Copper- and Palladium-Catalyzed Cross-Coupling Reactions for the

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Copper and Palladium Catalyzed Cross-Coupling Reactions for the Synthesis of N-Fused Benzo[4,5]imidazo[2,1-b]thiazole Derivatives via Substituted trans-1,2-Diiodoalkenes, 1H-Benzo[d]imidazole-2-thiols and Halobenzenes Guodong Shen, Bingchuan Yang, Xianqiang Huang, Yaxin Hou, Huan Gao, Jichun Cui, Chuansheng Cui, and Tongxin Zhang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00162 • Publication Date (Web): 16 Mar 2017 Downloaded from http://pubs.acs.org on March 16, 2017

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The Journal of Organic Chemistry

Copper and Palladium Catalyzed Cross-Coupling Reactions for the Synthesis of N-Fused Benzo[4,5]imidazo[2,1-b]thiazole Derivatives via Substituted trans1,2-Diiodoalkenes, 1H-Benzo[d]imidazole-2-thiols and Halobenzenes Guodong Shen,* Bingchuan Yang, Xianqiang Huang, Yaxin Hou, Huan Gao, Jichun Cui, Chuansheng Cui and Tongxin Zhang* School of Chemistry and Chemical Engineering, School of Pharmacy, Liaocheng University, Liaocheng 252000, Shandong, PR China Tel & Fax: (+)86-635-8239680; e-mail: [email protected], [email protected].

TOC Graphic S

I H

1

R

N R2

SH

I a

CuI 1,10-phenanthroline

N

K2CO3, DMF 100 oC, N2

N H

R

b

N

Pd(OAc)2/PPh3

R1

R3

S

X Cs2CO3, p-xylene 135 oC, N2 R

N

R1

3

2

R1=Ar, Bn, n-Bu, Cyclopropyl R2=H, CH3, Cl, F . R3=H, CH3, Cl X=Br, I

H

N

c

f

27 examples up to 82% yields

R2

d 18 examples up to 96% yields

Abstract Two transition metal (Cu and Pd) catalyzed C-S, C-N and C-C bonds cross-coupling reactions for the preparation of N-fused benzo[4,5]imidazo[2,1-b]thiazole derivatives were developed. A variety of 3-substituted and 2,3-disubstituted benzo[4,5]imidazo[2,1-b]thiazoles were efficiently and conveniently synthesized from the coupling reaction via trans-1,2-diiodoalkenes, 1Hbenzo[d]imidazole-2-thiols and halobenzenes in moderate to excellent yields.

Introduction Imidazol[2,1-b]-thiazole derivatives are important class of molecules for their biological and pharmaceutical activities, such as calcium channel antagonistic activity,1 antifungal properties,2 anti-inflammatory properties,3 antitumor agent,4 antidiabetic agent,5 antitubercular agent,6 anticardiovascular agent7 and so on.8 Although imidazol[2,1-b]-thiazole derivatives play important roles in medicinal chemistry, efficient synthetic routes are rare. The classical method for these Nfused heterocycles involves the reaction of 2-mercaptobenzoimidazole with α-bromoacetophenones9 and the photochemical recombination of 1-(2-benzothiazolyl)-benzotriazole.10 However, these methods have some shortcomings and limitations, such as requiring strong acid and special starting materials, tedious procedures, and suffering from the low efficiency and narrow scopes. Transition metal-catalyzed cross-coupling reactions are of paramount importance in organic synthesis.11 In the past decades, copper and palladium catalyzed C-X (X=C, N, O, S, etc.) bond formation reactions have drawn considerable attention for their convenience and efficiency.12 These reactions have been successfully applied in the preparation of pharmaceuticals,

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agrochemicals and advanced materials on both laboratory and industrialscales. In 2010, Chen et al. reported a copper-catalyzed method for the synthesis of imidazol[2,1-b]-thiazole derivatives through regioselective 1,2-aminothiolation of 1,1-dibromoalkenes.13 In 2011, Wu et al. reported another copper-catalyzed reaction of 2-iodoaniline and 2-iodobenzothiazole to give benzimidazo[2,1-b]benzothiazole derivatives.14 In 2012, Li et al. found a novel method for the preparation of N-fused heterocycles via a Csp-S coupling reaction and a sequence of 5-endo-dig cyclization.15 Lately, Abele et al. reported the synthesis of certain fused imidazo[2,1b]benzothiazoles from o-dihaloarenes and 2-mercaptoimidazoles using phase-transfer catalytic system.16 Recently, Lv et al. synthesized a variety of benzo[d]benzo[4,5]imidazo[2,1-b]thiazoles by the copper-catalyzed domino coupling of o-dihaloarenes with 2-mercaptobenzimidazoles.17 In continuation of our ongoing efforts to assemble heterocycles,18 we report two efficient copper and palladium-catalyzed cross-coupling reactions for the synthesis of benzo[4,5]imidazo[2,1b]thiazole derivatives via substituted trans-1,2-diiodoalkenes, 1H-benzo[d]imidazole-2-thiols and halobenzenes. Our designed and proposed approach was summarized in Figure 1. Figure 1. Designed synthesis of benzo[4,5]imidazo[2,1-b]thiazole derivatives.

