Synthesis of 1,3-diaryl-spiro[azetidine-2,3′-indoline]-2′,4-diones: Via the Staudinger reaction: Cis - Or trans -diastereoselectivity with different addition modes

Article abstract of DOI:10.1039/d0ra02374d

A new synthetic approach for realizing biologically relevant bis-aryl spiro[azetidine-2,3′-indoline]-2′,4-diones was developed based on Staudinger ketene-imine cycloaddition through the one-pot reaction of substituted acetic acids and Schiff bases in the presence of oxalyl chloride and an organic base. A series of [azetidine-2,3′-indoline]-2′,4-diones were synthesized using this method. For comparison, the same compounds were obtained using a known technique, where ketene is generated from pre-synthesized acyl chloride. It was shown that the use of oxalyl chloride for ketene generation in the one-pot reaction at room temperature allows for the reversal of the diastereoselectivity of spiro-lactam formation, unlike previously described procedures.

Full text of DOI:10.1039/d0ra02374d

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Synthesis of 1,3-diaryl-spiro[azetidine-2,30-
indoline]-20,4-diones via the Staudinger reaction:
cis- or trans-diastereoselectivity with different
addition modes†
Cite this: RSC Adv., 2020, 10, 14122
a
ab
Vadim Filatov,
Viktor Tafeenko,a Nikolay Zyk,a Alexander Majougaacd and Elena Beloglazkina
Maksim Kukushkin,a Juliana Kuznetsova,a Dmitry Skvortsov,
a
*
A new synthetic approach for realizing biologically relevant bis-aryl spiro[azetidine-2,30-indoline]-20,4-diones was
developed based on Staudinger ketene–imine cycloaddition through the one-pot reaction of substituted acetic
acids and Schiff bases in the presence of oxalyl chloride and an organic base. A series of [azetidine-2,30-
indoline]-20,4-diones were synthesized using this method. For comparison, the same compounds were
obtained using a known technique, where ketene is generated from pre-synthesized acyl chloride. It was
shown that the use of oxalyl chloride for ketene generation in the one-pot reaction at room temperature
allows for the reversal of the diastereoselectivity of spiro-lactam formation, unlike previously described procedures.
Received 14th March 2020
Accepted 30th March 2020
DOI: 10.1039/d0ra02374d
rsc.li/rsc-advances
example, the spiro-oxindoles SAR405838 and APG-115 (Fig. 1)
are currently under clinical phase I investigation;9,16,17 our
Introduction
research group has recently proposed 2-thiohydantoin-dispiro-
oxindones as inhibitors of the p53-MDM2 interaction, as one
2-thiohydantoin-dispiro-oxindone (Fig. 1) has now completed
preclinical studies.10,19
Spirocyclicoxindolo-b-lactams are generally tested for anti-
bacterial and antifungal activity but not for antiproliferative
activity. We assumed that the spiro-conjugation of oxindole
fragments with the four-membered ring of azetidin-2-one may
prevent the fast biodegradation of potential p53-MDM2 inhib-
itors and provide at the same time conformational rigidity to
synthesized molecules, which is necessary for effective binding
to MDM2. A similar approach was previously proposed for the
synthesis of combretastatin analogues.20
A number of alternative methods have been described in the
literature for the formation of the b-lactam cycle including the
Rh- or Ir-catalyzed reductive Mannich-type reaction,21,22 the
Reformatsky reaction using Schiff bases and a-bromosubstituted
esters derivatives,20,23 the direct regiospecic metal-catalyzed
carbonilation of aziridines,24 the intramolecular nucleophilic
The search for the most efficient and harmless way to treat
uncontrollable cell proliferation via targeted therapy is
currently a promising research area. The general idea of all
targeted methods is to use pharmacological agents that are
highly selective towards specic biomolecules in cancer cells
that are necessary for them to proliferate.1 One such target is the
MDM2 protein,2 which has great importance due to its function
in p53-protein activity control.3–5 p53 is known as a “genome
guardian”; its function is to check the integrity of DNA and to
trigger the repair mechanisms in the presence of inconsis-
tencies or to induce apoptosis if the DNA is deemed unrepair-
able.5–8 In this context, spiro-oxindoles are attractive molecules
for synthesis because the different spiro-oxindoles display
considerable anticancer action, which is apparently related to
their ability to inhibit p53-MDM2 protein–protein interac-
tion.9–15 Some spiro- and dispiro-oxindoles have been tested as
anticancer drugs during preclinical or clinical studies.9,16–18 For
aMoscow State University, Department of Chemistry, Leninskie gory 1-3, Moscow
119991, Russia. E-mail: bel@org.chem.msu.ru
bSkolkovo Institute of Science and Technology, 4 Alfred Nobel Street, Skolkovo, 143025,
Russian Federation
cNational University of Science and Technology “MISiS”, Leninskiy pr. 4, Moscow
119991, Russia
dDmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9,
Moscow 125047, Russia
† Electronic supplementary information (ESI) available: 1H and 13C NMR and
HRMS data for synthesised compounds. CCDC 1963617, 1963622–1963625. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0ra02374d
Fig.
1
Spiro-oxindoles SAR405838 and APG-115,16,17 which are
currently under clinical trials, and dispiro-oxindole KM-140 have
successfully completed preclinical studies.10,19
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cyclization of N-(p-hydroxyphenyl) cyanoacetamides,25 the intra- obtained diastereomers. For this, the molecular docking of
molecular N-alkylation of amides,26 the Kinugasa reaction ([3 + 2] stereoisomeric 1,3-bis(4-chlorophenyl)spiro[azetidine-2,30-
nitrones cycloaddition to acetylenide followed by acid-catalyzed indoline]-20,4-diones optimized with a MMFF94 procedure with
rearrangement to b-lactam),27–29 the Pd-catalyzed carbonylation AutoDock Vina48 in the active site of MDM2 shaped by
of allyl halides followed by the reaction with imines,30–33 the a complimentary fragment of p53 was carried out. We found
cyclization of b-amino acid esters,34–37 and Staudinger's ketene– that the best binding mode is observed for 2R,3R enantiomer
imine cycloaddition.38–40 Staudinger synthesis is the most and that in this binding mode, one of the lateral aryl fragments
common method and can be carried out using various synthetic is placed into the hydrophobic pocket of MDM2 (Fig. 2), which
techniques with a well-established mechanism. The rst stage of corresponds to an affinity energy of ꢀ7.7 kcal molꢀ1. The
Staudinger reaction is a nucleophilic addition of imine to the second “good” mode is one where an indolin-2-one fragment is
ketene carbonyl carbon atom with the formation of a zwitterionic placed into the said pocket albeit in a slightly shied manner
intermediate, which is cyclized to a four-membered ring at the (Fig. 2a). The affinity energy here is ꢀ7.7 kcal molꢀ1 as well. On
second stage of the reaction with the formation, as a rule, of the other hand, the 2R,3S (Fig. 2b) and 2S,3R (Fig. 2c) isomers of
a mixture of isomeric cis- and trans-lactones with the predomi- spiro-oxindoles did match the desired binding mode with
nance of one or the other diastereomer depending on the solvent, affinity energies of ꢀ7.8 kcal molꢀ1 and ꢀ8.7 kcal molꢀ1
,
addition order of the reagents, the electronic effects of the respectively. The 2S,3S enantiomer (Fig. 2d) is disallowed from
substituents in ketene and imine, and the nucleophilicity of the being placed in the cavity of MDM2 in an advantageous way,
base used for ketene generation.39,41,42 For the latter stage, two which turned out to be the furthest from the desired binding
alternative mechanisms have been proposed43 (Scheme 1): mode, with an affinity energy of ꢀ6.9 kcal molꢀ1, corresponding
intramolecular nucleophilic addition1 or electrocyclic conrotatory to its best position. Thus, only two out of four enantiomers of
reaction.44 The Staudinger reaction was previously successfully 1,3-diaryl-spiro[azetidine-2,30-indoline]-20,4-dione demonstrate
used to synthesize spiro-b-lactams,45,46 but the diastereoselectivity binding modes appropriate for the potential inhibition of p53-
of the reaction was not discussed in the cited articles.
