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Article

β,β-Difluoro Peroxides as Fluorinated C2-Building Blocks for the Construction of Functionalized Indolizines

by
Yangyang Ma
1,*,
Hua Zhang
2,
Xiaoxiao Du
1,
Shurui Fang
1,
Kexin Yin
1,
Gangfeng Du
1,
Zhengshan Tian
1 and
Zhonghao Zhou
3,*
1
School of Chemical & Environmental Engineering, Pingdingshan University, Pingdingshan 467000, China
2
College of Medicine, Pingdingshan University, Pingdingshan 467000, China
3
School of Material Science and Engineering, Dalian Jiaotong University, Dalian 116028, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(24), 5927; https://doi.org/10.3390/molecules29245927
Submission received: 20 November 2024 / Revised: 9 December 2024 / Accepted: 12 December 2024 / Published: 16 December 2024
(This article belongs to the Section Organic Chemistry)
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Versions Notes

Abstract

An effective method for the construction of functionalized indolizines has been developed in which β,β-difluoro peroxides act as novel C2-building blocks to implement [3+2] annulation with pyridinium ylides under base-mediated conditions. With this protocol, a broad range of multisubstituted indolizines were prepared in moderate to good yields under mild conditions, and many useful functional groups were tolerated.

1. Introduction

The incorporation of a fluorine or perfluoroalkyl fragment into organic molecules can dramatically alter their physicochemical and biological properties [1,2,3]. The construction of fluorinated heterocycles has always been of particular interest in drug design due to fluorine’s unique electronic and steric properties which can enhance the lipophilicity, metabolic stability, and bioavailability of drug candidates [4,5,6]. To this end, significant advances have been made in the preparation of fluoroalkyl-substituted organic skeletons with diverse fluoroalkylated reagents [7,8,9,10,11,12]. Nevertheless, the direct fluoroalkylation of N-heterocycles in the desired position is still difficult [13,14]. Therefore, by employing simple and readily accessible fluorine-containing moieties as foundational units, more adaptable synthetic strategies serve as crucial alternatives to the direct fluoroalkylation approach. This highlights the superior utility and significance in these alternative methodologies [15,16].
Indolizines, a class of nitrogen-containing heterocycles with 10 π-delocalized electrons [17], have been extensively studied for their molecular structure and applications [18,19,20]. Indolizine derivatives also exhibit a broad spectrum of biological activities, including antitubercular, anticancer, antineoplastic, anti-inflammatory, and antioxidant properties [21,22,23,24,25] (Figure 1). Given the significant value of this structure, chemists have made considerable efforts and have developed synthetic approaches to achieve its synthesis and functionalization [26,27]. One of the most frequently utilized approaches for indolizines was based on the intermolecular [3+2] cycloaddition of 2-pyridylacetates or pyridiniums with activated alkenes, alkynes [28,29,30,31,32,33,34] or α-CF3 ketones [35]. Meanwhile, the reaction of 2-vinylpyridines with dichlorocarbene [36] and the cyclization of pyridines with alkenyl diazo acetates etc. [37,38] are also effective methods for the construction of indolizines (Scheme 1a). Even so, there are still limited available methods for the synthesis of perfluoroalkyl-substituted indolizines.
In this context, our work introduces a novel and efficient method for the synthesis of functionalized indolizines through oxidative [3+2] annulation of β,β-difluoro peroxides with pyridinium salts. This approach utilizes β,β-difluoro peroxides as fluorine-containing C2-building blocks, providing a straightforward and regioselective route to a wide range of substituted indolizines (Scheme 1b). The use of β,β-difluoro peroxides as building blocks [39,40,41] offers several advantages, including their easy availability and low cost, and the ability to introduce different functional groups into the indolizine skeleton. This method opens up new possibilities for the rapid and scalable synthesis of fluorinated indolizines, paving the way for the development of novel bioactive compounds and pharmaceuticals.

