Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes: Synthesis of trihalomethylated spiroindenepyrroli(zi)dines

Article abstract of DOI:10.1016/j.jfluchem.2017.10.005

Reactions of (E)-3,3,3-trihalogeno-1-nitropropenes with stabilised azomethine ylides derived from ninhydrin and indenoquinoxalinones on the one hand, and sarcosine and proline on the other, proceed regio- and diastereoselectively to give a number of trihalomethylated spiroindenepyrrolidines and spiroindenepyrrolizidines in good yields.

Full text of DOI:10.1016/j.jfluchem.2017.10.005

Accepted Manuscript
Title: Highly regio- and stereoselective 1,3-dipolar
cycloaddition of stabilised azomethine ylides to
3,3,3-trihalogeno-1-nitropropenes: synthesis of
trihalomethylated spiroindenepyrroli(zi)dines
Authors: Alexey Yu. Barkov, Nikolay S. Zimnitskiy, Igor B.
Kutyashev, Vladislav Yu. Korotaev
PII:
S0022-1139(17)30255-5
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2017.10.005
FLUOR 9059
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6-6-2017
28-9-2017
13-10-2017
Please cite this article as: Alexey Yu.Barkov, Nikolay S.Zimnitskiy, Igor
B.Kutyashev, Vladislav Yu.Korotaev, Highly regio- and stereoselective 1,3-dipolar
cycloaddition of stabilised azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes:
synthesis of trihalomethylated spiroindenepyrroli(zi)dines, Journal of Fluorine
Chemistry https://doi.org/10.1016/j.jfluchem.2017.10.005
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Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised azome-
thine ylides to 3,3,3-trihalogeno-1-nitropropenes: synthesis of trihalomethylated
spiroindenepyrroli(zi)dines
Alexey Yu. Barkov, Nikolay S. Zimnitskiy, Igor B. Kutyashev, Vladislav Yu. Korotaev,
Vladimir S. Moshkin, Vyacheslav Ya. Sosnovskikh*
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg,
Russian Federation;
E-mail address: vy.sosnovskikh@urfu.ru
Graphical Abstract
Highlights
 Reactions of 3,3,3-trihalogeno-1-nitropropenes with stabilised azomethine ylides were stud-
ied.
 A number of CX3-containing spiropyrrolidines and spiropyrrolizidines was obtained.
 1,3-Cycloaddition proceeds with good efficiency and high regio- and stereoselectivity.
 Major products of the reaction with proline ylides showed different regioselectivity from the
products of -nitrostyrenes.
A B S T R A C T
Reactions of (E)-3,3,3-trihalogeno-1-nitropropenes with stabilised azomethine ylides derived from ninhydrin
and indenoquinoxalinones on the one hand, and sarcosine and proline on the other, proceed regio- and dia-
stereoselectively
to
give
a
number
of
trihalomethylated
spiroindenepyrrolidines
and
spiroindenepyrrolizidines in good yields.
Keywords: 3,3,3-Trihalogeno-1-nitropropenes; Azomethine Ylides; 1,3-Dipolar Cycloaddition; Spiroin-
denepyrrolidines; Spiroindenepyrrolizidines
1. Introduction

2
The introduction of a trihalomethyl group, especially a trifluoromethyl group, in organic mole-
cules is an important synthetic task since the resulting compounds possess a wide range of useful
properties and are of great interest for pharmacy and agrochemistry [1]. The importance of a trifluo-
romethyl group among several types of alkyl and haloalkyl moieties was observed in many thera-
peutic medicines [2]. However, despite the biological and chemical potential of CF3-containing het-
erocyclic compounds, the regio- and stereoselective synthesis of these molecules from readily
available synthons remains a challenge. Previously, the stereoselective syntheses of trifluorometh-
ylated pyrrolidines and pyrrolizidines via the 1,3-dipolar cycloaddition of non-fluorinated azome-
thine ylides with CF3-containing alkenes and alkynes [3a–d] or CF3-containing azomethine ylides
with non-fluorinated alkenes were reported [3e,f]. For example, 1-trifluoromethylated pyrrolizidines
were obtained in moderate yields and excellent diastereoselectivity by the reaction with β-
trifluoromethyl acrylamides and azomethine ylides generated from proline and several aldehydes
[3a]. On the other hand, while the reactions of unactivated alkenes, chalcones and β-nitrostyrenes
with stabilised azomethine ylides were studied thoroughly [4], very little information is available on
the stereoselective [3+2] cycloaddition reaction of azomethine ylides with CX3-substituted nitroal-
kenes (X = F, Cl, Br).
At the same time, we envisaged that introduction of such powerful electron-withdrawing substit-
uents like CF3, CCl3 and CBr3 groups into the conjugated nitroalkene moiety would increase their
reactivity toward 1,3-dipolar cycloaddition with azomethine ylides and open a new synthetic use of
these small molecules. Indeed, we have recently reported a convenient method for the synthesis of
trihalomethylated spiro[indoline-3,2'-pyrrolidin]-2-ones and spiro[indoline-3,3'-pyrrolizin]-2-ones
via the 1,3-dipolar cycloaddition of azomethine ylides generated from decarboxylative condensation
of isatins and N-alkyl-α-amino acids (sarcosine and proline) with (E)-3,3,3-trihalogeno-1-
nitropropenes [5].
In the present paper, we focused on the unique electronic and steric properties of trihalomethyl-
ated nitroolefins and report that these compounds are good dipolarophiles toward stabilised azome-
thine ylides derived from ninhydrin and indenoquinoxalinones on the one hand, and sarcosine and
proline on the other hand. These reactions provide a simple and efficient synthetic route to CX3-
and NO2-containing spiroindenepyrrolidines and spiroindenepyrrolizidines, the regio- and stereo-
chemistry of which, as well as all by-products, has been established by 1D and 2D NMR spectros-
copy and X-ray diffraction analysis. It is important that the major products of the reaction with pro-
line ylides showed different regioselectivity from the reported spiropyrrolizidines, prepared from -
nitrostyrenes [4e–j].
2. Results and discussion

