A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams

The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,β-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry.


Introduction
Recently, we reported [1] the synthesis of a variety of 3,5-diaryl substituted 5-hydroxy 3-pyrrolin-2-ones 1 (referred therein for simplicity as γ-hydroxy-γ-lactams, γ-hydroxy butyrolactams or γ-hydroxy lactams) from readily available 3-cyanoketones 2 through a base-assisted intramolecular cyclization (Scheme 1a). As a continuation of this work, we envisioned that the core of those α,β-unsaturated γ-hydroxy lactams could be easily functionalized further at the C4-position by introducing into the reaction mixture a nonenolizable aldehyde 3 as an electrophilic component (Scheme 1b). In this case, in a similar manner to that described for the preparation of γ-hydroxy butenolides [2], an aldol condensation followed by double-bond isomerization and a base catalyzed cyclization should happen in one pot affording corresponding 3,4,5-trisubstituted 5-hydroxy-3-pyrrolin-2-ones 4. Such highly functionalized γ-hydroxy butyrolactams, being an important subclass of 3-pyrrolin-2-ones [3,4], were found in the large number of biologically active natural products [5] either as simple heterocycles or as a part of more complex systems, including fused polycyclic ones. On the other hand, in addition to a hydroxyl group at the C5 quaternary carbon center, the skeleton of the herein-described lactams bears unsubstituted NH and conjugated enone moieties, meaning that these compounds can still be conveniently modified further [1,6] and, therefore, serve as useful synthetic intermediates in the preparation of other heterocyclic structures possessing interesting pharmacological properties.

Results and Discussion
By the time we embarked on this project, well-functioning reaction conditions (KOH/DMSO/H2O, rt, 1 h) for the ring closure of β-ketonitriles 2 to 3,5 disubstituted γ-hydroxy lactams 1 had been established [1]. Additionally, the feasibility of preparation of 3,4,5-trisubstituted lactams 4 (Scheme 1b) was demonstrated earlier [16] with indole-4-carbaldehyde as a non-enolizable carbonyl component 3 (Scheme 2). Still, the scope and limitations of the proposed method as well as optimized conditions for the expected cascade transformation-aldol condensation, double bond isomerization and successive cyclization-were yet to be found. Therefore, a number of experiments probing the effects of solvents, bases, concentrations and reaction time were carried out ( Table  1).

Results and Discussion
By the time we embarked on this project, well-functioning reaction conditions (KOH/ DMSO/H 2 O, rt, 1 h) for the ring closure of β-ketonitriles 2 to 3,5 disubstituted γ-hydroxy lactams 1 had been established [1]. Additionally, the feasibility of preparation of 3,4,5trisubstituted lactams 4 (Scheme 1b) was demonstrated earlier [16] with indole-4-carbaldehyde as a non-enolizable carbonyl component 3 (Scheme 2). Still, the scope and limitations of the proposed method as well as optimized conditions for the expected cascade transformation-aldol condensation, double bond isomerization and successive cyclization-were yet to be found. Therefore, a number of experiments probing the effects of solvents, bases, concentrations and reaction time were carried out (Table 1).