2. Results and Discussion

At the outset of our investigation, we selected β-perfluoroalkyl peroxide 1a and 1-(2-ethoxy-2-oxoethyl) pyridinium bromide 2a as the model to optimize the reaction conditions (Table 1). To our delight, the desired product 3a was obtained in a 54% yield in the presence of five equivalents of 1,4-diazabicyclo [2.2.2] octane (DABCO) as base in MeCN (Entry 1). Further screening of bases, such as N,N-diisopropylethylamine (DIPEA), triethylamine (NEt3), potassium phosphate tribasic (K3PO4), cesium carbonate (Cs2CO3), and potassium hydroxide (KOH), led to poor results (entries 2–6, respectively). These outcomes indicated DABCO (pKa = 8.8) [42] was exactly adequate to modulate the rate of Kornblum–DeLaMare rearrangement of β,β-difluoro peroxide [39,40,41]. The investigation of various solvents, including ethyl acetate (EA), dichloromethane (DCM), methanol, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO), was carried out (entries 7–11, respectively), and the results indicated that the case of DMSO afforded 3a an 82% yield (entry 11). In comparison, the yield of 3a was almost not affected at 60 °C (entry 12).
With the optimized conditions established, the scope of the substrates 1 and 2 were investigated (Figure 2). Representative results are summarized in Figure 2; β,β-difluoro peroxides 1, bearing a variety of functional groups (R = aryl), including both the electron-donating (tBu, Me, OMe) and electron-withdrawing (Cl, Br) groups, reacted smoothly with 1-(2-ethoxy-2-oxoethyl) pyridinium bromide 2. The substituents, regardless of the ortho-, meta- or para- position, were all tolerated to give the corresponding 2-perfluoro-substituted indolizines 3a–3h in good yields. The substrates with naphthalene could also react and give the desired products 3i in a 65% yield. Notably, other perfluoroalkyl groups, such as C5F11 (3j) and CF3 (3k), could also be successfully incorporated into the indolizine skeleton when the corresponding β-perfluoroalkyl peroxides were subjected to the standard conditions. In addition, indolizines could be adorned with other functionalities, including F (3l), Me (3m), H (3n), and ester (3o), via this [3 + 2] annulation protocol in regard to the corresponding β,β-difluorinated peroxides that were examined. Moreover, when the ester group of 2a was replaced with other electron-withdrawing substituents, such as ketone (2b) or cyanomethyl (2c), the desired products 3p and 3q were obtained in 70% and 62% yield respectively.
Based on the literature reports [35,43,44], a possible reaction mechanism is depicted in Scheme 2. The DABCO initiated Kornblum–DeLaMare rearrangement of peroxide 1 and the further elimination of one molecule of HF affords the key β- fluoro enone A [40]. Pyridinium ylide B, generated by the deprotonation of 1-(2-ethoxy-2-oxoethyl) pyridinium bromide 2, attacks the β- fluoro enone A, and then the intramolecular ring-closure process occurs to form an intermediate C. Intermediate C could be oxidized to obtain intermediate D, which provides target product 3 via sequential β-F elimination (path a). Alternatively, intermediate C would undergo β-F elimination to form intermediate E, and finally the target product 3 could be obtained by further oxidation (path b).

3. Materials and Methods

3.1. General Information

1H NMR spectra were recorded on Bruker 400 MHz and 600 MHz spectrometers, and the chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; m, multiplet; q, quartet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were obtained at Bruker 100 MHz and 150 MHz and referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3), and to the internal solvent signals (central peak is 39.9 ppm in DMSO). CDCl3 and DMSO were used as the NMR solvent. APEX II (Bruker Inc., Karlsruhe, Germany) was used for ESI-MS and EI-MS. IR spectra were recorded by a Bruker Tensor 27 infrared spectrometer. Flash column chromatography was performed over silica gel 200–300. All reagents were weighed and handled in air at room temperature. All chemical reagents were purchased from Alfa (Shanghai, China), Acros (Shanghai, China), Aldrich (Shanghai, China), TCI (Shanghai, China), Energy (Shanghai, China), and J&K (Guangzhou, China) and used without further purification.

