Synthesis of 3,4-Dihydro-2H-1,3-benzoxazines by Condensation of 2-Hydroxyaldehydes and Primary Amines: Application to the Synthesis of Hydroxy-Substituted and Deuterium-Labeled Compounds

We report the synthesis of several substituted 3,4-dihydro-2H-1,3-benzoxazines by simple ring closure of 2-hydroxybenzylamines with paraformaldehyde. The facile synthesis of the benzylamine precursors from commercially available salicylaldehyde derivatives affords a powerful general synthetic way to prepare a variety of substituted benzoxazines, avoiding the formation of undesirable oligomeric species, thus leading to a simple workup and improving the yield and purity of the final product. This straightforward method allows synthesis of hydroxy-substituted and deuterium-labeled 1,3-benzoxazines that are not attainable using other synthetic ways.     

Unexpected ambidoselectivity in crossed-aldol reactions of α-oxy aldehyde trichlorosilyl enolates

The ambido-, stereo- and enantioselectivity of the phosphoramide-promoted aldol reactions of α-oxy aldehyde trichlorosilyl enolates with benzaldehyde has been investigated. Analysis of the products from α-tert-butyldimethylsilyloxy α-deuterioacetaldehyde trichlorosilyl enolate confirmed that this 1,2-bis-silyloxyethene derivative reacted as a tert-butyldimethylsilyl enolate rather than trichlorosilyl enolate in the aldol reaction with very high ambidoselectivity. The phosphoramide-coordinated trichlorosilyl group acted as an organizing center for the aldol reaction. From the aldol process, excellent anti-diastereoselectivity could be achieved. The enantioselectivity remained moderate to low for both anti- and syn-diastereomer with a wide range of phosphoramide catalysts. α-Triisopropylsilyloxy, phenoxy and benzyloxy acetaldehyde trichlorosilyl enolates also reacted in a similar fashion with benzaldehyde to give aldol products with varying degrees of selectivities.     

Palladium-catalyzed reactions of vinylidenecyclopropanes with acetic acid

Pd(PPh₃)₄-catalyzed reactions of vinylidenecyclopropanes 1 with acetic acid proceeded smoothly at 80 °C in toluene to give the corresponding acetylated dienes 2 in moderate to good yields in the presence of DPEphos ligand. The plausible mechanism is proposed on the basis of the control and deuterium labeling experiments.     

Competitive kinetic processes in the thermal rearrangement of 1,1-difluoro-2-(dideuteriomethylene)-cyclopropane

The synthesis of 1,1-difluoro-2-(dideuteriomethylene)-cyclopropane is reported along with the kinetics of its competing, reversible, first order rearrangements: (a) the degenerate rearrangement to 1,1-difluoro-3,3-dideuterio-2-methylene-cyclopropane, and (b) its rearrangement to 2,2-dideuterio-1-(difluoromethylene)-cyclopropane. The observed experimental ratio of these two rate constants, 2.3, is consistent with Borden's theoretically predicted ratio of 3.     

Synthesis of 2-iminothiazoline derivatives by sequential conjugate addition/annulation/ring-opening reactions

1,2-Diaza-1,3-butadienes reacted with rhodanine affording 2-(mercaptoacetyl)iminothiazoline derivatives through conjugate addition/annulation/ring-opening/oxidative dimerization. The hypothesized ring-closure and ring-opening mechanism was supported by X-ray crystal structure analysis of a compound obtained by reaction of the same reagents with a chiral 1,3-oxazolidine-2-thione derivative.     

Synthesis of C-8 Deuterated Glycosides of 3-Deoxy-D-manno-oct-2-ulosonic Acid (Kdo) Related to Chlamydial Lipopolysaccharides

Summary.  Methyl glycosides of Kdo and a (2→8)-linked Kdo disaccharide were prepared which contain a deuterium label at C-8 of the reducing unit. The label was introduced in fair diastereoselectivity upon reduction of an aldehyde group using a chiral borane complex derived from N-benzyloxycarbonyl-(S)-proline which produced the 8-(S)-deuterated derivative as the major isomer. Further coupling with a Kdo bromide gave the α-(2→8)-linked disaccharide in good yield. The deprotected disaccharide serves as a model for NMR spectroscopic studies on the side chain conformation of a carbohydrate epitope from the bacterial pathogen Chlamydia. Received September 17, 2001. Accepted October 17, 2001     

Kinetic resolution of C1-substituted oxabenzonorbornadienes by Ir-catalyzed asymmetric [2+2] cycloaddition reactions with arylacetylenes

The kinetic resolution of racemic C1-substituted oxabenzonorbornadienes was realized by iridium-catalyzed asymmetric [2+2] cycloaddition reaction with arylacetylenes. Cyclobutene products and unreacted C1-substituted oxabenzonorbornadienes were obtained with high to excellent enantiomeric purities.     

