Photoredox-Mediated Remote C(sp3)-H Heteroarylation of N-Alkyl Sulfonamides

Article abstract of DOI:10.1021/acs.joc.9b02502

A Minisci-type δ-selective C(sp³)-H heteroarylation of sulfonyl-protected primary aliphatic amines with N-heteroarenes under photoredox-catalyzed conditions was developed. The reaction typically uses a slight excess of amine reactant. The use of benziodoxole acetate (BI-OAc) oxidant and hexafluoroisopropanol solvent is critical to achieve high yield. Besides methylene C-H bonds, heteroarylation reactions of δmethyl C-H bonds also worked under more forced conditions. The reactions show a broad scope for both amine and N-heteroarene substrates, offering a straightforward method for synthesis of complex δ-heteroarylalkylmines from simple precursors.

Full text of DOI:10.1021/acs.joc.9b02502

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Featured Article
Photoredox-Mediated Remote C(sp3)-
H Heteroarylation of N-Alkyl Sulfonamides
Zhiqiang Deng, Guo-Xing Li, Gang He, and Gong Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02502 • Publication Date (Web): 05 Dec 2019
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Photoredox-Mediated Remote C(sp3)-H Heteroarylation of N-Alkyl
Sulfonamides
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Zhiqiang Deng, Guo-Xing Li,* Gang He, and Gong Chen *
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
ABSTRACT: A Minisci-type δ-selective C(sp3)-H heteroarylation of sulfonyl-protected primary aliphatic amines with N-heteroarenes
under photoredox-catalyzed conditions was developed. The reaction typically uses a slight excess of amine reactant. The use of benzio-
doxole acetate (BI-OAc) oxidant and hexafluoroisopropanol solvent is critical to achieve high yield. Besides methylene C-H bonds,
heteroarylation reactions of δ methyl C-H bonds also worked under more forced conditions. The reactions show a broad scope for both
amine and N-heteroarene substrates, offering a straightforward method for synthesis of complex δ-heteroarylalkylmines from simple
precursors.
INTRODUCTION
Aliphatic amines of various structures are commonly used in or-
ganic synthesis.1 Selective functionalization of the C(sp3)-H
bonds of these amines could potentially streamline the synthesis
of complex amines.2 Among the existing methods3, radical-medi-
ated reactions featuring a 1,5-hydrogen atom transfer (1,5-HAT)
process of nitrogen-radical intermediates offer a convenient
strategy to selectively functionalize remote δ C-H bond of alkyl
amines.4 While the classic Hofmann-Loffler-Freytag (HLF) reac-
tion for synthesis of pyrrolidines uses N-halo-substituted amine
precursors,5 new protocols of HLF-type reactions can avoid the
pre-activation step via in situ generation of reactive amine species
using various activating reagents (Scheme 1A).6 More recently,
Knowles7 and Rovis8 independently reported a redox neutral pro-
cess for δ C-H alkylation reaction of acyl and sulfonyl protected
primary amines with electron-deficient alkenes under photore-
dox catalysis (Scheme 1B).9 Herein, we reported a new photore-
dox-mediated method for δ-C(sp3)-Hheteroarylation of sulfonyl
protected primary alkyl amines with N-heteroarenes using ben-
ziodoxole acetate (BI-OAc) oxidant (Scheme 1C). 10,11
RESULTS AND DISCUSSION
we wondered whether a similar protocol for C-H heteroarylation
of alkyl amine substrates can be developed. As shown in Table 1,
we were pleased to find that reaction of 1.5 equiv of 4-tert-bu-
tylphenylsulfonyl pentylamine 1, 1 equiv of 4-chloroquinoline 2,
2.5 equiv of benziodoxole
We recently reported a photoredox-mediated δ-selective C–
H heteroarylation reaction of free aliphatic alcohols with N-het-
eroarenes using perfluorinated hydroxybenziodoxole (PFBI-OH)
as oxidant.12 Encouraged by these results,
Table 1. Reaction optimization of δ C-H heteroarylation of pro-
tected pentylamine.a
Scheme 1. Radical-mediated remote C-H functionalization
of aliphatic amines via 1,5-HAT.
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Entry Change from the standard conditions
(equiv of reagents)
Yield of
3 (%)
85 (80b)
16
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2
3
4
5
Standard conditions
BIOAc ® PFBI-OH
BIOAc ® BI-OH
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BIOAc ® PhI(OAc)2
BIOAc ® PhI(OTFA)2
BIOAc (2.5 ® 2 equiv)
1 (1.5 ® 1.2 equiv)
1 (1.5 ® 2 equiv)
17
< 5
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68
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87
9
Ru(bpy)3Cl2 (0.5 ® 0.1 mol %)
No Ru(bpy)3Cl2
15
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15
< 5
< 5
< 5
< 5
57
CFL ® darkness
HFIP ® DCM
HFIP ® CH3CN
HFIP ® TFE
+ TEMPO (2.5 equiv)
0
a) Isolated yield on a 0.2 mmol scale. Unless otherwise indicated,
excellent δ regioselectivity (δ/other isomers > 20/1) was ob-
tained. b) 3 equiv of sulfonamide and 5 equiv of BI-OAc were
used. c) > 20/1 dr was observed. Stereochemistry has not been
established.
a) Unless otherwise indicated, reactions were conducted with 0.3
mmol of 1 and 0.2 mmol of 2 in 1 mL of solvent at 30 °C, yield of 3
was based on 1H-NMR of crude reaction mixture after workup. b)
Isolated yield.
lower yield (entries 12, 13). Lower loading of photosensitizer
Ru(bpy)3Cl2 (0.1 mol %) resulted in decreased yield (entry 9).
acetate (BI-OAc) and 0.5 mol % of Ru(bpy)3Cl2 under the irra-
diation of household compact fluorescent lamp (CFL, 23 W) in
hexafluoroisopropanol (HFIP) at 30 oC for 24 hours gave the de-
sired product 3 in 80% isolated yield (entry 1).13 Replacing BI-
OAc with other hypervalent iodine reagents gave lower yield (en-
try 2-5).14 Replacing the 4-tert-butylphenylsulfonyl group with
other acyl or sulfonyl group gave decreased yield under the same
reaction conditions. The use of 1.2 and 2.0 equiv of 1 gave 3 in
68% and 87% yield, respectively (entries 7, 8). Photosensitizer
Ru(bpy)3Cl2 and visible light irradiation were critical for the al-
kylation reaction (entries 10, 11). Use of dichloromethane
(DCM) and CH3CN as solvents gave significantly
The scope of amines was demonstrated in Scheme 2. Ali-
phatic sulfonamides of both linear and cyclic aliphatic scaffolds
were compatible with this protocol. Most sulfonamides carrying
simple linear alkyl chains proceeded with excellent δ regioselec-
tivity (δ/other isomers > 20/1). Notably, reaction of hexylamine
gave a moderate regioselectivity (4a: e/ δ ~7/1). Functional
groups including ester, carbamate, azido, terminal alkyne and al-
kene were tolerated (e.g. 4d–4h). Besides the δ methylene C–H
bonds, we were pleased to find that the heteroarylation at the
more inert δ methyl group also proceeded in moderate yield un-
der more forced conditions (using 3 equiv of amine substrate and
5 equiv of BI-OAc, see 4i). δMethylene C–H bonds of cyclic mo-
tifs can be heteroarylated in good yield with varied
Scheme 2. Scope of aliphatic sulfonamides.a
Scheme 3. Scope of N-heteroarenes.a
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along with significant amount of starting material (~50%) was re-
covered.
As shown in Scheme 4, the reaction of 4-chloroqunoline 2
with 4-tert-butylphenylsulfonyl pentylamine 1 conducted at 1
mmol scale worked well, giving product 3 in 74% yield. The 4-
tert-phenylsulfonamide group in product 5 can be cleanly re-
moved by the treatment of phenol in the aqueous hydrobromic
acid at 130 oC to give free amine product 20 in 90% yield.16
Preliminary experiments have been conducted to probe the
mechanism of this N-heteroarylation reaction (Scheme 5). In
our previous C-H heteroarylation reaction of free aliphatic alco-
hols, perfluorinated hydroxybenziodoxole (PFBI-OH) can read-
ily undergo substitution reaction with alcohols to give a new I-O
intermediate, which can be activated by Ru(II)* via single elec-
tron transfer (SET) to generate an alkoxyl radical.12 In contrast,
the corresponding substitution product 21 was not observed
when mixing BI-OAc with amine substrates. Furthermore, the re-
action of 22, a N-methylated derivative of 1, with 4-chloroquin-
oline 2 under the standard conditions did not gave any desired
alkylation product 23, supporting the involvement of a N-cen-
tered radical intermediate in this reaction system (Scheme 5A).17
Based on the these evidence and the related work by Knowles,7
Rovis8 and Itami,18 the following mechanism is proposed for this
reaction system (Scheme 5B). Photoexcited Ru(II)* is first oxi-
dized by BI-OAc via SET, forming Ru(III) and BI• radical 24.
The sulfonamide substrate 1 is oxidized by a Ru(III) species via
SET or proton-coupled electron transfer process to form N-rad-
ical 25. 25 undergoes 1,5-HAT to generate C-centered radical 26.
Following the typical Minisci reaction pathway,19,20 26 reacts
with protonated N-Heteroarenes to form intermediate 27. Reac-
tion of 27 with BI• via hydrogen atom abstraction or
SET/deprotonation give the final heteroarylation product21.
a) Isolated yield on a 0.2 mmol scale. b) 3 equiv of sulfonamide and 5
equiv of BI-OAc were used. c) 48 h. d) No di-alkylated product was de-
tected. e) Trace amount (<5%) of di-alkylated product was detected.
diastereoselectivity (e.g. 4j–4q). For example, reactions of sul-
fonamides of cyclohexylamine and cyclooctylamine gave 4j and
4k in 77% and 69% yield respectively as roughly a 1:1 mixture of
diastereomers. Interestingly, reaction of sulfonamide of cyclodo-
decylamine gave the heteroarylated product 4l in excellent syn di-
astereoselectivity (10/1) under the standard conditions. The
structure of 4l was confirmed by X-ray crystallography. As seen
in 4r, heteroarylation at the methine position gave little desired
product probably due to the facile oxidation of the resulting 3o C-
radical to a 3o carbocation.15
The scope of N-heteroarenes was then investigated with se-
lected 4-tert-butyl phenylsulfonyl protected aliphatic amines un-
der the optimized conditions (Scheme 3). In general, electron-
deficient N-heteroarenes showed much higher reactivity than
electron-rich ones (e.g. 5 vs 10). Chemoselectivity typical of
Minisci reactions was observed for heteroarenes as seen in quin-
olines (5–7), isoquinolines (9, 11) benzothiazole (12), quinox-
aline (13) and phenanthridine (14). Reaction of benzoyl pro-
tected drug molecule fasudil gave product 8 in 89% yield. As seen
in 4-chloroquinoline (15), quinaldine (16) and isoquinoline
(18), heteroarylation of δ methyl C-H bond worked in moderate
yield under modified conditions with 3 equiv of amine and 5
equiv of BI-OAc. Symmetric phthalazine (17) and pyridines (10,
19) mainly gave mono-alkylation products in moderate yields,
In summary, we have developed a new method for δ-selective
C(sp3)-H heteroarylation of sulfonyl-protected primary aliphatic
amines with N-heteroarenes under photoredox catalysis. The use
of the 4-tert-butylphenylsulfonyl protecting group for amine, cy-
clic hypervalent iodine BI-OAc as oxidant, and HFIP solvent is
critical to achieve high yield. The method show a broad scope for
both amine and
Scheme 4. Scale-up reaction and deprotection
Scheme 5. Mechanistic considerations.
