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Article

Synthesis of Some New Mono- and Bis-Polycyclic Aromatic Spiro and Bis-Nonspiro-β-Lactams

by
Aliasghar Jarrahpour
* and
Edris Ebrahimi
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71454, Iran
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(1), 515-531; https://doi.org/10.3390/molecules15010515
Submission received: 2 November 2009 / Revised: 3 December 2009 / Accepted: 9 December 2009 / Published: 22 January 2010
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Versions Notes

Abstract

:
Some new mono-and bis-polycyclic aromatic spiro-β-lactams and bis-non spiro-polycyclic aromatic β-lactams have been synthesized from imines derived from anthracene-9-carbaldehyde, 2-naphtaldehyde and a ketene derived from 9H-xanthene-9-carboxylic acid and phenoxyacetic acid by a [2+2] cycloaddition reaction. The cycloadducts were characterized by spectral data, including 1H-NMR, 13C-NMR, IR and elemental analyses. The configurations of some of these mono-spiro-β-lactams were established by X-ray crystal analysis.

1. Introduction

β-Lactams, being a structural unit found in the most widely used antibiotics [1], have occupied a basic position in medicinal chemistry for almost a century now. With the microbes responding to the traditional antibiotics through β-lactamases, the need for novel antibiotics prevails, making synthesis of newer β-lactams ever more important. In addition to their use as antibiotics, β-lactams are increasingly being used as synthons for other biologically important molecules [2,3,4,5,6,7,8,9,10,11]. β-Lactams have been found to act as cholesterol acyl transferase inhibitors [12], thrombin inhibitors [13], human cytomegalovirus protease inhibitors [14], matrix metalloprotease inhibitors [15], cysteine protease [16], and apoptosis inductors [17]. Spirocyclic β-lactams have attracted attention as they have been shown to be β-turn mimetics [18,19] and precursors for α,α-disubstituted β-amino acids [20]. The chartelline has a spiro-β-lactam moiety in its structure marine natural products [21]. It has been found that spiro-β-lactams act as poliovirus and human rhinovirus 3C-proteinases inhibitors [22]. These compounds are mostly synthesized by cycloaddition to an exocyclic bond. Several syntheses of spiro-β-lactams have been reported [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. Polycyclic aromatic β-lactams have shown anticancer and other biological activities [43,44,45]. Some polyaromatic β-lactams have been reported to have polyaromatic ring in part of imines that prepared by Staudinger reaction [46]. Therefore in continuation of our work on the synthesis of novel β-lactams [47,48,49], we present here for the first time the results obtained in the synthesis of mono- and bis-polyaromatic spiro and nonspiro-β-lactams using a modified Staudinger reaction.

2. Results and Discussion

Treatment of anthracene-9-carbaldehyde or 2-naphtaldehyde with different primary amines in refluxing ethanol afforded the polycyclic aromatic imines 1a–n [50,51,52,53]. These Schiff bases were then treated with 9H-xanthene-9-carboxylic acid in the presence of triethylamine and tosyl chloride to afford polycyclic aromatic spiro-β-lactams 2a–n as single diastereomers (Scheme 1). The reaction progress was monitored by TLC and the presence of a new compound was confirmed. In addition, the cycloadducts were characterized by spectral analysis. For 2a the IR spectrum showed the characteristic absorption of a β-lactam carbonyl at 1,747 cm−1. The 1H-NMR spectrum exhibited the methoxy protons as a singlet at 3.64 ppm, the β-lactam H-4 proton as a singlet at 6.29 and aromatic protons as a multiplet at 6.39–8.82. The 13C-NMR spectrum exhibited the C-3 (spiro carbon) at 64.3. The results for other polycyclic aromatic spiro-β-lactams 2a–n are shown in Table 1.
Then we decided to synthesize bis-spiro- and bis-nonspiro- polycyclic aromatic β-lactams 4a–d, 6b and 4e–h, 6a from bis-imines 3a–d and 5 [53] (Scheme 2). The structures of 4a–h and 5a–b are shown in Table 2. The cis-trans stereochemistry of 2-azetidinones 4e–h and 6a were deduced from the coupling constant of H-3 and H-4, which was calculated to be J3,4 = 4–9 Hz for the cis and J3,4 = 1–3 Hz for the trans stereoisomers.
The X-ray crystallography of 2a (Figure 1) confirmed the proposed spiro configuration at C3 [54,55,56,57,58,59]. The X-ray analysis also showed that the β-lactam ring is planar and it is perpendicular to xanthene ring. The anthracene ring has dihedral angles of 51.8° with the β-lactam ring.

3. Experimental Section

3.1. General

All needed chemicals were purchased from the Merck, Fluka or Acros chemical companies. All reagents and solvents were dried prior to use according to standard methods [60]. IR spectra were run on a Shimadzu FT-IR 8300 spectrophotometer. 1H-NMR and 13C-NMR spectra were recorded in DMSO-d6 or CDCl3 using a Bruker Avance DPX instrument (1H-NMR 250 MHz, 13C-NMR 62.9 MHz). Chemical shifts were reported in parts per million (δ) downfield from TMS. All of the coupling constants (J) are in hertz. The mass spectra were recorded on a Shimadzu GC-MS QP 1000 EX instrument. Elemental analyses were run on a Thermo Finnigan Flash EA-1112 series. Melting points were determined in open capillaries with Buchi 510 melting point apparatus. Thin-layer chromatography was carried out on silica gel F254 analytical sheets obtained from Fluka. Column chromatography was performed on Merck Kiesel gel (230–270 mesh).

