A regio- and stereocontrolled approach to the synthesis of 4-CF3-substituted spiro[chromeno[3,4-c]pyrrolidine-oxindoles] via reversible [3+2] cycloaddition of azomethine ylides generated from isatins and sarcosine to 3-nitro-2-(trifluoromethyl)-2H-chromenes

Article abstract of DOI:10.1039/c9nj04498a

A one-pot three-component reaction of azomethine ylides generated in situ from isatins and sarcosine with 3-nitro-2-(trifluoromethyl)-2H-chromenes in i-PrOH at 55-60 °C leads to the kinetically controlled products-exo-spiro[chromeno[3,4-c]pyrrolidine-3,3′-oxindoles]. When this reaction is carried out in 1,4-dioxane under reflux, the thermodynamically controlled endo-spiro[chromeno[3,4-c]pyrrolidine-1,3′-oxindoles] are preferably formed. The isomerization of the kinetic products in DMSO solution at different temperatures has been studied by NMR spectroscopy and the stepwise mechanism of reversible [3+2] cycloaddition has been confirmed. The cytotoxic activity of some CF₃-substituted spiro[chromeno[3,4-c]pyrrolidine-oxindoles] against the HeLa cell line was evaluated by the MTT test.

Full text of DOI:10.1039/c9nj04498a

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A regio- and stereocontrolled approach to the
synthesis of 4-CF3-substituted spiro[chromeno-
[3,4-c]pyrrolidine-oxindoles] via reversible [3+2]
cycloaddition of azomethine ylides generated
from isatins and sarcosine to 3-nitro-2-
(trifluoromethyl)-2H-chromenes†
Cite this: New J. Chem., 2019,
43, 18495
Igor B. Kutyashev, Maria V. Ulitko,
Alexey Yu. Barkov,
Nikolay S. Zimnitskiy,
Vladislav Yu. Korotaev * and Vyacheslav Ya. Sosnovskikh
A one-pot three-component reaction of azomethine ylides generated in situ from isatins and sarcosine
with 3-nitro-2-(trifluoromethyl)-2H-chromenes in i-PrOH at 55–60 1C leads to the kinetically controlled
products – exo-spiro[chromeno[3,4-c]pyrrolidine-3,30-oxindoles]. When this reaction is carried out in
1,4-dioxane under reflux, the thermodynamically controlled endo-spiro[chromeno[3,4-c]pyrrolidine-1,30-
oxindoles] are preferably formed. The isomerization of the kinetic products in DMSO solution at different
temperatures has been studied by NMR spectroscopy and the stepwise mechanism of reversible [3+2]
cycloaddition has been confirmed. The cytotoxic activity of some CF3-substituted spiro[chromeno-
[3,4-c]pyrrolidine-oxindoles] against the HeLa cell line was evaluated by the MTT test.
Received 31st August 2019,
Accepted 26th October 2019
DOI: 10.1039/c9nj04498a
rsc.li/njc
antipsychotic agent; 8-aryldiazenylchromeno[4,3-b]pyrrolidine-2-
carboxylates8 exhibited high activity against M. Tuberculosis
Introduction
Development of simple and efficient regio- and stereoselective H37RV bacteria (Fig. 1). Therefore, combining spirooxindole
methods for the synthesis of novel molecules with one or several and chromenopyrrolidine moieties in a single molecule clearly
bioactive scaffolds plays an important role in fragment-based should be of interest for medicinal chemistry.
