English

• 1.   Introduction

  The direct diamination reaction is a very useful tool for the construction of heterocyclic frameworks containing two or more nitrogens. This synthetic strategy includes direct C—H functionalization without pre-activation, simple and readily accessible substrates, and generation of fewer wasteful by-products. In recent years, impressive achievements have been made in this area. For example, iodine-mediated diamination of methyl ketones^[1] with appropriate amines can produce diverse diazaheterocyclic compounds, such as quinazoline-4(3H)-ones, isoquino-lines, and 1, 3, 4-oxadiazoles. Oxidative coupling of aminopyridines with β-keto esters, 1, 3-diones or propiolalde-hyde gives a variety of imidazo[1, 2-a]pyridine derivatives.^[2] In 2014, Hajra et al.^[3] reported diamination of chalcones with 2-amino substituted pyridines and benzo-thiazoles to prepare imidazo[1, 2-a]pyridines and related fused-ring compounds. Subsequently, Li et al.^[4] achieved such a transformation with amidines to synthesize tetrasubstituted imidazoles. Recently, Nguyen and Al-Mourabit et al.^[5] described a similar diamination using 2-cyclohexenones and cyclohexanones as substrates to prepare the corresponding tricyclic compounds.

  Imidazo[1, 2-a]pyridine^[6] is an important heterocyclic skeleton commonly found in drugs and bioactive molecules, ^[7] N-heterocyclic carbenes, ^[8] and organic materials.^[9] Specifically, imidazo[1, 2-a]pyridines bearing a 2- or 3-acyl moiety on the imidazole ring exhibit a broad spec-trum of biological and pharmacological properties, ^[10] in-cluding anti-tuberculosis, antitumor, calcium channel blocking, anesthetic, anticonvulsant, and kinase inhibitory activities. Further, they are also useful building-blocks in medicinal chemistry, ^[11] and the development of practical synthetic methods to access 2-acyl and/or 3-acyl imid-azo[1, 2-a]pyridines is of importance in medicinal and bi-omedical research. In 1984, Stanovnik et al.^[12] reported the synthesis of 3-acyl imidazo[1, 2-a]pyridines by alkylation of N, N-dime-thyl-N'-pyridylamidines with α-bromoketones and subsequent cyclization. In recent years, a number of oxidative annulation reactions have been developed using 2-aminopyridines or their derivatives as substrates. Such transformations afforded the 3-acyl products through transition-metal-catalyzed aerobic oxidation^{[2e~2f, 3a, 13]} or utilizing non-metal oxidants, such as tetrahalomethanes, ^{[2a, 2b]} tert-butyl hydroperoxide (TBHP), ^[2c] and hypervalent iodine.^[2d] However, to the best of our knowledge, few synthetic approaches to 2-acyl imidazo[1, 2-a]pyridines have been reported.

  Recently, we synthesized 2, 3-disubstituted imidazo[1, 2-a]pyridine frameworks by addition of 2-aminopyridines to nitriles or α, β-ynones followed by I₂-mediated intramole-cular C—H amination.^[14] In our continuing research into the synthesis of imidazo[1, 2-a]pyridine derivatives, we envisioned direct diamination of α, β-unsaturated ketones with 2-aminopyridines employing molecular iodine as the sole oxidant.^[15] By changing the solvent and substituents in 2-aminopyridines, 3-acyl and novel 2-acyl substituted imidazo[1, 2-a]pyridine derivatives can be prepared regio- selectively.

  2.   Results and discussion

  Initially, we took the chalcone (2a) as the model substrate with which to investigate the diamination reaction with 5-bromo-2-aminopyridine (1a) (Table 1). Solvent screening demonstrated that in the presence of iodine this oxidative annulation reaction proceeds under basic conditions in both 1, 2-dichloroethane (DCE) and toluene. The reaction in DCE afforded 46% of 3-benzoyl (3a) and 25% of 2-benzoyl imidazo[1, 2-a]pyridines (4a) (Entry 4). Switching the solvent to toluene significantly improved the yield of the 3-benzoyl product (3a) with excellent selectivity (Entry 5). Replacement of NaHCO3 with a stronger base such as K₂CO₃ slightly decreased the yield of 3a (Entry 6). The structure of 3a was further confirmed by X-ray crystallography.^[16]

  Table 1

  

  Table 1.  Optimization of reaction conditions for diamination of chalcone (2a) with 5-bromo-2-aminopyridine (1a)^a

  下载: 导出CSV

  Entry	Base	Solvent	T/℃	Yieldb/%
  				3a	4a
  1	NaHCO3	1, 4-Dioxane	Reflux	0	0
  2	NaHCO3	MeCN	Reflux	0	0
  3	NaHCO3	DMSO	80	0	0
  4	NaHCO3	DCE	Reflux	46	25
  5	NaHCO3	Toluene	Reflux	92	Trace
  6	K2CO3	Toluene	Reflux	89	Trace
  a Optimal reaction conditions (Entry 5): 1a (2 mmol), 2a (0.5 mmol), I2 (1 mmol), NaHCO3 (2.25 mmol), toluene (5 mL), reflux. b Isolated yields

  Having established the optimal reaction conditions (Conditions A), we sought to probe the substrate scope and the generality of this reaction. As shown in Table 2, reac-tions of α, β-unsaturated ketones with halogenated 2-aminopyridines give the 3-acyl compounds (3a~3l) as the major products. For unsubstituted chalcones (R²＝R³＝Ph), the 3-acyl isomers (3a~3c) were formed with high regioselectivity (Entries 1~3). Nevertheless, the stronger electron-withdrawing group (e.g. 3, 5-dibromo) in the sub-strate has a negative impact on the transformation with 41% of the chalcone being recovered (Entry 3). The pres-ence of electron-donating groups or mono-halogens on the olefinic phenyl ring (R²) did not affect either the yield or the selectivity (Entries 4~7). The 2-furyl substituted im-idazo[1, 2-a]pyridine (3h) was obtained in a satisfactory yield (Entry 8). The presence of electron-withdrawing groups on the phenyl ring in the chalcone (R²) or aliphatic groups at R³ lowered the yields of 3-acyl products (3i~3l) with greater amounts of the 2-acyl isomers (4i~4l) being generated (Entries 9~12). Diamination with alkyl- or un-subsituted 2-aminopyridines also favored the formation of the 2-acyl products (4m~4p) (Entries 13~16). An excep-tion is the reaction with 6-methyl-2-aminopyridine which, due to the steric hindrance from the 6-methyl group, re-sulted in only the 3-benzoylimidazo[1, 2-a]pyridine (3q) (Entry 17).

