Synthesis of N-alkylanthranilamides with a chiral substituent at the nitrogen atom

Article abstract of DOI:10.1016/j.tetasy.2010.07.001

Novel anthranilamides containing a chiral substituent at the nitrogen atom and different substituents on the benzene ring were prepared from the corresponding isatins in good yields and high enantioselectivities (up to 98%).

Full text of DOI:10.1016/j.tetasy.2010.07.001

Tetrahedron: Asymmetry 21 (2010) 2100–2107
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of N-alkylanthranilamides 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:
Novel anthranilamides containing a chiral substituent at the nitrogen atom and different substituents on
the benzene ring were prepared from the corresponding isatins in good yields and high enantioselectiv-
ities (up to 98%).
Received 27 May 2010
Accepted 1 July 2010
Available online 31 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
to enantio-enriched products. During our investigation, we found a
new synthetic approach to novel derivatives of anthranilamides
Anthranilic acids and its derivatives are usually used as non-ste-
roidal anti-inflammatory drugs1 and antibacterial agents.2 In re-
cent years, among a wide variety of anticancer drugs, a great
interest has been focused on the synthesis of different derivatives
of anthranilic acids. It is true not only for anthranilic acids and its
esters, but also for its amides, which may reveal high anticancer
activity.3 The anthranilamides inhibit angiogenesis4 and are re-
garded as new selective antagonists of cholecystokinin-2 receptors,
which are used for the treatment of adenocarcinoma such as Bar-
rett’s metaplasia and pancreatic cancer.5
Many pharmaceuticals are chiral and consist of two or more
enantiomers/stereoisomers, which may differ in biological activity,
toxicity, and effects on non-target organisms. In the last few years,
several racemic compounds have been substituted by enantiomer-
enriched or single-isomer compounds (‘chiral switch’).6,7 At the
present time, approximately 15% of all pharmaceuticals synthe-
sized correspond to pure enantiomers, such as levomicetin, levo-
floxacin, esomeprazole, levosalbutamol, and (S)-ketamine. In this
context, the stereoselective synthesis of new heterocycles is an
important task. Thus, the use of single enantiomer with an optimal
ratio of therapeutic efficiency and safety versus racemic mixtures
has become an area of significant interest.
with high enantiomeric purity. To the best of our knowledge, these
compounds have not been previously described.
Wealsoreportthesynthesisof thederivativesof anthranilicacids
withachiralsubstituentatthenitrogenatom. Surprisingly, therehas
been little synthetic work directed toward such compounds which
could exhibit interesting properties not only as new building-blocks,
but also as new biologically active compounds.
Two major approaches for the synthesis of N-alkanthranilic
acids could be applied: (1) the direct alkylation of anthranilic acids
and (2) the formation of anthranilic acids with a chiral substituent
at the nitrogen atom from optically active isatins. The first method
was not suitable for the preparation of optically active anthranilic
acids, because the racemization of the reaction products takes
place in basic media.8 Therefore, we focused our research on the
second method where the synthesis of enantiomerically pure
anthranilic acids from the corresponding isatins can be used. Re-
cently we reported the synthesis of the enantiomerically pure
substituted isatins, which were prepared from the substituted
(R)-arylalanines by Sandmeyer’s method in high yield and good
enantioselectivity (up to 99%).9 The enantiomerically pure deriva-
tives of anthranilic acids may be obtained from isatins with a chiral
substituent at the nitrogen atom (vide supra Scheme 1).
Our major goal was to develop a synthetic route for the racemic
derivatives of anthranilic acids and thereafter apply it to the opti-
cally active substrates.
2. Results and discussion
In the first set of experiments, we turned our attention to the
synthesis of N-alkylated isatins. Racemic N-alkylated isatins 1a–c
were prepared in high yields (>70%) from the corresponding com-
mercially available isatins by a standard procedure.10 The alkyl-
ation was carried out in DMF at room temperature over 12–14 h.
We used 10% molar excess of ethyl 2-bromopropionate as an alkyl-
ating agent and K2CO3 as a base (Scheme 2).
Herein, we report the development of a methodology, which
encompasses a broad range of new derivatives of anthranilamides,
achieves substrate-controlled enantioselectivity, and allows access
* Corresponding author. Tel.: +7 495 939 1714; fax: +7 495 939 2288.
E-mail address: kurkin@direction.chem.msu.ru (A.V. Kurkin).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.001

A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
2101
O
O
O
O
Nu
O
N
O
Me
N
NH
NH
Me
H
Me
H
Me
H
EtO
EtO
EtO
EtO
H
O
O
O
O
Scheme 1. Retrosynthetic strategy for the synthesis of the derivatives of anthranilic acids with a chiral substituent at the nitrogen atom.
Br
yields of the target anthranilamides in comparison with the other
methods.
O
OEt
R
O
Me
This is due to the fact that the addition of DMAP to the reaction
of isatoic anhydride and nucleophiles ensures the intermediacy of
an active ortho-aminobenzoylating agent A,16 generated in situ in
the presence of the nucleophile. Intermediate A is the orders of
magnitude more potent as a reagent for the introduction of the
anthraniloyl moiety when compared to either isatoic anhydride
or the range of active esters of anthranilic acid previously de-
scribed (Fig. 1).17,18
R
O
O
N
O
º
K2CO3, DMF, 25 C
N
OEt
Me
H
O
1a, R = H, 81%;
1b, R = Br, 78%;
1c, R = Me, 72%
Scheme 2. The synthesis of racemic N-alkylated isatins 1a–c.
O
N
In order to obtain N-alkylated isatoic anhydrides from the cor-
+
responding isatins several approaches were attempted. The oxida-
tion of isatins can be carried out under a mild condition by using
hydrogen peroxide,11 chromium trioxide,12 or various peracids11,13
as oxidants. Preliminary results indicated that these isatins could
not be easily oxidized using chromium trioxide in a solvent mix-
ture of AcOH/Ac2O (1:1) and the reaction led to the formation of
a complex mixture. The experiments carried out with freshly pre-
pared Et2O solution of monoperphthalic acid14 for 40 h at room
temperature resulted in the formation of isatoic anhydride 2a–c
in 10–30% yield.
CH3
NH
N
-
COOH
CH3
A
Figure 1. Intermediate A.
We carried out a comparative analysis of the methods listed
above. In order to obtain the amides of N-alkylanthranilic acids,
we used secondary cyclic amines and
nucleophiles (Table 1).
a-methylbenzylamine as
None of these approaches allowed the synthesis of isatoic anhy-
dridesinhighyields. Itis knownfromtheliteraturedatathatm-chlo-
roperoxybenzoic acid (MCPBA) is often used as the oxidative reagent
for the synthesis of isatoic anhydrides. The standard reaction condi-
tions were defined as follows: small excess of MCPBA (5 mol %),
room temperature, and about 48 h.11 However, we did not obtain
the desired isatoic anhydrides under these conditions. We found
thattheuseofa largeexcessofMCPBA(80 mol %) gavebetterresults.
Under these conditions, the reactions generally proceeded to com-
pletion in less than 6–8 h at room temperature and the products
were obtained in excellent yields (80–98%) (Scheme 3).
The method b was more effective in most cases (see Table 1)
and provided better yields in mild conditions. Thus, a convenient
approach to the synthesis of racemic N-alkylanthranilamides was
developed and applied on the optically active substrates. In the fol-
lowing part of the study, we endeavored to use these conditions for
the synthesis of N-alkylanthranilamides with a chiral substituent
at the nitrogen atom.
We synthesized isatoic anhydride (R)-2a from an optically ac-
tive isatin (R)-1a by using MCPBA as an oxidizing reagent, as de-
scribed above. Isatoic anhydride (R)-2a was purified by column
chromatography on silica gel to yield (R)-2a (78%). The analysis
of the isatoic anhydride (R)-2a enantiomeric purity by HPLC meth-
od indicated that there was no racemization under our reaction
conditions and its enantiomeric purity was 98% ee.
In order to obtain the optically active amides of N-alkylanthra-
nilic acids, we carried out the reaction between isatoic anhydride
(R)-2a and azepane via a methodology well established in the syn-
thesis of racemic compounds. Amide 8a (85%) was purified by col-
umn chromatography and its enantiomeric purity was 98% ee,
which was determined by HPLC with a chiral stationary phase.
