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Article

1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel–Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature

by
Juanjuan Gao
,
Zhaowen Liu
,
Xiaohua Guo
,
Longhui Wu
,
Zhixi Chen
* and
Kai Yang
*
College of Pharmacy, Gannan Medical University, Ganzhou 341000, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(22), 7522; https://doi.org/10.3390/molecules28227522
Submission received: 12 October 2023 / Revised: 6 November 2023 / Accepted: 8 November 2023 / Published: 10 November 2023
(This article belongs to the Special Issue Advances in the Synthesis of Heterocyclic Compounds and Their Applications)
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Abstract

:
A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel–Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp2)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope.

Graphical Abstract

1. Introduction

The incorporation of fluorine-containing groups within bioactive compounds is considered one of the most useful approaches to address important issues relevant to medicinal chemistry due to their unique chemical and biological properties, such as affinity, metabolic stability, lipophilicity, cell permeability, and bioavailability [1,2,3]. One of the more prominent examples is the CF2H unit, which is a good hydrogen bond donor and may serve as a bioisostere for hydroxy, thiol, and amide groups, and it has additional attractive properties such as its ability to modulate lipophilicity, polarity, and conformational preferences [4]. For these reasons, CF2H-containing compounds may be widely applied in the fields of pharmaceuticals, agrochemicals, and advanced functional materials [5,6,7]. Notably, difluoromethyl carbinols containing both the difluoromethyl and hydroxyl groups are prevalent in bioactive molecules, such as antitumor agents [8], antidiabetic agents [9], Gaucher disease inhibitors [10], farnesoid X receptor modulators [11], and estrogen receptor degraders [12] (Figure 1). Therefore, the exploration of a facile synthetic protocol of difluoromethylated carbinol derivatives is an undeniably important and valuable research topic in expanding the chemical space for drug discovery [13,14].
In addition, imidazo[1,2-a]pyridines are widely found in natural products. They are also extensively used in modern organic synthesis and pharmaceutical and materials science [15]. Imidazo[1,2-a]pyridine is considered to be an important scaffold due to its various biological and pharmaceutical activities, such as antiviral, antifungal, and antitumor activities. The core structure of many commercially available drugs includes alpidem, miroprofen, necopidem, olprinone, saripidem, zolpidem, and zolimidine (Figure 2) [16,17,18,19,20,21]. Therefore, the efficient and green preparation of imidazo[1,2-a]pyridine derivatives with various substituents has also drawn considerable attention, especially C3-functionalized imidazo[1,2-a]pyridine derivatives [22]. Therefore, a sustained effort is being made to develop new approaches to synthesize C3-functionalized imidazo[1,2-a]pyridine derivatives. However, there are no reports on the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines.
The strategy of C-H bond functionalization is known to be an ideal route for the preparation of diverse imidazo[1,2-a]pyridines as it is a straightforward, atom-economical, and synthetic step-economical method [23,24,25]. However, there are no reports on the C-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines. It has been reported that 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), with a much higher polarity, increased Brønsted acidity, and strong hydrogen-bond donation [26,27,28,29,30,31], was considered to be a promising catalyst or promoter for the Friedel–Crafts reaction. For example, as early as 2012, the Naájera research group reported that HFIP serves as a promoter for the substitution reaction of allylic alcohols with nucleophiles [26]. Subsequently, HFIP was studied and applied as a catalyst or promoter in various types of Friedel–Crafts reactions. Inspired by this strategy for HFIP-promoted Friedel–Crafts alkylation, we focused our interest on developing facile methods for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted cross-dehydrative coupling of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines (Scheme 1). This green protocol possesses many intrinsic advantages like operational simplicity, high efficiency, atom economy, mild reaction conditions (e.g., at room temperature, transition metal- and oxidant-free, without inert gas protection), and a wide substrate scope.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

The hydroxydifluoromethylation of imidazo[1,2-a]pyridine (1a) and commercially available difluoroacetaldehyde ethylacetal (2a) was selected as the model reaction for the optimization of the reaction conditions. The results are summarized in Table 1.
Initially, the effect of Brønsted acids and Lewis acids, such as trifluoroacetic acid (TFA), p-toluenesulfonic acid (TsOH), BF3.Et2O, Y(OTf)3, and Sc(OTf)3, employed as catalysts on the reaction was investigated (Entries 1–5); it was found that only a trace amount of product 3a was detected. HFIP was considered to be a promising catalyst or promoter considering its much higher polarity, increased Brønsted acidity, and strong hydrogen-bond donation [26,27,28,29,30,31]. Therefore, we investigated the effect of HFIP as a catalyst or promoter on this transformation. Regrettably, trace product 3a was afforded in dichloromethane when 10 mol% HFIP was employed in the reaction, indicating that the catalytic amount of HFIP was not enough to facilitate the hydroxydifluoromethylation process (Entry 6). We attempted to increase the dosage of HFIP to 1.0 or 2.0 equivalents; product 3a could be obtained in 50% and 73% yields, respectively (Entries 7 and 8). This result encouraged us to use HFIP as a solvent for the reaction. Excitingly, the hydroxydifluoromethylation could proceed completely to obtain 3a in 97% yield (Entry 9). Thus, using HFIP as the solvent, the reaction of 1a (0.2 mmol) and 2a (0.4 mmol) was successfully achieved at room temperature for 12 h to obtain 3a in satisfactory yield.

