New thiazolidinone and triazinethione conjugates derived from amino-β-lactams

DOI: 10.3987/COM-09-11668

Source and publish data:

Heterocycles p. 1729 - 1759 (2009)

Update date:2022-09-26

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Authors:

Radolovic, Katarina

Habus, Ivan

Kralj, Bogdan

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Article abstract of DOI:10.3987/COM-09-11668

Thioureas 3a-s, generated from amino-β-lactams la-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

Full text of DOI:10.3987/COM-09-11668

HETEROCYCLES, Vol. 78, No. 7, 2009

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HETEROCYCLES, Vol. 78, No. 7, 2009, pp. 1729 - 1759. © The Japan Institute of Heterocyclic Chemistry

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,^aIvan Habuš,^a,* and Bogdan Kralj^b

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

Croatia

^bJožef Stefan Institute, Jamova 39, SL-1000 Ljubljana, Slovenia

ihabus@irb.hr

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.^1-3Consequently their synthesis has been of considerable

interest to the synthetic community over the past five decades.^4-6The 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.^7-10Enantiopure 3-amino-β-lactams are the key intermediates for the

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HETEROCYCLES, Vol. 78, No. 7, 2009

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.^8,10-13Their hydrolysis affords

the corresponding α,β-diamino acids.¹⁴This 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.^1,6,16,17Thioureas,^18,19thiazolidinone^20-35and triazine^36,37moieties 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,³⁸anti-inflamatory,³⁹antimicrobial,⁴⁰anticancer,³⁸and antifungal⁴¹activities.

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,^13,42,43to the asymmetric

synthesis of trans-3-amino-β-lactams 1a-c.^11,12This synthetic methodology is generally used for the

formation of the azetidin-2-one nucleus and is also known as the β-lactam synthon method.^44,45Treatment

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 carbonate^29,34which resulted in the formation of a variety of iminothiazolidinones

4a-n (Scheme 2), and (ii) condensation with aqueous formaldehyde and methylamine^36,46,47which 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.

