Synthetic route to chiral indolines via ring-opening/C-N cyclization of activated 2-haloarylaziridines

Article abstract of DOI:10.1021/jo400287a

A practical approach for the synthesis of 3-substituted indolines via regio- and stereoselective S_N2-type ring-opening of 2-(2-halophenyl)-N-tosylaziridines with heteroatomic nucleophiles (O, N, and S) followed by palladium-catalyzed intramolecular C-N cyclization is reported in excellent yields (up to >99%) and enantiomeric excess (ee 99%).

Full text of DOI:10.1021/jo400287a

Article
pubs.acs.org/joc
Synthetic Route to Chiral Indolines via Ring-Opening/C−N
Cyclization of Activated 2‑Haloarylaziridines
Manas K. Ghorai* and Y. Nanaji
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: A practical approach for the synthesis of 3-
substituted indolines via regio- and stereoselective SN2-type
ring-opening of 2-(2-halophenyl)-N-tosylaziridines with heter-
oatomic nucleophiles (O, N, and S) followed by palladium-
catalyzed intramolecular C−N cyclization is reported in
excellent yields (up to >99%) and enantiomeric excess (ee
99%).
substrate and easily available phenols, anilines, and thiols as the
heteroatomic nucleophiles. Several interesting strategies have
been reported for the ring-opening of aziridines with different
heteroatomic and C-nucleophiles,12,13 and a number of reports
for aziridine-mediated heterocycle syntheses are known in the
literature.14 In continuation of our research activities in SN2-
type ring-opening cyclization of aziridines and azetidines,15 we
have developed a simple strategy for the synthesis of 3-
heteroatom-substituted racemic as well as chiral indolines with
excellent yields (up to 99%) and ee (99%) via the regio- and
stereoselective ring-opening of aziridines by phenols, anilines,
and thiophenols followed by palladium-catalyzed intramolecu-
lar C−N cyclization. Herein, we report our results.
INTRODUCTION
■
Indolines and their derivatives are found as essential subunits in
a number of naturally occurring and biologically active alkaloids
and other natural products.1 Some of the important natural
products containing the indoline ring system are pentopril (1),2
(−)-physostigmine (2),3 N-[1-(4-methoxybenzenesulfonyl)-
2,3-dihydro-1H-indol-7-yl]isonicotinamide (J30) (3),4 etc.
(Figure 1). Several of them exhibit a wide spectrum of
RESULTS AND DISCUSSION
■
To realize our idea, initially we studied the ring-opening of 2-
(2-bromophenyl)-N-tosylaziridine 4a with phenol 5a in the
presence of Cu(OTf)2 as the Lewis acid in CH2Cl2 at 0 °C to
produce the corresponding ring-opening product 6a (Scheme
1) in almost quantitative yield.
Scheme 1. Regioselective Ring-Opening of 4a with Phenol
Figure 1. Some biologically active indolines.
biological activities and also are of pharmacological utility as
antihypertensive2 and antitumor/anticancer agents,4 etc. A
number of attractive methodologies have been developed for
the synthesis of substituted indolines,5 although efficient routes
for their enantioselective synthesis are limited.6−10 Palladium-
catalyzed amination reactions made a significant contribution in
organic synthesis for the construction of Caryl−N bonds from
both activated and nonactivated aryl halogenides.11
We anticipated that indolines could easily be synthesized
from the ring-opening of 2-(2-haloaryl)-N-activated aziridines
with any nucleophile followed by palladium-catalyzed intra-
molecular C−N cyclization. For operational simplicity, we
considered 2-(2-halophenyl)-N-tosylaziridine as the starting
Next 6a was subjected to Pd-catalyzed cyclization to obtain
indoline 7a (Scheme 2).
To find out the optimum reaction conditions, 6a was
subjected to different Pd-catalysts, solvents, ligands, and a
number of bases. The results are summarized in Table 1, and
the best result was obtained with Pd(OAc)2, ( )-BINAP, and
Received: February 6, 2013
Published: April 2, 2013
© 2013 American Chemical Society
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diamino compound 9a in almost quantitative yield in 2 h.
When the aziridine 4a was treated with aniline (neat) at rt, the
corresponding diamino compound 9a was obtained in almost
quantitative yield within 1 h. Next, the Pd-catalyzed cyclization
of 9a employing Pd(OAc)2, ( )-BINAP, and K2CO3 afforded
the corresponding indoline 10a (Scheme 4) in almost
quantitative yield.
Scheme 2. Pd-Catalyzed C−N Cyclization of 6a
K2CO3 as the base in toluene at 115−120 °C (Table 1, entry
9).
Scheme 4. Synthesis of Indoline 10a
Table 1. Pd-Catalyzed Intramolecular C−N Cyclization of 6a
yield (%)
a
entry
1
reaction conditions
of 7a
Pd2(dba)3 (2 mol %), P(o-tolyl)3 (8 mol %), K2CO3,
toluene, 100 °C, 8 h
40
2
Pd2(dba)3 (5 mol %), P(2-furyl)3 (20 mol %), Cs2CO3,
toluene, 100 °C, 9 h
60
3
4
7
8
CuI (0.5 equiv), K2CO3, DMSO, 70 °C, 8 h
Pd(OAc)2, (o-tolyl)3P, K2CO3, DMF, 110 °C, 7 h
Pd(OAc)2, dppb, toluene, K2CO3, reflux, 5 h
Pd(OAc)2, dpp, toluene, K2CO3, reflux, 5 h
Pd(OAc)2, ( )-BINAP, K2CO3, toluene, 4 h
Pd(OAc)2, ( )-BINAP, Cs2CO3, toluene, 4 h
Pd(OAc)2, dppb, toluene, t-BuOK, reflux, 4 h
Pd(OAc)2, DPE-Phos, Cs2CO3, toluene, 100 °C, 4 h
30
Nr
38
12
To make our strategy more attractive and straightforward as
a synthetic methodology, a one-pot (stepwise) protocol for the
synthesis of indolines 10a−e via the ring-opening of
monosubstituted aziridine 4a was explored. Interestingly, the
same reaction sequence as shown in Scheme 4, under one-pot
conditions, produced the indoline 10a in excellent yield.
Generalization of this approach was made by studying the
reaction of aziridine 4a with a number of anilines 8b−e
(Scheme 5) and the results are shown in Table 3.
b
9
>99
85
b
10
11
12
25
30
a
All of the reactions were carried out with 6a (1.0 mmol), Pd catalyst
(20 mol %), ligand (40 mmol %), and base (2.5 equiv) in solvent (6.0
mL) under argon. The reaction mixtures were refluxed at 115−120
°C for 3−6 h.
b
Compound 7a was characterized by 1H NMR, 13C NMR, 1H
COSY spectra, and mass spectral data. The structure of 7b was
unequivocally confirmed by X-ray crystallographic analysis. To
generalize this approach, several N-[2-(2-bromophenyl)-2-
aryloxyethyl]-4-methylbenzenesulfonamides 6b−i were pre-
pared from aziridine 4a and phenols 5b−i. Similarly, N-[2-(2-
bromophenyl)-2-methoxyethyl]-4-methylbenzenesulfonamide
6j was prepared from 4a using MeOH as the nucleophile.
Compounds 6b−j were cyclized under the optimized
conditions to afford the corresponding indolines 7b−j (Scheme
3) in excellent yields, and the results are shown in Table 2.
To extend the scope of the methodology, the reaction of
aziridine 4a with a N-nucleophile was studied. The aziridine 4a
was treated with aniline in the presence of Cu(OTf)2 as the
Lewis acid in CH2Cl2 at 0 °C to afford the corresponding
Scheme 5. Synthesis of Indolines 10a−e
The strategy was further extended to sulfur-nucleophiles
(thiols). When the aziridine 4a was treated with thiophenol 11a
in the presence of Cu(OTf)2 as the Lewis acid in CH2Cl2 at rt,
the corresponding ring-opening product 12a was produced
(Scheme 6) in almost quantitative yield. Next, the Pd-catalyzed
cyclization of 12a employing Pd(OAc)2, ( )-BINAP, and
K2CO3 afforded the corresponding indoline 13a (Scheme 6) in
almost quantitative yield. Unfortunately, Cu(OTf)2-catalyzed
ring-opening followed by Pd-catalyzed cyclization was not
successful under the one-pot conditions. To make the one-pot
Scheme 3. Synthesis of Indolines 7a−j
Scheme 6. Synthesis of Indoline 13a
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a,b
Table 2. Regioselective Ring-Opening of 4a and Pd-Catalyzed Intramolecular C−N Cyclization of 6a−j
a
All of the reactions were carried out with 4a (1.0 mmol) and 5a−j (1.0 mmol) in dry DCM (2.0 mL) under N2 atmosphere in the presence of
b
Cu(OTf)2 (30 mol %). All of the reactions were carried out with 6a−j (1.0 mmol), Pd(OAc)2 (20 mol %), ( )-BINAP (40 mmol %), and K2CO3
(2.5 equiv) in toluene (6.0 mL) under argon for 2−6 h under reflux at 110−115 °C.
protocol to work, the reaction was studied in the absence of a
Lewis acid. The reaction of 4a with thiophenol was found to be
slower (2 h) without using a base, and it was completed within
25 min in the presence of K2CO3 as the base probably because
of greater nucleophilicity of a thiophenolate ion.
To our delight, 4a on treatment with thiophenol 11a in the
presence of K2CO3 as the base followed by Pd-catalyzed
cyclization under one-pot condition produced the correspond-
ing indoline 13a in excellent yield. To generalize this approach,
a number of thiols 11b−h (Scheme 7) were studied, and the
results are shown in Table 4.
Finally, the synthetic potential of the strategy is demon-
strated by the synthesis of chiral indolines. To our great
pleasure, ring-opening of chiral aziridine (S)-4b16 with aniline
8a afforded the ring-opening product 14a with excellent yield
and ee (99%) (Scheme 8).
The compound 14a upon Pd-catalyzed intramolecular
cyclization produced the corresponding indoline (R)-10a
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a
Table 3. Synthesis of Indolines 10a−e
Table 4. One-Pot Ring-Opening/C−N Cyclization of
a
Activated Aziridines with Sulfur Nucleophiles
a
All of the reactions were carried out with 4a (1.0 mmol), 8 (2.2
mmol), and toluene (6.0 mL), rt, 1 h; Pd(OAc)2 (20 mol),
( )-BINAP (40 mol %), K2CO3 (2.5 equiv), under reflux at 115−
120 °C, 2−4 h.
Scheme 7. Synthesis of Indolines 13a−h from 4a under One-
Pot Conditions
a
All of the reactions were carried out with 4a (1.0 mmol), 11 (1.1
mmol), K2CO3 (1.1 equiv), and toluene (6.0 mL), rt, 25 min;
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (2.5
equiv), under reflux at 110−115 °C, 2−4 h.
(Scheme 8) in good overall yield and excellent ee (99%).
Similar ring-opening cyclization of (S)-4b with the other
anilines 8b−d gave similar results (Scheme 8, Table 5).
Mechanism. We do believe that the reaction follows a
Scheme 8. Synthesis of Chiral 3-Substituted Indolines
similar mechanistic pathway as reported by us earlier.15f,g
A
probable mechanism for the formation of indolines 10a−d is
described in Figure 2. SN2-type ring-opening of N-tosylaziridine
4 by the heteroatomic nucleophiles (O, N, and S) generates the
corresponding ring-opening products 15a−d which undergo
Pd-catalyzed intramolecular C−N coupling to obtain the
corresponding indolines 10a−d.
CONCLUSION
■
In conclusion, we have developed a simple and practical
strategy for the synthesis of racemic and nonracemic 3-
heteroatom-substituted indolines via SN2-type ring-opening of
2-(2-halophenyl)-N-tosylaziridines with heteroatomic nucleo-
philes (O, N, and S) followed by Pd-catalyzed C−N cyclization
in excellent yields and ee’s under a two-step (for O-
nucleophiles) or one-pot (stepwise for N- and S-nucleophiles)
protocol.
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Table 5. Synthesis of Chiral 3-Substituted Indolines from Chiral Aziridine (S)-4b
a
ee was determined by HPLC using a Chiralpak AS-H or OD-H column.
spectra were recorded at 100 MHz/125 MHz. HRMS were obtained
using (ESI) mass spectrometer (TOF). IR spectra were recorded as
neat for liquid and in KBr for solids. Melting points were determined
using a hot-stage apparatus and are uncorrected. Optical rotations
were measured using a 2.0 mL cell with a 1.0 dm path length and are
reported as [α]25 (c in g per 100 mL of solvent) at 25 °C.
