Atom-Economic Synthesis of Pentaleno[2,1-b]indoles via Tandem Cyclization of Alkynones Initiated by Aminopalladation

Article abstract of DOI:10.1021/acs.joc.6b02817

An atom-economic Pd(OAc)₂-catalyzed tandem cyclization of alkynones to synthesize pentaleno[2,1-b]indoles was developed efficiently. In the formed tetracyclic indole framework, two neighboring stereocenters, one being all-carbon quaternary, are being constructed in a single process with excellent diastereoselectivity. This reaction was initiated by aminopalladation of alkynes and quenched by addition to the intramolecular carbonyl groups.

Full text of DOI:10.1021/acs.joc.6b02817

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Article
An Atom-Economic Synthesis of Pentaleno[2,1-b]indoles via
Tandem Cyclization of Alkynones Initiated by Aminopalladation
Junjie Chen, Xiuling Han, and Xiyan Lu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02817 • Publication Date (Web): 14 Jan 2017
Downloaded from http://pubs.acs.org on January 15, 2017
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An Atom-Economic Synthesis of Pentaleno[2,1-b]indoles via
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Tandem Cyclization of Alkynones Initiated by Aminopalladation
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Junjie Chen, Xiuling Han* and Xiyan Lu*
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State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China
ABSTRACT:
An atomꢀeconomic Pd(OAc)2ꢀcatalyzed tandem cyclization of alkynones to
synthesize pentaleno[2,1ꢀb]indoles was developed efficiently. In the formed
tetracyclic indole framework, two neighboring stereocenters, one being allꢀcarbon
quaternary, are being constructed in
a
single process with excellent
diastereoselectivity. This reaction was initiated by aminopalladation of alkynes and
quenched by addition to the intramolecular carbonyl groups.
INTRODUCTION
As an important structural unit widely found in heterocyclic compounds with
biological and medicinal applications, indoles, including cyclopenta[b]indoles, have
attracted much attention from organic as well as pharmaceutical chemists.1,2 As a
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result, various synthetic protocols have been developed to prepare this heterocyclic
skeletons.3,4 Among which, transitionꢀmetalꢀcatalyzed intramolecular cyclization of
2ꢀalkynylanilines is an established synthetic strategy due to the availability of starting
materials, tolerance for functional groups and mild reaction conditions.3d,5 The
success for these reactions lies in that the alkyne in 2ꢀalkynylanilines can be activated
by transition metals and then attacked by an intramolecular amino group easily.
Among the transition metals, palladium is one of the most often used metal and has
proven to be powerful for the synthesis of indoles.6 However, for all of these methods
established in the literature, examples to cyclopenta[b]indoles catalyzed by palladium
from 2ꢀalkynylanilines have not been reported.7
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Cascade cyclization sequences offer efficient routes for the expeditious assembly of
polycyclic products.8 The advantages for which include atom and synthetic step
economy, reduction of workup and purification, as well as minimization of wastes.
Especially, palladiumꢀcatalyzed cascade cyclization reactions have proven to be much
effective for construction of such compounds.9 In addition, our group has been
devoted to palladium(II)ꢀcatalyzed redoxꢀneutral reactions initiated by
nucleopalladation of alkynes for years.10 Recently, we developed
palladium(II)ꢀcatalyzed tandem cyclizations of alkynones or alkynenitriles initiated by
oxypalladation or aminopalladation and quenched by addition to carbonyl or cyano
group which provided convenient ways for the preparation of annulated isocoumarins,
naphthylamines and indoles, respectively (Scheme 1, equations aꢀc).11 As a
continuation of the work focused on Pd(II)ꢀcatalyzed tandem cyclization reactions, we
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report here a Pd(OAc)2ꢀcatalyzed cyclization of alkynones to synthesize
cyclopenta[b]indoles initiated by aminopalladation of alkynes (Scheme 1, equation d).
Scheme 1. Nucleopalladation Initiated Tandem Cyclization Developed in Our
Group
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RESULTS AND DISCUSSION
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In our previous study on aminopalladation initiated tandem cyclization of
alkynenitriles, it was found when a substrate bearing a cyclopentanone unit was
subjected to the reaction conditions, an addition to the carbonyl group occurred
preferentially to give a special cyclopenta[b]indole, pentaleno[2,1ꢀb]indole (Scheme
2).11c In the formed compound, two neighboring stereocenters, one being allꢀcarbon
quaternary, is being constructed in a single process with excellent diastereoselectivity.
Comparing to lots of methods for the synthesis of functionalized cyclopenta[b]indoles,
there are few examples for the synthesis of pentaleno[2,1ꢀb]indoles.12 Therefore, we
decided to use 2ꢀalkynylanilines which contain a cyclopentanone unit as substrates to
synthesize functionalized pentaleno[2,1ꢀb]indoles.
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Scheme 2. Initial Finding
First, a similar substrate 1a was chosen as the model to screen the reaction
conditions (Table 1). The reaction did not occur under the catalysis of
o
Pd(OAc)2/bipyridine at 100 C without additives (entry 1). When sodium phosphate
was added, only indole 3a was formed (entry 2). Subsequent screening showed that
the addition of acids was beneficial to the tandem cyclization, especially acetic acid,
giving the expected product pentaleno[2,1ꢀb]indole 2a successfully (entries 3ꢀ6).13
Then the effect of ligand was surveyed. Both 4,4’ꢀdinitroꢀbpy and
4,4’ꢀdimethoxyꢀbpy gave lower yields in contrast to bpy, and 1,10ꢀphenanthroline did
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not improve the reaction either (entries 7ꢀ9). The reaction became complicated under
the catalysis of Pd(COOCF3)2 or PdCl2 (entries 10 and 11). The catalyst
Pd(CH3CN)4(BF4)2 was also inferior to Pd(OAc)2, affording the product in a low yield
(entry 12). Performing the reaction at a lower or higher temperature resulted in
slightly lower yields of 2a (entries 13 and 14). The investigation of the solvents
revealed that THF gave a same yield as dioxane, and others such as DCE, toluene,
DME, DMF and CH3CN were less effective (entries 15ꢀ20). Without the catalyst, no
reaction occurred (entry 21). Finally, it was found that the addition of water can
improve this transformation to 80% yield (entry 22). It was worth noting that more or
less byproduct 3a was observed in above screened reactions and it cannot be
completely inhibited. AuPPh3Cl and PtCl2 were also used as the catalyst in the
reaction. For the catalyst AuPPh3Cl, only byproduct 3a was formed; When PtCl2 was
used as the catalyst, no reaction occurred.
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Table 1. Screening the Conditions for the Synthesis of 2aa
entry
catalyst
ligand
bpy
solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
T (oC)/t (h)
100 (10)
100 (4.0)
100 (1.5)
100 (6.5)
100 (1.0)
100 (1.5)
100 (20)
100 (3.5)
100 (15)
additives
/
2a (%)
trace
67 (3a)
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Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
bpy
Na3PO4
TsOH
PhCO2H
TFA
bpy
bpy
67
bpy
29
bpy
HOAc
HOAc
HOAc
HOAc
72
4ꢀNO2ꢀbpy
4ꢀOMeꢀbpy
1,10ꢀPhenb
27
66
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Pd(COOCF3)2
PdCl2
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
100 (1.5)
100 (1.5)
100 (4.0)
80 (6.5)
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc+H2O
complicated
complicated
Pd(CH3CN)4(BF4)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
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120 (1.0)
100 (4.0)
100 (4.0)
100 (2.0)
100 (2.0)
100 (1.0)
100 (3.5)
100 (10)
100 (1.5)
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toluene
THF
47
73
DME
45
DMF
66
49
CH3CN
dioxane
dioxane
no reaction
80
Pd(OAc)2
aReaction conditions: 1a (0.2 mmol, 1.0 equiv), catalyst (5 mol %), ligand (10 mol %)
and additives (For entries 2ꢀ5, 2 equiv of the additive was added; For entries 6ꢀ21,
0.25 mL of HOAc was added; For entry 22, 0.25 mL of HOAc and 0.25 mL of H2O
were added.) were dissolved in solvent (2 mL) as shown in the table, the mixture was
o
b
stirred at 100 C until the consumption of 1a as monitored by TLC. 1,10ꢀphen =
1,10ꢀ phenanthroline.
