Stereochemical implications in the synthesis of 3,3′-spirocyclopropyl oxindoles from β-aryl/alkyl-substituted alkylidene oxindoles

Article abstract of DOI:10.1016/j.tet.2015.06.004

3,3′-Spirocyclopropane oxindoles were synthesized in good to excellent yield and diastereoselectivity employing a Kukhtin-Ramirez reaction between readily accessible E-alkylidene oxindoles, commercially available P(NMe₂)₃, and α-keto

Full text of DOI:10.1016/j.tet.2015.06.004

Tetrahedron xxx (2015) 1e11
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereochemical implications in the synthesis of 3,30-spirocyclopropyl
oxindoles from
b
-aryl/alkyl-substituted alkylidene oxindoles
*
Erin E. Wilson, Kevin X. Rodriguez, Brandon L. Ashfeld
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
a r t i c l e i n f o
a b s t r a c t
3,30-Spirocyclopropane oxindoles were synthesized in good to excellent yield and diastereoselectivity
Article history:
Received 2 April 2015
Received in revised form 28 May 2015
Accepted 1 June 2015
Available online xxx
employing a KukhtineRamirez reaction between readily accessible E-alkylidene oxindoles, commercially
available P(NMe2)3, and a-keto esters. The stereoselectivity in the cyclopropanation event can be traced
to the starting alkylidene geometry and the propensity of the exocyclic alkene to undergo isomerization
in the presence of an electron rich phosphine.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
KukhtineRamirez reaction
Spirocyclopropyl oxindoles
Dioxaphospholenes
Redox condensations
Oxindole natural products
1. Introduction
The spirooxindole framework has remained a synthetically
challenging and privileged architectural motif that is prevalent in
many pharmaceuticals and bioactive natural products.1 In partic-
ular, the 3,30-spirocyclopropyl oxindole core has recently generated
considerable synthetic interest as an intriguing pharmacophore in
medicinal discovery chemistry.2 Additionally, this spirooxindole
core is a versatile synthetic intermediate toward the 3,30-spi-
ropyrrolidinyl oxindole ring system, a prevalent substructure in
numerous naturally occurring alkaloids (Fig. 1).3 For example, the
spirocyclopropyl oxindole motif has been implemented in the ac-
tivity of NNRT HIV-1 and polo-like kinase inhibitors (Fig. 1).2c,d,4
Furthermore, Carreira has elegantly demonstrated how Lewis-
acid assisted ring openings of 3,30-spirocyclopropyl oxindoles
provide the corresponding spiropyrrolidinyl oxindole core in
horsfiline and spirotryprostatin,5 which displayed an array of bi-
ological activities, such as anticancer and anti-migraine properties
as well as contraceptive activity.5,6
Fig. 1. Biologically active 3,30-spirooxindoles.
cyclopropane could be installed via a reductive condensation of an
a
-keto ester, with the third carbon unit coming from a readily
available alkylidene oxindole (Fig. 2a). Recently, the Kukh-
tineRamirez reaction of a trivalent phosphorus reagent to an
keto ester has experienced a renaissance due to the inherent ad-
vantages of generating an intermediate dioxaphospholene 2b in
equilibrium with its more reactive zwitterionic form 2a that ex-
hibits ambiphilic reactivity under exceptionally mild reaction
conditions.7 We speculated that the soft anionic reactivity of this
a
-
Due to the stereochemically dense framework of the spi-
rocyclopropyl oxindoles, which contain at least one quaternary
stereogenic center, combined with the potential for discovering
new biologically active small molecules, we became interested in
developing an efficient route toward this bicyclic motif. We envi-
sioned that the two-carbon component necessary to form the
dioxaphospholene would add selectively to the b-position of an
alkylidene oxindole 1 that would then set the stage for an intra-
molecular displacement of phosphine oxide via C-4 to form the
desired cyclopropane 5.8 Ultimately, the carbene-like reactivity of
phospholene 2 enables the ketone precursor to serve as a diazo
surrogate in this formal [2þ1] cycloaddition.2a,9 Recently, He and
* Corresponding author. E-mail address: bashfeld@nd.edu (B.L. Ashfeld).
http://dx.doi.org/10.1016/j.tet.2015.06.004
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
by NOE experiments. The X-ray crystal structure of 5a revealed that
the proton at C4 on the benzenoid ring of the spirooxindole was
ꢀ
a mere 3.291 A from the center of the phenyl ring originating from
1a. This proximity results in a distinct shielding of the nucleus and
a marked upfield shift in the 1H NMR (5.71 ppm) that is in contrast to
the comparable proton in 6a (6.93 ppm).18 While the corresponding
N-Boc protected alkylidene oxindole 3b underwent cyclo-
propanation in comparable yield, the ratio of spirooxindoles 5b/6b
improved to 8:1. Other phosphorus reagents (e.g., PPh3, P(OMe)3,
etc.) exhibited poor reactivity leading to little cyclopropane forma-
tion (<5%). An examination of P(NMe2)3 stoichiometry revealed that
employing a slight excess of phosphine and a-keto ester (1.1 equiv)
resulted in incomplete conversion of the alkylidene oxindole.
However, using 1.5 equiv resulted in 100% conversion of the starting
material. It is important to note that conducting the reaction at
ambient temperatures led to a significant decrease in the yield of 5.
After careful examination, we discovered that this loss in yield was
due to the formation of cis/trans epoxides 9 (Eq. 2).19 Minimization of
this undesired by product was achieved by the addition of P(NMe2)3
to 1a and 3a at ꢀ78 ꢁC before allowing the mixture to warm. Pre-
sumably, by keeping the reaction temperature low, the addition of 2
to 1a is mitigated.9c
Fig. 2. KukhtineRamirez condensation of alkylidene oxindoles.
co-workers demonstrated the utility of this approach toward
alkylidene oxindoles bearing an electron withdrawing ketone at
the
b-position to provide the anti spriocyclopropane selectively
(Fig. 2b).10,11 We speculated that the absence of an electron with-
drawing carbonyl group on the alkylidene would lead to conjugate
addition of 2 to initially generate the tertiary cyclopropane ster-
eocenter and subsequent oxindole spirocyclization. In contrast to
He’s proposal wherein the addition of 2 occurs at C3 of the oxindole
ring, this mechanistic divergence should provide the syn spi-
rocyclopropyl oxindole 5 preferentially. Additionally, this structural
modification would also provide greater substrate flexibility for
enhanced product diversity. Herein, we describe the successful
application of this approach employing
b-alkyl and b-aryl
substituted alkylidene oxindoles to provide the corresponding syn-
spirocyclopropyl oxindoles and mechanistic insights into the ste-
reochemical outcome of CeC bond formation.
2. Results and discussion
In his seminal work nearly 50 years ago on dioxaphospholene
synthesis, Ramirez discovered that more sterically hindered phos-
phines exhibited greater nucleophilicity.7a,12 Consequently, he sur-
mised that this was due to a prevalence of the zwitterionic species 2a
over the more stable heterocyclic form 2b.13 These findings have
since provided a basis for recent work by our group14 and those of
others,15 in particular the elegant work by Radosevich and co-
With optimal conditions in hand, we turned our attention to-
ward evaluating the substitution pattern and functional group tol-
erance within alkylidene oxindole 3. In general, a variety of aryl- and
alkyl-substituted alkylidene oxindoles 3 provided high yields of the
workers on the
a-acetoxylation and
a-amination of
a
-keto
corresponding spirocyclopropyl oxindoles 5 (Table 1). While
esters.2a,9c,16 Therefore, our initial foray into the synthesis of 3,30-
spirocyclopropyl oxindoles began by examining the efficacy of
hexamethylphosphorus triamine (P(NMe2)3) to mediate the cyclo-
propanation of alkylidene oxindoles. Thus, treatment of methyl-
benzoyl formate 1a and (E)-o-bromophenylalkylidene N-
methyloxindole 3a with P(NMe2)3 in CH2Cl2 at ꢀ78 ꢁC to room
temperature for 3 h afforded the highly substituted spirocyclopropyl
oxindole 5a in quantitative yield and in a 2.6:1 ratio to 6a. In-
terestingly, stereoisomers 7a/8a were not observed.17 The major
diastereomer 5a was unambiguously identified by single crystal X-
ray diffraction while the relative configuration of 6a was determined
phenyl-substituted alkylidene 3c provided the corresponding
oxindole 5c in highyield, a third diastereomer 7c was now formed in
the cyclopropanation reaction with 1a (entry 1).20 The diaster-
eoselectivity for the major diastereomer 5c was comparable to what
we observed in the formation of 5a albeit with less facial selectivity
for the dioxaphospolene upon initial alkylidene addition. Electron
rich aryl alkylidene 3d and electron poor substrates 3e and 3f
bearing electron donating and electron withdrawing groups at the
para positions, respectively, proceeded in high yields and compa-
rable diastereoselectivities (entries 2e4). Likewise, an ortho-CF3
substituent on aryl alkylidene 3g underwent cyclopropanation to
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E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
3
Table 1
and diastereoselectivity of cyclopropanations with
when mediated by a bulky electron rich phosphine.
a
-keto esters
Alkylidene oxindole structural variabilitya
To explore how oxindole substitution can impact the efficiency
of the cyclopropanation event, we chose to evaluate the perfor-
mance of oxindole 3a derivatives under our standard reaction
Table 2
Examination of 1,2-dicarbonyls 1 with alkylidenes 3a
Entry
1
R
Major product 5b
Yieldc
94%
5:6:7d
5:1:1.5
Entry
1
1
3
Major product 5b
Yieldc
91%
5:6:7d
2
ꢂ99%
6:1:2
1a
3j:
2:1:0
R¼Me
PG¼Me
3
4
5
91%
80%
98%
5:1:2
5:1:2
4:1:0
2
3
4
5
1a
1a
1a
1a
3k:
94%
ꢂ99%
ꢂ99%
85%
4:1:0
4:1:0
6:1:0
3:1:0
R¼OMe
PG¼Me
3l:
R¼Br
PG¼Me
6
7
21%
76%
2:1:0
3m:
R¼H
PG¼Bn
ꢂ98:1
3n:
R¼H
PG¼Ts
a
Reaction conditions: 0.15 mmol of 3, 0.23 mmol of P(NMe2)3, and 0.23 mmol of
1a in CH2Cl2 (0.25 M).
b
Major isomer isolated.
c
Combined yield of diastereomers.
d
Diastereomeric ratio determined by 1H NMR (500 MHz) of the crude reaction
mixture.
