HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 7, 2009, pp. 1729-1759
Received, 29th January, 2009, Accepted, 18th March, 2009, Published online, 19th March, 2009.
DOI: 10.3987/COM-09-11668

■ New Thiazolidinone and Triazinethione Conjugates Derived from Amino-β-lactams

Katarina Radolović, Ivan Habuš,* and Bogdan Kralj

Ruđer Bošković Institute, Bijenička c. 54, P.O.B. 180, HR-10002 Zagreb, Croatia

Abstract

Thioureas 3a-s, generated from amino-β-lactams 1a-c, were used to achieve two different cyclizations: (i) condensation with ethyl bromoacetate which resulted in the formation of a variety of iminothiazolidinones 4a/a'-n, and (ii) condensation with aqueous formaldehyde and methylamine which resulted in the formation of triazinethiones 5a-g. The condensation of thioureas 3b-f, 3h and 3m-s (R1 = cyclohexyl, exo-norbornyl, aryl, R2 = β-lactam) with ethyl bromoacetate proceeded with high regioselectivity leading exclusively to the formation of a single regioisomer A of iminothiazolidinones 4b-n. However, the cyclization of thiourea 3a (R1 = n-hexyl, R2= β-lactam) with ethyl bromoacetate led to the formation of a mixture of two regioisomers A (minor) and B (major) of the iminothiazolidinones 4a/a' in the ratio 23:77. Furthermore, condensation of thioureas 3d, 3g, 3i-l and 3n with aqueous formaldehyde and methylamine, furnished triazinethiones 5a-g.

INTRODUCTION
Monocyclic β-lactams occupy a central place among medicinally important compounds due to their diverse and interesting antibiotic activities.1-3 Consequently their synthesis has been of considerable interest to the synthetic community over the past five decades.4-6 The potential of β-lactams as intermediates for the access to α- and β-amino acid derived peptides, has helped research on this topic to achieve significant attention.7-10 Enantiopure 3-amino-β-lactams are the key intermediates for the synthesis of peptides and peptidomimetics. A variety of 3-amino-β-lactams with excellent enantiopurities can be obtained based on chiral ester enolate – imine cyclocondensations.8,10-13 Their hydrolysis affords the corresponding α,β-diamino acids.14 This creates the foundation for the applications of these β-lactams to the asymmetric synthesis of non-protein amino acids, peptides, dipeptide isosters and peptidomimetics that are not easily prepared by conventional methods. α,β-Diamino acids are frequently found to be components of peptide antibiotics including lavendomycin and glumamycin.15
On the other hand, the amino functionality in enantiopure 3-amino-β-lactams represents a good point for extension of the β-lactam class and provides new possibilities in asymmetric synthesis and the development of methods for preparation of diverse substances potentially with a broad spectrum of activity.1,6,16,17 Thioureas,18,19 thiazolidinone20-35 and triazine36,37 moieties represent building blocks for the generation of new compounds with possible pharmacological and biological application in the areas of antibacterial, antifungal, herbicidal, and pesticidal activity. Thioureas have attracted much attention due to their pharmaceutical and pesticidal activity. A variety of thiourea derivatives and their metal complexes exhibit analgetic,38 anti-inflamatory,39 antimicrobial,40 anticancer,38 and antifungal41 activities. Furthermore, thioureas are important building blocks in the synthesis of heterocycles, e.g. iminothiazolidinones and triazinethiones, that posses a broad spectrum of biological activity. The former group, beside antibacterial and antifungal properties, have a special importance as nonsteroidal anti-inflamatory drugs (NSAID’s) and in contrast with the majority of NSAID’s, they cause only minor disturbance of the gastrointestinal system.26,30

RESULTS AND DISCUSSION
We employed the chiral ester lithium enolate-imine condensation strategy,13,42,43 to the asymmetric synthesis of trans-3-amino-β-lactams 1a-c.11,12 This synthetic methodology is generally used for the formation of the azetidin-2-one nucleus and is also known as the β-lactam synthon method.44,45 Treatment of trans-3-amino-β-lactams 1a-c with a variety of isothiocyanates 2a-n in acetonitrile provided the corresponding thioureas 3a-s (Scheme 1).
Thioureas 3a-s were subjected to two different cyclizations: (i) condensation with ethyl bromoacetate in the presence of sodium carbonate29,34 which resulted in the formation of a variety of iminothiazolidinones 4a-n (Scheme 2), and (ii) condensation with aqueous formaldehyde and methylamine36,46,47 which led to the formation of triazinethiones 5a-g (Scheme 5). Iminothiazolidinones 4a-n were isolated in 45-98 % yields, when the reaction mixtures were heated in acetonitrile at 40-60 °C for 6 h. Crude products were purified by column chromatography on silica gel, followed by crystallization.

The construction of the iminothiazolidinone ring relies on the reaction of thioureas with α-halo esters or acids in the presence of an inorganic base in a polar solvent. For unsymmetrical thioureas (R1 ≠ R2, Scheme 3), regiocontrol in the cyclization step is influenced by electronic factors that predispose electron-withdrawing substituents (e.g. aryl or heteroaryl) to maintain conjugative stabilization with the imine nitrogen (e.g. R1 in structure A, Scheme 3).29 This electronic preference allows the regioselective cyclization of a thiourea bearing one alkyl and one aryl substituent or two aryl groups having significantly different electronic properties.29,48,49 However, for substituents with no difference in electronic properties (e.g. R1 = R2 = alkyl) the reaction of an unsymmetrical thiourea with an α-halo ester or acid could be expected to proceed with minimal regioselectivity.29

In our strategy to construct iminothiazolidinone ring we used unsymmetrical thioureas 3a-f, 3h and 3m-s (R1 = alkyl, aryl; R2 = β-lactam) in the reaction with ethyl bromoacetate in acetonitrile at 40-60 °C, in the presence of sodium carbonate. The cyclization led exclusively to the formation of a single regioisomer A in the cases of iminothiazolidinones 4b-n, (R1 = cyclohexyl, exo-norbornyl, aryl; R2 = β-lactam), whereas with less sterically hindered substances, R1 = n-hexyl, the formation of A (minor) and B (major) iminothiazolidinone regioisomers 4a (minor) and 4a' (major) in the ratio 23:77 was observed. When the mixture of 4a/4a' (in the ratio 23:77) was further subjected to prolonged heating (24 h) at 60 °C in acetonitrile and in the presence of sodium carbonate, the ratio of 4a/4a’ remained the same. Determination of the isomer ratio 4a and 4a' is based on the 1H NMR spectra (Figure 1) and HPLC analyses. The structures of regioisomers 4a/a'-n were determined by 1H and 13C NMR spectra analysis. The resonances of n-hexyl and β-lactam C3-Ha and C4-Hb protons allowed us to identify each regioisomer. In 4a' the CH2(CH2)4CH3 protons appeared as a triplet resonating at higher chemical shift (3.75 ppm) than the same protons of 4a (3.16 ppm). The chemical shifts are in accordance with the observation made by Ottanà and coworkers,26 for CH2CH2CH3 protons in the 2-imino-4-thiazolidinone regioisomers that they investigated. The β-lactam C3-Ha and C4-Hb protons of 4a' appear as two well-separated dublets at 4.97 and 4.54 ppm, whereas for 4a they appear as two very close dublets at 5.38 and 5.36 ppm, respectively (Figure 1, I). When 1H NMR spectra was recorded in DMSO-d6 the close doublets for the β-lactam C3-Ha and C4-Hb protons of 4a are well-separated and appear at 5.42 and 5.25 ppm, respectively (Figure 1, II).

1H NMR spectra analysis for iminothiazolidinones 4b-n, (R1 = cyclohexyl, exo-norbornyl, aryl; R2 = β-lactam), revealed the formation of a single regioisomer A. The CH protons for 4b,c appear as multiplets at 3.15 (cyclohexyl) and 3.09 (exo-norbornyl) ppm. The β-lactam C3-Ha and C4-Hb protons appear as very close doublets at 5.37 and 5.35 ppm for 4b and 5.35 and 5.30 ppm for 4c, respectively. 1H NMR spectra analysis for iminothiazolidinones 4d-n, (R1 = aryl; R2 = β-lactam), reveals the presence of a single set of doublets for the β-lactam C3-Ha and C4-Hb protons appearing in the area between 5.40-5.60 ppm, with exception of 4k (R1 = cyclohexyl; R2 = β-lactam) where a single multiplet peak for the cyclohexyl CH proton is also observed at 3.16 ppm.

The formation of a single regioisomer A (Scheme 3) in the cases of the iminothiazolidinones 4d-j and 4l-n (Scheme 4) originated from the condensation of ethyl bromoacetate with the sulphur atom of the most stable arylimino thiol intermediate C, generated from thioureas 3d-o and 3q-s (R1 = aryl; R2 = β-lactam), by delocalization of the lone pair on the nitrogen bearing aryl substituent on the adjacent thiocarbonyl group and followed by intramolecular cyclization of thus formed intermediate D (Scheme 4).

However, with R1 = R2 = alkyl the reaction might be expected to proceed with minimal regioselectivity. When thioureas 3b-c and 3p, bearing sterically hindered alkyls (R1 = cyclohexyl, exo-norbornyl; R2 = β-lactam), are employed in the condensation with ethyl bromoacetate, we believe that the reaction proceeds via intermediate E (Figure 2) caused by delocalization of the lone pairs involving both nitrogens adjacent to the thiocarbonyl group. Furthermore, intermediate E, proceeds to intermediate D, leading to the formation of a single regioisomer A (Scheme 3) in the cases of iminothiazolidinones 4b,c and 4k. The condensation of thiourea 3a (R1 = n-hexyl; R2 = β-lactam) with ethyl bromoacetate led to the formation of a mixture of two regioisomers A (minor) and B (major) of 4a/4a’ in the ratio 22:77. With the less sterically hindered alkyl compound (R1 = n-hexyl), the condensation proceeded via intermediate E, followed by intramolecular cyclization with minimal regioselectivity via intermediates D (minor) and F (major) (Figure 2).

Furthermore, a variety of triazinethiones 5a-g (Scheme 5) were prepared from the corresponding thioureas 3d, 3g, 3i-l and 3n in a reaction with aqueous formaldehyde and methylamine. The reaction mixture was heated in ethanol at 50 °C for 48 h and the crude products were purified by column chromatography on silica gel.

The reaction proceeded very slow. It needed 48 h to produce yields of 12-35% of triazinethiones 5a-g. We believe that the basic aqueous-ethanolic media caused by an excess of methyl amine at elevated temperature (50 °C) created conditions that promoted β-lactam ring hydrolysis thus reducing the yields of the triazinethiones.

CONCLUSION
In summary, the amino functionality in enantiopure 3-amino-β-lactams represents a good point for extension of the β-lactam class and provides new possibilities in asymmetric synthesis and the development of methods for preparation of diverse substances potentially with a broad spectrum of pharmacological and biological application. To the best of our knowledge for the first time, we report the synthesis of new thiazolidinone and triazinethione conjugates derived from amino-β-lactams.
Thioureas 3a-s (Scheme 1), generated from amino-β-lactams 1a-c, were employed in two different cyclizations: (i) condensation with ethyl bromoacetate which resulted in the formation of a variety of iminothiazolidinones 4a/a'-n (Scheme 2), and (ii) condensation with aqueous formaldehyde and methylamine which led to the formation of triazinethiones 5a-g (Scheme 5).

