Catalyst-free and metal-free electrophilic bromoamidation of unactivated olefins using the N-bromosuccinimide/sulfonamide Protocol

Article abstract of DOI:10.1021/jo502416r

An efficient, catalyst-free, and metal-free bromoamidation of unactivated olefins has been developed. 4-(Trifluoromethyl)benzenesulfonamide and N-bromosuccinimide were used as the nitrogen and halogen sources, respectively. The methodology is applicable to both cyclic and aliphatic olefins.

Full text of DOI:10.1021/jo502416r

Note
pubs.acs.org/joc
Catalyst-Free and Metal-Free Electrophilic Bromoamidation of
Unactivated Olefins Using the N‑Bromosuccinimide/Sulfonamide
Protocol
Wesley Zongrong Yu, Feng Chen, Yi An Cheng, and Ying-Yeung Yeung*
3 Science Drive 3, Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
S
* Supporting Information
ABSTRACT: An efficient, catalyst-free, and metal-free
bromoamidation of unactivated olefins has been developed.
4-(Trifluoromethyl)benzenesulfonamide and N-bromosuccini-
mide were used as the nitrogen and halogen sources,
respectively. The methodology is applicable to both cyclic
and aliphatic olefins.
(Scheme 1). This is also a metal-free process, making it suitable
for the pharmaceutical industry.7
aloamidation of unactivated olefins is an important
Hhalogenation process. In this type of reaction, both
carbon−halogen and carbon−nitrogen bonds are introduced in
a chemical operation. On the basis of the widely accepted
mechanism, it is believed that the reaction involves the
formation of a halonium intermediate followed by SN2 attack
of the nitrogen nucleophile to form the corresponding trans-
vicinal haloamide adduct. Because of its usefulness, this type of
reaction has been widely applied in various areas. The vicinal
haloamide compounds are valuable synthetic intermediates for
the construction of complex organic molecules.1 Furthermore,
biologically active molecules containing vicinal haloamide
functionalities exist in nature frequently.2
Unlike activated olefins, unactivated olefins are much less
reactive toward haloamidation. Over the decades, numerous
transition-metal-catalyzed strategies for haloamidation of
unactivated olefins have been documented.3 In many cases,
highly reactive and electrophilic N,N-dihalosulfonamides
(RSO2NX2, X = Cl, Br) were employed as the nitrogen and
halogen sources. It was noted that removal of the catalysts/
promoters would significantly diminish the reactivity and/or
regioselectivity in the reaction systems.4 Other catalytic systems
utilizing a combination of TsNH2/NBS for bromoamidation of
electron-deficient olefins have been described as well.5 In view
of these developments, a catalyst-free haloamidation process
with good regioselectivity would be greatly desired in organic
synthesis. To the best of our knowledge, haloamidation of
unactivated olefins using a simple halogen source such as N-
bromosuccinimide (NBS) but without the use of any catalyst is
highly lacking in the literature. An example was reported with a
TsNHMe/NBS combination, and the reaction was conducted
at an elevated temperature of 45 °C.6 However, subsequent
manipulation of the haloamide product is not trivial when the
N−Me moiety is not the desired substituent in the target
molecule. Herein, we are pleased to report a mild, efficient, and
catalyst-free electrophilic bromoamidation of olefins using
RSO2NH2/NBS with good regioselectivity and stereospecificity
Scheme 1. Catalyst-Free and Metal-Free Bromoamidation
Recently, we have reported several electrophilic multi-
component bromofunctionalizations of alkenes using cyclic
ethers or nitriles as the solvents and nucleophilic partners.8 It
was observed that the acidity of the secondary nucleophilic
partners (e.g., carboxylic acids, phenols, and sulfonamides) is
important for the efficiency of the reactions. Unexpectedly,
when the nucleophilic solvent was replaced with a relatively
nonpolar solvent such as methylene chloride, a direct
haloamidation took place efficiently without the need of any
external NBS activator. Initially, a reaction was performed using
styrene (1a) as the olefinic substrate and NBS. Benzamide and
trifluoromethanesulfonamide were first examined, but no
desired product was observed (Table 1, entries 1 and 2). To
our delight, a moderate yield of the desired product 2a was
obtained when 3-nosylamide or 4-nosylamide was used (entries
5 and 6). An improved yield (82%) was obtained with 4-
(trifluoromethyl)benzenesulfonamide (entry 7). The reaction
was also found to be readily scalable (entry 8). Other halogen
sources, including N-chlorosuccinimide (NCS) and N-
iodosuccinimide (NIS), were also examined, and NBS
remained superior (entries 9 and 10). The reaction yield was
further improved when 2 equiv of NBS was used (entry 13).
We also investigated the effect of the catalyst on this reaction.
Received: October 21, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502416r
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The Journal of Organic Chemistry
Note
a
a
Table 1. Reaction Optimization
Table 2. Bromoamidation of Aliphatic Olefins
b
entry
R
halogen source
X
yield (%)
1
2
3
4
5
6
7
PhCO
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
−
−
CF3SO2
4-Ts
62
69
67
68
82
75
−
58
68
20
93
PhSO2
3-Ns
4-Ns
4-CF3C6H4SO2
4-CF3C6H4SO2
4-CF3C6H4SO2
4-CF3C6H4SO2
4-CF3C6H4SO2
4-CF3C6H4SO2
4-CF3C6H4SO2
c
8
9
10
d
11
NBS
NBS
NBS
Br
Br
Br
e
12
f
13
a
Reactions were carried out with styrene (1a) (0.22 mmol), RNH2
(0.26 mmol), and NXS (0.26 mmol) in CH2Cl2 (3.0 mL) in the
b
c
absence of light. Isolated yields. The reaction was conducted on a 2.0
mmol scale. FeCl2 (0.027 mmol) was added. SPPh3 (0.027 mmol)
was added. NBS (0.37 mmol) was used.
d
e
f
a
Reactions were carried out with olefin 1 (0.22 mmol), 4-
CF3C6H4SO2NH2 (0.26 mmol), and NBS (0.26 mmol) in CH2Cl2
(3.0 mL) in the absence of light. Isolated yields. 0.37 mmol of NBS
was used.
b
c
Surprisingly, Lewis acidic iron(II) chloride resulted in a
decrease in the yield (entry 11) while Lewis basic
triphenylphosphine sulfide had a detrimental effect on the
conversion (entry 12).
