Preparation of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2: H -pyrrol-2-ones via base-assisted cyclization of 3-cyanoketones

Article abstract of DOI:10.1039/d1ra02279b

A convenient preparative method is developed allowing for expeditious assembly of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones from routinely available inexpensive synthetic precursors. These compounds could not be prepared via the previously known protocols, as 2-aminofuran derivatives were produced instead.

Full text of DOI:10.1039/d1ra02279b

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PAPER
Preparation of 3,5-diarylsubstituted 5-hydroxy-1,5-
dihydro-2H-pyrrol-2-ones via base-assisted
cyclization of 3-cyanoketones†
Cite this: RSC Adv., 2021, 11, 16236
a
a
a
*
Nicolai A. Aksenov,
Alexander V. Aksenov,
and Michael Rubin
Dmitrii A. Aksenov,
Igor A. Kurenkov,
Anton A. Skomorokhov,a Lidiya A. Prityko
a
a
ab
*
Received 22nd March 2021
Accepted 13th April 2021
A convenient preparative method is developed allowing for expeditious assembly of 3,5-diarylsubstituted 5-
hydroxy-1,5-dihydro-2H-pyrrol-2-ones from routinely available inexpensive synthetic precursors. These
compounds could not be prepared via the previously known protocols, as 2-aminofuran derivatives were
produced instead.
DOI: 10.1039/d1ra02279b
rsc.li/rsc-advances
ammonia14–17 or amines,18,19 reductive cyclization of nitroolens
Introduction
with
condensations.21–24 In application to the synthesis of 3,5-diary-
lsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one, just
1,3-diketones,20
or
various
aldol-type
cyclo-
Isomers of tetramic acid heterocyclic core of 3,5-disubstituted 5-
hydroxy-1,5-dihydro-2H-pyrrol-2-one are highly attractive for
modern medicinal chemistry. Compounds possessing this
structural unit are found in nature and oen demonstrate
a wide array of important biological activities. For example, an
array of alkaloids ianthellidones A–F, isolated from Australian
marine sponges of Ianthella genus showed promising anti-
cancer activity.1,2 Antimicrobial agents myceliothermophins A–
D, isolated from fungus Myceliophthora thermophila3 were
targets for synthetic exercises4 and subject for mechanistic
investigations.5 Recently, a new wave of interest in these
compounds was raised stimulated by their newly discovered
cytotoxic activity (Fig. 1).6 Tryptophan–polyketide hybrid, codi-
naeopsin, isolated from endophytic fungus Codinaeopsis gony-
trichoides demonstrated potent anti-malarial properties7 and
was also a target for total synthesis.8 Rollipyrrole, a representa-
tive of propentdyopents typical for animals, but highly unusual
for plants, was isolated from magnolia Rollinia mucosa (Fig. 1).9
Alkaloid cannabisin L originally isolated from seeds of black
henbane (Hyoscamus niger)10 was also recently discovered in
devil's trumpet plants (Datura metel).11,12 Finally, Penicillenol D,
an alkaloid with an ample anti-tumor effect was isolated from
a handful of synthetic approaches provided decent results,23,25
while most of the described protocols rely on the utilization of
precursors that are quite exotic. Herein, we report a novel
synthesis of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-
pyrrol-2-ones via unusual base-assisted cyclization of readily
available 3-cyanoketones (Scheme 1).
marine-derived fungus Trichoderma citrinoviride (Fig. 1).13
A
typical synthetic approach to these nitrogen-based heterocycles
involves the reaction of ve-membered lactone precursors with
aDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation. E-mail: aaksenov@ncfu.ru
bDepartment of Chemistry, University of Kansas, 1567 Irving Hill Rd, Lawrence, KS
66045-7582, USA. E-mail: mrubin@ku.edu; Tel: +1-785-864-5071
† Electronic supplementary information (ESI) available. CCDC 2069203 and
2069260. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ra02279b
Scheme 1 Alternative pathways for the cyclization of 3-cyanoketones.
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Scheme 2 Mechanistic rationales for the featured transformation.
Upon heating, a different cyclization was triggered resulting in
the formation of unstable 2-aminofuran, which could be iso-
lated in a form of imine 7 (Scheme 2 and Table 1, entry 2).29 It
should be pointed out, that the same result can be achieved
under acidic conditions in the presence of polyphosphoric acid,
which was demonstrated in our recent report.30
To gain access to the desired lactam 8 we decided to search
for alternative conditions for the cyclization of 6. To this end, we
tested KOH as a base in aqueous DMF for the reaction medium.
When performed at room temperature in air, this reaction
proceeded very sluggishly and provided the desired product in
low yield, and was isolated along with unreacted starting
material (entry 3). It should be stressed that the presence of the
oxidant is crucial for this cyclization, which does not proceed at
Fig. 1 Naturally occurring biologically active 5-hydroxy-1,5-dihydro-
2H-pyrrol-2-ones.
Results and discussion
During our research involving nitrogen-based heterocyclic
compounds26–28 we got very enthusiastic about the possibility of
employing synthetic equivalents of bis-electrophilic 3,4-dihy-
dro-2H-pyrrol-1-ium-4-ylium synthon for expeditious assembly
of bicyclic and tricyclic heterocyclic scaffolds. Although the
structure of 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones 8 seems to
be a suitable synthetic equivalent, lengthy and laborious
synthetic approaches to these molecules rendered this idea
cost-prohibitive and much less exciting. In 1985, Soto and co-
workers reported on a very appealing strategy allowing for the
preparation of very similar cyclic compound 5 from readily
available and very inexpensive precursors.29 Their method
involved Knoevenagel condensation between aldehyde 1 and
1,3-dicarbonyl compound 2 to obtain conjugate olen 3, which
was then subjected to hydrocyanation to provide nitrile 4. Next,
piperidine-assisted oxidative cyclization was carried out to
furnish 5 (Scheme 2).29 It should be pointed out, that this
method is specic for the cyclization of dicarbonyl compounds
4 and can provide only heterocyclic products 5 with requisite
acyl substituent at C-4 (Scheme 2). This substitution pattern is
not suitable for our purposes, since this electron-withdrawing
group would potentially revert the polarization of the C]C
double bond. So, we opted for the preparation of the lactam 8,
non-substituted at this position. However, an attempt to involve
mono-carbonyl precursor 6 into the reaction with piperidine did
not provide any reactivity at room temperature (Table 1, entry 1).
Table 1 Optimization of the reaction conditions
Time, h
#
Base
Oxidant/solvent
(temp., ꢀC) Yielda, %
1
2
3
4
5
6
7
8
9
Pyridine
Pyridine
KOH
KOH
KOH
Air/EtOH
Air/EtOH
Air/DMF–water
DMF–waterc
H2O2–urea/DMF
48 (20)
48 (100)
72 (20)
4 (20)
NR
Decompositionb
32% + 64% of 6a
NR
29
40
48
71
85
72
41
1.5 (20)
KOH
H2O2–urea/MeOH 1.5 (20)
KOH (2 equiv.) DMSO (0.2 mL)d,e 0.5 (20)
KOH (4 equiv.) DMSO (0.5 mL)d,e 1.0 (20)
KOH (4 equiv.) DMSO (1 mL)d
0.67 (20)
2 (20)
4.5 (20)
10 KOH (4 equiv.) DMSO (2 mL)d
11 KOH (4 equiv.) DMSO (3 mL)d
a
All test reactions were performed on 0.5 mmol scales. NMR yields are
provided unless specied otherwise. b Forms 7a (R1 ¼ R2 ¼ Ar ¼ Ph) in
c
the presence of benzaldehyde. Reaction was carried out under argon
d
atmosphere. 300 mL of water was added to improve the solubility of
the base. e Organic materials were poorly soluble in this mixture.