3.2. General Procedure for Preparation of Schiff Bases 1a–n

A mixture of an aromatic amine (1.00 mmol) and anthracene-9-carbaldehyde or 2-naphtaldehyde (1.00 mmol) was refluxed in ethanol (20 mL) for 1–5 hours. After cooling, the pure Schiff bases were separated as crystals. Some of these were recrystallized from ethanol.
(E)-N-(Anthracen-10-ylmethlene)-4-methxybenzenamine (1a): Yellow powder crystal (yield 91%); Mp: 140–148 °C; IR (CHCl3, cm−1): 1,608 (C=N); 1H-NMR δ (ppm): 3.88 (OMe, s, 3H), 6.52–7.64 (ArH, m, 13H), 9.80 (CHN, s, 1H). Analysis calculated for C22H17NO: C, 84.86; H, 5.50; N, 4.50%. Found: C, 84.83; H, 5.55; N, 4.48%.
(E)-N-(Anthracen-10-ylmethylene)-3-methoxybenzenamine (1b): Yellow powder crystal (yield 84%); Mp: 100–102 °C; IR (CHCl3, cm−1): 1,608 (C=N); 1H-NMR δ (ppm): 3.87 (OMe, s, 3H), 6.89–8.74 (ArH, m, 13H), 9.66 (CHN, s, 1H). Analysis calculated for C22H17NO: C, 84.86; H, 5.50; N, 4.50%. Found: C, 84.83; H, 5.55; N, 4.48%.
(E)-N-(Anthracen-10-ylmethylene)-2-methoxybenzenamine (1c): Orange powder crystal (yield 76%); Mp: 94–96 °C; IR (CHCl3, cm−1): 1,620 (C=N); 1H-NMR δ (ppm): 6.73–8.75 (ArH, m, 13H), 9.66 (CHN, s, 1H). Analysis calculated for C22H17NO: C, 84.86; H, 5.50; N, 4.50%. Found: C, 84.83; H, 5.55; N, 4.48%.
(E)-N-(Anthracen-10-ylmethylene)benzenamine (1d): Yellow powder crystal (yield 76%); Mp: 102–104 °C; IR (KBr, cm−1): 1,608 (C=N); 1H-NMR δ (ppm): 6.61–8.96 (ArH, m, 14H), 9.63 (CHN, s, 1H). Analysis calculated for C21H15N: C, 89.65; H, 5.37; N, 4.98%. Found: C, 89.61; H, 5.41; N, 4.95%.
(E)-N-(Anthracen-10-ylmethylene)-4-chlorobenzenamine (1e): Yllow crystal (yield 51%); Mp: 182–184 °C; IR (KBr, cm−1): 1,623 (C=N); 1H-NMR δ (ppm): 6.64–8.72 (ArH, m, 13H), 9.61 (CHN, s, 1H). Analysis calculated for C21H14ClN: C, 79.87; H, 4.47; N, 4.44%. Found: C, 79.85; H, 4.50; N, 4.49%.
(E)-N-(Anthracen-10-ylmethylene)-3-nitrobenzenamine (1f): Orange crystal (yield 67%); Mp: 166–168 °C; IR (KBr, cm−1): 1,666 (C=N); 1H-NMR δ (ppm): 6.62–8.96 (ArH, m, 13H), 9.66 (CHN, s, 1H). Analysis calculated for C21H14N2O2: C, 77.29; H, 4.32; N, 8.58%. Found: C, 77.35; H, 4.38; N, 8.60%.
(E)-N-(Anthracen-10-ylmethylene)-2-ethylbenzenamine (1g): Yellow crystal (yield 60%); Mp: 182–184 °C; IR (CHCl3, cm−1): 1,620 (C=N); 1H-NMR δ (ppm): 1.27 (CH2, t, 2H, J = 7.5), 2.89 (CH3, q, 4H, J = 7.5), 6.82–8.80 (ArH, m, 13H), 9.55 (CHN, s, 1H). Analysis calculated for C23H19N: C, 89.28; H, 6.19; N, 4.53%. Found: C, 89.32; H, 6.25; N, 4.55%.
(E)-N-(Anthracen-10-ylmethylene)-3-bromobenzenamine (1h): Yellow crystal (yield 77%); Mp: 122–124 °C; IR (KBr, cm−1): 1,620 (C=N); 1H-NMR δ (ppm): 6.84–8.71 (ArH, m, 13H), 9.60 (CHN, s, 1H). Analysis calculated for C21H14BrN: C, 70.01; H, 3.92; N, 3.89%. Found: C, 70.11; H, 3.98; N, 3.84%.
(E)-N-(Anthracen-10-ylmethylene)-2,4-dimethoxybenzenamine (1i): Orange crystal (yield 88%); Mp: 160–162 °C; IR (CHCl3, cm−1): 1,616 (C=N); 1H-NMR δ (ppm): 3.75, 3.98 (2OMe, s, 6H), 6.51–8.73 (ArH, m, 12H), 9.92 (CHN, s, 1H). Analysis calculated for C23H19NO2: C, 80.92; H, 5.61; N, 4.10%. Found: C, 80.96; H, 5.66; N, 4.17%.
(E)-N-(Anthracen-10-ylmethylene)-3,4-dimethoxybenzenamine (1j): Orange crystal (yield 90%); Mp: 160–162 °C; IR (CHCl3, cm−1): 1,605 (C=N); 1H-NMR δ (ppm): 3.88, 3.91 (2OMe, s, 6H), 6.88–8.68 (ArH, m, 12H), 9.92 (CHN, s, 1H). Analysis calculated for C23H19NO2: C, 80.92; H, 5.61; N, 4.10%. Found: C, 80.96; H, 5.66; N, 4.17%.
(E)-N-(Anthracen-10-ylmethylene)cyclohexanamine (1k): Orange crystal (yield 92%); Mp: 132–134 °C; IR (CHCl3, cm−1): 1,639 (C=N); 1H-NMR δ (ppm): 1.34–3.56 (cyclohexyl, m, 11H), 7.41–8.43 (ArH, m, 9H), 9.34 (CHN, s, 1H). Analysis calculated for C21H21N: C, 87.76; H, 7.36; N, 4.87%. Found: C, 87.71; H, 7.33; N, 4.91%.
(E)-N-(Anthracen-10-ylmethlene)naphthalene-1-amine (1l): Yellow crystal (yield 60%); Mp: 142–144° C; IR (CHCl3, cm−1): 1,624 (C=N); 1H–NMR δ (ppm): 6.67–8.94 (Ar-H, m, 16H), 8.80 (CHN, s, 1H). Analysis calculated for C25H17N: C, 90.60; H, 5.17; N, 4.23%. Found: C, 90.66; H, 5.20; N, 4.28%.
(E)-N-(Naphthalen-2-ylmethylene)naphthalen-1-amine (1m): Green crystal (yield 78%); Mp: 129–130° C. IR (CHCl3, cm−1): 1,624 (C=N); 1H–NMR δ (ppm): 6.73–8.63 (Ar-H, m, 14H), 8.94 (CHN, s, 1H). Analysis calculated for C25H17N: C, 90.60; H, 5.17; N, 4.23%. Found: C, 90.66; H, 5.20; N, 4.28%.
(E)-4-Methoxy-N-(naphthalen-2-ylmethylene)benzenamine (1n): Silver powder crystal (yield 80%); Mp: 118–120° C; IR (CHCl3, cm−1): 1,620 (C=N); 1H-NMR δ (ppm): 3.78 (OMe, s, 3H), 6.90–8.13 (ArH, m, 11H), 8.60 (CHN, s, 1H). Analysis calculated for C18H15NO: C, 82.73; H, 5.79; N, 5.36%. Found: C, 82.75; H, 5.83; N, 5.32%.