3
In connection with our interest in the chemistry of trihalomethylated nitroolefins [5, 6], which
are easily obtained from nitromethane and trihaloacetaldehydes [7, 8], we decided to study the reac-
tions of (E)-3,3,3-trihalogeno-1-nitropropenes 1a–c with a set of stabilised azomethine ylides gen-
erated from decarboxylative condensation of ninhydrin 2a and indenoquinoxalinones 2b,c with N-
alkyl-α-amino acids such as sarcosine and proline (Fig. 1).
In the initial study, we have developed the synthesis of the hitherto unknown spiroindenepyrroli-
dines 3a–c starting from CX3-nitropropenes 1a–c, ninhydrin 2a and sarcosine by a one-pot, three-
component procedure depicted in Scheme 1. We have found that these reactants in benzene at 35 ºC
for 4 h resulted in the formation of cycloadducts 3a–c in 63–81% (X = F, Cl) and 37% (X = Br)
yields as single isomers with trans-configuration of the CX3 and NO2 groups due to the synchro-
nism of the reaction, the structures of which were fully characterized by spectroscopic methods and
X-ray diffraction analysis (Fig. 2). The progress of the reaction was monitored by TLC, and the re-
sults are summarised in Table 1. Among various solvents with different polarities (benzene, toluene,
acetonitrile, isopropanol, dioxane, tert-butyl methyl ether, THF, DMSO, DMF), which have been
tested to perform the reaction, benzene was identified as the best solvent in terms of yield and selec-
tivity.
When proline was used as an α-amino acid, the desired spiroindenepyrrolizidines 4a–c were ob-
tained as endo-adducts (with respect to NO2) under the same conditions at room temperature in
moderate (48%) to very high yields (79–94%), depending on the steric properties of the trihalome-
thyl group (Scheme 1, Table 1). Thus, the cycloaddition proceeds in a high regio- and stereocon-
trolled fashion, however, in the case of more reactive CF3-nitropropene 1a, product 4a was isolated
as a mixture of two regioisomers in the ratio of 4a:4'a = 84:16, from which isomer 4a was obtained
as a single crystal for X-ray diffraction analysis (Fig. 3). All compounds 3 and 4 were isolated as
yellow powders.
The above results encouraged us to extend this methodology to azomethine ylides generated
from 11H-indeno[1,2-b]quinoxalin-11-one (2b) and 6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one
(2c), which were easily obtained by condensation of ninhydrin with o-phenylenediamine and 2,3-
diaminopyridine [9], to synthesise the corresponding spiroindenoquinoxalinepyrroli(zi)dines. It
should be noted that the number of articles concerning azomethine ylides based on compounds 2b
and 2c is limited [10].
We found that azomethine ylides derived from quinoxalinones 2b,c and sarcosine react with ni-
tropropenes 1a,b in isopropanol at 60 ºC for 2 days to give spiropyrrolidines in 32–40% isolated
yields either as single diastereomeric products 5b,d or as a mixture of two diastereomers 5a,c+5'a,c

4
(Scheme 2). The results are summarised in Table 2 and show that major products 5a–d were formed
almost exclusively as the endo-isomers. As in the case of spiroindenepyrrolidines 3, compounds 5
were formed as the regioisomers with the NO2 group at C-3' and the CX3 group at C-4' (in general,
the more electrophilic alkene atom reacts with the more nucleophilic and accessible terminal ylide
atom). The alternative regiochemistry does not look very favourable in terms of the steric repulsion
of the bulky CX3 group from the electron density of a π-system of the quinoxaline ring.
1
The appearance of the exo-adducts 5'a,c (15–16%, H NMR spectroscopic data) was observed
only in the case of CF3-alkene 1a. Thus, CCl3-alkene 1b reacted more selective then acceptor CF3-
alkene 1a, while bulky CBr3-alkene 1c did not give a positive result and an unidentifiable mixture
of products was obtained. In the case of alkene 1b and ylide from pyridopyrazine 2c, formation of
compounds 6 was observed (yield 46%), indicating that nucleophilic addition of isopropanol at the
alkene double bond had occurred under these conditions. Probably, this side reaction is a reason of
low yields for dispiroheterocycles 5a–d, however, the use of another solvent (benzene, toluene, ace-
tonitrile, methanol, dioxane, tert-butyl methyl ether, THF) gave only worse results.
A similar reaction of alkenes 1a,b with azomethine ylides derived from quinoxalinones 2b,c and
proline at 45 ºC for 12 h gave endo-adducts 7a–d. In contrast to the results found in the sarcosine
series, when proline was employed, the corresponding spiropyrrolizidines 7 were obtained in high
yields (76–89%). As in the cycloaddition reactions involving sarcosine, compounds 7 were formed
mainly as the same regioisomer in relation to the position of the trihalomethyl and nitro groups.
However, in the case of ylide from quinoxalinone 2b, the appearance of a small amount of regioi-
somers 7'a,b (4–6% according to the 1H NMR data) was observed in the crude products (Scheme 2,
Table 2). Note that in this type of 1,3-dipolar cycloaddition reactions β-nitrostyrenes react with sta-
bilised azomethine ylides in an opposite manner to give adducts of type 4' and 7' [4e–j, 10b]. The
indicated regio- and stereochemistry of spiropyrrolidines 5 and spiropyrrolizidines 7 was unambig-
uously confirmed by X-ray single crystal analysis of compounds 5b and 7a as representative exam-
ples (Fig. 4 and 5).
Although by-products 5' and 7' were not isolated in a pure state, their stereochemistry was estab-
1
lished by 2D H–1H NOESY experiments of an 84:16 mixture of stereoisomers 5a+5'a and a 96:4
mixture of regioisomers 7a+7'a. The most important proof of their relative configuration was the
NOE connectivities indicated with pink arrows in Fig. 6. The 2D NOESY experiment demonstrates
the spatial contiguity of the aromatic proton H-1 to H-4' for 5a and H-1 to H-3' for 5'a. These cross-