D
Enantiomeric ratios (er) were determined by HPLC using Chiralpak
AH-H and OD-H analytical column (detection at 254 nm). 2-(2-
Bromophenyl)-1-tosylaziridine and (2-(2-chlorophenyl)-1-tosylaziri-
dine were prepared from 2-bromo- and 2-chlorostyrene, respectively,
following a reported procedure.16a (S)-2-(2-Chlorophenyl)-1-tosylazir-
idine was prepared from the corresponding amino alcohol employing
known procedures.16b,c
2-(2-Bromophenyl)-1-tosylaziridine (4a). Obtained as a solid
compound in 90% yield: mp 85−87 °C; Rf 0.57 (20% ethyl acetate
in petroleum ether); IR νmax (KBr, cm−1) 3359, 3261, 3051, 1595,
1566, 1496, 1472, 1453, 1432, 1378, 1323, 1228, 1185, 1137, 1042,
Figure 2. Proposed reaction mechanism.
1
1023, 981, 908, 843, 817, 769, 728, 698, 673, 650, ; H NMR (500
MHz, CDCl3) 2.26 (d, J = 4.30 Hz, 1H), 2.44 (s, 3H), 3.02 (d, J = 7.45
Hz, 1H), 3.97−3.99 (m, 1H), 7.11−7.22 (m, 3 H), 7.35 (d, J = 8.00
Hz, 1H), 7.50 (d, J = 8.05 Hz, 2H), 7.90 (d, J = 8.05 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 21.7, 36.0, 41.3, 123.4, 126.5, 127.7, 127.9,
128.2, 129.7, 129.8, 130.0, 132.5, 134.7, 134.8, 145.0; HRMS (ESI)
calcd for C15H15BrNO2S (M + H)+ 352.0007, found 352.0007.
(S)-2-(2-Chlorophenyl)-1-tosylaziridine (4b). Obtained as a thick
liquid in 85% yield: Rf 0.57 (20% ethyl acetate in petroleum ether); IR
νmax (KBr, cm−1) 3646, 3066, 2925, 1595, 1453, 1379, 1325, 1227,
1162, 1093, 908, 843, 818, 766, 731, 712, 690, 656, 569, 557; 1H NMR
(500 MHz, CDCl3) 2.28 (d, J = 4.28 Hz, 1H), 2.44 (s, 3H), 3.03 (d, J
= 7.33 Hz, 1H), 4.02−4.04 (m, 1H), 7.15−7.22 (m, 3 H), 7.32 (d, J =
7.94 Hz, 1H), 7.35 (d, J = 7.94 Hz, 2H), 7.89 (d, J = 8.25 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 21.8, 35.7, 39.1, 127.1, 127.6, 128.2, 129.3,
129.4, 129.9, 133.2, 133.9, 134.7, 144.9; HRMS (ESI) calcd for
C15H15ClNO2S (M + H)+ 308.0512, found 308.0519. The
enantiomeric excess was 99%; the enantiomeric excess was determined
EXPERIMENTAL SECTION
■
General Procedures. Analytical thin-layer chromatography
(TLC) was carried out using silica gel 60 F254 precoated plates.
Visualization was accomplished with UV lamp or I2 stain. Silica gel
230−400 mesh size was used for flash column chromatography using
the combination of ethyl acetate and petroleum ether as eluent. Unless
noted, all of the reactions were carried out in oven-dried glassware
under an atmosphere of nitrogen/argon using anhydrous solvents.
Where appropriate, all of the reagents were purified prior to use
following the guidelines of Perrin and Armerego.17 All commercial
reagents were used as received. Proton nuclear magnetic resonance
(1H NMR) spectra were recorded at 400 MHz/500 MHz. Chemical
shifts were recorded in parts per million (ppm, δ) relative to
1
tetramethylsilane (δ 0.00). H NMR splitting patterns are designated
as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet
(q), multiplet (m). Carbon nuclear magnetic resonance (13C NMR)
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by chiral HPLC analysis (Chiralpak AS-H column), n-hexane/2-
propanol = 99:1, flow rate = 1.0 mL/min, tR(1) = 55.22 min (minor,
R), tR(2) = 65.26, min (major, S).
aniline (2.2 equiv) was taken under N2 atmosphere in a two-necked
round-bottom flask. The reaction mixture was stirred for 1 h at rt, and
the reaction was monitored by TLC. The solvent was removed under
reduced pressure to give the crude reaction mixture which was purified
by flash column chromatography on silica gel (230−400 mesh) using
ethyl acetate in petroleum ether to afford the pure product as a white
solid.
General Procedure for the Cu(OTf)2-Catalyzed Ring-Open-
ing of Aziridines. Method A. To a stirred suspension of anhydrous
copper triflate (30 mol %) in dry DCM (2.0 mL) under N2
atmosphere was added a solution of aziridine 4a (1.0 equiv) in dry
DCM (2.0 mL) dropwise at rt. The reaction mixture was stirred at rt
for 5 min, and a solution of phenols (1.0 equiv) in dry DCM (2.0 mL)
was added dropwise over a period of 1 min at rt. The reaction mixture
was further stirred for 1 h at rt. The reaction was monitored by TLC
and quenched with saturated aqueous sodium bicarbonate solution
(1.0 mL). The aqueous layer was extracted with DCM (3 × 15.0 mL).
The combined organic extract was washed with H2O (3 × 15.0 mL)
and brine (20.0 mL) and dried over Na2SO4. The solvent was removed
under reduced pressure to give the crude products 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.
General Procedure for the C−N Cyclization. Method B. N-(2-
(2-Bromophenyl)-2-aryloxyethyl)-4-methylbenzenesulfonamide 6 (1.0
equiv) in dry toluene (2.0 mL) was added to a suspension of
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (2.5
equiv) in 6.0 mL of dry toluene under argon at room temperature. The
reaction mixture was heated at 110−115 °C for 2−6 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 × 10 mL). The combined organic extract was washed with H2O (3
× 10 mL) and brine (30 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 products as white
solids.
General Procedure for a One-Pot (Stepwise) Protocol for the
Synthesis of Indolines (Ring-Opening with Nitrogen Nucleo-
philes). Method C. A solution of aziridine 4a (1.0 equiv) in anilines
(2.2 equiv) was taken under N2 atmosphere in a three-necked round-
bottom flask. The reaction mixture was further stirred for 1 h at rt.
Subsequently, Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), K2CO3
(2.5 equiv), and toluene (6.0 mL) were introduced to the reaction
mixture. Then the reaction mixture was heated at 115−120 °C for 2−4
h, and the progress of the reaction was monitored by TLC. It was
cooled to room temperature, quenched with water, and extracted with
ethyl acetate (3 × 10 mL). The combined organic extract was washed
with H2O (3 × 10.0 mL) and brine (30.0 mL) and dried over Na2SO4.
The solvent was removed under reduced pressure to give 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 solid.
General Procedure for a One-Pot (Stepwise) Protocol for the
Synthesis of Indolines (Ring-Opening with Sulfur Nucleo-
philes). Method D. To a stirred suspension of K2CO3 (1.1 equiv) in
dry toluene (2.0 mL) under N2 atmosphere was added a solution of
thiophenols 11 (1.1 equiv) in dry toluene (2.0 mL) dropwise at rt. The
reaction mixture was stirred at rt for 25 min, and a solution of aziridine
4a (1.0 equiv) in dry toluene (2.0 mL) was added dropwise over a
period of 1 min at rt. The reaction mixture was further stirred for 25
min at the same temperature. Pd(OAc)2 (20 mol %), ( )-BINAP (40
mol %), and K2CO3 (2.5 equiv) were added subsequently to the
reaction mixture, and then the reaction mixture was heated at 115−
120 °C for 2−5 h. The reaction was monitored by TLC. It was cooled
to room temperature, quenched with water, and extracted with ethyl
acetate (3 × 10.0 mL). The combined organic extract was washed with
H2O (3 × 10.0 mL) and brine (30.0 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.
N-(2-(2-Bromophenyl)-2-phenoxyethyl)-4-methylbenzenesulfo-
namide (6a). The general method A described above was followed
when 4a (71 mg, 0.2 mmol) was reacted with phenol 5a (19 μL, 0.22
mmol) in the presence of Cu(OTf)2 (30 mol %) at rt for 1 h to afford
6a (89.0 mg, 0.199 mmol) as a white solid in >99% yield: mp 59−61
°C; Rf 0.47 (30% ethyl acetate in petroleum ether); IR νmax (KBr,
cm−1) 3286, 2922, 2851, 1595, 1492, 1409, 1330, 1233, 1160, 1093,
1
1065, 1021, 753, 689, 661, 548; H NMR (500 MHz, CDCl3) δ 2.37
(s, 3H) 3.16−3.21 (m, 1H), 3.58−3.63 (m, 1H), 5.10−5.13 (m, 1H),
5.36−5.39 (m, 1H), 6.61 (d, J = 8.25 Hz, 2H), 6.87−6.90 (m, 1H),
7.10−7.21 (m, 6H), 7.29−7.31 (m, 1H), 7.51 (d, J = 7.95 Hz, 1H),
7.73 (d, J = 8.25 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.6, 47.5,
76.9, 115.4, 121.6, 121.9, 127.2, 127.9, 128.1, 129.5, 129.8, 129.9,
133.1, 136.9, 137.4, 143.5, 156.8; HRMS (ESI) calcd for
C21H20BrNNaO3S (M + Na)+ 468.0245, found 468.0245.
3-Phenoxy-1-tosylindoline (7a). The general method B described
above was followed when 6a (67.0 mg, 0.15 mmol) was reacted with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (51.8 mg,
0.375 mmol) at 110−115 °C for 3 h to afford 7a (55.0 mg, 0.150
mmol) as a white solid in >99% yield: mp 136−138 °C; Rf 0.25 (30%
ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3423, 3055,
2921, 1597, 1487, 1468, 1348, 1246, 1222, 1162, 1107, 1088, 1071,
1
1055, 755, 671, 578; H NMR (500 MHz, CDCl3) δ 2.37 (s, 3H),
4.03−4.06 (m, 1H), 4.13−4.17 (m, 1H), 5.55−5.56 (m, 1H), 6.71 (d, J
= 8.56 Hz, 2H), 6.98−7.01 (m, 1H), 7.05−7.08 (m, 1H), 7.19 (d, J =
8.25 Hz, 2H), 7.25−7.29 (m, 3H), 7.37−7.40 (m, 1H), 7.62 (d, J =
8.25 Hz, 2H), 7.76 (d, J = 7.95 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.6, 55.8, 74.6, 115.7, 115.8, 121.8, 124.2, 126.5, 127.4,
129.7, 129.8, 129.9, 130.8, 133.9, 142.8, 144.3, 156.7; HRMS (ESI)
calcd for C21H19NNaO3S (M + Na)+ 388.0983, found 388.0984.
N-(2-(2-Bromophenyl)-2-(4-methoxyphenoxy)ethyl)-4-methyl-
benzenesulfonamide (6b). The general method A described above
was followed when 4a (71 mg, 0.2 mmol) was reacted with phenol 5b
(27.3 mg, 0.22 mmol) in the presence of Cu(OTf)2 (30 mol %)] at rt
for 1 h to afford 6b (94.0 mg, 0.197 mmol) as a white solid in 99%
yield: mp 85−87 °C; Rf 0.35 (30% ethyl acetate in petroleum ether);
IR νmax (KBr, cm−1) 3289, 2921, 2837, 1506, 1439, 1325, 1228, 1159,
1093, 1059, 1033, 938, 830, 815, 760, 735, 665; 1H NMR (400 MHz,
CDCl3) δ 2.42 (s, 3H) 3.16−3.22 (m, 1H), 3.59−3.65 (m, 1H), 3.74
(s, 3H), 5.16−5.19 (m, 1H), 5.34−5.37 (m, 1H), 6.58−6.61 (m, 2H),
6.71−6.74 (m, 2H), 7.14−7.18 (m, 1H), 7.23−7.27 (m, 3H), 7.35−
7.37 (m, 1H), 7.53−7.55 (m, 1H), 7.77 (d, J = 6.2 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 21.6, 47.5, 55.7, 77.5, 114.6, 116.3, 122.0, 127.2,
128.0, 128.1, 129.8, 129.9, 133.1, 137.0, 137.3, 143.5, 150.8, 154.3;
HRMS (ESI) calcd for C22H22BrNNaO4S (M + Na)+ 498.0351, found
498.0357.
