Efficient synthesis of β-aryl-γ-lactams and their resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen

Article abstract of DOI:10.3390/molecules201219830

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.

Full text of DOI:10.3390/molecules201219830

Article
Efficient Synthesis of β-Aryl-γ-lactams and Their
Resolution with (S)-Naproxen: Preparation of (R)-
and (S)-Baclofen
Iris J. Montoya-Balbás †, Berenice Valentín-Guevara †, Estefanía López-Mendoza †,
Irma Linzaga-Elizalde *, Mario Ordoñez † and Perla Román-Bravo †
Received: 31 October 2015 ; Accepted: 2 December 2015 ; Published: 10 December 2015
Academic Editor: Derek J. McPhee
Centro de Investigaciones Químicas CIQ-IICBA, Universidad Autónoma del Estado de Morelos,
Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico; natzelane_k@hotmail.com (I.J.M.-B.);
b.valentinguevara@gmail.com (B.V.-G.); fa_pple@hotmail.com (E.L.-M.); palacios@uaem.mx (M.O.);
rperl@uaem.mx (P.R.-B.)
*
†
Correspondence: linzaga@uaem.mx; Tel.: +52-777-329-7997
These authors contributed equally to this work.
Abstract:
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.
Keywords: β-aryl-γ-lactams; Michael addition; resolution; (S)-naproxen; baclofen; phenibut
1. Introduction
γ-lactams have attracted considerable attention due to their fascinating properties and
potential applications in many fields, especially in organic synthesis and medicinal chemistry [1–3].
In particular, enantiomerically-pure β-aryl-γ-lactams, such as the (R)-Rolipram 1, considered
as a cyclic derivative of GABA, which has shown antipsychotic [4–6], antidepressive [7,8],
anti-inflammatory, immunosuppressive, and antitumor activity. Additionally, the β-aryl-γ-lactams
2a and 2b are precursors for the synthesis of Phenibut 3 and Baclofen 4, two β-aryl-γ-amino butyric
acids (GABA analogues), which are important biological active compounds Figure 1. Phenibut is
used as a psychotropic drug, anticonvulsant, antidepressant, and for its anti-neuropathic pain
properties [9,10], whereas Baclofen is a GABAB receptor agonist and is marketed for the treatment
of multiple neurological disorders, and acts as a muscle relaxant [11]. The biological activity of these
compounds depends on its absolute configuration, and the (R)-enantiomer is much more active than
the (S)-enantiomer [12–15]. Additionally, the β-aryl-γ-lactams are also important key intermediates
for the synthesis of more complex compounds [1,16].
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 [18–22]; 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.
Molecules 2015, 20, 22028–22043; doi:10.3390/molecules201219830
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Molecules 2015, 20, 22028–22043
Figure 1. Structures of γ-lactams and GABA derivatives used as pharmaceuticals.
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].
Scheme 1. Preparation of nitro derivatives (6a–f).
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).
Scheme 2. Catalytic reduction of γ-nitroesters 6a–f.
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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).
Figure 2. X-ray structures of γ-lactams 7c (a) and 7e (b).
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).
Scheme 3. Preparation of racemic γ-lactams (2a–f).
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 [26–30]. 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).
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Scheme 4. Resolution of γ-lactams 2a–d with (S)-Naproxen.
Subsequently removing the chiral agent in the diastereoisomerically-pure imides (R,S)-10a–d
and (S,S)-10a–d was carried out using 1 N potassium hydroxide in THF to obtain the
enantiomerically-pure β-aryl-γ-lactams (R)-2a–d and (S)-2a–d in excellent yield (Scheme 5).
20
20
The absolute configuration of γ-lactams (R)-2a–b [(R)-2a: rαsD ´ 19.21; (R)-2b: rαsD ´ 24.2] and
(S)-2a: rαs2D0 + 19.78; (S)-2b: rαs2D0 + 13.53 was assigned by comparing the sign of optical rotation with
those reported in the literature [31–35]. The other β-aryl-γ-lactams showed similar characteristics in
NMR and the configuration was also assigned by comparing the sign of optical rotation.
Scheme 5. Preparation of enantiomerically-pure β-aryl-γ-lactams (R)- and (S)-2a–d.
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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).
Scheme 6. Preparation of (R)- and (S)-Baclofen hydrochloride 4.
3. Materials and Methods
3.1. 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 1H and 100 MHz for 13C) and Varian Gemini 200 MHz, 200 MHz for 1H and
50 MHz for 13C). 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
= 0.71073 Å,
Kα
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.
3.2. 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. 1H- and 13C-NMR data for the compounds 5a,d [36], 5b,c [37], are identical with
those described in the literature.
3.2.1. Diethyl 2-(2-Chlorobenzylidene)malonate 5e
According to the general procedure, diethyl malonate (3.0 g, 18.7 mmol), toluene (35 mL),
2-chlorobenzaldehyde (2.63 g, 18.7 mmol), and piperidine were reacted. The crude product was
purified by column chromatography using hexane/AcOEt (9:1) as eluent to afford 5e (4.2 g, 80%)
as a slightly yellow liquid. IR (cm´1): 2983, 1724, 1632, 1469, 1248, 1200, 756. 1H-NMR (CDCl3,
400 MHz,) δ: 1.18 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.33 (q, J = 7.2 Hz,
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Molecules 2015, 20, 22028–22043
2H), 7.21–7.33 (m, 1H), 7.29–7.33 (m, 1H), 7.41–7.45 (m, 2H), 8.02 (s, 1H). 13C-NMR (CDCl3, 100 MHz)
δ: 14.0, 14.3, 61.8, 61.9, 127.0, 129.1, 129.5, 130.0, 131.3, 132.3, 134.9, 139.4, 163.9, 165.9. MS (CI+): m/z
283 (10%), 237 (100%), 219 (12%), 173 (30%). HRMS (CI): calculated for C14H16ClO4 [M+H]+, m/z
283.0737; found for [M + H]+, m/z 283.0712.
