Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones based on cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride

Article abstract of DOI:10.1016/j.tet.2009.03.102

The acid-mediated reaction of amines with γ-alkylidenebutenolides, readily available by cyclization of 1,3-bis(silyloxy)-1,3-butadienes with oxalyl chloride, allows a convenient synthesis of a variety of 5-alkylidene-2,5-dihydropyrrol-2-ones. The configur

Full text of DOI:10.1016/j.tet.2009.03.102

Tetrahedron 65 (2009) 4530–4539
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Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones based on cyclizations
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride
,b,
Christian Haase a, Peter Langer a
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The acid-mediated reaction of amines with g-alkylidenebutenolides, readily available by cyclization of
Received 2 January 2009
Received in revised form 24 March 2009
Accepted 30 March 2009
Available online 5 April 2009
1,3-bis(silyloxy)-1,3-butadienes with oxalyl chloride, allows a convenient synthesis of a variety of 5-al-
kylidene-2,5-dihydropyrrol-2-ones. The configuration of the exocyclic double bond of the products de-
pends on the substitution pattern of the products.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
5-Alkylidene-3-aryltetramic acids, such as 6, bind as antagonists
at N-methyl-D-aspartate-receptors, which represent ion channels
Tetramic acids (pyrrolidine-2,4-diones 1) are of considerable
pharmacological relevance and occur in a variety of natural products.
They occur, for example, in 3-alkylidene-3,5-dihydropyrrol-2,4-dio-
present in neurons (Scheme 2). Therefore, these substances are
promising drugs for the treatment of epilepsis and related CNS-
based diseases.6
nes such as tenuazoic acid 2,
a-cyclopiazoic acid 3 or in the
macrocyclic discodermides 4 (Scheme 1).1 The related 5-alkylidene-
2,5-dihydropyrrol-2-ones are also of pharmacological importance
and are found in nature. This structural class includes the amar-
yllidacae alkaloids,2 the pukeleimides 5,3 holomycin,4 isoampullicin,5
and linear oligopyrroles (for example, bilirubine).
O
NH
HO
O
OH
HO
6
O
O
N
H
Scheme 2. 5-Alkylidene-3-aryltetramic acid 6.
H
HN
HN
O
H
O
Last but not least, 5-alkylidene-2,5-dihydropyrrol-2-ones rep-
resent versatile synthetic building blocks, which have been used as
key intermediates during the synthesis of antibiotics.1,7
O
H
NH
1
2
3
5-Alkylidene-2,5-dihydropyrrol-2-ones are synthetically avail-
able by Wittig reaction of maleimides with stabilized ylides.8,9 They
have been prepared also by hydrogenolysis of the isoxazolidines,
which are available by 1,3-dipolar cycloadditions of nitrones with
alkenes and alkynes.10 An alternative approach relies on the re-
H
O
N
OR
O
OMe
O
H
H
H
N
O
OR
H
NH
N
action of amines with alkylidenetetronic acids11 or dimethyl-
b-oxo-
O
O
Me
alkanedioates.12 Abell and co-workers have reported an efficient
two-step synthesis of cyclic enamino esters from enol lactones.13 5-
Alkylidene-pyrrolidin-2-ones have been prepared also by reaction
of protected 2,2-diethoxypyrrolidines with ketones.14 Recently, we
have developed a new approach to 5-alkylidene-3-amino-2,5-
dihydropyrrol-2-ones by cyclization of 1,3-dicarbonyl dianions
with oxalic acid-bis(imidoyl)chlorides.15 However, this method is
limited to the synthesis of N-aryl derivatives.
H
H
R=H/Me
O
OH
R=H/COCH3
4
5
Scheme 1. Tetramic acids in nature.
* Corresponding author. Fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.102

C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
4531
Some years ago we developed an efficient approach to
g
-alkyl-
reaction mixture was stirred under reflux until all starting material
was converted into the product (20 h, TLC control). The deprotection
of 13a using BBr3 proceeded smoothly and afforded product 14a in
91% yield without cleavage of the methoxy group. During the opti-
mization, the use of an excess of BBr3 (3.9 equiv) and a short reaction
time (30 min at 0 ꢁC, TLC control) proved to be important.
idenebutenolides based on the cyclization of 1,3-bis(silyloxy)-1,3-
butadienes with oxalyl chloride.16 Stachel and Saalfrank were the
first to report a two-step synthesis of 5-alkylidene-2,5-dihy-
dropyrrol-2-ones by reaction of
g-alkylidenebutenolides with
amines.17 The yields of the reactions, which were carried out under
basic conditions, were relatively low. Recently, we have commu-
nicated18 an efficient and practical method for the synthesis of
O
OMe
O
OMe
5-alkylidene-2,5-dihydropyrrol-2-ones based on the reaction of g-
H
O
alkylidenebutenolides with ammonium acetates and amines in
glacial acetic acid. The conditions of these reactions follow those
reported9,19 for the transformation of maleic anhydrides into maleic
imides. Herein, we report full details of our methodology.
N
NH4OAc
HOAc
130 °C
O
O
OMe
OMe
HO
H2N
11 (22%)
8a
BnBr, K2CO3
20 °C, 24 h
2. Results and discussion
1,3-Bis(silyloxy)-1,3-butadiene 7a was prepared in two steps
from methyl 4-methoxyacetoacetate.20,21 Some years ago, we
O
OMe
OMe
O
H
N
reported the synthesis of g-alkylidenebutenolide 8a by Me3SiOTf-
catalyzed cyclization of 7a with oxalyl chloride (Scheme 3).22
Product 8a was formed with very good Z-diastereoselectivity,
which can be explained by the steric effect of the methoxy group
located at carbon atom C-4 of the butenolide.
O
NH4OAc
O
O
HOAc
130 °C
OMe
OMe
13a (96%)
BnO
BnO
12a (62%)
O
OMe
Me3SiO
Me3SiO
Cl
1) BBr3, CH2Cl2
0 °C, 30 min
2) HCl (10%)
O
H
N
OMe
OMe
O
i
O
O
O
+
Ref. 22
OMe
OMe
O
HO
OMe
14a (91%)
Cl
HO
7a
8a
Scheme 3. Synthesis of
(0.3 equiv), CH2Cl2, ꢀ78/20 ꢁC.
g-alkylidenebutenolide 8a. Conditions: (i) Me3SiOTf
Scheme 5. Reaction of 8a and 12a with ammonium acetate.
Stirring of 8a with aniline (neat) resulted in the formation of
a complex, unseparable mixture of products containing 9 and 10
(Scheme 4). The use of different solvents (THF, MeOH, CH2Cl2),
variation of the stoichiometry and the temperature (room tem-
perature or reflux) did not result in an improvement.
Pyrrol-2-one 13a was formed with very good Z-diastereo-
selectivity, which can be explained by the steric effect of the
methoxy group. In addition, a stable intramolecular hydrogen bond
N–H/O is formed, which is not possible for the E-isomer. The
stereochemical assignment of all products relies on NOESY exper-
iments and detailed analysis of the chemical shifts (vide infra).
The transformation of 12a into 13a may proceed by acid-me-
diated attack of ammonia onto the lactone (intermediate A), ring
cleavage (to give intermediate B) and subsequent acid-mediated
recyclization by attack of the amide nitrogen atom onto the car-
bonyl group (Scheme 6). This mechanism has to be taken into
O
OMe
O
O
O
NHPh
OMe
O
OMe
HO
PhNH2
i
9
O
+
O
O
OMe
O
OMe
O
various
Ph
N
OMe
conditions
O
OMe
NH2
HO
O
[H+]
HO
8a
NHPh
OMe
O
H2N
BnO
OMe
OMe
BnO
HO
B
A
10
[H+]
H2O
[H+]
NH3
Scheme 4. Reaction of butenolide 8a with aniline. Conditions: (i) neat, THF, MeOH or
CH2Cl2, 20 ꢁC or reflux.
_
NH4OAc
HOAc
130 °C
The problem could be solved by the application of acidic condi-
tions. The reaction of 8a with ammonium acetate in glacial acetic
acid (130 ꢁC, 2 h) resulted in the formation of a complex mixture
from which product 11 could be isolated in 22% yield (Scheme 5).
Although the desired transformation of the lactone into a lactam
was achieved, the enolic OH group was also replaced bya NH2 group.
To solve this problem, the hydroxyl group was protected by a benzyl
group (product 12a). The reaction of 12a with ammonium acetate
afforded the desired 5-alkylidene-2,5-dihydropyrrol-2-one 13a in
excellent yield (96%). The best yields were obtained when glacial
acetic acid was used as the solvent and when an excess of ammo-
nium acetate (5.0 equiv) was used. To avoid decomposition, the
12a
13a
[H+]
NH3
[H+]
H2O
_
O
OMe
O
H2N
OMe
HO
O
[H+]
O
NH2
OMe
O
OMe
BnO
BnO
C
D
Scheme 6. Possible mechanisms of the formation of 12a.

4532
C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
account as the related transformation of maleic anhydrides into
maleic imides (under identical conditions) has been previously
reported.9,19 Alternatively, the ring-transformation may proceed by
acid-mediated attack of ammonia onto the exocyclic double bond
to give intermediate C, ring cleavage (intermediate D), and sub-
sequent acid-mediated recyclization by attack of the enamine ni-
trogen atom onto the carboxylic acid group. The need of using
glacial acetic acid can be explained by acid-mediated activation of
the lactone and the ester group during the formation of in-
termediates A and C, respectively. In addition, the acid presumably
plays an important role in the cyclization step by activation of the
carbonyl and the carboxylic acid group of intermediates B and D,
respectively. Last but not the least, the acid facilitates the extrusion
of water in the final step of the reaction.
