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- Organosilver chemistry
- Silver and gold-catalyzed multicomponent reactions
Deakyne, and Silvia S. Inorganic Chemistry , 55 , The Journal of Organic Chemistry , 82 , Tetrahedron , Jones and Michael Harmata. Organic Letters , — Tetrahedron Letters , 56 , The Journal of Organic Chemistry , , 80 , — The Journal of Organic Chemistry , , 81 , Advanced Synthesis and Catalysis , , Altenhofer and Michael Harmata. The Journal of Organic Chemistry , 80 , — Carissa S.
Carbohydrate Research , , Organic Letters , 16 , — Hampton, Erich F. Chemistry A European Journal , 20 , — Organic Letters , 16 , Schreiner, and Michael Harmata. Thomas, Jack R. Wass, Michael Harmata and Daniel A. Journal of the American Chemical Society , , A Synthesis of Pseudopteroxazole.
Organic Letters , 8 , Journal of the American Chemical Society , , , Fletcher and R. Claassen II. Skip to main content. Michael Harmata. Rabjohn Distinguished Professor of Chemistry. HarmataM missouri. Harmata Group Homepage. Curriculum Vitae. Research Emphasis:. Professional Experience:. National Chemistry Week, Scheme Synthesis of 2-aminopyrazolo[5,1- a ]isoquinolines Scheme Synthesis of 1- isoquinolinyl guanidines Further intramolecular rearrangement yields the desired 1- isoquinolinyl guanidine The overall process proceeds efficiently to generate the 2-amino- H -pyrazolo[5,1- a ]isoquinolines 58 in moderate to excellent yields under mild conditions and with good substrate tolerance.
Cycloaddition reactions of activated cyclopropanes with nitrones under Lewis acid catalysis have been previously described by Kerr and may proceed on the activated cyclopropane by a stepwise or concerted mechanism . Similar mechanisms could be also operative in the reaction of ylidic species 43 for the synthesis of Good substrate tolerance and moderate to excellent yields are reported.
We focus on Mannich-type reactions characterized by the addition of a nucleophile to an imine.
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In several MCRs with this type of reactivity, silver I salts and complexes have been used to activate either the nucleophile or the imine. Isocyanides have been found to be versatile reagents in heterocyclic synthesis [82,83]. The scope of these reactions could be extended to isocyanides with other substituents by using methanol as a solvent. Scheme Synthesis of dihydroimidazoles The reaction occurs via a Mannich-type addition of the deprotonated isocyanide intermediate 64 to an in situ generated iminium salt, a subsequent intramolecular cyclization and proton shift results in dihydroimidazole 65 showing predominantly cis -arrangment around the C4—C5 bond.
Additionally, the use of sterically demanding amines results in lower yields. The reaction proceeds through the formation of iminium ion 67 . The isocyanide carbon atom is sufficiently nucleophilic to attack iminium ion Scheme Synthesis of oxazoles The reaction proceeds in the presence of amino acid-based chiral phosphine ligands and AgOAc via bidentate chelation of a properly substituted aldimine. Chiral phosphine—silver I complexes are emerging as a valuable tool for carbon—carbon bond forming reactions. These catalysts are effective in promoting enantioselective allylations, aldol reactions, Mannich-type reactions, hetero Diels—Alder reactions, 1,3-dipolar cycloadditions and nitroso aldol reactions .
The process was firstly accomplished with preformed aryl-substituted aldimines  and then developed as a MCR for less stable alkyl-substituted aldimines, which were prepared in situ from arylamines 72 and alkylaldehydes 73 to avoid decomposition . Scheme Stereoselective synthesis of chiral butenolides The two main features of the reported three-component Ag-catalyzed process are i the mild reaction conditions and ii the high degree of diastereo- and enantioselectivity.
Moreover, the N -aryl group can be easily removed from the final compounds under oxidative conditions yielding the corresponding amino compounds. An OMe substituent is essential as a directing group for aryl-substituted aldimines. The substrate is bound anti to the bulky amino acid substituent R and reacts with the siloxyfuran via endo -type addition. Intramolecular silyl transfer, iPrOH mediated desilylation of the amide terminus, and protonation of the N—Ag bond delivers the final product and the catalyst.
