Synthesis of fused-tricyclic indole derivatives through an acid-promoted skeletal rearrangement

Article abstract of DOI:10.1016/j.tet.2014.01.074

We developed a novel method for synthesizing fused-tricyclic indole derivatives with a 3-aminomethyl indole motif through a reaction cascade involving ipso-Friedel-Crafts alkylation of phenols, rearomatization of the spirocyclohexadienone unit, and iso-Pictet-Spengler reaction. Using TFA as an acid promoter, six-, seven-, and eight-membered ring-fused indoles were obtained in 31-99% yield.

Full text of DOI:10.1016/j.tet.2014.01.074

Tetrahedron 70 (2014) 2151e2160
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of fused-tricyclic indole derivatives through an
acid-promoted skeletal rearrangement
Takuya Yokosaka, Tomoya Kanehira, Hiroki Nakayama, Tetsuhiro Nemoto,
*
Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 January 2014
Received in revised form 30 January 2014
Accepted 31 January 2014
Available online 6 February 2014
We developed a novel method for synthesizing fused-tricyclic indole derivatives with a 3-aminomethyl
indole motif through a reaction cascade involving ipso-FriedeleCrafts alkylation of phenols, rear-
omatization of the spirocyclohexadienone unit, and iso-PicteteSpengler reaction. Using TFA as an acid
promoter, six-, seven-, and eight-membered ring-fused indoles were obtained in 31e99% yield.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reaction
ipso-FriedeleCrafts alkylation
iso-PicteteSpengler reaction
Indoloazepine
Tetrahydro-g-carboline
1. Introduction
Fused-polycyclic indole derivatives bearing a tetrahydro-
b
-car-
boline framework are potential candidates for drug discovery be-
cause this structural motif is present in a wide variety of
biologically active alkaloids. The development of an efficient syn-
thetic method of tetrahydro-b-carboline derivatives has attracted
broad attention in medicinal chemistry and synthetic organic
chemistry. Extensive efforts are therefore focused on this topic.1
3-Alkylidene indolenium cations are useful electrophiles for
preparing functionalized indole derivatives. As part of our ongoing
studies aimed at developing novel synthetic methods for spi-
rocyclohexadienone derivatives,2 we applied these electrophiles
to the nucleophilic dearomatization of phenols. We first expected
that, using compound 1 as a substrate, an intramolecular ipso-
FriedeleCrafts-type addition of phenol to the 3-alkylidene indole-
nium cation should occur in the presence of trifluoroacetic
acid (TFA), producing spirocyclohexadienones with an indole
substituent. The postulated spirocyclic adduct, however, was
not obtained and the tetrahydro-b-carboline derivative 2 was ob-
tained with high efficiency (Scheme 1). Deuterium labeling
studies revealed that the reaction mechanism of this transformation
was based on an acid-promoted skeletal rearrangement. First,
* Corresponding author. Tel./fax: þ81 43 226 2920; e-mail addresses: y-hamada@
Scheme 1. Synthesis of tetrahydro-b-carboline derivatives via a spirocyclohex-
adienone intermediate.
faculty.chiba-u.jp, hamada@p.chiba-u.ac.jp (Y. Hamada).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.074

2152
T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
3-alkylidene indolenium cation A was formed from 1 in the pres-
ence of TFA (Step a). Subsequent intramolecular ipso-FriedeleCrafts
alkylation of phenol to the 3-alkylidene indolenium cation afforded
spirocyclohexadienone intermediate B (Step b). Sequential rear-
omatization of the spirocyclohexadienone moiety accompanying
the carbonecarbon bond cleavage resulted in the generation of
iminium cation intermediate C (Step c). Finally, an intramolecular
2-indolyllithium at ꢀ78 ꢁC to give linear substrate 4a in 65% yield.
Compound 4a was then treated with 8 equiv of TFA in CH2Cl2
(0.025 M) at 0 ꢁC, which are the optimum reaction conditions for
the synthesis of tetrahydro-b-carboline derivatives. The reaction
proceeded to completion in 2.5 h, affording the desired indoloa-
zepine derivative 5a in 93% yield (Scheme 3).9
The results led us to investigate the scope and limitations of the
synthesis of indoloazepine derivatives. Preparation of the linear
substrates 4bei was performed as shown in Scheme 4. Reduction of
Weinreb amide derivative 4b using DIBAL-H, followed by conden-
sation with N-tosyl 2-indolylmagnesium chloride prepared using
Knochel’s method10 provided the substrate 4b. Subsequent
deprotection of the tert-butyldimethylsilyl (TBS) group gave the
phenol derivative 4c. Substrates 4d and e were also prepared from
the corresponding Weinreb amide derivatives 6d and e and N-tosyl
indolylmagnesium chloride derivatives using essentially the same
methods. Moreover, substrates 4fei were prepared using a cou-
pling reaction between aldehyde 3a and several N-Ts-5-substituted
2-indolyllithium reagents.
Results using the various substrates are summarized in Table 1.
In addition to para-substituted O-methyl ether derivative 4a (en-
try 1), TBS ether derivative 4b, phenol derivative 4c, and benzyl
ether derivative 4d were effective substrates for this reaction, and
the corresponding indoloazepine derivatives 5bed were obtained
in 87%e99% yield (entries 2e4). ortho-Substituted substrate 4e was
also tolerant to this reaction and the product 5e was obtained in
93% yield (entry 5). Furthermore, substrates 4fei bearing electron-
withdrawing and electron-donating groups on the indole ring were
applicable to this reaction, affording the desired products 5fei in
88%e99% yield (entries 6e9).
PicteteSpengler reaction occurred to give the tetrahydro-
line derivative 2 (Step d). Using TFA as an acid promoter, various
tetrahydro- -carbolines and the related seven- and eight-mem-
b-carbo-
b
bered ring-fused tricyclic indole derivatives were obtained in
moderate to excellent yield.3 The present reaction mode could be
extended to the synthesis of functionalized piperidine derivatives4
and fused-polycyclic cyclopenta[b]indole derivatives.5,6
In striking contrast to the ubiquity of the tetrahydro-
framework in natural products, fused-tricyclic indole frameworks
with a 3-aminomethyl indole motif, such as tetrahydro- -carbo-
b-carboline
g
lines7 are unknown in natural product structure. These heterocyclic
frameworks, however, hold considerable potential as templates for
drug discovery. Several synthetic bioactive molecules including this
structural motif have been developed (Fig.1).8 The reaction pathway
shown in Scheme 1 led us to hypothesize that fused-tricyclic indole
derivatives with a 3-aminomethyl indole motif would be obtained
from 2-substituted indole derivatives through a reaction cascade
involving ipso-FriedeleCrafts alkylation of phenols, rearomatization
of the spirocyclohexadienone unit, and an iso-PicteteSpengler re-
action (Scheme 2). Herein, we describe the synthesis of fused-
tricyclic indole derivatives with a 3-aminomethyl indole motif
through an acid-promoted skeletal rearrangement.
Compared with N-tosyl groups, nitrobenzenesulfonyl groups
are easily deprotectable under mild reaction conditions.11 A sub-
strate with a para-nosyl (p-Ns) amide tether was also applicable
to this cascade process (Scheme 5). N-p-Ns-protected 4-
methoxybenzylamine was reacted with acrolein under basic re-
action conditions to give aldehyde 3j in 49% yield, which was then
transformed into the corresponding 2-substituted indole derivative
4j in 90% yield. TFA-promoted cascade cyclization proceeded under
the optimized reaction conditions, affording compound 5j in 90%
yield. The p-Ns group in 5j could be removed by treatment with
thiophenol and K2CO3 in DMF and compound 8 was obtained in 82%
yield. On the other hand, the N-Ts group on the indole nitrogen was
deprotectable using TBAF (compound 9: 68% yield). Selective
deprotection of each protecting group on the nitrogen atoms en-
ables programmed derivatizations of the fused-heterocyclic struc-
ture. Furthermore, the N-Ns group in 9 was deprotected by using
thiophenol and K2CO3 (compound 10: 65% yield), demonstrating
Scheme 2. Cascade reaction design of this work.
Fig. 1. Examples of bioactive molecules with a 3-aminomethyl indole motif.
2. Results and discussions
the versatility of the developed method for drug candidate
screening.
We first confirmed the feasibility of the target sequential
Synthesis of a tetrahydro-g-carboline derivative was also ex-
process using
a
2-substituted indole derivative. The known
amined using 4k, a substrate bearing a CH2-unit-shorter tether
than that in 4a (Scheme 6). When compound 4k was treated under
aldehyde 3a was reacted with in situ-generated N-tosyl

T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
2153
Scheme 3. Feasibility study using 4a as a model substrate.
Scheme 4. Synthesis of substrates 4bei.
Table 1
Scope and limitationsa
Entry
Substrates
Products
Time
Yielda
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a (RO¼p-MeO, X¼H)
5b (RO¼p-TBSO, X¼H)
5c (RO¼p-HO, X¼H)
5d (RO¼p-BnO, X¼H)
5e (RO¼o-MeO, X¼H)
5f (RO¼p-MeO, X¼F)
5g (RO¼p-MeO, X¼Cl)
5h (RO¼p-MeO, X¼Me)
5i (RO¼p-MeO, X¼OMe)
2.5 h
4 h
5 h
1.5 h
2.5 h
2.5 h
11 h
3 h
93%
87%
94%
99%
93%
96%
88%
99%
89%
3
4b
5
6
7b
8
9
3 h
a
Isolated yield.
Reaction was performed in CH2Cl2 (0.01 M).
b
the optimized conditions, the reaction gave complex mixtures and
the desired tetrahydro- -carboline derivative 5k and compound
g
11k were obtained in 34% yield and 47% yield, respectively. More-
over, a reaction using substrate 4l, bearing a CH2-unit longer tether
Scheme 5. Substrate with a p-Ns group on the linker nitrogen.

2154
T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
Scheme 6. Synthesis of six-or eight-membered ring-fused tricyclic indole derivatives.
than that in 4a, was performed under the optimized reaction
conditions. The corresponding eight-membered ring-fused tricyclic
indole derivative 5l was obtained in 31% yield, accompanied by the
formation of pyrrolidine derivative 12l in 49% yield.
as an acid promoter, six-, seven-, and eight-membered ring-fused
indoles were obtained in 31%e99% yield. Further investigations
into the biological activity of a series of tricyclic indole derivatives
are in progress.
Extension of the developed process to catalytic asymmetric
synthesis was examined using chiral Brønsted acid catalysts
(Table 2).12 No reaction occurred when compound 4a was treated
with 20 mol % of the known chiral phosphoric acids (S)-13aed in
toluene at 100 ꢁC (entries 1e4). Although the reaction was sluggish,
more acidic N-triflyl thiophosphoramide catalyst (S)-13e promoted
the reaction to produce 5a in 36% yield (entry 5). Furthermore,
introducing electron-withdrawing aromatic substituents on the
3,30-positions of the (S)-BINOL unit dramatically affected the re-
activity. The reaction proceeded at 50 ꢁC in the presence of 20 mol %
of (S)-13f, affording 5a in 82% yield (entry 6). The enantiomeric
excess of the products was, however, less than 5% ee. There was no
improvement in the enantiomeric excess when the phenol type
substrate 4c was used as a substrate (entry 7). To achieve asym-
metric synthesis, it will be necessary to explore other strategies.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 230 Fourier
transform infrared spectrophotometer, equipped with ATR (Smiths
Detection, DuraSample IR II). NMR spectra were recorded on JEOL
ecs 400 spectrometer, JEOL ecp 400 spectrometer, and JEOL eca 600
spectrometer. Chemical shifts in CDCl3 were reported downfield
from TMS (¼0 ppm) for 1H NMR. For 13C NMR, chemical shifts were
reported in the scale relative to the solvent signal [CHCl3
(77.0 ppm)] as an internal reference. ESI mass spectra were mea-
sured on JEOL AccuTOF LC-plus JMS-T100LP. Melting points were
measured with a SIBATA NEL-270 melting point apparatus. Ana-
lytical thin layer chromatography was performed on Merck Art.
