Synthesis of isatins with a chiral substituent at the nitrogen atom

Article abstract of DOI:10.1016/j.tetasy.2009.05.015

(R)-Ethyl 2-(isatin-1-yl)propanoates 8a-c were prepared from the corresponding (R)-arylalanines by Sandmeyer's method in high yield and good enantioselectivity (up to 99%). The key step of the process is the Mitsunobu reaction.

Full text of DOI:10.1016/j.tetasy.2009.05.015

Tetrahedron: Asymmetry 20 (2009) 1500–1505
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Tetrahedron: Asymmetry
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Synthesis of isatins with a chiral substituent at the nitrogen atom
*
Alexander V. Kurkin , Anna A. Bernovskaya, Marina A. Yurovskaya
Chemical Department of M.V. Lomonosov, Moscow State University, Moscow 119899, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
(R)-Ethyl 2-(isatin-1-yl)propanoates 8a–c were prepared from the corresponding (R)-arylalanines by
Sandmeyer’s method in high yield and good enantioselectivity (up to 99%). The key step of the process
is the Mitsunobu reaction.
Received 30 April 2009
Accepted 12 May 2009
Available online 26 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
tive isatins is the direct alkylation of the corresponding NH-isatins
by ethyl (S)-2-hydroxypropionate. The use of such a hydroxyester
Isatin and its derivatives are widely used for the synthesis of
different heterocyclic compounds, amongst which a great number
of drugs and drug candidates have been found. The variety of use-
ful applications of isatin derivatives is due to their extremely wide
range of biological activities. They demonstrate antibacterial, anti-
protozoal, antifungal, antiviral, anti-HIV, anticonvulsant, and anti-
helminthic activities; influence CNS; participate in metabolism;
and stimulate the growth of plants.1 There is a tendency nowadays
to use pure or practically pure enantiomers of heterocyclic com-
pounds instead of their racemic mixtures as starting materials in
the preparation of pharmaceuticals.2 It is true for the derivatives
of isatin. In this context the purpose of our study is the develop-
ment of a synthetic approach to new isatin derivatives with a chiral
C-atom adjacent to the N-atom of the heterocycle.
During our investigation, we found a new approach to the
derivatives of isatin, chiral (R)-2-methyl-2-indolyl-propanoates of
high enantiomeric purity. To the best of our knowledge, these com-
pounds have not been described. The method makes it possible to
prepare different chiral substances as a result of modification of
both five-membered and benzene rings (e.g., in some cross-cou-
pling reactions).
as an alkylating agent requires its preliminary activation, which
is why we have synthesized the corresponding methanesulfonyl
derivative of the hydroxyester (Scheme 1). There is no loss in the
enantiomeric purity of compound 1 during the transformation.3,4
O
S
Me
S
O
O
Me
O
O
O
Cl
O
HO
Me
OEt
OEt
Py, 0-5ºC
Me
H
H
1
Scheme 1. Synthesis of methanesulfonyl derivative of hydroxyester 1.
For the alkylation of the isatins, we used equimolar amounts of
the starting reagents. However, the starting isatins remained in the
reaction mixture for 12 h after the beginning of the process. Only
after the addition of 15% molar excess of an optically active meth-
anesulfonyl derivative of hydroxyester, were the isatins consumed
during the nucleophilic substitution (Scheme 2).
O
O
R
R
1
2. Results and discussion
O
O
K2CO3, DMF, 25ºC
N
N
Me
H
Our synthetic plan includes an alkylation of the corresponding
NH-isatins under Mitsunobu reaction conditions. However, our at-
tempts to alkylate (time of reaction, temperature, and ratio of re-
agents) isatins under different conditions did not give alkylated
products. This is most likely due to the insufficient nucleophilicity
of substrate because of the negative charge at the N-atom of the
isatin molecule, which delocalizes between the O-atom and the
N-atom. An alternative method for the preparation of optically ac-
EtO
H
O
2a, R = Me, [α]D20 = -1.3, 30% ee
2b, R = Br, (rac)
Scheme 2. Alkylation of isatins by methanesulfonyl derivative of hydroxyester 1.
However in this case, the process is accompanied by racemiza-
tion. The enantiomeric purity of compound 2a determined by HPLC
with a chiral stationary phase did not exceed 30% ee, while isatin
2b was obtained as a racemate. The racemization over the course
* Corresponding author. Tel./fax: +7 495 939 22 88.