With the optimized conditions (Table 1, entry 22) in hand, substrate generality was
examined for the synthesis of functionalized pentaleno[2,1ꢀb]indoles (Table 2). To
our delight, the reaction showed broad substrate scope and furnished the desired
products 2bꢀ2o in good yields. Substrates with electronꢀdonating group such as
methyl or methoxyl reacted smoothly to give the corresponding products successfully
(2b, 2c, 2g and 2j). When the benzene ring was substituted with an
electronꢀwithdrawing group such as an ester or trifluoromethyl, the reaction also
conducted well, albeit in slightly lower yields (2f and 2h). In addition, fluorine or
chlorine atom can also be well tolerated in the transformation (2d and 2e). Changing
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the substituent on the nitrogen atom from Ts to Ms did not influence the cyclization
(2m). Similarly, the substrate bearing two carbonyl groups worked efficiently to
provide 2n in a good yield. However, when substrate 1o was tried under the standard
conditions, only indole 3o was obtained. This experiment indicates the important role
of substituent effect (R2 in Table 2) for the addition to carbonyl group (Scheme 3,
equation a), and which may be due to the ThorpeꢀIngold effect.14 Then, substrate 1p
was used to synthesize polycyclic indole. We were pleased to find that the reaction
occurred effectively to give the desired product 2p in excellent yield (Scheme 3,
equation b). It is worth noting that only one diastereomer is formed in our new
reaction. Besides Ts and Ms, we also tested the reaction of substrate with acetyl (Ac)
or benzoyl (Bz) group substituted on the nitrogen atom. When the substituent was an
Ac group, no reaction occurred. When Bz was substituted, only an unidentified
product was formed. We also tried to increase the size of the ring annulated to the
indole from 5 to 6, however, the according substrate could not be prepared at present.
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Table 2. Tandem Cyclization of Substrates 1b-1na
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HO
HO
HO
CO2Me
F
CO2Me
Me
CO2Me
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N
N
Me
N
Ts
Ts
2d
Ts
, 82%
2c, 81%
2b, 82%
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HO
HO
HO
MeO
CO2Me
CO2Me
F3C
Cl
CO2Me
N
N
N
Ts
Ts
Ts
2e, 74%
2f, 70%
2g, 80%
HO
HO
HO
Me
CO2Me
MeO2C
CO2Me
CO2Me
MeO2C
N
N
N
Ts
Ts
Ts
Me
Me
2j, 81%
2i, 80%
2h, 73%
HO
O
HO
HO
HO
OMe
CO2Me
Me
CN
N
N
N
N
Ms
Ts
Ts
Ts
2k, 75%
2m
, 84%
2n, 83%
2l, 80%
aReaction conditions: 1 (0.2 mmol, 1.0 equiv), Pd(OAc)2 (5 mol %) and bpy (10
mol %) were dissolved in dioxane/HOAc/H2O (2 mL/0.25 mL/0.25 mL), the mixture
was stirred at 100 oC until the consumption of 1 as monitored by TLC.
Scheme 3. The Reactions of Substrates 1o and 1p
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Next, the asymmetric version of the reaction was studied. Compound 1p was
chosen as the substrate (Scheme 4). Our preliminary results showed that the reaction
of 1p in the presence of Pd(OAc)2 and chiral pyridine oxazoline ligand L515 at 100 oC
can give the product 2p in a good yield with moderate ee value (Scheme 4).
Scheme 4. Asymmetric Tandem Cyclization of 1p
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In order to understand the mechanism, we conducted the reaction of 3a in the same
reaction conditions as Table 2 and it was found that no reaction occurred. This result
excludes that compound 3a is the actual precursor of product 2a upon acidic catalysis,
which indicates that our reaction is a tandem process, not a oneꢀpot, twoꢀstep reaction.
Based on the above result and our previous work11, a proposed mechanism is outlined
in Scheme 5. Taking substrate 1a as an example, the palladium(II) catalyst
coordinates with the carbonꢀcarbon triple bond in the substrate at the first step of the
reaction, then transꢀaminopalladation occurs to generate the intermediate B. The
nucleophilic addition of the CꢀPd bond to the intramolecular carbonyl group generates
C and the protonolysis of C results in the formation of product 2a. Meanwhile, the
protonolysis of B gives rise to the byproduct 3a.
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Scheme 5. Proposed Mechanism
O
CO2Me
(AcO)2Pd
NHTs
O
A
CO2Me
trans-
aminopalladation
coordination
NHTs
1a
O
AcOPd
Pd(OAc)2
CO2Me
N
Ts
B
hydrolysis
addition
HO
CO2Me
protonolysis
HOAc + H2O
AcOPdO
N
O
CO2Me
Ts
2a
N
Ts
X
CO2Me
N
c
Ts
3a
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CONCLUSIONS
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In conclusion, we have developed a palladium(II)ꢀcatalyzed tandem cyclization of
2ꢀalkynylanilines substituted with a cyclopentanone, which is initiated by
aminopalladation of alkynes and quenched by addition to the intramolecular carbonyl
group. In the formed compounds, two neighboring stereocenters, one being allꢀcarbon
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quaternary, are being constructed in
a
single process with excellent
diastereoselectivity. This reaction provides an efficient and atomꢀeconomic way for
the synthesis of pentaleno[2,1ꢀb]indoles. Studies are ongoing to expand the scope and
application of the present methodology.
EXPERIMENTAL SECTION
General Information. All solvents were dried and distilled using standard
procedures. Unless otherwise noted, reagents were obtained from commercial sources
1
and used without further purification. H NMR, 13C NMR and 19F NMR were
1
recorded in deuterated chloroform (CDCl3). For H NMR spectroscopic analysis,
trimethylsilane (TMS) (δ = 0) in CDCl3 served as an internal standard. For 13C NMR
spectroscopic analysis, CDCl3 (δ = 77.0) served as an internal standard. For 19F NMR
spectroscopic analysis, PhOCF3 (δ = ꢀ57.8) served as an external standard. Coupling
constants are recorded in hertz, and chemical shifts are recorded as δ values in ppm.
The following abbreviations are used to describe multiplicities: s = singlet, d =
doublet, dd = double doublet, t = triplet, m = multiplet. Highꢀresolution mass spectra
were carried out on a mass spectrometer with a TOF analyzer (ESI). Infrared spectra
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were recorded on a FTꢀIR spectrometer. Melting points were determined by using a
local hotꢀstage melting point apparatus and were uncorrected. For column
chromatography, silica gel of 200−300 mesh size was used.
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General
Procedure
for
Preparation
of
Substrates
1a-1p.16
2ꢀ(Propꢀ2ꢀyn1ꢀyl)cyclopentanones17(2 mmol) was added to a solution of PdCl2(Ph3P)2
(28 mg, 0.04 mmol), CuI (11 mg, 0.06 mmol) and 2ꢀiodoanilines (2.2 mmol) in 10 mL
o
of triethylamine and the mixture was stirred at 50 C until the consumption of
2ꢀ(Propꢀ2ꢀyn1ꢀyl)cyclopentanones as monitored by TLC. The resulting mixture was
quenched with water (10 mL), extracted with ethyl acetate (3 x 15 mL). The organic
layer was dried over anhydrous Na2SO4, and then evaporated under reduced pressure.
The residue was purified by flash chromatography (petroleum ether : ethyl acetate =
4:1) to give the coupling products which are used for the next step directly.
The above Sonogashira coupling product was dissolved in CH2Cl2 (10 mL) in a
50ꢀmL flask, then pyridine (4 mmol) and TsCl (2.4 mmol) were added to the solution.
