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Sustainable Three-Component Synthesis of Isothioureas from Isocyanides, Thiosulfonates, and Amines
Angewandte Chemie International Edition
Abstract
Multiple applications of isothioureas as fine chemicals (or their precursors) are known, but a general sustainable method for their synthesis was hitherto unavailable. We report a novel general approach towards S-alkyl and S-aryl isothioureas through a copper(I)-catalyzed three-component reaction between amines, isocyanides, and thiosulfonates. The formal synthesis of a superpotent sweetener further illustrates the applicability of our method.
... [15] As far as we know, isocyanides, which not only could be inserted into metal-carbon and metal-heteroatom bonds in transition-metal-catalyzed system, but also react with electrophiles, nucleophiles and radicals under suitable conditions, are an important C1 synthons. [16] Recently, the monofunctionalization of isocyanides have been reported to synthesize carbodiimides by electrochemical oxidation (Scheme 1 b). [17] In order to realize difunctionalization of isocyanides, we hypothesized that isocyanides could afford imine radical when attacked by radicals. ...
... Furthermore, thiophenols containing one group or two groups in different position also showed good reaction efficiency in this transformation (12)(13)(14)(15). Afterwards, we turned our attention to expand the scope from aryl mercaptans to alkyl mercaptans (16)(17)(18)(19)(20)(21)(22)(23). To our delight, the electrochemical protocol was shown to be compatible with a variety of alkyl mercaptans including those bearing dodecyl (17), benzyl (19), cycloalkyl (22, 23) and ester (20). ...
Ethers (C−O/S) are ubiquitously found in a wide array of functional molecules and natural products. Nonetheless, the synthesis of imino sulfide ethers, containing an N(sp²)=C(sp²)−O/S fragment, still remains a challenge because of its sensitivity to acid. Developed here in is an unprecedented electrochemical oxidative carbon‐atom difunctionalization of isocyanides, providing a series of novel multisubstituted imino sulfide ethers. Under metal‐free and external oxidant‐free conditions, isocyanides react smoothly with simple and readily available mercaptans and alcohols. Importantly, the procedure exhibited high stereoselectivities, excellent functional‐group tolerance, and good efficiency on large‐scale synthesis, as well as further derivatization of the products.
... [13] For example, Maes and co-workers reported a copper-catalyzed three-component reaction of thiosulfonates, amines, and isocyanides leading to S-aryl isothioureas (Scheme 1c). [14] Phukan and co-workers presented base promoted three-component reaction of N,N-dibromoarylsulfonamides, thiols and isonitriles to access S-substituted isothioureas (Scheme 1d). [15] Although some obvious progress has been made, the development of facile, efficient and green multicomponent reaction from simple and readily available materials is still highly desirable in synthetic chemistry. ...
Base‐free method has been developed for the synthesis of S‐alkyl substituted isothioureas via three‐component ring‐opening reaction of cyclic sulfonium salts with isothiocyanates and amines. A series of aryl, alkenyl, and alkynyl sulfonium salts were successfully transformed into the S‐alkyl substituted isothioureas in moderate to excellent yields with favorable functional group tolerance. The advantages of operational simplicity, broad substrate scope, gram‐scale synthesis and good reaction efficiency make this protocol attractive in the synthetic chemistry. image
... Moreover, benzenesulfonothioate is a useful and essential synthon that offers several advantages over other sulfuration agents [240][241][242][243]. Benzenesulfonothioate is an electrophile that is air-stable, easy to prepare and has no unpleasant odours [244][245][246][247][248]. The scope of gem-difluoroalkenes (128) with additional bulky S-(2, 6-dimethyl phenyl) benzenesulfonothioate (129) using these optimized reaction conditions and the reaction limitation in hand. ...
Reductive cross-electrophile transformations have recently been made into a robust and long-lasting synthetic technique for the production of specific C-C bonds. The use of inexpensive and plentiful electrophiles eliminates the need for pre-formation and handling of organometallics. In stereospecific reductive cross-coupling, nickel is one of the most cost-effective and flexible transition metals. This paper examines current developments in nickel catalyzed reductive cross-coupling reactions and their potential application for the synthesis of biologically active molecules over the previous nine years.
... [5][6][7][8] In the synthetic, organic chemistry these compounds are used as popular sulfenylating agents. [9][10][11][12][13][14] As opposed to sulfinyl halides, thiosulfonates exhibit a higher stability and compared to disulfides accompanied by a higher reactivity at the same time. [15] Due to the significance of this substance class, many synthetic strategies have been developed during the past decades. ...
The anodic generation of symmetrical and unsymmetrical thiosulfonates is presented. First, the oxidation of disulfides yielding symmetrical thiosulfonates was realized. The direct synthesis is performed using a simple quasi‐divided cell design, whereby using a supporting electrolyte is unnecessary. Its principle was then expanded to the conversion of unsymmetrical disulfides that were generated in situ through metathesis of two symmetrical disulfides. This enables a direct access to unsymmetrical thiosulfonates without any pre‐functionalization or elaborate synthesis of the starting materials for the first time. The reaction scope was investigated by converting differently functionalized aliphatic and aromatic disulfides in moderate to very good yields. Furthermore, a sensitivity assessment for an improved reproducibility and a robustness screen to determine the compatibility of the reaction against functional groups were performed.
Rapid access to unsymmetrical diaryl sulfides through a bifunctional single‐sulfur source is a very attractive strategy. Here we report the utilization of bis(phenylsulfonyl)sulfide as a bielectrophilic sulfide platform molecule for chemoselective and sequential installation of two different aryl nucleophiles by twice copper‐catalyzed Chan–Lam‐type cross couplings to access diverse unsymmetrical diaryl sulfides. This strategy demonstrates good tolerance to a wide range of aryl boronic acids under different metal catalysts, good functional group compatibility, as well as the extension to the modification of complex bioactive molecules.