The reaction of 12a with methylammonium chloride in glacial
acetic acid afforded a separable mixture of Z-13b (17%) and E-13b
(40%) (Scheme 7, Table 1). Starting with isobutylamine and cyclo-
hexylamine, products 13c and 13d were isolated, respectively. Both
products were formed as separable mixtures of E/Z-isomers. The
loss of the stereoselectivity in favour of the Z-configured isomer can
be explained (a) by the fact that an intramolecular hydrogen bond
cannot be formed (due to the absence of a hydrogen atom located at
the nitrogen) and (b) by the competing steric influence of the
methoxy group (located at carbon C-4 of the pyrrol-2-one) and of
the alkyl group attached to the nitrogen atom. Upon standing, pure
Z-13b undergoes a slow isomerization to give a mixture of E-13b
and Z-13b (ratio 1:3). Pure Z-13c slowly rearranges to a mixture E-
13c/Z-13c¼2:3. Pure E-13d slowly rearranges to a mixture E-13d/Z-
13d¼5:1.
O
OEt
Me3SiO
Me3SiO
Cl
OEt
O
i
O
O
+
Ref. 22
OBn
OBn
O
HO
Cl
7b
8b
BnBr, K2CO3
20 °C, 24 h
O
OEt
O
OEt
H
N
O
NH4OAc
O
O
HOAc
130 °C
OBn
13e (91%)
OBn
BnO
BnO
12b (83%)
Scheme 8. Synthesis of 13e. Conditions: (i) Me3SiOTf (0.3 equiv), CH2Cl2, ꢀ78/20 ꢁC.
deprotected to give 14h. The E-diastereoselective formation of 8d
can be explained by the higher thermodynamic stability of the E-
compared to the Z-configured butenolide. The selective formation
of E-configured pyrrol-2-one 13h is a result of the steric effect of the
methyl group located at the nitrogen atom and the absence of
a substituent located at carbon C-4. The reaction of 12d with am-
monium acetate afforded a separable mixture of Z-13i and E-13i.
Upon standing, the E-isomer underwent a slow isomerization into
the Z-isomer. The higher stability of the latter can be explained by
the presence of the intramolecular hydrogen bond N–H/O.
We have recently reported the synthesis of butenolide 16 by
Suzuki reaction of triflate 15a with phenylboronic acid (Scheme
11).23 The reaction of 16 with NH4OAc afforded the 5-alkylidene-
2,5-dihydropyrrol-2-one 17 as a separable mixture of E/Z-isomers.
Due to the formation of an N–H/O hydrogen bond, the Z-isomer
O
OMe
R
N
MeNH3Cl
or
R-NH2
R
N
OMe
O
O
+
O
12a
HOAc
130 °C
OMe
OMe
BnO
BnO
Z-13b-d
E-13b-d
Scheme 7. Synthesis of 13b–d.
O
OMe
Me3SiO
Me3SiO
Cl
OMe
O
The cyclization of diene 7b, prepared from ethyl 4-(benzyloxy)-
acetoacetate, with oxalyl chloride gave butenolide 8b,22 which was
transformed (via 12b) into the Z-configured 5-alkylidene-2,5-
dihydropyrrol-2-one 13e (Scheme 8).
i
O
O
+
Ref. 22
Me
Me
O
HO
Cl
7c
8c
The cyclization of diene 7c, prepared from methyl 3-oxopenta-
noate, with oxalyl chloride afforded butenolide 8c,22 which was
transformed into the benzylated derivative 12c (Scheme 9). The
reaction of the latter with ammonium acetate gave the Z-config-
ured 5-alkylidene-2,5-dihydropyrrol-2-one 13f, which was sub-
sequently transformed into the deprotected derivative 14f. The
reaction of 12c with methylammonium chloride afforded a sepa-
rable mixture of Z-13g and E-13g. Upon standing, pure E-13g un-
dergoes a slow isomerization to give a mixture of Z-13g and E-13g
(ratio 1:1).
The cyclization of diene 7d, prepared from methyl acetoacetate,
with oxalyl chloride gave butenolide 8d,22 which was transformed
into the benzyl-protected derivative 12d (Scheme 10). The reaction
of 12d with methylammonium chloride gave the E-configured 5-
alkylidene-2,5-dihydropyrrol-2-one 13h, which was subsequently
BnBr, K2CO3
20 °C, 24 h
O
OMe
O
OMe
H
N
NH4OAc
O
O
O
HOAc
Me
13f (76%)
Me
130 °C
BnO
BnO
12c (64%)
1) BBr3, CH2Cl2
0 °C, 30 min
2) HCl (10%)
MeNH3Cl
HOAc
130 °C
O
OMe
O
OMe
Me
H
N
Me
N
Table 1
Synthesis of 13b–d
OMe
N
O
O
O
+
Me
O
% (Z)a
% (E)a
Me
14f (86%)
Compound 13
R
Me
HO
BnO
BnO
E-13g (27%)
b
c
d
Me
i-Bu
c-Hex
17
25
40
40
40
30
Z-13g (28%)
Scheme 9. Synthesis of 14f and 13g. Conditions: (i) Me3SiOTf (0.3 equiv), CH2Cl2,
ꢀ78/20 ꢁC.
a
Isolated yields of pure E/Z-isomers.

C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
4533
Me3SiO
Me3SiO
Cl
synthesis of this product from methylmaleic anhydride (two steps,
24% yield) and its transformation into pukeleimide A.9
OMe
OMe
O
O
i
O
+
O
Ref. 22
O
O
O
O
HO
O
7d
8d (76%)
ii
Cl
OEt
OEt
RO
Me
O
O
BnBr, K2CO3
20 °C, 24 h
8e (R = H)
19 (60%)
i
15b (R = Tf)
92%
Me
N
iii
OMe
OMe
O
MeNH3Cl
O
O
O
O
HOAc
130 °C
Me
N
BnO
BnO
Me
N
OMe
O
13h (85%)
12d (65%)
O
N
OEt
O
1) BBr3, CH2Cl2
0 °C, 30 min
2) HCl (10%)
NH4OAc
HOAc
130 °C
Me
O
O
20 (78%)
Ref. 9
OH
Pukeleimide A
Scheme 12. Synthesis of an intermediate of the Pattenden synthesis of pukeleimide A:
(i) Tf2O, pyridine, ꢀ78 ꢁC/ꢀ10 ꢁC; (ii) MeB(OH)2, Pd(PPh3)4 (3 mol %), K3PO4
(1.5 equiv), 1,4-dioxane, reflux; (iii) MeNH3Cl, HOAc, 140 h, 130 ꢁC.
O
OMe
Me
N
H
N
H
N
OMe
OMe
The scope of the ring-transformation seems to be limited to b-
O
O
O
+
O
O
ketoester-derived butenolides containing a hydrogen atom located
at the exocyclic double bond. In fact, all attempts to transform
benzylated butenolide 12e into the corresponding 5-alkylidene-
2,5-dihydropyrrol-2-one (by reaction with ammonium acetate)
failed (Scheme 13). Likewise, the reaction of ammonium acetate
with 12f, derived from 2-acetyltetralone, failed.
HO
BnO
Z-13i (55%)
BnO
E-13i (22%)
14h (78%)
Scheme 10. Synthesis of 14h and 13i. Conditions: (i) Me3SiOTf (0.3 equiv), CH2Cl2,
ꢀ78/20 ꢁC.
was the major product. It is worth to be noted that no isomerization
of E-17 was observed upon standing. This result suggests that
the presence of an oxygen atom located at carbon atom C3 of
the pyrrol-2-one results in a decrease of the energetic barrier of the
isomerization process. Treatment of 16 with MeNH3Cl gave the E-
configured product 18 in 85% yield. Like in the case of 13h, the E-
diastereoselectivity is a result of the steric effect of the methyl
group located at the nitrogen atom and of the absence of a sub-
stituent located at carbon C-4.
O
O
O
O
O
O
O
BnO
BnO
12e
12f
Scheme 13. Starting materials 12e,f.
The configuration of the exocyclic double bond of the 5-alkyli-
dene-2,5-dihydropyrrol-2-ones was established by spectroscopic
methods (NOESY experiments and chemical shift analyses). For
example, the NOSEY-spectrum of 13e shows an interaction be-
tween the methyl group attached to carbon atom C-4 of the pyrrol-
2-one and proton H-10 located at the exocyclic double bond
(Scheme 14). In case of 20, an NOE interaction is observed between
the protons located at the exocyclic double bond (H-10) and at the
pyrrol-2-one moiety (H-4).
O
O
O
O
ii
OMe
OMe
Ref. 23
RO
Ph
O
O
8d (R = H)
16 (88%)
i
15a (R = Tf)
86%
iii
iv
Some general trends are observed for the chemical shifts of 5-
alkylidene-2,5-dihydropyrrol-2-ones. The NH proton involved in an
H
O
H
OMe
O
N
N
O
Me
N
OMe
+
NOE
Ph
Z-17 (70%)
Ph
E-17 (20%)
O
O
O
OMe
8.92
O
H
N
OMe
H
5.45
OEt
Me
N
Ph
H 5.27
O
18 (85%)
O
O
7.74
Me
NOE
H
BnO
Me
Scheme 11. Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones 17 and 18. Conditions
(i) Tf2O, pyridine, ꢀ78 ꢁC/ꢀ10 ꢁC; (ii) PhB(OH)2, Pd(PPh3)4 (3 mol %), K3PO4
(1.5 equiv), 1,4-dioxane, reflux; (iii) MeNH3Cl, AcOH, 130 ꢁC, 12 h; (iv) NH4OAc, AcOH,
130 ꢁC, 12 h.