HETEROCYCLES, Vol. 78, No. 7, 2009

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R²NH

H₂N

R¹

R²-NCS

2a-n

PMP

1a-c

3a-s

2a: R²= n-hexyl

(3R,4R)-3a: 54%; R¹= Ph; R²= n-hexyl

(3R,4R)-3b: 72%; R¹= Ph; R²= cyclohexyl

(3R,4R)-3c: 94%; R¹= Ph; R²= norbornyl

(3R,4R)-3d: 96%; R¹= Ph; R²= Ph

(3R,4R)-1a: R¹= Ph

(3S,4S)-1b: R¹= Ph

(3R,4R)-1c: R¹= Fc

2b: R²= cyclohexyl

2c: R²= norbornyl

2d: R²= Ph

PMP = 4-MeO-C₆H₄

Ph = Phenyl

Fc = Ferrocenyl

2e: R²= 2-Cl-C₆H₄

2f: R²= 4-Cl-C₆H₄

2g: R²= 2-F-C₆H₄

2h: R²= 4-F-C₆H₄

2i: R²= 4-CF₃-C₆H₄

2j: R²= 4-CF₃O-C₆H₄

2k: R²= PMP

2l: R²= 4-N₃-C₆H₄

2m: R²= 4-NO₂-C₆H₄

2n: R²= 4--NC-C₆H₄

(3S,4S)-3e: 98%; R¹= Ph; R²= Ph

(3R,4R)-3f: 94%; R¹= Ph; R²= 2-Cl-C₆H₄

(3R,4R)-3g: 94%; R¹= Ph; R²= 4-Cl-C₆H₄

(3R,4R)-3h: 66%; R¹= Ph; R²= 2-F-C₆H₄

(3R,4R)-3i: 89%; R¹= Ph; R²= 4-F-C₆H₄

(3R,4R)-3j: 97%; R¹= Ph; R²= 4-CF₃-C₆H₄

(3R,4R)-3k: 84%; R¹= Ph; R²= 4-CF₃O-C₆H₄

(3R,4R)-3l: 99%; R¹= Ph; R²= PMP

(3R,4R)-3m: 85%; R¹= Ph; R²= 4-N₃-C₆H₄

(3R,4R)-3n: 81%; R¹= Ph; R²= 4-NO₂-C₆H₄

(3R,4R)-3o: 97%; R¹= Ph; R²= 4-NC-C₆H₄

(3R,4R)-3p: 72%; R¹= Fc; R²= cyclohexyl

(3R,4R)-3q: 96%; R¹= Fc; R²= Ph

(3R,4R)-3r: 88%; R¹= Fc; R²= 2-Cl-C₆H₄

(3R,4R)-3s: 81%; R¹= Fc; R²= 4-NO₂-C₆H₄

Scheme 1

R²NH

R²

R¹

BrCH₂CO₂Et

MeCN, 40-60 ^oC

R²

PMP

4a'

4a-n

3a-f; 3h and 3m-s

(3R,4R)-4a/4a': 67% (4a:4a'=23:77); R¹= Ph; R²= n-hexyl

(3R,4R)-4b: 77%; R¹= Ph; R²= cyclohexyl

(3R,4R)-4c: 99%; R¹= Ph; R²= norbornyl

(3R,4R)-4d: 73%; R¹= Ph; R²= Ph

(3R,4R)-3a: R¹= Ph; R²= n-hexyl

(3R,4R)-3b: R¹= Ph; R²= cyclohexyl

(3R,4R)-3c: R¹= Ph; R²= norbornyl

(3R,4R)-3d: R¹= Ph; R²= Ph

(3S,4S)-4e: 62%; R¹= Ph; R²= Ph

(3S,4S)-3e: R¹= Ph; R²= Ph

(3R,4R)-4f: 92%; R¹= Ph; R²= 2-Cl-C₆H₄

(3R,4R)-4g: 90%; R¹= Ph; R²= 2-F-C₆H₄

(3R,4R)-4h: 45%; R¹= Ph; R²= 4-N₃-C₆H₄

(3R,4R)-4i: 96%; R¹= Ph; R²= 4-NO₂-C₆H₄

(3R,4R)-4j: 84%; R¹= Ph; R²= 4-NC-C₆H₄

(3R,4R)-4k: 70%; R¹= Fc; R²= cyclohexyl

(3R,4R)-4l: 67%; R¹= Fc; R²= Ph

(3R,4R)-3f: R¹= Ph; R²= 2-Cl-C₆H₄

(3R,4R)-3h: R¹= Ph; R²= 2-F-C₆H₄

(3R,4R)-3m: R¹= Ph; R²= 4-N₃-C₆H₄

(3R,4R)-3n: R¹= Ph; R²= 4-NO₂-C₆H₄

(3R,4R)-3o: R¹= Ph; R²= 4-NC-C₆H₄

(3R,4R)-3p: R¹= Fc; R²= cyclohexyl

(3R,4R)-3q: R¹= Fc; R²= Ph

(3R,4R)-4m: 57%; R¹= Fc; R²= 2-Cl-C₆H₄

(3R,4R)-4n: 70%; R¹= Fc; R²= 4-NO₂-C₆H₄

(3R,4R)-3r: R¹= Fc; R²= 2-Cl-C₆H₄

(3R,4R)-3s: R¹= Fc; R²= 4-NO₂-C₆H₄

Scheme 2

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HETEROCYCLES, Vol. 78, No. 7, 2009

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. R¹in structure A, Scheme 3).²⁹This 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.^29,48,49However, 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

R¹

R²

BrCH₂CO₂Et

R¹

R²

R¹

Scheme 3

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 H NMR spectra (Figure 1) and HPLC

analyses. The structures of regioisomers 4a/a'-n were determined by H and C NMR spectra analysis.

