One-pot synthesis of 3-aryltetramic acids

Article abstract of DOI:10.1002/ejoc.200901092

Tetramic acids substituted in the 3-position by various aryl groups were prepared in one-pot from amino esters and methyl arylacetates, by treatment with potassium tert-butoxide. A tandem process, involving the formation of an amide and a condensation reaction, is likely to occur. N-Unsubstituted tetramic acids were obtained from adducts containing a N-(2,4-dimethoxybenzyl) group.

Full text of DOI:10.1002/ejoc.200901092

FULL PAPER
DOI: 10.1002/ejoc.200901092
One-Pot Synthesis of 3-Aryltetramic Acids
Aurélie Mallinger,[a] Brice Nadal,[a] Nicolas Chopin,[a] and Thierry Le Gall*[a]
Keywords: Tetramic acid / Nitrogen heterocycles / Amides / Ring closure / Dieckmann condensation / Synthetic methods
Tetramic acids substituted in the 3-position by various aryl
groups were prepared in one-pot from amino esters and
methyl arylacetates, by treatment with potassium tert-butox-
ide. A tandem process, involving the formation of an amide
and a condensation reaction, is likely to occur. N-Unsubsti-
tuted tetramic acids were obtained from adducts containing
a N-(2,4-dimethoxybenzyl) group.
made use of a palladium-catalyzed arylation was recently
reported.[7] In a recent study, we described a one-pot prepa-
ration of 3-aryltetronic acids from the corresponding aryl-
and hydroxyacetates, by a tandem process involving a trans-
esterification and a subsequent Dieckmann condensation.[8]
It was of interest to evaluate the preparation of 3-aryl-
tetramic acids by means of an analogous process (Scheme 1,
route b), which would make use of arylacetic acid esters
and α-amino esters as reaction partners and proceed by the
formation of an amide bond prior to the Dieckmann con-
densation. The results obtained are reported herein.
Introduction
The tetramic acid unit is a structural feature found in
many natural products, which display a wide spectrum of
biological activities.[1] Examples include the phytotoxin ten-
uazonic acid and the antibiotic tirandamycin A (Figure 1).
Most of these compounds contain a 3-acyl group. However,
non-natural, 3-aryltetramic acid derivatives have been re-
ported as herbicides, acaricides, insecticides, and pesti-
cides.[2] For example, spirotetramat (movento®), which acts
as a lipid biosynthesis inhibitor, is currently under develop-
ment at Bayer CropScience as an insecticide.[3] Several 5-
arylidene-3-phenyltetramic acids have been reported as gly-
cine-site N-methyl--aspartate receptor antagonists.[4]
Scheme 1.
Results and Discussion
Initially, we tested the feasibility of the reaction starting
from methyl (4-methoxyphenyl)acetate (1a) and glycine
methyl ester hydrochloride (2a, Scheme 2). We employed
this hydrochloride directly in the reactions; hence we em-
ployed an additional base equivalent in order to neutralize
the acid.
Several tests, carried out in refluxing THF with variable
quantities of potassium tert-butoxide, did not lead to
tetramic acid 3. On the other hand, starting from glycine
tert-butyl ester hydrochloride (2b), we isolated tetramic acid
3, albeit only in 20% yield, using 2.5 base equiv. after
1 night. We observed unreacted ester 1a in the crude prod-
uct. However, we could not improve the yield by increasing
either the number of base equivalents or the reaction time.
Figure 1. Structural formulas of the parent tetramic acid, natural
products tenazuonic acid and tyrandamycin A, and the insecticide
spirotetramat.
Since the first report by King and McMillan,[5] the
Dieckmann condensation of a previously synthesized amide
is usually employed for the preparation of 3-aryltetramic
acids (Scheme 1, route a).[6] Interestingly, a synthesis that
[a] CEA Saclay, iBiTecS, Service de Chimie Bioorganique et de
Marquage, Bât. 547,
91191 Gif-sur-Yvette, France
Fax: +33-1-69087991
E-mail: thierry.legall@cea.fr
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Eur. J. Org. Chem. 2010, 1142–1148

One-Pot Synthesis of 3-Aryltetramic Acids
prior to the reaction. It thus seemed more judicious to use
an amino ester in the free amine form as the starting mate-
rial.
We selected two amino esters, the commercially available
ethyl benzylaminoacetate (6a) and ethyl 2-[(2,4-dimethoxy-
benzyl)amino]acetate (6b,[9] Scheme 4). We initially carried
out reactions with 6a and 1a, using various numbers (from
1.0 to 2.2) of base equivalents. A comparison of the 1H
NMR spectra of the crude products indicated that
1.2 equiv. of potassium tert-butoxide was sufficient to ob-
tain a good conversion to the expected N-benzyltetramic
acid 7a. In this case, we obtained 7a in 67% yield after
purification (Table 2, Entry 1). An excess of base led to the
formation of secondary products.
Scheme 2.
We then employed N-alkylamino esters as starting mate-
rials. We first carried out experiments with sarcosine methyl
ester hydrochloride (4) and methyl 2-(4-methoxyphenyl)acet-
ate (1a). Thus, we treated 4 with 1a in the presence of
2.5 equiv. of potassium tert-butoxide in refluxing THF
(Scheme 3). After 4 h, we obtained tetramic acid 5a in 38%
yield (Table 1, Entry 1). The yield improved when we re-
fluxed the reaction mixture overnight (Table 1, Entry 2).
Moreover, we obtained a better yield (76%) when was puri-
fied 5a by precipitation instead of silica gel chromatography
(Table 1, Entry 3). Indeed, since this N-methyltetramic acid
was not very soluble in most solvents, we observed signifi-
cant losses during the chromatographic purification. We
note that the use of sarcosine tert-butyl ester hydrochloride
instead of 4 also led to 5a in a satisfying 73% yield.
Scheme 4.
We then prepared tetramic acids 7 substituted in position
3 by various aryl groups in a similar way (Scheme 4,
Table 2). We synthesized N-benzyltetramic acids 7b–g first.
As we observed in the tetronic acids synthesis,[8] the posi-
tion of the methoxy substituent on the aromatic nucleus of
the starting ester had little influence on the yield (Table 2,
Entries 3 and 4). We also isolated tetramic acids substituted
by 4-halophenyl groups in good yields, varying between 54
and 64% (Table 2, Entries 5 to 7). On the other hand, when
the phenyl group was para-substituted by a nitro group, we
did not obtain the expected tetramic acid 7h (Table 2, Entry
8). This result was similar to that observed during an at-
tempt to prepare the corresponding tetronic acid.[8] We as-
sumed that under the reaction conditions, ester 1i was read-
ily converted into the corresponding stable potassium enol-
ate. We prepared tetramic acids 7j–n, N-substituted by a
2,4-dimethoxybenzyl group, by the same process in 54–71%
yield.
Scheme 3.
Table 1. One-pot synthesis of N-methyltetramic acids 5.
