Journal of Chemistry
Volume 2019 (2019), Article ID 7496512, 7 pages
https://doi.org/10.1155/2019/7496512

Research Article

Synthesis of New Bis(spiro-β-lactams) via Interaction of Methyl 1-Bromocycloalcanecarboxylates with Zinc and N,N′-Bis(arylmethylidene)benzidines

N. F. Kirillov, E. A. Nikiforova, D. V. Baibarodskikh, T. A. Zakharova, and L. S. Govorushkin

Department of Organic Chemistry, Faculty of Chemistry, Perm State University, Perm, Russia

Correspondence should be addressed to N. F. Kirillov; kirillov@psu.ru

Received 25 July 2018; Revised 4 December 2018; Accepted 30 December 2018; Published 3 February 2019

Academic Editor: Vinod Kumar Tiwari

Copyright © 2019 N. F. Kirillov et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Interaction of the Reformatsky reagents, prepared from methyl 1-bromocyclopentane-1-carboxylate or methyl 1-bromocyclohexane-1-carboxylate, with N,N′-bis(arylmethylidene)benzidines has given rise to a set of intermediates as a result of nucleophilic addition to the C=N group of a substrate. Further intramolecular attack of the amide nitrogen atom onto the ester carbonyl group is responsible for the ring closure, which affords two series of spirocompounds: 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.4]octan-1-one) or 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones).

1. Introduction

Diverse biological activities of β-lactam derivatives still inspire the interest of synthetic organic chemists in synthesis of new compounds containing the azetidinone fragment in their structures [1–13]. The β-lactams were firstly synthesized in 1907 by H. Staudinger via [2 + 2] cycloaddition reaction of Schiff base from aniline and benzaldehyde with diphenylketene [14, 15]. Even now the Staudinger reaction is one of the most widely used method of the azetidinone ring formation, which allows to obtain its various derivatives [1, 16, 17].

Another way to prepare β-lactams is the well-known Reformatsky reaction. The first synthesis of azetidinone by this method was performed by H. Gilman and M. Speeter [18]. In the process of this reaction, the Reformatsky reagent interacts with azomethine to form a corresponding adduct able to give β-aminoesters under hydrolysis conditions or to undergo the spontaneous cyclization to form β-lactams with elimination of bromozinc alkoxide (Scheme 1) [19]:

Scheme 1

Though the Reformatsky reaction with Schiff bases has already been the subject of numerous researches [20–29], the interest in this field of organic synthesis is still significant [30–34].

Previously, we have reported that alicyclic Reformatsky reagents react with aromatic azomethynes to give the intermediates, which undergo further cyclization to form the spiro-β-lactams (Scheme 2) [35, 36].

Scheme 2

Generally, the interaction of aromatic aldehyde phenylhydrazones (except furfural phenylhydrazone) with carbocyclic Reformatsky reagents afforded various spiroazetidinone derivatives (3-aryl-2-phenylaminospiro[3.5]nonan-1-ones), but not the pyrazolone ones (Scheme 3). Formation of the azetidinones in this case occurs despite the fact that the five-membered ring formation is energetically more favorable if compared with the four-membered ring formation [37].

Scheme 3

In our previous study, we have shown that the Reformatsky reagents derived from methyl 1-bromocycloalkanecarboxylates react with the aromatic aldehyde azines to form, as in the previous cases, bis(spiroazetidinones) [35].

The embedding of the spirofragments into the structure of the compound might result in the significant, often unpredictable, changes in the biological activity; for instance, some spiro-β-lactams [16, 38–48] and compounds with two spiroazetidinones fragments [2, 49] were described as compounds with different types of biological activity. With an aim to synthesize new biologically active compounds, we have studied the interaction of methyl 1-bromocycloalkanecarboxylates 1-2 with N,N′-bis(arylmethylidene)benzidines (3a–k) in presence of zinc.

2. Experimental

2.1. General

The IR spectra were recorded on a PerkinElmer Spectrum Two FTIR spectrometer using Nujol films of samples. The ¹H-NMR, ¹³C-NMR, and ¹⁹F-NMR spectra were obtained on a Bruker Avance III HD 400 instrument (400 MHz (¹H), 100 MHz (¹³C), and 376 MHz (¹⁹F)) in CDCl₃ with hexamethyldisiloxane (HMDS) (¹H) or the solvent peak (¹³C) or PhCF₃ (¹⁹F) as an internal standard. Elemental analysis was performed by the vario MICRO cube elemental analyzer. Melting points were measured with a MP-70 Mettler Toledo instrument.