The resonances of n-hexyl and β-lactam C3-H_aand C4-H_bprotons allowed us to identify each

regioisomer. In 4a' the CH₂(CH₂)₄CH₃protons 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,²⁶for CH₂CH₂CH₃protons in the 2-imino-4-thiazolidinone

regioisomers that they investigated. The β-lactam C3-H_aand C4-H_bprotons 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-d₆the close doublets

for the β-lactam C3-H_aand C4-H_bprotons of 4a are well-separated and appear at 5.42 and 5.25 ppm,

respectively (Figure 1, II).

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1733

n-C₆H₁₃

H_a

H_b

H_a

H_b

n-C₆H₁₃

PMP

4a'

4a’-H_b

J_{Ha-Hb (4a')}= 1.61 Hz

4a’-H_a

J_{Ha-Hb (4a')}= 1.61 Hz

4a-H_a+H_b

J_{Ha-Hb (4a)}= 2.41 Hz

PPM

5.2

5.0

4.8

4.6

4a’-H_b

J_{Ha-Hb (4a')}= 1.82 Hz

4a’-H_a

J_{Ha-Hb (4a')}= 1.82 Hz

4a-H_a

4a-H_b

J_{Ha-Hb (4a)}= 2.62 Hz

PPM 5.40

5.30

5.20

5.10

5.00

4.90

4.80

4.70

4.60

4.50

Figure 1 H NMR spectra recorded in CDCl₃(I) and DMSO-d₆(II) of the β-lactam C3-H_aand C4-H_b

protons in the mixture of iminothiazolidinone regioisomers 4a and 4a’

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-H_aand C4-H_bprotons appear as

very close doublets at 5.37 and 5.35 ppm for 4b and 5.35 and 5.30 ppm for 4c, respectively. H 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-H_aand C4-H_bprotons 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

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HETEROCYCLES, Vol. 78, No. 7, 2009

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).

H₂

OEt

R¹

MeCN

Na₂CO₃, 40 - 60 ^oC

PMP

3d-o, 3q-s; R¹= aryl

H₂

OEt

R¹

PMP

4d-j, 4l-n; R¹= aryl

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).

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1735

R¹

PMP

H₂

OEt

R¹

EtO

R¹

PMP

3a-c, 3p; R¹= n-hexyl, cyclohexyl, exo-norbornyl

Figure 2 Intermediates D, E and F

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.

R²

R²NH

H₃C

R¹

CH₂O (aq), MeNH₂(aq)

EtOH, 50 ^oC

PMP

5a-g

3d;3g; 3i-l and 3n

(3R,4R)-3d: R¹= Ph; R²= Ph

(3R,4R)-5a: 30%; R¹= Ph; R²= Ph

(3R,4R)-3g: R¹= Ph; R²= 4-Cl-C₆H₄

(3R,4R)-3i: R¹= Ph; R²= 4-F-C₆H₄

(3R,4R)-3j: R¹= Ph; R²= 4-CF₃-C₆H₄

(3R,4R)-3k: R¹= Ph; R²= 4-CF₃O-C₆H₄

(3R,4R)-3l: R¹= Ph; R²= PMP

(3R,4R)-5b: 27%; R¹= Ph; R²= 4-Cl-C₆H₄

(3R,4R)-5c: 15%; R¹= Ph; R²= 4-F-C₆H₄

(3R,4R)-5d: 24%; R¹= Ph; R²= 4-CF₃-C₆H₄

(3R,4R)-5e: 29%; R¹= Ph; R²= 4-CF₃O-C₆H₄

(3R,4R)-5f: 13%; R¹= Ph; R²= PMP

(3R,4R)-3n: R¹= Ph; R²= 4-NO₂-C₆H₄

(3R,4R)-5g: 36%; R¹= Ph; R²= 4-NO₂-C₆H₄

Scheme 5

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HETEROCYCLES, Vol. 78, No. 7, 2009

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 H and C NMR spectra (in CDCl₃, CD₃OD and DMSO-d₆at 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,

HETEROCYCLES, Vol. 78, No. 7, 2009

1737

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 F₂₅₄and 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^–1mmol) and 2a (23.50 mg, 25.0 μL, 1.64 × 10^–1mmol).

