Phosphine-catalyzed synthesis of 3,3-spirocyclopenteneoxindoles from γ-substituted allenoates: Systematic studies and targeted applications

Article abstract of DOI:10.1021/jo302460d

The phosphine-promoted [3 + 2] cyclizations between γ-substituted allenoates and arylideneoxindoles have been applied to the stereoselective synthesis of spiro(cyclopentene)oxindoles with trisubstituted cyclopentene units. It has been demonstrated that PP

Full text of DOI:10.1021/jo302460d

Article
pubs.acs.org/joc
Phosphine-Catalyzed Synthesis of 3,3-Spirocyclopenteneoxindoles
from γ‑Substituted Allenoates: Systematic Studies and Targeted
Applications
Catherine Gomez,† Maxime Gicquel,† Jean-Christophe Carry,‡ Laurent Schio,‡ Pascal Retailleau,†
Arnaud Voituriez,*,† and Angela Marinetti*,†
†Institut de Chimie des Substances Naturelles - CNRS, UPR 2301, Centre de Recherche de Gif-1, av de la Terrasse, 91198
Gif-sur-Yvette, France
‡Chimie Med
́
icinale Oncologie, Sanofi, 13 quai Jules Guesde, 94400 Vitry-sur-Seine, France
S
* Supporting Information
ABSTRACT: The phosphine-promoted [3 + 2] cyclizations between γ-
substituted allenoates and arylideneoxindoles have been applied to the
stereoselective synthesis of spiro(cyclopentene)oxindoles with trisub-
stituted cyclopentene units. It has been demonstrated that PPh3 operates
a very efficient control of the relative stereochemistry of the three
stereogenic centers of the final spiranic products. Focused experiments
have been carried out then so as to access carbocyclic analogues of an
important series of anticancer agents inhibiting MDM2-p53 interactions.
strategy to isatin-derived enones:5 these doubly activated
INTRODUCTION
■
substrates reacted properly with ethyl 2,3-pentadienoate via a
supposed γ-addition process while they afforded intractable
mixtures in their reactions with ethyl 2,3-butadienoate. Other
phosphine-promoted annulations have been also applied to the
synthesis of spirocyclic oxindoles, including the reaction of
arylidene oxindoles with Morita−Baylis−Hillman adducts6 and
other 1,3-dipolar cycloadditions.7 Given the significance and
biological relevance of the spiro-cyclopentane core structures,
as well as the potential synthetic usefulness of our organo-
catalytic method above, we decided to expand its scope so as to
access spiranes with trisubstituted cyclopentene units, starting
from 3-arylidene oxindoles and 4-substituted allenoates.
Through systematic studies, we have demonstrated that these
reactions take place with different regio- and stereochemical
control, with respect to those described by Wei and Shi.5
Moreover, we have demonstrated that the method enables the
synthesis of new carbon analogues of a well-known series of
P53-MDM2 inhibitors, via a simple, three-step reaction
sequence. The method thus affords a new starting point for
the synthesis of bioinspired compound collections. The main
results of these studies are summarized hereafter.
Spirocyclic oxindoles are common scaffolds for natural products
as well as privileged core elements of medicinal agents largely
inspired by those natural products. In particular, spirooxindoles
with carbocyclic five-membered rings are featured in some
series of naturally occurring products including citrinadins,
cyclopiamines, and notoamides as well as in synthetic bioactive
compounds.1 For the synthesis of these challenging sub-
structures, organocatalytic approaches have been eagerly sought
in recent years.2 Our contribution to this effort has been to
define an efficient access to 3-cyclopentene-spirooxindoles
under phosphine catalysis, based on Lu’s [3 + 2] cyclization3
between electron-poor olefins and allenes.4 Starting from
arylideneoxindoles and 2,3-butadienoates, our method affords
multifunctional 2,5-disubstituted cyclopentene units in a
diastereoselective and highly enantioselective manner (Scheme
1). Later, Wei and Shi adapted the same [3 + 2] cyclization
Scheme 1. Phosphine-Promoted Synthesis of 2,5-
Disubstituted Spiro(cyclopentene)oxindoles4
RESULTS AND DISCUSSION
■
The phosphine-based organocatalytic cyclization methods
known so far to access spirocyclopentene oxindoles, afford
complementary series of spiranic derivatives whose specific
substitution patterns depend on the substrate pairs and
cyclization modes.5−8 The [3 + 2] cyclizations of 2,3-
Received: November 23, 2012
Published: January 23, 2013
© 2013 American Chemical Society
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butadienoates with 3-arylideneoxindoles developed in our
previous work (Scheme 1)4 give 5-substituted cyclopentene
units bearing an ester function on their 2-positions as the major
products. This means that the preferred cyclization mode
involves a Michael-type addition of the key zwitterionic
intermediate I through its γ-carbon to the electron-poor olefin
(γ-addition).
In these cyclization reactions, the final product displays a
cyclopentene unit with trans-configuration of the two
contiguous stereogenic centers (Ph trans to the carbonyl
function of the oxindole unit). The high regio- and stereo-
chemical control of these cyclizations encouraged us to expand
the scope of the reaction to γ-substituted allenoates, with the
aim of obtaining spirocyclic oxindoles with trisubstituted five-
membered rings.
cyclopentenes with a trans arrangements of the two ring
substituents with respect to the carbonyl function.9b,c
The preference for α-adducts with trans,trans stereochemistry
has been confirmed through more extended studies by which
variously substituted substrates have been combined in the
presence of PPh3. In a first series of experiments, the
benzylidene oxindole (E)-1a has been reacted with allenes
with alkyl substituents on the γ-carbon (Table 1). All these
Table 1. Synthesis of the 2,3,5-Trisubstituted
Spiro(cyclopentene)oxindoles 4 and 5 from γ-Substituted
Allenoates under PPh3 Catalysis
As a model reaction we have considered the [3 + 2]
cyclization of (E)-N-acetyl-3-benzylideneoxindole (1a) with 4-
phenyl-2,3-butadienoate (3a), shown in Scheme 2. Under PPh3
Scheme 2. Synthesis of 4a by PPh3-Promoted [3 + 2]
Annulation
yield
entry substrate R1
R
product
dr
(%)
1
2
3
4
5
6
7
3b
3c
3d
3e
3f
Et
Et
Et
Et
Et
Et
Bn
n-Pr
i-Pr
4b
4c
4d
4e
90:10
88:12
95:5
82
71
65
68
55
51
67
CH2CH2Ph
CH2-t-Bu
>95:5
95:5
a
CH2-cyclo-C5H9
CH2CH2CO2Me
n-Pr
4f
a
3g
3h
4g
95:5
5
95:5
a
Small amounts of a minor isomer (<10%) have been observed in the
crude reaction mixture.
catalysis, the reaction occurs at room temperature leading to
the spirooxindole 4a as the major product, together with a <5%
amount of a minor isomer (82% total yield). The reaction thus
proceeds with excellent regio- and diastereoselectivity.
reactions afforded the corresponding trans,trans cycloadducts
4b−g in very high isomer ratios (>8:1) for both linear and
branched γ-substituents. Changing the ester group R1 from
ethyl to benzyl does not change the isomer ratio significantly
(entry 1 vs 7).
Similarly, 4-phenyl-2,3-butadienoate was reacted with a
variety of (E)-arylideneoxindoles in the presence of PPh3 as
the catalysts to afford the spirocyclic compounds 6−10 shown
in Figure 1. The desired spiro(cyclopentene)oxindoles have
been obtained from arylidene oxindoles with ethoxycarbonyl as
the nitrogen protecting group (6), with substituted aromatic
and heteroaromatic groups as the olefin substituent (7a−c, 10),
and with oxindole units functionalized at their 5- and 6-
positions (8−10). Good yields and diastereomeric ratios >95:5
Compound 4a results from the α-addition of the allenoate to
the arylidene oxindole 1a, which is in agreement with previous
studies showing that α-addition is favored for [3 + 2]
cyclizations involving γ-substituted allenoates or the corre-
sponding alkynes.9 The observed α-addition mode should have
here mainly steric origins, as far as the γ-substituent of the
allenoate might disfavor a γ-addition mode. The X-ray crystal
structure of 4a (see Supporting Information) confirms the
structural assignment and demonstrates the trans,trans config-
uration of the trisubstituted cyclopentene.10,11 The observed
stereochemistry is consistent with that of analogous cyclizations
on simple α,β-unsaturated ketones which also afforded
Figure 1. Trisubstituted spiro(cyclopentene)oxindoles.
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Scheme 3. Synthesis of the Diastereomeric Spiranes 10
have been obtained for the whole series. The reaction also
applies to alkylideneoxidoles as shown by the synthesis of 7d.