Interestingly enough, isatoic anhydride (R)-2a reacted with enanti-
O
O
R
R
O
MCPBA
O
º
CH2Cl2, 20 C
N
N
O
OEt
OEt
Me
Me
O
O
2a, 90%; 2b, 98%;
2c, 80%
omerically pure (S)-
reoisomer 9a0. The reaction between enantiopure isatoic anhydride
(R)-2a and racemic -methylbenzylamine ((S)/(R) = 3/1) provided
the mixture of diastereoisomers 9a with a ratio that correlates with
the ratio of (S)- and (R)-isomers of the initial a-methylbenzylamine
(Fig. 2).
The aforementioned observations proved our assumption that
the racemization did not occur under our reaction conditions at
the stage of isatoic anhydride opening. The enantiomeric purity
a-methylbenzylamine to give only one diaste-
Scheme 3. Oxidation of isatins to isatoic anhydride 2a–c.
It is well-known that the amides of N-alkylanthranilic acids
a
may be obtained from the corresponding isatoic anhydrides and
nucleophiles under various conditions, for example, at reflux in
CH3CN15 (method a), stirring in a solvent mixture of DMF/THF in
the presence of 4-dimethylaminopyridine (DMAP) as a catalyst5
(method b), or in DMF at different temperatures4,5,15 (method c).
It was found that method b was more effective and gave higher

2102
A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
Table 1
dride (R)-2a and 4-dimethylaminopyridine (DMAP) is an effective
method for the synthesis of new enantiomerically pure N-alkylan-
thranilamides with high enantioselectivities (up to 98%). We have
also found that under these conditions racemization did not occur
when using active substrates.
The comparison of the methods a, b and c on a number of racemic anthranilamides 3–
7a–c
O
O
R1
R1
R2H
R2
O
NH
N
O
4. Experimental
4.1. General
OEt
OEt
Me
Me
O
O
2a-c
3-7 a-c
The NMR spectra were recorded on a ‘Bruker Avance-400’ spec-
trometer (400.1 and 100.6 MHz for 1H and 13C, respectively) at
room temperature; the chemical shifts d were measured in ppm
with respect to the solvent (1H: CDCl3, d = 7.27 ppm; 13C: CDCl3,
d = 77.13 ppm), coupling constants J are given in Hertz. IR spectra
were recorded on Thermo Nicolet IR200 FT-IR spectrometer. Mass
spectral detector ITD-700 (Finnigan MAT), EU, energy of ionizing
electrons 70 eV, range of mass m/z 45–400. Optical rotations were
measured using a Jasco DIP-360 (589 nm) polarimeter. Melting
points were measured in an open capillary tube. Analytical thin
layer chromatography (TLC) was carried out with ‘Silufol’ silica
gel plates (supported on aluminum); the revelation was done by
UV lamp (254 and 365 nm), and chemical staining (iodine vapor
and potassium permanganate solution in water). Column chroma-
tography was performed on Silica Gel 60 (230–400 mesh, Merck).
Enantiomeric purities were tested using HPLC with a chiral station-
ary phase: Chiralpak AD-RH 4.6 ꢀ 150 mm 5 mkm, eluent:
H2O + CF3COOH/CH3CN 50/50 flow: 1.0 mL/min, rt, 250 nm. All
the reagents, except for the commercial products of satisfactory
quality, were purified according to the literature procedures before
use. Compounds obtained as mixtures of diastereomers were not
separated into the single isomers.
Product
R1
H
R2
Method
Yields%
Method aa
Method bb
61
54
3a
3b
3c
N
Br
Method b
Method b
51
43
N
N
Me
4a
4b
4c
5a
H
Method b
Method b
Method b
Method b
56
59
42
83
N
N
N
Br
Me
H
N
5b
5c
6a
Br
Me
H
Method b
Method b
70
45
N
N
4.2. General procedure for the preparation of isatins 1a–c
4.2.1. Ethyl 2-(isatin-1-yl)propanoate (1a)
N
O
O
Method a
Method b
57
69
At first, K2CO3 (2.11 g, 0.015 mol) was added to a solution of
isatin (1.5 g, 0.01 mol) in DMF (30 mL), the reaction mixture was
stirred until isatin was completely dissolved. After 30 min, the
solution became bright red, after which ethyl 2-bromopropanoate
(1.46 mL, 0.011 mol) was added dropwise to a reaction mixture,
and then stirred at rt for 12–14 h. The resulting mixture was di-
luted 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 chro-
matography on silica gel (eluent: ethyl acetate/petroleum
ether = 10/1) to afford 1a (2.01 g, 81%) as an orange solid, mp
58 °C (petroleum ether/ethyl acetate). 1H NMR (400 MHz, CDCl3,
25 °C): d = 1.22 (t, J = 7.2, 3H, CH2CH3), 1.69 (d, J = 7.5, 3H, CHCH3),
4.18–4.27 (m, 2H, CH2CH3), 5.16 (q, J = 7.5, 1H, CHCH3), 6.85 (br d,
J = 7.7, 1H, CHAr), 7.15 (ddd, J = 7.7, 7.7, 0.7, 1H, CHAr), 7.57 (ddd,
Method a
Method b
49
72
6b
6c
Br
N
N
Me
O
Method b
42
Method a
Method b
48
85
57
CH3
7a
7b
7c
H
Method cc
HN
HN
HN
Ph
Method a
Method b
50
53
CH3
Br
Me
Ph
CH3
Method b
43
Ph
a
b
c
Method a: CH3CN, 85 °C, 10–15 min.
Method b: DMAP (cat. amounts), THF/DMF (0.2 M), 25°C, 16 h;
Method c: DMF, 80°C, 3 h.
J = 7.7, 7.7, 1.4, 1H, CHAr), 7.65 (ddd, J = 7.7, 1.4, 0.7, 1H, CHAr
)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 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), 157.69 (CO), 169.43
of the resulting amides of N-alkylanthranilic acids was determined
by the enantiomeric purity of the initial enantiomerically pure isa-
tins (Table 2).
(CO), 182.70 (CO) ppm. IR (KBr) m: 3467, 2993, 1739 (CO), 1608,
1468, 1367, 1309, 1246, 1113, 750, 476 cmꢁ1. Mass-spectr., m/z
(I,%): 247 [M+], 174 [M+ꢁCO2Et], 146 [M+ꢁCH3CHCO2Et], 128
(0.8), 117 (6), 91 (12), 77 (26), 51 (9). Anal. Calcd for C13H13NO4:
C, 63.15; H, 5.30; N, 5.66. Found: C, 63.20; H, 5.43; N, 5.81.
3. Conclusion
In conclusion, we have developed a synthetic route for new
anthranilamides containing a chiral substituent at the nitrogen
atom and different substituents on the benzene ring. The results
of our research work indicate that the sequential conversion of
an optically active isatin into the isatoic anhydride (R)-2a under
oxidative conditions (MCPBA) and combination of the isatoic anhy-
4.2.2. Ethyl 2-(5-bromisatin-1-yl)propanoate (1b)
Compound 1b was obtained as an orange solid, 78%, mp 125°C
(petroleum ether/ethyl acetate). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 1.25 (t, J = 7.1, 3H, CH2CH3), 1.69 (d, J = 7.5, 3H, CHCH3), 4.24

A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
2103
.
1
4
1
7
1
1
1
9
3
4
1.42
H
H
H
HN
O
H
NH
H
H
H
O
H
H
H
O
(R)-9a
1.60
1.55
1.50
1.45
1.40
1.35
1.30
1.25
1.20
.
1
1
3
1
8
1.250
H
H
HN
H
H
O
H
NH
H
H
H
O
H
H
H
O
(R,S)-9a'
1.60
1.55
1.50
1.45
1.40
1.35
1.30
1.25
Figure 2. Fragments of the spectrum (range of aliphatic protons) of the mixture of diastereomers (R)-9a and (R,S)-diastereomer 9a0 in CDCl3.
(q, J = 7.1, 2H, CH2CH3), 5.18 (q, J = 7.5, 1H, CHCH3), 6.77 (d, J = 8.4,
d = 14.08 (CH3), 14.27 (CH3), 20.59 (CH3), 49.13 (CH), 62.09 (CH2),
111.28 (CH), 117.94 (C), 125.92 (CH), 133.74 (C), 138.60 (CH),
147.26 (C), 157.83 (CO), 169.54 (CO), 182.95 (CO) ppm. IR (KBr)
1H, CHAr), 7.69 (dd, J = 8.4, 2.0, 1H, CHAr), 7.77 (br d, J = 2.0, 1H, CHAr
)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.10 (CH3), 14.26
(CH3), 49.30 (CH), 62.33 (CH2), 113.23 (CH), 116.81 (C), 119.13
(C), 128.41 (CH), 140.34 (CH), 148.18 (C), 156.98 (CO), 169.18
m
: 3456, 2989, 1739 (CO), 1622, 1597, 1491, 1309, 1227, 1107,
837, 478 cmꢁ1. Mass-spectr., m/z (I,%): 261 (23) [M+], 188 (12)
[M+ꢁCO2Et], 160 (100) [M+ꢁCH3CHCO2Et], 130 (11), 117 (33), 91
(40), 65 (44), 51 (20). Anal. Calcd for C14H15NO4: C, 64.36; H,
5.79; N, 5.36. Found: C, 64.32; H, 5.92; N, 5.23.
