A new approach to the synthesis of highly substituted 3-pyrrolin-2-ones

Article abstract of DOI:10.1055/s-2006-942393

The base-promoted cyclization of internal N-propargylmalonamides in the presence of carbonate bases at room temperature or at 80°C affords highly substituted 3-pyrrolin-2-ones in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942393

PAPER
2019
A New Approach to the Synthesis of Highly Substituted 3-Pyrrolin-2-ones
Synthesis of
Highl
n
y Substituted
t
3-Pyrr
o
olin-2-ones nio Arcadi, Fabio Marinelli,* Leucio Rossi, Mirella Verdecchia
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università dell’Aquila, via Vetoio, 67100 L’Aquila, Italy
Fax +39(086)2433753; E-mail: fmarinel@univaq.it
Received 19 January 2006; revised 20 February 2006
cycles through 5-exo-dig and 6-exo-dig base-promoted
processes.22–24 To the best of our knowledge this strategy
has not yet applied to the synthesis of 3-pyrrolin-2-ones.
We have recently reported that propargylamines25 react
with tetraethylammonium carbonate and hydrogen car-
bonate to give 5-methylene-1,3-oxazolidin-2-ones
through the formation of a carbamate anion/5-exo-dig cy-
clization. Therefore, we decided to investigate the use of
terminal propargylamines 1 as starting materials for the
synthesis of 3-pyrrolin-2-ones. This new approach takes
advantage from the easy functionalization of Csp–H
through Pd or Pd/Cu catalyzed coupling with
electrophiles26 that generates molecular diversity.
Abstract: The base-promoted cyclization of internal N-propargyl-
malonamides in the presence of carbonate bases at room tempera-
ture or at 80 °C affords highly substituted 3-pyrrolin-2-ones in good
yields.
Key words: cyclizations, 3-pyrrolin-2-ones, lactams, propargyl-
amines, palladium
Compounds incorporating the 3-pyrrolin-2-one ring sys-
tem are of great importance due to their wide range of bi-
ological activities. Indeed, they are very useful in the field
of crop protection.1 In addition they exhibit remarkable
pharmacological activities: 4-substituted-1,5-diphenyl-
pyrrolin-2-ones show antimicrobial and antineoplastic ac-
tivities;2 3-acyl-3-pyrrolin-2-ones bearing long-chain
alkoxy substituents possess useful neuritogenic proper-
ties, and represent a promising class of chemotherapeutics
for neuroblastoma tumors;3 1,3,4-triaryl-3-pyrrolin-2-
ones can act as selective and potent cyclooxygenase-2-in-
hibitors,4 and chiral-5-substituted 3-pyrrolin-3-ones ex-
hibited selective inhibitory activity against cathepsin B.5
Moreover, 3-pyrrolin-2-ones have been employed as use-
ful synthetic intermediates for the synthesis of (+)-lacta-
cystin,6 (+)-rolipam,7 and in the assembly of aromatic
congeners of bilirubin.8
Indeed, terminal propargylamines 1a–d were coupled
with aryl and heteroaryl halides to give internal prop-
argylamines 2 in good yields. Subsequent acylation with
ethyl malonyl chloride gave the corresponding internal N-
propargylmalonamides 4 (Scheme 1). Alternatively, com-
pounds 4 could be obtained through the Pd-catalyzed cou-
pling of terminal N-propargylmalonamides with aryl
halides. This procedure was found to give satisfactory re-
sults in the formation of secondary N-propargylmalon-
amides 4ea, 4ee and 4ek from 3e (Scheme 2), but was less
effective in the synthesis of tertiary N-propargylmalon-
amides.27
N-Propargylmalonamides 4 were prone to undergo base-
promoted chemoselective 5-exo-dig carbocyclization fol-
lowed by double bond migration to accomplish the forma-
tion of the title compounds 5 in good yields (Scheme 3).
Recently, the development of new synthetic procedures
for their preparation has gained great interest in organic
synthesis. One of the most investigated approach to
polysubstituted 3-pyrrolin-2-ones rely on multicompo-
nent reactions (MCRs).9–11 Other recently reported meth-
odologies include cyclization of a,b-unsaturated-g-amino
esters,12 rearrangement of chlorinated pyrrolin-2-ones,13
Ru-catalyzed cyclocarbonylation of a-allenic sulfon-
amides,14 cyclization of 3-phenylsulfanyl-2-propen-
amides,15 reaction of g-keto thioesters with amines16,
oxidative cyclization of phenacyl amide in the presence of
atmospheric oxygen,17 alkaline hydrolysis of N-substitut-
ed 2-acetoxypyrroles,18 intramolecular aldol reaction/
oxidation19 and cyclization of 3-aryl-4,4-dichlorobutan-
amides.20
In order to develop a synthetic protocol under mild condi-
tions, the cyclization was attempted using different base/
solvent/temperature combinations. Selected results for the
cyclization of 4aa (Scheme 4) are summarized in Table 1.
The 3-pyrrolin-2-one 5aa was isolated in high yield under
the reaction conditions (NaH in DMSO at 80 °C) previ-
ously developed for the related cyclization of propargyl
ethyl malonates to butenolides22 (Table 1, entry 1).
Cs2CO3 in DMSO at 80 °C afforded 5aa in moderate
yield, together with some unidentified by-products (entry
2). The latter base afforded better results at room temper-
ature, leading to the formation of 5aa in high yields (en-
tries 3, 6). The screening of different bases showed that t-
BuOK, K2CO3 and even NaHCO3 are able to promote the
cyclization at room temperature. K2CO3 resulted slightly
less effective than Cs2CO3, at least in our model system,
but its lower cost could justify the choice to use it. Be-
tween the solvents tested, DMSO and NMP gave compa-
As a part of our ongoing research activities on find out
new synthetic routes to heterocycles,21 we focused on
alkynes bearing proximate pronucleophiles as useful
building blocks for the preparation of a variety of hetero-
SYNTHESIS 2006, No. 12, pp 2019–2030
x
x.
x
x
.
2
0
0
6
Advanced online publication: 11.05.2006
DOI: 10.1055/s-2006-942393; Art ID: Z01806SS
© Georg Thieme Verlag Stuttgart · New York

2020
A. Arcadi et al.
PAPER
O
O
R
R
Ar
OEt
H
OEt
OEt
Ar-I
ClCCH2COEt,
base
R-I
O
Pd(OAc2)(PPh3)2
R3
R2
O
Pd(OAc2)(PPh3)2
O
R3
R2
R3
R2
Et3N, DMF, 80 °C
74–75%
HN
R1
CH2Cl2, r.t.
60–83%
Et3N, DMF
50 °C
O
N
R1
HN
O
N
H
O
N
H
R1
66–89%
1a–d
2
4
4
3e
R = aryl, heteroaryl
Scheme 2
R1
Bn
R2
R3
compound
R
H
O
R
CH3
CH3
1a
OEt
O
R
EtO
base
CH3
CH3
CH3
CH3
CH3
CH3
3-CF3C6H4
3-MeO2CC6H4
3-CNC6H4
2aa, 4aa
2ab, 4ab
2ac, 4ac
Bn
Bn
Bn
R3
R2
56–91%
O
R3
R2
N
R1
O
N
R1
CH3
CH3
CH3
3-pyridyl
H
2ad, 4ad
1b
Bn
Bn
4
5
C2H5
CH3
CH3
CH3
CH3
C2H5 3-MeO2CC6H4
C2H5 4-MeCOC6H4
2bb, 4bb
2be, 4be
2bf, 4bf
Scheme 3
Bn
Bn
Bn
Bn
C2H5
2-ClC6H4
rable results, whereas MeCN was almost completely
ineffective (Table 1, entry 9).
C2H5 4-MeSO2C6H4
2bg, 4bg
OCH3
CH3
CH3
CH3
CH3
H
1c
OCH3
OCH3
These mild reaction conditions were then extended to the
cyclization of N-propargylmalonamides, and our results
are shown in Table 2. The reactions were usually carried
out in NMP or DMSO at room temperature in the presence
of 1.5 equivalents of Cs2CO3 or K2CO3. t-BuOK and
NaHCO3 could also be used (entries 3 and 6), although the
latter base was less effective and required long reaction
times. The scope of the reaction includes electron-poor
and electron-rich aryl and heteroaryl substituents on the
alkyne framework. On the other hand, the nature of sub-
stituents on the propargyl carbon and on the nitrogen ap-
pears to play a crucial role in the reaction outcome. The
cyclization of 4db, bearing a secondary propargylic car-
bon (R2 = H) with Cs2CO3 in NMP at room temperature
met with failure. Carrying out the reaction at 80 °C result-
ed in the decomposition of starting material (entries 17,
18). With the secondary N-propargylmalonamide 4ea
(R1 = H) Cs2CO3 was ineffective in promoting the reac-
tion at room temperature (entry 19); raising the tempera-
ture allowed to isolate 5ea in good yields (entries 20, 21).
N-Unsubstituted pyrrolinones 5ee,ek were obtained in
similar manner (entries 22, 23). Furthermore, the cycliza-
tion of secondary N-propargylmalonamides 4ea,ee,ek ap-
pears very sensitive to the water content of the reaction
medium, and better results were obtained using commer-
cially available anhydrous solvents.
3-CF3C6H4
2ca, 4ca
OCH3
OCH3
CH3
CH3
CH3
CH3
4-FC6H4
2ch, 4ch
2ci, 4ci
OCH3
OCH3
1-naphthyl
OCH3
OCH3
CH3
CH3
2-thienyl
2cj, 4cj
OCH3
C5H11
C5H11
1d
Bn
H
H
H
3-MeO2CC6H4
2db, 4db
Bn
Scheme 1
Table 1 Experimental Conditions for the Synthesis of 5aa from
4aaa
Entry
Base, solvent
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
NaH, DMSO
80
80
25
25
25
25
25
25
25
0.45
1
90
60
89
78
85
90
73
70
12
Cs2CO3, DMSO
Cs2CO3, DMSO
K2CO3, DMSO
NaHCO3, DMSO
Cs2CO3, NMP
K2CO3, NMP
1
1.5
2.5
0.45
1.5
1.5
1.5
CF3
O
t-BuOK, NMP
K2CO3, MeCN
OEt
EtO
base
CF3
O
solvent
O
a Reactions were carried out on a 0.35 mmol scale, in 2 mL of solvent,
using the following molar ratios: 4aa:base = 1:1.5.
