A novel access to 2-aminofuranones via cyclization of functionalized γ-hydroxy-α,β-butenoates derived from N-hydroxybenzotriazole esters of α-hydroxy acids

Article abstract of DOI:10.1055/s-2003-41040

The reaction between the N-hydroxybenzotriazole esters of substituted glycolic acids and alkyl cyanoacetates or malononitrile leads to the synthesis of γ-hydroxy-functionalized butenoates which are cyclized under mild conditions to the corresponding 2-amino-3,5-disubstituted-4-furanones. That the products are optically active is confirmed by measurements of their optical rotations. On the other hand, replacement of N-hydroxybenzotriazole by N-hydroxysuccinimide might lead to by-products depending on the functionalized glycolic acid used.

Full text of DOI:10.1055/s-2003-41040

PAPER
2015
A Novel Access to 2-Aminofuranones via Cyclization of Functionalized
g-Hydroxy-a,b-butenoates Derived from N-Hydroxybenzotriazole Esters
of a-Hydroxy Acids
2
-Amino
F
uranone
i
s
via
C
o
yclization of
r
Functio
g
nalized
g
-
Hy
o
droxy-
a
,
b
-b
s
utenoates Athanasellis,a Anastasia Detsi,a Kyriakos Prousis,a Olga Igglessi-Markopoulou,*a John Markopoulosb
a
Laboratory of Organic Chemistry, Department of Chemical Engineering, National Technical University of Athens, Zografou Campus,
15773 Athens, Greece
Fax +3(210)7723072; E-mail: ojmark@orfeas.chemeng.ntua.gr
b
Laboratory of Inorganic Chemistry, Department of Chemistry, University of Athens, Athens, Greece
Received 24 February 2003; revised 5 June 2003
NH2
O
O
Y
Y
4
3
O
Abstract: The reaction between the N-hydroxybenzotriazole esters
of substituted glycolic acids and alkyl cyanoacetates or malononi-
trile leads to the synthesis of g-hydroxy-functionalized butenoates
which are cyclized under mild conditions to the corresponding 2-
amino-3,5-disubstituted-4-furanones. That the products are optical-
ly active is confirmed by measurements of their optical rotations.
On the other hand, replacement of N-hydroxybenzotriazole by N-
hydroxysuccinimide might lead to by-products depending on the
functionalized glycolic acid used.
5
2
NH2
NH2
O
N
O
H
I
II
III
OH
Key words: acylations, furans, heterocycles, lactones, alkenes, car-
boxylic acids
R2
COOR
R1
R2
COOR
R1
OAc
OAc
The synthesis of compounds incorporating the aminofura-
none ring system is of great interest for organic chemists
because these substances are found in many natural prod-
ucts, have biological and pharmacological activities, are
used as versatile intermediates and may also be used as
chelating agents for transition metal ions.
V
IV
Figure 1 Compounds of biological interest
clization
reaction
of
the
functionalized
g-
The class of 3-amino-2-furanones (Figure 1, I) is well-
known in the literature and very recently a stereoselective
method for their synthesis was established.1 On the other
hand, 4-amino-3-furanones were prepared as inhibitors of
cruzipain (a gene product of Trypanosoma cruzi parasite)
and other cysteine proteases for use as therapeutic agents2
whereas a convenient synthesis of 4-amino-2-furanones
from (S)-ketone cyanohydrins was recently proposed.3
Sotolone (3-hydroxy-4,5-dimethyl-2-furanone), a power-
ful flavour compound found in several foods and spices,
was synthesized from 3-amino-4,5-dimethyl-2-furanone.4
hydroxybutenoates (Figure 1, IV).9 These functionalized
intermediates were prepared through a C-acylation reac-
tion between the appropriate active methylene com-
pounds and the N-hydroxybenzotriazole esters of chiral a-
hydroxy acids.
As a logical extension to this chemistry we decided to in-
vestigate the condensation reactions of N-hydroxybenzo-
triazole activated a-hydroxy carboxylic acids with a-
cyano methylene compounds and subsequent deprotec-
tion–cyclization approach of the intermediate g-hydroxy-
a-cyanobutenoates (g-hydroxy-a,b-alkenoic esters) to 2-
amino-4-furanones. It is known that g-hydroxy-a,b-alk-
enoic esters (Figure 1, V) are versatile synthetic interme-
diates and part of many natural products.10
Our experience in the synthesis of 2-aminopyrrolinone
derivatives (Figure 1, II)5,6 prompted us to investigate the
construction of the novel class of 2-amino furanones
(Figure 1, III) with potential biological activity.
In this paper we present an efficient method for preparing
functionalized a-cyano-g-hydroxy-a,b-butenoic esters
(Figure 2, VI) and their corresponding cyclized products,
2-amino-4-furanones (Figure 2, VII) using the above
strategy.
Over the past number of years we have been involved in
the synthesis of tetramic acids via a cyclization reaction of
functionalized g-aminobutenoates derived from N-hy-
droxybenzotriazole esters of a-amino acids.7,8 We have
recently reported the successful synthesis of optically ac-
tive tetronic acids by an analogous methodology via a cy-
The N-hydroxybenzotriazole esters of substituted a-hy-
droxy carboxylic acids have been used as precursors for
the synthesis of the functionalized intermediates
(Figure 2, VI), which were cyclized to the corresponding
2-amino-3-substituted-4-furanones (Figure 2, VII) under
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 28 08 2003.
Art Id.1437-210X,E;2003,0,13,2015,2022,ftx,en;T01903SS.pdf.
DOI: 10.1055/s-2003-41040
© Georg Thieme Verlag Stuttgart · New York

2016
G. Athanasellis et al.
PAPER
Figure 2 Functionalized butenoates (VI) and 2-amino-3-substituted-4-furanones (VII)
mild acidic conditions (Scheme 1). The optical activity of The proposed synthesis comprises a C-acylation reaction
the final products confirms that neither the N-hydroxy- between an active a-cyano methylene compound and the
benzotriazole esterification nor the C-acylation–cycliza- N-hydroxybenzotriazole ester of the appropriate substitut-
tion reaction cause racemization.
