Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles

Article abstract of DOI:10.1016/j.tet.2006.04.005

A small library of 2-oxo-5-(hetero)arylpyrroles was prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The large synthetic possibilities of these 2-oxopyrroles were investigated. The 2-oxopyrroles offer a large number of possible derivatizations

Full text of DOI:10.1016/j.tet.2006.04.005

Tetrahedron 62 (2006) 6018–6028
Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for
highly substituted pyrroles
*
Bert Metten, Maarten Kostermans, Gitte Van Baelen, Mario Smet and Wim Dehaen
Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 18 February 2006; revised 27 March 2006; accepted 3 April 2006
Available online 2 May 2006
Abstract—A small library of 2-oxo-5-(hetero)arylpyrroles was prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The large syn-
thetic possibilities of these 2-oxopyrroles were investigated. The 2-oxopyrroles offer a large number of possible derivatizations including
reactions with electrophiles. The chloroformylation of 2-oxo-5-(hetero)arylpyrroles provides pyrrole carbaldehydes. Some pyrrole
carbaldehydes were used to synthesize polycyclic compounds like pyrrolo[3,4-d]pyridazinones, a thienopyrrole, a pyrrolobenz[1,4]oxazepine,
a pyrrolobenzo[1,4]thiazepine, and a pyrrolobenzo[1,4]diazepine. Hereby we showed through a short exploration that the oxopyrroles and
analogues are interesting and versatile synthetic building blocks.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
R'
O
O
R
X
New versatile and easily available starting materials are of
great importance in organic and medicinal chemistry to
allow a combinatorial approach.
R
Ar
N
R
1
N
O
R
2
2aAr = Ph, R =
R' = Et
2-Oxopyrroles 1 show such versatility and they are important
substructures in a variety of pharmaca, including products
active against viral infections (HIV,1,2 influenza,3 cytomega-
lovirus4), anticancer agents,5 and products active against mi-
crobiological diseases6–8 (bacterial or fungal). Furthermore,
2-oxopyrroles are known as building blocks in the synthesis
of alkaloids9–12 and materials such as 2,20-bipyrroles, terpyr-
roles,13 and pigments.14–19 Besides the well known 5-alkyl-
2-oxopyrroles,20,21 first described in 1890 by Emery,22
relatively little attention was given toward 5-aryl-2-oxopyr-
role derivatives 2 in the open literature (see Fig. 1). In
our research group, we envisaged to use the 5-aryl-2-oxopyr-
roles as a starting material for the synthesis of highly fluores-
cent diketopyrrolopyrroles and potential non-nucleoside
reverse transcriptase inhibitors (NNRTI). For the screening
of the properties of these products a wide variability of pos-
sible substituents is necessary. Therefore we wished to
develop a short, inexpensive, and simple synthesis of 2-oxo-
pyrroles, which would allow a great variety of substituents.
2bAr = Ph, R = H, R' = t-Bu
Figure 1. 2-Oxopyrroles 1 and 5-aryl-2-oxopyrroles 2.
In the open literature, the synthesis of only few N-substituted
pyrrolinones 2 was described including a five-step synthesis
of an N-alkenylpyrrolinone 2a via oxazolinones.23 In the
patent literature the synthesis of 2b was described in
a two-step reaction starting with a base-catalyzed condensa-
tion between di-tert-butyl succinate and benzonitrile.24
2. Results and discussion
Recently Morton et al. have reported a short and convenient
method to synthesize 2 starting from commercially available
alkyl benzoylacetates 3.15,25 We reinvestigated Morton’s
synthesis of oxopyrroles and found some limitations. The di-
alkyl benzoylsuccinates 4 are available via monoalkylation
of alkyl benzoylacetates 3 with alkyl chloroacetates. Unfor-
tunately, the ring closure affording the corresponding 2 was
not possible starting from 4-nitrobenzoylsuccinates 4a
(X¼NO2). Probably the strongly electron withdrawing
group did not allow condensation between the ketone func-
tion and the amine but the imine/enamine function on this
Keywords: Heterocycles; Pyrrole; Fused ring system; Polycycles; Multi-
component reaction.
* Corresponding author. Tel.: +32 16 32 7439; fax: +32 16 32 7990; e-mail:
wim.dehaen@chem.kuleuven.be
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.005

B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
6019
intermediate was deactivated, preventing ring closure
(Scheme 1).
and aromatic aldehydes 8. Two general methods were
used. The first method consists of shortly heating the re-
agents in acetic acid, stirring for 16–24 h at room tempera-
ture, and precipitation after addition of water. The second
method consists of dissolving the reagents in ethanol and
heating this mixture for about 30 min. After dilution with
water and acidifying, the product could be filtered. Both
methods gave the desired product 5a–l in moderate yield
but high purity (Scheme 3, Table 1).
O
O
O
O
ClCH2COOR'
O
O
O
NaI, base,
reflux
X
R'
X
O
80%-quant.
3a X = NO2
3b X = H
4a X = NO2, R' = Et
4b X = H, R' = Et
4c X= OMe, R' = Me
3c X = OMe
H N R
10equiv.
2
AcOH, reflux
40 - 50%
O
O
O
O
O
HO
O
AcOH or
Ar
EtOH
+
+
RNH2
O
O
O
H
Ar
O
N
O
Na
R
5
X
N
6
7
8
O
R
Scheme 3. Synthesis of 2,3-dioxopyrrolidines via a multicomponent
reaction.
2c R = H, X = H
2d R = H, X = OMe
2e R = Bn, X = H
Scheme 1. Synthesis of simple 2-oxo-5-arylpyrroles 2c and 2d starting from
benzoylacetates.
Table 1. Synthesis of 2,3-dioxopyrrolidines via multicomponent reaction
Dioxopyrrolidine
1-R
5-Ar
Yield (%)
In contrast to 4a, benzoylsuccinates 4b and 4c reacted with
ammonium acetate and benzylamine to afford the desired
oxopyrroles 2c–e in moderate yield. The condensation in
acetic acid with a large excess (10 equiv) of ammonium ace-
tate or benzylamine gave the best results while aniline did
not give any product 2 under these conditions. Clearly, the
benzoylsuccinate method suffers from (i) lack of general
applicability (e.g., X¼NO2 or aromatic R), (ii) the obliga-
tory use of excess of amine reagent, and (iii) the modest
yields in the final step. Moreover, only a few benzoylacetates
3 are commercially available at a reasonable price.
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-ClPh
Benzyl
Cyclohexyl
PMBc
PMBc
3,4,5-(CH3O)3Ph
H
CH3
CH3
CH3
CH3
4-ClPh
4-ClPh
4-ClPh
4-CH3OPh
4-ClPh
3-HOPh
Ph
4-NO2Ph
4-(CH3)2NPh
Ph
77a
32a
18a, 31b
40a
64a
38a
61b
50b
48b
5j
5k
5l
59b
2-HOPh
2-Thienyl
52b
Allyl
62b
a
Method 1 in acetic acid.
Method 2 in ethanol.
p-Methoxybenzyl.
b
c
We describe here a more general synthesis of N-substituted
(or N-protected) 2-oxopyrroles 2 starting from 2,3-dioxo-
pyrrolidines 5 (Scheme 2). To obtain the latter compounds,
we applied the synthesis described by Merchant and Sriniva-
san, and before them by Schiff.26,27 These authors published
an interesting three-component reaction starting from so-
dium alkyl oxalacetate with several amines and aldehydes
under various reaction conditions. Most of the 2,3-dioxo-
pyrrolidines 5 synthesized had aryl substituents at the 1- and
5-position. A significant advantage of these products 5 is the
fact that most of them can be crystallized out of the reaction
mixture.
Dioxopyrrole 5i was prepared in a reasonable yield but the
reaction mixture had to be heated at reflux for several days
instead of the usual 30 min. Acidification in this case was
not necessary because 5i precipitated out of the reaction
mixture after cooling to room temperature. An excess of
aqueous ammonia was used in the synthesis of 5g.
These dioxopyrrolidines 5 could easily be transformed into
the desired oxopyrrole 2. Reduction of the enolates 5 gave
the corresponding secondary alcohols 9. Without further
purification these alcohol groups could be eliminated by
mesylation and treatment with base affording the pyrroli-
nones 2c, 2f–j after isomerization of the double bond
(Scheme 4, Table 2).
O
O
O
O
HO
O
X
O
X
N
R
N
R
O
O
O
O
2 R = alkyl or aryl
O
O
5
HO
O
HO
O
Zn, H+
AcOH
CH3SO2Cl
Scheme 2. Synthesis of a great variety of 2-oxopyrroles 2 starting from 5.
Ar
Ar
Ar
TEA, CHCl3
N
R
N
R
N
O
R
All three necessary reagents are relatively cheap and a large
variety of aldehydes and amines are possible. This allowed
us to create a library of 5 and subsequently of the desired
oxopyrroles 2. 2,3-Dioxopyrrolidines 5 that are new to the
best of our knowledge were synthesized by us starting from
sodium ethyl oxalacetate 6, ammonia or primary amines 7,
5
9
2
Scheme 4. Transformation of dioxopyrrolidines 5 to pyrrolinones 2.
The alcohols 9 were obtained by reduction of 5 with zinc
dust in acetic acid and a few drops of sulfuric acid. As an

6020
B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
Table 2. Transformation of dioxopyrrolidines 5 to pyrrolinones 2
temperature in chloroform, mesylation followed by com-
plete elimination of the corresponding sulfonic acid was
accomplished at the same time to afford 2.