N
O
N
CH2Ph
CH2Ph
5aa
4aa
Scheme 4
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Substituted 3-Pyrrolin-2-ones
2021
Table 2 Base-Promoted Synthesis of 3-Pyrrolin-2-ones 5 from Ethyl N-Propargylmalonamides 4a
Entry
Ethyl N-propargylmalonamide 4
Base, solvent
Time (h)
1.5
3-Pyrrolin-2-one 5
Yieldb (%)
COOMe
O
EtO
COOMe
1
Cs2CO3, DMSO
72
N
Bn
O
N
OEt
O
O
CH2Ph
4ab
5ab
N
C
O
EtO
C
N
2
3
4
K2CO3, NMP
t-BuOK, NMP
Cs2CO3, NMP
4
75
70
91
N
O
N
Bn
OEt
O
O
CH2Ph
5ac
5ac
4ac
4ac
0.45
N
N
O
EtO
N
Bn
3
O
N
OEt
O
O
CH2Ph
4ad
5ad
COOMe
O
EtO
COOMe
5
6
K2CO3, NMPc
4
90
60
N
Bn
O
N
OEt
O
O
CH2Ph
4bb
4bb
5bb
5bb
NaHCO3, DMSO
22
O
O
O
EtO
N
7
Cs2CO3, DMSO
2
87
Bn
OEt
O
N
O
O
CH2Ph
4be
5be
Cl
Cl
O
EtO
8
9
Cs2CO3, NMP
K2CO3, NMP
2
3
82
79
N
Bn
O
N
OEt
O
O
CH2Ph
4bf
4bf
5bf
5bf
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

2022
A. Arcadi et al.
PAPER
Table 2 Base-Promoted Synthesis of 3-Pyrrolin-2-ones 5 from Ethyl N-Propargylmalonamides 4a (continued)
Entry
10
Ethyl N-propargylmalonamide 4
Base, solvent
Time (h)
1.5
3-Pyrrolin-2-one 5
Yieldb (%)
SO2Me
O
SO2Me
EtO
N
Cs2CO3, DMSO
K2CO3, DMSO
84
79
Bn
O
N
OEt
O
O
CH2Ph
4bg
4bg
5bg
5bg
11
2.5
O
CF3
EtO
CF3
O
N
N
O
12
Cs2CO3, NMP
1
62
OMe
O
OEt
OMe
OMe
OMe
4ca
5ca
F
O
EtO
F
O
N
N
O
O
13
14
15
Cs2CO3, NMP
K2CO3, NMP
C2CO3, NMP
3
85
65
84
OMe
OEt
OMe
OMe
OMe
4ch
4ch
5ch
5ch
4
O
EtO
O
N
N
1.5
O
O
OMe
OMe
OMe
OEt
OMe
4ci
5ci
O
EtO
S
S
O
N
N
O
O
16
C2CO3, NMP
2
60
OMe
OEt
OMe
OMe
OMe
4cj
5cj
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Substituted 3-Pyrrolin-2-ones
2023
Table 2 Base-Promoted Synthesis of 3-Pyrrolin-2-ones 5 from Ethyl N-Propargylmalonamides 4a (continued)
Entry
17
Ethyl N-propargylmalonamide 4
Base, solvent
Time (h)
3-Pyrrolin-2-one 5
Yieldb (%)
COOMe
n-C5H11
d
e
Cs2CO3, NMP
Cs2CO3, NMP
Cs2CO3, DMSOc
1.5
2
–
–
–
–
N
Bn
OEt
O
O
4db
4db
18
CF3
O
EtO
5f
CF3
19
2
HN
O
N
H
OEt
O
O
5ea
5ea
4ea
4ea
20
21
Cs2CO3, DMSOc
Cs2CO3, DMSOc
1
1
70e
67e
4ea
5ea
COMe
O
COMe
EtO
22
23
K2CO3, DMSOc
1
83e
HN
O
N
H
OEt
O
O
5ee
4ee
COOMe
O
COOMe
EtO
Cs2CO3, DMSOc
1.5
56g
HN
O
N
H
OEt
O
O
4ek
5ek
a Unless otherwise stated, the reactions were carried out at r.t. using the following molar ratio: 1/base = 1:1.5.
b Yields refer to single runs and are given based on pure isolated products.
c Commercially available anhyd solvent.
d Compound 4db was recovered in 85% yield.
e Carried out at 80 °C.
f Compound 4ea was recovered in 82% yield.
g Carried out at 60 °C.
Interestingly, 3-pyrrolin-2-ones 5 could be also prepared
from propargylamines 1 through a more convenient one-
pot protocol in which the acylation step is carried out on
the crude reaction mixture resulting from the Pd-catalyzed
coupling, and the cyclization on the crude reaction mix-
ture resulting from the acylation (in both cases after ex-
traction and evaporation of the solvent). Some examples
of the one-pot procedure are shown in Table 3. Usually,
this procedure gave higher overall yields than the stepwise
protocol; only the conversion of 3e to 5ea resulted less ef-
fective (5ea was isolated in 35% overall yield).
Table 3 Synthesis of 3-Pyrrolin-2-ones 5 from Propargylamines 1
through a One-Pot, Three-Step Processa
Propargylamine 1
3-Pyrrolin-2-one 5
Yield (%)b
1a
1a
1b
1c
5aa
5ab
5be
5ca
75
57
60
62
a Reactions were carried out according to the following procedure:
1/ArX/Pd(OAc)2/PPh3 = 1:1.2:0.02:0.04, Et3N, DMF, 50 °C, extrac-
tion, then ethyl malonyl chloride/2,6-di-tert-butyl-4-methylpyr-
idine = 2:2, CH2Cl2, 0 °C, extraction, then K2CO3 = 1.5, DMSO, r.t.
b Overall yield.
In conclusion, we have reported a new efficient approach
to the synthesis of highly substituted 3-pyrrolin-2-ones 5
through (a) combined Pd-catalyzed cross-coupling of
propargylamines/acylation/base-promoted
cyclization
and (b) Pd-catalyzed cross-coupling of ethyl N-propargyl-
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

2024
A. Arcadi et al.
PAPER
IR (neat): 3300, 1740, 1660 cm–1.
1H NMR: d = 7.52 (br s, 1 H, NH), 4.19 (q, J = 7.1 Hz, 2 H), 3.32
malonamides/base-promoted cyclization. The cyclization
takes place under mild conditions, and in many cases pro-
ceeds at room temperature. The transformation of propar- (s, 2 H, CH2), 2.43 (s, 1 H, C≡CH), 2.14–1.54 (m, 10 H), 1.28 (t,
gylamines 1 to the title compounds can also be carried out
in good overall yields through a one-pot process.
J = 7.1 Hz, 3 H).
13C NMR: d = 166.7, 163.8 (C=O), 84.9, 70.9 (C≡C), 60.9, 50.9,
41.8, 36.1, 24.7, 21.7, 13.7.
EI-MS: m/z (%) = 237 (100, [M+]).
Melting points are uncorrected. 1H NMR (200 MHz) and 13C NMR
(50.3 MHz) spectra were recorded on a Bruker AC 200 spectrome-
ter in CDCl3. EI (70 eV) and and ESI mass spectra were recorded
respectively on a Varian Saturn 2100T/GC apparatus or on a Ther-
moFinnigan LCQ DecaXP equipped with an orthogonal ESI source.
IR spectra were recorded in KBr pellets or neat in NaCl disks using
a Perkin-Elmer 683 spectrometer.
Propargylamine 1a28 and 1b29 are known compounds; propargy-
lamines 1c,d were prepared from the corresponding acetates ac-
cording to the literature.29 Propargylamines 2 were obtained
through Pd-catalyzed coupling of 1a–d with aryl halides.26 Propar-
gylamides 4ea,ee,ek were obtained through Pd-catalyzed coupling
of 3e with aryl halides;26 other propargylamides 4 were obtained
through acylation of 2 with ethyl malonyl chloride. Propargylamide
3e was obtained through acylation of commercially available 1-
ethynylcyclohexylamine with ethyl malonyl chloride.
Propargylamines 2; Benzyl[3-(3-trifluoromethylphenyl)-1,1-
dimethylprop-2-ynyl]amine (2aa); Typical Procedure
To a solution of 1a (0. 376 g, 2.17 mmol) in DMF (1 mL) and Et3N
(3 mL) were added 3-iodobenzotrifluoride (0.377 mL, 2.61 mmol),
Pd(OAc)2 (0.010 g, 0.04 mmol) and PPh3 (0.023 g, 0.09 mmol).30
The mixture was stirred under N2 at 50 °C for 5 h, and then extract-
ed with 0.5 M NH4Cl (100 mL) and EtOAc (3 × 50 mL). The organ-
ic layer was dried (Na2SO4) and evaporated. Column
chromatografic purification on silica gel (hexane–EtOAc, 95:5) af-
forded 2aa; yield: 0.548 g (80%); oil.
IR (neat): 3300, 2200 cm–1.
1H NMR: d = 7.68 (s, 1 H, Ar), 7.64–7.50 (m, 2 H, Ar), 7.47–7.26
(m, 6 H, Ar), 3.95 (s, 2 H, NCH2), 1.51 (s, 6 H).
13C NMR: d = 140.5, 134.8, 130.9 (q, J = 31.7 Hz, CCF3), 128.8,
128.6, 128.5, 128.4 (q, J = 3.9 Hz), 127.1, 124.5 (q, J = 3.9 Hz, Ar),
122.7 (q, J = 272 Hz, CF3), 96.2, 81.1 (C≡C), 50.7, 49.1, 29.6.
Benzyl(1,1-dimethylprop-2-ynyl)amine (1a)
Mp 45–46 °C (Lit29 mp 47 °C).
EI-MS: m/z (%) = 317 (1, [M+]), 302 (100), 91 (79).
Benzyl(1-ethyl-1-methylprop-2-ynyl)amine (1b)
EI-MS: m/z (%) = 187 (100, [M+]), 158 (58), 91 (96) {Lit.30 m/z (%) =
172 (5, [M+ – 15], 158 (60), 91 (100)}.
3-(3-Benzylamino-3-methylbut-1-ynyl)benzoic Acid Methyl
Ester (2ab)
Yield: 90%; oil.
IR (neat): 3320, 2210, 1730 cm–1.
1H NMR: d = 8.12 (s, 1 H, Ar), 7.95 (d, J = 7.7 Hz, 1 H, Ar), 7.60
(d, J = 7.7 Hz, 1 H, Ar), 7.40–7.22 (m, 6 H, Ar), 3.95 (s, 2 H,
NCH2), 3.89 (s, 3 H, CO2CH3), 1.51 (s, 6 H).
13C NMR: d = 166.4 (C=O), 140.6, 135.8, 132.7, 130.3, 128.8,
128.44, 128.38, 126.9, 123.8 (Ar), 95.5, 81.4 (C≡C), 52.2, 50.6,
49.1, 29.6.