E-mail address: kurkin@direction.chem.msu.ru (A.V. Kurkin).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.015

A. V. Kurkin et al. / Tetrahedron: Asymmetry 20 (2009) 1500–1505
1501
of alkylation may be explained by giving an example of esters by
effect of bases (alcoholates of alkaline and alkaline-earth metals,
e.g., K2CO3). Similar to its chemical nature, racemization has been
commercially available ethyl (S)-2-hydroxypropionate 5 to give
N,N-disubstituted 2-nitrobenzenesulfonamides 6a–c in 68–75%
yield. Triphenylphosphine/diisopropyl azadicarboxylate (DIAD)
was chosen as a redox system.
observed during the alkaline hydrolysis of esters of a
-aminoacids.5
Thus, the alkylation of isatins by a methanesulfonyl derivative of
(S)-2-hydroxypropionic acid is accompanied by a partial loss of
It is known that the Mitsunobu reaction is accompanied by
complete inversion of the configuration under the formation of
the alkylated product.9,10 Edwards et al.11 performed some trans-
formations to demonstrate that the Mitsunobu reaction proceeded
with inversion of configuration and that the reductive removal of
the activating group (Tf-group) did not result in a loss of enantio-
purity. The authors compared the specific rotation of the materials
prepared by well-known methods with predicted results and with
that of the materials prepared by the Mitsunobu reaction and fol-
lowing removal of the activating group. Samples prepared by these
enantiomeric purity because of high CH-acidity of the
a-carbon
atom in 1. This does not allow us to apply the direct alkylation of
isatins for the preparation of optically active isatins of the above
type.
As a result we suggested a sequence of conversions in which the
key step is construction of the isatin molecule with a chiral substi-
tuent at the nitrogen atom from an optically active aniline.
It should be noted that Liu et al.6 recently proposed a synthetic
method for optically active anilines, for example, 7b, with enanti-
oselectivities up to 98% ee. This method is based on using of com-
plexes of Cu(I) with chiral spirobisoxazolynic ligands as catalysts.
However, our variant has considerable advantages in its being
inexpensive as well as the availability of the starting materials
and the simplicity of the experimental work.
We used the Mitsunobu reaction for the synthesis of optically
active anilines 6a–c, alkylation of the NH-acid substances by an
optically active alcohol in the presence of a redox-system, triphen-
ylphosphine/diisopropyl azadicarboxylate. The Mitsunobu reaction
has frequently been used as a reliable method for the alkylation of
moderately acidic heteroatoms (pKa 6 11). Anilines have low NH-
acidity, hence it is necessary to introduce an activating group in or-
der to increase the NH-acidity of the aniline (Scheme 3).
We chose the activating group by taking into account two fac-
tors. First, the activating group should increase NH-acidity of ani-
line to such an extent, that the Mitsunobu reaction becomes
possible. Second, such an activating group should be easily re-
moved to give the product of alkylation. As an activating group,
we used the 2-nitrophenylsulfonyl (o-nosyl). The use of this pow-
erful electron-withdrawing group has been reported recently. The
Ns-group could be readily removed under mild conditions, giving
secondary amines in high yields and without losing enantiomeric
purity.7,8 N-Aryl-2-nitrobenzenesulfonamides 4a–c, prepared from
anilines 3a–c and 2-nitrobenzenesulfonyl chloride in 72–90% yield,
were efficiently alkylated under the Mitsunobu conditions9 with
methods gave similar values of ½a D20
ꢀ
and proved an inversion of the
configuration under the Mitsunobu conditions and retention of
chirality after removal of the activating group.
The deprotection of secondary amines with the 2-nitrophenyl-
sulfonyl group under extremely mild conditions could be carried
out by two alternative methods: upon treatment with PhSH/
K2CO3/DMF at 23 °C,7 or with HSCH2CO2H/LiOH/DMF at the same
temperature.8 As a rule, both methods give similar results. The
reaction, presumably, proceeds via the formation of the Meisenhei-
mer complex8 (Scheme 4).
In our experiments we used PhSH/K2CO3/DMF system with sat-
isfactory results: optically active ethyl (R)-2-(N-aryl)aminopropan-
oates 7a–c were prepared in 73–78% yield and in >99% ee.
The enantiomeric purity of ester (R)-N-arylalanine was de-
termined by 1H NMR analysis (spectrum) for (R)-7b and sub-
stance (R,S)-7b with equimolar amounts of chiral solvating agent
(S)-1,10-binaphthyl-2.20-diol. There were two doublet signals
(J = 6.8, 2.9 Hz) of the –CHCH3 group in a 1:1 ratio of integral
intensities in the spectrum of substance (R,S)-7b (B) in the range
1.13–1.16 ppm (Fig. 1A). In the spectrum of substance (R)-7b (A)
only one doublet signal of the protons of the aforementioned
group was obtained (Fig. 1A). The configuration of the multiplet
signal of the CH2CH3 group (Fig. 1B) indicated the excellent
enantioselectivity of substance (R)-7b (A) which was obtained
under alkylation by ethyl (S)-lactate under Mitsunobu reaction
conditions.
O
HO
OEt
R
R
R
R
5
Me
PhSH, K2CO3
MeCN
o-NsCl
O
O
O
S
S
Et3N, THF, 25ºC
DIAD, Ph3P, THF
N
NH
NH2
N
O
O
H
H
H
NO2
O
3a, R = H
3b, R = Br
3c, R = Me
O2N
Me
Me
4a-c
OEt
OEt
7a, [α]D20 = +40, > 99% ee
7b, [α]D20 = +67, > 99% ee
7c, [α]D20 = +49, > 99% ee
6a, [α]D20 = +10
6b, [α]D20 = -8
6c, [α]D20 = +2
Scheme 3. Synthesis of optically active anilines 7a–c.
