Showing papers on "Nucleophile published in 2008"

Metal-catalyzed enantioselective allylation in asymmetric synthesis.

Abstract: Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.

Copper/amino acid catalyzed cross-couplings of aryl and vinyl halides with nucleophiles.

Abstract: Copper-assisted Ullmann-type coupling reactions are valuable transformations for organic synthesis. Researchers have extensively applied these reactions in both academic and industrial settings. However, two important issues, the high reaction temperatures (normally above 150 °C) and the stoichiometric amounts of copper necessary, have greatly limited the reaction scope. To solve these problems, we and other groups have recently explored the use of special ligands to promote these coupling reactions. We first showed that the structure of α-amino acids can accelerate Cu-assisted Ullmann reactions, leading to the coupling reactions of aryl halides and α-amino acids at 80−90 °C. In response to these encouraging results, we also discovered that an l-proline ligand facilitated the following transformations: (1) coupling of aryl halides with primary amines, cyclic secondary amines, and N-containing heterocycles at 40−90 °C; (2) coupling of aryl halides with sulfinic acid salts at 80−95 °C; (3) azidation of aryl...

Recent advances in carbon–carbon bond-forming reactions involving homoenolates generated by NHC catalysis

Abstract: Homoenolate, a species containing anionic carbon β to a carbonyl group or a moiety that can be transformed into a carbonyl group, is a potential three carbon synthon. Recent introduction of a protocol for the generation of homoenolate directly from enals by NHC (nucleophilic heterocyclic carbene) catalysis has made it possible to explore the synthetic utility of this unique reactive intermediate. The versatility of NHC-bound homoenolate is illustrated by its annulation with various carbonyl compounds leading to γ-butyrolactones, spiro-γ-butyrolactones, and δ-lactones. Interception of homoenolate with imines afforded γ-lactams and bicyclic β-lactams. Formation of cyclopentenes and spirocyclopentanones respectively by reaction with enones and dienones is also noteworthy. This tutorial review focuses on these and other types of reactions which attest to the synthetic potential of NHC-bound homoenolates in organic synthesis.

Preparation, Structure, and Reactivity of Nonstabilized Organoiron Compounds. Implications for Iron-Catalyzed Cross Coupling Reactions

Abstract: A series of unprecedented organoiron complexes of the formal oxidation states −2, 0, +1, +2, and +3 is presented, which are largely devoid of stabilizing ligands and, in part, also electronically unsaturated (14-, 16-, 17- and 18-electron counts). Specifically, it is shown that nucleophiles unable to undergo β-hydride elimination, such as MeLi, PhLi, or PhMgBr, rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate the metal center. The resulting homoleptic organoferrate complexes [(Me4Fe)(MeLi)][Li(OEt2)]2 (3) and [Ph4Fe][Li(Et2O)2][Li(1,4-dioxane)] (5) could be characterized by X-ray crystal structure analysis. However, these exceptionally sensitive compounds turned out to be only moderately nucleophilic, transferring their organic ligands to activated electrophiles only, while being unable to alkylate (hetero)aryl halides unless they are very electron deficient. In striking contrast, Grignard reagents bearing alkyl residues amenable to β-hydride elimination reduce FeXn (n = 2, 3) to clusters of...

Novel syntheses of azetidines and azetidinones.

Abstract: 2.1.5. Electrophilic Attack on CdC 3994 2.1.6. NH Insertions in Diazo Compounds 3994 2.1.7. Pd Catalyzed Cyclizations 3994 2.2. Cyclizations by C-C Bond formation 3995 2.2.1. Nucleophilic Displacement of Halides 3995 2.2.2. Cyclizations Involving CdO Group 3995 2.3. Cycloadditions 3996 2.4. Ring Rearrangements 3997 2.4.1. Rearrangements of Four-Membered Rings 3997 2.4.2. Rearrangements of Larger Rings 3998 2.5. Reduction of Azetidin-2-ones 3998 2.6. Miscellaneous Syntheses 3999 2.7. Important Classes of Compounds 4000 2.7.1. Natural Products 4000 2.7.2. Azetidine Carboxylic Acids 4001 2.7.3. Exomethylene Azetidines 4002 2.7.4. Ligands for Metal-Catalyzed Reactions and Chiral Auxiliaries 4003

Electronic design criteria for O-O bond formation via metal-oxo complexes.

