(E)-3-Arylidene-4-diazopyrrolidine-2,5-diones: Preparation and Use in Rh II-Catalyzed X-H Insertion Reactions towards Novel, Medicinally Important Michael Acceptors

Article abstract of DOI:10.1055/s-0040-1706556

The use of readily available 1-aryl-3-arylidenepyrrolidine-2,5-diones in high yielding direct diazo-transfer reactions and subsequent involvement of the resulting diazo compounds in Rh ^II-catalyzed O-H, S-H, and N-H insertion reactions delivered 4-substituted 1-aryl-3-arylidenepyrrolidine-2,5-diones of defined regiochemistry and geometrical configuration. These products are intended to be studied as Michael acceptors capable of inhibiting thioredoxin reductase, a promising cancer target.

Full text of DOI:10.1055/s-0040-1706556

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–I
paper
A
en
E. Chupakhin et al.
Paper
Synthesis
(E)-3-Arylidene-4-diazopyrrolidine-2,5-diones: Preparation and
Use in RhII-Catalyzed X–H Insertion Reactions towards Novel,
Medicinally Important Michael Acceptors
'Tunable' Michael acceptors
Evgeny Chupakhina
for thioredoxin reductase inhibition
Martha Gechta
Alexander Ivanova
Grigory Kantina
Dmitry Dar’in*a
TrxR-Sec
O
Wittig
reaction
from
Ar
starting
maleimides
N
R
Mikhail Krasavin*a,b
0
0
0
0
-
0
0
0
2
-0
2
0
0
-
4
7
7
2
X
diazo transfer
O
followed by
RhII-catalyzed
XH insertion
14 examples
a Institute of Chemistry, Saint Petersburg State University, Saint
Petersburg, 199034, Russian Federation
m.krasavin@spbu.ru
82–97% (diazo transfer)
68–94% (X–H insertion)
X = R'S, R'O, R'COO, R'NH
d.dariin@spbu.ru
b Immanuel Kant Baltic Federal University, Kaliningrad, 236016,
Russian Federation
Corresponding Authors
Received: 14.09.2020
Accepted after revision: 07.10.2020
Published online: 05.11.2020
cells. This could be due to their intrusion in the critical sur-
vival mechanisms of cancer cells (such as overactive ubiqui-
tin proteasome5 or upregulated thioredoxin system6).
DOI: 10.1055/s-0040-1706556; Art ID: ss-2020-t0487-op
Recently, our efforts have been directed at developing
anticancer small-molecule inhibitors of thioredoxin reduc-
tase (TrxR), a redox defense enzyme overexpressed in can-
cer cells.7 Michael acceptors incorporated into various pep-
tidomimetic scaffolds (thus mimicking the enzyme’s pro-
tein substrate thioredoxin) received particular priority in
these efforts. These included the Michael acceptor DVD-445
identified as a lead compound for further development7a,b
and ,-unsaturated amides (so-called ‘piper-amides’8)
which were synthesized using the diazo chemistry tool-
box.9 The synthetic and medicinal chemistry development
of these scaffolds was motivated by the built-in orthogonal
vectors of molecular diversity. The facility in varying the
periphery substituent is essential for optimizing the selec-
tivity of TrxR inhibitors. Fine-tuning the electrophilicity of
the Michael acceptor moiety from an electronic as well as a
steric perspective can afford selective targeting of the cata-
lytic selenocysteine (Sec-SeH) residue (ionized at physio-
logical pH) of TrxR over cysteines (Cys-SH) generally abun-
dant in proteins.10 We reasoned that another chemotype
worthy investigation in this medicinal chemistry context
would be that of 1-substituted 3-arylidenepyrrolidine-2,5-
diones 1. Indeed, the scaffold comprises a Michael acceptor
moiety and the two easily and independently variable pe-
riphery groups, one of which (arylidene) could potentially
assume two distinct geometrical configurations. Unsurpris-
ingly, compounds such as 1 have been explored in connec-
tion with various biological activities (e.g., anticancer,11
Abstract The use of readily available 1-aryl-3-arylidenepyrrolidine-
2,5-diones in high yielding direct diazo-transfer reactions and subse-
quent involvement of the resulting diazo compounds in RhII-catalyzed
O–H, S–H, and N–H insertion reactions delivered 4-substituted 1-aryl-
3-arylidenepyrrolidine-2,5-diones of defined regiochemistry and geo-
metrical configuration. These products are intended to be studied as
Michael acceptors capable of inhibiting thioredoxin reductase, a prom-
ising cancer target.
Key words Michael acceptors, pyrrolidine-2,5-diones, Wittig reac-
tion, diazo transfer, rhodium(II) carbenes, X–H insertion, thioredoxin
reductase inhibitors
Electron-deficient olefins which can react with nucleo-
philes via the Michael (1,4-conjugate) addition are some-
what colloquially referred to as ‘Michael acceptors’. Such
motifs have received certain negative stigma in the context
of screening-based drug discovery as they can display po-
tentially non-specific reactivity towards nucleophilic amino
acid residues in proteins and behave as false positive hits in
biological assays.1 However, the reactivity of Michael accep-
tors, in particular, towards cysteine residues has been suc-
cessfully exploited in the medicinal chemistry design of tar-
geted covalent inhibitors.2 Michael acceptor motifs are also
omnipresent in natural products3 and sometimes consid-
ered essential for the anticancer activity displayed by such
compounds.4 Michael acceptors are often selective toward
cancer cells and do not perturb vital processes of normal
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
E. Chupakhin et al.
Paper
Synthesis
vasorelaxant,12 anti-HIV13), some of which could indeed be
attributed to these compounds’ Michael acceptor behavior.
Moreover, the ability of these compounds to react with thi-
ols via the conjugate addition was exploited in a recent
study on bioconjugation.14 However, compounds 1 contain
an obvious additional site for further scaffold diversifica-
tion, that is the fairly acidic15 methylene group. This consid-
eration as well as our recent involvement in the develop-
ment of synthetic methodology involving diazocarbonyl
compounds16 prompted us to consider converting com-
pounds 1 into their 4-diazo derivatives 2. The latter are
known, in principle, and have been prepared in two steps
from pyrrolidine-2,3,5-trione17 or via the thermal decom-
position of 3H-pyrazoles fused to a succinimide moiety.18
However, the preparation of 2 via the direct Regitz diazo
transfer had not been explored. This prompted us to inves-
tigate such an approach to diazo compounds 2 as this would
open access to libraries of Michael acceptors 3 (Figure 1)
containing three vectors of substituent diversity one of
which would be introduced via classical metal carbene X–H
insertion chemistry19 characteristic of diazo compounds in
general. When this work was in progress, a report from
Bhat and Laha appeared in the literature which also explored a
diazo-transfer approach to compounds 2 and their use in sil-
ver-catalyzed [2+1] cycloaddition with aldehydes.20 This
prompts us to disclose our findings in this regard that can,
on the one hand, provide some distinct practical conve-
nience at the diazo-transfer stage towards 2 and, on the
other hand, firmly validate the use of 2 in transition-metal-
catalyzed X–H insertion reactions as the means to prepare
novel Michael acceptors 3 for biological investigation.
