Transformation of l-phenylalanine to (S)-indoline-2-carboxylic acid without group-protection

Article abstract of DOI:10.1007/s11164-012-0673-z

(S)-Indoline-2-carboxylic acid was synthesized by use of a nitro amination approach with l-phenylalanine as chiral pool. The first step of the synthesis was nitration of l-phenylalanine, with urea nitrate (UN)/H₂SO ₄ as nitrating reagent, to give 2,4-dinitro-l-phenylalanine in 75.7 % yield in one-pot synthesis and 69.1 % yield by step-wise nitration. Intramolecular nitro amination of 2,4-dinitro-l-phenylalanine gave (S)-6-nitro-indoline-2-carboxylic acid in 65.7 % yield and more than 99.5 % enantiomeric excess (ee). The title compound, (S)-indoline-2-carboxylic acid, was obtained in 85.9 % yield and high ee by one-pot transformation of (S)-6-nitroindoline-2-carboxylic acid. The total synthesis consisted of three operations and gave the title compound in 42 % yield and more than 99.5 % ee.

Full text of DOI:10.1007/s11164-012-0673-z

Res Chem Intermed (2013) 39:1143–1152
DOI 10.1007/s11164-012-0673-z
Transformation of L-phenylalanine to (S)-indoline-
2
-carboxylic acid without group-protection
Jin-Qiang Liu
•
•
Xin-Zhi Chen
Baoming Ji Bang-Tun Zhao
•
Received: 21 April 2012 / Accepted: 29 May 2012 / Published online: 27 June 2012
Ó Springer Science+Business Media B.V. 2012
Abstract (S)-Indoline-2-carboxylic acid was synthesized by use of a nitro ami-
nation approach with L-phenylalanine as chiral pool. The first step of the synthesis
was nitration of L-phenylalanine, with urea nitrate (UN)/H SO as nitrating reagent,
2
4
to give 2,4-dinitro-L-phenylalanine in 75.7 % yield in one-pot synthesis and 69.1 %
yield by step-wise nitration. Intramolecular nitro amination of 2,4-dinitro-L-phen-
ylalanine gave (S)-6-nitro-indoline-2-carboxylic acid in 65.7 % yield and more than
9
9.5 % enantiomeric excess (ee). The title compound, (S)-indoline-2-carboxylic
acid, was obtained in 85.9 % yield and high ee by one-pot transformation of (S)-6-
nitroindoline-2-carboxylic acid. The total synthesis consisted of three operations
and gave the title compound in 42 % yield and more than 99.5 % ee.
Keywords (S)-Indoline-2-carboxylic acid Á L-Phenylalanine Á 2,4-Dinitro-L-
phenylalanine Á Nitro amination Á Chiral pool Á One-pot Á Group-protection-free
Introduction
Indolines are, because of their bioactivity, of great importance both in natural
chemistry and pharmaceuticals. Among these compounds, (S)-indoline-2-carboxylic
acid and analogues are of particularly interest because of their antihypertension
activity. Optically pure (S)-indoline-2-carboxylic acid is always obtained by
resolution of racemic indoline-2-carboxylic acid, which is produced by reduction of
indole-2-carboxylic acid [1]. The disadvantages are obvious, for example low yield
J.-Q. Liu (&) Á B. Ji Á B.-T. Zhao
College of Chemistry and Chemical Engineering, Luoyang Normal University,
Luoyang 471022, China
e-mail: liuque.zju@hotmail.com
X.-Z. Chen
Department of Chemical Engineering, Zhejiang University, Hangzhou 310027, China
123

1144
J.-Q. Liu et al.
