Unexpected cyclization ofortho-nitrochalcones into 2-alkylideneindolin-3-ones

Article abstract of DOI:10.1039/d0ra03520c

An original, facile, and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles fromortho-nitrochalcones is described. The featured transformation is a triggered Michael addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related to the Baeyer-Drewson reaction.

Full text of DOI:10.1039/d0ra03520c

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Unexpected cyclization of ortho-nitrochalcones
into 2-alkylideneindolin-3-ones†
Cite this: RSC Adv., 2020, 10, 18440
a
a
*
Nicolai A. Aksenov,
Dmitrii A. Aksenov,
Nikolai A. Arutiunov,a
Daria S. Aksenova,a Alexander V. Aksenov
and Michael Rubin
a
ab
*
Received 20th April 2020
Accepted 8th May 2020
An original, facile, and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)
acetonitriles from ortho-nitrochalcones is described. The featured transformation is a triggered Michael
addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related
to the Baeyer–Drewson reaction.
DOI: 10.1039/d0ra03520c
rsc.li/rsc-advances
1),29–32 and cascade reactions of anilines with a-ketoesters
involving an electrophilic aromatic substitution step (path C,
Scheme 1)10,33 Herein we wish to report on our recent seren-
dipitous discovery of the unexpected one-pot cascade trans-
formation of ortho-nitrochalcones 1 via a Baeyer–Drewson-like
pathway, but affording 2-alkylideneindolin-3-ones 2 rather
than indigo-like dimers (Scheme 1).
Introduction
It would be hard to overstate the importance of 2-
alkylideneindolin-3-one derivatives in modern medicinal
chemistry. The bis-indole indirubin, a main component of
“Tyrian purple” dye, is also a known active component of
a traditional Chinese herbal medicine, while its numerous
synthetic derivatives show potent and highly selective pharma-
cological inhibition of glycogen synthase kinases and cycline-
dependent kinases.1–6 These molecules induce apoptosis of
human cancer cells and have promising potential for applica-
tions in the treatment of several neurodegenerative conditions,
such as Alzheimer's disease.1–6 Indirubin, as well as other
related dyes, can be easily prepared via base-assisted conden-
sation of ortho-nitrobenzaldehydes with acetone according to
the classical Baeyer–Drewson reaction.7–9 2-Alkylideneindolin-3-
one derivatives possessing a single indoline subunit (or two
remotely positioned subunits) also occur in nature and also
exhibit a wide spectrum of important biological properties
(Fig. 1).10–17 Normally, preparation of such compounds relies
heavily on the chemistry of isatins, which makes synthetic
approaches to certain substitution patterns hardly accessible.
An alternative synthetic platform for assembling indoline
alkaloids and related non-natural, biologically active target
molecules has also emerged, relying on the chemistry of 2-
alkylidene-3-oxindoles.18–23 Various synthetic approaches to
these synthons have been developed based on the aldol
condensation of 3H-indol-3-ones with carbonyl compounds
(path A, Scheme 1),24–28 transition metal-catalyzed carbonylative
coupling of ortho-iodoanilines to acetylenes (path B, Scheme
Results and discussion
In the frame of our ongoing project dealing with the synthesis of
nitrogen-based heterocyclic compounds and evaluation of their
biological activity, we were interested in the preparation of
a series of minaprine analogs 4,34–37 possessing an additional
amino-group handle at C-20.38,39 To tackle this task, we decided
to employ a routine cyclocondensation of hydrazine with 3-
cyanoketone 3 bearing an ortho-nitro group, which was
supposed to be routinely reduced and properly modied in
subsequent steps (Scheme 2). We planned to access precursor 3
via conjugate addition of hydrogen cyanide to a,b-unsaturated
aDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation
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: Spectral data. CCDC
1992506. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0ra03520c
Fig. 1 Biologically active 2-alkylideneindolin-3-ones.
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with benzaldehyde (7a) – was treated with KCN in EtOH in the
presence of acetic acid (1.3 equiv.) at room temperature.
Unexpectedly, this reaction provided only marginal yields,
which was initially attributed to poor solubility of 1aa in
ethanol. To address this situation, we tried to perform this
reaction in methanol at elevated temperature, which also failed
(Table 1, entry 1). In one of the trial experiments, a mixture of
chalcone 1aa and KCN was pre-heated in MeOH to reux prior
to addition of the acetic acid. To our great surprise, within
15 min the reaction mixture turned emerald green. The starting
material (m/z 276, M + Na) disappeared, but the expected
product 3aa (m/z 303, M + Na) did not form, while cyclic
hydroxylamine product 5aa was detected in MS (m/z 285, M +
Na) and NMR spectra of the crude reaction mixture instead. The
following treatment with acetic acid in boiling methanol led to
the conversion of 5aa into indoline 2aa (m/z 269, M + Na), which
was isolated in 57% yield (entry 2) as a yellowish-orange crys-
talline solid with properties identical to those reported in the
literature.44 Next, we attempted to increase the loading of KCN,
which had a signicant positive effect – although not dramatic
(entry 3). Nearly the same efficiency was achieved in a test in
which the second stage of the reaction was carried out at room
temperature for 12 h (entry 4). The best results were obtained in
the experiment involving the initial treatment of chalcone 1aa
with KCN in methanol in the presence of water (entry 5), which
improves the solubility of cyanide. It is important to mention,
that ideal homogenization of the reaction mixture seems to be
crucial for achieving good yields of 2aa. Indeed, KCN reagent
did not dissolve in the mixtures when the test reactions were
carried out in THF or acetone even in the presence of additional
water. In these cases, product 2aa did not form at all (Table 1,
entries 6–9). The reaction in polar aprotic solvents, such as
DMSO and DMF, was also tested. It was found that the outcome
of these reactions also improves in the presence of water, but
the overall performance in these solvents remains relatively
poor (entries 10–13).
Scheme 1 Synthetic approaches to 2-alkylideneindolin-3-ones.
With optimized conditions in hand we decided to evaluate
the scope of the reaction of various chalcones and with respect
to the nature of substituent R1 (originated from an aldehyde
precursor). To this end, a series of chalcones 1 were prepared
from o-nitroacetophenones 6 and aldehydes 7. These chalcones
were subjected to the reaction with KCN under the optimized
reaction conditions. The results are presented in Scheme 3. The
preparative reaction of chalcone 1aa proceeded uneventfully
affording product 1aa in 76% isolated yield (entry 1). Reactions
of chalcones 1ab–1ae, derived from benzaldehydes 7b–e bearing
alkyl substituents also proceeded smoothly to yield the corre-
sponding indolines 2ab–2ae in good yields (Scheme 3, entries
2–5). Next, the tolerance to substitution with halogenes was
tested. We were pleased to nd that the corresponding products
2af–2aj formed in good to high yields (entries 6–10). The reac-
tivity of chalcones 1ak and 2ak derived from electron-rich
benzaldehydes 7k,l was also examined (entries 11 and 12).
These materials also reacted smoothly, although isolation of
product 2al bearing NMe2 substituent proved to be more chal-
lenging due to the partial decomposition, which reduced the
overall efficiency of the process (entry 12). The same problem
Scheme 2 Unexpected assembly of 2-benzylideneindolin-3-one 2a.
ketones 1.40–43 Although hydrocyanation of conjugate carbonyl
compounds is unknown for specic substrates of type 1, pos-
sessing ortho-nitro functionality, we did not initially expect any
problems with this well-established chemistry.
To evaluate the planned synthetic route, chalcone 1aa –
prepared by aldol condensation of ortho-nitroacetophenone (6a)
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Table 1 Optimization of the reaction condition towards formation of
product 2aa
indole N-oxide 11, which should quickly transform into the
thermodynamically more stable 1-hydroxy-2-methyleneindolin-3-
one form 5. It should be pointed out, that this intermediate was
detected in MS and 1H NMR spectra of the crude reaction mixture
involving chalcone 1aa (R ¼ Ph). Evidently, the formation of this
structure is responsible for the intense color of the reaction
mixtures. Finally, upon acidication with acetic acid, emerald-
green 5 is reduced into orange-red product 2. Although the
precise mechanism of this reduction was not elucidated, we
believe it could involve the methanol used as a solvent. Since the
product 2 is an enamine, it should exist in tautomeric equilib-
rium between E and Z forms. Only E-tautomers were observed,
suggesting that they are thermodynamically much more favored.
This stereochemical outcome could be easily rationalized taking
into account greater steric hindrance provided by aryl substituent
as compared to nitrile functional group.
