Studies on pyrrolidinones. Reaction of pyroglutamic acid and vinylogues with aromatics in Eaton's reagent

Article abstract of DOI:10.1016/j.tet.2011.11.080

The optimization of the synthesis of 5-aryl-2-pyrrolidinones through decarbonylation of pyroglutamic acid in Eaton's reagent, in presence of aromatic derivatives, is described. The utilization of these reaction conditions in the arylation of enaminoester vinylogues (17, 24) of pyroglutamic acid was also realized, confirming that these derivatives are subject to decarbonylation? in the same way as the parent acid. Depending on the nature of the aromatic derivative (15, 21, 28, and 32), two different families of compounds were obtained. Many by-products were also formed, suggesting a utilization of this reaction for compounds more stable than the enaminoesters and enaminonitriles used in this study. The possibility of enaminoesters reacting with aromatics in bimolecular reactions to give enaminoketones should also be noted. Five synthesized compounds were evaluated for their antiproliferative activity on the NCI-60 cancer cell lines panel.

Full text of DOI:10.1016/j.tet.2011.11.080

Tetrahedron 68 (2012) 1109e1116
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on pyrrolidinones. Reaction of pyroglutamic acid and vinylogues with
aromatics in Eaton’s reagent
,
b
, ,
,
c
,
,
,
Alina Ghinet a
y, Nathalie Van Hijfte b y, Philippe Gautret a b, Benoît Rigo a b, Hassan Oulyadi d,
*
Jolanta Rousseau a
,
b
a Univ Lille Nord de France, F-59000 Lille, France
b UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France
c
ꢀ
URCOM, EA 3221, INC3M, FR-CNRS 3038, UFR des Sciences et Techniques de l’Universite du Havre, 25 rue Philippe Lebon, F-76058 Le Havre, France
IRCOF-UMR 6014 CNRS, INC3M, FR-CNRS 3038, Place Emile Blondel, Universite de Rouen, F-76131 Mt-St-Aignan Cedex, France
d
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2011
Received in revised form 21 November 2011
Accepted 24 November 2011
Available online 7 December 2011
The optimization of the synthesis of 5-aryl-2-pyrrolidinones through decarbonylation of pyroglutamic acid
in Eaton’s reagent, in presence of aromatic derivatives, is described. The utilization of these reaction con-
ditions in the arylation of enaminoester vinylogues (17, 24) of pyroglutamic acid was also realized, con-
firming that these derivatives are subject to decarbonylationî in the same wayas the parent acid. Depending
on the nature of the aromatic derivative (15, 21, 28, and 32), two different families of compounds were
obtained. Many by-products were also formed, suggesting a utilization of this reaction for compounds more
stable than the enaminoesters and enaminonitriles used in this study. The possibility of enaminoesters
reacting with aromatics in bimolecular reactions to give enaminoketones should also be noted. Five syn-
thesized compounds were evaluated for their antiproliferative activity on the NCI-60 cancer cell lines panel.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
anodic oxidation. This method leading to the N-acyliminium salt 2
was first described in 1979,13 and we later reported its use in the
The 2-pyrrolidinone ring system is common to many mole-
cules of great value in medicinal chemistry.1 In particular, 2-
pyrrolidinone-5-carboxylic acid (pyroglutamic acid, 1), which has
been called ‘the forgotten amino acid’2 is an essential biological
member of the ‘chiral pool’.3 In addition, N-acyliminium salts4 are
very important in organic synthesis since they are reactive in-
termediates involved in the preparation of many compounds with
interesting biological properties. Nucleophilic addition to N-acyli-
minium salts has been used as a key method for the synthesis of
synthesis of new heterocycles.14 We also showed that enami-
noesters issued from pyroglutamic acid (1), in which the lactamic
carbonyl group is exchanged with an isosteric enaminoester func-
tionality, contain an NeCeCO2H group, displaying similar behavior
under anodic oxidation conditions. Indeed, decarboxylation leads
to the formation of vinylogues of N-acyliminium salts, which either
can add (silyl)nucleophiles15 or evolve into pyrroles.16
Interestingly, we also observed the formation of an N-acylimi-
nium salt 2, by decarbonylation (elimination of carbon monoxide) of
pyroglutamic acid derivatives in presence of Eaton’s reagent17 or
polyphosphoric acid (Scheme 1) (or the corresponding acid chloride
with Lewis acids3e,18e20), which is able to react in situ with aromatics
to give 5-aryl-2-pyrrolidinones 3 (Scheme 2).18 This method of
obtention of the N-acyliminium salt 2 was extended to the use of
triflic anhydride as a promoting reagent,21 and was applied to the
synthesis of agonists of sphingosine-1-phosphate receptors.22
In the present paper, we describe the results in optimization of
the synthesis of 5-aryl-2-pyrrolidinones through decarbonylation
of pyroglutamic acid in Eaton’s reagent, in the presence of aromatic
derivatives. We also studied, because of our interest in these
compounds as starting building blocks in heterocyclic synthesis,23
particularly in the field of DNA ligands,24 the utilization of these
reaction conditions in the arylation of enaminoester vinylogues of
pyroglutamic acid.
a
-functionalized amino compounds and many biologically active
nitrogen heterocycles.5,6 Manyclasses of nucleophiles can react with
N-acyliminium ions, including allylsilanes,7 TMSCN,8 isonitriles,9
organotrifluoroborates,5 enol derivatives,10 and aromatics.11
12c
Diacetoxyiodobenzene/I2,12a,d CAN12b or NaIO4
are able to
decarboxylate pyroglutamic acid (1) or its derivatives to the N-
acyliminium salt intermediate 2, which can be further transformed,
for example, into a 5-allyl-2-pyrrolidone, 5-hydroxy-2-pyrrolidone,
5-methoxy-2-pyrrolinone or maleimide. Decarboxylation (elimi-
nation of carbon dioxide) of pyroglutamic acid (1) is also possible by
* Corresponding author. Tel.: þ33 328384858; e-mail address: alina.ghinet@
hei.fr (A. Ghinet).
y
Both authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.080

1110
A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
Scheme 1. Syntheses of N-acyliminium salts from pyroglutamic acid (1).
P2O5/MeSO3H
R
CO
+
+
R
O
CO2H
O
O
N
H
N
H
N
H
+
60°C
1
2
3
O
S
P2O5/MeSO3H
60°C
S
S
N
+
CO2H
O
N
H
O
N
H
N
H
N
H
O
1
4
5
6
Scheme 2. Reactions of pyroglutamic acid (1) with aromatic derivatives in Eaton’s reagent.
2. Results and discussion
disappointing, as treatment with 1,2,3-trimethoxybenzene (15)
gave a very complex mixture from which the aryl product 16 could
not be isolated (Scheme 3).
2.1. Synthesis of 5-aryl-2-pyrrolidinones
The presence of the Meldrum’s group in 14 might explain the
poor result as it is a rather unstable group under acidic condi-
tions.27 We thus decided to study the reactivity of the cyanoena-
minoester derivative 1726 in Eaton’s reagent. However, the desired
compound resulting from decarbonylation of acid 17 was not ob-
tained, and enaminoketone 18 was isolated in 51% yield (Scheme 4).
Interestingly, the acid group was esterified by the methanol formed
during the acylation reaction (nb: proof that the methyl group or-
igin was not the contamination of acid 17 by the corresponding
methyl ester is provided in the next section: see Scheme 5).
Intramolecular reactions of N-arylaminoesters are well docu-
mented, often in Eaton’s reagent,28 but to the best of our knowledge
the analogue bimolecular reaction had yet to be described.
