Asymmetric organocatalytic aza-michael reactions of isatin derivatives

Article abstract of DOI:10.1055/s-0034-1379956

Isatin was activated by derivatization to a Schiff base with aniline and used as an aza-Michael donor in organocatalytic asymmetric reactions with symmetric and nonsymmetric unsaturated 1,4-diketones. After hydrolysis (in situ), the N-substituted isatins were obtained in high yields (up to >95%) with high enantioselectivity (up to 95%).

Full text of DOI:10.1055/s-0034-1379956

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 875–886
paper
875
S. Žari et al.
Paper
Synthesis
Asymmetric Organocatalytic Aza-Michael Reactions of Isatin
Derivatives
path A
low reactivity
moderate stereoselectivity
by-product formation
yield up to 59%
Sergei Žari
O
Andrus Metsala
Marina Kudrjashova
Sandra Kaabel
Ivar Järving
path A
X = O
X
O
O
R2
ee up to 62%
thiourea catalyst (10 mol%)
N
+
R1
1 = Me, Ar
R2 = Me, Ar, OMe
+ other electrophiles
O
path B
X = N-Ph
1. thiourea catalyst (10 mol%)
2. THF–HCl (10%)
path B
high reactivity
high stereoselectivity
no by-product formation
yield up to 97%
N
O
R2
R
H
*
R1
Tõnis Kanger*
O
O
ee up to 95%
Department of Chemistry, Tallinn University of Technology,
Akadeemia tee 15, 12618 Tallinn, Estonia
tonis.kanger@ttu.ee
Received: 05.11.2014
Accepted after revision: 05.12.2014
Published online: 14.01.2015
ric reactions of 1,4-dicarbonyl compounds15 and oxindole
derivatives,16 we have previously applied the concept of re-
mote activation of the nucleophilicty of isatin for the enan-
tioselective aza-Michael addition.17 (Scheme 1). It was
found that derivatization of isatin (1) to Schiff base 2 was
the crucial step for obtaining aza-Michael products 4 in
high yields with high enantioselectivity (Scheme 1, path A
vs path B), as well as reducing the reaction time and block-
ing possible by-product formation. The obtained N-alkylat-
ed products were easily converted back to isatins by acidic
hydrolysis with no loss of yield or enantiomeric excess. The
reactivity of the Schiff base strongly depended on the pri-
mary amine used. Imine derived from aniline (R3 = Ph) was
significantly more efficient than the others. NMR studies
revealed strong interactions between isatin Schiff bases 2
and thiourea catalyst I, but the results could not explain the
activation mechanism. In the current work, we focus on
broadening of the scope of aza-Michael reactions with oth-
er electrophiles, including nonsymmetric unsaturated 1,4-
diketones 5, symmetric diketones 6, and other typical
Michael acceptors. Computational chemistry methods are
used to rationalize this aza-Michael reaction.
In our previous work, keto esters were used as acceptors
(Scheme 1, R2 = OMe). Full regioselectivity was obtained
and only one isomer derived from the attack on the α-posi-
tion of the ester carbonyl was found. The transformation of
isatin 1 to imine 2 is essential due to the nucleophilicity of
the N-atom. Under thiourea catalysis, isatin itself reacts
with enolizable carbonyl compounds (such as unsaturated
diketones 5) via aldol condensation at C3.18 The reaction of
imine 2 with nonsymmetric 1,4-diketone 5a afforded,
through an aza-Michael reaction, two regioisomers derived
from either attack on the α-position of aliphatic (compound
7a, major product) or aromatic carbonyl (compound 8a, mi-
nor product) (Table 1).
DOI: 10.1055/s-0034-1379956; Art ID: ss-2014-t0676-op
Abstract Isatin was activated by derivatization to a Schiff base with
aniline and used as an aza-Michael donor in organocatalytic asymmetric
reactions with symmetric and nonsymmetric unsaturated 1,4-dike-
tones. After hydrolysis (in situ), the N-substituted isatins were obtained
in high yields (up to >95%) with high enantioselectivity (up to 95%).
Key words Michael addition, asymmetric catalysis, enantioselectivity,
chemoselectivity, imines
Isatin (1) is a well-known natural indole derivative.1 Be-
cause isatin derivatives display a broad spectrum of biolog-
ical activities,2 massive efforts have been made to access
them via chemical synthesis.3 The presence of the 1,2-
disubstituted aromatic ring, carbonyl group, and γ-lactam
moiety make isatin a versatile starting compound for a
wide range of chemical transformations4 including multi-
component reactions5 and the synthesis of spirocyclic com-
pounds.6 The nucleophilicity of the nitrogen atom is mainly
used for its alkylation,7 acylation,8 arylation,9 or aza-
Michael additions.10 However, not much attention has been
paid to the stereochemical aspects, as the obtained prod-
ucts are in most cases achiral or racemic. Medicinal chemis-
try studies have shown that N-substituted isatins,11 includ-
ing chiral ones in a racemic form,12 possess different phar-
maceutical properties. This makes a search for new
asymmetric N-derivatization methods of isatin actual. So
far, there have only been a few examples, where the N-sub-
stitution of isatin has been performed in an asymmetric
manner. Shi et al. reported allylic amination of Morita–
Baylis–Hillman carbonates with isatin in the presence of
cinchona alkaloids.13 Very recently, enantioselective proli-
nol-catalyzed N-alkylation of isatin acetals by enals was
disclosed by Lu.14 In our ongoing research on the asymmet-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886

876
S. Žari et al.
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Synthesis
with 1: low reactivity,
moderate stereoselectivity
yield 59%
O
path A
catalyst I (10 mol%)
toluene, r.t.
O
R2
O
ee 62%
+
R1
N
3
O
H
1
O
R
R
1 = Ph
R3
O
2 = OMe
N
path B
N
O
O
1.catalyst I (10 mol%)
toluene, r.t.
2. THF–HCl (10%)
4
R2
R2
O
+
R1
R1
N
3
H
O
2
O
R3 = Ph
R
R
1 = Ar, Me
2 = Ar, OMe
with 2: high reactivity,
high stereoselectivity
yield 97%
previous work: R1 = Ar, Me; R2 = OMe (3)
ee 94%
current work: R1 = Ar, R2 = Me (5) or R1 = R2 = Ar or Me (6) + other electrophiles
Scheme 1 Asymmetric aza-Michael addition of isatin (1) and isatin Schiff base 2 to unsaturated 1,4-dicarbonyl compounds
Table 1 Screening of Catalysts and Reaction Conditionsa
O
O
N
O
1) catalyst (10 mol%)
2) THF–HCl (10%)
O
N
O
O
N
O
+
O
Ph
+
Ph
N
O
H
O
O
5a
2
Ph
7a
8a
major product
minor product
Entry
Catalyst
Time (h)
Yield (%)b
7a/8ac
7a ee (%)d
1
2e
3f
I
4
20
3.5
20
72
7
91
85
8:1
85 (S)
88 (S)
87 (S)
86 (S)
92 (S)
83 (R)
86 (S)
80 (R)
67 (R)
35 (R)
nd
I
6.5:1
5:1
I
>95
>95
>95
>95
95
4g
5h
6
I
9.5:1
I
12:1
II
6:1
6:1
7
III
IV
V
VI
VII
VIII
IX
48
20
20
60
96
96
96
8
95
11.5:1
3.3:1
2.1:1
nd
9
95
10
11
12i
13i
94
traces
traces
traces
nd
nd
nd
nd
a Reaction was conducted in toluene at r.t. (unless otherwise stated).