5715, Kieselgel 60F254/0.25 mm thickness plates. Column chroma-
tography was performed with Kanto Kagaku, silica gel 60 N
(spherical, neutral 63e210 mesh). The enantiomeric excesses were
determined by HPLC analysis. HPLC was performed on JASCO HPLC
systems consisting of the following: pump, PU-980; detector, UV-
970, measured at 254 nm; column, DAICEL CHIRALPAK AD-H;
mobile phase, 2-propanol/n-hexane. Optical rotation was mea-
sured on a JASCO P-1020 polarimeter. Reactions were carried out in
dry solvent. Reactions were carried out in dry solvent. Other re-
agents were purified by the usual methods.
Table 2
Trials for the extension of catalytic asymmetric synthesisa
Entry Substrate Product Catalyst (mol %) Temp Time Yieldb eec
(ꢁC)
(h)
(%)
(%)
1
2
3
4
4a
4a
4a
4a
4a
4a
4c
5a
5a
5a
5a
5a
5a
5c
(S)-13a (20)
(S)-13b (20)
(S)-13c (20)
(S)-13d (20)
(S)-13e (20)
(S)-13f (20)
(S)-13f (20)
100
100
100
100
80
24
17
24
24
18
0
0
0
n.d.
n.d.
n.d.
n.d.
5
0
5
36
82
77
6
50
50
3.5
3
3
5
7d
a
Reactions were performed in toluene (0.1 M).
Isolated yield.
Determined by chiral HPLC analysis.
Reaction was performed in toluene (0.02 M).
b
c
4.2. Experimental procedure for the synthesis of in-
doloazepine derivatives and product characterizations
d
4.2.1. Typical experimental procedure for the acid-promoted skeletal
rearrangement (Table 1, entry 1). To a stirred solution of 4a
(30.9 mg, 0.05 mmol) in CH2Cl2 (1.6 mL) at 0 ꢁC was added TFA
(0.4 mL, 1.0 M in CH2Cl2, 0.4 mmol). After being stirred for 2.5 h at
0
ꢁC, the reaction mixture was concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/
EtOAc¼3/1) to give 5-(4-methoxyphenyl)-2,6-ditosyl-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole 5a (28.0 mg, 93% yield) as white
solids. Mp 159e162 ꢁC; Rf 0.56 (n-hexane/EtOAc¼1/1); 1H NMR
3. Conclusion
In conclusion, we developed a novel method for synthesizing
fused-tricyclic indole derivatives with a 3-aminomethyl indole
motif through an acid-promoted skeletal rearrangement. Using TFA
(400 MHz, CDCl3) d 2.13e2.21 (m, 1H), 2.27 (s, 3H), 2.25e2.31
(m, 1H), 2.37 (s, 3H), 3.13 (td, J¼12.4, 2.8 Hz, 1H), 3.36 (dt, J¼12.4,
2.8 Hz, 1H), 3.75 (s, 3H), 4.47 (d, J¼16.0 Hz, 1H), 4.56 (d, J¼16.0 Hz,

T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
2155
1H), 5.35 (dd, J¼6.0, 3.2 Hz, 1H), 6.66 (d, J¼8.8 Hz, 2H), 6.87
(d, J¼8.8 Hz, 2H), 6.93 (d, J¼8.0 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H), 7.18
(d, J¼8.0 Hz, 2H), 7.31e7.36 (m, 2H), 7.55 (d, J¼8.0 Hz, 1H), 7.56 (d,
J¼8.0 Hz, 2H), 8.22 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
IR (ATR) n ;
1508, 1454, 1264, 1161, 1091, 971, 811, 731, 701, 666 cmꢀ1
(þ)-ESI-HRMS. Calcd for C39H36N2NaO5Sþ2 (MþNa)þ: 699.1958.
Found: 699.1971.
d
21.4, 21.5, 33.4, 40.7, 41.6, 45.3, 55.2, 113.8 (2C), 115.1, 118.0, 119.2,
4.2.5. 5-(2-Methoxyphenyl)-2,6-ditosyl-1,2,3,4,5,6-hexahydroazepino
[4,3-b]indole (5e). Compound 5e was prepared from 4e according to
the typical experimental procedure shown in Section 4.2.1. White
solids; Mp 95 ꢁC; Rf 0.37 (n-hexane/EtOAc¼2/1); 1H NMR (400 MHz,
123.5, 124.8, 126.3 (2C), 127.1 (2C), 128.2, 129.4 (2C), 129.4 (2C),
129.6 (2C), 131.5, 135.5, 136.0, 136.2, 139.4, 143.3, 144.3, 158.3; IR
(ATR)
n 1509, 1453, 1341, 1247, 1157, 1089, 1028, 970, 810, 735,
664 cmꢀ1; (þ)-ESI-HRMS. Calcd for C33H32N2NaO5Sþ2 (MþNa)þ:
CDCl3) d 2.13e2.22 (m, 1H), 2.26 (s, 3H), 2.33e2.39 (m, 1H), 2.37 (s,
623.1645. Found: 623.1670.
3H), 3.09 (td, J¼12.0, 3.2 Hz,1H), 3.29 (dt, J¼12.0, 3.2 Hz,1H), 3.92 (s,
3H), 4.54 (d, J¼16.0 Hz, 1H), 4.58 (d, J¼16.0 Hz, 1H), 5.65 (dd, J¼6.0,
3.6 Hz, 1H), 6.53e6.58 (m, 2H), 6.87 (d, J¼8.4 Hz, 1H), 6.92 (d,
J¼8.4 Hz, 2H), 7.12e7.22 (m, 5H), 7.30e7.35 (m, 2H), 7.55 (dd, J¼8.0,
2.4 Hz, 1H), 7.59 (d, J¼8.4 Hz, 2H), 8.22 (dd, J¼6.8, 2.8 Hz, 1H); 13C
4.2.2. 5-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-2,6-ditosyl-
1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (5b). Compound 5b was
prepared from 4b according to the typical experimental procedure
shown in Section 4.2.1. White solids; Mp 82 ꢁC; Rf 0.58 (n-hexane/
NMR (100 MHz, CDCl3)
d 21.5, 21.5, 29.9, 36.1, 41.7, 45.8, 55.6, 110.6,
EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d
0.18 (s, 6H), 0.97 (s, 9H),
115.1, 117.8, 119.7, 120.2, 123.4, 124.7, 126.4 (2C), 127.2 (2C), 127.7,
127.9, 128.2, 129.4 (2C), 129.6 (2C), 129.7, 135.6, 135.9, 136.1, 139.5,
2.13e2.21 (m, 1H), 2.21e2.30 (m, 1H), 2.27 (s, 3H), 2.37 (s, 3H), 3.04
(td, J¼12.4, 2.8 Hz, 1H), 3.43 (dt, J¼12.4, 2.8 Hz, 1H), 4.36 (d,
J¼16.0 Hz, 1H), 4.62 (d, J¼16.0 Hz, 1H), 5.37 (dd, J¼5.6, 3.2 Hz, 1H),
6.59 (d, J¼8.8 Hz, 2H), 6.79 (d, J¼8.8 Hz, 2H), 6.96 (d, J¼8.8 Hz, 2H),
7.17 (d, J¼8.8 Hz, 2H), 7.22 (d, J¼8.0 Hz, 2H), 7.29e7.38 (m, 2H), 7.55
(dd, J¼6.8, 2.0 Hz, 1H), 7.57 (d, J¼8.0 Hz, 2H), 8.21 (dd, J¼6.8, 2.0 Hz,
143.2, 144.3, 156.5; IR (ATR)
n 1597, 1453, 1341, 1240, 1157, 1090,
1026, 970, 812, 733, 701, 665 cmꢀ1; (þ)-ESI-HRMS. Calcd for
C
33H32N2NaO5Sþ2 (MþNa)þ: 623.1645. Found: 623.1666.
4.2.6. 9-Fluoro-5-(4-methoxyphenyl)-2,6-ditosyl-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole (5f). Compound 5f was prepared
from 4f according to the typical experimental procedure shown in
Section 4.2.1. White solids; Mp 91 ꢁC; Rf 0.40 (n-hexane/EtOAc¼2/
1H); 13C NMR (100 MHz, CDCl3)
(3C), 33.5, 40.5, 41.8, 45.4, 115.1, 118.0, 119.2, 119.8 (2C), 123.5, 124.8,
126.3 (2C), 127.2 (2C), 128.2, 129.2 (2C), 129.4 (2C), 129.6 (2C), 131.9,
d
ꢀ4.45 (2C), 18.1, 21.5, 21.5, 25.6
135.5, 135.8, 136.1, 139.5, 143.3, 144.4, 154.2; IR (ATR)
n
1507, 1453,
1); 1H NMR (400 MHz, CDCl3)
d 2.16e2.25 (m, 1H), 2.28 (s, 3H),
1342, 1262, 1159, 1089, 970, 913, 808, 733, 702, 664 cmꢀ1; (þ)-ESI-
HRMS. Calcd for C38H44N2NaO5S2Siþ (MþNa)þ: 723.2353. Found:
723.2336.
2.33e2.43 (m, 1H), 2.39 (s, 3H), 3.13 (td, J¼12.0, 2.8 Hz,1H), 3.34 (dt,
J¼12.0, 2.8 Hz, 1H), 3.76 (s, 3H), 4.42 (s, 2H), 5.34 (dd, J¼5.2, 2.8 Hz,
1H), 6.67 (d, J¼8.8 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 6.95 (d, J¼8.0 Hz,
2H), 7.08 (td, J¼8.8, 1.8 Hz, 1H), 7.15 (d, J¼8.0 Hz, 2H), 7.17e7.23 (m,
3H), 7.60 (d, J¼8.4 Hz, 2H), 8.16e8.20 (m, 1H); 13C NMR (100 MHz,
4.2.3. 4-(2,6-Ditosyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-5-yl)
phenol (5c). Compound 5c was prepared from 4c according to the
typical experimental procedure shown in Section 4.2.1. White
solids; Mp 119 ꢁC; Rf 0.29 (n-hexane/EtOAc¼1/1); 1H NMR
CDCl3)
d
21.4, 21.4, 33.3, 40.7, 41.5, 45.2, 55.1, 103.7 (d, J¼23.9 Hz),
112.6 (d, J¼24.8 Hz), 113.8 (2C), 116.2 (d, J¼8.5 Hz), 119.1 (d,
J¼3.8 Hz), 126.2 (2C), 127.1 (2C), 129.2 (d, J¼9.5 Hz), 129.4 (2C),
129.4 (2C), 129.7 (2C), 131.0, 132.4, 135.2, 135.6, 141.2, 143.4, 144.5,
(400 MHz, CDCl3)
d 2.11e2.20 (m, 1H), 2.22 (s, 3H), 2.23e2.33 (m,
1H), 2.36 (s, 3H), 3.14 (td, J¼12.4, 3.2 Hz, 1H), 3.29 (dt, J¼12.4,
3.2 Hz, 1H), 4.46 (d, J¼16.4 Hz, 1H), 4.52 (d, J¼16.4 Hz, 1H), 5.32 (dd,
J¼6.0, 3.2 Hz, 1H), 5.43 (br s, 1H), 6.56 (d, J¼8.8 Hz, 2H), 6.80
(d, J¼8.8 Hz, 2H), 6.92 (d, J¼8.0 Hz, 2H), 7.16 (d, J¼8.0 Hz, 2H), 7.19
(d, J¼8.0 Hz, 2H), 7.27e7.36 (m, 2H), 7.54 (dd, J¼7.2, 2.0 Hz,1H), 7.59
(d, J¼8.0 Hz, 2H), 8.20 (dd, J¼7.2, 2.0 Hz, 1H); 13C NMR (100 MHz,
158.3, 159.7 (d, J¼240.2 Hz); IR (ATR)
n 1509, 1456, 1340, 1265, 1156,
1089, 1034, 890, 810, 732, 666 cmꢀ1; (þ)-ESI-HRMS. Calcd for
C
33H31FN2NaO5Sþ2 (MþNa)þ: 641.1551. Found: 641.1551.