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]_D+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); C 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^–1mmol) and 2b (52.10 mg, 50.6 μL, 3.69 × 10^–1mmol).

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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^–1mmol) and 2c (44.0 mg, 2.87 × 10^–1mmol). 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^–1mmol) and 2d (27.70 mg, 24.2 μL, 2.05 × 10^–1mmol).

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-

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1739

95 °C; [α]_D–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^–1mmol) and 2d (16.60 mg, 15.4 μL, 1.23 × 10^–1mmol).

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]_D+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^–1mmol) and 2e (63.30 mg, 49.5 μL, 3.73 × 10^–1mmol).

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; H 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

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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); C 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^–1mmol) and 2f (28.0 mg, 1.64 × 10^–1mmol). 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); C 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^–1mmol) and 2g (56.50 mg, 46.2 μL, 3.69 × 10^–1mmol).

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; H 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),

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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^–1mmol) and 2h (62.8 mg, 4.10 × 10^–1mmol). 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; H 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^–1mmol) and 2i (41.5 mg, 2.05 × 10^–1mmol). 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]_D+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); C 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.

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HETEROCYCLES, Vol. 78, No. 7, 2009

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^–1mmol) and 2j (45.0 mg, 2.75 × 10^–1mmol). 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]_D+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); C 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^–1mmol) and 2k (27.10 mg, 23.0 μL, 1.64 × 10^–1mmol).

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; H 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)

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1743

Prepared from 1a (51.0 mg, 1.91 × 10^–1mmol) and 2l (37.0 mg, 2.10 × 10^–1mmol). 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]_D+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^–1mmol) and 2m (59.4 mg, 23.28 × 10^–1mmol). 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; H 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^–1mmol) and 2n (56.1 mg, 3.49 × 10^–1mmol). 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,

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HETEROCYCLES, Vol. 78, No. 7, 2009

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^–2mmol) and 2b (15.10 mg, 14.6 μL, 1.07 × 10^–1mmol).

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); C 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^–1mmol) and 2d (21.80 mg, 20.0 μL, 1.61 × 10^–1mmol).

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,

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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^–2mmol) and 2e (10.90 mg, 8.50 μL, 6.40 × 10^–2mmol).

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%); H

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^–2mmol) and 2m (11.5 mg, 6.14 × 10^–2mmol). 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

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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^–2mmol), ethyl bromoacetate (14.70 mg, 10.0 μL, 8.80 × 10^–2

mmol) and Na₂CO₃(17.0 mg, 1.60 × 10^–1mmol). 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’). H-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’,

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1747

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^–2mmol), ethyl bromoacetate (9.02 mg, 6.00 μL, 5.40 × 10^–2

mmol) and Na₂CO₃(10.5 mg, 9.80 × 10^–2mmol). 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^–2mmol), ethyl bromoacetate (16.50 mg, 11.0 μL, 9.90 × 10^–2

mmol) and Na₂CO₃(19.0 mg, 1.80 × 10^–1mmol). 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]_D+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; H 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

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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^–2mmol), ethyl bromoacetate (15.50 mg, 10.5 μL, 9.30 × 10^–2

mmol) and Na₂CO₃(18.0 mg, 1.68 × 10^–1mmol). 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; H 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^–2mmol), ethyl bromoacetate (12.0 mg, 8.00 μL, 7.20 × 10^–2mmol)

and Na₂CO₃(14.0 mg, 1.31 × 10^–2mmol). 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; H 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); C 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),