ed O-protected glycolic acid. The N-hydroxybenzotria-
zole esters of a-amino acids are well-known activated
O
N
R1
CN
+
OH
+
N
R2
N
Y
OCOCH3
OH
3a Y = COOMe
1a R1 = H R2 = H
2a
3b
3c
COOEt
CN
1b
1c
1d
1e
H
H
H
Ph
iso-Pr
iso-Bu
Me
a
Me
O
HO
Y
O
CN
4
3
3
4
R1
CN
b
4
2
R1
R2
3
R1
R2
2
5
R2
2
5
Y
NH2
OCOCH3
NH2
O
O
16 R1 = H R2 = Ph Y = COOMe
7 R1 = H R2 = Ph Y = COOMe
4 R1 = H R2 = H
17
18
19
20
21
22
23
H
H
H
H
H
Me
Me
Ph
COOEt
8
9
H
H
H
H
H
Ph
COOEt
5
6
H
H
Ph
iso-Bu
iso-Pr COOMe
iso-Pr COOEt
iso-Bu COOMe
iso-Bu COOEt
Me
Me
iso-Pr COOMe
iso-Pr COOEt
iso-Bu COOMe
iso-Bu COOEt
10
11
12
13
14
15
COOMe
COOEt
Me
Me
Me
Me
Me
Me
COOMe
COOEt
CN
a: NaH, DCC, THF anhd.
b: 10% HCl, MeOH
Compound
Starting materials
1a and 3c
Yield
81%
Compound
Starting material
1e and 3b
1e and 3c
Yield
50%
72%
59%
65%
70%
75%
58%
62%
86%
60%
4
5
6
7
8
14
15
16
17
18
19
20
21
22
23
1b and 3c
1d and 3c
1b and 3a
1b and 3b
1c and 3a
1c and 3b
1d and 3a
1d and 3b
1e and 3a
64%
56%
82%
77%
62%
59%
78%
63%
75%
7
8
9
10
11
12
13
14
9
10
11
12
13
Scheme 1 Synthesis of compounds by using N-hydroxybenzotriazole
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York

PAPER
2-Amino Furanones via Cyclization of Functionalized g-Hydroxy-a,b-butenoates
2017
synthons applied in peptide synthesis.11 The requisite N- Then, we decided to replace the N-hydroxybenzotriazole
hydroxybenzotriazole ester was synthesized by treatment with N-hydroxysuccinimide, an esterification agent which
of the appropriate substituted glycolic acid [O-acetyl-a- has been extensively used by our research group for the
glycolic acid (1a),12 O-acetyl-S-a-mandelic acid (1b),13 synthesis of tetramic and tetronic acids.16,17 We used O-
O-acetyl-L-a-isovaleric acid (1c),14 O-acetyl-L-a-isocap- acetyl-a-glycolic acid (1a), O-acetyl-S-a-mandelic acid
roic acid (1d)14 or O-acetyl-a-isobutyric acid (1e15)] (10 (1b), O-acetyl-L-a-isovaleric acid (1c) or O-acetyl-a-
mmol) with 1-hydroxybenzotriazole (10 mmol) and DCC isobutyric acid (1e), N-hydroxysuccinimide (2b), and me-
(10 mmol) in anhydrous THF (40 mL) at 0 °C for 1 hour. thyl cyanoacetate (3a) or ethyl cyanoacetate (3b) as start-
The reaction mixture was filtered off and the filtrate was ing materials in the reaction showed in Scheme 2.
added into a thick slurry mixture containing the sodium
salt of the active methylene compound [prepared from the
addition of NaH (20 mmol) in anhydrous THF (80 mL)
and methyl cyanoacetate 3a, ethyl cyanoacetate 3b or ma-
From Scheme 2 it is obvious that O-acetyl-a-glycolic acid
(1a) reacts perfectly with N-hydroxysuccinimide (2b), an
esterification agent similar to N-hydroxybenzotriazole,
and gives the new substituted butenoates 28 and 29 which
lononitrile 3c)]. After stirring for 2.5 hours the solvent
are cyclized to the corresponding 4-furanones 30 and 31
was removed under reduced pressure, the residue was di-
by the treatment discussed before. In contrast, O-acetyl-S-
a-mandelic acid (1b) and O-acetyl-L-a-isovaleric acid
(1e) worked perfectly with both N-hydroxybenzotriazole
luted with water, washed with diethyl ether and the aque-
ous layer was acidified with HCl (10%) to give the 2-
amino-4-furanones 4–6 (from 3c) and the g-hydroxy b-
(Scheme 1) and N-hydroxysuccinimide (Scheme 2). Nev-
keto esters 7–15 (from 3a and 3b) in their enolic form.
ertheless, in the first situation (through N-hydroxysuccin-
The g-hydroxy b-keto esters 7–15 were isolated as solids
imide esters) a by-product in very small yield (8%) was
also detected apart from the synthesis of the major product
of the reaction 8. The problem became bigger when we
applied O-acetyl-a-isobutyric acid (1e) in the methodolo-
gy with N-hydroxysuccinimide. In this situation, the ex-
pected butenoates were not detected but side products
were formed exclusively. It therefore appears as if the use
of N-hydroxybenzotriazole instead of N-hydroxysuccin-
imide is beneficial concerning the chemoselectivity of the
reaction.
(7, 13, 14) or oily products (8–12, 15) and characterized
by IR and NMR spectroscopy. The oily intermediates
contained small amounts of the active methylene com-
pounds and they proved to be unstable on silica gel col-
umn chromatography (see experimental). It is noteworthy
that the 2-amino-3-cyano-5-substituted-4-furanones 5 and
6 were not isolated directly after the reaction. The isolated
oily mixture containing malononitrile 3c, the C-acylation
product and possibly the 4-furaranone 5 or 6 in very small
quantity, was set aside at room temperature for 5–7 days
In conclusion, we have successfully applied the method-
to give a gummy solid. This solid was triturated with
ology of N-hydroxybenzotriazole in the synthesis of a
dichloromethane to afford the 2-amino-4-furanones 5 and
novel class of optically active functionalized butenoic es-
ters and their corresponding aminofuranones. The conve-
nient access to these highly functionalized derivatives
6 as creamy solids. On the other hand, the reaction be-
tween O-acetyl-a-isobutyric acid (1e) with malononitrile
afforded the corresponding C-acylation product which
broadens the type of heterocycles we can synthesize using
was not cyclized to the 2-amino-4-furanone even upon
N-hydroxybenzotriazole as the esterification agent. Fur-
ther application of this methodology in the synthesis of
standing at room temperature for one month. The C-acy-
lation compounds 7–14 were treated with HCl (10%) in
complex natural products is currently under investigation
MeOH for 24 hours at room temperature and the cyclized
in our laboratories.
products 16–23 were obtained either by simple filtration
(when a solid was precipitated) or by evaporation of the
methanol, extraction of the aqueous layer with ethyl ace-
tate and evaporation of the organic extracts to afford the
products as white solids. The basic merit of the described
methodology is that there is no need for isolating the in-
termediate N-hydroxybenzotriazole esters, so the prod-
ucts are obtained in a one-step reaction. This fact
increases the overall yield and reduces the reaction time.