Scheme 2. Competition Experiments
Next, we expanded the scope by examining a range of
aliphatic to cyclic olefinic substrates, as shown in Table 2. Good
yields were obtained when styrenes with electron-rich and
electron-deficient substituents were subjected to the reaction
conditions (2b−d). Only Markovnikov products were obtained
with the amide substituted at the benzylic position when
benzylic olefins were used as the substrates (2b−g). For
aliphatic non-benzylic olefins cis-3-hexene (1i) and trans-3-
hexene (1j), the corresponding products 2i and 2j were
obtained in excellent yields. A 1:1 product mixture of 2k and
2k′ was obtained with an alkyl-substituted terminal olefin. For
the case of various ring systems, generally good to excellent
yields of the bromoamide adducts were obtained (2l−p).
Interestingly, 2q containing a trans-1,2-bromoamide with the Br
syn to the hydroxyl groups was obtained in 66% yield. The
stereoselectivity could be attributed to the directing effect of the
bromination by the hydroxyl groups.9 The structures of 2l and
2q were confirmed by an X-ray crystallographic study. These
mild reaction conditions were also suitable for the bromoami-
dation of highly functionalized cholesterol derivative 1r, which
contains O-silyl and ketone groups, to furnish 2r in 82% yield.10
We were also interested in studying whether the reaction is
selective toward unactivated alkenes. A competition experiment
was conducted using a 1:1 mixture of styrene (1a) and
chalcone (3) under the optimized conditions (Scheme 2).
Product 2a was obtained in 66% yield, and the relatively
electron-deficient olefinic system 3 was recovered quantita-
tively. Notably, the other competition reaction between 1a and
phenylacetylene (4) gave bromoamide 2a in 67% yield together
with total recovery of 4, suggesting that this catalyst-free
bromoamidation is highly chemoselective.
To obtain a better understanding on the reaction, particularly
the sole origin of the reactivity, a series of experiments were
performed. First, an 1H NMR study of a mixture of 4-
CF3C6H4SO2NH2 and NBS in CDCl3 was performed. Two
new sets of signals were observed that could be assigned to 4-
CF3C6H4SO2NHBr and 4-CF3C6H4SO2NBr2.11 The signals of
4-CF3C6H4SO2NBr2 disappeared upon the addition of styrene,
whereas the signal intensities for 4-CF3C6H4SO2NHBr
exhibited no significant change. We also attempted to mix 4-
CF3C6H4SO2NH2 and 4-CF3C6H4SO2NBr2 in CDCl3, and
some 4-CF3C6H4SO2NHBr was generated, as indicated by the
1H NMR signals.11,12 This result suggests that the Br in 4-
CF3C6H4SO2NBr2 was readily exchangeable with 4-
CF3C6H4SO2NH2 to give 4-CF3C6H4SO2NHBr. However, we
cannot rule out the possibility that 4-CF3C6H4SO2NHBr might
also be the active species, since attempts to prepare pure 4-
CF3C6H4SO2NHBr were unsuccessful. Nevertheless, a combi-
nation of 4-CF3C6H4SO2NHMe/NBS was used as a mimic of
the monobromide CF3C6H4SO2NHBr in the same reaction
under the optimized conditions with styrene as the substrate. A
significant amount of 4-CF3C6H4SO2NMeBr was detected, but
no bromoamidation of styrene was observed after 24 h
(Scheme 3), which suggests that 4-CF3C6H4SO2NHBr might
not be a good brominating agent. On the basis of these
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DOI: 10.1021/jo502416r
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Note
Scheme 3. Plausible Reaction Mechanism
EXPERIMENTAL SECTION
■
General Information. Commercially available reagents and
solvents were used without further treatment. Tetrahydrofuran
(THF) was freshly distilled from sodium/benzophenone ketyl under
N2 prior to use. CH2Cl2 was freshly distilled from CaH2. Thin-layer
chromatography (TLC) was performed using precoated silica gel foils,
and compounds were visualized with a spray of 5% (w/v)
dodecamolybdophosphoric acid in ethanol and subsequent heating.
Chromatographic purification was performed on silica gel (0.040−
0.063 mm). 1H and 13C NMR spectra were recorded on either a
spectrometer operating at 300 MHz for protons and 75 MHz for
carbon nuclei or a spectrometer operating at 500 MHz for protons and
125 MHz for carbon nuclei. Data for 1H NMR spectra are reported as
follows: chemical shift (δ) in parts per million (multiplicity, coupling
1
constant (Hz), integration). Data for H NMR spectra are referenced
to the center line of CDCl3 (δ 7.26) as the internal standard. Data for
13C NMR spectra are referenced to the center line of CDCl3 (δ 77.0).
High-resolution mass spectra were obtained on a mass spectrometer in
ESI or EI mode using a TOF mass analyzer. Optical rotations were
recorded by the use of a polarimeter and are reported as follows: [α]DT
(c in g per 100 mL, solvent).
Preparation of 1r Using a Literature Procedure.15 To a
solution of trans-dehydroandrosterone (577 mg, 2 mmol, 1.0 equiv)
and imidazole (163 mg, 2.4 mmol, 1.2 equiv) was added tert-
butyldimethylsilyl chloride (317 mg, 2.1 mmol, 1.1 equiv) at 25 °C.
The reaction solution was stirred at 25 °C for 12 h and then quenched
with saturated aqueous NaHCO3. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 3 mL). The
combined organic extracts were washed with brine, dried with MgSO4,
filtered, and concentrated under vacuum. The residue was purified by
flash column chromatography (hexane/EtOAc 12:1 as the eluent) to
yield 1r.
(3S,10R,13S)-3-((tert-Butyldimethylsilyl)oxy)-10,13-dimethyl-
1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta-
[a]phenanthren-17-one (1r). 692 mg, 86%; white solid, mp 151.1−
153.0 °C; IR (KBr) 2949, 2929, 2891, 2859, 1747, 1470, 1379, 1253,
1092, 1007, 888, 870, 837, 774, 668 cm−1; 1H NMR (300 MHz,
CDCl3) δ 5.34 (d, J = 5.1 Hz, 1H), 3.53−3.43 (m, 1H), 2.50−2.41 (m,
1H), 2.31−2.02 (m, 5H), 1.98−1.90 (m, 1H), 1.89−1.78 (m, 2H),
1.75−1.45 (m, 8H), 1.32−1.23 (m, 2H), 1.02 (s, 3H), 0.88 (s, 12H),
0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 163.2, 141.8, 120.4, 72.4,
51.8, 50.3, 47.5, 42.8, 37.3, 36.7, 35.8, 32.0, 31.5, 31.4, 30.8, 25.9, 21.9,
20.3, 19.4, 18.2, 13.5, −4.6; HRMS (ESI) calcd for C25H42NaO2Si m/z
[M + Na]+ 425.2846, found 425.2862; Rf = 0.44 (hexane/EtOAc =
3:1).
observations, it appears that the in situ-generated 4-
CF3C6H4SO2NBr2 might be the active brominating source.13
A plausible reaction mechanism is depicted in Scheme 3. We
speculate that the highly electrophilic brominating species 4-
CF3C6H4SO2NBr2 could be generated in situ through Br
exchange between NBS and 4-CF3C6H4SO2NH2. Indeed, it was
found that the bromoamidation proceeded effectively when 4-
CF3C6H4SO2NBr2 was used. The olefinic substrate 1 could
then be brominated to give bromonium intermediate A.
