Synthesis of N-aryl-5-alkylidene-2,5-dihydropyrrol-2-ones by "cyclization/Dimroth rearrangement" reactions of 1,3-dicarbonyl dianions with diimidoyl dichlorides of oxalic acid

Article abstract of DOI:10.1002/ejoc.200300727

The reaction of dilithiated dicarbonyl compounds with oxaldiimidoyl dichlorides resulted in regio- and (E)/(Z)-diastereo-selective formation of 5-alkylidene-3-arylamino-2,5-dihydropyrrol-2-ones. The products were formed by a domino "cyclization/Dimroth rearrangement" reaction. The mechanism and preparative scope of the cyclization was studied. The arylamino groups of the products were removed chemoselectively under mild conditions and in high yields by hydrolytic cleavage. The products, N-aryl-5-alkylidene-3-hydroxy-2,5- dihydropyrrol-2-ones, are of considerable interest from pharmacological and synthetic viewpoints. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300727

FULL PAPER
Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones by
‘‘Cyclization/Dimroth Rearrangement’’ Reactions of 1,3-Dicarbonyl Dianions
with Diimidoyl Dichlorides of Oxalic Acid
Joachim T. Anders,[a] Helmar Görls,[b] and Peter Langer*[a]
Keywords: Cyclization / Dianions / Heterocycles / Oxalic acid derivatives / Regioselectivity
The reaction of dilithiated dicarbonyl compounds with oxal-
diimidoyl dichlorides resulted in regio- and (E)/(Z)-diastereo- cleavage. The products, N-aryl-5-alkylidene-3-hydroxy-2,5-
selective formation of 5-alkylidene-3-arylamino-2,5-dihy- dihydropyrrol-2-ones, are of considerable interest from phar-
tively under mild conditions and in high yields by hydrolytic
dropyrrol-2-ones. The products were formed by a domino macological and synthetic viewpoints.
‘‘cyclization/Dimroth rearrangement’’ reaction. The mechan-
ism and preparative scope of the cyclization was studied. The
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
arylamino groups of the products were removed chemoselec- Germany, 2004)
Introduction
5-Alkylidene-2,5-dihydropyrrol-2-ones, which are of con-
siderable pharmacological relevance, occur in a variety of
natural products, such as amaryllidacae alkaloids[1aϪ1c] α-
lycorane and 4,5-dehydroanhydrolycorine,[1cϪ1d] the pukele-
imides AϪG,[2aϪ2c,3] holomycin,[4] and isoampullicin
(Scheme 1).[5] 5-Alkylidene-2,5-dihydropyrrol-2-ones rep-
resent synthetic precursors to γ-lactam and tetramic acid
antibiotics[6] and to γ-lactam analogues of carbapenems.[7]
2-Alkylidenepyrrolidines represent key intermediates during
the synthesis of mitomycin antitumor agents possessing
antibacterial activity.[8] They are potent inhibitors of serine
Scheme 1. 5-Alkylidene-2,5-dihydropyrrol-2-one natural products
protease and have been used for the treatment of tumors
and arthritis.[9] In addition, 2-alkylidenepyrrolidines have
been used as peptide mimics,[9] angiotensin II antagon-
ists,[10] and prostaglandin analogues.[11] An unsubstituted 2-
alkylidenepyrrolidine has been used during the synthesis of
cancerostatic camptothecin.[12] 5-Alkylidene-2,5-dihydro-
pyrrol-2-ones and 2-alkylidenepyrrolidines represent pre-
cursors to functionalized pyrroles[13] that are building
blocks of natural tetrapyrrol pigments, such as porphobilin-
ogen or bilirubin,[14,15] and other natural products.[16]
5-Alkylidene-2,5-dihydropyrrol-2-ones have been pre-
pared by Wittig reactions of imides with stabilized ylides.[17]
Alternative syntheses rely, for example, on 1,3-dipolar
cycloadditions of nitrones with alkenes and alkynes to give
isoxazolidines, which can be transformed into α-hydroxy-γ-
lactams by hydrogenolysis,[18] and on the reaction of amines
with alkylidenetetronic acids[19] and dimethyl-β-oxoalkane-
dioates.[20] 5-Alkylidenepyrrolidin-2-ones have been pre-
pared, for example, by the reactions of cyclic enol lactones
with amines[9] and protected 2,2-diethoxypyrrolidines with
ketones.[21]
A few years ago we reported a new approach to γ-alkylid-
enebutenolides by cyclization of 1,3-dicarbonyl dianions
with N,NЈ-dimethoxy-N,NЈ-dimethylethanediamide, the bis-
Weinreb amide of oxalic acid.[22,23] Recently, we developed
a new synthesis of 5-alkylidene-3-amino-2,5-dihydropyrrol-
2-ones, aza-analogous γ-alkylidenebutenolides,[24] by cycli-
zation reactions[25] of 1,3-dicarbonyl dianions[26] with oxal-
diimidoyl dichlorides, which can be regarded as aza-ana-
logues of oxalyl chloride.[27] Herein, we report the full de-
tails, the extension of the preparative scope, and studies re-
[a]
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt
Universität Greifswald,
Soldmannstrasse 16, 17487 Greifswald, Germany
[b]
Institut für Anorganische und Analytische Chemie der
Universität Jena,
August-Bebel-Str. 2, 07740 Jena, Germany
Eur. J. Org. Chem. 2004, 1897Ϫ1910
DOI: 10.1002/ejoc.200300727
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1897

P. Langer, J. T. Anders, H. Görls
FULL PAPER
lated to the mechanism of this reaction. In addition, we was added within 5 min to a 0.075  THF solution of 2a
describe a mild and efficient hydrolytic transformation of at Ϫ78 °C. The solution was warmed to 20 °C during 1 h
the cyclization products into N-aryl-5-alkylidene-3- and then stirred at 20 °C for 5 h. The yield decreased and
hydroxy-2,5-dihydropyrrol-2-ones.
significant amounts of isocyanide and oligomers were
formed when a) the reaction was carried out at 0 °C rather
than Ϫ78 °C, b) a more concentrated solution of 2a was
used (0.2 ), c) the inverse addition protocol was employed,
and d) the dianion was added too rapidly (0.3 min). The
dianion was prepared by addition of 1a to a THF solution
of LDA. The use of NaH/nBuLi resulted in a minor de-
crease of the yield.
Results and Discussion
Optimization: The reaction of dilithiated ethyl acetoacet-
ate 1a with cyanogen[28] resulted in formation of a complex
mixture. The reaction of the dianion of 1a with diethyl
N,NЈ-bis(p-methoxyphenyl)oxaldiimidoate, C2[N(PMP)]2-
(OEt)2 [PMP ϭ p-MeOC6H4], resulted in formation of a
complex mixture. In contrast, the reaction of the dianion
of 1a with N,NЈ-bis(p-methoxyphenyl)oxaldiimidoyl di-
chloride (2a), which is more reactive than the corresponding
diester, afforded the 5-alkylidene-2,5-dihydropyrrol-2-one
3a (Scheme 2). Similar to the observations made concerning
the synthesis of γ-alkylidenebutenolides from 1,3-dicar-
bonyl dianions,[23] matching the reactivity of the dianion
and dielectrophile is an important parameter for optimiz-
ation.
Next, we studied the deprotection of the 5-alkylidene-2,5-
dihydropyrrol-2-one 3a (Table 1). The p-methoxyphenyl
(PMP) protective group is frequently used in the chemistry
of N-heterocycles such as β-lactams.[29] Our initial attempts,
however, to achieve cleavage of the enamine moiety of 3a
were unsuccessful. An attempted oxidative cleavage of the
PMP group by CAN in CH3CN resulted in decomposition.
Only starting material was recovered in the reaction of 3a
with an aqueous solution (1 ) of sulfuric acid. The use
of an aqueous solution of sodium hydroxide also proved
unsuccessful. Treatment of 3a with BBr3 and subsequent
addition of methanol resulted in hydrolytic cleavage and
formation of the desired N-aryl-5-alkylidene-3-hydroxy-2,5-
dihydropyrrol-2-one 4a, but in low yield. After much
experimentation, we found that the enamine moiety could
be removed in high yield (87%) by treatment of 3a with
a 5:3 mixture of THF and 1  aqueous hydrochloric acid
(Scheme 3). The use of less- or more-concentrated solutions
of HCl resulted in a decrease of the yield; the presence of
THF was mandatory.
Table 1. Optimization of the synthesis of 4a
Entry
Conditions
t [h]
(%)[a]
1
2
3
4
5
6
7
8
9
BBr3, MeOH
NaOH, H2O
CAN, CH3CN
H2SO4/H2O (1M)
HCl/H2O (37%), THF
HCl/H2O (10%), THF
HCl/H2O (1 ), THF
HCl/H2O (1 ), THF
HCl/H2O (0.1 ), THF
12
120
120
4
1
1
1
12
12
22
0
0
Scheme 2. Mechanism of the formation of 3a. Conditions: 1) 2.2
equiv. LDA, 2) 2a, THF, Ϫ78 then 20 °C, 56%
0
50
49
87
86
48
The formation of 3a can be explained by a regioselective
attack of the terminal carbon atom of the dianion onto the
dielectrophile and cyclization mediated by the oxygen atom
to give intermediate A. The latter underwent a Dimroth re-
arrangement to give the final product. The domino ‘‘cycli-
zation/Dimroth rearrangement’’ reaction proceeded with
excellent (E)/(Z)-diastereoselectivity, due to the stereodi-
recting effect of the substituent attached to the pyrrole ni-
trogen atom.
[a]
Isolated yield
Oligomerization and isocyanide formation proved to be
major side reactions. (p-Methoxyphenyl)isocyanide could
be isolated in up to 10% yield and was formed presumably
by reduction of 2a by the dianion. The formation of small
amounts of isocyanide was observed even under optimized
Scheme 3. Hydrolytic cleavage of the enamine moiety 3a. For con-
conditions. Optimal yields were obtained when the dianion ditions see Table 1.
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Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones
FULL PAPER
In all experiments, 4a was obtained as a single isomer, with N,NЈ-diphenyloxaldiimidoyl dichloride (2b) afforded
containing an (E)-configured exocyclic double bond. The the (E)-configured heterocycles 3fϪg, each of which con-
reaction proceeded with very good chemoselectivity: no tains a substituent at the exocyclic double bond. Starting
cleavage of either the ester group or the heterocyclic moiety with the dianions of methyl 3-oxopentanoate and ethyl 3-
was observed. The transformation of 3a into 4a has pre- oxohexanoate, the (Z)-configured 5-alkylidene-2,5-dihydro-
parative value because the hydroxy group of α-hydroxy-γ- pyrrol-2-ones 3hϪi were obtained. The change from the (E)
alkylidenebutenolides can be functionalized by palladium- to (Z) configuration can be explained by the relative steric
catalyzed cross-coupling reactions via their corresponding influence of the methyl and ethyl group, respectively.
enol triflates.[23c,30]
Heterocycles 3jϪm were prepared with very good regio-
Variation of the substituent attached to the diimidoyl di- and (E)-diastereoselectivities from α-acetyl-γ-butyrolac-
chloride (R ϭ Ph, Tol) had no major effect on the yield tones 1jϪm. 5-Alkylidene-2,5-dihydropyrrol-2-ones 3nϪo
of heterocycles 3 and 4 (vide infra). To date, however, the were prepared with very good (E) diastereoselectivities from
methodology is limited to aryl-substituted oxaldimidoyl di- 3-acetyl-2,3-dihydrobenzofuran-2-one and N-methyl-3-ace-
chlorides. The cyclization of N,NЈ-bis(p-tolylsulfonyl)oxal- tylindol-2-one. The reaction of 2a with dilithiated cyclohex-
diimidoyl dichloride (2d)[27] with dilithiated 1a resulted in ane-1,3-diones afforded the bicyclic 5-alkylidene-2,5-di-
the formation of a complex mixture (vide infra). We are cur- hydropyrrol-2-ones 3pϪq.
rently studying the removal of the second PMP group of 4a
As described above, esters (e.g., ethyl acetoacetate) and
and also working on the synthesis of bis(imidoyl) dichlor- amides have been used mainly as the 1,3-dicarbonyl com-
ides containing other protective groups, which is an import- pounds and gave the desired 5-alkylidene-2,5-dihydropyr-
ant feature for applications in natural product syntheses. rol-2-ones 3aϪq. The hydrolytic deprotection of hetero-
We believe, however, that N-aryl-5-alkylidene-3-hydroxy- cycles 3aϪq proceeded uneventfully in most cases and af-
2,5-dihydropyrrol-2-ones, such as 4a, represent interesting forded a variety of N-aryl-5-alkylidene-3-hydroxy-2,5-di-
and useful molecules for their own sake from both a syn- hydropyrrol-2-ones 4aϪq in moderate to excellent yields
thetic and pharmacological viewpoint. Therefore, herein we (Scheme 4).
report the results of our efforts that we believe constitute a
significant expansion of the methods known today for the yellow solids. Inspection of the UV/Vis spectra (Table 2)
synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones. showed that the influence of both the aryl group attached
Heterocycles 4aϪq were obtained as colorless or slightly
Preparative Scope: To study the preparative scope of our to the nitrogen atom (4aϪc) and the presence of an alkyl
methodology, we varied the substituents of the starting ma- group attached to the heterocyclic moiety or to the ex-
terials systematically. The reactions of oxaldiimidoyl di- ocyclic double bond was relatively low (cf. 4b, 4f, 4h and
chlorides 2aϪc with the 1,3-dicarbonyl compounds 1 af- 4i). A small bathochromic effect was observed for dinuclear
forded a large variety of 5-alkylidene-2,5-dihydropyrrol-2- esters with respect to mononuclear ones (4b/4j). The influ-
ones (3aϪq; Scheme 4, Table 2).
ence of an amide group was relatively low. A bathochromic
shift was observed for the oxindole-derived product 4o, as
well as for the bicyclic product 4q. The strongest effect was
observed for the dihydrobenzofuranone 4n because of its
larger conjugated π-electron system. In contrast to the other
2-alkylidene-2,5-dihydropyrrol-2-ones, which are yellow, 4n
has a deep-red color.
Treatment of 5-methylisoxazole with two equivalents of
LDA afforded the dianion of α-cyanoacetone.[31] Treatment
of the latter with 2b,c afforded the cyano-substituted 5-
alkylidene-2,5-dihydropyrrol-2-ones 6a,b as 10:1 mixtures
of (E)/(Z)isomers (Scheme 5). Treatment of 6a,b with HCl/
H2O afforded the desired products 7a,b.
Structure: The structures of 3c and 4c were established
by NOESY experiments and, independently, by crystal
structure analyses (Figure 1). The exocyclic double bond
possesses an E configuration. The ester group and the het-
erocyclic moiety are in-plane. Inspection of the crystal lat-
tice exhibits the presence of a dimeric structure (Figure 2).
