Three-component access to 2-pyrrolin-5-ones and their use in target-oriented and diversity-oriented synthesis

Article abstract of DOI:10.1039/c6ra06317a

The Hantzsch-type microwave-assisted, solvent-free sequential three-component reaction between primary amines, β-dicarbonyl compounds and α-bromoesters in the presence of indium trichloride afforded 2-pyrrolin-5-ones, which are difficult to access by alternative methods. Ready access to these compounds allowed their use as synthetic building blocks in a target-oriented project aimed at the synthesis of a compound that had previously been postulated as a candidate for HIV integrase inhibition on the basis of computational studies. The versatility of 2-pyrrolin-5-ones was further verified by their use in a diversity-oriented synthesis context, leading to a library of highly functionalized bispiro compounds. The overall process leading to these compounds involved the generation of six bonds and two cycles over three steps, two of which are multicomponent, and the fully controlled generation of up to four stereocenters, including two quaternary ones.

Full text of DOI:10.1039/c6ra06317a

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Three-component access to 2-pyrrolin-5-ones and their use in
target-oriented and diversity-oriented synthesis
Ángel Cores,a Verónica Estévez,a Mercedes Villacampaa and J. Carlos Menéndeza*
Received 00th January 20xx,
Accepted 00th January 20xx
The Hantzsch-type microwave-assisted, solvent-free sequential three-component reaction between primary amines, β-
dicarbonyl compounds and α-bromoesters in the presence of indium trichloride afforded 2-pyrrolin-5-ones, which are
difficult to access by alternative methods. Ready access to these compounds allowed their use as synthetic building blocks
in a target-oriented project aimed at the synthesis of a compound that had previously been postulated as a candidate for
HIV integrase inhibition on the basis of computational studies. The versatility of 2-pyrrolin-5-ones was further verified by
their use in a diversity-oriented synthesis context, leading to a library of highly functionalized bispiro compounds. The
overall process leading to these compounds involved the generation of six bonds and two cycles over three steps, two of
which are multicomponent, and the fully controlled generation of up to four stereocenters, including two quaternary ones.
DOI: 10.1039/x0xx00000x
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described in the literature, although there is some precedent
for the use of multicomponent approaches for the preparation
Introduction
Pyrrole is one of the most important simple heterocycles and
constitutes the structural core of a large number of natural
products1 and synthetic bioactive compounds,2 including some
drugs in clinical use such as the cholesterol-lowering agent
atorvastatin, the best-selling drug of all time.3 Nevertheless,
some promising pyrrole-derived simple frameworks have
received very little attention because of their poor synthetic
accessibility. This is the case of the 2-pyrrolin-5-one system,
which has been described only a few times, and has normally
been accessed by complex multistep routes in very modest
yields.4
of their conjugated isomers derived from the 2-pyrrolin-3-one
skeleton.6 Furthermore, the 2-pyrrolin-5-one thus prepared
should be suitably functionalized to allow subsequent
manipulation.
We envisioned that it should be possible to adapt the classical
Hantzsch pyrrole synthesis7 for our purpose. This endeavour
would involve developing the three-component reaction
between primary amines,
α
-haloesters and
β-dicarbonyl
, and we describe in this
compounds to furnish compounds
1
article the translation of this idea into practice. A two-
component process somewhat related to the one we propose
Multicomponent reactions (MCRs) have emerged as powerful
here and involving the reaction of β-enamino esters with α-
synthetic strategies because of their
efficiency, atom
ketoaldehydes affords mixtures of regioisomers, giving good
results only for N-hydroxyethyl or N-hydroxypropyl enamino
esters, presumably because of the stabilization of the 5-oxo
product by intramolecular hydrogen bonding.8,9 A three-
component variation of this reaction, starting from primary
economy, high selectivity, and convenient construction of
multiple new bonds; these characteristics give rapid access to
combinatorial libraries of complex organic molecules for
efficient lead structure identification and optimization in drug
discovery. From the point of view of the generation of
molecular diversity, the development of MCRs with a broad
range of functional group tolerance are ideal because such
reactions allow performing complexity-generating post-MCR
transformations, such as cyclizations.5
amines,
exclusively 4-hydroxypyrroles.10
α-ketoaldehydes and β-dicarbonyl compounds gives
In order to further establish the synthetic usefulness of this
new method, we demonstrated its application to two
situations with very different requirements, i.e. target-
oriented and diversity-oriented synthesis (Scheme 1). For the
In this context, it would be advantageous a synthetic efficiency
perspective to devise a multicomponent approach to the 2-
pyrrolin-5-one framework in order to pave the way to a deeper
knowledge of its chemistry and pharmacology. Furthermore,
to our knowledge such a reaction would be the first one to be
first goal, we chose as our target compound 2, which has been
recently postulated as a candidate for HIV integrase inhibition.
This proposal arose from a computational study aimed at the
identification of new pharmacophores for the design of
integrase inhibitors based on shape-based virtual screening of
drug-like databases followed by in silico ADMET optimization,
a.Departamento de Química Orgánica
Universidad Complutense, 28040 Madrid, Spain.
y Farmacéutica. Facultad de Farmacia,
Electronic Supplementary Information (ESI) available: [copies of spectra of all
compounds]. See DOI: 10.1039/x0xx00000x
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ethanol in the presence of 5% Ce(IV) ammonium nitrate (CAN)
as a Lewis acid,18 initially at room temperature and then under
reflux conditions, but no reaction was observed (entries 1 and
2). The use of focused microwave irradiation was also
unsuccessful (entries 3 and 4). However, when the reaction
was performed under solvent-free conditions, compound 1a
was obtained in 53% yield (entry 5), with no improvement
being observed upon increase of the catalyst load (entry 6).
Lanthanide triflates, represented by yttrium and ytterbium
triflates, were also assayed, again with no improvement
(entries 7 and 8). Boron trifluoride etherate failed to catalyze
the reaction (entry 9), and aluminium trichloride gave only
modest yields, even with 10% catalyst load (entries 10 and 11).
Finally, indium trichloride was found to improve the results
obtained with CAN, giving a 60% yield of 1a with a 5% loading
(entry 12) and almost the same result with 10% of the catalyst
(entry 13). One final attempt was made using Montmorillonite
K10, a clay with acidic properties that is compatible with
microwave irradiation,19 but it failed to promote our reaction
(entry 14).
Scheme 1. Summary of the objectives of our work
QSAR predictions and docking studies.11 Furthermore, in order
to verify the possibility of generating molecular diversity from
Scheme 2. Synthesis of compound 1a from butylamine, ethyl bromoacetate and ethyl
acetoacetate
compounds
frameworks
1
3
, we chose to study the preparation of bispiro
and 4 via the combination of our initial MCR
with a second one, namely a three-component reaction
involving the [3+2] dipolar cycloaddition of non-stabilized
azomethine ylides with activated olefins, which offers a
concise entry into functionalized spiropyrrolidine motifs with a
high regio- and diastereoselectivity. The combination of two
multicomponent reactions is generally recognized as an
excellent approach to the generation of molecular
diversity,12,13 although it has not been widely exploited.
Spirocyclic frameworks are present in many natural products
and are increasingly recognized as interesting scaffolds in drug
Table 1. Optimization of the synthesis of compound 1a
Entry Catalyst (%)
Temp (°C)
r.t.
Time (h)
20
Solvent Yield (%)
1
2
3
4
5
6
7
CAN (5)
CAN (5)
CAN (5)
CAN (5)
CAN (5)
CAN (10)
Y(OTf)3 (5)
EtOH
EtOH
EtOH
EtOH
--
0a
80
14
0
80 (MW)
120 (MW)
120 (MW)
120 (MW)
120 (MW)
0.5
0.5
0.5
0.5
0.5
0
0
53
52
50
discovery
compounds are present in numerous natural products, such as
(−)-horsfiline and spirotryprostatin and have shown
interesting pharmacological activities including
antiproliferative15 and antitubercular16 properties as well as
acetylcholinesterase inhibition,17 among others. Compounds
and have the advantage over related structures reported in
the literature of the high functionalization of their
programs.14
Furthermore,
spiropyrrolidine
--
--
A
8
Yb(OTf)3 (10)
BF3.Et2O (10)
AlCl3 (5)
120 (MW)
120 (MW)
120 (MW)
120 (MW)
120 (MW)
120 (MW)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
--
--
--
--
--
--
--
26
9
Traces
19
3
4
10
pyrrolidinone moiety, which provides synthetic handles for 11
future transformations.
