Br?nsted Acid-Catalyzed Tandem Cyclizations of Tryptamine-Ynamides Yielding 1H-Pyrrolo[2,3-d]carbazole Derivatives

Article abstract of DOI:10.1002/chem.201705189

Ynamides, as versatile synthetic precursors, have attracted much attention from synthetic chemists and sparked the development of a number of methodologies for the construction of various structures. 1H-Pyrrolo[2,3-d]carbazole is a core scaffold of a series of monoterpene indole alkaloids found in Kopsia, Strychnos, and Aspidosperma, for example. In this study, 1H-pyrrolo[2,3-d]carbazole derivatives were synthesized by a Br?nsted acid-catalyzed tandem cyclization starting from tryptamine-based ynamides. This strategy prevented Wagner–Meerwein rearrangement by instantaneous intramolecular nucleophilic trapping of the indoleninium to afford a tetracyclic indoline via an in situ-formed enol species induced by the formation of a more stable conjugate diene moiety. The functional group tolerances were investigated by using a series of readily available substrates. A plausible mechanism has been proposed based on the evidence of the capture of the hemiaminal intermediate. Lastly, a Büchi ketone, which is the pivotal intermediate in the synthesis of the indole alkaloid vindorosine, was synthesized by utilizing our newly developed methodology.

Full text of DOI:10.1002/chem.201705189

A Journal of
Accepted Article
Title: Brønsted Acid-Catalyzed Tandem Cyclizations of Tryptamine-
Ynamides Yielding 1H-Pyrrolo[2,3-d]carbazole Derivatives
Authors: Yanshi Wang, Jingsheng Lin, Xiaoyu Wang, Guanghui Wang,
Xinhang Zhang, Bo Yao, Yuandong Zhao, Pengfei Yu, Bin
Lin, Yongxiang Liu, and Maosheng Cheng
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201705189
Link to VoR: http://dx.doi.org/10.1002/chem.201705189
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Brønsted Acid-Catalyzed Tandem Cyclizations of Tryptamine-
Ynamides Yielding 1H-Pyrrolo[2,3-d]carbazole Derivatives
Yanshi Wang,[a,b] Jingsheng Lin,[a,b,c] Xiaoyu Wang,[a,b] Guanghui Wang,[a,b,c] Xinhang Zhang,[a,b,c] Bo
Yao,[a,b] Yuandong Zhao,[a,b,c] Pengfei Yu,[d] Bin Lin,[a,b] Yongxiang Liu,*[a,b,c] and Maosheng Cheng*[a,b]
Abstract: Ynamide, as a versatile synthetic precursor has gained
much attention from synthetic chemists and sparked the
development of a number of methodologies in constructing various
structures. The 1H-pyrrolo[2,3-d]carbazole was a core scaffold of a
series of monoterpene indole alkaloids such as Kopsia, Strychnos
and Aspidosperma. In this study, the 1H-pyrrolo[2,3-d]carbazole
derivatives were synthesized via a Brønsted acid-catalyzed tandem
cyclization from tryptamine-based ynamides. This strategy prevented
skeletons and was demonstrated by many pioneering works.[2]
For example, Hsung and co-workers developed an acid-
catalyzed Pictet-Spengler-type cyclization of arene-ynamides,
which represented one of the first applications of ynamides in
indole alkaloid synthesis.[2a] Yang and co-workers reported a
gold-catalyzed intramolecular consecutive annulation of indole-
ynamide to generate pyrrolidinoindoline by using alcohol as the
nucleophile to capture the indoleninium.[2b] Recently, Ye and co-
workers described a copper-catalyzed regioselectivity-reverse
cyclization of arene-ynamide[2c] (Scheme 1). Such examples of
tryptamine-derived ynamides cyclizations demonstrated that the
substrates and conditions (i.e. the substitutions, the nucleophiles,
the types of catalysts, etc.) had a profound influence on the
cyclization pathways. In this study, we intended to synthesize
1H-pyrrolo[2,3-d]carbazoles by applying tryptamine-derived
ynone substrates and to prevent Wagner-Meerwein
rearrangement by capturing the spirocyclic indoleninium
intermediate with in situ enolized ketone, which was promoted
by the conjugation with the nearby enamide, through an
intramolecular Mannich-type reaction via an acid-catalyzed
tandem cyclization.
Wagner-Meerwein
rearrangement
by
an
instantaneous
intramolecular nucleophilic trap to indoleninium via in situ formed
enol species induced by the formation of a more stable conjugate
diene moiety. The functional group tolerances were investigated by a
series of readily avalaible substrates. A plausible mechanism was
proposed based on the evidence of the capturing of the hemiaminal
intermediate. Lastly,
a Büchi ketone, which is the pivotal
intermediate in the synthesis of indole alkaloid vindorosine, was
synthesized by utilizing our newly developed methodology.
Introduction
Ynamides have acted as significant building blocks in organic
synthesis, and a number of synthetic methodologies on the
basis of ynamides have been developed in the past decade,
which afforded unique approaches to diverse structures.[1]
Among them, the metal- or acid-catalyzed cycloisomerization of
tryptamine-derived ynamide provided a straightforward and
atom-economical strategy to prepare polycyclic indoline
[a]
Y. Wang, J. Lin, X. Wang, G. Wang, X. Zhang, B. Yao, Y. Zhao,
Prof. Dr. B. Lin, Prof. Dr. Y. Liu, Prof. Dr. M. Cheng
Key Laboratory of Structure-Based Drug Design and Discovery,
Ministry of Education
Shenyang Pharmaceutical University
Shenyang 110016, P. R. China
E-mail: yongxiang.liu@syphu.edu.cn (Y. Liu)
mscheng@syphu.edu.cn (M. Cheng)
Y. Wang, J. Lin, X. Wang, G. Wang, X. Zhang, B. Yao, Y. Zhao, Dr.
B. Lin, Prof. Dr. Y. Liu, Prof. Dr. M. Cheng
Institute of Drug Research in Medicine Capital of China
Benxi, 117000, P. R. China
J. Lin, G. Wang, X. Zhang, Y. Zhao, Prof. Dr. Y. Liu
Wuya College of Innovation
Shenyang Pharmaceutical University
Shenyang 110016, P. R. China
[b]
[c]
[d]
Dr. P. Yu
State Key Laboratory of Hollow-fiber Membrane Materials and
Membrane Processes
School of Environmental and Chemical Engineering, Tianjin
Polytechnic University
Scheme 1. Tryptamine-derived ynamide cyclizations.