3.3. General Procedure for Preparation of Bis-Schiff Bases 3a–d and 5

A mixture of anthracene-9-carbaldehyde (1.00 mmol) and bisamine (0.50 mmol) was refluxed in ethanol (20 mL) for (1–5) h. After cooling, the pure Schiff bases were separated as crystals. Some of these were recrystallized from ethanol.
(E)-4-(E)-4-[(E)-Anthracen-10-ylmethyleneamino)benzyl]-N-(anthracen-10-ylmethylene)benzene-amine (3a): Yellow powder (yield 96%); Mp: 216–218 °C; IR (KBr, cm−1): 1,623 (C=N); 1H-NMR δ (ppm): 4.15 (CH2, s, 2H), 6.68–9.70 (ArH, m, 26H), 10.02 (CH=N, s, 2H); Analysis calculated for C43H30N2: C, 89.86; H, 5.26; N, 4.87%. Found: C, 89.81; H, 5.22; N, 4.83%.
(E)-3-(E)-3-[(E)-Anthracen-10-ylmethyleneamino)benzyl]-N-(anthracen-10-yl-methylene)benzenenamine (3b): Yellow powder (yield 95%); Mp: 184–186 °C; IR (KBr, cm−1): 1,623 (C=N); 1H-NMR δ (ppm): 4.19 (CH2, s, 2H), 7.24–8.92 (ArH, m, 26H), 9.73 (CH=N, s, 2H); Analysis calculated for C43H30N2: C, 89.86; H, 5.26; N, 4.87%. Found: C, 89.81; H, 5.22; N, 4.83%.
(E)-N-(Anthracen-10-yl-methylene)-4-(4-[(E)-anthracen-10-ylmethyleneamino]phenoxy)benzene-amine (3c): Orange powder (yield 96%); Mp: 202–204 °C; IR (KBr, cm−1): 1,608 (C=N); 1H-NMR δ (ppm): 6.73–8.78 (ArH, m, 26H), 9.60 (CH=N, s, 2H); Analysis calculated for C42H28N2O: C, 87.47; H, 4.89; N, 4.86%. Found: C, 87.51; H, 4.95; N, 4.81%.
(E)-N-(Anthracen-10-ylmethylene)-3-(4-[(E)-anthracen-10-ylmethyleneamino]phenoxy)benzeneamine (3d): Yellow powder (yield 88%); Mp: 216–218 °C; IR (KBr, cm−1): 1,620 (C=N); 1H-NMR δ (ppm): 6.20–9.01 (ArH, m, 26H), 9.71 (CH=N, s, 2H); Analysis calculated for C42H28N2O: C, 87.47; H, 4.89; N, 4.86%. Found: C, 87.51; H, 4.95; N, 4.81%.
(N1E,N4E)-N1,N4-bis(Anthracen-10-ylmethylene)benzene-1,4-diamine (5): Yellow powder (yield 95%); Mp: > 240 °C; IR (KBr, cm−1): 1,604 (C=N); 1H-NMR δ (ppm): 7.25–8.84 (ArH, m, 22H), 9.81 (CHN, s, 2H). Analysis calculated for C36H24N2: C, 89.23; H, 4.99; N, 5.78%. Found: C, 89.28; H, 5.05; N, 5.73%.