3-(4-Methoxyphenoxy)-1-tosylindoline (7b). The general method
B described above was followed when 6b (72.0 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 6 h to afford 7b
(55.0 mg, 0.139 mmol) as a white solid in 93% yield: mp 50−52 °C; Rf
0.38 (30% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3388, 3047, 2924, 2835, 1600, 1505, 1465, 1355, 1221, 1166, 1108,
1
1090, 1035, 825, 673, 578; H NMR (500 MHz, CDCl3) δ 2.36 (s,
3H), 3.77 (s, 3H), 4.06−4.09 (m, 2H), 5.44−5.46 (m, 1H), 6.63 (d, J
= 9.17 Hz, 2H), 6.80 (d, J = 9.17 Hz, 2H), 7.03−7.06 (m, 1H), 7.19
(d, J = 8.56 Hz, 2H), 7.22 (d, J = 7.34 Hz, 1H), 7.35−7.38 (m, 1H),
7.63 (d, J = 8.25 Hz, 2H), 7.75 (d, J = 7.95 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 21.7, 55.7, 55.8, 75.7, 114.8, 115.6, 117.5, 124.1,
126.4, 127.5, 129.8, 130.0, 130.8, 134.0, 142.7, 144.2, 150.6 154.7;
HRMS (ESI) calcd for C22H21NNaO4S (M + Na)+ 418.1089, found
418.1089.
General Procedure for the Ring-Opening of Chiral
Aziridines. Method E. A solution of aziridine 4b (1.0 equiv) in
3872
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Article
1
N-(2-(2-Bromophenyl)-2-(o-tolyloxy)ethyl)-4-methylbenzenesul-
fonamide (6c). The general method A described above was followed
when 4a (71 mg, 0.2 mmol) was reacted with phenol 5c (23 μL, 0.22
mmol) in the presence of Cu(OTf)2 (30 mol %) at rt for 1 h to afford
6c (92.0 mg, 0.199 mmol) as a white solid in >99% yield: mp 75−77
°C; Rf 0.40 (20% ethyl acetate in petroleum ether); IR νmax (KBr,
cm−1) 3296, 2921, 2851, 1596, 1492, 1464, 1437, 1330, 1236, 1160,
1124, 1093, 1020, 813, 750, 660, 550; 1H NMR (500 MHz, CDCl3) δ
2.29 (s, 3H) 2.36 (s, 3H), 3.21−3.26 (m, 1H), 3.58−3.63 (m, 1H),
5.03−5.06 (m, 1H), 5.29−5.41 (m, 1H), 6.20 (d, J = 8.02 Hz, 1H),
6.78−6.81 (m, 1H), 6.88−6.91 (m, 1H), 7.10−7.13 (m, 2H), 7.17−
7.21 (m, 3H), 7.25−7.26 (m, 1H), 7.51 (d, J = 8.02 Hz, 1H), 7.71 (d, J
= 8.31 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 16.6, 21.6, 47.6, 76.5,
112.2, 121.2, 121.9, 126.5, 126.8, 127.1, 127.7, 128.2, 129.8, 130.0,
130.9, 133.1, 136.9, 137.3, 143.6, 154.6; HRMS (ESI) calcd for
C22H22BrNNaO3S (M + Na)+ 482.0401, found 482.0407.
3-(o-Tolyloxy)-1-tosylindoline (7c). The general method B
described above was followed when 6c (69.0 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 5 h to afford 7c
(55.0 mg, 0.144 mmol) as a white solid in 97% yield: mp 106−108 °C;
Rf 0.44 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3417, 2918, 1599, 1492, 1462, 1353, 1237, 1186, 1160, 1110, 1010,
978, 937, 814, 748, 675, 653, 581, 541; 1H NMR (500 MHz, CDCl3) δ
1.85 (s, 3H), 2.35 (s, 3H), 4.06 (dd, J = 3.06, 12.53 Hz, 1H), 4.20 (dd,
J = 7.03, 12.53 Hz, 1H), 5.54 (dd, J = 2.45, 6.72 Hz, 1H), 6.77 (d, J =
8.25 Hz, 1H), 6.89−6.92 (m, 1H), 7.03−7.06 (m, 1H), 7.11 (d, J =
7.34 Hz, 1H), 7.14−7.25 (m, 4H), 7.36−7.39 (m, 1H), 7.66 (d, J =
8.25 Hz, 2H), 7.76 (d, J = 8.25 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 16.1, 21.6, 56.1, 75.1, 112.9, 115.3, 121.6, 124.0, 126.4,
126.8, 127.4, 128.2, 129.8, 130.1, 130.7, 131.3, 134.0, 142.6, 144.3,
155.1; HRMS (ESI) calcd for C22H21NNaO3S (M + Na)+ 402.1140,
found 402.1140.
N-(2-(2-Bromophenyl)-2-(4-tert-butylphenoxy)ethyl)-4-methyl-
benzenesulfonamide (6d). The general method A described above
was followed when 4a (71 mg, 0.2 mmol) was reacted with phenol 5d
(33.0 mg, 0.22 mmol) in the presence of Cu(OTf)2 (30 mol %) at rt
for 1 h to afford 6d (99.0 mg, 0.197 mmol) as a white solid in 99%
yield: mp 62−64 °C; Rf 0.28 (20% ethyl acetate in petroleum ether);
IR νmax (KBr, cm−1) 3287, 2961, 2867, 1605, 1511, 1331, 1237, 1184,
1161, 1094, 1070, 830, 813, 756, 661; 1H NMR (500 MHz, CDCl3) δ
1.24 (s, 9H) 2.37 (s, 3H), 3.13−3.19 (m, 1H), 3.55−3.60 (m, 1H),
5.08−5.10 (m, 1H), 5.31−5.33 (m, 1H), 6.54 (d, J = 8.86 Hz, 2H),
7.10−7.25 (m, 6H), 7.31−7.33 (m, 1H), 7.50−7.51 (m, 1H), 7.72 (d, J
= 8.25 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.6, 31.5, 34.1, 47.6,
77.0, 114.8, 121.8, 126.3, 127.2, 128.0, 128.1, 129.8, 129.9, 133.0,
137.1, 137.3, 143.5, 144.3, 154.6; HRMS (ESI) calcd for
C25H28BrNNaO3S (M + Na)+ 524.0871, found 524.0876.
1060, 1021, 957, 904, 861, 807, 766, 683, 545; H NMR (500 MHz,
CDCl3) δ 2.24 (s, 3H) 2.38 (s, 3H), 3.14−3.19 (m, 1H), 3.56−3.61
(m, 1H), 5.07−5.10 (m, 1H), 5.35−5.37 (m, 1H), 6.35−6.37 (m, 1H),
6.48 (s, 1H), 6.70 (d, J = 7.45 Hz, 1H), 7.01 (t, J = 7.73 Hz, 1H),
7.10−7.13 (m, 1H), 7.19−7.21 (m, 3H), 7.29−7.31 (m, 1H), 7.51 (d, J
= 8.02 Hz, 1H), 7.72 (d, J = 8.02 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 21.5, 21.6, 47.6, 76.8, 112.1, 116.4, 121.8, 122.5, 127.2,
127.9, 128.1, 129.2, 129.8, 129.9, 133.0, 137.0, 137.5, 139.6, 143.5,
156.8; HRMS (ESI) calcd for C22H22BrNNaO3S (M + Na)+ 482.0401,
found 482.0401.
3-(m-Tolyloxy)-1-tosylindoline (7e). The general method B
described above was followed when 6e (69.0 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 2 h to afford 7e
(54.0 mg, 0.142 mmol) as a white solid in 95% yield: mp 52−54 °C; Rf
0.55 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3404, 3046, 2920, 1601, 1488, 1465, 1356, 1254, 1166, 1090, 1065,
765, 735, 675, 653; 1H NMR (500 MHz, CDCl3) δ 2.32 (s, 3H), 2.37
(s, 3H), 4.02 (dd, J = 2.45, 12.53 Hz, 1H), 4.15 (dd, J = 6.72, 12.84
Hz, 1H), 5.54 (dd, J = 2.45, 6.72 Hz, 1H), 6.49−6.54 (m, 2H), 6.81 (d,
J = 7.34 Hz, 1H), 7.06−7.09 (m, 1H), 7.16 (t, J = 7.64 Hz, 1H), 7.19
(d, J = 7.95 Hz, 2H), 7.29 (d, J = 7.34 Hz, 1H), 7.36−7.39 (m, 1H),
7.62 (d, J = 8.25 Hz, 2H), 7.76 (d, J = 8.25 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 21.6, 21.7, 55.8, 74.5, 112.5, 115.7, 116.7, 122.6,
124.2, 126.4, 127.5, 129.4, 129.8, 130.0, 130.8, 133.9, 139.9, 142.7,
144.2, 156.7; HRMS (ESI) calcd for C22H21NNaO3S (M + Na)+
402.1140, found 402.1145.
N-(2-(2-Bromophenyl)-2-(p-tolyloxy)ethyl)-4-methylbenzenesul-
fonamide (6f). The general method A described above was followed
when 4a (71 mg, 0.2 mmol) was reacted with phenol 5f (23.8 mg, 0.22
mmol) in the presence of Cu(OTf)2 (30 mol %) at rt for 1 h to afford
6f (90.0 mg, 0.195 mmol) as a white solid in 98% yield: mp 144−146
°C; Rf 0.41 (20% ethyl acetate in petroleum ether); IR νmax (KBr,
cm−1) 3295, 2919, 1615, 1509, 1439, 1329, 1229, 1160, 1092, 1021,
1
813, 757, 660; H NMR (500 MHz, CDCl3) δ 2.21 (s, 3H) 2.37 (s,
3H), 3.13−3.19 (m, 1H), 3.56−3.61 (m, 1H), 5.12−5.14 (m, 1H),
5.33−5.35 (m, 1H), 6.51 (d, J = 8.59 Hz, 2H), 6.94 (d, J = 8.88 Hz,
2H), 7.09−7.12 (m, 1H), 7.18−7.20 (m, 3H), 7.29−7.31 (m, 1H),
7.50 (d, J = 7.73 Hz, 1H), 7.73 (d, J = 8.31 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 20.5, 21.6, 47.5, 77.0, 115.2, 121.9, 127.2, 127.9,
128.1, 129.8, 129.9, 130.0, 130.9, 133.0, 137.0, 137.4, 143.5, 154.7;
HRMS (ESI) calcd for C22H22BrNNaO3S (M + Na)+ 482.0401, found
482.0409.
3-(p-Tolyloxy)-1-tosylindoline (7f). The general method B
described above was followed when 6f (69.0 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 3 h to afford 7f
(55.0 mg, 0.145 mmol) as a white solid in 97% yield: mp 104−106 °C;
Rf 0.50 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3415, 2921, 1603, 1508, 1355, 1289, 1226, 1166, 1109, 1090, 812, 755,
723, 704, 673, 651, 578; 1H NMR (500 MHz, CDCl3) δ 2.29 (s, 3H),
2.36 (s, 3H), 4.03 (dd, J = 2.45, 12.55 Hz, 1H), 4.13 (dd, J = 6.70,
12.55 Hz, 1H), 5.51−5.52 (m, 1H), 6.60 (d, J = 8.55 Hz, 2H), 7.04−
7.07 (m, 3H), 7.18 (d, J = 8.55 Hz, 2H), 7.25−7.28 (m, 1H), 7.36−
7.39 (m, 1H), 7.62 (d, J = 8.25 Hz, 2H), 7.74 (d, J = 8.25 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 20.6, 21.6, 55.8, 74.9, 115.6, 115.8, 124.2,
126.5, 127.5, 129.8, 130.0, 130.2, 130.8, 131.2, 133.9, 142.7, 144.2,
154.6; HRMS (ESI) calcd for C22H21NNaO3S (M + Na)+ 402.1140,
found 402.1146.
