Stereocontrolled [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes to Iminooxindoles: Access to Spiro[oxindole-3,2′-pyrrolidines]

Article abstract of DOI:10.1021/acs.joc.8b03208

A novel stereocontrolled assembly of spiro[oxindole-3,2′-pyrrolidines] via [3+2]-cycloaddition of donor-acceptor cyclopropanes to electron-poor ketimines, iminooxindoles, was developed. The method allows for efficient employment of common readily available donor-acceptor cyclopropanes, functionalized with ester, keto, nitro, cyano etc. groups, and N-unprotected iminooxindoles. The stereospecificity of the initial S_N2-like imine attack on a cyclopropane molecule together with a high diastereoselectivity of further C-C bond formation facilitate a rapid access to spiro[oxindole-3,2′-pyrrolidines] in their optically active forms. Preliminary in vitro testing of the synthesized compounds against LNCaP (p53+) and PC-3 (p53-) cells revealed good antiproliferative activities and p53-selectivity indices for several compounds that are intriguing in terms of their further investigation as inhibitors of MDM2-p53 interaction.

Full text of DOI:10.1021/acs.joc.8b03208

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Article
Stereocontrolled [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes
to Iminooxindoles: Access to Spiro[oxindole-3,2’-pyrrolidines]
Andrey A. Akaev, Stanislav I. Bezzubov, Victor G. Desyatkin, Nataliya S. Vorobyeva,
Alexander G. Majouga, Mikhail Ya. Melnikov, and Ekaterina M. Budynina
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Feb 2019
Downloaded from http://pubs.acs.org on February 8, 2019
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Stereocontrolled [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes to Iminooxindoles:
Access to Spiro[oxindole-3,2’-pyrrolidines]
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Andrey A. Akaev,† Stanislav I. Bezzubov,‡ Victor G. Desyatkin,† Nataliya S. Vorobyeva,§
Alexander G. Majouga,†,§,ǁ Mikhail Ya. Melnikov,† and Ekaterina M. Budynina*†
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†Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1-3, Moscow
119991, Russia
‡Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
Leninskiy pr. 31, Moscow 119991, Russia
§National University of Science and Technology “MISiS”, Leninskiy pr. 4, Moscow 119991,
Russia
ǁDmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow
125047, Russia
*E-mail: ekatbud@kinet.chem.msu.ru
ABSTRACT: A novel stereocontrolled assembly of spiro[oxindole-3,2’-pyrrolidines] via [3+2]-
cycloaddition of donor-acceptor cyclopropanes to electron poor ketimines, iminooxindoles, was
developed. The method allows for efficient employment of common readily available donor-
acceptor cyclopropanes, functionalized with ester, keto, nitro, cyano etc. groups, and N-
unprotected iminooxindoles. The stereospecificity of the initial SN2-like imine attack on a
cyclopropane molecule together with high diastereoselectivity of further C–C bond formation
facilitate a rapid access to spiro[oxindole-3,2’-pyrrolidines] in their optically active forms.
Preliminary in vitro testing of the synthesized compounds against LNCaP (p53+) and PC-3
(p53-) cells revealed good antiproliferative activities and p53-selectivity indices for several
compounds that are intriguing in terms of their further investigation as inhibitors of MDM2-p53
interaction.
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INTRODUCTION
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Over the past couple of decades, the design and development of synthetic strategies to access
spirooxindole molecules have gained a lot of momentum.1–3 Intense interest in these structures is
determined by their various biological activities which provide ample opportunities for drug
discovery.4 Spiro[oxindolepyrrolidines] are of particular interest as potential anticancer agents.
The most extensive investigations in this area are related to spiro[oxindole-3,3’-pyrrolidines],
among which natural and artificial bioactive structures (e.g., elacomine, horsfiline,
spirotryprostatine A and B, MI-77301 and MI-888) are well-known5 (Fig. 1, A). At the same
time, the isomeric tricyclic spiro[oxindole-3,2’-pyrrolidine] systems, while also promising in the
context of bioactivity, are rarely studied. Nevertheless, anticancer activity, particularly via
inhibition of p53-MDM2 interaction, was revealed for the representatives of this subclass6 (Fig.
1, B). Therefore, the development of efficient methods allowing for stereoselective synthesis of
functionalized spiro[oxindole-3,2’-pyrrolidines] is highly desirable.
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H
A.
Spiro[oxindole-3,3'-pyrrolidines]
N
H
O
N
O
MeO
Horsfiline
MeO
H
N
O
Me
N
N
O
N
H
H
Spirotryprostatin A
O
MeN
H
N
Cl
N
HO
H
H
NH
F
(±)-Strychnofoline
Cl
O
HN
H
HO
N
NH
O
O
Elacomine
MI-77301
(SAR405838)
anticancer
N
H
OH
Cl
B.
Spiro[oxindole-3,2'-pyrrolidines]
EtO2C
CO2Et
O
CO2Et
EtO2C
O
R'
NH
RN
NMe
O
O
S
N
HN
R"
NMe
H
N
cytotoxic
P53 - MDM2
interaction inhibitor
Me
antitumor
O
N
Me
Figure 1. Examples of natural and synthetic bioactive spiro[oxindolepyrrolidines].
Among the typical synthetic approaches to these compounds, [3+2]-cycloaddition of isatin-
derived azomethine ylides to dipolarophiles is the one reported most widely7,8 (Scheme 1, A).
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Some other approaches are based on the reactivity of iminooxindoles and involve 1,5-cyclization
of oxindole-containing -aminocarbonyl compounds obtained via Mannich-aza-Michael
reactions as well as via nucleophilic addition of organometallic compounds to iminooxindoles.9–
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The possibility for assembling a pyrrolidine ring with a pre-existing oxindole bicycle is a
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common feature of the aforementioned methods.
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In the recent years, Lewis acid (LA) catalyzed [3+2]-cycloaddition of donor-acceptor (DA)
cyclopropanes12 to imines emerged as a highly efficient alternative to the existing methods of
pyrrolidine formation13,14 (Scheme 1, B). Moreover, in their pioneering works, Carreira and co-
workers successfully employed activated cyclopropanes in the synthesis of
spiro[pyrrolidineoxindoles]. Their strategy relied upon MgI2-catalyzed [3+2]-cycloaddition of
spiro[oxindole-3,1’-cyclopropanes] to aldimines affording spiro[oxindole-3,3'-pyrrolidines]
(Scheme 1, C), including () strychnofoline and (-)-spirotryprostatin B.15
Scheme 1. Overview and Strategy of This Work
A.
Spiro[pyrrolidine-3,2'-oxindoles] via pyrrolidine assembly
O
Y'
Y
Y
Y
R''
NHR'
NR'
X
X
X
2'
[3+2]
1,5
NR'
O
Y''
3
O
O
N
N
N
R
R
R
B.
Pyrrolidines via [3+2]-cycloaddition of DA cyclopropanes to imines
EWG
Lewis acid
EWG
R'
RN
EDG
EDG
R'
N
R
C.
DA cyclopropanes in spiro[oxindolepyrrolidine] assembly
3,3'
3,2' Our strategy This work
 Carreira's strategy


NR
R'
EDG
NY
O
O
EWG
N
R
N
X
H
EWG:
MgI2
Lewis acid
CO2R  COR
R'
CN  NO2  2-Py
EDG
NY
EWG
2'
3'
NR
X
3
3
O
O
yield
dr
up to 96%
up to 95:5
up to 98:2
N
N
H
er
R
In this work, we report a new approach to isomeric spiro[oxindole-3,2'-pyrrolidines], applying
[3+2]-cycloaddition of DA cyclopropanes to iminooxindoles for diastereo- and enantioselective
assembly of the pyrrolidine unit. Recently, Pd-catalyzed [3+2]-cycloaddition of
vinylcyclopropane-1,1-diesters to isatins was reported, leading to diastereo- and enantioselective
construction of spiro[oxindole-3,2'-tetrahydrofurans].16 Our technique provides possibilities for
efficient employment of readily accessible DA cyclopropanes with ester groups as acceptors.
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Moreover, cyclopropanes functionalized with COR, CN, NO2, etc. groups were employed as
well. This method allows for a direct synthesis of biologically relevant spiro[oxindole-3,2'-
pyrrolidines] with an N-unprotected oxindole unit, thus avoiding redundant
N-protection/deprotection steps. In this work, [3+2]-cycloaddition proceeds with high diastereo-
and enantioselectivity. This mechanism facilitates the synthesis of optically active
spiro[oxindole-3,2'-pyrrolidines] from enantiomerically enriched DA cyclopropanes.
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RESULTS AND DISCUSSION
In order to optimize the reaction conditions, we carried out a short series of experiments using
iminooxindole 1a and cyclopropane-1,1-diester 2a as model substrates (Table 1). Several LA,
such as MgI2, Sc(OTf)3 and Yb(OTf)3, typically used as catalysts in reactions with DA
cyclopropanes, were examined. We found that, at ambient temperature, MgI2 did not trigger the
formation of spiro[oxindole-3,2'-pyrrolidine] 3a at all, while the use of Sc(OTf)3 resulted in trace
amounts of 3a under the same conditions (entries 1,2). An increase in temperature led to an
increase in reaction efficiency. The heating of the reaction mixture in DCE under reflux for 2 h
in the presence of Sc(OTf)3 or Yb(OTf)3 was found to be the most efficient, affording 3a in 73%
and 88% yields, respectively (entries 3,4). Further increase in the duration of the reaction (up to
8 h) led to a reduction in the yield of 3a (entries 5,6). It is noteworthy that the use of MgI2 under
similar conditions induced an incomplete conversion of 2a and gave the product 3a in a
moderate yield, whereas in the presence of MgBr2OEt2 the reaction did not occur at all (entries
7,9). The increase in concentration and MgI2 loading allowed for complete conversion of 2a in 5
h and formation of 3a in 76% yield (entry 8). All successful experiments displayed similar
diastereoselectivity in regard to the formation of 3a. Therefore, heating of the reaction mixture in
DCE under reflux for 2 h in the presence of Yb(OTf)3 (entry 4) was determined as optimal in
terms of selecting conditions for further experiments.
Table 1. Optimization of [3+2]-Cycloaddition between 1a and 2a
Ph
Ph
NPh
N
MeO2C
MeO2C
CO2Me
LA (0.1 equiv)
+
O
CO2Me
DCE (0.1 M)
N
Ph
O

H
2a
N
H
1a
(1.05 equiv)
T (C)
25
3a
Entry
1
LA
MgI2
t (h)
Yield (%) [dr]a
b
6
-
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c
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7d
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Sc(OTf)3
25
83
83
83
83
83
83
83
6
-
Sc(OTf)3
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
MgI2
2
2
8
8
8
5
8
73 [92:8]
88 [93:7]
29 [95:5]
69 [92:8]
50 [94:6]
76 [94:6]
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e
MgI2
b
-
MgBr2OEt2
aDiastereomeric ratios [dr] were determined by NMR analysis of crude
products. bNo reaction. cTrace amounts of 3a were formed. d77%-Conversion
of 2a was observed. eMgI2 (0.2 equiv.), DCE (0.7 M).
Under the optimized conditions, a series of iminooxindoles 1a–j, containing various
substituents in their benzene unit as well as at the imine N center, and cyclopropane-1,1-diesters
2b–r with a variety of aryl and hetaryl substituents at C2 were examined in the [3+2]-
cycloaddition reaction (Table 2). In most cases, reactions proceeded with high efficiency, leading
to desired products 3 in 47–96% yields. The introduction of halogens into the oxindole fragment
of imines 1b–d had no significant influence on the reaction outcome, affording 3b–h in high
yields. Similarly, 1e–j, bearing both electron-donating and electron-withdrawing groups in the
aromatic substituent at the imine N atom, efficiently reacted with 2a and gave 3i–n in high
yields. Unfortunately, when using imines 1 with alkyl groups (e.g. Bu, 1k) at the N atom, slow
degradation of imines was observed with no formation of the desired [3+2]-cycloadduct 3. The
replacement of Yb(OTf)3 with MgI2 also did not facilitate a reaction with 1k.
Varying substituents at the C2 atom of 2 allowed us to reveal a tendency to decelerate for the
reaction involving 2i–k which contain aryls with acceptor groups, such as NO2, CO2Me, CN. As
a result, the reaction time was increased to 16–20 h, leading to noticeable tarring and a
reasonable decrease in the yields of 3v–x (as low as 51%). Moreover, the presence of an ortho-
group (2d) also led to significant deceleration and decline in the yield of the corresponding
spiro[oxindole-3,2’-pyrrolidine] 3q. On the other hand, for electron-abundant aryls (2e–h),
shorter time (1 h) was required to achieve a complete conversion of the reactants into the
corresponding products 3. 2-Thienyl derivative 2n displayed good tolerance to the reaction
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conditions, efficiently yielding 3aa (92%). However, for the reactions of acidophobic indolyl-
derivatives 2o,p, the decrease in the yields of the corresponding products 3ab,ac was observed,
owing to significant tarring. Meanwhile, N-Me-pyrrolyl derivative 2q and the even more tolerant
N-Ts-pyrrolyl derivative 2r underwent complete polymerization under the studied conditions.