Oxopyrrole Educt Alcohol N-R
5-Ar
Yield (%)a
2c
2f
2g
2h
2i
5g
5j
5i
5b
5l
9a
9b
9c
9d
9e
9f
H
CH3
CH3
Benzyl 4-ClPh
Allyl
4-ClPh 4-ClPh
Ph
Ph
42
40
The moderate yield (40–66%) of these oxopyrroles 2c, 2f–j
was more than compensated by the ease of these reactions
and the possibility to prepare a library of pyrrolinones 2
from readily available starting materials. Moreover, unsub-
stituted, N-aryl and N-alkyl-5-arylpyrrolinones 2 could
also be prepared by the described method.
4-(CH3)2NPh 40
42b
51
2-Thienyl
2j
5a
66
a
Isolated overall yield starting from 5.
Triethylamine (TEA), POCl3.
b
Pyrrolinone 2 possesses an active methylene group, which
can react with electrophilic reagents. The ester function
(rather a vinylogous carbamate function) and the amide
function (if unsubstituted) may react with nucleophilic re-
agents. In comparison with the 5-alkylpyrrolinones the nitro-
gen atom of the 5-arylpyrrolinones is relatively shielded
from electrophilic reagents. Thus, the aryl group gives the
pyrrolinones extra chemical and physical stability.
example the mixture of diastereoisomers of 9c–9c0 (87:13),
obtained starting from 5i, was separated by column chroma-
tography. NMR spectroscopy showed that mainly the isomer
with the all-trans configuration 9c was formed. The NOESY
spectrum shows that the proton in a of the ester function of
the main product 9c is located in the proximity of the aryl
protons. The position of this proton with respect to the aryl
ring is confirmed by the low d-value of this proton in the
1H NMR spectrum due to the anisotropic effect of the ring
current. The NOESY spectrum also confirmed that the 3,5-
protons in b of the ester group are located at the same side
of the five-membered ring. The minor product 9c0 showed
in its NOESY spectrum no correlation between the proton
at 4.55 and 4.68 ppm. From the 1H NMR and 13C NMR spec-
tra it is clear that the signals of the ester function are shifted
upfield. Hence, the ester function and the phenyl ring are on
the same side as the pyrrole moiety.
Benzylidenepyrrolinones 10 were synthesized by condensa-
tion of pyrrolinone 2 and different arylaldehydes 11. Bright
yellow compounds 10 were obtained in the Z-configuration.
Using the ortho-substituted salicylaldehyde 12 and pyrroli-
none 2c in acetic acid and heating for 20 min under
microwave irradiation the dioxopyrrolo[3,4-c]benzoxepine
(DPO) 13 was obtained next to phenylchromeno[2,3-b]pyr-
role 14. The yellow 13 shows a strong yellow fluorescence
and is only slightly soluble in common organic solvents.
Because there is no NOESY correlation between the protons
at 4.55 and 4.68 ppm and the proton signal at 4.55 is shifted
to higher field (in comparison with the corresponding proton
of 9c), we can assume that these protons are located on
opposite sides of the ring and therefore assign the trans–cis
structure 9c0 (Fig. 2).
As an example of a reaction between 2 and an activated ester
the condensation of 2c with diethyl oxalate 15 under basic
conditions gave diester 16, which could be isolated by filtra-
tion after acidification. Phenyldiazonium salt 17 reacted
smoothly with oxopyrrole 2c providing hydrazone 18. Pyr-
rolinone 2c was transformed into ketene dithioacetal 19 in
a one pot reaction by treatment with carbon disulfide in
the presence of triethylamine and subsequent methylation
with 2 equiv of methyl iodide (Scheme 5).
The reduction rate is increased by heating but the reaction
time should be carefully controlled in this case because of
the possibility of formation of small amounts of Fischer
esterification side products resulting from the alcohol 9
and acetic acid. The next step was the elimination of water
from 9 in order to obtain the desired oxopyrroles 2. Several
possibilities were tested. The alcohols 9 react with acid chlo-
rides, sulfonyl chlorides, anhydrides, POCl3, and SOCl2
under the influence of base. With pyridine as the base the
reaction with tosyl, mesyl or phosphorus oxychloride was
incomplete. With triethylamine as the base at reflux
These pyrrolinones 2 seemed to be ideal building blocks for
the synthesis of a large variety of multisubstituted pyrroles.
In the literature, methods have been described to chloro-
formylate heterocyclic compounds such as pyrazolones and
oxoindoles using Vilsmeier–Haack conditions affording the
corresponding pyrazoles and 2-chloroindoles.28 The synthe-
sis of 5-aryl-2-chloro-3-formylpyrrole 20a is based on these
transformations.
At relatively high temperature (100–120 ꢀC) and a ratio of
1:2:8 pyrrolinone (R¼H)–DMF–POCl3, the desired alde-
hyde 20a was obtained in reasonable to good yield. The
nitrogen atom on this pyrrole 20a was easily alkylated with
benzyl bromide or a-bromoacetophenone using potassium
carbonate as a base to form 20b and 20c. The transformation
of N-substituted pyrrolinones 2f and 2j into their chloro-
formylated derivatives 20b and 20d was also investigated.
TheadditionofPCl5 andtheuseofhightemperature(120 ꢀC)
were necessary for a complete transformation (Scheme 6).
upfield
4.18
H2
3.06 O
H H
3.59 O3.78 & 3.88
4.55
4.66
H
H
O
H H
1.22
0.94
CH3
C
C
HO
HO
CH3
O
H 4.53
H7.13
H 4.68
7.11
H
O
O
N
CH3
9c
N
CH3
9c'
N
N
all-trans
87
trans-cis
13
:
Pyrrole carbaldehydes 20a–d possess at least three electro-
philic reaction sites and thus provide numerous synthetic
possibilities. They offer a number of interesting options for
Figure 2. Diastereoisomers of 9c–9c0 obtained after reduction of 5 with
zinc.

B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
6021
O
O
O
O
O
O
Y
+
O
N
O
N
H
O
N
X
H
10a X = OMe, Y = COOH 69%
14 13%
13 8%
10b X = H, Y = OMe 89%
HCl,
EtOH
reflux
O
OH
AcOH,
reflux
O
H
Y
12
H
11
O
O
O
O
O
X
N2+Cl-
17
O
N
H
O
15
O
O
O
O
O
O
N
EtOH,kt
2c,d
1) CS2,TEA
NaOEt, EtOH
reflux
O
H
N
H
N
H
18 60%
N
H
O
O
DMSO
2) CH3I
16 40%
O
S
O
S
N
O
H
19
60%
Scheme 5. Reactions of 2 with various electrophiles.
R
N
O
N
O
O
O
H
H
N
Cl
N
Cl
Bn
Br
R
Bn
N
C
O
3
H
O
H2N-NH
21a R = H 64%
O
C
,
3
O
20b 80%
22
21b R = CH3 42%
C
2
POCl3, DMF
100-120 °C
K
H
EtOH
2c
reflux
O
O
N
O
Cl
O
O
Br
H
O
O
O
O
20a 80%
K
H
O
O
2 C
HS
O
O
3
C
,
23
H
H
N
Cl
3 CN
O
K2CO , EtOH,
re3flux
S
N
Bn
37%
O
N
O
O
Cl
O
POCl3, PCl5,
DMF
Bn
20b
H
24
Ar
2f,j
20c 76%
N
R
100-120 °C
Cl
piperidine
EtOH, reflux
O
X
O
20b Ar = Ph, R = Bn 66%
20d Ar = 4-ClPh, R = 4-ClPh 50%
NH2
N
N
Bn
Scheme 6. Synthesisof pyrrolecarbaldehydes 20 via chloroformylationof 2.
X
28 X = OH, SH of NH2
25 X = O 38%
26 X = S 45%
27 X = NH 36%
ring closure besides the condensation reactions on the inde-
pendent chloro, aldehyde, and ester functions.
Scheme 7. Synthesis of poly(hetero)cycles starting from 20.
The two adjacent carbonyl functions can react with bis-
nucleophilic molecules. Thus a reagent, which contributes
two atoms, can provide a six-membered ring fused to the
pyrrole moiety. Hydrazines, for example, gave after reaction
with 20b pyrrolo[3,4-d]pyridazinones 21a and 21b in
moderate yields (Scheme 7).
of these compounds was based on the work of Latif.29 All
structures could readily be analyzed by 1H NMR spec-
troscopy.
As an example of a ring fusion involving the chloro and
aldehyde functions, N-benzylated pyrrole 20b was used as
the substrate for the cyclocondensation with ethyl mercapto-
acetate 23. 5-Phenyl-thieno[2,3-b]pyrrole 24 precipitated
from the reaction mixture. Compounds 25, 26, and 27 were
prepared by condensing ortho-substituted anilines with pyr-
role carbaldehyde 21 in yields of about 40%. The synthesis
3. Conclusion
We prepared a small library of pyrrolinones 2 starting from
2,3-dioxopyrrolidines 5. The 2,3-dioxopyrrolidines 5 are
easily prepared through the multicomponent reaction be-
tween diethyl oxalacetate and a variety of aldehydes and
primary amines.

6022
B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
We have explored the large synthetic possibilities of the
oxopyrroles. The 2-oxopyrroles offer a large number of
possible derivatizations including reactions with aldehydes,
diazonium salts, reactive esters, and carbon disulfide. The
chloroformylation of 2 provides pyrrole carbaldehydes 20.