Ph3P
O
Ph3P
O
PPh3 (1.1 equiv)
O
N
O
O
N
MeOH, r.t., 30 min
N
O
R
R
R
4a, R = 4-MeC6H4
4b, R = 4-F3CC6H4
4c, R = 4-ClC6H4
ArCHO
4–16 h
Ar
Ar
N2
NsN3
O
O
DBU, DCM
r.t., 1–2 h
N
O
N
O
R
R
2a–f
1a–f
Scheme 1 Preparation of 1-substituted 3-arylidenepyrrolidine-2,5-di-
ones 1a–f and their use in diazo-transfer reactions
nium ylide with aromatic aldehydes.21 Contrary to observa-
tions made by Kalia and co-workers,14 the reaction pro-
ceeded very well at room temperature in methanol and af-
forded excellent yields of target (E)-configured compounds
1a–f.21 Further, we considered the high lipophilicity of sub-
strates 1a–f that would probably make them unsuitable for
diazo transfer in aqueous medium which we recently per-
formed successfully for some more hydrophilic sub-
strates.22,23 For this reason, we decided to perform diazo
transfer in dichloromethane using 4-nitrobenzenesulfonyl
azide (NsN3) and DBU24 for all substrates. This resulted in
excellent yields of all diazo compounds 2a–f (Table 1). A no-
table feature of this protocol is the redundancy of aqueous
workup (in contrast to the Bhat procedure20), as in our case
the crude reaction mixture was loaded directly onto a silica
gel column for chromatographic purification. For Table 1,
entry 1, we compared the yield of the diazo product to that
obtained in aqueous medium using the recently developed
‘sulfonyl-azide-free’ (SAFE) diazo transfer.22 Not unexpect-
edly, the apparent solubility issues encountered with lipo-
philic substrate 1a led to a 23% drop in chemical yield of
product 2a. All diazo compounds 2a–f were obtained with
retention of the double bond configuration as confirmed by
the singe-crystal X-ray analysis of compound 2d (Figure 2).
F
R1
R2
N
O
H
N
R4
O
R3
N
O
O
O
F
DVD445
"Piper-amides"
Table 1 Structures and Chemical Yields of Compounds 1a–f and 2a–f
metal
carbene
X–H
direct
diazo
transfer
O
O
O
insertion
Entry
1,2
R
Ar
Yield of 1 Yield of 2
(%) (%)
Ar
Ar
Ar
N
R
N
R
N R
N2
X
1
2
3
4
5
6
a
b
c
d
e
f
4-MeC6H4
4-F3CC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
91
97a
O
O
O
2-furyl
96
94
92
88
95
94
96
84b
92
91
3
2
1
2-MeOC6H4
Ph
Figure 1 Michael acceptor DVD445 and piper-amides currently investi-
gated as TrxR inhibitors and the diversification path for 1-substituted 3-
arylidenepyrrolidine-2,5-diones 1 investigated in this work
4-MeC6H4
4-FC6H4
Six
1-aryl-3-(hetero)arylidenepyrrolidine-2,5-diones
a SAFE protocol in aqueous medium [NaN3 (2.0 equiv), m-HO2CC6H4SO2Cl
(2.0 equiv), K2CO3 (4.0 equiv), H2O/MeCN, r.t., 1–2 h] applied to this sub-
strate gave 74% yield.
1a–f (Scheme 1) were prepared from three known maleim-
ides 4a–c using the fairly straightforward literature ap-
proach based on conjugate addition of triphenylphosphine
and subsequent Wittig reaction of the resulting phospho-
b Structure of the product was confirmed by single-crystal X-ray analysis
(Figure 2).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
E. Chupakhin et al.
Paper
Synthesis
Interestingly, the similar insertion into N–H bonds did
not occur with synthetically useful yields under the same
protocol. However, with Rh2(esp)2 (esp = ,,′,′-te-
tramethyl-1,3-benzenedipropionate)27 as the catalyst, the
reactions worked and the respective aniline 3o–r as well as
an example of a sulfamido substituted compound 3s com-
pound were obtained in good yields and good chemical pu-
rity (Scheme 3).
The structure of products 3a–s was duly examined as
the allylic RhII carbene 5 could, in principle, undergo a viny-
logous X–H insertion28 (Scheme 4).
Figure 2 Single-crystal X-ray analysis of compound 2d (CCDC
2014382, thermal ellipsoids shown at 50% probability)
The possibility of the formation of regioisomeric prod-
ucts 3′ (as well as of the products 3′′ of isomerization of the
double bond in 3) was excluded based on the observed
combination of HMBC NMR correlations and through-space
correlations observed in the NOESY spectrum of 3 which
would not be expected either for 3′ or for 3′′ (Figure 3).
Having synthesized diazo compounds 2a–f, we proceed-
ed to investigate their behavior in RhII-catalyzed O–H, S–H,
and N–H insertion reactions.19 Using Rh2(OAc)4 (1 mol%)
provided good to excellent yields of products 3a–n (Scheme
2). Therefore, the protocol was not optimized further. Sev-
eral observations emerge from the results presented in
Scheme 2. Firstly, the reaction proceeded quite well with
the majority of alcohols and carboxylic acids. Secondly, the
yield of the benzyl mercaptan insertion product 3h was
high and comparable to that of the benzyl alcohol insertion
product 3i. Thirdly, 2-mercaptoethanol displayed a remark-
able selectivity for the O–H over S–H insertion products in
3b and 3l. This selectivity was unequivocally established by
the characteristic appearance and chemical shift of the
mercaptoethyl substituent in similar scaffolds.25,26
H
H
Y
Y
HMBC
H
H
strong C–H
correlation
Y
H
H
X
H
H
C
X
NOE
through 3 bonds
H
O
X
O
O
O
N
O
N
N
O
R
R
R
3
3''
3'
Figure 3 Structure assignment of products 3 based on HMBC and
NOESY correlations
Ar
Ar
X
N2
X–H
Rh2(AcO)4
(1 mol%)
O
O
N
N
O
O
DCM, r.t.
R
R
2a–f
3a–r
O
O
Cl
Cl
Cl
Cl
O
O
O
O
OMe
MeO
O
O
N
N
Me
Me
Me
O
O
MeO
O
O
O
O
O
O
HS
O
O
O
p-Tol
O
O
O
O
N
N
N
N
N
O
p-Tol
p-Tol
p-Tol
CF3
CF3
p-Tol
3a, 90%
3b, 90%
3c, 91%
3d, 84%
3e, 87%
3f, 79%
3g, 93%
p-Tol
p-Tol
p-Tol
p-Tol
Ph
S
Ph
O
F
Me
Ph
Ph
O
MeO
O
O
O
HS
O
O
O
O
O
O
O
N
O
N
N
N
N
N
O
O
O
O
Me
O
O
O
O
N
p-Tol
3n, 68%
Cl
Cl
Cl
Cl
Cl
Cl
3i, 94%
3j, 92%
3k, 91%
3l, 89%
3m, 90%
3h, 89%
Scheme 2 Preparation and structures of products 3a–n of insertion into O–H and S–H bonds of RhII carbenes derived from compounds 2a–f
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
E. Chupakhin et al.
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Synthesis
In summary, we described the use of readily available 1-
substituted 3-arylidenepyrrolidine-2,5-diones in high
yielding direct diazo-transfer reactions and the use of the
resulting diazo compounds in RhII-catalyzed O–H, S–H, and
N–H reactions which delivered trisubstituted succinimide 3
of defined regiochemistry and geometrical configuration
which was confirmed by single-crystal X-ray analysis.