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Table 2. [3+2]-Cycloaddition between Imines 1a–j and 2-Arylcyclopropane-1,1-diesters 2a–ra
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Ar
NR'
CO2Me
CO2Me
(1.05 equiv)
R'
MeO2C
MeO2C
N
Ar
R
R
2a-r
O
O
N
N
Yb(OTf)3 (0.1 equiv)
DCE (0.1 M), , 2 h
H
H
1a-j
3a-ac
1a:
1b:
1c:
1d:
1e:
1f:
1g:
1h:
1i:
2a:
Ar = Ph
R = H, R' = Ph
R = F, R' = Ph
R = Cl, R' = Ph
R = Br, R' = Ph
R = H, R' = 4-FC6H4
R = H, R' = 4-ClC6H4
R = H, R' = 2-ClC6H4
R = H, R' = 4-BrC6H4
R = H, R' = 4-MeC6H4
R = H, R' = 4-MeOC6H4
2k:
2l:
Ar = 4-NCC6H4
Ar = -naphtyl
Ar = -naphtyl
Ar = 2-thienyl
Ar = 2-(N-Me)indolyl
Ar = 4-(N-Me)indolyl
Ar = 2-(N-Me)pyrrolyl
Ar = 2-(N-Ts)pyrrolyl
2b:
2c:
2d:
2e:
2f:
2g:
2h:
2i:
Ar = 4-FC6H4
Ar = 4-BrC6H4
Ar = 2-BrC6H4
Ar = 4-MeC6H4
Ar = 4-MeOC6H4
Ar = 3,4-(MeO)2C6H3
Ar = 3,4,5-(MeO)3C6H2
Ar = 4-O2NC6H4
Ar = 4-MeO2CC6H4
2m:
2n:
2o:
2p:
2q:
2r:
1j:
2j:
3a:
3b:
3c:b
R = H, Ar = Ph, 88%, dr 93:7
R = F, Ar = Ph, 90%, dr 94:6
Ar
MeO2C
MeO2C
R = F, Ar = 4-MeC6H4, 89%, dr 94:6
R = Cl, Ar = Ph, 85%, dr 94:6
3d:
NPh
O
R
3e:
3f:
R = Cl, Ar = 4-FC6H4, 95%, dr 93:7
N
H
R = Br, Ar = Ph, 90%, dr 94:6
3g:b
3h:b
R = Br, Ar = 4-MeC6H4, 90%, dr 93:7
R = Br, Ar = 4-MeOC6H4, 95%, dr 95:5
3i:
3j:
3k:
3l:
R' = 4-FC6H4, 92%, dr 94:6
R' = 4-ClC6H4, 91%, dr 94:6
R' = 2-ClC6H4, 83%, dr 95:5
R' = 4-BrC6H4, 89%, dr 94:6
Ph
MeO2C
MeO2C
NR'
O
3m:
3n:
R' = 4-MeC6H4, 89%, dr 93:7
R' = 4-MeOC6H4, 93%, dr 92:8
N
H
3o:
3p:
Ar = 4-FC6H4, 96%, dr 91:9
Ar = 4-BrC6H4, 92%, dr 91:9
3q:c
3r:b
3s:b
3t:b
3u:b
3v:c
Ar = 2-BrC6H4, 49%, dr 91:9
Ar = 4-MeC6H4, 89%, dr 93:7
Ar = 4-MeOC6H4, 79%, dr 93:7
Ar = 3,4-(MeO)2C6H3, 79%, dr 93:7
Ar = 3,4,5-(MeO)3C6H2, 81%, dr 93:7
Ar = 4-O2NC6H4, 51%, dr 91:9
Ar
MeO2C
MeO2C
NPh
O
3w:d
3x:d
Ar = 4-MeO2CC6H4, 54%, dr 92:8
Ar = 4-NCC6H4, 60%, dr 91:9
Ar = -naphtyl, 91%, dr 93:7
Ar = -naphtyl, 71%, dr 93:7
Ar = 2-thienyl, 92%, dr 91:9
Ar = 2-(N-Me)indolyl, 58%, dr 93:7
Ar = 4-(N-Me)indolyl, 47%, dr 93:7
Ar = 2-(N-Me)pyrrolyl, 0%
N
H
3y:
3z:
3aa:
3ab:
3ac:
3ad:
3ae:
Ar = 2-(N-Ts)pyrrolyl, 0%
aDiastereomeric ratios (dr) were determined by NMR analysis of crude
products. bReactions were carried out for 1 h. cReactions were carried out for
20 h, extra portions of Yb(OTf)3 (0.1 equiv) were added in 8 and 16 h; 86%-
conversion of was observed. dReactions were carried out for 16 h, extra
2
portion of Yb(OTf)3 (0.1 equiv) was added in 8 h.
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The studied reactions exhibited high diastereoselectivity, affording products 3, predominantly
as trans-isomers (dr 91:9 to 95:5). Relative configuration was initially assigned according to the
results of a NOESY experiment for 3a. The presence of the characteristic H4-Hortho cross-peak
(Fig. 2) allowed us to assign the major isomer to trans-3a. Thereafter, this conclusion was
supported by the results of single crystal X-ray analysis for the major isomers of 3f,g,r.17
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H
H
X
X
5'
H
4
NPh
O
1
N
H
7
H
Figure 2. Representative NOE interactions for trans-3a.
We succeeded in the synthesis of optically active spiro[oxindole-3,2’-pyrrolidines] 3 via
[3+2]-cycloaddition of the enantiomerically enriched cyclopropane (R)-2e (er 99:1) to imines
1a,d (Scheme 2). The reaction of (R)-2e with imine 1a yielded (3S,5'S)-3r with 91:9 er (with a
slight loss in er vs. the initial cyclopropane 2e). The use of Br-derivative 1d afforded (3S,5'S)-3g
with no notable decline in er. The recently reported [3+2]-cycloaddition between triphenyl-1,3,5-
triazinane and (S)-2-phenylcyclopropane-1,1-diester exhibited
a
significant loss in
stereochemical information.13b The absolute configuration of stereocenters in (3S,5'S)-3g was
supported by single crystal X-ray analysis.17 Without imines 1, (R)-2e underwent complete
racemization under similar conditions.
Scheme 2. Synthesis of Optically Active (3S,5'S)-3g,r from Enantiomerically Enriched
Cyclopropane (R)-2e
4-Tol
NPh
CO2Me
CO2Me
Ph
MeO2C
MeO2C
N
4-Tol
R
R
2e
(R)- , er 99:1
O
O
N
N
(1.05 equiv)
Yb(OTf)3 (0.1 equiv)
DCE (0.1 M), , 1 h
H
H
1a,d
1a:
3g,r
3r:
R = H
(3S,5'S)-
R = H, 89%
dr 92:8, er 91:9
R = Br, 94%
1d:
R = Br
3g:
(3S,5'S)-
dr 93:7, er 98:2
In order to determine the scope of EWG variation, we examined [3+2]-cycloaddition with D-
A cyclopropanes 2s–aa functionalized with keto, nitro, cyano, 2-pyridyl and sulfonyl groups
(Table 3). Keto-derived cyclopropanes 2s–u were able to undergo [3+2]-cycloaddition at lower
temperatures (DCM under reflux instead of DCE), although the reaction time increased. The
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replacement of the CO2Me group (2s) by the bulkier CO2Et (2t) led to deceleration; thus, an
additional amount of the catalyst was required. For the nitro derivative 2v, the complete
conversion of the reactant was observed only under heating in DCE. The desired [3+2]-
cycloadduct 3ai was actually formed; however, only in a moderate yield (41%). Meanwhile,
methyl 5-phenyl-4,5-dihydro-1,2-oxazole-3-carboxylate 2-oxide was formed as the major
product (49%) via Cloke-like rearrangement of nitrocyclopropane 2v. In reactions with cyano
derivatives 2w,x, Yb(OTf)3 was found to be unsuitable as a catalyst. This is apparently related to
the shift of complexation equilibrium toward a relatively strong complex between the CN group
and Yb(OTf)3, precluding further interactions. As a result, Yb(OTf)3 loses its catalytic ability.
Subsequently, the yield of [3+2]-cycloadduct 3 corresponds to the amount of Yb(OTf)3 added to
the reaction mixture. Sc(OTf)3 was found to be more appropriate as a catalyst in this reaction;
however, in the case of dinitrile 2x, an equivalent of Sc(OTf)3 was added in total. Moreover, the
reactions could only be facilitated by replacing DCE by toluene which has a higher boiling point.
A significant increase in reaction time and temperature led to 3ak only forming in a 35% yield
due to considerable tarring. The reactions between 1a and 2-pyridyl-derived cyclopropane 2y as
well as cyclopropane 2z (bearing a fragment of Meldrum’s acid) exhibited similar efficiencies,
affording the corresponding products 3al and 3am in 56% and 51% yields respectively. The
sulfonyl derivative 2aa was found to be inert under heating in DCE in the presence of both
Yb(OTf)3 and Sc(OTf)3. Heating in toluene led to a slow decay of 2aa.
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The reactions with 2s–z proceeded with very high diastereoselectivities in regard to the
relative configurations of C2’ and C5’ stereocenters. Similarly to diesters 3a–ac, the products
3af–am were formed as trans-C2’-C5’ isomers (dr > 95:5). However, for compounds
3af,ag,ai,aj,al containing the third stereocenter at C3’, the diastereomeric ratios of C3’-epimers
were not very high and varied from 60:40 to 80:20 (Table 3). It is noteworthy that these ratios
differ from those for the initial cyclopropanes 2s,t,v,w,y.
Table 3. [3+2]-Cycloaddition with Variation of Electron-Withdrawing Groups in Cyclopropanes
2
Ph
EWG
EWG'
2s-aa
Ph
EWG
EWG'
5'
Ph
N
3'
2'
NPh
O
O
N
N
(1.05 equiv)
H
H
LA, 
1a
3af-am
2
EWG
EWG’
LA (equiv)
t (h)
3
Yield (%) [dr]a
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s
CO2Me
CO2Et
COMe
CO2Me
CO2Me
CN
COMe
Yb(OTf)3 (0.1)b
Yb(OTf)3 (0.1)b,c
Yb(OTf)3 (0.1)b
Yb(OTf)3 (0.1)d
Sc(OTf)3 (0.2)f
Sc(OTf)3 (0.5)f, h
Yb(OTf)3 (0.1)d
Yb(OTf)3 (0.1)b
Sc(OTf)3 (0.2)d
4
af
90 [60:40]
73 [63:37]
89
t
COMe
COMe
NO2
12
4
ag
u
v
w
x
y
z
ah
aie
ajg
akg
alg
am
an
9
2
41 [80:20]
73 [64:36]
35
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CN
8
CN
16
8
CO2Me
2-Py
56 [71:29]
51
Meldrum’s acid
CO2Me SO2Ph
2
i
aa
12
-
aDiastereomeric ratios (dr) for 3’-epimers were determined by NMR analysis of crude products;
b
dr associated with C2’-C5’ related configuration were > 95:5. DCM was used as a solvent.
cExtra portion of Yb(OTf)3 (0.1 equiv) was added in 8 h. dDCE was used as a solvent. eMethyl 5-
phenyl-4,5-dihydro-1,2-oxazole-3-carboxylate 2-oxide was obtained as the major product in a
49% yield. fToluene was used as a solvent. g95% conversion of 1a was observed. hExtra portion
of Sc(OTf)3 (0.5 equiv) was added in 8 h. iNo reaction.
An unexpected result was obtained in the reaction of imine 1a with the DA cyclopropane 2ab
containing the oxindole unit as an acceptor (Scheme 3). Besides the regular [3+2]-cycloadduct
3ao forming via the insertion of 1a into the C1’–C2’ bond of 2ab, regioisomer 3ao’ was also
obtained. A similar reactivity of DA cyclopropanes was earlier observed in the reactions of 2-
arylcyclopropane-1,1-diesters with diazenes and nitrosoarenes. It was associated with insertion
into the C2’-C3’ bond of cyclopropanes or fragmentation /recombination of reaction
intermediates.18 The structures of 3ao and 3ao’ were unambiguously proved by single crystal X-
ray analysis.17
Scheme 3. Reaction of Imine 1a with Spiro[cyclopropane-3,1’-oxindole] 2ab
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3'
2'
NPh
Ph
1'
4
5
6
O
+
O
N
N
S 2
-like
N
H
Me
1a
2ab
7
8
9
Sc(OTf)3
(0.2 equiv)
DCE (0.1 M)
, 16 h
after
after
ref 18a
ref 18b
H
N
H
N
O
O
H
N
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O
NPh
Ph
NPh
1,5
retro
N Ph
Ph
cyclization
Michael
Ph
O
+
O
N
N
Me
Me
3ao
, 29%
O
+
+
N
Me
H
H
N
O
N
O
NPh
Ph
1,5
NPh
Ph
cyclization
[3+2]
O
O
N
N
3ao'
, 19%
Me
Me
We carried out preliminary in vitro tests for a series of synthesized spiro[oxindole-3,2’-
pyrrolidines] 3 against human prostate cancer cell lines LNCaP (p53+) and PC-3 (p53-), noting
the potential ability of spiro[oxindole-3,2’-pyrrolidines] to inhibit MDM2-p53 interaction that
can result in regression of cancer cells. Nutlin-3a was used as a reference compound. The
samples containing 3a,k,l,o–r,v,aa, were found to have no significant antiproliferative effect
against these cells (IC50 > 100 M). Compounds 3i,y,z,ai exhibited an antiproliferative effect
towards LNCaP comparable to that of Nutlin-3a (Table 4). However, the selectivity that is
associated with the difference between the effects against p53-containing LNCaP and 53-free
PC-3 was not observed. Meanwhile, 3j,s,x displayed high selectivity against LNCaP (p53+) in
combination with an acceptable IC50 value. Within the examined series, compound 3j was found
to be the most promising for its further investigation as a selective inhibitor of MDM2-p53
interaction.
Table 4. Cell Assay
Compound
IC50 (µM)a
LNCaP (p53+)
PC-3 (p53-)
8.2–9.3
>100
3i
3j
6.2–8.3
6.3–7.4
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3m,n,w
>50
>20
4
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9
3s
>100
18–20
18–20
17–20
18–20
6.7–8.2
7.9–8.9
>20
3t
18–20
17–20
>100
3u
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3x
3y
13–16
9.8–11.2
>20
3z
3af
3ai
6.8–8.5
28.1–29.6
6.2–7.9
2.4–2.8
Nutlin-3a
aMTS assay was used.
CONCLUSIONS
A new approach to spiro[oxindole-3,2’-pyrrolidines] was developed based on the [3+2]-
cycloaddition of DA cyclopropanes to iminooxindoles. Commonly used 2-substituted
cyclopropane-1,1-diesters were found to be highly appropriate substrates in their efficient
transformations into the desired heterocycles under catalytic conditions with Yb(OTf)3 or
Sc(OTf)3. The extension of this method to DA cyclopropanes of other types revealed that keto,
cyano, nitro, 2-pyridyl-functionalized derivatives can undergo similar transformations quite
efficiently.
The reactions exhibit high diastereoselectivity, producing spiro[oxindole-3,2’-pyrrolidine]
with a strong predominance of trans-C3–C5’ isomers. Moreover, the use of enantiomerically
enriched DA cyclopropanes results in straightforward formation of optically active products with
high er. The stereochemical results allow for a mechanistic explanation that relies upon
stereospecific C–N bond formation via an initial SN2-like attack of the imine on the DA
cyclopropane-LA complex, followed by diastereoselective pyrrolidine ring closure. This
mechanism is in agreement with the reported ones.
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In vitro tests of a series of the synthesized compounds towards p53-containing and p53-free
cell lines, LNCaP (p53+) and PC-3 (p53-), allow for selection of several structures that are
promising in terms of their further investigation as p53-MDM inhibitors.
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EXPERIMENTAL SECTION
General Information
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NMR spectra were acquired either on Bruker Avance 600 MHz spectrometer at room
temperature; the chemical shifts  were measured in ppm with respect to solvent (1Н: CDCl3, δ =
13
7.27 ppm; DMSO-d6, δ = 2.50 ppm; C{1H}: CDCl3, δ = 77.0 ppm; DMSO-d6, δ = 39.5 ppm).
Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
double doublet. Coupling constants (J) are given in Hertz (Hz). The structures of compounds
1
were elucidated with the aid of 1D NMR (1H, 13C{1H}) and 2D NMR (1H-1H COSY, H-1H
1
NOESY, H-13C HSQC and HMBC) spectroscopy. High resolution and accurate mass
measurements were carried out using a BrukermicroTOF-QTM ESI-TOF (Electro Spray
Ionization / Time of Flight) and Thermo ScientificTM LTQ Orbitrap mass spectrometers. IR
spectra were recorded on Agilent FTIR Cary 630 spectrometers with ATR (Attenuated Total
Reflectance) module. Melting points (mp) were determined using Electrothermal IA 9100
capillary melting point apparatus. Crystallographic data were collected using MoKα (λ =
0.71073 Å) using a w-scan mode. Absorption corrections based on measurements of equivalent
reflections were applied. For 3f and 3r, the X-ray single crystal data have been collected on a
Bruker D8Venture (Photon100 CMOS detector, IμS-microsource, focusing mirrors)
diffractometer equipped with a Cryostream (Oxford Cryosystems) open-flow nitrogen cryostats
at the temperature 120.0(2) K. For (3RS,5’RS)-3g, (3S,5’S)-3g, 3ao, and 3ao’, the X-ray single
crystal data have been collected on a Bruker SMART(Photon II CMOS detector, fine-focus
sealed X-ray tube) diffractometer equipped with a Cryostream (Oxford Cryosystems) open-flow
nitrogen cryostats at the temperature 150.0(2) K. All structures were solved by direct method and
refined by full-matrix least squares on F2 for all data using Olex2119 and SHELXTL220 software.