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d The absolute configuration was determined by an X-ray structure analysis of compound 9b and is presumed to be the same. nd: not determined.
e The reaction was performed in THF.
f The reaction was performed in 1,2-DCE.
g Reaction at 2 °C.
h Reaction at –25 °C.
i Benzoic acid (10 mol%) was used as a co-catalyst.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886

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Synthesis
We started the optimization of this model reaction by
screening the catalyst and solvent (Table 1). Thioureas I–III
(Figure 1) exhibited a similar stereoselectivity pattern in
toluene (Table 1, entries 1, 6, 7). The reactions proceeded
smoothly, affording the product 7a in high yield with high
enantioselectivity; the ratio of regioisomers varied from
8:1 to 6:1.
Takemoto catalyst IV gave the highest regioselectivity,
but enantioselectivity was slightly lower (Table 1, entry 8).
Pihko’s catalysts V and VI,19 squaramide VII, and catalysts
with a primary amino group VIII and IX were not suitable
for the reaction (entries 9–13). Catalyst I showed a better
cumulative result (higher reactivity, allowing for further
improvement of both enantio- and regioselectivity by run-
ning the reaction at a lower temperature). By lowering the
temperature, the best regio-/enantioselectivity combina-
tion was achieved (entry 5), although the reaction became
significantly slower. Changing toluene to 1,2-DCE resulted
in a slightly faster reaction and better enantioselectivity at
the expense of regioselectivity, while THF made the reac-
tion sluggish, along with lowering regioselectivity.
yl aryl diketones 5 (Table 2). Decreasing the reaction tem-
perature allowed us to obtain most of the products in >90%
ee and in a high regioisomeric ratio. (As most of the prod-
ucts were obtained with moderate enantioselectivity at r.t.,
reactions were also conducted at 2 °C or –25 °C. The results
obtained at room temperature and a short discussion are
presented in a Table, see Supporting Information.) As ex-
pected, reaction rates and selectivities strongly depended
on the substituent R of the diketone 5. The major regioiso-
mer was always formed by attack on the α-carbon of meth-
yl ketone moiety. While electronegative or electron-with-
drawing groups on the phenyl ring 5d, 5e, 5f (entries 4–6)
activated the substrate for the favorable regioisomer 7 for-
mation, the electron-donating methoxy group in 5c (entry
3) resulted in significantly lower regioselectivity. Replacing
the phenyl ring with naphthyl did not change the result no-
ticeably (entries 1 and 2). Diketones with ketones with het-
eroaromatic substituents 5g, 5h were less suitable for the
reaction due to moderate enantioselectivity (entries 7, 8),
while the reaction with 2-pyrrolyl substituted diketone 5i
afforded a racemic product in very low yield and regioselec-
tivity (entry 9).
With the optimal conditions in hand (10 mol% of cata-
lyst I in toluene), we turned our attention to the scope of
the reaction starting with a variety of nonsymmetric meth-
N
N
N
i-Pr
S
S
S
MeO
Ar
Ar
MeO
N
N
N
N
N
N
H
H
H
H
H
H
i-Pr
N
N
N
III
II
I
F3C
CF3
O
O
Ar
N
N
Ar
H
Me
H
Me
N
N
N
H
H
O
H
N
H
O
N
OMe
S
S
N
Ar
N
S
N
N
H
HN
H
H
N
IV
V
VI
Me
Me
N
O
O
N
N
N
N
N
MeO
S
MeO
OMe
MeO
N
N
N
H
H
NH2
N
H
NH2
H
N
N
N
VIII
VII
IX
Ar = 3,5-(CF3)2Ph
Figure 1 Catalysts screened
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886

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Synthesis
Table 2 Reactions of Isatin Schiff Base 2 with Unsaturated Nonsymmetric 1,4-Diketones 5a–i
O
O
O
O
N
N
N
1. catalyst I (10 mol%)
toluene
O
R
+
O
+
R
N
O
2. THF–HCl (10%)
O
H
O
O
R
O
2
5a–i
8a–i
7a–i
7/8a
12:1
Entry
R
Temp (°C)
Time (h)
Yield (%)b
ee of 7 (%)c
1
2
3
4
5
6
7
8
9
a, Ph
–25
2
72
24
24
72
72
24
72
60
72
>95
>95
>95
>95
>95
85
92
90
93
90
92
89
66
74
rac
b, 2-naphthyl
c, 4-MeOC6H4
d, 4-ClC6H4
8.5:1
4.5:1
2
–25
–25
2
15.5:1
15:1
e, 4-BrC6H4
f, 4-O2NC6H4
g, 2-thiophenyl
h, 2-furanyl
i, 2-pyrrolyl
16.5:1
4:1
2
76
2
19.5:1
4:1
>95
10
r.t.
a Determined by 1H NMR spectroscopy.
b Isolated yield.
c Determined by chiral HPLC.
Table 3 Reactions of Isatin Schiff Base 2 with Unsaturated Symmetric 1,4-Diketones 6a–g
O
1. catalyst I (10 mol%)
1,2-DCE, r.t.
N
O
2. THF–HCl (10%)
O
R
N
O
R
O
+
R
N
O
H
6a–g
2
O
R
9a–g
Entry
R
Time (h)
Yield (%)
ee (%)a
1b
2c
3
a, Me
a, Me
b, Ph
b, Ph
16
36
2
66
93
40
83
95
44
95
84
87
64
ndf
>95
53
4d
5
24
c, 4-MeC6H4
d, 4-MeOC6H4
e, 4-ClC6H4
3.5
>95
>95
>95
72
6
36
30
7
8e
9
f, 4-BrC6H4
228
g, 4-O2NC6H4
4.5
74
a Determined by chiral HPLC; nd = not determined.
b The reaction was performed in toluene.
c The reaction was performed in toluene in the presence of 10 mol% of catalyst IV.
d The reaction was carried out in toluene with isatin (1) instead of Schiff base 2.
e The reaction was carried out under more diluted conditions (0.2 M).
f Resolution of the enantiomers was not possible.