drug discovery.1 From this point of view, spiro[chromeno[3,4-c]-
The [3+2] cycloaddition of isatin-derived azomethine ylides
pyrrolidine-oxindoles] are of interest as drug-like molecules. to electron-deficient alkenes represents the shortest and most
Indeed, the spiro[pyrrolidine-oxindole] motif is found in natural convenient approach for construction of spiro[pyrrolidine-
and synthetic products with a broad spectrum of biological oxindole] and spiro[pyrrolizidine-oxindole] ring systems.9,10
activities (Fig. 1).2 For example, (ꢀ)-horsfiline, a natural product Within this methodology, 3-nitro-2H-chromenes11 are affordable
isolated from Horsfieldia superba, as well as its analogues, have and highly reactive dipolarophiles for the one-stage annulation
an anaesthetic effect.3 Some spiro[pyrrolidine-3,30-oxindoles] of the chromene moiety with the spiro[pyrrolidine-oxindole]
(e.g., MI-888 and SAR405838) are promising anticancer drugs system. An intensive study of 1,3-dipolar cycloaddition of
due to inhibition of the p53–MDM2 interaction.2c, f,4,5
stabilized azomethine ylides based on a-amino acids and cyclic
On the other hand, chromenopyrrolidine derivatives also carbonyl compounds to 3-nitro-2H-chromenes over the past five
possess significant pharmacological properties: fiduxosin6 is a years has allowed the advance of regio- and stereoselective methods
selective antagonist of a1-adrenoceptors, and has been for the synthesis of D3-annulated spiro[chromenopyroli(zi)dines],
proposed as a promising pharmaceutical agent for the treatment containing the spiro atom at the a-position to the C-4 atom of
of benign prostatic hyperplasia; compound S331387 has been 3-nitrochromene.12
characterized as a dopamine D3-receptor antagonist and potential
At the same time, the cycloaddition of azomethine ylide
generated from isatin and sarcosine to nitroalkenes was less
studied. The peculiarity of this ylide is that its C-1 terminal
atom is much more accessible for attack by a dipolarophile
than the C-3 atom, on which the negative charge of the dipole is
localized (Scheme 1). For this reason reactions of isatin–sarco-
sine ylide with nitroalkenes proceeded ambiguously and
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000,
Ekaterinburg, Russian Federation. E-mail: korotaev.vladislav@urfu.ru
† Electronic supplementary information (ESI) available: General methods, experi-
mental procedures, characterization data, 1H, 13C and 19F NMR spectra, X-ray
crystallographic data. CCDC 1939935–1939937. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c9nj04498a
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Fig. 1 Naturally occurring and synthetic bioactive spiro[pyrrolidine-
oxindoles] and chromenopyrrolidines.
depending on the reaction conditions led to various regioisomeric
products. That is, in methanol or acetonitrile under reflux, from
nitrostyrene and benzonitrooxepines the spiro[pyrrolidine-
oxindole] derivatives 2 and 3 were obtained, respectively, as a
result of exo or endo addition of the dipole through the C-1
atom to the most electrophilic b-C atom of the corresponding
dipolarophile.13,14 Under more severe conditions (in toluene
under reflux) the spiro[chromeno[3,4-c]pyrrolidine-1,30-oxindoles]
6 were synthesized from nitrochromenes 4 as a result of endo
addition of the ylide through the more substituted C-3 atom to the
b-C (C-4) atom of nitrochromene.15
Our attention is focused on the study of 2-trifluoromethyl-
substituted 3-nitro-2H-chromenes 4 (R1 = CF3),11 in which the
double bond of the pyran ring is activated by the electron-
withdrawing trifluoromethyl group. Moreover, the CF3 group is
a pharmacophore which is present in a wide variety of drugs.16
The introduction of the fluoroalkyl substituent into bioactive
molecules minimizes side effects by improving their transport
characteristics and avoids undesirable metabolic transforma-
tions due to the greater strength of the C–F bond compared to
the C–H bond.17 In previous research, the reactions of these
chromenes with various nucleophilic and ambiphilic reagents
have been studied and stereoselective approaches for the synthesis
Scheme 1 Synthesis of spiro[pyrrolidine-oxindole] derivatives from isatins,
sarcosine and conjugated nitroalkenes.
sarcosine as a method for the synthesis of 4-CF3-substituted
spiro[chromeno[3,4-c]pyrrolidine-oxindoles] (Scheme 1). To
indicate the breadth of application of the method, 3-nitro-2-
phenyl-2H-chromene (4j) was also used as a substrate in this
reaction. Our recent study showed that 1,3-dipolar cycloaddi-
tion of a stabilized ylide to CF3-nitrochromenes 4 is a reversible
process.12d We hypothesized that the reaction of chromenes 4
with isatin–sarcosine ylide is also reversible, and products 5
and 6 can be formed under kinetic or thermodynamic reaction
control, respectively. To understand the reaction mechanism,
the isomerization of kinetic products 5 in DMSO solution at
different temperatures has been explored. The cytotoxic activity
of compounds 5 and 6 against human cervical cancer HeLa was
studied on a number of representative samples.