Analytical thin layer chromatography (TLC) was carried out with silica gel plates (silica gel 60,
F254, supported on aluminium) visualized with UV lamp (254 nm). Column chromatography was
performed on silica gel 60 (230-400 mesh). Cyclopropanes 2 were synthesized according to
procedures reported earlier: 2a-r,w,y-ab,21 2s-u,x,22 2v,23 (R)-2e.24 The samples of
cyclopropanes 2 used here were identical to those used in our previous works.3h,25
Synthesis of iminooxindoles 1 (General procedure).26 The suspension of isatin (1.0 equiv) in
ethanol was heated under reflux. After isatin dissolving, acetic acid (3 drops) and amine (1.0
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equiv) were added to the reaction mixture. Then the reaction mixture was heated under reflux for
the specified time and cooled down to room temperature. The precipitate was collected by
filtration, washed with cold water and dried under reduced pressure.
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3-(Phenylimino)-1,3-dihydro-2H-indol-2-one (1a).27a A mixture of indoline-2,3-dione (5.000
g, 34.01 mmol) and aniline (3.1 mL, 34.01 mmol) in ethanol (75 mL) in the presence of acetic
acid was heated under reflux for 6 h yielding 1a (6.508 g, 86%) as yellow solid, mp 220–221 °C.
Two diastereomers E:Z = 85:15. (E)-1a: 1Н NMR (DMSO-d6, 600 MHz): δ = 6.33 (d, 3J 7.6 Hz,
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1H, Ar), 6.70 (ddd, J 7.6, 3J 7.7, 4J 0.7 Hz, 1H, Ar), 6.89 (d, J 7.8 Hz, 1H, Ar), 6.96–7.00 (m,
2H, Ar), 7.25 (t, 3J 7.4 Hz, 1H, Ar), 7.33 (ddd, 3J 7.7, 3J 7.8, 4J 1.1 Hz, 1H, Ar), 7.46 (dd, 3J 7.4,
3J 8.4 Hz, 2H, Ar), 10.99 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 111.5 (CH,
Ar), 117.2 (2 × CH, Ar), 119.1 (C, Ar), 121.7 (CH, Ar), 124.9 (CH, Ar), 125.4 (CH, Ar), 129.6
(2 × CH, Ar), 134.4 (CH, Ar), 147.0 (C, Ar), 150.6 (C, Ar), 155.0 (C=N), 163.5 (C=O). (Z)-1a:
3
1Н NMR (DMSO-d6, 600 MHz): δ = 6.86 (d, J 7.8 Hz, 1H, Ar), 6.96–7.00 (m, 2H, Ar), 7.05
(ddd, 3J 7.6, 3J 7.8, 4J 0.7 Hz, 1H, Ar), 7.10 (t, 3J 7.4 Hz, 1H, Ar), 7.28–7.31 (m, 2H, Ar), 7.43–
7.46 (m, 1H, Ar), 7.58 (d, 3J 7.2 Hz, 1H, Ar), 10.87 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6,
150 MHz): δ = 110.8 (CH, Ar), 115.7 (2 × CH, Ar), 121.4 (C, Ar), 122.3 (CH, Ar), 122.8 (CH,
Ar), 124.4 (CH, Ar), 128.3 (2 × CH, Ar), 134.2 (CH, Ar), 145.7 (C, Ar), 149.0 (C, Ar), 152.8
(C=N), 158.4 (C=O).
5-Fluoro-3-(phenylimino)-1,3-dihydro-2H-indol-2-one (1b).27b A mixture of 5-fluoroindoline-
2,3-dione (1.000 g, 6.06 mmol) and aniline (550 µL, 6.06 mmol) in ethanol (20 mL) in the
presence of acetic acid was heated under reflux for 6 h yielding 1b (1.253 g, 86%) as orange
solid, mp 237–238 °C. Two diastereomers E:Z = 82:18. (E)-1b: 1Н NMR (DMSO-d6, 600 MHz):
3
3
δ = 5.95 (dd, JHF 8.5, 4J 2.7 Hz, 1H, Ar), 6.89 (dd, J 8.6, 4JHF 4.3 Hz, 1H, Ar), 6.97–7.00 (m,
2H, Ar), 7.19 (ddd, 3J 8.6, 3JHF 9.2, 4J 2.7 Hz, 1H, Ar), 7.25–7.29 (m, 1H, Ar), 7.48 (dd, 3J 7.5, 3J
13
8.4 Hz, 2H, Ar), 10.99 (br. s, 1H, NH); C{1H} NMR (DMSO-d6, 150 MHz): δ = 111.87 (3JCF
10 Hz, C, Ar), 111.92 (2JCF 26 Hz, CH, Ar), 112.6 (3JCF 8 Hz, CH, Ar), 117.2 (2 × CH, Ar),
120.8 (2JCF 24 Hz, CH, Ar), 125.3 (CH, Ar), 129.7 (2 × CH, Ar), 143.3 (C, Ar), 150.1 (C, Ar),
154.6 (4JCF 2 Hz, C=N, Ar), 156.7 (1JCF 238 Hz, C, Ar), 163.5 (C=O). (Z)-1b: 1Н NMR (DMSO-
3
3
d6, 600 MHz): δ = 6.85 (dd, J 8.6, 4JHF 4.1 Hz, 1H, Ar), 7.01–7.03 (m, 2H, Ar), 7.12 (t, J 7.4
Hz, 1H, Ar), 7.25–7.29 (m, 1H, Ar), 7.31 (dd, 3J 7.4, 3J 8.3 Hz, 2H, Ar), 7.37 (dd, 3JHF 7.6, 4J 2.6
Hz, 1H, Ar), 10.99 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 109.7 (2JCF 25 Hz,
CH, Ar), 116.0 (3JCF 8 Hz, CH, Ar), 119.2 (2 × CH, Ar), 120.4 (2JCF 24 Hz, CH, Ar), 122.6 (3JCF
8 Hz, C, Ar), 124.8 (CH, Ar), 128.3 (2 × CH, Ar), 141.9 (C, Ar), 148.6 (C, Ar), 152.5 (4JCF 3 Hz,
C=N, Ar), 158.2 (1JCF 238 Hz, C, Ar), 158.5 (C=O).
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5-Chloro-3-(phenylimino)-1,3-dihydro-2H-indol-2-one (1c).27c A mixture of 5-chloroindoline-
2,3-dione (1.000 g, 5.51 mmol) and aniline (500 µL, 5.51 mmol) in ethanol (18 mL) in the
presence of acetic acid was heated under reflux for 12 h yielding 1c (1.113 g, 79%) as orange
solid, mp 256–257 °C. Two diastereomers E:Z = 83:17. (E)-1c: 1Н NMR (DMSO-d6, 600 MHz):
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δ = 6.20 (dd, J 2.3, 5J 0.5 Hz, 1H, Ar), 6.90 (dd, J 8.4, 5J 0.5 Hz, 1H, Ar), 6.98–7.01 (m, 2H,
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Ar), 7.29 (t, J 7.5 Hz, 1H, Ar), 7.38 (dd, J 8.4, 4J 2.3 Hz, 1H, Ar), 7.49 (dd, J 7.5, J 8.4 Hz,
2H, Ar), 11.10 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 113.1 (CH, Ar), 116.8
(C, Ar), 117.2 (2 × CH, Ar), 124.7 (CH, Ar), 125.26 (C, Ar), 125.29 (CH, Ar), 129.7 (2 × CH,
1
Ar), 133.7 (CH, Ar), 145.7 (C, Ar), 150.2 (C, Ar), 154.2 (C=N), 163.2 (C=O). (Z)-1c: Н NMR
(DMSO-d6, 600 MHz): δ = 6.87 (dd, 3J 8.4, 5J 0.4 Hz, 1H, Ar), 7.02–7.04 (m, 2H, Ar), 7.13 (t, 3J
7.5 Hz, 1H, Ar), 7.31 (dd, J 7.5, J 8.4 Hz, 2H, Ar), 7.47 (dd, J 8.4, 4J 2.2 Hz, 1H, Ar), 7.55
(dd, 4J 2.2, 5J 0.4 Hz, 1H, Ar), 11.10 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ =
112.3 (CH, Ar), 119.3 (2 × CH, Ar), 122.3 (CH, Ar), 123.0 (C, Ar), 124.9 (CH, Ar), 126.4 (C,
Ar), 128.3 (2 × CH, Ar), 133.4 (CH, Ar), 144.3 (C, Ar), 148.5 (C, Ar), 152.0 (C=N), 158.2
(C=O).
3
3
3
5-Bromo-3-(phenylimino)-1,3-dihydro-2H-indol-2-one (1d).26d,27c
A
mixture of 5-
bromoindoline-2,3-dione (452 mg, 2.00 mmol) and aniline (180 µL, 2.00 mmol) in ethanol (6.7
mL) in the presence of acetic acid was heated under reflux for 6 h yielding 1d (510 mg, 85%) as
orange solid, mp 261–262 °C. Two diastereomers E:Z = 84:16. (E)-1d: 1Н NMR (DMSO-d6, 600
MHz): δ = 6.34 (dd, 4J 2.1, 5J 0.3 Hz, 1H, Ar), 6.86 (dd, 3J 8.4, 5J 0.3 Hz, 1H, Ar), 6.98–7.00 (m,
2H, Ar), 7.29 (t, 3J 7.5 Hz, 1H, Ar), 7.47–7.52 (m, 3H, Ar), 11.11 (br. s, 1H, NH); 13C{1H} NMR
(DMSO-d6, 150 MHz): δ = 112.9 (C, Ar), 113.5 (CH, Ar), 117.2 (2 × CH, Ar), 117.3 (C, Ar),
125.3 (CH, Ar), 127.6 (CH, Ar), 129.7 (2 × CH, Ar), 136.5 (CH, Ar), 146.0 (C, Ar), 150.2 (C,
Ar), 154.1 (C=N), 163.0 (C=O). (Z)-1d: 1Н NMR (DMSO-d6, 600 MHz): δ = 6.83 (dd, 3J 8.3, 5J
3
3
3
0.4 Hz, 1H, Ar), 7.02–7.04 (m, 2H, Ar), 7.13 (t, J 7.4 Hz, 1H, Ar), 7.32 (dd, J 7.4, J 8.3 Hz,
2H, Ar), 7.60 (dd, 3J 8.3, 4J 2.1 Hz, 1H, Ar), 7.67 (dd, 4J 2.1, 5J 0.4 Hz, 1H, Ar), 11.11 (br. s, 1H,
NH); C{1H} NMR (DMSO-d6, 150 MHz): δ = 112.8 (CH, Ar), 113.9 (C, Ar), 119.3 (2 × CH,
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Ar), 123.4 (C, Ar), 124.9 (CH, Ar), 125.0 (CH, Ar), 128.3 (2 × CH, Ar), 136.2 (CH, Ar), 144.7
(C, Ar), 148.5 (C, Ar), 151.8 (C=N), 158.0 (C=O).
3-[(4-Fluorophenyl)imino]-1,3-dihydro-2H-indol-2-one (1e).27a A mixture of indoline-2,3-
dione (1.000 g, 6.80 mmol) and 4-fluoroaniline (645 µL, 6.80 mmol) in ethanol (15 mL) in the
presence of acetic acid was heated under reflux for 10 h yielding 1e (1.318 g, 81%) as red solid,
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mp 221–222 °C. Two diastereomers E:Z = 81:19. (E)-1e: Н NMR (DMSO-d6, 600 MHz): δ =
6.44 (d, J 7.8 Hz, 1H, Ar), 6.75 (ddd, J 7.7, 3J 7.8, 4J 1.0 Hz, 1H, Ar), 6.89 (d, J 7.8 Hz, 1H,
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Ar), 7.04 (dd, J 8.9, JHF 5.0 Hz, 2H, Ar), 7.30 (dd, JHF 8.8, J 8.9 Hz, 2H, Ar), 7.34 (ddd, J
7.7, 3J 7.8, 4J 1.2 Hz, 1H, Ar), 10.98 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ =
111.6 (CH, Ar), 115.6 (C, Ar), 116.4 (2JCF 23 Hz, 2 × CH, Ar), 119.4 (3JCF 8 Hz, 2 × CH, Ar),
121.8 (CH, Ar), 125.3 (CH, Ar), 134.5 (CH, Ar), 146.7 (4JCF 2 Hz, C, Ar), 147.0 (C, Ar), 155.5
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(C=N), 159.7 (1JCF 242 Hz, C, Ar), 163.4 (C=O). (Z)-1e: Н NMR (DMSO-d6, 600 MHz): δ =
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6.86 (d, 3J 7.8 Hz, 1H, Ar), 7.02–7.06 (m, 1H, Ar), 7.07–7.10 (m, 2H, Ar), 7.13 (dd, 3J 8.9, 3JHF
8.9 Hz, 2H, Ar), 7.44 (ddd, 3J 7.7, 3J 7.8, 4J 1.3 Hz, 1H, Ar), 7.57 (dd, 3J 7.5, 4J 0.6 Hz, 1H, Ar),
10.86 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 110.7 (CH, Ar), 114.9 (2JCF 23
Hz, 2 × CH, Ar), 121.4 (3JCF 9 Hz, 2 × CH, Ar), 121.5 (C, Ar), 122.3 (CH, Ar), 122.7 (CH, Ar),
134.2 (CH, Ar), 145.1 (4JCF 2 Hz, C, Ar), 145.6 (C, Ar), 153.4 (C=N), 158.5 (C=O), 159.7 (1JCF
242 Hz, C, Ar).
3-[(4-Chlorophenyl)imino]-1,3-dihydro-2H-indol-2-one (1f).27a A mixture of indoline-2,3-
dione (1.000 g, 6.80 mmol) and 4-chloroaniline (867 mg, 6.80 mmol) in ethanol (15 mL) in the
presence of acetic acid was heated under reflux for 10 h yielding 1f (1.537 g, 88%) as orange
solid, mp 259–260 °C. Two diastereomers E:Z = 77:23. (E)-1f: 1Н NMR (DMSO-d6, 600 MHz):
δ = 6.43 (d, 3J 7.7 Hz, 1H, Ar), 6.75 (dd, 3J 7.6, 3J 7.7 Hz, 1H, Ar), 6.90 (d, 3J 7.8 Hz, 1H, Ar),
7.02 (d, 3J 8.5 Hz, 2H, Ar), 7.31–7.37 (m, 1H, Ar), 7.50 (d, 3J 8.5 Hz, 2H, Ar), 10.99 (br. s, 1H,
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NH); C{1H} NMR (DMSO-d6, 150 MHz): δ = 111.9 (CH, Ar), 115.7 (C, Ar), 119.6 (2 × CH,
Ar), 122.1 (CH, Ar), 125.6 (CH, Ar), 129.3 (C, Ar), 129.8 (2 × CH, Ar), 135.0 (CH, Ar), 147.2
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(C, Ar), 149.3 (C, Ar), 155.6 (C=N), 163.6 (C=O). (Z)-1f: Н NMR (DMSO-d6, 600 MHz): δ =
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6.87 (d, J 7.8 Hz, 1H, Ar), 7.00–7.03 (m, 2H, Ar), 7.06 (dd, J 7.2, J 7.7 Hz, 1H, Ar), 7.31–
7.37 (m, 2H, Ar), 7.45 (ddd, 3J 7.7, 3J 7.8, 4J 0.6 Hz, 1H, Ar), 7.57 (d, 3J 7.2 Hz, 1H, Ar), 10.88
(br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 111.1 (CH, Ar), 121.1 (2 × CH, Ar),
121.3 (C, Ar), 122.6 (CH, Ar), 123.2 (CH, Ar), 128.5 (2 × CH, Ar), 128.7 (C, Ar), 134.7 (CH,
Ar), 146.0 (C, Ar), 148.1 (C, Ar), 153.8 (C=N), 158.7 (C=O).