5
peaks show that the protons are sited close to each other, thus establishing the indicated stereochem-
istry. The NOESY spectrum of regioisomers 7a and 7'a exhibits NOE cross-peaks H-1 ↔ H-1', H-
7'a ↔ H-2' for 7a and H-1 ↔ H-2' for 7'a revealing that these atoms are in a cis relationship. The
absence of the NOE contact between the nodal proton H-7'a and H-2' in the latter case indicates that
these protons are in a trans relationship (Fig. 6–8).
Establishing the structure of minor isomer 7' as the 1'-NO2-regioisomer with the
1'S*,2'S*,7a'S*,11S* stereochemistry, allowed us to prove the structure of by-product 4'a. A com-
parison of the chemical shifts and multiplicity of the aliphatic methine protons H-1', H-2' and H-7'a
of compound 7'a with the data for compound 4'a confirms the similarity of their pyrrolizidine
fragments. In the case of spiroheterocycle 7'a, the corresponding protons are more deshielded due
to the deshielding effect of the quinoxaline system (Fig. 9).
3. Conclusion
In conclusion, we have studied the reactivity of (E)-3,3,3-trihalogeno-1-nitropropenes in the 1,3-
dipolar cycloaddition and obtained a wide range of CX3-containing spiropyrrolidines and spiro-
pyrrolizidines by three-component [3+2] cycloaddition with azomethine ylides generated from nin-
hydrin or indenoquinoxalinones and N-alkyl--amino acids (sarcosine, proline), which proceeds
with good efficiency and selectivity. Replacement of aryl substituent in β-nitrostyrene by bulky
electron-withdrawing CX3 group leads to a change of regioselectivity in the reactions with proline-
based ylides. The products constitute an important structural subunit of a variety of biologically ac-
tive compounds, which may be of interest for medicinal chemistry. The advantages of this reaction
included usage of readily available starting compounds, milder reaction conditions and simple sepa-
ration process.
4. Experimental
4.1. General
19
13
NMR spectra were recorded on Bruker DRX-400 (1H – 400 MHz, F – 376, C – 101 MHz)
19
13
and AVANCE-500 (1H – 500 MHz, F – 471 MHz, C – 126 MHz) spectrometers in DMSO-d6
and CDCl3 with TMS, C6F6 or chloroform (δC = 77.0 ppm) as internal standards, respectively. IR
spectra were recorded on a Nicolet 6700 instruments (FTIR mode, ZnSe crystal). Mass spectra were
recorded on a Waters Xevo Q-ToF mass spectrometer (ESI) with Acquity UPLC system. Melting

6
points were determined on a Stuart SMP40 apparatus. Nitroolefins 1a–c were synthesised by one of
the known methods starting from nitro alcohols, prepared by condensation of equimolecular
amounts of nitromethane with the corresponding trihaloacetaldehyde in the presence of K2CO3 [7,
8].
4.2. General procedure for the synthesis of compounds 3
The mixture of ninhydrin (0.18 g, 1.0 mmol), sarcosine (0.13 g, 1.5 mmol) and the correspond-
ing nitroalkene 1 (1.0 mmol) was stirred in benzene (3 mL) at 35 C for 4 h (the reaction progress
was monitored by TLC). Upon completion, the excess of sarcosine was filtered off, the solvent was
evaporated and the residue was treated with hexane. In some cases, additional recrystallisation from
the mixture hexane/CH2Cl2 (2:1) was necessary.
4.2.1.
(3'R*,4'S*)-1'-Methyl-3'-nitro-4'-(trifluoromethyl)spiro[indene-2,2'-pyrrolidine]-1,3-dione
(3a). Yield 0.27 g (81%), mp 149–150 ºC, yellow powder. IR (ATR): 1745, 1707, 1566, 1464, 1356
cm–1; 1H NMR (400 MHz, CDCl3) δ 2.19 (s, 3H, Me), 3.39 (dd, J = 10.1, 3.5 Hz, 1H, H-5'a), 3.64
(t, J = 9.9 Hz, 1H, H-5'b), 4.10–4.22 (m, 1H, H-4'), 5.41 (d, J = 6.8 Hz, 1H, H-3'), 7.94–8.13 (m,
19
13
4H, Ar); F NMR (376 MHz, CDCl3) δ 90.7 (d, J = 8.8 Hz, CF3); C NMR (101 MHz, CDCl3) δ
2
3
3
35.9, 43.6 (q, J = 30.1 Hz, C-4'), 53.1 (q, J = 2.3 Hz), 73.7, 86.1 (q, J = 1.9 Hz), 123.3, 123.9,
1
125.8 (q, J = 278.4 Hz, CF3), 137.0, 137.1, 140.7, 141.8, 196.5, 199.2. HRMS (ESI): calcd for
C14H12F3N2O4 [M+H]+ 329.0744, found 329.0748.
4.2.2. (3'R*,4'S*)-1'-Methyl-3'-nitro-4'-(trichloromethyl)spiro[indene-2,2'-pyrrolidine]-1,3-dione
(3b). Yield 0.24 g (63%), mp 165–166 ºC, yellow powder. IR (ATR): 1736, 1698, 1590, 1557,
1452, 1354, 1334 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.23 (s, 3H, Me), 3.52 (dd, J = 10.3, 3.7 Hz,
1H, H-5'a), 3.81 (br t, J = 9.8 Hz, 1H, H-5'b), 4.74 (ddd, J = 9.3, 6.5, 3.7 Hz, 1H, H-4'), 5.48 (d, J =
13
6.5 Hz, 1H, H-3'), 7.94–8.12 (m, 4H, Ar); C NMR (101 MHz, CDCl3) δ 35.8, 57.0, 59.4, 75.4,
89.1, 99.3, 123.4, 123.8, 137.1 (2C), 140.5, 141.7, 196.7, 198.7. HRMS (ESI): calcd for
C14H12Cl3N2O4 [M+H]+ 376.9857, found 376.9861.
4.2.3. (3'R*,4'S*)-1'-Methyl-3'-nitro-4'-(tribromomethyl)spiro[indene-2,2'-pyrrolidine]-1,3-dione
(3c). Yield 0.19 g (37%), mp 155–156 ºC, yellow powder. IR (ATR): 1703, 1590, 1547, 1352, 1272
cm–1; 1H NMR (500 MHz, CDCl3) δ 2.23 (s, 3H, Me), 3.45 (dd, J = 10.2, 3.8 Hz, 1H, H-5'a), 3.82
(br t, J = 9.7 Hz, 1H, CHH), 4.91 (ddd, J = 9.2, 6.4, 3.8 Hz, 1H, H-4'), 5.33 (d, J = 6.4 Hz, 1H, H-
3'), 7.91–8.13 (m, 4H, Ar). HRMS (ESI): calcd for C14H12Br3N2O4 [M+H]+ 508.8342, found
508.8348.

