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Synthesis of 2-Alkylsulfonyl-imidazoles with Three Diversity Positions from Immobilized alpha-Acylamino Ketones Petra Kralova, and Miroslav Soural ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00075 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 4, 2018

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ACS Combinatorial Science

Synthesis of 2-Alkylsulfonyl-imidazoles with Three Diversity Positions from Immobilized α-Acylamino Ketones Petra Králová1 and Miroslav Soural2* 1

Department of Organic Chemistry, Faculty of Science, Palacký University, 771 46 Olomouc, Czech Republic 2

Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 779 00, Olomouc, Czech Republic *Corresponding author. E-mail: [email protected]

TOC

Keywords: amino acid, bromoketone, imidazole, solid-phase synthesis

Abstract

The synthesis of novel imidazole derivatives via immobilized α-acylamino ketones is reported in this article. The key intermediates were prepared from the Wang-piperazine resinsupported Fmoc-amino acids. After their sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl) followed by alkylation with α-bromoketones and cleavage of Nos group, the resulting α-acylamino ketones were reacted with Fmoc-isothiocyanate. The corresponding Fmoc-thioureas were subjected to the Fmoc-cleavage and spontaneous ring-closure to imidazole scaffold. The resulting imidazole-thiones were alkylated with alkyl halides and oxidized using meta-chloroperbenzoic acid (mCPBA). Trifluoroacetic acid (TFA)-mediated cleavage yielded the corresponding trisubstituted 2-alkylsulfonyl imidazoles in good crude

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purity and acceptable overall yields. In the case of sulfides, prepared from alkyl bromides, the unexpected products brominated at the C4 position of the imidazole were obtained. Introduction

α-Acylamino ketones are multireactive compounds readily available from primary amines and α-bromoketones. These versatile intermediates are applicable in the preparation of different nitrogen-containing heterocycles using traditional solution-phase1–6 or solid-phase syntheses.7–14 In the last decade, particular attention has been paid to α-acylamino ketones prepared from immobilized amino acids alkylated with bromoketones via activation with 2- or 4-nitrobenzenesulfonyl chloride.15 In 2009, Krchnak et al. used such polymer-supported αacylamino ketones for the reagent-based, diversity-oriented synthesis of morpholin-3-ones, pyrrol-2-ones, pyrazin-2-ones, imidazo-triazepines, 1H-imidazoles and β-lactams.7 More recently, the same intermediates have been used to prepare benzodiazepin-5-ones,8 and serine-based Wang resin-supported α-acylamino ketones were used in the synthesis of chiral morpholines9 and their derivatives bearing fused [6+6]10,11 or [7+6]12,13 heterocyclic scaffolds. The latest article in this field was devoted to the synthesis of 2-thiohydantoins, imidazo[2,1-b]thiazol-4-iums and imidazole-2-thiones.14 Inspired by the diversity of heterocycles accessible from polymer-supported α-acylamino ketones,15 we suggested their use for the convenient synthesis of 2-alkylsulfonyl-imidazoles derived from natural amino acids. To avoid the spontaneous formation of thiohydantoins that has been reported previously,14 the starting amino acids were not immobilized directly on Wang resin via the ester functionality, and instead, Wang-piperazine resin16 was used to avoid the unwanted cyclative cleavage during the reaction sequence. It is worth mentioning that 2-alkylsulfonyl-imidazoles and related compounds are pharmacologically attractive agents with diverse biological effects.17–20 These derivatives serve as biocidal,21 anti-HIV,22 antibacterial,23 antitrichomonal,24 antiviral25 and antiinflammatory agents26 and selective COX-2 inhibitors26 (see Figure 1 for representative


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examples). On the other hand, the target 2-alkylsulfonyl-imidazoles derived from natural amino acids are an unexplored class of derivatives.