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Table 2 Oxidative cyclization of 3-cyanoketones
6, 8
R1
R2
Yielda, %
1
2
3
4
5
6
7
8
6a, 8a
6b, 8b
6c, 8c
6d, 8d
6e, 8e
6f, 8f
6g, 8g
6h, 8h
6i, 8i
6j, 8j
6k, 8k
6l, 8l
6m, 8m
6n, 8n
6o, 8o
6p, 8p
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
72
71
65
88
70
68
71
66
68
76
59
77
59
77
61
64
p-MeC6H4
p-EtC6H4
p-MeOC6H4
o-MeOC6H4
p-Me2NC6H4
p-FC6H4
o-FC6H4
p-ClC6H4
o-ClC6H4
p-BrC6H4
Ph
9
Ph
Ph
Ph
10
11
12
13
14
15
16
p-MeOC6H4
p-ClC6H4
2-Naphthyl
2,3-Dihydrobenzo[b][1,4]dioxin-6-yl
p-MeOC6H4
Ph
Ph
Ph
p-MeOC6H4
a
Isolated yields of puried materials are provided.
all under an inert atmosphere (entry 4). In an attempt to facil- [b][1,4]dioxin-6-yl moieties are very well tolerated in the featured
itate the oxidation step, we tested reactions in the presence of transformation.
hydrogen peroxide/urea complex taking DMF or methanol as
The formation of the 1,5-dihydro-2H-pyrrol-2-one ring in the
solvents. In both cases reaction proceeded much faster, going to reaction of ketonitrile 6e (entry 5) was unambiguously
completion within 1.5 h and affording 29 and 40% of lactam 8a, conrmed by single-crystal X-ray analysis of the product 8e
respectively (entries 5 and 6).
(Fig. 2).
We envision the described transformation to proceed via the
Next, we tried to employ DMSO as an oxidant. This reaction
was carried out in the presence of water as a co-solvent to following mechanistic pathway. Initial base-assisted cleavage of
improve the solubility of the base in the reaction mixture. The acidic a-CH-bond of nitrile would lead to the formation of
initial attempt involved 2 equiv. of KOH and 0.2 mL of DMSO to anionic moiety 9, which should be susceptible to oxidation in
trigger a rather quick reaction, which provided, however, only the presence of DMSO. The resulting acrylonitrile 10 would then
marginal yield (entry 7). To facilitate the reaction, amounts of experience a nucleophilic attack with hydroxide species trig-
both base and DMSO were increased, and the yield was greatly gering subsequent 5-exo-trig cyclization to afford 5-hydroxy-2H-
improved (entry 8). However, organic materials were still quite
poorly soluble in this combination of solvents, so we decided to
increase the concentration of DMSO. In a mixture of water/
DMSO 0.3 : 1, the observed rate of the reaction hits the
maximum. The reaction was complete in 40 min at room
temperature, affording 85% NMR yield, which translated into
a 72% isolated yield of puried material (entry 9). Further
increase in concentration of DMSO proved detrimental. The
rate of the reaction slowed down, and the yields dropped quite
noticeably (entries 10 and 11).
With optimized conditions in hand, we proceeded to
perform the reaction on a 1 mmol scale to isolate the product 8a
in 72% yield (Table 2, entry 1). The reaction proved very general,
and a series of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-
pyrrol-2-ones were easily obtained in good to high isolated
yields under the same conditions (Table 2). It was demon-
Fig. 2 X-ray structure of 5-hydroxy-3-(2-methoxyphenyl)-5-phenyl-
strated, that phenyl groups with different alkyl, alkoxy, and
1,5-dihydro-2H-pyrrol-2-one 8e (the thermal ellipsoids are shown at
50% probability) (CCDC #2069260).
halide substituents as well as 2-naphthyl and 2,3-dihydrobenzo
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reactions were carried out in a sealed tube upon heating at
ꢀ
160 C with microwave irradiation (Scheme 3). Gratifyingly, all
the tested reactions proceeded smoothly affording compounds
15a, k–m and 16a in moderate to good yields (Scheme 3).
Successful installation of the new aniline moiety at C-5 was
unambiguously conrmed by the single-crystal X-ray diffraction
analysis of compound 15k re-crystallized from benzene (Fig. 3).
As suggested by the reviewer of this paper, we also evaluated
the possibility of lowering the reaction temperature employing
Brønsted acid catalysis. To this end, reactions of phenol with
lactam 8a were carried out in the presence of 20 mol% of HClO4
(70% aqueous, the 0.60 M reaction mixture was heated in
nitromethane at 70 ꢀC for 1 h)31,32 or MeSO3H33 (0.60 M reaction
mixture was heated in toluene at 70 ꢀC for 1 h). Upsettingly,
these reactions afforded only marginal yields of the corre-
sponding product 16a, 46% and 48%, respectively. The reaction
of 8a with aniline carried out in the presence of MeSO3H under
the same reaction conditions was accompanied by signicant
decomposition and allowed for the isolation of 15a in very low
yield (12%).
Scheme 3 Further modification of 1,5-dihydro-2H-pyrrol-2-ones via
electrophilic aromatic substitution.
pyrrol-2-olate 11. Re-protonation of this species, followed by tau-
tomerization of the imidic acid entity into lactam function would
nally provide product 8 (Scheme 2). An alternative pathway would
include initial hydrolysis of nitrile function in 6 to afford primary
amide 12, which could undergo a subsequent 5-exo-trig cyclization
providing lactam 13. Deprotonation of a-CH-bond would lead to
the formation of anionic intermediate 14, which would be further
oxidized into 1,5-dihydro-2H-pyrrol-2-one 8 with DMSO. The latter
rationale, however, seems less likely, as in the absence of DMSO as
an oxidizing agent we failed to detect the formation of interme-
diate 12 or 13. The hydrolysis step did not proceed and nitrile
function remained unchanged. This suggests that the oxidation
process should proceed prior to cyclization.
Next, we evaluated the possibility of further increasing the
molecular complexity of the synthesized scaffolds by targeting
the introduction of a third aryl substituent to obtain products
15, 16 (Scheme 2). To this end, we tested the SEAr reaction
between 1,5-dihydro-2H-pyrrol-2-ones and electron-rich
aromatic compounds, such as aniline and phenol. The
Conclusion
In conclusion, a novel synthetic method allowing for highly
efficient preparation of formerly poorly-accessible 3,5-diary-
lsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was devel-
oped. The method relies on the employment of routinely
available and very inexpensive precursors and provides good
yields of the target products. Following the modication of the
prepared structures via thermally-induced SEAr reaction with
aniline or phenol allowed for the introduction of the third aryl
substituent at this heterocyclic scaffold, which seems attractive
for building diverse libraries for drug discovery. Evaluation of
biological activities of the synthesized compounds and further
exploration of their reactivity as bis-electrophiles is currently
underway in our laboratories.
Experimental part
General information
1H and 13C NMR spectra were recorded on a Bruker Avance-III
spectrometer (400 or 100 MHz, respectively) equipped with
a BBO probe in CDCl3 or DMSO-d6, using TMS as an internal
standard. High-resolution mass spectra were obtained using
a Bruker Maxis spectrometer (electrospray ionization, MeCN
solution, using HCO2Na–HCO2H for calibration). Melting
points were measured with a Stuart SMP30 apparatus. All
reactions were performed in oven-dried asks equipped with
reux condensers and magnetic stir bars. All reactions were
followed by thin-layer chromatography (TLC) using ALUGRAM
Xtra SIL G UV254 plates, which were visualized under UV light
(254 nm), with hexane/EtOAc mixtures as eluent. Nitriles 6c,34
6h, 6n,34 6o, 6p35 were synthesized according to the protocols
provided below from the corresponding chalcones. All other
nitriles were prepared according to known procedures and their
physical and spectral properties were identical to those
described in the literature.36 Reagents and solvents were
Fig. 3 X-ray structure of 5-(4-aminophenyl)-3-(4-bromophenyl)-5-
phenyl-1,5-dihydro-2H-pyrrol-2-one 15k as solvate with benzene.