[2-(3,4-Dimethoxyphenyl)ethyl](1,1-dimethylprop-2-
ynyl)amine (1c)
Yield: 50%; oil.
IR (neat): 3300, 1510 cm–1.
1H NMR: d = 6.80–6.78 (m, 3 H, Ar), 3.87 (s, 3 H, OCH3), 3.86 (s,
3 H, OCH3), 2.98 (t, J = 7.0 Hz, 2 H, NCH2), 2.78 (t, J = 7.0 Hz, 2
H, ArCH2), 2.34 (s, 1 H, C≡CH), 1.36 (s, 6 H).
13C NMR: d = 148.8, 147.4, 132.2, 120.6, 117.7, 111.2 (Ar), 88.8,
69.7 (C≡C), 55.9, 55.8, 49.6, 45.2, 35.9, 29.5.
EI-MS: m/z (%) = 307 (13, [M+]), 292 (100), 91 (24).
EI-MS: m/z (%) = 247 (44, [M+]), 152 (58).
3-(3-Benzylamino-3-methylbut-1-ynyl)benzonitrile (2ac)
Yield: 83%; oil.
IR (neat): 3310, 2210 cm–1.
1H NMR: d = 7.64–7.57 (m, 2 H, Ar), 7.49–7.44 (m, 1 H, Ar), 7.40–
7.24 (m, 6 H, Ar), 3.92 (s, 2 H, NCH2), 1.49 (s, 6 H).
13C NMR: d = 140.2, 135.3, 134.5, 130.7, 128.8, 128.1, 128.0,
126.7, 124.6, 112.3 (Ar), 117.7 (C≡N), 96.9, 79.9 (C≡C), 50.2, 48.7,
29.1.
Benzyl(1-ethynylhexyl)amine (1d)
Yield: 30%; oil.
IR (neat): 3300, 1500 cm–1.
1H NMR: d = 7.36–7.20 (m, 5 H, Ar), 4.00 (d, J = 12.8 Hz, 1 H, one
NCH2), 3.78 (d, J = 12.8 Hz, 1 H, one NCH2), 3.30 (dt, J = 6.3, 2.1
Hz, 1 H, NCH), 2.30 (d, J = 2.1 Hz, 1 H, C≡CH), 1.65–1.18 (m, 8
H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR: d = 139.9, 128.41, 128.40, 127.0 (Ar), 85.5, 71.6 (C≡C),
51.3, 49.3, 35.9, 31.6, 25.7, 22.6, 14.1.
EI-MS: m/z (%) = 274 (20, [M+]), 260 (100), 91 (10).
Benzyl(1,1-dimethyl-3-pyridin-3-yl-prop-2-ynyl)amine (2ad)31
Yield: 83%; oil.
EI-MS: m/z (%) = 215 (85, [M+]), 144 (65), 91 (100).
IR (neat): 3300, 2210 cm–1.
N-(1-Ethynylcyclohexyl)malonamic Acid Ethyl Ester (3e)
To a solution of 1-ethynylcyclohexylamine (0.950 g, 7.72 mmol) in
CH2Cl2 (6 mL) cooled in an ice-bath were added 2,6-di-tert-butyl-
4-methylpyridine (3.165 g, 15.44 mmol) and ethyl malonyl chloride
(1.97 mL, 15.44 mmol). After 15 min, the ice bath was removed, the
mixture was stirred at r.t. for 2 h, and then extracted with aq 1 M
Na2CO3 (100 mL) and CH2Cl2 (3 × 50 mL). The organic layer was
dried (Na2SO4) and evaporated. Column chromatographic purifica-
tion on silica gel (hexane–EtOAc, 95:5, then 60:40) afforded, in the
order, recovered 2,6-di-tert-butyl-4-methylpyridine (2.690 g) and
3; yield: 1.492 g (82%).
1H NMR: d = 8.68 (s, 1 H, Ar), 8.52 (br s, 1 H, Ar), 7.70 (d, J = 7.9
Hz, 1 H, Ar), 7.39–7.20 (m, 6 H, Ar), 3.94 (s, 2 H, NCH2), 1.51 (s,
6 H).
13C NMR: d = 152.3, 148.2, 140.5, 138.4, 128.5, 128.4, 127.0,
122.9 (Ar), 98.0, 79.1 (C≡C), 50.6, 49.1, 26.5.
EI-MS: m/z (%) = 235 (100, [M+ – CH3]), 91 (48).
3-(3-Benzylamino-3-methylpent-1-ynyl)benzoic Acid Methyl
Ester (2bb)
Yield: 80%; oil.
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Substituted 3-Pyrrolin-2-ones
2025
IR (neat): 3310, 2200, 1730 cm–1.
13C NMR: d = 148.4, 147.0, 134.1, 131.7, 130.1 (q, J = 32.2 Hz,
CCF3), 128.1, 127.6 (q, J = 3.7 Hz), 123.9, 123.6 (q, J = 3.5 Hz),
120.0, 111.4, 110.8 (Ar), 123.2 (q, J = 271 Hz, CF3), 95.7, 80.1
(C≡C), 55.0, 54.9, 49.6, 44.9, 35.4, 28.7.
1H NMR: d = 8.12 (s, 1 H, Ar), 7.96 (d, J = 7.7 Hz, 1 H, Ar), 7.59
(d, J = 7.7 Hz, 1 H, Ar), 7.61–7.20 (m, 6 H, Ar), 3.94 (s, 2 H,
NCH2), 3.86 (s, 3 H, CO2CH3), 1.78–1.73 (m, 2 H, CH2CH3), 1.45
(s, 3 H, CH3), 1.09 (t, J = 7.4 Hz, 3 H, CH2CH3).
EI-MS: m/z (%) = 391 (100, [M+]).
13C NMR: d = 166.3 (C=O), 140.5, 135.8, 132.7, 130.3, 128.8,
128.42, 128.41, 127.0, 123.9 (Ar), 94.6, 82.6 (C≡C), 54.7, 52.1,
48.6, 34.6, 26.3, 8.9.
[2-(3,4-Dimethoxyphenyl)ethyl][3-(4-fluorophenyl)-1,1-di-
methylprop-2-ynyl]amine (2ch)
Yield: 63%; oil.
IR (neat): 3350, 2210 cm–1.
EI-MS: m/z (%) = 306 (10, [M+ – CH3]), 292 (100), 91 (69).
1-[4-(3-Benzylamino-3-methylpent-1-ynyl)phenyl]ethanone
(2be)
Yield: 85%; mp 59–60 °C.
IR (neat): 3300, 2200, 1690 cm–1.
1H NMR: d = 7.90 (d, J = 7.9 Hz, 2 H, Ar), 7.51 (d, J = 7.9 Hz, 2
H, Ar), 7.40–7.22 (m, 5 H, Ar), 3.94 (s, 2 H, NCH2), 2.59 (s, 3 H,
COCH3), 1.78–1.74 (m, 2 H, CH2CH3), 1.45 (s, 3 H, CH3), 1.09 (t,
J = 7.4 Hz, 3 H, CH2CH3).
13C NMR: d = 197.3 (C=O), 140.7, 135.9, 131.8, 128.5, 128.4,
128.2, 127.0 (Ar), 97.5, 82.9 (C≡C), 54.7, 48.7, 34.6, 26.6, 26.3,
8.9.
1H NMR: d = 7.35 (d, J = 5.4 Hz, 1 H, Ar), 7.31 (d, J = 5.4 Hz, 1
H, Ar), 6.96 (t, J = 8.7 Hz, 2 H, Ar), 6.79–6.77 (m, 3 H, Ar), 3.84
(s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.06 (t, J = 7.2 Hz, 2 H,
NCH2), 2.81 (t, J = 7.2 Hz, 2 H, ArCH2), 1.43 (s, 6 H).
13C NMR: d = 161.9 (d, J = 250 Hz, CF), 148.7, 147.3, 133.2 (d,
J = 8.3 Hz), 132.1, 120.4, 119.3 (d, J = 3.6 Hz), 115.2 (d, J = 21.9
Hz), 111.7, 111.1 (Ar), 93.8, 80.8 (C≡C), 55.6, 55.5, 50.0, 45.2,
35.8, 29.4.
EI-MS: m/z (%) = 326 (2, [M+ – CH3]), 161 (100).
[2-(3,4-Dimethoxyphenyl)ethyl](1,1-dimethyl-3-naphthalen-1-
ylprop-2-ynyl)amine (2ci)
Yield: 70%; oil.
EI-MS: m/z (%) = 305 (30, [M+]), 290 (9), 276 (100).
IR (neat): 3320, 2230 cm–1.
Benzyl[3-(2-chlorophenyl)-1-ethyl-1-methylprop-2-ynyl]amine
(2bf)
Yield: 73%; oil.
IR (neat): 3310, 2220 cm–1.
1H NMR: d = 7.47–7.12 (m, 9 H, Ar), 3.99 (d, A part of an AB sys-
tem, J = 13.1 Hz, 1H, one NCH2), 3.97 (d, B part of an AB system,
J = 13.1 Hz, 1 H, one NCH2), 1.78–1.74 (m, 2 H, CH2CH3), 1.45 (s,
3 H, CH3), 1.10 (t, J = 7.4 Hz, 3 H, CH2CH3).
13C NMR: d = 140.8, 135.8, 133.2, 129.1, 128.8, 128.5, 128.4,
126.9, 126.3, 123.4 (Ar), 99.3, 80.3 (C≡C), 54.8, 48.8, 34.7, 26.3,
8.9.
1H NMR: d = 8.27 (d, J = 7.9 Hz, 1 H, Ar), 7.77–7.29 (m, 6 H, Ar),
6.79–6.67 (m, 3 H, Ar), 3.74 (s, 3 H, OCH3), 3.64 (s, 3 H, OCH3),
3.15 (t, J = 6.8 Hz, 2 H, NCH2), 2.81 (t, J = 6.8 Hz, 2 H, ArCH2),
1.54 (s, 6 H).
13C NMR: d = 148.9, 147.4, 133.2, 133.1, 132.2, 130.1, 128.2,
126.6, 126.2, 126.0, 125.1, 121.0, 120.6, 111.8, 111.3 (Ar), 99.5,
80.1 (C≡C), 55.7, 55.5, 50.6, 45.6, 36.0, 29.7.
EI-MS: m/z (%) = 373 (2, [M+]), 193 (100).
[2-(3,4-Dimethoxyphenyl)ethyl](1,1-dimethyl-3-thiophen-2-yl-
prop-2-ynyl)amine (2cj)
Yield: 77%; oil.