Abstract: Metal-oxos are critical intermediates for the management of oxygen and its activation. The reactivity of the metal-oxo is central to the formation of O-O bonds, which is the essential step for oxygen generation. Two basic strategies for the formation of O-O bonds at metal-oxo active sites are presented. The acid-base (AB) strategy involves the attack of a nucleophilic oxygen species (e.g., hydroxide) on an electrophilic metal-oxo. Here, active-site designs must incorporate the assembly of a hydroxide (or water) proximate to a high-valent metal-oxo of even d electron count. For the radical coupling (RC) strategy, two high-valent metal-oxos of an odd d electron count are needed to drive O-O coupling. This Forum Article focuses on the different electronic structures of terminal metal-oxos that support AB and RC strategies and the design of ligand scaffolds that engender these electronic structures.

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

Abstract: The covalent binding of complement components C3 and C4 is critical for their activities. This reaction is made possible by the presence of an internal thioester in the native protein. Upon activation, which involves a conformational change initiated by the cleavage of a single peptide bond, the thioester becomes available to react with molecules with nucleophilic groups. This description is probably sufficient to account for the binding of the C4A isotype of human C4 to amino nucleophiles. The binding of the C4B isotype, and most likely C3, to hydroxyl nucleophiles, however, involves a histidine residue, which attacks the thioester to form an intramolecular acyl-imidazole bond. The released thiolate anion then acts as a base to catalyze the binding of hydroxyl nucleophiles, including water, to the acyl function. This mechanism allows the complement proteins to bind to the hydroxyl groups of carbohydrates found on all biological surfaces, including the components of bacterial cell walls. In addition, the fast hydrolysis of the thioester provides a means to contain this very damaging reaction to the immediate proximity of the site of activation.

Ylide-initiated michael addition-cyclization reactions beyond cyclopropanes.

Abstract: Ylides are nucleophiles that bear a unique leaving group, LnM, and can attack aldehydes, ketones, imines, and electron-deficient alkenes. Over the course of the reaction, they react with C═X (X = C, N, O, etc.) double bonds to form betaine or oxetane intermediates, which further eliminate the heteroatom-containing group in one of two ways to give the corresponding olefination or cyclization product. Since the discovery of the Wittig reaction, ylide olefination has developed as one of the most useful approaches in constructing carbon−carbon double bonds. These reactions provide unambiguous positioning of the C−C double bond and good stereoselectivity. Researchers have also widely used ylides for the synthesis of small ring compounds such as epoxides, cyclopropanes, and aziridines. However, the use of ylides to prepare larger cyclic structures was very limited. This Account outlines our recent work on ylide-initiated Michael addition/cyclization reactions. By altering the heteroatoms and the ligands of the ...

Cooperative, highly enantioselective phosphinothiourea catalysis of imine-allene [3 + 2] cycloadditions.

Abstract: A new family of phosphinthiourea catalysts was developed for the highly enantioselective synthesis of 2-aryl-2,5-hydropyrroles via a [3 + 2] cycloaddition of an electron-deficient allene with aryl and heteroaryl diphenylphosphinoylimines. The presence of both H2O and Et3N as additives was found to be important for achieving optimal rates. Dual activation of both nucleophile and electrophile by the bifunctional catalyst is invoked to account for the observed high reactivity and enantioselectivity.

Carbon-nitrogen bond formation involving well-defined aryl-copper(III) complexes

Abstract: Carbon−heteroatom bond formation from copper(III) is commonly invoked as a key step in catalytic reactions, including the century-old Ullmann reactions. Well-defined examples of such reactions have never been observed. Here, we demonstrate that a well-defined Cu(III)−aryl species reacts with a variety nitrogen nucleophiles to undergo facile carbon−nitrogen bond formation.