Tianjin 300387, P. R. China
The 1H-pyrrolo[2,3-d]carbazole scaffold was the core motif of
a series of monoterpene indole alkaloids, such as Kopsia[3a,3c,3d]
Supporting information for this article is given via a link at the end of
the document.
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Strychnos[3b-3e] and Aspidosperma[3c-3f] (Scheme 2).[3] The
Later on, the tedious functional group transformation from a p-
toluenesulfonyl (Ts) group to a methoxyl group had to be
performed to achieve the synthesis of
diverse
bioactivities[4]
(e.g.
adrenergic
blocking,[4a]
and
anticancer,[4b,4c] antiarrhythmic[4b,4c] and anti-malarial[4d]
)
intriguing molecular architectures of these indole alkaloids
rendered them highly attractive targets for synthesis.[5] A variety
of methodologies have been developed, especially in the
construction of the tetracyclic indoline core structure,[6] such as
Büchi's
Robinson-type
annulation,[6a]
Padwa’s
[4+2]-
cycloaddition/rearrangement,[6e] Macmillan’s organocascade
catalysis[6g] and Renaud’s cascade radical cyclization.[6h] Herein,
we proposed a new method giving access to the tetracyclic
indoline core structure based on ynamide chemistry, a field
booming in recent years (Scheme 3).
Scheme 2. 1H-pyrrolo[2,3-d]carbazole-containing indole alkaloids.
Results and Discussion
Scheme 3. Our tryptamine-based ynamide strategy and Büchi’s tryptamine-
based enamide strategy to tetracyclic indolines.
In the synthesis of the spiroindolines by the indoleninium
intermediate, the inherent tendency of C-C bond migration
through Wagner-Meerwein rearrangement to generate tricyclic
fused ring system was the chief problem. Numerous efforts have
been made to restrict such a high tendency to Wagner-
Meerwein rearrangement,[6a,7] such as employing strongly
nucleophilic intramolecular traps,[6a,7b] introducing electron-
deficient groups on the indole and aliphatic nitrogen,[7a,7c]
interrupting the Bischler-Napieralski reaction,[7d,7e] introducing
electron-withdrawing group to the alkenes, etc.[7f−7j] In this study,
we intended to prevent Wagner-Meerwein rearrangement by an
instantaneous intramolecular nucleophilic trap to indoleninium as
illustrated in Scheme 3a. In our strategy, the active
spiroindoleninium intermediate of tryptamine-based ynamide
would be trapped to afford a tetracyclic indoline by the easily in
situ generated enol species, whose formation was facilitated by
the presence of the enamide to produce a more stable conjugate
diene moiety, and the Wagner-Meerwein rearrangement was
prevented by the existence of the enone, which reduced the
migratory aptitude of the alkene through electronic effects
(Scheme 3a).[7f−7j] In contrast, in the absence of such an
enamide, Büchi and his colleagues had to resort to a detour
strategy by introducing an electron-withdrawing group (i.e. p-
toluenesulfonyl) at the indole 6-position in order to ensure the
formation of the tetracyclic system instead of a tricyclic product
derived from Meerwein-Wagner rearrangement (Scheme 3b).7a
vindoline. Therefore, on the basis of ynamide cycloisomerization,
we developed a unique and straightforward method to access
Büchi-ketone-like tetracyclic indoline scaffold.[8]
Firstly, we screened the reaction conditions for the cyclization
from ynesulfonamide substrate 1’ to 1H-pyrrolo[2,3-d]carbazole
2. This substrate could be prepared easily by a copper-catalyzed
coupling reaction of tryptamine derived sulfonamide with alkynyl
bromide and sequential deprotection/oxidation procedures (see
Supporting Information for the details).[9] In the condition
screening of the cyclizations, a variety of Brønsted acids,[3a,10]
including p-toluenesulfonic acid (TsOH), p-nitrobenzenesulfonic
acid
(PNBSA),
camphorsulfonic
acid
(CSA),
bis(trifluoromethanesulfonyl) imide (HNTf2) and diphenyl
phosphate (DPP) were examined, which led to the identification
of DPP as the optimal catalyst in catalyzing this transformation
(Table 1, entries 1-5). Decrease of reaction temperature to
−10 °C resulted in a much lower yield for the same reaction time
(Table 1, entry 6). When the reaction was performed at room
temperature, a similar yield was obtained (Table 1, entry 7).
Lowering the catalyst loading to 5 mol% gave a relatively lower
yield (Table1, entry 8) and increasing of the catalyst loading to
20 mol% gave no obvious elevation to yield (Table 1, entry 9).
As for the screening of solvents, several solvents such as
toluene, dichloromethane (DCM), 1,2-dichloroethane (DCE),
acetonitrile and tetrahydrofuran (THF) were examined, and DCM
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was found to be the best solvent (Table 1, entries 10-13). Finally,
the optimal conditions were determined as to stir the ketone in
dichloromethane (DCM) at 0 °C for 30 minutes at the catalysis of
10 mol% diphenyl phosphate (DPP).
To probe the mechanism of the tandem cyclizations, an
intermediate capture experiment was conducted by exposing the
substrate 1f’ into weak acid media silica gel, aiming to trap the
spiroindoleninium 1f’-1 intermediate by certain nucleophiles. To
our delight, water physisorbed in the silica gel could act as the
Table 1. Screening of cyclization conditions[a]
entry
catalyst
loading (mol%)
T (ºC )
solvent
yield (%)[b]
1
2
TsOH
PNBSA
CSA
10
10
10
10
10
10
10
5
0
0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
DCE
49
61
64
60
69
37
67
54
70
60
66
65
33
3
0
4
HNTf2
DPP
0
5
0
6
DPP
−10
23
0
7
DPP
8
DPP
9
DPP
20
10
10
10
10
0
Scheme 4. Substrate scopes of the tetracyclic indolines.
