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. Author manuscript; available in PMC: 2012 Dec 28.
Published in final edited form as: Tetrahedron Lett. 2011 Dec 28;52(52):7030–7033. doi: 10.1016/j.tetlet.2011.10.064

Parallel Solid-Phase Synthesis of disubstituted 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones

Sureshbabu Dadiboyena 1, Adel Nefzi 1,2,*
PMCID: PMC3244722  NIHMSID: NIHMS332087  PMID: 22199408

Abstract

A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimidazole provided following Fmoc elimination free amine. Treatment of the free amine with 1,1′-carbonyldiimidazole or 1,1′-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoin or thiohydantoins were isolated in good yields.

Keywords: Solid phase synthesis, Benzimidazole, Amino acid, Hydantoin, Thiohydantoin, Heterocycles, Intramolecular cyclization

Solid phase organic synthesis (SPOS) is a powerful technique for the rapid synthesis of small molecules endowed with potential bioactive properties.1–4 A recurring feature of this approach is the synthesis of substituted heterocycles of structural diversity which aroused greater attention and have proven to be broadly and economically useful as therapeutic agents.4,5 Benzimidazoles are an important class of heterocycles displaying a wide variety of biological properties,6–10 they represent a key structural motif in angiotensin-II-antagonists, anticoagulants, and gastric proton-pump inhibitors.8–16 We previously reported the application of resin-bound amino-benzimidazoles as a template for the synthesis of a variety of heterocyclic compounds such as tetracyclic benzimidazoles,13 triazino-benzimidazoles,14 and branched thiohydantoin benzimidazoline-thiones.16 In continuation of our efforts directed toward the synthesis of combinatorial libraries of heterocyclic compounds utilizing amino acids and benzimidazole scaffolds,11–16 we describe herein a multistep approach for the parallel solid-phase synthesis of compounds containing amino-benzimidazole tethered to pharmacologically known hydantoin or thiohydantoin.

Hydantoins represent ubiquitous structural core sporadically found in a number of natural products 1–6,17,18 and bioactive heterocycles such as phenytoin 7 and mephenytoin 8.19–21 The high incidence of this pharmacophore in several drugs and drug-like candidates has resulted in the development of a plethora of methods to construct this valuable fragment.18,22–30 In addition to hydantoins, thiohydantoins constitute analogous structural frameworks of synthetic and biomedical importance.17,18,31–35 Due to aforementioned applications, the synthesis of hydantoins and thiohydantoins units has received greater attention and few reports representing pharmaceutical and medicinal applications of hydantoins and thiohydantoins (Fig. 1).

Figure 1.

Figure 1

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Natural and pharmaceutically occurring hydantoins and some reported bioactive properties of hydantoin/thiohydantoin structural motifs

We envisioned the preparation of hydantoins and thiohydantoin nuclei from the amino acid coupled benzimidazole precursor 11 following intramolecular cyclization. Aminobenzimidazoles 9 required for the synthesis are conveniently accessed in several steps from the corresponding resin bound 4-fluoro-3-nitrobenzoic acid.11–16 The retrosynthetic rationale for the synthesis of aminobenzimidazole tethered hydantoins and thiohydantioins is illustrated in scheme 1.

Scheme 1.

Scheme 1

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Retrosynthetic illustration of synthetic work to construct hydantoins and thiohydantoins

The synthesis of all compounds described was carried out utilizing the tea-bag technology, wherein the resin is packed within sealed polypropylene mesh packets.15 This method is convenient and allow the parallel synthesis of a large number of compounds in a specified time period. Based on previous literature precedents,13–15 we introduced the first position (R1) of diversity with five different amines via nucleophilic substitution of 4-fluoro-3-nitrobenzoic acid, and the second position (R2) of diversity was introduced by coupling resin-bound aminobenzimidazole 9 with four different amino acids using PyBOP in anhydrous DMF conditions. The protected Fmoc group was later deprotected using 20% piperidine to afford the free amine 11. Treatment of the amine 11 with 1,1′-carbonyldiimidazole or 1,1′-thiocarbonyldiimidazole generated an intermediate isocyanate or isothiocyanate which, later underwent intramolecular cyclization pathway and furnished the corresponding hydantoins or thiohydantoins, respectively.43 The synthetic protocol for the parallel solid-phase synthesis of hydantoins is outlined in Scheme 2.

Scheme 2.

Scheme 2

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Parallel solid-phase synthesis of hydantoin and thiohydantoin derivatives

The competitive reaction leading to the formation of the fused tricyclic diketotriazepines 16 and 17 was not observed. The structural assignment of hydantoin was identified based upon the unique nature of the 13C chemical shift of the –(CO)NH joining the amino acid and benzimidazole. The carbonyl in diketotriazepine 16 or 17, is in conjugation with the imine C=N bond, and would tend to exhibit 13C chemical shift greater than 200 ppm. However, in case of hydantoin, the two carbonyls are attached to same nitrogen, and the 13C chemical shift for those compounds would be ~160–180 ppm, which is in accordance with our experimental data (Fig. 2).43 All of these intramolecular cyclizations leading to the formation of hydantoins or thiohydantoins occurred in good isolated yields and the results are shown in Table 1.

Figure 2.

Figure 2

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13C NMR based structural assignment of hydantoin nuclei.

Table 1.