In order to avoid utilization of highly toxic KCN reagent,
other cyanide ion sources were also tested, such as Me3SiCN
and K4[Fe(CN)6]. In both cases, however, formation of the (E)-2-
(3-oxoindolin-2-ylidene)-2-arylacetonitrile products was not
detected. Evidently, the reaction requires a high concentration
of nucleophile, which cannot be achieved in the presence of
reagents, slowly releasing free cyanide.
Solvent,
1.5 mL
H2O,
mg
#
KCN, mg
Yield of 2aaa, %
1
2
3
4
5
6
7
8
65
40
65
40
40
40
40
40
40
40
40
40
40
MeOH
MeOH
MeOH
MeOH
MeOH
THF
0
0
0
0
200
0
200
0
200
0
200
0
0b
57
65
62c
78
0d
0d
0d
0d
24
50
0d
44
THF
Acetone
Acetone
DMSO
DMSO
DMF
9
10
11
12
13
DMF
200
a
NMR yields are reported. b All reagents were mixed in one pot and the
c
reaction was carried out at reux for 1 h. The second stage of the
reaction was carried out at RT for 12 h. KCN is insoluble in this
d
reaction mixture.
Conclusion
In conclusion, an unusual cascade cyclization triggered by the
conjugate addition of the cyanide anion to ortho-nitro-
substituted chalcones was unexpectedly discovered. This novel
transformation involves an intramolecular 5-exo-trig attack of
an enolate on the electrophilic nitro-group, which is mecha-
nistically related to the Baeyer–Drewson reaction. A series of (E)-
2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles was efficiently,
obtained in good to excellent yield.
was encountered in the attempt to employ pyridine carbox-
aldehyde derivatives 1am–1ao. The corresponding indolines
2am–2ao formed smoothly, but were isolated in moderate yields
(entries 13–15). Reaction of piperonal derivative 1ap was
accompanied by a notable decomposition of the target product
2ap, which was isolated in quite marginal yield (entry 16). Such
decomposition became much greater issue in the experiments
involving chalcones 1aq and 1ar, derived from thiophene-2- Experimental part
carbaldehyde and hydrocinnamic aldehyde, respectively. The
1
General information. H and 13C NMR spectra were recorded
corresponding products 2aq and 2ar were not isolated (entries
17 and 18). Finally, the reaction of chalcone 1ba, derived from 1-
(4,5-dimethoxy-2-nitrophenyl)ethan-1-one (6b) and benzalde-
hyde (7a), was also tested. The corresponding product 2ba was
isolated in 51% yield (Scheme 3, entry 19), thus conrming the
possibility for the installation of additional substituents onto
the aromatic ring of the indoline. Formation of the (E)-2-(3-
oxoindolin-2-ylidene)-2-arylacetonitrile moiety was unambigu-
ously conrmed by single crystal X-ray diffraction of compound
2ad (CCDC #1992506, Fig. 2).
The putative mechanistic rationale proposed for the featured
transformation is shown in Scheme 4. It is assumed that the
reaction begins with the Michael-type addition of the CN-anion
across the conjugate C]C bond of chalcone 1 to afford enolate
8. This enolate triggers a 5-exo-trig cyclization involving the ortho-
nitro group in the substrate molecule. Mechanistically related to
the Baeyer–Drewson reaction, this step affords cyclic nitronate 9,
which should exist in equilibrium with tautomeric cyclic enolate
form 10. Subsequent elimination of water would afford 3-oxo-3H-
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 registered with a Bruker Maxis spectrometer
(electrospray ionization, in MeCN solution, using HCO2Na–
HCO2H for calibration). Melting points were measured with
a Stuart smp30 apparatus. Unless specied otherwise, all
reactions were performed in 5 mL round-bottomed asks
equipped with reux condensers. The reaction progress and
purity of isolated compounds were controlled by TLC on
Silufol UV-254 plates, with hexanes/EtOAc mixtures used as
eluents. 1-(4,5-Dimethoxy-2-nitrophenyl)ethan-1-one was
prepared according to the known procedure45 and had phys-
ical and spectral properties identical to those reported in
literature. (E)-1-(2-Nitrophenyl)-5-phenylpent-2-en-1-one was
obtained according to the known procedure and was identical
to the material described in literature.46 All other reagents and
solvents were purchased from commercial vendors and used
as received.
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Scheme 3 Preparation of (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles via featured cyanide-induced cyclization of chalcones.
nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.214 g
(4.80 mmol, 96%), colorless solid, mp 124.1–126.0 ꢀC, lit.47
Preparation of chalcones
(E)-1-(2-Nitrophenyl)-3-phenylprop-2-en-1-one (1aa). This
compound was prepared according to the known procedure46
employing benzaldehyde (1a) (825 mg, 5.00 mmol) and 1-(2-
1
130 ꢀC, Rf 0.40 (EtOAc/Hex, 1 : 4). H NMR (400 MHz, CDCl3)
d 8.19 (d, J ¼ 8.1 Hz, 1H), 7.77 (t, J ¼ 7.3 Hz, 1H), 7.66 (t, J ¼
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d 193.9, 147.0, 143.8, 138.2, 136.5, 134.1, 133.0, 131.0, 130.9,
130.8, 129.0, 127.1, 126.8, 126.6, 124.6, 19.7; FTIR (KBr, cmꢁ1):
2931, 2363, 1673, 1561, 1525, 1363, 1327, 1218, 1030; HRMS (ES
TOF) calc'd for C16H13NNaO3 (M + Na)+ 290.0788, found
290.0783 (1.6 ppm).
(E)-1-(2-Nitrophenyl)-3-(p-tolyl)prop-2-en-1-one (1ac). This
compound was prepared according to the known procedure46
employing 4-methylbenzaldehyde (7c) (600 mg, 5.00 mmol) and
1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield
1.295 g (4.85 mmol, 97%), colorless solid, mp 130.8–131.6 ꢀC
(EtOH), lit.47 mp 134–135 ꢀC, Rf 0.28 (EtOAc/Hex, 1 : 4); 1H NMR
(400 MHz, CDCl3) d 8.17 (d, J ¼ 8.2 Hz, 1H), 7.76 (t, J ¼ 7.4 Hz,
1H), 7.65 (t, J ¼ 7.8 Hz, 1H), 7.50 (d, J ¼ 7.4 Hz, 1H), 7.39 (d, J ¼
7.9 Hz, 2H), 7.24–7.16 (m, 3H), 6.97 (d, J ¼ 16.2 Hz, 1H), 2.37 (s,
3H); 13C NMR (101 MHz, CDCl3) d 193.2, 146.9, 146.7, 141.9,
136.6, 134.1, 131.3, 130.6, 129.9 (2C), 129.0, 128.7 (2C), 125.5,
124.7, 21.7; FTIR (KBr, cmꢁ1): 3067, 1668, 1591, 1524, 1364,
1320, 1230, 1210, 1029; HRMS (ES TOF) calc'd for
Fig. 2 ORTEP drawing of crystal structure of compound 2ad (CCDC
#1992506) showing 50% probability thermal ellipsoids and atom
numbering scheme.
C
16H13N1NaO3 (M + Na)+ 290.0788, found 290.0790 (0.8 ppm).
3-(2-Fluorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1af).
This compound was prepared according to the known proce-
dure46 employing 2-uorobenzaldehyde (7f) (620 mg, 5.00
mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00
mmol). Yield 1.246 g (4.60 mmol, 92%), colorless crystals, mp
97.3–97.9 ꢀC, Rf 0.46 (EtOAc/Hex, 1 : 4); 1H NMR (400 MHz,
CDCl3) d 8.17 (d, J ¼ 8.1 Hz, 1H), 7.77 (dd, J ¼ 7.4, 6.8 Hz, 1H),
7.72–7.62 (m, 1H), 7.59–7.47 (m, 2H), 7.41–7.33 (m, 2H), 7.16 (t, J
¼ 7.5 Hz, 1H), 7.13–7.00 (m, 2H); 13C NMR (101 MHz, CDCl3)
d 193.0, 161.5 (d, J ¼ 254.6 Hz), 146.8, 138.5 (d, J ¼ 3.3 Hz),
136.2, 134.2, 132.7 (d, J ¼ 8.9 Hz), 130.8, 129.1 (d, J ¼ 2.5 Hz),
128.9, 128.3 (d, J ¼ 5.9 Hz), 124.72 (d, J ¼ 3.8 Hz), 124.68, 122.2
(d, J ¼ 11.5 Hz), 116.3 (d, J ¼ 21.7 Hz); FTIR (KBr, cmꢁ1): 3289,
3065, 1651, 1603, 1531, 1340, 1290, 1215; HRMS (ES TOF) calc'd
for C15H10FNNaO3 (M + Na)+ 294.0537, found 294.0538 (0.4
ppm).
3-(4-Fluorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1ag).
