A concise synthesis of cyclobrassinin and its analogues via a thiyl radical aromatic substitution

Article abstract of DOI:10.1039/c8nj02037j

A simple and concise approach for the synthesis of cyclobrassinin has been developed through a thiyl radical-mediated intramolecular aromatic substitution, with benzoyl peroxide as an efficient initiator and oxidant. The current method can also be utilized in the synthesis of 6 and 7-membered ring cyclobrassinin analogues in moderate to good yields. The transformation involves a formal radical 6 and 7-endo-trig cyclization of the corresponding dithiocarbamate derivatives, which were generated from indole-3-methanamines and tryptophan.

Full text of DOI:10.1039/c8nj02037j

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A concise synthesis of cyclobrassinin and its analogues via
thiyl radical aromatic substitution
Received 00th January 20xx,
Accepted 00th January 20xx
Xin Zhong, Ning Chen*, Jiaxi Xu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: A simple and concise approach for the synthesis of cyclobrassinin has been developed through a thiyl radical-
mediated intramolecular aromatic substitution, with benzoyl peroxide as efficient initiator and oxidant. The current
method can also be utilized in the synthesis of 6 and 7-membered ring cyclobrassinin analogues in moderate to good
yields. The transformation undergoes a formal radical 6 and 7-endo-trig cyclization of the corresponding dithiocarbamate
derivatives, which were generated from indole-3-methanamines and tryptophan.
dearomatization step during reaction process.
Introduction
To develop a new chemical transformation is always exciting and
As typical molecules of cruciferous phytoalexins, cyclobrassinin and
its analogues play notable roles in the plant disease resistance,1-3
human health,4 and soil ecology.5,6 Moreover, high consumption of
cruciferous vegetables is also known as lowering the risk of human
diseases like lung and colorectal cancers.4 General methods to
obtain such indole-sulfur-containing phytoalexins are designed
through biosynthesis, but with low efficiency in transformations.7-9
More effective approaches are designed by chemical synthesis,
most of which have been developed through the oxidation of
brassinin by use of bromination oxidants, such as NBS (N-
bromosuccimide),1 pyridinium tribromide,10 dioxane dibromide,11
and PhMe3NBr3.12 In such transformations, sulfenyl bromide
intermediates are in situ generated. The electrophilic sulfenyl
bromides undergo an intramolecular aromatic substitution with the
indole moiety to afford cyclobrassinin [Scheme 1, eqn (1)]. To our
best knowledge, there is still no approach that utilizes the thiyl
radical aromatic substitution to realize the synthesis of
cyclobrassinin and its analogues through the aromatic carbon-sulfur
bond formation. Although thiyl radicals have been identified as
weak electrophilic radicals,13 they preferably react with olefins
rather than arenes probably due to the high activation energy in the
challenging. The formation of the aromatic C-S bond has been
usually realized from the transition-metal-catalyzed cross-coupling
of aryl halides (or sulfonates) with thiols or disulfides.9,14,15 The
recent
methodologies
fascinate
the
direct
oxidative
dehydrogenative C-H/S-H cross-coupling of arenes and thiophenols,
some of which proceed under the thiyl radical mechanism.16-20
Generally, thiyl radicals play a significant role in the construction of
carbon−carbon and carbon−heteroatom bonds and display broad
applications in organic synthesis,21-23 pharmaceutical synthesis,24
and polymer preparations.25-27 In these cases, all thiyl radicals are
generated from thiols or disulfides, none of which is obtained from
dithiocarbamates. Recently, our group disclosed that N-substituted
dithiocarbamates were used as active thiyl radical (II) precursors
(Scheme 1, eqn (2)).28,29 Interestingly, when N-substituents are allyl
groups,28 the active thiyl radicals are captured by the electron-rich
olefins in the allyl group to afford thiazoline derivatives (eqn (3)).13
However, when N-substituents are aryl groups,29 the in situ
generated thiyl radicals prefer dimerization to the aromatic radical
substitution probably due to their low electrophilicity caused by the
delocalization effect of the aryl groups (eqn (4)). To circumvent the
conjugation effect of aryls with thiyl radicals, N-benzyl
dithiocarbamates were investigated, but no target molecule was
obtained possibly because of difficult dearomatization of a phenyl
ring (eqn (5)). As we known, the aromaticity of pyrrole is weaker
than that of benzene, thus comparing with benzene, the
dearomatization of pyrrole should be easier. Moreover, to fascinate
the radical aromatic substitution , a more electron-rich arene, like
indole, might be more reactive. Therefore, we rationalized that alkyl
a.State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing
100029, People’s Republic of China.
Email: chenning@mail.buct.edu; jxxu@mail.buct.edu.cn.
Electronic Supplementary Information (ESI) available:
NMR spectra of dithiocarbamates
DOI: 10.1039/x0xx00000x
[
Copies of 1H and 13C
1 and cyclobrassinin 2 and its analogues]. See
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N-(indol-3-yl)alkyldithiocarbamates should be suitable substrates of cyclobrassinin and its analogues from N-(indol-3-
for the synthesis of cyclobrassinin and its analoguesthrough radical yl)alkyldithiocarbamates through a formal 6/7-endo-trig radical
aromatic electrophilic substitution. We, herein, report the synthesis cyclization (intramolecular radical aromatic substitution).
Scheme 1. Synthesis of Cyclobrassinin and dithiocarbamate radical chemistry
.
Results and discussion
Brassinin (1a), the model reaction substrate, and its analogues,
were synthesized from indole-3-carbaldehyde (3) in 3 to 4 steps
(Scheme 2). Initially, brassinin (1a) was obtained from indole-3-
carbaldehyde (3) through a reductive amination with hydroxyamine
hydrochloride followed by a direct condensation with carbon
disulfide and methyl iodide in a total yield of 49% for three steps. In
the synthesis of N-substituted brassinins 1b-d, (N-substituted indol-
3-yl)methanamines 6 were prepared from 3 through a substitution
followed by a reductive amination via their oxime intermediates.
Two approaches were examined for the reduction of oximes 5 to
amines 6. N-Benzyl indole-3-carbaldehyde oxime (5d) was reduced
with NaBH4 under the aid of the NiCl2 promotion. N-Tosyl and N-
methyl indoles 5b and 5c were reduced under the catalytic
hydrogenation in the presence of Pd/C. Treatment of 6 with carbon
Synthesis of Brassinin (1a) and its dithiocarbamate analogues
(1b−1h)
To begin our study, all methyl N-(indol-3-yl)alkyldithiocarbamates 1
were synthesized from the corresponding (indol-3-yl)alkylamines
(or their hydrochloride salts), carbon disulfide, and alkyl halides,28
or from (indol-3-yl)alkyl isothiocyanoates and mercaptans.29 The
corresponding amines (or their hydrochloride salts) were prepared
according to the literature procedure or a modified procedure of
literature.30-32
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Scheme 3. Synthesis of dithiocarbamates 1e−1h from L-tryptophan.
disulfide and methyl iodide directly resulted in the formation of
brassinin (1a) and its analogues 1b−1d in good to excellent yields.
