A Synthetic Route to 2-Alkyl Indoles via Thiophenol-Mediated Ring-Opening of N-Tosylaziridines Followed by Copper Powder-Mediated C-N Cyclization/Aromatization

Article abstract of DOI:10.1021/acs.joc.5b02251

A simple strategy for the syntheses of 2-alkyl indoles via regioselective ring-opening of 2-(2-haloaryl)-3-alkyl-N-tosylaziridines with thiophenol, followed by copper powder-mediated intramolecular C-N cyclization and subsequent aromatization by the elimi

Full text of DOI:10.1021/acs.joc.5b02251

Note
pubs.acs.org/joc
A Synthetic Route to 2‑Alkyl Indoles via Thiophenol-Mediated Ring-
Opening of N‑Tosylaziridines Followed by Copper Powder-Mediated
C−N Cyclization/Aromatization
Masthanvali Sayyad, Yerramsetti Nanaji, and Manas K. Ghorai*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: A simple strategy for the syntheses of 2-alkyl
indoles via regioselective ring-opening of 2-(2-haloaryl)-3-
alkyl-N-tosylaziridines with thiophenol, followed by copper
powder-mediated intramolecular C−N cyclization and sub-
sequent aromatization by the elimination of thiophenol, with
good yields is described. Utilizing this protocol, 2-carbox-
yindole has been synthesized easily.
ndoles are one of the most valuable and hence desired
heterocyclic scaffolds in organic and medicinal chemistry. To
straightforward strategy for the synthesis of 2-substituted
indoles via SN2-type ring-opening of 2-(2-haloaryl)-N-activated
aziridines with thiophenol, followed by Cu-mediated C−N
cyclization/aromatization (Scheme 1). Herein, we report our
results as a Note.
To realize our idea, initially, we studied the reaction of 2-(2-
bromophenyl)-1-tosylaziridine 3a with thiophenol in the
presence of K2CO3 in toluene at 90 °C, and the ring-opening
product 4a was obtained in 95% yield as a single regioisomer
(Scheme 2).8h
The compound 4a was subjected to C−N cyclization with
copper powder (1.0 equiv) in DMF at 120 °C for 8 h, and
indole 5a was obtained in 65% yield along with indoline 6a in
25% yield (Table 1, entry 1). To find out the optimized
reaction conditions for the exclusive formation of 5a, the ring-
opening product 4a was subjected to C−N cyclization and
subsequent aromatization with different Cu catalysts and
ligands. The optimization results are summarized in Table 1.
The best result was obtained with a super stoichiometric
amount of copper powder (2.0 equiv) in DMF at 120 °C
(Table 1, entry 4), where the expected product 5a was obtained
in 85% yield as the only product. It is worth mentioning that
thiophenol was recovered back completely during column
chromatographic purification of the indole product 5a.
To establish our strategy as a practical and useful general
synthetic methodology for this purpose, a one-pot (stepwise)
protocol for the synthesis of indole 5a from 3a was explored.
When aziridine 3a was treated with PhSH, followed by Cu
powder under the reaction conditions as shown in Scheme 3,
the expected indole 5a was obtained in 82% yield.
I
date, more than 4000 indole alkaloids have been isolated from
different natural sources; many of them are of immense
biological, pharmacological, and synthetic importance.1 Some
of the natural products and other commercial drug molecules
containing an indole skeleton as the key molecular framework,
e.g., Birnbaumin A, Meridianin C, Apaziquone, Indomethacin,
Fluvastatin, etc., are shown in Figure 1. Because of the
biological relevance and chemical versatility of indole hetero-
cycles, development of their practical synthetic routes has been
extensively explored over the years.2 Although the classical
“Fischer indole synthesis” is a unique method for the large-scale
production of a variety of indoles,3 a number of other
interesting protocols based on metal catalysis were introduced
in the literature.4,5 Although 2-alkyl indoles can be easily
obtained via alpha lithiation of indoles,5e it is difficult to make
halogenated 2-alkyl indoles via the same route. In this context,
an interesting protocol to 2-alkyl indoles via Pd-catalyzed C−H
activation of indole has recently been developed by Bach et al.5f
Although the synthesis of indoles from azirines is well-known,6
to the best of our knowledge, no such synthetic route to indoles
from aziridines has been reported in the literature so far.
Recently, we have developed a simple route for the synthesis of
3-heteroatom substituted-indolines via ring-opening of 2-(2-
haloaryl)-N-tosylaziridines with various heteroatomic nucleo-
philes including thiophenol, followed by C−N cyclization.7
Inspired by our results, we envisioned that 2-substituted indoles
can easily be synthesized from the ring-opening of 2-(2-
haloaryl)-N-activated aziridines with thiophenol, followed by
metal-catalyzed C−N cyclization and simultaneous aromatiza-
tion via elimination of thiophenol. Several interesting strategies
are known for the ring-opening of aziridines with sulfur atomic
nucleophiles8 and other nucleophiles.9 In recent time, copper-
catalyzed C−N cyclization has become a powerful tool in
organic synthesis.8h,10,11 In continuation of our research
activities in this area, we have developed a simple and
To demonstrate the scope of our strategy, it was further
extended for the synthesis of 2-methyl indole 5b from the ring-
opening of an inseparable mixture (1:1) of cis and trans isomers
of 2-(2-bromophenyl)-3-methyl-1-tosylaziridine 3b with thio-
Received: September 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02251
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The Journal of Organic Chemistry
Note
Figure 1. Indole core structure containing commercial drugs and natural products.
was found to be consumed after 12 h. The reaction was
continued for another 12 h; however, no further progress of the
reaction could be noted. We could isolate the ring-opening
product 4b along with the unreacted aziridine 3b as a pure cis
isomer12 (Scheme 4). Trans disubstituted aziridines are more
Scheme 1. Proposed Reaction Pathway
Scheme 4. Regioselective Ring-Opening of 3b
Scheme 2. Regioselective Ring-Opening of 3a
Table 1. Optimization Study
reactive than the cis isomer due to steric reasons, and under
basic conditions, only the trans isomer reacted and the cis
isomer was recovered completely.
To overcome this problem, we explored the LA (Lewis acid)-
catalyzed ring-opening of aziridines (as a mixture of both cis
and trans isomers) with thiophenol. Various Lewis acids were
screened for the ring-opening of aziridine 3b (1:1 mixture of cis
and trans isomers) with thiophenol, and the results are shown
in Table 2. The best result was obtained with BF3·OEt2 (15 mol
%) in CH2Cl2 for 2 h, and the ring-opening product 4b was
obtained in 94% yield with dr 4:1 (Table 2, entry 2). LA-
catalyzed ring-opening of disubstituted aziridines by thiophenol
follows an SN2-pathway. Under acidic conditions, starting from
aziridine 3b (trans/cis 1:1), the ring-opening product 4b was
obtained with enhanced dr (trans/cis 4:1) in 94% yield. The
5a yield 6a yield
a
entry
reaction conditions
(%)
(%)
1
2
3
4
Cu powder (1.0 equiv), DMF, 120 °C, 8 h
Cu powder (1.0 equiv), DMF, 90 °C, 7 h
CuI (1.0 equiv), DMF, 120 °C, 1 h
Cu powder (2.0 equiv), DMF, 120 °C, 4 h
CuI, ligand L1, K2CO3, DMF, 120 °C, 5 h
CuI, ligand L2, K2CO3, DMF, 120 °C, 5 h
CuI, ligand L3, K2CO3, DMF, 120 °C, 5 h
65
0
25
87
90
0
0
85
0
b
5
80
85
84
b
6
b
0
7
0
a
All reactions were carried out with 4a (0.2 mmol), N,N-
Table 2. Optimization Study of Ring-Opening Product 4b
dimethylformamide (DMF) (1.0 mL), in solvent under an argon
atmosphere. CuI (10 mol %), L1, L2, and L3 (20 mol %), K2CO3 (1.0
b
equiv). L1 = ( )-trans-1,2-diaminocyclohexane, L2 = L-proline, L3 =
ethylenediamine.
Scheme 3. Synthesis of Indole 5a
entry
Lewis acids
time (h)
yield (%)
1
2
3
4
5
BF3·OEt2 (10 mol %)
BF3·OEt2 (15 mol %)
Cu(OTf)2 (15 mol %)
Sc(OTf)3 (15 mol %)
Zn(OTf)2 (15 mol %)
3
2
90
94
65
67
55
24
24
24
phenol at 90 °C in toluene. Under the optimized conditions,
when aziridine 3b was reacted, only 50% of the starting material
B
DOI: 10.1021/acs.joc.5b02251
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The Journal of Organic Chemistry
Note
observed enhanced diastereoselectivity of 4b is probably due to
epimerization of the benzylic carbon center from the unreacted
cis isomer of 3b during the reaction. This could be possible as
the epimerization would lead to the formation of the more
stable trans isomer of 3b.
followed by copper powder-mediated C−N cyclization/
aromatization, were studied, and the corresponding 2-alkyl
indoles 5a,c−p were obtained with good yields (Table 3). It is
needless to mention that, in all the cases, thiophenol was
recovered back completely.
Next, we intended to apply both the optimization conditions
(Tables 1 and 2) for the one-pot synthesis of 2-methyl indole
5b from aziridine 3b. To our great pleasure, the strategy
worked well and the expected product 5b was obtained in 73%
yield (Scheme 5).
For wider applicability of our protocol in terms of substrate
scope, indole functionalized with a carbethoxy group at the 2-
position (10) was synthesized from ethyl 3-(2-chlorophenyl)-1-
tosylaziridine-2-carboxylate in good yield (Scheme 6).
