Copper-Catalyzed Aza-Michael Addition of Aromatic Amines or Aromatic Aza-Heterocycles to α,β-Unsaturated Olefins

Article abstract of DOI:10.1021/acs.joc.6b00341

A highly efficient and mild Cu-catalyzed conjugate addition reaction of aromatic amines and aromatic aza-heterocycles to α,β-unsaturated olefins is described. The transformation is promoted by 3-7 mol % of a Cu complex generated in situ from a mixture of inexpensive CuCl, a readily available phosphine or imidazolium salt, and KOt-Bu at ambient temperature. A wide range of β-amino sulfone, β-amino nitrile, and β-amino carbonyl compounds is efficiently and selectively synthesized in high yields (62-99%).

Full text of DOI:10.1021/acs.joc.6b00341

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Article
Copper-Catalyzed Aza-Michael Addition of Aromatic Amines or
Aromatic Aza-Heterocycles to alpha,beta-Unsaturated Olefins
Seongcheol Kim, Seongil Kang, Gihyeon Kim, and Yunmi Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00341 • Publication Date (Web): 15 Apr 2016
Downloaded from http://pubs.acs.org on April 15, 2016
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The Journal of Organic Chemistry
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Copper-Catalyzed Aza-Michael Addition of Aromatic
Amines or Aromatic Aza-Heterocycles to α,β-
Unsaturated Olefins
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Seongcheol Kim, Seongil Kang, Gihyeon Kim and Yunmi Lee*
Department of Chemistry, Kwangwoon University, Seoul 01897, Republic Korea
* To whom correspondence should be addressed.
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Tel: +82-2-940-8116; Fax: +82-2-942-0108; E-mail: ymlee@kw.ac.kr
Table of Contents
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ABSTRACT: A highly efficient and mild Cu-catalyzed conjugate addition reaction of aromatic amines
and aromatic aza-heterocycles to α,β-unsaturated olefins is described. The transformation is promoted
by 3-7 mol % of a Cu complex generated in situ from a mixture of inexpensive CuCl, a readily available
phosphine or imidazolium salt, and KOt-Bu at ambient temperature. A wide range of β-amino sulfone,
β-amino nitrile, and β-amino carbonyl compounds is efficiently and selectively synthesized in high
yields (62-99%).
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INTRODUCTION
The development of synthetic approaches to β-amino sulfone, β-amino nitrile, and β-amino
carbonyl compounds bearing aromatic amine or aromatic aza-heterocycle substituents has received great
attention because of its numerous synthetic applications to diverse natural products, drugs, and
functional materials.1 The direct addition of (hetero)aryl amines to α,β-unsaturated olefins (aza-Michael
reaction) is one of the simplest and most effective strategies to prepare β-amino carbonyls with high
atom economy from readily available starting materials.2 Traditionally, aza-Michael reactions proceed
under strongly acidic or basic conditions; however, several challenging issues remain.3 For example,
high temperatures and long reaction times are required. Such reactions exhibit poor compatibility with
various substrate functional groups and generate side products, e.g., polymeric compounds, due to the
use of a strong base. Furthermore, these methods are limited in substrate scope to aliphatic amine
additions. In order to overcome these limitations, a variety of Lewis acid metal catalysts, including
early- and late-transition metals as well as lanthanides, have been intensively developed and used to
efficiently catalyze the conjugate addition of aromatic amines to electron-deficient olefins under mild
conditions. 4 , 5 , 6 Despite great advances in metal-catalyzed aza-Michael additions, there are still
shortcomings for their practical utility; namely, the use of expensive precious metals, the use of air- and
moisture-sensitive metal catalysts, and the less efficiency for the addition of less nucleophilic aryl
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The Journal of Organic Chemistry
amines or aza-heterocycles vs. aliphatic amine addition. Over the past decades, reaction conditions
using ionic liquids or water as solvents have been successfully developed and partially addressed the
above-described drawbacks.7,8
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8
9
Among the numerous protocols involving aza-Michael additions, copper-catalyzed processes are
particularly attractive due to ease of handling, the use of environmentally benign and low cost copper
salts, and mild reaction conditions. Although Cu-catalyzed Michael additions of carbon-based
nucleophiles to α,β-unsaturated alkenes for the formation of carbon-carbon bonds are well studied,9 the
corresponding aza-Michael addition of (hetero)aromatic amines has received less attention.10 In most
previous studies, a Cu catalyst such as Cu(OTf)2 has been used as a Lewis acid to activate an alkene by
increasing its electrophilicity.10 In contrast, Cu-catalyzed systems using an electron-donating ligand to
activate an amine by enhancing its nucleophilicity are rare.11 One example was reported by Gunnoe and
co-workers: the well-defined copper amido complex L13, coordinated to an electron-rich N-heterocyclic
carbene (NHC) ligand,12 catalyzes the conjugate addition of aniline to activated olefins, affording the
desired β-amino carbonyls under mild conditions [Scheme 1 (a)].11 However, several synthetic steps are
required for the preparation of the catalyst NHC-Cu-NHPh L13, and glove box techniques are required
for the overall process as the catalyst is highly air- and moisture-sensitive. Additionally, the
transformations were only carried out in C6D6 solvent without isolation of products; the substrate scope
was not examined in detail. Therefore, there is still a need for a more practical and synthetically useful
method for the synthesis of β-aryl amine- or β-aza-heterocycle-substituted sulfone, nitrile, and carbonyl
compounds.
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Herein we describe a highly efficient and mild Cu-catalyzed aza-Michael addition of various
weak nucleophilic aromatic amines and aza-heterocycles to α,β-unsaturated olefins. The use of
inexpensive CuCl, commercially available phosphine or imidazolium salts, and KOt-Bu to generate a
Cu-amido catalyst in situ is an attractive feature of this method, and the catalytic transformation can be
performed on a bench top without the use of glove box techniques. A broad range of (hetero)aryl amine
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substrates including aniline, indole, carbazole, pyrrole, imidazole, pyrazole, and triazole derivatives is
converted to the desired β-amino compounds with a catalyst loading of 3-7 mol % at ambient
temperature and in isolated yields of up to >99%.
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9
Scheme 1. Cu-Catalyzed Aza-Michael Additions of Aromatic Amines
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(a) Gunnoe's work: Aniline addition to electron-deficient alkenes in C6D6
i-Pr
i-Pr
N
N
Cu
i-Pr i-Pr
55~100% NMR yields
Few examples
H
N
NH
NH2
5 mol %
Ph
L13
EWG
+
EWG
C6D6, 22 C
Glove box required
1a
EWG = CN, COMe, CO2Me
This work:
(b)
cat. CuCl
cat. phosphine or [imid]+Cl-
cat. KOt-Bu
R1
N
R1
R3
Approaches to a wide
range of -amino
compounds
N
H
+
EWG
R2
EWG
R2
toluene, 22 C
R3
R1, R2 = aryl or
heterocycles
up to >99% yield
EWG = SO2Ph,
CN, COEt, CO2Me
RESULTS AND DISCUSSION
We began by examining the ability of N-heterocyclic carbene- or phosphine-based copper
catalysts to promote the aza-Michael addition of aniline (1a) to phenyl vinyl sulfone (2). Inspired by
previous studies of NHC-Cu-NHPh L13 (Scheme 1), we investigated catalytic conjugate additions using
a copper complex generated in situ from air- and moisture stable and readily available imidazolium salts,
CuCl, and KOt-Bu without the use of glove box techniques (entries 1-4 in Table 1). When 3 mol % of
imidazolinium salt L1 and CuCl in the presence of 6 mol % KOt-Bu were used, the reaction of 1.2
equiv of 1a at room temperature proceeded to full conversion in 5 h, providing the desired product 3a;
however, the undesired dialkylated product 4a was also obtained in 11% yield (entry 2). Amination
using the more sterically demanding ligand L2 afforded only the desired product 3a with 95%
conversion (entry 3). Use of 3 mol % of the cyclohexyl-substituted imidazolium salt L3 led to complete
conversion in 3 h; however, 3% of the undesired product 4a was also formed (entry 4). In order to
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search for a more efficient catalytic system, various phosphine-based ligands were examined (entries 5-
13). As shown in entries 5-13 of Table 1, the copper catalyst coordinated with bidentate phosphine
ligands (L6-L12 in Figure 1)13 was more reactive than that with monodentate phosphines (L4 and L5 in
Figure 1), affording 3a with higher conversion (up to >98% vs. 66-77%). In addition, bidentate
phosphine ligands with a larger bite angle such as binap L9, DPEPhos L10, dppf L11 and Xantphos
L12 were more selective for the formation of the monoaminated product 3a (>98:<2) than dppe L6,
dppp L7 and dppbz L8 (76:24-89:11).14 These results are consistent with the proposal that an NHC-Cu
catalyst with a more sterically demanding ligand is more selective for mono-amination. It was
noteworthy that the use of 3 equiv of phenyl vinyl sulfone with 6 mol % CuCl and the ligand dppbz
provided the dialkylated amine product 4b in 75% yield (eq 1). Entries 14-18 of Table 1 indicate that
CuCl, an electron-donating ligand, and KOt-Bu are required to promote aniline addition to phenyl vinyl
sulfone (2). When 3 mol % of CuCl and DPEPhos in the absence of KOt-Bu were used, no reaction was
observed (entry 14). Additionally, without phosphine ligand or Cu salt, amination did not proceed (<2%
conversion, entries 15-18). Based on these results, it can be postulated that a CuOt-Bu intermediate
complexed with an electron-donating bidentate phosphine ligand is generated and subsequently reacts
with aniline to form a phosphine-Cu-amido complex in situ as the catalytic species. Electron-donating
ligands appear to enhance the nucleophilic attack of aromatic amines towards electron deficient
alkenes.15 Finally, we selected DPEPhos L10 as the optimal ligand for the conjugate addition of anilines
to 2, taking into account the cost and efficiency of bidentate phosphines as summarized in entries 7-13.
