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Volume 2025
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Communication

Efficient Synthesis of Unsymmetrical 7,7′-Biindolizines

by
Roxana Ciorteanu
1,2,
Andreea Danila
2,
Catalina Ionica Ciobanu
3,
Ioana Radu
2,
Ionel I. Mangalagiu
2 and
Ramona Danac
2,*
1
Institute of Interdisciplinary Research–RECENT AIR Center, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania
2
Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania
3
Institute of Interdisciplinary Research–CERNESIM Centre, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania
*
Author to whom correspondence should be addressed.
Molbank 2025, 2025(4), M2074; https://doi.org/10.3390/M2074 (registering DOI)
Submission received: 11 September 2025 / Revised: 9 October 2025 / Accepted: 13 October 2025 / Published: 15 October 2025
Browse Figures
Versions Notes

Abstract

Six new unsymmetrical 7,7′-biindolizines were synthesized through an efficient metal-free [2+2+1] cycloaddition of ethyl 3-benzoyl-7-(pyridin-4-yl)indolizine-1-carboxylate with two equivalents of dimethyl acetylenedicarboxylate in methanol. The transformation involves one C≡C triple bond cleavage and provides access to previously unexplored unsymmetrical functionalized 7,7′-biindolizines.

1. Introduction

Indolizines are an attractive class of bridged nitrogen-containing heterocycles, characterized by a 10-π electron aromatic architecture and strong fluorescence. Their structural versatility, combined with tunable photophysical and biological properties, have made them valuable scaffolds in both medicinal chemistry and materials science. Thus, indolizine derivatives have shown applications in medicinal chemistry, biology, and medicine, with reported activities including anticancer, antioxidant, antimicrobial, antidiabetic, antiviral, anti-inflammatory, enzyme inhibitory, and calcium-channel blocking effects [1,2,3,4,5]. Beyond bioactivity, their fluorescence and electrochromic properties support applications in dyes, biomarkers, optoelectronic devices, and sensors [6,7,8,9,10,11,12,13].
Over time, numerous strategies have been developed for their synthesis, ranging from multistep classical methods to more efficient one-pot approaches. Traditional pathways include the Tschitschibabin reaction, cycloadditions, intramolecular cyclizations, metal-catalyzed C–H functionalization, cycloisomerization of 2-pyridine derivatives, and trans-cyclization of pyridotriazoles with alkynes [1,14,15,16]. Although many classical methods involve multiple steps, intermediate purifications, and heavy solvent use, recent advances have introduced efficient one-pot multicomponent protocols, with metal catalysts playing a key role in these transformations [1,14,15,16].
A particularly intriguing derivative is 7,7′-biindolizine, featuring two indolizine units connected at their 7-positions. This dimeric structure extends π-conjugation and promises enhanced optoelectronic behavior, such as improved charge mobility, tunable absorption/emission spectra, and potential applications in organic semiconductors, light-emitting devices, or photodynamic systems [17,18,19,20]. Thus, 7,7′-biindolizine occupies a captivating intersection of electronic conjugation and bioactivity potential, making it a valuable target for exploration in functional materials and drug discovery.
While the construction of symmetrical 7,7′-biindolizines is relatively straightforward [21,22,23,24], accessing unsymmetrical analogues generally requires additional steps [18,20,25,26,27,28]. Streamlining these multistep routes remains an important challenge, and success in this area could greatly expand structural diversity and enable finer control over electronic and optical properties.
Inspired by previous literature reports employing the direct reactions of simple or fused pyridine derivatives with electron-deficient alkynes, either with or without transition-metal catalysis [29,30,31], we accessed unsymmetrical 7,7′-biindolizines using a similar strategy [29,30,31]. In our approach, the second indolizine moiety is constructed in the final step via a metal-free [2+2+1] cycloaddition between ethyl 3-benzoyl-7-(pyridin-4-yl)indolizine-1-carboxylate and dimethyl acetylenedicarboxylate, achieving perfect atom economy [29,30,31]. Notably, the transformation proceeds through cleavage of one C≡C triple bond. This strategy improves efficiency and opens the way toward multiple esters decorated 7,7′-biindolizines that can be further functionalized.

2. Results

Chemistry
The synthetic approach to build the first indolizine ring is based on a 3+2 cycloaddition of pyridinium ylides to ethyl propiolate, a strategy successfully applied in our group to synthesize various fused pyrrolo-heterocycles [11,12,25,26,27,28,32,33]. The synthetic process began with the preparation of the monoquaternary salts of 1-(2-(p-R-phenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium 3a–f through an SN2 alkylation reaction of 4,4′-bipyridine 1 and para-substituted acetophenones 2a–f (Scheme 1) [25,26,27,28]. Under the applied reaction conditions, only mono-alkylation of compound 1 was observed.
Treatment of salt 3 with triethylamine generates the corresponding ylide 4 in situ. The reactivity of cycloimmonium ylides is strongly dependent on the reaction partner: in the presence of electron-deficient dipolarophiles such as alkynes or alkenes, they behave as 1,3-dipole and undergo [3+2] cycloaddition reactions. Thus, when ethyl propiolate was employed as a dipolarophile, the corresponding monoindolizines 6a–f were obtained via a mechanism involving non-isolable intermediates 5a–f which subsequently underwent aromatization under the reaction conditions (Scheme 1). The Supplementary Materials contain IR and 1H NMR spectra of intermediate compounds 3a–f and 6a–f (Figures S1–S28).
The monoindolizines 6 was employed as the starting material in a [2+2+1] cycloaddition with dimethyl acetylenedicarboxylate (DMAD) in methanol at reflux, producing 7,7′-biindolizines 7a–f in moderate yields (52–59%) as shown in Scheme 2.
The structures of the newly synthesized 7,7′-biindolizine compounds were proven by spectral (IR, NMR) methods (Supplementary Materials contain IR, 1H, and 13C-NMR spectra of compounds 7a–f (Figures S29–S46)).
In the proton NMR spectra, all compounds exhibit distinct singlet signals corresponding to the methyl ester protons: H15 at 3.94–3.95 ppm, H11 at 3.95–3.96 ppm, and H13 at 4.02–4.03 ppm. All indolizine protons appear as doubled signals, with the exception of proton H2 which is present on only one indolizine ring of the biindolizine. The 13C-NMR spectra further confirm the structures of compounds 7a–f showing four ester carbonyl (COO) signals and three methyl ester carbon signals.
On the basis of the literature precedent [30,31], a plausible mechanism is proposed (Scheme 3). The reaction is initiated by the nucleophilic attack of ethyl 3-benzoyl-7-(pyridin-4-yl)indolizine-1-carboxylate 6 on dimethyl acetylenedicarboxylate (DMAD), generating the corresponding betaine 8. Dimerization affords intermediate 9, which undergoes cyclization to form intermediate 10. A subsequent 1,3-hydrogen shift produces intermediate 11. Aromatization accompanied by the cleavage of the remaining σ bond of what had originally been a C≡C triple bond then leads to the expected 7,7′-indolizine 7 and pyridinium ylide 12. A plausible continuation involves the nucleophilic attack of pyridinium ylide 12 to betaine 8 to afford intermediate 13, which, after intramolecular cyclization and oxidative aromatization, furnishes the target unsymmetrical 7,7′-biindolizine 7 along with the starting material 6. The latter can re-enter the cycle, enabling an efficient atom-economical process.
To confirm that methanol, used as a solvent, is not involved in the reaction pathway, we carried out the reaction of monoindolizine 6e in ethanol, dichlomethane, and diethylether under analogous conditions. The same biindolizine 7e was obtained, albeit in a slightly lower yield, which suggests that the solvent is unlikely to participate directly in the transformation. To explore milder conditions, we carried out the reaction of 6a with DMAD in methanol using similar conditions, but at room temperature. The same biindolizine 7e was obtained, but in a lower yield (40%) compared to the reaction performed under reflux, presumably caused by the formation of some minor by-products detected by TLC, which we were unable to isolate and characterize.