Results and Discussion Initially, (E)-(1,2-diiodovinyl)benzene 1a and 1H-benzo[d]imidazole-2-thiol 1b were selected as the model substrates to identify and optimize the reaction parameters including transition metal catalysts, reaction temperature, base and solvent. When the reaction was carried out with CuI (0.075 mmol)/N, N-dimethylglycine (0.15 mmol), (E)-(1,2-diiodovinyl)benzene 1a (0.5 mmol), 1H-benzo[d]imidazole-2-thiol 1b (0.5 mmol) and K2CO3 (1.0 mmol) in DMF (2.0 mL) under N2 atmosphere for 24 h, the desired product 3-phenylbenzo[4,5]imidazo[2,1-b]thiazole 1c could be isolated in 28% yield (Table 1, entry 1). N, N’-Dimethylethane-1,2-diamine (DMEDA) or 1,10-phenanthroline (1,10-Phen) was tested as the ligand under the reaction condition, and 1,10-phenanthroline provided better yield (Table 1, entries 2-3). The reaction was investigated in other solvents (toluene, MeCN, dioxane and DMSO) and DMF was found to be the best choice (Table 1, entries 3-7). During the study of bases, Cs2CO3 also showed good efficiency (Table 1, entries 8-9). The solvents such as toluene, MeCN, dioxane and DMSO were also investigated in the presence of Cs2CO3, but the product yields were not good (Table 1, entries 10-13). From the experiment we can see K2CO3 showed the best efficiency. However, the reaction at lower (90oC) or higher (110 oC) temperatures evidently decreased the reaction yields (Table 1, entries 14-15). Other copper salts such as CuCl and CuBr were also investigated and CuI provided the best yield (Table 1, entries 16-17). Without the ligand or the base, the product was obtained in low yield (Table 1, entries 18-19). From the above experiments we can conclude that the entry 3 shows the best reaction conditions.


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Table 1. Optimization of the reaction conditions.a

Entry

Catalyst

Solvent

T (oC)

Base

Yield (%)b

CuI/N,NDMF K2CO3 100 28 dimethylglycine 2 CuI/DMEDA DMF K2CO3 100 41 100 81 3 CuI/1,10-Phen DMF K2CO3 4 CuI/1,10-Phen toluene K2CO3 100 20 5 CuI/1,10-Phen MeCN K2CO3 100 45 6 CuI/1,10-Phen dioxane K2CO3 100 36 7 CuI/1,10-Phen DMSO K2CO3 100 44 8 CuI/1,10-Phen DMF Cs2CO3 100 80 9 CuI/1,10-Phen DMF KOAc 100 61 31 10 CuI/1,10-Phen toluene Cs2CO3 100 11 CuI/1,10-Phen MeCN Cs2CO3 100 40 12 CuI/1,10-Phen dioxane Cs2CO3 100 64 13 CuI/1,10-Phen DMSO Cs2CO3 100 15 14 CuI/1,10-Phen DMF K2CO3 90 65 110 70 15 CuI/1,10-Phen DMF K2CO3 16 CuBr/1,10-Phen DMF K2CO3 100 73 17 CuCl/1,10-Phen DMF K2CO3 100 62 100 22 18 CuI DMF K2CO3 19 CuI/1,10-Phen DMF / 100 18 a Reaction conditions: copper salt (0.075 mmol), ligand (0.15 mmol), (E)-(1,2-diiodovinyl)benzene 1a (0.5 mmol), 1H-benzo[d]imidazole-2-thiol 1b (0.5 mmol) and base (1.0 mmol) in solvent (2.0 mL) under N2 atmosphere for 24 h. bIsolated yield after flash chromatography based on 1a. 1

Table 2 Scope of the copper catalyzed cross-coupling reaction for the synthesis of 3substituted benzo[4,5]imidazo[2,1-b]thiazoles.a

Entry 1 2 3

4

a

b 1a 2a 3a

4a

Yield (%)b

c

82 1b

1c 80

1b 2c

78

1b 3c

80

1b 4c



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

5

5a

6

6a

7 7a 8 8a 9

9a

10

10a

11

83

1b 5c

79

1b 6c

73

1b 7c

71

1b 8c

72

1b 9c

78

1b 10c

79

1b 11a

12

11c

14

13a

12c 13c 83(1:1.2)c

1a 14c+15c

75(1:1) c

1a 3b

16

66

1b

2b 15

73

1b 12a

13

4a

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16c+17c 83(1:1.2)c

2b 18c+19c

17

4a

73(1:1.2)c

3b 20c+21c

18

6a

75(1:1.2)

2b 22c+23c

19

6a

70(1:1.2)

3b 24c+25c


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20

76

4a 4b

21

26c

71 27c a Reaction conditions: CuI (0.075 mmol), 1,10-Phen (0.15 mmol), trans-1,2-diiodoalkenes a (0.5 mmol), 1Hbenzo[d]imidazole-2-thiols b (0.5 mmol) and K2CO3 (1.0 mmol) in DMF (2.0 mL) under N2 atmosphere for 24 h. bIsolated yields after flash chromatography based on a. cA mixture of two isomers was obtained (the isomeric ratio was approximately determined by 1H NMR). 6a

4b

With the optimized reaction conditions in hand, the scope of substrates was further investigated (Table 2). From the experimental results we could conclude that the reaction yields were influenced by electronic effects. The substrates of trans-1,2-diiodoalkenes a with electrondonating groups (CH3, n-Bu and t-Bu) and electron-withdrawing groups (F, Cl and Br) generated the desired products in moderate to good yields (Table 2, entries 2-9). The yields of substrates a bearing electron-donating groups were better than substrates a bearing electron-withdrawing groups. When (E)-1,2-diiodohex-1-ene 10a, (E)-(2,3-diiodoallyl)benzene 11a and (E)-(1,2diiodovinyl)cyclopropane 12a were used, the desired products were got in moderate yields (Table 2, entries 10-12). (E)-3-(1,2-Diiodovinyl)pyridine 13a could react with 1b and generate the product 13c in 66% yield (Table 2, entry 13). The reactions of 1a with substituted 1Hbenzo[d]imidazole-2-thiols b were also investigated (Table 2, entries 14-21). The yields were also much lower when 1H-benzo[d]imidazole-2-thiols b bearing electron-withdrawing groups (Table 2, entries 14-16). When mono-substituted1H-benzo[d]imidazole-2-thiols b were used to proceed the reaction, the mixtures of two isomers were obtained, the isomeric ratio were approximately determined by 1H NMR (Table 2, entries 14-15, 17-20). 5, 6-Difluoro-1Hbenzo[d]imidazole-2-thiol 4b reacted with a and gave the corresponding products in moderate yields (Table 2, entries 20-21). Table 3. Optimization of the reaction conditions.a