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Procedure for synthesis of 4-tert-butylphenylsulfonyl pen-
1
tylamine 1. Pentan-1-amine (0.22 g, 2.5 mmol, 1.0 equiv), tri-
ethylamine (0.28 g, 2.8 mmol, 1.1 equiv) and DMAP (31 mg,
0.25 mmol, 0.1 equiv) were dissolved in DCM (10 mL) at 0 oC.
4-(tert-Butyl)benzenesulfonyl chloride (651.6 mg, 2.8 mmol, 1.1
equiv) was added portionwisely. The reaction mixture was
stirred at room temperature for 1 hour, then washed with satu-
rated NaHCO3 (aq), and brine. The organic phase was dried
over Na2SO4, filtered and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography on silica gel to give
compound 1 in 86% yield (0.67 g) as white solid. Mp 66.5-
68.0 °C; Rf = 0.7 (petroleum ether/ethyl acetae = 4:1). 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 6.9 Hz, 2H), 7.52 (d, J = 8.5 Hz,
2H), 4.43 (br s, 1H), 2.97-2.91 (m, 2H), 1.47-1.42 (m, 2H), 1.34
(s, 9H), 1.25-1.21 (m, 4H), 0.83 (t, J = 5.7 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.5, 137.0, 127.1, 126.2, 43.4, 35.3,
31.2, 29.4, 28.8, 22.3, 14.0. HRMS Calcd for C15H26NO2S+
[M+H+]: 284.1679, Found: 284.1684.
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All the N-protected amines used in this study were synthesized
following the same procedur as compound 1 with the corre-
sponding protecting reagent. The starting materials are num-
bered as “product number-1”, such as 4a-1 for the pre-het-
eroarylated amine of compound 4a. Compounds 1-PG1,23 1-
PG2,24 1-PG4,25 1-PG5,26 1-PG7,26 1-PG8,23 and 1-PG9,27 are
known compounds, the spectra data are consistent with those re-
ported in literature.
Procedure for synthesis of 1,1,1-trifluoro-N-pentylme-
thanesulfonamide (1-PG10). Pentan-1-amine (0.22 g, 2.5 mmol,
1.0 equiv), triethylamine (0.28 g, 2.8 mmol, 1.1 equiv) and
DMAP (31 mg, 0.25 mmol, 0.1 equiv) were dissolved in DCM
(10 mL) at -20 oC. Trifluoromethanesulfonic anhydride (0.79 g,
2.8 mmol) was added dropwise, and the mixture was stirred at
room temperature for 1 hour. The mixture was then washed with
saturated NaHCO3 (aq.) and brine. The organic phase was dried
over Na2SO4, filtered and concentrated in vacuo. The crude prod-
uct was purified by silica gel flash chromatography to give com-
pound 1-PG10 as a colorless oil in 82% yield (0.45 g). The spectra
data of 1-PG10 is consistent with the reported in literature.28
4-nitro-N-pentylbenzenesulfonamide (1-PG6). Yellow solid
(0.66 g, 97% yield); mp 61.3-62.4 °C; Rf = 0.7 (petroleum
ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3) δ 8.37 (d,
J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 4.73 (t, J = 5.8 Hz, 3H),
3.03-2.98 (m, 2H), 1.52-1.45 (m, 2H), 1.28-1.20 (m, 4H), 0.86-
0.83 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
150.2, 146.1, 128.4, 124.5, 43.5, 29.5, 28.7, 22.2, 14.0. HRMS
Calcd for C11H16N2NaO4S+ [M+Na+]: 295.0723, Found:
295.0724.
4-(tert-butyl)-N-hexylbenzenesulfonamide (4a-1). White
solid (0.63 g, 85% yield); mp 59.7-61.3 °C; Rf = 0.8 (petroleum
ether/ethyl acetae = 4:1). δ 1H NMR (400 MHz, CDCl3) δ 7.79
(d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.55 (br s, 1H), 2.97-
2.92 (m, 2H), 1.48-1.40 (m, 2H), 1.34 (s, 9H), 1.28-1.20 (m,
6H), 0.83 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 156.4, 137.0, 127.0, 126.2, 43.4, 35.3, 31.4, 31.2, 29.7, 26.3, 22.6,
14.1. HRMS Calcd for C16H28NO2S+ [M+H+]: 298.1835, Found:
298.1840.
N-heteroarene substrates, offering a straightforward method for
synthesis of complex δ-heteroarylalkylmines from simple precur-
sors.
EXPERIMENTAL SECTION
General Information. All commercial materials were used as re-
ceived unless otherwise noted. The amine starting materials were
either purchased from TCI or synthesized according to the re-
ported procedure. [Ru(bpy)3]Cl2 (98%, Ru＞15.75%, Energy
Chemical) and HFIP (99.0%, ACS grade, J&K Chemical) were
used as received unless otherwise noted. Hydroxylbenziodoxole
(BI-OH) and acetoxybenziodoxole (BI-OAc) were synthesized
according to reported procedures and used as freshly prepared.22
All reactions were carried out in a 4 mL glass vial (Thermo
SCIENTIFIC National B7999-2, made from superior quality 33
expansion borosilicate clear glass), sealed with a PTFE cap on
bench top. 23 W CFL(made by NVC, 50Hz/S-RR) was used for
visible-light promoted reactions. Analytical thin layer chroma-
tography (TLC) were performed on silica gel Huanghai
HSGF254 plates and visualization of the developed chromato-
gram was performed by fluorescence quenching (λmax = 254
nm). Flash chromatography was performed using silica gel (200-
300 mesh) purchased from Qingdao Haiyang Chemical Co.,
China. NMR spectra were recorded on Bruker AVANCE AV 400
instruments and all NMR experiments were reported in units,
parts per million (ppm), using residual solvent peaks as internal
reference (CDCl3, δ 7.26 for 1H and δ 77.16 for 13C). Multiplici-
ties are recorded as: s = singlet, d = doublet, t = triplet, br s =
broad singlet, m = multiplet. High resolution ESI mass experi-
ments were operated on a Thermo Q Exactive Focus instrument
with Quadrupole-Orbitrap mass analyzer.
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4-(tert-butyl)-N-(hexan-2-yl)benzenesulfonamide (4b-1). 5.75 (m, 1H), 5.00-4.91 (m, 1H), 4.55 (br s, 1H), 2.96-2.91 (m,
1
2
3
4
5
6
7
8
White solid (0.67 g, 86% yield); mp 58.6-60.0 °C; Rf = 0.8 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.80 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 4.41 (br s,
1H), 3.33-3.26 (m, 1H), 1.36-1.30 (m, 2H), 1.33 (s, 9H), 1.21-
1.08 (m, 4H), 1.04 (d, J = 6.5 Hz, 3H), 0.76 (t, J = 7.0 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 156.3, 138.3, 127.0, 126.1,
50.1, 37.3, 35.2, 31.2, 27.7, 22.4, 22.0, 14.1. HRMS Calcd for
C16H28NO2S+ [M+H+]: 298.1835, Found: 298.1831.
2H), 2.05-1.99 (m, 2H), 1.46-1.41 (m, 2H), 1.36-1.31 (m, 2H),
1.34 (s, 9H), 1.27-1.18 (m, 11H). 13C{1H} NMR (101 MHz,
CDCl3) δ 156.4, 139.3, 137.1, 127.1, 126.2, 114.3, 43.4, 35.3,
33.9, 31.2, 29.7, 29.49, 29.48, 29.2, 29.0, 26.6. HRMS Calcd for
C21H36NO2S+ [M+H+]: 366.2461, Found: 366.2457.
4-(tert-butyl)-N-butylbenzenesulfonamide (4i-1). White
solid (0.60 g, 89% yield); mp 86.9-88.0 °C; Rf = 0.9 (petroleum
ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J = 8.4 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 4.54 (t, J = 5.9 Hz, 1H),
2.95-2.92 (m, 2H), 1.48-1.40 (m, 2H), 1.34 (s, 9H), 1.30-1.24
(m, 2H), 0.84 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 156.4, 137.0, 127.0, 126.2, 43.1, 35.3, 31.8, 31.2, 19.8,
13.7. HRMS Calcd for C14H24NO2S+ [M+H+]: 270.1522, Found:
270.1525.
9
4-(tert-butyl)-N-hexadecylbenzenesulfonamide
(4c-1).
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White solid (0.92 g, 84% yield); mp 64.4-65.4 °C; Rf = 0.8 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.78 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.43 (br s,
1H), 2.97-2.92 (m, 2H), 1.48-1.41 (m, 2H), 1.34 (s, 9H), 1.25-
1.21 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 156.5, 137.1, 127.1, 126.2, 43.4, 35.3, 32.1, 31.2,
29.83, 29.80, 29.76, 29.68, 29.58, 29.5, 29.2, 26.7, 22.8, 14.3.
HRMS Calcd for C26H48NO2S+ [M+H+]: 438.3400, Found:
438.3395.
4-(tert-butyl)-N-cycloheptylbenzenesulfonamide
(4j-1).
White solid (0.67 g, 87% yield); mp 84.5-85.4 °C; Rf = 0.8 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.79 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 4.65-4.55 (m,
1H), 3.39-3.30 (m, 1H), 1.80-1.75 (m, 2H), 1.54-1.40 (m, 8H),
1.39-1.30 (m, 2H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz,
CDCl3) δ 156.2, 138.2, 126.9, 126.1, 54.9, 36.01, 35.99, 35.2,
31.2, 28.1, 23.6. HRMS Calcd for C17H28NO2S+ [M+H+]:
310.1835, Found: 310.1838.
Methyl-8-((4-(tert-butyl)phenyl)sulfonamido)octanoate
(4d-1). Colorless oil (0.60 g, 65% yield); Rf = 0.2 (petroleum
ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3) δ7.77 (d,
J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 1H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.42
(t, J = 6.1 Hz, 1H), 3.66 (s, 3H), 2.93 (dd, J = 13.5, 6.9 Hz, 2H),
2.27 (t, J = 7.5 Hz, 2H), 1.56 (dd, J = 14.3, 7.1 Hz, 2H), 1.50–
1.40 (m, 2H), 1.34 (s, 9H), 1.25 (t, J = 7.2 Hz, 6H)., 3.66 (s, 3H),
2.96-2.91 (m, 2H), 2.27 (t, J = 7.5 Hz, 2H), 1.59-1.54 (m, 2H),
1.49-1.42 (m, 2H), 1.34 (s, 9H), 1.27-1.24 (m, 6H). 13C{1H}
NMR (101 MHz, CDCl3) δ 174.3, 156.3, 137.0, 127.0, 126.1,
51.5, 43.3, 35.2, 34.0, 31.2, 29.5, 28.9, 28.7, 26.4, 24.8. HRMS
Calcd for C19H32NO4S+ [M+H+]: 370.2047, Found: 370.2042.
4-(tert-butyl)-N-cyclooctylbenzenesulfonamide
(4k-1).
White solid (0.68 g, 84% yield); mp 94.0-95.6 °C; Rf = 0.8 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.79 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.51 (d, J =
7.6 Hz, 1H), 3.40-3.37 (m, 1H), 1.74-1.68 (m, 2H), 1.59-1.39 (m,
12H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.3,
138.3, 127.0, 126.1, 54.0, 35.2, 32.8, 31.3, 27.4, 25.4, 23.3. HRMS
Calcd for C18H30NO2S+ [M+H+]: 324.1992, Found: 324.1996.
Tert-butyl-(10-((4-(tert-butyl)phenyl)sulfon-
4-(tert-butyl)-N-cyclododecylbenzenesulfonamide (4l-1).
White solid (0.85 g, 90% yield); mp 141.2-142.5 °C; Rf = 0.7 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.81 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.24 (d, J =
7.8 Hz, 1H), 3.25-3.22 (m, 1H), 1.55-1.47 (m, 2H), 1.34 (s, 9H),
1.31-1.09 (m, 20H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.4,
137.8, 127.2, 126.1, 50.4, 35.3, 31.3, 23.6, 23.5, 23.4, 23.3, 21.3.
