Copper(I)-Catalyzed Dearomative (3 + 2) Cycloaddition of 3-Nitroindoles with Propargylic Nucleophiles: An Access to Cyclopenta[ b]indolines

Article abstract of DOI:10.1021/acs.joc.9b03459

The copper(I)-catalyzed dearomatization of 3-nitroindoles with propargylic nucleophiles is described. In mild reaction conditions, this original dearomative (3 + 2) cycloaddition process gives access to a wide variety of cyclopenta[b]indolines in good to excellent yields, with high functional group tolerance. The proof of concept that an enantioselective version of this reaction is accessible by employing chiral phosphorous ligands was obtained. A mechanism proposal is given based on kinetic studies.

Full text of DOI:10.1021/acs.joc.9b03459

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Article
Copper(I)-Catalyzed Dearomative (3 + 2) Cycloaddition of
3‑Nitroindoles with Propargylic Nucleophiles: An Access to
Cyclopenta[b]indolines
Johanne Ling, David Mara, Baptiste Roure, Maxime Laugeois, and Maxime R. Vitale*
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ABSTRACT: The copper(I)-catalyzed dearomatization of 3-
nitroindoles with propargylic nucleophiles is described. In mild
reaction conditions, this original dearomative (3 + 2) cycloaddition
process gives access to a wide variety of cyclopenta[b]indolines in
good to excellent yields, with high functional group tolerance. The
proof of concept that an enantioselective version of this reaction is
accessible by employing chiral phosphorous ligands was obtained. A mechanism proposal is given based on kinetic studies.
with all-carbon 1,3-dipoles.5−7 In this field, in addition to
INTRODUCTION
■
recent achievements based on the use of allenoates (or
Indolines constitute an important family of naturally occurring
surrogates) via nucleophilic organocatalysis [Scheme 1, (a)],5
molecules,1 within which several biologically active com-
metal catalysis revealed itself a privileged approach.6,7 In
pounds, such as vindolinine, polyveoline, spermacoceine, and
particular, Trost et al. reported the dearomative (3 + 2)
kopsinitarine E, display a 2,3-fused cyclopentane ring (Figure
cycloaddition reaction of 3-nitroindoles via transiently
1).2
generated palladium trimethylenemethane complexes [Scheme
1, (b)],6 a metal-catalyzed strategy which our group and that of
Hyland later adopted by capitalizing on the palladium(0)-
catalyzed ring opening of vinylcyclopropanes [Scheme 1,
(c)].7,9
In continuation of our interest for such dearomative
processes,7a,10 we report here that by merging the use of a
base with that of a catalytic copper(I) complex, cyclopenta-
[b]indolines can alternatively be obtained via the formal (3 +
2) cycloaddition of 3-nitroindole with simple and easily
Figure 1. Relevant natural products containing a cyclopenta[b]-
accessible propargylic nucleophiles [Scheme 1, (d)].11
indoline core.
RESULTS AND DISCUSSION
■
For this reason, the cyclopenta[b]indoline core has attracted
̀
At the onset of our study, inspired by the work of Dulcere et al.
a lot of attention, and many efforts have been dedicated to the
preparation of this particular scaffold.3 Among all possible
methods, the direct introduction of the cyclopentane ring by
means of a formal (3 + 2) cycloaddition process between an
all-carbon 1,3-dipole and an indole partner remains undeniably
the most straightforward method.3 Such a dearomative
annulation strategy, which has long depended on the use of
electron-rich indoles, based upon the seminal work of Kerr et
al.,4 has recently witnessed a change in paradigm, wherein
electron-deficient indoles could be employed instead.5−7
More specifically, in direct connection with the seminal
works from the groups of Chataigner and Gribble that
showcased the unconventionally high reactivity of some
nitroaromatics toward nitrogen-based 1,3-dipoles,8 others and
we demonstrated that cyclopenta[b]indolines could be
straightforwardly obtained when 3-nitroindoles were engaged
regarding the base-catalyzed annelation of nitrostyrene with
propargylic nucleophiles,12 we wondered if 3-nitroindoles
could behave likewise and would afford cyclopenta[b]-
indolines. To this aim, we studied the formal (3 + 2)
cycloaddition of N-tosyl-3-nitroindole 1a with dimethyl
propargylmalonate 2a (1.5 equiv) (Table 1). However, in
the reaction conditions previously reported by Dulcere et al.,
12
̀
in the presence of Triton B (benzyltrimethylammonium
hydroxide) at 50 °C in dichloromethane, only traces of the
Received: December 23, 2019
Published: February 3, 2020
https://dx.doi.org/10.1021/acs.joc.9b03459
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desired cycloaddition product 3aa could be observed (Table 1,
entry 1). For this reason, based on our previous interest for the
metal-catalyzed carbocyclizations of formyl alkynes and other
literature precedents, including Balme’s and Dixon’s seminal
works,13,14 we decided to evaluate if, using cesium carbonate as
base (1 equiv), the use of a π-Lewis acid metal catalyst (5 mol
%) could favor the desired dearomative process. Among the
various metal sources which were tested, Pd(OAc)2,
PPh3AuNTf2, and FeCl3 could not promote the expected
reaction (Table 1, entries 2−4). Nevertheless, we witnessed
that several silver salts, including silver nitrate or its
bis(triflimide) analogue, permitted the desired dearomatization
reaction to take place with good yields of 72 and 84%,
respectively (Table 1, entries 5−6). Encouraged by these
results, we turned ourselves toward less expensive metal
sources such as copper. In the presence of triphenylphosphine,
copper(I) bromide, copper(I) iodide, and copper(II) triflate,
all allowed to obtain the cycloaddition product 3aa in good
yields, comparable to that obtained with AgNO3 (Table 1,
entries 7−9). It is noteworthy that in the absence of
triphenylphosphine, copper(II) triflate showed poor capability
of activating 2a ((Table 1, entry 10). In accordance with
previous observations,14e,f we concluded that Cu(OTf)2 is
actually a precatalyst and that, in such case, triphenylphosphine
serves both as a ligand and as a reductant to promote the in
situ generation of the more catalytically competent copper(I)
trifluoromethanesulfonate complex. In order to reach milder
reaction conditions, the cycloaddition reaction was then
Scheme 1. Dearomative (3 + 2) Cycloaddition Reaction of
3-Nitroindoles with in Situ Generated All-Carbon 1,3-
Dipoles
Table 1. Optimization of the Dearomative (3 + 2) Cycloaddition of N-Tosyl-3-nitroindole 1a with Dimethyl
a
Propargylmalonate 2a
b
entry
catalyst
ligand (x mol %)
base
solvent
temperature (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
Triton B
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Li2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeOH
1,2-DCE
THF
50
50
50
50
50
50
50
50
50
50
rt
rt
rt
rt
rt
rt
rt
rt
rt
1
c
Pd(OAc)2
PPh3AuNTf2
FeCl3
AgNO3
AgNTf2
CuBr
CuI
Cu(OTf)2
Cu(OTf)2
AgNTf2
c
c
72
84
69
66
72
16
55
63
86
PPh3 (20)
PPh3 (20)
PPh3 (20)
d
11
12
d
AgNO3
13
14
15
16
17
18
19
20
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
18
c
81
30
71
71
64
DMF
CH2Cl2
rt
rt
f
e
21
91 (79)
a
Reaction conditions: 1a (0.4 mmol), 2a (0.6 mmol), catalyst (5 mol %), ligand (x mol %), and base (0.4 mmol) in 2 mL of solvent (0.2 M) for 2
b
c
d
e
h. 1H NMR yields determined using propylene carbonate as an internal standard. No reaction occurred. Reaction run overnight. Isolated yield.
f
Reaction run with 1.1 equiv 2a.
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surveyed at room temperature. While, even after prolonged
reaction times, silver salts exhibited a poorer reactivity in these
new reaction conditions (Table 1, entries 11−12), we
witnessed that the Cu(OTf)2/PPh3 system allowed to obtain
although competitive N-deprotection could be observed,
especially for 1e and 1g. In the case of the Boc-substituted
substrate 1h, the inherent steric hindrance of this protecting
group limited this side process, which allowed to obtain the
cyclopenta[b]indoline 3ha in a good 77% yield in the standard
reaction conditions and up to 85% yield when 1h was used in
excess. Reminiscent of previous studies,7 the N-methyl and N-
benzyl substrates 1i an 1j, in which a push−pull effect is
supposed to happen, remained completely unreactive. Addi-
tionally, such a dearomatization strategy could be successfully
applied to the efficient preparation of the cyclopenta[b]-
benzofuran 5 in 82% yield (starting from 3-nitrobenzofuran 4),
suggesting that this dearomatization process is compatible with
a wider range of nitroaromatics.
1
3aa in 86% H NMR yield after only 2 h. The screening of a
larger variety of bases and solvents led to no significant
improvements (Table 1, entries 14−20), but the desired
dearomative cycloaddition worked efficiently when only 1.1
equiv of propargylic derivative 1a was used. In the later
reaction conditions, which we used for the rest of our studies,
the cyclopenta[b]indoline 3aa was obtained in a good 79%
isolated yield (Table 1, entry 21).
With these optimized reaction conditions in hand, we then
investigated the scope of this original dearomatization reaction,
starting by evaluating the influence of the indole N-substitution
pattern (Scheme 2).
We next explored the scope of propargylic nucleophiles
compatible with this annelative process. For this purpose,
nitroindole 1a was engaged with 2b−m (Scheme 3, left).