6
7
1b
1c
3a
3a
ꢂ99%
3:1:1
3:1:1
provide 5g in 98% yield and as a 4:1:0 ratio of diastereomers (entry
5). However, in contrast to the oxindoles 3a and 3g, alkylidene 3h
bearing a methyl group at the ortho position underwent cyclo-
propanation in relativelylow yield to provide adduct 5h as the major
diastereomer in a 2:1:0 diastereomeric ratio (entry 6). This result
would indicate that while ortho substitution may inhibit the con-
jugate addition of the dioxaphospholene from 1a, the steric hin-
drance is mitigated by the presence of an electron withdrawing
group. Interestingly, in contrast to the aryl alkylidene oxindoles,
cyclohexyl alkylidene oxindole 3i underwent smooth conversion to
the spirocyclopropyl oxindole 5i in 76% yield as a single diastereomer
(entry 7). These results underscore the impact that subtle stereo-
electronic effects within alkylidene oxindole 3 can have on the yield
65%
a
Reaction conditions: 0.15 mmol of 3, 0.23 mmol of P(NMe2)3, and 0.23 mmol of 1
in CH2Cl2 (0.25 M).
b
Major isomer isolated.
c
Combined yield of diastereomers.
d
Diastereomeric ratio determined by 1H NMR (500 MHz) of the crude reaction
mixture.
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4
E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
Table 3
conditions (Table 2). In general, C5-substituted alkylidene oxin-
doles 3jel underwent cyclopropanation with 1a and P(NMe2)3 in
good to excellent yields and proceeded with comparable diaster-
eoselectivity from what we observed with 3a (entries 1e3). The
reaction conditions also tolerated a variety of N-substituted oxin-
doles. Both N-benzyl and N-tosyl protected oxindoles 3m and 3n
were efficiently converted to the corresponding spirocyclopropyl
oxindoles 5m and 5n in 85% and quantitative yields and with better
diastereoselectivity than 3a, respectively (entries 4 and 5). Not
surprisingly, substitution of the oxindole nitrogen proved critical,
as we observed no product formation in cases where the free NeH
was present. Additionally, the reaction proved tolerant, yet sensi-
Alkylidene isomerization of oxindole 3a,b,c
tive to electronic variations on the aryl
oxindole 3a with -keto ester 1b bearing a chloride in the 4-
position of the phenyl ring provided spirocyclopropyl oxindole 5o
in near quantitative yield (entry 6). However, p-methoxyphenyl
a-keto ester 1. Treatment of
a
a
-
keto ester 1c gave the corresponding penta-substituted cyclopro-
pane 5p in only 65% yield (entry 7). The diminished yield of 5p
when compared to 5a and 5o is consistent with a mechanism in-
volving nucleophilic addition of P(NMe2)3 to the
a-keto ester,
which should be favored for more electron deficient substrates.
Given the emergence of natural products and pharmaceutically
relevant targets bearing the 1,2-bisoxindole motif,21 we sought to
expand this method to include isatin derivatives as the 1,2-
dicarbonyl component. Thus, treatment of alkylidene oxindole
3m and N-methyl isatin 10 with P(NMe2)3 provided the corre-
sponding bis-spirooxindole cyclopropane 11 in 78% yield albeit in
2:1 diastereoselectivity (Eq. 3). Remarkably only two stereoisomers
of this highly substituted cyclopropane were observed from this
reaction. Additionally, 1,2,3-tricarbonyls proved competent under
these reaction conditions. For example, dihydroxymalonate 1222
aReaction conditions: 0.15 mmol of 3 and 0.23 mmol of P(NMe2)3 in CH2Cl2
(0.25 M). bRatio of alkene isomers determined by 1H NMR (500 MHz) of the
crude reaction mixture. cDiastereoselectivities in the cyclopropanation of each
alkylidene oxindole with 1a are provided for comparison.
ꢀ
substrate to reach equilibrium, we chose to measure the alkylidene
geometry after 3 h given that the cyclopropanation event is com-
plete over this period of time. Exposing electron deficient, ortho-
substituted alkylidenes 3a and 3g to 1.5 equiv of P(NMe2)3 in CH2Cl2
at ꢀ78 ꢁC, allowing the reaction to warm to room temperature, and
stirring for an additional 3 h led to a slight erosion in the ratio of E/
Z-alkylidenes for 3a while 3g retained the corresponding E-isomer.
E-Alkylidene oxindoles 3h and 3i also proved resilient to isomeri-
zation showing no erosion in alkene geometry under the reaction
conditions. However, independent treatment of a 7:1 E/Z mixture of
alkylidenes 3c and 3d led to significant isomerization of the double
bond resulting in a 1:1 ratio after 3 h. Additionally, electron de-
ficient E-alkylidenes 3e and 3f bearing para substitution underwent
isomerization to provide a 2:1 and 3:1 mixture of E- and Z-alkenes,
respectively. These results would seem to indicate a correlation
between the propensity of the E-alkylidene oxindole to isomerize
under the reaction conditions and the formation of the minor
spirocyclopropyl oxindole diastereomer 7. More specifically, we
conclude that the minor diastereomer 7 arises from phospholene
addition to the corresponding Z-alkylidene.
underwent dehydration in the presence of 4 A molecular sieves
followed by phospholene formation and addition to alkylidene 3m
to yield the diester substituted spirocyclopropyl oxindole 13 in 62%
yield and 3:1 diastereoselectivity (Eq. 4). Likewise, unsubstituted
alkylidene oxindoles participated in the cyclopropanation event
with malonate 12. Peterson olefination of b-silanol 14 followed by
ꢀ
treatment with 12 and P(NMe2)3 in the presence of 4 A MS provided
cyclopropane 15 in 31% yield over two steps (Eq. 5).
With increasing evidence that the propensity for isomerization
under the reaction conditions of the double bond in the starting
alkylidene oxindole played an important role in the diaster-
eoselectivity of the cyclopropanation event, we next sought to
evaluate how the stereochemical outcome is affected when the
reaction is performed on the corresponding Z-alkylidene. Thus, we
chose to examine oxindole 3i, based on its apparent strong pref-
erence for the E-isomer, by first evaluating the extent of double
bond isomerization when subjecting alkylidene Z-3i to P(NMe2)3 in
CH2Cl2 from ꢀ78 ꢁC to room temperature (Scheme 1). What we
discovered was that Z-3i and P(NMe2)3 led to a 1:1.3 ratio of E/Z
alkylidenes after 3 h that continued to isomerize to 4:1 over the
course of an additional 16 h. The E/Z ratio of alkylidenes did not
change significantly after allowing the mixture to stir at room
temperature for 43 h. Treatment of Z-3i to the cyclopropanation
Irrespective of the oxindole protecting group, we observed
overall that o-substituted aryl alkylidene oxindoles (3a, 3g, and 3h)
or bulky alkyl substitutions (3i) seemed to provide spi-
rocyclopropanes with superior diastereoselectivities. Hypothesiz-
ing that the stereoselectivity of this reaction is influenced by the
geometry of the starting alkylidene upon addition of the in-
termediate 2, we decided to examine the tendency of the E-alky-
lidene oxindoles to isomerize in the presence of the nucleophilic
phosphorus reagent P(NMe2)3 (Table 3). Rather than allowing the
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E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
5
reaction conditions in the presence of
a
-keto ester 1a gave spi-
and intermediate 17a over those present in 16b/16c and 17b/17c
lead to the observed preference for formation of cyclopropane 5a
over diastereomers 6a or 7a. However, double bond isomerization is
kept at bay with sterically encumbered alkylidenes, thereby en-
abling the formation of cyclopropane 5a to predominate.
rocyclopropyl oxindole 7i as the major diastereomer in 83% yield
and in a ratio of 7i/5i/6i¼2:1:0. Formation of cyclopropane 7i as the
major isomer, which is epimeric at the former
b-carbon, from
oxindole Z-3i is consistent with our hypothesis that the alkylidene
geometry influences the diastereoselectivity in the cyclo-
propanation event.
3. Conclusion
In summary, we have developed an efficient approach toward
the synthesis of the 3,30-spirocyclopropane oxindole core via mild
enolate generation using a KukhtineRamirez condensation event
with a broad range of aryl alkylidenes. Overall, high yields were
obtained of the cyclopropanes with electron-deficient, o-
substituted aryl alkylidenes affording particularly high diaster-
eoselectivity. Mechanistic studies indicate a strong correlation be-
tween the substitution on the alkylidene, tendency of the
alkylidene to undergo E/Z isomerization under the reaction con-
ditions, and the diastereoselectivity of the cyclopropanation event.
Further studies on expanding this method to a catalytic enantio-
selective variant, as well as the application of this reaction for the
synthesis of biologically active natural products is currently being
pursued, and will be reported in due course.
Scheme 1. Impact of Z-3i alkylidene geometry on the diastereoselectivity.
Overall, we were highly encouraged by the ease of this process as
the reaction typically produced a high yield of the corresponding
spirocyclopropyl oxindole and exhibited interesting trends in dia-
stereoselectivity based on the geometry of the starting alkylidene
oxindole. Based on these findings, our working mechanistic hy-
pothesis involves initial formation of phosphine adducts 2a and 2b
4. Experimental section
4.1. General
resulting from the addition of P(NMe2)3 to a
-keto ester 1a.7a,9c In
All solvents and reagents were ACS reagent grade, obtained from
commercial sources, and used without further purification unless
otherwise stated. Acetonitrile (CH3CN), dimethylformamide (DMF),
toluene (PhMe), tetrahydrofuran (THF), dichloromethane (CH2Cl2)
and diethyl ether (Et2O) were passed through a column of molec-
ular sieves and stored under argon. Chlorobenzene (C6H5Cl) was
contrast to He’s proposed initial enone conjugate addition, sub-
sequent 1,4-addition to the alkylidene oxindole 3 affords oxindole
enolate intermediates 17aec via the corresponding transition states
16aec (Fig. 3).10,23 Finally, C-alkylation and displacement of O¼PL3
provides the corresponding spirocyclopropyl oxindoles 5a, 6a and
7a.24 In light of our studies on the propensity of ortho-substituted
aryl substituents alkylidenes to be resistant to alkene isomerization
under the reaction conditions, and the resulting correlation to the
formation of cyclopropane diastereomers, it seems prudent to
speculate that steric interactions in the initial CeC bond forming
event impact the stereoselectivity of the cyclopropanation event. If
we assume that the initial phospholene addition is reversible,16b
then minimization of gauche interactions in transition state 16a
ꢀ
distilled over CaH2 and stored over 4 A molecular sieves. All re-
actions were carried out in oven-dried glassware under nitrogen
unless otherwise specified. Alkylidene oxindoles 3a,25 3cef,26 3h,25
and 3i,26 methylbenzoyl formate derivatives 1bec,27 N-methyl
isatin 10,28 hydrate 12,29 and
b
-silanol 1430 were prepared
according to the literature and spectral data (1H NMR and 13C NMR)
were consistent with reported data.
