Copper-Cocatalyzed Synthesis of Imidazo[1,2-a:3,4-a

Article pubs.acs.org/joc

Cobalt/Copper-Cocatalyzed Synthesis of Imidazo[1,2‑a:3,4‑a′]dipyridiniums from 2H‑[1,2′-Bipyridin]-2-ones and 2‑Bromoacetophenones Ting Li,*,† Chen Fu,‡ Qinge Ma,† Zhipei Sang,† Yuhan Yang,*,† Hao Yang,† Rongrong Lv,† and Bo Li*,† †

College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, P. R. China College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P. R. China

‡

S Supporting Information *

ABSTRACT: A cobalt/copper-cocatalyzed facile synthesis of imidazo[1,2-a:3,4-a′]dipyridiniums from 2H-[1,2′-bipyridin]2-ones and 2-bromoacetophenones is presented. This strategy provides an alternative to the imidazo[1,2-a:3,4-a′]dipyridinium synthesis by employing readily available substrates and a simple procedure, which would render this method potentially useful in organic synthesis.

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INTRODUCTION Imidazo[1,2-a:3,4-a′]dipyridiniums are structural motifs found in numerous biologically active natural products, pharmacologically active molecules, and molecular sensors (Figure 1),1 and they are also widely employed as versatile building blocks in organic synthesis.2 However, synthetic methods that provide selective access to these novel nitrogen-containing heterocycles still remain scarce. To the best of our knowledge, the only effective strategy for the construction of imidazo[1,2-a:3,4a′]dipyridiniums prior to our study was reported by Sheffler in 1985, and these were prepared from the Binz−Marx reaction (Scheme 1a, eq 1).3 In this context, the development of the novel methods for the preparation of imidazo[1,2-a:3,4a′]dipyridiniums continues to be actively pursued, especially those based on assembling structures directly from several readily available and easily diversified building blocks with safe and simple conditions.4,5 Recently, catalytic transformations involving the selective functionalization6 of the 2-pyridone moiety have gained increasing attention from the synthetic community, which provides access for the regioselective functionalization of 2pyridone and the construction of a variety of useful complex Nfused structures.7 In our recent work toward rhodiumcatalyzed/copper-mediated C−H alkynylation of 2H-[1,2′bipyridin]-2-ones, our group has described an efficient and flexible methodology for the synthesis of 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olates through tandem C(sp2)− H alkynylation and the following intramolecular annulation (Scheme 1a, eq 2).8 During our ongoing studies on the transition-metal-mediated selective functionalization of 2pyridones with 2-bromoacetophenone as the coupling partner, we have serendipitously isolated the 11-acylated imidazo[1,2a:3,4-a′]dipyridin-5-ium-4-olates from the reaction mixture in good yields (Scheme 1b). In this paper, we would like to present a cobalt/copper-cocatalyzed tandem reaction for the synthesis of 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium© 2017 American Chemical Society

4-olates from 2H-[1,2′-bipyridin]-2-ones and 2-bromoacetophenones under relatively mild reaction conditions.9 To the best of our knowledge, this represents the rare examples of the cocatalyzed pyridine [4+1] annulation reactions with 2bromoacetophenone as a one-carbon synthon.10

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RESULTS AND DISCUSSION We initiated our study by choosing 2H-[1,2′-bipyridin]-2-one (1a) and 2-bromoacetophenone (2a) as the model substrates, which led to the formation of imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3aa) serendipitously. After some initial experiments including catalyst screenings (Table 1, entries 1−6) and solvent effect investigations (Table 1, entries 6−9), the optimal reaction conditions were defined as using 5 mol % CoCl2 and 10 mol % CuI as the cocatalyst with 3.0 equiv of Cs2CO3 as the additive, performed at 130 °C under air for 24 h, providing the product 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium (3aa) in 85% isolated yield as the major product (Table 1, entry 6). The definite structure of 3 was confirmed by an X-ray crystallographic study of compound 3ac.11 Further studies with other substrates including 2-chloroacetophenone and 2iodoacetophenone instead of 2-bromoacetophenone (2a) as the coupling partner were also screened, and 2-bromoacetophenone was found to be the best choice for this reaction.12 Note that running the reaction without CoCl2 or CuI led to substrate decomposition and either no or low yield of 3aa (entries 10 and 11). The basic additive Cs2CO3 was also very important for the optimal yield as its absence (entry 12) or replacement with NaHCO3 (entry 13), Na2CO3 (entry 14), or K2CO3 (entry 15) all led to inferior results. In addition, the air atmosphere was critical for the success of the transformation as the reaction in N2 led to only 35% yield of product formation (entry 16). In contrast, when the reaction was performed under Received: July 13, 2017 Published: September 4, 2017 10263

DOI: 10.1021/acs.joc.7b01742 J. Org. Chem. 2017, 82, 10263−10270

Article

The Journal of Organic Chemistry

Figure 1. Selected bioactive molecules containing imidazo[1,2-a:3,4-a′]dipyridinium skeletons.

Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Synthesis of Imidazo[1,2-a:3,4-a′]dipyridin-5iums

conditions

base

solvent

yieldb (%) 36

PhMe

41

PhMe

0

PhMe

35

PhMe

0

PhMe

85

DCE

62

DMF

0

PhCl

41

PhMe

0

11

CoCl2 (5 mol %), 130 °C

PhMe

7

12

CoCl2 (5 mol %), mol %), 130 °C CoCl2 (5 mol %), mol %), 130 °C CoCl2 (5 mol %), %), 130 °C CoCl2 (5 mol %), mol %), 130 °C CoCl2 (5 mol %), mol %), 130 °C CoCl2 (5 mol %), mol %), 130 °C CoCl2 (5 mol %), mol %), 110 °C

CuI (10

Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) CsCO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) no

PhMe

10

FeCl2 (5 mol %), CuI (10 mol %), 130 °C FeI2 (5 mol %), CuI (10 mol %), 130 °C Fe(OAc)2 (5 mol %), CuI (10 mol %), 130 °C Co(acac)3 (5 mol %), CuI (10 mol %), 130 °C CoCp*(CO)I2 (5 mol %), CuI (10 mol %), 130 °C CoCl2 (5 mol %), CuI (10 mol %), 130 °C CoCl2 (5 mol %), CuI (10 mol %), 130 °C CoCl2 (5 mol %), CuI (10 mol %), 130 °C CoCl2 (5 mol %), CuI (10 mol %), 130 °C CuI (10 mol %), 130 °C

PhMe

0

CuI (10

NaHCO3

PhMe

39

CuI (10 mol

Na2CO3

PhMe

37

CuI (10

K2CO3

PhMe

0

CuI (10

Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv) Cs2CO3 (3.0 equiv)

PhMe

35

PhMe

88

PhMe

70

entry 1 2 3 4 5 6 7

a pure O2 atmosphere, a slightly high yield of 3aa was isolated from the reaction mixture (entry 17). The reaction may be conducted under a relatively low temperature of 110 °C with a long reaction time and a small yield loss (entry 18). Under the optimized reaction conditions in Table 1, we thus sought to further explore the scope and limitation of this transformation (Scheme 2). First, the generality of the 2pyridone ring was examined. The installation of a Me substituent on the pyridyl C-3 or C-4 position on the 2pyridone ring furnished product 3ba or 3ca in 71% or 85% yield, respectively. In contrast, when the Me group was at the C-5 position, the reaction was completely suppressed (3da), probably as a result of steric factors. Then, other substrates containing electron-donating or electron-withdrawing substituents such as F, Cl, CF3, or OBn at the C-3 or C-4 position of the pyridone ring were compatible with this transformation, affording products 3ea−3jb in good yields. The transformation also accommodated F, Cl, OMe, and Me groups on the para position of the phenyl ring of the 2-bromoacetophenone substrates. While substrate 2d with a Me group at the meta position showed a relatively low conversion (3ad, 49%), the reaction was completely suppressed when the Me group moved to the ortho position. Moreover, the thiophene-containing substrate 2i also proceeded smoothly to afford the corresponding product 3ai, which was isolated in about a 75% yield. It should be mentioned that furan- or aliphatic-containing substrates were also tested, and only a little product of 3aj could be detected, while substrate 2k did not work at all. Finally, the influence of the substituent on the pyridyl-directing group was also investigated. Gratifyingly, it was found that the

8 9

13 14 15 16c 17d 18e

CuI (10 CuI (10

a

Conditions: 1a (0.20 mmol), 2a (0.60 mmol, 3 equiv), catalyst, solvent (2 mL), air, 24 h. bThe yields of the isolated products are based on 1a. cThe reaction was performed under N2. dThe reaction was performed under O2. eThe reaction was performed for 48 h.

installation of a Me substituent on the pyridyl C-2 or C-3 position furnished product 3ka or 3la in 74% or 75% yield, respectively. Other substituent groups including F or CF3 at the C-2 or C-3 position of the pyridyl-directing group were also 10264


Article

The Journal of Organic Chemistry Scheme 2. Substrate Scope for the Transformationa

a

Standard reaction conditions: A mixture of derivative 1 (0.20 mmol), 2-bromoacetophenone (2a) (0.60 mmol), CoCl2 (5 mol %), CuI (10 mol %), Cs2CO3 (3.0 equiv), and toluene (2 mL) was added to a Schlenk tube under air. Then the mixture was allowed to stir at 130 °C (bath temperature) under air for 24 h. The isolated products are based on 1. 10265