AlCl3 (10)
InCl3 (5)
29
12
60
13
InCl3 (10)
58
Results and discussion
14
Montmorillonite 120 (MW)
K10
Traces
We started our optimization study by examining the model
preparation of compound 1a from butylamine, ethyl
bromoacetate and ethyl acetoacetate (Table 1). In our first
experiments, these starting materials were combined in
aUsing either ethyl bromoacetate or ethyl iodoacetate
2 | J. Name., 2012, 00, 1-3
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These optimal conditions (5% InCl3, solvent-free microwave iodide, and aluminium trichloride proved to be more efficient
irradiation, 120 °C) were applied to obtain a library of diversely in promoting the reaction than indium trichloride. Finally, we
substituted pyrrolinones in a 40-76% range of yields (Scheme 3 also examined several reactions starting from ethyl
β-
and Table 2), employing simple and commercially available aminocrotonate. Thus, its reaction with ethyl 2-bromoacetate
starting materials. The scope of the R1 substituent on nitrogen gave the N-unsubstituted pyrrolinone 1n in 55% yield (entry
included a variety of groups such as alkyl (entries 1-4, 7-9 and 14). This is a significant result because a previous preparation
13), arylalkyl (entries 5, 6 and 12), allyl (entry 10) and of this compound by reaction of the same aminocrotonate
functionalized alkyl (entry 11). The R2 chain was chosen among with glyoxal required a 7-h reflux in ethanol and afforded 1n in
several primary alkyl chains, including methyl, ethyl (entry 7) only 29% yield.8 Three additional examples of N-unsubstituted
and propyl (entries 4 and 9). The reaction was compatible with pyrrolinones were obtained by the same method (entries 15-
the presence of ester or ketone functions at C-3. While most 17). Interestingly, we did not observe the isomerization of 2-
compounds 1 were unsubstituted at C-4 because our planned pyrrolyn-5-ones to their regioisomeric 4-hydroxypyrroles
applications involved a condensation at this position, we also noticed by previous authors.9
demonstrated the possibility to prepare a C4-phenyl derivative Mechanistically, our three-component process was expected
(entry 13). In this case, the
α
-haloester component was an
to proceed via a Hantzsch-type mechanism that is depicted in
Scheme 4 for the reaction leading to compound 1a. Thus, the
reaction would start with the InCl3-catalyzed formation of a
enamino ester20, which would then react with the
-haloester
to give intermediate , which can tautomerize to species II or
β-
α
I
III. However, only the E isomer II can undergo cyclization, thus
driving these equilibria to the final product.
An alternative Paal-Knorr-like mechanism would involve the
formation of a 1,4-dicarbonyl species IV that would then react
with the primary amine to give the previous intermediate II
.
However, we verified that ethyl acetoacetate and ethyl
bromoacetate did not react at all in the presence of InCl3
Scheme 3. Sequential multicomponent synthesis of 2-pyrrolin-5-ones
1
Table 2. Results of the synthesis of compounds 1a
Entry Cmpd
R1
R2
Me
Me
Me
n-Pr
Me
Me
Et
R3
R4
H
H
H
H
H
H
H
Yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
n-Bu
n-Bu
n-Bu
n-Bu
Bn
OEt
OMe
Me
60
50
42
52
52
55
59
OEt
OEt
OMe
OEt
Bn
1g
n-Bu
8
9
1h
1i
Me
n-Hex
Me
n-Pr
Me
Me
OEt
OEt
H
H
H
H
76
72
50
43
10
11
1j
Allyl
OMe
OMe
1k
2-Hydroxyethyl
12
1l
Me
OMe
H
52
13
14
15
16
17
1m
1n
1o
1p
1q
n-Bu
H
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
Ph
H
58b
55 c
43 c
40 c
41 c
H
Me
Et
H
H
Ph
Scheme 4. Mechanistic proposal for the three-component 2-pyrrolin-5-one
synthesis
a
The X leaving group was Br in all cases except for entry 13, where X = I. b In this
case the catalyst was aluminium trichloride (10%). c From ethyl β-aminocrotonate
and the suitable α-bromoester.
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under our conditions. Furthermore, we found that treatment
of the known21 ethyl acetosuccinate IV with n-butylamine
failed to give the 2-pyrrolin-5-one 1a under our conditions.
Onthe contrary, the isolated β-enamino ester arising from n-
butylamine and ethyl acetoacetate22 furnished compound 1a
when treated with ethyl bromoacetate in the presence of InCl3
under our usual conditions.
We next turned our attention to the application of the method
to
mentioned in the Introduction, we chose as our target a 2-
pyrrolin-5-one derivative (compound that had been
a target-oriented synthesis project. To this end, as
2)
previously proposed as an inhibitor of HIV integrase on the
basis of thorough computational studies,11 but which has
never been studied experimentally owing to the lack of
suitable synthetic access. Our synthesis of
Scheme 5, and comprised the preparation of pyrrolinone 1r
from -phenetylamine, methyl acetoacetate and ethyl
2 is shown in
β
bromoacetate under our standard conditions, followed by its
Knoevenagel condensation with piperonal.23
Scheme 6. Regio- and diastereoselective synthesis of 2-pyrrolin-5-one-derived dispiro
compounds via a three-component reaction having a 1,3-dipolar cycloaddition as the
key step
Table 3. Results obtained in the synthesis of dispiro compounds 3 and 4
Entry Cmpd R1
R2
R3
H
H
H
H
H
H
R4
H
R5
H
H
H
H
H
H
Yield (%)
50
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
n-Bu
n-Bu
Bn
Me
Me
Me
Me
Me
Me
Cl
Cl
I
56
73
Bn
52
Bn
Me
H
55
Bn
65
7
3g
3h
3i
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
OMe
OMe
OMe
OMe
OMe
Cl
H
H
Bn
Bn
H
75
68
55
73
50
54
78
88
42
38
Scheme 5. Synthesis of compound
proposed by computational methods
2, a HIV integrase inhibition candidate
8
Bn
9
Bn
H
Finally, we examined the construction of a library of complex
spirocyclic systems by combining our Hantzsch-like process
with a second multicomponent reaction having as the key step
the [3+2] dipolar cycloaddition between non-stabilized
10
11
12
13
14
15
16
3j
Bn
Cl
I
H
3k
3l
Bn
H
azomethine ylides, prepared in situ from isatin and
acids, with activated olefins prepared by Knoevenagel
reactions of our 2-pyrrolin-5-ones
with aromatic aldehydes.24
Compounds thus obtained were then used as dipolarophiles
α-amino
Bn
Me
H
H
3m
3n
4a
4b
Bn
H
1
5
Bn
Br
H
H
for the construction of the spiropyrrolidine library. Starting
from five isatine derivatives and two N-substituted amino
acids, the target dispiro compounds were obtained generally in
good yields under focused microwave irradiation at 100 °C in
ethanol solution (Scheme 6 and Table 3). Probably because of
n-Bu
n-Bu
H
H
H
H
H
H
4 | J. Name., 2012, 00, 1-3
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steric hindrance, our protocol was more efficient in the case of
reactions starting from sarcosine as the amino acid component
in comparison with those involving the use of proline.
The compounds thus obtained were fully characterized by
NMR studies. Thus, a NOESY experiment carried out on
compound 4b shows NOE enhancements between the phenyl
o-proton and the
structure (see Scheme 6 below). Furthermore, the benzylic
proton gives a NOE with one of the CH2 hydrogens, which is
compatible only with structure , since in the alternative exo
structure II the benzyl hydrogen and the CH2 are too far away
to provide NOE. The proposed structure was finally
single-crystal X-Ray diffraction study of
α-amino proton, suggesting the endo
I
I
a
confirmed by
a
compound 4b (Figure 1).25
Figure 1. Single-crystal X-Ray diffraction study of compound 4b, including a
summary of the NOE effects observed in the NOESY experiment.
Scheme 7. Mechanistic proposal accounting for the regio- and
diastereoselectivity of the three-component reaction leading to dispiro
A mechanism that explains the regio- and diastereoselective
isolation of compounds
3 and 4 is given in Scheme 7, using the
compounds
3 and 4
case of 4b as a representative example. Condensation of
proline with isatin followed by decarboxylation26 furnishes a
nitrogen ylide, which acts as the 1,3-dipole in the reaction. This
intermediate could in principle react with the dipolarophile
conventional silica gel columns. Melting points were measured
with a Kofler-type heating platine microscope from Reichert,
723 model, and are uncorrected. Infrared spectra were
recorded with an Agilent Cary630 FTIR spectrophotometer
with a diamond ATR accessory for solid and liquid samples,
requiring no sample preparation; wavenumbers are given in
cm−1. NMR spectroscopic data were obtained using
spectrometers maintained by the CAI de Resonancia
Magnética, UCM, operating at 250 MHz for 1H NMR and 63
MHz for 13C NMR; chemical shifts are given in (δ) parts per
million and coupling constants (J) in hertz. Elemental analyses
were determined by the CAI de Microanálisis, Universidad
following the alternative pathways
afford two different regioisomers
A
I
and
B
, which would
respectively.
was
and II
,
However, only product
I,
formed through path
A
,
observed, which can be explained by the steric clash between
the phenyl and carbonyl groups of both reacting species in
pathway
B
. The preference for the structure endo
I over the
exo III, arising through pathway
C
, can be attributed to a
favourable secondary orbital interaction (SOI) effect between
the carbonyl groups of the dipolarophile and the dipole in the
transition state corresponding to pathway A 27
.
Complutense, using
microanalyzer.
a
Leco CHNS-932 combustion
Experimental Section
General procedure for the synthesis of 2-pyrrolin-5-one
derivatives 1
General experimental details.
All reagents and solvents were of commercial quality and were
used as received. Reactions were monitored by thin layer
chromatography on aluminium plates coated with silica gel
and fluorescent indicator. Microwave-assisted reactions were
performed on a CEM Discover focused microwave reactor.
Separations by flash chromatography were performed using a
Combiflash Teledyne automated flash chromatograph or on
To a suspension of indium trichloride (5% mmol) in the
corresponding β-dicarbonyl compound (1 eq), placed in a
microwave reaction vial, was added the suitable amine (1-1.2
eq). The mixture was stirred at room temperature for 30
minutes and monitored by TLC. After the reaction completion,
the excess of amine was evaporated under reduced pressure.