3. Materials and Methods

3.1. Chemistry

All commercially available reagents and solvents were used without further purification. Thin-layer chromatography (TLC) was performed on Merck 60F254 silica gel plates (Merck, Darmstadt, Germany). Visualization of the plates was achieved using a UV lamp (λmax = 254 nm or 365 nm). Melting points were recorded on an A. Krüss Optronic Melting Point Meter KSP1N (Kruss, Hamburg, Germany) and are uncorrected. Proton and carbon nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III 500 MHz spectrometer (500 MHz, Bruker BioSpin GmbH, Rheinstetten, Germany), using CDCl3 or DMSO as internal standards. Chemical shifts (δ) are reported in part per million (ppm) and coupling constants (J) in Hz. The following abbreviations are used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets. Infrared (IR) spectra were recorded as films with preparation performed by pelletizing with potassium bromide (KBr), on a Jasco 660 plus FTIR spectrophotometer (Jasco Corporation, Tokyo, Japan). Elemental analyses indicated by the symbols of the elements were within ±0.4% of the theoretical values.

3.1.1. General Procedure for the Synthesis of Monoquaternary Salts 3a–f

4,4′-Bipyridine (1 mmol, 1 eq.) was dissolved in 10 mL of acetone. Separately, ω-bromo-4-acetophenone 2 (1.1 mmol, 1.1 eq.) was dissolved in 5 mL of acetone, and the resulting solution was then added dropwise to the 4,4′-bipyridine solution under stirring. The reaction mixture was stirred continuously at room temperature overnight. The formation of a precipitate was observed during the reaction, which was isolated by filtration. The obtained solid was washed with acetone and dried to yield salt 3 that was used in the next step without further purification.

3.1.2. General Procedure for the Synthesis of Monoindolizines 6a–f

Salt 3 (1.0 mmol, 1 eq.) and ethyl propiolate (1.1 mmol, 1.1 eq.) were suspended in 10 mL of dichloromethane (DCM). Then, a solution containing triethylamine (3.0 mmol, 3 eq.) and 3 mL of dichloromethane was added dropwise to the reaction mixture under magnetic stirring. The obtained reaction mixture was stirred overnight at room temperature. Methanol was added dropwise to the reaction mixture and the resulting precipitate was collected by filtration and dried. The purification of compounds 6a–f was achieved by crystallization from dichloromethane/methanol (1:2, v/v).

3.1.3. General Procedure for the Synthesis of 7,7′-biindolizines 7a–f

Monoindolizine 6 (1 mmol, 1 eq.) was suspended in methanol (10 mL). Then, 2.5 mL of DMAD previously diluted in 3 mL of methanol was added dropwise. Upon addition of DMAD, the reaction mixture color changed from yellow to reddish-brown. The reaction mixture was magnetic stirred under reflux overnight. The formed precipitate was isolated by filtration and dried to give the first fraction of pure compound 7. The remaining solution was concentrated under reduced pressure and the residue was purified using silica gel column chromatography (dichloromethane used as an eluent) to obtain the second fraction of compound 7. In case of compounds 7a, 7b, and 7d, supplementary purification of the combined fractions was achieved by crystallization from a dichloromethane/methanol mixture (1:1, v/v).

