Note

Cite This: J. Org. Chem. 2018, 83, 8695−8709 pubs.acs.org/joc

Nucleophilic Ring Opening of Donor−Acceptor Cyclopropanes with

the Cyanate Ion: Access to Spiro[pyrrolidone-3,3′-oxindoles]
Sergey V. Zaytsev,† Konstantin L. Ivanov,† Dmitry A. Skvortsov,† Stanislav I. Bezzubov,‡
Mikhail Ya. Melnikov,† and Ekaterina M. Budynina*,†
†
Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991 Russia
‡
Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskiy pr. 31, Moscow 119991 Russia
*
S Supporting Information
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ABSTRACT: The nucleophilic ring opening of donor−acceptor

Downloaded via INDIAN INST OF TECH KANPUR on March 4, 2024 at 06:04:31 (UTC).

cyclopropanes with the cyanate ion is reported for the first time.
Cyclopropanes, spiro-activated with oxindole fragments as acceptors,
are shown to undergo transformations into biologically relevant
spiro[pyrrolidone-3,3′-oxindoles] while being treated with potassi-
um cyanate under microwave assistance.

T he strain-driven ring opening of donor−acceptor (DA)

cyclopropanes1 with nucleophiles is of great importance
as a simple stereocontrolled pathway toward 1,3-functionalized
Scheme 1. Strategy of This Work

compounds.2 In a broad range of nucleophiles studied as

initiators of DA cyclopropane ring opening, N-nucleophiles are
of particular significance since they provide numerous
opportunities to synthesize structurally diverse N-containing
molecules, especially the most privileged and significant N-
heterocycles.3 Most N-nucleophiles that were investigated in
reactions with DA cyclopropanes are organic compounds, such
as amines,4 hydrazines,5 amides,6 nitriles,7 and N-heterocycles8
(Scheme 1a). Among inorganic salts, only sodium azide was
systematically studied in DA cyclopropane ring opening
toward the synthesis of functionalized organic azides and,
subsequently, N-heterocycles.9 Our previous study revealed
that, in general, nucleophilic ring opening of commonly used
2-arylcyclopropane-1,1-diesters triggered by an SN2-like attack
of the azide ion proceeded under prolonged heating at 100
°C.9b In this regard, less reactive nucleophiles can require more
demanding conditions, additionally activating undesired side
processes that invalidate the utility of the target reaction.
Despite these challenges, we attempted to design a new type of
a nucleophilic ring opening of DA cyclopropanes with the
cyanate ion, which is isoelectronic to the azide ion (Scheme
1b). Among DA cyclopropanes of several subclasses, cyclo-
propanes 1 spiro-activated with the oxindole were found to
tolerate severe reaction conditions. The discovered reaction isocyanate with an anionic center stabilized with an electron-
allowed for a new rapid access to spiro[pyrrolidone-3,3′- withdrawing group (EWG) (Scheme 1b). Therefore, this
oxindoles] 2, which are representatives of a large family of process can be compared with (3+2)-cycloadditions and
biologically relevant spiro[pyrrolidine-3,3′-oxindoles] (Scheme related reactions between DA cyclopropanes and isocyanates
1c).10
Spontaneous assembly of the pyrrolidone unit in 2 should be Received: April 12, 2018
obvious when accounting for intermediate formation of acyclic Published: June 12, 2018

© 2018 American Chemical Society 8695 DOI: 10.1021/acs.joc.8b00922

J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry Note

as well as their thio analogues (Scheme 2). As early as the late obtained results are in agreement with those reported by Kerr
1980s, Graziano and co-workers demonstrated that (3+2)- and co-workers and related to lactonization of cyclopropanes
proceeding presumably via SN2-like ring opening with the
Scheme 2. Pyrrolidine Core Formation via Reactions of DA chloride ion.16 Therefore, for the ester-substituted DA
Cyclopropanes with Iso(thio)cyanates cyclopropanes, lactonization and dealkoxycarbonylation are
more preferable under the studied conditions, while the
tendency of such cyclopropanes to undergo ring opening with
NCO− is much lower than that for the isoelectronic N3−.
We recently revealed that the SN2-like ring opening of DA
cyclopropanes with N3− is a convenient model to estimate
their relative reactivity.9b According to this model, 2-phenyl-
cyclopropane-1,1-dinitrile is more reactive than the diester
analogue. However, its reaction with NCO− led only to
products of oligomerization. In this regard, we recognized that
two key conditions should be satisfied. First, cyclopropane
should not be functionalized with an EWG prone to participate
in Cloke-type ring enlargements 17 or reactions with
nucleophiles, e.g., Krapcho dealkoxycarbonylation. Second,
the use of an EWG with lower acceptor properties requires
additional activation of the DA cyclopropane. Since one of the
common tricks for this is spiro-activation,18 we examined
cyclopropanes 1 spiro-activated with oxindole as an EWG in
reaction with NCO−, giving priority to biologically relevant
structures. Recently, similar cyclopropanes were found to
exhibit reactivity against N3− that was comparable to
arylcyclopropane-1,1-diesters.9a
Our initial experiments displayed that, despite significant
tarring, the reaction of cyclopropane 1a with KNCO in DMF
at 150 °C indeed resulted in the product of nucleophilic ring
opening/cyclization 2a in 20 and 50% yields for conventional
and microwave heating, respectively (Table 1, entries 1 and 2).
Due to the demonstrated superiority of microwave heating,
further optimization was carried out under microwave
assistance. A further study revealed that only 85% conversion
cycloadditions of dialkoxy-activated DA cyclopropanes to of 1a could be achieved, regardless of duration of heating and
iso(thio)cyanates provided the formation of γ-(thio)lactams.11
Reissig et al. carried out a related process with cyclopropyl Table 1. Optimization of the Reaction Conditions
anions yielding pyrroline derivatives.12 At the same time, Tsuji
et al. revealed a similar reactivity for vinyl-substituted DA
cyclopropanes when activated with Pd(0) catalysts.13 Recently,
Stoltz and co-workers reported analogous (3+2)-cycloaddition
between isocyanates and aryl-substituted DA cyclopropanes,14
which have been intensively studied in the recent years. A
more relevant example of this reaction with spirocyclopropa-
neoxindole being used was reported by Marti and Carreira.15
Our initial attempts were directed toward determining
reaction conditions for the chemoselective nucleophilic ring
opening and, thus, were related to the screening of starting DA
cyclopropanes with appropriate donor (EDG) and acceptor entry solvent additive (equiv) t (h) T (°C)a yield (%)b
(EWG) activating groups tolerant to these conditions. First, we 1 DMF 9.5 150 c
20
examined the common dimethyl 2-phenylcyclopropane-1,1- 2 DMF 7 150 50d
diester, which was treated with KNCO in DMF at several 3 DMF 18-crown-6 (2) 1.5 150 56d
temperatures. Its visible conversion was detected starting from 4 NMP 18-crown-6 (2) 1.5 170 55d
140 °C. However, Krapcho dealkoxycarbonylation was found 5 DMSO 18-crown-6 (2) 1 170 25
to be the main process (also caused by a nucleophilic attack 6 DMF 3 130 46
but on the ester group). Since the nucleophilic ring opening of 7 DMSO 4 150c trace
DA cyclopropanes with N3− was proved to be a reversible step, 8 DMF Et3N·HCl (1) 7 150 42
requiring a H+ source to complete the reaction, we checked 9 DMF Et3N·HCl (1) 10e 150 62
whether protic additives influenced the reaction of 2- 10 THF MgBr2·OEt2 (1) 3 130 f
phenylcyclopropane-1,1-diester with NCO− as well. We
found that the presence of Et3N·HCl did not allow for a
Microwave heating. bNMR yield. cConventional heating. dIsolated
reducing the temperature of the reaction, ultimately leading to yield. eAn extra portion of KNCO (2 equiv) was added in 4 h. fA
significant tarring along with detectable lactonization. The mixture of unidentified products.