2.2. Scope of Reaction Substrates

Under the optimized reaction conditions, the substrate scope of this approach was examined by using different 2-substituted imidazo[1,2-a]pyridines. The results are summarized in Table 2.
It was found that 2-phenyl imidazo[1,2-a]pyridine could react smoothly with 2a to give the corresponding product 3b in 95% yield. Then, a series of substituents, such as methyl, methoxyl, fluoro, chloro, and bromo groups on the C2-phenyl ring of 2-phenyl imidazo[1,2-a]pyridines, were well tolerated under the standard conditions. This showed that both methyl and methoxyl substituted substrates proceeded smoothly to give the corresponding products 3c–3f in 79–92% yields. The halo-substituted substrates exhibited good reactivity in the hydroxydifluoromethylation to obtain products 3g–3l in 82–92% yields. Dichloro-substituted and dimethoxy-substituted substrates were also subjected to smooth transformation to afford products 3m and 3n in 84% and 82% yields, respectively. As anticipated, 2-(naphthalen-1-yl) and 2-(naphthalen-2-yl) imidazo[1,2-a]pyridines underwent hydroxydifluoromethylation to give the desired products 3o and 3p in 78% and 80% yields, respectively. To our delight, 2-heteroaryl imidazo[1,2-a]pyridines were also successfully employed for the synthesis of the desired products. Using 2-(2-pyridyl)imidazo[1,2-a]pyridine and 2-(2-thienyl)imidazo[1,2-a]pyridine as substrates, corresponding products 3q and 3r were obtained in 68% and 73% yields, respectively. Furthermore, this conversion could be readily carried out on the 5 mmol scale to obtain the desired product 3a in 87% yield, which proved to be easily applied to a gram-scale preparation.
To further extend the scope of this methodology, a series of imidazo[1,2-a]pyridines with different substituents on the pyridine ring were used to evaluate the universality of this hydroxydifluoromethylation (Table 3). As anticipated, imidazo[1,2-a]pyridines with an electron-donating group as well as a halogen group on the pyridine rings all worked well with 2a and afforded the desired target molecules 3aa–3ah in satisfactory yields (83–95%). Trifluoromethyl, as a strong electron-withdrawing group, can also be tolerated in this conversion, giving the products in good yields (3ai, 89% and 3aj, 87%). 6-Bromo-7-methyl-2-phenylimidazo[1,2-a]pyridine as a polysubstituted substrate was also suitable for this conversion, resulting in the product 3ak with 90% yield.
The structures of the desired products were confirmed by NMR (1H, 13C, and 19F) and HM-RS data, and the structure of 3b (CCDC 2295549) was unambiguously confirmed by single-crystal X-ray analysis, which can be seen in Supplementary Materials for details [32].

2.3. Mechanism Investigation

To gain insight into the details of the mechanism, we performed two control experiments accordingly. Adding 2.0 equivalent radical scavenger 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO) or BHT (butylated hydroxytoluene) to the reaction system, it was found that the corresponding compound 3a could also be obtained in 91% and 88% isolation yields, respectively (Scheme 2). These results indicated that the reaction may not be involved in the pathway of radical participation.
It has been reported that HFIP can be used to promote the generation of a C-C bond by cleavage of a C-O bond (the substrates of aromatic aldehyde hydrate, propargyl alcohol, difluoroacetaldehyde ethyl hemiacetal, etc.) via the Friedel–Crafts alkylation pathway [26,27,28,33,34,35]. Based on the properties of HFIP and the above-mentioned control experimental results, a plausible mechanism of HFIP-promoted Friedel–Crafts alkylation was put forward (Scheme 3). Initially, under the action of proton donor HFIP, the difluoroacetaldehyde ethyl hemiacetal 2a has a tendency to remove one molecule of ethanol to generate difluoroacetaldehyde A, then with proton exchange with HFIP taking place and forming carbonium ions to active difluoroacetaldehyde A, making it more susceptible for nucleophilic addition with imidazo[1,2-a]pyridine 1a, to generate the corresponding B. Finally, B undergoes the dehydrogenation process to produce the final product 3a.

2.4. Synthetic Derivatization

Moreover, the reactions are highly practical because of their wide range of applications in pharmaceutical chemistry for the production of diversified structural scaffolds and combinatorial libraries for drug discovery. The desired targets derivatized at hydroxyl positions may be promising candidates for such applications in pharmaceutical chemistry and organic synthesis. For instance, C3-difluoroacetyl imidazo[1,2-a]pyridines 4a and 4b have been prepared through Dess–Martin periodinane oxidation with 3a and 3b with yields of 77% and 79%, respectively (Scheme 4).

3. Materials and Methods

3.1. General Information

Melting point (m.p.) was performed on a Büchi Melting Point B-545 instrument without correcting. The 1H, 13C and 19F NMR spectra were collected on a BRUKER DRX-400 spectrometer in CDCl3 using tetramethylsilane (TMS) as an internal standard. High-resolution mass spectra (HRMS) were obtained with an LCMS-IT-TOF mass spectrometer. Single-crystal X-ray analysis was obtained using Bruker APEX2 Smart CCD. TLC was performed by using commercially prepared 100–400 mesh silica gel plates (GF254), and visualization was detected at 254 or 365 nm. All reagents and solvents were purchased from commercial sources and used without further purification, The 2-substituted imidazo[1,2-a]pyridines 1 (except for 1a) were synthesized from 2-bromoacetophenones (or acetophenones) and various 2-aminopyridines [36,37].

3.2. Experimental Procedure for Compounds 3a–3ak

The mixture of substituted imidazo[1,2-a]pyridine 1 (0.2 mmol, 1.0 equiv.) and difluoroacetaldehyde ethyl hemiacetal 2a (0.30 mmol, 1.5 equiv.) in 1,1,1,3,3,3-hexafluoro-2-propanol (1.0 mL) was stirred at room temperature for 12 h. After the completion of the reaction, the reaction mixture was quenched with H2O (15 mL) and extracted three times with ethyl acetate (3 × 15 mL). Then, the organic layer was dried over anhydrous Na2SO4. After the filtration and evaporation of the solvents under reduced pressure, the crude products were purified by column chromatography on silica gel to afford the desired products 3a–3ak.