Bifunctional Asymmetric Catalysis: Cooperative Lewis Acid/Base Systems

Abstract: In the field of catalytic, asymmetric synthesis, there is a growing emphasis on multifunctional systems, in which multiple parts of a catalyst or multiple catalysts work together to promote a specific reaction These efforts, in part, are result-driven, and they are also part of a movement toward emulating the efficiency and selectivity of nature’s catalysts, enzymes In this Account, we illustrate the importance of bifunctional catalytic methods, focusing on the cooperative action of Lewis acidic and Lewis basic catalysts by the simultaneous activation of both electrophilic and nucleophilic reaction partners For our part, we have contributed three separate bifunctional methods that combine achiral Lewis acids with chiral cinchona alkaloid nucleophiles, for example, benzoylquinine (BQ), to catalyze highly enantioselective cycloaddition reactions between ketene enolates and various electrophiles Each method requires a distinct Lewis acid to coordinate and activate the electrophile, which in turn increase

Scope and Mechanism for Lewis Acid-Catalyzed Cycloadditions of Aldehydes and Donor−Acceptor Cyclopropanes: Evidence for a Stereospecific Intimate Ion Pair Pathway

Abstract: In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted tetrahydrofurans via Lewis acid catalyzed [3 + 2] cycloadditions of donor-acceptor (D-A) cyclopropanes and aldehydes is described. The scope and limitations with respect to both reaction partners are provided. A detailed examination of the mechanism has been performed, including stereochemical analysis and electronic profiling of both reactants. Experimental evidence supports an unusual stereospecific intimate ion pair mechanism wherein the aldehyde functions as a nucleophile and malonate acts as the nucleofuge. The reaction proceeds with inversion at the cyclopropane donor site and allows absolute stereochemical information to be transferred to the products with high fidelity. The mechanism facilitates the stereospecific synthesis of a range of optically active tetrahydrofuran derivatives from enantioenriched D-A cyclopropanes.

Catalytic Intermolecular Linear Allylic C−H Amination via Heterobimetallic Catalysis

Abstract: A novel heterobimetallic Pd(II)sulfoxide/(salen)Cr(III)Cl-catalyzed intermolecular linear allylic C−H amination (LAA) is reported. This reaction directly converts densely functionalized α-olefin substrates (1 equiv) to linear (E)-allylic carbamates with good yields and outstanding regio- and stereoselectivities (>20:1). Chiral bis-homoallylic and homoallylic oxygen, nitrogen, and carbon substituted α-olefins undergo allylic C−H amination with good yields, excellent selectivities, and no erosion in enantiomeric purity. Streamlined routes to (E)-allylic carbamates that can be further elaborated to medicinally and biologically relevant allylic amines are also demonstrated. Valuable 15N-labeled allylic amines may be generated directly from allyl moieties at late stages of synthetic routes by using the readily available 15N-(methoxycarbonyl)-p-toluenesulfonamide nucleophile. Evidence is provided that this reaction proceeds via a heterobimetallic mechanism where Pd/sulfoxide mediates allylic C−H cleavage to for...

Enamides and Enecarbamates as Nucleophiles in Stereoselective C–C and C–N Bond-Forming Reactions

Abstract: Because the backbone of most of organic compounds is a carbon chain, carbon-carbon bond-forming reactions are among the most important reactions in organic synthesis. Many of the carbon-carbon bond-forming reactions so far reported rely on nucleophilic attack of enolates or their derivatives, because those nucleophiles can be, in general, readily prepared from the corresponding carbonyl compounds. In this Account, we summarize the recent development of reactions using enamide and enecarbamate as a novel type of nucleophile. Despite their ready availability and their intrinsic attraction as a synthetic tool that enables us to introduce a protected nitrogen functional group, enamide and enecarbamate have rarely been used as a nucleophile, since their nucleophilicity is low compared with the corresponding metal enolates and enamines. A characteristic of enamides and enecarbamates is that those bearing a hydrogen atom on nitrogen are relatively stable at room temperature, while enamines bearing a hydrogen atom on nitrogen are likely to tautomerize into the corresponding imine form. Enamides and enecarbamates can be purified by silica gel chromatography and kept for a long time without decomposition. During the investigation of nucleophilic addition reactions using enamides and enecarbamates, it has been revealed that enamides and enecarbamates bearing a hydrogen atom on nitrogen react actually as a nucleophile with relatively reactive electrophiles, such as glyoxylate, N-acylimino ester, N-acylimino phosphonate, and azodicarboxylate, in the presence of an appropriate Lewis acid catalyst. Those bearing no hydrogen atom on nitrogen did not react at all. The products initially obtained from the nucleophilic addition of enamides and enecarbamates are the corresponding N-protected imines, which can be readily transformed to important functional groups, such as ketones by hydrolysis and N-protected amines by reduction or nucleophilic alkylation. In the nucleophilic addition reactions of enamides and enecarbamates to aldehydes, it was unveiled that the reaction proceeds stereospecifically, that is, (E)-enecarbamate gave anti product and (Z)-enecarbamate afforded syn product with high diastereoselectivity (>97/3). This fact can be rationalized by consideration of a concerted reaction pathway via a hydrogen-involved cyclic six-membered ring transition state. In the addition reactions to N-acylimino phosphonates, much higher turnover frequency was observed when enamides and enecarbamates were used as a nucleophile than was observed when silicon enolates were used. When silicon enolates were used, the intermediates bearing a strong affinity for the catalyst inhibited catalyst turnover, resulting in low enantioslectivity because of the dominance of the uncatalyzed racemic pathway. In the case of nucleophilic addition of enamides and enecarbamate, however, a fast intramolecular hydrogen transfer from the enecarbamate nitrogen may prevent the intermediate from trapping the catalyst for a long time, to afford the product with a high enantioselectivity. In conclusion, enamides and enecarbamates, although originally employed as just N-analogues to silicon enolates, have emerged as remarkably useful nucleophiles in a variety of Lewis acid-catalyzed reactions.