3.2.2. Diethyl 2-(2-Nitrobenzyliden)malonate 5f
According to the general procedure, diethyl malonate (3.0 g, 18.7 mmol), toluene (35 mL),
2-nitrobenzaldehyde (2.82 g, 18.7 mmol), and piperidine were reacted. The crude product was
purified by column chromatography on using hexane/AcOEt (8:2) as eluent to afford 5f (4.4 g, 80%),
˝
as a white crystalline solid, m.p.: 64–66 C. IR (cm´1): 2989, 1714, 1626, 1477, 1259, 1201, 757. 1H-NMR
(CDCl3, 400 MHz) δ: 1.32 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 4.36 (m, 4H), 7.57–7.61 (m, 1H),
7.75–7.80 (m, 2H), 8.2–8.26 (m, 1H), 8.34 (s, 1H). 13C-NMR (CDCl3, 100 MHz) δ: 14.1, 14.3, 62.3, 62.4,
123.9, 125.0, 129.6, 130.1, 134.8, 135.3, 139.2, 148.6, 163.6, 165.9. MS (FAB+): m/z 294 (75%), 248 (100%),
232 (13%), 220 (<10%), 202 (<10%), 176 (<10%), 154 (15%), 136 (20%), 107 (<10%), 89 (10%), 77 (<10%).
HRMS (FAB): calculated for C14H16NO6 [M + H]+, m/z 294.0978; found for [M + H]+, m/z 294.0959.
3.3. 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 (4 ˆ 25 mL). The organic layer was dried over Na2SO4, filtered,
evaporated, and purified by column chromatography. 1H- and 13C-NMR data for the compounds
6a,b [38], 6c,d [39], 6e,f [23,40], are identical with those described in the literature.
3.4. 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. 1H- and 13C-NMR data for the compound 7a was identical
with those described in the literature [41].
3.4.1. Ethyl 2-Oxo-4-(4-chlorophenyl)-pyrrolidine-3-carboxylate (˘)-7b
Following the general procedure, 6b (0.9 g, 2.8 mmol) was treated with Ra-Ni in MeOH.
The crude product was recrystallized (hot EtOH) to give (˘)-7b as a white solid (0.54 g, 75%), m.p.:
˝
131–133 C. IR (cm´1): 3193, 3094, 2867, 1740, 1701, 1434, 1198, 1161, 821. 1H-NMR (CDCl3, 400 MHz)
δ: 3.40 (ddd, J = 10.0, 8.4, 6.0 Hz, 1H), 3.54 (d, J = 10 Hz, 1H), 3.78–3.83 (m, 1H), 3.78 (s, 3H), 4.09
(dd, J = 18.0, 8.4 Hz, 1H), 7.20 (d, J = 8.8, 2H), 7.32 (d, J = 8.0, 2H), 7.43 (bs, 1H). 13C-NMR (CDCl3,
100 MHz) δ: 43.9, 47.8, 53.1, 55.3, 128.6, 129.4, 133.7, 138.3, 169.6, 172.7. ME (FAB+): m/z 254 (60%),
235 (<10%), 222 (<10%), 176 (<10%), 154 (100%), 136 (65%), 107 (18%), 89 (15%), 77 (12%), 65 (<10%),
51 (<10%). HRMS (FAB) calculated for C12H13ClNO3 (M + 1): 254.0584, found 254.0596.
3.4.2. Methyl 2-Oxo-4-(4-methylphenyl)-pyrrolidine-3-carboxylate (˘)-7c
Following the general procedure, 6c (1.8 g, 6.09 mmol) was treated with Ra-Ni in MeOH.
The crude product was recrystallized (CH2Cl2/hexane) to give (˘)-7c as a beige solid (1.2 g, 87%),
˝
m.p.: 120–123 C. IR (cm´1): 3186, 3095, 2953, 1742, 1701, 1518, 1158, 1196, 815. 1H-NMR (CDCl3,
400 MHz) δ: 2.33 (s, 3H), 3.40 (dd, J = 17.6, 9.2 Hz, 1H), 3.57 (d, J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.77–7.80
(m, 1H), 4.07 (ddd, J = 9.2, 9.2, 8.8 Hz, 1H), 7.15 (s, 4 H). 13C-NMR (CDCl3, 100 MHz) δ: 21.2, 44.2,
48.1, 53.0, 55.5, 127.1, 129.8, 136.9, 137.5, 169.9, 173.0. ME (CI+): m/z 234 (100%), 233 (5%), 202 (30%),
174 (30%). HRMS (CI) calculated for C13H16NO3 (M + 1): 234.1130, found 234.1136.
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3.4.3. Methyl 2-Oxo-4-(3-methylphenyl)-pyrrolidine-3-carboxylate (˘)-7d
According to the general procedure, 6d (0.8 g, 2.7 mmol) was hydrogenated in the presence of a
catalytic amount of Ra-Ni in MeOH (15 mL). The crude product was recrystallized from hot EtOH, to
˝
give (˘)-7d (0.56 g, 88 %) as a white solid, m.p.: 105–109 C. IR (cm´1): 3208, 2948, 1739, 1694, 1433,
1
1167, 786, 775, 701. H-NMR (CDCl3, 400 MHz) δ: 2.34 (s, 3H), 3.40–3.44 (m, 1H), 3.60 (d, J = 9.6 Hz,
3H), 3.78 (dd, J = 17.6, 9.2 Hz, 1H), 3.79 (s, 3H), 4.07 (dd, J = 17.6, 8.4 Hz, 1H), 7.04–7.10 (m, 2H),
7.21–7.26 (m, 2H), 7.34 (bs, 1H). 13C-NMR (CDCl3, 100 MHz) δ: 21.6, 44.4, 48.1, 53.0, 55.4, 124.2, 127.9,
128.5, 129.1, 138.9, 139.9, 169.8, 173.0. MS (FAB+): m/z HRMS 234 (100%), 202 (25%), 174 (15%), 159
(<10%), 137 (<10%), 91 (<10%), 77 (<10%). (FAB): calculated for C13H16NO3 [M + H]+, m/z 234.1130;
found for [M + H]+, m/z 234.1135.