Entry

Catalyst

Solvent

Base

1 2 3 4 5 6 7 8 9 10 11 12

Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 Pd(OAc)2/PPh3 PdCl2/PPh3 Pd(dppf)Cl2/PPh3 Pd(OAc)2 Pd(OAc)2/PPh3

DMA DMA DMF DMSO dioxane p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 /


T (oC) 145 150 145 145 145 145 135 130 135 135 135 135

Yield (%)b 45 46 51 21 35 96 96 90 31 13 47 15


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a

Reaction conditions: Pd salt (0.015 mmol), ligand (0.03 mmol), 3-phenylbenzo[4,5]imidazo[2,1-b]thiazole 1c (0.3 mmol), iodobenzene 1f (0.40 mmol) and base (0.6 mmol) in solvent (1.5 mL) under N2 atmosphere for 24 h. bIsolated yield after flash chromatography based on 1c.

With the 3-substituted benzo[4,5]imidazo[2,1-b]thiazoles c in hand, we tried to synthesize a new series of 2,3-disubstituted benzo[4,5]imidazo[2,1-b]thiazolesderivatives d by the palladiumcatalyzed cross-coupling reactions of c with halobenzenes f. Firstly, 3phenylbenzo[4,5]imidazo[2,1-b]thiazole 1c and iodobenzene 1f were selected as the model substrates to identify and optimize the reaction parameters. When the reaction was carried out with Pd(OAc)2 (0.015 mmol)/PPh3 (0.03 mmol), benzo[4,5]imidazo[2,1-b]thiazoles c (0.3 mmol), iodobenzene 1f (0.40 mmol) and Cs2CO3 (0.6 mmol) in DMA (1.5 mL) at 145 oC under N2 atmosphere for 24 h, the desired product 2,3-diphenylbenzo[4,5]imidazo[2,1-b]thiazole 1d could be isolated in 45% yield (Table 3, entry 1). The structure of 1d was unambiguously elucidated by X-ray crystallography (Figure 2). Raising the reaction temperature (150 oC) did not improve the yield of 1d (Table 3, entry 2). To our delight, when the reaction was investigated in other solvents (DMF, DMSO, dioxane and p-xylene), p-xylene was found to be the best choice and 1d was obtained in 96% yield (Table 3, entries 3-6). The screened reaction temperature (135 oC) provided the best yield (Table 3, entries 7-8). Other Pd source such as PdCl2 and Pd(dppf)Cl2 were also investigated and Pd(OAc)2 was the best choice (Table 3, entries 9-10). Without the ligand or the base, the reaction yields decreased obviously (Table 3, entries 11-12). From the above experiments we can conclude that the entry 7 shows the best reaction conditions. Figure 2. X-ray crystallographic structure of 1d.

Then the scope of substrates was also investigated. The substrates of 3-substituted benzo[4,5]imidazo[2,1-b]thiazoles c could react well with halobenzenes f, and generated the corresponding products d in moderate to excellent yields (Table 4, 1d-16d). When the group R1 were aliphatic substituted or aromatic substituted groups, the yields were got in good to excellent (Table 4, 1d-7d). The reaction yields were mainly influenced by the electronic effect of group R2. The 3-substituted benzo[4,5]imidazo[2,1-b]thiazoles c bearing electron-donating R2 groups generated better yields than electron-withdrawing R2 groups (Table 4, 8d-10d, 15-16d). The substituted halobenzenes f were also tested and the products were got in excellent yield (Table 4, 11d-14d). A mixture of two isomers 20c and 21c was reacted with 1f to give a mixture of 15d and 16d, and the isomeric ratio was approximately determined by 1H NMR (Table 4, 15d and 16d). When bromobenzene was used, the reactions could also proceed successfully (Table 4, 1d2d). Through the methods (Condition A and Condition B) of Pd-catalyzed cross-coupling reaction, two synthetic routes for 18d from 9c were developed (Figure 3).


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Table 4. Scope of the palladium catalyzed cross-coupling reaction for the synthesis of 2,3disubstituted benzo[4,5]imidazo[2,1-b]thiazoles.a,b

1d,96%(69%)c

2d,90%(65%)c

3d, 95%

4d, 90%

5d, 93%

6d, 85%

7d, 80%

8d, 78%

9d, 79%

10d, 75%

11d, 90%

12d, 91%

13d, 90% 14d, 92% 15d+16d, 94% (1:1.2)d Reaction conditions: Pd(OAc)2 (0.015 mmol), PPh3 (0.03 mmol), 3-substituted benzo[4,5]imidazo[2,1b]thiazoles c (0.3 mmol), halobenzenes f (0.4 mmol) and Cs2CO3 (0.6 mmol) in p-xylene (1.5 mL) at 135 oC under N2 atmosphere for 24 h. bIsolated yield after flash chromatography based on c. cBromobenzene was used. d A mixture of 15d and 16d was obtained (the isomeric ratio was approximately determined by 1H NMR). a

Figure 3. Two synthetic routes for the same benzo[4,5]imidazo[2,1-b]thiazole 18d.

Condition A: Pd(OAc)2/PPh3, Cs2CO3, p-xylene, N2, 24h, 135 oC; Condition B: Pd(PPh3)4, 2M Na2CO3, toluene, EtOH, N2, 24h, 100 oC.

Figure 4. Proposed mechanisms of the Cu and Pd catalyzed cross-coupling reactions.