EI-MS: m/z (%) = 299 (7, [M+ + 2]), 297 (20, [M+]), 270 (34), 268
(100), 91 (50).
IR (neat): 3330, 2220 cm–1.
Benzyl[1-ethyl-3-(4-methanesulfonylphenyl)-1-methylprop-2-
1H NMR: d = 7.17 (dd, J = 5.1, 1.1 Hz, 1 H, Ar), 7.11 (dd,
J = 3.6, 1.1 Hz, 1 H, Ar), 6.94–6.91 (m, 1 H, Ar), 6.79–6.77 (m, 3
H, Ar), 3.83 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.04 (t, J = 6.8
Hz, 2 H, NCH2), 2.80 (t, J = 6.8 Hz, 2 H, ArCH2), 1.42 (s, 6 H).
13C NMR: d = 148.8, 147.4, 132.1, 131.3, 126.8, 126.3, 123.3,
120.6, 111.7, 111.2 (Ar), 98.2, 75.2 (C≡C), 55.8, 55.7, 50.4, 45.3,
35.9, 29.3.
ynyl]amine (2bg)31
Yield: 66%; oil.
IR (neat): 3320, 2210 cm–1.
1H NMR: d = 7.88 (d, J = 8.5 Hz, 2 H, Ar), 7.60 (d, J = 8.5 Hz, 2
H, Ar), 7.41–7.24 (m, 5 H, Ar), 3.93 (s, 2 H, NCH2), 3.04 (s, 3 H,
SO2CH3), 1.79–1.73 (m, 2 H, CH2CH3), 1.46 (s, 3 H, CH3), 1.09 (t,
J = 7.3 Hz, 3 H, CH2CH3).
EI-MS: m/z (%) = 314 (3, [M+ – CH3]), 149 (100).
13C NMR: d = 140.5, 139.1, 132.3, 129.3, 128.4, 128.2, 127.2,
126.9 (Ar), 98.2, 81.9 (C≡C), 54.5, 48.6, 44.3, 34.4, 26.1, 8.7.
EI-MS: m/z (%) = 312 (2, [M+ – C2H5]), 236 (53), 234 (54), 173
3-(3-Benzylaminooct-1-ynyl)benzoic Acid Methyl Ester (2db)
Yield: 43%; oil.
IR (neat): 3320, 2240 cm–1.
(100), 171 (98).
1H NMR: d = 8.13 (s, 1 H, Ar), 7.95 (d, J = 7.8 Hz, 1 H, Ar), 7.60
(d, J = 7.8 Hz, 1 H, Ar), 7.39–7.23 (m, 6 H, Ar), 4.07 (d, A part of
an AB system, J = 12.8 Hz, 1 H, one NCH2Ph), 3.89 (s, 3 H,
CO2CH3), 3.89 (d, B part of an AB system, J = 12.8 Hz, 1 H, one
NCH2Ph), 3.58 (t, J = 7.0 Hz, 1 H, NCH), 1.73–1.26 (m, 8 H), 0.90
(t, J = 6.2 Hz, 3 H).
13C NMR: d = 166.4 (C=O), 140.0, 135.8, 132.8, 130.3, 128.9,
128.4, 127.0, 123.9 (Ar), 92.2, 82.9 (C≡C), 52.2, 51.5, 50.0, 36.0,
31.6, 25.8, 22.6, 14.1.
[2-(3,4-Dimethoxyphenyl)ethyl][3-(3-trifluoromethylphenyl)-
1,1-dimethylprop-2-ynyl]amine (2ca)
Yield: 76%; oil.
IR (neat): 3310, 2210 cm–1.
1H NMR: d = 7.64 (s, 1 H, Ar), 7.52 (d, J = 7.9 Hz, 2 H, Ar), 7.43–
7.35 (m, 1 H, Ar), 6.80–6.78 (m, 3 H, Ar), 3.86 (s, 3 H, OCH3), 3.81
(s, 3 H, OCH3), 3.06 (t, J = 7.1 Hz, 2 H, NCH2), 2.82 (t, J = 7.12
Hz, 2 H, ArCH2), 1.44 (s, 6 H).
EI-MS: m/z (%) = 350 (100, [M+]), 279 (53, [M+ – C5H11]).
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

2026
A. Arcadi et al.
PAPER
Tertiary Propargylamides 4; N-Benzyl-N-[3-(3-trifluorometh-
ylphenyl)-1,1-dimethylprop-2-ynyl]malonamic Acid Ethyl
Ester (4aa); Typical Procedure
3-{3-[Benzyl(2-ethoxycarbonylacetyl)amino]-3-methylpent-1-
ynyl}benzoic Acid Methyl Ester (4bb)
Yield: 67%; oil.
To a solution of 2aa (0.350 g, 1.10 mmol) and 2,6-di-tert-butyl-4-
methylpyridine (0.451 g, 2.20 mmol) in anhyd CH2Cl2 (5 mL),
cooled in an ice-bath, was added ethyl malonyl chloride (0.282 mL,
2.20 mmol). The mixture was stirred under N2 at 0 °C for 1 h, and
then at r.t for 1 h and treated with aq 0.5 M Na2CO3 (50 mL) and
extracted with CH2Cl2 (3 × 25 mL). The organic layer was dried
(Na2SO4) and evaporated. Column chromatographic purification on
silica gel (hexane–EtOAc, 85:15) afforded, in the order, 2,6-di-tert-
butyl-4-methylpyridine (0.342 g) and 4aa; yield: 0.396 g (83%); oil.
IR (neat): 1730, 1660 cm–1.
1H NMR: d = 7.90 (d, J = 7.8 Hz, 1 H, Ar), 7.73 (s, 1 H, Ar), 7.39–
7.19 (m, 7 H, Ar), 5.05 (d, A part of an AB system, J = 17.2 Hz, 1
H, one NCH2Ph), 4.80 (d, B part of an AB system, J = 17.2 Hz, 1
H, one NCH2Ph), 4.14 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.89 (s, 3
H, CO2CH3), 3.47 (d, A part of an AB system, J = 15.7 Hz, 1 H, one
COCH2CO), 3.40 (d, B part of an AB system, J = 15.7 Hz, 1 H, one
COCH2CO), 2.80–2.60 (m, 1 H, one CH2CH3), 2.18–2.00 (m, 1 H,
one CH2CH3), 1.97 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3)
1.14 (t, J = 7.3 Hz, 3 H, CH2CH3).
IR (neat): 1740, 1660 cm–1.
1H NMR: d = 7.40–7.19 (m, 9 H, Ar), 4.88 (s, 2 H, NCH2), 4.18 (q,
J = 7.1 Hz, 2 H, CO2CH2CH3), 3.43 (s, 2 H, COCH2CO), 1.94 (s, 6
H), 1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.8, 167.4 (C=O), 138.4, 134.5, 130.7 (q, J = 32.4
Hz, CCF3), 128.9, 128.8, 128.3 (q, J = 3.7 Hz), 127.4, 125.8, 124.8
(q, J = 3.6 Hz), 123.8 (Ar), 122.7 (q, J = 271 Hz, CF3), 94.5, 82.9
(C≡C), 61.4, 57.2, 51.3, 43.8, 28.1, 14.1.
13C NMR: d = 167.8, 167.2, 166.1 (C=O), 138.4, 135.5, 132.4,
130.3, 129.2, 128.8, 128.3, 127.2, 125.9, 122.9 (Ar), 92.3, 84.8
(C≡C), 62.6, 61.3, 52.6, 52.2, 44.0, 32.6, 26.7, 14.1, 9.7.
EI-MS: m/z (%) = 435 (30, [M+]), 91 (100).
N-[3-(4-Acetylphenyl)-1-ethyl-1-methylprop-2-ynyl]-N-benzyl-
malonamic Acid Ethyl Ester (4be)
Yield: 68%; oil.
IR (neat): 2210, 1740, 1690, 1660 cm–1.
1H NMR: d = 7.78 (d, J = 8.3 Hz, 2 H, Ar), 7.39–7.28 (m, 5 H, Ar),
7.07 (d, J = 8.3 Hz, 2 H, Ar), 5.07 (d, A part of an AB system,
J = 17.1 Hz, 1 H, one NCH2Ph), 4.83 (d, B part of an AB system,
J = 17.2 Hz, 1 H, one NCH2Ph), 4.19 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.45 (d, A part of an AB system, J = 15.6 Hz, 1 H,
one COCH2CO), 3.40 (d, B part of an AB system, J = 15.6 Hz, 1 H,
one COCH2CO), 2.70–2.55 (m, 1 H, one CH2CH3), 2.56 (s, 3 H,
COCH3), 2.10–1.95 (m, 1 H, one CH2CH3), 1.96 (s, 3 H), 1.27 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3) 1.14 (t, J = 7.3 Hz, 3 H, CH2CH3).
EI-MS: m/z (%) = 431 (78, [M+]), 91 (100).
3-{3-[Benzyl(2-ethoxycarbonylacetyl)amino]-3-methylbut-1-
ynyl}benzoic Acid Methyl Ester (4ab)
Yield: 77%; oil.
IR (neat): 1730, 1660 cm–1.
1H NMR: d = 7.90 (d, J = 7.2 Hz, 1 H, Ar), 7.77 (s, 1 H, Ar), 7.39–
7.22 (m, 7 H, Ar), 4.90 (s, 2 H, NCH2), 4.18 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.90 (s, 3 H, CO2CH3), 3.44 (s, 2 H, COCH2CO),
1.94 (s, 6 H), 1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.7, 167.2, 166.2 (C=O), 138.3, 135.5, 132.5,
130.3, 129.2, 128.8, 128.3, 127.2, 125.9, 123.0 (Ar), 93.7, 83.5
(C≡C), 61.3, 57.3, 52.1, 51.2, 43.8, 28.2, 14.1.
13C NMR: d = 196.6, 167.6, 167.0 (C=O), 138.1, 135.9, 131.2,
128.6, 127.8, 127.1, 127.0, 125.7 (Ar), 94.5, 84.9 (C≡C), 62.4, 61.2,
52.3, 43.8, 32.3, 26.4, 26.3, 13.9, 9.5.
EI-MS: m/z (%) = 421 (3, [M+]), 293 (100), 91 (67).
EI-MS: m/z (%) = 347 (100, [M+ – EtOCO]), 91 (100).
N-Benzyl-N-[3-(3-cyanophenyl)-1,1-dimethylprop-2-ynyl]mal-
onamic Acid Ethyl Ester (4ac)
Yield: 67%; oil.
IR (neat): 2210, 1740, 1660 cm–1.