1H nuclear magnetic resonance (NMR) spectra were obtained at
either 300, 400, 500 or 600 MHz. 13C NMR were obtained at 100,125
or 150 MHz. Chemical shifts are reported in parts per million (ppm,
d), and referenced from the solvent or tetramethylsilane (TMS).
Coupling constants are reported in Hertz (Hz). Spectral splitting
patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet;
p, pentet; m, multiplet; comp, complex; app, apparent; hom, higher
order multiplet; and br, broad. Infrared (IR) spectra were obtained
using a Thermo Electron Nicolet 380 FT-IR using a silicon (Si) crystal
in an attenuated total reflectance (ATR) tower and reported as
wavenumbers (cmꢀ1). High and Low resolution electrospray ioni-
zation (ESI) measurements were made with a Bruker MicroTOF II
mass spectrometer. Analytical thin layer chromatography (TLC) was
performed using EMD 250 micron 60 F254 silica gel plates, visualized
with UV light and stained with either p-anisaldehyde, ceric am-
monium nitrate (CAN) or potassium permanganate (KMnO4) solu-
tions. Flash column chromatography was performed according to
31
ꢀ
Still’s procedure using EMD 40e63 mm 60 A silica gel.
4.2. tert-Butyl (E)-3-(2-bromobenzylidene)-2-oxoindoline-1-
carboxylate ((E)-3b)
To a solution of (E)-3-(2-bromobenzylidene)indolin-2-one32
(510 mg, 1.7 mmol) in CH2Cl2 (8.5 mL) at 0 ꢁC was added NaH
(82 mg, 2.0 mmol, 60% mineral oil dispersion) and stirred for
30 min at which point hydrogen gas evolution had ceased. Then
Fig. 3. Proposed origin of diastereoselectivity in the cyclopropanation.
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6
E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
DMAP (10.4 mg, 0.09 mmol) was added in one portion followed by
Boc2O (445 mg, 2.0 mmol) portionwise over 5 min. The resulting
mixture was allowed to warm to room temperature by removal of
the ice bath, and stirred for 20 min. The residual NaH was quenched
by the addition of water (5 mL) and the layers separated. The or-
ganic phase was washed with saturated aqueous NaCl (10 mL),
dried (MgSO4), and then concentrated under reduced pressure. The
resulting crude mixture was purified by flash chromatography
eluting with hexanes/EtOAc (3:1) to provide 626 mg (94%) of (E)-3b
130.5, 130.3, 129.0, 128.5, 127.8, 127.6, 127.4, 124.4, 123.2, 122.1,
121.2, 109.5, 44.0; IR (neat) 3063, 2920, 1709, 1609, 1463, 1341, 1179,
1015, 733, 692 cmꢀ1; HRMS (ESI) m/z¼412.0332 [C22H16BrNNaO
(MþNa) requires 412.0307]; mp¼106e110 ꢁC.
4.5. (E)-3-(2-Bromobenzylidene)-1-tosylindolin-2-one ((E)-
3n)
To a solution of (E)-3-(2-bromobenzylidene)indolin-2-one32
(1.50 g, 5.0 mmol) in THF (14 mL) at 0 ꢁC was added NaH
(260 mg, 6.5 mmol, 60% mineral oil dispersion) and stirred for
30 min at which point hydrogen gas evolution had ceased. Then
tosyl chloride (1.04 g, 5.5 mmol) was added dropwise. The resulting
mixture was allowed to warm to room temperature by removal of
the ice bath, and stirred for overnight at room temperature. The
residual NaH was quenched by the addition of saturated water
(50 mL) and the layers were separated. The organic phase was
washed with saturated aqueous NaCl (10 mL), dried (MgSO4), and
then concentrated under reduced pressure. The resulting crude
mixture was purified by flash chromatography hexanes/EtOAc (3:1)
to afford 1.37 g (60%) of (E)-3n as an orange solid. 1H NMR
as an orange solid. 1H NMR (600 MHz, CDCl3)
d
7.92 (d, J¼7.8 Hz,
1H), 7.83 (s, 1H), 7.70 (d, J¼8.4 Hz, 1H), 7.62 (d, J¼7.2 Hz, 1H), 7.39 (t,
J¼7.2 Hz, 1H), 7.32e7.29 (m, 3H), 6.94 (t, J¼7.2 Hz, 1H), 1.67 (s, 9H);
13C NMR (150 MHz, CDCl3)
d 166.2, 149.5, 136.8, 135.5, 133.5, 131.2,
130.6, 130.1, 127.5, 124.3, 124.0, 122.8, 121.3, 115.5, 84.5, 28.3; IR
(neat) 3084, 2959, 2886, 1752, 1720, 1460, 1372, 1363, 1333, 1304,
1291, 1249, 1159, 1088, 1063, 1043, 1026, 1002, 769, 755, 745 cmꢀ1
;
HRMS (ESI) m/z¼422.0388 [C20H18BrNaNO3 (MþNa) requires
422.0368]; mp¼112e116 ꢁC.
4.3. (E)-1-Methyl-3-(2-(trifluoromethyl)benzylidene)indolin-
2-one ((E)-3g)
(500 MHz, THF-d8)
d
8.05 (d, J¼8 Hz, 2H), 8.02 (d, J¼8 Hz, 1H), 7.75
To a solution of (E)-3-(2-(trifluoromethyl)benzylidene)indolin-
2-one33 (300 mg, 1.04 mmol) in DMF (5.2 mL) at 0 ꢁC was added
NaH (50 mg, 1.25 mmol, 60% mineral oil dispersion) and stirred for
30 min at which point hydrogen gas evolution had ceased. Then
methyl iodide (177 mg, 1.25 mmol) was added dropwise. The
resulting mixture was allowed to warm to room temperature by
removal of the ice bath, and stirred for 20 min. The residual NaH
was quenched by the addition of saturated NH4Cl (5 mL) and the
layers were separated. The organic phase was washed with satu-
rated aqueous NaCl (10 mL), dried (MgSO4), and then concentrated
under reduced pressure. The resulting crude mixture was purified
by flash chromatography eluting with hexanes/EtOAc (3:1) to
provide 195 mg (62%) of (E)-3g as an orange solid. 1H NMR
(d, J¼8 Hz, 1H), 7.69 (d, J¼8 Hz, 1H), 7.68 (s, 1H), 7.46e7.30 (m, 6H),
6.96 (t, J¼8 Hz, 1H), 2.43 (s, 3H); 13C NMR (125 MHz, THF-d8)
d
165.2, 145.7, 140.1, 136.3, 135.1, 133.4, 132.5, 131.5, 130.8, 130.2,
128.2, 128.1, 127.7, 126.7, 123.9, 123.8, 123.0, 121.5, 113.8, 20.8; IR
(neat) 2955, 2923, 2854, 2359, 1743, 1714, 1630, 1596, 1454, 1366,
1312, 1294, 1234, 1186, 1174, 1159, 1138, 1116, 1084 cmꢀ1; HRMS
(ESI) m/z¼454.0122 [C22H17BrNO3S (MþH) requires 454.0107];
mp¼156e159 ꢁC.
4.6. General procedure for the preparation of alkylidene ox-
indoles 3jel
To a solution of the corresponding oxindole (1.0 equiv) in EtOH
(0.7 M) at room temperature was added sequentially 2-
bromobenzaldehyde (1.2 equiv) and piperidine (0.1 equiv). The
reaction mixture was heated to reflux and stirred until the starting
oxindole was consumed as judged by TLC (ca. w4 h). The reaction
was allowed to cool to room temperature by removal of the oil bath,
and then concentrated under reduced pressure. The crude mixture
was purified by flash chromatography eluting with hexanes/EtOAc
at the indicated ratio to afford the title compound.
(600 MHz, CDCl3)
d
7.97 (app d, J¼2.4 Hz, 1H), 7.79 (d, J¼8.4 Hz, 1H),
7.67 (app d, J¼7.8 Hz,1H), 7.61 (t, J¼7.2 Hz,1H), 7.55 (t, J¼7.8 Hz,1H),
7.24 (dt, J¼1.2, 7.8 Hz, 1H), 6.93 (t, J¼7.8 Hz, 1H), 6.81 (d, J¼7.8 Hz,
1H), 6.78 (dt, J¼1, 7.2 Hz, 1H), 3.28 (s, 3H); 13C NMR (150 MHz,
CDCl3)
d 167.8, 134.1, 134.1, 133.1, 132.0, 132.0, 130.4, 130.4, 129.8,
129.3, 129.2, 129.0, 126.6 (q, J¼5.1 Hz), 124.9, 123.2, 123.0, 122.1,
120.9,108.5, 26.4; IR (neat) 3023, 2923,1701,1609,1484, 1466,1376,
1335, 1311, 1298, 1170, 1163, 1124, 1103, 1058, 1023, 776, 749,
650 cmꢀ1; HRMS (EI) m/z¼303.0873 [C17H12F3NO (M) requires
303.0871]; mp¼122e127 ꢁC.
4.6.1. (E)-3-(2-Bromobenzylidene)-1,5-dimethylindolin-2-one
(3j). Conversion of the corresponding oxindole34 was performed
on a 4.0 mmol scale and purified with hexanes/EtOAc (4:1) to afford
4.4. (E)-1-Benzyl-3-(2-bromobenzylidene)indolin-2-one ((E)-
3m)
450 mg (34%) of 3j as a red oil. 1H NMR (500 MHz, CDCl3)
d 7.78 (s,
1H), 7.70 (d, J¼8 Hz, 1H), 7.66 (dd, J¼7.6, 2 Hz, 1H), 7.38 (td, J¼7.5,
To a solution of (E)-3-(2-bromobenzylidene)indolin-2-one32
(831 mg, 2.77 mmol) in DMF (14 mL) at 0 ꢁC was added NaH
(133 mg, 3.32 mmol, 60% mineral oil dispersion) and stirred for
30 min at which point hydrogen gas evolution had ceased. Then
benzyl bromide (497 mg, 2.90 mmol) was added dropwise. The
resulting mixture was allowed to warm to room temperature by
removal of the ice bath, and stirred for 20 min. The residual NaH
was quenched by the addition of saturated NH4Cl (10 mL) and the
layers were separated. The organic phase was washed with satu-
rated aqueous NaCl (10 mL), dried (MgSO4), and then concentrated
under reduced pressure. The resulting crude mixture was purified
by flash chromatography eluting with hexanes/EtOAc (3:1) to
provide 294 mg (27%) of (E)-3m as an orange solid. 1H NMR
1 Hz), 7.30 (td, J¼7.5, 2 Hz, 1H), 7.06 (comp, 2H), 6.70 (d, J¼8.5 Hz,
1H), 3.26 (s, 3H), 2.17 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 168.1,
142.5, 135.9, 135.4, 133.4, 131.4, 130.9, 130.7, 130.5, 128.9, 127.3,
124.4, 123.8, 121.0, 108.2, 26.4, 21.3; IR (neat) 2926, 2857, 1706,
1644, 1617, 1491, 1435, 1105, 1023, 802, 750 cmꢀ1; HRMS (ESI) m/
z¼328.0349 [C17H15BrNO (MþH) requires 328.0332].