13e
20
O
OMe
Triflate 15b was prepared from butenolide 8e (Scheme 12). The
Stille reaction of 15b with SnMe4, using our recently published
protocol,24 was unsuccessful. In contrast, the Suzuki reaction of 15b
with methylboronic acid afforded the desired butenolide 19 in good
yield. Treatment of 19 with MeNH3Cl afforded the E-configured 5-
alkylidene-2,5-dihydropyrrol-2-one 20 (33% over four steps from
oxalyl chloride). Pattenden and co-workers earlier reported the
9.16
H 5.50
OMe
H
N
7.79
O
H
N
H 5.24
5.79
O
O
7.00
H
H
BnO
BnO
Z-13i
E-13i
Scheme 14. Characteristic NOE-interactions and chemical shifts.

4534
C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
Table 2
Characteristic chemical shifts
3.2. 3-Amino-4-methoxy-5-[E-(methoxycarbonyl-
methylidene)]-pyrrol-2-one (11)
0a
b
c
Compound
Config.
dH-1
dNH
dH-4
A solution of 8a (350 mg, 1.75 mmol, 1.0 equiv) and ammonium
acetate (680 mg, 8.75 mmol, 5.0 equiv) in glacial acetic acid (5 mL)
was heated under reflux for 10 h. The solvent was removed in vacuo
and the residue was purified by chromatography (silica gel, hex-
anes/EtOAc¼1:1) to give 11 as a yellow solid (90 mg, 23%), mp 124–
13a
Z
E
Z
E
Z
E
Z
Z
Z
E
Z
E
E
Z
E
Z
E
E
5.44
5.54
5.46
5.54
5.45
5.50
5.62
5.49
5.27
5.46
5.29
5.45
5.50
5.24
5.63
5.43
5.58
5.45
8.48
d
d
d
d
d
d
d
d
d
d
d
d
E-13b
Z-13b
E-13c
Z-13c
E-13d
Z-13d
13e
d
d
d
d
ꢀ1
126 ꢁC. IR (KBr, cm ):
¼ 3416ðsÞ, 3343 (s), 2275 (s), 3199 (m),
~
n
d
8.48
8.92
d
2952 (m),1728 (s), 1707 (s), 1676 (s),1676 (s),1644 (s),1607 (s), 1439
(s). 1H NMR (CDCl3, 300 MHz):
¼3.69 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 3.95 (br s, 2H, NH2), 5.37 (s, 1H, CH), 8.62 (br s, 1H, NH). 13
NMR (CDCl3, 75 MHz):
13f
d
E-13g
Z-13g
13h
E-13i
Z-13i
E-17
Z-17
18
C
d
d
¼51.5, 59.7 (OCH3), 90.8 (CH), 122.5, 134.2,
d
6.98
7.00
5.79
8.24
7.12
8.25
7.74
7.79
9.16
br
9.18
d
146.7 (C), 166.6, 167.7 (C]O). MS (EI, 70 eV): m/z (%)¼198 ([M]þ,
95), 183 (13), 166 (62), 150 (100), 123 (26), 95 (38), 69 (49). HRMS
(EI, 70 eV): calcd for C8H10N2O4: 198.0641; found: 198.0641ꢂ
2 ppm. Anal. Calcd for C8H10N2O4 (198.18): C 48.48, H 5.09, N 14.14.
Found: C 48.65, H 5.19, N 12.29.
20
d
a
Proton located at the exocyclic double bond (CDCl3).
Proton NH (CDCl3).
Proton located at carbon C-4 of the pyrrol-2-one moiety (CDCl3).
b
c
3.3. 3-Benzyloxy-4-methoxy-5-[Z-(methoxycarbonyl-
methylidene)]-2-furanone (12a)
To a suspension of K2CO3 (3.93 g, 28.4 mmol, 2.0 equiv) in ace-
tone (60 mL) were added 8a (2.84 g, 14.2 mmol, 1.0 equiv) and
benzylbromide (2.41 g, 1.7 mL, 14.2 mmol, 1.0 equiv) at 20 ꢁC. After
stirring for 24 h, the solid formed was filtered off and the filtrate was
concentrated in vacuo. The residue was purified by chromatography
(silica gel, hexane/EtOAc¼10:1/4:1) to give 12a as a colourless
solid (2.40 g, 62%), mp¼126–128 ꢁC. Rf¼0.20 (hexane/EtOAc¼4:1).
~
intramolecular hydrogen bond is significantly shifted downfield
with respect to the signal of the NH group of the other isomer. For
example, the signal of the NH group of Z-13i appears at
whereas the respective signal of E-13i appears at
(Scheme 14, Table 2). Proton H-4 of E-configured pyrrol-2-ones is
considerably shifted downfield with respect to the respective signal
of the Z-configured isomers. For example, the signal of proton H-4
d
¼9.16 ppm
d¼7.79 ppm
IR (KBr, cmꢀ1):
n
¼ 2954ðwÞ, 1794 (s), 1729 (s), 1721 (s), 1673 (s),
1466 (m),1443 (m).1H NMR (CDCl3, 300 MHz):
3.97 (s, 3H, OCH3), 5.30 (s, 2H, CH2Ph), 5.50 (s, 1H, CH), 7.40 (m, 5H,
Ph). 13C NMR (CDCl3, 75 MHz):
d
¼3.78 (s, 3H, OCH3),
of E-13i appears at
13i appears at
exocyclic double bond of E-configured pyrrol-2-ones is slightly
shifted downfield with respect to the respective signal of the Z-
configured isomers. For example, the signal of proton H-10 of E-13i
d
¼7.00 ppm whereas the respective signal of Z-
d
¼5.79 ppm. In addition, proton H-10 attached to the
d
¼51.9, 59.6 (OCH3), 74.0 (CH2Ph),
95.8 (CH),124.2 (C),128.8,128.96,128.99 (CH, Ph),135.2,148.5,150.7
(C), 163.3, 163.6 (C]O). MS (EI, 70 eV): m/z (%)¼290 ([M]þ, 12), 262
(4), 244 (1), 219 (1), 91 (100). HRMS (EI, 70 eV): calcd for C15H14O6:
290.0790; found: 290.0790ꢂ2 ppm. Anal. Calcd for C15H14O6
(290.27): C 62.07, H 4.86. Found: C 61.90, H 5.51.
appears at
pears at
¼5.24 ppm.
In conclusion, we have reported the synthesis of a variety of 5-
alkylidene-2,5-dihydropyrrol-2-ones by reaction of -alkylidene-
d¼5.50 ppm whereas the respective signal of Z-13i ap-
d
g
butenolides with amines in glacial acetic acid. The butenolides are
readily available by cyclization of 1,3-bis(silyloxy)-1,3-butadienes
with oxalyl chloride. The configuration of the exocyclic double
bond of the products depends on the substitution pattern of the
products. A Z-configuration is generally observed for pyrrol-2-ones
containing an NH group, due to formation of an intramolecular
hydrogen bond. An E-configured exocyclic double bond is selec-
tively formed for products containing an alkyl group located at the
nitrogen atom and a hydrogen located at carbon C-4 of the pyrrol-
2-one (due to the steric effect of the N-alkyl group). Isomeric
mixtures are formed for pyrrol-2-ones containing substituents lo-
cated at both the nitrogen atom and at carbon C-4. In many cases,
the pure minor component undergoes a slow isomerization upon
standing in solution. These results suggest that the E/Z-diaster-
eoselectivity is presumably thermodynamically controlled.
3.4. 3,4-Dibenzyloxy-5-[Z-(ethoxycarbonylmethylidene)]-2-
furanone (12b)
The reaction was carried out by application of the procedure
given for the synthesis of 12a. Starting with K2CO3 (760 mg,
5.5 mmol, 2.0 equiv), 8b (760 mg, 2.75 mmol, 1 equiv) and benzyl-
bromide (470 mg, 0.3 mL, 2.75 mmol, 1.0 equiv) in acetone (15 mL),
12b was isolated by chromatography (silica gel, hexane/
EtOAc¼10:1/3:1) as a colourless oil (840 mg, 83%). Rf¼0.65 (hex-
~
ane/EtOAc¼3:1). IR (KBr, cmꢀ1):
n
¼ 2985ðwÞ, 1789 (s), 1721 (s),
1661 (s), 1590 (w), 1458 (m), 1416 (w). 1H NMR (CDCl3, 300 MHz):
d
¼1.29 (t, 3J¼7.1 Hz, 3H, CH2CH3), 4.22 (q, 3J¼7.1 Hz, 2H, CH2CH3),
5.24 (s, 2H, CH2Ph), 5.25 (s, 2H, CH2Ph), 5.56 (s, 1H, CH), 7.22 (m, 5H,
Ph), 7.35 (m, 5H, Ph). 13C NMR (CDCl3, 75 MHz):
d
¼14.1 (CH2CH3),
60.8 (CH2CH3), 73.4 (CH2Ph), 73.9 (CH2Ph), 96.2 (CH),124.5 (C),127.6,
128.6, 128.73, 128.76, 128.86, 128.91 (Ph, CH), 135.01, 135.27, 147.33,
150.72 (C),163.08,163.20 (C]O). MS (EI, 70 eV): m/z (%)¼380 ([M]þ,
1), 205 (4), 159 (5), 91 (100), 66 (19). HRMS (EI, 70 eV): calcd for
C22H20O6: 380.1260; found: 380.1260ꢂ2 ppm. Anal. Calcd for
C22H20O6 (380.39): C 69.46, H 5.30. Found: C 64.43, H 5.64.