EXPERIMENTAL
Melting points were determined on a Reichert Thermovar 7905 apparatus and are not corrected. The IR spectra were recorded on a Perkin Elmer Spectrum RX I FT-IR System spectrometer (KBr pellets technique). The 1H and 13C NMR spectra (in CDCl3, CD3OD and DMSO-d6 at rt) were measured on a Bruker AV 300 and/or AV 600 spectrometer, δ in ppm relative to tetramethylsilane as the internal reference. Microanalyses were performed on a Perkin Elmer 2400 Series II CHNS/O Analyzer. Optical rotations: Optical Activity Automatic Polarimeter AA-10 in a 1 dm cell; c in g/100 mL. HPLC analyses were performed on a Knauer HPLC System supplied with Knauer UV/VIS WellChrom Diode Array Detector K-2800 using Macherey-Nagel 5µm Kromasil C18 4.0 × 250 mm HPLC column operated at a rt and a flow rate 1 mL/min; linear gradient of water containing 0.1% formic acid (solvent A) and MeOH (solvent B); 60% A + 40% B, 10 min; 40% A + 60% B, 5 min; 5% A + 95% B, 10 min. LC-MS spectra were recorded on a Waters LC-MS System equipped with a binary solvent pump (Waters 515 HPLC Pump), an autosampler (Waters 2767 Sample Manager, volume injection set to 20 µL), Waters 2996 Photodiode Array Detector and Waters Micromass ZQ Detector (2040 Da) with electrospray ionization (ESI) using Waters SunFire™, C18, 3.5 μm, 4.6 x 75 mm HPLC column operated at rt and a flow rate 3 mL/min; linear gradient of water containing 0.05% formic acid (solvent A) and MeCN (solvent B); 50% A + 50% B, 2.50 min; 5% A + 95% B, 0.90 min; 5% A + 95% B, 0.10 min; 50% A + 50% B, 1.50 min. Operating conditions of the ESI interface in positive ion mode were: source temperature 120 °C, desolvation temperature 350 °C, cone gas flow 50 L/h, desolvation gas flow 700 L/h, capillary voltage 3000 V. Column chromatography was performed on a Merck’s silica gel 60, 70-230 mesh, 60 Å at rt. Thin layer and preparative thin layer chromatographies were carried out on Merck’s TLC aluminium sheets, 20 × 20 cm, silica gel 60 F254 and PLC plates, 20 × 20 cm, silica gel 60 F254, 2 mm, respectively. Electrospray mass spectra (ESI-MS) of positive ions were performed on a Waters Q-TOF Premier mass spectrometer. Aqueous sodium formate was used for calibration. Acetonitrile-water (0.1% formic acid) sample solutions were injected at a flow rate 5 μL/min. Needle voltage was 2.0 kV and sample cone voltage varied from 20 to 40 V. Desolvation gas flow was at 600 L/h and desolvating temperature was varied from 80 and 150 ºC.
trans-3-Amino-β-lactams 1a-c were prepared according to the literature.11,12

Preparation of thiuoreas 3a-s
General Procedure. – To a solution of a trans-3-amino-β-lactam (1a-c; 1.0 equiv) in MeCN (1.0 mL) was added dropwise a solution of an isothiocyanate (2a-n; 1.10 equiv) in MeCN (1.0 mL). The reaction mixture was stirred at rt for 24 h, followed by evaporation to dryness. Crude thioureas 3a-s were purified by preparative thin layer chromatography or by silica gel column chromatography, using a mixture of EtOAc-petroleum ether (bp 40-70 ºC) in ratio 1:1 or 1:2 as eluent.

N-(n-Hexyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3a)
Prepared from 1a (40.0 mg, 1.49 × 10–1 mmol) and 2a (23.50 mg, 25.0 μL, 1.64 × 10–1 mmol). Evaporation of the solvent and purification of the residue by means of preparative thin layer chromatography with EtOAc-petroleum ether (1:2) as the eluent, furnished thiourea 3a as a yellow oil; yield: 33.0 mg (54%); [α]D20 +68.03 (c 0.15, CH2Cl2); IR (KBr): 3249, 2924, 2853, 1730, 1652, 1498, 1468, 1446, 1409, 1342, 1246, 1228, 1184, 1026, 924, 829, 760, 706, 689, 556, 454 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.88 (t, 3H, J1 = J2 = 6.32 Hz, CH3, n-hexyl), 1.26-1.37 (m, 8H, 4xCH2, n-hexyl), 1.60 (m, 2H, CH2N, n-hexyl), 3.70 (s, 3H, OCH3, PMP), 4.96 (bs, 1H, C4, β-lactam), 5.33 (bs, 1H, C3, β-lactam), 6.65 (d, 2H, J = 8.46 Hz, PMP), 7.08 (d, 2H, J = 8.82 Hz, PMP), 7.29-7.45 (m, 7H, 5H-Ph and 2H-NHCSNH); 13C NMR (75 MHz, CDCl3): δ 14.00 (C6, n-hexyl), 22.52 (C5, n-hexyl), 26.56 (C4 and C3, n-hexyl), 28.79 (C2, n-hexyl), 31.43 (C1, n-hexyl), 55.25 (OCH3, PMP), 64.70 (C4, β-lactam), 68.84 (C3, β-lactam), 114.19 (C3 and C5, PMP), 118.92 (C2 and C6, PMP), 126.58 (C2 and C6, Ph), 128.78 (C4, Ph), 128.91 (C3 and C5, Ph), 129.94 (C1, Ph), 135.60 (C1, PMP), 156.52 (C4, PMP), 164.73 (CO), 180.76 (CS). HRMS: m/z [M+H]+ calcd for C23H29N3O2S: 412.2059; found: 412.2049.

N-(Cyclohexyl)-N'-[trans-(3R,4R)-1-(4-metoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3b)
Prepared from 1a (90.0 mg, 3.35 × 10–1 mmol) and 2b (52.10 mg, 50.6 μL, 3.69 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent, furnished thiourea 3b as a white solid; yield: 99.0 mg (72%); mp 95-98 °C; [α]D20 –60.58 (c 0.40, CH2Cl2); IR (KBr): 3678, 3651, 3630, 3292, 3062, 2931, 2853, 1732, 1612, 1516, 1453, 1396, 1300, 1248, 1177, 1145, 1067, 1030, 971, 945, 891, 863, 828, 797, 778, 751, 697 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.84-0.87 (m, 1H, cyclohexyl), 1.20-1.27 (m, 2H, cyclohexyl), 1.37-1.39 (m, 2H, cyclohexyl), 1.61-1.73 (m, 3H, cyclohexyl), 2.04 (d, 2H, J = 10.08 Hz, cyclohexyl), 3.69 (s, 3H, OCH3, PMP), 4.07 (bs, 1H, C1, cyclohexyl), 4.91 (s, 1H, C4, β-lactam), 5.30 (bs, 1H, C3, β-lactam), 6.63 (bs, 2H, PMP), 7.06 (d, 2H, J = 7.08 Hz, PMP), 7.32-7.38 (m, 6H, 5H-Ph and 1H-NH-β-lactam), 7.43 (bs, 1H, NHCS); 13C NMR (150 MHz, CDCl3): δ 24.65, 24.68 (C3 and C5, cyclohexyl), 25.39 (C4, cyclohexyl), 32.61, 32.68 (C2 and C6, cyclohexyl), 55.25 (OCH3, PMP), 55.40 (C1, cyclohexyl), 64.84 (C4, β-lactam), 68.78 (C3, β-lactam), 114.18 (C3 and C5, PMP), 118.89 (C2 and C6, PMP), 126.61 (C2 and C6, Ph), 128.77 (C4, Ph), 128.90 (C3 and C5, Ph), 129.93 (C1, Ph), 135.59 (C1, PMP), 156.51 (C4, PMP), 164.66 (CO), 181.77 (CS). Anal. Calcd for C23H27N3O2S: C, 67.45; H, 6.64; N, 10.26; S, 7.83. Found: C, 67.46; H, 6.92; N, 9.90; S, 7.62.

N-(exo-Norbornyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3c)
Prepared from 1a (70.0 mg, 2.61 × 10–1 mmol) and 2c (44.0 mg, 2.87 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3c as a white solid; yield: 103.0 mg (94%); mp 95-98 °C; [α]D20 –39.29 (c 0.28, CH2Cl2); IR (KBr): 3651, 3630, 3294, 2953, 2870, 1735, 1511, 1248, 828, 750, 697 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.86 (m, 1H, norbornyl), 1.13-1.55 (m, 6H, norbornyl), 1.72 (m, 1H, norbornyl), 1.81-1.91 (m, 1H, norbornyl), 2.32 (m, 2H, norbornyl), 3.69 (s, 3H, OCH3, PMP), 4.92 (bs, 1H, C4, β-lactam), 5.35 (bs, 1H, C3, β-lactam), 6.63 (d, 2H, J = 8.04 Hz, PMP), 7.06 (d, 2H, J = 8.67 Hz, PMP), 7.33-7.42 (m, 7H, 5H-Ph and 2H-NHCSNH); 13C NMR (75 MHz, CDCl3): δ 26.27 (C3, norbornyl), 28.14 (C4, norbornyl), 40.28 (C6 and C7, norbornyl), 42.18 (C2 and C5, norbornyl), 55.25 (OCH3, PMP), 64.75 (C1, norbornyl), 64.82 (C4, β-lactam), 68.90 (C3, β-lactam), 114.16 (C3 and C5, PMP), 118.88 (C2 and C6, PMP), 126.62 (C2 and C6, Ph), 128.74 (C4, Ph), 128.88 (C3 and C5, Ph), 129.95 (C1, Ph), 135.62 (C1, PMP), 156.46 (C4, PMP), 164.59 (CO), 182.04 (CS). Anal. Calcd for C24H27N3O2S: C, 68.38; H, 6.46; N, 9.97; S, 7.61. Found: C, 68.74; H, 6.66; N, 9.57; S, 7.48.

N-Phenyl-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3d)
Prepared from 1a (50.0 mg, 1.86 × 10–1 mmol) and 2d (27.70 mg, 24.2 μL, 2.05 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3d as a white solid; yield: 72.0 mg, (96%); mp 91-95 °C; [α]D20 –47.36 (c 0.78, CH2Cl2); IR (KBr): 3651, 3630, 3234, 1735, 1513, 1248, 1029, 828, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H, OCH3, PMP), 4.96 (d, 1H, J = 1.65 Hz, C4, β-lactam), 5.27 (dd, 1H, J1 = 1.44 Hz, J2 = 5.01 Hz, C3, β-lactam), 6.65 (d, 2H, J = 8.94 Hz, PMP), 6.68 (m, 1H, NH-β-lactam), 7.08 (d, 2H, J = 8.94 Hz, PMP), 7.33-7.45 (m, 10H, 5H-PhN and 5H-Ph-β-lactam), 8.33 (bs, 1H, PhNH); 13C NMR (75 MHz, CDCl3): δ 55.26 (OCH3, PMP), 64.58 (C4, β-lactam), 69.14 (C3, β-lactam), 114.16 (C3 and C5, PMP), 118.84 (C2 and C6, PMP), 125.26 (C2 and C6, PhN), 126.72 (C2 and C6, Ph-β-lactam), 127.42 (C4, PhN), 128.71 (C4, Ph-β-lactam), 128.82 (C3 and C5, Ph-β-lactam), 130.06 (C3 and C5, PhN), 130.12 (C1, Ph-β-lactam), 135.83 (C1, PMP), 136.16 (C1, PhN), 156.38 (C4, PMP), 163.22 (CO), 181.38 (CS). Anal. Calcd for C23H21N3O2S: C, 68.46; H, 5.25; N, 10.41; S, 7.95. Found: C, 68.64; H, 5.17; N, 10.22; S, 8.19.

N-Phenyl-N'-[trans-(3S,4S)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3e)
Prepared from 1b (30.0 mg, 1.12 × 10–1 mmol) and 2d (16.60 mg, 15.4 μL, 1.23 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3e as a white solid; yield: 44.0 mg, (98%); mp 91-95 °C; [α]D20 +48.22 (c 0.80, CH2Cl2); IR (KBr): 3651, 3630, 3234, 1735, 1513, 1248, 1029, 828, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.69 (s, 3H, OCH3, PMP), 4.98 (d, 1H, J = 1.65 Hz, C4, β-lactam), 5.27 (dd, 1H, J1 = 1.65 Hz, J2 = 5.82 Hz, C3, β-lactam), 6.66 (d, 2H, J = 8.94 Hz, PMP), 6.69 (m, 1H, NH-β-lactam), 7.10 (d, 2H, J = 8.91 Hz, PMP), 7.30-7.44 (m, 10H, 5H-PhN and 5H-Ph-β-lactam), 8.43 (bs, 1H, NH-Ph); 13C NMR (75 MHz, CDCl3): δ 55.27 (OCH3, PMP), 64.56 (C4, β-lactam), 69.13 (C3, β-lactam), 114.20 (C3 and C5, PMP), 118.88 (C2 and C6, PMP), 125.19 (C2 and C6, PhN), 126.73 (C2 and C6, Ph-β-lactam), 127.37 (C4, PhN), 128.71 (C4, Ph-β-lactam), 128.82 (C3 and C5, Ph-β-lactam), 130.03 (C3 and C5, PhN), 130.13 (C1, Ph-β-lactam), 135.84 (C1, PhN), 136.21 (C1, PMP), 156.41 (C4, PMP), 163.23 (CO), 181.32 (CS). Anal. Calcd for C23H21N3O2S: C, 68.46; H, 5.25; N, 10.41; S, 7.95. Found: C, 68.49; H, 5.18; N, 10.29; S, 8.09.