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On the basis of the above results and previous work, two possible reaction mechanisms for the Cu and Pd catalyzed cross-coupling reactions were proposed in Figure 4. Firstly the intermediate g was generated in the presence of CuI and base. Because of the steric hindrance of a, the intermediate g could reacted with a to generate h via the selective oxidative addition reaction. Then an reductive elimination reaction proceeded and h converted to intermediate e. Finally intermediate e would proceed the same procedure of oxidative addition and reductive elimination reaction to get the product c (Figure 4, eq 1). For the Pd catalyzed coupling reaction, halobenzene f could convert to ArPdIIX in the presence of Pd(OAc)2 and PPh3, then ArPdIIX could react with c to generate the intermediate i via the oxidative addition reaction, and reductive elimination reaction would happen, leading to the product d (Figure 4, eq 2). In summary, we have developed two Cu and Pd catalyzed C-S, C-N and C-C bonds crosscoupling reactions for the preparation of benzo[4,5]imidazo[2,1-b]thiazole derivatives. The reactions exhibit some functional group tolerance and allow for the preparation of a number of 3substituted and 2,3-disubstituted benzo[4,5]imidazo[2,1-b]thiazoles in moderate to excellent yields. The importance of the imidazol[2,1-b]-thiazole derivatives would render this protocol attractive for both synthetic and medicinal chemistry.

Experimental Section General. All reagents and solvents were pure analytical grade materials purchased from commercial sources and were used without further purification, if not stated otherwise. All melting points are uncorrected. All starting substrates were prepared according to the known literatures. The NMR spectra were recorded in CDCl3 on a 400 MHz instrument with TMS as internal standard. High-resolution mass spectra (HRMS) were obtained with a Q-TOF Premier (ESI). TLC was carried out with 0.2 mm thick silica gel plates (GF254). Visualization was accomplished by UV light. Column chromatography was hand packed with silica gel (200-300 mesh). All reactions were carried out in an over-dried Schlenk tube equipped with a magnetic stir bar. General procedure for the synthesis of 3-substituted benzo[4,5]imidazo[2,1-b]thiazoles 1c-27c. An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, CuI (0.075 mmol), 1,10-Phen (0.15 mmol), trans-1,2-diiodoalkenes a (0.5 mmol), 1Hbenzo[d]imidazole-2-thiols b (0.5 mmol) and K2CO3 (1.0 mmol). The tube was placed under vacuum for twenty minutes and backfilled with N2, then DMF (2.0 mL) was added via syringe. The reaction mixture was stirred at 100 oC for 24 h. The reaction was monitored by TLC. When 1H-benzo[d]imidazole-2-thiols b consumed completely, the reaction was stopped and cooled to room temperature, EtOAc (40 mL) was added and the mixture was washed with brine (20 mL × 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by


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column chromatography on silica gel using petrol/EtOAc (3:1, v:v) as eluent to give c. General procedure for the synthesis of 2,3-disubstituted benzo[4,5]imidazo[2,1b]thiazoles 1d-16d. An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, Pd(OAc)2 (0.015 mmol), PPh3 (0.03 mmol), 3-phenylbenzo[4,5]imidazo[2,1b]thiazoles c (0.3 mmol), iodobenzenes f (0.40 mmol) and Cs2CO3 (0.6 mmol). The tube was placed under vacuum for twenty minutes and backfilled with N2, then p-xylene (2.0 mL) was added via syringe. The reaction mixture was stirred at 135 oC for 24 h. The reaction was monitored by TLC. When 3-phenylbenzo[4,5]imidazo[2,1-b]thiazoles c consumed completely, the reaction was stopped and cooled to room temperature, then the resulting suspension was filtered through a pad of filter paper with 20 mL of ethyl acetate for 3 times. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography on silica gel using petrol/EtOAc (4:1, v:v) as eluent to give d. Typical procedure for the application of the Suzuki-coupling reaction. An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, Pd(PPh3)4, (0.015 mmol), 3-(2-bromophenyl)benzo[4,5]imidazo[2,1-b]thiazole 9c (0.3 mmol), ptolylboronic acid (0.36 mmol). The tube was placed under vacuum for twenty minutes and backfilled with N2, then 2M Na2CO3 (0.3 mL, 0.6 mmol), toluene (0.5 mL), EtOH (0.5 mL) were added via syringe. The reaction mixture was stirred at 100 oC for 24 h. The reaction was monitored by TLC. When 3-(2-bromophenyl)benzo[4,5]imidazo[2,1-b]thiazole 9c (0.3 mmol) consumed completely, the reaction was stopped and cooled to room temperature, then the resulting suspension was filtered through a pad of filter paper with 20 mL of ethyl acetate, then the aqueous layer was removed by a separatory funnel. The organic phase was dried over Na2SO4 and concentrated, the residue was purified by column chromatography on silica gel using petrol/EtOAc (4:1, v:v) as eluent to give 17d. 3-Phenylbenzo[4,5]imidazo[2,1-b]thiazole19(1c). Yellow solid (61.5 mg, 82% yield), mp: 138139 °C (Lit. mp: 138-140 °C). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.67-7.64 (m, 2H), 7.58-7.57 (m, 3H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.60 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.3, 148.8, 134.4, 130.2, 130.2, 129.5, 129.1, 129.0, 123.5, 120.6, 119.3, 111.8, 107.3. 3-(o-Tolyl)benzo[4,5]imidazo[2,1-b]thiazole (2c). Yellow solid (63.4 mg, 80% yield), mp: 104-108 oC. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H),7.45-7.35 (m, 3H), 7.29 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.70 (dd, J1 = 0.8 Hz, J2 = 8.4 Hz, 1H), 6.58 (d, J = 0.8 Hz, 1H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 156.7, 148.6, 138.4, 133.0, 130.8, 130.7, 130.6, 130.1, 129.0, 126.5, 123.4, 120.8, 119.1, 110.7, 107.1, 19.7. HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0770. 3-(m-Tolyl)benzo[4,5]imidazo[2,1-b]thiazole (3c). Yellow solid (61.8 mg, 78% yield), mp: 164-168 oC. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 1H), 7.46-7.38 (m, 4H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.57 (s, 1H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.4, 148.8, 139.0, 134.5, 131.0, 130.2, 129.6, 129.4, 128.9, 126.0, 123.4, 120.5, 119.3, 111.9, 107.0, 21.6. HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0777. 3-(p-Tolyl)benzo[4,5]imidazo[2,1-b]thiazole19 (4c). Yellow solid (63.4 mg, 80% yield), mp: 118-120 oC (Lit. mp: 118-121 °C). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.38-7.30 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.56 (s,