Entry Ar
Reaction time
4-(MeO)C6H4 4 h
4-(MeO)C6H4 overnight
4-(MeO)C6H4 overnight
3-(MeO)C6H4 overnight
4-BrC6H4
4-ClC6H4
thien-2-yl
1
5
Yield [%]
1
2
3
4
6
7
9
1a
1a
1a
1b
1c
1d
1e
5a
5a
5a
5b
5c
5d
5e
38[a]
62[a]
76[b]
50[b]
32[a]
48[a]
28[a]
Direct access to N-unsubstituted tetramic acids was not
readily feasible from glycine esters 2a and 2b. On the other
hand, we quantitatively converted 7i–m, in which the amide
function was protected by a 2,4-dimethoxybenzyl group,
into the corresponding N-unsubstituted tetramic acids by
treatment with trifluoroacetic acid (Scheme 5).[10] However,
overnight
overnight
overnight
[a] Purified by silica gel chromatography. [b] Purified by precipi-
tation.
We then prepared several other N-methyltetramic acids we observed that 7n, substituted by a 2-thienyl group, de-
from 4 and various methyl arylacetates 1b–e (Scheme 3, composed under these conditions.
1
Table 1). We characterized the products particularly by H
Several bicyclic tetramic acids have been shown to dis-
NMR (400 MHz, [D6]DMSO) chemical shifts of the meth- play biological activities.[6c,11] It was thus of interest to eval-
ylene protons (δ = 3.88–3.92 ppm) and the methyl group (δ uate the preparation of such a compound using this one-
= 2.85–2.87 ppm). In most cases, the precipitation of the pot method. As an example, we obtained indolizinone 9 in
crude product was not efficient, and purification by 37% yield from methyl pipecolinate and ester 1a under the
chromatography was needed. We note, however, that what- usual conditions.
ever the starting ester, the yields obtained were not satisfac-
A suggested pathway for the formation of N-methyl-3-
tory. This could be due to the use of an amino ester hydro- aryltetramic acids under these conditions is outlined in
chloride, for which a delicate drying operation was needed Scheme 6. The reaction of the anion generated from the
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A. Mallinger, B. Nadal, N. Chopin, T. Le Gall
FULL PAPER
Table 2. One-pot synthesis of N-benzyl- and N-(2,4-dimethoxybenzyl)tetramic acids 7.
Entry
6
ArЈ
1
Ar
7
Yield [%]
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
2,4-(MeO)2C6H3
1a
1f[a]
1b
1g
1c
4-(MeO)C6H4
C6H5
3-(MeO)C6H4
3,4-(MeO)2C6H3
4-BrC6H4
4-ClC6H4
4-FC6H4
4-(NO2)C6H4
C6H5
4-(MeO)C6H4
3-(MeO)C6H4
4-BrC6H4
4-FC6H4
thien-2-yl
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
67
54
62
52
64
62
54
0
63
59
53
55
71
54
1d
1h
1i
9
1f[a]
1a
1b
1c
10
11
12
13
14
1h
1e
[a] Ethyl phenylacetate was used in this reaction.
Scheme 7.
Scheme 5.
Conclusions
In summary, a convenient, one-pot synthesis of 3-aryl-
tetramic acids from amino esters and methyl arylacetates
is described. It consists of a tandem process involving the
formation of an amide and a condensation reaction. Good
yields were obtained in particular from ethyl benzylamino-
acetate (6a) and ethyl (2,4-dimethoxybenzyl)aminoacetate
(6b). The facile cleavage of the 2,4-dimethoxybenzyl group
of adducts 7i–m allows for an efficient preparation of N-
unsubstituted tetramic acids.
amino ester with the methyl arylacetate would give the cor-
responding amide. This precursor can then undergo a
Dieckmann condensation, yielding the tetramic acid salt.
Experimental Section
General Methods: THF was freshly distilled from sodium benzo-
phenone ketyl. Reactions were performed under an argon atmo-
sphere. TLC: Silica Gel 60F254 plates with detection by UV light
and by an ethanol solution of phosphomolybdic acid. Column
chromatography: 40–63 µm silica gel. Melting points were not cor-
rected. NMR: 400.133 and 100.624 MHz for 1H and 13C, respec-
tively. Chemical shifts (δ) are given in ppm (s singlet, d doublet, t
triplet, m multiplet, and br. broad), coupling constants (J) are given
in Hz.
Scheme 6.
However, we could not produce evidence that the forma-
tion of the tetramic acids actually follows this route. Hence,
an alternative pathway, depicted in Scheme 7, cannot be
ruled out. A Claisen condensation between the methyl aryl-
acetate-derived enolate and the amino ester would lead to a
β-keto ester. Under the reaction conditions, this compound
would easily cyclize, affording the tetramic acid salt. This
pathway might actually be more favorable, since the methyl-
ene protons of the arylacetate are more acidic than the sec-
ondary amine proton.
General Procedure for the Synthesis of a Tetramic Acid from an
Amino Ester Hydrochloride: To a solution of alkyl arylacetate
(1 equiv.) and amino ester hydrochloride (1.5 equiv.) in anhydrous
THF was added potassium tert-butoxide (1  in THF, 2.5 equiv.).
The suspension obtained was then refluxed under argon overnight.
After the mixture was cooled to room temperature, it was poured
into cooled aqueous HCl (1 ). The aq phase was extracted with
AcOEt, and the combined organic layers were then washed with
water and dried with Na2SO4. After the mixture was filtered and
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One-Pot Synthesis of 3-Aryltetramic Acids
concentrated under vacuum, the residue was precipitated in diethyl
ether, or chromatographed on silica gel, to give the corresponding
tetramic acid.
2 H, Ar-H), 3.92 (s, 2 H, CH2), 2.85 (s, 3 H, CH3N) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 171.1, 167.8, 132.2, 131.0,
128.7, 118.6, 102.1, 51.2, 28.6 ppm. MS (ESI-TOF): m/z = 268, 270
[M + H]+. HRMS (ESI-TOF): calcd. for C11H1079BrNNaO2 [M +
Na]+ 289.9793; found 289.9780; calcd. for C11H1081BrNNaO2 [M
+ Na]+ 291.9772; found 291.9765.
General Procedure for the Synthesis of a Tetramic Acid from an N-
Alkylamino Ester: To a solution of alkyl arylacetate (1 equiv.) and
N-alkylamino ester (1.2 equiv.) in anhydrous THF was added po-
tassium tert-butoxide (1  in THF, 1.2 equiv.). The suspension ob-
tained was then refluxed under argon overnight, and the reaction
was then processed as described above.
3-(4-Chlorophenyl)-4-hydroxy-1-methyl-1H-pyrrol-2(5H)-one (5d):
Following the general procedure, from methyl (4-chlorophenyl)ace-
tate (1d, 0.28 g, 1.5 mmol), methyl sarcosinate hydrochloride (4,
0.32 g, 2.3 mmol), and potassium tert-butoxide (3.8 mL, 3.8 mmol,
1  in THF) in THF (7 mL), tetramic acid 5d (0.16 g, 48%) was
obtained as a white solid; m.p. 236–238 °C; TLC: Rf = 0.20 (95:5
4-Hydroxy-3-(4-methoxyphenyl)-1H-pyrrol-2(5H)-one (3): Follow-
ing the general procedure, from methyl (4-methoxyphenyl)acetate
(1a, 0.18 g, 1.0 mmol), glycine tert-butyl ester hydrochloride (2b,
0.25 g, 1.5 mmol), and potassium tert-butoxide (2.5 mL, 2.5 mmol,
1  in THF) in THF (5 mL), tetramic acid 3 (40 mg, 20%) was
obtained as a yellow solid; m.p. 226–227 °C; TLC: Rf = 0.30 (9:1
CH Cl /MeOH). IR (KBr pellet): ν = 3096, 2907, 2616, 2522, 1666,
˜
2
2
1604, 1589, 1439, 1414, 1385, 1223, 1084, 1012, 973, 905, 826, 757,
704 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.04 (d, J =
9.6 Hz, 2 H, Ar-H), 7.34 (d, J = 9.6 Hz, 2 H, Ar-H), 3.92 (s, 2 H,
CH2), 2.85 (s, 3 H, CH3N) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 171.2, 167.7, 131.9, 130.0, 128.4, 128.1, 102.1, 51.2,
28.6 ppm. MS (ESI-TOF): m/z = 224, 226 [M + H]+. HRMS (ESI-
TOF): calcd. for C11H1035ClNNaO2 [M + Na]+ 246.0298; found
246.0289.
