Exotic amino acids. 8. Synthesis of monomethyl esters of N-aryl-aminomethylenemalonic acids

Article abstract of DOI:10.1023/A:1020641922707

N-Arylaminomethyleneisopropylidenemalonates, obtained from ethoxymethyleneisopropylidenemalonate and aromatic amines, underwent methanolysis to form monomethyl esters of N-arylaminomethylenemalonic acids. The conditions of their formation and their yields depend on the nature and positions of the substituents in the aromatic ring of the initial amine.

Full text of DOI:10.1023/A:1020641922707

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
EXOTIC AMINO ACIDS. 8*. SYNTHESIS
OF MONOMETHYL ESTERS OF N-ARYL-
AMINOMETHYLENEMALONIC ACIDS
D. Zicane1, I. Ravina1, Z. Tetere1, I. Rijkure1, M. Petrova1, and U. Kalejs2
N-Arylaminomethyleneisopropylidenemalonates, obtained from ethoxymethyleneisopropylidenemalonate
and
aromatic
amines,
underwent
methanolysis
to
form
monomethyl
esters
of
N-arylaminomethylenemalonic acids. The conditions of their formation and their yields depend on the
nature and positions of the substituents in the aromatic ring of the initial amine.
Keywords: N-arylaminomethyleneisopropylidenemalonates, aromatic amines, monomethyl esters of
N-arylaminomethylenemalonic acids, ethoxymethyleneisopropylidenemalonate.
We have previously [2] established that N-hetarylaminomethyleneisopropylidenemalonates are valuable
sources for the synthesis of substituted β-amino acids.
Since β-amino acids are of great interest because of their biological activity [1-5], we have extended the
search for new methods for the synthesis of non-proteinogenic (exotic) amino acids and in this study we have
investigated the methanolysis of aromatic aminomethyleneisopropylidenemalonates 3. Compounds 3a-k
(Tables 1 and 2) were synthesized from ethoxymethyleneisopropylidenemalonate (1) and aromatic amines 2a-k
in ethanol at room temperature [6, 7].
R
O
O
O
O
O
H2N
H
N
2
R
H
O
C
O
C
H
OC2H5
O
1
3
H
N
1. KOH/CH3OH
HOOC
R
3
C
H
+
2. H
H3COOC
4
2–4 a R = H; b R = CH3(o-, m-, p-); c R = NO2 (o-, m-, p-); d R = OH (o-, m-, p-); e R = OCH3 (o-, m-, p-);
f R = COOH (o-, m-, p-); g R = o-COOCH3; h R = o-Cl; i R = o-Br;
j R = Br(o-), NO2(p-); k R = p-COCH3
_______
* For part 7 see [1].
__________________________________________________________________________________________
1
2
Riga Technical University, Riga LV-1048; e-mail: gudr@ktf.rtu.lv. VAPEKS Ltd., Riga LV-1048,
Latvia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 949-954, July, 2002. Original article
submitted March 23, 2002.
840
0009-3122/02/3807-0840$27.00©2002 Plenum Publishing Corporation