4.6.2. (E)-3-(2-Bromobenzylidene)-5-methoxy-1-methylindolin-2-
one (3k). Conversion of the corresponding oxindole34 was per-
formed on a 3.2 mmol scale and purified with hexanes/EtOAc (4:1)
to afford 419 mg (38%) of 3k as an orange solid. 1H NMR (500 MHz,
CDCl3)
d
7.81 (s, 1H), 7.69 (dd, J¼9.2, 1.1 Hz, 1H), 7.65 (dd, J¼7.6,
1.5 Hz, 1H), 7.39 (td, J¼7.6, 1.1 Hz, 1H), 7.28 (td, J¼9.2, 1.5 Hz, 1H),
(600 MHz, CDCl3)
d
7.89 (s, 1H), 7.71 (dt, J¼1.2, 8.4 Hz, 2H), 7.39 (dt,
6.85 (d, J¼2.5 Hz, 1H), 6.8 (dd, J¼8.5, 2.5 Hz, 1H), 6.70 (d, J¼8.5 Hz,
J¼1.0, 7.2 Hz, 1H), 7.37e7.28 (comp, 7H), 7.16 (dt, J¼1.2, 7.8 Hz, 1H),
1H), 3.62 (s, 3H), 3.25 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 167.9,
6.79 (dt, J¼1.2, 7.8 Hz, 1H), 6.72 (d, J¼7.8 Hz, 1H), 5.0 (s, 2H). 13C
155.3,138.6,135.9,135.7,133.4,131.0,130.4,129.1,127.4,124.3,121.9,
114.9, 110.3, 108.7, 55.9, 26.4; IR (neat) 3055, 3002, 2932, 2829,
NMR (150 MHz, CDCl3) d 168.2, 143.7, 136.1, 136.1, 135.8, 133.4, 131.0,
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E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
7
1844, 1698, 1643, 1600, 1488, 1434, 1367, 1225, 1104, 1026 cmꢀ1
;
7.26e7.22 (m, 1H), 7.18e7.13 (m, 2H), 7.07e7.03 (ddd, J¼1 Hz), 6.82
(t, J¼7.6 Hz,1H), 5.71 (d, J¼7.6 Hz,1H), 4.41 and 3.49 (s,1H), 3.61 and
HRMS (ESI) m/z¼344.0262 [C17H15BrNO2 (MþH) requires
344.0281]; mp¼150e152 ꢁC.
3.51 (s, 3H), 1.61 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 169.9, 169.2,
168.3,167.6,149.5,149.3,140.7,139.9,134.7,133.5,132.8,132.6,132.2,
132.1, 132.0, 131.9, 131.1, 130.1, 129.3, 129.1, 128.8, 128.8, 128.5, 128.4,
128.3, 128.2, 127.6, 127.2, 127.0, 126.8, 125.9, 125.9, 125.4, 124.2,
123.4,122.1,120.3,114.8, 114.7, 84.5, 84.2, 54.9, 53.3, 53.2, 52.8, 45.9,
43.1, 41.5, 40.5, 28.6, 28.4, 28.3; IR (neat) 3058, 2923, 2853, 1709,
1619, 1471, 1434, 1339, 1262, 1234, 1156, 1030, 751, 715 cmꢀ1; HRMS
(ESI) m/z¼570.0909 [C29H26BrNNaO5 (MþNa) requires 570.0887];
mp¼215e220 ꢁC. 6b: White solid. 1H NMR (500 MHz, CDCl3) 8.1 (s,
1H), 7.39e7.37 (m, 2H), 7.34e7.32 (m, 2H), 7.29e7.24 (m, 4H), 7.13 (d,
J¼7.5 Hz, 1H), 7.09e7.03 (m, 3H), 6.9 (d, J¼7.5 Hz, 1H), 4.43 (s, 1H),
4.6.3. (E)-5-Bromo-3-(2-bromobenzylidene)-1-methylindolin-2-one
(3l). Conversion of the corresponding oxindole35 was performed
on a 0.68 mmol scale and purified with hexanes/EtOAc (3:1) to
afford 196 mg (73%) of 3l as a yellow solid. 1H NMR (500 MHz,
CDCl3)
d
7.86 (s, 1H), 7.71 (dd, J¼8.2, 1.1 Hz, 1H), 7.62 (dd, J¼7.7,
1.4 Hz, 1H), 7.41 (td, J¼7.6, 0.7 Hz, 1H), 7.39e7.34 (m, 2H), 7.31
(comp, J¼0.7 Hz, 1H), 6.70 (d, J¼8.2 Hz, 1H), 3.27 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 167.5, 143.5, 137.4, 135.2, 133.6, 132.9, 131.4,
130.3, 127.6, 127.6, 125.9, 124.4, 122.8, 114.7, 109.9, 26.5; IR (neat)
3056, 2967, 1889, 1868, 1843, 1698, 1603, 1461, 1365, 1322, 1253,
1105, 1026 cmꢀ1; HRMS (ESI) m/z¼391.9281 [C16H12Br2NO (MþH)
requires 391.9280]; mp¼163e165 ꢁC.
3.55 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 171.8, 169.3, 140.6, 132.5,
132.3,131.8,131.8,130.2,128.6,128.2,127.8,127.4,126.8,126.5,122.1,
120.8, 109.5, 53.3, 53.0, 42.7, 40.3, 29.7; IR (neat) 3057, 2980, 1788,
1758,1726,1608,1465,1349,1295,1249,1148,1098,1026,1002, 749,
697 cmꢀ1; HRMS (ESI) m/z¼448.0569 [C24H19BrNO3 (Mþ1) requires
448.0543]; mp¼81e85 ꢁC.
4.7. General procedure for the phosphine-mediated cyclo-
propanation of alkylidene oxindoles
To a solution of 3 (1 equiv) and 1 (1.5 equiv) in CH2Cl2 (0.25 M) at
ꢀ78 ꢁC was added P(NMe2)3 (1.5 equiv) dropwise. The reaction was
allowed to warm to room temperature over 3 h and stirring con-
tinued until full consumption of the starting materials was in-
dicated by TLC analysis (ca. 2 h). The solvent was removed under
reduced pressure and the resulting crude reaction mixture was
purified by flash chromatography eluting with hexanes/EtOAc (3:1)
to give the title spirocyclopropane oxindoles. The ratio of di-
astereomers was determined 1H NMR (500 or 600 MHz) of the
crude reaction mixture.
4.7.3. Methyl-10-methyl-20-oxo-2,3-diphenylspiro[cyclopropane-1,30-
indoline]-2-carboxylate (5ce7c). Cyclopropanation of (E)-3c with 1a
was performed on a 0.21 mmol scale over 3 h to provide 77 mg (94%)
of 5ce7c in a ratio of 4.7:1.4:1. The ratio of diastereomers was de-
termined by comparing the integrations of peaks at 5.82 ppm,
5.69 ppm and 6.94 ppm in the 1H NMR of the crude reaction mixture.
5c/7c: White solid. 1H NMR (500 MHz, CDCl3)
d 7.53e7.33 (m, 1H),
7.26e7.17 (m, 10H), 6.95 and 6.92 (d, J¼8.0 Hz, 1H), 6.72 and 6.67 (t,
J¼7.5 Hz, 1H), 5.82 and 5.69 (d, J¼7.5 Hz, 1H), 4.13 and 3.64 (s, 1H),
3.73 and 3.58 (s, 3H), 3.37 and 3.33 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
174.3,171.9,170.7,167.9,144.8,144.2,135.5,132.6,132.4,132.1,131.2,
4.7.1. Methyl-3-(2-bromophenyl)-10-methyl-20-oxo-2-phenylspiro
[ c y c l o p r o p a n e - 1 , 3 0- i n d o l i n e ] - 2 - c a r b o x y l a t e
(5ae7a). Cyclopropanation of (E)-3a with 1a was performed on
a 0.16 mmol scale over 3 h to provide 73 mg (>99%) of 5a and 6a in
a ratio of 2.6:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 5.71 ppm and 6.93 ppm in
the 1H NMR of the crude reaction mixture. 5a: White solid. 1H NMR
130.9, 130.8, 130.7, 128.7, 128.7, 128.4, 128.1, 128.1, 127.8, 127.7, 127.5,
127.4, 127.3, 127.1, 126.6, 123.4, 122.1, 121.5, 120.9, 108.1, 107.9, 53.1,
52.5, 51.9, 50.6, 44.9, 42.4, 41.3, 40.1, 27.0, 26.8; IR (neat) 3057, 2853,
1726, 1698, 1608, 1494, 1471, 1455, 137, 1253, 1229, 698 cmꢀ1; HRMS
(ESI) m/z¼384.1620 [C25H22NO3 (Mþ1) requires 384.1594];
mp¼151e156 ꢁC. 6c: Yellow solid. Isolated as an inseparable mixture
with epoxide 9. 1H NMR (500 MHz, CDCl3)
d
7.41e7.16 (comp, 11H),
7.11e7.09 (m, 2H), 6.94 (d, J¼7.5 Hz,1H), 4.04 (s,1H), 3.57 (s, 3H), 3.28
(s, 3H); 13C NMR (150 MHz, CDCl3)
170.3, 170.1, 167.8, 143.6, 132.5,
(600 MHz, CDCl3)
d
8.31 (d, J¼6.5 Hz, 2H), 7.51e7.49 (m, 3H),
7.38e7.36 (m, 4H), 7.22 (t, J¼6.5 Hz, 1H), 7.15 (t, J¼6.5 Hz, 1H), 6.89
(d, J¼6.5 Hz, 1H), 6.73 (t, J¼6.5 Hz, 1H), 5.71 (d, J¼6 Hz, 1H), 3.59 (s,
d
131.7, 130.9, 129.9, 128.8, 128.4, 128.3, 127.9, 127.9, 127.8, 127.7, 127.7,
127.5, 127.4, 122.2, 119.8, 108.1, 69.2, 53.4, 53.2, 52.5, 44.6, 40.5, 26.8;
IR (neat) 3062, 2925, 2850, 1746, 1727, 1604, 1492, 1441, 1335, 1251,
697 cmꢀ1; HRMS (ESI) m/z¼384.1622 [C25H22NO3 (Mþ1) requires
384.1594]; mp¼149e156 ꢁC.