Employing other malonate derivatives, such as the diisopropyl
propargylmalonate 2b or its dibenzyl analogue 2c, allowed to
obtain the corresponding cyclopenta[b]indoles 3ab and 3ac in
71 and 86% yields, respectively. However, in the case of the
Meldrum’s acid propargyl derivative 2d, no (3 + 2)
cycloaddition product could be detected. We assume that in
this case, the deprotonated form of 2d, in line with the low pKa
of such compounds (Meldrum’s acid pKa ≈ 5), possesses a
weak nucleophilicity so that the initial Michael addition step
would become inoperative. Nevertheless, the less acidic
propargyl malonitrile 2e could be employed to generate 3ae
in a satisfactory 82% yield. A slow cyclization rate was
observed, which could be easily overcome by using 10 mol %
of Cu(OTf)2 and 40 mol % PPh3. We next envisioned using
unsymmetrical activated methylene derivatives (2f−i) to probe
the diastereoselectivity of this cycloaddition reaction. Starting
from the tert-butyl methyl propargyl malonate 2f, the
corresponding cycloadduct 3af was isolated as a 3:1 mixture
of diastereomers. On the other hand, the phenylketone
derivative 2g did not afford the expected product 3ag and
provided the intramolecular cyclization product 8 in 87% yield
instead.15 Better results were obtained with the propargylic
cyanoacetates 2h and 2i, with which up to 5:1 dr and 84% yield
were reached in the latter case, probably because of a better
steric discrimination between the tert-butoxycarbonyl and the
cyano groups. Heteroatom-based propargylic nucleophiles
were tested next. While the N-Ts protected 2j allowed to
successfully obtain the corresponding desired pyrroloindoline
3aj in 65% yield, the N-Ns equivalent 2k remained completely
unreactive and the N-Boc propargylamine 2l only afforded very
less amount of 3al (11% yield). On the other hand, neither the
propargyl alcohol 2m nor the nonterminal phenyl-substituted
propargylic malonate allowed the preparation of the corre-
sponding cycloadducts 3am and 3an.
Scheme 2. Scope of the ReactionInfluence of the
Nitrogen Substitution Pattern of the Nitroindole Partner
a
Extension to 3-Nitrobenzofuran
a
Reaction conditions: 1a−j or 4 (0.40 mmol), 2a (0.44 mmol, 1.1
equiv), Cu(OTf)2 (5 mol %), PPh3 (20 mol %), and Cs2CO3 (0.40
mmol) in 2 mL of CH2Cl2 (0.2 M) at rt. Starting from 1a (2.50
mmol), 1.08 g of 3aa was obtained. With 1h (2 equiv.). No
b
c
d
reaction occurred.
With regard to the influence of the indole aromatic
substitution, we assessed it by engaging a variety of diversely
substituted N-tosyl 3-nitroindoles 6a−o with dimethyl
propargyl malonate 1a (Scheme 3, right).
In either position 4, 5, 6, or 7, we observed little influence of
the substitution pattern of the starting nitroarene on the
efficiency of this new dearomatization process. Indeed, in all
the cases studied, the desired cyclopenta[b]indolines 7aa−7la
(15 examples) were obtained in good yields ranging from 66 to
98%. Various electron-donating (Me) as well as electron-
withdrawing (halogens, CN, and CO2Me) groups were well
tolerated.
The model reaction of 1a with 2a could be scaled up to the
gram-scale preparation of 3aa with a good 88% yield, and
replacing the tosyl protecting group by a nosyl moiety had no
detrimental effect (3ba, 79% yield). On the other hand,
increasing the steric demand on the sulfonyl aromatic group
tended to hamper the cyclization process. Indeed, 3-nitro-
indole 1c possessing a 2,4,6-trimethylbenzene sulfonyl moiety
and its 2,4,6-triisopropyl analogue 1d led to the corresponding
dearomatized products 3ca and 3da in lower 61 and 42%
yields, respectively. The reaction also proved compatible with
carbonyl-based protected indoles such as 1e (benzoyl), 1f
(acetyl), 1g (ethoxycarbonyl), and 1h (tert-butoxycarbonyl),
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a
Scheme 3. Scope of the ReactionInfluence of Both the Propargylic Nucleophile and the Nitroindole Aromatic Substitution
a
Reaction conditions: 1a or 6a−o (0.40 mmol), 2a−l (0.44 mmol, 1.1 equiv), Cu(OTf)2 (5 mol %), PPh3 (20 mol %), and Cs2CO3 (0.40 mmol)
b
c
d
in 2 mL of CH2Cl2 (0.2 M) at rt. 10 mol % Cu(OTf)2 and 40 mol % PPh3 were used. 8 was isolated in 87% yield. No reaction occurred.
In order to test the feasibility of developing an
enantioselective version of this reaction, a screening of few
chiral diphosphine ligands was performed. To our delight, after
a quick optimization study,16 we could demonstrate that the
readily available atropoisomeric diphosphine (R)-difluorphos17
allowed to induce a significant level of enantioselectivity in the
model reaction of nitroindole 1a with dimethyl propargylmal-
onate 2a. Indeed, when starting the reaction at −10 °C and
slowly warming up the reaction mixture to room temperature,
the cyclopenta[b]indoline 3aa was obtained in encouraging
51% enantiomeric excess (Scheme 4).
the resulting nitronate would then cyclize according to a chair-
like transition state through either an anti-carbocupration (C)
or a syn-carbocupration (C′) pathway to afford the
vinylcopper(I) intermediate D.18 After protodecupration,
either mediated by hydrogenocarbonate, 2a or A, the
dearomatization product would be released, together with
the regeneration of the catalytically competent copper(I)
complex.
To support this mechanistic picture further, we decided to
perform some kinetic analyses. More specifically, we aimed to
determine the order in catalyst so as to rule out a mechanistic
scenario in which alkyne activation would entail the formation
of a π-coordinated copper(I)acetylide copper(I) complex
[second order in copper(I)]. Indeed, the involvement of
such binuclear copper intermediates, uncovered by Fokin in
the context of the copper(I)-catalyzed alkyne/azide cyclo-
addition,19 could have explained why the nonterminal
propargylic derivative 2n did not allow to obtain the
corresponding dearomatization product 3an.
Scheme 4. Proof of Concept for an Enantioselective Version
of This Dearomatization Process
For this purpose, considering the dearomatization reaction
of 1a with 2a, we applied the variable time normalization
20
́
analysis (VTNA) method developed by Bures. The
This result represents the proof of concept that the
development of an enantioselective version of this dearomative
cycloaddition process is reachable, even if higher stereocontrol
would require an in-depth chiral ligand screening.
concentration of cycloadduct 3aa was monitored over time
1
by H NMR while employing two different initial catalyst
loadings [Scheme 5, (b)].21 By plotting product concentration
against t[Cu]γ for several values of γ (0.5, 1, 2), the best
overlay was obtained when γ = 1,16 which allowed to confirm a
first order in the catalyst, in line with our mechanistic proposal,
and to confirm the occurrence of binuclear copper
intermediates.
From a mechanistic perspective [Scheme 5, (a)], in line with
previous works,13,14 we propose that the copper(I) complex
resulting from the reduction of copper(II) triflate with
triphenylphosphine may form the π-alkyne copper intermedi-
ate A in the presence of a propargylic nucleophile. Although in
basic reaction conditions, A may likely exist in equilibrium with
the corresponding alkynylcopper(I) derivative A′, the former
would be prone to deprotonation in the presence of cesium
carbonate and should thereby generate the pseudo all-carbon
1,3-dipole B. Upon Michael addition onto the 3-nitroindole,
In conclusion, we have developed a straightforward access to
cyclopenta[b]indolines. This new method, which is based on a
copper(I)-catalyzed dearomative (3 + 2) cycloaddition
reaction between 3-nitroindoles and propargylic nucleophiles,
occurs with remarkably mild reaction conditions and is
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Scheme 5. Mechanistic Proposal and Kinetic Analyses
1
(461 mg, 35% yield) after trituration in methanol. H NMR (400
MHz, CDCl3): δ 8.60 (s, 1H), 8.50 (s, 1H), 7.90−7.80 (m, 2H), 7.75
(dd, J = 1.8, 1.2 Hz, 2H), 7.40−7.29 (m, 2H), 2.41 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 147.0, 135.7, 133.7, 132.9,
132.1, 130.8 (2C), 130.2, 128.4, 127.6 (2C), 123.7, 115.4, 90.7, 21.9
ppm; IR (film): ν 3145, 2360, 2338, 1738, 1535, 1386, 1220 cm−1;
mp (°C) 206−208; HRMS (ESI): [M + H+] calcd for
(C15H12IN2O4S)+, 442.9557; found, 442.9557.
compatible with a large substrate scope. Thereby, chiral
phosphorus ligands can be used and induce relevant levels of
enantioselectivity. Finally, a plausible mechanistic proposal is
given, supported by kinetic analyses.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under an argon
atmosphere unless specified. Reaction vessels were oven-dried, cooled
under vacuum, and flushed with argon before use. Cyclohexane and
ethyl acetate were distilled under reduced pressure prior to silica gel
chromatography. 1,2-Dichloroethane was distilled over calcium
hydride. Methanol was distilled over sodium. Tetrahydrofuran
(THF), CH2Cl2, dimethylformamide (DMF), and toluene were
dried over alumina columns. Reagent grade diisopropyl ether and
hexane were purchased and used without further purification. Every
reagent was either purified following the methods described in the
literature or used without further purification. Starting materials 1a−j,
4, 2a−n, and 6a−o were prepared according to known protocols.7,9,22
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded at 400 MHz. Chemical shifts are reported in delta (δ) units
parts per million (ppm) relative to the residual protiated solvent.
Coupling constants are reported in hertz (Hz). The following
abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet,
sept = septuplet, m = multiplet, and brs = broad singlet. Carbon-13
nuclear magnetic resonance (13C NMR) spectra were recorded at 101
MHz. Chemical shifts are reported in delta (δ) units parts per million
(ppm) relative to the center line of the triplet at 77.16 ppm for
deuterochloroform. 13C NMR experiments were routinely run with
1H broadband decoupling. Fluorine-19 nuclear magnetic resonance
(19F NMR) spectra were recorded at 376 MHz.