  Table 2

  

  Table 2.  Substrate scope for imidazo[1, 2-a]pyridine synthesis under conditions A^a

  下载: 导出CSV

  Entry	R1	R2	R3	Yieldb/%
  				3	4
  1	5-Br	Ph	Ph	92 (3a)	Trace (4a)
  2	5-Cl	Ph	Ph	88 (3b)	Trace (4b)
  3c	3, 5-Br2	Ph	Ph	54 (3c)	Trace (4c)
  4	5-Br	4-MeC6H4	Ph	88 (3d)	Trace (4d)
  5	5-Br	4-MeOC6H4	Ph	60 (3e)	Trace (4e)
  6	5-Br	4-ClC6H4	Ph	85 (3f)	Trace (4f)
  7	5-Br	4-BrC6H4	Ph	81 (3g)	Trace (4g)
  8	5-Br	2-Furyl	Ph	71 (3h)	Trace (4h)
  9	5-Br	2, 4-Cl2C6H3	Ph	47 (3i)	40 (4i)
  10	5-Br	4-NO2C6H4	Ph	29 (3j)	14 (4j)
  11	5-Br	4-MeC6H4	iPr	65 (3k)	8 (4k)
  12	5-Br	4-MeC6H4	tBu	52 (3l)	21 (4l)
  13	H	Ph	Ph	27 (3m)	49 (4m)
  14	3-Me	Ph	Ph	12 (3n)	59 (4n)
  15	4-Me	Ph	Ph	21 (3o)	43 (4o)
  16	5-Me	Ph	Ph	38 (3p)	57 (4p)
  17	6-Me	Ph	Ph	87 (3q)	0 (4q)
  aConditions A: 1 (2 mmol), 2 (0.5 mmol), I2 (1 mmol), NaHCO3 (2.25 mmol), toluene (5 mL), reflux; b isolated yields; c41% of the ketone was recovered

  In light of these encouraging results, we further opti-mized the diamination conditions for 2-acylimidazo[1, 2-a]pyridine synthesis. Inspired by observation of the higher yield of the 2-acyl product that are produced in DCE (Table 1, Entry 4), we performed the oxidative coupling of 2-aminopyridine with chalcone using DCE as the solvent. This elevated the yield of the 2-benzoyl product (4m) with better selectivity (Entry 1 in Table 3 vs. Entry 13 in Table 2). With a stronger base, K₂CO₃, both the yield and the selectivity were further improved (Table 3, Entry 2). However, use of KOH as base disfavors the formation of 4m (Entry 3). Under the optimal conditions (Conditions B), diaminations of α, β-unsaturated ketones by alkyl- or unsubsituted 2-aminopyridines produced mainly the cor-responding 2-acyl imidazo[1, 2-a]pyridines (4m~4t). Taking the product 4s as an example, the structure of this type of 2-acylimidazo[1, 2-a]pyridine has been confirmed by X-ray crystallography.^[16] Even the reaction with 5-bromo-2-aminopyridine resulted in the 2-benzoyl prod-ucts (4a, 4j~4k) as the major products (Table 3, Entry 11 vs. Table 2 Entry 1; Table 3 Entries 12~13 vs. Table 2 Entries 10, 11), which further supports the theory that DCE favors the 2-acyl product formation. Consistent with the results in toluene (Table 2, Entry 17), diamination with 6-methyl-2-aminopyridine in DCE also produced the 3-benzoyl isomer (3q) due to the steric effect (Table 3, Entry 9). It is noteworthy that the present diamination reaction is insensitive to air and moisture either in toluene or in DCE.

  Table 3

  

  Table 3.  Substrate scope for imidazo[1, 2-a]pyridine synthesis under conditions B^a

  下载: 导出CSV

  Entry	R1	R2	R3	Yieldb/%
  				4	3
  1c	H	Ph	Ph	73 (4m)	18 (3m)
  2	H	Ph	Ph	84 (4m)	14 (3m)
  3d	H	Ph	Ph	53 (4m)	35 (3m)
  4	3-Me	Ph	Ph	76 (4n)	7 (3n)
  5	4-Me	Ph	Ph	77 (4o)	13 (3o)
  6	5-Me	Ph	Ph	58 (4p)	18 (3p)
  7e	6-Me	Ph	Ph	0 (4q)	43 (3q)
  8	H	4-ClC6H4	Ph	41 (4r)	23 (3r)
  9	H	4-BrC6H4	4-BrC6H4	56 (4s)	18 (3s)
  10f	H	4-MeC6H4	tBu	50 (4t)	Trace (3t)
  11	5-Br	Ph	Ph	62 (4a)	33 (3a)
  12	5-Br	4-NO2C6H4	Ph	35 (4j)	14 (3j)
  13	5-Br	4-MeC6H4	iPr	44 (4k)	26 (3k)
  a Conditions B: 1 (2 mmol), 2 (0.5 mmol), I2 (1 mmol), K2CO3 (2.25 mmol), DCE (5 mL), reflux; b isolated yields; c NaHCO3 was used as base; d KOH was used as base; e 40% of the ketone was recovered; f 42% of the ketone was recovered.

  We proposed plausible mechanisms for the regioselec-tive formation of 2-acyl and 3-acyl substituted imid-azo[1, 2-a]pyridines (Scheme 1). The I₂-mediated regiose-lective diamination of α, β-unsaturated ketones by 2-amino-pyridines may proceed via two pathways. In the case of path a, conjugated addition of ketone 2 with the 2-amino group in 1 results in the intermediate B. Then, the I₂-mediated cyclization of B via an intramolecular Or-toleva-King reaction^{[17, 9a]} generates 2, 3-dihydroimidazo-[1, 2-a]pyridine D. Finally, oxidative aromatization of D by iodine forms the 3-acyl product (3). The second path (path b) involves conjugated addition of ketone 2 with the pyridine nitrogen in 1 (path b), leading eventually to the 2-acyl product (4). The presence of halo groups in substrates 1 favors the path a transformation due to its electron defi-ciency effect on the pyridine nitrogen. On the other hand, when R¹ is H or an alkyl group, the diamination will undergo path b mechanism as the pyridine nitrogen in 1 is the more nucleophilic. Moreover, the results demonstrated that the reaction is more likely to proceed via path a in toluene (see Table 2), but via path b in DCE (Table 3).

  Scheme 1

  

  Scheme 1.  Proposed mechanisms for the regioselective formation of 3-acyl (3) and 2-acyl imidazo[1, 2-a]pyridines (4)

  下载: 全尺寸图片 幻灯片

  3.   Conclusions

  In summary, we have established an I₂-mediated direct diamination reaction of α, β-unsaturated ketones with 2-aminopyridines under basic conditions. Under the optimal reaction conditions, the versatile synthetic approach presented here can not only produce 3-acyl imidazo[1, 2-a]pyridines, but can also afford a series of novel 2-acyl products regioselectively by changing the solvent and substituents in the 2-aminopyridine substrates. Using DCE as the solvent and un-/alkyl-substituted aminopyridines as susbtrates favor the formation of the 2-acyl imidazo[1, 2-a]pyridines. This new and transition metal-free methodology is operationally simple, insensitive to air and moisture, and applicable to a variety of α, β-unsaturated ketone and 2-aminopyridine substrates.

  4.   Experimental

  4.1   General information

  ¹H NMR and ¹³C NMR spectra were recorded on a 400 MHz (100 MHz for ¹³C NMR) spectrometer. Chemical shift values are given in parts per million (ppm) relative to the internal standard, tetramethylsilane (TMS). Melting points were determined on a micromelting point apparatus and uncorrected. High-resolution mass spectra (HRMS) were obtained on a TOF-Q mass spectrometer equipped with an electrospray ion source (ESI) and operated in the positive mode. Flash column chromatography was per-formed over 200~300 mesh silica gel and the solvents were distilled prior to use. Toluene and DCE were analyti-cal reagent (AR) grade and used without any pretreatment.

  4.2   General procedure for imidazo[1, 2-a]pyridine synthesis

  Conditions A: A reaction mixture of 1 (2 mmol), 2 (0.5 mmol), NaHCO₃ (189 mg, 2.25 mmol) and iodine (254 mg, 1 mmol) in toluene (5 mL) was refluxed for 15 h (TLC indicated that the conversion was complete). After cooling to room temperature, it was quenched with 5% Na₂S₂O₃ (0.5 mL), followed by the addition of brine (15 mL), and then extracted with CH₂Cl₂ (15 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄, concen-trated, and purified through column chromatography using a mixture of EtOAc and petroleum ether (PE) as the eluent to afford the products 3 (and 4).