N-(2-Chlorophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3f)
Prepared from 1a (91.0 mg, 3.39 × 10–1 mmol) and 2e (63.30 mg, 49.5 μL, 3.73 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3f as a white solid; yield: 139.0 mg, (94%), mp 75-77 °C; [α]D20 –37.95 (c 0.32, CH2Cl2); IR (KBr): 3678, 3651, 3631, 3234, 2930, 1735, 1512, 1389, 1299, 1248, 1171, 1137, 1030, 827, 751, 733, 697 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.69 (s, 3H, OCH3, PMP), 4.92 (d, 1H, J = 1.68 Hz, C4, β-lactam), 5.28 (dd, 1H, J1 = 1.53 Hz, J2 = 6.29 Hz, C3, β-lactam), 6.64 (d, 2H, J = 9.00 Hz, PMP), 7.07 (d, 2H, J = 9.00 Hz, PMP), 7.29-7.40 (m, 7H, 5H-Ph-β-lactam and 2H-ClPh), 7.47 (dd, 1H, J1 = 1.43 Hz, J2= 7.96 Hz, ClPh), 7.65 (d, 1H, J = 6.30 Hz, NH-β-lactam), 7.75 (dd, 1H, J1 = 1.35 Hz, J2 = 7.94 Hz, ClPh), 8.15 (bs, 1H, NHCS); 13C NMR (75 MHz, CDCl3): δ 55.27 (OCH3, PMP), 64.93 (C4, β-lactam), 69.00 (C3, β-lactam), 114.17 (C3 and C5, PMP), 118.94 (C2 and C6, PMP), 126.73 (C2 and C6, Ph), 127.48 (C4, ClPh), 127.84 (C5, ClPh), 127.98 (C6, ClPh), 128.72 (C4, Ph), 128.79 (C3 and C5, Ph), 129.50 (C2, ClPh), 129.93 (C1, Ph), 130.35 (C3, ClPh), 134.05 (C1, ClPh), 135.67 (C1, PMP), 156.49 (C4, PMP), 163.53 (CO), 181.75 (CS). Anal. Calcd for C23H20N3O2SCl: C, 63.08; H, 4.60; N, 9.59; S, 7.32. Found: C, 63.44; H, 4.98; N, 9.34; S, 7.55.

N-(4-Chlorophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3g)
Prepared from 1a (40.0 mg, 1.49 × 10–1 mmol) and 2f (28.0 mg, 1.64 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3g as a yellow solid; yield: 61.0 mg, (94%); mp 80-84 °C; [α]D20 +27.74 (c 0.14, CH2Cl2); IR (KBr): 3630, 3568, 1742, 1498, 1468, 1438, 1250, 1094, 824, 733, 683 cm-1; 1H NMR (300 MHz, CD3OD): δ 3.68 (s, 3H, OCH3, PMP), 5.15 (d, 1H, J = 1.98 Hz, C4, β-lactam), 5.26 (d, 1H, J = 1.92 Hz, C3, β-lactam), 6.70 (m, 2H, 2H-PhCl), 6.78 (d, 2H, J = 8.97 Hz, PMP), 7.19 (d, 2H, J = 8.97 Hz, PMP), 7.28-7.50 (m, 7H, 5H-Ph, 2H-PhCl); 13C NMR (75 MHz, CD3OD): δ 55.85 (OCH3, PMP), 65.01 (C4, β-lactam), 70.24 (C3, β-lactam), 115.29 (C3 and C5, PMP), 120.25 (C2 and C6, PMP), 126.90 (C2 and C6, PhCl), 127.75 (C2 and C6, Ph), 129.61 (C4, Ph), 129.94 (C3 and C5, Ph), 130.00 (C3 and C5, PhCl), 131.82 (C1, Ph), 131.85 (C4, PhCl), 138.05 (C1, PMP), 138.58 (C1, PhCl), 158.01 (C4, PMP), 165.98 (CO), 183.21 (CS). HRMS: m/z [M+H]+ calcd for C23H20N3O2SCl: 438.1043; found: 438.1060.

N-(2-Fluorophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3h)
Prepared from 1a (90.0 mg, 3.35 × 10–1 mmol) and 2g (56.50 mg, 46.2 μL, 3.69 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3h as a yellow solid; yield: 98.0 mg, (66%); mp 99-102 °C; [α]D20 –34.98 (c 0.46, CH2Cl2); IR (KBr): 3678, 3651, 3630, 3226, 2952, 2835, 1732, 1514, 1455, 1388, 1300, 1251, 1178, 1138, 1101, 1067, 1030, 827, 754, 698 cm-1; 1H NMR (600 MHz, CDCl3): δ 3.67 (s, 3H, OCH3, PMP), 4.92 (bs, 1H, C4, β-lactam), 5.29 (bs, 1H, C3, β-lactam), 6.61 (d, 2H, J = 8.58 Hz, PMP), 7.03 (d, 2H, J = 8.64 Hz, PMP), 7.16-7.26 (m, 3H, 1H-NH-β-lactam and 2H-FPh), 7.34-7.36 (m, 5H, Ph), 7.69-7.76 (m, 2H, FPh), 8.31 (bs, 1H, NHCS); 13C NMR (150 MHz, CDCl3): δ 55.28 (OCH3, PMP), 64.82 (C4, β-lactam), 69.00 (C3, β-lactam), 114.20 (C3 and C5, PMP), 116.58 (d, J = 19.94 Hz, C3, FPh), 118.97 (C2 and C6, PMP), 124.89 (d, J = 3.79 Hz, C5, FPh,), 126.74 (C2 and C6, Ph), 127.21 (C6, FPh), 128.32 (d, J = 7.28 Hz, C4, FPh,), 128.74 (C4, Ph), 128.80 (C3 and C5, Ph), 129.94 (C1, Ph), 135.68 (C1, PMP), 135.75 (C1, FPh), 156.13 (d, J = 249.15 Hz, C2, FPh,), 156.51 (C4, PMP), 163.49 (CO), 181.89 (CS). Anal. Calcd for C23H20N3O2SF: C, 65.54; H, 4.78; N, 9.97; S, 7.61. Found: C, 65.51; H, 4.82; N, 9.95; S, 7.85.

N-(4-Fluorophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3i)
Prepared from 1a (100.0 mg, 3.73 × 10–1 mmol) and 2h (62.8 mg, 4.10 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3i as a yellow solid; yield: 140.0 mg, (89%); mp 89-93 °C; [α]D20 –12.82 (c 0.16, CH2Cl2); IR (KBr): 3220, 2953, 1734, 1511, 1455, 1249, 1217, 1152, 1067, 1029, 882, 750, 697, 538, 506 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.66 (s, 3H, OCH3, PMP), 4.94 (bs, 1H, C4, β-lactam), 5.34-5.36 (m, 1H, C3, β-lactam), 6.58 (d, 2H, J = 8.70 Hz, PMP), 7.00 (d, 2H, J = 8.79 Hz, PMP), 7.08 (t, 2H, J1 = J2 = 8.40 Hz, FPh), 7.27-7.35 (m, 7H, 5H-Ph-β-lactam and 2H-FPh), 7.43 (m, 1H, NH-β-lactam), 8.53 (bs, 1H, FPh-NH); 13C NMR (75 MHz, CDCl3): δ 55.19 (OCH3, PMP), 64.53 (C4, β-lactam), 68.99 (C3, β-lactam), 114.09 (C3 and C5, PMP), 116.73 (d, J = 22.94 Hz, C3 and C5, FPh), 118.81 (C2 and C6, PMP), 126.59 (C2 and C6, Ph-β-lactam), 127.83 (d, J = 8.30 Hz, C2 and C6, FPh), 128.78 (C4, Ph-β-lactam), 128.91 (C3 and C5, Ph-β-lactam), 129.92 (C1, Ph-β-lactam), 132.22 (d, J = 3.10 Hz, C1, FPh), 135.69 (C1, PMP), 156.41 (C4, PMP), 161.41 (d, J = 247.91 Hz, C4, FPh), 163.66 (CO), 181.80 (CS). HRMS: m/z [M+H]+ calcd for C23H20N3O2SF: 422.1339; found: 422.1325.

N-(4-Trifluoromethylphenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3j)
Prepared from 1a (50.0 mg, 1.86 × 10–1 mmol) and 2i (41.5 mg, 2.05 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3j as a yellow solid; yield: 85.6 mg, (97%); mp 105-107 °C; [α]D20 +43.71 (c 0.11, CH2Cl2); IR (KBr): 3461, 2925, 1744, 1513, 1468, 1326, 1249, 1109, 1067, 827, 686 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.69 (s, 3H, OCH3, PMP), 5.10 (bs, 1H, C4, β-lactam), 5.26-5.27 (m, 1H, C3, β-lactam), 6.66 (d, 2H, J = 8.94 Hz, PMP), 7.08 (d, 2H, J = 8.91 Hz, PMP), 7.37 (s, 5H, Ph-β-lactam), 7.57 (s, 4H, CF3Ph), 7.78 (bs, 1H, NH-β-lactam), 8.69 (bs, 1H, CF3Ph-NH); 13C NMR (75 MHz, CDCl3): δ 55.28 (OCH3, PMP), 64.31 (C4, β-lactam), 68.70 (C3, β-lactam), 114.29 (C3 and C5, PMP), 119.09 (C2 and C6, PMP), 123.53 (d, J = 273.45 Hz, CF3), 123.86 (C2 and C6, CF3Ph), 126.49 (d, J = 3.79 Hz, C3 and C5, CF3Ph), 126.61 (C2 and C6, Ph-β-lactam), 127.88 (d, J = 33.31 Hz, C4, CF3Ph), 128.97 (C4, Ph-β-lactam), 129.01 (C3 and C5, Ph-β-lactam), 129.76 (C1, Ph-β-lactam), 135.45 (C4, PMP), 140.55 (d, J = 1.41 Hz, CF3Ph), 156.74 (C1, PMP), 164.17 (CO), 181.36 (CS). Anal. Calcd for C24H20N3O2SF3: C, 61.14; H, 4.28; N, 8.91; S, 6.80. Found: C, 61.33; H, 4.63; N, 8.78; S, 6.57.

N-(4-Trifluoromethoxyphenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3k)
Prepared from 1a (67.0 mg, 2.50 × 10–1 mmol) and 2j (45.0 mg, 2.75 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3k as a yellow solid; yield: 102.2 mg, (84%); mp 92-94 °C; [α]D20 +22.43 (c 0.22, CH2Cl2); IR (KBr): 3220, 2926, 1744, 1513, 1469, 1256, 1204, 1150, 827, 761, 685 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H, OCH3, PMP), 4.95 (d, 1H, J = 1.68 Hz, C4, β-lactam), 5.44 (m, 1H, C3, β-lactam), 6.56 (d, 2H, J = 8.94 Hz, PMP), 6.66-6.78 (m, 2H, CF3OPh), 6.97 (d, 2H, J = 8.94 Hz, PMP), 7.24 (d, 2H, J = 8.49 Hz, CF3OPh), 7.36 (s, 5H, Ph-β-lactam), 7.83 (m, 1H, NH-β-lactam), 8.99 (bs, 1H, CF3OPh-NH); 13C NMR (75 MHz, CDCl3): δ 55.11 (OCH3, PMP), 64.46 (C4, β-lactam), 68.77 (C3, β-lactam), 114.01 (C3 and C5, PMP), 118.80 (C2 and C6, PMP), 120.39 (CF3O), 122.14 (C2 and C6, CF3OPh), 126.46 (C2 and C6, Ph-β-lactam), 127.03 (C3 and C5, CF3OPh), 128.81 (C4, Ph-β-lactam), 128.92 (C3 and C5, Ph-β-lactam), 132.52 (C1, Ph-β-lactam), 135.08 (C1, CF3OPh), 135.53 (C4, PMP), 147.55 (d, J = 8.31 Hz, CF3OPh), 156.41 (C1, PMP), 164.00 (CO), 181.56 (CS). Anal. Calcd for C24H20N3O3SF3: C, 59.13; H, 4.14; N, 8.62; S, 6.58. Found: C, 59.22; H, 4.54; N, 8.37; S, 6.31.

N-(4-Methoxyphenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3l)
Prepared from 1a (40.0 mg, 1.49 × 10–1 mmol) and 2k (27.10 mg, 23.0 μL, 1.64 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3l as a yellow solid; yield: 63.6 mg, (99%); mp 96-100 °C; [α]D20 +47.69 (c 0.13, CH2Cl2); IR (KBr): 3650, 3630, 1735, 1654, 1560, 1509, 1246, 1028, 827 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H, OCH3, PMP-2), 3.77 (s, 3H, OCH3, PMP-1), 4.91 (d, 1H, J = 1.80 Hz, C4, β-lactam), 5.25 (dd, 1H, J1 = 1.74 Hz, J2 = 6.69 Hz, C3, β-lactam), 6.62 (d, 2H, J = 9.06 Hz, PMP-2), 6.95 (d, 2H, J = 8.88 Hz, PMP-1), 7.05 (d, 2H, J = 9.03 Hz, PMP-1), 7.22 (d, 2H, J = 8.82 Hz, PMP-2), 7.33-7.38 (m, 6H, 5H-Ph-β-lactam and 1H-NH-β-lactam), 8.09 (bs, 1H, PMP-2-NH); 13C NMR (75 MHz, CDCl3): δ 55.23 (OCH3, PMP-2), 55.53 (OCH3, PMP-1), 64.71 (C4, β-lactam), 69.30 (C3, β-lactam), 114.11 (C3 and C5, PMP-1), 115.32 (C3 and C5, PMP-2), 118.77 (C2 and C6, PMP-1), 126.69 (C2 and C6, PMP-2), 127.80 (C2 and C6, Ph-β-lactam), 128.28 (C1, PMP-2), 128.67 (C4, Ph-β-lactam), 128.80 (C3 and C5, Ph-β-lactam), 130.17 (C1, Ph-β-lactam), 135.99 (C1, PMP-1), 156.32 (C4, PMP-1), 159.11 (C4, PMP-2), 163.14 (CO), 181.96 (CS). Anal. Calcd for C24H23N3O3S: C, 66.49; H, 5.35; N, 9.69; S, 7.40. Found: C, 66.79; H, 5.76; N, 9.39; S, 7.13.

