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  Isocyanide-based multicomponent reactions are in accord with green chemistry standards as a powerful tool for the construction of novel and diverse molecular structures due to "one-pot" advantages over conventional multistep syntheses. ^[1]The Groebke-Blackburn-Bienayme (GBB) reaction is a four-centre, three-component reaction, which involves starting materials of aldehyde, aminoazine and isocyanide in the presence of a suitable catalyst to afford a highly substituted and imidazo-fused heterocycles. ^[2] In recent decades, imidazo-fused heterocycles exhibit a broad spectrum of biological activities. Many commercially available drugs with these scaffolds have been developed, such as the anxiolytic drug alpidem, ^[3] the sedative drug zol-pidem, ^[4] the anti-ulcer drug zolimidine, ^[5]the heart failure drug olprinone ^[6] (Figure 1) and many other compounds are being investigated in the stage of biological testing or preclinical evaluation. ^[7]

  Figure 1.  Some examples of imidazo-fused drugs

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  The GBB reaction catalysts are generally acid in various kinds, occasionally base, such as Br nsted acids like CH₃COOH, ^[8] HClO₄, ^[9] cellulose sulfuric acid, ^[10] p-toluene sulfonic acid, ^[11]CH₃SO₃H; ^[12] Lewis acids like Sc(OTf)₃, ^[13] SnCl₂, ^[14] LaCl₃, ^[15] LaCl₃•7H₂O, ^[16] MgCl₂, ^[17] CeCl₃• 7H₂O, ^[18] ZrCl₄, ^[19] ZnCl₂, ^[20] RuCl₃ ^[21] and InCl₃, ^[22]solid acid catalyst like LaMnO₃, ^[23] ionic liquid like 1-butyl-3-methylimidazolium bromide, ^[24] base like piperidine. ^[25] However, most of these catalysts suffer from several drawbacks such as long reaction time, harsh reaction conditions, poor yield, vastvast toxic metal-containing waste, and expensive reagents. In addition, different catalysts for a variety of substrates have different catalytic effect and each catalyst is not generally highly efficient. In order to overcome these disadvantages, development of novel methods to construct a variety of imidazo-fused heterocycles is still necessary and attractive. As for substrates, this reaction has a broad reactivity domain. Aminoazines include 2-amino-pyridine, 2-aminopyrimidine, 2-aminopyrazine, 2-amino-thiazole, 2-aminopyrazole, and a few more. Similarly, aromatic and aliphatic aldehydes participate in GBB reaction. ^[26] Commercial isocyanides can be widely used.

  CeCl₃ and CeCl₃•nH₂O, as ecofriendly, efficient and economical catalysts, ^[27] have been continuously studied to enhance the reactivity and selectivity of organic reactions. ^[28] With our continuous interest in exploring green catalyst, we knew that LaCl₃ ^[15] and LaCl₃•7H₂O ^[16] catalysts had exhibited high activities at relative low reaction temperature of 60 ℃ in ethanol in GBB reaction. However, CeCl₃•7H₂O was reported as catalyst of GBB reaction in DMSO at 70 ℃ with a relatively low yield at 42% (Eq. 1). ^[18] Therefore, these findings gave us full interest to enhance the activities of CeCl₃•7H₂O catalyst by optimization of the reaction conditions applied for the GBB reaction. According to further attempts with different equivalent catalyst, temperature and solvent, we have successfully developed an efficient method for synthesis of imidazo-fused heterocycles using simple starting materials in the presence of 10 mol% CeCl₃•7H₂O in ethanol at 60 ℃. Using this method the reaction yield could be enhanced to 97%. In addition, we made a comparative study of CeCl₃•7H₂O with LaCl₃•7H₂O, which was reported to be a good catalyst in GBB reaction, and a series of new compounds were obtained.