Figure 1. Pharmacologically relevant compounds structurally related to the target derivatives

Results and Discussion The proposed synthetic route (see Scheme 1) was tested using a combination of Wang-piperazine resin-immobilized Fmoc-Ala-OH 1(1), phenylethan-1-one and methyl iodide. The key intermediate, α-acylamino ketone 2{1,1}, was synthetized in three steps according to a previously reported protocol.9 After the reaction of 2{1,1} with Fmocisothiocyanate, the Fmoc protecting group was removed to afford imidazole-2-thione 4{1,1}. The S-alkylation of this compound with methyl iodide yielded sulfide 5{1,1}, which upon oxidation with mCPBA followed by TFA-mediated cleavage from the resin, afforded final sulfone 7{1,1,1} in an excellent crude purity (95%, measured by LC-UV traces at 205-400 nm).

Scheme 1. Synthetic pathway leading to target imidazoles 7-10



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To evaluate the applicability of this synthetic methodology for parallel/combinatorial synthesis of a library of target compounds, different Fmoc-amino acids with functionalized side chains, bromoketones with electron-donating and electron-withdrawing substituents and various alkylating agents were tested (see Figure 2).

Figure 2. List of tested building blocks to obtain different R1, R2 and R3 substituents


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The preparation of α-acylamino ketones 2{R1,R2} was successful for all building blocks in the various tested combinations. After the formation of intermediates 4{R1,R2}, the alkylation of these compounds was tested with alkyl iodides (ethyl iodoacetate, benzyl iodide, phenacyl iodide, and allyl iodide) and alkyl bromides (ethyl bromoacetate, benzyl bromide, and phenacyl bromide). The resulting sulfides 5{R1,R2,R3} were obtained in good crude purities (57-94%, measured by LC-UV traces at 205-400 nm) with exception of phenacyl iodide, which afforded a mixture of unknown products. Subsequent oxidation with mCPBA and TFA-mediated cyclization furnished sulfones 7{R1,R2,R3} in 55-97% crude purities and 10-36% overall yields (see Table 2); however, the reaction outcome was dependent on the substitution of the starting material. In the case of intermediate 5{2,4,1}, we managed to isolate corresponding sulfoxide 8{2,4,1} after adjusting the reaction time to only 30 min. The purified product was obtained as a mixture of two inseparable diastereoisomers in a 68:32 ratio (calculated from the

1

H NMR spectrum). Prolonged oxidation (5 h) furnished

corresponding sulfone 6{2,4,1}. Similarly, oxidation and cleavage of 5{1,3,2} yielded the iodinated sulfoxide 10{1,3,2} (see later in the text). In the case of the other intermediates, the isolation of the sulfoxide was impossible due to their immediate oxidation in the presence of excess of mCPBA.



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The oxidation of sulfide 5{1,1,3}, prepared from benzyl bromide, resulted in expected sulfone 6{1,1,3} along with a by-product with a molecular weight corresponding to the oxidized and brominated product 9{1,1,3}. The by-product was isolated and investigated with NMR spectroscopy. The structural elucidation indicated that bromination took place on the imidazole scaffold based on the disappearance of the corresponding aromatic signal HC4 (see Figure 3).

Figure 3. Disappearance of the HC4 signal of imidazole 7{1,1,3} after oxidation


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The similar behavior was observed using ethyl bromoacetate and phenacyl bromide; the corresponding brominated products were obtained. The ratios of sulfones 7{R1,R2,R3} and brominated analogues 9{R1,R2,R3} varied depending on the overall substitution; however, no systematic relationship was observed (see Table 1).

Table 1. Ratios of 7{R1,R2,R3} and 9{R1,R2,R3} depended on R1-3 Starting cmpd 5{1,1,3} 5{1,2,4} 5{2,1,2} 5{2,2,2} 5{2,2,4} 5{3,1,3} 5{3,1,4} 5{5,1,3}

R1

R2

R3

ratios 7:9a

Me Me CH2OH CH2OH CH2OH CH2Ph CH2Ph (CH2)4NH2

Ph 4-Me-Ph Ph 4-Me-Ph 4-Me-Ph Ph Ph Ph

Bn CH2COPh CH2COOEt CH2COOEt CH2COPh Bn CH2COPh Bn

0:1 1:2 1:1 0:1 1:2 1:2 1:1 1:3

a

Calculated from HPLC-UV-MS (205-400 nm).