3H), 3.53 (s, 1H), 3.25 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 171.7,
167.8, 144.6, 135.3, 133.2, 132.7, 132.3, 130.9, 128.9, 128.6, 128.6,
128.5, 127.8, 127.5, 127.3, 126.8, 126.2, 125.6, 122.1, 121.3, 52.5, 51.5,
44.7, 41.0, 26.6; IR (neat) 3016, 2928, 1740, 1707, 1615, 1470, 1378,
1343, 1252, 1132, 745, 699 cmꢀ1; HRMS (ESI) m/z¼462.0674
[C25H21BrNO3 (Mþ1) requires 462.0699]; mp¼174e179 ꢁC. 6a:
Yellow solid. Isolated as an inseparable mixture with epoxide 9. 1H
4.7.4. Methyl-3-(4-methoxyphenyl)-10-methyl-20-oxo-2-phenylspiro
[ c y c l o p r o p a n e - 1 , 3 0- i n d o l i n e ] - 2 - c a r b o x y l a t e
(5de7d). Cyclopropanation of (E)-3d with 1a was performed on
a 0.18 mmol scale over 3 h to provide 72 mg (>99%) of 5de7d in
a ratio of 5.5:1:1.8. The ratio of diastereomers was determined by
comparing the integrations of peaks at 5.83 ppm, 5.67, and 6.90 ppm
in the 1H NMR of the crude reaction mixture. 5d/7d: Orange oil. 1H
NMR (500 MHz, CDCl3)
(d, J¼1.0, 7.5 Hz, 1H), 7.06e7.04 (m, 2H), 6.93 (d, J¼8 Hz, 1H), 4.46 (s,
1H), 3.54 (s, 3H), 3.26 (s, 3H); 13C NMR (150 MHz, CDCl3)
170.3,
d 7.39e7.37 (m, 2H), 7.28e7.26 (m, 6H), 7.08
d
170.1, 167.8, 143.6, 132.5, 131.7, 130.9, 129.9, 128.8, 128.4, 128.3,
127.9, 127.9, 127.8, 127.8, 127.7, 127.5, 127.4, 122.2, 119.8, 108.1, 69.2,
53.4, 53.2, 52.5, 44.6, 40.5, 26.8; IR (neat) 3053, 2956, 1727, 1710,
1612, 1494, 1469, 1446, 1432, 1376, 1344, 1170, 1043, 1025, 742,
696 cmꢀ1; mp¼195e200 ꢁC.
NMR (500 MHz, CDCl3)
d 7.45e7.43 (m, 1H), 7.36e7.33 (m, 1H),
7.26e7.18 (m, 4H), 7.12 (d, J¼8.5 Hz, 2H), 6.94 and 6.91 (d, J¼8.0 Hz,
1H), 6.87 and 6.73 (d, J¼8.0 Hz, 2H), 6.68 (t, J¼7.5 Hz), 5.83 and 5.67
(d, J¼7.5 Hz,1H), 4.07 and 3.56 (s,1H), 3.80 and 3.74 (s, 3H), 3.72 and
4.7.2. 10-(tert-Butyl)-2-methyl-3-(2-bromophenyl)-20-oxo-2-
phenylspiro[cyclopropane-1,30-indoline]-10,2-dicarboxylate
(5b). Cyclopropanation of (E)-3b with 1a was performed on
a 0.13 mmol scale over 3 h to provide 59 mg (>99%) of 5b and un-
protected (NeH) 6b in a ratio of 8:1. The ratio of diastereomers was
determined by comparing the integrations of peaks at 5.71 ppm and
6.90 ppm in the 1H NMR of the crude reaction mixture. 5b/6b: White
3.56 (s, 3H), 3.36 and 3.32 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 174.4,
171.9, 171.4, 167.9, 158.8, 158.7, 144.8, 144.2, 135.6, 132.7, 132.0, 131.9,
131.2, 130.9,128.7, 128.6,128.4,128.1,127.6,127.5,127.0,126.7,124.3,
124.1, 123.5, 122.1, 121.5, 120.8, 113.5, 113.3, 108.1, 107.9, 60.6, 55.3,
52.5, 51.9, 50.6, 44.5, 42.0, 41.4, 40.2, 30.8, 27.0, 26.8, 21.2, 19.3, 14.4,
13.9; IR (neat) 3053, 2947, 1733, 1709, 1610, 1514, 1469, 1247, 1225,
1177, 1030, 1012, 750, 733, 697 cmꢀ1; HRMS (ESI) m/z¼414.1668
[C26H24NO4 (Mþ1) requires 414.1700]. 6d: Yellow solid. Isolated as
an inseparable mixture with epoxide 9. 1H NMR (500 MHz, CDCl3)
solid. 1H NMR (500 MHz, CDCl3)
J¼2.0, 5.0, 7.3 Hz, 1H), 7.46e7.44 (m, 2H), 7.40e7.29 (m, 3H),
d
7.89 (d, J¼5.5 Hz, 1H), 7.51 (dd,
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8
E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
d
7.38e7.28 (m, 6H), 7.22e7.20 (m, 2H), 7.07e706 (m, 2H), 6.90 (d,
a ratio of 4:1. The ratio of diastereomers was determined by com-
paring the integrations of peaks at 5.78 ppm and 6.94 ppm in the 1H
NMR of the crude reaction mixture. 5g: White solid. 1H NMR
J¼7.8 Hz,1H), 6.72 (d, J¼8.6 Hz, 2H), 3.98 (s,1H), 3.74 (s, 3H), 3.53 (s,
3H), 3.25 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
169.5, 158.8, 143.4,
140.1,134.3,133.7,132.5,128.9,128.7,128.4,128.3,128.3,127.9,127.8,
127.4, 123.9, 122.1, 119.6, 55.2, 53.9, 53.4, 53.0, 51.3, 43.9, 26.6; IR
(neat) 3016, 2950, 1724, 1705, 1610, 1514, 1469, 1375, 1341, 1260,
1226, 1186, 1060, 1031, 833, 697 cmꢀ1; HRMS (ESI) m/z¼436.1520
[C26H23NaNO4 (MþNa) requires 436.1519]; mp¼177e181 ꢁC.
(600 MHz, CDCl3)
d
8.56 (d, J¼7.8 Hz, 1H), 7.61e7.58 (m, 2H),
7.43e7.32 (m, 7H), 7.22 (dt, J¼1.2, 7.8 Hz, 1H), 6.89 (d, J¼7.8 Hz, 1H),
6.72 (dt, J¼1, 7.2 Hz, 1H), 5.78 (d, J¼7.8 Hz, 1H), 3.81 (s, 1H), 3.62 (s,
3H), 3.21 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 172.1, 168.3, 144.6,
135.7, 133.2, 131.7, 131.6, 130.9, 129.3, 129.1, 128.9, 128.7, 127.7, 127.7,
126.2 (q, J¼5.9 Hz), 126.1, 122.3, 121.5, 107.9, 52.8, 51.1, 41.5, 41.4,
26.6; IR (neat) 3047, 2984, 1739, 1702, 1614, 1493, 1470, 1375, 1309,
1258, 1141, 1121, 1037, 1006, 767, 729 cmꢀ1; HRMS (ESI) m/
z¼474.1286 [C26H20F3NaNO3 (MþNa) requires 474.1287];
mp¼177e180 ꢁC. 6g: Yellow solid. Isolated as an inseparable mix-
4.7.5. Methyl-3-(4-chlorophenyl)-10-methyl-20-oxo-2-phenylspiro
[ c y c l o p r o p a n e - 1 , 3 0- i n d o l i n e ] - 2 - c a r b o x y l a t e
(5ee7e). Cyclopropanation of (E)-3e with 1a was performed on
a 0.19 mmol scale over 3 h to provide 86 mg (91%) of 5ee7e in
a ratio of 3:1:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 5.77 ppm and 6.97 ppm in
the 1H NMR of the crude reaction mixture. 5e: White solid. 1H NMR
ture with epoxide 9. 1H NMR (500 MHz, CDCl3)
d
7.65 (d, J¼8.4 Hz,
1H), 7.55 (d, J¼9.0 Hz, 1H), 7.39e7.33 (comp, 5H), 7.29e7.26 (comp,
3H), 7.11e7.71 (m, 2H), 6.94 (d, J¼8.4 Hz, 1H), 4.48 (s, 1H), 3.57 (s,
(600 MHz, CDCl3)
d
7.27e7.19 (m, 7H), 7.18e7.14 (m, 4H), 6.95 (d,
3H), 3.26 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 169.8, 167.8, 143.7,
J¼7.8 Hz, 1H), 6.69 (dt, J¼1, 7.8 Hz, 1H), 5.77 (dd, J¼1, 7.8 Hz, 1H),
132.5, 132.3, 130.9, 130.6, 130.0, 128.8, 128.6, 128.1, 127.9, 127.8,
127.1, 126.9, 125.9, 122.4, 120.2, 108.2, 53.4, 53.3, 40.6, 38.4, 26.8; IR
(neat) 3066, 2960, 1747, 1726, 1705, 1614, 1448, 1378, 1260, 1168,
1120,1062,1041,1001, 822, 747, 695 cmꢀ1; HRMS (EI) m/z¼451.1432
[C26H20F3NO3 (M) requires 451.1434]; mp¼123e128 ꢁC.