(
never greater than 50 %), the need for a special resolution reagent, lengthy steps,
etc. New asymmetric synthetic methods have been developed to achieve high yield
and enantiomeric excess (ee) [2]. However, the unusual raw materials used made
the strategy unsuitable for the large-scale application. Thus, new synthetic methods
are still needed. In these efforts, chiral pool synthesis based on the great similarity
between L-phenylalanine and (S)-indoline-2-carboxylic acid is of particular interest
[
3, 4]. We described the first chiral pool synthesis of (S)-6-nitroindoline-2-
carboxylic acid (5) from L-phenylalanine by successive nitration, bromination, and
intramolecular cyclization [5]. Yu [3] and Chen [4] independently developed
palladium(II)-catalyzed C–H activation of L-phenylalanine, which required group
protection and moisture and oxygen-free operation. As part of our investigations in
this area, it was also of interest to examine the synthesis of (S)-indoline-2-
carboxylic acid from L-phenylalanine by another approach. In the work discussed in
this paper, we developed a new synthetic approach to 1 without group protection
(
Scheme 1).
Results and discussion
Our synthesis started with nitration of L-phenylalanine, because nitro-substituted
L-phenylalanines are not only intermediates for (S)-indoline-2-carboxylic acid but
also of great interest in biochemistry. Peptides bearing the 4-nitro-L-phenylalanine
moiety can trap HIV-1 protease [6, 7], which could be used in the design of drugs
against AIDS, whereas others can be used for investigation of DNA [8–10]. 2,4-
Dinitrophenylalanine derivatives of three stereoisomers of diaminopimelic acid
(
DAP), thought to be chiefly synthesized by bacteria incorporated in the
peptidoglycan of bacterial cell walls [11], have been successfully separated by
HPLC [12, 13]. Thus, the synthesis of nitro-substituted L-phenylalanine would be of
great interest in related fields.
According to the literature, mono-nitration of L-phenylalanine results in poor
yield [14–18] of no more than 70 % and usually approximately 50 %. In our
previous work, 4-nitro-L-phenylalanine (3) was obtained in high yield by use of a
tubular reactor [19].
COOH
COOH
a
b
NH2
NH2
O N
2
2
3
c
COOH
NH
COOH
COOH
e, f, g
d
NH
NH
2
O N
NO
O2N
2
2
1
5
4
Scheme 1 Synthesis of (S)-6-nitroindoline-2-carboxylic acid by nitroamination of L-phenylalanine.
(
(
(
a) HNO
3
/H
2
SO
4
0 °C, 3 h, 80.9 %; (b) UN/H
SO
(nphe:nUN = 1:1.2), 60 °C, 4 h, 75.7 %; (d) H
, Pd/C, 60 °C; (f): HCl, NaNO , 0 °C; (g): ethanol, 55 °C, 85.9 % three steps
2
SO
4
, 60 °C, 3 h, 85.4 %; (c): (i) UN/H
2
SO
, 5 h, 65.7 %;
4
, 0 °C, 2 h
nphe:nUN = 1:1); (ii) UN/H
2
4
2
O, K CO
2
3
e): H
2
2
1
23

Transformation of L-phenylalanine to (S)-indoline-2-carboxylic acid
1145
In contrast with mono-nitration, direct multi-nitration of phenylalanine has been
reported in the literature, with different results. For example, Block et al. [20]
nitrated phenylalanine with KNO in concentrated H SO at approximately 100 °C.
3
2
4
They believed the product was 3,4-dinitrophenylalanine, and this was supported by
Kapeller-Alder et al. [21]. However, Beer et al. [22] examined the nitration of
phenylalanine and confirmed that the main product was 2,4-dinitrophenylalanine.
When Monnier et al. [23] used the same method, 2,4-dinitrophenylalanine was
thought to be the main product in a mixture of 2,4-dinitrophenylalanine, 3,4 and 3,5-
dinitrobenzoic acid, and traces of trinitrobenzoic acid. To obtain 2,4-dinitro-L-
phenylalanine, we initially investigated nitration of L-phenylalanine with K CO /
2
3
H SO ; the results are listed in Table 1.
