Studies on the stereochemical assignment of 3-acylidene 2-oxindoles

Article abstract of DOI:10.1039/c4ob00496e

The designation of E/Z-geometrical isomers in 3-acylidene 2-oxindoles by NMR spectroscopy can lead to erroneous assignment of alkene stereochemistry because of the narrow chemical shift range observed over a large series of analogues. In contrast, UV-Vis spectroscopy offers a convenient and more reliable method for alkene stereochemical assignment. A combination of X-ray crystallography and theoretical studies shows that the observed differences in UV-Vis spectroscopic behaviour relate to the twisted conformation of the Z-isomers that provides reduced conjugation and weaker hypsochromic (blue-shifted) absorbances relative to those of the E-isomers.

Full text of DOI:10.1039/c4ob00496e

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Studies on the stereochemical assignment of
3-acylidene 2-oxindoles†
Cite this: Org. Biomol. Chem., 2014,
12, 3201
Steven J. Edeson,a Julong Jiang,a Stephen Swanson,b Panayiotis A. Procopiou,b
Harry Adams,a Anthony J. H. M. Meijer*a and Joseph P. A. Harrity*a
The designation of E/Z-geometrical isomers in 3-acylidene 2-oxindoles by NMR spectroscopy can lead
to erroneous assignment of alkene stereochemistry because of the narrow chemical shift range observed
over a large series of analogues. In contrast, UV-Vis spectroscopy offers a convenient and more reliable
method for alkene stereochemical assignment. A combination of X-ray crystallography and theoretical
studies shows that the observed differences in UV-Vis spectroscopic behaviour relate to the twisted con-
formation of the Z-isomers that provides reduced conjugation and weaker hypsochromic (blue-shifted)
absorbances relative to those of the E-isomers.
Received 5th March 2014,
Accepted 7th April 2014
DOI: 10.1039/c4ob00496e
www.rsc.org/obc
been employed as substrates in cycloaddition reactions for the
synthesis of spiro-fused compounds.5
Introduction
3-Alkenyl-oxindoles are an attractive template for the discovery
An important challenge associated with the characteris-
of new medicines, and there are several compounds contain- ation of these compounds is the assignment of alkene stereo-
ing this and related moieties that exhibit useful biological chemistry around the acylidene moiety. In many cases, this
activity (Fig. 1).1 For example, Sunitinib 1 is a tyrosine kinase assignment is ambiguous and there are few reports that offer
inhibitor that was approved in 2006 for the treatment of renal any general guidance as to how this can be done in a routine
cell carcinoma and gastrointestinal stromal tumours.2 In way. However, Righetti and co-workers described the use of
addition, Woodard et al. identified a series of selective plasmo- NMR spectroscopy for the assignment of alkene stereo-
dial CDK inhibitors (e.g. 2),3 while Khosla and co-workers chemistry.6 This assignment is made on the basis of a down-
described 3-acylidene-oxindoles such as 3 as inhibitors of field shift of the acylidene protons at the β-carbon and at C-4
human transglutaminase-2.4 Our own interest in these com- in the E-isomer. Indeed, this method was employed by Khosla
pounds stems from the use of these functionalised hetero- in assigning E-stereochemistry of compounds derived from
cycles as useful synthetic building blocks, where they have their study.4 This approach is straightforward when a mixture
of isomers is prepared, however, 3-acylidene 2-oxindoles are
generally formed with high stereocontrol and so an assign-
ment based on comparative shift values is not always straight-
forward. Indeed, a recent report by Jing and co-workers
highlighted that an example substrate previously assigned as
an E-acylidene oxindole, was in fact the Z-isomer, moreover,
the olefin geometry was found to have a significant impact on
stereocontrol in Michael spirocyclisation reactions.7 In connec-
tion with our own interests in the chemistry of 3-acylidene
2-oxindoles, we therefore set out to address this issue by estab-
lishing a routine and consistent method for the assignment of
alkene stereochemistry in this class of compounds and report
herein our findings.
Fig. 1 Biologically active 3-acylidene oxindole derivatives.
aDepartment of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK.
E-mail: j.harrity@sheffield.ac.uk; Fax: +44 (0)114 222 9303;
Tel: +44 (0)114 222 9496
bGlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK
Results and discussion
†Electronic supplementary information (ESI) available: Compounds 5, 6, 11, 14,
18. CCDC 981300–981304. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c4ob00496e
In order to cover a reasonably broad scope of acylidene oxi-
ndoles, we opted to prepare representative examples with vari-
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Fig. 2 Representative 3-acylidene oxindoles.
ation at the acylidene unit with both N-unsubstituted and sub-
stituted heterocycles (4, Fig. 2). We also wanted to generate
analogues containing substituents on the oxindole ring,
especially those with C-4 substitution as these have been
shown to exhibit useful biological activity.4
3-Acylidene 2-oxindoles are easily prepared by a two-step
aldol condensation sequence following the method of Braude
and Lindwall.8 Condensation of isatin with a small series of
acetophenones provided oxindoles 5–8 and 12–16 in good
overall yield and as single isomers (as judged by 1H NMR spec-
troscopy). This method was readily extended to N-Me isatins9
and delivered the heterocyclic compounds 9–11 and 17–18,
with similarly high levels of stereocontrol. Using this
approach, we were able to quickly generate 14 acylidene oxi-
ndoles from commercially available starting materials on pre-
paratively useful scales (Fig. 3).
In order to begin the task of characterising the product
stereochemistry, we attempted to grow crystals of representa-
tive oxindoles. We were able to characterise compounds 5, 6,
11, 14 and 18 by X-ray crystallography, and the structures are
depicted in Fig. 4. Compounds 5, 6 and 11 were found to
exhibit E-stereochemistry and adopted conformations that
minimised interaction of the acyl-aromatic group with C4–H of
the oxindole ring. In contrast, and contrary to the reports of
Khosla and co-workers,4 4-chlorooxindoles 14 and 18 were
Fig. 3 3-Acylidene oxindoles prepared by the aldol condensation
reaction.
found to adopt the Z-configuration. Interestingly, the solid this study (δ 7.69–8.03), together with the potential for N-sub-
state structures of these Z-acylidene oxindoles deviate signifi- stitution to affect peak position suggests that the use of NMR
cantly from a planar orientation, and this presumably reflects spectroscopy alone for assignment of configuration could be
dipole–dipole alignment or allylic strain that arises in these unreliable, especially when only a single isomer is available.
arrangements.