  1   Results and discussion

  The GBB reaction is a very powerful tool for the efficient synthesis of libraries of diverse complex small molecules. To explore a kind of green and available method, we tried to search a high-performance catalyst to improve the synthetic reactions of imidazo-fused heterocycles into one step. A preliminary examination of the reaction of 5-chloropyridin-2-amine, benzaldehyde and t-butyl isocyanide in ethanol was selected as the model reaction for optimum reaction conditions. The time taken to achieve complete conversions, temperature and the isolated yields were recorded in Table 1.

  Table 1.  Optimization of GBB reaction conditions^a

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  Entry	Solvent	CeCl3•7H2O/ mol%	T/℃	Time/min	Yieldb/%
  1	Ethanol	—c	r.t.	120	N.R.d
  2	Ethanol	5	r.t.	150	82
  3	Ethanol	5	35	100	86
  4	Ethanol	5	60	60	89
  5	Ethanol	10	r.t.	110	96
  6	Ethanol	10	60	60	97
  7	Methanol	10	60	90	65
  8	Trifluoroethanol	10	60	90	78
  9	H2O	10	60	160	74
  10	H2O	10	80	120	83
  11	—e	10	60	60	56
  12	Ethanol	10	70	60	96
  13	Ethanol	15	60	60	95
  14	DMSO	10	70	120	83
  15	Toluene	10	60	120	77
  16	Dichloromethane	10	35	120	81
  17	Acetonitrile	10	60	120	84
  a Reaction conditions: 5-chloropyridin-2-amine (1.0 mmol), benzaldehyde (1.0 mmol), t-butyl isocyanide (1.0 mmol); b Isolated yield; c No catalyst used; dN.R. means no reaction; eSolvent-free condition.

  Table 1.  Optimization of GBB reaction conditions^a

  In our investigation, initially we found that no reaction occurred in the absence of catalysts at room temperature. However, when CeCl₃•7H₂O (5 mol%) was added at room temperature, the corresponding N-(tert-butyl)-6-chloro-2-phenylimidazo[1, 2-a]-pyridine-3-amine was obtained in 82% yield (Table 1, Entry 2). Upon varying the temperature of the reaction from room temperature to 70 ℃, the best yield was obtained at 60 ℃. Further increase of the temperature neither increased the yield nor shortened the reaction time. The solvents including methanol, water, DMSO, toluene, trifluoroethanol, dichloromethane and acetonitrile did not give excellent yields. Hence, we chose 10 mol% CeCl₃•7H₂O under ethanol and 60 ℃ conditions as the GBB reaction optimal condition for our further study.

  To explore the scope of substrates in the CeCl₃•7H₂O-catalyzed GBB reaction substrates, we examined the generality of the reaction by using different aldehydes, aminoazines and isocyanides to achieve a wide range of imidazo-fused heterocycles and a series of novel compounds in satisfactory yields with short reaction time (Table 2). A variety of aldehydes were used, some with electron-with-drawing and eletron-donating groups being attached. It was found that electron-withdrawing groups like Cl and CN on the phenyl ring gave the products in good yields 93%~94% (Table 2, 4b~4c). At the same time, electron-donating groups like methoxyl on the phenyl ring afforded the unexpected yield in 93% (Table 2, 4d). When we further tried to replace the phenyl ring with the pyridyl ring on the aldehyde, yield of some products decreased slightly, and the reaction time need to be extended to 6 h (Table 2, 4m~4o). Further, scope of the substrates was extended to bicyclic aldehyde, which provided products in high yield 91% (Table 2, 4f). Different scaffolds of imidazo-fused heterocycles were successfully obtained by extension of various aminoa-zines. What's more, to extend scope of the reaction, t-butyl isocyanide, n-butyl isocynide and cyclohexylisocyanide were also used as synthetic substrates.