The resulting mixture was stirred at room temperature for 15 hours. The organic phase
was washed with 20 mL of 1 M HCl solution and the aqueous phase was extracted
with 20 mL of CH2Cl2 for 2 times. The combined organic phase was dried with
anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography (petroleum ether : ethyl acetate = 4:1 )
to give the products 1a-1p.
Methyl
1-(3-(2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-oxocyclo-
1
pentanecarboxylate (1a). Yellow oil; (544 mg; 64% yield for two steps); H NMR
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(400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8 Hz, 1H), 7.51 (s, 1H),
7.29ꢀ7.19 (m, 4H), 6.95 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H), 2.95 (d, J = 16.8 Hz, 1H),
2.84 (d, J = 17.2 Hz, 1H), 2.61ꢀ2.51 (m, 2H), 2.39ꢀ2.30 (m, 4H), 2.21ꢀ2.08 (m, 2H),
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2.05ꢀ1.97 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ 212.9, 170.5, 143.4, 137.8,
135.7, 131.4, 129.0, 128.7, 126.7, 123.4, 118.4, 113.2, 92.5, 76.8, 58.3, 52.4, 37.5,
32.9, 23.6, 20.8, 19.1; IR (neat, cmꢀ1): ν 3248, 2959, 1724, 1589, 1488, 1399, 1332,
1379, 1156, 1097, 903, 814, 758, 670; HRMS (ESI) calcd for C23H27N2O5S
(M+NH4)+: 443.1635; Found: 443.1629.
Methyl 1-(3-(5-methyl-2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-oxo-
1
cyclopentanecarboxylate (1b).Yellow oil; (641 mg; 73% yield for two steps); H
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 9.2 Hz, 1H), 7.29 (s,
1H), 7.21 (d, J = 8 Hz, 2H), 7.01 (d, J = 7.2 Hz, 2H), 3.78 (s, 3H), 2.92 (d, J = 16.8
Hz, 1H), 2.81 (d, J = 17.2 Hz, 1H), 2.59ꢀ2.50 (m, 2H), 2.37ꢀ2.28 (m, 4H), 2.19ꢀ2.07
(m, 5H), 2.05ꢀ1.99 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 213.2, 170.8, 143.6,
136.2, 135.6, 133.6, 132.1, 130.0, 129.4, 127.1, 119.3, 113.6, 92.0, 76.6, 58.8, 52.9,
38.0, 33.2, 24.1, 21.4, 20.3, 19.5; IR (neat, cmꢀ1): ν 3263, 2955, 2922, 1749, 1724,
1597, 1495, 1435, 1399, 1228, 1160, 1090, 1013, 905, 866, 814, 663; HRMS (ESI)
calcd for C24H29N2O5S (M+NH4)+: 457.1792; Found: 457.1791.
Methyl 1-(3-(4-methyl-2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-oxo-
1
cyclopentanecarboxylate (1c).Yellow oil; (598 mg; 68% yield for two steps); H
NMR (400 MHz, CDCl3): δ 7.72 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 10.0 Hz, 2H), 7.22
(d, J = 8 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 3.77 (s, 3H), 2.93
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(d, J = 16.8 Hz, 1H), 2.82 (d, J = 17.2 Hz, 1H), 2.59ꢀ2.49 (m, 2H), 2.35ꢀ2.33 (m, 4H),
2.28 (s, 3H), 2.19ꢀ2.09 (m, 2H), 2.04ꢀ1.98 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3):
δ 213.3, 170.8, 143.6, 139.6, 137.9, 136.1, 131.4, 129.3, 127.0, 124.6, 119.4, 110.5,
91.7, 76.6, 58.8, 52.8, 37.9, 33.2, 24.0, 21.5, 21.3, 19.4; IR (neat, cmꢀ1): ν 3264, 2956,
2921, 1749, 1725, 1611, 1564, 1398, 1335, 1228, 1152, 1090, 1015, 955, 890, 813,
731, 661; HRMS (ESI) calcd for C24H29N2O5S (M+NH4)+: 457.1792; Found:
457.1792.
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Methyl 1-(3-(5-fluoro-2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-oxo-
1
cyclopentanecarboxylate (1d). Yellow oil; (648 mg; 73% yield for two steps); H
NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8 Hz, 2H), 7.56ꢀ7.53 (m, 1H), 7.36 (br, 1H),
7.22 (d, J = 8 Hz, 2H), 6.96ꢀ6.88 (m, 2H), 3.79 (s, 3H), 2.91 (d, J = 17.2 Hz, 1H),
3.80 (d, J = 16.8 Hz, 1H), 2.56ꢀ2.52 (m, 2H), 2.37ꢀ2.30 (m, 4H), 2.15ꢀ2.09 (m, 2H),
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2.04ꢀ1.98 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ 213.1, 170.8, 158.0 (d, J =
243.2 Hz), 143.8, 136.0, 134.5, 129.4, 127.2, 121.1 (d, J = 8.2 Hz), 118.1 (d, J = 24.5
Hz), 116.3 (d, J = 22.4 Hz), 115.7 (d, J = 9.7 Hz), 93.5, 76.6, 58.7, 53.0, 37.9, 33.4,
24.0, 21.4, 19.5; 19F NMR (376 MHz, CDCl3): δ ꢀ117.94; IR (neat, cmꢀ1): ν 3260,
2957, 1749, 1725, 1597, 1491, 1436, 1399, 1337, 1229, 1157, 1090, 1040, 908, 873,
813, 755, 701, 663; HRMS (ESI) calcd for C23H26FN2O5S (M+NH4)+: 461.1541;
Found: 461.1540.
Methyl 1-(3-(5-chloro-2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-oxo-
1
cyclopentanecarboxylate (1e). Yellow oil; (643 mg; 70% yield for two steps); H
NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.52 (dd, J1 = 6 Hz,
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J2 = 4 Hz, 1H), 7.24 (d, J = 8 Hz, 2H), 7.17 (t, J = 2.8 Hz, 2H), 3.79 (s, 3H), 2.93 (d,
J = 16.8 Hz, 1H), 2.82 (d, J = 17.2 Hz, 1H), 2.60ꢀ2.52 (m, 2H), 2.39ꢀ2.31 (m, 4H),
2.17ꢀ2.08 (m, 2H), 2.04ꢀ1.98 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 213.1,
170.8, 143.9, 136.9, 135.8, 131.2, 129.5, 129.1, 128.8, 127.1, 120.0, 115.0, 93.9, 76.3,
58.6, 52.9, 37.9, 33.4, 24.0, 21.3, 19.4; IR (neat, cmꢀ1): ν 3257, 2957, 2891, 1748,
1724, 1596, 1483, 1395, 1338, 1229, 1161, 1089, 902, 813, 755, 704, 662; HRMS
(ESI) calcd for C23H26ClN2O5S (M+NH4)+: 477.1245; Found: 477.1246.
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Methyl 1-(3-(2-(4-methylphenylsulfonamido)-5-(trifluoromethyl)phenyl)prop-2-yn-1
-yl)-2-oxocyclopentanecarboxylate (1f). Colorless oil; (592 mg; 60% yield for two
steps); 1H NMR(400 MHz, CDCl3): δ 8.00 (br, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.68 (d,
J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 3.81
(s, 3H), 2.97 (d, J = 16.8 Hz, 1H), 2.89 (d, J = 17.2 Hz, 1H), 2.64ꢀ2.54 (m, 2H),
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2.43ꢀ2.35 (m, 4H), 2.19ꢀ2.11 (m, 2H), 2.07ꢀ2.02 (m, 1H); C{1H} NMR (100 MHz,
CDCl3): δ 213.2, 170.9, 144.1, 141.4, 135.9, 129.6, 128.7, 127.1, 125.7, 125.1 (q, J =
32.8 Hz), 123.3 (q, J = 270 Hz), 117.2, 112.9, 94.5, 76.0, 58.5, 52.8, 37.8, 33.6, 23.9,
21.2, 19.3; 19F NMR (376 MHz, CDCl3): δ ꢀ62.40; IR (neat, cmꢀ1): ν 3259, 2960,
1748, 1725, 1615, 1595, 1500, 1435, 1332, 1254, 1163, 1119, 1087, 900, 846, 814,
734, 658; HRMS (ESI) calcd for C24H26F3N2O5S (M+NH4)+: 511.1509; Found:
511.1512.