3. Experimental section
3.1. General comments
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR
spectra the deuterated solvents indicated were used. Mass spec-
trometric data (MS) were obtained byelectron ionization (EI, 70 eV),
chemical ionization (CI, isobutane) or electrospray ionization (ESI).
For preparative scale chromatography silica gel 60 (0.063–
0.200 mm, 70–230 mesh) was used.
3.5. 3-Benzyloxy-4-methyl-5-[Z-(methoxycarbonyl-
methylidene)]-2-furanone (12c)
Thereactionwascarriedout byapplicationof theprocedure given
for the synthesis of 12a. Starting with K2CO3 (1.50 g, 10.9 mmol,
2.0 equiv), 8c (1.00 g, 5.45 mmol, 1.0 equiv) and benzylbromide

C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
4535
(0.93 g, 1.1 mL, 5.45 mmol, 1 equiv) in acetone (20 mL), 12c was iso-
lated by chromatography (silica gel, hexane/EtOAc¼1:0/4:1) as
a yellow solid (0.95 g, 64%), mp¼108–110 ꢁC. Rf¼0.40 (hexane/
~
(%)¼332 ([M]þ, 3), 304 (16), 276 (5), 114 (8), 91 (100). HRMS (EI,
70 eV): calcd for C21H16O4: 332.1049; found: 332.1049ꢂ2 ppm.
EtOAc¼4:1). IR (KBr, cmꢀ1):
n
¼ 1792ðsÞ,1696 (s),1641 (s),1457 (w),
3.9. 3-Benzyloxy-4-methoxy-5-[Z-(methoxycarbonyl-
methylidene)]-pyrrol-2-one (13a)
1436 (m), 1405 (m). 1H NMR (CDCl3, 300 MHz):
3.78 (s, 3H, OCH3), 5.30 (s, 1H, CH), 5.49 (s, 2H, CH2Ph), 7.39 (m, 5H,
d¼1.90 (s, 3H, CH3),
Ph). 13C NMR (CDCl3, 75 MHz):
d
¼7.5 (CH3), 51.2 (OCH3), 72.7
Butenolide 12a (292 mg, 1.0 mmol, 1.0 equiv) and ammonium
acetate (385 mg, 5.0 mmol, 5.0 equiv) were dissolved in glacial
acetic acid (5 mL) and the solution was stirred under reflux for 20 h.
The solution was cooled to 20 ꢁC and EtOAc was added. The mixture
was washed several times with an aqueous solution of sodium bi-
carbonate until the organic layer was neutral. The combined
aqueous layers were three times washed with EtOAc. The combined
organic layers were dried (Na2SO4). The solution was filtered and
the solvent of the filtrate was removed in vacuo to give 13a as
a colourless solid (280 mg, 96%), mp¼102–104 ꢁC. Rf¼0.25 (hexane/
~
(CH2Ph), 96.2 (CH), 128.1 (C), 128.2, 128.72, 128.73 (CH, Ph), 135.7,
144.3, 156.4 (C), 162.6, 163.8 (C]O). MS (EI, 70 eV): m/z (%)¼274
([M]þ, 2), 246 (1), 213 (1),190(2), 91 (100). HRMS(EI, 70 eV): calcdfor
C15H14O6: 274.0841; found: 274.0841ꢂ2 ppm. Anal. Calcd for
C15H14O6 (274.27): C 65.69, H 5.15. Found: C 65.98, H 5.61.
3.6. 3-Benzyloxy-5-[E-(methoxycarbonylmethylidene)]-2-
furanone (12d)
The reaction was carried out by application of the procedure
given for the synthesis of 12a. Starting with K2CO3 (830 mg,
6.0 mmol, 2.0 equiv), 8d (510 mg, 3.0 mmol, 1 equiv) and benzyl-
bromide (513 mg, 0.6 mL, 3.0 mmol, 1 equiv) in acetone (10 mL),
EtOAc¼4:1). IR (KBr, cmꢀ1):
n
¼ 3401ðbr wÞ, 3332 (s), 3263 (w),
3257 (w), 3036 (w), 3003 (w), 2953 (m), 2928 (w), 2859 (w), 1733
(s), 1702 (s), 1674 (s), 1451 (s), 1414 (w). 1H NMR (CDCl3, 300 MHz):
d
¼3.75 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.30 (s, 2H, CH2Ph), 5.44 (s,
1H, CH), 7.37 (m, 5H, Ph), 8.48 (br s, 1H, NH). 13C NMR (CDCl3,
75 MHz):
12d was isolated (silica gel, hexane/EtOAc¼10:1/3:1) as a yellow
ꢀ1
solid (510 mg, 65%), mp¼133–135 ꢁC. IR (KBr, cm ): ¼ 1812ðsÞ,
d
¼51.6, 59.4 (OCH3), 74.2 (CH2Ph), 92.6 (CH), 127.3 (C),
~
n
1716 (s), 1654 (s), 1617 (s), 1457 (w), 1441 (m). 1H NMR (CDCl3,
128.6, 128.6, 128.7 (CH, Ph), 136.0, 144.4, 144.5 (C), 166.3, 167.3
(C]O). MS (EI, 70 eV): m/z (%)¼289 ([M]þ, 6), 261 (3), 170 (3), 109
(5), 91 (100). HRMS (EI, 70 eV): calcd for C15H15NO5: 289.0950;
found: 289.0950ꢂ2 ppm. Anal. Calcd for C15H15NO5 (289.28): C
62.28, H 5.23, N 4.84. Found: C 62.51, H 5.60, N 4.55.
300 MHz):
CH), 7.29 (s, 1H, ring-CH), 7.42 (m, 5H, Ph). 13C NMR (CDCl3,
75 MHz):
d¼3.77 (s, 3H, OCH3), 5.16 (s, 2H, CH2Ph), 5.75 (s, 1H,
d
¼51.7 (CH3), 74.2 (CH2Ph), 99.1 (CH), 107.9 (ring-CH),
128.0, 128.8, 129.1 (CH, Ph), 133.6, 150.8, 159.1 (C), 162.3, 166.2
(C]O). MS (EI, 70 eV): m/z (%)¼260 ([M]þ, 4), 229 (1), 204 (1), 170
(1), 91 (100). HRMS (EI, 70 eV): calcd for C14H12O5: 260.0685;
found: 260.0685ꢂ2 ppm. Anal. Calcd for C14H12O5 (260.24): C
64.61, H 4.65. Found: C 64.04, H 5.35.
3.10. 3-Benzyloxy-4-methoxy-5-[E/Z-(methoxymethylidene)]-
N-methylpyrrol-2-ones (E-13b) and (Z-13b)
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 12a (58 mg, 0.2 mmol,
1.0 equiv) and methylammonium chloride (68 mg, 1.0 mmol,
5.0 equiv) and AcOH (2 mL), E-13b (25 mg, 40%) and Z-13b (11 mg,
17%) were isolated by chromatography (silica gel, hexane/
EtOAc¼10:1/4:1) as yellow solids.
3.7. 4-Benzyloxy-40,50-dihydro-[2,30]bifuranylidene-5,20-
dione (12e)
The reaction was carried out by application of the procedure
given for the synthesis of 12a. Starting with K2CO3 (330 mg,
2.4 mmol,
2.0 equiv),
4-hydroxy-40,50-dihydro-[2,30]bifur-
anylidene-5,20-dione (219 mg, 1.2 mmol, 1.0 equiv) and benzyl-
bromide (205 mg, 0.1 mL, 1.2 mmol, 1.0 equiv) in acetone (5 mL),
12e was isolated by chromatography (silica gel, hexane/EtOAc¼4:1)
as a yellow solid (50 mg, 15%), mp¼174–176 ꢁC. Rf¼0.25 (hexane/
3.10.1. Compound E-13b
Mp¼83–85 ꢁC. Rf¼0.55 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
n
¼ 2950ðwÞ, 1723 (s), 1679 (s), 1637 (s), 1460 (m). 1H NMR (CDCl3,
~
300 MHz):
d
¼3.30 (s, 3H, NCH3), 3.73 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
EtOAc¼3:1). 1H NMR (CDCl3, 300 MHz):
d
¼3.17 (t, 3J¼7.2 Hz, 2H,
5.25 (s, 2H, CH2Ph), 5.54 (s,1H, CH), 7.38 (m, 5H, Ph). 13C NMR (CDCl3,
150 MHz):
–CH2–, 4-H), 4.46 (t, 3J¼7.2 Hz, 2H, –CH2–, 5-H), 5.15 (s, 2H, CH2Ph),
d¼29.5 (NCH3), 51.8 (OCH3), 59.7 (OCH3), 74.4 (CH2Ph),
7.33 (s, 1H, CH), 7.39 (m, 5H, Ph). 13C NMR (CDCl3, 75 MHz):
d
¼25.7
95.2 (CH),125.8 (C),128.7,128.8,128.9 (CH, Ph),136.4,143.3,145.2 (C),
165.4, 167.5 (C]O). MS (EI, 70 eV): m/z (%)¼303 ([M]þ, 32), 272 (5),
215 (8), 156 (6), 91 (100). HRMS (EI, 70 eV): calcd for C16H17NO5:
303.1107; found: 303.1107ꢂ2 ppm. Anal. Calcd for C16H17NO5
(303.31): C 63.36, H 5.65, N 4.62. Found: C 63.04, H 5.77, N 5.44.