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Then, the non-isolated enamino ester and the appropriate α- 1250. Anal. calcd. for C14H15NO3: C 68.56, H 6.16, N 5.71%.
haloester (1 eq) were exposed to focused microwave Found: C 68.53, H 6.08, N 5.78%.
irradiation at 120 °C for 30 minutes. Once the reaction was Ethyl
completed, the mixture was diluted with CHCl3 (20 mL) and carboxylate (1g). Yellow oil (142 mg, 59%); 1H-NMR: (250 MHz,
washed with water (2 x 5 mL). The organic phase was dried CDCl3): 4.22 (q, J = 7.1 Hz, 2H), 3.55-3.48 (m, 2H), 3.27 (s, 2H),
over anhydrous sodium sulphate and then evaporated under 2.90-2.83 (m, 2H), 1.65-1.40 (m, 4H), 1.39-1.23 (m, 6H), 0.93 (t,
reduced pressure. The mixture was cromatographed on silica J = 7.2 Hz, 3H); 13C-NMR: (63 MHz, CDCl3):
176.4, 163.9,
gel using as eluent a mixture of hexane/ethyl acetate. 159.8, 102.9, 59.6, 40.0, 36.6, 31.5, 20.1, 19.2, 14.4, 13.7, 12.9;
Ethyl
1-butyl-2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3- IR (neat, cm-1): 1726, 1693, 1228. Anal. calcd. for C13H21NO3: C
carboxylate (1a). Orange solid (135 mg, 60%): mp 62-68 °C; 1H- 65.25, H 8.84, N 5.85%. Found: C 65.16, H 8.89, N 5.79%.
NMR (250 MHz, CDCl3): 4.21 (q, J = 7.2 Hz, 2H), 3.55-3.49 (m, Ethyl 1,2-dimethyl-5-oxo-4,5-dihydro-1H-pyrrole-3-
2H), 3.27 (q, J = 2.4 Hz, 2H), 2.47 (t, J = 2.4 Hz, 3H), 1.61-1.49 carboxylate (1h). Yellow oil (140 mg, 76%); 1H-NMR: (250 MHz,
(m, 2H), 1.43-1.24 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 0.96 (t, J = CDCl3): 4.17 (q, J = 7.1 Hz, 2H), 3.05 (s, 3H), 3.23 (q, J = 2.4 Hz,
7.2 Hz, 3H); 13C-NMR (63 MHz, CDCl3): 176.4, 163.9, 159.8, 2H), 2.42 (t, J = 7.1 Hz, 3H), 1.27 (t, 3H, J = 2.4 Hz); 13C-NMR:
103.3, 59.6, 37.0, 36.6, 31.5, 20.1, 14.4, 13.7, 12.9; IR (neat, (63 MHz, CDCl3): 176.0, 164.2, 154.1, 103.2, 59.7, 36.5, 26.3,
cm-1): 1725, 1691, 1226. Anal. calcd. for C12H19NO3: C 63.98, H 14.3, 12.4; IR (neat, cm-1): 1725, 1692, 1228. Anal. calcd. for
8.50, N 6.22%. Found: C 63.66, H 8.33, N 5.97%. C9H13NO3: C 59.00, H 7.15, N 7.65%. Found: C 59.22, H 7.30, N
Methyl 1-butyl-2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3- 7.52%.
carboxylate (1b). Yellow oil (111 mg, 50%); 1H NMR (250 MHz, Ethyl
CDCl3):
3.72 (s, 3H), 3.50 (t, J = 7.2 Hz, 2H), 3.24 (q, J = 2.3 Hz, carboxylate (1i). Orange oil (203 mg, 72%); 1H-NMR: (250
2H), 2.44 (t, J = 2.3 Hz, 3H), 1.59-1.45 (m, 2H), 1.43-1.23 (m, MHz, CDCl3): 4.20 (q, J = 7.1 Hz, 2H), 3.57-3.48 (m, 2H), 3.27
2H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3):
176.4, (s,2H), 2.82-2.76 (m, 2H), 1.63-1.57 (m, 4H), 1.34-1.26 (m, 6H),
165.1, 155.0, 103.4, 51.4, 40.4, 37.0, 31.8, 20.5, 14.1, 12.7; IR 1.29 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.0
(neat, cm-1): 1723, 1690, 1223. Anal. calcd. for C11H17NO3: C Hz, 3H); 13C-NMR: (63 MHz, CDCl3):
176.4, 163.9, 158.3,
62.54, H 8.11, N 6.63%. Found: C 62.43, H 7.89, N 6.19%. 102.9, 59.6, 40.3, 36.6, 31.3, 29.3, 27.7, 26.5, 22.5, 22.0, 14.4,
4-Acetyl-1-butyl-5-methyl-1,3-dihydro-2H-pyrrole-2-one (1c). 14.1, 14.0; IR (neat, cm-1): 1726, 1702, 1227. Anal. calcd. for
Yellow oil (82 mg, 42%); 1H-NMR (250 MHz, CDCl3):
3.57-3.51 C16H27NO3: C 68.29, H 9.67, N 4.98%. Found: C 68.22, H 9.30, N
1-butyl-2-ethyl-5-oxo-4,5-dihydro-1H-pyrrole-3-
δ
δ
δ
δ
δ
δ
1-hexyl-5-oxo-2-propyl-4,5-dihydro-1H-pyrrole-3-
δ
δ
δ
δ
δ
(m, 2H), 3.34 (q, J = 2.3 Hz, 2H), 2.50 (t, J = 2.3 Hz, 3H), 2.22 (s, 4.82%.
3H), 1.58 -1.49 (m, 2H), 1.44-1.29 (m, 2H), 0.96 (t, J = 7.0 Hz, Methyl
1-allyl-2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-
1
3H); 13C-NMR (63 MHz, CDCl3):
δ
192.8, 175.4, 154.0, 111.8, carboxylate (1j). Yellow oil (98 mg, 50%); H NMR (250 MHz,
39.8, 37.1, 31.2, 29.5, 20.0, 13.6, 12.8; IR (neat, cm-1): 1721, CDCl3):
5.84-5.62 (m, 1H), 5.16-4.96 (m, 2H), 4.11 (dt, J = 5.0,
1659. Anal. calcd. for C11H17NO2: C 67.66, H 8.78, N 7.17%. 1.7 Hz, 2H), 3.67 (s, 3H), 3.24 (q, J = 2.4 Hz, 2H), 2.36 (t, J = 2.4
Found: C 67.32, H 8.44, N 6.81%. 174.6, 163.6, 153.5, 131.3,
Hz, 3H); 13C NMR (63 MHz, CDCl3):
Ethyl
1-butyl-5-oxo-2-propyl-4,5-dihydro-1H-pyrrole-3- 115.8, 102.1, 50.1, 41.0, 35.5, 11.2; IR (neat, cm-1): 1720, 1685,
carboxylate (1d). Orange oil (132 mg, 52%); 1H-NMR: (250 1228. Anal. calcd. for C10H13NO3 C 61.53, H 6.71, N 7.18%.
MHz, CDCl3): 4.18 (q, J = 7.1 H, 2H), 3.50-3.44 (m, 2H), 3.24 Found: C 61.19, H 6.65, N 6.98%.
δ
δ
δ
(s, 2H), 2.82-2.76 (m, 2H), 1.64-1.48 (m, 4H), 1.40-1.23 (m, 2H), Methyl 1-(2-hydroxyethyl)-2-methyl-5-oxo-4,5-dihydro-1H-
1.28 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H), 0.93 (t, J = 7.2 pyrrole-3-carboxylate (1k). Pale red solid (86 mg, 43%): mp
Hz, 3H); 13C-NMR: (63 MHz, CDCl3):
δ 176.3, 163.9, 158.3, 111-114 °C; NMR data are identical to those found in the
102.9, 59.6, 40.0, 36.6, 31.3, 27.6, 22.0, 20.0, 14.3, 14.0, 13.6; literature.9 IR (neat, cm-1): 3482, 2940, 1715, 1669, 1616, 1231.
IR (neat, cm-1): 1728, 1694, 1218. Anal. calcd. for C14H23NO3: C Anal. calcd. for C9H13NO: C 54.26, H, 6.58, N, 7.03%. Found: C
66.37, H 9.15, N 5.53%. Found: C 65.33, H 9.00, N 5.36%.
54.14, H 6.39, N 6.79%.
Ethyl
1-benzyl-2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3- Methyl
1-(3,4-dimethoxyphenethyl)-2-methyl-5-oxo-4,5-
carboxylate (1e). Yellow oil (135 mg, 52%); 1H-NMR: (250 MHz, dihydro-1H-pyrrole-3-carboxylate (1l). Beige solid (166 mg,
1
7.39-7.30 (m, 3H), 7.22 (dd, J = 8.0 Hz, J = 1.8 Hz, 2H), 52%): mp 99-103 °C; H NMR (250 MHz, CDCl3):
CDCl3):
δ
δ
6.73 (d, J =
4.79 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.41 (q, J = 2.4 Hz, 2H), 8.0 Hz, 1H), 6.65 (d, J = 1.9 Hz, 1H), 6.60-6.59 (m, 1H), 3.79 (s,
2.37 (t, J = 2.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C-NMR: (63 3H), 3.78 (s, 3H), 3.68-3.59 (m, 5H), 3.19 (q, J = 2.3 Hz, 2H),
MHz, CDCl3):
103.7, 59.8, 43.4, 36.6, 14.4, 12.6; IR (neat, cm-1): 1726, 1693, MHz, CDCl3):
1227. Anal. calcd. for C15H17NO3: C 69.48, H 6.61, N 5.40%. 110.9, 110.3, 101.8, 88.8, 54.9, 50.0, 41.1, 35.5, 33.7, 11.0. IR
Found: C 69.16, H 6.89, N 5.31%.