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1H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.4, 148.7, 140.5, 134.5, 130.2, 129.8, 128.9, 126.6, 123.5, 120.5, 119.3, 111.9, 106.9, 21.6. 3-(4-Butylphenyl)benzo[4,5]imidazo[2,1-b]thiazole (5c). Yellow liquid (76.2 mg, 83% yield), mp: 61-63 oC. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.53 (s, 1H), 1.74-1.66 (m, 2H), 1.46-1.41 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.3, 148.8, 145.4, 134.5, 130.2, 129.0, 128.8, 126.7, 123.4, 120.4, 119.2, 111.9, 106.7, 35.7, 33.5, 22.5, 14.1. HRMS (ESI): m/z calcd for C19H19N2S [M+H]+: 307.1269; found: 307.1280. 3-(4-(tert-Butyl)phenyl)benzo[4,5]imidazo[2,1-b]thiazole (6c). Yellow solid (72.5 mg, 79% yield), mp: 116-117 oC. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.4 Hz, 1H), 7.58 (m, 4H), 7.34-7.26 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H), 6.55 (s, 1H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 157.4, 153.6, 148.8, 134.5, 130.2, 128.6, 126.5, 126.0, 123.4, 120.5, 119.2, 112.0, 106.9, 35.1, 31.4. HRMS (ESI): m/z calcd for C19H19N2S [M+H]+: 307.1269; found: 307.1268. 3-(4-Fluorophenyl)benzo[4,5]imidazo[2,1-b]thiazole (7c). Yellow solid (58.7 mg, 73% yield); mp: 174-177 oC. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.67-7.63 (m, 2H), 7.36-7.26 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.61 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 163.83 (d, J = 249 Hz), 157.3, 148.9, 133.2, 131.0 (d, J = 8.3 Hz), 130.2, 125.6 (d, J = 3.6 Hz), 123.5, 120.6, 119.5, 116.3 (d, J = 21.9 Hz), 111.5, 107.5. 3-(4-Chlorophenyl)benzo[4,5]imidazo[2,1-b]thiazole19 (8c). Yellow solid (60.5 mg, 71% yield), mp: 200-202 oC (Lit. mp: 199-201 °C). 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.4 Hz, 1H), 7.63-7.56 (m, 4H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 6.65 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.2, 148.7, 136.5, 133.2, 132.8, 130.2, 129.5, 127.9, 123.7, 120.8, 119.5, 111.6, 108.0. HRMS (ESI): m/z calcd for C15H10ClN2S [M+H]+: 285.0253; found: 285.0256. 3-(2-Bromophenyl)benzo[4,5]imidazo[2,1-b]thiazole (9c). Yellow solid (70.8 mg, 72% yield), mp: 164-167 oC. 1H NMR (400 MHz, CDCl3): δ 7.82-7.77 (m, 2H), 7.56-7.46 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 156.4, 148.5, 133.5, 132.5, 132.1, 132.0, 130.8, 130.1, 128.0, 124.7, 123.5, 120.8, 119.2, 111.0, 108.9. HRMS (ESI): m/z calcd for C15H10BrN2S [M+H]+: 328.9748; found: 328.9757. 3-Butylbenzo[4,5]imidazo[2,1-b]thiazole19 (10c). Yellow solid (53.8 mg, 78% yield), mp: 8586 oC (Lit. mp: 85-87 °C). 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.26 (s, 1H), 2.97 (t, J = 7.6 Hz, 2H), 1.81-1.74 (m, 2H), 1.54-1.46 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.5, 148.6, 134.6, 130.1, 123.2, 120.7, 119.2, 110.9, 103.8, 28.9, 28.1, 22.3, 13.8. 3-Benzylbenzo[4,5]imidazo[2,1-b]thiazole20 (11c). Brown solid (62.6 mg, 79% yield), mp: 8083 oC (Lit. mp: 82-83 °C). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.40-7.29 (m, 6H), 7.16 (t, J = 8.0 Hz, 1H), 6.16 (s, 1H), 4.40 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 157.5, 148.5, 135.0, 133.3, 130.2, 129.2, 128.9, 127.7, 123.4, 120.9, 119.3, 111.1, 106.7, 34.8. HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0798.