  Table 2.  Synthesis of imidazo-fused heterocycles via GBB reaction^a

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  Entry	Aminoazine 1	Aldehyde 2	R3	Compd.	Time/h	Yieldb/%
  1	R1＝5-Cl	R2＝Ph	t-Butyl	4a	1	97
  2	R1＝5-Cl	R2＝4-ClC6H4	t-Butyl	4b	1	93
  3	R1＝5-Cl	R2＝4-CNC6H4	t-Butyl	4c	1	94
  4	R1＝5-Cl	R2＝4-MeOC6H4	t-Butyl	4d	1	93
  5	R1＝5-Cl	R2＝4-Et2NC6H4	t-Butyl	4e	2.5	94
  6	R1＝5-Cl	R2＝4-C8H7O	t-Butyl	4f	3	91
  7	R1＝5-Cl	R2＝Ph	n-Butyl	4g	3	88
  8	R1＝5-Cl	R2＝4-ClC6H4	Cyclohexyl	4h	3	91
  9	2-NH2-pyrazine	R2＝Ph	Cyclohexyl	4i	3.5	93
  10	2-NH2-thiazole	R2＝Ph	t-Butyl	4j	3	84
  11	2-NH2-pyrazine	R2＝Ph	t-Butyl	4k	3	90
  12	2-NH2-pyrimidine	R2＝3, 5-Me2C6H3	t-Butyl	4l	3.5	85
  13	R1＝H	R2＝3-BrC5H3N	Cyclohexyl	4m	6	85
  14	3-NH2-1, 2, 4-triazole	R2＝3-BrC5H3N	t-Butyl	4n	6	87
  15	2-NH2-5-Cl-pyrazine	R2＝3-BrC5H3N	t-Butyl	4o	6	80
  a Reaction conditions: aldehyde (1.0 mmol), aminoazine (1.0 mmol), isocyanide (1.0 mmol), CeCl3•7H2O (10 mol %), ethanol, 60 ℃; bIsolated yield.

  Table 2.  Synthesis of imidazo-fused heterocycles via GBB reaction^a

  Due to obtain the best conditions of the CeCl₃•7H₂O-catalyzed GBB reaction, the catalytic activity of CeCl₃• 7H₂O for the synthesis of compounds 4n and 4o at a relatively low yield was compared with LaCl₃• 7H₂O in ethanol at 60 ℃. As shown in Table 3, CeCl₃• 7H₂O-catalyzed GBB product 4o resulting in 83% yield is substantially the same as CeCl₃•7H₂O in a 80% yield. However, LaCl₃• 7H₂O-catalyzed GBB product 4n resulting in 76% yield is lower than CeCl₃•7H₂O yield 87%. Hence, it is sure that CeCl₃•7H₂O as a very valuable and available catalyst is comparable to LaCl₃•7H₂O in GBB reaction.

  Table 3.  Comparison of efficiency of CeCl₃•7H₂O and LaCl₃• 7H₂O in the synthesis of products 4o and 4n

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  Entry	Compd.	Catalysta	Yieldb/%
  1	4o	CeCl3•7H2O	80
  2	4o	LaCl3•7H2O	83
  3	4n	CeCl3•7H2O	87
  4	4n	LaCl3•7H2O	76
  a10 mol%; bIsolated yield.

  Table 3.  Comparison of efficiency of CeCl₃•7H₂O and LaCl₃• 7H₂O in the synthesis of products 4o and 4n

  The structures of obtained GBB products 4a~4o were fully characterized by HRMS, ¹H NMR and ¹³C NMR spectra. The single crystal structures of the two GBB products 4m and 4o were also determined by X-ray diffraction analysis in order to confirm the products (Figure 2). Crystallographic data of 4m (CCDC 1498341) and 4o (CCDC 1498345) have been deposited at the Cambridge Crystallographic Database Centre.