3.4. General Procedure for the Synthesis of Polycyclic Aromatic Spiro-β-Lactams 2a–n

A mixture of Schiff base (1.00 mmol), triethylamine (5.00 mmol), 9H-xanthene-9-carboxylic acid (1.50 mmol) and tosyl chloride (1.50 mmol) in dry CH2Cl2 (15 mL) was stirred at room temperature for 24 h. Then it was washed with HCl 1N (20 mL), saturated NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated to give the product as a crystal which was then purified by recrystallization from appropriate organic solvents.
2-(Anthracen-9-yl)-1-(4-methoxyphenyl)spiro[azetidine-3,9’-xanthen]-4-one (2a): Light yellow crystals from EtOAc (yield 25%); Mp: 223–225 °C; IR (CHCl3, cm−1): 1,740 (CO β-lactam); 1H-NMR δ (ppm): 3.64 (OMe, s, 3H) 6.29 (H-4, s, 1H), 6.51–8.82 (ArH, m, 21H); 13C-NMR δ (ppm) 64.3 (OMe) 82.8 (C-3), 75.6 (C-4), 116.4–152.2 (aromatic carbon), 167.3 (CO β-lactam); GC-MS m/z = 519 [M+]; Analysis calculated for C36H25NO3: C, 83.22; H, 4.85; N, 2.70%. Found: C, 83.95; H, 4.90; N, 2.82.
2-(Anthracen-9-yl)-1-(3-methoxyphenyl)spiro[azetidine-3,9’-xanthen]-4-one (2b): Yellow crystals from EtOAc (yield 54%); Mp: 212–214 °C; IR (CHCl3, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 3.75 (OMe, s, 3H) 6.33 (H-4, s, 1H), 6.53–8.80 (ArH, m, 21H); 13C-NMR δ (ppm): 55.3 (OMe) 65.6 (C-3), 75.6 (C-4), 103.5–160.4 (aromatic carbon), 167.6 (CO β-lactam); GC-MS m/z = 519 [M+]; Analysis calculated for C36H25NO3: C, 83.22; H, 4.85; N, 2.70%. Found: C, 83.95; H, 4.90; N, 2.82%.
2-(Anthracen-9-yl)-1-(2-methoxyphenyl)spiro[azetidine-3,9’-xanthen]-4-one (2c): Light yellow crystals from EtOAc (yield 57%); Mp: 214–216 °C (dec.); IR (KBr, cm−1): 1,739 (CO β-lactam); 1H-NMR δ (ppm): 2.94 (OMe, s, 3H), 6.34 (H-4, s, 1H), 6.55–9.20 (ArH, m, 21H);13C-NMR δ (ppm): 55.4 (OMe), 66.0 (C-3), 78.5 (C-4), 112.8–152.0 (aromatic carbon), 168.0 (CO β-lactam); GC-MS m/z = 519 [M+]; Analysis calculated for C36H25NO3: C, 83.22: H, 4.85; N, 2.70%. Found: C, 83.90; H, 4.80; N, 2.81%.
2-(Anthracen-9-yl)-1-phenylspiro[azetidine-3,9’-xanthen]-4-one (2d): Light yellow crystals from EtOAc (yield 63%); Mp: 238–240 °C (dec.); IR (KBr, cm−1): 1,758 (CO β-lactam); 1H-NMR δ (ppm): 6.34 (H-4, s, 1H), 6.51–8.83 (ArH, m, 22H); 13C-NMR δ (ppm): 65.6 (C-3), 75.4 (C-4), 115.9–152.0 (aromatic carbon), 167.5 (CO β-lactam); GC-MS m/z = 489 [M+]; Analysis calculated for C35H23NO2: C, 85.87; H, 4.74; N, 2.86%. Found: C, 85.87; H, 4.74; N 2.86%.
2-(Anthracen-9-yl)-1-(4-chlorophenyl)spiro[azetidine-3,9’-xanthen]-4-one (2e): Yellow crystals from EtOAc (yield 70%); Mp: 254–256 °C (dec.); IR (KBr, cm−1): 1,743 (CO β-lactam); 1H-NMR δ (ppm): 6.30 (H-4, s, 1H), 6.52–9.06 (ArH, m, 21H); 13C-NMR δ (ppm): 66.0 (C-3), 75.5 (C-4), 116.0–151.9 (aromatic carbon), 167.4 (CO β-lactam); GC-MS m/z = 524 [M+, 35Cl], 526 [M+, 37Cl]; Analysis calculated for C35H22ClNO2: C, 80.22; H, 4.23; N 2.67%. Found: C, 80.28; H, 4.18; N, 2.53%.
2-(Anthracen-9-yl)-1-(3-nitrophenyl)spiro[azetidine-3,9’-xanthen]-4-one (2f): Yellow crystals from EtOAc (yield 40%); Mp: 212–214 °C; IR (KBr, cm−1): 1,762 (CO β-lactam); 1H-NMR δ (ppm): 5.98 (H-4, s, 1H), 6.40–9.16 (ArH, m, 21H); 13C-NMR δ (ppm): 66.4 (C-3), 75.8 (C-4), 112.4–152.1 (aromatic carbon), 169.2 (CO β-lactam); GC-MS m/z = 534 [M+]; Analysis calculated for C35H22N2O4: C, 78.64; H, 4.15; N, 5.24%. Found: C, 78.63; H, 4.20; N, 5.32%.
2-(Anthracen-9-yl)-1-(2-ethylphenyl)spiro[azetidine-3,9’-xanthen]-4-one (2g): White solid (yield 35%); Mp: 208–210 °C; IR (KBr, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 1.14 (t, 3H, Me, J = 7.1), 4.00 (CH2, q, 2H, J = 7.1), 4.92 (s, 1H, H-4), 6.30–8.74 (ArH, m, 21H); 13C-NMR δ (ppm): 15.1 (CH3), 25.8 (CH2), 64.5 (C-3), 75.1 (C-4), 115.9–152.2 (aromatic carbon), 168.1 (CO β-lactam); GC-MS m/z = 517 [M+]; Analysis calculated for C37H27NO2: C, 85.85; H, 5.26; N, 2.71%. Found: C, 85.83; H, 5.30; N, 2.76%.