(neat, cm-1): 1717, 1685, 1220. Anal. calcd. for C17H21NO5: C
Methyl 1-benzyl-2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3- 63.94, H 6.63, N 4.39%. Found: C 63.77, H 6.47, N 4.29%.
carboxylate (1f). Pale brown solid (135 mg, 55%): mp 82-84 °C; Ethyl 1-butyl-2-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-
1H NMR (250 MHz, CDCl3): 7.42-7.15 (m, 5H), 4.79 (s, 2H), pyrrole-3-carboxylate (1m). Orange oil (175 mg, 58%); 1H NMR
3.75 (s, 3H), 3.40 (q, J = 2.4 Hz, 2H), 2.37 (t, J = 2.4 Hz, 3H); 13
(250 MHz, CDCl3): 7.35-7.15 (m, 5H), 4.36 (q, J = 2.0 Hz, 1H),
NMR (63 MHz, CDCl3): 176.4, 154.8, 136.9, 129.3, 128.2, 4.13-3.97 (m, 2H), 3.58 (m, 2H), 2.48 (d, J = 2.0 Hz, 3H), 1.65-
127.3, 103.8, 51.5, 43.9, 37.0, 13.0; IR (neat, cm-1): 1727, 1685, 1.53 (m, 2H), 1.41-1.28 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.95 (t,
δ
176.0, 164.2, 154.0, 136.5, 128.9, 127.7, 126.8, 2.75 (t, J = 7.3 Hz, 2H), 2.13 (t, J = 2.4 Hz, 3H); 13C NMR (63
δ
175.0, 163.6, 153.5, 148.0, 146.9, 129.4, 119.8,
δ
C
δ
δ
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J = 7.0 Hz, 3H); 13C NMR (63 MHz, CDCl3):
δ 177.8, 164.5, 155.0, anhydrous sodium sulphate and then evaporated under
137.0, 129.0, 128.3, 127.6, 108.9, 60.0, 53.2, 40.4, 31.8, 20.4, reduced pressure. The mixture was cromatographed on silica
14.5, 14.1, 12.7. IR (neat, cm-1): 1721, 1696, 1218. Anal. calcd. gel using as eluent a mixture of hexane/ethyl acetate.
for C18H23NO3: C 71.73, H 7.69, N, 4.65%. Found: C 71.65, H Methyl (Z)-4-(benzo[d][1,3]dioxol-5-ylmethylene)-2-methyl-
7.64, N 4.69%.
5-oxo-1-phenethyl-4,5-dihydro-1H-pyrrole-3-carboxylate (2).
Ethyl 2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate Yellow solid (235 mg, 60%): mp 179 °C; 1H NMR (250 MHz,
1
(1n). Beige solid (93 mg, 55%): mp 119-123 °C; H NMR (250 CDCl3):
δ 8.17 (d, J = 1.6Hz, 1H), 8.13 (s, 1H), 7.56 (dd, J = 8.2,
MHz, CDCl3):
= 2.3 Hz, 2H), 2.39 (t, J = 2.3 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13
NMR (63 MHz, CDCl3):
δ
8.72 (br s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.32 (q, J 1.6 Hz, 1H), 7.38-7.11 (m, 5H), 6.88 (d, J = 8.2 Hz, 1H), 6.05 (s,
2H), 3.87 (t, J = 7.3 Hz, 2H), 3.85 (s, 3H), 2.93 (t, J = 7.3 Hz, 2H,),
166.1, 165.3, 151.9,
C
δ
178.7, 164.6, 152.0, 104.9, 60.3, 38.0, 2.25 (s, 3H); 13C NMR (63 MHz, CDCl3)
δ
14.8, 13.9; IR (neat, cm-1): 3165, 1702, 1682, 1251. Anal. calcd. 149.9, 147.8, 141.9, 138.6, 129.6, 129.3, 129.1, 127.2, 125.1,
for C8H11NO3: C 56.80, H 6.55, N 8.28%. Found: C 56.42, H 6.36, 111.7, 108.3, 103.9, 101.9, 51.3, 42.5, 35.8, 13.4. IR (neat, cm-
N 7.90%.
1): 1672, 1264. Anal. calcd. for C23H11NO5: C 70.58, H 5.41, N
Ethyl
2,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrrole-3- 3.58%. Found: C 70.38, H 5.32, N 3.67%.
1
carboxylate (1o). Yellow oil (79 mg, 43%); H NMR (250 MHz, Methyl
CDCl3): 8.11 (br s, 1H), 4.42-4.09 (m, 2H), 3.29 (qq, J = 7.6, 2.1 dihydro-1H-pyrrole-3-carboxylate (5a). Yellow solid (210 mg,
Hz, 1H), 2.40 (d, J = 2.1 Hz, 3H), 1.44 (d, J = 7.6 Hz, 3H), 1.33 (t, 70%): mp 84-87 °C; H NMR (250 MHz, CDCl3):
J = 7.1 Hz, 3H); 13C NMR (63 MHz, CDCl3):
182.1, 164.7, 150.9, 8.11-7.99 (m, 2H), 7.45-7.30 (m, 3H), 3.84 (s, 3H), 3.68-3.52 (m,
110.7, 60.1, 43.5, 15.6, 14.8, 14.0; IR (neat, cm-1): 1723.1, 2H), 2.53 (d, J = 0.5 Hz, 3H), 1.67-1.47 (m, 2H), 1.44-1.22 (m,
1690.4, 1223.0; IR (neat, cm-1): 3186, 1721, 1686, 1249. Anal. 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3):
166.1,
calcd. for C9H13NO3: C 59.00, H 7.15, N 7.65%. Found: C 58.79, 165.3, 155.9, 153.5, 141.6, 135.1, 131.9, 130.3, 128.3, 127.1,
H 6.95, N 7.73%.
51.3, 40.4, 31.9, 20.6, 14.2, 13.8; IR (neat, cm-1): 1699, 1689,
Ethyl 4-ethyl-2-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3- 1601, 1213. Anal. calcd. for C18H21NO3: C 72.22, H 7.07, N
carboxylate (1p). Yellow oil (79 mg, 40%); H NMR (250 MHz, 4.68%. Found: C 72.17, H 6.94, N 4.59%.
CDCl3): 8.22 (br s, 1H), 4.34-4.14 (m, 2H), 3.43-3.29 (m, 1H), Ethyl (Z)-4-benzylidene-1-butyl-2-methyl-5-oxo-4,5-dihydro-
2.41 (d, J = 2.2 Hz, 3H), 2.18-1.88 (m, 2H), 1.33 (t, J = 7.1 Hz, 1H-pyrrole-3-carboxylate (5b). Yellow solid (179 mg, 57%): mp
3H), 0.83 (t, J = 7.5 Hz, 3H); 13C NMR (63 MHz, CDCl3): 181.5, 161-163 °C; 1H NMR (250 MHz, CDCl3):
8.20 (s, 1H), 7.41 (dd,
(Z)-4-benzylidene-1-butyl-2-methyl-5-oxo-4,5-
δ
1
δ
8.14 (s, 1H),
δ
δ
1
δ
δ
δ
164.7, 151.8, 108.1, 60.1, 48.9, 22.7, 14.8, 14.1, 9.4; IR (neat, J = 4.8, 2.5 Hz, 2H), 7.43-7.29 (m, 3H), 4.35 (q, J = 7.1 Hz, 2H),
cm-1): 3257, 1715, 1689, 1223. Anal. calcd. for C10H15NO3: C 3.64 (t, J = 7.6 Hz, 2H), 2.56 (s, 3H), 1.66-1.51 (m, 2H), 1.42 (t, J
60.90, H 7.67, N 7.10%. Found: C 60.88, H 7.48, N 7.13%.
Ethyl 2-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrrole-3- NMR (63 MHz, CDCl3):
carboxylate (1q) Yellow oil (101 mg, 41%); H NMR (250 MHz, 131.9, 130.3, 128.4, 127.2, 103.9, 60.2, 40.3, 31.9, 20.6, 14.9,
CDCl3):
8.21 (br s, 1H), 7.44-7.15 (m, 5H), 4.42 (app. d, J = 2.2 14.2, 13.8; IR (neat, cm-1): 1672, 1158. Anal. calcd. for
Hz, 1H), 4.18-3.93 (m, 2H), 2.47 (d, J = 2.2 Hz, 3H), 1.09 (t, J = C19H23NO3: C 72.82, H 7.40, N 4.47%. Found: C 72.85, H 7.34, N
7.1 Hz, 3H); 13C NMR (63 MHz, CDCl3):
179.4, 164.3, 152.9, 4.51%.
