.59 – 7.46 (m, 8H), 7.27 (dd, J = 3.5, 0.7 Hz, 1H),
6.53 (dd, J = 3.5, 1.7 Hz, 1H), 5.03 (td, J = 8.1, 4.6 Hz, 1H), 4.66 – 4.57 (m, 2H), 4.43
(dd, J = 16.1, 8.5 Hz, 1H), 3.95 (dt, J = 8.5, 4.3 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 158.4, 150.2, 147.7, 146.8, 145.9, 144.4, 139.6, 136.5, 134.1, 130.0, 129.6, 129.2,
128.9, 128.7, 128.4, 126.6, 121.7, 118.7, 112.1, 80.5, 63.8, 49.2. HRMS (ESI): m/z
(M + H+) calcd for C30H26O8N3S2, 620.1156, found: 620.1139.
(E)-N-(3-(1,3-dioxoisoindolin-2-yl)-2-(((quinolin-8-ylmethylene)amino)oxy)propyl)-N
-(phenylsulfonyl)benzenesulfonamide (19), a colorless oil (75 mg, 57% yield). Rf =
1
0.4 (Petroleum ether/EtOAc/DCM = 20:2:5). H NMR (400 MHz, CDCl3) δ 9.21 (s,
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1H), 8.94 (dd, J = 4.1, 1.5 Hz, 1H), 8.20 – 8.09 (m, 5H), 8.07 – 8.02 (m, 1H), 7.85 –
7.78 (m, 3H), 7.68 – 7.62 (m, 2H), 7.58 – 7.47 (m, 6H), 7.46 – 7.40 (m, 2H), 5.03
–4.95 (m, 1H), 4.35 (dd, J = 16.1, 7.9 Hz, 1H), 4.11 (dd, J = 14.2, 6.2 Hz, 1H), 4.01
(dd, J = 14.2, 6.1 Hz, 1H), 3.94 (dd, J = 16.1, 3.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 168.4, 150.1, 147.5, 145.8, 139.7, 136.5, 134.1, 134.0, 132.2, 129.8, 129.6,
129.2, 128.7, 128.6, 128.3, 126.5, 123.5, 121.6, 80.5, 49.9, 39.6. HRMS (ESI): m/z
(M + H+) calcd for C33H27O7N4S2, 655.1316, found: 655.1300.
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(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl 4-phenylbutanoate (20), a colorless oil (87 mg, 65% yield). Rf = 0.3
(Petroleum ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H),
8.95 (dd, J = 4.0, 1.4 Hz, 1H), 8.21 – 8.15 (m, 2H), 8.12 (dd, J = 8.1, 1.5 Hz, 4H),
7.91 – 7.81 (m, 1H), 7.59 – 7.43 (m, 8H), 7.29 – 7.22 (m, 2H), 7.20 – 7.12 (m, 3H),
4.95 – 4.82 (m, 1H), 4.39 – 4.26 (m, 3H), 3.85 (dd, J = 16.0, 3.4 Hz, 1H), 2.65 (t, J =
7.5 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H), 2.02 – 1.90 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 173.2, 150.1, 147.5, 145.8, 141.5, 139.7, 136.5, 134.0, 129.9, 129.6, 129.1,
128.6, 128.5, 128.4, 126.6, 126.5, 126.1, 121.6, 80.4, 63.3, 49.2, 35.2, 33.6, 26.5.
HRMS (ESI): m/z (M + H+) calcd for C35H33O7N3S2, 672.1833, found: 672.1818.
(E)-3-(N-(phenylsulfonyl)phenylsulfonamido)-2-(((quinolin-8-ylmethylene)amino)oxy)
propyl naphthalene-2-sulfonate (21), a colorless oil (87 mg, 61% yield). Rf = 0.4
1
(Petroleum ether/EtOAc/DCM = 4:1:1). H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H),
8.87 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 7.7 Hz, 4H), 7.90 –
7.78 (m, 4H), 7.76 (d, J = 7.3 Hz, 1H), 7.56 – 7.44 (m, 8H), 7.34-7.40 (m, 3H), 4.82 –
4.73 (m, 1H), 4.44 (dd, J = 11.2, 3.7 Hz, 1H), 4.40 – 4.30 (m, 2H), 3.82 (dd, J = 16.2,
2.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 149.9, 147.8, 147.5, 139.5, 135.3, 134.0,
132.4, 131.8, 130.1, 123.0, 129.8, 129.3, 129.2, 129.1, 128.8, 128.7, 128.6, 128.4,
128.4, 127.7, 127.5, 126.5, 122.8, 121.7, 80.0, 69.0, 48.8. HRMS (ESI): m/z (M + H+)
calcd for C35H30O8N3S3, 716.1189, found: 716.1179.