The results above demonstrate that the cyclization takes
place with extremely high regio- and diastereoselectivity when
PPh3 is used as the catalyst. More extended studies have shown
then that the stereochemical course of the reaction is highly
dependent on the nature of the phosphorus catalyst. A
representative example is shown in Scheme 3 below: the
reaction between the arylidene oxindole (E)-1b and allenoate
3e promoted by PMe2Ph affords a mixture of three isomeric
spiranes in approximately equal amounts (Scheme 3 b). Besides
the expected trans,trans isomer 10-A, the trans,cis and cis,trans
isomers, 10-B and 10-C, have been isolated and fully
characterized. Their stereochemistry has been secured by X-
ray diffraction studies (see Supporting Information). The cis,cis
isomer has not been detected in these reactions.12
Scheme 4. Postulated Reaction Intermediates
disubstituted olefins (mainly (E)-enones) are still rare.9b,c They
highlight the selective formation of trans,trans isomers of the
final cyclopentenes, with only trace amounts of other
diastereomers: overall the (E)-configuration of the starting
enones translates apparently into the final product. A notable
exception to this general trend can be noticed in the above-
mentioned work of Wei and Shi,5 which shows formation of
several stereoisomers in the [3 + 2] cyclization of ethyl 2,3-
pentadienoate with isatin-derived 3-(2-oxopropylidene)indolin-
2-ones. This paper also highlights a very efficient control of the
product distribution by an appropriate choice of the
phosphorus catalyst: the electron-poor P(p-FC6H4)3 catalyst
gives the trans,trans diastereomer with total diastereoselectivity,
while PBu3 affords a mixture of trans,trans and cis,trans isomers
in a 1:2 ratio. The stereochemical control of these reactions
cannot be compared effectively to that of reactions in Scheme 3
as far as γ-additions are postulated by Shi,15 while α-additions
occur in our experiments. Most certainly, additional systematic
studies are required to enlighten the mechanisms and the
stereochemical courses of these reactions, as well as the role of
the phosphorus catalyst in their stereocontrol.
From a synthetic point of view, the key information afforded
by reactions in Schemes 2−4 is that triphenylphosphine affords
a stereoselective access to the trans,trans stereoisomers of the
trisubstituted spirocyclopentenes 4−10, while other stereo-
isomers are available by using PMe2Ph as the phosphorus
catalyst, although this last reaction is not selective. Both the
stereochemical control of these cyclizations and the oppor-
tunity to access various stereoisomers will be of prime
importance when targeted syntheses are envisioned. In spite
of the remarkable synthetic potential of the method, so far only
Among the other phosphorus catalysts tested so far, 1,2-
diphenylphosphinoethane (dppe) and PBu3 give mixtures of
10-A and 10-C, while P(p-MeOC6H4)3, P(p-FC6H4)3, and
PPhCy2 afford 10-A selectively, albeit in lower yields compared
to PPh3.
According to theoretical mechanistic studies on phosphine-
promoted [3 + 2] cyclizations between allenes and olefins,13
these are assumed to be stepwise processes in which the
zwitterionic phosphine allenoate adduct undergoes at first a
Michael-type addition to the olefin, followed by a cyclization
step. Although these theoretical studies mainly relate to
reactions between methyl 2,3-butadienoate and methyl acrylate,
we can assume that stepwise mechanisms operate also in
reactions involving substituted substrates, as typified in this
work. Accordingly, the key reaction intermediates can be drawn
as shown in Scheme 4. An α-addition of the phosphine-
allenoate adduct to the olefin affords II, and then a cyclization
step occurs by which the relative stereochemistry of the final
product will be determined.14 Thus, it can be reasonably
anticipated that the nature of the phosphorus catalysts will
affect the stereochemical course of the reaction, as far as it
might control the relative stabilities (or the relative rates of
formation) of intermediates III and IV. The favored
intermediate, trans-III, accounts for the final product of eq
(a) in Scheme 3 (10-A) as well as for 2/3 of the final products
of eq (b) (10-A + 10-B), while the spirooxindole 10-C is
produced from cis-IV.
Previous literature reports on [3 + 2] cyclizations involving γ-
substituted allenoates (or the corresponding alkynes) and 1,2-
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a few articles report on the use of phosphine-promoted [3 + 2]
cyclizations in the synthesis of targeted cyclopentene or
cyclopentane derivatives.16 The pioneering work of Pyne has
shown the suitability of the method to the synthesis of
conformationally restricted L-glutamate analogues,9a,17 while
Xiao, Chen,18 Jørgensen,19 and Shi20 have developed stereo-
selective accesses to non-natural amino acids, including cyclic
analogues of aspartic acid. In addition, phosphine-promoted [3
+ 2] cyclizations have been envisioned as key steps in the
formal or total synthesis of natural products and bioactive
compounds, namely for the synthesis of carbocyclic analogues
of the potent herbicide hydantocidin,21 for the total syntheses
of (−)-hinesol22 and (+)-geniposide,23 as well as for the formal
synthesis of hirsutene.24
Scheme 5. Synthesis of the Spirocyclopentane Oxindole 14, a
Carbocyclic Analogue of 11
In this work also, the [3 + 2] cyclization reactions above have
been considered as a suitable tool for the synthesis of targeted
analogues of known bioactive compounds. Thus, the cyclization
reactions in Scheme 3 have been specifically inspired by recent
studies by Wang on a series of potent anticancer agents which
display a 3-pyrrolidine−spirooxindole scaffold.25 These com-
pounds, typified by 11 in Figure 2, are selective inhibitors of the
aminoethylmorpholine in the presence of AlCl3 afforded 12-B
and 12-C in 62% and 69% yields, respectively (Figure 3).
Figure 2. Representative example of the Wang’s MDM2 inhibitors
displaying spiro(pyrrolidine)oxindole core structures.25
Figure 3. Unsaturated carbocyclic analogues of 11.
MDM2-p53 interaction, giving excellent inhibition of the
proliferation of cancer cells with wild-type p53 status and
minimal toxicity to normal cells. We envisioned that the
organocatalytic, phosphine-based methodology would be
perfectly suitable to access new carbocyclic analogues of these
bioactive compounds, with various relative stereochemistries of
their stereogenic centers.
Compounds 12 and 14 are the first representatives of a new
class of carbocyclic analogues of the bioactive pyrrolidine-
spirooxindoles 11. The experiments above demonstrate that
these phosphine-promoted [3 + 2] cyclizations on arylideneox-
indoles can be successfully employed as key steps in the
synthesis of highly functionalized, specifically targeted mole-
cules.
In a preliminary study oriented toward this target, the
reaction sequence shown in Scheme 5 has been implemented
to convert the spiro(cyclopentene)oxindole ester trans,trans-10-
A into the corresponding saturated amide 14. The sequence
involves at first catalytic hydrogenation of 10-A in MeOH, with
Pd/C under an H2 atmosphere, to afford the saturated spiranic
derivative 13. The acetyl N-protecting group was also removed
under these reaction conditions. The molecular structure of 13
and the all-trans stereochemistry of the cyclopentane unit have
been unambiguously established by X-ray diffraction studies (X-
ray data for this compound are given as Supporting
Information). In the second step, ester 13 was transformed
into the corresponding amide 14 by reaction with 2-
aminoethylmorpholine in the presence of AlMe3.
Moreover, starting from 10-A, an unsaturated analogue of 11,
i.e. compound 12-A, has been prepared in 81% yield by
amidation with 2-aminoethylmorpholine (Scheme 5). Similarly,
other unsaturated analogues of 11 have been prepared which
display different relative stereochemistries of the 2- and 5-
carbon centers, with respect to the quaternary carbon at the
ring junction. Amidation of esters 10-B and 10-C with 2-
In conclusion, this work expands the scope of the phosphine-
promoted [3 + 2] cyclizations between allenoates and
arylideneoxindoles to the stereoselective synthesis of spiro-
(cycopentene)oxindoles with trisubstituted cyclopentene units.
It has been demonstrated that PPh3 operates a very efficient
control of the relative stereochemistry of the three stereogenic
centers of the final products. After a systematic screening of a
range of substrates, focused experiments have been carried out
so as to access specifically targeted spiranic scaffolds. In
particular, we have demonstrated the suitability of these
phosphine-promoted cyclizations for the straightforward syn-
thesis of carbocyclic analogues of an important series of
inhibitors of MDM2-p53 interactions with anticancer proper-
ties. Ongoing studies are oriented toward asymmetric variants
of these reactions.
EXPERIMENTAL SECTION
■
General Procedures. All non-aqueous reactions were run under
an inert atmosphere (argon) by using standard techniques for
manipulating air-sensitive compounds. Anhydrous solvents were
obtained by filtration through drying columns (THF, toluene,
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CH2Cl2). All reagents and solvents were of commercial quality and
were used without further purification. Analytical thin-layer
chromatography (TLC) was performed on plates precoated with
silica gel layers. Visualization of the developed chromatogram was
followed by UV absorbance. Flash column chromatography was
performed using 40−63 mesh silica. NMR spectra (1H, 13C) were
recorded at 500 or 300 MHz spectrometers. IR spectra were recorded
with a FT-IR spectrophotometer and are reported in reciprocal
centimeters (cm−1). High-resolution mass spectrometry (HRMS) was
performed using electrospray ionization (ESI) and time-of-flight
(TOF) analyzer, in positive-ion or negative-ion detection mode.