2.2. General Procedure for the Bis(spiroazetidinones) 6 and 7 Synthesis

The mixture of zinc (3.0 g, 46 mmol), methyl 1-bromocycloalkanecarboxylate (12 mmol), HgCl₂ (5 mg), and N,N′-bis(arylmethylidene)benzidine 3 (5 mmol) in dry toluene (20 mL) with 2 mL of HMPA was heated for 4 h under reflux and then cooled down, decanted from the zinc excess, and treated with 5% acetic acid. Organic layer was separated, and the aqueous layer was twice extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and then concentrated. The residue was purified by the recrystallization from p-xylene to give the reaction products 6a–i and 7a–k as white or Slightly colored Solids.

2.2.1. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-phenyl-2-azaspiro[3.4]octan-1-one) (6a)

Yield: 1.88 g (68%), m.p. 296–299°C. IR (ν, cm⁻¹): 1729 (CO). ¹H-NMR (δ, ppm): 1.20–2.29 m [16H, 2 (CH₂)₄], 4.89 s (2H, 2 CH), 7.22–7.37 m (10H, 2 Ph), 7.33 d, and 7.40 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.33, 25.70, 28.99, 35.05, and 66.44 (Ccyclopentane); 67.62 (CH); 117.76, 126.88, 127.41, 127.80, 128.38, 134.83, 136.31, and 137.07 (CAr); 171.81 (CO). Anal. Calc. for C₃₈H₃₆N₂O₂: C, 82.58; H, 6.57; and N, 5.07. Found: C, 82.40; H, 6.67; and N, 4.99.

2.2.2. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(p-tolyl)-2-azaspiro[3.4]octan-1-one) (6b)

Yield: 2.44 g (84%), m.p. 234–236°C. IR (ν, cm⁻¹): 1737 (CO). ¹H-NMR (δ, ppm): 1.21–2.28 m [16H, 2 (CH₂)₄], 2.36 s (6H, 2 Me), 4.86 s (2H, 2 CH), 7.11 d, 7.17 d [8H, 2 (4-MeC₆H₄), J = 8.0 Hz], 7.34 d, and 7.39 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 21.26 (Me), 25.32, 25.67, 28.94, 34.97, and 66.27 (Ccyclopentane); 67.50 (CH); 117.72, 126.78, 127.31, 129.18, 129.66, 133.16, 137.07, and 138.08 (CAr); 171.85 (CO). Anal. Calc. for C₄₀H₄₀N₂O₂: C, 82.72; H, 6.94; and N, 4.82. Found: C, 82.89; H, 7.03; and N, 4.73.

2.2.3. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-methoxyphenyl)-2-azaspiro[3.4]octan-1-one) (6c)

Yield: 1.81 g (59%), m.p. 284–286°C. IR (ν, cm⁻¹): 1737 (CO). ¹H-NMR (δ, ppm): 1.19–2.26 m [16H, 2 (CH₂)₄], 3.80 s (6H, 2 MeO), 4.84 s (2H, 2 CH), 6.90 d, 7.15 d [8H, 2 (4-MeOC₆H₄), J = 8.8 Hz] 7.33 d, and 7.40 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.36, 25.71, 28.70, 34.98, and 67.37 (Ccyclopentane); 55.41 (MeO) and 66.39 (CH); 117.78, 127.37, 128.10, 129.06, 134.82, 135.88, 137.10, and 159.74 (CAr); 171.93 (CO). Anal. Calc. for C₄₀H₄₀N₂O₄: C, 78.40; H, 6.58; and N, 4.57. Found: C, 78.48; H, 6.42; and N, 4.65.