3.2. General Procedures for Synthesis of β,β-Difluoro Peroxides 1

To a dry Schlenk tube were added tBuOOH (T-hydro, 70% in water, 6.0 mmol, 6.0 equiv), alkene (1.0 mmol, 1.0 equiv), Co(acac)2 (0.1 mmol, 0.1 equiv), BrCX2R1 or ICnF2n+1 (2.0 mmol, 2.0 equiv), and anhydrous MeCN (4.0 mL) under N2 atmosphere at room temperature. Subsequently, NEt3 (5.0 mmol, 5.0 equiv) was added to the mixture, and the resulting solution was stirred at ambient temperature for 5 h. The resulting mixture and the solvent were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether, 1:200–1:25) to give the peroxides 1a–1k (Figure S1) [45,46].
To a mixture of alkene (1.0 mmol), acid (3.0 mmol), Na2CO3 (0.1 mmol) and FeCl2 (7.5 mg, 0.1 mmol), MeCN (10.0 mL) was added under nitrogen at room temperature. Then tert-butyl hydroperoxide (TBHP, 0.8 mmol, 5–6 M in decane) was added into the mixture under nitrogen at room temperature. The resulting mixture was stirred under rt, 390 nm, 10 W for 24 h. The resulting reaction solution was directly filtered through a pad of silica by chloroform. The solvent was evaporated in vacuo to give the crude products 1l (Figure S1) and 1m (Figure S1) [47].
To a dry sealed tube were added alkene (1.0 mmol), CF2HSO2Na (2.0 mmol), tBuOOH (5.5 M in decane, 5.0 mmol), CuI (0.15 mmol), and MeCN (10.0 mL), and the resulting solution was stirred at 25 °C under N2 atmosphere for 3 h. Then the resulting mixture was evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/dichloromethane) to give the pure product 1n (Figure S1) [48].