4.07 (s, 1H), 3.72 (s, 3H), 3.36 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
173.9, 170.3, 144.6, 133.1, 132.4, 132.1, 130.8, 130.4, 128.4, 128.1,
128.1, 127.7, 126.8, 122.9, 120.8, 108.1, 53.0, 50.3, 41.4, 41.0, 26.9; IR
(neat) 3013, 2884, 1731, 1702, 1605, 1493, 1466, 1433, 1374, 1349,
1315, 1254, 1231, 1085, 1013, 821, 765 cmꢀ1; HRMS (ESI) m/
z¼418.1190
[C25H21ClNO3
(Mþ1)
requires
418.1204];
4.7.8. Methyl-10-methyl-20-oxo-2-phenyl-3-(o-tolyl)spiro[cyclopro-
pane-1,30-indoline]-2-carboxylate (5he6h). Cyclopropanation of
(E)-3h with 1a was performed on a 0.24 mmol scale over 3 h to
provide 22 mg (21%) of 5h and 7h in a ratio of 2:1. The ratio of
diastereomers was determined by comparing the integrations of
peaks at 5.71 ppm and 5.61 ppm in the 1H NMR of the crude re-
action mixture. 5h/7h: Yellow solid. 1H NMR (500 MHz, CDCl3)
mp¼167e169 ꢁC. 6e: Yellow oil. Isolated as an inseparable mixture
with epoxide 9. 1H NMR (600 MHz, CDCl3)
d 7.36e7.27 (m, 6H),
7.18e7.12 (m, 4H), 7.08e7.04 (m, 2H), 6.97 (d, J¼7.8 Hz, 1H), 3.96 (s,
1H), 3.53 (s, 3H), 3.25 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
170.0,
169.7, 143.4, 133.2, 132.8, 132.2, 130.8, 129.2, 128.6, 128.4, 127.9,
127.8, 127.5, 122.1, 119.6, 108.1, 53.2, 52.2, 43.6, 40.2, 26.6; IR (neat)
3063, 2991, 1725, 1703, 1613, 1493, 1470, 1434, 1375, 1343, 1252,
1225, 1171, 1128, 1090, 1003, 746 cmꢀ1; HRMS (ESI) m/z¼418.1226
[C25H21ClNO3 (Mþ1) requires 418.1204].
d
7.94 (dd, J¼1.2, 7.2 Hz, 1H), 7.49e7.48 (m, 2H), 7.38e7.32 (m, 3H),
7.24e7.19 (m, 4H), 7.15e7.12 (m, 3H), 6.99 (d, J¼7.8 Hz, 1H minor),
6.94 (d, J¼7.8 Hz, 1H minor), 6.94 and 6.92 (d, J¼7.8 Hz, 1H), 6.73
and 6.62 (dt, J¼1.2, 7.8 Hz, 1H), 5.71 and 5.61 (d, J¼7.2 Hz, 1H), 4.03
and 3.53 (s,1H), 3.76 and 3.60 (s, 3H), 3.37 and 3.29 (s, 3H), 2.58 and
4.7.6. Methyl-10-methyl-20-oxo-2-phenyl-3-(4-(trifluoromethyl)phe-
nyl) sp iro[cyclopropane-1, 30-indoline]-2-carboxylate
(5fe7f). Cyclopropanation of (E)-3f with 1a was performed on
a 0.17 mmol scale over 3 h to provide 74 mg (>99%) of 5fe7f in
a ratio of 3:1:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 5.79 ppm and 6.96 ppm in
the 1H NMR of the crude reaction mixture. 5f: Orange solid. 1H NMR
2.06 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 174.2, 171.9, 170.6, 167.9,
144.5, 144.1, 139.4, 137.9, 135.6, 131.9, 131.7, 131.3, 131.2, 131.1, 130.9,
1304, 129.8, 128.7, 128.5, 128.4, 128.2, 128.0, 127.5, 127.4, 127.3,
126.4, 126.2, 125.3, 125.1, 123.5, 121.9, 121.4, 120.7, 107.9, 107.7, 52.9,
52.4, 51.6, 50.2, 43.6, 41.2, 40.5, 40.3, 29.7, 26.9, 26.6, 20.4, 20.3; IR
(neat) 3054, 2979, 1733, 1708, 1652, 1612, 1540, 1492, 1343, 1221,
1001, 728 cmꢀ1; HRMS (ESI) m/z¼398.1727 [C26H24NO3 (Mþ1) re-
quires 398.1751]; mp¼136e141 ꢁC.
(600 MHz, CDCl3)
d
7.46 (d, J¼8.4 Hz, 2H), 7.35 (d, J¼8.4 Hz, 2H),
7.29e7.26 (m, 2H), 7.23e7.19 (m, 4H), 6.97 (d, J¼8.4 Hz, 1H), 6.71 (t,
J¼7.2 Hz, 1H), 5.79 (d, J¼7.2 Hz, 1H), 4.13 (s, 1H), 3.74 (s, 3H), 3.78 (s,
3H); 13C NMR (150 MHz, CDCl3)
d
173.8, 170.2, 144.7, 136.6, 132.3,
4.7.9. Methyl-3-cyclohexyl-10-methyl-20-oxo-2-phenylspiro[cyclo-
propane-1,30-indoline]-2-carboxylate (5i). Cyclopropanation of (E)-
3i with 1a was performed on a 0.18 mmol scale over 3 h to provide
52 mg (76%) of 5i in a ratio of >20:1. 5i: 1H NMR (600 MHz, CDCl3)
131.0, 130.2, 129.4, 129.2, 128.5, 128.1, 127.9, 126.7, 124.8 (q,
J¼3.9 Hz), 122.7, 120.9, 108.2, 53.1, 50.3, 41.6, 41.1, 26.9; IR (neat)
3057, 2988, 1731, 1716, 1612, 1495, 1471, 1432, 1375, 1325, 1167, 1123,
1067, 1009, 853, 749, 731 cmꢀ1; HRMS (ESI) m/z¼452.1449 [C26H21
F3NO3 (Mþ1) requires 452.1468]; mp¼147e151 ꢁC. 6f: Yellow solid.
Isolated as an inseparable mixture with epoxide 9. 1H NMR
d
7.34e7.21 (m, 6H), 6.91 (d, J¼7.2 Hz,1H), 6.73 (t, J¼7.8 Hz,1H), 5.93
(d, J¼7.8 Hz, 1H), 3.67 (s, 3H), 3.31 (s, 3H), 2.62 (d, J¼9.6 Hz, 1H),
2.40e2.38 (m, 1H), 1.85 (d, J¼13.2 Hz, 1H), 1.59 (d, J¼13.2 Hz, 1H),
1.54e1.47 (m, 2H), 1.43e1.41 (m, 1H), 1.31e1.26 (m, 1H), 1.19e1.13
(500 MHz, CDCl3)
d
7.49 (d, J¼10.8 Hz, 2H), 7.44 (d, J¼10.2 Hz, 2H),
7.24e7.16 (m, 1H), 7.43e7.31 (comp, 5H), 7.12e7.09 (m, 2H), 6.96 (d,
(m, 1H), 0.95e0.85 (m, 3H); 13C NMR (150 MHz, CDCl3)
d 174.6,
J¼9.0 Hz, 1H), 4.06 (s, 1H), 3.57 (s, 3H), 3.29 (s, 3H); 13C NMR
170.4, 144.2, 131.9, 131.3, 128.3, 128.2, 127.0, 124.5, 124.4, 121.0,
107.9, 52.7, 50.6, 44.9, 39.4, 33.9, 33.4, 31.5, 26.7, 26.1, 25.9, 25.6; IR
(neat) 3062, 2922, 1731, 1701, 1608, 1494, 1468, 1375, 1348, 1256,
1216, 1162, 1013, 752 cmꢀ1; HRMS (ESI) m/z¼390.2083 [C25H28NO3
(Mþ1) requires 390.2064]; mp¼165e170 ꢁC.
(150 MHz, CDCl3)
d 169.9, 169.6, 167.5, 143.4, 136.4, 132.2, 131.8,
130.7, 129.7, 129.2, 129.0, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7, 127.5, 127.4, 127.1, 124.1, 124.1, 122.2, 119.6, 108.1,
108.0, 68.9, 53.2, 53.0, 52.4, 43.6, 40.4, 26.6, 24.4; IR (neat) 3063,
2960, 1746, 1740, 1725, 1614, 1471, 1436, 1378, 1277, 1197, 1111, 1063,
1017, 961, 822, 676 cmꢀ1; HRMS (EI) m/z¼451.1427 [C26H20F3NO3
(M) requires 451.1434]; mp¼173e176 ꢁC.
4.7.10. Methyl-3-(2-bromophenyl)-10,50-dimethyl-20-oxo-2-
phenylspiro[cyclopropane-1,30-indoline]-2-carboxylate
(5j). Cyclopropanation of (E)-3j with 1a was performed on
a 0.38 mmol scale over 3 h to provide 165 mg (91%) of 5j and 6j in
a ratio of 2.15:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 5.47 ppm and 6.96 ppm in
the 1H NMR of the crude reaction mixture. 5j: White solid. 1H NMR
4.7.7. Methyl-10-methyl-20-oxo-2-phenyl-3-(2(trifluoromethyl)phe-
nyl ) s p i ro [ c yc l o p ro p a n e - 1, 30- i n d o l i n e ] - 2 - c a r b o x yl a t e
(5ge7g). Cyclopropanation of (E)-3g with 1a was performed on
a 0.17 mmol scale over 3 h to provide 72 mg (>99%) of 5g and 6g in
Please cite this article in press as: Wilson, E. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.06.004

E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
9
(500 MHz, CDCl3)
d
8.30 (d, J¼7.8 Hz, 1H), 7.49 (m, 3H), 7.35 (m, 4H),
provide 68 mg (>99%) of 5m and 6m in a ratio of 6:1. The ratio of
diastereomers was determined by comparing the integrations of
peaks at 5.73 ppm and 6.97 ppm in the 1H NMR of the crude re-
7.14 (td, J¼8.1, 1.0 Hz, 1H), 7.01 (dd, J¼7.8, 1.0 Hz, 1H), 6.77 (d,
J¼7.9 Hz, 1H), 5.47 (s, 1H), 3.59 (s, 3H), 3.49 (s, 1H), 3.23 (s, 3H), 2.04
(s, 3H), 13C NMR (150 MHz, CDCl3)
d
171.8, 168.0, 142.5, 135.6, 133.4,
action mixture. 5m: Yellow solid. 1H NMR (600 MHz, CDCl3)
d 8.38
133.0, 132.5, 131.2, 130.8, 129.1, 128.8, 128.6, 127.8, 127.0, 126.5,
125.9, 123.4, 107.5, 52.7, 51.5, 44.8, 41.2, 26.8, 21.3; IR (neat) 3023,
2948, 1733, 1706, 1622, 1600, 1497, 1432, 1365, 1348, 1256, 1214,
1027, 748 cmꢀ1; HRMS (ESI) m/z¼476.0835 [C26H23BrNO3 (Mþ1)
requires 476.0856]; mp¼115e120 ꢁC. 6j: Yellow solid. Isolated as an
inseparable mixture with epoxide 9. 1H NMR (500 MHz, CDCl3)
(d, J¼7.8 Hz, 1H), 7.48e7.47 (hom, 3H), 7.39e7.32 (comp, 7H),
7.28e7.26 (m, 2H), 7.11 (dt, J¼1, 7.8 Hz, 1H), 7.18e7.17 (m, 1H), 6.81
(d, J¼7.8 Hz,1H), 6.69 (dt, J¼1, 7.8 Hz,1H), 5.73 (d, J¼7.8 Hz,1H), 5.10
(d, J¼15.6 Hz, 1H), 4.78 (d, J¼15.6 Hz, 1H); 13C NMR (150 MHz,
CDCl3)
d 171.9, 167.7, 143.6, 136.4, 135.1, 133.2, 132.7, 132.2, 130.9,
128.9, 128.7, 128.6, 128.5, 127.6, 127.4, 127.3, 126.8, 126.1, 125.6,
122.2, 121.2, 108.6, 52.5, 51.9, 44.5, 43.9, 41.0; IR (neat) 3032, 1968,
d
7.56 (comp, 1H), 7.38 (comp, 1H), 7.29e7.26 (m, 5H), 7.12 (comp,
1H), 7.04 (comp, 2H), 6.96 (s, 1H), 6.81 (d, J¼7.9 Hz, 1H), 4.41 (s, 1H),
1734, 1705, 1614, 1491, 1469, 1231, 1126, 1104, 1002, 751 cmꢀ1
;
3.55 (s, 3H), 3.24 (s, 3H), 2.37 (s, 3H), 13C NMR (150 MHz, CDCl3)
HRMS (ESI) m/z¼538.0986 [C31H25BrNO3 (Mþ1) requires
d
170.3, 169.7, 141.6, 132.7, 132.6, 132.2, 132.1, 131.8, 130.4, 128.7,
538.1012]; mp¼159e164 ꢁC.
