Synthesis of Aminofuran-Linked Benzimidazoles and Cyanopyrrole

Research Article pubs.acs.org/acscombsci

Synthesis of Aminofuran-Linked Benzimidazoles and CyanopyrroleFused Benzimidazoles by Condition-Based Skeletal Divergence Wei-Shun Hsu,§ Min-Huan Tsai,§ Indrajeet J. Barve,§ Gorakh S. Yellol,§ and Chung-Ming Sun*,§,† §

Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao-Tung University, Hsinchu 300-10, Taiwan Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan first Road, Kaohsiung 807-08, Taiwan

†

S Supporting Information *

ABSTRACT: A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles, while the same reaction afforded 3-cyano-benzopyrrolo-imidazoles under microwave irradiation. Two nonequivalent nucleophilic centers on benzimidazole moiety were manipulated elegantly by different reaction conditions to achieve the skeletal diversity.

KEYWORDS: 2-aminofuranyl-benzimidazole, 3-cyano-benzopyrrolo-imidazole, divergent synthesis, nonequivalent nucleophilicity, skeletal diversity

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INTRODUCTION A direct interaction of small molecules with proteins is a powerful tool to study complex biological systems. Efficient synthesis of structurally diverse small molecules provides a validated source of chemical probes for biomedical research.1 Consequently, diversification of the skeletal architecture of such compound libraries is particularly desirable to address biologically relevant chemical space to enable the discovery of new therapeutic agents with higher potency and selectivity.2,3 To generate a greater degree of structural diversity in the compound libraries, various synthetic strategies, like varying building blocks, functional groups, stereochemistry and scaffolds, were incorporated into the diversity-oriented synthesis. In particular, the condition-based skeletal divergence represents a powerful strategy to generate diverse compounds from the same starting materials by altering the reaction conditions such as temperature, pressure, solvent, catalyst and other factors.4,5 In addition to these parameters, conditionbased divergent synthesis under microwave irradiation, ultrasonication and in the presence of ionic liquids have provided additional opportunities to tune the selectivity.6 A challenging task in this context is the condensation of two simple subunits which leads to different products due to the presence of least nonequivalent reaction centers. Conceptually, a set of inputs A and B may produce distinct scaffolds C, D, and E, respectively via different mechanistic pathways under the different reaction conditions X, Y and Z (Figure 1). © 2017 American Chemical Society

Figure 1. Concept of condition-based skeletal divergence in DOS.

In our previous studies, we found that the 2-alkyl benzimidazole or equivalent skeletons in general can generate several different products due to the presence of nonequivalent nucleophilic centers and the regioselectivity can be tuned by activation of different nucleophilic centers under different reaction conditions (Scheme 1). In connection with our studies on the synthesis of biologically interesting heterocyclic systems,7 herein we demonstrated the condition-based skeletal divergent synthesis of Received: March 27, 2017 Revised: April 23, 2017 Published: April 26, 2017 492