The configuration of the exocyclic double bonds of 3c and
Scheme 4. Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones
4aϪq, a: 1) 2.2 equiv. LDA, 2) 2aϪc, THF, Ϫ78 to 20 °C; b: 1 
HCl, THF, 1 h, 20 °C.
The reaction of diimidoyl dichlorides with the dianions of other derivatives was established by NOESY experiments
of ethyl acetoacetate, N,N-diethylacetylacetic amide, and N- and by comparison of the 1H NMR spectroscopic chemical
(o-tolyl)acetylacetic amide gave the 5-alkylidene-2,5-di- shifts (Scheme 6, Table 2). The chemical shifts of the signals
hydropyrrol-2-ones 3aϪe with very good regio- and (E)- of the hydrogen atoms located at the pyrrole moiety and at
diastereoselectivities. The cyclization of dilithiated ethyl 2- the exocyclic double bond are generally higher for (E)- than
methylacetoacetate (1f) and ethyl 2-ethylacetoacetate (1g) for (Z)-configured isomers (by ca. 0.3 ppm). A related trend
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1899

P. Langer, J. T. Anders, H. Görls
FULL PAPER
Table 2. Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones 3aϪq and 4aϪq [PMP ϭ p-(MeO)C6H4]
3, 4
R1
R3
R2
R4
δ (3)[a]
(E)/(Z)[b]
3 (%)[c]
4 (%)[c]
UV (4)[d]
a
b
c
d
e
H
H
H
H
H
OEt
OEt
OEt
NH(o-Tol)
NEt2
H
H
H
H
H
PMP
Ph
Tol
Tol
Ph
5.46, 7.20
5.50, 7.20
5.46, 7.20
5.74,[e]
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
97:3
56
55
60
40
59
21
58
57
54
48
56
36
52
49
47
38
44
40
87
92
66
63
94
Ϫ
96
389
376
386
385
5.80,[e] (E)
5.35, 6.25 (Z)
Ϫ, 7.20
Ϫ, 7.35
5.16, Ϫ
5.19, Ϫ
Ϫ, 7.08
Ϫ, Ϫ
1:5
f
H
H
Me
Et
H
Me
H
H
H
H
OEt
OEt
OMe
OEt
Me
Et
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PMP
Ph
PMP
PMP
Ͼ 98:2
Ͼ 98:2
Ͻ 2:98
Ͻ 2:98
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ϫ
373
Ϫ
g
h
i
70[f]
100
63
100
52
100
99
42
97
376
374
384
391
384
384
470
425
382
394
H
j
k
l
m
n
o
p
q
ϪOCH2CH2Ϫ
ϪOCH2CH2Ϫ
ϪOCH(CH3)CH2Ϫ
ϪOCH(CH2CH3)CH2Ϫ
ϪO(C6H4)Ϫ
Ϫ, 7.20
Ϫ,[e]
Ϫ, 7.40
Ϫ,[e]
5.64, Ϫ
5.65, Ϫ
ϪNMe(C6H4)Ϫ
ϪCH2CH2Ϫ
ϪC(CH3)2CH2Ϫ
H
H
50
60
Ϫ
[a] 1H NMR spectroscopic signals (CH) of the exocyclic double bond and the pyrrole moiety (ppm). [b] Isomeric ratio of isolated products
[c]
[d]
[e]
[f]
(1H NMR). Isolated yields. UV/Vis (CH3CN, nm), λmax. Signal overlap in the aromatic region. Mixture of isomers (1:1).
Scheme 5. Synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones 7a,b.
Figure 1. ORTEP plot of 3c. The thermal ellipsoids of 50% prob-
a: 2.2 equiv. LDA [6a (R ϭ Tol), 44%; 6b (R ϭ Ph), 40%]; b: 2b,c,
ability are shown for the non-hydrogen atoms; selected bond
THF, Ϫ78 to 20 °C; c: 1  HCl, THF, 1 h, 20 °C [7a (R ϭ Tol),
63%; 7b (R ϭ Ph), 52%]
˚
lengths (A) and angles (°): O(1)ϪC(1) 1.212(5), N(1A)ϪC(1A)
1.371(5), C(2A)ϪC(12A) 1.342(5), N(1A)ϪC(2A) 1.414(5),
C(2A)ϪC(3A)
1.450(5),
C(1A)ϪC(4A)
1.504(5);
C(1A)ϪN(1A)ϪC(5A) 124.2(3), O(1A)ϪC(1A)ϪC(4A) 127.5(3),
N(1A)ϪC(1A)ϪC(4A) 106.0(3), C(4A)ϪC(3A)ϪC(2A) 108.4(3)
has been noted previously for γ-alkylidenebutenolides[23,30]
and for 2-alkylidenetetrahydrofurans.[32,33] The Z configu-
rations of 3h,i were proven by NOESY measurements with
3h and by comparison of the chemical shifts of the hydro- of 10 was improved (56%) by addition of 2 equiv. of lithium
gen atoms located at each exocyclic double bond. The con- chloride to the reaction mixture. The rearrangement pro-
figurations of 3j and 3f,g were established by NOESY ceeded stereoselectively and afforded the E-configured iso-
experiments and by comparison of the chemical shifts of mer exclusively. This result suggests that the stereoselectiv-
the pyrrole hydrogen atoms with those of (E)-configured 5- ity for all 5-alkylidene-2,5-dihydropyrrol-2-ones 3 was es-
alkylidene-2,5-dihydropyrrol-2-ones.
tablished during the Dimroth rearrangement. The selec-
Mechanism: The reaction of dilithiated 4-(phenylim- tivity can be explained by the steric effect of the N-aryl
ino)pentan-2-one (8)[34] with 2c resulted in regioselective C/ group, which can operate only in products 10 and 3, but
O-cyclization and formation of product 9 as an inseparable not in 9 and intermediate A. The rate of the Dimroth re-
1:1 mixture of (E)/(Z) isomers (Scheme 7). Upon standing, arrangement[35] is enhanced by the presence of a Lewis acid.
a solution of yellow-colored 9 isomerized slowly into the In fact, a Lewis acid, lithium chloride, was formed during
red-colored 5-alkylidene-2,5-dihydropyrrol-2-one 10 by the cyclization of 1,3-dicarbonyl dianions 1 with bis(imi-
Dimroth rearrangement (12%, low conversion). The yield doyl)dichlorides 2.
1900
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Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones
FULL PAPER
Figure 3. ORTEP plot of 10. The thermal ellipsoids of 50% prob-
ability are shown for the non-hydrogen atoms; selected bond
Figure 2. Dimeric structure of 3c
˚
lengths (A) and angles (°): OϪC(1) 1.211(4), N(1)ϪC(1) 1.368(5),
C(2)ϪC(3) 1.352(5), C(3)ϪC(4) 1.439(5), N(1)ϪC(4) 1.417(4),
C(2)ϪN(3) 1.349(4), C(4)ϪC(5) 1.341(5); C(1)ϪN(1)ϪC(4)
110.2(3), OϪC(1)ϪC(2) 127.8(4), N(3)ϪC(2)ϪC(3) 136.7(4),
N(2)ϪC(6)ϪC(5)
121.3(4),
C(2)ϪC(3)ϪC(4)
109.2(3),
OϪC(1)ϪN(1) 126.1(4)
Scheme 6. Chemical shifts and NOESY experiments
Figure 4. Dimeric structure of 10
The cyclization of the dianion of 1 with oxaldiimidoyl
dichlorides 2b and 2c afforded the 5-alkylidene-2-arylimino-
2,5-dihydropyrroles 12a and 12b, respectively (Scheme 8).
These products were formed with very good C/N regioselec-
tivities and (E) diastereoselectivities. Because of the lack of
a structural driving force, a Dimroth rearrangement of the
amidine moiety is unlikely, but cannot be ruled out. In the
case of 12b, the rearrangement would represent an ident-
ity-reaction.
Scheme 7. Cyclization of dilithiated 8 with 2c: a: 1) 2.2 equiv. LDA,
2) 2c, THF, Ϫ78 to 20 °C, 45% [(E)/(Z)ϭ 1:1, the product contains
ca. 20% of an unknown isomer]; b: THF, 72 h, 20 °C, 12% (low
conversion); alternatively: THF, LiCl, 72 h, 56%.
Lewis Acid-Mediated Cyclization: The tolylsulfonyl group
The structure of 5-alkylidene-2,5-dihydropyrrol-2-one 10 represents a useful protective group for pyrrole and indole
was confirmed independently by crystal structure analysis nitrogen atoms. The cyclization of dilithiated ethyl ace-
(Figure 3). The exocyclic double bond exhibits an (E) con- toacetate with bis(imidoyl)dichloride 2d resulted in forma-
figuration. The p-tolyl group of the enamine is in-plane tion of a complex mixture. In contrast, the TiCl4-mediated
with the pyrrole moiety. In contrast, the other p-tolyl group reaction of 2d with 1,3-bis(silyl enol ether) 13, which can
is twisted out of the plane. Similar to 3c, a dimeric structure be regarded as an electroneutral dianion equivalent, af-
is present in the crystal lattice (Figure 4).
forded the desired product 14, albeit in low yield
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1901

P. Langer, J. T. Anders, H. Görls
FULL PAPER
solvents, we used CDCl3 (δ ϭ 77.0 ppm), [D6]acetone (δ ϭ
29.8 ppm), [D6]DMSO (δ
ϭ 39.5 ppm), [D4]methanol (δ ϭ
49.0 ppm), and [D8]THF (δ ϭ 25.5, 67.7 ppm). The multiplicity of
each carbon atom was determined by the DEPT 135 (DEPT ϭ
Distortionless Enhancement by Polarization Transfer) and APT
techniques (APT ϭ Attached-Proton Test); they and quoted as
CH3, CH2, CH, and C for primary, secondary, tertiary, and quater-
nary carbon atoms, respectively. IR: PerkinϪElmer 2000 FT-IR,
FT-IR Bruker Vector 22, Bruker IFS 66, or Nicolett 205 FT-IR
spectrometers. UV spectroscopy: PerkinϪElmer UV/Vis/NR Ϫ
Spectrometer Lambda 19; CH3CN was used as solvent. Mass spec-
troscopy: Finnigan MAT 95 spectrometer [electron ionization (EI):
70 eV], Finnigan LC-Q (electrospray ionization, ESI). Chemical
ionization (CI): H2O. For preparative scale chromatography we
used silica gel (60Ϫ200 mesh); solvents: petroleum ether (PE, b.p.
40Ϫ70 °C) and diethyl ether. Melting points are uncorrected and
were measured using a Büchi apparatus. Elemental analyses: micro-
analytical laboratory of the University of Göttingen (Leco CHN
2000, Heraeus Mikro U/D).
Scheme 8. Cyclization of dilithiated 11 with 2b,c: a: 1) 2.2 equiv.
LDA, 2) 2b,c, THF, Ϫ78 to 20 °C [12a (R ϭ Tol), 35%; 12b (R ϭ
Ph), 32%].
General Procedure for the Synthesis of 5-Alkylidene-3-arylamino-
2,5-dihydropyrrol-2-ones (3): A THF solution of LDA was prepared
by addition of nBuLi (8.25 mL, 13.2 mmol, 1.6  solution in hex-
ane) to a THF solution (20 mL) of diisopropylamine (1.34 g,
1.86 mL, d ϭ 0.722, 13.2 mmol). A THF solution (20 mL) of ethyl
acetoacetate (0.72 g, d ϭ 1.021, 0.71 mL, 5.7 mmol) was added at
0 °C to the LDA solution. The yellow-colored solution was stirred
at 0 °C for 60 min and was then transferred to a THF solution
(80 mL) of N,NЈ-bis[(p-methoxyphenyl)oxaldiimidoyl dichloride
(2.02 g, 6.0 mmol) at Ϫ78 °C. The solution was warmed to 20 °C
within 1 h, stirred for 5 h, and then1  aqueous ammonium chlo-
ride was added. The organic layer was separated and the aqueous
layer was extracted with diethyl ether (4 ϫ 150 mL). The combined
organic layers were dried (MgSO4) and filtered, and then the filtrate
was concentrated in vacuo. The residue was purified by chromatog-
Scheme 9. Lewis acid-mediated cyclization of 1,3-bis(silyl enol
ether) 13 with 2d, a: 2.0 equiv. TiCl4, CH2Cl2, Ϫ78 to 20 °C, 15%
(Scheme 9). Only starting materials were recovered when
TMSOTf was employed in place of TiCl4.
Conclusion
We have developed a new and efficient domino reaction raphy (SiO2; diethyl ether/PE, 1:10 Ǟ 1:1) to give 3a [1.26 g, 56%,
(E)/(Z) Ͼ 98:2] as yellow crystals.
of 1,3-dicarbonyl dianions with oxaldiimidoyl dichlorides
that affords 5-alkylidene-3-arylamino-2,5-dihydropyrrol-2-
ones. The cyclizations proceed with excellent regio- and E/
Z-diastereoselectivity. The arylamino group of each prod-
uct can be hydrolyzed in high yields to give a variety of N-
aryl-5-alkylidene-3-hydroxy-2,5-dihydropyrrol-2-ones.
These products are of pharmacological and synthetic inter-
est. The chemistry reported constitutes an expansion of the
methods known today for the synthesis of 5-alkylidene-2,5-
dihydropyrrol-2-ones.
(E)-5-(Ethoxycarbonylmethylidene)-1-(4-methoxyphenyl)-3-(4-
methoxyphenylamino)-2,5-dihydropyrrol-2-one (3a): 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.32 (t, J ϭ 7 Hz, 3 H, CH2CH3), 3.82,
3.85 (2 ϫ s, 2 ϫ 3 H, OCH3), 4.21 (q, J ϭ 7 Hz, 2 H, CH2), 5.46
(s, 1 H, ϭCH), 6.95 (d, J ϭ 11 Hz, 4 H, Ar), 7.05 (s, 1 H, 4-H),
7.15, 7.51 (2 ϫ d, J ϭ 11 Hz, 2 ϫ 2 H, Ar) ppm. 13C NMR (CDCl3,
62.5 MHz): δ ϭ 14.41 (CH2CH3), 55.29, 55.40 (OCH3), 59.76
(OCH2), 90.45, 95.53 (CH), 114.04, 114.69, 120.08, 126.90 (CH,
Ar), 132.59, 136.31, 140.39, 149.50, 155.85, 158.01, 167.07, 167.56
(C) ppm. IR (KBr): ν˜ ϭ 3385 (w), 3285 (w), 2978 (w), 2957 (w),
2933 (w), 2836 (w), 1696 (s), 1605 (s), 1524 (s), 1508 (s), 1462 (m),
1445 (m), 1418 (w), 1400 (w), 1296 (m), 1248 (s), 1229 (s), 1172 (m),
1133 (s), 1074 (s), 1038 (m), 935 (w), 834 (m), 812 (m) cmϪ1. UV/
Vis (CH3CN): λmax. (lg ε) ϭ 379.9 (4.46), 298.1 (3.98), 248.7 (4.36)
nm. MS (EI, 70 eV): m/z (%) ϭ 394 (100) [Mϩ]; the exact molecular
mass m/z ϭ 394.1528 (Ϯ2 mD) [Mϩ] of C22H22N2O5 was con-
firmed by HRMS (EI, 70 eV). C22H22N2O5 (394.42): calcd. C
66.99, H 5.62; found C 67.17, H 5.84.