3.3. Experimental Procedure for Compounds 4a and 4b

Compounds 3a or 3b (0.1 mmol, 1.0 equiv.) and Dess–Martin periodinane (0.37 mmol, 3.7 equiv.) in DCM (1.0 mL) were stirred in a ground glass test tube at room temperature for 4 h. After monitoring the end of the reaction on TLC, the residues were purified by column chromatography on silica gel to give the pure products 4a or 4b.

3.4. Characterization Data for All Products 3a–3ak and 4a–4b

  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-imidazo[1,2-a]pyridine (3a), white solid (38 mg, 97%); m.p. 160–162 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH: 5.16–5.23 (m, 1H), 6.10 (td, J = 55.6, 3.2 Hz, 1H), 6.85–6.90 (m, 1H), 7.23–7.28 (m, 1H), 7.49–7.56 (m, 2H), 8.41 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC: 65.7 (t, J = 26.0 Hz), 112.7, 115.1 (t, J = 243.0 Hz), 116.9, 119.9, 125.6, 125.7, 131.8, 146.2; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −126.14 (d, J = 285.8 Hz, 1F), 127.05 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C9H9F2N2O [M + H]+, 199.0677, found: 199.0669.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-phenyl-imidazo[1,2-a]pyridine (3b), white solid (52 mg, 95%); m.p. 161–163 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.31–5.38 (m, 1H), 6.14 (td, J = 55.6, 3.2 Hz, 1H), 7.18–7.23 (m, 1H), 7.30–7.35 (m, 3H), 7.44–7.50 (m, 3H), 8.63 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.2 (t, J = 25.0 Hz), 112.3, 115.4 (t, J = 245.0 Hz), 115.6, 116.5, 125.9, 127.3, 128.3, 128.4, 128.8, 133.1, 145.4, 145.5; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.70 (d, J = 282.0 Hz, 1F), −124.88 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H13F2N2O [M + H]+, 275.0990, found: 275.0979.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(p-tolyl)-imidazo[1,2-a]pyridine (3c), white solid (53 mg, 92%); m.p. 187–189 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 2.35 (s, 3H), 5.31–5.38 (m, 1H), 6.13 (J = 55.6, 3.2 Hz, 1H), 6.75–6.80 (m, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.16–7.21 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 9.2 Hz, 1H), 8.61 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 21.2, 66.2 (t, J = 24.6 Hz), 112.2, 115.4 (t, J = 244.0 Hz), 116.4, 125.8, 127.3, 128.6, 128.8, 129.1, 129.3, 130.1, 138.1, 145.4; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.68 (d, J = 282.0 Hz, 1F), −124.96 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O [M + H]+, 289.1147, found: 289.1136.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(4-methoxyphenyl)-imidazo[1,2-a]pyridine (3d), white solid (55 mg, 90%); m.p. 178–180 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 3.83 (s, 3H), 5.29–5.36 (m, 1H), 6.14 (td, J = 55.6, 2.4 Hz, 1H), 6.71–6.81 (m, 1H), 6.86–6.90 (m, 2H), 7.81–7.21 (m, 1H), 7.40–7.46 (m, 3H), 8.62 (d, J = 4.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 55.2, 66.2 (t, J = 25.0 Hz), 112.2, 113.9, 115.1, 115.4 (t, J = 244.0 Hz), 116.3, 115.6, 125.8, 127.2, 130.1, 145.2, 145.4, 159.6; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.74 (d, J = 282.0 Hz, 1F), −124.87 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O2 [M + H]+, 305.1096, found: 305.1081.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(3-methoxyphenyl)-imidazo[1,2-a]pyridine (3e), white solid (52 mg, 85%); m.p. 176–178 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.34–5.42 (m, 1H), 6.13 (td, J = 55.6, 3.6 Hz, 1H), 6.75–6.79 (m, 1H), 6.84–6.87 (m, 1H), 7.00–7.05 (m, 2H), 7.14–7.23 (m, 2H), 7.41 (d, J = 7.2 Hz, 1H), 8.61 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 55.2, 66.3 (t, J = 26.0 Hz), 112.3, 112.9, 114.1, 114.2, 115.4 (t, J = 245.0 Hz), 115.5, 116.6, 1221.2, 125.9, 127.3, 129.5, 134.4, 145.3, 145.4, 159.4; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.62 (d, J = 282.0 Hz, 1F), −124.75 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O2 [M + H]+, 305.1096, found: 305.1081.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(2-methoxyphenyl)-imidazo[1,2-a]pyridine (3f), white solid (48 mg, 79%); m.p. 177–179 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 3.56 (s, 1H), 5.07–5.14 (m, 1H), 5.91 (td, J = 55.6, 1.6 Hz, 1H), 6.70–6.77 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 7.09–7.16 (m, 2H), 7.21–7.25 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 55.2, 66.5 (t, J = 24.0 Hz), 111.0, 112.1, 115.7 (t, J = 246.0 Hz),, 116.6, 116.9, 120.8, 122.1, 125.4, 127.2, 130.0, 132.1, 141.3, 145.6, 156.3; 19F NMR (376 MHz, CDCl3), δF, ppm: −123.06 (d, J = 278.2 Hz, 1F), −127.67 (d, J = 278.2 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O2 [M + H]+, 305.1096, found: 305.1081.