Synthesis of γ-(Arylamino)butyric Acid Derivatives via Ring-Opening Addition of Arylamines to Cyclopropane-1,1-Dicarboxylates

Article abstract of DOI:10.1134/S1070428019090252

A rapid and efficient catalytic approach has been proposed for the synthesis of dimethyl 2-[2-(aryl-amino)but-3-en-1-yl]- and 2-[2-(arylamino)-2-phenylethyl]malonates in good yields (49-95%) by ring-opening reaction of dimethyl 2-vinyl- and 2-phenylcyclopropane-1,1-dicarboxylates with arylamines in the presence of Yb(III) catalyst under microwave irradiation. The synthesized compounds are convenient precursors to γ-(aryl-amino)butyric acid derivatives.

Full text of DOI:10.1134/S1070428019090252

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 9, pp. 1432–1438. © Pleiades Publishing, Ltd., 2019.
Synthesis of γ-(Arylamino)butyric Acid Derivatives
via Ring-Opening Addition of Arylamines
to Cyclopropane-1,1-Dicarboxylates
S. K. Lia, L. L. Huanga,* Y. D. Lva, and H. D. Fenga
a College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 201620 Shanghai
*e-mail: llhuang999@126.com
Received March 28, 2019; revised May 31, 2019; accepted July 2, 2019
Abstract—A rapid and efficient catalytic approach has been proposed for the synthesis of dimethyl 2-[2-(aryl-
amino)but-3-en-1-yl]- and 2-[2-(arylamino)-2-phenylethyl]malonates in good yields (49–95%) by ring-opening
reaction of dimethyl 2-vinyl- and 2-phenylcyclopropane-1,1-dicarboxylates with arylamines in the presence of
Yb(III) catalyst under microwave irradiation. The synthesized compounds are convenient precursors to γ-(aryl-
amino)butyric acid derivatives.
Keywords: γ-(arylamino)butyric acid, ring-opening additions, dimethyl 2-[2-(arylamino)but-3-en-1-yl]- and
2-[2-(arylamino)-2-phenylethyl]malonates, cyclopropane-1,1-dicarboxylates.
DOI: 10.1134/S1070428019090252
γ-Aminobutyric acid (GABA) is the chief inhibitory
neurotransmitter in the developmentally mature mam-
malian central nervous system (CNS) [1–4]. The pre-
paration and pharmacological effect of many structural
analogs of GABA for the treatment of CNS disorders
has drawn attention of medicinal chemists [5]. In
particular, α-, β-, and γ-substituted γ-aminobutyric acid
derivatives have been researched extensively [6–12].
However, the synthesis of γ-(arylamino)butyric acid
derivatives has been explored relatively poorly because
of a long reaction time, high amount of catalysts, and
low yields [13–20].
ester derivatives and γ-(arylamino)butyric acids ac-
cording to a rapid and efficient strategy.
We commenced our studies by examining the reac-
tion of aniline (1a, 0.4 mmol) with 2-vinylcyclo-
propane-1,1-dicarboxylate (2a, 0.5 mmol) in 1,2-di-
chloroethane (DCE) in the presence of Lewis acids
(0.02 mmol); the reactions were carried out at 85°C for
30 min under general conditions [13–20]. No reaction
occurred with AgOTf and Cu(OTf)2 as catalysts
(Table 1; entry nos. 1–2) . When Sc(OTf)3, Yb(OTf)3,
FeCl3, or CuCl2 was used as catalyst, the yield of 3a
was 16, 41, 8, and 10%, respectively (entry nos. 3-6).
Several solvents were screened, and a higher yield of
3a was obtained in DCE. In order to further improve
the yield, microwave irradiation technique was applied
to accelerate the reaction. Microwave irradiation
provides an efficient and expeditious tool for achieving
the desired cyclopropane ring opening with weakly nu-
cleophilic aromatic amines in the presence of an ap-
The challenges toward the synthesis of γ-(aryl-
amino)butyric acid ester derivatives via ring opening
of cyclopropane-1,1-dicarboxylates by the action of
arylamines are as follows (Scheme 1): (1) how to
introduce an aryl substituent to the nitrogen atom and
(2) how to improve the yield and efficiency. Herein,
we report the synthesis of γ-(arylamino)butyric acid
β
H2N
COOH
β
NH2
H2N
Me
COOH
NH2
β
COOH
H2C
γ
COOH
Me
Pregabalin
Cl
Gabapentin
Vigabatrin
Baclofen
1432

SYNTHESIS OF γ-(ARYLAMINO)BUTYRIC ACID DERIVATIVES
1433
Scheme 1.
O
R
R
R
H2N
COOH
or
or
NH
R
α
γ
H2N
COOH
R1
β
H2N
COOH
R1
CO2Me
CO2Me
R2
R2
N
γ
Yb(III), MW
R1
N
CO2Me
+
NH
R2
R3
R3
CO2Me
R3
COOH
propriate Lewis acid catalyst (Scheme 1) [21]. The
reaction efficiency and yield were greatly improved at
115°C under microwave irradiation (entry no. 15).