Experimental Section
General: All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. All solvents were
distilled prior to use. 1H NMR: Bruker AM 250 (250 MHz), Varian
VXR-200 (200 MHz), Varian Mercury 200 (200 MHz), Varian Un-
ity 300 (300 MHz), Bruker AMX 300 (300 MHz), or Varian Inova
1
500 (500 MHz) spectrometers. For H NMR spectrosopy, we used
(E)-5-(Ethoxycarbonylmethylidene)-1-phenyl-3-phenylamino-2,5-
the solvents CDCl3 (δ ϭ 7.26 ppm), [D8]THF (δ ϭ 1.73, 3.58 ppm), dihydropyrrol-2-one (3b): Starting from ethyl acetoacetate (0.76 mL,
[D6]acetone (δ
ϭ
2.04 ppm), [D6]dimethyl sulfoxide (δ
ϭ
6.0 mmol) and N,NЈ-bis[(p-methoxyphenyl)oxaldiimidoyl dichlor-
ide (1.66 g, 6.0 mmol), 3b was isolated as a yellow solid [1.10 g,
55%, (E)/(Z) Ͼ 98:2]. 1H NMR (CDCl3, 200 MHz): δ ϭ 1.29 (t,
2.50 ppm), and [D4]methanol (δ ϭ 3.30 ppm). Tetramethylsilane
(TMS) was used as the internal standard. 13C NMR: Bruker AM
250 (62.9 MHz), Varian VXR-200 (50.3 MHz), Varian Mercury J ϭ 7 Hz, 3 H, CH2CH3), 4.20 (q, J ϭ 7 Hz, 2 H, CH2CH3), 5.50
200 (50.3 MHz), Varian Unity 300 (75.5 MHz), Bruker AMX 300
(75.5 MHz), or Varian Inova 500 (125.7 MHz) spectrometers. As
(s, 1 H, CHCO2Et), 7.00Ϫ7.50 (m, 12 H, 4-H, Ph, NH) ppm. 13C
NMR (CDCl3, 50 MHz): δ ϭ 14.39 (CH2CH3), 59.95 (CH2CH3),
1902
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 1897Ϫ1910

Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones
FULL PAPER
92.03, 97.61 (CH, CHCO2Et, C-4), 118.23, 123.42, 124.56, 126.09, (E)-5-[1-(Ethoxycarbonyl)ethylidene]-1-phenyl-3-phenylamino-2,5-
128.94, 129.61 (CH, Ph), 139.14, 139.33, 143.45 (C, C-3, Ph), dihydropyrrol-2-one (3f): Starting from ethyl 2-methylacetoacetate
151.26 (C, C-2), 166.50, 167.33 (C, C-5, CO2Et) ppm. IR (KBr): (0.58 g, 0.56 mL, 4.0 mmol) and N,NЈ-diphenyloxaldiimidoyl di-
ν˜ ϭ 3356 (m), 2976 (w), 2932 (w), 1704 (s), 1616 (s), 1596 (s),
chloride (1.11 g, 4.0 mmol), 3f was isolated as a yellow solid
1
1532 (s), 1380 (m), 1236 (s), 1132 (s), 1072 (s), 1040 (m) cmϪ1. MS- [806 mg, 58%, (E)/(Z) Ͼ 98:2]. H NMR (CDCl3, 250 MHz): δ ϭ
FAB: m/z (%) ϭ 335 [M ϩ 1]ϩ, 250 [M Ϫ TolNC]ϩ. C20H18N2O3 1.38 (t, J ϭ 7 Hz, 3 H, CH2CH3), 2.05 (s, 3 H, CH3), 4.32 (q, J ϭ
(334.36): calcd. C 71.84, H 5.43, N 8.37; found C 71.42, H 5.71,
N 8.68.
7 Hz, 2 H, CH2), 7.20 (s, 1 H, CH), 7.05Ϫ7.25 (m, 4 H, Ph), 7.38
(t, J ϭ 9 Hz, 4 H, Ph), 7.70 (d, J ϭ 9 Hz, 2 H, Ph) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ ϭ 14.00, 14.50 (CH3), 60.63 (OCH2), 97.61
(CH, Ring), 99.62 (C), 118.07, 123.13, 125.45, 126.16, 128.99,
129.63 (CH, Ph), 137.38, 139.76, 143.36, 152.12, 158.30, 166.72 (C)
ppm. IR (KBr): ν˜ ϭ 3352 (m), 3305 (w), 3061 (w), 3009 (w),
2983 (w), 2932 (w), 1778 (w), 1671 (s), 1620 (s), 1596 (s), 1533 (s),
1495 (m), 1445 (m), 1326 (m), 1293 (m), 1210 (s), 1132 (m),
1080 (m), 1027 (m), 873 (w), 762 (m), 753 (m), 688 (w), 589 (w)
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 376.1 (4.34), 248.1 (4.28)
nm. MS (EI, 70 eV): m/z (%) ϭ 348 (68) [Mϩ], 240 (100); the exact
molecular mass m/z ϭ 348.1473 (Ϯ2 mD) [Mϩ] of C21H20N2O3
was confirmed by HRMS (EI, 70 eV). C21H20N2O3 (348.39): calcd.
C 72.40, H 5.79; found C 72.18, H 5.75.
(E)-5-(Ethoxycarbonylmethylidene)-1-(4-tolyl)-3-(4-tolylamino)-2,5-
dihydropyrrol-2-one (3c): Starting from ethyl acetoacetate (0.76 mL,
6.0 mmol) and N,NЈ-di(p-tolyl)oxaldiimidoyl dichloride (1.83 g,
6.0 mmol), 3c was isolated as a yellow solid [1.30 g, 60%, (E)/(Z)
Ͼ 98:2]. 1H NMR (CDCl3, 200 MHz): δ ϭ 1.29 (t, J ϭ 7 Hz, 3 H,
CH2CH3), 2.30, 2.33 (s, 6 H, Tol-CH3), 4.19 (q, J ϭ 7 Hz, 2 H,
CH2CH3), 5.46 (s, 1 H, CHCO2Et), 7.00Ϫ7.40 (m, 10 H, 4-H, Tol,
NH) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 14.40 (CH2CH3),
20.79, 21.12 (Tol-CH3), 59.84 (CH2CH3), 91.25, 96.76 (CH,
CHCO2Et, C-4), 118.27, 124.77, 129.55, 130.06 (CH, Tol), 133.02,
136.04, 136.84 (C, C-3, Tol-C to CH3), 139.57, 140.80 (C, Tol-C to
N), 150.70 (C, C-2), 166.82, 167.48 (C, C-5, CO2Et) ppm. IR
(KBr): ν˜ ϭ 3360 (w), 2980 (w), 2928 (w), 1702 (s), 1638 (s), 1605 (s), (E)-5-[1-(Ethoxycarbonyl)propylidene]-1-phenyl-3-phenylamino-2,5-
1532 (s), 1232 (s), 1130 (m), 1075 (s), 1043 (m) cmϪ1. MS (CI, dihydropyrrol-2-one (3g): Starting from ethyl 2-ethylacetoacetate
H2O): m/z (%) ϭ 363 [M ϩ 1]ϩ, 250 [M Ϫ TolNC]ϩ. C22H22N2O3
(0.63 g, 0.64 mL, 4.0 mmol) and N,NЈ-diphenyloxaldiimidoyl di-
(362.42): calcd. C 72.91, H 6.12, N 7.73; found C 72.53, H 6.73, chloride (1.11 g, 4.0 mmol), 3g was isolated as a yellow solid
1
N 8.11.
[825 mg, 57%, (E)/(Z) Ͼ 98:2]. H NMR (CDCl3, 250 MHz): δ ϭ
1.13, 1.38 (2 ϫ t, J ϭ 7 Hz, 2 ϫ 3 H, CH3), 2.59 (q, J ϭ 7 Hz,
2 H, CCH2), 4.29 (q, J ϭ 7 Hz, 2 H, OCH2), 7.05 (d, J ϭ 11 Hz,
2 H, Ph), 7.15Ϫ7.50 (m, 9 H, Ph, NH) ppm. 13C NMR (CDCl3,
62.5 MHz): δ ϭ 14.40, 14.47 (CH3), 20.33 (CCH2), 60.23 (OCH2),
99.67 (CH), 114.01 (C), 117.78, 122.75, 125.03, 125.92, 128.95,
129.51 (CH, Ar), 137.68, 139.89, 143.78, 151.45, 161.79, 167.64 (C)
ppm. IR (KBr): ν˜ ϭ 3366 (m), 3317 (w), 3160 (w), 3060 (w),
2976 (w), 2935 (w), 2874 (w), 1775 (w), 1695 (s), 1628 (s), 1595 (s),
1527 (s), 1494 (m), 1447 (m), 1330 (m), 1253 (m), 1227 (s),
1126 (m), 1083 (s), 1030 (m), 981 (w), 805 (w), 752 (m), 692 (m)
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 378.0 (4.34), 248.7 (4.27),
202.9 (4.29) nm. MS (EI, 70 eV): m/z (%) ϭ 362 (100) [Mϩ], 347
(43); the exact molecular mass m/z ϭ 362.1630 (Ϯ2 mD) [Mϩ] of
C22H22N2O3 was confirmed by HRMS (EI, 70 eV). C22H22N2O3
(362.42): calcd. C 72.91, H 6.12; found C 73.12, H 5.97.
(E)-1-(4-Tolyl)-3-(4-tolylamino)-5-[N-(2-tolyl)carbamoyl-
methylidene]-2,5-dihydropyrrol-2-one (3d): Starting from N-(o-tolyl-
)acetoacetic amide (1.15 g, 6.0 mmol) and N,NЈ-di(p-tolyl)oxaldii-
midoyl dichloride (1.83 g, 6.0 mmol), 3d was isolated as a yellow
solid [1.02 g, 40%, (E)/(Z) Ͼ 98:2]. 1H NMR ([D8]THF, 200 MHz):
δ ϭ 2.26, 2.30, 2.33 (s, 9 H, Tol-CH3), 5.74 (s, 1 H, CHCONHTol),
6.40Ϫ7.70 (m, 13 H, 4-H, Tol), 8.05 (br., 1 H, NH), 8.29 (br., 1 H,
NH) ppm. 13C NMR ([D8]THF, 50 MHz): δ ϭ 18.00, 20.76, 21.01
(Tol-CH3), 94.72, 98.38 (CH, C-4, CHCONHTol), 119.55, 125.04,
126.66, 126.67, 129.95, 129.96, 130.51, 130.74 (CH, Tol), 133.10,
135.71, 138.09 (C, Tol-C to CH3), 138.28 (C, C-3), 138.90, 140.28,
142.86 (C, Tol-C to N), 152.15 (C, C-2), 164.88, 165.21 (C, C-5,
CONHTol) ppm. IR (KBr): ν˜ ϭ 3360 (w), 3025 (w), 1690 (m),
1655 (m), 1630 (s), 1605 (s), 1524 (s), 1450 (m), 1290 (m), 1245 (m),
1078 (m) cmϪ1. MS (CI, H2O): m/z (%) ϭ 424 [M ϩ 1]ϩ.
C27H25N3O2 (423.50): calcd. C 76.58, H 5.95, N 9.92; found C (Z)-5-(Methoxycarbonylmethylidene)-4-methyl-1-phenyl-3-phenyl-
76.24, H 5.93, N 9.88.
amino-2,5-dihydropyrrol-2-one (3h): Starting from methyl 3-oxopen-
tanoate (0.52 g, 0.50 mL, 4.0 mmol) and N,NЈ-diphenyloxaldiimi-
doyl dichloride (1.11 g, 4.0 mmol), 3h was isolated as a yellow solid
(E)- and (Z)-5-(N,N-Diethylcarbamoylmethylidene)-1-phenyl-3-
phenylamino-2,5-dihydropyrrol-2-one (3e): Starting from N,N-di-
ethylacetoacetic amide (314 mg, 0.32 mL, 2.0 mmol) and N,NЈ-di-
phenyloxaldiimidoyl dichloride (544 mg, 2.0 mmol), 3e was isolated
as a yellow solid [(E) isomer: 428 mg, 59%, (E)/(Z) ϭ 97:3; (Z)
isomer: 153 mg, 21%, (E)/(Z) ϭ 1:5]. After 2 months of storage at
room temperature, 80% of the isolated (Z) isomer had turned to
(E). 1H NMR (CDCl3, 250 MHz): (E) isomer, δ ϭ 1.20 (t, 3J ϭ
7.4 Hz, 6 H, NCH2CH3), 3.34Ϫ3.52 (m, 4 H, NCH2CH3), 5.83 (s,
1 H, CHϪCO), 7.03Ϫ7.45 (m, 12 H, NH, C-4, 2 Ph) ppm; (Z)
1
[720 mg, 54%, (E)/(Z) Ͻ 2:98]. H NMR (CDCl3, 250 MHz): δ ϭ
1.65 (s, 3 H, CH3), 3.79 (s, 3 H, OCH3), 5.16 (s, 1 H, CϭCH), 6.80
(s, 1 H, NH), 7.00Ϫ7.50 (m, 8 H, Ph), 7.74 (d, J ϭ 10 Hz, 2 H,
Ph) ppm. 13C NMR (CDCl3, 62.5 MHz): δ ϭ 10.42 (CH3), 51.34
(OCH3), 88.83 (CϭCH), 109.56 (CCH3), 121.79, 124.06, 125.84,
126.46, 128.96, 129.04 (CH, Ph), 136.13, 139.15, 143.24, 151.60,
164.39, 165.29 (C) ppm. IR (KBr): ν˜ ϭ 3320 (s), 3058 (w), 3030 (w),
3020 (w), 2950 (w), 2921 (w), 1678 (s), 1616 (s), 1592 (s), 1517 (s),
1493 (m), 1441 (s), 1339 (s), 1313 (m), 1275 (s), 1253 (m), 1148 (s),
1029 (m), 956 (w), 915 (w), 869 (w), 846 (w), 818 (m), 771 (m),
747 (m), 697 (m), 505 (m) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ
376.7 (4.32), 247.4 (4.34) nm. MS (EI, 70 eV): m/z (%) ϭ 334 (100)
[Mϩ], 301 (16), 275 (28); the exact molecular mass m/z ϭ 334.1317
(Ϯ2 mD) [Mϩ] of C20H18N2O3 was confirmed by HRMS (EI,
70 eV). C20H18N2O3 (334.36): calcd. C 71.84, H 5.43; found C
72.08, H 5.52.