(CO), 181.53 (CO) ppm. IR (KBr) m: 3086, 2989, 1736 (CO), 1604,
1469, 1439, 1242, 841, 719, 474 cmꢁ1. Mass-spectr., m/z (I,%): 327
(13) [M+], 325 (13) [M+], 254 (14) [M+ꢁCO2Et], 252 (14)
[M+ꢁCO2Et], 226 (95) [M+ꢁCH3CHCO2Et], 224 (98) [M+ꢁCH3
CHCO2Et], 197 (8), 170 (24), 168 (24), 155 (32), 145 (70)
[M+ꢁCH3CHCO2Et, ꢁBr], 117 (100), 90 (86), 75 (95), 63 (49), 45
(37). Anal. Calcd for C13H12BrNO4: C, 47.88; H, 3.71; N, 4.29. Found:
C, 47.69; H, 3.69; N, 4.40.
4.3. General procedure for the preparation of isatoic anhydride
2a–c
4.3.1. Ethyl 2-(2,4-dioxo-2H-3,1-benzoxazin-1(4H)-
yl)propanoate (2a)
4.2.3. Ethyl 2-(5-methylisatin-1-yl)propanoate (1c)
Isatin 1a (2 g, 0.008 mol) was added to a solution of meta-chlo-
roperoxybenzoic acid (2.51 g, 0.0145 mol) in CH2Cl2. The reaction
mixture was stirred at rt for 6–8 h. The resulting mixture was
washed with an aqueous solution of sodium carbonate (2.5 g
Na2CO3 in 250 mL H2O), saturated with a solution of NaHSO3,
and dried over anhydrous Na2SO4. The solvent was evaporated un-
der reduced pressure. Purification of the residue was carried out by
Compound 1c was obtained as a red solid, 72%, mp 64°C (petro-
leum ether/ethyl acetate). 1H NMR (400 MHz, CDCl3, 25 °C):
d = 1.23 (t, J = 7.1, 3H, CH2CH3), 1.68 (d, J = 7.4, 3H, CHCH3), 2.35
(s, 3H, CH3Ar), 4.23 (q, J = 7.1, 2H, CH2CH3), 5.16 (q, J = 7.4, 1H,
CHCH3), 6.74 (d, J = 8.0, 1H, CHAr), 7.37 (br d, J = 8.0, 1H, CHAr),
7.48 (br s, 1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):

2104
A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 13.93 (CH3),
14.03 (CH3), 20.37 (CH3), 53.57 (CH), 62.25 (CH2), 113.72 (CH),
126.30 (C), 130.99 (CH), 134.38 (C), 138.06 (CH), 138.27 (CO),
Table 2
The synthesis of N-alkylanthranilamides 8a, 9a, 9a0 from optically active isatoic
anhydride (R)-2a
O
O
147.39 (C), 158.26 (CO), 169.20 (CO) ppm. IR (KBr) m: 2985, 1774,
1720, 1512, 1304, 1225, 1063, 750, 540 cmꢁ1. Mass-spectr., m/z
(I,%): 277 (10) [M+], 249 (2), 204 (1) [M+ꢁCO2Et], 176 (34), 160
(100) [M+ꢁCH3CH(NH)CO2Et], 117 (23), 91 (13), 65 (11), 39 (5).
Anal. Calcd for C14H15NO5: C, 60.65; H, 5.45; N, 5.05. Found: C,
60.60; H, 5.50; N, 5.10.
R2H
R2
O
method b
N
O
NH
Me
H
Me
H
EtO
EtO
O
O
4.3.4. (R)-Ethyl 2-(2,4-dioxo-2H-3,1-benzoxazin-1(4H)-
yl)propanoate ((R)-2a)
(R)-2a
Product R2
Yield% Isomeric composition
Compound (R)-2a was obtained as a white solid, 78%, mp 105 °C
(petroleum ether/ethyl acetate) after purification by column chro-
matography on silica gel (eluent: ethyl acetate/petroleum
(R)-Enantiomer 98% ee, ½a D20
¼ þ9 (c 1.00
ꢂ
8a
85
80a
83
CH2Cl2)
N
CH3
ether = 1/10), ½a D20
ꢂ
¼ þ15 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3,
25 °C): d = 1.22 (t, J = 7.1, 3H, CH2CH3), 1.75 (d, J = 7.1, 3H, CHCH3),
4.20–4.29 (m, 2H, CH2CH3), 5.32–5.44 (m, 1H, CHCH3), 7.07 (d,
J = 8.5, 1H, CHAr), 7.32–7.37 (m, 1H, CHAr), 7.76 (ddd, J = 8.5, 7.6,
1.6, 1H, CHAr), 8.22 (dd, J = 7.6, 1.6, 1H, CHAr) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): d = 13.93 (CH3), 14.03 (CH3), 53.64 (CH),
62.31 (CH2), 111.50 (C), 113.75 (CH), 124.25 (CH), 131.39 (CH),
137.02 (CH), 140.38 (CO), 146.03 (C), 158.03 (CO), 169.09 (CO)
ppm.
9a
The mixture of diastereomers
HN
Ph
CH3
(R,S)-Diastereomer, ½a D20
¼ ꢁ114 (c 1.00
ꢂ
9a0
HN
Ph
CH2Cl2)
H
a
Compound 9a obtained as mixture of diastereomers was not separated into the
single isomers.
4.4. General procedure for the preparation of anthranilamides
3–9a–c
recrystallization from ethanol to afford 2a as a white solid (1.89 g,
90%, mp 104–106 °C). 1H NMR (400 MHz, CDCl3, 25 °C): d = 1.23 (t,
J = 7.1, 3H, CH2CH3), 1.76 (d, J = 7.1, 3H, CHCH3), 4.18–4.31 (m, 2H,
CH2CH3), 5.34–5.43 (m, 1H, CHCH3), 7.06 (d, J = 7.9, 1H, CHAr), 7.34
(ap.t, J = 7.9, 1H, CHAr), 7.72–7.79 (m, 1H, CHAr), 8.22 (dd, J = 7.9,
1.1, 1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 13.92
(CH3), 14.02 (CH3), 53.64 (CH), 62.30 (CH2), 112.05 (C), 113.76
(CH), 124.26 (CH), 131.37 (CH), 137.06 (CH), 140.47 (CO), 146.63
Method a: A mixture of morpholine (0.1 g, 1.045 mmol) and isa-
toic anhydride 2a (0.25 g, 0.95 mmol) in the acetonitrile (8 mL)
was stirred at reflux for 10–15 min. The reaction mixture was
cooled to rt, after which the solvent was evaporated under reduced
pressure. The crude product was purified by column chromatogra-
phy on silica gel (eluent: ethyl acetate/petroleum ether = 1/10) to
afford 6a (57%) as a yellowish oil.
(C), 158.04 (CO), 169.07 (CO) ppm. IR (KBr) m: 2993, 1772, 1726,
1606, 1475, 1335, 1209, 1038, 756 cmꢁ1. Mass-spectr., m/z (I,%):
263 (8) [M+], 218 (2), 191 (1) [M+ꢁCO2Et], 160 (100)
[M+ꢁCH3CH(NH)CO2Et], 130 (11), 117 (33), 91 (40), 65 (44), 51
(20). Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32. Found:
C, 59.55; H, 5.07; N, 5.15.
Method
b:
4-Dimethylaminopyridine
(DMAP,
9.3 mg,
0.076 mmol) and pyrrolidine (0.063 mL, 0.76 mmol) were added
to a solution of isatoic anhydride 2a (0.2 g, 0.76 mmol) in a mixture
of THF/DMF = 5/1 (0.2 M). The reaction mixture was stirred at rt for
16 h. Then ethyl acetate was added to a reaction mixture, after
which the organic layer was washed with water twice and dried
over anhydrous Na2SO4. 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 = 1/10) to afford 3a (54%) as a yellowish oil.