Cyclopropane-1,1-dicarboxylate should undergo
aminolysis in reactions with anilines [15]. However,
1-phenylpyrrolidin-2-one failed to react under these
conditions. Further prolongation of the reaction time
did not improve the yield (entry no. 16). Thus, the
optimized reaction conditions were established as
follows: microwave irradiation for 15 min at 115°C,
DCE as solvent, and Yb(OTf)3 as catalyst.
The scope and limitations of the reaction were
tested under the optimized conditions (Scheme 2).
Anilines with electron-donating substituents such as
methyl, isopropyl, and methoxy groups afforded ring-
opening products 3a–3f in 71–95% yield. Approxi-
mately the same yields of 3h–3k (75–92%) were ob-
tained in the reactions with anilines bearing electron-
withdrawing substituents (F, I, NO2) on the benzene
ring. Thus, both electron-donating and electron-with-
drawing substituents on the phenyl ring can be present
in the substrate molecule, as demonstrated by the
Table 1. Optimization of the reaction conditionsa
Lewis acid, solvent
MW
CO2Me
CO2Me
NH
CO2Me
CO2Me
+
H2C
NH2
H2C
1a
2a
3a
Entry no. Lewis acid (10 mol %)
Solvent
Temperature, °C Reaction time, min Yield of 3a,b %
30
30
30
30
30
30
30
30
30
30
30
15
30
01
02
AgOTf
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
Toluene
085
085
085
085
085
085
085
085
085
085
115
115
115
00
00
16
41
08
10
35
25
30
33
71
95
94
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
FeCl3
03
04
05
06
CuCl2
07
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
08
Acetonitrile
09
Tetrahydrofuran
1,4-Dioxane
10
14
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
c15c
c16c
a
b
c
The reactions were carried out with 0.4 mmol of 1a, 0.5 mmol of 2a, 0.02 mmol of Lewis acid, and 2 mL of solvent in a pressure tube.
Isolated yield.
Under microwave irradiation.
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LI et al.
1434
Scheme 2.
Yb(III), ClCH2CH2Cl
MW
(1) NaOH
(2) HCl
R1
R1
R1
CO2Me
CO2Me
R2
NH
R2
N
CO2Me
CO2Me
NH
CO2H
+
R3
R3
R3
4j, 4m
1a–1m
2a, 2b
3a–3q
1, R2 = H, R1 = H (a), 4-Me (b), 2,4-Me2 (c), 2,4,6-Me3 (d), 3,5-(i-Pr)2 (e), 2-MeO (f), 2-F-6-Me (g). 4-F (h), 2-I (i), 4-O2N (j),
2-F-6-O2N (k), 2-MeO-6-O2N (l); R1 = H, R2 = Me (m); 2, R3 = CH2=CH (a), Ph (b); 3, 4, R2 = H, R3 = CH2=CH, R1 = H (a),
4-Me (b), 2,4-Me2 (c), 2,4,6-Me3 (d), 3,5-(i-Pr)2 (e), 2-MeO (f), 2-F-6-Me (g). 4-F (h), 2-I (i), 4-O2N (j), 2-F-6-O2N (k),
2-MeO-6-O2N (l); R2 = H, R3 = Ph, R1 = H (m), 4-Me (n), 3,5-(i-Pr)2 (o), 4-F (p); R1 = H, R2 = Me, R3 = CH2=CH (q).
Yb(III), ClCH2CH2Cl
MW
CO2Me
CO2Me
( )n
N
CO2Me
CO2Me
( )n
+
N
H2C
H2C
H
2a
3r, 3s
1n, 1o
1n, 3r, 4r, n = 1; 1o, 3s, 4s, n = 2.
synthesis of 3g and 3l. Steric hindrances created by
substituents on the benzene ring had little effect on the
reaction; for instance, dimethyl-, trimethyl-, and diiso-
propyl-substituted anilines 1c–1e gave rise to com-
pounds 3c, 3d, and 3e in 75, 73, and 71% yield,
respectively.
EXPERIMENTAL
The IR spectra were obtained on a Specord 75 IR
spectrophotometer in KBr. The mass spectra were
obtained using an Agilent 1200 Series LC/MSD instru-
ment (electron impact, 70 eV; samples were introduced
1
as solutions in formic acid). The H and 13C NMR
The reaction with dimethyl 2-phenylcyclopropane-
1,1-carboxylate (2b) was also efficient, and com-
pounds 3m–3p were isolated in good to excellent
yields (78–93%). Next, the scope of the reaction was
explored with respect to secondary arylamines 1m–1o.
The corresponding ring-opening products 3q–3s were
isolated in 49–70% yield. Obviously, the nucleo-
philicity of secondary arylamines is lower than that of
primary amines in the ring-opening addition to cyclo-
propanes.
spectra were recorded on a Bruker Avance II spec-
trometer (400 and 100 MHz, respectively) in CDCl3
using tetramethylsilane as internal standard. The
melting points were measured on an X-5A microscopic
melting point apparatus. The elemental compositions
were determined with a Perkin Elmer CHN analyzer.
Microwave-assisted reactions were performed with
a Biotage initiator. Dimethyl 2-vinylcyclopropane-1,1-
dicarboxylate (2a) [22] and dimethyl 2-phenylcyclo-
propane-1,1-dicarboxylate (2b) [23] were prepared by
known methods.