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Table 1. Optimization of the Cu-Catalyzed Aza-Michael Addition Reaction of Aniline 1a to
Alkenyl Sulfone 2a
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2
3
4
5
6
7
8
9
10
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CuCl
(mol %)
KOt-Bu
(mol %)
entry
ligands
time (h)
yield (%)b
3a : 4b
1
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
0
3
0
3
6
6
6
6
3
3
3
3
3
3
3
3
3
0
0
3
3
0
3
5
5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
82
>98
95
76 : 6
89 : 11
95 : 0
97 : 3
73 : 3
63 : 3
83 : 15
89 : 11
76: 24
76 : 0
>98 : <2
>98 : <2
>98 : <2
<2
L1
L1
3
L2
4
>98
76
L3
5
L4
6
66
L5
7
98
L6
8
>98
>98
76
L7
9
L8
10
11
12
13
14
15
16
17
18
L9
>98
>98
>98
<2
L10
L11
L12
L10
L10
no
<2
<2
<2
<2
no
<2
<2
no
<2
<2
aReaction conditions: aniline 1a (0.60 mmol), vinyl sulfone 2 (0.50 mmol), CuCl (0.015 mmol), ligand (0.015
b
mmol), KOt-Bu (0.015 mmol), toluene (1.5 mL) under N2. Determined by H NMR spectrum analysis using
1
1,3,5-trimethoxybenzene as an internal standard.
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Figure 1. Various ligands studied for conjugate addition reactions
The Cu-catalyzed aza-Michael addition reaction can be successfully performed with a variety of
anilines, as shown in Table 2. All transformations were selective and efficient: >98% conversion was
observed in 3-6 h using a combination of 3 mol % CuCl and DPEphos L10 with KOt-Bu, affording only
monoaminated products in excellent yield (90->99%). The additions were carried out in toluene at
ambient temperature. Catalytic reactions of 2 with anilines including a fluoro-, chloro-, and bromo-
substituent in the para- or ortho-position were highly efficient and afforded the desired products 3b-c
and 3h-i in more than 97% yield (entries 2-3 and 8-9). Neither electron-donating (methoxy, methyl, tert-
butyl) nor electron-withdrawing (CF3, CO2Me) groups in the para- or ortho-position of the aryl ring
affected the high reactivity observed (90->99% yields, entries 4-7 and 10-12).16 When the sterically
demanding aniline 1l was used, the corresponding aminated product 3l was obtained in 99% yield (entry
12).
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Table 2. Cu-Catalyzed Aza-Michael Addition Reactions of Various Anilinesa
1
2
3
4
5
H
L10
3 mol % CuCl, 3 mol % DPEPhos
NH2
N
SO2Ph
3 mol % KOt-Bu
+
SO2Ph
6
7
toluene, 22 C, 3-5 h
R
R
1
2
3
8
9
entry
1
products
time (h) yield (%)b
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3
3
4
3
99
98
3a
3b
3c
3d
2
3
4
5
6
97
>99
5
3
98
90
3e
3f
7
3
93
3g
8
6
3
3
5
5
>99
99
3h
3i
9
10
11
12
98
3j
3k
3l
96
99
aReaction conditions: aniline 1 (0.60 mmol), vinyl sulfone 2 (0.50 mmol), CuCl (3 mol %), DPEPhos (L10, 3
mol %), KOt-Bu (3 mol %), toluene (1.5 mL) under N2. bYields of the isolated products.
We next explored Cu-catalyzed aza-Michael addition reactions of a wide range of readily
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available N-substituted aromatic amines and aza-heterocycles such as methyl aniline, indole, carbazole,
pyrrole, imidazole, pyrazole, and triazole derivatives. As the data in Table 3 illustrate, dppbz L8 is more
effective than DPEphos L10 as a ligand for promoting additions of N-substituted anilines or aza-
heterocycles to 2. For example, when 3 mol % of CuCl and DPEphos L10 were used in the reaction of
diphenyl amine (5a), only 10% of the aminated product 6a was observed (vs. 92% yield with dppbz L8,
entry 1). Therefore, dppbz L8 was selected as the optimal ligand for this class of amine additions.
Additions of N-methyl anilines to 2 proceeded to >98% conversion in 3 h to give the desired products
6b-c in 94-96% yields (entries 2-3). As the data in entries 4-10 in Table 3 indicate that β-amino sulfones
bearing indole, pyrrole and imidazole substituents 6d-j, which are among the most useful building-
blocks for biologically active molecules, were produced efficiently and selectively from the
corresponding amines in high yields (up to >99%, entries 4-10). Cu-catalyzed additions of pyrazole 5k
and triazole 5l showed less efficiency; a longer reaction time (15 h vs. 3 h) and higher catalyst loading
(6 mol % vs. 3 mol %) for reaction of 5k was required (entries 11-12).
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2
3
4
5
6
7
8
9
10
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Table 3. Cu-Catalyzed aza-Michael Addition Reactions with Substituted Aromatic Aminesa
entry
1
products
time (h)
3
yield (%)b
92
6a
6b
2
3
3
3
94
96
6c
4
5
3
3
98
94
6d
6e
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1
2
3
6
3
98
6f
4
5
6
7
8
9
7
8
9
3
5
3
84
98
6g
6h
6i
10
11
12
13
14
15
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>99
10
5
>99
6j
11c
12
15
15
90
54
6k
6l
aReaction conditions: 5 (0.60 mmol), vinyl sulfone 2 (0.50 mmol), CuCl (3 mol %), dppbz (L8, 3 mol %), KOt-
Bu (3 mol %), toluene (1.5 mL) under N2. bYields of the isolated products. c6 mol % of dppbz (L8, 0.030 mmol)
used.
A more sterically demanding disubstituted alkene can also be applied to copper-catalyzed aza-
Michael additions. As illustrated in Scheme 2, indole 5d was successfully added to alkene 7a in the
presence of 5 mol % of CuCl and L3, affording the desired β-amino sulfone 8a in 99% yield. On the
other hand, reactions of anisidine 1d or imidazole 5i with a disubstituted alkene 7a were much more
sluggish than that with 2 (entry 4 in Table 2 and entry 9 in Table 3); with 7 mol % of CuCl and L3 for
15 h, the products 8b-c were obtained in moderate yields (68-75%). A phenyl-substituted alkene 7b also
underwent catalytic amination to give the corresponding amine 8d in 62% yield. Development of more
effective ligands is required to promote amine additions to sterically hindered olefins.
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Scheme 2. Cu-Catalyzed Aza-Michael Addition Reactions to Disubstituted Olefin 7.