A number of pyrrole carbaldehydes 20 were used to synthe-
size polycyclic compounds. Pyrrolo[3,4-d]pyridazinones
21a and 21b were obtained after aldehyde–ester ring fusion
of 2 with hydrazines 22 while chloroaldehyde ring fusions
provided thienopyrrole 24, pyrrolobenz[1,4]oxazepine 25,
pyrrolobenzo[1,4]thiazepine 26, and pyrrolobenzo[1,4]di-
azepine 27. Thus we showed by means of a short explora-
tion that the oxopyrroles and analogues are interesting and
versatile synthetic building blocks. Many possibilities
offered by 2 and 20 show these compounds to be novel
key intermediates in the synthesis of highly substituted
pyrroles.
pressure 2c (11.87 g, 49% starting from benzoylacetate) was
obtained as a white powder.
Compound 2c was also obtained starting from 5g (general
procedure A+D) using 3 equiv of aqueous ammonia as amine
(GP D) or starting from alcohol 9a (general procedure A).
1H NMR (300 MHz, CDCl3): d¼1.21 (t, 3H, J¼7.3 Hz),
3.49 (s, 2H), 4.14 (q, 2H, J¼7.3 Hz), 7.41–7.49 (m, 3H),
7.58–7.62 (m, 2H), 9.12 (br s, 1H); 13C NMR (75 MHz,
CDCl3): d¼14.5, 39.1, 60.4, 105.0, 128.6, 129.1, 130.0,
130.9, 151.6, 163.6, 177.5; LRMS (CI): 232 MH+; mp:
181–182 ꢀC (lit. 173–176 ꢀC).30
4.2.2. 5-(4-Methoxyphenyl)-2-oxo-2,3-dihydro-1H-pyr-
role-4-carboxylic acid ethyl ester (2d). A suspension
of ethyl (4-methoxybenzoyl)acetate (88.8 g, 0.40 mol),
K2CO3 (57.9 g, 0.42 mol), NaI (8.0 g), and methyl chloro-
acetate (45.1 g, 36.7 mL, 0.41 mol) in acetone/DME
160 mL:240 mL was heated under reflux for 24 h. Treatment
as for 2c afforded 2d (46.2 g, 47%) as a white powder. After
extraction of the combined filtrates with dichloromethane
(mL), drying over MgSO4 and evaporation in vacuo, addi-
tional product 2d (10.1 g, 10.3%) was isolated by column
4. Experimental
4.1. Instrumental techniques
NMR spectra were acquired on commercial instruments
(Bruker Avance 300 MHz or Bruker AMX 400 MHz) and
chemical shifts (d) are reported in parts per million refer-
enced to internal residual solvent protons (1H) or the carbon
signal of deuterated solvents (13C). Mass spectrometry data
were obtained with an HP MS apparatus 5989A, at 70 eV for
EI spectra and with methane as reagent gas for CI spectra.
UV–vis spectra were taken on a Perkin–Elmer Lambda 20
spectrometer. Melting points (not corrected) were deter-
mined using a Reichert Thermovar or Electrothermal 9200
apparatus. The microwave oven used is a Monomode Dis-
cover MW Reactor. All reactions were done in a 10 mL glass
tube sealed with a Teflon stopper.
1
chromatography of the residue on silica gel (CH2Cl2). H
NMR (300 MHz, CDCl3): d¼1.23 (t, 3H, J¼7.3 Hz), 3.48
(s, 2H), 3.85 (s, 3H), 4.13 (q, 2H, J¼7.3 Hz), 6.94 (d, 2H,
J¼8.8 Hz), 7.62 (d, 2H, J¼8.8 Hz), 8.94 (br s, 1H); 13C
NMR (75 MHz, CDCl3): d¼14.3, 39.0, 55.4, 60.1, 103.1,
113.7, 121.4, 130.6, 151.4, 161.4, 163.5, 178.0; LRMS
(CI): 262 MH+; mp: 101 ꢀC.
4.2.3. 1-Benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-pyrrole-
4-carboxylic acid ethyl ester (2e). To crude product 4b
(1.00 mmol, 278 mg) in ethanol (15 mL) was added acetic
acid (10.0 mmol, 0.60 mL) and benzylamine (10.0 mmol,
1.05 g). The reaction mixture was then heated at reflux for
4 h. After cooling to room temperature the reaction mixture
was diluted with water (15 mL). The aqueous mixture was
extracted with ethyl acetate. The organic phase was washed
with water and brine and finally dried with magnesium
sulfate. The solvents were evaporated in vacuo and the vis-
cous residue was chromatographed on silica gel (ethyl
acetate/petroleum ether 9:1) to furnish the pure 2e as a
4.2. Materials
Chemicals and solvents were either purchased puris p.A.
from commercial suppliers or purified by standard tech-
niques. For thin layer chromatography (TLC), precoated
0.25 mm silica plates (Macherey–Nagel 60 AlugramÒ Sil G/
UV254) were used and spots were visualized either with
UV light or ethanolic phosphomolybdic acid followed by
heating.
1
yellow oil (128 mg, 40%); H NMR (300 MHz, CDCl3):
d¼1.06 (t, 3H, J¼7.1 Hz), 3.53 (s, 2H), 4.07 (q, 2H,
J¼7.1 Hz), 4.52 (s, 2H), 6.83 (m, 2H), 7.44–7.15 (m, 8H);
13C NMR (CDCl3, 75 MHz): d¼14.3, 37.7, 44.3, 60.9,
105.4, 126.0, 127.4, 128.1, 128.4, 129.3, 136.0, 154.3,
163.9, 176.2; LRMS (CI): 322 MH+.
4.2.1. 2,3-Dihydro-2-oxo 5-phenyl-1H-pyrrole-4-carbox-
ylic acid ethyl ester (2c). A suspension of ethyl benzoyl-
acetate 3b (20.2 g, 18.3 mL, 105 mmol), K2CO3 (15.2 g,
110 mmol), NaI (2.0 g), and ethyl chloroacetate (13.2 g,
11.6 mL, 108 mmol) in acetone/DME 120 mL:80 mL was
heated under reflux for 24 h. After cooling to room temper-
ature the salts were filtered and washed with acetone. The
combined filtrates were evaporated to dryness under reduced
pressure affording 4b quantitatively with sufficient purity.
This crude product 4b was dissolved in a mixture of acetic
acid (200 mL) and ammonium acetate (78.7 g, 1.02 mol)
and the reaction mixture was then stirred at reflux for 3 h.
After cooling to room temperature, the reaction mixture
was added to ice-water (800 mL). The acquired precipitate
was filtered and washed with water. The residue was recrys-
tallized from ethanol/water 4:1. After drying under reduced
4.3. General procedure A: synthesis of 5-aryl-2-oxo-
pyrroles 2
The crude products or purified alcohols 9 (1 equiv) were
dissolved in chloroform. Subsequently mesyl chloride
(1.1 equiv) and triethylamine (4 equiv) were added portion-
wise. After heating under reflux for 30 min the reaction mix-
ture was diluted with 5% HCl solution. The aqueous mixture
was extracted with CH2Cl2. The combined organic phases
were washed with 5% HCl solution, saturated NaHCO3 so-
lution until neutral, water and finally dried with magnesium
sulfate. The solvents were evaporated under reduced

B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
6023
pressure and the residue was chromatographed on silica gel
(ethyl acetate/petroleum ether 50:50) to furnish the pure
oxopyrroles 2.
K2CO3 (15.2 g, 110 mmol), NaI (2.0 g), and ethyl chloroace-
tate (13.2 g, 11.6 mL, 108 mmol) in acetone/DME 120 mL:
80 mL was heated under reflux for 24 h. After cooling to
room temperature the salts were filtered and washed with
acetone. The combined filtrates were evaporated to dryness
under reduced pressure affording 4b (9.40 g, 71%) as a red
brown oil with sufficient purity. A sample was extra purified
by column chromatography on silica gel (CH2Cl2) affording
4b as a colorless to green oil. 1H NMR (300 MHz, CDCl3):
d¼1.2 (m, 6H), 3.13–3.16 (m, 2H), 4.12–4.17 (m, 4H),
4.84 (t, 1H, J¼7.7 Hz), 7.51 (t, 2H, J¼7.7 Hz), 7.60 (t, 1H,
J¼7.7 Hz), 8.04 (d, 2H, J¼8.4 Hz); LRMS (CI): 279 MH+.
Product 2f (1.96 g, 40%) was prepared as described in the
general procedure A (GP A) and was obtained as a red pow-
der. 1H NMR (300 MHz, CDCl3): d¼1.06 (t, 3H, J¼7.3 Hz),
2.86 (s, 3H), 3.46 (s, 2H), 4.02 (q, 2H, J¼7.3 Hz), 7.31–7.34
(m, 2H), 7.46–7.48 (m, 3H); 13C NMR (CDCl3, 75 MHz):
d¼14.3, 28.2, 37.5, 60.1, 105.5, 128.7, 129.1, 130.1, 130.3,
155.4, 163.5, 176.4; LRMS (CI): 246 MH+; mp: 35 ꢀC.
4.3.1. 5-(4-(Dimethylamino)phenyl)-1-methyl-2-oxo-2,3-
dihydro-1H-pyrrole-4-carboxylic acid ethyl ester (2g).