Herein, we introduce a novel method for the synthesis of S‐substituted isothiourea compounds via the selective 1,2‐carboimination between oxime esters as bifunctional reagents and the C=S bond of isothiocyanates under visible‐light catalysis. This approach deviates from conventional methods by precisely modulating the substrate electronics to selectively functionalize the C=S bond of isothiocyanates over the C=N bond, eliminating the need for strong bases and high temperatures and bypassing the formation of thiourea intermediates. Consequently, this protocol enables the efficient one‐step synthesis of S‐alkyl isothioureas, with featuring mild reaction conditions, operational simplicity and broad substrate scope.
Due to the high reactivity and versatility of benzenesulfonothioates, significant advancements have been made in constructing C-S bonds. However, there are certain limitations in the synthesis of S-thiosulfonates and SS-thiosulfonates, especially when dealing with substantial steric hindrance, which poses a significant challenge. Herein, we present an innovative approach for assembling unsymmetric S-thiosulfonates and unsymmetric SS-thiosulfonates through the integration of dual copper/photoredox catalysis. Moreover, we also realized the one-pot strategy by directly using carboxylic acids as raw materials by in-situ activation of them to access S-thiosulfonates and SS-thiosulfonates without further purification and presynthesis of NHPI esters. The envisaged synthesis and utilization of these reagents are poised to pioneer an innovative pathway for fabricating a versatile spectrum of mono-, di-, and polysulfide compounds. Furthermore, they introduce a class of potent sulfenylating reagents, empowering the synthesis of intricate unsymmetrical disulfides that were previously challenging to access.
Herein, we describe an electrochemical strategy that enables the aminotrideuteromethylthiolation of isocyanides with anilines and CD3SSO3Na, providing an unprecedented route to access S-CD3 isothioureas in satisfactory yields. Mechanistic studies reveal...
Isothiourea is an important class of sulfur-containing molecules showing unique catalytic and biological activities. As such, polyisothiourea is envisioned to be an interesting type of polymer that potentially exhibits a number of interesting properties. However, there is no access to synthesizing well-defined polyisothiourea, and currently isothiourea-containing polymers are mainly prepared by immobilizing onto other polymer’s side chain. Herein, we report the first facile synthesis of polyisothioureas via alternating copolymerization of aziridines and isothiocayanates. Mediated by the catalytic system of phosphazene superbases/alcohol, a broad scope of aziridines and isothiocayanates could be transformed into polyisothioureas with adjustable substitutions (11 examples). The structures of obtained polyisothioureas were fully characterized with 1H-NMR, 13C-NMR, and 1H-13C HMBC NMR. Moreover, the polyisothioureas show tunable thermal properties depending on substitutions on the isothiourea linkages. The novel structure of these polyisothioureas will enable a powerful platform for the discovery of next-generation functional plastics.
An energy economical and radical‐involved regioselective difunctionalization annulation of 1,6‐enynes with thiosulfonates or selenosulfonates accessing to pyrrolidine derivatives has been developed. The catalytic amount of TBHP was sufficient to initiate and enable the simultaneous formation of a C(sp³)−S(O2Ar) bond and a C(sp²)−S(Ar) or C(sp²)−Se(Ph) bond across the C=C and C≡C bond of 1,6‐enynes by utilizing two different sulphur radicals. The reaction shows broad substrate scope, moderate to good yields, and 100 % atom economy.
A reductive coupling reaction of sodium sulfinates for the synthesis of symmetrical/unsymmetrical thiosulfonates is developed. The reaction takes place in the presence of acetyl chloride and Hantzsch ester under mild conditions and exhibits broad functional group tolerance. Mechanistic studies suggest that a radical process is involved.
A controllable and rapid synthesis of disulfides and thiosulfonates from sodium sulfinates mediated by hydroiodic acid is presented for the first time. In these reactions, ethanol and H2O are employed as solvents to generate different products, thiosulfonates can be further transformed to corresponding disulfides in an ethanol reaction system. Moreover, these simple methods are environmentally benign and can be performed under mild conditions with a short reaction time, showing good functional group tolerance.
Unsymmetrical sulfides are widely found in the pharmaceutical industry, organic synthesis, and materials science. As a result, it will be of great significance to discover mild and efficient methodologies and electrophilic sulfur transfer reagents, avoiding the general employment of odorous and toxic thiols. Herein, we present a highly efficient nickel-catalyzed cross-electrophile coupling of organic halides with “thiol-free” synthesized N-thiophthalimides as direct thiolating surrogates. This practical strategy features extremely low catalyst loading, good functional group tolerance and diverse downstream synthesis, enabling the construction of a broad range of sulfides under “base-free” conditions. Notably, a modified and more efficient reductive thiolation of disulfides was developed by employing our mild reaction conditions.
A metal‐free and green iodine‐catalyzed protocol is described herein for the synthesis of unsymmetrical thiosulfonates by sulfonylation of thiols using I2/Oxone. It's shown that oxidative cross‐coupling of thiyl radicals with sulfonyl radicals – generated from thiols and sulfonyl hydrazides, respectively, by the redox chemistry between thiol/Oxone and I2/Oxone – occurs in a facile manner at rt, providing access to unsymmetrical thiosulfonates. Diverse unsymmetrical thiosulfonates are synthesized in good‐to‐excellent isolated yields by the reactions of aryl/(hetero)aryl/alkyl thiols with a variety of aryl/(hetero)aryl/alkyl/benzyl sulfonyl hydrazides. The protocol can be further extended to the synthesis of alkyl/aryl sulfonate esters by the reactions of sulfonyl hydrazides with alcohols/phenols using I2/Oxone.
A copper-catalyzed multicomponent reaction of secondary amines bearing allyl substitution, isothiocyanates, and Togni reagent II has been developed under Cs2CO3 in DCE at 75 °C. An intermolecular multicomponent reaction of thioureas, activated and unactivated alkenes, and Togni reagent II has also been developed under DMAP in acetonitrile at room temperature. These two alkene difunctionalization reactions provide CF3-containing 2-iminothiazolindines and isothioureas in moderate to excellent yields with broad substrate scope and good functional group tolerance, respectively.
An approach to unsymmetrical thiosulfonates has been developed using sulfenylation of sodium sulfinates by arenediazonium tetrafluoroborate/CS2 combination with iodine as catalyst. The reaction is simple, high yielding, scalable, and proceeds smoothly with good substrate scope and functional group tolerance.
