Synthesis and characterization of novel β-amino acid derivatives

Article abstract of DOI:10.1007/s11164-012-0601-2

In the work discussed in this paper, novel β-amino acid derivatives were prepared by Michael addition between 3-substituted-2-propenic acid and hydrazine hydrate. The optimum reaction conditions were determined by analyzing the effects of the ratio of the

Full text of DOI:10.1007/s11164-012-0601-2

Res Chem Intermed (2013) 39:875–880
DOI 10.1007/s11164-012-0601-2
Synthesis and characterization of novel b-amino acid
derivatives
•
Yu-Ting Liu Li Feng Da-Wei Yin
•
Received: 28 December 2011 / Accepted: 10 May 2012 / Published online: 31 May 2012
Ó Springer Science+Business Media B.V. 2012
Abstract In the work discussed in this paper, novel b-amino acid derivatives were
prepared by Michael addition between 3-substituted-2-propenic acid and hydrazine
hydrate. The optimum reaction conditions were determined by analyzing the effects
of the ratio of the starting materials, temperature, and reaction time. The conclusions
were: reaction temperature 80 °C, reaction time 8 h, n (3-substituted-2-propenic
acid)/n (hydrazine hydrate) = 1:15. Products were characterized by measurement of
1
melting point, elemental analysis, and IR and H NMR spectroscopy.
Keywords b-Amino acid derivatives Á Synthesis Á Characterization
Introduction
b-Amino acids are widely used in the synthesis of antibiotics [1]. b-Amino acids are
the substrates of many antibiotics and are common intermediates in drug synthesis [2].
b-Amino acids are also the direct raw materials in the synthesis of b-amino alcohols
[3]. b-Amino alcohols are important intermediates in the synthesis of peptides, which
are important in asymmetric synthesis and medicinal chemistry [4, 5].
Structurally, b-amino acids are formed by addition of ammonia to acrylic acid
and its derivatives, which is the simplest synthetic method [6]. Generally, b-amino
acids are formed by addition of ammonia to acrylonitrile and acrylate, then
hydrolysis to the corresponding amino acid under acidic or alkaline condition [7].
Y.-T. Liu Á L. Feng Á D.-W. Yin
College of Chemistry & Chemical Engineering, Shaanxi University of Science & Technology,
Xi’ an 710021, China
Y.-T. Liu Á L. Feng (&) Á D.-W. Yin
Key Laboratory of Auxiliary Chemistry & Technology for Chemical Industry,
Ministry of Education, Shaanxi University of Science & Technology, Xi’ an 710021, China
e-mail: Fengli870708@163.com
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Y.-T. Liu et al.
H2N
O
O
NH
°
80 C
OH
+ H2N-NH2
OH
R
R
R=a, H; b, 4-CH3; c, 4-C2H5; d, 4-C3H7; e, 4-OCH3
Scheme 1 Synthesis of novel b-amino acid derivatives
b-Amino acids can be directly prepared by Michael addition reaction between
ammonia and a,b-unsaturated acids. But the reaction can take a long time and must
be in a closed tube or in the autoclave [8, 9]. b-Amino acids can be prepared by
Michael addition reaction between hydrazine and a,b-unsaturated acids at normal
pressure.
In the work discussed in this paper, novel b-amino acid derivatives were prepared
by Michael addition between 3-substituted-2-propenic acid and hydrazine hydrate.
The product is prone to cyclization. It has a heterocyclic intermediate, and has
important significance in the study of organic reactions. b-Amino acids have been
widely used in drug design because of their similarity to a-amino acids. a-Amino
acids are the components of human proteins which are important materials in the
body [10, 11]. The attention of medicinal and organic chemists is increasingly being
devoted to methods of synthesis of these compounds. The medicinal nature of the
b-amino acid derivatives synthesized in the work discussed in this paper has not yet
been studied (Scheme 1).
Results and discussion
The effect of reaction conditions on yield
Effect of the molar ratio of reactants on yield
Under the conditions reaction temperature 80 °C and reaction time 8 h, the effect of
molar ratio of reactants on yield was studied. The results are summarized in
Table 1.
The results showed that the yield was maximum at n (3-phenyl-2-propenic
acid):n (hydrazine hydrate) = 1:15.
Table 1 Effect of the molar ratio of reactants on yield
n (3-phenyl-2-propenic acid):n (hydrazine hydrate)
1:10
50
1:13
53
1:15
71
1:17
51
1:20
45
Yield (%)
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b-Amino acid derivatives
877
Table 2 Effect of temperature on yield
Temperature (°C)
60
55
70
57
80
71
90
56
100
53
Yield (%)
Table 3 Effect of reaction time on yield
Reaction Time (h)
Yield (%)
6
7
8
9
10
66
55
68
71
69
Effect of temperature on yield
Under the reaction conditions n (3-phenyl-2-propenic acid):n (hydrazine hydrate) =
1:15 and reaction time 8 h, the effect of temperature on yield was studied. The
results are summarized in Table 2.