These products are expected to act as Michael acceptor in-
hibitors of selenocysteine enzyme thioredoxin reductase, a
promising cancer target. The results of the biological testing
will be reported in due course.
Ar
Ar
N2
X
X–H
Rh2(esp)2
(1 mol%)
O
O
N
N
O
O
DCM, r.t.
R
R
2a,c–e
3o–s
Ph
Cl
H
N
OMe
O
Ph
O
N
O
H
N
H
N
O
O2N
F
N
N
O
O
p-Tol
p-Tol
Cl
3p, 64%
3q, 75%
3o, 71%
All commercial reagents were used without purification. NMR spectra
were recorded using a Bruker Avance III spectrometer (1H: 400.13
MHz; 13С: 100.61 MHz; the residual solvent peaks were used as inter-
nal standards:  = 7.26 and 2.50 for 1H in CDCl3 and DMSO-d6, respec-
tively,  = 39.52 and 77.16 for 13C in DMSO-d6 and CDCl3, respectively).
Mass spectra were recorded using a Bruker microTOF spectrometer
(ionization by electrospray, positive ions detection). Melting points
were determined in open capillary tubes on Stuart SMP50 Automatic
Melting Point Apparatus.
p-Tol
Cl
H
N
O
MeO
O
H
N
N
O
O
S
O
N
Ph
O
p-Tol
Cl
3s, 33%
CCDC 2014382 (2d) and 20011269 (3a) contain the supplementary
crystallographic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
3r, 58%
Scheme 3 Preparation and structures of products 3o–s of insertion
into N–H bonds of RhII carbenes derived from compounds 2a,c–e
Ar
Ar
Ar
Ar
X
1-Aryl-3-(hetero)arylidenepyrrolidine-2,5-diones 1a–f; General
Procedure 1 (GP1)
N2
O
X
Rh2L4
L4Rh2
O
X–H
O
O
O
or
O
To a solution of maleimide 4 (4.0 mmol) in MeOH (60 mL) was added
PPh3 (4.4 mmol) and the mixture was stirred for 30 min, followed by
addition of the aldehyde (4.4 mmol). Within minutes, a precipitate
started to form and the mixture was stirred at r.t. for 4–16 h. After
cooling in an ice bath, the precipitate was filtered off, washed with
cold MeOH (25 mL), and dried in air to afford 1-aryl-3-benzylide-
nepyrrolidine-2,5-diones 1, which were used in the diazo-transfer
step without further purification.
N
N
N
O
O
N
R
R
R
R
3'
not observed
2
3
5
Scheme 4 Plausible formation of regioisomeric X–H insertion prod-
ucts from RhII carbenes 5
To our delight, the above structural assignment was
confirmed by the single-crystal X-ray diffraction structure
of compound 3a (Figure 4).
1-Aryl-3-(hetero)arylidene-4-diazopyrrolidine-2,5-diones 2a–f;
General Procedure 2 (GP2)
To a stirred solution/suspension of imide 1 (2 mmol) in DCM (15 mL)
were added 4-nitrobenzenesulfonyl azide (479 mg, 2.1 mmol) and
DBU (313 L, 2.1 mmol) and the mixture was stirred at r.t. for 1–2 h
(TLC monitoring). The resulting mixture was loaded directly onto a
silica gel column and subjected to flash chromatography (DCM or
CHCl3) to afford pure diazo compound 2.
3-Acyloxy- or 3-Alkoxy-1-aryl-4-(hetero)arylidenepyrrolidine-2,5-
diones 3a–n; General Procedure 3 (GP3)
Diazo compound 2 (1 mmol) was dissolved in dry DCM (5 mL) (reac-
tions with MeOH and i-PrOH were performed using the alcohol as
solvent), the appropriate substrate for XH-insertion (2 mmol) was
added followed by addition of Rh2(OAc)4 (4.4 mg, 10 mol, 1 mol%).
The mixture was stirred at r.t. overnight, evaporated, and the crude
material was purified by flash column chromatography (silica gel,
n-hexane/acetone, gradient 9:1 to 2:1).
Figure 4 Single-crystal X-ray diffraction structure of compound 3a
(CCDC 20011269, thermal ellipsoids shown at 50% probability)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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E. Chupakhin et al.
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Synthesis
(E)-1-Aryl-3-(arylamino)-4-(hetero)arylidenepyrrolidine-2,5-di-
(E)-3-(4-Fluorobenzylidene)-1-(p-tolyl)pyrrolidine-2,5-dione (1f)
ones 3o–s; General Procedure 4 (GP4)
Following GP1 using 1-(p-tolyl)-1H-pyrrole-2,5-dione (748 mg, 4.0
mmol) and 4-fluorobenzaldehyde (544 mg, 4.4 mmol) gave 1f as a
white solid; yield: 1.12 g (95%); mp 164.7–165.3 °C.
1H NMR (400 MHz, СDСl3):  = 7.72 (t, J = 2.2 Hz, 1 H, =CH), 7.55 (dd, J
= 8.7, 5.3 Hz, 2 H, 2 ArH), 7.33 (d, J = 8.2 Hz, 2 H, 2 ArH), 7.27 (d, J = 8.7
Hz, 2 H, 2 ArH), 7.20 (t, J = 8.6 Hz, 2 H, 2 ArH), 3.74 (d, J = 2.2 Hz, 2 H,
CH2), 2.42 (s, 3 H, CH3).
Diazo compound 2 (1 mmol) was dissolved in dry DCM (5 mL), the
appropriate partner (1 mmol) was added followed by addition of
Rh2(esp)2 (4.4 mg, 10 mol, 1 mol%). The mixture was stirred at r.t. (TLC
monitoring), the crude material was filtered off and purified, if neces-
sary, by flash column chromatography (silica gel, n-hexane/acetone,
gradient 9:1 to 2:1).
(E)-3-(4-Chlorobenzylidene)-1-(p-tolyl)pyrrolidine-2,5-dione
(E)-3-(4-Сhlorobenzylidene)-4-diazo-1-(p-tolyl)pyrrolidine-2,5-
dione (2a)
(1a)29
Following GP1 using 1-(p-tolyl)-1H-pyrrole-2,5-dione (748 mg, 4.0
mmol) and 4-chlorobenzaldehyde (618 mg, 4.4 mmol) gave 1a as a
white solid; yield: 1.13 g (91%); mp 237.5–238.3 °C.
1H NMR (400 MHz, СDСl3):  = 7.70 (t, J = 2.5 Hz, 1 H, =CH), 7.47 (s, 4
H, 4 ArH), 7.31 (d, J = 8.5 Hz, 2 H, 2 ArH), 7.27 (d, J = 8.5 Hz, 2 H, 2
ArH), 3.71 (d, J = 2.4 Hz, 2 H, CH2), 2.42 (s, 3 H, CH3).