  Figure 2.  Single crystal structure of products 4m and 4o

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  2   Conclusions

  In conclusion, we had successfully developed an efficient and simple protocol for the synthesis of imidazo-fused heterocycles via one-pot three component GBB reaction catalyzed by CeCl₃•7H₂O. The salient features of our protocol include less reaction time, high substrate adaptability, easy purification, fewer column chromatography, cheap and green catalyst and easy separation for catalyst. Hence, this method can be easily applied to synthesis of N-fused and S-fused heterocycles at industrial scale. In addition, a serious of new imidazo-fused heterocycles which can ultimately lead to diverse medicinally relevant compounds were synthesized. This green methodology might provide a better manners alternative to the existing literature reports.

  3   Experimental section

  3.1   Instruments and reagents

  All reagents and solvents were obtained from commercial suppliers and used as received without further purification. Melting points were determined using a WRS-1B digital melting point apparatus from Shanghai Measuring Instruments Equipment Co., Ltd. ¹H NMR and ¹³C NMR spectra were measured on a VARIAN Mercury 600 MHz spectrometer in deuterated solvents with TMS as an internal standard. ¹H NMR and ¹³C NMR spectra were obtained in CDCl₃ or DMSO-d₆ solutions as indicated. High-resolution mass spectra (HRMS) were recorded on Thermo Scientific LTQ Orbitrap Discovery. Thin-layer chromatography (TLC) was performed using silica gel GF254. All reactions progress was monitored by TLC and column chromatography was performed with silica gel (200~300 mesh).

  3.2   Experimental method

  A mixture of aldehyde (1.0 mmol), aminoazine (1.0 mmol), isocyanide (1.0 mmol) and 10 mol% CeCl₃•7H₂O in ethanol (2.0 mL) was stirred at 60 ℃ in an oil bath. After completion of the reaction as indicated by TLC, the resulting mixture was cooled to room temperature. Then ethanol was removed at reduced pressure and the residue was distributed in dichloromethane (20 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product which was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (V:V＝5:1) as eluent (4g~4o). In some cases, TLC showed that the product was nearly pure, so that the crude residue could be used directly purification by recrystallization with petroleum and slight ethyl acetate to obtain pure compounds (4a~4f).

  N-(tert-Butyl)-6-chloro-2-phenylimidazo[1, 2-a]pyri-din-3-amine (4a): White solid, yield 97%. m.p. 207~209 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.50 (s, 1H), 8.14 (d, J＝7.5 Hz, 2H), 7.51 (d, J＝9.4 Hz, 1H), 7.38 (t, J＝7.6 Hz, 2H), 7.27 (t, J＝7.3 Hz, 1H), 7.20 (dd, J＝9.4, 1.5 Hz, 1H), 4.67 (s, 1H), 0.98 (s, 9H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 139.9, 139.5, 135.4, 128.4, 128.1, 127.6, 125.1, 122.2, 118.9, 118.1, 56.4, 30.4. HRMS calcd for C₁₇H₁₉ClN₃ [M+H]⁺ 300.1262, found 300.1263.

  N-(tert-Butyl)-6-chloro-2-(4-chlorophenyl)imidazo[1, 2-a]pyridin-3-amine (4b): White solid, yield 93%. m.p. 196~198 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.55~8.52 (m, 1H), 8.22~8.20 (m, 1H), 8.20~8.19 (m, 1H), 7.56~7.51 (m, 1H), 7.49~7.44 (m, 2H), 7.24 (dd, J＝9.4, 2.1 Hz, 1H), 4.74 (s, 1H), 1.01 (s, 9H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 140.0, 138.2, 134.3, 132.2, 129.7, 128.4, 125.4, 122.3, 119.0, 118.1, 56.6, 30.4. HRMS calcd for C₁₇H₁₈Cl₂N₃ [M+H]⁺ 334.0872, found 334.0871.