3.4.4. Ethyl 2-Oxo-4-(2-chlorophenyl)-pyrrolidine-3-carboxylate (˘)-7e
According to the general procedure, 6e (1.2 g, 3.5 mmol) was hydrogenated in the presence
of a catalytic amount of Ra-Ni in MeOH (18 mL). The crude product was recrystallized from
˝
hexane/CH2Cl2 mixture, to give (˘)-7e (0.77 g, 83%) as a white solid, m.p.: 108–110 C. IR (cm´1):
1
3207, 3100, 2868, 1732, 1698, 1481, 1175, 1152, 757. H-NMR (CDCl3, 400 MHz) δ: 1.28 (t, J = 7.2 Hz,
3H), 3.40 (dd, J = 9.6, 7.6 Hz, 1H), 3.66 (d, J = 7.6 Hz, 1H), 3.92 (dd, J = 9.6, 8.8 Hz, 1H), 4.23 (q,
J = 7.2 Hz, 2H), 4.52 (ddd, J = 8.8, 7.6, 7.6 Hz, 1H), 7.21–7.33 (m, 3H), 7.39–7.41 (d, J = 7.6 Hz, 1H),
7.51 (bs, 1H). 13C-NMR (CDCl3, 100 MHz) δ: 14.2, 41.4, 47.1, 54.4, 62.1, 127.6, 128.0, 129.0, 130.4, 134.1,
169.2, 173.0. MS (CI+): m/z 268 (100%), 267 (5%), 222 (45%), 194 (20%). HRMS (CI) calculated for
C13H15ClNO3 [M + H]+, m/z 268.0740; found for [M + H]+, m/z 268.0745.
3.4.5. Ethyl 2-Oxo-4-(2-aminophenyl)-pyrrolidine-3-carboxylate (˘)-7f
According to the general procedure, 6f (0.7 g, 1.9 mmol) was hydrogenated in the presence
of a catalytic amount of Ra-Ni in MeOH (15 mL). The crude product was recrystallized from
˝
Et2O/CH2Cl2/hexane to give the trans-7f (0.40 g, 83%) as a white solid, m.p.: 102–105 C. IR (cm´1):
3458, 3352, 3210, 3105, 2956, 1721, 1701, 1470, 1178, 787. 1H-NMR (CDCl3, 400 MHz) δ: 1.27 (t,
J = 7.2 Hz, 3H), 3.39 (m, 1H), 3.54 (d, J = 9.6 Hz, 3H), 3.76 (m, 1H), 3.98 (dd, J = 17.6, 8.4 Hz, 1H),
4.22 (q, J = 7.2 Hz, 2H), 6.59 (m, 3H), 7.11 (m, 1H), 7.24 (bs, 1H).13C-NMR (CDCl3, 100 MHz) δ: 14.3,
44.5, 47.9, 55.4, 62.0, 113.7, 114.4, 117.1, 130.1, 141.3, 147.2, 169.6, 173.1. MS (FAB+): m/z 249 (75%),
248 (27%), 203 (28%), 175 (40%), 149 (100%), 132 (<10%), 113 (15%), 71 (35%), 57 (47%). HRMS (FAB)
calculated for C13H17N2O3 [M + H]+, m/z 249.1239; found for [M + H]+, m/z 249.1251.
3.5. 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.
3.5.1. 2-Oxo-4-phenyl-pyrrolidine-3-carboxylic Acid 8a
According to the general procedure, 7a (0.38 g, 1.7 mmol) was treated with 1 N NaOH (1.5 mL) to
˝
give 8a (0.31 g, 89%) as a white solid, m.p.: 158–162 C. IR (cm´1): 3283, 1686, 1489, 766, 703. 1H-NMR
(MeOD, 400 MHz) δ: 3.39 (dd, J = 9.2, 8.8 Hz, 1H), 3.58 (d, J = 10.0 Hz, 1H), 3.75 (dd, J = 9.2, 8.8 Hz,
1H), 4.01 (ddd, J = 10.0, 8.8, 8.8 Hz, 1H), 7.24–7.35 (m, 5H). 13C-NMR (MeOD, 100 MHz) δ: 46.4, 48.9,
56.9, 128.2, 128.6, 130.1, 141.6, 172.8, 175.1. MS (FAB+): m/z 206 (100%), 188 (20%), 154 (55%), 136
(38%), 107 (11%), 77 (14%). HRMS (FAB) calculated for C11H12NO3 [M + H]+, m/z; 206.0817, found
for [M + H]+, m/z 206.0815.
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3.5.2. 2-Oxo-4-(4-chlorophenyl)-pyrrolidine-3-carboxylic Acid 8b
According to the general procedure, 7b (0.2 g, 0.79 mmol) was treated with 1 N NaOH (0.8 mL)
˝
to give 8b (0.15 g, 82%) as a beige solid, m.p.: 140–142 C. IR (cm´1): 2883, 1739, 1670, 1486, 822.
1H-NMR (MeOD, 400 MHz) δ: 3.37 (t, J = 9.6 Hz, 1H), 3.57 (d, J = 9.6 Hz, 1H), 3.75 (dd, J = 9.6, 8.8 Hz,
1H), 4.01 (t, J = 8.8 Hz, 1H), 7.32 (s, 4H). 13C-NMR (MeOD, 100 MHz) δ: 45.9, 48.7, 56.8, 130.0, 130.1,
134.4, 140.3, 172.7, 175.0. MS (FAB+): m/z 240 (98%), 222 (20%), 176 (10%), 154 (100%), 137 (70%), 107
(23%), 89 (22%), 77 (20%), 65 (<10%), 51 (<10%). HRMS calculated for C11H11ClNO3 [M + H]+, m/z
240.0427; found for [M + H]+, m/z 240.0431.
3.5.3. 2-Oxo-4-(4-methylphenyl)-pyrrolidine-3-carboxylic Acid 8c
According to the general procedure, 7c (0.2 g, 0.85 mmol) was treated with 1 N NaOH (0.8 mL)
˝
to give 8c (0.17 g, 94%) as a white solid, m.p.: 166–169 C. IR (cm´1): 3255, 2964, 1738, 1667, 1488,
808. 1H-NMR (MeOD, 400 MHz) δ: 2.30 (s, 3H), 3.30–3.31 (m, 1H), 3.36 (t, J = 9.6 Hz, 1H), 3.57
(d, J = 9.6 Hz, 1H), 3.72 (t, J = 9.6 Hz, 1H), 3.93–4.0 (m, 1H), 7.12–7.20 (m, 4H). 13C-NMR (MeOD,
100 MHz) δ: 21.2, 46.1, 49.0, 56.0, 128.0, 128.8, 130.1, 130.5, 138.3, 172.8, 175.1. MS (CI+): m/z
219 (<10%), 202 (18%), 175 (100%), 145 (10%), 118 (85%), 91 (<10%). HRMS (CI+) calculated for
C12H14NO3 [M + H]+, m/z 220.0974; found for [M + H]+, m/z 220.0976.