Construction of Heterocyclesby the Strategic Use of Alkyne π-Activation in CatalyzedCascade Reactions

Abstract: This review highlights the synthesis of heterocycles via cascadereactions that involve the activation of an alkyne using carbophilicLewis acids. Primarily guided by the type of reactivity evolvingfrom the alkyne activation, such key steps are categorized as theaddition of simple heteroatom nucleophiles, intramolecular carboalkoxylations,addition of carbonyl nucleophiles, rearrangement of propargylicesters, and enyne cycloisomerizations. Additionally, the functionalizationof existing heterocycles is discussed. 1 Introduction 2 Functionalization of Existing Heterocycles 3 Synthesis of Heterocycles through Cyclization Reactions 3.1 Intramolecular Addition of Simple Heteroatom Nucleophiles 3.2 Intramolecular Carboalkoxylations and Carboaminations 3.3 Carbonyls and Imines as Nucleophiles 3.4 Propargylic Esters 3.5 Enyne Cycloisomerizations 4 Miscellaneous Reactions 5 Conclusions

Synthesis and structural characterization of stable organogold(I) compounds. Evidence for the mechanism of gold-catalyzed cyclizations.

Abstract: The vast majority of homogeneous Au-catalyzed reactions have exploited the propensity of Au to activate unsaturated carbon−carbon bonds as electrophiles. It is generally assumed that a nucleophile attacks a gold-activated carbon−carbon multiple bond to give an alkenyl Au intermediate, notwithstanding the fact that these intermediates are hitherto unknown. We have obtained room temperature stable γ-lactone gold(I) complexes through the reaction of cationic Au(I) reagents with allenoates, under mild conditions. The reactions of one such complex with electrophiles yielded the expected products of Au-catalyzed cyclizations. These results furnish experimental evidence for the mechanism of Au-catalyzed cyclizations.