3.1.4. Spectral Data

1-(2-(4-cyanophenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium bromide 3a: Starting from 4,4′ bipyridine (156 mg, 1mmol, 1 eq.) and 2-bromo-4′-cyanoacetophenone (246.5 mg, 1.1 mmol, 1.1 eq.), the product was obtained (292 mg, 75% yield) as a white solid, m.p. = 275–277 °C. IR (KBr) ν(cm−1): 3011, 2990, 2868, 2228, 1690, 1642, 1524, 1410, 1222, 1202, 1000, 822. 1H-NMR (500 MHz, DMSO-d6), δppm: 6.62 (s, 2H, H7), 8.09 (d, J = 4.5 Hz, 2H, H16, H20), 8.18 (d, J = 8.0 Hz, 2H, H11, H13), 8.25 (d, J = 8.0 Hz, 2H, H10, H14), 8.80 (d, J = 7.0 Hz, 2H, H3, H5), 8.90 (d, J = 4.5 Hz, 2H, H17, H19), 9.18 (d, J = 7.0 Hz, 2H, H2, H6). 13C-NMR (125 MHz, DMSO-d6), δppm: 66.1 (C7), 116.4 (1C, C12), 118.0 (CN), 122.0 (C16, C20), 125.3 (C3, C5), 128.9 (C10, C14), 133.2 (C11, C13), 136.8 (C9), 140.9 (C15), 146.8 (C2, C6), 151.1 (C17, C19), 153.2 (C4), 190.3 (C8). Anal. Calcd. for C19H14BrN3O: C, 60.02; H, 3.71; N, 11.05. Found: C, 60.03; H, 3.70; N, 11.07.
1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)-[4,4′-bipyridin]-1-ium bromide 3b: Starting from 4,4′ bipyridine (156 mg, 1mmol, 1 eq.) and 2-bromo-4′-(trifluoromethyl) acetophenone (294 mg, 1.1 mmol, 1.1 eq.), the product was obtained (296 mg, 70% yield) as a blue solid, m.p. = 266–267 °C. IR (KBr) ν (cm−1): 3016, 2930, 2886, 1702, 1689, 1640, 1546, 1412, 1323, 1187, 1139, 1066, 822. 1H-NMR (500 MHz, DMSO-d6), δppm: 6.68 (s, 2H, H7), 8.07 (d, J = 8.0 Hz, 2H, H11, H13), 8.12 (d, J = 6.0 Hz, 2H, H16, H20), 8.30 (d, J = 8.0 Hz, 2H, H10, H14), 8.81 (d, J = 7.0 Hz, 2H, H3, H5), 8.91 (d, J = 6.0 Hz, 2H, H17, H19), 9.22 (d, J = 7.0 Hz, 2H, H2, H6). 13C-NMR (125 MHz, DMSO-d6), δppm: 66.1 (C7), 122.1 (C16, C20), 123.6 (q, J = 271.3 Hz, CF3), 125.3 (C3, C5), 126.2 (q, J = 3.8 Hz, C11, C13), 129.2 (C10, C14), 133.7 (q, J = 32.5 Hz, C12), 136.9 (C9), 141.1 (C15), 146.8 (C2, C6), 150.9 (C17, C19), 153.1 (C4), 190.4 (C8). Anal. Calcd. for C19H14BrF3N2O: C, 53.92; H, 3.33; N, 6.62. Found: C, 53.92; H, 3.32; N, 6.63.
1-(2-oxo-2-phenylethyl)-[4,4′-bipyridin]-1-ium bromide 3c: Starting from 4,4′ bipyridine (156 mg, 1mmol, 1 eq.) and 2-bromo-1-phenylethanone (219 mg, 1.1 mmol, 1.1 eq.), the product was obtained (334 mg, 94% yield) as a white solid, m.p. = 285–287 °C. IR (KBr) ν(cm−1): 3027, 2890, 1697, 1638, 1618, 1385, 1227, 1198, 996. 1H-NMR (500 MHz, DMSO-d6), δppm: 6.52 (s, 2H, H7), 7.69 (t, J = 8.0 Hz, 2H, H11, H13), 7.82 (t, J = 7.5 Hz, 1H, H12), 8.08-8.11 (overlapping signals, 4H, H10, H14, H16, H20), 8.76 (d, J = 7.0 Hz, 2H, H3, H5), 8.91 (d, J = 4.5 Hz, 2H, H17, H19), 9.14 (d, J = 7.0 Hz, 2H, H2, H6). Anal. Calcd. for C18H15BrN2O: C, 60.86; H, 4.26; N, 7.89. Found: C, 60.86; H, 4.25; N, 7.90.
1-(2-(4-chlorophenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium bromide 3d: Starting from 4,4′ bipyridine (156 mg, 1mmol, 1 eq.) and 2-bromo-4′-chloroacetophenone (257 mg, 1.1 mmol, 1.1 eq.), the product was obtained (292 mg, 75% yield) as a white solid, m.p. = 310–312 °C. IR (KBr) ν(cm−1): 3025, 2927, 1693, 1642, 1618, 1589, 1229, 1177, 1093, 795. 1H-NMR (500 MHz, DMSO-d6), δppm: 6.56 (s, 2H, H7), 7.77 (d, J = 8.0 Hz, 2H, H11, H13), 8.09 (d, J = 6.0 Hz, 2H, H16, H20), 8.11 (d, J = 8.5 Hz, 2H, H10, H14), 8.78 (d, J = 6.5 Hz, 2H, H3, H5), 8.90 (d, J = 5.0 Hz, 2H, H17, H19), 9.17 (d, J = 6.0 Hz, 2H, H2, H6). Anal. Calcd. for C18H14BrClN2O: C, 55.48; H, 3.62; N, 7.19. Found: C, 55.49; H, 3.60; N, 7.21.
1-(2-oxo-2-(p-tolyl)ethyl)-[4,4′-bipyridin]-1-ium bromide 3e: Starting from 4,4′ bipyridine (156 mg, 1mmol, 1 eq.) and 2-bromo-1-(p-tolyl)ethanone (234 mg, 1.1 mmol, 1.1 eq.), the product was obtained (321 mg, 87% yield) as a white solid, m.p. 295–297 °C. IR (KBr) ν(cm−1): 3031, 2948, 1682, 1639, 1616, 1603, 1544, 1407, 1134, 1235, 1185, 994, 808. 1H-NMR (500 MHz, DMSO-d6), δppm: 2.45 (s, 3H, CH3), 6.52 (s, 2H, H7), 7.49 (d, J = 8.0 Hz, 2H, H11, H13), 7.99 (d, J = 8.0 Hz, 2H, H10, H14), 8.09 (d, J = 4.5 Hz, 2H, H16, H20), 8.77 (d, J = 7.0 Hz, 2H, H3, H5), 8.90 (d, J = 4.5 Hz, 2H, H17, H19), 9.16 (d, J = 7.0 Hz, 2H, H2, H6). Anal. Calcd. for C19H17BrN2O: C, 61.80; H, 4.64; N, 7.59. Found: C, 61.80; H, 4.63; N, 7.60.
1-(2-(4-methoxyphenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium bromide 3f: Starting from 4,4′ bipyridine (156 mg, 1mmol, 1 eq.) and 2-bromo-4′-methoxyacetophenone (229 mg, 1.1 mmol, 1.1 eq.), the product was obtained (300 mg, 78% yield) as a white solid, m.p. = 263–264 °C. IR (KBr) ν(cm−1): 3027, 2942, 1676, 1641, 1595, 1411, 1337, 1271, 1246, 1173, 990, 829. 1H-NMR (500 MHz, DMSO-d6), δppm: 6.52 (s, 2H, H7), 7.20 (d, J = 9.0 Hz, 2H, H11, H13), 8.07 (d, J = 9.0 Hz, 2H, H10, H14), 8.10 (d, J = 6.5 Hz, 2H, H16, H20), 8.76 (d, J = 6.5 Hz, 2H, H3, H5), 8.89 (d, J = 6.5 Hz, 2H, H17, H19), 9.17 (d, J = 7.0 Hz, 2H, H2, H6). Anal. Calcd. for C19H17BrN2O2: C, 59.23; H, 4.45; N, 7.27. Found: C, 59.23; H, 4.43; N, 7.28.