2.2.4. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(3,4-dimethoxyphenyl)-2-azaspiro[3.4]octan-1-one) (6d)

Yield: 2.25 g (67%), m.p. 248–250°C. IR (ν, cm⁻¹): 1733 (CO). ¹H-NMR (δ, ppm): 1.24–2.26 m [16H, 2 (CH₂)₄], 3.80 s (6H, 2 MeO), 3.87 s (6H, 2 MeO), 4.82 s (2H, 2 CH), 6.70 d (J 2.0 Hz), 6.79 dd (J = 8.4 Hz, J = 2.0 Hz), 6.86 d (J = 8.4 Hz) [6H, 2 (3,4-MeO)₂C₆H₃)], 7.33 d, and 7.40 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.48, 25.75, 28.99, 35.04, and 67.65 (Ccyclopentane); 56.08 (MeO), 56.22 (MeO), and 66.40 (CH); 109.98, 111.74, 117.77, 119.46, 127.33, 128.74, 135.85, 137.12, 149.24, and 149.62 (CAr); 171.98 (CO). Anal. Calc. for C₄₂H₄₄N₂O₄: C, 74.98; H, 6.59; and N, 4.16. Found: C, 75.23; H, 6.42; and N, 4.31.

2.2.5. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(benzo[d][1,3]dioxol-5-yl)-2-azaspiro[3.4]octan-1-one) (6e)

Yield: 2.02 g (63%), m.p. 289–292°C. IR (ν, cm⁻¹): 1732 (CO). ¹H-NMR (δ, ppm): 1.25–2.30 m [16H, 2 (CH₂)₄], 4.80 s (2H, 2 CH), 5.96 dd (4H, 2 OCH₂O, J = 4.4 Hz, J = 1.6 Hz), 6.69 d, 6.71 dd, 6.80 d [6H, 2 (3,4-OCH₂OC₆H₃), J = 8.0 Hz, J = 1.6 Hz], 7,33 d, and 7.41 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.44, 25.72, 28.94, 35.01, and 67.50, (Ccyclopentane); 66.46 (CH); 101.43 (OCH₂O); 107.08, 108.76, 117.74, 120.44, 127.41, 130.18, 135.94, 137.00, 147.79, and 148.42 (CAr); 171.80 (CO). Anal. Calc. for C₄₀H₃₆N₂O₆: C, 74.98; H, 5.66; and N, 4.37. Found: C, 75.14; H, 5.48; and N, 4.31.

2.2.6. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-fluorophenyl)-2-azaspiro[3.4]octan-1-one) (6f)

Yield: 1.74 g (59%), m.p. 298–300°C. IR (ν, cm⁻¹): 1740 (CO). ¹H-NMR (δ, ppm): 1.16–2.28 m [16H, 2 (CH₂)₄], 4.88 s (2H, 2 CH), 7.07 t, 7.21 t [8H, 2 (4-FC₆H₄), J = 8.4 Hz] 7.31 d, and 7.41 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.29, 25.67, 29.00, 34.96, and 66.49 (Ccyclopentane); 66.94 (CH); 116.00, 116.22, 117.73, 127.46, 127.48, 128.49, 129.07, 135.98, 136.01, 136.91, 161.54, and 164.00 (CAr); 171.63 (CO). ¹⁹F-NMR (δ, ppm): −114.59. Anal. Calc. for C₃₈H₃₄F₂N₂O₂: C, 77.53; H, 5.82; and N, 4.76. Found: C, 77.71; H, 5.92; and N, 4.59.

2.2.7. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-chlorophenyl)-2-azaspiro[3.4]octan-1-one) (6)

Yield: 1.68 g (54%), m.p. 274–276°C. IR (ν, cm⁻¹): 1746 (CO). ¹H-NMR (δ, ppm): 1.17–2.30 m [16H, 2 (CH₂)₄], 4.87 s (2H, 2 CH), 7.17 d, 7.30 d [8H, 2 (4-ClC₆H₄), J = 8.8 Hz], 7.35 d, and 7.41 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.28, 25.64, 29.01, 34.96, and 66.53 (Ccyclopentane); 66.90 (CH); 117.69, 127.47, 128.22, 129.32, 134.30, 134.89, and 136.03, 136.84 (CAr); 171.48 (CO). Anal. Calc. for C₃₈H₃₄Cl₂N₂O₂: C, 73.43; H, 5.51; Cl, 11.41; and N, 4.51. Found: C, 73.21; H, 5.34; Cl, 11.59; and N, 4.33.