4.2.7. 9-Chloro-5-(4-methoxyphenyl)-2,6-ditosyl-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole (5g). Compound 5g was prepared
from 4g according to the typical experimental procedure shown in
Section 4.2.1. White solids; Mp 99e100 ꢁC; Rf 0.36 (n-hexane/
CDCl3) d 21.4, 21.4, 33.2, 40.6, 41.5, 45.2,115.0, 115.2 (2C),117.9, 119.1,
123.5, 124.8, 126.3 (2C), 127.1 (2C), 128.1, 129.4 (2C), 129.6 (2C),
129.7 (2C), 131.1, 135.7, 136.1, 136.2, 139.4, 143.5, 144.5, 154.5; IR
EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d 2.14e2.19 (m, 1H), 2.29 (s,
(ATR)
n
1732, 1511, 1453, 1372, 1264, 1154, 1090, 971, 813, 733, 702,
3H), 2.25e2.30 (m, 1H), 2.38 (s, 3H), 3.11 (td, J¼12.4, 2.8 Hz, 1H),
3.32 (dt, J¼12.4, 2.8 Hz, 1H), 3.75 (s, 3H), 4.39 (d, J¼16.0 Hz, 1H),
4.44 (d, J¼16.0 Hz,1H), 5.33 (dd, J¼5.6, 3.2 Hz,1H), 6.66 (d, J¼8.4 Hz,
2H), 6.86 (d, J¼8.4 Hz, 2H), 6.94 (d, J¼8.4 Hz, 2H), 7.14 (d, J¼8.4 Hz,
2H), 7.22 (d, J¼8.4 Hz, 2H), 7.29 (dd, J¼8.8, 1.6 Hz, 1H), 7.49 (d,
J¼1.6 Hz, 1H), 7.60 (d, J¼8.4 Hz, 2H), 8.15 (d, J¼8.8 Hz, 1H); 13C NMR
665 cmꢀ1; (þ)-ESI-HRMS. Calcd for C32H30N2NaO5Sþ2 (MþNa)þ:
609.1488. Found: 609.1512. The enantiomeric excess was de-
termined by chiral HPLC analysis (DAICEL CHIRALPAK AD-H, hex-
ane/2-propanol¼60/40, flow rate: 1.0 mL/min, tR 19.5 min and
41.8 min, detection at 254 nm).
(100 MHz, CDCl3) d 21.4, 21.4, 33.3, 40.7, 41.4, 45.2, 55.2, 113.8, 113.8
4.2.4. 5-(4-(Benzyloxy)phenyl)-2,6-ditosyl-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole (5d). Compound 5d was prepared
from 4d according to the typical experimental procedure shown in
Section 4.2.1. White solids; Mp 68 ꢁC; Rf 0.41 (n-hexane/EtOAc¼2/
(2C),116.1,117.6,118.6,124.9,126.2 (2C),127.2 (2C),129.3,129.4 (2C),
129.5 (2C), 129.7 (2C), 130.9, 134.5, 135.2, 135.5, 140.9, 143.4, 144.6,
158.3; IR (ATR)
n 1509, 1443, 1338, 1246, 1160, 1090, 808, 738, 696,
665 cmꢀ1; (þ)-ESI-HRMS. Calcd for C33H31ClN2NaO5Sþ2 (MþNa)þ:
1); 1H NMR (400 MHz, CDCl3)
d
2.13e2.22 (m, 1H), 2.25 (s, 3H),
657.1255. Found: 657.1257.
2.26e2.34 (m, 1H), 2.37 (s, 3H), 3.14 (td, J¼12.4, 2.8 Hz, 1H), 3.36 (dt,
J¼12.4, 2.8 Hz, 1H), 4.46 (d, J¼16.0 Hz, 1H), 4.55 (d, J¼16.0 Hz, 1H),
4.98 (d, J¼16.0 Hz, 1H), 5.00 (d, J¼16.0 Hz, 1H), 5.36 (dd, J¼6.0,
3.2 Hz, 1H), 6.75 (d, J¼8.0 Hz, 2H), 6.90 (d, J¼8.0 Hz, 2H), 6.91 (d,
J¼8.0 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H), 7.19 (d, J¼8.0 Hz, 2H), 7.29e7.46
(m, 7H), 7.50 (dd, J¼6.8, 2.0 Hz, 1H), 7.59 (d, J¼8.0 Hz, 2H), 8.21 (dd,
4.2.8. 5-(4-Methoxyphenyl)-9-methyl-2,6-ditosyl-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole (5h). Compound 5h was prepared
from 4h according to the typical experimental procedure shown in
Section 4.2.1. White solids; Mp 47e48 ꢁC; Rf 0.37 (n-hexane/
EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d 2.12e2.19 (m, 1H), 2.26 (s,
J¼6.8, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
21.5, 21.5, 33.4, 40.7,
3H), 2.23e2.29 (m, 1H), 2.37 (s, 3H), 2.47 (s, 3H), 3.10 (td, J¼12.4,
2.8 Hz, 1H), 3.34 (dt, J¼12.4, 2.8 Hz, 1H), 3.74 (s, 3H), 4.43 (d,
J¼15.6 Hz, 1H), 4.52 (d, J¼15.6 Hz, 1H), 5.33 (dd, J¼6.0, 3.2 Hz, 1H),
6.65 (d, J¼8.4 Hz, 2H), 6.86 (d, J¼8.4 Hz, 2H), 6.92 (d, J¼8.4 Hz, 2H),
41.6, 45.3, 69.9, 114.6 (2C) 115.1, 118.0, 119.2, 123.5, 124.8, 126.3 (2C),
127.2 (2C), 127.5 (2C), 128.0, 128.2, 128.6 (2C), 129.4 (2C), 129.5 (2C),
129.6 (2C), 131.8, 135.4, 135.8, 136.1, 137.0, 139.4, 143.3, 144.3, 157.5;

2156
T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
7.16 (d, J¼8.4 Hz, 2H), 7.16 (d, J¼8.4 Hz, 1H), 7.19 (d, J¼8.4 Hz, 2H),
7.32 (s, 1H), 7.59 (d, J¼8.4 Hz, 2H), 8.08 (d, J¼8.4 Hz, 1H); 13C NMR
were washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was passed through a short pad of silica
gel. After concentration in vacuo, the obtained aldehyde was uti-
lized for the next reaction without further purification. i-PrMgCl
(1.3 mL, 2 M in THF, 2.6 mmol) was added to a stirred solution of 2-
iodo-N-Ts-indole (1039 mg, 2.6 mmol) in THF (13 mL) at 0 ꢁC. After
being stirred for 30 min, the crude aldehyde dissolved in THF
(13 mL) was added to the reaction mixture at 0 ꢁC. After being
stirred for 40 min at the same temperature, the reaction was
quenched with saturated aqueous NH4Cl, and the resulting mixture
was extracted twice with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (n-hexane/EtOAc¼3/1) to give 4b (652 mg, 61% yield) as
white solids. Mp 49 ꢁC; Rf 0.42 (n-hexane/EtOAc¼1/1); 1H NMR
(100 MHz, CDCl3)
d 21.3, 21.4, 21.4, 33.4, 40.6, 41.6, 45.3, 55.1, 113.7
(2C), 114.8, 117.8, 119.0, 126.2, 126.2 (2C), 127.2 (2C), 128.3, 129.3
(2C), 129.4 (2C), 129.6 (2C), 131.5, 133.1, 134.4, 135.4, 135.9, 139.4,
143.3,144.2,158.2; IR (ATR) n 1509,1337,1247,1156,1088,1033, 882,
807, 732, 665 cmꢀ1; (þ)-ESI-HRMS. Calcd for C34H34N2NaO5S2þ
(MþNa)þ: 637.1801. Found: 637.1813.
4.2.9. 9-Methoxy-5-(4-methoxyphenyl)-2,6-ditosyl-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole (5i). Compound 5i was prepared
from 4i according to the typical experimental procedure shown in
Section 4.2.1. White solids; Mp 101e102 ꢁC; Rf 0.46 (n-hexane/
EtOAc¼1.5/1); 1H NMR (400 MHz, CDCl3)
d 2.10e2.19 (m, 1H),
2.23e2.28 (m, 1H), 2.27 (s, 3H), 2.37 (s, 3H), 3.11 (td, J¼12.4, 2.8 Hz,
1H), 3.36 (dt, J¼12.4, 2.8 Hz, 1H), 3.75 (s, 3H), 3.90 (s, 3H), 4.41 (d,
J¼16.0 Hz, 1H), 4.52 (d, J¼16.0 Hz, 1H), 5.31 (dd, J¼6.0, 3.2 Hz, 1H),
6.65 (d, J¼8.4 Hz, 2H), 6.86 (d, J¼8.4 Hz, 2H), 6.92 (d, J¼8.4 Hz, 2H),
6.94 (s, 1H), 6.95 (d, J¼8.4 Hz, 1H), 7.16 (d, J¼8.4 Hz, 2H), 7.19 (d,
J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz, 2H), 8.11 (d, J¼8.4 Hz, 1H); 13C NMR
(400 MHz, CDCl3)
d 0.12 (s, 6H), 0.94 (s, 9H), 1.82e1.91 (m, 1H),
2.03e2.11 (m, 1H), 2.31 (s, 3H), 2.43 (s, 3H), 3.15 (ddd, J¼14.8, 7.2,
4.0 Hz, 1H), 3.44 (s, 1H), 3.51 (dt, J¼14.8, 8.0 Hz, 1H), 4.28 (d,
J¼14.4 Hz, 1H), 4.36 (d, J¼14.4 Hz, 1H), 5.24 (dd, J¼9.2, 4.8 Hz, 1H),
6.43 (s, 1H), 6.70 (d, J¼8.4 Hz, 2H), 7.08 (d, J¼8.4 Hz, 2H), 7.19
(d, J¼8.0 Hz, 2H), 7.19 (t, J¼8.0 Hz, 1H), 7.27 (t, J¼8.0 Hz, 1H), 7.31 (d,
J¼8.0 Hz, 2H), 7.40 (d, J¼8.0 Hz, 1H), 7.69 (d, J¼8.0 Hz, 2H), 7.74 (d,
J¼8.0 Hz, 2H), 8.11 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3) d 21.4, 21.4, 33.3, 40.7, 41.7, 45.2, 55.1, 55.8, 100.6,
113.4, 113.7 (2C),116.1, 119.2, 126.2 (2C), 127.2 (2C), 129.2, 129.3 (2C),
129.3 (2C), 129.6 (2C), 130.8, 131.4, 135.4, 135.8, 140.1, 143.3, 144.2,
156.6, 158.2; IR (ATR)
n
1509, 1474, 1338, 1155, 1089, 1033, 982, 883,
d
ꢀ4.46 (2C), 18.1, 21.5, 21.5, 25.6 (3C), 34.6, 44.8, 52.0, 63.8, 109.0,
810, 732, 665 cmꢀ1; (þ)-ESI-HRMS. Calcd for C34H34N2NaO6S2þ
114.8, 120.2 (2C), 121.0, 123.7, 124.7, 126.4 (2C), 127.2 (2C), 128.7,
129.2, 129.7 (2C), 129.8 (2C), 129.9 (2C), 135.4, 136.5, 137.1, 143.2,
(MþNa)þ: 653.1750. Found: 653.1746.