DOI: 10.1021/acscombsci.7b00052 ACS Comb. Sci. 2017, 19, 492−499

Research Article

ACS Combinatorial Science

Consequently, as a representative example one of the products was further analyzed by X-ray crystallography and it revealed the structure of obtained product was 10{9,1} rather than the expected alkylated product 9{9,1}. The ORTEP diagram of 10{9,1} is depicted in Figure 2.9 The furan moiety is linked to benzimidazole scaffold at 3-position with amino functionality at 2-position. Excellent regioselectivity was observed during this condensation under the conventional heating condition, and no traces of other products were detected in the crude product. These combined studies clearly indicated the intramolecular cascade cyclization between the keto and the cyano groups of regioselective alkylated product 9{9,1} to afford the 2-aminofuranyl benzimidazole 10{9,1}. We next turned our attention to improving the yield of the unexpected product 10{9,1}. Accordingly, the condensation was carried out in 10 equiv of K2CO3 to obtain 10{9,1} in 61% yield (Table 1, entry 4). Similarly, when the same reaction was done in 1.2 equiv of 8{1} and 10 equiv of K2CO3, the yield was 72% (Table 1, entry 5). Next, the screening of solvents such as xylene, ethylene dichloride (EDC) afforded 10{9,1} in 5% and 0%, respectively (Table 1, entries 6 and 7). The increase in equivalents of 8{1} lowered the yield of 10{9,1} (Table 1, entry 8). The use of other bases such as triethylamine afforded 10{9,1} in 42% yield, whereas t-BuOK or DMAP did not afford any cyclized product 10{9,1} (Table 1, entries 9−11). After successful achievement of the regioselective condensation of 7{9} with 8{1} by selective activation of the nonequivalent reaction centers under the conventional heating condition, the same reaction was performed under microwave irradiation to further improve the reaction efficiency. Hence, initially the same reaction that was performed in toluene under microwave irradiation failed to deliver any desired product 10{9,1} (Table 1, entries 12, 13). However, when the reaction was carried out in EDC under microwave irradiation, a new spot having different Rf value as compared to 10{9,1} was observed (Table 1, entry 14). The newly formed spot was isolated in inferior yield and subjected to characterization. Spectroscopic analysis of this microwave product did not match the structure of either the alkylated product 9{9,1} or the cyclized product 10{9,1}. Consequently, as a representative example one of the obtained products was further analyzed by X-ray crystallography. To our surprise, it revealed the formation of benzimidazole fused pyrrole 12{9,5}. The ORTEP diagram in Figure 3 9 demonstrated the benzimidazole fused pyrrole structure which can be formed by intramolecular cyclization of N-alkylated product 11{9,5}.

Scheme 1. Nonequivalent Nucleophilic Centers in 2-Alkyl Benzimidazole Moiety

2-aminofuranyl-benzimidazole and 3-cyano-benzopyrroloimidazole through condensation of cyanomethylbenzimidazole with α-bromoketones under conventional heating and microwave irradiation, respectively.

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RESULTS AND DISCUSSION For the current study, the key precursor, N-alkylated 2-(cyanometyl)-benzimidazoles 7 was prepared by a literature method (Scheme 2).8 In a model reaction, methyl 2-(cyanomethyl)-1-pentyl1H-benzo[d]imidazole-5-carboxylate 7{9} was treated with 4-chloro-2′-bromo acetophenone 8{1} using K2CO3 in toluene in a sealed tube at 110 °C for 24 h. Disappointingly, only unconsumed starting materials 7{9} and 8{1} were recovered (Table 1, entry 1). Moreover, when the same reaction was carried out at 180 °C for 4 h, no coupling product was observed (Table 1, entry 2). When the reaction was performed in 5 equiv of K2CO3 at 180 °C for 8 h, a new spot was observed (Table 1, entry 3). The newly formed product was isolated (55%) and subjected to spectroscopic analysis. Spectroscopic analysis of the obtained product did not match the structure of the expected alkylated product 9{9,1}. The corresponding peaks of the methylene protons adjacent to carbonyl group were not observed in the proton NMR spectrum, while an unexpected singlet at ∼6.83 ppm and a broad singlet peak for −NH2 protons at ∼6.45 ppm was clearly present in the proton NMR spectrum. In addition, the carbon NMR spectrum also showed an extra peak in the aromatic region. Scheme 2. Synthesis of Cyanomethyl Benzimidazoles 7

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Table 1. Optimization of the Condensation of 7{9} and 8{1} under Conventional Heating and Microwave Irradiationa

entry

8{1} (equiv)

base (equiv)

solvent

temp (°C)

T (h)

1 2 3 4 5 6 7 8 9 10 11 12b 13b 14b

2 2 2 2 1.2 1.2 1.2 5 1.2 1.2 1.2 2 5 2

K2CO3 (5) K2CO3 (2) K2CO3 (5) K2CO3 (10) K2CO3 (10) K2CO3 (10) K2CO3 (10) K2CO3 (10) Et3N (10) t-BuOK (10) DMAP (10) K2CO3 (10) K2CO3 (5) K2CO3 (2)

toluene toluene toluene toluene toluene xylene EDC toluene toluene toluene toluene toluene toluene EDC

110 180 180 180 180 180 180 180 180 180 180 150 150 120

24 4 8 8 8 8 8 8 8 8 8 60 15 15

10{9,1} yield (%)c NR NR 55 61 72 5 NR 10 42 NR NR NR NR 10d

a

Reaction conditions: 7{9} (1 equiv), 8{1} (equiv), K2CO3 (equiv), sealed tube. bReactions were performed under MW condition (reaction time in min). cIsolated product after column chromatography. dIsolated product was 12{9,1}. NR: No reaction.