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Figure 2 Two-component complexes between catalyst I and imine 2 (A) and isatin (B)
Next, the reaction with symmetric diketones 6a–g was
investigated. As in this case no regioisomers can be formed,
1,2-DCE was the optimal solvent. (A Table comparing the
reactions in 1,2-DCE and toluene together with a short dis-
cussion is presented in Supporting Information.) The re-
sults are shown in Table 3.
antiomeric purity. In the reactions with unsaturated 1,4-
keto sulfone and β-nitro ester, only traces of products 14
and 15 were detected. In our previous work, we had shown
that unsaturated keto esters were excellent Michael accep-
tors affording product 16. To rationalize the reactivity of
imines derived from isatin and the stereochemical out-
come, this reaction was investigated by theoretical calcula-
tions. Pre-reaction states of imine or isatin with thiourea
catalyst I were determined by molecular dynamics simula-
tions using an AMBER99 force field. The formation of the
hydrogen bonding between the catalyst and imine 2 versus
isatin (1) was compared. The simulation results revealed
that the imine was more involved in the hydrogen bonding
network. The prevailing number of hydrogen bonds along
the molecular dynamic trajectory for imine ranges from
two to three, whereas for isatin this number is one (Table
4). In the case of imine there are two bonds between N–H
atoms of the catalyst and the carbonyl group of oxindole
ring together with the hydrogen bond between N–H (oxin-
dole ring) and the tertiary amino group in the catalyst. For
isatin only one bond is formed in the participation of the
sulfur atom of the catalyst and N–H of the imine (Figure 2).
In the pre-reaction state, a well-defined complex with
imine was formed whereas the complex with isatin had
more conformational diversity. Adding the keto ester, meth-
yl (E)-4-oxopent-2-enoate, to those two-component sys-
tems changed the hydrogen bondings network substantial-
ly. In the case of a three-component system (catalyst I +
isatin + keto ester), the complex of sulfur hydrogen-bonded
with isatin nitrogen disappeared, but very large numbers of
different lowly populated hydrogen-bonded complexes ap-
peared making these states very diverse. With imine 2 the
lowest energy complexes were nonreactive. However, the
complex where the nucleophilicity of the nitrogen atom
was increased by a hydrogen bond between the tertiary
amino group of the catalyst and between the carbonyl
group and N–H atoms was also present (Figure 3).
Aliphatic diketone 6a afforded product 9a in low yield
due to the formation of by-products (Table 3, entry 1). Re-
placing thiourea I with Takemoto catalyst IV resulted in ob-
taining a high yield of the product with acceptable enantio-
selectivity (Table 3, entry 2). Phenyl and tolyl-substituted
aromatic diketones 6b and 6c reacted smoothly, affording
the product in high yields and with excellent enantioselec-
tivities (entries 3, 4). The reaction with a methoxy-substi-
tuted inactivated Michael acceptor diketone 6d was consid-
erably slower, but the product was also obtained in excel-
lent yield and slightly lower enantioselectivity (entry 6).
The diketones 6e and 6f substituted with 4-ClC6H4 and 4-
BrC6H4 showed a substantial difference in reactivity: in the
case of 6e the reaction was complete in a reasonable time,
while a longer reaction time was needed for the bromophe-
nyl compound 6f, most probably due to solubility issues
(entries 7, 8). Nitro-substituted diketone 6g reacted
smoothly, but we were unable to determine its enantiomer-
ic purity by chiral HPLC. An additional experiment showed
that, as in the case of unsaturated 1,4-keto esters, derivat-
ization of isatin (1) to a Schiff base 2 was essential for high
yield and enantioselectivity (entry 3 vs 4). We next exam-
ined the reaction of isatin Schiff base 2 with other typical
Michael acceptors (Scheme 2). Reactions with chalcone and
its methyl analogue afforded the aza-Michael products 10,
11 with high enantioselectivities; however, chalcone was
less reactive, probably due to sterical hindrance near the
stereogenic center. The symmetric unsaturated diester af-
forded the product 12 in low yield and with moderate enan-
tioselectivity. For the reaction with alkylidenemalonate, a
more reactive nitro analogue of Schiff base 2 was needed.
Still, the product 13 was obtained in low yield with low en-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886

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Synthesis
N
1. catalyst I (10 mol%)
solvent, r.t.
2. THF/HCl (10%)
R
O
electrophile
+
products 10–16
N
H
2
R = H, NO2
O
O
O
O
O
O
O
O
O
N
N
N
BnO
OBn
Ph
Ph
Ph
O
10
11
12
1,2-DCE, 96 h
yield 39%, ee 92%
1,2-DCE, 24 h
yield 93%, ee 93%
toluene, 128 h
yield 16%, ee 51%
O
O
O
O
O2N
O
O
O
O
N
O
N
N
N
O
O
O
MeO
EtO
NO2
S
Ph
O
O
O
EtO
OEt
13
O
14
15
16
toluene, 24 h
yield 25%, ee 23%
toluene, 48 h
trace
toluene, 18 h
yield 80%, ee 97%
toluene, 24 h
trace
Scheme 2 Reactions with other electrophiles
Table 4 Comparison of the Population of H-Bonds between Catalyst I
and Imine 2 or Isatin (1) During 270 ns of Simulation
In conclusion, we have demonstrated the organocatalyt-
ic enantioselective aza-Michael addition of isatin Schiff
base 2 to both symmetric and nonsymmetric unsaturated
1,4-diketones and other electrophiles. The activation of
isatin by derivatization to imine 2 is essential to reveal its
aza-Michael donor properties. The high reactivity of imine
2 has been rationalized by molecular dynamics simulations.
Compound Probability of number of H-bonds (%)
0
1
2
3
>3
sum
imine 2
5.90
2.46
14.66
97.47
37.57
0.06
41.87
0
0
0
100
100
isatin (1)
1
Full assignment of H and 13C chemical shifts is based on the 1D and
2D FT NMR spectra measured on a Bruker Avance 400 MHz instru-
ment. Residual solvent signals were used [CDCl3 δ = 7.26 (1H NMR),
77.16 (13C NMR) or DMSO-d6 δ = 2.54 (1H NMR), 40.45 (13C NMR)] as
internal standards, unless otherwise indicated. Standard abbrevia-
tions were used to denote the peak multiplicities. High-resolution
mass spectra were recorded on an Agilent Technologies 6540 UHD
Accurate-Mass Q-TOF LC/MS spectrometer by using AJ-ESI ionization.
MS spectra were measured on GC-MS spectrometer on a 70 eV EI. Op-
tical rotations were obtained with an Anton Paar GWB Polarimeter
MCP500. Chiral HPLC was performed using Chiralpak AD-H (250 × 4.6
mm), Chiralcel OD-H (250 × 4.6 mm), or Chiralpak AS-H (250 × 4.6
mm) columns. Precoated silica gel (Merck 60 F254) plates were used
for TLC. Silica gel was used for column chromatography. The mea-
sured melting points are uncorrected. Commercial reagents were
used as received. The solvents were freshly distilled using standard
methods (CH2Cl2 and EtOAc over P2O5; benzene, toluene, and MeOH
over Na). Commercial 1,2-DCE used for asymmetric reactions was dis-
tilled over CaH2. The reactions were performed under air atmosphere
Figure 3 Three-component complex between catalyst I, imine 2 and
methyl (E)-4-oxopent-2-enoate
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Synthesis
without additional moisture elimination, unless stated otherwise.
Melting points and specific optical rotations for products 7/8 are re-
ported for the ones with regioisomeric ratios >10:1.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C9H9NO2: 164.0706; found:
164.0706.
