An efficient synthesis of novel N-acetyl-3-alkanoyl and 3-dienoyl tetramic acids

Article abstract of DOI:10.1039/a702649h

A general synthesis of N-acetyl-3-alkanoyl- and 3-dienoyl-tetramic acids is presented. The condensation of N-(N-acetylglycyloxy)succinimide with β-keto esters bearing alkanoyl or dienoyl groups furnishes the new 3-substituted N-acetyltetramic acids 6-9 and 16 in good yields. The key intermediates 4 and 5 have been isolated and subsequently cyclized to the corresponding tetramic acids. Spectral data for and the physical characteristics of all compounds are reported.

Full text of DOI:10.1039/a702649h

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An efficient synthesis of novel N-acetyl-3-alkanoyl and 3-dienoyl
tetramic acids
Margarita Petroliagi and Olga Igglessi-Markopoulou*
Laboratory of Organic Chemistry, Department of Chemical Engineering,
National Technical University of Athens, Zografou Campus, 157 73 Athens, Greece
A general synthesis of N-acetyl-3-alkanoyl- and 3-dienoyl-tetramic acids is presented. The condensation
of N-(N-acetylglycyloxy)succinimide with â-keto esters bearing alkanoyl or dienoyl groups furnishes the
new 3-substituted N-acetyltetramic acids 6–9 and 16 in good yields. The key intermediates 4 and 5 have
been isolated and subsequently cyclized to the corresponding tetramic acids. Spectral data for and the
physical characteristics of all compounds are reported.
3-Alkanoyl- and 3-dienoyl-tetramic acids, the pyrrolidine-2,4-
diones bearing a 3-acyl substituent, constitute a growing class
of microbial natural products and exhibit a range of biological
activity.1 Such activity arises from the presence of the
β-dicarbonyl compounds for the synthesis of nitrogen hetero-
cycles12 we have developed a new synthetic sequence for the
construction of N-acetyl-3-alkanoyl- and 3-dienoyl-tetramic
acids. The proposed methodology is centred on the conden-
sation of the N-(N-acetylglycyloxy)succinimide with an excess
of the anion of an appropriate β-keto ester, generated by the
action of sodium hydride (Scheme 1). This strategy consists of
the following experimental stages: (i) the synthesis of β-keto
esters bearing an α-alkanoyl group, according to an extension
of the method proposed by Oikawa and Sugano,13 and (ii) the
C-acylation of β-keto esters via N-(N-acetylglycyloxy)succin-
imide. The crucial step in this reaction is the preparation of
suitable key intermediates 4 and 5 which cyclize to the desired
tetramic acids.
O
O
O
HO
(
)
n
(
)
n
R
R
4
3
5
2
1
N
O
O
N
pyrrolidine-2,4-dione ring, the C-3 carbonyl substituent and
the C-5 stereogenic centre, together with the ability of the com-
pounds to form complexes with metal ions.2 Tenuazonic acid
Ia,3 magnesidin Ib,4 tirandamycin5 and streptolydigin,6 are
among the most common 3-acyl substituted tetramic acids
which display antibiotic or antiviral activity. Since, recently,
5-arylidene-3-phenyltetramic acids Ic have been designed as
novel glycine-site NMDA receptor antagonists,7 their synthesis
represents a worthwhile and challenging goal.
In a typical C-acylation the β-keto ester 1 (3 equiv.) was
treated with sodium hydride (2 equiv.) in anhydrous benzene
and then the NHSuc ester 2 (1 equiv.). After ca. 3 h the inter-
mediate ethyl 4-acetylamino-2-alkanoyl-3-hydroxybut-2-eno-
ates 4 and 5 were isolated in pure form after recrystallization.
We noted that the corresponding C-acylation intermediate 3
having a short-chain alkanoyl substituent was obtained in
admixture with the corresponding cyclized compound 6. Ring
closure of the intermediates 3–5 to the tetramic acids 10–12
having a 3-alkanoyl substituent was achieved by heating them
in sodium ethoxide in ethanol–benzene. However, we noticed
that an increase in the molar proportion of sodium hydride
in the reaction mixture caused in situ formation of the 3-
substituted N-acetyltetramic acids 6–9. This C-acylation–
cyclization was carried out using 3 equiv. of the β-keto ester 1,
2.5–3 equiv. of sodium hydride in anhydrous benzene, 1 equiv.
of the NHSuc ester 2, and with the reaction mixture being
stirred for 5 h. The N-acetyltetramic acids 6–9 thus formed
through intramolecular condensation were deacetylated to their
corresponding tetramic acids 10–12 in the presence of sodium
ethoxide in ethanol–benzene.
The N-acetyl- and NH-3-alkanoyl-tetramic acids 6–9 and 10–
12 have not been previously prepared apart from the derivative
12, whose antimicrobial activity was reported by Matsuo and
co-workers.14 In the course of our synthetic programme with
nitrogen heterocycles of biological interest we needed the C-
acylation intermediates, ethyl 4-acetylamino-2-alkanoyl-3-
hydroxybut-2-enoates 3–5, containing the enolic β-dicarbonyl
system. It is noteworthy that these compounds have great inter-
est both as precursors for the preparation of chiral β-hydroxy-
γ-aminobutanoic acids and in the asymmetric synthesis of sta-
tine analogues.15
O
HO
H
Ac
– O
(
)
n
Mg2+
O
MeCH
O
N
H
N
EtCH
Me
Ac
2
Ia
Ib
n = 1,2
HO
Ph
ArCH
O
N
H
Ic
The first synthetic approach to 3-acetyltetramic acids was
reported by Lacey8 in a method later extended to the prepar-
ation of 3-substituted tetramic acids.9 An alternative strategy
for the preparation of 3-substituted pyrrolidine-2,4-diones was
described by Jones,10 using pyrones and, more recently,
isoxazole-4-carboxylates as precursors. Finally an important
method designed for the formation of 3-polyenoyl tetramic
acids was described by Ley,11 in which the key step provided a
series of β-keto amides as suitable precursors for synthesis of
the target compounds.