This compound was prepared according to the known proce-
dure46 employing 4-uorobenzaldehyde (7g) (620 mg, 5.00
mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00
mmol). Yield 1.233 g (4.55 mmol, 91%), colorless solid, mp
99.1–100.5 ꢀC, Rf 0.46 (EtOAc/Hex, 1 : 4); 1H NMR (400 MHz,
CDCl3) d 8.18 (d, J ¼ 8.2 Hz, 1H), 7.82–7.72 (m, 1H), 7.70–7.60
(m, 1H), 7.55–7.44 (m, 3H), 7.21 (d, J ¼ 16.3 Hz, 1H), 7.07 (t, J ¼
8.6 Hz, 2H), 6.92 (d, J ¼ 16.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)
d 192.8, 164.4 (d, J ¼ 252.8 Hz), 146.8, 145.0, 136.4, 134.2, 130.8,
130.7 (d, J ¼ 8.7 Hz, 2C), 130.3 (d, J ¼ 3.2 Hz), 128.9, 126.1 (d, J ¼
2.2 Hz), 124.7, 116.3 (d, J ¼ 22.0 Hz, 2C); FTIR (KBr, cmꢁ1): 3302,
3052, 1651, 1522, 1353, 1286, 1232, 1112; HRMS (ES TOF) calc'd
for C15H10FNNaO3 (M + Na)+ 294.0537, found 294.0538 (0.4
ppm).
Scheme 4 Proposed mechanistic rationale.
7.4 Hz, 1H), 7.50 (dd, J ¼ 7.7, 4.2 Hz, 3H), 7.39 (d, J ¼ 6.5 Hz,
3H), 7.24 (d, J ¼ 15.9 Hz, 1H), 7.01 (d, J ¼ 16.3 Hz, 1H); 13C NMR
(101 MHz, CDCl3) d 193.2, 146.9, 146.5, 136.5, 134.2, 134.1,
131.2, 130.7, 129.2 (2C), 129.0, 128.7 (2C), 126.4, 124.7; FTIR
(KBr, cmꢁ1): 3741, 3298, 3092, 1647, 1531, 1340, 1277, 1107;
HRMS (ES TOF) calc'd for C15H11NNaO3 (M + Na)+ 276.0631,
found 276.0634 (1.0 ppm).
(E)-1-(2-Nitrophenyl)-3-(o-tolyl)prop-2-en-1-one (1ab). This
compound was prepared according to the known procedure46
employing 2-methylbenzaldehyde (7b) (600 mg, 5.00 mmol) and
1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield
1.255 g (4.70 mmol, 94%), light yellow crystals, mp 95.0–96.2 ꢀC.
Rf 0.53 (EtOAc/Hex, 1 : 2); 1H NMR (400 MHz, CDCl3) d 8.17 (d, J
¼ 7.7 Hz, 1H), 7.82–7.72 (m, 1H), 7.71–7.63 (m, 1H), 7.61–7.56
(m, 2H), 7.54 (dd, J ¼ 7.5, 1.0 Hz, 1H), 7.33–7.14 (m, 3H), 6.91 (d,
J ¼ 16.1 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3)
(E)-3-(3-Chlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one
(1ah). This compound was prepared according to the known
procedure46 employing 3-chlorobenzaldehyde (7h) (700 mg, 5.00
mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00
mmol). Yield 1.291 g (4.50 mmol, 90%), light-yellow solid, mp
ꢀ
122.0–124.1 C (EtOH), Rf 0.27 (EtOAc/Hex, 1 : 4), 0.52 (EtOAc/
Hex, 1 : 2); 1H NMR (400 MHz, CDCl3) d 8.18 (d, J ¼ 8.0 Hz,
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1H), 7.82–7.73 (m, 1H), 7.71–7.62 (m, 1H), 7.50 (dd, J ¼ 7.5, 7.1 Hz, 1H), 7.63–7.54 (m, 1H), 7.53–7.43 (m, 1H), 7.36 (d, J ¼
1.0 Hz, 1H), 7.46 (s, 1H), 7.34 (tt, J ¼ 15.2, 7.4 Hz, 3H), 7.18 (d, J 8.8 Hz, 2H), 7.19 (d, J ¼ 16.0 Hz, 1H), 6.80 (d, J ¼ 16.0 Hz, 1H),
¼ 16.3 Hz, 1H), 6.98 (d, J ¼ 16.3 Hz, 1H); 13C NMR (101 MHz, 6.61 (d, J ¼ 8.8 Hz, 2H), 3.00 (s, 6H); 13C NMR (101 MHz, CDCl3)
CDCl3) d 192.7, 146.8, 144.4, 136.2, 135.9, 135.1, 134.3, 130.93, d 192.9, 152.4, 148.0, 146.9, 137.0, 133.8, 130.7, 130.2, 129.0,
130.89, 130.4, 128.9, 128.4, 127.5, 126.7, 124.7; FTIR 124.5, 121.5, 120.8, 111.8 (2C), 40.1 (2C); FTIR (KBr, cmꢁ1):
(KBr, cmꢁ1): 3050, 1647, 1514, 1340, 1284, 1254, 1205, 1099; 3096, 3029, 2900, 2820, 1598, 1522, 1433, 1348, 1299, 1237,
HRMS (ES TOF) calc'd for C15H10Cl1N1Na1O3 (M + Na)+ 1179, 1112; HRMS (ES TOF) calc'd for C17H16N2NaO3 (M + Na)+
310.0241, found 310.0246 (ꢁ1.5 ppm).
319.1053, found 319.1053 (0.1 ppm).
(E)-3-(4-Chlorophenyl)-1-(2-nitrophenyl)prop-2-en-1-one
(E)-1-(4,5-Dimethoxy-2-nitrophenyl)-3-phenylprop-2-en-1-
(1ai). This compound was prepared according to the known one (1ba). This compound was prepared according to the
procedure46 employing 4-chlorobenzaldehyde (7i) (700 mg, 5.00 known procedure52 employing benzaldehyde (1a) (825 mg, 5.00
mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol)
and
1-(4,5-dimethoxy-2-nitrophenyl)ethan-1-one45
mmol). Yield 1.409 g (4.90 mmol, 98%), white solid, mp 120.4– (1.126 g, 5.00 mmol). The titled compound was obtained as
121.4 ꢀC, lit.48 mp 123–124 ꢀC. Rf 0.35 (EtOAc/Hex, 1 : 4); 1H colorless solid, mp 113.4–116.3 ꢀC (benzene), lit.52 mp 159–
NMR (400 MHz, CDCl3) d 8.28–8.14 (m, 1H), 7.77 (t, J ¼ 7.1 Hz, 160 ꢀC (EtOH), Rf 0.28 (EtOAc/Hex, 1 : 2). Yield 1.330 g
1H), 7.70–7.63 (m, 1H), 7.50 (dd, J ¼ 7.6, 1.5 Hz, 1H), 7.43 (d, J ¼ (4.25 mmol, 85%). 1H NMR (400 MHz, CDCl3) d 7.69 (s, 1H),
8.6 Hz, 2H), 7.36 (d, J ¼ 8.5 Hz, 2H), 7.20 (d, J ¼ 16.3 Hz, 1H), 7.52–7.44 (m, 2H), 7.42–7.32 (m, 3H), 7.20 (d, J ¼ 16.2 Hz, 1H),
6.96 (d, J ¼ 16.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) d 192.7, 6.95 (d, J ¼ 16.2 Hz, 1H), 6.85 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H);
146.8, 144.7, 137.1, 136.3, 134.3, 132.6, 130.8, 129.8 (2C), 129.4 13C NMR (101 MHz, CDCl3) d 193.1, 153.9, 149.7, 145.4, 139.4,
(2C), 128.9, 126.7, 124.7; FTIR (KBr, cmꢁ1): 3258, 3056, 2868, 134.1, 131.0, 130.8, 129.1 (2C), 128.6 (2C), 126.7, 110.0, 107.1,
1906, 1638, 1527, 1343; HRMS (ES TOF) calc'd for C15H10
ClNNaO3 (M + Na)+ 310.0241, found 310.0246 (1.5 ppm).
(E)-3-(4-Bromophenyl)-1-(2-nitrophenyl)prop-2-en-1-one
-
56.8, 56.7; FTIR (KBr, cmꢁ1): 3036, 2977, 1650, 1571, 1514, 1445,
1337, 1287, 1217, 1122; HRMS (ES TOF) calc'd for C17H15NNaO5
(M + Na)+ 336.0842, found 336.0849 (1.9 ppm).