  Conditions B: A reaction mixture of 1 (2 mmol), 2 (0.5 mmol), K₂CO₃ (311 mg, 2.25 mmol) and iodine (254 mg, 1 mmol) in DCE (5 mL) was refluxed for 15 h (TLC indi-cated that the conversion was complete). After cooling to room temperature, it was quenched with 5% Na₂S₂O₃ (0.5 mL), followed by the addition of brine (15 mL), and then extracted with CH₂Cl₂ (15 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄, concentrated, and purified through column chromatography (or preparative TLC) using a mixture of EtOAc and PE as the eluent to afford the products 4 (and 3).

  (6-Bromo-2-phenylimidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (3a): 174 mg, 92% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90], white solid. m.p. 131~133 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.71 (d, J＝0.8 Hz, 1H), 7.69 (d, J＝9.2 Hz, 1H), 7.59 (dd, J＝9.6, 2.0 Hz, 1H), 7.51~7.50 (m, 2H), 7.32~7.30 (m, 2H), 7.27 (t, J＝4.0 Hz, 1H), 7.17~7.07 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.3, 154.9, 145.8, 138.2, 133.5, 132.5, 132.1, 130.2, 129.6, 128.5, 128.4, 127.9, 127.8, 120.1, 118.0, 109.4; HRMS calcd for C₂₀H₁₄Br⁷⁹N₂O [M+H]⁺ 377.0284, found 377.0274.

  (6-Chloro-2-phenylimidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (3b): Yield 146 mg, 88% yield [under con-ditions A, eluent: V(EtOAc):V(PE)＝10:90], yellow sol-id. m.p. 126~127 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.62 (s, 1H), 7.74 (d, J＝9.2 Hz, 1H), 7.51~7.48 (m, 3H), 7.32~7.26 (m, 3H), 7.15~7.09 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.3, 155.1, 145.6, 138.2, 133.5, 132.1, 130.4, 130.1, 129.6, 128.5, 127.9, 126.3, 122.9, 120.2, 117.7; HRMS calcd for C₂₀H₁₄ClN₂O [M+H]⁺ 333.0789, found 333.0785.

  (6, 8-Dibromo-2-phenylimidazo[1, 2-a]pyridin-3-yl)-(phenyl)methanone (3c) 123 mg, 54% yield [under condi-tions A, eluent: V(EtOAc):V(PE)＝5:95], yellow solid. m.p. 250~252 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.64 (d, J＝1.6 Hz, 1H), 7.87 (d, J＝1.6 Hz, 1H), 7.52~7.49 (m, 2H), 7.36~7.33 (m, 2H), 7.31~7.26 (m, 1H), 7.17~7.07 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.5, 154.8, 143.9, 137.7, 134.1, 133.1, 132.4, 130.4, 129.6, 128.7, 127.93, 127.90, 127.4, 121.3, 111.9, 108.3; HRMS (m/z) [M+H]⁺ C₂₀H₁₃Br₂⁸¹N₂O calcd for 456.9369, found 456.9358.

  (6-Bromo-2-(p-tolyl)imidazo[1, 2-a]pyridin-3-yl)(ph-enyl)methanone (3d): 172 mg, 88% yield [under condi-tions A, eluent: V(EtOAc):V(PE)＝10:90], white solid. m.p. 122~123 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.68 (dd, J＝2.0, 0.8 Hz, 1H), 7.68 (d, J＝9.6 Hz, 1H), 7.57 (dd, J＝9.6, 1.6 Hz, 1H), 7.52~7.50 (m, 2H), 7.31~7.27 (m, 1H), 7.20 (d, J＝8.0 Hz, 2H), 7.11 (t, J＝7.6 Hz, 2H), 6.89 (d, J＝8.0 Hz, 2H), 2.23 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) 187.4, 154.9, 145.7, 138.5, 138.2, 132.4, 132.0, 130.5, 130.1, 129.6, 128.6, 128.3, 127.8, 119.9, 117.9, 109.2, 21.2; HRMS calcd for C₂₁H₁₆Br⁸¹N₂O [M+H]⁺ 393.0420, found 393.0421.

  (6-Bromo-2-(4-methoxyphenyl)imidazo[1, 2-a]pyridin-3-yl)(phenyl)methanone (3e): 122 mg, 60% yield [under conditions A, eluent: V(EtOAc):V(PE)＝15:85], yellow solid. m.p. 94~97 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.68 (dd, J＝2.0, 0.8 Hz, 1H), 7.686 (dd, J＝9.2, 0.4 Hz, 1H), 7.57 (dd, J＝9.6, 2.0 Hz, 1H), 7.53~7.51 (m, 2H), 7.32~7.28 (m, 1H), 7.27~7.23 (m, 2H), 7.13 (t, J＝7.6 Hz, 2H), 6.63~6.61 (m, 2H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.3, 159.9, 154.6, 145.7, 138.2, 132.5, 132.0, 131.5, 129.6, 128.3, 127.9, 125.8, 119.7, 117.7, 113.4, 109.2, 55.3.; HRMS calcd for C₂₁H₁₆Br⁷⁹N₂O₂ [M+H]⁺ 407.0390, found 407.0395.

  (6-Bromo-2-(4-chlorophenyl)imidazo[1, 2-a]pyridin-3-yl)(phenyl)methanone (3f): 175 mg, 85% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90], white solid. m.p. 162~164 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.69 (d, J＝1.2 Hz, 1H), 7.69 (d, J＝9.6 Hz, 1H), 7.61 (dd, J＝9.6, 1.6 Hz, 1H), 7.51~7.49 (m, 2H), 7.38~7.34 (m, 1H), 7.26~7.23 (m, 2H), 7.16 (t, J＝7.6 Hz, 2H), 7.08~7.06 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.1, 153.5, 145.8, 138.0, 134.7, 132.8, 132.4, 132.1, 131.3, 129.6, 128.4, 128.09, 128.06, 120.1, 118.0, 109.6; HRMS calcd for C₂₀H₁₃Br⁸¹ClN₂O [M+H]⁺ 412.9874, found 412.9862.

  (6-Bromo-2-(4-bromophenyl)imidazo[1, 2-a]pyridin-3-yl)(phenyl)methanone (3g): 185 mg, 81% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90], white solid. m.p. 177~178 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.68 (s, 1H), 7.69 (d, J＝9.6 Hz, 1H), 7.60 (dd, J＝9.6, 1.6 Hz, 1H), 7.50 (d, J＝7.2 Hz, 2H), 7.36 (t, J＝7.2 Hz, 1H), 7.24~7.22 (m, 2H), 7.19~7.14 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.1, 153.5, 145.7, 138.0, 132.8, 132.5, 132.4, 131.6, 131.0, 129.6, 128.4, 128.1, 123.1, 120.1, 118.0, 109.7; HRMS calcd for C₂₀H₁₃Br⁸¹₂N₂O [M+H]⁺ 456.9369, found 456.9362.

  (6-Bromo-2-(furan-2-yl)imidazo[1, 2-a]pyridin-3-yl)-(phenyl)methanone (3h): 130 mg, 71% yield [under condi-tions A, eluent: V(EtOAc):V(PE)＝15:85], grey solid. m.p. 139~141 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.52~9.51 (m, 1H), 7.68 (d, J＝7.6 Hz, 2H), 7.65 (d, J＝9.6 Hz, 1H), 7.56 (dd, J＝9.2, 1.2 Hz, 1H), 7.46 (t, J＝7.6 Hz, 1H), 7.32 (t, J＝7.6 Hz, 2H), 7.07~7.06 (m, 1H), 6.48 (d, J＝3.6 Hz, 1H), 6.26 (dd, J＝3.2, 1.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.0, 147.1, 145.9, 143.8, 143.7, 138.9, 132.6, 132.3, 129.0, 128.2, 128.1, 119.3, 117.9, 112.5, 111.6, 109.4; HRMS calcd for C₁₈H₁₂Br⁷⁹N₂O₂ [M+H]⁺ 367.0077, found 367.0071.