Scheme 6. Synthesis of 2-Ethyl Carboxylate Indole 10
Scheme 5. Synthesis of 2-Methyl Indole 5b
Encouraged by this result, the reactions of several
disubstituted aziridines (as a mixture of cis and trans isomers)
and several monosubstituted aziridines with thiophenol,
We believe that the copper powder-mediated C−N
cyclization follows our earlier proposed mechanism.8h Most
probably, the final aromatization step follows Cu(I)-mediated
Table 3. Synthesis of 2-Alkyl Indoles and Indoles Derivatives
C
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Note
(neat, cm−1): 3281, 3059, 2923, 2854, 1597, 1470, 1438, 1329, 1159,
1092, 1024, 813, 691, 663, 551; H NMR (500 MHz, CDCl3) δ 2.42
desulfonylation via the formation of an intermediate cationic
1
thioether species D (Scheme 7).13
(s, 3H) 3.30−3.36 (m, 1H), 3.42−3.47 (m, 1H), 4.65 (t, J = 7.4 Hz,
1H), 4.82 (t, J = 6.4 Hz, 1H), 7.08−7.15 (m, 2H), 7.18−7.25 (m, 5H),
7.52 (dd, J = 8.0, 1.3 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 21.7, 46.1, 51.2, 124.8, 127.2, 127.9, 128.1,
128.7, 129.1, 129.5, 129.9, 132.5, 132.9, 133.4, 136.8, 137.4, 143.6;
HRMS (ESI) calcd for C21H21BrNO2S2 (M + H)+ 462.0197, found
462.0199.
Scheme 7. Plausible Mechanism
N-(1-(2-Bromophenyl)-1-(phenylthio)propan-2-yl)-4-methyl-
benzenesulfonamide (4b). Obtained only trans isomer 4b in 47%
yield under basic conditions: IR νmax (neat, cm−1): 3210, 3015 2923,
1594, 1560, 1478, 1376, 1228, 1185, 1163, 1093, 1051, 982, 910, 865,
815, 731, 690, 664, 576, 557; 1H NMR (500 MHz, CDCl3): δ 1.13 (d,
J = 6.9 Hz, 3H), 2.36 (s, 3H), 3.83−3.90 (m, 1H), 4.75 (d, J = 4.6 Hz,
1H), 5.02 (d, J = 9.2 Hz, 1H), 7.04 (dd, J = 7.5, 1.6 Hz, 1H), 7.07−
7.09 (m, 2H), 7.13−7.18 (m, 5H), 7.20 (td, J = 7.5, 1.7 Hz, 1H), 7.45
(dd, J = 8.0, 1.2 Hz, 1H), 7.64 (dd, J = 7.5, 1.7 Hz, 1H), 7.69 (d, J =
8.6 Hz, 2H); 13C NMR (125 MHz,CDCl3): δ 18.4, 21.6, 52.3, 58.4,
124.4, 126.9, 127.3, 127.7, 129.0, 129.2, 129.6, 130.2, 131.0, 133.0,
134.4, 138.0, 138.1, 143.3; HRMS (ESI) calcd for C22H26BrN2O2S2
(M + NH4)+ 493.0619, found 493.0618.
To conclude, we have developed a simple route to 2-alkyl
indoles via regioselective ring-opening of 2,3-disubstituted
aziridines with thiophenol, followed by copper powder-
mediated C−N cyclization and aromatization with good yields.
It is needless to mention that our strategy is very simple, based
on a C−N coupling step involving environmentally benign Cu
powder without using any ligand or a base. We strongly believe
that our described strategy can be used as an alternate general
methodology for the synthesis of 2-alkyl indoles.
2-(2-Bromophenyl)-3-methyl-1-tosylaziridine (cis-3b). Recov-
1
ered cis aziridine 3b obtained in 45% yield: H NMR (500 MHz,
CDCl3): δ 0.96 (d, J = 5.7 Hz, 3H), 2.44 (s, 3H), 3.26−3.31 (m, 1H),
3.96 (d, J = 7.5 Hz, 1H), 7.13 (td, J = 7.5, 2.3 Hz, 1H), 7.15−7.20 (m,
2H), 7.34 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 8.0
Hz, 2H); 13C NMR (125 MHz,CDCl3): δ 12.1, 21.7, 41.9, 47.1, 123.1,
127.3, 128.0, 129.4, 129.9, 130.1, 132.3, 133.0, 135.3, 144.7; HRMS
(ESI) calcd for C16H17BrNO2S (M + H)+ 366.0163, found 366.0164.
General Procedure for the C−N Cyclization. Method A. To N-
(2-(2-bromophenylthio)-2-phenylethyl)-4methylbenzenesulfonamide
4a (1.0 equiv) in dry DMF (2.0 mL) was added Cu powder (2.0
equiv). The reaction mixture was heated at 120 °C for 4 h, and the
progress of the reaction was monitored by TLC. It was cooled to room
temperature and quenched with water and extracted with ethyl acetate
(3 × 5.0 mL). The combined organic extract was washed with H2O (3
× 5.0 mL) and brine (30.0 mL) and dried over Na2SO4. The solvent
was removed under reduced pressure, and the crude product was
purified by flash column chromatography on silica gel (230−400
mesh) using ethyl acetate in petroleum ether to afford the pure
product 5a as a white solid.
EXPERIMENTAL SECTION
■
General Experimental. Analytical thin-layer chromatography
(TLC) was carried out using silica gel 60 F254 precoated plates.
Visualization was accomplished with a UV lamp or I2 stain. Silica gel
230−400 mesh size was used for column chromatography using the
combination of ethyl acetate and petroleum ether as an eluent. Unless
noted, all reactions were carried out in oven-dried glassware under an
atmosphere of nitrogen using anhydrous solvents. Where appropriate,
solvents and all reagents were purified prior to use following the
guidelines of Perrin and Armarego14 and Vogel.15 Monosubstituted N-
Ts aziridines and disubstituted N-Ts aziridines were prepared by
following earlier reports.16 All styrenes were prepared by following
earlier reports.17 All commercial reagents were used as received. IR
spectra were recorded in potassium bromide (KBr) pellets. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded at 400
and 500 MHz. Chemical shifts were recorded in parts per million
1-Tosyl-1H-indole (5a). The general method A described above was
followed when 4a (92.5 mg, 0.2 mmol) was reacted with Cu powder
(25.4 mg 0.4 mmol). The reaction mixture was heated 120 °C for 4 h
to afford 5a (46.1 mg, 0.170 mmol) as a white solid in 85% yield: mp
80−82 °C; Rf 0.46 (5% ethyl acetate in petroleum ether); IR νmax
(KBr, cm−1): 3143, 2924, 2853, 1735, 1597, 1527, 1493, 1445, 1371,
1306, 1290, 1262, 1204, 1187, 1174, 1130, 1091, 1018, 992, 879, 812,
1
(ppm, δ) relative to tetramethyl silane (δ 0.00). H NMR splitting
patterns are designated as singlet (s), doublet (d), double doublet
(dd), triplet (t), quartet (q), or multiplet (m). Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded at 100 and 125
MHz. Mass spectra (MS) were obtained using FAB and ESI mass
spectrometer (TOF). Melting points were determined using a hot
stage apparatus and are reported as uncorrected.
1
769, 747, 723, 703, 678, 644, 537; H NMR (400 MHz, CDCl3): δ
2.31 (s, 3H), 6.63 (d, J = 3.6 Hz, 1H), 7.18−7.31 (m, 4H), 7.51(d, J =
7.8 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.98
(d, J = 9.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 21.6, 109.1,
113.6, 121.4, 123.3, 124.6, 126.4, 126.9, 129.9, 130.8, 134.9, 135.4,
145.0; HRMS (ESI) calcd for C15H13 NNaO2S (M + Na)+ 294.0565,
found 294.0569.
General Procedure for Regioselective the Ring-Opening of
2-(2-Bromophenyl)-3-methyl-1-tosylaziridine with Thiophe-
nols. Method B. To a stirred solution of 3b (1.0 equiv) under a N2
atmosphere in dry DCM (0.5 mL) was added thiophenol (1.0 equiv),
followed by BF3·OEt2 (15 mol %). The reaction mixture was stirred at
rt for 15 min-2 h. The reaction was monitored by TLC. After
completion of the reaction mixture, it was quenched with water and
extracted with ethyl acetate (3 × 5.0 mL). The combined organic
extract was washed with H2O (3 × 5.0 mL) and brine (15.0 mL) and
dried over Na2SO4. The solvent was removed under reduced pressure
to give the crude product, which was purified by flash column
chromatography on silica gel (230−400 mesh) using ethyl acetate in
petroleum ether to afford the pure products as a thick liquid.
N-(2-(2-Bromophenyl)-2-(phenylthio)ethyl)-4-methyl-
benzenesulfonamide (4a).8h A solution of thiophenol (23 μL, 0.22
mmol) in dry toluene (1.0 mL) was added dropwise at 90 °C to a
stirred suspension of K2CO3 (1.1 equiv) in dry toluene (1.0 mL)
under a nitrogen atmosphere. The reaction mixture was stirred at 90
°C for 5 min, and a solution of 2-(2-bromophenyl)-1-tosylaziridine 3a
(71 mg, 0.2 mmol) in dry toluene (1.0 mL) was added dropwise over a
period of 1 min at 90 °C. The reaction mixture was further stirred for
15 min at the same temperature. The reaction was monitored by TLC.