7
4.3. General procedure for the synthesis of compounds 4
The mixture of ninhydrin 2a (0.18 g, 1.0 mmol), proline (0.17 g, 1.5 mmol) and the correspond-
ing nitroalkene 1 (1.0 mmol) was stirred in benzene (3 mL) at room temperature for 4 h (the reac-
tion progress was monitored by TLC). Then, the excess of proline was filtered off, the solvent was
evaporated and the residue was treated with hexane.
4.3.1. (1'S*,2'R*,7a'S*)-2'-Nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indene-2,3'-
pyrrolizine]-1,3-dione (4a) and (1'S*,2'S*,7a'S*)-1'-nitro-2'-(trifluoromethyl)-1',2',5',6',7',7a'-
hexahydrospiro[indene-2,3'-pyrrolizine]-1,3-dione (4'a). Yield 0.33 g (94%), (4a:4'a = 84:16), mp
149–150 ºC, 154–155 C (for monocrystals of 4a), yellow powder. IR (ATR): 1712, 1591, 1551,
1406, 1354 cm–1; 1H NMR (400 MHz, CDCl3): major isomer 4a (84%) δ 1.81−2.23 (m, 4H, 2CH2),
2.63 (td, J = 9.3, 7.0 Hz, 1H, CH), 2.75 (ddd, J = 10.0, 7.9, 3.1 Hz, 1H, CH), 3.95–4.05 (m, 2H, H-
1', H-7'a), 5.63 (d, J = 9.7 Hz, 1H, H-2'), 7.90–8.00 (m, 3H, Ar), 8.05–8.09 (m, 1H, Ar), minor iso-
mer 4'a (16%) δ 1.35−2.22 (m, 4H, 2CH2), 2.59–2.68 (m, 1H, CH), 3.10 (ddd, J = 11.1, 9.1, 6.0 Hz,
1H, CH), 4.53 (dq, J = 9.4, 8.5 Hz, 1H, H-2'), 4.65 (td, J = 9.0, 5.9 Hz, 1H, H-7'a), 5.90 (t, J = 9.4
19
Hz, 1H, H-1'), 7.90–8.00 (m, 3H, Ar), 8.09–8.13 (m, 1H, Ar); F NMR (376 MHz, CDCl3) major
isomer 4a (84%) δ 93.1 (d, J = 6.7 Hz, CF3), minor isomer 4'a (16%) δ 98.1 (d, J = 8.5 Hz, CF3);
13C NMR (126 MHz, CDCl3) major isomer 4a (84%) δ 27.6, 31.7, 47.9, 49.5 (q, 2J = 28.6 Hz, C-1'),
65.0 (q, 3J = 2.6 Hz), 73.7, 88.0 (q, 3J = 2.4 Hz), 123.5, 124.3, 125.0 (q, 1J = 278.8 Hz, CF3), 136.9,
137.2, 140.8, 141.4, 197.2, 199.0, minor isomer 4'a (16%) δ 25.3, 26.8, 49.4, 49.6 (q, 2J = 29.6 Hz,
C-1'), 66.3, 70.5, 88.4 (br s), 124.2, 124.8, 136.5, 137.0, 140.5, 141.1, 193.6, 193.9 (signal of CF3-
group is not found). HRMS (ESI): calcd for C16H14F3N2O4 [M+H]+ 355.0900, found 355.0909.
4.3.2. (1'S*,2'R*,7a'S*)-2'-Nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indene-2,3'-
pyrrolizine]-1,3-dione (4b). Yield 0.32 g (79%), mp 200–201 ºC, yellow powder. IR (ATR): 1711,
1588, 1559, 1457, 1411, 1357, 1333 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.81−2.35 (m, 4H, 2CH2),
2.61–2.70 (m, 1H, CH), 2.82 (ddd, J = 10.4, 9.1, 2.9 Hz, 1H, CH), 4.08 (dt, J = 8.9, 6.5 Hz, 1H, H-
7'a), 4.51 (dd, J = 8.8, 6.5 Hz, 1H, H-1'), 5.70 (d, J = 8.8 Hz, 1H, H-2'), 7.92–7.99 (m, 3H, Ar),
8.06–8.10 (m, 1H, Ar); 13C NMR (126 MHz, CDCl3) δ 27.6, 32.6, 47.9, 64.6, 69.4, 75.1, 92.0, 98.2,
123.6, 124.3, 137.1, 137.3, 140.8, 141.1, 197.0, 198.6. HRMS (ESI): calcd for C16H14Cl3N2O4
[M+H]+ 403.0014, found 403.0012.
4.3.3. (1'S*,2'R*,7a'S*)-2'-Nitro-1'-(tribromomethyl)-1',2',5',6',7',7a'-hexahydrospiro[indene-2,3'-
pyrrolizine]-1,3-dione (4c). Yield 0.26 g (48%), mp 196–197 ºC, yellow powder. IR (ATR): 1710,
1660, 1621, 1573, 1556, 1444, 1403, 1356 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.79−2.45 (m, 4H,