(C-4), 65.9 (C-5), 74.2 (CH2Ph), 104.6 (C), 107.1 (CH), 128.0, 128.8,
129.1 (CH, Ph), 133.6, 149.4, 153.0 (C), 162.3, 170.3 (C]O). MS (EI,
70 eV): m/z (%)¼272 ([M]þ, 1), 189 (1), 204 (2), 91 (100).
3.8. 3-Benzyloxy-5-(1-oxo-3,4-dihydro-1H-naphthalen-2-
ylidene)-2-furanone (12f)
3.10.2. Compound Z-13b
Mp 87–89 ꢁC. Rf¼0.25 (hexane/EtOAc¼4:1). 1H NMR (CDCl3,
The reaction was carried out by application of the procedure
given for the synthesis of 12a. Starting with K2CO3 (276 mg,
2.0 mmol, 2.0 equiv), 3-hydroxy-5-(1-oxo-3,4-dihydro-1H-naph-
thalen-2-ylidene)-2-furanone (218 mg, 0.9 mmol, 1.0 equiv) and
benzylbromide (154 mg, 0.1 mL, 0.9 mmol, 1.0 equiv) in acetone
(5 mL), 12f was isolated by chromatography (silica gel, hexane/
EtOAc¼20:1) as a yellow solid (50 mg, 17%), mp¼186–188 ꢁC.
300 MHz):
d
¼3.02 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 3.90 (s, 3H, OCH3),
5.28 (s, 2H, CH2Ph), 5.46 (s, 1H, CH), 7.38 (m, 5H, CH2Ph). 13C NMR
(CDCl3, 75 MHz):
d¼25.0 (NCH3), 52.0 (OCH3), 60.0 (OCH3), 74.2
(CH2Ph), 98.9 (CH), 128.5, 128.6, 128.7 (CH, Ph), 129.3, 136.2, 141.5,
143.7 (C), 165.1, 165.8 (C]O). MS (EI, 70 eV): m/z (%)¼303 ([M]þ, 5),
272 (1), 243 (1), 215 (2), 91 (100). HRMS (EI, 70 eV): calcd for
C16H17NO5: 303.1107; found: 303.1107ꢂ2 ppm. Pure Z-13b rearranges
to a mixture E-13b/Z-13b¼1:3 upon standing.
Rf¼0.25 (hexane/EtOAc¼20:1). 1H NMR (CDCl3, 300 MHz):
¼2.89
d
(m, 2H, –CH2–, 3-H), 3.07 (m, 2H, –CH2–, 4-H), 5.15 (s, 2H, CH2Ph),
7.30 (m, 8H, Ar–H), 7.48 (dt, 3J¼7.4 Hz, 4J¼1.4 Hz, 1H, Ar–H), 7.57 (s,
1H, CH), 8.05 (dd, 3J¼7.8 Hz, 4J¼1.3 Hz, 1H, Ar–H). 13C NMR (CDCl3,
3.11. 3-Benzyloxy-4-methoxy-5-[E/Z-(methoxycarbonyl-
methylidene)]-N-isobutyl-pyrrol-2-ones (E-13c) and (Z-13c)
75 MHz):
d
¼25.1 (C-3), 28.3 (C-4), 73.8 (CH2Ph), 110.1 (CH), 116.0
(C), 127.0, 127.6, 127.9, 128.4, 128.7, 128.9, 133.5 (CH, Ar), 133.9,
To glacial acetic acid (4 mL) was slowly added isobutylamine
(252 mg, 0.4 mL, 2.5 mmol, 5.0 equiv) at 0 ꢁC. To the solution
143.3, 143.3, 150.6, 152.5 (C), 162.7, 187.6 (C]O). MS (EI, 70 eV): m/z

4536
C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
was added 12a (146 mg, 0.5 mmol, 1.0 equiv) and the solution was
stirred for 20 h under reflux. After cooling to 20 ꢁC, EtOAc was
added and the mixture was repeatedly washed with a saturated
aqueous solution of sodium bicarbonate until the organic layer was
neutral. The combined aqueous layers were extracted three times
with EtOAc and the combined organic layers were dried (Na2SO4).
The solution was filtered and the filtrate was concentrated in vacuo.
The residue was purified by chromatography (silica gel, hexane/
EtOAc¼5:1) to give E-13c as a yellow solid (70 mg, 40%) and Z-13c
as a yellow oil (43 mg, 25%).
(m, 1H, NCH), 3.74 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 5.25 (s, 2H,
CH2Ph), 5.62 (s, 1H, CH), 7.36 (m, 5H, Ph). 13C NMR (CDCl3, 75 MHz):
d¼25.2, 26.3, 30.1 (CH2), 52.0 (NCH), 52.5 (OCH3), 59.8 (OCH3), 74.0
(CH2Ph), 99.0 (CH), 128.1 (C), 128.4, 128.5, 128.7 (CH, Ph), 136.37,
138.97, 143.32 (C), 165.30, 166.49 (C]O). MS (EI, 70 eV): m/z
(%)¼371 ([M]þ, 4), 340 (1), 315 (1), 289 (1), 252 (1), 230 (1), 91
(100). HRMS (EI, 70 eV): calcd for C21H25NO5: 371.1733; found:
371.1733ꢂ2 ppm. E-13d slowly rearranges to Z-13d/E-13d¼1:5
upon standing.
3.13. 3,4-Dibenzyloxy-5-[Z-(ethoxycarbonylmethylidene)]-
pyrrol-2-one (13e)
3.11.1. Compound E-13c
Mp¼69–71 ꢁC. Rf¼0.45 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
~
n
¼ 2956ðmÞ, 1724 (s), 1680 (s), 1635 (s), 1456 (s). 1H NMR (CDCl3,
300 MHz):
d
¼0.82 (d, 3J¼6.7 Hz, 6H, CH3, CH(CH3)2), 1.76 (m, 1H,
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 12b (540 mg,
1.40 mmol) and ammonium acetate (550 mg, 7.10 mmol), 13e was
isolated without further purification as a yellow solid (490 mg,
~
CH(CH3)2), 3.71 (s, 3H, OCH3), 3.85 (d, 3J¼7.5 Hz, 2H, NCH2), 3.89 (s,
3H, OCH3), 5.30 (s, 2H, CH2Ph), 5.54 (s, 1H, CH), 7.35 (m, 5H, Ph). 13
C
NMR (CDCl3, 75 MHz):
d
¼19.5 (CH3), 27.7 (CH(CH3)2), 47.9 (NCH2),
91%), 122–124 ꢁC. IR (KBr, cmꢀ1):
n
¼ 3412ðbrÞ, 3388 (br), 3302
51.7, 59.4 (OCH3), 74.1 (CH2Ph), 95.1 (CH), 124.8 (C), 128.49, 128.50,
128.8 (CH, Ph), 136.1, 141.0, 145.1 (C), 165.1, 167.5 (C]O). MS (EI,
70 eV): m/z (%)¼345 ([M]þ, 9), 314 (1), 302 (1), 257 (1), 226 (1), 91
(100). HRMS (EI, 70 eV): calcd for C19H23NO5: 345.1576; found:
345.1576ꢂ2 ppm. Anal. Calcd for C19H23NO5 (345.39): C 66.07, H
6.71, N 4.06. Found: C 66.00, H 8.29, N 4.11.
(m), 1724 (s), 1697 (s), 1664 (s), 1651 (s), 1459 (m), 1416 (m). 1H NMR
(CDCl3, 300 MHz):
d
¼1.28 (t, 3J¼7.2 Hz, 3H, CH2CH3), 4.20 (q,
3J¼7.2 Hz, 2H, CH2CH3), 5.16 (s, 2H, CH2Ph), 5.27 (s, 2H, CH2Ph), 5.49
(s, 1H, CH), 7.25–7.39 (m, 10H, Ph), 8.48 (br s, 1H, NH). 13C NMR
(CDCl3, 150 MHz):
d
¼14.1 (CH2CH3), 60.8 (CH2CH3), 73.4, 74.3
(CH2Ph), 93.5 (CH), 127.8 (CH, Ph), 128.1 (C), 128.7, 128.8, 128.9,
129.0 (CH, Ph), 136.1, 136.4, 143.4, 144.7 (C), 166.3, 167.2 (C]O). MS
(EI, 70 eV): m/z (%)¼379 ([M]þ, 4), 333 (1), 288 (3), 273 (3), 227 (2),
199 (3), 91 (100). HRMS (EI, 70 eV): calcd for C22H21NO5: 379.1420;
found: 379.1420ꢂ2 ppm. Anal. Calcd for C22H21NO5 (379.41): C
69.88, H 5.58, N 3.69. Found: C 69.88, H 6.20, N 3.95.
3.11.2. Compound Z-13c
Rf¼0.25 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
¼ 3065ðwÞ,
~
n
3032 (m), 2957 (s), 2872 (m), 1709 (s), 1675 (s), 1638 (s), 1496 (m),
1461 (s), 1440 (s), 1415 (s). 1H NMR (CDCl3, 300 MHz):
d¼0.90 (d,
3J¼6.7 Hz, 6H, CH3, CH(CH3)2), 1.94 (m, 1H, CH(CH3)2), 3.32 (d,
3J¼7.6 Hz, 2H, NCH2), 3.73 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 5.29 (s,
2H, CH2Ph), 5.45 (s, 1H, CH), 7.35 (m, 5H, Ph). 13C NMR (CDCl3,
3.14. 3-Benzyloxy-4-methyl-5-[Z-(methoxycarbonyl-
methylidene)]-pyrrol-2-one (13f)
75 MHz):
d
¼19.6 (CH3), 27.5 (CH(CH3)2), 46.0 (NCH2), 51.9, 59.8
(OCH3), 73.9 (CH2Ph), 98.9 (CH), 124.8 (C), 128.42, 128.43, 128.6 (CH,
Ph), 136.2, 140.4, 143.5 (C), 165.3, 165.8 (C]O). MS (EI, 70 eV): m/z
(%)¼345 ([M]þ, 23), 314 (1), 257 (1), 226 (1), 197 (2), 91 (100). Anal.