Product 2g (220 mg, 40%) was prepared as described in
4.4. General procedure B: synthesis of 4-carbethoxy-2,3-
dioxopyrrolidines 5 in acetic acid
1
the GP A and was obtained as a red powder. H NMR
(300 MHz, CDCl3): d¼1.14 (t, 3H, J¼7.3 Hz), 2.92 (s,
3H), 3.02 (s, 6H), 3.43 (s, 2H), 4.06 (q, 2H, J¼7.3 Hz),
6.74 (d, 2H, J¼8.2 Hz), 7.22 (d, 2H, J¼8.2 Hz); 13C NMR
(CDCl3, 75 MHz): d¼14.6, 28.5, 37.7, 40.5, 60.0, 104.1,
111.5, 116.5, 130.7, 151.5, 156.6, 163.9, 176.9; LRMS
(CI): 289 MH+; mp: 87–88 ꢀC.
To a solution of sodium diethyl oxalacetate (1 equiv) in ace-
tic acid was added portionwise with constant stirring, amine
(1 equiv) followed by aldehyde (1 equiv). After heating the
mixture until everything dissolved, it was kept overnight at
room temperature. On dilution with water and stirring, a
yellow solid separated, which was filtered, washed with
water, dried under reduced pressure, and recrystallized from
toluene. After drying under reduced pressure the 2,3-dioxo-
pyrrolidines 5 were obtained with sufficient purity.
4.3.2. 1-Allyl-2-oxo-5-(thien-2-yl)-4,5-dihydro-1H-pyr-
role-4-carboxylic acid ethyl ester (2i). Product 2i (7.02 g,
51%) was prepared as described in the GP A and was
1
obtained as a red powder. H NMR (300 MHz, CDCl3):
4.4.1. 1,5-Bis-(4-chlorophenyl)-3-hydroxy-2-oxo-2,5-di-
hydro-1H-pyrrole-4-carboxylic acid ethyl ester (5a).
Product 5a was prepared as described in the GP B and was
obtained as a white powder (2.79 g, 71%). 1H NMR
(300 MHz, CDCl3): d¼1.20 (t, 3H, J¼7.3 Hz), 4.20 (q,
2H, J¼7.3 Hz), 5.68 (s, 1H), 7.19 (m, 6H), 7.41 (d, 2H,
J¼8.8 Hz), 8.99 (br s, 1H); 13C NMR (75 MHz, CDCl3):
d¼14.3, 61.2, 61.9, 113.3, 123.6, 129.2, 129.4, 129.6,
131.8, 133.8, 134.9, 156.7, 163.1, 165.2; LRMS (CI): 392
MH+; mp: 172 ꢀC.
d¼1.12 (t, 3H, J¼7.3 Hz), 3.49 (s, 2H), 4.02–4.10 (m,
4H), 4.97 (d, 1H, J¼14.6 Hz), 5.09 (d, 1H, J¼10.1 Hz),
5.62–5.75 (m, 1H), 7.10 (dd, 1H, J¼5.5 Hz), 7.16 (d, 1H,
J¼3.7 Hz), 7.52 (d, 1H, J¼6.4 Hz); 13C NMR (CDCl3,
75 MHz): d¼14.4, 37.8, 43.4, 60.4, 108.8, 117.4, 127.3,
128.9, 130.6, 132.7, 148.1, 163.2, 175.3; LRMS (CI): 278
MH+; mp: 58 ꢀC.
4.3.3. 1,5-Bis(4-chlorophenyl)-2-oxo-4,5-dihydro-1H-
pyrrole-4-carboxylic acid ethyl ester (2j). Product 2j
(7.44 g, 66%) was prepared as described in the GP A and
4.4.2. 1-Benzyl-5-(4-chlorophenyl)-3-hydroxy-2-oxo-2,5-
dihydro-1H-pyrrole-4-carboxylic acid ethyl ester (5b).
Product 5b (1.190 g, 32%) was prepared as described in the
GP B and was obtained as a white powder. 1H NMR
(300 MHz, CDCl3): d¼1.10 (t, 3H, J¼7.3 Hz), 4.10 (q, 2H,
J¼7.3 Hz), 4.38 (dd, 2H), 4.86 (s, 1H), 7.03–7.35 (m, 9H),
8.71 (br s, 1H); 13C NMR (75 MHz, CDCl3): d¼13.8, 44.0,
59.0, 61.1, 112.9, 128.0, 128.4, 128.9, 129.1, 129.2, 133.2,
134.6, 136.0, 157.4, 163.5, 165.0; LRMS (CI): 372 MH+;
mp: 195 ꢀC.
1
was obtained as a brownish powder. H NMR (300 MHz,
CDCl3): d¼1.13 (t, 3H, J¼7.3 Hz), 3.49 (s, 2H), 4.09 (q,
2H, J¼7.3 Hz), 6.88 (d, 2H, J¼8.2 Hz), 7.13 (d, 2H,
J¼8.2 Hz), 7.18–7.27 (m, 4H); 13C NMR (CDCl3,
75 MHz): d¼14.4, 37.9, 60.6, 106.9, 127.8, 128.5, 129.1,
129.6, 131.3, 132.8, 134.0, 136.1, 152.8, 163.2, 174.9;
LRMS (CI): 376–378 MH+; mp: 70 ꢀC.
4.3.4. Diethyl 2-(4-nitrobenzoyl)succinate (4a). To a solu-
tion of ethyl 4-nitrobenzoylacetate (2.0 g, 8.4 mmol), NaH
(202 mg, 8.4 mmol), and NaI (100 mg) in THF (100 mL)
was added ethyl chloroacetate (2.8 g, 16.8 mmol). After stir-
ring the mixture at 50 ꢀC for 1 h it was cooled and diluted
with ether (50 mL) and acidified with aqueous 5% HCl solu-
tion. After extraction with ether, drying over MgSO4 and
evaporation under reduced pressure, the product 4a (1.6 g,
58%) was isolated as a yellow oil after column chromato-
graphy of the residue on silica gel (CH2Cl2). 1H NMR
(300 MHz, CDCl3): d¼1.13–1.27 (m, 6H), 3.04 (dd, 1H, J¼
6.5 Hz, J¼23.4 Hz), 3.22 (dd, 1H, J¼9.2 Hz, J¼26.0 Hz),
4.09–4.16 (m, 4H), 4.85 (q, 1H, J¼9.1 Hz), 5.30 (s, 1H),
8.19 (d, 2H, J¼8.8 Hz), 8.34 (d, 2H, J¼8.8 Hz); LRMS
(CI): 324 MH+.
4.4.3. 5-(4-Chlorophenyl)-1-cyclohexyl-3-hydroxy-2-
oxo-2,5-dihydro-1H-pyrrole-4-carboxylic acid ethyl
ester (5c). Product 5c (671 mg, 31%) was prepared as
described in the GP B and was obtained as a white powder.
1H NMR (300 MHz, CDCl3): d¼1.20 (t, 3H), 1.40 (m, 10H),
3.71 (m, 1H), 4.11 (q, 2H), 5.13 (s, 1H), 7.18 (d, 2H,
J¼6.6 Hz), 7.31 (d, 2H, J¼7.3 Hz), 8.30 (br s, 1H); 13C
NMR (75 MHz, CDCl3): d¼13.9, 25.1, 25.7, 30.9, 54.3,
59.5, 60.9, 112.8, 128.6, 129.0, 134.2, 134.9, 156.9, 163.9,
164.6; LRMS (CI): 364 MH+; mp: >350 ꢀC.
4.4.4. 3-Hydroxy-1-(4-methoxybenzyl)-5-(4-methoxy-
phenyl)-2-oxo-2,5-dihydro-1H-pyrrole-4-carboxylic
acid ethyl ester (5d). Product 5d (1.59 g, 40%) was pre-
pared as described in the GP B and was obtained as a white
4.3.5. Diethyl 2-benzoylsuccinate (4b). A suspension of
ethyl benzoylacetate 3b (20.2 g, 18.3 mL, 105 mmol),

6024
B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
powder. 1H NMR (300 MHz, CDCl3): d¼1.07 (t, 3H,
J¼7.3 Hz), 3.48 (d, 1H, J¼14.6 Hz), 3.80 (s, 3H), 3.82
(s, 3H), 4.06 (q, 2H, J¼7.3 Hz), 4.82 (s, 1H), 5.12 (d,
1H, J¼14.6 Hz), 6.82 (d, 2H, J¼8.8 Hz), 6.86 (d, 2H,
J¼8.8 Hz), 7.02 (d, 2H, J¼8.1 Hz), 7.04 (d, 2H,
J¼8.1 Hz); 13C NMR (75 MHz, CDCl3): d¼14.3, 43.6,
55.6, 59.4, 60.9, 114.3, 114.4, 128.9, 129.4, 130.1, 130.2,
159.5, 160.0, 165.8; LRMS (CI): 398 MH+; mp: 174 ꢀC.
(7.7 g, 59%) was prepared as described in the GP C and
was obtained as a white powder. 1H NMR (300 MHz,
CDCl3): d¼corresponding with data literature;31 LRMS
(CI): 262 MH+; mp: 133 ꢀC (lit. 164–165 ꢀC).