General Protocol for the (3 + 2) Cycloaddition Reaction. In a
screw-capped vial under an argon atmosphere, cesium carbonate
(130.4 mg, 0.40 mmol), nitroindole (0.40 mmol), and dichloro-
methane (800 μL) were successively added. To the resulting mixture
was added the propargylated derivative (0.44 mmol), and the mixture
was stirred at room temperature for 5 min. A solution of Cu(OTf)2
(7.2 mg, 0.02 mmol) and PPh3 (21.0 mg, 0.08 mmol) in
dichloromethane (800 μL), previously stirred at room temperature
for 30 min, was then transferred via cannula. The cannula was washed
with additional dichloromethane (400 μL) (total volume of solvent =
2.0 mL), and the mixture was stirred at room temperature until thin-
layer chromatography indicated full conversion of the starting
nitroindole. The mixture was diluted with dichloromethane (10
mL), loaded onto a small silica plug, eluted with dichloromethane (40
mL), and evaporated under reduced pressure. The resulting crude
mixture was purified by flash column chromatography or trituration to
afford the desired cycloadduct.
Analytical data for the major isomer of compounds 3af, 3ah, and
3ai are described below. Selected 1H NMR peaks for minor isomers of
compounds 3af, 3ah, and 3ai are also reported.
(
)-Dimethyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate (3aa).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol), starting
from 1a (127 mg, 0.40 mmol), as a white solid (158 mg, 81% yield)
after flash column chromatography (petroleum ether/methyl tert-
High-resolution mass spectrometry (HRMS) analyses were
́
performed at Sorbonne Universite by ESI-orbitrap (electrospray
ionization−ion trapping). Melting point values were recorded on a
Kofler bench. Enantiomeric excesses were determined by high-
performance liquid chromatography using a chiral stationary phase
(Chiralpak IA). The optical rotation value was measured with
instruments operating at λ = 589 nm, corresponding to the sodium D
line at the temperatures indicated.
1
butyl ether 9:1−8:2). H NMR (400 MHz, CDCl3): δ 7.72 (dt, J =
8.3, 0.8 Hz, 1H), 7.53−7.40 (m, 4H), 7.23 (td, J = 7.6, 1.0 Hz, 1H),
7.17−7.07 (m, 2H), 6.50 (s, 1H), 5.29−5.22 (m, 1H), 5.21−5.14 (m,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.07 (dt, J = 16.1, 2.5 Hz, 1H), 2.94
(dt, J = 16.1, 1.1 Hz, 1H), 2.33 (s, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 169.6, 167.3, 145.2, 144.0, 143.2, 132.9, 132.3, 129.9
(2C), 127.7 (2C), 127.3, 127.2, 126.3, 118.3, 110.5, 100.1, 73.3, 63.9,
53.8, 53.5, 40.5, 21.7 ppm; IR (film): ν 2950, 2161, 2020, 1732, 1547,
5-Iodo-3-nitro-1-tosyl-1H-indole (6i). The product was ob-
tained according to the procedure described by Hyland et al.,9 starting
from 5-iodo-N-tosylindole (1.27 g, 3.2 mmol), as a pale yellow solid
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+
1292, 1169 cm−1; mp (°C) 147−149; HRMS (ESI): [M + NH4 ]
= 7.6 Hz, 1H), 6.78 (s, 1H), 5.77 (q, J = 1.9 Hz, 1H), 5.39 (q, J = 1.9
Hz, 1H), 3.65 (s, 3H), 3.48 (s, 3H), 3.27 (dt, J = 16.3, 2.0 Hz, 1H),
3.04 (d (broad), J = 16.3 Hz, 1H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 169.3, 169.1, 167.4, 142.9, 142.7, 135.3, 131.6, 131.1,
128.7 (2C), 127.6 (2C), 126.5, 126.0, 124.7, 116.2, 112.7, 98.3, 73.3,
61.4, 53.5, 53.1, 41.4 ppm; IR (film): ν 3008, 2953, 2360, 1732, 1660,
calcd for (C23H22N2O8SNH4)+, 504.1435; found, 504.1433.
(−)-Dimethyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate
((−)-3aa). The product was obtained following the general procedure
starting from 1a (127 mg, 0.40 mmol), 2a (75 mg, 0.44 mmol),
Cu(OTf)2 (8.6 mg, 0,024 mmol), and (R)-difluorphos (41 mg, 0,06
mmol). The reaction was started at −10 °C and slowly warmed up to
room temperature. 3aa was obtained as a white solid (175 mg, 90%
yield). The enantiomeric excess (51%) was determined by HPLC
(Daicel Chiralpak IA, T = 20 °C, 254 nm, 2-propanol/dichloro-
methane = 85:15, flow rate = 0.4 mL min−1): tR (minor) = 16.69 min
and tR (major) = 19.95 min. [α]2D0 −2.4 (c 0.01, dichloromethane).
1550, 1378 cm−1
(C23H20N2O7H)+, 437.1343; found, 437.1344.
)-Dimethyl 4-Acetyl-1-methylene-8b-nitro-1,3a,4,8b-
; HRMS (ESI): [M +
H+] calcd for
(
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate (3fa).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (150 mg, 0.88 mmol),
starting from 1f (163 mg, 0.80 mmol), as a pale brown solid (128
mg, 43% yield) after flash column chromatography (petroleum ether/
(
)-Dimethyl 1-Methylene-8b-nitro-4-((2-nitrophenyl)-
sulfonyl)-1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-di-
carboxylate (3ba). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44
mmol), starting from 1b (139 mg, 0.40 mmol), as a pale yellow solid
1
ethyl acetate 9:1−8:2). H NMR (400 MHz, CDCl3): δ 8.00 (br s,
1H), 7.60 (d, J = 7.7 Hz, 1H), 7.42 (td, J = 7.7, 1.4 Hz, 1H), 7.20 (td,
J = 7.6, 1.0 Hz, 1H), 6.66 (s, 1H), 5.58 (dt, J = 2.5, 1.3 Hz, 1H), 5.33
(dt, J = 2.5, 1.3 Hz, 1H), 3.85 (s, 3H), 3.57 (s, 3H), 3.30 (d, J = 16.6
Hz, 1H), 3.02 (d, J = 16.6 Hz, 1H), 2.41 (s, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 170.2, 169.5, 167.4, 143.3, 142.2, 132.2, 126.5,
125.5, 125.1, 118.1, 111.5, 99.9, 72.1, 62.7, 53.9, 53.4, 40.7, 23.9 ppm;
IR (film): ν 3008, 2957, 2360, 1756, 1732, 1677, 1543 cm−1; mp (°C)
118−120; HRMS (ESI): [M + H+] calcd for (C18H18N2O7H)+,
375.1187; found, 375.1186.
1
(164 mg, 79% yield) after trituration in diisopropyl ether. H NMR
(400 MHz, CDCl3): δ 7.85 (dd, J = 8.0, 1.3 Hz, 1H), 7.70 (td, J = 7.8,
1.4 Hz, 1H), 7.67−7.60 (m, 1H), 7.62−7.51 (m, 3H), 7.55−7.46 (m,
1H), 7.30 (td, J = 7.6, 1.1 Hz, 1H), 6.62 (d, J = 0.6 Hz, 1H), 5.52−
5.41 (m, 1H), 5.34−5.25 (m, 1H), 3.90 (s, 3H), 3.72 (s, 3H), 3.22−
3.06 (m, 1H), 3.05−2.94 (m, 1H) ppm; 13C{1H} NMR (101 MHz,
CDCl3): δ 169.5, 167.3, 148.5, 143.0, 142.7, 135.1, 132.5, 131.7,
131.2, 129.8, 127.0, 126.8, 126.6, 124.5, 117.9, 111.9, 99.8, 72.9, 63.2,
53.9, 53.5, 40.9 ppm; IR (film): ν 3103, 2957, 2360, 2173, 1978,
( )-4-Ethyl 3,3-Dimethyl 1-Methylene-8b-nitro-1,2,3a,8b-
tetrahydrocyclopenta[b]indole-3,3,4-tricarboxylate (3ga).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol), starting
from 1g (94 mg, 0.40 mmol), as a yellow oil (81 mg, 50% yield) after
flash column chromatography (petroleum ether/ethyl acetate 9:1−
+
1732, 1546 cm−1; mp (°C) 201−203; HRMS (ESI): [M + NH4 ]
calcd for (C22H19N3O10SNH4)+, 535.1129; found, 535.1130.
(
)-Dimethyl 4-(Mesitylsulfonyl)-1-methylene-8b-nitro-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (3ca). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 1c (138 mg, 0.40 mmol), as a brownish solid (126 mg,
61% yield) after trituration in diisopropyl ether. 1H NMR (400 MHz,
CDCl3): δ 7.57−7.51 (m, 2H), 7.46−7.40 (m, 1H), 7.28 (dd, J = 7.6,
1.1 Hz, 1H), 6.98−6.85 (m, 2H), 6.22 (s, 1H), 5.32−5.23 (m, 1H),
5.23−5.14 (m, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.09−2.86 (m, 2H),
2.45 (s, 6H), 2.29 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
169.6, 167.2, 144.4, 144.2, 144.0, 141.2, 132.6 (3C), 131.8, 131.1,
127.4 (2C), 126.3, 119.9, 110.4, 100.4, 72.5, 63.4, 53.7, 53.4, 40.8,
23.5 (2C), 21.2 ppm; IR (film): ν 2950, 2360, 2338, 1737, 1550,
1
8:2). H NMR (400 MHz, CDCl3): δ 7.81 (br s, 1H), 7.65 (dd, J =
7.6, 1.3 Hz, 1H), 7.48−7.35 (m, 1H), 7.13 (td, J = 7.6, 1.1 Hz, 1H),
6.56 (s, 1H), 5.69 (dt, J = 3.3, 1.6 Hz, 1H), 5.36 (dt, J = 2.9, 1.5 Hz,
1H), 4.37−4.13 (m, 2H), 3.86 (s, 3H), 3.49 (s, 3H), 3.23 (dt, J =
15.9, 1.9 Hz, 1H), 3.10 (dt, J = 15.9, 2.2 Hz, 1H), 1.35 (t, J = 7.2 Hz,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.7, 167.8, 152.3,
144.0, 142.7, 132.1, 126.5, 124.7, 123.9, 115.6, 112.4, 99.3, 72.4, 62.6,
62.1, 53.5, 53.1, 41.9, 14.4 ppm; IR (film): ν 2955, 2359, 1731, 1551,
1273, 1067 cm−1
(C19H20N2O8H)+, 405.1292; found, 405.1292.