1H NMR: d = 7.37–7.27 (m, 8 H, Ar), 7.17 (s, 1 H, Ar), 4.86 (s, 2 H,
NCH2), 4.18 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.42 (s, 2 H,
COCH2CO), 1.92 (s, 6 H), 1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.7, 167.3 (C=O), 138.2, 135.3, 134.8, 131.3,
129.0, 128.9, 127.4, 125.7, 124.2, 112.6 (Ar), 117.9 (C≡N), 95.3,
82.0 (C≡C), 61.4, 57.0, 51.1, 43.7, 28.0, 14.1.
N-Benzyl-N-[3-(2-chlorophenyl)-1-ethyl-1-methylprop-2-
ynyl]malonamic Acid Ethyl Ester (4bf)
Yield: 81%; oil.
IR (neat): 1740, 1660 cm–1.
1H NMR: d = 7.38–7.24 (m, 6 H, Ar), 7.21–6.97 (m, 3 H, Ar), 5.15
(d, A part of an AB system, J = 18.2 Hz, 1 H, one NCH2Ph), 4.80
(d, B part of an AB system, J = 18.2 Hz, 1 H, one NCH2Ph), 4.18
(q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.45 (d, A part of an AB system,
J = 15.6 Hz, 1 H, one COCH2CO), 3.36 (d, B part of an AB system,
J = 15.6 Hz, 1H, one COCH2CO), 2.80–2.60 (m, 1 H, one
CH2CH3), 2.15–2.01 (m, 1 H, one CH2CH3), 2.00 (s, 3 H), 1.26 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3) 1.15 (t, J = 7.3 Hz, 3 H, CH2CH3).
13C NMR: d = 167.8, 167.2 (C=O), 138.3, 135.8, 133.1, 129.3,
129.1, 128.7, 127.1, 126.2, 126.0, 122.4 (Ar), 96.4, 82.9 (C≡C),
63.0, 61.4, 52.7, 44.0, 32.6, 26.8, 14.1, 9.7.
EI-MS: m/z (%) = 270 (34), 268 (100, [M+ – EtOCOCH2CO, – Et +
H]), 91 (78).
EI-MS: m/z (%) = 388 (43, [M+]), 344 (14), 91 (100).
N-Benzyl-N-(1,1-dimethyl-3-pyridin-3-ylprop-2-ynyl)mal-
onamic Acid Ethyl Ester (4ad)
Yield: 70%; mp 58–60 °C.
IR (KBr): 1720, 1690 cm–1.
1H NMR: d = 8.45 (d, J = 3.6 Hz, 1 H, Ar), 8.25 (s, 1 H, Ar), 7.39–
7.29 (m, 6 H, Ar), 7.17–7.11 (m, 1 H, Ar), 4.89 (s, 2 H, NCH2), 4.18
(q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.43 (s, 2 H, COCH2CO), 1.94
(s, 6 H), 1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.7, 167.3 (C=O), 151.9, 148.5, 138.3, 138.2,
128.3, 127.3, 125.7, 122.8, 119.7 (Ar), 96.0, 81.1 (C≡C), 61.3, 57.1,
51.1, 43.7, 28.1, 14.1.
N-Benzyl-N-[1-ethyl-3-(4-methanesulfonylphenyl)-1-methyl-
prop-2-ynyl]malonamic Acid Ethyl Ester (4bg)
Yield: 65%; oil.
IR (neat): 1740, 1660 cm–1.
1H NMR: d = 7.77 (d, J = 8.4 Hz, 2 H, Ar), 7.39–7.30 (m, 5 H, Ar),
7.14 (d, J = 8.4 Hz, 2 H, Ar), 4.99 (d, A part of an AB system,
J = 18.6 Hz, 1 H, one NCH2Ph), 4.81 (d, B part of an AB system,
J = 18.6 Hz, 1 H, one NCH2Ph), 4.18 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.46 (d, A part of an AB system, J = 15.2 Hz, 1 H,
EI-MS: m/z (%) = 364 (1, [M+]), 251 (49), 236 (100).
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Substituted 3-Pyrrolin-2-ones
2027
one COCH2CO), 3.38 (d, B part of an AB system, J = 15.2 Hz, 1H,
one COCH2CO), 3.02 (s, 3 H, SO2CH3), 2.75–2.55 (m, 1 H, one
CH2CH3), 2.15–2.01 (m, 1 H, one CH2CH3), 2.00 (s, 3 H), 1.27 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3) 1.12 (t, J = 7.3 Hz, 3 H, CH2CH3).
Hz, 2 H, CO2CH2CH3), 3.82 (s, 3 H, OCH3), 3.72 (t, J = 8.5 Hz, 2
H, NCH2), 3.60 (s, 3 H, OCH3), 3.41 (s, 2 H, COCH2CO), 2.96 (t,
J = 8.5 Hz, 2 H, ArCH2), 1.94 (s, 6 H), 1.28 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3).
13C NMR: d = 167.8, 167.3 (C=O), 139.6, 138.3, 132.1, 128.9,
128.4, 127.3, 127.2, 125.8 (Ar), 95.6, 84.1 (C≡C), 62.5, 61.5, 52.5,
44.4, 44.0, 32.5, 26.6, 14.1, 9.7.
13C NMR: d = 167.7, 166.0 (C=O), 149.1, 147.8, 132.3, 130.6,
127.5, 127.1, 120.6, 111.8, 111.4 (Ar), 98.2, 78.0 (C≡C), 61.3, 57.4,
55.9, 55.4, 50.7, 43.8, 37.0, 28.2, 14.1.
EI-MS: m/z (%) = 456 (2, [M+]), 204 (59), 190 (100), 91 (10).
EI-MS: m/z (%) = 444 (1, [M+]), 399 (10), 355 (26, [M+
–
EtOCOCH3].
N-[3-(3-Trifluoromethylphenyl)-1,1-dimethylprop-2-ynyl]-N-
[2-(3,4-dimethoxyphenyl)ethyl]malonamic Acid Ethyl Ester
(4ca)
3-{3-[Benzyl(2-ethoxycarbonylacetyl)amino]oct-1-ynyl}benzo-
ic Acid Methyl Ester (4db)
Yield: 76%; mp 105–107 °C.
Yield: 76%; oil.
IR (KBr): 1750, 1660 cm–1.
IR (neat): 2280, 1750, 1670 cm–1.
1H NMR: d = 7.72 (s, 1 H, Ar), 7.68–7.58 (m, 2 H, Ar), 7.47 (t,
J = 7.8 Hz, 1 H, Ar), 6.81–6.65 (m, 3 H, Ar), 4.19 (q, J = 7.1 Hz, 2
H, CO2CH2CH3), 3.83 (s, 3 H, OCH3), 3.83–3.75 (m, 2 H, NCH2),
3.63 (s, 3 H, OCH3), 3.42 (s, 2 H, COCH2CO), 3.01 (t, J = 8.6 Hz,
2 H, ArCH2), 1.99 (s, 6 H), 1.28 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.6, 166.0 (C=O), 149.1, 147.8, 134.8, 130.8 (q,
J = 32.5 Hz, CCF3), 130.5, 129.0, 128.2 (q, J = 3.9 Hz), 125.0 (q,
J = 3.5 Hz), 123.6, 120.5, 111.7, 111.5 (Ar), 123.5 (q, J = 271 Hz,
CF3), 94.4, 83.0 (C≡C), 61.2, 56.8, 55.7, 55.4, 50.3, 43.7, 36.8, 28.3,
14.0.
1H NMR: d = 7.93–7.88 (m, 1 H, Ar), 7.79 (s, 1 H, Ar), 7.34–7.21
(m, 7 H, Ar), 5.78 (t, J = 7.5 Hz, 1 H, NCH), 4.90–4.65 (m, 2 H,
NCH2), 4.17 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.90 (s, 3 H, OCH3),
3.36 (d, A part of an AB system, J = 15.4 Hz, 1 H, one COCH2CO),
3.28 (d, B part of an AB system, J = 15.4 Hz, 1 H, one COCH2CO),
1.75 (t, J = 7.7 Hz, 2 H), 1.55–1.30 (m, 6 H), 1.26 (t, J = 7.1 Hz, 3
H, CO2CH2CH3), 0.93–0.86 (m, 3 H).
13C NMR: d = 167.4, 166.9, 166.2 (C=O), 137.5, 135.6, 132.5,
129.2, 128.8, 128.3, 127.4, 126.1 (Ar), 88.2, 84.2 (C≡C), 61.4, 52.2,
48.4, 47.8, 41.9, 34.3, 31.3, 25.7, 22.5, 14.1, 14.0.
EI-MS: m/z (%) = 506 (10, [M+]), 151 (100).
EI-MS: m/z (%) = 377 (30, [M+ – EtOCOCH2]), 301 (100), 91 (63).
N-[3-(4-Fluorophenyl)-1,1-dimethylprop-2-ynyl]-N-[2-(3,4-
dimethoxyphenyl)ethyl]malonamic Acid Ethyl Ester (4ch)
Yield: 68%; mp 110–112 °C.
IR (KBr): 1740, 1660 cm–1.
Secondary Propargylamides 4ea,ee,ek; General Procedure
Alkyne 3e was subjected to Pd-catalyzed coupling with aryl halides
at 80 °C, following the same procedure used for the preparation of
2.
1H NMR: d = 7.47–7.40 (m, 2 H, Ar), 7.07–6.95 (m, 2 H, Ar), 6.80–
6.63 (m, 3 H, Ar), 4.21 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.84 (s,
3 H, OCH3), 3.76 (t, J = 8.7 Hz, 2 H, NCH2), 3.61 (s, 3 H, OCH3),
3.40 (s, 2 H, COCH2CO), 2.98 (t, J = 8.6 Hz, 2 H, ArCH2), 1.95 (s,
6 H), 1.28 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.8, 166.0 (C=O), 162.6 (d, J = 250 Hz, CF),
149.1, 147.8, 133.6 (d, J = 8.3 Hz), 130.6, 120.5, 118.7 (d, J = 3.6
Hz), 115.7 (d, J = 21.9 Hz), 111.7, 111.4 (Ar), 92.5, 83.6 (C≡C),
61.4, 57.2, 55.9, 55.5, 50.5, 43.8, 37.0, 28.5, 14.1.
N-[1-(3-Trifluoromethylphenylethynyl)cyclohexyl]malonamic
Acid Ethyl Ester (4ea)
Yield: 75%; mp 100–101 °C.
IR (KBr): 3300, 1740, 1650 cm–1.