3-(4-tert-Butylphenoxy)-1-tosylindoline (7d). The general method
B described above was followed when 6d (75.4 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 5 h to afford 7d
(61.0 mg, 0.144 mmol) as a white solid in 96% yield: mp 97−99 °C; Rf
0.44 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3426, 3029, 2968, 2870, 1602, 1510, 1366, 1356, 1225, 1180, 1166,
1
1055, 1010, 832, 805, 756, 647; H NMR (500 MHz, CDCl3) δ 1.30
(s, 9H), 2.37 (s, 3H), 4.01−4.05 (m, 1H), 4.13−4.17 (m, 1H), 5.53−
5.55 (m, 1H), 6.67 (d, J = 8.88 Hz, 2H), 7.05−7.08 (m, 1H), 7.19 (d, J
= 8.02 Hz, 2H), 7.25−7.38 (m, 4H), 7.63 (d, J = 8.31 Hz, 2H), 7.74
(d, J = 8.02 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.6, 31.6, 34.2,
55.9, 74.7, 115.2, 115.5, 124.2, 126.4, 126.5, 127.5, 129.8, 130.0, 130.8,
134.0, 142.7, 144.3, 144.6, 154.5; HRMS (ESI) calcd for
C25H27NNaO3S (M + Na)+ 444.1609, found 444.1609.
N-(2-(2-Bromophenyl)-2-(m-tolyloxy)ethyl)-4-methylbenzenesul-
fonamide (6e). The general method A described above was followed
when 4a (71 mg, 0.2 mmol) was reacted with phenol 5e (23 μL, 0.22
mmol) in the presence of Cu(OTf)2 (30 mol %) at rt for 1 h to afford
6e (91.0 mg, 0.197 mmol) as a white solid in 99% yield: mp 106−108
°C; Rf 0.40 (20% ethyl acetate in petroleum ether); IR νmax (KBr,
cm−1) 3279, 2922, 1591, 1491, 1468, 1422, 1332, 1258, 1157, 1091,
N-(2-(2-Bromophenyl)-2-(2,3-dimethylphenoxy)ethyl)-4-methyl-
benzenesulfonamide (6g). The general method A described above
was followed when 4a (71 mg, 0.2 mmol) was reacted with phenol 5g
(26.9 mg, 0.22 mmol) in the presence of Cu(OTf)2 (30 mol %) at rt
for 1 h to afford 6g (93.0 mg, 0.196 mmol) as a white solid in 98%
yield: mp 119−121 °C; Rf 0.45 (20% ethyl acetate in petroleum
ether); IR νmax (KBr, cm−1) 3284, 3060, 2922, 1584, 1469, 1432, 1326,
1
1251, 1156, 1093, 1067, 952, 875, 861, 811, 756, 708, 662; H NMR
(500 MHz, CDCl3) δ 2.21 (s, 3H) 2.26 (s, 3H), 2.37 (s, 3H), 3.21−
3.26 (m, 1H), 3.57−3.62 (m, 1H), 5.01−5.03 (m, 1H), 5.37−5.40 (m,
1H), 6.10 (d, J = 8.31 Hz, 1H), 6.71 (d, J = 7.45 Hz, 1H), 6.80 (t, J =
3873
dx.doi.org/10.1021/jo400287a | J. Org. Chem. 2013, 78, 3867−3878

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Article
8.02 Hz, 1H), 7.09−7.12 (m, 1H), 7.18−7.27 (m, 4H), 7.50 (d, J =
8.02 Hz, 1H), 7.71 (d, J = 8.31 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 12.0, 20.2, 21.6, 47.6, 76.8, 110.0, 121.9, 123.0, 124.9, 125.8,
127.1, 127.7, 128.2, 129.8, 129.9, 133.0, 137.1, 137.3, 138.2, 143.5,
154.4; HRMS (ESI) calcd for C23H24BrNNaO3S (M + Na)+ 496.0558,
found 496.0558.
130.1, 133.2, 136.6, 137.3, 143.6, 152.9, 156.6, 158.5; HRMS (ESI)
calcd for C21H19BrFNNaO3S (M + Na)+ 486.0151, found 486.0151.
3-(4-Fluorophenoxy)-1-tosylindoline (7i). The general method B
described above was followed when 6i (70.0 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 4 h to afford 7i
(53.0 mg, 0.138 mmol) as a white solid in 92% yield: mp 64−66 °C; Rf
0.45 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3436, 2924, 2854, 1601, 1503, 1466, 1355, 1292, 1201, 1166, 1091,
3-(2,3-Dimethylphenoxy)-1-tosylindoline (7g). The general meth-
od B described above was followed when 6g (71.0 mg, 0.15 mmol)
was reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 4 h to afford 7g
(55.0 mg, 0.139 mmol) as a white solid in 93% yield: mp 147−149 °C;
Rf 0.6 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3437, 3068, 2922, 1600, 1581, 1466, 1356, 1253, 1167, 1090, 1019,
840, 813, 756, 669, 579; 1H NMR (500 MHz, CDCl3) δ 1.78 (s, 3H),
2.23 (s, 3H), 2.35 (s, 3H), 4.05 (dd, J = 3.06, 12.53 Hz, 1H), 4.17 (dd,
J = 7.03, 12.53 Hz, 1H), 5.51(dd, J = 2.25, 7.03 Hz, 1H), 6.66 (d, J =
7.95 Hz, 1H), 6.82 (d, J = 7.64 Hz, 1H),7.02−7.07 (m, 2H), 7.19 (d, J
= 8.25 Hz, 2H), 7.22 (d, J = 7.64 Hz, 1H), 7.35−7.38 (m, 1H), 7.67
(d, J = 8.56 Hz, 2H), 7.75 (d, J = 8.25 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 11.7, 20.2, 21.6, 56.1, 75.5, 111.0, 115.2, 123.5, 124.0, 125.9,
126.4, 126.7, 127.4, 129.8, 130.1, 130.6, 134.0, 138.6, 142.6, 144.3,
155.0; HRMS (ESI) calcd for C23H23NNaO3S (M + Na)+ 416.1296,
found 416.1297.
1
1065, 1006, 979, 911, 828, 765, 725, 704, 673, 651; H NMR (500
MHz, CDCl3) δ 2.36 (s, 3H), 4.03−4.12 (m, 2H), 5.46−5.48 (m, 1H),
6.62−6.65 (m, 2H), 6.94−6.97 (m, 2H), 7.04−7.07 (m, 1H), 7.19 (d, J
= 7.95 Hz 1H), 7.23 (d, J = 7.34 Hz, 2H), 7.37−7.40 (m, 1H), 7.62−
7.64 (m, 2H), 7.76 (d, J = 8.25 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 21.7, 55.6, 75.6, 115.7, 116.1, 116.3, 117.3, 117.4, 124.2,
126.4, 127.5, 129.6, 129.8, 131.0, 133.8, 142.8, 144.3, 152.7, 157.0,
158.5; HRMS (ESI) calcd for C21H18ClFNO3S (M + Cl)− 418.0680,
found 418.0689.
N-(2-(2-Bromophenyl)-2-methoxyethyl)-4-methylbenzenesulfo-
namide (6j). The general method A described above was followed
when 4a (71 mg, 0.2 mmol) was reacted with methanol 5j (1.0 mL) in
the presence of Cu(OTf)2 (100 mol %) at rt for 5 h to afford 6j (58.0
mg, 0.15 mmol) as a white solid in 75% yield: mp 99−101 °C; Rf 0.3
(20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3265,
3988, 2922, 2821, 1597, 1567, 1493, 1459, 1417, 1354, 1325, 1259,
N-(2-(2-Bromophenyl)-2-(naphthalen-1-yloxy)ethyl)-4-methyl-
benzenesulfonamide (6h). The general method A described above
was followed when 4a (71 mg, 0.2 mmol) was reacted with phenol 5h
(31.0 mg, 0.22 mmol) in the presence of Cu(OTf)2 (30 mol %) at rt
for 1 h to afford 6h (99.0 mg, 0.199 mmol) as a white solid in >99%
yield: mp 47−49 °C; Rf 0.3 (20% ethyl acetate in petroleum ether); IR
νmax (KBr, cm−1) 3370, 2919, 1628, 1599, 1466, 1439, 1329, 1254,
1
1160, 1113, 1093, 1077, 967, 911, 870, 813, 768, 681; H NMR (500
MHz, CDCl3) δ 2.40 (s, 3H), 2.81−2.86 (m, 1H), δ 3.15 (s, 3H)
3.35−3.40 (m, 1H), 4.56 (dd, J = 3.05, 9.61 Hz, 1H), 5.11−5.13 (m,
1H), 7.11−7.15 (m, 1H), 7.25−2.31 (m, 4H), 7.48 (d, J = 7.94 Hz,
1H), 7.74 (d, J = 8.25 Hz, 2H), 13C NMR (125 MHz, CDCl3) δ 21.6,
47.6, 57.2, 80.7, 123.1, 127.3, 127.6, 127.9, 129.7, 129.8, 133.1, 137.2,
137.3, 143.5; HRMS (ESI) calcd for C16H19BrNO3S (M + H)+
384.0264, found 384.0260.
3-Methoxy-1-tosylindoline (7j). The general method B described
above was followed when 6j (58.0 mg, 0.15 mmol) was reacted with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (51.8 mg,
0.375 mmol) at 110−115 °C for 4 h to afford 7j (43.0 mg, 0.14 mmol)
as a white solid in 93% yield: mp 56−58 °C; Rf 0.32 (20% ethyl acetate
in petroleum ether); IR νmax (KBr, cm−1)2925, 1599, 1475, 1465,
1354, 1165, 1237, 1210, 1165, 1091, 1026, 974, 814, 756, 731, 676; 1H
NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 3.18 (s, 3H), 3.83−3.88 (m,
1H), 3.95−3.97 (m, 1H), 4.71 (bd, J = 6.59 Hz, 1H), 7.04 (t, J = 7.45
Hz, 1H), 7.20 (d, J = 7.73 Hz, 2H), 7.29 (d, J = 7.45 Hz 1H), 7.33 (t, J
= 7.45 Hz, 1H), 7.67 (d, J = 8.31 Hz, 2H), 7.71 (d, J = 8.31 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 21.6, 55.2, 55.3, 77.8, 115.2, 123.8,
126.3, 127.4, 129.7, 130.3, 130.5, 133.8, 142.5, 144.3; HRMS (ESI)
calcd for C16H18NO3S (M + H)+ 304.1002, found 304.1004.
1
1214, 1159, 1121, 1092, 1019, 969, 811, 750, 661; H NMR (500
MHz, CDCl3) δ 2.22 (s, 3H) 3.23−3.28 (m, 1H), 3.65−3.70 (m, 1H),
5.14−5.17 (m, 1H), 5.48−5.50 (m, 1H), 6.64 (d, J = 8.31, 2.58 Hz,
1H), 7.03 (dd, J = 2.58, 8.88 Hz, 1H), 7.10−7.13 (m, 3H), 7.17−7.19
(m, 1H), 7.29−7.38 (m, 4H), 7.52−7.55 (m, 2H), 7.67−7.73 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 21.4, 47.6, 76.9, 109.0, 118.4, 122.1,
124.2, 126.5, 127.0, 127.1, 127.6, 127.8, 128.2, 129.3, 129.6, 129.7,
130.0, 133.1, 134.2, 136.7, 137.5, 143.6, 154.5; HRMS (ESI) calcd for
C25H22BrNNaO3S (M + Na)+ 518.0401, found 518.0406.
3-(Naphthalen-1-ylosy)-1-tosylindoline (7h). The general method
B described above was followed when 6h (74.0 mg, 0.15 mmol) was
reacted with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (51.8 mg, 0.375 mmol) at 110−115 °C for 5 h to afford 7h
(60.0 mg, 0.144 mmol) as a white solid in 96% yield: mp 62−64 °C; Rf
0.4 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3399,
3056, 2921, 2850, 1628, 1599, 1509, 1465, 1357, 1253, 1214, 1167,
1118, 1064, 1007, 965, 812, 751, 672, 579; 1H NMR (500 MHz,
CDCl3) δ 2.39 (s, 3H), 4.10−4.13 (m, 1H), 4.25 (dd, J = 6.59, 12.60
Hz, 1H), 5.68−5.70 (m, 1H), 6.83 (d, J = 2.58, 8.88 Hz, 1H), 7.02 (d,
J = 2.29 Hz, 1H), 7.10 (t, J = 7.45 Hz 1H), 7.18 (d, J = 8.31 Hz, 2H),
7.39−7.42 (m, 3H), 7.48 (t, J = 7.16 Hz, 1H), 7.61 (d, J = 8.31 Hz,
2H), 7.72 (d, J = 8.59 Hz, 2H), 7.78 (t, J = 8.02 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 21.7, 55.6, 74.6, 108.3, 115.8, 119.3, 124.3,
124.4, 126.6, 126.8, 126.9, 127.5, 127.8, 129.4, 129.8, 129.9, 131.0,
133.8, 134.2, 142.9, 144.3, 154.5; HRMS (ESI) calcd for
C25H21NNaO3S (M + Na)+ 438.1140, found 438.1140.