3
Isomer, δ ϭ 1.17 (t, J ϭ 7.1 Hz, 6 H, NCH2CH3), 3.37Ϫ3.49 (m,
4 H, NCH2CH3), 5.35 (s, 1 H, CH-CO), 6.25 (s, 1 H, C-4),
7.03Ϫ7.45 (m, 10 H, NH, Ph), 7.65 (d, 3J ϭ 7.4 Hz, 1 H, Ph) ppm.
13C NMR (CDCl3, 50.3 MHz): (E) and (Z) isomers: δ ϭ 13.42,
14.85 (NCH2CH3), 40.71, 42.56 (NCH2CH3), 92.18 (CH-CO),
98.98 (C-4), 117.93, 122.94, 124.11, 125.60, 128.89, 129.53 (CH,
Ph), 138.05, 139.54, 143.99, 151.98 (C), 164.68, 165.69 (NCO) ppm.
MS (EI, 70 eV): m/z (%) ϭ 361 (91) [Mϩ], 289 (100); the exact
molecular mass m/z ϭ 361.1790 (Ϯ2 mD) [Mϩ] of C22H23N3O2 (Z)-5-(Ethoxycarbonylmethylidene)-4-ethyl-1-phenyl-3-phenylamino-
was confirmed by HRMS (EI, 70 eV).
2,5-dihydropyrrol-2-one (3i): Starting from ethyl 3-oxohexanoate
Eur. J. Org. Chem. 2004, 1897Ϫ1910
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1903

P. Langer, J. T. Anders, H. Görls
FULL PAPER
(0.63 mL, 4.0 mmol) and N,NЈ-diphenyloxaldiimidoyl dichloride
160.38, 171.14 (C) ppm. IR (KBr): ν˜ ϭ 3338 (m), 3307 (s),
(1.11 g, 4.0 mmol), 3i was isolated as a yellow solid [695 mg, 48%, 3061 (w), 2973 (w), 2927 (w), 1731 (s), 1693 (m), 1664 (s), 1621 (s),
(E)/(Z) Ͻ 2:98). 1H NMR (CDCl3, 250 MHz): δ ϭ 0.89 (t, J ϭ 1622 (s), 1596 (s), 1533 (s), 1494 (m), 1441 (s), 1343 (m), 1318 (m),
7 Hz, 3 H, CCH2CH3), 1.36 (t, J ϭ 7 Hz, 3 H, OCH2CH3), 2.15 1225 (s), 1088 (m), 1004 (m), 941 (w), 871 (w), 797 (w), 774 (w),
(q, J ϭ 7 Hz, 2 H, CCH2), 4.32 (q, J ϭ 7 Hz, 2 H, OCH2), 5.19 (s, 751 (s), 689 (m) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 387.5
1 H, ϭCH), 6.73 (s, 1 H, NH), 7.10Ϫ7.45 (m, 8 H, Ph), 7.72 (d,
(4.18), 256.5 (4.26) nm. MS (EI, 70 eV): m/z (%) ϭ 346 (100) [Mϩ],
J ϭ 10 Hz, 2 H, Ph) ppm. 13C NMR (CDCl3, 62.5 MHz): δ ϭ 240 (70); the exact molecular mass m/z ϭ 346.1317 (Ϯ2 mD) [Mϩ]
12.51, 14.50 (CH3), 17.24 (CCH2), 60.10 (OCH2), 89.61 (ϭCH), of C21H18N2O3 was confirmed by HRMS (EI, 70 eV). C21H18N2O3
115.25 (CCH2), 122.43, 124.51, 125.85, 126.36, 128.96, 128.99 (CH, (346.38) C 72.82, H 5.24; found C 71.57, H 5.32.
Ph), 135.60, 139.12, 143.37, 151.80, 163.15, 165.10 (C) ppm. IR
(E)-5-(5-Ethyl-2-oxotetrahydrofuran-3-ylidene)-1-phenyl-3-phenyl-
(KBr): ν˜ ϭ 3350 (m), 3304 (w), 3060 (w), 3016 (w), 2979 (m),
amino-2,5-dihydropyrrol-2-one (3m): Starting from 2-acetyl-4-ethyl-
γ-butyrolactone (0.47 g, 3.0 mmol) and N,NЈ-diphenyloxaldiimi-
2937 (w), 2877 (w), 1690 (s), 1640 (s), 1613 (s), 1593 (s), 1528 (s),
1492 (m), 1451 (m), 1363 (m), 1328 (m), 1265 (s), 1250 (m),
1165 (s), 1143 (s), 1054 (m), 1039 (m), 989 (m), 807 (m), 770 (m),
doyl dichloride (831 mg, 3.0 mmol), 3m was isolated as a yellow
solid [530 mg, 49%, (E)/(Z) Ͼ 98:2]. 1H NMR (CDCl3, 250 MHz):
692 (m) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 375.3 (4.30), 246.9
δ ϭ 1.02 (t, J ϭ 7 Hz, 3 H, CH3), 1.75 (m, 2 H, CH2 CH3), 2.72
(4.34) nm. MS (EI, 70 eV): m/z (%) ϭ 362 (100) [Mϩ], 289 (46);
(dd, J ϭ 6, 16 Hz, 1 H, CH2), 3.25 (dd, J ϭ 8, 16 Hz, 1 H, CH2),
the exact molecular mass m/z ϭ 362.1630 (Ϯ2 mD) [Mϩ] of
4.52 (m, 1 H, CHCH2), 7.00Ϫ7.25 (m, 6 H, Ph, CH, NH),
C22H22N2O3 was confirmed by HRMS (EI, 70 eV). C22H22N2O3
(362.42): calcd. C 72.91, H 6.12; found C 72.71, H 6.07.
7.30Ϫ7.50 (m, 6 H, Ph) ppm. 13C NMR (CDCl3, 62.5 MHz): δ ϭ
9.16 (CH3), 29.33, 31.33 (CH2), 78.95, 96.76 (CH), 97.53 (C),
(E)-5-(2-Oxotetrahydrofuran-3-ylidene)-1-phenyl-3-phenylamino- 118.05, 123.30, 124.76, 126.19, 129.00, 129.66 (CH, Ph), 137.78,
2,5-dihydropyrrol-2-one (3j): Starting from 2-acetyl-γ-butyrolactone
(0.43 mL, 4.0 mmol) and N,NЈ-diphenyloxaldiimidoyl dichloride 3355 (w), 3336 (m), 2972 (w), 2937 (w), 1733 (s), 1694 (m), 1659 (s),
(1.11 g, 4.0 mmol), 3j was isolated as a yellow solid [744 mg, 56%, 1621 (s), 1596 (s), 1536 (s), 1493 (m), 1447 (m), 1351 (m), 1324 (m),
(E)/(Z) Ͼ 98:2]. 1H NMR (CDCl3, 250 MHz): δ ϭ 3.18 (t, J ϭ 1294 (w), 1223 (s), 1212 (s), 1089 (m), 1074 (m), 1005 (s), 795 (w),
7 Hz, 2 H, CH2), 4.25 (t, J ϭ 7 Hz, 2 H, OCH2), 7.08 (s, 1 H, 4-
775 (w), 751 (m), 691 (m) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ
H), 7.20Ϫ7.50 (m, 10 H, Ar) ppm. 13C NMR (CDCl3, 62.5 MHz): 388.6 (4.40), 249.3 (4.30) nm. MS (EI, 70 eV): m/z (%) ϭ 360 (100)
δ ϭ 25.82, 65.53 (CH2), 96.26 (C), 96.55 (CH, C-4), 118.08, 123.36,
[Mϩ]; the exact molecular mass m/z ϭ 360.1473 (Ϯ2 mD) [Mϩ] of
124.72, 126.22, 128.97, 129.65 (CH, Ph), 137.89, 139.22, 143.25, C22H20N2O3 was confirmed by HRMS (EI, 70 eV). C22H20N2O3
139.29, 143.33, 151.14, 160.31, 171.25 (C) ppm. IR (KBr): ν˜ ϭ
151.06, 160.61, 171.66 (C) ppm. IR (KBr): ν˜ ϭ 3448 (w), 3354 (w),
3333 (m), 1731 (s), 1691 (m), 1657 (s), 1621 (s), 1596 (s), 1537 (s),
1491 (m), 1446 (m), 1373 (m), 1325 (m), 1291 (m), 1226 (s),
1208 (s), 1091 (m), 1074 (m), 1022 (m), 1000 (s), 955 (m), 773 (m),
750 (m), 691 (m) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 388.1
(4.39), 249.4 (4.30) nm. MS (EI, 70 eV): m/z (%) ϭ 332 (100) [Mϩ];
the exact molecular mass m/z ϭ 332.1160 (Ϯ2 mD) [Mϩ] of
C20H16N2O3 was confirmed by HRMS (EI, 70 eV). C20H16N2O3
(332.35): calcd. C 72.28, H 4.85; found C 72.04, H 4.73.
(360.40): calcd. C 73.32, H 5.59; found C 72.17, H 5.90.
(E)-1-(4-Methoxyphenyl)-3-(4-methoxyphenylamino)-5-(2-oxo-2,3-
dihydrobenzofuran-3-ylidene)-2,5-dihydropyrrol-2-one (3n): Starting
from 3-acetyl-2,3-dihydrobenzofuran-2-one (0.35 g, 2.0 mmol) and
N,NЈ-bis(p-methoxyphenyl)oxaldiimidoyl
dichloride
(674 mg,
2.0 mmol), 3n was isolated as a yellow solid [412 mg, 47%, (E)/(Z)
1
Ͼ 98:2]. H NMR (CDCl3, 250 MHz): δ ϭ 3.83, 3.90 (2 ϫ s, 2 ϫ
3 H, OCH3), 6.87Ϫ7.25 (m, 11 H, Ar, CH), 7.32 (s, 1 H, NH), 7.59
(m, 2 H, Ar) ppm. 13C NMR (CDCl3, 62.5 MHz): δ ϭ 55.45, 55.50
(OCH3), 95.05 (CH), 110.05 (C), 114.30, 114.93, 120.59, 121.33,
123.59, 123.71, 126.88, 127.06 (CH, Ar), 128.21, 131.67, 135.67,
141.64, 148.25, 151.04, 156.55, 158.65, 163.83, 168.75 (C) ppm. MS
(E)-4-Methyl-5-(2-oxotetrahydrofuran-3-ylidene)-1-phenyl-3-phenyl-
amino-2,5-dihydropyrrol-2-one (3k): Starting from 2-propionyl-γ-
butyrolactone (0.43 g, 3.0 mmol) and N,NЈ-diphenyloxaldiimidoyl
dichloride (831 mg, 3.0 mmol), 3k was isolated as a yellow solid (EI, 70 eV): m/z (%) ϭ 440 (4) [Mϩ], 322 (100); the exact molecular
1
[372 mg, 36%, (E)/(Z) Ͼ 98:2]. H NMR (CDCl3, 250 MHz): δ ϭ
mass m/z ϭ 440.1372 (Ϯ2 mD) [Mϩ] of C26H20N2O5 was con-
2.12 (s, 3 H, CH3), 3.21, 4.39 (2 ϫ t, J ϭ 8 Hz, 2 ϫ 2 H, CH2), 6.65 firmed by HRMS (EI, 70 eV). C26H20N2O5 (440.45): calcd. C
(s, 1 H, NH), 6.90Ϫ7.55 (m, 10 H, Ph) ppm. 13C NMR (CDCl3,
62.5 MHz): δ ϭ 13.85 (CH3), 28.19, 65.44 (CH2), 100.42, 113.13
(C), 120.67, 123.45, 124.71, 125.89, 128.93, 129.04 (CH, Ph),
137.69, 139.47, 143.82, 151.28, 160.70, 170.11 (C) ppm. MS (EI,
70 eV): m/z (%) ϭ 346 (100) [Mϩ]; the exact molecular mass m/z ϭ
346.1317 (Ϯ2 mD) [Mϩ] of C21H18N2O3 was confirmed by HRMS
(EI, 70 eV). C21H18N2O3 (346.38): calcd. C 72.82, H 5.24; found C
74.00, H 5.83.
70.90, H 4.58; found C 69.74, H 5.14.
(E)-5-(1-Methyl-2-oxo-2,3-dihydroindol-3-ylidene)-1-phenyl-3-
phenylamino-2,5-dihydropyrrol-2-one (3o): Starting from 3-acetyl-1-
methyl-2,3-dihydroindol-2-one (0.57 g, 3.0 mmol) and N,NЈ-di-
phenyloxaldiimidoyl dichloride (831 mg, 3.0 mmol), 3o was isolated
as a yellow solid [448 mg, 38%, (E)/(Z) Ͼ 98:2]. 1H NMR (CDCl3,
250 MHz): δ ϭ 3.22 (s, 3 H, CH3), 6.69, 6.95 (2 ϫ m, 2 ϫ 1 H,
Ar), 7.08 (m, 2 H, Ar), 7.22Ϫ7.65 (m, 12 H, Ar, CH, NH) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 25.76 (CH3), 97.99 (CH), 101.47
(C), 107.53, 118.24, 121.87, 122.32, 123.60, 124.39, 126.39, 127.03,
129.02, 129.64 (CH, Ph), 121.69, 138.95, 139.06, 140.86, 143.37,
(E)-5-(5-Methyl-2-oxotetrahydrofuran-3-ylidene)-1-phenyl-3-phenyl-
amino-2,5-dihydropyrrol-2-one (3l): Starting from 2-acetyl-4-methyl-
γ-butyrolactone (0.38 g, 3.0 mmol) and N,NЈ-diphenyloxaldiimi-
doyl dichloride (831 mg, 3.0 mmol), 3l was isolated as a yellow solid 151.04, 160.57, 168.17 (C) ppm. IR (KBr): ν˜ ϭ 3354 (w), 3239 (w),
1
[540 mg, 52%, (E)/(Z) Ͼ 98:2]. H NMR (CDCl3, 250 MHz): δ ϭ
1.50 (d, J ϭ 7 Hz, 3 H, CH3), 2.75 (dd, J ϭ 7, J ϭ 16 Hz, 1 H,
3150 (w), 3126 (w), 3056 (m), 1689 (s), 1683 (s), 1636 (s), 1611 (s),
1575 (s), 1537 (s), 1486 (s), 1470 (m), 1449 (m), 1418 (m), 1374 (s),
CH2), 3.31 (dd, J ϭ 8, J ϭ 16 Hz, 1 H, CH2), 4.73 (m, 1 H, 1347 (m), 1284 (m), 1268 (s), 1230 (m), 1180 (m), 1140 (m),
CHCH3), 7.05Ϫ7.30 (m, 5 H, Ph, 4-H), 7.45 (m, 5 H, Ph), 7.70 (d, 1077 (s), 975 (m), 957 (m), 771 (m), 746 (m), 690 (m), 547 (m)
2 H, Ph) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 22.28 (CH3), cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 429.2 (4.37), 242.1 (4.40)
33.47 (CH2), 74.19, 96.79 (CH), 97.55 (C), 118.11, 119.80, 124.68,
nm. MS (EI, 70 eV): m/z (%) ϭ 393 (100) [Mϩ]; the exact molecular
128.98, 129.27, 129.69 (CH, Ph), 137.87, 139.28, 143.33, 151.17, mass m/z ϭ 393.1477 (Ϯ2 mD) [Mϩ] of C25H19N3O2 was con-
1904
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1897Ϫ1910

Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones
firmed by HRMS (EI, 70 eV). C25H19N3O2 (394.28): calcd. C 1645 (s), 1622 (s), 1619 (s), 1531 (s), 1512 (s), 1464 (m), 1443 (m),
FULL PAPER
76.32, H 4.87; found C 76.55, H 5.04.