The X-ray structures of compounds 5, 6, 11, 14, 18
The X-ray crystallography study provided an unambiguous suggested that E- and Z-alkylidene oxindoles should exhibit
method of assigning E/Z-stereochemistry, and provided a basis different degrees of conjugation, and this in turn suggested
from which to make comparisons towards a general method of that UV-Vis spectroscopy could offer an additional tool for
alkene stereochemical assignment. As discussed earlier, NMR assigning product stereochemistry. Indeed, it is notable that
spectroscopy has the potential to provide the most direct compounds 5–13 are an intense red or orange colour while
method for assignment and so we decided to compare CH compounds 14–18 are pale yellow. We therefore recorded
shift values in the 1H NMR spectrum of the β-carbon at the UV-Vis spectra of compounds 5–18. Stock solutions were pre-
acylidene group for the major isomer generated each case. As pared in anhydrous MeOH (75 μM) and the spectrum of each
highlighted in Table 1, the NMR shift values follow the trend compound was recorded over 200–700 nm. As shown in Fig. 5,
highlighted by Righetti and co-workers6 in that Z-acylidene the spectra of compounds 5–13 are very similar and show
products show an downfield shift in the NMR spectrum as three distinct maxima (red bands). In contrast, compounds
compared to the corresponding E-isomers (cf. 5, 6, 11 versus 14–18 also have UV-Vis spectra that are all similar to one
14, 18). Interestingly, N-Me derivatives also display a slight another but are quite different from the spectra of 5–13,
downfield shift relative to their N-H analogues (e.g. compare showing two distinct peaks and one shoulder, all at higher
5–8 with 9–11, and 14, 16 with 17–18). Overall, the relatively energy than the corresponding features in the spectra of 5–13.
narrow shift range observed for the compounds analysed in These are highlighted as green bands in Fig. 5.
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Fig. 5 UV-Vis spectra of compounds 5–18 (75 µM in MeOH). Spectra
are grouped according to relatively strong (red) and weak (green) bands
in regions II and III.
Table 2 UV-Vis data for compounds 5–18a
II
III
Fig. 4 X-ray crystal structures of compounds 5, 6, 11, 14, 18. Selected
dihedral angles Labcd (°); 5: 176.9(1). 6: 178.2(4). 11: 149.7(2). 14: 87.8(3).
18: 84.1(2).
Entry
Compound
λ/nm
ε/M−1 cm−1
λ/nm
ε/M−1 cm−1
1
2
3
4
5
6
7
8
5(E)
6(E)
7
8
9
10
11(E)
12
13
14(Z)
15
16
17
334
337
341
339
334
337
341
336
338
294
298
302
292
302
10 200
11 000
11 520
9080
422
426
426
436
424
431
426
419
422
380
380
380
380
380
1870
1800
1960
1670
1200
1290
1890
2520
2890
1190
940
Table 1 1H NMR shift values of the alkylidene CH in compounds 5–18
8890
Entry
Compounda
Alkylidene CHb (ppm)
11 470
13 820
11 500
13 660
5720
6390
4080
1
2
3
4
5
6
7
8
5(E)
6(E)
7
8
9
10
11(E)
12
13
14(Z)
15
16
17
7.72
7.69
7.69
7.72
7.80
7.77
7.77
7.76
7.74
7.94
7.91
7.92
8.03
8.01
9
10
11
12
13
14
760
1080
910
5320
3980
18(Z)
a Samples recorded as 75 µM solutions in MeOH.
9
10
11
12
13
14
absorption coefficient between 1190–2890 M−1 cm−1, whereas
the maxima for 14–18 are again blue-shifted (370–390 nm)
with smaller extinction coefficients in the range 760–1190 M−1
cm−1. It is clear from this data that the absorption spectral be-
haviour of compounds 5–18 can be separated into two classes,
18(Z)
a Compound configuration in parenthesis assigned on the basis of
X-ray crystallography. b NMR data for compounds dissolved in d6-DMSO.
For the purposes of this study, we chose to focus on three with compounds 14–18 having blue-shifted absorption
main absorptions in regions I, II, and III indicated in Fig. 5. maxima with lower extinction coefficients for absorptions II
Although differences in absorption bands in region I were and III than compounds 5–13. Given that we were able to
apparent, the differences were relatively small and so we confirm the Z-stereochemistry for compounds 14 and 18 by
decided to concentrate on bands II and III, these data are com- X-ray crystallography, we assign substrates 15, 16, and 17 also
piled in Table 2. With regard to absorption II, compounds as Z-isomers on the basis of similarities shown in their UV-Vis
5–13 were all found to exhibit a maximum in the range of spectra. Similarly, we assign compounds 7, 8, 9, 10, 12, and 13
334–341 nm with an extinction coefficient between as E-stereoisomers.
8890–13 820 M−1 cm−1. In contrast, substrates 14–18 all exhibit
We envisaged that the potential of UV-Vis spectroscopy to
a shorter-wavelength maximum in the range of 292–302 nm aid stereochemical assignment of acylidene oxindoles could be
with a smaller extinction coefficient between 3980–6390 M−1 further demonstrated by conducting this analysis on individ-
cm−1. With regard to absorption III compounds 5–13 all ual E/Z-isomers of one specific substrate. In this context, AlCl3
exhibit a maximum in the range of 419–436 nm with an has been established as an effective reagent for the E-Z isomer-
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UV-Vis spectra are pronounced and consistent with the trends
highlighted in Fig. 5.
In an effort to further validate our methodology for assign-
ment of alkene geometry through UV-Vis spectroscopy, 3-acyli-
dene oxindole 19 was prepared. Compound 19 was isolated as
a single isomer in a good overall yield of 50% via a slightly
modified aldol condensation reaction. The UV-Vis spectra of
19 (75 μM solution in MeOH) showed two distinctive maxima
and a broad shoulder at 252 nm (I), 293 nm (II), and
370–390 nm (III), respectively (Fig. 8). The molar absorption
coefficients calculated for peaks II and III were 4460 M−1 cm−1
and 900 M−1 cm−1 (at 380 nm) respectively. The pattern of
peaks and intensities in the spectrum strongly indicated that
this alkene has Z-geometry, and further support for this
assignment was gathered by nOe spectroscopy.
Fig. 6 E–Z Isomerisation of compound 5. Isomerisation was monitored
by 400 MHz 1H NMR spectroscopy.
isation of acylidene oxindoles,6 and so we opted to use this
method to generate Z-5.
Accordingly, a sample of E-5 was treated with one equi-
valent of AlCl3 over three days at room temperature to give an
inseparable mixture of the E and Z-acylidene oxindoles. Before
carrying out detailed spectroscopic studies on Z-5, we first
investigated the configurational stability of this compound.
Interestingly, a slow isomerisation of Z-5 back to the thermo-
dynamically more stable E-isomer was observed under ambient
conditions when the compound was stored in CDCl3 solution.
