Efficient Synthesis of β-Aryl-γ-lactams and Their Resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen

An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.

Due to the utility of β-aryl-γ-lactams as key synthetic intermediates for the synthesis of γ-amino acids [17] in conjunction with their biological activity, several methods have been reported for the synthesis of γ-lactams [18][19][20][21][22]; however, it is yet highly desirable to develop convenient and milder protocols for its preparation, especially with various substitution patterns and enantiomerically purity. In this paper, we report an efficient synthesis of a series of β-aryl-γ-lactams and its resolution by derivatization with (S)-Naproxen. The utility of this methodology was highlighted by the preparation of enantiomerically-enriched (R)-and (S)-Baclofen hydrochloride.

Results and Discussion
For the synthesis of the target β-aryl-γ-lactams (2a-f), we first carried out the Knoevenagel reaction of diethyl or methyl malonate with different aromatic aldehydes in toluene at reflux in the presence of a catalytic amount of piperidine, leading to the expected arylidenemalonates (5a-f) in 80% to 92% yield. The reaction proceeds efficiently with electron-rich and electron-withdrawing aromatic substituents. The Michael addition of nitromethane to arylidenemalonates (5a-f) in the presence of K2CO3 as a base in toluene at room temperature, furnished the γ-nitro derivatives 6a-f in 60% to 76% yield (Scheme 1) [23,24].

Results and Discussion
For the synthesis of the target β-aryl-γ-lactams (2a-f), we first carried out the Knoevenagel reaction of diethyl or methyl malonate with different aromatic aldehydes in toluene at reflux in the presence of a catalytic amount of piperidine, leading to the expected arylidenemalonates (5a-f) in 80% to 92% yield. The reaction proceeds efficiently with electron-rich and electron-withdrawing aromatic substituents. The Michael addition of nitromethane to arylidenemalonates (5a-f) in the presence of K 2 CO 3 as a base in toluene at room temperature, furnished the γ-nitro derivatives 6a-f in 60% to 76% yield (Scheme 1) [23,24].

Results and Discussion
For the synthesis of the target β-aryl-γ-lactams (2a-f), we first carried out the Knoevenagel reaction of diethyl or methyl malonate with different aromatic aldehydes in toluene at reflux in the presence of a catalytic amount of piperidine, leading to the expected arylidenemalonates (5a-f) in 80% to 92% yield. The reaction proceeds efficiently with electron-rich and electron-withdrawing aromatic substituents. The Michael addition of nitromethane to arylidenemalonates (5a-f) in the presence of K2CO3 as a base in toluene at room temperature, furnished the γ-nitro derivatives 6a-f in 60% to 76% yield (Scheme 1) [23,24]. Catalytic hydrogenation of the nitro derivatives (6a-f) in the presence of catalytic amounts of Raney nickel at 60 psi proceeds efficiently to produce the racemic γ-lactams (7a-f) in 75% to 95% yield (Scheme 2). Catalytic hydrogenation of the nitro derivatives (6a-f) in the presence of catalytic amounts of Raney nickel at 60 psi proceeds efficiently to produce the racemic γ-lactams (7a-f) in 75% to 95% yield (Scheme 2).

