4’-Ethyl 1,2-dimethyl 1’,5-dibenzyl-4,4-dicyano-2’-oxo-5’-phenyl-1’,2’,4a,5-tetrahydro-4H-spiro[benzo[4,5]imidazo[1,2-a]pyridine-3,3’-pyrrole]-1,2,4’-tricarboxylate

Abstract

The 1,4-dipolar cycloaddition of the ylidene derivative of 1H-pyrrole-2,3-dione to a dipole generated in situ from 1-benzylbenzimidazole and dimethyl acetylenedicarboxylate proceeds via the exocyclic multiple bond of the ylidene derivative and affords a mixture of diastereomeric spiro[benzo[4,5]imidazo[1,2-a]pyridine-3,3’-pyrroles], which slowly epimerized in a solution.

1. Introduction

The utility of 1,4-dipolar cycloadditions for synthesizing cyclic compounds is well-documented. Zwitterionic 1,4-dipoles, which are readily accessible, have been widely employed for this purpose, providing efficient routes to various carbo- and heterocycles [1,2,3,4,5,6].

Our research has long focused on the chemistry of 1H-pyrrole-2,3-diones and their derivatives [7,8]. These compounds are highly reactive substrates, featuring at least three dipolarophilic sites that enable diverse reactivity in dipolar cycloadditions. For instance, 1H-pyrrole-2,3-diones react with 1,4-dipoles derived from activated acetylenes and pyridine to afford diastereomeric spiro[pyrido[2,1-b][1,3]oxazine-2,3’-pyrroles] (Scheme 1) [9], which exist in a rapid equilibrium in solution. This rapid epimerization is a characteristic feature of other similar spiropyrido[2,1-b][1,3]oxazines and related spirocyclic quinolizines [8]. To further explore the scope of this chemistry, we herein report the previously unknown reaction of an ylidene derivative of 1H-pyrrole-2,3-dione with a 1,4-dipole generated in situ from DMAD and 1-benzylbenzimidazole, including an evaluation of the epimerization tendency of the resulting product.

2. Results and Discussion

In this work, we employed the Knoevenagel condensation product of 1,5-diphenyl-4-ethoxycarbonyl-1H-pyrrole-2,3-dione with malononitrile, namely, 3-ylidenepyrrol-2-one 1, as a dipolarophile (Scheme 2). The 1,4-dipolar cycloadditions of this compound have not been previously studied.

We carried out the three-component reaction of 3-ylidenepyrrole-2-one 1 with DMAD and 1-benzylbenzimidazole in CHCl₃ at room temperature and isolated the spirocyclic [4+2] cycloadduct 2 as a diastereomeric mixture in 53% yield (Scheme 3). Notably, only cycloaddition product 2 at the exocyclic multiple bond was detected in the reaction mixture by LC-MS, while isomeric products were observed only in trace amounts.

The structure of compound 2 was unambiguously confirmed by single-crystal X-ray diffraction analysis (CCDC 2512081) (Figure 1). The crystal exclusively contains the R,R-diastereomer as a racemate. Due to the potential for epimerization in solution [8], the relative configurations of the chiral centers are not assigned in the structural schemes despite being determined by X-ray diffraction. Both diastereomers coexist in the solution, but the equilibrium can shift toward the more stable R,R-form upon crystallization, consistent with the epimerization tendency of such compounds. One of the stabilizing factors may be the intramolecular hydrogen bond involving the ethoxycarbonyl group: C23–H23⋯O3 (d(H⋯O) = 2.288 Å, d(C⋯O) = 3.054 (3) Å, angle C–H–O = 134.4°). For the R,S-diastereomer, a weaker intramolecular hydrogen bond involving the lactam group (C23–H23⋯O1) is expected. Indeed, similar structures derived from isatylidenes, benzylbenzimidazole, and acetylenedicarboxylates crystallize as the opposite diastereomer, where analogous C–H⋯O (lactam) bonds are observed with less favorable geometric parameters (d(H⋯O) = 2.38–2.78 Å, angle 95–125°) [9].