Proline-catalysed Mannich reactions of acetaldehyde

Abstract: Traditionally, catalysts for organic chemical reactions have been either enzymes or metal complexes. But small organic molecules, known as organocatalysts, have recently burst on to the scene. Organocatalysts are effective in promoting in a wide range of useful transformations, including a carbon–carbon bond forming process known as the Mannich reaction. But frustratingly, these reactions have always failed when the simplest possible substrate, acetaldehyde, was used. Yang et al. have now filled this gap in the organocatalysis spectrum by establishing effective catalytic conditions for Mannich reactions with acetaldehyde. This greatly expands the chemical 'toolkit' of organic chemists, and will be especially useful for making chiral, biologically active compounds. Organocatalysts are useful in a wide range of useful transformations, including a carbon–carbon bond forming process known as the Mannich reaction. But these reactions always failed when the simplest possible substrate, acetaldehyde, was used. This paper has now filled this gap in the market by devising effective organocatalytic conditions for Mannich reactions with acetaldehyde, greatly expanding the chemical 'toolkit' of organic chemists. Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts that direct reactions to yield predominantly one chiral product, complementing enzymes and metal complexes1. For instance, the amino acid proline and its derivatives are useful for the catalytic activation of carbonyl compounds via nucleophilic enamine intermediates. Several important carbon–carbon bond-forming reactions, including the Mannich reaction, have been developed using this approach2, all of which are useful for making chiral, biologically relevant compounds. Remarkably, despite attempts3,4, the simplest of all nucleophiles, acetaldehyde, could not be used in this way. Here we show that acetaldehyde is a powerful nucleophile in asymmetric, proline-catalysed Mannich reactions with N-tert-butoxycarbonyl (N-Boc)-imines, yielding β-amino aldehydes with extremely high enantioselectivities—desirable products as drug intermediates and in the synthesis of other biologically active molecules. Although acetaldehyde has been used as a nucleophile in reactions with biological catalysts such as aldolases5 and thiamine-dependent enzymes6, and has also been employed indirectly7,8,9, its use as an inexpensive and versatile two-carbon nucleophile in asymmetric, small-molecule catalysis will find many practical applications.

A general and efficient method for the Suzuki-Miyaura coupling of 2-pyridyl nucleophiles.