-
O
O
O
O
N
-
N
+
PhS
N
+
PhS
-
-
O
O
O
+
-
R
N
-
R
R
R
O
+
-
PhS
+
S
S
S
O
O
O
PhS
N
NH
N
N
-SO2
O
O
O
H3C
CO2Et
H3C
CO2Et
H3C
CO2Et
H3C
CO2Et
Scheme 4. Mechanism of 2-nitrophenylsulfonyl group deprotection.

1502
A. V. Kurkin et al. / Tetrahedron: Asymmetry 20 (2009) 1500–1505
Br
Br
a
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
a
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1.15
1.13
A
B
NH
NH
O
CH3
O
CH3
H
H
H
H
H
H
H
H
H
O
H
O
a
b
a
b
2.96
3.00
1.21 1.20 1.19 1.18 1.17 1.16 1.15 1.14 1.13 1.12 1.11 1.10 1.09 1.08 1.07 1.06
Chemical Shift (ppm)
1.25
1.20
1.15
1.10
1.05
Chemical Shift (ppm)
b
b
0.30
0.25
0.20
0.15
0.10
0.05
0
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
A
B
3.88
3.90
3.86
3.92
1.99
1.94
3.97 3.96 3.95 3.94 3.93 3.92 3.91 3.90 3.89 3.88 3.87 3.86 3.85 3.84 3.83 3.82 3.81
Chemical Shift (ppm)
3.97 3.96 3.95 3.94 3.93 3.92 3.91 3.90 3.89 3.88 3.87 3.86 3.85 3.84 3.83 3.82
Chemical Shift (ppm)
Figure 1. Fragments of spectrum (range of aliphatic protons) of ethyl esters (R)-7b (A) and (R,S)-7b (B) with (S)-1,10-binaphthyl-2.20-diol in C6D6.
We synthesized isatins 8a–c from optically active anilines 7a–c
which may be used for obtaining chiral isatins with high
enantioselectivity.
by Sandmeyer’s method (Scheme 5). In addition we used ethanol
as a solvent in order to increase the aniline solubility. Isatins 8a–
c were purified by column chromatography and their enantiomeric
purities that were achieved were 97–99% ee, which were deter-
mined by HPLC with a chiral stationary phase. Since Sandmeyer’s
method has sufficiently harsh reaction conditions (concd H2SO4),
we attempted to synthesize N-alkylated isatin by Stolle’s method
(oxalyl chloride/AlCl3 in CH2Cl2). However, we did not obtain the
chiral isatin. This method seems applicable for N-unsubstituted
anilines, while Sandmeyer’s method makes it possible to prepare
optically active isatins 8a–c in high yield with good enantioselec-
tivity. We determined the absolute configuration to be (R) for isatin
8b by X-ray structure analysis.12
4. Experimental
4.1. General
HRMS spectra were recorded on Carlo Erba/Kratos Fractovap
Series 4200 gas–liquid chromatograph, column Ultra-1, Hewlett
Packard, 25 m ꢁ 0.2 mm, thickness of phase layer 0.33 mkm, car-
rier gas—helium (1 ml/min), flow divider 1:10, temperature of
evaporator 280 °C, gradient of temperature from 150 °C to 280 °C
(5 °C/min). Mass spectral detector ITD-700 (Finnigan MAT), EU,
with ionizing electrons of energy 70 eV, and range of mass m/z
45–400 was used. NMR spectra were recorded with a Bruker
AMX-400 spectrometer at 400.13 (1H NMR) and at 100.61(13
C
O
NMR) MHz with CDCl3 and DMSO-d6 as solvents. Chemical shifts
are reported in parts per million downfield from internal Me4Si.
Optical rotations were measured using a Jasco DIP-360 (589 nm)
polarimeter. Melting points were measured in an open capillary,
and are uncorrected. IR spectra were recorded on a Thermo Nicolet
200 IR spectrometer. Reaction control and control of products pur-
ity were carried out by thin-layer chromatography on slices of Silu-
fol UV-254 and by gas chromatography with mass spectral
detector. Enantiomeric purities were tested using HPLC with chiral
stationary phase: Chiralpak AD-RH 4.6 ꢁ 150 mm 5 mkm, eluent:
H2O + CF3COOH/CH3CN 50:50 flow: 1.0 ml/min, rt, and 250 nm.
R
R
1. Cl3CH(OH)2,Na2SO4
2. NH2OH·HCl
alcohol-water
O
N
NH
H
3. H2SO4
H
EtO
EtO
Me
Me
O
O
7a-c
8a, 99% ee
8b, 97% ee
8c, 99% ee
Scheme 5. Synthesis of isatins 8a–c.