2.2.8. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(2,4-dichlorophenyl)-2-azaspiro[3.4]octan-1-one) (6h)

Yield: 2.31 g (67%), m.p. 264–267°C. IR (ν, cm⁻¹): 1743 (CO). ¹H-NMR (δ, ppm): 1.11–2.35 m [16H, 2 (CH₂)₄], 5.31 s (2H, 2 CH), 7.10 d (J = 8.4 Hz), 7.21 dd (J = 8.4 Hz, J = 2.0 Hz), 7.49 d (J = 2.0 Hz), [6H, 2 (2,4-Cl₂C₆H₃)], 7,30 d, and 7.44 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.89, 26.07, 29, 59, 34.37, and 66.19 (Ccyclopentane); 63.18 (CH); 117.65, 127.60, 127.81, 128.80, 129.95, 132.81, 134.02, 134.60, 136.14, and 136.68 (CAr); 171.91 (CO). Anal. Calc. for C₃₈H₃₂Cl₄N₂O₂: C, 66.10; H, 4.67; Cl, 20.54; and N, 4.06. Found: C, 66.23; H, 4.83; Cl, 20.22; and N, 4.01.

2.2.9. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-(dimethylamino)phenyl)-2-azaspiro[3.4]octan-1-one) (6i)

Yield: 2.52 g (79%), m.p. 265–268°C. IR (ν, cm⁻¹): 1738 (CO). ¹H-NMR (δ, ppm): 1.25–2.25 m [16H, 2 (CH₂)₄], 2.97 s (12H, 2 Me₂N), 4.81 s (2H, 2 CH), 6.79 b, 7.10 d [8H, 2 (4-Me₂NC₆H₄), J = 8.4 Hz], 7.33 d, and 7.38 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 25.45, 25.75, 29.00, 35.00, and 66.38 (Ccyclopentane); 41.03 (Me), 41.19 (Me), and 67.65 (CH); 113.65, 117.82, 127.33, 127.98, 135.80, and 137.21 (CAr); 172.14 (CO). Anal. Calc. for C₄₂H₄₆N₄O₂: C, 78.96; H, 7.26; and N, 8.77. Found: C, 79.17; H, 7.39; and N, 8.58.

2.2.10. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-phenyl-2-azaspiro[3.5]nonan-1-one) (7a)

Yield: 2.18 g (75%), m.p. 312–314°C. IR (ν, cm⁻¹): 1730 (CO). ¹H-NMR (δ, ppm): 1.08–2.15 m [20H, 2 (CH₂)₅], 4.79 s (2H, 2 CH), 7.28–7.35 m (10H, 2 Ph), 7.37 d, and 7.42 d (8H, biphenyl, J = 8.2 Hz). ¹³C-NMR (δ, ppm): 21.99, 22.31, 25,11, 27.50, 33.40, and 59.75 (Ccyclohexane); 66.44 (CH); 117.43, 127.02, 127.08, 127.96, 128.42, 135.16, 135.60, and 136.84 (CAr); 171.16 (CO). Anal. Calc. for C₄₀H₄₀N₂O₂: C, 82.72; H, 6.94; and N, 4.82. Found: C, 82.61; H, 7.08; and N, 4.63.

2.2.11. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(p-tolyl)-2-azaspiro[3.5]nonan-1-one) (7b)

Yield: 2.56 g (84%), m.p. 316–319°C. IR (ν, cm⁻¹): 1732 (CO). ¹H-NMR (δ, ppm): 1.02–2.15 m [20H, 2 (CH₂)₅], 2.35 s (6H, 2 Me), 4.74 s (2H, 2 CH), 7.49 s [8H, 2 (4-MeC₆H₄)], 7.31 d, and 7.39 d (8H, biphenyl, J = 8.4 Hz). ¹³C-NMR (δ, ppm): 20.98 (Me); 22.02, 23.31, 25.12, 27.46, 33.36, and 59.63 (Ccyclohexane); 66.32 (CH); 117.44, 126.95, 127.02, 129.12, 132.05, 135.53, 136.88, and 137.71 (CAr); 171.29 (CO). Anal. Calc. for C₄₂H₄₄N₂O₂: C, 82.86; H, 7.28; and N, 4.60. Found: C, 82.59; H, 7.17; and N, 4.69.