In contrast, a much slower rate of isomerisation was noted
when the compound was stored as a pure solid (Fig. 6).10
Given the relatively slow rate of isomerisation, we were con-
fident that we could isolate and characterise a pure sample of
Z-5, and were pleased to find that the isomers could be separ-
ated via preparative reverse phase HPLC. The UV-Vis spectrum
(75 μM solution in MeOH) of Z-5 was recorded and compared
with the E-isomer (Fig. 7). The spectra of E/Z-5 closely match
the two types of UV-Vis spectrum described earlier in Fig. 5,
with the Z-compound showing a characteristic blue-shift and
reduced absorbance intensity relative to the E-isomer.
Theoretical studies
In order to better understand the origin of the observed spec-
troscopic differences of E- and Z-3-acylidene oxoindoles, we
computationally modelled the UV-Vis spectrum of optimised
structures of E/Z-5. The first 100 singlet-to-singlet electronic
transitions for each isomer were calculated and our results are
shown in Fig. 9. In addition, the wavelength of each significant
transition, the corresponding energy, the oscillator strength
and the major molecular orbital contribution (based on FMO
analysis) for the UV-Vis spectrum of each isomer are shown in
Tables 3 and 4, respectively. For full details, see the ESI,†
whereby we note that similar calculations have been used for
structure determination previously.11
Our calculations show that Z-5 exhibits four absorptions
after 220 nm. The absorption at 244 nm is the strongest, and
1
Additionally, the H NMR spectrum of Z-5 shows a resonance
at δ 7.70 for the olefinic proton whereas E-5 has a signal at
δ 7.72. Once again, the small variations in proton shift values
do not provide a basis from which to confidently assign
product stereochemistry, whereas the observed changes in the
Fig. 7 UV-Vis spectra of compounds E/Z-5 (75 µM in MeOH). Spectra
are classified according to relatively strong (red) and weak (green) bands
in regions II and III.
Fig. 8 UV-Vis spectra of compound 19 (75 µM in MeOH).
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Table 5 Selected FMO energy levels of E/Z-5 (level of theory: B3LYP/
6-311++G**)
FMO
E-5
Z-5
LUMO
HOMO
HOMO−1
−3.27 eV
−6.45 eV
−7.15 eV
−2.46 eV
−6.38 eV
−7.06 eV
of the major FMO contributions to these bands depicted in
Tables 3 and 4 showed that electronic transitions involving the
HOMO−1, HOMO and LUMO orbitals were dominant. Thus
their energies were calculated and they are summarised in
Table 5.
From Table 5, it is clear that the energy levels of both the
HOMO and HOMO−1 orbitals are similar for both alkene
isomers. In contrast, the energy levels of the respective LUMO
orbitals are significantly different, whereby the LUMO of E-5 is
0.81 eV lower in energy than the LUMO of Z-5. Thus, the
observed relative shift of the transitions in regions II and III of
the UV-Vis spectrum of these compounds appears to be
caused solely by the different LUMO energies for each of the
isomers. Hereby, the lower energy LUMO of the E-isomer
results in a relative red-shift of bands in this region. The
apparent specificity of the LUMO-lowering effect for E-stereo-
chemistry compared to Z-stereochemistry (as evidenced by the
experimental data) is intriguing. Inspection of the HOMO and
the HOMO−1 of E/Z-5 shows that these molecular orbitals are
localised on the alkylidene oxindole moiety, as well as the acyl
carbonyl lone pair in both isomers. In contrast, the corres-
ponding LUMO orbitals are more generally delocalised
through the 3-acylidene 2-oxindole structure, and the confor-
mational twist in the Z-isomer leads to less efficient overlap
and less stabilisation than in the E-isomer (Fig. 10).
Fig. 9 Calculated UV-Vis spectra of E/Z-5.
Table 3 Calculated electronic spectrum for E-5
Wavelength
(nm)
Energy
(eV)
Oscillator
strength
Major contributions
(>10%)a
485.32
363.51
252.93
2.56
3.41
4.90
0.082
0.516
0.202
H → L (97.2%)
H−1 → L (93.8%)
H → L+3 (43.9%)
H−6 → L (40.5%)
H−7 → L (65.0%)
H → L+2 (15.5%)
H−1 → L+1 (13.1%)
H−1 → L+1 (39.5%)
H → L+3 (29.6%)
H−6 → L (10.2%)
H−4 → L+1 (50.7%)
H−2 → L+1 (16.3%)
H−3 → L+1 (11.4%)
H−2 → L+2 (10.4%)
237.78
229.32
220.63
5.21
5.41
5.62
0.154
0.168
0.143
a H: HOMO and L: LUMO.
Evidence of this is found in the differential density maps12
for the S0–S1 transition for both isomers. Comparison of the
two panels in Fig. 11 clearly shows that, while the decrease in
the electron density for both isomers is mainly located on the
Table 4 Calculated electronic spectrum for Z-5
Wavelength
(nm)
Energy
(eV)
Oscillator
strength
Major contributions
(>10%)a
381.03
299.11
3.25
4.15
0.039
0.169
H → L (95.7%)
H−1 → L (60.5%)
H−4 → L (13.8%)
H−3 → L+1 (34.5%)
H−2 → L+1 (30.3%)
H−5 → L+1 (21.2%)
H → L+3 (72.5%)
258.85
4.79
0.332
243.86
5.08
0.325
a H: HOMO and L: LUMO.
is followed by medium and weak absorption bands at around
259 nm, 299 nm and 381 nm, respectively. In contrast, the cal-
culated spectrum of E-5 is quite different. The absorption at
the lowest energy region is located at 485 nm with a stronger
absorbance 353 nm. Similar to the experimental spectra
shown in Fig. 5, the calculated spectra also exhibit diagnostic
bands of type II and III. As in the experimental spectra these
are stronger and red-shifted for E-5 relative to Z-5. Inspection
Fig. 10 Selected FMO of E/Z-5.
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Fig. 11 Differential Density maps for the S0–S1 transition of the Z-5
isomer and the E-5 isomer. Green denotes a decrease in the electron
density upon excitation, whereas purple denotes an increase.
Fig. 13 Three E/Z-acylidene 2-oxindole conformers.
corresponding Z-configuration B cannot readily adopt a planar
conformation because of attendant dipole–dipole interactions
or allylic strain, these interactions force the acyl group to twist
out of conjugation. Compound C (R ≠ H) cannot be generated
synthetically, but we were able to produce a minimised struc-
ture for the compound theoretically. Unsurprisingly, this com-
pound also showed a twist at the acyl group to minimise steric
interactions leading to a concomitant change in the absorp-
tion spectrum (Fig. 13).
oxindole subunit, the concomitant increase for the Z-isomer is
more localized than for the E-isomer, clearly showing the
effect of the planarity of the E-isomer, leading to a lower exci-
tation energy for the S0–S1 transition in the E-isomer.