8
2CH2), 2.64 (dt, J = 10.7, 8.2 Hz, 1H, CH), 2.85 (ddd, J = 10.7, 9.2, 3.3 Hz, 1H, CH), 3.95 (dt, J =
9.6, 6.1 Hz, 1H, H-7'a), 4.60 (dd, J = 8.3, 5.8 Hz, 1H, H-1'), 5.60 (d, J = 8.3 Hz, 1H, H-2'), 7.92–
8.00 (m, 3H, Ar), 8.07–8.11 (m, 1H, Ar). HRMS (ESI): calcd for C16H14Br3N2O4 [M+H]+ 534.8498,
found 534.8493.
4.4. General procedure for the synthesis of compounds 5
A mixture of the corresponding indenoquinoxalinone 2 (1.0 mmol) and sarcosine (0.13 g, 1.5
mmol) was stirred in isopropanol (4 mL), and nitroalkene 1 (1.0 mmol) was added in one portion.
The resulting mixture was stirred with heating at 60 С for 48 h and the reaction progress was
monitored by TLC. Upon completion, the solvent was evaporated and the residue was purified by
flash chromatography (eluent – CHCl3) and recrystallised from methanol.
4.4.1.
(3'R*,4'S*,11R*)-1'-Methyl-3'-nitro-4'-(trifluoromethyl)spiro[indeno[1,2-b]quinoxaline-
11,2'-pyrrolidine] and (3'S*,4'R*,11R*)-1'-methyl-3'-nitro-4'-(trifluoromethyl)spiro[indeno[1,2-
b]quinoxaline-11,2'-pyrrolidine] (5a and 5'a). Yield 0.16 g (40%), (5a:5'a = 84:16), mp 79–80 ºC,
1
beige powder. IR (ATR): 1557, 1516, 1461, 1375, 1336 cm–1; H NMR (400 MHz, CDCl3) major
isomer 5a (88%) δ 1.91 (s, 3H, Me), 3.64 (t, J = 9.4 Hz, 1H, H-5'a), 3.87 (dd, J = 9.7, 7.2 Hz, 1H,
H-5'b), 4.44 (sept, J = 8.4 Hz, 1H, H-4'), 5.81 (d, J = 7.8 Hz, 1H, H-3'), 7.46 (d, J = 7.6 Hz, 1H, H-
1), 7.55 (td, J = 7.5, 1.3 Hz, 1H, Ar), 7.62 (td, J = 7.5, 1.0 Hz, 1H, Ar), 7.74–7.84 (m, 2H, Ar),
8.15–8.22 (m, 3H, Ar), minor isomer 5'a (12%) δ 1.86 (s, 3H, Me), 3.53 (dd, J = 9.9, 2.9 Hz, 1H,
H-5'a), 4.06 (t, J = 9.8 Hz, 1H, H-5'b), 4.63–4.72 (m, 1H, H-4'), 5.49 (d, J = 7.4 Hz, 1H, H-3'),
7.62–7.84 (m, 5H, Ar), 8.07–8.13 (m, 3H, Ar); 19F NMR (376 MHz, CDCl3) major isomer 5a
13
(88%) δ 92.0 (d, J = 8.5 Hz, CF3), minor isomer 5'a (12%) δ 90.5 (d, J = 9.1 Hz, CF3); C NMR
2
3
(126 MHz, CDCl3) major isomer 5a (88%) δ 34.6, 44.7 (q, J = 30.1 Hz, C-4'), 52.3 (q, J = 2.0
1
Hz), 75.1, 89.6, 122.8, 125.4, 125.8 (q, J = 278.1 Hz, CF3), 129.3, 129.5, 129.9, 130.5, 131.2,
2
132.0, 138.4, 141.2, 141.7, 143.1, 153.3, 159.8, minor isomer 5'a (12%) δ 34.1, 43.2 (q, J = 30.2
3
Hz, C-4'), 52.2 (q, J = 2.5 Hz), 74.6, 88.7, 122.6, 124.1, 129.4, 129.7, 129.9, 130.4, 130.9, 132.5,
138.6, 140.9, 142.7, 144.1, 153.7, 159.7 (signal of the CF3 group is not found). HRMS (ESI): calcd
for C20H16F3N4O2 [M+H]+ 401.1220, found 401.1226.
4.4.2.
(3'R*,4'S*,11R*)-1'-Methyl-3'-nitro-4'-(trichloromethyl)spiro[indeno[1,2-b]quinoxaline-
11,2'-pyrrolidine] (5b). Yield 0.15 g (34%), mp 186–187 ºC, white powder. IR (ATR): 1558, 1463,
1
1369, 1338 cm–1; H NMR (400 MHz, CDCl3) δ 1.93 (s, 3H, Me), 3.80 (t, J = 9.4 Hz, 1H, H-5'a),
4.00 (dd, J = 10.0, 6.6 Hz, 1H, H-5'b), 4.92−5.01 (m, 1H, H-4'), 5.89 (d, J = 7.5 Hz, 1H, H-3'),
7.51–7.65 (m, 3H, Ar), 7.72–7.83 (m, 2H, Ar), 8.13–8.22 (m, 3H, Ar). 13C NMR (126 MHz,