3-[(2-Chlorophenyl)imino]-1,3-dihydro-2H-indol-2-one (1g).27a A mixture of indoline-2,3-
dione (1.000 g, 6.80 mmol) and 2-chloroaniline (715 µL, 6.80 mmol) in ethanol (15 mL) in the
presence of acetic acid was heated under reflux for 10 h yielding 1g as a 35:65 mixture with the
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starting isatin. Yield 1g (343 mg, 20%). Two diastereomers E:Z = 77:23. (E)-1g: Н NMR
(DMSO-d6, 600 MHz): δ = 6.25 (d, 3J 7.6 Hz, 1H, Ar), 6.74 (dd, 3J 7.6, 3J 7.6 Hz, 1H, Ar), 6.88–
6.93 (m, 1H, Ar), 7.07–7.11 (m, 1H, Ar), 7.24–7.28 (m, 1H, Ar), 7.36 (dd, 3J 7.7, 3J 7.7 Hz, 1H,
Ar), 7.40–7.43 (m, 1H, Ar), 7.54–7.59 (m, 1H, Ar), 11.02 (br. s, 1H, NH); 13C{1H} NMR
(DMSO-d6, 150 MHz): δ = 112.0 (CH, Ar), 116.0 (C, Ar), 119.1 (CH, Ar), 121.3 (C, Ar), 122.4
(CH, Ar), 125.3 (CH, Ar), 126.5 (CH, Ar), 128.7 (CH, Ar), 130.3 (CH, Ar), 135.4 (CH, Ar),
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147.2 (C, Ar), 147.4 (C, Ar), 156.8 (C=N), 163.4 (C=O). (Z)-1g: Н NMR (DMSO-d6, 600
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7.5, J 7.5 Hz, 1H, Ar), 7.45–7.48 (m, 2H, Ar), 7.54–7.59 (m, 1H, Ar), 7.64 (d, J 7.4 Hz, 1H,
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Ar), 11.02 (br. s, 1H, NH); C{1H} NMR (DMSO-d6, 150 MHz): δ = 111.3 (CH, Ar), 119.9
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(CH, Ar), 120.7 (C, Ar), 121.9 (C, Ar), 122.8 (CH, Ar), 123.5 (CH, Ar), 125.4 (CH, Ar), 127.5
(CH, Ar), 129.3 (CH, Ar), 135.2 (CH, Ar), 146.4 (C, Ar), 147.0 (C, Ar), 155.1 (C=N), 158.5
(C=O).
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3-[(4-Bromophenyl)imino]-1,3-dihydro-2H-indol-2-one (1h).27a A mixture of indoline-2,3-
dione (1.000 g, 6.80 mmol) and 4-bromoaniline (1.163 g, 6.80 mmol) in ethanol (15 mL) in the
presence of acetic acid was heated under reflux for 6 h yielding 1h (1.825 g, 89%) as orange
solid, mp 272–273 °C. Two diastereomers E:Z = 77:23. (E)-1h: 1Н NMR (DMSO-d6, 600 MHz):
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δ = 6.44 (dd, J 7.8, J 0.9 Hz, 1H, Ar), 6.77 (ddd, J 7.7, 3J 7.8, 4J 0.9 Hz, 1H, Ar), 6.90 (d, J
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7.8 Hz, 1H, Ar), 6.95–6.99 (m, 2H, Ar), 7.36 (ddd, J 7.7, 3J 7.8, 4J 1.1 Hz, 1H, Ar), 7.64 (d, J
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8.7 Hz, 2H, Ar), 10.97 (br. s, 1H, NH); C{1H} NMR (DMSO-d6, 150 MHz): δ = 111.6 (CH,
Ar), 115.6 (C, Ar), 117.1 (C, Ar), 119.8 (2 × CH, Ar), 121.9 (CH, Ar), 125.4 (CH, Ar), 132.5 (2
× CH, Ar), 134.7 (CH, Ar), 147.1 (C, Ar), 149.6 (C, Ar), 155.3 (C=N), 163.3 (C=O). (Z)-1h: 1Н
NMR (DMSO-d6, 600 MHz): δ = 6.86 (d, 3J 7.8 Hz, 1H, Ar), 6.95–6.99 (m, 2H, Ar), 7.06 (ddd,
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3J 7.5, J 7.8, J 0.8 Hz, 1H, Ar), 7.44–7.48 (m, 3H, Ar), 7.58 (d, J 7.6, J 0.8 Hz, 1H, Ar),
10.97 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 110.8 (CH, Ar), 116.7 (C, Ar),
121.19 (C, Ar), 121.23 (2 × CH, Ar), 122.4 (CH, Ar), 123.0 (CH, Ar), 131.1 (2 × CH, Ar), 134.5
(CH, Ar), 145.9 (C, Ar), 148.4 (C, Ar), 153.5 (C=N), 158.5 (C=O).
3-[(4-Methylphenyl)imino]-1,3-dihydro-2H-indol-2-one (1i).27a A mixture of indoline-2,3-
dione (1.349 g, 9.18 mmol) and p-toluidine (982 mg, 9.18 mmol) in ethanol (20 mL) in the
presence of acetic acid was heated under reflux for 6 h yielding 1i (1.887 g, 87%) as yellow
solid, mp 225–226 °C. Two diastereomers E:Z = 86:14. (E)-1i: 1Н NMR (DMSO-d6, 600 MHz):
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6.87–6.90 (m, 3H, Ar), 7.26 (d, J 8.1 Hz, 2H, Ar), 7.33 (ddd, J 7.6, 3J 7.7, 4J 1.0 Hz, 1H, Ar),
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10.96 (br. s, 1H, NH); C{1H} NMR (DMSO-d6, 150 MHz): δ = 20.58 (CH3), 111.5 (CH, Ar),
115.7 (C, Ar), 117.5 (2 × CH, Ar), 121.7 (CH, Ar), 125.2 (CH, Ar), 130.0 (2 × CH, Ar), 134.2
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(C, Ar), 134.3 (CH, Ar), 146.9 (C, Ar), 147.8 (C, Ar), 154.8 (C=N), 163.6 (C=O). (Z)-1i: Н
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NMR (DMSO-d6, 600 MHz): δ = 2.29 (s, 3H, CH3), 6.85 (d, J 7.8 Hz, 1H, Ar), 6.94 (d, J 8.2
Hz, 2H, Ar), 7.04 (dd, 3J 7.4, 3J 7.6 Hz, 1H, Ar), 7.11 (d, 3J 8.2 Hz, 2H, Ar), 7.43 (ddd, 3J 7.6, 3J
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7.8, J 1.1 Hz, 1H, Ar), 7.56 (d, J 7.4 Hz, 1H, Ar), 10.96 (br. s, 1H, NH); 13C{1H} NMR
(DMSO-d6, 150 MHz): δ = 20.61 (CH3), 110.7 (CH, Ar), 119.7 (2 × CH, Ar), 122.3 (CH, Ar),
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(C, Ar), 152.5 (C=N), 158.5 (C=O).
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3-[(4-Methoxyphenyl)imino]-1,3-dihydro-2H-indol-2-one (1j).27a A mixture of indoline-2,3-
dione (1.294 g, 8.80 mmol) and 4-methoxyaniline (1.083 g, 8.80 mmol) in ethanol (20 mL) in
the presence of acetic acid was heated under reflux for 6 h yielding 1j (2.007 g, 90%) as orange
solid, mp 234–235 °C. Two diastereomers E:Z = 83:17. (E)-1j: 1Н NMR (DMSO-d6, 600 MHz):
δ = 3.79 (s, 3H, OCH3), 6.65 (d, 3J 7.7 Hz, 1H, Ar), 6.73 (ddd, 3J 7.6, 3J 7.7, 4J 0.8 Hz, 1H, Ar),
6.87–6.90 (m, 1H, Ar), 6.98 (d, 3J 8.9 Hz, 2H, Ar), 7.02 (d, 3J 8.9 Hz, 2H, Ar), 7.32 (ddd, 3J 7.7,
3J 7.8, 4J 1.2 Hz, 1H, Ar), 10.92 (br. s, 1H, NH); 13C{1H} NMR (DMSO-d6, 150 MHz): δ = 55.3
(OCH3), 111.5 (CH, Ar), 114.7 (2 × CH, Ar), 115.8 (C, Ar), 119.5 (2 × CH, Ar), 121.7 (CH, Ar),
125.0 (CH, Ar), 134.2 (CH, Ar), 143.1 (C, Ar), 146.8 (C, Ar), 154.5 (C, Ar), 157.1 (C=N), 163.7
(C=O). (Z)-1j: 1Н NMR (DMSO-d6, 600 MHz): δ = 3.76 (s, 3H, OCH3), 6.84 (d, 3J 7.8 Hz, 1H,
Ar), 6.87–6.90 (m, 2H, Ar), 7.01–7.04 (m, 1H, Ar), 7.18 (d, 3J 8.9 Hz, 2H, Ar), 7.40 (ddd, 3J 7.7,
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3J 7.8, J 1.2 Hz, 1H, Ar), 7.54 (d, J 7.4 Hz, 1H, Ar), 10.92 (br. s, 1H, NH); C{1H} NMR
(DMSO-d6, 150 MHz): δ = 55.2 (OCH3), 110.6 (CH, Ar), 113.4 (2 × CH, Ar), 115.8 (C, Ar),
122.2 (CH, Ar), 122.3 (CH, Ar), 122.8 (2 × CH, Ar), 133.5 (CH, Ar), 141.1 (C, Ar), 145.0 (C,
Ar), 151.6 (C, Ar), 157.6 (C=N), 158.7 (C=O).
3-(Butylimino)-1,3-dihydro-2H-indol-2-one (1k).27d A mixture of indoline-2,3-dione (3.000 g,
20.41 mmol) and butylamine (2.0 mL, 20.41 mmol) in ethanol (30 mL) was stirred for 2 h
yielding 1k (3.760 g, 91%) as yellow solid, mp 102–103 °C. Two diastereomers E:Z = 75:25.
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(E)-1k: Н NMR (CDCl3, 600 MHz): δ = 0.94–0.99 (m, 3H, CH3), 1.43–1.55 (m, 2H, CH2),
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1.89–1.95 (m, 2H, CH2), 4.02 (t, J 7.1 Hz, 2H, NCH2), 6.97 (d, J 7.8 Hz, 1H, Ar), 6.99–7.05
(m, 1H, Ar), 7.34 (ddd, 3J 7.6, 3J 7.8, 3J 0.8 Hz, 1H, Ar), 7.63 (d, 3J 7.5 Hz, 1H, Ar), 10.31 (br. s,
1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 13.78 (CH3), 20.8 (CH2), 32.6 (CH2), 54.1
(NCH2), 111.9 (CH, Ar), 117.1 (C, Ar), 122.74 (CH, Ar), 126.8 (CH, Ar), 133.2 (CH, Ar), 145.1
(C, Ar), 154.7 (C=N), 165.9 (C=O). (Z)-1k: 1Н NMR (CDCl3, 600 MHz): δ = 0.94–0.99 (m, 3H,
CH3), 1.43–1.55 (m, 2H, CH2), 1.75–1.81 (m, 2H, CH2), 4.38 (t, 3J 7.2 Hz, 2H, NCH2), 6.86 (d,
3J 7.7 Hz, 1H, Ar), 6.99–7.05 (m, 1H, Ar), 7.29 (ddd, 3J 7.7, 3J 7.7, 4J 1.0 Hz, 1H, Ar), 7.57 (d,
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3J 7.5 Hz, 1H, Ar), 9.57 (br. s, 1H, NH); C{1H} NMR (CDCl3, 150 MHz): δ = 13.84 (CH3),
20.6 (CH2), 33.3 (CH2), 52.0 (NCH2), 110.6 (CH, Ar), 121.9 (CH, Ar), 122.1 (C, Ar), 122.74
(CH, Ar), 132.4 (CH, Ar), 143.2 (C, Ar), 153.1 (C=N), 160.6 (C=O).
Methyl 2-phenyl-1-(phenylsulfonyl)cyclopropanecarboxylate (2aa).
A
mixture of
benzaldehyde (1.700 g, 16 mmol), methyl 2-(phenylsulfonyl)acetate (2.3 mL, 14 mmol),
piperidine (135 µL) and acetic acid (160 µL) in benzene (7 mL) was heated at reflux temperature
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with a Dean-Stark trap for 1 h. After cooling to ambient temperature, the reaction mixture was
washed twice with brine, dried with Na2SO4, and concentrated under reduced pressure. The
resulting alkene (3.729 g, 88%) was further used without purification. To a suspension of NaH
(892 mg, 13.38 mmol, 60% suspension in mineral oil) in dry DMSO (10 mL) Me3SOI (2.706 g,
12.26 mmol) was added in one portion under inert atmosphere. After stirring for 25 min at
ambient temperature, solution of alkene (3.370 g, 11.15 mmol) in DMSO (20 mL) was added
dropwise under vigorous stirring. The mixture was stirred for additional 3.5 h, quenched with ice
water and extracted with EtOAc. Combined organic fractions were washed with water, dried
with Na2SO4 and concentrated under reduced pressure yielding 2aa (2.7 g, 77%) as yellowish
oil, dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.41 (dd, 2J 5.7, 3J 8.5 Hz, 1H, CH2), 2.46 (dd, 2J
5.7, 3J 10.0 Hz, 1H, CH2), 3.25 (s, 3H, OCH3), 3.47 (dd, 3J 8.5, 3J 10.0 Hz, 1H, CH), 7.04–7.07
(m, 2H, Ar), 7.20–7.24 (m, 3H, Ar), 7.58–7.62 (m, 2H, Ar), 7.67–7.71 (m, 1H, Ar), 8.05–8.08
(m, 2H, Ar); 13C{1H} NMR (CDCl3, 150 MHz): δ = 17.6 (CH2), 32.9 (CH), 52.16 (OCH3), 52.22
(C), 127.7 (CH, Ar), 128.2 (2 × CH, Ar), 128.4 (2 × CH, Ar), 128.7 (2 × CH, Ar), 129.1 (2 ×
CH, Ar), 132.8 (C, Ar), 133.7 (CH, Ar), 139.5 (C, Ar), 164.2 (CO2Me). HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C17H17O4S+, 317.0842, found 317.0837.