Hydantoins and thiohydantoins isolated from intramolecular cyclization.

graphic file with name nihms332087u1.jpg
Entry R1 R2 (Amino acid) Mass calcd./found (MH+) Yield (%)a
12a Cyclopentyl Phe 417.4/418.2 71
12b n-Butyl Phe 405.4/406.3 92
12c Cyclohexanemethyl Phe 445.5/446.3 93
12d i-Butyl Phe 405.4/406.2 89
12e 3-(trifluoromethyl)benzyl Phe 507.5/508.3 85
12f Cyclopentyl Leu 383.4/384.2 81
12g n-Butyl Leu 371.4/372.3 83
12h Cyclohexanemethyl Leu 411.5/412.2 96
12i i-Butyl Leu 371.4/372.2 74
12j 3-(trifluoromethyl)benzyl Leu 473.4/474.1 98
12k Cyclopentyl Tyr 433.4/434.3 81
12l n-Butyl Tyr 421.4/422.2 72
12m Cyclohexanemethyl Tyr 461.5/462.3 91
12n i-Butyl Tyr 421.4/422.2 95
12o 3-(trifluoromethyl)benzyl Tyr 523.5/524.3 77
12p Cyclopentyl Pro 367.4/368.4 92
12q n-Butyl Pro 355.4/356.4 95
12r Cyclohexanemethyl Pro 395.4/386.2 81
12s i-Butyl Pro 355.4/356.4 91
12t 3-(trifluoromethyl)benzyl Pro 457.4/458.2 73
13a Cyclopentyl Pro 383.5/384.3 91
13b n-Butyl Pro 371.5/372.3 88
13c Cyclohexanemethyl Pro 411.5/413.4 92
13d i-Butyl Pro 371.5/372.2 89
13e 3-(trifluoromethyl)benzyl Pro 473.5/474.4 65
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The products were run on a Vydac column, gradients 5 to 95% formic acid in ACN in 7 min.

a

The yields are based on the weight of purified products and are relatives to the initial loading of the resin. (The purity of the purified compounds is higher than 95% for all the compounds).

In summary, we have developed an efficient solid-phase synthesis of aminobenzimidazole tethered hydantoins and thiohydantoins via intramolecular cyclization as an essential step. The coupling of resin-bound aminobenzimidazoles13–16 with several amino acids led to the formation of benzimidazole coupled amino acid residues. Following Fmoc elimination, the free amino group was used as the precursor to prepare a library of hydantoins and thiohydantoins tethered benzimidazole.43

Acknowledgments

The authors would like to thank the State of Florida Funding, NIH (1R03DA025850-01A1, Nefzi; 5P41GM081261-03, Houghten; 3P41GM079590-03S1, Houghten) for providing generous financial support.

Footnotes

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  • 43.General Procedure for the Solid-Phase Synthesis of amino-benzimidazole tethered hydantoins and thiohydantoins: p-Methylbenzhydrylamine (MBHA) resin (100 mg, 1.10 meq/g, 100–200 mesh) was sealed inside a polypropylene mesh packet. Polypropylene bottles were used for all of the reactions. Resin bound amino-benzimidazoles were synthesized according to a previous literature.13–16 Fmoc-amino acid (8 eq., 0.2M in anhyd. DMF) was coupled to MBHA resin bound benzimidazole for 12h at room temperature using the coupling reagent PyBOP (8 eq., 0.2M), DIEA (8 eq., 0.2M) followed by washes with DMF (3x) and DCM (3x). Following Fmoc deprotection with a solution of 20% piperidine in DMF, the resin-bound N-terminal amino acid residue was treated with 1,1′-carbonyldiimidazole (1,1′-thiocarbonyldiimidazole) in anhydrous DMF (0.2M) at 80°C for 12h. The reaction mixture was decanted, and the resulting resin-bound hydantion (thiohydantoin) product was washed with DMF (3x) and DCM (3x). The resin was cleaved with HF/anisole for 90 min at 0°C, and the desired hydantoin (thiohydantoin) was obtained following extraction with 95% AcOH in H2O and lyophilization as a white powder. The final products were purified by preparative reverse-phase HPLC. NMR data for entry 12b: 1H NMR (DMSO-d6): δ 0.75 (m, 3H), 0.92 (t, J = 7.5 Hz, 2H), 1.23 (s, 1H), 1.30–1.35 (m, 2H), 3.12 (br s, 2H), 3.67–3.75 (m, 1H), 4.89 (br s, 1H), 7.27–7.38 (m, 6H), 7.63–7.65 (m, 1H), 7.87 (d, J = 10 Hz, 1H), 7.98–8.01 (m, 1H), 8.22 (s, 1H), 8.98 (br s, 1H); 13C NMR: δ 13.5, 19.0, 43.0, 58.0, 110.7, 119.2, 123.0, 127.1, 128.3, 128.8, 130.0, 139.6, 140.0, 153.5, 168.0; LC-MS m/z data calcd for C22H23N5O3 (MH+): 405.4; found: 406.3; NMR data for entry 12d: 1H NMR (DMSO-d6): δ 0.50–78 (m, 4H), 0.91 (d, J = 7 Hz, 2H), 1.23 (s, 1H), 3.12–3.13 (m, 2H), 3.67 (m, 1H), 3.91 (d, J = 7.5 Hz, 1H), 4.90 (br s, 1H), 7.18 (d, J = 5 Hz, 1H), 7.28–7.38 (m, 6H), 7.67–7.72 (m, 1H), 7.87 (d, J = 9.8 Hz, 1H), 7.98–8.02 (m, 1H), 8.22 (br s, 1H), 8.97 (br s, 1H); 13C NMR: δ 19.5, 27.1, 50.2, 58.1, 111.0, 119.1, 123.0, 128.1, 128.4, 128.8, 128.9, 130.0, 139.92, 139.98, 153.5, 168.0; LC-MS m/z data calcd for C22H23N5O3 (MH+): 405.4; found: 406.3.

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