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3-(N-(phenylsulfonyl)phenylsulfonamido)-2-((((E)-quinolin-8-ylmethylene)amino)oxy)
propyl 2-((3r,5r,7r)-adamantan-1-yl)acetate (22), a colorless oil (86 mg, 61% yield).
Rf = 0.3 (Petroleum ether/EtOAc/DCM = 20:1:5). 1H NMR (400 MHz, CDCl3) δ 9.22
(s, 1H), 8.98 – 8.91 (m, 1H), 8.24 – 8.11 (m, 6H), 7.87 (d, J = 7.5 Hz, 1H), 7.62 –
7.41 (m, 8H), 4.94 – 4.86 (m, 1H), 4.53 – 4.24 (m, 3H), 3.86 (dd, J = 16.0, 3.1 Hz,
1H), 2.11 (s, 2H), 1.93 (s, 3H), 1.69 – 1.53 (m, 12H). 13C NMR (100 MHz, CDCl3) δ
171.6, 150.1, 147.5, 145.9, 139.8, 136.4, 134.0, 129.9, 129.7, 129.2, 128.7, 128.4,
126.5 (×2), 121.6, 80.4, 63.1, 49.5, 49.0, 42.6, 36.9, 33.0, 28.8. HRMS (ESI): m/z (M
+ H+) calcd for C37H40O7N3S2, 702.2302, found: 702.2294.
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3-(N-(phenylsulfonyl)phenylsulfonamido)-2-((((E)-quinolin-8-ylmethylene)amino)oxy)
propyl
(4R)-4-((3R,10S,12S,13R,17R)-3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyc
lopenta[a]phenanthren-17-yl)pentanoate (23), a colorless oil (67 mg, 37% yield). Rf
= 0.3 (Petroleum ether/EtOAc/DCM = 20:2:5). 1H NMR (400 MHz, CDCl3) δ 9.23 (s,
1H), 9.00 (s, 1H), 8.27 – 8.17 (m, 2H), 8.13 (dd, J = 7.7, 1.7 Hz, 4H), 7.90 (d, J = 8.1
Hz, 1H), 7.66 – 7.49 (m, 9H), 4.90 (d, J = 4.5 Hz, 1H), 4.37 (dd, J = 21.6, 9.9 Hz, 3H),
3.93 (s, 1H), 3.86 (dd, J = 15.8, 3.1 Hz, 1H), 3.67 – 3.54 (m, 1H), 2.46 – 2.36 (m, 1H),
2.35 – 2.23 (m, 1H), 1.84 – 1.73 (m, 6H), 1.63 (d, J = 9.3 Hz, 8H), 1.54 – 1.42 (m,
7H), 1.37 (s, 8H), 1.22 (d, J = 23.9 Hz, 5H), 1.17 – 1.06 (m, 2H), 0.99 – 0.91 (m, 5H),
0.89 (s, 4H), 0.65 – 0.60 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.1, 150.1, 147.4,
145.6, 139.8, 136.8, 134.1, 130.0, 129.6, 129.2, 128.8, 128.5, 126.8, 126.7, 121.7,
80.5, 73.3, 72.1, 63.4, 49.3, 48.4, 47.5, 47.5, 46.7, 42.3, 36.7, 36.2, 35.4, 35.2, 34.3,
33.9, 31.5, 31.4, 31.0, 30.7, 29.9, 28.8, 27.6, 27.3, 26.3, 23.8, 23.4, 17.5, 12.9. HRMS
(ESI): m/z (M + H+) calcd for C49H62O9N3S2, 900.3922, found: 900.3893.
N-(2-hydroxy-3-phenylpropyl)-N-(phenylsulfonyl)benzenesulfonamide
(24).
Compound 10 (0.1mmol, 58.5 mg) was dissolved in 10 mL ethyl actetate, and 600 mg
Pd/C (10%) was added. The reaction mixture was stirred under H2 atmosphere at
room temperature until the starting material was consumed completely. Then the
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mixture was filtered through a pad of Celite and washed with ethyl acetate. The
filtrate was concentrated, and the residue was purified with flash column
chromatography (Petroleum ether/ethyl acetate/DCM = 20:2:5) to afford product 24
as a colorless oil (37 mg, 86% yield), Rf = 0.3 (Petroleum ether/EtOAc/DCM =
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20:3:5). H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.9 Hz, 4H), 7.64 (t, J = 7.4 Hz,
2H), 7.52 (t, J = 7.8 Hz, 4H), 7.33 (t, J = 7.3 Hz, 2H), 7.28 (d, J = 7.1 Hz, 1H), 7.19
(d, J = 7.2 Hz, 2H), 4.31 – 4.22 (m, 1H), 3.80 (dd, J = 15.7, 8.8 Hz, 1H), 3.69 (dd, J =
13
15.6, 3.0 Hz, 1H), 2.84 – 2.73 (m, 2H). C NMR (100 Hz, CDCl3) δ 139.3, 137.1,
134.0, 129.5 129.1, 128.7, 128.5 126.8 71.3, 53.5, 41.6. HRMS (ESI): m/z (M + H+)
calcd for C21H22O5NS2, 432.0934, found: 432.0922.