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Synthesis of spiro[oxindole-3,2’-pyrrolidines] 3 (General procedure).
The solution of iminooxindole 1 (1.0 equiv), cyclopropane 2 (1.05 equiv) and Lewis acid in
appropriate solvent (0.1 M) was heated under reflux for specified time. Then the reaction
mixture was concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel.
Dimethyl (3RS,5'RS)-2-oxo-1',5'-diphenyl-1,2-dihydro-3'H-spiro[indole-3,2'-pyrrolidine]-
3',3'-dicarboxylate (3a). A solution of imine 1a (117 mg, 0.53 mmol), cyclopropane 2a (130
mg, 0.56 mmol) and Yb(OTf)3 (33 mg, 0.05 mmol) in DCE (5.3 mL) was heated under reflux for
2 h yielding 3a (213 mg, 88%) as yellow foam. Rf = 0.50 (ethyl acetate/petroleum ether; 1:1), dr
93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.79 (dd, 2J 13.7, 3J 7.8 Hz, 1H, CH2), 3.37 (dd, 2J 13.7,
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3J 8.5 Hz, 1H, CH2), 3.56 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 5.77 (dd, J 7.8, J 8.5 Hz, 1H,
CH), 6.66–6.69 (m, 2H, Ar), 6.72 (t, 3J 7.3 Hz, 1H, Ar), 6.76 (ddd, 3J 7.8, 4J 0.9, 5J 0.5 Hz, 1H,
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Ar), 6.90 (dd, J 7.3, 3J 8.6 Hz, 2H, Ar), 7.06 (ddd, J 7.6, J 7.6, J 1.0 Hz, 1H, Ar), 7.17 (t, J
7.4 Hz, 1H, Ar), 7.24–7.29 (m, 3H, Ar), 7.36–7.38 (m, 1H, Ar), 7.48–7.50 (m, 2H, Ar), 7.70 (br.
s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.5 (CH2), 52.6 (OCH3), 53.0 (OCH3), 62.3
(CH), 66.4 (C), 76.3 (C), 110.1 (CH, Ar), 122.1 (2 × CH, Ar), 122.48 (CH, Ar), 122.50 (CH, Ar),
125.4 (CH, Ar), 127.0 (CH, Ar), 127.2 (2 × CH, Ar), 128.2 (C, Ar), 128.26 (2 × CH, Ar), 128.33
(2 × CH, Ar), 129.9 (CH, Ar), 141.3 (C, Ar), 142.3 (C, Ar), 143.5 (C, Ar), 169.4 (CO2Me), 169.6
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(CO2Me), 176.5 (C=O). IR (film, cm-1): 3305, 2950, 2915, 2850, 1730, 1615, 1595. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for С27Н25N2O5, 457.1758, found 457.1758.
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pyrrolidine]-3',3'-dicarboxylate (3b). A solution of imine 1b (184 mg, 0.77 mmol),
cyclopropane 2a (188 mg, 0.80 mmol) and Yb(OTf)3 (48 mg, 0.08 mmol) in DCE (7.7 mL) was
heated under reflux for 2 h yielding 3b (326 mg, 90%) as yellow foam. Rf = 0.36 (ethyl
acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.77 (dd, 2J 13.6, 3J 7.6
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Hz, 1H, CH2), 3.42 (dd, J 13.6, 3J 8.5 Hz, 1H, CH2), 3.60 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
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5.79 (dd, J 7.6, J 8.5 Hz, 1H, CH), 6.65 (dd, J 8.5, JHF 4.2 Hz, 1H, Ar), 6.68–6.71 (m, 2H,
Ar), 6.73 (t, 3J 7.4 Hz, 1H, Ar), 6.91 (dd, 3J 7.4, 3J 8.6 Hz, 2H, Ar), 6.95 (ddd, 3J 8.5, 3JHF 8.8, 4J
2.6 Hz, 1H, Ar), 7.16 (dd, 3J 8.2, 4J 2.6 Hz, 1H, Ar), 7.20 (t, 3J 7.4 Hz, 1H, Ar), 7.29 (dd, 3J 7.6,
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3J 7.9 Hz, 2H, Ar), 7.49–7.51 (m, 2H, Ar), 8.78 (br. s, 1H, NH); C{1H} NMR (CDCl3, 150
MHz): δ = 40.5 (CH2), 52.7 (OCH3), 53.0 (OCH3), 62.5 (CH), 66.3 (C), 76.6 (C), 111.0 (3JCF
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Hz, CH, Ar), 113.1 (2JCF 26 Hz, CH, Ar), 116.3 (2JCF 23 Hz, CH, Ar), 121.9 (2 × CH, Ar), 122.6
(CH, Ar), 127.1 (3 × CH, Ar), 128.4 (4 × CH, Ar), 129.7 (3JCF 7 Hz, C, Ar), 137.5 (C, Ar), 141.9
(C, Ar), 143.2 (C, Ar), 158.9 (1JCF 241 Hz, C, Ar), 169.1 (CO2Me), 169.3 (CO2Me), 177.3
(C=O). HRMS (ESI-TOF) m/z: [M + H]+ calcd for С27Н24FN2O5, 475.1664, found 475.1668.
Dimethyl
(3RS,5'RS)-5-fluoro-5'-(4-methylphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3c). A solution of imine 1b (174 mg, 0.73
mmol), cyclopropane 2e (189 mg, 0.76 mmol) and Yb(OTf)3 (45 mg, 0.07 mmol) in DCE (7.3
mL) was heated under reflux for 1 h yielding 3c (316 mg, 89%) as yellowish foam. Rf = 0.40
(ethyl acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.29 (s, 3H, CH3),
2.74 (dd, 2J 13.7, 3J 7.6 Hz, 1H, CH2), 3.39 (dd, 2J 13.7, 3J 8.5 Hz, 1H, CH2), 3.60 (s, 3H, OCH3),
3.70 (s, 3H, OCH3), 5.75 (dd, 3J 7.6, 3J 8.5 Hz, 1H, CH), 6.65 (dd, 3J 8.5, 4JHF 4.2 Hz, 1H, Ar),
6.67–6.70 (m, 2H, Ar), 6.73 (t, 3J 7.3 Hz, 1H, Ar), 6.91 (dd, 3J 7.4, 3J 8.7 Hz, 2H, Ar), 6.95 (ddd,
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3J 8.5, JHF 8.8, J 2.6 Hz, 1H, Ar), 7.09 (d, J 7.7 Hz, 2H, Ar), 7.15 (dd, J 8.2, J 2.6 Hz, 1H,
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Ar), 7.37 (d, J 8.1 Hz, 2H, Ar), 8.66 (br. s, 1H, NH); C{1H} NMR (CDCl3, 150 MHz): δ =
21.0 (CH3), 40.6 (CH2), 52.7 (OCH3), 53.0 (OCH3), 62.3 (CH), 66.3 (C), 76.5 (C), 111.0 (3JCF
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Hz, CH, Ar), 113.2 (2JCF 26 Hz, CH, Ar), 116.3 (2JCF 23 Hz, CH, Ar), 121.8 (2 × CH, Ar), 122.5
(CH, Ar), 127.0 (2 × CH, Ar), 128.3 (2 × CH, Ar), 129.1 (2 × CH, Ar), 129.9 (3JCF 7 Hz, C, Ar),
136.6 (C, Ar), 137.5 (C, Ar), 138.9 (C, Ar), 143.3 (C, Ar), 158.9 (1JCF 241 Hz, C, Ar), 169.1
(CO2Me), 169.4 (CO2Me), 177.3 (C=O). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
С28Н26FN2O5, 489.1820, found 489.1833.
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Dimethyl
(3RS,5'RS)-5-chloro-2-oxo-1',5'-diphenyl-1,2-dihydro-3'H-spiro[indole-3,2'-
pyrrolidine]-3',3'-dicarboxylate (3d). A solution of imine 1c (161 mg, 0.63 mmol),
cyclopropane 2a (154 mg, 0.66 mmol) and Yb(OTf)3 (39 mg, 0.06 mmol) in DCE (6.3 mL) was
heated under reflux for 2 h yielding 3d (262 mg, 85%) as yellowish oil. Rf = 0.52 (ethyl
acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.78 (dd, 2J 13.6, 3J 7.3
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Hz, 1H, CH2), 3.41 (dd, J 13.6, 3J 8.8 Hz, 1H, CH2), 3.64 (s, 3H, OCH3), 3.69 (s, 3H, OCH3),
5.76 (dd, 3J 7.3, 3J 8.8 Hz, 1H, CH), 6.63 (dd, 3J 8.3, 5J 0.3 Hz, 1H, Ar), 6.70–6.73 (m, 2H, Ar),
6.76 (t, 3J 7.3 Hz, 1H, Ar), 6.92 (dd, 3J 7.3, 3J 8.6 Hz, 2H, Ar), 7.19 (t, 3J 7.4 Hz, 1H, Ar), 7.21
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(dd, J 8.3, J 2.1 Hz, 1H, Ar), 7.29 (dd, J 7.4, J 7.9 Hz, 2H, Ar), 7.37 (dd, J 2.1, J 0.3 Hz,
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1H, Ar), 7.50–7.52 (m, 2H, Ar), 8.50 (br. s, 1H, NH); C{1H} NMR (CDCl3, 150 MHz): δ =
40.3 (CH2), 52.8 (OCH3), 53.0 (OCH3), 62.5 (CH), 66.3 (C), 76.5 (C), 111.3 (CH, Ar), 122.6 (2
× CH, Ar), 123.1 (CH, Ar), 125.7 (CH, Ar), 127.1 (CH, Ar), 127.2 (2 × CH, Ar), 127.8 (C, Ar),
128.3 (2 × CH, Ar), 128.4 (2 × CH, Ar), 129.6 (C, Ar), 129.8 (CH, Ar), 140.1 (C, Ar), 141.8 (C,
Ar), 143.1 (C, Ar), 169.2 (CO2Me), 169.4 (CO2Me), 177.1 (C=O). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for С27Н24ClN2O5, 491.1368, found 491.1357.
Dimethyl
(3RS,5'RS)-5-chloro-5'-(4-fluorophenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3e). A solution of imine 1c (171 mg, 0.67
mmol), cyclopropane 2b (176 mg, 0.70 mmol) and Yb(OTf)3 (41 mg, 0.07 mmol) in DCE (6.7
mL) was heated under reflux for 2 h yielding 3e (321 mg, 95%) as yellowish foam. Rf = 0.46
(ethyl acetate/petroleum ether; 1:1), dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.76 (dd, 2J 13.7,
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3J 6.9 Hz, 1H, CH2), 3.41 (dd, J 13.7, 3J 9.0 Hz, 1H, CH2), 3.66 (s, 3H, OCH3), 3.68 (s, 3H,
OCH3), 5.71 (dd, 3J 6.9, 3J 9.0 Hz, 1H, CH), 6.59 (dd, 3J 8.2, 5J 0.3 Hz, 1H, Ar), 6.76–6.81 (m,
3H, Ar), 6.92 (dd, 3J 7.4, 3J 8.6 Hz, 2H, Ar), 6.95 (dd, 3J 8.7, 3JHF 8.8 Hz, 2H, Ar), 7.19 (dd, 3J
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8.2, J 2.1 Hz, 1H, Ar), 7.35 (dd, J 2.1, J 0.3 Hz, 1H, Ar), 7.52 (dd, J 8.7, JHF 5.4 Hz, 2H,
Ar), 8.55 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.1 (CH2), 52.8 (OCH3), 52.9
(OCH3), 61.7 (CH), 65.9 (C), 76.6 (C), 111.3 (CH, Ar), 115.1 (2JCF 21 Hz, 2 × CH, Ar), 123.87
(2 × CH, Ar), 123.91 (CH, Ar), 125.8 (CH, Ar), 127.6 (C, Ar), 128.4 (2 × CH, Ar), 128.9 (C,
Ar), 129.0 (3JCF 8 Hz, 2 × CH, C, Ar), 129.9 (CH, Ar), 137.4 (4JCF 2 Hz, C, Ar), 140.3 (C, Ar),
142.8 (C, Ar), 161.9 (1JCF 244 Hz, C, Ar), 169.50 (CO2Me), 169.54 (CO2Me), 177.2 (C=O).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for С27Н23ClFN2O5, 509.1274, found 509.1263.
Dimethyl
(3RS,5'RS)-5-bromo-2-oxo-1',5'-diphenyl-1,2-dihydro-3'H-spiro[indole-3,2'-
pyrrolidine]-3',3'-dicarboxylate (3f). A solution of imine 1d (128 mg, 0.43 mmol),
cyclopropane 2a (105 mg, 0.45 mmol) and Yb(OTf)3 (26 mg, 0.04 mmol) in DCE (4.3 mL) was
heated under reflux for 2 h yielding 3f (205 mg, 90%) as yellowish crystals, mp 203–204 C. Rf
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= 0.52 (ethyl acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.79 (dd, 2J
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13.6, 3J 7.2 Hz, 1H, CH2), 3.41 (dd, J 13.6, 3J 8.8 Hz, 1H, CH2), 3.65 (s, 3H, OCH3), 3.68 (s,
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3H, OCH3), 5.76 (dd, 3J 7.2, 3J 8.8 Hz, 1H, CH), 6.58 (d, 3J 8.3 Hz, 1H, Ar), 6.71–6.74 (m, 2H,
Ar), 6.76 (t, 3J 7.4 Hz, 1H, Ar), 6.92 (dd, 3J 7.4, 3J 8.6 Hz, 2H, Ar), 7.19 (t, 3J 7.4 Hz, 1H, Ar),
7.29 (dd, 3J 7.4, 3J 7.9 Hz, 2H, Ar), 7.35 (dd, 3J 8.3, 3J 2.0 Hz, 1H, Ar), 7.50–7.53 (m, 3H, Ar),
8.63 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.2 (CH2), 52.8 (OCH3), 53.0
(OCH3), 62.4 (CH), 66.3 (C), 76.5 (C), 111.9 (CH, Ar), 114.9 (C, Ar), 122.7 (2 × CH, Ar), 123.1
(CH, Ar), 127.1 (CH, Ar), 127.2 (2 × CH, Ar), 128.3 (2 × CH, Ar), 128.4 (2 × CH, Ar), 128.5
(CH, Ar), 129.8 (C, Ar), 132.7 (CH, Ar), 140.7 (C, Ar), 141.8 (C, Ar), 143.1 (C, Ar), 169.2
(CO2Me), 169.4 (CO2Me), 177.0 (C=O). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
С27Н2479BrN2O5, 535.0863, found 535.0849.