Synthesis of Cyclobrassinin and its analogues via thiyl radical
aromatic substitution
The thiyl radical cyclization was commenced with brassinin (1a) as a
model substrate (Table 1). Generally, dilauroyl peroxide (DLP) has
been used as the efficient initiator to trigger the radical initiation of
xanthates and dithiocarbamates,33,34 but in the current case, its
initiation only produced cyclobrassinin (2a) in a very poor yield,
while most of brassinin (1a) was recovered (Table 1, entries 1 & 2).
The yield was slightly increased when additional 1 equiv. of 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) was added, but an over-
oxidation product, dehydrocyclobrassinin (9), was also detected in
6% yield (Table 1, entry 3). Although it is
a widely-used
dehydrogenation reagent, DDQ showed no reactivity in the reaction
when it was used as the sole dehydrogenation reagent (Table 1,
entry 4). To our best knowledge, benzoyl peroxide (BPO) was
seldom used as the initiator in xanthate chemistry because of its
poor efficiency,33-35 but, herein, the reaction efficiency was
obviously promoted when it was applied (Table 1, entry 5).
Moreover, increasing amount of BPO from 1.0 to 1.5 equiv.
improved the product yield to 42% (Table 1, entry 6). Such
intramolecular oxidative coupling that the homolytic aromatic
substitution requires over 1.0 equiv. initiator has been previously
discovered in the system of ArX/Bu3SnH (2.2 equiv.)-AMBN (1.0
Reagents and conditions: Method A: TsCl (for 4b) or MeI (for 4c), TBAB (0.1
equiv), NaOH (50% aq)/C6H6 = 1:1, 4 h; Method B: BnBr (1.1 equiv), Cs2CO3
(1.1 equiv), reflux for 2 h in dry CH3CN.
Scheme 2. Synthesis of brassinin (1a) and its analogues (1b−1d).
For further application, we envisioned that tryptophan, a naturally
occurring indole alkylamine derivative, might also be an effective
substrate in this reaction. More significantly, tryptophan is also the
raw material for biosynthesis of brassinin under enzyme catalysis.8
Thus, tryptophan-based dithiocarbamates 1e−1g with various S-
substituents were designed as following (Scheme 3). First, methyl L-
tryptophanate hydrochloride (7) was synthesized from L-tryptophan
in a quantitative yield according to literature.32 The following
treatment with carbon disulfide and alkyl halides in the presence of
Et3N gave rise to substrates 1e−1g in moderate to good yields. In
the preparation of 1f from 7 and benzyl chloride, thioisocyanate 8
was generated as a byproduct with 22% yield of isolated product
under the column chromatography. We thus reacted 8 with
thiophenol to prepare S-phenyl substituted substrate 1h in 62%
yield.
equiv.),36 ArI/Bu3SnH (2.0 equiv.)-AIBN (1.0
equiv.),37 and
ArBr/Bu3SnH (3.7 equiv.)-AIBN (1.0 equiv.).38 In these
transformations, equimolecular AIBN or AMBN, obviously acted as
not only an initiator to trigger the Bu3Sn. Radical, but also an
oxidant to convert the 5-electron π-radical intermediates into the
cyclized arenes or heteroarenes in the rearomatization steps.
Similar results were also demonstrated by Zard in their
stoichiometric DLP-triggered homolytic aromatic substitution from
the arylalkyl xanthate intermediates.33,39 The screening of solvents
indicated that only 1,2-dichloroethane (DCE) and toluene (PhMe)
provided moderate yields, but DCE had better selectivity (Table 1,
entries 6−8). Experimental results from entries 9−11 demonstrated
alkyl peroxides, such as di-t-butyl peroxide (DTBPO), tert-butyl
peroxide (TBPO), and tert-butyl peroxybenzoate (TBPBO), provided
no desired products at neither 80 oC in DCE nor at 132 oC in
chlorobenzene. The addition of metal catalyst diminished the
product yield (Table 1, entry 12). Finally, microwave irradiation was
tested (30 min), but it was still hard to promote the reaction
efficiency (Table 1, entry 13).
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Table 1. Optimization of the intramolecular thiyl radical cyclization
Initiator (equiv.)
Solvent
Yielda (%)
Entry
Temp (oC)
2a
＜1
5
9
1
2b
3
trace
83
83
DLP (1.0)
DLP (1.5)
DCE
DCE
DCE
trace
6
83
DLP (1.5), DDQ (1.0)
DDQ (1.0−2.0)
BPO (1.0)
8
4
1
r.t. to 80
83
CH3CN
N.D.
17
5
1
DCE
DCE
6
7
83
BPO (1.5)
42
7
12
17
N.D.
N.D.
N.D.
18
9
110
BPO (1.5)
PhMe
43
8
81
BPO (1.5)
CH3CN
36
9c
10
11
12
13
80/132
80/132
80/132
83
DTBPO (1.0)
TBPO (1.0)
TBPBO
DCE/PhCl
DCE/PhCl
DCE/PhCl
DCE
trace
trace
Trace
3
BPO (1.5), Cu(OTf)
2 (0.2)
BPO (1.5), MWd (0.5 h)
DCE
34
83
a) Yields of isolated products are given. b).Reaction time was prolonged to 4 h. c) N. D. not detected. 80 oC for DCE, 132 oC for PhCl. d) MW =
Microwave irradiation.
With the optimized conditions in hand, we further investigated the compound 2b was detected through the analyses of both NMR and
reaction scope and the effect of N-substituents on the indole ring HRMS analyses. Curran identified that 2-halo-N-((1-tosylindolin-3-
and S-substituents on dithiocarbamates. Notably, although 1.5 yl)methyl)anilines could be converted to the corresponding
equiv. of BPO were required for N-H and N-tosyl substrates (1a and spiroindoline products by Bu3SnH/AIBN involving
a 5-exo-trig
1b), only 1.0 equiv. of BPO was enough for N-alkyl substrates 1c and cyclization followed by a β-fragmentation of tosyl group to afford
1d to consume all starting materials according to the monitor of TLC cyclic imines.40,41 In our case, only a trace yield of spirocyclic imine
and 1H-NMR analyses. The reaction results are summarized in Table G (scheme 4) was generated in the reaction system determined by
2. Obviously, the electron-withdrawing tosyl group on the nitrogen 1H NMR and HR-MS. Instead, the corresponding isothiocyanate 8
atom of indole is unfavourable to the reaction. Substrate 1b gave was isolated as a major side product in 17% yield (the detailed
rise to a complex system under optimized conditions and no target
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removed by column chromatography. The results demonstrate that
both S-alkyl and S-aryl substituted dithiocarbamates afford the
cyclization products in moderate yields because the formation of
the seven-membered ring is more difficult than the generation of
the six-membered ring in the radical aromatic substitution.
information are listed in Supporting Information, see pages S3 and
S4).