Synthesis of Substrates. Ethyl 5-tert-Butylpenta-2,3-dienoate
(3e). A solution of acrylic acid (2.75 mL, 40.0 mmol) in
tetrahydrofuran (220 mL) was cooled to −78 °C and added slowly
to a tert-butyllithium (1.75 M, 50.0 mL, 88.0 mmol) solution in
tetrahydrofuran (60 mL) at −78 °C. After 2 h at −78 °C, the yellow
mixture was stirred for 12 h at room temperature. Water (300 mL)
was added at 0 °C, and the solvent was partly evaporated under
reduced pressure. The residue was extracted with TBME. The aqueous
layer was acidified under stirring and ice-cooling by slow addition of
concentrated hydrochloric acid and extracted with ethyl acetate (2 ×
250 mL), and the organic layer was dried. Evaporation of the solvent
afforded the desired 4,4-dimethylpentanoic acid which was used in the
next step without further purification. To the acid (2.2 g, 16.9 mmol)
in dichloromethane (80 mL) was added slowly at room temperature
SOCl2 (1.48 mL, 20.0 mmol) and 0.5 mL of DMF. The resulting
mixture was stirred at reflux for 3 h. After evaporation of the solvent,
the crude acyl chloride was used in the next step. Triethylamine (1.7
mL, 12.0 mmol) was added to a solution of (carbethoxymethylene)-
triphenylphosphorane (3.8 g, 11.0 mmol) in dichloromethane (20
mL) under argon at room temperature. After 10 min, a solution of
crude 4,4-dimethylpentanoyl chloride (1.6 g, 11.0 mmol) in
dichloromethane (17 mL) was added. During the addition, the color
of the reaction changed to orange. The mixture was stirred for 18 h
and concentrated to afford a gummy residue which was purified by
flash chromatography on silica gel (1% MTBE/pentane) to furnish the
desired compound 3e (1.12 g, 37% yield, over two steps, colorless oil):
1H NMR (300 MHz, CDCl3) δ 5.60−5.50 (m, 2H), 4.25−4.10 (m,
and extracted with ethyl acetate. The combined organic phases were
washed with water, brine, dried over MgSO4, and evaporated. 3-
Chloro-2-fluorobenzaldehyde (1.5 mL, 13.0 mmol) and piperidine
(0.2 mL, 24.0 mmol) were added dropwise to the crude N-
acetylindolinone dissolved in ethanol (16 mL). The mixture was
heated at 80 °C for 24 h. After cooling to rt, the precipitate was filtered
and recrystallized in chloroform. The isolated solid contained mainly
(E)-1b. (Z)-1b was obtained by evaporation of the filtrate (0.89 g,
22%, yellow powder, mp >200 °C): Rf 0.25 (10% EtOAc/heptanes);
1H NMR (300 MHz, CDCl3) δ 8.34 (d, J = 1.8 Hz, 1H), 8.17 (t, J =
7.8 Hz, 1H), 7.71 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.8 Hz,
1H), 7.23 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 2.69 (s, 3H), IR νmax
=
1742, 1714, 1602, 1471, 1452, 1373, 1282, 1263, 1157, 931, 921, 818
cm−1; HRMS (ESI) calcd for C17H11Cl2FNO2 [M + H]+ 350.0151,
found 350.0148.
Procedure for the Catalytic [3 + 2] Annulations. Degassed
toluene (0.50 mL) was added to a mixture of arylidene oxindole 1 (0.5
mmol), allenoate 3 (0.75 mmol, 1.5 equiv), and PPh3 (0.1 mmol, 20
mol %) under an argon atmosphere. The solution was stirred at room
temperature for 12−24 h. The crude mixture was concentrated in
vacuo, and the final product was purified by flash chromatography on
silica gel (EtOAc/heptanes).
Ethyl 1′-acetyl-2′-oxo-2,5-diphenylspiro[cyclopent[3]ene-1,3′-in-
doline]-3-carboxylate (4a): 186 mg, 82% yield, dr > 95:5; Rf 0.26
1
(15% EtOAc/heptanes); H NMR (500 MHz, CDCl3) δ 7.81 (d, J =
8.1 Hz, 1H), 7.34 (t, J = 2.4 Hz, 1H), 7.14−6.92 (m, 8H), 6.9−6.8 (m,
3H), 6.54 (td, J = 7.5, 0.9 Hz, 1H), 6.33 (dd, J = 7.5, 0.9 Hz, 1H), 4.95
(t, J = 2.4 Hz, 1H), 4.84 (t, J = 2.4 Hz, 1H), 4.30−4.05 (m, 2H), 2.80
(s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 181.2
(C), 170.6 (C), 164.4 (C), 143.9 (CH), 139.4 (C), 138.2 (C), 137.10
(C), 137.06 (C), 128.4 (CH), 128.2 (CH), 128.1 (CH), 128.07 (CH),
127.9 (CH), 127.5 (CH), 127.1 (CH), 126.9 (CH), 125.8 (C), 123.3
(CH), 115.5 (CH), 65.8 (C), 60.8 (CH2), 60.7 (CH), 59.1 (CH), 27.1
(CH3), 14.1 (CH3); IR νmax = 1748, 1713, 1464, 1463, 1370, 1274,
1171, 1099, 1015, 755, 699 cm−1; HRMS (ESI) calcd for C29H24NO4
[M − H]− 450.1705, found 450.1722.
Ethyl 1′-acetyl-2′-oxo-2-phenyl-5-propylspiro[cyclopent[3]ene-
1,3′-indoline]-3-carboxylate (4b): 82% yield, dr = 90/10; Rf 0.30
1
2H), 2.04−1.99 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.95 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 213.1 (C), 166.6 (C), 92.2 (CH), 87.2
(CH), 60.8 (CH2), 42.4 (CH2), 29.5 (C), 29.1 (CH3), 14.3 (CH3); IR
νmax = 2956, 1741, 1366, 1258, 1163, 1030, 801 cm−1; HRMS (ESI)
calcd for C11H19O2 [M + H]+ 183.1385, found 183.1375.
(15% EtOAc/heptanes); H NMR (300 MHz, CDCl3) δ 7.97 (d, J =
8.4 Hz, 1H), 7.10−6.98 (m, 5H), 6.92−6.84 (m, 2H), 6.83−6.75 (m,
2H), 4.79 (t, J = 2.5 Hz, 1H), 4.20−4.00 (m, 2H), 3.43 (br, 1H), 2.73
(s, 3H), 1.50−1.40 (m, 1H), 1.35−1.20 (m, 1H), 1.20−1.00 (m, 2H),
1.08 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 181.1 (C), 170.8 (C), 164.6 (C), 146.3 (CH), 139.7 (C),
137.0 (C), 135.9 (C), 128.5 (CH), 128.1 (CH), 127.8 (CH), 127.1
(CH), 126.3 (CH), 126.1 (C), 123.8 (CH), 116.1 (CH), 64.4 (C),
61.2 (CH), 60.6 (CH2), 53.3 (CH), 32.7 (CH2), 27.0 (CH3), 21.1
(CH2), 14.1 (CH3), 14.0 (CH3); IR νmax = 1748, 1711, 1463, 1368,
1256, 1168, 1096, 930, 758, 739, 700 cm−1; HRMS (ESI) calcd for
C26H26NO4 [M − H]− 416.1862, found 416.1876. The minor isomer
observed in the crude mixture has been tentatively assigned as a
diastereomer of 4b, based on the 1H NMR signals for the cyclopentene
(E)-6-Chloro-3-(3-chloro-2-fluorobenzylidene)-N-acetylindolin-2-
one ((E)-1b). Piperidine (59 μL, 0.6 mmol) was added dropwise to a
mixture of 6-chlorooxindole (500 mg, 3.0 mmol) and 3-chloro-2-
fluorobenzaldehyde (0.39 mL, 3.3 mmol) in ethanol (4 mL). The
mixture was heated at 80 °C for 2 h. The yellow solid was filtered and
washed with ethanol to afford 6-chloro-3-(3-chloro-2-
fluorobenzylidene)indolin-2-one (861 mg, 94%). This compound
was dissolved in tetrahydrofuran (3 mL) and treated with acetic
anhydride (1.6 mL, 16.8 mmol) and sodium carbonate (1.8 g, 16.8
mmol). The mixture was stirred for 12 h at room temperature, diluted
with water (20 mL), and extracted with ethyl acetate (50 mL). The
combined organic layers were washed with water (50 mL) and brine
(50 mL) and dried over MgSO4. The crude mixture was concentrated
in vacuo and purified by flash chromatography on silica gel (10%
EtOAc/heptanes) to furnish the desired compound (E)-1b (841 mg,
86%, yellow powder, mp = 138−140 °C): Rf 0.20 (10% EtOAc/
1
CH groups: H NMR (300 MHz, CDCl3) δ 4.60 (t, J = 2.5 Hz, 1H),
3.37 (br, 1H) ppm.