2
4
As is apparent from Table 1, all the products were viscous slurries, or oils. They
were acidic mixtures possibly comprising 2,4-dinitrophenylalanine, 3,4 and 3,5-
dinitrobenzoic acid, and traces of trinitrobenzoic acid, as reported by Monnier et al.
[
23]. Recrystallization of these from ethanol and other solvents did not afford the
desired 2,4-dinitro-L-phenylalanine. The sole pure product obtained from the
slurries was 2,4-dinitrobenzoic acid, which might have predominated in the reaction
mixtures. Thus, the reason for the failure in the direct nitration of L-phenylalanine
with KNO /H SO might be that the L-phenylalanine was oxidized at high
3
2
4
temperature (100 °C) by either HNO , or H SO , or both, which led to the formation
3
2
4
of 2,4-dinitrobenzoic acid. However, lower temperature only afforded 4-nitro-L-
phenylalanine (Entry 5). A reasonable explanation of these results might be that the
methylene in L-phenylalanine was active and readily oxidized at high temperature.
High temperature was, however, necessary for the dinitration because the electron
cloud density of the benzene ring was greatly reduced by the first nitro group, thus
oxidation seemed unavoidable with KNO /H SO as nitrating reagent and 2,4-
3
2
4
dinitrobenzoic acid was obtained (Scheme 2).
After the re-examination of the formation of 2,4-dinitrobenzoic acid, we found
that both dinitration and oxidation occurred at high temperature. If low temperature
was adopted, oxidation could not occur, so more active nitration reagents were
required. Fortunately, recent developments in the nitration of deactivated aromatics
provided an alternative [24]. Initially, we used urea nitrate (UN)/H SO and
2
4
nitrourea (NU)/H SO [25] as nitrating reagent for 4-nitro-L-phenylalanine, because
4
2
of their ready availability and low cost. The results obtained after optimization of
the reaction are shown in Table 2.
Table 1 Results from nitration of L-phenylalanine with different nitrating reagents
Entry
Nitrating reagent
Temperature (°C)
Time (h)
Product
1
2
3
4
5
HNO
KNO
HNO
HNO
HNO
3
3
3
3
3
/H
2
SO
SO
4
80
100
70
6
6
6
5
6
Yellow slurry
Red slurry
/H
2
4
(f)/H
2
2
SO
4
Red slurry
(f)/H
SO (f)
4
65
Red slurry
/H SO
2
4
40
4-Nitro-L-phenylalanine
123

1146
J.-Q. Liu et al.
NO2
COOH
O N
2
nitration
nitration
high temp.
high temp.
NO2
COOH
COOH
O N
2
high temp. oxidation
NO2
high temp. oxidation
COOH
oxidation
COOH low temp.
COOH
+
NH2
1
NH2
O N
NH2
2
nitration
high temp.
nitration
high
temp.
NO2
COOH
NH2
O N
2
Scheme 2 The supposed mechanism for formation of 2,4-dinitrobenzoic acid
The results showed yield and regioselectivity were good. Both UN and NU could
be used as the nitrating reagent for nitration of 4-nitro-L-phenylalanine. 2,4-Dinitro-
L-phenylalanine could obtained with comparable yields (Entries 1 and 2). 60 °C was
regarded as a better choice, considering time-consumption and yield (Entries 1,
3–5). Higher temperature than 60 °C could lead to lower yield because of the
formation of sulfamide (Entry 5). Nitrourea (NU) was not investigated further
because of its complex preparation procedure. A mole ratio of substrate to UN of
1:1.2 was regarded as the best choice (Entries 4, 6–8). There was no need to enlarge
the ratio to 1.5:1 although the yield was better (Entries 4 and 8).