It was cooled to room temperature, quenched with water, and
extracted with ethyl acetate (3 × 5.0 mL). The combined organic
extract was washed with H2O (3 × 5.0 mL) and brine (15.0 mL) and
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure to give the crude product, which was purified by flash
column chromatography on silica gel (230−400 mesh) by using ethyl
acetate in petroleum ether to afford the pure products as a thick liquid
in 95% yield. Rf 0.52 (30% ethyl acetate in petroleum ether); IR νmax
D
DOI: 10.1021/acs.joc.5b02251
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The Journal of Organic Chemistry
Note
N-(1-(2-Bromophenyl)-1-(phenylthio)propan-2-yl)-4-methyl-
benzenesulfonamide (4b). The general method B described above
was followed when 3b (73.3 mg, 0.2 mmol) was reacted with
thiophenol (20.4 μL,0.2 mmol) in the presence of BF3·OEt2 (15 mol
%) at rt for 2 h to afford 4b (92.4 mg, 0.188 mmol) as a thick liquid in
94% yield (dr 4:1): Rf 0.52 (20% ethyl acetate in petroleum ether); IR
νmax (neat, cm−1): 3270, 3059, 2925, 1597, 1480, 1461, 1438, 1380,
2H), 2.31 (s, 3H), 2.95 (t, J = 8.2 Hz, 2H), 6.36 (s, 1H), 7.15−7.18
(m, 2H), 7.20−7.25 (m, 2H), 7.38−7.40 (m, 1H), 7.60 (d, J = 8.3 Hz,
2H), 8.15 (d, J = 8.3 Hz 1H); 13C NMR (125 MHz, CDCl3): δ 14.0,
21.6, 22.2, 108.8, 114.9, 120.1, 123.5, 123.8, 126.3, 129.8, 129.9, 136.3,
137.3, 142.4, 144.6; HRMS (ESI) calcd for C18H20NO2S (M + H)+
314.1215, found 314.1210.
5-Fluoro-2-methyl-1-tosyl-1H-indole (5e). The general method C
described above was followed when 3e (76.8 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 120 °C for 16 h to afford 5e (39.4 mg,
0.13 mmol) as a thick liquid in 65% yield; Rf 0.61 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 2929, 2855, 1732, 1599, 1494,
1469, 1447, 1390, 1369, 1313, 1292, 1216, 1180, 1168, 1129, 1115,
1091, 1054, 1017, 1004, 958, 897, 859, 810, 778, 704, 684, 668, 635,
592, 566, 545, 494, 433; 1H NMR (500 MHz, CDCl3): δ 2.34 (s, 3H),
2.57 (s, 3H), 6.29 (s, 1H), 6.96 (td, J = 2.5, 9.2 Hz, 1H), 7.03 (dd, J =
2.5, 8.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H),
8.08 (dd, J = 4.3, 8.6 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 15.0,
15.8, 21.6, 105.5, 105.7, 109.4, 109.4, 111.5, 115.4, 115.5, 126.3, 129.9,
130.6, 130.7, 133.3, 136.1, 139.2, 144.9, 158.8, 160.7; HRMS (ESI)
calcd for C16H15FNO2S (M + H)+ 304.0808, found 304.0807.
2-Ethyl-5-fluoro-1-tosyl-1H-indole (5f). The general method C
described above was followed when 3f (79.7 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 120 °C for 17 h to afford 5f (41.2 mg,
0.13 mmol) as a thick liquid in 65% yield; Rf 0.62 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 2974, 2928, 1597, 1493, 1468,
1448, 1370, 1306, 1267, 1230, 1210, 1189, 1179, 1156, 1131, 1117,
1091, 1055, 1017, 986, 958, 877, 860, 808, 778, 734, 703, 683, 663,
1
1331, 1161, 1092, 1023, 986, 907, 814, 738, 689, 670, 549; H NMR
(400 MHz, CDCl3) δ 1.12 (t, J = 6.9 Hz, 3H), 1.20 (t, J = 6.4 Hz, 3H),
2.35 (s, 3H), 2.39 (s, 3H), 3.70−3.75 (m, 1H), 3.82−3.90 (m, 1H),
4.74 (d, J = 4.9 Hz, 1H), 5.09 (d, J = 9.2 Hz, 1H), 6.98−7.08 (m, 5H),
7.13−7.15 (m, 6H), 7.18−7.21 (m, 3H), 7.43−7.45 (m, 3H), 7.61−
765 (m, 4H), 7.68−7.69 (m, 2H); 13C NMR (125 MHz,CDCl3) δ
18.3, 20.5, 21.6, 52.3, 58.4, 124.4, 126.9, 127.1, 127.3, 127.5, 127.6,
127.7, 129.1, 129.3, 129.6, 130.1, 131.0, 131.8, 133.0, 134.4, 138.0,
138.0, 143.3; HRMS (ESI) calcd for C22H26BrN2O2S2 (M + NH4)+
493.0619, found 493.0618.
General Procedure for a One-Pot Protocol for the Synthesis
of 2-Alkyl Indole. Method C. To a stirred solution of aziridine (1.0
equiv) under a N2 atmosphere in dry DCM (0.5 mL) was added
thiophenol (1.0 equiv), followed by BF3·OEt2 (15 mol %). The
reaction mixture was stirred at rt for 0.15−2 h. Cu powder (2.0 equiv)
and DMF were added, and the mixture was heated to 120−125 °C for
8−24 h. The reaction was monitored by TLC. It was cooled to room
temperature and quenched with water and extracted with ethyl acetate
(3 × 5.0 mL). The combined organic extract was washed with H2O (3
× 5.0 mL) and brine (5.0 mL) and dried over Na2SO4. The solvent
was removed under reduced pressure to give the crude product, which
was purified by flash column chromatography on silica gel (230−400
mesh) using ethyl acetate in petroleum ether to afford the pure
products as white solids.
1
2-Methyl-1-tosyl-1H-indole (5b). The general method C described
above was followed when 3b (73.2 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 2 h, followed by treatment with Cu powder (2.0 equiv) and 2
mL of DMF at 120 °C for 22 h to afford 5b (41.7 mg, 0.146 mmol) as
a thick liquid in 73% yield; Rf 0.53 (5% ethyl acetate in petroleum
ether); IR νmax (KBr, cm−1): 2926, 1596, 1452, 1367, 1294, 1240,
1218, 1187, 1174, 1150, 1091, 1052, 1022, 1001, 913, 810, 747, 704,
690, 659, 632, 583, 543; 1H NMR (500 MHz, CDCl3): δ 2.33 (s, 3H),
2.59 (s, 3H), 6.33 (s, 1H), 7.18−7.20 (m, 3H), 7.23−7.26 (m, 1H),
7.49 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 8.15 (d, J = 8.6 Hz
1H); 13C NMR (100 MHz, CDCl3): δ 15.9, 21.6, 109.6, 114.6, 120.0,
123.5, 123.8, 126.4, 129.8, 129.9, 136.4, 137.1, 137.4, 144.8; HRMS
(ESI) calcd for C16H16NO2S (M + H)+ 286.0902, found 286.0901.
2-Ethyl-1-tosyl-1H-indole (5c). The general method C described
above was followed when 3c (76.0 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 2 h, followed by treatment with Cu powder (2.0 equiv) and 2
mL of DMF at 120 °C for 22 h to afford 5c (41.3 mg, 0.14 mmol) as a
thick liquid in 70% yield; Rf 0.66 (5% ethyl acetate in petroleum
ether); IR νmax (KBr, cm−1): 3065, 2973, 2927, 1913, 1739, 1596,
1567, 1493, 1451, 1432, 1369, 1305, 1292, 1276, 1225, 1205, 1187,
1174, 1146, 1119, 1091, 1051, 1022, 986, 937, 905, 812, 747, 705, 694,
581, 557, 542; H NMR (400 MHz, CDCl3): δ 1.31 (t, J = 7.3 Hz,
3H), 2.33 (s, 3H), 2.96−3.01 (m, 2H), 6.33 (s, 1H), 6.95 (td, J = 2.3,
8.7 Hz, 1H), 7.05 (dd, J = 2.3, 8.7 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H),
7.58 (d, J = 8.5 Hz, 2H), 8.10 (dd, J = 4.6, 9.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 12.9, 21.6, 22.5, 105.7, 105.8, 107.6, 107.7,
111.4, 111.6, 115.7, 115.8, 126.3, 130.0, 130.9, 130.9, 133.6, 136.1,
144.9, 145.7, 158.8, 160.7; HRMS (ESI) calcd for C17H17FNO2S (M +
H)+ 318.0964, found 318.0969.
5-Fluoro-2-propyl-1-tosyl-1H-indole (5g). The general method C
described above was followed when 3g (82.5 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 120 °C for 16 h to afford 5g (43.1 mg,
0.13 mmol) as a thick liquid in 65% yield; Rf 0.66 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 2963, 2873, 1693, 1597, 1466,
1449, 1369, 1266, 1209, 1189, 1179, 1157, 1116, 1091, 1053, 959, 859,
1
810, 780, 736, 711, 670, 616, 584, 573, 543; H NMR (400 MHz,
CDCl3): δ 1.00 (t, J = 7.3 Hz, 3H), 1.76 (h, J = 7.3 Hz, 2H), 2.32 (s,
3H), 2.91−2.95 (m, 2H), 6.32 (d, J = 0.9 Hz, 1H), 6.95 (td, J = 2.8, 9.2
Hz, 1H), 7.04 (dd, J = 2.8, 8.7 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H),
7.56−7.59 (m, 2H), 8.08 (dd, J = 4.6, 9.2 Hz, 1H); 13C NMR (125
MHz, CDCl3): δ 14.0, 21.7, 22.2, 31.2, 105.6, 105.8, 108.6, 108.7,
111.4, 111.6, 115.9, 116.0, 126.3, 129.9, 130.9, 131.0, 133.5, 136.0,
144.2, 144.9, 158.8, 160.8; HRMS (ESI) calcd for C18H18FNNaO2S
(M + Na)+ 354.0940, found 354.0949.