The goal of our methodology was not only the synthesis of 3-
alkanoyltetramic acids, but also their use as precursors in the
synthesis of the magnesidin-related tetramic acids 13 and 14 by
In the course of our research programme on the use of enolic
J. Chem. Soc., Perkin Trans. 1, 1997
3543

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O
α
β
γ
δ
ε
ζ
η
θ
ι
CCH2CH2CH2CH2CH2CH2CH2CH2CH3
OH
CH3CONHCH2C
9
1
2
3
C
4
5
6
7
8
COCH2CH3
O
Table 1 13C NMR chemical shifts for C-acylation of compounds 4 and 5 (CDCl3)
Compd. C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-α
31.47 166.17 46.42 197.22 106.72 170.40 60.98 14.00 196.15 36.42 29.23 28.79 26.29 22.88 22.40
C-β
C-γ
C-δ
C-ε
C-ζ
C-η C-θ
C-ι
4
5
—
—
13.85
31.79 166.06 46.53 197.09 106.72 170.20 61.05 14.14 196.02 36.52 29.38 29.35 29.26 29.19 26.43 23.06 22.59 14.03
phenylpyrrolidine-2,4-diones Ic have been designed as novel
glycine NMDA receptor antagonists in the treatment of neuro-
O
O
O
logical diseases, their biological properties arising from the
(
)
+
R
Cl
n
O
enolic β-dicarbonyl moiety, the hydrophobic 5-substituent and
the lipophilic 3-phenyl substituent.7
O
The IR spectra of the newly prepared 3-substituted N-acetyl-
tetramic acids (see Experimental section) showed CO absorp-
tion at 1740, 1720 and 1650 cmϪ1 for the β-dicarbonyl system
i
R
OH
( )
CO᎐CH᎐CO
C(OH)᎐C᎐CO and carbon–carbon double
᎐
n
O
O
bond absorption at 1600 cmϪ1
.
O
O
ii
Considerable emphasis has been given to the influence of the
N-substituent on the tautomeric equilibrium of tetramic acids
(Scheme 2).12a,16 Structural assignments for the previously
(
)
R
OEt
n
O
O
1
O
O
H
O
H
O
6
C
O
HO
3
2
(
)
O
R
O
C
R
n
R
O
N
4
3
iii
4
+
1
CO2Et
2
5
NH
Ac
O
NH
Ac
1
N
O
O
N
3 n = 3, R = Me
4 n = 5, R = Me
5 n = 7, R = Me
a
b
2
iv
R
R
iii
O
O
C
C
O
O
H
H
O
O
O
O
HO
HO
N
N
(
)
n
(
)
R
R
n
v
c
d
O
O
N
N
H
Scheme 2 Tautomeric forms of 3-substituted tetramic acids
Ac
6 n = 3, R = Me
7 n = 5, R = Me
8 n = 7, R = Me
9 n = 0, R = Ph
10 n = 3, R = Me
11 n = 5, R = Me
12 n = 7, R = Me
unknown N-acetyl-3-alkanoyltetramic acids were confirmed by
1H and 13C NMR spectroscopy (Table 2). Two sets of signals
were observed for certain protons in CDCl3 solution, showing
1
the presence of the ‘external’ tautomers ab and cd. In the H
vi
vi
NMR spectrum the 5-methylene signal was split into two parts
(ab) and (cd), indicating that the dominant form should be the
‘external’ tautomers ab with an intensity ratio of ab/cd = 1.52,
whereas for the NH tetramic acid the dominant form should be
the ‘external’ tautomers cd with a ratio of cd/ab = 3.44. As we
have reported in a previous paper for the N-benzyloxycarbonyl-
3-acetyltetramic acid the major form is the tautomer cd (cd/
ab = 1.4).12b These observations suggested that electron donat-
ing N-substituents increase the possibility for hydrogen bond-
ing on the C-4 carbonyl (ab), whereas electron-withdrawing
substituents enhance the C-2 hydrogen bond (cd).
Of particular importance is the applicability of the proposed
methodology to the construction of 3-dienoyl tetramic acids
(Scheme 3). An investigation of structure–activity relationships
showed that the 3-dienoyl unit of tetramic acids is crucial for
activity.17 As a model experiment, the active methylene com-
pound 15 was synthesized starting from sorbyl chloride and
proceeding via Meldrum’s acid with a modification of the con-
ditions used for the construction of β-keto esters. Preliminary
experiments showed that reaction of 2 with the β-keto ester 15,
O
HO
(
)
n
R
PhCH
O
N
H
13 n = 3, R = Me
14 n = 5, R = Me
Scheme 1 Reagents and conditions: i, pyridine, nitrogen atmosphere,
CH2Cl2; ii, EtOH, reflux; iii, NaH, anhydrous benzene, 5–10 ЊC; iv,
EtONa, EtOH–anhydrous benzene, reflux; v, EtONa, EtOH, reflux; vi,
8% HCl in EtOH, benzaldehyde, reflux
a convenient and straightforward route (Scheme 1). The syn-
thesisemployedforthepreparationof 5-benzylidenepyrrolidine-
2,4-diones 13 and 14 involved the condensation of compounds
6 and 7 and 10 and 11 with benzaldehyde in the presence of
an 8% solution of HCl in ethanol. Recently, 5-arylidene-3-
3544
J. Chem. Soc., Perkin Trans. 1, 1997

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H
O
α
β
γ
δ
ε
ζ
η
θ
ι
6
O
CCH2CH2CH2CH2CH2CH2CH2CH2CH3
4
3
2
5
1
O
N
8
7COCH3
Table 2 13C NMR chemical shifts for the tetramic acids 6–8 and 10–12 (CDCl3)
Compd.