143.3, 145.0, 155.3; IR (ATR) n 1509, 1451, 1263, 1156, 1091, 910, 813,
4.3. Substrate syntheses shown in Schemes 3 and 4 and
product characterizations
733, 702 cmꢀ1
;
(þ)-ESI-HRMS. Calcd for C38H46N2NaO6S2Siþ
741.2459 (MþNa)þ. Found 741.2470.
4.3.1. N-(3-Hydroxy-3-(1-tosyl-1H-indol-2-yl)propyl)-N-(4-
methoxybenzyl)-4-methylbenzenesulfonamide (4a). To a stirred so-
lution of N-Ts-indole (190 mg, 0.70 mmol) in THF (5 mL) at ꢀ78 ꢁC
was added n-BuLi (0.44 mL, 1.6 M in n-hexane, 0.70 mmol). After
being stirred for 1 h at the same temperature, a THF solution of 3a3
(122 mg, 0.35 mmol in THF 4 mL) was added to the reaction mix-
ture. After being stirred for 10 min at the same temperature, the
reaction was quenched with saturated aqueous NH4Cl, and the
resulting mixture was extracted twice with EtOAc. The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/EtOAc¼2/1) to give 4a (141 mg,
65% yield) as white solids. Mp 59 ꢁC; Rf 0.48 (n-hexane/EtOAc¼1/1);
4.3.3. N-(3-Hydroxy-3-(1-tosyl-1H-indol-2-yl)propyl)-N-(4-
hydroxybenzyl)-4-methylbenzenesulfonamide (4c). To a stirred so-
lution of 4b (100 mg, 0.14 mmol) and AcOH (10 mL, 0.17 mmol) in
THF (1.2 mL) at 0 ꢁC was added TBAF (0.17 mL, 1.0 M in THF). After
being stirred for 5 min at 0 ꢁC, the reaction was quenched with
saturated aqueous NH4Cl, and the resulting mixture was extracted
three times with EtOAc. The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromatography (n-
hexane/EtOAc¼1.5/1) to give 4c (76.4 mg, 91% yield) as white solids.
Mp 166e170 ꢁC; Rf 0.34 (n-hexane/EtOAc¼1/1); 1H NMR (400 MHz,
CDCl3)
d 1.83e1.92 (m, 1H), 2.09e2.17 (m, 1H), 2.33 (s, 3H), 2.44 (s,
3H), 3.14 (ddd, J¼14.4, 7.6, 4.0 Hz, 1H), 3.37 (s, 1H), 3.47 (dt, J¼14.4,
7.6 Hz, 1H), 4.29 (d, J¼14.4 Hz, 1H), 4.33 (d, J¼14.4 Hz, 1H), 4.96 (s,
1H), 5.22 (dd, J¼9.2, 3.6 Hz, 1H), 6.47 (s, 1H), 6.71 (d, J¼8.4 Hz, 2H),
7.09 (d, J¼8.4 Hz, 2H), 7.20 (d, J¼8.0 Hz, 2H), 7.21 (t, J¼7.2 Hz, 1H),
7.28 (t, J¼7.2 Hz, 1H), 7.32 (d, J¼8.0 Hz, 2H), 7.42 (d, J¼7.2 Hz, 1H),
7.67 (d, J¼8.0 Hz, 2H), 7.74 (d, J¼8.0 Hz, 2H), 8.09 (d, J¼7.2 Hz, 1H);
1H NMR (400 MHz, CDCl3)
d 1.83e1.92 (m, 1H), 2.08e2.16 (m, 1H),
2.32 (s, 3H), 2.43 (s, 3H), 3.12e3.18 (m, 1H), 3.40 (d, J¼5.2 Hz, 1H),
3.48 (dt, J¼14.4, 7.6 Hz,1H), 3.73 (s, 3H), 4.31 (d, J¼14.8 Hz,1H), 4.35
(d, J¼14.8 Hz, 1H), 5.20e5.25 (m, 1H), 6.46 (s, 1H), 6.76 (d, J¼8.8 Hz,
2H), 7.13 (d, J¼8.8 Hz, 2H), 7.19 (d, J¼8.0 Hz, 2H), 7.21 (t, J¼8.0 Hz,
1H), 7.27 (t, J¼8.0 Hz, 1H), 7.31 (d, J¼8.0 Hz, 2H), 7.41 (d, J¼8.0 Hz,
1H), 7.67 (d, J¼8.0 Hz, 2H), 7.74 (d, J¼8.0 Hz, 2H), 8.10 (d, J¼8.0 Hz,
13C NMR (100 MHz, CDCl3)
d 21.6, 21.6, 34.8, 44.7, 52.0, 64.1, 109.2,
114.8, 115.6 (2C), 121.1, 123.8, 124.9, 126.5 (2C), 127.3 (2C), 128.2,
129.3, 129.8 (2C), 130.0 (2C), 130.2 (2C), 135.5, 136.6, 137.2, 143.3,
1H); 13C NMR (100 MHz, CDCl3)
d 21.5, 21.5, 34.7, 44.6, 51.8, 55.2,
64.0, 109.2, 114.0 (2C), 114.8, 121.0, 123.7, 124.8, 126.4 (2C), 127.2
(2C), 127.9, 129.2, 129.7 (2C), 129.9 (2C), 129.9 (2C), 135.4, 136.6,
143.4, 145.1, 155.4; IR (ATR) n 1515, 1375, 1285, 1173, 1141, 1088,
1052, 921, 812, 753, 671 cmꢀ1
;
(þ)-ESI-HRMS. Calcd for
137.1, 143.3, 143.4, 145.0, 159.3; IR (ATR)
n
1597, 1512, 1451, 1335,
C
32H32N2NaO6Sþ2 627.1594 (MþNa)þ. Found 627.1588.
1247, 1152, 1089, 1034, 916, 812, 733, 702, 675 cmꢀ1; (þ)-ESI-HRMS.
Calcd for C33H34N2NaO6Sþ2 641.1750 (MþNa)þ. Found 641.1780.
4.3.4. 3-(N-(4-(Benzyloxy)benzyl)-4-methylphenylsulfonamido)-N-
methoxy-N-methylpropanamide (6d). To a stirred solution of 74
(1.35 g, 4.7 mmol) in THF (16 mL) at 0 ꢁC was added NaH (60% in
oil, 207 mg, 5.2 mmol). After being stirred for 30 min, a THF solu-
tion of p-benzyloxybenzyl chloride (9.4 mmol in THF 8 mL) and
TBAI (174 mg, 0.47 mmol) were added to the reaction mixture at
0 ꢁC. After being stirred for 2 h at 60 ꢁC, the reaction was quenched
with saturated aqueous NH4Cl at room temperature, and the
resulting mixture was extracted three times with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
4.3.2. N-(4-((tert-Butyldimethylsilyl)oxy)benzyl)-N-(3-hydroxy-3-
(1-tosyl-1H-indol-2-yl)propyl)-4-methylbenzenesulfonamide
(4b). To a stirred solution of 6b4 (750 mg, 1.5 mmol) in CH2Cl2
(7 mL) at ꢀ78 ꢁC was added dropwise DIBAL-H (2.1 mL, 1.0 M in n-
hexane). After being stirred for 20 min at ꢀ78 ꢁC, the reaction was
quenched with aqueous 2 M potassium sodium tartrate. The solu-
tion was warmed up to room temperature and kept stirring until
the organic and aqueous layers were separated. The aqueous layer
was extracted twice with EtOAc and the combined organic layers

T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
2157
purified by silica gel column chromatography (n-hexane/EtOAc¼2/
1) to give 6d (1.74 g, 77% yield) as yellow solids. Mp 75e78 ꢁC; Rf
derivative according to the experimental procedure shown in
Section 4.3.1. White solids; Mp 34 ꢁC; Rf 0.27 (n-hexane/EtOAc¼2/
0.21 (n-hexane/EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d
2.40 (s,
1); 1H NMR (400 MHz, CDCl3)
d 1.80e1.86 (m, 1H), 2.09e2.12 (m,
3H), 2.51 (t, J¼7.2 Hz, 2H), 3.03 (s, 3H), 3.37 (t, J¼7.2 Hz, 2H), 3.45 (s,
3H), 4.25 (s, 2H), 5.02 (s, 2H), 6.90 (d, J¼8.0 Hz, 2H), 7.22 (d,
J¼8.0 Hz, 2H), 7.25e7.41 (m, 7H), 7.71 (d, J¼8.4 Hz, 2H); 13C NMR
1H), 2.33 (s, 3H), 2.44 (s, 3H), 3.12 (ddd, J¼14.4, 7.2, 4.0 Hz, 1H), 3.44
(d, Jv5.2 Hz, 1H), 3.49 (dt, J¼14.4, 6.8 Hz, 1H), 3.73 (s, 3H), 4.31
(d, J¼14.4 Hz, 1H), 4.35 (d, J¼14.4 Hz, 1H), 5.23e5.26 (m, 1H), 6.43
(s, 1H), 6.76 (d, J¼8.8 Hz, 2H), 7.00 (td, J¼8.8, 2.4 Hz, 1H), 7.05 (dd,
J¼8.8, 2.4 Hz, 1H), 7.11 (d, J¼8.8 Hz, 2H), 7.21 (d, J¼8.4 Hz, 2H), 7.32
(d, J¼8.4 Hz, 2H), 7.66 (d, J¼8.4 Hz, 2H), 7.74 (d, J¼8.4 Hz, 2H), 8.05
(100 MHz, CDCl3)
d 21.3, 31.6, 31.9, 43.8, 52.4, 60.9, 69.7, 114.7 (2C),
127.0 (2C), 127.2 (2C), 127.8, 128.4 (2C), 128.4, 129.5 (2C), 129.6 (2C),
136.2, 136.6, 143.1, 158.3, 171.7; IR (ATR)
n 1655, 1509, 1454, 1335,
1239, 1155, 1091, 987, 916, 814, 734, 697 cmꢀ1; (þ)-ESI-HRMS. Calcd
(dd, J¼8.8, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.5, 21.5, 34.8,
for C26H30N2NaO5Sþ 505.1768 (MþNa)þ. Found 505.1764.
44.5, 51.8, 55.2, 63.9, 106.5 (d, J¼23.9 Hz), 108.9 (d, J¼3.8 Hz), 112.5
(d, J¼24.8 Hz), 114.0 (2C), 115.9 (d, J¼8.6 Hz), 126.4 (2C), 127.2 (2C),
127.8, 129.8 (2C), 129.9 (2C), 130.2 (2C), 130.3 (d, J¼10.5 Hz), 133.4,
135.0,136.4,143.4,145.1,145.2,159.2,159.7 (d, J¼240.2 Hz); IR (ATR)
4 . 3 . 5 . N - M e t h o x y - 3 - ( N - ( 2 - m e t h o x y b e n z y l ) - 4 -
methylphenylsulfonamido)-N-methylpropanamide (6e). Compound
6e was prepared from 7 and o-methoxybenzyl chloride according to
the experimental procedure shown in Section 4.3.4. White solids;
Mp 69e71 ꢁC; Rf 0.28 (n-hexane/EtOAc¼1/1); 1H NMR (400 MHz,
n
3366, 1611, 1512, 1464, 1334,1247, 1155, 1089, 1031, 809, 734 cmꢀ1
;
(þ)-ESI-HRMS. Calcd for C33H33FN2NaO6Sþ2 659.1656 (MþNa)þ.
Found 659.1671.