4.5.3. 3-Hydroxy-5-(2-hydroxy-phenyl)-1-methyl-2-oxo-
2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester
(5k). Product 5k (3.58 g, 52%) was prepared as described
in the GP C and was obtained as a white powder. 1H NMR
(300 MHz, DMSO): d¼1.02 (t, 3H, J¼7.3 Hz), 2.63 (s,
3H), 3.94–3.99 (m, 2H), 5.43 (s, 1H), 6.73 (t, 1H,
J¼7.3 Hz), 6.82 (d, 2H, J¼7.3 Hz), 7.10 (t, 1H, J¼8.8 Hz),
9.58 (s, 1H), 11.31 (s, 1H); 13C NMR (75 MHz, DMSO):
d¼14.9, 28.0, 60.1, 111.5, 116.6, 120.1, 122.7, 129.9,
155.2, 157.0, 163.1, 165.6; LRMS (CI): 305 MH+; mp:
196–197 ꢀC.
4.4.5. 5-(4-Chlorophenyl)-3-hydroxy-1-(4-methoxy-
benzyl)-2-oxo-2,5-dihydro-1H-pyrrole-4-carboxylic acid
ethyl ester (5e). Product 5e (2.58 g, 64%) was prepared as
described in the GP B and was obtained as a white powder.
1H NMR (300 MHz, CDCl3): d¼1.00 (t, 3H, J¼7.3 Hz),
3.66 (d, 1H, J¼15.3 Hz), 3.83 (s, 3H), 3.90–4.06 (m, 2H),
4.76 (d, 1H, J¼15.3 Hz), 4.91 (s, 1H), 6.83 (d, 2H,
J¼8.8 Hz), 6.98 (d, 2H, J¼8.1 Hz), 7.11 (d, 2H,
J¼8.1 Hz), 7.37 (d, 2H, J¼8.1 Hz); 13C NMR (75 MHz,
CDCl3): d¼14.9, 44.1, 56.0, 60.2, 60.5, 112.2, 115.0,
129.2, 129.5, 130.1, 133.7, 136.0, 154.8, 159.5, 162.8,
165.6; LRMS (CI): 402 MH+; mp: 180–181 ꢀC.
4.5.4. 1-Allyl-3-hydroxy-2-oxo-5-thiophen-2-yl-2,5-dihy-
dro-1H-pyrrole-3-carboxylic acid ethyl ester (5l). Product
5l (17.3 g, 62%) was prepared as described in the GP C and
was obtained as a white powder. 1H NMR (300 MHz,
DMSO): d¼1.12 (t, 3H, J¼7.3 Hz), 3.49 (s, 2H), 4.02–
4.11 (m, 4H), 5.00 (d, 1H, J¼16.4 Hz), 5.10 (d, 1H,
J¼10.1 Hz), 5.62–5.75 (m, 1H), 7.11 (t, 1H, J¼5.49 Hz),
7.17 (d, 1H, J¼3.7 Hz), 7.52 (d, 1H, J¼6.4 Hz); 13C NMR
(75 MHz, DMSO): d¼14.3, 43.0, 55.6, 61.4, 112.9, 119.2,
126.5, 127.1, 128.3, 132.4, 138.5, 157.6, 163.1, 165.3;
LRMS (CI): 294 MH+; mp: 119 ꢀC.
4.4.6. 3-Hydroxy-5-(3-hydroxyphenyl)-2-oxo-1-(3,4,5-
trimethoxyphenyl)-2,5-dihydro-1H-pyrrole-4-carboxylic
acid ethyl ester (5f). Product 5e (851 mg, 38%) was pre-
pared as described in the GP B and was obtained as a white
powder. 1H NMR (300 MHz, DMSO): d¼1.07 (t, 3H,
J¼7.3 Hz), 3.57 (s, 3H), 3.69 (s, 6H), 3.99–4.06 (m, 2H),
5.99 (s, 1H), 6.56 (d, 2H, J¼8.1 Hz), 6.63 (s, 1H), 6.74 (d,
2H, J¼8.1 Hz), 6.93 (s, 2H), 7.03 (t, 1H, J¼8.1 Hz), 9.38
(s, 1H); 13C NMR (75 MHz, DMSO): d¼14.9, 56.8, 60.6,
60.9, 61.6, 101.2, 112.7, 115.1, 115.9, 119.6, 130.1, 133.3,
135.7, 139.1, 153.4, 153.6, 158.0, 162.9, 164.9; LRMS
(CI): 430 MH+; mp: 205 ꢀC.
4.6. General procedure D: synthesis of alcohols 9
A suspension of enol 5 (1 equiv), zinc powder (6 equiv),
and a few drops of sulfuric acid in acetic acid 150 mL
was vigorously stirred at 100 ꢀC for 2 h. A second portion
of zinc powder (6 equiv) was added and the reaction mix-
ture was then stirred at 100 ꢀC until completion of the reac-
tion (followed by TLC). After cooling to room temperature
the excess of zinc and the inorganic salts were filtered off.
The filtrate was then diluted with water (300 mL). The
aqueous layer was extracted with CH2Cl2, and the com-
bined organic phases were washed with saturated NaHCO3
solution until neutral and finally dried with magnesium
sulfate. The solvents were evaporated under reduced pres-
sure and the residue used directly in the next step or was
chromatographed on silica gel (EtOAc) to furnish the pure
alcohol 9.
4.5. General procedure C: synthesis of 2,3-dioxopyrro-
lidines 5 in ethanol
A suspension of sodium diethyl oxalacetate (1 equiv), amine
(1 equiv), and aldehyde (1 equiv) in ethanol was heated at re-
flux toward complete solution (30 min) or until completion
(TLC). After cooling the mixture was added on ice-water
and then acidified with H2SO4 or H3PO4 until pH 2. The pre-
cipitate was filtered, washed with water, and dried under
reduced pressure. The powder was washed with petroleum
ether in order to remove traces of aldehyde or if necessary
recrystallized with toluene. After drying under reduced
pressure the 2,3-dioxopyrrolidines 5 were obtained with suf-
ficient purity.
4.6.1. (3S,4R,5S)-5-(4-Dimethylamino-phenyl)-3-
hydroxy-1-methyl-2-oxo-pyrrolidine-3-carboxylic acid
ethyl ester (9ctrans–trans) and (3R,4S,5S)-5-(4-dimethyl-
amino-phenyl)-3-hydroxy-1-methyl-2-oxo-pyrrolidine-
3-carboxylic acid ethyl ester (9ctrans–cis). Products
9ctrans–trans and 9ctrans–cis were prepared as described
in the GP D. Product 9ctrans–trans (560 mg, 36%) was ob-
tained as a white powder and 9ctrans–cis (83 mg, 5.4%) was
obtained as a viscous colorless oil. Product 9ctrans–trans 1H
NMR (400 MHz, CDCl3): d¼1.22 (t, 3H, J¼7.3 Hz), 2.62 (s,
4.5.1. 5-(4-Dimethylamino-phenyl)-3-hydroxy-1-methyl-
2-oxo-2,5-dihydro-1H-pyrrole-4-carboxylic acid ethyl
ester (5i). Product 5i (7.4 g, 48%) was prepared as described
in the GP C and was obtained as a white powder. Heating at
reflux for 3 days was necessary and acidification was unnec-
1
essary. H NMR (300 MHz, DMSO): d¼0.95 (s, 3H), 2.56
(s, 3H), 2.84 (s, 6H), 3.80 (q, 2H, J¼7.3 Hz), 4.78 (s, 1H),
6.63 (d, 2H, J¼8.8 Hz), 6.94 (d, 2H, J¼8.8 Hz); 13C NMR
(75 MHz, DMSO): d¼15.3, 28.0, 41.1, 57.8, 62.5, 99.9,
112.9, 128.9, 129.1, 129.8, 150.5, 166.1, 169.9, 170.6;
LRMS (CI): 305 MH+; mp: 186 ꢀC.
3
3H), 2.96 (s, 6H), 3.06 (t, 1H, 2ꢁ J¼8.4 Hz), 4.18 (q, 2H,
J¼7.3 Hz), 4.53 (d, 1H, J¼8.1 Hz), 4.66 (d, 1H, J¼
8.8 Hz), 6.71 (d, 2H, J¼8.8 Hz), 7.13 (d, 2H, J¼8.8 Hz);
13C NMR (100 MHz, CDCl3): d¼14.1, 28.1, 40.3, 56.1,
61.3, 62.9, 72.6, 112.5, 124.6, 128.3, 150.8, 171.5, 173.0;
LRMS (CI): 307 MH+; mp: 45 ꢀC.
4.5.2. 3-Hydroxy-1-methyl-2-oxo-5-phenyl-2,5-dihydro-
1H-pyrrole-3-carboxylic acid ethyl ester (5j). Product 5j

B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
6025
Product 9ctrans–cis 1H NMR (300 MHz, CDCl3): d¼0.94 (t,
3H, J¼7.3 Hz), 2.74 (s, 3H), 2.94 (s, 6H), 3.59 (t, 1H,
7.45–7.49 (m, 3H), 7.55–7.59 (m, 2H), 8.21 (s, 1H), 8.31
(d, 2H, J¼8.78 Hz), 8.61 (br s, 1H); LRMS (CI): 350
MH+; mp: 188 ꢀC.
