High Throughput Synthesis of Functionalised 1,3-Diones and Subsequent Heterocycle Formation

Abstract

A functionalisation of 1,3-diones using hypervalent iodine has been developed that is useful in the preparation of libraries of heterocyclic compounds.The use of high throughput chemistry has been shown to be an important development in the discovery of drugs in the modern pharmaceutical industry. 1 It fulfils the need to generate large chemical libraries which have utility both for the generation of lead candidates in the drug design process and for the optimisation of structure-activity relationships within a series of compounds. In particular the efficient construction of heterocyclic scaffolds such as oxadiazoles in a combinatorial paradigm has been a focus of interest. 2 The reactions used in high throughput synthesis need to be robust and applicable to a variety of substrates. This enables the introduction of diversity into the library so that compounds prepared possess a range of structural features. Herein we describe the application of hypervalent iodine reagents to the functionalisation of 1,3-diones and their use in heterocycle formation. 3 A recent publication in this area of chemistry has prompted us to disclose our results on the use of iodosylbenzene. 4,5 As part of our research it became necessary to prepare a range of pyrazoles 1 with an oxygen linker at the 4-position of the template. It was a goal that the chemistry should be designed for the simple variation of commercially available building blocks 2, 3 and 4 to enable the introduction of diversity. For synthetic expedience we were keen that both dione functionalisation and heterocycle formation be performed in a single reaction well ( Figure 1). Figure 1 Retrosynthesis of 4-alkoxy pyrazoles.Initial attempts to functionalise the dione were made using diazotransfer reagents to prepare a diazodiketone for transition metal mediated insertion chemsitry. 6 This is well precedented in the literature, however, rhodium or copper mediated intermolecular OH insertion reactions are capricious. They often require a large excess of the alcohol and optimisation of metal ligands and reaction conditions. 7 In our hands this approach was low yielding and therefore of limited general utility in the preparation of libraries of functionalised diones for heterocycle synthesis.We were intrigued at the number of publications that used hypervalent iodine for the functionalisation of carbonyl compounds and the potentially simple reaction conditions, which were amenable to high throughput synthesis. A publication by Moriarty was particularly interesting in which a simple dione 5 was functionalised using iodosylbenzene. 8 A small number of nucleophiles were considered including azide and methanesulfonate that were used as reactants in stoichiometric ratios. Alcohols were also investigated and coupled into the dione in reasonable yield, however, the alcohol was used as solvent. Obviously the use of alcohols as solvent would be severely limiting in our work and it was imperative to reduce the alcohol to a stoichiometric level as had been demonstrated for azidotrimethylsi...

Why Is the Spontaneous Deprotonation of [Cu(uracil)2]2+Complexes Accompanied by Enolization of the System?

“…These reactions proceed via an ionic mechanism involving the attack of the electrophilic iodine atom on the enol of the dicarbonyl compound followed by the replacement of the iodine‐containing moiety by a O‐nucleophile to form a CO coupling product 18–21. Iodine compounds were used to perform the coupling reactions of dicarbonyl compounds with alcohols,18,22,23 sulfonic acids,18,19,21,22,24 carboxylic acids,18,25 and phosphorus compounds 18,20…”

Iminoxyl Radical‐Based Strategy for Intermolecular CO Bond Formation: Cross‐Dehydrogenative Coupling of 1,3‐Dicarbonyl Compounds with Oximes

“…The literature data were thoroughly analyzed to determine the scope of the C À O cross-dehydrogenative coupling reactions. Aldehydes, [12,56,57] formamides, [58] alkylarenes, [56,[59][60][61][62][63] isochromanes, [64a] alcohols, [57,65,66] compounds containing the allyl moiety, [59,64b,67-83] 1,3dicarbonyl compounds, [84][85][86][87][88][89][90] malononitriles and cyanoacetic esters, [88,91] monocarbonyl compounds [66,[92][93][94][95][96] and pyrrolidines [97] were used as C À H reagents for the C À O coupling. Alcohols, [12,65,[84][85][86]97] N-hydroxy imides, [12,57,59,63,88] hydroxamic acids, [88,90] oximes, [64] sulfonic acids, [66,84,…”

“…Depending on the nature of C À H and O À H reagents for the cross-dehydrogenative C À O coupling, various catalysts, oxidants, oxidizing systems and conditions were used: (n-Bu) 4 NBr/t-BuOOH, [12] A C H T U N G T R E N N U N G (n-Bu) 4 NI/t-BuOOH, [12,61,67,87,96] NH 4 I/MCPBA, [92] I 2 /MCPBA, [93] DDQ, [64] iodineA C H T U N G T R E N N U N G (III) and iodine(IV) compounds, [57,[84][85][86] iodoarene/peroxide, [66,[93][94][95] CuCl/PhIA C H T U N G T R E N N U N G (OAc) 2 , [59] Cu 2+ /t-BuOOH, [56,58,89,91] CuCl 2 / LiCl, [69] CuA C H T U N G T R E N N U N G (OTf) 2 /ligand/MnO 2 , [90] ruthenium complexes, [65] MnA C H T U N G T R E N N U N G (OAc) 3 , [88] Co 2+ /KMnO 4 , [88] NaBrO 3 / NaHSO 3 , [60] (NH 4 ) 2 CeA C H T U N G T R E N N U N G (NO 3 ) 6 , [63] Pd(II)-based systems, [62,[68][69][70][71][72][73][74][75][76][77][78]…”

“…Aldehydes,12,56,57 formamides,58 alkylarenes,56,59–63 isochromanes,64a alcohols,57,65,66 compounds containing the allyl moiety,59,64b,67–83 1,3‐dicarbonyl compounds,84–90 malononitriles and cyanoacetic esters,88,91 monocarbonyl compounds66,92–96 and pyrrolidines97 were used as CH reagents for the CO coupling. Alcohols,12,65,84–86,97 N ‐hydroxy imides,12,57,59,63,88 hydroxamic acids,88,90 oximes,64 sulfonic acids,66,84,85,92–95 carboxylic acids,60–62,67–83,85,87,96 phosphonic acids,85 t‐ BuOOH,89,91 phenols,58 and 1,3‐keto esters58 were used as OH reagents.…”

“…Depending on the nature of CH and OH reagents for the cross‐dehydrogenative CO coupling, various catalysts, oxidants, oxidizing systems and conditions were used: ( n‐ Bu) 4 NBr/ t‐ BuOOH,12 ( n‐ Bu) 4 NI/ t‐ BuOOH,12,61,67,87,96 NH 4 I/MCPBA,92 I 2 /MCPBA,93 DDQ,64 iodine(III) and iodine(IV) compounds,57,84–86 iodoarene/peroxide,66,93–95 CuCl/PhI(OAc) 2 ,59 Cu 2+ / t‐ BuOOH,56,58,89,91 CuCl 2 /LiCl,69 Cu(OTf) 2 /ligand/MnO 2 ,90 ruthenium complexes,65 Mn(OAc) 3 ,88 Co 2+ /KMnO 4 ,88 NaBrO 3 /NaHSO 3 ,60 (NH 4 ) 2 Ce(NO 3 ) 6 ,63 Pd(II)‐based systems,62,68–83 and anodic oxidation 97…”