To demonstrate the synthetic utility of this Yb(III)-
catalyzed ring-opening addition reaction, further
transformation of some products was carried out
(Scheme 2). Choosing randomly 3j and 3m as starting
materials, γ-(arylamino)butyric acids 4j and 4m were
obtained by hydrolysis followed by decarboxylation.
General procedure for the synthesis of com-
pounds 3a–3s. A mixture of 0.4 mmol of aromatic
amine 1a–1o, 0.5 mmol of cyclopropane 2a or 2b, and
0.02 mmol of Yb(OTf)3 in 2 mL of 1,2-dichloroethane
was heated under microwave irradiation at 115°C for
15 min. The mixture was cooled to room temperature,
the solvent was removed under reduced pressure, and
the crude product was purified by silica gel chromatog-
raphy with 10−50% ethyl acetate in petroleum ether as
eluent. Compounds 3a–3s were isolated as light yellow
viscous oils.
In summary, we were the first to synthesize γ-(aryl-
amino)butyric acid derivatives by reaction of aryl-
amines with cyclopropane-1,1-dicarboxylates under
microwave irradiation. The described method is gen-
eral, and it can be applied to anilines having both
electron-donating and electron-withdrawing groups in
the benzene ring. It lays a foundation for the develop-
ment and application of γ-(arylamino)butyric acid
substrates, and further research is under way.
Dimethyl 2-(2-anilinobut-3-en-1-yl)malonate
(3a). Yield 105 mg (95%). IR spectrum, ν, cm–1: 2963 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SYNTHESIS OF γ-(ARYLAMINO)BUTYRIC ACID DERIVATIVES
1435
1
(C–H), 1734 s (C–O), 1595 s (C=Carom). H NMR
spectrum, δ, ppm: 2.28–2.37 m (2H, CH2), 3.57 t (1H,
CH, J = 6.0 Hz), 3.69 s (3H, OCH3), 3.73 s (3H,
OCH3), 4.14–4.20 m (1H, CH), 5.22–5.27 m (2H,
HC=CH2), 5.74-5.82 m (1H, HC=CH2), 6.64 t (1H,
C6H5, J = 8.0 Hz), 6.85 d (1H, C6H5, J = 8.0 Hz),
7.39 t (1H, C6H5, J = 8.0 Hz), 7.99 d (1H, C6H5, J =
8.0 Hz), 8.12 d (1H, C6H5, J = 8.0 Hz). 13C NMR
spectrum, δC, ppm: 33.9, 48.5, 52.7, 53.6, 114.7, 115.9,
117.2, 126.7, 132.5, 136.1, 136.8, 144.4, 169.2, 169.3.
Mass spectrum: m/z 277.1 (Irel 100%) [M]+. Found, %:
C 64.93; H 6.86; N 5.01; O 23.02. C15H19NO4. Cal-
culated, %: C 64.97; H 6.91; N 5.05; O 23.08.
34.8, 49.1, 52.5, 58.6, 116.1, 128.8, 129.5, 129.6,
131.2, 139.2, 141.3, 169.8, 170.0. Mass spectrum: m/z
319.2 (Irel 100%) [M]+. Found, %: C 67.64; H 7.82;
N 4.35; O 20.00. C18H25NO4. Calculated, %: C 67.69;
H 7.89; N 4.39; O 20.04.
Dimethyl 2-{2-[3,5-di(propan-2-yl)anilino]but-3-
en-1-yl}malonate (3e). Yield 102 mg (71%). IR spec-
trum, ν, cm–1: 2946 s (C–H), 1730 s (C=O), 1595 s
1
(C=Carom). H NMR spectrum, δ, ppm: 1.22 t (12H,
CH3, J = 6.0 Hz), 2.23–2.40 m (2H, CH2), 3.15–
3.22 m (2H, CH) 3.39–3.45 m (1H, CH), 3.75–3.81 m
(6H, COOCH3), 4.82 d (1H, HC=CH2, J = 20.0 Hz),
4.97 d (1H, HC=CH2, J = 12.0 Hz), 5.60–5.69 m (1H,
HC=CH2), 7.04–7.10 m (3H, C6H3). 13C NMR spec-
trum, δC, ppm: 35.9, 36.7, 53.5, 53.6, 59.7, 60.9, 62.9,
73.2, 111.5, 117.1, 125.3, 129.8, 136.5, 138.1, 138.9,
149.7, 161.0, 167.7, 168.6. Mass spectrum: m/z 361.2
(Irel 100%) [M]+. Found, %: C 69.72; H 8.61; N 3.82;
O 17.64. C16H21NO4. Calculated, %: C 69.78; H 8.64;
N 3.87; O 17.70.
Dimethyl 2-[2-(4-methylanilino)but-3-en-1-yl]-
malonate (3b). Yield 102 mg (88%). IR spectrum, ν,
cm–1: 2962 s (C–H), 1734 s (C=O), 1582 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.20–2.37 m (5H, CH2,
CH3), 3.67–3.70 m (1H, CH), 3.76 s (3H, OCH3),
3.77 s (OCH3), 3.92–3.97 m (1H, CH), 5.17–5.27 m
(2H, HC=CH2), 5.73-5.81 m (1H, HC=CH2), 6.56 d
(2H, C6H4, J = 8.0 Hz), 7.01 d (2H, C6H4, J = 8.0 Hz).