4.3.2. Ethyl 2-(6-bromo-2,4-dioxo-2H-3,1-benzoxazin-1(4H)-
yl)propanoate (2b)
Compound 2b was obtained as a pale brown solid, 98%, mp
118–120 °C (ethanol). 1H NMR (400 MHz, CDCl3, 25 °C): d = 1.24
(t, J = 7.0, 3H, CH2CH3), 1.74 (d, J = 6.8, 3H, CHCH3), 4.16–4.32 (m,
2H, CH2CH3), 5.28–5.45 (m, 1H, CHCH3), 6.95 (br d, J = 8.7, 1H,
CHAr), 7.82 (br d, J = 8.7, 1H, CHAr), 8.32 (br s, 1H, CHAr) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): d = 13.92 (CH3), 14.05 (CH3), 53.86
(CH), 62.49 (CH2), 115.65 (CH), 117.07 (C), 126.48 (C), 133.58
(CH), 139.79 (CH), 143.59 (CO), 156.83 (C), 163.84 (CO), 179.41
Method c:
A
mixture of a-methylbenzylamine (2.25 g,
0.021 mol) in DMF (4 mL) and isatoic anhydride 2a (3.26 g,
0.020 mol) in DMF (10 mL) was stirred at 45–50 °C for 3 h. The reac-
tion mixture was cooled to rt, diluted with cold water (100 mL), and
then basified with 50% KOH to a medium basic pH of 9. The result-
ing mixture was 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 chro-
matography on silica gel (eluent: ethyl acetate/petroleum
ether = 1/10) to afford 7a (57%) as a yellowish oil.
(CO) ppm. IR (KBr) m: 2985, 1782, 1741, 1603, 1487, 1439, 1315,
1061, 816, 748 cmꢁ1. Mass-spectr., m/z (I,%): 343 (11) [M+], 341
(11) [M+], 298 (2), 271 (2) [M+ꢁCO2Et], 269 (2) [M+ꢁCO2Et], 226
(100) [M+ꢁCH3CH(NH)CO2Et], 224 (100) [M+ꢁCH3CH(NH)CO2Et],
197 (4), 160 (8), 155 (15), 145 (30) [M+ꢁCH3CH(NH)CO2Et, ꢁBr],
117 (57), 90 (29), 75 (35), 63 (13). Anal. Calcd for C13H12BrNO5:
C, 45.64; H, 3.54; N, 4.09. Found: C, 45.82; H, 3.52; N, 4.28.
All of these anthranilamides 3–9a–c were obtained by using
method b.
4.4.1. Ethyl N-[2-(pyrrolidin-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (3a)
4.3.3. Ethyl 2-(6-methyl-2,4-dioxo-2H-3,1-benzoxazin-1(4H)-
yl)propanoate (2c)
1H NMR (400 MHz, CDCl3, 25 °C): d = 1.21 (t, J = 7.1, 3H,
CH2CH3), 1.46 (d, J = 7.1, 3H, CHCH3), 1.76–1.99 (m, 4H,
2 ꢀ CH2CH2N), 3.33–3.70 (m, 4H, 2 ꢀ CH2CH2N), 4.08 (q, J = 7.1,
1H, CHCH3), 4.15 (q, J = 7.1, 2H, CH2CH3), 5.99 (br d, 1H, NH),
6.52 (d, J = 7.6, 1H, CHAr), 6.61–6.66 (m, 1H, CHAr), 7.14–7.21 (m,
1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.19 (CH3),
Compound 2c was obtained as a white solid, 80%, mp 112–
114 °C (ethanol). 1H NMR (400 MHz, CDCl3, 25 °C): d = 1.22 (t,
J = 7.2, 3H, CH2CH3), 1.73 (d, J = 7.1, 3H, CHCH3), 2.43 (s, 3H, CH3Ar),
4.18–4.28 (m, 2H, CH2CH3), 5.31–5.40 (m, 1H, CHCH3), 6.96 (d,
J = 8.6, 1H, CHAr), 7.55 (dd, J = 8.6, 1.5, 1H, CHAr), 8.00 (br s, 1H,

A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
2105
18.71 (CH3), 24.44 (CH2), 26.32 (CH2), 46.03 (CH2), 49.68 (CH2),
4.4.5. Ethyl N-[4-bromo-2-(piperidin-1-ylcarbonyl)phenyl]-2-
51.97 (CH), 61.03 (CH2), 111.67 (CH), 116.27 (CH), 120.72 (C),
128.27 (CH), 130.94 (CH), 145.69 (C), 169.49 (CO), 174.35 (CO)
aminopropionic acid (4b)
Compound 4b was obtained as a yellowish oil, 59%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.23 (t, J = 7.1, 3H, CH2CH3), 1.45 (d,
J = 7.0, 3H, CHCH3), 1.52–1.71 (m, 6H, CH2CH2CH2N, 2 ꢀ CH2CH2N),
3.34–3.70 (m, 4H, 2 ꢀ CH2CH2N), 4.01–4.10 (m, 1H, CHCH3), 4.15
(q, J = 7.1, 2H, CH2CH3), 5.07–5.25 (br s, 1H, NH), 6.44 (d, J = 8.8,
ppm. IR (KBr) m: 3340, 2976, 2877, 1739 (CO), 1622, 1585, 1516,
1410, 1174, 1051, 752, 658, 513 cmꢁ1. Mass-spectr., m/z (I,%):
290 (17) [M+], 217 (73) [M+ꢁCO2Et], 146 (100) [M+ꢁC4H8N], 118
(15), 91 (14), 77 (23), 70 (28), 42 (22). Anal. Calcd for
C
16H22N2O3: C, 66.19; H, 7.64; N, 9.65. Found: C, 66.28; H, 7.59;
1H, CHAr), 7.18 (d, J = 2.3, 1H, CHAr), 7.27 (dd, J = 8.8, 2.3, 1H, CHAr)
N, 9.50.
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.18 (CH3), 18.58
(CH3), 24.52 (3C, 3 ꢀ CH2), 26.16 (2C, 2 ꢀ CH2), 51.71 (CH), 61.21
(CH2), 108.57 (C), 113.22 (CH), 122.81 (C), 130.28 (CH), 133.04
4.4.2. Ethyl N-[4-bromo-2-(pyrrolidin-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (3b)
(CH), 143.56 (C), 167.95 (CO), 173.74 (CO) ppm. IR (KBr) m: 3390,
Compound 3b was obtained as a yellowish oil, 51%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.24 (t, J = 7.1, 3H, CH2CH3), 1.47 (d,
J = 6.8, 3H, CHCH3), 1.79–2.04 (m, 4H, 2 ꢀ CH2CH2N), 3.35–3.71
(m, 4H, 2 ꢀ CH2CH2N), 3.98–4.07 (m, 1H, CHCH3), 4.17 (q, J = 7.1,
2H, CH2CH3), 5.97 (br d, 1H, NH), 6.43 (d, J = 8.7, 1H, CHAr), 7.27
(dd, J = 8.7, 2.4, 1H, CHAr), 7.31 (d, J = 2.4, 1H, CHAr) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): d = 14.18 (CH3), 18.56 (CH3), 24.40
(CH2), 26.32 (CH2), 46.13 (CH2), 49.65 (CH2), 51.89 (CH), 61.18
(CH2), 107.88 (C), 113.38 (CH), 122.40 (C), 130.69 (CH), 133.45
2981, 2937, 2856, 1736 (CO), 1630, 1506, 1433, 1311, 1163,
1003, 808, 638 cmꢁ1. Mass-spectr., m/z (I,%): 384 (9) [M+], 382
(9) [M+], 311 (45) [M+ꢁCO2Et], 309 (49) [M+ꢁCO2Et], 226 (99)
[M+ꢁC5H10N], 224 (88) [M+ꢁC5H10N], 198 (5), 146 (63)
[M+ꢁC5H10N, ꢁBr], 117 (54), 84 (100), 42 (40). Anal. Calcd for
C17H23BrN2O3: C, 53.27; H, 6.05; N, 7.31. Found: C, 53.32; H,
6.12; N, 7.31.