3. Conclusion
4.2. Ethyl-O-methanesulfonyl-(S)-2-hydroxypropanoate 1
In conclusion, we not only have developed a synthetic method
for isatins with a chiral substituent on the nitrogen atom but have
also revealed that under these conditions racemization did not oc-
cur when using active substrates. Thus, we have reported a method
Methanesulfonyl chloride (5.82 g, 0.05 mol) was added to a
solution of ethyl ester (S)-2-hydroxypropionic acid (5 g, 0.04 mol)
in pyridine (40 ml) and stirred at 0–5 °C for 3 h. The reaction

A. V. Kurkin et al. / Tetrahedron: Asymmetry 20 (2009) 1500–1505
1503
mixture was kept overnight at 0–5 °C. The resulting mixture was
diluted with water (300 ml) and ice, and extracted with Et2O
(50 ml) five times. The extract was washed with diluted hydrochlo-
ric acid (50 ml) four times, and with a saturated solution of NaHSO4
(100 ml) and a saturated solution of NaCl (100 ml), and dried over
anhydrous Na2SO4. The solvent was concentrated under reduced
4.2.4. N-(4-Phenyl)-2-nitrobenzenesulfonamide 4a
Compound 4a was obtained as a white solid (90%, mp 120 °C,
ethanol).1H NMR (CDCl3), d, ppm, J (Hz): 7.18–7.23 (m, 3H, 2-H,
6-H, NH), 7.28–7.32 (m, 3H, 3-H, 4-H, 5-H), 7.59 (t, J = 7.8, 1H, 50-
H), 7.71 (t, J = 7.8, 1H, 40-H), 7.84 (d, J = 7.8, 1H, 30-H), 7.87 (d,
J = 7.8, 1H, 60-H). 13C NMR (CDCl3), d, ppm: 123.27 (2C, CH),
125.32 (CH), 126.66 (CH), 129.50 (2C, CH), 131.80 (CH), 132.08
(C), 132.61 (CH), 134.07 (CH), 135.47 (C), 148.18 (C).
pressure to afford a red oil (79%), ½a D20
¼ ꢂ65 (c 1, CHCl3). This sub-
ꢀ
stance was used in further transformations without extra purifica-
tion. 1H NMR (CDCl3), d, ppm, J (Hz): 1.30 (t, J = 7.2, 3H, –CH2–CH3),
1.60 (d, J = 7.0, 3H, –CH–CH3), 3.14 (s, 3H, –SO2CH3), 4.25 (q, J = 7.2,
2H, –CH2–CH3), 5.11 (q, J = 7.0, 1H, –CH–CH3).
4.2.5. N-(4-Methylphenyl)-2-nitrobenzenesulfonamide 4c
Compound 4c was obtained as a yellow solid (88%, mp 110 °C,
ethanol). 1H NMR (CDCl3), d, ppm, J (Hz): 2.27 (s, 3H, 4-CH3),
7.05 (br s, 4H, 2-H, 3-H, 5-H, 6-H), 7.16 (br s, 1H, NH), 7.56 (t,
J = 7.8, 1H, 50-H), 7.68 (t, J = 7.8, 1H, 40-H), 7.78 (d, J = 7.8, 1H, 30-
H), 7.84 (d, J = 7.8, 1H, 60-H). 13C NMR (CDCl3), d, ppm: 20.92
(CH3), 123.72 (2C, CH), 125.26 (CH), 130.04 (2C, CH), 131.86 (CH),
132.19 (C), 132.56 (CH), 132.72 (C), 133.95 (CH), 136.74 (C),
148.20 (C).
4.2.1. Ethyl 2-(5-methylisatin-1-yl)propanoate 2a
At first K2CO3 (1.28 g, 0.009 mol) was added to a solution of 5-
methylisatin (1 g, 0.006 mol) in DMF (5 ml). The reaction mixture
was stirred until the complete dissolution of isatin. After 30 min,
the solution became bright red in color, after which (S)-ethyl 2-
(methanesulfonyl)propanoate (1.6 ml, 0.01 mol) was added drop-
wise to the reaction mixture. This was stirred at rt for 12–14 h.
The resulting mixture was diluted with water, extracted with
CH2Cl2, washed with water, and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography on silica gel (elu-
ent—ethyl acetate/petroleum ether = 10:1) to afford 2a (1.08 g,
4.2.6. Ethyl-(R)-N-(2-nitrophenylsulfonyl)-N-(4-bromophenyl)-
2-aminopropanoate 6b
Diisopropyl azadicarboxylate (3.54 ml, 0.018 mol) was added
dropwise to
(0.017 mol), triphenylphosphine (4.72 g, 0.018 mol), and ethyl
(S)-2-hydroxypropionate (2.04 ml, 0.018 mol) in dry THF
a solution of N-(2-nitrophenylsulfonyl)aniline 5
67%) as a red solid, ½a D20
ꢀ
¼ ꢂ1:3 (c 3.8, CHCl3), 30% ee, Mp 63 °C.
6
1H NMR (DMSO-d6), d, ppm, J (Hz): 1.14 (t, J = 7.0, 3H, –CH2–
CH3), 1.55 (d, J = 7.3, 3H, –CH–CH3), 2.29 (s, 3H, 5-CH3), 4.14 (q,
J = 7.0, 2H, –CH2–CH3), 5.12 (q, J = 7.3, 1H, –CH–CH3), 7.03 (d,
J = 8.1, 1H, 7-H), 7.43 (s, 1H, 4-H), 7.49 (d, J = 8.1, 1H, 6-H). 13C
NMR (DMSO-d6), d, ppm: 14.34 (CH3), 16.53 (CH3), 20.44 (CH3),
49.46 (CH), 61.81 (CH2), 111.59 (CH), 118.08 I, 125.49 (CH),
133.38 I, 139.10 (CH), 148.01 I, 158.18 (CO), 169.91 (CO), 183.37
(CO). Mass-spectroscopy, m/z (I, %): 261 [M+], 188 [M+ꢂCO2Et],
160 [M+ꢂCH3CHCO2Et], 117 (34), 91 (50), 43 (60). Calcd for
C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.32; H, 5.92;
N, 5.23.