MDM2 interaction, and these isomers are compounds with
Herein, we report a method for the synthesis of bis-aryl spiro a trans arrangement of six-membered aromatic rings of the
[azetidine-2,3-indole]-2,4(1H)-diones via the Staudinger reac- starting phenyl acetic acid and isatin.
tion with an in situ technique based on ketene generation from
The synthesis of target spiro-b-lactams was started with the
substituted phenyl acetic acid, oxalyl chloride and DIPEA. The preparation of the initial Schiff bases using the method
proposed modication of the Staudinger reaction makes it described in (ref. 48) by the condensation of isatin with amines
possible to reverse the diastereoselectivity of b-lactam cycle in reuxing ethyl alcohol in the presence of acetic acid (Table 1).
formation, unlike previously described classic methods,45–47 and Initial imines 1–21 were obtained in good yields as mixtures of
to shi the reaction stereoselectivity to the formation of dia- E/Z isomers with an E-isomer predominance in accordance with
1
stereomers, which are considered as the most promising the NMR H spectra and literature data.49 The resulting
inhibitors of the p53-MDM2 protein–protein interaction mixtures were introduced into further reactions without sepa-
according to molecular docking data.
ration of the individual geometric isomers. It may be noted that
the imine formation reactions did not occur with aliphatic
amines and in the presence of anilines with strong electron
donor/electron withdrawing substituents (4-NO2, 4-OH, 3,4-
Results and discussion
Given the well-known fact that even different optical isomers of
the same substance can provide completely different biological
activity, with one isomer being acure while the other is toxic,7 we
determined which enantiomer can become a possible inhibitor
of the targeted MDM2 molecules among the potentially
Fig. 2 Molecular docking of 1,3-bis(4-chlorophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione stereoisomers on MDM2 active site: (a)
(2R,3R), (b) (2R,3S), (c) (2S,3R), (d) (2S,3S).
Scheme 1 The possible mechanisms for the Staudinger reaction.3,43
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Table 1 Synthesis of the initial Schiff bases 1–21
were then easily separated by column chromatography.
However, in most of these reactions, the diastereomer ratio was
close to 1 : 2, with a predominance of the undesired cis
(2R*,3R*) isomers azetidinones 22b–28b (Table 2).
Thus, the diastereoselectivity of the literature method was
unsatisfactory for the selective preparation of trans-isomeric
2,3- diaryl-spiro[azetidine-2,30-indoline]-20,4-diones. To nd
a convenient way to change the diastereoselectivity, we exam-
ined the possibility of using ketene–imine Staudinger cycload-
dition in more mild conditions by avoiding the use of moisture-
sensitive acyl chlorides. Some methods described in earlier
publications40,50,51 seemed attractive, but poor solubility of the
reagents or difficulties with the nal work-up made them
unacceptable in our case.
Starting from the idea of acid activation by strengthening the
electron-withdrawing character of the carboxylic group, we
guessed that oxalyl chloride, which we previously used for
formation of acyl halide from acid, can be used in a one-pot
process as an acid activator in a fashion similar to that
described in the aforementioned publications. Using this novel
one-pot technique of b-lactam synthesis (Scheme 3) by activa-
tion of a-substituted acetic acids with oxalyl chloride in a reac-
tion mixture at room temperature, we have successfully
synthesized a series of target spiro-oxindoles 22–43 with
a predominance or exceptional formation of the target trans-
diastereomers 22a–43a (Table 3).
Entry (compound #)a
R1
R2
Yield, %b [Z/E]c
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Br
Br
Br
2-F
3-F
4-F
3-Cl
4-Cl
3-Br
4-Br
3-I
3-Cl, 4-F
4-OH
4-OMe
4-OEt
3-Me
4-Me
4-F
4-OMe
3-Me
4-Me
4-F
36 [1/2]
60 [1/4]
56 [1/2]
52 [1/2]
83 [1/2]
51 [1/2]
89 [1/3]
96 [1/3]
89 [2/5]
92 [1/5]
93 [1/4]
87 [1/5]
84[1/3]
93[1/4]
63 [1/2]
88 [1/4]
85 [1/3]
91 [1/3]
73 [3/5]
79 [1/4]
82 [2/5]
9
10
11
12
13
14
15
16
17
18
19
20
21
4-OMe
3-Me
a
All reactions were carried out at room temperature. For the
base, we used diisopropylethylamine (DIPEA); however, the use
of other similar tertiary amines, such as TEA, does not affect the
reaction course signicantly.
Reaction conditions: isatin (1.0 eq.), aniline (1.2 eq.), AcOH (2 drops)
b
c
in 96% EtOH, reux for 0.5–3 h. Isolated yield. Z/E ratios were
determined based on 1H NMR data.
According to the LCMS and 1H NMR data, compounds 34b–
41b and 43b were obtained in trace amounts but were not
(OMe)2). Moreover, the imine formation reaction is also difficult
in the presence of substituents in the ortho position of the
starting aniline. Although 2-uoroaniline reacts with isatin to
give Schiff base 1, the isolated yield of imine 1 (36%) is signif-
icantly lower than that in other cases, and the reaction of 2-Cl
and 2-Br-substituted anilines did not yield the desired Schiff
bases.
Imines 1–21 were then used for Staudinger's imine–ketene
cycloaddition. There are various methods of b-lactam synthesis
involving the Staudinger reaction;23,39,42 these methods differ in
the solvent used and the route for ketene generation (photolysis
or thermolysis of a-diazoketones,44 the dehydrohalogenation of
halides of substituted acetic acids20,38), and the use of different
one-pot techniques for ketene generation (phosphonitrile
Scheme 2 Staudinger synthesis of bis-aryl spiro[azetidine-2,30-indo-
line]-20,4-diones using pre-synthesized acyl chloride.
chloride, SOCl2, or a DMSO–Ac2O complex40,50,51). First, we Table 2 Spirooxindoles obtained with pre-synthesized acyl chloridea
tested the known literature method used for the synthesis of
Compound #
R1
R2
R3
a/b
Yield,%
target spiro-b-lactams with the trans arrangement of aromatic
rings in the 2 and 3 positions of the four-membered cycle. It was
found that isatin imines 1, 3, 5, 7, 9, 10, 12 interact in the
presence of Et3N with 4-chlorophenyl acetyl chloride pre-
generated from acid by addition of oxalyl chloride/DMF. This
experimental technique allows one to create desired the spi-
roconjugation in a similar way to that reported previously45
(Scheme 2). Reuxing of the imines 1, 3, 5, 7, 9, 10, 12 with acyl
chloride and Et3N in DMF gives pairs of diastereomers, which
22a,b
23a,b
24a,b
25a,b
26a,b
27a,b
28b
H
H
H
H
H
H
H
4F
4-Cl
4-Br
4-OH
4-OEt
3-Cl, 4-F
2-F
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
1/2
1/2
1/2
1/2
1/5
2/5
—
64
53
49
62
57
55
44
a
Reaction conditions: Schiff base (1.0 eq.), 4-chlorophenylacetyl
chloride (1.5 eq.), Et3N (3.0 eq.), DMF, reux for 6–9 h.
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Table 4 Optimization of the reaction conditions (Scheme 3) in the
example of compounds 23a,b synthesis
T,
DIPEA, Diastereomers
ratio (23a/23b) Yield, %
Entry Solvent ꢁC Acid, mol mol
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
DCM
DCM
Acetone 20 1.5
Acetone
Et2O
20
20 1.5
20 1.5
1
3.00
3.00
6.00
6.00
3.00
3.00
3.00
3.00
3.00
1 : 1
1.2 : 1
1 : 1
1 : 1
1 : 1
1.2 : 1
1 : 1
—
56
73
58
60
4
Scheme 3 Staudinger synthesis of bis-aryl spiro[azetidine-2,30-indo-
line]-20,4-diones without using presynthesized acyl chloride.
0
1.5
20 1.5
1.5
0
9
Table 3 Spirooxindoles obtained without the use of pre-synthesized
acyl chloride
26
n/a
n/a
0
1.5
20 1.5
—
Compound #
R1
R2
R3
a/b
Yields,%
22a,b
23a,b
24a,b
25a,b
26a,b
27a,b
28b
29a,b
30b
31a,b
32a,b
33a,b
34a
35a
36a
37a
38a
39a
40a
41a
42a,b
43a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Br
Br
Br
H
4-F
4-Cl
4-Br
4-OH
4-OEt
3-Cl, 4-F
2-F
3-F
3-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Br
2/1
1.2/1
1.5/1
—
3.4/1
5/1
—
1.5/1
—
1.4/1
1.3/1
4.5/1
—
—
—
—
—
—
—
—
4/1
-/1
65
71
59
0
our surprise, the choice of solvent did not noticeably affect the
diastereoselectivity of the model reaction. The excess of acid
proved necessary to lower the byproduct yields. It may be
assumed that the oxalyl chloride used to convert starting acid
into ketene may interact with the Schiff base as well as DIPEA,
but, in the presence of an excess of acid, the probability of the
target interaction becomes greater. However, the addition of too
much excess acid negatively affected the yield, supposedly due
to a drop in the solubility of the imine. In addition, the simul-
taneous mixing of all components as well as the excessive
addition of oxalyl chloride resulted in a decline in the product
yield and an increase in the colored byproduct content.