Following GP2 using imide 1a (622 mg, 2.0 mmol) gave 2a as an or-
ange solid; yield: 656 mg (97%); mp 134.4–135.1 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.69 (s, 1 H, =CH), 7.45 (d, J = 8.4 Hz, 2
H, 2 ArH), 7.36–7.27 (m, 6 H, 6 ArH), 2.42 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3):  = 166.0, 163.9, 138.7, 135.6, 131.8,
130.2, 129.8, 129.1, 126.4, 126.3, 117.2, 60.1 (C=N2), 21.2.
HRMS (ESI): m/z [M + Na]+ calcd for C18H12ClN3NaO2: 360.0510;
found: 360.0524.
(E)-3-(Furan-2-ylmethylene)-1-[4-(trifluoromethyl)phenyl]pyrro-
lidine-2,5-dione (1b)
Following GP1 using 1-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-
dione (964 mg, 4.0 mmol) and furan-2-carbaldehyde (422 mg, 4.4
mmol) gave 1b as a white solid; yield: 1.23 g (96%); mp 181.1–182.3
°C (decomp).
1H NMR (400 MHz, СDСl3):  = 7.78 (d, J = 8.4 Hz, 2 H, 2 ArH), 7.68 (s, 1
H, =CH), 7.60 (d, J = 8.3 Hz, 2 H, 2 ArH), 7.53 (t, J = 4.5 Hz, 1 H, ArH),
6.81 (d, J = 3.5 Hz, 1 H, ArH), 6.60 (dd, J = 3.4, 1.8 Hz, 1 H, ArH), 3.86 (d,
J = 2.3 Hz, 2 H, CH2).
(E)-3-Diazo-4-(furan-2-ylmethylene)-1-[4-(trifluoromethyl)phenyl]-
pyrrolidine-2,5-dione (2b)
Following GP2 using imide 1b (642 mg, 2.0 mmol) gave 2b as an or-
ange solid; yield: 652 mg (94%); mp 161.0–164.2 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.77 (d, J = 8.5 Hz, 2 H, 2 ArH), 7.64 (d, J
= 8.4 Hz, 2 H, 2 ArH), 7.58 (s, 1 H, =CH), 7.40 (s, 1 H, CH), 6.81 (d, J = 3.4
Hz, 1 H, CH), 6.64–6.57 (m, 1 H, CH).
13C NMR (101 MHz, CDCl3):  = 166.3, 163.9, 151.0, 146.3, 135.1, 130.1
(q, J = 33.0 Hz), 126.4, 126.2 (q, J = 3.6 Hz), 123.7 (q, J = 272.5 Hz),
117.6, 113.4, 113.4, 112.0, 62.1 (C=N2).
HRMS (ESI): m/z [M + Na]+ calcd for C16H8F3N3NaO3: 370.0410; found:
370.0416.
(E)-3-(2-Methoxybenzylidene)-1-(p-tolyl)pyrrolidine-2,5-dione (1c)
Following GP1 using 1-(p-tolyl)-1H-pyrrole-2,5-dione (748 mg, 4.0
mmol) and 2-methoxybenzaldehyde (598 mg, 4.4 mmol) gave 1c as a
white solid; yield: 1.15 g (94%); mp 135.7–136.5 °C.
1H NMR (400 MHz, СDСl3):  = 8.16 (t, J = 2.2 Hz, 1 H, =CH), 7.45 (d, J =
7.6 Hz, 1 H, ArH), 7.42 (d, J = 7.8 Hz, 1 H, ArH), 7.32 (d, J = 8.4 Hz, 2 H,
2 ArH), 7.28 (d, J = 8.3 Hz, 2 H, 2 ArH), 7.06 (t, J = 7.5 Hz, 1 H, ArH),
6.99 (d, J = 8.3 Hz, 1 H, ArH), 3.93 (s, 3 H, OCH3), 3.70 (d, J = 2.3 Hz, 2 H,
CH2), 2.42 (s, 3 H, CH3).
(E)-3-Diazo-4-(2-methoxybenzylidene)-1-(p-tolyl)pyrrolidine-2,5-
dione (2c)
Following GP2 using imide 1c (614 mg, 2.0 mmol) gave 2c as an or-
ange solid; yield: 639 mg (96%); mp 120.2–121.1 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.84 (s, 1 H, =CH), 7.43–7.37 (m, 1 H,
ArH), 7.31 (s, 4 H, ArH), 7.27 (dd, J = 7.5, 1.5 Hz, 1 H, ArH), 7.04 (t, J =
7.5 Hz, 1 H, ArH), 6.97 (d, J = 8.3 Hz, 1 H, ArH), 3.91 (s, 3 H, OCH3), 2.42
(s, 3 H, CH3).
13C NMR (101 MHz, CDCl3):  = 166.4, 164.2, 157.4, 138.5, 131.2,
130.0, 129.8, 129.3, 126.4, 124.5, 122.3, 120.3, 116.9, 110.9, 60.9
(C=N2), 55.4, 21.2.
(E)-3-Benzylidene-1-(4-chlorophenyl)pyrrolidine-2,5-dione (1d)12
Following GP1 using 1-(4-chlorophenyl)-1H-pyrrole-2,5-dione (828
mg, 4.0 mmol) and benzaldehyde (466 mg, 4.4 mmol) gave 1d as a
white solid; yield: 1.09 g (92%); mp 205.3–207.1 °C.
1H NMR (400 MHz, СDСl3):  = 7.77 (t, J = 2.4 Hz, 1 H, =CH), 7.56 (dd,
J = 7.9, 1.6 Hz, 2 H, 2 ArH), 7.54–7.47 (m, 5 H, 5 ArH), 7.38 (d, J = 8.8
Hz, 1 H, ArH), 3.78 (d, J = 2.4 Hz, 2 H, CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C19H15N3NaO3: 356.1006; found:
356.1003.
(E)-1-(4-Chlorophenyl)-3-(4-methylbenzylidene)pyrrolidine-2,5-
dione (1e)
(E)-3-Benzylidene-1-(4-chlorophenyl)-4-diazopyrrolidine-2,5-di-
Following GP1 using 1-(4-chlorophenyl)-1H-pyrrole-2,5-dione (828
mg, 4.0 mmol) and p-tolualdehyde (528 mg, 4.4 mmol) gave 1e as a
white solid; yield: 1.09 g (88%); mp 209.2–210.7 °C.
1H NMR (400 MHz, СDСl3):  = 7.74 (t, J = 2.3 Hz, 1 H, =CH), 7.49 (d, J =
8.8 Hz, 2 H, ArH), 7.46 (d, J = 8.1 Hz, 2 H, ArH), 7.38 (d, J = 8.8 Hz, 2 H,
ArH), 7.31 (d, J = 8.1 Hz, 2 H, ArH), 3.77 (d, J = 2.3 Hz, 2 H, CH2), 2.44 (s,
3 H, CH3).
one (2d)
Following GP2 using imide 1d (594 mg, 2.0 mmol) gave 2d as an or-
ange solid; yield: 542 mg (84%); mp 152.1–154.2 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.78 (s, 1 H, =CH), 7.52–7.46 (m, 4 H,
ArH), 7.45–7.40 (m, 3 H, ArH), 7.39–7.35 (m, 2 H, ArH).
13C NMR (101 MHz, CDCl3):  = 165.9, 163.7, 134.2, 133.3, 130.3,
129.7, 129.3, 129.0, 128.8, 128.5, 127.6, 116.4, 60.3 (C=N2).