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-α
C-β
C-γ
C-δ
C-ε
C-ζ
C-η
C-θ
C-ι
6
7
ab
cd
ab
cd
ab
cd
ab
cd
ab
cd
ab
cd
170.09 105.38 198.08 49.73 194.10 165.54 35.26 31.30 25.39 24.66 22.26
173.53 102.64 192.68 53.60 188.99 169.32 33.11 25.62 25.05
—
—
—
—
—
—
—
—
—
—
—
—
13.79
—
13.82
—
—
—
170.00 104.80 198.00 49.70 193.90 165.45 35.30 31.50 27.57 25.70 22.99 22.80 21.88
173.50 102.00 192.50 53.62 189.00 169.00 33.15 27.80
—
—
—
—
—
8
170.11 105.38 198.11 49.73 194.12 165.53 35.31 31.79 29.19 25.95 25.04 25.03 22.68 22.59 21.84 14.04
173.54 102.62 192.72 53.61 188.99 169.33
—
—
—
—
—
—
—
33.19 29.30
33.41 31.94 25.12
—
—
—
—
—
—
25.48
—
—
—
—
—
—
—
—
—
25.53
—
—
—
—
—
—
—
—
13.67
—
13.89
—
10
11
12
170.29 105.00 199.25 48.58 193.59
176.73 101.42 192.98 51.86 189.75
170.05 105.00 199.05 48.56 193.79
176.65 101.37 192.91 51.81 189.79
170.16 105.00 198.79 48.48 193.09
176.38 101.15 192.60 51.73 189.24
—
—
—
—
—
—
32.61 31.20 25.47 22.16
33.46
—
—
—
32.69 29.06 28.84 28.80 25.82 22.45
33.56 29.47
—
—
—
—
32.74 31.79 29.39 29.32 29.19 28.93 25.90 22.59 14.03
can be easily converted into deacetylated tetramic acids in good
yields (yield 50–80%); (iv) the proposed strategy is also appli-
cable to the controlled synthesis of 3-dienoyltetramic acids; (v)
the condensation of tetramic acids with benzaldehyde favours
the straightforward formation of 5-benzylidenetetramic acids.
In conclusion, the new synthetic sequence described here
constitutes a method for the construction of interesting
pyrrolidine-2,4-diones bearing a different side chain at position
3. With the aid of this method, the application of our strategy
to natural products synthesis is currently being pursued.
OH
O
O
O
O
O
i
+
Cl
O
O
ii
O
O
OEt
Experimental
15
Melting points were determined on a Gallenkamp MFB-595
melting point apparatus and are uncorrected. The IR spectra
were recorded on a Perkin-Elmer 267 spectrometer. The NMR
spectra were recorded on either Varian EM-360 60 MHz, Var-
ian Gemini-2000 300 MHz or Bruker AC-300 300 MHz spec-
trometers, using Me4Si as internal reference. Chemical shifts are
quoted in ppm (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad); J values are given in Hz. The mass
spectra were recorded on a Varian Saturn 2000 (GC-MS) or
GC/MS HP 5890/5971 instrument using electron impact ioniz-
ation (EI). Elemental analyses were obtained from the Uni-
versity of Liverpool, Chemistry Department, and the micro-
analytical laboratory of CNRS (France). Column chrom-
atography was performed using Merck Kieselgel 60 (70–230
mesh ASTM) silica. Thin layer chromatography (TLC) was car-
ried out using Merck Kieselgel 60 F259 pre-coated silica gel
plates of thickness 0.2 mm. Solvents and reagents were dried or
purified according to the procedure described by Perrin and
Armarego.19
O
O
O
HO
O
N
iii
+
15
NH
Ac
O
CO2Et
NH
Ac
2
O
O
O
HO
HO
iv
O
N
H
N
Ac
17
16
Scheme 3 Reagents and conditions: i, pyridine, nitrogen atmosphere,
absence of light, CH2Cl2; ii, EtOH, reflux; iii, NaH, anhydrous benzene,
room temp.; iv, EtONa, EtOH–anhydrous benzene, room temp.
Preparation of â-keto esters
The requisite β-keto esters 1 and 15 were prepared following the
method of Oikawa and Sugano,13 but with minor modifi-
cations: the mixture of the Meldrum’s acid with the sorbyl
chloride in the presence of pyridine was stirred under nitrogen
atmosphere, in the absence of light, for 1.5 h at 0 ЊC and then
at room temperature for 2.5 h. The ethanolysis of the acyl
Meldrum’s acid was carried out under reflux for 1.5 h. The
pure compound 15 was isolated by column chromatography on
silica gel eluting with 10% ethyl acetate–diethyl ether.
in the presence of NaH (2 equiv.) in anhydrous benzene, resulted
in the rapid formation (2 h) of the N-acetyl-3-dienoyltetramic
acid 16. The crude product was N-deacetylated with sodium
ethoxide in ethanol–benzene to form the corresponding 3-
dienoyltetramic acid 17 (mp 211–213 ЊC, lit.,18 211–212 ЊC).
The proposed methodology has the following merits: (i) the
NHSuc esters of N-acetyl-α-amino acids are useful acylating
agents. The N-hydroxysuccinimide formed as a by-product is
soluble in water and easily removed from the reaction mixture;
(ii) the key intermediates can be isolated under controlled reac-
tion conditions; (iii) the C-acylation–cyclization leads directly
to the newly obtained N-acetyl-3-alkanoyltetramic acids which
N-(N-Acetylglycyloxy)succinimide 2
A mixture of N-acetylglycine (6 g, 0.05 mol), N-hydroxy-
succinimide (5.8 g, 0.05 mol) and THF (160 ml) was stirred at
60 ЊC for 0.5 h, after which it was treated with a solution of
J. Chem. Soc., Perkin Trans. 1, 1997
3545

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N,N-dicyclohexylcarbodiimide (10.3 g, 0.05 mol) in THF (20
ml), added dropwise, the temperature of the reaction mixture
being kept at 60 ЊC. The resulting mixture was stirred at 60 ЊC
for 1 h after which it was refrigerated overnight. The precipi-
tated N,N-dicyclohexylurea was filtered off and the filtrate was
concentrated in vacuo to give a residue. This was treated with
diethyl ether to afford 2 as a white powdered solid (8.4 g,
76.4%), mp 100–103 ЊC (from ethyl acetate–diethyl ether) (lit.,20
mp 98 ЊC); δH(60 MHz; CDCl3; Me4Si) 2.00 (3 H, s, COCH3),
2.74 [4 H, s, CO(CH2)2CO], 4.25 (2 H, d, J 6, CH2CO) and 6.00
(1 H, br, NH).