Results and discussion
of CF3-containing 2,3,4-trisubstituted and D3-annulated chromanes To assess the feasibility of regio- and stereocontrolled synthesis
have been evolved.18
of spiro[chromeno[3,4-c]pyrrolidine-oxindoles] 5 and 6 from
Within the framework of a project on the synthetic opportu- CF3-substituted 3-nitro-2H-chromenes 4a–i, the optimization
nities offered by 3-nitro-2-(trifluoromethyl)-2H-chromenes for the of the conditions for a model three-component reaction between
preparation of organic molecules of potential interest in bio- nitrochromene 4a, isatin 1a and sarcosine was performed
medicinal chemistry, in this work we studied the three-component (Table 1). First, based on the previous results,13–15 we carried
reaction between 3-nitro-2H-chromenes 4a–i, isatins 1a–f, and out this reaction in methanol, acetonitrile and toluene under
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Table 1 Optimization of the reaction conditions for the reaction of isatin–sarcosine azomethine ylide with 3-nitro-2-(trifluoromethyl)-2H-chromene 4a
Entry
Solvent
Temperature (1C)
Time (h)
Total yielda (%)
Yieldb 5a (%)
Yieldb 6a (%)
Ratioc of 5a : 50a : 6a
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
i-PrOH
EtOH
n-PrOH
n-BuOH
(CH2OH)2
EtOH
n-BuOH
(CH2OH)2
i-PrOH
MeCN
MeCN
MeCN
MeCN
Me2SO
Me2SO
Me2SO
1,4-Dioxane
PhH
PhH
PhMe
Reflux
Reflux
55
55
55
55
55
55
Reflux
Reflux
120
150 (MW)
55
Reflux
Reflux
120 (MW)
80
12
24
8
5
8
8
8
8
24
24
24
1
52
49
20
26
25
52
15
18
22
36
5
6
8
2
5
54 : 25 : 21
57 : 16 : 27
67 : 23 : 10
90 : 0 : 10
69 : 7 : 24
71 : 5 : 24
95 : 1 : 4
100 : 0 : 0
29 : 10 : 60
0 : 0 : 100e
0 : 0 : 100e
0 : 0 : 100e
89 : 11 : 0
71 : 20 : 9
72 : 3 : 25
11 : 3 : 85e
32 : 13 : 55
1 : 1 : 98
41
64d
31
10
12
Trace
0
10
Trace
Trace
Trace
0
Trace
10
18
20
44
24
49
NR
5
28
11
46
36
36
30
Trace
Trace
10
30
70
67
31
32
50
74
71
NR
57
55
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
0
0
8
25
42
40
Trace
5
Trace
35
10
NR
31
9
12
24
3
24
24
2
48
8
48
24
1
100
110 (MW)
Reflux
55
47 : 17 : 36
19 : 5 : 76
NR
67 : 20 : 13
23 : 8 : 69
26 : 10 : 5e
Refluxf
Refluxf
150 (MW)
1,2-Me2C6H4
24
Trace
Yields refer to the isolated crude mixture of regio- and stereoisomers. Isolated yield. Determined by 1H and 19F NMR spectroscopy of the crude
a
b
c
d
e
f
product. Total yield 67% when 3.5 eq. of anhydrous MgSO4 was added. Strong resinification. Reflux with a Dean–Stark trap.
reflux for 24 h (entries 2, 15 and 23). In all cases, after removal of after 5 h and the isomer 5a was obtained in 52% yield without
the solvent and washing the residue with water and hexane, a further purification.
mixture of two diastereomeric spiro[chromeno[3,4-c]pyrrolidine-
The percentage of isomer 6a increased with increasing
3,30-oxindoles] exo-5a and endo-50a with the inversed relative temperature, solvent polarity and reaction time. Nevertheless,
configuration of the spiro carbon atom and spiro[chromeno[3,4-c]- in n-butanol under reflux and in ethylene glycol at 120 1C only
pyrrolidine-1,30-oxindole] endo-6a was obtained with different iso- trace amounts of the product were isolated due to strong
meric ratios in a total yield of 49–67%. The isomer 5a prevailed in resinification (entries 10 and 11). In DMSO at 100 1C for 24 h
methanol and acetonitrile, while the isomer 6a was the main (entry 18) the mixture of isomers (5a : 50a : 6a = 1 : 1 : 98) was
reaction product in toluene. The crude products were purified by obtained in a total yield of 50%, from which the individual
column chromatography and individual isomers 5a and 6a were isomer 6a was isolated in 44% yield. At the same time, due to
isolated in 9–40% and 8–28% yields, respectively. It was not the difficulty of solvent removal, this method is not as con-
possible to isolate isomer 50a in its pure form. When the reaction venient as the previous ones. The most suitable solvents for
time was reduced to 12 h, the amount of isomer 6a decreased obtaining the isomer 6a are toluene and 1,4-dioxane. The best
almost twofold in acetonitrile, while in methanol the ratio of the isolated yield of isomer 6a (49%) was observed in 1,4-dioxane
products only slightly changed (entries 1 and 14). On the contrary, under reflux for 48 h (entry 20). The use of microwave heating
reducing the reaction time in these solvents to 8 h and lowering the to increase the reaction rate in i-PrOH, acetonitrile or o-xylene
temperature to 55 1C increased the mole fraction of isomer 5a in was unsuccessful due to the occurrence of side processes and
the mixture to 67% and 89%, respectively (entries 3 and 13). In resinification (entries 12, 16 and 24).