9
CDCl3): δ 29.7, 34.7, 56.4, 60.7, 76.4, 92.4, 98.9, 122.7, 125.8, 129.3, 129.5, 130.0, 130.5, 131.2,
131.9, 138.3, 141.2, 141.7, 143.0, 153.2, 159.8. HRMS (ESI): calcd for C20H16Cl3N4O2 [M+H]+
449.0333, found 449.0330.
4.4.3.
(3'R*,4'S*,6R*)-1'-Methyl-3'-nitro-4'-(trifluoromethyl)spiro[indeno[1,2-b]pyrido[3,2-e]-
(5c) and (3'S*,4'R*,6R*)-1'-methyl-3'-nitro-4'-(trifluoromethyl)-
pyrazine-6,2'-pyrrolidine]
spiro[indeno[1,2-b]pyrido[3,2-e]pyrazine-6,2'-pyrrolidine] (5'c). Yield 0.14 g (34%), (5c:5'c =
1
85:15), mp 153–154 ºC, brown powder. IR (ATR): 1558, 1499, 1466, 1387, 1371, 1343 cm–1; H
NMR (400 MHz, CDCl3) major isomer 5c (85%) δ 1.92 (s, 3H, Me), 3.66 (t, J = 9.4 Hz, 1H, H-5'a),
3.83 (dd, J = 9.7, 7.1 Hz, 1H, H-5'b), 4.40–4.51 (m, 1H, H-4'), 5.81 (d, J = 7.7 Hz, 1H, H-3'), 7.48
(d, J = 7.3 Hz, 1H, H-1), 7.57–7.59 (m, 2H, H-2, H-3); 7.72–7.76 (m, 1H, H-8), 8.33 (d, 1H, J = 7.3
Hz, H-4), 8.55 (dd, J = 8.1, 1.7 Hz, 1H, H-9), 9.15–9.19 (m, 1H, H-7), minor isomer 5'c (15%) δ
1.89 (s, 3H, Me), 3.55 (dd, J = 9.9, 2.7 Hz, 1H, H-2'a), 4.02 (t, J = 10.0 Hz, 1H, H-2'b), 5.51 (d, J =
7.4 Hz, 1H, H-3') (other signals are masked by the major isomer). HRMS (ESI): calcd for
C19H14F3N5NaO2 [M+Na]+ 402.0990, found 424.0992.
4.4.4.
(3'R*,4'S*,6R*)-1'-Methyl-3'-nitro-4'-(trichloromethyl)spiro[indeno[1,2-b]pyrido[3,2-
e]pyrazine-6,2'-pyrrolidine] (5d). Yield 0.14 g (32%), beige oil. 1H NMR (400 MHz, CDCl3) δ 1.93
(s, 3H, Me), 3.81 (t, J = 9.5 Hz, 1H, H-5'a), 3.95 (dd, J = 10.2, 6.2 Hz, 1H, H-5'b), 4.93−5.01 (m,
1H, H-4'), 5.90 (d, J = 7.5 Hz, 1H, H-3'), 7.54–7.59 (m, 3H, H-1, H-2, H-3); 7.71–7.75 (m, 1H, H-
8), 8.33 (dd, 1H, J = 7.1, 1.4 Hz, H-4), 8.53 (dd, J = 8.2, 1.8 Hz, 1H, H-9), 9.14–9.18 (m, 1H, H-7).
HRMS (ESI): calcd for C19H15Cl3N5O2 [M+H]+ 450.0286, found 450.0286.
4.4.5. 1,1,1-Trichloro-2-isopropoxy-3-nitropropane (6) [11]. 1H NMR (400 MHz, CDCl3) δ 1.14 (d,
J = 6.2 Hz, 3H, Me), 1.30 (d, J = 6.2 Hz, 3H, Me), 4.16 (sept, J = 6.2 Hz, 1H, CH(Me)2), 4.63 (dd, J
= 12.8, 7.9 Hz, 1H, CHHNO2), 4.77 (dd, 1H, J = 7.9, 2.5 Hz, 1H, CHCCl3), 5.00 (dd, J = 12.8, 2.5
Hz, 1H, CHHNO2).
4.5. General procedure for the synthesis of compounds 7
A mixture of the corresponding indenoquinoxalinone 2 (1.0 mmol) and proline (0.17 g, 1.5
mmol) was stirred in isopropanol (4 mL), and nitroalkene 1 (1.0 mmol) was added in one portion.
The resulting mixture was stirred with heating at 45 С for 12 h and the reaction progress was
monitored by TLC. Upon completion, the mixture was diluted with brine, resulting precipitate was
filtered off, washed with water and hexane and vacuum dried. In some cases, additional recrystalli-
sation from the mixture hexane/CH2Cl2 (2:1) was necessary.