Abstract: The Suzuki-Miyaura reaction has become one of the most valuable synthetic processes for the construction of carbon-carbon bonds,[1] and our laboratories has developed many highly active catalyst systems that efficiently process challenging combinations of aryl halides and boronic acids.[2] Recently, we have been able to extend our methodology to the cross-coupling of heteroaryl boronic acids and esters, which serve as important building blocks for the assembly of biologically active molecules.[3]-[4] However, 2-substituted nitrogen-containing heteroaryl organoboranes, which are of importance for the construction of numerous natural products and pharmaceutically interesting compounds,[5] were not effectively coupled using our standard conditions. Further examination of the literature indicated that only a few methods have been developed that allow for the Suzuki-Miyaura reaction of 2-pyridyl nucleophiles with aryl halides, and in these examples, only aryl iodides have been demonstrated as suitable coupling partners.[3],[6]-[10] The difficulty can be attributed to several factors: (1) electron-deficient heteroaryl boron derivatives undergo transmetallation at a relatively slow rate (2) these reagents rapidly decompose via a protodeboronation pathway. The lack of an efficient method to process this class of nucleophiles led us to develop a technique specifically designed to accomplish this transformation. We found that catalysts based upon phosphite or phosphine oxide ligands (1-4) were highly active for the Suzuki-Miyaura reaction of 2-pyridyl boron derivatives with 1-bromo-4-butylbenzene (Scheme 1).[6] The use of these has been pioneered by the work of Li, and elegant applications by Ackermann and Wolf have appeared more recently. However, the reaction remained sensitive to the nature of the nucleophile and base. For example, the reaction of commercially-available reagents, such as 2-pyridyl boronic acid,[7] pinacol boronate ester[8] or N-phenyl diethanolamine boronate ester,[9] with 4-n-butylbromobenzene produced low yields of the desired biaryl product (Table 1, Entries 1-3). Similarly, attempts to use organotrifluoroborates resulted in a low conversion of the aryl bromide (Table 1, Entry 4).[10] Although 2-pyridylboronates have been employed in Suzuki-Miyaura reactions, the cross-coupling processes result in only poor to modest yields of the desired biaryl product.[11] However, when lithium triisopropyl 2-pyridyl boronate (A) was employed as the nucleophile, the desired product could be obtained in an 85% yield with 100% conversion of the aryl halide (Table 1, Entry 5). Although A is not yet commercially available, it is stable under an argon atmosphere for up to a month, and it can be prepared in near quantitative yield from 2-bromopyridine via lithium halogen exchange and immediate in situ quenching of the resulting anion with triisopropylborate. In addition, this reaction could be performed in multigram quantities to provide A in an excellent yield. Lithium triisopropyl 2-(6-methoxypyridyl)boronate (B) and lithium triisopropyl 2-(5-fluoropyridyl)boronate (C) were also prepared employing this protocol in 90% and 96% yield, respectively. Similarly, under these conditions, 2-bromopyridines possessing a protected aldehyde (D) or a nitrile (E) could be efficiently transformed to the corresponding boronates.[12] Scheme 1 Effective Phosphite and Phosphine Oxide Ligands Table 1 The Effects of the Base and Nucleophile[a] A catalyst based upon Pd2dba3 and 1 proved to be highly effective for the Suzuki-Miyaura reactions of A with aryl and heteroaryl bromides. For example, this system efficiently combined 3,5-(bis-trifluoromethyl)bromobenzene (Table 2, Entry 2) and 4-bromoanisole (Table 2, Entry 3) with A to furnish the desired biaryl in 82% and 74% yield, respectively. In addition, ortho-substituted aryl bromides were coupled in good to excellent yields (Table 2, Entries 4-5). Heteroaryl bromides were also suitable coupling partners as seen in the reactions of A with 5-bromopyrimidine (Table 2, Entry 6) and 4-bromoisoquinoline (Table 2, Entry 7) which smoothly resulted in a 91% and 82% yield, respectively, of the desired heterobiaryl compound. Utilizing a Pd2dba3/2 catalyst, a range of lithium triisopropyl 2-pyridylboronates possessing functional groups were successfully cross-coupled with aryl bromides. Indeed, this catalyst system allowed for the reaction of B and C with a variety of electron-poor, -neutral, -rich and ortho-substituted aryl bromides (Table 2, Entries 9-12). In addition, the reaction of 4-bromobenzonitrile and D furnished the desired biaryl in a 63% yield (Table 2, Entry 13). However, the cross-coupling reactions utilizing E resulted in incomplete conversion in its reaction with a variety of aryl bromides. We attributed this difficulty to the relatively slow rate of transmetallation of the highly electron deficient 2-pyridylboronate. Overall, however, this protocol still represents the most general method for the Suzuki-Miyaura reaction of 2-pyridyl nucleophiles with aryl or heteroaryl bromides. Table 2 The Reaction of A-D with Aryl Bromides[a] Despite the efficacy of the Pd2dba3/1 catalyst system for the reactions of lithium triisopropyl 2-pyridylboronates with aryl bromides, more modest yields of the desired biaryls were obtained in the reactions of the corresponding aryl or heteroaryl chlorides. Employing 2 as the supporting ligand, however, provided a more active catalyst for this transformation. For example, the reaction of A with 4-chlorobenzonitrile furnished the desired product in 73% yield (Table 3, Entry 1). In addition, unactivated aryl chlorides were efficiently coupled as the reactions of 4-n-butylchlorobenzene (Table 3, Entry 2) and 4-chloroanisole (Table 3, Entry 4) with A resulted in a 76% and 78% yield, respectively, of the desired product. Similarly, under these conditions, ortho-substituted aryl chlorides were suitable substrates as the reaction of 2-chloro-p-xylene and A proceeded in a 70% yield (Table 3, Entry 3). In addition, a heteroaryl chloride, 3-chloropyridine, was coupled with A in an excellent yield to give o,m-bipyridine (Table 3, Entry 6). Table 3 The Reaction of A and B with Aryl Chlorides[a] In summary, we have developed an efficient method for the Suzuki-Miyaura reaction of lithium triisopropyl 2-pyridylboronates. The boronates can be readily prepared in one step from the corresponding 2-bromo or 2-iodopyridine. This represents the first relatively general Suzuki-Miyaura cross-coupling reaction of these substrates with aryl and heteroaryl bromides and chlorides.

An improved Cu-based catalyst system for the reactions of alcohols with aryl halides.

Abstract: The use of 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4Phen) as a ligand improves the Cu-catalyzed cross-coupling reactions of aryl iodides and bromides with primary and secondary aliphatic, benzylic, allylic, and propargylic alcohols. Most importantly, by employing this catalyst system, the need to use an excessive quantity of the alcohol coupling partner is alleviated. The relatively mild conditions, short reaction times, and moderately low catalyst loading allow for a wide array of functional groups to be tolerated on both the electrophilic and nucleophilic coupling partners.