The simultaneous binding/dissociation of multiple bonds in a one-pot manner by multicomponent reactions provide an important approach for developing novel and sustainable pathway in the drug discovery process. Herein we develop an electrocatalytic three-component reaction to construct multifunctional and valuable isothiourea compounds, which uses thiols, isocyanides and amines as substrates. Compared with the previous work, the organic electrosynthesis technique can avoid the requirement of heavy metal catalysts and stoichiometric oxidants. In addition, using thiol as a substrate to participate in the three-component reaction broadens the source of sulfur, which can also construct more abundant isothiourea derivatives.
A nickel-catalyzed reductive cross coupling between organic iodides and thiosulfonates and a selenosulfonate under mild conditions is disclosed. This practical method provides a facile access to a series of unsymmetrical thioethers with low catalyst loading, good functional group tolerance, and excellent chemo-selectivity. Notably, the synthetic applications of the approach feature scaling-up of reactions, late-stage modification of pharmaceuticals, and preparation of various useful targeted compounds, including sulfoximine, bipyridine, and vortioxetine. Primary mechanistic studies showed that a radical pathway was involved. Moreover, diverse C-S/C-Se bond formations were achieved under mild reaction conditions.
The construction of C(sp2)-X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn growing attention since heteroatomic compounds play a prominent role from biological to pharmaceutical sciences. The current study demonstrates the C(sp2)-S/Se and C(sp2)-N bond formation of one carbon of isocyanides with thiophenols or disulfides or diselenides and azazoles simultaneously. The reported findings could provide access to novel multiple isothioureas, especially hitherto rarely reported selenoureas. The protocol showed good atom-economy and step-economy with only hydrogen evolution and theoretical calculations accounted for the stereoselectivity of the products. Importantly, the electrochemical reaction could exclusively occur at the isocyano part regardless of the presence of susceptible radical acceptors, such as a broad range of arenes and alkynyl moieties, even alkenyl moieties.
A green electrochemical oxidative cross-coupling protocol for the generation of thiosulfonates and sulfonate esters using sodium arenesulfinates and thiophenols/phenols is disclosed. The protocol involves using inorganic and non-toxic NaI as both redox catalyst and supporting electrolyte at room temperature without oxidant and base. The reactions provide good yields of products and tolerate broad substrate scope. The mechanistic studies revealed that the reactions proceed via a radical pathway for the formation of SO2–S and SO2–O bonds.
Aromatic α-aminoazaheterocycles are the focus of significant investigations and exploration by researchers owing to their key role in diverse biological and physiological processes. The existence of their derivatives in numerous drugs and alkaloids is due to their heterocyclic nitrogenous nature. Therefore, the synthesis of a structurally diverse range of their derivatives through simple and convenient methods represents a vital field of synthetic organic chemistry. Multicomponent reactions (MCRs) provide a platform to introduce desirable structure diversity and complexity into a molecule in a single operation with a significant reduction in the use of harmful organic waste, and hence have attracted particular attention as an excellent tool to access these derivatives. This review covers the advances made from 2010 to the beginning of 2020 in terms of the utilization of α-aminoazaheterocycles as synthetic precursors in MCRs.
Sulfur‐containing molecules are of utmost topical importance towards the effective development of pharmaceuticals and functional materials. Herein, we present an efficient and mild electrochemical thiolation by cross‐electrophile coupling of alkyl bromides with functionalized bench‐stable thiosulfonates to access alkyl sulfides with excellent efficacy and broad functional group tolerance. Cyclic voltammetry and potentiostatic analysis were performed to elucidate mechanistic insights into this electrocatalytic thiolation reaction.
Sulfonyl compounds have attracted considerable interest due to their extensive applications in drug discovery. Access to the assembly of SO2-containing compounds via the oxygenation oxidative-state introduction of hypervalent sulfur has come to the fore in recent years. This review discusses the application of the same oxygenation-state introduction of hypervalent sulfur strategy under transition-metal-free conditions, and presents it in light of different atoms being linked to the sulfonyl group, including sulfones, sulfonamides, sulfonyl fluorides and thiosulfonates.
An unprecedented electrochemical oxidative carbon‐atom difunctionalization of isocyanides has been developed and it provides a series of novel multisubstituted imino sulfide ethers. Under metal‐free and external‐oxidant‐free conditions, isocyanides react smoothly with simple and readily available mercaptans and alcohols.
Abstract
Ethers (C−O/S) are ubiquitously found in a wide array of functional molecules and natural products. Nonetheless, the synthesis of imino sulfide ethers, containing an N(sp²)=C(sp²)−O/S fragment, still remains a challenge because of its sensitivity to acid. Developed here in is an unprecedented electrochemical oxidative carbon‐atom difunctionalization of isocyanides, providing a series of novel multisubstituted imino sulfide ethers. Under metal‐free and external oxidant‐free conditions, isocyanides react smoothly with simple and readily available mercaptans and alcohols. Importantly, the procedure exhibited high stereoselectivities, excellent functional‐group tolerance, and good efficiency on large‐scale synthesis, as well as further derivatization of the products.
In current era the scientific community is very much interested to utilize green house gas carbon dioxide through chemical fixation in order to produce value based fine organic chemicals. The chemical combination of atmospheric carbon dioxide, isocyanides and 2-iododaniline in one pot reaction for the synthesis of Quinazoline-2,4(1H,3H)-diones derivatives is a straight forward and attractive methodology to avoid multi-steps and more toxic reagent containing routes. In this paper a heterogeneous catalyst was designed and synthesized from aminically modified Graphene Oxide by incorporation of palladium metal. The catalyst was characterized by FT-IR, XRD, ICP-AES, Raman spectroscopy, XPS, TEM, SEM, EDX and N2 absorption desorption studies. In this report, the formation of N3-substituted 2,4(1H,3H)-Quinazolinediones was performed under mild and heterogeneous reaction conditions in 1 bar CO2 pressure. The catalyst is very efficient to produce the Quinazoline derivatives. For the investigation of mechanistic route of catalytic reaction Density Functional Theory (DFT) calculations was also monitored. We have checked the recyclability of the catalyst, the results indicates that the catalyst maintained its catalytic efficacy even after use of six cycles.