10
11
12
13
DPP
0
nucleophile to attack the spiroindoleninium to generate
isolatable intermediate hemiaminal 1f’-2. When the hemiaminal
1f’-2 was subjected to the standard acidic conditions, the
iminium ion moiety in 2f-1 was generated, which was then
captured by the in situ formed enol through an intramolecular
Mannich-type reaction to give the desired cyclization product 2f
(Scheme 5).
DPP
0
DPP
0
CH3CN
THF
DPP
0
[a] All reactions were carried out with 0.3 mmol of 1’ in 5.0 mL of solvent within
30 min. [b] Isolated yield.
During the condition screening, we found that the ketone
substrates were prone to decomposition in the isolation process.
To address this issue, a two-step procedure was developed by
performing the oxidation and tandem cyclizations in sequence
with only one isolation operation afterward. Next, the scopes of
this two-step transformation were examined with a variety of
substrates in Scheme 4. The substrates with electron-donating
substitutions on indoles gave better yields than those with
electron-withdrawing groups (Scheme 4, 2a-2e). The electron-
donating substitutions on the nitrogens of indoles were
necessary for the cyclization (Scheme 4, 2f-2h). The substrates
bearing 4-nitrobenzenesulfonyl (Ns) and methanesulfonyl (Ms)
groups on the nitrogens of tryptamines were tested, which
afforded similar results to those with Ts groups (Scheme 4, 2i-
2j). Substituents such as alkyl and phenyl on the α position of
ketone could be tolerated well in the reaction conditions to
provide satisfactory yields (Scheme 4, 2k-2l). The structures of
the tetracyclic indoline compounds were determined by 2D NMR
spectra and a single crystal X-ray diffraction of 2i.[11] The relative
stereochemistry of 2k-2l was confirmed by 2D NOE
spectroscopy (see Supporting Information for the details).
Scheme 5. Intermediate capture experiments.
Based on these experimental results, a plausible mechanism
was proposed in Scheme 6. Under the catalysis of a strong
Brønsted acid, the activation of carbonyl in 1f' by proton
promoted a Michael addition of indole to ynone, providing the
spiroindoleninium intermediate 1f’-1b followed by an
isomerization to afford 1f’-1. The following enolization of the
methyl ketone led to the formation of enol 2f-1, which underwent
a Mannich-type cyclization to generate 2f after a proton transfer
(Scheme 6). The structure of the intermediate 1f’-2 was
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determined by 2D NMR specra (see Supporting Information for
the details).
tandem cyclization was probed by capturing the reaction
intermediate. The applications of the methodology were
demonstrated by the formal synthesis of vindorosine on the
basis of the preparation of Büchi ketone intermediate. It is
expected that such
a
methodology should find broad
applications in the syntheses of various indole alkaloids with
diverse structures.
Experimental Section
General Procedures for the Preparation of Tetracyclic Indolines 2,
2a-2l
To a solution of substrates 1, 1a-1l (0.2 mmol) in DCM (3 mL) were
added 4 Å molecular sieves (30 mg) and NMO (35 mg, 0.30 mmol). The
mixture was stirred at 0 °C for 5 min and TPAP (14 mg, 0.04 mmol) was
added. The reaction was stirred at 0 °C for 30 min before filtered through
a plug of calcined Celite (rinsed with 10% ethyl acetate/n-hexane). The
filtrate was concentrated to give the crude ketone products, which were
dissolved in anhydrous DCM (2.5 mL) at 0 °C under a N2 atmosphere. A
solution of diphenyl phosphate (5.0 mg, 0.020 mmol) in anhydrous DCM
(0.2 mL) was added to the reaction mixture and the reaction was stirred
at 0 °C for 30 min before TEA was added to quench the reaction. The
solvents were removed in vacuo to give a residue, which was purified by
a flash column chromatography on silica gel to provide the products 2,
2a-2l.
Scheme 6. Proposed mechanism for the formation of tetracyclic indoline.
The methodology developed so far can be utilized to construct
important synthetic precursors for the syntheses of a number of
indole alkaloids after some functional group manipulations.[6] As
a demonstration, 2h was transformed into Büchi ketone (2h-2), a
key intermediate in the syntheses of many indole alkaloids such
as vindorosine[6a] after several facile functional group
transformations as depicted in Scheme 7.
3-Tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazol-5(6H)-one (2)
White solid (52 mg, 0.137 mmol, 69%); m.p. 231.0–232.8 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.94 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz,
2H), 6.99 (td, J = 7.8 Hz, 0.8, 1H), 6.64 (d, J = 7.8 Hz, 1H), 6.37 (t, J =
7.5 Hz, 1H), 5.91 – 5.88 (m, 3H), 4.05 (dd, J = 10.5, 8.4 Hz, 1H), 3.95 (dd,
J = 9.8, 6.2 Hz, 1H), 3.72 (td, J = 10.5, 5.4 Hz, 1H), 2.46 (s, 3H), 2.41 (dd,
J = 16.8, 6.2 Hz, 1H), 2.08 (td, J = 12.0, 8.4 Hz, 1H), 1.87 (dd, J = 16.8,
9.8 Hz, 1H), 1.82 (dd, J = 12.0, 5.4 Hz, 1H); 13C NMR (150 MHz,
[D6]DMSO) δ = 195.5, 159.6, 148.9, 145.7, 134.2, 130.6, 129.9, 128.7,
127.2, 121.7, 117.9, 111.1, 105.3, 62.5, 54.4, 48.8, 40.3, 34.8, 21.2; IR
(thin film, cm−1): 3438, 3328, 2954, 2924, 2854, 1733, 1640, 1620, 1463,
1359, 1204, 1168, 1056; HRMS (ESI) (m/z) [M+H]+: calcd. for
C21H21N2O3S 381.1267, found 381.1265.