In addition, measurements of the optical rotations of com-
pounds 5–12 and 16–21 were obtained and are presented
in Table 1.
Mps were determined on a Gallenkamp MFB-595 mp apparatus and
are uncorrected. The FT-IR spectra were recorded on a Nicolet Ma-
gna IR 560. The NMR spectra were recorded on a Varian Gemini-
2000 300 MHz spectrometer; chemical shifts are quoted in ppm
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad); J values are given in Hz. Elemental analyses were ob-
tained on a Euro EA3000 Series Euro Vector CHNS Elemental
Analyser.
O-Acetyl a-Hydroxy acids 1a–e; General Procedure
A mixture of the appropriate a-hydroxy acid (50 mmol) and acetyl
chloride (6.4 mL; 90 mmol) was stirred at r.t. for 2 h. The resulting
Table 1 Optical rotations of compounds 5–12 and 16–21
Comp.
5
6
7
8
9
10
11
12
16
17
18
19
20
21
[a]D
(c 1, MeOH)
+40.3 –145.3 +40.5 +34.1 +21.8 +30.5 +4.4
+5.2
+60.8 +58.9 –178.3 –157.9 –119.2 –103.7
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York

2018
G. Athanasellis et al.
PAPER
O
O
O
O
R1
R2
DCC
THF
R1
R2
OH
+
NOH
ON
O
OCOCH3
OCOCH3
O
1a R1 = H R2 = H
24 R1 = H R2 = H
2b
1b
1c
1e
H
H
Me
Ph
iso-Pr
Me
25
26
27
H
H
Me
Ph
iso-Pr
Me
CN
Y
HO
O
Y
4
3
R1
R2
10% HCl
MeOH
CN
4
2
3
R1
R2
2
5
NaH, THF
Y
NH2
OCOCH3
O
3a Y = COOMe
3b
COOEt
28 R1 = H R2 = H Y = COOMe
30 R1 = H R2 = H Y = COOMe
29
7
H
H
H
H
H
H
Ph
Ph
COOEt
COOMe
COOEt
31
16
17
18
19
H
H
H
H
H
H
Ph
Ph
COOEt
COOMe
COOEt
8
9
10
iso-Pr COOMe
iso-Pr COOEt
iso-Pr COOMe
iso-Pr COOEt
Compound Starting material
Yield
98%
96%
97%
99%
90%
78%
76%
82%
Compound Starting material Yield
24
25
26
27
28
29
30
31
1a
1b
1c
1e
24 and 3a
24 and 3b
28
7
25 and 3a
82%
81%
66%
63%
59%
65%
70%
75%
8
25 and 3b
9
26 and 3a
10
16
17
18
19
26 and 3b
7
8
9
29
10
Scheme 2 Synthesis of compounds by using N-hydroxysuccinimide
solution was rotary evaporated and the oily residue was extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts were
dried (Na2SO4) and rotary evaporated to afford the corresponding
O-acetyl-a-hydroxy acids as solids or oily products.
1H NMR (CDCl3): d = 0.94 [d, J = 6.9 Hz, 6 H, (CH3)2CHCH2],
1.65–1.84 [m, 3 H, (CH3)2CHCH2], 2.11 (s, 3 H, OCOCH3), 5.04 (d
J = 3.6 Hz, 1 H, CH), 9.21 (br s, 1 H, OH).
O-Acetyl-a-isobutyric Acid (1e)
O-Acetyl-a-glycolic Acid (1a)
Yield: 4.3 g (59%); mp 62–63 °C (Lit.15 60 °C).
Yield: 5.8 g (98%); mp 68–69 °C (Lit.12 mp 61–63 °C).
1H NMR (CDCl3): d = 1.58 (s, 6 H, 2 × CH3), 2.06 (s, 3 H,
OCOCH3).
1H NMR (CDCl3): d = 2.16 (s, 3 H, OCOCH3), 4.65 (s, 2 H, CH2),
8.91 (br s, 1 H, OH).
O-Acetyl-Substituted Butenoates (7–14) and 2-Amino-3-cyano-
5-substituted-4-furanones (4-6) Using N-Hydroxybenzotriazole
(Method A); General Procedure
O-Acetyl-(S)-a-mandelic Acid (1b)
Yield: 9.6 g (99%); mp79–80 °C (Lit.13 79–80 °C); [a]D +152.3 (c
1, MeOH) [Lit. +107.8 c 1.25, CHCl3)].
In a typical reaction, the appropriate O-acetyl-a-hydroxy acid 1a–e
(10 mmol) was treated with 1-hydroxybenzotriazole (2a) (10 mmol,
1.35 g) and DCC (10 mmol, 2.05 g) in anhyd THF (40 mL) at 0 °C
for 1 h. The resulting suspension was refrigerated overnight at 3–
5 °C. The precipitated solid (DCCU) was filtered off and discarded,
and the THF filtrate was added to a solution of NaH (60% suspen-
sion in oil) (20 mmol, 0.8 g) and methyl cyanoacetate (3a), ethyl cy-
anoacetate (3b) or malononitrile (3c) (10 mmol) in anhyd THF (80
mL). The resulting mixture was stirred at r.t. for 2.5 h and then con-
centrated in vacuo. The obtained gummy solid was diluted with
H2O (20 mL) and washed with Et2O (5 mL). The aq extract was
acidified with aq HCl (10%) in an ice–H2O bath to afford a white
solid which was filtered off and washed with CH2Cl2 (10 mL). The
aq filtrate was extracted with CH2Cl2 (3 × 15 mL) and the combined
organic extracts were dried (Na2SO4) and concentrated in vacuo to
afford the O-acetyl-substituted butenoates as solids (7, 13, 14) or
1H NMR (CDCl3): d = 2.19 (s, 3 H, OCOCH3), 5.93 (s, 1 H, CH),
7.39–7.50 (m, 5 H, aromatic protons).
O-Acetyl-a-isovaleric Acid (1c)
Yield: 8.1 g (99%); colourless oil; [a]D –24.6 (c 1, MeOH) [Lit.14
–28.2 (c 1.5, CH2Cl2)].
1H NMR (CDCl3): d = 1.01 [d, J = 6.9 Hz, 6 H, (CH3)2CH], 2.12 (s,
3 H, OCOCH3), 2.21–2.31 [m, 1 H, (CH3)2CH], 4.87 (d, J = 3.6 Hz,
1 H, CH), 9.38 (br s, 1 H, OH).
O-Acetyl-a-isocaproic Acid (1d)
Yield: 9.1 g (98%); colourless oil; [a]D –34.1 (c 1, MeOH) [Lit.14
–25.6 (c 6, CH2Cl2)].