4.4.6. Ethyl N-[4-methyl-2-(piperidin-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (4c)
(CH), 144.65 (C), 167.88 (CO), 173.87 (CO) ppm. IR (KBr) m: 3298,
Compound 4c was obtained as a yellowish oil, 42%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.25 (t, J = 7.1, 3H, CH2CH3), 1.46 (d,
J = 6.9, 3H, CHCH3), 1.54–1.73 (m, 6H, CH2CH2CH2N, 2 ꢀ CH2CH2N),
2.23 (s, 3H, CH3Ar), 3.27–3.78 (m, 4H, 2 ꢀ CH2CH2N), 4.09 (q, J = 6.9,
1H, CHCH3), 4.16 (q, J = 7.1, 2H, CH2CH3), 4.79–5.05 (br s, 1H, NH),
6.49 (d, J = 8.3, 1H, CHAr), 6.92 (br d, J = 1.8, 1H, CHAr), 7.01 (dd,
J = 8.3, 1.8, 1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
d = 14.18 (CH3), 18.79 (CH3), 20.26 (CH3), 24.63 (3C, 3 ꢀ CH2),
26.22 (2C, 2 ꢀ CH2), 52.04 (CH), 60.98 (CH2), 111.85 (CH), 121.57
(C), 126.28 (C), 128.20 (CH), 130.92 (CH), 142.06 (C), 169.66 (CO),
2978, 2873, 1724 (CO), 1620, 1448, 1319, 1288, 1178, 1053, 806,
679 cmꢁ1. Mass-spectr., m/z (I,%): 370 (1) [M+], 368 (1) [M+], 297
(10) [M+ꢁCO2Et], 295 (11) [M+ꢁCO2Et], 226 (25) [M+ꢁC4H8N],
146 (28) [M+ꢁC4H8N, Br], 117 (68), 90 (37), 73 (100), 42 (48). Anal.
Calcd for C16H21BrN2O3: C, 52.04; H, 5.73; N, 7.59. Found: C, 52.10;
H, 5.81; N, 7.40.
4.4.3. Ethyl N-[4-methyl-2-(pyrrolidin-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (3c)
Compound 3c was obtained as a yellowish oil, 43%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.24 (t, J = 7.1, 3H, CH2CH3), 1.47 (d,
J = 6.9, 3H, CHCH3), 1.78–2.02 (m, 4H, 2 ꢀ CH2CH2N), 2.21 (s, 3H,
CH3Ar), 3.34–3.73 (m, 4H, 2 ꢀ CH2CH2N), 4.05 (q, J = 6.9, 1H,
CHCH3), 4.17 (q, J = 7.1, 2H, CH2CH3), 5.65 (br s, 1H, NH), 6.48 (d,
174.38 (CO) ppm IR (KBr) m: 3363, 2981, 2935, 2856, 1739 (CO),
1630, 1518, 1442, 1174, 1025, 810, 644 cmꢁ1. Mass-spectr., m/z
(I,%): 318 (5) [M+], 245 (31) [M+ꢁCO2Et], 160 (100) [M+ꢁC5H10N],
132 (6), 117 (10), 84 (56), 41 (40). Anal. Calcd for C18H26N2O3: C,
67.90; H, 8.23; N, 8.80. Found: C, 67.95; H, 8.19; N, 8.71.
J = 8.2, 1H, CHAr), 6.98–7.05 (m, 2H, CHAr
)
ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): d = 14.17 (CH3), 18.76 (CH3), 20.24
(CH3), 24.47 (CH2), 26.25 (CH2), 45.94 (CH2), 49.52 (CH2), 52.24
(CH), 60.95 (CH2), 112.01 (CH), 121.43 (C), 125.67 (C), 128.49
(CH), 131.33 (CH), 143.10 (C), 169.54 (CO), 174.53 (CO) ppm. IR
4.4.7. Ethyl N-[2-(azepan-1-ylcarbonyl)phenyl]-2-aminopro-
pionic acid (5a)
Compound 5a was obtained as a yellowish oil, 83%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.19 (t, J = 7.1, 3H, CH2CH3), 1.43 (d,
J = 6.9, 3H, CHCH3), 1.48–1.90 (m, 8H, 2 ꢀ CH2CH2CH2N,
2 ꢀ CH2CH2N), 3.24–3.78 (m, 4H, 2 ꢀ CH2CH2N), 4.03–4.10 (m,
1H, CHCH3), 4.13 (q, J = 7.1, 2H, CH2CH3), 5.02 (br d, 1H, NH),
6.53 (d, J = 8.2, 1H, CHAr), 6.65 (ap.t, J = 7.4, 1H, CHAr), 7.05 (dd,
J = 7.4, 1.2, 1H, CHAr), 7.11–7.18 (m, 1H, CHAr) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): d = 14.14 (CH3), 18.73 (CH3), 26.36
(CH2), 27.43 (CH2), 27.79 (CH2), 29.20 (CH2), 45.96 (CH2), 49.69
(CH2), 51.70 (CH), 61.00 (CH2), 111.49 (CH), 116.85 (CH), 122.24
(C), 127.26 (CH), 130.11 (CH), 144.05 (C), 170.67 (CO), 174.07
(KBr)
m: 3342, 2976, 2875, 1739 (CO), 1628, 1520, 1423, 1279,
1174, 1053, 810, 671, 526 cmꢁ1. Mass-spectr., m/z (I,%): 304 (4)
[M+], 231 (37) [M+ꢁCO2Et], 176 (2), 160 (100) [M+ꢁC4H8N], 117
(23), 91 (38), 70 (50), 43 (44). Anal. Calcd for C17H24N2O3: C,
67.08; H, 7.95; N, 9.20. Found: C, 67.29; H, 8.07; N, 9.35.
4.4.4. Ethyl N-[2-(piperidin-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (4a)
Compound 4a was obtained as a yellowish oil, 56%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.22 (t, J = 7.1, 3H, CH2CH3), 1.46 (d,
J = 6.9, 3H, CHCH3), 1.50–1.71 (m, 6H, CH2CH2CH2N, 2 ꢀ CH2CH2N),
3.32–3.70 (m, 4H, 2 ꢀ CH2CH2N), 4.05–4.12 (m, 1H, CHCH3), 4.15
(q, J = 7.1, 2H, CH2CH3), 5.14–5.27 (br s, 1H, NH), 6.55 (d, J = 8.3,
1H, CHAr), 6.67 (ap.t, J = 7.5, 1H, CHAr), 7.08 (dd, J = 7.5, 1.4, 1H,
CHAr), 7.14–7.21 (m, 1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): 14.14 (CH3), 18.69 (CH3), 24.59 (3C, 3 ꢀ CH2), 26.19 (2C,
2 ꢀ CH2), 51.73 (CH), 60.98 (CH2), 111.57 (CH), 116.80 (CH),
120.98 (C), 127.83 (CH), 130.45 (CH), 144.63 (C), 169.60 (CO),
(CO) ppm. IR (KBr) m: 3373, 2979, 2931, 2856, 1739 (CO), 1626,
1514, 1419, 1303, 1173, 750, 737, 633 cmꢁ1. Mass-spectr., m/z
(I,%): 318 (9) [M+], 245 (30) [M+ꢁCO2Et], 146 (100) [M+ꢁC6H12N],
98 (37), 77 (27), 42 (22). Anal. Calcd for C18H26N2O3: C, 67.90; H,
8.23; N, 8.80. Found: C, 68.07; H, 8.36; N, 9.01.
4.4.8. Ethyl N-[4-bromo-2-(azepan-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (5b)
Compound 5b was obtained as a yellowish oil, 70%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.23 (t, J = 7.1, 3H, CH2CH3), 1.44 (d,
J = 7.0, 3H, CHCH3), 1.51–1.93 (m, 8H, 2 ꢀ CH2CH2CH2N,
2 ꢀ CH2CH2N), 3.29–3.79 (m, 4H, 2 ꢀ CH2CH2N), 4.00–4.09 (m, 1H,
CHCH3), 4.16 (q, J = 7.1, 2H, CH2CH3), 5.02 (br d, 1H, NH), 6.44 (d,
J = 8.7, 1H, CHAr), 7.17 (br d, J = 2.3, 1H, CHAr), 7.26 (dd, J = 8.7, 2.3,
1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.16 (CH3),
174.09 (CO) ppm. IR (KBr) m: 3365, 2981, 2935, 2856, 1739 (CO),
1626, 1512, 1423, 1271, 1173, 1001, 854, 750, 632 cmꢁ1. Mass-
spectr., m/z (I,%): 304 (20) [M+], 231 (81) [M+ꢁCO2Et], 188 (3),
146 (100) [M+ꢁC5H10N], 118 (16), 91 (14), 84 (46), 77 (20), 42
(13). Anal. Calcd for C17H24N2O3: C, 67.08; H, 7.95; N, 9.20. Found:
C, 67.21; H, 8.15; N, 9.25.

