Chameleon-Like Activating Nature of the Spirooxindole Group in Donor-Acceptor Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.9b04153

The concept of a chameleon activating group is considered in the context of donor-acceptor cyclopropane chemistry. When spiro-conjugated with cyclopropane, oxindole can act as an acceptor or a donor depending on the electronic nature of vicinal substituents. This dichotomy is reflected in the alteration of chemoselectivity of spiro[oxindole-1,3′-cyclopropane] ring opening with nucleophiles.

Full text of DOI:10.1021/acs.orglett.9b04153

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chameleon-Like Activating Nature of the Spirooxindole Group in
Donor−Acceptor Cyclopropanes
Andrey A. Akaev, Mikhail Ya. Melnikov, and Ekaterina M. Budynina*
Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russia
S
* Supporting Information
ABSTRACT: The concept of a chameleon activating group is
considered in the context of donor−acceptor cyclopropane
chemistry. When spiro-conjugated with cyclopropane, oxindole
can act as an acceptor or a donor depending on the electronic
nature of vicinal substituents. This dichotomy is reflected in the
alteration of chemoselectivity of spiro[oxindole-1,3′-cyclopropane]
ring opening with nucleophiles.
onor−acceptor (D−A) cyclopropanes1 are well-known
cyclopropanes wherein the activating oxindole unit can act as
both donor and acceptor (Scheme 1C).
D
as versatile building blocks in synthetic chemistry.2 Their
most common reactivity is associated with 1,3-zwitterionic
behavior providing opportunities for reactions of such
cyclopropanes with both nucleophiles and electrophiles as
well as ambiphilic compounds3 (Scheme 1A). This reactivity is
As an acceptor, oxindole is a quite weak activating group.
Therefore, despite spiro-activation that facilitates ring opening
of spiro[oxindole-1,3′-cyclopropanes] which can contain an
additional electron-donating group at the vicinal position to
the oxindole moiety, these reactions usually require harsher
conditions compared to those for common 2-substituted
cyclopropane-1,1-diesters. The systematic study of the
synthetic value of spiro[oxindole-1,3′-cyclopropanes] was
initiated by Carreira and co-workers who successfully applied
Lewis-acid-catalyzed (3 + 2)-cycloaddition of these com-
pounds to imines for the synthesis of pharmaceutically
important spiro[oxindole-3,3′-pyrrolidines].5,6 Recently, Yan
and Zhou et al. demonstrated possibilities for these cyclo-
propanes (when additionally activated with an electron-
withdrawing N-protecting group) to undergo (3 + 3)-
cycloadditions to nitrones and (3 + 2)-cycloaddition to
aldehydes, producing spirooxindoleoxazines and furans,
respectively.7 The same authors described ring-opening
reactions with dithiane and aniline derivatives.7 Moreover,
other examples of spiro[oxindole-1,3′-cyclopropane] reactivity
were reported, including nucleophilic ring opening with
dimethylamine8 and (3 + 2)-cycloaddition to alkenes9a,b and
isatines.9c Our group reported reactions of spiro[oxindole-1,3′-
cyclopropanes] with pseudohalides, such as the azide and
cyanate ions, as convenient approaches to spiro[oxindole-3,3′-
pyrrolidine] derivatives.10 In all of these cases, the primary
nucleophilic attack is directed toward the cyclopropane C2
atom substituted with a donor group (R = H, Alk, Vinyl, Ar)
(Scheme 1C, path a).