Results and Discussion
For the synthesis of the target β-aryl-γ-lactams (2a-f), we first carried out the Knoevenagel reaction of diethyl or methyl malonate with different aromatic aldehydes in toluene at reflux in the presence of a catalytic amount of piperidine, leading to the expected arylidenemalonates (5a-f) in 80% to 92% yield. The reaction proceeds efficiently with electron-rich and electron-withdrawing aromatic substituents. The Michael addition of nitromethane to arylidenemalonates (5a-f) in the presence of K2CO3 as a base in toluene at room temperature, furnished the γ-nitro derivatives 6a-f in 60% to 76% yield (Scheme 1) [23,24]. Catalytic hydrogenation of the nitro derivatives (6a-f) in the presence of catalytic amounts of Raney nickel at 60 psi proceeds efficiently to produce the racemic γ-lactams (7a-f) in 75% to 95% yield (Scheme 2).
The racemic γ-lactams with trans-stereochemistry were obtained as major product, according to the coupling constants (J = 10 Hz) for the hydrogens H2 and H3. Additionally, suitable crystals for the γ-lactams 7c and 7e were obtained, which were subjected to X-ray analysis (Supplementary Materials) [25], in which it has been confirmed that the orientation of the hydrogens in C7 and C10 are in a trans relationship ( Figure 2).
Molecules 2015, 20, page-page 3 The racemic γ-lactams with trans-stereochemistry were obtained as major product, according to the coupling constants (J = 10 Hz) for the hydrogens H2 and H3. Additionally, suitable crystals for the γ-lactams 7c and 7e were obtained, which were subjected to X-ray analysis (Supplementary Materials) [25], in which it has been confirmed that the orientation of the hydrogens in C7 and C10 are in a trans relationship ( Figure 2). In the next step we carried out the hydrolysis and decarboxylation of the ester moiety, by treatment of (7a-f) with 1N-NaOH in ethanol followed by the protonation, obtaining the carboxylic acids derivatives (8a-f) in 53% to 100% yield which, by heating in toluene, afforded the β-aryl-γlactams (2a-f) in excellent yield (Scheme 3). With the racemic β-aryl-γ-lactams (2a-f) in hand, the next step was to explore the scope of (S)-Naproxen as a resolution agent [26][27][28][29][30]. For this purpose, and after several attempts using Et3N/DMAP as base, we found that the reaction of the racemic β-phenyl-γ-lactam (2a) with lithium diisopropylamide (LDA) in dry tetrahydrofuran at −78 °C, followed by the addition of (S)-Naproxen acyl chloride 9 freshly prepared after reaction of (S)-Naproxen with oxalyl chloride, produced the imides (R,S)-10a and (S,S)-10a as a diastereoisomeric mixture which, by careful separation by column chromatography, afforded the diastereoisomerically pure imides (R,S)-10a as minor polar and (S,S)-10a as more polar in 26% and 27% yield, respectively. Under identical conditions, the resolution of the β-aryl-γ-lactams (2c-d) with 9, afforded the diastereoisomerically pure imides (R,S)-10b-d and (S,S)-10b-d in good yields (Scheme 4). In the next step we carried out the hydrolysis and decarboxylation of the ester moiety, by treatment of (7a-f) with 1 N NaOH in ethanol followed by the protonation, obtaining the carboxylic acids derivatives (8a-f) in 53% to 100% yield which, by heating in toluene, afforded the β-aryl-γ-lactams (2a-f) in excellent yield (Scheme 3). The racemic γ-lactams with trans-stereochemistry were obtained as major product, according to the coupling constants (J = 10 Hz) for the hydrogens H2 and H3. Additionally, suitable crystals for the γ-lactams 7c and 7e were obtained, which were subjected to X-ray analysis (Supplementary Materials) [25], in which it has been confirmed that the orientation of the hydrogens in C7 and C10 are in a trans relationship ( Figure 2). In the next step we carried out the hydrolysis and decarboxylation of the ester moiety, by treatment of (7a-f) with 1N-NaOH in ethanol followed by the protonation, obtaining the carboxylic acids derivatives (8a-f) in 53% to 100% yield which, by heating in toluene, afforded the β-aryl-γlactams (2a-f) in excellent yield (Scheme 3). With the racemic β-aryl-γ-lactams (2a-f) in hand, the next step was to explore the scope of (S)-Naproxen as a resolution agent [26][27][28][29][30]. For this purpose, and after several attempts using Et3N/DMAP as base, we found that the reaction of the racemic β-phenyl-γ-lactam (2a) with lithium diisopropylamide (LDA) in dry tetrahydrofuran at −78 °C, followed by the addition of (S)-Naproxen acyl chloride 9 freshly prepared after reaction of (S)-Naproxen with oxalyl chloride, produced the imides (R,S)-10a and (S,S)-10a as a diastereoisomeric mixture which, by careful separation by column chromatography, afforded the diastereoisomerically pure imides (R,S)-10a as minor polar and (S,S)-10a as more polar in 26% and 27% yield, respectively. Under identical conditions, the resolution of the β-aryl-γ-lactams (2c-d) with 9, afforded the diastereoisomerically pure imides (R,S)-10b-d and (S,S)-10b-d in good yields (Scheme 4). With the racemic β-aryl-γ-lactams (2a-f) in hand, the next step was to explore the scope of (S)-Naproxen as a resolution agent [26][27][28][29][30]. For this purpose, and after several attempts using Et 3 N/DMAP as base, we found that the reaction of the racemic β-phenyl-γ-lactam (2a) with lithium diisopropylamide (LDA) in dry tetrahydrofuran at´78˝C, followed by the addition of (S)-Naproxen acyl chloride 9 freshly prepared after reaction of (S)-Naproxen with oxalyl chloride, produced the imides (R,S)-10a and (S,S)-10a as a diastereoisomeric mixture which, by careful separation by column chromatography, afforded the diastereoisomerically pure imides (R,S)-10a as minor polar and (S,S)-10a as more polar in 26% and 27% yield, respectively. Under identical conditions, the resolution of the β-aryl-γ-lactams (2c-d) with 9, afforded the diastereoisomerically pure imides (R,S)-10b-d and (S,S)-10b-d in good yields (Scheme 4). 20 D + 13.53 was assigned by comparing the sign of optical rotation with those reported in the literature [31][32][33][34][35]. The other β-aryl-γ-lactams showed similar characteristics in NMR and the configuration was also assigned by comparing the sign of optical rotation.  20 D + 13.53 was assigned by comparing the sign of optical rotation with those reported in the literature [31][32][33][34][35]. The other β-aryl-γ-lactams showed similar characteristics in NMR and the configuration was also assigned by comparing the sign of optical rotation. Finally, the hydrolysis of the β-chlorophenyl-γ-lactam (R)-2b with 6N HCl, gave the (R)-baclofen hydrochloride 4 in 79% yield. Under identical conditions, the β-chlorophenyl-γ-lactam (S)-2b was transformed into (S)-Baclofen hydrochloride 4 in 97% yield (Scheme 6). Finally, the hydrolysis of the β-chlorophenyl-γ-lactam (R)-2b with 6N HCl, gave the (R)-baclofen hydrochloride 4 in 79% yield. Under identical conditions, the β-chlorophenyl-γ-lactam (S)-2b was transformed into (S)-Baclofen hydrochloride 4 in 97% yield (Scheme 6).