7-Benzyl-10-methoxy-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2a)
White solid (88 mg, 0.176 mmol, 88%); m.p. 188.5–190.5 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.94 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz,
2H), 7.39 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.26 (t, J = 7.4 Hz,
1H), 6.60 (dd, J = 8.5, 2.5 Hz, 1H), 6.33 (d, J = 8.5 Hz, 1H), 5.99 (s, 1H),
5.39 (d, J = 2.5 Hz, 1H), 4.24 (d, J = 15.1 Hz, 1H), 4.10 – 4.06 (m, 2H),
3.95 (dd, J = 9.9, 5.9 Hz, 1H), 3.73 (td, J = 10.7, 5.6 Hz, 1H), 3.47 (s, 3H),
2.46 – 2.41 (m, 4H), 2.20 (td, J = 11.8, 8.4 Hz, 1H), 2.01 – 1.99 (m, 1H),
1.89 (dd, J = 16.7, 10.0 Hz, 1H); 13C NMR (150 MHz, [D6]DMSO) δ =
195.3, 159.3, 152.6, 146.0, 142.3, 138.2, 134.1, 132.2, 130.7, 128.5,
127.4, 127.1, 127.0, 112.8, 109.4, 109.3, 105.6, 67.5, 55.5, 53.7, 49.0,
48.8, 35.0, 34.3, 21.2; IR (thin film, cm−1): 3442, 2924, 2852, 1648, 1622,
1481, 1361, 1216, 1170, 1072, 1029; HRMS (ESI) (m/z) [M+H]+: calcd.
for C29H29N2O4S 501.1843, found 501.1848.
Scheme 7. Synthesis of Büchi ketone from tetracyclic indoline 2h.
Conclusions
In conclusion, an oxidation/Brønsted acid-catalyzed tryptamine-
derived ynesulfonamide-based tandem cyclizations strategy to
preparing tetracyclic indoline scaffolds has been developed,
which represents a unique and straightforward method to access
1H-pyrrolo[2,3-d]carbazoles. The plausible mechanism of this
7-Benzyl-10-chloro-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2b)
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White solid (72 mg, 0.143 mmol, 72%); m.p. 217.1–219.1 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.95 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz,
2H), 7.38 – 7.33 (m, 4H), 7.29 – 7.25 (m, 1H), 7.02 (dd, J = 8.4, 2.1 Hz,
1H), 6.41 (d, J = 8.4 Hz, 1H), 6.06 (s, 1H), 5.42 (d, J = 2.1 Hz, 1H), 4.32
(d, J = 15.3 Hz, 1H), 4.17 (d, J = 15.3 Hz, 1H), 4.09 – 4.01 (m, 2H), 3.67
(td, J = 10.5, 5.6 Hz, 1H), 2.53 (d, J = 6.0 Hz, 1H), 2.45 (s, 3H), 2.22 (td,
J = 11.8, 8.3 Hz, 1H), 2.03 – 1.97 (m, 1H), 1.90 (dd, J = 16.8, 9.9 Hz, 1H);
13C NMR (150 MHz, [D6]DMSO) δ = 195.0, 158.5, 147.1, 146.2, 137.7,
133.9, 132.9, 130.9, 128.63, 128.60, 127.4, 127.3, 126.9, 121. 4, 121.3,
110.1, 106.1, 67.3, 53.5, 48.6, 48.3, 35.5, 34.1, 21.4; IR (thin film, cm−1):
3443, 2952, 2923, 2853, 1651, 1620, 1473, 1358, 1203, 1167, 1079,
1054; HRMS (ESI) (m/z) [M+Na]+: calcd. for C28H27ClN2NaO3S 527.1167,
found 527.1151.
2170, 1697, 1650, 1622, 1491, 1454, 1358, 1254, 1168, 1073; HRMS
(ESI) (m/z) [M+H]+: calcd. for C29H29N2O4S 501.1843, found 501.1841.
7-Benzyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazol-5
(6H)-one (2f)
White solid (80 mg, 0.170 mmol, 85%); m.p. 165.8–167.5 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.95 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz,
2H), 7.41 – 7.32 (m, 4H), 7.28 – 7.25 (m, 1H), 7.01 (t, J = 7.5 Hz, 1H),
6.43 (d, J = 7.5 Hz, 1H), 6.40 (t, J = 7.3 Hz, 1H), 5.93 (s, 1H), 5.87 (d, J =
7.3 Hz, 1H), 4.33 (d, J = 15.3 Hz, 1H), 4.16 (d, J = 15.3 Hz, 1H), 4.07 (dd,
J = 9.8, 8.4 Hz, 1H), 3.99 (dd, J = 9.8, 6.0 Hz, 1H), 3.74 (td, J = 10.7, 5.5
Hz, 1H), 2.46 (s, 3H), 2.16 (td, J = 12.0, 8.4 Hz, 1H), 1.98 (dd, J = 12.0,
5.5 Hz, 1H), 1.88 (dd, J = 16.7, 9.8 Hz, 1H); 13C NMR (150 MHz,
[D6]DMSO) δ = 195. 1, 159.4, 148.2, 145.8, 138.1, 134.1, 130.8, 130.6,
128.9, 128.5, 127.4, 127.2, 127.1, 121.4, 118.0, 109.0, 105.4, 67.0, 53.4,
48.8, 48.3, 35.4, 34.5, 21.1; IR (thin film, cm−1): 3444, 2924, 2852, 1651,
1622, 1475, 1454, 1356, 1257, 1204, 1165; HRMS (ESI) (m/z) [M+Na]+:
calcd. for C28H26N2NaO3S 493.1556, found 493.1555.
7-Benzyl-10-bromo-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2c)
White solid (82 mg, 0.149 mmol, 75% yield); m.p. 231.0–232.3 °C; 1H
NMR (600 MHz, [D6]DMSO) δ = 7.95 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2
Hz, 2H), 7.37 – 7.33 (m, 4H), 7.27 (t, J = 6.7 Hz, 1H), 7.15 (dd, J = 8.4,
1.9 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 5.62 (d, J = 1.8 Hz,
1H), 4.32 (d, J = 15.3 Hz, 1H), 4.17 (d, J = 15.3 Hz, 1H), 4.11 – 4.00 (m,
2H), 3.67 (td, J = 10.7, 5.5 Hz, 1H), 2.53 (d, J = 6.0 Hz, 1H), 2.46 (s, 3H),
2.23 (dt, J = 11.7, 8.4 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.90 (dd, J = 16.8,
9.9 Hz, 1H); 13C NMR (150 MHz, [D6]DMSO) δ = 195.0, 158.5, 147.5,
146.2, 137.7, 133.9, 133.4, 131.5, 131.0, 128.6, 127.4, 127.3, 126.9,
123.9, 110.7, 108.8, 106.0, 67.2, 53.6, 48.6, 48.3, 35.5, 34.2, 21.5; IR
(thin film, cm−1): 3425, 3025, 2952, 2888, 2854, 1644, 1620, 1467, 1358,
1243, 1188, 1169, 1092, 1067, 1035; HRMS (ESI) (m/z) [M+Na]+: calcd.
for C28H25BrN2NaO3S 571.0661, found 571.0638.