13C NMR spectrum, δC, ppm: 34.1, 48.8, 52.7, 52.8,
54.7, 86.0, 112.0, 116.5, 119.2, 129.3, 137.9, 139.1,
146.1, 169.5, 169.7. Mass spectrum: m/z 291.2
(Irel 100%) [M]+. Found, %: C 65.91; H 7.22; N 4.80;
O 21.92. C16H21NO4. Calculated, %: C 65.96; H 7.27;
N 4.81; O 21.97.
Dimethyl 2-[2-(2-methoxyanilino)but-3-en-1-yl]-
malonate (3f). Yield 98 mg (80%), IR spectrum, ν,
cm–1: 2962 s (C–H), 1732 s (C=O), 1583 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.27–2.31 m (2H, CH2)
3.68 t (1H, CH, J = 6.0 Hz), 3.75 s (3H, COOCH3),
3.76 s (3H, COOCH3), 3.87 s (3H, OCH3), 3.98 t (1H,
CH, J = 8.0 Hz), 5.16–5.26 m (2H, HC=CH2), 5.72–
5.81 m (1H, HC=CH2), 6.61 d (1H, C6H4, J = 8.0 Hz),
6.69 t (1H, C6H4, J = 8.0 Hz), 6.78–6.87 m (2H,
C6H4). 13C NMR spectrum, δC, ppm: 34.4, 48.9, 52.6,
54.0, 55.4, 109.6, 111.0, 116.0, 116.8, 121.2, 136.9,
138.7, 146.9, 169.7, 169.9. Mass spectrum: m/z 319.1
(Irel 100%) [M]+. Found, %: C 63.10; H 7.75; N 4.30;
O 24.66. C17H25NO5. Calculated, %: C 63.14; H 7.79;
N 4.33; O 24.74.
Dimethyl 2-[2-(2,4-dimethylanilino)but-3-en-1-
yl]malonate (3c). Yield 91 mg (75%). IR spectrum, ν,
cm–1: 2965 s (C–H), 1730 s (C=O), 1595 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.17 s (3H, CH3) 2.26 s
(3H, CH3), 2.30–2.34 m (2H, CH2), 3.68 t (1H, CH,
J = 8.0 Hz), 3.75 s (3H, OCH3), 3.79 s (3H, OCH3),
3.99–4.04 m (1H, CH), 5.22 t (2H, HC=CH2, J =
16.0 Hz), 5.75–5.84 m (1H, HC=CH2), 6.93 d (2H,
C6H3, J = 8.0 Hz), 6.53 d (1H, C6H3, J = 12.0 Hz).
13C NMR spectrum, δC, ppm: 17.5, 20.3, 34.4, 49.0,
52.6, 54.5, 111.3, 116.0, 122.4, 127.2, 131.0, 138.9,
142.6, 169.9, 170.1. Mass spectrum: m/z 305.3
(Irel 100%) [M]+. Found, %: C 66.83; H 7.51; N 4.54;
O 20.92. C17H23NO4. Calculated, %: C 66.86; H 7.59;
N 4.59; O 20.96.
Dimethyl 2-[2-(2-fluoro-6-methylanilino)but-3-
en-1-yl]malonate (3g). Yield 96 mg (78%). IR spec-
trum, ν, cm–1: 2960 s (C–H), 1733 s (C=O), 1584 s
1
(C=Carom). H NMR spectrum, δ, ppm: 2.11 s (3H,
CH3) 2.27–2.31 m (2H, CH2), 3.60 t (1H, CH, J =
8.0 Hz), 3.75 s (3H, OCH3), 3.76 s (3H, OCH3), 3.94–
3.99 m (1H, CH), 5.21–5.25 m (2H, HC=CH2), 5.72–
5.80 m (1H, HC=CH2), 6.53 s (1H, C6H3), 6.62 d (1H,
C6H3, J = 8.0 Hz), 6.95 d (1H, C6H3, J = 8.0 Hz).
13C NMR spectrum, δC, ppm: 33.7, 48.4, 52.7, 53.8,
55.7, 76.8, 77.1, 77.4, 96.3, 105.2, 117.5, 129.0, 136.6,
146.7, 166.0, 169.2, 169.3. Mass spectrum: m/z 309.3
(Irel 100%) [M]+. Found, %: C 62.10; H 6.50; F 6.08;
N 4.46; O 20.69. C16H20FNO4. Calculated, %: C 62.13;
H 6.52; F 6.14; N 4.53; O 20.69.
Dimethyl 2-[2-(2,4,6-trimethylanilino)but-3-en-
1-yl]malonate (3d). Yield 93 mg (73%). IR spectrum,
ν, cm–1: 2963 s (C–H), 1732 s (C=O), 1600 s
(C=Carom). 1H NMR spectrum, δ, ppm: 2.19 s (1H, CH)
2.24–2.35 m (11H, CH3, CH2), 3.60–3.65 m (1H, CH)
3.77–3.82 m (6H, COOCH3), 4.90–5.00 m (2H,
HC=CH2), 5.62–5.68 m (1H, HC=CH2), 6.82 s (2H,
C6H2). 13C NMR spectrum, δC, ppm: 17.1, 18.9, 20.5,
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LI et al.