8696 DOI: 10.1021/acs.joc.8b00922

J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
extra amounts of KNCO. Suspecting poor solubility of KNCO
under studied conditions, we carried out experiments with 18-
crown-6 (entries 3−5); however, only modest yields of 2a were
obtained at incomplete conversions of 1a, along with further
drops in 2a yields at additional heating. Varying solvents and
reaction temperatures did not provide enhancements in the 2a
yield (entries 4−7). Since the obtained results pointed to
reversibility, we carried out the reactions in the presence of
Et3N·HCl (entries 8 and 9), which would protonate the
intermediate anion A. Due to a high probability of KNCO
decomposition under the studied conditions, an extra amount
of KNCO was added in 4 h after initiation. In this case, the
reaction afforded a 96% conversion of 1a and a 62% isolated
yield of 2a (entry 9). A pilot experiment with a Lewis acid,
MgBr2·OEt2, produced a mixture of unidentified products
(entry 10). Consequently, the heating of 1a, KNCO (2 equiv),
and Et3N·HCl (1 equiv) in DMF at 150 °C (with an extra
amount of KNCO (2 equiv) in 4 h after initiation) was
considered optimal for nucleophilic ring opening of 1a with
NCO− (entry 9).
Under the optimized conditions, spiro[cyclopropane-1,3′-
oxindoles] 1 were examined to assess compatibilities of
substituents in spirooxindole and cyclopropane units (Scheme
3). A series of N-PMB-substituted cyclopropanes 1b−j (PMB
= para-methoxybenzyl), containing both donor and acceptor
groups in the cyclopropane aryl fragment, generally provided
products 2b−i in good yields, despite harsh reaction
conditions. Cyclopropanes 1b,c,i,j, containing electron-abun-
Scheme 3. Reaction Scope
8697
Note
dant aryls, as well as their counterparts 1d,e with electron-
deficient aryls, underwent nucleophilic ring opening with
NCO− more efficiently (3−6 h) than their phenyl analogue 1a
(10 h). The exception is para-NO2-substituted cyclopropane
1f, which did not produce the corresponding product 2f,
undergoing complete decomposition in 2 h instead. α-
Naphthyl derivative 1h was the slowest to react, due to the
ortho-bulkiness affecting the kinetics unfavorably. Its complete
conversion was observed in 16 h, leading to significant tarring
and, thus, decreasing the isolated yield of 2h down to 34%. 2-
Thienyl derivative 1k was also sufficiently tolerant toward
harsh reaction conditions, affording 2k in 3 h with a 56% yield.
The introduction of substituents in the benzene core of the
oxindole moiety allowed for more significant manipulations of
the reaction rate. Although 5-methyl derivative 1l underwent
ring opening by NCO− with a rate similar to that for 1a,
complete conversions of 5-halogen derivatives 1m−p were
achieved in 100−120 min. Competitive reactions of two
cyclopropanes 1l and 1p with KNCO allowed us to reveal that
for 90 min, 95% conversion of the Br derivative 1p was
achieved, whereas the Me derivative 1l exhibited only 18%
conversion. This tendency is in accordance with results of our
DFT calculations of SN2-like ring opening of 1 with NCO−:
the replacement of H or Me by halogens leads to lowering of
the corresponding energy barriers.19 Replacing the N-PMB
group with a Me one (1q−u) did not influence the reaction
times and the yields of the products 2q−u. The structure of 2r
was unambiguously proved by single crystal X-ray analysis.
The combination of N-unprotected pyrrolidone and N-
protected oxindole units in 2 allows for selective protection/
deprotection of both cyclic amides. The presence of the PMB
N-protecting group in oxindole allowed for the deprotection of
2,20 producing doubly N-unprotected spiro[pyrrolidone-3,3′-
oxindoles] 3 (Scheme 4). The evolution of 2 can also be
related to their selective reduction into the corresponding
pyrrolidines.21
Scheme 4. N-Deprotection of PMB Derivatives 2a,i,o
Preliminary in vitro tests of compounds 2 and 3 revealed
their moderate antiproliferative activity toward HEK293T,
MCF7, and A549 cell lines.19
In conclusion, we have demonstrated the use of the cyanate
ion as a new N-nucleophile for DA cyclopropane ring opening.
In comparison with the isoelectronic azide ion, the cyanate ion
was found to be less reactive toward small ring opening that
required a delicate trade-off between harsh reaction conditions
and DA cyclopropane reactivity. Based on the obtained results,
a method for nucleophilic ring opening of DA cyclopropanes,
spiro-activated with oxindole, with the cyanate ion was
developed. A series of cyclopropanes containing various
substituents in the oxindole and cyclopropane units exhibited
a good tolerance toward reaction conditions, ultimately
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
affording spiro[pyrrolidone-3,3′-oxindoles] with the N-unpro-
tected pyrrolidone unit.
■
EXPERIMENTAL SECTION
General Information. NMR spectra were acquired either on a
Bruker Avance 400 MHz spectrometer or on a Bruker Avance 600
MHz spectrometer at room temperature; the chemical shifts (δ) were
measured in ppm with respect to the solvent (1H CDCl3, δ = 7.27
ppm, DMSO-d6, δ = 2.50 ppm; 13C CDCl3, δ = 77.0 ppm, DMSO-d6,
δ = 39.5 ppm). Splitting patterns are designated as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet.
Coupling constants (J) are given in hertz. The structures of the
synthesized compounds were elucidated with the aid of 1D (1H, 13C,
APT, Gated 1H-Decoupling) and 2D (1H−1H COSY, 1H−13C
HMBC) NMR spectroscopy. High resolution mass spectra (HRMS)
were obtained using Thermo ScientificTM LTQ Orbitrap and AB
Sciex TripleTOF 5600+ mass spectrometers with a TurboV ESI
source. Single crystal X-ray analysis was performed with a Bruker
SMART APEX II diffractometer. Crystallographic data were collected
at 150 K using graphite monochromatized Mo Kα radiation (λ =
0.71073 A) using a ω-scan mode. Absorption corrections based on
measurements of equivalent reflections were applied (APEX II). The
structures were solved by direct methods and refined by full matrix
least-squares on F2 with anisotropic thermal parameters for all non-
hydrogen atoms. Melting points (mp) were determined using an
Electrothermal IA 9100 capillary melting point apparatus. Microwave
reactions were performed in a Monowave 300-Anton Paar microwave
reactor in sealed reaction vessels. The temperature was monitored
with an installed IR detector. Analytical thin layer chromatography
(TLC) was carried out with silica gel plates (silica gel 60, F254,
supported on aluminum) visualized with an ultraviolet lamp (254
nm). Column chromatography was performed on silica gel 60 (230−
400 mesh).
General Procedure for the Synthesis of Alkenes S1. NaOH
(158 mg, 3.95 mmol) was dissolved in a mixture of EtOH (7.9 mL)
and water (7.9 mL). The corresponding 1-(4-methoxybenzyl)-1H-
indole-2,3-dione or 1-methyl-1H-indole-2,3-dione (1.98 mmol) and
aldehyde (2.18 mmol) were then added successively to the mixture
under vigorous stirring. To ensure solubility of product under the
reaction conditions, CH2Cl2 (ca. 20% of the initial solvent volume, 3
mL) was added. The reaction mixture was stirred vigorously at room
temperature for the time specified. Then reaction mixture was poured
into water (30 mL) and extracted with ethyl acetate (3 × 30 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(petroleum ether−ethyl acetate). Spectral data for alkenes S1a,22
S1j,23 and S1q−u9a are consistent with those reported previously.
1-(4-Methoxybenzyl)-3-(4-methylbenzylidene)-1,3-dihydro-2H-
indol-2-one (S1b). This compound was obtained from 4-methyl-
benzaldehyde (209 mg, 0.205 mL, 1.74 mmol) and 1-(4-
methoxybenzyl)-1,3-dihydro-2H-indol-2-one (400 mg, 1.58 mmol):
reaction time 2 h; yield 362 mg (64%); yellow solid, mp 172−173 °C;
E/Z = 84:16; Rf = 0.50 (E), 0.60 (Z) (petroleum ether−ethyl acetate,
3:1). (E)-S1b: 1H NMR (600 MHz, CDCl3) δ 2.44 (s, 3H, CH3),
3.78 (s, 3H, CH3O), 4.95 (s, 2H, CH2), 6.76 (d, 3J = 7.9 Hz, 1H, Ar),
6.85−6.88 (m, 3H, Ar), 7.16 (t, 3J = 7.7 Hz, 1H, Ar), 7.29−7.31 (m,
4H, Ar), 7.60 (d, 3J = 7.8 Hz, 2H, Ar), 7.72 (d, 3J = 7.6 Hz, 1H, Ar),
7.92 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 21.5 (CH3),
43.2 (CH2), 55.2 (CH3O), 109.1 (CH), 114.1 (2 × CH), 121.4 (C),
121.7 (CH), 122.7 (CH), 126.3 (C), 128.1 (C), 128.7 (2 × CH),
129.3 (3 × CH), 129.4 (2 × CH), 132.0 (C), 137.8 (CH), 140.0
(C), 143.2 (C), 159.0 (C), 168.6 (CO); HRMS (ESI) m/z [M + H]+
calcd for C24H22NO2+ 356.1641, found 356.1645.
1-(4-Methoxybenzyl)-3-(4-methoxybenzylidene)-1,3-dihydro-2H-
indol-2-one (S1c). This compound was obtained from 4-methox-
ybenzaldehyde (118 mg, 0.106 mL, 0.87 mmol) and 1-(4-
methoxybenzyl)-1,3-dihydro-2H-indol-2-one (200 mg, 0.79 mmol):
reaction time 2.5 h; yield 181 mg (62%); yellow solid, mp 166−167
8698
Note
°C; E/Z = 85:15; Rf = 0.36 (E), 0.46 (Z) (petroleum ether−ethyl
acetate, 3:1). (E)-S1c: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H,
CH3O), 3.90 (s, 3H, CH3O), 4.95 (s, 2H, CH2), 6.77 (d, 3J = 7.6 Hz,
1H, Ar), 6.86 (d, 3J = 8.7 Hz, 2H, Ar), 6.88 (t, 3J = 7.6 Hz, 1H, Ar),
7.01 (d, 3J = 8.7 Hz, 2H, Ar), 7.16 (t, 3J = 7.6 Hz, 1H, Ar), 7.29 (d, 3J
= 8.7 Hz, 2H, Ar), 7.68 (d, 3J = 8.7 Hz, 2H, Ar), 7.76 (d, 3J = 7.6 Hz,
1H, Ar), 7.88 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2
(CH2), 55.2 (CH3O), 55.4 (CH3O), 109.1 (CH), 114.07 (2 × CH),
114.09 (2 × CH), 121.58 (C), 121.64 (CH), 122.4 (CH), 125.2 (C),
127.3 (C), 128.2 (C), 128.7 (2 × CH), 129.2 (CH), 131.4 (2 × CH),
137.7 (CH), 143.1 (C), 159.0 (C), 160.8 (C), 168.8 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C24H22NO3+ 372.1605, found
372.1594.
3-(4-Bromobenzylidene)-1-(4-methoxybenzyl)-1,3-dihydro-2H-
indol-2-one (S1d). This compound was obtained from 4-
bromobenzaldehyde (322 mg, 1.74 mmol) and 1-(4-methoxyben-
zyl)-1,3-dihydro-2H-indol-2-one (400 mg, 1.58 mmol): reaction time
3 h; yield 285 mg (43%); yellow solid, mp 166−167 °C; E/Z = 86:14;
Rf = 0.54 (E), 0.66 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-
S1d: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.94 (s,
2H, CH2), 6.77 (d, 3J = 7.6 Hz, 1H, Ar), 6.85−6.87 (m, 3H, Ar), 7.18
(td, 3J = 7.6, 4J = 1.1 Hz, 1H, Ar), 7.28−7.30 (m, 2H, Ar), 7.52−7.54
(m, 2H, Ar), 7.58 (d, 3J = 7.6 Hz, 1H, Ar), 7.60−7.62 (m, 2H, Ar),
7.81 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2),
55.2 (CH3O), 109.3 (CH), 114.1 (2 × CH), 120.9 (C), 121.8 (CH),
122.7 (CH), 123.7 (C), 127.6 (C), 127.9 (C), 128.7 (2 × CH), 130.0
(CH), 130.8 (2 × CH), 131.9 (2 × CH), 133.8 (C), 135.7 (CH),
143.4 (C), 159.0 (C), 168.2 (CO); HRMS (ESI) m/z [M + H]+
calcd for C23H19BrNO2+ 420.0594, found 420.0601.
4-{[1-(4-Methoxybenzyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-
methyl}benzonitrile (S1e). This compound was obtained from 4-
cyanobenzaldehyde (285 mg, 2.174 mmol) and 1-(4-methoxybenzyl)-
1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol): reaction time 2
h; yield 343 mg (47%); orange solid, mp 171−172 °C; E/Z = 80:20;
Rf = 0.39 (E), 0.48 (petroleum ether−ethyl acetate, 3:1). (E)-S1e: 1H
NMR (600 MHz, CDCl3) δ 3.77 (s, 3H, CH3O), 4.92 (s, 2H, CH2),
6.78 (d, 3J = 7.8 Hz, 1H, Ar), 6.84−6.87 (m, 3H, Ar), 7.20 (t, 3J = 7.8
Hz, 1H, Ar), 7.29 (d, 3J = 8.5 Hz, 2H, Ar), 7.43 (d, 3J = 7.6, 1H, Ar),
7.73 (d, 3J = 8.3 Hz, 2H, Ar), 7.76 (d, 3J = 8.3 Hz, 2H, Ar), 7.82 (s,
1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2
(CH3O), 109.5 (CH), 112.7 (C), 114.1 (2 × CH), 118.3 (C), 120.4
(C), 121.9 (CH), 122.8 (CH), 127.7 (C), 128.6 (2 × CH), 129.3
(C), 129.6 (2 × CH), 130.6 (CH), 132.3 (2 × CH), 134.0 (CH),
139.7 (C), 143.8 (C), 159.0 (C), 167.8 (CO); HRMS (ESI) m/z [M
+ H]+ calcd for C24H19N2O2+ 367.1441, found 367.1452.
1-(4-Methoxybenzyl)-3-(4-nitrobenzylidene)-1,3-dihydro-2H-
indol-2-one (S1f). This compound was obtained from 4-nitro-
benzaldehyde (3.28 g, 21.7 mmol) and 1-(4-methoxybenzyl)-1,3-
dihydro-2H-indol-2-one (5 g, 19.8 mmol): reaction time 2 h; yield
4.30 g (56%); orange solid, mp 165−166 °C; E/Z = 73:27; Rf = 0.29
(E) (petroleum ether−ethyl acetate, 3:1). (E)-S1f: 1H NMR (600
MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.94 (s, 2H, CH2), 6.79 (d, 3J =
7.9 Hz, 1H, Ar), 6.84−6.88 (m, 3H, Ar), 7.20−7.23 (m, 1H, Ar),
7.28−7.30 (m, 2H, Ar), 7.43−7.45 (m, 1H, Ar), 7.79−7.82 (m, 1H,
Ar), 7.86 (s, 1H, CH), 8.32−8.34 (m, 2H, Ar); 13C NMR (150
MHz, CDCl3) δ 43.3 (CH2), 55.2 (CH3O), 109.6 (CH), 114.2 (2 ×
CH), 120.4 (C), 122.0 (CH), 122.9 (CH), 124.0 (2 × CH), 127.7
(C), 128.7 (2 × CH), 129.8 (C), 129.9 (2 × CH), 130.8 (CH), 133.5
(CH), 141.7 (C), 144.0 (C), 147.9 (C), 159.1 (C), 167.7 (CO);
HRMS (ESI) m/z [M + H]+ calcd for C23H19N2O4+ 387.1339, found
387.1342.
3-(Biphenyl-4-ylmethylidene)-1-(4-methoxybenzyl)-1,3-dihydro-
2H-indol-2-one (S1g). This compound was obtained from 4-
phenylbenzaldehyde (396 mg, 2.174 mmol) and 1-(4-methoxyben-
zyl)-1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol): reaction
time 2.5 h; yield 460 mg (56%); yellow solid, mp 123−124 °C; E/Z =
81:19; Rf = 0.53 (E), 0.63 (Z) (petroleum ether−ethyl acetate, 3:1).
(E)-S1g: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O), 4.98 (s,
2H, CH2), 6.82 (d, 3J = 7.8 Hz, 1H, Ar), 6.90−6.93 (m, 3H, Ar), 7.21
(td, 3J = 7.7, 4J = 1.0 Hz, 1H, Ar), 7.35−7.37 (m, 2H, Ar), 7.43 (tt, 3J
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
= 7.4, 4J = 1.1 Hz, 1H, Ar), 7.49−7.52 (m, 2H, Ar), 7.70−7.72 (m,
2H, Ar), 7.73−7.75 (m, 2H, Ar), 7.79−7.80 (m, 2H, Ar), 7.82 (d, 3J =
7.6, 1H, Ar), 8.02 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ
43.0 (CH2), 55.0 (CH3O), 109.0 (CH), 113.9 (2 × CH), 121.1 (C),
121.6 (CH), 123.0 (CH), 126.7 (C), 126.8 (2 × CH), 127.0 (2 ×
CH), 127.7 (CH), 127.9 (C), 128.5 (2 × CH), 128.7 (2 × CH),
129.5 (CH), 129.8 (2 × CH), 133.6 (C), 136.8 (CH), 139.8 (C),
142.1 (C), 143.2 (C), 158.8 (C), 168.3 (CO); HRMS (ESI) m/z [M
+ H]+ calcd for C29H24NO2+ 418.1802, found 418.1804.
1-(4-Methoxybenzyl)-3-(naphth-1-ylmethylidene)-1,3-dihydro-
2H-indol-2-one (S1h). This compound was obtained from 1-