Article

The Journal of Organic Chemistry Scheme 3. Mechanism Studies

Scheme 4. Tentative Reaction Mechanism for the Transformation

the pyridine unit of substrate 1a with bromoacetophenone 2a would easily generate intermediate I.14 With CoCl2 acting as a Lewis acid to activate the pyridone unit as an electrophile, intramolecular annulation would proceed in the presence of a base to provide the annulation product III via intermediate II. We might envision that the resulting annulation product III is very unstable, and the subsequent aerobic oxidation of III is expected to generate intermediate IV in the presence of the Cu/O2 oxidative system via a radical pathway.15 Then the stable aromatized product 3aa is formed finally. Besides, to demonstrate the synthetic potential of this transformation, 10 mmol scale reactions were conducted using 2a and 2b as substrates, and the reaction proceeded smoothly to give products 3aa and 3ab in 82% and 78% yields, respectively (Scheme 5). This transformation thus further

investigated, and products 3ma and 3na were obtained in good yields. To get some mechanistic insights into this transformation, several experiments were carried out. First, substrate 1a was allowed to be treated with excess CD3OD (10 equiv) for 4 h under standard reaction conditions, and no D-exchange was detected (Scheme 3, 1). This result clearly showed that the reaction may not undergo the C−H bond-activation step. Then, the potential intermediate 4 was prepared13 and allowed to be subjected to the procedure. It was found that intermediate 4 could convert into the final product 3aa and that the addition of CoCl2, CuI, and Cs2CO3 was essential to promote the transformation (Scheme 3, 2c). In contrast, only 4% of product 3aa was isolated when only CoCl2 and Cs2CO3 were used (Scheme 3, 2a), and no desired product could be observed in the absence of CoCl2 (Scheme 3, 2b). These results clearly revealed that the formation of intermediate 4 was possibly the initial step in the catalytic cycle and that CoCl2, CuI, Cs2CO3, and the air may account for the transformation of 4 to 3aa. In addition, adding 2 equiv of TEMPO, known as a radical scavenger, to the reaction mixture inhibited this transformation, which indicated that the transformation may involve a radical process (Scheme 3, 3). On the basis of these experiment results and the previous reports,13 a tentative mechanism for the formation of product 3aa is proposed as shown in Scheme 4. Initially, the reaction of

Scheme 5. Gram-Scale Synthesis of C−H Bond-Activation Compounds 3aa and 3ab

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strengthens the synthetic impact of this protocol for the preparation of these new nitrogen-containing heterocycles, 11acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olates. Due to the rapidly growing bacterial antibiotic resistance and the lack of novel antibiotics reaching the market, bacterial infections are still a severe global problem. Therefore, exploring new types of antibacterial drugs with a novel mechanism or chemical structure is urgently needed.16 With these novel compounds in hand, we thus set out to study the antimicrobial activities preliminarily in this study. Accordingly, serial solutions of compounds 3aa−3al prepared in DMSO with concentrations ranging from 2 to 256 μg/mL were added to the mid-log phase of four different bacterial strains and incubated for 2 days to observe the cell growth (Table 2). The MIC was