3.3. General Procedures for Synthesis of 1,2,3-Trifunctionalized Indolizines 3

To a dry Schlenk tube were added 1 (0.1 mmol), 2 (0.2 mmol), DABCO (0.5 mmol), and DMSO (1.0 mL) at room temperature and the resulting solution was stirred at 25 °C for 5 h. After the mixture was cooled to room temperature, EtOAc (20.0 mL) was added and the mixture was washed with H2O (5.0 mL each) 3 times. The combined organic layer was dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the indolizines 3.
Ethyl 1-(4-(tert-butyl)benzoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3a. (40 mg, 78%). Yellow solid, mp 136–138 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.50 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.22–7.20 (m, 1H), 7.08–7.03 (m, 1H), 6.98–6.94 (m, 1H), 4.44 (q, J = 14.4 Hz, 7.0 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.34 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 191.3, 160.7, 157.6, 135.6, 134.5, 129.8, 127.4, 125.6, 123.8, 119.2 (t, J = 27.8), 118.7, 116.2 (t, J = 4.1), 115.2, 113.8, 61.3, 35.2, 31.1, 13.8, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.2, 3F), −97.7 to −97.8 (m, 2F), −121.9 to −122.0 (m, 2F); HRMS (ESI) calcd for C25H23F7NO3 [M + H+]: 518.1561; found: 518.1551.
Ethyl 2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)-1-(4-methylbenzoyl)indolizine-3-carboxylate 3b. (40 mg, 84%). Yellow solid, mp 125–126 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.50 (d, J = 7.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.9 Hz, 1H), 7.06–7.03 (m, 1H), 6.97–6.94 (m, 1H), 4.44 (q, J = 14.4 Hz, 7.1 Hz, 2H), 2.41 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 191.3, 160.7, 144.7, 135.8, 134.6, 130.0, 129.3, 127.4, 123.7, 119.1 (t, J = 28.5), 118.6, 116.1 (t, J = 4.0), 115.2, 113.8, 61.3, 21.7, 13.7, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.7, 3F), −97.8 to −97.7 (m, 2F), −121.9 to −122.0 (m, 2F); HRMS (ESI) calcd for C22H17F7NO3 [M + H+]: 476.1091; found: 476.1083.
Ethyl 2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)-1-(4-methoxybenzoyl)indolizine-3-carboxylate 3c. (43 mg, 87%). Yellow solid, mp 93–96 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.49 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 9.0 Hz, 1H), 7.07–7.03 (m, 1H), 6.98–6.94 (m, 1H), 6.91 (d, J = 8.9 Hz, 2H), 4.44 (q, J = 14.3 Hz, 7.1 Hz, 2H), 3.87 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 190.2, 164.1, 160.7, 134.4, 132.2, 131.3, 127.4, 123.7, 119.0 (t, J = 28.9), 118.6, 116.3 (t, J = 4.2), 115.2, 113.8, 113.7, 61.3, 55.5, 13.8, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.3, 3F), −97.9 to −98.0 (m, 2F), −121.9 to −122.0 (m, 2F); HRMS (ESI) calcd for C22H17F7NO4 [M + H+]: 492.1040; found: 492.1026.
Ethyl 1-benzoyl-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3d. (38 mg, 82%). Yellow solid, mp 98–100 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.49 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 8.8 Hz, 1H), 7.06 (t, J = 6.8 Hz, 1H), 6.96 (t, J = 6.9 Hz, 1H), 4.44 (q, J = 14.2 Hz, 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 191.7, 160.6, 138.3, 134.7, 133.6, 129.8, 128.6, 127.4, 123.9, 119.3 (t, J = 28.0), 118.6, 115.8 (t, J = 4.1), 115.3, 113.9, 61.4, 13.8, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.6, 3F), −97.6 to −97.7 (m, 2F), −121.8 to −121.9 (m, 2F); HRMS (ESI) calcd for C21H15F7NO3 [M + H+]: 462.0935; found: 462.0921.
Ethyl 1-(4-bromobenzoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3e. (45 mg, 84%). Yellow solid, mp 96–98 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.48 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.9 Hz, 1H), 7.09 (t, J = 6.8 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 4.44 (q, J = 14.4 Hz, 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 190.6, 160.6, 137.1, 134.7, 134.7, 132.0, 131.2, 129.0, 127.5, 124.2, 119.2 (t, J = 27.8), 118.4, 115.4, 115.1 (t, J = 4.0), 114.1, 61.5, 13.8, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.3, 3F), −97.7 to −97.7 (m, 2F), −121.9 to −122.0 (m, 2F); HRMS (ESI) calcd for C21H14F7BrNO3 [M + H+]: 540.0040; found: 540.0028.