Dithiocarbamates 1c and 1d with electron-donating alkyl groups
(Me and Bn) promoted the yields to 53% and 62%, respectively. The
results indicate that electron-rich indoles show more efficient than
the electron deficient ones because α-imino thiyl radicals are
electrophilic.8 In summary, electron-donating alkyl groups (Me and
Bn) on the nitrogen atom not only greatly enhanced the electron
density of the indole ring, but also effectively inhibited the further
oxidation to afford the undesired dehydrocyclobrassinin (3a).
Proposed mechanism for the radical cyclization process
Finally, on the basis of our previous work,28,29,35 and insights on the
thiyl radical reactions of dithiocarbamates, a plausible mechanism
was proposed in Scheme 4. Generally, BPO acts as both the radical
initiator and the oxidant. First, BPO dissociates under heating to
produce a benzoyloxy radical, which then abstracts a hydrogen
atom from dithiocarbamates 1 to yield the electrophilic α-imino
thiyl radicals A. Active radials A can attack both 2- and 3-positions
of the indole ring via an endo-trig or exo-trig type cyclization to
generate tertiary benzyl radicals B or secondary carbon radicals C,
respectively. Generally, radicals B are more thermodynamically
stable, but radicals C are more kinetically favoured because 5-exo-
trig cyclization is much more efficient than 6-endo-trig according to
the Baldwin rule.42,43 In the 6-endo-trig pathway, intermediates B
Table 2. N-Substituent effect on the 6-endo-trig thiyl radical
cyclizationa
H
N
N
R2
BPO (1.0~1.5 equiv.)
DCE, reflux, 2 h
S
S
R2
S
S
N
R1
H
N
R1
1
2
N
N
NH
NH
S
S
S
S
S
S
S
N
H
N
S
N
N
H
1a
Tos
Tos
2a, 43%
1b
2b, 0%b
could directly lose
a hydrogen through abstraction by the
benzoyloxy radical to afford the target cyclobrassinin 2, or are first
oxidized by the benzoyloxy radical to generate cations D, which lose
a proton to afford 2. Both pathways are possible, especially the
latter one when the radicals are stabilized by an adjacent electron-
donating substituent.34 While in the 5-exo-trig pathway, spiro-
intermediates C are generated. Subsequently, intermediates D are
generated through an oxidation of C by the benzoyloxy radical
followed by a cation rearrangement. To identify the possibility, we
analyzed the reaction system with LC-HRMS and 1H-NMR. Both
spectroscopic analyses showed the trace existence of spiro-
intermediates G (see supporting information, pages S5 and S6).
Moreover, if indole is electron-deficient 1b, the electrophilic thiyl
radical A-1b could not attack the indole, so it prefers to lose an
alkylthio radical to provide the corresponding isothiocyanate 8.
N
S
NH
N
NH
S
S
S
S
S
S
S
N
N
N
N
Me
Me
Ph
Ph
1d
1c
2c, 53%
2d, 62%
CO2Me
NH
CO2Me
N
CO2Me
NH
CO2Me
N
Bn
Bn
S
S
S
S
S
S
S
S
N
H
N
N
H
H
N
H
1e
2e, 33%
CO2Me
1f
2f, 29%
CO2Me
NH
CO2Me
NH
CO2Me
N
N
Ph
S
S
S
S
S
S
S
S
Ph
N
H
N
N
H
N
H
H
1g
2g, 30%
1h
2h, 15%
a
Reactions were conducted on a 0.3 mmol scale of 1 in 2.5 mL of dry DCE. b.The
reaction system was very complicated and the corresponding isothiocyanate 8 was
isolated as a major product in 17% yield.
After synthesis of cyclobrassinin (2a) and its analogs (2c and 2d),
we next turned to investigate the synthesis of seven-membered
cyclobrassinin analogs from tryptophan-derived dicarbamates and
the influence of S-substituents of dithiocarbamates with substrates
1e−1g. As shown in Table 2, all S-alkyl substrates, such as methyl
(1e), benzyl (1f), and n-propyl (1g), afforded the corresponding
intramolecular cyclization products with the similar isolated yields
range from 29% to 33%. In these transformations, no oxidized
products, analogues of 9, were detected. In comparison, S-phenyl
substrate 1h, bearing an aromatic substituent, only produced the
desired product 2h in 15% yield. Increasing the loading of BPO to
1.5 and 2 equivalents did not improve the reaction efficiency. The
reaction system was also much more complicated than those of 1e,
1f, and 1g, and the cyclization product 2h was always mixed with a
little amount of an unknown byproduct with the similar polarity
(almost same Rf value with different eluents), which was hard to be
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commercially available reactants were used directly. 1,2-
Dichloroethane (DCE) is dehydrated with CaH2 under refluxing.
Melting points were obtained on a Yanaco MP-500 melting point
1
apparatus and are uncorrected. H-NMR and 13C-NMR spectra were
measured with a Bruker 400 spectrometer in CDCl3 and DMSO-d6
with tetramethylsilane (TMS). IR spectra were recorded directly on
a Nicolet AVATAR 330 FTIR spectrometer. HRMS spectra were
determined with an Agilent Liquid Chromatography/Mass
Spectrometry/Data and Time-of-Flight (LC/MSD TOF) mass
spectrometer.
Synthesis of Brassinin (1a) and its dithiocarbamate analogues (1)
Synthesis of 1a and 1d
Procedure for the synthesis of 4d
Indole-3-carboxaldehyde (2.9 g, 20 mmol) and Cs2CO3 (13 g, 40
mmol) were dissolved in 150 mL of dry acetonitrile and the reaction
mixture was refluxed for 2.5 h. Then BnBr (3.76 g, 2.6 mL, 22 mmol)
was added into the reaction system which was then refluxed for 1
h. After evaporation of solvent in vacuum, water was added (150
mL) and the aqueous phase was extracted with EtOAc (3 × 150 mL),
the organic layer was dried over anhydrous Na2SO4. The crude
product was obtained in a quantitative yield after evaporation of
EtOAc and was used for the next step without further purification.
Scheme 4. A plausible mechanism of thiyl radical cyclization of 1.