CH Cl /MeOH). IR (KBr pellet): ν = 3349, 2918, 2597, 1624, 1605,
˜
2
2
1514, 1440, 1383, 834, 750 cm–1. 1H NMR (400 MHz, [D6]DMSO):
δ = 11.33 (br. s, 1 H, OH), 7.91 (d, J = 9.1 Hz, 2 H, Ar-H), 7.38
(br. s, 1 H, NH), 6.88 (d, J = 9.1 Hz, 2 H, Ar-H), 3.82 (s, 2 H,
CH2), 3.74 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 171.3, 167.2, 157.0, 127.9, 125.0, 113.1, 102.9, 54.9, 44.7 ppm.
HRMS (ESI-TOF): calcd. for C11H11NNaO3 [M + Na]+ 228.0637;
found 228.0642.
4-Hydroxy-1-methyl-3-(thien-2-yl)-1H-pyrrol-2(5H)-one (5e): Fol-
lowing the general procedure, from methyl 2-thienylacetate (1e,
0.19 g, 1.2 mmol), methyl sarcosinate hydrochloride (4, 0.25 g,
1.8 mmol), and potassium tert-butoxide (3.0 mL, 3.0 mmol, 1  in
THF) in THF (9 mL), tetramic acid 5e (65 mg, 28%) was obtained
as a white solid; m.p. 202–203 °C (dec.); TLC: Rf = 0.20 (95:5
4-Hydroxy-3-(4-methoxyphenyl)-1-methyl-1H-pyrrol-2(5H)-one (5a):
Following the general procedure, from methyl (4-methoxyphenyl)-
acetate (1a, 0.23 g, 1.3 mmol), methyl sarcosinate hydrochloride (4,
0.26 g, 1.9 mmol), and potassium tert-butoxide (3.2 mL, 3.2 mmol,
1  in THF) in THF (7 mL), tetramic acid 5a (0.21 g, 76%) was
obtained as a white solid; m.p. 232–233 °C (dec.); TLC: Rf = 0.30
CH Cl /MeOH). IR (KBr pellet): ν = 2930, 2566, 1665, 1604, 1435,
˜
2
2
1397, 1337, 1226, 933, 842, 725, 677 cm–1. 1H NMR (400 MHz,
[D6]DMSO): δ = 7.52 (d, J = 3.6 Hz, 1 H, SCH=CH-CH), 7.23 (d,
J = 4.8 Hz, 1 H, SCH), 6.98 (dd, J = 4.8, 3.6 Hz, 1 H, SCH=CH),
3.88 (s, 2 H, CH2), 2.85 (s, 3 H, CH3N) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 170.3, 165.0, 133.6, 126.6, 123.4, 123.0, 100.8,
51.4, 28.7 ppm. MS (ESI-TOF): m/z = 196 [M + H]+.
(9:1 CH Cl /MeOH). IR (KBr pellet): ν = 2935, 2569, 1598, 1515,
˜
2
2
1450, 1384, 1288, 1252, 1214, 1177, 1028, 836, 727 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 11.35 (br. s, 1 H, OH), 7.90 (d, J =
9.1 Hz, 2 H, Ar-H), 6.89 (d, J = 9.1 Hz, 2 H, Ar-H), 3.91 (s, 2 H,
CH2), 3.74 (s, 3 H, CH3O), 2.86 (s, 3 H, CH3N) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 171.3, 164.8, 157.0, 127.8, 125.0,
113.2, 100.8, 54.9, 50.7, 28.2 ppm. HRMS (ESI-TOF): calcd. for
C12H12NNaO3 [M – H]– 218.0817; found 218.0813.
Ethyl (2,4-Dimethoxybenzyl)aminoacetate (6b): Ethyl bromoacetate
(6.63 mL, 59.8 mmol, 1 equiv.) was added dropwise to a solution
of (2,4-dimethoxybenzyl)amine (10 g, 59.8 mmol, 1 equiv.) and tri-
ethylamine (20.8 mL, 149.5 mmol, 2.5 equiv.) in anhydrous THF
(75 mL) cooled to 0 °C under argon. The reaction mixture was
warmed to room temperature and then stirred overnight. Brine
(250 mL) was added, and the aq phase was extracted with AcOEt
(2ϫ200 mL). The combined organic layers were dried with
MgSO4. After filtration and concentration under vacuum, the resi-
due was purified by column chromatography (silica gel, 4:1 Ǟ 1:1
cyclohexane/AcOEt), to give amino ester 6b as a colorless oil
(11.5 g, 76%). TLC: Rf = 0.30 (1:1 cyclohexane/AcOEt). IR (KBr
4-Hydroxy-3-(3-methoxyphenyl)-1-methyl-1H-pyrrol-2(5H)-one (5b):
Following the general procedure, from methyl (3-methoxyphenyl)-
acetate (1b, 0.25 g, 1.4 mmol), methyl sarcosinate hydrochloride (4,
0.29 g, 2.1 mmol), and potassium tert-butoxide (3.5 mL, 3.5 mmol,
1  in THF) in THF (8 mL), tetramic acid 5b (0.15 g, 50%) was
obtained as a beige solid; m.p. 195–196 °C (dec.); TLC: Rf = 0.25
(95:5 CH Cl /MeOH). IR (KBr pellet): ν = 2937, 2562, 1743, 1600,
˜
2
2
1380, 1287, 1239, 1215, 1053, 914, 785, 731, 693 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.64 (br. s, 1 H, OH), 7.58 (d, J =
8.0 Hz, 1 H, Ar-H), 7.22 (t, J = 8.0 Hz, 1 H, Ar-H), 6.74 (d, J =
8.0 Hz, 1 H, Ar-H), 3.92 (s, 2 H, CH2), 3.72 (s, 3 H, CH3O), 2.87
(s, 3 H, CH3N) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 171.4,
167.2, 159.1, 134.1, 128.9, 119.6, 112.6, 111.3, 103.2, 55.2, 51.2,
28.6 ppm. MS (ESI-TOF): m/z = 220 [M + H]+. HRMS (ESI-
TOF): calcd. for C12H13NO3Na [M + Na]+ 242.0793; found
242.0794.
pellet): ν = 3342, 2938, 2836, 1737, 1613, 1588, 1507, 1464, 1290,
˜
1
1261, 1208, 1187, 1156, 1134, 1035, 933, 832, 789 cm–1. H NMR
(400 MHz, CDCl3): δ = 7.08 (d, J = 8.1 Hz, 1 H, Ar-H), 6.41–6.37
(m, 2 H, Ar-H), 4.11 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.76 (s, 3 H,
CH3O), 3.74 (s, 3 H, CH3O), 3.70 (s, 2 H, NCH2Ar), 3.33 (s, 2 H,
CH2CO2Et), 2.03 (br. s, 1 H, NH), 1.21 (t, J = 7.1 Hz, 3 H,
CH3CH2) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 172.4,
160.2, 158.7, 130.5, 120.1, 103.7, 98.5, 60.5, 55.3, 55.2, 50.1, 48.1,
14.2 ppm. HRMS (ESI-TOF): calcd. for C13H19NNaO4 [M +
Na]+ 276.1212; found 276.1215.