1
2
3
4
5
6
7
8
9
L3
L3
5 mol % CuCl, 5 mol %
N
10 mol % KOt-Bu
PhO2S
PhO2S
+
+
PhO2S
PhO2S
N
toluene, 22 C, 15 h
H
5d
7a
7a
8a
(99%)
N
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
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59
60
7 mol % CuCl, 7 mol %
N
N
14 mol % KOt-Bu
HN
toluene, 22 C, 15 h
5i
8b (75%)
OMe
OMe
NH2
7 mol % CuCl, 7 mol % L3
14 mol % KOt-Bu
HN
PhO2S
+
PhO2S
MeO
MeO
toluene, 22 C, 15 h
1d
1d
7a
7b
8c (68%)
7 mol % CuCl, 7 mol % L3
14 mol % KOt-Bu
NH2
PhO2S
HN
+
Ph
toluene, 22 C, 15 h
PhO2S
Ph
8d (62%)
Additional attributes of our new Cu-catalyzed aza-Michael reaction are illustrated by the
synthesis of a wide range of β-amino nitrile and β-amino carbonyl compounds 10a-k. As shown in
Table 4, various α,β-unsaturated alkenes bearing a nitrile, ester or ketone group undergo conjugate
additions of anilines in the presence of 7 mol % CuCl and L1 or L2, affording the corresponding amine
products with high efficiency. When acrylonitrile (9a) was reacted with anilines, the β-amino nitriles
10a-f were obtained in high yields (84-95%, entries 1-6) within 15 h. Additions of anilines to methyl
acrylate (9b) were less efficient, resulting in lower yields of the desired products 10g-h (70-73% yields,
entries 7-8). In the case of aza-Michael addition involving pent-1-en-3-one (9c), >98% conversion was
observed within 1 h, albeit in moderate yields (75-89%) due to the generation of unidentified side
products (entries 9-11).
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Table 4. Cu-Catalyzed aza-Michael Addition of Anilines to Various α,β-Unsaturated Olefinsa
1
2
3
4
5
6
7
8
9
10
11
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entry ligand
products
time (h) yield (%)b
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2
15
15
94
95
L2
L2
10a
10b
3
4
15
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15
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15
15
0.5
1
94
84
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89
70
73
81
89
L2
L2
L1
L1
L2
L2
L2
L2
10c
10d
10e
10f
10g
10h
10i
5
6
7
8
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10
10j
11
0.5
75
L2
10k
aReaction conditions: aniline 1 (0.50 mmol), olefin 9 (0.75 mmol), CuCl (7 mol %), ligand (L1 or L2, 7 mol %),
KOt-Bu (18 mol %), toluene (1.5 mL) under N2. bYields of the isolated products.
CONCLUSIONS
In summary, we have developed efficient and mild Cu-catalyzed aza-Michael addition reactions
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of less nucleophilic aromatic amines or aza-heterocycles to α,β-unsaturated olefins. A readily available
electron-donating phosphine or NHC-based ligand, complexed to an inexpensive copper salt, plays a
crucial role in enhancing the nucleophilic addition of aromatic amines or aza-heterocycles to alkenes.
The catalytic protocols enable the synthesis of a broad range of new β-amino sulfone, β-amino nitrile,
and β-amino carbonyl compounds including aniline, indole, carbazole, pyrrole, imidazole, pyrazole, and
triazole derivatives in high yields; these represent a less well-studied category of substrates for catalytic
conjugate addition. Further efforts will be directed toward expansion of substrate scope to more
sterically demanding olefins and development of Cu-catalyzed enantioselective amination.
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EXPERIMENTAL SECTION
General. Infrared (IR) spectra were recorded in reciprocal centimeters (cm-1). Bands are characterized
1
as broad (br), strong (s), medium (m), and weak (w). H NMR spectra were recorded on a 400 MHz
spectrometer. Chemical shifts are reported in ppm from tetramethylsilane, with the solvent resonance as
the internal standard (CDCl3: δ 7.27 ppm). Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13C
NMR spectra were recorded on a 100 MHz spectrometer with complete proton decoupling. Chemical
shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard
(CDCl3: δ 77.26 ppm). High-resolution mass spectra (HRMS) were obtained using an electron
ionization (EI) or an electrospray ionization (ESI) time-of-flight mass spectrometer. Unless otherwise
noted, all reactions were carried out with distilled solvents under an atmosphere of dry N2 in oven-dried
o
(130 C) glassware. Toluene was purified by distillation from sodium benzophenone ketyl immediately
prior to use unless otherwise specified. All work-up and purification procedures were carried out with
reagent grade solvents in air.
Representative experimental procedures for Cu-catalyzed aza-Michael addition of aromatic
amines or aza-heterocycles to α,β-unsaturated olefins:
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General procedure A: CuCl (1.50 mg, 0.0150 mmol), DPEphos L10 (8.10 mg, 0.0150 mmol) and KOt-
Bu (1.70 mg, 0.0150 mmol) were added to a vial (8 mL) charged with a magnetic bar, which was
purged by N2 gas. After purging for 5 min, toluene (0.8 mL) and aniline (1a) (55.0 ꢀL, 0.600 mmol)
were added to the mixture and allowed to premix for 10 min. And then a solution of phenyl vinyl
sulfone (2) (84.1 mg, 0.500 mmol) in toluene (0.7 mL) was added to the reaction solution, which was
allowed to stir at room temperature for 3 h. After that time, reaction was quenched with a saturated
aqueous solution of NH4Cl (1 mL) and washed with EtOAc (3 x 3 mL). The organic layers were
combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by
silica gel column chromatography (hexanes:EtOAc = 5:1) to afford the desired aminated product 3a
(130 mg, 0.497 mmol, 99% yield) as a white solid.
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General procedure B: CuCl (1.50 mg, 0.0150 mmol), ICy L3 (4.80 mg, 0.0150 mmol) and KOt-Bu
(3.40 mg, 0.0300 mmol) were added to a vial (8 mL) charged with a magnetic bar, which was purged by
N2 gas. After purging for 5 min, toluene (0.8 mL) was added and allowed to premix for 30 min. And
then aniline (1a) (55.0 ꢀL, 0.600 mmol) was added to the mixture, which was allowed to stir for further
20 min. A solution of phenyl vinyl sulfone (2) (84.1 mg, 0.500 mmol) in toluene (0.7 mL) was added to
the reaction solution and it was allowed to stir at room temperature for 3 h. After that time, reaction was
quenched with a saturated aqueous solution of NH4Cl (1 mL) and washed with EtOAc (3 x 3 mL). The
combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by silica gel column chromatography (hexanes:EtOAc = 5:1) to afford the desired
aminated product 3a (127 mg, 0.485 mmol, 97% yield) as a white solid.
N-(2-(Phenylsulfonyl)ethyl)aniline (3a). This compound has been previously reported and spectra data
match described.3d 1H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 7.4 Hz, 2H), 7.69 (dd, J = 7.4, 7.4 Hz,
1H), 7.58 (dd, J = 7.4, 7.4 Hz, 2H), 7.18 (dd, J = 7.6, 7.6 Hz, 2H), 6.76 (dd, J = 7.6, 7.6 Hz, 1H), 6.54
(d, J = 7.6 Hz, 2H), 4.19 (br s, 1H), 3.59 (t, J = 6.3 Hz, 2H), 3.37 (t, J = 6.3 Hz, 2H); 13C NMR (CDCl3,
100 MHz): δ 146.4, 138.8, 133.9, 129.3, 129.2, 127.7, 118.1, 112.8, 54.4, 37.3.
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4-Fluoro-N-(2(phenylsulfonyl)ethyl)aniline (3b). Compound 3b was synthesized according to general
procedure A using 4-fluoroaniline (1b) to obtain as a light yellow white solid in 98% yield (137 mg,
0.490 mmol). mp 105-106 °C; IR (neat): 3387 (s), 2926 (s), 2846 (s), 1516 (s), 1316 (s), 1288 (s), 1140
1
2
3
4
5
6
7
8
9
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(s), 1083 (s), 821 (s) cm-1; H NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 7.6 Hz, 2H), 7.68 (dd, J = 7.6,
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7.6 Hz, 1H), 7.58 (dd, J = 7.6, 7.6 Hz, 2H), 6.87 (m, 2H), 6.48 (m, 2H), 4.13 (br s, 1H), 3.55 (t, J = 6.2
Hz, 2H), 3.35 (t, J = 6.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 156.2 (d, J = 235.9 Hz), 142.8, 138.9,
134.0, 129.4, 127.8, 115.8 (d, J = 22.3 Hz), 114.0 (d, J = 7.4 Hz), 54.4, 38.1; HRMS (EI) m/z: [M]+
Calcd for C14H14FNO2S 279.0729, Found 279.0736.