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(4-fluorophenyl)-imidazo[1,2-a]pyridine 2,2- (3g), white solid (49 mg, 85%); m.p. 208–210 °C; 1H-NMR (400 MHz, CD3OD), δH, ppm: 5.28–5.35 (m, 1H), 6.33 (td, J = 55.6, 3.6 Hz, 1H), 6.92–6.96 (m, 1H), 7.18–7.24 (m, 2H), 7.35–7.39 (m, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.63–7.67 (m, 2H), 8.75 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CD3OD), δC, ppm: 66.1 (t, J = 25.0 Hz), 112.3, 115.1 (t, J = 22.0 Hz), 115.7 (t, J = 243.0 Hz), 115.8, 116.1, 126.4, 127.5, 129.6 (d, J = 3.0 Hz), 130.8 (d, J = 9.0 Hz), 145.5, 144.2, 163.0 (d, J = 246.0 Hz); 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −115.40, −125.45 (d, J = 285.8 Hz, 1F), −126.28 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12F3N2O [M + H]+, 293.0896, found: 293.0885.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(2-fluorophenyl)-imidazo[1,2-a]pyridine (3h), white solid (48 mg, 82%); m.p. 173–175 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 5.04–5.11 (m, 1H), 5.95 (td, J = 55.6, 2.0 Hz, 1H), 6.68–6.72 (m, 1H), 6.92–7.00 (m, 2H), 7.09–7.13 (m, 1H), 7.17–7.23 (m, 1H), 7.26–7.31 (m, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.57 (d, J = 6.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 66.4 (t, J = 24.0 Hz), 112.4, 115.4 (t, J = 246.0 Hz), 115.6, 115.8, 116.6, 120.9 (d, J = 15.0 Hz), 124.3 (d, J = 4.0 Hz), 126.0, 127.5, 130.4 (d, J = 8.0 Hz), 132.0, 138.9, 145.9, 159.4 (d, J = 245.0 Hz); 19F NMR (376 MHz, CDCl3), δF, ppm: −123.88 (d, J = 285.8 Hz, 1F), −124.66 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12F3N2O [M + H]+, 293.0896, found: 293.0885.
  • (±)-2-(4-Chlorophenyl)-3-(2,2-difluoro-1-hydroxy)ethyl-imidazo[1,2-a]pyridine (3i), white solid (55 mg, 90%); m.p. 198–200 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.26–5.32 (m, 1H), 6.16 (td, J = 55.6, 3.2 Hz, 1H), 6.80–6.85 (m, 1H), 7.22–7.31 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 9.2 Hz, 1H), 8.60 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.3 (t, J = 26.0 Hz), 112.6, 115.2 (t, J = 245.0 Hz), 115.6, 116.6, 126.2, 127.3, 128.7, 129.9, 131.5, 134.4, 144.2, 145.5; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.74 (d, J = 282.0 Hz, 1F), −124.57 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12ClF2N2O [M + H]+, 309.0601, found: 309.0616.
  • (±)-2-(3-Chlorophenyl)-3-(2,2-difluoro-1-hydroxy)ethyl-imidazo[1,2-a]pyridine (3j), white solid (57 mg, 92%); m.p. 174–176 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.28–5.26 (m, 1H), 6.15 (td, J = 55.6, 3.6 Hz, 1H), 6.78–6.83 (m, 1H), 7.20–7.23 (m, 1H), 7.25–7.32 (m, 2H), 7.35–7.38 (m, 1H), 7.44–7.51 (m, 2H), 8.63 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.1 (t, J = 25.0 Hz), 112.6, 115.3 (t, J = 245.0 Hz), 115.9, 116.5, 126.2, 126.9, 127.4, 128.3, 128.7, 129.7, 134.3, 134.9, 143.8, 145.5; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.86 (d, J = 285.8 Hz, 1F), −124.63 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12ClF2N2O [M + H]+, 309.0601, found: 309.0616.
  • (±)-2-(4-Bromophenyl)-3-(2,2-difluoro-1-hydroxy)ethyl-imidazo[1,2-a]pyridine (3k), white solid (60 mg, 86%); m.p. 190–192 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.24–5.31 (m, 1H), 6.16 (td, J = 55.6, 3.6 Hz, 1H), 6.80–6.85 (m, 1H), 7.22–7.26 (m, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.43–7.47 (m, 3H), 8.59 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.2 (t, J = 25.0 Hz), 112.5, 115.2 (t, J = 245.0 Hz), 115.7, 116.6, 122.7, 126.2, 127.3, 130.2, 131.6, 131.9, 144.2, 145.5; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.74 (d, J = 282.0 Hz, 1F), −124.56 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15BrF2N2O [M + H]+, 353.0096, found: 353.0107.
  • (±)-2-(3-Bromophenyl)-3-(2,2-difluoro-1-hydroxy)ethyl-imidazo[1,2-a]pyridine (3l), white solid (59 mg, 84%); m.p. 186–188 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.27–5.35 (m, 1H), 6.01–6.16 (m, 1H), 6.78–6.82 (m, 1H), 7.17–7.22 (m, 2H), 7.38–7.45 (m, 3H), 7.67 (s, 1H), 8.62 (d, J = 6.4 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.22 (t, J = 25.0 Hz), 112.6, 115.3 (t, J = 245.0 Hz), 115.9, 116.6, 122.5, 126.3, 127.4, 130.0, 131.3, 131.7, 135.2, 143.7, 145.6; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.88 (d, J = 285.8 Hz, 1F), −124.66 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12BrF2N2O [M + H]+, 353.0096, found: 353.0107.