In this successful nitration of L-phenylalanine, conc. H SO was the only solvent,
2
4
and the strong nitrating power of UN suggested to us that 2,4-dinitro-L-
Table 2 Results from nitration of 4-nitro-L-phenylalanine with different nitrating reagents
Entry
Nitrating reagent
Ratio (n(UN or NU):n(3))
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
UN/H
NU/H
UN/H
UN/H
UN/H
UN/H
UN/H
UN/H
2
SO
2
SO
2
SO
2
SO
2
SO
2
SO
2
SO
2
SO
4
4
4
4
4
4
4
4
1.2
1.2
1.2
1.2
1.2
1.0
1.1
1.5
30
30
45
60
75
60
60
60
16
16
10
6
83.6
84.4
85.7
87.8
65.3
73.4
82.7
88.3
4
6
6
6
1
23

Transformation of L-phenylalanine to (S)-indoline-2-carboxylic acid
1147
phenylalanine might be obtained by direct one-pot nitration of L-phenylalanine.
Initial experiments to introduce the first nitro group with mixed acids and the
second with UN failed—4-nitro-L-phenylalanine was obtained as the sole product.
According to Amog et al., nitration with UN/H SO is an electrophilic substitution
2
4
?
reaction and the NO2 was the only active spices. The water in HNO made the
3
?
reaction solution so dilute it was unsuitable for generation of NO2 . Thus, the
UN/H SO could not introduce the second nitro group to L-phenylalanine. For this
2
4
reason, UN was chosen as the only nitrating reagent for nitration of
L-phenylalanine in the one-pot reaction. In this procedure the first nitro group
was introduced to L-phenylalanine with the ratio of L-phenylalanine/UN 1:1 at
0
2
°C for 2 h; 1.2 mol UN was then added to the reaction mixture after addition of
mol H SO and a higher reaction temperature (60–65 °C) for 4 h was used. The
2
4
results showed that the yield was high—up to 75.7 %. Also, the fact that the
second nitro group was introduced to the aromatic compound was not in
agreement with Among et al., who stated that the second nitro group could not be
introduced to deactivated aromatics even with a molar ratio as high as 4:1. In our
experiment, L-phenylalanine was not a deactivated aromatic, on the contrary it was
a weakly activated aromatic. Thus, the second nitro group could be successively
introduced to L-phenylalanine. However, a third nitro group was not introduced to
the L-phenylalanine even by use of a molar ratio of UN/L-phenylalanine of more
than 5.0, because of the high electron-deficiency of 2,4-dinitro-L-phenylalanine
[
25]. The oxidation product of L-phenylalanine was not found, probably because
urea was a rather suitable reductant for eliminating the oxidation capability of
nitrate acid.
The intramolecular amination of 2,4-dinitro-L-phenylalanine generated the title
compound in good yield (65.7 %) and high enantiomeric excess (ee [ 99.5 %).
Our experiments were based on previous investigation of the amination of
multinitro aromatics [26, 27]. In this previous work, we investigated the amination
of multi-nitro aromatics. N-Alkyl-substituted 3,5-dinitroanilines could be obtained
from 1,3,5-trinitrobenzene in excellent yields [26]. With dinitrobenzene, one nitro
group could undergo amination to afford nitroaniline with good yields [27]. In
agreement with our work, Horaguchi et al. [28] found that the nitro group was a
facile leaving group at high temperature in the presence of the basic catalyst
CaO. In our experiments the reductive reaction conditions always led to
intramolecular diazotization to form (R)-7-nitro-3,4-dihydrocinnoline-3-carboxylic
acid (Scheme 3), again as observed by Horaguchi et al. [28].
In our experiments, therefore, the process was therefore conducted under an
oxidative atmosphere. Furthermore, to promote intramolecular rather than inter-
molecular reaction, the reaction mixture used was a dilute solution.
Scheme 3 Possible side
reaction
COOH
NH
COOH
+ H2O
N
2
O N
NO
O N
2
N
O
2
2
123

1148
J.-Q. Liu et al.