3-(4-Bromophenyl)-4-hydroxy-1-methyl-1H-pyrrol-2(5H)-one (5c):
Following the general procedure, from methyl (4-bromophenyl)-
acetate (1c, 0.38 g, 1.7 mmol), methyl sarcosinate hydrochloride (4,
0.35 g, 2.5 mmol), and potassium tert-butoxide (4.2 mL, 4.2 mmol, 1-Benzyl-4-hydroxy-3-(4-methoxyphenyl)-1H-pyrrol-2(5H)-one (7a):
1  in THF) in THF (9 mL), tetramic acid 5c (0.14 g, 32%) was
obtained as an orange solid; m.p. 212–214 °C (dec.); TLC: Rf =
Following the general procedure, from methyl (4-methoxyphenyl)-
acetate (1a, 0.18 g, 1.0 mmol), N-benzylglycine ethyl ester (6a,
0.22 mL, 1.2 mmol), and potassium tert-butoxide (1.2 mL,
1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7a (0.19 g,
67%) was obtained as a yellow solid; m.p. 196–197 °C; TLC: Rf =
0.20 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 2931, 2719, 1605,
˜
2
2
1490, 1444, 1379, 1216, 827 cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 7.98 (d, J = 8.2 Hz, 2 H, Ar-H), 7.48 (d, J = 8.2 Hz,
Eur. J. Org. Chem. 2010, 1142–1148
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1145

A. Mallinger, B. Nadal, N. Chopin, T. Le Gall
FULL PAPER
0.25 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 3349, 2918, 2597,
1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7e (0.22 g,
64%) was obtained as a yellow solid; m.p. 216–217 °C (dec.); TLC:
˜
2
2
1624, 1605, 1514, 1440, 1383, 834, 750 cm–1. H NMR (400 MHz,
1
[D6]acetone): δ = 8.07 (d, J = 9.1 Hz, 2 H, Ar-H), 7.26–7.36 (m, 5
R = 0.25 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 3026, 2920,
˜
f 2 2
H, Ph-H), 6.90 (d, J = 9.1 Hz, 2 H, Ar-H), 4.62 (s, 2 H, CH2Ph), 2701, 1665, 1622, 1492, 1459, 1448, 1436, 1413, 1379, 1214, 829,
1
3.80 (s, 3 H, CH3O), 3.90 [s, 2 H, NCH2C(OH)=] ppm. 13C NMR 737, 697 cm–1. H NMR (400 MHz, [D6]acetone): δ = 8.14 (d, J =
(100 MHz, [D6]acetone): δ = 45.7, 49.4, 55.4, 105.1, 113.9, 125.9,
128.0, 128.6, 129.4, 139.5, 158.8, 165.0, 172.2 ppm. MS (ESI-TOF):
m/z = 296 [M + H]+. HRMS (ESI-TOF): calcd. for C18H17NNaO3
[M + Na]+ 318.1106; found 318.1109.
8.3 Hz, 2 H, Ar-H), 7.51 (d, J = 8.3 Hz, 2 H, Ar-H), 7.27–7.37 (m,
5 H, Ph-H), 4.63 (s, 2 H, CH2Ph), 3.94 [s, 2 H, NCH2C(OH)=]
ppm. 13C NMR (100 MHz, [D6]acetone): δ = 171.6, 167.1, 139.2,
132.7, 131.6, 129.9, 129.5, 128.6, 128.1, 119.9, 104.2, 49.5, 45.7
ppm. MS (ESI-TOF): m/z = 344, 346 [M + H]+. HRMS (ESI-
TOF): calcd. for C17H1479BrNNaO2 [M + Na]+ 366.0106; found
366.0112; calcd. for C17H1481BrNNaO2 [M + Na]+ 368.0085; found
368.0099.
1-Benzyl-4-hydroxy-3-phenyl-1H-pyrrol-2(5H)-one (7b): Following
the general procedure, from ethyl phenylacetate (1f, 0.16 g,
1.0 mmol), N-benzylglycine ethyl ester (6a, 0.22 mL, 1.2 mmol),
and potassium tert-butoxide (1.2 mL, 1.2 mmol, 1  in THF) in
THF (7 mL), tetramic acid 7b (0.14 g, 54%) was obtained as a yel-
low solid; m.p. 197–198 °C; TLC: Rf = 0.25 (95:5 CH2Cl2/MeOH).
1-Benzyl-3-(4-chlorophenyl)-4-hydroxy-1H-pyrrol-2(5H)-one
(7f):
Following the general procedure, from methyl (4-chlorophenyl)ace-
tate (1d, 0.23 g, 1.0 mmol), N-benzylglycine ethyl ester (6a,
0.22 mL, 1.2 mmol), and potassium tert-butoxide (1.2 mL,
1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7f (0.18 g,
62%) was obtained as a yellow solid; m.p. 207–208 °C (dec.); TLC:
IR (KBr pellet): ν = 2923, 2610, 1656, 1595, 1497, 1453, 1391,
˜
1
1312, 1217, 780, 696 cm–1. H NMR (400 MHz, [D6]acetone): δ =
8.12 (d, J = 6.9 Hz, 2 H, Ar-H), 7.25–7.37 (m, 7 H, Ar-H), 7.16–
7.21 (m, 1 H, Ar-H), 4.63 (s, 2 H, CH2Ph), 3.93 [s, 2 H,
NCH2C(OH)=] ppm. 13C NMR (100 MHz, [D6]acetone): δ =
171.9, 166.4, 139.4, 133.4, 129.5, 128.6, 128.5, 128.3, 128.0, 126.8,
105.4, 49.5, 45.7 ppm. MS (ESI-TOF): m/z = 266 [M + H]+. HRMS
(ESI-TOF): calcd. for C17H15NNaO3 [M + Na]+ 288.1000; found
288.1011.
R = 0.25 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 2920, 2700,
˜
f
2
2
1666, 1620, 1494, 1460, 1449, 1437, 1414, 1381, 1215, 831, 816,
1
740, 699 cm–1. H NMR (400 MHz, [D6]acetone): δ = 8.20 (d, J =
9.0 Hz, 2 H, Ar-H), 7.36 (d, J = 9.0 Hz, 2 H, Ar-H), 7.24–7.38 (m,
5 H, Ph-H), 4.63 (s, 2 H, CH2Ph), 3.95 [s, 2 H, NCH2C(OH)=]
ppm. 13C NMR (100 MHz, [D6]acetone): δ = 171.7, 167.2, 139.2,
132.3, 131.7, 129.6, 129.5, 128.6, 128.6, 128.1, 104.0, 49.5, 45.7
ppm. MS (ESI-TOF): m/z = 300, 302 [M + H]+. HRMS (ESI-
TOF): calcd. for C17H1435ClNNaO2 [M + Na]+ 322.0611; found
322.0604.