)-4-(tert-Butyl) 3,3-Dimethyl 1-Methylene-8b-nitro-
; HRMS (ESI): [M +
H+] calcd for
(
+
1355, 1166 cm−1; mp (°C) 158−160; HRMS (ESI): [M + NH4 ]
1,2,3a,8b-tetrahydrocyclopenta[b]indole-3,3,4-tricarboxylate
(3ha). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 1h (105 mg, 0.40 mmol), as a yellow solid (133 mg,
77% yield) after flash column chromatography (petroleum ether/
calcd for (C25H26N2O8SNH4)+, 532.1748; found, 532.1748.
(
)-Dimethyl 1-Methylene-8b-nitro-4-((2,4,6-
triisopropylphenyl)sulfonyl)-1,3a,4,8b-tetrahydrocyclopenta-
[b]indole-3,3(2H)-dicarboxylate (3da). The product was obtained
following the general procedure with dimethyl 2-(prop-2-yn-1-
yl)malonate 2a (75 mg, 0.44 mmol), starting from 1d (171 mg,
0.40 mmol), as a white solid (100 mg, 42% yield) after flash column
chromatography (petroleum ether/ethyl acetate 98:2−8:2). 1H NMR
(400 MHz, CDCl3): δ 7.58−7.48 (m, 2H), 7.44 (td, J = 7.6, 1.4 Hz,
1H), 7.25 (td, J = 7.6, 1.1 Hz, 1H), 7.12 (s, 2H), 6.30 (s, 1H), 5.33−
5.24 (m, 1H), 5.22−5.12 (m, 1H), 3.95 (hept, J = 6.7 Hz, 2H), 3.79
(s, 3H), 3.71 (s, 3H), 3.03 (dt, J = 16.0, 2.3 Hz, 1H), 2.98−2.79 (m,
2H), 1.25 (d, J = 5.4 Hz, 6H), 1.23 (d, J = 5.4 Hz, 6H), 0.89 (s, 6H)
ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.5, 167.3, 154.2, 152.0
(2C), 144.2, 143.9, 131.7, 130.1, 127.9, 127.4, 126.4, 124.6 (2C),
120.0, 110.3, 99.8, 72.0, 63.4, 53.6, 53.3, 40.7, 34.3, 30.9 (2C), 24.9
(2C), 24.8 (2C), 23.61, 23.57 ppm; IR (film): ν 2955, 2359, 1735,
1600, 1551, 1172 cm−1; mp (°C) 197−199; HRMS (ESI): [M + H+]
calcd for (C31H38N2O8SH)+, 599.2422; found, 599.2423.
1
methyl tert-butyl ether 9:1−7:3). H NMR (400 MHz, CDCl3): δ
7.74 (br s, 1H), 7.62 (dd, J = 7.6, 1.1 Hz, 1H), 7.45−7.34 (m, 1H),
7.11 (td, J = 7.6, 1.1 Hz, 1H), 6.56 (s, 1H), 5.72−5.51 (m, 1H),
5.40−5.23 (m, 1H), 3.86 (s, 3H), 3.56 (s, 3H), 3.29−3.01 (m, 2H),
1.56 (s, 9H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.8, 168.0,
151.4, 144.3, 143.1, 132.1, 126.6, 124.8, 123.6, 115.8, 111.5, 99.4,
83.0, 72.3, 62.5, 53.6, 53.2, 41.8, 28.3 (3C) ppm; IR (film): ν 2996,
2968, 2360, 2342, 1734, 1716, 1548 cm−1; mp (°C) 123−125; HRMS
(ESI): [M + Na+] calcd for (C21H24N2O8Na)+, 455.1425; found,
455.1424.
(
)-Dimethyl 7-Acetoxy-1-methylene-8b-nitro-1,2,3a,8b-
tetrahydro-3H-cyclopenta[b]benzofuran-3,3-dicarboxylate
(5). The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol), starting
from 4 (89 mg, 0.40 mmol), as a pale yellow solid (129 mg, 82%
yield) after flash column chromatography (petroleum ether/ethyl
acetate 9:1−8:2). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 2.4 Hz,
1H), 7.06 (dd, J = 8.8, 2.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.57 (d,
J = 1.2 Hz, 1H), 5.69−5.54 (m, 1H), 5.36−5.23 (m, 1H), 3.83 (s,
3H), 3.75 (s, 3H), 3.27−3.10 (m, 1H), 3.10−2.96 (m, 1H), 2.28 (s,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.6, 168.9, 166.7,
157.3, 145.5, 143.8, 126.0, 123.3, 119.1, 111.9, 111.1, 101.1, 92.1,
63.3, 53.7, 53.3, 39.3, 21.1 ppm; IR (film): ν 3019, 2955, 2359, 1738,
(
)-Dimethyl 4-Benzoyl-1-methylene-8b-nitro-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate (3ea).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (150 mg, 0.88 mmol),
starting from 1e (213 mg, 0.80 mmol), as a yellow oil (223 mg,
61% yield) after flash column chromatography (petroleum ether/ethyl
1
acetate 8:2−6:4). H NMR (400 MHz, CDCl3): δ 7.67 (dt, J = 7.7,
0.9 Hz, 1H), 7.57 (s, 1H), 7.55 (p, J = 2.0 Hz, 2H), 7.52 (t, J = 1.5
Hz, 1H), 7.48 (dd, J = 7.9, 6.6 Hz, 2H), 7.26−7.18 (m, 1H), 7.14 (t, J
3843
https://dx.doi.org/10.1021/acs.joc.9b03459
J. Org. Chem. 2020, 85, 3838−3848

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1556, 1481, 1216 cm−1; mp (°C) 136−138; HRMS (ESI): [M +
yield) after trituration in diisopropyl ether. 1H NMR (400 MHz,
CDCl3): δ 8.28−8.03 (m, 2H), 7.74 (dd, J = 8.6, 0.6 Hz, 1H), 7.56−
7.39 (m, 2H), 7.21−7.02 (m, 2H), 6.54 (d, J = 1.0 Hz, 1H), 5.44−
5.29 (m, 1H), 5.29−5.14 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.82 (s,
3H), 3.08 (dt, J = 16.2, 2.4 Hz, 1H), 2.97 (dq, J = 16.2, 1.2 Hz, 1H),
2.31 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.4,
167.15, 165.7, 146.6, 145.6, 143.1, 133.9, 132.8, 130.0 (2C), 129.0,
128.2, 127.5 (2C), 127.3, 117.3, 111.5, 99.3, 73.8, 63.8, 53.8, 53.5,
52.4, 40.6, 21.7 ppm; IR (film): ν 3012, 2955, 2360, 2342, 1737,
+
NH4 ] calcd for (C18H17NO9NH4)+, 409.1242; found, 409.1242.
(
)-Dimethyl 8-Methyl-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7aa). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6a (132 mg, 0.40 mmol), as a pale brown
solid (140 mg, 70% yield) after flash column chromatography
1
(petroleum ether/methyl tert-butyl ether 9:1−7:3). H NMR (400
+
1718, 1558 cm−1; mp (°C) 181−183; HRMS (ESI): [M + NH4 ]
MHz, CDCl3): δ 7.59 (d, J = 7.9 Hz, 1H), 7.48−7.40 (m, 2H), 7.36
(t, J = 7.9 Hz, 1H), 7.16−7.08 (m, 2H), 6.98 (d, J = 7.9 Hz, 1H), 6.38
(d, J = 1.0 Hz, 1H), 5.41−5.31 (m, 1H), 5.07−4.96 (m, 1H), 3.89 (s,
3H), 3.88 (s, 3H), 3.06 (dt, J = 15.5, 2.6 Hz, 1H), 2.89 (dd, J = 15.5,
0.9 Hz, 1H), 2.35 (s, 3H), 2.24 (s, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 169.6, 167.1, 145.2, 144.1, 141.8, 139.4, 133.1,
132.3, 129.9 (2C), 129.3, 127.7 (2C), 124.5, 116.4, 113.6, 101.6, 74.0,
63.5, 53.9, 53.6, 40.9, 21.7, 18.6 ppm; IR (film): ν 3004, 2955, 2360,
2342, 1732, 1552, 1171 cm−1; mp (°C) 176−178; HRMS (ESI): [M
calcd for (C25H24N2O10SNH4)+, 562.1490; found, 562.1486.
(
)-Dimethyl 7-Fluoro-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7fa). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 6f (135 mg, 0.40 mmol), as a white solid (197 mg, 98%
yield) after flash column chromatography (petroleum ether/methyl
1
tert-butyl ether 8:2). H NMR (400 MHz, CDCl3): δ 7.68 (dd, J =
+
+ NH4 ] calcd for (C24H24N2O8SNH4)+, 518.1592; found, 518.1590.