polar protic solvents at 55 1C (entries 5–8) the isomer 5a always
Under the optimized conditions, the exo-spiro[chromeno-
prevailed, but due to losses arising from the isolation and purifica- [3,4-c]pyrrolidine-3,30-indolin]-20-ones 5a–n and the endo-spiro-
tion its yield was low (15–36%). However, when the reaction was [chromeno[3,4-c]pyrrolidine-1,30-indolin]-20-ones 6a–n were
carried out in i-PrOH at 55 1C (entry 4), the greatest amount of synthesized from nitrochromenes 4a–j, isatins 1a–d and sarcosine
product has precipitated from the reaction mixture in pure form in i-PrOH at 55–60 1C for 3.5–9 h (method A) or in 1,4-dioxane
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Table 2 Synthesis of spiro[chromeno[3,4-c]pyrrolidine-3,30-indolin]-20-ones 5 and spiro[chromeno[3,4-c]pyrrolidine-1,30-indolin]-20-ones 6
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Ratioa of 5 : 50 : 6
Total yieldb (%)/time (h)
Products 5, 50, 6
R1
R2
R3
R4
R5
Method A
Method B
Method A
Method B
Yieldc 5 (%)
Yieldd 6 (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
CF3
CF3
CF3
CF3
H
H
H
H
EtO
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
90 : 0 : 10
100 : 0 : 0
95 : 0 : 5
19 : 5 : 76
15 : 4 : 81
27 : 7 : 66
10 : 3 : 88
20 : 5 : 75
21 : 4 : 75
28 : 5 : 67
11 : 2: 87
2 : 9 : 89
32 : 13 : 55
13 : 3 : 84
21 : 4 : 75
21 : 6 : 73
43 : 4 : 63
64/5
40/7
60/9
74/9
89/3.5
85/3.5
75/3.5
62/5
87/3.5
70/12
70/5
98/3.5
53/6
75/8
71/48
69/48
66/48
58/72
95/48
94/48
96/48
94/48
99/48
87/48
75/48
80/48
69/48
71/48
52
40
51
38
65
62
61
44
67
30
28
43
42
48
49
51
32
39
60
52
54
62
69
47
55
36
49
41
Me
MeO
H
68 : 23 : 9
84 : 2 : 14
78 : 8 : 14
88 : 2 : 10
76 : 14 : 10
86 : 0 : 14
61 : 31 : 8
53 : 23 : 24
49 : 23 : 28
64 : 21 : 15
68 : 20 : 12
Cl
Br
Br
Br
NO2
H
H
Cl
H
Br
EtO
H
H
H
H
H
H
H
Cl
H
Method A. i-PrOH, 55–60 1C, 3.5–9 h. Method B. 1,4-Dioxane, reflux, 48 h.a Regio- and stereoisomeric ratio determined by the NMR analysis of the
b
c
d
crude product. Yields refer to the isolated crude mixture of regio- and stereoisomers. Isolated yield (method A). Isolated yield (method B).
under reflux for 48 h (method B) in 28–67% and 32–69% yields, spiro atom configuration. The maximum content of isomer 50
respectively (Table 2). Due to the low solubility, the main quan- was observed in the crude products obtained from chromenes
tities of exo isomers 5 were isolated from the reaction mixture by 4d and j and isatin–sarcosine ylide as well as in the reactions of
filtration. The regioisomers 6 were purified from impurities of chromenes 4a and e with ylides from isatins 1b–d under the
other isomers by column chromatography. Regardless of the conditions of method A. By using column chromatography, we
method used, the highest total yield (75–99%) of products 5 and managed to isolate in a pure form only compound 50j with a
6 was observed in reactions with chromenes 4e–g and i bearing phenyl substituent at the 4-position. In other cases, isomer 50
electron-acceptor substituents at the 6 position (R2 = Cl, Br, NO2). always contained an impurity of the corresponding diastereomer 5.
In contrast, electron donating substituents at the 6 and 8 All our attempts to find the conditions for the selective synthesis of
positions of chromene (R2 = Me, MeO; R3 = EtO) reduced the isomers 50 were unsuccessful.