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3-Cyclopropylbenzo[4,5]imidazo[2,1-b]thiazole (12c). Yellow solid (46.9 mg, 73% yield), mp: 101-103 oC. 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 6.31 (d, J = 1.6 Hz, 1H), 2.23-2.18 (m, 1H), 1.19-1.15 (m, 2H), 0.92-0.88 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 157.1, 148.6, 136.0, 130.4, 123.5, 120.8, 119.2, 111.5, 104.8, 8.9, 6.3. HRMS (ESI): m/z calcd for C12H11N2S [M+H]+: 215.0643; found: 215.0640. 3-(Pyridin-3-yl)benzo[4,5]imidazo[2,1-b]thiazole (13c). Yellow solid (49.7 mg, 66% yield), mp: 132-134 oC. 1H NMR (400 MHz, CDCl3): δ 8.93 (d, J = 1.2 Hz, 1H), 8.82 (dd, J1 = 1.2 Hz, J2 = 5.6 Hz, 1H), 8.00 (td, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.52 (dd, J1 = 4.8 Hz, J2 = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.70 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 156.3, 148.3, 133.4, 132.3, 132.0, 130.6, 129.9, 127.9, 124.6, 123.4, 120.8, 119.0, 110.9, 108.8. 6-Methyl-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (14c) and 7-methyl-3phenylbenzo[4,5]imidazo[2,1-b]thiazole (15c). Yellow solid (65.7 mg, 83% yield, ratio = 1:1.2). 1 H NMR (400 MHz, CDCl3): δ 7.67-7.63 (m, 5H), 7.57-7.55 (m, 7H), 7.14 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.54 (s, 2H), 2.47 (s, 3H), 2.35 (s, 3H). HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0796. 6-Chloro-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (16c) and 7-chloro-3phenylbenzo[4,5]imidazo[2,1-b]thiazole (17c). Yellow solid (63.9 mg, 75% yield, ratio = 1:1.2). 1 H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.64-7.57 (m, 10H), 7.29 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 6.623 (s, 1H), 6.618 (s, 1H). HRMS (ESI): m/z calcd for C15H10ClN2S [M+H]+: 285.0253; found: 285.0251. 6-Methyl-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (18c) and 7-methyl-3-(ptolyl)benzo[4,5]imidazo [2,1-b]thiazole (19c). Yellow solid (69.2 mg, 83% yield, ratio = 1:1.2). 1 H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.4 Hz, 1H), 7.56-7.51 (m, 5H), 7.38-7.35 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.503 (s, 1H), 6.497 (s, 1H), 2.50 (s, 3H), 2.49 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H). HRMS (ESI): m/z calcd for C17H15N2S [M+H]+: 279.0956; found: 279.0955. 3-(4-Chlorophenyl)-6-methylbenzo[4,5]imidazo[2,1-b]thiazole (20c) and 3-(4-chlorophenyl)7-methylbenzo[4,5]imidazo[2,1-b]thiazole (21c). Yellow solid (65.3 mg, 73% yield, ratio = 1:1.2). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz, 1H), 7.62-7.54 (m, 9H), 7.16 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 2.48 (s, 3H), 2.39 (s, 3H). HRMS (ESI): m/z calcd for C16H12ClN2S [M+H]+: 299.0410; found: 299.0411. 6-Chloro-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (22c). Yellow solid (30.5 mg, 34.1% yield), mp: 175-176 oC. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.30-7.24 (m, 2H), 6.57 (s, 1H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 158.1, 147.4, 140.8, 134.3, 123.0, 129.9, 128.8, 128.7, 126.1, 124.1, 120.0, 112.0, 107.4, 21.7. HRMS (ESI): m/z calcd for C16H12ClN2S [M+H]+: 299.0410; found: 299.0405.



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7-Chloro-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (23c). Yellow solid (36.6 mg, 40.9 % yield), mp: 178-179 oC. 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H) , 6.58 (s, 1H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.3, 149.8, 140.7, 134.4, 130.09, 129.9, 129.1, 128.8, 126.2, 120.9, 119.0, 112.5, 107.4, 21.7. HRMS (ESI): m/z calcd for C16H12ClN2S [M+H]+: 299.0410; found: 299.0409. 6-Chloro-3-(4-chlorophenyl)benzo[4,5]imidazo[2,1-b]thiazole (24c). Yellow solid (30.2 mg, 31.8% yield), mp: 219-221 oC. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.8 Hz, 1H), 7.59 (m, 4H), 7.32 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 6.67 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 158.2, 148.9, 136.8, 133.2, 130.2, 129.7, 129.6, 128.5, 127.5, 121.3, 119.1, 112.3, 108.7. HRMS (ESI): m/z calcd for C15H9Cl2N2S [M+H]+: 318.9863; found: 318.9862. 7-Chloro-3-(4-chlorophenyl)benzo[4,5]imidazo[2,1-b]thiazole (25c). Yellow solid (36.4 mg, 38.2 %yield), mp: 240-244 oC. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.58 (m, 4H), 7.12 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.8, 146.7, 136.9, 133.1, 130.1, 129.8, 129.7, 127.3, 126.7, 124.6, 120.0, 111.8, 108.9. HRMS (ESI): m/z calcd for C15H9Cl2N2S [M+H]+: 318.9863; found: 318.9866. 6, 7-Difluoro-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (26c). Yellow solid (68.4 mg, 76% yield), mp: 202-206 oC. 1H NMR (400 MHz, CDCl3): δ 7.54-7.48 (m, 3H), 7.38 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 8.4 Hz, 1H), 6.58 (s, 1H), 2.49 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 158.3, 148.3 (q, J1 = 14.9 Hz, J2 = 241.5 Hz), 146.0 (q, J1 = 15.4 Hz, J2 = 240.2 Hz), 144.2 (d, J = 10.4 Hz), 140.9, 134.0, 130.0, 128.7, 125.9, 125.1 (d, J = 10.8 Hz), 107.3, 106.5 (d, J = 19.8 Hz), 100.2 (d, J = 24.0 Hz), 21.6. HRMS (ESI): m/z calcd for C16H11F2N2S [M+H]+: 301.0611; found: 301.0615. 3-(4-Chlorophenyl)-6,7-difluorobenzo[4,5]imidazo[2,1-b]thiazole (27c). Yellow solid (68.2 mg, 71% yield), mp: 168-172 oC. 1H NMR (400 MHz, CDCl3): δ 7.59-7.52 (m, 5H), 7.01 (t, J = 8.4 Hz, 1H), 6.65 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 158.2, 148.4 (q, J1 = 14.7 Hz, J2 = 242.6 Hz), 146.1 (q, J1 = 15.3 Hz, J2 = 241.0 Hz), 144.4, 136.9, 132.7, 130.1, 129.8, 128.2 (d, J = 129.7 Hz), 127.3, 108.5, 106.7 (d, J = 20.0 Hz), 100.0 (d, J = 24.0 Hz). HRMS (ESI): m/z calcd for C15H8ClF2N2S [M+H]+: 321.0065; found: 321.007. 2,3-Diphenylbenzo[4,5]imidazo[2,1-b]thiazole (1d). White solid (93.9 mg, 96% yield), mp: 196-197 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.60-7.55 (m, 5H), 7.317.27 (m, 6H), 6.99 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 154.7, 148.1, 131.4, 130.6, 130.4, 130.3, 129.5, 129.1, 128.8, 128.7, 128.4, 128.3, 123.7, 123.4, 120.6, 119.1, 111.5. HRMS (ESI): m/z calcd for C21H15N2S [M+H]+: 327.0956; found: 327.0960. 2-Phenyl-3-(o-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (2d). Yellow solid (91.8 mg, 90% yield), mp: 144-148 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.45-7.36 (m, 3H), 7.30-7.26 (m, 6H), 6.96 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.5, 148.0, 138.8, 131.7, 131.1, 130.8, 130.3, 129.0, 128.9, 128.5, 128.3, 127.8, 127.6, 127.1, 123.7, 123.5, 121.0, 119.1, 110.8, 19.6. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1117.