Two enantiomers of 15k are disordered in the crystalline lattice and
their overlay is shown (the thermal ellipsoids are shown at 50%
probability) (CCDC #2069203).
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purchased from commercial vendors and used as received. 7.32 (m, 1H), 4.63 (dd, J ¼ 8.0, 5.9 Hz, 1H), 3.87 (dd, J ¼ 17.8,
Abbreviation “PE” is used for light petroleum ether employed as 8.0 Hz, 1H), 3.65 (dd, J ¼ 17.8, 6.0 Hz, 1H). 13C NMR (101 MHz,
an eluent for preparative chromatography.
CDCl3) d 194.7, 136.0, 135.5, 133.1, 132.5, 130.2, 129.7, 129.4
(2C), 129.1, 128.9, 128.5, 128.0, 127.7 (2C), 127.2, 123.6, 120.8,
44.7, 32.2. FTIR (ZnSe) n (cmꢁ1): 2241, 1680, 1624, 1595, 1455,
1405, 1366, 1258, 1173, 1128, 1017; HRMS (ES TOF, m/z) calcd
for C20H15NNaO+ ([M + Na]+): 308.1046, found 308.1042 (1.1
ppm).
2-(4-Ethylphenyl)-4-oxo-4-phenylbutanenitrile (6c)34
Use of well-ventilated fume hood is necessary as the release of
hydrogen cyanide occurs during the reaction. In a 25 mL round
bottom ask equipped with magnetic stir bar (E)-3-(4-ethyl-
phenyl)-1-phenylprop-2-en-1-one37 (472 mg, 2.00 mmol), KCN
(195 mg, 3 mmol), EtOH (5 mL), H2O (0.3 mL) AcOH (114 mL,
120 mg, 2.00 mmol) were placed, closed with reux condenser
4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxo-2-
phenylbutanenitrile (6o)
and allowed to stir under reux for 2 h (TLC control). Aer the Product 6o was obtained via the method described in literature
consumption of the starting material, the reaction mixture was employing (E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenyl-
cooled to room temperature and the precipitated product was prop-2-en-1-one40 (532 mg, 2.00 mmol), and puried by recrys-
collected by vacuum ltration, washed twice with H2O. Color- tallization from ethanol. White solid, mp 108.9–109.4 ꢀC
ꢀ
less solid, mp 114.3–115.4 C (EtOH); yield 420 mg (1.6 mmol, (EtOH); yield 410 mg (1.4 mmol, 70%). Rf ¼ 0.27, EtOAc/hexane
1
80%). Rf ¼ 0.49, EtOAc/hexane (1 : 4, v/v). H NMR (400 MHz, (1 : 4, v/v). 1H NMR (400 MHz, chloroform-d) d 7.53–7.29 (m,
CDCl3) d 8.00–7.85 (m, 2H), 7.63–7.56 (m, 1H), 7.52–7.42 (m, 7H), 6.90 (d, J ¼ 8.2 Hz, 1H), 4.55 (dd, J ¼ 7.9, 6.0 Hz, 1H), 4.36–
2H), 7.38–7.30 (m, 2H), 7.26–7.19 (m, 2H), 4.54 (dd, J ¼ 7.9, 4.23 (m, 4H), 3.64 (dd, J ¼ 17.7, 7.9 Hz, 1H), 3.42 (dd, J ¼ 17.7,
6.0 Hz, 1H), 3.72 (dd, J ¼ 17.9, 8.0 Hz, 1H), 3.50 (dd, J ¼ 18.0, 6.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) d 193.1, 148.8, 143.6,
6.0 Hz, 1H), 2.65 (q, J ¼ 7.6 Hz, 2H), 1.23 (t, J ¼ 7.6 Hz, 3H). 13
C
135.5, 129.7, 129.4 (2C), 128.5, 127.6 (2C), 122.4, 120.9, 117.8,
NMR (101 MHz, CDCl3) d 194.9, 144.7, 135.9, 134.0, 132.6, 120.0 117.6, 64.8, 64.2, 44.3, 32.1. FTIR (ZnSe) n (cmꢁ1): 2241, 1665,
(2C), 128.9 (2C), 128.2 (2C), 127.6 (2C), 120.9, 44.7, 31.7, 28.6, 1602, 1501, 1431, 1345, 1284, 1260, 1166, 1135, 1063; HRMS (ES
15.6. FTIR (ZnSe) n (cmꢁ1): 2969, 2241, 1769, 1675, 1595, 1511, TOF, m/z) calcd for C18H15NNaO3+ ([M + Na]+): 316.0944, found
1443, 1352, 1246, 1053, 998; HRMS (ES TOF, m/z) calcd for 316.0948 (ꢁ1.1 ppm).
C
18H17NNaO+ ([M + Na]+): 286.1202, found 286.1200 (0.9 ppm).
2,4-Bis(4-methoxyphenyl)-4-oxobutanenitrile (6p)35
2-(2-Fluorophenyl)-4-oxo-4-phenylbutanenitrile (6h)
Product 6p was obtained via the method described for 6c
Product 6h was obtained via the method described for 6c employing
employing
(E)-3-(2-uorophenyl)-1-phenylprop-2-en-1-one38 (536 mg, 2.00 mmol), and puried by recrystallization from
(E)-1,3-bis(4-methoxyphenyl)prop-2-en-1-one41
(452 mg, 2.00 mmol), and puried by recrystallization from ethanol. White crystals, mp 112.6–113.3 ꢀC (EtOH); yield
ethanol. Colorless solid, mp 125.3–126.4 ꢀC (EtOH); yield 0.354 mg (1.20 mmol, 60%). Rf ¼ 0.21, EtOAc/hexane (1 : 1, v/v).
385 mg (1.52 mmol, 76%). Rf ¼ 0.51, EtOAc/hexane (1 : 4, v/v). 1H NMR (400 MHz, CDCl3) d 7.94–7.85 (m, 2H), 7.39–7.30 (m,
1H NMR (400 MHz, chloroform-d) d 7.99–7.91 (m, 2H), 7.65– 2H), 6.97–6.86 (m, 4H), 4.52 (dd, J ¼ 7.7, 6.3 Hz, 1H), 3.87 (s,
7.52 (m, 2H), 7.52–7.43 (m, 2H), 7.42–7.30 (m, 1H), 7.21 (td, J ¼ 3H), 3.80 (s, 3H), 3.63 (dd, J ¼ 17.6, 7.6 Hz, 1H), 3.43 (dd, J ¼
7.6, 1.2 Hz, 1H), 7.12 (ddd, J ¼ 10.3, 8.2, 1.2 Hz, 1H), 4.75 (dd, J ¼ 17.6, 6.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) d 193.3, 164.2,
8.5, 5.4 Hz, 1H), 3.74 (dd, J ¼ 18.0, 8.5 Hz, 1H), 3.55 (dd, J ¼ 18.0, 159.6, 130.6 (2C), 129.0 (2C), 128.8, 127.5, 121.2, 114.7 (2C),
5.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) d 194.6, 160.1 (d, J ¼ 114.1 (2C), 55.7, 55.5, 44.3, 31.3. FTIR (ZnSe) n (cmꢁ1): 2246,
248.2 Hz), 135.7, 134.1, 130.6 (d, J ¼ 8.4 Hz), 129.8 (d, J ¼ 3.2 1675, 1598, 1516, 1361, 1306, 1248, 1219, 1164, 1022; HRMS (ES
Hz), 129.0 (2C), 128.2 (2C), 125.1 (d, J ¼ 3.7 Hz), 122.4 (d, J ¼ TOF, m/z) calcd for C18H17NNaO3+ ([M + Na]+): 318.1101, found
