Convenient procedure for synthesis of N-protected β-aminomalonates and β-amino acids from α-amidosulfones

Article abstract of DOI:10.1080/00397910600602537

A synthesis of N-protected β-aminomalonates starting from α-amidosulfones under very mild and simple reaction conditions is described. Treatment of the sulfones with malonate esters in the presence of 2.5 equivalents of potassium carbonate affords the des

Full text of DOI:10.1080/00397910600602537

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Convenient Procedure for Synthesis of
N‐Protected β‐Aminomalonates and β‐Amino
Acids From α‐Amidosulfones
Cheeraporn Ananthanawat a , Vorawit Banphavichit a & Tirayut Vilaivan a
a Organic Synthesis Research Unit, Department of Chemistry, Faculty of
Science, Chulalongkorn University, Bangkok, Thailand
Published online: 18 Aug 2006.
To cite this article: Cheeraporn Ananthanawat , Vorawit Banphavichit & Tirayut Vilaivan (2006) Convenient
Procedure for Synthesis of N‐Protected β‐Aminomalonates and β‐Amino Acids From α‐Amidosulfones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:13, 1845-1855
To link to this article: http://dx.doi.org/10.1080/00397910600602537
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Synthetic Communicationsw, 36: 1845–1855, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602537
Convenient Procedure for Synthesis of
N-Protected b-Aminomalonates and
b-Amino Acids From a-Amidosulfones
Cheeraporn Ananthanawat, Vorawit Banphavichit, and
Tirayut Vilaivan
Organic Synthesis Research Unit, Department of Chemistry, Faculty of
Science, Chulalongkorn University, Bangkok, Thailand
Abstract: A synthesis of N-protected b-aminomalonates starting from a-amidosulfones
under very mild and simple reaction conditions is described. Treatment of the sulfones
with malonate esters in the presence of 2.5 equivalents of potassium carbonate affords
the desired products in good yield. A variety of N-Z and N-Boc protected aliphatic
and aromatic a-aminosulfones and malonate esters have been successfully used as
starting materials. Hydrolysis with concomitant decarboxylation of the N-protected
b-aminomalonates provides a convenient access to racemic b-amino acids.
Keywords: b-Amino acid, b-aminomalonate, imine, nucleophilic addition
b-Amino acid is an important building block of unnatural peptides, which may
fold into well-defined secondary structures.[1] These foldamers, apart from being
fundamentally interesting from a structural point of view, also display a range of
biological activities such as antibacterial properties[2a] and inhibition of lipid
uptake.[2b] Incorporation of b-amino acid into peptides was shown to improve
stability toward enzymatic degradation.[3] Some b-amino acids also occur in
nature, either as a single entity or as part of a more complex structure, and
they usually possess some biological activities.[3] Although there are many strat-
egies available for constructing b-amino acids, the addition of enolate anion
Received in India December 17, 2005
Address correspondence to Tirayut Vilaivan, Organic Synthesis Research Unit,
Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai
Road, Patumwan, Bangkok 10330, Thailand. Fax: þ66-2-2187598; E-mail:
vtirayut@chula.ac.th
1845

1846
C. Ananthanawat, V. Banphavichit, and T. Vilaivan
equivalents to imines may be considered as the most conceptually simple and
allows a very convenient structural variation.[4] Masked N-acylimines such as
a-amidobenzotriazoles[5] and a-amidosulfones[6] have been employed as the
electrophiles in the synthesis of racemic b-amino acids.[7] In the presence of a
suitable activator (usually a Lewis acid for amidobenzotriazoles and a base
for a-amidosulfones), the highly reactive N-acylimine is regenerated and
readily reacts with the enolate. However, generation of ester enolates usually
requires a strong base such as LDA, which may not be compatible for certain
substrates.[5a,6] The use of malonate esters offers a possibility of generating
the enolates under much milder conditions and hence should be more compatible
for a wider range of substrates. Nevertheless, unactivated imines are not usually
good substrates for malonate addition.[8] Therefore, we propose that addition of
malonate anion to N-acylimines, both generated in situ from malonate esters and
a-amidosulfones under basic conditions, should provide an efficient entry to N-
acyl protected b-aminomalonates, which can be subsequently hydrolyzed with
concomitant decarboxylation to form racemic b-amino acids. The same
concept was also very recently developed by Nejman et al.[9] In their work,
sodium hydride functioned as the base under inert conditions. Here we
demonstrate that the reactions can still take place even in the presence of a
weak base such as potassium carbonate[10] and have expanded the scope of
the reaction to cover a wide variety of a-amidosulfones and malonates.
The reaction condition was first optimized by treatment of N-Boc-a-ami-
nosulfone 1a derived from benzaldehyde with diethyl malonate under a
variety of conditions (Scheme 1). The desired product was obtained from
the reactions using inorganic bases such as NaOH or K2CO3 and strong
organic bases including 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) but not
Et3N. Judging from the yield of the product and the ease of workup, it was
concluded that anhydrous potassium carbonate in acetonitrile at room temp-
erature (308C) was optimal (Scheme 1). The role of potassium carbonate
was thought to be both abstraction of the benzenesulfinate anion from the
Scheme 1.