N-(4-Azidophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3m)
Prepared from 1a (51.0 mg, 1.91 × 10–1 mmol) and 2l (37.0 mg, 2.10 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3m as a yellow solid; yield: 71.0 mg, (85%); mp 190-193 °C; [α]D20 +58.08 (c 0.21, CH2Cl2); IR (KBr): 3630, 3386, 2123, 2088, 1742, 1654, 1638, 1511, 1468, 1439, 1420, 1289, 1248, 1182, 987, 827, 760, 740, 711, 683, 513 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H, OCH3, PMP), 4.97 (d, 1H, J = 1.86 Hz, C4, β-lactam), 5.29-5.32 (m, 1H, C3, β-lactam), 6.62 (d, 2H, J = 9.00 Hz, PMP), 7.02-7.06 (m, 4H, 2H-PMP and 2H-N3Ph), 7.32 (d, 2H, J = 8.73 Hz, N3Ph), 7.36 (m, 5H, Ph), 7.43 (m, 1H, NH-β-lactam), 8.51 (bs, 1H, NHCS); 13C NMR (75 MHz, CDCl3): δ 55.24 (OCH3, PMP), 64.51 (C4, β-lactam), 68.99 (C3, β-lactam), 114.15 (C3 and C5, PMP), 118.87 (C2 and C6, PMP), 120.23 (C2 and C6, N3Ph), 126.61 (C2 and C6, Ph), 126.99 (C3 and C5, N3Ph), 128.82 (C4, Ph), 129.91 (C3 and C5, Ph), 129.94 (C1, Ph), 133.08 (C1, N3Ph), 135.66 (C1, PMP), 138.98 (C4, N3Ph), 156.46 (C4, PMP), 163.63 (CO), 181.56 (CS). HRMS: m/z [M+Na]+ calcd for C23H20N6O2S: 467.1266; found: 467.1263.

N-(4-Nitrophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3n)
Prepared from 1a (80.0 mg, 2.98 × 10–1 mmol) and 2m (59.4 mg, 23.28 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3n as a yellow solid; yield: 107.0 mg, (81%); mp 120-122 °C; [α]D20 +30.95 (c 0.58, CH2Cl2); IR (KBr): 3677, 3651, 3630, 3327, 3064, 2933, 2834, 1730, 1598, 1513, 1454, 1440, 1401, 1330, 1111, 1030, 848, 828, 750, 698 cm-1; 1H NMR (600 MHz, CDCl3): δ 3.70 (s, 3H, OCH3, PMP), 5.21 (bs, 2H, 1H-C4-β-lactam and 1H-C3-β-lactam), 6.68 (d, 2H, J = 8.82 Hz, PMP), 7.10 (d, 2H, J = 8.82 Hz, PMP), 7.38 (bs, 5H, Ph), 7.74 (d, 2H, J = 8.88 Hz, NO2Ph), 8.11 (m, 3H, 2H-NO2Ph and 1H-NH-β-lactam), 9.05 (bs, 1H, NHCS); 13C NMR (150 MHz, CDCl3): δ 55.33 (OCH3, PMP), 64.15 (C4, β-lactam), 68.38 (C3, β-lactam), 114.41 (C3 and C5, PMP), 119.28 (C2 and C6, PMP), 122.09 (C2 and C6, NO2Ph), 124.61 (C3 and C5, NO2Ph), 126.59 (C2 and C6, Ph), 127.69 (C4, Ph), 129.10 (C3 and C5, Ph), 129.51 (C1, Ph), 135.15 (C1, PMP), 144.00 (C1, NO2Ph), 144.15 (C4, NO2Ph), 157.01 (C4, PMP), 164.51 (CO), 180.99 (CS). Anal. Calcd for C23H20N4O4S: C, 61.59; H, 4.49; N, 12.49; S, 7.15. Found: C, 61.50; H, 4.58; N, 12.44; S, 7.40.

N-(4-Cyanophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]thiourea (3o)
Prepared from 1a (85.0 mg, 3.17 × 10–1 mmol) and 2n (56.1 mg, 3.49 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3o as a yellow solid; yield: 131.0 mg, (97%); mp 123-126 °C; [α]D20 +14.05 (c 0.50, CH2Cl2); IR (KBr): 3319, 2949, 2225, 1725, 1605, 1510, 1404, 1302, 1251, 1147, 1033, 945, 824, 742, 698 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.70 (s, 3H, OCH3, PMP), 5.16 (d, 1H, J = 1.80 Hz, C4, β-lactam), 5.23 (bs, 1H, C3, β-lactam), 6.67 (d, 2H, J = 9.03 Hz, PMP), 7.10 (d, 2H, J = 9.00 Hz, PMP), 7.38 (bs, 5H, Ph), 7.55 (d, 2H, J = 8.82 Hz, CNPh), 7.65 (d, 2H, J = 8.76 Hz, CNPh), 8.00 (bs, 1H, NH-β-lactam), 8.89 (bs, 1H, NHCS); 13C NMR (75 MHz, CDCl3): δ 55.31 (OCH3, PMP), 64.18 (C4, β-lactam), 68.41 (C3, β-lactam), 108.19 (CN), 114.34 (C3 and C5, PMP), 118.58 (C4, CNPh), 119.18 (C2 and C6, PMP), 122.91 (C2 and C6, CNPh), 126.57 (C2 and C6, Ph), 129.05 (C3 and C5, Ph), 129.55 (C1, Ph), 129.61 (C4, Ph), 132.99 (C3 and C5, CNPh), 135.19 (C1, PMP), 142.12 (C1, CNPh), 156.89 (C4, PMP), 164.52 (CO), 181.01 (CS). HRMS: m/z [M+Na]+ calcd for C24H20N4O2S: 451.1205; found 451.1209.

N-(Cyclohexyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-ferrocenylazetidin-3-yl]thiourea (3p)
Prepared from 1c (36.6 mg, 9.72 × 10–2 mmol) and 2b (15.10 mg, 14.6 μL, 1.07 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3p as a brown solid; yield: 36.0 mg, (72%); mp 86-87 °C; [α]D20 +287.08 (c 0.02, CH2Cl2); IR (KBr): 3294, 2925, 2850, 1726, 1512, 1464, 1450, 1298, 1247, 1178, 1029, 1001, 828 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.83-0.92 (m, 1H, cyclohexyl), 1.11-1.44 (m, 5H, cyclohexyl), 1.59-1.63 (m, 1H, cyclohexyl), 1.68-1.78 (m, 2H, cyclohexyl), 2.04-2.17 (m, 2H, cyclohexyl), 3.75 (s, 3H, OCH3, PMP), 4.10-4.20 (m, 4H, Fc), 4.22 (s, 5H, Fc), 4.50 (d, J = 0.84 Hz, 1H, C4, β-lactam), 5.30 (bs, 1H, C3, β-lactam), 6.19 (bs, 1H, NH-cyclohexyl), 6.65 (d, 2H, J = 6.93 Hz, PMP), 7.07 (d, 2H, J = 8.01 Hz, PMP), 7.45 (bs, 1H, NHCS); 13C NMR (75 MHz, CDCl3): δ 24.78, 24.82 (C3 and C5, cyclohexyl), 25.41 (C4, cyclohexyl), 32.52, 32.79 (C2 and C6, cyclohexyl), 55.26 (OCH3, PMP), 55.40 (C1, cyclohexyl), 60.99 (C4, β-lactam), 66.09 (C3, β-lactam), 66.67, 68.23, 68.89, 68.98, 70.22, 82.75 (Fc), 114.03 (C3 and C5, PMP), 119.88 (C2 and C6, PMP), 129.45 (C1, PMP), 156.60 (C4, PMP), 166.54 (CO), 175.35 (CS). Anal. Calcd for C27H31N3O2SFe: C, 62.67; H, 6.04; N, 8.12; S, 6.20. Found: C, 63.00; H, 6.45; N, 7.73; S, 6.39.

N-Phenyl-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-ferrocenylazetidin-3-yl]thiourea (3q)
Prepared from 1c (55.0 mg, 1.46 × 10–1 mmol) and 2d (21.80 mg, 20.0 μL, 1.61 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3q as a brown solid; yield: 71.0 mg, (96%); mp 123-126 °C; [α]D20 –116.05 (c 0.10, CH2Cl2); IR (KBr): 3651, 3630, 3227, 2953, 1734, 1514, 1248, 1034, 693 cm-1; 1H NMR (600 MHz, CDCl3): δ 3.74 (s, 3H, OCH3, PMP), 4.15-4.22 (m, 9H, Fc), 4.56 (bs, 1H, C4, β-lactam), 4.83 (bs, 1H, C3, β-lactam), 6.01 (bs, 1H, NH-β-lactam), 6.70 (d, 2H, J = 8.46Hz, PMP), 7.13 (d, 2H, J = 8.46 Hz, PMP), 7.26-7.42 (m, 5H, Ph), 8.38 (bs, 1H, NH-Ph); 13C NMR (150 MHz, CDCl3): δ 55.33 (OCH3, PMP), 60.39 (C4, β-lactam), 66.73 (C3, β-lactam), 68.24, 68.71, 68.84, 68.98, 70.07, 83.42 (Fc), 114.14 (C3 and C5, PMP), 120.03 (C2 and C6, PMP), 125.68 (C2 and C6, Ph), 127.26 (C4, Ph), 129.76 (C1, Ph), 129.82 (C3 and C5, Ph), 136.59 (C1, PMP), 156.59 (C4, PMP), 164.79 (CO), 181.69 (CS). Anal. Calcd for C27H25N3O2SFe: C, 63.41; H, 4.93; N, 8.22; S, 6.27. Found: C, 63.86; H 4.77; N, 7.98; S, 5.97.

N-(2-Chlorophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-ferrocenylazetidin-3-yl]thiourea (3r)
Prepared from 1c (22.0 mg, 5.80 × 10–2 mmol) and 2e (10.90 mg, 8.50 μL, 6.40 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished thiourea 3r as a brown solid; yield: 28.0 mg, (88%); 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 3H, OCH3, PMP), 4.10-4.21 (m, 9H, Fc), 4.55 (d, 1H, J = 1.02 Hz, C4, β-lactam), 4.74 (d, 1H, J = 1.80 Hz, C3, β-lactam), 6.07 (d, 1H, J = 7.29 Hz, NH-β-lactam), 6.68 (d, 2H, J = 8.97 Hz, PMP), 7.07 (d, 2H, J = 8.97 Hz, PMP), 7.20-7.26 (m, 1H, ClPh), 7.35-7.40 (m, 1H, ClPh), 7.45-7.48 (m, 1H, ClPh), 7.70-7.76 (m, 1H, ClPh), 8.36 (bs, 1H, NHCS); 13C NMR (75 MHz, CDCl3): δ 55.31 (OCH3, PMP), 60.73 (C4, β-lactam), 66.41 (C3, β-lactam), 66.66, 68.17, 68.86, 70.04, 83.32 (Fc), 114.05 (C3 and C5, PMP), 120.07 (C2 and C6, PMP), 127.82 (C4, ClPh), 128.35 (C5, ClPh), 128.93 (C6, ClPh), 129.42 (C2, ClPh), 130.18 (C3, ClPh), 130.57 (C1, ClPh), 134.12 (C1, PMP), 156.65 (C4, PMP), 165.02 (CO), 182.02 (CS); HRMS: m/z [M+Na]+ calcd for C27H24N3O2SClFe: 568.0525; found 568.0504.

N-(4-Nitrophenyl)-N'-[trans-(3R,4R)-1-(4-methoxyphenyl)-2-oxo-4-ferrocenyl-azetidin-3-yl]thiourea (3s)
Prepared from 1c (21.0 mg, 5.58 × 10–2 mmol) and 2m (11.5 mg, 6.14 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished thiourea 3s as a brown solid; yield: 25.0 mg, (81%); 1H NMR (300 MHz, CDCl3): δ 3.73 (s, 3H, OCH3, PMP). 4.17-4.23 (m, 9H, Fc), 4. 41 (bs, 1H, C4, β-lactam), 5.08 (bs, 1H, C3, β-lactam), 6.01 (bs, 1H, NH-β-lactam), 6.69 (d, 2H, J = 8.82 Hz, PMP), 7.13 (d, 2H, J = 8.79 Hz, PMP), 7.74 (d, 2H, J = 9.00 Hz, NO2Ph), 8.11 (d, 2H, J = 8.55 Hz, NO2Ph), 9.14 (bs, 1H, NHCS); 13C NMR (75 MHz, CDCl3): δ 55.34 (OCH3, PMP), 60.49 (C4, β-lactam), 65.60 (C3, β-lactam), 66.48, 68.61, 68.92, 69.54, 70.13, 81.77 (Fc), 114.27 (C3 and C5, PMP), 120.13 (C2 and C6, PMP), 122.53 (C2 and C6, NO2Ph), 124.37 (C3 and C5, NO2Ph), 135.58 (C1, PMP), 144.93 (C1, NO2Ph), 144.24 (C4, NO2Ph), 157.13 (C4, PMP), 163.55 (CO), 181.03 (CS). LRMS: m/z [M+H]+ calcd for C27H24N4O4SFe: 557.09; found 557.09.