N-(2-(2-Bromophenyl)-2-(4-fluorophenoxyoxy)ethyl)-4-methyl-
benzenesulfonamide (6i). The general method A described above was
followed when 4a (71 mg, 0.2 mmol) was reacted with phenol 5i (24.7
mg, 0.22 mmol) in the presence of Cu(OTf)2 (30 mol %) at rt for 1 h
to afford 6i (88.0 mg, 0.189 mmol) as a white solid in 95% yield: mp
46−48 °C; Rf 0.3 (20% ethyl acetate in petroleum ether); IR νmax
(KBr, cm−1) 3434, 2923, 2853, 1637, 1502, 1439, 1241, 1329, 1203,
1159, 1093, 1021, 813, 741, 661; 1H NMR (500 MHz, CDCl3) δ 2.38
(s, 3H) 3.14−3.19 (m, 1H), 3.56−3.61 (m, 1H), 5.09−5.12 (m, 1H),
5.31−5.34 (m, 1H), 6.53−6.57 (m, 2H), 6.83 (t, J = 8.56 Hz, 2H),
7.11−7.15 (m, 1H), 7.20−7.29 (m, 4H), 7.52 (d, J = 7.95 Hz, 1H),
7.73 (d, J = 7.95 Hz, 2H), 13C NMR (125 MHz, CDCl3) δ 21.6, 47.5,
77.6, 115.9, 116.0, 116.4, 116.5, 122.0, 127.2, 127.8, 128.2, 129.8,
N-Phenyl-1-tosylindolin-3-amine (10a). The general method C
described above was followed when 4a (71 mg, 0.2 mmol) was reacted
with aniline 8a (40 μL, 0.44 mmol) at rt for 1 h followed by treatment
with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3
(69.1 mg, 0.5 mmol) at 110−115 °C for 2 h to afford 10a (72.0 mg,
0.197 mmol) as a white solid in 99% yield: mp 153−155 °C; Rf 0.43
(20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3388,
2992, 1600, 1502, 1476, 1461, 1353, 1307, 1165, 1090, 1017, 813, 751,
1
693, 673; H NMR (500 MHz, CDCl3) δ 2.39 (s, 3H), 3.24 (bd, J =
7.95 Hz, 1H), 3.84 (dd, J = 3.67, 11.62 Hz, 1H), 4.12 (dd, J = 7.34,
11.62 Hz, 1H), 4.84−4.87 (m, 1H), 6.42 (d, J = 7.64 Hz, 2H), 6.75−
6.78 (m, 1H), 7.05−7.08 (m, 1H), 7.16−7.21 (m, 4H), 7.25−7.27 (m,
1H), 7.33−7.36 (m, 1H), 7.60 (d, J = 8.25 Hz, 2H) 7.74 (d, J = 8.25
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.7, 53.3, 56.8, 113.3,
116.0, 118.5, 124.5, 125.6, 127.4, 129.5, 129.8, 130.1, 132.4, 133.8,
142.2, 144.3, 145.7; HRMS (ESI) calcd for C21H21N2O2S (M + H)+
365.1324, found 365.1325.
(R)-N-(2-(2-Chlorophenyl)-2-(phenylamino)ethyl)-4-methylben-
zenesulfonamide (14a). The general method E described above was
followed when (S)-4b (62.0 mg, 0.2 mmol) was reacted with aniline
8a (40 μL, 0.44 mmol) at rt for 1 h to to afford (R)-14a (80.0 mg,
0.199 mmol) as a white solid in >99% yield: mp 150−152 °C; Rf 0.40
(20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1); 3396,
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3288, 3055, 2924, 1602, 1499, 1468, 1438, 1321, 1267, 1158, 1092,
1047, 1034, 873, 813, 752, 706, 692, 663; 1H NMR (500 MHz,
CDCl3) δ 2.42 (S, 3H), 3.14−3.20 (m, 1H), 3.40−3.45 (m, 1H),
4.73−4.84 (m, 3H), 6.41 (d, J = 7.64 Hz, 2H), 6.66 (t, J = 7.33 Hz,
1H), 7.07 (t, J = 7.33 Hz, 2H), 7.17−7.20 (m, 2H), 7.28 (d, J = 8.55
Hz, 2H), 7.32−7.34 (m, 1H), 7.43−7.44 (m, 1H), 7.23 (d, J = 8.25
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.6, 46.9, 54.3, 113.6,
118.1, 127.2, 127.6, 128.3, 129.1, 129.2, 130.0, 132.8, 136.8, 137.0,
143.9, 146.3; HRMS (ESI) calcd for C21H22ClN2O2S (M + H)+
401.1085, found 401.1090; [α]25D = +43.6 (c 0.92, CH2Cl2) for a 99%
ee sample, the enantiomeric excess was determined by chiral HPLC
analysis (chiralpak AS-H column), n-hexane/2-propanol = 70:30, flow
rate = 1.0 mL/min, tR(1) = 19.39 min (minor, S), tR(2) = 59.59, min
(major, R).
rate = 1.0 mL/min, tR(1) = 19.90 min (major, S), tR(2) = 29.56, min
(minor, R).
N-(3-Fluorophenyl)-1-tosylindolin-3-amine (10c). The general
method C described above was followed when 4a (71 mg, 0.2
mmol) was reacted with aniline 8c (42 μL, 0.22 mmol) at rt for 1 h
followed by treatment with Pd(OAc)2 (20 mol %), ( )-BINAP (40
mol %), and K2CO3 (69.1 mg, 0.5 mmol) at 110−115 °C for 4 h to
afford 10c (69.0 mg, 0.180 mmol) as a white solid in 90% yield: mp
106−108 °C; Rf 0.45 (20% ethyl acetate in petroleum ether); IR νmax
(KBr, cm−1); 3393, 2919, 2849, 1619, 1477, 1462, 1354, 1165, 1090,
1
1018, 813, 757, 704, 674, 578, 543; H NMR (500 MHz, CDCl3) δ
2.39 (s, 3H), 3.31 (bd, J = 8.31 Hz, 1H), 3.84 (dd, J = 3.15, 11.74 Hz,
1H), 4.08 (dd, J = 7.16, 11.7 Hz, 1H), 4.77−4.81 (m, 1H), 6.06−6.08
(m, 1H), 6.16−6.18 (m, 1H), 6.42−6.46 (m, 1H), 7.06−7.12 (m, 2H),
7.20 (d, J = 8.31 Hz, 2H), 7.25−7.26 (m, 1H), 7.34−7.37 (m, 1H),
7.59 (d, J = 8.31 Hz, 2H), 7.75 (d, J = 8.31 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 21.5, 53.1, 56.4, 100.0, 100.2, 104.8, 105.0, 108.8,
116.1, 124.5, 125.5, 127.3, 129.8, 130.2, 130.5, 130.6, 131.8, 133.7,
142.1, 144.3, 147.2, 147.3, 162.9, 164.9; HRMS (ESI) calcd for
C21H20FN2O2S (M + H)+ 383.1230, found 383.1230.
(R)-N-Phenyl-1-tosylindolin-3-amine (10a). The general method B
described above was followed when (R)-14a (60.0 mg, 0.15 mmol)
obtained from (S)-4b was reacted with Pd(OAc)2 (20 mol %),
( )-BINAP (40 mol %), and K2CO3 (51.8 mg, 0.375 mmol) at 110−
115 °C for 5 h to afford (R)-10a (35.0 mg, 0.096 mmol) as a white
solid in 64% yield; [α]25 = +4.8 (c 0.58, CH2Cl2) for a 99% ee
D
(R)-N-(2-(2-Chlorophenyl)-2-(2-fluorophenylamino)ethyl)-4-
methylbenzenesulfonamide (14c). The general method E described
above was followed when (S)-4b (62.0 mg, 0.2 mmol) was reacted
with aniline 8c (42 μL, 0.44 mmol) at rt for 1 h to afford (R)-14c
(83.0 mg, 0.198 mmol) as a white solid in 99% yield: mp 90−92 °C; Rf
0.40 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3394, 3283, 3065, 2924, 1621, 1595, 1517, 1495, 1442, 1325, 1092,
1042, 813, 756, 681, 662, 550; 1H NMR (500 MHz, CDCl3) δ 2.42 (s,
3H), 3.16−3.21 (m, 1H), 3.40−3.45 (m, 1H), 4.69−4.72 (m, 2H),
4.78−4.81 (m, 1H), 5.01−5.02 (m, 1H), 6.02−6.04 (m, 1H), 6.21−
6.22 (m, 1H), 6.32−6.36 (m, 1H), 6.98−7.03 (m, 1H), 7.20−7.23 (m,
2H), 7.29 (d, J = 8.25 Hz, 2H), 7.34−7.36 (m, 1H), 7.41−7.42 (m,
1H), 7.73 (d, J = 8.25 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.6,
46.7, 54.4, 100.2, 100.4, 104.4, 104.6, 109.4, 127.1, 127.7, 128.2, 129.3,
130.0, 130.1, 130.3, 130.3, 132.8, 136.4, 136.8, 144.1, 148.1, 148.2;
HRMS (ESI) calcd for C21H21ClFN2O2S (M + H)+ 419.0991, found
sample, the enantiomeric excess was determined by chiral HPLC
analysis (Chiralpak AS-H column), n-hexane/2-propanol = 95:5, flow
rate =1.0 mL/min, tR(1) = 68.2 min (minor, S), tR(2) = 82.8, min
(major, R).
N-(4-tert-Butylphenyl)-1-tosylindolin-3-amine (10b). The general
method C described above was followed when 4a (71 mg, 0.2 mmol)
was reacted with aniline 8b (70 μL, 0.44 mmol), at rt for 1 h followed
by treatment with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %),
and K2CO3 (69.1 mg, 0.5 mmol) at 110−115 °C for 3 h to afford 10b
(80.0 mg, 0.190 mmol) as a white solid in 95% yield: mp 114−116 °C;
Rf 0.45 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3387, 2953, 2864, 1613, 1518, 1476, 1461, 1351, 1317, 1257, 1165,
1
1100, 1089, 947, 808, 766, 670, 586; H NMR (500 MHz, CDCl3) δ
1.29 (s, 9H), 2.39 (s, 3H), 3.22 (bd, J = 8.3 Hz, 1H), 3.83 (dd, J =
3.72, 11.74 Hz, 1H), 4.13 (dd, J = 7.45, 11.46 Hz, 1H), 4.83−4.87 (m,
1H), 6.40 (d, J = 8.59 Hz, 2H), 7.04−7.07 (m, 1H), 7.20−7.25 (m,
5H), 7.32−7.35 (m, 1H), 7.62 (d, J = 8.31 Hz, 2H), 7.73 (d, J = 8.31
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.7, 31.6, 34.0, 53.5, 57.0,
113.0, 115.9, 124.4, 125.6, 126.3, 127.4, 129.8, 129.9, 132.6, 133.9,
141.4, 142.1, 143.4, 144.3; HRMS (ESI) calcd for C25H29N2O2S (M +
H)+ 421.1950, found 421.1956.
(R)-N-(2-(4-tert-Butylphenylamino)-2-(2-chlorophenyl)ethyl)-4-
methylbenzenesulfonamide (14b). The general method E described
above was followed when (S)-4b (62.0 mg, 0.2 mmol) was reacted
with aniline 8b (70 μL, 0.44 mmol) at rt for 1 h to afford (R)-14b
(91.0 mg, 0.199 mmol) as a white solid in >99% yield: mp 160−162
°C; Rf 0.35 (10% ethyl acetate in petroleum ether); IR νmax (KBr,
cm−1) 3393, 3239, 2956, 1615, 1522, 1468, 1362, 1288, 1194, 1100,
1034, 961, 819, 755, 707, 663, 546, 499; 1H NMR (500 MHz, CDCl3)
δ 1.22 (s, 9H), 2.42 (s, 3H), 3.17−3.13 (m, 1H), 3.41−3.36 (m, 1H),
4.65 (m, 1H), 4.86−4.80 (m, 1H), 6.37 (d, J = 8.25 Hz, 2H), 7.10 (d, J
= 8.25 Hz, 2H), 7.19−7.18 (m, 2H), 7.28−7.25 (m, 2H), 7.34−7.32
(m, 1H), 7.47−7.45 (m, 1H), 7.73 (d, J = 7.94 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 21.7, 31.6, 33.9, 47.02, 54.7, 113.3, 126.0, 127.2,
127.6, 128.4, 129.1, 129.9, 130.0, 132.8, 136.8, 137.3, 140.8, 143.9,
144.1; HRMS (ESI) calcd for C25H30ClN2O2S (M + H)+ 457.1711,
found 457.1710; [α]25D = +24.8 (c 0.68, CH2Cl2) for a 99% ee sample,
the enantiomeric excess was determined by chiral HPLC analysis
(chiralpak AS-H column), n-hexane/2-propanol = 80:20, flow rate =
1.0 mL/min, tR(1) = 25.10 min (minor, S), tR(2) = 40.4, min (major,
R).