1436
Dimethyl 2-[2-(4-fluoroanilino)but-3-en-1-yl]-
COOCH3), 3.76 s (3H, COOCH3), 4.04–4.11 m (1H,
CH), 5.27 t (2H, HC=CH2, J = 8.0 Hz), 5.74–5.82 m
(1H, HC=CH2), 6.36–6.41 m (1H, NH), 6.51–6.54 m
(1H, C6H3), 8.14–8.22 m (2H, C6H3). 13C NMR spec-
trum, δC, ppm: 33.81, 48.4, 52.8, 54.0, 69.1, 100.2,
100.5, 104.4, 104.6, 117.7, 129.8, 129.9, 136.2, 146.4,
146.5, 166.1, 168.7. Mass spectrum: m/z 340.2
(Irel 100%) [M]+. Found, %: C 52.87; H 5.01; F 5.52;
N 8.20; O 28.16. C15H17FN2O6. Calculated, %:
C 52.94; H 5.04; F 5.58; N 8.23; O 28.21.
malonate (3h). Yield 109 mg (88%). IR spectrum, ν,
cm–1: 2964 s (C–H), 1736 s (C=O), 1586 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.18–2.23 m (2H, CH2)
3.63 t (2H, CH, NH, J = 6.0 Hz), 3.71 s (3H,
OCH3), 3.72 s (3H, OCH3), 3.83–3.88 m (1H, CH),
5.13–5.21 m (2H, HC=CH2), 5.57–5.67 m (1H,
HC=CH2), 6.51–6.54 m (2H, C6H4), 6.85 t (2H, C6H4,
J = 8.0 Hz). 13C NMR spectrum, δC, ppm: 29.6, 30.0,
48.2, 52.7, 61.6, 115.7, 118.4, 119.0, 125.1, 126.0,
126.1, 133.0, 133.1, 133.5, 136.6, 137.3, 159.1, 161.5,
169.3, 170.1. Mass spectrum: m/z 295.2 (Irel 100%)
[M]+. Found, %: C 60.96; H 6.09; F 6.41; N 4.70;
O 21.61. C15H18FNO4. Calculated, %: C 61.01; H 6.14;
F 6.43; N 4.74; O 21.67.
Dimethyl 2-[2-(2-methoxy-6-nitroanilino)but-3-
en-1-yl]malonate (3l). Yield 99 mg (71%). IR spec-
trum, ν, cm–1: 2964 s (C–H), 1730 s (C=O), 1604 s
1
(C=Carom). H NMR spectrum, δ, ppm: 2.27–2.31 m
(2H, CH2) 3.68 t (1H, CH, J = 6.0 Hz), 3.75 s (3H,
COOCH3), 3.76 s (3H, COOCH3), 3.87 s (3H, OCH3),
3.98 d (1H, CH, J = 8.0 Hz), 5.16–5.26 m (2H,
HC=CH2), 5.61 d (1H, C6H3, J = 8.0 Hz), 5.72–5.81 m
(1H, HC=CH2), 6.67–6.71 m (1H, C6H3), 6.78–6.81 m
(1H, C6H3), 6.84–6.88 m (1H, C6H3). 13C NMR spec-
trum, δC, ppm: 17.0, 34.1, 49.0, 52.7, 54.2, 110.8,
116.5, 116.9, 120.4, 130.9, 132.5, 137.9, 145.9, 169.7,
169.9. Mass spec-trum: m/z 352.1 (Irel 100%) [M]+.
Found, %: C 54.46; H 5.67; N 7.91; O 31.72.
C16H20N2O7. Calculated, %: C 54.54; H 5.72; N 7.95;
O 31.79.
Dimethyl 2-[2-(2-iodoanilino)but-3-en-1-yl]-
malonate (3i). Yield 143 mg (89%). IR spectrum, ν,
cm–1: 2960 s (C–H), 1733 s (C=O), 1580 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.31 t (2H, CH2, J =
8.0 Hz) 3.63 t (1H, CH, J = 6.0 Hz), 3.72 s (3H,
OCH3), 3.76 s (3H, OCH3), 4.04 t (1H, CH, J =
6.0 Hz), 4.17 d (1H, NH, J = 8.0 Hz), 5.18–5.24 m
(2H, HC=CH2), 5.72–5.81 m (1H, HC=CH2), 6.43–
6.47 m (1H, C6H4), 6.57 d (1H, C6H4, J = 8.0 Hz),
7.15–7.19 m (1H, C6H4), 7.66 d (1H, C6H4, J =
8.0 Hz). 13C NMR spectrum, δC, ppm: 20.4, 34.4, 49.0,
52.6, 54.6, 113.8, 116.0, 126.9, 129.7, 138.9, 144.8,
169.8, 171.1. Mass spectrum: m/z 403.1 (Irel 100%)
[M]+. Found, %: C 44.62; H 4.43; I 31.46; N 3.42;
O 15.83. C15H18INO4. Calculated, %: C 44.68; H 4.50;
I 31.47; N 3.47; O 15.87.