Subsequent nucleophilic attack on A by 4-CF3C6H4SO2NBr−
in a Markovnikov fashion could give the desired product 2.
We attempted to synthesize morpholine 6 by initial
conversion of 2a into aziridine 5 followed by ring opening
with 2-chloroethanol and cyclization.14 Subsequent deprotec-
tion of 6 with Mg in MeOH gave morpholine 7 in 99% yield
(Scheme 4).
Preparation of N,N-Dibromo-4-(trifluoromethyl)-
benzenesulfonamide Using a Modified Literature Proce-
dure.11 To a suspension of 4-(trifluoromethyl)benzenesulfonamide
(5 g, 22.2 mmol) in water (25 mL) in a 100 mL two-neck flask was
added KOH (3.6 g, 64.2 mmol) at 25 °C. The resultant solution was
stirred vigorously, and bromine (10 g, 62.6 mmol) was added
dropwise. The resulting precipitate was filtered, washed with water,
and dried under vacuum to give N,N-dibromo-4-(trifluoromethyl)-
benzenesulfonamide.
Scheme 4. Synthesis of 7
N,N-Dibromo-4-(trifluoromethyl)benzenesulfonamide. 8.3 g,
1
98%; yellow solid; H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.0
Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
131.8, 126.2.
Preparation of N-Methyl-4-(trifluoromethyl)-
benzenesulfonamide Using a Modified Literature Proce-
dure.16 To a solution of 4-(trifluoromethyl)benzenesulfonyl chloride
(248 mg, 1.0 mmol, 1.0 equiv) and NaOH (48.7 mg, 1.2 mmol, 1.2
equiv) in anhydrous dichloromethane (1 mL) was added methylamine
(0.18 mL, 4.0 mmol, 4.0 equiv) dropwise at 0 °C. The resulting
mixture was stirred for 5 h at 25 °C. Upon completion, the reaction
mixture was diluted with water (2 mL) and extracted with CH2Cl2 (3
× 5 mL). The combined organic extracts were washed with brine (5
mL), dried with MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
In summary, we have developed a catalyst-free bromoami-
dation reaction using 4-(trifluoromethyl)benzenesulfonamide
as the nucleophilic partner and NBS as the halogen source.
Mechanistic studies suggest that 4-CF3C6H4SO2NBr2 was
generated in situ and might be the active halogenating species.
Further mechanistic study is underway.
C
DOI: 10.1021/jo502416r
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The Journal of Organic Chemistry
Note
(hexane/EtOAc 9:1 → 3:1 as the eluent) to yield N-methyl-4-
(trifluoromethyl)benzenesulfonamide.
N-(2-Iodo-1-phenylethyl)-4-(trifluoromethyl)benzenesulfonamide
(2a; R = 4-CF3C6H4SO2, X = I). 58 mg, 58%; yellow solid, mp 138.3−
139.6 °C; IR (KBr) 3261, 1458, 1407, 1326, 1166, 1123, 1060, 928,
844, 709, 609, 431 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J =
8.2 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.26−7.17 (m, 3H), 7.03 (d, J =
7.3 Hz, 2H), 5.33 (d, J = 6.8 Hz, 1H), 4.51 (q, J = 6.8 Hz, 1H), 3.48−
3.39 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.5, 137.7, 134.2 (q,
J = 32.7 Hz), 128.7 (2C), 128.5, 127.6 (4C), 126.4 (2C), 125.9 (q, J =
3.8 Hz), 58.9, 10.3; HRMS (ESI) calcd for C15H13F3INNaO2S m/z [M
+ Na]+ 477.956, found 477.9569; Rf = 0.35 (hexane/EtOAc = 3:1).
N-(2-Bromo-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-
benzenesulfonamide (2b). 77 mg, 80%; white solid, mp 141.7−143.2
°C; IR (KBr) 3246, 2959, 2844, 1613, 1515, 1454, 1322, 1257, 1167,
1128, 1059, 831, 711, 614, 427 cm−1; 1H NMR (500 MHz, CDCl3) δ
7.77 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.5 Hz,
2H), 6.70 (d, J = 8.5 Hz, 2H), 5.31 (d, J = 5.5 Hz, 1H), 4.61 (q, J = 6.0
Hz, 1H), 3.74 (s, 3H), 3.61−3.55 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 159.7, 143.6, 134.2 (q, J = 32.7 Hz), 128.8, 128.0 (4C),
127.7 (2C), 125.9 (q, J = 3.8 Hz), 114.0 (2C), 58.0, 55.2, 36.5; HRMS
(ESI) calcd for C16H1579BrF3NNaO3S m/z [M + Na]+ 459.9800,
found 459.9795; Rf = 0.25 (hexane/EtOAc = 3:1).
N-Methyl-4-(trifluoromethyl)benzenesulfonamide. 186 mg, 78%;
white solid, mp 81.3−83.0 °C; IR (KBr) 3295, 1420, 1328, 1172, 1131,
1
1108, 1061, 1014, 836, 718, 597, 428 cm−1; H NMR (300 MHz,
CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 4.72 (d, J
= 4.2 Hz, 1H), 2.70 (d, J = 5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 127.7, 126.3, 126.3, 29.3; HRMS (ESI) calcd for C8H8F3NNaO2S m/
z [M + Na]+ 262.0120, found 262.0128; Rf = 0.21 (hexane/EtOAc =
3:1).
Representative Procedure for the Catalyst-Free Bromoami-
dation of Olefins. To a solution of 4-trifluoromethylbenzenesulfo-
namide (40.0 mg, 0.18 mmol, 1.0 equiv) in CH2Cl2 (3 mL) in the
absence of light was added styrene (1a) (30.6 μL, 0.27 mmol, 1.5
equiv) and N-bromosuccinimide (47.2 mg, 0.27 mmol, 1.5 equiv) at
25 °C. Upon completion, 0.26 g of silica gel was added, and the
mixture was concentrated under vacuum. The residue was purified by
flash column chromatography (hexane/EtOAc 9:1 → 7:1 as the
eluent) to yield 2a.