TABLE 1. Characteristics of Compounds 3a-k*
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С*2
Yield, %
С
Н
N
Hal
C13H13NO4
C14H15NO4
C14H15NO4
C14H15NO4
C13H12N2O6
158-160 (CCl4)
154-156 [8]
(Ethanol)
125-126
120.2-121.8 [8]
(Ethanol)
119-120
115-116.6 [8]
(Ethanol)
151-152
150-152 [8]
(Ethanol)
77
3a
79 [8]
3b(o-)
3b(m-)
3b(p-)
3c(o-)
85
76 [8]
62
75 [8]
85.5
67 [8]
185-186 (dec.)
96
(Ethanol)
180-181(dec.) [8]
(Acetonitryle)
48 [8]
3c(m-)
3c(p-)
C13H12N2O6
C13H12N2O6
200-203 (dec.)
84.5
197-203.8
78 [8]
(dec.) [8]
(Acetonitryle)
217-218 (dec.)
215-216(dec.) [8]
(Acetonitryle)
99
67 [8]
3d(o-)
3d(m-)
3d(p-)
C13H13NO5
C13H13NO5
C13H13NO5
59.50
59.31
5.07
4.98
5.50
5.32
213-214 (dec.)
70
77
(Ethanol)
59.11
4.81
5.50
208-210 (dec.)
(Ethanol)
59.31
4.93
5.32
214-215 (dec.)
85
(Ethanol)
21 [9]
207-209 (dec.) [9]
3e(o-)
C14H15NO5
150-151
154-155.8 [8]
(Ethanol)
89
83[8]
3e(m-)
3e(p-)
C14H15NO5
C14H15NO5
60.72
60.64
5.51
5.45
5.25
5.05
115-117
69
164-165
163-165 [8]
(Ethanol)
87
55 [8]
3f(o-)
C14H13NO6
245-246 (dec.)
70
(Ethanol)
233-235 (dec.) [7]
248-250 (dec.)
78 [7]
98
3f(m-)
3f(p-)
C14H13NO6
C14H13NO6
57.89
57.73
4.56
4.50
4.90
4.81
239-241 (dec.)
(Ethanol)
89
236-238 (dec.) [7]
55 [7]
95
C15H15NO6
58.93
59.02
5.03
4.95
4.70
4.59
169-171
3g
3h
(Ethanol)
C13H12ClNO4
55.48
4.36
5.03
12.64
12.58
125-126
82
55.43
4.29
4.97
(Ethanol)
C13H12BrNO4
C13H11BrN2O6
48.02
47.88
3.86
3.71
4.20
4.29
27.53
157-158
85
55
3i
3j
27.43
42.11
2.90
3.81
21.70
21.52
233-234
(dec.)
42.06
2.98
3.77
C15H15NO5
62.31
62.28
5.30
5.23
4.88
4.84
209-210
58
3k
(dec.)
_______
* Elemental analyses are cited for compounds synthesized for the first time.
*2 The recrystallization solvent is given in brackets.
841

The aromatic amines used were aniline 2a and anilines with substituents in the aromatic ring 2b-k.
Methanolysis of the aminomethyleneisopropylidenemalonates 3a-k was carried out in methanol in the presence
of an equimolar quantity (for compounds 3f (o-, m-, p-) 2 moles) of potassium hydroxide with subsequent
acidification of the solution of the potassium salts of compounds 4a-k.
It was established experimentally that the conditions of formation and the yield of the monomethyl
N-arylaminomethylenemalonates 4a-k (N-aryl-substituted β-amino acids) depends on both the nature of the
substituents on the aromatic ring and their dispositions.
Most of the methyl esters of the arylaminomethylenemalonic acids (4b (o-, m-, p-), 4c (o-), 4d (m-),
4e (o-, m-, p-), 4f (o-, m-, p-), 4g-i,k) are formed over a few hours at room temperature, while for splitting of
the 1,3-dioxane ring in compounds containing aniline 3a, m- and p-nitroaniline 3c (m-, p-), o- and
p-aminophenol 3d (o-, p-), and o-bromo-p-nitroaniline 3j it was necessary to boil the components in methanol
for 2 h.
The yields of compounds 4a-k ranged from 37-82%. The decreased yields of compounds 4d (o-, p-)
containing hydroxy groups in the o- and p-positions of the benzene ring explained by the formation of secondary
products during their formation and is connected with the necessity to carry out two recrystallization to obtain
pure compounds.
Characteristics of the monomethyl N-arylaminomethylenemalonates 4a-k are given in Table 3, and their
1
structures are given on the basis of the H NMR spectra (see Table 4). The spectroscopic data for the
arylaminomethyleneisopropylidenemalonate starting materials 3a-k are cited in Table 2. The presence of a six
proton singlet for two methyl groups in the region 1.63-1.77 ppm is characteristic of the spectra of compounds
TABLE 2. Spectroscopic Characteristics of Compounds 3a-k
1Н NMR spectrum, δ, ppm
НС=(1Н, d)
Coupling
constants,
3J=CHNH, Hz
Compound
2СН3(6Н, s)
NH(1Н, d)
1.73
1.67
1.71
1.68
1.72
1.74
1.77
1.64
1.71
1.67
1.71
1.69
1.68
1.73
1.68
1.63
1.76
1.73
1.67
1.71
1.71
8.51
8.51
8.49
8.44
8.66
8.60
8.73
8.58
8.53
8.45
8.62
8.49
8.44
8.76
8.53
8.68
8.68
8.60
8.54
8.80
8.67
11.13
11.42
11.27
11.39
12.94
11.31
11.46
11.44
11.07
11.18
11.49
11.11
11.18
11.36
11.28
11.42
13.10
11.62
11.51
11.73
11.18
14
14
14.5
15
14.5
14
14
15
15
14
15
15
15
15
14
15
14
14
14
14
15
3a
3b(o-)
3b(m-)
3b(p-)
3c(o-)
3c(m-)
3c(p-)
3d(o-)
3d(m-)
3d(p-)
3e(o-)
3e(m-)
3e(p-)
3f(o-)
3f(m-)
3f(p-)
3g
3h
3i
3j
3k
842