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York

PAPER
2-Amino Furanones via Cyclization of Functionalized g-Hydroxy-a,b-butenoates
2019
oily products (8–12, 15) and the 2-amino-3-cyano-5-substituted-4-
furanones 4–6 as orange solids. The obtained solids were filtered
off, washed with Et2O and dried under vacuum.
13C NMR (DMSO-d6): d = 66.3 (C-5), 86.3 (C-3), 113.7 (CN),
126.9 (aromatic C),129.0 (aromatic C), 129.3 (aromatic C), 134.1
(aromatic C), 178.3 (C-2), 191.2 (C-4).
Anal. Calcd for C11H8N2O2 (200): C, 66.00; H, 4.00; N, 14.00.
Found: C, 66.13; H, 4.19; N, 13.91.
N-Hydroxysuccimide Esters of O-Acteyl a-Hydroxy Acids 24–
27
In a typical reaction, O-acetyl-a-glycolic acid (1a), O-acetyl-S-a-
mandelic acid (1b), O-acetyl-L-a-isovaleric acid (1c) and O-acetyl-
a-isobutyric acid (1e) (10 mmol) was treated with N-hydroxysuc-
cinimide (2b) (10 mmol, 1.35 g) and DCC (10 mmol, 2.05 g) in an-
hyd THF (40 mL) at 0 °C for 1 h. The resulting suspension was
refrigerated overnight at 3–5 °C. The precipitated solid (DCCU)
was filtered off and discarded, the THF filtrate was evaporated un-
der reduced pressure to afford the N-hydroxysuccinimide esters of
the corresponding hydroxy acids 24–27 as white solids, which were
filtered off and dried under vacuum.
2-Amino-3-cyano-5-isobutyl-4-furanone (6) (According to
Method A)
Yield: 1.0g (56%); mp 250–251 °C.
IR (KBr): 3265 (NH2), 2232 (CN), 1659 (C=O) cm–1.
1H NMR (DMSO-d6): d = 0.91 [d, J = 6.6 Hz, 6 H, (CH3)2CHCH2],
1.44–1.63 [m,
2 H, (CH3)2CHCH2], 1.73–1.82 [m, 1 H,
(CH3)2CHCH2], 4.82 (dd, J1 = 3.3, J2 = 9.6 Hz, 1 H, CH), 9.19/9.23
(2 s, 2 H, NH2).
13C NMR (DMSO-d6):
[(CH3)2CHCH2], 24.5 [(CH3)2CHCH2], 66.4 (C-5), 85.1 (C-3),
d = 21.6 [(CH3)2CHCH2], 22.9
O-Acetyl-Substituted Butenoates 7–10, 28 and 29 Using N-Hy-
droxysuccinimide (Method B); General Procedure
113.8 (CN), 177.8 (C-2), 193.4 (C-4).
Anal. Calcd for C9H12N2O2 (180): C, 60.00; H, 6.67; N, 15.56.
Found: C, 59.82; H, 6.85; N, 15.77.
The esters 24–27 were added to a slurry mixture of NaH (60% sus-
pension in oil) (20 mmol, 0.8 g) and methyl cyanoacetate (3a) (10
mmol) and ethyl cyanoacetate (3b) (10 mmol) in anhyd THF (80
mL). The resulting mixture was stirred at r.t. for 2.5 h and then con-
centrated in vacuo. The obtained gummy solid was diluted with
H2O (20 mL) and washed with Et2O (5 mL). The aq extract was
acidified with aq HCl (10%) in an ice–H2O bath to afford an oily
mixture, which was extracted with CH2Cl2 (3 × 15 mL) and the
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo to afford either the O-acetyl-substituted butenoates 7–10, 28
and 29 as yellow oils or white solids which were filtered off, washed
with Et2O and dried under vacuum.
Methyl-4-acetoxy-2-cyano-3-hydroxy-4-phenyl-2-butenoate (7)
(According to Method A)
Yield: 2.25 g (82%); mp 90–91 °C.
IR (KBr): 2227 (CN), 1757 (C=O), 1666 (C=O), 1588 (C=C) cm–1.
1H NMR (CDCl3): d = 2.22 (s, 3 H, OCOCH3), 3.87 (s, 3 H,
CO2CH3), 6.34 (s, 1 H, CH), 7.42–7.58 (m, 5 H, aromatic H), 13.82
(br s, 1 H, OH).
13C NMR (CDCl3): d = 20.3 (OCOCH3), 53.3 (CO2CH3), 74.2 (C-
4), 79.8 (C-2), 113.4 (CN), 127.8 (aromatic C), 129.1, (aromatic C),
130.0, (aromatic C), 133.4 (aromatic C), 170.1 (CO2CH3), 170.7
(OCOCH3), 185.6 (C-3).
Cyclization Reaction of the O-Acetyl Butenoates to the Corre-
sponding 2-Amino-3,5-substituted-4-furanones (Method C);
General Procedure
Anal. Calcd for C14H13NO5 (275): C, 61.09; H, 4.73; N, 5.09.
Found: C, 60.91; H, 4.99; N, 5.00.
The butenoates 7–14, 28 and 29 (5 mmol) were dissolved in MeOH
(10 mL) and treated with aq HCl (10%; 15 mL) for 24 h (com-
pounds 7–12, 28 and 29) or 48 h (compounds 13 and 14) at r.t. to
afford the corresponding 2-amino-3,5-substituted-4-furanones 16–
19, 30 and 31 as white solids. In cases where no solid was precipi-
tated, the MeOH was evaporated and the aq layer was extracted
EtOAc (3 × 15 mL). The organic extracts were dried (Na2SO4) and
rotary evaporated to afford the corresponding 2-amino-3,5-substi-
tuted-4-furanones 20–23 as white solids. In both cases, solids were
filtered off, washed with light petroleum (bp 40–60ºC) and dried
under vacuum.
Ethyl-4-acetoxy-2-cyano-3-hydroxy-4-phenyl-2-butenoate (8)
(According to Method A)
Yield: 2.22 g (77%); yellow oil.
IR (oil): 2228 (CN), 1749 (C=O), 1665 (C=O), 1595 (C=C) cm–1.
1H NMR (CDCl3): d = 1.34 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 2.22
(s, 3 H, OCOCH3), 4.32 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 6.34 (s,
1 H, CH), 7.41–7.60 (m, 5 H, aromatic H).
13C NMR (CDCl3): d = 13.8 (CO2CH2CH3), 20.4 (OCOCH3), 63.0
(CO2CH2CH3), 74.3 (C-4), 80.0 (C-2), 113.5 (CN), 127.8 (aromatic
C), 129.0 (aromatic C), 130.1 (aromatic C), 133.6 (aromatic C),
170.2 (CO2CH2CH3), 170.4 (OCOCH3), 185.6 (C-3).