S. aureus 25129

S. aureus 49

P. aeruginosa

E. coli

3aa 3ea 3fa 3ha 3ja 3ag 3al ampicillin

8 16 8 4 8 16 8 4

16 8 16 4 16 32 32 >256

>256 >256 >256 >256 >256 >256 >256 >256

>256 >256 >256 >256 >256 >256 >256 >256

EXPERIMENTAL SECTION

General Remarks. All reactions were carried out in flame-dried sealed tubes with magnetic stirring. Unless otherwise noted, all experiments were performed under a N2 atmosphere. Commercially available reagents and solvents were used without further purification except as noted. Products were purified by column chromatography on 200−300 mesh silica gels. All melting points were determined without correction. 1H NMR and 13C NMR spectra were recorded at 400 and 100 MHz, respectively, in CDCl3. Splitting patterns are designated as singlet (s), doublet (d), triplet (t), or quartet (q). All chemical shifts are given as δ values (in ppm) with reference to tetramethylsilane (TMS) as an internal standard. Splitting patterns that could not be interpreted or easily visualized are designated as multiplet (m). Highresolution mass spectra were recorded on an FT-MS instrument using the ESI technique. Crystallographic data were recorded on a diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.710 73 Å). Structures were solved by direct methods in SHELXS-97. Copies of the 1H NMR and 13C NMR spectra and crystallographic data in CIF are provided in the Supporting Information. The substrates, 2H-[1,2′-bipyridin]-2-ones,18 were prepared by previously reported procedures. General Procedure for the Synthesis of 3. Synthesis of compound 3aa is representative. To a 25 mL flame-dried Schlenk tube was added a mixture of 2H-[1,2′-bipyridin]-2-one (1a) (0.20 mmol), 2bromoacetophenone (2a) (0.60 mmol), CoCl2 (5 mol %), CuI (10 mol %), Cs2CO3 (0.6 mmol, 3.3 equiv), and toluene (2 mL) under an air atmosphere. Then the tube was allowed to stir at 130 °C (bath temperature, preheated) under air for a desired time (usually 24 h) until complete consumption of starting materials, judged by TLC. Then the reaction mixture was filtered through a short plug of silica gel, washed with ethyl acetate, and concentrated. Then the residue was purified by chromatography with CH2Cl2/ethyl acetate (v/v, 1:1) to afford 11-acylated imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3aa) in 85% yield. 11-Benzoylimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3aa): red solid (42 mg, 85%); mp 147−148 °C; 1H NMR (500 MHz, CDCl3) δ 10.43 (d, J = 6.7 Hz, 1H), 9.57 (d, J = 8.8 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.59 (m, 2H), 7.54 (m, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.22 (t, J = 8.5 Hz, 1H), 5.99 (d, J = 8.8 Hz, 1H), 5.53 (d, J = 8.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.0, 159.4, 140.8, 140.4, 139.5, 136.3, 131.2, 130.9, 128.9, 128.4, 127.6, 120.6, 116.0, 109.1, 101.8, 92.0; HRMS m/z (ESI) calcd for C18H13N2O2 [M + H]+ 289.0972, found 289.0974. 11-Benzoyl-3-methylimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ba): red solid (43 mg, 71%); mp 174−175 °C; 1H NMR (400 MHz, CDCl3) δ 10.56 (d, J = 6.7 Hz, 1H), 9.66 (d, J = 8.9 Hz, 1H), 7.86 (t, J = 8.3 Hz, 1H), 7.66 (t, J = 7.2 Hz, 2H), 7.61 (t, J = 7.9 Hz, 2H), 7.55 (t, J = 7.2 Hz, 2H), 7.26 (d, J = 7.9 Hz, 1H), 5.58 (d, J = 8.1 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.4, 158.8, 140.6, 139.1, 139.0, 136.1, 131.1, 130.7, 128.9, 128.4, 127.6, 120.7, 115.9, 111.3, 108.7, 91.9, 15.9; HRMS m/z (ESI) calcd for C19H15N2O2 [M + H]+ 303.1128, found 303.1138. 11-Benzoyl-2-methylimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ca): red solid (50 mg, 85%); mp 171−172 °C; 1H NMR (500 MHz, CDCl3) δ 10.36 (t, J = 8.5 Hz, 1H), 9.43 (d, J = 8.8 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.48 (m, 2H), 7.42 (t, J = 7.5 Hz, 2H), 5.85 (s, 1H), 5.32 (s, 1H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 182.8, 151.7, 140.4, 139.9, 136.2, 131.1, 131.0, 128.8, 128.5, 127.6, 120.5, 115.7, 108.5, 102.6, 93.8, 22.5; HRMS m/z (ESI) calcd for C19H15N2O2 [M + H]+ 303.1128, found 303.1138. 11-Benzoyl-3-fluoroimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3ea): red solid (48 mg, 78%); mp 156−157 °C; 1H NMR (400 MHz, CDCl3) δ 10.52 (d, J = 6.7 Hz, 1H), 9.63 (d, J = 8.8 Hz, 1H), 7.88 (ddd, J = 8.7, 7.4, 1.1 Hz, 1H), 7.63 (m, 4H), 7.54 (m, 2H), 7.28 (m, 1H), 5.44 (dd, J = 8.8, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 182.6, 151.5 (d, JC−F = 4.0 Hz), 142.3, 140.5, 140.2, 137.1, 135.9, 131.3, 130.7, 129.0, 128.6, 127.6, 124.3 (d, J = 18.9 Hz), 121.2, 116.0, 108.7, 99.1 (d, JC−F = 4.2 Hz), 88.6; HRMS m/z (ESI) calcd for C18H12FN2O2 [M + H]+ 307.0877, found 307.0877.

Table 2. In Vitro Antimicrobial Activity of Selected Compounds and Positive Control Drug Ampicillin (MIC, μg/mL) compounds

Article

determined as the lowest concentration of the compounds inhibiting visible microbial growth. Meanwhile, we also set the typical positive drug ampicillin as the control group and determined the MIC values as well. As displayed in Table 2, compound 3ha exhibited the best antimicrobial activity against the growth of both S. aureus 25129 and S. aureus 49 with the MIC values of 4 and 4 μg/mL, respectively; nevertheless, ampicillin was almost inactive against S. aureus 49. The results also showed that the MIC values of the other compounds were comparable to that of compound 3ha. However, all the compounds showed only very limited activity against Gramnegative bacteria (P. aeruginosa and E. coli), with MIC values of greater than 256 μg/mL.17 We are convinced that these imidazo dipyridinium compounds could exhibit better antibacterial activity against S. aureus with the proper modification in the future.

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CONCLUSIONS In conclusion, we have successfully developed a convenient cobalt/copper-cocatalyzed synthesis of imidazo[1,2-a:3,4-a′]dipyridin-5-iums from 2H-[1,2′-bipyridin]-2-ones and 2bromoacetophenone. This present protocol provides an alternative to the synthesis of imidazo[1,2-a:3,4-a′]dipyridin5-iums by employing readily available substrates and a simple procedure, which would render this method potentially useful for the synthesis of the skeleton of imidazo[1,2-a:3,4a′]dipyridin-5-iums in organic synthesis. Given the simplicity of this reaction and the importance of heterocyclic quaternary ammonium salts as functional molecules in organic chemistry, we anticipate this transformation may find applications. Further investigations on the detailed mechanism and synthetic applications are currently underway in our laboratory. 10267