An efficient strategy for the construction of fused imidazole derivatives through a palladium-catalyzed isocyanide insertion reaction has been accomplished. The methodology provides an operationally simple and versatile route for the synthesis of indeno[1,2-d]imidazole and imidazo[1,2-a]indole skeletons which are rarely reported. The key features of the protocol are construction of sequential C-C/C-C/C-N bonds via C(sp2)-H functionalization of imidazole at C2 and C4-position respectively. The compounds can be synthesized with diverse scaffolds, easily accessible starting materials and moderate to good yields.
In many reactions involving selenosulfonate or thiosulfonate, the sulfone group often leaves in form of benzenesulfinic acid or sodium benzenesulfinate. A one-pot two-step reaction of selenosulfonate with isocyanides and allyl alcohol under aqueous conditions to afford selenocarbamates and allyl sulfone compounds is reported. The sulfinic acid as the first-step side product is converted to the allyl sulfone compound by water promoted reaction with allyl alcohol. Water acts as both an oxygen source of selenocarbamates and as a promoter to drive the second step reaction. The reactions have the advantages of mild conditions, green, environment-friendly, and high atomic economy.
A metal-free method for the vicinal thiosulfonylation of unactivated alkenes with thiosulfonates using 9-mesityl-10-methylacridinium perchlorate as photo-organocatalyst with visible-light irradiation has been developed. The method can be performed in dimethyl carbonate under air at room temperature and features a broad functional group compatibility. Metrics indicate the green potential of the developed versus the state-of-the-art methodologies. Mechanistic studies revealed no single electron transfer but involvement of an energy transfer from the excited photo-organocatalyst to thiosulfonate reactant, subsequently providing a sulfenyl and a sulfonyl radical via homolytic cleavage.
In this paper, a visible-light-promoted cross-coupling of 4-alkyl-1,4-dihydropyridines with thio-/selenium sulfonates under transition-metal-free conditions is described. This strategy features easily available substrates, mild reaction conditions, high yields, and high chemoselectivity. A novel synthetic route for the construction of a sulfide or selenide Csp3-S or Csp3-Se bond under transition-metal-free conditions without an additive oxidant or base is developed. This method is well extended to the synthesis of a class of thiolated or selenylated glycosides that has not been explored before. Sulfoxides were also successfully chemoselectively observed via a facile variation of the atmosphere under photocatalyzed conditions.
In this study, we report a straightforward oxidative cross-coupling synthesis of carbodiimide tethered amino acid conjugates from amino acid-derived isocyanides and aryl amines mediated by I2/tert-butyl hydroperoxide. Using this protocol, the title compounds were obtained in good isolated yields. This protocol is of short reaction duration, base-free, racemization free and avoids the necessity of transition metal catalysts.
Herein we report a novel copper-catalyzed imidoylative cross-coupling/cyclocondensation between 2-isocyano-benzoates and amines efficiently producing quinazolin-4-ones. The reaction utilizes Cu(II) acetate as an environmentally benign catalyst in combination with a mild base and proceeds well in anisole, a recommended, sustainable solvent. Additionally, the reaction does not require dry conditions or inert atmospheres for optimal performance. The scope of this isocyanide insertion reaction is rather broad, tolerating various functionalized isocyanobenzoates, and a range of substituted amines, although the use of aromatic amines as nucleophiles requires microwave heating
A visible-light promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labelled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.
A nickel-catalyzed ring opening and subsequently reductive cross-coupling of cycloketone oxime esters with thiosulfonate or seleniumsulfonate is reported, which involves C-C bond cleavage and C(sp3)-S or C(sp3)-Se bond formation. Notably, S-aryl/alkyl sulfonothioates and Se-alkyl seleniumsulfonothioates could be employed in this reaction to afford a variety of 1º, 2º alkyl sulfides, aryl sulfides and 1º, 2º alkyl selenides in one step. This strategy features easily available substrates and mild reaction conditions.
A metal‐free sequential one‐pot three‐component protocol is described for the synthesis of C3‐functionalized imidazo[1,2‐a]pyridines. A successive construction of imidazo[1,2‐a]pyridine followed by iodine‐catalysed sulfenylation has been achieved in a one‐pot operation from readily available α‐bromomethyl ketones, 2‐aminopyridines and thiosulfonates. An immense array of 3‐sulfenylimidazo[1,2‐a]pyridines were obtained in good to high yields. Also, the method extended for the synthesis of C3‐halogenated imidazo[1,2‐a]pyridines using sodium halides in the presence of K2S2O8. Notably, the reaction between α‐bromomethyl ketones and 2‐aminopyridines in the presence of K2S2O8 to yield 3‐bromo‐2‐aryl‐imidazo[1,2‐a]pyridines, thus implies α‐bromomethyl ketones also served as brominating agent. Overall, the present sequential one‐pot protocol is straightforward, operationally simple, tolerates a broad range of functional groups, and is reliable for gram‐scale experiments.
Process mass intensity (PMI) is a key mass-based metric to evaluate the green credentials of an individual or sequence of reactions during process and chemical development. The increasing awareness to consider greenness already at the initial discovery level, requires a set of parameters suitable to assess it at this stage of development, and guidelines to apply them correctly. This paper evaluates when and how PMI can be used in a correct manner. Different simulations for key reactions in the organic synthesis toolbox - i.e. amide bond formation and Mitsunobu reactions – illustrate that PMI can be easily misleading without a due consideration of yield, concentration and molecular weight of reactants and product. A fair appraisal of the green potential of different methodologies therefore requires careful analysis of the examples and metrics data generated.
The synthetic strategies towards thiosulfonates (RSO2SR¹) are comprehensively reviewed from their original discovery to recent advances. Incorporation of the green credentials of the synthetic procedures towards thiosulfonates allows one to judge the merits of the state of the art, beyond the typical yield of a product and availability of the reactants. As reactant for organic transformations, thiosulfonates are particularly interesting given their possibility to react with nucleophiles, electrophiles and radicals. This review aims to give researchers, not familiar with the field, a good understanding of the general applications of thiosulfonates, while not skipping the recent important advances. The related, but less explored, selenosulfonates (RSO2SeR¹) are also covered.