H, two s, COCH3), 2.68 (2 H, t, J 7, COCH2), 4.27 (2 H, q, J 7,
CH2CH3), 4.48 (2 H, d, J 6, NHCH2), 6.50 (1 H, br, NH) and
17.30 (1 H, br, OH); δC(CDCl3; Me4Si), see Table 1; m/z (EI) 340
([M Ϫ H]ϩ, 25%), 281 ([M Ϫ CH3CONH Ϫ 2H]ϩ, 100), 221
(20), 147 (25) and 73 (74).
N-Acetyl-3-hexanoyltetramic acid 6
The reaction mixture [compound 2 (1.2 g, 5.3 mmol), ethyl hex-
anoylacetate 1 (n = 3, R = Me) (2.9 g, 15.9 mmol) and sodium
hydride (13.3 mmol) in anhydrous benzene (30 ml)] was stirred
at 5–10 ЊC for 5 h after which it was acidified with 10% hydro-
chloric acid to give a solid. This was filtered off and washed
with light petroleum to afford the product 6 (0.7 g, 50.9%), mp
74–79 ЊC (from CHCl3–light petroleum) (Found: C, 56.18; H,
7.29; N, 5.39. C12H17O4NؒH2O requires C, 56.02; H, 7.44; N,
5.44); νmax(Nujol)/cmϪ1 3310m (OH), 1740m and 1720m (CO
diketone, keto form and CONCO), 1640s (CO diketone, enol
General procedure for the reactions of N-(N-acetylglycyloxy)-
succinimide 2 with active methylene compounds
The active methylene compounds 1 and 15 (15.9 mmol) were
added dropwise to a mixture of sodium hydride (55–60%
sodium hydride in oil; 10.6 mmol) in anhydrous benzene (30 ml)
and the thick slurry thus formed was stirred at room temper-
ature for 3 h. Compound 2 (1.2 g, 5.3 mmol) was then added to
the mixture and stirring continued at 5–10 ЊC for 2–5 h. Water
was added to the reaction mixture and the aqueous layer was
separated and acidified with 10% hydrochloric acid, in an ice–
water bath, to give either a solid or an oily product that was
extracted with chloroform.
form) and 1600m (C᎐C); δ (60 MHz; CDCl ; Me Si), 0.70–2.00
᎐
H
3
4
[9 H, m, (CH2)3CH3], 2.60 (3 H, s, COCH3), 3.00 (2 H, t, J 7,
COCH2), 4.10 (cd) and 4.30 (ab) (two s, 2 H, CH2-ring, ab:cd
1.5) and 8.40 (1 H, br, OH); δC(CDCl3; Me4Si), see Table 2; m/z
(EI) 240 ([M ϩ H]ϩ, 100%).
N-Acetyl-3-octanoyltetramic acid 7
The reaction mixture [compound 2 (1.2 g, 5.3 mmol), ethyl
octanoylacetate 1 (n = 5, R = Me) (3.4 g, 15.9 mmol) and
sodium hydride (15.9 mmol) in anhydrous benzene (30 ml)] was
stirred at 5–10 ЊC for 5 h after which it was acidified with 10%
hydrochloric acid to give a solid. This was filtered off and
washed with light petroleum to afford the product 7 (0.8 g,
Ethyl 4-acetylamino-2-octanoyl-3-hydroxybut-2-enoate 4
The reaction mixture [compound 2 (1.2 g, 5.3 mmol), ethyl
octanoylacetate 1 (n = 5, R = Me) (3.3 g, 15.9 mmol) and
sodium hydride (10.6 mmol) in anhydrous benzene (30 ml)] was
stirred at 5–10 ЊC for 4 h after which it was acidified with 10%
hydrochloric acid to give an oily product which was extracted
with chloroform. The organic layer was dried (Na2SO4) and
evaporated in vacuo to give a residue. This was treated with light
petroleum to afford the C-acylation product 4 as a yellowish
solid (0.6 g, 36.3%) after it had been filtered off and washed
with small amounts of light petroleum; mp 67–70 ЊC (from
CHCl3–light petroleum) (Found: C, 61.20; H, 8.60; N, 4.40.
C16H27O5N requires C, 61.32; H, 8.68; N, 4.47); νmax(Nujol)/
cmϪ1 3280m (NH), 1690s (CO ester and CO ketone, keto form
and amide I), 1630s (CO ester and CO ketone, enol form and
52.9%), mp 67–70 ЊC (from CHCl3–light petroleum); νmax
-
(Nujol)/cmϪ1 3300m (OH), 1740m and 1720m (CO diketone,
keto form and CONCO), 1650s (CO diketone, enol form) and
1600m (C᎐C); δ (60 MHz; CDCl ; Me Si) 0.70–2.00 [13 H, m,
᎐
H
3
4
(CH2)5CH3], 2.60 (3 H, s, COCH3), 2.85 (2 H, t, J 7, COCH2),
4.00 (cd) and 4.20 (ab) (two s, 2 H, CH2-ring, ab:cd 1.49) and
11.6 (1 H, br, OH); δC(CDCl3; Me4Si), see Table 2; m/z (EI) 267
([M]ϩ, 3%), 223 ([M Ϫ H Ϫ COCH3]ϩ, 8), 196 ([M Ϫ (CH2)4-
CH3]ϩ, 100), 168 ([M Ϫ (CH2)6CH3]ϩ, 13), 141 ([M ϩ H Ϫ
CO(CH2)6CH3]ϩ, 59), 127 (3), 126 ([M ϩ H Ϫ (CH2)6CH3 Ϫ
COCH3]ϩ, 39) and 99 (11).