Methyl
1-(3-(5-Methoxy-2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-
oxocyclopentanecarboxylate (1g). Colorless oil; (547 mg; 60% yield for two steps);
1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 7.20
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(d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 6.80 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 6.71 (d, J =
2.8 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 2.89 (d, J = 17.2 Hz, 1H), 2.78 (d, J = 17.2 Hz,
1H), 2.57ꢀ2.49 (m, 2H), 2.36ꢀ2.27 (m, 4H), 2.18ꢀ2.03 (m, 2H), 2.02ꢀ1.97 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 213.2, 170.8, 156.1, 143.5, 136.1, 131.2, 129.3,
127.1, 122.4, 116.2, 115.9, 115.3, 92.0, 77.6, 58.7, 55.3, 52.9, 38.0, 33.2, 24.0, 21.4,
19.5; IR (neat, cmꢀ1): ν 3263, 2958, 1748, 1724, 1602, 1575, 1495, 1450, 1399, 1334,
1288, 1261, 1158, 1090, 904, 864, 833, 703, 664; HRMS calcd (ESI) for
C24H29N2O6S (M+NH4)+: 473.1741; Found: 473.1741.
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Methyl
3-(3-(1-(methoxycarbonyl)-2-oxocyclopentyl)prop-1-yn-1-yl)-4-(4-methyl-
phenylsulfonamido)benzoate (1h). Colorless oil; (590 mg; 61% yield for two steps);
1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.89 (d, J = 2 Hz, 1H), 7.85 (dd, J1 = 8.8
Hz, J2 = 2 Hz, 1H), 7.82 (d, J = 8 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8 Hz,
2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.98 (d, J = 17.2 Hz, 1H), 2.89 (d, J = 17.2 Hz, 1H),
2.61ꢀ2.53 (m, 2H), 2.43ꢀ2.36 (m, 1H), 2.34 (s, 3H), 2.23ꢀ2.10 (m, 2H), 2.07ꢀ2.03 (m,
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1H); C{1H} NMR (100 MHz, CDCl3): δ 213.0, 170.7, 165.3, 143.9, 142.0, 135.7,
132.9, 130.1, 129.4, 126.9, 124.6, 116.4, 112.3, 93.7, 76.2, 58.4, 52.7, 51.7, 37.7, 33.3,
23.8, 21.1, 19.2; IR (neat, cmꢀ1): ν 3251, 2954, 1748, 1718, 1602, 1577, 1494, 1437,
1341, 1299, 1234, 1162, 1089, 901, 814, 764, 704, 660; HRMS (ESI) calcd for
C25H29N2O7S (M+NH4)+: 501.1690; Found: 501.1690.
Methyl
3-(3-(1-(methoxycarbonyl)-2-oxocyclopentyl)prop-1-yn-1-yl)-5-methyl-4-
(4-methylphenylsulfonamido)benzoate (1i). Yellow oil; (587 mg; 59% yield for two
steps); 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 2 Hz, 1H),
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7.53 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 2.65 (d, J
= 16.8 Hz, 1H), 2.57 (d, J = 17.2 Hz, 1H), 2.55ꢀ2.46 (m, 5H), 2.42 (s, 3H), 2.33ꢀ2.24
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213.3, 170.8, 165.8, 143.9, 139.7, 137.8, 136.6, 132.6, 130.8, 129.3, 128.2, 127.4,
121.2, 91.6, 77.9, 58.6, 52.9, 52.2, 38.1, 33.1, 24.0, 21.5, 19.7, 19.5; IR (neat, cmꢀ1):
ν 3247, 2954, 2924, 1750, 1721, 1595, 1434,1400, 1333, 1282, 1232, 1158, 1087,
1001, 886, 839, 814, 768, 750, 706, 669, 628; HRMS (ESI) calcd for C26H31N2O7S
(M+NH4)+: 515.1846; Found: 515.1848.
Methyl 1-(3-(3,5-dimethyl-2-(4-methylphenylsulfonamido)phenyl)prop-2-yn-1-yl)-2-
oxocyclopentanecarboxylate (1j). Yellow solid; (472 mg; 52% yield for two steps);
m.p.: 105ꢀ107 oC; 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8 Hz, 2H), 7.21 (d, J =
8 Hz, 2H), 6.99 (s, 1H), 6.86 (s, 1H), 6.52 (s, 1H), 3.73 (s, 3H), 2.63 (d, J = 17.2 Hz,
1H), 2.58 (d, J = 16.8 Hz, 1H), 2.50ꢀ2.40 (m, 8H), 2.36ꢀ2.22 (m, 4H), 2.17ꢀ2.10 (m,
1H), 2.08ꢀ1.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 213.4, 170.7, 143.3,
137.5, 136.9, 136.6, 132.7, 132.3, 130.3, 129.0, 127.3, 121.2, 89.7, 78.9, 58.6, 52.6,
38.0, 32.7, 23.9, 21.3, 20.4, 19.5, 19.1; IR (neat, cmꢀ1): ν 3261, 2955, 2922, 1749,
1724, 1597, 1436, 1398, 1329, 1225, 1157, 1090, 891, 859, 812, 667, 623; HRMS
(ESI) calcd for C25H31N2O5S (M+NH4)+: 471.1948; Found: 471.1949.
N-(2-(3-(1-Cyano-2-oxocyclopentyl)prop-1-yn-1-yl)phenyl)-4-methylbenzenesulfonam
o
1
ide (1k).11c Yellow solid; (526 mg; 67% yield for two steps); m.p.: 132ꢀ134 C; H
NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (s,
1H), 7.27ꢀ7.21 (m, 4H), 6.97 (t, J = 7.6 Hz, 1H), 2.97 (d, J = 17.2 Hz, 1H), 2.86 (d, J
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= 17.2 Hz, 1H), 2.64ꢀ2.55 (m, 2H), 2.47ꢀ2.38 (m, 1H), 2.35 (s, 3H), 2.27ꢀ2.20 (m, 1H),
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25.0, 21.4, 19.1; IR (neat, cmꢀ1): ν 3249, 3062, 2975, 2883, 2238, 1754, 1589, 1447,
1399, 1158, 1092, 908, 817, 763, 669; HRMS (ESI) calcd for C22H24N3O3S
(M+NH4)+: 410.1533; Found: 410.1532.
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N-(2-(3-(1-(Methoxymethyl)-2-oxocyclopentyl)prop-1-yn-1-yl)phenyl)-4-methylbenzen
esulfonamide (1l). White solid; (428 mg; 52% yield for two steps); m.p.: 80ꢀ82 oC; 1H
NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8 Hz, 2H), 7.63 (br, 1H), 7.57 (d, J = 8 Hz,
1H), 7.22ꢀ7.13 (m, 3H), 6.95 (t, J = 7.6 Hz, 1H), 3.48 (d, J = 8.8 Hz, 1H), 3.41 (d, J =
8.8 Hz, 1H), 3.33 (s, 3H), 2.58 (d, J = 17.2 Hz, 1H), 2.52 (d, J = 17.2 Hz, 1H),
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2.36ꢀ2.31 (m, 5H), 2.27ꢀ2.23 (m, 1H), 2.01ꢀ1.90 (m, 3H); C{1H} NMR (100 MHz,
CDCl3): δ 219.5, 143.6, 138.1, 136.3, 131.7, 129.4, 128.9, 127.1, 123.6, 118.6, 113.6,
93.1, 77.3, 75.2, 59.3, 52.0, 38.5, 31.5, 23.9, 21.3, 18.9; IR (neat, cmꢀ1): ν 3247, 2954,
2923, 2887, 1733, 1597, 1572, 1488, 1427, 1399, 1333, 1285, 1263, 1163, 1095, 1039,
959, 878, 813, 772, 742, 710, 634; HRMS (ESI) calcd for C23H29N2O4S (M+NH4)+:
429.1843; Found: 429.1844.