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Copper acetate mediated regioselective ortho-arylthiolation of 2-aryl pyridines has been accomplished for the first time using S-aryl arenesulfonothioate as the arythiolating agent. Reaction shows good functional group tolerance and gives thioarylated products in 67-89% yields. This reagent is a good alternative of the unpleasant smelling arylthiols. Experimental evidences suggest an unprecedented insertion of arylthio unit from both the parts of the reagent (SPh and p-TolSO2) in the presence of copper acetate. Indoles and imidazopyridines also undergo facile reaction at C-3 position, and furnish thioarylated derivates in good yields.
A Copper‐catalyzed reaction of aryl isocyanides with active methylene isocyanides and arylsulfonothioates is developed for the synthesis of sulfur‐containing trisubstituted imidazoles. This reaction not only forms new C−C, C−N, and C−S bonds in one step, but also provides a new strategy for the construction of trisubstituted imidazoles based on the isocyanide‐isocyanide [3+2] cycloaddition.
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A nickel-catalyzed defluorinative reductive cross-coupling of gem-difluoroalkenes with thiosulfonate or selenosulfonates is described. The reaction involves the formation of thiolated or selenylated monofluoroolefins via regio-selective C-F bond cleavage and C-S or C-Se bond formation and features easily available substrates, mild reaction conditions and high E-selectivity. One of the derivatives by further cross coupling with PhMgBr exhibited aggregation induced emission (AIE) enhancementeffect.
A new multicomponent reaction has been developed between isocyanides, sulfur and alcohols or thiols under mild reaction conditions to afford O-thiocarbamates and dithiocarbamates in moderate to good yields. The one-pot reaction cascade involves the formation of an isothiocyanate intermediate, thus a catalyst-free synthesis of isothiocyanates, as valuable building blocks from isocyanides and sulfur is proposed, as well. The synthetic procedure suits the demand of a modern organic chemist, as it tolerates a wide range of functional groups, it is atom economic and easily scalable.
Hexyltriphenylphosphonium bromide (HTPB) is used as an efficient ionic liquid catalyst in the chemoselective addition of malononitrile to carbonyl group moiety of chalcones through the three‐component reaction of aryl aldehydes, acetophenone derivatves, and malononitrile to produce (E)‐2‐(1,3‐diarylallylidene)malononitriles at ambient temperature. The method is simple, solvent‐free, environmentally friendly, and gives excellent yields in a short reaction times. image
An unprecedented reactivity of (E)‐β‐iodovinyl sulfones in the presence of NaOAc is reported. The (E)‐β‐iodovinyl sulfones were treated with NaOAc in DMSO/H2O to yield β‐keto sulfones in moderate to high yields. A novel oxidative difunctionalization of β‐iodovinyl sulfones with thiosulfonates and NaOAc in DMF has been developed. This metal‐free oxosulfenylation is an operationally simple to access a wide range of β‐keto thiosulfones (α‐thioaryl‐β‐keto sulfones) in moderate to high yields. The transformations were reliable at gram‐scale, thus illustrating its efficiency and practicality. A plausible mechanism for the protocol is also proposed.
From organosuperbases capable of base-catalyzing organic reactions, through versatile 'ligand-sets' for use in coordination chemistry, to fundamental entities in medicinal chemistry, guanidines are amongst the most interesting, attractive, valuable, and versatile organic molecules. Since the discovery of these compounds, synthetic chemists have developed new methodologies that are mainly based on multi-step and stoichiometric reactions. Despite the fact that these methodologies are still being used by the interested scientific and industrial communities, drawbacks such as the poor availability of precursors, low yields, and use and production of undesirable substances highlight the need for safe, simple and efficient syntheses of these entities. This review focuses on the metal-mediated catalytic addition of amines to carbodiimides as an atom-economical alternative to the classical synthesis.
S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H3 receptor (H3R) antagonists. Among them, four N-alkyl S-[3-(piperidin-1-yl)propyl]isothioureas 18, 19, 22, and 23 were found to exhibit potent and selective H3R antagonistic activities against in vitro human H3R, but were inactive against in vitro human H4R. Furthermore, three alkyl homologs 18-20 showed inactivity for histamine release in in vivo rat brain microdialysis, suggesting differences in antagonist affinities between species. In addition, in silico docking studies of N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea 19 and a shorter homolog 17 with human/rat H3Rs revealed that structural differences between the antagonist-docking cavities of rat and human H3Rs were likely caused by the Ala122/Val122 mutation.
Copper(I)-modified zeolites, especially CuI–USY, proved to be very efficient catalysts in multi-component reactions of epoxides with sodium azide and terminal alkynes. Such catalysts allow highly regio- and stereoselective syntheses ofhydroxymethylated triazoles. These heterogeneous, modified zeolites can easily be recovered and reused. Moreover, the cascade reaction was best performed in water at room temperature, rendering all the processes truly green. Detailed investigations revealed the role the CuI-modified zeolites play both during the epoxide ring-opening and cycloaddition steps.
Dinitrogen tetroxide was easily impregnated on activated charcoal to give a stable heterogeneous reagent (N2O4/charcoal). The chemoselective oxidation of sulfides to sulfoxides in the presence of different sensitive functional groups was achieved using this reagent in CH 2Cl2 at room temperature. Dialkyl sulfides were also selectively converted to their corresponding sulfoxides in the presence of diaryl or alkyl-aryl sulfides. Oxidation of disulfides to thiosulfonates without any over oxidation was also performed at room temperature by this system.