3.5.4. 2-Oxo-4-(3-methylphenyl)-pyrrolidine-3-carboxylic Acid 8d
According to the general procedure, 7d (0.2 g, 0.85 mmol) was treated with 1 N NaOH (0.8 mL)
˝
to give 8d (0.18 g, 100%) as a white solid, m.p.: 173–177 C. IR (cm´1): 3332, 2891, 1731, 1666, 1427,
731, 686, 642. 1H-NMR (MeOD, 400 MHz) δ: 2.32 (s, 3H), 3.38 (dd, J = 10.0, 8.8 Hz, 1H), 3.56 (d,
J = 10.0 Hz, 1H), 3.73 (dd, J = 10.0, 8.8 Hz, 1H), 3.97 (ddd, J = 10.0, 8.8, 8.8 Hz, 1H), 7.07–7.14 (m, 3H),
7.20–7.23 (m, 1H). 13C-NMR (MeOD, 50 MHz) δ: 21.6, 46.6, 48.9, 57.0, 125.3, 128.9, 129.3, 130.0, 141.5,
172.9, 175.3. MS (FAB+): m/z 220 (100%), 202 (37%), 154 (65%), 136 (55%), 89 (25%), 77 (23%), 57 (12%).
HRMS (FAB) calculated for C12H14NO3 [M + H]+, m/z 220.0974; found for [M + H]+, m/z 220.0966.
3.5.5. 2-Oxo-4-(2-chlorophenyl)-pyrrolidine-3-carboxylic Acid 8e
According to the general procedure, 7e (0.2 g, 0.7 mmol) was treated with 1 N NaOH (0.8 mL) to
˝
give 8e (0.89 g, 53%) as a white solid, m.p.: 154–156 C. IR (cm´1): 3290, 2887, 1751, 1656, 1478, 760.
1H-NMR (MeOD, 400 MHz) δ: 3.61 (dd, J = 10.0, 7.6 Hz, 1H), 3.68 (d, J = 8.4 Hz, 1H), 3.85 (dd, J = 10.0,
8.4 Hz, 1H), 4.44–4.50 (m, 1H), 7.24–7.29 (m, 1H), 7.31–7.35 (m, 1H), 7.41–7.47 (m, 2H). 13C-NMR
(MeOD, 50 MHz) δ: 43.1, 48.0, 55.6, 128.9, 129.3, 130.1, 131.2, 135.1, 138.9, 172.6, 174.9. MS (FAB+):
m/z 240 (85%), 222 (25%), 154 (100%), 136 (80%), 107 (25%), 89 (26%), 77 (23%). HRMS calculated for
C11H11ClNO3 [M + H]+, m/z 240.0427; found for [M + H]+, m/z 240.0429.
3.5.6. 2-Oxo-4-(2-aminophenyl)-pyrrolidine-3-carboxylic Acid 8f
According to general procedure, 7f (0.2 g, 0.8 mmol) was treated with 1 N NaOH (0.8 mL) to
give 8f (0.14 g, 80%) as a brown liquid. IR (cm´1): 3366, 2883, 1674, 1493, 793. 1H-NMR (MeOD,
400 MHz) δ: 3.44 (dd, J = 9.6, 8.8 Hz, 1H), 3.63 (d, J = 10 Hz, 1H), 3.81 (dd, J = 9.6, 9.2 Hz, 1H),
4.08–4.12 (m, 1H), 7.34 (d, J = 7.2, 1H), 7.41 (s, 1H), 7.48–7.56 (m, 2H). 13C-NMR (MeOD, 100 MHz)
δ: 45.9, 47.0, 56.6, 123.1, 123.2, 129.1, 132.0, 133.0, 144.3, 172.4, 174.6. MS (FAB+) m/z 220 (<10%), 203
(<10%), 176 (10%), 154 (100%), 136 (85%), 120 (12%) 107 (18%), 89 (<10%). HRMS (FAB) calculated for
C11H13N2O3 [M + H]+, m/z 221.0926; found for [M + H]+, m/z 221.0976.
3.6. 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
1
temperature, the solvent was evaporated and the pure product was obtained. H- and 13C-NMR data
for the compounds (˘)-2a–c [42], are identical with those described in the literature.
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Molecules 2015, 20, 22028–22043
3.6.1. 4-(3-Methylphenyl)-pyrrolidin-2-One (˘)-2d
According to the general procedure 8d (0.15 g, 0.7 mmol) was refluxed to give (˘)-2d (0.12 g,
˝
100%) as a beige solid, m.p.: 103–104 C. IR (cm´1): 3211, 3095, 2892, 1677, 1489, 790, 706, 684.
1H-NMR (CDCl3, 200 MHz) δ: 2.35 (s, 3H), 2.49 (dd, J = 16.8, 8.6 Hz, 1H), 2.72 (dd, J = 16.8, 8.6 Hz,
1H), 3.41 (dd, J = 16.8, 8.6 Hz, 1H), 3.57–3.68 (m, 1H), 3.77 (dd, J = 16.8, 8.6 Hz, 1H), 7.03–7.08 (m,
2H), 7.19–7.27 (m, 2H). 13C-NMR (CDCl3, 50 MHz) δ: 36.9, 37.3, 48.5, 127.2, 127.5, 128.4, 130.0, 133.9,
139.6, 178.0. MS (FAB+) m/z 176 (100%), 131 (<10%), 105 (10%), 91 (11%), 69 (12%), 55 (14%), 43 (12%).
HRMS (FAB) calculated for C11H14NO [M + H]+, m/z 176.1075; found for [M + H]+, m/z 176.1077.
3.6.2. 4-(2-Chlorophenyl)-pyrrolidin-2-One (˘)-2e
According to general procedure, 8e (0.11 g, 0.46 mmol) was refluxed to give (˘)-2e (80 mg, 86%)
˝
as a beige solid, m.p.: 112–115 C. IR (cm´1): 3174, 3080, 2884, 1686, 1486, 746. 1H-NMR (CDCl3,
200 MHz) δ: 2.48 (dd, J = 17.2, 7.4 Hz, 1H), 2.74 (dd, J = 17.2, 8.8 Hz, 1H), 3.41 (dd, J = 9.8, 6.2 Hz,
1H), 3.85 (dd, J = 9.8, 8.4 Hz, 1H), 4.18–7.25 (m, 1H), 7.25–7.29 (m, 1H), 7.33–7.34 (d, J = 7.2 Hz,
1H), 7.38–7.40 (d, J = 7.6 Hz, 2H). 13C-NMR (CDCl3, 50 MHz) δ: 36.9, 37.3, 48.5, 127.2, 127.5, 128.4,
130.0, 133.9, 139.6, 178.0. MS (FAB+) m/z 196 (100%), 162 (<10%), 154 (10%), 137 (11%), 107 (<10%),
77 (<10%), 55 (<10%), 41 (<10%). HRMS (FAB) calculated for C10H11ClNO [M + H]+, m/z 196.0529;
found for [M + H]+, m/z 196.0541.