  4-(3-(tert-Butylamino)-6-chloroimidazo[1, 2-a]pyridin-2-yl)benzonitrile (4c): Light yellow solid, yield 94%. m.p. 226~228 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.57 (d, J＝0.5 Hz, 1H), 8.40~8.37 (m, 1H), 7.89~7.84 (m, 1H), 7.57 (d, J＝9.4 Hz, 1H), 7.28 (d, J＝9.5 Hz, 1H), 4.85 (s, 1H), 1.02 (d, J＝1.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 140.6, 139.3, 138.5, 132.1, 128.4, 126.3, 124.83, 121.3, 120.5, 119.0, 118.0, 110.9, 56.8, 30.4. HRMS calcd for C₁₈H₁₈ClN₄ [M+H]⁺ 325.1215, found 325.1217.

  N-(tert-Butyl)-6-chloro-2-(4-methoxyphenyl)imida-zo[1, 2-a]pyridin-3-amine (4d): White solid, yield 93%. m.p. 175~177 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.50 (s, 1H), 8.11 (d, J＝9.6 Hz, 1H), 7.50 (dd, J＝9.4, 1.9 Hz, 1H), 7.21~7.17 (m, 1H), 6.97 (d, J＝9.7 Hz, 1H), 4.64 (d, J＝1.8 Hz, 1H), 3.79 (d, J＝1.4 Hz, 1H), 1.00 (d, J＝1.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 159.2, 140.7, 140.2, 129.3, 127.4, 125.1, 123.4, 121.3, 119.6, 117.5, 113.7, 56.4, 55.2, 30.3. HRMS calcd for C₁₈H₂₁ClN₃O [M+H]⁺ 330.1368, found 330.1371.

  N-(tert-Butyl)-6-chloro-2-(4-(diethylamino)phenyl)im-idazo[1, 2-a]pyridin-3-amine (4e): Yellow solid, yield 94%. m.p. 163~165 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.45~8.43 (m, 1H), 8.01~7.97 (m, 1H), 7.45 (dd, J＝9.4, 0.4 Hz, 1H), 7.15 (dd, J＝9.4, 2.1 Hz, 1H), 6.67 (d, J＝9.0 Hz, 1H), 4.54 (s, 1H), 3.36 (t, J＝7.0 Hz, 1H), 1.11 (t, J＝7.0 Hz, 2H), 1.03 (s, 5H); ¹³C NMR (150 MHz, CDCl₃) δ: 147.3, 141.3, 140.1, 124.6, 122.7, 121.6, 121.1, 119.2, 117.2, 111.5, 56.4, 44.3, 30.4, 12.6. HRMS calcd for C₂₁H₂₈ClN₄ [M+H]⁺ 371.1997, found 371.1997.

  N-(tert-Butyl)-6-chloro-2-(2, 3-dihydrobenzofuran-5-yl)-imidazo[1, 2-a]pyridin-3-amine (4f): Yellow solid, yield 91%. m.p. 185~187 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.48 (s, 1H), 8.03 (s, 1H), 7.93 (d, J＝8.1 Hz, 1H), 7.48 (d, J＝9.4 Hz, 1H), 7.19 (d, J＝9.3 Hz, 1H), 6.78 (d, J＝8.3 Hz, 1H), 4.61 (s, 1H), 4.56 (t, J＝8.6 Hz, 2H), 3.22 (t, J＝8.6 Hz, 2H), 1.01 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 159.8, 141.0, 140.1, 128.0, 127.2, 125.1, 124.9, 123.2, 121.2, 119.6, 117.4, 108.9, 71.4, 56.4, 30.4, 29.6. HRMS calcd for C₁₉H₂₁ClN₃O [M+H]⁺ 342.1368, found 342.1368.