8.9, 4.4 Hz, 1H), 7.48−7.38 (m, 2H), 7.21−7.08 (m, 4H), 6.48 (d, J =
1.0 Hz, 1H), 5.20 (ddt, J = 7.9, 2.6, 1.3 Hz, 2H), 3.88 (s, 3H), 3.86 (s,
3H), 3.07 (dt, J = 16.2, 2.6 Hz, 1H), 2.95 (dq, J = 16.2, 1.2 Hz, 1H),
2.35 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.4, 167.1,
160.8 (d, JC−F = 246.6 Hz), 145.5, 143.8, 139.3, 132.4, 130.0 (2C),
129.0 (d, JC−F = 8.9 Hz), 127.7 (2C), 119.79 (d, JC−F = 8.5 Hz),
119.77 (d, JC−F = 23.8 Hz), 114.2 (d, JC−F = 25.0 Hz), 110.9, 99.6,
73.7, 63.9, 53.9, 53.6, 40.3, 21.7 ppm; 19F NMR (376 MHz, CDCl3):
δ −114.77 (m) ppm; IR (film): ν 3008, 2955, 2360, 2338, 1732,
1547, 1483, 1167 cm−1; mp (°C) 150−152; HRMS (ESI): [M +
(
)-Trimethyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3,8(2H)-tricarboxylate (7ba).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol), starting
from 6b (151 mg, 0.40 mmol), as a pale pink solid (153 mg, 70%
yield) after trituration in diisopropyl ether. 1H NMR (400 MHz,
CDCl3): δ 8.02 (dd, J = 8.3, 1.1 Hz, 1H), 7.75 (dd, J = 7.7, 1.1 Hz,
1H), 7.58−7.47 (m, 3H), 7.23−7.14 (m, 2H), 5.92 (s, 1H), 5.37−
5.31 (m, 2H), 3.87 (s, 3H), 3.87 (s, 3H), 3.74 (s, 3H), 2.93 (d, J = 1.6
Hz, 2H), 2.35 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
169.4, 167.1, 165.0, 145.6, 145.6, 139.7, 132.9, 132.0, 130.1 (2C),
128.27, 128.25, 128.0, 127.9 (2C), 122.1, 117.4, 97.8, 76.6, 63.4, 53.8,
53.6, 52.4, 41.5, 21.8 ppm; IR (film): ν 3004, 2955, 2359, 2340, 1731,
+
NH4 ] calcd for C23H21FN2O8SNH4, 522.1341; found, 522.13437.
(
)-Dimethyl 7-Chloro-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ga). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6g (140 mg, 0.40 mmol), as a white solid
(168 mg, 81% yield) after flash column chromatography (petroleum
ether/methyl tert-butyl ether 8:2−7:3). 1H NMR (400 MHz, CDCl3):
δ 7.65 (dd, J = 8.6, 0.6 Hz, 1H), 7.50−7.42 (m, 2H), 7.46−7.36 (m,
2H), 7.21−7.11 (m, 2H), 6.48 (s, 1H), 5.24 (dt, J = 2.5, 1.2 Hz, 1H),
5.20 (dt, J = 2.6, 1.2 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.08 (dt, J =
16.2, 2.6 Hz, 1H), 2.95 (dq, J = 16.2, 1.1 Hz, 1H), 2.35 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 169.4, 167.1, 145.5, 143.5,
+
1559, 1365 cm−1; mp (°C) 163−165; HRMS (ESI): [M + NH4 ]
calcd for (C25H24N2O10SNH4)+, 562.1490; found, 562.1486.
(
)-Dimethyl 8-Chloro-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ca). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 6c (140 mg, 0.40 mmol), as a white solid (182 mg, 88%
yield) after flash column chromatography (petroleum ether/methyl
tert-butyl ether 8:2−7:3). 1H NMR (400 MHz, CDCl3): δ 7.68 (dd, J
= 8.3, 0.9 Hz, 1H), 7.48−7.34 (m, 3H), 7.20−7.11 (m, 3H), 6.24 (d, J
= 1.1 Hz, 1H), 5.45 (dt, J = 2.6, 1.0 Hz, 1H), 5.19 (dt, J = 2.7, 0.7 Hz,
1H), 3.88 (s, 3H), 3.88 (s, 3H), 3.07 (dt, J = 15.7, 2.6 Hz, 1H), 2.96
(dd, J = 15.7, 1.1 Hz, 1H), 2.36 (s, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 169.4, 167.0, 145.7, 145.6, 139.6, 134.0, 133.2,
132.6, 130.1 (2C), 128.1, 127.5 (2C), 124.1, 117.0, 116.3, 100.4, 75.0,
63.5, 53.9, 53.6, 40.8, 21.7 ppm; IR (film): ν 3020, 2957, 2358, 2338,
1731, 1552, 1365 cm−1; mp (°C) 147−149; HRMS (ESI): [M +
141.8, 132.5, 132.5, 131.7, 130.0 (2C), 128.7, 127.6 (2C), 127.4,
119.3, 111.1, 99.5, 73.6, 63.8, 53.8, 53.5, 40.4, 21.7 ppm; IR (film): ν
3103, 2998, 2359, 1736, 1563, 1171 cm−1; mp (°C) 156−158; HRMS
+
(ESI): [M + NH4 ] calcd for (C23H21ClN2O8SNH4)+, 538.1045;
found, 538.1046.
(
)-Dimethyl 7-Bromo-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ha). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6h (159 mg, 0.40 mmol), as a yellow solid
NH4 ] calcd for (C23H21ClN2O8SNH4)+, 538.1045; found, 538.1045.
+
(
)-Dimethyl 7-Methyl-1-methylene-8b-nitro-4-tosyl-
1
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7da). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6d (132 mg, 0.40 mmol), as a yellow solid
(165 mg, 79% yield) after trituration in diisopropyl ether. H NMR
(400 MHz, CDCl3): δ 7.63−7.53 (m, 3H), 7.49−7.44 (m, 2H),
7.19−7.14 (m, 2H), 6.48 (d, J = 0.9 Hz, 1H), 5.25 (dt, J = 2.6, 1.2 Hz,
1H), 5.21 (dt, J = 2.6, 1.3 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.08
(dt, J = 16.2, 2.5 Hz, 1H), 2.96 (dq, J = 16.1, 1.1 Hz, 1H), 2.36 (s,
3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.4, 167.2, 145.6,
143.5, 142.3, 135.4, 132.6, 130.4, 130.1 (2C), 129.0, 127.7 (2C),
119.7, 119.1, 111.2, 99.5, 73.5, 63.9, 53.9, 53.6, 40.5, 21.8 ppm; IR
1
(158 mg, 79% yield) after trituration in diisopropyl ether. H NMR
(400 MHz, CDCl3): δ 7.57 (d, J = 8.3 Hz, 1H), 7.48−7.40 (m, 2H),
7.28−7.21 (m, 1H), 7.21−7.15 (m, 1H), 7.10 (d, J = 8.1 Hz, 2H),
6.47 (d, J = 0.9 Hz, 1H), 5.24−5.18 (m, 1H), 5.18−5.05 (m, 1H),
3.86 (s, 3H), 3.84 (s, 3H), 3.05 (dt, J = 16.1, 2.5 Hz, 1H), 2.91 (dq, J
= 16.1, 1.1 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H) ppm; 13C{1H} NMR
(101 MHz, CDCl3): δ 169.6, 167.2, 145.0, 144.0, 140.8, 136.3, 133.2,
132.8, 129.8 (2C), 127.7 (2C), 127.4, 127.1, 118.0, 110.3, 100.1, 73.4,
63.8, 53.7, 53.4, 40.3, 21.6, 21.2 ppm; IR (film): ν 3002, 2957, 2359,
1735, 1561, 1170 cm−1; mp (°C) 176−178; HRMS (ESI): [M +
(film): ν 2998, 2955, 2360, 2342, 2024, 1736, 1171 cm−1; mp (°C)
+
164−166; HRMS (ESI): [M
+
NH4
]
calcd for
(C23H21BrN2O8SNH4)+, 582.0540; found, 582.0543.
)-Dimethyl 7-Iodo-1-methylene-8b-nitro-4-tosyl-
(
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ia). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 6i (177 mg, 0.40 mmol), as a brown solid (199 mg, 81%
yield) after trituration in diisopropyl ether. 1H NMR (400 MHz,
CDCl3): δ 7.80−7.66 (m, 2H), 7.53−7.43 (m, 3H), 7.21−7.10 (m,
2H), 6.46 (d, J = 0.9 Hz, 1H), 5.27−5.22 (m, 1H), 5.22−5.16 (m,
1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.08 (dt, J = 16.2, 2.6 Hz, 1H), 2.95
+
NH4 ] calcd for (C24H24N2O8SNH4)+, 518.1592; found, 518.1591.
(
)-Trimethyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3,7(2H)-tricarboxylate (7ea).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol), starting
from 6e (151 mg, 0.40 mmol), as a pale brown solid (160 mg, 73%
3844
https://dx.doi.org/10.1021/acs.joc.9b03459
J. Org. Chem. 2020, 85, 3838−3848

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(dq, J = 16.2, 1.1 Hz, 1H), 2.36 (s, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 169.4, 167.1, 145.5, 143.4, 143.0, 141.2, 136.2,
132.6, 130.1 (2C), 129.2, 127.6 (2C), 119.9, 111.2, 99.4, 89.4, 73.3,
63.9, 53.9, 53.6, 40.5, 21.7 ppm; IR (film): ν 2953, 2360, 2342, 1736,
( )-Trimethyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3,5(2H)-tricarboxylate (7na).
The product was obtained following the general procedure with
dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol), starting
from 6n (151 mg, 0.40 mmol), as a yellow solid (148 mg, 68% yield)
after flash column chromatography (petroleum ether/methyl tert-
+
1562, 1173 cm−1; mp (°C) 173−175; HRMS (ESI): [M + NH4 ]
calcd for(C23H21IN2O8SNH4)+, 630.0402; found, 630.0403.