Two other products were isolated from this reaction; methyl-
sulfonate ester 19 obtained in 7% yield, issued from acid deme-
thylation29 of trimethoxybenzene (15), then reaction of the 1,3-
dimethoxyphenol obtained with methanesulfonic anhydride
present in Eaton’s reagent.17b Sulfone 20, previously obtained using
a P2O5/H3PO4/H2SO4 mixture,30 was also isolated as a by-product in
2% yield (Scheme 4).
Acid 17 was also reacted with N-methylbenzoxazolone (21) and
aryl enaminoester 22 was isolated in 38% yield, confirming that
Eaton’s reagent promoted decarbonylation of pyroglutamic acid
vinylogues. Again, esterification of the acid group of 17 occurred,
and methyl ester 23 was isolated in 24% yield. In order to rule out
contamination of the starting 17 acid by some undetected initial
methyl ester, methyl ester 2723a,31 was saponified to acid 24 as
described for compound 17,26 and then 25 was subjected to re-
action in Eaton’s reagent (Scheme 5). Amides32 25 and 26 were
obtained in yields similar to those of 22 and 23, confirming that the
acid functionality was esterified by the EtOH/MeOH group of the
Eaton’s reagent17a is prepared as a 1:10 solution by weight of
phosphorus pentoxide in methanesulfonic acid. Organic com-
pounds often dissolve rapidly17c in this mobile liquid, and the so-
lutions obtained are easily stirred. This condensing agent is often
more efficient than PPA, and is rapidly hydrolyzed at the end of the
reaction. According to Eaton,17a methanesulfonic anhydride is
formed in this mixture, but other species are also present, such as
PPA and mixed anhydrides of PPA and MeSO3H.17b In some reactions,
P2O5 is mainly used as a drying agent.17b Indeed, methanesulfonic
acid is a hygroscopic liquid containing 0.5% water and, in the case of
our study of the synthesis of 5-aryl-2-pyrrolidinones 3 (Scheme 2), it
was observed that old bottles of MeSO3H often lead to poor results.
Previously18 a 1/7 ratio of pyroglutamic acid versus Eaton’s reagent
was utilized at temperatures between 65 ꢀC and 100 ꢀC. These
conditions were optimized to a 1/4 ratio at 60 ꢀC without lowering
yield. The results obtained are described in Table 1. This preparative
synthetic method gave average yields of products 3, but is more
efficient than the other syntheses of 5-aryl-2-pyrrolidones de-
scribed,25 as it is much faster, with fewer steps for comparable global
yields. In contrast, acid sensitive indole leads to the formation of
a complex and inseparable mixture (Table 1, entry 7), and amino
heterocycle phenothiazine 4 was acylated by pyroglutamic acid
yielding 55% of amide 5 along with side-product 6 (3%) (Scheme 2).
2.2. Reactions of vinylogues of pyroglutamic acid
Under the same optimized decarbonylation/arylation conditions
established for pyroglutamic acid (1), we investigated the reactivity
of vinylogues. The first enaminoester considered was the acid 14,26
derived from Meldrum’s acid. However, the results were rather

A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
1111
Table 1
enaminoester of the scaffold and that the nature of the ester moiety
has no influence on the mechanism pathway.
Synthesis of 5-aryl-2-pyrrolidinonesa
Reaction of N-ethylcarbazole (28) with the acid 24 in Eaton’s
reagent, similarly, gave identical results to those previous
(Scheme 6): ketone 29 was isolated in 40% yield, accompanied by
20% ethyl ester 30, and 9% amide 26 issuing from hydrolysis of the
nitrile group of 30. The methyl ketone 31 was also obtained in 1%
yield. This surprising product is thought to come from acylation of
28, promoted by methanesulfonic acid traces, during ethyl acetate
chromatographic purification of the reaction mixture.
Entry
Product
t (h)
Yield (%)
53
O
O
1
24
O
N
H
O
7
Subsequently, acid 24 was reacted with 1,2,3-trimethylbenzene
(32) (Scheme 7), and the expected aryl enaminoester 33 was iso-
lated in 21% yield, accompanied, respectively, by amides 34 (12%)
and 26 (15%), by 13% of diaryl product 35, and also by 2% enami-
noester 36, produced by hydrolysis and then decarboxylation of
nitrile 33. It is noteworthy that, 3% of methylsulphone 37 was
formed, again underlining the chemical reactivity of Eaton’s reagent.
Spectral investigation of compound 34 allowed determination
of the exact geometry, using NMR at 600 MHz. A correlation be-
tween the methylene group of the ethyl ester and the methylene of
the pyrrolidine ring was also visualized (Scheme 8), corresponding
to a stronger intramolecular hydrogen bond formed between the
pyrrolidine nitrogen and the carbonyl of the amide moiety versus
that of the ester group, thus leading to preferential formation of the
corresponding isomer (Scheme 8).
2
3
O
24
24
61
63
N
H
8
O
N
H
N
9
O
O
4
43
52
O
N
N
H
10
It is interesting to note that the chemical shift of the proton in
position 5 of the compounds synthesized in this study was char-
acteristic, facilitating deduction of the structures of the resulting
products: when an ester group is placed in this position (18, 23, 26,
27, 30), the chemical shift of the angular proton was between 4.47
and 4.67 ppm, while aryl groups in this position (22, 25, 33, 34, 35,
and 36) result in a downfield shift, leading to values between 5.06
and 5.42 ppm (Table 2).
S
O
O
N
H
5
6
24
24
0b
N
H
11
S
N
H
60
N
2.3. Reaction mechanism
12
Although we have not carried out any mechanistic study, we
suggest that the different reactivities observed during the reaction
of the pyroglutamic acid vinylogues (17 and 24) with aromatic
derivatives (15, 21, 28, and 32), could be due to a competition be-
tween two reactions: Eaton’s reagent lead to a rapid and reversible
protonation of the carbonyl group of the ester. This is followed by
the attack of a reactive aromatic residue (15 or 28) that rapidly
leads to acid 39, and after esterification, to a ketoester (18 or 29).
When the aromatic moiety is less reactive, this ketone formation
doesn’t take place; a slow decarbonylation corresponding to the
7
19
dc
O
N
H
N
H
13
a
Reactions carried out at 60 ꢀC.
Amide 5 (Scheme 2) was isolated in 55% yield.
Inseparable mixture.
b
c
OMe
O
O
OMe
OMe
OMe
OMe
OMe
(i)
O
O
+
CO2H
N
N
H
H
O
O
O
O
14
15
16
Scheme 3. Reagents and conditions: (i) 1,2,3-trimethoxybenzene (15) 1 equiv, Eaton’s reagent 4 equiv, 60 ꢀC, 7 h.
OMe
O O
NC
OMe
OMe
O
OMe
OMe
S
NC
N
H
OSO2Me
OMe
OMe
OMe
(i)
+
+
+
CO2H
O
N
H
O
MeO
OMe
MeO2C
MeO
MeO
OMe
OMe
17
15
18 51%
19 7%
20 2%
Scheme 4. Reagents and conditions: (i) 1,2,3-trimethoxybenzene (15) 1.15 equiv, Eaton’s reagent 4 equiv, 60 ꢀC, 24 h.

1112
A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
O
NC
O
N
NC
R'
R'
(ii)
(i)
O
CO2Me
CO2H
+
+
CO2R
O
N
H
N
H
N
H
N
H
N
RO2C
RO2C
RO2C
RO2C
23 R = Me
27 R = Et
17 R = Me
24 R = Et
21
22 R = Me, R' = CN 38%
25 R = Et, R' = CONH2 33%
23 R = Me, R' = CN 24%
26 R = Et, R' = CONH2 27%
Scheme 5. Reagents and conditions: (i) NaOH, rt, 1 h; (ii) N-methylbenzoxazolone (21) 1.15 equiv, Eaton’s reagent 4 equiv, 60 ꢀC, 24 h.