  N-Butyl-6-chloro-2-phenylimidazo[1, 2-a]pyridin-3-ami-ne (4g): White solid, yield 88%. m.p. 128~130 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.08 (d, J＝1.8 Hz, 1H), 7.95 (d, J＝7.3 Hz, 2H), 7.51~7.44 (m, 3H), 7.34 (t, J＝7.4 Hz, 1H), 7.09 (dd, J＝9.4, 2.0 Hz, 1H), 3.14 (t, J＝6.3 Hz, 1H), 3.05 (dd, J＝13.8, 6.8 Hz, 2H), 1.63~1.57 (m, 2H), 1.47~1.40 (m, 2H), 0.94 (t, J＝7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 139.4, 136.3, 133.4, 128.7, 127.7, 126.9, 126.8, 125.5, 120.3, 117.6, 48.0, 32.8, 20.2, 13.9. HRMS calcd for C₁₇H₁₉ClN₃ [M+H]⁺ 300.1262, found 300.1262.

  6-Chloro-2-(4-chlorophenyl)-N-cyclohexylimidazo[1, 2-a]pyridin-3-amine (4h): White solid, yield 91%. m.p. 219~221 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.11 (d, J＝1.6 Hz, 1H), 7.98 (d, J＝8.5 Hz, 2H), 7.47 (d, J＝9.5 Hz, 1H), 7.42 (d, J＝8.5 Hz, 2H), 7.10 (dd, J＝9.4, 1.9 Hz, 1H), 3.04 (d, J＝4.5 Hz, 1H), 2.97~2.91 (m, 1H), 1.79 (d, J＝11.9 Hz, 2H), 1.74~1.67 (m, 2H), 1.28~1.13 (m, 5H); ¹³C NMR (150 MHz, CDCl₃) δ: 139.6, 136.5, 133.5, 132.1, 128.7, 128.2, 125.8, 125.3, 120.6, 120.4, 117.6, 56.8, 34.1, 25.6, 24.7. HRMS calcd for C₁₉H₂₀Cl₂N₃ [M+H]⁺ 360.1029, found 360.1032.

  N-Cyclohexyl-2-phenylimidazo[1, 2-a]pyrazin-3-amine (4i): White solid, yield 93%. m.p. 156~158 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.92 (d, J＝1.4 Hz, 1H), 8.36 (dd, J＝4.6, 1.4 Hz, 1H), 8.22 (dd, J＝8.3, 1.2 Hz, 2H), 7.85 (d, J＝4.6 Hz, 1H), 7.53~7.41 (m, 2H), 7.38~7.30 (m, 1H), 5.05 (d, J＝7.0 Hz, 1H), 2.90~2.83 (m, 1H), 1.71 (d, J＝11.9 Hz, 2H), 1.68~1.59 (m, 2H), 1.49 (s, 1H), 1.34~1.22 (m, 2H), 1.15~1.02 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 143.4, 138.9, 136.7, 133.6, 129.0, 128.7, 128.1, 127.3, 115.5, 56.9, 34.3, 25.6, 24.8. HRMS calcd for C₁₈H₂₁N₄ [M+H]⁺ 293.1761, found 293.1764.

  N-(tert-Butyl)-6-phenylimidazo[2, 1-b]thiazol-5-amine (4j): White solid, yield 84%. m.p. 150~152 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.09 (dd, J＝8.2, 1.0 Hz, 2H), 7.72 (d, J＝4.5 Hz, 1H), 7.34 (t, J＝7.7 Hz, 2H), 7.19 (t, J＝7.4 Hz, 1H), 7.16 (d, J＝4.5 Hz, 1H), 4.49 (s, 1H), 1.02 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 145.5, 140.1, 135.3, 128.2, 127.2, 126.7, 125.5, 117.8, 111.4, 55.8, 30.2. HRMS calcd for C₁₅H₁₈N₃S [M+H]⁺ 272.1216, found 272.1217.

