Approach to the library of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a three-component condensation

Article abstract of DOI:10.1021/co300082t

A convenient procedure for the parallel synthesis of 3-hydroxy-1,5-dihydro- 2H-pyrrol-2-ones through a three-component condensation of active methylene compounds, aldehydes, and amines was developed. It was shown that the use of acetic acid as the reactio

Full text of DOI:10.1021/co300082t

Letter
pubs.acs.org/acscombsci
Approach to the Library of 3‑Hydroxy-1,5-dihydro‑2H‑pyrrol-2-ones
through a Three-Component Condensation
Sergey V. Ryabukhin,*,†,‡ Dmitriy M. Panov,‡,§ Andrey S. Plaskon,§ and Oleksandr O. Grygorenko‡,§
†The Institute of High Technologies, Kyiv National Taras Shevchenko University, Glushkov St. 4, Kyiv 03187, Ukraine
‡Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska St. 60, Kyiv 01033, Ukraine
§Enamine, Ltd., Alexandr Matrosov St. 23, Kyiv 01103, Ukraine
S
* Supporting Information
ABSTRACT: A convenient procedure for the parallel synthesis
of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a three-
component condensation of active methylene compounds,
aldehydes, and amines was developed. It was shown that the
use of acetic acid as the reaction medium was suitable for the
considerably reactive substrates with no additional function-
alities. The substrates with low reactivity and those possessing
carboxylic groups or additional basic centers required the use of
DMF as the solvent and chlorotrimethylsilane as the reaction promoter was necessary. More than 3000 pyrrolones were
synthesized by the developed procedure. To demonstrate the scope of the described approach 114 library representatives were
fully characterized.
KEYWORDS: multicomponent reaction, pyrrole, condensation, chlorotrimethylsilane, aldehyde, amine
daptation of synthetic procedures to the requirements of
combinatorial chemistry has always been a tremendous
Scheme 1. Synthesis of 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-
ones 1 (a) by the Two-Step Reaction Sequence and (b) by
the One-Pot MCR and (c) Examples of the Products
A
task to solve.1 Multicomponent reactions (MCR)2 represent a
useful tool to the combinatorial chemistry tasks because of the
high diversity of the compound libraries thus produced and
one-pot procedures employed. Nevertheless, in many cases
using a two-step reaction sequence, with the need to introduce
reagents to affect the second step, is more effective because of
the usually higher yields and a simplified isolation and
purification of the products. The synthesis of 3-hydroxy-1,5-
dihydro-2H-pyrrol-2-ones 1 represents an example of such a
transformation. In most cases, pyrrolones 1 were obtained
using a two-step procedure, that is, via the formation of imines
2 followed by their condensation with pyruvates 3 (Scheme 1),
whereas only a limited number of examples of the pyrrolone
syntheses by the one-pot three-component reaction of 3, 4, and
5 were reported in the literature.3−8 The latter method was
shown to be high-yielding with the most reactive substrates.9,10
At the same time the use of substrates with low reactivity led to
moderate or low yields of 1.11−14 Therefore the previously
reported procedures for the one-pot three-component
preparation of 1 need further improvement to become
compatible with parallel synthesis conditions.