Analytical and spectroscopical data of compounds 1–31.
2-Amino-3-cyano-4-furanone (4) (According to Method A)
Yield: 1.0 g (81%); mp 260–261 °C.
IR (KBr): 3263 (NH2), 2224 (CN), 1660 (C=O) cm–1.
1H NMR (DMSO-d6): d = 1.60 (s, 2 H, CH2), 8.32 (s, 2 H, NH2).
13C NMR (DMSO-d6): d = 67.4 (C-5), 75.1 (C-3), 113.8 (CN),
179.3 (C-2), 191.8 (C-4).
Methyl-4-acetoxy-2-cyano-3-hydroxy-5-isopropyl-2-butenoate
(9) (According to Method A)
Yield: 1.50 g (62%); yellow oil.
IR (oil): 2227 (CN), 1750 (C=O), 1651 (C=O), 1593 (C=C) cm–1.
1H NMR (CDCl3): d = 1.04 [d, J = 6.9 Hz, 6 H, (CH3)2CH], 2.16 (s,
3 H, OCOCH3), 2.23–2.29 [m, 1 H, (CH3)2CH], 3.90 (s, 3 H,
CO2CH3), 5.11 (d, J = 6.3 Hz, 1 H, CH), 13.45 (br s, 1 H, OH).
Anal. Calcd for C5H4N2O2 (124): C, 48.39; H, 3.23; N, 22.58.
Found: C, 48.11; H, 3.41; N, 22.66.
13C NMR (CDCl3): d = 17.5 [(CH3)2CH], 18.4 [(CH3)2CH], 20.2
(OCOCH3), 31.0 [(CH3)2CH], 53.3 (CO2CH3), 77.1 (C-4), 80.7 (C-
2), 113.4 (CN), 170.5 (CO2CH3), 170.7 (OCOCH3), 186.9 (C-3).
2-Amino-3-cyano-5-phenyl-4-furanone (5) (According to Meth-
od A)
Yield: 1.3 g (64%); mp 270–271 °C.
IR (KBr): 3252 (NH2), 2238 (CN), 1660 (C=O) cm–1.
1H NMR (DMSO-d6): d = 5.74 (s, 1 H, CH), 7.19–7.32 (m, 5 H, ar-
omatic H), 9.36 (s, 2 H, NH2).
Ethyl-4-acetoxy-2-cyano-3-hydroxy-5-isopropyl-2-butenoate
(10) (According to Method A)
Yield: 1.5 g (59%); yellow oil.
IR (oil): 2227 (CN), 1751 (C=O), 1660 (C=O), 1594 (C=C) cm–1.
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York

2020
G. Athanasellis et al.
PAPER
4-Acetoxy-2-cyano-4,4-dimethyl-3-hydroxy-2-butenonitrile
(15) (According to Method A)
Yield: 1.40 g (72%); brown oil.
1H NMR (CDCl3): d = 1.04 [d, J = 6.6 Hz, 6 H, (CH3)2CH], 1.36 (t,
J = 7.2 Hz, 3 H, CO2CH2CH3), 2.16 (s, 3 H, OCOCH3), 2.23–2.30
[m, 1 H, (CH3)2CH], 4.34 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 5.11
(d, J = 6.6 Hz, 1 H, CH).
13C NMR (CDCl3): d = 13.8 (CO2CH2CH3), 17.5 [(CH3)2CH], 18.4
[(CH3)2CH], 20.2 (OCOCH3), 31.0 [(CH3)2CH], 62.9
(CO2CH2CH3), 77.1 (C-4), 80.9 (C-2), 113.5 (CN), 170.4
(CO2CH3), 170.5 (OCOCH3), 186.8 (C-3).
IR (MeOH): 3350 (OH), 2207 (CN), 2178 (CN), 1745 (C=O), 1667
(C=O), 1578 (C=C) cm–1.
1H NMR (CDCl3): d = 1.66 (s, 6 H, 2 × CH3), 2.16 (s, 3 H,
OCOCH3).
13C NMR (CDCl3): d = 20.8 (OCOCH3), 25.0 (CH3), 80.6 (C-4),
108.2 (C-2), 113.0 (CN), 114.3 (CN), 170.5 (OCOCH3), 192.1 (C-
3).
Methyl-4-acetoxy-2-cyano-3-hydroxy-5-isobutyl-2-butenoate
(11) (According to Method A)
Yield: 2.0 g (78%); yellow oil.
IR (oil): 2227 (CN), 1749 (C=O), 1662 (C=O), 1594 (C=C) cm–1.
2-Amino-3-methoxycarbonyl-5-phenyl-4-furanone (16) (Ac-
cording to Method C)
Yield: 0.7 g (59%); mp 241–242 °C.
IR (KBr): 3283 (NH2), 1692 (C=O), 1658 (C=O), 1630 (C=C) cm–1.
1H NMR (DMSO-d6): d = 3.64 (s, 3 H, CO2CH3), 5.64 (s, 1 H, CH),
7.25–7.43 (m, 5 H, aromatic H), 8.40/9.37 (2 s, 2 H, NH2).
13C NMR (DMSO-d6): d = 50.2 (CO2CH3), 84.1 (C-5), 85.2 (C-3),
126.7 (aromatic C), 128.8 (aromatic C), 128.9 (aromatic C), 135.0
(aromatic C), 164.0 (CO2CH3), 179.5 (C-2), 188.9 (C-4).
1H NMR (CDCl3): d = 0.98 [d, J = 6.6 Hz, 6 H, (CH3)2CHCH2],
1.55–1.63 [m,
1 H, (CH3)2CHCH2], 1.75–1.95 [m, 2 H,
(CH3)2CHCH2], 2.15 (s, 3 H, OCOCH3), 3.89 (s, 3 H, CO2CH3),
5.37 (dd, J1 = 9.3, J2 = 3.9 Hz, 1 H, CH).
13C NMR (CDCl3): d = 20.2 (OCOCH3), 21.2 [(CH3)2CHCH2], 22.9
[(CH3)2CHCH2], 24.5 [(CH3)2CHCH2], 40.6 [(CH3)2CHCH2], 53.2
(CO2CH3), 71.3 (C-4), 79.4 (C-2), 113.1 (CN), 170.4 (CO2CH3),
170.7 (OCOCH3), 187.9 (C-3).
Anal. Calcd for C12H11NO4: C, 61.80; H, 4.72; N, 6.01. Found: C,
61.63; H, 4.89; N, 5.92.