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Dimethyl
(3RS,5'RS)-5-bromo-5'-(4-methylphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3g). A solution of imine 1d (174 mg, 0.58
mmol), cyclopropane 2e (151 mg, 0.61 mmol) and Yb(OTf)3 (36 mg, 0.06 mmol) in DCE (5.8
mL) was heated under reflux for 1 h yielding 3g (284 mg, 90%) as yellowish crystals, mp 231–
232 C. Rf = 0.54 (ethyl acetate/petroleum ether; 1:1), dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ =
2.30 (s, 3H, CH3), 2.78 (dd, 2J 13.6, 3J 7.4 Hz, 1H, CH2), 3.39 (dd, 2J 13.6, 3J 8.7 Hz, 1H, CH2),
3.64 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 5.74 (dd, 3J 7.4, 3J 8.7 Hz, 1H, CH), 6.57 (d, 3J 8.3 Hz,
1H, Ar), 6.71–6.73 (m, 2H, Ar), 6.75 (t, 3J 7.3 Hz, 1H, Ar), 6.92 (dd, 3J 7.3, 3J 8.7 Hz, 2H, Ar),
7.10 (d, 3J 8.2 Hz, 2H, Ar), 7.35 (dd, 3J 8.3, 4J 2.0 Hz, 1H, Ar), 7.40 (d, 3J 8.2 Hz, 2H, Ar), 7.51
(d, 4J 2.0 Hz, 1H, Ar), 8.73 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 21.0 (CH3),
40.3 (CH2), 52.7 (OCH3), 52.9 (OCH3), 62.2 (CH), 66.3 (C), 76.4 (C), 111.9 (CH, Ar), 114.9 (C,
Ar), 122.4 (2 × CH, Ar), 122.9 (CH, Ar), 127.1 (2 × CH, Ar), 128.3 (2 × CH, Ar), 128.4 (CH,
Ar), 129.0 (2 × CH, Ar), 130.0 (C, Ar), 132.6 (CH, Ar), 136.6 (C, Ar), 138.8 (C, Ar), 140.6 (C,
Ar), 143.2 (C, Ar), 169.1 (CO2Me), 169.4 (CO2Me), 177.0 (C=O). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for С28Н2679BrN2O5, 549.1020, found 549.1020.
Dimethyl
(3S,5'S)-5-bromo-5'-(4-methylphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate ((3S,5’S)-3g) was obtained by the same
procedure from 1d and (R)-2e (er 99:1); NMR spectra coincide with that of 3g. Yellowish
crystals, mp 211–212 C. []D25 = +172.0 (c 0.50, EtOH), er 98:2.
Dimethyl
(3RS,5'RS)-5-bromo-5'-(4-methoxyphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3h). A solution of imine 1d (132 mg, 0.44
mmol), cyclopropane 2f (122 mg, 0.46 mmol) and Yb(OTf)3 (27 mg, 0.04 mmol) in DCE (4.4
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mL) was heated under reflux for 1 h yielding 3h (235 mg, 95%) as yellowish foam. Rf = 0.46
(ethyl acetate/petroleum ether; 1:1), dr 95:5. 1Н NMR (CDCl3, 600 MHz): δ = 2.79 (dd, 2J 13.7,
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3J 7.2 Hz, 1H, CH2), 3.39 (dd, J 13.7, 3J 8.8 Hz, 1H, CH2), 3.66 (s, 3H, OCH3), 3.66 (s, 3H,
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OCH3), 3.73 (s, 3H, OCH3), 5.71 (dd, J 7.2, J 8.8 Hz, 1H, CH), 6.53 (d, J 8.2 Hz, 1H, Ar),
6.74–6.77 (m, 3H, Ar), 6.82 (d, 3J 8.9 Hz, 2H, Ar), 6.91 (dd, 3J 7.3, 3J 8.8 Hz, 2H, Ar), 7.33 (dd,
3J 8.2, 4J 2.0 Hz, 1H, Ar), 7.46 (d, 3J 8.9 Hz, 2H, Ar), 7.51 (d, 4J 2.0 Hz, 1H, Ar), 8.83 (br. s, 1H,
NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.2 (CH2), 52.7 (OCH3), 52.9 (OCH3), 55.0
(OCH3), 61.8 (CH), 66.0 (C), 76.4 (C), 111.8 (CH, Ar), 113.6 (2 × CH, Ar), 114.7 (C, Ar), 123.0
(2 × CH, Ar), 123.2 (CH, Ar), 128.2 (2 × CH, Ar), 128.4 (3 × CH, Ar), 129.7 (C, Ar), 132.5
(CH, Ar), 133.7 (C, Ar), 140.7 (C, Ar), 143.0 (C, Ar), 158.5 (C, Ar), 169.3 (CO2Me), 169.4
(CO2Me), 177.1 (C=O). HRMS (ESI-TOF) m/z: [M + H]+ calcd for С28Н2679BrN2O6, 565.0969,
found 565.0947.
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Dimethyl
(3RS,5'RS)-1'-(4-fluorophenyl)-2-oxo-5'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3i). A solution of imine 1e (150 mg, 0.63 mmol),
cyclopropane 2a (154 mg, 0.66 mmol) and Yb(OTf)3 (39 mg, 0.06 mmol) in DCE (6.3 mL) was
heated under reflux for 2 h yielding 3i (272 mg, 92%) as yellow foam. Rf = 0.46 (ethyl
acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.82 (dd, 2J 13.7, 3J 7.2
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Hz, 1H, CH2), 3.40 (dd, J 13.7, 3J 9.0 Hz, 1H, CH2), 3.65 (s, 3H, OCH3), 3.68 (s, 3H, OCH3),
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5.67 (dd, J 7.2, J 9.0 Hz, 1H, CH), 6.57 (dd, JHF 8.4, J 9.2 Hz, 2H, Ar), 6.71 (ddd, J 7.8, J
0.9, 5J 0.5 Hz, 1H, Ar), 6.77 (dd, 3J 9.2, 4JHF 4.9 Hz, 2H, Ar), 7.06 (ddd, 3J 7.6, 3J 7.6, 4J 0.9 Hz,
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1H, Ar), 7.18 (t, J 7.4 Hz, 1H, Ar), 7.23 (ddd, J 7.6, J 7.8, J 1.1 Hz, 1H, Ar), 7.24–7.28 (m,
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2H, Ar), 7.37 (ddd, J 7.6, 4J 1.1, J 0.5 Hz, 1H, Ar), 7.53–7.55 (m, 2H, Ar), 8.22 (br. s, 1H,
NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.3 (CH2), 52.7 (OCH3), 52.9 (OCH3), 62.5 (CH),
65.9 (C), 76.8 (C), 110.3 (CH, Ar), 114.9 (2JCF 22 Hz, 2 × CH, Ar), 122.3 (CH, Ar), 125.5 (CH,
Ar), 125.8 (3JCF 8 Hz, 2 × CH, Ar), 127.1 (C, Ar), 127.2 (CH, Ar), 127.6 (2 × CH, Ar), 128.3 (2
× CH, Ar), 130.1 (CH, Ar), 139.1 (4JCF 2 Hz, C, Ar), 141.7 (C, Ar), 141.8 (C, Ar), 159.1 (1JCF
243 Hz, C, Ar), 169.8 (CO2Me), 169.9 (CO2Me), 177.4 (C=O). IR (film, cm-1): 3290, 3065,
2955, 2880, 1735, 1720, 1700, 1620, 1600. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
С27Н24FN2O5, 475.1664, found 475.1673.
Dimethyl
(3RS,5'RS)-1'-(4-chlorophenyl)-2-oxo-5'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3j). A solution of imine 1f (166 mg, 0.65 mmol),
cyclopropane 2a (159 mg, 0.68 mmol) and Yb(OTf)3 (40 mg, 0.06 mmol) in DCE (6.5 mL) was
heated under reflux for 2 h yielding 3j (287 mg, 91%) as yellow foam. Rf = 0.46 (ethyl
acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.80 (dd, 2J 13.7, 3J 7.8
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Hz, 1H, CH2), 3.35 (dd, J 13.7, 3J 8.5 Hz, 1H, CH2), 3.54 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
5.73 (dd, 3J 7.8, 3J 8.5 Hz, 1H, CH), 6.58 (d, 3J 9.0 Hz, 2H, Ar), 6.77 (d, 3J 7.8 Hz, 1H, Ar), 6.85
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(d, J 9.0 Hz, 2H, Ar), 7.07 (ddd, J 7.6, J 7.6, J 0.9 Hz, 1H, Ar), 7.20 (t, J 7.3 Hz, 1H, Ar),
7.26–7.30 (m, 3H, Ar), 7.36 (d, 3J 7.5 Hz, 1H, Ar), 7.45–7.48 (m, 2H, Ar), 8.37 (br. s, 1H, NH);
13C{1H} NMR (CDCl3, 150 MHz): δ = 40.6 (CH2), 52.6 (OCH3), 53.0 (OCH3), 62.6 (CH), 66.4
(C), 76.3 (C), 110.5 (CH, Ar), 122.6 (CH, Ar), 122.9 (2 × CH, Ar), 125.1 (CH, Ar), 127.1 (2 ×
CH, Ar), 127.2 (CH, Ar), 127.4 (C, Ar), 127.9 (C, Ar), 128.4 (2 × CH, Ar), 128.5 (2 × CH, Ar),
130.2 (CH, Ar), 141.4 (C, Ar), 141.7 (C, Ar), 142.1 (C, Ar), 169.2 (CO2Me), 169.4 (CO2Me),
176.6 (C=O). IR (film, cm-1): 3160, 3090, 2950, 2915, 2850, 1750, 1720, 1700, 1615, 1600.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for С27Н23ClN2NaO5, 513.1188, found 513.1190.
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(3RS,5'RS)-1'-(2-chlorophenyl)-2-oxo-5'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3k). A solution of imine 1g (166 mg, 0.65 mmol),
cyclopropane 2a (159 mg, 0.68 mmol) and Yb(OTf)3 (40 mg, 0.06 mmol) in DCE (6.5 mL) was
heated under reflux for 2 h yielding 3k (264 mg, 83%) as yellow foam. Rf = 0.42 (ethyl
acetate/petroleum ether; 1:1), dr 95:5. 1Н NMR (CDCl3, 600 MHz, 328 K): δ = 3.05 (dd, 2J 13.8,
3J 6.7 Hz, 1H, CH2), 3.44 (dd, J 13.8, 3J 9.4 Hz, 1H, CH2), 3.69 (s, 3H, OCH3), 3.82 (s, 3H,
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OCH3), 5.53 (br. s, 1H, CH), 6.58 (d, 3J 7.7 Hz, 1H, Ar), 6.82 (ddd, 3J 7.6, 3J 7.6, 4J 1.5 Hz, 1H,
Ar), 6.90–6.94 (m, 2H, Ar), 7.00 (dd, 3J 7.4, 3J 7.4 Hz, 1H, Ar), 7.11 (ddd, 3J 7.7, J 7.7, 4J 1.1
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Hz, 1H, Ar), 7.15 (t, J 7.3 Hz, 1H, Ar), 7.19–7.22 (m, 2H, Ar), 7.52 (d, J 7.7 Hz, 1H, Ar),
7.68–7.73 (m, 4H, Ar, NH); C{1H} NMR (CDCl3, 150 MHz, 328 K): δ = 40.1 (CH2), 52.57
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(OCH3), 52.59 (OCH3), 64.9 (CH), 65.6 (C), 77.8 (C), 109.3 (CH, Ar), 121.5 (CH, Ar), 124.5 (C,
Ar), 126.8 (CH, Ar), 127.3 (CH, Ar), 127.5 (CH, Ar), 127.6 (CH, Ar), 127.8 (2 × CH, Ar), 128.5
(CH, Ar), 129.2 (2 × CH, Ar), 130.0 (CH, Ar), 130.1 (CH, Ar), 135.2 (C, Ar), 140.76 (C, Ar),
140.84 (C, Ar), 141.6 (C, Ar), 170.2 (CO2Me), 170.5 (CO2Me), 177.9 (C=O). IR (film, cm-1):
3330, 3060, 3030, 2950, 1725, 1715, 1700, 1620, 1600. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
+
for C27H23ClN2NaO5 , 513.1188, found 513.1190.
Dimethyl
(3RS,5'RS)-1'-(4-bromophenyl)-2-oxo-5'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3l). A solution of imine 1h (177 mg, 0.59 mmol),
cyclopropane 2a (145 mg, 0.62 mmol) and Yb(OTf)3 (37 mg, 0.06 mmol) in DCE (5.9 mL) was
heated under reflux for 2 h yielding 3l (280 mg, 89%) as yellow foam. Rf = 0.61 (ethyl
acetate/petroleum ether; 1:1), dr 94:6. 1Н NMR (CDCl3, 600 MHz): δ = 2.79 (dd, 2J 13.7, 3J 7.8
Hz, 1H, CH2), 3.35 (dd, J 13.7, 3J 8.4 Hz, 1H, CH2), 3.53 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
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5.73 (dd, 3J 7.8, 3J 8.4 Hz, 1H, CH), 6.51 (d, 3J 9.0 Hz, 2H, Ar), 6.77 (d, 3J 7.8 Hz, 1H, Ar), 7.00
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(d, J 9.0 Hz, 2H, Ar), 7.07 (ddd, J 7.6, J 7.6, J 0.9 Hz, 1H, Ar), 7.21 (t, J 7.3 Hz, 1H, Ar),
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7.27–7.30 (m, 3H, Ar), 7.36 (d, 3J 7.4 Hz, 1H, Ar), 7.44–7.47 (m, 2H, Ar), 8.22 (br. s, 1H, NH);
13C{1H} NMR (CDCl3, 150 MHz): δ = 40.6 (CH2), 52.6 (OCH3), 53.0 (OCH3), 62.5 (CH), 66.5
(C), 76.1 (C), 110.5 (CH, Ar), 115.0 (C, Ar), 122.7 (CH, Ar), 123.0 (2 × CH, Ar), 125.1 (CH,
Ar), 127.1 (2 × CH, Ar), 127.2 (CH, Ar), 127.9 (C, Ar), 128.5 (2 × CH, Ar), 130.2 (CH, Ar),
131.3 (2 × CH, Ar), 141.3 (C, Ar), 141.7 (C, Ar), 142.7 (C, Ar), 169.1 (CO2Me), 169.3
(CO2Me), 176.3 (C=O). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for С27Н2379BrN2NaO5,
557.0683, found 557.0669.