1400 (m), 1351 (m), 1299 (m), 1261 (s), 1230 (s), 1176 (m), 1140 (s),
1083 (s), 1036 (s), 933 (w), 816 (m), 772 (m) cmϪ1
.
UV/Vis
1-(4-Methoxyphenyl)-3-(4-methoxyphenylamino)-2,4,5,6-tetrahydro-
1H-indole-2,6-dione (3p): Starting from 1,3-cyclohexanedione
(0.34 g, 3.0 mmol) and N,NЈ-bis(p-methoxyphenyl)oxaldiimidoyl
dichloride (1.01 g, 3.0 mmol), 3p was isolated as a yellow solid
(495 mg, 44%). 1H NMR (CDCl3, 250 MHz): δ ϭ 2.42 (t, J ϭ
4 Hz, 4 H, CH2), 3.80 (s, 6 H, OCH3), 5.64 (s, 1 H, CH), 6.66 (s,
1 H, NH), 6.92 (m, 4 H, Ar), 7.10 (d, J ϭ 12 Hz, 2 H, Ar), 7.48
(d, J ϭ 12 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 62.5 MHz): δ ϭ
20.07, 35.74 (CH2), 55.42, 55.49 (OCH3), 99.85 (CH), 104.61 (C),
114.18, 114.28, 125.59, 126.72 (CH, Ar), 131.13, 135.11, 136.13,
149.62, 157.658, 158.13, 170.49, 197.59 (C) ppm. MS (EI, 70 eV):
m/z (%) ϭ 376 (12) [Mϩ], 361 (6), 268 (22), 69 (100); the exact
molecular mass m/z ϭ 376.1423 (Ϯ2 mD) [Mϩ] of C22H20N2O4
was confirmed by HRMS (EI, 70 eV). C22H20N2O4 (376.40): calcd.
C 70.20, H 5.36; found C 70.10, H 5.38.
(CH3CN): λmax. (lg ε) ϭ 388.6 (4.25), 287.4 (3.92), 236.2 (4.23) nm.
MS (EI, 70 eV): m/z (%) ϭ 289 (100) [Mϩ], 244 (20), 217 (44), 174
(8); the exact molecular mass m/z ϭ 289.0950 (Ϯ2 mD) [Mϩ] of
C15H15NO5 was confirmed by HRMS (EI, 70 eV). C15H15NO5
(289.29): calcd. C 62.28, H 5.23, N 4.84; found C 62.44, H 5.00,
N 4.69.
(E)-5-(Ethoxycarbonylmethylidene)-3-hydroxy-1-phenyl-2,5-dihydro-
pyrrol-2-one (4b): Starting from 3b (31 mg, 92.7 µmol), 4b was iso-
lated as a yellow solid (22 mg, 84.9 µmol, 92%). 1H NMR (CDCl3,
250 MHz): δ ϭ 1.32 (t, 3J ϭ 7.1 Hz, 3 H, OCH2CH3), 4.23 (q, 3J ϭ
7.1 Hz, 2 H, OCH2CH3), 5.69 (s, 1 H, CH-CO), 6.92 (br. s, 1 H,
OH), 7.00Ϫ7.24 (m, 3 H, Ar), 7.30Ϫ7.41 (m, 3 H, Ar) ppm. 13C
NMR (CDCl3, 50.3 MHz):
δ ϭ 14.27 (OCH2CH3), 60.46
(OCH2CH3), 97.03 (CH-CO), 101.27 (C-4), 118.18, 124.05, 129.76
(CH, Ph), 133.59, 138.67, 161.77 (C), 166.22 (NCO), 166.38
(CO2Et) ppm. IR (KBr): ν˜ ϭ 3341 (s), 3299 (w), 3076 (w), 2927 (w),
2853 (w), 1782 (s), 1707 (s), 1647 (s), 1620 (s), 1597 (s), 1542 (m),
1499 (m), 1448 (w), 1403 (w), 1381 (w), 1274 (s), 1235 (w), 1143 (s),
1083 (s), 1040 (m), 804 (m), 752 (m) cmϪ1. UV/Vis (CH3CN): λmax.
(lg ε) ϭ 376.2 (4.27), 278.0 (3.79), 241.7 (4.06) nm. MS (EI, 70 eV):
m/z (%) ϭ 259 (100) [Mϩ], 214 (35), 187 (72); the exact molecular
mass m/z ϭ 259.0845 (Ϯ2 mD) [Mϩ] of C14H13NO4 was confirmed
by HRMS (EI, 70 eV).
1-(4-Methoxyphenyl)-3-(4-methoxyphenylamino)-4,4-dimethyl-
2,4,5,6-tetrahydro-1H-indole-2,6-dione (3q): Starting from 5,5-di-
methylcyclohexane-1,3-dione (0.42 g, 3.0 mmol) and N,NЈ-bis(p-
methoxyphenyl)oxaldiimidoyl dichloride (1.01 g, 3.0 mmol), 3q was
isolated as a yellow solid (485 mg, 40%). 1H NMR (CDCl3,
250 MHz): δ ϭ 0.94 (s, 6 H, OCH3), 2.28 (s, 2 H, CH2), 3.79 (s, 6
H, OCH3), 5.65 (s, 1 H, CH), 6.57 (s, 1 H, NH), 6.85 (m, 4 H, Ar),
7.12 (d, J ϭ 12 Hz, 2 H, Ar), 7.45 (d, J ϭ 12 Hz, 2 H, Ar) ppm.
13C NMR (CDCl3, 62.5 MHz): δ ϭ 27.17 (CH3), 33.14 (C), 54.14
(CH2), 55.38, 55.47 (OCH3), 99.54 (CH), 114.13, 114.33 (CH, Ar),
116.43 (C), 126.77, 127.57 (CH, Ar), 134.20, 136.15, 136.45, 150.53,
158.09, 158.11, 169.76, 197.69 (C) ppm. IR (KBr): ν˜ ϭ 3264 (s),
3004 (w), 2954 (w), 2932 (w), 2835 (w), 1695 (s), 1650 (s), 1586 (s),
1523 (s), 1509 (s), 1462 (m), 1385 (s), 1295 (s), 1250 (s), 1170 (s),
(E)-5-(Ethoxycarbonylmethylidene)-3-hydroxy-1-(4-tolyl)-2,5-
dihydropyrrol-2-one (4c): Starting from 3c (36 mg, 99.3 µmol), 4c
1
was isolated as a yellow solid (18 mg, 65.9 µmol, 66%). H NMR
(CDCl3, 250 MHz): δ ϭ 1.32 (t, 3J ϭ 7.1 Hz, 3 H, OCH2CH3),
3
2.33 (s, 3 H, MeTol), 4.23 (q, J ϭ 7.1 Hz, 2 H, OCH2CH3), 5.67
(s, 1 H, CH-CO), 6.82 (br. s, 1 H, OH), 7.05Ϫ7.31 (m, 5 H, Ar)
ppm. 13C NMR (CDCl3, 50.3 MHz): δ ϭ 14.28 (OCH2CH3), 20.82
(CH3, Tol), 60.40 (OCH2CH3), 96.62 (CH-CO), 100.61 (C-4),
118.28, 130.25 (CH, Tol), 133.85, 133.93, 133.96, 136.13 (C), 161.95
(NCO), 161.97 (CO2Et) ppm. IR (KBr): ν˜ ϭ 3131 (w), 3067 (w),
3038 (w), 2977 (w), 2924 (w), 2857 (w), 1779 (s), 1710 (s), 1610 (s),
1540 (s), 1516 (s), 1427 (m), 1399 (m), 1342 (m), 1270 (s), 1232 (s),
1161 (m), 1140 (s), 1109 (m), 1081 (s), 1038 (m), 821 (m), 803 (m)
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 385.6 (4.18), 286.4 (3.77),
245.1 (4.14) nm. MS (EI, 70 eV): m/z (%) ϭ 273 (100) [Mϩ], 228
(24), 201 (50); the exact molecular mass m/z ϭ 273.1001 (Ϯ2 mD)
[Mϩ] of C15H15NO4 was confirmed by HRMS (EI, 70 eV).
1129 (m), 1042 (s), 977 (w), 842 (m), 800 (w) cmϪ1
. UV/Vis
(CH3CN): λmax. (lg ε) ϭ 386.1 (4.35), 295.3 (4.01), 251.8 (4.22),
243.4 (4.21) nm. MS (EI, 70 eV): m/z (%) ϭ 404 (100) [Mϩ], 389
(24); the exact molecular mass m/z ϭ 404.1736 (Ϯ2 mD) [Mϩ] of
C24H24N2O4 was confirmed by HRMS (EI, 70 eV). C24H24N2O4
(404.46): calcd. C 71.27, H 5.98; found C 71.13, H 5.94.
General Procedure for the Synthesis of 5-Alkylidene-3-hydroxy-2,5-
dihydropyrrol-2-ones (4): 3a (44.5 mg, 112.8 µmol) was dissolved in
THF (25 mL) at room temperature. 1  Aqueous hydrochloric acid
(15 mL,) was added to this solution under vigorous stirring. The
temperature of the mixture rose to ca. 40 °C during the addition
and the color changed from yellow to orange. After stirring for 1 h
at 25 °C, the solution was poured into water (150 mL). The organic
and aqueous layers were separated and the latter was extracted with
diethyl ether (3 ϫ 100 mL). The combined organic layers were dried
(MgSO4) and filtered, and then the filtrate was concentrated in
vacuo. The residue was purified by chromatography (SiO2; diethyl
ether/PE, 1:10 Ǟ 1:1) to give 4a [28.5 mg, 98.5 µmol, 87%, (E)/(Z)
Ͼ 98:2] as yellow crystals.
(E)-3-Hydroxy-1-(4-tolyl)-5-[N-(2-tolyl)carbamoylmethylidene]-2,5-
dihydropyrrol-2-one (4d): Starting from 3d (73 mg, 172.4 µmol), 4d
1
was isolated as a yellow solid (36 mg, 107.7 µmol, 63%). H NMR
([D6]acetone, 250 MHz): δ ϭ 2.28 (s, 3 H, Me-Tol), 2.30 (s, 3 H,
Me-Tol), 6.04 (s, 1 H, CH-CO), 7.03Ϫ7.31 (m, 7 H, Tol), 7.53 (s,
1 H, C-4), 7.77 (d, 1 H, Ar), 8.25 (br. s, 1 H, OH), 8.74 (br. s, 1 H,
NH) ppm. 13C NMR ([D6]acetone, 50.3 MHz): δ ϭ 18.08, 20.74
(MeTol), 99.30 (CH-CO), 101.64 (C-4), 119.34 (p-Tol), 124.15,
125.49, 126.71 (o-Tol), 130.60 (p-Tol), 131.00 (o-Tol), 133.56,
134.69, 137.29, 138.28, 160.76, 164.30, 165.12, 166.01 (C) ppm. IR
(KBr): ν˜ ϭ 3336 (s), 3298 (m), 3035 (w), 2960 (w), 2924 (m),
2855 (w), 1781 (s), 1638 (s), 1612 (s), 1527 (s), 1454 (s), 1297 (m),
1263 (s), 1220 (m), 1087 (s), 815 (m), 799 (m), 748 (m) cmϪ1. UV/
Vis (CH3CN): λmax. (lg ε) ϭ 384.7 (4.36), 286.4 (3.93), 245.7 (4.27)
nm. MS (EI, 70 eV): m/z (%) ϭ 334 (42) [Mϩ], 228 [M Ϫ NHTol]ϩ
(100), 107 (40); the exact molecular mass m/z ϭ 334.1317 (Ϯ2 mD)
[Mϩ] of C20H18N2O3 was confirmed by HRMS (EI, 70 eV).
(E)-5-(Ethoxycarbonylmethylidene)-3-hydroxy-1-(4-methoxyphenyl)-
2,5-dihydropyrrol-2-one (4a): 1H NMR (CDCl3, 250 MHz): δ ϭ
3
1.30 (t, J ϭ 7.1 Hz, 3 H, OCH2CH3), 3.79 (s, 3 H, OCH3), 4.20
3
(q, J ϭ 7.1 Hz, 2 H, OCH2CH3), 5.62 (s, 1 H, CH-CO), 6.85 (br.
s, 1 H, OH), 6.90 (d, J ϭ 8.9 Hz, AAЈ, 2 H, Ar), 7.12 (d, J ϭ
9.0 Hz, XXЈ, 2 H, Ar), 7.21 (s, 1 H, C-4) ppm. 13C NMR (CDCl3,
50.3 MHz):
δ ϭ 14.24 (OCH2CH3), 55.50 (OCH3), 60.32
(OCH2CH3), 96.16 (CϭCH-CO), 99.66 (C-4), 114.90 (C-3Ј, C-5Ј),
120.16 (C-2Ј, C-6Ј), 131.81 (C-1Ј), 134.42 (C-3), 156.35 (C-4Ј),
162.05 (C-5), 166.20 (C-2), 166.48 (CO2Et) ppm. IR (KBr): ν˜ ϭ (E)-5-(N,N-Diethylcarbamoylmethylidene)-3-hydroxy-1-phenyl-2,5-
3151 (w), 3070 (w), 2981 (w), 2934 (w), 2839 (w), 1777 (s), 1708 (s), dihydropyrrol-2-one (4e): Starting from the (E)-isomer of 3e (43 mg,
Eur. J. Org. Chem. 2004, 1897Ϫ1910
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1905

P. Langer, J. T. Anders, H. Görls
FULL PAPER
3
3
119 µmol), 4e was isolated as a yellow solid [32 mg, 111.8 µmol,
(t, J ϭ 7.4 Hz, 1 H, Ph), 7.34 (t, J ϭ 7.8 Hz, 2 H, Ph) ppm. 13C
94%, (E)/(Z) Ͼ 98:2]. 1H NMR (CDCl3, 250 MHz): δ ϭ 1.14Ϫ1.25 NMR (CDCl3, 50.3 MHz):
δ
ϭ
12.54 (CCH2CH3), 14.23
(m, 6 H, NCH2CH3), 3.34Ϫ3.50 (m, 4 H, NCH2CH3), 6.01 (s, 1 (OCH2CH3), 17.21 (CCH2CH3), 60.44 (OCH2CH3), 94.17 (CH-
H, CH-CO), 6.87 (br. s, 1 H, OH), 7.03Ϫ7.36 (m, 5 H, Ph), 7.55
CO), 120.69 (C), 122.43, 125.07, 129.13 (CH, Ph), 129.99, 138.44,
(s, 1 H, C-4) ppm. 13C NMR (CDCl3, 50.3 MHz): δ ϭ 13.26, 14.85 158.35 (C), 163.92 (NCO), 166.31 (CO2Et) ppm. IR (KBr): ν˜ ϭ
(NCH2CH3), 40.83, 42.75 (NCH2CH3), 96.90 (CH-CO), 102.71 (C- 3356 (s), 3069 (w), 3039 (w), 2980 (m), 2939 (w), 2877 (w), 1776 (s),
4), 117.88, 123.49, 129.60 (CH, Ph), 132.80, 138.96, 160.04 (C),
164.74, 166.50 (NCO) ppm. IR (KBr): ν˜ ϭ 3058 (w), 2978 (w), 1448 (m), 1385 (w), 1366 (m), 1331 (s), 1261 (m), 1172 (s), 1145 (s),
2931 (w), 1783 (s), 1626 (s), 1595 (s), 1542 (m), 1496 (m), 1483 (m), UV/Vis
1046 (s), 824 (m), 778 (w), 753 (m), 699 (m) cmϪ1
1718 (s), 1696 (s), 1662 (s), 1626 (s), 1596 (s), 1528 (s), 1497 (m),
.