NC
NC
NC
+
+
+
CO2H
CO2Et
CO2Et
N
H
N
H
N
H
EtO2C
EtO2C
N
Et
O
N
Et
24
28
29 40%
30 20%
O
EtO2C
H2N
CO2Et
+
N
H
N
O
Et
31 1%
26 9%
Scheme 6. Reagents and conditions: (i) N-ethylcarbazole (28) 1.15 equiv, Eaton’s reagent 4 equiv, 60 ꢀC, 30 h.
Me
Me
Me
Me
Me
EtO2C
H2N
NC
+
N
H
N
H
EtO2C
Me
O
O
33 21%
34 12%
Me
Me
Me
Me
EtO2C
NC
NC
Me
Me
Eaton's reagent
+
CO2Et
Me
CO2H
+
+
N
H
N
H
N
H
60°C
24h
EtO2C
H2N
O
Me
24
32
26 15%
35 13%
Me
Me
SO2Me
Me
Me
Me
N
H
Me
EtO2C
Me
36 2%
37 3%
Scheme 7. Reagents and conditions: (i) 1,2,3-trimethylbenzene (32) 1.15 equiv, Eaton’s reagent 4 equiv, 60 ꢀC, 24 h.
irreversible formation of the iminium salt 38 (vinylogue of an N-
acyliminium salt) occurs, as in case of the pyroglutamic acid. This
step is followed by the condensation of the intermediate 38 with
the aromatic derivative (21 or 32) (Scheme 9).
O
O
H2N
O
N
H
N
H
Me
Me
H
O
N
Me
Me
O
O
Me
Me
H
3. Conclusion
different
protons
Minor form
Major form
3%
97%
In this paper, we have shown that enaminoesters, vinylogues of
pyroglutamic acid, are subject to decarbonylation in the same way
as the parent acid, for which this condensation was optimized.
However, many by-products are also formed, suggesting utilization
of this reaction with compounds, more stable than the enami-
noesters and enaminonitriles used in this study. The possibility of
enaminoesters reacting with aromatics in bimolecular reactions to
give enaminoketones also should be noted.
Scheme 8. Structure elucidation of pyrrolidine 34.
Table 2
Chemical shift comparison of the angular hydrogen of some synthesized compounds
H
H
O
R
R
O
Compounds 5, 12, 18, 22, and 29 were selected by NCI (National
Cancer Institution, USA) for screening against 60 human tumor cell
lines. Molecule 18 showed very modest cell growth inhibition at
R'
Ar
N
H
N
H
z
z
O
O
a 10
mM concentration (only 34% inhibition of renal cancer line
Compound 18
23
26
27
30
22
25
33
34
35
36
d
H (ppm) 4.67 4.58 4.47 4.60 4.54 5.06 5.07 5.29 5.22 5.42 5.12
A498, 40% of HL-60 (TB) and 48% of RPMI-8226 (leukemia)),
whereas all other tested compounds were inactive.

A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
1113
k1
R''
R''
NC
RO2C
NC
NC
OH
(slow reaction)
N
H
38
N
H
N
H
+
RO2C
RO2C
O
17 R = Me
24 R = Et
k2 (rapid reaction)
NC
NC
OH
OR
NC
RO
OH
R'
- ROH
ROH
(transesterification)
R'
N
H
N
H
N
O
O
H
O
O
O
O
39
H+
R'
Scheme 9. Proposed mechanistic pathways for the reaction of pyroglutamic acid vinylogous with aromatic derivatives in Eaton’s reagent.
4. Experimental section
4.1. General
98e100 ꢀC; Rf (EtOAc/n-heptane 5/5)¼0.14; 1H (CDCl3, 200 MHz)
d
(ppm) 1.90e2.06 (m, 1H, CH2CH2CH), 2.38e2.49 (m, 1H,
CH2CH2CH), 2.50e2.68 (m, 2H, CH2CH2CH), 3.86 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.99 (t, J¼6.3 Hz, 1H, CH2CH2CH),
5.83 (s, 1H, NH), 6.66 (d, J¼8.6 Hz, 1H, ArH), 6.95 (d, J¼8.6 Hz, 1H,
Starting materials are commercially available. Melting points
were measured on an MPA 100 OptiMeltÒ apparatus and are un-
corrected. NMR spectra were acquired at 200 MHz for 1H NMR and
50 MHz for 13C NMR on a Varian Gemini 2000Ò spectrometer, or at
400 MHz for 1H NMR and 100 MHz for 13C NMR on a Varian
ArH). 13C NMR (CDCl3, 50 MHz)
d 27.5 (CH2), 33.0 (CH2), 48.0 (CH),
56.6 (CH3), 60.3 (CH3), 60.9 (CH3), 107.0 (CH), 115.2 (C), 119.8 (CH),
142.9 (C), 149.6 (C), 153.6 (C), 182.2 (C). IR
n
cmꢁ1: 1088, 1261, 1273,
1420, 1448, 1460, 1492, 1681, 3185. Found: C, 61.75; H, 6.76; N, 5.41.
Calcd for C13H17O4N: C, 62.14; H, 6.82; N, 5.57%.
400 MHz Premium ShieldedÒ spectrometer. Chemical shifts (
d) are
expressed in parts per million relative to TMS as internal standard.
Thin layer chromatography (TLC) was realized on Macherey Nagel
silica gel plates with fluorescent indicator and was visualized under
a UV-lamp at 254 nm and 366 nm. Column chromatography was
performed on silica gel (40e60 mm; MachereyeNagel). IR spectra
were recorded on a Varian 640eIR FT-IR Spectrometer. Elemental
analysis (C, H, N, S) of new compounds was determined by ‘Service
4.2.2. 5-(2,3,4-Trimethylphenyl)pyrrolidin-2-one (8). The general
procedure was followed using pyroglutamic acid
1 (1.00 g,
7.75 mmol), 1,2,3-trimethylbenzene (32) (1.15 mL, 8.52 mmol), and
Eaton’s reagent (0.36 g P2O5 in 2.50 mL CH3SO3H). The mixture was
heated at 60 ꢀC for 24 h. The final solid was recrystallized from
diethyl ether to give pure pyrrolidinone 8 (61%) as a white solid; mp
de Microanalyses’, Faculte de Sciences Mirande, Universite de
(Et2O) 110e111 ꢀC; 1H (CDCl3, 400 MHz)
d (ppm) 1.83e1.90 (m, 1H,
ꢀ
ꢀ
Bourgogne, Dijon, France.