According to the results shown in Table 3, the ratio of the
obtained diastereomers depends on the electron-donating
ability of the substituent connected with the imine nitrogen.
In general, the greater the donating character of the substituent
in the phenyl ring of the isatin imine, the greater the diaster-
eoselectivity shied towards the formation of trans-spiro-oxin-
dolo-b-lactams. The overall diastereomer yields in these cases
were higher as well.
75
41
32
45
25
47
80
78
65
73
27
48
58
54
51
74
84
75
3-Br
3-I
4-OMe
3-Me
4-Me
4-F
4-OMe
3-Me
4-Me
4-F
4-OMe
3-Me
4-OMe
isolated in pure form, so in Table 3, only the diastereomers 34a–
41a and 43a are indicated. Unlike all the other reactions, in the
case of the spiro-compounds 28 and 30, we were able to isolate
only cis diastereomers 28b, 30b. Note also that, unlike the
classical Staudinger method, we could not manage to obtain the
4-hydroxy-substituted derivative 25 using an acyl chloride-free
technique.
To increase the yield of the nal product, an optimization of
the reaction conditions was carried out using Schiff base 5 and
4-chlorophenyl acetic acid as a model system. We varied the
solvent, temperature, ratio of starting acid, DIPEA and oxalyl
chloride as well as the order of component addition. The results
obtained from optimization are shown in Table 4.
Aer optimization, it was discovered that the rate of the
reaction, yield and presence of byproducts depends greatly on
the solubility of the Schiff bases in the reaction solvent as well
as the ratio of imine and acid. It was emphasized that THF
dissolves the components of the reaction mixture much better
than other tested solvents, which may explain why the best
results were obtained using such a solvent. A decrease in the
temperature of most solvents aside from THF leads to a decline
in the solubility, and, as a consequence, a decline in yields. To
This can be explained by the assumption that Schiff bases
with more electron-donating substituents have more electron
density on the imine nitrogen, leading to increased nucleo-
philicity. Since the rst stage of the Staudinger reaction is
known to be a nucleophilic attack of the lone electron pair of the
imine nitrogen by the electron-decit carbonyl of ketene, this
explanation seems plausible. A similar trend is observed when
moving from nonsubstituted isatin to 5-chloroisatin. The yield
of 5-chloroxindole spiro-b-lactams tended to be lower. On the
contrary 5-bromoisatin derivatives have been obtained with
generally better yields which seems to be related to better
solubility of 5-bromo substituted Schiff bases.
To check whether the reaction proceeds with the formation
of acyl halide in the reaction mixture or without intermediate
formation, we tried to carry out the target reaction by mixing all
components (Schiff base, 4-chlorophenylacetic acid and oxalyl
chloride) except for the base (DIPEA). In this case, Staudinger
ketene–imine cycloaddition did not occur, supposedly due to
the absence of the ketene in the reaction mixture. The same
result occurred when mixing imine, acid and DIPEA without
oxalyl chloride. Additionally, we tried to carefully mix together
oxalyl chloride and DIPEA and to add the resulting brown
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mixture to the remaining components. In this case, the
formation of the target spiro-b-lactam was also not observed.
Hence, contrary to the reaction with DMF, the oxalyl chloride/
DIPEA mixture does not yield an active chlorinating agent.
Thus, for the key stage of the Staudinger synthesis without
using pre-synthesized acyl chloride, we used the addition of
oxalyl chloride to acetic acid with the generation of mixed
anhydride (Scheme 4). Acid chloride apparently does not form
in the reaction mixture.
The proposed method of the Staudinger ketene–imine
cycloaddition at room temperature without acyl chloride allows
one to reverse the diastereoselectivity of the formation of spiro-
b-lactams compared to the classical high-temperature method
for generating ketene in the Staudinger reaction (see Tables 2
and 3). It should also be noted that oxalyl chloride converts acid
into ketene during the reaction without formation of acyl
halide, which was proven by a series of trials wherein we mixed
4-chlorophenyl acetic acid with oxalyl chloride and tertiary
amine but with no DMF present.
In summary, the two synthetic techniques used in this work,
as summarized in Scheme 5, complement each other, making it
possible to selectively obtain cis or trans diastereomers of the
target bis-aryl spiro[azetidine-2,30-indoline]-20,4-diones.
To conrm the structures of the synthesized spiro-oxindolo-
b-lactams as well as correlate the 1H NMR data with the
specic diastereomers, the structures of ve obtained
compounds (22a, 22b, 25a, 28b, 29b) were determined using X-
ray diffraction analysis. The molecular structures of these
compounds are shown in Fig. 3; the selected bond lengths and
angles together with the numbering scheme used are all
summarized in Table 5.
By analyzing the X-ray data, we note that the compounds 22a
and 25a are enantiomeric pairs of (2R,3S)- and (2S,3R)- spiro
Scheme 4 The proposed mechanism for acid activation and ketene
formation.
Fig. 3 Molecular structures spiro-oxindolo-b-lactams: (a) compound
22a (CCDC 1963622); (b) compound 22b (CCDC 1963623); (c)
compound 25a (CCDC 1963617); (d) compound 28b (CCDC 1963625);
(e) compound 29b (CCDC 1963624).
Scheme 5 Generalization of two approaches for spirocyclic oxindolo-
b-lactams synthesis by Staudinger ketene imine-cycloaddition applied
in the present work (predominantly formed diastereomers are
indicated).
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Table 5 Selected bond lengths (A˚) and angles (ꢁ) for the compounds
22a,b, 25a, 28b and 29b
base by attachment to a ketene carbonyl either on the side of the
hydrogen atom or phenyl ring (Fig. 4).
It is obvious that ketene attack from the side of the phenyl
ring will have a greater activation barrier compared with attack
from the hydrogen side, but it is important to determine how
large this energy gap is, and, moreover, what the difference
between the E- and Z-imines is. We found that the 2R*,3S*-
isomer of 1,3-bis(4-chlorophenyl)spiro[azetidine-2,30-indoline]-
20,4-dione (trans-product) is obtained by the cyclization of the
intermediate formed from Z-imine attacking ketene from the
phenyl side as well as E-imine attacking ketene from the
hydrogen side. In contrast, the 2R*,3R*-isomer (cis-product) is
obtained by the cyclization of the intermediate formed from the
E-imine attacking ketene from the phenyl side as well as the Z-
imine attacking ketene from the hydrogen side. For the E-imine,
a zwitterionic Staudinger intermediate leading to a 2R*,3S*
product is formed with 0.11 kcal molꢀ1 lower activation energy
compared to that leading to the 2R*,3R* conguration, whereas
the next stage of the process (cyclization) proceeds without an
activation barrier, contrary to that of 2R*,3R* precursor, which
is cyclized with an activation energy of approximately
Bond/angle
22a
22b
1.540
25a
1.539
28b
1.534
1.495
1.476
1.592
1.523
1.384
1.415
1.479
29b
1.524
1.501
1.475
1.579
1.53
1.371
1.415
1.495
C2–C3
C3–C9
C3–N2
C3–C10
C10–C11
N2–C11
N2–C12
C10–C18
C2–C3–C9
C2–C3–N2
C9–C3–C10
C3–N2–C11
C3–C10–C11
N2–C3–C10
N2–C11–C10
C18–C10–H
1.541
1.494
1.468
1.582
1.525
1.363
1.404
1.493
103.31
114.04
117.74
95.48
84.84
86.68
92.81
113.21
1.489
1.458
1.609
1.527
1.378
1.407
1.493
103.50
118.04
118.88
96.05
84.46
86.54
92.75
111.12
1.495
1.480
1.583
1.522
1.353
1.417
1.493
103.31
115.27
118.00
95.16
84.77
86.45
93.63
110.07
103.3
103.7
117.7
118.3
95.1
85.3
86.5
117.9
118.4
94.7
85.4
86.3
22.8 kcal molꢀ1
.
92.7
109.9
92.9
110.9
For the Z-imine, the calculations show a completely opposite
result; the generation of the 2R*,3S* product proceeds with
a higher activation barrier for both the formation of the inter-
mediate (approximately 4 kcal molꢀ1 higher) and its cyclization
[azetidine-2,30-indoline]-20,4-diones that crystallized in a mono-
clinic centrosymmetric P21/c group. This correlates with the
characteristic signals observed in the 1H NMR spectra at
ꢂ10.9 ppm (NH of oxindole) and ꢂ5.35 ppm (g-CH of azetidin-
2-one ring). Compounds 22b, 28b, and 29b are enantiomeric
pairs of (2R,3R)- and (2S,3S)-3-(4-chlorophenyl)-1-(4-aryl)spiro
[azetidine-2,30-indoline]-20,4-diones. These pairs crystallize in
a noncentrosymmetric P41 group with a pseudo center of
symmetry. These structures correlate with the characteristic
into
a
four-membered b-lactam cycle (approximately
18.5 kcal molꢀ1 higher). Thus, the results of the quantum-
chemical calculations indicate the predominant formation of
a diastereomer with the a 2R*,3S* conguration only if the
1
signals observed in the H NMR spectra at ꢂ11.1 ppm (NH of
oxindole) and ꢂ5.1 ppm (g-CH of azetidin-2-one ring).