= 7.1 Hz, 3H), 1.42-1.30 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C
166.2, 164.8, 153.3, 141.6, 135.1,
δ
1
δ
δ
136.4, 129.1, 128.3, 127.9, 109.8, 60.1, 54.2, 14.5, 14.0; IR Methyl
(Z)-1-benzyl-4-benzylidene-2-methyl-5-oxo-4,5-
(neat, cm-1): 3238, 1719, 1687, 1223. Anal. calcd. for dihydro-1H-pyrrole-3-carboxylate (5c). Yellow solid (167 mg,
1
C14H15NO3: C 68.56, H 6.16, N 5.71%. Found: C 68.41, H 6.16, N 50%): mp 83-86 °C; H NMR (250 MHz, CDCl3):
δ 8.28 (s, 1H),
8.22-8.11 (m, 2H), 7.54-7.14 (m, 8H), 4.90 (s, 2H), 3.87 (s, 3H),
5.57%.
Methyl 2-methyl-5-oxo-1-phenethyl-4,5-dihydro-1H-pyrrole- 2.45 (s, 3H); 13C NMR (63 MHz, CDCl3):
δ 166.2, 165.2, 153.4,
3-carboxylate (1r). Light brown solid (140 mg, 54%): mp 99- 142.2, 137.1, 135.0, 132.1, 130.5, 129.3, 128.4, 128.0, 127.2,
103 °C; 1H NMR (250 MHz, CDCl3): 7.20-6.91 (m, 5H), 3.56 (t, 126.8, 104.3, 51.4, 43.8, 14.2; IR (neat, cm-1): 1684, 1599,
J = 7.3 Hz, 2H), 3.53 (s, 3H), 3.08 (q, J = 2.2 Hz, 2H), 2.69 (t, J = 1193. Anal. calcd. for C21H19NO3: C 75.66, H 5.74, N 4.20%.
7.3 Hz, 2H), 2.00 (t, J = 2.2 Hz, 3H); 13C NMR (63 MHz, CDCl3):
Found: C 75.55, H 5.68, N 4.18%.
δ
δ
175.0, 163.6, 153.5, 137.0, 127.8, 127.7, 125.9, 101.9, 50.0, Methyl (Z)-1-benzyl-4-(4-methoxybenzylidene)-2-methyl-5-
41.0, 35.5, 34.2, 11.0; IR (neat, cm-1): 1703, 1669, 1230. Anal. oxo-4,5-dihydro-1H-pyrrole-3-carboxylate (5d). Yellow solid
1
calcd. for C15H17NO3: C 69.48, H 6.61, N 5.40%. Found: C 69.19, (218 mg, 60%): mp 121-124 °C; H NMR (250 MHz, CDCl3):
δ
H 6.50, N 5.15%.
8.39-8.08 (m, 3H), 7.47-7.10 (m, 5H), 7.03-6.83 (m, 2H), 4.93 (s,
2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.44 (s, 3H); 13C NMR (63 MHz,
CDCl3): 164.2, 163.2, 159.6, 149.4, 140.2, 135.1, 132.6, 130.5,
General procedure for the synthesis of 4-arylmethylen-2-pyrrolin-
5-ones (compound 2 and compounds 5)
δ
In a round-bottomed flask, the suitable 2-pyrrolin-5-one (1 eq) 127.1, 125.8, 125.0, 122.4, 111.8, 102.3, 53.6, 49.2, 41.6, 12.0;
was suspended in ethanol (10 mL). Then, the corresponding IR (neat, cm-1): 1679.0, 1589.4, 1254.4. Anal. calcd. for
aldehyde (1.1 eq) and piperidine (2 eq) were added. The C22H21NO4: C 72.71, H 5.82, N 3.85%. Found: C 72.46, H 5.84, N
mixture was refluxed for 1 h and monitored by TLC. Once the 3.92%.
reaction was completed the mixture was cooled to room Methyl (Z)-1-benzyl-4-(4-chlorobenzylidene)-2-methyl-5-oxo-
temperature, diluted with ethyl acetate (20 mL) and washed 4,5-dihydro-1H-pyrrole-3-carboxylate (5e). Yellow solid (166
1
with water (2 x 10 mL) The organic phase was dried over mg, 45%): mp 97-100 °C; H NMR (250 MHz, CDCl3):
δ 8.09 (s,
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1H), 8.00 (d, J = 8.4 Hz, 2H), 7.35-7.20 (m, 5H), 7.16-7.06 (m, pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3c). Beige solid (396
2H), 4.81 (s, 2H), 3.76 (s, 3H), 2.36 (d, J = 0.6 Hz, 3H); 13C NMR mg, 73%): mp 166-169 °C; 1H NMR (250 MHz, CDCl3):
8.06 (br
(63 MHz, CDCl3): 166.2, 165.1, 153.6, 140.6, 136.9, 136.3, s, 1H), 7.49-7.34 (m, 2H), 7.28-6.89 (m, 8H), 6.67 (d, J = 8.3 Hz,
δ
δ
133.4, 129.4, 129.3, 128.7, 128.1, 127.3, 127.1, 104.2, 51.4, 1H), 6.23 (d, J = 7.0 Hz, 2H), 5.37 (dd, J = 10.0, 8.5 Hz, 1H), 4.81
43.8, 14.2; IR (neat, cm-1): 1691, 1677, 1602, 1196. Anal. calcd. (d, J = 16.3 Hz, 1H), 4.24 (t, J = 8.5 Hz, 1H), 3.88 (d, J = 16.3 Hz,
for C21H18ClNO3: C 68.57, H 4.93, N 3.81%. Found: C 68.20, H 1H), 3.77-3.51 (m, 4H), 2.30 (s, 3H), 1.72 (s, 3H); 13C NMR (63
4.88, N 3.81%.
MHz, CDCl3): δ 177.7, 175.0, 165.4, 156.1, 141.0, 137.3, 136.1,
Methyl (Z)-1-benzyl-4-(4-bromobenzylidene)-2-methyl-5-oxo- 129.9, 129.6, 129.1, 128.6, 128.2, 127.9, 127.5, 127.4, 126.2,
4,5-dihydro-1H-pyrrole-3-carboxylate (5f). Yellow solid (219 111.3, 103.7, 78.4, 77.6, 68.8, 56.0, 51.3, 43.5, 43.0, 36.3, 13.2;
δ
mg, 53%): mp 136 °C; 1H NMR (250 MHz, CDCl3): 8.16 (s, 1H), IR (neat, cm-1): 3224, 1721, 1692, 1617, 1255, 1181. Anal.
8.02 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5, 2H), 7.48-7.14 (m, 5H), calcd. for C31H28ClN3O4: C 68.69, H 5.21, N 7.75%. Found C
4.90 (s, 2H), 3.86 (s, 3H), 2.45 (s, 3H); 13C NMR (63 MHz, CDCl3): 68.75, H 5.10, N 7.67%.
δ
166.2, 165.1, 153.7, 140.6, 136.9, 133.8, 133.6, 131.6, 129.3, Methyl (3S*,3'R*,4'R*)-1''-benzyl-5-iodo-1',5''-dimethyl-2,2''-
128.1, 127.3, 127.2, 124.9, 104.2, 51.4, 43.8, 14.2; IR (neat, cm- dioxo-4'-phenyl-1'',2''-dihydrodispiro[indoline-3,2'-
1): 1691.8, 1674.4, 1602.0, 1196.6; IR (neat, cm-1): 3190, 1708, pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3d). Beige solid
1
1681, 1612, 1249, 1203. Anal. calcd. for C21H18BrNO3: C 61.18, (329 mg, 52%): mp 140-143 °C; H NMR (250 MHz, CDCl3):
δ
7.70-7.61 (m, 2H), 7.55 (dd, J = 8.2, 1.8 Hz, 1H), 7.52-7.43 (m,
H 4.40, N 3.40%. Found: C 60.99, H 4.38, N 3.26%.
General procedure for the synthesis of dispirooxindoles 3 and 4
The suitable isatine (1.5 eq.) and the appropriate aminoacid
(1.5 eq) were placed in a microwave reaction vial. Then the
2H), 7.36-7.27 (m, 3H), 7.19-7.00 (m, 3H), 6.61 (d, J = 8.2 Hz,
1H), 6.32 (d, J = 6.9 Hz, 2H), 5.44 (dd, J = 10.1, 8.5 Hz, 1H), 4.96
(d, J = 16.3 Hz, 1H), 4.34 (t, J = 8.5 Hz, 1H), 3.95 (d, J = 16.3 Hz,
1H), 3.80 (s, 3H), 3.72 (app. t, J = 9.6 Hz, 1H), 2.42 (s, 3H), 1.82
corresponding
4-arylmethylen-2-pyrrolin-5-one
(1 eq)
(s, 3H); 13C NMR (63 MHz, CDCl3):
δ 175.0, 165.3, 156.3, 142.0,
suspended in ethanol (2 mL) was added and irradiated at 100
°C for 1h. After the reaction completion, the mixture was
cooled at room temperature and a precipitate was formed.
The solid compound was filtered and washed twice with cold
ethanol. No further purification was needed.
138.7, 138.7, 136.1, 134.7, 129.6, 129.2, 128.7, 127.5, 127.4,
126.2, 112.3, 103.6, 85.1, 78.1, 77.6, 68.8, 56.1, 51.4, 43.4,
43.0, 36.5, 31.4, 13.2; IR (neat, cm-1): 3222, 1719, 1688, 1607,
1177. Anal. calcd. for C31H28IN3O4: C 58.78, H 4.46, N 6.63%.
Found C 58.67, H 4.39, N 6.71%.