Procedure for the synthesis of 5a and 5d
Conclusions
To a solution of indole-3-carboxaldehyde (3, 1.96 g, 13.5 mmol) or
1-benzyl-indole-3-carboxaldehyde (4d, 3.18 g, 13.5 mmol) in a
mixture of ethanol (90 mL) and water (9 mL) were added
hydroxyamine hydrochloride (1.61 g, 23.1 mmol) and anhydrous
sodium carbonate (1.11 g, 10.5 mmol). The mixture was stirred for
30 min at room temperature (for 3) or 1 h at 60 oC (for 4d). After
evaporation of solvent in vacuum, water (90 mL) was added and the
aqueous phase was extracted with EtOAc (3 X 120 mL). The organic
phase was collected and then dried over anhydrous Na2SO4. After
removal of EtOAc, the crude oxime 5a (2.1 g) or 5d (2.9 g) was
obtained with the yield of 98% and 86%, respectively.
In summary, we have developed a simple approach for the
synthesis of cyclobrassinin and its 6- and 7-membered-ring
analogues. Inole-3-carbaldehyde was used as starting materials to
provide brassinin and its analogues through the reductive
amination with hydroxyamine hydrochloride followed by a direct
condensation with carbon disulfide and methyl iodide in three to
four steps. After esterification with methanol, L-tryptophan was
converted into its carbamates in moderate to good yields through
the reaction with carbon disulfide and various alkyl halides. During
the following cyclization, benzoyl peroxide was found as the
efficient initiator to promote the intramolecular radical aromatic
electrophilic substitution via a formal 6 and 7-endo-trig cyclization
process. The formation mechanism of cyclobrassinin was proposed
through both 5-exo-trig and 6-endo-trig cyclization. Finally, the
current process can be utilized in the synthesis of cyclobrassinin and
its 6 and 7-membered-ring analogues.
Procedure for the synthesis of 6a and 6d
To a solution of the crude oxime 5a (1.0 g, 6.2 mmol) or 5d (1.6 g,
6.4 mmol) in methanol (120 mL) was added nickel(II) chloride
hexahydrate puratrem (1.63 g, 6.86 mmol). The system was cooled
o
to 0 C by an ice water bath, and then sodium borohydride (1.65 g,
43.7 mmol) was added in one portion. A black precipitate was
generated in
5 min and was filtered off. The filtrate was
Experimental
concentrated in vacuum to approx. 30 mL and was poured into 200
mL of ammonia water (0.67 mol/L: 10 mL ammonia water (25%) in
190 mL of deionized water). After extraction with EtOAc (3 × 200
mL), the organic layer was dried over anhydrous Na2SO4 followed by
an evaporation of the solvent, the crude amine 6a (0.78 g) or 6d
(1.21 g) was obtained as a viscous and yellowish oil. Pure 6a was
obtained as colorless crystals after column chromatograph with
CHCl3/MeOH/TEA = 80:20:1 as eluent. 565 mg, yield 62%, mp. 124 −
127 oC (CHCl3/MeOH), lit. mp. 102 − 104 oC (DCM/n-Hexane).30 1H
Unless otherwise noted, all materials were purchased from
commercial suppliers. Flash column chromatography was
performed using silica gel (normal phase, 200-300 mesh) from
Branch of Qingdao Haiyang Chemical Industry. Petroleum ether (PE)
used for column chromatography is 60−90 oC fraction, and the
removal of residue solvent was accomplished under rotovap.
Reactions were monitored by thin-layer chromatography on silica
gel GF254 coated 0.2 mm plates from Institute of Yantai Chemical
Industry. The plates were visualized under UV light. All
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NMR (400 MHz, DMSO-d6): δ = 11.15 (s, 1H, NH), 7.66 (d, J = 7.6 Hz, extracted with benzene (2 × 20 mL). After drying over anhydrous
1H, ArH), 7.37 (m, 2H, ArH), 7.10 (dt, J = 0.8, 7.6 Hz, 1H, ArH), 7.01 Na2SO4 and evaporation of benzene, the corresponding crude
(dt, J = 0.8, 7.6 Hz, 1H, ArH), 5.21 (br. s, 2H, NH2), 4.01 (s, 2H, CH2) aldehyde 4b or 4c was obtained in 100% and 95% crude yields,
ppm. 13C NMR (100.6 MHz, DMSO-d6): δ = 136.2, 126.3, 124.1, respectively. They were used directly in the next step reaction
121.2, 118.6, 118.5, 112.4, 111.5, 35.4 ppm. The crude 6d was used without further purification.
directly in the next step reaction without further purification.
To a solution of the crude 4b (4.04 g) or 4c (2.15 g) in ethanol (90
Procedure for the synthesis of 1a and 1d
mL) and water (9 mL) were added hydroxylamine hydrochloride
(1.61 g, 23.1 mmol) and anhydrous sodium carbonate (1.11 g, 10.5
mmol). The mixture was stirred for 30 min at 90 oC (for 4b) or at
room temperature for 3 h (for 4c). After evaporation of ethanol,
water (90 mL) was added and followed by an extraction with EtOAc
(3 × 120 mL). After drying over anhydrous Na2SO4, the organic
phase was removed in vacuum and the crude oximes 5b (3.4 g) and
5c (2.9 g) were obtained with the yields of 81% and 100%,
respectively.
To a solution of 6a (565 mg, 3.86 mmol) or crude 6d (1.21 g) in 20
mL of methanol was added TEA (1.17 g, 1.61 mL, 11.6 mmol), CS2
(882 mg, 0.70 mL, 11.6 mmol), and MeI (1.64 g, 0.72 mL, 11.6
mmol) at 0 oC. The mixture was stirred at 0 oC for 10 min and
warmed up to room temperature for 2 h. After evaporation of
solvent in vacuum, water (40 mL) was added followed by an
extraction of EtOAc (3 × 30 mL and 2 × 20 mL). The organic layer
was dried over anhydrous Na2SO4 and the solvent was then
removed in vacuum. The pure dithiocarbamates 1a (729 mg) and 1d 5% Pd on C (300 mg) and 36%wt HCl (4 mL) were added into a
(210 mg) were obtained after the purification of column solution of the crude oxime 5b (2.2 g) or 5c (1.3 g) in methanol (60
chromatography with PE/EtOAc = 20/1−10/1−7/1 as eluent.
mL). The suspension was stirred under H2 (10 bar) at room
temperature overnight. After filtration on celite, the solvent was
evaporated. The residue was dissolved in EtOAc (25 mL) and water
(30 mL), then 2 mol/L NaOH aqueous solution was added to the
solution to adjust the pH to 11. The water layer was extracted with
EtOAc (3 × 40 mL) and organic layer was dried over Na2SO4. After
removal of solvent, the crude amines 6b and 6c were obtained and
used directly in the following step. The in situ generated 6b or 6c
was dissolved in a mixture of methanol (30 mL) and EtOAc (20 mL)
and the system was cooled to 0 oC in an ice water bath. TEA (1.82 g,
2.5 mL, 18.0 mmol), CS2 (1.37 g, 1.1 mL, 18.0 mmol), and MeI (2.55
g, 1.1 mL, 18.0 mmol) were added into the reaction system in
sequence. The mixture was stirred at 0 oC for 10 min and then
warmed up to room temperature for 2 h. After removal of solvent,
water (60 mL) was added and followed by extraction with EtOAc (3
× 70 mL). The organic layer was dried over anhydrous Na2SO4 and
the solvent was removed. Pure dithiocarbamates 1b (1.83 g) and 1c
(1.20 g) were obtained after the purification of column
chromatograph with PE/EA = 20/1 − 10/1 − 7/1 as eluent.