5-Chloro-2-methyl-1-tosyl-1H-indole (5h). The general method C
described above was followed when 3h (71.3 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 125 °C for 21 h to afford 5h (44.8 mg,
0.14 mmol) as a thick liquid in 70% yield; Rf 0.56 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 2925, 2853, 1596, 1441, 1370,
1305, 1239, 1217, 1174, 1151, 1132, 1090, 1072, 1003, 885, 808, 722,
672, 664, 600, 543; 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 2.56
(s, 3H), 6.26 (s, 1H), 7.17−7.21 (m, 3H), 7.34 (d, J = 1.8 Hz, 1H),
7.62 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 9.2 Hz, 1H); 13C NMR (125
MHz, CDCl3): δ 15.8, 21.7, 108.9, 115.6, 119.6, 123.9, 126.4, 129.2,
130.0, 131.0, 135.4, 136.1, 139.0, 145.1; HRMS (ESI) calcd for
C16H15ClNO2S (M + H)+ 320.0512, found 320.0513.
1
659, 626, 542, 492, 431; H NMR (400 MHz, CDCl3): δ 1.32 (t, J =
7.3 Hz, 3H), 2.31 (s, 3H), 2.96−3.03 (m, 2H), 6.37 (s, 1H), 7.15−7.18
(m, 3H), 7.20−7.26 (m, 1H), 7.40 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 8.7
Hz, 2H), 8.16 (d, J = 8.2 Hz 1H); 13C NMR (125 MHz, CDCl3): δ
13.0, 21.6, 22.4, 107.8, 114.8, 120.2, 123.5, 123.9, 126.3, 129.9, 136.4,
137.3, 143.9, 144.7; HRMS (ESI) calcd for C17H18NO2S (M + H)+
300.1058, found 300.1055.
2-Propyl-1-tosyl-1H-indole (5d). The general method C described
above was followed when 3d (78.9 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 2 h, followed by treatment with Cu powder (2.0 equiv) and 2
mL of DMF at 120 °C for 20 h to afford 5d (42.0 mg, 0.134 mmol) as
a thick liquid in 67% yield; Rf 0.73 (10% ethyl acetate in petroleum
ether); IR νmax (KBr, cm−1): 2927, 1594, 1451, 1366, 1219, 1173,
1
1144, 1118, 1090, 1050, 809, 745, 705, 688, 666, 577, 541; H NMR
(400 MHz, CDCl3): δ 1.01 (t, J = 7.3 Hz, 3H), 1.77 (h, J = 7.4 Hz,
E
DOI: 10.1021/acs.joc.5b02251
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
5-Chloro-2-propyl-1-tosyl-1H-indole (5i). The general method C
described above was followed when 3i (76.8 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 125 °C for 24 h to afford 5i (45.2 mg,
0.13 mmol) as a thick liquid in 65% yield; Rf 0.73 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 2961, 2928, 2871, 1596, 1444,
1371, 1271, 1221, 1199, 1173, 1148, 1132, 1091, 1072, 1052, 871, 808,
738, 723, 689, 668, 601, 581, 543, 564; 1H NMR (400 MHz, CDCl3):
δ 1.00 (t, J = 7.3 Hz, 3H), 1.75 (h, J = 7.3 Hz, 2H), 2.33 (s, 3H),
2.90−2.94 (m, 2H), 6.3 (d, J = 0.9 Hz, 1H), 7.17−7.19 (m, 3H),
7.35(d, J = 2.3 Hz, 1H), 7.56−7.59 (m, 2H), 8.07 (d, J = 9.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 14.0, 21.7, 22.1, 31.1, 108.1, 115.91,
119.7, 123.9, 126.3, 129.1, 129.2, 130.0, 131.2, 135.6, 136.0, 143.9,
145.0; HRMS (ESI) calcd for C18H19ClNO2S (M + H)+ 348.0825,
found 348.0817.
126.9, 130.1, 135.0, 136.9, 137.0 145.3, 154.6, 157.2; HRMS (ESI)
calcd for C15H13 FNO2S (M + H)+ 290.0651, found 290.0657.
5-Chloro-1-tosyl-1H-indole (5m). The general method C described
above was followed when 3m (68.4 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 15 min, followed by treatment with Cu powder (2.0 equiv)
and 2 mL of DMF at 125 °C for 16 h to afford 5m (52.0 mg, 0.17
mmol) as a white solid in 85% yield: mp 65−67 °C; Rf 0.46 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2922, 2850, 1596,
1440, 1374, 1336, 1285, 1249, 1197, 1170, 1145, 1129, 1092, 991, 810,
762, 720, 669, 586, 538; 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H),
6.57 (d, J = 3.7 Hz, 1H), 7.20−7.25 (m, 3H), 7.5 (d, J = 1.8 Hz, 1H),
7.56 (d, J = 3.6 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.9 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 21.7, 108.5, 114.6, 121.0, 124.9,
126.9, 127.8, 129.2, 130.1, 132.0, 133.2, 135.1, 145.3; HRMS (ESI)
calcd for C15H13ClNO2S (M + H)+ 306.0356, found 306.0350.
6-Chloro-1-tosyl-1H-indole (5n). The general method C described
above was followed when 3n (68.4 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 15 min, followed by treatment with Cu powder (2.0 equiv)
and 2 mL of DMF at 125 °C for 16 h to afford 5n (49.7 mg, 0.163
mmol) as a white solid in 82% yield: mp 102−104 °C; Rf 0.46 (5%
ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 3141, 2919,
1723, 1596, 1523, 1493, 1454, 1423, 1374, 1306, 1267, 1203, 1188,
1172, 1138, 1092, 1018, 996, 899, 867, 812, 761, 714, 668, 609, 596,
578, 541, 525; 1H NMR (500 MHz, CDCl3): δ 2.34 (s, 3H), 6.60 (d, J
= 3.68 Hz, 1H), 7.17−7.24 (m, 3H),7.41 (d, J = 8.2 Hz, 1H), 7.53 (d, J
= 3.6 Hz, 1H), 7.75 (d, J = 10.6 Hz, 2H), 7.99 (d, J = 1.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 21.7, 108.8, 113.8, 122.2, 124.1, 126.9,
127.0, 129.3, 130.1, 130.7, 135.1, 135.2, 145.4; HRMS (ESI) calcd for
C15H13ClNO2S (M + H)+ 306.0356, found 306.0350.
6-Chloro-2-ethyl-1-tosyl-1H-indole (5j). The general method C
described above was followed when 3j (74.1 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 125 °C for 20 h to afford 5j (44.7 mg,
0.13 mmol) as a thick liquid in 67% yield; Rf 0.62 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 3114, 2973, 2924, 1589, 1561,
1494, 1453, 1420, 1369, 1307, 1289, 1219, 1203, 1187, 1173, 1151,
1123, 1092, 1061, 1049, 1017, 988, 929, 866, 829, 811, 731, 703, 680,
1
661, 543, 490, 430; H NMR (400 MHz, CDCl3): δ 1.30 (t, J = 7.3
Hz, 3H), 2.34 (s, 3H), 2.94−3.00 (m, 2H), 6.33 (s, 1H), 7.15−7.21
(m, 3H), 7.31 (d, J = 8.3 Hz, 1H), 7.60−7.63(m, 2H), 8.20 (d, J = 1.8
Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 12.8, 21.7, 22.3, 107.2,
114.9, 120.8, 124.1, 126.4, 128.3, 129.8, 130.1, 136.1, 137.6, 144.6,
145.1; HRMS (ESI) calcd for C17H17ClNO2S (M + H)+ 334.0669,
found 334.0668.
4-Chloro-1-tosyl-1H-indole (5o). The general method C described
above was followed when 3o (68.4 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 15 min, followed by treatment with Cu powder (2.0 equiv)
and 2 mL of DMF at 125 °C for 16 h to afford 5o (49.1 mg, 0.16
mmol) as a white solid in 80% yield: mp 78−80 °C; Rf 0.6 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2924, 2850, 1596,
1572, 1523, 1471, 1419, 1374, 1285, 1225, 1194, 1169, 1132, 1101,
6-Chloro-2-propyl-1-tosyl-1H-indole (5k). The general method C
described above was followed when 3k (76.8 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 125 °C for 24 h to afford 5k (44.5 mg,
0.127 mmol) as a thick liquid in 64% yield; Rf 0.73 (10% ethyl acetate
in petroleum ether); IR νmax (KBr, cm−1): 3113, 2958, 2926, 2868,
1694, 1586, 1557, 1493, 1460, 1419, 1372, 1306, 1283, 1249, 1219,
1199, 1171, 1152, 1123, 1073, 1049, 1034, 1015, 948, 904, 859, 844,
823, 812, 741, 703, 663, 543 543; 1H NMR (500 MHz, CDCl3): δ 1.01
(t, J = 7.5 Hz, 3H), 1.74 (h, J = 7.5 Hz, 2H), 2.34 (s, 3H), 2.91 (t, J =
6.9 Hz, 2H), 6.33 (s, 1H), 7.16−7.18 (m, 1H), 7.20 (d, J = 8.0 Hz,
2H), 7.30 (d, J = 8.6 Hz, 1H), 7.61 (m, J = 8.6 Hz 2H), 8.19 (s, 1H);
13C NMR (125 MHz, CDCl3): δ 14.0, 21.7, 22.1, 31.0, 108.2, 115.1,
120.8, 124.1, 126.2, 126.4, 128.4, 129.7, 130.1, 134.2, 136.1, 137.6,
137.6, 143.1, 145.0; HRMS (ESI) calcd for C18H18ClNNaO2S (M +
H)+ 370.0644, found 370.0642.