N-(2-Bromo-1-phenylethyl)benzenesulfonamide (2a; R = PhSO2,
X = Br). 52 mg, 69%; pale-yellow solid, mp 84.6−86.6 °C; IR (KBr)
3297, 1457, 1421, 1325, 1165, 1091, 938, 835, 752, 719, 701, 685, 604,
N-(2-Bromo-1-(p-tolyl)ethyl)-4-(trifluoromethyl)-
benzenesulfonamide (2c). 85 mg, 92%; white solid, mp 171.5−173.1
°C; IR (KBr) 3245, 1607, 1515, 1455, 1424, 1405, 1342, 1174, 1080,
1
521 cm−1; H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H),
7.52 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.24−7.22 (m, 3H),
7.11−7.09 (m, 2H), 5.20 (d, J = 6.5 Hz, 1H), 4.61 (q, J = 6.0 Hz, 1H),
3.60 (d, J = 6.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 139.9, 137.5,
132.7, 128.9 (2C), 128.6 (2C), 128.3, 127.1 (2C), 126.7 (2C), 58.2,
36.5; HRMS (ESI) calcd for C14H14NNaO2S81Br m/z [M + Na]+
363.9800, found 363.9808; Rf = 0.28 (hexane/EtOAc = 3:1).
N-(2-Bromo-1-phenylethyl)-4-methylbenzenesulfonamide (2a; R
= Ts, X = Br).4 48 mg, 62%; white solid; 1H NMR (300 MHz, CDCl3)
δ 7.63 (d, J = 8.4 Hz, 2H), 7.25−7.19 (m, 5H), 7.13−7.10 (m, 2H),
5.21 (d, J = 6.0 Hz, 1H), 4.58 (q, J = 6.0 Hz, 1H), 3.59 (dd, J = 1.5, 6.0
Hz, 2H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 143.7, 137.6,
136.9, 129.6 (2C), 128.7 (2C), 128.4, 127.2 (2C), 126.7 (2C), 58.0,
36.8, 21.5; HRMS (ESI) calcd for C15H1679BrNNaO2S m/z [M + Na]+
375.9977, found 375.9981; Rf = 0.29 (hexane/EtOAc = 3:1).
1
938, 843, 816, 725, 710, 606, 554, 515, 434 cm−1; H NMR (500
MHz, CDCl3) δ 7.76 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 10.0 Hz, 2H),
6.97 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 7.5 Hz, 2H), 5.38 (d, J = 6.5 Hz,
1H), 4.65−4.61 (m, 1H), 3.63−3.54 (m, 2H), 2.27 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 143.6, 138.6, 134.2 (q, J = 32.7 Hz), 133.9, 129.3
(2C), 127.7 (4C), 126.7 (2C), 125.8 (q, J = 3.8 Hz), 58.3, 36.5, 20.9;
HRMS (ESI) calcd for C16H1579BrF3NNaO2S m/z [M + Na]+
443.9851, found 443.9858; Rf = 0.38 (hexane/EtOAc = 3:1).
N-(2-Bromo-1-(4-fluorophenyl)ethyl)-4-(trifluoromethyl)-
benzenesulfonamide (2d). 86 mg, 92%; white solid, mp 148.1−150.0
°C; IR (KBr) 3247, 2959, 2915, 1606, 1512, 1454, 1407, 1324, 1171,
1060, 1016, 935, 834, 712, 613, 426 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.07 (dd,
J = 13.5, 3.5 Hz, 2H), 6.92−6.89 (m, 2H), 5.32 (d, J = 6.0 Hz, 1H),
4.66 (q, J = 6.0 Hz, 1H), 3.61−3.52 (m, 2H); 13C NMR (125 MHz,
CDCl3) 143.5, 134.5 (q, J = 32.7 Hz), 132.9 (d, J = 2.5 Hz), 128.6,
128.5 (2C), 127.6 (4C), 126.0 (q, J = 3.8 Hz), 115.7 (d, J = 21.4 Hz,
2C), 57.7, 36.3; HRMS (ESI) calcd for C15H1179BrF4NO2S m/z [M −
H]− 423.9635, found 423.9638; Rf = 0.32 (hexane/EtOAc = 3:1).
N-(2-Bromo-1-(naphthalene-2-yl)ethyl)-4-(trifluoromethyl)-
benzenesulfonamide (2e). 80 mg, 80%; yellow solid, mp 123.1−124.8
°C; IR (KBr) 3256, 3060, 2959, 1605, 1454, 1404, 1337, 1166, 1061,
N-(2-Bromo-1-phenylethyl)-4-nitrobenzenesulfonamide (2a; R =
4-Ns, X = Br). 57 mg, 68%; yellow solid, mp 144.1−146.1 °C; IR
(KBr) 3250, 1607, 1531, 1454, 1347, 1313, 1165, 1092, 938, 853, 736,
1
704, 682, 637, 522, 465 cm−1; H NMR (500 MHz, CDCl3) δ 8.17
(dd, J = 1.5, 8.8 Hz, 2H), 7.82 (dd, J = 2.0, 9.0 Hz, 2H), 7.25−7.19 (m,
2H), 7.08 (d, J = 8.5 Hz, 2H), 5.39 (d, J = 6.5 Hz, 1H), 4.73 (q, J = 6.0
Hz, 1H), 3.67−3.57 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 149.9,
145.8, 136.8, 128.8 (2C), 128.8, 128.4 (2C), 126.7 (2C), 124.0 (2C),
58.6, 36.3; HRMS (ESI) calcd for C14H1279BrN2O4S m/z [M − H]−
382.9707, found 382.9704; Rf = 0.26 (hexane/EtOAc = 3:1).
N-(2-Bromo-1-phenylethyl)-3-nitrobenzenesulfonamide (2a; R =
3-Ns, X = Br). 57 mg, 67%; white solid, mp 150.6−152.2 °C; IR (KBr)
3305, 3082, 1604, 1523, 1425, 1353, 1165, 1019, 945, 880, 734, 673,
605, 526 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 8.28 (dd,
J = 1.5, 8.3 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H),
7.19−7.16 (m, 3H), 7.07 (dd, J = 1.5, 7.3 Hz, 2H), 5.45 (broad s, 1H),
4.75 (q, J = 6.0 Hz, 1H), 3.68−3.56 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 147.8, 142.3, 136.6, 132.5, 130.1, 128.8 (2C), 128.7, 126.9,
126.8 (2C), 122.6, 58.7, 36.2; HRMS (ESI) calcd for
C14H1379BrN2NaO4S m/z [M + Na]+ 406.9672, found 406.9669; Rf
= 0.21 (hexane/EtOAc = 3:1).