1H NMR: d = 7.69 (br s, 1 H, NH), 7.63–7.40 (m, 4 H, Ar), 4.21 (q,
J = 7.1 Hz, 2 H, CO2CH2CH3), 3.32 (s, 2 H, COCH2CO), 2.20–1.50
(m, 10 H), 1.30 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 169.9, 163.8 (C=O), 135.0, 130.7 (q, J = 32.4 Hz,
CCF3), 128.7, 128.6 (q, J = 3.5 Hz), 124.5 (q, J = 3.7 Hz), 124.2
(Ar), 123.8 (q, J = 271 Hz, CF3), 92.7, 82.0 (C≡C), 61.6, 52.1, 41.7,
36.9, 25.3, 22.5, 14.1.
EI-MS: m/z (%) = 456 (3, [M+]), 161 (100).
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-(1,1-dimethyl-3-naph-
thalen-1-ylprop-2-ynyl)malonamic Acid Ethyl Ester (4ci)
Yield: 74%; oil.
IR (neat): 1740, 1650 cm–1.
1H NMR: d = 7.83 (d, J = 7.9 Hz, 1 H, Ar), 7.90–7.40 (m, 6 H, Ar),
6.67 (s, 2 H, Ar), 6.46 (s, 1 H, Ar), 4.22 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.84–3.76 (m, 2 H, NCH2), 3.75 (s, 3 H, OCH3), 3.47
(s, 2 H, COCH2CO), 3.17 (s, 3 H, OCH3), 3.04 (t, J = 8.5 Hz, 2 H,
ArCH2), 2.09 (s, 6 H), 1.28 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 167.8, 166.1 (C=O), 149.0, 147.7, 133.3, 133.2,
130.7, 130.5, 129.1, 128.4, 127.2, 126.6, 125.7, 125.2, 120.5, 120.1,
111.6, 111.3 (Ar), 97.7, 82.9 (C≡C), 61.3, 57.6, 55.8, 55.0, 50.9,
43.9, 37.1, 28.9, 14.1.
EI-MS: m/z (%) = 381 (13, [M+]), 327 (100), 209 (79).
N-[1-(4-Acetylphenylethynyl)cyclohexyl]malonamic Acid Ethyl
Ester (4ee)
Yield: 74%; mp 81–82 °C.
IR (KBr): 3300, 1750, 1700, 1650 cm–1.
1H NMR: d = 7.86 (d, J = 8.5 Hz, 2 H, Ar), 7.53–7.49 (m, 3 H, Ar
+ NH), 4.20 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.34 (s, 2 H,
COCH2CO), 2.58 (s, 3 H, COCH3), 2.25–1.50 (m, 10 H), 1.29 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 197.2, 169.4, 163.6 (C=O), 135.7, 131.6, 128.0,
127.8 (Ar), 94.5, 82.5 (C≡C), 61.3, 51.9, 41.7, 36.6, 25.0, 22.3,
13.9.
ESI-MS: m/z (%) = 489 (25, [M – H]), 488 (100, [M]).
EI-MS: m/z (%) = 355 (14, [M+]), 301 (54), 198 (100).
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-(1,1-dimethyl-3-
thiophen-2-ylprop-2-ynyl)malonamic Acid Ethyl Ester (4cj)
Yield: 60%; oil.
IR (neat): 1740, 1660 cm–1.
1H NMR: d = 7.29–7.23 (m, 2 H, Ar), 6.99 (dd, J = 5.1, 3.6 Hz, 1
H, Ar), 6.79–6.27 (m, 2 H, Ar), 6.64 (s, 1 H, Ar), 4.20 (q, J = 7.1
4-[1-(2-Ethoxycarbonylacetylamino)cyclohexylethynyl]benzo-
ic Acid Methyl Ester (4ek)
Yield: 75%; mp 78–80 °C.
IR (KBr): 3320, 1750, 1680, 1630 cm–1.
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

2028
A. Arcadi et al.
PAPER
1-Benzyl-5,5-dimethyl-2-oxo-4-pyridin-3-ylmethyl-2,5-di-
hydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester (5ad)
Oil.
1H NMR: d = 7.95 (d, J = 6.9 Hz, 2 H, Ar), 7.52–7.47 (m, 3 H, Ar
+ NH), 4.21 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.91 (s, 3 H,
CO2CH3), 3.36 (s, 2 H, COCH2CO), 2.29–1.48 (m, 10 H), 1.30 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 170.0, 166.6, 163.6 (C=O), 132.2, 131.7, 129.3,
128.0 (Ar), 94.1, 82.8 (C≡C), 61.6, 52.1, 41.6, 36.9, 25.3, 22.5,
14.1.
IR (neat): 1740, 1680 cm–1.
1H NMR: d = 8.55–8.40 (m, 2 H, Ar), 7.55 (d, J = 7.7 Hz, 1 H, Ar),
7.34–7.18 (m, 6 H, Ar), 4.60 (s, 2 H, NCH2), 4.30 (q, J = 7.1 Hz, 2
H, CO2CH2CH3), 4.02 (s, 2 H, ArCH2C=C), 1.29 (t, J = 7.1 Hz, 3
H, CO2CH2CH3), 1.04 (s, 6 H, 2 CH3).
EI-MS: m/z (%) = 371 (13, [M+]), 317 (88), 214 (100).
13C NMR: d = 169.6, 165.6, 162.9 (C=O + C-4), 149.8, 148.2,
138.2, 135.8, 132.4, 128.5, 127.8, 127.3, 126.0, 123.5 (Ar + C-3),
65.5 (C5), 61.3, 42.7, 29.6, 24.2, 14.1.
3-Pyrrolin-2-ones 5; General Procedure
To a solution of 4 (0.5 mmol) in N-methyl pyrrolidinone or DMSO
(1.5 mL) was added the base (0.75 mmol). The mixture was stirred
at r.t. or at 60–80 °C (see Table 2), and monitored by TLC (hexane–
EtOAc, 40:60). After disappearance of starting material, the mix-
ture was diluted with aq 0.5 M NH4Cl (100 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic layers were
dried(Na2SO4) and evaporated. Column chromatographic purifica-
tion on silica gel (hexane–EtOAc) afforded 5.
ESI-MS: m/z (%) = 365 (100, [MH+]).
Anal. Calcd for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C,
72.77; H, 6.67; N, 7.71.
1-Benzyl-5-ethyl-4-(3-methoxycarbonylbenzyl)-5-methyl-2-
oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester
(5bb)
Mp 84–85 °C.
IR (KBr): 1740, 1720, 1680 cm–1.
1-Benzyl-4-(3-trifluoromethylbenzyl)-5,5-dimethyl-2-oxo-2,5-
dihydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester (5aa)
Oil.
1H NMR: d = 7.90 (s, 1 H, Ar), 7.88 (d, J = 7.8 Hz, 1 H, Ar), 7.50–
7.20 (m, 7 H), 4.76 (d, A part of an AB system, J = 15.4 Hz, 1 H,
one NCH2), 4.35–4.20 (m, 4 H, CO2CH2CH3 + one NCH2 + one
ArCH2C=C), 3.90 (s, 3 H, CO2CH3), 3.79 (d, B part of an AB sys-
tem, J = 14.8 Hz, 1 H, one ArCH2C=C), 1.85–1.60 (m, 2 H,
CH2CH3), 1.33 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 0.96 (s, 3 H,
CH3), 0.30 (t, J = 7.2 Hz, 3 H, CH2CH3).
13C NMR: d = 166.5, 166.8, 166.7, 162.9 (C=O + C-4), 137.9,
137.6, 133.1, 130.3, 129.7, 128.6, 128.3, 128.1, 128.0, 127.2, 127.1
(Ar + C-3), 69.1 (C-5), 61.3, 52.2, 42.8, 32.1, 28.5, 24.6, 14.1, 7.0.
IR (neat): 1770, 1710 cm–1.
1H NMR: d = 7.50–7.19 (m, 9 H, Ar), 4.60 (s, 2 H, NCH2), 4.29 (q,
J = 7.1 Hz, 2 H, CO2CH2CH3), 4.08 (s, 2 H, ArCH2C=C), 1.28 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3), 1.10 (s, 6 H, 2 CH3).
13C NMR: d = 169.3, 165.6, 162.8 (C=O + C-4), 138.0, 137.4,
131.7, 130.8 (q, J = 32.0 Hz, CCF3), 129.0, 128.3, 127.6, 127.1,
125.9, 125.1 (q, J = 3.7 Hz), 123.5 (q, J = 3.7 Hz, Ar + C-3), 123.8
(q, J = 271 Hz, CF3), 65.4 (C-5), 61.1, 42.6, 31.9, 24.0, 13.8.
EI-MS: m/z (%) = 431 (100, [M+]), 386 (15), 91 (89).
Anal. Calcd for C21H18F3NO2: C, 67.55; H, 4.86; N, 3.75. Found: C,
67.12; H, 4.89; N, 3.74.
ESI-MS: m/z (%) = 436 (100, [MH+]).
Anal. Calcd for C26H29NO5: C, 71.70; H, 6.71; N, 3.22. Found: C,
71.34; H, 6.69; N, 3.22.
1-Benzyl-4-(3-methoxycarbonylbenzyl)-5,5-dimethyl-2-oxo-
2,5-dihydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester (5ab)
Mp 80–81 °C.
IR (KBr): 1740, 1720, 1670 cm–1.
4-(4-Acetylbenzyl)-1-benzyl-5-ethyl-5-methyl-2-oxo-2,5-di-
hydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester (5be)
Oil.
1H NMR: d = 7.91–7.88 (m, 2 H, Ar), 7.40–7.20 (m, 7 H, Ar), 4.75
(s, 2 H, NCH2), 4.30 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.08 (s, 2
H, ArCH2C=C), 3.90 (s, 3 H, CO2CH3), 1.30 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.08 (s, 6 H, 2 CH3).
13C NMR: d = 170.0, 166.8, 165.9, 163.0 (C=O + C-4), 138.3,
137.0, 133.0, 130.5, 129.6, 128.8, 128.5, 128.1, 127.8, 127.3, 125.8
(Ar + C-3), 65.6 (C-5), 61.3, 52.2, 42.7, 32.2, 24.3, 14.1.
IR (neat): 1740, 1680 cm–1.
1H NMR: d = 7.87 (d, J = 8.4 Hz, 2 H, Ar), 7.34–7.23 (m, 7 H, Ar),
4.77 (d, A part of an AB system, J = 15.2 Hz, 1 H, one NCH2),
4.32–4.20 (m, 4 H, CO2CH2CH3 + one NCH2 + one ArCH2C=C),
3.76 (d, B part of an AB system, J = 14.9 Hz, 1 H, one ArCH2C=C),
2.56 (s, 3 H, COCH3), 1.90–1.60 (m, 2 H, CH2CH3), 1.31 (t, J = 7.1
Hz, 3 H, CO2CH2CH3), 0.95 (s, 3 H, CH3), 0.33 (t, J = 7.3 Hz, 3 H,
CH2CH3).