Methyl
1-(3-(2-(methylsulfonamido)phenyl)prop-2-yn-1-yl)-2-oxocyclopentane-
1
carboxylate (1m). Colorless oil; (461 mg; 66% yield for two steps); H NMR (400
MHz, CDCl3): δ 7.59 (d, J = 7.6 Hz, 1H), 7.36 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 2H),
7.33ꢀ7.29 (m, 1H), 7.10ꢀ7.06 (m, 1H), 3.77 (s, 3H), 3.02 (s, 3H), 2.96 (d, J = 17.2 Hz,
1H), 2.89 (d, J = 17.2 Hz, 1H), 2.62ꢀ2.50 (m, 2H), 2.41ꢀ2.34 (m, 1H), 2.21ꢀ2.01 (m,
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3H); C{1H} NMR (100 MHz, CDCl3): δ 213.2, 170.8, 138.3, 131.8, 129.4, 124.2,
119.4, 113.9, 92.8, 77.4, 58.7, 52.8, 39.2, 37.9, 33.5, 24.0, 19.4; IR (neat, cmꢀ1):
ν 3264, 2956, 2891, 1747, 1732, 1600, 1574, 1490, 1423, 1397, 1333, 1277, 1228,
1151, 1103, 1042, 1024, 998, 965, 869, 819, 755, 734, 631; HRMS (ESI) calcd for
C17H23N2O5S (M+NH4)+: 367.1322; Found: 367.1324.
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4-Methyl-N-(2-(3-(1-methyl-2,5-dioxocyclopentyl)prop-1-yn-1-yl)phenyl)benzene-
sulfonamide (1n).Yellow solid; (569 mg; 72% yield for two steps); m.p.: 121ꢀ123 oC;
1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J = 8
Hz, 1H), 7.23ꢀ7.18 (m, 4H), 6.96 (t, J = 7.6 Hz, 1H), 2.96ꢀ2.77 (m, 4H), 2.68 (s, 2H),
2.36 (s, 3H), 1.27 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ 214.5, 143.7, 138.2,
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136.3, 131.8, 129.5, 129.4, 127.2, 123.6, 118.6, 112.9, 91.13, 78.1, 54.89, 35.1, 24.4,
21.4, 19.0; IR (neat, cmꢀ1): ν 3237, 2962, 2922, 1722, 1598, 1575, 1489, 1451, 1397,
1338, 1287, 1224, 1165, 1092, 1038, 998, 949, 902, 817, 761, 724, 680, 618; HRMS
(ESI) calcd for C22H25N2O4S (M+NH4)+: 413.1530; Found: 413.1531.
4-Methyl-N-(2-(3-(2-oxocyclopentyl)prop-1-yn-1-yl)phenyl)benzenesulfonamide (1o).
Colorless oil; (500 mg; 68% yield for two steps); 1H NMR (400 MHz, CDCl3): δ 7.70
(d, J = 8.4 Hz, 2H), 7.55 (d, J = 8 Hz, 1H), 7.44 (br, 1H), 7.23ꢀ7.20 (m, 4H),
6.98ꢀ6.94 (m, 1H), 2.71 (dd, J1 = 17.2 Hz, J2 = 5.6 Hz, 1H), 2.61 (dd, J1 = 17.2 Hz, J2
= 6.4 Hz, 1H), 2.44ꢀ2.31 (m, 6H), 2.23ꢀ2.16 (m, 1H), 2.10ꢀ2.06 (m, 1H), 1.87ꢀ1.86 (m,
1H), 1.77ꢀ1.73 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 218.8, 143.9, 138.1,
136.3, 131.9, 129.6, 129.1, 127.3, 124.0, 119.1, 114.2, 94.8, 76.6, 47.7, 38.0, 29.1,
21.6, 20.5, 19.7; IR (neat, cmꢀ1): ν 3249, 2959, 2877, 1730, 1590, 1490, 1450, 1402,
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1336, 1278, 1245, 1158, 1093, 1043, 907, 813, 755, 665; HRMS (ESI) calcd for
C21H25N2O3S (M+NH4)+: 385.1580; Found: 385.1577.
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N-(2-(3-(1,3-Dioxo-2-phenyl-2,3-dihydro-1H-inden-2-yl)prop-1-yn-1-yl)phenyl)-4-me
thylbenzenesulfonamide (1p). Yellow solid; (758 mg; 75% yield for two steps); m.p.:
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162ꢀ164 C; H NMR (400 MHz, CDCl3): δ 8.10 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 2H),
7.89 (dd, J1 = 6 Hz, J2 = 3.2 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.51ꢀ7.48 (m, 3H),
7.37ꢀ7.29 (m, 4H), 7.18ꢀ7.10 (m, 3H), 6.91ꢀ6.89 (m, 1H), 6.82 (t, J = 7.6 Hz, 1H),
3.31 (s, 2H), 2.34 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ 199.6, 143.6, 141.5,
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138.0, 136.4, 136.0, 134.9, 131.8, 129.4, 129.1, 129.0, 128.2, 127.2, 126.8, 124.0,
123.5, 118.8, 113.1, 91.5, 78.0, 60.5, 25.6, 21.5; IR (neat, cmꢀ1): ν 3428, 3281, 3062,
1740, 1703,1594, 1491, 1448, 1398, 1329, 1295, 1242, 1160, 1091, 1038, 964, 921,
881, 813, 781, 755, 696, 657; HRMS (ESI) calcd for C31H27N2O4S (M+NH4)+:
523.1686; Found: 523.1686.
General procedure of the tandem cyclization of alkynones initiated by
aminopalladation. To an ovenꢀdried Schlenk tube were added alkynone 1 (0.2 mmol),
palladium acetate (2.3 mg, 0.01 mmol, 5 mol %) and 2,2’ꢀbipyridine (3.2 mg, 0.02
mmol, 10 mol %), then 2 mL of dioxane, 0.25 mL of acetic acid, 0.25 mL of H2O
o
were added sequentially. The resulting mixture was stirred at 100 C. The progress of
the reaction was monitored by TLC. After completion of the reaction, the solvents
were evaporated under reduced pressure and the residue was purified by flash column
chromatography (petroleum ether : ethyl acetate = 4:1) to give product 2.
Methyl 9c-hydroxy-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]indole-3a-
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carboxylate (2a). White solid; (68 mg; 80% yield); m.p.: 131ꢀ132 C; H NMR (400
MHz, CDCl3): δ 7.98 (d, J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 2H), 7.49 (d, J = 7.6 Hz,
1H), 7.25ꢀ7.19 (m, 4H), 4.01 (d, J =17.6 Hz, 1H), 3.74 (s, 3H), 3.03 (d, J = 17.6 Hz,
1H), 2.74 (s, 1H), 2.63ꢀ2.55 (m, 1H), 2.34ꢀ2.29 (m, 4H), 2.04ꢀ1.97 (m, 1H), 1.87ꢀ1.81
(m, 2H), 1.33ꢀ1.26 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 174.9, 145.0, 142.3,
140.4, 135.2, 129.9, 126.8, 126.6, 124.7, 124.0, 123.6, 118.7, 114.3, 90.6, 66.9, 52.2,
39.4, 38.7, 37.5, 23.9, 21.5; IR (neat, cmꢀ1): ν 3477, 2956, 2874, 1701, 1596, 1443,
1406, 1373, 1298, 1210, 1177, 1143, 1097, 1044, 993, 959, 927, 878, 856, 809, 745,
707, 664; HRMS (ESI) calcd for C23H27N2O5S (M+NH4)+: 443.1635; Found:
443.1637.