Symmetric Diketones 6a–g; General Procedure
Molecular Dynamics Simulations
Diketones 6b, 6c, 6e, and 6f were prepared by Friedel–Crafts acylation
of substituted benzenes with fumaryl chloride.27 Compounds 6a and
6d were prepared by the same principle as the nonsymmetric dike-
tones. Compound 6g was prepared by a Wittig reaction with the cor-
responding α-ketoaldehyde.15a
The force field chosen was AMBER9920 with a cutoff value of 7.86 Å
for the Van der Waals forces; for the long range electrostatics the Par-
ticle Mesh Ewald approach (PME)21 was used. The simulation was run
under periodic boundary conditions, and at 298 K temperature and
1.0 atm of pressure. The NVT ensemble was simulated. Multiple time-
step was used: 1.25 fs for intramolecular and 2.50 fs for intermolecu-
lar forces. After each 10 ps all the coordinates of the complex were
saved as a snapshot. These MDS snapshots were prevailingly analyzed
with the help of Yasara software; however, part of the trajectory anal-
ysis was performed with the VMD molecular visualization and ana-
lyze package. All the trajectory snapshots were analyzed in terms of
hydrogen bond structure and dihedrical angle values. These values
were sorted and the duplicate snapshots were removed from the
analysis procedure. In such a way, the population analysis of all the
unique structures were performed. In order to mimic the influence of
solvent during subsequent MD runs, the simulation cell was ‘filled’
with toluene solvent in such a way that the solvent density fulfills the
density values of 0.87 g/mL. In this way, 478 toluene molecules ap-
pear in the corresponding simulation cell. The cell had dimensions of
44 × 44 × 44 Å.
Asymmetric Aza-Michael Reaction; General Procedure
Isatin Schiff base 2 (22.2 mg, 0.1 mmol), the corresponding electro-
phile (0.2 mmol), and catalyst I (6.0 mg, 0.01 mmol) were stirred in
toluene or 1,2-DCE (0.3 mL) at the reported temperature for the ap-
propriate time (Tables 2 and 3). In the case of the reactions carried
out at 2 or –25 °C, the reaction vessel containing the reagents and the
solvent were cooled prior to mixing together. The reactions were fol-
lowed by TLC (CH2Cl2–EtOAc, 20:1). The hydrolysis was carried out in
situ by adding a mixture of THF and 10% aq HCl (3:1, 1 mL) with vig-
orous stirring for 15–20 min. The reaction mixture was transferred to
separatory funnel, diluted with H2O (10 mL), and extracted with
CH2Cl2 (3 × 10 mL). The combined extracts were dried (MgSO4), con-
centrated, and the product was isolated by column chromatography.
The racemic standards were obtained by the same procedure using 1
equiv of K2CO3 as catalyst. After the completion of the reaction, the
mixture was separated from K2CO3, hydrolyzed, and purified in the
same manner.
The above prepared complex was allowed to run an MD simulation
within the time interval of 2000 ps for preliminary optimization of
the solvated structure. After that initial relaxation and optimization
step the actual simulation procedure was launched.
(S)-1-(1,4-Dioxo-1-phenylpentan-3-yl)indoline-2,3-dione (7a)
25
Yield: 30.5 mg (95%); orange amorphous solid; [α]D –136 (c 0.25,
CHCl3).
Chiral Catalysts
The catalysts I,22 II,22 VIII,22, III,16a IV,23 V,19 VI,19 VII,24 and IX25 were
prepared by the corresponding literature procedures and the analyti-
cal data matched with those previously reported.
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 17.56 min (major isomer), tR = 12.69 min (minor
isomer); enantiomeric ratio 96:4, ee 92%, regioisomeric ratio 12:1.
IR (KBr): 1742, 1683, 1612, 1469, 1358, 754, 690 cm–1
.
Isatin Schiff Bases
1H NMR (400 MHz, CDCl3): δ = 7.97–7.92 (m, 2 H), 7.68–7.61 (m, 2 H),
7.61–7.55 (m, 1 H), 7.46 (t, J = 7.7 Hz, 2 H), 7.21–7.15 (m, 1 H), 7.12 (d,
J = 8.0 Hz, 1 H), 5.46 (t, J = 6.3 Hz, 1 H), 4.13 (dd, J = 18.1, 6.4 Hz, 1 H),
3.50 (dd, J = 18.1, 6.3 Hz, 1 H), 2.26 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.1, 196.2, 182.1, 158.3, 149.9,
138.9, 136.0, 134.0, 128.9, 128.3, 126.0, 124.5, 118.2, 111.2, 56.8, 36.4,
26.9.
MS (70 eV): m/z = 321 [M+], 279, 250, 174, 159, 146, 119, 105, 92, 77,
43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H15NO4 + Na: 344.0893;
found: 344.0897.
The compounds 2 were prepared by condensation on isatin and ani-
line in boiling MeOH with AcOH as a catalyst.17
Nonsymmetric Unsaturated 1,4-Diketones; General Procedure
All compounds were prepared by the in situ oxidation/Wittig reaction
procedure, based on the method described in the literature.26 The
corresponding ylide (2.5 mmol, 1 equiv) was dissolved in CH2Cl2 (25
mL, 0.1 M), followed by the addition of 58% MnO2 (2.2 g, 10 equiv)
and hydroxyacetone (520 μL, 7.5 mmol, 3 equiv). The reaction mix-
ture was stirred for 24 h at r.t., filtered through Celite, concentrated
under reduced pressure, and the residue purified by column chroma-
tography on silica gel using heptane–EtOAc mixtures as eluent.
(S)-1-[1-(Naphthalen-2-yl)-1,4-dioxopentan-3-yl]indoline-2,3-di-
one (7b)
(E)-1-(1H-Pyrrol-2-yl)pent-2-ene-2,4-dione (5i)
Yield: 269 mg (66%); yellow crystalline solid; mp >105 °C (dec.).
Yield: 37 mg (>95%); orange amorphous solid.
IR (KBr): 3271, 1670, 1642, 1592, 1543, 1405, 1253, 1145, 991, 765,
IR (KBr): 2923, 1741, 1678, 1611, 1469, 1358, 1179, 860, 820, 753,
603, 567, 520 cm–1
.
475 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.99 (br s, 1 H), 7.52 (d, J = 15.7 Hz, 1
H), 7.19 (s, 1 H), 7.15 (d, J = 15.7 Hz, 1 H), 7.11 (s, 1 H), 6.42–6.33 (m, 1
H), 2.42 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 198.2, 177.8, 136.8, 134.2, 132.9,
127.4, 118.7, 111.8, 29.2.
1H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1 H), 7.96 (dd, J = 8.7, 1.7 Hz, 1
H), 7.93 (d, J = 8.0 Hz, 1 H), 7.88–7.83 (m, 2 H), 7.69–7.62 (m, 2 H),
7.62–7.57 (m, 1 H), 7.57–7.51 (m, 1 H), 7.21–7.14 (m, 2 H), 5.51 (t, J =
6.3 Hz, 1 H), 4.26 (dd, J = 18.0, 6.3 Hz, 1 H), 3.64 (dd, J = 18.0, 6.4 Hz, 1
H), 2.28 (s, 3 H).
MS (70 eV): m/z = 163 [M+], 148, 120, 94, 66, 43.
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S. Žari et al.