419.0997; [α]25 = +4.1 (c 0.77, CH2Cl2) for a 99% ee sample, the
D
enantiomeric excess was determined by chiral HPLC analysis
(Chiralpak AS-H column), n-hexane/2-propanol = 70:30, flow rate
= 1.0 m.L/min, tR(1) = 17.17 min (minor, S), tR(2) = 66.42, min
(major, R).
(R)-N-(3-Fluorophenyl)-1-tosylindolin-3-amine (10c). The general
method B described above was followed when (R)-14c (62.0 mg, 0.15
mmol) obtained from (S)-4b was reacted with Pd(OAc)2 (20 mol %),
( )-BINAP (40 mol %), and K2CO3 (51.8 mg, 0.375 mmol) at 110−
115 °C for 5 h to afford (R)-10c (43.0 mg, 0.112 mmol) as a white
solid in 75% yield; [α]25 = +8.1 (c 0.44, CH2Cl2) for a 99% ee
D
sample, the enantiomeric excess was determined by chiral HPLC
analysis (Chiralpak AS-H column), n-hexane/2-propanol = 95:5, flow
rate = 1.0 mL/min, tR(1) = 33.85 min (major, S), tR(2) = 45.50, min
(minor, R).
N-(4-Fluorophenyl)-1-tosylindolin-3-amine (10d). The general
method C described above was followed when 4a (71 mg, 0.2
mmol) was reacted with aniline 8d (42 μL, 0.44 mmol) at rt for 1 h
followed by treatment with Pd(OAc)2 (20 mol %), ( )-BINAP (40
mol %), and K2CO3 (69.1 mg, 0.5 mmol) at 110−115 °C for 3h to
afford 10d (68.0 mg, 0.177 mmol) as a white solid in 89% yield: mp
55−57 °C; Rf 0.45 (20% ethyl acetate in petroleum ether); IR νmax
(KBr, cm−1); 3398, 2923, 1600, 1511, 1511, 1477, 1353, 1223, 1166,
1
1091, 1052, 819, 757, 731, 704; H NMR (500 MHz, CDCl3) δ 2.39
(s, 3H), 3.13 (bs, 1H), 3.82 (dd, J = 3.36, 11.62 Hz, 1H), 4.07 (dd, J =
7.34, 11.62 Hz, 1H), 4.79 (bs, 1H), 6.33−6.36 (m, 2H), 6.86−6.90 (m,
2H), 7.04−7.08 (m, 1H), 7.20 (d, J = 7.95 Hz, 2H), 7.24−7.25 (m,
1H), 7.33−7.36 (m, 1H), 7.60 (d, J = 8.25 Hz, 2H), 7.74 (d, J = 8.25
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.7, 53.9, 56.4, 114.2,
114.3, 115.9, 116.0, 124.5, 125.6, 127.4, 129.9, 130.1, 132.2, 133.8,
142.0, 142.1, 144.3, 155.4, 157.3; HRMS (ESI) calcd for
C21H20FN2O2S (M + H)+ 383.1230, found 383.1237.
(R)-N-(4-tert-Butylphenyl)-1-tosylindolin-3-amine (10b). The gen-
eral method B described above was followed when (R)-14b (68.0 mg,
0.15 mmol) obtained from (S)-4b was reacted with Pd(OAc)2 (20 mol
%), ( )-BINAP (40 mol %), and K2CO3 (51.8 mg, 0.375 mmol) at
110−115 °C for 4 h to afford (R)-10b (45.0 mg, 0.107 mmol) as a
white solid in 71% yield; [α]25D = +1.6 (c 0.83, CH2Cl2) for a 99% ee
sample, the enantiomeric excess was determined by chiral HPLC
analysis (Chiralpak OD-H column), n-hexane/i-propanol = 95:5, flow
(R)-N-(2-(2-Chlorophenyl)-2-(4-fluorophenylamino)ethyl)-4-
methylbenzenesulfonamide (14d). The general method E described
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above was followed when (S)-4b (62 mg, 0.2 mmol) was reacted with
aniline 8d (42 μL, 0.44 mmol) at rt for 1 h to afford (R)-14d (83.0 mg,
0.198 mmol) as a white solid in 99% yield: mp 76−78 °C; Rf 0.40
(20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3394,
3284, 2925, 1598, 1511, 1444, 1322, 1222, 1093, 1047,1035, 819, 757,
662, 551; 1H NMR (500 MHz, CDCl3) δ 2.41(s, 3H), 3.12−3.17 (m,
1H), 3.38−3.43 (m, 1H), 4.75 (bs, 1H), 4.94 (t, J = 6.59 Hz 1H),
6.31−6.34 (m, 2H), 6.76 (t, J = 8.59 Hz, 2H), 7.17−7.20 (m, 2H),
7.25−7.28 (m, 2H), 7.32−7.34 (m, 1H), 7.40−7.42 (m, 1H), 7.72 (d, J
= 8.31 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.6, 46.9, 54.9,
114.3, 114.4, 115.6, 115.8, 127.2, 127.6, 128.2, 129.2, 129.98, 130.0,
132.9, 136.8, 136.8, 142.7, 144.0, 155.2, 157.1; HRMS (ESI) calcd for
4.64 (dd, J = 3.97, 8.25 Hz, 1H), 6.99−7.02 (m, 1H), 7.18−7.22 (m,
3H), 7.24−7.27 (m, 6H), 7.62−7.65 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 21.7, 46.9, 57.0, 115.0, 124.0, 125.8, 127.5, 127.9, 129.3,
129.6, 129.8, 130.7, 132.2, 133.6, 134.0, 141.9, 144.4; HRMS (ESI)
calcd for C21H19NNaO2S2 (M + Na)+ 404.0755, found 404.0750.
3-(p-Tolylthio)-1-tosylindoline (13b). The general method D
described above was followed when 4a (71 mg, 0.2 mmol) was
reacted with thiophenoxide from 11b [(27.3 mg, 0.22 mmol), K2CO3
(30.4 mg, 0.22 mmol)] at rt for 25 min followed by treatment with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (69.1 mg,
0.5 mmol) at 110−115 °C for 4 h to afford 13b (79.0 mg, 0.199
mmol) as a white solid in >99% yield: mp 79−81 °C; Rf 0.34 (10%
ethyl acetate in petroleum ether); IR νmax (KBr, cm−1); 3394, 3030,
2920, 1598, 1492, 1475, 1462, 1356, 1253, 1168, 1105, 1055, 811, 754,
C21H21ClFN2O2S (M + H)+ 419.0991, found 419.0999; [α]25
=
D
−12.8 (c 0.5, CH2Cl2) for a 99% ee sample, the enantiomeric excess
was determined by chiral HPLC analysis (Chiralpak AS-H column), n-
hexane/2-propanol = 70:30, flow rate = 1.0 mL/min, tR(1) = 19.05
min (minor, S), tR(2) = 74.02, min (major, R).
1
731, 670, 578; H NMR (500 MHz, CDCl3) δ 2.33 (s, 3H), 2.37 (s,
3H), 3.98 (dd, J = 4.30, 11.74 Hz, 1H), 4.13 (dd, J = 8.31, 11.74 Hz,
1H), 4.57 (dd, J = 4.30, 8.59 Hz, 1H), 6.98−7.01 (m, 1H), 7.08 (d, J =
8.02 Hz, 2H), 7.15−7.26 (m, 6H), 7.62 (d, J = 8.02 Hz, 1H), 7.65 (d, J
= 8.31 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.3, 21.7, 47.4, 56.9,
115.0, 123.9, 125.8, 127.5, 129.5, 129.7, 130.0, 131.0, 133.0, 134.1,
138.2, 141.9, 144.3; HRMS (ESI) calcd for C22H21NNaO2S2 (M +
Na)+ 418.0911, found 418.0916.
(R)-N-(4-Fluorophenyl)-1-tosylindolin-3-amine (10d). The general
method B described above was followed when (R)-14d (62.0 mg, 0.15
mmol) obtained from (S)-4b was reacted with Pd(OAc)2 (20 mol %),
( )-BINAP (40 mol %), and K2CO3 (51.8 mg, 0.375 mmol) at 110−
115 °C for 4 h to afford (R)-10d (35.0 mg, 0.09 mmol) as a white
solid in 60% yield; α]25D = +1.0 (c 0.2, CH2Cl2) for a 99% ee sample,
the enantiomeric excess was determined by chiral HPLC analysis
(Chiralpak OD-H column), n-hexane/2-propanol = 98:2, flow rate =
0.5 mL/min, tR(1) = 88.47 min (minor, S), tR(2) = 98.03 min (major,
R).
3-(Naphthalen-1-ylthio)-1-tosylindoline (13c). The general meth-
od D described above was followed when 4a (71 mg, 0.2 mmol) was
reacted with thiophenoxide from 11c [(35.2 mg, 0.22 mmol), K2CO3
(30.4 mg, 0.22 mmol)] at rt for 25 min followed by treatment with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (69.1 mg,
0.5 mmol) at 110−115 °C for 4 h to afford 13c (81.0 mg, 0.187
mmol) as a white solid in 94% yield: mp 40−42 °C; Rf 0.33 (10% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1); 3448, 3051, 2923,
2853, 1729, 1623, 1596, 1475, 1461, 1355, 1253, 1185, 1104, 1089,
N-(3-Chloro-4-fluorophenyl)-1-tosylindolin-3-amine (10e). The
general method C described above was followed when 4a (71 mg,
0.2 mmol) was reacted with aniline 8e (64.0 mg, 0.44 mmol) at rt for 1
h followed by treatment with Pd(OAc)2 (20 mol %), ( )-BINAP (40
mol %), and K2CO3 (69.1 mg, 0.5 mmol) at 110−115 °C for 4 h to
afford 10e (79.0 mg, 0.189 mmol) as a white solid in 95% yield: mp
104−106 °C; Rf 0.40 (20% ethyl acetate in petroleum ether); IR νmax
(KBr, cm−1) 3393, 2924, 2853, 1603, 1504, 1463, 1353, 1223, 1166,
1
1054, 850, 811, 747, 704, 670, 578; H NMR (500 MHz, CDCl3) δ
2.35 (s, 3H), 4.03 (dd, J = 4.30, 11.74 Hz, 1H), 4.22 (dd, J = 8.31,
11.74 Hz, 1H), 4.75 (dd, J = 4.30, 8.02 Hz, 1H), 7.00−7.03 (m, 1H),
7.16 (d, J = 8.31 Hz, 2H), 7.23−7.31 (m, 3H), 7.48−7.52 (m, 2H),
7.61−7.64 (m, 3H), 7.71−7.74 (m, 3H), 7.80−7.81 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 21.7, 46.8, 56.9, 115.1, 124.0, 125.8, 126.6,
126.9, 127.4, 127.6, 127.8, 128.9, 129.2, 129.6, 129.7, 130.7, 131.0,
131.1, 132.6, 133.6, 134.0, 142.0, 144.3; HRMS (ESI) calcd for
C25H21NNaO2S2 (M + Na)+ 454.0911, found 454.0919.
3-(4-tert-Butylphenylthio)-1-tosylindoline (13d). The general
method D described above was followed when 4a (71 mg, 0.2
mmol) was reacted with thiophenoxide from 11d [(36.6 mg, 0.22
mmol), K2CO3 (30.4 mg, 0.22 mmol)] at rt for 25 min followed by
treatment with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and
K2CO3 (69.1 mg, 0.5 mmol) at 110−115 °C for 3 h to afford 13d
(84.0 mg, 0.191 mmol) as a white solid in 96% yield: mp 59−61 °C; Rf
0.47 (10% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1);
3400, 3067, 2961, 2868, 1598, 1475, 1462, 1398, 1357, 1305, 1291,
1168, 1090, 1055, 1028, 979, 813, 752, 733, 705 ; 1H NMR (500 MHz,
CDCl3) δ 1.31 (s, 9H), 2.37 (s, 3H), 4.02 (dd, J = 4.01, 11.46 Hz, 1H),
4.14 (dd, J = 8.02, 11.74 Hz, 1H), 4.60 (dd, J = 4.01, 8.02 Hz, 1H),
6.99−7.02 (m, 1H), 7.19−7.27 (m, 6H), 7.30−7.32 (m, 2H), 7.63 (d, J
= 8.31 Hz, 1H), 7.67 (d, J = 8.31 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 21.7, 31.3, 34.7, 47.3, 57.3, 115.1, 124.0, 125.8, 126.4, 127.5,
129.5, 129.8, 130.2, 130.9, 132.3, 134.1, 141.9, 144.3, 151.3; HRMS
(ESI) calcd for C25H27NNaO2S2 (M + Na)+ 460.1381, found
460.1385.