Preparation of iminothiazolidinones 4a-n
General Procedure. – To a stirred suspension of anhydrous sodium carbonate (2.0 equiv) in MeCN (1.0
mL), a solution of a thiourea (3a-f; 3h and 3m-s; 1.0 equiv) in MeCN (3.0 mL) was added dropwise. Thereafter, a solution of ethyl bromoacetate (1.1 equiv) in MeCN (1.0 mL) was added and the mixture was stirred at 40-60 °C for 6h. The reaction mixture was then cooled, filtered and evaporated to dryness. Crude iminothiazolidinone (4a-n) was purified by silica gel column chromatography using a mixture of EtOAc-pethroleum ether (bp 40-70 °C) in the ratio 1:1 or 1:2.

2-(n-Hexyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4a) / 2-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-imino-3-(n-hexyl)thiazolidin-4-one (4a’)
Prepared from 3a (33.0 mg, 8.00 × 10–2 mmol), ethyl bromoacetate (14.70 mg, 10.0 μL, 8.80 × 10–2 mmol) and Na2CO3 (17.0 mg, 1.60 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished a mixture of isomers 4a/4a’; yield: 24.0 mg, (67%); IR (KBr): 3440, 3032, 2930, 2858, 1748, 1732, 1652, 1634, 1515, 1456, 1386, 1299, 1247, 1181, 1141, 1068, 1033, 830, 794, 750, 700, 524, 485 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.81 (t, 3H, J1 = 6.47 Hz, J2 = 7.22 Hz, CH3, n-hexyl, 4a), 0.88 (t, 3H, J1 = J2 = 6.47 Hz, CH3, n-hexyl, 4a’), 1.07-1.06 (m, 2H, n-hexyl, 4a and 4a’), 1.26-1.40 (m, 2 x 6H, n-hexyl, 4a and 4a’), 1.61-1.65 (m, 2H, n-hexyl, 4a and 4a’), 3.17 (t, 2H, J1 = J2 = 6.41 Hz , C1, n-hexyl, 4a), 3.74 (s, 2 x 3H, OCH3, PMP, 4a and 4a’), 3.78 (m, 2H, C1, n-hexyl, 4a’), 3.80 (d, 2H, J = 5.34 Hz, CH2, thiazolidinone, 4a’), 3.87 (s, 2H, CH2, thiazolidinone, 4a), 4.54 (d, 1H, J = 1.61 Hz, C3, β-lactam, 4a’), 4.97 (d, 1H, J = 1.61 Hz, C4, β-lactam, 4a’), 5.37 (m, 2H, C3 and C4, β-lactam, 4a), 6.77-6.81 (m, 2 x 2H, PMP, 4a and 4a’), 7.21 (d, 2H, J = 9.12 Hz, PMP, 4a), 7.26 (d, 2H, J = 8.91 Hz, PMP, 4a’), 7.36-7.38 (m, 2 x 5H, Ph, 4a and 4a’); 13C NMR (75 MHz, CDCl3): δ 13.99 (C6, n-hexyl, 4a’), 14.04 (C6, n-hexyl, 4a), 22.48 (C5, n-hexyl, 4a), 22.51 (C5, n-hexyl, 4a’), 26.44 (C4, n-hexyl, 4a’), 26.91 (C3, n-hexyl, 4a), 27.00 (C3, n-hexyl, 4a’), 30.37 (C4, n-hexyl, 4a), 31.31 (C2, n-hexyl, 4a), 31.50 (C2, n-hexyl, 4a’), 32.70 (CH2, thiazolidinone, 4a), 32.94 (CH2, thiazolidinone, 4a’), 43.14 (C1, n-hexyl, 4a’), 51.75 (C1, n-hexyl, 4a), 55.36 (OCH3, PMP, 4a), 55.39 (OCH3, PMP, 4a’), 59.32 (C4, β-lactam, 4a), 64.21 (C4, β-lactam, 4a’), 65.80 (C3, β-lactam, 4a), 76.34 (C3, β-lactam, 4a’), 114.20 (C3 and C5, PMP, 4a), 114.30 (C3 and C5, PMP, 4a’), 118.66 (C2 and C6, PMP, 4a and 4a’), 126.20 (C2 and C6, Ph, 4a’), 126.31 (C2 and C6, Ph, 4a), 128.69 (C4, Ph, 4a’), 128.81 (C4, Ph, 4a), 129.12 (C3 and C5, Ph, 4a’), 129.19 (C3 and C5, Ph, 4a), 130.87 (C1, Ph, 4a’), 131.12 (C1, Ph, 4a), 136.43 (C1, PMP, 4a), 136.70 (C1, PMP, 4a’), 148.62 (C=N, thiazolidinone, 4a), 156.22 (C4, PMP, 4a and 4a’), 157.30 (C=N, thiazolidinone, 4a’), 161.84 (CO, β-lactam, 4a), 163.31 (CO, β-lactam, 4a’), 170.09 (CO, thiazolidinone, 4a), 171.39 (CO, thiazolidinone, 4a’). 1H-NMR and RP-HPLC analysis of isomeric mixture showed the ratio of 4a’/4a to be 77:23 (4a’, 18.18 min and 4a, 18.37 min). LC-MS: m/z [M+H]+ calcd for C25H29N3O3S: 452.20; found 452.20 (4a’, 2.35 min) and 452.20 (4a, 2.50 min); HRMS: m/z [M+H]+ calcd. for C25H29N3O3S (4a/4a’): 452.2008; found 452.1991.

2-(Cyclohexyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4b)
Prepared from 3b (20.0 mg, 4.90 × 10–2 mmol), ethyl bromoacetate (9.02 mg, 6.00 μL, 5.40 × 10–2 mmol) and Na2CO3 (10.5 mg, 9.80 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using ethyl acetate-petroleum ether (1:2) as the eluent furnished 4b as a white solid; yield: 17.0 mg, (77%); mp 61-64 °C; [α]D20 +13.37 (c 0.22, CH2Cl2); IR (KBr): 3630, 3504, 3032, 2928, 2852, 1764, 1724, 1654, 1513, 1452, 1350, 1298, 1245, 1141, 1112, 1069, 1029, 990, 892, 828, 740, 698, 512 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.80-1.09 (m, 2H, cyclohexyl), 1.12-1.44 (m, 6H, cyclohexyl), 1.48-1.69 (m, 2H, cyclohexyl), 3.15 (bs, 1H, cyclohexyl), 3.75 (s, 3H, OCH3, PMP), 3.88 (s, 2H, CH2, thiazolidinone), 5.35 (d, 1H, J = 2.52 Hz, C4, β-lactam), 5.37 (d, 1H, J = 2.55 Hz, C3, β-lactam), 6.79 (d, 2H, J = 9.00 Hz, PMP), 7.22 (d, 2H, J = 8.97 Hz, PMP), 7.36 (bs, 5H, Ph); 13C NMR (75 MHz, CDCl3): δ 23.22, 23.40 (C3 and C5, cyclohexyl), 25.56 (C4, cyclohexyl), 32.64 (C2, cyclohexyl), 32.82 (CH2, thiazolidinone), 33.04 (C6, cyclohexyl), 55.40 (OCH3, PMP), 59.25 (C4, β-lactam), 60.30 (C1, cyclohexyl), 65.88 (C3, β-lactam), 114.20 (C3 and C5, PMP), 118.63 (C2 and C6, PMP), 126.32 (C2 and C6, Ph), 128.79 (C4, Ph), 129.17 (C3 and C5, Ph), 131.22 (C1, Ph), 136.46 (C1, PMP), 146.26 (C=N, thiazolidinone), 156.12 (C4, PMP), 161.89 (CO, β-lactam), 170.10 (CO, thiazolidinone). Anal. Calcd for C25H27N3O3S: C, 66.79; H, 6.05; N, 9.35; S, 7.13. Found: C, 66.49; H, 5.96; N, 9.39; S, 7.40.

2-(exo-Norbornyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4c)
Prepared from 3c (38.0 mg, 9.00 × 10–2 mmol), ethyl bromoacetate (16.50 mg, 11.0 μL, 9.90 × 10–2 mmol) and Na2CO3 (19.0 mg, 1.80 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4c as a white solid; yield: 41.0 mg, (99%); mp 72-75 °C; [α]D20 +20.90 (c 0.34, dichloromethane); IR (KBr): 3630, 2953, 2867, 1763, 1725, 1648, 1513, 1394, 1361, 1246, 1144, 1030, 966, 794, 698, 513 cm-1; 1H NMR (300 MHz, CDCl3): δ 0.74-1.61 (m, 8H, norbornyl), 1.94 (dd, 1H, J1 = 3.18 Hz, J2 = 12.31 Hz, norbornyl), 2.04 (d, 1H, J = 3.06 Hz, norbornyl), 3.09 (d, 1H, J = 5.99 Hz, norbornyl), 3.74 (s, 3H, OCH3, PMP), 3.87 (s, 2H, CH2, thiazolidinone), 5.29-5.35 (m, 2H, 1H-C4-β-lactam and 1H-C3-β-lactam), 6.78 (d, 2H, J = 8.97 Hz, PMP), 7.22 (d, 2H, J = 8.97 Hz, PMP), 7.36 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): δ 26.14 (C3, norbornyl), 28.82 (C4, norbornyl), 32.89 (CH2, thiazolidinone), 34.96, 35.04 (C6 and C7, norbornyl), 35.73 (C5, norbornyl), 43.78 (C2, norbornyl), 55.42 (OCH3, PMP), 59.21 (C4, β-lactam), 64.58 (C1, norbornyl), 65.85 (C3, β-lactam), 114.21 (C3 and C5, PMP), 118.51 (C2 and C6, PMP), 126.28 (C2 and C6, Ph), 128.80 (C4, Ph), 129.20 (C3 and C5, Ph), 131.28 (C1, Ph), 136.48 (C1, PMP), 146.51 (C=N, thiazolidinone), 156.12 (C4, PMP), 161.98, (CO, β-lactam), 169.95 (CO, thiazolidinone). Anal. Calcd for C26H27N3O3S: C, 67.66; H, 5.90; N, 9.10; S, 6.95. Found: C, 68.00; H, 6.22; N, 8.98; S, 6.65.

2-Phenylimino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4d)
Prepared from 3d (34.0 mg, 8.40 × 10–2 mmol), ethyl bromoacetate (15.50 mg, 10.5 μL, 9.30 × 10–2 mmol) and Na2CO3 (18.0 mg, 1.68 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 4d as a white solid; yield: 27.0 mg, (73%); mp 65-68 °C; [α]D20 +51.57 (c 0.50, CH2Cl2); IR (KBr): 3630, 3569, 1655, 1509, 1247, 828, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 3H, OCH3, PMP), 3.90 (s, 2H, CH2, thiazolidinone), 5.46 (d, 1H, J = 2.40 Hz, C4, β-lactam), 5.55 (d, 1H, J = 2.28 Hz, C3, β-lactam), 6.76 (d, 2H, J = 8.88 Hz, PMP), 6.91 (d, 2H, J = 7.32 Hz, PMP), 7.11 (m, 1H, PhN), 7.23-7.41 (m, 9H, 4H-PhN and 5H-Ph-β-lactam). 13C NMR (150 MHz, CDCl3): δ 32.57 (CH2, thiazolidinone), 55.39 (OCH3, PMP), 59.74 (C4, β-lactam), 66.02 (C3, β-lactam), 114.32 (C3 and C5, PMP), 119.03 (C2 and C6, PMP), 121.05 (C2 and C6, Ph-β-lactam), 124.94 (C2 and C6, PhN), 126.41 (C4, PhN), 129.01 (C4, Ph-β-lactam), 129.17 (C3 and C5, Ph-β-lactam), 129.29 (C3 and C5, PhN), 130.81 (C1, Ph-β-lactam), 136.19 (C1, PMP), 146.80 (C1, PhN), 151.63 (C=N, thiazolidinone), 156.38 (C4, PMP), 161.43 (CO, β-lactam), 170.39 (CO, thiazolidinone). Anal. Calcd for C25H21N3O3S: C, 67.70; H, 4.77; N, 9.47; S, 7.23. Found: C, 67.98; H, 4.85; N, 9.29; S, 7.28.