Methyl ((1H-indol-3-yl)methyl)carbamodithioate (Brassinin, 1a)
Pale yellow solid, the three-step yield was 49% with indole-3-
carboxaldehyde (3) as starting material. M.p. 135−137 oC
o
(CHCl3/MeOH) lit. m. p. 133 − 135 C (DCM/ n-Hexane).12 IR (CHCl3)
1
(cm-1): 3406, 3324, 2918, 1498, 1080, 918, 744. H NMR (400 MHz,
CDCl3): δ = 8.19 (s, 1H, NH), 7.62 (d, J = 8.0 Hz, 1H, ArH), 7.39 (d, J =
8.0 Hz, 1H, ArH), 7.23 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H, 6-H overlapped
with 2-H), 7.16 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H, ArH), 7.03 (br s, 1H,
NH), 5.04 (d, J = 3.6 Hz, 2H, CH2), 2.63 (s, 3H, SCH3) and minor
signals (1/4 intensity of the major ones) due to a rotamer at δ =
7.85 (br. s, NH), 4.76 (d, J = 4.0 Hz, 2H, CH2), 2.73 (s, SCH3). 13C NMR
(100.6 MHz, CDCl3): δ = 198.2, 136.2, 126.4, 124.0, 122.8, 120.3,
118.7, 112.4, 111.4, 43.2, 18.1.
N-(1-Benzyl-1H-indol-3-yl)methyl-S-methyl dithiocarbamate (1d)
White solid, 210 mg, the four-step yield was 22% with indole-3-
carboxaldehyde (3) as starting material, m.p. 146−148 oC (PE/EA). IR
(CHCl3) (cm-1): 3335, 2917, 1495, 1467, 1301, 1076, 920, 742. 1H
NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 7.6 Hz, 1H, ArH), 7.32 − 7.13
(m, 9H, ArH), 7.00 (br s, 1H, NH), 5.29 (s, 2H, CH2Ar), 5.04 (with a
minor rotamer signal at 4.77)(d, J = 4.0 Hz, 2H, CH2N), 2.64 (with a
minor rotamer signal at 2.74)(s, 3H, SCH3). 13C NMR (100.6 MHz,
CDCl3): δ = 198.0, 136.9, 136.7, 128.9, 127.9, 127.8, 127.2, 126.9,
122.5, 120.0, 118.9, 110.1, 109.8, 50.1, 43.2, 18.1. HRMS (ESI), m/z,
S-Methyl-N-(1-(p-toluenesulfonyl)-1H-indol-3-yl)methyl
dithiocarbamate (1b)
Yellow solid, 1.83 g, the four-step yield was 54% with indole-3-
carboxaldehyde (3) as starting material, m.p. 114–116 oC (CHCl3). IR
(CHCl3) (cm-1): 3326, 2920, 1596, 1494, 1369, 1172, 979, 746. 1H
NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 1H, ArH), 7.77 (d, J =
8.4 Hz, 2H, ArH), 7.57 (s, 1H, ArH), 7.53(d, J = 8.0 Hz, 1H, ArH), 7.35
(dd, J = 7.6, 8.0 Hz, 1H, ArH), 7.27 − 7.22 (m, 3H, ArH), 7.04 (br. s,
NH), 5.02 (d, J = 4.4 Hz, 2H, CH2N), 2.65 (s, 3H, SCH3), 2.34 (s, 3H,
CH3). 13C NMR (100.6 MHz, CDCl3): δ = 199.3, 145.2, 135.2, 135.0,
130.0, 126.9, 126.7, 125.3, 125.1, 123.6, 119.6, 117.3, 113.7, 42.4,
+
calcd for [M+Na]+: C16H18N2NaS2 , 349.0804. Found: 349.0798.
One-pot procedure for the synthesis of 1b and 1c
To a solution of indole-3-carboxaldehyde (3, 2.0 g, 13.8 mmol) in
benzene (50 mL) were added an aqueous sodium hydroxide
solution (50 mL, 30% wt.), tetrabutylammonium bromide (440 mg,
1.38 mmol), and TsCl (2.76 g, 14.4 mmol, for 4b) or MeI (1.96 g,
0.86 mL, 13.8 mmol, for 4c). The mixture was stirred at room
temperature and monitored with TLC. When the reaction was
finished, the benzene layer was separated and water layer was
+
21.6, 18.3. HRMS (ESI), m/z, calcd for [M+H]+: C18H19N2O2S3 ,
391.0603. Found: 391.0603.
N-(1-Methyl-1H-indol-3-yl)methyl-S-methyl dithiocarbamate (1c)
Yellow solid, 1.20 g, the four-step yield was 65% with indole-3-
carboxaldehyde (3) as starting material, m.p. 114−116 oC (CHCl3). IR
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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ARTICLE
Journal Name
(CHCl3) (cm-1): 3321, 2916, 1475, 1388, 1301, 1074, 919, 742. 1H 109.3, 59.4, 52.6, 39.8, 26.6. HRMS (ESI), m/z, calcd for [M+H]+:
NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.0 Hz, 1H, ArH), 7.33 (d, J = C20H21N2O2S2+, 385.1039. Found: 385.1043.
8.0 Hz, 1H, ArH), 7.27 (dd, J = 7.2, 8.0 Hz, 1H, ArH), 7.15(dd, J = 7.2,
Methyl ((propylthio)carbonothioyl)-L-tryptophanate (1g)
8.0 Hz, 1H, ArH), 7.09(s, 1H, ArH), 7.02 (br. s, NH), 5.02 (d, J = 4.4 Hz,
2H, CH2N), 3.76 (s, 3H, NCH3), 2.62 (s, 3H, SCH3), 2.34 (s, 3H, CH3).
13C NMR (100.6 MHz, CDCl3): δ = 197.9, 137.0, 128.6, 126.9, 122.2,
119.7, 118.7, 109.5, 109.0, 43.0, 32.8, 18.0.