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The Journal of Organic Chemistry 3-Fluoro-11-(4-methoxybenzoyl)imidazo[1,2-a:3,4-a′]dipyridin5-ium-4-olate (3eb): red solid (57 mg, 85%); mp 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 10.30 (d, J = 6.8 Hz, 1H), 9.56 (d, J = 8.8 Hz, 1H), 7.81−7.73 (m, 1H), 7.64−7.59 (m, 2H), 7.56 (td, J = 7.3, 1.2 Hz, 1H), 7.27 (dd, J = 11.1, 8.9 Hz, 1H), 7.00−6.92 (m, 2H), 5.65 (dd, J = 8.9, 3.0 Hz, 1H), 3.85 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.3, 162.5, 151.5 (d, J = 29.0 Hz), 142.2, 139.9, 137.0, 135.7, 132.3, 130.3, 130.0, 128.2, 124.4 (d, J = 18.9 Hz), 121.0, 116.1, 114.2, 109.0, 88.5 (d, J = 5.4 Hz), 55.5; HRMS m/z (ESI) calcd for C19H14FN2O3 [M + H]+ 337.0983, found 337.0985. 3-Fluoro-11-(4-methylbenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3ec): red solid (49 mg, 77%); mp 170−171 °C; 1H NMR (400 MHz, CDCl3) δ 10.40 (d, J = 6.8 Hz, 1H), 9.57 (d, J = 8.8 Hz, 1H), 7.79 (ddd, J = 8.7, 7.5, 1.1 Hz, 1H), 7.58 (td, J = 7.3, 1.3 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.32−7.22 (m, 3H), 5.52 (dd, J = 8.9, 3.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.9, 157.1, 151.5 (d, J = 29.0 Hz), 142.7, 142.1, 139.9, 137.3, 137.1, 135.8, 130.4, 129.7, 128.4, 127.9, 124.4 (d, J = 18.7 Hz), 121.1, 116.1, 108.9, 88.6, 21.7; HRMS m/z (ESI) calcd for C19H14FN2O2 [M + H]+ 321.1034, found 321.1037. 11-Benzoyl-3-chloroimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3fa): red solid (53 mg, 83%); mp 161−162 °C; 1H NMR (500 MHz, CDCl3) δ 10.36 (d, J = 6.7 Hz, 1H), 9.55 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 12.0, 4.2 Hz, 1H), 7.56 (m, 4H), 7.46 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.1, 154.7, 139.9, 139.4, 138.1, 135.8, 131.5, 131.2, 129.0, 128.4, 127.7, 121.0, 116.1, 109.1, 106.4, 91.6; HRMS m/z (ESI) calcd for C18H12ClN2O2 [M + H]+ 323.0582, found 323.0587. 3-Chloro-11-(4-methoxybenzoyl)imidazo[1,2-a:3,4-a′]dipyridin5-ium-4-olate (3fb): red solid (56 mg, 82%); mp 100−103 °C; 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 9.57 (d, J = 7.9 Hz, 1H), 7.82 (dd, J = 25.2, 18.0 Hz, 1H), 7.62 (t, J = 10.2 Hz, 2H), 7.57 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.04−6.81 (m, 2H), 5.80 (t, J = 17.2 Hz, 1H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.7, 162.8, 154.8, 139.2, 138.0, 135.6, 132.0, 130.7, 130.5, 128.1, 120.9, 116.3, 114.2, 109.5, 105.7, 91.8, 55.6; HRMS m/z (ESI) calcd for C19H14ClN2O3 [M + H]+ 353.0687, found 353.0690. 3-Chloro-11-(4-methylbenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3fc): red solid (56 mg, 83%); mp 100−103 °C; 1H NMR (400 MHz, CDCl3) δ 10.33 (d, J = 6.8 Hz, 1H), 9.58 (d, J = 8.8 Hz, 1H), 8.00−7.73 (m, 1H), 7.59 (dd, J = 10.2, 3.9 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 5.66 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 183.4, 154.8, 142.4, 139.3, 138.1, 137.0, 135.7, 131.0, 129.7, 128.3, 128.1, 121.0, 116.3, 109.4, 106.1, 91.9, 21.7; HRMS m/z (ESI) calcd for C19H14ClN2O2 [M + H]+ 337.0738, found 337.0742. 11-Benzoyl-2-chloroimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3ga): red solid (48 mg, 74%); mp 157−158 °C; 1H NMR (400 MHz, CDCl3) δ 10.42 (d, J = 6.7 Hz, 1H), 9.54 (d, J = 8.9 Hz, 1H), 7.90 (t, J = 8.2 Hz, 1H), 7.65 (m, 4H), 7.57 (t, J = 7.4 Hz, 2H), 6.05 (s, 1H), 5.60 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 183.3, 157.8, 146.7, 139.7, 136.1, 131.7, 131.5, 129.0, 128.6, 127.6, 120.8, 115.8, 108.8, 101.1, 92.5; HRMS m/z (ESI) calcd for C18H12ClN2O2 [M + H]+ 323.0582, found 323.0587. 2-Chloro-11-(4-methoxybenzoyl)imidazo[1,2-a:3,4-a′]dipyridin5-ium-4-olate (3gb): red solid (53 mg, 75%); mp 100−103 °C; 1H NMR (400 MHz, CDCl3) δ 10.18 (d, J = 6.7 Hz, 1H), 9.46 (d, J = 8.8 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.53 (t, J = 6.9 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 5.97 (d, J = 1.3 Hz, 1H), 5.84 (d, J = 1.5 Hz, 1H), 3.86 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.7, 162.9, 157.9, 146.5, 139.5, 135.9, 131.8, 131.0, 130.5, 128.4, 120.7, 115.9, 114.2, 109.1, 100.5, 92.5, 55.6; HRMS m/z (ESI) calcd for C19H14ClN2O3 [M + H]+ 353.0687, found 353.0690. 11-Benzoyl-3-(trifluoromethyl)imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3ha): red solid (60 mg, 84%); mp 171−172 °C; 1H NMR (500 MHz, CDCl3) δ 10.38 (d, J = 6.7 Hz, 1H), 9.64 (d, J = 8.9 Hz, 1H), 7.97 (t, J = 8.1 Hz, 1H), 7.67 (ddd, J = 22.6, 10.6, 4.1 Hz, 4H), 7.59−7.49 (m, 3H), 5.62 (d, J = 8.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 184.1, 155.8, 141.9, 139.5, 136.5, 136.3 (m), 132.2, 132.0, 129.0, 128.7, 127.9, 121.0, 116.4, 112.3 (d, JC−F = 274.5 Hz),