13.6 Hz), 119.6, 116.3 (d, J ¼ 21.0 Hz), 42.6 (d, J ¼ 1.6 Hz), 26.8 318.1104 (ꢁ1.0 ppm).
(d, J ¼ 3.1 Hz). FTIR (ZnSe) n (cmꢁ1): 2242, 1677, 1595, 1496,
1451, 1410, 1357, 1304, 1246, 1212, 1000; HRMS (ES TOF) calcd 5-Hydroxy-3,5-diphenyl-1,5-dihydro-2H-pyrrol-2-one (8a)
for C16H12FNNaO+ ([M + Na]+): 276.0795, found 276.0795 (0.0
ppm).
In a 5 mL vial equipped with a magnetic stirring bar, KOH
(224 mg, 4 mmol) was dissolved in H2O (0.6 mL), followed by the
addition of 4-oxo-2,4-diphenylbutanenitrile36 (235 mg, 1 mmol)
4-(Naphthalen-2-yl)-4-oxo-2-phenylbutanenitrile (6n)
and DMSO (2 mL). The reaction mixture was allowed to stir at
Product 6n was obtained via the method described for 6c, r.t. for approximately 1 hour. Aer the consumption of all the
employing
(E)-1-(naphthalen-2-yl)-3-phenylprop-2-en-1-one39 starting compound, the reaction mixture was diluted with water
(516 mg, 2.00 mmol), and puried by recrystallization from (15 mL), extracted with ethyl acetate (4 ꢂ 15 mL), washed with
ethanol. Colorless solid, mp 109.6–110.4 ꢀC (EtOH), lit40 mp water (2 ꢂ 15 mL) and puried by column chromatography
128 ꢀC (EtOH); yield 496 mg (1.74 mmol, 87%). Rf ¼ 0.54, EtOAc/ (gradient: EtOAc/PE 1 : 3–1 : 1). The fractions were concentrated
1
hexane (1 : 4, v/v). H NMR (400 MHz, chloroform-d) d 8.42 (s, on a rotary evaporator. Compounds can also be puried by
1H), 8.00 (dd, J ¼ 8.7, 1.8 Hz, 1H), 7.94 (d, J ¼ 8.1 Hz, 1H), 7.91– recrystallization from a suitable solvent. White solid, mp 234.1–
7.85 (m, 2H), 7.62 (ddd, J ¼ 8.2, 7.0, 1.3 Hz, 1H), 7.56 (ddd, J ¼ 236.1 ꢀC (EtOAc); yield 181 mg (0.72 mmol, 72%). Rf ¼ 0.31,
8.0, 6.9, 1.2 Hz, 1H), 7.51–7.45 (m, 2H), 7.44–7.38 (m, 2H), 7.38– EtOAc/hexane (1 : 2, v/v), Rf ¼ 0.42, EtOAc/hexane (1 : 1, v/v). 1H
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NMR (400 MHz, DMSO-d6) d 9.17–9.05 (m, 1H), 8.05–7.90 (m, NMR (101 MHz, DMSO-d6) d 171.1, 159.5, 143.6, 141.1, 131.2,
2H), 7.59–7.47 (m, 2H), 7.46–7.24 (m, 7H), 6.63 (s, 1H). 13C NMR 128.6 (2C), 128.2 (2C), 127.8, 125.7 (2C), 123.6, 113.8 (2C), 86.0,
(101 MHz, DMSO-d6) d 170.8, 145.8, 140.8, 131.8, 131.15, 128.5, 55.1. FTIR (ZnSe) n (cmꢁ1): 3297, 1699, 1667, 1446, 1255, 1048,
+
128.3 (2C), 128.3 (2C), 127.9, 127.2 (2C), 125.7 (2C), 86.1. FTIR 966; HRMS (ES TOF, m/z) calcd for C17H15NNaO3 ([M + Na]+):
(ZnSe) n (cmꢁ1): 3242, 2960, 1767, 1617, 1605, 1501, 1463, 1447, 304.0944, found 304.0944 (ꢁ0.3 ppm).
1433, 1363, 1234, 1204; HRMS (ES TOF, m/z) calcd for
16H13NNaO2 ([M + Na]+): 274.0838, found 274.0839 (ꢁ0.2 5-Hydroxy-3-(2-methoxyphenyl)-5-phenyl-1,5-dihydro-2H-
+
C
ppm).
pyrrol-2-one (8e)
Product 8e was obtained via the method described for
compound 8a, employing 2-(2-methoxyphenyl)-4-oxo-4-phenyl-
butanenitrile36 (265 mg, 1.00 mmol), and puried by column
5-Hydroxy-5-phenyl-3-(p-tolyl)-1,5-dihydro-2H-pyrrol-2-one
(8b)
Product 8b was obtained via the method described for chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystalli-
compound 8a employing 4-oxo-4-phenyl-2-(p-tolyl)butaneni- zation from ethanol. Reaction time: 1 h. Colorless crystals, mp
trile36 (249 mg, 1.00 mmol), and puried by column chroma- 193.9–195.4 ꢀC (EtOH); yield 0.196 g (0.7 mmol, 70%). Rf ¼ 0.61,
tography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystallization EtOAc/hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6) d 9.05 (s,
from ethanol. Reaction time: 1 hour. Yellow solid, mp 161.6– 1H), 8.22 (dt, J ¼ 7.7, 1.6 Hz, 1H), 7.51 (d, J ¼ 8.3 Hz, 2H), 7.42–
163.8 ꢀC (EtOH); yield 188 mg (0.71 mmol, 71%). Rf ¼ 0.45, 7.27 (m, 5H), 7.07 (dd, J ¼ 8.5, 1.1 Hz, 1H), 6.98 (td, J ¼ 7.5,
EtOAc/hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6) d 9.09 (s, 1.1 Hz, 1H), 6.59 (s, 1H), 3.80 (s, 3H). 13C NMR (101 MHz,
1H), 7.86 (dd, J ¼ 8.3, 2.2 Hz, 2H), 7.56–7.49 (m, 2H), 7.40–7.29 DMSO-d6) d 171.4, 157.9, 148.7, 141.2, 129.6, 129.6, 128.3 (2C),
(m, 4H), 7.20 (d, J ¼ 7.9 Hz, 2H), 6.60 (d, J ¼ 2.3 Hz, 1H), 2.31 (s, 127.8, 127.8, 125.7 (2C), 119.9, 119.6, 111.2, 86.1, 55.5. FTIR
3H). 13C NMR (101 MHz, DMSO-d6) d 171.0, 144.8, 141.0, 138.0, (ZnSe) n (cmꢁ1): 3268, 3195, 1670, 1614, 1489, 1407, 1243, 1216,
131.6, 128.9 (2C), 128.3, 128.2 (2C), 127.8, 127.1 (2C), 125.7 (2C), 1045; HRMS (ES TOF, m/z) calcd for C17H15NNaO3+ ([M + Na]+):
86.0, 20.9. FTIR (ZnSe) n (cmꢁ1): 3268, 2362, 1672, 1508, 1489, 304.0944, found 304.0951 (2.2 ppm).