Sticky pale yellow oil, 1.27 g, the two-step yield was 54% from 7. IR
(CHCl3) (cm-1): 3349, 2972, 1735, 1488, 1457, 1091, 1049, 909. 1H
NMR (400 MHz, CDCl3): δ = 8.09 (s, 1H, NH), 7.51 (d, J = 7.6 Hz, 1H,
ArH), 7.38 − 7.34 (m, 2H, the signal of NHCS overlapped with ArH),
7.20 (ddd, J = 7.6, 6.8, 1.2 Hz, 1H, ArH), 7.12 (ddd, J = 8.0, 6,8, 1.2
Synthesis of 1e and 1h
General procedure for the synthesis of dithiocarbamates 1e, 1f, Hz, 1H, ArH), 6.96 (d, J = 2.4 Hz, 1H, ArH), 5.56 (ddd, J = 7.6, 5.2, 4.4
and 1h and isothiocyanate 8
Hz, 1H, CHCO2), 3.70 (s, 3H, CO2Me), 3.62 (dd, J = 14.8, 5.2 Hz, 1H,
CH2CH), 3.40 (dd, J = 14.8, 4.4 Hz, 1H, CH2CH), 3.21 (dt, J = 13.2, 7.2
Hz, 1H, SCHH), 3.16 (dt, J = 13.2, 7.2 Hz, 1H, SCHH), 1.69 (sextet, J =
7.2 Hz, 2H, CH2), 0.99 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ =
198.4, 171.4, 136.0, 127.6, 122.9, 122.3, 119.8, 118.7, 111.2, 109.6,
59.2, 52.5, 37.2, 26.7, 22.3, 13.4. HRMS (ESI), m/z, calcd for [M+H]+:
C16H21N2O2S2+, 337.1039. Found: 337.1040.
Methyl L-tryptophanate hydrochloride (7) was synthesized in a
quantitive yield according to the method reported in literatures.32
7 (1.78 g, 7 mmol) and anhydrous Na2CO3 (0.45 g, 4.2 mmol) were
dissolved in a mixture of methanol (20 mL) and water (1.5 mL) and
the mixture was cooled to 0 oC. TEA (1.42 g, 1.95 mL, 14 mmol) and
CS2 (1.07 g, 0.85 mL, 14 mmol) were added into the mixture for 30
minutes then MeI (1.99 g, 0.87 mL, 14 mmol, for 1e), or BnCl (0.93 Methyl (S)-3-(1H-indol-3-yl)-2-isothiocyanatopropanoate (8)
g, 0.85 mL, 7.35 mmol, for 1f), or 1-bromopropane (1.72 g, 1.28 mL,
Sticky yellow oil, 0.4 g, the two-step yield was 22% from 7. IR
(CHCl3) (cm-1): 3410, 2924, 2069, 1742, 1213, 744. 1H NMR (400
MHz, CDCl3): δ = 8.14 (s, 1H, NH), 7.56 (d, J = 8.0 Hz, 1H, ArH), 7.36
(d, J = 8.4 Hz, 1H, ArH), 7.19 (dt, J = 0.8, 7.2 Hz, 1H, ArH), 7.17 − 7.13
(m, 2H, ArH), 4.57 (dd, J = 4.8, 8.0 Hz, 1H, CHCO2Me), 3.44 (dd, J =
4.8, 14.4 Hz, 1H, CH2), 3.34 (dd, J = 8.0, 14.8 Hz, 1H, CH2). 13C NMR
(100.6 MHz, CDCl3): δ = 168.7, 126.8, 124.0, 122.3, 119.8, 111.4,
109.1, 60.2, 53.1, 30.0. HRMS (ESI), m/z, calcd for [M+H]+:
C13H13N2O2S+, 261.0692. Found: 261.0693.
14 mmol, for 1h) was added into the reaction system. The whole
mixture was stirred for 20 min and then warmed up to room
temperature until the reaction was finished monitored by TLC (ca. 2
h). After removal of solvent, water (60 mL) was added and the
aqueous phase was extracted with EtOAc (3 × 70 mL). The organic
layer was dried over anhydrous Na2SO4 and followed by removal of
solvent. The pure dithiocarbamates 1e (1.94 g), 1f (0.94 g) and 1g
(1.27 g) were obtained after the purification of column
chromatography with PE/EA = 20/1 − 10/1 − 4/1 as eluent.
Isothiocyanate 8 was isolated (0.4 g, 22% yield) as a byproduct in
the reaction system of 1f.
Procedure for the synthesis of dithiocarbamates 1h44
Methyl (S)-3-(1H-indol-3-yl)-2-isothiocyanatopropanoate (8) (0.56 g,
2.15 mmol), thiophenol (355 mg, 0.33 mL, 3.23 mmol) and TEA (218
mg, 0.3 mL, 2.15 mmol) were added into 10 mL of dry toluene and
the mixture was refluxed for 8 h. The whole system was cooled to
room temperature. After evaporation of solvent, the residue was
submitted to the column chromatography with PE/EA = 20/1 − 10/1
− 2/1 as eluent to afford the target product 1h. Pale yellow solid,
493 mg, yield 62%, m.p. 124−126 oC (DCM/n-Hexane). IR (CHCl3)
(cm-1): 3399, 3321, 1737, 1489, 1375, 1213, 745. 1H NMR (400 MHz,
CDCl3): δ = 8.00 (s, 1H, NH), 7.49 (d, J = 8.0 Hz, 1H, ArH), 7.34 (m,
2H, ArH), 7.22 (m, 2H, ArH), 7.17 (m, 3H, ArH), 7.02 (ddd, J = 6.8 Hz,
1H, ArH), 6.68 (ddd, J = 2.4 Hz, 1H, ArH), 5.39 (ddd, J = 4.0, 5.6, 7.2
Hz, 1H, CHCO2), 3.66 (s, 3H, CO2Me), 3.60 (dd, J = 5.6, 4.8 Hz, 1H in
CH2CH), 3.27 (dd, J = 4.0, 14.8 Hz, 1H in CH2CH). 13C NMR (100.6
MHz, CDCl3): δ = 195.0, 171.0, 135.9, 135.3, 130.9, 130.0, 127.6,
Methyl ((methylthio)carbonothioyl)-L-tryptophanate (1e): Sticky
colorless oil, 1.94 g, the two-step yield was 90% from methyl L-
tryptophanate hydrochloride (7). IR (CHCl3) (cm-1): 3403, 2951,
1733, 1490, 1356, 1213, 744. 1H NMR (400 MHz, CDCl3): δ = 8.12 (s,
1H, NH), 7.51 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 7.41 (d, J = 7.6 Hz, 1H,
NHCS), 7.34 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 7.19 (dt, J = 8.0, 1.2 Hz,
1H, ArH), 7.12 (dt, J = 8.0, 1.2 Hz, 1H, ArH), 6.95 (d, J = 2.4 Hz, 1H,
ArH), 5.56 (ddd, J = 7.6, 4.8, 4.8 Hz, 1H, CHCO2Me), 3.69 (s, 3H,
CO2Me), 3.60 (dd, J = 14.8, 4.8 Hz, 1H, CH2CH), 3.40 (dd, J = 14.8, 4.8
Hz, 1H, CH2CH), 2.57 (s, 3H, SCH3). 13C NMR (100.6 MHz, CDCl3): δ =
198.9, 171.3, 136.0, 127.5, 122.9, 122.3, 119.8, 118.6, 111.2, 109.5,
59.4, 52.6, 26.7, 18.1.