2.2.12. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-methoxyphenyl)-2-azaspiro[3.5]nonan-1-one) (7c)

Yield: 2.60 g (81%), m.p. 306–308°C. IR (ν, cm⁻¹): 1729 (CO). ¹H-NMR (δ, ppm): 1.00–2.10 m [20H, 2 (CH₂)₅], 3.80 s (6H, 2 MeO), 4.73 s (2H, 2 CH), 6.89 d, 7.20 d [8H, 2 (4-MeOC₆H₄), J = 8.4 Hz], 7.32 d, and 7.39 d (8H, biphenyl, J = 8.4 Hz). ¹³C-NMR (δ, ppm): 22.00, 23.31, 25.12, 27.42, 33.29, and 59.66 (Ccyclohexane); 55.09 (MeO); 66.07 (CH); 113.91, 125.62, 127.04, 128.19, 129.44, 135.54, 136.88, and 159.37 (CAr); 171.30 (CO). Anal. Calc. for C₄₂H₄₄N₂O₄: C, 78.72; H, 6.92; and N, 4.37. Found: C, 78.86; H, 7.04; and N, 4.22.

2.2.13. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(3,4-dimethoxyphenyl)-2-azaspiro[3.5]nonan-1-one) (7d)

Yield: 2.66 g (76%), m.p. 234–236°C. IR (ν, cm⁻¹): 1729 (CO). ¹H-NMR (δ, ppm): 1.02–2.11 m [20H, 2 (CH₂)₅], 3.78 s (6H, 2 MeO), 3.85 s (6H, 2 MeO), 4.69 s (2H, CH), 6.73 s, 6.82 d, 6.83 d [6H, 2 (3,4-(MeO)₂C₆H₃), J = 8.4 Hz], 7.30 d, and 7.37 d (8H, biphenyl, J = 8.4 Hz). ¹³C-NMR (δ, ppm): 22.36, 23.58, 25.37, 27.69, 33.59, and 59.96 (Ccyclohexane); 56.02 (MeO); 56.19 (MeO); 66.59 (CH); 111.48, 117.69, 119.89, 127.24, 127.80, 128.97, 135.77, 137.16, 149.12, and 149.30 (CAr); 171.61 (CO). Anal. Calc. for C₄₄H₄₈N₂O₆: C, 75.40; H, 6.90; and N, 4.00. Found: C, 75.66; H, 7.01; and N, 4.18.

2.2.14. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(benzo[d][1,3]dioxol-5-yl)-2-azaspiro[3.5]nonan-1-one) (7e)

Yield: 2.57 g (77%), m.p. 257–260°C. IR (ν, cm⁻¹): 1729 (CO). ¹H-NMR (δ, ppm): 1.09–2.10 m [20H, 2 (CH₂)₅], 4.68 s (2H, 2 CH), 5.97 s (4H, 2 OCH₂O), 6.74 s, 6.76 d, 6.80 d [6H, 2 (3,4-OCH₂OC₆H₃), J = 8.4 Hz], 7.32 d, and 7.41 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 22.40, 23.62, 25.45, 27.71, 33.65, and 60.02 (Ccyclohexane); 66.61 (CH); 101.55 (OCH₂O); 107.14, 108.88, 117.78, 120.48, 127.47, 130.17, 136.04, 137.22, 147.75, and 148.40 (CAr); 171.77 (CO). Anal. Calc. for C₄₂H₄₀N₂O₆: C, 75.43; H, 6.03; and N, 4.19. Found: C, 75.70; H, 5.96; and N, 4.31.

2.2.15. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-fluorophenyl)-2-azaspiro [3.5]nonan-1-one) (7f)

Yield: 2.25 g (73%), m.p. 284–286°C. IR (ν, cm⁻¹): 1729 (CO). ¹H-NMR (δ, ppm): 1.02–2.12 m [20H, 2 (CH₂)₅], 4.76 s (2H, 2 CH), 7.03–7.08 m, 7.22–7.27 m [8H, 2 (4-FC₆H₄)], 7.29 d, and 7.40 d (8H, biphenyl, J = 8.6 Hz). ¹³C-NMR (δ, ppm): 22.00, 23.29, 25,05, 27.48, 33.31, and 59.79 (Ccyclohexane); 65.76 (CH); 115.41, 115.62, 117.40, 127.12, 127.14, 128.57, 128.65, 135.63, 135.66, 136.68, 161.19, and 163.65 (CAr); 170.97 (CO). ¹⁹F-NMR (δ, ppm): −114.76. Anal. Calc. for C₄₀H₃₈F₂N₂O₂: C, 77.90; H, 6.21; and N, 4.54. Found: C, 78.14; H, 6.40; and N, 4.68.