1-Tosyl-1H-indole (5a). The general method C described above
was followed when 3a (71 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03
mmol)] at rt for 15 min, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 120 °C for 5 h to afford 5a (46.1 mg,
0.172 mmol) as a white solid in 86% yield: mp 80−82 °C; Rf 0.46 (5%
ethyl acetate in petroleum ether);
4-Fluoro-1-tosyl-1H-indole (5l). The general method C described
above was followed when 3l (65.1 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 15 min, followed by treatment with Cu powder (2.0 equiv)
and 2 mL of DMF at 125 °C for 16 h to afford 5l (46.3 mg, 0.16
mmol) as a white solid in 80% yield: mp 72−74 °C; Rf 0.53 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2924, 2854, 1626,
1583, 1527, 1486, 1430, 1375, 1307, 1289, 1248, 1208, 1182, 1165,
1145, 1127, 1089, 1052, 1029, 946, 812, 786, 751, 703, 688, 670, 580,
560, 546, 520; 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 6.73 (dd
J = 0.9, 3.9, Hz, 1H), 6.86−6.91 (m, 1H),7.19−7.25 (m, 3H), 7.52 (d,
J = 3.6 Hz, 1H), 7.74−7.46 (m, 3H); 13C NMR (100 MHz, CDCl3): δ
21.7, 104.6, 108.5, 108.7, 109.6, 109.6, 119.9, 125.4, 125.5, 126.3,
1
1003, 896, 811, 753, 703, 678, 643, 626, 576, 542; H NMR (500
MHz, CDCl3): δ 2.33 (s, 3H), 6.74−6.82 (m, 1H), 7.18−7.29 (m,
4H), 7.58−7.64 (m, 1H), 7.74 (d, J = 7.4 Hz, 2H), 7.88−7.94 (m,
1H); 13C NMR (100 MHz, CDCl3): δ 21.7, 107.2, 112.1, 123.2, 125.3,
126.6, 126.9, 129.6, 130.1, 135.1, 135.5, 145.4; HRMS (ESI) calcd for
C15H13ClNO2S (M + H)+ 306.0356, found 306.0350.
5-Fluoro-1-tosyl-1H-indole (5p). The general method C described
above was followed when 3p (74.0 mg, 0.2 mmol) was reacted with
thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL, 0.03 mmol)]
at rt for 15 min, followed by treatment with Cu powder (2.0 equiv)
and 2 mL of DMF at 120 °C for 8 h to afford 5p (49.7 mg, 0.163
mmol) as a white solid in 81% yield: mp 102−104 °C; Rf 0.54 (5%
ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 3145, 2924,
1615, 1594, 1530, 1493, 1460, 1444, 1399, 1372, 1348, 1307, 1291,
1259, 1216, 1188, 1172, 1139, 1114, 1091, 1040, 1018, 996, 950, 857,
810, 799, 761, 721, 703, 674, 626, 613, 590, 541, 524, 491, 473, 429;
1H NMR (500 MHz, CDCl3): δ 2.33 (s, 3H), 6.60 (d, J = 3.4 Hz, 1H),
7.02 (td, J = 2.9, 9.2 Hz, 1H), 7.16 (dd, J = 2.9, 9.2 Hz, 1H), 7.21 (d, J
= 8.0 Hz, 2H), 7.58 (d, J = 3.4 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.91
(dd, J = 4.6, 9.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 21.7, 106.8,
107.0, 109.0, 109.1, 112.6, 112.8, 114.6, 114.7, 126.9, 128.1, 130.0,
131.3, 131.8, 135.1, 145.2, 158.7, 160.6; HRMS (ESI) calcd for
C15H13FNO2S (M + H)+ 290.0651, found 290.0651.
Ethyl 1-Tosyl-1H-indole-2-carboxylate (10). The general method
C described above was followed when 9 (76.0 mg, 0.2 mmol) was
reacted with thiophenoxide [(20.4 μL, 0.20 mmol), BF3·OEt2 (3.8 μL,
0.03 mmol)] at rt for 2 h, followed by treatment with Cu powder (2.0
equiv) and 2 mL of DMF at 125 °C for 20 h to afford 10 (41.2 mg,
0.12 mmol) as a thick liquid in 60% yield; Rf 0.53 (5% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1): 2924, 2854, 1742, 1626, 1583,
1527, 1486, 1430, 1375, 1307, 1289, 1248, 1208, 1182, 1165, 1145,
F
DOI: 10.1021/acs.joc.5b02251
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1127, 1089, 1052, 1029, 946, 812, 786, 751, 703, 688, 670, 580, 560,
546, 520; H NMR (400 MHz, CDCl3): δ 1.38 (t, J = 7.3 Hz, 3H),
(s, 3H), 2.70−2.74 (m, 1H), 3.26−3.31 (m, 1H), 3.92 (d, J = 1.7 Hz,
1H), 3.92−3.94 (m, 2H), 6.56 (dd, J = 9.1, 2.8 Hz, 1H), 6.81 (td, J =
8.0, 2.8 Hz, 1H), 6.86 (td, J = 8.0, 2.8 Hz, 1H), 6.91 (dd, J = 9.1, 2.8
Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.44 (dd, J
= 8.2, 4.5 Hz, 1H), 7.45−7.47 (m, 1H), 7.87−7.89 (m, 4H); 13C NMR
(125 MHz, CDCl3) 12.0, 14.0, 21.7, 42.1, 46.6, 48.8, 49.3, 114.7,
114.9, 116.5, 116.7, 117.1, 117.3, 127.5, 128.0, 130.0, 133.6, 133.7,
137.5, 137.9, 138.0, 144.6, 161.1, 163.0; HRMS (ESI) calcd for
C16H16BrFNO2S (M + H)+ 384.0069, found 384.0068.
2-(2-Bromo-5-fluorophenyl)-3-ethyl-1-tosylaziridine (3f). Ob-
tained as a thick liquid in 65% yield with cis/trans ratio 1:1: Rf 0.46
(5% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 3068,
2969, 2934, 2878, 1598, 1579, 1469, 1418, 1328, 1305, 1290, 1270,
1220, 1184, 1162, 1091, 1038, 1018, 957, 940, 904, 876, 850, 813, 736,
714, 695, 673, 607, 575, 564; 1H NMR (500 MHz, CDCl3): δ 0.77 (t,
J = 7.4 Hz, 3H), 1.00−1.06 (m, 1H), 1.23 (t, J = 7.4, Hz, 3H), 1.28−
1.33 (m, 1H), 2.16−2.22 (m, 1H), 2.30−233 (m, 1H), 2.42 (s, 3H),
2.45 (s, 3H), 2.59−2.62 (m, 1H), 3.09−3.13 (m, 1H), 3.95 (d, J = 4.0
Hz, 1H), 3.99 (d, J = 7.4 Hz, 1H), 6.59 (dd, J = 9.1, 2.8 Hz, 1H), 6.80
(td, J = 8.0, 2.8 Hz, 1H), 6.85 (td, J = 8.6, 3.4 Hz, 1H), 6.96 (dd, J =
9.1, 2.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),
7.44 (m, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H); 13C
NMR (1 MHz, CDCl3): 11.2, 12.6, 20.1, 21.7, 21.8, 22.1, 114.4, 114.6,
116.5, 116.6, 116.7, 116.8, 117.1, 117.3, 127.4, 128.1, 129.4, 129.8,
129.9, 133.6, 133.7, 133.8, 134.9, 135.5, 135.6, 137.5, 137.8, 144.5,
144.9, 160.8, 161.1, 162.8, 163.1; HRMS (ESI) calcd for
C17H18BrFNO2S (M + H)+ 398.0226, found 398.0229.
1
2.35 (s, 3H), 4.39 (q, J = 7.3 Hz, 2H), 7.13 (d, J = 1.1 Hz, 1H), 7.23−
7.27 (m, 3H), 7.38−7.43 (m, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.90 (d, J
= 8.7 Hz, 2H), 8.309 (d, J = 9.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 14.2, 21.7, 62.1, 115.5, 116.6, 122.5, 124.1, 127.0, 127.5,
128.3, 129.6, 131.9, 135.7, 138.2, 145.0, 161.5; HRMS (ESI) calcd for
C18H18NO4S (M + H)+ 344.0957, found 344.0955.
General Procedure for Preparation of Aziridines.16 To a
mixture of styrene derivatives (230 mg, 1.329 mmol) and anhydrous
Chloramine-T (375 mg, 1.329 mmol) in CH3CN (10 mL) was added
PTAB (101 mg, 0.265 mmol) at 25 °C. After vigorous stirring for 12 h,
the reaction mixture was diluted with ethyl acetate (40 mL) and water
(20 mL). The organic layer was separated and washed with brine (20
mL), followed by drying over MgSO4. The solvent was removed under
reduced pressure to give the crude product, which was purified by flash
column chromatography on silica gel (60−120 mesh) using ethyl
acetate in petroleum ether to afford the pure products as white solids
in good to moderate yield.
2-(2-Bromophenyl)-3-methyl-1-tosylaziridine (3b). Obtained as a
thick liquid in 68% yield with cis/trans ratio 1:1: Rf 0.45 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2928, 1596, 1566,
1473, 1439, 1405, 1325, 1305, 1291, 1235, 1184, 1162, 1117, 1090,
1
1047, 1026, 985, 888, 815, 756, 710, 685, 589, 577, 552; H NMR
(400 MHz, CDCl3) δ 0.96 (d, J = 5.5 Hz, 3H), 1.19 (d, J = 5.9 Hz,
3H), 2.42 (s, 3H), 2.43 (s, 3H), 2.71−2.75 (m, 1H), 3.96 (dd, J = 7.2
Hz, 1H), 3.97 (dd, J = 4.5 Hz, 1H), 6.82−6.84 (m, 1H), 7.05−7.18
(m, 5H), 7.20−7.35 (m, 4H), 7.46−7.50 (m, 2H), 7.86−7.89 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 12.1, 14.1, 21.7, 21.8, 41.9, 47.1, 49.0,
49.5, 123.0, 123.2, 127.3, 127.6, 128.0, 129.4, 129.7, 129.9, 130.0,
132.3, 132.9, 135.2, 135.6, 137.7, 144.3, 144.7; HRMS (ESI) calcd for
C16H17 BrNO2S (M + H)+ 366.0163, found 366.0164.