naphthaldehyde (339 mg, 0.295 mL, 2.174 mmol) and 1-(4-
methoxybenzyl)-1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol):
reaction time 2 h; yield 598 mg (77%); yellow solid, mp 166−167 °C;
E/Z = 97:3; Rf = 0.49 (E), 0.58 (Z) (petroleum ether−ethyl acetate,
3:1). (E)-S1h: 1H NMR (600 MHz, CDCl3) δ 3.80 (s, 3H, CH3O),
5.00 (s, 2H, CH2), 6.72 (td, 3J = 7.7, 4J = 1.0 Hz, 1H, Ar), 6.78 (br d,
3
J = 7.8 Hz, 1H, Ar), 6.89−6.91 (m, 2H, Ar), 7.13 (td, 3J = 7.7, 4J =
1.1 Hz, 1H, Ar), 7.17−7.19 (m, 1H, Ar), 7.35−7.37 (m, 2H, Ar),
7.54−7.59 (m, 3H, Ar), 7.85 (dt, 3J = 7.1, 4J = 1.0 Hz, 1H, Ar), 7.94−
7.98 (m, 2H, Ar), 8.06−8.08 (m, 1H, Ar), 8.44 (s, 1H, CH); 13C
NMR (150 MHz, CDCl3) δ 43.2 (CH2), 55.2 (CH3O), 109.1 (CH),
114.1 (2 × CH), 121.3 (C), 121.7 (CH), 123.1 (CH), 124.8 (CH),
125.1 (CH), 126.5 (CH), 126.7 (CH), 126.8 (CH), 128.1 (C), 128.6
(CH), 128.75 (2 × CH), 128.79 (C), 129.6 (CH), 129.9 (CH), 131.3
(C), 132.2 (C), 133.6 (C), 135.4 (CH), 143.4 (C), 159.0 (C),
168.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C27H22NO2+
392.1645, found 392.1650.
3-(1,3-Benzodioxol-5-ylmethylidene)-1-(4-methoxybenzyl)-1,3-
dihydro-2H-indol-2-one (S1i). This compound was obtained from
3,4-(methylenedioxy)benzaldehyde (261 mg, 1.739 mmol) and 1-(4-
methoxybenzyl)-1,3-dihydro-2H-indol-2-one (400 mg, 1.581 mmol):
reaction time 3 h; yield 215 mg (35%); yellow solid, mp 159−160 °C;
E/Z = 78:22; Rf = 0.47 (E), 0.56 (Z) (petroleum ether−ethyl acetate,
3:1). (E)-S1i: 1H NMR (600 MHz, CDCl3) δ 3.78 (s, 3H, CH3O),
4.94 (s, 2H, CH2), 6.06 (s, 2H, OCH2O), 6.76 (d, 3J = 7.6 Hz, 1H,
Ar), 6.85−6.96 (m, 2H, Ar), 6.88−6.92 (m, 2H, Ar), 7.15−7.19 (m,
2H, Ar), 7.22−7.24 (m, 1H, Ar), 7.27−7.29 (m, 2H, Ar), 7.76−7.77
(m, 1H, Ar), 7.82 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ
43.2 (CH2), 55.2 (CH3O), 101.5 (OCH2O), 108.6 (CH), 109.1
(CH), 109.4 (CH), 114.1 (2 × CH), 121.3 (C), 121.7 (CH), 122.6
(CH), 124.7 (CH), 125.7 (C), 128.1 (C), 128.7 (2 × CH), 128.8
(C), 129.4 (CH), 137.5 (CH), 143.2 (C), 147.9 (C), 148.9 (C),
159.0 (C), 168.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C24H20NO4+ 386.1387, found 386.1392.
1-(4-Methoxybenzyl)-3-(thien-2-ylmethylidene)-1,3-dihydro-2H-
indol-2-one (S1k). This compound was obtained from 2-thiophene-
carboxaldehyde (244 mg, 0.205 mL, 2.174 mmol) and 1-(4-
methoxybenzyl)-1,3-dihydro-2H-indol-2-one (500 mg, 1.976 mmol):
reaction time 2.5 h; yield 569 mg (83%); brown oil; E/Z = 63:37; Rf =
0.48 (E), 0.59 (Z) (petroleum ether−ethyl acetate, 3:1). (E)-S1k: 1H
NMR (600 MHz, CDCl3) δ 3.69 (s, 3H, CH3O), 4.90 (s, 2H, CH2),
6.76 (d, 3J = 7.8 Hz, 1H, Ar), 6.82−6.84 (m, 2H, Ar), 6.98−7.01 (m,
1H, Ar), 7.10−7.11 (m, 1H, Ar), 7.15−7.17 (m, 1H, Ar), 7.27−7.28
(m, 2H, Ar), 7.51−7.52 (m, 1H, Ar), 7.54−7.55 (m, 1H, Ar), 8.02 (s,
1H, CH), 8.22 (d, 3J = 7.7 Hz, 1H, Ar); 13C NMR (150 MHz,
CDCl3) δ 42.8 (CH2), 54.7 (CH3O), 108.7 (CH), 113.7 (2 × CH),
120.7 (C), 121.5 (CH), 122.9 (C), 123.1 (CH), 127.7 (CH), 127.8
(C), 128.1 (CH), 128.3 (2 × CH), 129.0 (CH), 130.3 (CH), 134.3
(CH), 137.4 (C), 142.6 (C), 158.6 (C), 168.6 (CO); HRMS (ESI)
m/z [M + H]+ calcd for C21H18NO2S+ 348.1053, found 348.1050.
3-Benzylidene-5-methyl-1-(4-methoxybenzyl)-1,3-dihydro-2H-
indol-2-one (S1l). This compound was obtained from benzaldehyde
(3.5 g, 3.4 mL, 33 mmol) and 5-methyl-1-(4-methoxybenzyl)-1,3-
dihydro-2H-indol-2-one (8.01 g, 30 mmol): reaction time 2.5 h; yield
5.19 g (58%); yellow foam; E/Z = 85:15; Rf = 0.43 (E), 0.51 (Z)
(petroleum ether−ethyl acetate, 3:1). (E)-S1l: 1H NMR (600 MHz,
CDCl3) δ 2.20 (CH3), 3.73 (s, 3H, CH3O), 4.92 (s, 2H, CH2), 6.67
(br d, 3J = 7.8 Hz, 1H, Ar), 6.86−6.88 (m, 2H, Ar), 6.96−6.98 (m,
1H, Ar), 7.31−7.33 (m, 2H, Ar), 7.43−7.45 (m, 1H, Ar), 7.46−7.49
8699
Note
(m, 2H, Ar), 7.51−7.52 (m, 1H, Ar), 7.68−7.70 (m, 2H, Ar), 7.96 (br
s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 20.78 (CH3), 42.8
(CH2), 54.75 (CH3O), 108.6 (CH), 113.8 (2 × CH), 120.9 (C),
123.1 (CH), 127.0 (C), 127.91 (CH), 127.93 (C), 128.3 (2 × CH),
128.37 (2 × CH), 129.0 (2 × CH), 129.8 (CH), 130.7 (C), 134.7
(C), 136.6 (CH), 140.9 (C), 158.7 (C), 168.1 (CO). (Z)-S1l: 1H
NMR (600 MHz, CDCl3) δ 2.36 (CH3), 3.72 (s, 3H, CH3O), 4.90 (s,
2H, CH2), 6.65 (br d, 3J = 7.6 Hz, 1H, Ar), 6.84−6.87 (m, 2H, Ar),
6.98−7.00 (m, 1H, Ar), 7.30−7.32 (m, 2H, Ar), 7.35−7.36 (m, 1H,
Ar), 7.42−7.44 (m, 3H, Ar), 7.46−7.49 (m, 2H, Ar), 7.54 (br s, 1H,
CH), 8.40−8.42 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ
20.81 (CH3), 42.6 (CH2), 54.74 (CH3O), 108.2 (CH), 113.7 (2 ×
CH), 119.4 (CH), 124.1 (C), 125.8 (C), 128.1 (C), 128.41 (2 ×
CH), 128.9 (CH), 129.2 (2 × CH), 130.1 (CH), 130.8 (C), 131.8 (2
× CH), 133.6 (C), 136.5 (CH), 139.0 (C), 158.6 (C), 165.7
(CO); HRMS (ESI) m/z [M + H]+ calcd for C24H22NO2+ 356.1645,
found 356.1651.
3-Benzylidene-5-fluoro-1-(4-methoxybenzyl)-1,3-dihydro-2H-
indol-2-one (S1m). This compound was obtained from benzaldehyde
(2.16 g, 2.1 mL, 20.4 mmol) and 5-fluoro-1-(4-methoxybenzyl)-1,3-
dihydro-2H-indol-2-one (5 g, 18.5 mmol): reaction time 2.5 h; yield
3.45 g (52%); yellow foam; E/Z = 90:10; Rf = 0.45 (E), 0.58 (Z)
(petroleum ether−ethyl acetate, 3:1). (E)-S1m: 1H NMR (600 MHz,
CDCl3) δ 3.79 (s, 3H, CH3O), 4.93 (s, 2H, CH2), 6.66 (dd, 3J = 8.5,
4
J = 4.3 Hz, 1H, Ar), 6.85−6.89 (m, 3H, Ar), 7.27−7.29 (m, 2H, Ar),
7.35 (dd, 3J = 9.0, 4J = 2.5 Hz, 1H, Ar), 7.45−7.52 (m, 3H, Ar), 7.63−
7.65 (m, 2H, Ar), 7.99 (s, 1H, CH); 13C NMR (150 MHz, CDCl3)
δ 43.3 (CH2), 55.2 (CH3O), 109.5 (3JCF = 8 Hz, CH), 110.4 (2JCF =
26 Hz, CH), 114.2 (2 × CH), 115.8 (2JCF = 24 Hz, CH), 122.3 (3JCF
= 9 Hz, C), 126.8 (4JCF = 3 Hz, C), 127.8 (C), 128.7 (2 × CH), 128.8
(2 × CH), 129.1 (2 × CH), 129.9 (CH), 134.5 (C), 138.9 (CH),
139.4 (C), 158.4 (1JCF = 239 Hz, C), 159.1 (C), 168.3 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C23H19FNO2+ 360.1394, found
360.1401.
Ethyl 4-{[5-Fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-3H-
indol-3-ylidene]methyl}benzoate (S1n). This compound was
obtained from methyl 4-formylbenzoate (3.54 g, 21.6 mmol) and 5-
fluoro-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (5.32 g, 19.6
mmol): reaction time 2 h; transesterification of the methyl ester into
the ethyl one under the reaction conditions; yield 3.13 g (37%);
orange solid, mp 145−146 °C; E/Z = 81:19; Rf = 0.25 (E), 0.35 (Z)
(petroleum ether−ethyl acetate, 3:1). (E)-S1n: 1H NMR (600 MHz,
CDCl3) δ 1.44 (t, 3J = 7.2 Hz, 3H, CH3), 3.79 (s, 3H, CH3O), 4.44
(q, 3J = 7.2 Hz, 2H, CH2O), 4.92 (s, 2H, CH2), 6.66 (dd, 3J = 8.5, 4J
= 4.3 Hz, 1H, Ar), 6.85−6.90 (m, 3H, Ar), 7.24 (dd, 3J = 8.9, 4J = 2.6
Hz, 1H, Ar), 7.25−7.28 (m, 3H, Ar), 7.68−7.70 (m, 2H, Ar), 7.96 (s,
1H, CH), 8.16−8.18 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ
14.3 (CH3), 43.4 (CH2), 55.2 (CH3O), 61.3 (CH2O), 109.8 (3JCF = 8
Hz, CH), 110.6 (2JCF = 26 Hz, CH), 114.2 (2 × CH), 116.4 (2JCF =
24 Hz, CH), 121.8 (3JCF = 9 Hz, C), 127.6 (C), 128.2 (4JCF = 3 Hz,
C), 128.7 (2 × CH), 129.0 (2 × CH), 130.0 (2 × CH), 131.4 (C),
137.2 (CH), 138.9 (C), 139.7 (C), 158.4 (1JCF = 239 Hz, C), 159.1
(C), 165.9 (CO), 167.9 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C26H23FNO4+ 432.1606, found 432.1613.
3-Benzylidene-5-chloro-1-(4-methoxybenzyl)-1,3-dihydro-2H-
indol-2-one (S1o). This compound was obtained from benzaldehyde
(2.16 g, 2.1 mL, 20.4 mmol) and 5-chloro-1-(4-methoxybenzyl)-1,3-
dihydro-2H-indol-2-one (5.33 g, 18.5 mmol): reaction time 2.5 h;
yield 4.25 g (61%); yellow foam; E/Z = 88:12; Rf = 0.44 (E), 0.56 (Z)
(petroleum ether−ethyl acetate, 3:1). (E)-S1o: 1H NMR (600 MHz,
CDCl3) δ 3.78 (s, 3H, CH3O), 4.93 (s, 2H, CH2), 6.67 (d, 3J = 8.4
Hz, 1H, Ar), 6.86−6.88 (m, 2H, Ar), 7.13 (dd, 3J = 8.4, 4J = 2.1 Hz,
1H, Ar), 7.26−7.27 (m, 2H, Ar), 7.46−7.52 (m, 3H, Ar), 7.60 (br d,
2
J = 2.1 Hz, 1H, Ar), 7.64−7.66 (m, 2H, Ar), 7.98 (s, 1H, CH); 13C
NMR (150 MHz, CDCl3) δ 43.3 (CH2), 55.2 (CH3O), 110.0 (CH),
114.2 (2 × CH), 122.6 (C), 122.8 (CH), 126.2 (C), 127.1 (C), 127.6
(C), 128.6 (2 × CH), 128.8 (2 × CH), 129.2 (2 × CH), 129.3 (CH),
130.0 (CH), 134.4 (C), 139.1 (CH), 141.8 (C), 159.1 (C), 168.1
(CO); HRMS (ESI) m/z [M + H]+ calcd for C23H19ClNO2+
376.1099, found 376.1105.
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
3-Benzylidene-5-bromo-1-(4-methoxybenzyl)-1,3-dihydro-2H-
indol-2-one (S1p). This compound was obtained from benzaldehyde
(2.16 g, 2.1 mL, 20.4 mmol) and 5-bromo-1-(4-methoxybenzyl)-1,3-
dihydro-2H-indol-2-one (6.14 g, 18.5 mmol): reaction time 2.5 h;
yield 3.77 g (49%); yellow foam; E/Z = 95:5; Rf = 0.35 (E), 0.44 (Z)
(petroleum ether−ethyl acetate, 3:1). (E)-S1p: 1H NMR (600 MHz,
CDCl3) δ 3.79 (s, 3H, CH3O), 4.93 (s, 2H, CH2), 6.63 (d, 3J = 8.4
Hz, 1H, Ar), 6.86−6.87 (m, 2H, Ar), 7.25−7.27 (m, 3H, Ar), 7.48−
7.53 (m, 3H, Ar), 7.64−7.66 (m, 2H, Ar), 7.75 (br d, 2J = 1.9 Hz, 1H,
Ar), 7.97 (s, 1H, CH); 13C NMR (150 MHz, CDCl3) δ 43.3
(CH2), 55.3 (CH3O), 110.5 (CH), 114.2 (2 × CH), 114.5 (C), 123.1
(C), 125.6 (CH), 126.1 (C), 127.6 (C), 128.7 (2 × CH), 128.8 (2 ×
CH), 129.2 (2 × CH), 130.1 (CH), 132.1 (CH), 134.4 (C), 139.2
(CH), 142.2 (C), 159.1 (C), 168.0 (CO); HRMS (ESI) m/z [M +
H]+ calcd for C23H19BrNO2+ 420.0594, found 420.0599.
General Procedure for the Synthesis of Cyclopropanes 1.
Trimethylsulfoxonium iodide (660 mg, 3.00 mmol, 2.0 equiv) was
added to a suspension of NaH (120 mg, 3.00 mmol, 2.0 equiv) in
anhydrous DMF (2.5 mL) under an argon atmosphere. The resulting
suspension was stirred for 20 min, and then a solution of alkene S1
(1.50 mmol, 1.0 equiv) in DMF (15 mL) was added in one portion.
The reaction mixture was stirred at room temperature for the time
specified. The resulting mixture was poured into 30 mL of ice water
and extracted with EtOAc (3 × 30 mL). Combined organic layers
were washed with brine (5 × 15 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (petroleum ether−ethyl
acetate). Spectral data for cyclopropanes 1q−u9a are consistent with
those reported previously.
1′-(4-Methoxybenzyl)-2-phenylspiro[cyclopropane-1,3′-indol]-
2′(1′H)-one (1a). This compound was obtained from S1a (550 mg,
1.61 mmol): reaction time 2 h; yield 500 mg (87%); yellowish foam;
dr 70:30; Rf = 0.83 (petroleum ether−ethyl acetate, 1:1); 1H NMR
(600 MHz, CDCl3) δ 2.05 (dd, 2J = 4.5, 3J = 7.9 Hz, 1H, CH2, A),
2.13 (dd, 2J = 4.9, 3J = 9.1 Hz, 1H, CH2, B), 2.28 (dd, 2J = 4.5, 3J =
9.4 Hz, 1H, CH2, A), 2.49 (dd, 2J = 4.9, 3J = 8.7 Hz, 1H, CH2, B),
3.20 (dd, 3J = 9.1 3J = 8.7 Hz, 1H, CH, B), 3.42 (dd, 3J = 9.4, 3J = 7.9
Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.81
(d, 2J = 15.5 Hz, 1H, CH2, B), 4.84 (d, 2J = 15.5 Hz, 1H, CH2, B),
4.95 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.02 (d, 2J = 15.5 Hz, 1H, CH2,
A), 5.97 (dd, 3J = 7.6, 4J = 0.8 Hz, 1H, Ar, A), 6.65−6.68 (m, 1H, Ar,
A), 6.80−6.84 (m, 2H + 1H, Ar, A, B), 6.88−6.90 (m, 2H, Ar, A),
6.98−6.99 (m, 1H, Ar, B), 7.04−7.07 (m, 1H + 1H, Ar, A, B), 7.18−
7.22 (m, 3H + 1H, Ar, A, B), 7.26−7.37 (m, 3H + 9H, Ar, A). A: 13C
NMR (150 MHz, CDCl3) δ 22.6 (CH2), 33.2 (C), 36.0 (CH), 43.6
(CH2), 55.22 (CH3O), 108.72 (CH), 114.1 (2 × CH), 120.7 (CH),
121.4 (CH), 126.4 (CH), 127.4 (CH), 127.5 (C), 128.32 (C), 128.34
(2 × CH), 128.7 (2 × CH), 129.9 (2 × CH), 135.1 (C), 142.9 (C),
159.0 (C), 176.5 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.3
(CH2), 33.8 (C), 38.4 (CH), 43.3 (CH2), 55.18 (CH3O), 108.73
(CH), 114.0 (2 × CH), 118.1 (CH), 121.8 (CH), 126.6 (CH), 127.2
(CH), 127.9 (2 × CH), 128.5 (C), 128.8 (2 × CH), 129.3 (2 × CH),
130.8 (C), 134.4 (C), 142.5 (C), 158.9 (C), 173.7 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C24H22NO2+ 356.1645, found
356.1630.
1′-(4-Methoxybenzyl)-2-(p-tolyl)spiro[cyclopropane-1,3′-indol]-
2′(1′H)-one (1b). This compound was obtained from S1b (310 mg,
0.873 mmol): reaction time 2 h; yield 250 mg (76%); yellow oil; dr
72:28; Rf = 0.58 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600
MHz, CDCl3) δ 2.12 (dd, 2J = 4.4, 3J = 7.9 Hz, 1H, CH2, A), 2.17
(dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.36 (dd, 2J = 4.4, 3J = 9.2 Hz,
1H, CH2, A), 2.42 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.56 (dd, 2J = 4.9,
3
J = 8.6 Hz, 1H, CH2, B), 3.25 (dd, 3J = 9.0, 3J = 8.6 Hz, 1H, CH, B),
3.50 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.81 (s, 3H, CH3O, B),
3.83 (s, 3H, CH3O, A), 4.92 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.95 (d, 2J
= 15.7 Hz, 1H, CH2, B), 5.04 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.11 (d,
2
J = 15.4 Hz, 1H, CH2, A), 6.15 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.75−
6.78 (m, 1H, Ar, A), 6.90−6.93 (m, 2H + 1H, Ar, A, B), 6.97−6.98
(m, 2H, Ar, A), 7.03−7.04 (m, 1H, Ar, B), 7.11−7.15 (m, 1H + 1H,
Ar, A, B), 7.19−7.20 (m, 2H + 5H, Ar, A, B), 7.24−7.26 (m, 1H, Ar,
8700
Note
A), 7.28−7.29 (m, 2H, Ar, B), 7.34−7.36 (m, 2H, Ar, B), 7.40−7.41
(m, 2H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 20.9 (1JCH = 125
Hz, CH3), 22.4 (1JCH = 165 Hz, CH2), 33.0 (C), 35.7 (1JCH = 165 Hz,
CH), 43.3 (1JCH = 139 Hz, CH2), 54.90 (1JCH = 144 Hz, CH3O),
108.47 (CH), 113.9 (2 × CH), 120.5 (CH), 121.2 (CH), 126.2
(CH), 127.4 (C), 128.1 (C), 128.4 (2 × CH), 128.8 (2 × CH), 129.5
(2 × CH), 131.7 (C), 136.7 (C), 142.7 (C), 158.8 (C), 176.3 (CO).
B: 13C NMR (150 MHz, CDCl3) δ 21.0 (1JCH = 125 Hz, CH3), 22.1
(1JCH = 165 Hz, CH2), 33.6 (C), 38.1 (1JCH = 162 Hz, CH), 43.0
(1JCH = 139 Hz, CH2), 54.87 (1JCH = 144 Hz, CH3O), 108.49 (CH),
113.7 (2 × CH), 117.9 (CH), 121.6 (CH), 126.3 (CH), 128.3 (C),
128.4 (2 × CH), 128.5 (2 × CH), 128.9 (2 × CH), 130.6 (C), 131.1
(C), 136.5 (C), 142.2 (C), 158.7 (C), 173.5 (CO); HRMS (ESI) m/
z [M + H]+ calcd for C25H24NO2+ 370.1802, found 370.1795.
1′-(4-Methoxybenzyl)-2-(4-methoxyphenyl)spiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1c). This compound was obtained from S1c
(1.02 g, 3.85 mmol): reaction time 2.5 h; yield 0.90 g (84%); yellow
viscous oil; dr 68:32; Rf = 0.59 (petroleum ether−ethyl acetate, 1:1);
1
H NMR (600 MHz, CDCl3) δ 2.04 (dd, 2J = 4.4, 3J = 8.0 Hz, 1H,
CH2, A), 2.12 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.31 (dd, 2J =