3.6.3. 4-(2-Aminophenyl)-pyrrolidin-2-one (˘)-2f
According to general procedure, 8f (0.2 g, 0.7 mmol) was refluxed in toluene for five hours to
˝
give (˘)-2f (60 mg, 18%) as a beige solid, m.p.: 122–125 C. IR (cm´1): 3422, 3347, 3243, 2923, 1668,
1
792. H-NMR (CDCl3, 200 MHz) δ: 2.47 (dd, J = 17.0, 8.6 Hz, 1H), 2.69 (dd, J = 17.0, 8.6 Hz, 1H), 3.57
(dddd, J = 8.6, 8.2, 8.2, 7.6 Hz, 1H), 3.73 (dd, J = 9.0, 8.2 Hz, 2H), 6.55–6.63 (m, 2H), 7.06–7.14 (m, 2H).
13C-NMR (CDCl3, 50 MHz) δ: 38.0, 40.3, 49.6, 113.4, 114.0, 117.0, 129.8, 143.6, 147.0, 178.4. MS (CI+):
m/z 177 (100%), 176 (78%) 160 (11%), 119 (45%). HRMS (CI) calculated for C10H13N2O [M + H]+, m/z
177.1028; found for [M + H]+, m/z 177.1025.
3.7. Synthesis of (S)-Naproxen Acyl Chloride 9
To a solution of (S)-Naproxen (2.5 eq.) in anhydrous CH2Cl2 (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.
3.8. 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 (3 ˆ 15 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.
3.8.1. (R)-1-((S)-2(6-Methoxynaphth-2-yl)propionyl)-4-phenyl-pyrrolidin-2-one (R,S)-10a and
(S)-1-((S)-2(6-methoxynaphth-2-yl)propionyl)-4-phenyl-pyrrolidin-2-one (S,S)-10a
According to the general procedure, the reaction of 8a (50 mg, 0.31 mmol) with LDA (39 mg,
0.37 mmol) and (S)-9 (190 mg, 0.77 mmol), followed by purification in column chromatography using
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Molecules 2015, 20, 22028–22043
hexane/AcOEt (90:10), afforded the diastereoisomers (R,S)-10a (30 mg, 26%) and (S,S)-10a (31 mg,
27%), both as an amber liquid.
20
(R,S)-10a: rαsD + 87.13 (c 0.95, CHCl3). IR (cm´1): 2933, 1734, 1685, 1604, 1482, 1190, 760, 698.
1H-NMR (CDCl3, 400 MHz) δ: 1.57 (d, J = 7.2 Hz, 3H), 2.76 (dd, J = 17.6, 10.4 Hz, 1H), 2.84 (dd,
J = 17.6, 8.4 Hz, 1H), 3.38 (dddd, J = 10.4, 8.8, 8.4, 8.4 Hz, 1H), 3.79 (dd, J = 12.0, 8.8 Hz, 1H), 3.91
(s, 3H), 4.19 (dd, J = 12.0, 8.4 Hz, 1H), 5.25 (q, J = 7.2 Hz, 1H), 7.11–7.20 (m, 4H), 7.25–7.29 (m, 1H),
7.29–7.36 (m, 2H), 7.48–7.51 (m 1H), 7.70–7.75 (m, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 19.4, 35.8, 41.1,
44.7, 52.5, 55.3, 105.6, 118.9, 126.6, 126.7, 127.0, 127.1, 127.4, 129.0, 129.4, 133.7, 136.2, 140.3, 157.6, 173.4,
175.4. MS (CI+): m/z 374 (100%), 373 (38%) 212 (70%), 185 (23%), 162 (18%). HRMS (CI) calculated for
C24H24NO3 [M + H]+, m/z 374.1756; found for [M + H]+, m/z 374.1772.
20
(S,S)-10a: rαsD + 83.53 (c 0.82, CHCl3). IR (cm´1): 2933, 1734, 1686, 1604, 1482, 1189, 760, 698.
1H-NMR (CDCl3, 400 MHz) δ: 1.55 (d, J = 6.8 Hz, 3H), 2.57 (dd, J = 17.6, 8.0 Hz, 1H), 2.91 (dd,
J = 17.6, 8.8 Hz, 1H), 3.45–3.49 (m, 1H), 3.67 (dd, J = 11.6, 6.8 Hz, 1H), 3.90 (s, 3H), 4.30 (dd, J = 11.6,
8.0 Hz, 1H), 5.22 (q, J = 6.8 Hz, 1H), 6.91–6.93 (m, 2H), 7.05–7.14 (m, 5H), 7.45–7.46 (m, 1H), 7.67–7.68
(m, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 19.5, 36.2, 41.4, 44.9, 52.8, 55.5, 105.8, 119.0, 126.5, 126.6, 127.2,
127.4, 127.4, 129.0, 129.1, 129.6, 133.9, 136.2, 141.2, 157.8, 173.8, 175.6. MS (CI+): m/z 374 (70%), 373
(55%) 212 (100%), 185 (32%), 184 (19%), 162 (18%), 141 (<10%). HRMS (CI) calculated for C24H24NO3
[M + H]+, m/z 374.1756; found for [M + H]+, m/z 374.1772.
3.8.2. (R)-4-(4-Chlorophenyl)-1-((S)-2-(6-methoxynaphth-2-yl)propionyl)-pyrrolidin-2-one (R,S)-10b
and (S)-4-(4-Chlorophenyl)-1-((S)-2-(6-methoxynaphth-2-yl)propionyl)-pyrrolidin-2-one (S,S)-10b
According to the general procedure, 8b (86 mg, 0.4 mmol) with LDA (56 mg, 0.52 mmol) and
(S)-9 (27 mg, 1.1 mmol), followed by purification in column chromatography using hexane/AcOEt
(85:15), afforded the diastereoisomers (R,S)-10b (86 mg, 49%) and (S,S)-10b (92 mg, 51%), both as an
colorless liquid.