2.2.16. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-chlorophenyl)-2-azaspiro [3.5]nonan-1-one) (7)

Yield: 2.34 g (72%), m.p. 318–320°C. IR (ν, cm⁻¹): 1743 (CO). ¹H-NMR (δ, ppm): 1.03–2.13 m [20H, 2 (CH₂)₅], 4.74 s (2H, 2 CH), 7.22 d, 7.29 d [8H, 2 (4-ClC₆H₄), J = 8.8 Hz], 7.34 d, and 7.40 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 22.04, 23.30, 25.03, 27.52, 33.34, and 59.92 (Ccyclohexane); 65.76 (CH); 117.36, 127.14, 128.33, 128.74, 133.78, 133.90, 135.67, and 136.62 (CAr); 170.84 (CO). Anal. Calc. for C₄₀H₃₈Cl₂N₂O₂: C, 73.95; H, 5.90; Cl, 10.91; and N, 4.31. Found: C, 74.11; H, 5.79; Cl, 11.13; and N, 4.18.

2.2.17. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(2,4-dichlorophenyl)-2-azaspiro [3.5]nonan-1-one) (7h)

Yield: 3.59 g (82%), m.p. 291–293°C. IR (ν, cm⁻¹): 1742 (CO). ¹H-NMR (δ, ppm): 1.08–2.23 m [20H, 2 (CH₂)₅], 5.12 s (2H, 2 CH), 7.12 d (J = 8.4 Hz), 7.19 dd (J = 8.4 Hz, J = 2.0 Hz), 7.49 d (J = 2.0 Hz) [6H, 2 (2,4-Cl₂C₆H₃)], 7.30 d, and 7.45 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 22.90, 23.54, 25.48, 28.20, 33.63, and 60.71 (Ccyclohexane); 62.61 (CH); 117.59, 127.48, 127.56, 129.38, 129.96, 132.08, 133.90, 134.54, 136.08, and 136.77 (CAr); 171.16 (CO). Anal. Calc. for C₄₀H₃₆Cl₄N₂O₂: C, 66.86; H, 5.05; Cl, 19.73; and N, 3.90. Found: C, 66.98; H, 4.89; Cl, 19.51; and N, 4.02.

2.2.18. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-(dimethylamino)phenyl)-2-azaspiro[3.5]nonan-1-one) (7i)

Yield: 2.60 g (78%), m.p. 273–276°C. IR (ν, cm⁻¹): 1729 (CO). ¹H-NMR (δ, ppm): 1.10–2.04 m [20H, 2 (CH₂)₅], 2.95 s (12H, 2 Me₂N), 4.69 s, (2H, 2 CH), 6.69 d, 7.13 d [8H, 2 (4-Me₂NC₆H₄), J = 8.8 Hz], 7.33 d, and 7.38 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 22.35, 23.64, 25.51, 27.74, 33.59, and 59.90 (Ccyclohexane); 40.52 (Me), 66.67 (CH); 112.38, 117.82, 122.56, 127.29, 128.24, 135.76, and 137.37, 150.44 (CAr); 171.93 (CO). Anal. Calc. for C₄₄H₅₀N₄O₂: C, 79.24; H, 7.56; and N, 8.40. Found: C, 79.48; H, 7.42; and N, 8.29.

2.2.19. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(3-bromophenyl)-2-azaspiro [3.5]nonan-1-one) (7j)

Yield: 2.55 g (69%), m.p. 340–341°C. IR (ν, cm⁻¹): 1745 (CO). ¹H-NMR (δ, ppm): 1.08–2.13 m [20H, 2 (CH₂)₅], 4.70 s (2H, 2 CH), 7.38 s, 7.42 t, 7.49 d, 7.46 d [8H, 2 (3-BrC₆H₄), J = 7.2 Hz], 7.29 d, and 7.42 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 22.42, 23.62, 25.36, 27.93, 33.72, and 60.37 (Ccyclohexane); 66.04 (CH); 117.66, 123.01, 125.85, 127.51, 130.29, 130.36, 131.54, 136.04, 136.91, and 138.10 (CAr); 171.10 (CO). Anal. Calc. for C₄₀H₃₈Br₂N₂O₂: C, 65.05; H, 5.19; Br, 21.64; and N, 3.79. Found: C, 65.22; H, 5.02; Br, 21.32; and N, 3.66.