4.4, 3J = 9.2 Hz, 1H, CH2, A), 2.49 (dd, 2J = 4.9, 3J = 8.5 Hz, 1H,
CH2, B), 3.18 (dd, 3J = 9.0 3J = 8.5 Hz, 1H, CH, B), 3.42 (dd, 3J =
9.2, 3J = 8.0 Hz, 1H, CH, A), 3.75 (s, 3H, CH3O, B), 3.78 (s, 3H,
CH3O, A), 3.79 (s, 3H, CH3O, A), 3.81 (s, 3H, CH3O, B), 4.84 (d, 2J
= 15.4 Hz, 1H, CH2, B), 4.88 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.99 (d,
2
J = 15.4 Hz, 1H, CH2, A), 5.05 (d, 2J = 15.4 Hz, 1H, CH2, A), 6.08
(br d, 3J = 7.4 Hz, 1H, Ar, A), 6.70−6.73 (m, 1H, Ar, A), 6.84−6.90
(m, 3H + 3H, Ar, A, B), 6.91−6.94 (m, 2H + 2H, Ar, A, B), 6.98−
6.99 (m, 1H, Ar, B), 7.05−7.08 (m, 1H, Ar, B), 7.07−7.10 (m, 1H,
Ar, A), 7.16−7.17 (m, 2H, Ar, A), 7.19−7.22 (m, 1H, Ar, B), 7.22−
7.24 (m, 2H, Ar, B), 7.31−7.33 (m, 2H, Ar, B), 7.35−7.36 (m, 2H,
Ar, A). A: 13C NMR (150 MHz, CDCl3) δ 22.6 (CH2), 33.1 (C),
35.4 (CH), 43.3 (CH2), 54.85 (CH3O), 54.88 (CH3O), 108.4 (CH),
113.5 (2 × CH), 113.9 (2 × CH), 120.5 (CH), 121.2 (CH), 126.1
(CH), 126.8 (C), 127.3 (C), 128.2 (C), 128.4 (2 × CH), 130.7 (2 ×
CH), 142.7 (C), 158.6 (C), 158.8 (C), 176.2 (CO). B: 13C NMR
(150 MHz, CDCl3) δ 22.1 (CH2), 33.6 (C), 38.0 (CH), 42.9 (CH2),
54.8 (CH3O), 54.85 (CH3O), 108.4 (CH), 113.1 (2 × CH), 113.7 (2
× CH), 117.8 (CH), 121.6 (CH), 126.3 (CH), 128.3 (C), 128.5 (2 ×
CH), 128.6 (C), 130.1 (2 × CH), 130.6 (C), 142.1 (C), 158.4 (C),
158.7 (C), 173.5 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C25H24NO3+ 386.1751, found 386.1759.
2-(4-Bromophenyl)-1′-(4-methoxybenzyl)spiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1d). This compound was obtained from S1d
(413 mg, 0.983 mmol): reaction time 3 h; yield 231 mg (54%);
yellow solid, mp 123−124 °C; dr 60:40; Rf = 0.66 (petroleum ether−
ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.00 (dd, 2J = 4.6,
3
J = 7.9 Hz, 1H, CH2, A), 2.13 (dd, 2J = 5.0, 3J = 9.0 Hz, 1H, CH2, B),
2.30 (dd, 2J = 4.6, 3J = 9.2 Hz, 1H, CH2, A), 2.45 (dd, 2J = 5.0, 3J =
8.5 Hz, 1H, CH2, B), 3.13 (dd, 3J = 9.0, 3J = 8.5 Hz, 1H, CH, B), 3.35
(dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.76 (s, 3H, CH3O, B), 3.78 (s,
3H, CH3O, A), 4.82 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.85 (d, 2J = 15.4
Hz, 1H, CH2, B), 4.96 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.04 (d, 2J =
15.5 Hz, 1H, CH2, A), 6.03 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.72−6.74
(m, 1H, Ar, A), 6.84−6.89 (m, 2H + 2H, Ar, A, B), 6.90−6.92 (m,
2H, Ar, A), 6.98−6.99 (m, 1H, Ar, B), 7.05−7.08 (m, 1H, Ar, B),
7.09−7.11 (m, 2H + 2H, Ar, A, B), 7.20−7.22 (m, 2H, Ar, B), 7.23−
7.25 (m, 2H, Ar, B), 7.33−7.34 (m, 2H, Ar, A), 7.44−7.45 (m, 2H,
Ar, A), 7.46−7.48 (m, 2H, Ar, B). A: 13C NMR (150 MHz, CDCl3) δ
22.2 (1JCH = 165 Hz, CH2), 32.9 (C), 35.0 (1JCH = 165 Hz, CH), 43.4
(1JCH = 139 Hz, CH2), 54.99 (1JCH = 144 Hz, CH3O), 108.71 (CH),
114.0 (2 × CH), 120.5 (CH), 121.2 (C), 121.4 (CH), 126.5 (CH),
126.8 (C), 128.0 (C), 128.3 (C), 128.5 (2 × CH), 131.3 (2 × CH),
131.4 (2 × CH), 134.0 (C), 142.7 (C), 158.8 (C), 176.0 (CO). B:
13
C NMR (150 MHz, CDCl3) δ 22.0 (1JCH = 165 Hz, CH2), 33.6 (C),
37.4 (1JCH = 165 Hz, CH), 43.1 (1JCH = 139 Hz, CH2), 54.97 (1JCH =
144 Hz, CH3O), 108.68 (CH), 113.8 (2 × CH), 118.0 (CH), 121.0
(C), 121.8 (CH), 126.7 (CH), 128.1 (C), 128.6 (2 × CH), 130.2
(C), 130.78 (2 × CH), 130.80 (2 × CH), 131.2 (C), 133.3 (C),
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
142.2 (C), 158.7 (C), 173.3 (CO); HRMS (ESI) m/z [M + H]+
calcd for C24H21BrNO2+ 434.0750, found 434.0768.
4-[1′-(4-Methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro-
[cyclopropane-1,3′-indol]-2-yl]benzonitrile (1e). This compound
was obtained from S1e (291 mg, 0.795 mmol): reaction time 2 h;
yield 250 mg (83%); beige solid, mp 136−137 °C; dr 58:42; Rf = 0.31
(petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ
2.03 (dd, 2J = 4.7, 3J = 7.8 Hz, 1H, CH2, A), 2.15 (dd, 2J = 5.2, 3J =
8.8 Hz, 1H, CH2, B), 2.30 (dd, 2J = 4.7, 3J = 9.1 Hz, 1H, CH2, A),
2.44 (dd, 2J = 5.2, 3J = 8.4 Hz, 1H, CH2, B), 3.17 (dd, 3J = 8.8, 3J =
8.4 Hz, 1H, CH, B), 3.38 (dd, 3J = 9.1, 3J = 7.8 Hz, 1H, CH, A), 3.70
(s, 3H, CH3O, B), 3.72 (s, 3H, CH3O, A), 4.76 (d, 2J = 15.5 Hz, 1H,
CH2, B), 4.80 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.93 (d, 2J = 15.4 Hz,
1H, CH2, A), 5.00 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.96 (br d, 3J = 7.5
Hz, 1H, Ar, A), 6.67−6.70 (m, 1H, Ar, A), 6.80−6.81 (m, 2H, Ar, B),
6.85−6.87 (m, 4H, Ar, A), 6.92−6.99 (m, 1H, Ar, B), 7.03−7.08 (m,
1H + 1H, Ar, A, B), 7.16−7.20 (m, 3H, Ar, B), 7.29−7.32 (m, 3H +
1H, Ar, A, B), 7.42−7.43 (m, 2H, Ar, B), 7.54−7.57 (m, 2H + 2H, Ar,
A, B). A: 13C NMR (150 MHz, CDCl3) δ 21.5 (1JCH = 165 Hz, CH2),
33.0 (C), 35.0 (1JCH = 166 Hz, CH), 43.2 (1JCH = 139 Hz, CH2),
54.75 (1JCH = 144 Hz, CH3O), 108.7 (CH), 110.7 (C), 113.8 (2 ×
CH), 118.3 (C), 120.1 (CH), 121.2 (CH), 126.0 (C), 126.6 (CH),
127.7 (C), 128.32 (2 × CH), 130.3 (2 × CH), 131.7 (2 × CH), 140.3
(C), 142.6 (C), 158.7 (C), 175.3 (CO). B: 13C NMR (150 MHz,
CDCl3) δ 21.7 (1JCH = 165 Hz, CH2), 33.9 (C), 37.0 (1JCH = 163 Hz,
CH), 42.9 (1JCH = 139 Hz, CH2), 54.73 (1JCH = 144 Hz, CH3O),
108.6 (CH), 110.3 (C), 113.6 (2 × CH), 118.1 (CH), 118.6 (C),
121.8 (CH), 126.8 (CH), 127.8 (C), 128.33 (2 × CH), 129.5 (C),
129.7 (2 × CH), 131.1 (2 × CH), 139.8 (C), 142.1 (C), 158.6 (C),
172.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H21N2O2+
381.1598, found 381.1598.
1′-(4-Methoxybenzyl)-2-(4-nitrophenyl)spiro[cyclopropane-1,3′-
indol]-2′(1′H)-one (1f). This compound was obtained from S1f (830
mg, 2.2 mmol): reaction time 2 h; yield 675 mg (77%); yellow foam;
dr 72:28; Rf = 0.33 (petroleum ether−ethyl acetate, 3:1); 1H NMR
(600 MHz, CDCl3) δ 2.07 (dd, 2J = 4.8, 3J = 8.0 Hz, 1H, CH2, A),
2.22 (dd, 2J = 5.2, 3J = 8.9 Hz, 1H, CH2, B), 2.35 (dd, 2J = 4.8, 3J =
9.1 Hz, 1H, CH2, A), 2.50 (dd, 2J = 5.2, 3J = 8.5 Hz, 1H, CH2, B),
3.22 (dd, 3J = 8.9, 3J = 8.5 Hz, 1H, CH, B), 3.41 (dd, 3J = 9.1, 3J = 8.0
Hz, 1H, CH, A), 3.76 (s, 3H, CH3O, B), 3.79 (s, 3H, CH3O, A), 4.79
(d, 2J = 15.6 Hz, 1H, CH2, B), 4.82 (d, 2J = 15.6 Hz, 1H, CH2, B),
4.94 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.03 (d, 2J = 15.4 Hz, 1H, CH2,
A), 5.95 (br d, 3J = 7.6 Hz, 1H, Ar, A), 6.68−6.70 (m, 1H, Ar, A),
6.81−6.83 (m, 2H, Ar, B), 6.85−6.87 (m, 1H + 1H, Ar, A, B), 6.87−
6.90 (m, 2H, Ar, A), 7.00−7.02 (m, 1H, Ar, B), 7.06−7.10 (m, 1H +
1H, Ar, A, B), 7.15−7.18 (m, 2H, Ar, B), 7.20−7.23 (m, 1H, Ar, B),
7.28−7.32 (m, 2H, Ar, A), 7.37−7.39 (m, 2H, Ar, A), 7.50−7.52 (m,
2H, Ar, B), 8.16−8.19 (m, 2H + 2H, Ar, A, B). A: 13C NMR (150
MHz, CDCl3) δ 22.1 (CH2), 33.3 (C), 35.0 (CH), 43.6 (CH2), 55.13
(CH3O), 109.1 (CH), 114.1 (2 × CH), 120.3 (CH), 121.6 (CH),
123.5 (2 × CH), 126.2 (C), 127.0 (CH), 128.0 (C), 128.6 (2 × CH),
130.7 (2 × CH), 142.8 (C), 143.0 (C), 147.0 (C), 159.0 (C), 175.6
(CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2 (CH2), 34.3 (C), 37.0
(CH), 43.3 (CH2), 55.11 (CH3O), 109.0 (CH), 114.0 (2 × CH),
118.3 (CH), 122.0 (CH), 122.1 (CH), 123.0 (2 × CH), 128.0 (C),
128.7 (2 × CH), 129.7 (C), 130.1 (2 × CH), 142.2 (C), 142.5 (C),
146.8 (C), 158.9 (C), 173.1 (CO); HRMS (ESI) m/z [M + H]+
calcd for C24H21N2O4+ 401.1496, found 401.1501.
2-([1,1′-Biphenyl]-4-yl)-1′-(4-methoxybenzyl)spiro-
[cyclopropane-1,3′-indol]-2′(1′H)-one (1g). This compound was
obtained from S1g (395 mg, 0.947 mmol): reaction time 2.5 h; yield
320 mg (78%); light yellow solid, mp 158−160 °C; dr 65:35; Rf =
0.43 (petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz,
CDCl3) δ 2.18 (dd, 2J = 4.5, 3J = 7.9 Hz, 1H, CH2, A), 2.22 (dd, 2J =
4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.42 (dd, 2J = 4.5, 3J = 9.2 Hz, 1H,
CH2, A), 2.63 (dd, 2J = 4.9, 3J = 8.6 Hz, 1H, CH2, B), 3.30 (dd, 3J =
9.0, 3J = 8.6 Hz, 1H, CH, B), 3.58 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH,
A), 3.80 (s, 3H, CH3O, B), 3.84 (s, 3H, CH3O, A), 4.91 (d, 2J = 15.7
Hz, 1H, CH2, B), 4.94 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.07 (d, 2J =
15.4 Hz, 1H, CH2, A), 5.13 (d, 2J = 15.4 Hz, 1H, CH2, A), 6.22 (br d,
8701
Note
3
J = 7.6 Hz, 1H, Ar, A), 6.76−6.79 (m, 1H, Ar, A), 6.91−6.95 (m, 1H
+ 3H, Ar, A, B), 6.98−7.01 (m, 2H, Ar, A), 7.06 (d, 3J = 7.4 Hz, 1H,
Ar, B), 7.13−7.17 (m, 1H + 1H, Ar, A, B), 7.28−7.31 (m, 1H + 1H,
Ar, A, B), 7.36−7.41 (m, 2H, Ar, A), 7.42−7.45 (m, 2H + 3H, Ar, A,
B), 7.51−7.55 (m, 2H + 4H, Ar, A, B), 7.64−7.68 (m, 2H, Ar, A),
7.69−7.71 (m, 1H + 4H, Ar, A, B), 7.73 (d, 3J = 7.8 Hz, 1H, Ar, A).
A: 13C NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 33.1
(C), 35.6 (1JCH = 166 Hz, CH), 43.4 (1JCH = 139 Hz, CH2), 54.91
(1JCH = 144 Hz, CH3O), 108.57 (CH), 113.9 (2 × CH), 120.6 (CH),
121.3 (CH), 126.30 (CH), 126.33 (CH), 126.68 (2 × CH), 126.72
(2 × CH), 127.17 (C), 128.1 (C), 128.48 (2 × CH), 128.6 (2 ×
CH), 130.1 (2 × CH), 133.9 (C), 139.8 (C), 140.2 (C), 142.7 (C),
158.8 (C), 176.1 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2
(1JCH = 165 Hz, CH2), 33.9 (C), 38.1 (1JCH = 163 Hz, CH), 43.0
(1JCH = 139 Hz, CH2), 54.87 (1JCH = 144 Hz, CH3O), 108.56 (CH),
113.8 (2 × CH), 118.0 (CH), 121.7 (CH), 126.5 (CH), 126.8 (2 ×
CH), 126.9 (CH), 127.15 (2 × CH), 128.2 (C), 128.45 (2 × CH),
128.6 (2 × CH), 129.5 (2 × CH), 130.5 (C), 133.3 (C), 139.6 (C),
140.6 (C), 142.2 (C), 158.7 (C), 173.4 (CO); HRMS (ESI) m/z [M
+ H]+ calcd for C30H26NO2+ 432.1958, found 432.1952.
1′-(4-Methoxybenzyl)-2-(naphthalen-1-yl)spiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1h). This compound was obtained from S1h
(570 mg, 1.46 mmol): reaction time 2.5 h; yield 540 mg (91%);
orange solid, mp 137−138 °C; dr 86:14; Rf = 0.45 (petroleum ether−
ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.25 (dd, 2J = 4.6,
3
J = 8.8 Hz, 1H, CH2, B), 2.30 (dd, 2J = 4.5, 3J = 8.0 Hz, 1H, CH2, A),
2.54 (dd, 2J = 4.6, 3J = 9.0 Hz, 1H, CH2, A), 2.68 (dd, 2J = 4.7, 3J =
8.5 Hz, 1H, CH2, B), 3.49 (dd, 3J = 8.8, 3J = 8.5 Hz, 1H, CH, B), 3.74
(s, 3H, CH3O, B), 3.77 (dd, 3J = 9.0, 3J = 8.0 Hz, 1H, CH, A), 3.80 (s,
3H, CH3O, A), 4.45 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.92 (d, 2J = 15.4
Hz, 1H, CH2, A), 4.96 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.31 (d, 2J =
15.4 Hz, 1H, CH2, A), 5.97 (dd, 3J = 7.6, 4J = 0.8 Hz, 1H, Ar, A),
6.44−6.47 (m, 1H, Ar, A), 6.71−6.74 (m, 2H, Ar, B), 6.77 (d, 3J = 7.8
Hz, 1H, Ar, A), 6.87−6.93 (m, 1H + 3H, Ar, A, B), 6.98−7.00 (m,
2H, Ar, A), 7.13−7.18 (m, 2H, Ar, B), 7.14−7.27 (m, 1H, Ar, A),
7.26−7.32 (m, 2H, Ar, B), 7.34−7.37 (m, 1H, Ar, A), 7.42−7.45 (m,
2H, Ar, A), 7.49−7.52 (m, 2H, Ar, B), 7.54 (dd, 3J = 8.0, 3J = 7.2 Hz,
1H, Ar, A), 7.60 (dd, 3J = 8.0, 3J = 7.2 Hz, 1H, Ar, B), 7.62−7.63 (m,
1H, Ar, A), 7.67 (br d, 3J = 8.5 Hz, 1H, Ar, A), 7.72−7.73 (m, 1H, Ar,
B), 7.77 (br d, 3J = 8.1 Hz, 1H, Ar, A), 7.82 (br d, 3J = 8.1 Hz, 1H, Ar,
A), 7.87 (br d, 3J = 8.2 Hz, 1H, Ar, B), 7.91 (br d, 3J = 8.1 Hz, 1H, Ar,
B). A: 13C NMR (150 MHz, CDCl3) δ 21.7 (1JCH = 165 Hz, CH2),
33.3 (C), 34.3 (1JCH = 166 Hz, CH), 43.2 (1JCH = 139 Hz, CH2), 54.9
(1JCH = 144 Hz, CH3O), 108.4 (CH), 113.9 (2 × CH), 119.3 (CH),
121.1 (CH), 123.2 (CH), 124.8 (CH), 125.6 (CH), 125.8 (CH),
126.1 (CH), 126.2 (CH), 126.9 (C), 128.08 (2 × CH), 128.2 (C),
128.33 (2 × CH), 131.6 (C), 132.9 (C), 133.1 (C), 142.2 (C), 158.8
(C), 176.1 (CO). B: 13C NMR (150 MHz, CDCl3) δ 21.8 (1JCH =
165 Hz, CH2), 33.2 (C), 35.9 (1JCH = 163 Hz, CH), 42.8 (1JCH = 139
Hz, CH2), 54.8 (1JCH = 144 Hz, CH3O), 108.6 (CH), 113.5 (2 ×
CH), 118.1 (CH), 121.8 (CH), 123.1 (CH), 125.0 (CH), 125.1
(CH), 126.0 (CH), 126.7 (CH), 126.8 (CH), 127.86 (CH), 127.94
(C), 128.05 (C), 128.29 (2 × CH), 128.6 (CH), 130.0 (C), 131.4
(C), 133.2 (C), 142.4 (C), 158.5 (C), 173.1 (CO); HRMS (ESI) m/
z [M + H]+ calcd for C28H24NO2+ 406.1802, found 406.1803.
2 -( 1 , 3 - B e nz od i ox o l -5 - yl )- 1′-(4-methoxybenzyl)spiro-
[cyclopropane-1,3′-indol]-2′(1′H)-one (1i). This compound was
obtained from S1i (370 mg, 0.961 mmol): reaction time 2.5 h;
yield 320 mg (83%); yellow oil; dr 64:36; Rf = 0.40 (petroleum
ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ 2.00 (dd, 2J
= 4.4, 3J = 7.9 Hz, 1H, CH2, A), 2.08 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H,
CH2, B), 2.26 (dd, 2J = 4.4, 3J = 9.1 Hz, 1H, CH2, A), 2.42 (dd, 2J =
4.9, 3J = 8.5 Hz, 1H, CH2, B), 3.14 (dd, 3J = 9.0, 3J = 8.5 Hz, 1H, CH,
B), 3.37 (dd, 3J = 9.1, 3J = 7.9 Hz, 1H, CH, A), 3.74 (s, 3H, CH3O,
B), 3.76 (s, 3H, CH3O, A), 4.82 (d, 2J = 15.4 Hz, 1H, CH2, B), 4.90
(d, 2J = 15.4 Hz, 1H, CH2, B), 4.97 (d, 2J = 15.4 Hz, 1H, CH2, A),
5.03 (d, 2J = 15.4 Hz, 1H, CH2, A), 5.87−5.88 (m, 2H, OCH2O, B),
5.89−5.90 (m, 2H, OCH2O, A), 6.18 (br d, 3J = 7.5 Hz, 1H, Ar, A),
6.69 (br s, 1H, Ar, A), 6.73−6.75 (m, 3H, Ar, B), 6.76 (br s, 1H, Ar,
B), 6.76−6.78 (m, 1H, Ar, B), 6.79−6.80 (m, 1H, Ar, B), 6.84−6.89
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
(m, 4H, Ar, A), 6.90−6.91 (m, 2H, Ar, A), 6.94−6.96 (m, 1H, Ar, B),
7.03−7.06 (m, 1H, Ar, B), 7.07−7.10 (m, 1H, Ar, A), 7.18−7.20 (m,
1H, Ar, B), 7.23−7.24 (m, 2H, Ar, B), 7.33−7.34 (m, 2H, Ar, A). A:
13
C NMR (150 MHz, CDCl3) δ 22.5 (1JCH = 165 Hz, CH2), 33.1 (C),
35.6 (1JCH = 165 Hz, CH), 43.2 (1JCH = 139 Hz, CH2), 54.82 (1JCH =
144 Hz, CH3O), 100.8 (1JCH = 174 Hz, OCH2O), 107.7 (CH), 108.5
(CH), 110.0 (CH), 113.8 (2 × CH), 120.5 (CH), 121.2 (CH), 122.7
(CH), 126.1 (CH), 127.1 (C), 128.06 (C), 128.4 (2 × CH), 128.53
(C), 142.7 (C), 146.5 (C), 147.3 (C), 158.7 (C), 176.0 (CO). B: 13C
NMR (150 MHz, CDCl3) δ 22.2 (1JCH = 165 Hz, CH2), 33.5 (C),
38.1 (1JCH = 162 Hz, CH), 42.9 (1JCH = 139 Hz, CH2), 54.79 (1JCH =
144 Hz, CH3O), 100.7 (1JCH = 174 Hz, OCH2O), 107.5 (CH), 108.4
(CH), 109.4 (CH), 113.7 (2 × CH), 117.8 (CH), 121.5 (CH), 122.4
(CH), 126.3 (CH), 128.07 (C), 128.18 (C), 128.46 (2 × CH), 130.4
(C), 142.1 (C), 146.4 (C), 147.1 (C), 158.6 (C), 173.4 (CO);
HRMS (ESI) m/z [M + H]+ calcd for C25H22NO4+ 400.1543, found
400.1553.
1′-(4-Methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)spiro-
[cyclopropane-1,3′-indol]-2′(1′H)-one (1j). This compound was
obtained from S1j (395 mg, 0.917 mmol): reaction time 2.5 h;