Thus, our investigations of E/Z-5 show that direct, semi-
quantitative, comparison between experimentally and theoreti-
cally derived UV-Vis spectra is possible for these systems.
Therefore, the UV-Vis spectra for the 5- and 7-Cl oxindole
isomers not studied experimentally, together with the 4- and
6-Cl isomers 12 and 14 were also calculated. The UV-Vis
spectra for these E/Z-chloro-oxindoles are depicted in Fig. 12.
With regard to the Z-isomers, a consistent pattern was
observed for the calculated spectra that matched the experi-
mentally derived data quite well (cf. Fig. 5). In the case of the
E-isomers however, only the 5-, 6-, 7-Cl compounds gave the
expected UV-Vis spectra, whilst the E-4-Cl-oxindole provided a
spectrum that was inconsistent with the expected pattern of
absorbance bands. Inspection of the structure of this com-
pound shows that in this case the steric clash between the
chlorine atom and the phenyl ring ensures that the E-isomer,
like the corresponding Z-isomer, is also not planar, which
clearly results in a blue-shift of the absorptions and a corres-
ponding increase in the intensity of the region II band.
Conclusions
In conclusion, we believe that alkene geometry of 3-acylidene
oxindoles can be assigned through UV-Vis spectroscopy based
on the following general empirical observations (75 µM solu-
tions in MeOH): E-isomers are expected to have two diagnostic
peaks in the range of 330–345 nm and 415–440 nm, with
extinction coefficients of 8890–13 820 M−1 cm−1 and
1200–2890 M−1 cm−1, respectively. In contrast, 3Z-acylidene
oxindoles have a weaker band in the range of 290–305 nm,
with a shoulder band around 370–390 nm, and with smaller
extinction coefficients of between 3980–6390 M−1 cm−1 and
890–1170 M−1 cm−1. Our studies also suggest that 3-acylidene
oxindoles typically exist as E-isomers with a configurationally
labile double bond, but that those analogues bearing a substi-
tuent at the 4-position are exceptions that exist as Z-geometri-
cal isomers. These findings have implications for structure–
activity relationship data for this compound class (e.g. com-
pounds 2, 3 in Fig. 1), and could prove to be of use in the
design of new bioactive molecules.
The X-ray crystallography studies together with calculated
optimised structures allow us to formulate a rationale for the
observed trends in these UV-Vis spectra. 3E-Acylidene 2-oxin-
doles can adopt a fully planar orientation A with the carbonyl
groups opposing to minimise dipole–dipole interactions. The
Experimental
Representative procedure: preparation of E-3-(2-oxo-2-
phenylethylidene)indolin-2-one 58
Isatin (5.00 g, 34.0 mmol) was dissolved in MeOH (340 mL)
and acetophenone (6.10 g, 34.0 mmol) was added, followed by
diethylamine (10 drops). The reaction mixture was stirred at
20 °C for 18 hours upon which the condensation product pre-
cipitated as a colourless solid (8.85 g, 64%).
The colourless solid (5.00 g, 18.7 mmol) was dispersed in
EtOH (200 mL) and treated with 37% HCl(aq.) (2 mL) and
glacial ethanoic acid (50 mL). The reaction mixture was heated
to reflux upon which it became homogeneous and turned red.
After heating at reflux for 16 hours, the reaction mixture was
Fig. 12 The calculated UV-Vis spectrum for chloro-oxindole isomers.
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cooled to room temperature and quenched with saturated 114.4, 110.3, 55.7; FTIR (thin film cm−1)νmax: 1715 (s),
NaHCO3(aq.). The reaction mixture was extracted with ethyl 1655 (m), 1614 (m), 1572 (m), 1465 (w), 1335 (w), 1241 (m),
acetate (2 × 100 mL), and the combined extracts were dried 1181 (m), 1015 (w), 842 (w), 782 (m); HRMS (TOF MS ES+); m/z
over magnesium sulfate. The solvent was removed in vacuo to calculated for 280.0974, found 280.0983.
give the title compound 5 as an orange solid, 4.10 g, 95%
E-3-(2-Oxo-2-(pyridin-3-yl)ethylidene)indolin-2-one 8
(2 steps: 61% overall yield). The compound was further puri-
fied by recrystallisation from hot isopropyl alcohol; m.p. = Following the representative procedure, isatin (1.00 g,
179–180 °C; 1H NMR (250 MHz, DMSO) δ 10.82 (s, 1H, NH), 6.80 mmol), 3-acetylpyridine (1.23 g, 3.40 mmol) and diethyl-
8.07 (d, J = 7.0 Hz, 2H, ArH), 8.01 (d, J = 7.5 Hz, 1H, ArH), amine (3 drops) in MeOH (20 mL) gave the intermediate crude
7.75–7.67 (m, 2H, ArH, CH alkene), 7.65–7.55 (m, 2H, ArH), aldol addition product (1.60 g, 88%). Dehydration of this inter-
7.35 (td, J = 7.5, 1.0 Hz, 1H, ArH), 6.95 (td, J = 7.5, 1.0 Hz, 1H, mediate (1.00 g, 3.40 mmol) in EtOH (36 mL) using HCl(aq.)
ArH), 6.88 (d, J = 7.5 Hz, 1H, ArH); 13C NMR (100.6 MHz, (0.4 mL) and glacial ethanoic acid (10 mL) provided 8 as a
CDCl3) δ 191.1, 169.7, 143.4, 137.5, 136.9, 133.9, 132.8, 129.0, dark red solid, 0.23 g, 48% (2 steps: 42% overall yield). The
128.8, 128.0, 126.5, 122.9, 120.6, 110.3; FTIR (thin film compound was further purified by recrystallisation from EtOH;
1
cm−1)νmax: 1714 (s), 1660 (s), 1462 (m), 1326 (s), 1228 (s), m.p. = 160–161 °C; H NMR (250 MHz, DMSO) δ 10.84 (s, 1H,
1016 (m), 780 (w), 749 (w); HRMS (TOF MS ES+); m/z calculated NH), 9.21 (s, 1H, ArH), 8.86 (dd, J = 4.5, 1.0 Hz, 1H, ArH),
for 250.0869, found 250.0871.