2-(Anthracen-9-yl)-1-(3-bromophenyl)spiro[azetidine-3,9’-xanthen]-4-one (2h): Yellow crystals from EtOAc (yield 55%); Mp: 222–224 °C; IR (KBr, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 6.18 (H-4, s, 1H), 6.23–8.65 (ArH, m, 21H); 13C-NMR δ (ppm): 66.0 (C-3), 75.6 (C-4), 115.7–151.9 (aromatic carbon), 167.7 (CO β-lactam); GC-MS m/z = 567 [M+, 80Br], 569 [M+, 82Br]; Analysis calculated for C35H22BrNO2: C, 73.95; H, 3.90; N, 2.46%. Found: C, 73.90; H, 3.93; N, 2.51%.
2-(Anthracen-9-yl)-1-(2,4-dimethoxyphenyl)spiro[azetidine-3,9’-xanthen]-4-one (2i): Light green crystals from EtOAc (yield 69%); Mp: 180–182 °C (dec.); IR (KBr, cm−1): 1,739 (CO β-lactam); 1H-NMR δ (ppm): 2.91, 3.58 (2OMe, s, 6H) 6.16 (H-4, s, 1H), 6.17–8.18 (ArH, m, 20H); 13C-NMR δ (ppm): 55.4, 55.5 (s, 6H, 2 OMe) 65.9 (C-3), 78.1 (C-4), 100.2–158.2 (aromatic carbon), 167.7 (CO β-lactam); GC-MS m/z = 549 [M+]; Analysis calculated for C37H27NO4: C, 80.86; H, 4.95; N, 2.55%. Found: C, 80.03; H, 4.98; N, 2.83%.
2-(Anthracen-9-yl)-1-(3,4-dimethoxyphenyl)spiro[azetidine-3,9’-xanthen]-4-one (2j): Yellow solid (yield 91%); Mp: 172–174 °C; IR (KBr, cm−1): 1,743 (CO β-lactam); 1H-NMR δ (ppm): 3.69, 3.97 (2OMe, s, 6H) 6.30 (H-4, s, 1H), 6.50–8.77 (ArH, m, 20H); 13C-NMR δ (ppm): 55.9, 56.1 (2 OMe) 65.6 (C-3), 75.6 (C-4), 102.3–153.0 (aromatic carbon), 166.9 (CO β-lactam); GC-MS m/z = 549 [M+]; Analysis calculated for C37H27NO4: C, 80.86; H, 4.95; N, 2.55%. Found: C, 80.81; H, 4.97; N, 2.53%.
2-(Anthracen-9-yl)-1-cyclohexylspiro[azetidine-3,9’-xanthen]-4-one (2k): Orange crystals from EtOAc (yield 69%); Mp: 216–218 °C; IR (KBr, cm−1): 1,743 (CO β-lactam); 1H-NMR δ (ppm): 1.53, 1.75, 1.95, 2.22, 2.65, 3.81 (cyclohexyl, m, 11H) 5.96 (H-4, s, 1H), 6.36–9.19 (ArH, m, 17H); 13C-NMR δ (ppm): 24.5, 25.5, 30.0, 31.0, 56.7 (cyclohexyl) 64.5 (C-3), 72.8 (C-4), 115.9–152.4 (aromatic carbon), 169.6 (CO β-lactam); GC-MS m/z = 495 [M+]; Analysis calculated for C35H29NO2: C, 84.82; H, 5.90; N, 2.83%. Found: C, 84.81; H, 5.92; N, 2.81%.
2-(Anthracen-9-yl)-1-(naphthalen-1-yl)spiro[azetidine-3,9’-xanthen]-4-one (2l): Orange crystals from EtOAc (yield 68%); Mp: 184–186 °C (dec.); IR (CHCl3, cm−1): 1,759 (CO β-lactam); 1H-NMR δ (ppm): 6.45 (H-4, s, 1H), 6.61–9.8 (ArH, m, 24H); 13C-NMR δ (ppme) 90.3 (C-3), 74.8 (C-4), 116.7–152.1 (aromatic carbon), 168.3 (CO β-lactam); GC-MS m/z = 539 [M+]; Analysis calculated for C39H25NO2: C, 86.80; H, 4.67; N, 2.60%. Found: C, 86.52; H, 4.63; N, 2.61%.
1-(Naphthalen-1-yl)-2-(naphthalen-2-yl)spiro[azetidine-3,9’-xanthen]-4-one (2m): White solid (yield 50%); Mp: 187–189 °C; IR (KBr, cm−1): 1,758 (CO β-lactam); 1H-NMR δ (ppm) 5.73 (H-4, s, 1H), 6.50–9.00 (ArH, m, 22H); 13C-NMR δ (ppm): 62.8 (C-3), 75.8 (C-4), 116.4–152.29 (aromatic carbon), 196.3 (CO β-lactam); GC-MS m/z = 489 [M+]; Analysis calculated for C35H23NO2: C, 85.87; H, 4.74; N, 2.86%. Found: C, 85.67; H, 4.65; N, 2.79%.
1-(4-Methoxyphenyl)-2-(naphthalen-2-yl)spiro[azetidine-3,9’-xanthen]-4-one (2n): Gray solid (yield 40%); Mp: 184–186 °C; IR (CHCl3, cm−1): 1,751 (CO β-lactam); 1H-NMR δ (ppm): 3.81 (OMe, s, 3H) 5.21 (H-4, s, 1H), 6.64–8.33 (ArH, m, 19H); 13C-NMR δ (ppm): 55.5 (OMe) 64.0 (C-3), 74.6 (C-4), 113.9–151.8 (aromatic carbon), 167.0 (CO β-lactam); GC-MS m/z = 469 [M+]; Analysis calculated for C32H23NO3: C, 81.86; H, 4.94; N, 2.98%. Found: C, 81.53; H, 4.98; N, 2.83%.