For all studied compounds, the bond lengths and bond
angles are found to be weakly dependent on the substituents in
the aryl fragments. The planes of the spiro-fused heterocycles
are nearly perpendicular to each other. The nitrogen atom of the
azetidine fragment has an approximately planar trigonal envi-
ronment, and the aryl substituent is almost coplanar with the
four-membered ring.
To explain the change in the diastereoselectivity of the acyl
chloride-free Staudinger synthesis at room temperature
compared with the high-temperature technique described in
the literature, we employed quantum chemical calculations.
Geometry optimization for the compounds, vibrational
frequency analysis, transition state (TS) searches of the studied
transformations and intrinsic reaction coordinate calculations
(IRC) were carried out using PRIRODA-04 soware52 with the
Perdew–Burke–Ernzerhof (PBE)53 functional in combination
with a 3z basis set for the model reaction of compound 23
synthesis. We assumed that the structure of the nal product
depends on the organization of Staudinger's zwitterionic
intermediate, which in turn can be formed from a Z- or E-Schiff
Fig. 4 Schiff base attacking a ketene carbonyl: (a) E-imine attacks
from the hydrogen side; (b) E-imine attacks from the phenyl side; (c) Z-
imine attacks from the hydrogen side; (d) Z-imine attacks from the
phenyl side.
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Table 6 The results obtained from a MTT test (IC50 values are shown)
for 23a,b and 27a,b
million relative to TMS. High resolution mass spectra (HRMS)
were recorded on an Orbitrap Elite (Thermo Scientic) mass
spectrometer with electrospray ionization (ESI) and orbital trap.
To inject solutions with a concentration of 0.1 to 9 mg mLꢀ1 (in
1% formic acid in acetonitrile), direct injection into the ion
source using a syringe pump (5 mL minꢀ1) was used. The spray
voltage was ꢃ3.5 kV, the temperature of the capillary was
IC50 (mM)
No.
LNCap
PC3
HCTwt (P53+)
HCTꢀ/ꢀ (P53ꢀ)
23a
23b
27a
27b
14.3 ꢃ 4.5
37.0 ꢃ 8.1
13.1 ꢃ 5.8
17.2 ꢃ 3.3
27.6 ꢃ 3.0
>50 M
>50 M
81.8 ꢃ 16.0
141.6 ꢃ 40.1
29.6 ꢃ 16.9
127.7 ꢃ 14.3
152.1 ꢃ 26.6
>50 M
>50 M
ꢁ
275 C.
>50 M
>50 M
General procedure for preparation of Schiff base 1–21
initial mixture of isomeric Schiff bases is enriched with the E-
isomer.
Aromatic amine (1.1 mmol) was added into boiling solution of
isatin (1 mmol) in 25 mL of absolute ethanol containing a few
drops of glacial acetic acid. The reaction mixture was reuxed
for 3 hours. Completion was checked by TLC. Aer the cooling
of the reaction mixture to room temperature it was ltered
under reduced pressure. Precipitate was washed with cold EtOH
(2 ꢄ 5 mL) then dried. The spectral characteristics of the ob-
tained compounds correspond to the literature data:56
(compounds 1, 2),57 (compounds 3–4, 6, 7, 19),58 (compounds 4–
9, 11, 13, 14),59 (compound 10),60 (compound 10),61 (compound
12),62 (compound 15),63 (compounds 16, 18),64 (compound 17),65
(compounds 18, 20, 21).
4-Chlorophenylacyl chloride. Oxalyl chloride (1.2 mmol) was
added to the stirring solution of 4-chlorophenylacetic acid (1
mmol) in anhydrous THF (20 mL) with the addition of 1–2 drops
of dry DMF as a catalyst. The reaction mixture was reuxed for 2
hours, then the solvent was removed under reduced pressure to
obtain thick yellow oil.
Synthesis of spirooxindoles (22a,b–28a,b) using pre-
synthesised acyl chloride (general procedure). 4-Chlor-
ophenylacyl chloride (2 mmol) was added to a boiling mixture of
Schiff base 1–21 (1 mmol) and Et3N (3 mmol) in anhydrous DMF
(30 mL). The reaction mixture was reuxed for 7–9 hours then
cooled to room temperature and mixed with cold water. The
solvent was evaporated under reduced pressure. The residue
was puried by column chromatography on silica gel using
petroleum ether (65%) : ethyl acetate (35%) mixture. The
products were recrystallized from diethyl ether giving a white
solid.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(4-uorophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (22a). 1H NMR (400 MHz, DMSO-d6)
d ppm 10.88 (s, 1H), 7.67 (d, J ¼ 7.34 Hz, 1H), 7.36–7.42 (m, 3H),
7.15–7.22 (m, 4H), 7.12 (t, J ¼ 7.58 Hz, 1H), 7.02–7.07 (m, 2H),
7.00 (d, J ¼ 7.70 Hz, 1H), 5.35 (s, 1H). 13C NMR (101 MHz,
DMSO-d6) d ppm 172.52, 164.06, 141.93, 133.04, 132.87, 131.05,
130.33, 130.23, 128.48, 124.78, 123.99, 122.91, 118.10, 118.02,
Summarizing everything up to this point we have obtained
some qualitative explanation for presence of diastereoselectivity
in formation of our spiro-b-lactams. Yet according to calcula-
tions diastereomeric ratio should correlate with ratio of E/Z
Schiff base in mixture, which doesn't seem to occur.
So further computational research is necessary in order to
verify whether isomerization of Schiff base or more signicantly
isomerization of zwitterionic intermediate takes place. This
could have explained dependency of diastereoselectivity on
temperature as well as polarity of solvent.
To verify the correctness of the assumptions made on the
basis of molecular docking in terms of the preference of trans-
2,3-diaryl-spiro[azetidine-2,30-indoline]-20,4-diones as p53-
MDM2 interaction inhibitors, we carried out preliminary in
vitro cytotoxicity tests for compounds 23a,b and 27a,b. Cyto-
toxicity was evaluated using the standard MTT method.54 For
testing, we selected the cell cultures of prostate cancer LNCap,
PC3 and colorectal cancer HCT(p53+), HCT(p53ꢀ), both of
which express p53 protein (LNCap and HCT (p53+)) and do not
express PC3 and HCT116 (p53ꢀ). The results are shown in Table
6.
According to the data presented in Table 6, it is seen that all
studied compounds are more cytotoxic to cell lines expressing
p53 protein than to lines not expressing it. Moreover, the cyto-
toxicity of compounds 23a and 27a on p53-positive cell lines
LNCap and HCT (p53+) is higher than for the corresponding
isomeric compounds 23b and 27b. Such results are consistent
with the molecular docking data for the higher affinity of trans-
isomeric spiro[azetidine-2,30-indoline]-20,4-diones towards the
MDM2 protein, and, accordingly, their higher anticancer
activity associated with the inhibition of p53-MDM2
interaction.
Experimental
General techniques
116.67, 116.44, 111.07, 66.29, 64.63. HRMS (ESI) Calc for C22
-
H15ClFN2O2 [M + H+]: 393.0801, found: 393.0792.
All solvents used were puried and dehydrated using methods
(2R*,3R*)-3-(4-Chlorophenyl)-1-(4-uorophenyl)spiro[azetidine-
described in (ref. 55). All starting reagents were purchased from 2,30-indoline]-20,4-dione (22b). 1H NMR (400 MHz, DMSO-d6)
Sigma-Aldrich. Reactions were checked by TLC analysis using d ppm 11.14 (s, 1H), 7.34 (d, J ¼ 8.31 Hz, 2H), 7.21–7.25 (m, 3H),
silica plates with a uorescent indicator (254 nm) and visualized 7.17–7.21 (m, 2H), 7.05 (dd, J ¼ 9.11, J ¼ 4.71 Hz, 2H), 6.95 (d, J
with a UV lamp. 1H and 13C NMR spectra were recorded on ¼ 7.82 Hz, 1H), 6.71–6.74 (m, 2H), 5.08 (s, 1H). 13C NMR (101
1
a Bruker Avance spectrometer (400 MHz for H, 100 MHz for MHz, DMSO-d6) d ppm 174.72, 163.81, 142.53, 132.87, 131.45,
13C) in DMSO-d6. Chemical shis are reported in parts per 130.92, 130.77, 130.68, 128.70, 128.25, 125.50, 122.04, 120.99,
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118.13, 116.70, 116.47, 111.02, 65.55, 63.69. HRMS (ESI) Calc for 118.30, 115.86, 110.75, 65.44, 63.27. HRMS (ESI) Calc for
C
22H15ClFN2O2 [M + H+]: 393.0801, found: 393.0798.