8.49–8.36 (m, 1H, ArH), 8.16 (d, J = 8.0 Hz, 1H, ArH), 7.72 (s,
1H, CH alkene), 7.64 (dd, J = 7.5, 5.0 Hz, 1H, ArH), 7.64 (dd, J =
7.5, 5.0 Hz, 1H, ArH), 7.38 (t, J = 7.5 Hz, 1H, ArH), 6.98 (t, J =
E-3-(2-(4-Chlorophenyl)-2-oxoethylidene)indolin-2-one 6
Following the representative procedure, isatin (0.50 g, 7.5 Hz, 1H, ArH), 6.89 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
3.40 mmol), 4-chloroacetophenone (0.53 g, 3.40 mmol) and (100.6 MHz, DMSO) δ 191.3, 169.1, 154.8, 150.5, 146.2, 138.2,
diethylamine (2 drops) in MeOH (35 mL) gave the intermediate 137.0, 134.3, 133.6, 128.0, 125.7, 125.1, 122.7, 120.8, 111.4;
crude aldol addition product (1.00 g, 100%). Dehydration of FTIR (thin film cm−1)νmax: 1714 (m), 1599 (s), 1462 (w),
this intermediate (1.00 g, 3.40 mmol) in EtOH (35 mL) using 1015 (m), 786 (m), 751 (m); HRMS (TOF MS ES+); m/z calcu-
HCl(aq.) (0.4 mL) and glacial ethanoic acid (10 mL) provided 6 lated for 251.0821, found 251.0828.
as a dark red solid, 0.68 g, 70% (2 steps: 70% overall yield).
E-1-Methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one 9
The compound was further purified by recrystallisation from
1
hot isopropyl alcohol; m.p. = 177–178 °C; H NMR (250 MHz, Following the representative procedure, N-methyl isatin
DMSO) δ 10.83 (s, 1H, NH), 8.09 (d, J = 8.5 Hz, 2H, ArH), 8.05 (1.00 g, 6.20 mmol), acetophenone (1.12 g, 9.32 mmol) and
(d, J = 7.5 Hz, 1H), 7.69 (s, 1H, CH alkene), 7.67 (d, J = 8.5 Hz, diethylamine (5 drops) in MeOH (60 mL) gave the intermediate
2H, ArH), 7.36 (td, J = 7.5, 1.0 Hz, 1H, ArH), 6.96 (td, J = 7.5, crude aldol addition product (1.08 g, 65%). Dehydration of
1.0 Hz, 1H, ArH), 6.89 (d, J = 7.5 Hz, 1H, ArH); 13C NMR this intermediate (0.90 g, 3.20 mmol) in EtOH (30 mL) using
(100.6 MHz, DMSO) δ 190.1, 168.1, 145.1, 139.0, 136.8, 135.8, HCl(aq.) (0.4 mL) and glacial ethanoic acid (10 mL) provided 9
133.2, 130.5, 129.3, 126.9, 125.3, 121.8, 119.9, 110.4; FTIR (thin as a red solid, 0.54 g, 94% (2 steps: 61% overall yield). The
film cm−1)νmax: 1717 (s), 1667 (w), 1602 (m), 1403 (w), 1332 compound was further purified by recrystallisation by slow
(m), 1233 (w), 1009 (w), 839 (m), 782 (m); HRMS (TOF MS ES+); diffusion of petroleum ether (40–60) in a CH2Cl2 solution;
1
m/z calculated for 284.0478, found 284.0490.
m.p. = 97–98 °C; H NMR (400 MHz, DMSO) δ 8.08 (d, J = 7.5
Hz, 2H, ArH), 7.99 (d, J = 7.5 Hz, 1H, ArH), 7.80 (s, 1H, CH
alkene), 7.73 (t, J = 7.5 Hz, 1H, ArH), 7.61 (t, J = 7.5 Hz, 2H,
E-3-(2-(4-Methoxyphenyl)-2-oxoethylidene)indolin-2-one 7
Following the representative procedure, isatin (2.00 g, ArH), 7.44 (t, J = 7.5 Hz, 1H, ArH), 7.07 (d, J = 7.5 Hz, 1H, ArH),
13.6 mmol), 4-methoxyacetophenone (3.10 g, 20.4 mmol) and 7.02 (t, J = 7.5 Hz, 1H, ArH), 3.21 (s, 3H, CH3); 13C NMR
diethylamine (1.50 g, 20.4 mmol) in MeOH (150 mL) (gave the (100.6 MHz, CDCl3) δ 188.6, 146.3, 137.3, 135.7, 134.7, 133.3,
intermediate crude aldol addition product (3.00 g, 72%). Dehy- 129.7, 129.3, 129.1, 127.4, 126.6, 122.8, 119.7, 109.7, 26.7; FTIR
dration of this intermediate (1.00 g, 3.37 mmol) in EtOH (thin film cm−1)νmax: 1715 (s), 1662 (s), 1601 (s), 1367 (m),
(35 mL) using HCl(aq.) (0.4 mL) and glacial ethanoic acid 1338 (m), 1228 (s), 1100 (w), 1011 (w), 778 (w), 750 (m); HRMS
(10 mL) gave a crude red solid which was purified by flash (TOF MS ES+); m/z calculated for 264.1025, found 264.1036.
column chromatography on silica gel (1 : 1 ethyl acetate–
E-3-(2-(4-Chlorophenyl)-2-oxoethylidene)-1-methylindolin-2-
one 10
petroleum ether) providing 7 as an orange solid, 0.58 g, 62%
(2 steps: 44% overall yield). The compound was further puri-
fied by recrystallisation from hot isopropyl alcohol; m.p. = Following the representative procedure, N-methyl isatin
169–170 °C; 1H NMR (250 MHz, DMSO) δ 10.78 (s, 1H, NH), (0.50 g, 3.10 mmol), 4-chloroacetophenone (0.72 g, 4.66 mmol)
8.03 (d, J = 9.0 Hz, 2H, ArH), 7.96 (d, J = 7.5 Hz, 1H, ArH), 7.65 and diethylamine (5 drops) in MeOH (30 mL) gave the inter-
(s, 1H, ArH), 7.31 (td, J = 7.5, 1.0 Hz, 1H, ArH), 7.08 (d, J = mediate crude aldol addition product (0.81 g, 97%). Dehy-
9.0 Hz, 2H, ArH), 6.90 (dd, J = 16.0, 8.0 Hz, 2H, ArH), 3.85 (s, dration of this intermediate (0.81 g, 2.60 mmol) in EtOH
3H, CH3); 13C NMR (100.6 MHz, DMSO) δ 189.6, 168.3, 163.9, (25 mL) using HCl(aq.) (0.3 mL) and glacial ethanoic acid
144.7, 135.7, 132.6, 131.1, 130.0, 126.6, 126.5, 121.7, 120.1, (8 mL) provided 10 as an red solid, 0.73 g, 94% (2 steps: 91%
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overall yield). The compound was further purified by recrystal- 1016 (m), 842 (m), 824 (s) 722 (s), 682 (s); HRMS (TOF MS
lisation by slow diffusion of petroleum ether (40–60) in a ES+); m/z calculated for 284.0478, found 284.0487.