HRMS Calcd for C22H38NO2S+ [M+H+]: 380.2618, Found:
380.2621.
amido)decyl)carbamate (4e-1). Colorless oil (0.96 g, 82%
1
yield); Rf = 0.3 (petroleum ether/ethyl acetae = 2:1). H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.5 Hz,
2H), 4.61 (s, 1H), 4.51 (br s, 1H), 3.01-3.06 (m, 2H), 2.95-2.90
(m, 2H), 1.45-1.40 (m, 13H), 1.33 (s, 9H), 1.25-1.20 (m, 12H).
13C{1H} NMR (101 MHz, CDCl3) δ 156.4, 156.1, 137.1, 127.0,
126.2, 79.1, 43.4, 40.7, 35.2, 31.2, 30.2, 29.7, 29.5, 29.4, 29.3, 29.2,
28.6, 26.9, 26.6. HRMS Calcd for C25H45N2O4S+ [M+H+]:
469.3095, Found: 469.3090.
4-(tert-butyl)-N-(2-cyclopentylethyl)benzenesulfonamide
(4m-1). White solid (0.66 g, 86% yield); mp 97.9-99.0 °C; Rf =
4-(tert-butyl)-N-(undec-10-yn-1-yl)benzenesulfonamide
(4g-1). White solid (0.84 g, 93% yield); mp 48.6-51.0 °C; Rf =
1
0.7 (petroleum ether/ethyl acetae = 4:1); H NMR (400 MHz,
1
0.7 (petroleum ether/ethyl acetae = 4:1). H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.68
(br s, 1H), 2.97-2.92 (m, 2H), 1.71-1.63 (m, 3H), 1.56-1.48 (m,
2H), 1.46-1.43 (m, 4H), 1.34 (s, 9H), 1.02-0.94 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.4, 137.0, 127.1, 126.2, 42.7, 37.3,
35.9, 35.2, 32.5, 31.2, 25.1. HRMS Calcd for C17H28NO2S+
[M+H+]: 310.1835, Found: 310.1832.
CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.44
(br s, 1H), 2.96-2.91 (m, 2H), 2.19-2.14 (m, 2H), 1.93 (t, J = 2.6
Hz, 1H), 1.53-1.41 (m, 4H), 1.37-1.32 (m, 2H), 1.34 (s, 9H),
1.25-1.18 (m, 8H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.5,
137.0, 127.0, 126.2, 84.9, 68.2, 43.4, 35.3, 31.2, 29.7, 29.4, 29.14,
29.08, 28.8, 28.6, 26.6, 18.5. HRMS Calcd for C21H34NO2S+
[M+H+]: 364.2305, Found: 364.2301.
4-(tert-butyl)-N-(2-cyclohexylethyl)benzenesulfonamide
(4n-1). White solid (0.77 g, 91% yield); mp 122.5-123.8 °C; Rf =
1
4-(tert-butyl)-N-(undec-10-en-1-yl)benzenesulfonamide
(4h-1). White solid (0.80 g, 87% yield); mp 45.5-46.7 °C; Rf =
0.7 (petroleum ether/ethyl acetae = 4:1). H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 4.45
(t, J = 5.3 Hz, 1H), 2.99-2.94 (m, 2H), 1.64-1.54 (m, 5H), 1.34
(s, 9H), 1.31 (d, J = 7.1 Hz, 2H), 1.25 -1.11 (m, 4H), 0.84-0.76
1
0.6 (petroleum ether/ethyl acetae = 4:1); H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 5.85-
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solution, CuSO4·5H2O (6.25 mg, 0.025 mmol), K2CO3 (0.97
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.4, 137.0,
127.1, 126.2, 41.1, 37.1, 35.3, 34.9, 33.1, 31.2, 26.5, 26.2. HRMS
Calcd for C18H29NNaO2S+ [M+Na+]: 346.1811, Found:
346.1813.
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4
5
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7
8
g, 7.0 mmol) and 1-H-imidazole-1-sulfonyl azide (0.25 g, 1.2
mmol) were added. The reaction mixture was stirred at room
temperature for 18 h. Water was added and the organic solvent
was removed in vacuo. The aqueous phase was adjusted to pH =
1 using HCl (1 N), and extracted with EtOAc. The ombined or-
ganic phase was washed with brine, dried over Na2SO4 and con-
centrated in vacuo. The crude prouct was purified by flash chro-
matography on silica gel to give compound 4f-1 as a colorless oil
in 85% yield (0.33 g). Rf = 0.2 (petroleum ether/ethyl acetae =
4-(tert-butyl)-N-(2-cycloheptylethyl)benzenesulfonamide
(4o-1). White solid (0.76 g, 91% yield); mp 103-104 °C; Rf = 0.8
(petroleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 4.45
(t, J = 5.9 Hz, 1H), 2.99-2.94 (m, 2H), 1.59-1.47 (m, 6H), 1.45-
1.39 (m, 3H), 1.38-1.29 (m, 4H), 1.34 (s, 9H), 1.11-1.02 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.4, 137.0, 127.1,
126.2, 41.6, 37.7, 36.4, 35.3, 34.3, 31.2, 28.5, 26.3. HRMS Calcd
for C19H32NO2S+ [M+H+]: 338.2148, Found: 338.2151.
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4:1). H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.6 Hz, 2H),
7.50 (d, J = 8.6 Hz, 2H), 1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.99 (t, J = 6.1 Hz, 1H),
3.22 (t, J = 7.0 Hz, 2H), 2.91 (dd, J = 13.4, 6.9 Hz, 2H), 1.60-1.51
(m, 2H), 1.47-1.38 (m, 2H), 1.36-1.28 (m, 11H), 1.23 (m, 10H).,
3.22 (t, J = 7.0 Hz, 2H), 2.93-2.88 (m, 2H), 1.59-1.52 (m, 2H),
1.46-1.39 (m, 2H), 1.35-1.28 (m, 2H), 1.32 (s, 9H), 1.26-1.19
(m, 10H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.3, 137.0,
127.0, 126.1, 51.5, 43.3, 35.2, 31.1, 29.6, 29.4, 29.3, 29.11, 29.07,
28.9, 26.7, 26.5. HRMS Calcd for C20H34N4O2SNa+ [M+Na+]:
417.2295, Found: 417.2289.
4-(tert-butyl)-N-(cycloheptylmethyl)benzenesulfonamide
(4p-1). White solid (0.67 g, 87% yield); mp 109.5-111.0 °C; Rf =
1
0.8 (petroleum ether/ethyl acetae = 4:1); H NMR (400 MHz,
CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.62
(br s, 1H), 2.77 (t, J = 6.6 Hz, 2H), 1.69-1.40 (m, 9H), 1.37-1.29
(m, 2H), 1.33 (s, 9H) 1.18-1.07 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 156.4, 137.2, 127.0, 126.2, 49.8, 39.4, 35.3, 31.9,
31.2, 28.4, 26.3. HRMS Calcd for C18H30NO2S+ [M+H+]:
324.1992, Found: 324.1987.
Procedure for synthesis of (4-(isoquinolin-5-ylsulfonyl)-
1,4-diazepan-1-yl)(phenyl)methanone (8-1). Fasudil (0.58 g,
2.0 mmol, 1.0 equiv), triethylamine (0.71 g, 7.0 mmol, 3.5 equiv)
and DMAP (31 mg, 0.25 mmol, 0.12 equiv) were dissolved in
4-(tert-butyl)-N-(1-cyclohexylethyl)benzenesulfonamide
(4q-1). White solid (0.65 g, 85% yield); mp 107.9-109.5 °C; Rf =
1
0.4 (petroleum ether/ethyl acetae = 4:1); H NMR (400 MHz,
o
DCM (10 mL) at 0 C. Benzoyl chloride (0.31 g, 2.2 mmol, 1.1
CDCl3) δ 7.79 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 4.64
(br s, 1H), 3.20-3.11 (m, 1H), 1.66-1.49 (m, 5H), 1.33 (s, 9H),
1.28-1.19 (m, 1H), 1.17-0.99 (m, 4H), 0.92 (d, J = 6.8 Hz, 3H),
0.88-0.77 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.2,
138.4, 127.0, 126.0, 54.5, 43.5, 35.2, 31.2, 28.8, 28.5, 26.4, 26.3,
26.2, 18.4. HRMS Calcd for C18H30NO2S+ [M+H+]: 324.1992,
Found: 324.1987.
4-(tert-butyl)-N-(4-methylpentyl)benzenesulfonamide (4r-
1). White solid (0.6 g, 81% yield); mp 86.3-87.8 °C; Rf = 0.6 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.79 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.55 (br s,
1H), 2.96-2.91 (m, 2H), 1.48-1.39 (m, 3H), 1.34 (s, 9H), 1.14-
1.08 (m, 2H), 0.80 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 156.4, 137.1, 127.1, 126.2, 43.7, 35.8, 35.3, 31.2, 27.7,
27.6, 22.5. HRMS Calcd for C16H27NNaO2S+ [M+Na+]:
320.1655, Found: 320.1665.
equiv) was added dropwise, and the reaction mixture was stirred
at room temperature for 1 hour. Then the reaction mixture was
washed with saturated NaHCO3 (aq), brine. The organic phase
was dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel
to afford compounds 8-1 as yellow solid in 95% yield (0.75 g).
mp 137.2-138.5 °C; Rf = 0.5 (dichloromethane/methanol =
1
40:1). H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.63 (t, J =
7.2 Hz, 1H), 8.35-8.24 (m, 2H), 8.14 (t, J = 7.1 Hz, 1H), 7.66-
7.59 (m, 1H), 7.32-7.20 (m, 5H), 3.83-3.75 (m, 2H), 3.52-3.27
(m, 6H), 2.10-2.03 (m, 1H), 1.78-1.71 (m, 1H).13C{1H} NMR
(101 MHz, CDCl3) δ 171.8, 153.4, 145.3, 136.1, 134.2, 133.8,
133.3, 131.5, 129.7, 129.3, 128.6, 126.6, 126.4, 126.0, 117.4, 51.8,
50.5, 48.7, 48.3,48.2, 47.9, 46.6, 45.0, 29.8, 27.7. HRMS Calcd for
C21H22N3O3S+ [M+H+]: 396.1376, Found: 396.1377.
Procedure for Synthesis of 4-(tert-butyl)-N-methyl-N-pen-
tylbenzenesulfonamide (22)30. NaH (0.1 g, 2.5 mmol, 2.5
equiv) was added to a solution of compound 1 (0.28 g, 1.0 mmol,
1.0 equiv) in DMF (10 mL) at 0 oC, and the mixture was stirred
for 5 min. Then MeI (0.16 g, 1.1 mmol) was added, and the reac-
tion mixture was stirred at room temperature for 0.5 h. Water (10
mL) was added and the resulting mixture was extracted with
EtOAc. The combined organic layer was washed with water (10
mL x 3) and brine. The organic phase was dried over Na2SO4, fil-
tered and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (PE:EA = 15:1) to give
compounds 22 as colorless oil in 84% yield (0.62 g). Rf = 0.8 (pe-
troleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.69 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 3.01–2.97 (t,
J = 8.5 Hz, 2H), 2.72 (s, 3H), 1.56-1.48 (m, 2H), 1.34 (s, 9H),
1.32-1.28 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (101
4-(tert-butyl)-N-isopentylbenzenesulfonamide (15-1 or 16-
1). White solid (0.61 g, 86% yield); mp 90.6-92.0 °C; Rf = 0.7
(petroleum ether/ethyl acetae = 4:1). 1H NMR (400 MHz,
CDCl3) δ 7.79 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 4.49
(br s, 1H), 2.99-2.93 (m, 2H), 1.61-1.52 (m, 1H), 1.36-1.30 (m,
2H), 1.34 (s, 9H), 0.82 (d, J = 6.6 Hz, 6H).13C{1H} NMR (101
MHz, CDCl3) δ 156.5, 137.0, 127.0, 126.2, 41.6, 38.5, 35.3, 31.2,
25.5, 22.4. HRMS Calcd for C15H25NNaO2S+ [M+Na+]:
306.1498, Found: 306.1498.