CDCl3)
d
2.41 (s, 3H), 2.61 (t, J¼7.2 Hz, 2H), 3.07 (s, 3H), 3.44 (t,
J¼7.2 Hz, 2H), 3.54 (s, 3H), 3.73 (s, 3H), 4.41 (s, 2H), 6.80 (d, J¼7.2 Hz,
1H), 6.91 (t, J¼7.2 Hz, 1H), 7.23 (t, J¼7.2 Hz, 1H), 7.28 (d, J¼7.6 Hz,
2H), 7.35 (d, J¼7.2 Hz,1H), 7.69 (d, J¼7.6 Hz, 2H); 13C NMR (100 MHz,
4.3.9. N-(3-(5-Chloro-1-tosyl-1H-indol-2-yl)-3-hydroxypropyl)-N-
(4-methoxybenzyl)-4-methylbenzenesulfonamide (4g). Compound
4g was prepared from 3a and the corresponding N-Ts-indole
derivative according to the typical procedure shown in Section
4.3.1. White solids. Mp 57e58 ꢁC; Rf 0.31 (n-hexane/EtOAc¼2/1);
CDCl3) d 21.4, 31.8, 31.8, 44.5, 46.9, 55.0, 61.0,110.1,120.5,124.3,127.0
(2C), 128.8, 129.5 (2C), 130.1, 136.7, 143.0, 157.2, 172.0; IR (ATR)
n
1655, 1493, 1460, 1336, 1243, 1155, 1092, 1027, 985, 917, 815,
732 cmꢀ1; (þ)-ESI-HRMS. Calcd for C20H26N2NaO5Sþ 429.1455
(MþNa)þ. Found 429.1435.
1H NMR (400 MHz, CDCl3)
d 1.73e1.87 (m, 1H), 2.03e2.16 (m, 1H),
2.32 (s, 3H), 2.43 (s, 3H), 3.12 (ddd, J¼14.0, 7.2, 4.0 Hz, 1H), 3.46
(d, J¼2.4 Hz, 1H), 3.50 (dt, J¼14.0, 8.0 Hz, 1H), 3.72 (s, 3H), 4.30 (d,
J¼14.8 Hz, 1H), 4.35 (d, J¼14.8 Hz, 1H), 5.23e5.27 (m, 1H), 6.39 (s,
1H), 6.74 (d, J¼8.8 Hz, 2H), 7.10 (d, J¼8.8 Hz, 2H), 7.20 (d,
J¼8.0 Hz, 2H), 7.22 (dd, J¼8.8, 2.4 Hz, 1H), 7.31 (d, J¼8.0 Hz, 2H),
7.35 (d, J¼2.4 Hz, 1H), 7.66 (d, J¼8.0 Hz, 2H), 7.74 (d, J¼8.0 Hz, 2H),
4.3.6. N-(4-(Benzyloxy)benzyl)-N-(3-hydroxy-3-(1-tosyl-1H-indol-
2-yl)propyl)-4-methylbenzenesulfonamide (4d). Compound 4d was
prepared from 6d according to the experimental procedure shown
in Section 4.3.2. White solids; Mp 48 ꢁC; Rf 0.29 (n-hexane/
8.03 (d, J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.5, 21.5,
EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d
1.83e1.92 (m, 1H),
34.8, 44.4, 51.8, 55.1, 63.8, 108.3, 113.9 (2C), 115.8, 120.5, 124.8,
126.4 (2C), 127.2 (2C), 127.8, 129.4, 129.7 (2C), 129.9 (2C), 130.0
2.07e2.15 (m, 1H), 2.28 (s, 3H), 2.42 (s, 3H), 3.14 (ddd, J¼14.0, 7.6,
3.6 Hz, 1H), 3.39 (d, J¼4.8 Hz, 1H), 3.47 (dt, J¼14.0, 8.0 Hz, 1H), 4.30
(d, J¼14.8 Hz, 1H), 4.35 (d, J¼14.8 Hz, 1H), 4.96 (s, 2H), 5.22 (t,
J¼4.8 Hz,1H), 6.46 (s, 1H), 6.83 (d, J¼8.8 Hz, 2H), 7.12e7.41 (m, 14H),
7.66 (d, J¼8.8 Hz, 2H), 7.73 (d, J¼8.4 Hz, 2H), 8.10 (d, J¼8.4 Hz, 1H);
(2C), 130.5, 135.0, 135.4, 136.4, 143.4, 144.8, 145.3, 159.2; IR (ATR)
n
1597, 1512, 1445, 1368, 1248, 1155, 1090, 911, 811, 736 cmꢀ1
;
(þ)-ESI-HRMS. Calcd for C33H33ClN2NaO6Sþ2 675.1361 (MþNa)þ.
Found 675.1366.
13C NMR (100 MHz, CDCl3)
d 21.5, 21.5, 34.7, 44.7, 51.9, 64.0, 70.0,
109.1, 114.8, 114.9 (2C), 121.0, 123.7, 124.8, 126.4 (2C), 127.2 (2C),
127.3 (2C), 127.9, 128.3, 128.5 (2C), 129.2, 129.7 (2C), 129.9 (2C),
129.9 (2C), 135.4, 136.6, 136.8, 137.1, 143.3, 143.3, 145.0, 158.5; IR
4.3.10. N-(3-Hydroxy-3-(5-methyl-1-tosyl-1H-indol-2-yl)propyl)-N-
(4-methoxybenzyl)-4-methylbenzenesulfonamide (4h). Compound
4h was prepared from 3a and the corresponding N-Ts-indole
derivative according to the experimental procedure shown in
Section 4.3.1. Pale orange solids; Mp 57e58 ꢁC; Rf 0.27 (n-hexane/
(ATR) n ;
1509, 1452, 1364, 1264, 1152, 1090, 917, 813, 732, 699 cmꢀ1
(þ)-ESI-HRMS. Calcd for
C
39H38N2NaO6Sþ2 717.2063 (MþNa)þ.
Found 717.2090.
EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d 1.82e1.91 (m, 1H),
2.07e2.15 (m, 1H), 2.31 (s, 3H), 2.37 (s, 3H), 2.43 (s, 3H), 3.15 (ddd,
J¼14.0, 8.0, 4.0 Hz, 1H), 3.41 (d, J¼4.8 Hz, 1H), 3.47 (dt, J¼14.0,
7.6 Hz, 1H), 3.73 (s, 3H), 4.31 (d, J¼14.4 Hz, 1H), 4.35 (d, J¼14.4 Hz,
1H), 5.19 (dt, J¼9.6, 4.8 Hz, 1H), 6.38 (s, 1H), 6.76 (d, J¼8.4 Hz, 2H),
7.08 (dd, J¼8.8, 1.2 Hz, 1H), 7.13 (d, J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz,
2H), 7.18 (d, J¼1.2 Hz, 1H), 7.31 (d, J¼8.4 Hz, 2H), 7.65 (d, J¼8.4 Hz,
2H), 7.74 (d, J¼8.4 Hz, 2H), 7.96 (d, J¼8.8 Hz, 1H); 13C NMR
4.3.7. N-(3-Hydroxy-3-(1-tosyl-1H-indol-2-yl)propyl)-N-(2-
methoxybenzyl)-4-methylbenzenesulfonamide (4e). Compound 4e
was prepared from 6e according to the experimental procedure
shown in Section 4.3.2. White solids; Mp 37 ꢁC; Rf 0.52 (n-hexane/
EtOAc¼1/1); 1H NMR (400 MHz, CDCl3)
d 1.89e1.95 (m, 1H),
2.17e2.25 (m, 1H), 2.33 (s, 3H), 2.42 (s, 3H), 3.26 (ddd, J¼14.4, 7.2,
4.4 Hz, 1H), 3.44 (d, J¼3.2 Hz, 1H), 3.54 (dt, J¼14.4, 8.0 Hz, 1H), 3.69
(s, 3H), 4.44 (d, J¼14.8 Hz, 1H), 4.49 (d, J¼14.8 Hz, 1H), 5.26e5.30
(m, 1H), 6.51 (s, 1H), 6.78 (d, J¼7.6 Hz, 1H), 6.85 (t, J¼7.6 Hz, 1H),
7.19e7.24 (m, 4H), 7.27e7.30 (m, 4H), 7.42 (d, J¼7.6 Hz, 1H), 7.69 (d,
J¼7.6 Hz, 2H), 7.69 (d, J¼7.6 Hz, 2H), 8.10 (d, J¼7.6 Hz, 1H); 13C
(100 MHz, CDCl3)
d 21.1, 21.5, 21.5, 34.6, 44.6, 51.8, 55.2, 64.0, 109.1,
114.0 (2C), 114.4, 120.9, 126.1, 126.4 (2C), 127.2 (2C), 127.9, 129.4,
129.7 (2C), 129.9 (2C), 129.9 (2C), 133.3, 135.3, 135.3, 136.6, 143.3,
143.3, 144.9, 159.2; IR (ATR) n 1511, 1333, 1247, 1155, 1089, 914, 810,
734, 702, 673 cmꢀ1; (þ)-ESI-HRMS. Calcd for C34H36N2NaO6S2þ
N¼MR (100 MHz, CDCl3)
d 21.5, 21.5, 35.0, 45.4, 46.8, 55.1, 64.1,
109.1, 110.3, 114.8, 120.6, 121.0, 123.7, 124.2, 124.7, 126.5 (2C), 127.3
(2C), 129.1, 129.3, 129.6 (2C), 129.9 (2C), 130.7, 135.4, 136.8, 137.1,
655.1907 (MþNa)þ. Found 655.1937.
4.3.11. N-(3-Hydroxy-3-(5-methoxy-1-tosyl-1H-indol-2-yl)propyl)-
N-(4-methoxybenzyl)-4-methylbenzenesulfonamide (4i). Compound
4i was prepared from 3a and the corresponding N-Ts-indole de-
rivative according to the experimental procedure shown in Section
4.3.1. Pale yellow solids; Mp 47e48 ꢁC; Rf 0.39 (n-hexane/
143.1, 143.5, 145.0, 157.4; IR (ATR)
n 1598, 1493, 1451, 1335, 1244,
1152, 1089, 1025, 918, 811, 749 cmꢀ1; (þ)-ESI-HRMS. Calcd for
C
33H34N2NaO6Sþ2 641.1750 (MþNa)þ. Found 641.1765.
4.3.8. N-(3-(5-Fluoro-1-tosyl-1H-indol-2-yl)-3-hydroxypropyl)-N-
(4-methoxybenzyl)-4-methylbenzenesulfonamide (4f). Compound 4f
was prepared from 3a and the corresponding N-Ts-2-indolyllithium
EtOAc¼1.5/1); 1H NMR (400 MHz, CDCl3)
d 1.81e1.89 (m, 1H),
2.08e2.16 (m, 1H), 2.32 (s, 3H), 2.44 (s, 3H), 3.14 (ddd, J¼14.8, 8.0,
4.0 Hz, 1H), 3.39 (s, 1H), 3.47 (dt, J¼14.8, 8.0 Hz, 1H), 3.74 (s, 3H),

2158
T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
3.80 (s, 3H), 4.33 (s, 2H), 5.19 (br d, J¼8.4 Hz, 1H), 6.39 (s, 1H), 6.77
(d, J¼8.8 Hz, 2H), 6.85 (d, J¼2.0 Hz, 1H), 6.88 (dd, J¼9.2, 2.0 Hz, 1H),
7.13 (d, J¼8.8 Hz, 2H), 7.18 (d, J¼8.4 Hz, 2H), 7.32 (d, J¼8.4 Hz, 2H),
7.63 (d, J¼8.4 Hz, 2H), 7.74 (d, J¼8.4 Hz, 2H), 7.99 (d, J¼9.2 Hz, 1H);
827, 732, 666 cmꢀ1; (þ)-ESI-HRMS. Calcd for C32H29N3NaO7S2þ
(MþNa)þ: 654.1339. Found: 654.1345.