Gold(I)-Catalyzed Intermolecular Addition of Carbon Nucleophiles to 1,5- and 1,6-Enynes

Abstract: Gold(I)-catalyzed addition of carbon nucleophiles to 1,6-enynes gives two different type of products by reaction at the cyclopropane or at the carbene carbons of the intermediate cyclopropyl gold carbenes. The 5-exo-dig cyclization is followed by most 1,6-enynes, although those bearing internal alkynes and alkenes react by the 6-endo-dig pathway. The cyclopropane versus carbene site-selectivity can be controlled in some cases by the ligand on the gold catalyst. In addition to electron-rich arenes and heteroarenes, allylsilanes and 1,3-dicarbonyl compounds can be used as the nucleophiles. In the reaction of 1,5-enynes with carbon nucleophiles, the 5-endo-dig pathway is preferred.

Understanding the Participation of Quadricyclane as Nucleophile in Polar [2σ + 2σ + 2π] Cycloadditions toward Electrophilic π Molecules

Abstract: The formal [2σ + 2σ + 2π] cycloaddition of quadricyclane, 1, with dimethyl azodicarboxylate, 2, in water has been studied using DFT methods at the B3LYP/6−31G** and MPWB1K/6−31G** levels. In the gas phase, the reaction of 1 with 2 has a two-stage mechanism with a large polar character and an activation barrier of 23.2 kcal/mol. Inclusion of water through a combined discrete-continuum model changes the mechanism to a two-step model where the first nucleophilic attack of 1 to 2 is the rate-limiting step with an activation barrier of 14.7 kcal/mol. Analysis of the electronic structure of the transition state structures points out the large zwitterionic character of these species. A DFT analysis of the global electrophilicity and nucleophilicity of the reagents provides a sound explanation about the participation of 1 as a nucleophile in these cycloadditions. This behavior is reinforced by a further study of the reaction of 1 with 1,1-dicyanoethylene.

Hot water-promoted ring-opening of epoxides and aziridines by water and other nucleopliles.

Abstract: Effective hydrolysis of epoxides and aziridines was conducted by heating them in water at 60 or 100 °C. Other types of nucleophile such as amines, sodium azide, and thiophenol could also efficiently open epoxides and aziridines in hot water. It was proposed that hot water acted as a modest acid catalyst, reactant, and solvent in the hydrolysis reactions.

Nickel-catalyzed decarbonylative addition of phthalimides to alkynes.

Abstract: An intermolecular nickel-catalyzed addition reaction has been developed where N-arylphthalimides react with alkynes to afford substituted isoquinolones. A mechanistic rationale is proposed, implying nucleophilic attack of Ni(0) to an amide as the primary step of the catalytic cycle.

Mechanistic studies on the Cu-catalyzed three-component reactions of sulfonyl azides, 1-alkynes and amines, alcohols, or water: dichotomy via a common pathway.

Abstract: Combined analyses of experimental and computational studies on the Cu-catalyzed three-component reactions of sulfonyl azides, terminal alkynes and amines, alcohols, or water are described. A range of experimental data including product distribution ratio and trapping of key intermediates support the validity of a common pathway in the reaction of 1-alkynes and two distinct types of azides substituted with sulfonyl and aryl(alkyl) groups. The proposal that bimolecular cycloaddition reactions take place initially between triple bonds and sulfonyl azides to give N-sulfonyl triazolyl copper intermediates was verified by a trapping experiment. The main reason for the different outcome from reactions between sulfonyl and aryl(alkyl) azides is attributed to the lability of the N-sulfonyl triazolyl copper intermediates. These species are readily rearranged to another key intermediate, ketenimine, into which various nucleophiles such as amines, alcohols, or water add to afford the three-component coupled products: amidines, imidates, or amides, respectively. In addition, the proposed mechanistic framework is in good agreement with the obtained kinetics and competition studies. A computational study (B3LYP/LACV3P*+) was also performed confirming the proposed mechanistic pathway that the triazolyl copper intermediate plays as a branching point to dictate the product distribution.