Procedure for Synthesis of N-(10-azidodecyl)-4-(tert-bu-
tyl)benzenesulfonamide (4f-1).29 HCl/EtOAc (4 N, 1.0 mL)
was added to a solution of substrate 4e-1 (0.47 g, 1.0 mmol) in
DCM (3 mL), and the reaction mixture was stirred at room tem-
perature for 0.5 h. Then the organic solvent was removed in vacuo.
The resulting residue was dissolved in MeOH (5 mL). To this
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The Journal of Organic Chemistry
1
MHz, CDCl3) δ 156.2, 134.7, 127.4, 126.1, 50.2, 35.2, 34.7, 31.2,
0.3 (petroleum ether/ethyl acetae = 3:1); H NMR (400 MHz,
CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.73
(t, J = 7.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 7.6 Hz,
1H), 7.31 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 5.44 (t, J = 5.8 Hz,
1H), 3.00-2.84 (m, 3H), 2.35 (s, 3H), 1.845-1.75 (m, 1H), 1.67-
1.58 (m, 1H), 1.48-1.41 (m, 1H), 1.39-1.32 (m, 1H), 1.27 (d, J =
6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 148.5,
143.2, 143.1, 137.0, 130.5, 129.7, 129.3, 127.1, 127.0, 125.2,
124.0, 119.9, 43.1, 41.9, 33.6, 27.2, 21.5, 21.0. HRMS Calcd for
C21H24ClN2O2S+ [M+H+]: 403.1242, Found: 403.1240.
28.8, 27.4, 22.4, 14.1. HRMS Calcd for C16H28NO2S+ [M+H+]:
298.1835, Found: 298.1838.
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7
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General Procedure for Minisci Alkylation Reaction. N-het-
eroarene substrate (0.2 mmol, 1.0 equiv), N-alkyl sulfonamide
(0.3 mmol, 1.5 equiv) and BI-OAc (0.5 mmol, 2.5 equiv) were
added to a solution of Ru(bpy)3Cl2 (0.001 mmol, 0.5 mol%) in
HFIP (1.0 mL). The reaction vial was purged with Ar for 1 min
and sealed with PTFE cap, then the mixture was stirred at 30 oC
under the irradiation of Compact Fluorescent Lamps irradiation
(23 W, palced 5 cm away from the vial) for 24 h. The solvent was
removed in vacuo and the residue was dissolved in DCM (1 mL).
K2CO3 (approximate 150 mg) was added to the solution, and the
resulting mixture was vigorously stirred for 10 min. Then the
mixture was filtrated through a pad of Celite and washed with
DCM. The filtrate was concentrated in vacuo and the residue was
purified by preparative thin layer chromatography or flash chro-
matography on silica gel to give the desired product.
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N-(4-(4-chloroquinolin-2-yl)pentyl)methanesulfonamide
(3-PG7). Colorless oil (10 mg, 15%, Isolated yield); Rf = 0.2 (pe-
troleum ether/ethyl acetae = 2:1); 1H NMR (400 MHz, CDCl3)
δ 8.18 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.74 (t, J =
7.7 Hz, 1H), 7.59 (t, J = 8.2 Hz, 1H), 7.39 (s, 1H), 5.11 (br s, 1H),
3.18-3.04 (m, 3H), 2.88 (s, 3H), 1.98-1.88 (m, 1H), 1.78-1.72
(m, 1H), 1.62-1.44 (m, 2H), 1.36 (d, J = 6.9 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 166.1, 148.5, 143.2, 130.6, 129.3,
127.1, 125.3, 124.1, 120.0, 43.3, 42.1, 40.2, 33.6, 27.8, 21.1.
HRMS Calcd for C15H20ClN2O2S+ [M+H+]: 327.0929, Found:
327.0929.
N-(4-(4-chloroquinolin-2-yl)pentyl)benzamide (3-PG1).
Yellow oil (6 mg, 8%, Isolated yield); Rf = 0.2 (petroleum
1
ether/ethyl acetae = 3:1); H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.1 Hz,
2H), 7.71 (t, J = 7.7 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.49-7.46
(m, 1H), 7.42-7.38 (m, 3H), 6.51 (br s, 1H), 3.52-3.38 (m, 2H),
3.18-3.09 (m, 1H), 2.00-1.90 (m, 2H), 1.83-1.74 (m, 1H), 1.70-
1.61 (m 1H), 1.59-1.47 (m, 1H), 1.38 (d, J = 6.9 Hz, 3H).13C{1H}
NMR (101 MHz, CDCl3) δ 167.7, 166.5, 148.7, 143.1, 135.0,
131.4, 130.4, 129.4, 128.6, 127.1, 127.0, 125.3, 124.1, 120.0, 42.4,
40.3, 34.4, 27.6, 21.0. HRMS Calcd for C21H22ClN2O+ [M+H+]:
353.1415, Found: 353.1415.
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)pentyl)ben-
zenesulfonamide (3). Yellow oil (71 mg, 80% yield); Rf = 0.5
1
(petroleum ether/ethyl acetate = 4:1); H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 7.4 Hz, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.75-
7.70 (m, 3H), 7.58-7.55 (m, 1H), 7.44-7.42 (m, 2H), 7.33 (s,
1H). 5.49 (br s, 1H), 3.02-2.87 (m, 3H), 1.86-1.77 (m, 1H),
1.68-1.60 (m, 1H), 1.53-1.34 (m, 2H), 1.29 (s, 9H), 1.26 (d, J =
6.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 156.2,
148.5, 143.0, 137.0, 130.5, 129.3, 127.0, 126.0, 125.2, 124.0,
119.9, 43.2, 41.9, 35.1, 33.5, 31.1, 27.3, 20.9. HRMS Calcd for
C24H30ClN2O2S+ [M+H+]: 445.1711, Found: 445.1711.
N-(4-(4-chloroquinolin-2-yl)pentyl)benzenesulfonamide
(3-PG2). Yellow oil (44 mg, 57%, Isolated yield); Rf = 0.3 (pe-
troleum ether/ethyl acetae = 3:1); 1H NMR (400 MHz, CDCl3)
δ 8.14 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.79 (d, J =
7.3 Hz, 2H), 7.71 (t, J = 7.1 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H),
7.44 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.29 (s, 1H),
5.70 (t, J = 5.7 Hz, 1H), 2.99-2.85 (m, 3H), 1.81-1.72 (m, 1H),
1.65-1.56 (m, 1H), 1.48-1.39 (m, 1H), 1.36-1.28 (m, 1H), 1.25
(d, J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.1,
148.3, 143.0, 139.9, 132.4, 130.5, 129.2, 129.0, 127.0, 126.9,
125.1, 123.9, 119.8, 43.1, 41.8, 33.5, 27.2, 20.8. HRMS Calcd for
C20H22ClN2O2S+ [M+H+]: 389.1085, Found: 389.1083.
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)hexyl)benzene-
sulfonamide (4a). An inseparable mixture of δ- and ε-arylated
products (7:1), yellow oil (70 mg, 76% yield); Rf = 0.5 (petro-
leum ether/ethyl acetate = 4:1); 1H NMR (400 MHz, CDCl3) δ
8.18 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.77-7.71 (m,
3H), 7.60 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.35 (s,
1H), 5.28 (br s, 1H), 3.01-2.84 (m, 2H), 2.79-2.72 (m, 1H),
1.79-1.65 (m, 4H), 1.36-1.32 (m, 2H), 1.31 (s, 9H), 0.78 (t, J =
7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.2, 156.3,
148.6, 143.1, 137.1, 130.6, 129.5, 127.1, 127.0, 126.14, 126.08,
125.3, 124.1, 120.4, 49.4, 43.3, 35.2, 32.1, 31.2, 28.7, 27.2, 12.1.
HRMS Calcd for C25H32ClN2O2S+ [M+H+]:459.1868, Found:
459.1866.
N-(4-(4-chloroquinolin-2-yl)pentyl)-4-methoxybenzene-
sulfonamide (3-PG4). Yellow oil (32 mg, 38%, Isolated yield);
1
Rf = 0.3 (petroleum ether/ethyl acetae = 3:1); H NMR (400
MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H),
7.73 -7.70 (m, 3H), 7.57 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 6.86 (d,
J = 8.8 Hz, 2H), 5.45 (t, J = 5.8 Hz, 1H), 3.79 (s, 3H), 3.00-2.83
(m, 3H), 1.84-1.75 (m, 1H), 1.67-1.58 (m, 1H), 1.48-1.41 (m,
1H), 1.39 -1.32 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 166.1, 162.7, 148.4, 143.0, 131.6, 130.5,
129.3, 129.2, 127.0, 125.2, 124.0, 119.9, 114.2, 55.6, 43.1, 41.9,
33.6, 27.2, 20.9. HRMS Calcd for C21H24ClN2O3S+ [M+H+]:
419.1191, Found: 419.1188.
4-(tert-butyl)-N-(5-(4-chloroquinolin-2-yl)hexan-2-yl)ben-
zenesulfonamide (4b). Two separable diastereomers were ob-
tained. For one isomer 4b’: colorless oil (33 mg, 36% yield); Rf =
0.4 (petroleum ether/ethyl acetate = 4:1); 1H NMR (400 MHz,
CDCl3) δ 8.23 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.83
(d, J = 8.6 Hz, 2H), 7.78 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.6 Hz,
1H), 7.47 (d, J = 8.5 Hz, 2H), 7.31 (s, 1H), 5.47 (br s, 1H), 3.32-
3.22 (m, 1H), 2.95-2.86 (m, 1H), 1.69-1.60 (m, 1H), 1.48-1.37
(m, 2H), 1.33-1.28 (m, 1H), 1.30 (s, 9H), 1.17 (d, J = 7.0 Hz,
3H), 1.05 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 166.0, 156.3, 148.6, 143.1, 138.0, 130.8, 129.4, 127.1, 126.0,
N-(4-(4-chloroquinolin-2-yl)pentyl)-4-methylbenzenesul-
fonamide (3-PG5). Yellow oil (39 mg, 49%, Isolated yield); Rf =
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125.2, 124.0, 120.7, 50.3, 41.9, 34.7, 31.2, 31.1, 22.5, 21.7. HRMS CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 7.76-
Calcd for C25H32ClN2O2S+ [M+H+]: 459.1868, Found:
459.1865. For the another isomer 4b’’: colorless oil (29 mg, 32%
yield); Rf = 0.35 (petroleum ether/ethyl acetate = 4:1); 1H NMR
(400 MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.5 Hz,
1H), 7.77-7.73 (m, 3H), 7.59 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.6
Hz, 2H), 7.32 (s, 1H), 5.20 (br s, 1H), 3.34-3.24 (m, 1H), 2.93-
2.84 (m, 1H), 1.74-1.59 (m, 2H), 1.44-1.30 (m, 2H), 1.28 (s,
9H), 1.24 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 166.2, 156.2, 148.6, 143.0, 138.2,
130.6, 129.5, 127.01, 126.94, 126.0, 125.2, 124.0, 120.0, 50.5,
41.9, 35.2, 35.0, 32.7, 31.2, 22.3, 20.8. HRMS Calcd for
C25H32ClN2O2S+ [M+H+]: 459.1868, Found: 459.1867.