Methyl ((benzylthio)carbonothioyl)-L-tryptophanate (1f)
Sticky yellow oil, 0.94 g, the two-step yield was 35% from 7. IR 127.6, 122.4, 122.4, 120.0, 118.7, 111.1, 109.2, 58.4, 52.6, 26.1.
+
(CHCl3) (cm-1): 3411, 1736, 1494, 1341, 1212, 744. 1H NMR (400 HRMS (ESI), m/z, calcd for [M+H]+: C19H19N2O2S2 , 371.0882. Found:
MHz, CDCl3): δ = 8.05 (s, 1H, NH), 7.48 (d, J = 8.0 Hz, 1H, ArH), 7.40 371.0888.
(d, J = 6.8 Hz, 1H, NHCS), 7.25 – 7.32 (m, 6H, ArH), 7.17 (dd, J = 7.2,
General procedure of Cyclobrassinin (2a) and its analogues (2)
7.6 Hz, 1H, ArH), 7.07 (dd, J = 7.2, 7.6 Hz, 1H, ArH), 6.85 (d, J = 1.6
Hz, 1H, ArH), 5.54 ((ddd, J = 4.4, 5.6, 6.8 Hz, 1H, CHCO2Me), 4.49 (d,
J = 13.6 Hz, 1H, SCH2), 4.43 (d, J = 13.6 Hz, 1H, SCH2), 3.66 (s, 3H,
CO2Me), 3.59 (dd, J = 5.6, 14.8 Hz, 1H, CH2CH), 3.37 (dd, J = 4.4, 14.8
Hz, 1H, CH2CH). 13C NMR (100.6 MHz, CDCl3): δ = 197.4, 171.2,
136.1, 136.0, 129.0, 128.6, 127.5, 122.9, 122.3, 119.8, 118.6, 111.2,
Under the nitrogen protection, dithiocarbamate 1 (0.5 mmol) and
benzoyl peroxide [(182 mg, 0.75 mmol for 1a, 1b and 1g), (121 mg,
0.5 mmol for 1c-1f and 1g)] was dissolved in 1,2-dichloroethane (2.5
mL). The reaction mixture vessel was put into a pre-heated oil bath
8 | J. Name., 2012, 00, 1-3
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Journal Name
to reflux for 2 h. Then the system was allowed to cool to room Methyl
ARTICLE
(S)-2-(benzylthio)-5,10-dihydro-4H-[1,3]thiazepino[7,6-
temperature and was washed with satuarated NaHCO3 aqueous b]indole-4-carboxylate (2f)
solution (8 mL) to remove benzoic acid. The aqueous phase was
Yellow oil, 55 mg, yield 29%, [α]20 = +3.2 (c = 4 mg/mL, CHCl3). IR
D
extracted with 1,2-dichloroethane (2 × 9 mL) and then dried over
anhydrous Na2SO4. After evaporation of the solvent, the residue
was purified by flash chromatography on silica gel with a mixture of
PE and EtOAc (50 : 1 − 40 : 1,, v/v, for 2a-2d , 30 : 1 − 20 : 1, v/v, for
2e-2h) as the eluent to afford the desired cyclization product 2.
(CHCl3) (cm-1): 3383, 3060, 2924, 1733, 1584, 1451, 1276. 1H NMR
(400 MHz, CDCl3): δ = 7.77 (s, 1H, NH), 7.42 (d, J = 7.6 Hz, 1H, ArH),
7.35 − 7.23 (m, 6H, ArH), 7.17(dt, J = 0.8, 7.2 Hz, 1H, ArH), 7.11 (dt, J
= 0.8, 7.2 Hz, 1H, ArH), 5.12 (dd, J = 2.4, 12.0 Hz, 1H, CHCO2Me),
4.39 (d, J = 13.6 Hz, 1H, SCH2), 4.14 (d, J = 13.6 Hz, 1H, SCH2), 3.88
(s, 3H, CO2Me), 3.56 (dd, J = 2.4, 16.4 Hz, 1H, CH2CH), 3.19 (dd, J =
12.0, 16.4 Hz, 1H, CH2CH). 13C NMR (100.6 MHz, CDCl3): δ = 172.6,
157.3, 136.7, 135.0, 129.2, 128.6, 128.5, 127.3, 122.9, 120.2, 119.2,
117.8, 111.2, 110.4, 64.6, 52.4, 37.3, 27.0. HRMS (ESI), m/z, calcd
2-(Methylthio)-4,9-dihydro-[1,3]thiazino[6,5-b]indole
(cyclobrassinin; 2a)
Colorless solid, 37 mg, yield 32%, m.p. 139 – 140 oC(PE/EtOAc), lit.
m. p. 136–137 oC.10 IR (CHCl3) (cm-1): 3390, 3373, 2851, 1598, 1448,
1426. 1H NMR (400 MHz, DMSO-d6): δ = 11.44 (s, 1H, NH), 7.48 (d, J
+
for [M+H]+: C20H19N2O2S2 , 383.0882. Found: 383.0873.
= 8.0 Hz, 1H, H-5), 7.33 (d, J = 8.0 Hz, 1H, H-8), 7.09 (dt, J = 1.2, 8.0 Methyl
(S)-2-(propylthio)-5,10-dihydro-4H-[1,3]thiazepino[7,6-
Hz, 1H, H-7), 7.03 (dt, J = 1.2, 8.0 Hz, 1H, H-6), 5.06 (s, 2H, CH2), 2.53 b]indole-4-carboxylate (2g)
(s, 3H, SCH3) ppm. 13C NMR (100.6 MHz, DMSO-d6): δ = 150.7(C-2),
Yellow oil, 50 mg, yield 30%, [α]20D = +0.70 (c = 7 mg/mL, CHCl3). IR
136.5 (C-8a), 124.5 (C-4b), 121.4 (C-9a), 121.3 (C-7), 119.3 (C-6),
117.0 (C-5), 111.0 (C-8), 101.6 (C-4a), 48.0 (C-4), 14.6 (CH3).