1
1090, 1051, 976, 945, 909, 811, 785, 757, 734, 704, 672; H NMR
(500 MHz, CDCl3) δ 2.41 (s, 3H), 3.07 (bd, J = 8.59 Hz, 1H), 3.81
(dd, J = 2.86, 11.74 Hz, 1H), 4.05 (dd, J = 7.16, 11.74 Hz, 1H), 4.71−
4.75 (m, 1H), 6.22−6.25 (m, 1H), 6.33−6.34 (m, 1H), 6.93−6.96 (m,
1H), 7.07−7.10 (m, 1H), 7.20−7.25 (m, 3H), 7.35−7.38 (m, 1H),
7.59 (d, J = 8.59 Hz, 2H), 7.75 (d, J = 8.02 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 21.7, 53.7, 56.2, 112.2, 112.3, 114.6, 116.3, 117.0,
117.2, 121.0, 121.2, 124.7, 125.6, 127.4, 129.9, 130.4, 131.8, 133.8,
142.2, 142.5, 144.4, 150.56, 152.47; HRMS (ESI) calcd for
C21H19ClFN2O2S (M + H)+ 417.0840, found 417.0846.
N-(2-(2-Bromophenyl)-2-(phenylthio)ethyl)-4-methylbenzenesul-
fonamide (12a). The general method A described above was followed
when 4a (71 mg, 0.2 mmol) was reacted with thiophenol 11i (23 μL,
0.22 mmol) in the presence of Cu(OTf)2 (30 mol %) at rt for 6 min to
afford 12a (91.6 mg, 0.198 mmol) as a thick liquid in 99% yield: Rf
0.52 (30% ethyl acetate in petroleum ether); IR νmax (neat, cm−1):
3281, 3059, 2923, 2854, 1597, 1470, 1438, 1329, 1159, 1092, 1024,
813, 691, 663, 551; 1H NMR (500 MHz, CDCl3) δ 2.42 (s, 3H) 3.30−
3.36 (m, 1H), 3.42−3.47 (m, 1H), 4.65 (t, J = 7.35 Hz, 1H), 4.82 (t, J
= 6.40 Hz, 1H), 7.08−7.15 (m, 2H), 7.18−7.25 (m, 5H), 7.52 (dd, J =
7.95, 1.25 Hz, 1H), 7.64 (d, J = 8.55 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.
3-(Phenylthio)-1-tosylindolinone (13a). The general method D
described above was followed when 4a (71 mg, 0.2 mmol) was reacted
with thiophenoxide from 11a [(23 μL, 0.22 mmol), K2CO3 (30.4 mg,
0.22 mmol)] at rt for 25 min followed by treatment with Pd(OAc)2
(20 mol %), ( )-BINAP (40 mol %), and K2CO3 (69.1 mg, 0.5
mmol) at 110−115 °C for 3 h to afford 13a (75.0 mg, 0.196 mmol) as
a white solid in 98% yield: mp 110−112 °C; Rf 0.33 (10% ethyl acetate
in petroleum ether); IR νmax (KBr, cm−1); 3419, 3070, 2919, 2885,
1596, 1580, 1477, 1350, 1254, 1165, 1102, 1087, 1061, 1027, 976, 868,
807, 756, 738, 666, 578; 1H NMR (500 MHz, CDCl3) δ 2.37 (s, 3H),
3.99 (dd, J = 3.97, 11.62 Hz, 1H), 4.17 (dd, J = 8.25, 11.62 Hz, 1H),
3-(2,4-Dimethylphenylthio)-1-tosylindoline (13e). The general
method D described above was followed when 4a (71 mg, 0.2
mmol) was reacted with thiophenoxide from 11e [(29 μL, 0.22
mmol), K2CO3 (30.4 mg, 0.22 mmol)] at rt for 25 min followed by
treatment with Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %) and
K2CO3 (69.1 mg, 0.5 mmol) at 110−115 °C for 4 h to afford 13e
(80.0 mg, 0.195 mmol) as a white solid in 98% yield: mp 63−65 °C; Rf
0.35 (10% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
2920, 1599, 1475, 1463, 1357, 1253, 1169, 1105, 1090, 979, 812, 754,
1
671, 579; H NMR (400 MHz, CDCl3) δ 2.23 (s, 3H), 2.30 (s, 3H),
2.96 (s, 3H), 3.97 (dd, J = 3.72, 11.46 Hz, 1H), 4.12 (dd, J = 8.02,
11.74 Hz, 1H), 4.53 (dd, J = 3.72, 7.75 Hz, 1H), 6.93−6.98 (m, 2H),
3876
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Article
7.02 (s, 1H), 7.05 (dd, J = 7.45 Hz, 1H), 7.14 (d, J = 8.02 Hz, 1H),
7.22 (d, J = 8.59 Hz, 2H), 7.25 (t, 1H), 7.65 (d, J = 8.02 Hz, 1 H), 7.67
(d, J = 8.31 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 20.6, 21.1, 21.6,
46.5, 57.0, 115.0, 123.9, 125.6, 127.5, 129.5, 129.6, 129.7, 131.1, 131.6,
132.8, 134.2, 138.1, 140.2, 141.8, 144.3; HRMS (ESI) calcd for
C23H27N2O2S2 (M + NH4)+ 427.1514, found 427.1513.
ACKNOWLEDGMENTS
■
M.K.G. is grateful to DST, India, and IIT-Kanpur for financial
support. Y.N. thanks CSIR, India, for a research fellowship.
REFERENCES
■
3-(o-Tolylthio)-1-tosylindoline (13f). The general method D
described above was followed when 4a (71 mg, 0.2 mmol) was
reacted with thiophenoxide from 11f [(26 μL, 0.22 mmol), K2CO3
(30.4 mg, 0.22 mmol)] at rt for 10 min followed by treatment with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %) and K2CO3 (69.1 mg,
0.5 mmol) at 110−115 °C for 3 h to afford 13f (78.0 mg, 0.197 mmol)
as a white solid in 99% yield: mp 102−104 °C; Rf 0.35 (10% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3061, 2924, 2855,
(1) (a) Schammel, A. W.; Boal, B. W.; Zu, L.; Mesganaw, T.; Garg, N.
K. Tetrahedron 2010, 66, 4687. (b) Liu, D.; Zhao, G.; Xiang, L. Eur. J.
Org. Chem. 2010, 3975. (c) Va, P.; Campbell, E. L.; Robertson, W. M.;
Boger, D. L. J. Am. Chem. Soc. 2010, 132, 8489. (d) Newhouse, T.;
Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
7119. (e) Nicolaou, K. C.; Bheema Rao, P.; Hao, J.; Venkat Reddy, M.;
Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S, A. Angew. Chem., Int.
Ed. 2003, 42, 1753. (f) Gan, Z.; Thirupathi Reddy, P.; Quevillon, S.;
Couve-Bonnaire, S.; Arya, P. Angew. Chem., Int. Ed. 2005, 44, 1366.
(2) (a) Rakhit, A.; Hurley, M. E.; Tipnis, V.; Coleman, J.; Rommel,
A.; Brunner, H. R. J. Clin. Pharmacol. 1986, 26, 156. (b) Gruenfeld, N.;
Stanton, J. L.; Yuan, A. M.; Ebetino, F. H.; Browne, L. J.; Gude, C.;
Huebner, C. F. J. Med. Chem. 1983, 26, 1277.
(3) (a) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009,
131, 8758. (b) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56,
872. (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
(d) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. Org. Lett. 2006,
8, 83.
(4) Liou, J.-P.; Hsu, K.-S.; Kuo, C.-C.; Chang, C.-Y.; Chang, J.-Y. J.
Pharm. Exp. Ther. 2007, 323, 398.
(5) (a) Liu, K. G.; Lo, J. R.; Robichaud, A. J. Tetrahedron 2010, 66,
573. (b) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J. Org. Chem. 2006, 71, 4255. (c) Ruano, J. L. G.; Parra, A.;
1
1598, 1475, 1357, 1169, 1105, 1090, 750, 670, 579, 545; H NMR
(400 MHz, CDCl3) δ 2.24 (s, 3H), 3.36 (s, 3H), 3.99 (dd, J = 4.01,
11.74 Hz, 1H), 4.19 (dd, J = 8.02, 11.74 Hz, 1H), 4.61 (dd, J = 3.72,
8.02 Hz, 1H), 6.98 (t, 1H), 7.07 (d, J = 7.45 Hz, 1H), 7.12−7.16 (m,
1H), 7.18−7.28 (m, 6 H), 7.65−7.68 (m, 3 H); 13C NMR (125 MHz,
CDCl3) δ 20.6, 21.6, 45.9, 57.1, 115.1, 123.9, 125.7, 126.8, 127.5,
127.6, 129.6, 129.8, 130.7, 130.9, 131.3, 133.5, 134.1, 139.5, 141.9,
144.3; HRMS (ESI) calcd for C22H21NNaO2S2 (M + Na)+ 418.0911,
found 418.0911.
3-(4-Fluorophenylthio)-1-tosylindoline (13g). The general method
D described above was followed when 4a (71 mg, 0.2 mmol) was
reacted with thiophenoxide from 11g [(23 μL, 0.22 mmol), K2CO3
(30.4 mg, 0.22 mmol)] at rt for 25 min followed by treatment with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (69.1 mg,
0.5 mmol) at 110−115 °C for 4 h to afford 13g (78.0 mg, 0.195
mmol) as a white solid in 98% yield: mp 73−75 °C; Rf 0.35 (10% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3067, 2924, 2855,
1589, 1489, 1475, 1463, 1356, 1226, 1169, 1105, 1090, 1056, 832, 754,
́
Marcos, V.; del Pozo, C.; Catalan, S.; Monteagudo, S.; Fustero, S.;
Poveda, A. J. Am. Chem. Soc. 2009, 131, 9432. (d) Wang, Z.; Wan, W.;
Jiang, H.; Hao, J. J. Org. Chem. 2007, 72, 9364. (e) Kang, K. H.; Do, J.;
Park, Y. S. J. Org. Chem. 2012, 77, 808. (f) Clive, D. L. J.; Peng, J.;
Fletcher, S. P.; Ziffle, V. E.; Wingert, D. J. Org. Chem. 2008, 73, 2330.
(g) Wipf, P.; Maciejewski, J. P. Org. Lett. 2008, 10, 4383. (h) Sun, K.;
Sachwani, R.; Richert, K. J.; Driver, T. G. Org. Lett. 2009, 11, 3598.
(i) Tan, M.; Zhang, Y. Tetrahedron Lett. 2009, 50, 4912. (j) Correa, A.;
Tellitu, I.; Domínguez, E.; Sanmartin, R. J. Org. Chem. 2006, 71, 8316.
(k) Beemelmanns, C.; Lentz, D.; Reissig, H.-U. Chem.Eur. J. 2011,
17, 9720.
1
671, 579; H NMR (400 MHz, CDCl3) 2.37 (s, 3 H), 3.92 (dd, J =
4.58, 10.6 Hz, 1H), 4.12 (dd, J = 8.59, 11.46 Hz, 1H), 4.53 (dd, J =
4.30, 8.31 Hz, 1H), 6.89−6.92 (m, 2 H), 6.99−7.02 (m, 1H), 7.17−
7.26 (m, 6 H), 7.59 (d, J = 8.02 Hz, 1H), 7.62 (d, J = 8.31 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 21.6, 47.5, 56.4, 114.8, 116.2, 116.4,
123.8, 125.8, 127.4, 127.6, 129.6, 129.7, 130.6, 134.0, 135.8, 135.9,
142.0, 144.4, 162.0, 164.0; HRMS (ESI) calcd for C21H18NFNaO2S2
(M + Na)+ 422.0661, found 422.0670.