2-Phenylimino-3-[trans-(3’S,4’S)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4e)
Prepared from 3e (26.5 mg, 6.60 × 10–2 mmol), ethyl bromoacetate (12.0 mg, 8.00 μL, 7.20 × 10–2 mmol) and Na2CO3 (14.0 mg, 1.31 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4e as a brown solid; yield: 18.0 mg, (62%). mp 65-68 °C; [α]D20 –51.70 (c 0.50, CH2Cl2); IR (KBr): 3630, 3569, 1655, 1509, 1247, 828, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 3H, OCH3, PMP), 3.89 (s, 2H, CH2, thiazolidinone), 5.46 (d, 1H, J = 2.64 Hz, C4, β-lactam), 5.55 (d, 1H, J = 2.61 Hz, C3, β-lactam), 6.77 (d, 2H, J = 9.06 Hz, PMP), 6.91 (d, 2H, J = 8.37 Hz, PMP), 7.10 (m, 1H, PhN), 7.22-7.44 (m, 9H, 4H-PhN and 5H-Ph-β-lactam); 13C NMR (75 MHz, CDCl3): δ 32.57 (CH2, thiazolidinone), 55.38 (OCH3, PMP), 59.73 (C4, β-lactam), 65.99 (C3, β-lactam), 114.30 (C3 and C5, PMP), 119.02 (C2 and C6, PMP), 121.04 (C2 and C6, Ph-β-lactam), 124.93 (C2 and C6, PhN), 126.40 (C4, PhN), 129.00 (C4, Ph-β-lactam), 129.17 (C3 and C5, Ph-β-lactam), 129.28 (C3 and C5, PhN), 130.78 (C1, Ph-β-lactam), 136.16 (C1, PMP), 146.79 (C1, PhN), 151.64 (C=N, thiazolidinone), 156.36 (C4, PMP), 161.44 (CO, β-lactam), 170.40 (CO, thiazolidinone). Anal. Calcd for C25H21N3O3S: C, 67.70; H, 4.77; N, 9.47; S, 7.23. Found: C, 67.92; H, 4.85; N, 9.51; S, 7.19.

2-(2-Chlorophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4f)
Prepared from 3f (60.0 mg, 1.37 × 10–1 mmol), ethyl bromoacetate (25.20 mg, 17.0 μL, 1.51 × 10–1 mmol) and Na2CO3 (29.0 mg, 2.74 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4f as a yellow solid; yield: 60.0 mg, (92%), mp 80-83 °C; [α]D20 +109.14 (c 0.50, CH2Cl2); IR (KBr): 3449, 2930, 1763, 1637, 1584, 1513, 1473, 1455, 1364, 1247, 1181, 1144, 1030, 828, 794, 755, 742, 697, 515 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.71 (s, 3H, OCH3, PMP), 3.93 (d, 2H, J = 0.86 Hz, CH2, thiazolidinone), 5.54 (d, 1H, J = 2.65 Hz, C4, β-lactam), 5.70 (d, 1H, J = 2.65 Hz, C3, β-lactam), 6.75 (d, 2H, J = 8.90 Hz, PMP), 6.97-7.08 (m, 2H, ClPh), 7.17-7.20 (m, 1H, ClPh), 7.22 (d, 2H, J = 9.08 Hz, PMP), 7.33-7.42 (m, 6H, 5H-Ph and 1H-ClPh); 13C NMR (75 MHz, CDCl3): δ 32.82 (CH2, thiazolidinone), 55.34 (OCH3, PMP), 59.48 (C4, β-lactam), 65.81 (C3, β-lactam), 114.23 (C3 and C5, PMP), 119.16 (C2 and C6, PMP), 121.37 (C4, ClPh), 125.84 (C5, ClPh), 126.44 (C2 and C6, Ph), 127.43 (C6, ClPh), 128.98 (C4, Ph), 129.24 (C3 and C5, Ph), 129.99 (C3, ClPh), 130.60 (C1, Ph), 135.27 (C1, ClPh), 136.04 (C1, PMP), 144.11 (C1, ClPh), 153.75 (C=N, thiazolidinone), 156.33 (C4, PMP), 161.11 (CO, β-lactam), 170.19 (CO, thiazolidinone). Anal. Calcd for C25H20N3O3SCl: C, 62.82; H, 4.22; N, 8.79; S, 6.71. Found: C, 62.98; H, 4.58; N, 8.35; S, 6.85.

2-(2-Fluorophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4g)
Prepared from 3h (75.0 mg, 1.78 × 10–1 mmol), ethyl bromoacetate (32.70 mg, 22.0 μL, 1.96 × 10–1 mmol) and Na2CO3 (38.0 mg, 3.56 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4g as a white solid; yield: 74.0 mg, (90%); mp 82-85 °C; [α]D20 +83.61 (c 0.42, CH2Cl2); IR (KBr): 3630, 3504, 2932, 1763, 1637, 1605, 1513, 1491, 1364, 1247, 1222, 1176, 1145, 1029, 829, 754, 698 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.71 (s, 3H, OCH3, PMP), 3.93 (s, 2H, CH2, thiazolidinone), 5.54 (bs, 2H, 1H-C4-β-lactam and 1H-C3-β-lactam), 6.76 (d, 2H, J = 8.97 Hz, PMP), 7.05-7.08 (m, 4H, FPh), 7.23 (d, 2H, J = 8.94 Hz, PMP), 7.36-7.41 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): δ 32.82 (CH2, thiazolidinone), 55.36 (OCH3), 59.48 (C4, β-lactam), 65.89 (C3, β-lactam), 114.25 (C3 and C5, PMP), 116.26 (d, J = 19.61 Hz, C3, FPh), 119.13 (C2 and C6, PMP), 122.43 (d, J = 1.33 Hz, C6, FPh), 124.35 (d, J = 3.89 Hz, C5, FPh), 125.97 (d, J = 7.29 Hz, C4, FPh), 126.42 (C2 and C6, Ph), 128.98 (C4, Ph), 129.26 (C3 and C5, Ph), 130.63 (C1, Ph), 134.70 (d, J = 12.22 Hz, C1, FPh), 136.05 (C1, PMP), 152.24 (d, J = 274.42 Hz, C2, FPh), 154.14 (C=N, thiazolidinone), 156.35 (C4, PMP), 161.13 (CO, β-lactam), 170.27 (CO, thiazolidinone). Anal. Calcd for C25H20N3O3SF: C, 65.06; H, 4.37; N, 9.10; S, 6.95. Found: C, 65.38; H, 4.64; N, 8.77; S, 6.83.

2-(4-Azidophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4h)
Prepared from 3m (57.0 mg, 1.28 × 10–1 mmol), ethyl bromoacetate (23.50 mg, 16.0 μL, 1.41 × 10–1 mmol) and Na2CO3 (27.0 mg, 2.57 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4h as brown solid; yield: 28.0 mg, (45%); mp 87-90 °C; [α]D20 +60.84 (c 0.26, CH2Cl2); IR (KBr): 3651, 3631, 2931, 2116, 1763, 1654, 1637, 1512, 1499, 1364, 1247, 1029, 829, 794, 699 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 3H, OCH3, PMP), 3.91 (s, 2H, CH2, thiazolidinone), 5.44 (d, 1H, J = 2.61 Hz, C4, β-lactam), 5.53 (d, 1H, J = 2.61 Hz, C3, β-lactam), 6.77 (d, 2H, J = 8.97 Hz, PMP), 6.92 (m, 4H, N3Ph), 7.23 (d, 2H, J = 8.97 Hz, PMP), 7.40 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): δ 32.61 (CH2, thiazolidinone), 55.36 (OCH3, PMP), 59.70 (C4, β-lactam), 65.98 (C3, β-lactam), 114.29 (C3 and C5, PMP), 118.94 (C2 and C6, PMP), 119.72 (C2 and C6, N3Ph), 122.60 (C3 and C5, N3Ph), 126.36 (C2 and C6, Ph), 129.02 (C4, Ph), 129.28 (C3 and C5, Ph), 130.72 (C1, Ph), 136.07 (C1, N3Ph), 136.54 (C1, PMP), 143.62 (C4, N3Ph), 151.97 (C=N, thiazolidinone), 156.37 (C4, PMP), 161.35 (CO, β-lactam), 170.23 (CO, thiazolidinone). HRMS: m/z [M+Na]+ calcd for C25H20N6O3S: 507.1215; found 507.1220.

2-(4-Nitrophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4i)
Prepared from 3n (20.0 mg, 4.50 × 10–2 mmol), ethyl bromoacetate (8.18 mg, 5.50 μL, 4.90 × 10–2 mmol) and Na2CO3 (9.50 mg, 8.90 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4i as a yellow solid; yield: 21.0 mg, (96%); mp 180-182 °C; [α]D20 +75.26 (c 0.40, CH2Cl2); IR (KBr): 3630, 3448, 2937, 1745, 1638, 1512, 1458, 1370, 1347, 1250, 1180, 1154, 1026, 861, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 3H, OCH3, PMP), 3.96 (s, 2H, CH2, thiazolidinone), 5.43 (d, 1H, J = 2.64 Hz, C4, β-lactam), 5.53 (d, 1H, J = 2.64 Hz, C3, β-lactam), 6.77 (d, 2H, J = 9.03 Hz, PMP), 7.01 (d, 2H, J = 9.00 Hz, 4-NO2Ph), 7.22 (d, 2H, J = 9.03 Hz, PMP), 7.41 (s, 5H, Ph), 8.17 (d, 2H, J = 9.00 Hz, 4-NO2Ph); 13C NMR (75 MHz, CDCl3): δ 32.73 (CH2, thiazolidinone), 55.36 (OCH3, PMP), 59.73 (C4, β-lactam), 66.00 (C3, β-lactam), 114.34 (C3 and C5, PMP), 118.93 (C2 and C6, PMP), 121.72 (C2 and C6, 4-NO2Ph), 125.13 (C3 and C5, 4-NO2Ph), 126.34 (C2 and C6, Ph), 129.18 (C4, Ph), 129.36 (C3 and C5, Ph), 130.54 (C1, Ph), 135.83 (C1, PMP), 144.71 (C4, 4-NO2Ph), 152.63 (C=N, thiazolidinone), 154.00 (C1, 4-NO2Ph), 156.49 (C4, PMP), 160.91 (CO, β-lactam), 170.02 (CO, thiazolidinone). Anal. Calcd for C25H20N4O5S: C, 61.47; H,
4.13; N, 11.47; S, 6.56. Found: C, 61.93; H, 4.48; N, 10.97; S, 6.25.

2-(4-Cyanophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]thiazolidin-4-one (4j)
Prepared from 3o (70.0 mg, 1.63 × 10–1 mmol), ethyl bromoacetate (30.10 mg, 20.0 μL, 1.80 × 10–1 mmol) and Na2CO3 (35.0 mg, 3.27 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4j as a yellow solid; yield: 64.0 mg, (84%); mp 91-94 °C; [α]D20 +53.29 (c 0.54, CH2Cl2); IR (KBr): 3504, 2934, 2224, 1763, 1636, 1595, 1513, 1455, 1366, 1299, 1247, 1182, 1145, 1028, 828, 793, 744, 698, 550, 514 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.73 (s, 3H, OCH3, PMP), 3.95 (s, 2H, CH2, thiazolidinone), 5.41 (d, 1H, J = 2.61 Hz, C4, β-lactam), 5.52 (d, 1H, J = 2.61 Hz, C3, β-lactam), 6.77 (d, 2H, J = 9.03 Hz, PMP), 6.98 (d, 2H, J = 8.58 Hz, CNPh), 7.22 (d, 2H, J = 9.03 Hz, PMP), 7.40-7.42 (m, 5H, Ph), 7.58 (d, 2H, J = 8.58 Hz, CNPh); 13C NMR (75 MHz, CDCl3): δ 32.69 (CH2, thiazolidinone), 55.37 (OCH3, PMP), 59.71 (C4, β-lactam), 65.99 (C3, β-lactam), 108.32 (CN), 114.32 (C3 and C5, PMP), 118.81 (C4, CNPh), 118.93 (C2 and C6, PMP), 121.97 (C2 and C6, CNPh), 126.34 (C2 and C6, Ph), 129.17 (C4, Ph), 129.36 (C3 and C5, Ph), 130.56 (C1, Ph), 133.41 (C3 and C5, CNPh), 135.85 (C1, PMP), 150.75 (C1, CNPh), 153.68 (C=N, thiazolidinone), 156.46 (C4, PMP), 160.95 (CO, β-lactam), 170.04 (CO, thiazolidinone). HRMS: m/z [M+Na]+ calcd for C25H20N4O3S: 491.1154; found 491.1150.