yield 360 mg (88%); yellow viscous oil; dr 65:35; Rf = 0.16
(petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ
1.98 (dd, 2J = 4.4, 3J = 7.9 Hz, 1H, CH2, A), 2.05 (dd, 2J = 4.8, 3J =
9.1 Hz, 1H, CH2, B), 2.20 (dd, 2J = 4.4, 3J = 9.2 Hz, 1H, CH2, A),
2.38 (dd, 2J = 4.8, 3J = 8.6 Hz, 1H, CH2, B), 3.08 (dd, 3J = 9.1, 3J =
8.6 Hz, 1H, CH, B), 3.32 (dd, 3J = 9.2, 3J = 7.9 Hz, 1H, CH, A), 3.63
(s, 3H, CH3O, B), 3.64 (s, 6H, CH3O, B), 3.68 (s, 6H, CH3O, A),
3.75 (s, 3H, CH3O, A), 3.795 (s, 3H, CH3O, A), 3.801 (s, 3H, CH3O,
B), 4.68 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.81 (d, 2J = 15.5 Hz, 1H,
CH2, A), 4.84 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.00 (d, 2J = 15.5 Hz,
1H, CH2, A), 6.12 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.39 (s, 2H, Ar, A),
6.54 (s, 2H, Ar, B), 6.63−6.66 (m, 1H, Ar, A), 6.71−6.73 (m, 2H, Ar,
B), 6.77−6.79 (m, 3H + 1H, Ar, A, B), 6.88−6.90 (m, 1H, Ar, B),
6.94−6.97 (m, 1H, Ar, B), 6.98−7.00 (m, 1H, Ar, A), 7.08−7.11 (m,
1H, Ar, B), 7.11−7.13 (m, 2H, Ar, B), 7.23−7.24 (m, 2H, Ar, A). A:
13
C NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 32.8 (C),
35.8 (1JCH = 163 Hz, CH), 43.0 (1JCH = 139 Hz, CH2), 54.53 (1JCH =
144 Hz, CH3O), 55.5 (1JCH = 144 Hz, 2 × CH3O), 60.3 (1JCH = 144
Hz, CH3O), 106.6 (2 × CH), 108.3 (CH), 113.5 (2 × CH), 120.3
(CH), 121.0 (CH), 126.0 (CH), 126.8 (C), 127.8 (C), 128.18 (2 ×
CH), 130.2 (C), 136.9 (C), 142.3 (C), 152.5 (2 × C), 158.5 (C),
175.8 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.2 (1JCH = 164 Hz,
CH2), 33.4 (C), 38.4 (1JCH = 164 Hz, CH), 42.6 (1JCH = 139 Hz,
CH2), 54.52 (1JCH = 144 Hz, CH3O), 55.4 (1JCH = 144 Hz, 2 ×
CH3O), 60.2 (1JCH = 144 Hz, CH3O), 106.0 (2 × CH), 108.2 (CH),
113.4 (2 × CH), 117.7 (CH), 121.4 (CH), 126.2 (CH), 128.0 (C),
128.16 (2 × CH), 128.4 (C), 129.8 (C), 136.6 (C), 141.9 (C), 152.2
(2 × C), 158.4 (C), 173.1 (CO); HRMS (ESI) m/z [M + H]+ calcd
for C27H27NO5+ 446.1962, found 446.1964.
1′-(4-Methoxybenzyl)-2-(thien-2-yl)spiro[cyclopropane-1,3′-
indol]-2′(1′H)-one (1k). This compound was obtained from S1k (547
mg, 1.58 mmol): reaction time 2.5 h; yield 490 mg (86%); yellow oil;
dr 68:32; Rf = 0.44 (petroleum ether−ethyl acetate, 3:1); 1H NMR
(600 MHz, CDCl3) δ 2.12 (dd, 2J = 4.5, 3J = 7.6 Hz, 1H, CH2, A),
2.20 (dd, 2J = 4.9, 3J = 9.0 Hz, 1H, CH2, B), 2.40 (dd, 2J = 4.5, 3J =
9.2 Hz, 1H, CH2, A), 2.49 (dd, 2J = 4.9, 3J = 8.2 Hz, 1H, CH2, B),
3.26 (dd, 3J = 9.0, 3J = 8.2 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.2, 3J = 7.6
Hz, 1H, CH, A), 3.74 (s, 3H, CH3O, B), 3.76 (s, 3H, CH3O, A), 4.83
(d, 2J = 15.5 Hz, 1H, CH2, B), 4.94 (d, 2J = 15.5 Hz, 1H, CH2, A),
4.97 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.06 (d, 2J = 15.5 Hz, 1H, CH2,
A), 6.34 (br d, 3J = 7.5 Hz, 1H, Ar, A), 6.78−6.80 (m, 1H, Ar, A),
6.87−6.89 (m, 2H, Ar, A), 6.91−6.94 (m, 2H + 1H, Ar, A, B), 6.96−
6.97 (m, 3H, Ar, B), 6.98−7.00 (m, 1H, Ar, A), 7.03−7.04 (m, 1H,
Ar, B), 7.05−7.07 (m, 1H, Ar, B), 7.12−7.15 (m, 1H + 1H, Ar, A, B),
7.19−7.20 (m, 1H, Ar, A), 7.21−7.23 (m, 2H, Ar, B), 7.27−7.28 (m,
2H, Ar, B), 7.35−7.36 (m, 2H, Ar, A). A: 13C NMR (150 MHz,
CDCl3) δ 23.4 (1JCH = 165 Hz, CH2), 29.9 (1JCH = 169 Hz, CH), 33.7
(C), 43.2 (1JCH = 139 Hz, CH2), 54.74 (1JCH = 144 Hz, CH3O),
108.52 (CH), 113.8 (2 × CH), 120.0 (CH), 121.3 (CH), 125.0
(CH), 126.4 (CH), 126.49 (CH), 126.50 (C), 127.1 (CH), 127.9
8702
Note
(C), 128.3 (2 × CH), 138.5 (C), 142.6 (C), 158.7 (C), 175.3 (CO).
B: 13C NMR (150 MHz, CDCl3) δ 23.3 (1JCH = 165 Hz, CH2), 32.3
(1JCH = 166 Hz, CH), 33.9 (C), 42.9 (1JCH = 139 Hz, CH2), 54.72
(1JCH = 144 Hz, CH3O), 108.49 (CH), 113.7 (2 × CH), 117.8 (CH),
121.5 (CH), 124.4 (CH), 126.3 (CH), 126.52 (CH), 126.8 (CH),
128.0 (C), 128.4 (2 × CH), 129.6 (C), 137.6 (C), 142.1 (C), 158.6
(C), 172.7 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C22H20NO2S+ 362.1209, found 362.1213.
5-Methyl-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1l). This compound was obtained from S1l
(5.3 g, 15 mmol): reaction time 2.5 h; yield 4.72 g (85%); white
foam; dr 65:35; Rf = 0.50 (petroleum ether−ethyl acetate, 2:1); 1H
NMR (600 MHz, CDCl3) δ 2.05 (dd, 2J = 4.4, 3J = 8.0 Hz, 1H, CH2,
A), 2.04 (s, 3H, CH3, A), 2.12 (dd, 2J = 4.9, 3J = 9.1 Hz, 1H, CH2, B),
2.29 (dd, 2J = 4.4, 3J = 9.2 Hz, 1H, CH2, A), 2.39 (s, 3H, CH3, B),
2.50 (dd, 2J = 4.9, 3J = 8.6 Hz, 1H, CH2, B), 3.20 (dd, 3J = 9.1, 3J =
8.6 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.2, 3J = 8.0 Hz, 1H, CH, A), 3.78
(s, 3H, CH3O, B), 3.81 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.5 Hz, 1H,
CH2, B), 4.84 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.97 (d, 2J = 15.5 Hz,
1H, CH2, A), 5.03 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.81−5.82 (m, 1H,
Ar, A), 6.72 (d, 3J = 7.9 Hz, 1H, Ar, A), 6.75 (d, 3J = 7.9 Hz, 1H, Ar,
B), 6.83−6.85 (m, 3H, Ar, B), 6.87−6.89 (m, 1H, Ar, A), 6.90−6.92
(m, 2H, Ar, A), 7.01−7.02 (m, 1H, Ar, B), 7.19−7.22 (m, 2H, Ar, B),
7.23−7.25 (m, 2H, Ar, A), 7.28−7.40 (m, 5H + 5H, Ar, A, B). A: 13C
NMR (150 MHz, CDCl3) δ 20.8 (CH3), 22.4 (CH2), 33.1 (C), 35.8
(CH), 43.5 (CH2), 55.10 (CH3O), 108.3 (CH), 114.0 (2 × CH),
121.6 (CH), 126.6 (CH), 127.2 (CH), 127.5 (C), 128.2 (2 × CH),
128.4 (C), 128.52 (2 × CH), 129.9 (2 × CH), 130.7 (C), 135.1 (C),
140.5 (C), 158.9 (C), 176.3 (CO). B: 13C NMR (150 MHz, CDCl3)
δ 21.0 (CH3), 22.1 (CH2), 33.7 (C), 38.3 (CH), 43.2 (CH2), 55.07
(CH3O), 108.4 (CH), 113.9 (2 × CH), 118.9 (CH), 126.8 (CH),
127.1 (CH), 127.8 (2 × CH), 128.50 (C), 128.7 (2 × CH), 129.2 (2
× CH), 131.3 (C), 130.8 (C), 134.4 (C), 140.1 (C), 158.8 (C), 173.6
(CO); HRMS (ESI) m/z [M + H]+ calcd for C25H24NO2+ 370.1802,
found 370.1808.
5-Fluoro-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1m). This compound was obtained from
S1m (3.40 g, 9.5 mmol): reaction time 2.5 h; yield 3.05 g (86%);
yellow foam; dr 74:26; Rf = 0.63 (petroleum ether−ethyl acetate,
2:1); 1H NMR (600 MHz, CDCl3) δ 2.06 (dd, 2J = 4.5, 3J = 8.0 Hz,
1H, CH2, A), 2.12 (dd, 2J = 5.0, 3J = 9.1 Hz, 1H, CH2, B), 2.32 (dd, 2J
= 4.5, 3J = 9.2 Hz, 1H, CH2, A), 2.53 (dd, 2J = 5.0, 3J = 8.7 Hz, 1H,
CH2, B), 3.18 (dd, 3J = 9.1, 3J = 8.7 Hz, 1H, CH, B), 3.47 (dd, 3J =
9.2, 3J = 8.0 Hz, 1H, CH, A), 3.78 (s, 3H, CH3O, B), 3.80 (s, 3H,
CH3O, A), 4.79 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.83 (d, 2J = 15.5 Hz,
1H, CH2, B), 4.94 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.01 (d, 2J = 15.5
Hz, 1H, CH2, A), 5.73 (dd, 3J = 8.6, 4J = 2.6 Hz, 1H, Ar, A), 6.69 (dd,
3
J = 8.6, 4J = 4.3 Hz, 1H, Ar, A), 6.71−6.76 (m, 1H + 2H, Ar, A, B),
6.82−6.85 (m, 2H, Ar, B), 6.86−6.89 (m, 1H, Ar, B), 6.89−6.92 (m,
2H, Ar, A), 7.16−7.18 (m, 2H, Ar, B), 7.21−7.22 (m, 2H, Ar, A),
7.28−7.31 (m, 2H + 4H, Ar, A, B), 7.32−7.35 (m, 2H + 1H, Ar, A,
B), 7.35−7.36 (m, 1H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ
22.9 (1JCH = 165 Hz, CH2), 33.5 (4JCF = 2 Hz, C), 36.4 (1JCH = 165
Hz, CH), 43.7 (1JCH = 139 Hz, CH2), 55.14 (1JCH = 144 Hz, CH3O),
108.7 (2JCF = 26 Hz, CH), 109.0 (3JCF = 8 Hz, CH), 112.5 (2JCF = 24
Hz, CH), 114.1 (2 × CH), 127.6 (CH), 128.0 (C), 128.5 (2 × CH),
128.6 (2 × CH), 129.3 (3JCF = 9 Hz, C), 129.7 (2 × CH), 134.4 (C),
138.7 (C), 158.3 (1JCF = 239 Hz, C), 159.0 (C), 176.1 (CO). B: 13C
NMR (150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 34.1 (4JCF =
2 Hz, C), 38.9 (1JCH = 164 Hz, CH), 43.3 (1JCH = 139 Hz, CH2),
55.11 (1JCH = 144 Hz, CH3O), 106.3 (2JCF = 25 Hz, CH), 109.1 (3JCF
= 8 Hz, CH), 112.7 (2JCF = 23 Hz, CH), 114.0 (2 × CH), 127.4
(CH), 127.7 (2 × CH), 128.1 (C), 128.7 (2 × CH), 129.2 (2 × CH),
132.5 (3JCF = 9 Hz, C), 133.9 (C), 138.3 (C), 158.9 (C), 159.0 (1JCF
= 239 Hz, C), 173.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C24H21FNO2+ 374.1551, found 374.1560.
Ethyl 4-(5′-Fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-
dihydrospiro[cyclopropane-1,3′-indol]-2-yl)benzoate (1n). This
compound was obtained from S1n (6.87 g, 16 mmol): reaction
time 2.5 h; yield 4.27 g (60%); yellow foam; dr 65:35; Rf = 0.29
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
(petroleum ether−ethyl acetate, 3:1); 1H NMR (600 MHz, CDCl3) δ
1.39 (t, 3J = 7.2 Hz, 3H, CH3, A), 141 (t, 3J = 7.2 Hz, 3H, CH3, A),
2.06 (dd, 2J = 4.8, 3J = 8.1 Hz, 1H, CH2, A), 2.15 (dd, 2J = 5.1, 3J =
9.0 Hz, 1H, CH2, B), 2.33 (dd, 2J = 4.8, 3J = 9.1 Hz, 1H, CH2, A),
2.54 (dd, 2J = 5.1, 3J = 8.6 Hz, 1H, CH2, B), 3.18 (dd, 3J = 9.0, 3J =
8.6 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.0, 3J = 8.1 Hz, 1H, CH, A), 3.77
(s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.39 (q, 3J = 7.2 Hz, 2H +
2H, CH2O, A, B), 4.75 (d, 2J = 15.5 Hz, 1H, CH2, B), 4.80 (d, 2J =
15.5 Hz, 1H, CH2, B), 4.90 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.01 (d, 2J
= 15.5 Hz, 1H, CH2, A), 5.70 (dd, 3J = 8.5, 4J = 2.5 Hz, 1H, Ar, A),
6.68 (dd, 3J = 8.5, 4J = 4.4 Hz, 1H, Ar, A), 6.71−6.77 (m, 1H + 2H,
Ar, A, B), 6.80−6.84 (m, 2H, Ar, B), 6.84−6.86 (m, 1H, Ar, B),
6.86−6.90 (m, 2H, Ar, A), 7.11−7.15 (m, 2H, Ar, B), 7.26−7.28 (m,
4H, Ar, A), 7.39−7.41 (m, 2H, Ar, B), 8.00−8.03 (m, 2H + 2H, Ar, A,
B). A: 13C NMR (150 MHz, CDCl3) δ 13.9 (1JCH = 127 Hz, CH3),
22.12 (1JCH = 165 Hz, CH2), 33.4 (C), 35.8 (1JCH = 166 Hz, CH),
43.4 (1JCH = 139 Hz, CH2), 54.77 (1JCH = 144 Hz, CH3O), 60.7 (1JCH
= 147 Hz, CH2O), 108.3 (2JCF = 26 Hz, CH), 108.96 (3JCF = 7 Hz,
CH), 112.6 (2JCF = 24 Hz, CH), 113.9 (2 × CH), 127.6 (C), 128.3 (2
× CH), 128.5 (3JCF = 9 Hz, C), 129.10 (C), 129.43 (2 × CH), 129.44
(2 × CH), 138.6 (C), 139.4 (C), 158.0 (1JCF = 239 Hz, C), 158.8
(C), 165.7 (CO2Et), 175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ
14.0 (1JCH = 127 Hz, CH3), 22.05 (1JCH = 165 Hz, CH2), 34.1 (C),
38.0 (1JCH = 162 Hz, CH), 43.0 (1JCH = 139 Hz, CH2), 54.75 (1JCH =
144 Hz, CH3O), 60.5 (1JCH = 148 Hz, CH2O), 106.2 (2JCF = 25 Hz,
CH), 109.01 (3JCF = 7 Hz, CH), 112.7 (2JCF = 24 Hz, CH), 113.7 (2
× CH), 127.7 (C), 128.4 (2 × CH), 128.8 (2 × CH), 129.05 (C),
129.5 (2 × CH), 131.8 (3JCF = 9 Hz, C), 138.1 (C), 139.1 (C), 158.7
(C), 158.7 (1JCF = 240 Hz, C), 165.9 (CO2Et), 172.7 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C27H25FNO4+ 446.1762, found
446.1767.
5-Chloro-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1o). This compound was obtained from S1o
(4.20 g, 11.2 mmol): reaction time 2.5 h; yield 3.54 g (81%); yellow
foam; dr 69:31; Rf = 0.65 (petroleum ether−ethyl acetate, 2:1); 1H
NMR (600 MHz, CDCl3) δ 2.07 (dd, 2J = 4.6, 3J = 7.9 Hz, 1H, CH2,
A), 2.13 (dd, 2J = 5.0, 3J = 9.1 Hz, 1H, CH2, B), 2.32 (dd, 2J = 4.6, 3J
= 9.2 Hz, 1H, CH2, A), 2.53 (dd, 2J = 5.0, 3J = 8.8 Hz, 1H, CH2, B),
3.20 (dd, 3J = 9.1, 3J = 8.8 Hz, 1H, CH, B), 3.47 (dd, 3J = 9.2, 3J = 7.9
Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.78
(d, 2J = 15.5 Hz, 1H, CH2, B), 4.82 (d, 2J = 15.5 Hz, 1H, CH2, B),
4.94 (d, 2J = 15.5 Hz, 1H, CH2, A), 5.01 (d, 2J = 15.5 Hz, 1H, CH2,
A), 5.93 (dd, 4J = 2.1, 5J = 0.4 Hz, 1H, Ar, A), 6.70 (br d, 3J = 8.4 Hz,
1H, Ar, A), 6.73 (br d, 3J = 8.4 Hz, 1H, Ar, B), 6.82−6.84 (m, 2H, Ar,
B), 6.89−6.91 (m, 2H, Ar, A), 6.96 (dd, 4J = 2.1, 5J = 0.4 Hz, 1H, Ar,
B), 7.01 (dd, 3J = 8.3, 4J = 2.1 Hz, 1H, Ar, A), 7.14 (dd, 3J = 8.3, 4J =
2.1 Hz, 1H, Ar, B), 7.14−7.17 (m, 2H, Ar, B), 7.20−7.22 (m, 2H, Ar,
A), 7.27−7.29 (m, 2H, Ar, A), 7.29−7.32 (m, 4H, Ar, B), 7.33−7.36
(m, 3H + 1H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3) δ 22.9
(1JCH = 165 Hz, CH2), 33.2 (C), 36.5 (1JCH = 165 Hz, CH), 43.6
(1JCH = 139 Hz, CH2), 55.2 (1JCH = 144 Hz, CH3O), 109.5 (CH),
114.1 (2 × CH), 121.0 (CH), 126.2 (CH), 126.8 (C), 127.7 (CH),
127.8 (C), 128.45 (2 × CH), 128.53 (2 × CH), 129.3 (C), 129.7 (2
× CH), 134.4 (C), 141.4 (C), 159.0 (C), 175.9 (CO). B: 13C NMR
(150 MHz, CDCl3) δ 22.4 (1JCH = 165 Hz, CH2), 33.8 (C), 38.9
(1JCH = 162 Hz, CH), 43.3 (1JCH = 139 Hz, CH2), 55.1 (1JCH = 144
Hz, CH3O), 109.6 (CH), 114.0 (2 × CH), 118.6 (CH), 126.4 (CH),
127.2 (C), 127.4 (CH), 127.88 (2 × CH), 127.92 (C), 128.7 (2 ×
CH), 129.2 (2 × CH), 132.5 (C), 133.8 (C), 140.9 (C), 158.9 (C),
173.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for C24H21ClNO2+
390.1255, found 390.1264.
5-Bromo-1′-(4-methoxybenzyl)-2-phenylspiro[cyclopropane-
1,3′-indol]-2′(1′H)-one (1p). This compound was obtained from S1p
(2.99 g, 7.14 mmol): reaction time 2.5 h; yield 2.36 g (76%); yellow
foam; dr 69:31; Rf = 0.60 (petroleum ether−ethyl acetate, 2:1); 1H
NMR (600 MHz, CDCl3) δ 2.06 (dd, 2J = 4.6, 3J = 8.0 Hz, 1H, CH2,
A), 2.13 (dd, 2J = 5.1, 3J = 9.1 Hz, 1H, CH2, B), 2.29 (dd, 2J = 4.6, 3J
= 9.2 Hz, 1H, CH2, A), 2.51 (dd, 2J = 5.1, 3J = 8.7 Hz, 1H, CH2, B),
3.19 (dd, 3J = 9.1, 3J = 8.7 Hz, 1H, CH, B), 3.44 (dd, 3J = 9.1, 3J = 8.0
Hz, 1H, CH, A), 3.77 (s, 3H, CH3O, B), 3.80 (s, 3H, CH3O, A), 4.77
8703
Note
(d, 2J = 15.6 Hz, 1H, CH2, B), 4.79 (d, 2J = 15.6 Hz, 1H, CH2, B),
4.91 (d, 2J = 15.5 Hz, 1H, CH2, A), 4.99 (d, 2J = 15.5 Hz, 1H, CH2,
A), 6.02 (dd, 4J = 2.0, 5J = 0.4 Hz, 1H, Ar, A), 6.64 (br d, 3J = 8.3 Hz,
1H, Ar, A), 6.67 (br d, 3J = 8.3 Hz, 1H, Ar, B), 6.80−6.82 (m, 2H, Ar,
B), 6.87−6.89 (m, 2H, Ar, A), 7.08 (dd, 4J = 2.0, 5J = 0.4 Hz, 1H, Ar,
B), 7.11−7.14 (m, 2H, Ar, B), 7.15 (dd, 3J = 8.3, 4J = 2.0 Hz, 1H, Ar,
A), 7.18−7.20 (m, 2H, Ar, A), 7.24−7.26 (m, 2H, Ar, A), 7.27−7.32
(m, 4H, Ar, B), 7.33−7.35 (m, 3H + 1H, Ar, A, B). A: 13C NMR (150
MHz, CDCl3) δ 22.7 (CH2), 33.0 (C), 36.4 (CH), 43.4 (CH2), 55.0
(CH3O), 109.85 (CH), 113.96 (C), 114.00 (2 × CH), 123.6 (CH),
127.5 (CH), 127.6 (C), 127.7 (CH), 128.3 (2 × CH), 128.4 (2 ×
CH), 129.5 (C), 129.6 (2 × CH), 134.2 (C), 141.7 (C), 158.9 (C),
175.6 (CO). B: 13C NMR (150 MHz, CDCl3) δ 22.3 (CH2), 33.6
(C), 38.8 (CH), 43.1 (CH2), 54.9 (CH3O), 109.91 (CH), 113.8 (2 ×
CH), 114.3 (C), 121.2 (CH), 127.2 (CH), 128.1 (C), 128.46 (C),
128.50 (2 × CH), 129.0 (2 × CH), 129.12 (2 × CH), 132.8 (CH),
133.7 (C), 141.2 (C), 158.8 (C), 172.8 (CO); HRMS (ESI) m/z [M
+ H]+ calcd for C24H21BrNO2+ 434.0750, found 434.0761.
General Procedure for the Synthesis of Spiro[Pyrrolidone-
3,3′-oxindoles] 2. A solution of cyclopropane 1 (0.20 mmol, 1.0
equiv) in dry DMF (2.0 mL, 0.1 M), KNCO (33 mg, 0.40 mmol, 2.0