Dimethyl 2-(2-anilino-2-phenylethyl)malonate
(3m). Yield 121 mg (93%). IR spectrum, ν, cm–1:
2966 s (C–H), 1736 s (C=O), 1580 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.48 t (2H, CH2, J =
6.0 Hz) 3.63 t (1H, CH, J = 6.0 Hz), 3.75 s (3H,
COOCH3), 3.78 s (3H, COOCH3), 4.51 t (1H, CH, J =
8.0 Hz), 6.59 d (2H, C6H5, J = 8.0 Hz), 6.71 t (1H,
C6H5, J = 8.0 Hz), 7.14 t (2H, C6H5, J = 8.0 Hz), 7.28 t
(1H, C6H5, J = 6.0 Hz), 7.35–7.40 m (4H, C6H5).
13C NMR spectrum, δC, ppm: 33.11, 33.2, 48.4, 52.9,
57.7, 68.8, 110.9, 126.6, 126.7, 128.8, 129.3, 142.6.
Mass spectrum: m/z 327.2 (Irel 100%) [M]+. Found, %:
C 69.64; H 6.42; N 4.21; O 19.50. C19H21NO4. Calcu-
lated, %: C 69.71; H 6.47; N 4.28; O 19.55.
Dimethyl 2-[2-(4-nitroanilino)but-3-en-1-yl]-
malonate (3j). Yield 118 mg (92%). IR spectrum, ν,
cm–1: 2968 s (C–H), 1735 s (C=O), 1582 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.25 t (2H, CH2, J =
8.0 Hz) 3.57 t (1H, CH, J = 8.0 Hz), 3.70 s (6H,
COOCH3), 3.99–4.06 m (1H, CH), 5.07 d (1H, NH,
J = 8.0 Hz), 5.18–5.24 m (2H, HC=CH2), 5.68–5.76 m
(1H, HC=CH2), 6.54 d (2H, C6H4, J = 8.0 Hz), 8.01 d
(2H, C6H4, J = 8.0 Hz). 13C NMR spectrum, δC, ppm:
33.7, 48.7, 52.8, 54.1, 111.8, 117.1, 126.2, 136.8,
138.2, 152.6, 169.5, 169.7. Mass spectrum: m/z 322.0
(Irel 100%) [M]+. Found, %: C 55.86; H 5.61; N 8.65;
O 29.70. C15H18N2O5. Calculated, %: C 55.90; H 5.63;
N 8.69; O 29.78.
Dimethyl 2-[2-(4-methylanilino)-2-phenylethyl]-
malonate (3n). Yield 121 mg (89%). IR spectrum, ν,
cm–1: 2962 s (C–H), 1736 s (C=O), 1586 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.22 s (3H, CH3) 2.45 t
(2H, CH2, J = 8.0 Hz), 3.62 t (1H, CH, J = 8.0 Hz),
3.75 s (3H, COOCH3), 3.78 s (3H, COOCH3), 4.47 t
(1H, CH, J = 8.0 Hz), 6.50 d (2H, C6H5, J = 8.0 Hz),
6.94 d (2H, C6H5, J = 8.0 Hz), 7.25–7.28 m (1H,
C6H5), 7.30–7.38 m (4H, C6H4). 13C NMR spectrum,
δC, ppm: 14.7, 31.2, 48.5, 52.8, 52.9, 56.1, 111.1,
Dimethyl 2-[2-(2-fluoro-6-nitroanilino)but-3-en-
1-yl]malonate (3k). Yield 102 mg (75%). IR spec-
trum, ν, cm–1: 2966 s (C–H), 1730 s (C=O), 1584 s
1
(C=Carom). H NMR spectrum, δ, ppm: 2.26–2.40 m
(2H, CH2) 3.56 t (1H, CH, J = 8.0 Hz), 3.72 s (3H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SYNTHESIS OF γ-(ARYLAMINO)BUTYRIC ACID DERIVATIVES
1437
1
119.3, 126.3, 128.2, 129.0, 168.7, 169.0. Mass spec-
trum: m/z 341.1 (Irel 100%) [M]+. Found, %: C 70.32;
H 6.71; N 4.12; O 18.70. C20H23NO4. Calculated, %:
C 70.36; H 6.79; N 4.10; O 18.74.
(C=Carom). H NMR spectrum, δ, ppm: 2.35 t (2H,
CH2, J = 8.0 Hz), 2.95–3.00 m (2H, CH2), 3.32–
3.46 m (2H, CH2), 3.66 t (1H, CH, J = 8.0 Hz), 3.68 s
(3H, COOCH3), 3.70 s (3H, COOCH3), 4.09–4.15 m
(1H, CH), 5.25 t (2H, HC=CH2, J = 8.0 Hz), 5.78–
5.86 m (1H, HC=CH2), 6.47 d (1H, C6H4, J = 8.0 Hz),
6.66 t (1H, C6H4, J = 8.0 Hz), 7.07 t (2H, C6H4, J =
8.0 Hz). 13C NMR spectrum, δC, ppm: 32.6, 48.1, 53.0,
56.7, 110.6, 117.3, 118.9, 119.8, 134.0, 143.9, 144.8,
168.6. Mass spectrum: m/z 345.1 (Irel 100%) [M]+.
Found, %: C 67.26; H 6.95; N 4.60; O 21.05.