Figure 2. ORTEP diagram of compound 10{9,1}. Figure 3. ORTEP diagram of compound 12{9,5}.

This interesting discovery motivated us to optimize the reaction conditions for 12{9,1} and the results are summarized in Table 2. A slight increase in the yield (15%) was observed when the transformation was carried out at 150 °C (Table 2, entry 2). When the amount of K2CO3 was increased (5 equiv), the desired product 12{9,1} was obtained in inferior yield (Table 2, entry 3). The decrease in the amount of K2CO3 (0.5 equiv) afforded 12{9,1} in slightly better yield (Table 2,

entry 4). The desired product 12{9,1} was obtained in good yield when the reaction was carried out with 5 equiv of 8{1} and 0.5 equiv of K2CO3 (Table 2, entry 5). A change in the solvent to CH3CN did not give any product (Table 2, entry 6). The screening of other bases such as triethylamine, t-BuOK, DMAP and piperidine resulted in 12{9,1} in low to moderate yield (Table 2, entries 7−10). We next examined the substrate 494


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ACS Combinatorial Science Table 2. Optimization of the Condensation Reaction of 7{9} and 8{1} under Microwave Irradiationa

entry

8{1} (equiv)

base (equiv)

solvent

12{9,1} yield (%)c

1 2 3 4 5 6 7 8 9 10

2 2 2 2 5 5 5 5 5 5

K2CO3 (2) K2CO3 (2) K2CO3 (5) K2CO3 (0.5) K2CO3 (0.5) K2CO3 (0.5) Et3N (0.5) t-BuOK (0.5) DMAP (0.5) piperidine (0.5)

EDC EDC EDC EDC EDC toluene EDC EDC EDC EDC

10b 15 5 23 75 NR 39 62 40 65

Reaction conditions: 7{9} (1 equiv), 8{1} (equiv), K2CO3, MW (150 W, 150 °C), 15 min. bReaction was performed under MW (150 W, 120 °C). Isolated product after column chromatography. NR: No reaction.

a c

pyrrole ring by the expulsion of a water molecule from M3 furnished pyrrolo-benzimidazole product 12.

scope of this unprecedented condition-based skeletal divergence approach for the synthesis of 2-aminofuranyl benzimidazoles 10 and 3-cyano benzopyrrolo benzimidazoles 12 (Tables 3 and 4). Accordingly, cyanomethyl benzimidazole derivatives 7{1−9} were treated with various α-bromoketones 8{1−5} under the optimized conditions of thermal heating as well as microwave irradiation. Moderate to good yields were obtained with a variety of substitutions. To investigate a plausible reaction pathway, attempts were made to isolate C- and N-alkylated intermediates 9{10,1} and 11{10,1}. Subsequently, all the attempts made to arrest alkylation reaction of 7{10} with 8{1} under microwave irradiation ended up with the cyclized product 12{10,1}, which indicated the fast conversion of intermediate 11{10,1} to product 12{10,1}. However, alkylation reaction of 7{10} with 8{1} under conventional heating condition was successfully arrested after 4 h and the intermediate 9{10,1} was isolated from the reaction mixture. The obtained reaction intermediate 9{10,1} was unambiguously studied by X-ray crystallographic study (Figure 4). The efforts of trapping of the reaction intermediate clearly revealed that the intramolecular cyclization under conventional thermal condition proceeded through C-alkylated intermediate 9{10,1}, whereas the intramolecular cyclization under microwave irradiation progressed through N-alkylated intermediate 11{10,1}. On the basis of our intermediate isolation study and the obtained results, the plausible steps involved in the intramolecular ring closure of intermediate 9 and 11 to product 10 and 12 respectively are shown in Scheme 4. The cyclization of intermediate T2 through an attack of the oxygen atom of the enol on the nearby cyano group afforded T3. Subsequent aromatization to the furan ring by proton exchange yielded product 10. However, under microwave irradiation, benzimidazole nitrogen’s lone pair driven cyclization yielded M2. The proton shift and consequent aromatization to