The results showed that the yield was maximum when the reaction temperature
was 80 °C. If the temperature was increased further, the yield decreased.
Effect of reaction time on yield
Under the reaction conditions
n (3-phenyl-2-propenic acid):n (hydrazine
hydrate) = 1:15 and reaction temperature 80 °C, the effect of reaction time on
yield was studied. The results were summarized in Table 3.
The results showed that as reaction time increased the yield gradually increased.
When the reaction time was 8 h the reaction was complete, so yield did not increase
further.
Orthogonal experiments to determine the optimum conditions
The optimum reaction conditions were obtained by means of three factors : n (3-
phenyl-2-propenic acid):n (hydrazine hydrate) (A), reaction temperature/°C (B), and
reaction time/h (C) and a three-level orthogonal experiment L9 (33). The levels and
factors in the orthogonal experiments were designed as summarized in Table 4. The
experimental results and analytical results are summarized in Table 5.
The results show that the effects of the three factors on the condensation reaction
descending in the order: A [ B [ C, the optimum reaction conditions were:
A2B2C2, i.e. n (3-phenyl-2-propenic acid):n (hydrazine hydrate) = 1:15, reaction
temperature 80 °C, and reaction time 8 h.
Table 4 L9 (33) orthogonal
experiment design of levels and
factors
Level
A
B
C
1
2
3
1:13
1:15
1:17
70
80
90
7
8
9
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Y.-T. Liu et al.
Yield (%)
Table 5 L9 (33) orthogonal
experimental design and results
from analysis
A
B
C
1
1
1
1
49
56
53
57
71
55
51
52
54
2
1
2
2
3
1
3
3
4
2
1
3
5
2
2
2
6
2
3
1
7
3
1
3
8
3
2
1
9
3
3
2
K1
K2
K3
R
52.667
57.500
52.333
5.167
52.333
56.167
54.000
3.834
52.000
55.667
54.833
3.667
Replicate experiments
Under the optimum conditions, replicate experimental verification was conducted.
The results are summarized in Table 6. The results (Tables 7, 8, and 9) show the
repeatability of the experiment is good.
Conclusions
Novel b-amino acid derivatives were prepared by Michael addition of 3-substituted-
2-propenic acid and hydrazine hydrate. The optimum experimental conditions for
preparation of the target compounds were determined by means of single factor or
orthogonal experiments: reaction temperature 80 °C, reaction time 8 h, n (3-
substituted-2-propenic acid)/n (hydrazine hydrate) = 1:15. The novel b-amino acid
1
derivatives were characterized by melting point, elemental analysis, and IR and H
NMR spectroscopy.
Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra
1
were recorded on a Tensor 27 spectrometer as KBr pellet. H NMR spectra was
Table 6 Repeatability experiments
Repetition
Yield (%)
1
2
3
4
5
Average yield
71
70.9
71
70.8
70.8
70.9
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b-Amino acid derivatives
879
Table 7 Elemental analysis data for compounds a–e
Compound
Formula
Mr
wi (calc.)/%
wi (found)/%
M.P. (°C)
Yield (%)
C
H
N
a
b
c
d
e
C9H12N2O2
180.20
194.23
208.56
222.28
210.23
59.99
59.86
61.84
61.70
63.44
63.30
64.84
64.70
57.13
57.00
6.71
6.69
7.27
7.25
7.74
7.72
8.16
8.13
6.71
6.69
15.55
15.51
14.42
14.38
13.45
13.41
12.60
12.56
13.33
13.30
251–253
245–247
250–252
247–248
257–259
71