Ethyl-4-acetoxy-2-cyano-3-hydroxy-5-isobutyl-2-butenoate
(12) (According to Method A)
Yield: 1.7 g (63%); yellow oil.
IR (oil): 2227 (CN), 1750 (C=O), 1661 (C=O), 1597 (C=C) cm–1.
1H NMR (CDCl3): d = 0.98 [d, J = 6.6 Hz, 6 H, (CH3)2CHCH2],
1.36 (t, J = 7.5 Hz, 3 H, CO2CH2CH3), 1.55–1.64 [m, 1 H,
(CH3)2CHCH2], 1.76–1.95 [m, 2 H, (CH3)2CHCH2], 2.15 (s, 3 H,
OCOCH3), 4.35 (q, J = 7.5 Hz, 2 H, CO2CH2CH3), 5.37 (dd,
J1 = 9.3, J2 = 3.9 Hz, 1 H, CH), 13.62 (br s, 1 H, OH).
2-Amino-3-ethoxycarbonyl-5-phenyl-4-furanone (17) (Accord-
ing to Method C)
Yield: 0.8 g (65%); mp 211–212 °C.
IR (KBr): 3285 (NH2), 1690 (C=O), 1657 (C=O), 1628 (C=C) cm–1.
1H NMR (DMSO-d6): d = 1.20 (t, J = 6.9 Hz, 3 H, CO2CH2CH3),
4.14 (q, J = 6.9 Hz, 2 H, CO2CH2CH3), 5.62 (s, 1 H, CH), 7.26–7.41
(m, 5 H, aromatic H), 8.34/9.35 (2 s, 2 H, NH2).
13C NMR (CDCl3): d = 13.9 (CO2CH2CH3), 20.3 (OCOCH3), 21.3
[(CH3)2CHCH2], 22.9 [(CH3)2CHCH2], 24.5 [(CH3)2CHCH2], 40.6
[(CH3)2CHCH2], 62.9 (CO2CH2CH3), 71.3 (C-4), 79.6 (C-2), 113.2
(CN), 170.4 (CO2CH2CH3), 170.5 (OCOCH3), 187.9 (C-3).
13C NMR (DMSO-d6): d = 14.4 (CO2CH2CH3), 58.6 (CO2CH2CH3),
85.0 (C-5), 85.9 (C-3), 126.4 (aromatic C), 127.7 (aromatic C),
128.1 (aromatic C), 128.6 (aromatic C), 128.7 (aromatic C), 134.8
(aromatic C), 163.5 (CO2CH2CH3), 179.3 (C-2), 188.5 (C-4).
Anal. Calcd for C13H13NO4 (247): C, 63.16; H, 5.26; N, 5.67.
Found: C, 62.89; H, 5.01; N, 5.62.
Methyl-4-acetoxy-2-cyano-4,4-dimethyl-3-hydroxy-2-but-
enoate (13) (According to Method A)
Yield: 1.7 g (75%); mp 97–98 °C.
IR (KBr): 2225 (CN), 1744 (C=O), 1662 (C=O), 1582 (C=C) cm–1.
2-Amino-5-isopropyl-3-methoxycarbonyl-4-furanone (18) (Ac-
cording to Method C)
1H NMR (CDCl3): d = 1.66 (s, 6 H, 2 × CH3), 2.15 (s, 3 H,
OCOCH3), 3.89 (s, 3 H, CO2CH3).
Yield: 0.7 g (70%); mp 193–194 °C.
IR (KBr): 3291 (NH2), 1705 (C=O), 1663 (C=O), 1628 (C=C) cm–1.
13C NMR (CDCl3): d = 20.6 (OCOCH3), 24.7 (CH3), 53.3
(CO2CH3), 76.9 (C-4), 79.1 (C-2), 113.8 (CN), 170.2 (CO2CH3),
171.9 (OCOCH3), 192.6 (C-3).
1H NMR (CDCl3): d = 0.87/1.10 [2 d, J = 6.9 Hz, 6 H, (CH3)2CH],
2.27–2.37 [m, 1 H, (CH3)2CH], 3.84 (s, 3 H, CO2CH3), 4.47 (d,
J = 3.3 Hz, 1 H, CH), 6.18/7.93 (2 s, 2 H, NH2).
13C NMR (CDCl3): d = 14.8 [(CH3)2CH], 18.7 [(CH3)2CH], 30.0
[(CH3)2CH], 51.3 (CO2CH3), 87.8 (C-5), 91.0 (C-3), 165.6
(CO2CH3), 180.6 (C-2), 191.3 (C-4).
Anal. Calcd for C10H13NO5 (227): C, 52.86; H, 5.73; N, 6.17.
Found: C, 52.91; H, 5.94; N, 6.00.
Ethyl-4-acetoxy-2-cyano-4,4-dimethyl-3-hydroxy-2-butenoate
(14) (According to Method A)
Yield: 1.20 g (50%); mp 87–88 °C.
Anal. Calcd for C9H13NO4 (199): C, 54.27; H, 6.53; N, 7.04. Found:
C, 53.99; H, 6.77; N, 6.98.
IR (KBr): 2226 (CN), 1747 (C=O), 1668 (C=O), 1590 (C=C) cm–1.
2-Amino-3-ethoxycarbonyl-5-isopropyl-4-furanone (19) (Ac-
cording to Method C)
Yield: 0.8 g (75%); mp 168–169 °C.
IR (KBr): 3293 (NH2), 1690 (C=O), 1660 (C=O), 1625 (C=C) cm–1.
1H NMR (CDCl3): d = 1.37 (t, J = 7.5 Hz, 3 H, CO2CH2CH3), 1.67
(s, 6 H, 2 × CH3), 2.16 (s, 3 H, OCOCH3), 4.34 (q, J = 7.5 Hz, 2 H,
CO2CH2CH3).
13C NMR (CDCl3): d = 20.6 (OCOCH3), 24.7 (CH3), 53.3
(CO2CH3), 76.9 (C-4), 79.1 (C-2), 113.8 (CN), 170.2 (CO2CH3),
171.9 (OCOCH3), 192.6 (C-3).
1H NMR (DMSO-d6): d = 0.76/1.01 [2 d, J = 6.9 Hz, 6 H,
(CH3)2CH], 1.20 (t, J = 7.5 Hz, 3 H, CO2CH2CH3), 2.08–2.12 [m, 1
H, (CH3)2CH], 4.08–4.16 (m, 2 H, CO2CH2CH3), 4.47 (d, J = 3.3
Hz, 1 H, CH), 8.14/9.15 (2 s, 2 H, NH2).
Anal. Calcd for C11H15NO5 (241): C, 54.77; H, 6.22; N, 5.81.
Found: C, 54.91; H, 5.99; N, 5.99.