CH2CH2CH), 2.21 (s, 3H, ArCH3), 2.24 (s, 3H, ArCH3), 2.29 (s, 3H,
ArCH3), 2.32e2.46 (m, 2H, CH2CH2CH), 2.57e2.64 (m, 1H,
CH2CH2CH), 5.02 (dd, J¼8.0, 6.0 Hz,1H, CH2CH2CH), 6.02 (s, 1H, NH),
7.04 (d, J¼8.0 Hz, 1H, ArH), 7.09 (d, J¼8.0 Hz, 1H, ArH). 13C NMR
4.2. General procedure for FriedeleCrafts reactions in the
presence of Eaton’s reagent
(CDCl3, 100 MHz)
d 15.1 (CH3), 15.8 (2CH3), 20.8 (CH2), 29.9 (CH2),
55.0 (CH), 121.1 (CH), 127.7 (CH), 132.8 (C), 135.8 (C), 135.9 (C), 138.0
Eaton’s reagent was prepared from phosphorus pentoxide
(P2O5) and methanesulfonic acid (CH3SO3H) (weight ratio P2O5/
CH3SO3H 1:10). The mixture was heated at 40 ꢀC under nitrogen
atmosphere until complete homogeneity. Carboxylic acid
(1.0 equiv) and aromatic derivative (1.1e1.5 equiv) were then added
to Eaton’s reagent. The mixture was heated at 60 ꢀC under inert
atmosphere for 7e43 h. After cooling to room temperature, the
reaction medium was diluted with dichloromethane and carefully
poured into a separatory funnel containing sodium bicarbonate
aqueous solution (50% NaHCO3). The aqueous solution was
extracted with dichloromethane, and the combined organic layers
were dried (MgSO4). Solvent was removed under reduced pressure
to give a brownish oil. The crude product was purified by column
chromatography on silica gel or recrystallized to provide pure
compounds.
(C), 178.5 (C). IR
n
cmꢁ1: 559, 796, 1025, 1126, 1247, 1275, 1511, 1574,
1683, 1731, 2941. Found: C, 76.38; H, 8.32; N, 7.27. Calcd for
C13H17ON: C, 76.81; H, 8.43; N, 6.89%.
4.2.3. 3-Methyl-6-(5-oxopyrrolidin-2-yl)-1,3-benzoxazol-2(3H)-one
(9). The general procedure was followed using pyroglutamic acid 1
(1.00 g, 7.75 mmol), 3-methylbenzoxazol-2-one 21 (1.27 g,
8.52 mmol), and Eaton’s reagent (0.36 g P2O5 in 2.5 mL CH3SO3H).
The mixture was heated at 60 ꢀC for 24 h. The final solid was
recrystallized from H2O to give pure pyrrolidinone 9 (63%) as
a white solid; mp (H2O) 168e170 ꢀC (lit. 166 ꢀC);16 Rf (dichloro-
methane/methanol 95/5)¼0.24; 1H (CDCl3, 400 MHz)
d (ppm)
1.91e2.01 (m, 1H, CH2CH2CH), 2.38e2.55 (m, 2H, CH2CH2CH),
2.56e2.65 (m, 1H, CH2CH2CH), 3.41 (s, 3H, NCH3), 4.78 (t, J¼7.1 Hz,
1H, CH2CH2CH), 5.92 (s, 1H, NH), 6.94 (d, J¼7.8 Hz, 1H, ArH), 7.15
(dd, J¼7.8, 1.6 Hz, 1H, ArH), 7.17 (d, J¼1.6 Hz, 1H, ArH). Found: C,
62.34; H, 5.14; N, 12.31. Calcd for C12H12O3N2: C, 62.06; H, 5.21; N,
12.06%.
4.2.1. 5-(2,3,4-Trimethoxyphenyl)pyrrolidin-2-one (7). The general
procedure was followed using pyroglutamic acid
1 (2.00 g,
15.5 mmol), 1,2,3-trimethoxybenzene (15) (2.87 g, 17.0 mmol), and
Eaton’s reagent (0.73 g P2O5 in 4.91 mL CH3SO3H). The mixture was
heated at 60 ꢀC for 24 h. The final brown oil was purified by column
chromatography on silica gel with EtOAc/n-heptane 5/5 to give
pure pyrrolidinone 7 (53%) as an off-white solid; mp (EtOAc)
4.2.4. 5-(9-Ethyl-9H-carbazol-3-yl)pyrrolidin-2-one (10). The gen-
eral procedure was followed using pyroglutamic acid 1 (4.00 g,
30.97 mmol), N-ethylcarbazole (28) (4.03 g, 20.65 mmol), and

1114
A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
Eaton’s reagent (1.45 g P2O5 in 9.82 mL CH3SO3H). The mixture was
heated at 60 ꢀC for 43 h. The final brown oil was purified by column
chromatography on silica gel with a gradient EtOAc/n-heptane from
25/75 to 100/0 and recrystallized from Et2O to give pure pyrroli-
dinone 10 (52%) as a beige solid; mp (Et2O) 126e128 ꢀC; Rf
9.06; S, 10.68. Calcd for C18H18N2OS 1/5H2O: C, 68.85; H, 5.91; N,
8.92; S, 10.21%.
4.2.8. Methyl
5-[1-cyano-2-oxo-2-(2,3,4-trimethoxyphenyl)ethyl-
idene]prolinate (18). The general procedure was followed using
carboxylic acid 17 (4.00 g, 19.03 mmol), 1,2,3-trimethoxybenzene
(15) (3.68 g, 21.88 mmol), and Eaton’s reagent (1.45 g P2O5 in
9.82 mL CH3SO3H). The mixture was heated at 60 ꢀC for 24 h. The
final brown oil was purified by column chromatography on silica
gel with EtOAc/n-heptane 6/4 to give pure compound 18 (51%) as
a white solid; mp (EtOAc/n-heptane) 144e145 ꢀC; Rf (EtOAc/n-
(EtOAc)¼0.22; 1H (CDCl3, 400 MHz)
d
(ppm) 1.43 (t, J¼7.1 Hz, 3H,
CH2CH3), 2.05e2.15 (m, 1H, CH2CH2CH), 2.44e2.70 (m, 3H,
CH2CH2CH), 4.37 (q, J¼14.2 Hz, 2H, CH2CH3), 4.95 (t, J¼7.2 Hz, 1H,
CH2CH2CH), 5.80 (s, 1H, NH), 7.25 (td, J¼7.1, 1.2 Hz, 1H, ArH),
7.39e7.52 (m, 4H, ArH), 8.03 (s, 1H, ArH), 8.09 (d, J¼7.8 Hz, 1H, ArH).
13C NMR (CDCl3, 100 MHz)
d 13.8 (CH3), 30.6 (CH2), 32.2 (CH2), 37.7
(CH2), 58.6 (CH), 108.6 (CH), 108.8 (CH), 117.6 (CH), 119.1 (CH), 120.5
(CH), 122.5 (C), 123.2 (C), 123.4 (CH), 126.0 (CH), 132.8 (C), 139.7 (C),
heptane 5/5)¼0.39; 1H (CDCl3, 200 MHz)
d (ppm) 2.21e2.61 (m, 2H,
CH2CH2CH), 2.94e3.26 (m, 2H, CH2CH2CH), 3.83 (s, 3H, OCH3), 3.88
(s, 6H, 2OCH3), 3.96 (s, 3H, OCH3), 4.67 (dd, J¼8.5, 5.7 Hz, 1H,
CH2CH2CH), 6.68 (d, J¼8.5 Hz, 1H, ArH), 7.12 (d, J¼8.5 Hz, 1H, ArH),
140.4 (C), 178.2 (C). IR
n
cmꢁ1: 1232, 1331, 1349, 1471, 1686, 1726,
3192. Found: C, 76.30; H, 7.39; N, 8.48. Calcd for C18H18N2O ½ Et2O:
C, 76.30; H, 7.39; N, 8.48%.