Such a pathway is not allowed for the siloxyfuran bearing a methyl group in position 3, which reacts by an exo addition. Alkyl-substituted aldimines can also participate in these reactions. However, they must be generated in situ MCR. In the latter reactions, best results were obtained when arylamines 72 bear an o -thiomethyl and a p -methoxy substituent instead of a single o -methoxy substituent. The corresponding electron-rich aldimines are less electrophilic and subsequently more stable under the reported reaction conditions. Scheme Proposed reaction mechanism for the synthesis of butenolides Two more examples of enantioselective reactions involving silver catalysts have been recently reported.
However, the adopted method to induce chirality in the final products is rather dissimilar. Scheme Stereoselective three-component approach to pirrolidines 77 by means of a chiral auxiliary. On the one hand, as an electron withdrawing group, it decreases the nucleophilicity of the amine, thus avoiding the formation of detrimental Michael-type adducts with the alkene.
Moreover, as a chiral auxiliary it promotes the cycloaddition governing the stereochemistry of the process. The chiral auxiliary can be removed at the end of the reaction. The reaction was developed mainly as a two-component reaction and only two examples of MC approaches have been included in the manuscript. The reported examples involve hetero aryl aldehydes 77 , methyl glycinate 78 and maleimide 79 or E -1,2-bis phenylsulfonyl ethylene 80 as electrophilic alkenes.
Scheme Stereoselective three-component approach to pyrrolidines 81 and 82 by means of a chiral catalyst. The reported work is an extension of a previous paper dealing with the use of BINAP—AgClO 4 as a chiral catalyst in the same two-component reaction . An interesting application of silver catalysis in the allene chemistry field has been recently proposed by Jia and co-workers .
Thus, they believed that new cycloaddition reactions could be accessed if isocyanide was employed as a nucleophile instead of phosphine. Scheme Synthesis of substituted five-membered carbocyles This behavior originates from the involvement of the isocyanide in the cyclization step. Reactions involving organosilver reagents. Information about organosilver compound chemistry with respect to the coordination chemistry of silver salts and complexes is scarce in the literature. This could be related to the lower stability of these compounds, increasing in the order C sp3 —Ag, C sp2 —Ag, C sp —Ag, compared to other organometallic compounds.
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The majority of the screened literature discusses the use of organosilver compounds as reagents. A recent review on organosilver compounds by Pouwer and Williams exhaustively highlights all these aspects of silver chemistry . For example, functionalized propiolic acids can be selectively prepared by an AgI catalyzed carboxylation of terminal alkynes with CO 2 under ligand free conditions with the intermediacy of an organosilver compound, namely silver acetilide C sp —Ag .
The direct carboxylation of active C—H bonds of hetero arenes  and terminal alkynes  with CO 2 in the presence of copper or gold-based catalysts has also been reported. However, these latter transformations require expensive ligands and often harsh bases, whereas the silver-mediated process depends on a simple but efficient catalyst such as AgI and Cs 2 CO 3 as base. In the reaction sequence a 1,6-diyne was generated in situ and cyclized to afford the two possible regioisomeric compounds.
The level of regioselectivity can be enhanced by the tuning of electronic properties of the reactant species. The latter approach was successfully adopted for the preparation of dehydrodimethylconidendrin and dehydrodimethylretroconidendrin. Scheme Synthesis of regioisomeric arylnaphthalene lactones. In gold I and gold III -catalyzed reactions the metal acts as a carbophilic Lewis acid, facilitating nucleophilic addition to unsaturated systems.
Moreover, also the oxophilic character of gold species has been highlighted by several authors. More recently, gold-promoted transformations involving higher oxidation states from Au I precatalysts have been achieved by the addition of a stoichiometric oxidant enabling two-electron redox cycles typically exhibited by other late transition metals. With respect to Ag I -mediated MCRs, less information can be found in the literature about the corresponding gold-mediated processes. Thus, major research efforts have been directed to the development of tandem, sequential or cascade reactions and to the area of asymmetric transformations.