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Dimethyl
(3RS,5'RS)-1'-(4-methylphenyl)-2-oxo-5'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3m). A solution of imine 1i (146 mg, 0.62 mmol),
cyclopropane 2a (152 mg, 0.65 mmol) and Yb(OTf)3 (38 mg, 0.06 mmol) in DCE (6.2 mL) was
heated under reflux for 2 h yielding 3m (260 mg, 89%) as yellow foam. Rf = 0.52 (ethyl
1
acetate/petroleum ether; 1:1), dr 93:7. Н NMR (CDCl3, 600 MHz): δ = 2.02 (s, 3H, CH3), 2.79
(dd, 2J 13.6, 3J 7.3 Hz, 1H, CH2), 3.39 (dd, 2J 13.6, 3J 8.8 Hz, 1H, CH2), 3.58 (s, 3H, OCH3), 3.69
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(s, 3H, OCH3), 5.74 (dd, J 7.3, J 8.8 Hz, 1H, CH), 6.62 (d, J 8.6 Hz, 2H, Ar), 6.67 (d, J 8.6
Hz, 2H, Ar), 6.71 (d, 3J 7.8 Hz, 1H, Ar), 7.05 (ddd, 3J 7.6, 3J 7.6, 4J 0.9 Hz, 1H, Ar), 7.17 (t, 3J
7.3 Hz, 1H, Ar), 7.23 (ddd, 3J 7.6, 3J 7.8, 4J 1.2 Hz, 1H, Ar), 7.25–7.28 (m, 2H, Ar), 7.38 (d, 3J
7.6 Hz, 1H, Ar), 7.51–7.54 (m, 2H, Ar), 8.32 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz):
δ = 20.5 (CH3), 40.5 (CH2), 52.6 (OCH3), 52.9 (OCH3), 62.3 (CH), 66.2 (C), 76.6 (C), 110.3
(CH, Ar), 122.3 (CH, Ar), 122.7 (2 × CH, Ar), 125.4 (CH, Ar), 126.9 (CH, Ar), 127.3 (2 × CH,
Ar), 127.9 (C, Ar), 128.2 (2 × CH, Ar), 128.8 (2 × CH, Ar), 129.8 (CH, Ar), 132.2 (C, Ar), 140.8
(C, Ar), 141.6 (C, Ar), 142.4 (C, Ar), 169.65 (CO2Me), 169.72 (CO2Me), 177.4 (C=O). IR (film,
cm-1): 3125, 3070, 3020, 2950, 2890, 2835, 1730, 1700, 1685, 1620, 1600. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for С28Н27N2O5, 471.1914, found 471.1908.
Dimethyl (3RS,5'RS)-1'-(4-methoxyphenyl)-2-oxo-5'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3n). A solution of imine 1j (158 mg, 0.63 mmol),
cyclopropane 2a (154 mg, 0.66 mmol) and Yb(OTf)3 (39 mg, 0.06 mmol) in DCE (6.3 mL) was
heated under reflux for 2 h yielding 3n (284 mg, 93%) as yellow foam. Rf = 0.33 (ethyl
acetate/petroleum ether; 1:1), dr 92:8. 1Н NMR (CDCl3, 600 MHz): δ = 2.81 (dd, 2J 13.7, 3J 6.8
2
Hz, 1H, CH2), 3.43 (dd, J 13.7, 3J 9.3 Hz, 1H, CH2), 3.49 (s, 3H, OCH3), 3.66 (s, 3H, OCH3),
3.68 (s, 3H, OCH3), 5.66 (dd, 3J 6.8, 3J 9.3 Hz, 1H, CH), 6.39 (d, 3J 9.1 Hz, 2H, Ar), 6.64 (d, 3J
7.8 Hz, 1H, Ar), 6.81 (d, 3J 9.1 Hz, 2H, Ar), 7.04 (ddd, 3J 7.6, 3J 7.6, 4J 0.9 Hz, 1H, Ar), 7.15 (t,
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3J 7.3 Hz, 1H, Ar), 7.19 (ddd, J 7.6, J 7.8, J 1.2 Hz, 1H, Ar), 7.25 (dd, J 7.7, J 7.7 Hz, 2H,
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Ar), 7.37 (d, J 7.6 Hz, 1H, Ar), 7.57–7.59 (m, 2H, Ar), 8.29 (br. s, 1H, NH); C{1H} NMR
(CDCl3, 150 MHz): δ = 40.2 (CH2), 52.6 (OCH3), 52.7 (OCH3), 54.8 (OCH3), 62.3 (CH), 65.6
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(C), 77.0 (C), 110.2 (CH, Ar), 113.2 (2 × CH, Ar), 122.0 (CH, Ar), 125.5 (CH, Ar), 126.5 (2 ×
CH, Ar), 126.9 (CH, Ar), 127.0 (C, Ar), 127.8 (2 × CH, Ar), 128.1 (2 × CH, Ar), 129.8 (CH,
Ar), 135.9 (C, Ar), 141.9 (C, Ar), 142.3 (C, Ar), 156.1 (C, Ar), 170.0 (CO2Me), 170.2 (CO2Me),
178.0 (C=O). IR (film, cm-1): 3280, 3030, 2950, 2835, 1720, 1700, 1695, 1620, 1600. HRMS
+
(ESI-TOF) m/z: [M + Na]+ calcd for C28H26N2NaO6 , 509.1683, found 509.1679.
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Dimethyl
(3RS,5'RS)-5'-(4-fluorophenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3o). A solution of imine 1a (126 mg, 0.57 mmol),
cyclopropane 2b (150 mg, 0.60 mmol) and Yb(OTf)3 (35 mg, 0.06 mmol) in DCE (5.7 mL) was
heated under reflux for 2 h yielding 3o (257 mg, 96%) as yellow foam. Rf = 0.46 (ethyl
acetate/petroleum ether; 1:1), dr 91:9. 1Н NMR (CDCl3, 600 MHz): δ = 2.75 (dd, 2J 13.7, 3J 7.2
Hz, 1H, CH2), 3.38 (dd, J 13.7, 3J 8.9 Hz, 1H, CH2), 3.60 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
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5.73 (dd, 3J 7.2, 3J 8.9 Hz, 1H, CH), 6.69–6.72 (m, 3H, Ar), 6.73–6.77 (m, 1H, Ar), 6.90 (dd, 3J
7.6, 3J 8.3 Hz, 2H, Ar), 6.94 (dd, 3J 8.7, 3JHF 8.7 Hz, 2H, Ar), 7.06 (ddd, 3J 7.6, 3J 7.7, 4J 0.6 Hz,
1H, Ar), 7.23 (ddd, 3J 7.7, 3J 7.8, 4J 1.0 Hz, 1H, Ar), 7.35 (d, 3J 7.6 Hz, 1H, Ar), 7.49 (dd, 3J 8.7,
4JHF 5.5 Hz, 2H, Ar), 8.03 (br. s, 1H, NH); C{1H} NMR (CDCl3, 150 MHz): δ = 40.4 (CH2),
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52.6 (OCH3), 52.9 (OCH3), 61.6 (CH), 66.1 (C), 76.5 (C), 110.3 (CH, Ar), 115.1 (2JCF 22 Hz, 2 ×
CH, Ar), 122.4 (CH, Ar), 123.0 (2 × CH, Ar), 123.1 (CH, Ar), 125.3 (CH, Ar), 127.6 (C, Ar),
128.3 (2 × CH, Ar), 128.9 (3JCF 7 Hz, 2 × CH, Ar), 130.0 (CH, Ar), 137.9 (4JCF 2 Hz, C, Ar),
141.6 (C, Ar), 143.1 (C, Ar), 161.8 (1JCF 244 Hz, C, Ar), 169.6 (CO2Me), 169.7 (CO2Me), 176.9
(C=O). IR (film, cm-1): 3300, 3060, 2990, 2955, 2915, 2850, 1730, 1700, 1620, 1595. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for С27Н24FN2O5, 475.1664, found 475.1669.
Dimethyl
(3RS,5'RS)-5'-(4-bromophenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3p). A solution of imine 1a (112 mg, 0.51 mmol),
cyclopropane 2c (166 mg, 0.53 mmol) and Yb(OTf)3 (31 mg, 0.05 mmol) in DCE (5.1 mL) was
heated under reflux for 2 h yielding 3p (250 mg, 92%) as yellow foam. Rf = 0.44 (ethyl
acetate/petroleum ether; 1:1), dr 91:9. 1Н NMR (CDCl3, 600 MHz): δ = 2.73 (dd, 2J 13.6, 3J 7.0
Hz, 1H, CH2), 3.38 (dd, J 13.6, 3J 9.1 Hz, 1H, CH2), 3.62 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
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5.70 (dd, 3J 7.0, 3J 9.1 Hz, 1H, CH), 6.70–6.73 (m, 3H, Ar), 6.78 (t, 3J 7.3 Hz, 1H, Ar), 6.91 (dd,
3J 7.3, 3J 8.6 Hz, 2H, Ar), 7.06 (ddd, 3J 7.6, 3J 7.6, 4J 1.0 Hz, 1H, Ar), 7.24 (ddd, 3J 7.7, 3J 7.7, 4J
1.2 Hz, 1H, Ar), 7.34 (ddd, 3J 7.6, 4J 0.6, 5J 0.6 Hz, 1H, Ar), 7.38 (d, 3J 8.6 Hz, 2H, Ar), 7.41 (d,
3J 8.6 Hz, 2H, Ar), 7.58 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.1 (CH2), 52.7
(OCH3), 53.0 (OCH3), 61.6 (CH), 66.0 (C), 76.5 (C), 110.2 (CH, Ar), 120.8 (C, Ar), 122.4 (CH,
Ar), 123.3 (2 × CH, Ar), 123.5 (CH, Ar), 125.4 (CH, Ar), 127.4 (C, Ar), 128.3 (2 × CH, Ar),
129.2 (2 × CH, Ar), 130.1 (CH, Ar), 131.4 (2 × CH, Ar), 141.4 (C, Ar), 141.5 (C, Ar), 143.0 (C,
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Ar), 169.6 (CO2Me), 169.7 (CO2Me), 176.6 (C=O). IR (film, cm-1): 3295, 2955, 2915, 2870,
2850, 1730, 1700, 1620, 1595. HRMS (ESI-TOF) m/z: [M + H]+ calcd for С27Н2479BrN2O5,
535.0863, found 535.0863.
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Dimethyl
(3RS,5'RS)-5'-(2-bromophenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3q). A solution of imine 1a (106 mg, 0.48 mmol),
cyclopropane 2d (156 mg, 0.50 mmol) and Yb(OTf)3 (30 mg, 0.05 mmol) in DCE (4.8 mL) was
heated under reflux for 20 h yielding 3q (125 mg, 49%, 58% brsm) as brown oil. Extra portions
of Yb(OTf)3 (30 mg, 0.05 mmol) were added twice in 8 and 16 h. Rf = 0.61 (ethyl
acetate/petroleum ether; 1:1), dr 91:9. 1Н NMR (CDCl3, 600 MHz): δ = 2.62 (dd, 2J 13.7, 3J 6.7
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Hz, 1H, CH2), 3.57 (s, 3H, OCH3), 3.65 (dd, J 13.7, 3J 9.1 Hz, 1H, CH2), 3.71 (s, 3H, OCH3),
6.09 (dd, 3J 6.7, 3J 9.1 Hz, 1H, CH), 6.64–6.67 (m, 2H, Ar), 6.75 (t, 3J 7.3 Hz, 1H, Ar), 6.76 (d,
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3J 7.5 Hz, 1H, Ar), 6.91 (dd, J 7.4, J 8.6 Hz, 2H, Ar), 7.05 (ddd, J 7.5, J 7.8, J 1.7 Hz, 1H,
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Ar), 7.08 (ddd, J 7.6, J 7.6, J 1.0 Hz, 1H, Ar), 7.20 (ddd, J 7.6, J 7.6, J 0.9 Hz, 1H, Ar),
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7.28 (ddd, J 7.7, J 7.7, J 1.2 Hz, 1H, Ar), 7.36 (d, J 7.5 Hz, 1H, Ar), 7.52 (dd, J 7.9, J 1.1
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Hz, 1H, Ar), 7.69 (dd, J 7.8, J 1.7 Hz, 1H, Ar), 7.98 (br. s, 1H, NH); C{1H} NMR (CDCl3,
150 MHz): δ = 38.1 (CH2), 52.6 (OCH3), 53.0 (OCH3), 61.4 (CH), 66.3 (C), 76.3 (C), 110.4
(CH, Ar), 121.8 (2 × CH, Ar), 122.4 (CH, Ar), 122.6 (CH, Ar), 123.2 (C, Ar), 125.3 (CH, Ar),
127.3 (CH, Ar), 127.9 (C, Ar), 128.37 (CH, Ar), 128.42 (2 × CH, Ar), 128.9 (CH, Ar), 130.1
(CH, Ar), 132.5 (CH, Ar), 141.1 (C, Ar), 141.6 (C, Ar), 143.4 (C, Ar), 169.37 (CO2Me), 169.41
(CO2Me), 176.5 (C=O). IR (film, cm-1): 3295, 2950, 2920, 2850, 1735, 1720, 1700, 1620, 1595.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for С27Н2481BrN2O5, 537.0843, found 537.0842.
Dimethyl
(3RS,5'RS)-5'-(4-methylphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3r). A solution of imine 1a (129 mg, 0.58 mmol),
cyclopropane 2e (151 mg, 0.61 mmol) and Yb(OTf)3 (36 mg, 0.06 mmol) in DCE (5.8 mL) was
heated under reflux for 1 h yielding 3r (244 mg, 89%) as yellowish crystals, mp 189–190 C. Rf
= 0.45 (ethyl acetate/petroleum ether; 1:1), dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.29 (s, 3H,
CH3), 2.78 (dd, 2J 13.6, 3J 7.9 Hz, 1H, CH2), 3.34 (dd, 2J 13.6, 3J 8.3 Hz, 1H, CH2), 3.51 (s, 3H,
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OCH3), 3.71 (s, 3H, OCH3), 5.78 (dd, J 7.9, J 8.3 Hz, 1H, CH), 6.63 (d, J 7.9 Hz, 2H, Ar),
6.69 (t, 3J 7.3 Hz, 1H, Ar), 6.75 (d, 3J 7.8 Hz, 1H, Ar), 6.89 (dd, 3J 7.3, 3J 8.5 Hz, 2H, Ar), 7.05
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(ddd, J 7.6, J 7.6, J 0.7 Hz, 1H, Ar), 7.09 (d, J 7.9 Hz, 2H, Ar), 7.25 (ddd, J 7.6, J 7.8, J
0.8 Hz, 1H, Ar), 7.35–7.39 (m, 3H, Ar), 8.50 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz):
δ = 21.0 (CH3), 40.7 (CH2), 52.5 (OCH3), 53.0 (OCH3), 62.1 (CH), 66.5 (C), 76.2 (C), 110.4
(CH, Ar), 121.1 (2 × CH, Ar), 121.8 (CH, Ar), 122.5 (CH, Ar), 125.1 (CH, Ar), 126.9 (2 × CH,
Ar), 128.3 (2 × CH, Ar), 128.5 (C, Ar), 129.1 (2 × CH, Ar), 129.9 (CH, Ar), 136.5 (C, Ar), 139.2
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(C, Ar), 141.3 (C, Ar), 143.5 (C, Ar), 169.2 (CO2Me), 169.5 (CO2Me), 176.9 (C=O). IR (film,
cm-1): 3340, 3000, 2950, 2915, 2850, 1730, 1710, 1595. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for С28Н27N2O5, 471.1914, found 471.1918.
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Dimethyl (3S,5'S)-5'-(4-methylphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'-
pyrrolidine]-3',3'-dicarboxylate ((3S,5'S)-3r) was obtained by the same procedure from 1a and
(R)-2e (er 99:1); NMR spectra coincide with that of 3r. []D25 = +137.9 (c 0.50, EtOH), er 91:9.