20
1
(R,S)-10b: rαsD + 44.48 (c 1.0, CHCl3). IR (cm´1): 2929, 1735, 1686, 810. H-NMR (CDCl3, 400 MHz)
δ: 1.54 (d, J = 7.2 Hz, 3H), 2.69 (dd, J = 17.2, 10.0 Hz, 1H), 2.82 (dd, J = 17.2, 8.4 Hz, 1H), 3.35 (dddd,
J = 10.0, 8.8, 8.4, 8.4 Hz, 1H), 3.74 (dd, J = 12.0, 8.8 Hz, 1H), 3.90 (s, 3H), 4.17 (dd, J = 12.0, 8.4 Hz,
1H) 5.21 (q, J = 7.2 Hz, 1H), 7.10–7.14 (m, 4H), 7.29–7.31 (m, 2H), 7.45–7.48 (m, 1H), 7.68–7.71 (m, 3H).
13C-NMR (CDCl3, 100 MHz) δ: 19.5, 35.5, 41.2, 44.9, 52.5, 55.5, 105.7, 119.1, 126.8, 127.2, 127.3, 128.2,
129.1 129.3, 129.5, 133.4, 133.8, 136.2, 138.9, 157.8, 173.2, 175.6. MS (FAB+): m/z 408 (25%), 185 (100%),
136 (24%), 95 (28%), 69 (55%), 55 (30%). HRMS (FAB) calculated for C24H23ClNO3 [M + H]+, m/z
408.1366; found for [M + H]+, m/z 408.1383.
20
1
(S,S)-10b: rαsD + 39.08 (c 0.97, CHCl3). IR (cm´1): 2932, 1735, 1688, 811. H-NMR (CDCl3, 200 MHz)
δ: 1.55 (d, J = 7.2 Hz, 3H), 2.50 (dd, J = 17.2, 7.2 Hz, 1H), 2.90 (dd, J = 17.2, 8.4 Hz, 1H), 3.42 (m,
1H), 3.62 (dd, J = 11.6, 6.0 Hz, 1H), 3.92 (s, 3H), 4.25 (dd, J = 11.6, 8.0 Hz, 1H), 5.20 (q, 7.2 Hz,
1H), 6.76–6.78 (m, 2H), 6.92–6.95 (m, 2H), 7.12–7.15 (m, 2H), 7.41–7.44 (m, 1H), 7.66–7.69 (m, 3H).
13C-NMR (CDCl3, 100 MHz) δ: 19.3, 35.6, 41.2, 45.0, 52.7, 55.5, 105.7, 119.1, 126.6, 127.2, 127.8, 129.1,
129.6, 133.1, 133.9, 136.0, 139.9, 157.9, 173.4, 175.6. MS (FAB+): m/z 408 (12%), 407 (<10%), 307 (27%),
289 (13%), 212 (18%), 185 (12%), 154 (100%), 136 (66%), 107 (18%), 77 (13%). HRMS (FAB) calculated
for C24H23ClNO3 [M + H]+, m/z 408.1366; found for [M + H]+, m/z 408.1383.
3.8.3. (R)-1-((S)-2-(6-Methoxynaphth-2-yl)propionyl-4-(4-methylphenyl)-pyrrolidin-2-one (R,S)-10c
and (S)-1-((S)-2-(6-Methoxynaphth-2-yl)propionyl-4-(4-methylphenyl)-pyrrolidin-2-one (S,S)-10c,
(R,S)-10c and (S,S)-10c
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.
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Molecules 2015, 20, 22028–22043
20
1
(R,S)-10c: rαsD + 92.96 (c 0.88, CHCl3). IR (cm´1): 2930, 1735, 1686, 1604, 1481, 1189, 812. H-NMR
(CDCl3, 400 MHz) δ: 1.54 (d, J = 6.8 Hz, 3H), 2.33 (s, 3H), 2.73 (dd, J = 17.6, 10.4 Hz, 1H), 2.82 (dd,
J = 17.6, 8.4 Hz, 1H), 3.36 (dddd, J = 10.4, 9.2, 8.4, 8.0 Hz, 1H), 3.76 (dd, J = 11.6, 9.2 Hz, 1H), 3.91
(s, 3H), 4.17 (dd, J = 11.6, 8.0 Hz, 1H), 5.22 (q, J = 6.8 Hz, 1H), 7.07–7.15 (m, 6H), 7.46–7.49 (m, 1H),
7.68–7.72 (m, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 19.5, 21.1, 35.7, 41.4, 44.8, 52.8, 55.5, 105.7, 118.9,
126.7, 126.7, 127.2, 129.1, 129.5, 129.8, 133.8, 136.3, 137.3, 137.2, 137.4, 157.8, 173.7, 175.6. MS (CI+):
m/z 388 (100%), 387 (55%) 212 (90%), 185 (20%), 176 (15%). HRMS (CI) calculated for C25H26NO3
[M + H]+, m/z 388.1913; found for [M + H]+, m/z 388.1905.
20
(S,S)-10c. rαsD + 98.96 (c 1.1, CHCl3). IR (cm´1): 2931, 1735, 1686, 1604, 1482, 1185, 813. 1H-NMR
(CDCl3, 400 MHz) δ: 1.55 (d, J = 6.8 Hz, 3H), 2.23 (s, 3H), 2.57 (dd, J = 17.6, 8.4 Hz, 1H), 2.90 (dd,
J = 17.6, 8.4 Hz, 1H), 3.41–3.49 (m, 1H), 3.64 (dd, J = 12.0, 7.6 Hz, 1H), 3.91 (s, 3H), 4.29 (dd, J = 12.0,
7.6 Hz, 1H), 5.21 (q, J = 6.8 Hz, 1H), 6.81–6.88 (m, 4H), 7.11–7.14 (m, 2H), 7.44–7.47 (m, 1H), 7.67–7.70
(m, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 19.5, 21.1, 35.9, 41.5, 44.9, 52.9, 55.5, 105.7, 118.9, 126.4, 126.6,
127.2, 127.4, 133.9, 136.2, 137.0, 138.1, 157.9, 173.9, 175.6. MS (CI+): m/z 388 (88%), 387 (48%) 212
(100%), 185 (23%), 176 (12%). HRMS (CI) calculated for C25H26NO3 [M + H]+, m/z 388.1913, found
for [M + H]+, m/z 388.1904.