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 202.2, 196.1, 182.1, 158.4, 149.9,
138.9, 135.9, 133.3, 132.5, 130.4, 129.8, 129.0, 128.8, 127.9, 127.1,
126.0, 124.5, 123.6, 118.2, 111.2, 56.9, 36.5, 26.8.
MS (70 eV): m/z = 371 [M+], 329, 224, 181, 155, 127, 119, 105, 92, 77,
43.
IR (KBr): 1742, 1683, 1612, 1469, 1358, 1091, 996, 818, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.6 Hz, 2 H), 7.67–7.61 (m, 2
H), 7.42 (d, J = 8.6 Hz, 2 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 8.2 Hz, 1
H), 5.43 (t, J = 6.3 Hz, 1 H), 4.09 (dd, J = 18.0, 6.5 Hz, 1 H), 3.42 (dd, J =
18.0, 6.2 Hz, 1 H), 2.25 (s, 3 H).
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C23H17NO4 + Na: 394.1050;
found: 394.1055.
13C NMR (101 MHz, CDCl3): δ = 202.1, 195.1, 182.1, 158.3, 149.8,
140.4, 138.9, 134.3, 129.7, 129.2, 126.1, 124.6, 118.2, 111.1, 56.7, 36.3,
26.8.
MS (70 eV): m/z = 355 [M+], 313, 284, 208, 193, 139, 119, 111, 92, 75,
(S,E)-1-(Naphthalen-2-yl)-3-[2-oxo-3-(phenylimino)indolin-1-
yl]pentane-1,4-dione (7b imine)
43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H14ClNO4 + Na:
378.0504; found: 378.0508.
Obtained by the general procedure without hydrolysis to determine
the ee of 7b; orange amorphous solid.
HPLC: Chiralpak AS-H column; 254 nm, 7:3 hexane–i-PrOH, 0.8
mL/min, 35 °C; tR = 39.12 min (major isomer), tR = 19.02 min (minor
isomer); enantiomeric ratio 95:5.
(S)-1-[1-(4-Bromophenyl)-1,4-dioxopentan-3-yl]indoline-2,3-di-
one (7e)
25
IR (KBr): 1733, 1678, 1605, 1466, 1359, 1185, 1124, 862, 823, 751,
Yield: 39 mg (>95%); orange crystals; mp 159–161 °C; [α]D –108 (c
0.25, CHCl3).
659 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H), 8.00 (dd, J = 8.7, 1.6 Hz, 1
H), 7.94 (d, J = 8.0 Hz, 1 H), 7.90–7.83 (m, 2 H), 7.63–7.51 (m, 2 H),
7.46–7.39 (m, 3 H), 7.27–7.22 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.01–
6.95 (m, 2 H), 6.81 (t, J = 7.6 Hz, 1 H), 6.69 (d, J = 7.7 Hz, 1 H), 5.59 (t, J
= 5.9 Hz, 1 H), 4.32 (dd, J = 17.9, 6.3 Hz, 1 H), 3.68 (dd, J = 17.8, 6.2 Hz,
1 H), 2.32 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.8, 196.5, 163.3, 153.3, 150.2,
146.3, 135.9, 134.5, 133.5, 132.5, 130.4, 129.8, 129.6, 128.9, 128.7,
127.9, 127.0, 126.7, 125.6, 123.7, 123.4, 117.7, 116.2, 110.5, 56.9, 36.6,
26.8.
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 34.11 min (major isomer), tR = 21.16 min (minor
isomer); enantiomeric ratio 96:4, ee 92%, regioisomeric ratio 15:1.
IR (KBr): 1742, 1684, 1612, 1469, 1358, 1178, 1071, 997, 817, 755 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.5 Hz, 2 H), 8.68–8.62 (m, 2
H), 7.60 (d, J = 8.5 Hz, 2 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 7.9 Hz, 1
H), 5.43 (t, J = 6.3 Hz, 1 H), 4.09 (dd, J = 18.0, 6.5 Hz, 1 H), 3.41 (dd, J =
18.0, 6.2 Hz, 1 H), 2.25 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.1, 195.3, 182.0, 158.3, 149.8,
138.9, 134.7, 132.2, 129.8, 129.3, 126.1, 124.6, 118.2, 111.1, 56.7, 36.3,
26.8.
MS (70 eV): m/z = 446 [M+], 375, 355, 263, 222, 194, 155, 127, 77, 43.
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C29H22N2O3: 447.1703;
MS (70 eV): m/z = 401, 399 [M+], 359, 357, 330, 328, 254, 252, 239,
237, 211, 209, 185, 183, 157, 155, 147, 119, 92, 76, 43.
found: 447.1717.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H14BrNO4 + Na:
421.9998; found: 421.9999.
(S)-1-[1-(4-Methoxyphenyl)-1,4-dioxopentan-3-yl]indoline-2,3-
dione (7c)
Yield: 35 mg (>95%); orange amorphous solid.
(S)-1-[1-(4-Nitrophenyl)-1,4-dioxopentan-3-yl]indoline-2,3-dione
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 59.12 min (major isomer), tR = 23.25 min (minor
isomer); enantiomeric ratio 96.5:3.5, regioisomeric ratio 4.5:1.
(7f)
25
Yield: 31 mg (95%); orange crystalline solid; mp 149–152 °C; [α]D
–96 (c 0.25, CHCl3).
IR (KBr): 2926, 1742, 1673, 1611, 1469, 1358, 1260, 1172, 1025, 834,
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 41.01 min (major isomer), tR = 44.16 min (minor
isomer); enantiomeric ratio 94.5:5.5, ee 89%, regioisomeric ratio
16.5:1.
755 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.93–7.87 (m, 2 H), 7.66–7.59 (m, 2 H),
7.19–7.10 (m, 2 H), 6.93–6.88 (m, 2 H), 5.43 (t, J = 6.3 Hz, 1 H), 4.05
(dd, J = 17.9, 6.2 Hz, 1 H), 3.85 (s, 3 H), 3.47 (dd, J = 17.9, 6.5 Hz, 1 H),
2.25 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.2, 194.6, 182.2, 164.1, 158.3,
150.0, 138.8, 130.6, 129.0, 125.9, 124.4, 118.1, 114.0, 111.2, 56.9, 55.6,
36.0, 26.8.
IR (KBr): 1742, 1693, 1612, 1525, 1470, 1347, 1178, 856, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.33–8.27 (m, 2 H), 8.16–8.09 (m, 2 H),
7.71–7.63 (m, J = 7.3, 4.1, 1.2 Hz, 2 H), 7.21 (t, J = 7.7 Hz, 1 H), 7.09 (d,
J = 8.3 Hz, 1 H), 5.44 (t, J = 6.3 Hz, 1 H), 4.19 (dd, J = 18.1, 6.9 Hz, 1 H),
3.43 (dd, J = 18.1, 5.9 Hz, 1 H), 2.26 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.0, 195.0, 181.8, 158.3, 150.8,
149.6, 140.4, 139.0, 129.5, 126.2, 124.8, 124.1, 118.2, 110.9, 56.7, 36.9,
26.7.
MS (70 eV): m/z = 351 [M+], 309, 204, 146, 135, 107, 92, 77, 43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C20H17NO5 + Na: 374.0999;
found: 374.1003.