total yield to 40–74%. Moreover, the introduction of electron-
It should be noted that in the reactions of chromene 4a with
deficient substituents into the benzene ring of chromene reduced azomethine ylides from sarcosine and isatins 1e and f under
the reaction time to 3.5 h under the conditions of method A, the conditions of method A, instead of the expected products 5,
while the reactions of the isatin–sarcosine ylide with chromenes oxazolidine-dispirooxindoles 7a and b were obtained in 43 and
4c (R2 = MeO) and 4d (R3 = EtO) under the same conditions were 70% yield, respectively, as a result of endo cycloaddition of the
completed after 9 h. At the same time, the regioselectivity of the corresponding ylides to the carbonyl group of isatins 1e and f
cycloaddition process is not very dependent on the donor–acceptor (Scheme 2).19 At the same time, under the conditions of
properties of the substituents in the aromatic cycle of the chromane method B, spiro[chromeno[3,4-c]pyrrolidine-oxindole] 6o was
system. However, the replacement of the trifluoromethyl group by a synthesized from chromene 4a, sarcosine and N-benzylisatin 1e
phenyl substituent as well as the introduction of an acceptor in 36% yield and only the starting compounds 4a and 1f were
chlorine atom at the 5 position of isatin (isatin 1d: R4 = H, isolated from the reaction involving isatin 1f. These facts
R5 = Cl) led to an increase in the content of isomers 5j and 5n indicate the reversibility of the oxo-1,3-dipolar cycloaddition.
under the conditions of method B to 32 and 43%, respectively.
However, 2-nitro-3-(trifluoromethyl)-3H-benzo[ f ]chromene
The replacement of the hydrogen atom at the nitrogen atom in (4k) with a sterically hindered double CQC bond also reacts
the oxindole moiety (isatin 1b: R4 = Me, R5 = H) by a methyl with azomethine ylide from isatin 1a and sarcosine in i-PrOH at
group leads to an increase in the content of isomers 6k and 6l 55–60 1C for 8 h (Method A) or in 1,4-dioxane under reflux for
under the conditions of method A to 24 and 28%, respectively. 48 h (Method B), resulting in the formation of spiroadducts 5p
In addition to the main products 5 and 6, the crude mixtures and 6p in 47 and 38% yield, respectively (Scheme 3).
contained from 2 to 31% of endo-spiro[chromeno[3,4-c]pyrrolidine-
In order to establish the reason for the formation of
3,30-indolin]-20-ones 50, differing from the isomers 5 only in the three isomeric products in the reaction of chromenes 4 with
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Scheme 2 Reactions of chromene 4a with azomethine ylides generated
from sarcosine and isatins 1e and f.
Fig. 2 19F NMR spectra of the mixture 5a # 50a 5 min (a), 2 days (b), 7 days
(c), 16 days (d), and 37 days (e) after dissolving of compound 5a (DMSO-d6,
25 1C).
Scheme 3 Synthesis of spiro[chromenopyrrolidine-oxindoles] 5p and 6p
from nitrochromene 4k.
transform into each other as a result of rotation around the
C(3)–N bond (Table 3). In this case, the relative configuration of
the spiro carbon atom is reversed. A similar isomerization was
isatin–sarcosine azomethine ylide and a change of the isomeric previously observed in solutions of compound MI-888.4b
ratio between adducts 5, 50 and 6 depending on the reaction
Heating of isomers exo-5a–i in DMSO at 80 1C for 48 h leads
conditions, we investigated the isomerization of individual to mixtures of corresponding adducts 5, 50, and 6 and chro-
isomers 5a–i and k in a DMSO solution at various temperatures menes 4. In this case, the mole fraction of isomer 6 grew with
using NMR spectroscopy.
increasing acceptor properties of the substituent R2 as well
Studying the behaviour of compound 5a in DMSO-d6 at (Table 4). At the same time, a mixture containing 68% of
room temperature in the NMR ampoule by using 19F NMR chromene 4j and only 13% of isomer 6j was obtained from
spectroscopy (Fig. 2) showed that after 2 days 10% of isomer 50a product 5j with the phenyl substituent at the 4-position under
was found in the solution. After 7 days, its content increased to the same conditions. When compounds 5a, e, and i were heated
20%. After 16 days, the amount of isomer 50a reached 25% and at 100 1C for 48 h, individual isomers endo-6a, e and i were
remained almost unchanged over the next 21 days. The forma- formed along with chromenes 4a, e and i (Table 4). The
tion of starting chromene 4a was not observed.