Ethyl 1-(4-chlorobenzoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3f. (40 mg, 82%). Yellow solid, mp 110–113 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.40 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.12–7.10 (m, 1H), 7.03–6.99 (m, 1H), 6.92–6.88 (m, 1H), 4.36 (q, J = 14.4 Hz, 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 190.4, 160.6, 140.2, 136.7, 134.6, 131.1, 129.0, 127.5, 124.2, 119.2 (t, J = 27.7), 118.4, 115.4, 115.2 (t, J = 4.1), 114.1, 61.5, 13.7, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.4, 3F), −97.8 to −97.6 (m, 2F), −121.9 to −122.0 (m, 2F); HRMS (ESI) calcd for C21H14F7ClNO3 [M + H+]: 496.0545; found: 496.0536.
Ethyl 1-(3-bromobenzoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3g. (44 mg, 81%). Yellow solid, mp 90–91 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.49 (d, J = 7.4 Hz, 1H), 7.97 (s, 1H), 7.71 (t, J = 6.8 Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), 7.11 (t, J = 6.8 Hz, 1H), 7.00 (t, J = 6.8 Hz, 1H), 4.44 (q, J = 14.2 Hz, 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 190.3, 160.5, 140.2, 136.4, 134.8, 132.4, 130.2, 128.4, 127.5, 124.4, 123.0, 119.3 (t, J = 27.1), 118.4, 115.4, 114.9 (t, J = 4.0), 114.2, 61.5, 13.8, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.7, 3F), −97.6 to −97.4 (m, 2F), −121.9 to −122.0 (m, 2F); HRMS (ESI) calcd for C21H14F7BrNO3 [M + H+]: 540.0040; found: 540.0036.
Ethyl 1-(2-bromobenzoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3h. (39 mg, 73%). Yellow oil. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.18–9.16 (m, 1H), 7.58–7.56 (m, 1H), 7.40–7.38 (m, 1H), 7.30–7.24 (m, 2H), 7.07–7.00 (m, 2H), 6.90–6.86 (m, 1H), 4.38 (q, J = 14.4 Hz, 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 189.9, 160.8, 141.3, 136.6, 134.1, 132.4, 131.0, 127.4, 127.3, 125.3, 120.7, 119.7 (t, J = 28.5), 118.7, 116.1, 115.5, 115.4, 61.8, 13.7, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.3 (t, J = 10.1, 3F), −96.4 to −96.5 (m, 2F), −120.9 to −121.0 (m, 2F); HRMS (ESI) calcd for C21H14F7BrNO3 [M + H+]: 540.0040; found: 540.0034.
Ethyl 1-(2-naphthoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carboxylate 3i. (33 mg, 65%). Yellow solid, mp 138–142 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.51 (d, J = 7.3 Hz, 1H), 8.20 (s, 2H), 8.02 (d, J = 8.7 Hz, 1H), 7.92–7.82 (m, 3H), 7.60 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 6.9 Hz, 1H), 6.97 (t, J = 7.1 Hz, 1H), 4.46 (q, J = 14.3 Hz, 7.1 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 191.6, 160.7, 135.9, 135.7, 134.8, 132.6, 132.5, 129.7, 128.9, 128.6, 127.9, 127.5, 126.9, 124.6, 124.0, 119.4 (t, J = 28.4 Hz), 118.6, 116.0 (t, J = 4.1 Hz), 115.3, 114.0, 61.4, 13.8, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.2 (t, J = 10.4, 3F), −97.6 to −97.7 (m, 2F), −121.8 to −121.9 (m, 2F); HRMS (ESI) calcd for C25H17F7NO3 [M + H+]: 512.1091; found: 512.1085.
Ethyl 1-(4-(tert-butyl)benzoyl)-2-(5,5,5,5,5,5,5,5,5,5,5-undecafluoro-5λ12-penta-1,3-diyn-1-yl)indolizine-3-carboxylate 3j. (47 mg, 77%). Yellow solid, mp 118–120 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.50 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.9 Hz, 1H), 7.07–7.04 (m, 1H), 6.96 (td, J = 7.3 Hz, 1.2 Hz, 1H), 4.44 (q, J = 14.3 Hz, 7.3 Hz, 2H), 1.40 (t, 3H), 1.34 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 191.3, 160.7, 157.6, 135.6, 134.5, 129.8, 127.4, 125.6, 123.7, 119.3 (t, J = 28.0), 118.7, 116.3 (t, J = 4.3), 115.2, 113.8, 61.3, 35.2, 31.1, 13.7, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.8 (t, J = 10.7, 3F), −97.2 to −97.3 (m, 2F), −117.9 (m, 2F), −122.6 to −122.7 (m, 2F), −126.0 to −126.1 (m, 2F); HRMS (ESI) calcd for C27H23F11NO3 [M + H+]: 618.1497; found: 618.1488.