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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^–1mmol), ethyl bromoacetate (25.20 mg, 17.0 μL, 1.51 × 10^–1

mmol) and Na₂CO₃(29.0 mg, 2.74 × 10^–1mmol). 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; H

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^–1mmol), ethyl bromoacetate (32.70 mg, 22.0 μL, 1.96 × 10^–1

mmol) and Na₂CO₃(38.0 mg, 3.56 × 10^–1mmol). 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; H 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,

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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^–1mmol), ethyl bromoacetate (23.50 mg, 16.0 μL, 1.41 × 10^–1

mmol) and Na₂CO₃(27.0 mg, 2.57 × 10^–1mmol). 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); C 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^–2mmol), ethyl bromoacetate (8.18 mg, 5.50 μL, 4.90 × 10^–2mmol)

and Na₂CO₃(9.50 mg, 8.90 × 10^–2mmol). 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]_D+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; H 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,

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1751

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^–1mmol), ethyl bromoacetate (30.10 mg, 20.0 μL, 1.80 × 10^–1

mmol) and Na₂CO₃(35.0 mg, 3.27 × 10^–1mmol). 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^–2mmol), ethyl bromoacetate (11.0 mg, 8.0 μL, 6.60 × 10^–2mmol)

and Na₂CO₃(13.0 mg, 1.20 × 10^–1mmol). 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; H 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); C

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

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HETEROCYCLES, Vol. 78, No. 7, 2009

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^–2mmol), ethyl bromoacetate (5.03 mg, 3.50 μL, 3.01 × 10^–2mmol)

and Na₂CO₃(6.00 mg, 5.47 × 10^–2mmol). 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^–2mmol), ethyl bromoacetate (9.42 mg, 6.50 μL, 5.64 × 10^–2mmol)

and Na₂CO₃(11.0 mg, 1.03 × 10^–1mmol). 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; H 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); C 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

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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^–2mmol), ethyl bromoacetate (6.60 mg, 4.50 μL, 3.95 × 10^–2mmol)

and Na₂CO₃(7.60 mg, 7.19 × 10^–2mmol). 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); C 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-methylhexa-

hydro-2-thioxo-1,3,5-triazine (5a)

Prepared from 3d (70.0 mg, 1.73 × 10^–1mmol) and aqueous solutions of formaldehyde (26.0 mg, 63.0 μL,

8.67 × 10^–1mmol) and methylamine (10.80 mg, 30.0 μL, 3.47 × 10^–1mmol). 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,

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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^–1mmol) and aqueous solutions of formaldehyde (15.80 mg, 38.0

μL, 5.25 × 10^–1mmol) and methylamine (8.17 mg, 23.0 μL, 2.63 × 10^–1mmol). 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^–1mmol) 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),

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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^–1mmol) and aqueous solutions of formaldehyde (19.10 mg, 46.0

μL, 6.36 × 10^–1mmol) and methylamine (9.88 mg, 27.0 μL, 3.18 × 10^–1mmol). 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]_D+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; H 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); C 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^–1mmol) and aqueous solutions of formaldehyde (21.60 mg, 52.0

μL, 7.18 × 10^–1mmol) and methylamine (11.10 mg, 31.0 μL, 3.59 × 10^–1mmol). 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]_D–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),

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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^–1mmol) and aqueous solutions of formaldehyde (17.70 mg, 43.0 μL,

5.88 × 10^–1mmol) and methylamine (9.13 mg, 25.0 μL, 2.94 × 10^–1mmol). 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^–1mmol) and aqueous solutions of formaldehyde (16.70 mg, 40.0

μL, 5.57 × 10^–1mmol) and methylamine (6.92 mg, 20.0 μL, 2.23 × 10^–1mmol). 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]_D+360.82 (c 0.02,

CH₂Cl₂); IR (KBr): 3630, 3569, 2931, 1752, 1736, 1593, 1513, 1458, 1347, 1300, 1247, 1066, 827, 696

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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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