Synthesis of pyrrolidin-3-ones from dihydropyran precursors via spiro-N,O-acetals

2,2-Disubstituted pyrrolidin-3-ones are prepared in three steps from simple dihydropyran derivatives; the key spiro-N,O-acetal intermediate is a useful N-sulfonylketoiminium ion precursor. This route represents a formal synthesis of the indolizidine alkaloid core, with potential application to pyrrolizidines and quinolizidines.     

Isothiocyanato derivatives of sugars in the stereoselective synthesis of spironucleosides and spiro-C-glycosides

A stereocontrolled synthesis of pyranoid and furanoid spironucleosides and spiro-C-glycosides (d-ribo and d-arabino configurations) of oxazolidines, oxazolines and perhydrooxazines via isothiocyanato sugar derivatives is reported. The intermediate isothiocyanates are prepared from sugar spiroketals by stereoselective opening of the acetal ring with trimethylsilyl N- and C-nucleophiles, and later formation of the isothiocyanato group.     

Fluorsilylsubstituierte N,N- und N,O-bis(trimethylsilyl)-hydroxylamine

Fluoro- und aminofluoro-silanes react with the lithium salt of N,O-bis(trimethylsilyl)hydroxylamine under LiF elimination and substitution. Alkyl- and amino-fluorosilanes give O-fluorosilyl-N,N-bis(trimethylsilyl)hydroxylamines, arylfluorosilanes give N-fluorosilyl-N,O-bis(trimethylsilyl)hydroxylamines. By the further reaction of O-difluorosilyl-N,N-bis(trimethylsilyl)hydroxylamine with the lithiated hydroxylamine, O,O′-fluoromethylsilyldi[N,N-bis(trimethylsilyl)hydroxylamine] is formed. On heating N-difluorophenylsilyl-N,O-bis(trimethylsilyl)hydroxylamine di[fluorophenylsilyl(methyl)amino]pentamethylsiloxane is formed by methyl group migration. The NMR and mass spectra of the compounds are reported.     

[4+1] Cycloaddition of N-acylimine derivatives with isocyanides: efficient synthesis of 5-aminooxazoles and 5-aminothiazoles

[4+1] Cycloaddition reaction between isocyanides and N-acylimine derivatives generated from N-acyl N,O-acetals acting as isocyanophiles has been developed. These reactions proceeded smoothly and cleanly to afford the corresponding 5-aminooxazoles in high yields. This reaction was extended to the syntheses of 5-aminothiazoles by using N-thioacyl N,O-acetals. A wide range of N-acyl N,O-acetals, N-thioacyl N,O-acetals, and isocyanides were found to be applicable to this reaction.     

Alkylation of 2-(methylsulfanyl)-6-polyfluoroalkylpyrimidin-4(3<Emphasis Type="Italic">H</Emphasis>)-ones with haloalkanes

The alkylation of ambident anions of 2-(methylsulfanyl)-6-(polyfluoroalkyl)pyrimidin-4(3H)-ones with 4-bromobutyl acetate leads to concurrent formation of O- and N-(4-acetoxybutyl) derivatives. Polar aprotic solvents favor formation of the O-isomer, and weakly polar dioxane favors N-alkylation. The reaction of 2-(methylsulfanyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one with an equimolar amount of 1,2-dibromoethane in polar acetonitrile gives a mixture of N,N-, O,O-, and N,O-bridged bis-pyrimidines, as well as N- and O-[2-(methylsulfanyl)ethyl] derivatives, whereas in the presence of 10 equiv of 1,2-dibromoethane the N,O-isomer is formed as the only product. The reaction in weakly polar tetrahydrofuran yields N,N- and N,O-bispyrimidines.     

A convenient method for the synthesis of N-hydroxyureas

Treatment of amines with 1-(4-nitrophenol)-N-(O-benzylhydroxy)carbamate yields the O-benzyl protected N-hydroxyureas. Hydrogenation of the O-benzyl protected N-hydroxyureas over 5% Pd/BaSO₄ cleanly gives the N-hydroxyureas in good yield. In addition to primary and secondary aliphatic and aromatic amines, this method converts amino sugars to the corresponding N-hydroxyureas without extensive protecting group chemistry.     