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CONCLUSION In conclusion, condition-based scaffold divergence in the condensation reaction of cyanomethyl benzimidazole with α-bromoketone under classical heating and microwave irradiation conditions is reported. Under conventional thermal conditions, cyanomethyl benzimidazole was regioselectively C-alkylated which on subsequent intramolecular cyclization furnished 2-aminofuranyl-benzimidazoles. However, under microwave irradiation conditions, 3-cyano-pyrrolo-benzimidazoles were obtained through regioselective N-alkylation of 2-cyanomethyl benzimidazole. This method demonstrated that the competitive reaction pathways or nonequivalent nucleophilicity could be utilized to achieve skeletal diversity in the condition-based diversity-oriented synthesis.

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EXPERIMENTAL PROCEDURES General Methods. 1H (300 MHz) and 13C NMR (75 MHz) spectra were recorded on Bruker DX-300 spectrometer. Chemical shifts are reported in parts per million (ppm) on the δ scale from an internal standard (TMS). Analytical thin-layer chromatography (TLC) was performed using 0.25 mm silica gel-coated Kiselgel 60 F254 plates. Flash chromatography was performed using the indicated solvent and silica gel 60 (Merck, 230−400 mesh). High-resolution mass spectra (HRMS) were recorded in ESI mode using TOF mass spectrometer. IR spectra were obtained using FT-IR spectrometer. Microwave irradiation experiments were performed in a CEM Discover single-mode microwave reactor equipped with an IR temperature sensor using standard 10 mL CEM process vial sealed with Teflon cap. All materials were purchased from commercial sources and used without further purification. 495


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ACS Combinatorial Science Table 3. Substrate Scope for the Synthesis of 2-Aminofuranyl-Benzimidazoles 10 under Thermal Conditiona

a

Reaction conditions: 7 (1 equiv), 8 (1.2 equiv), K2CO3 (10 equiv), toluene (8 mL), sealed tube, 180 °C, 8 h.

Representative Procedure for the Synthesis of Methyl 2-(2-Amino-5-(4-chlorophenyl)furan-3-yl)-1-pentyl-1Hbenzo[d]imidazole-5-carboxylate 10{9,1}. To a solution of

methyl 2-(cyanomethyl)-1-isopentyl-1H-benzo[d]imidazole-5carboxylate 7{9} (0.1 g, 0.3506 mmol) in toluene (5 mL) were added 2-bromo-1-(4-chlorophenyl)ethanone 8{1} (0.097 g, 496


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Table 4. Substrate scope for the synthesis of 3-cyano-benzopyrrolo-benzimidazoles 12 under microwave irradiationa

a

Reaction conditions: 7 (1 equiv), 8 (5 equiv), K2CO3 (0.5 equiv), EDC (4 mL), MW (150 W, 150 °C), 15 min.