(1aj). This compound was prepared according to the known
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(2-nitrophenyl)prop-2-en-1-
procedure46 employing 4-bromobenzaldehyde (7j) (920 mg, 5.00 one (1ap). This compound was prepared according to known
mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 procedure,53 employing piperonal (7p) (1.50 g, 10.00 mmol) and
mmol). Yield 1.572 g (4.75 mmol, 95%), colorless solid, mp 20-nitroacetophenone (6a) (1.65 g, 10.00 mmol). The title
130.4–132.1 ꢀC (EtOH), lit.49 mp 145–147 ꢀC, Rf 0.25 (EtOAc/ compound was obtained as colorless solid, mp 129.2–130.9 ꢀC,
hexanes 1 : 4); 1H NMR (400 MHz, DMSO) d 8.21 (d, J ¼ lit.53 mp 126–128 ꢀC, Rf 0.55 (EtOAc/Hex, 1 : 2). Yield 2.525 g
8.0 Hz, 1H), 7.91 (t, J ¼ 7.3 Hz, 1H), 7.81 (t, J ¼ 7.4 Hz, 1H), 7.76– (8.5 mmol, 85%). 1H NMR (400 MHz, CDCl3) d 8.16 (d, J ¼
7.68 (m, 3H), 7.62 (d, J ¼ 8.3 Hz, 2H), 7.44–7.27 (m, 2H); 13C 8.1 Hz, 1H), 7.75 (t, J ¼ 7.1 Hz, 1H), 7.69–7.61 (m, 1H), 7.49 (dd, J
NMR (101 MHz, DMSO) d 192.2, 146.7, 144.6, 135.3, 134.5, ¼ 7.5, 0.9 Hz, 1H), 7.16 (d, J ¼ 16.1 Hz, 1H), 7.03 (d, J ¼ 1.2 Hz,
133.3, 132.0 (2C), 131.5, 130.8 (2C), 129.1, 126.4, 124.6, 124.6; 1H), 6.95 (dd, J ¼ 8.0, 1.2 Hz, 1H), 6.87–6.75 (m, 2H), 6.01 (s,
FTIR (KBr, cmꢁ1): 3255, 3061, 1638, 1584, 1527, 1487, 1347, 2H); 13C NMR (101 MHz, CDCl3) d 192.9, 150.5, 148.6, 146.9,
1307, 1290; HRMS (ES TOF) calc'd for C15H10BrNNaO3 (M + Na)+ 146.4, 136.6, 134.1, 130.6, 128.9, 128.5, 125.7, 124.7, 124.4,
353.9736, found 353.9739 (0.9 ppm).
108.8, 106.8, 101.9; FTIR (lm, NaCl, cmꢁ1): 3262, 3101, 3014,
(E)-3-(4-Methoxyphenyl)-1-(2-nitrophenyl)prop-2-en-1-one
2913, 1645, 1524, 1498, 1447, 1337, 1243, 1106; HRMS (ES TOF)
(1ak). This compound was prepared according to the known calc'd for C16H11NNaO5 (M + Na)+ 320.0529, found 320.0527 (0.7
procedure46 employing anisaldehyde (7k) (680 mg, 5.00 mmol) ppm).
and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol).
(E)-1-(2-Nitrophenyl)-3-(pyridin-2-yl)prop-2-en-1-one (1am).
Yield 1.316 g (4.65 mmol, 93%), white solid, mp 97.0–97.5 C, This compound was prepared via modied literature protocol48
lit.50 mp 101–103 ꢀC, Rf 0.13 (EtOAc/Hex, 1 : 4), 0.56 (EtOAc/Hex, (typical procedure A): a 15 mL Erlenmeyer ask equipped with
1 : 1). 1H NMR (400 MHz, CDCl3) d 8.17 (d, J ¼ 8.2 Hz, 1H), 7.79– magnetic stirring bar was charged with picolinaldehyde (7m)
7.71 (m, 1H), 7.69–7.60 (m, 1H), 7.50 (dd, J ¼ 7.5, 1.1 Hz, 1H), (535 mg, 5.00 mmol), 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg,
7.45 (d, J ¼ 8.7 Hz, 2H), 7.20 (d, J ¼ 16.2 Hz, 1H), 6.94–6.82 (m, 5.00 mmol) and EtOH (3 mL). The stirred reaction mixture was
3H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) d 193.1, 162.2, cooled in the ice bath, and a solution of KOH (56 mg, 1.00
146.9, 146.5, 136.7, 134.1, 130.6 (2C), 130.5, 129.0, 126.8, 124.7, mmol) in water (300 mL) was added upon stirring maintaining
124.1, 114.6 (2C), 55.6; FTIR (KBr, cmꢁ1): 3288, 2939, 1654, the reaction temperature below +10 ꢀC. Aer consumption of
1521, 1347, 1251, 1172, 1026; HRMS (ES TOF) calc'd for the starting acetophenone (TLC, EtOAc : Hex 1 : 4) the reaction
ꢀ
C
16H13NNaO4 (M + Na)+ 306.0737, found 306.0730 (2.3 ppm).
mixture was diluted with cold water (20 mL) and extracted with
3-(4-(Dimethylamino)phenyl)-1-(2-nitrophenyl)prop-2-en-1-
EtOAc (4 ꢂ 15 mL). Combined organic extracts were washed
one (1al). This compound was prepared according to the known consecutively with water (3 ꢂ 15 mL) and brine (15 mL). Aer
procedure46 employing 4-(dimethylamino)benzaldehyde (7l) concentration in vacuo the crude product was recrystallized
(745 mg, 5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) from EtOH to afford the titled compound as colorless solid, mp
(825 mg, 5.00 mmol). Yield 1.391 g (4.70 mmol, 94%), orange 101.2–103.5 C (EtOH), lit.48 mp 102–105 (isopropanol), Rf 0.40
ꢀ
solid, 101.4–102.6 ꢀC, lit.51 mp 157 ꢀC. Rf 0.27 (EtOAc/Hex, 1 : 4); (EtOAc/Hex, 1 : 1). Yield 1.143 g (0.45 mmol, 90% yield). 1H
1H NMR (400 MHz, CDCl3) d 8.11 (d, J ¼ 8.1 Hz, 1H), 7.71 (t, J ¼ NMR (400 MHz, CDCl3) d 8.62 (d, J ¼ 4.1 Hz, 1H), 8.18 (d, J ¼
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8.2 Hz, 1H), 7.81–7.69 (m, 2H), 7.69–7.61 (m, 1H), 7.55–7.46 (m, employing isonicotinaldehyde (7o) (535 mg, 5.00 mmol), 1-(2-
2H), 7.41 (d, J ¼ 16.1 Hz, 1H), 7.33–7.22 (m, 2H); 13C NMR (101 nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield
MHz, CDCl3) d 193.1, 152.7, 150.3, 146.7, 144.6, 137.0, 136.4, 1041.4 mg (4.1 mmol, 82%), colorless crystals, mp 140.0–
134.3, 130.9, 129.7, 128.9, 124.8, 124.7, 124.5; FTIR (KBr, cmꢁ1): 141.6 ꢀC (EtOH), Rf 0.22 (EtOAc/hexanes 1 : 1); 1H NMR (400
3074, 1752, 1661, 1528, 1431, 1337, 1277, 1247; HRMS (ES TOF) MHz, CDCl3) d 8.63 (d, J ¼ 5.1 Hz, 2H), 8.19 (d, J ¼ 8.1 Hz, 1H),
calc'd for C14H10N2NaO3 (M + Na)+ 277.0584, found 277.0593 7.78 (t, J ¼ 7.4 Hz, 1H), 7.68 (t, J ¼ 7.6 Hz, 1H), 7.50 (d, J ¼ 7.3 Hz,
(3.4 ppm).
3-(4-Ethylphenyl)-1-(2-nitrophenyl)prop-2-en-1-one
1H), 7.32 (d, J ¼ 5.0 Hz, 2H), 7.13 (q, J ¼ 16.3 Hz, 2H); 13C NMR
(1ad). (101 MHz, CDCl3) d 192.3, 150.8 (2C), 146.7, 142.4, 141.2, 135.9,
This compound was prepared according to the typical proce- 134.5, 131.1, 130.1, 128.8, 124.7, 122.1 (2C); FTIR (KBr, cmꢁ1):
dure A employing 4-ethylbenzaldehyde (7d) (670 mg, 5.00 3308, 3060, 1661, 1598, 1524, 1413, 1343, 1286, 1109; HRMS (ES
mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 TOF) calc'd for C14H10N2NaO3 (M + Na)+ 277.0584, found
mmol). The crude product was puried by preparative column 277.0576 (2.8 ppm).
chromatography eluting with EtOAc/Hex, 1 : 4. Yield 1.306 g
(E)-1-(2-Nitrophenyl)-3-(thiophen-2-yl)prop-2-en-1-one (1aq).