3
2ꢁ J¼7.4 Hz), 3.78–3.88 (m, 2H), 4.08–4.17 (m, 1H),
4.55 (d, 1H, J¼7.3 Hz), 4.68 (d, 1H, J¼7.3 Hz), 6.67 (d,
2H, J¼8.8 Hz), 7.11 (d, 2H, J¼8.8 Hz); 13C NMR
(75 MHz, CDCl3): d¼13.6, 28.6, 40.2, 49.4, 60.7, 62.7,
70.4, 112.0, 121.8, 128.6, 151.0, 169.6, 173.2; LRMS (CI):
307 MH+.
4.7.3. 4-(Ethoxycarbonyl-hydroxy-methylene)-5-oxo-2-
phenyl-4,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl
ester (16). To a suspension of 2c (462 mg, 2.00 mmol) in
(5 mL) was added diethyl oxalate (0.55 mL, 4.00 mmol)
and sodium ethoxide (5 mmol from sodium (115 mg) dis-
solved in 3 mL ethanol). The mixture was heated at reflux
for 2 h, partially concentrated under reduced pressure,
diluted with water and acidified with acetic acid affording
a white precipitate. After filtering and drying under reduced
pressure compound 16 (250 mg, 40%) was obtained as
a white powder. 1H NMR (300 MHz, CDCl3): d¼1.03
(t, 3H, J¼6.9 Hz), 1.37 (t, 3H, J¼7.3 Hz), 4.17 (q, 2H,
J¼7.3 Hz), 4.39 (t, 3H, J¼7.3 Hz), 7.45 (s, 5H), 9.75 (br s,
1H), 14.41 (br s, 1H); LRMS (CI): 332 MH+; mp: 178 ꢀC.
4.6.2. (3S,4R,5S)-1-Benzyl-5-(4-chloro-phenyl)-3-hy-
droxy-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester
(9dtrans–trans) and (3R,4S,5S)-1-benzyl-5-(4-chloro-
phenyl)-3-hydroxy-2-oxo-pyrrolidine-3-carboxylic acid
ethyl ester (9dtrans–cis). Products 9dtrans–trans (6.4 g,
64%) and 9dtrans–cis (520 mg, 5.2%) were prepared as
described in the GP D and were obtained as white powders.
Product 9dtrans–trans 1H NMR (300 MHz, CDCl3):
d¼1.15 (t, 3H, J¼7.3 Hz), 3.06 (t, 1H, J¼8.1 Hz), 3.52 (d,
1H, J¼14.6 Hz), 4.13 (q, 2H, J¼7.3 Hz), 4.44 (d, 1H,
J¼7.3 Hz), 4.71 (d, 1H, J¼8.1 Hz), 5.05 (d, 2H,
J¼14.6 Hz), 6.95–6.99 (m, 2H), 7.15 (d, 2H, J¼8.8 Hz),
7.25–7.27 (m, 3H), 7.36 (d, 2H, J¼8.8 Hz); LRMS (CI):
374–376 MH+; mp: 99 ꢀC.
4.7.4. 3-(4-Methoxyphenyl)-2H-pyrrolo[3,4-c]benzo-
xepine-1,4-dione (13) and 2-(4-methoxyphenyl)chro-
meno[2,3-b]pyrrole-3-carboxylic acid ethyl ester (14).
A solution of methoxyphenylpyrrolinone 2d (512 mg,
2.00 mmol), salicylaldehyde (244 mg, 2.00 mmol) in acetic
acid (2 mL) was stirred and heated in a monomode micro-
wave oven at 120 ꢀC for 30 min. After cooling to room tem-
perature the mixture was poured on water and extracted with
ether. The organic phase was washed with water and finally
dried with MgSO4. The solvent was evaporated under re-
duced pressure and the residue was chromatographed on sil-
ica gel (CH2Cl2/EtOAc 95:5) to furnish the pure 14 (87 mg,
13%) as an orange powder. Washing the slightly impure frac-
tions containing product 13 with CH2Cl2 furnished pure 13
1
Product 9dtrans–cis H NMR (300 MHz, CDCl3): d¼0.92
(t, 3H, J¼7.3 Hz), 3.50 (t, 1H, J¼8.1 Hz), 3.61 (d, 1H,
J¼14.6 Hz), 3.67–3.81 (m, 3H), 4.56 (t, 2H, J¼6.6 Hz),
5.16 (d, 1H, J¼14.6 Hz), 6.98–7.02 (m, 2H), 7.23 (d, 2H,
J¼8.8 Hz), 7.26–7.28 (m, 3H), 7.30 (s, 2H, J¼8.8 Hz);
13C NMR (75 MHz, CDCl3): d¼14.0, 45.2, 48.7, 60.2,
61.6, 70.9, 128.4, 128.9, 129.2, 129.3, 130.1, 133.9, 135.2,
135.6, 169.7, 173.1; LRMS (CI): 374–376 MH+; mp: 117–
118 ꢀC.
1
(50 mg, 8%) as yellow-orange powder. Compound 13 H
4.7. General procedure E: synthesis of benzylidene-5-
aryl-2-oxopyrroles 10
NMR (300 MHz, DMSO): d¼3.85 (s, 3H), 7.04 (d, 2H, J¼
8.8 Hz), 7.16 (d, 1H, J¼8.8 Hz), 7.28 (t, 1H, J¼7.3 Hz),
7.39 (s, 1H), 7.48 (t, 1H, J¼7.3 Hz), 7.64 (d, 1H, J¼
7.3 Hz), 7.74 (d, 2H, J¼8.8 Hz), 11.41 (br s, 1H); 13C
NMR (75 MHz, DMSO): d¼56.3, 99.0, 114.2, 120.3, 122.8,
124.9, 126.3, 128.5, 130.7, 132.8, 133.7, 134.1, 150.7, 156.5,
159.0, 162.3, 166.7; UV (CH2Cl2): lmax (log 3)¼427 nm
(4.230), 310 (4.072); LRMS (CI): 320 MH+; mp: 287 ꢀC.
To a solution of oxopyrrole 2 (1 equiv) in ethanol was added
aromatic aldehyde (1 equiv). A catalytic amount of concen-
trated HCl was added and the mixture was heated under
reflux for 2 h. During cooling to room temperature orange
crystals precipitated. The solid was filtered and washed
with cold ethanol. After drying under reduced pressure,
compound 10 was obtained as orange powder.
Compound 14 1H NMR (300 MHz, CDCl3): d¼1.42 (t, 3H,
J¼7.3 Hz), 3.88 (s, 3H), 4.41 (q, 2H, J¼7.3 Hz), 6.99 (d, 2H,
J¼8.8 Hz), 7.48 (t, 1H, J¼7.3 Hz), 7.69 (t, 1H, J¼7.3 Hz),
7.76 (d, 1H, J¼7.3 Hz), 7.85 (d, 1H, J¼7.3 Hz), 8.25 (d,
1H, J¼8.8 Hz), 8.65 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼14.8, 55.7, 60.3, 103.4, 113.5, 118.2, 120.9, 125.4,
127.5, 128.8, 129.7, 132.0, 133.3, 136.4, 151.3, 161.8,
163.4, 164.5, 164.9; LRMS (CI): 348 MH+; mp: 134 ꢀC.
4.7.1. 4-(4-Carboxy-benzylidene)-2-(4-methoxy-phenyl)-
5-oxo-4,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl
ester (10a). Product 10a (1.09 g, 69%) was prepared as
described in the GP E and was obtained as an orange
1
powder. H NMR (300 MHz, DMSO): d¼1.1 (t, 3H), 3.8
(s, 1H), 4.1 (q, 2H), 7.0 (d, 2H, J¼8.8 Hz), 7.5 (d, 2H,
J¼8.8 Hz), 7.9 (d, 2H, J¼8.1 Hz), 8.0 (s, 1H), 8.1 (d, 2H,
J¼8.8 Hz), 10.9 (s, 1H); 13C NMR (75 MHz, DMSO):
d¼14.6, 56.2, 60.3, 102.9, 114.1, 122.7, 129.6, 131.6,
131.8, 131.9, 137.9, 139.3, 152.6, 161.8, 164.3, 167.3,
167.7; LRMS (CI): 394 MH+; mp: 282 ꢀC.
4.7.5. 5-Oxo-2-phenyl-4-(phenyl-hydrazono)-4,5-di-
hydro-1H-pyrrole-3-carboxylic acid ethyl ester (18).
To a suspension of 2c (924 mg, 4.00 mmol) in ethanol
(10 mL) was added freshly prepared phenyldiazonium chlo-
ride (560 mg, 4.00 mmol). The mixture was refluxed for 1 h.
After 5–6 min compound 18 started to precipitate. After
cooling, the precipitate was filtered and dried affording 18
(804 mg, 60%) as bright orange crystals. 1H NMR
(300 MHz, CDCl3): d¼0.98 (t, 3H, J¼6.9 Hz), 4.11 (q,
2H, J¼6.6 Hz), 7.01–7.57 (m, 10H), 9.04 (br s, 1H), 13.34
(br s, 1H); LRMS (CI): 366 MH+; mp: 199 ꢀC.
4.7.2. 4-(4-Methoxy-benzylidene)-5-oxo-2-phenyl-4,5-di-
hydro-1H-pyrrole-3-carboxylic acid ethyl ester (10b).
Product 10b (1.24 g, 89%) was prepared as described in
1
the GP E and was obtained as a yellow powder. H NMR
(300 MHz, CDCl3): d¼1.13 (t, 3H, J¼7.3 Hz), 3.90 (s,
3H), 4.23 (q, 2H, J¼7.3 Hz), 6.94 (dd, 2H, J¼8.8 Hz),

6026
B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
4.7.6. 4-(Bis(methylthio)methylene)-5-oxo-2-phenyl-4,5-
dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (19).