Calcd for C19H23NO5 (345.39): C 66.07, H 6.71, N 4.06. Found: C
66.03, H 6.93, N 3.87. Pure Z-13c slowly rearranges to E-13c/Z-
13c¼2:3 upon standing.
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 12c (250 mg,
0.90 mmol) and ammonium acetate (350 mg, 4.50 mmol), 13f was
isolated by chromatography (silica gel, hexane/EtOAc¼10:1) as
a yellow solid (188 mg, 76%), mp 118–120 ꢁC. Rf¼0.5 (hexane/
~
EtOAc¼4:1). IR (KBr, cmꢀ1):
n
¼ 3401ðbrÞ, 3341 (s), 1732 (s), 1696
(s), 1647 (s), 1582 (w), 1447 (m), 1410 (m). 1H NMR (CDCl3,
3.12. 3-Benzyloxy-4-methoxy-5-[E/Z-(methoxymethylidene)]-
N-cyclohexyl-2-pyrrolidones (Z-13d) and (E-13d)
300 MHz):
5.51 (s, 2H, CH2Ph), 7.34 (m, 5H, Ph), 8.92 (br s, 1H, NH). 13C NMR
(CDCl3, 75 MHz):
d¼1.84 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 5.27 (s, 1H, CH),
The reaction was carried out by application of the procedure
given for the synthesis of 13c. Starting with 12a (116 mg, 0.4 mmol),
cyclohexylamine (198 mg, 0.2 mL, 2.0 mmol) and AcOH (3.5 mL),
chromatographic purification (silica gel, hexane/EtOAc¼20:1/
5:1) afforded Z-13d as a yellow solid (60 mg, 40%) and E-13d as
a yellow oil (45 mg, 30%).
d
¼7.1 (CH3), 51.6 (OCH3), 72.5 (CH2Ph), 93.2 (CH),
121.1 (C), 128.0, 128.4, 128.5 (CH, Ph), 136.7, 147.6, 149.6 (C), 165.5,
167.6 (C]O). MS (EI, 70 eV): m/z (%)¼273 ([M]þ, 5), 267 (1), 244 (4),
216 (1), 195 (1), 167 (2), 91 (100). HRMS (EI, 70 eV): calcd for
C15H15NO4: 273.1001; found: 273.1001ꢂ2 ppm.
3.12.1. Compound Z-13d
3.15. 3-Benzyloxy-4-methyl-5-[E/Z-(methoxycarbonyl-
methylidene)]-N-methyl-pyrrol-2-ones (Z-13g) and (E-13g)
Mp¼66–68 ꢁC. Rf¼0.65 (hexane/EtOAc¼3:1). IR (KBr, cmꢀ1):
~
n
¼ 2942ðmÞ, 2856 (w), 1725 (s), 1706 (s), 1684 (s), 1633 (s), 1442
(m). 1H NMR (CDCl3, 300 MHz):
d
¼1.26–2.22 (m, 10H, –CH2–), 3.74
Starting with 12c (250 mg, 0.90 mmol) and methylammonium
chloride (304 mg, 4.50 mmol), chromatographic purification (silica
gel, hexane/EtOAc¼10:1) afforded Z-13g (70 mg, 27%) and E-13g
(72 mg, 28%) as colourless solids.
(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.18 (m, 1H, NCH), 5.23 (s, 2H,
CH2Ph), 5.50 (s, 1H, CH), 7.36 (m, 5H, Ph). 13C NMR (CDCl3, 75 MHz):
d
¼25.3, 26.3, 30.2 (CH2), 51.7 (NCH), 57.0 (OCH3), 59.4 (OCH3), 74.1
(CH2Ph), 94.4 (CH), 125.5 (C), 128.46, 128.51, 128.7 (CH, Ph), 136.2,
143.1, 144.8 (C), 165.4, 168.0 (C]O). MS (EI, 70 eV) m/z (%)¼371
([M]þ, 5), 340 (1), 289 (2), 280 (2), 230 (2), 91 (100). HRMS (EI,
70 eV): calcd for C21H25NO5: 371.1733; found: 371.1733ꢂ2 ppm.
3.15.1. Compound Z-13g
Mp 102–104 ꢁC. Rf¼0.60 (hexane/EtOAc¼4:1). 1H NMR (CDCl3,
300 MHz):
d
¼1.84 (s, 3H, CH3), 3.06 (s, 3H, NCH3), 3.74 (s, 3H,
OCH3), 5.29 (s, 1H, CH), 5.46 (s, 2H, CH2Ph), 7.36 (m, 5H, Ph). 13C
NMR (CDCl3, 75 MHz):
3.12.2. Compound E-13d
d¼7.5 (CH3), 29.9 (NCH3), 51.6 (OCH3), 72.5
Rf¼0.4 (hexane/EtOAc¼3:1). IR (KBr, cmꢀ1):
¼ 2334ðmÞ, 2856
(CH2Ph), 96.3 (CH), 123.1 (C), 128.0, 128.3, 128.5 (CH, Ph), 136.8,
145.9, 148.3 (C), 165.3, 166.5 (C]O). MS (EI, 70 eV): m/z (%)¼287
([M]þ, 20), 258 (4), 228 (1), 196 (1), 164 (1), 91 (100).
~
n
(m), 1724 (s), 1705 (s), 1642 (s), 1639 (s), 1452 (m), 1441 (m), 1406
(m). 1H NMR (CDCl3, 300 MHz):
d
¼1.28–2.07 (m, 10H, –CH2–), 3.65

C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
4537
3.15.2. Compound E-13g
methylboronic acid (195 mg, 3.25 mmol), Pd(PPh3)4 (85 mg,
0.08 mmol) and potassium phosphate (850 mg, 4.00 mmol), 19 was
isolated by chromatography (silica gel, hexane/EtOAc¼20:1) as
a colourless solid (275 mg, 60%), mp¼51–53 ꢁC. IR (KBr, cmꢀ1):
~
Mp 108–110 ꢁC. Rf¼0.55 (hexane/EtOAc¼4:1). 1H NMR (CDCl3,
300 MHz):
d
¼2.11 (s, 3H, CH3), 3.06 (s, 3H, NCH3), 3.74 (s, 3H, OCH3),
5.46 (s,1H, CH), 5.50 (s, 2H, CH2Ph), 7.36 (m, 5H, Ph).13C NMR (CDCl3,
75 MHz):
d
¼10.7 (CH3), 23.5 (NCH3), 51.6 (OCH3), 72.5 (CH2Ph), 96.5
n
¼ 2997ðwÞ, 1787 (s), 1742 (m), 1703 (s), 1654 (s), 1622 (s), 1439
(CH), 121.4 (C), 128.0, 128.2, 128.5 (CH, Ph), 136.9, 149.0, 149.2 (C),
164.1, 165.7 (C]O). MS (EI, 70 eV): m/z (%)¼287 ([M]þ, 18), 258 (3),
165 (1),139 (1), 91 (100). Pure E-13g rearranges to Z-13g/E-13g¼1:1.
(w). 1H NMR (CDCl3, 300 MHz):
d
¼1.33 (t, 3J¼7.2 Hz, 3H, CH2CH3),
2.10 (d, 4J¼1.5 Hz, 3H, CH3), 4.25 (q, 3J¼7.2 Hz, 2H, CH2CH3), 5.82 (s,
1H, CH), 8.02 (d, 4J¼1.5 Hz, 1H, CH). 13C NMR (CDCl3, 75 MHz):
d
¼11.1, 14.2 (CH3), 60.9 (CH2), 100.7 (CH), 135.4 (C), 135.9 (CH), 159.6
3.16. 3-Benzyloxy-5-[E-(methoxycarbonylmethylidene)]-N-
methyl-pyrrol-2-one (13h)
(C), 165.2, 169.0 (C]O). MS (EI, 70 eV): m/z (%)¼182 ([M]þ, 12), 154
(16), 137 (100), 124 (4), 110 (16), 98 (8). HRMS (EI, 70 eV): calcd for
C9H10O4: 182.0579; found: 182.0579ꢂ2 ppm. Anal. Calcd for
C9H10O4 (182.17): C 59.34, H 5.53. Found: C 59.24, H 5.94.
The reactionwas carried out byapplication of theprocedure given
for the synthesis of 13a. Starting with 12d (78 mg, 0.30 mmol) and
methylammonium chloride (135 mg, 1.50 mmol), 13h was isolated
by chromatography (silica gel, hexane/EtOAc¼3:1) as a slightly yel-
lowsolid (70 mg, 85%), mp¼117–119 ꢁC. Rf¼0.5 (hexane/EtOAc¼4:1).
3.20. 3-Phenyl-5-methoxycarbonylmethylidene-pyrrol-2-
ones (Z-17) and (E-17)
1H NMR (CDCl3, 300 MHz):
d¼3.10 (s, 3H, NCH3), 3.75 (s, 3H, OCH3),
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 16 (51 mg, 0.22 mmol)
and ammonium acetate (68 mg, 0.88 mmol) in glacial acetic acid
(2 mL) (12 h, reflux), chromatographic purification (silica gel, hex-
ane/EtOAc¼10:1) afforded Z-17 (35 mg, 70%) and E-17 (10 mg, 20%)
as colourless solids. The compounds were labile and readily
decomposed.