C
22H16ClN2O3 [M + H+]: 391.0844, found: 391.0838.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(4-chlorophenyl)spiro[azetidine-
(2R*,3S*)-3-(4-Chlorophenyl)-1-(4-ethoxyphenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (23a). 1H NMR (400 MHz, DMSO-d6) 2,30-indoline]-20,4-dione (26a). 1H NMR (400 MHz, DMSO-d6)
d ppm 10.91 (s, 1H), 7.67 (d, J ¼ 7.39 Hz, 1H), 7.42–7.38 (m, 5H), d ppm 10.82 (br. s., 1H), 7.64 (d, J ¼ 7.39 Hz, 1H), 7.35–7.41 (m,
7.16 (d, J ¼ 8.37 Hz, 2H), 7.12 (t, J¼ 7.52 Hz, 1H), 7.04–6.99 (m, 3H), 7.18 (d, J ¼ 8.30 Hz, 2H), 7.10 (t, J ¼ 7.50 Hz, 1H), 6.94–7.01
3H), 5.37 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm 172.27, (m, 3H), 6.87 (d, J ¼ 8.91 Hz, 2H), 5.28 (s, 1H), 3.92 (q, J ¼
164.14, 141.83, 135.27, 132.80, 130.95, 130.14, 130.10, 129.59, 6.90 Hz, 2H), 1.26 (t, J ¼ 6.93 Hz, 3H). 13C NMR (101 MHz,
128.38, 128.18, 124.70, 123.81, 110.98, 66.13, 64.91, 64.62, DMSO-d6) d ppm 172.65, 163.52, 155.30, 141.86, 132.63, 130.73,
15.16. HRMS (ESI) Calc for C22H15Cl2N2O2 [M + H+]: 409.0505, 130.52, 130.13, 129.70, 128.29, 124.55, 124.33, 122.65, 117.88,
found: 409.0496.
(2R*,3R*)-3-(4-Chlorophenyl)-1-(4-chlorophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (23b). 1H NMR (400 MHz, DMSO-d6)
115.21, 110.79, 66.12, 64.37, 63.21, 14.52. HRMS (ESI) Calc for
C
(2R*,3R*)-3-(4-Chlorophenyl)-1-(4-ethoxyphenyl)spiro[azeti-
24H20ClN2O3 [M + H+]: 419.1157, found: 419.1147.
d ppm 11.16 (s, 1H), 7.40 (d, J ¼ 8.80 Hz, 2H), 7.32 (d, J ¼ dine-2,30-indoline]-20,4-dione (26b). 1H NMR (400 MHz, DMSO-
8.44 Hz, 2H), 7.18–7.25 (m, 3H), 7.02 (d, J ¼ 8.80 Hz, 2H), 6.95 d6) d ppm 11.09 (s, 1H), 7.33 (d, J ¼ 8.31 Hz, 2H), 7.17–7.25 (m,
(d, J ¼ 7.76 Hz, 1H), 6.67–6.75 (m, 2H), 5.09 (s, 1H). 13C NMR 3H), 6.92–6.99 (m, 3H), 6.87 (d, J ¼ 8.93 Hz, 2H), 6.68–6.74 (m,
(101 MHz, DMSO-d6) d ppm 174.48, 174.36, 163.92, 142.26, 2H), 5.01 (s, 1H), 3.92 (q, J ¼ 6.95 Hz, 2H), 1.26 (t, J ¼ 6.94 Hz,
135.27, 132.80, 130.86, 130.69, 130.50, 129.64, 128.60, 128.41, 3H). 13C NMR (101 MHz, DMSO-d6) d ppm 174.91, 163.31,
125.44, 121.94, 120.76, 117.78, 110.90, 65.37, 63.65. HRMS (ESI) 155.45, 142.47, 132.65, 130.91, 130.66, 129.70, 128.56, 125.36,
Calc for C22H15Cl2N2O2 [M + H+]: 409.0505, found: 409.0496.
121.83, 121.33, 117.93, 115.23, 110.78, 65.38, 63.33, 63.23,
(2R*,3S*)-3-(4-Chlorophenyl)-1-(4-bromophenyl)spiro[azetidine- 14.56. HRMS (ESI) Calc for C24H20ClN2O3 [M + H+]: 419.1157,
2,30-indoline]-20,4-dione (24a). 1H NMR (400 MHz, DMSO-d6) found: 419.1150.
d ppm 10.91 (s, 1H), 7.67 (d, J ¼ 7.39 Hz, 1H), 7.53 (d, J ¼
(2R*,3S*)-3-(4-Chlorophenyl)-1-(3-chloro-4-uorophenyl)spiro
8.76 Hz, 2H), 7.35–7.43 (m, 3H), 7.16 (d, J ¼ 8.38 Hz, 2H), 7.12 (t, [azetidine-2,30-indoline]-20,4-dione (27a). 1H NMR (400 MHz,
J ¼ 7.58 Hz, 1H), 7.00 (d, J ¼ 7.99 Hz, 1H), 6.97 (d, J ¼ 8.76 Hz, DMSO-d6) d ppm 10.94 (s, 1H), 7.70 (d, J ¼ 7.52 Hz, 1H), 7.34–
2H), 5.37 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm 172.26, 7.43 (m, 5H), 7.09–7.18 (m, 3H), 7.00 (d, J ¼ 7.76 Hz, 1H), 6.72
164.17, 141.81, 135.66, 132.79, 132.47, 130.96, 130.11, 130.09, (dd, J ¼ 7.27, 4.46 Hz, 1H), 5.41 (s, 1H). 13C NMR (101 MHz,
128.39, 124.71, 123.78, 122.79, 118.00, 116.20, 110.98, 66.11, DMSO-d6) d ppm 171.90, 171.78, 170.12, 164.05, 152.33, 141.63,
64.62. HRMS (ESI) Calc for C22H15BrClN2O2 [M + H+]: 453.0000, 141.47, 133.23, 132.63, 130.93, 129.87, 129.73, 128.20, 124.67,
found: 452.9988.
123.17, 122.68, 120.21, 120.02, 117.97, 115.74, 110.75, 66.12,
(2R*,3R*)-3-(4-Chlorophenyl)-1-(4-bromophenyl)spiro[azetidine- 64.52. HRMS (ESI) Calc for C22H14Cl2FN2O2 [M + H+]: 427.0411,
2,30-indoline]-20,4-dione (24b). 1H NMR (400 MHz, DMSO-d6) found: 427.0402.
d ppm 11.16 (s, 1H), 7.53 (d, J ¼ 8.68 Hz, 2H), 7.29–7.36 (m, 2H),
(2R*,3R*)-3-(4-Chlorophenyl)-1-(3-chloro-4-uorophenyl)spiro
7.18–7.26 (m, 3H), 6.97 (t, J ¼ 9.18 Hz, 3H), 6.67–6.77 (m, 2H), [azetidine-2,30-indoline]-20,4-dione (27b). 1H NMR (400 MHz,
5.10 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm 174.43, DMSO-d6) d ppm 11.19 (s, 1H), 7.38–7.44 (m, 2H), 7.34 (d, J ¼
163.90, 142.40, 135.63, 132.77, 132.48, 130.81, 130.64, 130.45, 8.44 Hz, 2H), 7.21–7.28 (m, 3H), 6.97 (d, J ¼ 7.76 Hz, 1H), 6.69–
128.56, 125.39, 121.89, 120.76, 118.07, 116.42, 110.91, 65.34, 6.80 (m, 3H), 5.14 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm
63.65. HRMS (ESI) Calc for C22H14BrClN2O2 [M + H+]: 453.0000, 174.31, 164.02, 152.68, 142.48, 132.86, 131.02, 130.74, 130.36,
found: 452.9989.