Ethyl 1′-acetyl-5-isopropyl-2′-oxo-2-phenylspiro[cyclopent[3]-
ene-1,3′-indoline]-3-carboxylate (4c): 71% yield, dr = 88/12; Rf
1
0.32 (15% EtOAc/heptanes); H NMR (500 MHz, CDCl3) δ 7.86
(d, J = 8.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 2.5 Hz, 1H),
7.07 (t, J = 8.0 Hz, 1H), 6.97−6.90 (4H), 6.75−6.70 (m, 2H), 4.83 (t,
J = 3.0 Hz, 1H), 4.15−4.0 (m, 2H), 3.24 (d, J = 11.5 Hz, 1H), 2.72 (s,
3H), 1.80−1.70 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H), 1.04 (t, J = 7.0 Hz,
3H), 0.39 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.9
(C), 170.6 (C), 164.8 (C), 145.3 (CH), 139.4 (C), 136.0 (C), 135.9
(C), 128.6 (CH), 127.9 (CH), 127.6 (CH), 127.0 (CH), 126.3 (C),
125.4 (CH), 123.8 (CH), 116.2 (CH), 65.6 (C), 62.9 (CH), 60.6
(CH2), 60.4 (CH), 28.2 (CH3), 26.9 (CH3), 22.0 (CH), 20.6 (CH3),
14.1 (CH3); HRMS (ESI) calcd for C26H26NO4 [M − H]−: 416.1862,
found 416.1870. A small sample of the minor isomer of 4c has been
isolated by HPLC: 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 7.5 Hz,
1H), 7.50−7.44 (m, 1H), 7.35−7.28 (m, 2H), 7.15−7.05 (m, 4H),
1
heptanes); H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 2.0 Hz, 1H),
7.79 (bs, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.20
(t, J = 7.5 Hz, 1H), 7.04 (dd, J = 8.2, 2.0 Hz, 1H), 2.76 (s, 3H); IR νmax
= 1746, 1714, 1597, 1451, 1424, 1373, 1316, 1282, 1262, 1165, 930,
765 cm−1; HRMS (ESI) calcd for C17H11Cl2FNO2 [M + H]+
350.0151, found 350.0150.
(Z)-6-Chloro-3-(3-chloro-2-fluorobenzylidene)-N-acetylindolin-2-
one ((Z)-1b). 6-Chlorooxindole (2.0 g, 12.0 mmol) was dissolved in
tetrahydrofuran (40 mL) and treated with acetic anhydride (6.7 mL,
71.0 mmol) and sodium carbonate (7.6 g, 106.0 mmol). The mixture
was stirred for 12 h at room temperature, diluted with water (80 mL),
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Article
6.66 (br, 2H), 4.54 (t, J = 3.0 Hz, 1H), 4.20−4.02 (m, 2H), 3.09 (dt, J
= 11.0, 2.5 Hz, 1H), 2.22−2.14 (m, 1H), 2.06 (s, 3H), 1.12 (d, J = 6.5
Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H), 0.38 (d, J = 6.5 Hz, 3H) ppm.
Ethyl 1′-acetyl-2′-oxo-5-phenethyl-2-phenylspiro[cyclopent[3]-
ene-1,3′-indoline]-3-carboxylate (4d): 65% yield, dr = 95/5; Rf
181.0 (C), 170.8 (C), 164.4 (C), 147.1 (CH), 139.7 (C), 137.0 (C),
135.7 (C), 135.6 (C), 128.5 (CH), 128.3 (CH × 2), 128.2 (CH × 2),
128.1 (CH), 127.97 (CH × 2), 127.95 (CH × 2), 127.2 (CH), 126.3
(CH), 126.0 (C), 123.7 (CH), 116.1 (CH), 66.4 (CH2), 64.4 (C),
61.2 (CH), 53.3 (CH), 32.7 (CH2), 27.0 (CH3), 21.1 (CH2), 14.0
(CH3); IR νmax = 1749, 1713, 1464, 1372, 1339, 1267, 1170, 1098,
1017, 913, 737, 701 cm−1; HRMS (ESI) calcd for C31H28NO4 [M −
H]− 478.2018, found 478.2037.
1
0.24 (15% EtOAc/heptanes); H NMR (500 MHz, CDCl3) δ 8.01
(d, J = 8.1 Hz, 1H), 7.25−7.10 (m, 4H), 7.08−7.00 (m, 4H), 6.95−
6.86 (m, 4H), 6.85−6.76 (m, 2H), 4.82 (t, J = 2.5 Hz, 1H), 4.20−4.00
(m, 2H), 3.55−3.45 (m, 1H), 2.73 (s, 3H), 2.55−2.45 (m, 1H), 2.30−
2.20 (m, 1H), 1.90−1.76 (m, 1H), 1.60−1.48 (m, 1H), 1.08 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 181.0 (C), 170.7 (C), 164.5
(C), 145.8 (CH), 140.9 (C), 139.7 (C), 136.9 (C), 136.2 (C), 128.63
(CH), 128.56 (CH), 128.3 (CH), 128.1 (CH), 127.9 (CH), 127.2
(CH), 126.3 (CH), 126.2 (CH), 125.8 (C), 123.9 (CH), 116.2 (CH),
64.2 (C), 61.2 (CH), 60.7 (CH2), 53.0 (CH), 34.2 (CH2), 32.6
(CH2), 27.0 (CH3), 14.1 (CH3); IR νmax = 1749, 1711, 1463, 1371,
1339, 1268, 1173, 1114, 1014, 911, 758, 729, 700 cm−1; HRMS (ESI)
calcd for C31H28NO4 [M − H]− 478.2018, found 478.2036.
Diethyl 2′-oxo-2,5-diphenylspiro[cyclopent[3]ene-1,3′-indoline]-
1′,3-dicarboxylate (6): 70% yield, dr > 95:5; Rf 0.26 (15% EtOAc/
1
heptanes); H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.1 Hz, 1H),
7.32 (t, J = 2.4 Hz, 1H), 7.15−6.95 (m, 8H), 6.92−6.80 (m, 3H), 6.50
(td, J = 7.5, 0.9 Hz, 1H), 6.31 (d, J = 7.8 Hz, 1H), 4.97 (t, J = 2.4 Hz,
1H), 4.85 (t, J = 2.4 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 4.25−4.05 (m,
2H), 1.48 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 178.8 (C), 164.5 (C), 150.8 (C), 144.0 (CH), 138.7
(C), 138.3 (C), 137.3 (C), 137.2 (C), 128.35 (CH × 2), 128.31 (CH
× 2), 128.2 (CH × 2), 128.0 (CH), 127.9 (CH × 2), 127.4 (CH),
127.2 (CH), 127.0 (CH), 125.8 (C), 122.9 (CH), 114.0 (CH), 65.7
(C), 63.7 (CH2), 60.8 (CH2), 60.6 (CH), 59.1 (CH), 14.4 (CH3),
14.1 (CH3); IR νmax = 2982, 1734, 1719, 1466, 1371, 1290, 1238,
1163, 1097, 1047, 754, 700 cm−1; HRMS (ESI) calcd for C30H26NO5
[M − H]− 480.1811, found 480.1830.
Ethyl 1′-acetyl-2′-oxo-5-phenyl-2-(4-(trifluoromethyl)phenyl)-
spiro[cyclopent[3]ene-1,3′-indoline]-3-carboxylate (7a): 81% yield,
dr > 95:5; Rf 0.23 (15% EtOAc/heptanes); 1H NMR (500 MHz,
CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 2.4 Hz, 1H), 7.34−7.24
(m, 2H), 7.15−7.05 (m, 3H), 7.02−6.92 (m, 4H), 6.90 (d, J = 8.0 Hz,
1H), 6.58 (t, J = 7.5 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 5.00 (bs, 1H),
4.86 (bs, 1H), 4.25−4.10 (m, 2H), 2.80 (s, 3H), 1.15 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 180.9 (C), 170.5 (C), 164.0 (C),
144.9 (CH), 141.4 (C), 139.4 (C), 137.4 (C), 136.7 (C), 128.6 (CH
× 2), 128.51 (CH), 128.49 (CH × 2), 128.2 (CH × 2), 127.7 (CH),
126.6 (CH), 125.3 (C), 124.9 (q, J = 3.5 Hz, CH × 2), 123.5 (CH),
115.8 (CH), 65.7 (C), 61.1 (CH2), 60.2 (CH), 59.3 (CH), 27.1
(CH3), 14.1 (CH3); IR νmax = 1749, 1715, 1465, 1372, 1325, 1277,
1169, 1115, 1069, 1017, 756 cm−1; HRMS (ESI) calcd for
C30H23F3NO4 [M − H]− 518.1579, found 518.1581.
Ethyl 1′-acetyl-2-(3-bromophenyl)-2′-oxo-5-phenylspiro-
[cyclopent[3]ene-1,3′-indoline]-3-carboxylate (7b): 85% yield, dr >
95:5; Rf 0.23 (15% EtOAc/heptanes); 1H NMR (300 MHz, CDCl3) δ
7.83 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 2.4 Hz, 1H), 7.18−7.05 (m, 4H),
7.00 (t, J = 1.5 Hz, 1H), 6.98−6.85 (m, 4H), 6.75 (d, J = 7.7 Hz, 1H),
6.61 (dt, J = 7.6, 0.8 Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 4.88 (bs, 1H),
4.84 (bs, 1H), 4.30−4.10 (m, 2H), 2.79 (s, 3H), 1.16 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 180.9 (C), 170.6 (C), 164.1 (C),
144.7 (CH), 139.5 (C), 139.4 (C), 137.5 (C), 136.8 (C), 131.4 (CH),
130.2 (CH), 129.5 (CH), 128.5 (CH × 3), 128.2 (CH × 2), 127.7
(CH), 126.77 (CH), 126.74 (CH), 125.4 (C), 125.3 (CH), 122.0 (C),
115.7 (CH), 65.9 (C), 61.0 (CH2), 60.2 (CH), 59.0 (CH), 27.0
(CH3), 14.2 (CH3); IR νmax = 1749, 1713, 1477, 1371, 1266, 1171,
1102, 1015, 736, 701 cm−1; HRMS (ESI) calcd for C29H23BrNO4 [M
− H]− 528.0810, found 528.0831.