7-(4-Methoxybenzyl)-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2g)
White solid (97 mg, 0.194 mmol, 97%); m.p. 138.9–140.0 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.95 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz,
2H), 7.32 (d, J = 8.4 Hz, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 8.4 Hz,
2H), 6.49 (d, J = 7.7 Hz, 1H), 6.40 (t, J = 7.3 Hz, 1H), 5.94 (s, 1H), 5.86
(d, J = 7.3 Hz, 1H), 4.30 (d, J = 14.8 Hz, 1H), 4.08 – 4.04 (m, 2H), 3.94
(dd, J = 9.9, 6.0 Hz, 1H), 3.74 (s, 4H), 2.49 – 2.43 (m, 4H), 2.17 – 2.12
(m, 1H), 1.96 (dd, J = 11.9, 5.3 Hz, 1H), 1.88 (dd, J = 16.7, 9.9 Hz, 1H);
13C NMR (150 MHz, [D6]DMSO) δ = 195.1, 159.5, 158.4, 148.2, 145.7,
134.1, 130.8, 130.6, 129.6, 128.8, 128.7, 127.2, 121.3, 118.0, 113.9, 109.
0, 105.4, 66.8, 55.0, 53.4, 48.8, 47.7, 35.4, 34.5, 21.1; IR (thin film, cm−1):
3441, 2899, 1625, 1517, 1475, 1347, 1258, 1215, 1161; HRMS (ESI)
(m/z) [M+Na]+: calcd. for C29H28N2NaO4S 523.1662, found 523.1665.
7-Methyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazol-5(6H)-
one (2h)
White solid (58 mg, 0.147 mmol, 73%); m.p. 173.1–175.0 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.95 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz,
2H), 7.07 (td, J = 7.7, 1.2 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.40 (td, J =
7.5, 0.8 Hz, 1H), 5.93 (s, 1H), 5.85 (dd, J = 7.5, 0.8 Hz, 1H), 4.06 (dd, J =
10.2, 8.4 Hz, 1H), 4.00 (dd, J = 9.9, 6.0 Hz, 1H), 3.72 (td, J = 10.2, 5.6
Hz, 1H), 2.66 (s, 3H), 2.49 – 2.44 (m, 4H), 2.12 (td, J = 12.0, 8.4 Hz, 1H),
1.85 (dd, J = 12.0, 5.6 Hz, 1H), 1.74 (dd, J = 16.7, 9.9 Hz, 1H); 13C NMR
(150 MHz, [D6]DMSO) δ = 195.3, 159.4, 149.0, 145.8, 134.1, 130.60,
130.57, 129.0, 127.2, 121.2, 117.9, 108.7, 105.5, 68.4, 53.4, 48.8, 34.62,
34.60, 31.4, 21.1; IR (thin film, cm−1): 2959, 2923, 2896, 1648, 1619,
1477, 1359, 1255, 1169; HRMS (ESI) (m/z) [M+Na]+: calcd. for
C22H22N2NaO3S 417.1243, found 417.1254.
7-Benzyl-9-methyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2d)
White solid (81 mg, 0.167 mmol, 84%); m.p. 186.0–187.7 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.93 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz,
2H), 7.38 – 7.33 (m, 4H), 7.26 (t, J = 7.2 Hz, 1H), 6.28 (s, 1H), 6.21 (d, J
= 7.2 Hz, 1H), 5.92 (s, 1H), 5.74 (d, J = 7.5 Hz, 1H), 4.33 (d, J = 15.3 Hz,
1H), 4.12 (d, J = 15.3 Hz, 1H), 4.05 (dd, J = 10.4, 8.3 Hz, 1H), 3.94 (dd, J
= 9.8, 6.0 Hz, 1H), 3.71 (td, J = 10.4, 5.5 Hz, 1H), 2.49 – 2.44 (m, 4H),
2.15 – 2.09 (m, 4H), 1.94 (dd, J = 11.9, 5.5 Hz, 1H), 1.88 (dd, J = 16.7,
9.8 Hz, 1H); 13C NMR (150 MHz, [D6]DMSO) δ = 195.2, 159.6, 148.4,
145.8, 138.4, 138.1, 134.1, 130.6, 128.6, 128.1, 127.4, 127.2, 127.1,
121.1, 118.6, 109.7, 105.3, 67.0, 53.2, 48.9, 48.2, 35.5, 34.6, 21.3, 21.2;
IR (thin film, cm−1): 3437, 2955, 2922, 2853, 1650, 1623, 1456, 1382,
1360, 1207, 1169, 1076; HRMS (ESI) (m/z) [M+Na]+: calcd. for
C29H28N2NaO3S 507.1713, found 507.1709.