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Methyl 9c-hydroxy-8-methyl-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]-
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indole-3a-carboxylate (2b). White solid; (72 mg; 82% yield); m.p.: 164ꢀ166 C; H
NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.29 (s,
1H), 7.23ꢀ7.21 (d, J = 8.4 Hz, 2H), 7.08 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 4.01 (d, J
= 18 Hz, 1H), 3.72 (s, 3H), 3.03 (d, J = 18 Hz, 1H), 2.73 (s, 1H), 2.62ꢀ2.54 (m, 1H),
2.37 (s, 3H), 2.33 (s, 3H), 2.31ꢀ2.28 (m, 1H), 2.03ꢀ1.95 (m, 1H), 1.86ꢀ1.80 (m, 2H),
1.31ꢀ1.25 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ 174.9, 144.9, 142.4, 138.6,
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135.2, 133.3, 129.9, 126.7, 126.5, 125.2, 124.8, 118.8, 114.0, 90.5, 66.8, 52.2, 39.4,
38.7, 37.5, 23.8, 21.4, 21.1; IR (neat, cmꢀ1): ν 3486, 2952, 2921,2861, 1697, 1607,
1446, 1396, 1358, 1286, 1212, 1171, 1134, 1095, 1041, 999, 925, 893, 868, 743, 703,
660; HRMS (ESI) calcd for C24H29N2O5S (M+NH4)+: 457.1792; Found: 457.1791.
Methyl 9c-hydroxy-7-methyl-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]-
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indole-3a-carboxylate (2c). Yellow solid; (71.2 mg; 81% yield); m.p.: 120ꢀ121 oC; 1H
NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.6 Hz,
1H), 7.23 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 3.98 (d, J = 17.6 Hz, 1H), 3.71
(s, 3H), 3.00 (d, J = 17.6 Hz, 1H), 2.73 (s, 1H), 2.62ꢀ2.54 (m, 1H), 2.45 (s, 3H), 2.33
(s, 3H), 2.30ꢀ2.25 (m, 1H), 2.02ꢀ1.94 (m, 1H), 1.85ꢀ1.79 (m, 2H), 1.31ꢀ1.25 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ174.9, 144.9, 141.5, 140.8, 135.3, 134.1, 129.8,
126.8, 126.5, 124.9, 122.3, 118.4, 114.6, 90.6, 66.8, 52.2, 39.5, 38.6, 37.5, 23.8, 21.8,
21.4; IR (neat, cmꢀ1): ν 3483, 2952, 2866, 1718, 1620, 1596, 1490, 1436, 1365, 1295,
1276, 1238, 1170, 1089, 1033, 990, 960, 916, 879, 812, 731, 706, 663, 620; HRMS
(ESI) calcd for C24H29N2O5S (M+NH4)+: 457.1792; Found: 457.1792.
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Methyl
8-fluoro-9c-hydroxy-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]-
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indole-3a-carboxylate (2d). White solid; (72.7 mg; 82% yield); m.p.: 164ꢀ166 C; H
NMR (400 MHz, CDCl3): δ 7.91 (dd, J1 = 9.2 Hz, J2 = 4.4 Hz, 1H), 7.71 (d, J = 8.4
Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.14 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.97 (td, J1
= 8.8 Hz, J2 = 2.4 Hz, 1H), 4.00 (d, J = 18 Hz, 1H), 3.72 (s, 3H), 3.02 (d, J = 17.6 Hz,
1H), 2.81 (s, 1H), 2.62ꢀ2.54 (m, 1H), 2.34 (s, 3H), 2.28ꢀ2.23 (m, 1H), 2.03ꢀ1.95 (m,
1H), 1.87ꢀ1.80 (m, 2H), 1.32ꢀ1.24 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ174.8,
159.7 (d, J = 240 Hz), 145.2, 144.1, 136.6, 135.0, 129.9, 126.6 (d, J = 3.8 Hz), 126.5,
125.7 (d, J = 10.6 Hz), 115.3 (d, J = 9.9 Hz), 111.5 (d, J = 25.1 Hz), 104.7 (d, J =
24.3 Hz), 90.4, 66.8, 52.3, 39.4, 38.7, 37.5, 23.9, 21.5; 19F NMR (376 MHz, CDCl3):
δ ꢀ118.70; IR (neat, cmꢀ1): ν 3480, 2955, 2926, 1727, 1694, 1615, 1598, 1453, 1438,
1369, 1272, 1206, 1168, 1094, 996, 907, 836, 742, 663; HRMS (ESI) calcd for
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C23H26FN2O5S (M+NH4)+: 461.1541; Found: 461.1541.
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Methyl 8-chloro-9c-hydroxy-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]-
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indole-3a-carboxylate (2e). Yellow solid; (68 mg; 74% yield); m.p.: 163ꢀ165 C; H
NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8 Hz, 2H), 7.47 (d, J
= 1.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.21 (dd, J1 = 8.8 Hz, J2 = 2 Hz, 1H), 4.00 (d,
J = 18 Hz, 1H), 3.72 (s, 3H), 3.02 (d, J = 18 Hz, 1H), 2.80 (s, 1H), 2.62ꢀ2.54 (m, 1H),
2.35 (s, 3H), 2.96ꢀ2.49 (m, 1H), 2.03ꢀ1.95 (m, 1H), 1.87ꢀ1.81 (m, 2H), 1.32ꢀ1.23 (m,
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1H); C{1H} NMR (100 MHz, CDCl3): δ 174.8, 145.3, 143.8, 138.6, 134.9, 130.0,
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129.5, 126.5, 126.2, 125.8, 124.0, 118.5, 115.3, 90.4, 66.8, 52.3, 39.3, 38.8, 37.5, 23.9,
21.5; IR (neat, cmꢀ1): ν 3488, 2952, 2925, 2878, 2847, 1729, 1700, 1598, 1567, 1436,
1396, 1364, 1297, 1279, 1224, 1169, 1143, 1093, 1039, 994, 927, 909, 808, 777, 707,
662; HRMS (ESI) calcd for C23H26ClN2O5S (M+NH4)+: 477.1245; Found: 477.1243.
Methyl 9c-Hydroxy-5-tosyl-8-(trifluoromethyl)-2,3,3a,4,5,9c-hexahydro-1H-pentaleno
-[2,1-b]indole-3a-carboxylate (2f). White solid; (61.5 mg; 70% yield); m.p.: 164ꢀ166
oC; 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J =
8.4 Hz, 2H), 7.51 (dd, J1 = 8.8 Hz, J2 = 1.2 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 4.03 (d,
J = 17.6 Hz, 1H), 3.73 (s, 3H), 3.07 (d, J = 17.6 Hz, 1H), 2.87 (s, 1H), 2.63ꢀ2.55 (m,
1H), 2.36 (s, 3H), 2.33ꢀ2.30 (m, 1H), 2.07ꢀ1.99 (m, 1H), 1.91ꢀ1.84 (m, 2H), 1.33ꢀ1.26
(m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δδ 174.8, 145.7, 144.2, 141.8, 134.8,
130.2, 126.6, 126.0 (q, J = 32 Hz), 124.5, 124.3 (q, J = 270.7 Hz), 120.9 (d, J = 3.4
19
Hz), 116.3 (d, J = 4.2 Hz), 114.5, 90.4, 67.0, 52.3, 39.3, 39.1, 37.5, 23.9, 21.5; F
NMR (376 MHz, CDCl3): δ ꢀ61.21; IR (neat, cmꢀ1): 3486, 2958, 2883, 1697, 1623,
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1597, 1457, 1437, 1399, 1374, 1272, 1227, 1169, 1133, 1110, 1094, 1054, 996, 927,
886, 854, 816, 739, 707, 662, 630; HRMS calcd (ESI) for C24H26F3N2O5S (M+NH4)+:
511.1509; Found: 511.1509.