7.70 (m, 3H), 7.59 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H),
7.30 (s, 1H), 5.29 (br s, 1H), 3.19 (t, J = 6.9 Hz, 2H), 2.99-2.80
(m, 3H), 1.81-1.60 (m, 4H), 1.52-1.49 (m, 2H), 1.44-1.33 (m,
3H), 1.30 (s, 9H), 1.26-1.21 (m, 5H). 13C{1H} NMR (101 MHz,
CDCl3) δ 165.2, 156.2, 148.6, 143.0, 136.9, 130.6, 129.4, 127.1,
127.0, 126.1, 125.2. 124.0, 120.3, 51.5, 47.9, 43.2, 35.7, 35.2, 32.4,
31.2, 29.2, 28.8, 27.4, 27.3, 26.6. HRMS Calcd for
C29H39ClN5O2S+ [M+H+]: 556.2508, Found: 556.2508.
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4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)undec-10-yn-1-
yl)benzenesulfonamide (4g). Yellow oil (61 mg, 58% yield); Rf
= 0.3 (petroleum ether/ethyl acetate = 4:1); 1H NMR (400 MHz,
CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.76
-7.70 (m, 3H), 7.59 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H),
7.30 (s, 1H), 5.33 (br s, 1H), 2.98-2.90 (m, 1H), 2.89-2.79 (m,
2H), 2.12-2.08 (m, 2H), 1.89 (t, J = 2.6 Hz, 1H), 1.81-1.59 (m,
4H), 1.45-1.38 (m, 3H), 1.36-1.27 (m, 3H), 1.30 (s, 9H) 1.25-
1.21 (m, 1H), 1.14-1.04 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 165.2, 156.2, 148.6, 143.0, 136.9, 130.5, 129.4, 127.02,
126.95, 126.0, 125.2, 124.0, 120.3, 84.6, 68.3, 47.8, 43.2, 35.6,
35.1, 32.4, 31.2, 28.8, 28.3, 27.2, 27.0.18.4. HRMS Calcd for
C30H38ClN2O2S+ [M+H+]: 525.2337, Found: 525.2338.
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4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)hexadecyl)ben-
zenesulfonamide (4c). Colorless oil (86 mg, 72% yield); Rf =
0.6 (petroleum ether/ethyl acetate = 4:1); 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.77-
7.70 (m, 3H), 7.62-7.58 (m, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.30
(s, 1H), 5.27 (t, J = 5.28 Hz, 1H), 2.99-2.92 (m, 1H), 2.91-2.80
(m, 2H), 1.78-1.60 (m, 4H), 1.43 -1.33 (m, 3H), 1.31 (s, 9H),
1.25-1.18 (m, 18H), 1.10-1.02 (m, 1H), 0.86 (t, J = 6.9 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 165.4, 156.3, 148.6, 143.0,
137.0, 130.6, 129.5, 127.1, 127.0, 126.1, 125.3, 124.1, 120.3, 47.9,
43.3, 13.3, 35.9, 35.2, 32.5, 32.0, 31.2, 29.8, 29.76, 29.74, 29.69,
29.56, 29.46, 27.6, 27.2, 22.8, 14.3. HRMS Calcd for
C35H52ClN2O2S+ [M+H+]: 599.3433, Found: 599.3431.
Methyl-8-((4-(tert-butyl)phenyl)sulfonamido)-5-(4-chlo-
roquinolin-2-yl)octanoate (4d). Colorless oil (59 mg, 56%
yield); Rf = 0.5 (petroleum ether/ethyl acetate = 2:1); 1H NMR
(400 MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.5 Hz,
1H), 7.77-7.69 (m, 3H), 7.60 (t, J = 8.2 Hz, 1H), 7.43 (d, J = 8.6
Hz, 2H), 7.30 (s, 1H), 5.19 (br s, 1H), 3.61 (s, 3H), 2.97-2.90 (m,
1H), 2.88-2.83 (m, 2H), 2.25 (t, J = 7.5 Hz, 2H), 1.83-1.65 (m,
4H), 1.61-1.50 (m, 1H), 1.47-1.36 (m, 2H), 1.34-1.32 (m, 1H),
1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 164.6,
156.3, 148.6, 143.2, 136.9, 130.6, 129.5, 127.1, 127.0, 126.1,
125.3, 124.1, 120.3, 51.6, 47.6, 43.2, 35.2, 35.0, 34.0, 32.4, 31.2,
27.2, 22.9. HRMS Calcd for C28H36ClN2O4S+ [M+H+]:
531.2079, Found: 531.2082.
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)undec-10-en-1-
yl)benzenesulfonamide (4h). Colorless oil (63 mg, 60% yield);
1
Rf = 0.4 (petroleum ether/ethyl acetate = 4:1); H NMR (400
MHz, CDCl3) δ 8.19 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H),
7.77-7.74 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 7.5 Hz,
1H), 7.43 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 5.79-5.69 (m, 1H),
5.21 (s, 1H), 4.95-4.88 (m, 2H), 3.00-2.92 (m, 1H), 2.91-2.79
(m, 2H), 1.99-1.94 (m, 2H), 1.82-1.59 (m, 4H), 1.42-1.34 (m,
2H), 1.31 (s, 9H), 1.28-1.23 (m, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 165.3, 156.3, 148.6, 143.1, 139.1, 136.9, 130.6, 129.5,
127.1, 127.0, 126.1, 125.3, 124.1, 120.3, 114.4, 47.9, 43.3, 35.8,
35.2, 33.8, 32.5, 31.2, 29.24, 28.8, 29.2, 28.8, 27.4, 27.2. HRMS
Calcd for C30H40ClN2O2S+ [M+H+]: 527.2494, Found:
527.2494.
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)butyl)benzene-
sulfonamide (4i). Colorless oil (35 mg, 41% yield); Rf = 0.2 (pe-
troleum ether/ethyl acetate = 4:1); 1H NMR (400 MHz, CDCl3)
δ 8.18 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.77-7.73 (m,
3H), 7.59 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.34 (s,
1H), 5.33 (br s, 1H), 3.04-2.99 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H),
1.88-1.81 (m, 2H), 1.62-1.55 (m, 2H), 1.31 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 161.9, 156.4, 148.7, 143.0, 137.1,
130.7, 129.3, 127.05, 127.03, 126.1, 125.1, 124.1, 121.5, 43.0,
37.7, 35.2, 31.2, 28.8, 26.2. HRMS Calcd for C23H28ClN2O2S+
[M+H+]: 431.1555, Found: 431.1552.
Tert-butyl(10-((4-(tert-butyl)phenyl)sulfonamido)-7-(4-
chloroquinolin-2-yl)decyl)carbamate (4e). An inseparable
mixture of δ- and other-arylated products (7:1), colorless oil (99
mg, 79% yield); Rf = 0.4 (petroleum ether/ethyl acetate = 2:1);
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 1H), 8.08 (d,
J = 8.4 Hz, 1H), 7.75-7.69 (m, 3H), 7.58 (t, J = 7.1 Hz, 1H), 7.42
(d, J = 8.6 Hz, 2H), 7.29 (s, 1H), 5.38 (t, J =5.7 Hz, 1H), 4.51 (t,
J = 6.1 Hz, 1H), 3.05-3.00 (m, 2H), 2.96-2.89 (m, 1H), 2.88-2.78
(m, 2H), 1.77-1.61 (m, 4H), 1.40-1.35 (m, 13H), 1.29 (s, 9H),
1.24-1.20 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.3,
156.2, 148.6, 143.0, 137.0, 130.5, 129.5, 127.00, 126.95, 126.1,
126.0, 125.2, 124.0, 120.3, 79.0，47.9, 43.2, 40.6, 35.7, 35.1, 32.4,
31.2, 30.0, 29.4, 28.5, 27.4, 27.3, 26.6. HRMS Calcd for
C34H49ClN3O4S+ [M+H+]: 630.3127, Found: 630.3127.
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)cyclohep-
tyl)benzenesulfonamide (4j). Two separable diastereomers
were obtained. For one isomer 4j’: colorless oil (40 mg, 42%
yield); Rf = 0.6 (petroleum ether/ethyl acetate = 4:1); 1H NMR
(400 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.4 Hz,
1H), 7.83 (d, J = 8.4 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.58-7.51
(m, 3H), 7.31 (s, 1H), 4.81 (br s, 1H), 3.52-3.47 (m, 1H), 3.03-
2.97 (m, 1H), 2.08-1.99 (m, 2H), 1.96-1.89 (m, 2H), 1.80-1.65
(m, 5H), 1.59-1.50 (m, 1H), 1.34 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 167.0, 156.4, 148.6, 142.8, 138.2, 130.4, 129.4,
N-(10-azido-4-(4-chloroquinolin-2-yl)decyl)-4-(tert-bu-
tyl)benzenesulfonamide (4f). Yellow oil (78 mg, 70% yield); Rf
= 0.3 (petroleum ether/ethyl acetate = 2:1); 1H NMR (400 MHz,
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The Journal of Organic Chemistry
126.93, 126.87, 126.2, 125.2, 124.0, 120.0, 55.0, 49.2, 35.6, 35.4, (400 MHz, CDCl3) δ 8.18 (t, J = 7.8 Hz, 2H), 7.79 (t, J = 7.6 Hz,
35.3, 34.2, 31.2, 30.4, 22.2. HRMS Calcd for C26H32ClN2O2S+
[M+H+]: 471.1868, Found: 471.1866. For the another isomer
4j’’: yellow oil (33 mg, 35% yield); Rf = 0.2 (petroleum
ether/ethyl acetate = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.42
(d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.5 Hz,
2H), 7.79 (t, J = 7.1 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.45 (d, J
= 8.5 Hz, 2H), 7.32 (s, 1H), 7.22 (d, J = 9.1 Hz, 1H), 3.79 (br s,
1H), 3.30-3.24 (m, 1H), 2.21-2.11 (m, 1H), 2.00-1.94 (m, 1H),
1.90-1.68 (m, 4H), 1.64-1.60 (m, 2H), 1.53-1.44 (m, 1H), 1.37-
1.30 (m, 1H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
166.8, 155.9, 148.2, 143.2, 139.0, 130.9, 129.4, 127.1, 126.8,
126.0, 125.1, 123.9, 121.0, 53.2, 45.9, 36.5, 35.1, 34.1, 32.4, 31.2,
26.4, 21.6. HRMS Calcd for C26H32ClN2O2S+ [M+H+]:
471.1868, Found: 471.1866.
1H), 7.62 (t, J = 7.7 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.33 (s,
1H), 7.30-7.26 (m, 2H), 6.19 (br s, 1H), 3.03-2.95 (m, 1H),
2.89-2.83 (m, 1H), 2.76-2.68 (m, 1H), 2.54-2.44 (m, 1H), 2.19-
2.11 (m, 1H), 1.95-1.88 (m, 1H), 1.78-1.62 (m, 4H), 1.53-1.45
(m, 1H), 1.34-1.30 (m, 1H), 1.26 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 165.0, 155.9, 148.3, 143.0, 137.0, 130.9, 129.3,
127.1, 126.8,125.8, 125.2, 124.0, 120.8, 53.3, 41.8, 41.5, 35.1,
34.8, 34.5, 33.1, 31.1, 24.7. HRMS Calcd for C26H32ClN2O2S+
[M+H+]: 471.1868, Found: 471.1866.