HRMS (ESI): m/z [M + Na]+ calcd for C17H10ClN3NaO2: 346.0354;
found: 346.0348.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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E. Chupakhin et al.
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Synthesis
(E)-1-(4-Chlorophenyl)-3-diazo-4-(4-methylbenzylidene)pyrroli-
(E)-3-Acetoxy-4-(4-chlorobenzylidene)-1-(p-tolyl)pyrrolidine-2,5-
dine-2,5-dione (2e)
dione (3c)
Following GP2 using imide 1e (622 mg, 2.0 mmol) gave 2e as a light
orange solid; yield: 622 mg (92%); mp 129.2–130.0 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.75 (s, 1 H, =CH), 7.48 (d, J = 8.9 Hz, 2
H, 2 ArH), 7.41 (d, J = 8.9 Hz, 2 H, 2 ArH), 7.27 (s, 4 H, 4 ArH), 2.42 (s, 3
H, CH3).
13С NMR (101 MHz, CDCl3):  = 166.1, 163.8, 140.2, 134.2, 130.4,
130.3, 129.6, 129.3, 129.1, 128.9, 127.6, 115.4, 60.3 (C=N2), 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H13ClN3O2: 338.0691; found:
338.0697.
Following GP3 using 2a (337 mg, 1 mmol) and acetic acid (120 mg,
2 mmol) gave 3c as a white solid; yield: 335 mg (91%); mp 123.4–
124.6 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.76 (d, J = 8.6 Hz, 2 H, 2 ArH), 7.72
(d, J = 2.0 Hz, 1 H, =CH), 7.60 (d, J = 8.5 Hz, 2 H, 2 ArH), 7.35 (d, J = 8.2
Hz, 2 H, 2 ArH), 7.21 (d, J = 8.2 Hz, 2 H, 2 ArH), 6.40 (d, J = 2.1 Hz, 1 H,
CH), 2.38 (s, 3 H, COOCH3), 1.95 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3):  = 170.5, 169.5, 167.7, 138.9, 137.7,
137.3, 131.9, 130.9, 129.8, 129.4, 128.9, 126.2, 123.6, 67.9, 21.2, 20.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H16ClNNaO4: 392.0660; found:
392.0658.
(E)-3-Diazo-4-(4-fluorobenzylidene)-1-(p-tolyl)pyrrolidine-2,5-
dione (2f)
(E)-3-(4-Chlorobenzylidene)-4-(propynoyloxy)-1-(p-tolyl)pyrroli-
dine-2,5-dione (3d)
Following GP2 using imide 1f (590 mg, 2.0 mmol) gave 2f as a yellow
solid; yield: 584 mg (91%); mp 129.6–130.1 °C (decomp).
Following GP3 using 2a (337 mg, 1 mmol) and propiolic acid (140 mg,
2 mmol) gave 3d as a white solid; yield: 318 mg (84%); mp 141.8–
143.0 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.72 (s, 1 H, =CH), 7.37 (dd, J = 8.7, 5.3
Hz, 2 H, ArH), 7.31 (s, 4 H, ArH), 7.17 (t, J = 8.6 Hz, 2 H, ArH), 2.42 (s, 3
H, CH3).
1H NMR (400 MHz, CDCl3):  = 7.85 (d, J = 2.0 Hz, 1 H, =CH), 7.57 (d, J =
8.6 Hz, 2 H, 2 ArH), 7.49 (d, J = 8.6 Hz, 2 H, 2 ArH), 7.34–7.31 (m, 2 H, 2
ArH), 7.29–7.27 (m, 2 H, 2 ArH), 6.16 (d, J = 2.1 Hz, 1 H, CH), 3.00 (s, 1
H, C≡CH), 2.43 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3):  = 169.4, 167.5, 150.9, 139.2, 138.9,
137.7, 132.0, 130.6, 129.9, 129.6, 128.7, 126.1, 122.1, 77.8, 72.7, 69.1,
21.3.
13С NMR (101 MHz, CDCl3):  = 166.1, 164.0, 163.1 (d, J = 251.7 Hz),
138.7, 130.9 (d, J = 8.4 Hz), 129.8, 129.6 (d, J = 3.5 Hz), 129.1, 126.8,
126.3, 116.7 (d, J = 1.4 Hz), 116.1 (d, J = 22.0 Hz), 60.0 (C=N2), 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H13FN3O2: 322.0986; found:
322.0980.
(E)-3-(4-Chlorobenzylidene)-4-methoxy-1-(p-tolyl)pyrrolidine-
2,5-dione (3a)
HRMS (ESI): m/z [M + Na]+ calcd for C21H14ClNNaO4: 402.0504; found:
402.0492.
Following GP3 using 2a (337 mg, 1 mmol) in MeOH (5 mL) gave 3a as
a white solid; yield: 307 mg (90%); mp 211.5–212.8 °C.
(E)-3-(Cyclohexyloxy)-4-(furan-2-ylmethylene)-1-[4-(trifluoro-
methyl)phenyl]pyrrolidine-2,5-dione (3e)
1H NMR (400 MHz, CDCl3):  = 7.90 (d, J = 1.7 Hz, 1 H, =CH), 7.70 (d, J =
8.5 Hz, 2 H, 2 ArH), 7.48 (d, J = 8.5 Hz, 2 H, 2 ArH), 7.35–7.25 (m, 4 H, 4
ArH), 5.00 (d, J = 1.9 Hz, 1 H, CH), 3.65 (s, 3 H, OCH3), 2.43 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3):  = 172.4, 168.3, 139.6, 138.9, 137.4,
132.5, 131.5, 129.8, 129.4, 128.8, 126.1, 124.1, 73.4, 55.9, 21.2.
Following GP3 using 2b (347 mg, 1 mmol) and cyclohexanol (200 mg,
2 mmol) gave 3e as red needle crystals; yield: 364 mg (87%); mp
154.0–155.7 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.77 (d, J = 8.5 Hz, 2 H, 2 ArH), 7.69 (d, J
= 1.6 Hz, 1 H, =CH), 7.66 (d, J = 1.7 Hz, 1 H, ArH), 7.60 (d, J = 8.4 Hz, 2
H, 2 ArH), 7.00 (d, J = 3.5 Hz, 1 H, CH), 6.63 (dd, J = 3.5, 1.8 Hz, 1 H, CH),
5.30 (d, J = 1.7 Hz, 1 H, CH), 4.17–4.09 (m, 1 H, CH), 2.22–2.12 (m, 1 H,
CH), 2.06–1.96 (m, 1 H, CH), 1.89–1.72 (m, 2 H, CH2), 1.64–1.55 (m, 1
H, CH), 1.50–1.28 (m, 4 H, 2 CH2), 1.26–1.14 (m, 1 H, CH)
HRMS (ESI): m/z [M + Na]+ calcd for C19H16ClNNaO3: 364.0711; found:
364.0727.
(E)-3-(4-Chlorobenzylidene)-4-(2-mercaptoethoxy)-1-(p-tolyl)-
pyrrolidine-2,5-dione (3b)
Following GP3 using 2a (337 mg, 1 mmol) and 2-mercaptoethanol
(156 mg, 2 mmol) gave 3b as a white solid; yield: 348 mg (90%); mp
174.1–175.0 °C (decomp).