4.4.4. 5-(4-Methoxyphenyl)-6-tosyl-1,2,3,4,5,6-hexahydroazepino
[4,3-b]indole (8). To a stirred solution of 5i (94.8 mg, 0.15 mmol) in
DMF (3 mL) at room temperature were added K2CO3 (62.2 mg,
13C NMR (100 MHz, CDCl3)
d 21.4, 21.4, 34.7, 44.4, 51.7, 55.1, 55.4,
64.1,103.3,109.4,113.5,113.9 (2C),115.6,126.3 (2C),127.1 (2C),127.8,
129.7 (2C), 129.8 (2C), 129.8 (2C), 130.2, 131.6, 135.1, 136.5, 143.3,
0.45 mmol) and thiophenol (31 mL, 0.3 mmol). The resulting mixture
144.0, 144.8, 156.5, 159.1; IR (ATR)
n
1611, 1512, 1472, 1214, 1155,
(þ)-ESI-HRMS. Calcd for
was kept stirring for 1.5 h at room temperature. The reaction was
quenched with aqueous saturated NaHCO3, and the mixture with
extracted twicewith Et2O. The combined organic layers werewashed
with aqueous saturated NaHCO3 and water, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane/EtOAc¼15/1 to 10/1) to give
8 (55.0 mg, 82% yield) as white solids. Mp 55e58 ꢁC; Rf 0.37 (CHCl3/
1089, 1032, 811, 733, 702 cmꢀ1
;
C
34H36N2NaO7Sþ2 671.1856 (MþNa)þ. Found 671.1855.
4.4. Experimental procedures for the reactions shown in
Scheme 5 and product characterizations
4.4.1. N-(4-Methoxybenzyl)-4-nitro-N-(3-oxopropyl)benzenesulfo-
namide (3j). To a stirred solution of p-Ns-p-methoxybenzylamine
(2.00 g, 6.2 mmol), acrolein (0.67 mL, 9.9 mmol), and n-Bu4NCl
(172 mg, 0.62 mmol) in toluene (20 mL) and THF (20 mL) at 0 ꢁC
was added NaOAc (509 mg, 6.2 mmol). After being stirred for 3 h
at room temperature, the reaction was quenched with H2O, and
the resulting mixture extracted twice with EtOAc. The combined
organic layers were washed with brine, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (n-hexane/EtOAc¼2/1) to give
3j (1.39 g, 49% yield) as white solids. Mp 84e85 ꢁC; Rf 0.55 (n-
CH3OH¼10/1); 1H NMR (400 MHz, CDCl3)
d 2.06 (br s,1H), 2.19e2.26
(m, 2H), 2.26 (s, 3H), 2.67e2.75 (m, 1H), 3.04e3.09 (m, 1H), 3.76 (s,
3H), 3.93 (d, J¼16.4 Hz, 1H), 4.14 (d, J¼16.4 Hz, 1H), 5.46 (t, J¼4.0 Hz,
1H), 6.69 (d, J¼11.2 Hz, 2H), 6.86 (d, J¼11.2 Hz, 2H), 6.95 (d, J¼7.6 Hz,
2H), 7.25e7.35 (m, 4H), 7.44e7.46 (m, 1H), 8.26e8.29 (m, 1H); 13C
NMR (100 MHz, CDCl3)
d 21.4, 36.6, 40.5, 43.1, 45.7, 55.1, 113.6 (2C),
115.2, 118.0, 118.0, 123.2, 124.5, 124.5, 126.2 (2C), 128.9 (2C), 129.3
(2C),132.9,135.9,136.4,139.4,144.2,157.8; IR (ATR) n 1508,1451,1367,
1244,1170, 1088, 1030, 936, 809, 734, 702, 662 cmꢀ1; (þ)-ESI-HRMS.
Calcd for C26H27N2O3Sþ 447.1737 (MþH)þ. Found 447.1720.
hexane/EtOAc¼1/1); 1H NMR (400 MHz, CDCl3)
d
2.59 (t,
4.4.5. 5-(4-Methoxyphenyl)-2-((4-nitrophenyl)sulfonyl)-1,2,3,4,5,6-
hexahydroazepino[4,3-b]indole (9). To a stirred solution of 5i
J¼7.2 Hz, 2H), 3.43 (t, J¼7.2 Hz, 2H), 3.80 (s, 3H), 4.30 (s, 2H), 6.85
(d, J¼8.4 Hz, 2H), 7.18 (d, J¼8.4 Hz, 2H), 7.99 (d, J¼8.8 Hz, 2H),
8.37 (d, J¼8.8 Hz, 2H), 9.56 (s, 1H); 13C NMR (100 MHz, CDCl3)
(50.0 mg, 0.079 mmol) in THF (0.79 mL) at room temperature was
added TBAF (0.396 mL, 1.0 M in THF, 0.396 mmol). The resulting
mixture was stirred for 24 h at room temperature, and then kept
stirring for 24 h at 40 ꢁC. The reaction was quenched by the addition
of water and the mixture was extracted three times with CH2Cl2
and then dried over Na2SO4. After concentration in vacuo, the crude
residue was purified by silica gel column chromatography (n-hex-
ane/EtOAc¼3/1) to give 9 (25.8 mg, 68% yield) as white solids, ac-
companied by the recovery of 5i (5.5 mg, 11% yield) as yellow solids.
Mp 74e76 ꢁC; Rf 0.33 (CHCl3/CH3OH¼5/1); 1H NMR (400 MHz,
d
41.8, 43.8, 52.7, 55.2, 114.2 (2C), 124.4 (2C), 126.9, 128.3 (2C),
129.7 (2C), 145.0, 150.0, 159.6, 199.6; IR (ATR)
n 1719, 1609, 1511,
1346, 1246, 1158, 1028, 909, 854, 743, 686 cmꢀ1; (þ)-ESI-HRMS.
Calcd for C18H22N2NaO7Sþ 433.1040 (MþMeOHþNa)þ. Found
433.1020.
4.4.2. N-(3-Hydroxy-3-(1-tosyl-1H-indol-2-yl)propyl)-N-(4-
methoxybenzyl)-4-nitrobenzenesulfonamide (4j). Compound 4j was
prepared from 3j and N-Ts-indole according to the experimental
procedure shown in Section 4.3.1. Yellow solids; Mp 133e135 ꢁC; Rf
CDCl3)
d
2.11e2.17 (m,1H), 2.22e2.31 (m,1H), 3.62 (ddd, J¼2.8,10.0,
14.0 Hz, 1H), 3.80 (s, 3H), 3.85 (ddd, Jv3.2, 6.0, 14.0 Hz, 1H), 4.00 (dd,
J¼3.2, 10.0 Hz, 1H), 4.83 (s, 2H), 6.85 (d, J¼8.4 Hz, 2H), 6.94 (d,
J¼8.4 Hz, 2H), 7.13e7.19 (m, 4H), 7.26 (s, 1H), 7.58 (d, J¼7.2 Hz, 1H),
7.79 (d, J¼8.8 Hz, 2H), 8.03 (d, J¼8.8 Hz, 2H); 13C NMR (100 MHz,
0.60 (n-hexane/EtOAc¼1/1); 1H NMR (400 MHz, CDCl3)
d 1.89e1.97
(m, 1H), 2.14e2.22 (m, 1H), 2.34 (s, 3H), 3.27e3.32 (m, 2H), 3.56 (dt,
J¼14.8, 7.6 Hz, 1H), 3.75 (s, 3H), 4.43 (s, 2H), 5.20 (br s, 1H), 6.50 (s,
1H), 6.77 (d, J¼8.8 Hz, 2H), 7.13 (d, J¼8.8 Hz, 2H), 7.20e7.31 (m, 4H),
7.43 (d, J¼7.6 Hz, 1H), 7.65 (d, J¼8.0 Hz, 2H), 7.99 (d, J¼8.4 Hz, 2H),
8.08 (d, J¼8.4 Hz, 1H), 8.34 (d, J¼8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3)
d 34.0, 43.0, 43.7, 48.5, 55.3, 109.3, 110.8, 114.4 (2C), 117.3,
120.1, 122.0, 123.7 (2C), 127.2, 128.3 (2C), 128.9 (2C), 132.8, 134.1,
137.8, 145.6, 149.5, 158.9; IR (ATR)
n 1608, 1527, 1510, 1461, 1346,
CDCl3)
d
21.5, 34.6, 44.7, 51.5, 55.2, 64.2, 109.3, 114.1 (2C), 114.7,
1247, 1158, 1092, 1031, 938, 832, 738 cmꢀ1; (þ)-ESI-HRMS. Calcd for
121.0, 123.9, 124.3 (2C), 124.9, 126.3 (2C), 127.0, 128.2 (2C), 129.1,
129.9 (2C), 129.9 (2C), 135.1, 137.1, 143.0, 145.2, 145.7, 149.8, 159.4; IR
C
25H23N3NaO5Sþ 500.1251 (MþNa)þ. Found 500.1253.
(ATR)
n
1528, 1512, 1451, 1347, 1248, 1158, 1089, 917, 813, 741,
4.4.6. 5-(4-Methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,3-b]in-
dole (10). To a stirred solution of 9 (47.8 mg, 0.1 mmol) in CH3CN
676 cmꢀ1; (þ)-ESI-HRMS. Calcd for C32H31N3NaO8Sþ2 672.1445
(MþNa)þ. Found 672.1450.
(4 mL) at room temperature were added thiophenol (41
mL,
0.4 mmol) and K2CO3 (50.5 mg, 0.3 mmol), and the resulting mix-
ture was stirred for 24 h at 30 ꢁC. After concentration in vacuo,
aqueous saturated NaHCO3 was added to the reaction. The mixture
was extracted two times with AcOEt and the combined organic
layers were washed with aqueous saturated NaHCO3 and brine, and
then dried over Na2SO4. After evaporation under reduced pressure,
the obtained residue was purified by silica gel column chroma-
tography (CHCl3/MeOH¼1/1 to 1/2) to give 10 (19.1 mg, 65% yield)
as yellow solids. Mp 86e89 ꢁC; Rf 0.15 (CHCl3/CH3OH¼5/1); 1H
4.4.3. 5-(4-Methoxyphenyl)-2-((4-nitrophenyl)sulfonyl)-6-tosyl-
1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (5j). Compound 5j was
prepared from 4j according to the experimental procedure shown
in Section 4.2.1. Yellow solids; Mp 46e48 ꢁC; Rf 0.68 (n-hexane/
EtOAc¼1/1); 1H NMR (400 MHz, CDCl3)
d 2.22e2.30 (m, 2H), 2.28
(s, 3H), 3.24 (br t, J¼12.0 Hz, 1H), 3.46 (br d, J¼12.0 Hz, 1H), 3.75 (s,
3H), 4.52 (d, J¼16.0 Hz, 1H), 4.64 (d, J¼16.0 Hz, 1H), 5.37 (br s, 1H),
6.65 (d, J¼8.4 Hz, 2H), 6.81 (d, J¼8.4 Hz, 2H), 6.94 (d, J¼8.0 Hz, 2H),
7.19 (d, J¼8.0 Hz, 2H), 7.33e7.40 (m, 2H), 7.56 (d, J¼6.4 Hz, 1H), 7.84
(d, J¼8.4 Hz, 2H), 8.16 (d, J¼8.4 Hz, 2H), 8.22 (d, J¼6.4 Hz, 1H); 13C
NMR (400 MHz, CDCl3)
d 2.14e2.29 (m, 2H), 3.12e3.20 (m, 1H),
3.32e3.38 (m, 1H), 3.81 (s, 3H), 4.14e4.29 (m, 3H), 4.93 (br s, 1H),
6.89 (d, J¼8.4 Hz, 2H), 7.07e7.17 (m, 3H), 7.11 (d, J¼8.4 Hz, 2H),
NMR (100 MHz, CDCl3) d 21.4, 33.1, 40.5, 41.5, 45.5, 55.2, 113.8 (2C),
115.2, 117.7, 118.4, 123.7, 124.2 (2C), 125.1, 126.3 (2C), 127.8, 128.2
(2C), 129.1 (2C), 129.4 (2C), 131.0, 135.7, 136.0, 139.4, 144.5, 144.6,
7.45e7.48 (m, 1H), 7.87 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 36.5,
43.5, 44.2, 48.7, 55.3, 110.6, 114.3 (2C), 117.6, 119.5, 121.4, 127.5, 129.2
(2C), 133.7, 134.2, 138.8, 158.7; IR (ATR) 2925, 1509, 1459, 1245,
149.8,158.3; IR (ATR)
n
1529,1509, 1453, 1348, 1247,1163, 1090, 970,
n

T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
2159
1175, 1032, 832, 734 cmꢀ1; (þ)-ESI-HRMS. Calcd for C19H21N2Oþ
293.1648 (MþH)þ. Found 293.1636.