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Methyl 9c-hydroxy-8-methoxy-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno-[2,1-b]-
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indole-3a-carboxylate (2g). White solid; (72.8 mg; 80% yield); m.p.: 154ꢀ156 C; H
NMR (400 MHz, CDCl3): δ 7.86 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.23 (d,
J = 8 Hz, 2H), 6.93 (d, J = 2.4 Hz, 1H), 6.85 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 3.98
(d, J = 17.6 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 2.99 (d, J = 17.6 Hz, 1H), 2.82 (s, 1H),
2.62ꢀ2.54 (m, 1H), 2.34ꢀ2.27 (m, 4H), 2.20ꢀ1.95 (m, 1H), 1.86ꢀ1.80 (m, 2H),
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1.31ꢀ1.25 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ 174.9, 156.5, 144.9, 143.0,
135.1, 134.9, 129.8, 126.7, 126.5, 125.6, 115.2, 112.4, 101.5, 90.5, 66.8, 55.5, 52.2,
39.4, 38.6, 37.4, 23.8, 21.4; IR (neat, cmꢀ1): ν 3450, 2950, 2865, 1724, 1622, 1597,
1457, 1441, 1402, 1362, 1338, 1297, 1274, 1237, 1169, 1138, 1090, 1029, 997, 929,
864, 798, 734, 706, 665; HRMS (ESI) calcd for C24H29N2O6S (M+NH4)+: 473.1741;
Found: 473.1739.
Dimethyl
9c-hydroxy-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]indole-
o
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3a,8-dicarboxylate (2h). White solid; (70.6 mg; 73% yield); m.p.: 165ꢀ167 C; H
NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz,
1H), 7.75 (d, J = 8 Hz, 2H), 7.25 (d, J = 8 Hz, 2H), 4.02 (d, J = 18 Hz, 1H), 3.89 (s,
3H), 3.74 (s, 3H), 3.06 (d, J = 18 Hz, 1H), 2.81 (s, 1H), 2.62ꢀ2.56 (m, 1H), 2.36ꢀ2.33
(m, 4H), 2.08ꢀ2.01 (m, 1H), 1.90ꢀ1.82 (m, 2H), 1.35ꢀ1.27 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 174.8, 166.9, 145.4, 143.7, 142.9, 135.0, 130.3, 127.0, 126.6,
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125.6, 125.3, 124.4, 120.8, 114.0, 90.5, 67.0, 52.3, 52.0, 39.4, 39.0, 37.6, 23.9, 21.5;
IR (neat, cmꢀ1): ν 3469, 2957, 2877, 1717, 1702, 1619, 1594, 1458, 1434, 1397, 1366,
1285, 1254, 1235, 1206, 1170, 1125, 1091, 1043, 998, 970, 923, 898, 856, 836, 815,
707; HRMS (ESI) calcd for C25H29N2O7S (M+NH4)+: 501.1690; Found: 501.1689.
Dimethyl 9c-hydroxy-6-methyl-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]-
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indole-3a,8-dicarboxylate (2i). White solid; (79.6 mg; 80% yield); m.p.: 149ꢀ151 C;
1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 7.70 (s, 1H), 7.51 (d, J = 8 Hz, 2H), 7.23
(d, J = 8 Hz, 2H), 4.06 (d, J = 18.4 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.10 (d, J =
18.4 Hz, 1H), 2.83 (s, 1H), 2.62ꢀ2.56 (m, 4H), 2.37ꢀ2.33 (m, 4H), 2.09ꢀ2.01 (m, 1H),
1.88ꢀ1.84 (m, 2H), 1.33ꢀ1.26 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 175.1,
167.0, 146.3, 145.1, 143.6,136.5, 130.1, 129.4, 128.1, 126.8, 126.5, 126.3, 118.4, 90.4,
66.7, 52.5, 52.2, 41.6, 39.1, 37.6, 24.0, 22.2, 21.5; IR (neat, cmꢀ1): ν 3492, 2954, 2871,
1709, 1634, 1594, 1574, 1437, 1365, 1297, 1271, 1234, 1208, 1169, 1117, 1086, 1065,
1038, 923, 894, 814, 730, 701, 668; HRMS (ESI) calcd for C26H31N2O7S (M+NH4)+:
515.1846; Found: 515.1851.
Methyl
9c-hydroxy-6,8-dimethyl-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno-
[2,1-b]-indole-3a-carboxylate (2j). White solid; (73.5 mg; 81% yield); m.p.: 145ꢀ147
oC; 1H NMR (400 MHz, CDCl3): δ 7.49 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),
7.14 (s, 1H), 6.83 (s, 1H), 4.01 (d, J = 18 Hz, 1H), 3.75 (s, 3H), 3.03 (d, J = 17.2 Hz,
1H), 2.74 (s, 1H), 2.58ꢀ2.52 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H), 2.31ꢀ2.27 (m, 1H),
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2.03ꢀ1.94 (m, 1H), 1.84ꢀ1.79 (m, 2H), 1.28ꢀ1.19 (m, 1H); C{1H} NMR (100 MHz,
CDCl3): δ 175.2, 145.1, 144.6, 139.4, 136.4, 134.1, 129.8, 129.7, 128.3, 127.2, 126.4,
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126.3, 116.7, 90.5, 66.6, 52.4, 41.6, 38.7, 37.5, 23.9, 22.0, 21.6, 20.8; IR (neat, cmꢀ1):
ν 3499, 3446, 2951, 2925, 2872, 1699, 1635, 1596, 1437, 1364, 1329, 1297, 1234,
1171, 1086, 1035, 991, 900, 844, 816, 733, 702, 668, 617; HRMS (ESI) calcd for
C25H31N2O5S (M+NH4)+: 471.1948; Found: 471.1947.
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9c-Hydroxy-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]indole-3a-carbo-
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nitrile (2k). Yellow solid; m.p.: 136ꢀ137 C; (58.8 mg; 75% yield); H NMR (400
MHz, CDCl3): δ 7.99 (d, J = 8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 7.2 Hz,
1H), 7.31 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 7.27ꢀ7.23 (m, 3H), 3.85 (d, J = 17.6 Hz,
1H), 3.31 (d, J = 17.6 Hz, 1H), 2.74 (s, 1H), 2.47ꢀ2.39 (m, 1H), 2.36 (s, 3H),
2.34ꢀ2.29 (m, 1H), 2.13ꢀ2.03 (m, 2H), 1.93ꢀ1.88 (m, 1H), 1.42ꢀ1.36 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 145.5, 140.3, 139.7, 134.9, 130.1, 126.5, 126.4, 124.6,
124.0, 123.8, 121.9, 118.9, 114.3, 89.7, 56.0, 40.5, 39.9, 38.3, 24.3, 21.5; IR (neat,
cmꢀ1): ν 3436, 3061, 2959, 2866, 2244, 1602, 1482, 1409, 1366, 1295, 1222, 1172,
1095, 1046, 987, 910, 811, 731, 661; HRMS (ESI) calcd for C22H24N3O3S (M+NH4)+:
410.1533; Found: 410.1531.
3a-(Methoxymethyl)-5-tosyl-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]indol-9c-ol
(2l). Colorless oil; (65.8 mg; 80% yield); 1H NMR (400 MHz, CDCl3): δ 7.96 (dd, J1
= 6.4 Hz, J2 = 2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.52 (dd, J1 = 6.8 Hz, J2 = 3.2 Hz,
1H), 7.25ꢀ7.18 (m, 4H), 3.66 (d, J = 8.8 Hz, 1H), 3.50 (d, J = 17.6 Hz, 1H), 3.48 (d, J
= 8.8 Hz, 1H), 3.34 (s, 4H), 2.93 (d, J = 17.2 Hz, 1H), 2.32 (s, 3H), 2.24ꢀ2.19 (m, 1H),
13
1.93ꢀ1.87 (m, 1H), 1.75ꢀ1.69 (m, 3H), 1.29ꢀ1.25 (m, 1H); C{1H} NMR (100 MHz,
CDCl3): δ 144.7, 142.1, 140.3, 135.4, 129.7, 129.3, 126.5, 125.3, 123.6, 123.5, 118.8,
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114.3, 88.1, 77.3, 59.7, 59.0, 39.2, 39.2, 37.5, 23.8, 21.4; IR (neat, cmꢀ1): ν 3517,
3056, 2947, 2860, 1617, 1597, 1475, 1446, 1402, 1366, 1298, 1220, 1171, 1146, 1089,
1042, 1019, 990, 951, 878, 810, 746, 702, 663; HRMS (ESI) calcd for C23H25NO4SNa
(M+Na)+: 434.1397; Found: 434.1397.