General Comments
Reagents were obtained from commercial suppliers and were used without further purification. Melting points were determined in a Fischer Johns apparatus (Pittsburgh, PA, USA) and are uncorrected. NMR spectra were recorded on Varian System instrument (Palo Alto, CA, USA), 400 MHz for 1 H and 100 MHz for 13 C) and Varian Gemini 200 MHz, 200 MHz for 1 H and 50 MHz for 13 C). The spectra were obtained in CD3OD and CDCl3 solution using TMS as an internal reference. High-resolution CI + and FAB + mass experiments were made in a JEOL HRMStation JHRMS-700 (Akishima, Tokyo, Japan). X-ray diffraction studies were performed on a Bruker-APEX diffractometer (Madison, WI, USA) with a CCD area detector at 100 K (λMo Kα = 0.71073 Å, monochromator:graphite). Specific rotations were measured in a Perkin-Elmer 341 polarimeter (Shelton, CT, USA) at room temperature and λ = 589 nm. The purification of all compounds was carried out by column chromatography using (silica gel 70-230). The dichloromethane was refluxed on phosphorous pentoxide and THF with sodium and benzophenone.

General Procedure for the Preparation of Arylidenemalonates 5a-f
A mixture of dialkyl malonate (1 eq.), toluene, aryl aldehyde (1 eq.), and 10 drops of piperidine, was refluxed for 48 h. Then, the reaction mixture was acidified to pH = 6-7 by addition of 1M HCl, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography. 1 H-and 13 C-NMR data for the compounds 5a,d [36], 5b,c [37], are identical with those described in the literature.

General Comments
Reagents were obtained from commercial suppliers and were used without further purification. Melting points were determined in a Fischer Johns apparatus (Pittsburgh, PA, USA) and are uncorrected. NMR spectra were recorded on Varian System instrument (Palo Alto, CA, USA), 400 MHz for 1 H and 100 MHz for 13 C) and Varian Gemini 200 MHz, 200 MHz for 1 H and 50 MHz for 13 C). The spectra were obtained in CD 3 OD and CDCl 3 solution using TMS as an internal reference. High-resolution CI + and FAB + mass experiments were made in a JEOL HRMStation JHRMS-700 (Akishima, Tokyo, Japan). X-ray diffraction studies were performed on a Bruker-APEX diffractometer (Madison, WI, USA) with a CCD area detector at 100 K (λ Mo Kα = 0.71073 Å, monochromator:graphite). Specific rotations were measured in a Perkin-Elmer 341 polarimeter (Shelton, CT, USA) at room temperature and λ = 589 nm. The purification of all compounds was carried out by column chromatography using (silica gel 70-230). The dichloromethane was refluxed on phosphorous pentoxide and THF with sodium and benzophenone.

General Procedure for the Preparation of Arylidenemalonates 5a-f
A mixture of dialkyl malonate (1 eq.), toluene, aryl aldehyde (1 eq.), and 10 drops of piperidine, was refluxed for 48 h. Then, the reaction mixture was acidified to pH = 6-7 by addition of 1M HCl, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography. 1 H-and 13 C-NMR data for the compounds 5a,d [36], 5b,c [37], are identical with those described in the literature.