2-(2-Bromophenyl)-3-ethyl-1-tosylaziridine (3c). Obtained as a
thick liquid in 71% yield with cis/trans ratio 1:1: Rf 0.48 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2968, 1596, 1439,
1327, 1231, 1184, 1162, 1091, 1019, 939, 908, 814, 754, 677, 591, 576,
557; 1H NMR (400 MHz, CDCl3) δ 0.76 (t, J = 14.7 Hz, 3H), 0.97−
1.06 (m, 1H), 1.22 (t, J = 7.8 Hz, 3H), 1.27−1.34 (m, 1H), 2.15−2.22
(m, 1H), 2.24−2.34 (m, 1H), 2.40 (s, 3H), 2.43 (s, 3H), 2.61−2.66
(m, 1H), 3.07−3.12 (m, 1H), 3.99−4.02 (m, 2H), 6.85−6.88 (m, 1H),
7.05−7.14 (m, 3H), 7.16−7.22 (m, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.33
(d, J = 8.7 Hz, 2H), 7.47−7.50 (m, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.89
(d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 11.3, 12.6, 21.7,
22.2, 47.1, 48.0, 48.8, 55.3, 123.1, 123.3, 127.2, 127.3, 127.5, 127.6,
128.2, 129.3, 129.4, 129.7, 129.8, 129.9, 132.3, 132.4, 133.1, 135.1,
135.4, 137.7, 144.2, 144.7; HRMS (ESI) calcd for C17H19 BrNO2S (M
+ H)+ 380.0320, found 380.0320.
2-(2-Bromo-5-fluorophenyl)-3-propyl-1-tosylaziridine (3g). Ob-
tained as a thick liquid in 67% yield with cis/trans ratio 1:1.4: Rf
0.48 (5% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 2961,
2932, 2873, 1598, 1580, 1470, 1418, 1328, 1305, 1269, 1218, 1184,
1162, 1093, 1031, 1018, 957, 922, 866, 814, 716, 693, 675, 590, 575,
1
538; H NMR (400 MHz, CDCl3): δ 0.76 (t, J = 7.3 Hz, 3H), 0.91−
0.96 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H), 1.16−1.29 (m, 2H), 1.58−1.70
(m, 3H), 2.07−2.17 (m, 1H), 2.23−2.33 (m, 1H), 2.41 (s, 3H), 2.44
(s, 3H), 2.62−2.66 (m, 1H), 3.14−3.19 (m, 1H), 3.95−3.97 (m, 2H),
6.58 (dd, J = 9.1, 3.2 Hz, 1H), 6.79 (td, J = 8.2, 3.2 Hz, 1H), 6.85 (td, J
= 8.2, 3.2 Hz, 1H), 6.94 (dd, J = 9.1, 2.7 Hz, 1H), 7.30 (d, J = 8.2 Hz,
2H), 7.34 (d, J = 8.2 Hz, 2H), 7.42−7.46 (m, 2H), 7.85 (d, J = 8.2 Hz,
2H), 7.88 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3): 13.7,
14.0, 20.3, 21.5, 21.7, 21.8, 28.6, 30.5, 46.4, 46.7, 48.2, 54.3, 114.4,
114.5, 116.5, 116.6, 116.7, 116.8, 117.0, 117.1, 117.3, 127.5, 128.1,
129.8, 129.9, 133.7, 133.7, 133.8, 134.9, 135.5, 135.6, 137.4, 137.7,
137.8, 144.5, 145.0, 160.8, 161.1, 162.7, 163.1; HRMS (ESI) calcd for
C18H20BrFNO2S (M + H)+ 412.0382, found 412.0382.
2-(2,5-Dichlorophenyl)-3-methyl-1-tosylaziridine (3h). Obtained
as a thick liquid in 62% yield with cis/trans ratio 1:2.8: Rf 0.42 (5%
ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 2929, 1597,
1469, 1398, 1327, 1234, 1185, 1162, 1091, 1054, 987, 912, 858, 814,
748, 714, 685, 598, 568, 528; 1H NMR (400 MHz, CDCl3): δ 0.95 (d,
J = 5.9 Hz, 3H), 1.86 (d, J = 5.9 Hz, 3H), 2.43 (s, 3H), 2.44 (s, 3H),
2.72−2.78 (m, 1H), 3.23−3.27 (m, 1H), 3.95−3.96 (m, 2H), 6.78 (d, J
= 2.2 Hz, 1H), 7.11 (dd, J = 8.2, 2.2 Hz, 1H), 7.16−7.19 (m, 2H),
7.23−7.26 (m, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H),
7.83−7.89 (m, 4H); 13C NMR (125 MHz, CDCl3): 12.1, 139, 21.7,
21.8, 42.1, 44.3, 46.4, 49.0, 127.5, 127.6, 128.0, 129.2, 129.3, 129.8,
129.9, 130.3, 131.8, 132.8, 133.0, 133.1, 134.7, 135.6, 137.4, 144.6,
145.0; HRMS (ESI) calcd for C16H16Cl2NO2S (M + H)+ 356.0279,
found 356.0279.
2-(2-Bromophenyl)-3-propyl-1-tosylaziridine (3d). Obtained as a
thick liquid in 65% yield with cis/trans ratio 1:1: Rf 0.51 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2959, 1596, 1439,
1
1327, 1184, 1162, 1092, 1025, 917, 814, 758, 678, 592, 576, 546; H
NMR (400 MHz, CDCl3) δ 0.76 (t, J = 7.36 Hz, 3H), 0.90−0.97 (m,
1H), 0.99 (t, J = 14.68 Hz, 3H), 1.18−1.33 (m, 4H), 1.62−1.71 (m,
2H), 2.08−2.17 (m, 1H), 2.24−2.35 (m, 1H), 2.40 (s, 3H), 2.43 (s,
3H), 2.66−2.70 (m, 1H), 3.15−3.19 (m, 1H), 3.99−4.02 (m, 2H),
6.85−6.88 (m, 1H), 7.05−7.10 (m, 2H), 7.11−7.14(m, 1H), 7.19 (d, J
= 4.6 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H),
7.46−7.50 (m, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 13.7, 14.1, 20.3, 21.5, 21.7, 21.8, 28.7,
30.7, 46.5, 47.0, 48.9, 53.9, 123.1, 123.3, 127.2, 127.5, 127.6, 128.1,
129.4, 129.7, 129.8, 129.8, 132.3, 132.5, 133.2, 135.1, 135.4, 137.7,
144.2, 144.7; HRMS (ESI) calcd for C18H21 BrNO2S (M + H)+
394.0476, found 394.0474.
2-(2-Bromo-5-fluorophenyl)-3-methyl-1-tosylaziridine (3e). Ob-
tained as a thick liquid in 58% yield with cis/trans ratio 1:4: Rf 0.43
(5% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 3052,
2924, 2855, 1730, 1624, 1596, 1480, 1460, 1408, 1379, 1360, 1304,
1293, 1237, 1185, 1122, 1090, 1054, 1026, 1001, 943, 870, 847, 800,
813, 740, 705, 690, 658, 628, 583, 530; 1H NMR (500 MHz, CDCl3) δ
0.97 (d, J = 5.7 Hz, 3H), 1.89 (d, J = 5.7 Hz, 3H), 2.44 (s, 3H), 2.45
2-(2,5-Dichlorophenyl)-3-propyl-1-tosylaziridine (3i). Obtained as
a thick liquid in 54% yield with cis/trans ratio 1:2: Rf 0.52 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2960, 2932, 2873,
1597, 1494, 1467, 1398, 1329, 1305, 1291, 1256, 1230, 1185, 1162,
1120, 1092, 1054, 1019, 999, 925, 814, 760, 730, 694, 673, 637, 593,
1
570, 561, 529; H NMR (500 MHz, CDCl3): δ 0.75 (t, J = 7.3 Hz,
3H), 0.91−0.96 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H), 1.14−1.28 (m, 3H),
1.57−1.66 (m, 2H), 2.04−2.13 (m, 1H), 2.21−2.30 (m, 1H), 2.42 (s,
3H), 2.44 (s, 3H), 2.65−2.69 (m, 1H), 3.11−3.16 (m, 1H), 3.97 (d, J
= 4.1 Hz, 1H), 4.00 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 7.10
(dd, J = 8.6, 2.7 Hz, 1H), 7.15−7.21 (m, 2 H), 7.23−7.25 (m, 2H),
G
DOI: 10.1021/acs.joc.5b02251
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.31 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 8.2 Hz,
2H), 7.88 (d, J = 7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): 13.6,
14.0, 20.2, 21.4, 21.7, 21.8, 28.6, 30.5, 44.1, 45.8, 46.7, 53.8, 127.2,
127.6, 128.2, 129.2, 129.3, 129.6, 129.8, 129.9, 130.3, 130.4, 131.8,
132.8, 133.1, 133.4, 134.8, 135.6, 137.3, 144.6, 150.0; HRMS (ESI)
calcd for C18H20Cl2NO2S (M + H)+ 384.0592, found 384.0594.