To a solution of 2c (462 mg, 2.00 mmol) in DMSO
(10 mL) was added triethylamine (0.55 mL, 4.00 mmol). Af-
ter 3 min, CS2 (0.132 mL, 2.00 mmol) was added and methyl
iodide was added after the color change. The reaction mix-
ture was stirred at room temperature for 4 h and then poured
on ice-water and acidified with acetic acid (1 mL). The aque-
ous mixture was extracted with ethyl acetate. The organic
phase was washed with water and brine and finally dried
with magnesium sulfate. The solvents were evaporated
in vacuo and the viscous residue was chromatographed
on silica gel (CH2Cl2/EtOAC 4:1) to furnish the pure 19
(400 mg, 60%) as yellow crystals. 1H NMR (300 MHz,
CDCl3): d¼1.25 (t, 3H, J¼7.3 Hz), 2.50 (s, 3H), 2.63 (s,
3H), 4.23 (q, 2H, J¼7.0 Hz), 7.38–7.43 (m, 3H), 7.58–7.62
(m, 2H), 9.17 (br s, 1H); LRMS (CI): 336 MH+; mp: 118 ꢀC.
99%) was prepared as described in the GP F and was
obtained as an orange-brown powder.
The same product 20b (76 mg, 66%) was also prepared as
described in the GP G. 1H NMR (300 MHz, CDCl3):
d¼1.01 (t, 3H, J¼7.1 Hz), 4.10 (q, 2H, J¼7.2 Hz), 5.05 (s,
2H), 6.82 (m, 2H), 7.26 (m, 8H), 10.49 (s, 1H); 13C NMR
(75 MHz, CDCl3): d¼13.7, 48.0, 60.3, 114.3, 119.1, 123.3,
126.1, 127.8, 128.1, 128.7, 129.3, 130.2, 130.5, 135.4,
139.2, 163.3, 186.7; LRMS (CI): 368: MH+; mp: 82–84 ꢀC.
4.9.2. 5-Chloro-4-formyl-1-(2-oxo-2-phenyl-ethyl)-2-
phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (20c).
Product 20c (300 mg, 76%) was prepared as described in
the GP F and was obtained as an orange-brown powder. 1H
NMR (300 MHz, CDCl3): d¼1.03 (t, 3H, J¼7.1 Hz), 4.11
(q, 2H, J¼7.1 Hz), 5.18 (s, 2H), 7.40–7.53 (m, 10H), 10.50
(s, 1H); 13C NMR (75 MHz, CDCl3): d¼13.8, 50.8, 60.4,
114.0, 119.1, 123.4, 127.3, 128.4, 129.1, 129.5, 130.2,
130.4, 133.8, 134.5, 139.5, 163.2, 187.0, 190.8; LRMS
(CI): 396: MH+; mp: 79–81 ꢀC.
4.7.7. 5-Chloro-4-formyl-2-phenyl-1H-pyrrole-3-carbox-
ylic acid ethyl ester (20a). To pyrrolinone 2c (5.00 g,
21.0 mmol) in DMF (3.40 mL, 43.0 mmol) was added
POCl3 (16.1 mL, 173 mmol) in a dropswise manner at
T<10 ꢀC. The mixture was heated overnight at 100 ꢀC and
then poured on ice (800 mL). After 2 h stirring the suspen-
sion was extracted with ethyl acetate (4ꢁ100 mL). The or-
ganic phase was washed with brine and water and finally
dried with magnesium sulfate. The solvents were evaporated
in vacuo and the residue was filtered over silica gel (CH2Cl2)
to furnish the pure 20a (4.82 g, 80%) as brownish powder.
1H NMR (300 MHz, CDCl3): d¼1.20 (t, 3H, J¼7.1 Hz),
4.23 (q, 2H, J¼7.2 Hz), 7.40 (m, 5H), 9.17 (s, 1H), 10.32
(s, 1H); 13C NMR (75 MHz, CDCl3): d¼14.0, 60.9, 112.8,
119.6, 122.0, 128.4, 128.9, 129.3, 130.1, 136.4, 163.8,
186.9; LRMS (CI): 278: MH+; mp: 160 ꢀC.
4.9.3. 5-Chloro-1,2-bis-(4-chlorophenyl)-4-formyl-1H-
pyrrole-3-carboxylic acid ethyl ester (20d). Product 20d
(740 mg, 66%) was prepared as described in the GP G and
was obtained as a white powder. 1H NMR (300 MHz,
CDCl3): d¼1.13 (t, 3H, J¼7.3 Hz), 4.19 (q, 2H, J¼7.3 Hz),
7.03 (d, 2H, J¼8.2 Hz), 7.08 (d, 2H, J¼8.2 Hz), 7.22 (d,
2H, J¼9.1 Hz), 7.34 (d, 2H, J¼9.1 Hz), 10.43 (s, 1H); 13C
NMR (75 MHz, CDCl3): d¼14.3, 61.2, 115.1, 119.7,
124.8, 128.4, 128.6, 130.0, 130.1, 133.4, 135.5, 136.1,
138.1, 163.5, 186.8; LRMS (CI): 422 MH+; mp: 199 ꢀC.
4.9.4. 6-Benzyl-5-chloro-7-phenyl-2,6-dihydro-pyr-
rolo[3,4-d]pyridazin-1-one (21a). To a solution of 20b
(183 mg, 0.50 mmol) in ethanol (10 mL) was added hydra-
zine monohydrate (50 mL, 1.00 mmol). The reaction mixture
was heated at reflux for 4 h. On cooling 21a precipitated.
Theprecipitatewas filtered and washed with cold ethanol fur-
4.8. General procedure F: synthesis of N-substituted
pyrroles 20 via alkylation
To pyrrole aldehyde 20a (1 equiv) in acetonitrile was added
alkylating agent (1.4 equiv) and K2CO3 (1.6 equiv). The
mixture was heated overnight at 60 ꢀC and then poured on
ice. The suspension was extracted with ethyl acetate. The
organic phase was washed with brine and water and finally
dried with magnesium sulfate. The solvents were evaporated
in vacuo and the residue was chromatographed over silica
gel (CH2Cl2/EtOAc) to furnish the pure N-substituted pyr-
roles 20.
1
nishing 21a (108 mg, 64%) as yellow crystals. H NMR
(300 MHz, DMSO): d¼5.35 (s, 2H), 6.84 (d, 2H,
J¼6.6 Hz), 7.23–7.28 (m, 3H), 7.40–7.46 (m, 5H), 8.09 (s,
1H); 13C NMR (75 MHz, DMSO): d¼48.5, 111.3, 112.1,
115.9, 126.1, 127.9, 128.4, 129.1, 129.3, 129.4, 131.2,
132.7, 136.3, 157.9; LRMS (CI): 336 MH+; mp: 249–251 ꢀC.
4.9.5. 6-Benzyl-5-chloro-2-methyl-7-phenyl-2,6-dihydro-
pyrrolo[3,4-d]pyridazin-1-one (21b). To a solution of
20b (877 mg, 2.40 mmol) in ethanol (40 mL) was added
methyl hydrazine (190 mL, 3.60 mmol). The reaction mix-
ture was heated at reflux overnight. The solvent was evapo-
rated in vacuo and the residue was chromatographed over
silica gel (CH2Cl2/EtOAc 9:1) to furnish the pure 21b
(352 mg, 42%) as orange crystals. 1H NMR (300 MHz,
CDCl3): d¼3.69 (s, 3H), 5.31 (s, 2H), 6.86 (m, 2H), 7.26
(m, 3H), 7.37 (m, 5H), 8.00 (s, 1H); 13C NMR (75 MHz,
CDCl3): d¼38.1, 48.7, 111.2, 112.4, 116.2, 126.0, 127.9,
128.2, 128.9, 129.2, 130.9, 132.9, 135.8, 157.6; LRMS
(CI): 350 MH+; mp: 77 ꢀC.
4.9. General procedure G: synthesis of N-substituted
pyrroles 20 via chloroformylation
To N-substituted oxopyrrole 2 (1 equiv) in DMF (2 equiv)
was added POCl3 (8 equiv) in a dropswise manner at
T<10 ꢀC. The mixture was heated overnight at 120 ꢀC and
then poured on ice. After 2 h stirring the suspension was ex-
tracted with ethyl acetate. The organic phase was washed
with brine and water and finally dried with magnesium sul-
fate. The solvents were evaporated in vacuo and the residue
was filtered over silica gel (CH2Cl2) to furnish the pure
N-substituted pyrrole 20.
4.9.6. Diethyl 6-benzyl-5-phenyl-6H-thieno[2,3-b]pyr-
role-2,4-dicarboxylate (24). To a solution of 20b (741 mg,
2.00 mmol) in ethanol (20 mL) was added mercapto ethyl
4.9.1. 1-Benzyl-5-chloro-4-formyl-2-phenyl-1H-pyrrole-
3-carboxylic acid ethyl ester (20b). Product 20b (3.97 g,

B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
6027
acetate (0.333 mL, 3.00 mmol). The reaction mixturewas re-
fluxed overnight. On standing 24 precipitated. The precipi-
tate was filtered and washed with water. After drying under
reduced pressure product 24 (323 mg, 37%) was obtained
as a white powder. 1H NMR (300 MHz, CDCl3): d¼1.24 (t,
3H, J¼7.1 Hz), 1.36 (t, 3H, J¼7.1 Hz), 4.22 (q, 2H,
J¼7.1 Hz), 4.33 (q, 2H, J¼7.1 Hz), 5.01 (s, 2H), 7.05 (m,
2H), 7.29 (m, 3H), 7.45 (m, 5H), 8.06 (s, 1H); 13C NMR
(75 MHz, CDCl3): d¼14.3, 14.4, 59.8, 61.1, 77.2, 126.3,
127.1, 127.5, 128.2, 128.4, 128.6, 128.9, 129.3, 129.5,
130.6, 130.7, 134.4, 139.5, 146.4, 163.4, 163.8; LRMS
(CI): 434: (MH+); mp: 137 ꢀC.
fellowship to B.M. The Fonds voor Wetenschappelijk
Onderzoek Vlaanderen (FWO grant G.0172.02) and the
Ministerie voor Wetenschapsbeleid (Belgium, DWTC-
IUAP-V-03) are thanked for continuous support. M.S. thanks
the FWO for a postdoctoral fellowship.