  N-(tert-Butyl)-2-phenylimidazo[1, 2-a]pyrazin-3-amine (4k): Gray solid, yield 90%. m.p. 148~150 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 9.00 (s, 1H), 8.14 (dd, J＝4.6, 1.2 Hz, 1H), 7.93~7.89 (m, 2H), 7.86 (d, J＝4.6 Hz, 1H), 7.46 (t, J＝7.7 Hz, 2H), 7.37 (t, J＝7.4 Hz, 1H), 1.05 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 143.3, 142.2, 137.23, 134.2, 128.8, 128.4, 128.1, 125.0, 116.3, 56.9, 30.3. HRMS calcd for C₁₆H₁₉N₄ [M+H]⁺ 267.1604, found 267.1607.

  N-(tert-Butyl)-2-(3, 5-dimethylphenyl)imidazo[1, 2-a]pyr-imidin-3-amine (4l): Yellow solid, yield 85%. m.p. 189~191 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.79 (dd, J＝6.8, 2.0 Hz, 1H), 8.47~8.44 (m, 1H), 7.85 (s, 2H), 7.01 (dd, J＝6.8, 4.0 Hz, 1H), 6.94 (s, 1H), 4.69 (s, 1H), 2.33 (s, 6H), 1.01 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 149.2, 145.0, 141.1, 137.6, 134.2, 130.9, 129.5, 126.1, 121.8, 107.7, 56.6, 30.4, 21.4. HRMS calcd for C₁₈H₂₃N₄ [M+H]⁺ 295.1917, found 295.1918.

  2-(3-Bromopyridin-4-yl)-N-cyclohexylimidazo[1, 2-a]-pyridin-3-amine (4m): Light yellow solid, yield 85%. m.p. 123~125 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.84 (s, 1H), 8.60 (d, J＝4.9 Hz, 1H), 8.31 (dt, J＝7.0, 1.0 Hz, 1H), 7.65 (d, J＝4.7 Hz, 1H), 7.51 (dt, J＝9.1, 0.9 Hz, 1H), 7.22 (ddd, J＝9.0, 6.6, 1.2 Hz, 1H), 6.95 (td, J＝6.8, 1.1 Hz, 1H), 4.59 (d, J＝6.0 Hz, 1H), 2.70~2.63 (m, 1H), 1.63~1.56 (m, 2H), 1.53 (dd, J＝11.5, 4.2 Hz, 2H), 1.44~1.36 (m, 1H), 1.09~0.92 (m, 5H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 152.1, 148.1, 144.1, 142.0, 134.1, 126.9, 126.6, 124.5, 123.0, 120.5, 117.8, 112.0, 56.6, 33.8, 25.5, 24.5. HRMS calcd for C₁₈H₂₀BrN₄ [M+H]⁺ 371.0866, found 371.0871.

  6-(3-Bromopyridin-4-yl)-N-(tert-butyl)-1H-imidazo[2, 1-c] ^{[1, 2, 4]}triazol-5-amine) (4n): White solid, yield 87%. m.p. 197~200 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 11.99 (s, 1H), 8.88 (s, 1H), 8.64 (d, J＝4.9 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J＝4.9 Hz, 1H), 4.30 (s, 1H), 0.97 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 153.1, 152.8, 148.2, 139.3, 126.4, 123.0, 120.3, 56.0, 29.9. HRMS calcd for C₁₃H₁₆BrN₆ [M+H]⁺ 335.0614, found 335.0617.

  2-(3-Bromopyridin-4-yl)-N-(tert-butyl)-6-chloroimidazo-[1, 2-a]pyrazin-3-amine (4o): White solid, yield 80%. m.p. 193~195 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 8.95 (d, J＝1.3 Hz, 1H), 8.89 (s, 1H), 8.70 (d, J＝1.3 Hz, 1H), 8.64 (d, J＝4.9 Hz, 1H), 7.72~7.70 (m, 1H), 4.64 (s, 1H), 0.90 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ: 152.3, 148.4, 143.3, 142.5, 140.9, 136.6, 134.9, 127.2, 126.8, 120.9, 114.5, 56.8, 30.0. HRMS calcd for C₁₅H₁₆BrClN₅ [M+H]⁺ 380.0272, found 380. 0272.