3.8.4. (R)-1-((S)-2-(6-Methoxynaphth-2-yl)propionyl)-4-(3-methylphenyl)-pyrrolidin-2-one (R,S)-10d
and (S)-1-((S)-2-(6-Methoxynaphth-2-yl)propionyl)-4-(3-methylphenyl)-pyrrolidin-2-one (S,S)-10d
According to the general procedure, the reaction of 8d (50 mg, 0.28 mmol) with LDA (36 mg,
0.34 mmol) and (S)-9 (0.17 g, 0.7 mmol), followed by purification in column chromatography using
hexane/AcOEt (90:10), afforded the diastereoisomers (R,S)-10d (33 mg, 31%) and (S,S)-10d (30 mg,
28%), both as an amber liquid.
20
(R,S)-10d: rαsD + 87.14 (c 0.95, CHCl3). IR (cm´1): 2931, 1735, 1686, 1604, 1482, 1198, 727, 701, 672.
1H-NMR (CDCl3, 400 MHz) δ: 1.55 (d, J = 7.2 Hz, 3H), 2.33 (s, 3H), 2.75 (dd, J = 17.6, 10.4 Hz, 1H),
2.83 (dd, J = 17.6, 8.4 Hz, 1H), 3.35 (dddd, J = 10.4, 9.2, 8.4, 8.4 Hz, 1H), 3.78 (dd, J = 12.0, 9.2 Hz, 1H),
3.90 (s, 3H), 4.17 (dd, J = 12.0, 8.4 Hz, 1H), 5.23 (q, J = 7.2 Hz, 1H), 6.98–7.0 (m, 2H), 7.07–7.14 (m,
3H), 7.20–7.25 (m, 1H), 7.46–7.49 (m, 1H), 7.68–7.73 (m, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 19.3, 21.4,
35.7, 41.2, 44.7, 52.5, 55.3, 105.5, 118.9, 123.7, 126.6, 127.0, 128.1, 128.9, 129.4, 133.6, 136.2, 138.7, 140.2,
157.6, 173.6, 175.4. MS (CI+): m/z 388 (100%), 387 (45%) 212 (90%), 185 (25%), 176 (25%), 141 (<10%),
115 (<10%). HRMS (CI) calculated for C25H26NO3 [M + H]+, m/z 388.1913; found for [M + H]+, m/z
388.1924.
20
(S,S)-10d: rαsD + 83.53 (c 0.8, CHCl3). IR (cm´1): 2931, 1734, 1686, 1604, 1482, 1197, 727, 701, 672.
1H-NMR (CDCl3, 400 MHz) δ: 1.55 (d, J = 7.2 Hz, 3H), 2.14 (s, 3H), 2.60 (dd, J = 17.6, 8.4 Hz, 1H), 2.91
(dd, J = 17.6, 8.4 Hz, 1H), 3.46 (m, 1H), 3.68 (dd, J = 12.0, 6.8 Hz, 1H), 3.91 (s, 3H), 4.31 (dd, J = 12.0,
8.0 Hz, 1H), 5.23 (q, J = 7.2 Hz, 1H), 6.74–6.80 (m, 2H), 6.97–6.98 (m, 2H), 7.11–7.13 (m, 2H), 7.45–7.48
(m, 1H), 7.68 (d, J = 8.4 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 19.4, 21.2, 35.9, 41.3, 44.6, 52.5, 53.5,
105.5, 118.8, 123.4, 126.5, 127.0, 127.1, 127.9, 128.7, 129.4, 133.6, 136.0, 138.6, 140.1, 157.6, 173.6, 175.3.
MS (CI+): m/z 388 (100%), 387 (45%) 212 (77%), 185 (20%), 176 (12%). HRMS (CI) calculated for
C25H26NO3 [M + H]+, m/z 388.1913, found for [M + H]+, m/z 388.1935.
3.9. 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 CH2Cl2 (4 ˆ 3 mL), the organic layer was
dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the corresponding
γ-lactams (R)-2a–d or (S)-2a–d.
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Molecules 2015, 20, 22028–22043
3.9.1. (R)-4-Phenylpyrrolidin-2-one 2a
According to the general procedure (R,S)-10a (23 mg, 0.06 mmol) in THF (0.6 mL) was reacted
˝
with 1 N KOH (0.3 mL), to give (R)-2a (7 mg, 100%) as a white solid, m.p.: 84–86 C, [43,44].
20
1
rαsD ´ 19.2 (c 0.9, CHCl3) [31]. H- and 13C-NMR data are identical to (˘)-2a.
3.9.2. (S)-4-Phenylpyrrolidin-2-one 2a
According to the general procedure (S,S)-10a (20 mg, 0.056 mmol) in THF (0.6 mL) was reacted
20
˝
with 1 N KOH (0.3 mL) to give (S)-11a (8 mg, 95%) as a white solid, m.p.: 87–89 C [43,44]. rαsD + 19.8
1
(c 0.9, CHCl3). H- and 13C-NMR data are identical to (R)-2a.
3.9.3. (R)-4-(4-Chlorophenyl)-pyrrolidin-2-one 2b
According to general procedure (R,S)-10b (19 mg, 0.05 mmol) in THF (0.5 mL) was reacted with
20
˝
1 N KOH (0.3 mL) to give (R)-11b (7 mg, 79%) as a white solid, m.p.: 102–105 C. rαsD ´ 24.2 (c 1.15,
1
CHCl3) [31]. H- and 13C-NMR data are identical to (˘)-2b.
3.9.4. (S)-4-(4-Chlorophenyl)-pyrrolidin-2-one 2b
According to the general procedure (S,S)-10b (28 mg, 0.07 mmol) in THF (0.5 mL) was reacted
20
˝
with 1 N KOH (0.3 mL) to give (S)-2b (12 mg, 94%) as a white solid, m.p.: 99–101 C. rαsD + 13.5
1
(c 0.9, CHCl3) [45]. H- and 13C-NMR data are identical to (˘)-2b.
3.9.5. (R)-4-(4-Methylphenyl)-pyrrolidin-2-one 2c
According to general procedure (R,S)-10c (30 mg, 0.06 mmol) in THF (0.6 mL) was reacted with
20
˝
1 N KOH (0.3 mL) to give (R)-2c (12 mg, 98%) as a white solid, m.p.: 108–110 C. rαsD ´ 33.7 (c 0.95,
CHCl3). IR (cm´1): 3189, 2917, 1685, 804. 1H-NMR (CDCl3, 400 MHz) δ: 2.28 (s, 3H), 2.48 (dd, J = 17.2,
9.2 Hz, 1H), 2.71 (dd, J = 17.2, 8.4 Hz, 1H), 3.39 (dd, J = 9.2, 7.6 Hz, 1H), 3.66 (dddd, J = 9.2, 8.4, 8.0,
7.6 Hz, 1H), 3.73–3.80 (m, 1H), 7.1 (s, 4H). 13C-NMR (CDCl3, 100 MHz): δ 21.2, 38.1, 40.2, 49.8, 126.8,
129.7, 137.0, 139.2, 177.9. MS (FAB+): m/z 176 (100%), 149 (25%), 113 (<10%), 73 (<10%), 57 (<10%).