Compounds of the general formula 1 have been shown to
possess a wide range of biological activities, that is, as peptide
−protein interaction inhibitors,4 HIV-1 integrase inhibitors,5
vasopressin-2 receptor antagonists,6 compounds with noo-
tropic,15 bacteriostatic, antiamnesic and antitumor,7 antiflo-
gistic,8 antibacterial,10,12,13,16 antiviral,14,17 antiarthritic,18 and
antineoplastic19 activity. Given the importance of 3-hydroxy-
1,5-dihydro-2H-pyrrol-2-ones (1) to medicinal chemistry and
drug discovery, we have turned our attention to the
development of a method for their preparation under parallel
synthesis conditions. In connection with this, a three-
Received: August 1, 2012
Revised: October 28, 2012
Published: November 6, 2012
© 2012 American Chemical Society
631
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ACS Combinatorial Science
Letter
component reaction depicted in the Scheme 1 (3 + 4 + 5)
would be the method of choice with all the advantages of MCR
discussed above. Apart from the high efficiency, this method
considers the possibility of introducing a variety of substituents
to improve the physicochemical parameters of the compounds
(that is, polar groups such as amino, carboxyl, or hetaryl),
allowing for a lead-oriented approach to the library design.20
On the basis of our previous experience with the use of
chlorotrimethylsilane as a mild and efficient promoter for
various condensation reactions of carbonyl compounds,21 we
proposed the similar conditions for the three-component
reaction of the active methylene compounds 3, aldehydes 4,
and amines 5. Thus, DMF was used as the solvent and
chlorotrimethylsilane as the condensation promoter. The
reaction temperature and time were 100 °C and 2−8 h,
respectively. In addition, the classical reaction conditions
involving heating of the starting materials in acetic acid in at
100 °C for 2−8 h were also tested. We have found that in the
case of pyruvates 3(1−9), aldehydes 4(1−7), and simple
aliphatic amines or anilines 5(1−7) (Figures 1−3), the use of
67−86% yields, whereas the preparation of these compounds in
acetic acid showed lower yields of 57−71%. The decreased
yields of 1{3(1−9),4(1−7),5(8−12)} can be attributed to the
formation of acetates which decreased the reactivity of the
amines. It should be noted that Me3SiCl was an effective
reaction promoter in the case of amine 5(13), presumably
because of the dynamic protection of the additional secondary
amine function. An attempt at the preparation of 5(13) in
acetic acid gave a complex mixture of products.
In the case of amines 5(14−16) with moderate nucleophil-
icity, both Me3SiCl and acetic acid were equally efficient,
although prolonged reaction times were required to obtain the
pyrrolones 1{3(1−9),4(1−7),5(14−16)} in 81−91% yields.
Me3SiCl was the reaction promoter of choice for the least
reactive heteroaromatic amines 5(17−27), which gave the
corresponding products 1{3(1−9),4(1−7),5(17−27)} in 73−
93% yields (vs 38−73% in the case of the reaction in acetic
acid).
Acetic acid showed low efficiency as the reaction promoter in
the case of amines 5(28−30) possessing the carboxyl moiety.
The formation of the desired products in less than 10% yield
was detected by LC−MS analysis of the crude precipitates
obtained after the aqueous workup of the reaction mixtures. On
the contrary, Me3SiCl was still useful for the reaction of 5(28−
30), and the corresponding pyrrolones 1{3(1−9),4(1−
7),5(28−30)} were isolated in 74−86% yields.
Notably, no significant influence of the structure of active
methylene compounds 3(1−9) and aldehyde component 4(1−
7) on the reaction outcome could be noticed. Yet again,
Me3SiCl was more effective as the reaction promoter than
acetic acid in the case of carboxy-substituted aldehyde 4(8).
The influence of the structure of various aliphatic, (hetero)-
aromatic and functionalized aldehydes on the outcome of
Me3SiCl-promoted condensations was extensively studied by us
earlier; the results obtained herein are in accordance with our
previous findings.22 In particular, the method described in this
work was not effective with nonbranched aliphatic aldehydes
and ketones (as the carbonyl components of the reaction) due
to their tendency to self-condense under the reaction
conditions.
Figure 1. Pyruvates 3(1−9) used in this work for the synthesis of
pyrrolones 1.
In conclusion, a convenient procedure for the parallel
synthesis of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones through
a three-component condensation involving active methylene
compounds, aldehydes, and amines was developed. It was
shown that the use acetic acid as the reaction medium would be
efficient in the case of reactive substrates possessing no
additional functionality. In the case of substrates with low
reactivity (that is, heteroaromatic amines), or those possessing
additional acidic or basic groups, Me3SiCl-promoted reaction
conditions were found to be more appropriate. The method
was used to prepare more than 3000 compounds of which 114
were characterized and described in this paper. The predicted
values of physicochemical properties for these library members
are within the accepted limits for the large portion of the library
1{3(1−9),4(1−7),5(1−30)} (Table 1, see also Supporting
Information),23 except the cut-offs proposed by Churcher et
al.20a (Figure 4).
Figure 2. Aldehydes 4(1−8) used in this work for the synthesis of
pyrrolones 1.
acetic acid as the reaction promoter was very efficient: the
pyrrolones 1{3(1−9),4(1−7),5(1−7)} were obtained in 73−
87% yields (see Table S1 of the Supporting Information).