to the experimental procedure shown in Section 4.3.1. White solids;
Mp 35 ꢁC; Rf 0.21 (n-hexane/EtOAc¼2/1); 1H NMR (400 MHz, CDCl3)
d
1.49e1.85 (m, 4H), 2.31 (s, 3H), 2.40 (s, 3H), 3.11e3.23 (m, 3H), 3.75
4.5. Experimental procedures for the reactions shown in
Scheme 6 and product characterizations
(s, 3H), 4.22 (d, J¼14.4 Hz,1H), 4.27 (d, J¼14.4 Hz,1H), 5.00e5.04 (m,
1H), 6.49 (s,1H), 6.82 (d, J¼8.4 Hz, 2H), 7.16 (d, J¼8.4 Hz, 2H), 7.20 (d,
J¼8.4 Hz, 2H), 7.21 (t, J¼7.6 Hz, 1H), 7.27 (t, J¼7.6 Hz, 1H), 7.28 (d,
J¼8.4 Hz, 2H), 7.45 (d, J¼7.6 Hz, 1H), 7.62 (d, J¼8.4 Hz, 2H), 7.72 (d,
J¼8.4 Hz, 2H), 8.06 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.5.1. N-(2-Hydroxy-2-(1-tosyl-1H-indol-2-yl)ethyl)-N-(4-
methoxybenzyl)-4-methylbenzenesulfonamide (4k). To a stirred so-
lution of 2-iodo-N-Ts-indole (167 mg, 0.42 mmol) in THF (43 mL)
was added i-PrMgCl (0.21 mL, 2 M in THF, 0.42 mmol) at 0 ꢁC. After
being stirred for 15 min, a THF solution of the known aldehyde3
(70 mg, 0.21 mmol in THF 4 mL) was added to the reaction mix-
ture at 0 ꢁC. After being stirred for 1.5 h at the same temperature,
the reaction was quenched with saturated aqueous NH4Cl, and the
resulting mixture was extracted twice with EtOAc. The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/EtOAc¼3/1) to give 4k
(108 mg, 85% yield) as white solids. Mp 61e63 ꢁC; Rf 0.48 (n-hex-
d
21.4, 21.5, 24.6, 32.3, 47.5, 51.5, 55.2, 66.2, 109.2, 113.9 (2C), 114.7,
121.1,123.8,124.8,126.3 (2C),127.1 (2C),128.2,129.1,129.7 (2C),129.8
(2C),129.9 (2C),135.4,136.8,137.0,143.2,143.8,145.0,159.2; IR (ATR)
n
1597, 1512, 1451, 1364, 1247, 1153, 1089, 1034, 813, 746 cmꢀ1
;
(þ)-ESI-HRMS. Calcd for
C
34H36N2NaO6Sþ2 655.1907 (MþNa)þ.
Found 655.1911.
4.5.5. 10-Methoxy-6-(4-methoxyphenyl)-2,7-ditosyl-2,3,4,5,6,7-
hexahydro-1H-azocino[4,3-b]indole (5l). Compound 5l was pre-
pared from 4l according to the typical experimental procedure
shown in Section 4.2.1. White solids; Mp 49e50 ꢁC; Rf 0.30
ane/EtOAc¼1/1); 1H NMR (400 MHz, CDCl3)
d
2.25 (s, 3H), 2.40 (s,
(n-hexane/EtOAc¼3/1); 1H NMR (400 MHz, CDCl3)
d 1.32e1.40 (m,
3H), 3.14 (dd, J¼14.8, 8.8 Hz 1H), 3.66 (d, J¼4.0 Hz, 1H), 3.71 (dd,
J¼14.8, 2.8 Hz, 1H), 3.78 (s, 3H), 4.22 (d, J¼15.2 Hz, 1H), 4.70 (d,
J¼15.2 Hz,1H), 5.23 (ddd, J¼8.8, 4.0, 2.8 Hz,1H), 6.75 (s,1H), 6.84 (d,
J¼8.4 Hz, 2H), 7.05 (d, J¼8.4 Hz, 2H), 7.19 (t, J¼8.0 Hz, 1H), 7.26 (t,
J¼8.0 Hz, 1H), 7.28 (d, J¼8.4 Hz, 2H), 7.34 (d, J¼8.4 Hz, 2H), 7.39 (d,
J¼8.4 Hz, 2H), 7.41 (d, J¼8.0 Hz, 1H), 7.69 (d, J¼8.4 Hz, 2H), 8.10 (d,
1H), 1.46e1.54 (m, 1H), 1.94e2.00 (m, 2H), 2.34 (s, 3H), 2.42 (s, 3H),
3.12e3.22 (m, 1H), 3.28e3.37 (m, 1H), 3.75 (s, 3H), 4.29
(d, J¼16.0 Hz, 1H), 4.52 (d, J¼16.0 Hz, 1H), 5.86e5.91 (m, 1H), 6.74
(d, J¼8.8 Hz, 2H), 7.02 (d, J¼8.8 Hz, 2H), 7.11 (t, J¼8.0 Hz, 1H),
7.19e7.24 (m, 4H), 7.31 (d, J¼8.4 Hz, 2H), 7.71 (d, J¼8.4 Hz, 2H), 7.77
(d, J¼8.4 Hz, 2H), 8.03 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
21.4, 53.0, 55.1, 55.5,
d 21.6, 21.6, 24.1, 29.1, 35.4, 50.0, 55.2, 58.6, 113.7 (2C), 115.3, 119.8,
66.3, 110.5, 113.8 (2C), 114.7, 121.0, 123.8, 124.6, 126.2 (2C), 127.1
(2C), 128.6, 129.4, 129.6 (2C), 129.7 (2C), 129.8 (2C), 134.8, 136.1,
121.8, 123.8, 124.8, 126.6 (2C), 127.8 (2C), 129.1 (2C), 129.7, 129.7
(2C), 129.8 (2C), 132.1, 133.5, 135.2, 136.7, 137.8, 143.8, 144.6, 157.8;
137.2, 140.8, 143.6, 145.0, 159.1; IR (ATR)
n
1512, 1450, 1334, 1246,
IR (ATR) n 1597, 1509, 1455, 1346, 1245, 1158, 1090, 1031, 814, 738,
1151,1089,1035, 910, 812, 732, 702, 656 cmꢀ1; (þ)-ESI-HRMS. Calcd
662 cmꢀ1; (þ)-ESI-HRMS. Calcd for C34H34N2NaO5Sþ2 (MþNa)þ:
for C32H32N2NaO6Sþ2 627.1594 (MþNa)þ. Found 627.1601.
637.1801. Found: 637.1801.
4.5.2. 4-(4-Methoxyphenyl)-2,5-ditosyl-2,3,4,5-tetrahydro-1H-pyr-
ido[4,3-b]indole (5k). Compound 5k was prepared from 4k
according to the typical experimental procedure shown in Section
4.2.1. White solids; Mp 176e179 ꢁC; Rf 0.37 (n-hexane/EtOAc¼2/1);
4.5.6. 1-Tosyl-2-(1-tosylpyrrolidin-2-yl)-1H-indole
(12l). White
solids; Mp 75e77 ꢁC; Rf 0.29 (n-hexane/EtOAc¼1/1); 1H NMR
(400 MHz, CDCl3) d 1.69e1.79 (m, 1H), 1.81e1.99 (m, 2H), 2.04e2.11
(m, 1H), 2.31 (s, 3H), 2.45 (s, 3H), 3.19 (td, J¼9.2, 6.8 Hz, 1H), 3.69 (t,
J¼7.6 Hz, 1H), 5.71 (d, J¼7.6 Hz, 1H), 6.80 (s, 1H), 7.16e7.26 (m, 4H),
7.35 (d, J¼7.6 Hz, 2H), 7.40 (d, J¼7.6 Hz, 1H), 7.75 (d, J¼7.6 Hz, 2H),
7.77 (d, J¼7.6 Hz, 2H), 8.00 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3)
d
2.25 (s, 3H), 2.40 (s, 3H), 3.18 (dd, J¼12.4,
3.6 Hz, 1H), 3.79 (s, 3H), 3.86 (dd, J¼12.4, 2.0 Hz, 1H), 3.98 (d,
J¼14.4 Hz, 1H), 4.76 (d, J¼14.4 Hz, 1H), 4.85 (dd, J¼3.6, 2.0 Hz, 1H),
6.68 (d, J¼8.4 Hz, 2H), 6.90 (d, J¼8.4 Hz, 2H), 6.96 (d, J¼8.4 Hz, 2H),
7.07 (d, J¼8.4 Hz, 2H), 7.24 (d, J¼8.4 Hz, 2H), 7.27 (t, J¼8.4 Hz, 1H),
7.34 (t, J¼8.4 Hz, 1H), 7.39 (d, J¼8.4 Hz, 1H), 7.59 (d, J¼8.4 Hz, 2H),
CDCl3)
d 21.5, 21.5, 23.4, 34.2, 48.9, 59.0, 111.4, 114.7, 120.9, 123.9,
124.3, 126.6 (2C), 127.5 (2C), 129.6, 129.8 (2C), 129.8 (2C), 134.3,
134.9,137.5,143.3,143.7, Hz 144.9; IR (ATR) n 1597, 1450,1366,1326,
8.10 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
21.4, 21.5, 39.9,
1151, 1089, 812, 736, 703, 658 cmꢀ1; (þ)-ESI-HRMS. Calcd for
42.3, 51.5, 55.2,113.6 (2C),114.6,118.0,123.4,125.0,126.5 (2C),126.8,
127.6 (2C), 129.2, 129.3 (2C), 129.6 (2C), 129.7 (2C), 132.5, 133.5,
C26H26N2NaO4Sþ2 (MþNa)þ: 517.1226. Found: 517.1219.
134.4, 135.4, 136.2, 143.6, 144.3, 158.7; IR (ATR)
n
1509, 1452, 1343,
4.6. Trials for the extension of catalytic asymmetric synthesis
1245, 1165, 1091, 1036, 982, 811, 738, 664 cmꢀ1; (þ)-ESI-HRMS.
Calcd for C32H30N2NaO5Sþ2 (MþNa)þ: 609.1488. Found: 609.1504.
4.6.1. Typical experimental procedure for the skeletal rearrangement
using chiral Brønsted acid (S)-13f (Table 2, entry 6). To a stirred
solution of compound 4a (12.4 mg, 0.02 mmol) in toluene (0.2 mL)
at room temperature was added (S)-13f (3.7 mg, 0.004 mmol), and
the resulting mixture was heated to 50 ꢁC. After being stirred for
3.5 h at the same temperature, the reaction mixture was concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/EtOAc¼3/1) to give 5a (9.8 mg, 82%
yield). The enantiomeric excess was determined by chiral HPLC
analysis (DAICEL CHIRALPAK AD-H, hexane/2-propanol¼60/40,
flow rate: 1.0 mL/min, tR 26.2 min and 36.7 min, detection at
254 nm).