equiv), and triethylamine hydrochloride (28 mg, 0.20 mmol, 1.0
equiv) was placed in a microwave vessel. The reaction mixture was
stirred (800 rpm) under the heating by microwave irradiation at 150
°C for a specified time; then it was cooled down to ambient
temperature, and an extra portion of KNCO (33 mg, 0.40 mmol, 2.0
equiv) was added (excluding synthesis of 2m−p). The resulting
mixture was further heated under microwave irradiation at 150 °C for
a specified time, cooled to ambient temperature, poured into water
(20 mL), and extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine (5 × 10 mL), dried
over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on conventional or
neutralized (2c−e,i−k,s−u) silica gel (petroleum ether−ethyl
acetate). For the preparation of neutralized silica gel, in an
Erlenmeyer flask, silica gel (ca. 12 g), petroleum ether (90 mL),
ethyl acetate (5 mL), and triethylamine (1 mL) were mixed. The
suspension was then shaken vigorously and left overnight. The
column was packed with the resulting silica gel slurry. In order to
remove the leftover polar solvent, petroleum ether was passed through
the column. (The total volume is approximately 8−10 volumes of
silica gel.)
1-(4-Methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′-pyrroli-
dine]-2,2′(1H)-dione (2a). This compound was obtained from 1a
(424 mg, 1.20 mmol): reaction time 4 + 6 h; yield 294 mg (62%);
white solid, mp 216−217 °C; dr 52:48; Rf = 0.38 (petroleum ether−
ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.41 (dd, 2J =
13.3, 3J = 8.2 Hz, 1H, CH2, A), 2.81 (dd, 2J = 13.5, 3J = 7.5 Hz, 1H,
CH2, B), 2.88 (dd, 2J = 13.5, 3J = 8.3 Hz, 1H, CH2, B), 3.11 (dd, 2J =
13.4, 3J = 7.2 Hz, 1H, CH2, A), 3.76 (s, 3H, CH3O), 3.77 (s, 3H,
CH3O), 4.83 (d, 2J = 15.6 Hz, 1H, CH2), 4.84 (d, 2J = 15.6 Hz, 1H,
CH2), 4.92 (d, 2J = 15.6 Hz, 1H, CH2), 4.98 (d, 2J = 15.6 Hz, 1H,
CH2), 5.10 (dd, 3J = 8.3, 3J = 7.5 Hz, 1H, CH, B), 5.34 (dd, 3J = 8.2,
3
J = 7.2 Hz, 1H, CH, A), 6.74−6.77 (m, 2H, Ar), 6.81−6.86 (m, 4H,
Ar), 6.89 (br s, 1H, NH), 6.95 (br s, 1H, NH), 7.04−7.09 (m, 2H,
Ar), 7.17−7.19 (m, 1H, Ar), 7.19−7.23 (m, 2H, Ar), 7.24−7.29 (m,
4H, Ar), 7.34−7.39 (m, 3H, Ar), 7.41−7.45 (m, 6H, Ar), 7.51−7.53
(m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 41.4 (CH2), 42.1
(CH2), 43.4 (CH2), 43.6 (CH2), 55.20 (CH3O), 55.21 (CH3O), 55.4
(CH), 56.5 (CH), 58.5 (C), 58.6 (C), 109.6 (CH), 109.8 (CH),
114.2 (2 × CH), 114.3 (2 × CH), 122.5 (CH), 123.0 (CH), 123.2
(CH), 123.3 (CH), 125.8 (2 × CH), 126.4 (2 × CH), 127.3 (2 × C),
128.3 (CH), 128.4 (3 × CH), 128.5 (2 × CH), 128.6 (C), 128.99
(CH), 129.02 (2 × CH), 129.08 (CH), 129.11 (2 × CH), 130.1 (C),
141.1 (C), 141.5 (C), 143.2 (C), 143.8 (C), 159.0 (C), 159.1 (C),
173.6 (CO), 173.8 (CO), 175.1 (CO), 175.5 (CO); HRMS (ESI) m/
z [M + H]+ calcd for C25H23N2O3+ 399.1703, found 399.1698.
1-(4-Methoxybenzyl)-5′-(p-tolyl)-2′H-spiro[indole-3,3′-pyrroli-
dine]-2,2′(1H)-dione (2b). This compound was obtained from 1b (77
mg, 0.21 mmol): reaction time 2 + 4 h; yield 57 mg (66%); yellowish
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
solid, mp 195−196 °C; dr 51:49; Rf = 0.40 (petroleum ether−ethyl
acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.36 (CH3), 2.38
(CH3), 2.39 (dd, 2J = 13.4, 3J = 8.4 Hz, 1H, CH2, A), 2.77 (dd, 2J =
13.3, 3J = 7.4 Hz, 1H, CH2, B), 2.85 (dd, 2J = 13.3, 3J = 8.3 Hz, 1H,
CH2, B), 3.09 (dd, 2J = 13.4, 3J = 7.1 Hz, 1H, CH2, A), 3.75 (s, 3H,
CH3O), 3.76 (s, 3H, CH3O), 4.81 (d, 2J = 15.6 Hz, 1H, CH2), 4.83
(d, 2J = 15.7 Hz, 1H, CH2), 4.92 (d, 2J = 15.6 Hz, 1H, CH2), 4.98 (d,
2
J = 15.7 Hz, 1H, CH2), 5.06 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B),
5.29 (dd, 3J = 8.4, 3J = 7.1 Hz, 1H, CH, A), 6.73−6.76 (m, 2H, Ar),
6.80−6.84 (m, 4H, Ar), 6.91 (br s, 1H, NH), 6.98 (br s, 1H, NH),
7.03−7.08 (m, 2H, Ar), 7.17−7.29 (m, 11H, Ar), 7.32−7.33 (m, 2H,
Ar), 7.35−7.36 (m, 1H, Ar), 7.39−7.40 (m, 2H, Ar); 13C NMR (150
MHz, CDCl3) δ 21.0 (1JCH = 127 Hz, 2 × CH3), 41.4 (1JCH = 138 Hz,
CH2), 42.1 (1JCH = 138 Hz, CH2), 43.3 (1JCH = 138 Hz, CH2), 43.5
(1JCH = 138 Hz, CH2), 55.13 (1JCH = 144 Hz, 2 × CH3O), 55.14 (1JCH
= 140 Hz, CH), 56.2 (1JCH = 140 Hz, CH), 58.5 (C), 58.6 (C), 109.5
(CH), 109.6 (CH), 114.1 (2 × CH), 114.2 (2 × CH), 122.5 (CH),
122.9 (CH), 123.1 (CH), 123.3 (CH), 125.7 (2 × CH), 126.3 (2 ×
CH), 127.3 (2 × C), 128.36 (2 × CH), 128.41 (2 × CH), 128.76
(C), 128.84 (CH), 128.9 (CH), 129.6 (2 × CH), 129.7 (2 × CH),
130.2 (C), 138.0 (C), 138.10 (C), 138.12 (C), 138.5 (C), 143.2 (C),
143.7 (C), 158.9 (C), 159.0 (C), 173.4 (CO), 173.5 (CO), 175.1
(CO), 175.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C26H25N2O3+ 413.1860, found 413.1864.
1-(4-Methoxybenzyl)-5′-(4-methoxyphenyl)-2′H-spiro[indole-
3,3′-pyrrolidine]-2,2′(1H)-dione (2c). This compound was obtained
from 1c (73 mg, 0.19 mmol): reaction time 2 + 2 h; purification
performed on neutralized silica gel; yield 45 mg (56%); orange solid,
mp 223−224 °C; dr 51:49; Rf = 0.42 (petroleum ether−ethyl acetate,
1:1); 1H NMR (600 MHz, CDCl3) δ 2.38 (dd, 2J = 13.3, 3J = 8.3 Hz,
1H, CH2, A), 2.77 (dd, 2J = 13.4, 3J = 7.4 Hz, 1H, CH2, B), 2.85 (dd,
2
J = 13.4, 3J = 8.3 Hz, 1H, CH2, B), 3.06 (dd, 2J = 13.3, 3J = 7.0 Hz,
1H, CH2, A), 3.75 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 3.81 (s, 3H,
CH3O), 3.83 (s, 3H, CH3O), 4.81 (d, 2J = 15.6 Hz, 1H, CH2), 4.83
(d, 2J = 15.6 Hz, 1H, CH2), 4.92 (d, 2J = 15.6 Hz, 1H, CH2), 4.98 (d,
2
J = 15.6 Hz, 1H, CH2), 5.05 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B),
5.29 (dd, 3J = 8.3, 3J = 7.0 Hz, 1H, CH, A), 6.69 (br s, 1H, NH),
6.74−6.76 (m, 2H + 1H, Ar, NH), 6.81−6.84 (m, 4H, Ar), 6.93−6.96
(m, 4H, Ar), 7.04−7.08 (m, 2H, Ar), 7.19−7.22 (m, 3H, Ar), 7.24−
7.28 (m, 4H, Ar), 7.34−7.37 (m, 3H, Ar), 7.43−7.45 (m, 2H, Ar);
13
C NMR (150 MHz, CDCl3) δ 41.5 (1JCH = 138 Hz, CH2), 42.3
(1JCH = 138 Hz, CH2), 43.4 (1JCH = 138 Hz, CH2), 43.6 (1JCH = 138
Hz, CH2), 54.9 (1JCH = 144 Hz, CH), 55.16 (1JCH = 144 Hz, CH3O),
55.18 (1JCH = 144 Hz, CH3O), 55.28 (1JCH = 144 Hz, CH3O), 55.30
(1JCH = 144 Hz, CH3O), 55.9 (1JCH = 144 Hz, CH), 58.5 (C), 58.6
(C), 109.5 (CH), 109.7 (CH), 114.15 (2 × CH), 114.21 (2 × CH),
114.3 (2 × CH), 114.4 (2 × CH), 122.5 (CH), 122.9 (CH), 123.2
(CH), 123.3 (CH), 127.1 (2 × CH), 127.3 (2 × C), 127.7 (2 × CH),
128.39 (2 × CH), 128.44 (2 × CH), 128.7 (C), 128.9 (CH), 129.0
(CH), 130.2 (C), 133.0 (C), 133.3 (C), 143.2 (C), 143.7 (C), 158.97
(C), 159.01 (C), 159.5 (C), 159.7 (C), 173.2 (CO), 173.3 (CO),
175.2 (CO), 175.6 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C26H25N2O4+ 429.1809, found 429.1816.
5′-(4-Bromophenyl)-1-(4-methoxybenzyl)-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2d). This compound was obtained from
1d (78 mg, 0.18 mmol): reaction time 2 + 2 h; purification performed
on neutralized silica gel; yield 41 mg (48%); orange solid, mp 199−
200 °C; dr 53:47; Rf = 0.58 (petroleum ether−ethyl acetate, 1:1); 1H
NMR (600 MHz, CDCl3) δ 2.32 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2,
A), 2.77 (dd, 2J = 13.5, 3J = 8.0 Hz, 1H, CH2, B), 2.82 (dd, 2J = 13.5,
3
J = 7.6 Hz, 1H, CH2, B), 3.09 (dd, 2J = 13.3, 3J = 7.1 Hz, 1H, CH2,
A), 3.75 (s, 3H, CH3O), 3.77 (s, 3H, CH3O), 4.80 (d, 2J = 15.6 Hz,
1H, CH2), 4.82 (d, 2J = 15.6 Hz, 1H, CH2), 4.91 (d, 2J = 15.6 Hz, 1H,
CH2), 4.96 (d, 2J = 15.6 Hz, 1H, CH2), 5.05 (dd, 3J = 8.3, 3J = 7.4 Hz,
1H, CH, B), 5.29 (dd, 3J = 8.3, 3J = 7.0 Hz, 1H, CH, A), 6.73−6.76
(m, 2H, Ar), 6.79−6.84 (m, 4H, Ar), 7.04−7.08 (m, 2H, Ar), 7.13−
7.14 (m, 1H, Ar), 7.18 (br s, 1H, NH), 7.19−7.26 (m, 6H + 1H, Ar,
NH), 7.30−7.33 (m, 3H, Ar), 7.37−7.38 (m, 2H, Ar), 7.51−7.55 (m,
4H, Ar); 13C NMR (150 MHz, CDCl3) δ 41.1 (1JCH = 138 Hz, CH2),
41.9 (1JCH = 138 Hz, CH2), 43.4 (1JCH = 138 Hz, CH2), 43.6 (1JCH =
8704
Note
138 Hz, CH2), 54.9 (1JCH = 144 Hz, CH), 55.21 (1JCH = 144 Hz,
CH3O), 55.23 (1JCH = 144 Hz, CH3O), 55.8 (1JCH = 144 Hz, CH),
58.3 (C), 58.5 (C), 109.7 (CH), 109.8 (CH), 114.2 (2 × CH), 114.3
(2 × CH), 122.1 (C), 122.3 (C), 122.5 (CH), 123.0 (CH), 123.2 (2
× CH), 127.2 (2 × C), 127.5 (2 × CH), 128.1 (2 × CH), 128.39 (2
× CH), 128.44 (2 × CH), 128.5 (C), 129.1 (CH), 129.2 (CH), 130.0
(C), 132.1 (2 × CH), 132.2 (2 × CH), 140.4 (C), 140.6 (C), 143.3
(C), 143.7 (C), 159.0 (C), 159.1 (C), 173.6 (CO), 173.7 (CO),
175.0 (CO), 175.4 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C25H22BrN2O3+ 477.0808, found 477.0821.
4-[1-(4-Methoxybenzyl)-2,2′-dioxo-1,2-dihydrospiro[indole-3,3′-
pyrrolidin]-5′-yl]benzonitrile (2e). This compound was obtained
from 1e (71 mg, 0.19 mmol): reaction time 2 + 1 h; purification
performed on neutralized silica gel; yield 32 mg (48%); orange solid,
mp 184−186 °C; dr 53:47; Rf = 0.46 (A), 0.39 (B) (petroleum
ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.30 (dd, 2J
= 13.4, 3J = 8.1 Hz, 1H, CH2, A), 2.74 (dd, 2J = 13.6, 3J = 7.4 Hz, 1H,
CH2, B), 2.88 (dd, 2J = 13.6, 3J = 7.9 Hz, 1H, CH2, B), 3.14 (dd, 2J =
13.4, 3J = 7.4 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O), 3.77 (s, 3H,
CH3O), 4.78 (d, 2J = 15.6 Hz, 1H, CH2), 4.79 (d, 2J = 15.6 Hz, 1H,
CH2), 4.90 (d, 2J = 15.6 Hz, 1H, CH2), 4.95 (d, 2J = 15.6 Hz, 1H,
CH2), 5.11−5.13 (m, 1H, CH), 5.35−5.37 (m, 1H, CH), 6.74−6.81
(m, 6H, Ar), 7.03−7.10 (m, 3H, Ar), 7.20−7.24 (m, 6H, Ar), 7.32−
7.33 (m, 1H, Ar), 7.51−7.52 (m, 2H, Ar), 7.57−7.58 (m, 2H, Ar),
7.61 (br s, 1H, NH), 7.63−7.65 (m, 2H, Ar), 7.66−7.67 (m, 2H, Ar),
7.70 (br s, 1H, NH); 13C NMR (150 MHz, CDCl3) δ 40.6 (CH2),
41.5 (CH2), 43.4 (CH2), 43.6 (CH2), 55.1 (CH), 55.19 (CH3O),
55.21 (CH3O), 55.9 (CH), 58.2 (C), 58.4 (C), 109.7 (CH), 109.9
(CH), 112.07 (C), 112.11 (C), 114.2 (2 × CH), 114.3 (2 × CH),
118.3 (C), 118.4 (C), 122.5 (CH), 123.13 (CH), 123.15 (CH), 123.3
(CH), 126.5 (2 × CH), 127.0 (2 × CH, 2 × C), 128.2 (C), 128.3 (2
× CH), 128.4 (2 × CH), 129.2 (CH), 129.3 (CH), 129.7 (C), 132.8
(2 × CH), 132.9 (2 × CH), 143.3 (C), 143.7 (C), 146.7 (C), 147.0
(C), 159.06 (C), 159.10 (C), 174.0 (CO), 174.1 (CO), 174.9 (CO),
175.3 (CO); HRMS (ESI) m/z [M + H]+ calcd for C26H22N3O3+
424.1656, found 424.1667.
5′-(Biphenyl-4-yl)-1-(4-methoxybenzyl)-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2g). This compound was obtained from
1g (86 mg, 0.20 mmol): reaction time 2 + 4 h; yield 53 mg (56%);
yellow solid, mp 244−245 °C; dr 53:47; Rf = 0.38 (petroleum ether−
ethyl acetate, 1:1); 1H NMR (600 MHz, DMSO-d6) δ 2.31 (dd, 2J =
13.3, 3J = 8.1 Hz, 1H, CH2, A), 2.50 (dd, 2J = 13.3, 3J = 8.5 Hz, 1H,
CH2, B), 2.83 (dd, 2J = 13.3, 3J = 7.3 Hz, 1H, CH2, B), 3.07 (dd, 2J =
13.3, 3J = 7.3 Hz, 1H, CH2, A), 3.71 (s, 3H, CH3O, B), 3.72 (s, 3H,
CH3O, A), 4.78 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.81 (d, 2J = 15.7 Hz,
1H, CH2, A), 4.90 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.95 (d, 2J = 15.7
Hz, 1H, CH2, B), 5.17 (dd, 3J = 8.1, 3J = 7.3 Hz, 1H, CH, A), 5.26
(dd, 3J = 8.5, 3J = 7.3 Hz, 1H, CH, B), 6.87−6.90 (m, 2H + 2H, Ar, A,
B), 6.92−6.94 (m, 1H + 1H, Ar, A, B), 7.01−7.04 (m, 1H, Ar, B),
7.07−7.10 (m, 1H, Ar, A), 7.22−7.32 (m, 3H + 4H, Ar, A, B), 7.37−
7.40 (m, 1H + 1H, Ar, A, B), 7.47−7.50 (m, 2H + 2H, Ar, A, B),
7.52−7.53 (m, 1H, Ar, A), 7.57−7.59 (m, 2H, Ar, A), 7.61−7.62 (m,
2H, Ar, B), 7.69−7.71 (m, 2H + 2H, Ar, A, B), 7.73−7.75 (m, 2H +
2H, Ar, A, B), 8.91 (br s, 1H, NH, B), 8.93 (br s, 1H, NH, A). A: 13C
NMR (150 MHz, DMSO-d6) δ 41.1 (CH2), 42.2 (CH2), 54.4 (CH),
55.0 (CH3O), 58.36 (C), 109.3 (CH), 114.03 (2 × CH), 122.7
(CH), 123.4 (CH), 126.7 (2 × CH), 126.9 (2 × CH), 126.69 (CH),
127.00 (2 × CH), 127.5 (CH), 127.9 (C), 128.5 (2 × CH), 129.0 (2
× CH), 129.4 (C), 139.7 (C), 139.78 (C), 141.6 (C), 143.5 (C),
158.58 (C), 172.4 (CO), 175.4 (CO). B: 13C NMR (150 MHz,
DMSO-d6) δ 40.7 (CH2), 42.4 (CH2), 54.8 (CH), 55.0 (CH3O),
58.41 (C), 109.4 (CH), 113.99 (2 × CH), 122.7 (CH), 122.8 (CH),
126.7 (2 × CH), 126.9 (2 × CH), 126.69 (CH), 127.00 (2 × CH),
127.5 (CH), 127.8 (C), 128.5 (2 × CH), 129.0 (2 × CH), 130.6 (C),
139.7 (C), 139.81 (C), 141.8 (C), 142.9 (C), 158.55 (C), 172.5
(CO), 175.2 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C31H27N2O3+ 475.2016, found 475.2015.
1-(4-Methoxybenzyl)-5′-(naphthalen-1-yl)-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2h). This compound was obtained from
1h (86 mg, 0.21 mmol): reaction time 4 + 4 + 8 h; yield 32 mg
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
(34%); orange viscous oil; dr 52:48; Rf = 0.47 (petroleum ether−ethyl
acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.45 (dd, 2J = 13.5, 3J =
6.8 Hz, 1H, CH2, A), 2.91 (dd, 2J = 13.5, 3J = 7.8 Hz, 1H, CH2, B),
3.12 (dd, 2J = 13.5, 3J = 7.8 Hz, 1H, CH2, B), 3.51 (dd, 2J = 13.5, 3J =
8.0 Hz, 1H, CH2, A), 3.70 (s, 3H, CH3O), 3.73 (s, 3H, CH3O), 4.82
(d, 2J = 15.5 Hz, 1H + 1H, CH2, A. B), 4.93 (d, 2J = 15.5 Hz, 1H,
CH2), 4.98 (d, 2J = 15.5 Hz, 1H, CH2), 5.93 (dd, 3J = 7.8, 3J = 7.8 Hz,
1H, CH, B), 6.06 (dd, 3J = 8.0, 3J = 6.8 Hz, 1H, CH, A), 6.71 (d, 3J =
7.8 Hz, 1H, Ar), 6.75−6.78 (m, 3H, Ar), 6.80−6.81 (m, 2H, Ar),
6.94−6.97 (m, 1H, Ar), 6.96 (br s, 1H, NH), 6.99 (br s, 1H, NH),
7.01−7.02 (m, 1H, Ar), 7.12−7.17 (m, 2H, Ar), 7.23−7.25 (m, 5H,
Ar), 7.48−7.49 (m, 1H, Ar), 7.52−7.60 (m, 6H, Ar), 7.73 (br d, 3J =
7.1 Hz, 1H, Ar), 7.82 (br d, 3J = 7.1 Hz, 1H, Ar), 7.85 (br d, 3J = 8.2
Hz, 1H, Ar), 7.87 (br d, 3J = 8.1 Hz, 1H, Ar), 7.92−7.94 (m, 2H, Ar),
8.05−8.08 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ 40.5 (CH2),
40.7 (CH2), 43.5 (CH2), 43.6 (CH2), 52.2 (CH), 52.9 (CH), 55.15
(CH3O), 55.17 (CH3O), 58.38 (C), 58.41 (C), 109.6 (CH), 109.8
(CH), 114.1 (2 × CH), 114.2 (2 × CH), 121.4 (CH), 122.2 (CH),
122.55 (CH), 122.61 (CH), 122.7 (CH), 123.06 (CH), 123.10
(CH), 123.4 (CH), 125.6 (CH), 125.85 (CH), 125.87 (CH), 126.1
(CH), 126.5 (CH), 126.7 (CH), 127.2 (C), 127.3 (C), 128.39 (2 ×
CH), 128.43 (2 × CH), 128.6 (2 × CH), 128.98 (CH), 129.04 (C),
129.06 (CH), 129.07 (CH), 129.2 (CH), 130.11 (C), 130.14 (C),
130.2 (C), 134.0 (C), 133.9 (C), 136.7 (C), 138.0 (C), 143.4 (C),
143.7 (C), 158.97 (C), 159.01 (C), 173.6 (CO), 173.7 (CO), 174.9