occurrence of chromene 4 indicates the reversibility of the
Keeping compounds exo-5b–i and k in DMSO-d6 at room [3+2] cycloaddition reaction. However, compounds 6a, e and i
temperature for 7 days also led to the appearance of endo-50b–i are stable during heating in DMSO at 100 1C for 48 h. There-
and k isomers in the solution, the content of which grew fore, compounds 5 and 50 can be considered as kinetically
slightly with increasing acceptor properties of the substituent controlled products, which transform into thermodynamically
R2 (Table 3). The isomerization 5a # 50a is probably a con- favoured isomers 6 at a higher temperature. Apparently, the
sequence of the reversible retro-Mannich reaction, leading to isomerization of compounds 5 to 6 occurs as a result of
the formation of zwitterionic intermediates A and B, which successive reversible retro-Michael addition/retro-Mannich
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Table 3 Isomerization 5 # 50 in DMSO-d6 at room temperature for
Table 4 Isomerization 5 # 6 in DMSO at 80 and 100 1C for 48 h
7 days
5
R2
R3
R4
Ratioa 5 : 50 (%)
Compounds 4, 5, 50, 6
R1
R2
R3
Ratioa 5 : 50 : 6 : 4 (%)
a
b
c
d
e
f
g
h
i
H
H
H
H
EtO
H
H
H
H
H
H
H
H
H
H
Me
80 : 20
78 : 22
80 : 20
82 : 18
80 : 20
80 : 20
76 : 24
76 : 24
76 : 24
85 : 15
a
a
b
c
d
e
e
f
g
h
i
i
j
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
H
H
Me
MeO
H
Cl
Cl
Br
Br
H
H
H
H
EtO
H
H
41 : 15 : 18 : 26
0 : 0 : 63 : 37b
34 : 15 : 22 : 28
44 : 19 : 17 : 20
28 : 14 : 18 : 40
46 : 19 : 20 : 15
0 : 0: 68 : 32b
44 : 20 : 22 : 14
38 : 18 : 32 : 12
37 : 20 : 24 : 20
48 : 20 : 25 : 8
0 : 0 : 83 : 17b
19 : 0 : 13 : 68
Me
MeO
H
Cl
Br
Br
Br
NO2
H
H
Br
EtO
H
H
Br
EtO
H
H
H
k
H
Br
a
Determined by 19F NMR spectroscopy.
NO2
NO2
H
reaction and Michael addition/Mannich reaction sequences.
Due to the higher activation energy, the reverse process proceeds
at a lower rate. The isomerization of compounds 5 to 6 in less
a
b
Determined by 1H and 19F NMR spectroscopy. At 100 1C for 48 h.
polar 1,4-dioxane proceeds more slowly: a mixture composed of model of the solvent effect on the 1,3-dipolar cycloaddition ratio.21
5a :50a :6a :4a = 55:1:8:36 was obtained by refluxing compound In protic solvents betaines are solvated better and the reaction
5a for 48 h in this solvent.
proceeds faster, leading to the formation of kinetically controlled
Due to the high electrophilicity of the double bond, the products 5 under mild conditions. In polar aprotic solvents
conjugated nitroalkenes behave as strong Michael acceptors. (MeCN, DMSO), which preferably solvate cations, this process
Therefore, many [3+2] cycloaddition reactions of 1,3-dipoles to slows down. However, due to the weak solvation of the anion
nitroalkenes actually occur through a nonconcerted mechanism. centre, these solvents are most favourable for interconversions
The zwitterionic pathway of these cycloaddition reactions was between isomers 5, 50, and 6, and in DMSO at 100 1C full
unambiguously confirmed by experimental data and quantum thermodynamic reaction control is achieved. In low polar toluene
chemical solutions.20 Based on these and our experimental data, and 1,4-dioxane both dipole and zwitterionic intermediates A–C
we assume that the reaction of azomethine ylides from isatins and are solvated weakly. Thus, in these solvents the ylide is formed
sarcosine with 3-nitro-2H-chromenes proceeds as a Michael under higher temperatures and cycloaddition proceeds more
addition/Mannich reaction sequence (Scheme 4). The addition slowly. In this case, thermodynamic control is achieved at an
of the azomethine ylide to chromene leads to the zwitterionic increased solvent boiling point and reaction duration.
intermediates A, B and C, which are then cyclized into the
It should be noted that the trifluoromethyl group makes a
corresponding products 5, 50 and 6. Under kinetic control, the significant contribution to the stabilization of the anionic
dipole attacks the C-4 chromene atom through the less sub- centre in intermediates A–C. Therefore, the selectivity of the
stituted C-1 atom, while under thermodynamic control the cycloaddition reaction of isatin–sarcosine ylide to 2-Ph-chromene
addition of ylide to chromene through the C-3 atom is more 4j is much lower and full thermodynamic reaction control was not
favourable. It should be noted that the attack by azomethine achieved even with prolonged heating in DMSO.
ylide on the CQC bond occurred from the side of the less bulky
To clarify the reasons for the formation of different regio-
substituent – the H-2 hydrogen atom of chromene. Therefore, isomers under kinetic and thermodynamic control, we studied
the substituent R1, nitro group and H-9a atom in products 5, the three-component reaction of chromenes 4 with the ylide
50and 6 are always in the cis relationship.