1463 (m), 1445 (m), 1377 (m), 1363 (m), 1266 (s), 1185 (m), (CH3CN): λmax. (lg ε) ϭ 373.7 (4.16), 272.4 (3.92), 234.0 (4.18) nm.
1135 (w), 1087 (m), 1072 (m), 820 (w), 753 (m) cmϪ1. UV/Vis MS (EI, 70 eV): m/z (%) ϭ 287 (100) [Mϩ], 242 (20), 213 (76); the
(CH3CN): λmax. (lg ε) ϭ 370.5 (4.23), 278.0 (3.79), 242.3 (4.06) nm. exact molecular mass m/z
ϭ
287.1158 (Ϯ2 mD) [Mϩ] of
MS (EI, 70 eV): m/z (%) ϭ 286 (100) [Mϩ], 214 [M Ϫ NEt2]ϩ (78),
187 [M Ϫ CONEt2]ϩ (28). C16H18N2O3 (286.32): calcd. C 67.12,
H 6.34, N 9.78; found C 66.88, H 6.64, N 9.71.
C15H15NO4 was confirmed by HRMS (EI, 70 eV). C16H17NO4
(287.31): calcd. C 66.89, H 5.96, N 4.88; found C 66.57, H 6.21,
N 4.77.
(E)-5-[1-(Ethoxycarbonyl)ethylidene]-3-hydroxy-1-phenyl-2,5- (E)-3-Hydroxy-5-(2-oxotetrahydrofuran-3-ylidene)-1-phenyl-2,5-
dihydropyrrol-2-one (4f): Starting from 3f (44 mg, 126.3 µmol), 4f
dihydropyrrol-2-one (4j): Starting from 3j (62 mg, 187 µmol), 4j was
1
was isolated as a yellow solid (33 mg, 120.8 µmol, 96%). H NMR isolated as a yellow solid (48 mg, 187 µmol, 100%). 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.34 (t, 3J ϭ 7.1 Hz, 3 H, OCH2CH3), (CDCl3, 250 MHz): δ ϭ 3.20 (t, 3J ϭ 7.3 Hz, 2 H, OCH2CH2),
3
2.05 (s, 3 H, Me), 4.28 (q, J ϭ 7.1 Hz, 2 H, OCH2CH3), 6.61 (s,
4.46 (t, 3J ϭ 7.4 Hz, 2 H, OCH2CH2), 6.82 (br. s, 1 H, OH),
1 H, CH-CO), 6.85 (br. s, 1 H, OH), 7.07Ϫ7.15 (m, 3 H, Ar), 7.09Ϫ7.18 (m, 3 H, Ar), 7.36Ϫ7.42 (m, 3 H, Ar) ppm. 13C NMR
3
7.36Ϫ7.42 (m, 2 H, Ar), 7.67 (d, J ϭ 7.8 Hz, 1 H, Ph) ppm. 13C
(CDCl3, 50.3 MHz): δ ϭ 25.95 (OCH2CH2), 65.83 (OCH2CH2),
13.78, 14.27 (CH3), 60.99 100.47 (C-4), 101.90 (C), 118.06, 123.99, 129.81 (CH, Ph), 132.23,
(OCH2CH3), 101.37 (C-4), 105.51 (C), 117.96, 123.65, 129.72 (CH, 138.64, 155.87 (C), 166.23 (NCO), 170.81 (CO2R) ppm. IR (KBr):
NMR (CDCl3, 50.3 MHz):
δ ϭ
Ph), 131.94, 139.17, 152.71 (C), 165.91 (NCO), 166.84 (CO2Et)
ν˜ ϭ 3284 (s), 3137 (m), 3086 (w), 2974 (w), 2916 (w), 2907 (w),
ppm. IR (KBr): ν˜ ϭ 3136 (w), 3060 (w), 3020 (w), 2980 (w),
1795 (s), 1739 (s), 1665 (s), 1632 (s), 1615 (s), 1595 (s), 1550 (m),
2929 (w), 2905 (w), 1772 (s), 1702 (s), 1670 (s), 1628 (s), 1619 (s), 1501 (m), 1446 (m), 1376 (m), 1324 (m), 1296 (w), 1248 (m),
1600 (s), 1532 (m), 1504 (m), 1446 (m), 1366 (w), 1304 (s), 1262 (m), 1229 (s), 1207 (s), 1182 (m), 1090 (m), 1030 (s), 1002 (s), 954 (m),
1232 (m), 1219 (m), 1129 (m), 1076 (s), 770 (w), 749 (m), 687 (w) 814 (m), 770 (m), 751 (m), 695 (m) cmϪ1. UV/Vis (CH3CN): λmax.
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 372.8 (4.17), 284.2 (3.78), (lg ε) ϭ 383.9 (4.38), 287.0 (3.77), 238.1 (4.22) nm. MS (EI, 70 eV):
242.0 (4.06) nm. MS (EI, 70 eV): m/z (%) ϭ 273 (100) [Mϩ], 228 m/z (%) ϭ 257 (100) [Mϩ], 199 (24), 117 (20); the exact molecular
(20), 201 (20); the exact molecular mass m/z ϭ 273.1001 (Ϯ2 mD)
mass m/z ϭ 257.0688 (Ϯ2 mD) [Mϩ] of C14H11NO4 was confirmed
[Mϩ] of C15H15NO4 was confirmed by HRMS (EI, 70 eV). by HRMS (EI, 70 eV). C14H11NO4 (257.24): calcd. C 65.37, H 4.31,
C15H15NO4 (273.29): calcd. C 65.93, H 5.53, N 5.13; found C
65.77, H 5.62, N 4.97.
N 5.44; found C 65.60, H 4.21, N 5.30.
(E)-3-Hydroxy-4-methyl-5-(2-oxotetrahydrofuran-3-ylidene)-1-
phenyl-2,5-dihydropyrrol-2-one (4k): Starting from 3k (663 mg,
1.914 mmol), 4k was isolated as a yellow solid (267.2 mg, 985 µmol,
(Z)-3-Hydroxy-5-(methoxycarbonylmethylidene)-4-methyl-1-phenyl-
2,5-dihydropyrrol-2-one (4h): Starting from 3h (67 mg, 200.0 µmol),
4h was isolated as a yellow solid (51.7 mg, 200.0 µmol, 100%, pure
1
52%). H NMR (CDCl3, 250 MHz): δ ϭ 2.12 (s, 3 H, CH3), 3.25
compound without purification). 1H NMR (CDCl3, 250 MHz): (t, 3J ϭ 7.3 Hz, 2 H, OCH2CH2), 4.43 (t, 3J ϭ 7.4 Hz, 2 H,
3
δ ϭ 1.72 (s, 3 H, Ar-CH3), 3.77 (s, 3 H, OMe), 5.30 (s, 1 H, CH- OCH2CH2), 6.22 (br. s, 1 H, OH), 6.95 (d, J ϭ 7.9 Hz, 2 H, Ph),
3
CO), 6.47 (br. s, 1 H, OH), 7.01 (d, J ϭ 8.0 Hz, 2 H, Ph), 7.12 (t,
7.09 (t, 3J ϭ 7.4 Hz, 1 H, Ph), 7.32 (d, 3J ϭ 7.6 Hz, 2 H, Ph) ppm.
3J ϭ 7.4 Hz, 2 H, Ph), 7.33 (t, 3J ϭ 7.5 Hz, 2 H, Ph) ppm. 13C 13C NMR (CDCl3, 50.3 MHz):
δ ϭ 14.10 (CH3), 28.32
NMR (CDCl3, 50.3 MHz): δ ϭ 10.25 (CH3), 51.55 (OCH3), 93.71 (OCH2CH2), 65.63 (OCH2CH2), 106.29, 118.76 (C), 120.54,
(CH-CO), 115.14 (C), 122.00, 124.73, 129.18 (CH, Ph), 130.70, 123.96, 129.14 (CH, Ph), 132.01, 138.78, 155.70 (C), 165.43 (NCO),
138.59, 159.37 (C), 164.33 (NCO), 166.13 (CO2Me) ppm. IR 168.10 (CO2R) ppm. IR (KBr): ν˜ ϭ 3336 (s), 3053 (w), 3009 (w),
(KBr): ν˜ ϭ 3264 (s), 3119 (w), 3050 (w), 3036 (w), 2947 (w), 2966 (w), 2926 (m), 2853 (w), 1783 (s), 1739 (s), 1647 (s), 1609 (s),
2927 (w), 1785 (s), 1696 (s), 1662 (m), 1620 (s), 1595 (s), 1532 (s), 1593 (s), 1521 (s), 1493 (m), 1450 (m), 1374 (m), 1253 (m), 1209 (s),
1493 (m), 1451 (m), 1427 (m), 1344 (s), 1299 (m), 1191 (s), 1151 (s), 1179 (s), 1101 (m), 1047 (s), 1015 (s), 990 (s), 955 (m), 757 (m)
1035 (m), 831 (m), 755 (w), 697 (w) cmϪ1. UV/Vis (CH3CN): λmax.
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 391.0 (4.14), 286.5 (3.96),
(lg ε) ϭ 375.5 (4.16), 272.2 (3.92), 246.2 (4.06) nm. MS (EI, 70 eV): 244.0 (4.13) nm. MS (EI, 70 eV): m/z (%) ϭ 271 (100) [Mϩ], 226
m/z (%) ϭ 259 (100) [Mϩ], 228 (16), 199 (50), 130 (30), 77 (44); the (16), 131 (16); the exact molecular mass m/z ϭ 271.0845 (Ϯ2 mD)
exact molecular mass m/z
ϭ
259.0845 (Ϯ2 mD) [Mϩ] of [Mϩ] of C15H13NO4 was confirmed by HRMS (EI, 70 eV).
C14H13NO4 was confirmed by HRMS (EI, 70 eV). C14H13NO4
(259.26): calcd. C 64.86, H 5.05, N 5.40; found C 65.05, H 5.33,
N 5.22.
C15H13NO4 (271.27): calcd. C 66.41, H 4.83, N 5.16; found C
66.31, H 5.00, N 4.99.
(E)-3-Hydroxy-5-(5-methyl-2-oxotetrahydrofuran-3-ylidene)-1-
phenyl-2,5-dihydropyrrol-2-one (4l): Starting from 3l (64 mg,
185 µmol), 4l was isolated as a yellow solid (50 mg, 185 µmol,
(Z)-5-(Ethoxycarbonylmethylidene)-4-ethyl-3-hydroxy-1-phenyl-2,5-
dihydropyrrol-2-one (4i): Starting from 3i (128 mg, 353 µmol), 4i
was isolated as a yellow solid (64 mg, 223 µmol, 63%). 1H NMR
1
3
100%). H NMR (CDCl3, 250 MHz): δ ϭ 1.46 (d, J ϭ 6.3 Hz, 3
(CDCl3, 250 MHz): δ ϭ 0.84 (t, 3J ϭ 7.5 Hz, 3 H, CCH2CH3), H, CH3), 2.71 & 2.79 (2 d, J ϭ 5.9 Hz, 1 H, CH2), 3.30 & 3.36 (2
3
3
1.30 (t, J ϭ 7.1 Hz, 3 H, OCH2CH3), 2.15 (q, J ϭ 7.5 Hz, 2 H, d, J ϭ 7.8 Hz, 1 H, CH2), 4.76 (m, 1 H, CH-CH3), 6.81 (br. s, 1
CCH2CH3), 4.23 (q, 3J ϭ 7.1 Hz, 2 H, CCH2CH3), 5.32 (s, 1 H, H, OH), 7.09Ϫ7.24 (m, 3 H, Ar), 7.36Ϫ7.69 (m, 3 H, Ar) ppm.
CH-CO), 6.42 (br. s, 1 H, OH), 7.05 (d, 3J ϭ 7.8 Hz, 2 H, Ph), 7.15
13C NMR (CDCl3, 50.3 MHz): δ ϭ 22.13 (CH3), 33.63 (CH2),
1906
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 1897Ϫ1910

Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones
FULL PAPER
74.55 (CH-CH3), 100.81 (C-4), 103.20 (C), 118.21, 124.04, 129.82
(4.24) nm. MS (EI, 70 eV): m/z (%) ϭ 318 (100) [Mϩ], 272 (4), 173
(CH, Ph), 132.43, 138.86, 155.68 (C), 166.22 (NCO), 170.14 (32), 117 (24); the exact molecular mass m/z ϭ 318.1004 (Ϯ2 mD)
(CO2R) ppm. IR (KBr): ν˜ ϭ 3342 (s), 3138 (w), 2981 (w), 1776 (s),
1730 (s), 1666 (s), 1628 (s), 1597 (s), 1519 (m), 1445 (m), 1343 (m),
1225 (s), 1205 (s), 1075 (m), 1000 (m), 940 (w), 819 (w), 770 (w),
755 (w), 700 (w) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 384.0
(4.00), 279.9 (3.72), 246.6 (3.85) nm. MS (EI, 70 eV): m/z (%) ϭ
271 (75) [Mϩ], 240 (84), 199 (55), 154 (10), 121 (40), 93 (100), 77
(60); the exact molecular mass m/z ϭ 271.0845 (Ϯ2 mD) [Mϩ] of
C15H13NO4 was confirmed by HRMS (EI, 70 eV).