1-Benzyl-4-hydroxy-3-(3-methoxyphenyl)-1H-pyrrol-2(5H)-one (7c):
Following the general procedure, from methyl (3-methoxyphenyl)-
acetate (1b, 0.22 mL, 1.0 mmol), N-benzylglycine ethyl ester (6a,
0.22 mL, 1.2 mmol), and potassium tert-butoxide (1.2 mL,
1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7c (0.18 g,
62%) was obtained as a white solid; m.p. 191–192 °C (dec.); TLC:
1-Benzyl-3-(4-fluorophenyl)-4-hydroxy-1H-pyrrol-2(5H)-one (7g):
Following the general procedure, from methyl (4-fluorophenyl)-
acetate (1h, 0.22 mL, 1.0 mmol), N-benzylglycine ethyl ester (6a,
0.22 mL, 1.2 mmol), and potassium tert-butoxide (1.2 mL,
1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7g (0.15 g,
54%) was obtained as a white solid; m.p. 180–181 °C (dec.); TLC:
R = 0.25 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 2934, 2617,
˜
f
2
2
1666, 1596, 1491, 1461, 1398, 1287, 1261, 1215, 1052, 883, 781,
1
730, 692 cm–1. H NMR (400 MHz, [D6]acetone): δ = 7.82 (dd, J
= 2.7, 1.4 Hz, 1 H, Ar-H), 7.71–7.73 (m, 1 H, Ar-H), 7.22–7.37 (m,
6 H, Ar-H), 6.77 (ddd, J = 8.2, 2.7, 0.9 Hz, 1 H, Ar-H), 4.62 (s, 2
H, CH2Ph), 3.93 [s, 2 H, NCH2C(OH)=], 3.78 (s, 3 H, CH3O) ppm.
13C NMR (100 MHz, [D6]acetone): δ = 171.9, 166.8, 160.3, 139.3,
134.6, 129.5, 129.4, 128.6, 128.0, 120.7, 113.7, 112.4, 105.2, 55.3,
49.4, 45.7 ppm. MS (ESI-TOF): m/z = 296 [M + H]+. HRMS (ESI-
TOF): calcd. for C18H17NNaO3 [M + Na]+ 318.1106; found
318.1101.
R = 0.25 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 2927, 2614,
˜
f
2
2
1659, 1588, 1511, 1452, 1420, 1383, 1301, 1277, 1239, 1216, 1161,
972, 844, 815, 698 cm–1. 1H NMR (400 MHz, [D6]acetone): δ =
8.19 (dd, J = 9.1, 5.7 Hz, 2 H, Ar-H), 7.25–7.36 (m, 5 H, Ph-H),
7.10 (t, J = 9.1 Hz, 2 H, Ar-H), 4.63 (s, 2 H, CH2Ph), 3.94 [s, 2 H,
NCH2C(OH)=] ppm. 13C NMR (100 MHz, [D6]acetone): δ =
171.8, 166.3, 160.8 (d, J = 243 Hz), 139.3, 129.9 (d, J = 7 Hz),
129.7 (d, J = 3 Hz), 129.5, 128.6, 128.0, 115.2 (d, J = 21 Hz), 104.4,
49.4, 45.7 ppm. HRMS (ESI-TOF): calcd. for C17H14FNNaO2 [M
+ Na]+ 306.0906; found 306.0895.
1-Benzyl-3-(3,4-dimethoxyphenyl)-4-hydroxy-1H-pyrrol-2(5H)-one
(7d): Following the general procedure, from methyl (3,4-dimeth-
oxyphenyl)acetate (1g, 0.22 mL, 1.0 mmol), N-benzylglycine ethyl
ester (6a, 0.22 mL, 1.2 mmol), and potassium tert-butoxide
(1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7d
(0.17 g, 52%) was obtained as a white solid; m.p. 171 °C (dec.);
1-(2,4-Dimethoxybenzyl)-4-hydroxy-3-phenyl-1H-pyrrol-2(5H)-one
(7i): Following the general procedure, from methyl phenylacetate
(1f, 150 mg, 1.0 mmol), ethyl 2-[(2,4-dimethoxybenzyl)amino]-
acetate (6b, 304 mg, 1.2 mmol), and potassium tert-butoxide
(1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7i
(205 mg, 63%) was obtained as a white solid; m.p. 169–170 °C;
TLC: R = 0.25 (95:5 CH Cl /MeOH). IR (KBr pellet): ν = 2936,
˜
f
2
2
2838, 2626, 1665, 1596, 1521, 1448, 1370, 1262, 1221, 1146, 1025,
817, 764, 714, 697 cm–1. 1H NMR (400 MHz, [D6]acetone): δ =
7.88 (d, J = 2.5 Hz, 1 H, Ar-H), 7.70 (dd, J = 8.5, 2.5 Hz, 1 H, Ar-
H), 7.27–7.37 (m, 5 H, Ph-H), 6.92 (d, J = 8.5 Hz, 1 H, Ar-H),
4.62 (s, 2 H, CH2Ph), 3.91 [s, 2 H, NCH2C(OH)=], 3.80 (s, 6 H, 2
CH3O) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 172.2, 165.1,
149.7, 148.8, 139.4, 129.5, 128.6, 128.0, 126.4, 121.1, 112.5, 112.4,
105.2, 56.1, 56.0, 49.4, 45.7 ppm. MS (ESI-TOF): m/z = 326 [M
+ H]+. HRMS (ESI-TOF): calcd. for C19H19NNaO4 [M + Na]+
348.1212; found 348.1210.
TLC: R = 0.20 (1:1 cyclohexane/AcOEt). IR (KBr pellet): ν =
˜
f
3002, 2971, 2913, 2839, 2618, 1652, 1614, 1504, 1456, 1397, 1358,
1315, 1210, 1181, 1134, 1038, 907, 822, 779, 739, 698 cm–1. 1H
NMR (400 MHz, [D6]acetone): δ = 10.20 (br. s, 1 H, OH), 8.10 (d,
J = 7.4 Hz, 2 H, Ar-H), 7.32 (t, J = 7.4 Hz, 2 H, Ar-H), 7.17 (t, J
= 7.4 Hz, 1 H, Ar-H), 7.10 (d, J = 8.3 Hz, 1 H, Ar-H), 6.56 (d, J
= 2.2 Hz, 1 H, Ar-H), 6.48 (dd, J = 8.3, 2.2 Hz, 1 H, Ar-H), 4.53
1-Benzyl-3-(4-bromophenyl)-4-hydroxy-1H-pyrrol-2(5H)-one (7e): (s, 2 H, CH2Ar), 3.93 [s, 2 H, NCH2C(OH)=], 3.85 (s, 3 H, CH3O),
Following the general procedure, from methyl (4-bromophenyl)ace-
tate (1c, 0.22 mL, 1.0 mmol), N-benzylglycine ethyl ester (6a,
0.22 mL, 1.2 mmol), and potassium tert-butoxide (1.2 mL,
3.78 (s, 3 H, CH3O) ppm. 13C NMR (100 MHz, [D6]acetone): δ =
171.8, 166.4, 161.4, 159.3, 133.4, 130.9, 128.5, 128.2, 126.7, 119.2,
105.6, 105.4, 99.1, 55.8, 55.6, 50.0, 40.0 ppm. MS (ESI-TOF): m/z
1146
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1142–1148

One-Pot Synthesis of 3-Aryltetramic Acids
= 326 [M + H]+. HRMS (ESI-TOF): calcd. for C19H19NNaO4 [M
+ Na]+ 348.1212; found 348.1204.
fluorophenyl)acetate (1h, 168 mg, 1.0 mmol), ethyl 2-[(2,4-dimeth-
oxybenzyl)amino]acetate (6b, 304 mg, 1.2 mmol), and potassium
tert-butoxide (1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL),
tetramic acid 7m (245 mg, 71%) was obtained as a yellow solid;
m.p. 144–145 °C; TLC: Rf = 0.20 (1:1 cyclohexane/AcOEt). IR
1-(2,4-Dimethoxybenzyl)-4-hydroxy-3-(4-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (7j): Following the general procedure, from methyl
(4-methoxyphenyl)acetate (1a, 180 mg, 1.0 mmol), ethyl 2-[(2,4-di-
methoxybenzyl)amino]acetate (6b, 304 mg, 1.2 mmol), and potas-
sium tert-butoxide (1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL),
tetramic acid 7j (153 mg, 43%) was obtained as a white solid; m.p.