(CO), 175.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C29H25N2O3+ 449.1860, found 449.1862.
5′-(1,3-Benzodioxol-5-yl)-1-(4-methoxybenzyl)-2′H-spiro[indole-
3,3′-pyrrolidine]-2,2′(1H)-dione (2i). This compound was obtained
from 1i (92 mg, 0.23 mmol): reaction time 2 + 4 h; purification
performed on neutralized silica gel; yield 55 mg (54%); yellowish
solid, mp 237−239 °C; dr 56:44; Rf = 0.49 (A), 0.55 (B) (petroleum
ether−ethyl acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.35 (dd, 2J
= 13.3, 3J = 8.3 Hz, 1H, CH2, A), 2.75 (dd, 2J = 13.4, 3J = 7.4 Hz, 1H,
CH2, B), 2.82 (dd, 2J = 13.4, 3J = 8.1 Hz, 1H, CH2, B), 3.04 (dd, 2J =
13.3, 3J = 7.0 Hz, 1H, CH2, A), 3.75 (s, 3H, CH3O, B), 3.76 (s, 3H,
CH3O, A), 4.81 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.82 (d, 2J = 15.7 Hz,
1H, CH2, B), 4.91 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.97 (d, 2J = 15.7
Hz, 1H, CH2, B), 5.00 (dd, 3J = 8.1, 3J = 7.4 Hz, 1H, CH, B), 5.23
(dd, 3J = 8.3, 3J = 7.0 Hz, 1H, CH, A), 5.95 (d, 2J = 1.3 Hz, 1H,
OCH2O, B), 5.96 (d, 2J = 1.3 Hz, 1H, OCH2O, B), 5.97 (d, 2J = 1.3
Hz, 1H, OCH2O, A), 5.98 (d, 2J = 1.3 Hz, 1H, OCH2O, A), 6.73−
6.75 (m, 1H + 1H, Ar, A, B), 6.78−6.84 (m, 4H + 3H, Ar, NH, A, B),
6.88−6.93 (m, 1H + 3H, Ar, A, B), 7.04−7.07 (m, 2H + 1H, Ar, A,
B), 7.18−7.22 (m, 2H + 1H, Ar, A, B), 7.23−7.25 (m, 2H, Ar, A),
7.26−7.28 (m, 2H, Ar, B), 7.32−7.33 (m, 1H, Ar, B). A: 13C NMR
(150 MHz, CDCl3) δ 42.2 (CH2), 43.4 (CH2), 55.17 (CH3O), 55.23
(CH), 58.6 (C), 101.3 (OCH2O), 106.1 (CH), 108.5 (CH), 109.5
(CH), 114.22 (2 × CH), 119.4 (CH), 123.2 (CH), 123.3 (CH),
127.29 (C), 128.38 (2 × CH), 128.7 (C), 129.0 (CH), 135.3 (C),
143.8 (C), 147.6 (C), 148.32 (C), 159.03 (C), 173.3 (CO), 175.5
(CO). B: 13C NMR (150 MHz, CDCl3) δ 41.4 (CH2), 43.6 (CH2),
55.16 (CH3O), 56.2 (CH), 58.4 (C), 101.2 (OCH2O), 106.7 (CH),
108.3 (CH), 109.7 (CH), 114.16 (2 × CH), 119.9 (CH), 122.4
(CH), 122.9 (CH), 127.31 (C), 128.43 (2 × CH), 128.9 (CH), 130.2
(C), 135.1 (C), 143.2 (C), 147.7 (C), 148.28 (C), 159.00 (C), 173.4
(CO), 175.1 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C26H23N2O5+ 443.1601, found 443.1603.
1-(4-Methoxybenzyl)-5′-(3,4,5-trimethoxyphenyl)-2′H-spiro-
[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (2j). This compound was
obtained from 1j (210 mg, 0.47 mmol): reaction time 2 + 4 h;
purification performed on neutralized silica gel; yield 145 mg (63%);
yellow solid, mp 166−168 °C; dr 54:46; Rf = 0.21 (A), 0.25 (B)
(petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, DMSO-
d6) δ 2.29 (dd, 2J = 13.1, 3J = 8.1 Hz, 1H, CH2, A), 2.47 (dd, 2J =
13.2, 3J = 8.1 Hz, 1H, CH2, B), 2.80 (dd, 2J = 13.2, 3J = 7.4 Hz, 1H,
CH2, B), 2.99 (dd, 2J = 13.1, 3J = 7.0 Hz, 1H, CH2, A), 3.669 (s, 3H,
CH3O, A), 3.673 (s, 3H, CH3O, B), 3.709 (s, 3H, CH3O, B), 3.713
(s, 3H, CH3O, A), 3.82 (s, 6H, CH3O, B), 3.84 (s, 6H, CH3O, A),
4.78 (d, 2J = 15.7 Hz, 1H, CH2, B), 4.81 (d, 2J = 15.6 Hz, 1H, CH2,
8705
Note
A), 4.88 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.94 (d, 2J = 15.7 Hz, 1H,
CH2, B), 5.09 (dd, 3J = 8.1, 3J = 7.0 Hz, 1H, CH, A), 5.15 (dd, 3J =
8.1, 3J = 7.4 Hz, 1H, CH, B), 6.81 (s, 2H, Ar, A), 6.83 (s, 2H, Ar, B),
6.87−6.90 (m, 2H + 2H, Ar, A, B), 6.92−6.93 (m, 1H + 1H, Ar, A,
B), 7.02−7.04 (m, 1H, Ar, A), 7.06−7.09 (m, 1H, Ar, B), 7.22−7.24
(m, 1H, Ar, A), 7.24−7.27 (m, 1H, Ar, B), 7.28−7.31 (m, 3H + 2H,
Ar, A, B), 7.48−7.49 (m, 1H, Ar, B), 8.87 (br s, 1H, NH, B), 8.88 (br
s, 1H, NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 41.1 (CH2),
42.1 (CH2), 54.9 (CH), 55.0 (CH3O), 56.0 (2 × CH3O), 58.4 (C),
60.00 (CH3O), 103.3 (2 × CH), 109.2 (CH), 114.02 (2 × CH),
122.60 (CH), 123.6 (CH), 127.9 (CH), 128.52 (2 × CH), 128.6 (C),
129.2 (C), 136.9 (C), 137.9 (C), 143.5 (C), 153.11 (2 × C), 158.57
(C), 172.4 (CO), 175.4 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ
40.6 (CH2), 42.4 (CH2), 55.0 (CH3O), 55.2 (CH), 55.9 (2 ×
CH3O), 58.3 (C), 60.02 (CH3O), 103.4 (2 × CH), 109.4 (CH),
113.97 (2 × CH), 122.62 (CH), 122.8 (CH), 127.8 (CH), 128.50 (2
× CH), 128.53 (C), 130.6 (C), 136.9 (C), 138.3 (C), 142.9 (C),
153.05 (2 × C), 158.55 (C), 172.4 (CO), 175.2 (CO); HRMS (ESI)
m/z [M + H]+ calcd for C28H29N2O6+ 489.2020, found 489.2027.
1-(4-Methoxybenzyl)-5′-(thien-2-yl)-2′H-spiro[indole-3,3′-pyrro-
lidine]-2,2′(1H)-dione (2k). This compound was obtained from 1k
(77 mg, 0.21 mmol). Purification was performed on neutralized silica
gel. Reaction time 2 + 1 h; yield 48 mg (56%); orange solid, mp 194−
196 °C; dr 52:48; Rf = 0.42 (A), 0.38 (B) (petroleum ether−ethyl
acetate, 1:1); 1H NMR (600 MHz, CDCl3) δ 2.55 (dd, 2J = 13.4, 3J =
7.8 Hz, 1H, CH2, A), 2.84 (ddd, 2J = 13.3, 3J = 7.3, 5J = 0.7 Hz, 1H,
CH2, B), 3.00 (dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, B), 3.15 (ddd, 2J =
13.4, 3J = 7.2, 5J = 0.6 Hz, 1H, CH2, A), 3.76 (s, 3H, CH3O, B), 3.77
(s, 3H, CH3O, A), 4.81 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.83 (d, 2J =
15.6 Hz, 1H, CH2, B), 4.92 (d, 2J = 15.6 Hz, 1H, CH2, A), 4.98 (d, 2J
= 15.6 Hz, 1H, CH2, B), 5.39 (dd, 3J = 8.2, 3J = 7.3 Hz, 1H, CH, B),
5.59 (dd, 3J = 7.8, 3J = 7.2 Hz, 1H, CH, A), 6.74−6.76 (m, 1H + 1H,
Ar, A, B), 6.82−6.86 (m, 2H + 2H, Ar, A, B), 6.87 (br s, 1H, NH, A),
6.94 (br s, 1H, NH, B), 7.00−7.02 (m, 1H + 1H, Ar, A, B), 7.05−7.08
(m, 1H + 1H, Ar, A, B), 7.11−7.12 (m, 1H, Ar, A), 7.19−7.23 (m, 1H
+ 1H, Ar, A, B), 7.24−7.26 (m, 2H, Ar, A), 7.28−7.29 (m, 2H, Ar, B),
7.30−7.33 (m, 1H + 2H, Ar, A, B). A: 13C NMR (150 MHz, CDCl3)
δ 42.3 (CH2), 43.4 (CH2), 51.5 (CH), 55.20 (CH3O), 58.43 (C),
109.6 (CH), 114.22 (2 × CH), 123.2 (CH), 123.4 (CH), 125.0
(CH), 125.3 (CH), 127.12 (CH), 127.2 (C), 128.4 (2 × CH), 128.5
(C), 129.1 (CH), 143.7 (C), 145.4 (C), 159.02 (C), 172.6 (CO),
175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ 41.6 (CH2), 43.6
(CH2), 52.1 (CH), 55.18 (CH3O), 58.40 (C), 109.8 (CH), 114.16 (2
× CH), 122.5 (CH), 123.0 (CH), 125.2 (CH), 125.5 (CH), 127.09
(CH), 127.3 (C), 128.5 (2 × CH), 129.0 (CH), 129.8 (C), 143.2
(C), 144.5 (C), 158.98 (C), 172.8 (CO), 174.7 (CO); HRMS (ESI)
m/z [M + H]+ calcd for C23H21N2O3S+ 405.1267, found 405.1271.
5-Methyl-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2l). This compound was obtained from
1l (369 mg, 1.0 mmol): reaction time 7 + 3 h; yield 260 mg (63%);
white foam; dr 52:48; Rf = 0.24 (petroleum ether−ethyl acetate, 1:1);
1
H NMR (600 MHz, CDCl3) δ 2.29 (s, 3H, CH3, A), 2.34 (s, 3H,
CH3, B), 2.40 (dd, 2J = 13.3, 3J = 8.5 Hz, 1H, CH2, A), 2.80 (dd, 2J =
13.4, 3J = 7.5 Hz, 1H, CH2, B), 2.88 (dd, 2J = 13.4, 3J = 8.3 Hz, 1H,
CH2, B), 3.08 (dd, 2J = 13.3, 3J = 7.0 Hz, 1H, CH2, A), 3.76 (s, 3H,
CH3O, B), 3.77 (s, 3H, CH3O, A), 4.81 (d, 2J = 15.6 Hz, 1H, CH2,
A), 4.83 (d, 2J = 15.6 Hz, 1H, CH2, B), 4.90 (d, 2J = 15.6 Hz, 1H,
CH2, A), 4.96 (d, 2J = 15.6 Hz, 1H, CH2, B), 5.10 (dd, 3J = 8.3, 3J =
7.56.9 Hz, 1H, CH, B), 5.35 (dd, 3J = 8.5, 3J = 7.0 Hz, 1H, CH, A),
6.52 (br s, 1H, NH, A), 6.55 (br s, 1H, NH, B), 6.63−6.64 (m, 1H +
1H, Ar, A, B), 6.81−6.85 (m, 2H + 2H, Ar, A, B), 7.00−7.02 (m, 2H
+ 2H, Ar, A, B), 7.17−7.18 (m, 1H, Ar, B), 7.21−7.28 (m, 2H + 2H,
Ar, A, B), 7.35−7.47 (m, 4H + 3H, Ar, A, B), 7.53−7.54 (m, 1H +
1H, Ar, A, B); 13C NMR (150 MHz, CDCl3) δ 21.1 (2 × CH3), 41.4
(CH2), 42.3 (CH2), 43.4 (CH2), 43.6 (CH2), 55.2 (2 × CH3O), 55.4
(CH), 56.4 (CH), 58.4 (C), 58.6 (C), 109.3 (CH), 109.5 (CH),
114.15 (2 × CH), 114.21 (2 × CH), 123.3 (CH), 124.1 (CH), 125.9
(2 × CH), 126.4 (2 × CH), 127.4 (2 × C), 128.3 (CH), 128.4 (2 ×
CH), 128.46 (3 × CH), 128.49 (C), 129.0 (2 × CH), 129.1 (2 ×
CH), 129.2 (CH), 129.4 (CH), 130.2 (C), 132.6 (C), 132.8 (C),
DOI: 10.1021/acs.joc.8b00922
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The Journal of Organic Chemistry
140.8 (C), 141.2 (C), 141.4 (C), 141.5 (C), 158.96 (C), 159.01 (C),
173.5 (CO), 173.6 (CO), 175.0 (CO), 175.4 (CO); HRMS (ESI) m/
z [M + H]+ calcd for C26H25N2O3+ 413.1860, found 413.1873.
5-Fluoro-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2m). This compound was obtained from
1m (373 mg, 1.0 mmol): reaction time 2 h; yield 266 mg (64%);
yellowish foam; dr 51:49; Rf = 0.18 (petroleum ether−ethyl acetate,
2:1); 1H NMR (600 MHz, CDCl3) δ 2.35 (dd, 2J = 13.4, 3J = 8.0 Hz,
1H, CH2, A), 2.79 (dd, 2J = 13.5, 3J = 7.5 Hz, 1H, CH2, B), 2.86 (dd,
2
J = 13.5, 3J = 8.2 Hz, 1H, CH2, B), 3.13 (dd, 2J = 13.4, 3J = 7.2 Hz,
1H, CH2, A), 3.74 (s, 3H, CH3O), 3.76 (s, 3H, CH3O), 4.78 (d, 2J =
15.7 Hz, 1H, CH2), 4.79 (d, 2J = 15.7 Hz, 1H, CH2), 4.91 (d, 2J =
15.7 Hz, 1H, CH2), 4.96 (d, 2J = 15.7 Hz, 1H, CH2), 5.06 (dd, 3J =
8.2, 3J = 7.5 Hz, 1H, CH, B), 5.31 (dd, 3J = 8.0, 3J = 7.2 Hz, 1H, CH,
A), 6.63−6.66 (m, 2H, Ar), 6.79−6.84 (m, 4H, Ar), 6.86−6.92 (m,
3H, Ar), 7.11−7.13 (m, 1H, Ar), 7.21−7.26 (m, 4H, Ar), 7.24 (br s,
1H, NH), 7.28 (br s, 1H, NH), 7.32−7.37 (m, 2H, Ar), 7.39−7.44
(m, 6H, Ar), 7.49−7.51 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3) δ
41.0 (1JCH = 133 Hz, CH2), 41.9 (1JCH = 133 Hz, CH2), 43.5 (1JCH =
139 Hz, CH2), 43.6 (1JCH = 139 Hz, CH2), 55.13 (1JCH = 144 Hz,
CH3O), 55.14 (1JCH = 144 Hz, CH3O), 55.3 (1JCH = 145 Hz, CH),
56.3 (1JCH = 145 Hz, CH), 58.8 (C), 58.9 (C), 110.1 (3JCF = 8 Hz,
CH), 110.2 (3JCF = 8 Hz, CH), 110.8 (2JCF = 25 Hz, CH), 111.5 (2JCF
= 25 Hz, CH), 114.16 (2 × CH), 114.22 (2 × CH), 115.1 (2JCF = 25
Hz, CH), 115.3 (2JCF = 25 Hz, CH), 125.7 (2 × CH), 126.3 (2 ×
CH), 126.9 (CH), 128.2 (CH), 128.3 (2 × CH), 128.4 (2 × CH),
129.0 (2 × CH), 129.1 (2 × CH), 130.1 (3JCF = 8 Hz, C), 131.4 (3JCF
= 8 Hz, C), 139.1 (C), 139.6 (C), 141.0 (C), 141.3 (C), 158.99 (C),
159.03 (C), 159.2 (1JCF = 242 Hz, C), 159.3 (1JCF = 242 Hz, C),
173.0 (CO), 173.1 (CO), 174.8 (CO), 175.2 (CO); HRMS (ESI) m/
z [M + H]+ calcd for C25H22FN2O3+ 417.1609, found 417.1611.
Ethyl 4-[5-Fluoro-1-(4-methoxybenzyl)-2,2′-dioxo-1,2-
dihydrospiro[indole-3,3′-pyrrolidine]-5′-yl]benzoate (2n). This
compound was obtained from 1n (356 mg, 0.80 mmol): reaction
time 2 h; yield 165 mg (42%); brown foam; dr 51:49; Rf = 0.47 (A),
0.38 (B) (petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz,
CDCl3) δ 1.38 (t, 3J = 7.1 Hz, 3H, CH3), 1.40 (t, 3J = 7.1 Hz, 3H,
CH3), 2.30 (dd, 2J = 13.4, 3J = 8.0 Hz, 1H, CH2, A), 2.78 (dd, 2J =
13.6, 3J = 7.8 Hz, 1H, CH2, B), 2.83 (dd, 2J = 13.6, 3J = 7.8 Hz, 1H,
CH2, B), 3.14 (dd, 2J = 13.4, 3J = 7.3 Hz, 1H, CH2, A), 3.71 (s, 3H,
CH3O), 3.73 (s, 3H, CH3O), 4.36 (q, 3J = 7.1 Hz, 2H, CH2O), 4.38
(q, 3J = 7.1 Hz, 2H, CH2O), 4.75 (d, 2J = 15.7 Hz, 1H, CH2), 4.76 (d,
2
J = 15.7 Hz, 1H, CH2), 4.88 (d, 2J = 15.7 Hz, 1H, CH2), 4.93 (d, 2J =
15.7 Hz, 1H, CH2), 5.10−5.13 (m, 1H, CH), 5.34−5.37 (m, 1H,
CH), 6.61−6.65 (m, 2H, Ar), 6.75−6.79 (m, 4H, Ar), 6.85−6.91 (m,
3H, Ar), 7.09−7.11 (m, 1H, Ar), 7.17−7.22 (m, 4H, Ar), 7.46−7.47
(m, 2H, Ar), 7.53−7.54 (m, 2H, Ar), 7.66−7.71 (m, 1H, NH), 7.71−
7.75 (m, 1H, NH), 8.04−8.07 (m, 4H, Ar); 13C NMR (150 MHz,
CDCl3) δ 14.2 (2 × CH3), 40.6 (CH2), 41.5 (CH2), 43.4 (CH2), 43.6
(CH2), 55.07 (CH3O), 55.09 (CH3O), 55.13 (CH), 55.9 (CH), 58.7
(C), 58.8 (C), 60.95 (CH2O), 61.01 (CH2O), 110.2 (3JCF = 9 Hz,
CH), 110.3 (3JCF = 9 Hz, CH), 110.8 (2JCF = 25 Hz, CH), 111.4 (2JCF
= 25 Hz, CH), 114.1 (2 × CH), 114.2 (2 × CH), 115.1 (2JCF = 24
Hz, CH), 115.4 (2JCF = 24 Hz, CH), 125.5 (2 × CH), 126.1 (2 ×
CH), 126.7 (C), 126.8 (C), 128.2 (2 × CH), 128.3 (2 × CH), 129.9
(3JCF = 8 Hz, C), 130.2 (2 × CH), 130.3 (2 × CH), 130.4 (3JCF = 8
Hz, 2 × C), 131.1 (3JCF = 8 Hz, C), 139.1 (C), 139.5 (C), 146.0 (C),
146.3 (C), 158.98 (C), 159.02 (C), 159.2 (1JCF = 242 Hz, C), 159.3
(1JCF = 242 Hz, C), 165.96 (CO2Et), 166.01 (CO2Et), 173.3 (CO),
173.4 (CO), 174.7 (CO), 175.1 (CO); HRMS (ESI) m/z [M + H]+
calcd for C28H26FN2O5+ 489.1820, found 489.1828.
5-Chloro-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2o). This compound was obtained from
1o (389 mg, 1.0 mmol): reaction time 100 min; yield 217 mg (50%);
white solid, mp 208−210 °C; dr 52:48; Rf = 0.56 (A), 0.43 (B)
(petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, DMSO-
d6) δ 2.36 (dd, 2J = 13.2, 3J = 8.1 Hz, 1H, CH2, A), 2.45 (dd, 2J =
13.3, 3J = 8.2 Hz, 1H, CH2, B), 2.85 (dd, 2J = 13.3, 3J = 7.4 Hz, 1H,
CH2, B), 3.00 (dd, 2J = 13.2, 3J = 6.9 Hz, 1H, CH2, A), 3.710 (s, 3H,
CH3O, B), 3.713 (s, 3H, CH3O, A), 4.77 (d, 2J = 15.7 Hz, 1H, CH2,
8706
Note
B), 4.80 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.91 (d, 2J = 15.7 Hz, 1H,
CH2, A), 4.96 (d, 2J = 15.7 Hz, 1H, CH2, B), 5.13 (dd, 3J = 8.1, 3J =
6.9 Hz, 1H, CH, A), 5.29 (dd, 3J = 8.2, 3J = 7.4 Hz, 1H, CH, B),
6.87−6.90 (m, 2H + 2H, Ar, A, B), 6.91−6.94 (m, 1H + 1H, Ar, A,
B), 7.26−7.28 (m, 2H, Ar, A), 7.29−7.31 (m, 1H + 2H, Ar, A, B),
7.32−7.37 (m, 1H + 2H, Ar, A, B), 7.40−7.41 (m, 1H, Ar, A), 7.43−
7.45 (m, 2H + 2H, Ar, A, B), 7.49−7.50 (m, 2H, Ar, B), 7.56−7.57
(m, 2H, Ar, A), 7.66−7.67 (m, 1H, Ar, B), 8.94 (br s, 1H, NH, B),
8.97 (br s, 1H, NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 40.9
(CH2), 42.2 (CH2), 54.84 (CH), 55.0 (CH3O), 58.7 (C), 110.6
(CH), 114.1 (2 × CH), 124.0 (CH), 126.6 (2 × CH), 126.9 (CH),
127.53 (C), 127.84 (C), 128.4 (CH), 128.5 (2 × CH), 128.6 (2 ×
CH), 131.1 (C), 142.0 (C), 142.4 (C), 158.62 (C), 171.7 (CO),
175.04 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ 40.3 (CH2),
42.5 (CH2), 54.81 (CH), 55.0 (CH3O), 58.7 (C), 110.7 (CH), 114.0
(2 × CH), 123.1 (CH), 126.3 (2 × CH), 126.8 (CH), 127.46 (C),
127.76 (C), 128.3 (CH), 128.5 (2 × CH), 128.7 (2 × CH), 132.4
(C), 141.9 (C), 142.0 (C), 158.59 (C), 171.8 (CO), 174.97 (CO);
HRMS (ESI) m/z [M + H]+ calcd for C25H22ClN2O3+ 433.1313,
found 433.1323.
5-Bromo-1-(4-methoxybenzyl)-5′-phenyl-2′H-spiro[indole-3,3′-
pyrrolidine]-2,2′(1H)-dione (2p). This compound was obtained from
1p (433 mg, 1.0 mmol): reaction time 100 min; yield 300 mg (63%);
white solid, mp 228−230 °C; dr 52:48; Rf = 0.56 (A), 0.47 (B)
(petroleum ether−ethyl acetate, 1:1); 1H NMR (600 MHz, DMSO-
d6) δ 2.36 (dd, 2J = 13.2, 3J = 8.2 Hz, 1H, CH2, A), 2.43 (dd, 2J =
13.3, 3J = 8.2 Hz, 1H, CH2, B), 2.85 (dd, 2J = 13.3, 3J = 7.5 Hz, 1H,
CH2, B), 3.00 (dd, 2J = 13.2, 3J = 7.0 Hz, 1H, CH2, A), 3.710 (s, 3H,