  Supporting Information  ¹H NMR and ¹³C NMR spec-tra for all products associated with this article. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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• 

  Figure 1  Some examples of imidazo-fused drugs

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  Figure 2  Single crystal structure of products 4m and 4o

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  Table 1.  Optimization of GBB reaction conditions^a

  Entry	Solvent	CeCl3•7H2O/ mol%	T/℃	Time/min	Yieldb/%
  1	Ethanol	—c	r.t.	120	N.R.d
  2	Ethanol	5	r.t.	150	82
  3	Ethanol	5	35	100	86
  4	Ethanol	5	60	60	89
  5	Ethanol	10	r.t.	110	96
  6	Ethanol	10	60	60	97
  7	Methanol	10	60	90	65
  8	Trifluoroethanol	10	60	90	78
  9	H2O	10	60	160	74
  10	H2O	10	80	120	83
  11	—e	10	60	60	56
  12	Ethanol	10	70	60	96
  13	Ethanol	15	60	60	95
  14	DMSO	10	70	120	83
  15	Toluene	10	60	120	77
  16	Dichloromethane	10	35	120	81
  17	Acetonitrile	10	60	120	84
  a Reaction conditions: 5-chloropyridin-2-amine (1.0 mmol), benzaldehyde (1.0 mmol), t-butyl isocyanide (1.0 mmol); b Isolated yield; c No catalyst used; dN.R. means no reaction; eSolvent-free condition.

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  Table 2.  Synthesis of imidazo-fused heterocycles via GBB reaction^a

  Entry	Aminoazine 1	Aldehyde 2	R3	Compd.	Time/h	Yieldb/%
  1	R1＝5-Cl	R2＝Ph	t-Butyl	4a	1	97
  2	R1＝5-Cl	R2＝4-ClC6H4	t-Butyl	4b	1	93
  3	R1＝5-Cl	R2＝4-CNC6H4	t-Butyl	4c	1	94
  4	R1＝5-Cl	R2＝4-MeOC6H4	t-Butyl	4d	1	93
  5	R1＝5-Cl	R2＝4-Et2NC6H4	t-Butyl	4e	2.5	94
  6	R1＝5-Cl	R2＝4-C8H7O	t-Butyl	4f	3	91
  7	R1＝5-Cl	R2＝Ph	n-Butyl	4g	3	88
  8	R1＝5-Cl	R2＝4-ClC6H4	Cyclohexyl	4h	3	91
  9	2-NH2-pyrazine	R2＝Ph	Cyclohexyl	4i	3.5	93
  10	2-NH2-thiazole	R2＝Ph	t-Butyl	4j	3	84
  11	2-NH2-pyrazine	R2＝Ph	t-Butyl	4k	3	90
  12	2-NH2-pyrimidine	R2＝3, 5-Me2C6H3	t-Butyl	4l	3.5	85
  13	R1＝H	R2＝3-BrC5H3N	Cyclohexyl	4m	6	85
  14	3-NH2-1, 2, 4-triazole	R2＝3-BrC5H3N	t-Butyl	4n	6	87
  15	2-NH2-5-Cl-pyrazine	R2＝3-BrC5H3N	t-Butyl	4o	6	80
  a Reaction conditions: aldehyde (1.0 mmol), aminoazine (1.0 mmol), isocyanide (1.0 mmol), CeCl3•7H2O (10 mol %), ethanol, 60 ℃; bIsolated yield.

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  Table 3.  Comparison of efficiency of CeCl₃•7H₂O and LaCl₃• 7H₂O in the synthesis of products 4o and 4n

  Entry	Compd.	Catalysta	Yieldb/%
  1	4o	CeCl3•7H2O	80
  2	4o	LaCl3•7H2O	83
  3	4n	CeCl3•7H2O	87
  4	4n	LaCl3•7H2O	76
  a10 mol%; bIsolated yield.

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•