10
4.5.1. (1'S*,2'R*,7a'S*,11R*)-2'-Nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indeno-
[1,2-b]quinoxaline-11,3'-pyrrolizine] (7a) and (1'S*,2'S*,7a'S*,11S*)-1'-nitro-2'-(trifluoromethyl)-
1',2',5',6',7',7a'-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine] (7'a). Yield 0.37 g
(86%, 7a:7'a = 96:4), mp 194–195 ºС, yellow prisms. IR (ATR): 1549, 1510, 1462, 1416, 1364,
1
1337 cm–1; H NMR (500 MHz, CDCl3): major isomer 7a (96%) δ 1.87–2.64 (m, 6H, 3CH2),
4.00−4.09 (m, 1H, H-1'), 4.44 (td, J = 8.5, 6.6 Hz, 1H, H-7'a), 6.09 (d, J = 10.1 Hz, 1H, H-2'), 7.49
(d, J = 7.6 Hz, 1H, H-1), 7.56 (td, J = 7.5, 1.2 Hz, 1H, Ar), 7.62 (td, J = 7.5, 0.9 Hz, 1H, Ar), 7.74–
7.82 (m, 2H, Ar), 8.16 (dd, J = 8.0, 1.5 Hz, 1H, Ar), 8.19–8.24 (m, 3H, Ar), minor isomer 7'a (4%)
δ 4.72 (quint, J = 8.7 Hz, 1H, H-2'), 5.23 (td, J = 9.0, 6.4 Hz, 1H, H-7'a), 6.26 (t, J = 9.0 Hz, 1H, H-
19
1'), 7.63–7.68 (m, 2H, Ar), 7.88 (d, J = 7.6 Hz, 1H, H-1), 8.05–8.26 (m, 5H, Ar); F NMR (471
MHz, CDCl3) major isomer 7a (96%) δ 93.2 (d, J = 7.4 Hz, CF3), minor isomer 7'a (4%) δ 98.1 (d,
J = 8.3 Hz, CF3); 13C NMR (126 MHz, CDCl3): major isomer 7a (96%) δ 27.6, 31.7, 46.7, 50.4 (q,
2J = 28.2 Hz, C-1'), 63.5 (d, 3J = 2.3 Hz), 77.4 (q, 3J = 2.6 Hz), 91.8, 123.0, 125.4 (q, 1J = 278.9 Hz,
CF3), 126.3, 129.3, 129.4, 129.9, 130.3, 131.2, 131.5, 138.7, 140.4, 142.1, 143.2, 152.6, 161.1.
HRMS (ESI): calcd for C22H18F3N4O2 [M+H]+ 427.1376, found 427.1374.
4.5.2.
(1'S*,2'R*,7a'S*,11R*)-2'-Nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydrospiro-
(7b) and (1'S*,2'S*,7a'S*,11S*)-1'-nitro-2'-
[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]
(trichloromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]
(7'b). Yield 0.36 g (76%, 7b:7'b = 94:6), mp 247–248 ºС, grey powder. IR (ATR): 1555, 1509,
1
1462, 1364, 1340 cm–1; H NMR (500 MHz, CDCl3) major isomer 7b (94%) δ 1.89–2.11 (m, 6H,
3CH2), 4.53 (td, J = 8.3, 7.4 Hz, 1H, H-7'a), 4.58 (t, J = 7.9 Hz, 1H, H-1'), 6.15 (d, J = 8.4 Hz, 1H,
H-2'), 7.53–7.64 (m, 3H, Ar), 7.70–7.81 (m, 2H, Ar), 8.09–8.22 (m, 3H, Ar), minor isomer 7'b
(6%) δ 5.33 (q, J = 7.4 Hz, 1H, H-7'a), 5.39 (d, J = 6.3 Hz, 1H, H-2'), 6.00 (dd, J = 7.7, 6.3 Hz, 1H,
13
H-1') (other signals are masked by the major isomer); C NMR (126 MHz, CDCl3) major isomer
7b (94%) δ 27.3, 32.2, 45.4, 65.3, 67.8, 74.3, 95.9, 98.5, 122.7, 126.4, 129.2, 129.3, 129.9, 130.3,
131.1, 131.6, 138.5, 141.2, 141.9, 143.1, 152.6, 161.2. HRMS (ESI): calcd for C22H18Cl3N4O2
[M+H]+ 475.0490, found 475.0493.
4.5.3. (1'S*,2'R*,6R*,7a'S*)-2'-Nitro-1'-(trifluoromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indeno-
[1,2-b]pyrido[3,2-e]pyrazine-6,3'-pyrrolizine] (7c). Yield 0.38 g (89%), mp 181–182 ºС, yellow
powder. IR (ATR): 1555, 1497, 1467, 1387, 1343, 1262 cm–1; 1H NMR (500 MHz, CDCl3) δ 1.86–
2.65 (m, 6H, 3CH2), 4.00−4.10 (m, 1H, H-1'), 4.38−4.44 (m, H-7'a), 6.08 (d, J = 10.1 Hz, 1H, H-
2'), 7.50 (d, J = 7.5 Hz, 1H, H-1), 7.62 (t, J = 7.4 Hz, 1H, H-2/H-3), 7.65 (t, J = 7.4 Hz, 1H, H-3/H-
2), 7.69–7.75 (m 1H, H-8), 8.33 (d, J = 7.3 Hz, 1H, H-4), 8.57 (dd, J = 8.3, 1.5 Hz, 1H, H-9), 9.12–
19
9.20 (m, 1H, H-7); F NMR (471 MHz, CDCl3) δ 93.1 (d, J = 7.3 Hz, CF3); 13C NMR (101 MHz,

11
2
CDCl3) δ 27.6, 31.7, 46.8, 50.4 (q, J = 28.3 Hz, C-1'), 63.6 (br s), 74.3, 91.6 (br s), 124.2, 124.6,
125.3 (q, 1J = 278.8 Hz, CF3), 126.2, 131.5, 132.4, 137.3, 138.1, 138.7, 141.0, 152.2, 153.8, 155.9,
162.6. HRMS (ESI): calcd for C21H17F3N5O2 [M+H]+ 428.1329, found 475.1328.
4.5.4. (1'S*,2'R*,6R*,7a'S*)-2'-Nitro-1'-(trichloromethyl)-1',2',5',6',7',7a'-hexahydrospiro[indeno-
[1,2-b]pyrido[3,2-e]pyrazine-6,3'-pyrrolizine] (7d). Yield 0.39 g (82%), mp 247–248 ºС, grey
1
powder. IR (ATR): 1556, 1509, 1462, 1363, 1340 cm–1; H NMR (500 MHz, CDCl3) δ 1.90–2.58
(m, 6H, 3CH2), 4.50 (q, J = 7.3 Hz, 1H, H-7'a), 4.60 (dd, J = 8.7, 7.6 Hz, 1H, H-1'), 6.16 (d, J = 8.7
Hz, 1H, H-2'), 7.56–7.68 (m, 3H, H-1, H-2, H-3), 7.69–7.75 (m, 1H, H-8), 8.32 (dd, J = 6.7, 1.6 Hz,
1H, H-4), 8.55 (dd, J = 8.3, 1.7 Hz, 1H, H-9), 9.12–9.20 (m, 1H, H-7); 13C NMR (126 MHz,
CDCl3) δ 27.4, 32.5, 45.7, 65.2, 68.0, 74.5, 95.5, 98.5, 123.9, 124.5, 126.5, 131.5, 132.5, 137.2,
137.9, 138.7, 141.8, 152.2, 153.8, 155.9, 162.6. Anal. Calcd for C21H17Cl3N5O2·0.33H2O: С, 52.25;
Н, 3.48; N, 14.51. Found: С, 52.33; Н, 3.39; N, 14.49.
4.6. X-ray diffraction study of compounds 3a, 4a, 5b and 7a
Intensity data for the compounds 3a, 4a, 5b and 7a were collected on a "Xcalibur Eos" (com-
pound 4a, 5b) and "Xcalibur S" (compounds 3a and 7a) diffractometer at 295(2) K, corresponding
(Mo-Kα or Cu-Kα radiation, graphite monochromator, -scan, radiation wavelength = 0.7107 and
1.54184 Å). The structures were solved by direct methods and refined by the full-matrix least-
squares method using the SHELX-97 program package [12]. All non-hydrogen atoms were refined
with anisotropic atomic displacement and hydrogen atoms were included at calculated position us-
ing a riding model.
4.6.1. Crystal data for 3a. C14H11F3N2O4, M = 328.25. Triclinic crystals space group P-1, a =
8.019(6), b = 10.033(17), c = 10.194(15) Å,  = 63.77(17),  = 72.94(9),  = 89.45(9), V =
696.4(16) Å3, Dc = 1.565 g/cm3, absorption coefficient  = 1.241 mm–1, Z = 2. The intensities of
2331 independent reflections (Rint = 0.0441) were measured. The final discrepancy factors R1 =
0.0453, wR2 = 0.1347, GooF = 1.001 for 2069 reflections with I > 2σ(I); R1 = 0.0492, wR2 = 0.1401
(all data). Largest different peak and hole: 0.187 and 0.213 eÅ–3. Completeness to θ = 66.01
(95.8%). Deposition number CCDC 1544703.
4.6.2. Crystal data for 4a. C16H13F3N2O4, M = 354.29. Monoclinic crystals space group P21/c, a =
11.4754(6), b = 12.1460(4), c = 12.2703(7) Å,  =  = 90.00,  = 117.035(7), V = 1523.35(13) Å3,
Dc = 1.545 g/cm3, absorption coefficient  = 0.135 mm–1, Z = 4. The intensities of 4154 independ-
ent reflections (Rint = 0.0196) were measured. The final discrepancy factors R1 = 0.0574, wR2 =