Table 3 Relative energy of different compounds calculated at different levels
Compound B3PW91/6- Relative energy B3PW91/6-
Relative energy
-1
-1
31G??(d,p) (a.u.) (kJ mol )
3
1G?(d,p) (a.u.)
(kJ mol
)
COOH
0
0
0
0
NH
2
O
2
N
NO
2
COOH
-0.005667
14.87
21.91
0.215219
564.65
+
2
H O
N
O
2
N
N
O
-0.008350
0.045903
120.43
COOH
+ HNO
2
O
2
N
N
H
To obtain a more mechanic insight into the intramolecular reaction, density
functional calculations were carried out at B3PW91 6-31G?(d,p)/B3PW91
-31G??(d,p) levels with the Gaussian 03 package. The results obtained are
6
shown in Table 3 and the optimized configuration is shown in Fig. 1.
It can be seen that formation of 6-nitro-(S)-indoline-2-carboxylic acid occurs
before dehydration at the different levels.
Fig. 1 Optimized configuration of the compounds at different levels
1
23

Transformation of L-phenylalanine to (S)-indoline-2-carboxylic acid
1149
Removal of the nitro group was followed the successive reduction, diazotization,
and deazotization steps. All three steps were conducted under one-pot conditions.
Reduction of 6-nitro-(S)-indoline-2-carboxylic acid with H /Pd/C in water at 60 °C
2
gave 6-amino-(S)-indoline-2-carboxylic acid, which was not further purified and
used in next step. Concentrated HCl was added to the aqueous 6-amino-(S)-
indoline-2-carboxylic acid solution, after which NaNO solution was added at 0 °C.
2
The diazoate was removed with ethanol at 55 °C and the (S)-indoline-2-carboxylic
acid could be obtained with high yield and excellent ee. Removal of the nitro group
was a standard operation, which means the reactions could be used for large-scale
production.
Conclusion
In conclusion, nitration of L-phenylalanine could give 4-nitro-L-phenylalanine and
,4-dinitro-L-phenylalanine in excellent yield, in either stepwise or one-pot
2
reactions, with UN as nitrating reagent. Intramolecular amination of 2,4-dinitro-L-
phenylalanine gave (S)-6-nitroindoline-2-carboxylic acid in moderate yield and high
ee. (S)-Indoline-2-carboxylic acid could be obtained from (S)-6-nitroindoline-2-
carboxylic acid by one-pot reduction, diazotization, and deazotization. The facile
synthetic operation made the method suitable for industrial application.
Experimental
All reagents were obtained commercially and used without further purification.
Melting points were determined on a WSR-I capillary melting point apparatus and
1
are uncorrected. H NMR and C NMR spectra were recorded on Bruker 400 MHz
13
1
spectrometers operating near 400 ( H) or 100 ( C) MHz, in D O solutions and with
13
2
TMS as internal standard for calibration. Optical rotation was were measured with a
Rudolph Research Autopol II polarimeter in a 1 dm cell.
4
4
-Nitro-L-phenylalanine
-Nitro-L-phenylalanine was prepared in 80.9 % yield in accordance with our
previous work [19]. Mp. 241.5–242.4 °C (dec.), lit [29]. Mp. 238–240 °C (dec.).
2
D
5
[
a] = -7.9° (c 1.01 in 1 M HCl, lit [29]. -8.9° (c 2.41 in 1 M HCl). IR (KBr)
-1 1
mmax (cm ): 3425 (bs), 1695 (s), 1535 (s), 1345 (s). H NMR (400 MHz, D O) d:
2
8
.05 (d, 2H, 3-H, 5-H, J = 8.8 Hz), 7.36 (d, 2H, 2-H; 6-H, J = 8.8 Hz), 4.27 (t, 1H,
1
3
CH–, J = 6.0 Hz), 3.24 (ddd, 2H, –CH –, J = 6.0, 7.2, 14.4 Hz). C NMR
–
2
(
101 MHz, D O) d: 170.7, 147.2, 141.9, 130.5, 124.1, 53.4, 35.2. LC–MS: 211
2
(100 %, M ? 1), Anal. Calcd. for C H N O : C, 51.43; H, 4.76; N, 13.33. Found:
C, 51.44; H, 4.75; N 13.34.