  • (±)-2-(3,4-Dichlorophenyl)-3-(2,2-difluoro-1-hydroxy)ethyl-imidazo[1,2-a]pyridine (3m), white solid (57 mg, 84%); m.p. 205–207 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.26–5.34 (m, 1H), 6.18 (td, J = 55.6, 3.6 Hz, 1H), 6.83–6.87 (m, 1H), 7.25–7.30 (m, 1H), 7.38–7.53 (m, 3H), 7.68 (s, 1H), 8.63 (d, J = 6.4 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD=7:1), δC, ppm: 66.2 (t, J = 26.0 Hz), 112.7, 115.2 (t, J = 245.0 Hz), 116.0, 116.6, 126.5, 127.4, 128.0, 130.5, 132.5, 132.6, 133.2, 142.9, 145.6; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.85 (d, J = 285.8 Hz, 1F), −124.66 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H11Cl2F2N2O [M + H]+, 343.0211, found: 343.0213.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(3,4-dimethoxyphenyl)-imidazo[1,2-a]pyridine (3n), white solid (55 mg, 82%); m.p. 178–180 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 3.86 (s, 3H), 3.90 (s, 3H), 5.35–5.42 (m, 1H), 6.19 (td, J = 55.6, 3.6 Hz, 1H), 6.78–6.86 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.19–7.23 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 8.61 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 55.7, 55.7, 66.3 (t, J = 25.0 Hz), 110.9, 112.1, 112.3, 115.1, 115.4 (t, J = 245.0 Hz), 116.3, 121.2, 125.8, 125.9, 127.2, 145.3, 145.4, 148.7, 149.0; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.54 (d, J = 282.0 Hz, 1F), −124.53 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C17H17F2N2O3 [M + H]+, 335.1202, found: 335.1195.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(naphthalen-1-yl)-imidazo[1,2-a]pyridine (3o), white solid (51 mg, 78%); m.p. 212–214 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 4.68–4.76 (m, 1H), 5.45 (td, J = 55.6, 2.8 Hz, 1H), 6.67–6.71 (m, 1H), 6.94–6.99 (m, 2H), 7.06–7.10 (m, 1H), 7.15–7.19 (m, 1H), 7.25–7.30 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 66.0 (t, J = 25.0 Hz), 112.3, 115.2 (t, J = 245.0 Hz), 116.4, 117.2, 124.9, 125.6, 125.9, 125.9, 126.2, 127.3, 128.0, 128.3, 129.0, 130.2, 132.2, 133.4, 143.8, 145.3; ESI-HRMS, m/z: Calcd for C19H15F2N2O [M + H]+, 325.1147, found: 325.1154.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(naphthalen-2-yl)-imidazo[1,2-a]pyridine (3p), white solid (52 mg, 80%); m.p. 210–212 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.38–5.42 (m, 1H), 6.14 (td, J = 55.6, 3.2 Hz, 1H), 6.57–6.61 (m, 1H), 6.96–7.01 (m, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.47–7.51 (m, 3H), 7.65 (d, J = 8.4 Hz, 1H), 7.73–7.77 (m, 2H), 7.85 (s, 1H), 8.53 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD=7:1), δC, ppm: 66.3 (t, J = 25.0 Hz), 112.2, 115.4 (t, J = 245.0 Hz), 115.8, 116.3, 125.8, 126.3, 126.3, 126.4, 127.2, 127.6, 127.8, 128.1, 128.3, 130.4, 132.9, 133.0, 145.2, 145.5; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.52 (d, J = 285.8 Hz, 1F), −124.60 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C19H15F2N2O [M + H]+, 325.1147, found: 325.1154.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(pyridin-2-yl)-imidazo[1,2-a]pyridine (3q), white solid (37 mg, 68%); m.p. 165–167 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 5.25–5.32 (m, 1H), 5.87 (td, J = 55.6, 5.6 Hz, 1H), 6.78–6.82 (m, 1H), 7.14–7.23 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H), 7.78–7.82 (m, 1H), 8.03 (d, J = 6.8 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.45 (d, J = 4.0 Hz, 1H), 9.82 (br, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 65.8 (t, J = 26.0 Hz), 113.3, 115.9 (t, J = 244.0 Hz), 118.0, 120.1, 123.0, 123.0, 124.0, 125.6, 138.4, 142.6, 145.1, 147.2, 152.6; 19F NMR (376 MHz, CDCl3), δF, ppm: −123.20 (d, J = 282.0 Hz, 1F), −127.07 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C14H12F2N3O [M + H]+, 276.0943, found: 276.0962.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-(thiophen-2-yl)-imidazo[1,2-a]pyridine (3r), white solid (41 mg, 73%); m.p. 163–165 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.46–5.54 (m, 1H), 6.10 (td, J = 55.6, 3.2 Hz, 1H), 6.69–6.73 (m, 1H), 6.96–6.99 (m, 1H), 7.11–7.16 (m, 1H), 7.19 (d, J = 3.6 Hz, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 8.57 (d, J = 7.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.4 (t, J = 25.0 Hz), 112.4, 114.9, 115.4 (t, J = 246.0 Hz), 116.4, 126.2, 126.3, 126.7, 127.4, 127.6, 135.5, 139.1, 145.7; 19F NMR (376 MHz, CDCl3), δF, ppm: −123.44 (d, J = 282.0 Hz, 1F), −127.37 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C13H11F2N2OS [M + H]+, 281.0555, found: 281.0566.