10.80 (large s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
d 24.6 (CH2), 33.1
(CH2), 53.0 (CH3), 56.0 (CH), 61.0 (CH3), 62.0 (CH3), 62.8 (CH3), 81.4
(C), 106.5 (CH), 119.8 (C), 123.3 (CH), 126.8 (C), 141.9 (C), 151.5 (C),
4.2.5. 5-(10H-Phenothiazin-10-ylcarbonyl)pyrrolidin-2-one (5). The
general procedure was followed using pyroglutamic acid 1 (2.24 g,
17.34 mmol), phenothiazine 4 (3.00 g, 15.05 mmol), and Eaton’s
reagent (0.81 g P2O5 in 5.49 mL CH3SO3H). The mixture was heated
at 60 ꢀC for 24 h. The final brown oil was purified by column
chromatography on silica gel with a gradient EtOAc/n-heptane from
50/50 to 100/0 to give pure pyrrolidinone 5 (55%) as a beige solid;
mp (EtOAc/n-heptane) 188e190 ꢀC; Rf (EtOAc/cyclohexane 6/4)¼
155.6 (C), 170.4 (C), 174.4 (C), 190.9 (C). IR n
cmꢁ1: 1208, 1438, 1536,
1590, 1745, 2208, 3266. Found: C, 59.61; H, 5.68; N, 7.69. Calcd for
C18H20N2O6: C, 59.99; H, 5.59; N, 7.77%.
4.2.9. 2,6-Dimethoxyphenyl methanesulfonate (19). By-product
from the synthesis of compound 18; white solid; 7% yield; mp
(Et2O) 99e101 ꢀC; Rf (EtOAc/cyclohexane 6/4)¼0.76; 1H (CDCl3,
0.12; 1H (CDCl3, 400 MHz)
d
(ppm) 1.76e1.90 (m, 1H, CH2CH2CH),
400 MHz) d (ppm) 3.30 (s, 3H, SO2CH3), 3.89 (s, 6H, 2OCH3), 6.62 (d,
1.99e2.12 (m, 1H, CH2CH2CH), 2.15e2.25 (m, 1H, CH2CH2CH),
2.29e2.40 (m, 1H, CH2CH2CH), 4.77 (m, 1H, CH2CH2CH), 5.78 (large
s, 1H, NH), 7.24e7.33 (m, 4H, ArH), 7.45e7.52 (m, 3H, ArH), 7.57 (d,
J¼8.6 Hz, 2H, ArH), 7.17 (t, J¼8.5 Hz, 1H, ArH). 13C NMR (CDCl3,
100 MHz)
(C), 153.4 (2C). IR
d 39.9 (CH3), 56.3 (2CH3), 105.1 (2CH), 127.5 (CH), 128.3
n
cmꢁ1: 1109, 1264, 1364, 1448, 1481, 1605. Found:
J¼8.1 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz)
d
25.1 (CH2), 29.1
C, 48.57; H, 5.85. Calcd for C9H12O5S 1/3 Et2O: C, 48.30; H, 6.01%.
(CH2), 54.3 (CH), 126.5 (CH), 127.2 (2CH), 127.3 (CH), 127.6 (CH),
127.7 (CH), 128.1 (CH), 128.5 (CH), 137.5 (2C), 138.0 (2C), 171.1 (C),
4.2.10. 1,2,3-Trimethoxy-4-[(2,3,4-trimethoxyphenyl)sulfonyl]ben-
zene (20). By-product from the synthesis of compound 18; white
solid with the same physical properties as described in the lit.;30 2%
yield; mp (Et2O) 150e151 ꢀC (lit. 152e153 ꢀC);30 Rf (EtOAc/cyclo-
177.7 (C). IR
n
cmꢁ1: 1252, 1459, 1678, 3260. LC/MS (APCIþ) m/z
311.0 (MHþ). Found: C, 65.41; H, 4.31; N, 9.29. Calcd for
C17H14N2O2S: C, 65.79; H, 4.55; N, 9.03%.
hexane 6/4)¼0.66; 1H (CDCl3, 400 MHz)
d (ppm) 3.64 (s, 6H,
2OCH3), 3.79 (s, 6H, 2OCH3), 3.93 (s, 6H, 2OCH3), 6.80 (d, J¼9.0 Hz,
4.2.6. 1-(10H-phenothiazin-3-yl)ethanone (6). By-product from the
synthesis of compound 5; beige solid with the same physical
properties as described in the lit.;33 3% yield; mp (EtOAc/n-hep-
tane) 186e188 ꢀC (lit. 178e179 ꢀC,33a 188e189 ꢀC,33b
2H, ArH), 7.89 (d, J¼9.0 Hz, 2H, ArH). 13C NMR (CDCl3, 100 MHz)
d
56.2 (2CH3), 60.9 (2CH3), 61.1 (2CH3), 106.2 (2CH), 125.4 (2CH),
127.9 (2C), 142.4 (2C), 151.8 (2C), 158.1 (2C). IR
n
cmꢁ1: 1086, 1288,
192e193 ꢀC33c); 1H (CDCl3, 400 MHz)
d
(ppm) 3.00 (s, 3H,
1411, 1484, 1574. LC/MS (APCIþ) m/z 399.1 (MHþ). Found: C, 54.10;
COCH3), 6.06 (s, 1H, NH), 6.55 (dd, J¼7.8, 1.2 Hz, 1H, ArH), 6.58 (d,
J¼8.2 Hz, 1H, ArH), 6.88 (td, J¼7.4, 1.2 Hz, 1H, ArH), 6.95 (dd, J¼7.8,
1.6 Hz, 1H, ArH), 7.02 (td, J¼7.4, 1.6 Hz, 1H, ArH), 7.47 (d, J¼2.0 Hz,
1H, ArH), 7.51 (dd, J¼8.2, 2.0 Hz, 1H, ArH). 13C NMR (CDCl3,
H, 5.57. Calcd for C18H22O8S: C, 54.26; H, 5.57%.
4.2.11. Methyl (2Z)-cyano[5-(3-methyl-2-oxo-2,3-dihydro-1,3-
benzoxazol-6-yl)pyrrolidin-2-ylidene]acetate (22). The general pro-
cedure was followed using carboxylic acid 17 (7.00 g, 33.30 mmol),
N-methylbenzoxazolone 21 (4.32 g, 28.96 mmol), and Eaton’s re-
agent (2.54 g P2O5 in 17.19 mL CH3SO3H). The mixture was heated at
60 ꢀC for 24 h. The final brown oil was purified by column chro-
matography on silica gel with a gradient EtOAc/n-heptane from 50/
50 to 100/0 to give pure pyrrolidine 22 (38%) as a beige solid; mp
(EtOAc) 172e175 ꢀC; Rf (EtOAc/cyclohexane 6/4)¼0.31; 1H (CDCl3,
100 MHz)
d 44.8 (CH3), 113.9 (CH), 114.9 (CH), 117.2 (C), 119.8 (C),
124.0 (CH), 126.0 (CH), 126.9 (CH), 127.3 (CH), 127.9 (CH), 133.9 (C),
139.4 (C), 146.2 (C), 189.0 (C). LC/MS (APCIþ) m/z 242.0 (MHþ).