C᎐C) and 1550s (amide II); δ (300 MHz; CDCl ; Me Si), 0.85
᎐
H
3
4
[6 H, t, J 7, (CH2)6CH3 and CH2CH3], 1.25–1.35 [8 H, m,
(CH2)4CH3], 1.58–1.66 [2 H, m, CH2(CH2)4], 2.03 and 2.04 (3
H, two s, COCH3), 2.66 (2 H, t, J 7, COCH2), 4.26 (2 H, q, J 7,
CH2CH3), 4.48 (2 H, d, J 6, NHCH2), 6.36 (1 H, br, NH) and
17.29 (1 H, br, OH); δC(CDCl3; Me4Si), see Table 1. Treatment
of 4 with MSTFA–MBTFA reagents yielded the corresponding
derivatives (C21H34NO6F3Si); m/z (EI) 367 ([M Ϫ (CH2)5-
CH3 Ϫ Et]ϩ, 24%), 352 ([M Ϫ H Ϫ (CH2)6CH3 Ϫ Et]ϩ, 100),
310 ([M Ϫ H Ϫ Si(Me)3 Ϫ COCF3]ϩ, 91), 282 ([M ϩ H Ϫ CO-
(CH2)6CH3 Ϫ CO2Et]ϩ, 52), 240 (25), 208 (10) and 73 (38).
N-Acetyl-3-decanoyltetramic acid 8
The reaction mixture [compound 2 (1.2 g, 5.3 mmol), ethyl
decanoylacetate 1 (n = 7, R = Me) (3.8 g, 15.9 mmol) and
sodium hydride (15.9 mmol) in anhydrous benzene (30 ml)] was
stirred at 5–10 ЊC for 5 h after which it was acidified with 10%
hydrochloric acid to give a solid. This was filtered off and
washed with light petroleum to afford the product 8 (0.9 g,
55.4%), mp 57–61 ЊC (from CHCl3–light petroleum) (Found: C,
63.20; H, 8.62; N, 4.85. C16H25O4Nؒ1/2H2O requires C, 63.14;
H, 8.61; N, 4.6); νmax(Nujol)/cmϪ1 3300m (OH), 1730m, 1720m
(CO diketone, keto form and CONCO), 1610s (CO diketone,
Ethyl 4-acetylamino-2-decanoyl-3-hydroxybut-2-enoate 5
The reaction mixture [compound 2 (1.2 g, 5.3 mmol), ethyl
decanoylacetate 1 (n = 7, R = Me) (3.8 g, 15.9 mmol) and
sodium hydride (10.6 mmol) in anhydrous benzene (30 ml)] was
stirred at 5–10 ЊC for 4 h after which it was acidified with 10%
hydrochloric acid to give an oily product which was extracted
with chloroform. The organic layer was dried (Na2SO4) and
evaporated in vacuo to give a residue. This was treated with light
petroleum to afford the C-acylation product 5 as a yellowish
solid (0.7 g, 36.5%) after it had been filtered off and washed
with small amounts of light petroleum; mp 77–80 ЊC (from
CHCl3–light petroleum) (Found: C, 63.50; H, 9.20; N, 4.06.
C18H31O5N requires C, 63.31; H, 9.15; N, 4.10); νmax(Nujol)/
cmϪ1 3280m (NH), 1690s (CO ester and CO ketone, keto form
and amide I), 1630s (CO ester and CO ketone, enol form and
enol form) and 1600m (C᎐C); δ (300 MHz; CDCl ; Me Si) 0.85
᎐
H 3 4
[3 H, t, J 7, (CH2)8CH3], 1.25–1.45 [12 H, m, (CH2)6CH3], 1.67–
1.75 [2 H, m, CH2(CH2)6], 2.57 and 2.59 (3 H, two s, COCH3),
2.89 and 2.94 (2 H, two t, J 7, COCH2), 4.08 (cd) and 4.27 (ab)
(two s, 2 H, CH2-ring, ab:cd 1.52); δC(CDCl3; Me4Si), see Table
2; m/z (EI) 295 ([M]ϩ, 10%), 242 (21), 239 ([M ϩ H Ϫ
(CH2)3CH3]ϩ, 17), 238 ([M Ϫ (CH2)3CH3]ϩ, 100).
N-Acetyl-3-phenylacetyltetramic acid 9
The reaction mixture [compound 2 (1.2 g, 5.3 mmol), ethyl
phenylacetylacetate 1 (n = 0, R = Ph) (3.4 g, 15.9 mmol) and
sodium hydride (13.25 mmol) in anhydrous benzene (30 ml)]
was stirred at 5–10 ЊC for 5 h after which it was acidified with
10% aq. hydrochloric acid to give a brownish solid. This was
filtered off and washed with light petroleum to afford the prod-
uct 9 (0.7 g, 53.9%); mp 73–75 ЊC (from PhH–light petroleum)
(Found: C, 64.75; H, 5.07; N, 5.37. C14H13O4N requires C,
C᎐C) and 1550s (amide II); δ (300 MHz; CDCl ; Me Si), 0.86
᎐
H
3
4
[6 H, t, J 7, (CH2)8CH3 and CH2CH3], 1.25–1.37 [12 H, m,
(CH2)6CH3], 1.61–1.63 [2 H, m, CH2(CH2)6], 2.03 and 2.04 (3
3546
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
64.86; H, 5.02; N, 5.41); νmax(Nujol)/cmϪ1 3340m (OH), 1740w,
40), 126 ([M Ϫ (CH2)6CH3]ϩ, 26), 98 ([M Ϫ CO(CH2)6CH3]ϩ,
1720m (CO diketone, keto form and CONCO), 1640s (CO
5), 69 (6) and 55 (5).
diketone, enol form) and 1595s (C᎐C ring stretching); δ (300
᎐
H
MHz; CDCl3; Me4Si) 2.59 and 2.62 (3 H, two s, COCH3), 4.14
(cd) and 4.24 (ab) (two s, 2 H, CH2-ring, ab:cd 3.5), 4.30 (2 H, s,
CH2C6H5), 7.26–7.38 (5 H, m, ArH) and 18.2–18.6 (1 H, br,
OH).