2106
A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
18.60 (CH3), 26.37 (CH2), 27.39 (CH2), 27.75 (CH2), 29.17 (CH2),
46.08 (CH2), 49.76 (CH2), 51.71 (CH), 61.18 (CH2), 108.61 (CH),
113.19 (CH), 123.98 (C), 129.77 (CH), 132.72 (CH), 143.11 (C),
J = 7.0, 3H, CHCH3), 3.50–3.77 (m, 8H, 2 ꢀ NCH2CH2O), 4.01–4.11
(m, 1H, CHCH3), 4.17 (q, J = 7.1, 2H, CH2CH3), 5.25 (br d, 1H, NH),
6.45 (d, J = 8.7, 1H, CHAr), 7.19 (br d, J = 2.2, 1H, CHAr), 7.29 (dd,
J = 8.7, 2.2, 1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
d = 14.18 (CH3), 18.58 (CH3), 43.23–47.92 (2C, 2 ꢀ CH2), 51.68
(CH), 61.29 (CH2), 66.93 (2C, 2 ꢀ CH2), 108.64 (C), 113.54 (CH),
121.58 (C), 130.56 (CH), 133.58 (CH), 143.84 (C), 168.25 (CO),
169.04 (CO), 173.66 (CO) ppm. IR (KBr) m: 3386, 2979, 2929, 2856,
1739 (CO), 1626, 1506, 1425, 1306, 1213, 1167, 808, 638 cmꢁ1
.
Mass-spectr., m/z (I,%): 398 (11) [M+], 396 (12) [M+], 325 (53)
[M+ꢁCO2Et], 323 (58) [M+ꢁCO2Et], 226 (77) [M+ꢁC6H12N], 224
(69) [M+ꢁC6H12N], 198 (3), 146 (65) [M+ꢁC6H12N, ꢁBr], 117 (53),
98 (100), 42 (89). Anal. Calcd for C18H25BrN2O3: C, 54.42; H, 6.34;
N, 7.05. Found: C, 54.25; H, 6.40; N, 7.18.
173.61 (CO) ppm. IR (KBr) m: 3381, 2979, 2856, 1738 (CO), 1631,
1506, 1427, 1238, 1174, 1115, 1020, 810, 737, 609 cmꢁ1. Mass-
spectr., m/z (I,%): 386 (15) [M+], 384 (16) [M+], 313 (56)
[M+ꢁCO2Et], 311 (63) [M+ꢁCO2Et], 226 (100) [M+ꢁC4H8NO], 224
(99) [M+ꢁC4H8NO], 197 (4), 146 (69) [M+ꢁC4H8NO, ꢁBr], 117
(58), 90 (25), 56 (42), 42 (43). Anal. Calcd for C16H21BrN2O4: C,
49.88; H, 5.49; N, 7.27. Found: C, 49.80; H, 5.54; N, 7.20.
4.4.9. Ethyl N-[4-methyl-2-(azepan-1-ylcarbonyl)phenyl]-2-
aminopropionic acid (5c)
Compound 5c was obtained as a yellowish oil, 45%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.24 (t, J = 7.1, 3H, CH2CH3), 1.45 (d,
J = 6.9, 3H, CHCH3), 1.52–1.95 (m, 8H, 2 ꢀ CH2CH2CH2N,
2 ꢀ CH2CH2N), 2.22 (s, 3H, CH3Ar), 3.23–3.85 (m, 4H, 2 ꢀ CH2CH2N),
4.02–4.23 (m, 3H, CHCH3, CH2CH3), 4.77 (br d, 1H, NH), 6.49 (d,
J = 8.3, 1H, CHAr), 6.90 (br d, J = 1.7, 1H, CHAr), 7.00 (dd, J = 8.3,
1.7, 1H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.19
(CH3), 18.83 (CH3), 20.29 (CH3), 26.44 (CH2), 27.46 (CH2), 27.84
(CH2), 29.23 (CH2), 45.93 (CH2), 49.67 (CH2), 52.02 (CH), 61.00
(CH2), 111.79 (CH), 122.77 (C), 126.29 (C), 127.68 (CH), 130.55
4.4.13. Ethyl N-[4-methyl-2-(morpholin-4-ylcarbonyl)phenyl]-
2-aminopropionic acid (6c)
Compound 6c was obtained as a yellowish oil, 42%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.23 (t, J = 7.1, 3H, CH2CH3), 1.45 (d,
J = 6.9, 3H, CHCH3), 2.21 (s, 3H, CH3Ar), 3.48–3.77 (m, 8H,
2 ꢀ NCH2CH2O), 4.08 (q, J = 6.9, 1H, CHCH3), 4.16 (q, J = 7.1, 2H,
CH2CH3), 4.83–5.18 (br s, 1H, NH), 6.50 (d, J = 8.4, 1H, CHAr), 6.91
(br d, J = 2.1, 1H, CHAr), 7.02 (ddd, J = 8.4, 2.1, 0.6, 1H, CHAr) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): d = 14.18 (CH3), 18.78 (CH3),
20.22 (CH3), 43.78–47.69 (2C, 2 ꢀ CH2), 51.98 (CH), 61.04 (CH2),
67.02 (2C, 2 ꢀ CH2), 112.17 (CH), 120.35 (C), 126.46 (C), 128.43
(CH), 131.46 (CH), 142.31 (C), 169.93 (CO), 174.24 (CO) ppm. IR
(CH), 141.56 (C), 170.78 (CO), 174.38 (CO) ppm. IR (KBr) m: 3373,
2979, 2927, 2858, 1739 (CO), 1630, 1518, 1425, 1308, 1173,
1053, 808, 642 cmꢁ1. Mass-spectr., m/z (I,%): 332 (14) [M+], 259
(56) [M+ꢁCO2Et], 160 (100) [M+ꢁC6H12N], 132 (13), 117 (22), 98
(58), 91 (32), 41 (15). Anal. Calcd for C19H28N2O3: C, 68.65; H,
8.49; N, 8.43. Found: C, 68.53; H, 8.47; N, 8.21.
(KBr)
m: 3354, 2970, 2864, 1743 (CO), 1626, 1527, 1439, 1178,
1111, 1028, 804, cmꢁ1. Mass-spectr., m/z (I,%): 320 (4) [M+], 247
(22) [M+ꢁCO2Et], 160 (100) [M+ꢁC4H8NO], 132 (6), 117 (10), 91
(13), 56 (14), 42 (10). Anal. Calcd for C17H24N2O4: C, 63.73; H,
7.55; N, 8.74. Found: C, 63.45; H, 7.75; N, 8.81.
4.4.10. Ethyl (R)-N-[2-(azepan-1-ylcarbonyl)phenyl]-2-
aminopropionic acid ((R)-8a)
Compound (R)-8a was obtained as a yellowish oil, 85%, ½a D20
¼ þ9
ꢂ
(c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3, 25 °C): d = 1.25 (t, J = 7.1, 3H,
CH2CH3), 1.48 (d, J = 6.9, 3H, CHCH3), 1.53–1.99 (m, 8H,
2 ꢀ CH2CH2CH2N, 2 ꢀ CH2CH2N), 3.31–3.84 (m, 4H, 2 ꢀ CH2CH2N),
4.06–4.16 (m, 1H, CHCH3), 4.18 (q, J = 7.1, 2H, CH2CH3), 5.05 (br d,
1H, NH), 6.58 (d, J = 8.2, 1H, CHAr), 6.66–6.75 (m, 1H, CHAr), 7.09
(dd, J = 7.5, 1.4, 1H, CHAr), 7.16–7.24 (m, 1H, CHAr) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): d = 14.17 (CH3), 18.77 (CH3), 26.41 (CH2),
27.48 (CH2), 27.81 (CH2), 29.26 (CH2), 46.02 (CH2), 49.73 (CH2),
51.77 (CH), 61.05 (CH2), 111.53 (CH), 116.88 (CH), 122.28 (C),
127.31 (CH), 130.14 (CH), 144.10 (C), 170.71 (CO), 174.14 (CO) ppm.