4.2.7. 5-(10-Ethyl-10H-phenothiazin-3-yl)pyrrolidin-2-one
(12). The general procedure was followed using pyroglutamic acid
1 (2.00 g, 15.49 mmol), N-ethylphenothiazine (3.20 g, 14.08 mmol),
and Eaton’s reagent (0.73 g P2O5 in 4.91 mL CH3SO3H). The mixture
was heated at 60 ꢀC for 24 h. The final brown oil was purified by
column chromatography on silica gel with a gradient EtOAc/n-
heptane from 35/65 to 100/0 to give pure pyrrolidinone 12 (60%) as
a white solid; mp (EtOAc/n-heptane) 195e198 ꢀC; Rf (EtOAc/
400 MHz) d (ppm) 1.94e2.05 (m, 1H, CH2CH2CH), 2.56e2.66 (m, 1H,
CH2CH2CH), 2.97e3.08 (m, 1H, CH2CH2CH), 3.11e3.20 (m, 1H,
CH2CH2CH), 3.42 (s, 3H, NCH3), 3.78 (s, 3H, CO2CH3), 5.06 (t,
J¼7.5 Hz,1H, CH2CH2CH), 6.95 (d, J¼8.0 Hz,1H, ArH), 7.08 (dd, J¼8.0,
1.8 Hz, 1H, ArH), 7.11 (d, J¼1.8 Hz, 1H, ArH), 9.15 (large s, 1H, NH). 13C
cyclohexane)¼0.26; 1H (CDCl3, 400 MHz)
d
(ppm) 1.41 (t, J¼7.0 Hz,
NMR (CDCl3, 100 MHz) d 28.3 (CH2), 31.6 (CH3), 33.0 (CH2), 51.7
3H, CH2CH3), 1.89e1.99 (m, 1H, CH2CH2CH), 2.35e2.57 (m, 3H,
CH2CH2CH), 3.92 (q, J¼7.0 Hz, 2H, CH2CH3), 4.64 (m,1H, CH2CH2CH),
5.62 (s, 1H, NH), 6.80e6.95 (m, 3H, ArH), 7.05 (d, J¼1.6 Hz, 2H, ArH),
(CH3), 65.0 (CH), 68.2 (C), 107.7 (CH), 108.3 (CH), 118.2 (C), 121.5
(CH), 132.0 (C), 135.1 (C), 143.1 (C), 154.6 (C), 168.2 (C), 173.3 (C). IR
n
cmꢁ1: 1242, 1444, 1565, 1628, 1680, 1746, 2207, 3289, 3514, 3597.
LC/MS (APCIþ) m/z 314.1 (MHþ). Found: C, 57.57; H, 5.11; N, 12.65.
Calcd for C16H15N3O4 1H2O: C, 58.00; H, 5.17; N, 12.68%.
7.12 (dd, J¼7.6, 1.6 Hz, 2H, ArH). 13C NMR (CDCl3, 100 MHz)
d 13.0
(CH3), 30.2 (CH2), 31.4 (CH2), 41.8 (CH2), 57.3 (CH), 115.1 (CH), 115.2
(CH), 122.5 (CH), 123.9 (C), 124.6 (CH), 124.7 (CH), 125.3 (C), 127.4
(CH), 127.5 (CH), 136.4 (C), 144.7 (C), 144.8 (C), 178.2 (C). IR
n
cmꢁ1
:
4.2.12. Methyl
5-(1-cyano-2-methoxy-2-oxoethylidene)prolinate
1233,1251,1325,1460,1600,1703, 3203. Found: C, 68.70; H, 6.40; N,
(23). By-product from the synthesis of compound 22; white solid

A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
1115
with the same physical properties as described in the lit.;23a 24%
CH2CH3), 7.27e7.57 (m, 4H, ArH), 8.10e8.15 (m, 2H, ArH), 8.76 (d,
yield; mp (AcOEt/n-heptane) 105e107 ꢀC; 1H (CDCl3, 200 MHz)
J¼1.8 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz)
d 13.8 (CH3), 26.7
d
(ppm) 2.20e2.41 (m, 1H, CH2CH2CH), 2.43e2.61 (m, 1H,
(CH3), 37.9 (CH2), 108.0 (CH), 109.0 (CH), 120.0 (CH), 120.7 (CH),
122.0 (CH), 122.7 (C), 123.3 (C), 126.5 (2CH), 128.8 (C), 140.7 (C),
CH2CH2CH), 2.96e3.08 (m, 2H, CH2CH2CH), 3.78 (s, 3H, CO2CH3),
3.80 (s, 3H, CO2CH3), 4.58 (dd, J¼8.6, 5.4 Hz, 1H, CH2CH2CH), 9.16
(large s, 1H, NH).
142.7 (C), 197.7 (C). IR
n
cmꢁ1: 1241, 1327, 1346, 1435, 1464, 1588,
1620, 1659. LC/MS (APCIþ) m/z 238.2 (MHþ). Found: C, 80.64; H,
6.69; N, 5.96. Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90%.
4.2.13. Ethyl 5-[2-amino-1-(ethoxycarbonyl)-2-oxoethylidene]proli-
nate (26). By-product from the syntheses of compounds 25, 29, and
33; white solid; 27%, 9%, and 15% yield, respectively, mp (EtOAc/n-
heptane) 148e150 ꢀC; Rf (EtOAc/cyclohexane 6/4)¼0.41; 1H (CDCl3,
4.2.17. Ethyl (2Z)-cyano[5-(2,3,4-trimethylphenyl)pyrrolidin-2-
ylidene]acetate (33). The general procedure was followed using
carboxylic acid 24 (1.50 g, 6.69 mmol), 1,2,3-trimethylbenzene (32)
(0.78 mL, 5.82 mmol), and Eaton’s reagent (0.55 g P2O5 in 3.68 mL
CH3SO3H). The mixture was heated at 60 ꢀC for 24 h. The final beige
oil was purified bycolumn chromatography on silica gel with EtOAc/
n-heptane 5/5 to give pure compound 33 (21%) as a white solid; Rf
400 MHz)
d
(ppm) 1.29 (t, J¼7.0 Hz, 3H, CO2CH2CH3), 1.31 (t,
J¼7.0 Hz, 3H, CO2CH2CH3), 2.12e2.22 (m, 1H, CH2CH2CH),
2.29e2.39 (m, 1H, CH2CH2CH), 3.17e3.30 (m, 2H, CH2CH2CH), 4.20
(q, J¼7.0 Hz, 2H, CO2CH2CH3), 4.22 (q, J¼7.0 Hz, 2H, CO2CH2CH3),
4.47 (dd, J¼9.1, 5.3 Hz, 1H, CH2CH2CH), 5.17 (large s, 1H, NH), 8.76
(large s, 1H, NH), 11.68 (large s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
(EtOAc/cyclohexane 6/4)¼0.55; 1H (CDCl3, 400 MHz)
d (ppm) 1.32 (t,
J¼7.2 Hz, 3H, CO2CH2CH3),1.80e1.89 (m,1H, CH2CH2CH), 2.16 (s, 3H,
ArCH3), 2.22 (s, 3H, ArCH3), 2.27 (s, 3H, ArCH3), 2.40e2.50 (m, 1H,
CH2CH2CH), 3.13e3.22 (m, 1H, CH2CH2CH), 3.37e3.47 (m, 1H,
CH2CH2CH), 4.21 (qd, J¼7.1, 1.2 Hz, 2H, CO2CH2CH3), 5.29 (dd, J¼7.2,
5.3 Hz, 1H, CH2CH2CH), 6.96 (d, J¼8.0 Hz, 1H, ArH), 7.00 (d, J¼8.0 Hz,
d
14.1 (CH3), 14.5 (CH3), 25.6 (CH2), 35.2 (CH2), 59.8 (CH2), 61.1 (CH),
61.8 (CH2), 87.8 (C),169.0 (C),171.2 (C),172.3 (C),174.3 (C). IR
n
cmꢁ1
:
1211, 1455, 1473, 1532, 1591, 1630, 1650, 1733, 3158, 3351. Found: C,
53.18; H, 6.61; N, 9.95. Calcd for C12H18N2O5: C, 53.33; H, 6.71; N,
10.36%.
1H, ArH), 11.60 (large s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
d 14.6
(CH3), 15.3 (CH3), 15.7 (CH3), 20.6 (CH3), 29.6 (CH2), 34.2 (CH2), 56.9
(C), 59.6 (CH2), 118.4 (C), 121.5 (C), 123.2 (C), 127.7 (C), 132.8 (CH),
135.8 (CH),135.9 (C),137.0 (C),162.5 (C),182.2 (C). LC/MS (APCIþ) m/z
299.1 (MHþ). Found: C, 72.82; H, 7.69; N, 9.70. Calcd for C18H22N2O2:
C, 72.46; H, 7.43; N, 9.39%.