Scheme 1. General Concept
furnished by donor and acceptor substituents located at
neighboring C atoms of the three-membered ring. In the
context of D−A cyclopropanes, CO, CN, or NO2 groups
are the most common activating acceptors, whereas Ar, CH2
CH, RO, R2N, or, more rarely, Alk substituents serve as
donors. Among those, there are groups which act as
unambiguous acceptors or unambiguous donors regardless of
the electronic properties of neighboring groups and reaction
conditions. Meanwhile, in a broad sense, donating and
accepting abilities are not fixed parameters since some
functionalities are able to exhibit chameleon behavior depend-
ing on their surroundings or other factors.4 However, in the
context of extensively researched D−A cyclopropanes, this
question has not been addressed (Scheme 1B). In our current
work, we implemented the concept of a chameleon D−A
group by using spiro[oxindole-1,3′-cyclopropanes] as D−A
Received: November 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The replacement of an electron-donating group R with an
electron-withdrawing one leads to simultaneous switching in
the activating role of the oxindole unit, from accepting to
donating. This results in an anomalous model of reactivity
wherein a nucleophile attacks the quaternary spiro-C atom
(Scheme 1C, path b). To the best of our knowledge, only two
random examples can illustrate this unusual inverse reactivity
of spiro[oxindole-1,3′-cyclopropanes]: their nucleophilic ring
opening with aniline11a and water.11b Therefore, this reactivity
is underexplored.
also revealed in our experiments with cyclopropanes 1a,b and
2a−c (Scheme 2).
The energy barrier ΔH⧧ of N3− attack on the quaternary C2
atom of 2a′ accompanied by cleavage of the longest C1−C2
bond is, respectively, 7.2 and 11.6 kcal/mol lower than those
for the attack on the secondary C3 atom, resulting in cleavage
of the C2−C3 and C1−C3 bonds (Figure 1). Surprisingly, the
Herein, we describe an approach to exploiting the
chameleon D−A nature of the oxindole group in the context
of ring opening of spiro[oxindole-1,3′-cyclopropanes] with
anionic and neutral N-nucleophiles, such as the azide ion and
primary amines. Cyclopropanes 1 and 2 were chosen as model
substrates, wherein the oxindole moiety was located vicinally in
relation to donating or accepting substituents.
Our recent study showed that nucleophilic ring opening of
1a with the azide ion efficiently proceeded in DMSO at 80 °C
in 4 h leading to azidoethyloxindole 3 (Scheme 2).10c
Figure 1. Bond lengths [Å] and relative TS energies ΔH⧧ [kcal/mol]
−
of the SN2 ring opening in 1a′ and in 2a′ with N3 : DFT data.
−
attack of N3 on the C1 atom is the second best option,
resulting in C1−C2 bond cleavage with only a 4.9 kcal/mol
penalty. Moreover, it can be partially associated with a higher
acidity of malonate in comparison with oxindole (pKa 15.9 vs
18.5),14 providing for a difference in the stability of the
corresponding ring-opened anions (according to DFT, ΔH298
= 3.3 kcal/mol). Therefore, the main factors controlling the
selectivity of the SN2 attack are the following: (1) C−C bond
length: a cyclopropane undergoes ring opening via cleavage of
the longest bond (although no correlation between bond
lengths and kinetic trends was observed for different D−A
cyclopropanes)15 and (2) the ability of functional groups to
stabilize the negative charge in the resulting ring-opened anion.
Meanwhile, degree of substitution of electrophilic sites has a
minor impact on the regioselectivity of the nucleophilic attack
that is preferably directed toward the quaternary or tertiary C
atoms rather than the secondary one. The activation of
electrophilic sites C2 together with simultaneous deactivation
of unsubstituted sites C3 toward nucleophilic attacks is
observed upon going from electrophilic cyclopropane 1b′ to
cyclopropanes 1a′ and 2a′. The same differences are observed
between mainstream D−A cyclopropanes (2-arylcyclopropane-
1,1-diesters) and their electrophilic counterparts (cyclo-
propane-1,1-diesters).13a
Next, we examined cyclopropanes 1 and 2 in reactions with
primary amines. To check the typical direction of nucleophilic
ring opening, we carried out reactions of 1a with aniline under
Lewis acid catalysis. In our initial experiments, Ni(ClO4)2·
6H2O was examined as a typical catalyst for reactions of other
carbonyl-derived D−A cyclopropanes with amines.16 When
performed at 40 °C in CH2Cl2 under reflux, the reaction did
not proceed at all (Table 2, entry 1), whereas an increase in
temperature to 110 °C (toluene under reflux) facilitated a
reaction: complete conversion of 1a was observed in 24 h
(entry 2). Under these harsh conditions, the typical product of
nucleophilic ring opening (5) was formed along with its
oxidized derivative 6. A brief screening of other Lewis acids
revealed that MgI2 and Yb(OTf)3 induced a more rapid
reaction of 1a with aniline, so that amine 5 ended up being the
major product (entries 3 and 4). Meanwhile, Sc(OTf)3 was
less efficient, leading to increased reaction time which resulted
in complete oxidation, forming aminocarbinol 6 exclusively
(entry 5). This result differs from that reported by Yan, Zhou,
and co-workers for the reaction between spiro[oxindole-1,3′-
cyclopropane] 1c activated with an electron-withdrawing N-
protecting group and p-toluidine.6a In their case, the reaction
Scheme 2. Nucleophilic Ring Openings of 1 and 2 with the
Azide Ion
However, a similar experiment with cyclopropane 2a revealed
a change in the chemoselectivity of the nucleophilic attack. In
this case, it was directed toward the spiro-C atom with azide 4a
yielded eventually. The nucleophilic ring opening of 2b,c
occurred under identical conditions, leading to 4b,c.