  (6-Bromo-2-(2, 4-dichlorophenyl)imidazo[1, 2-a]pyridin-3-yl)(phenyl)methanone (3i): 105 mg, 47% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90, with 40% of 4i isolated], yellow solid. m.p. 174~175 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.76~9.75 (m, 1H), 7.71 (dd, J＝9.2, 4.0 Hz, 1H), 7.64~7.60 (m, 1H), 7.46~7.44 (m, 2H), 7.33~7.28 (m, 1H), 7.20 (dd, J＝8.0, 2.0 Hz, 1H), 7.13~7.10 (m, 3H), 7.07 (dt, J＝8.4, 2.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 186.9, 150.7, 145.7, 138.1, 135.2, 134.2, 132.9, 132.8, 132.1, 131.9, 129.2, 129.1, 128.6, 127.5, 126.7, 121.4, 118.2, 110.0; HRMS calcd for C₂₀H₁₂Br⁸¹Cl₂N₂O [M+H]⁺ 446.9484, found 446.9466.

  (6-Bromo-2-(4-nitrophenyl)imidazo[1, 2-a]pyridin-3-yl)(phenyl)methanone (3J): 62 mg, 29% yield [under con-ditions A, eluent: V(EtOAc):V(PE)＝15:85, with 14% of 4J isolated], yellow solid. m.p. 192~194 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.68 (d, J＝0.8 Hz, 1H), 7.97~7.95 (m, 2H), 7.72 (d, J＝9.2 Hz, 1H), 7.65 (dd, J＝9.2, 1.6 Hz, 1H), 7.51~7.48 (m, 4H), 7.34 (t, J＝7.6 Hz, 1H), 7.14 (t, J＝7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 186.8, 151.8, 147.4, 145.8, 140.1, 138.0, 133.1, 132.8, 130.9, 129.5, 128.3, 128.2, 122.9, 120.6, 118.2, 110.2; HRMS calcd for C₂₀H₁₂Br⁸¹N₃O₃Na [M+Na]⁺ 445.9934, found 445.9913.

  1-(6-Bromo-2-phenylimidazo[1, 2-a]pyridin-3-yl)-2-methylpropan-1-one (3k): 116 mg, 65% yield [under con-ditions A, eluent: V(EtOAc):V(PE)＝5:95, with 8% of 4k isolated], white solid. m.p. 95~98 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.91 (s, 1H), 7.62 (d, J＝9.2 Hz, 1H), 7.56 (dd, J＝9.2, 1.6 Hz, 1H), 7.47 (d, J＝8.0 Hz, 2H), 7.30 (d, J＝8.0 Hz, 2H), 3.07 (heptet, J＝6.8 Hz, 1H), 2.45 (s, 3H), 1.02 (d, J＝6.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 197.8, 154.6, 145.3, 139.4, 132.4, 132.0, 129.4, 129.2, 129.1, 120.3, 117.7, 109.5, 36.9, 21.5, 19.3; HRMS calcd for C₁₈H₁₈Br⁷⁹N₂O [M+H]⁺ 357.0597, found 357.0595.

  1-(6-Bromo-2-(p-tolyl)imidazo[1, 2-a]pyridin-3-yl)-2, 2-dimethylpropan-1-one (3l): 97 mg, 52% yield [under con-ditions A, eluent: V(EtOAc):V(PE)＝10:90, with 21% of 4l isolated], white solid. m.p. 111 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.37~8.36 (m, 1H), 7.56 (d, J＝9.6 Hz, 1H), 7.47 (d, J＝8.0 Hz, 2H), 7.35 (dt, J＝9.6, 1.6 Hz, 1H), 7.26 (d, J＝8.0 Hz, 1H), 2.41 (s, 3H), 1.08 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 206.6, 147.9, 144.1, 139.2, 132.1, 130.0, 129.5, 129.0, 125.6, 120.2, 118.1, 108.1, 46.3, 27.5, 21.4; HRMS calcd for C₁₉H₂₀Br⁸¹N₂O [M+H]⁺ 373.0733, found 373.0742.

  Phenyl(2-phenylimidazo[1, 2-a]pyridin-3-yl)methan-one (3m): 40 mg, 27% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90, with 49% of 4m isolated], white solid. m.p. 119~121 ℃ (lit.[13d] m.p. 124~127 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 9.56 (d, J＝6.8 Hz, 1H), 7.81 (d, J＝8.8 Hz, 1H), 7.56~7.51 (m, 3H), 7.33~7.31 (m, 2H), 7.27~7.24 (m, 1H), 7.15~7.07 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.4, 155.0, 147.4, 138.7, 134.0, 131.8, 130.2, 129.6, 129.2, 128.3, 127.8 (overlap), 120.0, 117.5, 114.6; HRMS calcd for C₂₀H₁₅N₂O [M+H]⁺ 299.1179, found 299.1188.

  (8-Methyl-2-phenylimidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (3n): 19 mg, 12% yield [under conditions A, eluent: V(EtOAc):V(PE)＝5:95, with 59% of 4n iso-lated], white solid. m.p. 139~140 ℃ (lit.[13d] m.p. 140~143 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 9.41 (d, J＝6.8 Hz, 1H), 7.50~7.48 (m, 2H), 7.34~7.31 (m, 3H), 7.24~7.22 (m, 1H), 7.12~7.06 (m, 5H), 7.01 (t, J＝6.8 Hz, 1H), 2.74 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.5, 154.6, 147.7, 138.8, 134.3, 131.6, 130.3, 129.5, 128.2, 128.1, 127.8, 127.7, 127.5, 126.0, 120.5, 114.7, 17.2; HRMS calcd for C₂₁H₁₇N₂O [M+H]⁺ 313.1335, found 313.1331.

  (7-Methyl-2-phenylimidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (3o): 33 mg, 21% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90, with 43% of 4o iso-lated], white solid. m.p. 135~137 ℃ (lit.[13d] m.p. 137~140 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 9.45 (d, J＝7.2 Hz, 1H), 7.57 (s, 1H), 7.50~7.48 (m, 2H), 7.31~7.29 (m, 2H), 7.26~7.22 (m, 1H), 7.14~7.05 (m, 5H), 6.94 (dd, J＝7.2, 1.6 Hz, 1H), 2.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.1, 155.3, 147.9, 140.9, 138.8, 134.1, 131.6, 130.2, 129.5, 128.2, 127.7, 127.5, 119.8, 117.2, 116.1, 21.6; HRMS calcd for C₂₁H₁₇N₂O [M+H]⁺ 313.1335, found 313.1336.