IntroductionFuransPyrrolesOxazolesIsoxazolesThiazolesImidazolesPyrazolesOxadiazoles and TriazolesTetrazolesBenzofurans and BenzimidazolesIndolesQuinolinesQuinoxalineAbbreviationsReferences
The copper-catalyzed sulfonylation of thiols was performed by using sodium sulfinates under an oxygen atmosphere. The procedure afforded thiosulfonates in good yields by using a CuI–Phen·H2O (Phen = 1,10-phenanthroline) catalyst and tolerated numerous combinations of arene- and alkanethiols with sodium sulfinates. Furthermore, it was found that the coupling of diaryl disulfides with sodium arylsulfinates proceeded in air and both sulfide groups on the disulfide were available.
Seit der Entdeckung der Ugi-Reaktion und ähnlicher Isocyanid- basierter Mehrkomponentenreaktionen sind Isocyanide wichtige Bausteine für die organische Synthese. In den letzten zehn Jahren fanden Isocyanide als vielseitige C1-Bausteine in der Palladiumkatalyse eine neue Anwendung. Palladiumkatalysierte Reaktionen, die unter Isocyanidinsertion ablaufen, bieten ein enormes Potenzial für die Synthese stickstoffhaltiger Feinchemikalien. In diesem Kurzaufsatz werden alle erzielten Erfolge auf diesem neu entstehenden Gebiet diskutiert.
A new synthetic approach to 4-aminopyrido[2,3-d]pyrimidines and 4-aminopyrido[3,2-d]pyrimidines based on palladium-catalyzed reaction of isocyanides with readily available N-(bromopyridyl)amidines is reported. The target heterocycles were obtained in generally good to excellent yield. For the two regioisomeric pyrimidopyrimidines, we compared our approach involving oxidative addition with the analogous C–H activation protocol because both methods have been reported for the synthesis of 4-aminoquinazolines. We found that the C–H activation protocol does not allow one to obtain the target pyridopyrimidines, but the imidoylative cross-coupling protocol provided a new entry to the synthesis of these medicinally important scaffolds.
A three‐component reaction involving isocyanides, o ‐alkynyltrifluoroacetanilides, and amines for the efficient synthesis of 2‐substituted 1 H ‐indole‐3‐carboxamidines has been developed. The reaction proceeds through intramolecular aminopalladation of alkynes activated by isocyanide‐ligated palladium(II) species. Dioxygen acts as the sole oxidant to regenerate the active palladium(II) species.
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AbstractA highly practical method to access unsymmetrical and symmetrical thiosulfonates in moderate to excellent yields has been developed through NBS‐promoted sulfenylation of sulfinates with disulfides. The present process enables the use of two RS in RSSR and shows broad functional group tolerance, which represents an atom‐economical and practical procedure for the synthesis of thiosulfonates. A plausible mechanism for the role of NBS as a promoter for the cleavage of disul?des generating N‐(organothio)succinimide that then undergos facile sulenylation with sulfinates is proposed.
AbstractA novel and efficient domino process has been developed for the synthesis of 1,4‐benzoxazepine derivatives from a range of readily accessible N‐tosylaziridines, 2‐iodophenols and isocyanides. This process involves the aziridine ring‐opening reaction with 2‐iodophenol, followed by a palladium‐catalyzed isocyanide‐insertion reaction. This regioselective and high‐yielding transformation could be extended to its application for the synthesis of natural products and biologically interesting heterocycles.
Cobalt(II) acetylacetonate‐catalyzed isocyanide insertion reactions with amines utilizing tert ‐butyl hydroperoxide (TBHP) as an oxidant under ultrasound conditions have been developed, which lead to the synthesis of ureas, thioureas, as well as 2‐aminobenzimidazoles, 2‐aminobenzothiazoles, and 2‐aminobenzoxazoles under the general reaction conditions in up to 96% yields, respectively. The intermediate amino methylidyneaminiums, initiated by cobalt(II) acetylacetonate‐catalyzed reactions of isocyanides with amines, could be easily trapped by different nucleophiles such as water, sulfur, and intramolecular nucleophilic functional groups. This method provides a simple, general and practical protocol for the divergent synthesis of ureas, thioureas and azaheterocycles.
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The reaction of aromatic or benzylic disulfides with 2.5 equiv of Selectfluor (TM) in acetonitrile/water (10:1) at room temperature efficiently produced the corresponding thiosulfonates. Conversely, the reaction of disulfides with 6.5 equiv of Selectfluor (TM) or thiosulfonates with 4.5 equiv of Selectfluor (TM) in refluxing acetonitrile/water (10:1) provided sulfonyl fluorides in high yields. Accufluor (TM) and FP-T300 (TM) are also effective in preparing sulfonyl fluorides from disulfides under the similar reaction conditions. Sulfonyl chlorides or sulfonyl bromides were effectively obtained from the reaction of disulfides with 6 equiv of either N-chlorosuccinimide or N-bromosuccinimide in acetonitrile/water (10:1) at room temperature. Some other electrophilic chlorinating or brominating reagents are also able to be used instead of N-chlorosuccinimide or N-bromosuccinimide for the syntheses of sulfonyl halides from disulfides. These reactions of disulfides with electrophilic halogenating reagents are convenient methods to prepare thiosulfonates and sulfonyl halides.
We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3-pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay (Ki =0.46 nM; Ki (zanamivir) =0.16 nM) and in the viral replication inhibition assay in cell culture at 10(-8) M. As part of this lead optimization, we now report a novel spirolactam that shows comparable inhibitory activity in the cell culture assay to that of our lead compound at 10(-7) M. The compound was discovered serendipitously during the attempted synthesis of the isothiourea derivative of the original candidate. The X-ray crystal structure of the spirolactam in complex with the N8 subtype neuraminidase offers insight into the mode of inhibition.
To find new H(+) /K(+) -ATPase inhibitors for the treatment of peptic ulcer disease, a series of novel N-aryl isothiourea derivatives were synthesized and their structures were identified by (1) H NMR and GC-MS. The effects of these compounds on inhibiting gastric acid secretion were evaluated by the guinea pig stomach mucous membrane study with pantoprazole magnesium as a positive control. The results showed that, of the 37 N-aryl isothiourea compounds synthesized, 20 compounds have comparable or stronger gastric acid inhibitory activities than that of pantoprazole magnesium. The quantitative structure-activity relationships (QSARs) of the N-aryl isothiourea compounds were also studied by comparative molecular field analysis (CoMFA) computation, and the model structure that was supposed to give more powerful bioactivities was finally predicted.
