Addition Of Silyl Ketene Acetals Research Articles

Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis.

A straightforward methodology for the enantioselective synthesis of 1,2-dihydrophthalazines via dearomatization of phthalazines by anion-binding catalysis has been developed. The process involves the Mannich-type addition of silyl ketene acetals to in situ generated N-acylphthalazinium chlorides using a tert-leucine derived thiourea as a H-bond donor catalyst. Ensuing selective and high-yielding transformations provide appealing dihydro- and tetrahydro-phthalazines, phthalazones, and piperazic acid homologues, en route to biologically relevant molecules.

ChemInform Abstract: Silanediol‐Catalyzed Chromenone Functionalization.

Promising levels of enantiocontrol are observed in the silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl-containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones.

Silanediol-Catalyzed Chromenone Functionalization.

Promising levels of enantiocontrol are observed in the silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl-containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones.

A catalytic approach to the metal-free reaction of epoxides with ketene silyl acetals for accessing γ-lactones.

The first catalytic approach to the nucleophilic addition of silyl ketene acetals 2 to epoxides 1 is reported. The defined protocol is metal-free using tetrabutylammonioum fluoride as the catalyst. It works in a very efficient manner under solvent-free conditions (SolFC) allowing γ-lactones 3 to be directly obtained with high regioselectivities and yields.

Expedient synthesis of α-(2-azaheteroaryl) acetates via the addition of silyl ketene acetals to azine-N-oxides.

A new and expedient synthesis of α-(2-azaheteroaryl) acetates is presented. The reaction proceeds rapidly under mild conditions via the addition of silyl ketene acetals to azine-N-oxides in the presence of the phosphonium salt PyBroP. This procedure affords diverse α-(2-azaheteroaryl) acetates which are highly desirable components/building blocks in molecules of pharmaceutical interest but are traditionally challenging to synthesize via contemporary methods. The reaction optimization and mechanism as well as a novel electronically enhanced PyBroP derivative are described.

ChemInform Abstract: Chiral Silanediols in Anion‐Binding Catalysis.

A perfect pair: Silanediols are effective catalysts for the addition of silyl ketene acetals to N-acylisoquinolinium ions. Importantly, this is the first example of a silanediol plausibly participating in anion-binding catalysis, a relatively new direction in the field of hydrogen-bond-donor catalysis. The chiral, enantiopure C2 -symmetric silanediol 1 catalyzes enantioselective transformations.

Chiral Silanediols in Anion‐Binding Catalysis

A perfect pair: Silanediols are effective catalysts for the addition of silyl ketene acetals to N-acylisoquinolinium ions. Importantly, this is the first example of a silanediol plausibly participating in anion-binding catalysis, a relatively new direction in the field of hydrogen-bond-donor catalysis. The chiral, enantiopure C2 -symmetric silanediol 1 catalyzes enantioselective transformations.

Experimental and theoretical studies on Mannich-type reactions of chiral non-racemic N-(benzyloxyethyl) nitrones

The nucleophilic addition of both silyl ketene acetals and lithium enolates derived from methyl acetate to chiral non-racemic N-(benzyloxyethyl)nitrones has been studied both experimentally and theoretically. Aromatic nitrones showed lower reactivity that aliphatic nitrones and the addition of the silyl ketene acetal led to lower selectivities than the addition of the corresponding lithium enolate. Whereas low selectivity was obtained for the addition of the silyl ketene acetal, only one diastereomer could be detected in all cases for the addition of lithium enolate to aliphatic nitrones. The synthetic utility of the two chiral auxiliaries employed lies in the preparation of enantiomeric compounds. DFT theoretical calculations confirmed the stepwise mechanism for the addition of silyl ketene acetals to nitrones and are in good agreement with the observed experimental results.

Insights into Iminium Catalysis

The Mayr group prepared various cinnamaldehyde-derived iminium triflates 2 ×OTf. The kinetic analysis of the addition of silyl ketene acetals 3 to 2 ×OTf allowed for the determination of electrophilicities E of these iminium ions, which are comparable to those of highly electron-deficient Michael acceptors such as benzylidene ­malononitriles. Iminium ion 2c derived from MacMillan’s first generation imidazolidinone followed by iminium ion 2b derived from α,α-diarylprolinol trimethylsilyl ether were the most active compounds of this ­series reflecting the high catalytic potential of the corresponding secondary amines (see 1) in iminium catalysis. The iminium triflates 2×OTf were investigated by 2D-NMR spectroscopy indicating that 2b and 2c exist with (E)-configuration in solution.