Ethyl 1-(4-methylbenzoyl)-2-(trifluoromethyl)indolizine-3-carboxylate 3k. (29 mg, 76%). White solid, mp 92–94 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.54–9.51 (m, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.57–7.54 (m, 1H), 7.27–7.24 (m, 2H), 7.18–7.14 (m, 1H), 7.03–6.99 (m, 1H), 4.45 (q, J = 14.4 Hz, 7.3 Hz, 2H), 2.42 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 191.1, 160.4, 144.4, 136.3, 135.3, 129.7, 129.3, 127.3, 124.6, 122.3 (q, J = 270.3 Hz), 122.2 (q, J = 37.0 Hz), 119.0, 115.7, 114.2 (d, J = 2.2Hz), 112.4(d, J = 3.1Hz), 61.3, 21.7, 13.9; 19F NMR (564 MHz, CDCl3) δ −52.6 (s, 3F); HRMS (ESI) calcd for C20H17F3NO3 [M + H+]: 376.1155; found: 376.1145.
Ethyl 1-benzoyl-2-fluoroindolizine-3-carboxylate 3l [6,35]. (20 mg, 63%). Yellow solid, mp 118–120 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.57 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 7.83–7.80 (m, 2H), 7.59–7.55 (m, 1H), 7.51–7.44 (m, 3H), 7.13–7.09 (m, 1H), 4.41 (q, J = 14.3 Hz, 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).
Ethyl 1-benzoyl-2-methylindolizine-3-carboxylate 3m. (26 mg, 84%). Yellow solid, mp 96–98 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.60 (d, J = 7.1 Hz, 1H), 7.74–7.72 (m, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.58–7.54 (m, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.18–7.14 (m, 1H), 6.92–6.89 (m, 1H), 4.42 (q, J = 14.2 Hz, 7.1 Hz, 2H), 2.47 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 192.6, 162.4, 141.0, 138.9, 136.5, 132.0, 129.2, 128.5, 128.0, 125.5, 118.6, 114.7, 114.0, 60.2, 14.5, 14.4; HRMS (ESI) calcd for C19H18NO3 [M + H+]: 308.1281; found: 308.1273.
Ethyl 1-benzoylindolizine-3-carboxylate 3n. (21 mg, 61%). Yellow solid, mp 89–90 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.58 (d, J = 7.0 Hz, 1H), 8.64 (d, J = 8.9 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 1.42–1.39 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 191.3, 1161.3, 155.0, 140.1, 137.4, 129.0, 127.9, 126.9, 126.1, 125.3, 120.7, 115.5, 114.7, 113.0, 60.4, 35.0, 31.3, 14.6; HRMS (ESI) calcd for C22H24NO3 [M + H+]: 350.1751; found: 350.1738.
Diethyl 1-benzoylindolizine-2,3-dicarboxylate 3o. (30 mg, 82%). White solid, mp 89–91 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 9.57 (d, J = 7.1 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.73–7.71 (m, 2H), 7.57–7.53 (m, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.33–7.29 (m, 1H), 7.07–7.03 (m, 1H), 4.37 (q, J = 14.4 Hz, 7.2 Hz, 2H), 3.95 (q, J = 14.4 Hz, 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 190.7, 165.3, 160.4, 140.0, 138.0, 131.9, 130.4, 128.8, 128.2, 127.9, 126.8, 119.9, 115.7, 112.7, 112.5, 61.7, 61.0, 14.1, 13.8; HRMS (ESI) calcd for C21H20NO5 [M + H+]: 366.1336; found: 366.1323.
(3-Benzoyl-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizin-1-yl)(4-(tert-butyl)phenyl)methanone 3p. (38 mg, 70%). Yellow solid, mp 69–70 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 7.92 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.52–7.48 (m, 4H), 7.15 (d, J = 9.3 Hz, 1H), 6.95–6.91 (m, 1H), 6.73–6.69 (m, 1H), 1.37 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 190.5, 188.5, 157.2, 137.7, 136.3, 134.6, 134.4, 129.8, 129.7, 128.9, 125.6, 124.9, 123.6, 123.5, 122.9, 119.6, 114.4, 113.8, 35.2, 31.1, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −80.1 (t, J = 10.3, 3F), −100.0 to −100.1 (m, 2F), −123.5 to −123.6 (m, 2F); HRMS (ESI) calcd for C29H23F7NO2 [M + H+]: 550.1612; found: 550.1603.
1-(4-(tert-butyl)benzoyl)-2-(3,3,3,3,3,3,3-heptafluoro-3λ8-prop-1-yn-1-yl)indolizine-3-carbonitrile 3q. (29 mg, 62%). Yellow solid, mp 135–138 °C. Isolated by flash column chromatography (petroleum ether: ethyl acetate = 10:1, Rf = 0.4); 1H NMR (600 MHz, CDCl3, ppm) δ 8.42 (d, J = 6.9 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 6.9 Hz, 1H), 7.10 (t, J = 6.8 Hz, 1H), 1.36 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 188.8, 157.9, 135.6, 135.5, 129.8, 125.7, 125.3, 123.1, 122.8, 122.5, 120.0, 116.2, 115.1, 110.7, 35.3, 31.1, not all carbons are reported due to extensive 19F splitting; 19F NMR (564 MHz, CDCl3) δ −79.9 (t, J = 9.9, 3F), −103.9 to −104.0 (m, 2F), −124.2 to −124.3 (m, 2F); HRMS (ESI) calcd for C23H18F7N2O [M + H+]: 471.1302; found: 471.1288.