  (6-Methyl-3-phenylimidazo[1, 2-a]pyridin-2-yl)(phen-yl)methanone (3p): 59 mg, 38% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90, with 57% of 4p iso-lated], white solid. m.p. 160~161 ℃ (lit.[13d] m.p. 156~158 ℃); 1H NMR (400 MHz, CDCl₃) δ: 9.37 (s, 1H), 7.70 (d, J＝9.2 Hz, 1H), 7.50 (d, J＝7.6 Hz, 2H), 7.37 (d, J＝8.8 Hz, 1H), 7.31 (d, J＝7.6 Hz, 2H), 7.24 (d, J＝7.2 Hz, 1H), 7.12~7.07 (m, 5H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.3, 154.9, 146.4, 138.8, 134.2, 132.1, 131.7, 130.2, 129.6, 128.1, 127.7 (one signal missing due to overlap), 126.2, 124.6, 119.9, 116.7, 18.5; HRMS calcd for C₂₁H₁₇N₂O [M+H]⁺ 313.1335, found 313.1338.

  (5-Methyl-2-phenylimidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (3q): 136 mg, 87% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90], yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.82~7.80 (m, 2H), 7.71 (d, J＝8.8 Hz, 1H), 7.48~7.46 (m, 2H), 7.42~7.36 (m, 2H), 7.27~7.24 (m, 2H), 7.16~7.14 (m, 3H), 6.78 (d, J＝7.2 Hz, 1H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 188.0, 150.2, 147.8, 138.3, 137.9, 133.7, 133.3, 130.4, 129.4, 128.4, 128.1, 128.0, 127.6, 120.5, 115.3, 115.0, 22. 4; HRMS calcd for C₂₁H₁₆N₂ONa [M+Na]⁺ 335.1155, found 335.1149.

  (2-(4-Chlorophenyl)imidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (3r): 38 mg, 23% yield [under conditions B, eluent: V(EtOAc):V(PE)＝10:90, with 41% of 4r iso-lated], white solid. m.p. 133~135 ℃ (lit.[13d] m.p. 132~134 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 9.53 (s, 1H), 7.80 (s, 1H), 7.61~7.43 (m, 3H), 7.33~7.26 (m, 3H), 7.14~7.07 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.2, 153.5, 147.4, 138.5, 134.5, 132.5, 132.0, 131.4, 129.6, 129.4, 128.3, 128.0 (overlap), 120.1, 117.5, 114.8; HRMS calcd for C₂₀H₁₄ClN₂O [M+H]⁺ 333.0789, found 333.0794.

  (4-Bromophenyl)(2-(4-bromophenyl)imidazo[1, 2-a]py-ridin-3-yl)methanone (3s): 41 mg, 18% yield [under condi-tions B, eluent: V(EtOAc):V(PE)＝10:90, with 56% of 4s isolated], white solid. m.p. 212~215 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.50 (d, J＝6.8 Hz, 1H), 7.80 (d, J＝8.8 Hz, 1H), 7.56 (t, J＝8.0 Hz, 1H), 7.36 (d, J＝8.0 Hz, 2H), 7.30~7.27 (m, 4H), 7.18 (d, J＝8.0 Hz, 2H), 7.12 (t, J＝6.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 185.8, 153.7, 147.6, 137.3, 132.8, 131.6, 131.2, 131.1, 131.0, 129.7, 128.3, 127.0, 123.2, 119.8, 117.6, 115.0; HRMS calcd for C₂₀H₁₃Br₂⁸¹N₂O [M+H]⁺ 456.9369, found 456.9366.

  (6-Bromo-3-phenylimidazo[1, 2-a]pyridin-2-yl)(phenyl)-methanone (4a): 117 mg, 62% yield [under conditions B, eluent: V(EtOAc):V(PE)＝10:90, with 33% of 3a iso-lated], yellow solid. m.p. 191~194 ℃; 1H NMR (400 MHz, CDCl₃) δ: 8.19 (s, 1H), 8.15 (d, J＝7.6 Hz, 2H), 7.63 (d, J＝9.6 Hz, 1H), 7.56~7.48 (m, 6H), 7.43 (t, J＝7.6 Hz, 2H), 7.34 (d, J＝9.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 189.8, 142.3, 140.6, 137.6, 132.8, 130.7, 130.3, 129.7, 129.6, 129.2, 128.1, 127.6, 124.0, 119.8, 108.9 (one signal missing due to overlap); HRMS calcd for C₂₀H₁₄Br-⁷⁹N₂O [M+H]⁺ 377.0284, found 377.0290.

  (6-Bromo-3-(2, 4-dichlorophenyl)imidazo[1, 2-a]pyridin-2-yl)(phenyl)methanone (4i): 89 mg, 40% yield [under conditions A, eluent: V(EtOAc):V(PE)＝10:90, with 47% of 3i isolated], yellow solid. m.p. 149~151 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.23 (d, J＝7.6 Hz, 2H), 7.83 (s, 1H), 7.68 (d, J＝9.6 Hz, 1H), 7.60 (d, J＝1.6 Hz, 1H), 7.56 (t, J＝7.6 Hz, 1H), 7.48~7.44 (m, 3H), 7.43~7.38 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 189.3, 142.6, 141.7, 137.2, 136.9, 135.6, 134.2, 132.9, 130.7, 130.2, 130.0, 128.2, 127.9, 125.7, 125.2, 124.3, 119.9, 109.2; HRMS calcd for C₂₀H₁₁Br⁸¹Cl₂N₂ONa [M+Na]⁺ 468.9304, found 468.9306.

  (6-Bromo-3-(4-nitrophenyl)imidazo[1, 2-a]pyridin-2-yl)(phenyl)methanone (4J): 30 mg, 14% yield [under con-ditions A, eluent: V(EtOAc):V(PE)＝15:85, with 29% of 3J isolated], yellow solid. m.p. 211 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.42~8.40 (m, 2H), 8.22~8.20 (m, 2H), 8.17 (dd, J＝1.6, 0.8 Hz, 1H), 7.79~7.76 (m, 2H), 7.69 (dd, J＝9.6, 0.8 Hz, 1H), 7.61~7.57 (m, 1H), 7.50~7.47 (m, 2H), 7.43 (dd, J＝9.6, 1.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 189.4, 148.2, 142.8, 141.5, 137.1, 134.5, 133.2, 131.4, 130.8, 130.4, 128.3, 126.6, 124.4, 123.5, 120.1, 109.2; HRMS calcd for C₂₀H₁₂Br⁸¹N₃O₃Na [M+Na]⁺ 445.9934, found 445.9913.

  1-(6-Bromo-3-phenylimidazo[1, 2-a]pyridin-2-yl)-2-methylpropan-1-one (4k): 14 mg, 8% yield [under condi-tions A, eluent: V(EtOAc):V(PE)＝5:95, with 65% of 3k isolated], yellow solid. m.p. 132~133 ℃; 1H NMR (400 MHz, CDCl₃) δ: 8.08 (d, J＝5.6 Hz, 1H), 7.60~7.56 (m, 1H), 7.37~7.35 (m, 4H), 7.32~7.25 (m, 1H), 3.88 (heptet, J＝6.8 Hz, 1H), 2.45 (d, J＝6.8 Hz, 3H), 1.20 (t, J＝6.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 202.2, 142.2, 139.8, 139.2, 130.2, 129.8, 129.5, 128.1, 124.7, 124.2, 119.6, 108.6, 36.8, 21.5, 18.7; HRMS calcd for C₁₈H₁₇Br⁷⁹N₂ONa [M+Na]⁺ 379.0416, found 379.0419.

