Nitroso Acetals Research Articles

3+3]-Annulation of Cyclic Nitronates with Vinyl Diazoacetates: Diastereoselective Synthesis of Partially Saturated [1,2]Oxazino[2,3-b][1,2]oxazines and Their Base-Promoted Ring Contraction to Pyrrolo[1,2-b][1,2]oxazine Derivatives

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole. Both transformations can be performed in a one-pot fashion, thus constituting a quick approach to oxazine-annulated pyrroles from available starting materials, such as nitroalkenes, olefins, and diazo compounds.

Nitronate-aryne cycloaddition as a concise route to stereochemically complex fused benzisoxazolines and amino alcohols.

The reaction of cyclic nitronates (isoxazoline N-oxides and 5,6-dihydro-4H-1,2-oxazine N-oxides) with Kobayashi's aryne precursors affords tricyclic benzene-fused nitroso acetals as a result of [3 + 2]-cycloaddition. The process is regio- and stereoselective in most cases and produces the target cycloadducts possessing up to four contiguous stereogenic centers. These nitroso acetals were shown to be convenient precursors of valuable polysubstituted aminodiols through catalytic hydrogenolysis of the N-O bonds. Also, the action of protic acids resulted in an unusual fragmentation of the cyclic nitroso acetal moiety through heterolytic N-O bond cleavage and Beckmann-type reaction. Using this acid-mediated reaction, the synthesis of a hitherto unknown hexahydrobenzo[4,5]isoxazolo[2,3-a]azepine scaffold was accomplished.

Deoxygenative Arylation of 5,6-Dihydro-4H-1,2-oxazine-N-oxides with Arynes.

Six-membered cyclic nitronates (5,6-dihydro-4H-1,2-oxazine-N-oxides) react with Kobayashi's aryne precursors producing 3-(2-hydroxyaryl)-substituted 1,2-oxazines via deoxygenative C-H arylation. The process involves a hitherto unknown 1,3-dipolar cycloaddition of nitronate to the aryne to give an unusual tricyclic nitroso acetal, in which the N-O bond of the isoxazoline ring is selectively cleaved upon the action of a base (CsF) or an acid (TFA). The transient cycloadducts were isolated and characterized in some cases. The synthetic potential of the obtained 3-(2-hydroxyaryl)-substituted 1,2-oxazines was demonstrated by their stereoselective reduction to 1,4-amino alcohols and reductive 1,2-oxazine ring contraction to tetrahydrofuran derivatives.

Harnessing the ambiphilicity of silyl nitronates in a catalytic asymmetric approach to aliphatic \u03b23-amino acids

Nitronate anions, formally generated by α-deprotonating the corresponding nitroalkanes, are highly nucleophilic and versatile intermediates in many carbon–carbon bond-forming reactions. In contrast, the corresponding silyl nitronates are ambiphilic and react, at the same carbon atom, with both electrophiles and nucleophiles. However, while their nucleophilicity has been well exploited in catalytic enantioselective reactions with imines and aldehydes, utilizing the electrophilicity of silyl nitronates in asymmetric synthesis has remained elusive. Here we report the facile, efficient and general reactivity of readily available silyl nitronates with silyl ketene acetals, catalysed by highly Lewis-acidic and confined silylium imidodiphosphorimidate catalysts. The products of this reaction, so-called nitroso acetals, are obtained in excellent enantioselectivity and can be easily converted into N-Boc-β3-amino acid esters in a single step.

Fluoronitroalkenes in tandem [4 + 1]/[3 + 2]-cycloaddition: one-pot three-component assembly of fluorinated bicyclic nitroso acetals

Novel fluorinated bicyclic nitroso acetals were obtained in a highly regio- and diastereo-selective manner via tandem [4 + 1]/[3 + 2]-cycloaddition of fluoronitroalkenes.

Six‐Membered Cyclic Nitroso Acetals: Synthesis and Studies of the Nitrogen Inversion Process of N‐Silyloxy‐3,6‐dihydro‐2H‐1,2‐oxazines

Silyl nitronates undergo rhodium‐catalyzed formal [3+3]‐cycloaddition with enol diazoacetates to form N‐silyloxy‐3,6‐dihydro‐2H‐1,2‐oxazines. The scope of the reaction and the extent of the major side process were evaluated. A mechanistic scheme was proposed. The nitrogen inversion barrier in the obtained nitroso acetals was estimated based on both quantum calculations and kinetic measurements.

Synthesis and chemical transformations of six/six-membered bicyclic nitroso acetals

A synthesis of hitherto unknown bicyclic nitroso acetals possessing two annulated six-membered rings is accomplished. The synthesis comprises formal [3+3] cycloaddition of six-membered cyclic nitronates with donor-acceptor cyclopropanes. Some chemical transformations and conformational preferability of the obtained nitroso acetals are discussed.