109.9, 100.7 (d, JC−F = 31.0 Hz), 91.03; HRMS m/z (ESI) calcd for C19H12F3N2O2 [M + H]+ 357.0845, found 357.0847. 11-(4-Methoxybenzoyl)-3-(trifluoromethyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3hc): red solid (57 mg, 76%); mp 100−103 °C; 1H NMR (400 MHz, CDCl3) δ 10.25 (d, J = 6.7 Hz, 1H), 9.56 (d, J = 8.9 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 5.68 (d, J = 8.9 Hz, 1H), 2.42 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 183.2, 154.9, 142.0, 140.7, 138.5 (m), 135.6, 135.3, 135.0 (m), 131.0, 128.6, 127.6, 127.2, 123.70 (d, J = 269.7 Hz), 119.34, 115.4, 109.1, 103.4, 90.3, 20.7; HRMS m/z (ESI) calcd for C20H14F3N2O2 [M + H]+ 371.1002, found 371.1005. 11-Benzoyl-2-(trifluoromethyl)imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3ia): red solid (59 mg, 84%); mp 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 10.36 (d, J = 6.7 Hz, 1H), 9.55 (d, J = 8.9 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.60 (m, 4H), 7.48 (t, J = 7.4 Hz, 2H), 6.11 (s, 1H), 5.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 183.6, 158.5, 140.3, 139.5, 135.8, 131.9, 131.5, 129.0, 128.5, 127.7, 122.83 (d, JC−F = 274.5 Hz), 121.1, 116.1, 110.3, 96.8 (d, JC−F = 3.4 Hz), 87.94 (d, JC−F = 4.1 Hz); HRMS m/z (ESI) calcd for C19H12F3N2O2 [M + H]+ 357.0845, found 357.0847. 11-(4-Methoxybenzoyl)-2-(trifluoromethyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3ib): red solid (58 mg, 75%); mp 100−103 °C; 1H NMR (400 MHz, CDCl3) δ 10.19 (d, J = 6.8 Hz, 1H), 9.56 (d, J = 8.9 Hz, 1H), 7.82 (ddd, J = 8.7, 7.4, 1.1 Hz, 1H), 7.69−7.63 (m, 2H), 7.59 (td, J = 7.2, 1.2 Hz, 1H), 7.09−6.81 (m, 2H), 6.12 (d, J = 1.3 Hz, 1H), 6.02 (d, J = 1.1 Hz, 1H), 3.85 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.9, 163.2, 158.5, 140.1 (m), 139.9, 135.7, 131.5, 130.9, 130.6, 128.2, 123.0 (d, J = 274.5 Hz), 120.9, 116.3, 114.2, 110.6, 96.0 (d, J = 3.4 Hz), 88.1 (d, J = 4.2 Hz), 55.6; HRMS m/z (ESI) calcd for C20H14F3N2O3 [M + H]+ 387.0951, found 387.0955. 11-Benzoyl-2-(benzyloxy)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ja): red solid (72 mg, 91%); mp 200−201 °C; 1H NMR (400 MHz, CDCl3) δ 10.37 (d, J = 6.6 Hz, 1H), 9.37 (d, J = 8.8 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.45 (m, 4H), 7.24 (dd, J = 5.6, 9.6 Hz, 3H), 7.18 (t, J = 6.4 Hz, 1H), 5.64 (s, 1H), 5.19 (s, 1H), 4.78 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 182.6, 168.0, 160.0, 140.7, 140.4, 136.4, 135.7, 131.4, 131.1, 128.9, 128.7, 128.5, 128.1, 127.5, 127.4, 120.1, 115.2, 108.5, 87.9, 81.6, 69.9; HRMS m/z (ESI) calcd for C25H19N2O3 [M + H]+ 395.1390, found 395.1394. 2-(Benzyloxy)-11-(4-methoxybenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3jb): red solid (65 mg, 77%); mp 100−103 °C; 1H NMR (400 MHz, CDCl3) δ 10.21 (d, J = 6.6 Hz, 1H), 9.35 (d, J = 8.8 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.41 (t, J = 7.0 Hz, 1H), 7.28−7.15 (m, 6H), 6.91 (d, J = 8.5 Hz, 2H), 5.66 (s, 1H), 5.46 (s, 1H), 4.85 (s, 2H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.2, 167.9, 162.3, 156.0, 140.5, 136.2 135.8, 132.5, 130.8, 130.2, 128.6, 128.4, 128.2, 127.5, 120.0, 115.2, 114.1, 108.8, 87.34, 81.5, 70.1, 55.5; HRMS m/z (ESI) calcd for C26H21N2O4 [M + H]+ 425.1496, found 425.1498. 11-(4-Methoxybenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ab): red solid (56 mg, 88%); mp 167−168 °C; 1H NMR (500 MHz, CDCl3) δ 10.28 (d, J = 6.7 Hz, 1H), 9.57 (d, J = 8.8 Hz, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.52 (t, J = 7.0 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 5.99 (d, J = 8.6 Hz, 1H), 5.79 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 182.6, 162.5, 159.3, 140.7, 139.2, 136.1, 132.5, 130.3, 130.2, 128.1, 120.4, 116.1, 114.1, 109.4, 101.0, 92.0, 55.5; HRMS m/z (ESI) calcd for C19H15N2O3 [M + H]+ 319.1077, found 319.1084. 11-(4-Methylbenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ac): red solid (48 mg, 79%); mp 183−184 °C; 1H NMR (500 MHz, CDCl3) δ 10.34 (d, J = 6.7 Hz, 1H), 9.54 (d, J = 8.9 Hz, 1H), 7.75 (t, J = 8.4 Hz, 1H), 7.50 (m, 3H), 7.23 (m, 3H), 5.96 (d, J = 8.5 Hz, 1H), 5.64 (d, J = 8.2 Hz, 1H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.1, 159.3, 141.8, 140.7, 139.2, 137.5, 136.1, 130.5, 129.5, 128.2, 127.9, 120.4, 115.9, 109.2, 101.3, 92.0, 21.6; HRMS m/z (ESI) calcd for C19H15N2O2 [M + H]+ 303.1128, found 303.1138. 11-Benzoyl-2-(trifluoromethyl)imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3ad): red solid (30 mg, 49%); mp 188−189 °C; 1H NMR (400 MHz, CDCl3) δ 10.41 (d, J = 6.7 Hz, 1H), 9.49 (d, J = 8.7 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 7.0 Hz, 2H), 7.49 (m, 10268