Iodine-Mediated Electrophilic Cyclization of 2-Alkynyl-1-methylene Azide Aromatics Leading to Highly Substituted Isoquinolines and Its Application to the Synthesis of Norchelerythrine

Abstract: The reaction of 2-alkynyl-1-methylene azide aromatics 1 with iodine and/or other iodium donors, such as the Barluenga reagent (Py2IBF4/HBF4) and NIS, gave highly substituted cyclization products, namely, the 1,3-disubstituted 4-iodoisoquinolines 2, in good to high yields. Not only simple 2-alkynyl benzyl azides 1a-j and their substituted analogues 1k-u and 6 but also heteroaromatic analogues, including pyridine 8, pyrroles 10a-c, furane 10d, and thiophenes 10e-g, gave the corresponding isoquinoline derivatives in excellent to allowable yields. Electron-donating and electron-accepting substituents on the aromatic ring were equally tolerated, and either acidic or basic (or even neutral) reaction conditions, depending on the reactivity of the substrate, could be applied to smoothly convert the azide starting materials into the desired isoquinoline products in moderate to good yields. Limits were found only in connection with the substituent at the alkyne terminus, where electron-neutral or electron-donating substituents are clearly favored. The iodine-mediated electrophilic cyclization of 1 most probably proceeds through the iodonium ion intermediate 4 followed by nucleophilic cyclization of the azide and subsequent elimination of N2. This new methodology was successfully applied to the short synthesis of norchelerythrine.

The reaction mechanism of the hydroamination of alkenes catalyzed by gold(I)-phosphine: the role of the counterion and the N-nucleophile substituents in the proton-transfer step.

Abstract: The reaction mechanism of the gold(I)−phosphine-catalyzed hydroamination of 1,3-dienes was analyzed by means of density functional methods combined with polarizable continuum models. Several mechanistic pathways for the reaction were considered and evaluated. It was found that the most favorable series of reaction steps include the ligand substitution reaction in the catalytically active Ph3PAuOTf species between the triflate and the substrate, subsequent nucleophile attack of the N-nucleophile (benzyl carbamate) on the activated double bond, which is followed by proton transfer from the NH2 group to the unsaturated carbon atom. The latter step, the most striking one, was analyzed in detail, and a novel pathway involving tautomerization of benzyl carbamate nucleophile assisted by triflate anion acting as a proton shuttle was characterized by the lowest barrier, which is consistent with experimental findings.

Chiral anion-mediated asymmetric ring opening of meso-aziridinium and episulfonium ions.

Abstract: Reactions proceeding through cationic intermediates that lack a Lewis or Bronsted basic site present a challenge for traditional asymmetric catalysis based on chiral metals or organocatalysts. We present an enantioselective ring opening of tetrasubstituted meso-aziridinium ions with alcohol nucleophiles proceeding through a chiral ion pair with a binaphthol-phosphate anion. The reaction is initiated by silver-induced ring closure of β-chloroamines using the Ag salt of the chiral anion as in situ generated catalyst. Use of insoluble Ag2CO3 as silver source is essential to obtain high enantioselectivity; we believe the chiral phosphate acts as a “chiral anion phase transfer catalyst” to bring silver ion into the organic phase. The chiral anion concept can also be extended to the related asymmetric opening of meso-episulfonium ions generated by protonation of trichloroacetimidates vicinal to sulfides.

Tuning of chemo- and regioselectivities in multicomponent condensations of 5-aminopyrazoles, dimedone, and aldehydes.

Abstract: Regio- and chemoselective multicomponent protocols for the synthesis of 1,4,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinolin-5-ones, 5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8-ones, and 5a-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones starting from 5-amino-3-phenylpyrazole, cyclic 1,3-dicarbonyl compounds and aromatic aldehydes are described. Whereas the three-component coupling in ethanol under reflux conditions provides mixtures of pyrazoloquinolinones and pyrazoloquinazolinones, the condensation can be successfully tuned toward the formation pyrazoloquinolinones (Hantzsch-type dihydropyridines) by performing the reaction at 150 degrees C in the presence of triethylamine base applying sealed vessel microwave or conventional heating. On the other hand, using sonication at room temperature under neutral conditions favors the formation of the isomeric pyrazoloquinazolinones (Biginelli-type dihydropyrimidines). These products are also obtained when the three-component condensation is executed in the presence of trimethylsilylchloride as reaction mediator at high temperatures. A third reaction pathway leading to pyrazoloquinolizinones in a ring-opening/recyclization sequence can be accessed by switching from triethylamine to a more nucleophilic base such as sodium ethoxide or potassium tert-butoxide. The reaction mechanism and intermediates leading to these three distinct tricyclic condensation products are discussed.