(4.65 mmol, 93%), pale brown oil, Rf 0.51 (EtOAc/Hex, 1 : 4); 1H This compound was prepared according to the typical proce-
NMR (400 MHz, CDCl3) d 8.15 (d, J ¼ 8.2 Hz, 1H), 7.75 (td, J ¼ dure A employing thiophene-2-carbaldehyde (7q) (560 mg, 5
7.5, 0.9 Hz, 1H), 7.67–7.61 (m, 1H), 7.49 (dd, J ¼ 7.5, 1.2 Hz, 1H), mmol) and 20-nitroacetophenone (6a) (825 mg, 5.00 mmol). The
7.41 (d, J ¼ 8.1 Hz, 2H), 7.26–7.17 (m, 3H), 6.97 (d, J ¼ 16.3 Hz, title compound was obtained as colorless solid, mp 95.0–
1H), 2.65 (q, J ¼ 7.6 Hz, 2H), 1.22 (t, J ¼ 7.6 Hz, 3H); 13C NMR 96.2 ꢀC, lit.54 mp 94–95 ꢀC, Rf 0.35 (EtOAc/Hex, 1 : 4). Yield
(101 MHz, CDCl3) d 193.1, 148.1, 146.8, 146.7, 136.4, 134.1, 1.062 g (4.1 mmol, 82%). 1H NMR (400 MHz, CDCl3) d 8.14 (d, J
131.5, 130.6, 128.9, 128.8 (2C), 128.6 (2C), 125.4, 124.6, 28.9, ¼ 8.0 Hz, 1H), 7.75 (t, J ¼ 7.3 Hz, 1H), 7.64 (t, J ¼ 7.5 Hz, 1H),
15.3; FTIR (KBr, cmꢁ1): 3035, 2970, 2873, 1652, 1596, 1531, 7.54–7.33 (m, 3H), 7.29–7.17 (m, 1H), 7.12–6.99 (m, 1H), 6.78 (d,
1350, 1210; HRMS (ES TOF) calc'd for C17H15NNaO3 (M + Na)+ J ¼ 15.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) d 192.4, 146.7,
304.0944, found 304.0948 (1.1 ppm).
139.3, 138.8, 136.3, 134.1, 132.5, 130.7, 130.2, 128.8, 128.5,
124.8, 124.7; FTIR (KBr, cmꢁ1): 3107, 2859, 1651, 1604, 1521,
(E)-3-(4-Isopropylphenyl)-1-(2-nitrophenyl)prop-2-en-1-one
(1ae). This compound was prepared according to the typical 1420, 1343, 1280, 1253, 1193; HRMS (ES TOF) calc'd for C13-
procedure A employing 4-isopropylbenzaldehyde (7e) (740 mg, H9N1Na1O3S1 (M + Na)+ 282.0195, found 282.0195 (0.0 ppm).
5.00 mmol) and 1-(2-nitrophenyl)ethan-1-one (6a) (825 mg, 5.00
mmol). The crude product was puried by preparative column
Synthesis of (E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitriles
chromatography eluting with EtOAc/Hex, 1 : 4. Yield 1.292 g
(4.4 mmol, 88%), yellow oil, Rf 0.38 (EtOAc/Hex, 1 : 4); 1H NMR
(E)-2-(3-Oxoindolin-2-ylidene)-2-phenylacetonitrile
(2aa).
(400 MHz, CDCl3) d 8.15 (d, J ¼ 8.2 Hz, 1H), 7.75 (td, J ¼ 7.5, Typical procedure B: reaction vessel was charged with (E)-1-(2-
0.9 Hz, 1H), 7.67–7.61 (m, 1H), 7.50 (dd, J ¼ 7.5, 1.2 Hz, 1H), 7.44 nitrophenyl)-3-phenylprop-2-en-1-one (1aa) (253 mg, 1.00
(d, J ¼ 8.2 Hz, 2H), 7.24 (dd, J ¼ 12.1, 3.8 Hz, 3H), 6.99 (d, J ¼ mmol), KCN (80 mg, 1.23 mmol), water (400 mg), and methanol
16.3 Hz, 1H), 2.92 (septet, J ¼ 6.9 Hz, 1H), 1.24 (d, J ¼ 6.9 Hz, (3 mL). The mixture was stirred at reux for 15 min monitoring
6H); 13C NMR (101 MHz, CDCl3) d 193.1, 152.7, 146.8, 146.6, the reaction by TLC. When the starting chalcon was consumed,
136.4, 134.1, 131.6, 130.6, 128.9, 128.8 (2C), 127.2 (2C), 125.4, the emerald-green mixture was cooled down to room tempera-
124.6, 34.2, 23.7 (2C); FTIR (KBr, cmꢁ1): 2958, 1742, 1653, 1591, ture and acetic acid (40 mg, 0.66 mmol) was added slowly
151, 1360, 1300, 1280, 1244, 1201, 1109; HRMS (ES TOF) calc'd (Caution! This process is very exothermic and toxic HCN may
for C18H17N1Na1O3 (M + Na)+ 318.1101, found 318.1101 evolve, use well-ventilated fume hood. Residual materials con-
(0.1 ppm).
taining free cyanides should be quenched with KOH and FeCl3
(E)-1-(2-Nitrophenyl)-3-(pyridin-3-yl)prop-2-en-1-one (1an). aqueous solutions). The reuxing was continued for additional
This compound was prepared according to typical procedure A 15 min. Then, the mixture was diluted with water (10 mL),
employing nicotinaldehyde (7n) (535 mg, 5.00 mmol) and 1-(2- treated with saturated aqueous solution of sodium bicarbonate
nitrophenyl)ethan-1-one (6a) (825 mg, 5.00 mmol). Yield 1.092 g (5 mL), and extracted with ethyl acetate (4 ꢂ 20 mL). Crude
ꢀ
(4.30 mmol, 86%), colorless solid, mp 88.3–89.8 C (EtOH), Rf product was puried by preparative column chromatography
0.25 (EtOAc/hexanes 1 : 1); 1H NMR (400 MHz, CDCl3) d 8.66 (d, eluting with a mixture EtOAc/hexanes, gradient 1 : 2–1 : 1.
J ¼ 1.4 Hz, 1H), 8.60 (dd, J ¼ 4.7, 1.2 Hz, 1H), 8.19 (d, J ¼ 8.2 Hz, Additional purication can be performed by recrystallization
1H), 7.85 (d, J ¼ 8.0 Hz, 1H), 7.82–7.72 (m, 1H), 7.72–7.58 (m, from ethanol. The titled compound was obtained as red crys-
1H), 7.55–7.42 (m, 1H), 7.33 (dd, J ¼ 7.9, 4.8 Hz, 1H), 7.24 (d, J ¼ tals, mp 233.1–235.9 ꢀC (EtOH), lit.44 mp 236–237 ꢀC, Rf 0.32
16.4 Hz, 1H), 7.04 (d, J ¼ 16.4 Hz, 1H); 13C NMR (101 MHz, (EtOAc/hexanes 1 : 2), Rf 0.65 (EtOAc/hexanes 1 : 1). Yield
CDCl3) d 192.4, 151.7, 150.3, 146.7, 142.1, 136.1, 134.5, 134.4, 187 mg (0.76 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) d 10.51
131.0, 129.9, 128.9, 128.1, 124.8, 124.0; FTIR (KBr, cmꢁ1): 3308, (s, 1H), 7.70–7.43 (m, 7H), 7.09 (d, J ¼ 7.9 Hz, 1H), 7.02 (t, J ¼
3034, 1661, 1581, 1524, 1350, 1256, 1102; HRMS (ES TOF) calc'd 7.2 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d 184.2, 152.5, 142.5,
for C14H10N2NaO3 (M + Na)+ 277.0584, found 277.0585 (ꢁ0.6 137.5, 132.1, 129.3 (2C), 129.1, 128.8 (2C), 124.9, 121.5, 119.5,
ppm).
118.0, 112.7, 88.8; FTIR (KBr, cmꢁ1): 3308, 3060, 2222, 1708,
(E)-1-(2-Nitrophenyl)-3-(pyridin-4-yl)prop-2-en-1-one (1ao). 1601, 1470, 1447, 1391, 1340, 1213; HRMS (ES TOF) calc'd for
This compound was prepared according to typical procedure A
C
16H10N2NaO (M + Na)+ 269.0685, found 269.0692 (ꢁ2.3 ppm).
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(E)-2-(3-Oxoindolin-2-ylidene)-2-(o-tolyl)acetonitrile
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(2C), 127.4 (2C), 124.9, 121.4, 119.5, 118.0, 112.8, 89.2, 33.4, 23.7
(2C); FTIR (KBr, cmꢁ1): 3349, 2959, 2872, 2208, 1708, 1591,
1524, 1464, 1333, 1210; HRMS (ES TOF) calc'd for C19H16N2NaO
(M + Na)+ 311.1155, found 311.1155 (0.0 ppm).