Ethyl 1′-acetyl-2′-oxo-5-phenyl-2-(quinolin-2-yl)spiro-
[cyclopent[3]ene-1,3′-indoline]-3-carboxylate (7c): 97% yield, dr >
95:5; Rf 0.27 (25% EtOAc/heptanes); 1H NMR (500 MHz, CDCl3) δ
7.92 (d, J = 8.5 Hz, 1H), 7.80−7.72 (m, 2H), 7.66−7.58 (m, 2H), 7.41
(t, J = 7.5 Hz, 1H), 7.31 (bs, 1H), 7.16−7.00 (m, 5H), 6.79 (d, J = 8.5
Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.32 (t, J = 7.5 Hz, 1H), 6.23 (d, J =
7.5 Hz, 1H), 5.26 (bs, 1H), 4.86 (bs, 1H), 4.25−4.10 (m, 2H), 2.87 (s,
3H), 1.10 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 181.2
(C), 170.8 (C), 164.7 (C), 157.6 (C), 147.3 (C), 143.0 (CH), 139.4
(C), 138.1 (C), 136.9 (C), 135.7 (CH), 129.4 (CH), 129.1 (CH),
128.7 (CH × 2), 128.2 (CH × 2), 128.0 (CH), 127.5 (CH), 127.4
(CH), 126.8 (CH), 126.7 (C), 126.2 (CH), 125.7 (C), 123.3 (CH),
120.9 (CH), 115.3 (CH), 64.5 (C), 62.3 (CH), 60.7 (CH2), 60.1
(CH), 27.0 (CH3), 14.2 (CH3); IR νmax = 1750, 1713, 1600, 1464,
1371, 1266, 1171, 1099, 1015, 737, 701 cm−1; HRMS (ESI) calcd for
C32H25N2O4 [M − H]− 501.1814, found 501.1833.
Ethyl 1′-acetyl-5-isopropyl-2′-oxo-2-phenylspiro[cyclopent[3]-
ene-1,3′-indoline]-3-carboxylate (4e): 68% yield, dr > 95/5; Rf 0.36
1
(15% EtOAc/heptanes); H NMR (500 MHz, CDCl3) δ 7.91 (d, J =
8.7 Hz, 1H), 7.10−6.88 (m, 7H), 6.82−6.74 (m, 2H), 4.82 (t, J = 2.7
Hz, 1H), 4.2−4.0 (m, 2H), 3.54 (dd, J = 9.6, 2.4 Hz, 1H), 2.71 (s,
3H), 1.37 (dd, J = 14.5, 9.6 Hz, 1H), 1.06 (t, J = 6.9 Hz, 3H), 0.84 (s,
9H), 0.71 (dd, J = 14.5, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
180.4 (C), 170.7 (C), 164.8 (C), 147.9 (CH), 139.6 (C), 136.7 (C),
135.9 (C), 128.5 (CH), 128.0 (CH), 127.7 (CH), 127.0 (CH), 126.5
(C), 125.8 (CH), 123.9 (CH), 116.1 (CH), 67.0 (C), 60.8 (CH), 60.6
(CH2), 49.0 (CH), 43.9 (CH2), 30.8 (C), 29.5 (CH3), 26.9 (CH3),
14.1 (CH3); IR νmax = 1750, 1712, 1464, 1370, 1287, 1273, 1233,
1173, 1159, 1116, 1017, 911, 758, 730, 700 cm−1; HRMS (ESI) calcd
for C28H30NO4 [M − H]− 444.2175, found 444.2194.
Ethyl 1′-acetyl-5-(cyclopentylmethyl)-2′-oxo-2-phenylspiro-
[cyclopent[3]ene-1,3′-indoline]-3-carboxylate (4f): 55% yield, dr =
95/5; Rf 0.36 (15% EtOAc/heptanes); 1H NMR (500 MHz, CDCl3) δ
7.97 (d, J = 8.1 Hz, 1H), 7.14−7.06 (m, 2H), 7.05−6.98 (m, 3H),
6.95−6.85 (m, 2H), 6.83−6.75 (m, 2H), 4.79 (t, J = 2.7 Hz, 1H),
4.20−4.00 (m, 2H), 3.55−3.45 (m, 1H), 2.72 (s, 3H), 1.80−1.70 (m,
1H), 1.65−1.40 (m, 8H), 1.08 (t, J = 6.9 Hz, 3H), 0.95−0.85 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 181.0 (C), 170.8 (C), 164.6 (C), 146.5
(CH), 139.7 (C), 137.0 (C), 135.8 (C), 128.4 (CH), 128.1 (CH × 2),
127.8 (CH × 2), 127.1 (CH), 126.3 (CH), 126.1 (C), 123.7 (CH),
116.0 (CH), 64.6 (C), 61.1 (CH), 60.6 (CH2), 52.4 (CH), 38.2 (CH),
36.8 (CH2), 33.0 (CH2), 32.6 (CH2), 27.0 (CH3), 25.3 (CH2), 25.0
(CH2), 14.1 (CH3); IR νmax = 1749, 1711, 1464, 1371, 1309, 1270,
1171, 1111, 1014, 910, 758, 728, 700 cm−1; HRMS (ESI) calcd for
C29H30NO4 [M − H]− 456.2175, found 456.2194.
Ethyl 1′-acetyl-5-(3-methoxy-3-oxopropyl)-2′-oxo-2-phenyl-
spiro[cyclopent[3]ene-1,3′-indoline]-3-carboxylate (4g): 51% yield,
1
dr = 95/5; Rf 0.20 (25% EtOAc/heptanes); H NMR (500 MHz,
CDCl3) δ 7.98 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.06−6.98
(m, 4H), 6.89 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 6.8 Hz, 1H), 6.82−6.75
(m, 2H), 4.79 (t, J = 2.5 Hz, 1H), 4.20−4.05 (m, 2H), 3.61 (s, 3H),
3.45 (t, J = 8.0 Hz, 1H), 2.73 (s, 3H), 2.20−2.00 (m, 2H), 1.90−1.80
(m, 1H), 1.55−1.45 (m, 1H), 1.08 (t, J = 7.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 180.7 (C), 172.9 (C), 170.7 (C), 164.4 (C), 144.8
(CH), 139.7 (C), 136.8 (C), 136.6 (C), 128.8 (CH), 128.1 (CH × 2),
127.9 (CH × 2), 127.2 (CH), 126.2 (CH), 125.5 (C), 124.0 (CH),
116.2 (CH), 64.1 (C), 61.2 (CH), 60.7 (CH2), 52.5 (CH3), 51.9
(CH), 32.0 (CH2), 26.9 (CH3), 25.7 (CH2), 14.1 (CH3); IR νmax
=
1738, 1713, 14643, 1371, 1339, 1269, 1172, 1116, 912, 759, 730, 702
cm−1; HRMS (ESI) calcd for C27H26NO6 [M − H]− 460.1760, found
460.1783.
Benzyl 1′-acetyl-2′-oxo-2-phenyl-5-propylspiro[cyclopent[3]ene-
1,3′-indoline]-3-carboxylate (5): 67% yield, dr = 95/5; Rf 0.30 (15%
EtOAc/heptanes); 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz,
1H), 7.28−7.20 (m, 3H), 7.15−6.96 (m, 7H), 6.94−6.75 (m, 4H),
5.17 (d, J = 12.3 Hz, 1H), 5.02 (d, J = 12.3 Hz, 1H), 4.85 (t, J = 2.7
Hz, 1H), 3.50−3.40 (m, 1H), 2.74 (s, 3H), 1.50−1.25 (m, 2H), 1.20−
1.00 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
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Ethyl 1′-acetyl-2′-oxo-2-pentyl-5-phenylspiro[cyclopent[3]ene-
1,3′-indoline]-3-carboxylate (7d): 49% yield, dr > 95:5; Rf 0.32
(C), 129.2 (CH), 128.2 (CH), 127.5 (CH), 126.4 (CH), 126.1 (CH),
124.6 (C), 124.2 (CH), 116.9 (CH), 66.7 (C), 60.8 (CH2), 60.2
(CH), 49.1 (CH), 43.9 (CH2), 30.9 (C), 29.5 (CH3 × 3), 26.8 (CH3),
14.1 (CH3); IR νmax = 2957, 1753, 1713, 1600, 1573, 1474, 1421,
1370, 1336, 1283, 1257, 1232, 1198 1162, 1121, 1081, 1020, 930, 733
cm−1; HRMS (ESI) calcd for C28H29Cl2NNaO4 [M + Na]+ 536.1371,
found 536.1349.