Sequenced elimination-reduction and elimination-cyclopropanation reactions of 2,3-epoxyamides promoted by samarium diiodide. Synthesis of 2,3-dideuterioamides and cyclopropanamides

An easy and general sequenced elimination/reduction or elimination/cyclopropanation process promoted by samarium diiodide or/and CH₂I₂/Sm provide an efficient method for synthesising 2,3-dideuterioamides 3 or cyclopropanamides 8, respectively. The transformations take place in high yields and with total or high selectivity from the easily available 2,3-epoxyamides.     

Synthesis of trifluoromethyl-substituted cyclopropanes via sequential Kharasch-dehalogenation reactions

A two-step process for the synthesis of trifluoromethyl-substituted cyclopropanes is described. Halothane, an anesthetic agent, is added to olefins in a ruthenium-catalyzed Kharasch reaction. The resulting 1,3-dihalides are converted into cyclopropanes by dehalogenation with magnesium. This procedure represents an alternative to metal-catalyzed cyclopropanations involving trifluoromethyl diazomethane.     

Synthesis of Deuterium‐Labeled Perfume Ingredients as Internal Standards for Their GC/MS Quantification

The synthesis of various D‐labeled perfume ingredients (orris‐like, sandalwood‐like, musky, and amber‐like) is presented. These substances, possessing practically identical H₂O/solid and solid/gas partition coefficients as their unlabeled analogues, are used as internal standards for the validation of a new analytical GC/MS method for the determination of low residual concentrations in H₂O after biodegradability tests.     

Synthesis of novel fused isoxazoles and isoxazolines by sequential Ugi/INOC reactions

We report the synthesis of novel fused isoxazoles and isoxazolines by employing an unprecedented Ugi/INOC synthetic sequence. The coupling of the Ugi multicomponent reaction with the intramolecular N-oxide cyclization provides access to unique heterocyclic ring systems in two steps from easily available starting materials in moderate to good overall yields.     

Synthesis of allocolchicines using sequential ring-closing enyne metathesis-Diels-Alder reactions

New allocolchinoids having functionality in the C ring at position C10 or C11 have been synthesized using the enyne ring-closing metathesis (RCM) reaction for construction of the seven-membered ring and a Diels-Alder-aromatization sequence for the elaboration of the aromatic ring C. [reaction: see text].     

Synthesis of fused bicyclic imidazoles by sequential van Leusen/ring-closing metathesis reactions

[reaction: see text]. A new strategy employing the van Leusen three-component reaction and the ring-closing metathesis reaction in a sequential fashion to access fused bicyclic imidazole rings is reported. The two-step sequence generated compounds of significant molecular complexity from simple starting materials in an expedient fashion with excellent yields.     

Synthesis of fused imidazo azepine derivatives by sequential van Leusen/enyne metathesis reactions

A facile synthesis of fused imidazo azepine derivatives by a van Leusen/intramolecular enyne metathesis synthetic sequence is reported. The two-step reaction sequence generates compounds of significant molecular complexity from simple starting materials in an expedient fashion with good overall yields.     

Synthesis of substituted pyrrolidines by sequential radical cyclization and N-acyliminium ion reactions

Readily available N-acyl-2-pyrrolines are converted into functionalized -alkoxy-β-iodopyrrolidines by N-iodosuccinimide promoted alcohol addition to the enamine group. These compounds are readily cyclized using a sodium cyanoborohydride-catalytic tributylstannane system affording functionalized pyrrolidines in good yields. The cyclized products undergo N-acyliminium ion reactions, such as BF₃·OEt₂ mediated addition of allyltrimethylsilane.     

Synthesis of fused imidazo-pyridine and -azepine derivatives by sequential van Leusen/Heck reactions

Fused imidazo-pyridine and -azepine derivatives were synthesized using a sequential van Leusen/intramolecular Heck protocol. The combination of a multicomponent reaction followed by an intramolecular carbon-carbon bond forming reaction generates heterocycles of significant molecular complexity from readily available starting materials in just two steps.