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3-(4-Butylphenyl)-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (3d). Yellow solid (108.9 mg, 95% yield), mp: 108-112 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),7.30-7.24 (m, 6H), 6.99 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 2.75 (t, J = 8.0 Hz, 2H), 1.75-1.68 (m, 2H), 1.48-1.39 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 154.8, 148.1, 145.4, 131.7, 130.5, 130.4, 129.5, 128.8, 128.70, 128.65, 128.2, 126.3, 123.4, 123.4, 120.6, 119.1, 111.6, 35.7, 33.4, 22.5, 14.1. HRMS (ESI): m/z calcd for C25H23N2S [M+H]+: 383.1582; found: 383.1588. 3-(4-Chlorophenyl)-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (4d). Yellow solid (97.2 mg, 90% yield), mp: 329-333 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.32-7.23 (m, 6H), 7.02 (t, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 154.9, 148.2, 136.5, 132.0, 131.1, 130.3, 129.9, 129.0, 128.9, 128.6, 127.6, 127.1, 124.4, 123.6, 120.8, 119.3, 111.3. HRMS (ESI): m/z calcd for C21H14ClN2S [M+H]+: 361.0566; found: 361.0566. 3-(2-Bromophenyl)-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (5d). White solid (112.7 mg, 93% yield), mp: 180-182 oC. 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.52-7.44 (m, 3H), 7.32-7.26 (m, 6H), 7.00 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 154.3, 147.9, 133.6, 133.0, 132.2, 131.2, 130.9, 130.1, 129.0, 128.6, 128.5, 128.3, 126.8, 125.8, 125.2, 123.5, 121.0, 119.2, 110.8. HRMS (ESI): m/z calcd for C21H14BrN2S [M+H]+: 405.0061; found: 405.0066. 3-Butyl-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (6d). White solid (78.0 mg, 85% yield), mp: 116-120 °C. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49-7.36 (m, 6H), 7.27 (t, J = 7.6 Hz, 1H), 3.08 (t, J = 8.0 Hz, 2H), 1.88-1.80 (m, 2H), 1.52-1.43 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 155.7, 148.1, 131.8, 130.1, 130.0, 129.6, 129.1, 128.8, 123.4, 121.7, 121.0, 119.3, 111.0, 30.6, 26.1, 22.5, 13.8. HRMS (ESI): m/z calcd for C19H19N2S [M+H]+: 307.1269; found: 307.1266. 3-Cyclopropyl-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (7d). White solid (69.6 mg, 80% yield), mp: 124-126 °C. 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.59-7.57 (m, 2H), 7.50-7.42 (m, 4H), 7.35 (t, J = 8.0 Hz, 1H), 2.31-2.26 (m, 1H), 1.231.18 (m, 2H), 0.64-0.59 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 153.6, 148.3, 130.9, 129.8, 129.5, 129.1, 128.9, 128.4, 124.6, 122.0, 118.0, 112.6, 110.1, 9.5, 7.6. HRMS (ESI): m/z calcd for C18H15N2S [M+H]+: 291.0956; found: 291.0952. 6-Chloro-3-(4-chlorophenyl)-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (8d). Yellow solid (92.2 mg, 78% yield), mp: 188-191 °C. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.31-7.21 (m, 6H), 6.83 (d, J = 2.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 155.4, 146.7, 136.8, 131.9, 130.9, 130.4, 130.07, 129.1, 129.0, 128.9, 127.0, 126.9, 126.4, 125.2, 124.2, 120.1, 111.5. HRMS (ESI): m/z calcd for C21H13Cl2N2S [M+H]+: 395.0176; found: 395.0169. 7-Chloro-3-(4-chlorophenyl)-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (9d). Yellow solid (93.4 mg, 79% yield), mp: 209-213°C. 1H NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.30-7.23 (m, 5H), 6.98 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 155.9, 148.9, 136.7, 131.9, 130.8, 130.1, 123.0,