170–171 °C; TLC: Rf = 0.15 (1:1 cyclohexane/AcOEt). IR (KBr
(KBr pellet): ν = 3415, 3008, 2942, 2838, 2620, 1664, 1613, 1510,
˜
1455, 1419, 1385, 1301, 1209, 1158, 1034, 832, 815, 732, 570 cm–1.
1H NMR (400 MHz, [D6]acetone): δ = 8.17 (dd, J = 9.1, 5.7 Hz, 2
H, Ar-H), 7.11–7.06 (m, 3 H, Ar-H), 6.56 (d, J = 2.4 Hz, 1 H, Ar-
H), 6.48 (dd, J = 8.3, 2.4 Hz, 1 H, Ar-H), 4.52 (s, 2 H, CH2Ar),
3.94 [s, 2 H, NCH2C(OH)=], 3.85 (s, 3 H, CH3O), 3.78 (s, 3 H,
CH3O) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 171.8, 166.2,
161.7 (d, J = 243.3 Hz), 161.5, 159.4, 130.9, 129.9 (d, J = 7.7 Hz),
119.1, 115.1 (d, J = 20.7 Hz), 105.4, 104.4, 99.1, 55.8, 55.6, 49.9,
40.1 ppm. MS (ESI-TOF): m/z = 344 [M + H]+. HRMS (ESI-
TOF): calcd. for C19H18FNNaO4 [M + Na]+ 366.1118; found
366.1123.
pellet): ν = 3002, 2958, 2921, 2839, 2536, 1674, 1591, 1514, 1455,
˜
1442, 1392, 1358, 1290, 1246, 1210, 1178, 1117, 1032, 974, 948,
1
939, 902, 836, 819, 726, 661, 564 cm–1. H NMR (400 MHz, [D6]-
DMSO): δ = 11.37 (br. s, 1 H, OH), 7.94 (d, J = 9.0 Hz, 2 H, Ar-
H), 7.00 (d, J = 8.3 Hz, 1 H, Ar-H), 6.90 (d, J = 9.0 Hz, 2 H, Ar-
H), 6.58 (d, J = 2.3 Hz, 1 H, Ar-H), 6.49 (dd, J = 8.3, 2.3 Hz, 1
H, Ar-H), 4.43 (s, 2 H, CH2Ar), 3.81 [s, 2 H, NCH2C(OH)=], 3.80
(s, 3 H, CH3O), 3.74 (s, 6 H, 2 CH3O) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 171.1, 165.2, 159.9, 157.9, 157.1, 129.6, 127.9,
125.0, 117.9, 113.19, 104.7, 102.7, 98.4, 55.5, 55.2, 54.9, 49.1, 39.2
ppm. HRMS (ESI-TOF): calcd. for C20H21NNaO5 [M + Na]+
378.1317; found 378.1320.
1-(2,4-Dimethoxybenzyl)-4-hydroxy-3-(2-thienyl)-1H-pyrrol-2(5H)-
one (7n): Following the general procedure, from methyl 4-thienyl-
acetate (1e, 156 mg, 1.0 mmol), ethyl 2-[(2,4-dimethoxybenzyl)-
amino]acetate (6b, 304 mg, 1.2 mmol), and potassium tert-butoxide
(1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL), tetramic acid 7n
(205 mg, 61%) was obtained as a brown solid; m.p. 135–136 °C;
1-(2,4-Dimethoxybenzyl)-4-hydroxy-3-(3-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (7k): Following the general procedure, from methyl
(3-methoxyphenyl)acetate (1b, 156 mg, 1.0 mmol), ethyl 2-[(2,4-di-
methoxybenzyl)amino]acetate (6b, 304 mg, 1.2 mmol), and potas-
sium tert-butoxide (1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL),
tetramic acid 7k (190 mg, 53%) was obtained as a brown solid;
m.p. 150–151 °C; TLC: Rf = 0.15 (1:1 cyclohexane/AcOEt). IR
TLC: R = 0.15 (1:1 cyclohexane/AcOEt). IR (KBr pellet): ν =
˜
f
3399, 3002, 2939, 2836, 2686, 1667, 1613, 1591, 1509, 1456, 1438,
1
1401, 1337, 1294, 1266, 1209, 1157, 1131, 1035, 835, 694 cm–1. H
NMR (400 MHz, [D6]acetone): δ = 7.71 (d, J = 3.6 Hz, 1 H,
SCH=CH-CH), 7.28 (d, J = 5.2 Hz, 1 H, SCH), 7.10 (d, J = 8.5 Hz,
1 H, Ar-H), 7.03 (dd, J = 5.2, 3.6 Hz, 1 H, SCH=CH), 6.55 (d, J
= 2.3 Hz, 1 H, Ar-H), 6.47 (dd, J = 8.5, 2.3 Hz, 1 H, Ar-H), 4.52
(s, 2 H, CH2Ar), 3.88 [s, 2 H, NCH2C(OH)=], 3.84 (s, 3 H, CH3O),
3.78 (s, 3 H, CH3O) ppm. 13C NMR (100 MHz, [D6]acetone): δ =
170.9, 163.8, 161.5, 159.4, 134.3, 130.9, 126.9, 124.4, 124.0, 119.1,
105.4, 102.3, 99.1, 55.8, 55.6, 50.1, 40.3 ppm. MS (ESI-TOF): m/z
= 332 [M + H]+. HRMS (ESI-TOF): calcd. for C17H17NNaO4S
[M + Na]+ 354.0776; found 354.0765.
(KBr pellet): ν = 3433, 3005, 2956, 2836, 2624, 1609, 1510, 1455,
˜
1382, 1290, 1211, 1160, 1035, 987, 936, 878, 828, 815, 778, 691, 647
cm–1. 1H NMR (400 MHz, [D6]acetone): δ = 7.81 (dd, J = 2.6,
1.4 Hz, 1 H, Ar-H), 7.70 (ddd, J = 7.8, 1.4, 1.0 Hz, 1 H, Ar-H),
7.22 (t, J = 8.0 Hz, 1 H, Ar-H), 7.10 (d, J = 8.3 Hz, 1 H, Ar-H),
6.75 (ddd, J = 8.2, 2.6, 1.0 Hz, 1 H, Ar-H), 6.56 (d, J = 2.4 Hz, 1
H, Ar-H), 6.48 (dd, J = 8.3, 2.4 Hz, 1 H, Ar-H), 4.52 (s, 2 H,
CH2Ar), 3.93 [s, 2 H, NCH2C(OH)=], 3.85 (s, 3 H, CH3O), 3.78
(s, 6 H, 2 CH3O) ppm. 13C NMR (100 MHz, [D6]acetone): δ =
171.7, 166.6, 161.4, 160.2, 159.3, 134.7, 130.9, 129.3, 120.7, 119.2,
113.6, 112.3, 105.4, 105.3, 99.1, 55.8, 55.6, 55.3, 49.9, 40.1 ppm.