4.4.14. Ethyl N-[2-{[(1-phenylethyl)amino]carbonyl}phenyl]-2-
aminopropionic acid (7a)
Compound 7a was obtained as a yellowish oil, 85%, mixture of
diastereomers A:B = 1:2.4. 1H NMR (400 MHz, CDCl3, 25 °C) (mix-
ture of two diastereomers A:B = 1:2.4): d = 1.24, 1.27 (both t,
JA = 7.1, JB = 7.1, sum 3H, CH2CH3), 1.54 (d, J = 7.0, 3H, PhCHCH3),
1.59, 1.60 (both d, JA = 6.9, JB = 7.0, sum 3H, CHCH3), 4.10–4.24
(m, 3H, PhCHCH3, CH2CH3), 5.27–5.36 (m, 1H, CHCH3), 6.54–6.65
(m, 3H, 2ꢀCHAr, NH), 7.25–7.31 (m, 2H, 2 ꢀ CHAr), 7.34–7.45 (m,
5H, 5 ꢀ CHAr), 7.90–7.95 (m, 1H, NH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C) (isomer A): d = 14.20 (CH3), 18.68 (CH3), 21.94
(CH3), 48.92 (CH), 51.78 (CH), 61.07 (CH2), 112.05 (CH), 115.81
(CH), 116.10 (C), 126.25 (2C, 2 ꢀ CH), 127.35 (CH), 127.68 (CH),
128.71 (2C, 2 ꢀ CH), 132.73 (CH), 143.40 (C), 148.31 (C), 168.69
(CO), 174.24 (CO) ppm. 13C NMR (100 MHz, CDCl3, 25 °C) (isomer
B): d = 14.24 (CH3), 18.63 (CH3), 22.01 (CH3), 48.92 (CH), 51.72
(CH), 61.07 (CH2), 111.97 (CH), 115.76 (CH), 115.99 (C), 126.18
(2C, 2 ꢀ CH), 127.30 (CH), 127.68 (CH), 128.71 (2C, 2 ꢀ CH),
132.73 (CH), 143.53 (C), 148.31 (C), 168.74 (CO), 174.30 (CO)
4.4.11. Ethyl N-[2-(morpholin-4-ylcarbonyl)phenyl]-2-
aminopropionic acid (6a)
Compound 6a was obtained as a yellowish oil, 69%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.22 (t, J = 7.2, 3H, CH2CH3), 1.46 (d,
J = 6.9, 3H, CHCH3), 3.49–3.76 (m, 8H, 2 ꢀ NCH2CH2O), 4.06–4.13
(m, 1H, CHCH3), 4.15 (q, J = 7.2, 2H, CH2CH3), 5.30 (br d, 1H, NH),
6.56 (d, J = 8.2, 1H, CHAr), 6.68 (ap.t, J = 7.5, 1H, CHAr), 7.07 (dd,
J = 7.5, 1.3, 1H, CHAr), 7.18–7.22 (m, 1H, CHAr) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): d = 14.17 (CH3), 18.71 (CH3), 42.87–47.74
(2C, 2 ꢀ CH2), 51.68 (CH), 61.12 (CH2), 67.00 (2C, 2 ꢀ CH2), 111.86
(CH), 116.93 (CH), 119.68 (C), 128.19 (CH), 131.01 (CH), 144.92
ppm. IR (KBr) m: 3330, 2979, 2877, 1736 (CO), 1633, 1583, 1520,
1452, 1174, 1051, 748, 700, 569 cmꢁ1. Mass-spectr., m/z (I,%):
340 (13) [M+], 267 (30) [M+ꢁCO2Et], 163 (45), 146 (100)
[M+ꢁC8H9N], 105 (69), 77 (29), 42 (7). Anal. Calcd for
(C), 169.92 (CO), 174.06 (CO) ppm. IR (KBr) m: 3330, 2979, 2927,
2866, 1743 (CO), 1626, 1466, 1325, 1186, 1115, 1014, 758, cmꢁ1
.
C20H24N2O3: C, 70.57; H, 7.11; N, 8.23. Found: C, 70.35; H, 7.20;
Mass-spectr., m/z (I,%): 306 (11) [M+], 233 (39) [M+ꢁCO2Et], 146
(100) [M+ꢁC4H8NO], 118 (10), 77 (16), 42 (6). Anal. Calcd for
C16H22N2O4: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.77; H, 7.44; N,
9.13.
N, 8.17.
4.4.15. Ethyl N-[4-bromo-2-{[(1-phenylethyl)amino]carbonyl}
phenyl]-2-aminopropionic acid (7b)
Compound 7b was obtained as a yellowish oil, 53%, mixture of
diastereomers A:B =1:2.7. 1H NMR (400 MHz, CDCl3, 25 °C) (mix-
ture of two diastereomers A:B = 1:2.7): d = 1.25, 1.31 (both t,
JA = 7.15, JB = 7.15, sum 3H, CH2CH3), 1.52 (d, J = 7.0, 3H, PhCHCH3),
1.56–1.64 (m, 3H, CHCH3), 4.04–4.12 (m, 1H, PhCHCH3), 4.20, 4.26
4.4.12. Ethyl N-[4-bromo-2-(morpholin-4-ylcarbonyl)phenyl]-
2-aminopropionic acid (6b)
Compound 6b was obtained as a yellowish oil, 72%. 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.24 (t, J = 7.1, 3H, CH2CH3), 1.46 (d,

A. V. Kurkin et al. / Tetrahedron: Asymmetry 21 (2010) 2100–2107
2107
(both q, JA = 7.15, JB = 7.15, sum 2H, CH2CH3), 5.22–5.31 (m, 1H,
CHCH3), 6.39, 6.43 (both d, JA = 8.9, JB = 8.8, sum 1H, CHAr), 6.67,
6.93 (br d and br t, sum 1H, NH), 7.23–7.52 (m, 8H, 8 ꢀ CHAr),
7.84, 7.88 (both br d, sum 1H, NH) ppm. 13C NMR (100 MHz, CDCl3,
25 °C) (isomer A): d = 14.20 (CH3), 18.51 (CH3), 21.88 (CH3), 49.20
(CH), 51.70 (CH), 61.28 (CH2), 107.22 (C), 113.64 (CH), 117.66 (C),
126.31 (2C, 2 ꢀ CH), 127.42 (CH), 128.77 (2C, 2 ꢀ CH), 130.19
(CH), 135.17 (CH), 143.12 (C), 147.13 (C), 167.46 (CO), 173.97
(CO) ppm. 13C NMR (100 MHz, CDCl3, 25 °C) (isomer B): d = 14.24
(CH3), 18.51 (CH3), 22.08 (CH3), 49.27 (CH), 51.46 (CH), 61.42
(CH2), 107.27 (C), 113.25 (CH), 117.47 (C), 126.16 (2C, 2 ꢀ CH),
127.25 (CH), 128.67 (2C, 2 ꢀ CH), 130.14 (CH), 135.17 (CH),
(m, 3H, PhCHCH3, CH2CH3), 5.27–5.36 (m, 1H, CHCH3), 6.30–6.41
(m, 1H, NH), 6.56–6.68 (m, 2H, 2 ꢀ CHAr), 7.25–7.33 (m, 2H,
2 ꢀ CHAr), 7.34–7.44 (m, 5H, 5 ꢀ CHAr), 7.83–7.92 (m, 1H, NH)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C) (isomer A): d = 14.22
(CH3), 18.66 (CH3), 21.91 (CH3), 48.90 (CH), 51.76 (CH), 61.05
(CH2), 112.12 (CH), 115.78 (CH), 116.02 (C), 126.23 (2C, 2 ꢀ CH),
127.41 (CH), 127.47 (CH), 128.75 (2C, 2 ꢀ CH), 132.76 (CH),
143.35 (C), 148.33 (C), 168.61 (CO), 174.20 (CO) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C) (isomer B): d = 14.22 (CH3), 18.62 (CH3),
21.98 (CH3), 48.90 (CH), 51.72 (CH), 61.05 (CH2), 112.06 (CH),
115.74 (CH), 115.92 (C), 126.16 (2C, 2 ꢀ CH), 127.37 (CH), 127.47
(CH), 128.75 (2C, 2 ꢀ CH), 132.76 (CH), 143.35 (C), 148.33 (C),
168.64 (CO), 174.24 (CO) ppm.
143.61 (C), 146.94 (C), 167.53 (CO), 174.40 (CO) ppm. IR (KBr) m:
3350, 2979, 2935, 1739 (CO), 1631, 1506, 1321, 1240, 1178,
1020, 893, 806, 700, 542 cmꢁ1. Mass-spectr., m/z (I,%): 420 (4)
[M+], 418 (4) [M+], 347 (9) [M+ꢁCO2Et], 345 (10) [M+ꢁCO2Et],
268 (1) [M+ꢁCO2Et, -Ph], 241 (25), 226 (19) [M+ꢁC8H9N], 224
(20) [M+ꢁC8H9N], 163 (5), 146 (13) [M+ꢁC8H9N, ꢁBr], 120 (14),
105 (100), 77 (25), 42 (10). Anal. Calcd for C20H23BrN2O3: C,
57.29; H, 5.53; N, 6.68. Found: C, 57.21; H, 5.66; N, 6.27.