2-(2,4-Dichlorophenyl)-3-ethyl-1-tosylaziridine (3j). Obtained as a
thick liquid in 70% yield with cis/trans ratio 1:1: Rf 0.48 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2970, 2934, 2878,
1593, 1560, 1476, 1412, 1380, 1329, 1305, 1291, 1232, 1185, 1163,
1119, 1092, 1054, 1019, 940, 897, 866, 814, 782, 738, 715, 695, 673,
2-(2,6-Dichlorophenyl)-1-tosylaziridine (3o). Obtained as a thick
liquid in 45% yield: 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 3H), 2.52
(d, J = 4.60 Hz, 1H), 3.11 (d, J = 7.32 Hz, 1H), 3.86 (dd, J = 4.56, 6.88
Hz, 1H), 7.11−7.15 (m, 1H), 7.21−7.23 (m, 2H), 7.33 (d, J = 8.28
Hz, 2H), 7.88−7.90 (m, 2H); 13C NMR (100 MHz,CDCl3): δ 21.8,
35.1, 39.8, 128.7, 128.8, 129.7, 129.9, 130.6, 134.9, 136.2, 144.9.
2-(2-Bromo-5-fluorophenyl)-1-tosylaziridine (3p). Obtained as a
thick liquid in 67% yield: 1H NMR (400 MHz, CDCl3): δ 2.22 (d, J =
4.16 Hz, 1H), 2.44 (s, 3H), 3.02 (d, J = 6.88 Hz, 1H), 3.94 (dd, J =
4.12, 7.32 Hz, 1H), 6.82−6.92 (m, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.44
(dd, J = 5.04, 8.68 Hz, 1H), 7.88 (d, J = 8.24 Hz, 2H); 13C NMR (100
MHz,CDCl3): δ 21.8, 36.2, 40.8, 115.1, 115.3, 116.8, 117.0, 117.3,
128.2, 130.0, 133.8, 133.9, 134.5, 137.1, 137.2, 145.2, 161.1, 163.1
Ethyl 3-(2-Chlorophenyl)-1-tosylaziridine-2-carboxylate (9). Ob-
tained as a thick liquid in 62% yield with cis/trans ratio 1:1: Rf 0.27
(10% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1): 2982,
1749, 1596, 1477, 1444, 1370, 1337, 1292, 1197, 1163, 1090, 1035,
1
573, 563, 543; H NMR (400 MHz, CDCl3): δ 0.75 (t, J = 7.4 Hz,
3H), 1.01−1.07 (m, 1H), 1.19 (t, J = 7.4 Hz, 3H), 1.23−1.28 (m, 1H),
2.13−2.18 (m, 1H), 2.26−2.28 (m, 1H), 2.41 (s, 3H), 2.44 (s, 3H),
2.62−2.65 (m, 1H), 3.06−3.11 (m, 1H), 3.96 (d, J = 4.6 Hz, 1H), 4.00
(d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.0, 1.7 Hz,
1H), 7.12−7.17 (m, 2H), 7.28−7.35 (m, 6H), 7.84 (d, J = 8.5 Hz,
2H), 7.88 (d, J = 8.0 Hz, 2H); 13C NMR (1 MHz, CDCl3): 11.1, 12.4,
20.1, 21.8, 22.2, 44.4, 46.0, 47.9, 55.0, 127.1, 127.4, 127.5, 128.0, 128.2,
129.0, 129.7, 129.9, 130.2, 130.5, 132.5, 134.2, 134.3, 134.4, 134.9,
137.5, 144.4, 144.9; HRMS (ESI) calcd for C17H18Cl2NO2S (M + H)+
370.0435, found 370.0438.
1
917, 814, 759, 707, 684, 597, 561; H NMR (400 MHz, CDCl3): δ
0.94 (t, J = 6.8 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 2.43 (s, 3H), 2.45 (s,
3H), 3.40 (d, J = 3.6 Hz, 1H), 3.75 (d, J = 7.2 Hz, 1H), 3.91−4.00 (m,
2H), 4.21 (d, J = 7.1 Hz, 1H), 4.28−4.37 (m, 2H), 4.65 (d, J = 3.6 Hz,
1H), 7.05 (dd, J = 7.7, 1.8 Hz, 1H), 7.13−7.17 (m, 2H), 7.18−7.22
(m, 1H), 7.23−7.26 (m, 1H), 7.27−7.33 (m, 5H), 7.36 (d, J = 8.6 Hz,
2H), 7.82 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H); 13C NMR
(125 MHz, CDCl3): 13.8, 14.1, 21.7, 21.8, 42.7, 44.0, 45.9, 46.7, 61.7,
62.6, 126.6, 126.9, 127.8, 128.1, 128.3, 128.9, 129.5, 129.7, 129.9,
130.1, 131.2, 133.5, 133.9, 134.7, 140.0, 144.6, 145.5, 164.4, 165.5;
HRMS (ESI) calcd for C18H18ClNNaO4S (M + Na)+ 402.0543, found
402.0549.
2-(2,4-Dichlorophenyl)-3-propyl-1-tosylaziridine (3k). Obtained as
a thick liquid in 54% yield with cis/trans ratio 1:1: Rf 0.51 (5% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1): 2960, 2932, 2873,
1593, 1560, 1476, 1410, 1381, 1329, 1305, 1291, 1229, 1163, 1119,
1
1093, 1054, 1018, 997, 918, 897, 815, 762, 746, 717, 693, 594; H
NMR (400 MHz, CDCl3): δ 0.75 (t, J = 7.3 Hz, 3H), 1.00 (t, J = 7.3
Hz, 3H), 1.16−1.23 (m, 4H), 1.60−1.66 (m, 2H), 2.03−2.13 (m, 1H),
2.21−2.30 (m, 1H), 2.41 (s, 3H), 2.43 (s, 3H), 2.65−2.30 (m, 1H),
3.12−3.17 (m, 1H), 3.97−3.99 (m, 2H), 6.81 (d, J = 8.7 Hz, 1H), 7.04
(dd, J = 1.8, 8.2 Hz, 1H), 7.13 (m, 2H), 7.27 (s, 1H), 7.29 (s, 1H),
7.31−7.36 (m, 4H), 7.82 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H);
13C NMR (100 MHz, CDCl3): δ 13.7, 14.0, 20.2, 21.4, 21.7, 28.6, 30.6,
44.3, 46.0, 46.4, 53.6, 127.1, 127.4, 127.5, 128.0, 128.1, 129.0, 129.1,
129.7, 129.9, 130.5, 132.4, 134.2, 134.3, 134.4, 134.8, 137.5, 144.4,
144.9; HRMS (ESI) calcd for C18H20Cl2NO2S (M + H)+ 384.0592,
found 384.0598.
2-(2-Chloro-6-fluorophenyl)-1-tosylaziridine (3l). Obtained as a
thick liquid in 62% yield: IR νmax (neat, cm−1): 3509, 3092, 2924,
2854, 1606, 1576, 1494, 1453, 1370, 1329, 1306, 1291,1244, 1185,
1117, 1162, 1093, 1039, 1019, 985, 918, 896, 815, 788, 772, 730, 712,
694, 666, 640, 576, 555, 475; 1H NMR (400 MHz, CDCl3): δ 2.43 (s,
3H), 2.73 (d, J = 4.56 Hz, 1H), 3.02 (dd, J = 1.36, 7.32 Hz, 1H), 3.86
(dd, J = 4.60, 7.32 Hz, 1H), 6.86−6.91 (m, 1H), 7.10−7.20 (m, 2H),
7.33 (d, J = 7.8 Hz, 2H), 7.86−7.89 (m, 2H); 13C NMR (100
MHz,CDCl3): δ 21.8, 33.5, 36.5, 114.7, 114.9, 120.8, 120.9, 125.6,
125.6, 128.5, 129.7, 130.2, 130.3, 134.7, 136.1, 136.1, 144.8, 160.7,
163.2; HRMS (ESI) calcd for C15H14ClFNO2S (M + H)+ 326.0418,
found 326.0413.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02251.
■
S
NMR spectra for all the new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mkghorai@iitk.ac.in. Fax: (+91)-512-2597436. Phone:
(+91)-512-2597518.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.S. and Y.N. thank CSIR, India, for a research fellowship, and
M.K.G. is grateful to IIT-Kanpur and DST, India, for financial
support for conducting this research.
2-(2,5-Dichlorophenyl)-1-tosylaziridine (3m). Obtained as a thick
liquid in 52% yield: Rf 0.52 (30% ethyl acetate in petroleum ether); IR
νmax (neat, cm−1): 3067, 2924, 1596, 1563, 1493, 1469, 1398, 1373,
1330, 1306, 1292, 1257, 1228, 1186, 1163, 1138, 1109, 990, 919, 886,
REFERENCES
■
(1) Feniuk, W.; Humphrey, P. P. A. Drug Dev. Res. 1992, 26, 235.
(b) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620. (c) Gul, W.;
Hamann, M. T. Life Sci. 2005, 78, 442.
1
849, 814, 732, 706, 691, 664, 604, 586, 562, 513, 456; H NMR (500
MHz, CDCl3): δ 2.24 (d, J = 4.00 Hz, 1H), 2.45 (s, 3H), 3.01 (d, J =
6.9 Hz, 1H), 3.99 (dd, J = 2.65, 6.9 Hz, 1H), 7.16−7.18 (m, 2H),
7.24−7.26 (m, 1H), 7.36 (d, J = 8.05 Hz, 2H), 7.89 (d, J = 8.00 Hz,
2H); 13C NMR (100 MHz,CDCl3): δ 21.8, 36.0, 38.3, 127.6, 128.2,
129.4, 130.0, 130.4, 132.0, 133.2, 134.5, 135.0, 145.2; HRMS (ESI)
calcd for C15H14Cl2NO2S (M + H)+ 342.0122, found 342.0121.