In the case of Me3SiCl-promoted reactions, the yields of 1
were slightly lower (64−78%), possibly because of the high
reactivity of the amines 5(1−7), which led to considerable side
reactions and complicated the purification of the products.
Nevertheless, the efficiency of the Me3SiCl-promoted
reactions was reversed in the case of amines 5(8−12)
possessing an additional basic center. The successful action of
Me3SiCl gave rise to pyrrolones 1{3(1−9),4(1−7),5(8−12)} in
EXPERIMENTAL PROCEDURES
■
Solvents were purified according to the standard procedures.
All the starting materials were purchased from Acros, Merck,
Fluka, and Ukrorgsyntez. Melting points were measured on
MPA100 OptiMelt automated melting point system. Analytical
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ACS Combinatorial Science
Letter
Figure 3. Amines 5(1−30) used in this work for the synthesis of pyrrolones 1.
13C) as an internal standard. HPLC-MS analyses were done on
an Agilent 1100 LCMSD SL instrument (chemical ionization
(CI)) and Agilent 5890 Series II 5972 GCMS instrument
(electron impact ionization (EI)). Elemental analyses were
performed at the Laboratory of Organic Analysis, Department
of Chemistry, Kyiv National Taras Shevchenko University.
General Procedure for the Reaction of 3, 4, and 5.
Method A. Pyruvate 3 (1 mmol), aldehyde 4 (1 mmol), and
amine 5 (1 mmol) were placed in a 15 mL screw cap vial and
dissolved in DMF (1−2 mL). Chlorotrimethylsilane (544 mg, 5
mmol) was added portionwise to the solution. The tube was
thoroughly sealed and heated on a steam bath for 2−8 h. After
cooling, the flask was opened (Caution! Excessive pressure
inside), and H2O (10 mL) was added portionwise to the
solution. The suspension formed was sonicated at 20 °C in an
ultrasonic bath for 2 h. The precipitate formed was filtered and
washed with a small amount of i-PrOH (1−2 mL) or EtOH
(1−2 mL) to yield the targeted library member 1.
Table 1. Predicted Values of Physicochemical Properties of
114 Library Members 1{3(1−9),4(1−7),5(1−30)}
average
value
entry
parameter
value range
1
2
3
4
5
6
molecular weight (MW)
cLogP
299.4−502.6
−2.07−5.90
1−3
3−8
2−10
411.8
2.10
1.1
number of H-bond donors
number of H-bond acceptors
number of rotatable bonds
5.8
5.9
2
́
total polar surface area (TPSA), Å
53.4−164.3
95.8
Method B. Pyruvate 3 (1 mmol), aldehyde 4 (1 mmol), and
amine 5 (1 mmol) were placed in a 15 mL screw cap vial and
dissolved in AcOH (1−2 mL). The reaction mixture was
refluxed for 2−8 h. After cooling, the flask was opened, and
H2O (10 mL) was added portion-wise to the solution. The
suspension formed was sonicated at 20 °C in an ultrasonic bath
for 2 h. The precipitate formed was filtered and washed with a
small amount of i-PrOH (1−2 mL) or EtOH (1−2 mL) to
yield the targeted library member 1.
Figure 4. Physicochemical properties of 114 synthesized library
members 1{3(1−9),4(1−7),5(1−30)} shown in cLogP−MW plot.
TLC was performed using Polychrom Supporting Information
F254 plates. Column chromatography was performed using
Kieselgel Merck 60 (230−400 mesh) as the stationary phase.
1H and 13C NMR spectra were recorded on a Bruker 170
Avance 500 spectrometer (at 499.9 MHz for protons, 124.9
MHz for carbon-13) and Varian Unity Plus 400 spectrometer
(at 400.4 MHz for protons, 100.7 MHz for carbon-13).
Chemical shifts are reported in ppm downfield from TMS (1H,
ASSOCIATED CONTENT
■
S
* Supporting Information
Table S1, distributions of physicochemical properties for 114
library members, cLogP−MW plot for the 3615 library
1
members, compound characterization data, and copies of H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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ACS Combinatorial Science
Letter
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AUTHOR INFORMATION
Corresponding Author
*E-mail: s.v.ryabukhin@gmail.com.
Notes
■
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank Mr. Vitaliy V. Polovinko for NMR
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