(CHCl3) (cm-1): 3361, 2961, 1736, 1586, 1450, 1435, 1275, 741. 1H
NMR (400 MHz, CDCl3): δ = 7.81 (s, 1H, NH), 7.41 (d, J = 8.0 Hz, 1H,
ArH), 7.24 (d, J = 8.4 Hz, 1H, ArH), 7.17(t, J = 7.2 Hz, 1H, ArH), 7.10
(t, J = 7.2 Hz, 1H, ArH), 5.10 (dd, J = 2.4, 12.0 Hz, 1H, CHCO2), 3.85 (s,
3H, CO2Me), 3.55 (dd, J = 2.4, 16.4 Hz, 1H in CH2CH), 3.18 (dd, J =
12.0, 16.4 Hz, 1H in CH2CH), 3.12 (dt, J = 13.2, 7.2, 1H in SCH2), 2.89
(dt, J = 13.2, 7.2, 1H in SCH2), 1.68 (sextet, J = 7.2 Hz, 2H, CH2), 0.97
(s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ = 172.7, 158.0, 135.0,
128.6, 122.8, 120.1, 119.6, 117.7, 111.1, 110.4, 64.5, 52.4, 34.9,
9-Methyl-2-(methylthio)-4,9-dihydro-[1,3]thiazino[6,5-b]indole
(2c)
Yellow solid, 66 mg, yield 53%, m.p. 105–106 oC (CHCl3), lit. m. p.
97−99 oC.30 IR (CHCl3) (cm-1): 3342, 2971, 2925, 1615, 1465, 1091,
1050. 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.6 Hz, 1H, ArH),
7.28 (d, J = 8.4 Hz, 1H, ArH), 7.19 (ddd, J = 0.8, 7.2, 8.0 Hz, 1H, ArH),
7.12 (ddd, J = 0.8, 7.2, 7.6 Hz, 1H, ArH), 5.08 (s, 2H, CH2N), 3.63 (s,
2H, CH3N), 2.55 (s, 3H, SCH3). 13C NMR (100.6 MHz, CDCl3): δ =
152.8, 125.2, 124.9, 121.4, 119.7, 117.2, 108.7, 102.6, 49.2, 30.0,
15.4.
+
26.9, 21.9, 13.4. HRMS (ESI), m/z, calcd for [M+H]+: C16H19N2O2S2 ,
335.0882. Found: 335.0885.
Methyl
(S)-2-(phenylthio)-5,10-dihydro-4H-[1,3]thiazepino[7,6-
b]indole-4-carboxylate (2h)
9-Benzyl-2-(methylthio)-4,9-dihydro-[1,3]thiazino[6,5-b]indole
(2d)
Yellow oil, 15 mg, yield 15%. IR (CHCl3) (cm-1): 3359, 2917, 1734,
1593, 1472, 1450, 1271, 742. 1H NMR (400 MHz, CDCl3): δ = 7.76 (s,
1H, NH), 7.54 (m, 2H, ArH), 7.42 (d, J = 8.0 Hz, 1H, ArH), 7.35 (m, 3H,
ArH), 7.24 (d, J = 7.2 Hz, 1H, ArH), 7.18(dd, J = 6.8, 8.0 Hz, 1H, ArH),
7.11 (dt, J = 7.6, 7.2 Hz, 1H, ArH), 5.12 (dd, J = 2.4, 12.0 Hz, 1H,
CHCO2Me), 4.39 (d, J = 13.6 Hz, 1H in SCH2), 4.14 (d, J = 13.6 Hz, 1H
in SCH2), 3.88 (s, 3H, CO2Me), 3.56 (dd, J = 2.4, 16.4 Hz, 1H in
CH2CH), 3.19 (dd, J = 12.0, 16.4 Hz, 1H in CH2CH). 13C NMR (100.6
MHz, CDCl3): δ = 172.1, 158.2, 136.9, 135.0, 133.5, 129.1, 128.9,
128.6, 123.0, 120.2, 119.3, 117.9, 111.4, 110.4, 64.9, 52.4, 26.6.
o
Yellow solid, 100 mg, yield 62%, m.p. 118–120 C (CHCl3). IR (CHCl3)
(cm-1): 3054, 2924, 1615, 1495, 1453, 1337, 905, 739. 1H NMR (400
MHz, CDCl3): δ = 7.51 − 7.08 (m, 9H, ArH), 5.21 (s, 2H, ArCH2), 5.11
(s, 2H, CH2N), 2.53 (s, 3H, SCH3). 13C NMR (100.6 MHz, CDCl3): δ =
152.1, 137.7, 136.8, 128.8, 127.7, 126.7, 125.2, 125.0, 121.6, 119.9,
117.2, 109.3, 103.1, 49.2, 47.4, 15.3. HRMS (ESI), m/z, calcd for
[M+H]+: C18H17N2S2+, 325.0828. Found: 325.0833.
+
HRMS (ESI), m/z, calcd for [M+H]+: C19H17N2O2S2 , 369.0726. Found:
Methyl
(S)-2-(methylthio)-5,10-dihydro-4H-[1,3]thiazepino[7,6-
b]indole-4-carboxylate (2e)
369.0728.
Pale yellow solid, 50 mg, yield 33%, m.p. 159−161oC (CHCl3). [α]20
=
D
+45.5 (c = 10 mg/mL, CHCl3). IR (CHCl3) (cm-1): 3366, 2923, 2852,
1737, 1586, 1449, 1274. 1H NMR (400 MHz, CDCl3): δ = 7.90 (s, 1H,
NH), 7.40 (dd, J = 1.2, 7.6 Hz, 1H, ArH), 7.23 (dt, J = 1.2, 7.2 Hz, 1H,
ArH), 7.16 (ddd, J = 1.2, 7.2, 7.6 Hz, 1H, ArH), 7.10 (ddd, J = 1.2,
7.2, 7.6 Hz, 1H, ArH), 5.12 (dd, J = 2.4, 12.0 Hz, 1H, CHCO2Me), 3.86
(s, 3H, CO2Me), 3.54 (dd, J = 2.4, 16.4 Hz, 1H in CH2CH), 3.19 (dd, J
= 12.0, 16.4 Hz, 1H in CH2CH), 2.44 (s, 3H, SCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 172.7, 158.7, 135.0, 128.6, 122.8, 120.0,
119.3, 117.7, 111.0, 110.4, 64.5, 52.5, 27.0, 16.0 ppm. HRMS (ESI),
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 21572017, 21772010, and
21702014). Mr. Xiang Li and Mr. Jun Dong are greatly
appreciated for their generous helps for the replication
experiments after the graduation of Xin Zhong.
+
m/z, calcd for [M+H]+: C14H15N2O2S2 , 307.0569. Found: 307.0565.
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