The priority of the nucleophilic attack on the quaternary
spiro-C atom of cyclopropanes 2 was supported by DFT
calculations at the B3LYP/SVP/COSMO level of theory using
the ORCA 3.012 program package. SN2-like ring opening of
D−A cyclopropanes with the azide ion was used as a suitable
mechanistic model due to the satisfactory agreement of
variation trends for the calculated energy barriers with the
changes in reaction conditions.13
The comparison of energy barriers ΔG⧧298, calculated for the
−
N3 attack on the model N-unprotected D−A cyclopropanes
1a′ and 2a′, as well as electrophilic cyclopropane 1b′, where
the only substituent is the oxindole group (Table 1), points
toward a synergetic effect for vicinal substitution even when
both C1 and C2 positions are occupied with nominally
electron-withdrawing groups. This kind of synergetic effect is
Table 1. Energy Barriers for Cyclopropane Ring Opening
with the Azide Ion
B
DOI: 10.1021/acs.orglett.9b04153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
was found to be the most efficient for nucleophilic ring
opening of 2a with aniline (entry 2).
Table 2. Example of Typical Nucleophilic Ring Opening of
Cyclopropanes 1 with Anilines
Using these conditions, we examined a series of cyclo-
propanes 2 in reactions with anilines (Scheme 3). Amines 7
Scheme 3. Reaction of Cyclopropanes 2 with Anilines:
Substrate Scope
a
entry
LA
T [°C]
t [h]
yield 5/6 [%]
b
c
1
2
3
4
5
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
MgI2
Yb(OTf)3
Sc(OTf)3
40
3
24
3
6
12
-
110
110
110
110
11/19
45/8
19/-
-/29
a
b
c
Isolated yield. CH2Cl2 was used as a solvent. No reaction.
a
Reaction was carried out in 1,2-C2H4Cl2 under reflux.
proceeded with cleavage of the five-membered ring in the
bicyclic system of oxindole, yielding the aryl-substituted γ-
lactame.
The reactions of cyclopropane 2a with aniline proceeded via
an inverse nucleophilic attack on the spiro-C atom, leading to
amine 7a (Table 3). The use of Ni(ClO4)2·6H2O in CH2Cl2 at
were obtained in good to high yields (68−89%) regardless of
the electronic effects of substituents in oxindole or aniline. We
demonstrated that the introduction of halogens into the
oxindole unit (2d−f) led to deceleration of nucleophilic ring
opening. The same effect was observed when anilines with
hindered (2-methoxyaniline) or electron-deficient (4-nitroani-
line) nucleophilic centers were employed. To carry out the
latter reaction, harsher conditions were required (namely,
prolonged heating in 1,2-C2H4Cl2 under reflux). At the same
time, the use of highly nucleophilic 4-methoxyaniline
consistently led to slight acceleration of the main reaction.