13C NMR (101 MHz, CDCl3):  = 173.1, 168.0, 150.0, 146.8, 134.9, 130.3
(q, J = 32.9 Hz), 126.5), 126.1 (q, J = 3.7 Hz), 125.8, 123.7 (q, J = 272.3
Hz), 121.3, 119.9, 113.2, 78.6, 71.0, 33.7, 32.2, 25.5, 24.4, 24.3.
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 1.8 Hz, 1 H, =CH), 7.73 (d, J =
8.6 Hz, 2 H, 2 ArH), 7.49 (d, J = 8.5 Hz, 2 H, 2 ArH), 7.35–7.28 (m, 4 H, 4
ArH), 4.82 (d, J = 1.9 Hz, 1 H, CH), 4.08–3.93 (m, 2 H, CH2), 3.34 (ddd, J
= 14.5, 7.0, 4.2 Hz, 1 H, CHH), 2.92 (ddd, J = 14.5, 6.4, 4.2 Hz, 1 H, CHH),
2.43 (s, 3 H, CH3), 2.41–2.36 (m, 1 H, SH).
13C NMR (101 MHz, CDCl3):  = 174.5, 168.4, 138.9, 137.1, 136.8,
132.8, 131.3, 129.8, 129.3, 128.9, 126.1, 124.5, 62.4, 42.1, 34.9, 21.3.
HRMS (ESI): m/z [M + H]+ calcd for C20H19ClNO3S: 388.0769; found:
388.0774; m/z [M + Na]+ calcd for C20H18ClNNaO3S: 410.0588; found:
410.0596.
HRMS (ESI): m/z [M + H]+ calcd for C22H21F3NO4: 420.1417; found:
420.1426.
(E)-3-(Furan-2-ylmethylene)-4-(2-methoxyethoxy)-1-[4-(trifluoro-
methyl)phenyl]-pyrrolidine-2,5-dione (3f)
Following GP3 using 2b (347 mg, 1 mmol) and 2-methoxyethanol
(152 mg, 2 mmol) gave 3f as a white solid; yield: 312 mg (79%); mp
133.4–135.0 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.78 (d, J = 8.4 Hz, 2 H, ArH), 7.72–7.71
(m, 2 H, CH, ArH), 7.61 (d, J = 8.4 Hz, 2 H, ArH), 7.09 (d, J = 3.5 Hz, 1 H,
CHfuryl), 6.64 (dd, J = 3.3, 1.6 Hz, 1 H, CHfuryl), 5.15 (d, J = 1.5 Hz, 1 H,
CH), 4.37–4.31 (m, 1 H, CH), 4.06 (dt, J = 10.2, 4.8 Hz, 1 H, CH), 3.65–
3.62 (m, 2 H, CH2), 3.36 (s, 3 H, OCH3).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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E. Chupakhin et al.
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Synthesis
13C NMR (101 MHz, CDCl3):  = 172.6, 167.7, 149.9, 147.1, 134.8, 130.4
(q, J = 32.9 Hz), 126.6, 126.5, 126.1 (q, J = 3.7 Hz), 123.7 (q, J = 272.4
Hz), 120.1, 119.9, 113.3, 73.7, 71.7, 70.1, 58.9.
HRMS (ESI): m/z [M + H]+ calcd for C19H17F3NO5: 396.1053; found:
396.1061.
1H NMR (400 MHz, CDCl3):  = 7.93 (d, J = 1.5 Hz, 1 H, =CH), 7.75 (d, J =
8.1 Hz, 2 H, 2 ArH), 7.49 (d, J = 8.8 Hz, 2 H, 2 ArH), 7.39 (d, J = 8.8 Hz, 2
H, 2 ArH), 7.32 (d, J = 8.0 Hz, 2 H, 2 ArH), 5.36 (d, J = 1.7 Hz, 1 H, CH),
4.86 (dd, J = 16.0, 2.3 Hz, 1 H, CHH), 4.62 (dd, J = 16.0, 2.4 Hz, 1 H,
CHH), 2.67 (t, J = 2.4 Hz, 1 H, ≡CH), 2.46 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3):  = 172.3, 168.4, 142.4, 142.0, 134.4,
131.9, 130.0, 129.8, 129.3, 127.5, 121.5, 78.3, 70.1, 56.6, 21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C21H16ClNNaO3: 388.0711; found:
(E)-3-Isopropoxy-4-(2-methoxybenzylidene)-1-(p-tolyl)pyrroli-
dine-2,5-dione (3g)
388.0718.
Following GP3 using 2c (333 mg, 1 mmol) in i-PrOH (5 mL) gave 3g as
a white solid; yield: 340 mg (93%); mp 147.3–148.1 °C.
1H NMR (400 MHz, CDCl3):  = 8.35 (d, J = 1.7 Hz, 1 H, =СН), 7.92 (dd, J
= 7.7, 1.4 Hz, 1 H), 7.49–7.42 (m, 1 H), 7.34–7.28 (m, 4 H), 7.05 (t, J =
7.5 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 5.10 (d, J = 1.9 Hz, 1 H), 4.34
(hept, J = 6.1 Hz, 1 H), 3.92 (s, 3 H), 2.42 (s, 3 H), 1.26 (d, J = 6.1 Hz, 3
H), 1.21 (d, J = 6.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 173.6, 168.8, 158.7, 138.5, 135.6,
132.4, 131.2, 129.7, 129.1, 126.2, 124.7, 122.6, 120.4, 110.8, 71.4, 70.8,
55.6, 23.5, 21.7, 21.2.
(E)-1-(4-Chlorophenyl)-3-methoxy-4-(4-methylbenzylidene)-
pyrrolidine-2,5-dione (3k)
Following GP3 using 2e (337 mg, 1 mmol) in MeOH (5 mL) gave 3k as
a white solid; yield: 310 mg (91%); mp 153.2–154.0 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.80 (d, J = 1.8 Hz, 1 H, =CH), 7.73
(d, J = 8.1 Hz, 2 H, 2 ArH), 7.61 (d, J = 8.7 Hz, 2 H, 2 ArH), 7.45 (d, J = 8.7
Hz, 2 H, 2 ArH), 7.35 (d, J = 8.0 Hz, 2 H, 2 ArH), 5.32 (d, J = 2.1 Hz, 1 H,
CH), 3.47 (s, 3 H, OCH3), 2.39 (s, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C22H23NNaO4: 388.1519; found:
13C NMR (101 MHz, DMSO-d6):  = 173.2, 168.5, 141.7, 139.4, 133.4,
388.1521.
131.9, 131.3, 130.6, 130.1, 129.4, 129.2, 123.7, 73.9, 55.9, 21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C19H16ClNNaO3: 364.0711; found:
364.0699.
(Z)-3-Benzylidene-4-(benzylthio)-1-(4-chlorophenyl)pyrrolidine-
2,5-dione (3h)
Following GP3 using 2d (323 mg, 1 mmol) and benzyl mercaptan (248
mg, 2 mmol) gave 3h as a white solid; yield: 372 mg (89%); mp 200.2–
202.3 °C (decomp).