7-Benzyl-9-methoxy-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2e)
White solid (90 mg, 0.180 mmol, 90%); m.p. 182.6–183.7 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.94 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz,
2H), 7.38 – 7.34 (m, 4H), 7.27 (t, J = 7.1 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H),
5.93 (dd, J = 8.1, 2.2 Hz, 1H), 5.89 (s, 1H), 5.80 (d, J = 8.1 Hz, 1H), 4.36
(d, J = 15.2 Hz, 1H), 4.13 (d, J = 15.2 Hz, 1H), 4.07 – 4.04 (m, 1H), 3.95
(dd, J = 9.8, 6.0 Hz, 1H), 3.72 (td, J = 10.5, 5.5 Hz, 1H), 3.59 (s, 3H),
2.48 (d, J = 10.5 Hz, 1H), 2.46 (s, 3H), 2.11 (td, J = 11.9, 8.3 Hz, 1H),
1.95 (dd, J = 11.9, 5.5 Hz, 1H), 1.90 (dd, J = 16.7, 9.8 Hz, 1H); 13C NMR
(150 MHz, [D6]DMSO) δ = 195.1, 160.6, 159.6, 149.7, 145.7, 138.0,
134.1, 130.6, 128.5, 127.4, 127.2, 123.3, 121.8, 105.2, 102.0, 96.4, 67.2,
55.0, 52.8, 48.8, 48.1, 35.7, 34.7, 21.1; IR (thin film, cm−1): 3425, 2924,
7-Benzyl-3-((4-nitrophenyl)sulfonyl)-2,3,6a,7-tetrahydro-1H-pyrrolo
[2,3-d]carbazol-5(6H)-one (2i)
Yellow solid (74 mg, 0.147 mmol, 74%); m.p. 181.7–182.7 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 8.51 (d, J = 8.8 Hz, 2H), 8.36 (d, J = 8.8 Hz,
2H), 7.39 – 7.38 (m, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H),
7.04 (t, J = 7.7 Hz, 1H), 6.48 (dd, J = 15.5, 7.7 Hz, 2H), 6.16 (d, J = 7.3
Hz, 1H), 5.93 (s, 1H), 4.36 (d, J = 15.2 Hz, 1H), 4.19 – 4.11 (m, 2H), 4.00
(dd, J = 9.8, 5.9 Hz, 1H), 3.86 (td, J = 10.8, 5.6 Hz, 1H), 2.52 – 2.49 (m,
1H), 2.19 (td, J = 12.0, 8.6 Hz, 1H), 2.03 (dd, J = 12.0, 5.6 Hz, 1H), 1.93
(dd, J = 16.6, 9.8 Hz, 1H); 13C NMR (150 MHz, [D6]DMSO) δ = 195.1,
158.9, 151.0, 148.2, 141.9, 138. 0, 130.5, 129.0, 128.6, 127.4, 127.2,
125.3, 121.3, 118.2, 109.0, 105.9, 66.9, 53.4, 49.2, 48.3, 35.5, 34.6; IR
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10.1002/chem.201705189
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(thin film, cm−1): 3450, 3104, 2925, 2853, 1652, 1624, 1532, 1476, 1382,
1351, 1202, 1172; HRMS (ESI) (m/z) [M+H]+: calcd. for C27H24N3O5S
502.1431, found 502.1433.
DCM (2 mL) and silica gel (2.35 g, 200-300 mesh) was added. The
solvent was removed in vacuo to afford yellow powder, then it was added
H2O (45 mg, 2.5 mmol) and stirred vigorously at room temperature for 2 h.
TLC monitored the reaction till all the starting materials disappeared. The
powder was filtered, rinsed with ethyl acetate. The filtrate was
concentrated to a residue, which was recrystallized with n-hexane/ethyl
acetate (5:1) to provide the product 1f’-2 as a yellow solid (183 mg, 0.375
7-Benzyl-3-(methylsulfonyl)-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2j)
White solid (62 mg, 0.157 mmol, 79%); m.p. 159.3–161.3 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.43 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz,
2H), 7.28 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.1 Hz,
1H), 6.74 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 5.80 (s, 1H), 4.40
(d, J = 15.2 Hz, 1H), 4.22 (d, J = 15.2 Hz, 1H), 4.06 – 4.00 (m, 2H), 3.81
(td, J = 10.8, 5.5 Hz, 1H), 3.40 (s, 3H), 2.53 (dd, J = 16.5, 6.0 Hz, 1H),
2.23 (dt, J = 11.5, 8.7 Hz, 1H), 2.05 (dd, J = 11.5, 5.5 Hz, 1H), 1.99 (dd, J
= 16.5, 9.9 Hz, 1H); 13C NMR (150 MHz, [D6]DMSO) δ = 195.0, 160.0,
148.2, 138.1, 130.6, 129.0, 128.6, 127.4, 127.2, 122.0, 118.5, 108.9,
104.4, 67.2, 53.5, 48.5, 48.4, 38.1, 35.5, 35.2; IR (thin film, cm−1): 3441,
2957, 2923, 1619, 1476, 1453, 1384, 1354, 1205, 1167; HRMS (ESI)
(m/z) [M+H]+: calcd. for C22H23N2O3S 395.1424, found 395.1424.
7-Benzyl-6-propyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2k)
1
mmol, 78%); m.p. 126.7–127.5 °C; H NMR (600 MHz, CDCl3) δ = 7.76
(d, J = 8.3 Hz, 2H), 7.33 – 7.27 (m, 6H), 7.25 – 7.22 (m, 1H), 7.03 (td, J =
7.7, 1.2 Hz, 1H), 6.89 (s, 1H), 6.79 (dd, J = 7.4, 0.9 Hz, 1H), 6.62 (td, J =
7.4, 0.7 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 6.08 (d, J = 12.2 Hz, 1H), 4.52
(dd, J = 82.2, 16.2 Hz, 2H), 4.43 (d, J = 12.2 Hz, 1H), 4.13 (dd, J = 9.9,
8.0 Hz, 1H), 3.54 (ddd, J = 12.1, 10.0, 5.7 Hz, 1H), 2.43 (s, 3H), 2.16 (dd,
J = 13.0, 5.6 Hz, 1H), 2.10 – 2.05 (m, 1H), 2.05 (s, 3H); 13C NMR (150
MHz, CDCl3) δ = 200.2, 155.6, 149.1, 145.3, 138.9, 133.9, 130.0, 129.2,
128.8, 128.6, 127.7, 127.2, 127.1, 121.3, 118.0, 108.6, 106.3, 92.2, 62.7,
48.7, 46.9, 36.2, 30.8, 21.9; IR (thin film, cm−1): 3421, 3027, 2923, 1661,
1582, 1493, 1455, 1383, 1351, 1230, 1166, 1149, 1093, 1058; HRMS
(ESI) (m/z) [M+K]+: calcd. for C28H28KN2O4S 527.1401, found 527.1390.