from isatin 1a–c and N-methylalanine. Unlike the isatin–sarcosine
The proposed mechanism for [3+2] cycloaddition is consistent ylide, the addition of this ylide to chromenes 4 in isopropyl
with both the experimental data (Tables 1–4) and the theoretical alcohol at 55–60 1C for 5 h led exclusively to adducts endo-8a–j
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Table 5 Synthesis of spiro[chromeno[3,4-c]pyrrolidine-1,30-indolin]-20-
ones 8
4
8
R1
R2
R3
R4
R5
Yielda (%)
4a
4b
4c
4d
4e
4g
4i
4j
4a
4a
8a
8b
8c
8d
8e
8f
8g
8h
8i
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
H
H
H
H
EtO
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
89
85
88
87
93
91
79
95
87
70
Me
MeO
H
Cl
Br
NO2
H
H
CF3
CF3
8j
H
a
Isolated yield.
group manifests as a doublet of doublets at 4.10–4.31 ppm with
coupling constants 2J = 8.9–9.4 Hz and 3J = 6.4–6.8 Hz. The
signals of the upfield H-1a proton and H-9b benzylic proton
(H-11c proton in 5p) manifest as doublets in the range of
d 2.78–2.96 and 4.68–5.25 ppm, respectively. Due to the close
values of the coupling constants, both methylene protons and
the H-9b proton in compounds 50a–n were observed as triplets
Scheme 4 Proposed reaction mechanism.
at 3.24–3.88, 3.86–3.98 and 4.78–4.96 ppm with J = 8.5–9.2 Hz.
1
in high yields (Table 5). The formation of regioisomers did The H NMR spectra of regioisomers 6a–p contained a singlet
not occur.
of the H-9b benzylic proton (H-11c proton in 6p) in the range of
Such a different behaviour of azomethine ylides is most 4.39–5.20 ppm and two doublets of diastereotopic protons of
likely explained by the influence of the steric factor. In the the methylene group at 3.68–3.80 and 3.96–4.50 ppm with
2
isatin–sarcosine ylide, the terminal atom C-1 is more accessible coupling constants J = 12.2–12.3 Hz for 6a–i and k–n, 7.1 Hz
for electrophile attack than the C-3 atom, and the addition of for 6j and 10.2 Hz for 6p. The H-4 proton in isomers 5a–n and p
the ylide to chromene through the C-1 atom is faster. In the was shielded by the benzene ring of the oxindole moiety and its
ylide from N-methylalanine, the steric factor is levelled and the signal was shifted upfield relative to the signal of this proton in
[3+2] cycloaddition reaction proceeds according to the polarity compounds 6a–n and p and 50a–n and p (Dd 0.21–0.41 and
of the dipole and dipolarophile.
0.19–0.39 ppm, respectively). For the same reason the signal of
The structure and stereochemistry of the spiroadducts exo-5, the aromatic H-9 proton in isomers 6a–p was observed at an
endo-50, endo-6 and endo-8 are established by IR, NMR spectroscopy, upfield position relative to the signals of H-6, 7 and 8 protons.
2D 1H–1H NOESY experiments and X-ray diffraction analysis.
Doublets of the CF3 group in the 19F NMR spectra of com-
The IR spectra of compounds 5, 50, 6 and 8 contained absorp- pounds 5a–i, k–n and p, 50a–i, k–n and p and 6a–i and k–p
tion bands due to the stretching vibrations of the CQO (n 1687– are manifested in a narrow region of 95.4–96.3, 97.0–97.6 and
1722 cmꢀ1) group, as well as vibrational bands of the nitro group 90.0–91.7 ppm, respectively, which allows the detection and
in the regions of 1542–1565 and 1330–1372 cmꢀ1. The IR spectra identification of each of the isomers in a mixture with other
of N-unsubstituted spiro[chromenopyrrolidine-oxindoles] 5a–j, m, isomers.
n and p, 6a–j, m, n and p and 8a–h and j showed absorption
bands due to stretching vibrations of associated and free NH in istic singlet of the H-9b benzylic proton in the range of 4.83–5.02
the range of 3086–3414 cmꢀ1
ppm, doublet of the 3-Me group in the range of 0.97–1.24 ppm and
The 1H NMR spectra of compounds 8a–j contained a character-
.
1
In the H NMR spectra of compounds 5a–n and p acquired quartet of the H-3 proton at 4.01–4.27 ppm, respectively, with spin–
in DMSO-d6 solution, the downfield H-1b proton of the 1-CH2 spin coupling constants of 3J = 5.8–6.3 Hz. The chemical shift of
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Fig. 3 Main correlations in the 2D 1H–1H NOESY NMR spectrum of
compounds 5f, 50f and 6f.