3.5. General Procedure for the Synthesis of Bis-Polycyclic Aromatic Spiro and Nonspiro-β-Lactams 4a–h and 6a–b

A mixture of Schiff base (1.00 mmol), triethylamine (10.00 mmol), 9H-xanthen-9-carboxylic acid or phenoxyacetic acid (3.00 mmol) and tosyl chloride (3.00 mmol) in dry CH2Cl2 (15 mL) was stirred at room temperature for 24 h. Then it was washed with HCl 1N (20 mL), saturated NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated to give the product as a crystal which was then purified by recrystallization from suitable organic solvents.
2-(Anthracen-9-yl)-1-(4-(4-(2-(anthracen-9-yl)-4-oxospiro[azetidine-3,9’-xanthene]-1-yl)benzyl)-phenyl)spiro[azetidine-3,9’-xanthen]-4-one (4a): Orange solid (yield 92%); Mp: 162–164 °C (dec.); IR (KBr, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 3.76 (CH2, s, 2H) 6.15 (H-4, s, 2H), 6.19–8.99 (ArH, m, 42H); 13C-NMR δ (ppm): 40.8 (CH2) 65.7 (C-3), 75.4 (C-4), 115.9–152.0 (aromatic carbon), 167.3 (CO β-lactam). Analysis calculated for C71H46N2O4: C, 86.04; H, 4.68; N, 2.83%. Found: C, 86.10; H, 4.71; N, 2.80%.
2-(Anthracen-9-yl)-1-(3-(3-(2-(anthracen-9-yl)-4-oxospiro[azetidine-3,9’-xanthene]-1-yl)benzyl) phenyl)spiro[azetidine-3,9’-xanthen]-4-one (4b): Orange solid (Yield 87%); Mp: 220–222 °C (dec.); IR (KBr, cm−1): 1,758 (CO β-lactam); 1H-NMR δ (ppm): 3.78 (CH2, s, 2H,) 6.22 (H-4, s, 2H), 6.26–9.52 (ArH, m, 42H); 13C-NMR δ (ppm): 41.5 (CH2) 59.6 (C-3), 75.4 (C-4), 115.9–152.0 (aromatic carbon), 167.4 (CO β-lactam). Analysis calculated for C71H46N2O4: C, 86.04; H, 4.68; N, 2.83%. Found: C, 86.06; H, 4.70; N, 2.80%.
2-(Anthracen-9-yl)-1-(4-(4-(2-(anthracen-9-yl)-4-oxospiro[azetidine-3,9’-xanthene]-1-yl)phenoxy) phenyl)spiro[azetidine-3,9’-xanthen]-4-one (4c): Yellow solid (Yield 75%); Mp: 242–244 °C (dec.); IR (KBr, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 6.20 (H-4, s, 2H), 6.22–8.68 (ArH, m, 42H); 13C-NMR δ (ppm): 65.8 (C-3), 75.5 (C-4), 115.9–153.9 (aromatic carbon), 167.0 (CO β-lactam). Analysis calculated for C70H44N2O5: C, 84.66; H, 4.47; N, 2.82%. Found: C, 84.64; H, 4.48; N, 2.80%.
2-(Anthracen-9-yl)-1-(3-(4-(2-(anthracen-9-yl)-4-oxospiro[azetidine-3,9’-xanthene]-1-yl)phenoxy) phenyl)spiro[azetidine-3,9’-xanthen]-4-one (4d): Orange solid (Yield 85%); Mp: 140–142 °C; IR (KBr, cm−1): 1,759 (CO β-lactam); 1H-NMR δ (ppm): 6.15 (H-4, s, 2H), 6.40–8.79 (ArH, m, 42H). 13C-NMR δ (ppm): 65.8 (C-3), 75.7 (C-4), 117.5–157.4 (aromatic carbon), 167.4 (CO β-lactam). Analysis calculated for C70H44N2O5: C, 84.66; H, 4.47; N, 2.82%. Found: C, 84.63; H, 4.45; N, 2.81%.