HRMS (FAB) calculated for C11H14NO [M + H]+, m/z 176.1075; found for [M + H]+, m/z 176.1083.
3.9.6. (S)-4-(4-Methylphenyl)-pyrrolidin-2-one 2c
According to the general procedure (S,S)-10c (26 mg, 0.054 mmol) in THF (0.6 mL) was reacted
20
˝
with 1 N KOH (0.3 mL) to give (S)-2c (11 mg, 100%) as a white solid, m.p.: 100–103 C. rαsD + 30.3
(c 1.04, CHCl3). IR (cm´1): 3191, 2918, 1685, 804. 1H-NMR (CDCl3, 200 MHz) δ: 2.33 (s, 3H), 2.47
(dd, J = 16.8, 7.8 Hz, 1H), 2.70 (dd, J = 16.8, 9.0 Hz, 1H), 3.38 (dd, J = 8.2, 6.6 Hz, 1H), 3.56-3.80 (m,
2H), 7.14 (s, 4H). 13C-NMR (CDCl3, 50 MHz): δ 21.6, 38.1, 40.5, 49.7, 123.9, 127.7, 128.0, 128.9, 138.7,
142.3, 177.9. MS (FAB+): m/z 176 (100%), 147 (76%), 73 (58%), 57 (13%). HRMS (FAB) calculated for
C11H14NO [M + H]+, m/z 176.1075; found for [M + H]+, m/z 176.1043.
3.9.7. (R)-4-(3-Methylphenyl)-pyrrolidin-2-one 2d
According to the general procedure (R,S)-10d (24 mg, 0.06 mmol) in THF (0.6 mL) was reacted
20
with 1 N KOH (0.3 mL) to give (R)-2d (8 mg, 72%) as an amber liquid. rαsD ´ 20.0 (c 0.68, CHCl3). IR
1
(cm´1): 3228, 2922, 1686, 784, 700, 637. H-NMR (CDCl3, 200 MHz) δ: 2.35 (s, 3H), 2.50 (dd, J = 17.2,
9.0 Hz, 3H), 2.71 (dd, J = 17.2, 8.6 Hz, 1H), 3.41 (dd, J = 8.2, 6.6 Hz, 1H), 3.62–3.70 (m, 2H), 7.04–7.09 (m,
2H), 7.21–7.26 (m, 2H). 13C-NMR (CDCl3, 50 MHz): δ 21.6, 38.0, 40.4, 49.6, 123.9, 127.7, 128.0, 128.9,
138.7, 142.3, 177.9. MS (FAB+): m/z 176 (20%), 175 (15%), 145 (<10%), 131 (<10%), 118 (100%), 117
(30%), 91 (15%). HRMS (FAB) calculated for C11H14NO [M + H]+, m/z 176.1075; found for [M + H]+,
m/z 176.1069.
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Molecules 2015, 20, 22028–22043
3.9.8. (S)-4-(3-Methylphenyl)-pyrrolidin-2-one 2d
According to general procedure (S,S)-10d. (29 mg, 0.16 mmol) in THF (0.5 mL) was reacted with
20
1 N KOH (0.3 mL) to give (S)-2d (13 mg, 100%) as an amber liquid. rαsD + 17.5 (c 0.94, CHCl3).
IR (cm´1): 3222, 2919, 1682, 783, 699, 637. 1H-NMR (CDCl3, 200 MHz) δ: 2.34 (s, 3H), 2.46 (dd,
J = 16.8, 9.0 Hz, 1H), 2.69 (dd, J = 16.8, 8.6 Hz, 1H), 3.37 (dd, J = 8.6, 7.2 Hz, 1H), 3.53-3.76 (m, 2H),
6.66 (bs, 1H), 7.02–7.09 (m, 2H), 7.19–7.27 (m, 2H). 13C-NMR (CDCl3, 50 MHz) δ: 21.6, 38.1, 40.5,
49.7, 123.9, 127.7, 128.0, 128.9, 138.7, 142.3, 177.9. MS (FAB+): m/z 176 (20%), 175 (30%), 145 (<10%),
131 (<10%), 118 (100%), 117 (25%), 91 (12%). HRMS (FAB) calculated for C11H14NO [M + H]+, m/z
176.1075; found for [M + H]+, m/z 176.1076.
3.10. (R)-(´)-Baclofen Hydrochloride 4
The γ-lactam (R)-2b (7 mg, 0.03 mmol) and 6N HCl (2 mL) was refluxed for 3.5 h. After this
time, the mixture reaction was concentrated in vacuum to afford (R)-12b (10 mg, 79%) as a colorless
20
˝
1
solid, m.p.: 190–192 C. rαsD ´ 2.0 (c 0.6, H2O) [31,45]. H- and 13C-NMR data are identical to those
reported in the literature [46].
3.11. (S)-(+)-Baclofen Hydrochloride 4
The γ-lactam (S)-2b (18 mg, 0.09 mmol) and 6N HCl (2 mL) was refluxed for 5.0 h. After this time,
the mixture reaction was concentrated in vacuum to afford (S)-4 (23 mg, 97%) as a white solid, m.p.:
20
1
188–189 [47]. rαsD + 2.9 (c 0.76, H2O) [32,48]. H- and 13C-NMR data are identical to (S)-(+)-Baclofen
hydrochloride [46].
4. 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.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
20/12/19830/s1.
Acknowledgments: The authors thank CONACyT of México, for their financial support via Projects 181816,
and Laboratorio Nacional de Estructura de Macromoléculas (LANEM) 251613. We thank to Blanca E.
Domínguez-Mendoza and V. Labastida-Galván for the determination of the NMR spectra and HRMS. I.J.M-B.
also thank CONACYT for a Graduate Scholarship.
Author Contributions: I.L.-E. and M.O. provided the concepts of the work, interpreted the results and prepared
the manuscript, I.J.M.-B, B.V.-G., E.L.-M., carried out the experimental work and interpreted the results, P.R.-B.,
determined the X-ray structures. All authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
access article distributed under the terms and conditions of the Creative Commons by
Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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