5.11 (s, 2H, CH2Ph), 5.45 (s, 1H, CH), 6.98 (s, 1H, CH), 7.38 (m, 5H, Ph).
13C NMR (CDCl3, 75 MHz):
d¼25.7 (NCH3), 51.4 (OCH3), 73.0 (CH2Ph),
96.2 (CH),100.8 (CH),127.9,128.61,128.62 (CH, Ph),134.4,150.9,153.4
(C), 164.1, 166.6 (C]O). MS (EI, 70 eV): m/z (%)¼273 ([M]þ, 48), 244
(44), 241 (12), 213 (4), 195 (5), 91 (100). HRMS (EI, 70 eV): calcd for
C15H15NO4: 273.1001; found: 273.1001ꢂ2 ppm.
3.17. 3-Benzyloxy-5-[E/Z-(methoxycarbonylmethylidene)]-
pyrrol-2-ones (Z-13i) and (E-13i)
3.20.1. Compound Z-17
Mp¼128–130 ꢁC. Rf¼0.5 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
~
n
¼ 3408ðbr mÞ, 3346 (s), 2952 (w), 1712 (s), 1693 (s), 1651 (s), 1443
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 12d (91 mg, 0.35 mmol)
and ammonium acetate (135 mg, 1.75 mmol), chromatographic
purification (silica gel, hexane/EtOAc¼4:1) afforded Z-13i (50 mg,
55%) and E-13i (20 mg, 22%) as colourless solids.
(s),1409 (m).1H NMR (CDCl3, 300 MHz):
d¼3.81 (s, 3H, OCH3), 5.43 (s,
1H, CH), 7.12 (d, 4J¼1.6 Hz, 1H, CH), 7.43 (m, 3H, Ph), 7.93 (m, 2H, Ph),
9.18 (brs,1H, NH).13CNMR(CDCl3, 75 MHz):
d¼51.8(OCH3), 97.3(CH),
127.1 (C),127.7,128.7,129.6 (CH, Ph),129.9 (CH),137.4,148.4 (C),167.4,
170.0 (C]O). MS (EI, 70 eV): m/z (%)¼229 ([M]þ, 100), 230 ([Mþ1]þ,
15), 231 ([Mþ2]þ,1),198(64),171 (16),114 (6). HRMS (EI, 70 eV): calcd
for C13H11NO3: 229.0739; found: 229.0739ꢂ2 ppm.
3.17.1. Compound Z-13i
Mp¼139–141 ꢁC. Rf¼0.30 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
~
n
¼ 3358ðbr sÞ, 2952(w),1752 (s),1734(s),1683 (s),1649 (s),1620(s),
3.20.2. Compound E-17
1587 (s), 1442 (s). 1H NMR (CDCl3, 300 MHz):
5.10 (s, 2H, CH2Ph), 5.24 (s, 1H, CH), 5.79 (s, 1H, CH), 7.40 (m, 5H, Ph),
9.16 (br s, 1H, NH). 13C NMR (CDCl3, 150 MHz):
d¼3.75 (s, 3H, OCH3),
Mp¼164–166 ꢁC. Rf¼0.4 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
~
n
¼ 3418ðbr mÞ, 3319 (w), 3294 (w), 2923 (w), 1700 (s), 1643 (s),
d¼51.8 (OCH3), 73.5
1444 (w), 1412 (w). 1H NMR (CDCl3, 300 MHz):
d
¼3.80 (s, 3H,
(CH2Ph), 96.1 (CH), 103.5 (CH-ring), 128.0, 129.96, 128.97 (CH, Ph),
134.5,148.3,153.9 (C),164.8,167.7(C]O). MS (EI, 70 eV): m/z (%)¼259
([M]þ, 24), 230 (30), 227 (6), 203 (1), 169 (1), 91 (100). HRMS (EI,
70 eV): calcd for C14H13NO4: 259.0845; found: 259.0845ꢂ2 ppm.
OCH3), 5.63 (d, 4J¼0.6 Hz, 1H, CH), 7.43 (m, 3H, Ph), 7.99 (m, 2H, Ph),
8.24 (d, 4J¼0.6 Hz, 1H, CH). 13C NMR (CDCl3, 75 MHz):
d¼51.7
(OCH3), 99.7 (CH), 127.8, 127.9, 128.7 (CH, Ph), 130.0 (CH), 130.2,
137.6, 148.2 (C), 166.3, 170.3 (C]O). MS (EI, 70 eV): m/z (%)¼229
([M]þ, 66), 198 (96), 171 (31), 148 (25), 141 (14), 128 (13), 114 (33),
102 (28), 91 (47), 77 (17). HRMS (EI, 70 eV): calcd for C13H11NO3:
229.0739; found: 229.0739ꢂ2 ppm.
3.17.2. Compound E-13i
Mp 136–138 ꢁC. Rf¼0.2 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
¼ 3307ðmÞ, 1747 (s), 1699 (s), 1639 (s), 1617 (s), 1447 (s). 1H NMR
~
n
(CDCl3, 300 MHz):
d
¼3.75 (s, 3H, OCH3), 5.13 (s, 2H, CH2Ph), 5.50 (s,
3.21. 3-Phenyl-5-[E-(methoxycarbonylmethylidene)]-N-
methyl-pyrrol-2-one (18)
1H, CH), 7.00 (s, 1H, CH), 7.38 (m, 5H, Ph), 7.79 (m, 1H, NH). 13C NMR
(CDCl3, 75 MHz):
d
¼51.6 (OCH3), 73.3 (CH2Ph), 98.5 (CH),102.3 (CH),
128.1,128.7,128.8 (CH, Ph),134.3,147.8,154.0 (C),165.2,166.7 (C]O).
MS (EI, 70 eV):m/z (%)¼259([M]þ, 4), 230 (6), 203(1),167 (1),149 (1),
91 (100). HRMS (EI, 70 eV): calcd for C14H13NO4: 259.0845; found:
259.0845ꢂ2 ppm. E-13i slowly rearranges to Z-13i/E-13i¼1:3.
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 16 (45 mg, 0.20 mmol)
and methylammonium chloride (54 mg, 0.80 mmol) in glacial
acetic acid (2 mL) (12 h, reflux), 18 was isolated by chromatography
(silica gel, hexane/EtOAc¼10:1) as a yellow solid (42 mg, 85%),
mp¼108–110 ꢁC. The compound was unstable and readily decom-
~
3.18. 3-Phenyl-5-[E-(methoxycarbonylmethylidene)]-2-
furanone (16)
posed. Rf¼0.6 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
n
¼ 2951ðwÞ,
2924 (m), 1711 (s), 1632 (s), 1441 (w). 1H NMR (CDCl3 CDCl3,
The synthesis of 16 was carried out as previously reported.23
300 MHz):
d
¼3.18 (s, 3H, NCH3), 3.81 (s, 3H, OCH3), 5.58 (d,
4J¼0.5 Hz, 1H, CH), 7.43 (m, 3H, Ph), 7.98 (m, 2H, Ph), 8.25 (d,
3.19. 3-Methyl-5-[E-(ethoxycarbonylmethylidene)]-2-
furanone (19)
4J¼0.5 Hz, 1H, CH). 13C NMR (CDCl3, 150 MHz):
¼26.0 (NCH3), 51.8
d
(OCH3), 98.1 (CH), 127.0, 128.0, 128.9 (CH, Ph), 130.0 (ring-CH),
130.6, 136.9, 151.3 (C), 166.6, 169.4 (C]O). MS (EI, 70 eV): m/z
(%)¼243 ([M]þ, 100), 212 (75), 183 (53), 155 (20), 114 (18), 102 (14),
82 (20). HRMS (EI, 70 eV): calcd for C14H13NO3: 243.0895; found:
The synthesis was carried out by application of the procedure
reported earlier.23 Starting with 15b (790 mg, 2.50 mmol),

4538
C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
243.0895ꢂ2 ppm. Anal. Calcd for C14H13NO3 (243.26): C 69.12, H
3.25. 3-Trifluormethansulfonyloxy-5-[E-(methoxycarbonyl-
methylidene)]-2-furanone (15a)
5.39, N 5.76. Found: C 69.13, H 6.64, N 5.09.