4-Bromo-N-(2-(phenylsulfonyl)ethyl)aniline (3c). Compound 3c was synthesized according to general
procedure A using 4-bromoaniline (1c) to obtain as a white solid in 97% yield (165 mg, 0.485 mmol).
This compound has been previously reported and spectra data match described.17 1H NMR (CDCl3, 400
MHz): δ 7.92 (d, J = 7.5 Hz, 2H), 7.70 (dd, J = 7.5, 7.5 Hz, 1H), 7.60 (dd, J = 7.5, 7.5 Hz, 2H), 7.25 (d,
J = 8.8 Hz, 2H), 6.42 (d, J = 8.8 Hz, 2H), 4.25 (br s, 1H), 3.60 (t, J = 6.1 Hz, 2H), 3.38 (t, J = 6.1 Hz,
2H); 13C NMR (CDCl3, 100 MHz): δ 145.6, 138.9. 134.1, 132.1, 129.5, 127.9, 114.6, 110.1, 54.5, 37.6.
4-Methoxy-N-(2-(phenylsulfonyl)ethyl)aniline (3d). Compound 3d was synthesized according to
general procedure A using p-anisidine (1d) to obtain as a brown solid in >99% yield (145 mg, 0.498
mmol). This compound has been previously reported and spectra data match described.17 1H NMR
(CDCl3, 400 MHz): δ 7.93 (d, J = 7.5 Hz, 2H), 7.69 (dd, J = 7.5, 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz
2H), 6.77 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 8.5 Hz, 2H), 3.91 (br s, 1H), 3.75 (s, 3H), 3.56 (t, J = 5.8 Hz,
2H), 3.35 (t, J = 5.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 152.9, 140.5, 139.1, 134.0, 129.5, 128.0,
115.0, 114.8, 55.6, 54.7, 38.7.
N-(2-(Phenylsulfonyl)ethyl)-4-(trifluoromethyl)aniline (3e). Compound 3e was synthesized
according to general procedure A using 4-(trifluoromethyl)aniline (1e) to obtain as a white solid in 98%
o
yield (161 mg, 0.489 mmol). mp 142-143 C; IR (neat): 3382 (s), 3058 (w), 2955 (m), 2830 (w), 2361
1
(w), 1611 (s), 1519 (s), 1265 (s), 1142 (s), 1084 (s), 829 (s) cm-1; H NMR (CDCl3, 400 MHz): δ 7.93
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(d, J = 7.7 Hz, 2H), 7.71 (dd, J = 7.7, 7.7 Hz, 1H), 7.60 (dd, J = 7.7, 7.7 Hz, 2H), 7.40 (d, J = 8.5 Hz,
2H), 6.55 (d, J = 8.5 Hz, 2H), 4.60 (t, J = 6.1 1H), 3.64 (dt, J = 6.1, 6.1 Hz, 2H), 3.38 (t, J = 6.1 Hz,
2H); 13C NMR (CDCl3, 100 MHz): δ 149.1, 138.8, 134.2, 129.6, 127.9, 126.7 (q, J = 3.9 Hz), 124.7 (q,
J = 270.6 Hz), 119.8 (q, J = 32.5 Hz), 112.1, 54.4, 37.1; HRMS (EI) m/z: [M]+ Calcd for C15H14F3NO2S
329.0697, Found 329.0694.
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4-Methyl-N-(2-(phenylsulfonyl)ethyl)aniline (3f). Compound 3f was synthesized according to general
procedure A using p-toluidine (1f) as a white solid in 90% yield (124 mg, 0.450 mmol). This compound
has been previously reported and spectra data match described.17 1H NMR (CDCl3, 400 MHz): δ 7.93
(d, J = 7.5 Hz, 2H), 7.69 (dd, J = 7.5, 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz, 2H), 6.99 (d, J = 8.0 Hz,
2H), 6.47 (d, J = 8.0 Hz, 2H), 4.06 (br s, 1H), 3.59 (t, J = 6.1 Hz, 2H), 3.37 (t, J = 6.1 Hz, 2H), 2.24 (s,
3H); 13C NMR (CDCl3, 100 MHz): δ 144.1, 139.1, 134.0, 129.9, 129.5, 128.0, 127.8, 113.4, 54.7, 38.0,
20.2.
4-(tert-Butyl)-N-(2-(phenylsulfonyl)ethyl)aniline (3g). Compound 3g was synthesized according to
general procedure A using 4-tert-butylaniline (1g) to obtain as a white solid in 93% yield (148 mg,
o
0.466 mmol). mp 107-108 C; IR (neat): 3382 (s), 3058 (w), 2954 (m), 2832 (w), 2359 (w), 1611 (s),
1519 (s), 1265 (s), 1141 (s), 1083 (s), 830 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.95 (d, J = 7.5 Hz,
2H), 7.70 (dd, J = 7.5, 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 6.52 (d, J =
13
8.7 Hz, 2H), 4.12 (br s, 1H), 3.59 (t, J = 6.4 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H), 1.30 (s, 9H); C NMR
(CDCl3, 100 MHz): δ 144.0, 141.0, 138.9, 133.9, 129.4, 127.8, 126.1, 112.7, 54.6, 37.6, 33.6, 31.3;
HRMS (EI) m/z: [M]+ Calcd for C18H23NO2S 317.1449, Found 317.1431.
2-Fluoro-N-(2-(phenylsulfonyl)ethyl)aniline (3h). Compound 3h was synthesized according to
general procedure A using 2-fluoroaniline (1h) to obtain as a white solid in >99% yield (139 mg, 0.498
mmol). mp 67-68 oC; IR (neat): 3410 (s), 2927 (s), 1619 (s), 1520 (s), 1449 (s), 1288 (s), 1137 (s), 1079
1
(s), 806 (s) cm-1; H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 7.6 Hz, 2H), 7.69 (dd, J = 7.6, 7.6 Hz,
1H), 7.58 (dd, J = 7.6, 7.6 Hz, 2H), 6.99-6.93 (m, 2H), 6.67 (dd, J = 7.4, 7.4 Hz, 1H), 6.58 (dd, J = 8.3,
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8.3 Hz, 1H) 4.34 (br s, 1H), 3.64 (dt, J = 6.3, 6.3 Hz, 2H), 3.40 (t, J = 6.3 Hz, 2H); 13C NMR (CDCl3,
100 MHz): δ 151.6 (d, J = 239.2 Hz), 138.8, 134.9 (d, J = 11.6 Hz), 133.9, 129.4, 127.8, 124.5 (d, J =
4.7 Hz), 117.5, 114.6 (d, J = 19 Hz), 111.7, 54.5, 37.0; HRMS (EI) m/z: [M]+ Calcd for C14H14FNO2S
279.0729; Found 279.0723.
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2-Chloro-N-(2-(phenylsulfonyl)ethyl)aniline (3i). Compound 3i was synthesized according to general
procedure A using 2-chloroaniline (1i) to obtain as yellow liquid in 99% yield (147 mg, 0.497 mmol).
IR (neat): 3399 (m), 3066 (w), 2981 (w), 2360 (m), 1732 (s), 1596 (s), 1511 (s), 1295 (s), 1140 (s),
1
1082 (s), 736 (s) cm-1; H NMR (CDCl3, 400 MHz): δ 7.95 (d, J = 7.6 Hz, 2H), 7.69 (dd, J = 7.6, 7.6
Hz, 1H), 7.59 (dd, J = 7.6, 7.6 Hz, 2H), 7.25 (d, J = 7.7 Hz, 1H), 7.12 (dd, J = 7.7, 7.7 Hz, 1H), 6.67
(dd, J = 7.7, 7.7 Hz, 1H), 6.54 (d, J = 7.7, 7.7 Hz, 1H), 4.72 (br s, 1H), 3.67 (dt, J = 6.5, 6.5 Hz, 2H),
3.42 (t, J = 6.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 142.5, 139.0, 134.1, 129.5, 129.5, 128.0,
127.8, 119.7, 118.2, 110.7, 54.7, 37.2; HRMS (EI) m/z: [M]+ Calcd for C14H14ClNO2S 295.0434, Found
295.0415.