4.4.18. Ethyl (R)-N-[2-{[((S)-1-phenylethyl)amino]carbonyl}
phenyl]-2-aminopropionic acid ((R,S)-9a0)
Compound (R,S)-9a0 was obtained as a yellowish oil, 83%. 1H
NMR (400 MHz, CDCl3, 25 °C): d = 1.27 (t, J = 7.1, 3H, CH2CH3),
1.54 (d, J = 7.0, 3H, PhCHCH3), 1.60 (d, J = 6.9, 3H, CHCH3), 4.09–
4.26 (m, 3H, PhCHCH3, CH2CH3), 5.26–5.36 (m, 1H, CHCH3), 6.37
(br d, 1H, NH), 6.55–6.67 (m, 2H, 2 ꢀ CHAr), 7.25–7.33 (m, 2H,
2 ꢀ CHAr), 7.34–7.44 (m, 5H, 5 ꢀ CHAr), 7.89 (br d, 1H, NH) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): d = 14.22 (CH3), 18.62 (CH3),
21.98 (CH3), 48.91 (CH), 51.72 (CH), 61.06 (CH2), 112.02 (CH),
115.74 (CH), 115.92 (C), 126.16 (2C, 2 ꢀ CH), 127.35 (CH), 127.50
(CH), 128.73 (2C, 2 ꢀ CH), 132.75 (CH), 143.39 (C), 148.32 (C),
168.67 (CO), 174.25 (CO) ppm.
4.4.16. Ethyl N-[4-methyl-2-{[(1-phenylethyl)amino]carbonyl}
phenyl]-2-aminopropionic acid (7c)
Compound 7c was obtained as a yellowish oil, 43%, mixture of
diastereomers A:B =1:2.2. 1H NMR (400 MHz, CDCl3, 25 °C) (mix-
ture of two diastereomers A:B = 1:2.2): d = 1.23, 1.27 (both t,
JA = 7.1, JB = 7.1, sum 3H, CH2CH3), 1.48–1.55 (m, 3H, PhCHCH3),
1.60 (d, J = 6.9, 3H, CHCH3), 2.23, 2.24 (both s, sum 3H, CH3Ar),
4.06–4.24 (m, 3H, PhCHCH3, CH2CH3), 5.26–5.37 (m, 1H, CHCH3),
6.47–6.58 (m, 2H, 2 ꢀ CHAr), 7.05–7.13 (m, 1H, CHAr), 7.17–7.24
(m, 1H, NH), 7.25–7.32 (m, 1H, CHAr), 7.34–7.45 (m, 4H, 4 ꢀ CHAr),
7.52–7.66 (m, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C) (iso-
mer A): d = 14.23 (CH3), 18.67 (CH3), 20.29 (CH3), 21.90 (CH3),
48.88 (CH), 52.08 (CH), 61.00 (CH2), 112.52 (CH), 116.42 (C),
125.11 (C), 126.29 (2C, 2 ꢀ CH), 127.34 (CH), 127.87 (CH), 128.69
(2C, 2 ꢀ CH), 133.43 (CH), 143.40 (C), 146.04 (C), 168.61 (CO),
174.46 (CO) ppm. 13C NMR (100 MHz, CDCl3, 25 °C) (isomer B):
d = 14.23 (CH3), 18.67 (CH3), 20.29 (CH3), 22.00 (CH3), 48.88 (CH),
52.00 (CH), 61.00 (CH2), 112.36 (CH), 116.25 (C), 125.00 (C),
126.21 (2C, 2 ꢀ CH), 127.28 (CH), 127.87 (CH), 128.69 (2C,
2 ꢀ CH), 133.43 (CH), 143.54 (C), 146.04 (C), 168.67 (CO), 174.52
References
1. Blank, B.; Cohen, S. R.; Spiggle, D. W. J. Chem. Eng. Data 1968, 13, 577–579.
2. Thorarensen, A.; Wakefield, B. D.; Romero, D. L.; Marotti, K. R.; Sweeney, M. T.;
Zurenko, G. E.; Rohrer, D. C.; Han, F.; Bryant, G. L. Bioorg. Med. Chem. Lett. 2007,
17, 2823–2827.
3. Congiu, C.; Cocco, M. T.; Lilliu, V.; Onnis, V. J. Med. Chem. 2005, 48, 8245–8252.
4. Manley, P. W.; Furet, P.; Bold, G.; Brüggen, J.; Mestan, J.; Meyer, T.; Schnell, C.
R.; Wood, J. J. Med. Chem. 2002, 45, 5687–5693.
5. Allison, B. D.; Phuong, V. K.; McAtee, L. C.; Rosen, M.; Morton, M.; Prendergast,
C.; Barrett, T.; Lagaud, G.; Freedman, J.; Li, L.; Wu, X.; Venkatesan, H.; Pippel,
M.; Woods, C.; Rizzolio, M. C.; Hack, M.; Hoey, K.; Deng, X.; King, C.; Shankley,
N. P.; Rabinowitz, M. H. J. Med. Chem. 2006, 49, 6371–6390.
6. Patil, P. A.; Kothekar, M. A. Indian J. Med. Sci. 2006, 60, 427–437.
7. Srinivas, N.; Barbhaiya, R. H.; Midha, K. K. J. Pharmacol. Sci. 2001, 90, 1205–
1215.
8. Kurkin, A. V.; Belov, D. S.; Yurovskaya, M. A. Chem. Heterocycl. Compd. 2008, 44,
1123–1128.
9. Kurkin, A. V.; Bernovskaya, A. A.; Yurovskaya, M. A. Tetrahedron: Asymmetry
2009, 20, 1500–1505.
10. Radul, O. M.; Zhungietu, G. I.; Rekhter, M. A.; Bukhanyuk, S. M. Khim.
Geterotsikl. Soedin. 1980, 11, 1562 (CA 94:174794t).
11. Coppola, G. M. J. Heterocycl. Chem. 1987, 24, 1249–1251.
12. Castle, R. N.; Adachi, K.; Guither, W. D. J. Heterocycl. Chem. 1965, 2, 459–462.
13. Singh, S. K.; Govindan, M.; Hynes, J. B. J. Heterocycl. Chem. 1990, 27, 2101–2105.
14. Royals, E. E.; Harrel, L. L. J. Am. Chem. Soc. 1955, 77, 3405–3408.
15. Kozlowski, J. A., McCombie, S. W., Tagat, J. R. EP 1091956B1, 2004.
16. Venuti, M. C. Synthesis 1982, 266–268.
17. For reviews of the chemistry of isatoic anhydride, see Coppola, G. M. Synthesis
1980, 505–1091.
18. Hinman, C.; Vaughan, K. Synthesis 1980, 719–721. In this work, 4-
dimethylaminopyridine had been used in the preparation of an anthranilate
active ester, isolated before reaction with nucleophiles.
(CO) ppm. IR (KBr) m: 3336, 2979, 2933, 1738 (CO), 1643, 1520,
1450, 1279, 1174, 1051, 810, 700, 542 cmꢁ1. Mass-spectr., m/z
(I,%): 354 (4) [M+], 281 (10) [M+ꢁCO2Et], 204 (0.7) [M+ꢁCO2Et, -
Ph], 177 (25), 160 (83) [M+ꢁC8H9N], 105 (100), 91 (19), 77 (19),
42 (8). Anal. Calcd for C21H26N2O3: C, 71.16; H, 7.39; N, 7.90.
Found: C, 71.14; H, 7.50; N, 7.94.
4.4.17. Ethyl (R)-N-[2-{[(1-phenylethyl)amino]carbonyl}
phenyl]-2-aminopropionic acid ((R)-9a)
Compound (R)-9a was obtained as a yellowish oil, 80%, mixture
of diastereomers A:B = 1:2.8. 1H NMR (400 MHz, CDCl3, 25 °C)
(mixture of two diastereomers A:B = 1:2.8): d = 1.24, 1.27 (both t,
JA = 7.1, JB = 7.1, sum 3H, CH2CH3), 1.54, 1.55 (both d, JA = 7.0,
JB = 7.0, sum 3H, PhCHCH3), 1.61 (d, J = 6.9, 3H, CHCH3), 4.09–4.26