128.60, 125.58, 122.02, 120.46, 120.26, 118.46, 118.30, 118.08,
116.10, 110.95, 65.62, 63.86. HRMS (ESI) Calc for C22H14Cl2-
(2R*,3S*)-3-(4-Chlorophenyl)-1-(4-hydroxyphenyl)spiro[azeti-
dine-2,30-indoline]-20,4-dione (25a). 1H NMR (400 MHz, DMSO- FN2O2 [M + H+]: 427.0411, found: 427.0404.
d6) d ppm 10.78 (s, 1H), 9.43 (s, 1H), 7.62 (d, J ¼ 7.34 Hz, 1H),
(2R*,3R*)-3-(4-Chlorophenyl)-1-(2-uorophenyl)spiro[azetidine-
7.33–7.41 (m, 3H), 7.16 (d, J ¼ 8.44 Hz, 2H), 7.10 (t, J ¼ 7.58 Hz, 2,30-indoline]-20,4-dione (28b). 1H NMR (400 MHz, DMSO-d6)
1H), 6.97 (d, J ¼ 7.82 Hz, 1H), 6.88 (d, J ¼ 8.80 Hz, 2H), 6.68 (d, J d ppm 10.88 (s, 1H), 7.87 (td, J ¼ 7.58, 1.45 Hz, 1H), 7.33 (d, J ¼
¼ 8.80 Hz, 2H), 5.24 (s, 1H). 13C NMR (101 MHz, DMSO-d6) 8.45 Hz, 2H), 7.15–7.25 (m, 5H), 7.12 (td, J ¼ 7.63, 1.10 Hz, 1H),
d ppm 172.79, 163.41, 154.39, 141.86, 132.63, 130.71, 130.66, 6.83 (d, J ¼ 7.69 Hz, 1H), 6.69–6.74 (m, 1H), 6.61–6.68 (m, 1H),
130.20, 128.47, 128.32, 124.57, 124.50, 122.65, 118.24, 115.86, 5.14 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm 175.53,
110.80, 66.17, 64.33. HRMS (ESI) Calc for C22H16ClN2O3 [M + 164.75, 153.40, 150.94, 142.71, 132.73, 130.96, 130.51, 130.39,
H+]: 391.0844, found: 391.0834.
128.61, 127.22, 127.15, 125.28, 124.88, 123.20, 123.08, 122.72,
122.30, 121.46, 116.81, 116.61, 110.42, 67.73, 64.41. HRMS (ESI)
(2R*,3R*)-3-(4-Chlorophenyl)-1-(4-hydroxyphenyl)spiro[azeti-
dine-2,30-indoline]-20,4-dione (25b). 1H NMR (400 MHz, DMSO- Calc for C22H15ClFN2O2 [M + H+]: 393.0801, found: 393.0794.
d6) d ppm 11.04 (s, 1H), 9.46 (s, 1H), 7.33 (d, J ¼ 8.31 Hz, 2H),
Synthesis of spirooxindoles (22a,b–43a,b) without pre-
7.21 (d, J ¼ 8.44 Hz, 3H), 6.92 (d, J ¼ 7.83 Hz, 1H), 6.88 (d, J ¼ synthesised acyl chloride (general procedure). The solution of
8.80 Hz, 2H), 6.65–6.74 (m, 4H), 4.97 (s, 1H). 13C NMR (101 oxalyl chloride (1.5 mmol) in anhydrous THF (10 mL) was added
MHz, DMSO-d6) d ppm 175.03, 163.17, 154.54, 142.46, 132.63, dropwise to a stirring solution of Schiff base (1 mmol), a-
131.02, 130.65, 130.58, 128.56, 128.46, 125.34, 121.80, 121.48, substituted acetic acid (1.5 mmol) and DIPEA (3 mmol) in
anhydrous THF. The reaction completion was checked by TLC.
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The solvent was evaporated under reduced pressure. The
residue was puried by column chromatography over silica gel
using petroleum ether (65%): ethyl acetate (35%) mixture as an
eluent. The residue was recrystallized from diethyl ether giving
a white solid. In some cases the product was yellow or orange
solid or brown oil; for the additional purication it was washed
with eluent and then recrystallized with diethyl ether again or
puried by additional column chromatography until product
became white solid.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(3-uorophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (29a). 1H NMR (400 MHz, DMSO-d6)
d ppm 10.93 (s, 1H), 7.70 (d, J ¼ 7.40 Hz, 1H), 7.40 (d, J ¼
8.56 Hz, 3H), 7.32–7.38 (m, 1H), 7.11–7.18 (m, 3H), 7.02 (d, J ¼
7.70 Hz, 1H), 6.92–6.99 (m, 2H), 6.59 – 6.66 (m, 1H), 5.41 (s, 1H).
13C NMR (101 MHz, DMSO-d6) d ppm 172.26, 164.45, 141.86,
137.85, 132.88, 131.81, 131.71, 131.11, 130.15, 130.08, 128.47,
124.85, 123.77, 122.90, 111.60, 111.05, 103.70, 103.44, 66.29,
64.56. HRMS (ESI) Calc for C22H15ClFN2O2 [M + H+]: 393.0801,
found: 393.0790.
(2R*,3R*)-3-(4-Chlorophenyl)-1-(3-uorophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (29b). 1H NMR (400 MHz, DMSO-d6)
d ppm 11.19 (s, 1H), 7.31–7.40 (m, 3H), 7.20–7.27 (m, 3H), 6.93–
7.02 (m, 3H), 6.69–6.78 (m, 2H), 6.63 (dd, J ¼ 8.10, 1.19 Hz, 1H),
5.13 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm 174.40,
164.16, 163.43, 161.00, 142.44, 137.78, 132.84, 131.78, 131.69,
130.93, 130.71, 130.41, 128.62, 125.50, 121.98, 120.74, 111.65,
111.62, 111.54, 111.33, 110.94, 103.83, 103.57, 65.51, 63.61.
HRMS (ESI) Calc for C22H15ClFN2O2 [M + H+]: 393.0801, found:
393.0790.
(2R*,3R*)-3-(4-Chlorophenyl)-1-(3-chlorophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (30b). 1H NMR (400 MHz, DMSO-d6)
d ppm 11.20 (s, 1H), 7.31–7.37 (m, 3H), 7.23–7.28 (m, 4H), 7.19
(td, J ¼ 8.07, 1.10 Hz, 1H), 6.97 (d, J ¼ 7.82 Hz, 1H), 6.69–6.79
(m, 3H), 5.13 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm
174.41, 164.20, 142.43, 137.57, 133.82, 132.86, 130.97, 130.75,
130.40, 128.62, 125.55, 124.50, 122.01, 120.68, 116.27, 114.18,
110.94, 65.46, 63.66. HRMS (ESI) Calc for C22H15Cl2N2O2 [M +
H+]: 409.0505, found: 409.0498.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(3-bromophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (31a). 1H NMR (400 MHz, DMSO-d6)
d ppm 10.91 (s, 1H), 7.67 (d, J ¼ 7.27 Hz, 1H), 7.53 (d, J ¼
8.86 Hz, 2H), 7.37–7.43 (m, 3H), 7.16 (d, J ¼ 8.44 Hz, 2H), 7.12
(td, J ¼ 7.55, 0.67 Hz, 1H), 7.00 (d, J ¼ 7.70 Hz, 1H), 6.96 (d, J ¼
8.86 Hz, 2H), 5.37 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm
172.28, 164.20, 150.16, 141.82, 135.67, 132.80, 132.51, 130.99,
130.14, 130.12, 128.42, 124.75, 123.79, 122.82, 118.00, 116.22,
111.01, 66.11, 64.62. HRMS (ESI) Calc for C22H15BrClN2O2 [M +
H+]: 453.0000, found: 452.9981.
(2R*,3R*)-3-(4-Chlorophenyl)-1-(3-bromophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (31b). 1H NMR (400 MHz, DMSO-d6)
d ppm 11.20 (s, 1H), 7.42 (s, 1H), 7.32–7.36 (m, 2H), 7.30 (d, J ¼
6.42 Hz, 1H), 7.20–7.27 (m, 4H), 6.97 (d, J ¼ 7.76 Hz, 1H), 6.70–
6.79 (m, 3H), 5.13 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm
174.41, 164.18, 142.43, 137.68, 132.85, 131.77, 130.96, 130.75,
130.40, 128.61, 127.37, 125.56, 122.20, 120.67, 119.17, 114.48,
110.91, 65.43, 63.65. HRMS (ESI) Calc for C22H15BrClN2O2 [M +
H+]: 453.0000, found: 452.9984.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(3-iodophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (32a). 1H NMR (400 MHz, DMSO-d6)
d ppm 10.94 (s, 1H), 7.69 (d, J ¼ 7.34 Hz, 1H), 7.59 (s, 1H), 7.46
(d, J ¼ 7.82 Hz, 1H), 7.40 (d, J ¼ 8.50 Hz, 3H), 7.16 (d, J ¼ 8.56 Hz,
2H), 7.07–7.13 (m, 2H), 7.01 (d, J ¼ 7.76 Hz, 1H), 6.76 (d, J ¼
8.31 Hz, 1H), 5.39 (s, 1H). 13C NMR (101 MHz, DMSO-d6) d ppm
172.26, 164.35, 141.81, 137.59, 132.99, 132.83, 131.62, 131.07,
130.12, 128.43, 124.88, 124.84, 123.75, 122.86, 114.74, 110.94,
95.39, 66.07, 64.47. HRMS (ESI) Calc for C22H15ClFN2O2 [M +
H+]: 500.9861, found: 500.9848.