13C NMR: d = 197.5, 168.1, 166.6, 162.7 (C=O + C-4), 141.8,
138.0, 135.8, 128.9, 128.7, 128.4, 128.3, 127.4, 127.3 (Ar + C-3),
69.0 (C-5), 61.2, 42.8, 32.3, 28.5, 26.5, 24.5, 14.1, 7.0.
EI-MS: m/z (%) = 421 (56, [M+]), 361 (24) 91 (100).
Anal. Calcd for C25H27NO5: C, 71.24; H, 6.45; N, 3.31. Found: C,
71.45; H, 6.43; N, 3.33.
EI-MS: m/z (%) = 419 (5, [M+]), 404 (15, [M+ – CH3]), 359 (100),
91 (75).
1-Benzyl-4-(3-cyanobenzyl)-5,5-dimethyl-2-oxo-2,5-dihydro-
1H-pyrrole-3-carboxylic Acid Ethyl Ester (5ac)
Oil.
IR (neat): 2220, 1750, 1700 cm–1.
Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C,
74.18, H, 6.95, N, 3.36.
1H NMR: d = 7.52–7.21 (m, 9 H, Ar), 4.60 (s, 2 H, NCH2), 4.30 (q,
J = 7.1 Hz, 2 H, CO2CH2CH3), 4.05 (s, 2 H, ArCH2C=C), 1.30 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3), 1.09 (s, 6 H, 2 CH3).
1-Benzyl-4-(2-chlorobenzyl)-5-ethyl-5-methyl-2-oxo-2,5-di-
hydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester (5bf)
Mp 115–117 °C.
IR (KBr): 1740, 1680 cm–1.
1H NMR: d = 7.43–7.13 (m, 9 H, Ar), 4.78 (d, A part of an AB sys-
tem, J = 14.9 Hz, 1 H, one NCH2), 4.31–4.20 (m, 4 H, CO2CH2CH3
+ one NCH2 + one ArCH2C=C), 3.89 (d, B part of an AB system,
J = 15.4 Hz, 1 H, one ArCH2C=C), 1.75 (q, J = 7.5 Hz, 2 H,
13C NMR: d = 169.4, 165.6, 162.9 (C=O + C-4), 138.16, 138.12,
133.0, 132.0, 130.7, 129.5, 128.6, 127.9, 127.4, 126.2, 112.8 (Ar +
C-3), 118.5 (C≡N), 65.6 (C-5), 61.5, 42.8, 31.9, 24.2, 14.1.
EI-MS: m/z (%) = 388 (78, [M+]), 343 (11), 91 (100).
Anal. Calcd for C24H24N2O3: C, 74.21; H, 7.23; N, 7.21. Found: C,
74.47; H, 7.20; N, 7.23.
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Substituted 3-Pyrrolin-2-ones
2029
CH2CH3), 1.27 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 0.95 (s, 3 H,
CH3), 0.33 (t, J = 7.5 Hz, 3 H, CH2CH3).
120.7, 115.7 (d, J = 21.3 Hz), 112.1, 111.3 (Ar + C-3), 65.2 (C-5),
61.2, 55.9, 42.1, 34.5, 31.7, 23.7, 14.1.
13C NMR: d = 167.9, 166.7, 162.8 (C=O + C-4), 138.1, 134.0,
133.8, 130.2, 129.5, 128.6, 128.4, 128.3, 127.6, 127.3, 127.0 (Ar +
C-3), 69.1 (C-5), 61.2, 42.8, 29.2, 28.5, 24.2, 14.0, 7.0.
MS: m/z (%) = 506 (6, [M+]), 460 (18, [M+ – EtOH]), 309 (92, [M+
– EtOH – C7H5(OMe)2]), 280 (100).
Anal. Calcd for C26H30FNO5: C, 68.55; H, 6.64; N, 3.07. Found: C,
68.42; H, 6.62; N, 3.08.
EI-MS: m/z (%) = 413 (28), 411 (77, [M+]), 367 (18), 355 (7, [M+ –
EtOH]), 338 (27), 336 (74), 91 (100).
1-[2-(3,4-Dimethoxyphenyl)ethyl]-5,5-dimethyl-4-naphthalen-
1-ylmethyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid
Ethyl Ester (5ci)
Anal. Calcd for C24H26ClNO3: C, 69.98; H, 6.36; N, 3.40. Found: C,
69.63; H, 6.34; N, 3.41.
Oil.
1-Benzyl-5-ethyl-4-(4-methanesulfonylbenzyl)-5-methyl-2-oxo-
2,5-dihydro-1H-pyrrole-3-carboxylic Acid Ethyl Ester (5bg)
Mp 42–44 °C.
IR (neat): 1740, 1670 cm–1.
1H NMR: d = 8.07 (d, J = 7.1 Hz, 1 H, Ar), 7.88–7.83 (m, 1 H, Ar),
7.75 (d, J = 8.0 Hz, 1 H, Ar), 7.55–7.40 (m, 2 H, Ar), 7.35 (d,
J = 8.0 Hz, 1 H, Ar), 7.23 (d, J = 6.9 Hz, 1 H, Ar), 6.80–6.77 (m, 3
H, Ar), 4.46 (s, 2 H, ArCH2C=C), 4.16 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.86 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.44 (br t,
J = 7.4 Hz, 2 H, NCH2CH2Ar), 2.95 (br t, J = 7.7 Hz, 2 H,
NCH2CH2Ar), 1.14 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.06 (s, 6 H,
2 CH3).
13C NMR: d = 170.0, 165.9, 163.0 (C=O + C-4), 148.9, 147.6,
133.7, 132.2, 132.0, 131.8, 128.8, 127.7, 126.4, 126.2, 126.1, 125.9,
125.3, 123.2, 120.7, 112.2, 111.2 (Ar + C-3), 65.4 (C-5), 61.0, 55.9,
42.1, 34.4, 30.1, 23.3, 14.0.
IR: 1760, 1710, 1330 cm–1.
1H NMR: d = 7.85 (d, J = 8.3 Hz, 2 H, Ar), 7.47–7.22 (m, 7 H, Ar),
4.77 (d, A part of an AB system, J = 16.3 Hz, 1 H, one NCH2),
4.38–4.22 (m, 4 H, CO2CH2CH3 + one NCH2 + one ArCH2C=C),
3.79 (d, B part of an AB system, J = 15.0 Hz, 1 H, one ArCH2C=C),
3.03 (s, 3 H, SO2CH3), 1.90–1.60 (m, 2 H, CH2CH3), 1.31 (t, J = 7.1
Hz, 3 H, CO2CH2CH3), 0.96 (s, 3 H, CH3), 0.34 (t, J = 7.2 Hz, 3 H,
CH2CH3).
13C NMR: d = 167.9, 166.4, 162.7 (C=O + C-4), 142.8, 139.1,
137.8, 129.6, 128.4, 128.2, 127.7, 127.4 (Ar + C-3), 69.0 (C-5),
61.4, 44.4, 42.8, 32.2, 28.4, 24.5, 14.1, 7.0.
ESI-MS: m/z (%) = 488 (100, [MH+]).
ESI-MS: m/z (%) = 456 (100, [MH+]).
Anal. Calcd for C30H33NO5: C, 73.90; H, 6.82; N, 2.87. Found: C
73.58; H, 6.79; N, 2.86.
Anal. Calcd for C25H29NO5S: C, 65.91; H, 6.42; N, 3.07. Found: C,
65.71; H, 6.47; N, 3.08.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-5,5-dimethyl-2-oxo-4-
thiophen-2-ylmethyl-2,5-dihydro-1H-pyrrole-3-carboxylic
Acid Ethyl Ester (5cj)
Oil.
4-(3-Trifluoromethylbenzyl)-1-[2-(3,4-dimethoxyphenyl)ethyl]-
5,5-dimethyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid
Ethyl Ester (5ca)
Mp 124–125 °C.
IR (KBr): 1750, 1680 cm–1.
IR (neat): 1740, 1680 cm–1.
1H NMR: d = 7.15 (dd, J = 5.1, 1.1 Hz, 1 H, Ar), 6.91–6.87 (m, 1
H, Ar), 6.85–6.75 (m, 4 H, Ar), 4.30 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 4.18 (s, 2 H, ArCH2C=C), 3.87 (s, 3 H, OCH3), 3.85
(s, 3 H, OCH3), 3.43 (br t, J = 7.9 Hz, 2 H, NCH2CH2Ar), 2.94 (br
t, J = 7.8 Hz, 2 H, NCH2CH2Ar), 1.34 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.18 (s, 6 H, 2 CH3).
13C NMR: d = 169.9, 165.7, 162.8 (C=O + C-4), 148.9, 147.6,
138.8, 131.8, 126.7, 126.1, 124.5, 120.7, 112.2, 111.3 (Ar + C-3),
65.1 (C-5), 61.2, 55.9, 42.1, 34.5, 26.8, 23.3, 14.2.
1H NMR: d = 7.47 (br s, 2 H, Ar), 7.40 (d, J = 5.0 Hz, 2 H, Ar), 6.78
(br s, 3 H, Ar), 4.29 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.07 (s, 2 H,
ArCH2C=C), 3.87 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.45 (br t,
J = 7.8 Hz, 2 H, NCH2CH2Ar), 2.95 (br t, J = 7.8 Hz, 2 H,
NCH2CH2Ar), 1.29 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.11 (s, 6 H,
2 CH3).
13C NMR: d = 169.0, 165.7, 163.0 (C=O + C-4), 149.0, 147.7,
137.5, 131.9, 131.8, 130.0 (q, J = 32.2 Hz, CCF3), 129.2, 125.3 (q,
J = 3.7 Hz), 123.8 (q, J = 3.8 Hz), 121.3, 120.8, 112.2, 111.3 (Ar +
C-3), 123.9 (q, J = 269 Hz, CF3), 65.2 (C-5), 61.3, 55.9, 42.2, 34.5,
32.3, 23.7, 14.1.
ESI-MS: m/z (%) = 444 (100, [MH+]).
Anal. Calcd for C24H29NO5S: C, 64.99; H, 6.59; N, 3.16. Found: C,
64.61; H, 6.56; N, 3.18.
EI-MS: m/z (%) = 506 (6, [M+]), 460 (18, [M+ – EtOH]), 309 (92,
[M+ – EtOH & ndash; C7H5(OMe)2]), 280 (100).