Ethyl 3-(4-cyanobenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate 6a: Starting from 1-(2-(4-cyanophenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium bromide (380 mg, 1mmol, 1 eq.), ethyl propiolate (111.5 μL, 1.1 mmol, 1.1 eq.), and triethylamine (418 μL, 3 mmol, 3 eq.), the product was obtained (221 mg, 56% yield) as a yellow solid, m.p. = 233–235 °C. IR (KBr) ν(cm−1): 2923, 2229, 1702, 1638, 1617, 1384, 1211, 1082. 1H-NMR (500 MHz, CDCl3) δppm: 1.42 (t, J = 7.0 Hz, 3H, H25), 4.41 (q, J = 7.0 Hz, 2H, H24), 7.43 (d, J = 6.5 Hz, 1H, H6), 7.66 (d, J = 4.5 Hz, 2H, H18, H22), 7.77 (s, 1H, H2), 7.85 (d, J = 8.0 Hz, 2H, H13, H15), 7.92 (d, J = 7.5 Hz, 2H, H12, H16), 8.77–8.78 (overlapping signals, 3H, H19, H21, H8), 10.04 (d, J = 7.0 Hz, 1H, H5). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C25), 60.7 (C24), 108.3 (C1), 114.4 (C6), 115.2 (C14), 117.4 (C8), 118.2 (CN), 121.4 (C18, C22), 122.2 (C3), 129.4 (C2), 129.5 (C12, C16), 129.8 (C5), 132.5 (C13, C15), 137.8 (C7), 140.3 (C9), 143.5 (C11), 145.1 (C17), 150.9 (C19, C21), 163.7 (C23), 183.5 (1C, C10). Anal. Calcd. for C24H17N3O3: C, 72.90; H, 4.33; N, 10.63. Found: C, 72.89; H, 4.31; N, 10.64.
Ethyl 7-(pyridin-4-yl)-3-(4-(trifluoromethyl)benzoyl)indolizine-1-carboxylate 6b: Starting from 1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)-[4,4′-bipyridin]-1-ium bromide (423 mg, 1 mmol, 1 eq.), ethyl propiolate (111.5 μL, 1.1 mmol, 1.1 eq.), and triethylamine (418 μL, 3 mmol, 3 eq.), the product was obtained (232 mg, 53% yield) as a yellow solid, m.p. = 196–197 °C. IR (KBr) ν(cm−1): 3039, 2983, 1694, 1607, 1525, 1469, 1331, 1208, 1165, 1120, 1067, 806. 1H-NMR (500 MHz, CDCl3) δppm: 1.42 (t, J = 7.0 Hz, 3H, H25), 4.41 (q, J = 7.0 Hz, 2H, H24), 7.41 (dd, J = 6.5; 2.0 Hz, 1H, H6), 7.66 (d, J = 5.0 Hz, 2H, H18, H22), 7.79 (s, 1H, H2), 7.81 (d, J = 8.0 Hz, 2H, H13, H15), 7.93 (d, J = 8.0 Hz, 2H, H12, H16), 8.76–8.78 (overlapping signals, 3H, H19, H21, H8), 10.04 (d, J = 7.5 Hz, 1H, H5). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C25), 60.6 (C24), 108.1 (C1), 114.2 (C6), 117.4 (C8), 121.4 (C18, C22), 122.5 (C3), 122.9 (q, J = 270.0 Hz, CF3), 125.7 (q, J = 3.8 Hz, C13, C15), 129.5 (C2), 129.3 (C12, C16), 129.8 (C5), 132.6 (q, J = 32.5 Hz, C14), 137.6 (C7), 140.2 (C9), 142.9 (C11), 145.2 (C17), 150.9 (C19, C21), 163.9 (C23), 184.3 (C10). Anal. Calcd. for C24H17F3N2O3: C, 65.75; H, 3.91; N, 6.39. Found: C, 65.74; H, 3.90; N, 6.41.
Ethyl 3-benzoyl-7-(pyridin-4-yl)indolizine-1-carboxylate 6c: Starting from 1-(2-oxo-2-phenylethyl)-[4,4′-bipyridin]-1-ium bromide (355 mg, 1 mmol, 1 eq.), ethyl propiolate (111.5 μL, 1.1 mmol, 1.1 eq.), and triethylamine (418 μL, 3 mmol, 3 eq.), the product was obtained (215 mg, 58% yield) as a yellow solid, m.p. 190-192 °C. IR (KBr) ν(cm−1): 3024, 2978, 1689, 1637, 1610, 1459, 1346, 1199, 1084, 884. 1H-NMR (500 MHz, CDCl3) δppm: 1.42 (t, J = 7.0 Hz, 3H, H25), 4.40 (q, J = 7.0 Hz, 2H, H24), 7.38 (dd, J = 7.5; 2.0 Hz, 1H, H6), 7.55 (t, J = 7.0 Hz, 2H, H13, H15), 7.61 (t, J = 7.5 Hz, 1H, H14), 7.84–7.86 (overlapping signals, 5H, H12, H16, H18, H22, H2), 8.79–8.80 (overlapping signals, 3H, H19, H21, H8), 10.05 (d, J = 7.5 Hz, 1H, H5). Anal. Calcd. for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.57; H, 4.88; N, 7.57.
Ethyl 3-(4-chlorobenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate 6d: Starting from 1-(2-(4-chlorophenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium bromide (390 mg, 1 mmol, 1 eq.), ethyl propiolate (111.5 μL, 1.1 mmol, 1.1 eq.), and triethylamine (418 μL, 3 mmol, 3 eq.), the product was obtained (231 mg, 57% yield) as a yellow solid, m.p. 213–215 °C. IR (KBr) ν(cm−1): 3089, 3031, 2962, 1693, 1637, 1609, 1524, 1467, 1354, 1198, 1081, 804. 1H-NMR (500 MHz, CDCl3) δppm: 1.42 (t, J = 7.0 Hz, 3H, H25), 4.40 (q, J = 7.0 Hz, 2H, H24), 7.38 (dd, J = 7.5; 1.5 Hz, 1H, H6), 7.52 (d, J = 8.5 Hz, 2H, H13, H15), 7.65 (d, J = 6.0 Hz, 2H, H18, H22), 7.79 (d, J = 8.5 Hz, 2H, H12, H16), 7.81 (s, 1H, H2), 8.74–8.77 (overlapping signals, 3H, H19, H21, H8), 9.99 (d, J = 7.5 Hz, 1H, H5). Anal. Calcd. for C23H17ClN2O3: C, 68.23; H, 4.23; N, 6.92. Found: C, 68.23; H, 4.22; N, 6.93.
Ethyl 3-(4-methylbenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate 6e: Starting from 1-(2-oxo-2-(p-tolyl)ethyl)-[4,4′-bipyridin]-1-ium bromide (369 mg, 1 mmol, 1 eq.), ethyl propiolate (111.5 μL, 1.1 mmol, 1.1 eq.), and triethylamine (418 μL, 3 mmol, 3 eq.), the product was obtained (219 mg, 57% yield) as a yellow solid, m.p. 225–227 °C. IR (KBr) ν(cm−1): 2975, 1692, 1637, 1615, 1524, 1354, 1198, 1081, 805. 1H-NMR (500 MHz, CDCl3) δppm: 1.41 (t, J = 7.0 Hz, 3H, H25), 2.26 (s, 3H, CH3), 4.40 (q, J = 7.0 Hz, 2H, H24), 7.33–7.36 (overlapping signals, 3H, H13, H15, H6), 7.74–7.77 (overlapping signals, 4H, H12, H16, H18, H22), 7.85 (s, 1H, H2), 8.76–8.78 (overlapping signals, 3H, H19, H21, H8), 10.00 (d, J = 7.5 Hz, 1H, H5). Anal. Calcd. for C24H20N2O3: C, 74.98; H, 5.24; N, 7.29. Found: C, 74.97; H, 5.22; N, 7.31.