1426, 1207, 1087, 1058, 976; HRMS (ES TOF, m/z) calcd for
C
17H15NNaO2+ ([M + Na]+): 288.0995, found 288.0989 (1.9 ppm). 3-(4-(Dimethylamino)phenyl)-5-hydroxy-5-phenyl-1,5-dihydro-
2H-pyrrol-2-one (8f)
3-(4-Ethylphenyl)-5-hydroxy-5-phenyl-1,5-dihydro-2H-pyrrol-2-
one (8c)
Product 8f was obtained via the method described for
compound 8a 2-(4-(dimethylamino)phenyl)-4-oxo-4-phenyl-
Product 8c was obtained via the method described for butanenitrile36 (278 mg, 1.00 mmol), and puried by column
compound
8a,
employing
2-(4-ethylphenyl)-4-oxo-4- chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystalli-
phenylbutanenitrile (263 mg, 1.00 mmol), and puried by zation from ethanol. Reaction time: 1.5 h. Colorless solid, mp
column chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or 270.9–273.3 ꢀC (EtOH); yield 200 mg (0.68 mmol, 68%). Rf ¼
recrystallization from ethanol. White solid, mp 164.4–165.2 C 0.55, EtOAc/hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6)
ꢀ
(EtOH); yield 181 mg (0.65 mmol, 65%). Rf ¼ 0.23, EtOAc/hexane d 8.97 (s, 1H), 7.83 (d, J ¼ 8.3 Hz, 2H), 7.50 (d, J ¼ 8.1 Hz, 2H),
(1 : 2, v/v), Rf ¼ 0.58, EtOAc/hexane (1 : 1, v/v). 1H NMR (400 7.39–7.24 (m, 3H), 7.10 (s, 1H), 6.69 (d, J ¼ 8.5 Hz, 2H), 6.49 (d, J
MHz, DMSO-d6) d 9.09 (s, 1H), 7.90–7.83 (m, 2H), 7.56–7.48 (m, ¼ 1.2 Hz, 1H), 2.92 (s, 6H). 13C NMR (101 MHz, DMSO-d6)
2H), 7.41–7.26 (m, 4H), 7.22 (d, J ¼ 8.1 Hz, 2H), 6.60 (s, 1H), 2.61 d 172.0, 150.7, 142.0, 141.5, 132.1, 128.6 (2C), 128.5 (2C), 128.1,
(q, J ¼ 7.6 Hz, 2H), 1.17 (t, J ¼ 7.6 Hz, 3H). 13C NMR (101 MHz, 126.2 (2C), 119.2, 112.1 (2C), 86.5, 40.3 (2C). FTIR (ZnSe) n
DMSO-d6) d 171.0, 144.9, 144.3, 141.0, 131.8, 128.6, 128.2 (2C), (cmꢁ1): 3268, 2762, 2540, 2366, 1663, 1612, 1525, 1424, 1359,
127.8, 127.7 (2C), 127.2 (2C), 125.7 (2C), 86.1, 28.0, 15.5. FTIR 1198, 1051; HRMS (ES TOF, m/z) calcd for C18H18N2NaO2+ ([M +
(ZnSe) n (cmꢁ1): 3258, 1672, 1511, 1489, 1414, 1231, 1202, 1087, Na]+): 317.1260, found 317.1252 (2.7 ppm).
+
1058, 976; HRMS (ES TOF, m/z) calcd for C18H17NNaO2 ([M +
Na]+): 302.1151, found 302.1149 (0.9 ppm).
3-(4-Fluorophenyl)-5-hydroxy-5-phenyl-1,5-dihydro-2H-pyrrol-
2-one (8g)
5-Hydroxy-3-(4-methoxyphenyl)-5-phenyl-1,5-dihydro-2H-
pyrrol-2-one (8d)
Product 8g was obtained via the method described for
compound 8a employing 2-(4-uorophenyl)-4-oxo-4-phenyl-
Product 8d was obtained via the method described for butanenitrile36 (253 mg, 1.00 mmol), and puried by column
compound 8a, employing 2-(4-methoxyphenyl)-4-oxo-4-phenyl- chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystalli-
butanenitrile36 (265 mg, 1.00 mmol), and puried by column zation from ethanol. White solid, mp 186.1–187.1 ꢀC (EtOH);
chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystalli- yield 191 mg (0.71 mmol, 71%). Rf ¼ 0.26, EtOAc/hexane (1 : 2,
zation from ethanol. White solid, mp 163.4–164.1 ꢀC (EtOH); v/v). 1H NMR (400 MHz, DMSO-d6) d 9.16 (s, 1H), 8.08–7.98 (m,
yield 247 mg (0.88 mmol, 88%). Rf ¼ 0.15, EtOAc/hexane (1 : 2, 2H), 7.54–7.50 (m, 2H), 7.43 (d, J ¼ 1.7 Hz, 1H), 7.41–7.34 (m,
v/v), Rf ¼ 0.5, EtOAc/hexane (2 : 1, v/v). 1H NMR (400 MHz, 2H), 7.34–7.29 (m, 1H), 7.26–7.14 (m, 2H), 6.64 (s, 1H). 13C NMR
DMSO-d6) d 9.07 (d, J ¼ 1.8 Hz, 1H), 7.97–7.90 (m, 2H), 7.55–7.48 (101 MHz, DMSO-d6) d 170.8, 162.2 (d, J ¼ 246.1 Hz), 145.6 (d, J
(m, 2H), 7.40–7.34 (m, 2H), 7.33–7.28 (m, 1H), 7.27 (d, J ¼ ¼ 1.9 Hz), 140.8, 130.7, 129.4 (2C, d, J ¼ 8.1 Hz), 128.3 (2C),
1.7 Hz, 1H), 6.98–6.90 (m, 2H), 6.56 (s, 1H), 3.77 (s, 3H). 13C 127.9, 127.7 (d, J ¼ 3.2 Hz), 125.7 (2C), 115.3 (2C, d, J ¼ 21.3 Hz),
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86.1. FTIR (ZnSe) n (cmꢁ1): 3253, 1771, 1704, 1672, 1499, 1414,
3-(4-Bromophenyl)-5-hydroxy-5-phenyl-1,5-dihydro-2H-pyrrol-
2-one (8k)
+
1229, 1159, 1051; HRMS (ES TOF, m/z) calcd for C16H12FNNaO2
([M + Na]+): 292.0744, found 292.038 (2.1 ppm).
Product 8k was obtained via the method described for
compound 8a, employing 2-(4-bromophenyl)-4-oxo-4-phenyl-
butanenitrile36 (313 mg, 1.00 mmol), and puried by column
chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystalli-
zation from benzene. Reaction time: 2 hours. Colorless solid,
mp 152.6–155.2 ꢀC (benzene); yield 194 mg (0.59 mmol, 59%). Rf
¼ 0.54, EtOAc/hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6)
d 9.19 (s, 1H), 7.95 (d, J ¼ 8.2 Hz, 2H), 7.59 (d, J ¼ 8.3 Hz, 2H),
7.55–7.46 (m, 3H), 7.37–7.27 (m, 3H), 6.66 (s, 1H). 13C NMR (101
MHz, DMSO-d6) d 170.5, 146.5, 140.6, 131.3 (2C), 130.6, 130.4,
129.2 (2C), 128.3 (2C), 128.0, 125.8 (2C), 121.9, 86.1. FTIR (ZnSe)
n (cmꢁ1): 3248, 1663, 1612, 1487, 1451, 1424, 1210, 1055, 1010,
970; HRMS (ES TOF, m/z) calcd for C16H12BrNNaO2+ ([M + Na]+):
351.9944, found 351.9952 (ꢁ2.5 ppm).