Methyl (3S*,3'R*,4'R*)-1''-butyl-1',5''-dimethyl-2,2''-dioxo-4'-
phenyl-1'',2''-dihydrodispiro[indoline-3,2'-pyrrolidine-3',3''-
Methyl
dioxo-4'-phenyl-1'',2''-dihydrodispiro[indoline-3,2'-
pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3e) Beige solid
(287 mg, 55%): mp 217 °C; H NMR (250 MHz, CDCl3): 7.78
(3S*,3'R*,4'R*)-1''-benzyl-1',5,5''-trimethyl-2,2''-
pyrrole]-4''-carboxylate (3a). Pale brown solid (237 mg, 50%):
1
mp 215-218 °C; H NMR (250 MHz, CDCl3):
δ 7.90 (br s, 1H),
.
1
7.44-7.29 (m, 2H), 7.29-7.03 (m, 5H), 6.86 (td, J = 7.7, 0.9 Hz,
1H), 6.74 (d, J = 7.7 Hz, 1H), 5.34 (dd, J = 10.1, 8.7 Hz, 1H), 4.24
(t, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.65 (dd, J = 10.1, 8.7 Hz, 1H),
3.34-3.13 (m, 1H), 3.02-2.78 (m, 1H), 2.34 (s, 3H), 1.96 (s, 3H),
1.17-0.94 (m, 2H), 0.94-0.79 (m, 2H), 0.79-0.62 (m, 3H); 13C
δ
(br s, 1H), 7.61-7.42 (m, 2H), 7.31-7.29 (m, 3H), 7.20-6.93 (m,
5H), 6.70 (d, J = 7.8 Hz, 1H), 6.30 (d, J = 7.3 Hz, 2H), 5.48 (app.
t, J = 8.9 Hz, 1H), 4.86 (d, J = 16.3 Hz, 1H), 4.33 (app. t, J = 8.9
Hz, 1H), 3.96 (d, J = 16.3 Hz, 1H), 3.81 (s, 3H), 3.72 (app. t, J =
9.6 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 1.80 (s, 3H); 13C NMR (63
NMR (63 MHz, CDCl3):
δ 178.1, 175.2, 165.6, 156.0, 142.5,
137.7, 129.7, 129.3, 128.3, 127.1, 126.0, 122.4, 110.2, 103.6,
78.2, 68.2, 56.2, 51.2, 43.5, 39.7, 36.3, 30.9, 20.0, 14.1, 12.8;
IR (neat, cm-1): 3140, 1725, 1702, 1688, 1602, 1208. Anal.
calcd. for C28H31N3O4: C 71.02, H 6.60, N 8.87%. Found: C
70.84, H 6.54, N 8.85%.
MHz, CDCl3):
δ 177.9, 175.2, 165.5, 155.7, 140.0, 137.7, 136.3,
132.1, 130.1, 129.7, 129.1, 128.6, 127.5, 127.2, 126.5, 126.1,
126.0, 110.0, 104.1, 68.7, 56.1, 51.3, 43.5, 42.8, 36.4, 31.4,
21.5, 13.2; IR (neat, cm-1): 3155, 1705, 1682, 1616, 1216, 1190.
Anal. calcd. for C32H31N3O4: C 73.68, H 5.99, N 8.06%. Found: C
73.54, H 6.01, N 8.18%.
Methyl (3S*,3'R*,4'R*)-1''-butyl-5-chloro-1',5''-dimethyl-2,2''-
dioxo-4'-phenyl-1'',2''-dihydrodispiro[indoline-3,2'-
Methyl (3S*,3'R*,4'R*)-1''-benzyl-1',5''-dimethyl-2,2''-dioxo-
4'-phenyl-1'',2''-dihydrodispiro[indoline-3,2'-pyrrolidine-
pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3b). Pale brown
solid (284 mg, 56%): mp 102-104 °C; 1H NMR (250 MHz, CDCl3):
3',3''-pyrrole]-4''-carboxylate (3f). White solid (330 mg, 65%):
1
mp 200-203 °C; H NMR (250 MHz, CDCl3):
δ
8.55 (br s, 1H), 7.35 (dd, J = 7.9, 1.4 Hz, 2H), 7.29-7.05 (m,
δ 7.74 (br s, 1H),
5H), 6.74 (d, J = 8.3 Hz, 1H), 5.34 (dd, J = 9.9, 8.7 Hz, 1H), 4.22
(t, J = 8.7 Hz, 1H), 3.73 (s, 3H), 3.69-3.56 (m, 1H), 3.23-2.98 (m,
2H), 2.34 (s, 3H), 1.99 (s, 3H), 1.29-1.07 (m, 1H), 1.07-0.83 (m,
7.52 (s, 2H), 7.41-6.97 (m, 8H), 6.91 (t, J = 7.6 Hz, 1H), 6.79 (d, J
= 7.6 Hz, 1H), 6.31 (d, J = 7.3 Hz, 2H), 5.48 (app. t, J = 9.0 Hz,
1H), 4.91 (d, J = 16.3 Hz, 1H), 4.34 (app. t, J = 8.4 Hz, 1H), 3.91
(d, J = 16.3 Hz, 1H), 3.82 (s, 3H), 3.73 (app. t, J = 9.6 Hz, 1H),
3H), 0.78 (t, J = 6.4 Hz, 3H); 13C NMR (63 MHz, CDCl3):
δ 179.5,
2.40 (s, 3H), 1.81 (s, 3H); 13C NMR (63 MHz, CDCl3):
δ 175.1,
176.3, 166.8, 157.4, 142.5, 138.7, 131.0, 130.6, 129.6, 129.2,
129.2, 128.5, 127.7, 112.7, 104.6, 79.5, 69.6, 57.5, 52.5, 44.9,
41.2, 37.6, 32.4, 21.4, 15.3, 14.3; IR (neat, cm-1): 3238, 1717,
1689, 1613, 1210, 1175. Anal. calcd. for C28H30ClN3O4: C 66.20,
H 5.95, N 8.27%. Found: C 66.02, H 5.71, N 8.21%.
165.5, 155.9, 142.4, 137.7, 136.3, 129.9, 129.7, 129.0, 128.6,
127.5, 127.2, 126.3, 125.9, 125.8, 122.6, 110.2, 104.0, 78.4,
77.6, 68.7, 56.0, 51.3, 43.4, 43.0, 36.3, 13.1; IR (neat, cm-1):
3139, 1708, 1684, 1614, 1252, 1218. Anal. calcd. for
C31H29N3O5: C 73.35, H 5.76, N 8.28%. Found: C 73.13, H 5.60,
N 8.14%.
Methyl
(3S*,3'R*,4'R*)-1''-benzyl-5-chloro-1',5''-dimethyl-
2,2''-dioxo-4'-phenyl-1'',2''-dihydrodispiro[indoline-3,2'-
8 | J. Name., 2012, 00, 1-3
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Methyl
(3S*,3'R*,4'R*)-1,1''-dibenzyl-1',5''-dimethyl-2,2''- NMR (63 MHz, CDCl3):
δ
141.0, 136.1, 130.7, 129.8, 129.1, 129.0, 128.2, 128.0, 127.6,
177.7, 175.1, 165.4, 159.0, 156.0,
dioxo-4'-phenyl-1'',2''-dihydrodispiro[indoline-3,2'-
pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3g). Light yellow 126.2, 126.2, 114.0, 111.3, 103.7, 78.3, 68.9, 56.2, 55.5, 51.4,
solid (448 mg, 75%): mp 113-115 °C; 1H NMR (250 MHz, CDCl3): 42.9, 36.3, 31.4, 13.2; IR (neat, cm-1): 3199, 1721, 1688, 1605,
δ 7.53-7.54 (m, 2H), 7.39-7.25 (m, 9H), 7.17-7.02 (m, 4H), 6.89 1245, 1207. Anal. calcd. for C32H30ClN3O5: C 67.19, H 5.29, N
(t, J = 7.4 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.31 (d, J = 7.2 Hz, 7.35%. Found: C 67.02, H 5.34, N 7.30%.
2H), 5.56 (dd, J = 10.0, 8.4 Hz, 1H), 5.10 (d, J = 15.8 Hz, 1H), Methyl
(3S*,3'R*,4'R*)-1''-benzyl-5-iodo-4'-(4-
4.92 (d, J = 16.3 Hz, 1H), 4.58 (d, J = 15.8 Hz, 1H), 4.37 (t, J = 8.4 methoxyphenyl)-1',5''-dimethyl-2,2''-dioxo-1'',2''-
Hz, 1H), 3.90 (d, J = 16.3 Hz, 1H), 3.84-3.68 (m, 4H), 2.40 (s, dihydrodispiro[indoline-3,2'-pyrrolidine-3',3''-pyrrole]-4''-
3H), 1.79 (s, 3H); 13C NMR (63 MHz, CDCl3):
δ 175.7, 175.2, carboxylate (3k). Pale brown solid (331 mg, 50%): mp 141-143
1
165.3, 155.3, 144.3, 137.8, 136.3, 136.1, 129.8, 129.7, 129.2, °C; H NMR (250 MHz, CDCl3):
δ 8.35 (br s, 1H), 7.42 (d, J = 1.8
129.0, 128.6, 127.9, 127.6, 127.5, 127.2, 126.3, 125.4, 125.2, Hz, 1H), 7.32 (dd, J = 8.2, 1.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H),
122.6, 109.7, 104.2, 78.4, 68.9, 56.2, 51.3, 44.0, 43.5, 43.0, 7.00-6.80 (m, 3H), 6.63 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 8.2 Hz,
36.4, 13.1; IR (neat, cm-1): 1709, 1688, 1260, 1210. Anal. calcd. 1H), 6.10 (d, J = 7.0 Hz, 2H), 5.21 (dd, J = 10.0, 8.6 Hz, 1H), 4.77
for C38H35N3O4: C 76.36, H 5.90, N 7.03%. Found: C 76.23, H (d, J = 16.4 Hz, 1H), 4.07 (app. t, J = 8.6 Hz, 1H), 3.76 (d, J = 16.4
5.81, N 7.16%.