Ethyl 3-(4-methoxybenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate 6f: Starting from 1-(2-(4-methoxyphenyl)-2-oxoethyl)-[4,4′-bipyridin]-1-ium bromide (385 mg, 1 mmol, 1 eq.), ethyl propiolate (111.5 μL, 1.1 mmol, 1.1 eq.), and triethylamine (418 μL, 3 mmol, 3 eq.), the product was obtained (212 mg, 53% yield) as a yellow solid, m.p. 191–192 °C. IR (KBr) ν(cm−1): 2925, 1694, 1619, 1597, 1525, 1353, 1206, 1082, 804. 1H-NMR (500 MHz, CDCl3) δppm: 1.42 (t, J = 7.0 Hz, 3H, H25), 3.91 (s, 3H, OCH3), 4.40 (q, J = 7.0 Hz, 2H, H24), 7.03 (t, J = 9.0 Hz, 2H, H13, H15), 7.33 (dd, J = 7.5; 2.0 Hz,1H, H6), 7.65 (d, J = 6.0 Hz, 2H, H18, H22), 7.85–7.87 (overlapping signals, 3H, H12, H16, H2), 8.72 (d, J = 1.0 Hz, 1H, H8), 8.74 (d, J = 5.5 Hz, 2H, H19, H21), 9.94 (dd, J = 7.0; 0.5 Hz, 1H, H5). Anal. Calcd. for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C, 71.98; H, 5.01; N, 7.02.
1′-Ethyl-1,2,3-trimethyl-3′-(4-cyanobenzoyl)-[7,7′-biindolizine]-1,1′,2,3-tetracarboxylate 7a: Starting from ethyl 3-(4-cyanobenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate (395 mg, 1mmol, 1 eq.) and dimethyl acetylenedicarboxylate (2.5 mL, 20 mmol), the product was obtained (340 mg, 56% yield) as a yellow solid, m.p. = 233-235 °C. IR (KBr) ν(cm−1): 3111, 2952, 2229, 1749, 1705, 1687, 1611, 1530, 1463, 1347, 1219, 1112, 776. 1H-NMR (500 MHz, CDCl3) δppm: 1.44 (t, J = 7.0 Hz, 3H, H12′), 3.95 (s, 6H, H15, H11), 4.03 (s, 3H, H13), 4.42 (q, J = 7.0 Hz, 2H, H11′), 7.47–7.54 (overlapping signals, 2H, H6, H6′), 7.77 (s, 1H, H2′), 7.85 (d, J = 7.5 Hz, 2H, H16′, H18′), 7.92 (d, J = 7.5 Hz 2H, H15′, H19′), 8.75 (bs, 1H, H8), 8.79 (bs, 1H, H8′), 9.61 (d, J = 7.5 Hz, 1H, H5), 10.01 (d, J = 7.0 Hz, 1H, H5′). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C12′), 52.1 (C11), 52.4 (C15), 53.2 (C13), 60.5 (C11′), 104.5 (C1), 108.3 (C1′), 112.5 (C3), 114.0 (C6′), 114.2 (C6), 117.1 (C8′), 115.2 (C17′), 117.6 (C8), 118.2 (CN), 122.3 (C3′), 128.5 (C5), 129.5 (C15′, C19′, C2′), 129.7 (C5′), 131.2 (C2), 132.5 (C16′, C18′), 135.7 (C7′), 137.3 (C7), 137.8 (C9), 140.3 (C9′), 143.5 (C14′), 160.5 (C14), 163.3 (C10), 163.8 (C10′), 166.1 (C12), 183.5 (C13′). Anal. Calcd. for C33H25N3O9: C, 65.24; H, 4.15; N, 6.92. Found: C, 65.24; H, 4.13; N, 6.93.
1′-Ethyl-1,2,3-trimethyl-3′-(4-(trifluoromethyl)benzoyl)-[7,7′-biindolizine]-1,1′,2,3-tetracarboxylate 7b: Starting from ethyl 7-(pyridin-4-yl)-3-(4-(trifluoromethyl)benzoyl) indolizine-1-carboxylate (438 mg, 1 mmol, 1 eq.) and dimethyl acetylenedicarboxylate (2.5 mL, 20 mmol), the product was obtained (338 mg, 52% yield) as a yellow solid, m.p. = 225–226 °C. IR (KBr) ν(cm−1): 2954, 1739, 1698, 1606, 1527, 1328, 1247, 1199, 1171. 1H-NMR (500 MHz, CDCl3) δppm: 1.44 (t, J = 7.0 Hz, 3H, H12′), 3.94 (s, 3H, H15), 3.95 (s, 3H, H11), 4.02 (s, 3H, H13), 4.42 (q, J = 7.0 Hz, 2H, H11′), 7.48 (dd, J = 8.5; 2.0 Hz, 1H, H6), 7.52 (dd, J = 8.5; 2.0 Hz, 1H, H6′), 7.80 (s, 1H, H2′), 7.81 (d, J = 8.5 Hz, 2H, H16′, H18′), 7.94 (d, J = 8.0 Hz, 2H, H15′, H19′), 8.76 (d, J = 1.0 Hz, 1H, H8), 8.80 (d, J = 1.5 Hz, 1H, H8′), 9.61 (d, J = 7.5 Hz, 1H, H5), 10.03 (d, J = 7.5 Hz, 1H, H5′). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C12′), 52.1 (C11), 52.4 (C15), 53.2 (C13), 60.6 (C11′), 104.5 (C1), 108.1 (C1′), 112.5 (C3), 114.0 (C6′), 114.1 (C6), 117.1 (C8′), 117.5 (C8), 122.5 (C3′), 123.9 (q, J = 271.3 Hz, CF3), 128.5 (C5), 125.7 (q, J = 3.8 Hz, C16′, C18′), 129.4 (C15′, C19′), 129.5 (C2′), 129.7 (C5′), 131.2 (C2), 133.4 (q, J = 32.5 Hz, C17′), 135.9 (C7′), 137.0 (C7), 137.8 (C9), 140.2 (C9′), 142.9 (C14′), 160.5 (C14), 163.3 (C10), 163.9 (C10′), 166.1 (C12), 184.2 (C13′). Anal. Calcd. for C33H25F3N2O9: C, 60.93; H, 3.87; N, 4.31. Found: C, 60.92; H, 3.85; N, 4.32.