[Mϩ] of C19H14N2O3 was confirmed by HRMS (EI, 70 eV).
3-Hydroxy-1-(4-methoxyphenyl)-2,4,5,6-tetrahydro-1H-indole-2,6-
dione (4p): Starting from 3p (39 mg, 103 µmol), 4p was isolated as
an orange solid (14 mg, 52 µmol, 50%). 1H NMR (CDCl3,
250 MHz): δ ϭ 3.82 (s, 3 H, OMe), 6.90Ϫ7.00 (m, 3 H, Ar ϩ OH),
3
7.03Ϫ7.35 (m, 6 H, Ar), 7.80 (d, J ϭ 7.4 Hz, 1 H, Ar) ppm. 13C
NMR (CDCl3, 50.3 MHz):
δ ϭ 20.35 (CH2), 35.89 (CH2),
55.55 (OCH3), 104.14 (CHϪCO), 110.14 (C), 114.54 (PMP),
125.56 (PMP), 129.65, 130.44, 158.08, 165.22 (C), 165.45 (NCO),
196.85 (CO) ppm. IR (KBr): ν˜ ϭ 3273 (m), 3038 (w), 3009 (w),
2955 (m), 2923 (m), 2852 (m), 1798 (s), 1745 (w), 1645 (s), 1605 (s),
1520 (s), 1465 (m), 1417 (m), 1393 (s), 1317 (m), 1287 (m), 1242 (s),
1206 (m), 1184 (m), 1166 (s), 1028 (m), 990 (m), 827 (m), 763 (w)
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 382.0 (3.99), 281.0 (3.82),
247.5 (3.98) nm. MS (EI, 70 eV): m/z (%) ϭ 271 (100) [Mϩ], 256
(12), 214 (4), 200 (8); the exact molecular mass m/z ϭ 271.0845 (Ϯ2
mD) [Mϩ] of C15H13NO4 was confirmed by HRMS (EI, 70 eV).
(E)-5-(5-Ethyl-2-oxotetrahydrofuran-3-ylidene)-3-hydroxy-1-phenyl-
2,5-dihydropyrrol-2-one (4m): Starting from 3m (70 mg, 194 µmol),
4m was isolated as a yellow solid (55 mg, 192 µmol, 99%). 1H NMR
3
(CDCl3, 250 MHz): δ ϭ 0.96 (t, J ϭ 7.3 Hz, 3 H, CH2CH3), 1.70
(m, 2 H, CH2CH3), 2.68 & 2.77 (2 d, J ϭ 5.8 Hz, 1 H, CCH2CH),
3
3.17 & 3.26 (2 d, J ϭ 7.9 Hz, 1 H, CCH2CH), 4.51 (quint., J ϭ
6.6 Hz, 1 H, CCH2CH), 6.70 (br. s, 1 H, OH), 7.02Ϫ7.19 (m, 3 H,
Ar), 7.30Ϫ7.40 (m, 3 H, Ar) ppm. 13C NMR (CDCl3, 50.3 MHz):
δ ϭ 8.85 (CH2CH3), 29.17 (CH2CH3), 31.40 (CCH2CH), 79.21
(CH2CH), 100.69 (C-4), 103.06 (C), 118.14, 123.88, 129.70 (CH,
Ph), 132.33, 138.82, 155.50 (C), 166.12 (NCO), 170.16 (CO2R)
ppm. IR (KBr): ν˜ ϭ 3281 (m), 3137 (w), 2965 (w), 2935 (w),
1794 (s), 1738 (s), 1666 (s), 1634 (s), 1599 (s), 1547 (m), 1501 (m),
1447 (m), 1351 (s), 1324 (m), 1300 (w), 1283 (w), 1250 (m), 1228 (s),
1210 (s), 1182 (m), 1088 (m), 1070 (m), 1006 (s), 965 (m), 811 (w),
770 (w), 752 (m), 688 (w) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ
384.0 (4.31), 274.7 (4.14) nm. MS (EI, 70 eV): m/z (%) ϭ 285 (100)
[Mϩ], 256 (8), 228 (12), 199 (100), 154 (20); the exact molecular
mass m/z ϭ 285.1001 (Ϯ2 mD) [Mϩ] of C16H15NO4 was confirmed
by HRMS (EI, 70 eV). C16H15NO4 (285.30): calcd. C 67.36, H 5.30,
N 4.91; found C 67.23, H 5.52, N 5.03.
3-Hydroxy-1-(4-methoxyphenyl)-4,4-dimethyl-2,4,5,6-tetrahydro-
1H-indole-2,6-dione (4q): Starting from 3q (63 mg, 156 µmol), 4q
1
was isolated as an orange solid (28 mg, 93 µmol, 60%). H NMR
(CDCl3, 250 MHz): δ ϭ 1.08 (s, 6 H, Me), 2.35 (s, 2 H, CH2), 3.74
(s, 3 H, OMe), 5.75 (s, 1 H, CH-CO), 6.05 (br. s, 1 H, OH), 6.81
3
3
(d, J ϭ 8.8 Hz, 2 H, AAЈ, PMP), 7.00 (d, J ϭ 8.9 Hz, 2 H, XXЈ,
PMP) ppm. 13C NMR (CDCl3, 50.3 MHz): δ ϭ 27.40 (CH3), 29.64
(CH2), 53.51 (CMe2), 55.46 (OCH3), 103.56 (CHϪCO), 114.43
(PMP), 123.73 (C), 125.84 (PMP), 130.11, 132.42, 157.91, 163.75
(C), 164.79 (NCO), 196.94 (CO) ppm. IR (KBr): ν˜ ϭ 3334 (m),
3295 (m), 2959 (m), 2925 (s), 2853 (m), 1798 (s), 1660 (s), 1617 (s),
1513 (s), 1464 (m), 1418 (m), 1396 (m), 1382 (m), 1365 (m),
1295 (s), 1240 (s), 1179 (m), 1108 (m), 1031 (s), 1012 (s), 953 (w),
827 (m), 750 (w) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 393.5
(3.93), 289.0 (3.92), 247.2 (3.94) nm. MS (EI, 70 eV): m/z (%) ϭ
299 (100) [Mϩ], 284 (24), 256 (16), 228 (12); the exact molecular
mass m/z ϭ 299.1158 (Ϯ2 mD) [Mϩ] of C17H17NO4 was confirmed
by HRMS (EI, 70 eV).
(E)-3-Hydroxy-1-(4-methoxyphenyl)-5-(2-oxo-2,3-dihydro-
benzofuran-3-ylidene)-2,5-dihydropyrrol-2-one (4n): Starting from 3n
(64 mg, 144 µmol), 4n was isolated as a red solid (20 mg, 60 µmol,
42%). 1H NMR (CDCl3, 250 MHz): δ ϭ 3.82 (s, 3 H, OMe),
6.90Ϫ7.00 (m, 3 H, Ar & OH), 7.03Ϫ7.35 (m, 6 H, Ar), 7.80 (d,
3J ϭ 7.4 Hz, 1 H, Ar) ppm. 13C NMR ([D6]DMSO, 50.3 MHz):
δ
ϭ 55.43 (OCH3), 96.05 (C-4), 110.29 (CH, Ar), 114.92,
(E)-5-(Cyanomethylidene)-1-(4-tolyl)-3-(4-tolylamino)-2,5-dihydro-
pyrrol-2-one (6a): Starting from 5-methylisoxazole (499 mg,
0.49 mL, 6.0 mmol), 6a was isolated as a yellow solid (830 mg,
44%, E/Z ϭ 10:1). 1H NMR (CDCl3, 200 MHz): δ ϭ 2.33, 2.36 (s,
6 H, Tol-CH3), 4.47 (s, 1 H, CHCN), 6.11 (s, 1 H, 4-H), 7.00Ϫ7.60
(m, 8 H, Tol) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ 20.82, 21.20
(Tol-CH3), 66.77 (CH, CHCN), 95.20 (CH, C-4), 116.18 (C, CN),
118.70, 125.63, 129.79, 130.20 (CH, Tol), 133.79, 136.46, 137.10 (C,
C-3, Tol-C to CH3), 139.75, 140.42 (C, Tol-C to N), 148.92 (C, C-
2), 167.89 (C, C-5) ppm. IR (KBr): ν˜ ϭ 3360 (s), 3202 (m), 3075 (s),
3030 (s), 2920 (s), 2202 (s, CN), 1697 (m), 1639 (s), 1610 (s),
121.60 (PMP), 122.40 (CH, Ar), 122.61 (C), 123.85, 128.21 (CH,
Ar), 132.18, 137.14, 137.41, 150.70, 155.83, 155.99 (C), 160.01
(NCO), 164.17 (CO2R) ppm. IR (KBr): ν˜ ϭ 3273 (m), 3068 (w),
3001 (w), 2960 (m), 2924 (m), 2853 (m), 1795 (s), 1739 (s),
1654 (m), 1625 (s), 1577 (s), 1509 (s), 1461 (m), 1349 (m), 1328 (m),
1265 (m), 1244 (s), 1142 (s), 1092 (m), 1035 (m), 982 (s), 829 (m),
802 (m) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 469.5 (4.44), 247.5
(4.18) nm. MS (EI, 70 eV): m/z (%) ϭ 335 (100) [Mϩ], 291 (4), 174
(6), 147 (38); the exact molecular mass m/z ϭ 335.0794 (Ϯ2 mD)
[Mϩ] of C19H13NO5 was confirmed by HRMS (EI, 70 eV).
(E)-3-Hydroxy-5-(1-methyl-2-oxo-2,3-dihydroindol-3-ylidene)-1-
phenyl-2,5-dihydropyrrol-2-one (4o): Starting from 3o (85 mg,
215 µmol), 4o was isolated as a red solid (66 mg, 207 µmol, 97%).
1H NMR (CDCl3, 250 MHz): δ ϭ 3.26 (s, 3 H, nme), 6.81 (d, 3J ϭ
7.7 Hz, 1 H, Ar), 6.98 (br. s, 1 H, OH), 7.02Ϫ7.27 (m, 6 H, Ar),
7.37Ϫ7.43 (m, 2 H, Ar), 7.71 (s, 1 H, Ar, C-4), 7.81 (d, 3J ϭ 7.3 Hz,
1 H, Ar) ppm. 13C NMR (CDCl3, 50.3 MHz): δ ϭ 25.90 (NMe),
1531 (s), 1430 (m), 1321 (m), 1239 (m), 1080 (m), 952 (m) cmϪ1
.
MS-FAB: m/z (%) ϭ 316 [M ϩ 1]ϩ. C20H17N3O (315.36): calcd. C
76.17, H 5.43, N 13.32; found C 76.00, H 5.53, N 13.00.
(E)-5-(Cyanomethylidene)-1-phenyl-3-phenylamino-2,5-dihydro-
pyrrol-2-one (6b): Starting from 5-methylisoxazole (499 mg,
0.49 mL, 6.0 mmol), 6b was isolated as a yellow solid (688 mg,
1
101.81 (C-4), 105.73 (C), 107.87, 118.15 (CH), 120.99 (C), 122.42, 40%, E/Z ϭ 10:1). H NMR (CDCl3, 400 MHz): δ ϭ 4.52 (s, 1 H,
124.14, 124.44, 128.60, 129.82 (CH, Ar), 132.73, 138.59, 141.90, CHCN), 6.21 (s, 1 H, 4-H), 7.10Ϫ7.60 (m, 10 H, Ph) ppm. 13C
155.52 (C), 166.16, 167.79 (NCO) ppm. IR (KBr): ν˜ ϭ 3330 (s), NMR (CDCl3, 100 MHz): δ ϭ 67.60 (CH, CHCN), 96.02 (CH, C-
3263 (m), 3057 (w), 1781 (s), 1698 (s), 1644 (s), 1619 (s), 1587 (s), 4), 115.89 (C, CN), 118.52, 124.03, 125.63, 127.02, 129.21, 129.90
1539 (m), 1499 (m), 1485 (m), 1470 (m), 1447 (m), 1374 (m),
(CH, Ph), 138.91, 140.10, 142.30 (C, C-3, Ph), 149.50 (C, C-2),
1274 (s), 1231 (m), 1179 (m), 1137 (m), 1080 (s), 972 (m), 952 (m), 167.59 (C, C-5) ppm. IR (KBr): ν˜ ϭ 3366 (m), 3306 (w), 3070 (w),
746 (s) cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 425.3 (4.39), 274.1 2202 (s, CN), 1696 (s), 1669 (m), 1619 (s), 1592 (s), 1515 (s),
Eur. J. Org. Chem. 2004, 1897Ϫ1910
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1907

P. Langer, J. T. Anders, H. Görls
FULL PAPER
1492 (m), 1447 (m), 1320 (m), 1238 (m), 1174 (m), 1074 (m),
(E)-5-(2-Phenyliminopropylidene)-1-(4-tolyl)-3-(4-tolylamino)-2,5-
1027 (w), 996 (w), 950 (m), 794 (m), 773 (m), 747 (m), 691 (m) dihydropyrrol-2-one (10): A THF solution of 9 (250 mg, 0.61 mmol)
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 370.3 (4.36), 245.4 (4.30) was stirred in the presence of LiCl (2 equiv.) for 72 h. The solvent
nm. MS-FAB: m/z (%) ϭ 288 [M ϩ 1]ϩ. C18H13N3O (287.30):
calcd. C 75.25, H 4.56, N 14.62; found C 75.27, H 4.74, N 14.43.
was evaporated in vacuo and the residue was purified by chroma-
tography to give 10 as a red solid (140 mg, 56%). 1H NMR
([D8]THF, 200 MHz): δ ϭ 1.87, 2.26, 2.41 [s, 9 H, C(NPh)CH3,
Tol-CH3], 5.49 (s, 1 H, H-3), 6.60Ϫ7.35 [m, 14 H, CH(NPh)CH3,
Ar], 8.10 (br., 1 H, NH) ppm. 13C NMR ([D8]THF, 50 MHz): δ ϭ
20.65, 21.07, 21.48 [Tol-CH3, C(NPh)CH3], 97.02, 98.90 [CH, C-
3, CHC(NPh)CH3], 118.90, 120.29, 123.24, 129.24, 129.33, 130.02,
130.38 (CH, Ar), 132.27, 132.78 (C, Tol-C to CH3), 136.79, 138.54,
139.45 (C, Ph and Tol to N), 147.83 (C-4), 153.18 (C, C-2), 164.46
[C, C(NPh)CH3], 166.37 (C, C-5) ppm. MS (CI, H2O): m/z (%) ϭ
408 [M ϩ 1]ϩ. C27H25N3O (407.50): calcd. C 79.58, H 6.18, N
10.31; found C 79.22, H 6.49, N 10.78.