N-Protected Aminomalonates and b-Amino Acids
1847
amidosulfone to form the reactive N-acylimine as the electrophile and gener-
ation of malonate anion as the nucleophile. Although potassium carbonate was
usually considered as weak base and abstracting the proton from malonate
esters would not be expected to be complete, a further addition reaction to
form b-amidomalonate proceeded so readily that the deprotonation reaction
was driven to completion. The reaction required neither inert atmosphere
nor strictly anhydrous conditions—dried K2CO3 and reagent-grade aceto-
nitrile (0.1% water) worked well enough. Neither phase-transfer catalyst nor
high temperature, as usually required for similar reactions, were necessary.
This was considered advantageous compared to similar reactions previously
developed that usually employed strong bases under inert conditions.[5,6,8]
With the optimized conditions in hand, the generality of the reaction con-
ditions was tested (Table 1), first with varying the structure of the R part of the
amidosulfone 1. A range of substrates were found to be acceptable, including
aromatic with either electron withdrawing or electron-donating substituents
(entries 1–7) and linear or branched aliphatic substrates (entries 9–13)
including the easily enolizable benzylic substrate (entry 8). Both N-Boc and
N-Z aminosulfones effectively participate in the reaction. As for the malonate
component, various esters including ethyl, tert-butyl, and benzyl esters may
be used. Most importantly, a-substitution on the malonate may be tolerated
provided that the steric effect due to the substituent was not excessive. For
example, although a-methyl, a-methoxy, and a-acetamidomalonates gave
the product with 1a (R1 ¼ Ph) in comparable yield to unsubstituted malonate
(entries 15, 20, 21), the yield progressively decreased when the a-substituent
became larger (entries 15–18). In the most extreme case, whereby R4 ¼ tBu,
no product could be isolated at all. Interestingly, in spite of the apparent
steric bulkiness of the a-phenyl substituent, diethyl phenylmalonate afforded
better than expected yield of the products (entries 19 and 24). This might be
due to the increased acidity of the malonate, which counterbalances the
increased steric bulkiness caused by the a-phenyl substituent.
The N-Boc-b-aminomalonates 3 may be readily converted to the
corresponding amino acids 4 by refluxing with aqueous HCl. The amino
acid hydrochlorides were obtained simply by evaporation of the solvent and
washing of the residue with diethyl ether. Because the procedure has
already been described in detail,[9] only two representative examples are
provided here (Scheme 2).
In conclusion, a very efficient synthesis of N-protected-b-aminomalo-
nates based on nucleophilic addition of potassium derivatives of malonate
esters to N-acylimines, both generated in situ by the action of malonate
esters and a-amidosulfones, respectively, with potassium carbonate in aceto-
nitrile, was developed. Acid hydrolysis of the b-aminomalonates provided a
convenient preparation of both aliphatic and aromaic b-amino acids in
racemic forms. The procedure is very simple and provides results that
compares very well in terms of yield and compatibility with a wide range
of substrates to other existing methods of b-amino acid synthesis.