1′-Ethyl-1,2,3-trimethyl-3′-benzoyl-[7,7′-biindolizine]-1,1′,2,3-tetracarboxylate 7c: Starting from ethyl 3-benzoyl-7-(pyridin-4-yl)indolizine-1-carboxylate (370 mg, 1 mmol, 1 eq.) and dimethyl acetylenedicarboxylate (2.5 mL, 20 mmol), the product was obtained (338 mg, 58% yield) as a yellow solid, m.p. = 245–246 °C. IR (KBr) ν(cm−1): 2954, 1744, 1698, 1526, 1343, 1203. 1H-NMR (500 MHz, CDCl3) δppm: 1.43 (t, J = 7.0 Hz, 3H, H12′), 3.94 (s, 3H, H15), 3.95 (s, 3H, H11), 4.02 (s, 3H, H13), 4.41 (q, J = 7.0 Hz, 2H, H11′), 7.46–7.48 (overlapping signals, 2H, H6, H6′), 7.54 (t, J = 7.0 Hz, 2H, H16′, H18′), 7.61 (t, J = 7.0 Hz, 1H, H17), 7.84–7.85 (overlapping signals, 3H, H15′, H19′, H2′), 8.73 (bs, 1H, H8), 8.77 (bs, 1H, H8′), 9.59 (d, J = 7.5 Hz, 1H, H5), 10.01 (d, J = 7.5 Hz, 1H, H5′). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C12′), 52.0 (C11), 52.3 (C15), 53.1 (C13), 60.5 (C11′), 104.3 (C1), 107.6 (C1′), 112.4 (C3), 113.6 (C6′), 114.0 (C6), 117.0 (C8′), 117.4 (C8), 123.0 (C3′), 128.4 (C5), 128.6 (C16′, C18′), 129.2 (C15′, C19′), 129.4 (C2′), 129.6 (C5′), 131.2 (C2), 131.9 (C17′), 136.1 (C7′), 136.4 (C7), 137.8 (C9), 139.7 (C14′), 139.8 (C9′), 160.5 (C14), 163.3 (C10), 164.1 (C10′), 166.1 (C12), 185.8 (C13′). Anal. Calcd. for C32H26N2O9: C, 65.98; H, 4.50; N, 4.81. Found: C, 65.99; H, 4.48; N, 4.82.
1′-Ethyl-1,2,3-trimethyl-3′-(4-chlorobenzoyl)-[7,7′-biindolizine]-1,1′,2,3-tetracarboxylate 7d: Starting from ethyl 3-(4-chlorobenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate (405 mg, 1 mmol, 1 eq.) and dimethyl acetylenedicarboxylate (2.5 mL, 20 mmol), the product was obtained (333 mg, 54% yield) as a yellow solid, m.p. = 255–256 °C. IR (KBr) ν(cm−1): 2954, 1746, 1698, 1527, 1337, 1209, 1079. 1H-NMR (500 MHz, CDCl3) δppm: 1.44 (t, J = 7.0 Hz, 3H, H12′), 3.94 (s, 3H, H15), 3.95 (s, 3H, H11), 4.03 (s, 3H, H13), 4.42 (q, J = 7.0 Hz, 2H, H11′), 7.48–7.51 (overlapping signals, 2H, H6, H6′), 7.53 (d, J = 8.5 Hz, 2H, H16′, H18′), 7.81 (d, J = 8.5 Hz 2H, H15′, H19′), 7.82 (s, 1H, H2′), 8.75 (bs, 1H, H8), 8.79 (bs, 1H, H8′), 9.62 (d, J = 7.5 Hz, 1H, H5), 10.00 (d, J = 7.0 Hz, 1H, H5′). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C12′), 52.0 (C11), 52.3 (C15), 53.1 (C13), 60.6 (C11′), 104.4 (C1), 107.8 (C1′), 112.4 (C3), 113.8 (C6′), 114.0 (C6), 117.1 (C8′), 117.4 (C8), 122.7 (C3′), 128.5 (C5), 129.0 (C16′, C18′), 129.2 (C2′), 129.6 (C5′), 130.5 (C15′, C19′), 131.2 (C2), 136.0 (C7′), 136.7 (C7), 137.9 (C9), 138.1 (C14′), 138.2 (C9′), 139.9 (C17′), 160.5 (C14), 163.3 (C10), 164.0 (C10′), 166.1 (C12), 184.3 (C13′). Anal. Calcd. for C32H25ClN2O9: C, 62.29; H, 4.08; N, 4.54. Found: C, 62.28; H, 4.07; N, 4.56.
1′-Ethyl-1,2,3-trimethyl-3′-(4-methylbenzoyl)-[7,7′-biindolizine]-1,1′,2,3-tetracarboxylate 7e: Starting from ethyl 3-(4-methylbenzoyl)-7-(pyridin-4-yl)indolizine- 1-carboxylate (384 mg, 1 mmol, 1 eq.) and dimethyl acetylenedicarboxylate (2.5 mL, 20 mmol), the product was obtained (352 mg, 59% yield) as a yellow solid, m.p. = 281–282 °C. IR (KBr) ν(cm−1): 2955, 1743, 1697, 1527, 1444, 1385, 1337, 1227, 1208. 1H-NMR (500 MHz, CDCl3) δppm: 1.43 (t, J = 7.0 Hz, 3H, H12′), 2.46 (s, 3H, CH3), 3.95 (s, 3H, H15), 3.96 (s, 3H, H11), 4.02 (s, 3H, H13), 4.41 (q, J = 7.0 Hz, 2H, H11′), 7.34 (d, J = 8.0 Hz, 2H, H16′, H18′), 7.46–7.49 (overlapping signals, 2H, H6, H6′), 7.77 (d, J = 8.0 Hz 2H, H15′, H19′), 7.86 (s, 1H, H2′), 8.74 (bs, 1H, H8), 8.78 (bs, 1H, H8′), 9.60 (d, J = 7.5 Hz, 1H, H5), 10.00 (d, J = 7.5 Hz, 1H, H5′). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C12′), 21.8 (CH3), 52.0 (C11), 52.3 (C15), 53.2 (C13), 60.5 (C11′), 104.3 (C1), 107.5 (C1′), 112.4 (C3), 113.5 (C6′), 114.1 (C6), 117.0 (C8′), 117.4 (C8), 123.1 (C3′), 128.4 (C5), 129.2 (C2′), 129.3 (C16′, C18′), 129.4 (C15′, C19′), 129.6 (C5′), 131.2 (C2), 136.1 (C7′), 136.2 (C7), 137.0 (C14′), 137.9 (C9), 139.7 (C9′), 142.6 (C17′), 160.5 (C14), 163.4 (C10), 164.2 (C10′), 166.2 (C12), 185.6 (C13′). Anal. Calcd. for C33H28N2O9: C, 66.44; H, 4.73; N, 4.70. Found: C, 66.44; H, 4.71; N, 4.73.
1′-Ethyl 1,2,3-trimethyl-3′-(4-methoxybenzoyl)- [7,7′-biindolizine]-1,1′,2,3- tetracarboxylate 7f: Starting from ethyl 3-(4-methoxybenzoyl)-7-(pyridin-4-yl)indolizine-1-carboxylate (400 mg, 1 mmol, 1 eq.) and dimethyl acetylenedicarboxylate (2.5 mL, 20 mmol), the product was obtained (324 mg, 59% yield) as a yellow solid, m.p. = 254-255 °C. IR (KBr) ν(cm−1): 2953, 1745, 1698, 1527, 1445, 1343, 1226, 1204, 1177. 1H-NMR (500 MHz, CDCl3) δppm: 1.44 (t, J = 7.0 Hz, 3H, H12′), 3.92 (s, 3H, OCH3), 3.94 (s, 3H, H15), 3.95 (s, 3H, H11), 4.02 (s, 3H, H13), 4.42 (q, J = 7.0 Hz, 2H, H11′), 7.03 (d, J = 8.5 Hz, 2H, H16′, H18′), 7.44-7.49 (overlapping signals, 2H, H6, H6′), 7.86 (s, 1H, H2′), 7.88 (d, J = 8.5 Hz 2H, H15′, H19′), 8.73 (bs, 1H, H8), 8.76 (bs, 1H, H8′), 9.59 (d, J = 7.0 Hz, 1H, H5), 9.94 (d, J = 7.5 Hz, 1H, H5′). 13C-NMR (125 MHz, CDCl3), δppm: 14.7 (C12′), 52.0 (C11), 52.3 (C15), 53.1 (C13), 55.7 (OCH3), 60.5 (C11′), 104.3 (C1), 107.3 (C1′), 112.4 (C3), 113.4 (C6′), 113.9 (C16′, C18′), 114.1 (C6), 117.0 (C8′), 117.3 (C8), 123.2 (C3′), 128.4 (C5), 128.7 (C2′), 129.5 (C5′), 131.2 (C2), 131.4 (C15′, C19′), 132.2 (C14′), 136.0 (C7′), 136.2 (C7), 137.9 (C9), 139.6 (C9′), 160.5 (C14), 162.9 (C17′), 163.4 (C10), 164.2 (C10′), 166.2 (C12), 185.7 (C13′). Anal. Calcd. for C33H28N2O10: C, 64.70; H, 4.61; N, 4.57. Found: C, 64.70; H, 4.60; N, 4.58.