General Procedure for the Preparation of Nitroderivatives 6a-f
To a solution of arylidenemalonates 5a-f in toluene (20 mL) was added nitromethane (5.0 eq.) and potassium carbonate (1.7 eq.). The reaction mixture was stirred at room temperature for 48 h, and then the solvent was evaporated under reduced pressure. The crude product was treated with water (20 mL) and extracted with AcOEt (4ˆ25 mL). The organic layer was dried over Na 2 SO 4 , filtered, evaporated, and purified by column chromatography. 1 H-and 13 C-NMR data for the compounds 6a,b [38], 6c,d [39], 6e,f [23,40], are identical with those described in the literature.

General Procedure for the Synthesis of the γ-Lactams 7a-f
A mixture of 6a-f in MeOH (15 mL) and a catalytic amount of Ra-Ni was hydrogenated at room temperature for 2.5 h at 60 psi. The catalyst was filtered off in vacuum through Celite and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography or by recrystallization. 1 H-and 13 C-NMR data for the compound 7a was identical with those described in the literature [41].

General Procedure for The Preparation of the Carboxylic Acids 8a-f
To a suspension of 7a-f in ethanol (2 mL) was added 1 N NaOH (0.8 mL) was stirred at room temperature for 48 h. The ethanol was removed at reduced pressure and the residue was acidified with 1M HCl. The precipitate formed was filtered under vacuum.

General Procedure of the Synthesis of β-Aryl-γ-lactams (˘)-2a-f
A suspension of carboxylic acid in toluene was heated to reflux for 5 h. After cooling to room temperature, the solvent was evaporated and the pure product was obtained. 1 H-and 13 C-NMR data for the compounds (˘)-2a-c [42], are identical with those described in the literature.

Synthesis of (S)-Naproxen Acyl Chloride 9
To a solution of (S)-Naproxen (2.5 eq.) in anhydrous CH 2 Cl 2 (15 mL) and N,N-dimethyl formamide (one drop), oxalyl chloride (3 eq.) at 0˝C was added. The reaction mixture was stirred at room temperature for 2.5 h under a nitrogen atmosphere, and after this time, the solvent and residual oxalyl chloride were removed under reduced pressure to continue the reaction, obtaining the (S)-Naproxen acyl chloride 9, which was not isolated and used immediately in the next reaction.

General Procedures for The Resolution of β-Aryl-γ-lactams (˘)-2a-d
A solution of 8a-d (1 eq.) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a freshly prepared LDA (1.1 eq.) at´78˝C. The reaction mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. Then, the mixture was cooled to´78˝C followed by the addition of crude (S)-9. The reaction mixture was allowed to room temperature and stirred for 2 h under a nitrogen atmosphere. After, a saturated solution of ammonium chloride was added and extracted with dichloromethane (3ˆ15 mL). Finally the solvent was removed under reduced pressure and purified by column chromatography, to obtain the diastereoisomeric pure (R,S)-and (S,S)-imides 10a-d. According to the general procedure, the reaction of 8c (0.2 g, 1.14 mmol) with LDA (0.14 g, 1.37 mmol) and (S)-9 (0.709 g, 2.85 mmol), followed by purification in column chromatography using hexane/AcOEt (90:10), afforded the diastereoisomers (R,S)-10c (0.21 g, 49%) as a colorless liquid, and (S,S)-10c (0.19 g, 44%) as a beige solid, m.p.: 61-64˝C.

General Procedure for the Preparation of Enantiomerically-Pure β-Aryl-γ-lactams 2a-d
To a solution of (R,S)-10a-d or (S,S)-10a-d in tetrahydrofuran (0.6 mL) was added 1 N KOH (0.3 mL) and the reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure and extracted with CH 2 Cl 2 (4ˆ3 mL), the organic layer was dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give the corresponding γ-lactams (R)-2a-d or (S)-2a-d.

Conclusions
In conclusion, we have demonstrated the utility of (S)-Naproxen as an excellent resolution agent of β-aryl-γ-lactams, which are easily obtained through four steps from diethyl or methyl malonate and the appropriate aromatic aldehyde. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)-and (S)-Baclofen hydrochloride in excellent yields. Additionally, we anticipate that the use of this procedure could be used in the preparation of β-aryl-γ-lactams as key intermediates in the synthesis of compounds with important pharmacological properties.