2-Methoxy-N-(2-(phenylsulfonyl)ethyl)aniline (3j). Compound 3j was synthesized according to
general procedure A using o-anisidine (1j) to obtain as a white solid in 98% yield (143 mg, 0.490
mmol). This compound has been previously reported and spectra data match described.17 1H NMR
(CDCl3, 400 MHz): δ 7.94 (d, J = 7.5 Hz, 2H), 7.68 (dd, J = 7.5, 7.5 Hz, 1H), 7.58 (dd, J = 7.5, 7.5 Hz,
2H), 6.83 (dd, J = 7.6, 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.70 (dd, J = 7.6, 7.6 Hz, 1H), 6.47 (d, J =
13
7.6 Hz, 1H), 4.57 (s, 1H), 3.81 (br s, 3H), 3.63 (t, J = 6.6 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H); C NMR
(CDCl3, 100 MHz): δ 147.2, 139.2, 136.4, 133.8, 129.4, 127.9, 121.1, 117.4, 109.7, 109.5, 55.3, 54.8,
37.1.
Methyl 2-((2-(phenylsulfonyl)ethyl)amino)benzoate (3k). Compound 3k was synthesized according
to general procedure A using methyl anthranilate (1k) to obtain as a white solid in 96% yield (154 mg,
o
0.482 mmol). mp 88-89 C; IR (neat): 3359 (s), 2357 (w), 1678 (s), 1577 (s), 1516 (s), 1439 (s), 1231
(s), 1141 (s), 1080 (s), 992 (m), 753 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.92 (d, J = 7.6 Hz, 2H),
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7.87 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.6, 7.6 Hz, 1H), 7.55 (dd, J = 7.6, 7.6
Hz, 2H), 7.33 (dd, J = 8.0, 8.0 Hz, 1H), 6.62 (dd, J = 8.0, 8.0 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 3.82 (br
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s, 3H), 3.68 (dt, J = 6.9, 5.8 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 168.7,
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149.4, 139.0, 134.7, 133.8, 131.8, 129.3, 127.91, 115.5, 110.8, 110.4, 54.4, 51.5, 36.3; HRMS (EI) m/z:
[M]+ Calcd for C16H17NO4S 319.0878, Found 319.0884.
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2-Methyl-N-(2-(phenylsulfonyl)ethyl)aniline (3l). Compound 3l was synthesized according to general
procedure A using o-toluidine (1l) to obtain as a yellow solid in 99% yield (136 mg, 0.494 mmol). This
compound has been previously reported and spectra data match described.17 1H NMR (CDCl3, 400
MHz): δ 7.95 (d, J = 7.5 Hz, 2H), 7.70 (dd, J = 7.5, 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz, 2H), 7.14-
7.08 (m, 2H), 6.72 (dd, J = 7.2, 7.2 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 4.21 (br s, 1H), 3.65 (t, J = 5.9
13
Hz, 2H), 3.44 (t, J = 5.9 Hz, 2H), 2.13 (s, 3H); C NMR (CDCl3, 100 MHz): δ 144.6, 138.8, 133.9,
130.3, 129.4, 127.8, 127.0, 122.7, 117.7, 109.2, 54.6, 37.3, 17.1.
N,N-Bis(2-(phenylsulfonyl)ethyl)aniline (4a). Compound 4a was synthesized according to general
procedure A using aniline (1a) to obtain as a white solid. mp 158-159 oC; IR (neat): 3066 (w), 2958 (w),
2925 (m), 2853 (m), 2360 (m), 2337 (m), 1866 (w), 1702 (m), 1650 (m), 1557 (m), 1508 (s), 1456 (m),
1364 (m), 1303 (m), 1145 (s), 1084 (m), 992 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.90 (d, J = 7.5
Hz, 4H), 7.69 (dd, J = 7.5, 7.5 Hz, 2H), 7.59 (dd, J = 7.5, 7.5 Hz, 4H), 7.17 (dd, J = 7.7, 7.7 Hz, 2H),
6.78 (dd, J = 7.7, 7.7 Hz, 1H), 6.46 (d, J = 7.7 Hz, 2H), 3.71 (t, J = 7.2 Hz, 4H), 3.28 (t, J = 7.2 Hz, 4H);
13C NMR (CDCl3, 100 MHz): δ 145.1, 139.4, 134.0, 129.9, 129.5, 127.9, 118.8, 113.2, 52.9, 45.0;
HRMS (EI) m/z: [M]+ Calcd for C22H23NO4S2 429.1068, Found 429.1067.
4-Methoxy-N,N-bis(2-(phenylsulfonyl)ethyl)aniline (4b). Compound 4b was synthesized according to
general procedure A using p-anisidine (1d, 49.3 mg, 0.400 mmol) to obtain as a yellow solid in 75%
yield (139 mg, 0.302 mmol). mp 118-119 oC; IR (neat): 3066 (w), 2928 (m), 2359 (m), 1584 (m), 1512
(s), 1446 (s), 1296 (s), 1145 (s), 1083 (s), 817 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 7.5
Hz, 4H), 7.68 (dd, J = 7.5, 7.5 Hz, 2H), 7.58 (dd, J = 7.5, 7.5 Hz, 4H), 6.74 (d, J = 8.8 Hz, 2H), 6.49 (d,
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J = 8.8 Hz, 2H), 3.74 (s, 3H), 3.56 (t, J = 6.7 Hz, 4H), 3.19 (t, J = 6.7 Hz, 4H); 13C NMR (CDCl3, 100
MHz): δ 153.7, 139.2, 139.1, 133.8, 129.3, 127.7, 117.2, 114.9, 55.41, 52.8, 46.0; HRMS (ESI) m/z:
[M+H]+ Calcd for C23H26NO5S2 460.1252, Found 460.1251.
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N-Phenyl-N-(2-(phenylsulfonyl)ethyl)aniline (6a). Compound 6a was synthesized according to
general procedure A using diphenylamine (5a) to obtain as a white solid in 92% yield (155 mg, 0.460
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mmol). mp 124-125 C; IR (neat): 3066 (s), 2924 (s), 1947 (w), 1600 (s), 1500 (s), 1318 (s), 1311 (s),
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994 (s) cm-1; H NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 7.4 Hz, 2H), 7.70 (dd, J = 7.4, 7.4 Hz, 1H),
7.59 (dd, J = 7.4, 7.4 Hz, 2H), 7.24 (dd, J = 7.3, 7.3 Hz, 4H), 6.98 (dd, J = 7.3, 7.3 Hz, 2H), 6.86 (d, J =
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7.3 Hz, 4H), 4.17 (t, J = 7.6 Hz, 2H), 3.44 (t, J = 7.6 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 146.6,
139.3, 134.0, 129.6, 129.5, 127.9, 122.2, 120.8, 52.7, 45.5; HRMS (EI) m/z: [M]+ Calcd for
C20H19NO2S 337.1136, Found 337.1127.
N-Methyl-N-(2-(phenylsulfonyl)ethyl)aniline (6b). Compound 6b was synthesized according to
general procedure A using N-methylaniline (5b) to obtain as a white solid in 94% yield (129 mg, 0.470
o
mmol). mp 77-78 C; IR (neat): 3062 (s), 2917 (s), 1921 (w), 1600 (s), 1504 (s), 1446 (s), 1361 (s),
1307 (s), 1242 (s), 1180 (s), 1145 (s), 1087 (s), 991 (m), 860 (w), 806 (w) cm-1; 1H NMR (CDCl3, 400
MHz): δ 7.94 (d, J = 7.5 Hz, 2H), 7.69 (dd, J = 7.5, 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz, 2H), 7.22
(dd, J = 7.3, 7.3 Hz, 2H), 6.75 (dd, J = 7.3, 7.3 Hz, 1H), 6.60 (d, J = 7.3 Hz, 2H), 3.83 (t, J = 7.4 Hz,
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2H), 3.33 (t, J = 7.4 Hz, 2H), 2.88 (s, 3H); C NMR (CDCl3, 100 MHz): δ 147.6, 139.2, 133.8, 129.3,
129.3, 127.7, 117.4, 112.4, 51.7, 45.8, 38.1; HRMS (EI) m/z: [M]+ Calcd for C15H17NO2S 275.0980,
Found 275.0971.