1848
C. Ananthanawat, V. Banphavichit, and T. Vilaivan
Table 1. Reactions of [alpha]-amidosulfones with dialkyl malonates
Yield
%
Entry Product
R1
R2
R3
R4
1
2
3a
3b
3c
3d
3e
3f
Ph
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
H
76
74
75
85
63
89
79
56
79
42
62
74
82
89
72
33
26
0
1-naphthyl
4-MeC6H4
4-MeOC6H4
4-FC6H4
H
3
H
4
H
5
H
6
4-NO2C6H4
2-NO2C6H4
CH2Ph
H
7
3g
3h
3i
H
8
H
9
CH(CH3)2
CH(CH3)2
C(CH3)3
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3j
Me
H
3k
3l
CH2CH2CH2CH3 C(CH3)3 Et
H
3m
3n
3o
3p
3q
3r
3s
c-C6H11
Ph
Ph
C(CH3)3 Et
H
C(CH3)3 Me
C(CH3)3 Et
C(CH3)3 Me
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Et
C(CH3)3 Me
C(CH3)3 Et
C(CH3)3 CH2Ph
H
Me
Et
Ph
Ph
CH2CH2CH3
C(CH3)3
Ph
Ph
Ph
OMe
51
83
85
91
77
73
80
87
3t
Ph
Ph
3u
3v
3w
3x
3y
3z
NHCOCH3
Ph
Ph
H
H
Ph
H
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Et
Et
Ph
Ph
C(CH3)3
CH2Ph
Ph
EXPERIMENTAL
General
Melting points were recorded on an Electrothermal 9100 melting-point
apparatus and are uncorrected. Elemental analyses were performed on a
Perkin-Elmer Elemental Analyzer 2400 CHNS/O at the Research
Equipment Centre, Chulalongkorn University. Routine 1H NMR spectra

N-Protected Aminomalonates and b-Amino Acids
1849
Scheme 2.
were obtained on a Varian Mercury Plus operating at 400 MHz (1H) and
100 MHz (13C). Chemical shifts are reported in parts per million (ppm, d)
downfield relative to the internal standard tetramethylsilane. Unless
otherwise noted, all reagent-grade chemicals and solvents were obtained
from commercial suppliers (Aldrich, Fluka, and Merck) and were used as
received. Reactions were performed under ambient conditions without the
need for anhydrous solvents or inert atmosphere. The a-amidosulfones were
prepared according to literature procedures.[11]
Typical Procedure for the Synthesis of b-Aminomalonates
The a-amidosulfone (0.5 mmol), malonate ester (0.5 mmol), and potassium
carbonate (1.25 mmol) were stirred in acetronitrile under N2 at room tempera-
ture for 24 h. The solvent was removed under reduced pressure, and the
residue was dissolved in dichloromethane and extracted with 5% HCl. The
organic layer was dried with anhydrous MgSO4 and evaporated. The crude
product was purified by column chromatography. Compounds 3a, 3d, 3i,
3m, and 3y have already been described in the literature.[5a,8]
Spectroscopic and Analytical Data of New b-Aminomalonates
2-(tert-Butoxycarbonylamino-naphthalen-1-yl-methyl)-malonic Acid
Diethyl Ester 3b
1
Light yellow solid. Mp 73.8–74.4 8C; H NMR (400 MHz, CDCl3) d 8.18
(d J ¼ 8.4 Hz, 1H), 7.90 (d J ¼ 8.4 Hz, 1H), 7.80 (d J ¼ 8.0 Hz, 1H), 7.64
(t J ¼ 6.8 Hz, 1H), 7.50 (m, 2H), 7.40 (t J ¼ 8.0 Hz, 1H), 6.68 (br d
J ¼ 8.4 Hz, 1H), 6.35 (br m, 1H), 4.36–3.99 (m, 5H), 1.45 (s, 9H), 1.34
(t J ¼ 6.8 Hz, 3H), 1.09 (t J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
168.3, 167.4, 155.0, 135.0, 133.8, 130.1, 129.2, 128.5, 126.8, 125.8, 125.2,
123.8, 122.2, 79.7, 62.1, 61.5, 55.6, 50.2, 28.3, 14.1, 13.8: Anal. calcd. for
C23H29NO6: C, 66.49; H, 7.04; N, 3.37. Found: C, 66.49; H, 7.02; N, 3.38.