The unexpected bromination can be explained by the formation of imidazolehydrobromides at the stage of intermediates 5{R1,R2,R3} as a result of the generation of HBr 7 ACS Paragon Plus Environment


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and its capture after the alkylation step (see Scheme 1, step v). Subsequent treatment with perbenzoic acid may oxidize the bromide anion followed by bromination of the imidazole scaffold by radical mechanism. The crucial role of mCPBA is evident from the cleavage and analysis of sulfides 5{R1,R2,R3}, which showed no trace of the brominated sulfides. In the case of alkyl iodides, the halogenation of imidazole scaffold was generally not observed with the exception of intermediate 5{1,3,2}, which afforded the iodinated sulfoxide 10{1,3,2} (see Scheme 1 and Supporting information for more details). The product was obtained in good crude purity 63% and 14% yield as a mixture of two inseparable diastereoisomers in a ratio 86:14 (calculated from the 1H NMR spectrum). Finally, we tested the possible diversification of the amidic moiety. Surprisingly, when the Wang-piperazine resin was changed to Wang-ethylenediamine resin, the reaction pathway failed at the stage of Fmoc-thiourea formation. Similar results were obtained when Rink amide resin and BAL resin-immobilized secondary amines, respectively were used as the starting materials.

Table 2. The list of synthesized and fully characterized compounds 7-11

cmpd

R1

R2

R3

7{1,1,1} 7{1,1,3} 7{2,1,1} 7{2,2,5} 7{2,2,3} 7{2,3,1}

Me Me CH2OH CH2OH CH2OH CH2OH

Ph Ph Ph 4-Me-Ph 4-Me-Ph 4-MeO-Ph

Me Bn Me allyl Bn Me

crude purity [%]a 75 84 94 88 74 72

final overall purity yield [%]b [%]c 98 10 99 14 98 36 98 26 99 10 98 23 8

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7{2,4,1} 7{3,1,1} 7{3,4,2} 7{3,4,3} 7{4,1,1} 7{4,4,3} 7{5,1,1} 8{2,4,1} 9{1,1,3} 9{3,1,2} 9{5,1,3} 10{1,3,2} 11{2,1,4} 11{4,1,4}

CH2OH CH2Ph CH2Ph CH2Ph CH2COOH CH2COOH (CH2)4NH2 CH2OH Me CH2Ph (CH2)4NH2 Me CH2OH CH2COOH

4-F-Ph Ph 4-F-Ph 4-F-Ph Ph 4-F-Ph Ph 4-F-Ph Ph Ph Ph 4-MeO-Ph Ph Ph

Me Me CH2COOEt Bn Me Bn Me Me Bn CH2COOEt Bn CH2COOEt CH2COPh CH2COPh

81 95 69 65 71 63 87 65 76 58 80 63 82 75

97 99 99 99 99 98 99 99 99 98 99 99 99 99

21 20 17 16 13 22 15 12 15 11 16 14 16 11

a

Overall purity after the entire reaction sequence calculated from the HPLC-UV chromatogram (205400 nm); bPurity determined from the HPLC-UV chromatogram after purification (205-400 nm); c

1

Calculated from the H NMR spectrum of the purified product (see Supporting Information for more details).

Conclusion In conclusion, we developed a simple synthesis of 2-alkylsulfonyl-imidazoles with three positions available for diversification using immobilized α-acylamino ketones as the key intermediates. The methodology can be used for combinatorial synthesis of chemical library using a large number of readily available building blocks. In total, we synthetized and fully characterized 20 representative compounds. Additionally, the C4 halogenated products can be utilized for further diversification of the target scaffold using metal-catalyzed C-C couplings.

Acknowledgements The authors are grateful to the National Program of Sustainability (project LO1304) and an internal grants from Palacký University IGA_PrF_2018_29 and IGA_LF_2018_032.

Supporting Information Available Supporting information contains details of experimental, synthetic, and analytical procedures along with spectroscopic data for synthesized compounds. This material is available free of charge via the Internet at http://pubs.acs.org.



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