  1-(6-Bromo-3-(p-tolyl)imidazo[1, 2-a]pyridin-2-yl)-2, 2-dimethylpropan-1-one (4l): 39 mg, 21% yield [under con-ditions A, eluent: V(EtOAc):V(PE)＝5:95, with 52% of 3l isolated], yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.02 (dd, J＝1.6, 0.8 Hz, 1H), 7.55 (dd, J＝9.6, 0.8 Hz, 1H), 7.36~7.31 (m, 4H), 7.27 (dd, J＝9.6, 2.0 Hz, 1H), 2.45 (s, 3H), 1.45 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 203.4, 141.4, 140.0, 139.4, 130.2, 129.8, 129.0, 128.8, 125.3, 124.0, 119.6, 108.3, 44.8, 27.1, 21.5; HRMS calcd for C₁₉H₂₀Br⁷⁹N₂O [M+H]⁺ 371.0754, found 371.0743.

  (6-Bromo-3-phenylimidazo[1, 2-a]pyridin-2-yl)(phen-yl)methanone (4m): 125 mg, 84% yield [under conditions B, eluent: V(EtOAc):V(PE)＝10:90, with 14% of 3m isolated], white solid. m.p. 122~124 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.17~8.15 (m, 2H), 8.08 (d, J＝7.2 Hz, 1H), 7.73 (d, J＝9.2 Hz, 1H), 7.55~7.46 (m, 6H), 7.45~7.41 (m, 2H), 7.30~7.29 (m, 1H), 6.83 (t, J＝7.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.3, 143.9, 140.1, 137.8, 132.6, 130.8, 130.4, 129.2, 129.1, 129.0, 128.3, 128.1, 126.0, 124.1, 119.1, 113.7; HRMS calcd for C₂₀H₁₄N₂ONa [M+Na]⁺ 321.0998, found 321.0995.

  (8-Methyl-3-phenylimidazo[1, 2-a]pyridin-2-yl)(phen-yl)methanone (4n): 119 mg, 76% yield [under conditions B, eluent: V(EtOAc):V(PE)＝5:95, with 7% of 3n iso-lated], yellow solid. m.p. 127~129 ℃; 1H NMR (400 MHz, CDCl₃) δ: 8.17-8.15 (m, 2H), 8.23 (d, J＝7.6 Hz, 1H), 7.92 (d, J＝6.8 Hz, 1H), 7.49~7.43 (m, 5H), 7.42~7.36 (m, 3H), 7.05 (d, J＝6.8 Hz, 1H), 6.72 (t, J＝6.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.2, 144.6, 139.7, 137.8, 132.5, 131.0, 130.4, 129.4, 129.1, 128.9, 128.7, 128.0, 124.5, 121.8, 113.8, 17.2 (one signal missing due to overlap); HRMS calcd for C₂₁H₁₆N₂ONa [M+Na]⁺335.1155, found 335.1143.

  (7-Methyl-3-phenylimidazo[1, 2-a]pyridin-2-yl)(phen-yl)methanone (4o): 120 mg, 77% yield [under conditions B, eluent: V(EtOAc):V(PE)＝15:85, with 13% of 3o isolated], yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.15~8.13 (m, 2H), 7.95 (d, J＝7.2 Hz, 1H), 7.52~7.45 (m, 6H), 7.44~7.38 (m, 3H), 6.65 (dd, J＝7.2, 1.6 Hz, 1H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.4, 144.4, 139.9, 138.0, 137.1, 132.5, 130.7, 130.4, 129.1, 128.9, 128.7, 128.4, 128.0, 123.2, 117.1, 116.5, 21.4; HRMS calcd for C₂₁H₁₇N₂O [M+H]⁺ 313.1335, found 313.1339.

  (6-Methyl-2-phenylimidazo[1, 2-a]pyridin-3-yl)(phen-yl)methanone (4p): 90 mg, 58% yield [under conditions B, eluent: V(EtOAc):V(PE)＝15:85, with 18% of 3p iso-lated], white solid. m.p. 156~158 ℃; 1H NMR (400 MHz, CDCl₃) δ: 8.16 (d, J＝7.2 Hz, 2H), 7.83 (s, 1H), 7.63 (d, J＝9.2 Hz, 1H), 7.54~7.49 (m, 5H), 7.47~7.45 (m, 1H), 7.42 (t, J＝7.2 Hz, 2H), 7.13 (d, J＝9.6 Hz, 1H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.3, 143.1, 140.0, 138.0, 132.5, 130.7, 130.4, 129.4, 129.1, 129.0, 128.8, 128.5, 128.0, 123.6, 121.3, 118.4, 18.5; HRMS calcd for C₂₁H₁₇N₂O [M+H]⁺ 313.1335, found 313.1334.

  (3-(4-Chlorophenyl)imidazo[1, 2-a]pyridin-2-yl)(phen-yl)methanone (4r): 68 mg, 41% yield [under conditions B, eluent: V(EtOAc):V(PE)＝10:90, with 23% of 3r iso-lated], yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (s, 2H), 8.03 (s, 1H), 7.73 (d, J＝7.2 Hz, 1H), 7.62~7.36 (m, 7H), 7.29 (s, 1H), 6.86 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 190.1, 144.0, 140.2, 137.7, 135.2, 132.7, 131.8, 130.8, 129.3, 128.1, 127.7, 126.7, 126.3, 123.8, 119.1, 114.1; HRMS calcd for C₂₀H₁₄ClN₂O [M+H]⁺ 333.0789, found 333.0798.

  (4-Bromophenyl)(3-(4-bromophenyl)imidazo[1, 2-a]py-ridin-2-yl)methanone (4s): 128 mg, 56% yield [under con-ditions B, eluent: V(EtOAc):V(PE)＝10:90, with 18% of 3s isolated], yellow solid. m.p. 162~165 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.15~8.13 (m, 2H), 8.02 (d, J＝6.8 Hz, 1H), 7.73 (d, J＝9.2 Hz, 1H), 7.67 (d, J＝8.4 Hz, 2H), 7.61 (d, J＝8.4 Hz, 2H), 7.44 (d, J＝8.4 Hz, 2H), 7.34~7.30 (m, 1H), 6.87 (t, J＝6.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 188.7, 144.0, 139.8, 136.4, 132.4, 132.3, 132.0, 131.4, 128.1, 128.0, 127.1, 126.4, 123.83, 123.80, 119.3, 114.2; HRMS calcd for C₂₀H₁₂Br₂⁸¹N₂ONa [M+Na]⁺ 478.9188, found 478.9190.

  2, 2-Dimethyl-1-(3-(p-tolyl)imidazo[1, 2-a]pyridin-2-yl)propan-1-one (4t): 73 mg, 50% yield [under conditions B, eluent: V(EtOAc):V(PE)＝5:95], yellow solid. m.p. 98~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (d, J＝7.2 Hz, 1H), 7.54 (d, J＝9.2 Hz, 1H), 7.25~7.21 (m, 4H), 7.11~7.07 (m, 1H), 6.62 (t, J＝6.8 Hz, 1H), 2.33 (s, 3H), 1.38 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 203.8, 143.0, 139.5, 139.0, 130.3, 129.7, 128.6, 126.0, 125.4, 124.0, 118.9, 113.2, 44.7, 27.3, 21.5; HRMS calcd for C₁₉H₂₁N₂O [M+H]⁺ 293.1648, found 293.1657.

  Supporting Information  Copies of ¹H NMR and ¹³C NMR spectra of compounds 3 and 4. The Supporting In-formation is available free of charge via the Internet at http://sioc-journal.cn/

• 1. [1]

     (a) Zhu, Y. -P. ; Fei, Z. ; Liu, M. -C. ; Jia, F. -C. ; Wu, A. -X. Org. Lett. 2013, 15, 378.
     (b) Zhu, Y. -P. ; Liu, M. -C. ; Cai, Q. ; Jia, F. -C. ; Wu, A. -X. Chem. -Eur. J. 2013, 19, 10132.
     (c) Gao, Q. ; Liu, S. ; Wu, X. ; Zhang, J. ; Wu, A. Org. Lett. 2015, 17, 2960.