New bicyclic organylboronic esters derived from iminodiacetic acids

The reactions of phenylboronic acid or dinethylthexyboronic ester with iminodiacetic- or N-methyliminodiacetic acids lead to high yield to the air-stable bicyclic esters (N-B)phenyl[iminodiacete-O,N]borane (1), (N-B)phenyl[N-methyliminodiacetate-O,N]borane (2), (N-B)thexy[iminodiacetate[O,N]borane (3) and (N-B)thexyl[N-methyliminodiacetate-O,N]borane (4). These are shown by ¹H, ¹¹B and ¹³C NMR spectroscopy to have rigid bicyclic structures of strong intramolecular N-B coordination.     

Reductive removal of methoxyacetyl protective group using sodium borohydride

Herein, we have developed a mild and selective reductive deprotection method for the MAc protected alcohols using sodium borohydride. The new deprotection conditions provide a complete orthogonality between O-MAc and other protecting groups such as tert-butyl ester, N-Boc, Fmoc, Cbz, O-TBDMS, N-benzyl, O-benzyl, O-acetyl, N-acetyl, N-MAc, etc. In addition to O-MAc deprotection, this method is also applicable for S-MAc deprotection.     

One pot synthesis of α,α-bis(N-arylamido) lactams via iodide-catalyzed rearrangement of β,β-bis(N-arylamido) cyclic ketene-N,O-acetals

Five and six-membered cyclic ketene-N,O-acetals, generated in situ from 2,3-dimethyl-2-oxazolinium iodide or 2,3-dimethyl-2-oxazinium iodide and triethylamine, reacted with aryl isocyanates in refluxing THF producing α,α-bis(N-arylamido) lactams via the iodide-catalyzed rearrangement of β,β-bis(N-arylamido) cyclic ketene-N,O-acetal intermediates. The cyclic ketene-N,O-acetal generated in situ from 2,3,4,4-tetramethyl-2-oxazolinium iodide reacted with isocyanates to give β,β-bis(N-arylamido) cyclic ketene-N,O-acetals, which do not readily rearrange. The two methyls at C-4 hindered the nucleophilic attack of iodide on C-5, which is required for rearrangement.     

N-(Diethoxyphosphoryl)-O-benzylhydroxylamine—a convenient substrate for the synthesis of N-substituted O-benzylhydroxylamines

Easily available N-(diethoxyphosphoryl)-O-benzylhydroxylamine was shown to be convenient, orthogonally protected substrate for regioselective N-alkylation by means of diverse halides under basic conditions (sodium hydride/tetrabutylammonium bromide). An efficient procedure for dephosphorylation of N-substituted N-(diethoxyphosphoryl)-O-benzylhydroxylamine to provide N-substituted O-benzylhydroxylamines was also established.     

A crystalline paradise – three substances exhibiting the following crystallization modes: (1) conglomerate,kryptoracemic and unbalanced (2) conglomerate and kryptoracemic

The compound bis(ethylenediamine-N,N′)-(oxalato-O,O′)-cobalt biphenyl-4,4′-disulfonate hydrate, refcode TIQHOR, crystallizes with four Co(III) cations in the asymmetric unit. Another pair of compounds, rac-bis(ethylenediamine-N,N′)-(oxalato-O,O′)-cobalt(III) l-hydrogenaspartate, refcode VAGBOU, and tetra-ammine-(N-benzylethanediamine)-cobalt(III) trinitrate sesquihydrate, refcode ZIFHEB crystallize both as conglomerates and kryptoracemates. Their stereochemical characteristics are described, and the fact that they display more than one mode of crystallization in a single lattice, is illustrated numerically and visually.     

Selective functionalization at the small rim of calix[6]arene. Synthesis of novel non-symmetrical N3, N4 and N3ArO biomimetic ligands

Eight novel calix[6]arene-based biomimetic ligands for transition metal ions have been synthesized. They display a non-symmetrical N₃, N₄ or N₃ArO binding core that mimics enzyme active sites presenting histidine and tyrosine residues. The key step for their synthesis is the mono-alkylation at the small rim of the C_3v symmetrical trimethyl ether derivative of tBu-calix[6]arene with N-Boc-2-chloroethylamine to yield a novel calix[6]arene synthon. Its combined O-alkylation with a chloromethyl aromatic amine and N-deprotection or alkylation or reductive alkylation with a salicylaldehyde derivative yielded the calix[6]arene-based ligands with mixed N/O donors.     

Asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine,jaspine B (pachastrissamine) and its C(2)-epimer

The highly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to a γ-silyloxy-α,β-unsaturated ester and in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine has been used as the key step in the asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine, jaspine B (pachastrissamine) and its C(2)-epimer.     

Direct transformation of N,N-disubstituted amides and isopropyl esters to nitriles

Various N,N-dimethyl amides, N-methoxy-N-methyl amides, and isopropyl esters were smoothly transformed into the corresponding nitriles in good to moderate yields by the treatment with diisobutylaluminium hydride, followed by treatment with molecular iodine in aq ammonia. The present reactions are novel one-pot and practical methods for the transformation of N,N-disubstituted amides and isopropyl esters into nitriles, through the formation of hemiaminal O-AlBu₂ and hemiacetal O-AlBu₂, respectively.     

Trihaloacetaldehyde N,O-acetals: useful building blocks for dihalomethylene compounds

The reaction of trifluoroacetaldehyde N,O-acetals with more than 2 equiv of alkyllithiums at −78 °C resulted in regiospecific defluorinative alkylation with unusual regioselectivity to give α,α-difluoroketone N,O-acetals in excellent yield. In contrast, under similar conditions, trichloroacetaldehyde N,O-acetals gave simple mono-dechlorinated product without the alkyl transfer reaction from alkyllithiums to the generated intermediates.     

Rapid and efficient microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles

The microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles starting from N¹-aralkoxy-(methoxy)-N³-cyano-O-phenylisoureas and hydroxylamine is described. N¹-Aralkoxy(methoxy)-N³-cyano-O-phenylisoureas are readily accessible by treatment of diphenyl N-cyanimidocarbonate with O-substituted hydroxylamines.     

Access to Enantioenriched Spiro-ϵ-Lactam Oxindoles by an N-Heterocyclic Carbene-Catalyzed [4+3] Annulation of Flexible Oxotryptamines with Enals

Oxotryptamines were firstly used as flexible four-atom synthons in an NHC-catalyzed formal [4+3] annulation, providing a novel enantioselective method to access structurally diverse spiro-ϵ-lactam oxindoles with excellent enantioselectivities. This metal-free reaction features a broad substrate scope, excellent functional-group tolerance and proceeds under mild reaction conditions. Importantly, enantiopure privileged hexahydropyrroloindoles could be easily constructed by a one-pot process from the resulting spiro-ϵ-lactam oxindoles.     

Synthesis of per-6-guanidinylated cyclodextrins

Reaction of per(6-amino-6-deoxy-2,3-di-O-methyl)-α-, β- and γ-cyclodextrins with N,N′-bis(tert-butoxycarbonyl)-N″-triflylguanidine and triethylamine in tetrahydrofuran gave per[6-N,N′-bis(tert-butoxycarbonyl)guanidino-6-deoxy-2,3-di-O-methyl]-α-, β- and γ-cyclodextrins, respectively. Subsequent cleavage of the protective groups with trifluoroacetic acid in dichloromethane afforded per(6-deoxy-6-guanidino-2,3-di-O-methyl)-α-, β- and γ-cyclodextrins in very good overall yields.     

Chemoselective deprotection and functional group interconversion of ring-fused 2N,3O-oxazolidinones of N-acetyl-d-glucosamine

These studies describe the chemoselective deprotection of trans-fused 2N,3O-oxazolidinone derivatives of N-acetyl-β-d-glucosamine. Selective opening of the oxazolidinone ring or N-deacetylation without ring opening is demonstrated. Certain amines are shown to efficiently afford C-2 ureido sugars under mild conditions. This work demonstrates the high degree of chemoselective manipulation possible with ring-fused 2N,3O-oxazolidinone derivatives of N-acetyl-d-glucosamine.     

A rapid and convergent synthesis of α,α-difluoro-β-hydroxyketones through regiospecific defluorinative alkylation reaction

Both the defluorinative alkylation reaction of trifluoroacetaldehyde N,O-acetals using alkyllithiums and the following C-C bond formation with carbonyls as electrophiles were accelerated by a suitable diamine additive such as (−)-sparteine to give α,α-difluoro-β-hydroxyketone N,O-acetal products in an excellent yield. We also found that N-benzyl-N,O-acetal group of the resultant products can be removed under palladium-catalyzed hydrogenolysis conditions giving rise to the corresponding α,α-difluoro-β-hydroxyketones. The present two-step procedure is a useful and novel synthetic approach for functionalized α,α-difluoroketones.