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4-(tert-butyl)-N-(2-(2-(4-chloroquinolin-2-yl)cyclo-
hexyl)ethyl)benzenesulfonamide (4n). An inseparable mix-
ture of two diastereomers (> 16:1) was obtained. Colorless oil
(74 mg, 76% yield); Rf = 0.6 (petroleum ether/ethyl acetate =
1
4:1); H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.4 Hz, 1H),
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)cyclooctyl)ben-
zenesulfonamide (4k). Two separable diastereomers were ob-
tained. For one isomer 4k’: colorless oil (33 mg, 34% yield); Rf =
0.5 (petroleum ether/ethyl acetate = 4:1); 1H NMR (400 MHz,
CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.82
(d, J = 8.4 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz,
1H), 7.49 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 4.99 (d, J = 7.3 Hz,
1H), 3.50-3.48 (m, 1H), 3.01-2.97 (m, 1H), 1.92-1.74 (m, 9H),
1.65-1.52 (m, 3H), 1.31 (s, 9H). 13C{1H} NMR (101 MHz,
CDCl3) δ 167.5, 156.3, 148.6, 142.8, 138.2, 130.4, 129.4, 127.0,
126.9, 126.1, 125.1, 124.0, 120.3, 53.5, 47.3, 35.2, 32.4, 31.6, 31.5,
31.2, 28.4, 26.1, 23.3. HRMS Calcd for C27H34ClN2O2S+
[M+H+]: 485.2024, Found: 485.2021. For the another isomer
4k’’: colorless oil (34 mg, 35% yield); Rf = 0.45 (petroleum
ether/ethyl acetate = 4:1); 1H NMR (400 MHz, CDCl3) δ 8.16
(d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.5 Hz,
2H), 7.74-7.69 (m, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J = 8.6 Hz,
2H), 7.31 (s, 1H), 4.85 (d, J = 7.3 Hz, 1H), 3.57-3.51 (m, 1H),
3.06-3.00 (m, 1H), 2.04-1.93 (m, 4H), 1.87-1.71 (m, 4H), 1.65-
1.42 (m, 4H), 1.32 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
167.6, 156.3, 148.5, 142.8, 138.2, 130.4, 129.4, 127.0, 126.9,
126.1, 125.1, 124.0, 120.2, 54.0, 48.1, 35.2, 32.3, 31.7, 31.5, 31.2,
29.8, 26.8, 23.3. HRMS Calcd for C27H34ClN2O2S+ [M+H+]:
485.2024, Found: 485.2021.
8.18 (d, J = 8.3 Hz, 1H), 7.83-7.77 (m, 1H), 7.73 (d, J = 8.4 Hz,
2H), 7.67-7.60 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H),
6.10 (br s, 1H), 2.94-2.89 (m, 2H), 2.57-2.52 (m, 1H), 1.94-1.88
(m, 1H), 1.82-1.68 (m, 4H), 1.36-1.33 (m, 2H), 1.30 (s, 9H),
1.19-0.96 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.6,
156.1, 148.6, 143.3, 136.9, 131.0, 129.4, 127.2, 127.1, 126.0,
125.2, 124.1, 121.4, 51.9, 40.8, 37.1, 35.2, 35.1, 33.4, 32.3, 31.2,
26.4, 26.1. HRMS Calcd for C27H34ClN2O2S+ [M+H+]:
485.2024, Found: 485.2024.
4-(tert-butyl)-N-(2-((2-(4-chloroquinolin-2-yl)cyclohep-
tyl)ethyl)benzenesulfonamide (4o). Yellow oil (62 mg, 62%
yield); Rf = 0.6 (petroleum ether/ethyl acetate = 4:1); 1H NMR
(400 MHz, CDCl3) δ 8.34 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.0 Hz,
1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.64 (t, J
= 7.4 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.34 (s, 1H), 6.15 (t, J =
4.4 Hz, 1H), 2.94-2.89 (m, 2H), 2.75-2.70 (m, 1H), 2.18-2.15 (m,
1H), 1.88-1.82 (m, 1H), 1.76-1.67 (m, 3H), 1.60-1.39 (m, 7H),
1.36-1.33 (m, 1H), 1.30 (s, 9H), 1.27-1.20 (m, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 166.7, 156.0, 148.0, 143.3, 136.9,
131.1, 129.4, 127.3, 127.0, 126.0, 125.1, 124.0, 121.8, 53.7, 41.1,
38.6, 35.2, 34.9, 34.7, 31.8, 31.2, 29.1, 26.2, 26.1. HRMS Calcd
for C28H36ClN2O2S+ [M+H+]: 499.2181, Found: 499.2179.
4-(tert-butyl)-N-((3-(4-chloroquinolin-2-yl)cyclohep-
tyl)methyl)benzenesulfonamide (4p). Two separable dia-
stereomers were obtained. For one isomer 4p’: colorless oil (39
mg, 40% yield); Rf = 0.6 (petroleum ether/ethyl acetate = 4:1);
1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.5 Hz, 1H), 8.12 (d,
J = 8.3 Hz, 1H), 7.76-7.69 (m, 3H), 7.55 (t, J = 7.6 Hz, 1H), 7.37
(d, J = 8.5 Hz, 2H), 7.29 (s, 1H), 6.68 (br s, 1H), 3.14-3.09 (m,
1H), 3.00-2.94 (m, 1H), 2.79-2.72 (m, 1H), 2.23-2.15 (m, 2H),
1.92-1.90 (m, 1H), 1.82-1.76 (m, 2H), 1.65-1.39 (m, 5H), 1.31-
1.23 (m, 1H), 1.23 (s, 9H), 1.20-1.08 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 166.9, 156.0, 148.4, 143.0, 137.1, 130.9,
129.2, 127.1, 127.0, 126.0, 125.1, 123.9, 120.8, 49.7, 43.2, 35.2,
35.0, 34.6, 34.5, 34.3, 31.2, 29.4, 26.9. HRMS Calcd for
C27H34ClN2O2S+ [M+H+]: 485.2024, Found: 485.2021. For the
another isomer 4p’’: colorless oil (45 mg, 47% yield); Rf = 0.4
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)cyclodo-
decyl)benzenesulfonamide (4l). An inseparable mixture of
two diastereomers (10:1) was obtained, white solid (86 mg, 80%
yield); mp 186.1-187.5 °C; Rf = 0.7 (petroleum ether/ethyl ace-
1
tate = 4:1); H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.6 Hz,
1H), 8.08 (d, J = 8.4 Hz,5 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.73 (t,
J = 7.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.27-7.25
(m, 2H), 4.51 (d, J = 8.2Hz, 1H), 3.58-3.52 (m, 1H), 3.08-3.02
(m, 1H), 1.92-1.84 (m, 1H), 1.80-1.70 (m, 3H), 1.68-1.63 (m,
1H), 1.61-1.51 (m, 1H), 1.46-1.28 (m, 12H), 1.20-1.12 (m, 2H),
1.16 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 156.2,
149.0, 142.4, 138.4, 130.2, 129.7, 126.9, 126.7, 125.9, 125.3,
124.0, 121.6, 50.4, 42.6, 35.0, 31.6, 31.2, 31.1, 30.8, 27.6, 24.3,
23.6, 23.1, 23.0, 22.9, 22.1. HRMS Calcd for C31H42ClN2O2S+
[M+H+]: 541.2650, Found: 541.2649.
1
(petroleum ether/ethyl acetate = 4:1); H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.75
(d, J = 8.4 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz,
1H), 7.46 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 5.02 (t, J = 6.3 Hz,
1H), 3.00-2.95 (m, 1H), 2.83 (t, J = 6.3 Hz, 2H), 2.00-1.92 (m,
4-(tert-butyl)-N-(2-(2-(4-chloroquinolin-2-yl)cyclopen-
tyl)ethyl)benzenesulfonamide (4m). Colorless oil (76 mg, 81%
yield); Rf = 0.6 (petroleum ether/ethyl acetate = 4:1); 1H NMR
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2H), 1.80-1.71 (m, 4H), 1.68-1.54 (m, 4H), 1.36-1.32 (m, 1H),
7.32 (s, 1H), 5.03 (t, J = 5.9 Hz, 1H), 3.00-2.90 (m, 3H), 1.87-
1.29 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.5, 156.4,
148.5, 142.9, 137.0, 130.4, 129.3, 127.0, 126.8, 126.1, 125.2,
124.0, 119.9, 49.8, 48.2, 39.1, 38.4, 35.3, 35.2, 31.8, 31.2, 26.4,
25.2. HRMS Calcd for C27H34ClN2O2S+ [M+H+]: 485.2024,
Found: 485.2024.
1.77 (m, 1H), 1.70-1.61 (m, 1H), 1.52-1.37(m, 2H), 1.31 (s, 9H),
1.28 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
167.6, 156.4, 149.0, 143.0, 137.0, 136.6, 128.4, 128.0, 127.0,
126.1, 125.5, 123.8, 120.3, 43.2, 42.0, 35.2, 33.5, 31.2, 27.5, 20.8.
HRMS Calcd for C24H29Cl2N2O2S+ [M+H+]: 479.1321, Found:
479.1322.
1
2
3
4
5
6
7
4-(tert-butyl)-N-(1-(3-(4-chloroquinolin-2-yl)cyclo-
hexyl)ethyl)benzenesulfonamide (4q). Two separable dia-
stereomers were obtained. For one isomer 4q’: colorless oil (9
mg, 9% yield); Rf = 0.5 (petroleum ether/ethyl acetate = 4:1); 1H
NMR (400 MHz, CDCl3) 8.17 (d, J = 8.1 Hz, 1H), 8.03 (d, J =
8.5 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.72 (t, J = 7.4 Hz, 1H),
7.57 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.40 (s, 1H),
4.45 (d, J = 8.6 Hz, 1H), 3.48 -3.39 (m, 1H), 3.08-3.00 (m, 1H),
2.12-2.02 (m, 1H), 1.88-1.79 (m, 3H), 1.71-1.65 (m, 2H), 1.53-
1.44 (m, 2H), 1.40-1.37 (m, 1H), 1.32 (s, 9H), 1.05 (d, J = 6.5
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.4, 156.4,
148.7, 142.7, 138.1, 130.3, 129.6, 127.1, 126.9, 126.1, 124.0,
120.1, 51.5, 40.8, 39.6, 32.4, 31.4, 31.2, 31.1, 27.3, 21.2, 19.7.
HRMS Calcd for C27H33ClN2NaO2S+ [M+Na+]: 507.1843,
Found: 507.1843. For the another isomer 4q’’: colorless oil (57
mg, 59% yield); Rf = 0.4 (petroleum ether/ethyl acetate = 4:1);
1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 8.01 (d,
J = 8.3 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.71 (t, J = 7.7 Hz, 1H),
7.56 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.35 (s, 1H),
4.80 (br s, 1H), 3.29-3.19 (m, 1H), 2.82-2.76 (m, 1H), 1.96-1.88
(m, 2H), 1.79 (t, J = 11.1 Hz, 2H), 1.56-1.45 (m, 2H), 1.41-1.30
(m, 3H), 1.23 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 166.0, 156.3, 148.7, 142.8, 138.0, 130.3,
129.4, 127.0, 126.8, 126.0, 125.3, 124.0, 119.9, 54.3, 47.0, 43.4,
35.1, 34.7, 32.2, 31.1, 27.8, 25.9, 18.7. HRMS Calcd for
C27H34ClN2O2S+ [M+H+]: 485.2024, Found: 485.2023.