1850
C. Ananthanawat, V. Banphavichit, and T. Vilaivan
2-(tert-Butoxycarbonylamino-(4-methyl-phenyl)-malonic Acid Diethyl
Ester 3c
1
Colorless oil. H NMR (400 MHz, CDCl3) d 7.20 (d J ¼ 7.6 Hz, 2H), 7.13
(d J ¼ 7.6 Hz, 2H), 6.20 (br d J ¼ 8.8 Hz, 1H), 5.48 (br m, 1H), 4.26-4.06
(m, 4H), 3.89 (br d J ¼ 4.0 Hz, 1H), 2.32 (s, 3H), 1.42 (s, 9H), 1.27
(t J ¼ 7.2 Hz, 3H), 1.16 (t J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
168.1, 167.2, 155.0, 137.1, 136.6, 129.2, 126.1, 79.5, 61.9, 61.5, 57.0, 53.2,
28.3, 21.0, 14.0, 13.9: Anal. calcd. for C20H29NO6: C, 63.31; H, 7.70; N,
3.69. Found: C, 63.11; H, 7.70; N, 3.69.
2-[tert-Butoxycarbonylamino-(4-fluoro-phenyl)-methyl]-malonic Acid
Diethyl Ester 3e
1
White solid. Mp 72.9–75.58C; H NMR (400 MHz, CDCl3) d 7.30 (m, 2H),
7.01 (m, 2H), 6.23 (br m, 1H), 5.48 (br m, 1H), 4.24–4.06 (m, 4H), 3.86
(br m, 1H), 1.42 (s, 9H), 1.28 (t J ¼ 7.2 Hz, 3H), 1.17 (t J ¼ 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 168.0, 167.0, 163.3 (1J13C-19F ¼ 245 Hz),
160.8, 155.0, 135.4, 128.0 (3J13C-19F ¼ 8.1 Hz), 115.5 (2J13C-19F ¼ 21.5 Hz),
79.8, 62.0, 61.7, 56.9, 52.9, 28.3, 14.0, 13.9; Anal. calcd. for C19H26FNO6:
C, 59.52; H, 6.84; N, 3.65. Found: C, 59.53; H, 6.84; N, 3.70.
2-[tert-Butoxycarbonylamino-(4-nitro-phenyl)-methyl]-malonic Acid
Diethyl Ester 3f
Yellow solid. Mp 82.0–84.08C; 1H NMR (400 MHz, CDCl3) d 8.20
(d J ¼ 8.8 Hz, 2H), 7.54 (d J ¼ 9.2 Hz, 2H), 6.34 (br d J ¼ 8.4 Hz, 1H),
5.58 (br m, 1H), 4.27–4.06 (m, 4H), 3.93 (br d J ¼ 2.8 Hz, 1H), 1.43
(s, 9H), 1.28 (t J ¼ 7.2 Hz, 3H), 1.17 (t J ¼ 8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 167.7, 166.6, 155.0, 147.3, 147.1, 127.4, 123.8, 80.3,
62.4, 62.0, 56.3, 53.1, 28.2, 14.0, 13.9: Anal. calcd. for C19H26N2O8: C,
55.60; H, 6.39; N, 6.83. Found: C, 55.61; H, 6.44; N, 6.83.
2-[tert-Butoxycarbonylamino-(2-nitro-phenyl)-methyl]-malonic Acid
Diethyl Ester 3 g
Yellow oil. 1H NMR (400 MHz, CDCl3) d 8.01 (d J ¼ 7.6 Hz, 1H), 7.64–7.57
(m, 2H), 7.44 (t J ¼ 8.0 Hz, 1H), 6.61 (br d J ¼ 8.4 Hz, 1H), 6.02 (br d
J ¼ 4.8 Hz, 1H), 4.29-4.04 (m, 5H), 1.37 (s, 9H), 1.26 (t J ¼ 6.8 Hz, 3H),
1.11 (t J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 168.4, 166.9, 154.7,
147.9, 135.3, 133.6, 129.5, 128.9, 125.3, 78.0, 62.2, 61.7, 54.9, 50.4, 28.2,
14.0, 13.8: Anal. calcd. for C19H26N2O8: C, 55.60; H, 6.39; N, 6.83. Found:
C, 55.46; H, 6.41; N, 6.84.