CH3O, B), 3.711 (s, 3H, CH3O, A), 4.76 (d, 2J = 15.8 Hz, 1H, CH2,
B), 4.79 (d, 2J = 15.7 Hz, 1H, CH2, A), 4.90 (d, 2J = 15.7 Hz, 1H,
CH2, A), 4.95 (d, 2J = 15.8 Hz, 1H, CH2, B), 5.12 (dd, 3J = 8.2, 3J =
7.0 Hz, 1H, CH, A), 5.28 (dd, 3J = 8.2, 3J = 7.5 Hz, 1H, CH, B),
6.87−6.90 (m, 3H + 3H, Ar, A, B), 7.25−7.27 (m, 2H, Ar, A), 7.28−
7.30 (m, 2H, Ar, B), 7.34−7.37 (m, 1H + 1H, Ar, A, B), 7.42−7.46
(m, 3H + 3H, Ar, A, B), 7.48−7.49 (m, 2H, Ar, B), 7.51−7.52 (m,
1H, Ar, A), 7.56−7.57 (m, 2H, Ar, A), 7.76−7.77 (m, 1H, Ar, B),
8.94 (br s, 1H, NH, B), 8.97 (br s, 1H, NH, A); 13C NMR (150 MHz,
DMSO-d6) δ 40.3 (CH2), 40.8 (CH2), 42.2 (CH2), 42.4 (CH2),
54.79 (CH), 54.84 (CH), 55.0 (2 × CH3O), 58.6 (2 × C), 111.1
(CH), 111.3 (CH), 114.0 (2 × CH), 114.1 (2 × CH), 114.54 (C),
114.56 (C), 125.7 (CH), 126.3 (2 × CH), 126.6 (2 × CH), 126.7
(CH), 127.4 (C), 127.5 (C), 127.75 (CH), 127.83 (CH), 128.5 (4 ×
CH), 128.6 (2 × CH), 128.7 (2 × CH), 131.2 (CH), 131.3 (CH),
131.4 (C), 132.8 (C), 142.0 (C), 142.3 (C), 142.6 (C), 142.9 (C),
158.59 (C), 158.61 (C), 171.7 (CO), 171.8 (CO), 174.94 (CO),
174.88 (CO); HRMS (ESI) m/z [M + H]+ calcd for C25H22BrN2O3+
477.0808, found 477.0829.
1-Methyl-5′-phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-
dione (2q).17 This compound was obtained from 1q (397 mg, 1.59
mmol): reaction time 2 + 6 h; yield 280 mg (67%, based on 90%
conversion); yellow solid, mp 195−196 °C (lit. 198−200 °C); dr
50:50; Rf = 0.6 (ethyl acetate). A: 1H NMR (600 MHz, CDCl3) δ
2.33 (dd, 2J = 13.5, 3J = 8.0 Hz, 1H, CH2), 3.01 (dd, 2J = 13.5, 3J = 7.4
Hz, 1H, CH2), 3.20 (s, 3H, CH3N), 5.22 (dd, 3J = 8.0, 3J = 7.4 Hz,
1H, CH), 6.84 (d, 3J = 7.8 Hz, 1H, Ar), 7.04−7.06 (m, 1H, Ar), 7.12
(d, 3J = 7.9 Hz, 1H, Ar), 7.28−7.33 (m, 3H, Ar), 7.37−7.40 (m, 3H +
1H, Ar, NH); 13C NMR (150 MHz, CDCl3) δ 26.4 (CH3N), 41.8
(CH2), 55.3 (CH), 58.6 (C), 108.6 (CH), 123.16 (CH), 123.22
(CH), 125.7 (2 × CH), 128.2 (CH), 128.5 (C), 129.0 (2 × CH),
129.2 (CH), 141.4 (C), 144.5 (C), 173.7 (CO), 175.6 (CO).
1-Methyl-5′-(4-tolyl)-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-
dione (2r). This compound was obtained from 1r (400 mg, 1.52
mmol): reaction time 2 + 7 h; yield 255 mg (61%, based on 90%
conversion); white solid, mp 234−235 °C; dr 50:50; Rf = 0.67 (ethyl
acetate); 1H NMR (600 MHz, CDCl3) δ 2.36 (dd, 2J = 13.5, 3J = 8.3
Hz, 1H, CH2, A), 2.37 (CH3), 2.38 (CH3), 2.72 (dd, 2J = 13.4, 3J =
7.2 Hz, 1H, CH2, B), 2.79 (dd, 2J = 13.4, 3J = 8.4 Hz, 1H, CH2, B),
3.02 (dd, 2J = 13.5, 3J = 7.1 Hz, 1H, CH2, A), 3.23 (s, 3H, CH3N, A),
3.26 (s, 3H, CH3N, B), 5.04 (dd, 3J = 8.4, 3J = 7.2 Hz, 1H, CH, B),
5.26 (dd, 3J = 8.3, 3J = 7.1 Hz, 1H, CH, A), 6.43 (br s, 1H, NH, A),
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
6.49 (br s, 1H, NH, B), 6.86−6.89 (m, 1H + 1H, Ar, A, B), 7.08−7.13
(m, 1H + 1H, Ar, A, B), 7.18−7.24 (m, 3H + 2H, Ar, A, B), 7.30−
7.36 (m, 3H + 2H, Ar, A, B), 7.38−7.39 (m, 2H, Ar, B). A: 13C NMR
(150 MHz, CDCl3) δ 21.1 (CH3), 26.5 (CH3N), 42.3 (CH2), 55.1
(CH), 58.5 (C), 108.5 (CH), 123.2 (CH), 123.3 (CH), 125.8 (2 ×
CH), 128.6 (C), 129.2 (CH), 129.74 (2 × CH), 138.2 (C), 138.5
(C), 144.7 (C), 173.2 (CO), 175.4 (CO). B: 13C NMR (150 MHz,
CDCl3) δ 21.1 (CH3), 26.7 (CH3N), 41.8 (CH2), 56.1 (CH), 58.4
(C), 108.7 (CH), 122.4 (CH), 123.0 (CH), 126.4 (2 × CH), 129.1
(CH), 129.65 (2 × CH), 130.1 (C), 138.0 (C), 138.3 (C), 144.2 (C),
173.4 (CO), 174.8 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C19H19N2O2+ 307.1441, found 307.1438.
5′-(4-Methoxyphenyl)-1-methyl-2′H-spiro[indole-3,3′-pyrroli-
dine]-2,2′(1H)-dione (2s). This compound was obtained from 1s
(120 mg, 0.43 mmol). Reaction time 2 + 4 h; purification performed
on neutralized silica gel; yield 89 mg (64%); white solid, mp 231−232
°C; dr 54:46; Rf = 0.11 (petroleum ether−ethyl acetate, 1:1); 1H
NMR (600 MHz, CDCl3) δ 2.31 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2,
A), 2.68 (dd, 2J = 13.3, 3J = 7.4 Hz, 1H, CH2, B), 2.73 (dd, 2J = 13.3,
3
J = 8.3 Hz, 1H, CH2, B), 2.99 (dd, 2J = 13.3, 3J = 7.1 Hz, 1H, CH2,
A), 3.20 (s, 3H, CH3N, A), 3.23 (s, 3H, CH3N, B), 3.79 (s, 3H,
CH3O, B), 3.81 (s, 3H, CH3O, A), 5.00 (dd, 3J = 8.1, 3J = 7.1 Hz, 1H,
CH, A), 5.20 (dd, 3J = 8.3, 3J = 7.4 Hz, 1H, CH, B), 6.84−6.93 (m,
3H + 3H, Ar, NH, A, B), 6.96 (br s, 1H, NH, B), 7.07−7.12 (m, 2H +
1H, Ar, A, B), 7.16−7.17 (m, 1H, Ar, B), 7.30−7.35 (m, 2H + 3H, Ar,
A, B), 7.37−7.39 (m, 2H, Ar, A). A: 13C NMR (150 MHz, CDCl3) δ
26.5 (CH3N), 42.2 (CH2), 54.8 (CH), 55.3 (CH3O), 58.52 (C),
108.5 (CH), 114.3 (2 × CH), 123.1 (CH), 123.2 (CH), 127.0 (2 ×
CH), 128.7 (C), 129.05 (CH), 133.4 (C), 144.5 (C), 159.4 (C),
173.4 (CO), 175.4 (CO). B: 13C NMR (150 MHz, CDCl3) δ 26.6
(CH3N), 41.7 (CH2), 55.2 (CH3O), 55.9 (CH), 58.46 (C), 108.6
(CH), 114.2 (2 × CH), 122.4 (CH), 122.9 (CH), 127.6 (2 × CH),
128.95 (CH), 130.1 (C), 133.0 (C), 144.0 (C), 159.5 (C), 173.5
(CO), 174.9 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C19H19N2O3+ 323.1390, found 323.1391.
5′-(1,3-Benzodioxol-5-yl)-1-methyl-2′H-spiro[indole-3,3′-pyrroli-
dine]-2,2′(1H)-dione (2t). This compound was obtained from 1t (86
mg, 0.29 mmol): reaction time 2 + 5 h; purification performed on
neutralized silica gel; yield 53 mg (54%); brown solid, mp 243−244
°C; dr 51:49; Rf = 0.67 (ethyl acetate); 1H NMR (600 MHz, CDCl3)
δ 2.32 (dd, 2J = 13.4, 3J = 8.3 Hz, 1H, CH2, A), 2.71 (ddd, 2J = 13.5,
3
J = 7.5, 5J = 0.7 Hz, 1H, CH2, B), 2.75 (dd, 2J = 13.5, 3J = 8.1 Hz,
1H, CH2, B), 2.98 (ddd, 2J = 13.4, 3J = 7.1, 5J = 0.8 Hz, 1H, CH2, A),
3.23 (s, 3H, CH3N, A), 3.26 (s, 3H, CH3N, B), 4.98 (dd, 3J = 8.1, 3J =
7.5 Hz, 1H, CH, B), 5.20 (dd, 3J = 8.3, 3J = 7.1 Hz, 1H, CH, A), 5.98
(br s, 2H, OCH2O), 5.99 (br s, 2H, OCH2O), 6.52 (br s, 1H, NH,
A), 6.57 (br s, 1H, NH, B), 6.80 (d, 3J = 7.9 Hz, 1H, Ar, B), 6.83 (d,
3
J = 7.8 Hz, 1H, Ar, A), 6.86−6.92 (m, 3H + 2H, Ar, A, B), 7.04−7.05
(m, 1H, Ar, B), 7.09−7.12 (m, 1H + 1H, Ar, A, B), 7.20−7.21 (m,
1H, Ar, A), 7.32−7.35 (m, 1H + 2H, Ar, A, B). A: 13C NMR (150
MHz, CDCl3) δ 26.6 (CH3N), 42.3 (CH2), 55.2 (CH), 58.5 (C),
101.30 (OCH2O), 106.1 (CH), 108.6 (2 × CH), 119.4 (CH), 123.2
(CH), 123.3 (CH), 128.5 (C), 129.2 (CH), 135.3 (C), 144.7 (C),
147.6 (C), 148.4 (C), 173.2 (CO), 175.3 (CO). B: 13C NMR (150
MHz, CDCl3) δ 26.8 (CH3N), 41.7 (CH2), 56.2 (CH), 58.3 (C),
101.27 (OCH2O), 106.7 (CH), 108.4 (CH), 108.7 (CH), 120.0
(CH), 122.4 (CH), 123.0 (CH), 129.1 (CH), 130.1 (C), 134.9 (C),
144.2 (C), 147.7 (C), 148.3 (C), 173.3 (CO), 174.9 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C19H17N2O4+ 337.1183, found
337.1184.
1-Methyl-5′-(3,4,5-trimethoxyphenyl)-2′H-spiro[indole-3,3′-pyr-
rolidine]-2,2′(1H)-dione (2u). This compound was obtained from 1u
(100 mg, 0.30 mmol): reaction time 2 + 5 h; purification performed
on neutralized silica gel; yield 64 mg (57%); white solid, mp 222−223
°C; dr 51:49; Rf = 0.50 (A), 0.43 (B) (ethyl acetate); 1H NMR (600
MHz, DMSO-d6) δ 2.24 (dd, 2J = 13.3, 3J = 8.1 Hz, 1H, CH2, A), 2.41
(dd, 2J = 13.3, 3J = 8.2 Hz, 1H, CH2, B), 2.73 (dd, 2J = 13.3, 3J = 7.4
Hz, 1H, CH2, B), 2.94 (dd, 2J = 13.3, 3J = 7.1 Hz, 1H, CH2, A), 3.15
(s, 3H, CH3N, A), 3.17 (s, 3H, CH3N, B), 3.67 (s, 3H + 3H, CH3O,
A, B), 3.82 (s, 3H + 3H, CH3O, A, B), 3.83 (s, 3H + 3H, CH3O, A,
8707
Note
B), 5.04 (dd, 3J = 8.1, 3J = 7.1 Hz, 1H, CH, A), 5.13 (dd, 3J = 8.2, 3J =
7.4 Hz, 1H, CH, B), 6.79 (s, 2H, Ar), 6.82 (s, 2H, Ar), 7.03−7.04 (m,
1H, Ar, A), 7.05−7.08 (m, 1H + 1H, Ar, A, B), 7.09−7.12 (m, 1H, Ar,
B), 7.27−7.29 (m, 1H, Ar, A), 7.31−7.37 (m, 1H + H, Ar, A, B),
7.46−7.48 (m, 1H, Ar, B), 8.81 (br s, 1H, NH, B), 8.83 (br s, 1H,
NH, A). A: 13C NMR (150 MHz, DMSO-d6) δ 26.2 (CH3N), 41.1
(CH2), 54.8 (CH), 56.0 (2 × CH3O), 58.28 (C), 60.01 (CH3O),
103.3 (2 × CH), 108.6 (CH), 122.55 (CH), 123.4 (CH), 128.71
(CH), 129.2 (C), 136.9 (C), 138.0 (C), 144.6 (C), 153.1 (2 × C),
172.4 (CO), 175.2 (CO). B: 13C NMR (150 MHz, DMSO-d6) δ 26.4
(CH3N), 40.7 (CH2), 55.2 (CH), 55.9 (2 × CH3O), 58.27 (C), 60.02
(CH3O), 103.4 (2 × CH), 108.7 (CH), 122.57 (CH), 122.59 (CH),
128.69 (CH), 130.5 (C), 136.9 (C), 138.3 (C), 144.0 (C), 153.0 (2 ×
C), 172.4 (CO), 175.0 (CO); HRMS (ESI) m/z [M + H]+ calcd for
C21H23N2O5+ 383.1601, found 383.1609.
General Procedure20 for PMB-N-deprotection of 2. To
solution of 2 (0.20 mmol, 1.0 equiv) in CH2Cl2 (2.50 mL, 0.08 M)
were sequentially added TFA (0.75 mL, 10.0 mmol, 50 equiv) and
TfOH (44 μL, 5.0 mmol, 2.5 equiv). The resulting solution was
stirred at room temperature for the time specified. The reaction
mixture was then poured into an ice−water mixture and extracted
with EtOAc (3 × 20 mL). The combined organic layers were washed
with NaHCO3 solution, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on neutralized silica gel (ethyl acetate−petroleum
ether).
5′-Phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-dione (3a).
This compound was obtained from 2a (89 mg, 0.224 mmol): reaction
time 54 h; yield 33 mg (53%); white solid, mp 274−275 °C; dr 54:46;
Rf = 0.72 (ethyl acetate); 1H NMR (600 MHz, DMSO-d6) δ 2.18 (dd,
2
J = 13.3, 3J = 7.9 Hz, 1H, CH2, A), 2.36 (dd, 2J = 13.2, 3J = 8.6 Hz,
1H, CH2, B), 2.71 (dd, 2J = 13.2, 3J = 7.3 Hz, 1H, CH2, B), 2.98 (dd,
2
J = 13.3, 3J = 7.3 Hz, 1H, CH2, A), 5.03 (dd, 3J = 7.9, 3J = 7.3 Hz,
1H, CH2, A), 5.15 (dd, 3J = 8.6, 3J = 7.3 Hz, 1H, CH2, B), 6.84−6.86
(m, 1H, Ar, A), 6.87−6.90 (m, 1H, Ar, B), 6.94−6.98 (m, 1H, Ar, A),
7.00−7.04 (m, 1H, Ar, B), 7.12−7.15 (m, 1H, Ar, A), 7.19−7.23 (m,
1H, Ar, A), 7.23−7.27 (m, 1H, Ar, B), 7.32−7.37 (m, 1H + 1H, Ar, A,
B), 7.41−7.51 (m, 4H + 5H, Ar, A, B), 8.77 (s, 1H, NH, B), 8.80 (s,
1H, NH, A), 10.56 (s, 1H, NH, A), 10.60 (s, 1H, NH, B); 13C NMR
(150 MHz, DMSO-d6) δ 40.9 (CH2), 41.2 (CH2), 54.6 (CH), 55.0
(CH), 58.7 (C), 58.8 (C), 109.4 (CH), 109.6 (CH), 121.9 (2 × CH),
122.9 (CH), 123.5 (CH), 126.23 (2 × CH), 126.24 (2 × CH), 127.7
(2 × CH), 128.55 (CH), 128.56 (CH), 128.6 (2 × CH), 128.7 (2 ×
CH), 130.2 (C), 131.4 (C), 142.5 (C), 142.66 (C), 142.71 (C), 143.1
(C), 172.6 (CO), 172.7 (CO), 176.6 (CO), 177.1 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C17H15N2O2+ 279.1128, found
279.1133.
5′-(3,4,5-Trimethoxyphenyl)-2′H-spiro[indole-3,3′-pyrrolidine]-
2,2′(1H)-dione (3b). This compound was obtained from 2j (105 mg,
0.215 mmol): reaction time 114 h; yield 40 mg (51%); yellow solid,
mp 249−250 °C; dr 53:47; Rf = 0.45 (ethyl acetate); 1H NMR (600
MHz, DMSO-d6) δ 2.21 (dd, 2J = 13.2, 3J = 8.2 Hz, 1H, CH2, A), 2.38
(dd, 2J = 13.2, 3J = 8.4 Hz, 1H, CH2, B), 2.71 (dd, 2J = 13.2, 3J = 7.4
Hz, 1H, CH2, B), 2.94 (dd, 2J = 13.2, 3J = 7.2 Hz, 1H, CH2, A), 3.66
(s, 6H, CH3O, B), 3.81 (s, 3H + 3H, CH3O, A, B), 5.01 (dd, 3J = 8.2,
3
J = 7.2 Hz, 1H, CH, A), 5.10 (dd, 3J = 8.4, 3J = 7.4 Hz, 1H, CH, B),
6.78 (s, 1H, Ar, A), 6.80 (s, 1H, Ar, B), 6.83−6.87 (m, 1H, Ar, A),
6.87−6.91 (m, 1H, Ar, B), 6.95−7.00 (m, 1H, Ar, A), 7.00−7.05 (m,
Ar, 1H, Ar, B), 7.19−7.27 (m, 2H + 1H, Ar, A, B), 7.39−7.42 (m, 1H,
Ar, B), 8.76 (br s, 1H, NH, B), 8.78 (br s, 1H, NH, A), 10.56 (br s,
1H, NH), 10.60 (br s, 1H, NH); 13C NMR (150 MHz, DMSO-d6) δ
40.7 (CH2), 41.1 (CH2), 54.8 (CH), 55.2 (CH), 55.9 (2 × CH3O),
56.0 (2 × CH3O), 58.7 (2 × C), 60.0 (2 × CH3O), 103.3 (2 × CH),
103.4 (2 × CH), 109.4 (CH), 109.6 (CH), 121.9 (2 × CH), 122.9
(CH), 123.7 (CH), 128.6 (2 × CH), 130.1 (C), 131.3 (C), 136.9 (2
× C), 138.1 (C), 138.3 (C), 142.5 (C), 143.1 (C), 153.0 (2 × C),
153.1 (2 × C), 172.6 (2 × CO), 176.7 (CO), 177.1 (CO); HRMS
(ESI) m/z [M + H]+ calcd for C20H21N2O5+ 369.1445, found
369.1446.
DOI: 10.1021/acs.joc.8b00922
J. Org. Chem. 2018, 83, 8695−8709
The Journal of Organic Chemistry
5-Bromo-5′-phenyl-2′H-spiro[indole-3,3′-pyrrolidine]-2,2′(1H)-
dione (3c). This compound was obtained from 2p (88 mg, 0.185
mmol): reaction time 114 h; yield 28 mg (42%); beige solid, mp
290−291 °C; dr 55:45; Rf = 0.66 (ethyl acetate); 1H NMR (600
MHz, DMSO-d6) δ 2.26 (dd, 2J = 13.2, 3J = 8.2 Hz, 1H, CH2, A), 2.33
(dd, 2J = 13.3, 3J = 8.5 Hz, 1H, CH2, B), 2.75 (dd, 2J = 13.3, 3J = 7.5
Hz, 1H, CH2, B), 2.93 (dd, 2J = 13.2, 3J = 7.0 Hz, 1H, CH2, A), 5.03
(dd, 3J = 8.2, 3J = 7.0 Hz, 1H, CH, A), 5.22 (dd, 3J = 8.5, 3J = 7.5 Hz,
1H, CH, B), 6.81 (d, 3J = 8.2 Hz, 1H, Ar, A), 6.84 (d, 3J = 8.3 Hz, 1H,
Ar, B), 7.31−7.37 (m, 1H + 1H, Ar, A, B), 7.38−7.48 (m, Ar, 4H +
5H, Ar, A, B), 7.50−7.55 (m, 2H, Ar, A), 7.67 (d, 4J = 1.9 Hz, 1H, Ar,
B), 8.81 (s, 1H, NH, B), 8.86 (s, 1H, NH, A), 10.71 (br s, 1H, NH,
B), 10.75 (br s, 1H, NH, A); 13C NMR (150 MHz, DMSO-d6) δ 40.4
(CH2), 40.9 (CH2), 54.8 (2 × CH), 59.0 (C), 111.3 (CH), 111.5
(CH), 113.6 (2 × C), 125.9 (CH), 126.2 (2 × CH), 126.6 (2 × CH),
126.8 (CH), 127.7 (CH), 127.8 (CH), 128.59 (3 × CH), 128.64 (2
× CH), 131.3 (2 × CH), 132.3 (C), 133.6 (C), 141.9 (C), 142.2 (C),
142.5 (C), 142.7 (C), 172.0 (CO), 172.1 (CO), 176.3 (CO), 176.6
(CO); HRMS (ESI) m/z [M + H]+ calcd for C17H14BrN2O2+
357.0233, found 357.0238.
■
ASSOCIATED CONTENT
* Supporting Information
S Cyclizations for the Synthesis of Pyrroloindoles: Progress toward the
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00922.
X-ray data, results of cell assay, DFT calculations,
Cartesian coordinates, and NMR spectra (PDF)
Crystal data of 2r (CIF)
Accession Codes
CCDC 1832110 contains the supplementary crystallographic
data for this paper (2r). These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif.
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: ekatbud@kinet.chem.msu.ru.
ORCID
Konstantin L. Ivanov: 0000-0002-1557-175X
Stanislav I. Bezzubov: 0000-0002-2017-517X
Ekaterina M. Budynina: 0000-0003-1193-7061
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This research was supported by the Russian Science
Foundation, grant no. 17-73-10418. The NMR measurements
were carried out at the Center for Magnetic Tomography and
Spectroscopy, Faculty of Fundamental Medicine of Lomono-
sov Moscow State University.
■
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The Journal of Organic Chemistry Note

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8709 DOI: 10.1021/acs.joc.8b00922

J. Org. Chem. 2018, 83, 8695−8709