N - ( 2 - B r o m o - 1 - p h e n y l e t h y l ) - 4 - ( t r i fl u o r o m e t h y l ) -
benzenesulfonamide (2a; R = 4-CF3C6H4SO2, X = Br). 73 mg, 82%;
white solid, mp 114.1−116.1 °C; IR (KBr) 3249, 2961, 1457, 1423,
1407, 1324, 1168, 1132, 1061, 842, 713, 614, 530, 428 cm−1; 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz,
2H), 7.24−7.16 (m, 3H), 7.06 (dd, J = 0.9, 7.7 Hz, 2H), 5.37 (d, J =
6.6 Hz, 1H), 4.68 (q, J = 6.3 Hz, 1H), 3.67−3.54 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 143.5, 136.9, 134.3 (q, J = 32.7 Hz), 128.7 (2C),
128.6, 127.6 (4C), 126.7 (2C), 125.9 (q, J = 3.7 Hz), 58.5, 36.3;
HRMS (ESI) calcd for C15H1279BrF3NO2S m/z [M − H]− 405.9730,
found 405.9730; Rf = 0.35 (hexane/EtOAc = 3:1).
1
937, 940, 750, 712, 677, 612, 475, 429 cm−1; H NMR (300 MHz,
CDCl3) δ 7.76−7.73 (m, 2H), 7.66−7.61 (m, 2H), 7.51−7.46 (m,
2H), 7.41 (d, J = 8.1 Hz, 2H), 7.13 (dd, J = 1.5, 6.9 Hz, 1H), 5.84 (d, J
= 6.9 Hz, 1H), 4.86 (q, J = 6.3 Hz, 1H), 3.69−3.67 (m, 2H); 13C
NMR (75 MHz, CDCl3) 143.4, 134.7, 134.1 (q, J = 33.2 Hz), 134.0,
132.9, 132.7, 128.7, 127.7, 127.6 (2C), 126.7 (2C), 126.6, 125.7 (q, J =
3.8 Hz), 123.6, 58.8, 35.9; HRMS (ESI) calcd for C19H1479BrF3NO2S
m/z [M − H]− 455.9886, found 455.9882; Rf = 0.36 (hexane/EtOAc
= 3:1).
N-(1-Bromo-2-phenylpropan-2-yl)-4-(trifluoromethyl)-
benzenesulfonamide (2f). 66 mg, 71%; white solid, mp 155.6−158.6
°C; IR (KBr) 3262, 1448, 1421, 1381, 1323, 1166, 1139, 1063, 989,
844, 712, 608, 554, 430 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.71 (d,
J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.25−7.21 (m, 3H), 7.19−
7.18 (m, 2H), 5.41 (broad s, 1H), 3.95 (d, J = 11.0 Hz, 1H), 3.68 (d, J
= 11.0 Hz, 1H), 1.80 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.4,
139.5, 133.9 (q, J = 3.3 Hz), 128.4 (4C), 128.1, 127.5 (2C), 126.4
(2C), 125.8 (q, J = 3.8 Hz), 60.8, 43.4, 25.7; HRMS (ESI) calcd for
C16H1579BrF3NNaO2S m/z [M + Na]+ 443.9851, found 443.9853; Rf =
0.41 (hexane/EtOAc = 3:1).
N-(2-Bromo-1-phenylpropyl)-4-(trifluoromethyl)-
benzenesulfonamide (2g). 68 mg, 73%; white solid, mp 136.4−138.4
°C; IR (KBr) 3281, 2919, 1495, 1405, 1336, 1172, 1061, 913, 841,
1
712, 611, 429 cm−1; H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.5
D
DOI: 10.1021/jo502416r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 7.25 Hz, 1H), 7.12−7.09
(m, 2H), 7.01 (d, J = 7.5 Hz, 2H), 5.92 (d, J = 9.0 Hz, 1H), 4.58 (q, J
= 4.5 Hz, 1H), 4.48−4.43 (m, 1H), 1.55 (d, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 143.5, 135.1, 134.0 (q, J = 32.7 Hz),
128.3, 128.1 (4C), 127.8 (2C), 127.5 (2C), 125.7 (q, J = 3.8 Hz), 62.6,
53.3, 22.2; HRMS (ESI) calcd for C16H1579BrF3NNaO2S m/z [M +
Na]+ 443.9851, found 443.9848; Rf = 0.37 (hexane/EtOAc = 3:1).
N-(2-Bromo-1,2-diphenylethyl)-4-(trifluoromethyl)-
benzenesulfonamide (2h). 61 mg, 57%; yellow solid, mp 168.2−169.8
°C; IR (KBr) 3280, 1456, 1419, 1326, 1166, 1130, 1063, 839, 699,
(d, J = 8.5 Hz, 2H), 4.87 (d, J = 5.5 Hz, 1H), 3.79 (td, J = 4.0, 10.5 Hz,
1H), 3.22−3.20 (m, 1H), 2.36−2.30 (m, 2H), 1.80 (qd, J = 3.5, 11.5
Hz, 1H), 1.72−1.68 (m, 2H), 1.56 (m, 1H), 1.37−1.25 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 143.7, 134.4 (q, J = 34.0 Hz), 127.9 (4C),
126.1 (q, J = 3.8 Hz), 59.4, 54.8, 36.4, 34.0, 25.7, 23.8; HRMS (ESI)
calcd for C13H1579BrF3NNaO2S m/z [M + Na]+ 407.9851, found
407.9863; Rf = 0.33 (hexane/EtOAc = 3:1).
N-(2-Bromocycloheptyl)-4-(trifluoromethyl)benzenesulfonamide
(2n). 80 mg, 91%; white solid, mp 108.5−110.0 °C; IR (KBr) 3249,
2926, 2860, 1455, 1404, 1324, 1161, 1142, 1061, 940, 863, 841, 714,
657, 630, 599, 426 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J =
8.0 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 4.94 (d, J = 6.5 Hz, 1H), 3.99
(td, J = 3.5, 7.5 Hz, 1H), 3.52−3.50 (m, 1H), 2.17−2.05 (m, 2H),
1.67−1.61 (m, 5H), 1.54−1.49 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 143.6, 134.4 (q, J = 32.7 Hz), 127.9 (4C), 126.1 (q, J = 3.8
Hz), 62.9, 58.3, 35.0, 32.2, 27.2, 24.0, 22.9; HRMS (ESI) calcd for
C14H1779BrF3NNaO2S m/z [M + Na]+ 422.0008, found 422.0016; Rf =
0.34 (hexane/EtOAc = 3:1).