N-Protected Aminomalonates and b-Amino Acids
1851
2-(1-tert-Butoxycarbonylamino-2-phenyl-ethyl)-malonic Acid Diethyl
Ester 3h
1
White solid. Mp 85.8–87.58C; H NMR (400 MHz, CDCl3) d 7.33–7.19
(m, 5H), 5.63 (br d J ¼ 9.2 Hz, 1H), 4.53 (br m, 1H), 4.31–4.13 (m, 4H),
3.52 (d J ¼ 4.8 Hz, 1H), 3.02 (dd J ¼ 7.2 Hz, 1H), 2.80 (dd J ¼ 7.6,
8.8 Hz, 1H), 1.39 (s, 9H), 1.33 (t J ¼ 7.2 Hz, 3H), 1.27 (t J ¼ 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 168.6, 168.0, 155.1, 137.4, 129.2,
128.6, 126.7, 79.3, 61.7, 61.5, 53.5, 51.8, 39.8, 28.3, 14.1, 14.0: Anal.
calcd. for C20H29NO6: C, 63.31; H, 7.70; N, 3.69. Found: C, 63.54;
H, 7.77; N, 3.64.
2-(1-tert-Butoxycarbonylamino-2-methyl-propyl)-2-methyl-malonic
Acid Diethyl Ester 3j
1
Colorless oil. H NMR (400 MHz, CDCl3) d 5.55 (br d J ¼ 11.2 Hz, 1H),
4.22–4.09 (m, 5H), 1.93 (m, 1H), 1.46 (s, 3H), 1.40 (s, 9H), 1.28
(t J ¼ 7.2 Hz, 3H), 1.24 (t J ¼ 7.2 Hz, 3H), 0.96 (d J ¼ 7.6 Hz, 3H), 0.77
(d J ¼ 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 171.6, 171.4, 155.7,
78.8, 61.6, 61.5, 58.6, 58.0, 29.5, 28.3, 22.3, 19.5, 17.4, 13.9: Anal. Calcd.
for C17H31NO6: C, 59.11; H, 9.05; N, 4.05. Found: C, 59.32; H, 9.05; N, 4.06.
2-(1-tert-Butoxycarbonylamino-2,2-dimethyl-propyl)-malonic Acid
Diethyl Ester 3 k
Colorless oil. 1H NMR (400 MHz, CDCl3) d 6.04 (d J ¼ 10.0 Hz, 1H), 4.24-
4.12 (m, 5H), 3.65 (d J ¼ 3.2 Hz, 1H), 1.40 (s, 9H), 1.31-1.24 (m, 6H), 0.91
(s, 9H); 13C NMR (100 MHz, CDCl3) d 169.5, 168.5, 155.7, 78.9, 61.9,
61.5, 58.3, 50.9, 35.9, 28.3, 26.9, 14.0, 13.9: Anal. calcd. for C17H31NO6:
C, 59.11; H, 9.05; N, 4.05. Found: C, 59.14; H, 9.21; N, 4.11.
2-(1-tert-Butoxycarbonylamino-pentyl)-malonic Acid Diethyl Ester 3l
Colorless oil. 1H NMR (400 MHz, CDCl3) d 5.38 (d J ¼ 10.0 Hz, 1H), 4.25-
4.12 (m, 5H), 3.56 (d J ¼ 4.4 Hz, 1H), 1.40 (s, 9H), 1.30-1.23 (m, 12H), 0.88
(t J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 168.4, 168.0, 155.3, 79.1,
61.5, 61.4, 55.1, 50.2, 33.4, 28.4, 28.3, 22.3, 14.0, 13.9, 13.8; Anal. Calcd. for
C17H31NO6: C, 59.11; H, 9.05; N, 4.05. Found: C, 59.12; H, 9.15; N, 4.09.
2-(tert-Butoxycarbonylamino-phenyl-methyl)-malonic Acid Dimethyl
Ester 3n
1
White solid. Mp 109.0–110.58C; H NMR (400 MHz, CDCl3) d 7.38-7.29
(m, 5H), 6.18 (br m, 1H), 5.54 (br m, 1H), 3.97 (br m, 1H), 3.79 (s, 3H),
3.68 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) d 168.4, 167.6,