4.2.14. Ethyl 5-[1-cyano-2-(9-ethyl-9H-carbazol-3-yl)-2-
oxoethylidene]prolinate (29). The general procedure was followed
using carboxylic acid 24 (2.00 g, 8.92 mmol), N-ethylcarbazole (28)
(1.16 g, 5.94 mmol), and Eaton’s reagent (0.73 g P2O5 in 4.91 mL
CH3SO3H). The mixture was heated at 60 ꢀC for 30 h. The final
brown oil was purified by column chromatography on silica gel
with a gradient EtOAc/n-heptane from 40/60 to 100/0 to give pure
compound 29 (40%) as a beige solid; Rf (EtOAc/cyclohexane 6/4)¼
4.2.18. Ethyl (2Z)-3-amino-3-oxo-2-[5-(2,3,4-trimethylphenyl)pyr-
rolidin-2-ylidene]propanoate (34). By-product from the synthesis of
compound 33; white solid; 12% yield; Rf (EtOAc/cyclohexane 6/4)¼
0.64; 1H (CDCl3, 400 MHz)
d
(ppm) 1.34 (t, J¼7.1 Hz, 3H,
0.48; 1H (CDCl3, 400 MHz)
d
(ppm) 1.31 (t, J¼7.0 Hz, 3H,
CO2CH2CH3), 1.46 (t, J¼7.0 Hz, 3H, CO2CH2CH3), 2.30e2.39 (m, 1H,
CH2CH2CH), 2.47e2.58 (m, 1H, CH2CH2CH), 3.09e3.28 (m, 2H,
CH2CH2CH), 4.29 (q, J¼7.0 Hz, 2H, CO2CH2CH3), 4.40 (q, J¼7.1 Hz, 2H,
CO2CH2CH3), 4.69 (dd, J¼8.6, 5.5 Hz, 1H, CH2CH2CH), 7.27e7.31 (m,
1H, ArH), 7.41e7.45 (m, 2H, ArH), 7.50 (td, J¼7.8, 1.2 Hz, 1H, ArH),
8.13 (dd, J¼8.6, 1.9 Hz, 1H, ArH), 8.16 (d, J¼7.8 Hz, 1H, ArH), 8.74 (d,
J¼1.6 Hz, 1H, ArH), 11.10 (large s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
CO2CH2CH3), 1.74e1.83 (m, 1H, CH2CH2CH), 2.21 (s, 3H, ArCH3), 2.25
(s, 3H, ArCH3), 2.28 (s, 3H, ArCH3), 2.47e2.56 (m, 1H, CH2CH2CH),
3.21e3.29 (m, 2H, CH2CH2CH), 4.21 (q, J¼14.1 Hz, 2H, CO2CH2CH3),
5.16 (large s, 1H, NH), 5.22 (dd, J¼8.3, 5.9 Hz, 1H, CH2CH2CH), 6.95
(d, J¼8.3 Hz, 1H, ArH), 7.00 (d, J¼8.3 Hz, 1H, ArH), 8.81 (large s, 1H,
NH), 11.67 (large s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
d 14.5 (CH3),
14.6 (CH3), 15.8 (CH3), 20.8 (CH3), 30.3 (CH2), 35.5 (CH2), 59.6 (CH2),
61.1 (CH), 121.4 (CH), 125.0 (C), 127.7 (CH), 132.8 (C), 135.8 (C), 135.9
(C), 137.4 (C), 169.4 (C), 172.7 (C), 174.6 (C). LC/MS (APCIþ) m/z 317.1
(MHþ). Found: C, 68.71; H, 7.80; N, 9.11. Calcd for C18H24N2O3: C,
68.33; H, 7.65; N, 9.11%.
d
13.8 (CH3), 14.2 (CH3), 24.7 (CH2), 33.4 (CH2), 37.8 (CH2), 62.3
(CH2), 63.0 (CH), 78.7 (C), 107.7 (CH), 108.8 (CH), 119.7 (CH), 120.9
(CH), 121.0 (C), 121.5 (CH), 122.6 (C), 123.3 (C), 126.2 (CH), 126.2 (C),
129.4 (C), 140.6 (C), 142.0 (C), 170.1 (C), 175.4 (C), 190.7 (C). LC/MS
(APCIþ) m/z 402.1 (MHþ). Found: C, 71.46; H, 5.51; N,10.13. Calcd for
C24H23N3O3: C, 71.80; H, 5.77; N, 10.47%.
4.2.19. (2Z)-3-Oxo-3-(2,3,4-trimethylphenyl)-2-[5-(2,3,4-
trimethylphenyl)pyrrolidin-2-ylidene]propanenitrile (35). By-prod-
uct from the synthesis of compound 33; white solid; 13% yield; 1H
4.2.15. Ethyl 5-(1-cyano-2-ethoxy-2-oxoethylidene)prolinate (30). By-
product from the synthesis of compound 29; white solid; 20% yield;
mp (EtOAc/n-heptane) 88e90 ꢀC; Rf (EtOAc/cyclohexane 6/4)¼0.63;
(CDCl3, 400 MHz)
d (ppm) 1.90e2.00 (m, 1H, CH2CH2CH), 2.20 (s,
3H, ArCH3), 2.23 (s, 3H, ArCH3), 2.28 (s, 3H, ArCH3), 2.30 (s, 3H,
ArCH3), 2.31 (s, 6H, 2ArCH3), 2.60e2.70 (m, 1H, CH2CH2CH),
3.03e3.20 (m, 2H, CH2CH2CH), 5.42 (t, J¼7.0 Hz, 1H, CH2CH2CH),
6.95 (d, J¼7.9 Hz, 1H, ArH), 7.04 (d, J¼4.7 Hz, 1H, ArH), 7.06 (d,
J¼4.7 Hz,1H, ArH), 7.14 (d, J¼7.9 Hz,1H, ArH),10.97 (large s,1H, NH).
1H (CDCl3, 400 MHz)
d
(ppm) 1.31 (t, J¼7.0 Hz, 3H, CO2CH2CH3), 1.32
(t, J¼7.0 Hz, 3H, CO2CH2CH3), 2.21e2.31 (m, 1H, CH2CH2CH),
2.41e2.51 (m,1H, CH2CH2CH), 2.92e3.10 (m, 2H, CH2CH2CH), 4.23 (q,
J¼7.0 Hz, 2H, CO2CH2CH3), 4.25 (q, J¼7.0 Hz, 2H, CO2CH2CH3), 4.54
(ddd, J¼8.8, 5.5, 0.9 Hz, 1H, CH2CH2CH), 9.17 (large s, 1H, NH). 13C
13C NMR (CDCl3, 100 MHz)
d 15.4 (CH3), 15.5 (CH3), 15.9 (CH3), 17.0
NMR (CDCl3,100 MHz)
d
14.1 (CH3),14.4 (CH3), 25.3 (CH2), 32.4 (CH2),
(CH3), 20.9 (CH3), 21.0 (CH3), 29.5 (CH2), 33.4 (CH2), 63.4 (CH), 80.7
(C), 120.2 (C), 121.3 (CH), 123.9 (CH), 127.0 (CH), 128.0 (CH), 132.9
(C), 133.0 (C), 135.6 (C), 136.0 (C), 136.2 (C), 136.6 (C), 138.1 (C), 138.2
(C), 174.6 (C), 195.5 (C). Found: C, 80.61; H, 7.58; N, 7.52. Calcd for
C25H28N2O: C, 80.43; H, 7.56; N, 7.31%.