CH2Cl2 solution; m.p. = 140–141 °C; 1H NMR (400 MHz,
E-6-Chloro-3-(2-(4-chlorophenyl)-2-oxoethylidene)indolin-2-one
13
DMSO) δ 8.10 (d, J = 8.5 Hz, 1H, ArH), 8.02 (d, J = 7.5 Hz, 1H,
ArH), 7.77 (s, 1H, CH alkene), 7.68 (d, J = 8.5 Hz, 1H, ArH),
7.46 (td, J = 8.0, 1.0 Hz, 1H, ArH), 7.08 (d, J = 8.0 Hz, 1H, ArH), Following the representative procedure 6-chloro isatin (0.50 g,
7.04 (td, J = 7.5, 1.0 Hz, 1H, ArH), 3.21 (s, 1H, CH3); 13C NMR 2.75 mmol), 4-chloroacetophenone (0.64 g, 4.13 mmol) and
(100.6 MHz, CDCl3) δ 189.7, 167.9, 146.3, 140.4, 137.2, 136.1, diethylamine (0.30 g, 4.13 mmol) in MeOH (30 mL) gave the
133.0, 130.3, 129.3, 128.0, 125.3, 122.9, 120.1, 108.4, 26.4; FTIR intermediate crude aldol addition product (0.67 g, 72%). Dehy-
(thin film cm−1)νmax: 1705 (s), 1660 (s), 1601 (s), 1470 (m), dration of this intermediate (0.50 g, 1.49 mmol) in EtOH
1402 (w), 1369 (m), 1336 (m), 1231 (s), 1093 (m), 1009 (m), (15 mL) using HCl(aq.) (0.5 mL) and glacial ethanoic acid
837 (m), 780 (m), 743 (s); HRMS (TOF MS ES+); m/z calculated (1.5 mL) provided 13 as a red solid, 0.34 g, 72% (2 steps: 52%
for 298.0635, found 298.0646.
overall yield). The compound was further purified by recrystal-
lisation from hot isopropyl alcohol; m.p. = 239–241 °C; 1H
NMR (250 MHz, DMSO) δ 10.99 (s, 1H, NH), 8.10 (t, J = 8.5 Hz,
3H, ArH), 7.73 (s, 1H, CH alkene), 7.67 (d, J = 8.5 Hz, 2H, ArH),
7.05 (dd, J = 8.0, 2.0 Hz, 1H, ArH), 6.90 (d, J = 2.0 Hz, 1H, ArH);
13C NMR (100.6 MHz, DMSO) δ 189.7, 168.1, 146.4, 139.0,
137.2, 135.9, 135.7, 130.5, 129.2, 128.4, 125.5, 121.6, 118.8,
110.4; FTIR (thin film cm−1)νmax: 3160 (w), 1726 (s), 1665 (m),
1622 (m) 1603 (m), 1436 (m), 1329 (m), 1231 (w), 1010 (w),
840 (m), 824 (m); HRMS (EI+); m/z calculated for 317.0010,
found 316.9999.
E-3-(2-(4-Methoxyphenyl)-2-oxoethylidene)-1-methylindolin-2-
one 11
Following the representative procedure, N-methyl isatin
(0.50 g, 3.10 mmol), 4-methoxyacetophenone (0.70 g,
4.66 mmol) and diethylamine (5 drops) in MeOH (30 mL) gave
the intermediate crude aldol addition product (0.88 g, 91%).
Dehydration of this intermediate (0.88 g, 2.82 mmol) in EtOH
(30 mL) using HCl(aq.) (0.3 mL) and glacial ethanoic acid
(8 mL) provided 11 as an orange solid, 0.77 g, 94% (2 steps:
86% overall yield). The compound was further purified by
recrystallisation by slow diffusion of petroleum ether (40–60)
Z-4-Chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one 144
Following the representative procedure 4-chloro isatin (1.00 g,
5.50 mmol), acetophenone (0.72 g, 6.00 mmol) and diethyl-
amine (0.44 g, 6.00 mmol) in MeOH (50 mL) gave the inter-
mediate crude aldol addition product (1.25 g, 75%).
Dehydration of this intermediate (0.50 g, 1.66 mmol) in EtOH
(15 mL) using HCl(aq.) (0.2 mL) and glacial ethanoic acid
(5 mL) provided 14 as a yellow solid, 0.21 g, 45% (2 steps: 34%
overall yield). The compound was further purified by recrystal-
lisation from hot isopropyl alcohol; m.p. = 156–158 °C; 1H
NMR (400 MHz, DMSO) δ 10.90 (s, 1H, NH), 7.95 (s, 1H, CH
alkene), 7.93 (d, J = 7.5 Hz, 2H, ArH), 7.67 (t, J = 7.5 Hz, 1H,
ArH), 7.54 (t, J = 7.5 Hz, 2H, ArH), 7.34 (t, J = 8.0 Hz, 1H, ArH),
7.11 (d, J = 8.0 Hz, 1H, ArH), 6.87 (d, J = 8.0 Hz, 1H, ArH); 13C
NMR (100.6 MHz, DMSO) δ 194.4, 166.2, 145.3, 138.9, 136.0,
1
in a CH2Cl2 solution; m.p. = 104–105 °C; H NMR (400 MHz,
DMSO) δ 8.06 (d, J = 9.0 Hz, 2H, ArH), 7.91 (d, J = 7.5 Hz, 1H,
ArH), 7.77 (s, 1H, CH, alkene), 7.43 (t, J = 7.5 Hz, 1H, ArH),
7.13 (d, J = 9.0 Hz, 2H, ArH), 7.07 (d, J = 7.5 Hz, 1H, ArH), 7.01
(t, J = 7.5 Hz, 1H, ArH), 3.87 (s, 3H, CH3), 3.21 (s, 3H, CH3); 13
C
NMR (100.6 MHz, CDCl3) δ 189.4, 167.9, 164.0, 145.7, 135.6,
132.1, 131.1, 130.6, 127.4, 126.7, 122.6, 120.0, 114.0, 108.0,
55.5, 26.1; FTIR (thin film cm−1)νmax: 1713 (m), 1656 (m),
1602 (s), 1469 (m), 1337 (m), 1238 (s), 1172 (m), 1100 (w),
1026 (m), 841 (w), 783 (w), 752 (w); HRMS (TOF MS ES+); m/z
calculated for 294.1130, found 294.1124.
E-6-Chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one 12
Following the representative procedure 6-chloro isatin (0.50 g, 135.0, 132.5, 131.3, 130.8, 129.8, 129.4, 123.3, 118.0, 109.6.