12
0.1641, GooF = 1.005 for 2736 reflections with I > 2σ(I); R1 = 0.0876, wR2 = 0.1974 (all data).
Largest different peak and hole: 0.256 and 0.310 eÅ–3. Completeness to θ = 28.22 (99.95%).
Deposition number CCDC 1544704.
4.6.3. Crystal data for 5b. C20H15Cl3N4O2, M = 449.72. Monoclinic crystals space group P21/c, a =
11.348(5), b = 23.839(14), c = 7.201(4) Å,  =  = 90.00,  = 91.64(4), V = 1947.2(18) Å3, Dc =
1.534 g/cm3, absorption coefficient  = 4.484 mm–1, Z = 4. The intensities of 3366 independent re-
flections (Rint = 0.0660) were measured. The final discrepancy factors R1 = 0.0439, wR2 = 0.0916,
GooF = 1.005 for 1965 reflections with I > 2σ(I); R1 = 0.0634, wR2 = 0.0938 (all data). Largest dif-
ferent peak and hole: 0.222 and 0.283 eÅ–3. Completeness to θ = 66.09 (98.6%). Deposition
number CCDC 1544705.
4.6.4. Crystal data for 7a. C22H17F3N4O2, M = 426.40. Monoclinic crystals space group C2/c, a =
21.4072(16), b = 8.8936(4), c = 23.9732(16) Å,  =  = 90.00,  = 121.981(10), V = 3871.4(4) Å3,
Dc = 1.463 g/cm3, absorption coefficient  = 0.116 mm–1, Z = 8. The intensities of 5005 independ-
ent reflections (Rint = 0.0189) were measured. The final discrepancy factors R1 = 0.0535, wR2 =
0.1540, GooF = 1.006 for 3413 reflections with I > 2σ(I); R1 = 0.0867, wR2 = 0.1830 (all data).
Largest different peak and hole: 0.262 and 0.234 eÅ–3. Completeness to θ = 28.22 (96.59%).
Deposition number CCDC 1544706.

13
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15
Fig. 1. Nitroalkenes 1a–c and indenes 2a–c used in this study.
Fig. 2. X-ray crystal structure of 3a (ORTEP drawing, 50% probability level).
Fig. 3. X-ray crystal structure of 4a (ORTEP drawing, 50% probability level).

16
Fig. 4. X-ray crystal structure of 5b (ORTEP drawing, 50% probability level).
Fig. 5. X-ray crystal structure of 7a (ORTEP drawing, 50% probability level).

17
Fig. 6. Diagnostic 2D 1H–1H NOESY correlations of stereoisomers 5a+5'a and regioisomers 7a+7'a.
Fig. 7. Fragments of the 2D 1H–1H NOESY spectrum of compounds 5a and 5'a.

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Fig. 8. Fragments of the 2D 1H–1H NOESY spectrum of compounds 7a and 7'a.
Fig. 9. Chemical shifts and coupling constants in compounds 4'a and 7'a in CDCl3.

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Scheme 1. Synthesis of compounds 3a–с and 4a–c by the reaction of nitroalkenes 1a–c with ninhydrin–
sarcosine/proline ylides (endo-adducts with respect to NO2).

20
Scheme 2. Synthesis of compounds 5a–d and 7a–d by the reaction of nitroalkenes 1a,b with indenoquinoxalinones–
sarcosine/proline ylides (endo-adducts with respect to NO2).

21
Table 1
Isolated yields of compounds 3a–c and 4a–c (all structures are racemic)
Nitropropene 1
X
Adduct
3a
Yield (%)
Adduct Yield (%)
F
81
63
37
4aa
4b
4c
94
79
48
1a
1b
1c
Cl
Br
3b
3c
a As a mixture of 4a:4'a = 84:16.
Table 2
Isolated yields of compounds 5a–d and 7a–d (all structures are racemic)
X
F
Y
Adduct
5a+5'a
5b
Ratio of 5:5' Yield (%)
Adduct
7a+7'a
7b+7'b
7c
Ratio of 7:7' Yield (%)
1
2
CH
CH
N
84:16
100:0
85:15
100:0
40
34
34
32
96:4
86
76
89
82
1a
1b
1a
1b
2b
2b
2c
2c
Cl
F
94:6
100:0
100:0
5c+5'c
5d
Cl
N
7d