C17H21NO4. Calculated, %: C 67.31; H 6.98; N 4.62;
O 21.10.
Dimethyl 2-{2-[3,5-di(propan-2-yl)anilino]-2-
phenylethyl}malonate (3o). Yield 128 mg (78%). IR
spectrum, ν, cm–1: 2965 s (C–H), 1733 s (C=O), 1584 s
1
(C=Carom). H NMR spectrum, δ, ppm: 0.94 d (6H,
CH3, J = 4.0 Hz), 1.20 d (6H, CH3, J = 8.0 Hz), 2.52–
2.59 m (1H, CH), 2.72–2.80 m (1H, CH), 2.96–3.03 m
(2H, CH2), 3.63–3.66 m (1H, CH), 3.73 s (3H, OCH3),
3.75 s (3H, OCH3), 3.94 t (1H, CH, J = 8.0 Hz), 7.02 s
(3H, C6H5), 7.09 t (2H, C6H5, J = 4.0 Hz), 7.22–
7.26 m (3H, C6H3). 13C NMR spectrum, δC, ppm: 23.9,
24.2, 27.7, 34.8, 49.6, 52.6, 62.8, 123.4, 123.7, 126.9,
127.6, 128.5, 140.5, 141.6, 142.5, 169.7, 169.9. Mass
spectrum: m/z 411.2 (Irel 100%) [M]+. Found, %:
C 72.91; H 8.02; N 3.35; O 15.50. C25H33NO4. Calcu-
lated, %: C 72.96; H 8.08; N 3.40; O 15.55.
Dimethyl 2-[2-(3,4-dihydroquinolin-1(2H)-yl)-
but-3-en-1-yl]malonate (3s). Yield 62 mg (49%). IR
spectrum, ν, cm–1: 2966 s (C–H), 1732 s (C=O), 1582 s
1
(C=Carom). H NMR spectrum, δ, ppm: 1.87–1.95 m
(2H, CH2), 2.35 t (2H, CH2, J = 8.0 Hz), 2.74–2.79 m
(2H, CH2), 3.12–3.16 m (2H, CH2), 3.51 t (1H, CH,
J = 6.0 Hz), 3.69 s (3H, COOCH3), 3.72 s (3H,
COOCH3), 4.48 d (1H, CH, J = 8.0 Hz), 5.18–5.25 m
(2H, HC=CH2), 5.81–5.86 m (1H, HC=CH2), 6.58–
6.68 m (2H, C6H4), 6.96–7.05 m (2H, C6H4). 13C NMR
spectrum, δC, ppm: 22.2, 28.4, 30.0, 42.2, 48.5, 52.5,
56.3, 111.4, 116.2, 116.7, 123.5, 127.0, 129.3, 136.0,
145.4, 169.7, 169.9. Mass spectrum: m/z 317.2
(Irel 100%) [M]+. Found, %: C 68.08; H 7.26; N 4.36;
O 20.10. C18H23NO4. Calculated, %: C 68.12; H 7.30;
N 4.41; O 20.16.
Dimethyl 2-[2-(4-fluoroanilino)-2-phenylethyl]-
malonate (3p). Yield 125 mg (91%). IR spectrum, ν,
cm–1: 2970 s (C–H), 1734 s (C=O), 1586 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.43 t (2H, CH2, J =
8.0 Hz), 3.57 t (1H, CH, J = 8.0 Hz), 3.73 s (3H,
COOCH3), 3.76 s (3H, COOCH3), 4.40 t (1H, CH, J =
8.0 Hz), 6.46–6.49 m (2H, C6H5), 6.81 t (2H, C6H5,
J = 8.0 Hz), 7.25–7.29 m (1H, C6H5), 7.32–7.35 m
(4H, C6H4). 13C NMR spectrum, δC, ppm: 33.2, 48.3,
53.0, 58.2, 110.6, 117.2, 119.0, 126.8, 129.3, 129.6,
136.6, 144.1, 168.6. Mass spectrum: m/z 345.1
(Irel 100%) [M]+. Found, %: C 66.01; H 5.81; F 5.46;
N 4.02; O 18.50. C19H20FNO4. Calculated, %: C 66.08;
H 5.84; F 5.50; N 4.06; O 18.53.
General procedure for the synthesis of com-
pounds 4j and 4m. A mixture of 0.4 mmol of com-
pound 3j or 3m, 5 mL of ethanol, and 5 mL of 6 M
aqueous sodium hydroxide was heated at 90°C until
the reaction was complete (TLC). The mixture was
cooled, acidified with 5 mL of 6 M aqueous HCl, and
heated at 90°C for 6 h. The mixture was then cooled,
diluted with water, and extracted three times with ethyl
acetate. The combined extracts were dried over magne-
sium sulfate and filtered, the solvent was removed
under reduced pressure, and the residue was purified
by flash chromatography using ethyl acetate–petro-
leum ether (1:1) as eluent. Compounds 4j or 4m were
isolated as light yellow viscous oils.