4-Fluoro-N-methyl-N-(2-(phenylsulfonyl)ethyl)aniline (6c). Compound 6c was synthesized according
to general procedure A using 4-fluoro-N-methylaniline (5c) to obtain as a white solid in 96% yield (141
o
mg, 0.481 mmol). mp 98-99 C; IR (neat): 3064 (s), 2962 (s), 2828 (m), 1855 (w), 1608 (s), 1518 (s),
1447 (s), 1365 (s), 1298 (s), 1086 (s), 1019 (m), 945 (m), 811 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ
7.92 (d, J = 7.4 Hz, 2H), 7.69 (dd, J = 7.4, 7.4 Hz, 1H), 7.59 (dd, J = 7.4, 7.4 Hz, 2H), 6.91 (dd, J = 8.8,
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8.8 Hz, 2H) 6.53 (dd, J = 8.8, 8.8 Hz, 2H), 3.78 (t, J = 7.4 Hz, 2H), 3.28 (t, J = 7.4 Hz, 2H), 2.81 (s,
3H); 13C NMR (CDCl3, 100 MHz): δ 156.0 (d, J = 236.7 Hz), 144.3 (d, J = 1.6 Hz), 139.3, 133.9,
129.4, 127.8, 115.9 (d, J = 22.4 Hz), 114.1 (d, J = 7.5 Hz), 51.7, 46.6, 38.7; HRMS (EI) m/z: [M] +
Calcd for C15H16FNO2S 293.0886, Found 293.0882.
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1-(2-(Phenylsulfonyl)ethyl)-1H-indole (6d). Compound 6d was synthesized according to general
procedure A using indole (5d) to obtain as a white solid in 98% yield (140 mg, 0.490 mmol). This
compound has been previously reported and spectra data match described.18 1H NMR (CDCl3, 400
MHz): δ 7.88 (d, J = 7.4 Hz, 2H), 7.65 (dd, J = 7.4, 7.4 Hz, 1H), 7.59-7.52 (m, 3H), 7.22-7.16 (m, 2H),
7.11 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (d, J = 3.2 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 4.61 (t, J = 7.4 Hz, 2H)
3.56 (t, J = 7.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 138.7, 135.3, 133.9, 129.3, 128.7, 127.6,
127.3, 121.9, 121.2, 119.8, 108.6, 102.4, 55.2, 39.6.
5-Bromo-1-(2-(phenylsulfonyl)ethyl)-1H-indole (6e). Compound 6e was synthesized according to
general procedure A using 5-bromoindole (5e) to obtain as a white solid in 94% yield (171 mg, 0.469
o
mmol). mp 158-159 C; IR (neat): 3054 (m), 2966 (m), 1971 (w), 1904 (w), 1849 (w), 1743 (w), 1469
(s), 1447 (s), 1302 (s), 1144 (s), 1086 (s), 871 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 7.5
Hz, 2H), 7.69 (d, J = 1.5 Hz, 1H), 7.65 (dd, J = 7.5, 7.5 Hz, 1H), 7.53 (dd, J = 7.5, 7.5 Hz, 2H), 7.30-
7.24 (m, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 3.2 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.59 (t, J = 7.2
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Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 138.8, 134.2, 134.1, 130.5, 129.5,
128.6, 127.7, 124.9, 123.8, 113.3, 110.2, 102.2, 55.3, 39.9; HRMS (EI) m/z: [M]+ Calcd for
C16H14BrNO2S 362.9929, Found 362.9903.
9-(2-(Phenylsulfonyl)ethyl)-9H-carbazole (6f). Compound 6f was synthesized according to general
procedure A using carbazole (5f) to obtain as a white solid in 98% yield (165 mg, 0.492 mmol). mp
162-163 oC; IR (neat): 3062 (m), 2968 (m), 1596 (m), 1485 (s), 1450 (s), 1307 (s), 1234 (m), 1176 (m),
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1141 (s), 1087 (m), 1002 (m), 914 (m), 817 (m) cm-1; H NMR (CDCl3, 400 MHz): δ 8.03 (d, J = 7.8
Hz, 2H), 7.84 (d, J = 7.4 Hz, 2H), 7.62 (dd, J = 7.4, 7.4 Hz, 1H), 7.50-7.43 (m, 4H), 7.29-7.22 (m, 4H),
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4.79 (t, J = 7.6 Hz, 2H), 3.58 (t, J = 7.6 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 139.5, 138.7, 134.0,
129.4, 127.6, 126.1, 123.3, 120.6, 119.8, 108.2, 53.5, 36.4; HRMS (ESI) m/z: [M+H]+ Calcd for
C20H18NO2S 336.1058, Found 336.1056.
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1-(2-(Phenylsulfonyl)ethyl)-1H-pyrrole (6g). Compound 6g was synthesized according to general
procedure A using pyrrole (5g) to obtain as a white solid in 84% yield (99.0 mg, 0.421 mmol). This
compound has been previously reported and spectra data match described.19 1H NMR (CDCl3, 400
MHz): δ 7.90 (d, J = 7.3 Hz, 2H), 7.69 (dd, J = 7.3, 7.3 Hz, 1H), 7.58 (dd, J = 7.3, 7.3 Hz, 2H), 6.57 (d,
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J = 1.4 Hz, 2H), 6.10 (d, J = 1.4 Hz, 2H), 4.34 (t, J = 7.8 Hz, 2H), 3.53 (t, J = 7.8 Hz, 2H); C NMR
(CDCl3, 100 MHz): δ 139.0, 134.2, 129.6, 127.9, 120.4, 109.3, 57.2, 42.7.
1-(1-(2-(Phenylsulfonyl)ethyl)-1H-pyrrol-2-yl)ethanone (6h). Compound 6h was synthesized
according to general procedure A using 2-acetylpyrrole (5h) to obtain as a white solid in 98% yield (136
mg, 0.490 mmol). mp 94-95 oC; IR (neat): 3112 (m), 3062 (m), 2985 (m), 2931 (m), 1647 (s), 1531 (m),
1307 (s), 1245 (m), 1153 (s), 1087 (s), 1026 (m), 945 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.85 (d,
J = 7.6 Hz, 2H), 7.64 (dd, J = 7.6, 7.6 Hz, 1H), 7.54 (dd, J = 7.6, 7.6 Hz, 2H), 6.94 (m, 1H), 6.90-6.88
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(m, 1H), 6.13-6.11 (m, 1H), 4.65 (t, J = 6.7 Hz, 2H) 3.65 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H); C NMR
(CDCl3, 100 MHz): δ 188.5, 139.4, 133.8, 131.5, 129.9, 129.3, 127.7, 121.2, 108.8, 56.2, 43.8, 26.9;
HRMS (EI) m/z: [M]+ Calcd for C14H15NO3S 277.0773, Found 277.0768.
1-(2-(Phenylsulfonyl)ethyl)-1H-imidazole (6i). Compound 6i was synthesized according to general
procedure A using imidazole (5i) to obtain as a white solid in >99% yield (118 mg, 0.499 mmol). This
compound has been previously reported and spectra data match described.20 1H NMR (CDCl3, 400
MHz): δ 7.88 (d, J = 7.5 Hz, 2H), 7.70 (dd, J = 7.5, 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.5 Hz, 2H), 7.44 (br
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s, 1H), 7.01 (br s, 1H), 6.85 (br s, 1H), 4.43 (t, J = 7.3 Hz, 2H), 3.54 (t, J = 7.3 Hz, 2H); C NMR
(CDCl3, 100 MHz): δ 138.7, 137.2, 134.4, 130.4, 129.7, 127.8, 118.4, 56.6, 40.2.
2-Methyl-1-(2-(phenylsulfonyl)ethyl)-1H-benzo[d]imidazole (6j). Compound 6j was synthesized
according to general procedure A using 2-methyl-1H-benzo[d]imidazole (5j) to obtain as a white solid
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o
in >99% yield (150 mg, 0.499 mmol). mp 178-179 C; IR (neat): 3061 (m), 3001 (m), 2981 (m), 2939
(m), 1616 (m), 1515 (s), 1458 (s), 1404 (s), 1361 (s), 1307 (s), 1234 (m), 1145 (s), 1083 (m), 1010 (m),
914 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 7.7 Hz, 2H), 7.70-7.58 (m, 2H), 7.53 (dd, J =
7.7, 7.7 Hz, 2H), 7.25-7.14 (m, 2H), 7.14-7.07 (m, 1H), 4.57 (t, J = 7.5 Hz, 2H), 3.53 (t, J = 7.5 Hz,
2H), 2.57 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 151.1, 142.7, 138.4, 134.3, 134.1, 129.6, 127.6,
122.5, 122.4, 119.5, 108.4, 54.3, 37.1, 13.6; HRMS (EI) m/z: [M]+ Calcd for C16H16N2O2S 300.0932,
Found 300.0903.