2.75 mmol), acetophenone (0.47 g, 4.13 mmol) and diethyl-
Z-4-Chloro-3-(2-(4-chlorophenyl)-2-oxoethylidene)indolin-2-one
amine (0.30 g, 4.13 mmol) in MeOH (30 mL) gave the inter-
mediate crude aldol addition product (0.65 g, 78%).
154
Dehydration of this intermediate (0.45 g, 1.49 mmol) in EtOH Following the representative procedure 4-chloro isatin (1.00 g,
(15 mL) using HCl(aq.) (0.5 mL) and glacial ethanoic acid 5.50 mmol), 4-chloroacetophenone (0.93 g, 6.00 mmol) and
(1.5 mL) provided 12 as an orange solid, 0.77 g, 99% (2 steps: diethylamine (5 drops) in MeOH (50 mL) gave the intermediate
77% overall yield). The compound was further purified by crude aldol addition product (1.26 g, 68%). Dehydration of
recrystallisation from hot isopropyl alcohol; m.p.
=
this intermediate (0.56 g, 1.66 mmol) in EtOH (15 mL) using
229–230 °C; 1H NMR (250 MHz, DMSO) 1H NMR (400 MHz, HCl(aq.) (0.2 mL) and glacial ethanoic acid (5 mL) provided 15
DMSO) δ 11.00 (s, 1H, NH), 8.09 (t, J = 7.5 Hz, 1H, ArH), 7.77 as a yellow solid, 0.43 g, 81% (2 steps: 55% overall yield). The
(s, 1H, CH alkene), 7.73 (t, J = 7.5 Hz, 1H, ArH), 7.61 (t, J = 7.5 compound was further purified by recrystallisation from hot
Hz, 1H, ArH), 7.04 (dd, J = 7.5, 2.0 Hz, 1H, ArH), 6.91 (d, J = 2.0 isopropyl alcohol; m.p. = 218–219 °C. 1H NMR (250 MHz,
Hz, 1H, ArH); 13C NMR (100.6 MHz, DMSO) δ 191.0, 168.2, DMSO) δ 10.91 (s, 1H, NH), 7.93 (d, J = 8.0 Hz, 2H, ArH), 7.91
146.3, 137.0, 135.4, 134.1, 129.1, 128.8, 128.6, 128.2, 126.2, (s, 1H, CH alkene), 7.59 (d, J = 8.0 Hz, 2H, ArH), 7.34 (t, J = 7.5
121.6, 118.8, 110.4. FTIR (thin film cm−1)νmax:, 1728 (s), Hz, 1H, ArH), 7.10 (d, J = 7.5 Hz, 1H, ArH), 6.86 (d, J = 7.5 Hz,
1663 (m), 1624 (w) 1600 (m), 1447 (w), 1334 (m), 1236 (w), 1H, ArH); 13C NMR (100.6 MHz, DMSO) δ 194.8, 165.7, 144.8,
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136.2, 135.7, 133.6, 131.9, 130.5, 129.3, 128.8, 128.5, 122.8, CH2Cl2 solution; m.p. = 187–189 °C; 1H NMR (400 MHz,
117.7, 109.0.
DMSO) δ 9.06 (d, J = 2.0 Hz, 1H, ArH), 8.82 (d, J = 5.0 Hz, 1H,
ArH), 8.28 (dt, J = 8.0, 2.0 Hz, 1H, ArH), 8.01 (s, 1H, CH
alkene), 7.58 (ddd, J = 8.0, 5.0, 0.5 Hz, 1H, ArH), 7.45 (t, J = 8.0
Hz, 1H, ArH), 7.19 (d, J = 8.0 Hz, 1H, ArH), 7.08 (d, J = 8.0 Hz,
Z-4-Chloro-3-(2-oxo-2-(pyridin-3-yl)ethylidene)indolin-2-one
164
Following the representative procedure 4-chloro isatin (0.50 g, 1H, ArH), 3.09 (s, 3H, CH3); 13C NMR (100.6 MHz, DMSO) δ
2.75 mmol) and 3-acetylpyridine (0.50 g, 4.13 mmol) and 194.8, 164.8, 154.2, 150.0, 146.5, 136.3, 135.8, 132.4, 131.7,
diethylamine (0.30 g, 4.13 mmol) in MeOH (30 mL) gave the 130.6, 129.7, 124.5, 123.9, 117.4, 108.7, 26.6.
intermediate crude aldol addition product (0.83 g, 100%).
Dehydration of this intermediate (0.25 g, 0.93 mmol) in EtOH
(10 mL) using HCl(aq.) (0.4 mL) and glacial ethanoic acid
(1 mL) provided 16 as a yellow solid, 0.04 g, 17% (2 steps: 17%
overall yield). The compound was further purified by recrystal-
lisation from hot isopropyl alcohol; m.p. = 193–194 °C; 1H
NMR (400 MHz, DMSO) δ 10.94 (s, 1H, NH), 9.05 (s, 1H, ArH),
8.81 (d, J = 4.0 Hz, 1H, ArH), 8.27 (dd, J = 6.0, 2.0 Hz, 1H, ArH),
7.92 (s, 1H, ArH), 7.62–7.54 (m, 1H, ArH), 7.33 (q, J = 8.0 Hz,
1H, ArH), 7.11 (d, J = 8.0 Hz, 1H, ArH), 6.88 (t, J = 8.0 Hz, 1H,
ArH); 194.5, 165.6, 153.6, 149.5, 144.9, 135.8, 134.8, 132.0,
131.2, 131.2, 129.4, 124.0, 122.8, 117.6, 109.2.
Z-4-Methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one 19
Following the representative procedure 4-chloro-1-methylindo-
line-2,3-dione (0.08 g, 0.50 mmol), acetophenone (0.09 g,
0.75 mmol) and diethylamine (0.06 g, 0.75 mmol) in MeOH
(5 mL) gave the intermediate crude aldol addition product.
This material was directly dispersed in EtOH (2 mL) and
treated with 37% HCl(aq.) (0.08 mL, 0.99 mmol) and glacial
ethanoic acid (0.23 mL, 3.96 mmol) to provide 19 as a yellow
solid. This compound was purified by recrystallisation by slow
diffusion of petroleum ether (40–60) in a CH2Cl2 solution to
1
give 19, 0.05 g, 80%; m.p. = 182–184 °C; H NMR (400 MHz,
CDCl3) δ 8.16–7.97 (m, 3H, ArH), 7.60 (t, J = 7.5 Hz, 1H, ArH),
7.49 (t, J = 7.5 Hz, 2H, ArH), 7.22–7.16 (m, 1H, ArH), 7.17 (s,
1H, CH alkene), 6.88 (d, J = 7.5 Hz, 1H, ArH), 6.64 (d, J = 7.5
Hz, 1H, ArH), 2.55 (s, 3H, CH3); 13C NMR (100.6 MHz, DMSO)
δ 195.5, 167.0, 142.1, 136.2, 135.7, 134.0, 133.6, 133.3, 130.6,
Z-4-Chloro-1-methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one
17
Following the representative procedure 4-chloro-3-hydroxy-1-
methyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)indolin-2-one (0.50 g,
2.56 mmol), acetophenone (0.46 g, 3.84 mmol) and diethyl-
amine (0.28 g, 3.84 mmol) in MeOH (25 mL) gave the inter-
mediate crude aldol addition product (0.81 g, 100%).