1852
C. Ananthanawat, V. Banphavichit, and T. Vilaivan
155.1, 139.3, 128.6, 127.7, 126.2, 80.8, 56.7, 53.4, 52.9, 52.6, 28.3: Anal.
calcd. for C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.54; H, 6.85;
N, 4.17.
2-(tert-Butoxycarbonylamino-phenyl-methyl)-2-methyl-malonic Acid
Diethyl Ester 3o
1
White solid. Mp 102.0–104.58C; H NMR (400 MHz, CDCl3) d 7.32-7.24
(m, 5H), 6.62 (br d J ¼ 10.0 Hz, 1H), 5.15 (d J ¼ 10.0 Hz, 1H), 4.28-4.16
(m, 4H), 1.38 (s, 12H), 1.29 (t J ¼ 6.8 Hz, 3H), 1.21 (t J ¼ 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 171.4, 170.8, 154.8, 138.1, 128.4, 128.1, 127.8,
79.3, 61.9, 61.6, 59.1, 58.9, 28.3, 20.3, 14.0, 13.9: Anal. calcd. for
C20H29NO6: C, 63.31; H, 7.70; N, 3.69. Found: C, 63.38; H, 7.76; N, 3.62.
2-(tert-Butoxycarbonylamino-phenyl-methyl)-2-ethyl-malonic Acid
Dimethyl Ester 3p
1
White solid. Mp 138.5–140.08C; H NMR (400 MHz, CDCl3) d 7.32–7.21
(m, 5H), 6.50 (d J ¼ 9.6 Hz, 1H), 5.22 (d J ¼ 9.6 Hz, 1H), 3.79 (s, 3H),
3.72 (s, 3H), 1.82 (m, 2H), 1.40 (s, 9H), 0.93 (t J ¼ 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 170.7, 170.6, 154.7, 138.1, 128.3, 127.9, 127.8, 79.5,
63.9, 58.5, 52.5, 52.4, 28.3, 27.7, 9.9: Anal. calcd. for C19H27NO6: C,
62.45; H, 7.45; N, 3.83. Found: C, 62.14; H, 7.47; N, 3.85.
2-(tert-Butoxycarbonylamino-phenyl-methyl)-2-propyl-malonic Acid
Diethyl Ester 3q
Colorless oil. 1H NMR (400 MHz, CDCl3) d 7.32–7.27 (m, 5H), 6.62
(d J ¼ 9.2 Hz, 1H), 5.22 (d J ¼ 9.2 Hz, 1H), 4.31-4.16 (m, 4H), 1.73-1.64
(m, 2H), 1.48-1.43 (m, 2H), 1.40 (s, 9H), 1.34–1.20 (m, 6H), 0.88
(t J ¼ 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 170.5, 170.3, 154.7,
138.5, 128.2, 127.9, 127.8, 79.3, 63.0, 61.6, 61.5, 58.7, 36.5, 28.3, 18.7,
14.5, 14.1, 13.8: Anal. calcd. for C22H33NO6: C, 64.84; H, 8.16; N, 3.44.
Found: C, 65.17; H, 8.08; N, 3.50.
2-(tert-Butoxycarbonylamino-phenyl-methyl)-2-phenyl-malonic Acid
Diethyl Ester 3s
Colorless oil. 1H NMR (400 MHz, CDCl3) d 7.27–7.15 (m, 10H), 6.27
(d J ¼ 10.0 Hz, 1H), 5.71 (d J ¼ 10.0 Hz, 1H), 4.30-4.15 (m, 4H), 1.37
(s, 9H), 1.27 (t J ¼ 6.8 Hz, 3H), 1.16 (t J ¼ 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 169.8, 169.5, 154.7, 138.4, 135.2, 128.9, 128.8, 127.8,
127.6, 127.5, 79.4, 68.7, 62.1, 61.8, 59.3, 28.3, 13.9, 13.7: Anal. calcd. for
C25H31NO6: C, 68.01; H, 7.08; N, 3.17. Found: C, 68.03; H, 7.06; N, 3.20.