1
(20% EtOAc/heptanes); H NMR (300 MHz, CDCl3) δ 7.93 (d, J =
8.1 Hz, 1H), 7.12−7.00 (m, 5H), 6.96 (t, J = 2.4 Hz, 1H), 6.93 (d, J =
7.2 Hz, 1H), 6.90−6.82 (m, 2H), 4.65 (t, J = 2.8 Hz, 1H), 4.40−4.20
(m, 2H), 3.74 (dq, J = 11.7, 3.0 Hz, 1H), 2.74 (s, 3H), 2.20−2.05 (m,
1H), 1.37 (t, J = 7.2 Hz, 3H), 1.30−1.22 (m, 1H), 1.10−0.85 (m, 5H),
0.64 (t, J = 6.6 Hz, 3H), 0.60−0.48 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 181.2 (C), 170.7 (C), 164.8 (C), 142.2 (CH), 139.6 (C),
139.5 (C), 136.5 (C), 128.5 (CH), 128.2 (CH × 2), 128.0 (CH × 2),
127.5 (CH), 126.0 (C), 125.6 (CH), 123.8 (CH), 116.1 (CH), 65.0
(C), 60.83 (CH2), 60.78 (CH), 53.5 (CH), 31.2 (CH2), 28.2 (CH2),
27.0 (CH3), 26.5 (CH2), 22.0 (CH2), 14.4 (CH3), 13.8 (CH3); IR νmax
= 2956, 2929, 2858, 1750, 1713, 1464, 1371, 1285, 1197, 1168, 1095,
1014, 755, 700 cm−1; HRMS (ESI) calcd for C28H32NO4 [M + H]+
446.2331, found 446.2316.
Ethyl 1′-acetyl-5′-methoxy-2′-oxo-2,5-diphenylspiro-
[cyclopent[3]ene-1,3′-indoline]-3-carboxylate (8a): 95% yield, dr >
95:5; Rf 0.15 (25% EtOAc/heptanes); 1H NMR (500 MHz, CDCl3) δ
7.82 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.20−7.08 (m, 3H), 7.07−7.02
(m, 3H), 6.94 (d, J = 6.5 Hz, 2H), 6.84 (d, J = 6.5 Hz, 2H), 6.42 (dd, J
= 8.5, 2.0 Hz, 1H), 5.37 (d, J = 2.0 Hz, 1H), 4.85 (s, 1H), 4.73 (s, 1H),
4.25−4.10 (m, 2H), 3.15 (s, 3H), 2.77 (s, 3H), 1.14 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 181.6 (C), 170.5 (C), 164.2 (C),
155.4 (C), 143.9 (CH), 138.4 (C), 137.6 (C), 137.3 (C), 133.1 (C),
128.6 (CH × 2), 128.3 (CH × 4), 128.0 (CH × 2), 127.6 (CH), 127.2
(CH), 127.1 (C), 116.3 (CH), 114.2 (CH), 112.4 (CH), 64.4 (C),
60.9 (CH2), 60.1 (CH), 59.1 (CH), 55.2 (CH3), 26.9 (CH3), 14.1
(CH3); IR νmax = 1750, 1711, 1485, 1453, 1372, 1269, 1207, 1177,
1098, 1018, 700 cm−1; HRMS (ESI) calcd for C30H26NO5 [M − H]−
480.1811, found 480.1826.
Ethyl 1′-acetyl-2′-oxo-2-(3-chloro-2-fluorophenyl)-5-
neopentylspiro[cyclopent[3]ene-6′-chloro-3′indoline]-3-carboxy-
late (10-A): 248 mg, 93%, white solid; mp 119−121 °C; Rf 0.45 (15%
1
EtOAc/heptanes); H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.08
(td, J = 7.5, 1.7 Hz, 1H), 7.04−7.00 (m, 1H), 6.95−6.89 (m, 2H), 6.78
(t, J = 8.0 Hz, 1H), 6.69 (td, J = 7.0, 1.5 Hz, 1H), 5.03 (bs, 1H), 4.20−
4.05 (m, 2H), 3.57 (dd, J = 9.8, 2.4 Hz, 1H), 2.71 (s, 3H), 1.32 (dd, J
= 14.5, 9.8 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 0.84 (s, 9H), 0.66 (dd, J
= 14.5, 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 179.6 (C), 170.6
(C), 164.2 (C), 157.7 (C), 154.4 (C), 148.1 (CH), 140.6 (C), 134.6
(C), 129.7 (CH), 128.1 (d, J = 3.3 Hz, CH), 126.2 (CH), 126.0 (C),
124.7 (C), 124.1 (CH), 123.8 (CH), 116.9 (CH), 65.3 (C), 60.9
(CH2), 53.8 (CH), 49.2 (CH), 44.0 (CH2), 30.9 (C), 29.5 (CH3 × 3),
26.6 (CH3), 14.1 (CH3); IR νmax = 2964, 1760, 1712, 1640, 1602,
1473, 1456, 1367, 1338, 1279, 1265, 1252, 1160, 1116, 1020, 930, 772,
759 cm−1; HRMS (ESI) calcd for C28H27Cl2FNO4 [M − H]−
530.1301, found 530.1299.
Ethyl 1′-acetyl-2′oxo-2-(3-chloro-2-fluorophenyl)-5-
neopentylspiro[cyclopent[3]ene-6′-chloro-3′-indoline]-3-carboxy-
late (10-B and 10-C). A solution of ethyl 5-tert-butylpenta-2,3-
dienoate (3e) (137 mg, 0.75 mmol) in toluene (1.5 mL) was added
under argon to a solution of the (E)-arylideneoxindole 1b (175 mg,
0.5 mmol) and dimethylphenylphosphine (0.1 mmol) in toluene (1
mL). The solution was stirred for 24 h at room temperature. The
crude mixture was concentrated in vacuo and purified by flash
chromatography on silica gel (10% EtOAc/heptanes) to furnish a
mixture of 10-A, 10-B, and 10-C (210 mg, 80%, white powder). Pure
isomers have been obtained from this mixture by HPLC separation
(heptane/EtOAc 0−15% gradient).
Ethyl 1′-acetyl-6′-chloro-2′-oxo-2,5-diphenylspiro[cyclopent[3]-
ene-1,3′-indoline]-3-carboxylate (8b): 82% yield, dr > 95:5; Rf 0.29
1
(25% EtOAc/heptanes); H NMR (500 MHz, CDCl3) δ 7.90 (d, J =
2.1 Hz, 1H), 7.31 (t, J = 2.4 Hz, 1H), 7.16−7.08 (m, 3H), 7.08−7.01
(m, 3H), 6.98−6.90 (m, 2H), 6.88−6.80 (m, 2H), 6.50 (dd, J = 8.4,
2.1 Hz, 1H), 6.14 (d, J = 8.4 Hz, 1H), 4.92 (t, J = 2.4 Hz, 1H), 4.80 (t,
J = 2.4 Hz, 1H), 4.25−4.10 (m, 2H), 2.79 (s, 3H), 1.13 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 180.9 (C), 170.5 (C), 164.2 (C),
143.7 (CH), 140.1 (C), 138.3 (C), 136.9 (C), 136.8 (C), 133.8
(C),128.6 (CH × 2), 128.2 (CH × 2), 128.1 (CH × 2), 128.0 (CH ×
2), 127.8 (CH), 127.7 (CH), 127.4 (CH), 124.4 (C), 123.5 (CH),
116.1 (CH), 65.3 (C), 60.9 (CH2), 60.6 (CH), 59.1 (CH), 26.9
(CH3), 14.1 (CH3); IR νmax = 1754, 1715, 1602, 1474, 1421, 1372,
1335, 1282, 1236, 1169, 1100, 931, 737, 701 cm−1; HRMS (ESI) calcd
for C29H23ClNO4 [M − H]− 484.1316, found 484.1331.
1
Compound 10-B: H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H),
7.30 (t, J = 7.1 Hz, 1H), 7.23−7.20 (m, 1H), 7.11 (t, J = 7.7 Hz, 1H),
7.08−7.02 (m, 1H), 6.80 (d, J = 7.7 Hz, 1H), 5.83 (d, J = 7.7 Hz, 1H),
4.69 (br s, 1H), 4.20−4.10 (m, 2H), 3.17 (d, J = 9.7 Hz, 1H), 2.71 (s,
3H), 1.62 (dd, J = 13.8, 10.4 Hz, 1H), 1.19 (t, J = 7.2 Hz, 3H), 0.77 (s,
9H), 0.75−0.70 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.5 (C),
170.8 (C), 163.5 (C), 157.4(C), 155.4 (C), 148.3 (CH), 141.4 (C),
134.9 (C), 134.8 (C), 130.3 (CH), 125.9 (CH), 125.0 (C), 124.6 (CH
× 2), 124.3 (CH), 122.0 (d, J = 11.0 Hz, C), 116.9 (CH), 62.6 (C),
61.0 (CH2), 50.6 (CH), 50.0 (CH), 41.4 (CH2), 29.9 (C), 29.4 (CH3
× 3), 26.9 (CH3), 14.3 (CH3); IR νmax = 2956, 1756, 1713, 1602,
1458, 1421, 1371, 1336, 1282, 1257, 1242, 1202, 1161, 1112, 1078,
1026, 930, 735 cm−1; HRMS (ESI) calcd for C28H27Cl2FNO4 [M −
H]−: 530.1301, found 530.1304.