2-Cyclohexylimino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-ferrocenylazetidin-3'-yl]thiazolidin-4-one (4k)
Prepared from 3p (31.0 mg, 6.00 × 10–2 mmol), ethyl bromoacetate (11.0 mg, 8.0 μL, 6.60 × 10–2 mmol) and Na2CO3 (13.0 mg, 1.20 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4k as a brown solid; yield: 23.0 mg, (70%); mp 79-81 °C; [α]D20 –174.90 (c 0.10, CH2Cl2); IR (KBr): 3630, 2929, 2853, 1762, 1654, 1648, 1513, 1389, 1351, 1298, 1245, 829 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.11-1.19 (m, 1H, cyclohexyl), 1.23-1.39 (m, 4H, cyclohexyl), 1.46-1.51 (m, 1H, cyclohexyl), 1.63-1.69 (m, 4H, cyclohexyl), 3.14-3.18 (m, 1H, cyclohexyl), 3.77 (s, 3H, OCH3, PMP), 3.93 (d, 2H, J = 1.98 Hz, CH2, thiazolidinone), 4.17 (s, 5H, Fc), 4.21-4.31 (m, 4H, Fc), 5.28 (d, 1H, J = 2.73 Hz, C4, β-lactam), 5.79 (d, 1H, J = 2.73 Hz, C3, β-lactam), 6.83 (d, 2H, J = 8.97 Hz, PMP), 7.29 (d, 2H, J = 8.94 Hz, PMP); 13C NMR (75 MHz, CDCl3): δ 23.63, 23.81 (C3 and C5, cyclohexyl), 25.55 (C4, cyclohexyl), 32.50 (CH2, thiazolidinone), 33.04, 33.28 (C2 and C6, cyclohexyl), 55.41 (OCH3, PMP), 55.65 (C1, cyclohexyl), 60.78 (C4, β-lactam), 63.31 (C3, β-lactam), 66.38, 68.21, 68.67, 69.25, 69.77, 83.79 (Fc), 114.14 (C3 and C5, PMP), 119.69 (C2 and C6, PMP), 130.81 (C1, PMP), 146.85 (C=N, thiazolidinone), 156.40 (C4, PMP), 162.16 (CO, β-lactam), 170.52 (CO, thiazolidinone). HRMS: m/z [M+H]+ calcd for
C29H31N3O3SFe: 558.1514; found 558.1500.

2-Phenylimino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-ferrocenylazetidin-3'-yl]thiazolidin-4-one (4l)
Prepared from 3q (14.0 mg, 2.73 × 10–2 mmol), ethyl bromoacetate (5.03 mg, 3.50 μL, 3.01 × 10–2 mmol) and Na2CO3 (6.00 mg, 5.47 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4l as a brown solid; yield: 10.0 mg, (67%); mp 75-79 °C; [α]D20 –123.08 (c 0.07, CH2Cl2); IR (KBr): 3630, 3448, 1752, 1637, 1511, 1246, 829 cm-1; 1H NMR (600 MHz, CDCl3): δ 3.75 (s, 3H, OCH3, PMP), 3.94 (d, 2H, J = 7.05 Hz, CH2, thiazolidinone), 4.19 (s, 5H, Fc), 4.24 (s, 2H, Fc), 4.31 (s, 1H, Fc), 4.35 (s, 1H, Fc), 5.39 (d, 1H, J = 2.34 Hz, C4, β-lactam), 5.97 (d, 1H, J = 2.34 Hz, C3, β-lactam), 6.81 (d, 2H, J = 8.82 Hz, PMP), 7.00 (d, 2H, J = 7.62 Hz, PMP), 7.15 (m, 1H, Ph), 7.28-7.35 (m, 4H, Ph); 13C NMR (150 MHz, CDCl3): δ 32.45 (CH2, thiazolidinone), 55.43 (OCH3, PMP), 56.55 (C4, β-lactam), 63.36 (C3, β-lactam), 66.35, 68.45, 68.77, 69.55, 70.03, 83.19 (Fc), 114.28 (C3 and C5, PMP), 120.25 (C2 and C6, PMP), 121.07 (C2 and C6, Ph), 124.99 (C4, Ph), 129.29 (C3 and C5, Ph), 130.49 (C4, PMP), 147.09 (C1, Ph), 152.30 (C=N, thiazolidinone), 156.74 (C4, PMP), 161.81 (CO, β-lactam), 170.91 (CO, thiazolidinone). HRMS: m/z [M+Na]+ calcd for C29H25N3O3SFe: 574.0864; found 574.0865; Anal. Calcd for C29H25N3O3SFe: C, 63.17; H, 4.57; N, 7.62; S, 5.81. Found: C, 62.89; H, 4.61; N, 7.51; S, 5.48.

2-(2-Chlorophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-ferrocenylazetidin-3'-yl]thiazolidin-4-one (4m)
Prepared from 3r (28.0 mg, 5.13 × 10–2 mmol), ethyl bromoacetate (9.42 mg, 6.50 μL, 5.64 × 10–2 mmol) and Na2CO3 (11.0 mg, 1.03 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4m as a brown solid; yield: 17.0 mg, (57%); mp 220-223 °C; [α]D20 –67.95 (c 0.18, CH2Cl2); IR (KBr): 3630, 3449, 2927, 1752, 1630, 1585, 1513, 1378, 1356, 1246, 1175, 1444, 1029, 824, 795, 758, 692, 481 cm-1; 1H NMR (600 MHz, CDCl3): δ 3.74 (s, 3H, OCH3, PMP), 3.98 (d, 2H, J = 14.45 Hz, CH2, thiazolidinone), 4.18 (s, 5H, Fc), 4.23 (s, 2H, Fc), 4.28 (s, 1H, Fc), 4.37 (s, 1H, Fc), 5.67 (s, 1H, C4, β-lactam), 5.92 (d, 1H, J = 1.98 Hz, C3, β-lactam), 6.81 (d, 2H, J = 8.70 Hz, PMP), 7.03 (d, 1H, J = 7.50 Hz, ClPh), 7.08 (t, 1H, J1 = J2 = 7.44 Hz, ClPh), 7.22 (t, 1H, J1 = J2 = 7.38 Hz, ClPh), 7.30 (d, 2H, J = 8.70 Hz, PMP), 7.41 (d, 1H, J = 7.86 Hz, ClPh); 13C NMR (150 MHz, CDCl3): δ 32.85 (CH2, thiazolidinone), 55.40 (OCH3, PMP), 55.99 (C4, β-lactam), 63.51 (C3, β-lactam), 66.51, 68.43, 68.69, 69.31, 69.91, 83.53 (Fc), 114.22 (C3 and C5, PMP), 120.51 (C2 and C6, PMP), 121.50 (C4, ClPh), 125.88 (C5, ClPh), 126.59 (C2, ClPh), 127.52 (C6, ClPh), 130.08 (C3, ClPh), 130.27 (C1, PMP), 144.34 (C1, ClPh), 154.24 (C=N, thiazolidinone), 156.75 (C4, PMP), 161.47 (CO, β-lactam), 170.52 (CO, thiazolidinone). LRMS: m/z [M+H]+ calcd for C29H24N3O3SClFe: 586.07; found 586.07.

2-(4-Nitrophenyl)imino-3-[trans-(3’R,4’R)-1'-(4'-methoxyphenyl)-2'-oxo-4'-ferrocenylazetidin-3'-yl]thiazolidin-4-one (4n)
Prepared from 3s (20.0 mg, 3.59 × 10–2 mmol), ethyl bromoacetate (6.60 mg, 4.50 μL, 3.95 × 10–2 mmol) and Na2CO3 (7.60 mg, 7.19 × 10–2 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:2) as the eluent furnished 4n as a brown solid; yield: 14.9 mg, (70%); mp 101-103 °C; [α]D20 –88.65 (c 0.11, CH2Cl2); IR (KBr): 3631, 3449, 2926, 1752, 1654, 1638, 1584, 1511, 1340, 1245, 828, 699 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 3H, OCH3, PMP), 4.01 (d, 2H, J = 0.72 Hz, CH2, thiazolidinone), 4.19 (s, 5H, Fc), 4.27 (t, 2H, J1 = J2 = 1.68 Hz, Fc), 4.30 (d, 1H, J = 1.62 Hz, Fc), 4.34 (d, 1H, J = 1.47 Hz, Fc), 5.35 (d, 1H, J = 2.67 Hz, C4, β-lactam), 5.93 (d, 1H, J = 2.67 Hz, C3, β-lactam), 6.81 (d, 2H, J = 8.97 Hz, PMP), 7.11 (d, 2H, J = 8.88 Hz, NO2Ph), 7.28 (d, 2H, J = 8.22 Hz, PMP), 8.22 (d, 2H, J = 8.88 Hz, NO2Ph); 13C NMR (75 MHz, CDCl3): δ 32.65 (CH2, thiazolidinone), 55.41 (OCH3, PMP), 56.55 (C3, β-lactam), 63.50 (C4, β-lactam), 66.24, 68.54, 68.74, 69.69, 69.95, 82.96 (Fc), 114.29 (C3 and C5, PMP), 120.10 (C2 and C6, PMP), 121.74 (C2 and C6, NO2Ph), 125.27 (C3 and C5, NO2Ph), 130.23 (C1, PMP), 144.82 (C4, NO2Ph), 152.85 (C=N, thiazolidinone), 154.47 (C1, NO2Ph), 156.82 (C4, PMP), 161.28 (CO, β-lactam), 170.45 (CO, thiazolidinone). HRMS: m/z [M+H]+ calcd for C29H24N4O5SFe: 597.0895; found 597.0900.

Preparation of triazinethiones 5a-g
General procedure. – To a stirred solution of a thiourea (3d, 3g, 3i-l and 3n; 1 equiv) in absolute EtOH (10 mL), aqueous solutions of formaldehyde (37%) (5 equiv) and methylamine (40%) (2 equiv) were added dropwise. The reaction mixture was heated at 50 °C for 48 h, then cooled, filtered and evaporated to dryness. Crude products 5a-g were purified by silica gel column chromatography using a mixture of EtOAc-pethroleum ether (bp 40-70 °C) in the ratio 1:1.

1-Phenyl-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5a)
Prepared from 3d (70.0 mg, 1.73 × 10–1 mmol) and aqueous solutions of formaldehyde (26.0 mg, 63.0 μL, 8.67 × 10–1 mmol) and methylamine (10.80 mg, 30.0 μL, 3.47 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5a as a white solid; yield: 24.0 mg, (30%); mp 155-158 °C; [α]D20 +336.13 (c 0.01, CH2Cl2); IR (KBr): 3631, 3463, 2949, 1736, 1655, 1638, 1586, 1521, 1498, 1298, 1259, 1137, 1028, 833, 754, 685 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.84 (s, 3H, NCH3, triazinethione), 3.73 (s, 3H, OCH3, PMP), 4.51 (m, 2H, CH2, triazinethione), 4.64 (d, 2H, J = 12.04 Hz, CH2, triazinethione), 5.02 (d, 1H, J = 1.98 Hz, C4, β-lactam), 6.32 (d, 1H, J = 1.98 Hz, C3, β-lactam), 6.78 (d, 2H, J = 8.94 Hz, PMP), 7.22-7.46 (m, 12H, 5H-PhN, 5H-Ph-β-lactam and 2H-PMP); 13C NMR (75 MHz, CDCl3): δ 39.83 (NCH3, triazinethione), 55.38 (OCH3, PMP), 62.22 (C4, β-lactam), 67.49 (C4, triazinethione), 72.62 (C6, triazinethione), 74.02 (C3, β-lactam), 114.31 (C3 and C5, PMP), 118.89 (C2 and C6, PMP), 126.51 (C2 and C6, Ph, β-lactam), 127.56 (C4, PhN), 127.96 (C2 and C6, PhN), 128.56 (C4, Ph, β-lactam), 128.88 (C3 and C5, PhN), 129.43 (C3 and C5, Ph, β-lactam), 130.48 (C1, Ph, β-lactam), 135.92 (C1, PMP), 144.46 (C1, PhN), 156.37 (C4, PMP), 162.54 (CO, β-lactam), 179.81 (CS, triazinethione). Anal. Calcd for C26H26N4O2S: C, 68.10; H, 5.71; N, 12.22; S, 6.99. Found: C, 67.75; H, 5.50; N, 12.27; S, 6.90.

1-(4-Chlorophenyl)-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5b)
Prepared from 3g (46.0 mg, 1.05 × 10–1 mmol) and aqueous solutions of formaldehyde (15.80 mg, 38.0 μL, 5.25 × 10–1 mmol) and methylamine (8.17 mg, 23.0 μL, 2.63 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5b as a yellow solid; yield: 14.0 mg, (27%); mp 150-153 °C; [α]D20 +312.50 (c 0.02, CH2Cl2); IR (KBr): 3650, 3630, 2924, 1735, 1654, 1560, 1508, 1458, 1245, 834 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.83 (s, 3H, NCH3, triazinethione), 3.74 (s, 3H, OCH3, PMP), 4.45-4.67 (m, 4H, triazinethione), 5.00 (d, 1H, J = 2.01 Hz, C4, β-lactam), 6.27 (d, 1H, J = 1.86 Hz, C3, β-lactam), 6.65 (d, 2H, J = 8.79 Hz, PMP), 6.73-6.80 (m, 4H, ClPh), 7.18 (d, 2H, J = 8.55 Hz, PMP), 7.32-7.37 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): δ 39.87 (NCH3, triazinethione), 55.42 (OCH3, PMP), 62.25 (C4, β-lactam), 67.61 (C4, triazinethione), 72.61 (C6, triazinethione), 74.06 (C3, β-lactam), 114.37 (C3 and C5, PMP), 118.94 (C2 and C6, PMP), 126.52 (C2 and C6, Ph), 128.69 (C4, Ph), 128.97 (C2 and C6, ClPh), 129.44 (C3 and C5, Ph), 129.70 (C3 and C5, ClPh), 130.46 (C1, Ph), 133.35 (C4, ClPh), 135.88 (C1, PMP), 142.92 (C1, ClPh), 156.46 (C4, PMP), 162.38 (CO, β-lactam), 179.93 (CS, triazinethione). HRMS: m/z [M+Na]+ calcd for C26H25N4O2SCl: 515.1284; found: 515.1287.