(2ab).
This compound was prepared according to the typical proce-
dure B employing (E)-1-(2-nitrophenyl)-3-(o-tolyl)prop-2-en-1-
one (1ab) (267 mg, 1.00 mmol). Eluent for chromatographic
purication: EtOAc/hexanes, 1 : 2. Yield 203 mg (0.78 mmol,
(E)-2-(2-Fluorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile
(2af). This compound was prepared according to the typical
procedure B employing (E)-3-(2-uorophenyl)-1-(2-nitrophenyl)
prop-2-en-1-one (1af) (271 mg, 1.00 mmol). Eluent for chro-
matographic purication: EtOAc/hexanes, 1 : 2. Yield 216 mg
(0.82 mmol, 82%), red crystals, mp 211.1–212.6 ꢀC (EtOH), lit.44
mp 215–216 ꢀC, Rf 0.26 (EtOAc/hexanes 1 : 2), Rf 0.63 (EtOAc/
hexanes 1 : 1); 1H NMR (400 MHz, DMSO-d6) d 10.42 (s, 1H),
7.70–7.50 (m, 4H), 7.47–7.33 (m, 2H), 7.12–6.96 (m, 2H); 13C
NMR (101 MHz, DMSO-d6) d 183.9, 159.4 (d, J ¼ 249.6 Hz), 152.3,
144.2, 137.8, 131.8 (d, J ¼ 8.5 Hz), 131.5 (d, J ¼ 1.8 Hz), 125.4 (d, J
¼ 3.4 Hz), 125.1, 121.6, 119.43 (d, J ¼ 14.7 Hz), 119.40, 117.3,
116.7 (d, J ¼ 20.8 Hz), 112.4, 81.9; FTIR (KBr, cmꢁ1): 3296, 3047,
2222, 1718, 1598, 1454, 1340, 1306; HRMS (ES TOF) calc'd for
ꢀ
78%), red crystals, mp 201.8–203.5 C (EtOH), Rf 0.29 (EtOAc/
hexanes 1 : 2); 1H NMR (400 MHz, DMSO-d6) d 10.06 (s, 1H),
7.65 (d, J ¼ 7.5 Hz, 1H), 7.55 (dd, J ¼ 11.2, 4.1 Hz, 1H), 7.44–7.28
(m, 4H), 7.08–6.87 (m, 2H), 2.31 (s, 3H); 13C NMR (101 MHz,
DMSO-d6) d 184.0, 152.5, 143.9, 137.6, 136.9, 131.0, 130.8, 130.0,
129.5, 126.8, 124.9, 121.3, 119.6, 117.6, 112.4, 87.7, 19.3; FTIR
(KBr, cmꢁ1): 3336, 2215, 1708, 1598, 1377, 1330, 1220, 1139,
1082, 965; HRMS (ES TOF) calc'd for C17H12N2NaO (M + Na)+
283.0842, found 283.0840 (0.5 ppm).
(E)-2-(3-Oxoindolin-2-ylidene)-2-(p-tolyl)acetonitrile
(2ac).
This compound was prepared according to the typical proce-
dure B employing (E)-1-(2-nitrophenyl)-3-(p-tolyl)prop-2-en-1-
one (1ac) (267 mg, 1.00 mmol). Eluent for chromatographic
purication: EtOAc/hexanes, 1 : 3. Yield 164 mg (0.63 mmol,
63%), orange crystals, mp 231–234 ꢀC (EtOH), lit.44 mp 236–
240 ꢀC, Rf 0.46 (EtOAc/hexanes 1 : 2); 1H NMR (400 MHz, DMSO-
d6) d 10.45 (s, 1H), 7.65 (d, J ¼ 7.6 Hz, 1H), 7.56 (dd, J ¼ 16.7,
7.8 Hz, 3H), 7.38 (d, J ¼ 7.9 Hz, 2H), 7.09 (d, J ¼ 8.0 Hz, 1H), 7.02
(t, J ¼ 7.4 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, DMSO)
d 184.2, 152.5, 142.2, 139.0, 137.4, 129.9 (2C), 129.2, 128.8 (2C),
124.9, 121.4, 119.5, 118.0, 112.7, 89.2, 20.9; FTIR (KBr, cmꢁ1):
3296, 2208, 1705, 1591, 1471, 1307, 1243, 811; HRMS (ES TOF)
calc'd for C17H12N2NaO+ (M + Na)+ 283.0842, found 283.0844
(0.8 ppm).
C
16H9FN2NaO (M + Na)+ 287.0591, found 287.0597 (1.9 ppm).
(E)-2-(4-Fluorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile
(2ag). This compound was prepared according to the typical
procedure B employing (E)-3-(4-uorophenyl)-1-(2-nitrophenyl)
prop-2-en-1-one (1ag) (271 mg, 1.00 mmol). Eluent for chro-
matographic purication: EtOAc/hexanes, 1 : 3. Yieꢀld 192 mg
(0.73 mmol, 73%), orange crystals, mp 281.1–282.8 C (EtOH),
lit.44 mp 282–284 ꢀC, Rf 0.54 (EtOAc/hexanes 1 : 2); 1H NMR (400
MHz, DMSO-d6) d 10.50 (s, 1H), 7.78–7.62 (m, 3H), 7.58 (t, J ¼
7.4 Hz, 1H), 7.42 (t, J ¼ 8.4 Hz, 2H), 7.08 (d, J ¼ 7.9 Hz, 1H), 7.02
(t, J ¼ 7.3 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d 184.2, 162.1
(d, J ¼ 247.8 Hz), 152.5, 142.7, 137.5, 131.3 (d, J ¼ 8.7 Hz, 2C),
128.5 (d, J ¼ 3.1 Hz), 124.9, 121.5, 119.5, 118.0, 116.4 (d, J ¼
22.0 Hz, 2C), 112.7, 87.8; FTIR (KBr, cmꢁ1): 3302, 2222, 1715,
1608, 1511, 1468, 1330, 1240, 1213, 1103, 965, 844; HRMS (ES
TOF) calc'd for C16H9FN2NaO (M + Na)+ 287.0591, found
287.0590 (0.5 ppm).
(E)-2-(3-Chlorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile
(2ah). This compound was prepared according to the typical
procedure B employing (E)-3-(3-chlorophenyl)-1-(2-nitrophenyl)
prop-2-en-1-one (1ah) (287 mg, 1.00 mmol). Eluent for chro-
matographic purication: EtOAc/hexanes, 1 : 3. Yield 185 mg
(0.66 mmol, 66%), orange solid, mp 267–269 ꢀC (EtOH), Rf 0.57
(EtOAc/hexanes 1 : 2); 1H NMR (400 MHz, DMSO-d6) d 10.63 (s,
1H), 7.66 (d, J ¼ 7.5 Hz, 2H), 7.64–7.51 (m, 4H), 7.09 (d, J ¼
8.0 Hz, 1H), 7.04 (t, J ¼ 7.4 Hz, 1H); 13C NMR (101 MHz, DMSO-
d6) 184.2, 152.4, 143.2, 137.6, 134.2, 133.9, 131.2, 129.0, 128.5,
127.6, 125.0, 121.7, 119.4, 117.7, 112.7, 87.0; FTIR (KBr, cmꢁ1):
3289, 2215, 1709, 1458, 1243, 1096, 1016; HRMS (ES TOF) calc'd
for C16H9ClN2NaO+ (M + Na)+ 303.0296, found 303.0293
(1.0 ppm).
(E)-2-(4-Ethylphenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile
(2ad). This compound was prepared according to the typical
procedure B employing (E)-3-(4-ethylphenyl)-1-(2-nitrophenyl)
prop-2-en-1-one (1ad) (281 mg, 1.00 mmol). Eluent for chro-
matographic purication: EtOAc/hexanes, 1 : 3. Yield 170 mg
(0.62 mmol, 62%), red crystals, mp 223.2–225.7 ꢀC (EtOH), Rf
0.56 (EtOAc/hexanes 1 : 2); 1H NMR (400 MHz, DMSO-d6)
d 10.46 (s, 1H), 7.65 (d, J ¼ 7.5 Hz, 1H), 7.60–7.50 (m, 3H), 7.41
(d, J ¼ 8.1 Hz, 2H), 7.09 (d, J ¼ 8.0 Hz, 1H), 7.02 (t, J ¼ 7.4 Hz,
1H), 2.68 (q, J ¼ 7.5 Hz, 2H), 1.22 (t, J ¼ 7.6 Hz, 3H); 13C NMR
(101 MHz, DMSO-d6) d 184.2, 152.5, 145.2, 142.1, 137.4, 129.4,
128.9 (2C), 128.8 (2C), 124.9, 121.4, 119.5, 118.0, 112.7, 89.2,
28.0, 15.4; FTIR (KBr, cmꢁ1): 3429, 2933, 2255, 2134, 1665, 1585,
1461, 1370, 1243, 1022, 998, 828; HRMS (ES TOF) calc'd for
C
18H14N2NaO (M + Na)+ 297.0998, found 297.0997 (0.4 ppm).