3-(Benzylthio)-1-tosylindoline (13h). The general method D
described above was followed when 4a (71 mg, 0.2 mmol) was
reacted with thiophenoxide from 11h [(26 μL, 0.22 mmol), K2CO3
(30.4 mg, 0.22 mmol)] at rt for 25 min followed by treatment with
Pd(OAc)2 (20 mol %), ( )-BINAP (40 mol %), and K2CO3 (69.1 mg,
0.5 mmol) at 110−115 °C for 4 h to afford 13h (74.0 mg, 0.187
mmol) as a white solid in 94% yield: mp 50−52 °C; Rf 0.43 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1); 3397, 2923, 2853,
1597, 1459, 1354, 1238, 1167, 1089, 1027, 812, 752, 703, 658, 578; 1H
NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 3.48 (s, 2H), 3.82−3.89 (m,
1H), 4.10−4.16 (m, 2H), 6.99−7.03 (m, 1H), 7.16−7.32 (m, 9H),
7.64−7.67 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 21.6, 35.1, 43.3,
57.4, 115.0, 124.2, 125.7, 127.4, 127.5, 128.7, 128.9, 129.3, 129.8,
131.3, 133.8, 137.4, 141.8, 144.4; HRMS (ESI) calcd for
C22H25N2O2S2 (M + NH4)+ 413.1357, found 413.1359.
(6) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264.
(b) Hou, X. L.; Zheng, B. H. Org. Lett. 2009, 11, 1789. (c) Mealy, M.
J.; Luderer, M. R.; Bailey, W. F.; Sommer, M. B. J. Org. Chem. 2004,
69, 6042. (d) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 8451. (e) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J.
Am. Chem. Soc. 2008, 130, 17638. (f) Anas, S.; Cordi, A.; Kagan, H. B.
Chem. Commun. 2011, 47, 11483. (g) Pineschi, M.; Bertolini, F.;
Crotti, P.; Macchia, F. Org. Lett. 2006, 8, 2627. (h) He, G.; Zhao, Y.;
Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3.
(7) (a) Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.;
Ito, Y. Tetrahedron: Asymmetry 2006, 17, 521. (b) Maj, A. M.; Suisse,
́
I.; Meliet, C.; Agbossou-Niedercorn, F. Tetrahedron: Asymmetry 2010,
21, 2010. (c) Wang, D.-S.; Tang, J.; Zhou, Y.-G.; Chen, M.-W.; Yu, C.-
B.; Duan, Y.; Jiang, G.-F. Chem. Sci. 2011, 2, 803. (d) Duan, Y.; Chen,
M.-W.; Chen, Q.-A.; Yu, C.-B.; Zhou, Y.-G. Org. Biomol. Chem. 2012,
10, 1235. (e) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653.
(f) Rueping, M.; Brinkmann, C.; Antonchick, A. P.; Atodiresei, I. Org.
Lett. 2010, 12, 4604. (g) Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.;
Zhou, Y.-G.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909. (h) Kuwano,
R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004,
6, 2213. (i) Vickers, C. J.; Mei, T.-S; Yu, J.-Q. Org. Lett. 2010, 12,
2511. (j) Wang, L.; Shao, Y.; Liu, Y. Org. Lett. 2012, 14, 3978.
(k) Anderson, J. C.; Noble, A.; Tocher, D. A. J. Org. Chem. 2012, 77,
6703.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra for all new compounds and X-ray crystallographic
data of 7b, 10e, and 12b (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(8) (a) Guthrie, D. B.; Curran, D. P. Org. Lett. 2009, 11, 249.
(b) Viswanathan, R.; Mutnick, D.; Johnston, J. N. J. Am. Chem. Soc.
2003, 125, 7266. (c) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.;
Prabhakaran, E. N. Org. Lett. 2001, 3, 1009. (d) Fuwa, H.; Sasaki, M.
Org. Lett. 2007, 9, 3347. (e) Leroi, C.; Bertin, D.; Dufils, P.-E.; Gigmes,
Corresponding Author
*E-mail: mkghorai@iitk.ac.in.
Notes
The authors declare no competing financial interest.
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D.; Marque, S.; Tordo, P.; Couturier, J.-L.; Guerret, O.; Ciufolini, M.
A. Org. Lett. 2003, 5, 4943. (f) Cossy, J.; Poitevin, C.; Pardo, D. G.
Synlett 1998, 251.
(9) (a) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J. Am. Chem. Soc.
2008, 130, 17638. (b) Minatti, A.; Buchwald, S. L. Org. Lett. 2008, 10,
2721. (c) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.;
Fukuyama, T. Tetrahedron 2008, 64, 11230.
(d) Baktharaman, S.; Afagh, N.; Vandersteen, A.; Yudin, A. K. Org.
Lett. 2010, 12, 240. (e) Samanta, K.; Panda, G. Chem.Asian J. 2011,
6, 189. (f) Wang, J.-Y.; Guo, X.-F.; Wang, D.-X.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2008, 73, 1979. (g) Wang, L.; Liu, Q.-B.; Wang,
D.-S.; Li, X.; Han, X.-W.; Xiao, W.-J.; Zhou, Y.-G. Org. Lett. 2009, 11,
1119. (h) Hong, D.; Lin, X.; Zhu, Y.; Lei, M.; Wang, Y. Org. Lett. 2009,
11, 5678. (i) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11,
1923. (j) D’hooghe, M.; Aelterman, W.; De Kimpe, N. Org. Biomol.
Chem. 2009, 7, 135. (k) Brabandt, W. V.; Dejaegher, Y.; Landeghem,
(10) (a) Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew.
̈
Chem., Int. Ed. 2009, 48, 6892. (b) Rogers, M. M.; Wendlandt, J. E.;
Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257. (c) Newman, S. S.;
Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am. Chem. Soc. 2011, 133,
14916. (d) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906.
(e) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806.
(f) Thansandote, P.; Raemy, M.; Rudolph, A.; Lautens, M. Org. Lett.
2007, 9, 5255. (g) Wantanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org.
̌
R. V.; De Kimpe, N. Org. Lett. 2006, 8, 1101. (l) Zukauskaite,
́
A.;
̌
Mangelinckx, S.; Buinauskaite,
́
V.; Sack
̌
us, A.; De Kimpe, N. Amino
Acids 2011, 41, 541.
(15) (a) Ghorai, M. K.; Tiwari, D. P. J. Org. Chem. 2010, 75, 6173.
(b) Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013.
(c) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48,
4373. (d) Ghorai, M. K.; Ghosh, K. Tetrahedron Lett. 2007, 48, 3191.
(e) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2009, 50,
1105. (f) Ghorai, M. K.; Nanaji, Y.; Yadav, A. K. Org. Lett. 2011, 13,
4256. (g) Ghorai, M. K.; Sahoo, S. K.; Kumar, S. Org. Lett. 2011, 13,
5972. (h) Ghorai, M. K.; Shukla, D.; Bhattacharyya, A. J. Org. Chem.
2012, 77, 3740. (i) Ghorai, M. K.; Tiwari, D. P. J. Org. Chem. 2013, 78,
2617.
(16) (a) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K.
B. J. Am. Chem. Soc. 1998, 120, 6844. (b) Ghorai, M. K.; Das, K.;
Kumar, A.; Das, A. Tetrahedron Lett. 2006, 47, 5393. (c) Jeffs, L.;
Arquier, D.; Kariuki, B.; Bethell, D.; Bulman page, P. C.; Hutchings, G.
J. Org. Biomol. Chem. 2011, 9, 1079.
Lett. 2008, 10, 1759. (h) Lop
́
ez-Iglesia, M.; Busto, E.; Gotor, V.;
Gotor-Fernandez, V. J. Org. Chem. 2012, 77, 8049. (i) Ganton, M. D.;
́
Kerr, M. A. Org. Lett. 2005, 7, 4777. (j) He, G.; Lu, C.; Zhao, Y.; Nack,
W. A.; Chen, G. Org. Lett. 2012, 14, 2944.
(11) (a) Wolfe, J. P.; Wangw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (b) Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109.
(c) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F.
Org. Lett. 2000, 2, 1423. (d) Charles, M. D.; Schultz, P.; Buchwald, S.
L. Org. Lett. 2005, 7, 3965. (e) Fors, B. P.; Watson, D. A.; Biscoe, M.
R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 13552. (f) Yang, B.
H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (g) Wolfe, J. P.; Rennels, R.
A.; Buchwald, S. L. Tetrahedron. 1996, 52, 7525. (h) Bower, J. F.;
Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem. 2010, 8, 1505.
(12) (a) Minakata, S.; Okada, Y.; Oleraotoshi, Y.; Komastu, M. Org.
Lett. 2005, 7, 3509. (b) D’hooghe, M.; Rottiers, M.; Kerkaert, I.; De
Kimpe, N. Tetrahedron. 2005, 61, 8746. (c) D’hooghe, M.; Waterinckx,
A.; Vanlangendonck, T.; De Kimpe, N. Tetrahedron 2006, 62, 2295.
(d) Karikomi, M.; D’hooghe, M.; Verniest, G.; De Kimpe, N. Org.
Biomol. Chem. 2008, 6, 1902. (e) D’hooghe, M.; Kenis, S.; Vervisch,
K.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N. Eur. J. Med.
Chem. 2011, 46, 579. (f) De Rycke, N.; David, O.; Couty, F. Org. Lett.
2011, 13, 1836. (g) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem.
(17) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.
́
Rev. 2007, 107, 2080. (h) Concellοn, J. M.; Rodriguez-Solla, H.; Amo,
V.; Diaz, P. J. Org. Chem. 2010, 75, 2407. (i) Hu, X. E. Tetrahedron
2004, 60, 2701 and references cited therein. (j) Forbeck, E. M.; Evans,
C. D.; Gilleran, J. A.; Li, P.; Joullie,
́
M. M. J. Am. Chem. Soc. 2007, 129,
14463. (k) Concellοn, J. M.; Bernad, P. L.; Suarez, J. R. J. Org. Chem.
2005, 70, 9411. (l) Kelley, B. T.; Joullie, M. M. Org. Lett. 2010, 12,
́
́
́
4244. (m) Couty, F.; Evano, G.; Prim, D. Tetrahedron Lett. 2005, 46,
2253. (n) Minakata, S.; Hotta, T.; Oderaotoshi, Y.; Komatsu, M. J. Org.
Chem. 2006, 71, 7471. (o) Zeng, F.; Alper, H. Org. Lett. 2010, 12,
5567. (p) Yadav, J. S.; Satheesh, G.; Murthy, C. V. S. R. Org. Lett.
2010, 12, 2544. (q) Bera, M.; Pratihar, S.; Roy, S. J. Org. Chem. 2011,
76, 1475. (r) Ghorai, M. K.; Kumar, A.; Das, K. Org. Lett. 2007, 9,
5441. (s) Ghorai, M. K.; Kumar, A.; Tiwari, D. P. J. Org. Chem. 2010,
75, 137. (t) Ghorai, M. K.; Das, K.; Shukla, D. J. Org. Chem. 2007, 72,
5859. (u) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V.
Angew. Chem., Int. Ed. 2009, 48, 1126. (v) Wu, B.; Parquette, J. R.;
RajanBabu, T. V. Science 2009, 326, 1662. (w) Stankovic, S.;
́
D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Speybroeck, V.
V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41, 643.
(13) (a) Minakata, S.; Murakami, Y.; Satake, M.; Hidaka, I.; Okada,
Y.; Komatsu, M. Org. Biomol. Chem. 2009, 7, 641. (b) Ding, C.-H.;
Dai, L.-X.; Hou, X.-L. Tetrahedron. 2005, 61, 9. (c) Blyumin, E. V.;
Gallon, H. J.; Yudin, A. K. Org. Lett. 2007, 9, 4677. (d) Moss, T. A.;
Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076.
(e) Paixao, M. W.; Nielsen, M.; Jacobsen, C. B.; Jørgensen, K. A. Org.
̃
Biomol. Chem. 2008, 6, 3467. (f) Enders, D.; Janeck, C. F.; Raabe, G.
Eur. J. Org. Chem. 2000, 3337. (g) Xu, Y.; Lin, L.; Kanai, M.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5791.
(14) For some recent examples of aziridine-mediated heterocycle
synthesis, see: (a) Kiss, L.; Mangelinckx, S.; Fulop, F.; De Kimpe, N.
̈
̈
Org. Lett. 2007, 9, 4399. (b) Du, X.; Yang, S.; Yang, J.; Liu, Y. Chem.
Eur. J. 2011, 17, 4981. (c) Wu, Y.-C.; Zhu, J. Org. Lett. 2009, 11, 5558.
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