Article


CDCl3) δ 10.43 (dd, J = 4.5, 2.3 Hz, 1H), 9.58 (dd, J = 9.6, 5.4 Hz, 1H), 7.59 (t, J = 6.9 Hz, 3H), 7.54 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 8.4 Hz, 1H), 6.04 (d, J = 8.7 Hz, 1H), 5.59 (d, J = 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.4, 158.44 (d, JC−F = 125.5 Hz), 156.0, 140.8, 139.9, 139.4, 133.2, 131.5, 129.0, 127.7, 119.4 (d, JC−F = 22.7 Hz), 116.6 (d, JC−F = 45.2 Hz), 116.1 (d, JC−F = 8.1 Hz), 116.0, 109.8, 102.4, 92.3; HRMS m/z (ESI) calcd for C18H12FN2O2 [M + H]+ 307.0877, found 307.0877.

4H), 5.86 (tr, 1H), 5.34 (tr, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.8, 158.9, 151.7, 140.4, 140.0, 136.4, 131.1, 131.0, 128.8, 128.5, 127.6, 120.4, 115.6, 111.3, 108.5, 102.7, 93.5, 22.5; HRMS m/z (ESI) calcd for C19H15N2O2 [M + H]+ 303.1128, found 303.1138. 11-(4-Chlorobenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3af): red solid (51 mg, 79%); mp 176−177 °C; 1H NMR (500 MHz, CDCl3) δ 10.47 (d, J = 6.7 Hz, 1H), 9.67 (d, J = 8.8 Hz, 1H), 7.89 (ddd, J = 8.7, 7.4, 1.2 Hz, 1H), 7.73 (m, 2H), 7.65 (m, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 6.11 (d, J = 8.7 Hz, 1H), 5.69 (d, J = 8.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 181.5, 159.4, 140.7, 139.6, 138.7, 137.5, 136.5, 131.3, 129.3, 129.2, 128.5, 120.7, 116.0, 109.0, 102.2, 91.8; HRMS m/z (ESI) calcd for C18H12ClN2O2 [M + H]+ 323.0582, found 323.0587. 11-(4-Fluorobenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ag): red solid (43 mg, 71%); mp 164−165 °C; 1H NMR (500 MHz, CDCl3) δ 10.37 (d, J = 6.6 Hz, 1H), 9.56 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.77 (m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.26 (m, 1H), 7.15 (m, 2H), 6.01 (d, J = 8.5 Hz, 1H), 5.59 (d, J = 8.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 181.6, 158.6 (d, JC−F = 125.4 Hz), 159.3, 140.8, 139.5, 136.4 (d, JC−F = 8.0 Hz), 131.0, 130.3, 130.2, 128.4, 120.6, 116.1 (d, JC−F = 22.2 Hz), 116.0, 109.0, 102.0, 91.7; HRMS m/z (ESI) calcd for C18H12FN2O2 [M + H]+ 307.0877, found 307.0877. 11-(4-Ethylbenzoyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3ah): red solid (51 mg, 81%); mp 160−161 °C; 1H NMR (500 MHz, CDCl3) δ 10.37 (d, J = 6.7 Hz, 1H), 9.57 (d, J = 8.7 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.53 (m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 8.4 Hz, 1H), 5.99 (d, J = 8.5 Hz, 1H), 5.66 (d, J = 8.2 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 183.2, 159.4, 148.1, 140.8, 139.3, 137.7, 136.2, 130.5, 128.3, 128.2, 128.0, 120.5, 116.0, 109.3, 101.4, 92.1, 28.9, 15.3; HRMS m/z (ESI) calcd for C20H17N2O2 [M + H]+ 317.1285, found 317.1292. 11-(Thiophene-3-carbonyl)imidazo[1,2-a:3,4-a′]dipyridin-5-ium4-olate (3ai): red solid (45 mg, 75%); mp 152−153 °C; 1H NMR (500 MHz, CDCl3) δ 10.33 (d, J = 6.9 Hz, 1H), 9.56 (d, J = 8.9 Hz, 1H), 7.78 (m, 2H), 7.52 (t, J = 7.1 Hz, 1H), 7.39 (dd, J = 2.9, 5.1 Hz, 1H), 7.34 (dd, J = 1.1, 5.