The synthesized γ-aminocarbonyl compounds 7 can be
easily transformed into spiro[oxindole-3,2′-pyrrolidones] 8
under Brønsted acid catalysis (Scheme 4). In most cases,
complete conversion of 7 was achieved in 1 h. However, due to
the ortho-effect, amine 7m was transformed into lactame 8m in
7 h. This led to a slight decrease in the yield of 8m compared
to other lactams 8 within this series. The studied reactions
exhibited good diastereoselectivity, affording 8, predominantly
Table 3. Reaction of Cyclopropane 2a with Aniline:
Optimization of the Reaction Conditions
a
entry
LA (equiv)
T [°C]/t [h] yield [%] /conversion [%]
b
1
2
3
4
5
6
7
8
9
Ni(ClO4)2 (0.1)
25/24
40/4.5
83 /1
72/90
78/>95
69/>95
37/78
12/48
57/>95
17/32
b
Ni(ClO4)2 (0.1)
b
c
Ni(ClO4)2 (0.1)
b
Co(ClO4)2 (0.1)
25/24
25/24
40/4.5
25/48
25/48
25/48
25/48
25/48
b
Zn(ClO4)2 (0.1)
MgI2 (0.1)
Yb(OTf)3 (0.1)
BF3·Et2O (1.1)
FeCl3 (0.5)
SnCl4 (1.2)
TiCl4 (1.2)
Scheme 4. Transformation of Amines 7 into Spiro[oxindole-
3,2′-pyrrolidones] 8 and Their Further Deprotection*
d
-
d
-
-
e
10
11
d
-
a
b
c
Isolated yield. Hexahydrates were used. 1,2-C2H4Cl2 was used as a
d
e
solvent. No reaction. Complex mixture of unidentified products.
ambient temperature did not provide a complete conversion of
2a into 7a even in 24 h (entry 1). A slight increase in
temperature up to 40 °C allowed for a complete conversion of
2a in 4.5 h (entry 2). A further increase in temperature led to a
decrease in reaction time, although the yield of 7a declined
(entry 3). Co(ClO4)2·6H2O, Zn(ClO4)2·6H2O, MgI2, and
Yb(OTf)3 were found to be less efficient as catalysts for the
studied reaction (entries 4−7). The use of BF3·Et2O or FeCl3
(entries 8 and 9) did not induce a reaction, whereas the
presence of stronger Lewis acids (SnCl4 or TiCl4) initiated the
oligomerization of the reactants (entries 10 and 11).
Therefore, the use of Ni(ClO4)2·6H2O in CH2Cl2 at 40 °C
*
Conditions: i. TsOH (0.2 equiv), toluene (0.15 M), 110 °C, 1 h; ii.
TfOH (2.5 equiv), TFA (50 equiv), CH2Cl2 (0.08 M), 25 °C.
a
Reaction was carried out for 7 h.
C
DOI: 10.1021/acs.orglett.9b04153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as trans-isomers (dr ≈ 80:20). Relative configuration was
assigned according to the results of a NOESY experiment for
8a.
It is noteworthy that N-PMB-protected spiro[oxindole-3,2′-
pyrrolidones] 8 can be readily deprotected into N-H-
spirooxindoles 9 (Scheme 4).
Our attempts to involve aliphatic amines in the studied
reaction did not result in nucleophilic ring opening of model
cyclopropane 2a; instead, nucleophilic acyl substitution
occurred, affording amidoesters 10a,b (Scheme 5). The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ekatbud@kinet.chem.msu.ru.
ORCID
Ekaterina M. Budynina: 0000-0003-1193-7061
Notes
The authors declare no competing financial interest.
Scheme 5. Transformations of 2a with Aliphatic Amine
Participation
ACKNOWLEDGMENTS
■
This research was supported by the Russian Foundation for
Basic Research, Grant Number 18-03-00549. The NMR
measurements were carried out at the Center for Magnetic
Tomography and Spectroscopy, Faculty of Fundamental
Medicine of Moscow State University.
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substituted electrophilic sites of such D−A cyclopropanes.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04153.
Experimental procedures, analytical data, details of DFT
1
calculations, and copies of H and 13C NMR spectra
(PDF)
Accession Codes
CCDC 1948999 and 1954544 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
D
DOI: 10.1021/acs.orglett.9b04153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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DOI: 10.1021/acs.orglett.9b04153
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