(50 ml) and stirred with ice-bath cooling under argon for 12 h.
The reaction mixture was then stirred at rt for 12 h and then con-
centrated under reduced pressure. The residue was dissolved in
Et2O at 0–5 °C, the precipitated triphenylphosphine oxide was fil-
tered off, and CH2Cl2 was added to an ether solution (Et2O/
CH2Cl2 = 3:1), which was washed with water, 10% hydrochloric
acid, and saturated solution of NaHSO4. The ether extract was dried
over anhydrous Na2SO4 and the solvent was evaporated under re-
duced pressure. The crude product was purified by column chro-
matography on silica gel (eluent—ethyl acetate/petroleum ether)
to give 6b as a white solid (68%, mp 89 °C), ½a D20
¼ ꢂ8:4 (c 3.2,
ꢀ
CHCl3). 1H NMR (CDCl3), d, ppm, J (Hz): 1.29 (t, J = 7.0, 3H, –CH2–
CH3), 1.33 (d, J = 7.4, 3H, –CH–CH3), 4.16–4.27 (m, 2H, –CH2–CH3),
5.16 (q, J = 7.4, 1H, –CH–CH3), 7.22 (d, J = 8.6, 2H, 2-H, 6-H), 7.47
(d, J = 8.6, 2H, 3-H, 5-H), 7.55–7.60 (m, 1H, 50-H), 7.65–7.74 (m,
3H, 30-H, 40-H, 60-H). 13C NMR (CDCl3), d, ppm: 14.10 (CH3), 16.69
(CH3), 57.46 (CH2), 61.71 (CH), 123.92 (CH), 124.11 (CH), 131.41
(CH), 132.07 (CH), 132.36 (2C, CH), 132.88 (C), 133.76 (C), 133.83
4.2.2. Ethyl 2-(5-bromisatin-1-yl)propanoate 2b
Compound 2b was obtained as a red solid (57%, mp 125 °C,
petroleum ether/ethyl acetate) due to the same method. 1H NMR
(DMSO-d6), d, ppm, J (Hz): 1.15 (t, J = 6.4, 3H, –CH2–CH3), 1.54 (d,
J = 6.3, 3H, –CH–CH3), 4.09–4.21 (m, 2H, –CH2–CH3), 5.11–5.21
(m, 1H, –CH–CH3), 7.13 (d, J = 7.7, 1H, 7-H), 7.78 (s, 1H, 4-H),
7.85 (d, J = 7.7, 1H, 6-H). Mass-spectroscopy, m/z (I, %): 224
[M+ꢂCH3CHCO2Et], 145 [M+ꢂCH3CHCO2Et, ꢂBr], 117 (8), 106 (5),
91 (36), 57 (100), 41 (39).
(CH), 134.36 (2C, CH), 147.82 (C), 171.69 (CO). IR (KBr) m: 3103,
2976, 1734 (CO), 1547 (NO2), 1485, 1371, 1360, 1165, 1101,
1011, 592, 565 cmꢂ1. Mass-spectroscopy, m/z (I, %): 456 [M+],
383 [M+ꢂCO2Et], 199 [M+ꢂCO2Et, ꢂNs], 186 [M+ꢂNs], 155 (32),
77 (18), 76 (43). Calcd for C17H17BrN2O6S: C, 44.65; H, 3.75; N,
6.13. Found: C, 44.61; H, 3.74; N, 6.08.
4.2.3. N-(4-Bromophenyl)-2-nitrobenzenesulfonamide 4b
Triethylamine (4.2 ml, 0.03 mol) was added to a stirred solution
of p-bromaniline (5 g, 0.03 mol) in THF (35 ml). The mixture was
kept in an ice-bath for 15 min, and then the solution of 2-nitro-
benzenesulfonyl chloride (6.4 g, 0.03 mol) in THF (15 ml) was
added dropwise. The mixture was stirred at rt for 6 h and was then
concentrated under reduced pressure up to 15 ml. The residue was
diluted with water (50 ml) and extracted with chloroform (50 ml)
four times. The combined extracts were washed with dilute hydro-
chloric acid and water (50 ml) twice and were then dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure. Purification of the residue by recrystallization from etha-
nol afforded 4b as a pale yellow solid (7.71 g, 72%, mp 105 °C). 1H
NMR (CDCl3), d, ppm, J (Hz): 7.11 (d, J = 8.8, 2H, H-2, H-6), 7.42 (d,
J = 8.8, 2H, 3-H, 5-H), 7.63 (t, J = 7.8, 1H, 50-H), 7.72 (br s, 1H, NH),
7.74 (t, J = 7.8, 1H, 40-H), 7.85 (d, J = 7.8, 1H, 30-H), 7.89 (d, J = 7.8,
1H, 60-H). 13C NMR (CDCl3), d, ppm: 120.13 (C), 124.86 (2C, CH),
125.45 (CH), 131.83 (CH), 132.60 (2C, CH), 132.79 (C), 134.26
(CH), 134.61 (C), 148.17 (C).