4. Conclusions

Overall, this study highlights a straightforward and atom-economical [2+2+1] cycloaddition approach that involves a C≡C triple bond cleavage to unsymmetrical 7,7′-biindolizines and demonstrates the synthetic potential of dimethyl acetylenedicarboxylate in accessing indolizine heteroaromatic frameworks.

Supplementary Materials

Figures S1, S4, S7, S9, S11, S13, S15, S18, S21, S23, S25, S27, S29, S32, S35, S38, S41, S44: 1H-NMR spectra of compounds 3a–f, 6a–f and 7a–f; Figures S2, S5, S16, S19, S30, S33, S36, S39, S42, S45: 13C-NMR spectra of compounds 3a–b, 6a–b and 7a–f; Figures S3, S6, S8, S10, S12, S14, S17, S20, S22, S24, S26, S28, S31, S34, S37, S40, S43, S46: IR spectra of compounds 3a–f, 6a–f and 7a–f.

Author Contributions

Conceptualization, R.D. Writing—original draft preparation, R.D. and R.C. Synthesis, R.C. and A.D. Spectral experiments and structure elucidation, R.C., C.I.C., I.R., I.I.M., and R.D. Writing—review and editing, R.D., I.I.M., and R.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The data are presented in the article/Supplementary Materials. Any inquiry can be directed to the corresponding author.