MS (70 eV): m/z = 366 [M+], 324, 295, 219, 204, 177, 150, 119, 104, 92,
76, 43.
(S)-1-[1-(4-Chlorophenyl)-1,4-dioxopentan-3-yl]indoline-2,3-di-
one (7d)
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C19H14N2O6 + Na: 389.0744;
found: 389.0747.
25
Yield: 35 mg (>95%); orange crystals; mp 149–153 °C; [α]D –123 (c
0.25, CHCl3).
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 27.51 min (major isomer), tR = 18.88 min (minor
isomer); enantiomeric ratio 95:5, ee 90%, regioisomeric ratio 15.5:1.
(S)-1-[1,4-Dioxo-1-(thiophen-2-yl)pentan-3-yl]indoline-2,3-dione
(7g)
Yield: 25 mg (76%); orange amorphous solid.
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Synthesis
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 17.40 min (major isomer), tR = 15.35 min (minor
isomer); enantiomeric ratio 83:17, regioisomeric ratio 4:1.
(R)-1-(2,5-Dioxohexan-3-yl)indoline-2,3-dione (9a)
25
Yield: 24 mg (93%); orange crystals; mp 123–125 °C; [α]D +129 (c
0.25, CHCl3).
IR (KBr): 1741, 1659, 1611, 1525, 1469, 1415, 1358, 1180, 1098, 1054,
HPLC: Chiralcel OD-H column; 254 nm, 7:3 hexane–i-PrOH,
mL/min, 35 °C; tR = 12.29 min (major isomer), tR = 14.39 min (minor
1
753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.76 (dd, J = 3.8, 1.1 Hz, 1 H), 7.67–7.61
(m, 3 H), 7.20–7.15 (m, 1 H), 7.14–7.10 (m, 2 H), 5.37 (t, J = 6.4 Hz, 1
H), 4.03 (dd, J = 17.7, 6.0 Hz, 1 H), 3.49 (dd, J = 17.7, 6.9 Hz, 1 H), 2.25
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 201.9, 189.0, 182.1, 158.3, 149.9,
142.9, 138.9, 134.8, 133.0, 128.5, 126.0, 124.5, 118.2, 111.1, 56.8, 36.9,
26.7.
isomer); enantiomeric ratio 91.5:8.5, ee 83%.
IR (KBr): 1757, 1736, 1723, 1610, 1472, 1449, 1364, 1193, 1172, 768
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65 (dd, J = 7.5, 0.8 Hz, 1 H), 7.61 (td,
J = 7.9, 1.4 Hz, 1 H), 7.18 (td, J = 7.6, 0.6 Hz, 1 H), 6.97 (d, J = 8.0 Hz, 1
H), 5.24 (t, J = 6.7 Hz, 1 H), 3.58 (dd, J = 18.0, 7.2 Hz, 1 H), 2.85 (dd, J =
18.0, 5.7 Hz, 1 H), 2.24 (s, 3 H), 2.19 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 204.5, 202.2, 182.1, 158.2, 149.7,
138.9, 126.1, 124.6, 118.2, 111.0, 56.5, 40.8, 30.2, 26.7.
MS (70 eV): m/z = 327 [M+], 299, 285, 256, 180, 146, 119, 111, 83.
HRMS (ESI-QTOF): m/z [M
+ + Na:
Na]+ calcd for C17H13NO4S
MS (70 eV): m/z = 259 [M+], 217, 188, 175, 146, 119, 90, 43.
350.0457; found: 350.0463.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C14H13NO4 + Na: 282.0737;
found: 282.0736.
(S)-1-[1-(Furan-2-yl)-1,4-dioxopentan-3-yl]indoline-2,3-dione
(7h)
25
Yield: 30 mg (>95%); orange amorphous solid; [α]D –113 (c 0.25,
CHCl3).
(S)-1-(1,4-Dioxo-1,4-diphenylbutan-2-yl)indoline-2,3-dione (9b)
25
Yield: 37 mg (>95%); yellow crystals; mp 74–76 °C; [α]D –228 (c
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 16.57 min (major isomer), tR = 13.78 min (minor
isomer); enantiomeric ratio 87:13, ee 74%, regioisomeric ratio 19.5:1.
0.25, CHCl3).
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 20.60 min (major isomer), tR = 19.11 min (minor
isomer); enantiomeric ratio 97.5:2.5, ee 95%.
IR (KBr): 1742, 1672, 1611, 1468, 1415, 1358, 1158, 1018, 755 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.67–7.60 (m, 2 H), 7.58 (dd, J = 1.6, 0.6
Hz, 1 H), 7.25–7.22 (m, 1 H), 7.20–7.14 (m, 1 H), 7.08 (d, J = 8.0 Hz, 1
H), 6.54 (dd, J = 3.6, 1.7 Hz, 1 H), 5.39 (t, J = 6.5 Hz, 1 H), 3.96 (dd, J =
17.8, 6.3 Hz, 1 H), 3.38 (dd, J = 17.8, 6.8 Hz, 1 H), 2.24 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 201.9, 185.0, 182.1, 158.3, 151.9,
149.8, 147.1, 138.9, 126.0, 124.5, 118.3, 112.8, 111.1, 56.4, 36.1, 26.7.
IR (KBr): 1740, 1682, 1611, 1469, 1449, 1348, 1221, 1179, 1001, 756,
690 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.04–7.93 (m, 4 H), 7.63–7.53 (m, 4 H),
7.51–7.39 (m, 4 H), 7.19 (d, J = 8.1 Hz, 1 H), 7.14–7.08 (m, 1 H), 6.55
(dd, J = 8.3, 5.0 Hz, 1 H), 4.36 (dd, J = 17.7, 8.4 Hz, 1 H), 3.46 (dd, J =
17.6, 5.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 196.1, 194.6, 181.9, 157.6, 149.5,
138.8, 136.1, 134.4, 134.3, 133.9, 129.2, 128.9, 128.7, 128.3, 125.9,
124.3, 118.2, 111.9, 51.7, 36.6.
MS (70 eV): m/z = 311 [M+], 269, 240, 196, 146, 119, 95, 76, 67, 43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C17H13NO5 + Na: 334.0686;
found: 334.0689.
MS (70 eV): m/z = 383 [M+], 355, 278, 236, 208, 147, 119,105, 77, 69.
(S)-1-[1,4-Dioxo-1-(1H-pyrrol-2-yl)pentan-3-yl]indoline-2,3-di-
one (7i)
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C24H17NO4 + Na: 406.1050;
found: 406.1053.
Yield: 3 mg (10%); yellow amorphous solid.
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR1 = 16.75 min, tR2 = 21.84 min; enantiomeric ratio
~50:50, regioisomeric ratio 4:1.
(S)-1-[1,4-Dioxo-1,4-di(-p-tolyl)butan-2-yl]indoline-2,3-dione (9c)
25
Yield: 40 mg (>95%); yellow needles; mp 115–117 °C; [α]D –204 (c
0.25, CHCl3).