9
10 2 4
123

1150
J.-Q. Liu et al.
2
,4-Dinitro-L-phenylalanine
UN was prepared by a literature method [25]. 4-Nitro-L-phenylalanine (21.0 g,
.10 mol) was dissolved in sulfuric acid (conc., 40 mL) and cooled to 0 °C in an
0
ice–water bath. The UN (18.5 g, 0.15 mol) was added slowly with rapid stirring
over a period of 30 min. After addition and dissolution of UN, the mixture was
stirred in the ice bath for an additional 30 min before being left to warm. It was then
stirred at 60 °C for 4 h. The mixture was poured into ice water (200 g) and conc.
aqueous ammonia was added until neutralization. The water of the solution was
completely evaporated. The residue was extracted with 2 9 250 mL 1-propanol.
The combined alcoholic solution was cooled in a refrigerator for 2 h, whereupon
2
,4-dinitro-L-phenylalanine crystallized from the 1-propanol as a golden yellow
2
5
solid (22.4 g, 87.8 % yield). Mp. 191.5–192.4 °C (dec.) [a] = -6.7° (c 1.95 in
H O). H NMR (400 MHz, D O) d: 3.48 (ddd, 2H, –CH –, J = 7.2, 8.4, 14.0 Hz),
D
1
2
2
2
3
.99 (t, 1H, –CH–, J = 7.2 Hz), 7.63 (d, 1H, 6-H, J = 8.4 Hz), 8.38 (dd, 1H, 5-H,
1
3
J = 2.0, 8.4 Hz), 8.85 (d, 1H, 3-H, J = 8.4 Hz). C NMR (101 MHz, D O) d:
2
1
70.23, 149.07, 148.29, 132.99, 131.80, 128.21, 122.60, 51.85, 35.77.
One-pot operation
L-Phenylalanine (21.0 g, 0.10 mol) was dissolved in sulfuric acid (conc., 40 mL)
and cooled to 0 °C in an ice water bath. UN (12.3 g, 0.10 mol) was added slowly
with rapid stirring over a period of 30 min. After addition and dissolution of the UN,
the mixture was stirred in an ice bath for an additional 2 h. Then, an additional
3
0 mL sulfuric acid was added dropwise over 20 min and, after that, another potion
of UN (14.8 g, 0.12 mol) was added to the reaction mixture in portions over a
period of 30 min. The mixture was then warmed to 60 °C and kept at this
temperature for 4 h before being poured into ice water (400 g). Conc. aqueous
ammonia was then added until neutralization. The water of the solution was
completely evaporated and the residue was extracted with 3 9 250 mL 1-propanol.
The combined 1-propanol solution was cooled in a refrigerator for 4 h, whereupon
2
,4-dinitro-L-phenylalanine crystallized as a golden yellow solid (19.3 g, 75.7 %
yield). Mp. 191.1–192.9 °C (dec.).
(
S)-6-Nitroindoline-2-carboxylic acid
,4-Dinitro-L-phenylalanine (12.7 g, 0.050 mol), potassium carbonate K CO3
6.9 g, 0.050 mol) and water (300 mL) were placed in a 500 mL autoclave.