A robust and regioselective palladium-catalyzed intermolecular aerobic oxidative cyclization of 2-ethynylanilines with isocyanides to the synthesis of 4-halo-2-aminoquinolines is reported herein. The procedure constructs various 4-halo-2-aminoquinolines with moderate to excellent yields (47%-94%) and broad substrates scope. Furthermore, this process can be easily extended to synthesis of various 6H-indolo[2,3-b]quinolines via an intramolecular Buchwald-Hartwig cross-coupling reaction in two-step one-pot manner.
A series of new non-phosphine 1-(2-picolyl)-3-benzoylsubstituted-2-benzyl-2-thiopseudourea ligands 2a–2f have been synthesized in two steps from commercially available benzoyl chlorides. Treatment of these ligands with Pd(OAc)2 in a 1:1 molar ratio in dichloromethane (DCM) at room temperature provided convenient access to the corresponding N,N,O-tridentate palladium(II) complexes [Pd(OAc){ArCONHC(N(CH2Py)}SCH2C6H5] (Ar = C6H5 (3a); 4-F-C6H4 (3b); 4-Br-C6H4 (3c); 4-I-C6H4 (3d); 4-Me-C6H4 (3e); 3,4,5-(OMe)3-C6H2 (3f)) in almost quantitative yields. The new ligands and their palladium complexes were characterized by NMR, IR, ESIMS, and HRMS analysis. The molecular structure of complex 3c has been determined by X-ray single-crystal diffraction. These Pd(II) complexes have been used as catalysts for the Suzuki–Miyaura, Sonogashira, Heck and Hiyama cross-coupling reactions.
Dinitrogen tetroxide was easily impregnated on activated charcoal to give a stable heterogeneous reagent (N2O4/charcoal). The chemoselective oxidation of sulfides to sulfoxides in e presence of different sensitive functional groups was achieved using this reagent in CH2Cl2 at room temperature. Dialkyl sulfides were also selectively converted to their corresponding sulfoxides in the presence of diaryl or alkyl-aryl sulfides. Oxidation of disulfides to thiosulfonates without any over oxidation was also performed at room temperature by this system.
Thiosulfonates were prepared by the iodine oxidative sulfenylation of sulfinates with various disulfides in good yields both in the presence and absence of solvent. One of the important biological applications of sulfenylation is the reaction of cyclic disulfides.
Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-containing fine chemicals. This Minireview discusses all the achievements in this emerging field.
A novel strategy for de novo synthesis of pyridines was described featuring an unprecedented alpha-addition of aldehyde and enamide to isonitrile as a key step. Under mild conditions, cascade reactions initiated by Zn(OTf)2-promoted [1+5] cycloaddition of isonitriles with N-formylmethyl-substituted enamides, followed by facile aerobic oxidative aromatization and intermolecular acyl transfer from pyridinium nitrogen to 5-hydroxy and acylation of the 4-amino group by an external acyl chloride afforded efficiently 2-substituted 4-acylamino-5-acyloxypyridines in good to excellent yields.
An efficient palladium-catalyzed three-component reaction that combines aryl halides, isocyanides, and diamines provides access to 2-aryl-2-imidazolines in yields up to 96%. Through variation of the diamine component, the reaction can be extended to the synthesis of 2-aryl-1H-benzimidazoles and 2-aryl-1,4,5,6-tetrahydropyrimidines.
As valuable C1 building blocks, isocyanides represent an important class of reactive species and synthons. During the past decades, exhaustive efforts have been devoted to the discovery of highly efficient reactions involving isocyanide on the basis of the development of the Passerini and Ugi reactions. Several types of reactions involving isocyanides have been reported, such as nucleophilic attack, electrophilic addition, imidoylation reactions, and oxidation etc. In this review, recent progress in isocyanide insertion chemistry is presented. Among all isocyanide insertions, two catalytic systems have been developed, that is, Lewis (Brønsted) acid-catalyzed isocyanide insertions and transition-metal-enabled isocyanide insertions, respectively. This review is hence written in the sequence of Lewis (Brønsted) acid-catalyzed isocyanide insertion and transitional metal-enabled isocyanide insertion, where isocyanide insertion into heteroatom-hydrogen bonds, carbon-halogen bonds, carbon-hydrogen bonds, and metal carbenes are summarized.
Isocyanides possess a rich history in the world of synthetic chemistry. Recently the scope of this already versatile class of reagent has been expanded into its use in palladium-catalysed cascade sequences. The scope of this type of reaction is explored in depth and this tutorial review focuses on its various applications in chemical synthesis, and the wide range of systems that can be efficiently prepared using this strategy are documented.
A convenient one-pot palladium-catalyzed cascade process for the preparation of both benzoxazoles and benzothiazoles has been developed. While these reactions proceed to give similar compounds the mechanisms governing the processes are different as are the experimental conditions employed.
Heterocycles containing a guanidine moiety are of great importance in medicinal chemistry (Scheme 1).[1] As a result, several methods for the synthesis of these "privileged scaffolds" have been reported.[2, 3] Classical approaches, such as the addition of diamines to isothiocyanates followed by condensation and the coupling of diamines with cyanogen bromide,[2, 4] have some clear limitations, such as the availability and toxicity of reagents. Moreover, these procedures suffer from poor atom and/or step efficiency, thus making them unattractive from a sustainability point of view.
Selective oxidation of thiols to disulfides (RSSR) was performed by using catalytic amounts of dinitrogen tetroxide/charcoal in chloroform at r.t. while the reaction of thiols with four molar equivalents of the reagent in dichloromethane afforded thiosulfonates (RSO 2 SR) with excellent yields.
We report a tin-free one-pot radical approach to the synthesis of N-acyl isothioureas and acylguanidines from N-acyl cyanamides. Photoactivated reduction of aromatic disulfides in the presence of Hünig's base results in hydrothiolation of the cyanamide moiety, followed by spontaneous 1,3-migration of the acyl group. Onward reaction of the isothioureas obtained with amines led to the corresponding N-acylguanidines, where the acyl group is attached to the nitrogen atom formerly at the cyano-end of the starting material.
Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong organic bases however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in organic synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalysing aldol reactions, Morita-Baylis-Hillman reactions, conjugate additions, carbonylations, methylations, silylations, and brominations.
Although several recent reviews dealt with transition metal catalyzed N-arylation of amines (all classes), to date no specific review covering the N-arylation of amidines and guanidines appeared. Amidines and guanidines are considered as fundamental entities in medicinal chemistry. The appearance of these functional groups in drugs, agrochemicals and natural products justifies a separate description of the current status of the literature on the N-arylation of the amidine and guanidine functionalities. Both acyclic and cyclic derivatives are taken into account. For cyclic amidines/guanidines only systems which possess an exocyclic nitrogen atom are considered. This critical review is largely organized by the type of amidine/guanidine and transition metal used and covers literature up to May 2011 (200 references).
Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.
The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.
The aim of this study was to establish the antimicrobial activities of S-(3,4-dichlorobenzyl)isothiourea hydrochloride (A22) and a series of structurally related compounds against multidrug-resistant (MDR) bacteria. The minimum inhibitory concentrations (MICs) of 21 compounds were determined against 18 strains of pathogenic bacteria in addition to Pseudomonas aeruginosa (n=19) and Burkholderia cepacia complex (BCC) (n=20) isolated from the sputa of cystic fibrosis patients. Selected compounds were tested against further isolates, including P. aeruginosa (n=100), BCC (n=12) and Stenotrophomonas maltophilia (n=19). The interaction of S-(4-chlorobenzyl)isothiourea hydrochloride (C2) in combination with conventional antimicrobials was examined against 10 P. aeruginosa strains. Selected compounds were also tested against Enterobacteriaceae producing NDM-1 carbapenemase (n=64) and meticillin-resistant Staphylococcus aureus (MRSA) (n=37). Of the 21 compounds, 14 showed antimicrobial activity that was generally more pronounced against Gram-negative bacteria. Against P. aeruginosa, the most active compound was C2 [MIC for 50% of the organisms (MIC(50))=32μg/mL]. This compound was also the most active against BCC, with all isolates inhibited by 64μg/mL. For all ten strains of P. aeruginosa subjected to combination testing with C2 and conventional antimicrobials, a bactericidal effect was achieved with at least one combination. C2 and A22 both showed strong activity [MIC for 90% of the organisms (MIC(90))=4μg/mL] against Enterobacteriaceae that produced NDM-1 carbapenemase. Finally, S-(4-chlorobenzyl)-N-(2,4-dichlorophenyl)isothiourea hydrochloride showed good activity (MIC(90)=8μg/mL) against MRSA. This work establishes the activity of isothiourea derivatives against a broad range of clinically important MDR bacteria.
Arynes, generated from trimethylsilyl phenyltriflate precursors, have been found to react with thioureas via a formal π-insertion into the C═S bond. The reaction contrasts with that of ureas, which proceeds via benzyne σ-insertion into the C-N bond, and represents a new, operationally simple route to functionalized amidines.
The sphingolipid bases, D-erythro- and D-threo-sphingosines, are the target molecules that have been synthesized to demonstrate the efficiency of a new methodology to control both absolute and relative configurations in acyclic systems. Tubulysins are compounds of extraordinary potency, rapidly degrading the tubulin cytoskeleton, with tubulysin D being the most active tubulin-modifier known so far. Among other isonitriles, isocyanoacetate derivatives occupy an important place in the field of synthetic application and reaction diversity, which makes them strongly attractive objects for investigation. The unique multifunctional nature of isocyanoacetic acid derivatives opens up a range of exciting reactions, especially tandem/cascade processes for the synthesis of complex cyclic and macrocyclic systems. Multicomponent chemistry of isocyanoacetates is also a powerful instrument to access different classes of biochemically relevant compounds such as peptides, peptide molecules, and nitrogen heterocycles.
Azido-functionalized analogs of potently sweet guanidinoacetic acids have been synthesized for use as sweetener receptor photoaffinity labeling reagents. These compounds have been synthesized using readily available starting materials. One of the azido-labeled guanidinoacetic acids has been evaluated in an electrophysiological model in the Rhesus monkey. We found that the photoaffinity-labeling reagent caused irreversible inhibition in electrophysiological response to sweeteners upon exposure of the monkey tongue to a combination of the reagent and UV light.
A series of 2-substituted sulfanyl-3,5-dihydro-imidazole-4-ones and 2-substituted sulfanyl-1H-imidazole-4,5-diones was prepared and shown to increase high density lipoprotein cholesterol over other lipid fractions. Compound 1f showed efficacy in additional animal models. The major metabolite of 1f was isolated and its synthesis is reported. The effects of the metabolite on the lipid profile in rats were investigated.
[reaction: see text] A facile conversion of formamides to isonitriles under very mild conditions and microwave irradiation is described. This simple and efficient method has been applied for the synthesis of both aliphatic and aromatic isonitriles in high yields.
The Brønsted acid catalyzed formal insertion of an isocyanide into a C-O bond of an acetal is described. A diverse array of acyclic and cyclic acetals can be applied to the catalytic insertion to form alpha-alkoxy imidates. Functional groups, such as nitro, cyano, halogen, ester, and alkoxy groups, are tolerant to the reaction conditions employed. The course of the reaction is highly dependent on the structure of the isocyanide. The use of an electron-deficient aryl isocyanide, such as 2c and 2d, is required to selectively obtain the monoinsertion product. When aryl isocyanides containing alkyl substituents, such as 2a and 2b, are employed, two molecules of the isocyanide are incorporated, and the double-insertion product is obtained. The reaction of tert-octyl isocyanide also induces a double incorporation, but the subsequent acid-mediated fragmentation leads to the 2-alkoxy imidoyl cyanide. The monoinsertion products, alpha-alkoxy imidates, can readily be hydrolyzed to alpha-alkoxy esters, realizing the formal carbonylation of an acetal.
- Qiu
- Katritzky