4-(3-Trifluoromethylbenzyl)-2-oxo-1-azaspiro[4.5]dec-3-ene-3-
carboxylic Acid Ethyl Ester (5ea)
Mp 200–201 °C.
Anal. Calcd for C27H30F3NO5: C, 64.15; H, 5.98; N, 2.77. Found: C,
64.46; H, 5.96; N, 2.77.
4-(4-Fluorobenzyl)-1-[2-(3,4-dimethoxyphenyl)ethyl]-5,5-di-
methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid Ethyl
Ester (5ch)
Mp 122–123 °C.
IR (KBr): 1740, 1660 cm–1.
1H NMR: d = 7.21–7.14 (m, 2 H, Ar), 6.97 (t, J = 8.7 Hz, 2 H, Ar),
6.78 (br s, 3 H, Ar), 4.30 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.98 (s,
2 H, ArCH2C=C), 3.87 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.39
(br t, J = 8.0 Hz, 2 H, NCH2CH2Ar), 2.93 (br t, J = 7.9 Hz, 2 H,
NCH2CH2Ar), 1.31 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.10 (s, 6 H,
2 CH3).
IR (KBr): 3200, 1740, 1680 cm–1.
1H NMR: d = 8.34 (br s, 1 H, NH), 7.47–7.38 (m, 4 H, Ar), 4.22 (q,
J = 7.1 Hz, 2 H, CO2CH2CH3), 4.07 (s, 2 H, ArCH2C=C), 1.90–1.25
(m, 10 H), 1.22 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 171.1, 168.3, 162.9 (C=O + C-4), 137.6, 131.9, 131.1
(q, J = 32.3 Hz, CCF3), 129.1, 126.5, 125.3 (q, J = 3.6 Hz), 123.7 (q,
J = 3.6 Hz) (Ar + C-3), 123.8 (q, J = 271 Hz, CF3), 64.9 (C-5), 61.1,
34.3, 32.3, 24.7, 22.7, 13.9.
EI-MS: m/z (%) = 381 (16, [M+]), 335 (60, [M+ – EtOH]), 306 (83).
Anal. Calcd for C20H22F3NO3: C, 62.98; H, 5.81; N, 3.67. Found: C,
63.07; H, 5.79; N, 3.68.
13C NMR: d = 169.9, 165.8, 163.1 (C=O + C-4), 161.7 (d, J = 245
Hz, C-F), 148.9, 147.6, 132.1, 131.8, 130.0 (d, J = 7.8 Hz), 126.0,
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York

2030
A. Arcadi et al.
PAPER
(2) Saudi, M. N. S.; El Semary, M. M. A.; El Sawaf, G.
4-(4-Acetylbenzyl)-2-oxo-1-azaspiro[4.5]dec-3-ene-3-carbox-
ylic Acid Ethyl Ester (5ee)
Pharmazie 2002, 57, 519.
(3) Kakeya, H.; Onozawa, C.; Sato, M.; Arai, K.; Osada, H. J.
Med. Chem. 1997, 40, 391.
Mp 198–200 °C.
IR (KBr): 3180, 1740, 1690, 1670 cm–1.
(4) Bosch, J.; Roca, T.; Catena, J. L.; Llorens, O.; Perez, J. J.;
Lagunas, C.; Fernandez, A. G.; Miquel, I.; Fernandez-Serrat,
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M. V.; Varma, L. Tetrahedron 2002, 58, 8113.
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42, 3831.
(13) (a) Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenen, E.;
Rogge, T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagnoni, U. M.; Schenetti, L. Tetrahedron
2003, 59, 1147. (b) Bellesia, F.; De Buyck, L.; Colucci, M.
V.; Ghelfi, F.; Laureyn, I.; Libertini, E.; Mucci, A.; Pagnoni,
U. M.; Pinetti, A.; Rogge, T. M.; Stevens, C. V. Tetrahedron
Lett. 2001, 42, 4573.
1H NMR: d = 8.22 (br s, 1 H, NH), 7.88 (d, J = 8.0 Hz, 2 H, Ar),
7.30 (d, J = 8.0 Hz, 2 H, Ar), 4.23 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 4.09 (s, 2 H, ArCH2C=C), 2.59 (s, 3 H, COCH3),
1.90–1.20 (m, 10 H), 1.24 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 197.7, 171.7, 168.3, 162.9 (C=O + C-4), 142.0,
135.7, 128.7, 126.1 (Ar + C-3), 64.9 (C-5), 61.1, 34.2, 32.6, 26.6,
24.6, 22.6, 14.0.
EI-MS: m/z (%) = 355 (31, [M+]), 310 (100, [M+ – EtOH]).
Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94. Found: C,
71.16; H, 7.11; N, 3.95.
4-(4-Methoxycarbonylbenzyl)-2-oxo-1-azaspiro[4.5]dec-3-ene-
3-carboxylic Acid Ethyl Ester (5ek)
Mp 178–180 °C.
IR (KBr): 3190, 1740, 1720, 1690 cm–1.
1H NMR: d = 7.96 (d, J = 8.2 Hz, 2 H, Ar), 7.71 (br s, 1 H, NH),
7.27 (d, J = 8.2 Hz, 2 H, Ar), 4.24 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 4.08 (s, 2 H, ArCH2C=C), 3.91 (s, 3 H, OCH3), 1.90–
1.20 (m, 10 H), 1.23 (t, J = 7.1 Hz, 3 H, CO2CH2CH3).
13C NMR: d = 171.6, 168.1, 166.8, 162.8 (C=O + C-4), 141.8,
129.9, 128.7, 128.5, 126.1 (Ar + C-3), 64.7 (C-5), 61.1, 52.1, 34.2,
32.6, 24.6, 22.7, 14.0.
EI-MS: m/z (%) = 371 (42, [M+]), 326 (27, [M+ – EtOH]), 283
(100).
(14) Kang, S. K.; Kim, K. J.; Yu, C. M.; Hwang, J. W.; Do, Y. K.
Org. Lett. 2001, 3, 2851.
(15) Naitoh, R.; Nakamura, Y.; Katano, E.; Nakamura, Y.;
Okada, E.; Asaoka, M. Heterocycles 2004, 63, 1009.
(16) Bouillon, J. P.; Tinant, B.; Nuzillard, J. M.; Portella, C.
Synthesis 2004, 711.
(17) Pal, M.; Swamy, N. K.; Hameed, P. S.; Padakanti, S.;
Yeleswarapu, K. R. Tetrahedron 2004, 60, 3987.
(18) Tsolomiti, G.; Tsolomitis, A. Tetrahedron Lett. 2004, 45,
9353.
Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C,
68.12; H, 6.77; N, 3.77.
One-Pot Preparation of 3-Pyrrolin-2-ones 5a–l; 1-Benzyl-4-(3-
trifluoromethylbenzyl)-5,5-dimethyl-2-oxo-2,5-dihydro-1H-
pyrrole-3-carboxylic Acid Ethyl Ester (5aa);
Typical Procedure
To a solution of 1a (0. 200 g, 1.16 mmol) in DMF (1 mL) and Et3N
(3 mL) were added 3-iodobenzotrifluoride (0.200 mL, 1.38 mmol),
Pd(OAc)2 (0.06 g, 0.026 mmol) and PPh3 (0.014 g, 0.052 mmol).
The mixture was stirred under N2 at 50 °C for 6 h, then diluted with
aq 0.5 M NH4Cl (100 mL) and extracted with EtOAc (3 × 50 mL).
The organic layer was dried (Na2SO4) and evaporated. The residue
was dissolved in anhyd CH2Cl2 (5 mL), and cooled in an ice-bath.
2,6-Di-tert-butyl-4-methylpyridine (0.474 g, 2.31 mmol) and ethyl
malonyl chloride (0.292 mL, 2.31 mmol) were added. The mixture
was stirred under N2 at 0 °C for 1 h, then at r.t for 1 h, diluted with
aq 0.5 M Na2CO3 (50 mL) and extracted with CH2Cl2 (3 × 25 mL).
The organic layer was dried (Na2SO4) and evaporated. The residue
was dissolved in DMSO (2 mL) and K2CO3 (0.240 g, 1.74 mmol)
was added. The mixture was stirred at r.t. for 2 h, then diluted with
aq 0.5 M NH4Cl (100 mL) and extracted with EtOAc (3 × 50 mL).
The organic layer was dried (Na2SO4) and evaporated. Column
chromatographic purification on silica gel (hexane–EtOAc, 60:40)
afforded 5aa (0.374 g, 75%).
(19) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004, 69, 8952.
(20) Verniest, G.; Boterberg, S.; Bombeke, F.; Stevens, C. V.; De
Kimpe, N. Synlett 2004, 1059.
(21) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610.
(22) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett
1993, 65.
(23) Arcadi, A.; Marinelli, F.; Pini, E.; Rossi, E. Tetrahedron
Lett. 1996, 37, 3387.
(24) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P.
Synlett 1998, 446.
(25) Arcadi, A.; Inesi, A.; Marinelli, F.; Rossi, L.; Verdecchia, M.
Synlett 2005, 67.
(26) Sonogashira, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis. Palladium-Catalyzed
Alkynylation, Vol. 1; Negishi, E.; de Meijere, A., Eds.;
Wiley: New York, 2002, 493–529.
(27) For example, when the amide 3a obtained from the reaction
of 1a with ethyl malonyl chloride was reacted with 3-iodo-
benzotrifluoride in Et3N–DMF at 50 °C for 5 h, in the
presence of PdCl2(PPh3)2, 4aa was obtained in 42% yield.
(28) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. J. Org.
Chem. 1994, 59, 2282.
(29) (a) Geri, R.; Polizzi, C.; Lardicci, L.; Caporusso, A. M.
Gazz. Chim. Ital. 1994, 124, 241. (b) Caporusso, A. M.;
Geri, R.; Polizzi, C.; Lardicci, L. Tetrahedron Lett. 1991, 32,
7471.
Acknowledgment
The Ministero dell’Università e della Ricerca Scientifica e Tecno-
logica, Rome, and the University of L’Aquila are gratefully ac-
knowledged.
References
(30) PdCl2 (PPh3)2 can be used as catalyst with similar results.
(31) Carried out using piperidine in place of Et3N, with 0.04
equiv of Cul.
(1) Ikeguky, S. M.; Sawaki, M.; Yoshii, H.; Maeda, K.;
Morishima, Y. J. Pestic. Sci. 2000, 25, 107.
Synthesis 2006, No. 12, 2019–2030 © Thieme Stuttgart · New York