(E)-N-(3-phenyl-2-(((quinolin-8-ylmethylene)amino)oxy)propyl)benzenesulfonamide
(25). Compound 10 (0.2 mmol, 117 mg) was dissolved in 1 mL con. H2SO4 at 0°C ,
and the reaction mixture was stirred for 2 mins. Then the mixture was poured
into 10 mL ice water, and extracted by ethyl acetate (2 × 15 mL). The combined
organic layer was washed with brine (15 mL) and then dried over anhydrous
sodium sulfate. The organic solvent was removed on a rotary evaporator in
vacuo. The residue was purified by column chromatography on silica gel
(Petroleum ether/ethyl acetate/DCM = 20:2:5) to afford product 25 as a colorless oil
(82 mg, 92% yield), Rf = 0.3 (Petroleum ether/EtOAc/DCM = 20:3:5). 1H NMR (400
MHz, CDCl3) δ 9.21 (s, 1H), 9.08 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.0
Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H),
7.53 – 7.46 (m, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.26 (d, J = 7.0
Hz, 1H), 7.23 (t, J = 6.7 Hz, 2H), 5.71 (s, 1H), 4.51 (d, J = 4.8 Hz, 1H), 3.40 (ddd, J =
13.1, 7.0, 2.7 Hz, 1H), 3.29 – 3.17 (m, 1H), 3.13 (dd, J = 14.0, 6.5 Hz, 1H), 2.90 (dd,
J = 14.0, 7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.7, 147.8, 145.8, 140.0,
136.6, 132.6, 130.2, 129.6, 129.5, 129.2, 128.7, 128.6, 127.6, 127.2, 126.8, 126.5,
121.8, 82.0, 46.4, 38.0. HRMS (ESI): m/z (M + H+) calcd for C25H24O3N3S, 446.1533,
found: 446.1528.
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(E)-N-(3-phenyl-2-(((quinolin-8-ylmethylene)amino)oxy)propyl)benzamide (26).
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step: Compound 25 (0.1 mmol, 44.5 mg) was dissolved in 2 mL DCM, and DMAP (2
mg), Et3N (28 μL), BzCl (14 μL) were added. The reaction mixture was stirred until
the starting material was consumed completely. The solvent was removed on a
rotary evaporator in vacuo, and the residue was purified by column
chromatography on silica gel (Petroleum ether/ethyl acetate = 6:1) to afford
benzoylated product as a colorless oil (53.8 mg, 98% yield), Rf = 0.3 (Petroleum
ether/EtOAc = 4:1).
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2 step: Benzoylated product (53.8 mg) was dissolved in 1 mL con. H2SO4 at 0°C , and
the reaction mixture was stirred for 2 mins. Then the mixture was poured into
10 mL ice water, and extracted by ethyl acetate (2 × 15 mL). The combined
organic layer was washed with brine (15 mL) and then dried over anhydrous
sodium sulfate. The organic solvent was removed on a rotary evaporator in
vacuo. The residue was purified by column chromatography on silica gel
(Petroleum ether/ethyl acetate/DCM = 20:1:5) to afford product 26 as a colorless oil
27.2 mg, 69% yield), Rf = 0.2 (Petroleum ether/EtOAc/DCM = 20:2:5). 1H NMR (400
MHz, CDCl3) δ 9.45 (s, 1H), 8.93 (s, 1H), 8.19 (dd, J = 14.0, 7.7 Hz, 2H), 7.87 (d, J =
8.1 Hz, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.44 (dd, J = 12.5, 5.2
Hz, 2H), 7.40 – 7.27 (m, 6H), 7.22 – 7.15 (m, 1H), 6.85 (s, 1H), 4.71 (s, 1H), 4.02 –
3.92 (m, 1H), 3.68 – 3.58 (dd, J = 12.8, 6.1 Hz, 1H), 3.18 (dd, J = 14.1, 6.6 Hz, 1H),
13
3.01 (dd, J = 14.1, 6.3 Hz, 1H). C NMR (100 MHz, CDCl3) δ 167.6, 150.3, 147.3,
146.0, 137.7, 136.6, 134.9, 131.5, 130.0, 129.8, 129.6, 128.7, 128.7, 128.6, 127.3,
127.2, 126.7, 126.6, 121.7, 82.9, 43.5, 38.5. HRMS (ESI): m/z (M + H+) calcd for
C26H24O2N3, 410.1863, found: 410.1860.
Acknowledgments
We thank the National Natural Science Foundation of China (No. 81273364
and No. 81573289) for financial support.
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Supporting information:
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Copies of 1H and 13C NMR spectra of oxime substrates and compounds of 2a, 3~26;
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Scheme of Proposed mechanism
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