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-6-methyl-2-phenyl-imidazo[1,2-a]pyridine (3aa), white solid (54 mg, 93%); m.p. 212–214 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 2.30 (s, 3H), 5.28–5.36 (m, 1H), 6.13 (td, J = 55.6, 4.0 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 7.26–7.31 (m, 4H), 7.38–7.41 (m, 2H), 8.35 (s, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 18.4, 66.3 (t, J = 25.0 Hz), 115.1, 115.2 (t, J = 245.0 Hz), 115.8, 122.0, 124.8, 128.0, 128.4, 128.7, 129.0, 133.1, 144.5, 145.2; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.27 (d, J = 282.0 Hz, 1F), −124.93 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O [M + H]+, 289.1147, found: 289.1136.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-7-methyl-2-phenyl-imidazo[1,2-a]pyridine (3ab), white solid (55 mg, 95%); m.p. 186–188 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 2.32 (s, 3H), 5.26–5.34 (m, 1H), 6.18 (td, J = 55.6, 3.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.17–7.29 (m, 6H), 8.43 (d, J = 9.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 21.3, 66.4 (t, J = 25.0 Hz), 114.8, 115.1, 115.3 (t, J = 245.0 Hz), 126.5, 128.1, 128.4, 128.6, 132.7, 137.3, 144.8, 145.7; 19F NMR (376 MHz, CDCl3), δF, ppm: −123.73 (d, J = 282.0 Hz, 1F), −124.81 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O [M + H]+, 289.1147, found: 289.1136.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-8-methyl-2-phenyl-imidazo[1,2-a]pyridine (3ac), white solid (49 mg, 84%); m.p. 184–186 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 2.53 (s, 3H), 5.21–5.28 (m, 1H), 6.08 (td, J = 55.6, 1.6 Hz, 1H), 6.70–6.74 (m, 1H), 7.03 (d, J = 6.0 Hz, 1H), 7.28–7.32 (m, 3H), 7.45–7.48 (m, 2H), 8.48 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 16.9, 66.2 (t, J = 25.0 Hz), 112.4, 115.2 (t, J = 245.0 Hz), 115.9, 124.8, 124.9, 126.7, 128.1, 128.3, 129.1, 133.3, 145.2, 145.9; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.51 (d, J = 282.0 Hz, 1F), −124.57 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O [M + H]+, 289.1147, found: 289.1136.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-7-methoxy-2-phenyl-imidazo[1,2-a]pyridine (3ad), white solid (52 mg, 85%); m.p. 201–203 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 3.86 (s, 3H), 5.27–5.32 (m, 1H), 5.99–6.28 (m, 1H), 6.78–6.81 (m, 1H), 7.31–7.42 (m, 3H), 7.49–7.59 (m, 2H), 8.46 (d, J = 4.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 55.5, 66.2 (t, J = 25.0 Hz), 93.7, 107.3, 114.3, 115.4 (t, J = 245.0 Hz), 127.8, 128.1, 128.4, 128.7, 133.3, 145.0, 147.3, 158.8; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.98 (d, J = 282.0 Hz, 1F), −125.18 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H15F2N2O2 [M + H]+, 305.1096, found: 305.1081.
  • (±)-6-Chloro-3-(2,2-difluoro-1-hydroxy)ethyl-2-phenyl-imidazo[1,2-a]pyridine (3ae), white solid (57 mg, 92%); m.p. 215–217 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.30–5.38 (m, 1H), 6.16 (td, J = 55.6, 3.2 Hz, 1H), 7.18–7.22 (m, 1H), 7.36–7.42 (m, 3H), 7.46 (d, J = 9.2 Hz, 1H), 7.51–7.54 (m, 2H), 8.72 (s, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.3 (t, J = 25.0 Hz), 115.3 (t, J = 245.0 Hz), 116.2, 116.9, 120.5, 125.3, 127.2, 128.5, 128.6, 128.8, 132.8, 144.0, 146.3; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.99 (d, J = 282.0 Hz, 1F), −124.97 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12ClF2N2O [M + H]+, 309.0601, found: 309.0616.
  • (±)-7-Chloro-3-(2,2-difluoro-1-hydroxy)ethyl-7-chloro-2-phenyl-imidazo[1,2-a]pyridine (3af), white solid (56mg, 91%); m.p. 219–221 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.34–5.41 (m, 1H), 6.16 (t, J = 55.6 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 7.33–7.47 (m, 3H); 7.59 (d, J = 4.4 Hz, 2H), 8.62 (d, J = 7.2 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6), δC, ppm: 65.8 (t, J = 24.0 Hz), 113.8, 116.0, 116.3 (t, J = 243.0 Hz), 116.8, 128.8, 128.9, 129.0, 129.2, 131.3, 133.8, 145.2, 146.0; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −124.13 (d, J = 285.8 Hz, 1F), −125.03 (d, d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12ClF2N2O [M + H]+, 309.0601, found: 309.0616.