1
butyl ether 8:2−6:4). H NMR (400 MHz, CDCl3): δ 7.90 (dd, J =
(
)-Dimethyl 7-Cyano-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ja). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 6j (137 mg, 0.40 mmol), as a white solid (192 mg, 94%
yield) after flash column chromatography (petroleum ether/methyl
tert-butyl ether 8:2−6:4). 1H NMR (400 MHz, CDCl3): δ 7.80 (dd, J
= 8.4, 0.7 Hz, 1H), 7.77−7.68 (m, 2H), 7.54−7.46 (m, 2H), 7.21−
7.14 (m, 2H), 6.53 (d, J = 0.9 Hz, 1H), 5.33 (dt, J = 2.7, 1.5 Hz, 1H),
5.30−5.24 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.08 (dt, J = 16.4, 2.4
Hz, 1H), 3.01 (dq, J = 16.4, 1.3 Hz, 1H), 2.34 (s, 3H) ppm; 13C{1H}
NMR (101 MHz, CDCl3): δ 169.2, 167.1, 146.4, 146.0, 142.9, 136.1,
132.6, 131.7, 130.2 (2C), 127.9, 127.4 (2C), 118.2, 117.8, 111.9,
109.7, 99.0, 73.6, 63.7, 53.9, 53.6, 40.6, 21.7 ppm; IR (film): ν 3000,
2959, 2359, 2234, 1737, 1566, 1171 cm−1; mp (°C) 130−140; HRMS
7.7, 1.4 Hz, 1H), 7.59 (dd, J = 7.7, 1.4 Hz, 1H), 7.39 (t, J = 7.7 Hz,
1H), 7.26 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.35 (s, 1H),
5.13−5.06 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 2.99 (dt,
J = 16.3, 2.6 Hz, 1H), 2.92−2.86 (m, 1H), 2.37 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 169.4, 167.1, 166.6, 145.8,
144.9, 141.4, 133.7, 131.8, 130.7, 130.0 (2C), 129.9, 128.2 (2C),
127.2, 125.8, 110.1, 99.6, 73.6, 63.9, 53.8, 53.5, 52.5, 39.8, 21.8 ppm;
IR (film): ν 3094, 3026, 2955, 2357, 1734, 1555, 1433 cm−1; mp (°C)
+
164−166; HRMS (ESI): [M
+
NH4
]
calcd for
(C25H24N2O10SNH4)+, 562.1490; found, 562.14825.
)-Dimethyl 5-Chloro-1-methylene-8b-nitro-4-tosyl-
(
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7oa). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6o (140 mg, 0.40 mmol), as a white solid
(179 mg, 86% yield) after flash column chromatography (petroleum
ether/ethyl acetate 8:2−6:4). 1H NMR (400 MHz, CDCl3): δ 7.62−
7.54 (m, 2H), 7.49 (dd, J = 7.8, 1.2 Hz, 1H), 7.39 (dd, J = 7.8, 1.2 Hz,
1H), 7.27 (t, J = 7.8 Hz, 1H), 7.23−7.17 (m, 2H), 6.59 (s, 1H), 5.14
(ddt, J = 7.2, 2.9, 1.5 Hz, 2H), 3.81 (s, 3H), 3.67 (s, 3H), 2.95−2.82
(m, 2H), 2.40 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ
169.4, 167.0, 145.5, 144.8, 141.0, 133.6, 133.2, 132.3, 129.8 (2C),
128.7, 128.5 (2C), 127.1, 126.3, 110.6, 99.8, 74.4, 63.4, 53.8, 53.5,
39.6, 21.8 ppm; IR (film): ν 3020, 2953, 2360, 2342, 1729, 1546,
+
(ESI): [M + NH4 ] calcd for (C24H21N3O8SNH4)+, 529.1388; found,
529.13874.
(
)-Dimethyl 6-Methyl-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ka). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6k (132 mg, 0.40 mmol), as a pale brown
1
solid (132 mg, 66% yield) after trituration in diisopropyl ether. H
NMR (400 MHz, CDCl3): δ 7.55−7.50 (m, 1H), 7.51−7.43 (m, 2H),
7.29 (d, J = 8.0 Hz, 1H), 7.16−7.08 (m, 2H), 7.03 (dq, J = 8.0, 0.7
Hz, 1H), 6.47 (d, J = 0.9 Hz, 1H), 5.20 (dt, J = 2.4, 1.1 Hz, 1H), 5.14
(dt, J = 2.5, 1.2 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.07 (dt, J = 16.0,
2.6 Hz, 1H), 2.92 (dq, J = 16.0, 1.1 Hz, 1H), 2.42 (t, J = 0.7 Hz, 3H),
2.33 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.5, 167.2,
145.0, 144.0, 143.2, 143.1, 132.8, 129.8 (2C), 127.5 (2C), 127.3,
126.7, 124.3, 118.5, 110.0, 99.9, 73.4, 63.7, 53.7, 53.4, 40.3, 21.9, 21.6
ppm; IR (film): ν 2957, 2359, 2023, 1749, 1724, 1550, 1172 cm−1;
+
1432 cm−1; mp (°C) 163−165; HRMS (ESI): [M + NH4 ] calcd for
(C23H21ClN2O8SNH4)+, 538.1045; found, 538.1044.
(
)-Diisopropyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate (3ab).
The product was obtained following the general procedure with 2b
(100 mg, 0.44 mmol), starting from 1a (127 mg, 0.40 mmol), as a
white solid (155 mg, 71% yield) after flash column chromatography
+
mp (°C) 177−179; HRMS (ESI): [M + NH4 ] calcd for
1
(petroleum ether/methyl tert-butyl ether 9:1−8:2). H NMR (400
(C24H24N2O8SNH4)+, 518.1592; found, 518.1583.
MHz, CDCl3): δ 7.73 (dd, J = 8.2, 0.8 Hz, 1H), 7.51−7.39 (m, 4H),
7.23 (td, J = 7.6, 1.0 Hz, 1H), 7.09 (dd, J = 8.0, 0.7 Hz, 2H), 6.49 (s,
1H), 5.28−5.14 (m, 2H), 5.18−5.11 (m, 1H), 5.07 (hept, J = 6.3 Hz,
1H), 3.16−2.99 (m, 1H), 2.99−2.76 (m, 1H), 2.32 (s, 3H), 1.42 (d, J
= 6.3 Hz, 3H), 1.34 (d, J = 6.3 Hz, 3H), 1.30 (d, J = 6.3 Hz, 3H), 1.29
(d, J = 6.3 Hz, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 168.6,
166.5, 145.1, 144.6, 143.4, 133.0, 132.2, 129.8, 127.7, 127.5, 127.4,
126.3, 118.6, 110.1, 100.4, 73.2, 71.1, 70.4, 63.8, 40.9, 21.8, 21.7 (3C),
21.6 ppm; IR (film): ν 3447, 2981, 2933, 2360, 2025, 1724, 1551,
(
)-Dimethyl 6-Chloro-1-methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7la). The product was obtained following the general procedure
with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg, 0.44 mmol),
starting from 6l (140 mg, 0.40 mmol), as a white solid (178 mg, 86%
yield) after flash column chromatography (petroleum ether/methyl
tert-butyl ether 8:2−7:3). 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J =
1.8 Hz, 1H), 7.57−7.44 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 7.22−7.13
(m, 3H), 6.49 (d, J = 0.9 Hz, 1H), 5.27−5.21 (m, 1H), 5.21−5.18 (m,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.09 (dt, J = 16.2, 2.5 Hz, 1H), 2.96
(dq, J = 16.2, 1.1 Hz, 1H), 2.35 (s, 3H) ppm; 13C{1H} NMR (101
MHz, CDCl3): δ 169.4, 167.2, 145.6, 144.2, 143.6, 138.6, 132.7, 130.1
(2C), 128.2, 127.7 (2C), 126.7, 125.6, 118.3, 110.9, 99.5, 73.7, 63.8,
53.9, 53.6, 40.5, 21.7 ppm; IR (film): ν 3026, 2959, 2359, 2338, 1748,
+
1167 cm−1; mp (°C) 132−134; HRMS (ESI): [M + NH4 ] calcd for
(C27H30N2O8SNH4)+, 560.2061; found, 560.2061.
(
)-Dibenzyl 1-Methylene-8b-nitro-4-tosyl-1,3a,4,8b-
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxylate (3ac).
The product was obtained following the general procedure with 2c
(142 mg, 0.44 mmol), starting from 1a (127 mg, 0.40 mmol), as a
white solid (219 mg, 86% yield) after flash column chromatography
+
1727, 1551 cm−1; mp (°C) 190−192; HRMS (ESI): [M + NH4 ]
calcd for (C23H21ClN2O8SNH4)+, 538.1045; found, 538.1046.
1
(petroleum ether/methyl tert-butyl ether 85:15−8:2). H NMR (400
(
)-Dimethyl 5-Methyl-1-methylene-8b-nitro-4-tosyl-
MHz, CDCl3): δ 7.68 (dd, J = 8.6, 1.0 Hz, 1H), 7.47−7.36 (m, 4H),
7.30 (m, 8H), 7.26−7.15 (m, 3H), 7.10−7.01 (m, 2H), 6.51 (s, 1H),
5.34 (d, J = 12.2 Hz, 1H), 5.24−5.18 (m, 1H), 5.18 (d, J = 5.6 Hz,
2H), 5.13 (d, J = 12.2 Hz, 1H), 5.12−5.05 (m, 1H), 3.04 (dt, J = 16.0,
2.5 Hz, 1H), 2.93 (dq, J = 16.0, 1.2 Hz, 1H), 2.29 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 168.8, 166.6, 145.2, 144.0,
143.2, 135.2, 134.9, 132.8, 132.3, 129.9 (2C), 128.7 (2C), 128.63
(2C), 128.62, 128.57 (2C), 128.55 (2C), 128.4, 127.7 (2C), 127.2,
127.1, 126.2, 118.3, 110.6, 100.1, 73.3, 68.6, 68.5, 64.1, 40.6, 21.7
ppm; IR (film): ν 3018, 2360, 1722, 1595, 1552, 1162 cm−1; mp (°C)
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (7ma). The product was obtained following the general
procedure with dimethyl 2-(prop-2-yn-1-yl)malonate 2a (75 mg,
0.44 mmol), starting from 6m (132 mg, 0.40 mmol), as a white solid
1
(118 mg, 59% yield) after trituration in diisopropyl ether. H NMR
(400 MHz, CDCl3): δ 7.37−7.30 (m, 1H), 7.31−7.24 (m, 1H),
7.28−7.21 (m, 3H), 7.15−7.07 (m, 2H), 6.42 (s, 1H), 5.04−4.96 (m,
2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.83−2.70 (m, 2H), 2.55 (s, 3H),
2.38 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 169.5, 167.2,
145.7, 145.5, 142.4, 134.6, 132.6, 131.9, 130.3, 129.9 (2C), 128.4
(2C), 127.8, 125.4, 109.2, 99.5, 73.4, 64.0, 53.8, 53.5, 39.6, 21.8, 20.2
ppm; IR (film): ν 3034, 2955, 2359, 2340, 1730, 1544, 1163 cm−1;
+
135−137; HRMS (ESI): [M + NH4 ] calcd for (C35H30N2O8SNH4)+,
656.2061; found, 656.2063.