3-(2-Fluorophenyl)-5-hydroxy-5-phenyl-1,5-dihydro-2H-pyrrol-
2-one (8h)
Product 8h was obtained via the method described for
compound
8a
employing
2-(2-uorophenyl)-4-oxo-4-
phenylbutanenitrile (253 mg, 1.00 mmol), and puried by
column chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or
ꢀ
recrystallization from ethanol. White solid, mp 183.0–184.0 C
(EtOH); yield 177 mg (0.66 mmol, 66%). Rf ¼ 0.25, EtOAc/hexane
(1 : 2, v/v). 0.62 (EtOAc/hexane, 2 : 1). 1H NMR (400 MHz,
DMSO-d6) d 9.23 (s, 1H), 8.13 (td, J ¼ 7.7, 1.9 Hz, 1H), 7.53 (dd, J
¼ 7.5, 1.8 Hz, 2H), 7.48–7.22 (m, 7H), 6.73 (s, 1H). 13C NMR (101
MHz, DMSO-d6) d 170.3, 160.3 (d, J ¼ 249.7 Hz), 149.5 (d, J ¼ 9.2
Hz), 140.6, 130.4 (d, J ¼ 8.6 Hz), 130.2 (d, J ¼ 2.9 Hz), 128.3 (2C),
128.0, 126.5 (d, J ¼ 1.6 Hz), 125.7 (2C), 124.2 (d, J ¼ 3.4 Hz),
118.9 (d, J ¼ 12.3 Hz), 115.7 (d, J ¼ 21.9 Hz), 86.5. FTIR (ZnSe) n
(cmꢁ1): 3253, 1672, 1489, 1446, 1224, 1053, 971; HRMS (ES TOF,
5-Hydroxy-5-(4-methoxyphenyl)-3-phenyl-1,5-dihydro-2H-
pyrrol-2-one (8l)
Product 8l was obtained via the method described for
compound 8a, employing 4-(4-methoxyphenyl)-4-oxo-2-phenyl-
butanenitrile35 (265 mg, 1.00 mmol), and puried by column
chromatography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystalli-
zation from ethanol. Colorless solid, mp 176.8–179.0 ꢀC
(ethanol); yield 216 mg (0.77 mmol, 77%). Rf ¼ 0.22, EtOAc/
m/z) calcd for C16H12FNNaO2 ([M + Na]+): 292.0744, found
+
292.0744 (0.2 ppm).
3-(4-Chlorophenyl)-5-hydroxy-5-phenyl-1,5-dihydro-2H-pyrrol-
2-one (8i)
1
Product 8i was obtained via the method described for
compound 8a employing 2-(4-chlorophenyl)-4-oxo-4-phenyl-
butanenitrile36 (269 mg, 1.00 mmol), and puried by column
chromatography (gradient: EtOAc : PE 1 : 2–2 : 1) or recrystalli-
zation from ethanol. Reaction time: 1 h. Colorless solid, mp
148.1–148.7 ꢀC (EtOH); yield 194 mg (0.68 mmol, 68%). Rf ¼
0.40, EtOAc/hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6)
d 9.18 (d, J ¼ 1.8 Hz, 1H), 8.07–7.97 (m, 2H), 7.51 (dd, J ¼ 8.1,
1.6 Hz, 3H), 7.49–7.43 (m, 2H), 7.42–7.26 (m, 3H), 6.66 (s, 1H).
13C NMR (101 MHz, DMSO-d6) d 170.6, 146.4, 140.6, 133.2,
130.5, 130.0, 128.9 (2C), 128.4 (2C), 128.3 (2C), 128.0, 125.8 (2C),
86.1. FTIR (ZnSe) n (cmꢁ1): 3292, 1708, 1670, 1487, 1455, 1417,
hexane (1 : 2, v/v), Rf ¼ 0.7, EtOAc/hexane (1 : 1, v/v). H NMR
(400 MHz, DMSO-d6) d 9.07 (s, 1H), 7.94 (d, J ¼ 7.6 Hz, 2H), 7.57–
7.27 (m, 6H), 6.93 (d, J ¼ 8.3 Hz, 2H), 6.53 (s, 1H), 3.75 (s, 3H).
13C NMR (101 MHz, DMSO-d6) d 170.8, 159.0, 146.0, 132.7,
131.4, 131.2, 128.5, 128.3 (2C), 127.2 (2C), 127.0 (2C), 113.6 (2C),
85.9, 55.2. FTIR (ZnSe) n (cmꢁ1): 3354, 3258, 1703, 1662, 1515,
1419, 1243, 1183, 1062; HRMS (ES TOF, m/z) calcd for
C
17H15NNaO3+ ([M + Na]+): 304.0944, found 304.0941 (1.1 ppm).
5-(4-Chlorophenyl)-5-hydroxy-3-phenyl-1,5-dihydro-2H-pyrrol-
2-one (8m)
Product 8m was obtained via the method described for
compound 8a, employing 4-(4-chlorophenyl)-4-oxo-2-phenyl-
butanenitrile36 (269 mg, 1.00 mmol), and puried by column
chromatography (gradient: EtOAc/PE 1 : 3–1 : 1) or recrystalli-
zation from benzene. White solid, mp 157.9–159.6 ꢀC (benzene);
yield 168 mg (0.59 mmol, 59%). Rf ¼ 0.33, EtOAc/hexane (1 : 2,
1200, 1089, 1051; HRMS (ES TOF, m/z) calcd for C16H12
-
ClNNaO2+ ([M + Na]+): 308.0449, found 308.0446 (0.8 ppm).
3-(2-Chlorophenyl)-5-hydroxy-5-phenyl-1,5-dihydro-2H-pyrrol-
2-one (8j)
Product 8j was obtained via the method described for
compound 8a, employing 2-(2-chlorophenyl)-4-oxo-4-phenyl-
butanenitrile36 (269 mg, 1.00 mmol), and puried by column
chromatography (gradient: EtOAc/PE 1 : 2–2 : 1). This product
is unstable upon heating above 60 ꢀC. Yellowish amorphous
solid; yield 217 mg (0.76 mmol, 76%). Rf ¼ 0.15, EtOAc/hexane
(1 : 2, v/v), Rf ¼ 0.53, EtOAc/hexane (2 : 1, v/v). 1H NMR (400
MHz, DMSO-d6) d 9.15 (s, 1H), 7.63–7.48 (m, 4H), 7.44–7.36 (m,
1
v/v). H NMR (400 MHz, DMSO-d6) d 9.17 (d, J ¼ 1.8 Hz, 1H),
8.01–7.91 (m, 2H), 7.56–7.50 (m, 2H), 7.48–7.32 (m, 6H), 6.75 (s,
1H). 13C NMR (101 MHz, DMSO-d6) d 170.8, 145.4, 140.0, 132.6,
132.1, 131.0, 128.6, 128.3 (2C), 128.3 (2C), 127.8 (2C), 127.3 (2C),
85.7. FTIR (ZnSe) n (cmꢁ1): 3354, 3258, 1768, 1698, 1667, 1414,
1243, 1062; HRMS (ES TOF, m/z) calcd for C16H12ClNNaO2+ ([M
+ Na]+): 308.0449, found 308.0440 (3.0 ppm).