Acknowledgments

The authors thank the CERNESIM Research Centre at Alexandru Ioan Cuza University of Iasi for recording the NMR spectra.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Botezatu, A.V.; Furdui, B.; Busuioc, A.; Dinică, R.M. Recent developments in the synthesis of indolizines and their derivatives as compounds of interest in medicinal chemistry: A review. Eur. J. Med. Chem. 2025, 297, 117908. [Google Scholar] [CrossRef] [PubMed]
  2. Ramalakshmi, N.; Amuthalakshmi, S.; Yamuna, R.; Anton Smith, A.; Arunkumar, S. Indolizine—A privileged biological scaffold. Der Pharma Chem. 2021, 13, 60–69. [Google Scholar]
  3. Sharma, V.; Kumar, V. Indolizine: A biologically active moiety. Med. Chem. Res. 2014, 23, 3593–3606. [Google Scholar] [CrossRef]
  4. Jadhav, M.; Mali, K.; Rajput, V.; Das, R.; Shard, A. Exploring the decadal evolution of indolizine scaffold for anticancer innovations: A comprehensive analysis. Med. Chem. Res. 2024, 33, 1491–1510. [Google Scholar] [CrossRef]
  5. Sandeep, C.; Venugopala, K.N.; Mohammed, A.K.; Attimarad, M.; Padmashali, B.; Kulkarni, R.S.; Venugopala, R.; Odhav, B. Review on chemistry of natural and synthetic indolizines with their chemical and pharmacological properties. J. Basic Clin. Pharm. 2017, 8, 49–60. [Google Scholar]
  6. Pareek, A.; Mehboob, M.Y.; Cieplak, M.; Majdecki, M.; Szabat, H.; Noworyta, K.; Połczyński, P.; Morawiak, M.; Sharma, P.; Foroutan-Nejad, C.; et al. Indoloindolizines: The complete story of a polycyclic aromatic scaffold from theoretical design to organic field-effect transistor applications. J. Am. Chem. Soc. 2025, 147, 5996–6005. [Google Scholar] [CrossRef]
  7. Delcamp, J.H.; Yella, A.; Holcombe, T.W.; Nazeeruddin, M.K.; Grätzel, M. The molecular engineering of organic sensitizers for solar-cell applications. Angew. Chem. Int. Ed. 2013, 52, 376–380. [Google Scholar] [CrossRef]
  8. Arun, V.; Kim, E.; Kim, H.Y.; Park, H.J.; Kim, W.; Lee, Y.; Kim, E. Bisindolizine: A new AIEgen and its application in latent fingerprint imaging. Dye. Pigm. 2025, 242, 112991. [Google Scholar] [CrossRef]
  9. Song, Y.R.; Lim, C.W.; Kim, T.W. Synthesis and photophysical properties of 1,2-diphenylindolizine derivatives: Fluorescent blue-emitting materials for organic light-emitting device. Luminescence 2016, 31, 364–371. [Google Scholar] [CrossRef]
  10. Kim, E.; Lee, Y.; Lee, S.; Park, S.B. Discovery, understanding, and bioapplication of organic fluorophore: A case study with an indolizine-based novel fluorophore, Seoul-Fluor. Acc. Chem. Res. 2015, 48, 538–547. [Google Scholar] [CrossRef]
  11. Pricope, G.; Ursu, E.L.; Sardaru, M.; Cojocaru, C.; Clima, L.; Marangoci, N.; Danac, R.; Mangalagiu, I.I.; Simionescu, B.C.; Pinteala, M.; et al. Novel cyclodextrin-based pH-sensitive supramolecular host–guest assembly for staining acidic cellular organelles. Polym. Chem. 2018, 9, 968–975. [Google Scholar] [CrossRef]
  12. Marangoci, N.L.; Popovici, L.; Ursu, E.L.; Danac, R.; Clima, L.; Mangalagiu, I.I.; Rotaru, A.V. Pyridyl-indolizine derivatives as DNA binders and pH-sensitive fluorescent dyes. Tetrahedron 2016, 72, 8215–8222. [Google Scholar] [CrossRef]
  13. Airinei, A.; Tigoianu, R.; Danac, R.; Al-Matarneh, C.M.; Isac, D.L. Steady state and time-resolved fluorescence studies of new indolizines with phenanthroline skeleton derivatives. J. Lumin. 2018, 202, 364–371. [Google Scholar] [CrossRef]
  14. Sadowski, B.; Klajn, J.; Gryko, D.T. Recent advances in the synthesis of indolizines and their π-expanded analogues. Org. Biomol. Chem. 2016, 14, 7804–7828. [Google Scholar] [CrossRef]
  15. Nevskaya, A.A.; Zinoveva, A.D.; Van der Eycken, E.V.; Voskressensky, L.G. Synthetic strategies for the construction of indolizines and indolizine-fused compounds: Thienoindolizines and indolizinoindoles. Asian J. Org. Chem. 2023, 12, e202300359. [Google Scholar] [CrossRef]
  16. Badaro, J.S.A.; Godlewski, B.; Gryko, D.T. Advances in the synthesis of indolizines and their π-expanded analogues: Update 2016–2024. Org. Chem. Front. 2025, 12, 2860–2907. [Google Scholar] [CrossRef]
  17. Leontie, L.; Danac, R.; Druta, I.; Carlescu, A.; Rusu, G.I. Electron transport properties of some newly synthesized nonsymmetrical bisindolizines in thin films. Synth. Met. 2010, 160, 2526–2533. [Google Scholar] [CrossRef]
  18. Anitha, I.; Sheela Gopal, M.; Thomas, D. A new fluorescent sensor based on bisindolizine derivative. J. Fluoresc. 2016, 26, 725–729. [Google Scholar] [CrossRef]
  19. Bonneau, R.; Collado, D.; Liu, M.T.H. Photolysis of m-phenylene-bis(chlorodiazirine)+2-vinylpyridine: Does an indolizine chromophore inhibit the photolysis of a diazirine? J. Photochem. Photobiol. A Chem. 2003, 161, 43–50. [Google Scholar] [CrossRef]
  20. Matsushima, T.; Kimura, R.; Asahara, M.; Murata, H. Photoluminescence and electroluminescence characteristics of 3,3′-dicyano-[7,7′-biindolizine]-1,1′,2,2′-tetracarboxylic acid 1,2-diethyl 1′,2′-dimethyl ester. Chem. Lett. 2008, 37, 1260–1261. [Google Scholar] [CrossRef]
  21. Dinică, R.M.; Druta, I.I.; Pettinari, C. The synthesis of substituted 7,7′-bis-indolizines via 1,3-dipolar cycloaddition under microwave irradiation. Synlett 2000, 7, 1013–1015. [Google Scholar] [CrossRef]
  22. Teodorescu, F.; Georgescu, E.; Georgescu, F.; Dumitrașcu, F.; Popa, M.M.; Draghici, C.; Nicolescu, A.; Deleanu, C. Simple One-Pot Three Component Synthesis of Symmetrically Substituted 7,7′-Bisindolizines. Rev. Roum. Chim. 2018, 63, 737–742. [Google Scholar]
  23. Botezatu, A.V.; Horincar, G.; Ghinea, I.O.; Furdui, B.; Bahrim, G.E.; Barbu, V.; Bălănescu, F.; Favier, L.; Dinică, R.M. Whole-cells of Yarrowia lipolytica applied in “One Pot” indolizine biosynthesis. Catalysts 2020, 10, 629. [Google Scholar] [CrossRef]
  24. Botezatu, A.V.; Bahrim, G.E.; Ungureanu, C.V.; Busuioc, A.C.; Furdui, B.; Dinică, R.M. Green “One-Pot” fluorescent bis-indolizine synthesis with whole-cell plant biocatalysis. Green Process. Synth. 2023, 12, 20230046. [Google Scholar] [CrossRef]
  25. Furdui, B.; Dinica, R.; Druta, I.; Demeunynck, M. Improved Synthesis of Cationic Pyridinium-Substituted Indolizines. Synthesis 2006, 16, 2640–2642. [Google Scholar] [CrossRef]
  26. Pinheiro, J.M.; Langer, P.; Wuckelt, J.; Döring, M. Synthesis of new isoxazole derivatives attached to sugar moieties. J. Heterocycl. Chem. 2004, 41, 877–882. [Google Scholar] [CrossRef]
  27. Rotaru, A.V.; Druta, I.I.; Müller, T.J.J. A novel coupling 1,3-dipolar cycloaddition sequence as a three-component approach to highly fluorescent indolizines. Helv. Chim. Acta 2005, 88, 1798–1812. [Google Scholar] [CrossRef]
  28. Danac, R.; Rotaru, A.; Druta, I.; Avram, E. Synthesis and properties of fluorescent 1,3-substituted mono and biindolizines. ARKIVOC 2009, 2009, 287–299. [Google Scholar] [CrossRef]
  29. Maghsoodlou, M.T.; Tahami Pour, B.; Marandi, G.; Akbarzadeh, N. Synthesis of some dipyrrolophenanthroline derivatives as novel macromolecules. ARKIVOC 2008, 2008, 153–159. [Google Scholar] [CrossRef]
  30. Sun, J.; Hu, H.; Wang, F.; Wu, H.; Liu, Y. Copper(II)-catalyzed cleavage of carbon–carbon triple bond to synthesize 1,2,3-triesterindolizines. RSC Adv. 2014, 4, 36498–36501. [Google Scholar] [CrossRef]
  31. Tiwari, S.; Rawat, D.S. Regiodivergent synthesis of densely functionalized indolizines via (2 + 2 + 1) cycloaddition. J. Org. Chem. 2023, 88, 6805–6815. [Google Scholar] [CrossRef]
  32. Al Matarneh, C.M.; Amarandi, R.M.; Craciun, A.M.; Mangalagiu, I.I.; Zbancioc, G.; Danac, R. Design, synthesis, molecular modelling and anticancer activities of new fused phenanthrolines. Molecules 2020, 25, 527. [Google Scholar] [CrossRef]
  33. Al Matarneh, C.M.; Apostu, M.O.; Mangalagiu, I.I.; Danac, R. Reactions of ethyl cyanoformate with cycloimmonium salts: A direct pathway to fused or substituted azaheterocycles. Tetrahedron 2016, 72, 4230–4238. [Google Scholar] [CrossRef]
Molbank 2025 m2074 sch001
Scheme 1. Synthesis pathway for the synthesis of monoindolizines 6a–f.
Scheme 1. Synthesis pathway for the synthesis of monoindolizines 6a–f.
Molbank 2025 m2074 sch001
Molbank 2025 m2074 sch002
Scheme 2. General scheme for the synthesis of unsymmetrical 7,7′-biindolizines 7a–f.
Scheme 2. General scheme for the synthesis of unsymmetrical 7,7′-biindolizines 7a–f.
Molbank 2025 m2074 sch002
Molbank 2025 m2074 sch003
Scheme 3. Suggested mechanism for the [2+2+1] cycloaddition of indolizines 6 and DMAD [31].
Scheme 3. Suggested mechanism for the [2+2+1] cycloaddition of indolizines 6 and DMAD [31].
Molbank 2025 m2074 sch003
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MDPI and ACS Style

Ciorteanu, R.; Danila, A.; Ciobanu, C.I.; Radu, I.; Mangalagiu, I.I.; Danac, R. Efficient Synthesis of Unsymmetrical 7,7′-Biindolizines. Molbank 2025, 2025, M2074. https://doi.org/10.3390/M2074

AMA Style

Ciorteanu R, Danila A, Ciobanu CI, Radu I, Mangalagiu II, Danac R. Efficient Synthesis of Unsymmetrical 7,7′-Biindolizines. Molbank. 2025; 2025(4):M2074. https://doi.org/10.3390/M2074

Chicago/Turabian Style

Ciorteanu, Roxana, Andreea Danila, Catalina Ionica Ciobanu, Ioana Radu, Ionel I. Mangalagiu, and Ramona Danac. 2025. "Efficient Synthesis of Unsymmetrical 7,7′-Biindolizines" Molbank 2025, no. 4: M2074. https://doi.org/10.3390/M2074

APA Style

Ciorteanu, R., Danila, A., Ciobanu, C. I., Radu, I., Mangalagiu, I. I., & Danac, R. (2025). Efficient Synthesis of Unsymmetrical 7,7′-Biindolizines. Molbank, 2025(4), M2074. https://doi.org/10.3390/M2074

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