As reported for silver, this part of the review is divided in sections relating to the nature of the activated functionalities. Reactions involving the activation of carbon—carbon multiple bonds. The reactions take advantage from the high functional group tolerance and from the generally mild reaction conditions.
These are the first examples of an intermolecular catalytic asymmetric synthesis of spiroacetals. Previously reported methodologies involved preformed substrates in intramolecular reactions .
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Scheme Enantioselective synthesis of spiroacetals by Gong . The condensation reaction between glyoxylic acid 93 and aniline gives rise to imine 94 which, by double interaction with the gold phosphate, leads to an activated species. Subsequent nucleophilic addition of 92 to 94 gives oxonium intermediate 95 , which provides the final product 96 upon cyclization regenerating the catalyst. Interestingly, in the first catalytic cycle the main role of the catalyst is played by its cationic part, the gold I ion, being responsible for the activation of the alkynol Meanwhile, in the second catalytic cycle, the main role is played by the anionic part of the catalyst, the phosphate, creating the appropriate chiral environment to produce the final enantioenriched product.
The key feature is the formation of a double hydrogen-bonded complex in which only the si face is fully accessible for the enol ether attack to afford the final cyclization product The key step of the sequence is again the addition of an enol ether to an imine followed by an intramolecular cyclization reaction. The enol ether 98 is generated from ortho -alkynylbenzyl alcohol 97 under gold catalysis, and the imine from salicylaldehyde 99 and aniline.
The MC synthesis of bi- and tricyclic ketals and takes advantage from a mechanism involving the oxyauration of a carbon—carbon triple bond . Thus, starting from 4-acyl-1,6-diynes , H 2 O and alkanols, under AuCl 3 -catalysis, polyfunctionalized fused bicyclic ketals and bridged tricyclic ketals have been prepared with a high degree of regio- and diastereocontrol. Scheme Synthesis of polyfunctionalized fused bicyclic ketals and bridged tricyclic ketals The reaction course can be directed toward the formation of and by a fine-tuning of the reaction conditions.
Scheme Proposed reaction mechanism for the synthesis of ketals and Under the optimized reaction conditions mentioned above, a double oxyauration reaction leads to intermediate I. The addition of water then results in the formal hydration of I affording dicarbonyl compound II. The subsequent addition of alcohol and the hydrochloric acid release affords the intermediate auric complex III , from which cyclic ketals and are formed by the inter- or intramolecular addition of alcohol, respectively.
The proposed reaction mechanism also accounts for the high degree of diastereoselectivity, which can be rationalized by a series of intramolecular chiral inductions. The initial steps of the MCR encompass the Au I -catalyzed hydration of the alkyne to give the ketone and the conversion of the aldehyde to the corresponding acetal The authors reported a nice investigation of the involved reaction mechanism and carried out a catalytic screening devoted to the selection of the best catalytic system and optimal reaction conditions. Newly reported examples of gold-catalyzed multicomponent reactions encompass the synthesis of nitrogen containing heterocycles, namely N -substituted 1,4-dihydropyridines  and tetrahydrocarbazoles .
The first example takes advantage of the ability of a cationic gold I catalyst to promote the formation of a new C—N bond through the hydroamination of a carbon—carbon triple bond. The three-component reaction includes methanamine , activated alkynes and aldehydes as reactants, a cationic gold I complex generated in situ from triphenylphosphine gold chloride and silver triflate as a catalyst, and KHCO 3 as base.
Scheme Synthesis of N -methyl-1,4-dihydropyridines Methyl butynoate and 1,3-diphenylpropynone were tested as alkynylic counterparts. A tentative mechanistic explanation for the formation of compounds was proposed by the authors. The overall process closely reminds of a modified Hantzsch synthesis of dihydropyridines.
However, they have been employed in a MC process only recently . Scheme Synthesis of tetrahydrocarbazoles — Interestingly, a change of the catalyst to [Au JohnPhos NTf 2 ] under similar reaction conditions afforded the isomeric tetrahydrocarbazoles as the only diastereoisomer. As expected, the formation of multicomponent cycloadducts was favored by using an excess of the allene 2. Various experiments showed that both and arise from compound In contrast, starting from the use of [Au JohnPhos NTf 2 ] as a catalyst in the presence of the allene 1.
