Synthesis and functionalization of cyclic sulfonimidamides: a novel chiral heterocyclic carboxylic Acid bioisostere.
ABSTRACT: An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids. By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The compounds could be further derivatized in the aryl ring using standard cross-coupling reactions to yield highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique nonplanar shape in combination with the relatively strong acidity (pK a 5-6) and the ease of modifying the chemical structure to fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available carboxylic acid isosteres.
Project description:Sulfoximines and sulfonimidamides are promising compounds for medicinal and agrochemistry. As monoaza analogues of sulfones and sulfonamides, respectively, they combine good physicochemical properties, high stability, and the ability to build complexity from a three-dimensional core. However, a lack of quick and efficient methods to prepare these compounds has hindered their uptake in molecule discovery programmes. Herein, we describe a unified, one-pot approach to both sulfoximines and sulfonimidamides, which exploits the high electrophilicity of sulfinyl nitrenes. We generate these rare reactive intermediates from a novel sulfinylhydroxylamine (R-O-N=S=O) reagent through an N-O bond fragmentation process. Combining sulfinyl nitrenes with carbon and nitrogen nucleophiles enables the synthesis of sulfoximines and sulfonimidamides in a reaction time of just 15 min. Alkyl, (hetero)aryl, and alkenyl organometallic reagents can all be used as the first or second component in the reaction, while primary and secondary amines, and anilines, all react with high efficiency as the second nucleophile. The tolerance of the reaction to steric and electronic factors has allowed for the synthesis of the most diverse set of sulfoximines and sulfonimidamides yet described. Experimental and computational investigations support the intermediacy of sulfinyl nitrenes, with nitrene formation proceeding via a transient triplet intermediate before reaching a planar singlet species.
Project description:Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100?%?es, es=enantiospecificity) generating sulfonimidamides with up to 99?%?ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.
Project description:Sulfonimidamides are obtained in moderate to very good yields from the key intermediates O-benzotriazolyl sulfonimidates, which are formed by reacting aryldiazonium tetrafluoroborates, N-tritylsulfinylamine, and N-hydroxybenzotriazole hydrate in a process mediated by a tertiary amine. The formation of the sulfonimidate proceeds in inexpensive and environmentally benign dimethyl carbonate as the solvent, it does not require anhydrous conditions, and the product yields generally exceed 70?%. The substrate scope is broad, and a wide range of sensitive organic functionalities is well tolerated. The reactions probably proceed via aryl radicals formed from diazonium cations with assistance from both the tertiary amine and the sulfinylamine.
Project description:An unprecedented set of structurally diverse sulfonimidamides (47?compounds) has been prepared by various N-functionalization reactions of tertiary =NH sulfonimidamide 2?aa. These N-functionalization reactions of model compound?2?aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X-ray analyses of selected N-functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N-functionalization reactions provide a short and efficient approach to structurally diverse sulfonimidamides which have been the subject of recent, growing interest in the life sciences.
Project description:<h4>Background</h4>The synthesis of sulfonimidamides involves the nucleophilic substitution of a sulfonimidoyl chloride with an amine. However, only four chlorinating systems have been reported for the preparation of the sulfonimidoyl chloride intermediates. Whereas some of them have shown a rather limited substrate spectrum, the most versatile and commonly used tert-butyl hypochlorite is known to be explosive. To establish alternative methods for the synthesis of these molecules is therefore desirable.<h4>Results</h4>The preparation of various p-tolylsulfonimidamides through the reaction of the corresponding N-protected p-tolylsulfinamides and a number of amines in the presence of N-chlorosuccinimide was achieved at room temperature in 50-97% yield.<h4>Conclusion</h4>A convenient alternative procedure for the synthesis of sulfonimidamides from sulfinamides and various amines and sulfonamides using N-chlorosuccinimide as halogenating agent has been developed.
Project description:Methods for establishing the absolute configuration of sulfur-stereogenic aza-sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials. We have addressed this by exploiting, for the first time, a feature of sulfonimidamides in which it is possible for tautomeric structures to also be enantiomeric. Such sulfonimidamides can readily generate prochiral ions, which we have exploited in an enantioselective alkylation process. Selectivity is achieved using a readily prepared bis-quaternized phase-transfer catalyst. The overall process establishes the capability of configurationally labile aza-sulfur species to be used in asymmetric catalysis.
Project description:Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one-pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X-ray analysis of NH sulfonimidamide 2?a and its behavior in selected in?vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences.
Project description:A new method for the enantioselective reductive coupling of aryl alkenes with activated carboxylic acid derivatives via copper hydride catalysis is described. Dual catalytic cycles are proposed, with a relatively fast enantioselective hydroacylation cycle followed by a slower diastereoselective ketone reduction cycle. Symmetrical aryl carboxyclic anhydrides provide access to enantioenriched ?-substituted ketones or alcohols with excellent stereoselectivity and functional group tolerance.
Project description:The stereospecific ring-opening of O-heterocycles to provide acyclic alcohols and carboxylic acids with controlled formation of a new C-C bond is reported. These reactions provide new methods for synthesis of acyclic polyketide analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic template is utilized to control relative configuration; subsequent stereospecific nickel-catalyzed ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an anti-dyslipidemia agent is demonstrated.
Project description:A new and diverse family of pyrene derivatives was synthesised via palladium-catalysed C–H ortho-arylation of pyrene-1-carboxylic acid. The strategy affords easy access to a broad scope of 2-substituted and 1,2-disubstituted pyrenes. The C1-substituent can be easily transformed into carboxylic acid, iodide, alkynyl, aryl or alkyl functionalities. This approach gives access to arylated pyrene ammonium salts, which outperformed their non-arylated parent compound during aqueous Liquid Phase Exfoliation (LPE) of graphite and compare favourably to state-of-the-art sodium pyrene-1-sulfonate PS1. This allowed the production of concentrated and stable suspensions of graphene flakes in water. Novel pyrene surfactants for aqueous graphene exfoliation were prepared via C–H arylation of pyrene-1-carboxylic acid.