  • (±)-8-Chloro-3-(2,2-difluoro-1-hydroxy)ethyl-8-chloro-2-phenyl-imidazo[1,2-a]pyridine (3ag), white solid (55 mg, 89%); m.p. 233–235 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.32–5.39 (m, 1H), 6.08 (td, J = 55.6, 3.2 Hz, 1H), 6.78–6.82 (m, 1H), 7.34–7.45 (m, 4H), 7.62 (d, J = 6.4 Hz, 2H), 8.64 (d, J = 7.2 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6), δC, ppm: 65.9 (t, J = 25.0 Hz), 112.5, 116.2 (t, J = 243.0 Hz), 118.4, 121.8, 125.2, 127.2, 128.9, 129.2, 129.2, 133.8, 142.5, 145.6; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −124.06 (d, J = 282.0 Hz, 1F), −125.11 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12ClF2N2O [M + H]+, 309.0601, found: 309.0616.
  • (±)-8-Bromo-3-(2,2-difluoro-1-hydroxy)ethyl-2-phenyl-imidazo[1,2-a]pyridine (3ah), white solid (58 mg, 83%); m.p. 259–261 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.32–5.38 (m, 1H), 6.01–6.30 (m, 1H), 6.73–6.77 (m, 1H), 7.41–7.46 (m, 3H), 7.55 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 6.8 Hz, 2H), 8.69 (d, J = 6.0 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6), δC, ppm: 66.0 (t, J = 25.0 Hz), 110.6, 113.0, 116.2 (t, J = 243.0 Hz), 118.4, 127.6, 128.6, 128.8, 129.1, 129.2, 133.8, 143.1, 145.6; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −123.98 (d, J = 282.0 Hz, 1F), −125.16 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C15H12BrF2N2O [M + H]+, 353.0096, found: 353.0107.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-phenyl-6-(trifluoromethyl)-imidazo[1,2-a]pyridine (3ai), white solid (61 mg, 89%); m.p. 193–195 °C; 1H-NMR (400 MHz, CDCl3:CD3OD = 7:1), δH, ppm: 5.35–5.43 (m, 1H), 6.17 (td, J = 55.6, 2.8 Hz, 1H), 7.33–7.39 (m, 4H), 7.48–7.51 (m, 2H), 7.59 (d, J = 9.8 Hz, 1H), 9.02 (s, 1H); 13C-NMR (100 MHz, CDCl3:CD3OD = 7:1), δC, ppm: 66.1 (t, J = 25.0 Hz), 115.5 (t, J = 245.0 Hz), 116.5 (q, J = 34.0 Hz), 116.9, 117.3, 121.6–121.8 (m), 123.5 (q, J = 270.0 Hz), 126.8 (q, J = 5.0 Hz), 128.6, 128.7, 128.7, 132.4, 145.4, 147.1; 19F NMR (376 MHz, CDCl3:CD3OD = 7:1), δF, ppm: −62.05, −123.79 (d, J = 282.0 Hz, 1F), −125.09 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H12F5N2O [M + H]+, 343.0864, found: 343.0857.
  • (±)-3-(2,2-Difluoro-1-hydroxy)ethyl-2-phenyl-7-(trifluoromethyl)-imidazo[1,2-a]pyridine (3aj), white solid (60 mg, 87%); m.p. 206–208 °C; 1H-NMR (400 MHz, CD3OD), δH, ppm: 5.37–5.45 (m, 1H), 6.36 (td, J = 55.6, 3.6 Hz, 1H), 7.18 (dd, J = 6.4, 3.2 Hz, 1H), 7.44–7.54 (m, 3H), 7.66–7.69 (m, 2H); 7.93 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H); 13C-NMR (CD3OD), δC, ppm: 66.1 (t, J = 25.0 Hz), 107.6–107.7 (m), 113.8 (q, J = 4.0 Hz), 115.8 (t, J = 245.0 Hz), 118.0 (t, J = 3.0 Hz), 123.4 (q, J = 272.0 Hz), 127.5 (q, J = 34.0 Hz), 128.4, 128.6, 128.8, 129.0, 132.7, 143.7, 147.3; 19F NMR (376 MHz, CD3OD), δF, ppm: −65.30, −125.65 (d, J = 285.8 Hz, 1F), −126.62 (d, J = 285.8 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H12F5N2O [M + H]+, 343.0864, found: 343.0857.
  • (±)-6-Bromo-3-(2,2-difluoro-1-hydroxy)ethyl-7-methyl-2-phenyl-6-(trifluoro-methyl)-imidazo[1,2-a]pyridine (3ak), white solid (66 mg, 90%); m.p. 237–239 °C; 1H-NMR (400 MHz, DMSO-d6), δH, ppm: 5.32–5.39 (m, 1H), 6.59 (t, J = 53.2 Hz, 1H), 6.86–6.88 (m, 1H), 7.40–7.51 (m, 3H), 7.54–7.70 (m, 3H), 8.85 (s, 1H); 13C-NMR (100 MHz, DMSO-d6), δC, ppm: 22.4, 65.8 (t, J = 24.0 Hz), 110.5, 116.0, 116.3 (t, J = 243.0 Hz), 116.6, 127.4, 127.7, 129.0, 129.1, 134.0, 135.7, 144.7, 145.6; 19F NMR (376 MHz, DMSO-d6), δF, ppm: −123.85 (d, J = 282.0 Hz, 1F), −124.80 (d, J = 282.0 Hz, 1F); ESI-HRMS, m/z: Calcd for C16H14BrF2N2O [M + H]+, 367.0252, found: 367.0244.
  • 3-(2,2-Difluoroacetyl)-imidazo[1,2-a]pyridine (4a), white solid (15 mg, 77%); m.p. 102–104 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 6.26 (t, J = 53.6 Hz, 1H), 7.21–7.25 (m, 1H), 7.63–7.68 (m, 1H), 7.87 (d, J = 9.2 Hz, 1H), 8.63 (s, 1H), 9.62 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 111.1 (t, J = 252.0 Hz), 116.2, 118.1, 119.9, 129.0, 131.0, 146.0 (t, J = 6.0 Hz), 149.7, 177.0 (t, J = 26.0 Hz); 19F NMR (376 MHz, CDCl3), δ, ppm: −121.40; ESI-HRMS, m/z: Calcd for C9H7F2N2O [M + H]+, 197.0521, found: 197.0539.
  • 3-(2,2-Difluoroacetyl)-2-phenyl-imidazo[1,2-a]pyridine (4b), white solid (22 mg, 79%); m.p. 121–123 °C; 1H-NMR (400 MHz, CDCl3), δH, ppm: 5.91 (t, J = 53.2 Hz, 1H), 7.23–7.26 (m, 1H), 7.52–7.58 (m, 3H), 7.62–7.65 (m, 2H), 7.66–7.72 (m, 1H), 7.85 (d, J = 8.8 Hz, 1H), 9.78 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3), δC, ppm: 106.0 (t, J = 244.0 Hz), 116.2, 117.7, 119.0, 128.8, 129.4, 129.7, 130.2, 131.6, 133.7, 148.5, 157.5, 177.2 (t, J = 25.0 Hz); 19F NMR (376 MHz, CDCl3), δF, ppm: −124.48; ESI-HRMS, m/z: Calcd for C15H11F2N2O [M + H]+, 273.0834, found: 273.0830.