Three-step assembly of 4-aminotetrahydropyran-2-ones from isoxazoline-2-oxides

Tetrahydropyran-2-ones with a 4-amino function connected to a tertiary carbon atom – a widely naturally occurring fragment – are constructed by a three step protocol from easily available isoxazoline 2-oxides. In the first stage, the carbon skeleton of the target product is formed upon a C,C-coupling of a silyl ketene acetal with a nitronate function, under silyl triflate catalysis. The key step of the assembly consists of the oxidative cleavage of an endocyclic N–O bond of intermediate cyclic nitroso acetals with mCPBA, accompanied with lactone ring closure, and gives rise to β-nitro-δ-lactones in 63–85% yields. The latter are reduced with amalgamated aluminium, to furnish the target scaffold.

Stereoselective Amine Addition to Six‐Membered Cyclic Nitronates Promoted by Silyl Triflate

AbstractSix‐membered cyclic nitronates couple with amines or their N‐silyl derivatives in a diastereoselective fashion to give 3‐amino‐substituted nitroso acetals in 53–89 % yield through silyl triflate electrophilic catalysis. Stereodifferentiation of this process is determined by thermodynamic control, which is realized due to reversibility of amine addition and a decreased nitrogen inversion barrier in the resulting nitroso acetals. Selected chemical transformations of nitroso acetals were examined.

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO4

Chiral nonracemic aminated nitroso acetals were synthesized via diastereoselective multicomponent [4 + 2]/[3 + 2] cycloadditions employing new (S,E)-γ-nitrogenated nitroalkenes 5a–c as heterodienes, ethyl vinyl ether (EVE) as a dienophile, and selected electron-deficient alkenes as 1,3-dipolarophiles. The employment of different organic solutions of LiClO4 or LiCl as promoter systems provided the respective nitroso acetals with yields from 34–72% and good levels of diastereoselectivity. In addition, the nitroso acetal 9c was transformed to the pyrrolizidin-3-one derivative 14c, proving the usefulness of the route in the synthesis of an interesting chiral compound. The elucidation of the stereostructures was based on 2D COSY, NOESY and HSQC NMR experiments as well as an X-ray diffraction experiment.

C–C Coupling of Acyclic Nitronates with Silyl Ketene Acetals under Silyl Triflate Catalysis: Reactivity Umpolung of Aliphatic Nitro Compounds

AbstractTBSOTf‐promoted C–C coupling of alkyl and trialkylsilyl nitronates with silyl ketene acetals yields functionalized nitroso acetals. This conversion may serve as a new simple procedure to reverse the conventional reactivity of aliphatic nitro compounds. Preliminary results on the hydrogenation of nitroso acetals into amino acids derivatives, as well as TFA‐catalyzed transformations of nitroso acetals, are examined to prove the possible utility of this umpolung procedure.

Stereocontrolled Oxidation of Six-Membered Cyclic O-Silyl Nitroso Acetals with mCPBA: Umpolung Approach to Functionalized Nitro Compounds

Easily available, six-membered cyclic nitroso acetals 2 are smoothly oxidized with meta-chloroperbenzoic acid to δ-nitro alcohols 3 or γ-nitro carbonyl compounds 4 with the retention of their relative configurations of stereocenters (diastereomeric ratio > 10:1). The reaction sequence – the generation of diastereomerically pure six-membered cyclic nitronates 1 from simple aliphatic nitro compounds (AN), C–C coupling of 1 with π-nucleophiles, and the oxidation of the resulting nitroso acetals 2 – is considered to be a new effective variant of the umpolung reactivity of AN. An original approach for the synthesis of alternative diastereomers of nitro derivatives 3 has also been suggested.

ChemInform Abstract: Tandem 6π‐Electrocyclization and Cycloaddition of Nitrodienes to Yield Multicyclic Nitroso Acetals.

AbstractUpon heating, nitrodienes rearrange through 6π‐electrocyclization to form nitronate intermediates, which can be captured through tandem [3 + 2] dipolar cycloadditions to form highly functionalized nitroso acetals.

Tandem 6π-Electrocyclization and Cycloaddition of Nitrodienes to Yield Multicyclic Nitroso Acetals

Upon heating, nitrodienes rearrange through 6pi-electrocyclization to form nitronate intermediates, which can be captured through tandem [3 + 2] dipolar cycloadditions to form highly functionalized nitroso acetals. The one-pot, two-step domino process is highly efficient, proceeding with good facial selectivity and exoselectivity. Dipolarophiles featuring electron-rich, -neutral, and -deficient carbon-carbon double bonds are viable substrates for [3 + 2] cycloadditions with the in situ generated nitronates. In addition, the highly functionalized nitroso acetal products can be hydrogenolyzed selectively to form densely functionalized spirocyclic hydroxy amides or hydroxy gamma-amino acids.