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129.2, 129.1, 128.9, 128.8, 127.2, 126.9, 125.1, 121.1, 119.0, 111.9. HRMS (ESI): m/z calcd for C21H13Cl2N2S [M+H]+: 395.0176; found: 395.0175. 6,7-Difluoro-2-phenyl-3-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (10d). Yellow solid (84.6 mg, 75% yield), mp: 194-195 °C. 1H NMR (400 MHz, CDCl3): δ 7.52 (t, J = 8.4 Hz, 1H), 7.407.26 (m, 9H), 6.60 (t, J = 8.4 Hz, 1H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.8, 149.5 (d, J = 15.0 Hz), 147.2 (q, J1 = 15.0 Hz, J2 = 22.6 Hz ), 144.9 (d, J = 15.2 Hz), 143.6, 140.9, 131.3, 130.5, 130.3, 128.9, 128.8, 128.6, 128.1, 125.4, 124.2, 106.4 (d, J = 20.1 Hz), 99.9 (d, J = 24.0 Hz), 21.8. HRMS (ESI): m/z calcd for C22H15F2N2S [M+H]+: 377.0924; found: 377.0930. 3-Phenyl-2-(o-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (11d). White solid (91.8 mg, 90% yield), mp: 150-155 °C. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 1H), 7.47-7.40 (m, 5H), 7.35-7.31 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.18-7.15 (m, 2H), 7.03 (d, J = 7.6 Hz, 2H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.8, 148.0, 138.3, 132.2, 130.5, 130.3, 130.00, 129.97, 129.85, 129.8, 129.5, 128.9, 128.7, 126.0, 123.4, 122.9, 120.5, 119.2, 111.8, 20.3. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1118. 3-Phenyl-2-(m-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (12d). White solid (92.8 mg, 91% yield), mp:165-167 oC. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.60-7.55 (m, 5H), 7.31-7.26 (m, 2H), 7.14-6.96 (m, 4H), 6.76 (d, J = 8.0 Hz, 1H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.9, 148.0, 138.6, 131.4, 130.7, 130.4, 130.3, 129.5, 129.5, 129.5, 129.3, 129.2, 128.7, 125.9, 124.1, 123.5, 120.7, 119.2, 111.5, 21.5. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1119. 3-Phenyl-2-(p-tolyl)benzo[4,5]imidazo[2,1-b]thiazole (13d). White solid (91.8 mg, 90% yield), mp: 211-212°C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.59-7.55 (m, 4H), 7.32-7.26 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.99 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 147.4, 138.6, 130.7, 130.7, 130.3, 129.6, 129.6, 129.5, 129.2, 128.7, 128.0, 124.4, 123.6, 120.8, 119.0, 111.6, 21.4. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1114. 2-(4-Chlorophenyl)-3-phenylbenzo[4,5]imidazo[2,1-b]thiazole (14d). Yellow solid (99.4 mg, 92% yield), mp: 198-202 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 1H), 7.63-7.51 (m, 5H), 7.30-7.15 (m, 5H), 6.98 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 154.5, 148.1, 134.3, 130.6, 130.5, 130.5, 130.3, 130.0, 129.9, 129.6, 129.1, 128.8, 123.5, 122.4, 120.7, 119.2, 111.5. HRMS (ESI): m/z calcd for C21H14ClN2S [M+H]+: 361.0566; found: 361.0558. 3-(4-Chlorophenyl)-6-methyl-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (15d) and 3-(4chlorophenyl)-7-methyl-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (16d). Yellow solid (105.5 mg, 94% yield, ratio = 1:1.2). 1H NMR (400 MHz, CDCl3): δ 7.70-7.65 (m, 3H), 7.56-7.46 (m, 9H), 7.28-7.23 (m, 8H),7.12 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 2.45 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 154.1, 148.4, 146.2, 136.37, 136.35, 133.4, 132.2, 132.11, 132.05, 132.0, 132.0, 131.2, 130.6, 130.3, 129.8, 129.7, 128.93, 128.88, 128.8, 128.6, 128.52, 128.50, 128.2, 127.6, 127.0, 125.0, 124.1, 124.0, 122.1, 119.1, 118.8, 111.3, 110.8, 21.9, 21.8. HRMS (ESI): m/z calcd for C22H16ClN2S [M+H]+: 375.0723; found: 375.0720.


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3-(4'-Methyl-[1,1'-biphenyl]-2-yl)benzo[4,5]imidazo[2,1-b]thiazole (17d). Yellow solid (72.4 mg, 71% yield), mp: 75-76 °C. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.066.99 (m, 3H), 6.94-6.89 (m, 3H), 6.37 (s, 1H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 156.6, 148.1, 143.0, 137.4, 136.6, 132.8, 131.1, 130.9, 130.8, 129.8, 129.1, 128.6, 127.60, 127.57, 123.5, 120.6, 118.9, 111.3, 108.3, 21.2. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1109. 3-(4'-Methyl-[1,1'-biphenyl]-2-yl)-2-phenylbenzo[4,5]imidazo[2,1-b]thiazole (18d). Compound 18d was prepared in a similar manner as described for compound 17d. Yellow solid, mp: 78-80 °C. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 1H), 7.68-7.65 (m, 2H), 7.597.51 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.22-7.16 (m, 3H), 7.03-7.00 (m, 3H), 6.82-6.76 (m, 3H), 6.71 (d, J = 8.0 Hz, 2H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 147.9, 143.7, 137.1, 136.6, 131.7 131.5, 131.1, 130.9, 130.2, 128.84, 128.79, 128.6, 128.1, 128.02, 127.96, 127.7, 127.5, 124.2, 123.4, 120.7, 119.0, 111.3, 21.1. HRMS (ESI): m/z calcd for C28H21N2S [M+H]+: 417.1425; found: 417.1428.

Acknowledgements This work was financially supported by the National Natural Science Foundation of China (No. 21402079 and 20401094)

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. 1H NMR and 13C NMR spectra of all products. X-ray Crystallographic Structure of 1d.

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