(7-Benzyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazol-5
(6H)-one (2f)
White solid (83 mg, 0.162 mmol, 81%); m.p. 204.6–205.8 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.92 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz,
2H), 7.35 – 7.23 (m, 5H), 6.95 (td, J = 7.8 Hz, 1.1, 1H), 6.39 (d, J = 7.8
Hz, 1H), 6.34 (td, J = 7.5, 1.1 Hz, 1H), 6.07 (d, J = 7.5 Hz, 1H), 5.81 (s,
1H), 4.56 (d, J = 15.8 Hz, 1H), 4.30 (d, J = 15.8 Hz, 1H), 4.11 (t, J = 9.6
Hz, 1H), 3.87 (td, J = 10.8, 6.0 Hz, 1H), 3.82 (d, J = 5.3 Hz, 1H), 2.44 (s,
3H), 2.16 (dt, J = 7.3, 5.0 Hz, 1H), 2.08 (dt, J = 11.4, 9.0 Hz, 1H), 2.00
(dd, J = 12.2, 6.0 Hz, 1H), 1.49 (ddt, J = 13.4, 10.8, 5.0 Hz, 1H), 1.25 –
1.16 (m, 1H), 1.08 – 1.02 (m, 1H), 1.01 – 0.92 (m, 1H), 0.69 (t, J = 7.3 Hz,
3H); 13C NMR (150 MHz, [D6]DMSO) δ = 198.4, 157.9, 148.1, 145.6,
138.2, 133.8, 132.6, 130.4, 128.9, 128.5, 127.4, 127.3, 127.2, 121.6,
117.4, 108.1, 103.3, 68.9, 54.0, 49.7, 49.1, 47.7, 35.7, 32.9, 21.1, 19.2,
14.0; IR (thin film, cm−1): 3438, 3289, 3089, 3051, 2956, 2924, 2858,
1726, 1652, 1629, 1596, 1482, 1456, 1355, 1299, 1165, 1089; HRMS
(ESI) (m/z) [M+Na]+: calcd. for C31H22N2NaO3S 535.2026, found
535.2023.
1f’-2 (98 mg, 0.20 mmol) was dissolved in anhydrous DCM (2 mL) at
0 °C under a N2 atmosphere. A solution of diphenyl phosphate (5 mg,
0.02 mmol) in anhydrous DCM (0.2 mL) was added to the reaction
mixture and the reaction was stirred at 0 °C for 10 min before TEA was
added to quench the reaction. The solvents were removed in vacuo to
give a residue, which was purified by a flash column chromatography
(petroleum ether/ethyl acetate = 5:1) on silica gel to provide the products
2f as a white solid (86 mg, 0.183 mmol, 92%).
Synthesis of Büchi Ketone
3-Acetyl-7-methyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazol-5
(6H)-one (2h-1)
Preparation of sodium naphthalenide solution: To
a solution of
naphthalene (256 mg, 2.00 mmol) in anhydrous THF (10 mL) was added
freshly cut sodium pieces (92 mg, 4.0 mmol). The mixture was sonicated
at room temperature for 20 min with occasional swirling to afford a dark
green solution of sodium naphthalenide (0.2 M) in THF.
7-Benzyl-6-phenyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]
carbazol-5(6H)-one (2l)
White solid (91 mg, 0.166 mmol, 83%); m.p. 109.0–110.9 °C; 1H NMR
(600 MHz, [D6]DMSO) δ = 7.99 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz,
2H), 7.31 – 7.26 (m, 3H), 7.20 – 7.10 (m, 5H), 6.99 (dd, J = 12.0, 4.3 Hz,
1H), 6.93 (d, J = 7.0 Hz, 2H), 6.38 – 6.36 (m, 2H), 6.05 (s, 1H), 5.87 (d, J
= 7.4 Hz, 1H), 4.45 (d, J = 8.5 Hz, 1H), 4.11 (dd, J = 10.1, 8.5 Hz, 1H),
4.05 (d, J = 15.7 Hz, 1H), 3.74 (td, J = 10.7, 5.6 Hz, 1H), 3.45 (d, J = 15.7
Hz, 1H), 3.33 (d, J = 8.5 Hz, 1H), 2.48 (s, 3H), 2.32 (td, J = 11.8, 8.5 Hz,
1H), 1.93 (dd, J = 11.8, 5.5 Hz, 1H); 13C NMR (150 MHz, [D6]DMSO) δ =
195.4, 158.6, 147.2, 145.8, 139.9, 138.1, 134.1, 131.0, 130.6, 129.9,
129.0, 128.30, 128.28, 127.3, 127.0, 126.8, 126.7, 121.2, 117.2, 107.9,
105.0, 73.4, 54.4, 54.0, 48.9, 48.5, 34.9, 21.2; IR (thin film, cm−1): 3424,
3028, 2923, 2854, 1654, 1628, 1601, 1478, 1452, 1383, 1360, 1166;
HRMS (ESI) (m/z) [M+Na]+: calcd. for C34H30N2NaO3S 569.1869, found
569.1859.
To a solution of 2h (100 mg, 0.253 mmol) in anhydrous THF (10 mL) was
added the freshly prepared sodium naphthalenide solution dropwise at –
78 °C with swirling until the dark green color persisted (4 mL, 0.8 mmol).
After confirmation of completion by TLC (30 min after dark green
persistence), MeOH (1 mL) was added to quench the reaction and the
mixture warmed to room temperature over 30 min. The mixture was
concentrated in vacuo to afford the crude product, which was used
without further purification.