TABLE 3. Characteristics of Compounds of Compounds 4a-k*
Found, %
——————
Com-
pound
Empirical
formula
Yield, %
45
Calculated, %
mp, °С*2
С
Н
N
Hal
C11H11NO4
59.81
59.72
5.11
5.01
6.50
6.33
127-130
4a
(2:1 ethanol–water)
4b(o-)
4b(m-)
4b(p-)
4c(o-)
C12H13NO4
C12H13NO4
C12H13NO4
C11H10N2O6
61.40
5.70
5.83
112-113
154-156
122-124
70
73
74
75
61.27
5.57
5.95
61.03
61.27
5.43
5.57
5.90
5.95
61.40
5.42
5.90
61.27
5.57
5.95
49.67
49.63
3.84
3.79
10.64
10.52
195-196
(Ethanol)
4c(m-)
4c(p-)
C11H10N2O6
C11H10N2O6
49.71
3.85
10.57
206-207 (dec.)
62
79
49.63
3.79
10.52
(Methanol)
49.71
49.63
3.64
3.79
10.61
10.52
183-185
(dec.)
4d(o-)
4d(m-)
4d(p-)
C11H11NO5
C11H11NO5
C11H11NO5
55.81
4.81
5.96
186-187 (dec.)
40
51
37
55.70
4.67
5.90
(2·diisopropyl ether)
55.96
55.70
4.71
4.67
5.98
5.90
177-178 (dec.)
(Ethanol)
55.45
4.79
5.96
204-206
(2·ethanol−water,
1:1)
55.70
4.67
5.90
4e(o-)
C12H13NO5
57.50
57.37
5.18
5.22
5.47
5.58
147-148
(Ethyl acetate–
hexane)
61
4е(m-)
4е(p-)
C12H13NO5
C12H13NO5
57.77
57.37
5.14
5.22
5.64
5.58
101-102
56
(Diisopropyl ether)
57.10
5.14
5.65
129-130
(Ethyl acetate-
hexane)
55.5
57.37
5.22
5.58
4f(o-)
4f(m-)
4f(p-)
4g
C12H11NO6
C12H11NO6
C12H11NO6
C13H13NO6
C11H10ClNO4
54.12
54.35
4.34
4.18
5.08
5.28
189-191 (dec.)
73
79
65
72
56
(Ethanol)
54.13
4.31
5.33
189-191 (dec.)
(Ethanol)
54.35
4.18
5.28
54.13
54.35
4.10
4.18
5.18
5.28
250-251 (dec.)
(1:2 DMF–ethanol)
55.64
4.70
5.24
163-165
55.92
4.69
5.02
(Ethanol)
51.97
51.68
3.72
3.94
5.26
5.48
13.69
13.87
140-141
4h
(Ethanol)
C11H10BrNO4
C11H9BrN2O6
44.29
3.26
4.75
27.12
140-141
82
50
4i
4j
44.02
3.36
4.67
26.63
38.50
38.28
2.87
2.63
8.12
8.12
22.92
23.15
195-196
(dec.)
C13H13NO5
59.56
4.80
5.55
174-175
53
4k
59.31
4.98
5.32
_______
* Elemental analysis data are given only for compounds described for the
first time.
*2 Recrystallization solvents are given in brackets.
3a-k. This signal has disappeared in the spectra of compounds 4a-k to be replaced by a three proton singlet in
the region 3.22-3.89 ppm, which is characteristic for monomethyl esters, and also by broad weak field signal of
the –COOH proton. The remaining proton signals of the fixed trans fragments of the aminomethylene groups,
which appear as two doublets =CH– (δ 8.3-8.8) and –NH (δ 11.07-13.31 ppm) with J = 12-15 Hz.
843