Methyl-2-(1-((4-(tert-butyl)phenyl)sulfonamido)undec-
10-yn-4-yl)-4-chloro-7-methoxyquinoline-6-carboxylate
(7). Yellow oil (88 mg, 72% yield); Rf = 0.2 (petroleum
ether/ethyl acetate = 2:1); 1H NMR (400 MHz, CDCl3) δ 8.65
(s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.64 (s, 1H), 7.51 (d, J = 8.6 Hz,
2H), 7.33 (s, 1H), 5.50 (br s, 1H), 4.12 (s, 3H), 4.04 (s, 3H),
3.06-2.84 (m, 3H), 2.20-2.17 (m, 2H), 1.98-1.94 (m, 1H), 1.90-
1.65 (m, 5H), 1.53-1.47 (m, 4H), 1.45-1.38 (m, 14H). 1.38 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.0, 166.1, 159.8,
156.3, 151.3, 143.8, 136.9, 128.6, 127.0, 126.1, 122.8, 119.2,
119.1, 108.8, 84.6, 68.4, 56.7, 52.7, 47.9, 43.2, 35.7, 35.2, 32.2,
31.2, 28.8, 28.3, 27.2, 27.1, 18.4. HRMS Calcd for
C33H42ClN2O5S+ [M+H+]: 613.2497, Found: 613.2492.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(2-(2-(4-((4-benzoyl-1,4-diazepan-1-yl)sulfonyl)iso-
quinolin-1-yl)cyclohexyl)ethyl)-4-(tert-butyl)benzenesul-
fonamide (8). Yellow solid (128 mg, 89% yield). mp 113.9-
115.2 °C; Rf = 0.2 (petroleum ether/Acetone = 10:1). 1H NMR
(400 MHz, CD3OD) δ 8.67 (t, J = 8.6 Hz, 1H), 8.59-8.54 (m,
1H), 8.43-8.36 (m, 1H), 8.31 (t, J = 6.3 Hz, 1H), 7.81-7.73 (m,
1H), 7.53-7.48 (m, 4H), 7.44-7.38 (m, 4H), 7.27 (d, J = 7.7 Hz,
1H), 3.83-3.79 (d, J = 4.4 Hz, 2H), 3.66-3.63 (m, 1H), 3.60-3.56
(m, 1H), 3.53-3.43 (m, 4H), 2.69-2.62 (m, 1H), 2.57-2.50 (m,
1H), 2.09-2.03 (m, 2H), 1.88-1.70 (m, 5H), 1.61-1.40 (m, 2H),
1.41-1.35 (m, 1H), 1.31 (s, 9H), 1.21- 1.15 (m, 1H), 1.11-1.06
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 174.0, 173.8,
167.6, 167.5, 157.2, 144.3, 138.6, 137.3, 136.4, 134.1, 133.6,
133.5, 131.9, 131.8, 130.8, 129.7, 129.3, 127.8, 127.4, 127.3,
127.1, 117.1, 101.3, 52.3, 50.4, 50.0, 48.0, 47.4, 47.3, 46.0, 42.0,
39.7, 39.6, 35.9, 35.7, 35.5, 33.0, 31.5, 31.2, 29.2, 27.4, 27.2.
1-((4-(tert-butyl)phenyl)sulfonyl)-2,2-dimethylpyrrolidine
(4r-by product). Colorless oil (47 mg, 53% yield). Rf = 0.7 (pe-
troleum ether/ethyl acetate = 4:1). 1H NMR (400 MHz, CDCl3)
δ 7.76 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 3.39 (t, J =
6.2 Hz, 2H), 1.83-1.77 (m, 4H), 1.45 (s, 6H), 1.33 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 155.6, 138.8, 127.1, 125.8,
65.2, 49.4, 43.1, 35.2, 31.3, 28.4, 22.6. HRMS Calcd for
C16H26NO2S+ [M+H+]: 296.1679, Found: 296.1677.
+
HRMS Calcd for C39H49N4O5S2 [M+H+]: 717.3139, Found:
717.3134.
Methyl-1-(3-(((4-(tert-butyl)phenyl)sulfonamido)me-
thyl)cycloheptyl)isoquinoline-3-carboxylate (9). Two sepa-
rable diastereomers were obtained. For one isomer 9’: yellow oil
(43 mg, 42% yield); Rf = 0.7 (petroleum ether/ethyl acetate =
3:1); 1H NMR (400 MHz, CDCl3) δ8.37 (s, 1H), 8.18 (d, J = 7.6
Hz, 1H), 7.94-7.87 (m, 3H), 7.74-7.67 (m, 2H), 7.43 (d, J = 8.6
Hz, 2H), 6.79 (d, J = 6.7 Hz, 1H), 4.10 (s, 3H), 3.98-3.92 (m,
1H), 2.94-2.89 (m, 2H), 2.63-2.55 (m, 2H), 2.34-2.26(m, 1H),
1.93-1.80 (m, 2H), 1.71-1.64 (m, 2H), 1.62-1.52 (m, 1H), 1.46-
1.37 (m, 1H), 1.34-1.32 (m, 2H), 1.29 (s, 9H). 13C{1H} NMR
(101 MHz, CDCl3) δ 167.9, 167.1, 155.5, 140.0, 137.8, 136.0,
130.5, 129.5, 129.1, 127.6, 127.2, 125.7, 125.2, 122.6, 53.0, 50.1,
39.0, 36.7, 35.6, 35.1, 35.0, 34.9, 31.2, 30.7, 26.4. HRMS Calcd
for C29H37N2O4S+ [M+H+]: 509.2469, Found: 509.2465. For the
another isomer 9’’: yellow oil (53 mg, 52% yield); Rf = 0.5 (pe-
troleum ether/ethyl acetate = 3:1); 1H NMR (400 MHz, CDCl3)
δ 8.36 (s, 1H), 8.20-8.17 (m, 1H), 7.94-7.91 (m, 1H), 7.75-7.67
(m, 4H), 7.45 (d, J = 8.6 Hz, 2H), 4.94 (br s, 1H), 3.99 (s, 3H),
3.73-3.67 (m, 1H), 2.89-2.78 (m, 2H), 2.05-1.61 (m, 11H), 1.30
4-(tert-butyl)-N-(4-(4-methylquinolin-2-yl)pentyl)ben-
zenesulfonamide (5). Yellow solid (68 mg, 80% yield); mp
128.1-129.4 °C; Rf = 0.1 (petroleum ether/ethyl acetate = 4:1);
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.95 (d,
J = 8.2 Hz, 1H), 7.73-7.68 (m, 3H), 7.53 (t, J = 7.2 Hz, 1H), 7.43
(d, J = 8.5 Hz, 2H), 7.09 (s, 1H), 5.50 (d, J = 5.4 Hz, 1H), 3.03-
2.85 (m, 3H), 2.68 (s, 3H), 1.88-1.79 (m, 1H), 1.69-1.60 (m,
1H), 1.48-1.38 (m, 2H), 1.31 (s, 9H), 1.28 (d, J = 7.0 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 158.9, 156.5, 152.9, 148.3,
137.0, 129.73, 129.68, 129.1, 127.0, 126.2, 125.6, 125.4, 122.8,
118.5, 43.3, 35.2, 34.1, 33.0, 31.2, 27.7, 25.6, 21.3. HRMS Calcd
for C25H33N2O2S+ [M+H+]: 425.2257, Found: 425.2253.
4-(tert-butyl)-N-(4-(4,7-dichloroquinolin-2-yl)pentyl)ben-
zenesulfonamide (6). Yellow oil (62 mg, 65% yield); Rf = 0.6
1
(petroleum ether/ethyl acetate = 4:1); H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.74
(d, J = 8.6 Hz, 2H), 7.54-7.50 (m, 1H), 7.47 (d, J = 8.5 Hz, 2H),
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The Journal of Organic Chemistry
(s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.9, 166.8, 156.3,
(m, 4H), 7.37 (d, J = 8.5 Hz, 2H), 5.06 (t, J = 5.7 Hz, 1H), 3.81-
1
2
3
4
5
6
7
8
140.4, 137.0, 136.2, 130.4, 129.4, 129.2, 127.4, 127.0, 126.1,
125.0, 122.7, 52.7, 49.8, 39.7, 37.6, 35.2, 34.9, 31.9, 31.2, 26.5,
25.4. HRMS Calcd for C29H37N2O4S+ [M+H+]: 509.2469,
Found: 509.2466.
3.73 (m,1H), 3.01-2.94 (m, 1H), 2.91-2.84 (m, 1H), 2.33-2.24
(m, 1H), 1.77-1.68 (m, 1H), 1.64-1.56(m, 1H), 1.47-1.40 (m,
1H), 1.37 (d, J = 6.9 Hz, 3H), 1.28 (s, 9H).13C{1H} NMR δ 164.6,
156.2, 143.7, 137.1, 133.3, 130.4, 130.0, 128.9, 127.4, 127.0,
126.6, 126.0, 125.6, 125.1, 123.5, 122.8, 122.0, 43.3, 36.5, 35.1,
31.6, 31.2, 27.7, 21.6. HRMS Calcd for C28H33N2O2S+ [M+H+]:
461.2257, Found: 461.2252.
4-(tert-butyl)-N-(4-(4-(tert-butyl)pyridin-2-yl)pentyl)ben-
zenesulfonamide(10). Yellow oil (22 mg, 26% yield); Rf = 0.2
1
(petroleum ether/ethyl acetate = 4:1); H NMR (400 MHz,
CDCl3)δ 8.39 (d, J = 5.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.49
(d, J = 8.6 Hz, 2H), 7.11-7.09 (m, 1H), 7.06 (d, J = 1.2 Hz, 1H),
4.98 (t, J = 5.4 Hz, 1H), 2.95-2.86 (m, 2H), 2.83-2.74 (m, 1H),
1.76-1.67 (m, 1H), 1.60–1.41 (m, 3H), 1.33 (s, 9H), 1.29 (s, 9H),
1.21 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
165.4, 160.9, 156.3, 148.9, 137.0, 127.0, 126.1, 118.7, 43.4, 41.4,
35.2, 34.8, 33.9, 31.2, 30.7, 27.6, 21.2. HRMS Calcd for
C24H37N2O2S+ [M+H+]: 417.2570, Found: 417.2572.
N-(4-(7-bromoisoquinolin-1-yl)pentyl)-4-(tert-butyl)ben-
zenesulfonamide (11). Colorless oil (56 mg, 57% yield); Rf =
0.3 (petroleum ether/ ethyl acetate = 2:1); 1H NMR (400 MHz,
CDCl3) δ 8.50 (d, J = 5.6 Hz, 1H), 8.30 (s, 1H), 7.75-7.69 (m,
4H), 7.48-7.46 (m, 3H), 4.87 (br s, 1H), 3.66-3.58 (m, 2H),
2.98-2.85 (m, 2H), 2.08-1.98 (m, 1H), 1.75-1.66 (m, 1H), 1.58-
1.47 (m, 1H), 1.38 (s, 1H),1.32 (s, 9H), 1.30 (d, J = 6.9 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 164.1, 156.4, 142.4, 135.0,
133.4, 129.5, 127.9, 127.11, 127.06, 126.1, 121.2, 119.0, 43.4,
36.1, 35.2, 32.5, 31.2, 27.7, 21.6.HRMS Calcd for
C24H30BrN2O2S+ [M+H+]: 489.1206, Found: 489.1209.
4-(tert-butyl)-N-(4-(4-chloroquinolin-2-yl)-3-methyl-
butyl)benzenesulfonamide (15). Yellow oil (43 mg, 48%
yield); Rf = 0.2 (petroleum ether/ethyl acetate = 4:1); 1H NMR
(400 MHz, CDCl3) δ 8.19 (d, J = 8.7 Hz, 2H), 7.80-7.76 (m, 3H),
7.62 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.33 (s, 1H),
6.21 (br s, 1H), 3.11-2.98 (m, 2H), 2.85-2.75 (m, 2H), 2.25-2.15
(m, 1H), 1.51-1.45 (m, 2H), 1.31 (s, 9H), 0.90 (d, J = 6.8 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.1, 156.2, 148.5,
143.1, 137.1, 130.9, 129.2, 127.2, 126.1, 125.1, 124.1, 112.3, 44.6,
41.0, 35.2, 31.2, 31.0, 20.2. HRMS Calcd for C24H30ClN2O2S+
[M+H+]: 445.1711, Found: 445.1710.
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
33
34
35
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39
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4-(tert-butyl)-N-(3-methyl-4-(2-methylquinolin-4-yl)bu-
tyl)benzenesulfonamide (16). Yellow oil (44 mg, 52% yield);
1
Rf = 0.2 (petroleum ether/ethyl acetate = 3:1); H NMR (400
MHz, CDCl3) δ7.99 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H),
7.74 (d, J = 8.6 Hz, 2H), 7.64 (t, J = 8.2 Hz, 1H), 7.49-7.45 (m,
3H), 7.04 (s, 1H), 4.66 (br s, 1H), 3.14-3.06 (m, 1H), 3.01-2.93
(m, 2H), 2.76-2.71 (m, 1H), 2.66 (s, 3H), 2.04-1.96 (m, 1H),
1.65-1.56 (m, 1H), 1.47-1.38 (m, 1H), 1.31 (s, 9H), 0.85 (d, J =
6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 156.6,
148.3, 146.6, 136.7, 129.5, 129.2, 127.0, 126.2, 126.1, 125.7,
123.6, 123.0, 41.3, 39.7, 36.8, 35.2, 31.4, 31.2, 25.4, 19.6. HRMS
Calcd for C25H33N2O2S+ [M+H+]: 425.2257, Found: 425.2254.