¹H NMR analysis (in CDCl₃) of isolated compound 2 showed a diastereomeric ratio (dr) of ~3.7:1 determined from the well-separated methyl groups of the ethoxycarbonyl substituent (Figure 2). We have previously shown that structurally related compound 3, obtained from isatylidene, pyridine, and DMAD, undergoes rapid epimerization in solution [8]. As a result, its apparent dr was dependent on the solvent used for NMR spectroscopy (dr ~9:1 in CDCl₃ vs. ~1.5:1 in DMSO-d₆). When the spectrum of compound 2 was recorded in DMSO-d₆, the dr value remained approximately unchanged (~4:1). However, when the spectrum was recorded in DMSO-d₆ 30 min after sample dissolution, the dr changed slightly to 3.7:1. This indicates that epimerization in solution does occur but significantly more slowly than for compound 3, which is likely due to the replacement of the pyridine moiety with a benzimidazole.

3. Materials and Methods

3.1. General Information

¹H and ¹³C NMR spectra (Supplementary Materials) were acquired on a Bruker Avance III 400 HD spectrometer (Faellanden, Switzerland) (at 400 and 100 MHz, respectively) in CDCl₃ using the solvent residual signal (CDCl₃: δ_H = 7.26 ppm, δ_C = 77.16 ppm) as an internal standard. IR spectra were recorded on a Perkin Elmer Spectrum Two Spectrometer (Shelton, CT, USA) as mulls in mineral oil. Melting points were measured on a Mettler Toledo MP70 Melting Point apparatus (Schwerzenbach, Switzerland). Elemental analysis was carried out on a Vario MICRO Cube analyzer (Langenselbold, Germany). TLC was performed on Silica gel 60 F₂₅₄ (Merck, Darmstadt, Germany) plates; spots were visualized with UV light (254 nm). The single crystal X-ray analysis of compound 2 was performed on an Xcalibur Ruby diffractometer (Agilent Technologies, Wroclaw, Poland). The empirical absorption correction was introduced by multi-scan method using SCALE3 ABSPACK algorithm [10]. Using OLEX2 [11], the structure was solved with the SHELXS [12] program and refined by the full-matrix least-squares minimization in the anisotropic approximation for all non-hydrogen atoms with the SHELXL [13] program. Hydrogen atoms were positioned geometrically and refined using a riding model. The disordered ethyl group was modeled using SAME, DELU, and SIMU restraints. 3-Ylidenepyrrol-2-one was obtained according to the reported procedure [7]. All solvents and reagents were purchased from commercial vendors and used as received.

3.2. 4’-Ethyl 1,2-dimethyl (3S*,4aR*)-1’,5-dibenzyl-4,4-dicyano-2’-oxo-5’-phenyl-1’,2’,4a,5-tetrahydro-4H-spiro[benzo[4,5]imidazo[1,2-a]pyridine-3,3’-pyrrole]-1,2,4’-tricarboxylate 2

A glass flask was charged with 3-ylidenepyrrol-2-one 1 (383 mg, 1 mmol), DMAD (147 µL, 1.2 mmol), and anhydrous chloroform (10 mL). 1-Benzylbenzimidazole (249 mg, 1.2 mmol) was added to the resulted solution, and the reaction mixture was stirred at RT for 2 h in the closed flask. The solvent was evaporated under reduced pressure. The residue was purified by crystallization from EtOH to yield the title compound 2. Yield: 388 mg (53%); yellow solid; m.p. 179–180 °C (decomp.); IR (cm⁻¹): 1743, 1711, 1679, 1652, 1613, and 1584; and ¹H NMR (400 MHz, CDCl₃), mixture of inseparable diastereomers, d.r. = ~4:1 (A:B):δ = 7.50–7.05 (m, A+B, Ar, 13H), 7.00–6.86 (m, A+B, Ar, 3H), 6.80–6.75 (m, A+B, Ar, 1H), 6.68–6.58 (m, A+B, Ar + C^4aH, 2.2H), 6.52 (s, A, C^4aH, 0.8H), 4.89 (d, J = 15.2 Hz, B, 0.2H), 4.86–4.80 (m, A+B, CH₂Ph, 1H), 4.68–4.57 (m, A+B, CH₂Ph, 2.6H), 4.27 (d, J = 15.2 Hz, B, CH₂Ph, 0.2H), 4.10–4.01 (m, B, CH₃CH₂, 0.2H), [4.06 (s, B, OMe), 4.03 (s, A, OMe), ∑ 3H], 3.93 (dq, J = 10.8, 7.1 Hz, B, CH₃CH₂, 0.2H), 3.76 (dq, J = 10.8, 7.1 Hz, A, CH₃CH₂, 0.8H), 3.61 (dq, J = 10.8, 7.1 Hz, A, CH₃CH₂, 0.8H), [3.53 (s, A, OMe), 3.51 (s, B, OMe), ∑ 3H], and [1.09 (t, J = 7.1 Hz, B, CH₃CH₂), 0.67 (t, J = 7.1 Hz, A, CH₃CH₂), ∑ 3H]. ¹³C NMR (101 MHz, CDCl₃): δ (A, major) = 174.40, 163.95, 163.14, 162.94, 160.99, 142.73, 142.36, 136.03, 135.70, 132.07, 130.05, 130.03, 129.15 (2C), 128.69 (2C), 128.51 (4C), 128.31 (2C, br.), 128.09, 128.00, 127.87 (2C), 124.87, 121.19, 111.69, 110.41, 110.38, 108.73, 107.64, 99.61, 81.13, 60.41, 54.72, 54.24, 53.44, 52.21, 45.88, 45.80, and 13.26. ¹³C NMR (101 MHz, CDCl₃): δ (B, minor) = 175.41, 163.89, 163.44, 161.22, 157.72, 142.64, 140.14, 136.13, 135.73, 131.58, 130.30, 129.01, 128.48, 128.19, 128.15, 127.94, 127.71, 124.56, 121.31, 111.48, 110.69, 109.88, 109.62, 109.15, 100.28, 78.41, 60.71, 55.35, 55.02, 53.39, 51.89, 45.74, 43.17, and 13.51; three carbon signals were not separated/found; Anal. Calcd (%) for C₄₃H₃₅N₅O₇: C 70.39; H 4.81; and N 9.54. Found: C 70.75; H 4.79; and N 9.31.