Interestingly, vinylindole , independently prepared, could not be converted into — under optimized reaction conditions, pointing out that the cyclization occurred through the proposed intermediate I. Scheme Plausible reaction mechanism for the synthesis of tetrahydrocarbazoles — Scheme Carboamination, carboalkoxylation and carbolactonization of terminal alkenes. The same concept has been extended to the MC heteroarylation of alkenes. Toste reported the fully intermolecular alkene heteroarylation by a gold-catalyzed three-component coupling reaction of alkenes , arylboronic acids , and several types of oxygen nucleophiles , including alcohols, carboxylic acids, and water .
The reaction employs a binuclear gold I bromide as a catalyst and the Selectfluor reagent as the stoichiometric oxidant. Scheme Oxyarylation of alkenes with arylboronic acids and Selectfluor as reoxidant. Ligand and halide effects play a dramatic role in the development of a mild catalytic system for the addition to alkenes.
The catalyst choice is a consequence of the screening, comparing the activity of simple Ph 3 PAuX complexes and bimetallic gold complexes, accomplished by the same authors in a related two-component process . Scheme Proposed reaction mechanism for oxyarylation of alkenes. The first step of the catalytic cycle involves the oxidation of Au I into Au III , which is the effective catalyst for the oxyauration step giving rise to the alkylgold III fluoride intermediate I. Then, the reaction of the boronic acid with intermediate I affords the desired final compounds with the release of fluoroboronate and the restoration of the catalyst by reductive elimination.
The authors proposed a synchronized mechanism for this step, which involves the five-centered transition state II. Under the reported conditions the formation of homocoupling side products of boronic acids can be reduced. Scheme Oxyarylation of alkenes with arylsilanes and Selectfluor as reoxidant. More recently, Russell and Lloyd-Jones expanded the scope of these reactions to more challenging substrates such as styrenes and gem -disubstituted olefins, which are unreactive under the Selectfluor-based methodology reported above . Scheme Oxyarylation of alkenes with arylsilanes and IBA as reoxidant.
The role of the acidic additive is unclear. However, the authors hinted at the in situ formation of a more electrophilic and soluble IBA-Ts oxidant. A solvent screening was carried out, and the scope of the reaction with monosubstituted, gem -disubstituted olefins and styrenes was carefully investigated. The development of multicomponent processes is a continuously growing research area. However, the practical and industrial importance of A 3 -coupling reactions fostered the efforts of many researchers.
Other classes of silver and gold catalyzed MCRs are described and studied to a lesser extent and are often the transposition of domino reactions to multicomponent processes. Both metals ideally include all the essential features required for a catalyst devoted to control multifaceted transformations such as MCRs.
For example, the high affinity of silver and gold catalysts for unsaturated carbon systems e. Au and Ag catalyzed cycloadditions itself are fields in continuous development, especially for those reactions that involve non-activated unsaturated systems. In this particular area the development of new chiral catalysts often allows to perform cycloaddition reactions in a stereocontrolled fashion. Finally, of utmost importance in the chemistry of silver and gold complexes is the possibility to control the reactivity and the properties of the metal by ligand or counterion variations.
All these statements are supported by literature data and, in particular, by two topical and outstanding books, which deeply cover the chemistry of these metals [,]. Thomas J. Mohammad Haji.
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Silver and gold-catalyzed multicomponent reactions
Jump to Scheme 9. Jump to Scheme Jump to Figure 2. Synlett , — Tetrahedron , 64, — Organometallics , 28, — Tetrahedron , 69, — Silver-Catalyzed Cycloisomerization Reactions. Tetrahedron , 67, — Synthesis , — Tetrahedron , 55, — Synlett , 24, — Nature , , — Silver in Organic Chemistry; Wiley: Hoboken, Return to citation in text: [ 1 ]. Reference References 86, References 82, References , References 90, Reference 1.