MS (ESI-TOF): m/z = 356 [M + H]+.
4-Hydroxy-3-phenyl-1H-pyrrol-2(5H)-one (8i): A solution of
tetramic acid 7i (100 mg, 0.31 mmol) in trifluoroacetic acid (3 mL)
was stirred at room temperature for 1 h. After the mixture was
concentrated under vacuum, toluene was added to the residue.
Concentration of the mixture under vacuum afforded tetramic acid
8i as a white solid (quantitative yield); m.p. 187–188 °C; TLC: Rf
3-(4-Bromophenyl)-1-(2,4-dimethoxybenzyl)-4-hydroxy-1H-pyrrol-
2(5H)-one (7l): Following the general procedure, from methyl (4-
bromophenyl)acetate (1c, 229 mg, 1.0 mmol), ethyl 2-[(2,4-dimeth-
oxybenzyl)amino]acetate (6b, 304 mg, 1.2 mmol), and potassium
tert-butoxide (1.2 mL, 1.2 mmol, 1  in THF) in THF (7 mL),
tetramic acid 7l (226 mg, 55%) was obtained as a white solid; m.p.
196–198 °C; TLC: Rf = 0.20 (1:1 cyclohexane/AcOEt). IR (KBr
= 0.55 (8:2 CH Cl /MeOH). IR (KBr pellet): ν = 3355, 3277, 3000,
˜
2
2
2939, 2834, 2709, 1642, 1615, 1508, 1453, 1391, 1315, 1299, 1223,
1202, 1184, 1116, 1094, 1037, 814, 784, 751, 697, 627 cm–1. 1H
NMR (400 MHz, [D6]DMSO): δ = 11.55 (br. s, 1 H, OH), 7.96 (d,
J = 7.3 Hz, 2 H, Ar-H), 7.42 (br. s, 1 H, NH), 7.30 (t, J = 7.3 Hz,
2 H, Ar-H), 7.14 (t, J = 7.3 Hz, 1 H, Ar-H), 3.86 [s, 2 H,
NCH2C(OH)=] ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
173.8, 168.8, 132.5, 127.6, 126.7, 125.4, 103.1, 44.8 ppm. MS (ESI-
TOF): m/z = 176 [M + H]+. HRMS (ESI-TOF): calcd. for
C10H9NNaO2 [M + Na]+ 198.0531; found 198.0522.
pellet): ν = 3009, 2924, 2834, 2587, 1665, 1608, 1509, 1454, 1409,
˜
1379, 1297, 1209, 1157, 1116, 1030, 826, 746 cm–1 1H NMR
.
(400 MHz, [D6]DMSO): δ = 11.94 (br. s, 1 H, OH), 8.02 (d, J =
8.7 Hz, 2 H, Ar-H), 7.50 (d, J = 8.7 Hz, 2 H, Ar-H), 7.01 (d, J =
8.3 Hz, 1 H, Ar-H), 6.57 (d, J = 2.3 Hz, 1 H, Ar-H), 6.48 (dd, J
= 8.3, 2.3 Hz, 1 H, Ar-H), 4.43 (s, 2 H, CH2Ar), 3.84 [s, 2 H,
NCH2C(OH)=], 3.80 (s, 3 H, CH3O), 3.74 (s, 3 H, CH3O) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 170.6, 168.0, 159.9, 157.9,
131.9, 130.7, 129.6, 128.3, 118.2, 117.7, 104.7, 101.5, 98.4, 55.5,
55.2, 49.2, 39.2 ppm. MS (ESI-TOF): m/z = 404, 406 [M + H]+.
HRMS (ESI-TOF): calcd. for C19H1879BrO4NNa [M + Na]+
426.0317; found 426.0301; calcd. for C19H1881BrO4NNa [M +
Na]+ 428.0296; found 428.0285.
4-Hydroxy-3-(3-methoxyphenyl)-1H-pyrrol-2(5H)-one (8k): Follow-
ing the procedure described for 8i, starting from tetramic acid 7k
(100 mg, 0.28 mmol), tetramic acid 8k was obtained as a brown
solid (quantitative yield); m.p. 180–181 °C; TLC: Rf = 0.55 (8:2
CH Cl /MeOH). IR (KBr pellet): ν = 3305, 2944, 2836, 2627, 1663,
˜
2
2
1614, 1508, 1463, 1440, 1371, 1296, 1256, 1204, 1178, 1114, 1095,
1
1035, 860, 839, 814, 784, 746, 693, 677, 640, 581 cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 11.57 (br. s, 1 H, OH), 7.58 (s, 1 H,
Ar-H), 7.53 (d, J = 7.9 Hz, 1 H, Ar-H), 7.38, (br. s, 1 H, NH), 7.16
(t, J = 7.9 Hz, 1 H, Ar-H), 6.68 (d, J = 7.9 Hz, 1 H, Ar-H), 3.80
1-(2,4-Dimethoxybenzyl)-3-(4-fluorophenyl)-4-hydroxy-1H-pyrrol-
2(5H)-one (7m): Following the general procedure, from methyl (4-
Eur. J. Org. Chem. 2010, 1142–1148
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1147

A. Mallinger, B. Nadal, N. Chopin, T. Le Gall
FULL PAPER
[s, 2 H, NCH2C(OH)=], 3.68 (s, 3 H, CH3O) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 173.7, 169.1, 158.7, 133.8, 128.6,
119.3, 112.4, 110.9, 102.8, 54.8, 4.8 ppm. MS (ESI-TOF): m/z =
206 [M + H]+. HRMS (ESI-TOF): calcd. for C11H11NNaO3 [M +
Na]+ 228.0637; found 228.0633.
TOF): m/z = 260 [M + H]+. HRMS (ESI-TOF): calcd. for
C15H17NNaO3 [M + Na]+ 282.1106; found 282.1098.
Acknowledgments
3-(4-Bromophenyl)-4-hydroxy-1H-pyrrol-2(5H)-one (8l): Following
the procedure described for 8i, starting from tetramic acid 7l
(100 mg, 0.25 mmol), tetramic acid 8l was obtained as a brown
solid (quantitative yield); m.p. 210 °C (dec.); TLC: Rf = 0.55 (8:2
B. N. thanks the Délégation Générale pour l’Armement (DGA) for
a research fellowship. The authors thank X. Monchaussat for per-
forming several experiments.
CH Cl /MeOH). IR (KBr pellet): ν = 3424, 3001, 2920, 2834, 2673,
˜
2
2
[1] Reviews: a) R. Schobert, A. Schlenk, Bioorg. Med. Chem. 2008,
16, 4203–4221; b) B. J. L. Royles, Chem. Rev. 1995, 95, 1981–
2001; c) H.-G. Henning, A. Gelbin, in: Advances in Heterocy-
clic Chemistry (Ed.: A. R. Katritzky), Academic Press, San Di-
ego, 1993, vol. 57, pp. 139–185.