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.01 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 177.3, 159.4, 142.1, 140.6, 139.5, 136.2, 130.8, 128.9, 128.2, 127.2, 126.6, 120.6, 116.1, 109.7, 101.7, 91.8; HRMS m/z (ESI) calcd for C16H11N2O2S [M + H]+ 295.0536, found 295.0541. 11-Benzoyl-7-methylimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3ka): red solid (45 mg, 74%); mp 178−179 °C; 1H NMR (500 MHz, CDCl3) δ 10.29 (d, J = 6.9 Hz, 1H), 9.37 (s, 1H), 7.56 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.35 (d, J = 6.8 Hz, 1H), 7.16 (m, 1H), 5.94 (d, J = 8.6 Hz, 1H), 5.47 (d, J = 8.2 Hz, 1H), 2.60 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 182.5, 159.5, 144.1, 141.1, 140.6, 139.4, 139.3, 136.6, 131.0, 128.9, 128.0, 127.6, 122.1, 115.6, 108.7, 101.5, 91.9, 22.0; HRMS m/z (ESI) calcd for C19H15N2O2 [M + H]+ 303.1128, found 303.1138. 11-Benzoyl-8-methylimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4olate (3la): red solid (45 mg, 75%); mp 176−177 °C; 1H NMR (500 MHz, CDCl3) δ 10.23 (s, 1H), 9.39 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.56 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.18 (m, 1H), 5.95 (d, J = 8.5 Hz, 1H), 5.46 (d, J = 8.1 Hz, 1H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 182.8, 159.2, 140.8, 140.5, 139.1, 134.8, 132.9, 131.3, 131.1, 128.8, 127.6, 127.1, 115.1, 108.8, 101.7, 92.0, 18.8; HRMS m/z (ESI) calcd for C19H15N2O2 [M + H]+ 303.1128, found 303.1138. 11-Benzoyl-7-(trifluoromethyl)imidazo[1,2-a:3,4-a′]dipyridin-5ium-4-olate (3ma): red solid (61 mg, 85%); mp 100−103 °C; 1H NMR (500 MHz, CDCl3) δ 10.43 (d, J = 7.1 Hz, 1H), 9.86 (s, 1H), 7.70 (dd, J = 7.0, 1.6 Hz, 1H), 7.62 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 8.5 Hz, 1H), 6.10 (d, J = 8.7 Hz, 1H), 5.67 (d, J = 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.8, 158.9, 140.7, 139.7, 139.6, 139.6, 135.1, 131.9, 130.39 (m), 129.0, 127.8, 122.3 (d, JC−F = 125.5 Hz), 116.9 (d, JC−F = 3.5 Hz), 113.1 (d, JC−F = 4.4 Hz), 110.2, 102.9, 92.5; HRMS m/z (ESI) calcd for C19H12F3N2O2 [M + H]+ 357.0845, found 357.0847. 11-Benzoyl-8-fluoroimidazo[1,2-a:3,4-a′]dipyridin-5-ium-4-olate (3na): red solid (54 mg, 89%); mp 166−167 °C; 1H NMR (500 MHz,

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01742. Crystal data for 3ac and copies of the 1H and 13C NMR spectra (PDF) Crystallographic data of 3ac (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ting Li: 0000-0002-2186-6992 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the Natural Science Foundation of China (21602120), Foundation of Henan Educational Committee (17A150043), and Nanyang Normal University (ZX2016016, QN2017050).

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REFERENCES

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Copper-Cocatalyzed Synthesis of Imidazo[1,2-a:3,4-a

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