4. Conclusions

In conclusion, we have developed a simple and efficient method for the synthesis of indolizines by base-mediated [3 + 2] annulation of β,β-difluoro peroxides as C2-Building Blocks and pyridinium ylides. With this protocol, a series of 1,2,3-trifunctionalized indolizines were afforded in moderate to good yields under ambient conditions. The operational simplicity and good functional group compatibility would render this protocol as a useful tool in organic synthesis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29245927/s1, S1: Figure S1. β,β-difluoro peroxides 1 and 1-(2-ethoxy-2-oxoethyl)pyridinium bromide 2; S2: Copies of 1H and 13C NMR spectra for 3.

Author Contributions

Synthesis and Characterization, Y.M., H.Z., X.D., S.F. and K.Y.; data curation, Y.M., H.Z. and Z.Z.; writing—original draft preparation, G.D., Z.Z. and Y.M.; writing—review and editing, H.Z., Z.Z. and Y.M.; funding acquisition, Y.M., Z.Z. and Z.T. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Natural Science Foundation of Henan Province of China (242300420568), the Key Scientific Programs of Higher Education of Henan Province of China (No. 24B150024), the Doctoral Scientific Research Foundation of Pingdingshan University (PXY-BSQD-2023002), the Henan Province science and technology research project (242102230037).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data will be made available upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 05927 g001
Figure 1. Representative bioactive indolizine derivatives.
Figure 1. Representative bioactive indolizine derivatives.
Molecules 29 05927 g001
Molecules 29 05927 sch001
Scheme 1. Representative protocols for the intermolecular synthesis of indolizines.
Scheme 1. Representative protocols for the intermolecular synthesis of indolizines.
Molecules 29 05927 sch001
Molecules 29 05927 g002
Figure 2. Scope of the substrates [a]. [a] Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), DABCO (0.6 mmol), 1,4-dioxane (2.0 mL), 60 °C, 6 h, unless otherwise noted. Reported yields were the isolated yields.
Figure 2. Scope of the substrates [a]. [a] Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), DABCO (0.6 mmol), 1,4-dioxane (2.0 mL), 60 °C, 6 h, unless otherwise noted. Reported yields were the isolated yields.
Molecules 29 05927 g002
Molecules 29 05927 sch002
Scheme 2. Proposed reaction mechanisms.
Scheme 2. Proposed reaction mechanisms.
Molecules 29 05927 sch002
Table 1. Optimization studies a.
Table 1. Optimization studies a.
Molecules 29 05927 i001
EntryBaseSolventT (°C)Yield (%) b
1DABCOMeCN2554
2DIPEAMeCN25N.R.
3NEt3MeCN25trace
4K3PO4MeCN25N.R.
5CsCO3MeCN25trace
6KOHMeCN25N.R.
7DABCOEA2511
8DABCODCM2513
9DABCOMeOH25trace
10DABCODMF2559
11DABCODMSO2582
12DABCODMSO6083
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), base (0.5 mmol), solvent (1.0 mL), 5 h, under air. b Reported yields were based on 1a and determined by 1H NMR using CH2Br2 as an internal standard.
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Ma, Y.; Zhang, H.; Du, X.; Fang, S.; Yin, K.; Du, G.; Tian, Z.; Zhou, Z. β,β-Difluoro Peroxides as Fluorinated C2-Building Blocks for the Construction of Functionalized Indolizines. Molecules 2024, 29, 5927. https://doi.org/10.3390/molecules29245927

AMA Style

Ma Y, Zhang H, Du X, Fang S, Yin K, Du G, Tian Z, Zhou Z. β,β-Difluoro Peroxides as Fluorinated C2-Building Blocks for the Construction of Functionalized Indolizines. Molecules. 2024; 29(24):5927. https://doi.org/10.3390/molecules29245927

Chicago/Turabian Style

Ma, Yangyang, Hua Zhang, Xiaoxiao Du, Shurui Fang, Kexin Yin, Gangfeng Du, Zhengshan Tian, and Zhonghao Zhou. 2024. "β,β-Difluoro Peroxides as Fluorinated C2-Building Blocks for the Construction of Functionalized Indolizines" Molecules 29, no. 24: 5927. https://doi.org/10.3390/molecules29245927

APA Style

Ma, Y., Zhang, H., Du, X., Fang, S., Yin, K., Du, G., Tian, Z., & Zhou, Z. (2024). β,β-Difluoro Peroxides as Fluorinated C2-Building Blocks for the Construction of Functionalized Indolizines. Molecules, 29(24), 5927. https://doi.org/10.3390/molecules29245927

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