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Dimethyl (3RS,5'RS)-5'-(4-methoxyphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3s). A solution of imine 1a (142 mg, 0.64 mmol),
cyclopropane 2f (177 mg, 0.67 mmol) and Yb(OTf)3 (40 mg, 0.06 mmol) in DCE (6.4 mL) was
heated under reflux for 1 h yielding 3s (244 mg, 79%) as yellow foam. Rf = 0.51 (ethyl
acetate/petroleum ether; 1:1), dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.77 (dd, 2J 13.6, 3J 7.6
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Hz, 1H, CH2), 3.34 (dd, J 13.6, 3J 8.5 Hz, 1H, CH2), 3.56 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
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3.75 (s, 3H, OCH3), 5.73 (dd, J 7.6, J 8.5 Hz, 1H, CH), 6.66–6.69 (m, 2H, Ar), 6.70–6.74 (m,
2H, Ar), 6.81 (d, 3J 8.8 Hz, 2H, Ar), 6.89 (dd, 3J 7.4, 3J 8.6 Hz, 2H, Ar), 7.05 (ddd, 3J 7.5, 3J 7.7,
4J 0.9 Hz, 1H, Ar), 7.23 (ddd, 3J 7.7, 3J 7.7, 4J 1.1 Hz, 1H, Ar), 7.37 (d, 3J 7.5 Hz, 1H, Ar), 7.42
(d, 3J 8.8 Hz, 2H, Ar), 8.10 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.6 (CH2),
52.6 (OCH3), 52.9 (OCH3), 55.1 (OCH3), 61.8 (CH), 66.3 (C), 76.3 (C), 110.2 (CH, Ar), 113.7
(2 × CH, Ar), 122.2 (2 × CH, Ar), 122.4 (CH, Ar), 122.5 (CH, Ar), 125.3 (CH, Ar), 128.1 (C,
Ar), 128.2 (2 × CH, Ar), 128.3 (2 × CH, Ar), 129.9 (CH, Ar), 134.3 (C, Ar), 141.4 (C, Ar), 143.4
(C, Ar), 158.5 (C, Ar), 169.5 (CO2Me), 169.6 (CO2Me), 176.8 (C=O). IR (film, cm-1): 3295,
2955, 2915, 2850, 1730, 1700, 1615, 1595. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
С28Н27N2O6, 487.1864, found 487.1871.
Dimethyl
(3RS,5'RS)-5'-(3,4-dimethoxyphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3t). A solution of imine 1a (208 mg, 0.94
mmol), cyclopropane 2g (289 mg, 0.98 mmol) and Yb(OTf)3 (58 mg, 0.09 mmol) in DCE (9.4
mL) was heated under reflux for 1 h yielding 3t (383 mg, 79%) as white solid, mp 119–120 °C.
Rf = 0.36 (ethyl acetate/petroleum ether; 1:1), dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.78 (dd,
2J 13.6, 3J 7.6 Hz, 1H, CH2), 3.34 (dd, 2J 13.6, 3J 8.5 Hz, 1H, CH2), 3.54 (s, 3H, OCH3), 3.70 (s,
3H, OCH3), 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 5.72 (dd, 3J 7.6, 3J 8.5 Hz, 1H, CH), 6.65–
6.68 (m, 2H, Ar), 6.69–6.75 (m, 3H, Ar), 6.89 (dd, 3J 7.4, 3J 8.5 Hz, 2H, Ar), 6.95 (dd, 3J 8.2, 4J
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2.0 Hz, 1H, Ar), 7.04 (ddd, J 7.6, J 7.6, J 0.9 Hz, 1H, Ar), 7.18 (d, J 2.0 Hz, 1H, Ar), 7.22
(ddd, 3J 7.6, 3J 7.8, 4J 1.1 Hz, 1H, Ar), 7.36 (d, 3J 7.6 Hz, 1H, Ar), 8.44 (br. s, 1H, NH); 13C{1H}
NMR (CDCl3, 150 MHz): δ = 40.6 (CH2), 52.5 (OCH3), 52.9 (OCH3), 55.7 (2 × OCH3), 62.0
(CH), 66.2 (C), 76.2 (C), 110.4 (2 × CH, Ar), 110.8 (CH, Ar), 119.3 (CH, Ar), 122.0 (2 × CH,
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Ar), 122.3 (CH, Ar), 122.4 (CH, Ar), 125.1 (CH, Ar), 128.1 (C, Ar), 128.2 (2 × CH, Ar), 129.9
(CH, Ar), 134.8 (C, Ar), 141.5 (C, Ar), 143.4 (C, Ar), 147.8 (C, Ar), 148.9 (C, Ar), 169.4
(CO2Me), 169.6 (CO2Me), 176.9 (C=O). IR (film, cm-1): 3295, 2955, 2915, 2850, 1730, 1700,
1620, 1595. HRMS (ESI-TOF) m/z: [M + H]+ calcd for С29Н29N2O7, 517.1969, found 517.1973.
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Dimethyl
(3RS,5'RS)-5'-(3,4,5-trimethoxyphenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-
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spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3u). A solution of imine 1a (193 mg, 0.87
mmol), cyclopropane 2h (296 mg, 0.91 mmol) and Yb(OTf)3 (54 mg, 0.09 mmol) in DCE (8.7
mL) was heated under reflux for 1 h yielding 3u (385 mg, 81%) as white solid, mp 210–211 °C.
Rf = 0.25 (ethyl acetate/petroleum ether; 1:1), dr 93:7. 1Н NMR (CDCl3, 600 MHz): δ = 2.76 (dd,
2J 13.7, 3J 7.8 Hz, 1H, CH2), 3.33 (dd, 2J 13.7, 3J 8.4 Hz, 1H, CH2), 3.52 (s, 3H, OCH3), 3.71 (s,
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3H, OCH3), 3.76 (s, 6H, OCH3), 3.79 (s, 3H, OCH3), 5.72 (dd, J 7.8, J 8.4 Hz, 1H, CH), 6.67
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(d, J 7.8 Hz, 2H, Ar), 6.71–6.75 (m, 4H, Ar), 6.91 (dd, J 7.5, J 8.3 Hz, 2H, Ar), 7.03 (dd, J
7.5, 3J 7.5 Hz, 1H, Ar), 7.23 (ddd, 3J 7.5, 3J 7.6, 4J 0.8 Hz, 1H, Ar), 7.36 (d, 3J 7.6 Hz, 1H, Ar),
8.41 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.6 (CH2), 52.5 (OCH3), 52.9
(OCH3), 55.9 (2 × OCH3), 60.7 (OCH3), 62.4 (CH), 66.3 (C), 76.1 (C), 103.9 (2 × CH, Ar),
110.4 (CH, Ar), 121.7 (2 × CH, Ar), 122.2 (CH, Ar), 122.3 (CH, Ar), 125.1 (CH, Ar), 128.2 (C,
Ar), 128.3 (2 × CH, Ar), 129.9 (CH, Ar), 136.5 (C, Ar), 138.0 (C, Ar), 141.5 (C, Ar), 143.4 (C,
Ar), 153.0 (2 × C, Ar), 169.2 (CO2Me), 169.5 (CO2Me), 176.5 (C=O). IR (film, cm-1): 3340,
2955, 2915, 2870, 2850, 1740, 1730, 1710, 1615, 1595. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for С30Н31N2O8, 547.2075, found 547.2081.
Dimethyl (3RS,5'RS)-5'-(4-nitrophenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-3,2'-
pyrrolidine]-3',3'-dicarboxylate (3v). A solution of imine 1a (127 mg, 0.57 mmol),
cyclopropane 2i (168 mg, 0.60 mmol) and Yb(OTf)3 (36 mg, 0.06 mmol) in DCE (5.7 mL) was
heated under reflux for 20 h yielding 3v (147 mg, 51%, 60% brsm) as brown oil. Extra portions
of Yb(OTf)3 (36 mg, 0.06 mmol) were added twice in 8 and 16 h. Rf = 0.54 (ethyl
acetate/petroleum ether; 1:1), dr 91:9. 1Н NMR (CDCl3, 600 MHz): δ = 2.74 (dd, 2J 13.7, 3J 6.7
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Hz, 1H, CH2), 3.49 (dd, J 13.7, 3J 9.4 Hz, 1H, CH2), 3.64 (s, 3H, OCH3), 3.68 (s, 3H, OCH3),
5.85 (dd, 3J 6.7, 3J 9.4 Hz, 1H, CH), 6.70 (d, 3J 7.8 Hz, 1H, Ar), 6.74–6.79 (m, 3H, Ar), 6.90 (dd,
3J 7.3, 3J 8.5 Hz, 2H, Ar), 7.07 (ddd, 3J 7.6, 3J 7.7, 4J 1.0 Hz, 1H, Ar), 7.24 (ddd, 3J 7.7, 3J 7.8, 4J
1.2 Hz, 1H, Ar), 7.34 (d, 3J 7.6 Hz, 1H, Ar), 7.72 (d, 3J 8.8 Hz, 2H, Ar), 8.12 (d, 3J 8.8 Hz, 2H,
Ar), 8.27 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 39.7 (CH2), 52.8 (OCH3), 52.9
(OCH3), 61.6 (CH), 65.8 (C), 76.6 (C), 110.5 (CH, Ar), 122.4 (CH, Ar), 123.55 (2 × CH, Ar),
123.60 (2 × CH, Ar), 124.0 (CH, Ar), 125.3 (CH, Ar), 126.8 (C, Ar), 128.3 (2 × CH, Ar), 128.4
(2 × CH, Ar), 130.2 (CH, Ar), 141.8 (C, Ar), 142.7 (C, Ar), 147.0 (C, Ar), 150.1 (C, Ar), 169.3
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(CO2Me), 169.7 (CO2Me), 177.0 (C=O). IR (film, cm-1): 3305, 2950, 2915, 2850, 1730, 1700,
1620, 1595. HRMS (ESI-TOF) m/z: [M + H]+ calcd for С27Н24N3O7, 502.1609, found 502.1617.
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spiro[indole-3,2'-pyrrolidine]-3',3'-dicarboxylate (3w). A solution of imine 1a (109 mg, 0.49
mmol), cyclopropane 2j (150 mg, 0.51 mmol) and Yb(OTf)3 (30 mg, 0.05 mmol) in DCE (4.9
mL) was heated under reflux for 16 h yielding 3w (135 mg, 54%) as yellow foam. An extra
portion of Yb(OTf)3 (30 mg, 0.05 mmol) was added in 8 h. Rf = 0.51 (ethyl acetate/petroleum
ether; 1:1), dr 92:8. 1Н NMR (CDCl3, 600 MHz): δ = 2.76 (dd, 2J 13.6, 3J 7.3 Hz, 1H, CH2), 3.42
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(dd, J 13.6, 3J 8.8 Hz, 1H, CH2), 3.56 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
5.83 (dd, 3J 7.3, 3J 8.8 Hz, 1H, CH), 6.67–6.69 (m, 2H, Ar), 6.71–6.74 (m, 2H, Ar), 6.88 (dd, 3J
7.4, 3J 8.6 Hz, 2H, Ar), 7.06 (ddd, 3J 7.6, 3J 7.7, 4J 0.9 Hz, 1H, Ar), 7.24 (ddd, 3J 7.7, 3J 7.8, 4J
1.1 Hz, 1H, Ar), 7.35 (d, 3J 7.6 Hz, 1H, Ar), 7.58 (d, 3J 8.4 Hz, 2H, Ar), 7.95 (d, 3J 8.4 Hz, 2H,
Ar), 8.37 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 40.1 (CH2), 51.9 (OCH3), 52.6
(OCH3), 52.9 (OCH3), 62.1 (CH), 66.2 (C), 76.4 (C), 110.4 (CH, Ar), 122.2 (2 × CH, Ar), 122.4
(CH, Ar), 122.9 (CH, Ar), 125.2 (CH, Ar), 127.3 (2 × CH, Ar), 127.7 (C, Ar), 128.3 (2 × CH,
Ar), 128.9 (C, Ar), 129.7 (2 × CH, Ar), 130.0 (CH, Ar), 141.6 (C, Ar), 143.1 (C, Ar), 147.8 (C,
Ar), 167.0 (CO2Me), 169.35 (CO2Me), 169.38 (CO2Me), 176.9 (C=O). IR (film, cm-1): 3265,
2950, 2915, 2870, 2850, 1720, 1700, 1695, 1685, 1615, 1595. HRMS (ESI-TOF) m/z: [M + H]+
calcd for С29Н27N2O7, 515.1813, found 515.1810.
Dimethyl
(3RS,5'RS)-5'-(4-cyanophenyl)-2-oxo-1'-phenyl-1,2-dihydro-3'H-spiro[indole-
3,2'-pyrrolidine]-3',3'-dicarboxylate (3x). A solution of imine 1a (61 mg, 0.28 mmol),
cyclopropane 2k (75 mg, 0.29 mmol) and Yb(OTf)3 (17 mg, 0.03 mmol) in DCE (2.8 mL) was
heated under reflux for 16 h yielding 3x (80 mg, 60%) as yellowish foam. An extra portion of
Yb(OTf)3 (17 mg, 0.03 mmol) was added in 8 h. Rf = 0.43 (ethyl acetate/petroleum ether; 1:1), dr
91:9. 1Н NMR (CDCl3, 600 MHz): δ = 2.72 (dd, 2J 13.6, 3J 6.7 Hz, 1H, CH2), 3.45 (dd, 2J 13.6,
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3J 9.3 Hz, 1H, CH2), 3.63 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 5.78 (dd, J 6.7, J 9.3 Hz, 1H,
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CH), 6.70 (d, J 7.7 Hz, 1H, Ar), 6.74 (d, J 8.3 Hz, 2H, Ar), 6.79 (t, J 7.3 Hz, 1H, Ar), 6.91
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(dd, J 7.3, J 8.3 Hz, 2H, Ar), 7.07 (dd, J 7.6, J 7.7 Hz, 1H, Ar), 7.24 (ddd, J 7.7, J 7.7, J
0.8 Hz, 1H, Ar), 7.33 (d, 3J 7.6 Hz, 1H, Ar), 7.55 (d, 3J 8.2 Hz, 2H, Ar), 7.66 (d, 3J 8.2 Hz, 2H,
Ar), 7.95 (br. s, 1H, NH); 13C{1H} NMR (CDCl3, 150 MHz): δ = 39.8 (CH2), 52.8 (OCH3), 53.0
(OCH3), 61.8 (CH), 65.8 (C), 76.6 (C), 110.4 (CH, Ar), 110.8 (CN), 118.9 (C, Ar), 122.4 (CH,
Ar), 123.7 (2 × CH, Ar), 124.0 (CH, Ar), 125.4 (CH, Ar), 126.8 (C, Ar), 128.3 (2 × CH, Ar),
128.4 (2 × CH, Ar), 130.2 (CH, Ar), 132.2 (2 × CH, Ar), 141.7 (C, Ar), 142.7 (C, Ar), 148.0 (C,
Ar), 169.4 (CO2Me), 169.7 (CO2Me), 176.8 (C=O). IR (film, cm-1): 3305, 2955, 2915, 2870,
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