The synthesis of 15a was carried out as previously reported.23
3.22. 3-Methyl-5-[E-(ethoxycarbonylmethylidene)]-N-
methyl-pyrrol-2-one (20)
3.26. 3-Trifluormethansulfonyloxy-5-[E-(ethoxycarbonyl-
methylidene)]-2-furanone (15b)
The reaction was carried out by application of the procedure
given for the synthesis of 13a. Starting with 19 (50 mg, 0.28 mmol)
and methylammonium chloride (74 mg 1.10 mmol) in glacial acetic
acid (2 mL) (140 h, reflux), 20 was isolated by chromatography
(silica gel, hexane/EtOAc¼5:1) as a colourless solid (42 mg, 78%),
mp 122–124 ꢁC. Rf¼0.35 (hexane/EtOAc¼4:1). IR (KBr, cmꢀ1):
~
The synthesis was carried out by application of the procedure
reported earlier.23 Starting with 8e (1.29 g, 7.0 mmol), pyridine
(1.11 g, 1.1 mL, 14.0 mmol) and Tf2O (2.37 g, 1.4 ml, 8.4 mmol) in
dichloromethane (70 mL), 15b was isolated (2.20 g, 92%) as a col-
ourless solid, mp¼38–40 ꢁC. Rf¼0.8 (dichloromethane). IR (KBr,
~
n
¼ 3403ðbr wÞ, 3072 (w), 2984 (m), 2930 (m), 2878 (m), 2854 (m),
cmꢀ1):
n
¼ 3418ðwÞ, 3378 (w), 3326 (w), 3317 (w), 3313 (w), 3301
1703 (s), 1638 (s), 1479 (m), 1443 (m), 1442 (m). 1H NMR (CDCl3,
(w), 3264 (w), 3261 (w), 3257 (w), 3225 (w), 3144 (m), 3080 (w),
2997 (m), 2947 (w), 2913 (w), 1814 (s), 1748 (s), 1718 (s), 1661 (s),
300 MHz):
d
¼1.34 (t, 3J¼7.2 Hz, 3H, CH2CH3), 2.02 (d, 4J¼1.8 Hz, 3H,
CH3), 3.09 (s, 3H, NCH3), 4.24 (q, 3J¼7.2 Hz, 2H, CH2CH3), 5.45 (s, 1H,
1619 (s), 1438 (s). 1H NMR (CDCl3, 300 MHz):
d
¼1.34 (t, 3J¼7.2 Hz,
CH), 7.74 (d, 4J¼1.8 Hz, 1H, ring-CH). 13C NMR (CDCl3, 150 MHz):
3H, CH2CH3), 4.29 (q, 3J¼7.2 Hz, 2H, CH2CH3), 6.09 (d, 4J¼0.65 Hz,
d
¼11.3, 14.5 (CH3), 26.0 (NCH3), 60.6 (CH2), 97.6 (CH), 129.3 (CH-
1H, CH), 8.23 (d, 4J¼0.65 Hz, 1H, CH). 13C NMR (CDCl3, 150 MHz):
ring), 137.6, 151.7 (C), 166.1, 171.0 (C]O). MS (EI, 70 eV): m/z
(%)¼195 ([M]þ, 100), 196 ([Mþ1]þ, 12), 180 (1), 167 (3), 150 (95), 136
(6), 123 (32). HRMS (EI, 70 eV): calcd for C10H13NO3: 195.0895;
found: 195.0895ꢂ2 ppm. Anal. Calcd for C10H13NO3 (195.21): C
61.53, H 6.71, N 7.18. Found: C 62.76, H 6.90, N 6.44.
d
¼14.3 (CH2CH3), 61.9 (CH2CH3), 107.2 (CH), 118.7 (q, J¼319.5 Hz,
CF3), 125.6 (CH-ring), 140.7, 155.1 (C), 159.5, 164.3 (C]O). MS (EI,
70 eV): m/z (%)¼316 ([M]þ, 4), 288 (3), 271 (10), 247 (3), 207 (20),
180 (3), 69 (100). HRMS (EI, 70 eV): calcd for C9H7F3O7S: 315.9865;
found: 315.9865ꢂ2 ppm. Anal. Calcd for C9H7F3O7S (316.21): C
34.19, H 2.23. Found: C 33.91, H 2.27.
3.23. 3-Hydroxy-4-methoxy-5-[Z-(methoxycarbonyl-
methylidene)]-pyrrol-2-one (14a)
3.27. 3-Hydroxy-5-[E-(methoxycarbonylmethylidene)]-N-
methyl-pyrrol-2-one (14h)
To a dichloromethane solution (2 mL) of 13a (51 mg, 0.18 mmol)
The reactionwas carried out by application of the procedure given
for the synthesis of 14a. Starting with 13h (109 mg, 0.40 mmol) and
boron tribromide (401 mg, 1.60 mmol), 14h was isolated by chro-
matography (silica gel, column size: 2.0ꢃ3.0 cm, hexane/
EtOAc¼10:1/1:4) as a yellow solid (57 mg, 78%), mp 88–90 ꢁC. IR
~
was added
a dichloromethane solution of boron tribromide
(175 mg, 0.70 mmol) at 0 ꢁC. After stirring for 30 min at 0 ꢁC,
hydrochloric acid (5 mL, 1 M) was added. The organic and the
aqueous layers were separated and the latter was extracted three
times with dichloromethane. The combined organic layers were
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by chromatography (silica gel: column
size: 2.0ꢃ3.0 cm, hexane/EtOAc¼1:1/1:4) to give 14a as a yellow
(KBr, cmꢀ1):
n
¼ 3186ðmÞ, 3169 (m), 3067 (w), 2957 (w), 1735 (s),
1679 (s), 1638 (s), 1626 (s), 1447 (s). 1H NMR (acetone-d6, 300 MHz):
¼3.09 (s, 3H, NCH3), 3.70 (s, 3H, OCH3), 5.52 (s, 1H, CH), 6.86 (s, 1H,
CH), 9.92 (br s, 1H, OH). 13C NMR (acetone-d6, 75 MHz):
d
ꢀ1
solid (32 mg, 91%), mp 128–130 ꢁC. IR (KBr, cm ):
¼ 3313ðbr mÞ,
d¼26.5
~
n
(NCH3), 52.1 (OCH3), 96.9 (CH), 102.3 (CH), 153.2, 153.3 (C), 166.3,
167.8 (C]O). MS (EI, 70 eV): m/z (%)¼183 ([M]þ, 56),152 (60),127 (8),
112 (5), 95 (8), 91 (30), 82 (100). HRMS (EI, 70 eV): calcd for C8H9NO4:
183.0532; found: 183.0532ꢂ2 ppm. Anal. Calcd for C8H9NO4
(183.16): C 52.46, H 4.95, N 7.65. Found: C 52.43, H 4.57, N 7.33.
3270 (br m), 2958 (w), 2924 (m), 1733 (s), 1692 (s), 1655 (s), 1462
(w), 1440 (m). 1H NMR (CDCl3, 300 MHz):
¼3.76 (s, 3H, OCH3), 4.11
(s, 3H, OCH3), 5.54 (s, 1H, CH), 8.54 (br, 1H, NH). 13C NMR (CDCl3,
150 MHz):
d
d
¼52.0, 59.3 (OCH3), 94.3 (CH), 126.1, 136.5, 145.3 (C),
167.4, 167.6 (C]O). MS (EI, 70 eV): m/z (%)¼199 ([M]þ, 48), 167
(100), 151 (65), 124 (26), 112 (3), 96 (9). HRMS (EI, 70 eV, ESI-
HRMS): calcd for C8H10NO5 [MþH]þ: 200.05535; found:
200.05541; calcd for C8H9NO5Na [MþNa]þ: 222.03729; found:
222.03738.
Acknowledgements
We are grateful to Dr. M. Kindermann for NOESY experiments.
Financial support from the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
3.24. 3-Hydroxy-4-methyl-5-[Z-(methoxycarbonyl-
methylidene)]-pyrrol-2-one (14f)
References and notes
rrThe reaction was carried out by application of the procedure
given for the synthesis of 14a. Starting with 13f (100 mg, 0.37 mmol)
and boron tribromide (366 mg, 1.48 mmol), 14f was isolated by
chromatography (silica gel, column size: 2.0ꢃ3.0 cm, hexane/
EtOAc¼10:1/1:4) as a slightly yellow solid (58 mg, 86%), mp 117–
1. For a review of tetramic acid natural products: Royles, B. J. L. Chem. Rev. 1995,
95, 1981.
2. (a) Grundon, M. F. Nat. Prod. Rep. 1987, 4, 89; (b) Lewis, J. R. Nat. Prod. Rep. 1993,
10, 291; (c) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329; (d) Rigby, J. H.; Hughes, R. C.;
Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834.
3. (a) Rigby, J. H. Tetrahedron 1996, 52, 10569 and references cited therein; (b)
Simmons, C. J.; Marner, F.-J.; Cardellina, J. H.; Moore, R. E.; Seff, K. Tetrahedron
Lett. 1979, 2003; (c) Cardellina, J. H.; Moore, R. E. Tetrahedron Lett. 1979, 2007.
4. (a) Celmer, W. D.; Salomons, J. A. J. Am. Chem. Soc. 1955, 77, 2861; (b) Dell, I.;
Godfrey, C. R. A.; Wadsworth, D. J. Total Synthesis of Naturally Occurring 1,2-
Dithiolo[4,3-b]pyrrolones and Related Compounds. In Synthesis and Chemistry
of Agrochemicals III. ACS Symposium Series; 1992; Vol. 504, p 384; (c) Abdullaev,
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5. (a) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pigments; Springer:
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ꢀ1
119 ꢁC. IR (KBr, cm ):
¼ 3323ðsÞ, 3241 (s), 3050 (s), 1732 (s), 1705
~
n
(s), 1690 (s), 1650 (s), 1440 (s), 1420 (s). 1H NMR (acetone-d6,
300 MHz):
¼1.90 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 5.33 (s, 1H, CH),
9.12 (br s,1H, NH).13C NMR (acetone-d6,150 MHz):
d
d
¼6.7 (CH3), 51.7
(OCH3), 93.0 (CH), 113.6, 148.0, 152.2 (C), 166.4, 168.3 (C]O). MS (EI,
70 eV): m/z (%)¼183 ([M]þ, 100), 184 ([Mþ1]þ, 8), 167 (1), 151 (72),
123 (12). HRMS (EI, 70 eV): calcd for C8H9NO4: 183.0532; found:
183.0532ꢂ2 ppm. Anal. Calcd for C8H9NO4 (183.16): C 52.46, H 4.95,
N 7.65. Found: C 52.50, H 5.19, N 7.26.

C. Haase, P. Langer / Tetrahedron 65 (2009) 4530–4539
4539
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