128.4, 128.3, 128.0, 127.8, 127.2, 127.0, 126.6, 121.2, 107.9, 53.1, 53.0,
42.5, 40.2, 26.9, 21.5; mp¼145e150 ꢁC.
4.7.14. Methyl 3-(2-bromophenyl)-20-oxo-2-phenyl-10-tosylspiro[cy-
clopropane-1,30-indoline]-2-carboxylate (5n). Cyclopropanation of
(E)-3n with 1a was performed on a 0.30 mmol scale over 3 h to
provide 171 mg (95%) of 5n and 6n in a ratio of 3:1. The ratio of
diastereomers was determined by comparing the integrations of
peaks at 3.40 ppm and 4.22 ppm in the 1H NMR of the crude re-
action mixture. 5n/6n: White solid. 1H NMR (500 MHz, CDCl3)
4.7.11. Methyl-(2-bromophenyl)-50-methoxy-10-methyl-20-oxo-2-
phenylspiro[cyclopropane-1,30-indoline]-2-carboxylate
(5k). Cyclopropanation of (E)-3k with 1a was performed on
a 0.26 mmol scale over 3 h to provide 121 mg (94%) of 5k and 6k in
a ratio of 3.76:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 3.52 ppm and 4.41 ppm in
the 1H NMR of the crude reaction mixture. 5k: White solid. 1H NMR
d
8.32 (d, J¼7.8 Hz, 1H), 8.10 (d, J¼8.3 Hz, 1H minor), 8.03 (d,
J¼8.2 Hz,1H), 7.90 (d, J¼8.4 Hz, 2H), 7.85 (d, J¼8.4 Hz,1H), 7.41e7.32
(m, 10H), 7.32e7.23 (m, 7H), 7.23e7.15e7.08 (m, 7H), 7.01 (comp,
1H), 6.82 (t, J¼7.6 Hz, 1H), 5.65 (d, J¼7.6 Hz, 1H), 4.22 (s, 1H minor),
3.51 (s, 3H), 3.50 (s, 3H minor), 3.40 (s, 1H), 2.44 (s, 3H), 2.44 (s, 3H
(500 MHz, CDCl3)
d
9.29 (dd, J¼7.8, 1.1 Hz, 1H), 7.52e7.49 (m, 3H),
7.37e7.34 (m, 4H), 7.15 (td, 8.0, 1.6 Hz, 1H), 6.79e6.74 (comp, 2H),
5.29 (dd, J¼2.1 Hz, 1H), 3.61 (s, 3H), 3.52 (s, 1H), 3.50 (s, 3H), 3.23 (s,
3H), 13C NMR (150 MHz, CDCl3)
d
171.6, 168.0, 155.0, 138.5, 135.5,
minor); 13C NMR (150 MHz, CDCl3)
d 169.8,167.0,145.3,140.0,135.3,
133.4, 132.9,132.5, 131.2, 129.1, 128.9,128.7,127.7, 127.0,125.9,112.9,
109.2, 108.2, 55.7, 52.7, 51.6, 45.1, 41.5, 26.9, IR (neat) 3057, 2979,
134.2,133.3,132.5,132.1,131.7,131.6,130.8,130.2,129.7,129.6,129.6,
129.3, 129.2, 128.8, 128.8, 128.7, 128.7, 128.5, 128.3, 128.2, 128.1,
127.9, 127.7, 127.2, 126.8, 125.7, 125.5, 124.6, 123.7, 122.4, 120.5,
113.8, 133.3, 53.7, 53.3, 52.81, 46.12, 43.7, 41.1, 21.88, 21.85; IR (neat)
2944,1735, 1707, 1604,1496,1434,1366,1251,1202,1027, 751 cmꢀ1
;
HRMS (ESI) m/z¼492.0788 [C26H23BrNO4 (Mþ1) requires
492.0805]; mp¼155e163 ꢁC. 6k: Yellow solid. 1H NMR (500 MHz,
3103, 2952, 1750, 1733, 1706, 1607, 1461, 1376, 1231, 945, 812 cmꢀ1
;
CDCl3)
d
7.56 (comp, J¼9.3 Hz, 1H), 7.37 (comp, J¼9.3 Hz, 1H),
HRMS (ESI) m/z¼602.0608 [C31H25BrNO5S (Mþ1) requires
7.29e7.26 (m, 5H), 7.05e7.03 (m, 2H), 6.85 (comp, 1H), 6.83 (s, 1H),
602.0631]; mp¼155e158 ꢁC.
6.80 (comp, 1H), 4.41 (s, 1H), 3.82 (s, 3H), 3.58 (s, 3H), 3.23 (s, 3H),
13C NMR (150 MHz, CDCl3)
d
170.1, 169.7, 156.0, 137.7, 132.7, 132.6,
4.7.15. Methyl-3-(2-bromophenyl)-2-(4-chlorophenyl)-10-methyl-20-
o x o s p i r o [ c y c l o p r o p a n e - 1, 3 0- i n d o l i n e ] - 2 - c a r b o x yl a t e
(5o). Cyclopropanation of (E)-3a with 1b was performed on
a 0.16 mmol scale over 3 h to provide 78 mg (>99%) of 5o and 6o in
a ratio of 3:1:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 3.48 ppm and 4.45 ppm in
the 1H NMR of the crude reaction mixture. 5o: Yellow solid. 1H NMR
132.2, 132.1, 130.8, 130.4, 128.7, 128.4, 128.0, 127.1, 126.6, 112.8,
108.4, 108.0, 56.2, 53.3, 53.1, 42.7, 40.5, 26.9; mp¼149e154 ꢁC.
4.7.12. Methyl-50-bromo-3-(2-bromophenyl)-10-methyl-20-oxo-2-
phenylspiro[cyclopropane-1,30-indoline]-2-carboxylate
(5l). Cyclopropanation of (E)-3l with 1a was performed on
a 0.19 mmol scale over 3 h to provide 102 mg (>99%) of 5l and 6l in
a ratio of 3.97:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 3.51 ppm and 4.41 ppm in the
1H NMR of the crude reaction mixture. 5l: White solid. 1H NMR
(500 MHz, CDCl3)
d
8.23 (d, J¼7.7 Hz, 1H), 7.51 (dd, J¼1.0, 8.0 Hz,
1H), 7.45 (d, J¼8.3 Hz, 2H), 7.35 (dd, J¼1.0, 7.6 Hz, 1H), 7.33 (d,
J¼8.7 Hz, 2H), 7.24 (dt, J¼1.0, 7.8 Hz, 1H), 7.15 (m, 1H), 6.91 (d,
J¼7.7 Hz, 1H), 6.78 (dt, J¼1.0, 7.6 Hz, 1H), 5.79 (s, J¼7.8 Hz, 1H), 3.59
(500 MHz, CDCl3)
d
8.34 (dd, J¼7.8,1.3 Hz,1H), 7.50 (dd, J¼8.0,1.3, Hz,
(s, 3H), 3.48 (s, 1H), 3.26 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 171.5,
1H), 7.45 (comp, 2H), 7.41e7.37 (m, 4H), 7.33 (dd, J¼8.2, 2.0, Hz, 1H),
7.16 (td, J¼8.0, 0.8 Hz, 1H), 6.76 (d, J¼8.2 Hz, 1H), 5.74 (d, J¼2.0 Hz,
1H), 3.61 (s, 3H), 3.51 (s,1H), 3.22 (s, 3H), 13C NMR (150 MHz, CDCl3)
167.5, 162.9, 144.6, 134.7, 133.8, 133.1, 132.4, 132.3, 129.0, 128.7,
127.6, 126.8, 125.8, 125.6, 122.1, 121.5, 107.8, 52.6, 50.7, 44.6, 40.9,
26.6; IR (neat) 3032, 2852, 1751, 1738, 1715, 1492, 1469, 1374, 1343,
1247, 1213, 1087, 1012, 752 cmꢀ1; HRMS (ESI) m/z¼496.0338
[C25H20BrClNO3 (Mþ1) requires 496.0310]; mp¼159e163 ꢁC. 6o:
Yellow solid. Isolated as an inseparable mixture with epoxide 9. 1H
d
171.3, 167.6, 143.8, 135.0, 133.4, 132.5, 132.5, 131.0, 130.3, 129.3,
129.2, 128.9, 128.6, 127.1, 125.8, 125.5, 114.1, 109.2, 52.8, 52.1, 45.3,
41.2, 26.9; IR (neat) 3058, 2980, 2884, 1733, 1715, 1609, 1488, 1431,
1249, 1138, 1096, 751 cmꢀ1
;
HRMS (ESI) m/z¼539.9776
NMR (500 MHz, CDCl3) d 7.59e7.57 (m, 1H), 7.36e7.30 (m, 5H), 7.23
[C25H20Br2NO3 (Mþ1) requires 539.9804]; mp¼112e120 ꢁC. 6l:
(d, J¼8.9 Hz, 2H), 7.17 (d, J¼8.8 Hz, 2H), 7.11e7.05 (m, 2H), 6.94 (d,
Yellow solid. 1H NMR (500 MHz, CDCl3)
d 7.56 (comp, 1H), 7.46 (dd,
J¼7.8 Hz, 1H), 4.45 (s, 1H), 3.55 (s, 3H), 3.27 (s, 3H); 13C NMR
J¼8.3, 1.9 Hz, 1H), 7.35 (comp, 1H), 7.31e7.26 (m, 6H), 7.06e7.04 (m,
(150 MHz, CDCl3) d 174.4, 170.3, 169.1, 143.9, 140.2, 134.4, 134.4,
2H), 6.80 (d, J¼8.3 Hz, 1H), 4.41 (s, 1H), 3.60 (s, 3H), 3.24 (s, 3H), 13
C
133.4, 132.9, 132.3, 132.1, 129.1, 128.9, 128.9, 128.6, 128.3, 127.0,
126.7, 122.4, 120.7, 54.1, 53.3, 52.2, 42.6, 40.5, 26.9; IR (neat) 3053,
2950,1729,1709,1612,1491,1471,1434,1346,1255,1225,1172,1091,
NMR (150 MHz, CDCl3) d 169.8,169.5,143.0,132.7,132.2,132.1,132.0,
130.9,130.0,129.2,128.9,128.5,128.1,127.0,126.6,123.7,115.0,109.5,
53.4, 53.4, 43.0, 40.0, 26.9; mp¼140e144 ꢁC.