1-(4-Fluorophenyl)-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5c)
Prepared from 3i (230 mg, 5.46 × 10–1 mmol) and aqueous solutions of formaldehyde (82.0 mg, 198 μL, 2.73 mmol) and methylamine (42.20 mg, 118 μL, 1.36 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5c as a yellow solid; yield: 40.0 mg, (15%); mp 167-170 °C; [α]D20 +53.57 (c 0.06, CH2Cl2); IR (KBr): 3651, 3630, 2950, 1736, 1512, 1484, 1438, 1298, 1260, 1220, 1154, 1136, 1029, 835, 681 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.83 (s, 3H, NCH3, triazinethione), 3.73 (s, 3H, OCH3, PMP), 4.45-4.67 (m, 4H, triazinethione), 5.01 (d, 1H, J = 2.13 Hz, C4, β-lactam), 6.29 (d, 1H, J = 2.10 Hz, C3, β-lactam), 6.78 (d, 2H, J = 8.97 Hz, PMP), 6.99 (m, 3H, FPh), 7.18-7.37 (m, 8H, 1H-FPh, 2H-PMP and 5H-Ph); 13C NMR (75 MHz, CDCl3): δ 39.84 (NCH3, triazinethione), 55.40 (OCH3, PMP), 62.21 (C4, β-lactam), 67.55 (C4, triazinethione), 72.71 (C6, triazinethione), 74.09 (C3, β-lactam), 114.34 (C3 and C5, PMP), 116.38 (d, J = 22.83 Hz, C3 and C5, FPh), 118.91 (C2 and C6, PMP), 126.50 (C2 and C6, Ph), 128.65 (C4, Ph), 128.94 (C3 and C5, Ph), 129.75 (d, J = 8.67 Hz, C2, C6, FPh), 130.46 (C1, Ph), 135.89 (C1, PMP), 140.39 (d, J = 3.27 Hz, C1, FPh), 156.42 (C4, PMP), 161.50 (d, J = 247.60 Hz, C4, FPh), 162.42 (CO, β-lactam), 180.12 (CS, triazinethione). HRMS: m/z [M+Na]+ calcd for C26H25N4O2SF: 499.1580; found: 499.1587.

1-(4-Trifluoromethylphenyl)-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5d)
Prepared from 3j (60.0 mg, 1.27 × 10–1 mmol) and aqueous solutions of formaldehyde (19.10 mg, 46.0 μL, 6.36 × 10–1 mmol) and methylamine (9.88 mg, 27.0 μL, 3.18 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5d as a yellow solid; yield: 16.0 mg, (24%); mp 149-152 °C; [α]D20 +80.65 (c 0.09, CH2Cl2); IR (KBr): 3753, 3631, 2953, 1736, 1612, 1542, 1512, 1490, 1329, 1298, 1258, 1128, 1066, 833, 523 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.84 (s, 3H, NCH3, triazinethione), 3.74 (s, 3H, OCH3, PMP), 4.48-4.69 (m, 4H, triazinethione), 5.02 (d, 1H, J = 2.07 Hz, C4, β-lactam), 6.26 (d, 1H, J = 2.01 Hz, C3, β-lactam), 6.78 (d, 2H, J = 9.12 Hz, PMP), 6.80 (d, 2H, J = 9.03, CF3Ph), 7.26 (d, 2H, J = 9.60 Hz, PMP), 7.32-7.44 (m, 5H, Ph), 7.65 (d, 2H, J = 8.31 Hz, CF3Ph); 13C NMR (75 MHz, CDCl3): δ 39.85 (NCH3, triazinethione), 55.41 (OCH3, PMP), 62.23 (C4, β-lactam), 67.68 (C4, triazinethione), 72.46 (C6, triazinethione), 73.94 (C3, β-lactam), 114.36 (C3 and C5, PMP), 118.92 (C2 and C6, PMP), 123.76 (d, J = 272.06 Hz, CF3), 126.50 (C2 and C6, Ph), 126.60 (d, J = 3.81 Hz, C3 and C5, CF3Ph), 128.62 (C2 and C6, CF3Ph), 128.70 (C4, Ph), 128.96 (C3 and C5, Ph), 129.52 (d, J = 32.94 Hz, C4, CF3Ph), 130.40 (C1, Ph), 135.82 (C1, PMP), 147.44 (d, J = 1.25 Hz, C1, CF3Ph), 156.47 (C4, PMP), 162.22 (CO, β-lactam), 179.72 (CS, triazinethione). LRMS: m/z [M+H]+ calcd for C27H25N4O2SF3: 527.17; found 527.17.

1-(4-Trifluoromethoxyphenyl)-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5e)
Prepared from 3k (70.0 mg, 1.44 × 10–1 mmol) and aqueous solutions of formaldehyde (21.60 mg, 52.0 μL, 7.18 × 10–1 mmol) and methylamine (11.10 mg, 31.0 μL, 3.59 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5c as a white solid; yield: 22.7 mg, (29%); mp 169-172 °C; [α]D20 –10.27 (c 0.10, CH2Cl2); IR (KBr): 3752, 3467, 2951, 1739, 1654, 1587, 1513, 1486, 1439, 1393, 1298, 1260, 1162, 1136, 1029, 834, 752, 682, 525 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.83 (s, 3H, NCH3, triazinethione), 3.73 (s, 3H, OCH3, PMP), 4.46-4.67 (m, 4H, triazinethione), 5.02 (d, 1H, J = 2.16 Hz, C4, β-lactam), 6.26 (d, 1H, J = 2.13 Hz, C3, β-lactam), 6.78 (d, 2H, J = 9.06 Hz, PMP), 6.79 (d, 2H, J = 9.03, CF3OPh), 7.21-7.38 (m, 9H, 5H-Ph, 2H-PMP and 2H-CF3OPh); 13C NMR (75 MHz, CDCl3): δ 39.83 (NCH3, triazinethione), 55.39 (OCH3, PMP), 62.22 (C4, β-lactam), 67.62 (C4, triazinethione), 72.59 (C6, triazinethione), 74.04 (C3, β-lactam), 114.34 (C3 and C5, PMP), 118.91 (C2 and C6, PMP), 121.81 (C2 and C6, CF3OPh), 122.06 (CF3O), 126.48 (C2 and C6, Ph), 128.66 (C4, Ph), 128.94 (C3 and C5, Ph), 129.61 (C3 and C5, CF3OPh), 130.43 (C1, Ph), 135.86 (C1, PMP), 142.79 (C1, CF3OPh), 147.96 (C4, CF3OPh), 156.44 (C4, PMP), 162.32 (CO, β-lactam), 179.92 (CS, triazinethione). Anal. Calcd for C27H25N4O3SF3: C, 59.77; H, 4.64; N, 10.33; S, 5.91. Found: C, 59.54; H, 4.93; N, 10.40; S, 5.77.

1-(4-Methoxyphenyl)-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5f)
Prepared from 3l (51.0 mg, 1.18 × 10–1 mmol) and aqueous solutions of formaldehyde (17.70 mg, 43.0 μL, 5.88 × 10–1 mmol) and methylamine (9.13 mg, 25.0 μL, 2.94 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5f as a yellow solid; yield: 7.2 mg, (13%); mp 160-162 °C; [α]D20 +126.90 (c 0.04, CH2Cl2); IR (KBr): 3651, 3469, 1742, 1686, 1654, 1560, 1511, 1388, 1246, 1166, 1029, 829, 725 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.83 (s, 3H, NCH3, triazinethione), 3.74 (s, 3H, OCH3, PMP-1), 3.80 (s, 3H, OCH3, PMP-2), 4.45-4.66 (m, 4H, triazinethione), 5.01 (d, 1H, J = 1.89 Hz, C4, β-lactam), 6.32 (d, 1H, J = 1.92 Hz, C3, β-lactam), 6.79 (d, 2H, J = 8.79 Hz, PMP-1), 6.91 (d, 2H, J = 8.85 Hz, PMP-2), 7.15 (d, 2H, J = 8.82 Hz, PMP-2), 7.24-7.38 (m, 7H, 2H-PMP-1 and 5H-Ph); 13C NMR (75 MHz, CDCl3): δ 39.89 (NCH3, triazinethione), 55.40 (OCH3, PMP-2), 55.43 (OCH3, PMP-1), 62.30 (C4, β-lactam), 67.47 (C4, triazinethione), 72.83 (C6, triazinethione), 74.18 (C3, β-lactam), 114.35 (C3 and C5, PMP-1), 114.66 (C3 and C5, PMP-2), 118.93 (C2 and C6, PMP-1), 126.65 (C2 and C6, PMP-2), 128.07 (C2 and C6, Ph), 128.60 (C4, Ph), 128.93 (C3 and C5, Ph), 130.67 (C1, Ph), 130.83 (C1, PMP-2), 135.96 (C1, PMP-1), 156.40 (C4, PMP-1), 159.83 (C4, PMP-2), 163.17 (CO, β-lactam), 180.93 (CS, triazinethione). HRMS: m/z [M+H]+ calcd for C27H28N4O3S: 489.1960; found: 489.1980.

1-(4-Nitrophenyl)-3-[trans-(3’R,4’R)-1'-(4-methoxyphenyl)-2'-oxo-4'-phenylazetidin-3'-yl]-5-methylhexahydro-2-thioxo-1,3,5-triazine (5g)
Prepared from 3n (50.0 mg, 1.11 × 10–1 mmol) and aqueous solutions of formaldehyde (16.70 mg, 40.0 μL, 5.57 × 10–1 mmol) and methylamine (6.92 mg, 20.0 μL, 2.23 × 10–1 mmol). Evaporation of the solvent and purification of the residue over a silica gel column using EtOAc-petroleum ether (1:1) as the eluent furnished 5g as a yellow solid; yield: 21.0 mg, (36%); mp 166-168 °C; [α]D20 +360.82 (c 0.02, CH2Cl2); IR (KBr): 3630, 3569, 2931, 1752, 1736, 1593, 1513, 1458, 1347, 1300, 1247, 1066, 827, 696 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.85 (s, 3H, NCH3, triazinethione), 3.74 (s, 3H, OCH3, PMP), 4.51 (d, 1H, J = 12.28 Hz, CH2, triazinethione), 4.56 (s, 2H, CH2, triazinethione), 4.68 (d, 1H, J = 12.07 Hz, CH2, triazinethione), 5.04 (d, 1H, J = 2.10 Hz, C4, β-lactam), 6.21 (d, 1H, J = 2.01 Hz, C3, β-lactam), 6.79 (d, 2H, J = 9.00 Hz, PMP), 7.25 (d, 2H, J = 8.94 Hz, PMP), 7.31-7.36 (m, 5H, Ph), 7.44 (d, 2H, J = 8.91 Hz, NO2Ph), 8.25 (d, 2H, J = 8.88 Hz, NO2Ph); 13C NMR (75 MHz, CDCl3): δ 39.84 (NCH3, triazinethione), 55.40 (OCH3, PMP), 62.11 (C4, β-lactam), 67.84 (CH2, C4, triazinethione), 72.34 (C6, triazinethione), 73.86 (C3, β-lactam), 114.36 (C3 and C5, PMP), 118.91 (C2 and C6, PMP), 126.51 (C2 and C6, Ph, β-lactam), 127.56 (C4, PhN), 127.96 (C2 and C6, PhN), 124.79 (C2 and C6, NO2Ph), 126.45 (C3 and C5, NO2Ph), 128.79 (C4, Ph), 129.01 (C2 and C6, Ph), 129.17 (C3 and C5, Ph), 130.30 (C1, Ph), 135.73 (C1, PMP), 146.33 (C1, NO2Ph), 149.93 (C4, NO2Ph), 156.49 (C4, PMP), 162.00 (CO, β-lactam), 179.55 (CS, triazinethione). Anal. Calcd for C26H25N5O4S: C, 62.01; H, 5.00; N, 13.91; S, 6.37. Found: C, 62.17; H, 5.13; N, 14.07; S, 6.46.

ACKNOWLEDGEMENTS
The financial supports from the Croatian Ministry of Science, Education and Sports (Program 098-0982915-2948) and Slovenian Ministry of Higher Education Science and Technology (Grants P-1-007 and PR-00132) are gratefully acknowledged. The author (I. H.) would like to thank Prof. Dr. Francis Johnson (State University of New York at Stony Brook, Stony Brook, NY, USA) and Dr. Davor Margetić (Ruđer Bošković Institute) for useful discussions.

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