1633, 1589, 1509, 1491, 1441, 1425, 1378, 1300, 1224, 1202, 1038,
828, 756, 711 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.86
(br. s, 1 H, OH), 7.99 (d, J = 8.5 Hz, 2 H, Ar-H), 7.50 (d, J =
8.5 Hz, 2 H, Ar-H), 7.49 (br. s, 1 H, NH), 3.86 [s, 2 H,
NCH2C(OH)=] ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
173.4, 169.7, 131.9, 130.6, 128.4, 118.2, 101.8, 44.8 ppm. MS (ESI-
TOF): m/z = 254, 256 [M + H]+. HRMS (ESI-TOF): calcd. for
C10H879BrNNaO2 [M + Na]+ 275.9636; found 275.9626; calcd. for
C10H881BrNNaO2 [M + Na]+ 277.9616; found 277.9603.
[2] For selected references, see: a) R. Fischer, E. Brueck, X. A.
van Waetermeulen, German Patent DE 102006022821, 2007
Chem. Abstr. 2007, 147, 497332; b) M. Ito, H. Okui, H. Naka-
gawa, S. Mio, A. Kinoshita, T. Obayashi, T. Miura, J. Nagai,
S. Yokoi, R. Ichinose, K. Tanaka, S. Kodama, T. Iwasaki, T.
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11, 489–494; c) M. Ito, H. Okui, H. Nakagawa, S. Mio, A.
Kinoshita, T. Obayashi, T. Miura, J. Nagai, S. Yokoi, R. Ichi-
nose, K. Tanaka, S. Kodama, T. Iwasaki, T. Miyake, M. Taka-
shio, J. Iwabuchi, Bioorg. Med. Chem. 2003, 11, 761–768; d)
M. Kato, Y. Yamada, A. Sato, A. Takahashi, Japanese Patent
2001072661, 2001; Chem. Abstr. 2001, 134, 237385.
[3] E. Brück, A. Elbert, R. Fischer, S. Krueger, J. Kühnhold, A. M.
Klueken, R. Nauen, J.-F. Niebes, U. Reckmann, H.-J. Schnor-
bach, R. Steffens, X. van Waetermeulen, Crop. Prot. 2009, 28,
838–844.
3-(4-Fluorophenyl)-4-hydroxy-1H-pyrrol-2(5H)-one (8m): Following
the procedure described for 8i, starting from tetramic acid 7m
(100 mg, 0.29 mmol), tetramic acid 8m was obtained as a yellow
solid (quantitative yield); m.p. 200 °C (dec.); TLC: Rf = 0.55 (8:2
CH Cl /MeOH). IR (KBr pellet): ν = 3398, 3002, 2931, 2834, 2355,
˜
2
2
1825, 1612, 1591, 1509, 1466, 1442, 1372, 1300, 1203, 1159, 1037,
836, 814, 749, 606, 593, 575 cm–1 1H NMR (400 MHz, [D6]-
.
DMSO): δ = 11.66 (br. s, 1 H, OH), 8.03 (dd, J = 9.0, 5.9 Hz, 2 H,
Ar-H), 7.44 (br. s, 1 H, NH), 7.13 (t, J = 9.0 Hz, 2 H, Ar-H), 3.86
[s, 2 H, NCH2C(OH)=] ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 173.7, 168.7, 160.0 (d, J = 243.6 Hz), 129.0 (d, J = 3.1 Hz), 128.4
(d, J = 7.8 Hz), 114.5, 102.1, 44.8 ppm. MS (ESI-TOF): m/z = 194
[M + H]+. HRMS (ESI-TOF): calcd. for C10H8FNNaO2 [M +
Na]+ 216.0437; found 216.0426.
[4] I. M. Mawer, J. J. Kulagowski, P. D. Leeson, S. Grimwood,
G. R. Marshall, Bioorg. Med. Chem. Lett. 1995, 5, 2643–2648.
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[6] a) M. Anwar, M. G. Moloney, Tetrahedron Lett. 2007, 48,
7259–7262; b) K. M. Dorward, N. J. Guthrie, E. T. Pelkey, Syn-
thesis 2007, 2317–2322; c) D. S. Dodd, S. Sheriff, C. Y. J.
Chang, D. K. Stetsko, L. M. Phillips, Y. Zhang, M. Launay, D.
Potin, W. Vaccaro, M. A. Poss, M. McKinnon, J. C. Barrish,
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Moloney, Tetrahedron: Asymmetry 1994, 5, 1477–1478.
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388; b) A. Mallinger, T. Le Gall, C. Mioskowski, J. Org. Chem.
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[9] M. Shiozaki, N. Ishida, T. Hiraoka, H. Maruyama, Tetrahe-
dron 1984, 40, 1795–1802.
1-Hydroxy-2-(4-methoxyphenyl)-6,7,8,8a-tetrahydroindolizin-3(5H)-
one (9): Following the general procedure, from methyl (4-meth-
oxyphenyl)acetate (1a, 180 mg, 1.0 mmol), methyl pipecolinate
(172 mg, 1.2 mmol), and potassium tert-butoxide (1.2 mL,
1.2 mmol, 1  in THF) in THF (5 mL), tetramic acid 9 (100 mg,
37%) was obtained as a gray solid; m.p. 212–213 °C; TLC: Rf =
0.15 (1:1 cyclohexane/AcOEt). IR (KBr pellet): ν = 3007, 2934,
˜
2862, 2836, 2678, 1663, 1610, 1514, 1461, 1427, 1378, 1308, 1290,
1248, 1206, 1184, 1165, 1034, 1016, 1000, 880, 834, 792, 718, 586,
1
532 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 11.16 (br. s, 1 H,
OH), 7.92 (d, J = 8.8 Hz, 2 H, Ar-H), 6.89 (d, J = 8.8 Hz, 2 H,
Ar-H), 4.12 (dd, J = 12.8, 4.0 Hz, 1 H, CHHЈN), 3.81 [dd, J =
11.4, 3.5 Hz, 1 H, NCHC(OH)=], 3.74 (s, 3 H, CH3O), 2.72 (dt, J
= 12.8, 2.8 Hz, 1 H, CHHЈN), 2.34 [m, 1 H, CHHЈ(CH2)3NC-
[10] R. H. Schlessinger, G. R. Bebernitz, J. Org. Chem. 1985, 50,
1344–1346.
[11] R. Fischer, A. Krebs, A. Marhold, H. J. Santel, R. R. Schmidt,
K. Luerssen, H. Hagemann, B. Becker, K. Schaller, W. Stendel,
EP0355599, 1990; Chem. Abstr. 2000, 113, 191153.
Received: September 24, 2009
(O)-], 1.83 [m,
1 H, CHHЈ(CH2)2NC(O)-], 1.64 [m, 1 H,
CHHЈCH2NC(O)-], 1.47 [m, 1 H, CHHЈ(CH2)2NC(O)-], 1.15 [m,
1 H, CHHЈCH2NC(O)-], 0.97 [m, 1 H, CHHЈ(CH2)3NC(O)-] ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 168.6, 168.2, 157.0, 128.0,
125.0, 113.1, 102.0, 56.3, 54.9, 37.6, 30.0, 25.6, 22.4 ppm. MS (ESI-
Published Online: January 4, 2010
1148
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Eur. J. Org. Chem. 2010, 1142–1148