Five‐Membered Cyclic Nitronates in C–C Coupling with 1‐(tert‐Butyldimethylsilyloxy)‐1‐methoxyethylene

AbstractFive‐membered cyclic nitronates 3 undergo TBSOTf‐catalysed C–C coupling reactions with silyl ketene acetal 4 to give good to excellent yields of 3,3‐disubstituted N‐(OTBS)‐isoxazolidines 5, which could not be obtained by previously known procedures. The problems of diastereoselectivity of the C–C coupling reactions are discussed. The transformations of the nitroso acetals 5 upon action of AcFOH/methanol or some reducing agents (H2/NiRa, LAH, Al/Hg) have been examined.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Tandem double intramolecular [4+2]/[3+2] cycloadditions of nitroalkenes: construction of the pentacyclic core structure of daphnilactone B

An asymmetric synthesis of the ABCD ring system of daphnilactone B is described. The synthesis features a tandem, double intramolecular, [4+2]/[3+2] cycloaddition of a highly functionalized, enantiomerically enriched nitroalkene to generate a pentacyclic nitroso acetal. The cycloaddition establishes six contiguous stereogenic centers including the critical CD ring junction that bears two quaternary stereogenic centers. Hydrogenolysis of the nitroso acetal followed by amide reduction and cyclization provided the AB rings. The methyl substituent on the A ring was installed in the correct configuration via hydrogenation of an exocyclic olefin in the final step.

ASYMMETRIC SYNTHESIS OF THE ABCD RING SYSTEM OF DAPHNILACTONE B VIA A TANDEM, DOUBLE INTRAMOLECULAR, [4+2]/[3+2] CYCLOADDITION STRATEGY.

An asymmetric synthesis of the ABCD ring system of daphnilactone B is described. The synthesis features a tandem, double intramolecular, [4+2]/[3+2] cycloaddition of a highly functionalized, enantiomerically enriched nitroalkene to generate a pentacyclic nitroso acetal. The cycloaddition establishes six contiguous stereogenic centers including the critical CD ring junction that bears two quaternary stereogenic centers. Hydrogenolysis of the nitroso acetal followed by amide reduction and cyclization provided the AB rings. The methyl substituent on the A ring was installed in the correct configuration via hydrogenation of an exocyclic olefin in the final step.

Synthesis, X-ray Crystallography, and Computational Analysis of 1-Azafenestranes

The tandem [4+2]/[3+2] cycloaddition of nitroalkenes has been employed in the synthesis of 1-azafenestranes, molecules of theoretical interest because of planarizing distortion of their central carbon atoms. The synthesis of c,c,c,c-[5.5.5.5]-1-azafenestrane was completed in good yield from a substituted nitrocyclopentene, and its borane adduct was analyzed through X-ray crystallography, which showed a moderate distortion from ideal tetrahedral geometry. The syntheses of two members of the [4.5.5.5] family of 1-azafenestranes are also reported, including one with a trans fusion at a bicyclic ring junction which brings about considerable planarization of one of the central angles (16.8 degrees deviation from tetrahedral geometry). While investigating the [4.5.5.5]-1-azafenestranes, a novel dyotropic rearrangement that converts nitroso acetals into tetracyclic aminals was discovered. Through conformational analysis, a means to prevent this molecular reorganization was formulated and realized experimentally with the use of a bulky vinyl ether in the key [4+2] cycloaddition reaction. Finally, DFT calculations on relative strain energy for the 1-azafenestranes, as well as their predicted central angles, are disclosed.

Synthesis and Rearrangement of N‐Organyloxy β‐Lactams Derived from a (4+2)/(3+2) Sequential Cycloaddition Reaction Involving Enol Ethers and Nitro Alkenes

AbstractThe synthesis of N‐organyloxy β‐lactams 2 by treatment of nitroso acetals 1 with a base is discussed. Based on the formation of a by‐product, a mechanism for the rearrangement to N‐organyloxy β‐lactams is proposed. This mechanism is supported by trapping of the intermediate acyl nitro compound 8 with dimethylamine. Furthermore, it was discovered that upon more forcing basic conditions these N‐organyloxy β‐lactams can rearrange further to 3‐organyloxy β‐lactams. By using a series of structurally diverse N‐organyloxy β‐lactams the generality of this novel rearrangement is demonstrated. A mechanism for the conversion of N‐organyloxy β‐lactams to 3‐organyloxy β‐lactams is proposed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

A Novel Domino [4 + 2]/[4 + 2]/[3 + 2] Cycloaddition Reaction Leading to Highly Functionalized Polycyclic Nitroso Acetals.

AbstractFor Abstract see ChemInform Abstract in Full Text.