  2. [2]

     (a) Huo, C. ; Tang, J. ; Xie, H. ; Wang, Y. ; Dong, J. Org. Lett. 2016, 18, 1016.
     (b) Roslan, I. I. ; Ng, K. -H. ; Chuah, G. -K. ; Jaenicke, S. Adv. Synth. Catal. 2016, 358, 364.
     (c) Ma, L. ; Wang, X. ; Yu, W. ; Han, B. Chem. Commun. 2011, 47, 11333.
     (d) Wang, X. ; Ma, L. ; Yu, W. Synthesis 2011, 2445.
     (e) Cao, H. ; Liu, X. ; Liao, J. ; Huang, J. ; Qiu, H. ; Chen, Q. ; Chen, Y. J. Org. Chem. 2014, 79, 11209.
     (f) Zhan, H. ; Zhao, L. ; Liao, J. ; Li, N. ; Chen, Q. ; Qiu, S. ; Cao, H. Adv. Synth. Catal. 2015, 357, 46

  3. [3]

     (a) Monir, K. ; Bagdi, A. K. ; Mishra, S. ; Majee, A. ; Hajra, A. Adv. Synth. Catal. 2014, 356, 1105.
     (b) Mishra, S. ; Monir, K. ; Mitra, S. ; Hajra, A. Org. Lett. 2014, 16, 6084.

  4. [4]

     Zhu, Y.; Li, C.; Zhang, J.; She, M.; Sun, W.; Wan, K.; Wang, Q.; Yin, B.; Liu, P.; Li, J. Org. Lett. 2015, 17, 3872. doi: 10.1021/acs.orglett.5b01854

  5. [5]

     (a) Nguyen, T. B. ; Corbin, M. ; Retailleau, P. ; Ermolenko, L. ; Al-Mourabit, A. Org. Lett. 2015, 17, 4956.
     (b) Nguyen, T. B. ; Ermolenko, L. ; Retailleau, P. ; Al-Mourabit, A. Org. Lett. 2016, 18, 2177.

  6. [6]

     (a) Couty, F. ; Evano, G. In Comprehensive Heterocyclic Chemistry Ⅲ, Vol. 11, Eds. : Katritzky, A. R. ; Ramsden, C. A. ; Scriven, E. F. V. ; Taylor, R. J. K., Elsevier, Oxford, 2008, pp. 409~499.
     (b) Bagdi, A. K. ; Santra, S. ; Monir, K. ; Hajra, A. Chem. Commun. 2015, 51, 1555.
     (c) Dymińska, L. Bioorg. Med. Chem. 2015, 23, 6087.
     (d) Enguehard-Gueiffier, C. ; Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7, 888.

  7. [7]

     (a) Mizushige, K. ; Ueda, T. ; Yukiiri, K. ; Suzuki, H. Cardiovasc. Drug Rev. 2002, 20, 163.
     (b) Igawa, H. ; Takahashi, M. ; Kakegawa, K. ; Kina, A. ; Ikoma, M. ; Aida, J. ; Yasuma, T. ; Kawata, Y. ; Ashina, S. ; Yamamoto, S. ; Kundu, M. ; Khamrai, U. ; Hirabayashi, H. ; Nakayama, M. ; Nagisa, Y. ; Kasai, S. ; Maekawa, T. J. Med. Chem. 2016, 59, 1116.
     (c) Trabanco, A. A. ; Tresadern, G. ; Macdonald, G. J. ; Vega, J. A. ; Lucas, A. I. ; Matesanz, E. ; García, A. ; Linares, M. L. ; Diego, S. A. A. ; Alonso, J. M. ; Oehlrich, D. ; Ahnaou, A. ; Drinkenburg, W. ; Mackie, C. ; Andrés, J. I. ; Lavreysen, H. ; Cid, J. J. Med. Chem. 2012, 55, 2688.
     (d) Gladysz, R. ; Adriaenssens, Y. ; Winter, H. D. ; Joossens, J. ; Lambeir, A. ; Augustyns, K. ; Veken, P. V. J. Med. Chem. 2015, 58, 9238.

  8. [8]

     (a) Song, G. ; Zhang, Y. ; Li, X. Organometallics 2008, 27, 1936.
     (b) John, A. ; Shaikh, M. M. ; Ghosh, P. Dalton Trans. 2009, 10581.
     (c) Ke, C. -H. ; Kuo, B. -C. ; Nandi, D. ; Lee, H. M. Organometallics 2013, 32, 4775.

  9. [9]

     (a) Stasyuk, A. J. ; Banasiewicz, M. ; Cyrański, M. K. ; Gryko, D. T. J. Org. Chem. 2012, 77, 5552.
     (b) Mutai, T. ; Sawatani, H. ; Shida, T. ; Shono, H. ; Araki, K. J. Org. Chem. 2013, 78, 2482.
     (c) Firmansyah, D. ; Ciuciu, A. I. ; Hugues, V. ; Blanchard-Desce, M. ; Flamigni, L. ; Gryko, D. T. Chem. -Asian J. 2013, 8, 1279.
     (d) Furukawa, S. ; Shono, H. ; Mutai, T. ; Araki, K. ACS Appl. Mater. Interfaces 2014, 6, 16065.
     (e) Nagarajan, N. ; Velmurugan, G. ; Prakash, A. ; Shakti, N. ; Katiyar, M. ; Venuvanalingam, P. ; Renganathan, R. Chem. -Asian J. 2014, 9, 294.
     (f) Yao, C. ; Xue, Z. ; Lian, M. ; Xu, X. ; Zhao, J. ; Zhou, G. ; Wu, Y. ; Yu, D. ; Wong, W. -Y. J. Organomet. Chem. 2015, 784, 31.

  10. [10]

      (a) Kang, S. ; Kim, R. Y. ; Seo, M. J. ; Lee, S. ; Kim, Y. M. ; Seo, M. ; Seo, J. J. ; Ko, Y. ; Choi, I. ; Jang, J. ; Nam, J. ; Park, S. ; Kang, H. ; Kim, H. J. ; Kim, J. ; Ahn, S. ; Pethe, K. ; Nam, K. ; No, Z. ; Kim, J. J. Med. Chem. 2014, 57, 52935.
      (b) Hirayama, T. ; Okaniwa, M. ; Banno, H. ; Kakei, H. ; Ohashi, A. ; Iwai, K. ; Ohori, M. ; Mori, K. ; Gotou, M. ; Kawamoto, T. ; Yokota, A. ; Ishikawa, T. J. Med. Chem. 2015, 58, 8036.
      (c) Moraski, G. C. ; Miller, P. A. ; Bailey, M. A. ; Ollinger, J. ; Parish, T. ; Boshoff, H. I. ; Cho, S. ; Anderson, J. R. ; Mulugeta, S. ; Franzblau, S. G. ; Miller, M. J. ACS Infect. Dis. 2015, 1, 85.
      (d) Li, R. ; Wang, H. ; Li, Y. ; Wang, Z. ; Wang, X. ; Wang, Y. ; Ge, Z. ; Li, R. Eur. J. Med. Chem. 2015, 93, 381.
      (e) Jaramillo, C. ; de Diego, J. E. ; Hamdouchi, C. ; Collins, E. ; Keyser, H. ; Sánchez-Martínez, C. ; del Prado, M. ; Norman, B. ; Brooks, H. B. ; Watkins, S. A. ; Spencer, C. D. ; Dempsey, J. A. ; Anderson, B. D. ; Campbell, R. M. ; Leggett, T. ; Patel, B. ; Schultz, R. M. ; Espinosa, J. ; Vieth, M. ; Zhang, F. ; Timm, D. E. Bioorg. Med. Chem. Lett. 2004, 14, 6095.
      (f) Sanfilippo, P. J. ; Urbanski, M. ; Press, J. B. ; Dubinsky, B. ; Moore, J. B. J. Med. Chem. 1988, 31, 2221.