Mercuric Iodide (HgI2) as an Oxidizing Agent for the Synthesis of Quinoxaline

Nitrogen-containing heterocyclic compounds are indispensable structural units for both the chemist and the biochemist. Among the various classes of heterocyclic compounds, quinoxalines form an important component of pharmacologically active compounds. Quinoxaline ring is a part of various antibiotics such as Hinomycin, Levomycin and Actinoleutin that are known to inhibit growth of grampositive bacteria and are active against various transplantable tumors. In addition, quinoxaline derivatives are also associated with a wide spectrum of biological activities ranging from anthelmintic and anticancer to antimicrobial, antifungal, antidepressant, antibacterial and anti-inflammatory activities. Recently, 2-substituted quinoxaline can be prepared by one-pot process commencing from hydroxy ketone using manganese dioxide-mediated tandem oxidation process (TOP). However, the requirement of excess of activated manganese dioxide (usually 10 equivalents) detracts the commercial attraction and green credential of this process. Furthermore, such reactions require longer reaction times and in some cases the yields are poor. Mercuric iodide has been used as a mild and efficient catalyst for the synthesis of oligosaccharide and for the addition of silyl ketene acetals to acrylate esters or other electrophiles. The condensation of C,O,O-tris(trimethylsilyl)ketene acetal with aldehydes in the presence of catalytic amounts of mercuric iodide at room temperature affords syn and anti βtrimethylsiloxy α-trimethylsilyl alkanoic acid silyl esters. Mercuric chloride is used as an oxidizing agent for 2-amino3-(2,3-dihydroxypropylideneamino)malenonitrile to give 5methyl-2,3-pyrazinedicrbonitrile. Mercuric chloride-mediated cyclization of tethered alkynedithioacetals has been established as a general route to fiveand six-membered carbocycles and heterocycles. However, there are no examples of the use of HgI2 as an oxidizing agent for the synthesis of quinoxaline derivatives. Herein, we report a general and practical route for the synthesis of quinoxaline using HgI2 as a catalyst. In the presence of mercuric iodide (HgI2), the reaction of hydroxy ketone and aromatic diamine was carried out in one-pot condition at 60 C and resulted in the formation of quinoxaline in 60-85% yield (Table 1). Many pharmacologically relevant substituents on the aromatic ring could be introduced with high efficiency in moderate to excellent yields with high purities. In conclusion, a simple and general method for the synthesis of substituted quinoxaline using mercuric iodide as an oxidizing agent is developed. The compatibility with various functional groups, mild reaction conditions, high yields and application of inexpensive, mild, readily and easily available mercuric iodide are the main advantages of the present procedure.

Catalytic Enantioselective Addition of Silyl Ketene Acetals to Ketones

Using a CuF/TaniaPhos/PhBF3K catalyst system with added (EtO)3SiF, a variety of unsymmetrical ketones and silyl ketene acetals were transformed to the corresponding chiral 3° alcohol with high levels of enantio- and diastereo­selectivity. For β-substituted silyl ketene acetals, the diastereomeric ratio is independent of the E/Z ratio of the starting material; thus this is the first example of catalytic and enantioselective addition of silyl ketene acetals to ketones.

A DFT Study of the Molecular Mechanisms of the Nucleophilic Addition of Ester‐Derived Lithium Enolates and Silyl Ketene Acetals to Nitrones: Effects of the Lewis Acid Catalyst

AbstractThe molecular mechanisms for the nucleophilic addition of lithium enolates and silyl ketene acetals to nitrones in the absence and in the presence of a Lewis acid (LA) catalyst to give isoxazolidin‐5‐ones or hydroxylamines have been investigated by DFT methods at the B3LYP/6‐31G* level. The addition of lithium enolates to nitrones gives the corresponding hydroxylamines, while the addition of silyl ketene acetals affords isoxazolidin‐5‐ones through a concerted 1,3‐dipolar cycloaddition. The addition of the silyl ketene acetals to LA‐coordinated nitrones yields isoxazolidin‐5‐ones by a polar concerted cycloaddition or a stepwise nucleophilic attack via zwitterionic intermediates. A silyl migration on the [3+2] cycloadduct yields the corresponding O‐silylhydroxylamine. An analysis of the global electrophilicity of the reagents accounts for the strong electrophile activation of the LA‐coordinated nitrone, and the analysis of the local indices leads to an explanation for the experimentally observed regioselectivity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Lewis Base Activation of Lewis Acids: Catalytic, Enantioselective Addition of Silyl Ketene Acetals to Aldehydes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Lewis Base Activation of Lewis Acids: Catalytic, Enantioselective Addition of Silyl Ketene Acetals to Aldehydes