4.5.3. N-(2-Hydroxy-2-(1-tosyl-1H-indol-2-yl)ethyl)-4-
methylbenzenesulfonamide (11k). Yellow solids; Mp 86e89 ꢁC; Rf
0.15 (CHCl3/CH3OH¼5/1); 1H NMR (400 MHz, CDCl3)
d 2.32 (s, 3H),
2.42 (s, 3H), 3.33e3.39 (m, 1H), 3.57e3.64 (m, 1H), 3.66e3.74 (m,
1H), 5.08 (dd, J¼5.2, 7.2 Hz, 1H), 5.32 (br s, 1H), 6.67 (s, 1H),
7.16e7.31 (m, 6H), 7.44 (d, J¼8.0 Hz, 1H), 7.59 (d, J¼8.0 Hz, 2H), 7.76
(d, J¼8.0 Hz, 2H), 8.07 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
21.5, 21.6, 47.5, 66.1, 110.2, 114.7, 121.3, 124.0, 125.2, 126.3 (2C),
127.1 (2C), 129.0, 129.8 (2C), 130.0 (2C), 134.8, 136.4, 137.1, 139.9,
143.7, 145.4; IR (ATR)
n 2925, 1609, 1459, 1245, 1175, 1031, 832,
734 cmꢀ1; (þ)-ESI-HRMS. Calcd for C24H24N2NaO5Sþ2 507.1019
(MþNa)þ. Found 507.1045.
4.6.2. N-((4S,11bS)-2,6-Bis(3,5-bis(trifluoromethyl)phenyl)-4-
sulfidodinaphtho[2,1-d:10,20-f][1,3,2]dioxaphosphepin-4-yl)-1,1,1-tri-
fluoromethanesulfonamide (13f). To a stirred solution of the known
BINOL derivative13 (345 mg, 0.49 mmol) in DMF (2.4 mL) at 0 ꢁC
was added NaH (60% in oil, 73 mg, 1.8 mmol). After being stirred for
4.5.4. N-(4-Hydroxy-4-(1-tosyl-1H-indol-2-yl)butyl)-N-(4-
methoxybenzyl)-4-methylbenzenesulfonamide (4l). Compound 4l
was prepared from the known aldehyde3 and N-Ts-indole according

2160
T. Yokosaka et al. / Tetrahedron 70 (2014) 2151e2160
Am. Chem. Soc. 2004, 126, 10558; (d) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
30 min at 0 ꢁC, PSCl3 (149
m
L, 1.5 mmol) was added to the reaction
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404; (e) Seayad, J.; Seayad, A. M.;
List, B. J. Am. Chem. Soc. 2006, 128, 1086; (f) Wanner, M. J.; van der Haas, R. N. S.;
de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007,
46, 7485; (g) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt,
G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796; (h) Cai, Q.; Liang, X.-W.; Wang,
S.-G.; Zhang, J.-W.; Zhang, X.; You, S.-L. Org. Lett. 2012, 14, 5022; (i) Huang, D.;
Xu, F.; Lin, X.; Wang, Y. Chem.dEur. J. 2012, 18, 3148; (j) Wang, S.; Chai, Z.; Zhou,
S.; Wang, S.; Zhu, X.; Wei, Y. Org. Lett. 2013, 15, 2628.
mixture at the same temperature. After being stirred for 2 h at room
temperature, the reaction mixture was concentrated in vacuo. The
residue was passed through a short pad of silica gel. After con-
centration in vacuo, the obtained thiophosphoryl chloride was
utilized for the next reaction without further purification. TfNH2
(116 mg, 0.78 mmol), Et3N (0.22 mL, 1.6 mmol) and DMAP (95 mg,
0.78 mmol) were added to the stirred solution of the residue in
EtCN (2.4 mL) at room temperature. The reaction mixture was
allowed to reflux for 13 h. The reaction mixture was concentrated.
The residue was purified by silica gel column chromatography
(n-hexane/EtOAc¼1/1). The obtained product was re-dissolved in
CH2Cl2, washed twice with 6 N HCl, dried over Na2SO4, filtered, and
concentrated in vacuo. The desired thiophosphoramide 13f
(236 mg, 56%) was obtained as white solids. Mp >200 ꢁC; Rf 0.16 (n-
2. (a) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.; Hamada, Y.
Org. Lett. 2010, 12, 5020; (b) Nemoto, T.; Zhao, Z.; Yokosaka, T.; Suzuki, Y.; Wu,
R.; Hamada, Y. Angew. Chem., Int. Ed. 2013, 52, 2217.
3. Yokosaka, T.; Nemoto, T.; Hamada, Y. Chem. Commun. 2012, 5431.
4. Yokosaka, T.; Nemoto, T.; Hamada, Y. Tetrahedron Lett. 2013, 54, 1562.
5. Yokosaka, T.; Nakayama, H.; Nemoto, T.; Hamada, Y. Org. Lett. 2013, 15, 2978.
6. For recent selected examples of the synthesis of cyclopenta[b]indole de-
rivatives, see: (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578;
(b) Venkatesh, C.; Singh, P. P.; Ila, H.; Junjappa, H. Eur. J. Org. Chem. 2006, 5378;
(c) Yadav, A. K.; Peruncheralathan, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72,
1388; (d) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 14648; (e) Tseng,
N.-W.; Lautens, M. J. Org. Chem. 2009, 74, 1809; (f) Churruca, F.; Fousteris, M.;
Ishikawa, Y.; von Wantoch Rekowski, M.; Hounsou, C.; Surrey, T.; Giannis, A.
Org. Lett. 2010, 12, 2096; (g) Saito, K.; Sogou, H.; Suga, T.; Kusama, H.; Iwasawa,
N. J. Am. Chem. Soc. 2011, 133, 689; (h) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.;
Peng, Y.-G.; Guo, Q.-X. Angew. Chem., Int. Ed. 2012, 51, 1059; (i) Chen, B.; Fan, W.;
Chai, G.; Ma, S. Org. Lett. 2012, 14, 3616.
hexane/EtOAc¼1/1); 1H NMR (600 MHz, CD3OD)
d 2.86e2.96 (m,
1H), 7.21 (br s, 4H), 7.38 (br s, 2H), 7.83 (s, 2H), 7.96e8.01 (m, 2H),
8.06e8.12 (m, 2H), 8.17 (br s, 2H), 8.20 (br s, 2H); 13C NMR
(150 MHz, CD3OD)
d
121.4 (q, J¼320 Hz), 121.9, 122.0, 124.9, 125.0
(q, J¼270 Hz), 125.3, 127.1, 127.1, 127.6, 127.7, 128.2, 128.3, 130.0,
7. For representative examples of the synthesis of tetrahydro-g-carboline de-
130.0, 131.8, 131.9, 132.4 (q, J¼17.3 Hz), 132.8, 133.1, 133.6, 133.9,
rivatives, see: (a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.;
Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424; (b) Bennasar, M.-L.; Roca, T.;
Garcia-Diaz, D. J. Org. Chem. 2007, 72, 4562; (c) Grigg, R.; Sridharan, V.; Sykes,
134.0, 141.3, 141.8; 19F NMR (376 MHz, CD3OD)
d
ꢀ80.4 (3F), ꢀ63.9
(12F); 31P NMR (162 MHz, CD3OD)
d 64.9; IR (ATR) n 1376, 1278,
1173, 1131, 986, 906, 846, 816, 753, 704, 678 cmꢀ1; (ꢀ)-ESI-HRMS.
ꢀ
D. A. Tetrahedron 2008, 64, 8952; (d) Bennasar, M. L.; Zulaica, E.; Sole, D.; Roca,
T.; García-Díaz, D.; Alonso, S. J. Org. Chem. 2009, 74, 8359; (e) Sheng, Y.-F.; Li, G.-
Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Chem.dEur. J. 2009, 15, 3351; (f) Lee, Y.;
Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2011, 13, 5564; (g) Dong, H.; Latka, R. T.;
ꢀ
Calcd for C37H16F15NO4PS2 918.0024 (MꢀH)ꢀ. Found 917.9937;
[
a]
26 þ201.3 (c 0.15, CHCl3).
D
ꢀ
ꢀ
Driver, T. G. Org. Lett. 2011, 13, 2726; (h) Sole, D.; Bennasar, M.-L.; Jimenez, I. Org.
Biomol. Chem. 2011, 9, 4535; (i) Reddy, S. B. V.; Swain, M.; Reddy, S. M.; Yadav, J.
S.; Sridhar, B. J. Org. Chem. 2012, 77, 11355; (j) Kong, C.; Jana, N.; Driver, T. G. Org.
Lett. 2013, 15, 824; (k) Lv, J.; Li, J.; Zhang-Negrerie, D.; Shang, S.; Gao, Q.; Du, Y.;
Zhao, K. Org. Biomol. Chem. 2013, 11, 1929.
Acknowledgements
This work was supported by a Grant-in Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan, the Research Foundation for Pharmaceutical
Sciences, JSPS Research Fellowship for Young Scientists (T.Y.), the
Uehara Memorial Foundation, and Chiba University.
8. (a) Butler, K. V.; Kalin, J.; Brochier, C.; Vistoli, G.; Langley, B.; Kozikowski, A. P. J.
Am. Chem. Soc. 2010, 132, 10842; (b) Dossetter, A. G.; Beeley, H.; Bowyer, J.;
Cook, C. R.; Crawford, J. J.; Finlayson, J. E.; Heron, N. M.; Heyes, C.; Highton, A. J.;
Hudson, J. A.; Jestel, A.; Kenny, P. W.; Krapp, S.; Martin, S.; MacFaul, P. A.;
McGuire, T. M.; Gutierrez, P. M.; Morley, A. D.; Morris, J. J.; Page, K. M.; Ribeiro,
L. R.; Sawney, H.; Steinbacher, S.; Smith, C.; Vickers, M. J. Med. Chem. 2012, 55,
6363; (c) Mit’kin, O. D.; Ivachtchenko, A. V.; Frolov, E. B.; Tkachenko, S. E.;
Kazey, V. I.; Okun, I. M. Pharm. Chem. J. 2012, 46, 103; (d) Fretz, H.; Valdenaire,
A.; Pothier, J.; Hilpert, K.; Gnerre, C.; Peter, O.; Leroy, X.; Riederer, M. A. J. Med.
Chem. 2013, 56, 4899.
Supplementary data
Supplementary data associated with this article (1H and 13C
NMR charts of the reported compounds) can be found. Supple-
mentary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.01.074.
9. The amount of TFA significantly affected the reactivity of this cascade process.
No reaction occurred when 1 equiv of TFA was used in CH2Cl2 at 0 ꢁC
€
10. Boymound, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. 1998,
37, 1701.
11. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373; (b)
Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
12. For reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744; (b) Terada, M.
Synthesis 2010, 1929; (c) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Ato-
diresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706; (d) Hirashima, S.; Yamamoto, H.
J. Synth. Org. Chem. Jpn. 2013, 71, 1116.
13. LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.; Toste, F. D. Angew. Chem., Int.
Ed. 2010, 49, 598.
References and notes
1. For recent reviews on the synthesis of tetrahydro-b-carboline derivatives, see:
(a) Lorenz, M.; Van Linn, M. L.; Cook, J. M. Curr. Org. Synth. 2010, 7, 189; (b)
€
Stockigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew. Chem., Int. Ed. 2011,
50, 8538 For recent selected examples, see; (c) Taylor, M. S.; Jacobsen, E. N. J.