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1-(2-(Phenylsulfonyl)ethyl)-1H-pyrazole (6k). Compound 6k was synthesized according to general
procedure A using pyrazole (5k) to obtain as a white solid in 90% yield (106 mg, 0.449 mmol). mp 122-
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123 C; IR (neat): 3117 (s), 2973 (s), 2915 (s), 2360 (m), 1445 (s), 1396 (s), 1296 (s), 1149 (s), 1084
(s), 998 (s), 963 (s), 809(s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 7.5 Hz, 2H), 7.65 (dd, J =
7.5, 7.5 Hz, 1H), 7.54 (dd, J = 7.5, 7.5 Hz, 2H), 7.40 (d, J = 4.4 Hz, 2H), 6.18 (s, 1H), 4.56 (t, J = 7.0
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Hz, 2H), 3.74 (t, J = 7.0 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 139.9, 138.7, 133.7, 129.8, 129.1,
127.5, 105.6, 55.2, 45.0; HRMS (ESI) m/z: [M+H]+ Calcd for C11H13N2O2S 237.0698, Found 237.0694.
1-(2-(Phenylsulfonyl)ethyl)-1H-1,2,3-trizole (6l). Compound 6l was synthesized according to general
procedure A using 1H-1,2,3-triazole (5l) to obtain as a white solid in 54% yield (64.0 mg, 0.270 mmol).
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mp 122-123 C; IR (neat): 3121 (w), 3004 (w), 2360 (m), 1446 (s), 1295 (s), 1149 (s), 1133 (s), 1083
(s), 999 (s), 802 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 7.6 Hz, 2H), 7.70 (dd, J = 7.6, 7.6
Hz, 1H), 7.65 (d, J = 5.1 Hz, 2H), 7.58 (dd, J = 7.6, 7.6 Hz, 2H), 4.84 (t, J = 6.9 Hz, 2H), 3.78 (t, J = 6.9
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Hz, 2H); C NMR (CDCl3, 100 MHz): δ 138.6, 134.4, 134.0, 129.6, 127.8, 124.4, 55.4, 43.3; HRMS
(EI) m/z: [M]+ Calcd for C10H11N3O2S 237.0572, Found 237.0559.
1-(1-(Phenylsulfonyl)octan-2-yl)-1H-indole (8a). Compound 8a was synthesized according to general
procedure B using alkene 7 (0.120 mmol) to obtain as colorless liquid in 99% yield (44.0 mg, 0.119
mmol). IR (neat): 3749 (w), 2963 (w), 2916 (m), 2858 (w), 2364 (w), 2339 (w), 1453 (m), 1305 (m),
1138 (s), 1081 (w), 914 (w), 786 (w), 728 (s), 695 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.59-7.52
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(m, 3H), 7.46 (dd, J = 8.3, 8.3 Hz, 1H), 7.33-7.19 (m, 3H), 7.12 (dd, J = 7.3, 7.4 Hz, 1H), 6.91 (d, J =
3.4 Hz, 1H), 6.36 (d, J = 3.1 Hz, 1H), 5.04-4.94 (m, 1H), 3.81 (dd, J = 14.6, 7.5 Hz, 1H), 3.62 (dd, J =
14.9, 5.4 Hz, 1H), 2.15-1.99 (m, 2H), 1.46-1.12 (m, 8H), 1.11-0.99 (m, 1H), 0.87 (t, J = 7.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz): δ 138.9, 135.7, 133.3, 128.8, 128.6 127.3, 123.9, 121.8, 121.0 119.8,
109.6, 103.0, 61.0, 51.6, 35.3, 31.3, 28.5, 25.7, 22.3, 12.8; HRMS (ESI) m/z: [M+H]+ Calcd for
C22H28NO2S 370.1841, Found 370.1835.
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1-(1-(Phenylsulfonyl)octan-2-yl)-1H-imidazole (8b). Compound 8b was synthesized according to
general procedure B using alkene 7 (0.120 mmol) to obtain as colorless oil in 75% yield (28.8 mg,
0.0899 mmol). IR (neat): 3747 (w), 2956 (w), 2930 (m), 2862 (w), 2354 (w), 2341 (w), 1505 (m), 1454
(w), 1299 (m), 1222 (w), 1142 (s), 1081 (m), 903 (w), 730 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.69
(d, J = 7.6 Hz, 2H), 7.60 (dd, J = 7.6, 7.6 Hz, 1H), 7.47 (dd, J = 7.6, 7.6 Hz, 2H), 7.37 (s, 1H) 6.87 (br s,
1H), 6.66 (br s, 1H), 4.71-4.58 (m, 1H), 3.60 (dd, J = 14.8, 8.2 Hz, 1H), 3.49 (dd, J = 14.7, 4.4 Hz, 1H),
1.98-1.84 (m, 1H), 1.83-1.67 (m, 1H), 1.35-1.10 (m, 7H), 1.10-0.94 (m, 1H), 0.84 (t, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz): δ 139.2, 136.8, 134.0, 130.4, 129.4, 127.5, 115.8, 61.4, 53.0, 36.1, 31.3,
28.3, 25.4, 22.3, 13.8; HRMS (ESI) m/z: [M+H]+ Calcd for C17H25N2O2S 321.1637, Found 321.1631.
4-Methoxy-N-(1-(phenylsulfonyl)octan-2-yl)aniline (8c). Compound 8c was synthesized according to
general procedure B using alkene 7a (0.120 mmol) to obtain as a brown solid in 68% yield (30.6 mg,
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0.0815 mmol). mp 76-77 C; IR (neat): 3394 (w), 2950 (w), 2947 (w), 2924 (m), 2375 (w), 1508 (s),
1439 (w), 1285 (m), 1242 (s), 1139 (s), 1075 (w), 1027 (m), 812 (s) cm-1; 1H NMR (CDCl3, 400 MHz):
δ 7.88 (d, J = 7.6 Hz, 2H), 7.66 (dd, J = 7.6, 7.6 Hz, 1H), 7.55 (dd, J = 7.6, 7.6 Hz, 2H), 6.73 (d, J = 8.8
Hz, 2H) 6.43 (d, J = 8.8 Hz, 2H), 3.83-3.76 (m, 1H), 3.75 (s, 3H), 3.36 (br s, 1H), 3.34 (dd, J = 14.4, 4.4
Hz, 1H), 3.14 (dd, J = 14.3, 7.0 Hz, 1H), 1.98-1.87 (m, 1H), 1.64-1.53 (m, 1H), 1.49-1.40 (m, 1H), 1.33-
1.22 (m, 7H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 152.6, 140.2, 140.1, 133.7,
129.3, 128.0, 115.1, 114.9, 59.5, 55.8, 50.0, 35.2, 31.6, 29.0, 25.7, 22.5, 13.9; HRMS (ESI) m/z:
[M+H]+ Calcd for C21H30NO3S 376.1946, Found 376.1940.
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4-Methoxy-N-(1-phenyl-2-(phenylsulfonyl)ethyl)aniline (8d). Compound 8d was synthesized
according to general procedure B using alkene 7b (0.120 mmol) to obtain as a brown solid in 62% yield
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(27.3 mg, 0.0744 mmol). mp 135-136 C; IR (neat): 3394 (m), 2938 (w), 2825 (w), 1518 (s), 1454 (m),
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1404 (w), 1290 (s), 1239 (s), 1133 (s), 1079 (w), 1027 (m), 809 (m), 736 (s), 695 (m) cm-1; 1H NMR
(CDCl3, 400 MHz): δ 7.88 (d, J = 7.3 Hz, 2H), 7.65 (dd, J = 7.3, 7.3 Hz, 1H), 7.53 (dd, J = 7.3, 7.3 Hz,
2H), 7.38-7.19 (m, 5H), 6.68 (d, J = 8.0 Hz, 2H), 6.44 (d, J = 8.0 Hz, 2H), 4.75-4.55 (m, 2H), 3.71 (s,
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3H), 3.51 (dd, J = 14.3, 10.1 Hz, 1H), 3.42 (dd, J = 9.8, 2.4 Hz, 1H); C NMR (CDCl3, 100 MHz): δ
152.8, 141.2, 140.6, 139.1, 134.0, 129.4, 129.1, 128.2, 128.0, 126.3, 115.5, 114.7, 62.5, 55.6, 55.1;
HRMS (ESI) m/z: [M+H]+ Calcd for C21H22NO3S 368.1320, Found 368.1321.