1
610, 534, 430 cm−1; H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.1
Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.28−7.22 (m, 3H), 7.17−7.04 (m,
5H), 6.67 (d, J = 7.5 Hz, 2H), 5.21−5.17 (m, 2H), 4.91−4.86 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 143.4, 136.7, 135.9, 129.0, 128.6,
128.5, 128.3, 128.2, 128.0, 127.9, 127.5, 127.4, 125.6 (q, J = 3.8 Hz),
63.3, 57.3; HRMS (ESI) calcd for C21H1779BrF3NNaO2S m/z [M +
Na]+ 506.0008, found 506.0007; Rf = 0.35 (hexane/EtOAc = 3:1).
N-(3R,4R)-(4-Bromohexan-3-yl)-4-(trifluoromethyl)-
benzenesulfonamide (2i). 78 mg, 92%; white solid, mp 85.2−87.2 °C;
IR (KBr) 3276, 2974, 1462, 1420, 1323, 1182, 1063, 1001, 906, 843,
N-(2-Bromocyclooctyl)-4-(trifluoromethyl)benzenesulfonamide
(2o). 84 mg, 92%; white solid, mp 110.1−112.1 °C; IR (KBr) 3251,
2930, 2870, 1445, 1404, 1322, 1166, 1060, 842, 811, 713, 668, 640,
1
711, 609, 430 cm−1; H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.1
1
599, 426 cm−1; H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.5 Hz,
Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 4.76 (d, J = 9.6 Hz, 1H), 4.02−3.97
(m, 1H), 3.35−3.31 (m, 1H), 1.82−1.45 (m, 4H), 0.98 (t, J = 7.2 Hz,
3H), 0.76 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 145.0,
134.3 (q, J = 32.7 Hz), 127.3 (4C), 126.2 (q, J = 3.8 Hz), 62.1, 59.3,
29.3, 27.8, 12.5, 10.4; HRMS (ESI) calcd for C13H1779BrF3NNaO2S
m/z [M + Na]+ 410.0008, found 410.0014; Rf = 0.47 (hexane/EtOAc
= 3:1).
2H), 7.79 (d, J = 8.0 Hz, 2H), 4.85 (d, J = 5.0 Hz, 1H), 4.05−4.01 (m,
1H), 3.56−3.51 (m, 1H), 2.29−2.23 (m, 1H), 2.15−2.10 (m, 1H),
2.06−1.99 (m, 1H), 1.82−1.63 (m, 5H), 1.56−1.49 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 143.3, 134.4 (q, J = 32.7 Hz), 128.0 (4C),
126.0 (q, J = 3.8 Hz), 61.5, 59.1, 32.4, 32.4, 25.6, 25.4, 25.4, 25.0;
HRMS (ESI) calcd for C15H1979BrF3NNaO2S m/z [M + Na]+
436.0164, found 436.0169; Rf = 0.38 (hexane/EtOAc = 3:1).
N-(2-Bromo-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethyl)-
benzenesulfonamide (2p).5f 79 mg, 86%; white solid, mp 160.4−
162.1 °C; IR (KBr) 3271, 2960, 1467, 1338, 1163, 1067, 934, 840,
736, 715, 615, 547, 430 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.11 (d,
J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.32−7.29 (m, 1H), 7.24−
7.18 (m, 3H), 5.01−4.98 (m, 1H), 4.93 (d, J = 8.5 Hz, 1H), 4.25 (q, J
= 6.5 Hz, 1H), 3.55 (dd, J = 7.0, 16.5 Hz, 1H), 3.21 (dd, J = 6.5, 16.5
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 144.0, 139.9, 139.0, 134.6 (q,
J = 32.5 Hz), 129.4, 127.9 (4C), 127.9, 126.3 (q, J = 3.8 Hz), 124.7,
124.3, 67.3, 31.2, 40.9; HRMS (ESI) calcd for C16H1279BrF3NO2S m/z
[M − H]− 417.9730, found 417.9729; Rf = 0.43 (hexane/EtOAc =
3:1).
N-(3R,4S)-(4-Bromohexan-3-yl)-4-(trifluoromethyl)-
benzenesulfonamide (2j). 84 mg, 99%; white solid, mp 81.3−82.9 °C;
IR (KBr) 3291, 2971, 1462, 1418, 1320, 1173, 1062, 1012, 844, 712,
1
617, 541, 429 cm−1; H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.5
Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 4.90 (d, J = 10.0 Hz, 1H), 3.90−
3.86 (m, 1H), 3.23 (tt, J = 3.0, 9.9 Hz, 1H), 1.79−1.75 (m, 2H), 1.61−
1.47 (m, 3H), 0.98 (t, J = 7.0 Hz, 3H), 0.78 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 144.7, 134.4 (q, J = 33.2 Hz), 127.4 (4C),
126.2 (q, J = 3.7 Hz), 64.9, 59.5, 29.1, 23.1, 12.7, 10.2; HRMS (ESI)
calcd for C13H1779BrF3NNaO2S m/z [M + Na]+ 410.0008, found
410.0005; Rf = 0.54 (hexane/EtOAc = 3:1).
N-(1-Bromooctan-2-yl)-4-(trifluoromethyl)benzenesulfonamide
(2k) and N-(2-Bromooctyl)-4-(trifluoromethyl)benzenesulfonamide
(2k′). 50 mg, 55% (2k:2k′ = 1:1); yellow solid, mp 60.9−62.0 °C; IR
(KBr) 3300, 2931, 2857, 1407, 1324, 1171, 1133, 1109, 1063, 842,
712, 603, 430 cm−1; 1H NMR (CDCl3, 500 MHz) (1) 2k δ 8.03−8.00
(m, 2H), 7.81−7.79 (m, 2H), 5.12 (t, J = 6.2 Hz, 1H), 4.02−3.97 (m,
1H), 3.47−3.37 (m, 2H), 1.77 (q, J = 7.5 Hz, 2H), 1.30−1.25 (m,
4H), 1.21−1.14 (m, 4H), 0.89−0.82 (m, 3H); (2) 2k′ δ 8.03−8.00
(m, 2H), 7.81−7.79 (m, 2H), 4.93 (d, J = 8.7 Hz, 1H), 3.47−3.37 (m,
2H), 3.25−3.19 (m, 1H), 1.57−1.44 (m, 3H), 1.30−1.25 (m, 4H),
1.21−1.14 (m, 3H), 0.89−0.82 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 144.4, 143.6, 134.6 (q, J = 34.0 Hz), 134.5 (q, J = 34.0 Hz),
127.5 (8C), 126.4 (q, J = 3.8 Hz), 126.3 (q, J = 3.8 Hz), 55.3, 53.7,
49.6, 38.1, 36.0, 33.6, 31.5, 28.6, 28.5, 27.2, 25.3, 22.5, 22.4, 14.0, 13.9;
HRMS (ESI) calcd for C15H2179BrF3NNaO2S m/z [M + Na]+
438.0326, found 438.0333; Rf = 0.52 (hexane/EtOAc = 3:1).