(2R*,3R*)-3-(4-Chlorophenyl)-1-(3-iodophenyl)spiro[azetidine-
2,30-indoline]-20,4-dione (32b). 1H NMR (400 MHz, DMSO-d6)
d ppm 11.20 (s, 1H), 7.64 (br. s., 1H), 7.46 (d, J ¼ 7.64 Hz, 1H),
7.34 (d, J ¼ 8.01 Hz, 2H), 7.19–7.28 (m, 3H), 7.09 (t, J ¼ 7.92 Hz,
1H), 6.97 (d, J ¼ 7.64 Hz, 1H), 6.69–6.78 (m, 3H), 5.11 (s, 1H). 13
C
NMR (101 MHz, DMSO-d6) d ppm 174.46, 164.10, 161.77,
153.07, 142.42, 137.55, 133.20, 132.83, 131.59, 130.74, 130.44,
128.60, 125.54, 125.06, 121.97, 114.76, 110.87, 95.39, 65.32,
63.58. HRMS (ESI) Calc for C22H15ClFN2O2 [M + H+]: 500.9861,
found: 500.9845.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(4-methoxyphenyl)spiro[azeti-
dine-2,30-indoline]-20,4-dione (33a). 1H NMR (400 MHz, DMSO-
d6) d ppm 10.83 (s, 1H), 7.64 (d, J ¼ 7.40 Hz, 1H), 7.35–7.40 (m,
3H), 7.18 (d, J ¼ 8.13 Hz, 2H), 7.10 (t, J ¼ 7.52 Hz, 1H), 6.96–7.00
(m, 3H), 6.86–6.90 (m, 2H), 5.28 (s, 1H), 3.66 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) d ppm 172.71, 163.57, 156.07, 141.92,
132.70, 130.79, 130.56, 130.19, 129.86, 128.35, 124.62, 124.36,
122.70, 117.89, 114.76, 110.85, 66.15, 64.40, 55.28. HRMS (ESI)
Calc for C23H18ClN2O3[M + H+]: 405.1000, found: 405.0997.
(2R*,3R*)-3-(4-Chlorophenyl)-1-(4-methoxyphenyl)spiro[azeti-
dine-2,30-indoline]-20,4-dione (33b). 1H NMR (400 MHz, DMSO-
d6) d ppm 11.10 (s, 1H), 7.34 (d, J ¼ 8.50 Hz, 2H), 7.23 (d, J ¼
8.50 Hz, 2H), 7.18–7.21 (m, 1H), 6.87–7.00 (m, 5H), 6.69–6.73
(m, 2H), 5.01 (s, 1H), 3.66 (s, 3H). 13C NMR (101 MHz, DMSO-d6)
d ppm 174.89, 163.29, 156.17, 142.48, 132.66, 131.32, 130.88,
130.62, 129.80, 128.55, 125.34, 121.81, 121.31, 117.93, 114.73,
110.76, 68.25, 65.38, 55.25. HRMS (ESI) Calc for C23H18ClN2O3
[M + H+]: 405.1000, found: 405.1000.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(m-tolyl)spiro[azetidine-2,30-
1
indoline]-20,4-dione (34a). H NMR (400 MHz, DMSO-d6) d ppm
10.87 (s, 1H), 7.64 (d, J ¼ 7.34 Hz, 1H), 7.36–7.42 (m, 3H), 7.14–
7.19 (m, 3H), 7.08–7.14 (m, 2H), 7.00 (d, J ¼ 7.76 Hz, 1H), 6.90 (d,
J ¼ 7.58 Hz, 1H), 6.58 (d, J ¼ 8.25 Hz, 1H), 5.32 (s, 1H), 2.21 (s,
3H). 13C NMR (101 MHz, DMSO-d6) d ppm 172.19, 163.85,
141.37, 138.74, 136.32, 132.48, 130.59, 129.92, 129.11, 128.13,
124.89, 124.38, 122.50, 116.81, 112.49, 110.55, 64.00, 59.53,
20.89. HRMS (ESI) Calc for C23H18ClN2O2 [M + H+]: 389.1051,
found: 389.1046.
(2R*,3S*)-3-(4-Chlorophenyl)-1-(p-tolyl)spiro[azetidine-2,30-
1
indoline]-20,4-dione (35a). H NMR (400 MHz, DMSO-d6) d ppm
10.86 (s, 1H), 7.63 (d, J ¼ 7.40 Hz, 1H), 7.37–7.41 (m, 3H), 7.17
(d, J ¼ 7.89 Hz, 2H), 7.10 (d, J ¼ 7.76 Hz, 3H), 7.00 (d, J ¼ 7.70 Hz,
1H), 6.93 (d, J ¼ 7.82 Hz, 2H), 5.31 (s, 1H), 2.19 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) d ppm 172.68, 163.91, 141.87, 134.18,
133.75, 132.77, 131.42, 130.87, 130.49, 130.23, 129.92, 128.42,
128.21, 124.64, 124.36, 122.78, 116.19, 110.93, 66.02, 64.38,
14130 | RSC Adv., 2020, 10, 14122–14133
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20.47. HRMS (ESI) Calc for C23H17ClN2O2 [M + H+]: 389.1051, DMSO-d6) d ppm 171.95, 163.04, 155.87, 140.95, 140.79, 133.28,
found: 389.1045.
132.54, 130.04, 129.41, 128.11, 127.42, 126.41, 117.60, 114.60,
114.23, 112.54, 65.70, 64.17, 55.03. HRMS (ESI) Calc for C23
(2R*,3S*)-50-Chloro-3-(4-chlorophenyl)-1-(4-uorophenyl)spiro
-
[azetidine-2,30-indoline]-20,4-dione (36a). 1H NMR (400 MHz, H17BrClN2O3 [M + H+]: 483.0106, found: 483.0100.
DMSO-d6) d ppm 11.01 (s, 1H), 7.87 (d, J ¼ 1.98 Hz, 1H), 7.45
(2R*,3S*)-50-Bromo-3-(4-chlorophenyl)-1-(m-tolyl)spiro[azeti-
(dd, J ¼ 8.38, 2.13 Hz, 1H), 7.39 (d, J ¼ 8.45 Hz, 2H), 7.15–7.25 dine-2,30-indoline]-20,4-dione (42a). 1H NMR (400 MHz, DMSO-d6)
(m, 4H), 6.98–7.09 (m, 3H), 5.41 (s, 1H). 13C NMR (101 MHz, d ppm 11.01 (br. s., 1H), 7.95 (d, J ¼ 1.59 Hz, 1H), 7.57 (dd, J ¼
DMSO-d6) d ppm 172.05, 163.69, 159.77, 157.37, 140.62, 132.90, 8.31, 1.65 Hz, 1H), 7.39 (d, J ¼ 8.38 Hz, 2H), 7.14–7.21 (m, 3H),
130.84, 130.28, 130.02, 128.60, 128.41, 126.87, 125.92, 125.12, 7.09 (s, 1H), 6.97 (d, J ¼ 8.31 Hz, 1H), 6.93 (d, J ¼ 7.52 Hz, 1H), 6.55
118.05, 116.67, 116.44, 112.47, 66.10, 64.65. HRMS (ESI) Calc for (d, J ¼ 7.95 Hz, 1H), 5.38 (s, 1H), 2.23 (s, 3H). 13C NMR (101 MHz,
C
22H14Cl2FN2O2 [M + H+]: 427.0411, found: 427.0404.
(2R*,3S*)-50-Chloro-3-(4-chlorophenyl)-1-(4-methoxyphenyl)
DMSO-d6) d ppm 172.17, 163.81, 141.10, 139.09, 136.43, 133.57,
132.84, 130.28, 130.12, 129.46, 128.39, 127.68, 126.68, 125.24,
spiro[azetidine-2,30-indoline]-20,4-dione (37a). 1H NMR (400 MHz, 117.05, 114.49, 112.84, 112.62, 64.95, 64.32, 21.15. HRMS (ESI)
DMSO-d6) d ppm 10.97 (s, 1H), 7.84 (s, 1H), 7.44 (dd, J ¼ 8.30, Calc for C23H17BrClN2O2 [M + H+]: 467.0156, found: 467.0148.