Ethyl 1′-acetyl-6′-methyl-2′-oxo-2,5-diphenylspiro[cyclopent[3]-
ene-1,3′-indoline]-3-carboxylate (8c): 87% yield, dr = 90:10; Rf
1
0.28 (15% EtOAc/heptanes); H NMR (500 MHz, CDCl3) δ 7.59
(bs, 1H), 7.28−7.22 (m, 1H), 7.05−6.98 (m, 3H), 6.97−6.90 (m, 3H),
6.88−6.82 (m, 2H), 6.80−6.70 (m, 2H), 6.26 (d, J = 7.5 Hz, 1H), 6.05
(d, J = 7.8 Hz, 1H), 4.82 (bs, 1H), 4.71 (bs, 1H), 4.15−4.00 (m, 2H),
2.70 (s, 3H), 2.00 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 181.7 (C), 170.7 (C), 164.4 (C), 144.0 (CH), 139.4
(C), 138.3 (C), 138.1 (C), 137.3 (C), 137.2 (C), 128.4 (CH × 2),
128.3 (CH × 2), 128.2 (CH × 2), 127.9 (CH × 2), 127.4 (CH), 127.1
(CH), 126.6 (CH), 124.1 (CH), 122.7 (C), 116.1 (CH), 65.6 (C),
60.8 (CH2), 60.6 (CH), 59.1 (CH), 27.1 (CH3), 21.8 (CH3), 14.1
(CH3); IR νmax = 1748, 1713, 1371, 1287, 1266, 1177, 1100, 737, 702
cm−1; HRMS (ESI) calcd for C30H26NO4 [M − H]− 464.1862, found
464.1872.
1
Compound 10-C: H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 1.8
Hz, 1H), 7.31 (td, J = 8.1, 1.8 Hz, 1H), 7.28−7.20 (m, 2H), 7.15 (dd, J
= 8.1, 1.8 Hz, 1H), 7.15−7.07 (m, 1H), 7.02−6.95 (m, 1H), 4.51 (bs,
1H), 4.22−4.05 (m, 2H), 3.46 (d, J = 9.4 Hz, 1H), 2.44 (s, 3H), 1.32−
1.22 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 0.82 (s, 9H), 0.62 (d, J = 12.2
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.4 (C), 170.7 (C), 163.4
(C), 156.8 (C), 154.7 (C), 150.1 (CH), 140.0 (C), 134.8 (C), 134.5
(C), 130.1 (CH), 129.6 (C), 126.6 (CH), 125.6 (CH), 124.7 (d, J =
4.3 Hz, CH), 123.4 (CH), 117.3 (CH), 63.6 (C), 61.1 (CH2), 54.2
(CH), 48.4 (CH), 42.7 (CH2), 30.9 (C), 29.5 (CH3 × 3), 26.3 (CH3),
14.2 (CH3); IR νmax = 2953, 1763, 1708, 1628, 1601, 1457, 1421,
1371, 1337, 1286, 1263, 1227, 1208, 1160, 1106, 1059, 1023, 928, 768
cm−1; HRMS (ESI) calcd for C28H27Cl2FNO4 [M − H]− 530.1301,
found 530.1317.
Ethyl 1′-acetyl-2′-oxo-2-(3-chlorophenyl)-5-neopentylspiro-
[cyclopent[3]ene-6′-chloro-3′-indoline]-3-carboxylate (9): 71%
1
yield, dr > 95:5; H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.02
(t, J = 2.3 Hz, 1H), 7.00−6.90 (m, 4H), 6.78 (t, J = 1.9 Hz, 1H), 6.65
(d, J = 7.6 Hz, 1H), 4.77 (t, J = 2.4 Hz, 1H), 4.20−4.03 (m, 2H), 3.52
(ddd, J = 9.7, 5.2, 2.4 Hz, 1H), 2.70 (s, 3H), 1.33 (dd, J = 14.4, 9.7 Hz,
1H), 1.09 (t, J = 7.1 Hz, 3H), 0.84 (s, 9H), 0.66 (dd, J = 14.4, 2.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 179.7 (C), 170.3 (C), 164.3
(C), 148.3 (CH), 140.4 (C), 138.7 (C), 135.2 (C), 134.5 (C), 133.9
Compound 10-D:12 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H),
7.43 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.24−7.18 (m, 1H),
7.08 (bs, 1H), 6.98−6.90 (m, 2H), 4.84 (bs, 1H), 4.18−4.05 (m, 2H),
3.33 (dt, J = 8.5 Hz, 1H), 2.27 (s, 3H), 1.68 (dd, J = 13.8, 10.0 Hz,
1H), 1.12 (t, J = 7.1 Hz, 3H), 0.92−0.87 (m, 1H), 0.82 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 175.5 (C), 170.4 (C), 163.9 (C), 157.3
1494
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Article
(C), 155.4 (C), 147.8 (CH), 140.7 (C), 134.9 (C), 129.9 (CH), 128.8
(C), 127.9 (C), 125.9 (CH), 125.7 (d, J = 8.3 Hz, C), 123.9 (CH),
123.8 (CH), 123.4 (CH), 116.9 (CH), 65.4 (C), 60.8 (CH2), 55.3
(CH), 50.3 (CH), 42.8 (CH2), 30.9 (C), 29.5 (CH3 × 3), 26.3 (CH3),
14.2 (CH3); IR νmax = 2955, 1755, 1716, 1634, 1601, 1473, 1458,
1421, 1371, 1337, 1279, 1256, 1225, 1200, 1158, 1118, 1075, 1024,
930, 778 cm−1; HRMS (ESI) calcd for C28H27Cl2FNO4 [M − H]−
530.1301, found 530.1300.
NMR (75 MHz, CDCl3) δ 180.6 (C), 164.1 (C), 157.9 (C), 154.7
(C), 141.9 (C), 136.9 (C), 134.2 (C), 129.9 (CH), 129.1 (d, J = 3.5
Hz, CH), 127.2 (CH), 126.0 (d, J = 13.9 Hz, C), 125.8 (C), 124.0 (d, J
= 4.9 Hz, CH), 121.4 (CH), 121.1 (d, J = 18.8 Hz, C), 110.5 (CH),
66.9 (CH2 × 2), 56.5 (CH2), 53.1 (2 × CH2, C), 51.9 (CH), 48.3
(CH), 44.0 (CH2), 35.4 (CH2), 30.8 (C), 29.5 (CH3 × 3); IR νmax
=
2957, 1721, 1654, 1614, 1516, 1484, 1457, 1367, 1327, 1238, 1143,
1118, 1070, 924, 750 cm−1; HRMS (ESI) calcd for C30H35Cl2FN3O3
[M + H]+ 574.2040, found 574.2057.
Ethyl 2′-Oxo-2-(3-chloro-2-fluorophenyl)-5-neopentylspiro-
[cyclopentane-6′-chloro-3′-indoline]-3-carboxylate (13). Com-
pound 10-A (121 mg, 0.23 mmol) was hydrogenated over Pd/C
(10%, 12 mg) in 11 mL of MeOH at room temperature for 5 h. The
resulting mixture was filtered on Celite and washed with methanol
twice. The filtrate was concentrated under reduced pressure and
purified by column chromatography on silica gel (0−10% EtOAc/
heptanes), affording compound 13 (36 mg, 30%, white powder, mp
N-2-Morpholinoethyl 2′-Oxo-2-(3-chloro-2-fluorophenyl)-5-
neopentylspiro[cyclopent[3]ene-6′-chloro-3′-indoline]-3-carboxa-
mide (12-B). Compound 12-B was obtained from 10-B (45 mg, 0.08
mmol) by the same procedure as for 14 (30 mg, 62% yield): Rf 0.21
1
(5% MeOH/CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H),
7.32 (td, J = 7.3, 1.7 Hz, 1H), 7.21−7.08 (m, 3H), 6.88 (d, J = 1.6 Hz,
1H), 6.61 (dd, J = 8.0, 1.6 Hz, 1H), 6.28 (bs, 1H), 5.73 (d, J = 8.0 Hz,
1H), 4.62 (bs, 1H), 3.57−3.39 (m, 4H), 3.37−3.20 (m, 2H), 3.13 (d, J
= 9.5 Hz, 1H), 2.48−2.38 (m, 1H), 2.37−2.26 (m, 3H), 2.22−2.12 (m,
2H), 1.66 (dd, J = 13.9, 10.3 Hz, 1H), 0.83−0.76 (m, 1H), 0.76 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 180.0 (C), 163.2 (C), 158.1 (C),
154.8 (C), 144.9 (CH), 142.6 (C), 136.9 (C), 134.4 (C), 130.3 (CH),
126.7 (CH), 126.4 (C), 124.9 (CH), 124.8 (d, J = 4.7 Hz, CH), 121.9
(d, J = 18.0 Hz, C), 121.8 (CH), 110.4 (CH), 66.9 (CH2 × 2), 62.9
(C), 56.5 (CH2), 53.2 (CH2 × 2), 49.3 (CH), 48.8 (CH), 41.5 (CH2),
35.6 (CH2), 30.7 (C), 29.5 (CH3 × 3); IR νmax = 2955, 1714, 1653,
1615, 1514, 1486, 1457, 1366, 1329, 1235, 1141, 1117, 1069, 914, 730
cm−1; HRMS (ESI) calcd for C30H35Cl2FN3O3 [M + H]+ 574.2040,
found 574.2047.