  11. [11]

      (a) Starrett, J. E. Montzka, T. A. ; Crosswell, A. R. ; Cavanagh, R. L. J. Med. Chem. 1989, 32, 2204.
      (b) Anderson, M. ; Beattie, J. F. ; Breault, G. A. ; Breed, J. ; Byth, K. F. ; Culshaw, J. D. ; Ellston, R. P. A. ; Green, S. ; Minshull, C. A. ; Norman, R. A. ; Pauptit, R. A. ; Stanway, J. ; Thomas, A. P. ; Jewsbury, P. J. Bioorg. Med. Chem. Lett. 2003, 13, 3021.

  12. [12]

      Podergajs, S.; Stanovnik, B.; Tišler, M. Synthesis 1984, 263.

  13. [13]

      For representative examples, see:(a) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678.
      (b) Mohan, D. C.; Rao, S. N.; Adimurthy, S. J. Org. Chem. 2013, 78, 1266.
      (c) Reddy, K. R.; Reddy, A. S.; Shankar, R.; Kant, R.; Das, P. Asian J. Org. Chem. 2015, 4, 573.
      (d) Kaswan, P.; Pericherla, K.; Saini, H. K.; Kumar, A. RSC Adv. 2015, 5, 3670.
      (e) Kaswan, P.; Pericherla, K.; Rajnikant; Kumar, A. Tetrahedron 2014, 70, 8539.
      (f) Xing, M.-M.; Xin, M.; Shen, C.; Gao, J.-R.; Jia, J.-H.; Li, Y.-J. Tetrahedron 2016, 72, 4201.
      (g) Meng, X.; Zhang, J.; Chen, B.; Jing, Z.; Zhao, P. Catal. Sci. Technol. 2016, 6, 890.
      (h) Yan, R.-L.; Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M. J. Org. Chem. 2012, 77, 2024.

  14. [14]

      (a) Tian, X. ; Song, L. Wang, Manman. ; Lv, Z. ; Wu, J. ; Yu, W. ; Chang, J. Chem. -Eur. J. 2016, 22, 7617.
      (b) Liu, J. ; Wei, W. ; Zhao, T. ; Liu, X. ; Wu, J. ; Yu, W. ; Chang, J. J. Org. Chem. 2016, 81, 9326.

  15. [15]

      Li, J. ; Zhu, Y. ; Li, C. ; Liu, P. ; Wang, Y. CN 105801575, 2016[Chem. Abstr. 2016, 165, 274501. ]

  16. [16]

      CCDC 1539194(3a) and 1539195(4s) contain the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre.

  17. [17]

      (a) King, L. C. J. Am. Chem. Soc. 1944, 66, 894.
      (b) Pearson, R. G. J. Am. Chem. Soc. 1947, 69, 3100.

• 

  Scheme 1  Proposed mechanisms for the regioselective formation of 3-acyl (3) and 2-acyl imidazo[1, 2-a]pyridines (4)

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of reaction conditions for diamination of chalcone (2a) with 5-bromo-2-aminopyridine (1a)^a

  Entry	Base	Solvent	T/℃	Yieldb/%
  				3a	4a
  1	NaHCO3	1, 4-Dioxane	Reflux	0	0
  2	NaHCO3	MeCN	Reflux	0	0
  3	NaHCO3	DMSO	80	0	0
  4	NaHCO3	DCE	Reflux	46	25
  5	NaHCO3	Toluene	Reflux	92	Trace
  6	K2CO3	Toluene	Reflux	89	Trace
  a Optimal reaction conditions (Entry 5): 1a (2 mmol), 2a (0.5 mmol), I2 (1 mmol), NaHCO3 (2.25 mmol), toluene (5 mL), reflux. b Isolated yields

  下载: 导出CSV

  Table 2.  Substrate scope for imidazo[1, 2-a]pyridine synthesis under conditions A^a

  Entry	R1	R2	R3	Yieldb/%
  				3	4
  1	5-Br	Ph	Ph	92 (3a)	Trace (4a)
  2	5-Cl	Ph	Ph	88 (3b)	Trace (4b)
  3c	3, 5-Br2	Ph	Ph	54 (3c)	Trace (4c)
  4	5-Br	4-MeC6H4	Ph	88 (3d)	Trace (4d)
  5	5-Br	4-MeOC6H4	Ph	60 (3e)	Trace (4e)
  6	5-Br	4-ClC6H4	Ph	85 (3f)	Trace (4f)
  7	5-Br	4-BrC6H4	Ph	81 (3g)	Trace (4g)
  8	5-Br	2-Furyl	Ph	71 (3h)	Trace (4h)
  9	5-Br	2, 4-Cl2C6H3	Ph	47 (3i)	40 (4i)
  10	5-Br	4-NO2C6H4	Ph	29 (3j)	14 (4j)
  11	5-Br	4-MeC6H4	iPr	65 (3k)	8 (4k)
  12	5-Br	4-MeC6H4	tBu	52 (3l)	21 (4l)
  13	H	Ph	Ph	27 (3m)	49 (4m)
  14	3-Me	Ph	Ph	12 (3n)	59 (4n)
  15	4-Me	Ph	Ph	21 (3o)	43 (4o)
  16	5-Me	Ph	Ph	38 (3p)	57 (4p)
  17	6-Me	Ph	Ph	87 (3q)	0 (4q)
  aConditions A: 1 (2 mmol), 2 (0.5 mmol), I2 (1 mmol), NaHCO3 (2.25 mmol), toluene (5 mL), reflux; b isolated yields; c41% of the ketone was recovered

  下载: 导出CSV

  Table 3.  Substrate scope for imidazo[1, 2-a]pyridine synthesis under conditions B^a

  Entry	R1	R2	R3	Yieldb/%
  				4	3
  1c	H	Ph	Ph	73 (4m)	18 (3m)
  2	H	Ph	Ph	84 (4m)	14 (3m)
  3d	H	Ph	Ph	53 (4m)	35 (3m)
  4	3-Me	Ph	Ph	76 (4n)	7 (3n)
  5	4-Me	Ph	Ph	77 (4o)	13 (3o)
  6	5-Me	Ph	Ph	58 (4p)	18 (3p)
  7e	6-Me	Ph	Ph	0 (4q)	43 (3q)
  8	H	4-ClC6H4	Ph	41 (4r)	23 (3r)
  9	H	4-BrC6H4	4-BrC6H4	56 (4s)	18 (3s)
  10f	H	4-MeC6H4	tBu	50 (4t)	Trace (3t)
  11	5-Br	Ph	Ph	62 (4a)	33 (3a)
  12	5-Br	4-NO2C6H4	Ph	35 (4j)	14 (3j)
  13	5-Br	4-MeC6H4	iPr	44 (4k)	26 (3k)
  a Conditions B: 1 (2 mmol), 2 (0.5 mmol), I2 (1 mmol), K2CO3 (2.25 mmol), DCE (5 mL), reflux; b isolated yields; c NaHCO3 was used as base; d KOH was used as base; e 40% of the ketone was recovered; f 42% of the ketone was recovered.

  下载: 导出CSV
•