4H), 7.37–7.29 (m, 1H), 7.22 (d, J ¼ 1.6 Hz, 1H), 6.75 (s, 1H). 13
C
5-Hydroxy-5-(naphthalen-2-yl)-3-phenyl-1,5-dihydro-2H-
pyrrol-2-one (8n)
NMR (101 MHz, DMSO-d6) d 170.0, 149.7, 140.7, 132.6, 132.1,
131.4, 130.2, 129.9, 129.7, 128.3 (2C), 128.0, 126.9, 125.7 (2C),
86.8. FTIR (ZnSe) n (cmꢁ1): 3330, 1696, 1663, 1448, 1255, 1058, Product 8n was obtained via the method described for
1036, 756; HRMS (ES TOF, m/z) calcd for C16H12ClNNaO2+ ([M + compound 8a, employing 4-(naphthalen-2-yl)-4-oxo-2-phenyl-
Na]+): 308.0449, found 308.0449 (ꢁ0.2 ppm).
butanenitrile34 (285 mg, 1.00 mmol), and puried by column
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ꢀ
chromatography (gradient: EtOAc/PE 1 : 3–1 : 1) or recrystalli- microwave oven and heated to 160 C for 40 min (temperature
zation from ethanol. White solid, mp 175.9–177.9 ꢀC (ethanol); control using an infrared sensor). Next, the mixture was trans-
yield 232 g (0.77 mmol, 77%). Rf ¼ 0.33, EtOAc/hexane (1 : 2, v/ ferred from the reactor to chromatography column (gradient:
v). 1H NMR (400 MHz, DMSO-d6) d 9.27 (s, 1H), 8.14 (s, 1H), EtOAc/PE 1 : 3–2 : 1) for anilines and (gradient: EtOAc/PE 1 : 4–
8.09–7.80 (m, 5H), 7.59 (d, J ¼ 8.7 Hz, 1H), 7.56–7.48 (m, 3H), 1 : 2) for phenols. The fractions were concentrated on a rotary
7.46–7.26 (m, 3H), 6.82 (s, 1H). 13C NMR (101 MHz, DMSO-d6) evaporator.
d 170.9, 145.7, 138.3, 132.7, 132.6, 132.2, 131.2, 128.6, 128.4
Anilines can also be puried by dissolving in 20% HCl,
(2C), 128.1, 127.9, 127.5, 127.3 (2C), 126.3, 126.3, 124.3, 124.2, rinsing with EtOAc, neutralizing with NaHCO3 and subsequent
86.2. FTIR (ZnSe) n (cmꢁ1): 3258, 1768, 1665, 1624, 1424, 1231, extraction with CH2Cl2 (4 ꢂ 15 mL) followed by evaporation on
1043; HRMS (ES TOF, m/z) calcd for C20H15NNaO2+ ([M + Na]+): a rotary evaporator.
324.0995, found 324.1003 (ꢁ2.4 ppm).
Yellowish transparent solid, mp 119.5–122.1 ꢀC; yield 143 mg
(0.44 mmol, 44%). Rf ¼ 0.36, EtOAc/hexane (1 : 1, v/v). 1H NMR
(400 MHz, DMSO-d6) d 9.59 (d, J ¼ 2.0 Hz, 1H), 8.20 (d, J ¼
1.9 Hz, 1H), 8.04–7.99 (m, 2H), 7.45–7.21 (m, 8H), 7.06–6.92 (m,
2H), 6.58–6.46 (m, 2H), 5.10 (s, 2H). 13C NMR (101 MHz, DMSO-
d6) d 170.6, 147.9, 147.8, 143.0, 131.6, 131.5, 128.9, 128.3 (5C),
127.5 (2C), 127.1, 126.9 (2C), 126.7 (2C), 113.5 (2C), 68.0. FTIR
(ZnSe) n (cmꢁ1): 3380, 3253, 2998, 1771, 1679, 1516, 1369, 1241,
1048; HRMS (ES TOF, m/z) calcd for C22H18N2NaO+ ([M + Na]+):
349.1311, found 349.1307 (1.2 ppm).
5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5-hydroxy-3-phenyl-
1,5-dihydro-2H-pyrrol-2-one (8o)
Product 8o was obtained via the method described for
compound 8a, employing 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)-4-oxo-2-phenylbutanenitrile (293 mg, 1.00 mmol), and puri-
ed by column chromatography (gradient/EtOAc : PE 1 : 3–
1 : 1) or recrystallization from ethanol. Reaction time: 1 h.
White solid, mp 161.8–164.6 ꢀC (EtOH); yield 0.189
g
(0.61 mmol, 61%). Rf ¼ 0.58, EtOAc/hexane (1 : 1, v/v). 1H NMR
(400 MHz, DMSO-d6) d 9.04 (s, 1H), 7.93 (d, J ¼ 7.2 Hz, 2H), 7.43–
7.30 (m, 4H), 6.99 (d, J ¼ 2.1 Hz, 1H), 6.94 (dd, J ¼ 8.4, 2.2 Hz,
1H), 6.84 (d, J ¼ 8.4 Hz, 1H), 6.53 (s, 1H), 4.22 (s, 4H). 13C NMR
(101 MHz, DMSO-d6) d 170.8, 145.8, 143.1, 143.0, 133.9, 131.5,
131.2, 128.5, 128.3 (2C), 127.2 (2C), 118.6, 116.8, 114.7, 85.7,
64.1, 64.1. FTIR (ZnSe) n (cmꢁ1): 3248, 1667, 1498, 1431, 1313,
5-(4-Aminophenyl)-3-(4-bromophenyl)-5-phenyl-1,5-dihydro-
2H-pyrrol-2-one (15k)
Product 15k was obtained via the method described for
compound 15a, employing 3-(4-bromophenyl)-5-hydroxy-5-
phenyl-1,5-dihydro-2H-pyrrol-2-one (329 mg, 1.00 mmol) and
aniline (186 mg, 2.00 mmol). Additional purication can be
achieved by recrystallization from ethanol. Colorless solid, mp
1277, 1253, 1060, 1000; HRMS (ES TOF, m/z) calcd for
+
18H15NNaO4 ([M + Na]+): 332.0893, found 332.0895 (ꢁ0.4
ꢀ
C
ppm).
247.0–249.5 C (ethanol); yield 271 mg (0.67 mmol, 67%). Rf ¼
0.36, EtOAc/hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6)
d 9.65 (d, J ¼ 1.9 Hz, 1H), 8.29 (d, J ¼ 1.9 Hz, 1H), 8.10–7.86 (m,
2H), 7.66–7.53 (m, 2H), 7.42–7.21 (m, 5H), 7.04–6.93 (m, 2H),
6.59–6.41 (m, 2H), 5.10 (s, 2H). 13C NMR (101 MHz, DMSO-d6)
d 170.4, 148.5, 148.0, 142.8, 131.3 (2C), 130.8, 130.3, 129.0 (2C),
128.7, 128.3 (2C), 127.5 (2C), 127.2, 126.7 (2C), 121.7, 113.6 (2C),
68.2. FTIR (ZnSe) n (cmꢁ1): 3431, 3349, 1679, 1619, 1513, 1489,
1294, 1178, 1074; HRMS (ES TOF, m/z) calcd for C22H17BrN2-
NaO+ ([M + Na]+): 427.0416, found 427.0407 (2.3 ppm).