1,1’-(4,4’-Methylenebis(4,1-phenylene))bis(4-(anthracen-9-yl)-3-phenoxyazetidin-2-one) (4e): Yellow solid (Yield 80%); Mp: 146–148 °C; IR (KBr, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 3.42 (CH2, s, 2H) 5.85 (H-4, d, 2H, J = 2.8), 6.40 (H-3, d, 2H, J = 2.8), 6.47–9.54 (ArH, m, 36H); 13C-NMR δ (ppm): 40.5 (CH2) 62.9 (C-3), 59.1 (C-4), 115.6–157.1 (aromatic carbon), 163.3 (CO β-lactam). Analysis calculated for C59H42N2O4: C, 84.06; H, 5.02; N, 3.32%. Found: C, 84.10; H, 5.08; N, 3.35%.
1,1’-(3,3’-Methylenebis(3,1-phenylene))bis(4-(anthracen-9-yl)-3-phenoxyazetidin-2-one) (4f): Orange solid (Yield 87%); Mp: 118–120 °C; IR (KBr, cm−1): 1,758 (CO β-lactam); 1H-NMR δ (ppm): 3.47 (CH2, s, 2H) 5.71 (H-4, d, 2H, J = 3.6), 6.38 (H-3, d, 2H, J = 3.6), 6.41–9.41 (ArH, m, 36H); 13C-NMR δ (ppm): 41.1 (CH2) 82.6 (C-3), 60.6 (C-4), 115.5–157.1 (aromatic carbon), 163.4 (CO β-lactam); Analysis calculated for C59H42N2O4: C, 84.06; H, 5.02; N, 3.32%. Found: C, 84.08; H, 5.05; N, 3.30%.
1,1’-(4,4’-Oxybis(4,1-phenylene))bis(4-(anthracen-9-yl)-3-phenoxyazetidin-2-one) (4g): Orange solid (Yield 90%); Mp: 126–128 °C; IR (KBr, cm−1): 1,755 (CO β-lactam); 1H-NMR δ (ppm): 5.71 (H-4, d, 2H, J = 5.1), 6.20 (H-3, d, 2H, J = 5.1), 6.36–8.78 (m, ArH, 36H);13C-NMR δ (ppm): 83.1 (C-3), 59.2 (C-4), 115.6–133.0 (aromatic carbon), 167.7 (CO β-lactam). Analysis calculated for C58H40N2O5: C, 82.45; H, 4.77; N, 3.32%. Found: C, 82.41; H, 4.79; N, 3.35%.
4-(Anthracen-9-yl)-1-(3-(4-(2-(anthracen-9-yl)-4-oxo-3-phenoxyazetidin-yl)phenoxy)phenyl)-3-phen oxyazetidin-2-one (4h): Yellow solid (Yield 95%); Mp: 118–120 °C; IR (KBr, cm−1): 1,758 (CO β-lactam); 1H-NMR δ (ppm): 5.75 (H-4, d, 2H, J = 3.8), 6.25 (H-3, d, 2H, J = 3.8), 6.42–8.79 (ArH, m, 36H); 13C-NMR δ (ppm): 83.1 (C-3), 65.4 (C-4), 107.7–157.4 (aromatic carbon), 163.5 (CO β-lactam). Analysis calculated for C58H40N2O5: C, 82.45; H, 4.77; N, 3.32%. Found: C, 82.43; H, 4.75; N, 3.30%.
1,1’-(1,4-Phenylene)bis(4-(anthracen-9-yl)-3-phenoxyazetidin-2-one) (6a): Gray solid (Yield 96%); Mp: 178–180 °C (dec.); IR (KBr, cm−1): 1,751 (CO β-lactam); 1H-NMR δ (ppm): 5.58 (H-4, d, 2H, J = 3.9), 6.30 (H-3, d, 2H, J = 3.9), 6.33–8.82 (ArH, m, 32H);13C-NMR δ (ppm): 83.0 (C-3), 59.1 (C-4), 114.6–156.8 (aromatic carbon), 163.0 (CO β-lactam). Analysis calculated for C52H36N2O4: C, 82.96; H, 4.82; N, 3.72% Found: C, 82.95; H, 4.81; N, 3.70%.
1,1’-(1,4-Phenylene)bis(2-(anthracen-9-yl)spiro[azetidine-3,9’-xanthen]-4-one) (6b): Orange solid (Yield 85%); Mp: 186–188 °C (dec.); IR (KBr, cm−1): 1,751 (CO β-lactam); 1H-NMR δ (ppm): 6.27 (H-4, s, 2H), 6.30–8.99 (ArH, m, 38H); 13C-NMR δ (ppm): 59.7 (C-3), 75.2 (C-4), 115.9–152.0 (aromatic carbon), 167.0 (CO β-lactam). Analysis calculated for C64H40N2O4: C, 85.31; H, 4.47; N, 3.11%. Found: C, 85.30; H, 4.45; N, 3.15%.