Results and Discussion
By the time we embarked on this project, well-functioning reaction conditions (KOH/DMSO/H2O, rt, 1 h) for the ring closure of β-ketonitriles 2 to 3,5 disubstituted γ-hydroxy lactams 1 had been established [1]. Additionally, the feasibility of preparation of 3,4,5-trisubstituted lactams 4 (Scheme 1b) was demonstrated earlier [16] with indole-4-carbaldehyde as a non-enolizable carbonyl component 3 (Scheme 2). Still, the scope and limitations of the proposed method as well as optimized conditions for the expected cascade transformation-aldol condensation, double bond isomerization and successive cyclization-were yet to be found. Therefore, a number of experiments probing the effects of solvents, bases, concentrations and reaction time were carried out ( Table  1). cess of sodium methoxide (entry 1). The latter can be reduced to just one equivalent (entry 3), although at the expense of the reaction time (28 vs. 4 h). Additionally, it seems that the given combination-4 equiv. of MeONa in methanol-is superior both in terms of yields and experiment duration to the other studied systems (entries 5-12) utilizing different bases or/and solvents. This result is in agreement with our previous finding [16] where the herein-discussed synthetic methodology towards highly functionalized γ-hydroxy lactams were used to construct the LSD-like polycyclic indoles (Scheme 2).
Thus, with the optimized reaction conditions in hand, we synthesized a focused, 30-substance-strong collection of novel 3,5-diaryl/heteroaryl-4-benzyl substituted 5-hydroxy 3-pyrrolin-2-ones 4 ( Table 2 and Scheme 3). Its distinguished features are its generally good yields (59-93%) and its versatility in regard to the starting (hetero)aromatic aldehydes 3 and β-ketonitriles 2. The latter can be conveniently prepared [1,2] from the corresponding substituted chalcones 5 which in turn are the products of typical cross aldol condensation between aldehydes 6 and acetophenones 7 (Scheme 1). As can be seen above, the highest yield was achieved through simple stirring of the staring materials in methanol at room temperature for 4 h in the presence of a 4-fold excess of sodium methoxide (entry 1). The latter can be reduced to just one equivalent (entry 3), although at the expense of the reaction time (28 vs. 4 h). Additionally, it seems that the given combination-4 equiv. of MeONa in methanol-is superior both in terms of yields and experiment duration to the other studied systems (entries 5-12) utilizing different bases or/and solvents. This result is in agreement with our previous finding [16] where the herein-discussed synthetic methodology towards highly functionalized γ-hydroxy lactams were used to construct the LSD-like polycyclic indoles (Scheme 2).
Thus, with the optimized reaction conditions in hand, we synthesized a focused, 30substance-strong collection of novel 3,5-diaryl/heteroaryl-4-benzyl substituted 5-hydroxy 3-pyrrolin-2-ones 4 ( Table 2 and Scheme 3). Its distinguished features are its generally good yields (59-93%) and its versatility in regard to the starting (hetero)aromatic aldehydes 3 and β-ketonitriles 2. The latter can be conveniently prepared [1,2] from the corresponding substituted chalcones 5 which in turn are the products of typical cross aldol condensation between aldehydes 6 and acetophenones 7 (Scheme 1). As can be seen above, the highest yield was achieved through simple stirring of the staring materials in methanol at room temperature for 4 h in the presence of a 4-fold excess of sodium methoxide (entry 1). The latter can be reduced to just one equivalent (entry 3), although at the expense of the reaction time (28 vs. 4 h). Additionally, it seems that the given combination-4 equiv. of MeONa in methanol-is superior both in terms of yields and experiment duration to the other studied systems (entries 5-12) utilizing different bases or/and solvents. This result is in agreement with our previous finding [16] where the herein-discussed synthetic methodology towards highly functionalized γ-hydroxy lactams were used to construct the LSD-like polycyclic indoles (Scheme 2).
As for a mechanism of this cascade transformation, we assume it (Scheme 4) likely runs through the deprotonation of a cyanoketone 2 to a corresponding enolate 8, that reacts further with an aldehyde 3 to give an intermediate 9.
The following intramolecular cycloaddition of the alkoxide ion into the nitrile group leads to an iminofuran 10. The latter undergoes the ring-opening reaction to give chalcone 11, which in turn under basic conditions is easily isomerized to an acrylamide 12. The nucleophilic attack of the amide group at the carbonyl carbon furnishes target lactams 4. Scheme 3. The library of novel 3,5-di-aryl/heteroaryl-4-benzyl-5-hydroxy 3-pyrrolin-2-ones 4 prepared by given procedure.
As for a mechanism of this cascade transformation, we assume it (Scheme 4) likely runs through the deprotonation of a cyanoketone 2 to a corresponding enolate 8, that reacts further with an aldehyde 3 to give an intermediate 9.
The following intramolecular cycloaddition of the alkoxide ion into the nitrile group leads to an iminofuran 10. The latter undergoes the ring-opening reaction to give chalcone 11, which in turn under basic conditions is easily isomerized to an acrylamide 12. The nucleophilic attack of the amide group at the carbonyl carbon furnishes target lactams 4.
In addition, we tried to run this reaction with a non-aromatic enolizable aldehyde, bearing an α-protons. For certain reasons, first we took the d-glucose 13, and a γ-hydroxy lactam 4 indeed was obtained but not the one we expected (Scheme 5a).

Scheme 4.
Plausible mechanism of a ring closure reaction between β-ketonitrile 2 and aromatic aldehyde 3.
In addition, we tried to run this reaction with a non-aromatic enolizable aldehyde, bearing an α-protons. For certain reasons, first we took the d-glucose 13, and a γ-hydroxy lactam 4 indeed was obtained but not the one we expected (Scheme 5a).  In addition, we tried to run this reaction with a non-aromatic enolizable aldehyde, bearing an α-protons. For certain reasons, first we took the d-glucose 13, and a γ-hydroxy lactam 4 indeed was obtained but not the one we expected (Scheme 5a). It should be noticed that the examples of glucose cleavage to glycolaldehyde and other small oxygenates, although in the rather harsh conditions (thermal cracking, hydrothermal pyrolysis, supercritical water, etc.), are known [17][18][19]; however, to our best knowledge, no precedents of such a transformation in a mild basic media have been reported. On the other hand, none of our attempts to use other aliphatic aldehydes as butyraldehyde, isobutyraldehyde and octanal were successful, probably due to the preferential self-condensation of the latter.

General Information
NMR spectra, 1 H, 13 C and 19 F were measured in solutions of CDCl 3 or DMSO-d 6 on a Bruker AVANCE-III HD instrument (at 400, 101 and 376 MHz, respectively). Residual solvent signals were used as internal standards, in DMSO-d 6 (2.50 ppm for 1 H, and 40.45 ppm for 13 C nuclei) or in CDCl 3 (7.26 ppm for 1 H, and 77.16 ppm for 13 C nuclei). HRMS spectra was measured on a Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO 2 Na-HCO 2 H for calibration). IR spectra was measured on an FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module. See Supplementary Materials for NMR ( Figures S1-S73) spectral charts. Reaction progress, purity of isolated compounds, and R f values were monitored with TLC on Silufol UV-254 plates. Column chromatography was performed on silica gel (32-63 µm, 60 Å pore size). Melting points were measured with Stuart SMP30 apparatus. All 3-cyanoketones 2 and chalcones 5 except 5ce, 5df, 5de, 2ce, 2df and 2de were synthesized according to the previously reported procedures and were identical to those described [1]. All reagents and solvents were purchased from commercial venders and used as received.

Preparation of 3-cyanoketones 2ce, 2df and 2de (General Procedure)
These compounds were prepared according to the method described in [1]. A 25 mL round bottom flask was charged with a corresponding chalcones 5 (3.00 mmol), KCN (4.5 mmol), EtOH (8 mL), water (0.5 mL) and acetic acid (0.17 mL). The reaction mixture was heated to reflux for 2-5 h (TLC control) then allowed to cool down to room temperature. The precipitated product was collected by filtration, washed with water and after drying at the open air purified if necessary by column chromatography (EtOAc/Hexane, v/v).