Methyl (3S*,3'R*,4'R*)-1,1''-dibenzyl-4'-(4-methoxyphenyl)- 2.18 (s, 3H), 1.61 (s, 3H); 13C NMR (63 MHz, CDCl3):
1',5''-dimethyl-2,2''-dioxo-1'',2''-dihydrodispiro[indoline-3,2'- 175.2, 165.4, 159.0, 156.1, 142.3, 138.6, 136.1, 134.5, 130.7,
pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3h) Light yellow 129.1, 129.0, 128.5, 127.6, 126.2, 113.9, 112.6, 103.6, 85.1,
solid (427 mg, 68%): mp 198-200 °C; 1H NMR (250 MHz, CDCl3): 78.2, 68.9, 56.3, 55.6, 51.4, 42.8, 42.8, 36.4, 13.3; IR (neat, cm-
7.37 (d, J = 8.7 Hz, 2H), 7.30-7.11 (m, 6H), 7.11-6.87 (m, 4H), 1): 3164, 1714, 1694, 1671, 1245, 1176. Anal. calcd. for
Hz, 1H), 3.63 (s, 3H), 3.54 (s, 3H), 3.48 (dd, J = 10.0, 9.1 Hz, 1H),
δ
177.5,
.
δ
6.85-6.68 (m, 3H), 6.48 (d, J = 7.7 Hz, 1H), 6.21 (d, J = 7.2 Hz, C32H30IN3O5: C 57.93, H 4.56, N 6.33%. Found: C 57.75, H 4.42,
2H), 5.41 (dd, J = 10.2, 8.4 Hz, 1H), 5.00 (d, J = 15.8 Hz, 1H), N 6.46%.
4.84 (d, J = 16.4 Hz, 1H), 4.48 (d, J = 15.8 Hz, 1H), 4.21 (t, J = 8.4 Methyl
Hz, 1H), 3.81 (d, J = 16.4 Hz, 1H), 3.74 (s, 3H), 3.71-3.57 (m, 1',5,5''-trimethyl-2,2''-dioxo-1'',2''-dihydrodispiro[indoline-
4H), 2.29 (s, 3H), 1.69 (s, 3H); 13C NMR (63 MHz, CDCl3):
3,2'-pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3l) Light
175.7, 175.3, 165.3, 158.9, 155.2, 144.3, 136.3, 136.1, 130.8, yellow solid (298 mg, 54%): mp 213-215 °C; 1H NMR (250 MHz,
129.8, 129.6, 129.2, 128.9, 127.9, 127.6, 127.5, 126.3, 125.4, CDCl3): 7.41 (br s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.10-6.85 (m,
(3S*,3'R*,4'R*)-1''-benzyl-4'-(4-methoxyphenyl)-
δ
.
δ
125.3, 122.6, 113.9, 109.7, 104.2, 78.3, 77.6, 69.0, 56.4, 55.5, 5H), 6.79-6.68 (m, 2H), 6.57 (d, J = 7.9 Hz, 1H), 6.22 (d, J = 7.1
51.3, 44.0, 42.9, 36.4, 13.0; IR (neat, cm-1): 1713, 1685, 1605, Hz, 2H), 5.32 (dd, J = 10.3, 8.6 Hz, 1H), 4.78 (d, J = 16.3 Hz, 1H),
1243, 1225. Anal. calcd. for C39H37N3O5: C 74.62, H 5.94, N 4.18 (t, J = 8.6 Hz, 1H), 3.88 (d, J = 16.3 Hz, 1H), 3.74 (s, 3H),
6.69%. Found C 74.33, H 6.02, N 6.81%.
Methyl (3S*,3'R*,4'R*)-1''-benzyl-4'-(4-methoxyphenyl)-1',5''- 3H), 1.70 (s, 3H); 13C NMR (63 MHz, CDCl3):
dimethyl-2,2''-dioxo-1'',2''-dihydrodispiro[indoline-3,2'- 165.5, 158.9, 155.6, 139.8, 136.3, 132.1, 130.7, 130.1, 129.5,
pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3i). Beige solid (296 128.9, 127.5, 126.6, 126.2, 113.9, 109.8, 104.1, 78.3, 77.6,
mg, 55%): mp 212-214 °C; 1H NMR (250 MHz, CDCl3): 7.57 (br 68.8, 56.3, 55.5, 51.3, 42.9, 42.8, 36.3, 21.5, 13.1; IR (neat, cm-
3.72 (s, 3H), 3.59 (dd, J = 10.3, 8.6 Hz, 1H), 2.29 (s, 3H), 2.16 (s,
δ
177.7, 175.3,
δ
s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.33-6.97 (m, 5H), 6.98-6.68 (m, 1): 3162.5, 1706.6, 1687.8, 1616.8, 1247.0, 1217.0; IR (neat,
4H), 6.31 (d, J = 7.2 Hz, 2H), 5.43 (dd, J = 10.2, 8.7 Hz, 1H), 4.93 cm-1): 3164, 1714, 1694, 1671, 1245, 1176. Anal. calcd. for
(d, J = 16.3 Hz, 1H), 4.29 (t, J = 8.7 Hz, 1H), 3.92 (d, J = 16.3 Hz, C33H33N3O5: C 71.85, H 6.03, N 7.62%. Found: C 71.91, H 5.97,
1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.70 (dd, J = 10.2, 8.7 Hz, 1H), N 7.58%.
2.39 (s, 3H), 1.81 (s, 3H); 13C NMR (63 MHz, CDCl3):
δ 177.9, Methyl (3S*,3'R*,4'R*)-1''-benzyl-4'-(4-chlorophenyl)-1',5''-
175.4, 165.7, 159.1, 155.9, 142.5, 136.4, 130.9, 130.0, 129.6, dimethyl-2,2''-dioxo-1'',2''-dihydrodispiro[indoline-3,2'-
129.1, 127.7, 126.5, 126.0, 122.8, 114.1, 110.3, 104.2, 78.5, pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3m). White solid
1
77.8, 69.0, 56.4, 55.7, 51.4, 43.1, 43.0, 36.5, 13.3; IR (neat, (423 mg, 78%): mp 118-120 °C; H NMR (250 MHz, CDCl3):
δ
cm-1): 3140, 1721, 1702, 1685, 1611, 1245, 1212. Anal. calcd. 7.45 (d, J = 8.5 Hz, 2H), 7.37 (br s, 1H), 7.29-7.03 (m, 7H), 6.92
for C32H31N3O5: C 71.49, H 5.81, N 7.82%. Found: C 71.36, H (td, J = 7.6, 0.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.39-6.20 (m,
5.57, N 7.88%.
2H), 5.45 (dd, J = 10.1, 8.3 Hz, 1H), 4.93 (d, J = 16.3 Hz, 1H),
Methyl
(3S*,3'R*,4'R*)-1''-benzyl-5-chloro-4'-(4- 4.28 (t, J = 8.3 Hz, 1H), 3.90 (d, J = 16.3 Hz, 1H), 3.83 (s, 3H),
3.79-3.66 (m, 1H), 2.40 (s, 3H), 1.82 (s, 3H); 13C NMR (63 MHz,
methoxyphenyl)-1',5''-dimethyl-2,2''-dioxo-1'',2''-
dihydrodispiro[indoline-3,2'-pyrrolidine-3',3''-pyrrole]-4''- CDCl3): δ 176.6, 174.1, 164.3, 154.9, 141.3, 135.2, 135.1, 132.1,
carboxylate (3j). Light yellow solid (418 mg, 73%): mp 181-185 130.1, 129.0, 128.1, 127.7, 126.8, 125.2, 124.7, 121.7, 109.3,
1
°C; H NMR (250 MHz, CDCl3):
δ 8.04 (br s, 1H), 7.42 (d, J = 8.8 102.7, 77.4, 67.6, 55.0, 50.4, 42.0, 41.8, 35.2, 30.4, 12.1; IR
Hz, 2H), 7.33 (d, J = 2.0 Hz, 1H), 7.23-7.01 (m, 4H), 6.84 (d, J = (neat, cm-1): 3142, 1724, 1705, 1686, 1615, 1286, 1209. Anal.
8.8 Hz, 2H), 6.76 (d, J = 8.3 Hz, 1H), 6.31 (d, J = 7.1 Hz, 2H), 5.41 calcd. for C31H28ClN3O4: C 68.69, H 5.21, N 7.75%. Found: C
(dd, J = 10.0, 8.6 Hz, 1H), 4.94 (d, J = 16.3 Hz, 1H), 4.28 (app. t, J 68.57, H 5.07, N 7.81%.