1H NMR (400 MHz, CDCl3):  = 7.71 (d, J = 1.9 Hz, 1 H, =CH), 7.60–7.56
(m, 2 H, 2 ArH), 7.53–7.46 (m, 4 H, 4 ArH), 7.44–7.38 (m, 4 H, 4 ArH),
7.33–7.30 (m, 4 H, 4 ArH), 4.46 (d, J = 13.8 Hz, 1 H, CHH), 4.29 (d, J =
1.8 Hz, 1 H, CH), 3.87 (d, J = 13.8 Hz, 1 H, CHH).
13C NMR (101 MHz, CDCl3):  = 173.6, 168.4, 138.3, 136.6, 134.4,
132.5, 131.7, 130.8, 130.3, 129.7, 129.3, 128.7, 128.7, 127.8, 127.6,
122.9, 39.7, 35.7.
(E)-1-(4-Chlorophenyl)-3-(2-mercaptoethoxy)-4-(4-methyl-
benzylidene)pyrrolidine-2,5-dione (3l)
Following GP3 using 2e (337 mg, 1 mmol) and 2-mercaptoethanol
(156 mg, 2 mmol) gave 3l as a white solid; yield: 344 mg (89%); mp
141.0–142.7 °C.
1H NMR (400 MHz, CDCl3):  = 7.80 (s, 1 H, =CH), 7.68 (d, J = 8.1 Hz, 2
H, 2 ArH), 7.50 (d, J = 8.8 Hz, 2 H, 2 ArH), 7.40 (d, J = 8.8 Hz, 2 H, 2
ArH), 7.34 (d, J = 8.0 Hz, 2 H, 2 ArH), 4.83 (d, J = 1.7 Hz, 1 H, CH), 4.07–
3.94 (m, 2 H, CH2), 3.33 (ddd, J = 14.5, 6.7, 4.3 Hz, 1 H, CHH), 2.94 (ddd,
J = 14.5, 6.5, 4.4 Hz, 1 H, CHH), 2.59 (dd, J = 7.1, 5.3 Hz, 1 H, SH), 2.45
(s, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C24H18ClNNaO2S: 442.0639;
found: 442.0626.
13C NMR (101 MHz, CDCl3):  = 174.4, 168.3, 142.0, 138.9, 134.5,
131.9, 130.3, 130.1, 129.8, 129.4, 127.6, 122.3, 62.2, 42.3, 35.0, 21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C20H18ClNNaO3S: 410.0588;
(E)-3-Benzylidene-4-(benzyloxy)-1-(4-chlorophenyl)pyrrolidine-
2,5-dione (3i)
found: 410.0595.
Following GP3 using 2d (323 mg, 1 mmol) and benzyl alcohol (216
mg, 2 mmol) gave 3i as a white solid; yield: 378 mg (94%); mp 221.7–
222.5 °C.
(E)-3-Acetoxy-1-(4-chlorophenyl)-4-(4-methylbenzylidene)pyrro-
lidine-2,5-dione (3m)
1H NMR (400 MHz, CDCl3):  = 7.97 (d, J = 1.7 Hz, 1 H, =CH), 7.75–7.70
(m, 2 H, 2 ArH), 7.55–7.42 (m, 6 H, 6 ArH), 7.41–7.34 (m, 6 H, 6 ArH),
5.21 (d, J = 1.8 Hz, 1 H, CH), 5.07 (d, J = 10.8 Hz, 1 H, CHH), 4.86 (d,
J = 10.8 Hz, 1 H, CHH).
13C NMR (101 MHz, CDCl3):  = 172.4, 168.2, 141.5, 136.2, 134.5,
132.9, 131.4, 131.3, 130.0, 129.3, 129.0, 129.0, 128.6, 128.5, 127.5,
126.9, 123.4, 71.7, 71.2.
Following GP3 using 2e (337 mg, 1 mmol) and acetic acid (120 mg, 2
mmol) gave 3m as a white solid; yield: 332 mg (90%); mp 139.0–
141.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.84 (d, J = 1.6 Hz, 1 H, =CH), 7.55 (d, J =
8.0 Hz, 2 H, 2 ArH), 7.49 (d, J = 8.7 Hz, 2 H, 2 ArH), 7.39 (d, J = 8.7 Hz, 2
H, 2 ArH), 7.31 (d, J = 8.0 Hz, 2 H, 2 ArH), 6.04 (d, J = 1.7 Hz, 1 H, CH),
2.45 (s, 3 H, CH3), 2.06 (s, 3 H, C(О)CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C24H18ClNNaO3: 426.0867; found:
13C NMR (101 MHz, CDCl3):  = 170.6, 169.6, 167.8, 142.2, 140.0,
426.0857.
134.5, 131.0, 130.2, 129.6, 129.3, 127.7, 121.3, 68.3, 21.6, 20.1.
HRMS (ESI): m/z [M + Na]+ calcd for C20H16ClNNaO4: 392.0660; found:
392.0667.
(E)-1-(4-Chlorophenyl)-3-(4-methylbenzylidene)-4-(prop-2-ynyl-
oxy)pyrrolidine-2,5-dione (3j)
Following GP3 using 2e (337 mg, 1 mmol) and propargyl alcohol (112
mg, 2 mmol) gave 3j as a white solid; yield: 335 mg (92%); mp 118.6–
119.8 °C (decomp).
(E)-3-Acetoxy-4-(4-fluorobenzylidene)-1-(p-tolyl)pyrrolidine-2,5-
dione (3n)
Following GP3 using 2f (321 mg, 1 mmol) and acetic acid (120 mg,
2 mmol) gave 3n as a white solid; yield: 240 mg (68%); mp 179.4–
181.6 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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E. Chupakhin et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.81 (d, J = 2.2 Hz, 1 H, =CH), 7.65 (dd, J
= 8.9, 5.3 Hz, 2 H, ArH), 7.33 (d, J = 8.3 Hz, 2 H, ArH), 7.29 (d, J = 8.6 Hz,
2 H, ArH), 7.19 (t, J = 8.6 Hz, 2 H, ArH), 6.06 (d, J = 2.2 Hz, 1 H, CHC=O),
2.43 (s, 3 H, CH3), 2.06 (s, 3 H, CH3C=O).
13C NMR (101 MHz, CDCl3):  = 170.7, 169.6, 167.9, 164.2 (d, J = 254.4
Hz), 139.0, 137.9, 132.9 (d, J = 8.8 Hz), 129.9, 128.9, 128.8 (d, J = 3.4
Hz), 126.2, 122.6 (d, J = 2.3 Hz), 116.4 (d, J = 21.9 Hz), 68.1, 21.3, 20.1.
HRMS (ESI): m/z [M + H]+ calcd for C25H22FN2O3: 417.1609; found:
417.1611.
(E)-1-(4-Chlorophenyl)-3-[(4-methoxyphenyl)amino]-4-(4-methyl-
benzylidene)pyrrolidine- 2,5-dione (3r)
Following GP4 using 2e (337 mg, 1 mmol) and 4-methoxyaniline (123
mg, 1 mmol) gave 3r as a white solid; yield: 250 mg (58%); mp 183.1–
186.7 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C20H16FNNaO4: 376.0956; found:
1H NMR (400 MHz, DMSO-d6):  = 7.72 (d, J = 1.9 Hz, 1 H, =CH), 7.66
(d, J = 8.2 Hz, 2 H, ArH), 7.61 (d, J = 8.7 Hz, 2 H, ArH), 7.39 (d, J = 8.7 Hz,
2 H, ArH), 7.19 (d, J = 8.1 Hz, 2 H, ArH), 6.76 (d, J = 3.0 Hz, 4 H, ArH),
6.01 (d, J = 9.2 Hz, 1 H, NH), 5.48 (dd, J = 9.2, 1.9 Hz, 1 H, CH), 3.67 (s, 3
H, OCH3), 2.32 (s, 3 H, CH3).