Fig. 5 Molecular structure of 6l (ORTEP drawing, 50% probability level).
the trifluoromethyl group in the 19F NMR spectra of com-
pounds 8a–j was observed as a slightly broadened singlet at
97.0–97.4 ppm.
The 13C NMR spectra of 4-CF3-spiro[chromenopyrrolidine-
oxindoles] 5, 50, 6 and 8 contained quartet signals of the CF3
group and C-4 carbon atom in the ranges of 122.0–123.2 and
71.8–76.2 ppm, respectively, with spin–spin coupling constants
1
2
of JCF = 281.3–290.6 and JCF = 29.5–33.2 Hz.
The stereochemistry of products 5, 50 and 6 was established
on the basis of 2D 1H–1H NOESY experiments for a mixture
of compounds 5f, 50f and 6f, which showed NOE cross-peaks
H-4 2 H-40 for 5f, H-9b 2 H-40 for 50f and H-4 2 H-3a and
H-9b 2 H-40 for 6f (Fig. 3 and Fig. S113, ESI†).
The relative configuration of cycloadducts 5, 6 and 8 was
unequivocally determined by monocrystal X-ray diffraction
analysis of products 5a, 6l and 8e (Fig. 4–6 and Fig. S20, ESI†).
Further, we evaluated the cytotoxic activity of spiro[chromeno-
[3,4-c]pyrrolidine-oxindoles] 5 and 6 in vitro against HeLa cervical
cancer cells for a number of representative samples (Fig. S2, ESI†).
Antitumor drug camptothecin22 was used for comparison. The
results of this investigation are shown in Table 6. It was found
that both regioisomers have a dose-dependent cytotoxic effect
on cervical cancer cells HeLa in the range of 10ꢀ7–10ꢀ5 M.
Compounds 5d and 6d with the ethoxy group at the 6-position
Fig. 6 Molecular structure of 8e (ORTEP drawing, 50% probability level).
Table 6 Cytotoxicity of selected compounds 5 and 6 against the HeLa
cancer cell line
Compound
IC50 (mM)
5a
5b
5c
5d
34.43 ꢁ 4.45
22.63 ꢁ 2.71
5.45 ꢁ 0.22
4100
5e
5g
6a
6b
6c
6d
10.83 ꢁ 1.85
17.34 ꢁ 8.77
25.73 ꢁ 2.35
44.59 ꢁ 4.91
17.49 ꢁ 3.50
4100
6e
6g
6k
6l
4100
57.64 ꢁ 2.23
0.10 ꢁ 0.01
4.36 ꢁ 0.57
1.66 ꢁ 0.97
Camptothecin
showed minimal cytotoxic effect. A significant increase in
activity was observed when the hydrogen atom at the nitrogen
atom of the oxindole fragment was replaced by a methyl group
(compare compounds 6a and e with 6k and l). Compound 6k
Fig. 4 Molecular structure of 5a (ORTEP drawing, 50% probability level).
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S. Wang, J. Med. Chem., 2013, 56, 5553; (b) Y. Zhao, L. Liu,
W. Sun, J. Lu, D. McEachern, X. Li, S. Yu, D. Bernard,
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showed a greater antitumor effect than camptothecin. These
results indicate that spiro[chromeno[3,4-c]pyrrolidine-oxindole]
analogues may be useful for further biological screening.
Conclusion
5 (a) S. Wang, W. Sun, Y. Zhao, D. McEachern, I. Meaux,
In summary, a general method has been developed for the
synthesis of exo-spiro[chromeno[3,4-c]pyrrolidine-3,30-oxindoles]
and endo-spiro[chromeno[3,4-c]pyrrolidine-1,30-oxindoles] bearing
a CF3 group at the 4-position. The regio- and stereochemistry of
the reaction products can be controlled by varying the tempera-
ture and solvent. It has been established that the [3+2] cycloaddi-
tion of 2-substituted 3-nitro-2H-chromenes to the azomethine
ylides from isatins and sarcosine proceeds as reversible tandem
Michael addition/Mannich reaction. This regio- and stereo-
controlled approach allows large libraries of drug-like molecules
to be synthesized. Most of the obtained 4-CF3-spiro[chromeno[3,4-c]-
pyrrolidine-oxindoles] revealed high cytotoxic activity and have great
promise as novel anticancer scaffolds.
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Acknowledgements
The work was financially supported by the Russian Foundation
for Basic Research (grant 18-33-00635) and the Ministry of
Science and Higher Education of the Russian Federation (project
4.6653.2017/8.9). Analytical studies were carried out using equip-
ment of the Centre for Joint Use ‘‘Spectroscopy and Analysis of
Organic Compounds’’ at the Postovsky Institute of Organic
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