N-Protected Aminomalonates and b-Amino Acids
1853
2-(tert-Butoxycarbonylamino-phenyl-methyl)-2-methoxy-malonic
Acid Dimethyl Ester 3t
Colorless oil. 1H NMR (400 MHz, CDCl3) d 7.34–7.25 (m, 5H), 5.92
(d J ¼ 10.4Hz, 1H), 5.41 (d J ¼ 10.4Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.57
(s, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) d 168.4, 167.6, 154.6,
137.2, 128.2, 128.0, 87.7, 79.7, 58.1, 56.3, 52.8, 52.6, 28.3: Anal. calcd. for
C18H25NO7: C, 58.84; H, 6.86; N, 3.81. Found: C, 58.88; H, 6.85; N, 3.81.
2-Acetylamino-2-(tert-butoxycarbonylamino-phenyl-methyl)-malonic
Acid Diethyl Ester 3u
1
White solid. Mp 133.4–135.08C; H NMR (400 MHz, CDCl3) d 7.39 (br d
J ¼ 4.0 Hz, 1H), 7.30-7.19 (m, 5H), 6.67 (s, 1H), 5.62 (br d J ¼ 4.8 Hz,
1H), 4.32-4.17 (m, 4H), 2.06 (s, 3H), 1.39 (br s, 9H), 1.32 (t J ¼ 7.2 Hz,
3H), 1.27 (t J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 171.8, 166.2,
165.0, 155.8, 137.8, 128.3, 128.1, 127.6, 79.2, 70.4, 63.8, 62.8, 59.6, 28.4,
23.2, 14.0, 13.9: Anal. calcd. for C21H30N2O7: C, 59.70; H, 7.16; N, 6.63.
Found: C, 59.59; H, 7.16; N, 6.67.
2-(tert-Butoxycarbonylamino-phenyl-methyl)-malonic Acid Dibenzyl
Ester 3v
White solid. Mp 95.0-96.88C; 1H NMR (400 MHz, CDCl3) d 7.41-7.25
(m, 13H), 7.16-7.12 (m, 2H), 6.22 (br m, 1H), 5.60 (br m, 1H), 5.24-5.13
(m, 2H), 5.09 (s, 2H), 4.04 (br d, 1H), 1.38 (s, 9H); 13C NMR (100MHz,
CDCl3) d 167.9, 166.9, 155.1, 139.3, 135.0, 134.9, 128.7, 128.6, 128.5, 128.4,
128.3, 128.1, 127.7, 126.3, 79.6, 67.8, 67.3, 56.9, 53.5, 28.3: Anal. calcd. for
C29H31NO6: C, 71.15; H, 6.38; N, 2.86. Found: C, 75.11; H, 6.37; N, 2.86.
2-(Benzyloxycarbonylamino-phenyl-methyl)-malonic Acid Diethyl
Ester 3w
White solid. Mp 78.6–79.68C; 1H NMR (400 MHz, CDCl3) d 7.38–7.30
(m, 10H), 6.54 (br d J ¼ 8.8 Hz, 1H), 5.59 (br m, 1H), 5.16 (m, 2H), 4.21–4.07
(m, 4H), 3.94 (br d J ¼ 3.6 Hz, 1H), 1.23 (t J ¼ 7.2 Hz, 3H), 1.14 (t J ¼ 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 168.0, 167.0, 155.7, 139.2, 136.4, 128.6,
128.4, 128.1, 127.8, 126.3, 66.9, 62.1, 61.7, 56.8, 53.9, 14.0, 13.9: Anal. calcd.
for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 66.27; H, 6.35; N, 3.56.
2-(Benzyloxycarbonylamino-phenyl-methyl)-2-phenyl-malonic Acid
Diethyl Ester 3x
Colorless oil. 1H NMR (400 MHz, CDCl3) d 7.43–7.08 (m, 15H), 6.63
(d J ¼ 10.0 Hz, 1H), 5.77 (d J ¼ 10.0 Hz, 1H), 5.15 (d J ¼ 12.4 Hz, 1H), 5.00

1854
C. Ananthanawat, V. Banphavichit, and T. Vilaivan
(d J ¼ 12.4 Hz, 1H), 4.25–4.18 (m, 4H), 1.25 (t J ¼ 7.2 Hz, 3H), 1.20 (t
J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 169.8, 169.2, 155.4, 138.0,
136.5, 135.0, 129.0–127.7, 68.5, 66.8, 62.2, 62.0, 60.1, 14.1, 13.9: Anal. calcd.
for C28H29NO6: C, 70.72; H, 6.15; N, 2.95. Found: C, 70.61; H, 6.16; N, 2.91.
2-(Benzyloxycarbonylamino-phenyl-methyl)-malonic Acid Dibenzyl
Ester 3z
White solid. Mp 96.9-97.88C; 1H NMR (400 MHz, CDCl3) d 7.40-7.26
(m, 18H), 7.15-7.11 (m, 2H), 6.50 (br d J ¼ 8.8 Hz, 1H), 5.65 (br m, 1H),
5.15 (br d, 2H), 5.11 (s, 2H), 5.08 (s, 2H), 4.06 (br m, 1H); 13C NMR
(100 MHz, CDCl3) d 167.9, 166.8, 155.8, 139.0, 136.5, 135.0, 134.9, 128.8,
128.7, 128.6, 128.5, 128.4, 128.2, 127.9, 126.4, 67.8, 67.5, 67.0, 56.9, 54.1:
Anal. calcd. for C23H29NO6: C, 73.41; H, 5.58; N, 2.68. Found: C, 73.50;
H, 5.60; N, 2.77.
ACKNOWLEDGMENT
Financial support comes from the Faculty of Science and a Rachadaphisek
Somphot Endowment grant from Chulalongkorn University (to the Organic
Synthesis Research Unit).
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