3-Decanoyltetramic acid 12
From N-acetyl-3-decanoyltetramic acid 8. The reaction
mixture [compound 8 (1.3 g, 4.4 mmol) dissolved in the sodium
ethoxide in ethanol] was refluxed for 5 h and then set aside
overnight at room temperature. Compound 12 was obtained
as a solid (0.8 g, 71.8%), mp 108–109 ЊC (from PhH–light pet-
roleum) (lit.,14 mp 107–110 ЊC).
From ethyl 4-acetylamino-2-decanoyl-3-hydroxybut-2-enoate
5. The reaction mixture [compound 5 (1.1 g, 3.3 mmol) dis-
solved in the sodium ethoxide in ethanol] was refluxed for 6.5 h
and then set aside overnight at room temperature. Compound
12 was obtained as a solid (0.7 g, 82%), mp 108–109 ЊC (from
PhH–light petroleum) (Found: C, 66.27; H, 9.22; N, 5.43.
C14H23O3N requires C, 66.37; H, 9.15; N, 5.53); νmax(Nujol)/
cmϪ1 3145br (NH), 1710s (CO diketone, keto form and CO
N-Acetyl-3-(hexa-2,4-dienoyl)tetramic acid 16
The reaction mixture [compound 2 (1.5 g, 7.2 mmol), ethyl
hexa-2,4-dienoylacetate 15 (1.3 g, 7.2 mmol) and sodium
hydride (14.3 mmol) in anhydrous benzene (15 ml)] was stirred
at room temperature for 2 h after which it was acidified with
10% hydrochloric acid to give an oily product which was
extracted with chloroform. The organic layer was dried
(Na2SO4) and evaporated in vacuo to give the crude product 16
(0.7 g, 40.3%), as a yellowish solid, which was used for the
deacetylation without further purification.
lactam), 1640s (CO diketone, enol form) and 1600s (C᎐C);
᎐
General method for the formation of NH-tetramic acids
A solution of the N-acetyltetramic acid or C-acylation com-
pound (2.3 mmol) in anhydrous benzene (20 ml) was added to a
solution of sodium ethoxide in ethanol [prepared from sodium
(0.1 g, 5.7 mmol) in absolute ethanol (20 ml)]. The reaction
mixture was refluxed for 3–6.5 h and, after being set aside over-
night at room temperature, was diluted with water. The aqueous
layer was separated and acidified with 10% aq. hydrochloric
acid, in an ice–water bath to give either a solid or an oily prod-
uct which was extracted with chloroform.
δH(300 MHz; CDCl3; Me4Si) 0.85 [3 H, t, J 7, (CH2)8CH3],
1.24–1.33 [12 H, m, (CH2)6CH3], 1.59–1.69 [2 H, m,
CH2(CH2)6], 2.83 and 2.89 (2 H, two t, J 7, COCH2), 3.78 (cd)
and 3.92 (ab) (2 H, two s, CH2-ring, cd:ab 3.44), 6.79 (1 H, br,
NH) and 11.50 (1 H, br, OH); δC(CDCl3; Me4Si), see Table 2;
m/z (EI) 253 ([M]ϩ, 3%), 168 ([M Ϫ (CH2)5CH3]ϩ, 4), 154
([M Ϫ (CH2)6CH3]ϩ, 29), 141 ([M ϩ H Ϫ (CH2)7CH3]ϩ, 100),
126 ([M Ϫ (CH2)8CH3]ϩ, 67), 80 (5), 69 (9) and 55 (6).
3-(Hexa-2,4-dienoyl)tetramic acid 17
From N-acetyl-3-(hexa-2,4-dienoyl)tetramic acid 16. The
reaction mixture [crude product 16 (0.7 g, 2.9 mmol) dissolved
in the sodium ethoxide in ethanol] was set aside overnight at
room temperature. Compound 17 was obtained as a solid (0.3
g, 50%), mp 211–213 ЊC (from CH3COCH3–light petroleum)
(lit.,18 211–212 ЊC) (Found: C, 60.86; H, 5.67; N, 6.91.