4. Conclusions

In conclusion, we have developed a facile and efficient method for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines via HFIP-promoted direct C(sp2)-H hydroxydifluoromethylation. A small library of difluoromethylated carbinols were prepared at room temperature in good to high yields by the practical green method. This HFIP-promoted strategy exhibited some definite benefits, such as being transition metal- and oxidant-free and having wide substrate generality, excellent functional group tolerance and mild reaction conditions. In addition, gram-scale and synthetic transformation experiments have also been demonstrated. Therefore, this simple and green synthesis strategy might be attractive for the further design and rapid synthesis of potentially bioactive fluorinated heterocyclic derivatives with multifunctional groups.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28227522/s1, which contains details on the crystallographic information parameters (Table S1), experimental procedure for compounds 1b–1c, experimental procedure for compounds 1z–1ac, 1H, 13C and 19F NMR spectra for all compounds 3a–3ak and 4a–4b. References [24,37] are cited in the supplementary materials.

Author Contributions

Conceptualization, K.Y. and Z.C.; methodology, J.G., X.G. and Z.L.; formal analysis, L.W.; data curation, L.W. and Z.C.; writing—original draft preparation, J.G. and K.Y.; writing—review and editing, K.Y. and Z.L.; project administration, K.Y.; funding acquisition, Z.C. and K.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (No. 81960883), the Natural Science Foundation of Jiangxi Province (No. 20224BAB203010), Scientific Research Fund of Jiangxi Provincial Education Department (No. GJJ201504) and Scientific Research Project of Gannan Medical University (No. YB201903).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data supporting the findings of this study are available within the paper and within its Supplementary Materials published online.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 07522 g001
Figure 1. Representative difluoromethyl carbinol-containing biologically active molecules.
Figure 1. Representative difluoromethyl carbinol-containing biologically active molecules.
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Molecules 28 07522 g002
Figure 2. Representative drugs containing imidazo[1,2-a]pyridine scaffolds.
Figure 2. Representative drugs containing imidazo[1,2-a]pyridine scaffolds.
Molecules 28 07522 g002
Molecules 28 07522 sch001
Scheme 1. The synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines.
Scheme 1. The synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines.
Molecules 28 07522 sch001
Molecules 28 07522 sch002
Scheme 2. Control experiments.
Scheme 2. Control experiments.
Molecules 28 07522 sch002
Molecules 28 07522 sch003
Scheme 3. A plausible reaction pathway.
Scheme 3. A plausible reaction pathway.
Molecules 28 07522 sch003
Molecules 28 07522 sch004
Scheme 4. Synthetic derivatization.
Scheme 4. Synthetic derivatization.
Molecules 28 07522 sch004
Table 1. Optimization of reaction conditions [a].
Table 1. Optimization of reaction conditions [a].
Molecules 28 07522 i001
EntryAdditive (Equiv.)SolventYield (%) [b]
1TFA (10%)DCMtrace
2TsOH (10%)DCMtrace
3BF3·OEt2DCMtrace
4Y(OTf)3 (10%)DCMtrace
5Sc(OTf)3 (10%)DCMtrace
6HFIP (10%)DCMtrace
7HFIP (1.0)DCM50
8HFIP (2.0)DCM73
9 HFIP97
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), solvent (1.0 mL), r.t., 12 h. [b] Isolated yield.
Table 2. Substrate scope of various 2-aryl imidazo[1,2-a]pyridines [a, b].
Table 2. Substrate scope of various 2-aryl imidazo[1,2-a]pyridines [a, b].
Molecules 28 07522 i002
Molecules 28 07522 i003
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), HFIP (1.0 mL), r.t., 12 h. [b] Isolated yield. [c] Reaction performed on a 5 mmol scale.
Table 3. Substrate scope of various substituted 2-phenyl imidazo[1,2-a]pyridines [a, b].
Table 3. Substrate scope of various substituted 2-phenyl imidazo[1,2-a]pyridines [a, b].
Molecules 28 07522 i004
Molecules 28 07522 i005
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), HFIP (1.0 mL), r.t., 12 h. [b] Isolated yield.
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Gao, J.; Liu, Z.; Guo, X.; Wu, L.; Chen, Z.; Yang, K. 1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel–Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature. Molecules 2023, 28, 7522. https://doi.org/10.3390/molecules28227522

AMA Style

Gao J, Liu Z, Guo X, Wu L, Chen Z, Yang K. 1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel–Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature. Molecules. 2023; 28(22):7522. https://doi.org/10.3390/molecules28227522

Chicago/Turabian Style

Gao, Juanjuan, Zhaowen Liu, Xiaohua Guo, Longhui Wu, Zhixi Chen, and Kai Yang. 2023. "1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel–Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature" Molecules 28, no. 22: 7522. https://doi.org/10.3390/molecules28227522

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