Dimethyl 2-[2-(N-methylanilino)but-3-en-1-yl]-
malonate (3q). Yield 75 mg (65%). IR spectrum, ν,
cm–1: 2966 s (C–H), 1733 s (C=O), 1582 s (C=Carom).
1H NMR spectrum, δ, ppm: 2.34 t (2H, CH2, J =
8.0 Hz) 2.72 s (3H, CH3), 3.49 t (1H, CH, J = 8.0 Hz),
3.67 s (3H, COOCH3), 3.69 s (3H, COOCH3), 4.43–
4.48 m (1H, CH), 5.14–5.22 m (2H, CH=CH2), 5.79–
5.86 m (1H, CH=CH2), 6.74–6.81 m (3H, C6H5), 7.22-
7.26 m (2H C6H5). 13C NMR spectrum, δC, ppm: 30.7,
31.4, 48.7, 52.5, 58.3, 113.8, 116.7, 117.4, 129.1,
136.0, 150.3, 169.7, 169.8. Mass spectrum: m/z 291.2
(Irel 100%) [M]+. Found, %: C 65.90; H 7.22; N 4.69;
O 21.93. C16H21NO4. Calculated, %: C 65.96; H 7.27;
N 4.81; O 21.97.
4-(4-Nitroanilino)hex-5-enoic acid (4j). Yield
76 mg (76%). IR spectrum, ν, cm–1: 2965 s (C–H),
1733 s (C=O), 1584 s (C=Carom). 1H NMR spectrum, δ,
ppm: 1.97–2.03 m (1H, CH2), 2.43–2.50 m (1H, CH2),
2.56–2.69 m (1H, CH2), 2.71–2.78 m (1H, CH2), 4.80 s
(1H, NH), 5.22–5.30 m (2H, HC=CH2), 5.79–5.88 m
(1H, HC=CH2), 7.78 d (2H, C6H4, J = 8.0 Hz), 8.23 d
Dimethyl 2-[2-(2,3-dihydro-1H-indol-1-yl)but-3-
en-1-yl]malonate (3r). Yield 84 mg (70%). IR spec-
trum, ν, cm–1: 2960 s (C–H), 1733 s (C=O), 1582 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

LI et al.
1438
(2H, C6H4, J = 8.0 Hz). 13C NMR spectrum, δC, ppm:
25.8, 31.0, 61.8, 117.7, 120.9, 124.4, 136.2, 143.7,
144.0, 174.8. Mass spectrum: m/z 250.2 (Irel 100%)
[M]+. Found, %: C 57.50; H 5.61; N 11.12; O 25.56.
C12H14N2O4. Calculated, %: C 57.59; H 5.64; N 11.19;
O 25.57.
8. Reznikov, A.N., Golovin, E.V., and Klimochkin, Y.N.,
Russ. J. Org. Chem., 2013, vol. 49, p. 663. doi 10.1134/
S107042801411027X
9. Liu, H., Yuan, J., Tian, Q., Ji, N., and He, W., J. Mater.
Sci. Chem. Eng., 2017, vol. 5, p. 25.
10. Dryanska, V. and Pashkuleva, I., Org. Prep. Proced.
Int., 1999, vol. 31, p. 232. doi 10.1080/
00304949909355722
11. Ramachandran, P.V., Mitsuhashi, W., and Biswas, B.,
Org. Chem. Front., 2015, vol. 2, p. 885. doi 10.1039/
C5QO00133A
12. Nair, V., Varghese, V., Babu, B.P., Sinu, C.R., and
Suresh, E., Org. Biomol. Chem., 2010, vol. 8, p. 761.
doi 10.1039/b922981g
13. Castillo, M.D.D., Corzo, N., González, L., and
Olano, A., J. Agric. Food Chem., 1999, vol. 47, p. 4137.
doi 10.1021/jf990150x
14. Usifoh, C.O., Lambert, D.M., Wouters, J., and
Scriba, G.K.E., Arch. Pharm. (Weinheim), 2001,
vol. 334, p. 323. doi 10.1002/1521-4184(200110)
334:10<323::aid-ardp323>3.0.co;2-o
4-Anilino-4-phenylbutanoic acid (4m). Yield
81 mg (80%). IR spectrum, ν, cm–1: 2965 s (C–H),
1733 s (C=O), 1584 s (C=Carom). 1H NMR spectrum, δ,
ppm: 2.01–2.06 m (1H, CH2), 2.61–2.81 m (3H, CH2),
5.26–5.29 m (1H, CH), 7.08 t (1H, C6H5, J = 8.0 Hz),
7.23–7.35 m (6H, C6H5), 7.44 d (2H, C6H5, J =
8.0 Hz). 13C NMR spectrum, δC, ppm: 29.2, 31.2, 63.9,
122.2, 124.9, 125.9, 127.7, 128.7, 128.9, 138.3, 141.3,
174.8. Mass spectrum: m/z 255.1 (Irel 100%) [M]+.
Found, %: C 75.21; H 6.68; N 5.43; O 12.51.
C16H17NO2. Calculated, %: C 75.27; H 6.71; N 5.49;
O 12.53.
CONFLICT OF INTERESTS
No conflict of interests is declared by the authors.
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