1066, 1014, 829, 747 cmꢀ1
;
HRMS (ESI) m/z¼496.0315
[C25H20BrClNO3 (Mþ1) requires 496.0310]; mp¼165e168 ꢁC.
4.7.13. Methyl-10-benzyl-3-(2-bromophenyl)-20-oxo-2-phenylspiro
[cyclopropane-1,30-indoline]-2-carboxylate (5m). Cyclopropanation
of (E)-3m with 1a was performed on a 0.13 mmol scale over 3 h to
4.7.16. Methyl-3-(2-bromophenyl)-2-(4-methoxyphenyl)-10-methyl-
20-oxospiro[cyclopropane-1,30-indoline]-2-carboxylate
Please cite this article in press as: Wilson, E. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.06.004

10
E.E. Wilson et al. / Tetrahedron xxx (2015) 1e11
(5p). Cyclopropanation of (E)-3a with 1c was performed on
a 0.16 mmol scale over 3 h to provide 52 mg (65%) of 5p and 6p in
a ratio of 3:1:1. The ratio of diastereomers was determined by
comparing the integrations of peaks at 5.80 ppm and 6.96 ppm in
the 1H NMR of the crude reaction mixture. 5p: Yellow oil. 1H NMR
(4ꢃ50 mL). The organic extracts were combined and then partially
concentrated under reduced pressure to a total volume of w5 mL. To
this crude reaction mixture was added sequentially 12 (656 mg,
ꢀ
4 mmol), P(NMe2)3 (0.726 mL, 4 mmol), and 4 A molecular sieves.
The mixture was stirred for 18 h at room temperature, then filtered
to remove the precipitate that had formed, and the filtrate con-
centrated under reduced pressure. The residue was purified by flash
chromatography eluting with hexanes/ethyl acetate (3:1) to provide
179 mg (31%) of 15 as a light yellow solid. 1H NMR (600 MHz, CDCl3)
(600 MHz, CDCl3)
d
8.29 (d, J¼8.4 Hz, 1H), 7.5 (d, J¼7.8 Hz, 1H), 7.41
(d, J¼6.5 Hz, 2H), 7.35 (t, J¼7.2 Hz, 1H), 7.22 (t, J¼7.2 Hz, 1H), 7.14 (t,
J¼7.2 Hz, 1H), 6.89 (d, J¼7.8 Hz, 1H), 6.86 (d, J¼8.4 Hz, 2H), 6.76 (t,
J¼7.2 Hz,1H), 5.80 (d, J¼7.2 Hz,1H), 3.83 (s, 3H), 3.58 (s, 3H), 3.49 (s,
3H), 3.25 (s, 3H), 13C NMR (150 MHz, CDCl3)
d
171.9, 168.2, 159.9,
d
7.35 (d, J¼8.4 Hz, 1H), 7.31 (t, J¼7.2 Hz, 1H), 7.01 (t, J¼7.8 Hz, 1H),
144.8, 133.4, 133.0, 132.5, 132.3, 129.1, 127.6, 127.5, 127.0, 126.5,
125.8, 122.4, 121.5, 114.0, 107.8, 100.0, 60.6, 55.5, 52.6, 51.0, 45.1,
41.3, 26.8, 21.3, 14.4; IR (neat) 3056, 2935, 1735, 1709, 1609, 1510,
6.89 (d, J¼8.4 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.26 (s, 3H), 2.49 (d,
J¼4.8 Hz, 1H), 2.45 (d, J¼4.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d
172.56, 166.03, 165.84, 144.73, 128.54, 124.36, 123.15, 122.35,
1470, 1434, 1375, 1346, 1248, 1175, 1163, 1027, 834, 751, 729 cmꢀ1
;
108.30, 53.32, 53.11, 45.35, 38.02, 26.76, 24.40; IR (neat) 3102, 3013,
2953, 2849, 1749, 1732, 1608, 1549, 1494, 1467, 1433, 1381, 1343,
1249, 1185, 1162, 1147, 1125, 1107, 1044, 1010; HRMS (ESI) m/z
290.1023 [C15H16NO5 (MþH) requires 290.1040]; mp¼146e148 ꢁC.
HRMS (ESI) m/z¼492.0804 [C26H23BrNO4 (Mþ1) requires
492.0805] mp¼149e156 ꢁC.
4.7.17. 30-(2-Bromophenyl)-1-methyl-100-tosyldispiro[indoline-3,10-
cyclopropane-20,300-indoline]-2,200-dione (11). Cyclopropanation of
(E)-3n with 10 was performed on a 0.20 mmol scale over 3 h to
provide 113 mg (95%) of 11 in a ratio of 3:1. The ratio of di-
astereomers was determined by comparing the integrations of
peaks at 4.13 ppm and 4.09 ppm in the 1H NMR of the crude re-
Acknowledgements
Financial support for this work was provided by the National
Science Foundation (CAREER CHE-1056242). Drs. Allen G. Oliver
and Jaroslav Zajicek at the University of Notre Dame for their as-
sistance with X-ray crystallography and NMR analysis that was
crucial for structure determination.
action mixture. 11: White solid. 1H NMR (500 MHz, CDCl3)
d (mix-
ture of major and minor diastereomers) 8.03 (dd, J¼7.9, 1.0, Hz, 1H),
7.95 (d, J¼8.3 Hz,1H, minor), 7.92 (d, J¼8.2 Hz,1H), 7.88 (d, J¼8.4 Hz,
1H), 7.82 (d, J¼7.8 Hz, 1H, minor), 7.76 (d, J¼8.4 Hz, 2H), 7.43 (comp,
2H), 7.38e7.33 (m, 2H), 7.31e7.27 (m, 2H), 7.24e7.10 (m, 10H), 7.04
(dd, J¼7.9, 1 Hz, 1H, minor), 6.99 (comp, 1H), 6.95e6.88 (m, 2H),
6.83 (comp, 2H), 4.13 (s, 1H), 4.09 (s, 1H, minor), 3.22 (s, 3H), 3.14 (s,
3H, minor), 2.38 (s, 3H), 2.38 (s, 3H, minor), 13C NMR (150 MHz,
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.06.004.
CDCl3)
d 170.7, 170.2, 167.5, 145.7, 145.4, 144.4, 143.9, 139.4, 135.1,
132.9, 132.9, 132.6, 132.2, 129.8, 129.8, 129.7, 129.6, 129.6, 129.0,
128.9, 128.4, 128.0, 128.0, 126.8, 126.7, 126.0, 125.8, 125.5, 124.2,
123.9, 123.6, 122.4, 122.1, 121.3, 120.8, 113.1, 113.0, 107.9, 107.8, 49.3,
47.2, 41.7, 41.2, 27.1, 26.8, 21.9; IR (neat) 3053, 2954, 1751, 1712,1610,
1460, 1374, 1233, 1176, 1142, 1086, 1027, 950, 749 cmꢀ1; HRMS (ESI)
References and notes
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m/z¼599.0608
[C31H24BrN2O4S(Mþ1)
requires
599.0635]
mp¼172e178 ꢁC.
4.7.18. Dimethyl-10-benzyl-3-(2-bromophenyl)-20-oxospiro[cyclopro-
pane-1,30-indoline]-2,2-dicarboxylate (13). Cyclopropanation of (E)-
3m with 12 was performed on a 0.35 mmol scale over 3 h to provide
113 mg (62%) of 11 in a ratio of 3:1. The ratio of diastereomers was
determined by comparing the integrations of peaks at 4.72 ppm
and 4.13 ppm in the 1H NMR of the crude reaction mixture. 13:
White solid. 1H NMR (500 MHz, CDCl3)
d
7.96 (dt, J¼1, 8.0 Hz, 1H),
7.55 (dd, J¼1.0, 8.0 Hz,1H), 7.50 (dd, J¼1.0, 7.5 Hz,1H), 7.37e7.25 (m,
7H), 7.24e7.15 (m, 1H), 7.05 (t, J¼8 Hz, 1H), 6.83 (d, J¼7.5 Hz, 1H),
5.10 (d, J¼16 Hz, 1H), 4.72 (d, J¼16 Hz, 1H), 4.13 (s, 1H), 3.82 (s, 3H),
3.65 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 170.6, 166.7, 164.8, 144.2,
136.1, 133.2, 132.5, 132.4, 131.6, 131.5, 129.6, 129.3, 128.9, 128.8,
128.6,128.5,127.9,127.8,1277,127.5,126.9,125.7,125.0,123.5,122.5,
109.2, 109.2, 53.9, 53.4, 53.3, 52.9, 50.2, 44.5, 44.2, 42.4, 42.2, 40.9;
IR (neat) 3063, 2971, 1713, 1748, 1611, 1468, 1430, 1245, 1176, 1133,
749, 696 cmꢀ1; HRMS (ESI) m/z¼520.0779 [C27H23BrNO5 (Mþ1)
requires 520.0754]; mp¼156e159 ꢁC.
4.7.19. Dimethyl 10-methyl-20-oxospiro[cyclopropane-1,30-indoline]-
2,2-dicarboxylate (15). Freshly distilled BF3$OEt2 (1.22 mL,
9.62 mmol) was added to a solution of 1430 (500 mg, 2.0 mmol) in
CH2Cl2 (40 mL) at ꢀ78 ꢁC. The reaction was allowed to warm to 0 ꢁC
by replacing the dry ice/acetone bath with an ice water bath, and
stirredfor 1 h. The resulting mixturewas transferred slowly toa flask
containing saturated aqueous NaHCO3 (50 mL), the layers were
separated, and the organic phase was extracted with CH2Cl2
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