+
mp (°C) 174−176; HRMS (ESI): [M + NH4 ] calcd for
(
) - 1 - M e t h y l e n e - 8 b - n i t r o - 4 - t o s y l - 1 , 3 a , 4 , 8 b -
(C24H24N2O8SNH4)+, 518.1592; found, 518.1584.
tetrahydrocyclopenta[b]indole-3,3(2H)-dicarbonitrile (3ae).
3845
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J. Org. Chem. 2020, 85, 3838−3848

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
The product was obtained following the general procedure with 2e
(46 mg, 0.44 mmol), starting from 1a (127 mg, 0.40 mmol), as a
brown solid (138 mg, 82% yield) after trituration in a mixture
diisopropyl ether/hexane (1:1). 1H NMR (400 MHz, CDCl3): δ 7.87
(dt, J = 8.3, 0.8 Hz, 1H), 7.69−7.62 (m, 1H), 7.60−7.53 (m, 3H),
7.30 (td, J = 7.7, 1.0 Hz, 1H), 7.19 (dd, J = 8.0, 0.6 Hz, 2H), 5.91 (dq,
J = 2.4, 1.3 Hz, 1H), 5.85 (s, 1H), 5.67−5.62 (m, 1H), 3.39 (dt, J =
15.6, 2.4 Hz, 1H), 3.22 (dt, J = 15.6, 1.4 Hz, 1H), 2.36 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 146.1, 142.2, 139.5, 133.3,
132.5, 130.3 (2C), 127.6 (2C), 126.7, 126.6, 125.2, 118.9, 117.6,
113.1, 111.4, 97.4, 75.8, 43.6, 41.1, 21.8 ppm; IR (film): ν 3008, 2360,
2338, 2022, 1743, 1557, 1370 cm−1; mp (°C) 178−180; HRMS
132.9, 132.6, 130.0 (2C), 127.3 (2C), 126.3, 125.9, 125.7, 117.4,
117.0, 115.3, 98.3, 86.1, 75.3, 55.2, 43.5, 27.8, 21.6 ppm; min: 163.1,
145.6, 143.2, 142.8, 132.4, 132.2, 130.0 (2C), 127.4 (2C), 126.7,
126.7, 126.1, 118.1, 117.0, 113.7, 99.4, 85.9, 76.3, 52.7, 42.1, 27.5,
21.6 ppm; IR (film): ν 2979, 2931, 1737, 1555, 1369, 1171, 1151
+
cm−1; HRMS (ESI): [M + NH4 ] calcd for (C25H25N3O6SNH4)+,
513.1802; found, 513.1802.
(
)-3-Methylene-3a-nitro-1,8-ditosyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (3aj). The product was obtained
following the general procedure with 2j (184 mg, 0.88 mmol), starting
from 1a (253 mg, 0.80 mmol), as an orange oil (275 mg, 65% yield)
after flash column chromatography (petroleum ether/ethyl acetate
8:2−6:4). 1H NMR (400 MHz, CDCl3): δ 8.04−7.91 (m, 2H), 7.62−
7.52 (m, 3H), 7.48−7.38 (m, 2H), 7.38−7.30 (m, 2H), 7.19 (td, J =
7.6, 1.1 Hz, 1H), 7.17−7.11 (m, 2H), 6.94 (s, 1H), 5.41 (q, J = 1.7
Hz, 1H), 5.18 (q, J = 1.8 Hz, 1H), 4.38 (dt, J = 14.6, 1.5 Hz, 1H),
3.74 (dt, J = 14.7, 2.3 Hz, 1H), 2.43 (s, 3H), 2.33 (s, 3H) ppm;
13C{1H} NMR (101 MHz, CDCl3): δ 145.1, 144.3, 141.8, 141.1,
135.5, 133.4, 132.3, 129.8 (2C), 129.7 (2C), 128.0 (2C), 127.5 (2C),
126.8, 126.1, 125.2, 117.8, 110.1, 99.0, 84.2, 52.5, 21.5, 21.5 ppm; IR
(film): ν 2917, 2359, 2340, 1748, 1597, 1553, 1160 cm−1; HRMS
+
(ESI): [M + NH4 ] calcd for (C21H16N4O4SNH4)+, 438.1231; found,
438.1230.
( )-3-(tert-Butyl) 3-Methyl 1-Methylene-8b-nitro-4-tosyl-
1,3a,4,8b-tetrahydrocyclopenta[b]indole-3,3(2H)-dicarboxy-
late (3af). The product was obtained following the general procedure
with 2f (93 mg, 0.44 mmol), starting from 1a (127 mg, 0.40 mmol),
as an orange oil (159 mg, 72% yield, dr 3:1) after flash column
chromatography (petroleum ether/methyl tert-butyl ether 85:15−
8:2). 1H NMR (400 MHz, CDCl3) δ maj: 7.76−7.69 (m, 1H), 7.50−
7.42 (m, 2H), 7.46−7.38 (m, 2H), 7.27−7.18 (m, 1H), 7.12−7.04
(m, 2H), 6.47 (s, 1H), 5.20−5.16 (m, 1H), 5.16−5.12 (m, 1H), 3.86
(s, 3H), 3.03 (dt, J = 16.3, 2.5 Hz, 1H), 2.90−2.80 (m, 1H), 2.31 (s,
3H), 1.51 (s, 9H) ppm; min (selected signals): 6.43 (s, 1H), 5.21 (dt,
J = 2.2, 1.0 Hz, 1H), 3.81 (s, 3H), 3.00−2.90 (m, 2H), 1.51 (s, 9H)
ppm; 13C{1H} NMR (101 MHz, CDCl3) δ maj: 170.1, 165.4, 145.1,
144.5, 143.4, 132.9, 132.2, 129.8 (2C), 127.6 (2C), 127.5, 127.4,
126.3, 118.6, 110.3, 100.4, 83.8, 73.2, 64.2, 53.4, 40.5, 27.7, 21.6 ppm;
min: 170.1, 167.6, 145.1, 144.4, 143.1, 132.8, 132.2, 129.8 (2C), 127.6
(2C), 127.4, 127.2, 126.2, 118.3, 109.7, 100.0, 83.5, 73.0, 64.5, 53.2,
40.5, 27.7, 21.6 ppm; IR (film): ν 2978, 2359, 1729, 1551, 1367, 1170
+
(ESI): [M + NH4 ] calcd for (C25H23N3O6S2NH4)+, 543.1367;
found, 543.1364.
(
)-tert-Butyl-3-methylene-3a-nitro-8-tosyl-3,3a,8,8a-
tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (3al). The
product was obtained following the general procedure with 2l (137
mg, 0.88 mmol), starting from 1a (253 mg, 0.80 mmol), as a yellow
oil (42 mg, 11% yield) after flash column chromatography (petroleum
ether/methyl tert-butyl ether 9:1−8:2). 1H NMR (400 MHz, CDCl3):
δ 7.72 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.53 (dd, J = 7.7, 1.3 Hz,
1H), 7.48−7.39 (m, 1H), 7.36−7.27 (m, 1H), 7.22−7.09 (m, 3H),
5.42 (dd, J = 2.7, 1.5 Hz, 1H), 5.25 (q, J = 1.8 Hz, 1H), 4.52 (dt, J =
15.2, 1.6 Hz, 1H), 3.76 (d, J = 15.3 Hz, 1H), 2.34 (s, 3H), 1.58 (s,
9H) ppm; 13C{1H} NMR (101 MHz, CDCl3): δ 153.2, 144.9, 143.0,
142.0, 133.9, 132.1, 129.9 (2C), 128.6, 127.7 (2C), 126.6, 125.6,
117.5, 110.3, 98.7, 83.4, 82.5, 51.0, 28.5, 21.7 ppm; IR (film): ν 2974,
2927, 2871, 2359, 2340, 1704, 1553 cm−1; HRMS (ESI): [M + Na +]
calcd for (C23H25N3O6SNa)+, 494.1356; found, 494.1354.
+
cm−1; HRMS (ESI): [M + NH4 ] calcd for (C26H28N2O8SNH4)+,
546.1905; found, 546.1904.
(
)-Methyl-3-cyano-1-methylene-8b-nitro-4-tosyl-
1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole-3-carboxylate
(3ah). The product was obtained following the general procedure
with 2h (60 mg, 0.44 mmol), starting from 1a (127 mg, 0.40 mmol),
as a yellow oil (125 mg, 69% yield, dr 3:1) after flash column
chromatography (petroleum ether/methyl tert-butyl ether 8:2−7:3).