Dehydration of this intermediate (0.75 g, 2.50 mmol) in EtOH
(25 mL) using HCl(aq.) (0.3 mL) and glacial ethanoic acid
(7 mL) provided 17 as a yellow solid, 0.54 g, 58% (2 steps: 58%
overall yield). The compound was further purified by recrystal-
128.8, 125.1, 119.4, 108.2 20.5; FTIR (thin film cm−1)νmax
:
2824 (w), 2853 (w), 1710 (s), 1662 (s), 1616 (m), 1597 (m),
1449 (w), 1336 (m), 1244 (w), 742 (m); HRMS (TOF MS ES+);
m/z calculated for 264.1025, found 264.1019.
Z-3-(2-Oxo-2-phenylethylidene)indolin-2-one Z-56
lisation by slow diffusion of petroleum ether (40–60) in a E-3-(2-Oxo-2-phenylethylidene)indolin-2-one
(0.50
g,
CH2Cl2 solution; m.p. = 196–198 °C; 1H NMR (250 MHz, 2.00 mmol) was dissolved in CH2Cl2 (25 mL) and treated with
DMSO) δ 8.03 (s, 1H, CH alkene), 7.97–7.87 (m, 2H, ArH), 7.67 aluminium trichloride (0.27 g, 2.00 mmol). The reaction
(t, J = 7.0 Hz, 1H, ArH), 7.59–7.48 (m, 2H, ArH), 7.43 (t, J = mixture was stirred at 20 °C for 18 hours upon which a black
8.0 Hz, 1H, ArH), 7.17 (d, J = 8.0 Hz, 1H, ArH), 7.07 (d, J = precipitate formed. The reaction was quenched via slow
7.0 Hz, 1H, ArH), 3.08 (s, 3H, CH3); 13C NMR (100.1 MHz, addition of saturated NaHCO3(aq.) at 0 °C and then extracted
DMSO) δ 195.1, 164.7, 146.3, 137.2, 136.2, 134.2, 132.3, 129.9, with ethyl acetate (2 × 40 mL). The combined extracts were
129.6, 129.3, 129.0, 123.8, 117.4, 108.6, 26.5; FTIR (thin film dried over magnesium sulfate and the solvent was removed
cm−1)νmax: 1713 (s), 1663 (s), 1609 (s), 1457 (m), 1330 (m), in vacuo to give an orange solid, which was found to be a
1241 (w), 1123 (m), 1057 (w), 768 (m), 704 (m); HRMS (TOF MS mixture of isomers E : Z = 1 : 2). A further two subjections of
ES+); m/z calculated for 298.0635, found 298.0633.
the mixture to the above reactions conditions provided a final
ratio E : Z = 2 : 5. Separation of isomers was achieved via
reverse phase preparative HPLC (Waters XBridgeTM Prep C18
5 μm OBD 19 × 25 mm; eluting with 70 : 30 methanol–water at
Z-4-Chloro-1-methyl-3-(2-oxo-2-(pyridin-3-yl)ethylidene)-
indolin-2-one 184
Following the representative procedure 4-chloro-3-hydroxy-1- 17 mL min−1.) affording Z-5 as a yellow solid, 19 mg, 4%; m.p.
methyl-3-(2-oxo-2-(pyridin-3-yl)ethyl)indolin-2-one (1.07 g, = 155–157 °C; H NMR (400 MHz, DMSO) δ 10.59 (s, 1H, NH),
1
5.50 mmol), 3-acetylpyridine (0.73 g, 6.00 mmol) and diethyla- 7.93 (d, J = 7.5 Hz, 2H, ArH), 7.70 (s, 1H, CH alkene), 7.77–7.63
mine (0.44 g, 6.00 mmol) in MeOH (50 mL) gave the inter- (m, 2H, ArH), 7.54 (t, J = 7.5 Hz, 2H, ArH), 7.31 (t, J = 7.5 Hz,
mediate crude aldol addition product (1.60 g, 92%). 1H, ArH), 7.04 (t, J = 7.5 Hz, 1H, ArH), 6.87 (d, J = 7.5 Hz, 1H);
Dehydration of this intermediate (0.10 g, 0.32 mmol) in EtOH 13C NMR (100.6 MHz, DMSO) δ 195.5, 166.8, 143.4, 136.4,
(3 mL) using HCl(aq.) (0.04 mL) and glacial ethanoic acid 132.7, 132.6, 131.4, 129.3, 129.0, 122.4, 122.1, 110.6 (×2C);
(1 mL) provided 18 as a yellow solid, 0.54 g, 57% (2 steps: 52% FTIR (thin film cm−1)νmax: 1706 (s), 1660 (m), 1619 (w),
overall yield). The compound was further purified by recrystal- 1468 (m), 1349 (m), 1196 (w), 745 (m); HRMS (TOF MS ES+);
lisation by slow diffusion of petroleum ether (40–60) in a m/z calculated for 250.0868, found 250.0865.
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7 S. Wu, X. Zhu, W. He, R. Wang, X. Xie, D. Qin, L. Jing and
Z. Chen, Tetrahedron, 2013, 69, 11084.
Acknowledgements
We are grateful to the EPSRC and GlaxoSmithKline for gene-
rous financial support. We also thank Prof. Michael D. Ward
for careful proof-reading of this manuscript.
8 F. Braude and H. G. Lindwall, J. Am. Chem. Soc., 1933, 55,
325.
9 For the synthesis of N-methylisatins see: N. Ohmura,
A. Nakamura, A. Hamasaki and M. Tokunaga, Eur. J. Org.
Chem., 2008, 5042; D. Chan, K. Monaco, R. Wang and
M. Winters, Tetrahedron Lett., 1998, 39, 2933.
10 Storage of Z-5 as a solid at −20 °C resulted in <2% isomeri-
sation after 1 week. Z–E Isomerisation of substrates 6, 7
and 9 was also observed when these samples were stored
in d6-dimethyl sulfoxide or CDCl3.
11 See e.g. J. C. Arens, F. Berrué, J. K. Pearson and
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