To a stirred solution of the crude product obtained above in DCM (10 mL)
was added Et3N (0.17 mL, 1.3 mmol) at 0 °C followed by the addition of
Ac2O (0.090 mL, 0.95 mmol) in one portion. The mixture was warmed to
room temperature. After 5 h, H2O (2 mL) was added to the mixture and it
was extracted with DCM (20 mL x 3). The combined organic layers were
washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by a flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to
afford 2h-1 as a white solid (60 mg, 0.213 mmol, 84% yield); m.p. 178.8–
179.6 °C; 1H NMR (600 MHz, [D6]DMSO) δ = 7.16 (t, J = 7.6 Hz, 1H),
7.01 (d, J = 7.2 Hz, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H),
6.56 (s, 1H), 4.04 (dd, J = 10.0, 6.0 Hz, 1H), 4.01 – 3.97 (m, 1H), 3.85 (td,
Intermediate Capture Experiment
(E)-1-(1-Benzyl-2-hydroxy-1'-tosylspiro[indoline-3,3'-pyrrolidin]-2'-
ylidene)propan-2-one (1f’-2)
The ketone product 1f’ were prepared from substrates 1f (235 mg, 0.481
mmol) according to the general procedure described in the synthesis of
tetracyclic indolines 2, 2a-2l. The ketone product 1f’ was dissolved in
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10.1002/chem.201705189
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2015, 48, 59−70; g) G. Evano, N Blanchard, G. Compain, A. Coste, C.
Zhang, Chem. Lett. 2016, 45, 574−585; h) F. Pan, C. Shu, L.-W. Ye,
Org. Biomol. Chem. 2016, 14, 9456−9465; i) G. Evano, B. Michelet, C.
Zhang, C. R. Chimie 2017, 20, 648−664.
J = 10.9, 5.8 Hz, 1H), 2.73 (s, 3H), 2.53 (m, 1H), 2.33 (s, 3H), 2.14 (td, J
= 11.7, 8.7 Hz, 1H), 1.92 – 1.85 (m, 2H); 13C NMR (150 MHz, [D6]DMSO)
δ = 197.0, 171.3, 159.9, 149.1, 131.1, 129.0, 122.1, 118.2, 108.8, 108.5,
68.7, 52.8, 47.5, 35.2, 35.0, 31.4, 24.9; IR (thin film, cm−1): 3732, 3421,
2928, 2311, 1692, 1650, 1632, 1606, 1481, 1388, 1313, 1270, 1208,
1179, 1127, 1009; HRMS (ESI) (m/z) [M+Na]+: calcd. for C17H18N2NaO2
305.1260, found 305.1272.
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Chen, Z.-S. Wang, B. Zhou, X. Liu, X. Lu, L.-W. Ye, ACS Catal. 2017, 7,
4004−4010.
3-Acetyl-7-methyl-2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3-d]carbazol
-5(6H)-one (2h-2)
a) T. Sévenet, L. Allorge, B. David, K. Awang, A. Hamid A. Hadi, C.
Kan-Fan, J.-C. Quirion, F. Remy, H. Schaller, L. E. Teo, J.
Ethnopharmacol. 1994, 41, 147−183; b) J. Bosch, J. Bonjoch, M. Amat,
in The Alkaloids, Vol. 48 (Ed.: G. A. Cordell), Academic Press, New
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559−590; d) J. Leonard, Nat. Prod. Rep. 1999, 16, 319−338; e) S. E.
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Gribble, J. A. Joule), Pergamon Press, Oxford, 2011, pp. 1−25.
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Madsen, J. Pharm. Biomed. Anal. 1994, 12, 1283−1287; b) J. E. Saxton,
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378−386.
In a round-bottomed flask, 2h-1 (50 mg, 0.18 mmol) was dissolved in
methanol (4 mL) and ethyl acetate (1 mL) at room temperature. Pd/C (38
mg, 0.036 mmol, palladium 10% on carbon) was added and the space
above the solution was purged with nitrogen to remove the air. The
reaction was stirred under a hydrogen atmosphere (hydrogen balloon) at
room temperature for 12 h. The Pd catalyst was removed via filtration
through a plug of silica gel. The filtrate was concentrated under reduced
pressure, and the residue was chromatographed on silica gel (petroleum
ether/acetone = 4:1) to afford 2h-2 as a white solid (42 mg, 0.148 mmol,
82% yield); m.p. 189.2–190.6 °C; 1H NMR (600 MHz, [D6]DMSO) δ =
7.16 (d, J = 7.3 Hz, 1H), 7.11 (td, J = 7.8, 1.0 Hz, 1H), 6.72 (t, J = 7.4 Hz,
1H), 6.59 (d, J = 7.8 Hz, 1H), 3.88 (dd, J = 5.2, 4.1 Hz, 1H), 3.82 – 3.77
(m, 1H), 3.72 (dt, J = 10.3, 7.4 Hz, 1H), 3.60 (t, J = 3.8 Hz, 1H), 2.94 (dd,
J = 16.9, 5.7 Hz, 1H), 2.67 – 2.64 (m, 5H), 2.45 (dt, J = 12.6, 9.1 Hz, 1H),
2.22 – 2.14 (m, 2H), 2.00 (s, 3H); 13C NMR (150 MHz, [D6]DMSO) δ =
208.2, 169.2, 152.2, 132.3, 128.7, 122.6, 118.7, 108.2, 70.3, 62.8, 51.7,
46.5, 39.1, 36.2, 33.3, 23.1; IR (thin film, cm−1): 3416, 2976, 2960, 2926,
2895, 2865, 1714, 1647, 1602, 1486, 1404, 1340, 1231, 1202, 1181,
1109; HRMS (ESI) (m/z) [M+Na]+: calcd. for C17H20N2NaO2 307.1417,
found 307.1431.
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Acknowledgements
This work was supported by the Natural Science Foundation of
Liaoning Province of China (No. 20170540855) and Municipal
Natural Science Foundation of Tianjin of China (No.
15JCQNJC13900). We acknowledged the program for
innovative research team of the Ministry of Education and the
program for Liaoning innovative research team in university.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: Büchi ketone • cyclization • synthetic methods •
tetracyclic indoline • tryptamine-ynamide
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A two-step
Y. Wang, J. Lin, X. Wang,
G. Wang, X. Zhang, B. Yao,
Y. Zhao, P. Yu, B. Lin, Y.
Liu,* M. Cheng*
transformation for
the synthesis of 1H-
pyrrolo[2,3-
d]carbazole
Page No. – Page No.
derivatives from
tryptamine-based
ynamides was
developed and
applied to the formal
synthesis of
Brønsted Acid-Catalyzed
Tandem Cyclizations of
Tryptamine-Ynamides
Yielding 1H-Pyrrolo[2,3-
d]carbazole Derivatives
vindorosine.
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