2-(2,4-Dichlorophenyl)-1-tosylaziridine (3n). Obtained as a thick
liquid in 74% yield: IR νmax (neat, cm−1): 2923, 1594, 1560, 1478,
1376, 1228, 1185, 1163, 1093, 1051, 982, 910, 865, 815, 731, 690, 664,
(2) For recent reviews on indole synthesis, see: (a) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (b) Higuchi, K.; Kawasaki,
T. Nat. Prod. Rep. 2007, 24, 843. (c) Humphrey, G. R.; Kuethe, J. T.
Chem. Rev. 2006, 106, 2875. (d) Cacchi, S.; Fabrizi, G. C. Chem. Rev.
2005, 105, 2873. (e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045. (f) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9608. (g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111,
PR215. (h) Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011,
50, 1977. (i) Shiri, M. Chem. Rev. 2012, 112, 3508.
(3) Robinson, B. The Fisher Indole Synthesis; Wiley-Interscience: New
York, 1982.
(4) (a) Vieira, T. O.; Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett.
2008, 10, 4899. (b) Wang, C.; Huang, Y. Org. Lett. 2013, 15, 5294.
1
576, 557; H NMR (400 MHz, CDCl3): δ 2.24 (d, J = 4.56 Hz, 1H),
2.43 (s, 3H), 3.01 (d, J = 7.32 Hz, 1H), 3.96 (dd, J = 4.12, 7.32 Hz,
1H), 7.09−7.15 (m, 2H), 7.32−7.35 (m, 3H), 7.85−7.88 (m, 2H); 13C
NMR (100 MHz,CDCl3): δ 21.8, 35.8, 38.5, 127.5, 128.2, 128.5,
129.2, 129.9, 131.9, 134.5, 134.5, 134.6, 145.1; HRMS (ESI) calcd for
C15H14Cl2NO2S (M + H)+ 342.0122, found 342.0128.
H
DOI: 10.1021/acs.joc.5b02251
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The Journal of Organic Chemistry
Note
(c) Xiao, X.; Chen, T.-Q.; Ren, J.; Chen, W.-D.; Zeng, B.-B.
Tetrahedron Lett. 2014, 55, 2056. (d) Yamagishi, M.; Nishigai, K.; Ishii,
A.; Hata, T.; Urabe, H. Angew. Chem., Int. Ed. 2012, 51, 6471.
(e) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416.
(f) Pan, Y.-Y.; Wu, Y.-N.; Chen, Z.-Z.; Hao, W.-J.; Li, G.; Tu, S.-J.;
Jiang, B. J. Org. Chem. 2015, 80, 5764. (g) Liang, Y.; Yu, K.; Li, B.; Xu,
S.; Song, H.; Wang, B. Chem. Commun. 2014, 50, 6130. (h) Zhu, C.;
Ma, S. Org. Lett. 2013, 15, 2782.
Org. Chem. 2010, 75, 6173. (b) Ghorai, M. K.; Shukla, D.;
Bhattacharyya, A. J. Org. Chem. 2012, 77, 3740.
(13) (a) Cohen, T.; Herman, G.; Falck, J. R.; Mura, A. J., Jr. J. Org.
Chem. 1975, 40, 812. (b) Cohen, T.; Kuhn, D.; Falck, J. R. J. Am.
Chem. Soc. 1975, 97, 4749. (c) Cohen, T.; Mura, A. J.; Shull, D. W.;
Fogel, E. R.; Ruffner, R. J.; Falck, J. R. J. Org. Chem. 1976, 41, 3218.
(d) Cotton, F. A.; Wilkinson, Q. Advanced lnorganic Chemistry: A
Comprehensive Text, 2nd ed.; John Wiley & Sons: New York, 1966; p
105.
(5) 2-Alkyl indoles synthesis, see: (a) Cajaraville, A.; Lopez, S.;
Varela, J. A.; Saa, C. Org. Lett. 2013, 15, 4576. (b) Gong, T.-J.; Cheng,
W.-M; Su, W.; Xiao, B.; Fu, Y. Tetrahedron Lett. 2014, 55, 1859.
(c) Nallagonda, R.; Rehan, M.; Ghorai, P. Org. Lett. 2014, 16, 4786.
(d) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 2007, 48,
7721. (e) Gschwend, H. W.; Rodriguez, H. R. Heteroatom-Facilitated
Lithiations in Organic Reactions 1979, 26, 1−360 and references
therein. (f) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990.
(6) Azirines to indoles references; see: (a) Li, X.; Du, Y.; Liang, Z.;
Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643. (b) Taber, D. F.;
Tian, W. J. Am. Chem. Soc. 2006, 128, 1058. (c) Novikov, M. S.;
Khlebnikov, A. F.; Rostovskii, N. V.; Tcyrulnikov, S.; Suhanova, A. A.;
Zavyalov, K. V.; Yufit, D. S. J. Org. Chem. 2015, 80, 18. (d) Candito, D.
A.; Lautens, M. Org. Lett. 2010, 12, 3312. (e) Jana, S.; Clements, M.
D.; Sharp, B. K.; Zheng, N. Org. Lett. 2010, 12, 3736. (f) Wendling, L.
A.; Bergman, R. G. J. Org. Chem. 1976, 41, 831. (g) Nair, V.; Kim, K.
H. J. Org. Chem. 1975, 40, 3784.
(14) Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, U.K., 1988.
(15) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
In Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman
Group: London, 1989.
(16) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844.
(17) Zhang, L., Jr.; Dolbier, W. R.; Sheeller, B.; Ingold, K. U. J. Am.
Chem. Soc. 2002, 124, 6362.
(7) Ghorai, M. K.; Nanaji, Y. J. Org. Chem. 2013, 78, 3867.
(8) Ring-opening of aziridines with sulfur nucleophiles; see
references: (a) Zeng, F.; Alper, H. Org. Lett. 2010, 12, 5567.
(b) Karikomi, M.; D'hooghe, M.; Verniest, G.; De Kimpe, N. Org.
Biomol. Chem. 2008, 6, 1902. (c) D'hooghe, M.; Rottiers, M.; Kerkaert,
I.; De Kimpe, N. Tetrahedron 2005, 61, 8746. (d) Cernerud, M.;
Adolfsson, H.; Moberg, C. Tetrahedron: Asymmetry 1997, 8, 2655.
́ ́
(e) Concellon, J. M.; Bernad, P. L.; Suarez, J. R.; García-Granda, S.;
Díaz, M. R. J. Org. Chem. 2005, 70, 9411. (f) Prasad, D. J. C.; Sekar, G.
Org. Biomol. Chem. 2009, 7, 5091. (g) Alcaide, A.; Llebaria, A. J. Org.
Chem. 2014, 79, 2993. (h) Ghorai, M. K.; Sayyad, M.; Nanaji, Y.; Jana,
S. Chem. - Asian J. 2015, 10, 1480. (i) Ghorai, M. K.; Sahoo, A. K.;
Bhattacharyya, A. J. Org. Chem. 2014, 79, 6468.
(9) (a) Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2005, 7, 3509. (b) Ghorai, M. K.; Kumar, A.; Tiwari, D. P. J. Org.
Chem. 2010, 75, 137. (c) Ghorai, M. K.; Das, K.; Shukla, D. J. Org.
Chem. 2007, 72, 5859. (d) Ghorai, M. K.; Tiwari, D. P. J. Org. Chem.
́
2013, 78, 2617. (e) Stankovic, S.; D'hooghe, M.; Catak, S.; Eum, H.;
Waroquier, M.; Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem.
Soc. Rev. 2012, 41, 643. (f) Xing, S.; Ren, J.; Wang, K.; Cui, H.; Li, W.;
Yan, H. Tetrahedron 2015, 71, 6290. (g) Wu, B.; Gallucci, J. C.;
Parquette, J. R.; Rajanbabu, T. V. Chem. Sci. 2014, 5, 1102.
(10) Copper powder-catalyzed C−N cyclization references; see:
(a) Wolf, C.; Liu, S.; Mei, X.; August, A. T.; Casimir, M. D. J. Org.
Chem. 2006, 71, 3270. (b) Chen, Z.-G.; Wei, J.-F.; Li, R.-T.; Shi, X.-Y.;
Zhao, P.-F. J. Org. Chem. 2009, 74, 1371. (c) Lee, H. K.; Cho, C. S.
Synth. Commun. 2013, 43, 915. (d) Jiao, J.; Zhang, X.-R.; Chang, N.-
H.; Wei, J.; Wang, J.-F.; Shi, X.-Y.; Chen, Z.-G. J. Org. Chem. 2011, 76,
1180. (e) Ghorai, M. K.; Shahi, C. K.; Bhattacharyya, A.; Sayyad, M.;
Mal, A.; Wani, I. A.; Chauhan, N. Asian J. Org. Chem. 2015, 4, 1103.
(11) Cu(I)-catalyzed C−N cyclization references; see: (a) Jiang, L.
Molecules 2014, 19, 13448. (b) Xu, H.; Wolf, C. Chem. Commun. 2009,
3035. (c) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(d) Mirallai, S. I.; Koutentis, P. A. J. Org. Chem. 2015, 80, 8329.
(e) Ma, D. W.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (f) He, C.;
Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew. Chem., Int.
Ed. 2008, 47, 6414. (g) Kong, L.; Zhou, Y.; Huang, H.; Yang, Y.; Liu,
Y.; Li, Y. J. Org. Chem. 2015, 80, 1275. (h) Liu, H.; Duan, T.; Zhang,
Z.; Xie, C.; Ma, C. Org. Lett. 2015, 17, 2932.
(12) Earlier, we reported that the cis-aziridines are less reactive
toward SN2-type nucleophilic ring-opening compared to trans-
aziridines, and under the present reaction conditions, cis-aziridines
remained unreactive to thiophenol. (a) Ghorai, M. K.; Tiwari, D. P. J.
I
DOI: 10.1021/acs.joc.5b02251
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