References and notes
1. Barreca, M. L.; Rao, A.; De Luca, L.; Zappala, M.; Gurnari, C.;
Monforte, P.; De Clercq, E.; Van Maele, B.; Debyser, Z.;
Witvrouw, M.; Briggs, J. M.; Chimirri, A. J. Chem. Inf.
Comput. Sci. 2004, 44, 1450–1455.
2. Ishihara, Y.; Imamura, S.; Hashiguchi, S.; Nishimura, O.;
Kanzaki, N.; Baba, M. World Patent WO 2,000,066,551,
2000.
3. Kolocouris, N.; Kolocouris, A.; Foscolos, G. B.; Fytas, G.;
Neyts, J.; Padalko, E.; Balzarini, J.; Snoeck, R.; Andrei, G.;
De Clercq, E. J. Med. Chem. 1996, 39, 3307–3318.
4. Wunberg, T.; Baumeister, J.; Betz, U.; Jensen, A.; Nikolic, S.;
Reefschlaeger, J.; Zimmermann, H.; Zumpe, F.; Grosser, R.;
Kleymann, G.; Bender, W.; Henninger, K.; Hewlett, G.; Kelde-
nich, J. World Patent WO 2,003,097,595, 2003.
5. Koz’minykh, V. O.; Igidov, N. M.; Zykova, S. S.; Kolla, V. E.;
Shuklina, N. S.; Odegova, T. Pharm. Chem. J., Khim.-Farm. Zh.
2002, 36, 188–191.
6. Silina, T. A.; Gein, V. L.; Gein, L. F.; Voronina, E. V. Pharm.
Chem. J., Khim.-Farm. Zh. 2003, 37, 585–587.
7. Gein, V. L.; Voronina, E. V.; Ryumina, T. E.; Novoselova,
G. N.; Potemkin, K. D.; Andreichikov, Y. S. Khim.-Farm. Zh.
1996, 30, 25–26.
4.10. General procedure H: synthesis of azepines 25, 26,
and 27
To N-benzylated pyrrole aldehyde 20b (1 equiv) in ethanol
was added the ortho functionalized aniline (1 equiv) and
a few drops of piperidine. The reaction mixture was heated
at reflux for 4 h. After partial evaporation of the solvent
under reduced pressure the mixture was diluted with diethyl
ether. The precipitated piperidine salts were filtered. The fil-
trate was evaporated in vacuo. The residue was chromato-
graphed over silica gel (CH2Cl2/EtOAc) to furnish the
pure azepines as brown viscous oils.
4.10.1. 8-Benzyl-10-ethoxycarbonyl-9-phenylpyr-
rolo[7,6-b]-1,4-benzoxazepine (25). Product 25 (81 mg,
38%) was prepared as described in the GP H and was ob-
tained as a brown viscous oil. 1H NMR (300 MHz, CDCl3):
d¼1.12 (t, 3H, J¼7.1 Hz), 4.13 (q, 2H, J¼7.1 Hz), 7.26 (m,
14H), 4.96 (s, 2H), 8.75 (s, 1H); 13C NMR (75 MHz,
CDCl3): d¼14.0, 46.3, 59.9, 103.9, 108.6, 120.3, 126.2,
126.3, 127.7, 128.0, 128.1, 128.8, 128.9, 130.2, 130.5,
134.5, 136.4, 140.7, 148.0, 151.7, 157.3, 163.6; LRMS
(CI): 423 MH+.
8. Lovren, F.; Gaon, I. D.; Bobarevic, B. Arch. Pharm. (Weinheim,
Ger.) 1989, 323, 901–904.
9. Sano, T.; Horiguchi, Y.; Toda, J.; Imafuku, K.; Tsuda, Y. Chem.
Pharm. Bull. 1984, 32, 497–503.
10. Aasen, A. J.; Culvenor, C. C. J. J. Org. Chem. 1969, 34, 4143–
4147.
11. Goldschmidt, B. M. J. Org. Chem. 1962, 27, 4057–4058.
12. Tufariello, J. J.; Tette, J. P. J. Org. Chem. 1975, 40, 3866–3869.
13. Bordner, J.; Rapoport, H. J. Org. Chem. 1965, 30, 3824–
3828.
14. Chamberlain, T. World Patent WO 2,001,074,950, 2001.
15. Morton, C. J. H.; Gilmour, R.; Smith, D. M.; Lightfoot, P.;
Slawin, A. M. Z.; MacLean, E. J. Tetrahedron 2002, 58,
5547–5565.
16. Ueda, A.; Sekiya, Y.; Taniguchi, M. Japanese Patent JP
2,003,165,918, 2003.
4.10.2. 8-Benzyl-10-ethoxycarbonyl-9-phenylpyr-
rolo[7,6-b]-1,4-benzothiazepine (26). Product 26 (100 mg,
45%) was prepared as described in the GP H and was ob-
tained as a brown viscous oil. 1H NMR (300 MHz, CDCl3):
d¼1.09 (t, 3H, J¼7.1 Hz), 4.10 (q, 2H, J¼7.1 Hz), 6.79 (m,
2H), 5.08 (s, 2H), 7.09 (m, 4H), 7.22 (m, 3H), 7.32 (m,
5H), 9.12 (s, 1H); 13C NMR (75 MHz, CDCl3): d¼14.0,
48.3, 60.0, 112.3, 121.7, 126.2, 126.8, 127.3, 127.4, 127.6,
128.0, 128.7, 128.8, 129.0, 129.3, 130.4, 130.8, 132.1,
136.8, 141.4, 150.8, 158.5, 163.3; LRMS (CI): 439 MH+.
4.10.3. 1-Benzyl-2-phenyl-1,10-dihydro-benzo[b]pyr-
rolo[2,3-e][1,4]diazepine-3-carboxylic acid ethyl ester
(27). Product 27 (67 mg, 36%) was prepared as described
17. Ohashi, Y. Europ. Patent EP 1,344,778, 2003.
18. Adam, J.-M.; Dalvi, P. V.; Ekkundi, V. S.; Bacher, J.-P.; Tiwari,
S. World Patent WO 2,004,083,170, 2004.
19. Adam, J.-M.; Dalvi, P. V.; Ekkundi, V. S.; Bacher, J.-P.;
Sreenivasan, R.; Rane, D. M. World Patent WO 2,004,089,941,
2004.
1
in the GP H and was obtained as a brown viscous oil. H
NMR (300 MHz, DMSO): d¼1.17 (t, 3H, J¼7.1 Hz), 4.02
(q, 2H, J¼7.1 Hz), 5.15 (s, 2H), 7.32 (m, 14H); 13C NMR
(75 MHz, DMSO): d¼14.2, 53.1, 60.9, 93.1, 113.9, 116.3,
123.3, 123.8, 126.7, 127.0, 127.7, 128.0, 129.0, 131.4,
136.3, 136.9, 139.2, 153.5, 157.5; LRMS (CI): 422 MH+.
20. Grob, C. A.; Ankli, P. Helv. Chim. Acta 1949, 32, 2010–
2038.
21. Fisher, H.; Muller, J. Hoppe-Seyler’s Z. Physiol. Chem. 1924,
132, 73–103.
¨
22. Emery, W. O. Liebigs Ann. Chem. 1890, 260, 137.
23. Steglich, W.; Gruber, P.; Heininger, H. U.; Kneidl, F. Chem.
Ber. 1971, 104, 3816–3830.
Acknowledgements
The authors are grateful to the Research Council of the Uni-
versity of Leuven (IDO-grant IDO/00/001) for a doctoral
24. Pfenninger, J.; Iqbal, A.; Rochat, A.; Wallquist, O. Europ.
Patent EP 0,184,982, 1986.

6028
B. Metten et al. / Tetrahedron 62 (2006) 6018–6028
25. Morton, C. J. H.; Riggs, R. L.; Smith, D. M.; Westwood, N. J.;
Lightfoot, P.; Slawin, A. M. Z. Tetrahedron 2005, 61, 727–738.
26. Schiff; Bertini. Ber. Dtsch. Chem. Ges. 1897, 30, 602.
27. Merchant, J. R.; Srinivasan, V. Recl. Trav. Chim. Pays-Bas
1962, 81, 144–155.
28. Becher, J.; Jorgensen, P. L.; Pluta, K.; Krake, N. J.; Falt-
Hansen, B. J. Org. Chem. 1992, 52, 2127–2134.
29. Abd El Latif, F. M. J. Heterocycl. Chem. 2000, 37, 1659–1662.
30. Schadeli, U.; Iqbal, A. World Patent WO 9,845,756, 1998.
31. Castagnoli, N., Jr.. J. Org. Chem. 1969, 34, 3187–3189.