13C NMR (101 MHz, DMSO-d6):  = 174.7, 169.1, 152.2, 141.2, 141.1,
137.2, 133.2, 132.1, 131.7, 130.8, 129.7, 129.4, 129.1, 126.4, 115.1,
115.0, 55.7, 54.2, 21.5.
376.0961.
(E)-3-(4-Chlorobenzylidene)-4-[(4-nitrophenyl)amino]-1-(p-tolyl)-
pyrrolidine-2,5-dione (3o)
Following GP4 using 2a (337 mg, 1 mmol) and 4-nitroaniline (138
mg, 1 mmol) gave 3a as a white solid; yield: 317 mg (71%); mp 215.7–
217.8 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.07 (d, J = 9.1 Hz, 2 H, ArH), 7.82
(d, J = 2.1 Hz, 1 H, =CH), 7.62 (d, J = 8.6 Hz, 3 H, Ar-NH), 7.40 (d, J = 8.5
Hz, 2 H, ArH), 7.35 (d, J = 8.3 Hz, 2 H, ArH), 7.26 (d, J = 8.3 Hz, 2 H,
ArH), 6.86 (d, J = 8.9 Hz, 2 H, ArH), 6.03 (dd, J = 8.9, 2.0 Hz, 1 H, CH),
2.38 (s, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C25H21ClN2NaO3: 455.1133;
found: 455.1139.
(E)-N-[4-(4-Chlorobenzylidene)-2,5-dioxo-1-(p-tolyl)pyrrolidin-3-
13C NMR (101 MHz, DMSO-d6):  = 173.8, 168.6, 153.8, 138.7, 137.8,
136.0, 135.6, 133.0, 132.0, 130.0, 129.9, 129.1, 127.1, 126.9, 126.5,
112.5, 52.8, 21.2.
yl]benzenesulfonamide (3s)
Following GP4 using 2a (338 mg, 1 mmol) and benzenesulfonamide
(157 mg, 1 mmol) gave 3s as a white solid; yield: 154 mg (33%); mp
226.5–227.7 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C24H18ClN3NaO4: 470.0878;
1H NMR (400 MHz, DMSO-d6):  = 8.95 (d, J = 7.5 Hz, 1 H, NH), 7.52–
7.44 (m, 5 H, ArH, =CH), 7.44–7.39 (m, 1 H, ArH), 7.36 (d, J = 8.5 Hz, 2
H, ArH), 7.35 (d, J = 7.9 Hz, 2 H, ArH), 7.27 (t, J = 7.8 Hz, 2 H), 7.18 (d, J
= 8.3 Hz, 2 H), 5.50 (dd, J = 7.5, 2.3 Hz, 1 H, CHC=O), 2.38 (s, 3 H, CH3).
found: 470.0879.
(E)-3-Benzylidene-1-(4-chlorophenyl)-4-(phenylamino)pyrroli-
dine-2,5-dione (3p)
Following GP4 using 2d (323 mg, 1 mmol) and aniline (93 mg, 1
mmol) gave 3p as a white solid; yield: 248 mg (64%); mp 205.8–207.3
°C.
13C NMR (101 MHz, DMSO-d6):  = 173.6, 168.9, 141.7, 138.6, 135.6,
135.5, 133.1, 132.5, 131.4, 130.1, 129.9, 128.81, 128.79, 127.0, 126.3,
124.7, 52.7, 21.2.
1H NMR (400 MHz, DMSO-d6):  = 7.77 (d, J = 2.0 Hz, 1 H, =CH), 7.72
(d, J = 7.2 Hz, 2 H, ArH), 7.62 (d, J = 8.7 Hz, 2 H, ArH), 7.42 (d, J = 8.7 Hz,
2 H, ArH), 7.40 (s, 1 H, NH), 7.35 (dd, J = 7.6, 6.9 Hz, 2 H, ArH). 7.13 (t, J
= 7.8 Hz, 2 H, ArH), 6.77 (d, J = 8.0 Hz, 2 H, ArH), 6.65 (t, J = 7.3 Hz, 1 H,
ArH), 6.35 (d, J = 9.3 Hz, 1 H, ArH), 5.66 (dd, J = 9.2, 2.0 Hz, 1 H, CH).
13C NMR (101 MHz, DMSO-d6):  = 174.6, 169.0, 147.4, 137.1, 133.4,
133.3, 131.9, 131.6, 130.8, 129.5, 129.4, 129.1, 129.0, 127.3, 117.7,
113.6, 53.4.
HRMS (ESI): m/z [M + Na]+ calcd for C24H19ClN2NaO4S: 489.0646;
found: 489.0638.
Funding Information
This research was supported by the Russian Foundation for Basic Re-
search (project grant 19-33-60010).
R
usia
n
F
o
u
n
datio
n
forBasic
R
esearch(19-33-6
0
0
1
0)
HRMS (ESI): m/z [M + H]+ calcd for C23H18ClN2O2: 389.1051; found:
389.1054.
Acknowledgement
(E)-3-[(4-Fluorophenyl)amino]-4-(2-methoxybenzylidene)-1-(p-tolyl)-
pyrrolidine-2,5-dione (3q)
We thank the Research Center for Magnetic Resonance, the Center for
Chemical Analysis and Materials Research and the Center for X-ray
Diffraction Methods of Saint Petersburg State University Research
Park for obtaining the analytical data.
Following GP4 using 2c (333 mg, 1 mmol) and 4-fluoroaniline (111
mg, 1 mmol) gave 3q as a white solid; yield: 312 mg (75%); mp 188.3–
190.4 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.02 (d, J = 2.1 Hz, 1 H, =CH), 7.61
(d, J = 7.7 Hz, 1 H, ArH), 7.39 (t, J = 7.8 Hz, 1 H, ArH), 7.33 (d, J = 8.1 Hz,
2 H, ArH), 7.23 (d, J = 8.2 Hz, 2 H, ArH), 7.07 (d, J = 8.4 Hz, 1 H, NH),
6.94 (t, J = 8.9 Hz, 2 H, ArH), 6.81 (t, J = 7.5 Hz, 1 H, ArH), 6.69 (dd, J =
8.9, 4.5 Hz, 2 H, ArH), 6.16 (d, J = 9.1 Hz, 1 H, ArH), 5.62 (dd, J = 9.0, 2.0
Hz, 1 H, CH), 3.86 (s, 3 H, OCH3), 2.37 (s, 3 H, CH3).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706556. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
13C NMR (101 MHz, DMSO-d6):  = 175.04, 169.25, 158.73, 155.35 (d, J
= 231.9 Hz), 144.22, 138.37, 132.59, 131.15, 130.76, 130.18, 129.85,
127.14, 126.84, 121.82, 120.61, 115.67 (d, J = 22.1 Hz), 114.50 (d, J =
7.5 Hz), 111.79, 56.20, 54.09, 21.22.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I