= 8.6 Hz, 1H), 3.99 (d, J = 16.4 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), Methyl (3S*,3'R*,4'R*)-1''-benzyl-4'-(4-bromophenyl)-1',5''-
3.68 (dd, J = 10.0, 9.2 Hz, 1H), 2.39 (s, 3H), 1.82 (s, 3H); 13C dimethyl-2,2''-dioxo-1'',2''-dihydrodispiro[indoline-3,2'-
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pyrrolidine-3',3''-pyrrole]-4''-carboxylate (3n). Pale brown allowed their use as synthetic building blocks, both in target-
solid (516 mg, 88%): mp 222 °C; 1H NMR (250 MHz, DMSO-d6): oriented and diversity-oriented synthesis contexts. Thus, we
δ
10.34 (br s, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, devised a two-step route to compound 2, which had previously
2H), 7.24-7.00 (m, 5H), 6.86 (td, J = 7.6, 0.9 Hz, 1H), 6.74 (d, J = been proposed as a suitable candidate for HIV integrase
7.6 Hz, 1H), 6.32 (d, J = 6.8 Hz, 2H), 5.32 (dd, J = 10.1, 8.2 Hz, inhibition on the basis of computational studies. The versatility
1H), 4.72 (d, J = 16.6 Hz, 1H), 4.25 – 3.95 (m, 2H), 3.70 (s, 3H), of 2-pyrrolin-5-ones was further verified by their use in a
3.57-3.46 (m, 1H), 2.15 (s, 3H), 1.71 (s, 3H); 13C NMR (63 MHz, diversity-oriented synthesis context, leading to a library of
DMSO-d6):
δ 176.6, 174.4, 164.5, 154.5, 143.7, 137.1, 136.6, highly functionalized bispiro compounds. The overall process
131.4, 131.3, 129.9, 128.6, 127.3, 125.9, 125.1, 124.8, 121.6, leading to these compounds involved the generation of six
120.5, 110.0, 103.2, 77.5, 67.7, 51.2, 42.0, 41.9, 35.5, 31.1, bonds and two cycles over three steps, two of which are
12.5; IR (neat, cm-1): 3141, 1724, 1704, 1686, 1614, 1285, multicomponent, and the fully controlled generation of up to
1208. Anal. calcd. for C31H28BrN3O4: C 63.49, H 4.81, N 7.16%. four stereocenters, including two quaternary ones.
Found: C 63.62, H 4.77, N 7.05%.
Methyl (1'R*,2'R*,3S*,7a’S)-1''-butyl-5''-methyl-2,2''-dioxo-1'-
Acknowledgements
phenyl-1'',2'',5',6',7',7a'-hexahydro-1'H-dispiro[indoline-3,3'-
pyrrolizine-2',3''-pyrrole]-4''-carboxylate (4a). Light yellow
solid (210 mg, 42%): mp 156-158 °C; 1H NMR (250 MHz, CDCl3):
Financial support from MINECO (grants CTQ2012-33272-BQU
and CTQ2015-68380-R) is gratefully acknowledged. We also
δ
7.81 (br s, 1H), 7.46 (d, J = 6.5 Hz, 2H), 7.38 (d, J = 7.5 Hz, 1H),
thank David Castaño and Nicola Anzani for experimental
assistance and Dr. Francisca Sanz (Servicio de Difracción de
Rayos X, Universidad de Salamanca) for the study of
7.28-7.09 (m, 4H), 6.90 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 7.7 Hz,
1H), 4.91 (s, 2H), 3.81 (s, 3H), 3.34-3.16 (m, 1H), 3.11-2.95 (m,
1H), 2.88 (t, J = 7.1 Hz, 1H), 2.81-2.64 (m, 1H), 2.31-2.00 (m,
4H), 1.94 (s, 3H), 1.22-1.05 (m, 2H), 1.04-0.88 (m, 2H), 0.80 (t, J
compound 4b
.
= 6.9 Hz, 3H); 13C NMR (63 MHz, CDCl3):
δ 178.7, 175.8, 165.8,
154.8, 141.4, 137.8, 129.4, 129.3, 128.4, 127.1, 126.0, 122.5,
109.8, 104.2, 77.3, 73.2, 68.7, 51.2, 49.7, 47.9, 39.8, 32.4, 31.0,
30.5, 20.1, 14.1, 12.7; IR (neat, cm-1): 3138, 1707, 1687, 1615,
1254, 1205. Anal. calcd. for C30H33N3O4: C 72.12, H 6.66, N
8.41%. Found: C 71.98, H 6.55, N 8.46%.
Notes and references
1
(a) V. M. Dembitsky, T. A. Gloriozova and V. V. Poroikov,
Mini-Rev. Med. Chem. 2005, , 319. (b) J. T. Gupton, Top.
Heterocycl. Chem. 2006, , 53. (c) H. Fan, J. Peng, M. T.
5
2
Hamann and J. F. Hu, Chem. Rev. 2008, 108, 264. (d) B. Forte,
B. Malgesini, C. Piutti, F. Quartieri, A. Scolaro and G. Papeo,
Ethyl (1'R*,2'R*,3S*,7a’S)-1''-butyl-5''-methyl-2,2''-dioxo-1'-
phenyl-1'',2'',5',6',7',7a'-hexahydro-1'H-dispiro[indoline-3,3'-
pyrrolizine-2',3''-pyrrole]-4''-carboxylate (4b). Light yellow
solid (195 mg, 38%): mp 155-157 °C; 1H NMR (250 MHz, CDCl3):
Marine Drugs 2009,
Zancanella, S. Tilvi and D. Romo, Nat. Prod. Rep. 2011, 28
7, 705. (e) A. Al-Mourabit, M. A.
,
1229.
(a) M. Biava, G. C. Porretta and F. Manetti, Mini Rev. Med.
Chem. 2007, , 65. (b) C. Teixeira, F. Barbault, J. Rebehmed,
2
δ
7.58 (br s, 1H), 7.46 (d, J = 6.9 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H),
7
K. Liu, L. Xie, H. Lu, S. Jiang, B. Fan and F. Maurel, Bioorg.
Med. Chem. 2008, 16, 3039. (c) M. Biava, G. C. Porretta, G.
Poce, C. Battilocchio, S. Alfonso, A. de Logu, F. Manetti and
7.28-7.00 (m, 4H), 6.87 (t, J = 7.7 Hz, 1H), 6.66 (d, J = 7.7 Hz,
1H), 4.91 (s, 1H), 4.99-4.77 (m, 2H), 4.32 (m, 1H), 4.16 (m, 1H),
3.29-3.13 (m, 1H), 3.06-2.91 (m, 1H), 2.85 (t, J = 7.5 Hz, 1H),
2.70 (dd, J = 16.4, 7.9 Hz, 1H), 2.26-1.96 (m, 4H), 1.91 (s, 3H),
1.39 (t, J = 7.1 Hz, 3H), 1.18-1.01 (m, 2H), 1.01-0.83 (m, 2H),
M. Botta, ChemMedChem 2011, 4, 593. (d) A. Kunfermann,
M. Witschel, B. Illarionov, R. Martin, M. Rottmann, H. W.
Höffken, M. Seet, W. Eisenreich, H.-J. Knölker, M. Fischer, A.
Bacher, M. Groll and F. Diederich, Angew. Chem. Int. Ed.
2014, 53, 1.
0.76 (t, J = 6.6 Hz, 3H); 13C NMR (63 MHz, CDCl3):
δ 178.6,
175.8, 165.4, 154.5, 141.4, 137.8, 129.4, 128.4, 128.0, 127.1,
126.0, 122.5, 109.8, 104.2, 77.3, 73.3, 68.7, 60.6, 49.7, 47.8,
39.8, 32.4, 31.0, 30.5, 30.1, 20.1, 14.6, 14.1, 12.6; IR (neat, cm-
1): 3190, 1708, 1681, 1612, 1249, 1203. Anal. calcd. for
C31H35N3O4: C 72.49, H 6.87, N 8.18%. Found: C 72.33, H 6.90,
N 7.97%.
3
4
B. D. Roth, Progress Med. Chem. 2002, 40, 1.
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5
6
7
Conclusions
A sequential reaction between primary amines, β-dicarbonyl
compounds and -bromoesters in the presence of indium
α
trichloride as a Lewis acid catalyst, which was performed
under microwave-assisted, solvent-free conditions, constitutes
the first multicomponent synthesis of 2-pyrrolin-5-ones and
proceeds via a Hantzsch-type mechanism. In spite of their
simplicity and potential importance in drug discovery, these
compounds are not easily synthesized by the few previously
known methods. Their ready preparation by our method
Chem. 2016, 5, DOI: 10.1002/ajoc.201600061.
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9
10 | J. Name., 2012, 00, 1-3
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ARTICLE
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β-enamino esters
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23 The evaluation of compound
integrase is in progress.
2 as an inhibitor of HIV
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25 Deposited at the Cambridge Crystallographic Data Centre
with code CCDC 1456952.
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decarboxylative coupling of an
α-amino acid and a ketone,
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DOI: 10.1039/C6RA06317A
Textual Abstract
The combination of two multicomponent reactions, i.e. a Hantzsch-type
synthesis of 2-pyrrolin-5-ones and a 1,3-dipolar cycloaddition generated
complex spirocyclic systems.