(E)-5-(Cyanomethylidene)-3-hydroxy-1-(4-tolyl)-2,5-dihydropyrrol-
2-one (7a): Starting from 6a (22 mg, 69.8 µmol), 7a was isolated as
a
yellow solid (10 mg, 44 µmol, 63%). 1H NMR (CDCl3,
250 MHz): δ ϭ 2.32 (s, 3 H, Me-Tol), 4.74 (s, 1 H, CH-CN), 6.33
(s, 1 H, C-4), 6.82 (br. s, 1 H, OH), 7.04 (d, 3J ϭ 8.5 Hz, 2 H, AAЈ,
p-Tol), 7.20 (d, 3J ϭ 8.5 Hz, 2 H, XXЈ, p-Tol) ppm. 13C NMR
(CDCl3, 150.8 MHz): δ ϭ 20.87 (CH3), 73.04 (CH-CN), 99.27 (C-
4), 114.46 (CN), 118.73 (p-Tol), 130.40 (p-Tol), 134.66, 134.78,
135.66, 163.16 (C), 164.78 (NCO) ppm. IR (KBr): ν˜ ϭ 3353 (s),
3066 (w), 3033 (w), 2959 (w), 2922 (w), 2852 (w), 2211 (s, CN),
1785 (s), 1652 (m), 1630 (s), 1526 (m), 1512 (m), 1412 (w), (E)-N-(4-Methylphenyl)-2-(4-methylphenyl)imino-5-(2-oxo-2-phenyl-
1330 (m), 1257 (m), 1235 (m), 1082 (m), 943 (m), 827 (w), 804 (s) ethylidene)-1-phenyl-2,5-dihydro-1H-pyrrol-3-amine (12a): Starting
cmϪ1. UV/Vis (CH3CN): λmax. (lg ε) ϭ 380.0 (3.23), 282.5 (2.65), from benzoylacetone anile 11 (1.42 g), 12a was isolated as a yellow
228.5 (3.15), 200.5 (3.19) nm. MS (EI, 70 eV): m/z (%) ϭ 226 (100)
solid (985 mg, 35%). 1H NMR ([D8]THF, 200 MHz): δ ϭ 2.09, 2.34
[Mϩ], 221 (12), 198 (10), 182 (16), 167 (20), 131 (20), 116 (12), 91 (s, 6 H, Tol-CH3), 5.92 (s, 1 H, H-3), 6.43 (d, J ϭ 8 Hz, 2 H, Ar),
(12); the exact molecular mass m/z ϭ 226.0742 (Ϯ2 mD) [Mϩ] of
C13H10N2O was confirmed by HRMS (EI, 70 eV).
6.64 (d, J ϭ 8 Hz, 2 H, Ar), 7.00Ϫ7.80 (m, 15 H, CHCOPh, Ar),
8.20 (br., 1 H, NH) ppm. 13C NMR ([D8]THF, 50 MHz): δ ϭ
20.65, 20.79 (Tol-CH3), 95.82 (CH, C-3), 95.44 (CH, CHCOPh),
119.51, 121.49, 127.95, 128.11, 128.80, 128.92, 129.36, 130.05,
130.54, 131.81 (CH, Ar), 132.18, 132.83, 137.32 (C, Ar to C),
139.04, 141.60, 142.93, 145.14 (C, C-4, Ar to N), 147.75 (C, C-2),
160.32 (C, C-5), 188.10 (C, COPh) ppm. IR (KBr): ν˜ ϭ 3325 (w),
3030 (w), 2923 (w), 1630 (s), 1613 (s), 1580 (s), 1555 (s), 1527 (s),
1425 (m), 1350 (m), 1240 (m), 1228 (m), 1180 (m), 1130 (m), 1005
(m) cmϪ1. MS (CI, H2O): 470 [M ϩ 1]ϩ. C32H27N3O (469.57):
calcd. C 81.85, H 5.80, N 8.94; found C 81.72, H 5.90, N 9.02.
(E)- and (Z)-5-(Cyanomethylidene)-3-hydroxy-1-phenyl-2,5-dihydro-
pyrrol-2-one (7b): Starting from 6b (92 mg, 318 µmol), 7b was iso-
lated as a yellow solid [35 mg, 165 µmol, 52%, (E)/(Z)ϭ 1:1]. 1H
NMR (CDCl3, 250 MHz): δ ϭ 4.91 [s, 1 H, CH-CN, (Z) isomer],
5.24 [s, 1 H, CH-CN, (E) isomer], 6.55 [s, 1 H, C-4, (Z) isomer],
6.82 [s, 1 H, C-4, (E) isomer], 7.13Ϫ7.40 (m, 4 H, Ph & OH),
7.40Ϫ7.60 (m, 2 H, Ph) ppm. 13C NMR (CDCl3, 50.3 MHz, (E)/
(Z) ϭ 1:1): δ ϭ 73.48, 74.86 (CHϪCN), 98.79, 99.92 (C-4), 114.05,
115.80 (CN), 118.59, 118.66 (Ph), 124.77, 124.92 (Ph), 129.90,
129.97 (Ph), 134.10, 134.15 (C), 138.20, 138.30 (C), 163.01, 164.90 (E)-N,1-Diphenyl-2-phenylimino-5-(2-oxo-2-phenylethylidene)-2,5-
(C), 165.10, 165.30 (NCO) ppm. IR (KBr): ν˜ ϭ 3330 (m), 3073 (m), dihydro-1H-pyrrol-3-amine (12b): Starting from 11 (1.42 g), 12b was
3021 (w), 2961 (w), 2923 (w), 2853 (w), 2219 (m, CN), 2209 (m, obtained as a yellow solid (847 mg, 32%). 1H NMR (CDCl3,
CN),
1492 (w),1447 (m), 1323 (m), 1295 (m), 1282 (m), 1234 (m), Ph), 9.35 (br., 1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz): δ ϭ
1181 (m), 1110 (m), 1092 (m), 949 (m), 795 (m), 755 (m) cmϪ1. UV/
96.19 (CH, C-3), 95.72 (CH, CHCOPh), 118.22, 119.82, 120.85,
Vis (CH3CN): λmax. (lg ε) ϭ 374.0 (4.35), 280.0 (3.73), 228.0 (4.23), 122.82, 122.89, 127.54, 127.94, 128.31, 128.80, 129.03, 129.61,
199.5 (4.26) nm. MS (EI, 70 eV): m/z (%) ϭ 212 (100) [Mϩ], 184
131.62 (CH, Ph), 135.70 (C, Ph to C), 139.79, 140.36, 141.04,
(12), 167 (8), 117 (32); the exact molecular mass m/z ϭ 212.0586 146.04 (C, C-4, Ph to N), 146.84 (C, C-2), 159.67 (C, C-5), 189.51
(Ϯ2 mD) [Mϩ] of C12H8N2O2 was confirmed by HRMS (EI,
(C, COPh) ppm. IR (KBr): ν˜ ϭ 3324 (w), 3030 (w), 2924 (w), 1631
1789 (s),
1625 (s),
1592 (s),
1543 (m),
1501 (m), 200 MHz): δ ϭ 5.95 (s, 1 H, H-3), 6.50Ϫ7.80 (m, 21 H, CHCOPh,
70 eV). C12H8N2O2 (212.20): calcd. C 67.92, H 3.80, N 13.20; (s), 1613 (s), 1580 (s), 1556 (s), 1527 (s), 1428 (m), 1352 (m), 1240
found C 67.63, H 4.07, N 13.18.
(m), 1179 (m), 1130 (m) cmϪ1. MS (FAB): 442 [M ϩ 1]ϩ.
C30H23N3O (441.51): calcd. C 81.61, H 5.25, N 9.51; found C
81.32, H 5.69, N 9.98.
(E/Z)-5-(2-Phenyliminopropylidene)-3-(4-tolylamino)-2-(4-tolyl-
imino)-2,5-dihydrofuran (9): Starting from 4-(phenylimino)pentan-
2-one (1.04 g, 6.0 mmol), 9 was isolated as a deep-yellow solid (E)-5-(Ethoxycarbonylmethylidene)-1-(4-tolylsulfonyl)-3-(4-tolyl-
1
[1.10 g, 45%, 1:1 mixture of (E)/(Z)Z isomers]. H NMR (CDCl3,
200 MHz): 2.14, 2.24, 2.33/2.28, 2.33, 2.54 [s,
C(NPh)CH3, Tol-CH3], 5.19/5.61 [s, 1 H, CH(NPh)CH3, both iso-
sulfonylamino)-2,5-dihydropyrrol-2-one (14): TiCl4 (0.24 mL,
H, 2.20 mmol) was added at Ϫ78 °C to a CH2Cl2 solution (18 mL) of
13 (300 mg, 1.10 mmol) and 2d (477 mg, 1.10 mmol). The solution
δ
ϭ
9
mers], 5.89/6.16 (s, 1 H, 4-H, both isomers), 6.70Ϫ7.50 (m, 14 H, was stirred at Ϫ78 °C for 1 h, warmed to 20 °C during 2 h, and
Ar, NH) ppm. 13C NMR ([D8]THF, 50 MHz): δ ϭ 19.68/20.71,
then stirred at 20 °C for 1 h before a 1:1 mixture of 10% aqueous
20.99/21.03, 21.41/27.51 [Tol-CH3, C(NPh)CH3], 95.89/97.89, hydrochloric acid and brine was added. The organic layer was sepa-
100.60/100.75 [CH, C-4, CHC(NPh)CH3], 120.45/120.54, 123.13/ rated and the aqueous layer was extracted with CH2Cl2. The com-
123.21, 124.91/125.07, 129.20/129.31, 129.36/129.95, 130.04/130.37, bined organic fractions were dried (MgSO4) and filtered, and then
130.42/130.47 (CH, Ar), 132.60/132.68, 132.69/132.96 (C, Tol-C to the filtrate was concentrated in vacuo. The residue was purified by
CH3), 135.62/135.87, 137.45/137.95, 138.93/139.01 (C, Ph and Tol
to N), 142.63/142.65 (C-3), 153.27/153.30 (C, C-2), 159.73/158.32
chromatography (SiO2; diethyl ether/PE, 1:10 Ǟ 1:1) to give 14 as
a yellow solid (81 mg, 15%). 1H NMR (CDCl3, 250 MHz): δ ϭ
(C, C-5), 163.97/164.05 [C, C(NPh)CH3] ppm. IR (KBr): ν˜ ϭ 1.35 (t, J ϭ 7 Hz, 3 H, CH2CH3), 2.45 (s, 6 H, Tol-CH3), 4.25 (q,
3362 (m), 3068 (w), 1640 (w); 1620 (s), 1598 (m), 1590 (s), 1450 (m),
J ϭ 7 Hz, 2 H, OCH2), 5.82 (s, 1 H, CHCO2Et), 7.30Ϫ7.35 (m, 5
1322 (m), 1239 (m), 1172 (m), 1074 (m) cmϪ1. MS (CI, H2O): m/z H, Ar, NH), 7.52 (s, 1 H, 4-H), 7.75Ϫ7.90 (2 ϫ d, 2 ϫ 2 H, Ar)
(%) ϭ 408 [M ϩ 1]ϩ. C27H25N3O (407.50): calcd. C 79.58, H 6.18, ppm. MS (EI): m/z (%) ϭ 490 (22) [Mϩ], 335 (20), 155 (84), 91
N 10.31; found C 79.18, H 6.56, N 10.95.
(100).
1908
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1897Ϫ1910

Synthesis of N-Aryl-5-alkylidene-2,5-dihydropyrrol-2-ones
FULL PAPER
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[8a]
Mitomycins:
1983, 105, 2859.
Crystal Structure Determination: The intensity data for the com-
pounds were collected on a Nonius CAD4 diffractometer, using
graphite-monochromated Mo-Kα radiation. Data were corrected
for Lorentz and polarization effects, but not for absorption.[36] The
structures were solved by direct methods (SHELXS)[37] and refined
by full-matrix least-squares techniques against F2o (SHELXL-
97).[38] The hydrogen atoms of the structures were included at cal-
culated positions with fixed thermal parameters. All non-hydrogen
atoms were refined anisotropically.[38] XP (SIEMENS Analytical
X-ray Instruments, Inc.) was used for structure representations.
[8b]
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[11]
[12]
Crystal Data for 3a:[39] C22H22N2O3, Mr ϭ 362.42 g·molϪ1, colour-
less prism, size 0.40 ϫ 0.36 ϫ 0.20 mm3, monoclinic, space group
[13]
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Cc, a ϭ 13.511(3), b ϭ 16.441(3), c ϭ 17.418(4) A, β ϭ 90.27(3)°,
3
V ϭ 3869.1(13) A , T ϭ Ϫ90 °C, Z ϭ 8, ρcalcd. ϭ 1.244 g·cmϪ3
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µ(Mo-Kα) ϭ 0.83 cmϪ1, F(000) ϭ 1536, 4455 reflections in h(Ϫ17/
0), k(0/21), l(Ϫ22/21), measured in the range 2.34° Յ Θ Յ 27.42°,
[15] [15a]
O. W. Woltersdorf, S. J. de Solms, E. H. Schultz, E. J.
completeness Θmax. ϭ 91.4%, 4199 independent reflections, Rint
0.031, 3164 reflections with Fo Ͼ 4σ(Fo), 487 parameters, 2 re-
straints, R1obsd. ϭ 0.048, wR2obsd. ϭ 0.123, R1all ϭ 0.083, wR2all
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Ϫ3
˚
peak and hole: 0.254/Ϫ0.282 e·A
.
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Crystal Data for 10:[39] C27H26N3O, Mr ϭ 408.51 g·molϪ1, red
prism, size 0.40 ϫ 0.38 ϫ 0.36 mm3, monoclinic, space group P21/
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[17c]
3
V ϭ 2321.7(8) A , T ϭ 20 °C, Z ϭ 4, ρcalcd. ϭ 1.169 g·cmϪ3, µ(Mo-
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Flitsch, S. R. Schindler, Synthesis 1975, 685.
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straints, R1obsd. ϭ 0.079, wR2obsd. ϭ 0.186, R1all ϭ 0.229, wR2all
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ϭ
[19]
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For reviews of work from our laboratory, see:
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Financial support from the Konrad-Adenauer-Stiftung (scholar-
ship for J. T. A.) and the Deutsche Forschungsgemeinschaft (Hei-
senberg Scholarship for P. L. and SFB 416) is gratefully acknowl-
edged.
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Eur. J. Org. Chem. 2004, 1897Ϫ1910
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1909

P. Langer, J. T. Anders, H. Görls
FULL PAPER
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R. N. Warrener, E.
CCDC-198694 (for 3c) and -198695 (for 10) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax:
ϩ 44-1223-336-033; or deposit@ccdc.cam.ac.uk].
Received November 16, 2003
[35d]
M. Waren, Z.
[36]
[37]
1910
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1897Ϫ1910