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Methyl 9c-hydroxy-5-(methylsulfonyl)-2,3,3a,4,5,9c-hexahydro-1H-pentaleno[2,1-b]-
indole-3a-carboxylate (2m). Colorless oil; (58.7 mg; 84% yield); 1H NMR (400 MHz,
CDCl3): δ 7.89ꢀ7.87 (m, 1H), 7.61ꢀ7.59 (m, 1H), 7.32ꢀ7.30 (m, 2H), 3.89 (d, J = 18
Hz, 1H), 3.75 (s, 3H), 3.09 (s, 3H), 2.94 (d, J = 18 Hz, 1H), 2.90 (s, 1H), 2.63ꢀ2.55 (m,
1H), 2.40ꢀ2.35 (m, 1H), 2.08ꢀ2.01 (m, 1H), 1.92ꢀ1.74 (m, 2H), 1.44ꢀ1.25 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 175.2, 142.4, 140.5, 126.6, 124.8, 124.4, 124.0,
119.2, 114.0, 90.8, 67.0, 52.5, 40.9, 39.1, 38.9, 37.8, 24.1; IR (neat, cmꢀ1): ν 3504,
2957, 2869 1718, 1619, 1477, 1446, 1410, 1362, 1325, 1277, 1221, 1168, 1139, 1116,
1092, 1035, 993, 961, 909, 786, 729, 684, 645; HRMS (ESI) calcd for C17H23N2O5S
(M+NH4)+: 367.1322; Found: 367.1324.
9c-Hydroxy-3a-methyl-5-tosyl-3a,4,5,9c-tetrahydro-1H-pentaleno[2,1-b]indol-3(2H)-
one (2n). Yellow solid; (65.6 mg; 83% yield); m.p.: 123ꢀ126 oC; 1H NMR (400 MHz,
CDCl3): δ 7.97 (d, J = 8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 6.8 Hz, 1H),
7.28ꢀ7.23 (m, 2H), 7.22 (d, J = 8 Hz, 2H), 3.56 (d, J = 17.6 Hz, 1H), 3.10 (d, J = 17.2
Hz, 1H), 2.77 (dd, J1 = 12.8 Hz, J2 = 9.2 Hz, 1H), 2.49ꢀ2.42 (m, 1H), 2.33 (s, 3H),
2.28ꢀ2.19 (m, 1H), 2.09 (s, 1H), 1.93ꢀ1.85 (m, 1H), 1.25 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 220.6, 145.2, 144.2, 140.0, 134.8, 130.0, 127.1, 126.6, 124.5, 124.3,
123.7, 118.7, 114.6, 83.9, 62.9, 37.7, 36.3, 29.8, 21.5, 15.5; IR (neat, cmꢀ1): ν 3348,
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3054, 2961, 2921, 2862, 1715, 1596, 1485, 1444, 1403, 1364, 1222, 1172, 1122, 1082,
1055, 983, 914, 849, 810, 737, 661; HRMS (ESI) calcd for C22H21NO4SNa (M+Na)+:
418.1083; Found: 418.1082.
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11b-Hydroxy-6a-phenyl-5-tosyl-6,6a-dihydro-5H-benzo[5,6]pentaleno[2,1-b]indol-7(
o
11bH)-one (2p). Yellow solid; (99 mg; 98% yield); m.p.: 184ꢀ186 C; 1H NMR (400
MHz, CDCl3): δ 7.99 (t, J = 7.2 Hz, 2H), 7.74ꢀ7.65 (m, 4H), 7.59 (d, J = 7.2 Hz, 1H),
7.41 (t, J = 7.2 Hz, 1H), 7.27ꢀ7.17 (m, 7H), 7.15 (d, J = 8 Hz, 2H), 4.16 (d, J = 18 Hz,
1H), 3.89 (d, J = 18.0 Hz, 1H), 2.45 (br, 1H), 2.24 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 204.6, 154.9, 145.4, 141.4, 139.7, 137.2, 135.9, 135.2, 135.0, 130.1, 129.4,
128.7, 128.2, 127.7, 127.6, 126.7, 124.8, 124.6, 124.4, 124.4, 123.8, 118.9, 114.4,
85.2, 75.0, 37.3, 21.5; IR (neat, cmꢀ1): ν 3501, 2094, 3057, 2960, 2928, 2867, 1698,
1599, 1495, 1470, 1444, 1396, 1360, 1343, 1316, 1282, 1255, 1173, 1148, 1102, 1065,
1026, 975, 933, 902, 853, 835, 811, 748, 727, 704, 665, 639, 619; HRMS (ESI) calcd
for C31H27N2O4S (M+NH4)+: 523.1686; Found: 523.1683.
Methyl 2-oxo-1-((1-tosyl-1H-indol-2-yl)methyl)cyclopentanecarboxylate (3a). Yellow
o
solid; m.p.: 125ꢀ127 C; 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8 Hz, 1H), 7.58
(d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.29ꢀ7.25 (m, 1H), 7.20 (d, J = 7.6 Hz,
1H), 7.16 (d, J = 8.4 Hz, 2H), 6.36 (s, 1H), 3.93 (d, J = 16 Hz, 1H), 3.70 (s, 3H), 3.48
(d, J = 15.6 Hz, 1H), 2.68ꢀ2.62 (m, 1H), 2.47ꢀ2.40 (m, 1H), 2.31 (s, 3H), 2.19ꢀ2.10 (m,
2H), 2.04ꢀ1.96 (m, 1H), 1.84ꢀ1.79 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ214.5,
171,1, 144.9, 137.2, 137.0, 135.5, 129.8, 129.8, 126.3, 124.5, 123.9, 120.6, 115.3,
112.1, 61.2, 52.9, 38.7, 32.4, 31.4, 21.6, 19.6; IR (neat, cmꢀ1): ν 2957, 2907, 1720,
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662; HRMS (ESI) calcd for C23H27N2O5S (M+NH4)+: 443.1635; Found:443.1631.
2-((1-Tosyl-1H-indol-2-yl)methyl)cyclopentanone (3o).Yellow oil; (49.2 mg; 67%
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yield); H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz,
2H), 7.39 (d, J = 7.6 Hz, 1H), 7.27 (td, J1 = 7.2 Hz, J2 = 1.6 Hz, 1H), 7.21 (td, J1 = 7.6
Hz, J2 = 1.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 3.60 (dd, J1 = 15.6 Hz, J2
= 4.0 Hz, 1H), 2.87ꢀ2.80 (m, 1H), 2.73ꢀ2.69 (m, 1H), 2.42ꢀ2.35 (m, 1H), 2.31 (s, 3H),
2.21ꢀ2ꢀ12 (m, 2H), 2.05ꢀ1.96 (m, 1H), 1.82ꢀ1.77 (m, 1H), 1.60ꢀ1.52 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ219.5, 144.9, 139.8, 137.4, 135.7, 129.9, 129.8, 126.4,
124.2, 123.7, 120.3, 115.1, 110.7, 49.4, 37.9, 29.7, 29.2, 21.6, 20.5; IR (neat, cmꢀ1):
ν 2968, 2926, 2254, 1743, 1595, 1447, 1366, 1215, 1162, 1086, 1046, 908, 859, 809,
734, 663; HRMS (ESI) calcd for C21H25N2O3S (M+NH4)+: 385.1580; Found:
385.1581.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: xlhan@mail.sioc.ac.cn; xylu@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21232006, 21272249)
and Chinese Academy of Sciences for financial support.
Supporting Information
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