73
74
76
79
C10H14N2O2
C11H16N2O2
C12H18N2O2
C10H14N2O3
Table 8 Main IR data for compounds a–e
Compound IR data for compounds
a
b
c
d
e
IR (KBr, m/cm-1): 3,450 cm-1, 3,387 cm-1 (mN–H); 3,094 cm-1 (vPhC–H); 3,030 cm-1
(vCOOH); 2,920 cm-1, 2855 cm-1 (mC–H); 1,598 cm-1, 1,588 cm-1, 1,495 cm-1
,
1,454 cm-1 (mPhC–C); 1,279 cm-1 (mC–N); 756 cm-1
IR (KBr, m/cm-1): 3,455 cm-1, 3,376 cm-1 (mN–H); 3,054 cm-1 (vPhC–H); 3,020 cm-1
(vCOOH); 2,921 cm-1, 2,845 cm-1 (mC–H); 1,608 cm-1, 1,589 cm-1, 1,498 cm-1
1,450 cm-1 (mPhC–C); 1,381 cm-1; 1,271 cm-1 (mC–N); 825 cm-1
,
IR (KBr, m/cm-1): 3,465 cm-1, 3,367 cm-1 (mN–H); 3,032 cm-1 (vPhC–H); 3,034 cm-1
(vCOOH); 2,931 cm-1, 2,851 cm-1 (mC-H); 1,603 cm-1, 1,587 cm-1, 1,501 cm-1
1,449 cm-1 (mPhC–C); 1,451 cm-1, 1,379 cm-1; 1,272 cm-1(mC–N); 836 cm-1
,
IR (KBr, m/cm-1): 3,470 cm-1, 3,359 cm-1 (mN–H); 3,024 cm-1 (vPhC–H); 3,013 cm-1
(vCOOH); 2,935 cm-1, 2,848 cm-1(mC–H); 1,599 cm-1, 1,583 cm-1, 1,499 cm-1
,
1,446 cm-1 (mPhC–C); 1,456 cm-1, 1,379 cm-1; 1,269 cm-1 (mC–N); 836 cm-1
IR (KBr, m/cm-1): 3,480 cm-1, 3,397 cm-1 (mN–H); 3,089 cm-1 (vPhC–H); 2,999 cm-1
(vCOOH); 2,929 cm-1, 2,856 cm-1 (mC–H); 1,604 cm-1, 1,576 cm-1, 1,504 cm-1
1,447 cm-1 (mPhC–C); 1,449 cm-1, 1,389 cm-1; 1,274 cm-1 (mC–N); 838 cm-1
,
obtained with an Inova-400 spectrometer, using DMSO-d6 or CDCl3 as solvents,
and Me4Si as internal standard. All reagents were analytically pure or chemically
pure. 3-Substituted-2-propenic acid was laboratory prepared.
Synthesis of novel b-amino acid derivatives
3-Substituted-2-propenic acid (0.01 mol) and hydrazine hydrate solution 7.4 ml
(0.15 mol) were well mixed in a dry flask (50 mL). The mixture was stirred at 80 °C
for 8 h. After completion of the reaction (TLC), the mixture was cooled to room
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Table 9 1H NMR data for compounds a–f
Compound 1H NMR data for compounds
a
b
c
1H NMR (DMSO-d6),d: 7.19–7.33 (m, 5H, Ar–H), 6.80 (d, 1H, –NH), 4.50 (t, 1H, –CH),
3.84 (d, 2H, –NH2), 2.89 (d, 2H, –CH2), 10.99 (hours, COOH)
1H NMR (DMSO-d6), d: 6.89–7.21 (m, 5H, Ar–H), 6.79 (d, 1H, –NH), 4.49 (t, 1H, –CH),
3.78 (d, 2H, –NH2), 2.69 (d, 2H, –CH2), 10.84 (hours, COOH), 2.35 (s, 3H, –CH3)
1H NMR (DMSO-d6), d: 6.76–7.20 (m, 5H, Ar–H), 6.76 (d, 1H, –NH), 4.46 (t, 1H, –CH),
3.67 (d, 2H, –NH2), 2.54 (d, 2H, –CH2), 10.76 (hours, COOH), 2.63 (s, 2H, –CH2), 1.21
(s, 3H, –CH3)
d
e
1H NMR (DMSO-d6), d: 6.69–7.23 (m, 5H, Ar–H), 6.79 (d, 1H, –NH), 4.47 (t, 1H, –CH),
3.69 (d, 2H, –NH2), 2.56 (d, 2H, –CH2), 10.80 (hours, COOH), 2.59 (s, 2H, –CH2), 1.65
(s, 2H, –CH2), 0.95 (s, 3H, –CH3)
1H NMR (DMSO-d6), d: 6.39–7.11 (m, 5H, Ar–H), 6.76 (d, 1H, –NH), 4.50 (t, 1H, –CH),
3.70 (d, 2H, –NH2), 2.36 (d, 2H, –CH2), 10.79 (hours, COOH), 3.73 (s, 3H, –CH3)
temperature, and 10 % dilute hydrochloric acid was added until pH 7 (neutrality).
The mixture was then filtered to give a white solid. Crude products were purified by
recrystallization from ethanol–water (1:1) to yield the pure compounds.
Acknowledgments The authors are grateful to Shaanxi University of Science and Technology for FTIR
spectroscopy, elemental analysis, and 1H NMR and 13C NMR spectroscopic analysis.
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