C10H11O3Nؒ1/4H2O requires C, 60.74; H, 5.86; N, 7.08);
νmax(Nujol)/cmϪ1 3200m (NH), 1710m (CO diketone, keto
form and CO lactam), 1665s (CO diketone, enol form and CO
3-Hexanoyltetramic acid 10
From N-acetyl-3-hexanoyltetramic acid 6. The reaction mix-
ture [compound 6 (1.1 g, 4.6 mmol) dissolved in the sodium
ethoxide in ethanol] was refluxed for 3 h and then set aside
overnight at room temperature. Compound 10 was obtained as
a solid (0.6 g, 66.5%), mp 116–119 ЊC (from PhH–light pet-
roleum) (Found: C, 60.98; H, 7.71; N, 7.03. C10H15O3N requires
C, 60.89; H, 7.67; N, 7.10); νmax(Nujol)/cmϪ1 3170br (NH),
1710s (CO diketone, keto form and CO lactam), 1640s (CO
α,β-unsaturated ketone) and 1625s (C᎐C); δ (300 MHz; [2H ]-
᎐
H
6
diketone, enol form) and 1590s (C᎐C); δ (300 MHz; CDCl ;
acetone; Me Si) 1.909 [3 H, d, J 6, (CH᎐CH) CH ], 3.79 (cd)
᎐
4 2 3
᎐
H
3
Me4Si) 0.88 [3 H, t, J 7, (CH2)4CH3], 1.26–1.40 [4 H, m,
(CH2)2CH3], 1.61–1.71 [2 H, m, CH2(CH2)2], 2.83 and 2.89 (2
H, two t, J 7, COCH2), 3.79 (cd) and 3.93 (ab) (two s, 2 H, CH2-
ring, cd:ab 3.33) and 6.60 (1 H, br, NH); δC(CDCl3; Me4Si), see
Table 2; m/z (EI) 198 ([M ϩ H]ϩ, 100%), 168 ([M Ϫ CH2CH3]ϩ,
1), 154 ([M Ϫ (CH2)2CH3]ϩ, 6), 141 ([M ϩ H Ϫ (CH2)3CH3]ϩ,
11), 126 ([M Ϫ (CH2)4CH3]ϩ, 14), 69 (2) and 55 (4).
and 3.92 (ab) (2 H, two s, CH2-ring, ab:cd 7), 5.60 (1 H, br, NH)
and 6.40–7.80 [4 H, m, (CH᎐CH) CH ].
᎐
2
3
Preparation of 5-benzylidene-3-alkanoyl tetramic acids
5-Benzylidene-3-hexanoyl tetramic acid 13. The tetramic acid
[2.2 mmol 6 (0.5 g) or 10 (0.4 g)] was stirred in a solution of 8%
hydrogen chloride in ethanol [prepared by addition of acetyl
chloride (4 ml) in anhydrous ethanol (30 ml)] until it dissolved
(ca. 15 min), after which benzaldehyde (0.5 g, 4.5 mmol) was
added to the mixture. The reaction mixture was refluxed for 3 h
and then set aside overnight at room temperature to give a
yellowish precipitate, which was filtered off and washed with
diethyl ether to afford the product 13 (0.3 g, 44%), mp 178–
182 ЊC (from EtOH) (Found: C, 71.78; H, 6.50; N, 4.79.
C17H19O3N requires C, 71.56; H, 6.71; N, 4.91); νmax(Nujol)/
cmϪ1 3180m (NH), 1700s (CO diketone, keto form and CO
3-Octanoyltetramic acid 11
From N-acetyl-3-octanoyltetramic acid 7. The reaction mix-
ture [compound 7 (1.3 g, 4.9 mmol) dissolved in the sodium
ethoxide in ethanol] was refluxed for 3 h and then set aside
overnight at room temperature. Compound 11 was obtained
as a solid (0.8 g, 70.3%), mp 113–116 ЊC (from PhH–light
petroleum).
From ethyl 4-acetylamino-2-octanoyl-3-hydroxybut-2-enoate
4. The reaction mixture [compound 4 (0.7 g, 2.2 mmol) dis-
solved in the sodium ethoxide in ethanol] was refluxed for 5 h
and then set aside overnight at room temperature. Compound
11 was obtained as a solid (0.3 g, 59.6%), mp 113–116 ЊC (from
PhH–light petroleum) (Found: C, 63.96; H, 8.55; N, 6.11.
C12H19O3N requires C, 63.97; H, 8.50; N, 6.22); νmax(Nujol)/
cmϪ1 3200br (NH), 1710s (CO diketone, keto form and CO
lactam), 1630s (CO diketone, enol form and C᎐C) and 1580s
᎐
(C᎐C ring stretching); δ (300 MHz; [2H ]DMSO; Me Si) 0.86
᎐
H
6
4
[3 H, t, J 7, (CH2)4CH3], 1.26–1.38 [4 H, m, (CH2)2CH3], 1.54–
1.64 [2 H, m, CH2(CH2)2], 2.86 (2 H, t, J 7, COCH2), 4.71 (1 H,
br, NH), 6.44 (1 H, s, CH᎐), 7.28–7.33 (1 H, m, para protons),
᎐
7.36 (2 H, t, J 7.8, meta protons), 7.62 (2 H, d, J 7, ortho pro-
tons) and 10.53 (1 H, br, OH); δC([2H6]DMSO; Me4Si), see
Table 3. Treatment of 13 with MSTFA–NH4I–DTE reagents
yielded the corresponding derivatives (C23H35NO3Si2); m/z (EI)
429 ([M]ϩ, 20%), 414 ([M Ϫ Me]ϩ, 50), 386 ([M Ϫ (CH2)2-
CH3]ϩ, 35), 358 ([M Ϫ (CH2)4CH3]ϩ, 7), 298 ([M Ϫ (CH2)3-
CH3 Ϫ Si(Me)3 Ϫ H]ϩ, 10), 73 (100) and 55 (3).