IR (KBr): 3307, 1741, 1643, 1612, 1545, 1469, 1406, 1359, 1113, 755
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 26.58 min (major isomer); tR = 33.55 min (minor
isomer); enantiomeric ratio 97.5:2.5, ee 95%.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.28 (br s, 1 H), 7.67–7.59 (m, 2 H),
7.19–7.14 (m, 1 H), 7.05–7.01 (m, 2 H), 6.97–6.93 (m, 1 H), 6.30–6.23
(m, 1 H), 5.42 (dd, J = 7.12, 6.13 Hz, 1 H), 3.84 (dd, J = 17.1, 5.8 Hz, 1
H), 3.39 (dd, J = 17.1, 7.4 Hz, 1 H), 2.25 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.3, 185.6, 182.1, 158.3, 149.9,
138.8, 131.1, 126.1, 125.5, 124.5, 118.2, 117.3, 111.4, 111.1, 57.0, 35.3,
26.9.
IR (KBr): 2922, 1740, 1679, 1610, 1469, 1348, 1182, 1004, 817, 755
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.2 Hz, 2 H), 7.86 (d, J = 8.2
Hz, 2 H), 7.60–7.51 (m, 2 H), 7.25–7.16 (m, 4 H), 7.09 (t, J = 7.5 Hz, 1
H), 6.52 (dd, J = 8.2, 5.1 Hz, 1 H), 4.30 (dd, J = 17.6, 8.3 Hz, 1 H), 3.43
(dd, J = 17.6, 5.1 Hz, 1 H), 2.40 (s, 3 H), 2.36 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 195.7, 194.2, 182.1, 157.6, 149.6,
145.4, 144.8, 138.7, 133.7, 131.8, 129.8, 129.5, 128.85, 128.4, 125.8,
124.2, 118.2, 112.0, 51.7, 36.4, 21.84, 21.82.
MS (70 eV): m/z = 310 [M+], 292, 268, 197, 146, 119, 94, 66, 43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C17H14N2O4 + Na: 333.0846;
found: 333.0847.
MS (70 eV): m/z = 411 [M+], 383, 386, 319, 264, 147, 119, 91, 65, 43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C26H21NO4 + Na: 434.1363;
found: 434.1361.
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Synthesis
(S)-1-[1,4-Bis(4-methoxyphenyl)-1,4-dioxobutan-2-yl]indoline-
MS (70 eV): m/z = 541 [M+], 394, 392, 317, 315, 287, 285, 211, 209,
2,3-dione (9d)
185, 183, 157, 155, 147, 119, 92, 76, 64.
25
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C24H15Br2NO4: 539.9441;
Yield: 44 mg (>95%); yellow crystals; mp 172–174 °C; [α]D –197 (c
0.25, CHCl3).
found: 539.9443.
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 72.59 min (major isomer), tR = 93.09 min (minor
isomer); enantiomeric ratio 92:8, ee 84%.
(S)-1-[1,4-Bis(4-nitrophenyl)-1,4-dioxobutan-2-yl]indoline-2,3-di-
one (9g)
25
Yield: 35 mg (74%); yellow crystalline solid; mp 255–258 °C; [α]D
–105 (c 0.125, DMSO).
IR (KBr): 2932, 1741, 1673, 1600, 1512, 1468, 1348, 1262, 1171, 1028,
837, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.06–7.97 (m, 2 H), 7.99–7.90 (m, 2 H),
7.61–7.49 (m, 2 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.10 (t, J = 7.8 Hz, 1 H),
6.97–6.84 (m, 4 H), 6.54 (dd, J = 8.4, 5.0 Hz, 1 H), 4.29 (dd, J = 17.4, 8.5
Hz, 1 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 3.39 (dd, J = 17.4, 5.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 194.5, 192.9, 182.2, 164.5, 164.1,
157.6, 149.7, 138.7, 131.3, 130.6, 129.3, 127.2, 125.8, 124.2, 118.2,
114.4, 114.0, 112.3, 55.7, 55.7, 51.4, 36.1.
IR (KBr): 1743, 1689, 1612, 1525, 1468, 1346, 1280, 1108, 1008, 855,
755 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.38–8.33 (m, 2 H), 8.32–8.26 (m, 2 H),
8.19–8.10 (m, 4 H), 7.70–7.59 (m, 2 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.17 (d,
J = 7.9 Hz, 1 H), 6.49 (dd, J = 8.7, 4.1 Hz, 1 H), 4.47 (dd, J = 17.8, 8.9 Hz,
1 H), 3.40 (dd, J = 17.8, 4.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 194.6, 193.4, 181.1, 157.6, 151.1,
151.0, 148.6, 140.1, 139.0, 138.8, 129.7, 129.5, 126.5, 125.1, 124.4,
124.3, 118.3, 111.4, 52.0, 37.1.
MS (70 eV): m/z = 443 [M+], 411, 374, 296, 253, 161, 147, 135, 119,
107, 92, 77, 64, 43.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C26H21NO6 + Na: 466.1261;
MS (70 eV): m/z = 351, 326, 298, 176, 150, 119, 104, 92, 76, 64.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C24H15N3O8 + Na: 496.0751;
found: 466.1264.
found: 496.0752.
(S)-1-[1,4-Bis(4-chlorophenyl)-1,4-dioxobutan-2-yl]indoline-2,3-
dione (9e)
1-(3-Oxo-1,3-diphenylpropyl)indoline-2,3-dione (10)
25
25
Yield: 44 mg (>95%); yellow crystals; mp 189–191 °C; [α]D –171 (c
0.25, CHCl3).
Yield: 23 mg (39%); orange crystals; mp 146–149 °C; [α]D +14 (c
0.25, CHCl3).
HPLC: Chiralpak AS-H column; 254 nm, 95:5 hexane–i-PrOH, 1.0
mL/min, 35 °C; tR = 89.06 min (major isomer), tR = 75.87 min (minor
isomer); enantiomeric ratio 93.5:6.5, ee 87%.
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 14.85 min major isomer, tR = 16.22 min (minor
isomer); enantiomeric ratio 96:4, ee 92%.
IR (KBr): 1741, 1685, 1612, 1469, 1357, 1219, 1093, 831, 755 cm–1
.
IR (KBr): 1734, 1679, 1611, 1468, 1350, 1211, 1020, 750, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.97–7.86 (m, 4 H), 7.62–7.55 (m, 2 H),
7.47–7.43 (m, 2 H), 7.40 (d, J = 8.6 Hz, 2 H), 7.17–7.10 (m, 2 H), 6.47
(dd, J = 8.7, 4.5 Hz, 1 H), 4.34 (dd, J = 17.6, 8.8 Hz, 1 H), 3.36 (dd, J =
17.6, 4.6 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 8.01–7.94 (m, 2 H), 7.61–7.49 (m, 5 H),
7.49–7.41 (m, 2 H), 7.41–7.29 (m, 3 H), 7.15–7.06 (m, 2 H), 5.75 (dd,
J = 9.1, 4.9 Hz, 1 H), 4.76 (dd, J = 18.1, 9.2 Hz, 1 H), 3.72 (dd, J = 18.1,
4.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 194.9, 193.4, 181.7, 157.6, 149.2,
141.1, 140.5, 138.8, 134.3, 132.5, 130.1, 129.7, 129.6, 129.3, 126.1,
124.6, 118.2, 111.8, 51.5, 36.5.