TABLE 4. Spectroscopic Characteristics of Compounds 4a-k
1Н NMR spectrum, δ, ppm
Coupling
constants,
3J=CHNH, Hz
Compound
СН3
НС=
NH
COOH
(3Н, s)
(1Н, s)
(1Н, s)
(1Н, s)
3.83
3.86
3.78
3.89
3.84
3.52
3.64
3.75
3.83
3.86
3.86
3.80
3.80
3.78
3.78
3.22
3.88
3.83
3.86
3.81
3.80
8.43
8.47
8.44
8.39
8.74
8.57
8.65
8.68
8.43
8.37
8.52
8.59
8.38
8.76
8.57
8.58
8.61
8.51
8.48
8.51
8.30
11.67
11.83
11.60
11.72
13.31
11.40
11.70
11.92
11.67
11.70
11.90
11.35
11.38
12.60
11.56
11.39
13.30
12.0
7.22
12.83
7.21
14
13.75
14
13.5
13.5
14
14
14
15
15
15
14
14
12
12.5
12
15
4a
4b(o-)
4b(m-)
4b(p-)
4c(o-)
4c(m-)
4c(p-)
4d(o-)
4d(m-)
4d(p-)
4e(o-)
4е(m-)
4е(p-)
4f(o-)
4f(m-)
4f(p-)
4g
12.86
12.71
12.56
14.28
13.19
12.86
12.83
12.80
12.72
12.80
13.16
13.05
12.83
12.63
12.69
12.75
7.46
13.75
13.75
15
4h
12.15
12.23
11.75
4i
4j
12.80
15
4k
EXPERIMENTAL
1H NMR spectra of CDCl3 and DMSO-d6 solutions with TMS as internal standard were recorded with a
Bruker WH-90/DS (90 MHz) instrument. Homogeneity of the compounds synthesized was monitored by TLC
on Silufol plates with the solvent systems: 9:1 chloroform–methanol (compounds 4a,d (o-), 4e (o-, m-), 4f (o-,
m-, p-), 4i-k), chloroform (compounds 4b (o-, m-, p-)), 4:1:1 butanol–glacial acetic acid–water (compounds 4d
(m-, p-), 4h), 35:35:7:23 butanol–acetone–glacial acetic acid–water (compound 4g), ethyl acetate (compounds
4c (o-, m-, p-), 4e (p-)).
N-Arylaminomethyleneisopropyildenmalonates (3a-k) were prepared analogously to N-hetaryl-
aminomethyleneisopropylidenemalonates [2]. Compounds 3b (o-, m-, p-), 3c (m-, p-), 3e (o-, m-, p-), 3f (m-),
and 3i-k were chromatographically homogeneous without recrystallization, whereas recrystallization was
necessary for compounds 3a,c (o-), 3d (o-, m-, p-), 3f (o-, p-), 3g and h.
Monomethyl Esters of N-Arylaminomethylenemalonic Acids (4a-k). An equimolar quantity of the
aminomethylenemalonates 3a-k was added to a solution of potassium hydroxide (2 mmol, 4 mmol for
compounds 3f (o-, m-, p-)) in methanol (20 ml). In the cases of compounds 3b (o-, m-, p-), 3c (o-), 3d (m-), 3e
(o-, m-, p-), 3f (o-, m-, p-), 3g-k the reaction mixture was stirred at room temperature for 3h, then kept at the
same temperature for 12 h. In the case of compounds 3a,c (m-, p-), 3d (o-, p-) and 3j the mixture was boiled for
2h. The potassium salts of compounds 4c (m-, p-), 4d (p-), 4f (o-, p-), and 4k were filtered off, whereas the
methanol solutions containing the potassium salts of compounds 4a,b (o-, m-, p-), 4c (o-), 4d (o-, m-), 4e (o-,
m-, p-) and 4g-j were evaporated. The residues after filtration and evaporation were dissolved in water and
acidified with 1N hydrochloric acid. The precipitates of the monomethyl esters 4a,b (o-, m-, p-), 4c (o-, m-, p-),
4d (o-, m-), 4e (p-), 4f (o-, m-, p-), 4g-i and 4k were filtered off, while the acid solutions containing compounds
4d (p-), 4e (o-, m-), and 4j were extracted with ethyl acetate, the extract was dried over MgSO4, filtered, and the
844

ethyl acetate was evaporated. Compounds 4b (o-, m-, p-), 4c (p-), 4i-k were chromatographically homogeneous
without recrystallization, while compounds 4a,c (o-, m-), 4d (o-, m-, p-), 4e (o-, m-, p-), 4f (o-, m-, p-), 4g,h
were chromatographically homogeneous after recrystallization from the solvents noted in Table 3.
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