4.2.7. Ethyl-(R)-N-(2-nitrophenylsulfonyl)-N-(4-phenyl)-2-
aminopropanoate 6a
Compound 6a was obtained as a white solid (71%, mp 123 °C,
petroleum ether/ethyl acetate), ½a D20
ꢀ
¼ þ10:1 (c 3.27, CHCl3). 1H
NMR (CDCl3), d, ppm, J (Hz): 1.27–1.36 (m, 6H, –CH2–CH3, –CH–
CH3), 4.16–4.28 (m, 2H, –CH2–CH3), 5.17 (q, J = 7.4, 1H, –CH–CH3),
7.27–7.42 (m, 5H, 2-H, 3-H, 4-H, 5-H, 6-H), 7.50–7.56 (m, 1H, 50-
H), 7.63–7.72 (m, 3H, 30-H, 40-H, 60-H). 13C NMR (CDCl3), d, ppm:
14.10 (CH3), 16.62 (CH3), 57.50 (CH2), 61.59 (CH), 123.96 (CH),
129.06 (2C, CH), 129.44 (CH), 131.22 (CH), 132.13 (CH), 132.67
(2C, CH), 133.21 (C), 133.57 (CH), 134.65 (C), 147.85 (C), 171.78
(CO). IR (KBr) m: 3099, 2991, 1745 (CO), 1545 (NO2), 1375, 1351,
1205, 1165, 592, 557 cmꢂ1. Mass-spectroscopy, m/z (I, %): 378
[M+], 305 [M+ꢂCO2Et], 186 [M+ꢂNs], 119 [M+ꢂCO2Et, ꢂNs], 104
(67), 77 (67), 51 (21). Calcd for C17H18N2O6S: C, 53.96; H, 4.79;
N, 7.40. Found: C, 53.94; H, 4.83; N, 7.49.

1504
A. V. Kurkin et al. / Tetrahedron: Asymmetry 20 (2009) 1500–1505
4.2.8. Ethyl (R)-N-(2-nitrophenylsulfonyl)-N-(4-methylphenyl)-
2-aminopropanoate 6c
(CH3)CO2Et], 57 (22), 43 (34). Calcd for C12H17NO2: C, 69.54; H, 8.27;
N, 6.76. Found: C, 69.53; H, 8.40; N, 6.77.
Compound 6c was obtained as a white solid (77%, mp 82 °C,
petroleum ether/ethyl acetate), ½a D20
ꢀ
¼ þ2:1 (c 3.27, CHCl3). 1H
4.2.12. (R)-Ethyl-2-(5-bromisatin-1-yl)propanoate 8b
NMR (CDCl3), d, ppm, J (Hz): 1.28 (t, J = 7.2, 3H, –CH2–CH3), 1.32
(d, J = 7.4, 3H, –CH–CH3), 2.35 (s, 3H, 4-CH3), 4.14–4.27 (m, 2H,
–CH2–CH3), 5.14 (q, J = 7.4, 1H, –CH–CH3), 7.08–7.19 (m, 4H, 2-H,
3-H, 5-H, 6-H), 7.50–7.57 (m, 1H, 50-H), 7.61–7.73 (m, 3H, 30-H,
40-H, 60-H).13C NMR (CDCl3), d, ppm: 14.09 (CH3), 16.58 (CH3),
21.18 (CH3), 57.42 (CH2), 61.53 (CH), 123.94 (CH), 129.74 (2C,
CH), 131.26 (CH), 131.82 (C), 132.11 (CH), 132.30 (2C, CH),
133.24 (C), 133.58 (CH), 139.58 (C), 147.79 (C), 171.80 (CO). IR
A mixture of chloralhydrate (0.003 mol) in water (5.1 ml), a
solution of aniline 7b (0.0018 mol) in water (1.23 ml) with con-
centrated hydrochloric acid (0.26 g), a solution of hydroxylamine
hydrochloride (0.0061 mol) in water (1.03 ml) and Na2SO4
(0.42 g), was stirred at reflux for 1–2 min. In addition we used
ethanol as a solvent to increase the aniline solubility. The reaction
mixture was cooled to rt, extracted with CH2Cl2, and dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure to afford isonitroso substance as a brown oil (83%).