¹H NMR (400 MHz, DMSO-d₆), mixture of inseparable diastereomers, d.r. = ~4:1 (A:B):δ = 7.57–7.43 (m, A+B, Ar, 3H), 7.43–7.20 (m, A+B, Ar, 8H), 7.20–7.13 (m, A+B, Ar, 2H), 7.03–6.77 (m, A+B, Ar, 5H), 6.65–6.58 (m, A+B, Ar + C^4aH, 1.2H), 6.43 (s, A, C^4aH, 0.8H), 5.06 (d, J = 16.5 Hz, A, CH₂Ph, 0.8H), 4.90 (d, J = 16.5 Hz, B, 0.2H), 4.79 (d, J = 15.8 Hz, B, CH₂Ph, 0.2H), 4.67 (d, J = 15.8 Hz, A, CH₂Ph, 0.8H), 4.61–4.50 (m, A+B, CH₂Ph, 1.8H), 4.38 (d, J = 15.7 Hz, B, CH₂Ph, 0.2H), [4.02 (s, B, OMe), 4.01 (s, A, OMe), ∑ 3H], 3.91 (dq, J = 10.8, 7.1 Hz, B, CH₃CH₂, 0.2H), 3.82–3.56 (m, A+B, CH₃CH₂, 1.8H), [3.58 (s, A, OMe), 3.53 (s, B, OMe), ∑ 3H], and [0.96 (t, J = 7.1 Hz, B, CH₃CH₂), 0.64 (t, J = 7.1 Hz, A, CH₃CH₂), ∑ 3H].

Crystal data of compound 2. C₄₃H₃₅N₅O₇, M = 733.76, triclinic, space group P–1, a = 10.5783(13) Å, b = 11.5582(14) Å, c = 15.551(2) Å, α = 86.823(10)°, β = 75.467(11)°, γ = 84.391(10)°, V = 1830.8(4) ų, T = 295(2) K, Z = 2, and µ(Mo Kα) = 0.092 mm⁻¹. The final refinement parameters: R₁ = 0.0663 (for observed 4284 reflections with I > 2σ(I)); wR₂ = 0.1432 (for all independent 8521 reflections, R_int = 0.0663); and S = 1.008. CCDC 2512081 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/structures/ (accessed on 29 December 2025) (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; and E-mail: deposit@ccdc.cam.ac.uk).

4. Conclusions

In conclusion, we have developed a method for the synthesis of spiro[benzo[4,5]imidazo[1,2-a]pyridine-3,3’-pyrrole] 2 as a diastereomeric mixture in moderate yield via a three-component reaction of 3-ylidenepyrrol-2-one, DMAD, and 1-benzylbenzimidazole. The product 2 is less prone to epimerization in solution than its pyridine-based analog 3.