2
2
(
Oxygen was introduced to the autoclave to a pressure of 0.4 MPa. The reaction
mixture was stirred 5 h at 120 °C then analyzed by thin-layer chromatography
(
ethanol–ethyl acetate–petroleum ether 2:2:1). As soon as the reaction was
complete, the contents were filtered to remove impurities. The pH of the filtrate
was adjusted to 3–4 with 1 M HCl and the resulting solution was extracted with
EtOAc (3 9 50 mL). The combined organic phase was successively washed with
dilute HCl, water, and brine, decolorized with charcoal, dried over MgSO , and
4
concentrated under vacuum. After recrystallization from EtOAc–petroleum ether,
1
23

Transformation of L-phenylalanine to (S)-indoline-2-carboxylic acid
1151
6
-nitro-(S)-indoline-2-carboxylic acid was obtained as a yellow solid, yield 65.7 %
2
0
(
6.8 g) and ee [ 99.5 %. Mp. 168.2–169.7 °C (dec.). [a] = -39.8° (c 0.1 in
D
-1
(cm ): 3396.8(s), 3113.7(bs), 1727.3(s), 1521.3(s),
DMSO). IR (KBr) m
max
1
1
335.6(s). H NMR (400 MHz, DMSO-d ), d (ppm): 12.84 (bs, 1H, COOH), 7.43
6
(
J = 8.0 Hz), 6.67 (s, 1H, NH), 4.44 (dd, 1H, –CH–, J = 5.6, 10.4 Hz), 3.37 (ddd,
dd, 1H, 5-H, J = 2.4, 8.0 Hz), 7.25 (d, 1H, 7-H, J = 2.4 Hz), 7.22 (d, 1H, 4-H,
1
3
2
1
H, –CH –, J = 5.6, 10.8, 18.4 Hz). C NMR (101 MHz, DMSO-d ), d (ppm):
2
6
75.0, 152.9, 148.3, 135.6, 124.8, 113.1, 101.6 (Ar-C7), 60.1, 33.3. LC–MS: 209
(100 %, M ? 1). Anal. Calcd. for C H N O : C, 51.92; H, 3.85; N, 13.46. Found:
9 8 2 4
C, 51.93; H, 3.86; N, 13.43.
(
S)-2-Carboxylic acid
6
-Nitro-(S)-indoline-2-carboxylic acid (10.4 g, 0.050 mol), 120 mL water, and
.5 g 5 % Pd/C were placed in a 250 mL autoclave. The atmosphere was replaced
0
with hydrogen three times and the hydrogen pressure was then set 0.5 MPa. The
resulting reaction mixture was stirred for 4 h. The catalyst was isolated by filtration.
The filtrate was added to 10 mL conc. HCl at 0 °C and stirred for 0.5 h. NaNO
2
(
3.5 g, 0.050 mol) was then added dropwise and the mixture was stirred for an
additional 1 h. Then, 50 mL ethanol was added. The resulting reaction mixture was
held at 55 °C for 3 h. After removal of the volatile constituents under reduced
pressure, the pH of the mixture was adjusted to 5. Crude (S)-indoline-2-carboxylic
acid was obtained as a white solid after cooling. Recrystallization from water–
ethanol gave the purified product (7.0 g, 85.9 %) with a melting point of
2
5
1
63.5–164.3 °C (lit [30] 154–156 °C). [a] = -123.8° (c 1.1, 1 M HCl, lit [30]
D
D
25 -1
[
a] = -112.5°, 1 M HCl). ee [ 99.5 %. FT-IR (KBr) m
(cm ): 3260.5(bs),
max
1
065.2(s), 1637.7(s), 1379.7(s), 1290.2(s). H NMR (400 MHz, DMSO-d6),
3
d (ppm): 12.46 (bs, 1H, COOH), 6.97 (d, 1H, 4-H, J = 7.2 Hz), 6.89 (t, 1H, 7-H,
J = 7.2 Hz), 6.53–6.50 (m, 2H, Ar-H), 5.87 (s, 1H, NH), 4.22 (dd, 1H, –CH–,
J = 5.6, 10.8 Hz), 3.13 (ddd, 2H, –CH –, J = 5.6, 8.0, 10.8 Hz). These were in
2
very good agreement with reported data [30].
Acknowledgments We gratefully acknowledge the generous financial support of a grant from the
National Natural Science Foundation of China (nos. 20776127 and 21172105).
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