N-(4-(benzo[d]thiazol-2-yl)pentyl)-4-(tert-butyl)benzene-
sulfonamide (12). Yellow solid (38 mg, 46% yield); mp 118.3-
1
119.6 °C; Rf = 0.2 (petroleum ether/ ethyl acetate = 4:1); H
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 1H), 7.84 (d, J =
7.9 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.48-7.44 (m, 3H), 7.38-
7.34 (m, 1H), 4.77 (t, J = 6.0 Hz, 1H), 3.27-3.18 (m, 1H), 3.04-
2.92 (m, 2H), 1.91-1.82 (m, 1H), 1.80-1.71 (m, 1H), 1.58-1.46
(m, 2H), 1.40 (d, J = 7.0 Hz, 3H), 1.32 (s, 9H). 13C{1H} NMR
(101 MHz, CDCl3) δ 177.1, 156.5, 153.0, 137.0, 134.7, 127.0,
126.18, 126.16, 125.0, 122.9, 121.7, 43.2, 39.0, 35.3, 34.1, 31.2,
27.3, 21.6. HRMS Calcd for C22H29N2O2S2+ [M+H+]: 417.1665,
Found: 417.1660.
4-(tert-butyl)-N-(4-(3-methylquinoxalin-2-yl)pentyl)ben-
zenesulfonamide (13). Yellow solid (38 mg, 45% yield); mp
107.8-109.0 °C; Rf = 0.1 (petroleum ether/ethyl acetate = 2:1);
1H NMR (400 MHz, CDCl3) δ 8.05-8.02 (m, 1H), 7.98-7.94 (m,
1H), 7.71 (d, J = 8.5 Hz, 2H), 7.68-7.65 (m, 2H), 7.44 (d, J = 8.5
Hz, 2H), 4.71 (t, J = 5.9 Hz, 1H), 3.26-3.17 (m, 1H), 3.00-2.87
(m, 2H), 2.73 (s, 3H), 2.09-2.00 (m, 1H), 1.71-1.62 (m, 1H),
1.58-1.51 (m, 1H), 1.38-1.34 (m, 1H), 1.31 (s, 9H), 1.26 (d, J =
6.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 156.4,
153.0, 141.3, 140.9, 137.0, 129.1, 129.0, 128.8, 128.4, 127.0,
126.1, 43.3, 37.2, 35.2, 32.0, 31.2, 27.7, 22.9, 20.5. HRMS Calcd
for C24H32N3O2S+ [M+H+]: 426.2210, Found: 426.2210.
4-(tert-butyl)-N-(4-(phthalazin-1-yl)butyl)benzenesulfona-
mide (17). Yellow oil (35 mg, 44% yield); Rf = 0.1 (petroleum
1
ether/acetone = 10:1); H NMR (400 MHz, CDCl3) δ 9.37 (s,
1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95-7.86 (m, 3H), 7.78 (d, J = 8.5
Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 5.34 (t, J = 6.1 Hz, 1H), 3.33
(t, J = 7.6 Hz, 2H), 3.07-3.01 (m, 2H), 2.00-1.92 (m, 2H), 1.73-
1.66 (m, 2H), 1.31 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
156.3, 150.6 137.0, 132.8, 132.3, 127.2, 127.01, 126.98, 126.6,
126.2, 125.7, 124.1, 43.0, 35.2, 32.3, 31.2, 29.4, 25.8. HRMS
Calcd for C22H28N3O2S+ [M+H+]: 398.1897, Found: 398.1895.
4-(tert-butyl)-N-(4-(isoquinolin-1-yl)butyl)benzenesulfon-
amide (18); Yellow oil (38 mg, 48% yield); Rf = 0.3 (petroleum
ether/ethyl acetate = 3:1); 1H NMR (400 MHz, CDCl3) δ 8.38
(d, J = 5.7 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.80-7.76 (m, 3H),
7.65 (t, J =7.5 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.49-7.45 (m,
3H), 5.88 (s, 1H), 3.24 (t, J = 7.5 Hz, 2H), 3.04-2.99 (m, 2H),
1.91-1.84 (m, 2H), 1.66-1.59 (m, 2H), 1.30 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 161.2, 156.2, 141.5, 137.0, 136.3,
130.1, 127.5, 127.3, 127.0, 126.1, 125.2, 119.6, 43.1, 35.1, 34.0,
31.2, 29.1, 25.9. HRMS Calcd for C23H29N2O2S+ [M+H+]:
397.1944, Found: 397.1940.
4-(tert-butyl)-N-(4-(phenanthridin-6-yl)pentyl)benzene-
sulfonamide (14). Yellow oil (77 mg, 84% yield); Rf = 0.4 (pe-
troleum ether/ ethyl acetate = 4:1); 1H NMR (400 MHz, CDCl3)
δ 8.66 (d, J = 8.2 Hz, 1H), 8.55 (d, J = 7.9 Hz, 1H), 8.26-8.20 (m,
2H), 7.83 (t, J = 7.6 Hz, 1H), 7.75 (t, J =8.1 Hz, 1H), 7.70-7.62
4-(tert-butyl)-N-(4-(4-(trifluoromethyl)pyridin-2-yl)bu-
tyl)benzenesulfonamide (19). Yellow oil (31 mg, 37% yield);
1
Rf = 0.2 (petroleum ether/ ethyl acetate = 4:1); H NMR (400
MHz, CDCl3) δ 8.68 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H),
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2016, 33, 491-522. (c) He, C.; Whitehurst, W. G.; Gaunt, M. J. Palla-
7.50 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 4.9 Hz, 2H), 4.77 (t, J = 6.1
Hz, 1H), 3.02-2.97 (M, 2H), 2.83 (t, J = 7.6 Hz, 2H), 1.81-1.74
(m, 2H), 1.60-1.53 (m, 2H), 1.33 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 163.2, 156.5, 150.3, 139.0(s), 138.8 (q, J = 33.7
Hz), 136.9, 127.0, 126.2, 126.2, 123.0 (q, J = 273.2 Hz), 118.6 (q,
J = 3.7 Hz), 117.0 (q, J = 6.9, 3.3 Hz), 43.1, 37.5, 35.3, 31.2, 29.2,
26.4. HRMS Calcd for C20H26F3N2O2S+ [M+H+]: 415.1662,
Found: 415.1658.
dium-Catalysed C(sp3)-H Bond Functionalization of Aliphatic
Amines. Chem 2019, 5, 1031-1058.
1
2
3
4
5
6
7
8
2. (a) He, G.; Wang, B.; Nack, W. A.; Chen, G. Syntheses and Transfor-
mations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Di-
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3. (a) Xu, J.-W.; Zhang, Z.-Z.; Rao, W.-H.; Shi, B.-F. Site-Selective
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4. For selected examples, see: (a) Chen, K.; Richter, J. M.; Baran, P. S.
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Unactivated C-H Bonds in Amides Using Sulfone Reagents. Angew.
Chem. Int. Ed. 2018, 57, 12940-12944. (c) Li, Z.; Wang, Q.; Zhu, J.
Copper-Catalyzed Arylation of Remote C(sp3)-H Bonds in Carbox-
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5. (a) Corey, E. J.; Hertler, W. R. A Study of the Formation of Haloam-
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Removal of 4-tert-phenylsulfonyl protecting group. A mix-
ture of compound 5 (84.8 mg, 0.2 mmol, 1.0 equiv), phenol
(56.4 mg, 0.2 mmol, 1.0 equiv) and HBr (1.0 mL, 48%) was
heated to 130 °C for 18 hours in a sealed tube (using heating
block). After being cooled to room temperature, the reaction so-
lution was diluted with iced water, then adjusted to pH = 8~9
with K2CO3. The resulting mixture was extracted with EtOAc (5
mL x 3). The combined organic phase was dried over Na2SO4,
filtered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel (DCM:MeOH = 5:1)
to give compounds 20 in 90% yield (41 mg) as yellow oil.16 Rf =
0.3 (Dichloromethane/Methanol = 20:1). 1H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.65
(t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 3.05-
2.99 (m, 1H), 2.67-2.64 (m, 5H), 1.92 (s, 2H), 1.87-1.79 (m,
1H), 1.73-1.64 (m, 1H), 1.55-1.44 (m, 1H), 1.36-1.30 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 166.5, 147.7, 144.5, 129.6,
129.1, 127.1, 125.6, 123.7, 120.3, 42.8, 42.2, 34.2, 31.7, 21.0, 19.0.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
HRMS Calcd for C15H21N2 [M+H+]: 229.1699, Found:
229.1697.
6. (a) Hernández, R.; Rivera, A.; Salazar, J. A.; Suárez, E. Nitroamine
Radicals as Intermediates in the Functionalization of Non-activated
Carbon Atoms. J. Chem. Soc.,Chem. Commun. 1980, 958-959. (b) Fan,
R.; Pu, D.; Wen, F.; Wu, J. δ and α sp3 C-H Bond Oxidation of Sulfon-
amides with PhI(OAc)2/I2 under Metal-Free Conditions. J. Org.
Chem. 2007, 72, 8994-8997. (c) Martίnez, C.; Muñiz, K. An Iodine-
Catalyzed Hoffmann-Löffler Reaction. Angew. Chem., Int. Ed. 2015,
54, 8287-8291. (d) Hu, X.; Zhang, G.; Bu, F.; Nie, L.; Lei, A. Electro-
chemical-Oxidation-Induced Site-Selective Intramolecular C(sp3)-H
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ASSOCIATED CONTENT
Supporting Information
1
Details for mechanistic investigation, copies of the H and 13C NMR
spectra, and X-ray structural analysis data of 4l (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
* E-mail: guoxing007@mail.nankai.edu.cn
7. Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Catalytic
alkylation of remote C-H bonds enabled by proton-coupled electron
transfer. Nature 2016, 539, 268-271.
* E-mail: gongchen@nankai.edu.cn
8. Chu, J. C.; Rovis, T. Amide-directed photoredox-catalysed C-C bond
formation at unactivated sp3 C–H bonds. Nature 2016, 539, 272-275.
9. (a) Ma, Z,-Y.; Guo, L.-N.; You, Y.; Yang, F.; Hu, M.; Duan, X.-H. Vis-
ible Light Driven Alkylation of C(sp3)-H Bonds Enabled by 1,6-Hy-
drogen Atom Transfer/Radical Relay Addition. Org. Lett. 2019, 21,
5500-5504. (b) Thullen, S. M.; Treacy, S. M.; Rovis, T. Regioselective
Alkylative Cross-Coupling of Remote Unactivated C(sp3)-H Bonds. J.
Am. Chem. Soc. 2019, 141, 14062-14067.
10. During the preparation of this manuscript, Zhu reported a related
work on Minisci-type δ C(sp3)–H heteroarylation of sulfonyl-pro-
tected aliphatic amines with N-heteroarenes using PhI(OTFA)2 oxi-
dant under LED irradiation. Tang, N.; Wu X.; Zhu C.; Practical,
metal-free remote heteroarylation of amides via unactivated C(sp3)-H
bond functionalization. Chem. Sci. 2019, 10, 6915–6919.
ORCID
Gong Chen: 0000-0002-5067-9889
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully thank Natural Science Foundation of China (21672105,
21725204, 91753124), Natural Science Foundation of Tianjin
(18JCZDJC32800), and Laviana for financial support of this work. This
work is dedicated to the 100th anniversary of Nankai University.
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