2.2.20. 2,2′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(4-bromophenyl)-2-azaspiro [3.5]nonan-1-one) (7k)

Yield: 2.81 g (76%), m.p. 322–325°C. IR (ν, cm⁻¹): 1744 (CO). ¹H-NMR (δ, ppm): 1.05–2.11 m [20H, 2 (CH₂)₅], 4.72 s (2H, 2 CH), 7.15 d, 7.28 d [8H, 2 (4-BrC₆H₄), J = 8.4 Hz], 7.40 d, and 7.49 d (8H, biphenyl, J = 8.8 Hz). ¹³C-NMR (δ, ppm): 22.38, 23.63, 25.36, 27.87, 33.67, and 60.22 (Ccyclohexane); 66.15 (CH); 117.69, 122.30, 127.48, 128.98, 132.02, 134.65, 136.01, and 136.93 (CAr); 171.16 (CO). Anal. Calc. for C₄₀H₃₈Br₂N₂O₂: C, 65.05; H, 5.19; Br, 21.64; and N, 3.79. Found: C, 65.30; H, 5.24; Br, 21.41; and N, 3.88.

3. Results and Discussion

There have been established that the Reformatsky reagents, prepared from α-bromoesters (1 or 2) and zinc, react with bis(azomethynes) (3a–k) via addition to the C=N bond of the substrate molecule to yield the intermediates 4a–i or 5a–k (Scheme 4), which further through spontaneous cyclization followed by elimination of bromozincmethylate has given rise to two groups of spirofused compounds: 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.4]octan-1-one) (6a–i) and 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones) (7a–k).

Scheme 4

The synthesized compounds (6a–i and 7a–k) were obtained in 54–84% yields as white or slightly colored (light yellow or beige) solids which melt with decomposition. In all cases, compounds containing a cyclohexane ring were obtained with better yield than the analogous compounds with a cyclopentane ring. This is probably due to the fact that the spirostructure, consisting of four-membered and five-membered cycles, is more strained if compared with the spirostructure, consisting of four-membered and six-membered cycles. Analogous results were observed in the synthesis of similar spiro-β-lactams [50] and in the synthesis of some carbocyclic spirosystems [51]. The influence of a substituent in the benzene ring of the arylmethylidene moiety is not clearly visible probably due to the fact that the first stage of the reaction (nucleophilic addition of the Reformatsky reagent) is promoted by electron-withdrawing substituents which increase a partial positive charge on the carbon atom of the bis(azomethyne) C=N group, while as the second stage (nucleophilic attack of the nitrogen atom on the carbonyl carbon atom leading to cyclization) is promoted by electron-donating substituents, which increase the nucleophilicity of the nitrogen atom in the intermediates (4 and 5).

The structure of bis(spiroazetidinones) (6a–i and 7a–k) was confirmed by elemental analyses and IR and ¹H-NMR, ¹³C-NMR, and ¹⁹F-NMR (6f and 7f) NMR spectra. The IR spectra of 6a–i and 7a–k contain the absorption bands typical for stretching vibrations of β-lactam carbonyl groups (1746–1729 cm⁻¹). The presence of the only one set of signals in the ¹H-NMR spectra of 6a–i and 7a–k (CDCl₃) indicates that, in solution, these compounds exist as a single diastereoisomer. A. Jarrahpour et al. have also reported about presence of only one set of signals in the ¹H-NMR spectra of bis(spiroazetidinones) they obtained [49]. The most characteristic feature of the ¹H-NMR spectra is the presence of singlet signals in the region δ 4.68–5.31 ppm corresponding to protons of the CH group of the lactam cycle. The most characteristic feature of the ¹³C-NMR spectra are signals of spirocarbon atoms (66.19–67.65 ppm for 6 and 59.63–60.71 for 7), carbon atoms of CH groups of the lactam cycle (62.61–67.65 ppm), and carbonyl carbon atoms (171.10–171.98 ppm).

Study of the antinociceptive activity of the synthesized compounds 7c–h with the help of the hot-plate test [52] has demonstrated that these compounds exhibit an activity greater than that of metamizole sodium, but less than that of ortophen. Antinociceptive activity study was carried out by R. R. Makhmudov, PhD, the associate professor, the head of the Research Laboratory of Biologically Active Compounds of PSU.

4. Conclusion

The carbocyclic Reformatsky reagents (1 and 2) interact with bis(arylmethylidene)benzidines (3) with formation of 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.4]octan-1-ones) 6 and 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones) 7. Compounds 7c–h have been found to exhibit antinociceptive activity.

Data Availability

The NMR spectra and elemental analysis data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

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