5-Hydroxy-3,5-bis(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-
one (8p)
Product 8p was obtained via the method described for
compound 8a, employing 2,4-bis(4-methoxyphenyl)-4-oxobuta-
nenitrile35 (295 mg, 1.00 mmol), and puried by column chro-
matography (gradient: EtOAc/PE 1 : 2–2 : 1) or recrystallization
from ethanol. Reaction time: 40 min. Yellow solid, mp 141.2–
143.1 ꢀC (EtOH); yield 199 mg (0.64 mmol, 64%). Rf ¼ 0.50,
1
EtOAc/hexane (1 : 1, v/v). H NMR (400 MHz, DMSO-d6) d 9.00 5-(4-Aminophenyl)-5-(4-methoxyphenyl)-3-phenyl-1,5-dihydro-
(d, J ¼ 1.8 Hz, 1H), 7.98–7.90 (m, 2H), 7.47–7.38 (m, 2H), 7.24 (d, 2H-pyrrol-2-one (15l)
J ¼ 1.7 Hz, 1H), 7.01–6.86 (m, 4H), 6.46 (s, 1H), 3.77 (s, 3H), 3.74
Product 15l was obtained via the method described for compound
(s, 3H). 13C NMR (101 MHz, DMSO-d6) d 171.1, 159.4, 158.9,
15a, employing 5-hydroxy-5-(4-methoxyphenyl)-3-phenyl-1,5-dihy-
dro-2H-pyrrol-2-one (281 mg, 1.00 mmol) and aniline (186 mg, 2.00
143.7, 133.0, 130.8, 128.5 (2C), 127.0 (2C), 123.7, 113.7 (2C),
113.5 (2C), 85.8, 55.1, 55.1. FTIR (ZnSe) n (cmꢁ1): 3335, 3244,
mmol). Additional purication can be achieved by recrystallization
1704, 1602, 1506, 1417, 1304, 1251, 1183, 1067; HRMS (ES TOF,
from ethanol. Colorless solid, mp 256.3–258.6 ꢀC; yield 1.015 g
+
m/z) calcd for C18H17NNaO4 ([M + Na]+): 334.1050, found
1
(3.44 mmol, 86%). Rf ¼ 0.25, EtOAc/hexane (1 : 2, v/v). H NMR
334.1048 (0.4 ppm).
(400 MHz, DMSO-d6) d 9.50 (d, J ¼ 2.0 Hz, 1H), 8.14 (d, J ¼ 1.9 Hz,
1H), 8.03–7.95 (m, 2H), 7.43–7.23 (m, 5H), 6.97 (d, J ¼ 8.2 Hz, 2H),
6.89 (d, J ¼ 8.7 Hz, 2H), 6.50 (d, J ¼ 8.2 Hz, 2H), 5.07 (s, 2H), 3.73 (s,
3H). 13C NMR (101 MHz, DMSO-d6) d 170.6, 158.2, 148.1, 147.8,
5-(4-Aminophenyl)-3,5-diphenyl-1,5-dihydro-2H-pyrrol-2-one
(15a)
5-Hydroxy-3,5-diphenyl-1,5-dihydro-2H-pyrrol-2-one (251 mg, 134.8, 131.7, 131.1, 129.1, 128.3 (2C), 128.2, 127.9 (2C), 127.4 (2C),
1.00 mmol) and aniline (186 mg, 2.00 mmol) were placed in 126.9 (2C), 113.6 (2C), 113.5 (2C), 67.5, 55.1. FTIR (ZnSe) n (cmꢁ1):
a glass vial G10 Anton PAAR, equipped with a magnetic stirring 3370, 1773, 1674, 1592, 1513, 1445, 1356, 1248, 1211; HRMS (ES
bar heated in a boiling water bath for 1 min to homogenize the TOF, m/z) calcd for C23H21N2O2 ([M + H]+): 357.1598, found
+
reaction mass. Then the vial was placed in an Anton PAAR 357.1588 (2.8 ppm).
© 2021 The Author(s). Published by the Royal Society of Chemistry
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Paper
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5-(4-Aminophenyl)-5-(4-chlorophenyl)-3-phenyl-1,5-dihydro-
2H-pyrrol-2-one (15m)
Product 15m was obtained via the method described for
compound 15a, employing 5-(4-chlorophenyl)-5-hydroxy-3-
phenyl-1,5-dihydro-2H-pyrrol-2-one (285 mg, 1.00 mmol) and
aniline (186 mg, 2.00 mmol). Colorless solid, mp 209.0–
211.9 ꢀC; yield 166 mg (0.46 mmol, 46%). Rf ¼ 0.36, EtOAc/
hexane (1 : 1, v/v). 1H NMR (400 MHz, DMSO-d6) d 9.61 (s,
1H), 8.19 (d, J ¼ 1.8 Hz, 1H), 8.07–7.95 (m, 2H), 7.48–7.21 (m,
7H), 6.99 (d, J ¼ 8.4 Hz, 2H), 6.52 (d, J ¼ 8.4 Hz, 2H), 5.13 (s, 2H).
13C NMR (101 MHz, DMSO-d6) d 170.6, 148.1, 147.4, 142.0,
131.8, 131.7, 131.5, 128.6 (2C), 128.4, 128.4, 128.3 (2C), 128.3
(2C), 127.4 (2C), 127.0 (2C), 113.6 (2C), 67.6. FTIR (ZnSe) n
(cmꢁ1): 3161, 2997, 1766, 1681, 1513, 1489, 1241, 1091; HRMS
(ES TOF, m/z) calcd for C22H17ClN2NaO+ ([M + Na]+): 383.0922,
found 383.0911 (2.8 ppm).
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2012, 60, 1682–1687.
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and K. H. Xue, Heterocycles, 2020, 100, 568–584.
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H.-x. Kuang, Zhongcaoyao, 2013, 44, 1877–1880.
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L. Chen and Q.-Q. Zhang, Heterocycles, 2014, 89, 189–196.
14 B. Almohaywi, T. T. Yu, G. Iskander, D. S. H. Chan,
K. K. K. Ho, S. Rice, D. S. Black, R. Griffith and N. Kumar,
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5-(4-Hydroxyphenyl)-3,5-diphenyl-1,5-dihydro-2H-pyrrol-2-one
(16a)
15 S.
Mykhaylychenko,
D.
Harakat,
G.
Dupas,
Product 16a was obtained via the method described for
compound 15a, employing 5-hydroxy-3,5-diphenyl-1,5-dihydro-
2H-pyrrol-2-one (251 mg, 1.00 mmol) and phenol (188 mg, 1.00
mmol). White solid, mp 138.1–140.6 ꢀC; yield 206 mg
(0.63 mmol, 63%). Rf ¼ 0.64, EtOAc/hexane (1 : 2, v/v). 1H NMR
(400 MHz, DMSO-d6) d 9.69 (d, J ¼ 1.7 Hz, 1H), 9.49 (s, 1H), 8.26
(d, J ¼ 1.9 Hz, 1H), 8.07–7.89 (m, 2H), 7.47–7.23 (m, 8H), 7.21–
7.12 (m, 2H), 6.78–6.69 (m, 2H). 13C NMR (101 MHz, DMSO-d6)
d 170.6, 156.6, 147.6, 142.6, 132.5, 131.8, 131.5, 128.4 (3C), 128.3
(2C), 128.0 (2C), 127.2, 127.0 (2C), 126.7 (2C), 115.1 (2C), 67.9.
FTIR (ZnSe) n (cmꢁ1): 3344, 3176, 1679, 1513, 1492, 1359, 1241,
1173, 1096; HRMS (ES TOF, m/z) calcd for C22H17NNaO2+ ([M +
Na]+): 350.1151, found 350.1139 (3.5 ppm).
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Conflicts of interest
22 W. Birru, R. T. Fernley, L. D. Graham, J. Grusovin, R. J. Hill,
A. Hofmann, L. Howell, P. J. James, K. E. Jarvis,
W. M. Johnson, D. A. Jones, C. Leitner, A. J. Liepa,
G. O. Lovrecz, L. Lu, R. H. Nearn, B. J. O'Driscoll, T. Phan,
M. Pollard, K. A. Turner and D. A. Winkler, Bioorg. Med.
Chem., 2010, 18, 5647–5660.
There are no conicts to declare.
Acknowledgements
This work was supported by the Russian Science Foundation
(grant #19-73-00091).
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