60.6 (CH), 62.1 (CH2), 62.2 (CH2), 69.3 (C), 118.1 (C), 167.5 (C), 170.2
(C), 173.3 (C). IR
n
cmꢁ1: 1239, 1264, 1447, 1586, 1729, 2207, 3326.
Found: C, 57.31; H, 6.33; N, 11.57. Calcd for C12H16N2O4: C, 57.13; H,
6.39; N, 11.10%.
4.2.16. 1-(9-Ethyl-9H-carbazol-3-yl)ethanone (31). By-product from
the synthesis of compound 29; yellow solid with the same physical
properties as described in the lit.;34 1% yield; mp (EtOAc/n-heptane)
110e113 ꢀC (lit. 109e111 ꢀC,34a 116e118 ꢀC,34b 115 ꢀC,34c
4.2.20. Ethyl (2Z)-[5-(2,3,4-trimethylphenyl)pyrrolidin-2-ylidene]ac-
etate (36). By-product from the synthesis of compound 33; white
solid; 21% yield; mp (EtOAc/n-heptane) 184e186 ꢀC; Rf (EtOAc/cy-
clohexane 6/4)¼0.87; 1H (CDCl3, 400 MHz)
(ppm) 1.28 (t, J¼7.1 Hz,
d
114e116 ꢀC,34d 113e115 ꢀC34e); 1H (CDCl3, 400 MHz)
d
(ppm) 1.47
3H, CO2CH2CH3), 1.70e1.78 (m, 1H, CH2CH2CH), 2.20 (s, 3H, ArCH3),
2.24 (s, 3H, ArCH3), 2.28 (s, 3H, ArCH3), 2.39e2.49 (m, 1H,
(t, J¼7.4 Hz, 3H, CH2CH3), 2.73 (s, 3H, COCH3), 4.41 (q, J¼7.4 Hz, 2H,

1116
A. Ghinet et al. / Tetrahedron 68 (2012) 1109e1116
8. (a) Renaud, P.; Seebach, D. Helv. Chim. Acta 1986, 69, 1704; (b) Katoh, T.; Nagata,
Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima, S. Tetrahedron 1994, 50, 6221;
(c) Oba, M.; Mita, A.; Kondo, Y.; Nishiyama, K. Synth. Commun. 2005, 35, 2966.
9. Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J. Chem. Soc., Chem. Commun. 1985, 633.
10. (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172; (b)
Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp, W. N. Tetrahe-
dron 1996, 52, 2603; Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66,
809.
CH2CH2CH), 2.58e2.73 (m, 2H, CH2CH2CH), 4.12 (qd, J¼7.1, 1.2 Hz,
2H, CO2CH2CH3), 4.61 (s, 1H, CHCO2Et), 5.12 (dd, J¼7.4, 5.3 Hz, 1H,
CH2CH2CH), 6.99 (d, J¼8.0 Hz, 1H, ArH), 7.04 (d, J¼8.0 Hz, 1H, ArH),
8.12 (large s, 1H, NH). 13C NMR (CDCl3, 100 MHz)
d 14.8 (CH3), 15.3
(CH3), 15.8 (CH3), 20.8 (CH3), 30.7 (CH2), 31.4 (CH2), 58.5 (CH2), 60.3
(CH), 97.1 (C), 121.6 (CH), 127.6 (CH), 132.8 (C), 135.6 (C), 135.7 (C),
138.2 (C), 166.2 (C), 170.7 (C). IR n
cmꢁ1: 706, 778, 1054, 1150, 1229,
11. (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Takata, J. Chem. Lett. 1981, 1121; (b)
Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
1261, 1308, 1477, 1604, 1650, 3343. Found: C, 74.85; H, 8.62; N, 5.39.
Calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12%.
ꢀ
ꢀ
12. (a) Boto, A.; Hernandez, R.; Suarez, E. J. Org. Chem. 2000, 65, 4930; (b) Haldar, P.;
Ray, J. K. Tetrahedron Lett. 2008, 49, 3659; (c) Barman, G.; Ray, J. K. Synlett 2009,
ꢀ
3333; (d) Iglesias-Arteaga, M.; Juaristi, E.; Gonzales, F. Tetrahedron 2004, 60,
3605.
4.2.21. 1,2,3-Trimethyl-4-(methylsulfonyl)benzene (37). By-product
from the synthesis of compound 33; yellowish oil; 3% yield; Rf
13. Iwasaki, T.; Horikawa, H.; Matsumoto, K.; Miyoshi, M. J. Org. Chem. 1979, 44,
1552.
14. (a) Rigo, B.; Lelieur, J.-P.; Kolocouris, N. Synth. Commun. 1986, 16, 1587; (b) Rigo,
B.; El Ghammarti, S.; Couturier, D. Tetrahedron Lett. 1996, 37, 485; (c) El
Ghammarti, S.; Rigo, B.; Mejdi, H.; Henichart, J.-P.; Couturier, D. J. Heterocycl.
Chem. 1996, 37, 143.
15. Fasseur, D.; Rigo, B.; Cauliez, P.; Debacker, M.; Couturier, D. Tetrahedron Lett.
1990, 31, 1713.
16. Rigo, B.; Fasseur, D.; Leduc, C.; Couturier, D. Synth. Commun. 1990, 20, 1769.
17. (a) Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38, 4071; (b) Zhao, D.;
Hughes, D. L.; Bender, D. R.; DeMarco, A. M.; Reider, P. J. J. Org. Chem. 1991, 56,
3001; (c) So, Y.-H.; Heeschen, J.-P. J. Org. Chem. 1997, 62, 3552.
18. Rigo, B.; Fasseur, D.; Cherepy, N.; Couturier, D. Tetrahedron Lett. 1989, 30, 7057.
(EtOAc/n-heptane 5/5)¼0.46; 1H (CDCl3, 400 MHz)
d (ppm) 2.21 (s,
3H, ArCH3), 2.24 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 2.55 (s, 3H,
SO2CH3), 7.06 (d, J¼8.0 Hz, 1H, ArH), 7.70 (d, J¼8.0 Hz, 1H, ArH).
Found: C, 60.90; H, 7.31; S, 15.98. Calcd for C10H14O2S: C, 60.57; H,
7.12; S, 16.17%.
ꢀ
Acknowledgements
ˇ
The authors gratefully acknowledge the PRES (Pole de Recher-
ꢀ
19. Legrand, A.; Rigo, B.; Henichart, J.-P.; Norberg, B.; Camus, F.; Durant, F.; Cou-
ꢀ
ꢀ
che et d’Enseignement Superieur, Universite Lille Nord de France)
turier, D. J. Heterocycl. Chem. 2000, 37, 215.
ꢀ
ꢀ
ꢀ
20. Akue-Gedu, R.; Al Akoum Ebrik, S.; Witczak-Legrand, A.; Fasseur, D.; El
Ghammarti, S.; Couturier, D.; Decroix, B.; Othman, M.; Debacker, M.; Rigo, B.
Tetrahedron 2002, 58, 9239.
for financial support, the Conseil Regional Nord-Pas-de-Calais and
Janssen Research & Development (Division of Janssen Pharmaceu-
tica NV) for N. V.-H.’s scholarship, and the NCI (National Cancer
Institute) for the biological evaluation of compounds on their 60-
cell panel.
21. Seong, M. R.; Kim, J. N. Bull. Korean Chem. Soc. 1999, 20, 1253.
22. Yan, L.; Budhu, R.; Huo, P.; Lynch, C. L.; Hale, J. J.; Mills, S. G.; Hajdu, R.; Keohane,
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