N-((3S, 5R)-2-Bromo-3, 5-dihydroxycyclopentyl)-4-
(trifluoromethyl)benzenesulfonamide (2q). 59 mg, 66%; white solid,
mp 116.7−117.9 °C; [α]2D5 −9.8 (c 1.0, MeOH); IR (KBr) 3358, 2978,
2924, 1718, 1599, 1456, 1396, 1298, 1231, 1150, 1113, 965, 843, 812,
1
694, 598, 534 cm−1; H NMR (500 MHz, MeOD) δ 8.10 (d, J = 8.5
Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 3.98−3.96 (m, 1H), 3.91−3.83 (m,
3H), 2.36−2.30 (m, 1H), 1.77−1.73 (m, 1H); 13C NMR (125 MHz,
MeOD) δ 147.2, 134.8 (q, J = 32.7 Hz), 129.1 (4C), 127.1 (q, J = 3.8
Hz), 75.5, 71.0, 69.3, 58.2, 40.5; HRMS (ESI) calcd for
C12H1379BrF3NNaO4S m/z [M + Na]+ 425.9593, found 425.9596; Rf
= 0.34 (CHCl3/MeOH = 8:1).
N-((3S,10R,13S)-5-Bromo-3-((tert-butyldimethylsilyl)oxy)-10,13-
dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-6-
yl)-4-(trifluoromethyl)benzenesulfonamide (2r). 127 mg, 82%; white
solid, mp 150.1−152.1 °C; [α]2D5 −4.5 (c 1.0, CHCl3); IR (KBr) 2952,
2859, 1741, 1472, 1444, 1406, 1324, 1254, 1171, 1139, 1096, 867, 836,
777, 713, 606, 429 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J =
8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 5.92 (d, J = 9.6 Hz, 1H), 4.31−
4.29 (m, 1H), 3.75−3.73 (m, 1H), 2.41−2.32 (dd, J = 7.8, 19.1 Hz,
1H), 2.27−2.19 (m, 2H), 2.05−2.03 (m, 1H), 1.99−1.89 (m, 1H),
1.76−1.71 (m, 3H), 1.64−1.53 (m, 6H), 1.31−1.22 (m, 8H), 0.86 (s,
9H), 0.78 (s, 3H), 0.02 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
143.7, 134.7 (q, J = 34.0 Hz), 127.8 (4C), 126.4, 86.7, 69.1, 60.3, 58.2,
50.0, 47.7, 47.3, 43.3, 41.1, 36.0, 35.5, 31.1, 31.0, 30.6, 30.1, 25.7 (3C),
21.2, 20.3, 18.4, 18.0, 14.1, 13.7, −4.8, −4.8; HRMS (ESI) calcd for
C32H4779BrF3NNaO4SSi m/z [M + Na]+ 728.2023, found 728.2036; Rf
= 0.27 (hexane/EtOAc = 3:1).
N-(2-Bromocyclopentyl)-4-(trifluoromethyl)benzenesulfonamide
(2l). 80 mg, 98%; white solid, mp 123.8−125.6 °C; IR (KBr) 3270,
2974, 1450, 1406, 1322, 1170, 1139, 1061, 922, 839, 712, 602, 558,
1
493, 430 cm−1; H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.1 Hz,
2H), 7.81 (d, J = 8.4 Hz, 2H), 5.19 (d, J = 6.3 Hz, 1H), 4.05 (q, J = 6.0
Hz, 1H), 3.72 (quintet, J = 6.0 Hz, 1H), 2.30−2.17 (m, 2H), 2.01−
1.92 (m, 1H), 1.87−1.67 (m, 2H), 1.50−1.40 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 143.5, 134.6 (q, J = 33.2 Hz), 127.8 (4C), 126.4 (q, J
= 3.8 Hz), 63.2, 53.5, 34.0, 30.9, 21.3; HRMS (ESI) calcd for
C12H1379BrF3NNaO2S m/z [M + Na]+ 393.9695, found 393.9707; Rf =
0.35 (hexane/EtOAc = 3:1).
N-(2-Bromocyclohexyl)-4-(trifluoromethyl)benzenesulfonamide
(2m). 38 mg, 45%; white solid, mp 137.1−138.8 °C; IR (KBr) 3270,
2937, 1451, 1405, 1329, 1166, 1090, 1060, 841, 715, 624, 551, 432
Synthesis of 2-Phenylmorpholine (7).14,17 The formation of
aziridine 5 was effected by treatment of bromoamide 2a (820 mg,
1
cm−1; H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 2H), 7.79
E
DOI: 10.1021/jo502416r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2.01 mmol, 1 equiv) in CH2Cl2 (35 mL) with KOH (451 mg, 8.04
mmol, 4 equiv). The resulting mixture was stirred for 0.5 h at 25 °C.
After completion of the reaction as monitored by TLC, the solvent was
removed under reduced pressure, and the residue was chromato-
graphed on silica gel, eluting with hexane/EtOAc 6:1, to yield 2-
phenyl-1-(4-(trifluoromethyl)phenylsulfonyl)aziridine (5).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank ASTAR-Public Sector Funding (Grant 143-000-536-
305) and GSK-EDB (Grant 143-000-564-592) for financial
support. We are also thankful for the scholarships to W.Z.Y.
(NUS Research Scholarship) and Y.A.C. (NGS Research
Scholarship).
The synthesis of morpholine 6 was effected by adding anhydrous
copper(II) triflate (101 mg, 0.28 mmol, 0.2 equiv) to a solution of 5
(456 mg, 1.39 mmol, 1 equiv) in 2-chloroethanol (0.94 mL, 13.9
mmol, 10 equiv) at 0 °C under a nitrogen atmosphere and stirring for
0.5 h. The reaction mixture was then diluted with anhydrous DMF
(13.9 mL), and LiOH·H2O (175 mg, 4.18 mmol, 3 equiv) was added.