MS (70 eV): m/z = 451 [M+], 339, 304, 269, 193, 165, 139, 119, 111, 92,
75, 64.
13C NMR (101 MHz, CDCl3): δ = 196.9, 183.2, 158.8, 151.6, 138.5,
138.4, 136.3, 133.8, 129.3, 128.9, 128.6, 128.4, 127.3, 125.5, 123.8,
117.9, 111.3, 54.0, 41.4.
MS (70 eV): m/z = 355 [M+], 250, 208, 179, 146, 119, 105, 92, 77.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C23H17NO3 + Na: 378.1101;
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C24H15Cl2NO4 + Na:
474.0270; found: 474.1287.
found: 378.1104.
1-(4-Oxo-4-phenylbutan-2-yl)indoline-2,3-dione (11)
(S)-1-[1,4-Bis(4-bromophenyl)-1,4-dioxobutan-2-yl]indoline-2,3-
dione (9f)
25
Yield: 27 mg (92%); reddish crystals; mp 116–118 °C; [α]D +9 (c
0.25, CHCl3).
25
Yield: 39 mg (72%); orange needles; mp 184–186 °C; [α]D –112 (c
HPLC: Chiralcel OJ-H column; 254 nm, 7:3 hexane–i-PrOH, 1 mL/min,
35 °C; tR = 22.00 min (major isomer), tR = 27.22 min (minor isomer);
enantiomeric ratio 96.5:3.5, ee 93%.
0.25, CHCl3).
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 39.27 min (major isomer), tR = 45.82 min (minor
isomer); enantiomeric ratio 82:18, ee 64%.
IR (KBr): 2980, 1731, 1683, 1613, 1470, 1353, 1219, 1311, 1220, 1003,
755, 691 cm–1
.
IR (KBr): 1740, 1682, 1612, 1585, 1469, 1348, 1179, 1071, 1005, 820,
1H NMR (400 MHz, CDCl3): δ = 7.97–7.89 (m, 2 H), 7.62 (td, J = 7.9, 1.4
Hz, 1 H), 7.59–7.53 (m, 2 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.19 (d, J = 8.1 Hz,
1 H), 7.12–7.05 (m, 1 H), 4.81–4.70 (m, 1 H), 4.12 (dd, J = 18.0, 7.9 Hz,
1 H), 3.43 (dd, J = 18.0, 5.5 Hz, 1 H), 1.61 (d, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 197.6, 183.5, 158.6, 151.4, 138.5,
136.4, 133.7, 128.9, 128.3, 125.6, 123.5, 117.8, 110.9, 45.9, 41.9, 18.0.
754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.91–7.76 (m, 4 H), 7.66–7.50 (m, 6 H),
7.20–7.05 (m, 2 H), 6.45 (dd, J = 8.7, 4.6 Hz, 1 H), 4.33 (dd, J = 17.7, 8.8
Hz, 1 H), 3.35 (dd, J = 17.6, 4.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 195.1, 193.7, 181.6, 157.6, 149.1,
138.8, 134.7, 132.9, 132.5, 132.3, 130.1, 129.9, 129.8, 129.3, 126.1,
124.6, 118.2, 111.8, 51.5, 36.4.
MS (70 eV): m/z = 293 [M+], 236, 160, 146, 105, 90, 77.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886

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Synthesis
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C18H15NO3 + Na: 316.0944;
found: 316.0949.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379956.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Dibenzyl 2-(2,3-Dioxoindolin-1-yl)succinate (12)
25
Yield: 7 mg (16%); yellow needles; mp 99–101 °C; [α]D –9 (c 0.25,
CHCl3).
References
HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 27.84 min (major isomer), tR = 14.63 min (minor
isomer); enantiomeric ratio 75.5:24.5, ee 51%.
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IR (KBr): 3034, 1739, 1613, 1471, 1361, 1310, 1218, 1169, 910, 753,
698 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 7.60–7.57 (m, 1 H), 7.48 (td, J =
7.9, 1.3 Hz, 1 H), 7.34–7.24 (m, 8 H), 7.24–7.18 (m, 2 H), 7.10 (t, J = 7.5
Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 5.36 (dd, J = 8.5, 6.0 Hz, 1 H), 5.18 (d,
J = 12.2 Hz, 1 H), 5.15 (d, J = 12.2 Hz, 1 H), 5.10 (d, J = 12.2 Hz, 1 H),
5.07 (d, J = 12.2 Hz, 1 H), 3.43 (dd, J = 16.9, 6.0 Hz, 1 H), 3.14 (dd, J =
16.9, 8.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 182.1, 169.8, 167.8, 158.1, 149.8,
138.5, 135.2, 134.7, 128.8, 128.7 (4C), 128.6, 128.5 (4C), 125.8, 124.1,
118.0, 110.8, 68.4, 67.3, 51.0, 33.9.
MS (70 eV): m/z = 443 [M+], 352, 280, 266, 236, 172, 146, 117, 107, 91,
77.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C26H21NO6 + Na: 466.1261;
found: 466.1269.
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Diethyl 2-[1-(5-Nitro-2,3-dioxoindolin-1-yl)ethyl]malonate (13)
Yield: 9 mg (25%); yellow viscous oil.
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HPLC: Chiralpak AD-H column; 254 nm, 7:3 hexane–i-PrOH, 1
mL/min, 35 °C; tR = 18.56 min (major isomer), tR = 34.31 min (minor
isomer); enantiomeric ratio 61.5:38.5.
IR (KBr): 2985, 1754, 1615, 1528, 1473, 1343, 1280, 1223, 1020, 839,
748 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.54 (dd, J = 8.8, 2.4 Hz, 1 H), 8.44 (d, J =
2.3 Hz, 1 H), 7.32 (d, J = 8.9 Hz, 1 H), 4.73 (dq, J = 13.7, 6.8 Hz, 1 H),
4.45 (d, J = 11.0 Hz, 1 H), 4.29 (q, J = 7.1 Hz, 2 H), 4.04 (qq, J = 10.8, 7.1
Hz, 2 H), 1.59 (d, J = 6.9 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.11 (t, J = 7.1
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 180.9, 167.1, 166.9, 158.1, 155.2,
144.1, 133.6, 121.1, 117.4, 111.7, 62.5, 62.4, 54.2, 49.7, 16.1, 14.2,
14.0.
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MS (70 eV): m/z = 378 [M+], 332, 286, 219, 191, 164, 141, 113, 85, 69.
HRMS (ESI-QTOF): m/z [M + Na]+ calcd for C17H18N2O8 + Na: 401.0955;
found: 401.0956.
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Acknowledgment
The authors thank the Estonian Ministry of Education and Research
(Grant Nos. IUT 19-32, IUT19-9, and B25) and the EU European Re-
gional Development Fund (3.2.0101.08-0017) for financial support.
We thank Dr. Aleksander-Mati Müürisepp and Ms. Tiina Aid from the
Tallinn University of Technology for assistance with MS and IR mea-
surements, respectively. We thank Mr. Dmitri Trubicyn for the syn-
thesis of the starting compounds and preliminary asymmetric
experiments.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886

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S. Žari et al.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 875–886