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York

PAPER
2-Amino Furanones via Cyclization of Functionalized g-Hydroxy-a,b-butenoates
2021
13C NMR (DMSO-d6): d = 14.4 [(CH3)2CH], 15.0 [(CH3)2CH], 18.4
(CO2CH2CH3), 29.4 [(CH3)2CH], 58.6 (CO2CH2CH3), 85.9 (C-5),
88.6 (C-3), 163.7 (CO2CH2CH3), 179.5 (C-2), 190.2 (C-4).
N-Hydroxysuccinimide Ester of O-Acetyl Glycolic Acid (24)
Yield: 2.10 g (98%); mp 88–90 °C.
IR (KBr): 1786 (C=O), 1731 (C=O), 1650 (C=O) cm–1.
Anal. Calcd for C10H15NO4: C, 56.34; H, 7.04; N, 6.57. Found: C,
56.21; H, 7.21; N, 6.77.
1H NMR (CDCl3): d = 2.18 (s, 3 H, OCOCH3), 2.85 (s, 4 H,
2 × CH2), 4.95 (s, 2 H, CH2).
Anal. Calcd for C8H9NO6 (215): C, 44.65; H, 4.19; N, 6.51. Found:
C, 44.48; H, 4.09; N, 6.73.
2-Amino-5-isobutyl-3-methoxycarbonyl-4-furanone (20) (Ac-
cording to Method C)
Yield: 0.62g (58%); mp 224–225 °C.
IR (KBr): 3268 (NH2), 1692 (C=O), 1658 (C=O), 1630 (C=C) cm–1.
1H NMR (DMSO-d6): d = 0.91 [d, J = 6.6 Hz, 6 H, (CH3)2CHCH2],
1.36–1.46/1.55–1.63 [m, 2 H, (CH3)2CHCH2], 1.73–1.83 [m, 1 H,
(CH3)2CHCH2], 3.62 (s, 3 H, CO2CH3), 4.62 (dd, J1 = 3.3, J2 = 9.9
Hz, 1 H, CH), 8.18/9.14 (2 s, 2 H, NH2).
N-Hydroxysuccinimide Ester of O-Acetyl-S-mandelic Acid (25)
Yield: 2.80 g (96%); mp 112–113 °C; [a]D (c 1, MeOH) +40.2.
IR (KBr): 1791 (C=O), 1738 (C=O), 1647 (C=O) cm–1.
1H NMR (CDCl3): d = 2.20 (s, 3 H, OCOCH3), 2.80 (s, 4 H,
2 × CH2), 6.33 (s, 1 H, CH), 7.43–7.56 (m, 5 H, aromatic H).
13C NMR (DMSO-d6):
[(CH3)2CHCH2], 24.6 [(CH3)2CHCH2], 50.1 (CO2CH3), 84.0 (C-5),
84.6 (C-3), 164.1 (CO2CH3), 179.0 (C-2), 191.2 (C-4).
d = 21.7 [(CH3)2CHCH2], 23.0
Anal. Calcd for C14H13NO6 (291): C, 57.73; H, 4.47; N, 4.81.
Found: C, 57.58; H, 4.29; N, 4.73.
N-Hydroxysuccinimide Ester of O-Acetyl-L-a-isovaleric Acid
(26)
Yield: 2.50 g (97%); mp 170–172 °C; [a]D (c 1, MeOH) –36.0.
Anal. Calcd for C10H15NO4 (213): C, 56.34; H, 7.04; N, 6.57.
Found: C, 56.21; H, 6.91; N, 6.68.
IR (KBr): 1790 (C=O), 1740 (C=O), 1639 (C=O) cm–1.
2-Amino-3-ethoxycarbonyl-5-isobutyl-4-furanone (21) (Ac-
cording to Method C)
Yield: 0.70g (62%); mp 198–199 °C.
IR (KBr): 3281 (NH2), 1689 (C=O), 1659 (C=O), 1622 (C=C) cm–1.
1H NMR (CDCl3): d = 1.72 [s, 6 H, (CH3)2CH], 2.11 (s, 3 H,
OCOCH3), 2.21–2.25 [m, 1 H, (CH3)2CH], 2.82 (s, 4 H, 2 × CH2),
6.21 (d, J = 3.6 Hz, 1 H, CH).
1H NMR (DMSO-d6): d = 0.92 [d, J = 6.3 Hz, 6 H, (CH3)2CHCH2],
1.20 (t, J = 7.5 Hz, 3 H, CO2CH2CH3), 1.36–1.46/1.54–1.63 [m, 2
H, (CH3)2CHCH2], 1.73–1.83 [m, 1 H, (CH3)2CHCH2], 4.12 (q,
J = 7.5 Hz, 2 H, CO2CH2CH3), 4.61 (dd, J1 = 3.3, J2 = 9.6 Hz, 1 H,
CH), 8.14/9.13 (2 s, 2 H, NH2).
Anal. Calcd for C11H15NO6 (257): C, 51.36; H, 5.84; N, 5.45.
Found: C, 51.08; H, 5.99; N, 5.43.
N-Hydroxysuccinimide Ester of O-Acetylisobutyric Acid (27)
Yield: 2.40 g (99%); mp 90–92 °C.
IR (KBr): 1788 (C=O), 1742 (C=O), 1642 (C=O) cm–1.
1H NMR (CDCl3): d = 1.72 (s, 6 H, 2 × CH3), 2.11 (s, 3 H,
OCOCH3), 2.82 (s, 4 H, 2 × CH2).
13C NMR (DMSO-d6):
d
=
14.5 (CO2CH2CH3), 21.7
[(CH3)2CHCH2], 23.0 [(CH3)2CHCH2], 24.6 [(CH3)2CHCH2], 58.6
(CO2CH2CH3), 83.9 (C-5), 84.7 (C-3), 163.9 (CO2CH2CH3), 179.1
(C-2), 191.1 (C-4).
Anal. Calcd for C10H13NO6 (243): C, 49.38; H, 5.35; N, 5.76.
Found: C, 49.18; H, 5.39; N, 5.73.
Anal. Calcd. for C11H17NO4: C, 58.15; H, 7.49; N, 6.17. Found: C,
58.29; H, 7.40; N, 6.02.
Methyl-4-acetoxy-2-cyano-3-hydroxy-2-butenoate (28) (Ac-
cording to Method B)
Yield: 1.8 g (90%); mp 61–62 C.
IR (KBr): 2226 (CN), 1751 (C=O), 1662 (C=O), 1606 (C=C) cm–1.
1H NMR (CDCl3): d = 2.18 (s, 3 H, OCOCH3), 3.92 (s, 3 H,
CO2CH3), 4.96 (s, 2 H, CH2), 13.72 (br s, 1 H, OH).