The concept of Lewis base activation of Lewis acids has been reduced to practice for catalysis of the aldol reaction of silyl ketene acetals and silyl dienol ethers with aldehydes. The weakly acidic species, silicon tetrachloride (SiCl4), can be activated by binding of a strongly Lewis basic chiral phosphoramide, leading to in situ formation of a chiral Lewis acid. This species has proven to be a competent catalyst for the aldol addition of acetate-, propanoate-, and isobutyrate-derived silyl ketene acetals to conjugated and nonconjugated aldehydes. Furthermore, vinylogous aldol reactions of silyl dienol ethers are also demonstrated. The high levels of regio-, anti diastereo-, and enantioselectivity observed in these reactions can be rationalized through consideration of an open transition structure where steric interactions between the silyl cation complex and the approaching nucleophile are dominant.

Lewis Base Activation of Lewis Acids. Addition of Silyl Ketene Acetals to Aldehydes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Lewis base activation of lewis acids. Addition of silyl ketene acetals to aldehydes.

The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral trichlorosilyl cation which is an extremely effective promoter of aldol addition reactions between aldehydes and silyl ketene acetals. The tert-butyldimethylsilyl ketene acetal of methyl acetate adds nearly instantaneously to aromatic and olefinic aldehydes as well as aliphatic aldehydes (albeit more slowly) with excellent enantioselectivity. The homologous tert-butyldimethylsilyl ketene acetal of tert-butyl propanoate adds with nearly exclusive anti diastereoselectivity to a similar range of aldehydes also with excellent enantioselectivity. The origin of the slower reaction rate with aliphatic aldehydes is revealed to be the formation of chlorosilyl ether adducts.

Facial selectivity in the addition of ketene acetals to nitrones towards chiral non-racemic isoxazolidin-5-ones. A semiempirical study

A semiempirical study (PM3) of the addition of silyl ketene acetals to D-glyceraldehyde derived nitrones has been carried out in order to rationalize the observed diastereofacial selectivity. Activation with Lewis acid must be considered in the calculations to achieve concordant results. Thus, the addition to trimethylsilyl trifluoromethane sulfonate-activated nitrones, leading to the preferential formation of syn adducts, may be explained by a stepwise mechanism. On the other hand, the diastereofacial anti selectivity observed in the addition to diethylaluminium chloride- activated nitrones can be interpreted in terms of a concerted mechanism.

ChemInform Abstract: Stereodivergent Approaches to the Synthesis of Isoxazolidine Analogues of α-Amino Acid Nucleosides. Total Synthesis of Isoxazolidinyl Deoxypolyoxin C and Uracil Polyoxin C.

The synthesis of new nucleoside analogues is currently of high interest. We report here full details of a study leading to the synthesis of novel isoxazolidinyl analogues of α-amino acid nucleosides. Three different synthetic approaches starting from l-serine have been evaluated for the construction of the isoxazolidine ring. These approaches consisted of Michael addition of N-benzylhydroxylamine to α,β-unsaturated esters, nucleophilic addition of silyl ketene acetals to nitrones and 1,3-dipolar cycloaddition of nitrones with vinyl acetate. Both Michael addition and nucleophilic addition of enolates could be carried out with stereocontrol at the newly formed stereogenic carbon. The stereocontrol observed in these reactions arises from the protecting group arrangement in the l-serine-derived substrates. Thus, whereas compounds having a diprotected nitrogen led to syn adducts, compounds having a monoprotected nitrogen gave rise to anti adducts. On the other hand, substrates having either a diprotected or mo...

ChemInform Abstract: Addition of Silyl Ketene Acetals to Nitrones Catalyzed by Lanthanoid Triflates.

ChemInform Abstract: Addition of Silyl Ketene Acetals to Nitrones Catalyzed by Lanthanoid Triflates.

Addition of Silyl Ketene Acetals to Nitrones Catalyzed by Lanthanide Triflates

α-Aryl- N-phenyl nitrones reacted with silyl ketene acetals mediated by lanthanum trifloromethanesulfonate (triflate) to afford the addition product in excellent yield under mild conditions. α-Aryl- N- tert-butyl nitrone reacted with ethyl trimethylsilylacetate to yield the unexpected α,β-unsaturated ester in a 100% E-form. A possible mechanism for the process is discussed.