(E)-2-(4-Isopropylphenyl)-2-(3-oxoindolin-2-ylidene)
acetonitrile (2ae). This compound was prepared according to
the typical procedure B employing (E)-3-(4-isopropylphenyl)-1-
(2-nitrophenyl)prop-2-en-1-one (1ae) (295 mg, 1.00 mmol).
Eluent for chromatographic purication: EtOAc/hexanes,
gradient 1 : 3–1 : 2. Yield 184 mg (0.64 mmol, 64%), red crys-
tals, mp 223.0–226.6 ꢀC (EtOH), lit.44 mp 228–230 ꢀC, Rf 0.47
(EtOAc/hexanes 1 : 2); 1H NMR (400 MHz, DMSO-d6) d 10.47 (s,
1H), 7.64 (d, J ¼ 7.4 Hz, 1H), 7.57 (d, J ¼ 7.5 Hz, 3H), 7.44 (d, J ¼
7.8 Hz, 2H), 7.09 (d, J ¼ 7.9 Hz, 1H), 7.01 (t, J ¼ 7.3 Hz, 1H), 2.96
(septet, J ¼ 6.7 Hz, 1H), 1.24 (d, J ¼ 6.7 Hz, 6H); 13C NMR (101
MHz, DMSO-d6) d 184.2, 152.5, 149.7, 142.1, 137.4, 129.6, 128.9
(E)-2-(4-Chlorophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile
(2ai). This compound was prepared according to the typical
procedure B employing (E)-3-(4-chlorophenyl)-1-(2-nitrophenyl)
prop-2-en-1-one (1ai) (287 mg, 1.00 mmol). Eluent for chro-
matographic purication: EtOAc/hexanes, gradient 1 : 2–1 : 1.
Yield 160 mg (0.57 mmol, 57%), orange crystals, mp 285.9–
287.8 ꢀC (EtOH), Rf 0.22 (EtOAc/hexanes 1 : 2); 1H NMR (400
MHz, DMSO-d6) d 10.55 (s, 1H), 7.74–7.51 (m, 6H), 7.13–6.94 (m,
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2H); 13C NMR (101 MHz, DMSO-d6) d 184.2, 152.4, 142.9, 137.6, (0.61 mmol, 61%), purple crystals, mp 202.6–204.9 ꢀC (EtOH), Rf
133.7, 131.0, 130.7 (2C), 129.4 (2C), 125.0, 121.6, 119.5, 117.8, 0.36 (EtOAc/hexanes 1 : 2); 1H NMR (400 MHz, DMSO-d6)
112.7, 87.5; FTIR (KBr, cmꢁ1): 3282, 2222, 1715, 1601, 1468, d 11.69 (s, 1H), 8.76 (d, J ¼ 3.9 Hz, 1H), 8.00 (t, J ¼ 7.2 Hz, 1H),
1407, 1336, 1250, 1096, 1015, 841; HRMS (ES TOF) calc'd for 7.80 (d, J ¼ 8.0 Hz, 1H), 7.72–7.54 (m, 2H), 7.49–7.28 (m, 2H),
C
16H9ClN2NaO (M + Na)+ 303.0296, found 303.0297 (0.5 ppm). 7.05 (t, J ¼ 7.4 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d 185.2,
(E)-2-(4-Bromophenyl)-2-(3-oxoindolin-2-ylidene)acetonitrile 152.4, 151.8, 149.2, 143.2, 138.0, 137.6, 125.0, 122.6, 122.5,
(2aj). This compound was prepared according to the typical 122.2, 119.1, 116.6, 113.5, 85.0; FTIR (KBr, cmꢁ1): 3228, 3121,
procedure employing (E)-3-(4-bromophenyl)-1-(2-nitrophenyl) 2214, 1708, 1591, 1464, 1434, 1343, 1236; HRMS (ES TOF) calc'd
prop-2-en-1-one (1aj) (331 mg, 1.00 mmol). Eluent for chro- for C15H9N3NaO (M + Na)+ 270.0638, found 270.0640 (0.9 ppm).
matographic purication: EtOAc/hexanes, gradient 1 : 4–1 : 2.
Yield 297 mg (0.92 mmol, 92%), red crystals, mp 278.8–282.5 ꢀC (2an). This compound was prepared according to the typical
(EtOH), Rf 0.66 (EtOAc/hexanes 1 : 2); 1H NMR (400 MHz, procedure
employing (E)-1-(2-nitrophenyl)-3-(pyridin-3-yl)
(E)-2-(3-Oxoindolin-2-ylidene)-2-(pyridin-3-yl)acetonitrile
B
DMSO-d6) d 10.55 (s, 1H), 7.76 (d, J ¼ 8.1 Hz, 2H), 7.65 (d, J ¼ prop-2-en-1-one (1an) (254 mg, 1.00 mmol). Eluent for chro-
7.5 Hz, 1H), 7.58 (d, J ¼ 8.1 Hz, 3H), 7.07 (d, J ¼ 8.0 Hz, 1H), 7.03 matographic purication: EtOAc. Yield 138 mg (0.56 mmol,
(t, J ¼ 7.5 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d 184.2, 152.4, 56%), light-brown crystals, mp 208.1–211.1 C (EtOH), Rf 0.34
ꢀ
142.9, 137.6, 132.3 (2C), 131.4, 130.9 (2C), 125.0, 122.4, 121.6, (EtOAc); 1H NMR (400 MHz, DMSO-d6) d 10.71 (s, 1H), 8.83 (d, J
119.4, 117.7, 112.7, 87.5; FTIR (KBr, cmꢁ1): 3282, 3060, 2215, ¼ 1.2 Hz, 1H), 8.66 (d, J ¼ 3.9 Hz, 1H), 8.02 (d, J ¼ 7.9 Hz, 1H),
1712, 1602, 1487, 1464, 1407, 1333, 1243; HRMS (ES TOF) calc'd 7.65 (d, J ¼ 7.5 Hz, 1H), 7.63–7.54 (m, 2H), 7.21–6.93 (m, 2H);
for C16H9BrN2NaO (M + Na)+ 346.9790, found 346.9790 13C NMR (101 MHz, DMSO-d6) d 184.1, 152.4, 149.6, 149.4,
(0.2 ppm).
(E)-2-(4-Methoxyphenyl)-2-(3-oxoindolin-2-ylidene)
143.5, 137.7, 136.4, 128.6, 125.1, 124.2, 121.7, 119.4, 117.6,
112.7, 85.2; FTIR (KBr, cmꢁ1): 3557, 2215, 1712, 1622, 1591,
acetonitrile (2ak). This compound was prepared according to 1541, 1467, 1417, 1387, 1337, 1219, 1190, 1136; HRMS (ES TOF)
the typical procedure B employing (E)-3-(4-methoxyphenyl)-1-(2- calc'd for C15H9N3NaO (M + Na)+ 270.0638, found 270.0635
nitrophenyl)prop-2-en-1-one (1ak) (283 mg, 1.00 mmol). Eluent (1.0 ppm).
for chromatographic purication: EtOAc/hexanes, 1 : 2–1 : 1.
(E)-2-(3-Oxoindolin-2-ylidene)-2-(pyridin-4-yl)acetonitrile
Yield 199 mg (0.72 mmol, 72%), red crystals, mp 250.1–251.1 ꢀC (2ao). This compound was prepared according to the typical
(EtOH), lit.44 mp 245–247 ꢀC, Rf 0.23 (EtOAc/hexanes 1 : 2), Rf procedure
B employing (E)-1-(2-nitrophenyl)-3-(pyridin-4-yl)
0.43 (EtOAc/hexanes 1 : 1); 1H NMR (400 MHz, DMSO-d6) prop-2-en-1-one (1ao) (254 mg, 1.00 mmol). Eluent for chro-
d 10.41 (s, 1H), 7.60 (td, J ¼ 15.9, 7.6 Hz, 4H), 7.11 (dd, J ¼ 14.9, matographic purication: EtOAc – EtOH/EtOAc, 1 : 3. Yield
8.4 Hz, 3H), 7.01 (t, J ¼ 7.4 Hz, 1H), 3.84 (s, 3H); 13C NMR (101 131 mg (0.53 mmol, 53%), red crystals, mp 266.3–268.4 ꢀC
1
MHz, DMSO-d6) d 184.1, 159.8, 152.4, 141.6, 137.3, 130.4 (2C), (EtOH), Rf 0.17 (EtOAc), 0.65 (EtOH/EtOAc 1 : 3); H NMR (400
124.8, 124.1, 121.3, 119.6, 118.0, 114.8 (2C), 112.7, 89.4, 55.5; MHz, DMSO-d6) d 10.78 (s, 1H), 8.74 (d, J ¼ 5.7 Hz, 2H), 7.67 (d, J
FTIR (KBr, cmꢁ1): 3289, 3060, 2208, 1705, 1594, 1300, 1246, ¼ 7.5 Hz, 1H), 7.60 (t, J ¼ 7.1 Hz, 3H), 7.10 (d, J ¼ 8.0 Hz, 1H),
1176; HRMS (ES TOF) calc'd for C17H12N2NaO2 (M + Na)+ 7.06 (t, J ¼ 7.4 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d 184.3,
299.0791, found 299.0794 (1.0 ppm).