3-(Phenylamino)propanenitrile (10a). Compound 10a was synthesized according to general procedure
B using aniline (1a) to obtain as a white solid in 94% yield (68.5 mg, 0.469 mmol). This compound has
been previously reported and spectra data match described.6i 1H NMR (CDCl3, 400 MHz): δ 7.23 (dd, J
= 7.6, 7.6 Hz, 2H), 6.80 (dd, J = 7.6, 7.6 Hz, 1H), 6.64 (d, J = 7.6, 7.6 Hz, 2H), 4.00 (br s, 1H), 3.53 (t, J
= 6.5 Hz, 2H), 2.65 (t, J = 6.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 146.1, 129.5, 118.6, 118.2,
113.0, 39.6, 17.9.
3-((4-Fluorophenyl)amino)propanenitrile (10b). Compound 10b was synthesized according to
general procedure B using 4-fluoroaniline (1b) to obtain as white liquid in 95% yield (78.0 mg, 0.475
mmol). This compound has been previously reported and spectra data match described.21 1H NMR
(CDCl3, 400 MHz): δ 6.96-6.90 (m, 2H), 6.57 (m, 2H), 3.92 (br s, 1H), 3.47 (dt, J = 6.5, 6.5 Hz, 2H),
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2.63 (t, J = 6.5 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 156.2 (d, J = 235.9 Hz), 142.5, 118.2, 115.8
(d, J = 22.3 Hz), 113.9 (d, J = 7.4 Hz), 40.1, 17.8.
3-((4-Methoxyphenyl)amino)propanenitrile (10c). Compound 10c was synthesized according to
general procedure B using p-anisidine (1d) to obtain as a yellow solid in 94% yield (82.9 mg, 0.470
mmol). This compound has been previously reported and spectra data match described.6i 1H NMR
(CDCl3, 400 MHz): δ 6.81 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 3.76 (s, 4H), 3.43 (t, J = 6.3 Hz,
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2H), 2.58 (t, J = 6.3 Hz, 2H); C NMR (CDCl3, 100 MHz): δ 152.7, 140.2, 118.3, 114.9, 114.5, 55.4,
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3-(p-Tolylamino)propanenitrile (10d). Compound 10d was synthesized according to general
procedure B using p-toluidine (1f) to obtain as a white solid in 84% yield (67.6 mg, 0.422 mmol). This
compound has been previously reported and spectra data match described.6i 1H NMR (CDCl3, 400
MHz): δ 7.04 (d, J = 8.7 Hz, 2H). 6.56 (d, J = 8.7 Hz, 2H), 3.85 (br s, 1H), 3.51 (t, J = 6.5 Hz, 2H), 2.63
(t, J = 6.5 Hz, 2H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 143.8, 130.0, 128.1, 118.2, 113.3,
40.1, 20.2, 18.0.
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3-((2-Methoxyphenyl)amino)propanenitrile (10e). Compound 10e was synthesized according to
general procedure B using aniline (1j) as a yellow solid in 93% yield (81.9 mg, 0.465 mmol). This
compound has been previously reported and spectra data match described.6i 1H NMR (CDCl3, 400
MHz): δ 6.94-6.88 (m, 1H), 6.83 (dd, J = 7.8, 1.3 Hz, 1H), 6.76 (ddd, J = 7.8, 7.8, 1.3 Hz, 1H), 6.59 (dd,
J = 7.8, 1.3 Hz, 1H), 4.58 (br s, 1H), 3.87 (s, 3H), 3.55 (dt, J = 6.7, 6.7 Hz, 2H), 2.65 (t, J = 6.7 Hz, 2H);
13C NMR (CDCl3, 100 MHz): δ 147.1, 136.1, 121.2, 118.2, 117.3, 109.8, 109.6, 55.3, 39.4, 17.9.
3-(o-Tolylamino)propanenitrile (10f). Compound 10f was synthesized according to general procedure
B using o-toluidine (1l) as a white solid in 89% yield (71.6 mg, 0.447 mmol). This compound has been
previously reported and spectra data match described.6i 1H NMR (CDCl3, 400 MHz): δ 7.17 (dd, J =
7.5, 7.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.75 (dd, J = 7.5, 7.5 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 3.88
(br s, 1H), 3.60 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.19 (s, 3H); 13C NMR (CDCl3, 100 MHz):
δ 144.0, 130.6, 127.1, 122.8, 118.2, 118.1, 109.5, 39.5, 18.0, 17.2.
Methyl 3-(phenylamino)propanoate (10g). Compound 10g was synthesized according to general
procedure B using aniline (1a) to obtain as a yellow solid in 70% yield (62.4 mg, 0.348 mmol). This
compound has been previously reported and spectra data match described.21 1H NMR (CDCl3, 400
MHz): δ 7.23 (dd, J = 8.0, 7.4 Hz, 2H), 6.77 (dd, J = 7.4, 7.4 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1H), 4.09 (br
s, 1H), 3.74 (s, 3H), 3.49 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
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172.7, 147.5, 129.1, 117.5, 112.8, 51.4, 39.1, 33.4.
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Methyl 3-((4-fluorophenyl)amino)propanoate (10h). Compound 10h was synthesized according to
general procedure B using 4-fluoroaniline (1b) to obtain as a yellow solid in 73% yield (72.0 mg, 0.365
mmol). This compound has been previously reported and spectra data match described.7 1H NMR
(CDCl3, 400 MHz): δ 6.87 (dd, J = 8.7, 8.7 Hz, 2H), 6.55-6.52 (m, 2H), 3.96 (br s, 1H), 3.67 (s, 3H),
3.38 (t, J = 6.3 Hz, 2H), 2.58 (t, J = 6.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 172.8, 156.1 (d, J =
235.1 Hz), 143.9, 115.7 (d, J = 22.3 Hz), 114.0 (d, J = 6.6 Hz), 51.7, 40.0, 33.5.
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1-(Phenylamino)pentan-3-one (10i). Compound 10i was synthesized according to general procedure B
using aniline (1a) as a white solid in 81% yield (71.8 mg, 0.405 mmol). This compound has been
previously reported and spectra data match described.3c 1H NMR (CDCl3, 400 MHz): δ 7.18 (dd, J =
7.3, 7.3 Hz, 2H), 6.72 (dd, J = 7.3, 7.3 Hz, 2H), 6.62 (d, J = 7.3 Hz, 1H), 4.00 (br s, 1H), 3.44 (t, J = 6.1
Hz, 2H), 2.73 (t, J = 6.1 Hz, 2H), 2.45 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ 210.9, 147.6, 129.2, 117.5, 112.9, 41.0, 38.2, 36.1, 7.4.
1-((4-Fluorophenyl)amino)pentan-3-one (10j). Compound 10j was synthesized according to general
procedure B using aniline (1b) to obtain as a white solid in 89% yield (86.9 mg, 0.445 mmol). mp 66-67
oC; IR (neat): 3371 (s), 3051 (w), 2977 (m), 2927 (s), 2360 (m), 1705 (s), 1508 (s), 1385 (s), 1206 (s),
1103 (s), 987 (m), 810 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 6.88 (dd, J = 8.7, 8.7 Hz, 2H), 6.55 (dd,
J = 8.7, 8.7 Hz, 2H), 3.88 (br s, 1H), 3.37 (t, J = 6.1 Hz, 2H), 2.71 (t, J = 6.1 Hz, 2H), 2.45 (q, J = 7.3
Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 210.9, 155.9 (d, J = 235.0 Hz), 144.1,
115.6 (d, J = 22.4 Hz), 114.0 (d, J = 1.5 Hz), 41.0, 39.1, 36.2, 7.5; HRMS (EI) m/z: [M]+ Calcd for
C11H14FNO 195.1059, Found 195.1047.
1-((4-Methoxyphenyl)amino)penta-3-one (10k). Compound 10k was synthesized according to general
procedure B using p-anisidine (1d) to obtain as a white solid in 75% yield (77.7 mg, 0.375 mmol). This
compound has been previously reported and spectra data match described.22 1H NMR (CDCl3, 400
MHz): δ 6.78 (dd, J = 8.8, 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 3.75 (s, 4H), 3.37 (t, J = 6.1 Hz, 2H),
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2.71 (t, J = 6.1 Hz, 2H), 2.44 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100
MHz): δ 211.0, 152.3, 141.9, 114.9, 114.5, 55.6, 41.2, 39.5, 36.2, 7.5.
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Supporting Information. H NMR and C NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +82-2-940-8116. E-mail: ymlee@kw.ac.kr
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS. This research was supported by Basic Science Research Program through
the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future
Planning (NRF-2014R1A1A1003650) and supported by the Research Grant of Kwangwoon University
in 2014. The authors thank the Korea Basic Science Institute for technical assistance in MS
spectrometry.
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