4. Conclusions

This article describes for the first time the synthesis and characterization of some examples of mono-and bis-spiro- and nonspiro-β-lactams bearing a polycyclic aromatic moiety by reaction of polycyclic aromatic imines and two ketenes derived from 9H-xanthene-9-carboxylic acid and phenoxyacetic acid. These ketenes were prepared in situ with triethylamine and p-toluenesulfonyl chloride.

Acknowledgments

The authors thank the Shiraz University Research Council for financial support (Grant No. 88-GR-SC-23).

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Sample Availability: Samples of the compounds 2a–n, 3a–d, 4a–h and 6a–b are available from authors.
Molecules 15 00515 sch001 550
Scheme 1. Synthesis of polycyclic aromatic spiro-β-lactams 2a–n.
Scheme 1. Synthesis of polycyclic aromatic spiro-β-lactams 2a–n.
Molecules 15 00515 sch001
Molecules 15 00515 sch002 550
Scheme 2. Synthesis of bis-spiro- and bis-nonspiro- polycyclic aromatic β-lactams 4a–h and 6a–b.
Scheme 2. Synthesis of bis-spiro- and bis-nonspiro- polycyclic aromatic β-lactams 4a–h and 6a–b.
Molecules 15 00515 sch002
Molecules 15 00515 g001 550
Figure 1. X-ray crystal structure of 2a.
Figure 1. X-ray crystal structure of 2a.
Molecules 15 00515 g001
Table
Table 1. Structures of spiro-β-lactams.
Table 1. Structures of spiro-β-lactams.
EntryProductYield (%) aEntryProductYield (%) a
1 Molecules 15 00515 i001
2a		256 Molecules 15 00515 i006
2f		40
2 Molecules 15 00515 i002
2b		547 Molecules 15 00515 i007
2g		35
3 Molecules 15 00515 i003
2c		518 Molecules 15 00515 i008
2h		53
4 Molecules 15 00515 i004
2d		639 Molecules 15 00515 i009
2i		70
5 Molecules 15 00515 i005
2e		7010 Molecules 15 00515 i010
2j		91
11 Molecules 15 00515 i011
2k		6913 Molecules 15 00515 i013
2m		50
12 Molecules 15 00515 i012
2l		6814 Molecules 15 00515 i014
2n		40
a Isolated yield of pure products.
Table
Table 2. Structures of bis-spiro and bis-nonspiro-β-lactams.
Table 2. Structures of bis-spiro and bis-nonspiro-β-lactams.
EntryProductYield(%)aEntryProductYield(%)a
1 Molecules 15 00515 i015
4a		926 Molecules 15 00515 i020
4f		87
2 Molecules 15 00515 i016
4b		877 Molecules 15 00515 i021
4g		90
3 Molecules 15 00515 i017
4c		968 Molecules 15 00515 i022
4h		95
4 Molecules 15 00515 i018
4d		859 Molecules 15 00515 i023
6a		96
5 Molecules 15 00515 i019
4e		8010 Molecules 15 00515 i024
6b		85
a Isolated yields of pure products.

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MDPI and ACS Style

Jarrahpour, A.; Ebrahimi, E. Synthesis of Some New Mono- and Bis-Polycyclic Aromatic Spiro and Bis-Nonspiro-β-Lactams. Molecules 2010, 15, 515-531. https://doi.org/10.3390/molecules15010515

AMA Style

Jarrahpour A, Ebrahimi E. Synthesis of Some New Mono- and Bis-Polycyclic Aromatic Spiro and Bis-Nonspiro-β-Lactams. Molecules. 2010; 15(1):515-531. https://doi.org/10.3390/molecules15010515

Chicago/Turabian Style

Jarrahpour, Aliasghar, and Edris Ebrahimi. 2010. "Synthesis of Some New Mono- and Bis-Polycyclic Aromatic Spiro and Bis-Nonspiro-β-Lactams" Molecules 15, no. 1: 515-531. https://doi.org/10.3390/molecules15010515

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