152.3, 150.5 (2C), 143.8, 140.1, 137.8, 125.2, 122.9 (2C), 122.1,
119.3, 117.2, 112.8, 85.3; FTIR (KBr, cmꢁ1): 2993, 2221, 1742,
(E)-2-(4-(Dimethylamino)phenyl)-2-(3-oxoindolin-2-ylidene)
acetonitrile (2al). This compound was prepared according to 1718, 1598, 1557, 1517, 1373, 1250, 1206; HRMS (ES TOF) calc'd
the typical procedure B employing (E)-3-(4-(dimethylamino) for C15H9N3NaO (M + Na)+ 270.0638, found 270.0630 (2.7 ppm).
phenyl)-1-(2-nitrophenyl)prop-2-en-1-one (1al) (296 mg, 1.00
(E)-2-(Benzo[d][1,3]dioxol-5-yl)-2-(3-oxoindolin-2-ylidene)
mmol). Reaction time was extended to 3 h at the rst stage, and acetonitrile (2ap). This compound was prepared according to
to 1 h at the second stage. Eluent for chromatographic puri- the typical procedure B employing (E)-3-(benzo[d][1,3]dioxol-5-
cation: EtOAc/hexanes, 1 : 1. Yield 135 mg (0.47 mmol, 47%), yl)-1-(2-nitrophenyl)prop-2-en-1-one (1ap) (297 mg, 1.00
violet crystals, mp 234.8–237.6 ꢀC (EtOH), lit.44 mp 220–225 ꢀC, mmol). The title compound was obtained as red solid, mp
1
Rf 0.20 (EtOAc/hexanes 1 : 2), Rf 0.69 (EtOAc/hexanes 1 : 1); H 247.9–248.7 ꢀC. Rf 0.62 (EtOAc/Hex, 1 : 2). Yield 133 mg
NMR (400 MHz, DMSO-d6) d 10.29 (s, 1H), 7.63 (d, J ¼ 7.4 Hz, (0.46 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) d 10.41 (s, 1H),
1H), 7.55 (t, J ¼ 9.7 Hz, 3H), 7.12 (d, J ¼ 8.0 Hz, 1H), 7.00 (t, J ¼ 7.64 (d, J ¼ 7.6 Hz, 1H), 7.57 (t, J ¼ 7.6 Hz, 1H), 7.23–7.07 (m,
7.3 Hz, 1H), 6.87 (d, J ¼ 8.6 Hz, 2H), 3.01 (s, 6H); 13C NMR (101 4H), 7.01 (t, J ¼ 7.4 Hz, 1H), 6.14 (s, 2H); 13C NMR (101 MHz,
MHz, DMSO-d6) d 183.7, 152.2, 150.5, 139.7, 136.8, 130.0 (2C), DMSO-d6) d 184.1, 152.4, 148.1, 148.0, 141.9, 137.4, 125.7, 124.8,
124.5, 121.0, 119.8, 118.6, 118.0, 112.8, 112.3 (2C), 91.4, 39.8 123.6, 121.4, 119.6, 118.0, 112.7, 109.2, 108.9, 101.9, 89.2; FTIR
(2C); FTIR (KBr, cmꢁ1): 3315, 2899, 2798, 2201, 1698, 1608, (lm, NaCl, cmꢁ1): 3316, 2926, 2208, 1712, 1595, 1481, 1350,
1521, 1364, 1323, 1199; HRMS (ES TOF) calc'd for C18H15N3NaO 1247, 1206, 1046; HRMS (ES TOF) calc'd for C17H10N2NaO3 (M +
(M + Na)+ 312.1107, found 312.1110 (ꢁ0.8 ppm).
Na)+ 313.0584, found 313.0586 (0.8 ppm).
(E)-2-(3-Oxoindolin-2-ylidene)-2-(pyridin-2-yl)acetonitrile
(E)-2-(5,6-Dimethoxy-3-oxoindolin-2-ylidene)-2-
(2am). This compound was prepared according to the typical phenylacetonitrile (2ba). This compound was prepared
procedure employing (E)-1-(2-nitrophenyl)-3-(pyridin-2-yl) according to the typical procedure B employing (E)-1-(4,5-
prop-2-en-1-one (1am) (254 mg, 1.00 mmol). Eluent for chro- dimethoxy-2-nitrophenyl)-3-phenylprop-2-en-1-one (1ba)
matographic purication: EtOAc/hexanes, 1 : 2. Yield 151 mg (313 mg, 1.00 mmol). Reaction time was extended to 1 h at the
B
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rst stage of the reaction. Eluent for chromatographic puri- 10 V. L. Gein, V. V. Tatarinov, N. A. Rassudikhina, M. I. Vakhrin
cation: EtOAc/hexanes, 1 : 1. Yield 156 mg (0.51 mmol, 51%), and E. V. Voronina, Pharm. Chem. J., 2011, 45, 231–232.
purple crystals, mp 205.2–207.6 ꢀC (EtOH), Rf 0.47 (EtOAc/ 11 N. A. Lack, P. Axerio-Cilies, P. Tavassoli, F. G. Han,
hexanes 1 : 1); 1H NMR (400 MHz, DMSO-d6) d 10.13 (s, 1H),
7.62 (d, J ¼ 7.5 Hz, 2H), 7.55 (t, J ¼ 7.5 Hz, 2H), 7.47 (t, J ¼ 7.1 Hz,
1H), 7.07 (s, 1H), 6.62 (s, 1H), 3.85 (s, 3H), 3.75 (s, 3H); 13C NMR
K. H. Chan, C. Feau, E. LeBlanc, E. T. Guns, R. K. Guy,
P. S. Rennie and A. Cherkasov, J. Med. Chem., 2011, 54,
8563–8573.
(101 MHz, DMSO-d6) d 181.9, 157.8, 150.2, 144.9, 143.9, 132.3, 12 N. A. Lack, P. Axerio-Cilies, P. Tavassoli, F. Q. Han,
129.3 (2C), 129.0, 128.8 (2C), 118.0, 110.4, 105.8, 95.9, 88.5, 56.1,
55.9; FTIR (KBr, cmꢁ1): 3282, 3000, 2839, 2215, 1682, 1598,
K. H. Chan, C. Feau, E. LeBlanc, E. T. Guns, R. K. Guy,
P. S. Rennie and A. Cherkasov, J. Med. Chem., 2012, 55, 565.
1491, 1441, 1323, 1203, 1172; HRMS (ES TOF) calc'd for 13 D.-Q. Liu, S.-C. Mao, H.-Y. Zhang, X.-Q. Yu, M.-T. Feng,
C
18H14N2NaO3 (M + Na)+ 329.0897, found 329.0901 (1.3 ppm).
It should be pointed out, that preparation of basic
B. Wang, L.-H. Feng and Y.-W. Guo, Fitoterapia, 2013, 91,
15–20.
compounds, containing dimethylamine functionality (2al) or 14 A. E. Medvedev, A. S. Ivanov, N. S. Kamyshanskaya,
pyridine ring (2am–2ao) requires twice more acetic acid (80 mg)
A. Z. Kirkel, T. A. Moskvitina, V. Z. Gorkin, N. Y. Li and
at the second stage of the procedure. It is also worth mentioning
V. Y. Marshakov, Biochem. Mol. Biol. Int., 1995, 36, 113–122.
that these compounds slowly decompose in solutions of ethyl 15 A. E. Medvedev, A. S. Ivanov, A. V. Veselovsky, V. S. Skvortsov
acetate or acetone, but perfectly shelf-stable in crystalline form.
and A. I. Archakov, J. Chem. Inf. Comput. Sci., 1996, 36, 664–
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
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