13C NMR (CDCl3): d = 19.9 (OCOCH3), 53.2 (CO2CH3), 61.4 (C-
4), 81.1 (C-2), 112.6 (CN), 169.8 (CO2CH3), 170.5 (OCOCH3),
183.7 (C-3).
2-Amino-5,5-dimethyl-3-methoxycarbonyl-4-furanone (22)
(According to Method C)
Yield: 0.80 g (86%); mp 248–249 °C.
IR (KBr): 3286 (NH2), 1705 (C=O), 1658 (C=O), 1631 (C=C) cm–1.
1H NMR (DMSO-d6): d = 1.28 (s, 6 H, 2 × CH3), 3.62 (s, 3 H,
CO2CH3), 8.18/9.07 (2 s, 2 H, NH2).
13C NMR (DMSO-d6): d = 23.1 (CH3), 50.1 (CO2CH3), 82.7 (C-5),
88.2 (C-3), 164.4 (CO2CH3), 177.4 (C-2), 193.1 (C-4).
Anal. Calcd for C8H11NO4 (185): C, 51.89; H, 5.95; N, 7.57. Found:
C, 52.10; H, 6.09; N, 7.41.
Anal. Calcd for C8H9NO5 (199): C, 48.24; H, 4.52; N, 7.04. Found:
C, 48.01; H, 4.33; N, 7.29.
2-Amino-5,5-dimethyl-3-ethoxycarbonyl-4-furanone (23) (Ac-
cording to Method C)
Yield: 0.60 g (60%); mp 205–206 °C.
Ethyl-4-acetoxy-2-cyano-3-hydroxy-2-butenoate (29) (Accord-
ing to Method B)
Yield 1.66 g (78%); mp 48–49 C.
IR (KBr) 3280 (NH2), 1698 (C=O), 1661 (C=O), 1632 (C=C) cm–1.
IR (KBr): 2225 (CN), 1752 (C=O), 1660 (C=O), 1609 (C=C) cm–1.
1H NMR (CDCl3): d = 1.36 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.44
(s, 6 H, 2 × CH3), 4.30 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 5.99/7.95
(2 s, 2 H, NH2).
1H NMR (CDCl3): d = 1.38 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 2.19
(s, 3 H, OCOCH3), 4.37 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 4.96 (s,
2 H, CH2), 13.86 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.3 (CO2CH2CH3), 23.1 (CH3), 60.2
(CO2CH2CH3), 84.9 (C-5), 90.8 (C-3), 166.7 (CO2CH2CH3), 178.6
(C-2), 194.3 (C-4).
13C NMR (CDCl3): d = 13.8 (CO2CH2CH3), 19.9 (OCOCH3), 61.4
(C-4), 63.1 (CO2CH2CH3), 81.4 (C-2), 112.7 (CN), 169.8
(CO2CH2CH3), 170.2 (OCOCH3), 183.6 (C-3).
Anal. Calcd for C9H13NO4: C, 54.27; H, 6.53; N, 7.04. Found: C,
54.18; H, 6.69; N, 6.93.
Anal. Calcd for C9H11NO5: C, 50.70; H, 5.16; N, 6.57. Found: C,
50.92; H, 5.18; N, 6.70.
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York

2022
G. Athanasellis et al.
PAPER
2-Amino-3-methoxycarbonyl-4-furanone (30) (According to
Method C)
Yield: 0.6 g (76%); mp 270 °C.
IR (KBr): 3285 (NH2), 1698 (C=O), 1657 (C=O), 1635 (C=C) cm–1.
1H NMR (DMSO-d6): d = 3.63 (s, 3 H, CO2CH3), 4.53 (s, 2 H, CH2),
8.19/9.17 (2 s, 2 H, NH2).
References
(1) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 2002, 67, 4380.
(2) Quibell, M. PCT Int. Appl. WO 2002-GB 190 20020117
135, 2002.
(3) Buhler, H.; Bayer, A.; Effenberger, F. Chem.–Eur. J. 2000,
6, 2564.
(4) Blank, I.; Lin, J.; Fumeaux, R.; Welti, D. H.; Fay, L. B. J.
Agric. Food Chem. 1996, 44, 1851.
(5) Petroliagi, M.; Igglessi-Markopoulou, O. J. Heterocycl.
Chem. 2001, 38, 917.
(6) Samartzi, E.; Gola, A.; Bardakos, V.; Markopoulos, J.;
Petroliagi, M.; Igglessi-Markopoulou, O. J. Heterocycl.
Chem. 2000, 37, 681.
13C NMR (DMSO-d6): d = 49.5 (CO2CH3), 73.7 (C-5), 85.1 (C-3),
163.5 (CO2CH3), 180.3 (C-2), 188.5 (C-4).
Anal. Calcd for C6H7NO4 (157): C, 45.86; H, 4.46; N, 8.92. Found:
C, 45.99; H, 4.41; N, 8.79.
2-Amino-3-ethoxycarbonyl-4-furanone (31) (According to
Method C)
Yield: 0.70 g (82%); mp 245–246 °C.
IR (KBr): 3282 (NH2), 1699 (C=O), 1657 (C=O), 1626 (C=C) cm–1.
(7) Athanasellis, G.; Gavrielatos, E.; Igglessi-Markopoulou, O.
Synlett 2001, 1653.
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Bull. Chem. Soc. Jpn. 2002, 12, 2691.
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B. Tetrahedron: Asymmetry 1999, 10, 3701.
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Trans. 1 1979, 2976.
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Commun. 1996, 1323.
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Heterocycl. Chem. 2002, 39, 1201.
1H NMR (DMSO-d6): d = 1.20 (t, J = 7.5 Hz, 3 H, CO2CH2CH3),
4.13 (q, J = 7.5 Hz, 2 H, CO2CH2CH3), 4.51 (s, 2 H, CH2), 8.13/9.14
(2 s, 2 H, NH2).
13C NMR (DMSO-d6): d = 13.8 (CO2CH2CH3), 58.1 (CO2CH2CH3),
73.7 (C-5), 85.2 (C-3), 163.3 (CO2CH3), 180.4 (C-2), 188.4 (C-4).
Anal. Calcd for C7H9NO4 (171): C, 49.12; H, 5.26; N, 8.19. Found:
C, 49.38; H, 5.34; N, 8.22.
Acknowledgments
We acknowledge financial support from the National Technical
University of Athens. We also thank Ms. V. Skouridou (National
Technical University of Athens, Biotechnology Laboratory) for re-
cording the IR spectra.
Synthesis 2003, No. 13, 2015–2022 © Thieme Stuttgart · New York