1
188−190 °C): Rf 0.27 (15% EtOAc/heptanes); H NMR (300 MHz,
CDCl3) δ 8.29 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.13−7.05 (m, 2H),
6.84 (d, J = 1.9 Hz, 1H), 6.62 (td, J = 8.0, 1.1 Hz, 1H), 6.45 (td, J =
6.5, 1.5 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 3.87−3.79 (m, 1H), 3.72−
3.59 (m, 2H), 2.61−2.49 (m, 3H), 0.93−0.87 (m, 1H), 0.81 (t, J = 6.9
Hz, 3H), 0.79 (s, 9H), 0.65 (d, J = 14.0, 1H); 13C NMR (75 MHz,
CDCl3) δ 180.1 (C), 174.2 (C), 155.0 (C), 142.1 (C), 134.2 (C),
129.3 (CH), 128.6 (CH), 127.2 (d, J = 2.6 Hz, CH), 126.8 (C), 126.2
(d, J = 13.2 Hz, C), 123.7 (d, J = 4.8 Hz, CH), 122.5 (CH), 120.9 (d, J
= 19.5 Hz, C), 110.7 (CH), 63.7 (C), 60.8 (CH2), 46.9 (CH), 46.7 (d,
J = 3.2 Hz, CH), 46.5 (CH), 44.1 (CH2), 36.8 (CH2), 30.4 (C), 29.9
(CH3 × 3), 13.7 (CH3); IR νmax = 2955, 1725, 1716, 1614, 1487, 1458,
1328, 1192, 1076, 916, 731 cm−1; HRMS (ESI) calcd for
C26H27Cl2FNO3 [M − H]−: 490.1352, found 490.1365.
N-2-Morpholinoethyl 2′-Oxo-2-(3-chloro-2-fluorophenyl)-5-
neopentylspiro[cyclo-pent[3]ene-6′-chloro-3′indoline]-3-carboxa-
mide (12-C). Compound 12-C was obtained from 10-C (86 mg, 0.16
mmol) by the same procedure as for 12-A (64 mg, 69% yield): Rf 0.38
N-2-Morpholinoethyl 2′-Oxo-2-(3-chloro-2-fluorophenyl)-5-
neopentylspiro[cyclopentane-6′-chloro-3′indoline]-3-carboxamide
(14). 4-(2-Aminoethyl)morpholine (53 μL, 0.41 mmol) was dissolved
in toluene (0.2 mL), and then a solution of trimethylaluminum 2 M
(0.4 mL, 0.81 mmol) was added dropwise at 0 °C. The mixture was
stirred for 30 min, and a solution of substrate 13 (31 mg, 0.06 mmol)
in toluene (0.3 mL) was added. After 22 h of stirring at 100 °C, the
solution was treated with citric acid 10% (10 mL) and extracted with
EtOAc (2 × 10 mL). The combined organic extracts were washed with
H2O (2 × 30 mL), dried over MgSO4, and concentrated under
reduced pressure. The crude mixture was purified by flash
chromatography on silica gel (0 to 2% MeOH/CH2Cl2) to give the
desired amide 14 (7 mg, 19%, white powder): Rf 0.31 (5% MeOH/
1
(5% MeOH/CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H),
7.45−7.35 (m, 1H), 7.27 (dd, J = 10.9, 2.3 Hz, 2H), 7.19−7.13 (m,
2H), 7.00 (dd, J = 8.0, 2.3 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H), 6.06 (bs,
1H), 4.49 (bs, 1H), 3.55−3.36 (m, 5H), 3.35−3.21 (m, 2H), 2.45−
2.36 (m, 1H), 2.34−2.21 (m, 3H), 2.19−2.09 (m, 2H), 1.25 (dd, J =
13.4, 9.3 Hz, 1H), 0.86 (s, 9H), 0.67 (d, J = 13.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 177.7 (C), 163.0 (C), 158.3 (C), 155.0 (C),
147.1 (CH), 141.5 (C), 136.9 (C), 134.2 (C), 130.3 (CH), 127.8
(CH), 125.2 (d, J = 14.4 Hz, C), 124.8 (d, J = 4.6 Hz, CH), 124.1
(CH), 122.5 (CH), 121.3 (d, J = 18.1 Hz, C), 110.9 (CH), 66.8 (CH2
× 2), 63.7 (C), 56.4 (CH2), 53.1 (CH2 × 2), 52.0 (CH), 47.6 (CH),
42.5 (CH2), 35.5 (CH2), 30.8 (C), 29.5 (CH3 × 3); IR νmax = 2956,
1721, 1650, 1614, 1513, 1485, 1457, 1366, 1321, 1272, 1233, 1142,
1116, 1069, 923, 735 cm−1; HRMS (ESI) calcd for C30H35Cl2FN3O3
[M + H]+ 574.2040, found 574.2044.
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.28 (s, 1H),
7.13 (td, J = 7.6, 1.8 Hz, 1H), 7.03 (dd, J = 8.0, 1.9 Hz, 1H), 6.85 (td, J
= 6.9, 1.8 Hz, 1H), 6.80−6.75 (m, 1H), 6.71 (d, J = 1.9 Hz, 1H), 5.88
(bs, 1H), 4.25 (d, J = 11.8 Hz, 1H), 3.66−3.59 (m, 1H), 3.56 (t, J =
4.6 Hz, 4H), 3.35- 3.18 (m, 2H), 2.96 (qd, J = 9.8, 1.8 Hz, 1H), 2.89−
2.78 (m, 1H), 2.36−2.19 (m, 6H), 2.17−2.07 (m, 1H), 0.91−0.86 (m,
1H), 0.82 (s, 9H), 0.72 (dd, J = 13.9, 1.8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 178.5 (C), 172.9 (C), 158.4 (C), 155.0 (C), 142.0
(C), 137.7 (C), 134.2 (C), 129.9 (CH), 128.2 (d, J = 3.3 Hz, CH),
126.7 (CH), 126.3 (C), 125.4 (d, J = 12.7 Hz, C), 124.2 (d, J = 3.9 Hz,
CH), 122.0 (CH), 110.6 (CH), 66.9 (CH2), 56.9 (CH2), 53.3 (CH2),
51.5 (CH), 48.8 (CH), 46.1 (CH2), 44.2 (CH), 36.5 (CH2), 35.8
(CH2), 30.7 (C), 30.0 (CH3); IR νmax = 2955, 2928, 2855, 1713, 1646,
1615, 1548, 1485, 1455, 1365, 1335, 1309, 1264, 1245, 1142, 1116,
1072, 916, 733 cm−1; HRMS (ESI) calcd for C30H37Cl2FN3O3 [M +
H]+ 576.2196, found 576.2191.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. X-ray crystal data for compounds 4a,
10-A, 13, 10-B, 10-C, and 10-D (CCDC deposit nos. 890163,
890164, 890165, 890166, 890167, and 891013). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: (A.M.) angela.marinetti@icsn.cnrs-gif.fr, (A.V.)
arnaud.voituriez@icsn.cnrs-gif.fr.
N-2-Morpholinoethyl 2′-Oxo-2-(3-chloro-2-fluorophenyl)-5-
neopentylspiro[cyclopent-[3]ene-6′-chloro-3′-indoline]-3-carboxa-
mide (12-A). Compound 12-A was prepared from 10-A (100 mg, 0.19
mmol) by following the same procedure as for 14. The crude mixture
was purified by flash chromatography on silica gel (1% MeOH/
CH2Cl2) to afford 12-A in 81% yield (89 mg): Rf 0.26 (5% MeOH/
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
■
CH2Cl2); H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 7.11 (td, J =
We thank Sanofi for a grant to C.G. and Carlos Garcia-
Echeverria for his kind support. The Cost actions ORCA
(CM0905) and PhoSciNet (CM0802) are warmly acknowl-
edged.
8.0, 1.9 Hz, 1H), 6.95−6.80 (m, 4H), 6.75−6.68 (m, 2H), 5.99 (bs,
1H), 5.02 (bs, 1H), 3.70−3.59 (m, 1H), 3.57−3.41 (m, 4H), 3.38−
3.20 (m, 2H), 2.38−2.24 (m, 3H), 2.11−1.95 (m, 3H), 1.29 (dd, J =
14.3, 9.8 Hz, 1H), 0.83 (s, 9H), 0.68 (dd, J = 14.3, 1.9 Hz, 1H); 13C
1495
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(13) (a) Dudding, T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8,
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(14) It is worth noting here that approximately the same product
distribution was observed in the crude reaction mixtures when either
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mechanism in Scheme 4, although isomerization of (Z)-1b into (E)-1b
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(10) The cis, trans stereochemical labels indicate the arrangements of
the two phenyl groups at C2 and C5, with respect to the carbonyl
group at the C1 position.
(11) The minor isomer, formed in <5% amount, has been tentatively
1
assigned as an isomer of the α-adduct 4a by H NMR analysis of the
mixture.
(12) A very small amount of the cis,cis isomer 10-D has been isolated
when the reaction was carried out at 80 °C in the presence of PMe2Ph.
X-ray data are given as Supporting Information.
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