The isonitroso substance (0.0015 mol) was added to concentrated
sulfuric acid (1.46 g) at 50 °C so that the temperature of the reac-
tion mixture did not exceed 70 °C. The reaction mixture was stir-
red at 80 °C for 10–15 min. The resulting mixture was cooled to
rt, diluted with cold water, extracted with CH2Cl2, and dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure. The crude product was purified by column chromatog-
raphy on silica gel (eluent—ethyl acetate/petroleum ether = 10:1)
to afford 8b as an orange solid (57%, 97% ee, mp 124–125 °C,
petroleum ether/ethyl acetate). 1H NMR (CDCl3), d, ppm, J (Hz):
1.15 (t, J = 7.0, 3H, –CH2–CH3), 1.53 (d, J = 7.1, 3H, –CH–CH3),
4.08–4.21 (m, 2H, –CH2–CH3), 5.15 (q, J = 7.1, 1H, –CH–CH3),
7.12 (d, J = 8.5, 1H, 7-H), 7.77 (s, 1H, 4-H), 7.85 (d, J = 8.1, 1H,
6-H). 13C NMR (DMSO-d6), d, ppm: 14.19 (CH3), 14.42 (CH3),
49.55 (CH), 61.89 (CH2), 113.94 (CH), 115.71 (C), 119.92 (C),
127.52 (CH), 140.41 (CH), 148.95 (C), 157.70 (CO), 169.73 (CO),
(KBr)
m: 3078, 2993, 1745 (CO), 1543 (NO2), 1373, 1346, 1205,
1174, 1103, 596, 573 cmꢂ1. Mass-spectroscopy, m/z (I, %): 392
[M+], 319 [M+ꢂCO2Et], 186 [M+ꢂNs], 133 [M+ ꢂCO2Et, ꢂNs], 118
(41), 91 (31), 65 (10). Calcd for C18H20N2O6S: C, 55.09; H, 5.14; N,
7.14. Found: C, 55.08; H, 5.11; N, 7.35.
4.2.9. Ethyl (R)-N-(4-bromophenylamino)-propanoate 7b
Potassium carbonate (3.2 g, 0.023 mol) and thiophenol (1.8 ml,
0.017 mol) were added to a solution of o-nitrophenylsulfonylani-
line 7 (2.28 g, 0.006 mol) in DMF (100 ml) and stirred at rt for 6 h.
The reaction mixture was diluted with water, extracted with
Et2O/CH2Cl2 = 3:1, and washed with water twice. The extract
was dried over anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The crude product was purified by col-
umn chromatography on silica gel (eluent—ethyl acetate/petro-
leum ether) to give 7b (73%) as a yellow oil, ½a D20
¼ þ67 (c 3.37,
ꢀ
CHCl3). 1H NMR (CDCl3), d, ppm, J (Hz): 1.28 (t, J = 7.1, 3H,
–CH2–CH3), 1.48 (d, J = 6.9, 3H, –CH–CH3), 4.09 (q, J = 6.9, 1H,
–CH–CH3), 4.21 (q, J = 7.1, 2H, –CH2–CH3), 6.50 (d, J = 8.9, 2H, 2-
H, 6-H), 7.27 (d, J = 8.9, 2H, 3-H, 5-H). 13C NMR (CDCl3), d, ppm:
14.20 (CH3), 18.75 (CH3), 52.00 (CH), 61.27 (CH2), 109.94 (C),
114.98 (2C, CH), 132.04 (2C, CH), 145.64 (C), 174.24 (CO). IR
181.87 (CO). IR (KBr)
m: 3086, 2989, 1736 (CO), 1604, 1469,
1439, 1242, 841, 719, 474 cmꢂ1. Mass-spectroscopy, m/z (I, %):
224 [M+ꢂCH3CHCO2Et], 145 [M+ꢂBr], 117 (8), 91 (36), 41 (39).
Calcd for C13H12BrNO4: C, 47.88; H, 3.71; N, 4.29. Found: C,
47.78; H, 3.64; N, 4.46.
(KBr)
m: 3388 (NH), 2981, 1734 (CO), 1595, 1500, 1315, 1161,
816 cmꢂ1. Mass-spectroscopy, m/z (I, %): 271 [M+], 198 [M+ꢂ
CO2Et], 155 (12), 118 [M+ꢂCO2Et, ꢂBr], 91 (30), 76 (34), 50
(34). Calcd for C11H14NO2: C, 48.55; H, 5.19; N, 5.15. Found: C,
48.71; H, 5.27; N, 5.27.
4.2.13. (R)-Ethyl-2-(isatin-1-yl)propanoate 8a
Compound 8a was obtained as an orange solid (52%, >99% ee, mp
69 °C, petroleum ether/ethyl acetate).1H NMR (CDCl3), d, ppm,
J (Hz): 1.22 (t, J = 7.2, 3H, –CH2–CH3), 1.69 (d, J = 7.4, 3H, –CH–
CH3), 4.23 (q, J = 7.2, 2H, –CH2–CH3), 5.16 (q, J = 7.4, 1H, –CH–CH3),
6.85 (d, J = 7.1, 1H, 7-H), 7.15 (t, J = 7.1, 1H, 5-H), 7.57 (t, J = 7.1,
1H, 6-H), 7.65 (d, J = 7.1, 1H, 4-H). 13C NMR (DMSO-d6), d, ppm:
14.08 (CH3), 14.27 (CH3), 49.18 (CH), 62.16 (CH2), 111.46 (CH),
117.89 (C), 123.89 (CH), 125.64 (CH), 138.19 (CH), 149.45 (C),
4.2.10. Ethyl-(R)-N-(4-phenylamino)-propanoate 7a
Compound 7a was obtained as a yellow oil, 70%, ½a D20
¼ þ40
ꢀ
(c 2.71, CHCl3). 1H NMR (CDCl3), d, ppm, J (Hz): 1.29 (t, J = 7.1,
3H, –CH2–CH3), 1.51 (d, J = 6.6, 3H, –CH–CH3), 4.12–4.27 (m, 3H,
–CH–CH3, –CH2–CH3), 6.66 (d, J = 8.4, 2H, 2-H, 6-H), 6.75–6.82
(m, 1H, 4-H), 7.17–7.27 (m, 2H, 3-H, 5-H). 13C NMR (CDCl3), d,
ppm: 14.19 (CH3), 18.94 (CH3), 52.03 (CH), 61.13 (CH2), 113.42
(2C, CH), 118.27 (CH), 129.32 (2C, CH), 146.63 (C), 174.62 (CO).