After 1 h of stirring at 25 °C, the reaction mixture was quenched with
saturated aqueous sodium bicarbonate solution (30 mL) and extracted
with EtOAc (3 × 30 mL). The combined organic extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated. The residue
was chromatographed on silica gel, eluting with hexane/EtOAc 6:1, to
yield 2-phenyl-4-(4-(trifluoromethyl)phenylsulfonyl)morpholine (6).
Deprotection of the sulfonyl group was effected by adding 6 (37
mg, 0.1 mmol, 1 equiv) to a suspension of Mg (24 mg, 1.0 mmol, 10
equiv) in MeOH (1 mL) under N2. The resulting suspension was
stirred vigorously for 12 h at 25 °C. The reaction mixture was then
quenched with aqueous HCl (10%, 5 mL) and diluted with CH2Cl2
(2.5 mL). The aqueous phase was washed with CH2Cl2 (5 mL). The
resulting mixture was adjusted to pH 9 by the addition of Na2CO3 and
saturated aqueous NaHCO3. The resulting mixture was extracted with
CH2Cl2 (2 × 5 mL), dried over Na2SO4, filtered, and concentrated to
yield 2-phenylmorpholine (7).
REFERENCES
■
(1) Kemp, J. E. G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 3, pp
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(2) (a) Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706.
(b) Gribble, G. W. In The Alkaloids; Knolker, H.-J., Ed.; Elsevier:
London, 2012; Vol. 71, pp 1−165.
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(3) For reviews, see: (a) Chemler, S. R.; Bovino, M. T. ACS Catal.
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G.; Kotti, S. R. S. S.; Timmons, C. Eur. J. Org. Chem. 2007, 2745. For
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2-Phenyl-1-(4-(trifluoromethyl)phenylsulfonyl)aziridine (5). 456
mg, 70%; white solid, mp 115.8−117.4 °C; IR (KBr) 1408, 1326,
1
1167, 1062, 914, 847, 803, 753, 699, 617, 568, 429 cm−1; H NMR
(500 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz,
2H), 7.33−7.31 (m, 3H), 7.24−7.22 (m, 2H), 3.88 (dd, J = 4.5, 14.0
Hz, 1H), 3.07 (d, J = 7.0 Hz, 1H), 2.47 (d, J = 4.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 141.8, 135.3 (q, J = 32.7 Hz), 134.4, 128.7 (4C),
128.6, 128.4 (2C), 126.5 (2C), 126.3 (q, J = 3.8 Hz), 41.6, 36.4;
HRMS (ESI) calcd for C15H13F3NO2S m/z [M + H]+ 328.0614, found
328.0615; Rf = 0.47 (hexane/EtOAc = 3:1).
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2010, 51, 987.
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7. (c) Curzons, A. D.; Constable, D. J. C.; Mortimer, D. N.;
Cunningham, V. L. Green Chem. 2001, 3, 1. (d) Constable, D. J. C.;
Curzons, A. D.; Cunningham, V. L. Green Chem. 2002, 4, 521.
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(b) Zhou, J.; Yeung, Y.-Y. Org. Lett. 2014, 16, 2134. (c) Zhou, J.;
Yeung, Y.-Y. J. Org. Chem. 2014, 79, 4644. (d) Tay, D. W.; Tsoi, I. T.;
Er, J. C.; Leung, G. Y. C.; Yeung, Y.-Y. Org. Lett. 2013, 15, 1310.
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2-Phenyl-4-(4-(trifluoromethyl)phenylsulfonyl)morpholine (6).
408 mg, 79%; white solid, mp 135.0−137.0 °C; IR (KBr) 1453,
1407, 1356, 1324, 1170, 1130, 1062, 969, 743, 706, 594, 551, 429
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 2H), 7.80
(d, J = 8.5 Hz, 2H), 7.36−7.30 (m, 5H), 4.61 (dd, J = 21.0, 2.5 Hz,
1H), 4.10 (dd, J = 3.5, 24.0 Hz, 1H), 3.87 (td, J = 2.6, 23.3 Hz, 1H),
3.81 (d, J = 11.6, 1H), 3.69 (d, J = 11.0, 1H), 2.56 (td, J = 3.4, 23.1 Hz,
1H), 2.29 (t, J = 10.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 139.0,
138.3, 134.7 (q, J = 32.8 Hz), 128.5 (4C), 128.4, 128.2 (2C), 126.3 (q,
J = 3.5 Hz), 125.9 (2C), 66.1, 51.8, 45.3; HRMS (ESI) calcd for
C17H16F3NNaO3S m/z [M + Na]+ 394.0695, found 394.0698; Rf =
0.38 (hexane/EtOAc = 3:1).
2-Phenylmorpholine (7).8i 16 mg, 99%; colorless oil; 1H NMR
(500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 4.49 (dd, J = 2.5, 20.2 Hz,
1H), 4.04 (d, J = 11.0 Hz, 1H), 3.78 (td, J = 3.0, 22.5 Hz, 1H), 3.07 (d,
J = 12.0 Hz, 1H), 3.01 (td, J = 2.5, 24.0 Hz, 1H), 2.90 (d, J = 12.0 Hz,
1H), 2.80 (t, J = 10.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 140.2,
128.4, 127.8, 126.0, 79.1, 68.1, 52.8, 45.4; MS (ESI) [M + H]+ 164.1;
Rf = 0.18 (EtOAc/MeOH/NH4OH = 9:1:0.1).
ASSOCIATED CONTENT
■
S
* Supporting Information
CIF files of 2a, 2b, 2g, 2l, 2q, and 5 and NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(9) Yeung, Y.-Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
9644.
(10) The anti-Markovnikov product 2r was obtained exclusively. We
AUTHOR INFORMATION
■
Corresponding Author
*Email: chmyyy@nus.edu.sg.
speculate that the bromination of 1r might take place at the less
F
DOI: 10.1021/jo502416r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
hindered α-face, followed by antiperiplanar attack by the sulfonamide
to yield the more favorable 2r.
(11) For details, see the Supporting Information.
(12) Pure 4-CF3C6H4SO2NBr2 was prepared using a literature
procedure. For details, see: Tajbakhsh, M.; Khazaei, A.; Mahalli, M. S.;
Vaghi, R. G. Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, 1159.
(13) Dihalosulfonamides have been reported to be good stoichio-
metric electrophilic halogen sources. For examples, see: (a) Kharasch,
M. S.; Priestley, H. M. J. Am. Chem. Soc. 1939, 61, 3425. (b) Ueno, Y.;
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S.; Ueno, Y. Chem. Pharm. Bull. 1975, 23, 640. (g) Terauchi, H.;
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556.
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G
DOI: 10.1021/jo502416r
J. Org. Chem. XXXX, XXX, XXX−XXX