Scheme 3. Isolation of the C- and N-Alkylated Intermediates 9{10,1} and 11{10,1}

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(300 MHz, CDCl3) δ 8.33 (d, J = 1.4 Hz, 1H), 7.93 (dd, J = 8.4, 1.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.33−7.24 (m, 3H), 6.79 (s, 1H), 6.57−6.40 (brs, 2H), 4.25 (t, J = 7.5 Hz, 2H), 3.95 (s, 3H), 1.89 (quin, J = 7.1 Hz, 2H), 1.47−1.36 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 160.2, 151.1, 143.5, 142.7, 138.9, 132.2, 129.3, 129.1, 124.3, 123.9, 123.5, 120.3, 108.6, 103.6, 88.7, 52.4, 44.8, 30.1, 29.5, 22.8, 14.4; IR (cm−1, neat) 3410, 3350, 2954, 2929, 1712, 1618; HRMS m/z calculated for C24H24ClN3O3, 437.1506; found, 437.1515. Representative Procedure for the Synthesis of Methyl 2-(tert-Butyl)-3-cyano-4-pentyl-4H-benzo[d]pyrrolo[1,2a]imidazole-7-carboxylate (12{9,5}). A mixture of methyl 2-(cyanomethyl)-1-isopentyl-1H-benzo[d]imidazole-5-carboxylate 7{9} (0.1 g, 0.3506 mmol), 2-bromo-1-(4-chlorophenyl)ethanone 8{1} (0.406 g, 1.753 mmol), and potassium carbonate (0.024 g, 0.1753 mmol) in 1,2-dichloroethane (5 mL) was irradiated in the microwave cavity (150 W, 150 °C) for 15 min. After completion of the reaction, as indicated by TLC, the solvent was removed under reduced pressure. The crude reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over magnesium sulfate and concentrated under reduced vacuum. The crude product was purified by column chromatography (eluent: 30% ethyl acetate in hexanes) to furnish methyl 2-(tert-butyl)-3-cyano-4-pentyl-4H-benzo[d]pyrrolo[1,2-a]imidazole-7-carboxylate 12{9,5} in 75% yields (0.963 g). This procedure was applied for the synthesis of rest of the all compound 12. Methyl 2-tert-Butyl-3-cyano-4-pentyl-4H-pyrrolo[1,2-a]benzimidazole-7-carboxylate (12{9,5}): Off-white solid; yield

0.420 mmol) and potassium carbonate (0.484 g, 3.506 mmol) at room temperature. The resulting reaction mixture was heated in sealed tube (180 °C) for 8 h. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The crude reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (eluent: 15% ethyl acetate in hexanes) to afford the corresponding methyl 2-(2-amino-5-(4-chlorophenyl)furan-3-yl)-1-pentyl-1H-benzo[d]imidazole-5-carboxylate 10{9,1}. This procedure was applied for the synthesis of rest of the all derivatives 10. Methyl 2-[2-Amino-5-(4-chlorophenyl)furan-3-yl]-1-pentyl-1H-benzimidazole-5-carboxylate (10{9,1}): Pale yellow solid; yield 109 mg, 72%; mp 161−163 °C; 1H NMR

Figure 4. ORTEP diagram of intermediate 9{10,1}.

Scheme 4. Plausible Mechanism for the Formation of Compound 10 and 12

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ACS Combinatorial Science 963 mg, 75%; mp 142−144 °C; 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.27 (m, 1H), 6.83 (s, 1H), 4.30 (t, J = 7.2 Hz, 2H), 3.97 (s, 3H), 1.98−1.94 (m, 2H), 1.47 (s, 9H), 1.44−1.37 (m, 4H), 0.92 (t, J = 6.6 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 167.1, 144.7, 142.2, 139.5, 126.1, 125.8, 122.7, 118.3, 112.5, 108.8, 100.9, 63.5, 52.7, 44.8, 32.8, 30.7, 29.4, 29.3, 22.8, 14.3; IR (cm−1, neat) 2958, 2929, 2866, 2200, 1718, 1589; HRMS m/z calculated for C22H27N3O2, 365.2103; found, 365.2108.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscombsci.7b00052. Characterization and full spectroscopic data (1H, 13C NMR, HRMS, and FT-IR) of compounds 10 and 12 (PDF) X-ray crystallographic data of compound 10{9,1} (CIF) X-ray crystallographic data of compound 12{9,5} (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chung-Ming Sun: 0000-0002-1804-1578 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Ministry of Science and Technology (MOST) of Taiwan for financial assistance and the authorities of the National Chiao Tung University for providing the laboratory facilities.

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REFERENCES

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Synthesis of Aminofuran-Linked Benzimidazoles and Cyanopyrrole

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