157.69 (CO), 169.43 (CO), 182.70 (CO). IR (KBr)
m: 3467, 2993,
1739 (CO), 1608, 1468, 1367, 1309, 1246, 1113, 750, 476 cmꢂ1
.
Mass-spectroscopy, m/z (I, %): 247 [M+], 174 [M+ꢂCO2Et], 146
[M+ꢂCH3CHCO2Et], 128 (1), 117 (6), 91 (12), 77 (26), 51 (9). Calcd
for C13H13NO4: C, 63.15; H, 5.30; N, 5.66. Found: C, 63.26; H, 5.42;
N, 5.78.
IR (KBr)
m: 3396 (NH), 2981, 1736 (CO), 1605, 1508, 1315, 1161,
750, 694 cmꢂ1
.
Mass-spectroscopy, m/z (I, %): 193 [M+], 120
[M+ꢂCO2Et], 104 (4), 91 (4), 77 [M+ꢂNHCH(CH3)CO2Et], 65 (8),
42 (2). Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C,
68.07; H, 7.69; N, 7.36.
4.2.14. (R)-Ethyl-2-(5-methylisatin-1-yl)propanoate 8c
Compound 8c was obtained as a red solid (67%, >99% ee, mp
64 °C, petroleum ether/ethyl acetate).1H NMR (CDCl3), d, ppm, J
(Hz): 1.23 (t, J = 7.1, 3H, –CH2–CH3), 1.68 (d, J = 7.3, 3H, –CH–
CH3), 2.90 (s, 3H, 5-CH3), 4.23 (q, J = 7.1, 2H, –CH2–CH3), 5.17 (q,
J = 7.3, 1H, –CH–CH3), 6.74 (d, J = 8.1, 1H, 7-H), 7.37 (d, J = 8.1, 1H,
6-H), 7.48 (s, 1H, 4-H). 13C NMR (DMSO-d6), d, ppm: 14.09 (CH3),
14.28 (CH3), 20.62 (CH3), 49.12 (CH), 62.10 (CH2), 111.27 (CH),
121.42 (C), 125.96 (CH), 133.74 (C), 138.57 (CH), 152.92 (C),
4.2.11. Ethyl-(R)-N-(4-methylphenylamino)-propanoate 7c
Compound 7c was obtained as a yellow oil, 75%, ½a D20
¼ þ49
ꢀ
(c 3.30, CHCl3). 1H NMR (CDCl3), d, ppm, J (Hz): 1.29 (t, J = 7.1, 3H,
–CH2–CH3), 1.50 (d, J = 6.9, 3H, –CH–CH3), 2.28 (s, 3H, 4-CH3), 3.95
(br s, 1H, NH), 4.15 (q, J = 6.9, 1H, –CH–CH3), 4.22 (q, J = 7.1, 2H,
–CH2–CH3), 6.59 (d, J = 8.2, 2H, 2-H, 6-H), 7.03 (d, J = 8.2, 2H, 3-H,
5-H). 13C NMR (CDCl3), d, ppm: 14.22 (CH3), 18.98 (CH3), 20.41
(CH3), 52.41 (CH), 61.04 (CH2), 113.69 (2C, CH), 127.55 (C), 129.82
157.83 (CO), 169.57 (CO), 178.89 (CO). IR (KBr)
m: 3456, 2989,
1739 (CO), 1622, 1597, 1491, 1309, 1227, 1107, 837, 478 cmꢂ1
.
Mass-spectroscopy, m/z (I, %): 261 [M+], 188 [M+ꢂCO2Et], 160
[M+ꢂCH3CHCO2Et], 130 (11), 117 (33), 91 (40), 65 (44), 51 (20).
Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.22;
H, 5.56; N, 5.70.
(2C, CH), 144.38 (C), 174.81 (CO). IR (KBr) m: 3390 (NH), 2981, 1734
(CO), 1620, 1522, 1304, 1159, 810 cmꢂ1. Mass-spectroscopy, m/z (I,
%): 207 [M+], 134 [M+ꢂCO2Et], 118 (9), 91 (19), 77 [M+ꢂNHCH

A. V. Kurkin et al. / Tetrahedron: Asymmetry 20 (2009) 1500–1505
1505
5. Kurkin, A. V.; Nesterov, A. V.; Karchava, A. B.; Yurovskaya, M. A. Khim. Get. Soed.
2003, 39, 1466.
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