lactam), 1640s (CO diketone, enol form) and 1600s (C᎐C);
᎐
δH(300 MHz; CDCl3; Me4Si) 0.87 [3 H, t, J 7, (CH2)6CH3],
1.26–1.39 [8 H, m, (CH2)4CH3], 1.61–1.71 [2 H, m, CH2(CH2)4],
2.84 and 2.90 (2 H, two t, J 7, COCH2), 3.79 (cd) and 3.93 (ab)
(two s, 2 H, CH2-ring cd:ab 4) and 6.43 (1 H, br, NH);
δC(CDCl3; Me4Si), see Table 2; m/z (EI) 226 ([M ϩ H]ϩ, 100%),
154 ([M Ϫ (CH2)4CH3]ϩ, 17), 141 ([M ϩ H Ϫ (CH2)5CH3]ϩ,
5-Benzylidene-3-octanoyltetramic acid 14. According to the
previous procedure the tetramic acid [2.2 mmol 7 (0.6 g) or 11
J. Chem. Soc., Perkin Trans. 1, 1997
3547

View Article Online
H
O
α
β
γ
δ
ε
ζ
η
6
O
CCH2CH2CH2CH2CH2CH2CH3
4
3
10′
9′
2
5
7
1
8
O
11
CH
N
H
10
9
Table 3 13C NMR chemical shifts for 5-benzylidenetetramic acids 13 and 14 ([2H6]DMSO)
Compd. C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9,9Ј C-10,10Ј C-11
C-α
C-β
C-γ
C-δ
C-ε
C-ζ
C-η
13
14
171.15 101.15 191.49 108.22 181.09 128.51 131.77 129.81 128.89
171.16 101.55 191.50 108.14 181.12 128.49 131.76 129.81 128.90
133.30 34.07 30.73 24.58 21.72
133.33 34.18 31.02 28.52 28.29 24.89 21.97 13.84
—
—
13.68
6 T. E. Elbe, C. M. Large, W. H. DeVries, G. F. Grum and J. W. Shell,
Antibiot. Ann., 1955–1956; 893; K. L. Rinehart, J. R. Beck, D. B.
Borders, T. H. Kinstle and D. Krauss, J. Am. Chem. Soc., 1963, 85,
4038.
7 I. M. Mawer, J. J. Kulagowski, P. D. Leeson, S. Grimwood and
G. R. Marshall, Bioorg. Med. Chem. Lett., 1995, 5(22), 2643.
8 R. N. Lacey, J. Chem. Soc., 1954, 850.
(0.5 g)] afforded the title compound 14 (0.3 g, 48.5%), mp 165–
169 ЊC (from EtOH) (Found: C, 72.73; H, 7.39; N, 4.45.
C19H23O3N requires C, 72.82; H, 7.40; N, 4.47); νmax(Nujol)/
cmϪ1 3180m (NH), 1700s (CO diketone, keto form and CO
lactam), 1630s (CO diketone, enol form and C᎐C) and 1580s
᎐
(C᎐C ring stretching); δ (300 MHz; [2H ]DMSO) 0.84 [3 H, t,
᎐
H
6
9 R. K. Boeckmann, Jr. and A. J. Thomas, J. Org. Chem., 1982,
47, 2823; L. A. Paquette, D. MacDonald, L. G. Anderson and
J. Wright, J. Am. Chem. Soc., 1989, 111, 8037.
10 R. C. F. Jones and J. M. Patience, Tetrahedron Lett., 1989, 30, 3217;
R. C. F. Jones, G. Bhalay, P. A. Carter, K. A. M. Duller and S. I. E.
Vulto, J. Chem. Soc., Perkin Trans. 1, 1994, 2513.
J 7, (CH2)6CH3], 1.24–1.28 [8 H, m, (CH2)4CH3], 1.54–1.61
[2 H, m, CH2(CH2)4], 2.86 (2 H, t, J 7, COCH2), 5.32 (1 H, br,
NH), 6.44 (1 H, s, CH᎐), 7.28–7.33 (1 H, m, para protons), 7.39
᎐
(2 H, t, J 7.8, meta protons), 7.62 (2 H, d, J 7, ortho protons)
and 10.53 (1 H, br, OH); δC([2H6]DMSO; Me4Si), see Table 3.
11 S. V. Ley, S. C. Smith and P. R. Woodward, Tetrahedron, 1992, 48,
1145.
Acknowledgements
12 (a) J. V. Barkley, J. Markopoulos and O. Markopoulou, J. Chem.
Soc., Perkin Trans. 2, 1994, 1271; (b) A. Detsi, J. Markopoulos and
O. Igglessi-Markopoulou, Chem. Commun., 1996, 1323; (c) A. Detsi,
V. Bardakos, J. Markopoulos and O. Igglessi-Markopoulou,
J. Chem. Soc., Perkin Trans. 1, 1996, 2909.
13 Y. Oikawa and K. Sugano, J. Org. Chem., 1978, 43(10), 2087.
14 K. Matsuo and I. Kitaguchi, Chem. Pharm. Bull., 1980, 28(8), 2494.
15 (a) D. Enders, R. Grobner, G. Raabe and J. Runsink, Synthesis,
1996, 941; (b) D. Ma, J. Ma, W. Ding and L. Dai, Tetrahedron:
Asym., 1996, 7(8), 2365.
We thank the University of Liverpool, Chemistry Department
for the microanalyses, Dr M. Skretta (National Institute of
Research, Athens) and Drs C. Georgakopoulos, C. Tsitsibikou
(Doping Control Laboratory of Athens, Olympic Athletic
Center) for recording the mass spectra. We also thank the
Committee of Research of the National Technical University
of Athens, Greece, for a doctoral assistantship (M. P.).
16 M. J. Nolte, P. S. Steyn and P. L. Wessels, J. Chem. Soc., Perkin
Trans. 1, 1980, 1057; N. Imamura, K. Adachi and H. Sano,
J. Antibiot., 1994, 47(2), 257.
17 T. Rosen, P. B. Fernandes, M. A. Marovich, L. Shen, J. Mao and
A. G. Pernet, J. Med. Chem., 1989, 32, 1062; R. A. DiCioccio,
B. I. S. Srivastava, K. L. Rinehart, V. J. Lee, A. R. Branfman and
L.-H. Li, Biochem. Pharmacol., 1980, 29, 2001.
18 V. J. Lee, A. R. Branfman, T. R. Herrin and K. L. Rinehart, J. Am.
Chem. Soc., 1978, 100, 4225.
19 D. D. Perrin and W. L. Armarego, Purification of Laboratory
Chemicals, Pergamon Press, Oxford, 1988.
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Paper 7/02649H
Received 17th April 1997
Accepted 14th August 1997
3548
J. Chem. Soc., Perkin Trans. 1, 1997