1.29 Hz, 1H), 7.39 (d, J ¼ 8.07 Hz, 2H), 7.20 (d, J ¼ 8.30 Hz, 2H),
(2R*,3R*)-50-Bromo-3-(4-chlorophenyl)-1-(m-tolyl)spiro[azeti-
6.95–7.02 (m, 3H), 6.91 (d, J ¼ 8.83 Hz, 2H), 5.36 (s, 1H), 3.68 (s, dine-2,30-indoline]-20,4-dione (42b). 1H NMR (400 MHz, DMSO-
3H). 13C NMR (101 MHz, DMSO-d6) d ppm 172.45, 163.31, d6) d ppm 11.27 (s, 1H), 7.34–7.42 (m, 3H), 7.27 (d, J ¼ 8.44 Hz,
156.12, 140.79, 132.79, 130.68, 130.29, 129.66, 128.36, 126.77, 2H), 7.13–7.22 (m, 2H), 6.87–6.97 (m, 3H), 6.54 (d, J ¼ 8.62 Hz,
126.35, 125.01, 117.88, 114.84, 112.36, 66.04, 64.41, 1H), 5.08 (s, 1H), 2.23 (s, 3H). 13C NMR (101 MHz, DMSO-d6)
55.27.HRMS (ESI) Calc for C23H17Cl2N2O3[M + H+]: 439.0611, d ppm 174.31, 163.44, 141.61, 139.12, 136.42, 133.37, 132.99,
found: 439.0601.
130.82, 130.45, 129.46, 128.58, 128.10, 125.47, 123.65, 117.23,
113.54, 112.66 (d, J ¼ 3.13 Hz), 65.05, 63.63, 21.13. HRMS (ESI)
(2R*,3S*)-50-Chloro-3-(4-chlorophenyl)-1-(m-tolyl)spiro[azeti-
dine-2,30-indoline]-20,4-dione (38a). 1H NMR (400 MHz, DMSO- Calc for C23H17BrClN2O2 [M + H+]: 467.0156, found: 467.0148.
d6) d ppm 11.00 (s, 1H), 7.84 (d, J ¼ 2.14 Hz, 1H), 7.45 (dd, J ¼
(2R*,3S*)-3-(4-Bromophenyl)-1-(4-methoxyphenyl)spiro[azeti-
8.38, 2.20 Hz, 1H), 7.39 (d, J ¼ 8.50 Hz, 2H), 7.15–7.21 (m, 3H), dine-2,30-indoline]-20,4-dione (43a). 1H NMR (400 MHz, DMSO-
7.09 (s, 1H), 7.01 (d, J ¼ 8.31 Hz, 1H), 6.92 (d, J ¼ 7.52 Hz, 1H), d6) d ppm 10.84 (s, 1H), 7.64 (d, J ¼ 7.34 Hz, 1H), 7.52 (d, J ¼
6.56 (dd, J ¼ 8.01, 1.71 Hz, 1H), 5.38 (s, 1H), 2.23 (s, 3H). 13C 8.38 Hz, 2H), 7.38 (t, J ¼ 7.37 Hz, 1H), 7.07–7.14 (m, 3H), 6.95–
NMR (101 MHz, DMSO-d6) d ppm 172.30, 163.82, 140.68, 7.01 (m, 3H), 6.89 (d, J ¼ 9.05 Hz, 2H), 5.27 (s, 1H), 3.66 (s, 3H).
139.08, 136.43, 132.84, 130.28, 130.11, 129.45, 128.39, 126.78, 13C NMR (101 MHz, DMSO-d6) d ppm 172.68, 163.50, 156.04,
126.32, 125.24, 125.01, 117.05, 112.64, 112.38, 65.86, 64.31, 141.89, 131.26, 130.98, 130.46, 129.82, 124.63, 124.32, 122.70,
21.14. HRMS (ESI) Calc for C23H17Cl2N2O2 [M + H+]: 423.0662, 121.28, 117.87, 114.76, 110.84, 66.06, 64.39, 55.27. HRMS (ESI)
found: 423.0657.
Calc for C23H18BrN2O3 [M + H+]: 449.0495, found: 449.0477.
(2R*,3S*)-50-Chloro-3-(4-chlorophenyl)-1-(p-tolyl)spiro[azeti-
dine-2,30-indoline]-20,4-dione (39a). 1H NMR (400 MHz, DMSO-
d6) d ppm 10.98 (s, 1H), 7.82 (s, 1H), 7.44 (dd, J ¼ 8.34, 1.94 Hz,
Conclusions
1H), 7.39 (d, J ¼ 8.38 Hz, 2H), 7.19 (d, J ¼ 8.30 Hz, 2H), 7.12 (d, J In this work, the possibility of using ketene–imine Staudinger
¼ 8.22 Hz, 2H), 7.01 (d, J ¼ 8.30 Hz, 1H), 6.92 (d, J ¼ 8.30 Hz, cyclization for synthesis of 2,3-diaryl-spiro[azetidine-2,30-indoline]-
2H), 5.37 (s, 1H), 2.21 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 20,4-diones with varying diastereoselectivity was demonstrated.
d ppm 172.33, 163.53, 140.71, 133.97, 133.75, 132.79, 130.65, Carrying out the reaction of isatin imines with acyl chlorides in the
130.25, 130.17, 129.90, 128.34, 126.74, 126.31, 124.94, 116.10, presence of Et3N under heating can yield cis-isomeric spiro-b-lac-
112.35, 65.85, 64.36, 20.40. HRMS (ESI) Calc for C23H17Cl2N2O2 tams as the main reaction products, and the reactions of isatin
[M + H+]: 423.0662, found: 423.0654.
(2R*,3S*)-50-Bromo-3-(4-chlorophenyl)-1-(4-uorophenyl)spiro
imines with substituted phenylacetic acids in the presence of
oxalyl chloride and DIPEA at room temperature mainly yields trans
[azetidine-2,30-indoline]-20,4-dione (40a). 1H NMR (400 MHz, isomeric spiro-b-lactams. The latter reaction proceeds, apparently,
DMSO-d6) d ppm 11.03 (s, 1H), 7.99 (d, J ¼ 1.83 Hz, 1H), 7.58 without the formation of acyl chloride in the reaction mixture and
(dd, J ¼ 8.31, 2.02 Hz, 1H), 7.36–7.42 (m, 2H), 7.17–7.24 (m, 4H), leads to the formation of products that demonstrate reasonable
7.02–7.09 (m, 2H), 6.97 (d, J ¼ 8.31 Hz, 1H), 5.41 (s, 1H). 13C cytotoxic activity in an MTT test, which may be associated with
NMR (101 MHz, DMSO-d6) d ppm 172.07, 163.69, 159.78, inhibition of the p53-MDM2 protein–protein interaction.
157.38, 141.22, 133.69, 132.91, 130.28, 130.05, 128.42, 127.79,
126.33, 118.04, 117.96, 116.69, 116.46, 114.58, 112.98, 66.05,
Conflicts of interest
64.67. HRMS (ESI) Calc for C22H14BrClFN2O2 [M + H+]:
470.9906, found: 470.9898.
There are no conicts to declare.
(2R*,3S*)-50-Bromo-3-(4-chlorophenyl)-1-(4-methoxyphenyl)
spiro[azetidine-2,30-indoline]-20,4-dione (41a). 1H NMR (400 MHz,
DMSO-d6) d ppm 10.98 (s, 1H), 7.94 (s, 1H), 7.57 (dd, J ¼ 8.31,
Acknowledgements
1.96 Hz, 1H), 7.39 (d, J ¼ 8.44 Hz, 2H), 7.19 (d, J ¼ 8.44 Hz, 2H), We are grateful to the Russian Foundation for Basic Research
6.88–6.99 (m, 5H), 5.36 (s, 1H), 3.67 (s, 3H). 13C NMR (101 MHz, (Projects 19-03-00201 and 19-33-90282) for the nancial support
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of this work. This work in part of NMR and X-ray study was 21 M. Isoda, K. Sato, Y. Kunugi, S. Tokonishi, A. Tarui,
supported by the M. V. Lomonosov Moscow State University
Program of Development.
M. Omote, H. Minami and A. Ando, Beilstein J. Org. Chem.,
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22 J. A. Townes, M. A. Evans, J. Queffelec, S. J. Taylor and
J. P. Morken, Org. Lett., 2002, 4, 2537–2540.
23 N. M. O'Boyle, M. Carr, L. M. Greene, O. Bergin,
S. M. Nathwani, T. McCabe, D. G. Lloyd, D. M. Zisterer and
M. J. Meegan, J. Med. Chem., 2010, 53, 8569–8584.
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