1H NMR (400 MHz, CDCl3) δ maj: 7.86 (dt, J = 8.3, 0.8 Hz, 1H),
Ethyl 5-Methylene-2-phenyltetrahydrofuran-3-carboxylate
(8). The product was obtained following the general procedure,
starting from 2g (101 mg, 0.44 mmol), as a colorless oil (88 mg, 87%
yield) after flash column chromatography (pure petroleum ether to
7.69 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 7.59−7.52 (m, 2H), 7.56−7.48
(m, 1H), 7.30−7.22 (m, 1H), 7.22−7.15 (m, 2H), 5.91 (ddd, J = 2.9,
1.6, 1.0 Hz, 1H), 5.88 (s, 1H), 5.60−5.54 (m, 1H), 4.03 (s, 3H), 3.36
(dt, J = 15.6, 2.8 Hz, 1H), 3.06 (dd, J = 15.6, 0.8 Hz, 1H), 2.35 (s,
3H) ppm; min (selected signals): 7.49−7.46 (m, 1H), 7.17−7.13 (m,
2H), 5.94 (s, 1H), 5.61 (m, 1H), 5.41 (m, 1H), 3.85 (s, 3H), 3.13−
3.09 (m, 2H), 2.33 (s, 3H) ppm; 13C{1H} NMR (101 MHz, CDCl3)
δ maj: 167.1, 145.6, 142.3, 141.6, 132.8, 132.5, 130.1 (2C), 127.3
(2C), 126.9, 126.3, 125.8, 118.1, 117.1, 116.8, 98.0, 75.9, 54.8, 54.5,
43.1, 21.7 ppm; min: 164.7, 145.1, 142.6, 142.4, 133.0, 132.4, 130.1
(2C), 127.5 (2C), 127.3, 126.4, 126.3, 117.6, 115.0, 113.6, 99.1,
76.017, 54.3, 52.1, 41.7, 21.7 ppm; IR (film): ν 3022, 2055, 2360,
1
petroleum ether/methyl tert-butyl ether 95:5). H NMR (400 MHz,
CDCl3): δ 7.94−7.80 (m, 2H), 7.50−7.34 (m, 3H), 4.72 (q, J = 2.9
Hz, 1H), 4.33 (q, J = 2.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.82 (t, J
= 2.9 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H) ppm. Spectral data of the
product were in accordance with those reported in the literature.14
ASSOCIATED CONTENT
■
sı
* Supporting Information
+
2340, 1748, 1555, 1170 cm−1; HRMS (ESI): [M + NH4 ] calcd for
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03459.
(C22H19N3O6SNH4)+, 471.1333; found, 471.1332.
(
)-tert-Butyl-3-cyano-1-methylene-8b-nitro-4-tosyl-
Copies of 1H and 13C NMR spectra for all new
compounds, more details concerning the screening of
chiral ligands for the enantioselective version, and
kinetic studies (PDF)
1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole-3-carboxylate
(3ai). The product was obtained following the general procedure with
2i (79 mg, 0.44 mmol), starting from 1a (127 mg, 0.40 mmol), as a
brown oil (167 mg, 84% yield, dr 5:1) after flash column
chromatography (petroleum ether/methyl tert-butyl ether 9:1−7:3).
1H NMR (400 MHz, CDCl3) δ maj: 7.84 (dd, J = 8.4, 1.3 Hz, 1H),
7.66 (dd, J = 7.9, 1.3 Hz, 1H), 7.55−7.52 (m, 2H), 7.52−7.47 (m,
1H), 7.23 (m, 1.1 Hz, 1H), 7.16 (m, 2H), 5.92 (s, 1H), 5.86−5.79
(m, 1H), 5.54−5.48 (m, 1H), 3.26 (dt, J = 15.5, 2.8 Hz, 1H), 3.08−
2.99 (m, 1H), 2.32 (d, J = 2.0 Hz, 3H), 1.64 (s, 9H) ppm; min
(selected signals): 7.74−7.69 (m, 1H), 7.63−7.59 (m, 1H), 7.13 (d, J
= 8.2 Hz, 2H), 5.90 (s, 1H), 5.62 (q, J = 1.9 Hz, 1H), 5.39 (q, J = 1.9
Hz, 1H), 3.21−3.10 (m, 2H), 2.31 (s, 3H), 1.42 (s, 9H) ppm;
13C{1H} NMR (101 MHz, CDCl3) δ maj: 165.0, 145.4, 142.4, 141.9,
AUTHOR INFORMATION
■
Corresponding Author
Maxime R. Vitale − Institute of Chemistry for Life and Health
́
Sciences, PSL Universite Paris, CNRS, Chimie ParisTech.
75005 Paris, France; orcid.org/0000-0002-6740-2472;
Email: maxime.vitale@chimieparistech.psl.eu
3846
https://dx.doi.org/10.1021/acs.joc.9b03459
J. Org. Chem. 2020, 85, 3838−3848

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Ramasastry, S. S. V. Recent Metal-Catalysed Approaches for the
Synthesis of Cyclopenta[b]Indoles. RSC Adv. 2018, 8, 18576−18588.
(4) (a) Kerr, M. A.; Keddy, R. G. The Annulation of 3-Alkylindoles
with 1,1-Cyclopropanediesters. Tetrahedron Lett. 1999, 40, 5671−
5675. (b) England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A.
Cyclopentannulation of 3-Alkylindoles: A Synthesis of a Tetracyclic
Subunit of the Kopsane Alkaloids. J. Org. Chem. 2001, 66, 4704−
4709.
Authors
Johanne Ling − Institute of Chemistry for Life and Health
Sciences, PSL Universite Paris, CNRS, Chimie ParisTech.
75005 Paris, France; orcid.org/0000-0003-2134-8711
David Mara − Institute of Chemistry for Life and Health
Sciences, PSL Universite Paris, CNRS, Chimie ParisTech.
75005 Paris, France
Baptiste Roure − Institute of Chemistry for Life and Health
Sciences, PSL Universite Paris, CNRS, Chimie ParisTech.
́
́
́
(5) (a) Birbaum, L.; Gillard, L.; Gerard, H.; Oulyadi, H.; Vincent,
́
G.; Moreau, X.; De Paolis, M.; Chataigner, I. Dearomatization of 3-
Nitroindoles with Highly γ-Functionalized Allenoates in Formal
(3+2) Cycloadditions. Chem.Eur. J. 2019, 25, 13688−13693.
75005 Paris, France
Maxime Laugeois − Institute of Chemistry for Life and Health
Sciences, PSL Universite Paris, CNRS, Chimie ParisTech.
́
(b) Cerveri, A.; Faza, O. N.; Lopez, C. S.; Grilli, S.; Monari, M.;
́
Bandini, M. Phosphine-Catalyzed Stereoselective Dearomatization of
75005 Paris, France
3-NO2-Indoles with Allenoates. J. Org. Chem. 2019, 84, 6347−6355.
(c) Li, K.; Gonca̧ lves, T. P.; Huang, K.-W.; Lu, Y. Dearomatization of
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03459
3-Nitroindoles by a Phosphine-Catalyzed Enantioselective [3+2]
Annulation Reaction. Angew. Chem., Int. Ed. 2019, 58, 5427−5431.
(d) Wang, H.; Zhang, J.; Tu, Y.; Zhang, J. Phosphine-Catalyzed
Enantioselective Dearomative [3+2]-Cycloaddition of 3-Nitroindoles
and 2-Nitrobenzofurans. Angew. Chem., Int. Ed. 2019, 58, 5422−5426.
(e) Liu, K.; Wang, G.; Cheng, S.-J.; Jiang, W.-F.; He, C.; Ye, Z.-S.
Phosphine-Catalyzed Dearomative [3+2] Annulation of 3-Nitro-
indoles and Allenoates. Tetrahedron Lett. 2019, 60, 1885−1890.
(f) Jin, L.-W.; Jiang, F.; Chen, K.-W.; Du, B.-X.; Mei, G.-J.; Shi, F.
Phosphine-Catalyzed Regiospecific (3 + 2) Cyclization of 3-
Nitroindoles with Allene Esters. Org. Biomol. Chem. 2019, 17,
3894−3901.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̀
J.L. and M.L. warmly thank the Ministere National de
l’Enseignement Superieur et de la Recherche for their PhD
́
research grants. The CNRS and ChimieParisTech are also
̀
́
acknowledged for their financial support. Charlene Ferard is
gratefully acknowledged for her previous involvement in the
preparation of some starting 3-nitroindoles. Dr Laurence
Grimaud is acknowledged for the fruitful discussions about the
(6) Trost, B. M.; Ehmke, V.; O’Keefe, B. M.; Bringley, D. A.
Palladium-Catalyzed Dearomative Trimethylenemethane Cycloaddi-
tion Reactions. J. Am. Chem. Soc. 2014, 136, 8213−8216.
́
Bures’ VTNA method and, together with Dr Olivia Bistri, for
́
(7) (a) Laugeois, M.; Ling, J.; Ferard, C.; Michelet, V.;
their thorough proofreading of this manuscript.
Ratovelomanana-Vidal, V.; Vitale, M. R. Palladium(0)-Catalyzed
Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with Vinyl-
cyclopropanes: An Entry to Stereodefined 2,3-Fused Cyclopentannu-
lated Indoline Derivatives. Org. Lett. 2017, 19, 2266−2269. (b) Gee,
Y. S.; Rivinoja, D. J.; Wales, S. M.; Gardiner, M. G.; Ryan, J. H.;
Hyland, C. J. T. Pd-Catalyzed Dearomative [3 + 2] Cycloaddition of
3-Nitroindoles with 2-Vinylcyclopropane-1,1-Dicarboxylates. J. Org.
Chem. 2017, 82, 13517−13529. . For enantioselective versions, see:
(c) Sun, M.; Zhu, Z.-Q.; Gu, L.; Wan, X.; Mei, G.-J.; Shi, F. Catalytic
Asymmetric Dearomative [3 + 2] Cycloaddition of Electron-Deficient
Indoles with All-Carbon 1,3-Dipoles. J. Org. Chem. 2018, 83, 2341−
2348. (d) Zhang, J.-Q.; Tong, F.; Sun, B.-B.; Fan, W.-T.; Chen, J.-B.;
Hu, D.; Wang, X.-W. Pd-Catalyzed Asymmetric Dearomative
Cycloaddition for Construction of Optically Active Pyrroloindoline
and Cyclopentaindoline Derivatives: Access to 3a-Aminopyrroloindo-
lines. J. Org. Chem. 2018, 83, 2882−2891.
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J. Org. Chem. 2020, 85, 3838−3848