Highly regio- and stereocontrolled brominations of gem-difluorinated vinyloxiranes

gem-Difluorinated vinyloxiranes, which are useful synthetic intermediates for difluorinated compounds, were brominated regio- and stereoselectively. Introduction of bromide at the allylic epoxide carbon with inversion of stereochemistry was realized by MgBr₂·Et₂O to furnish an anti vic-bromohydrine, whereas the reaction with LiBr/AcOH afforded the other diastereomer selectively. Moreover, both reactions at high temperature allowed to obtain, the thermodynamically favored products, E-allylic alcohols dominantly.     

Electrophilic monofluoromethylation of O-, S-, and N-nucleophiles with chlorofluoromethane

CH₂ClF has been found to be a useful electrophilic monofluoromethylating agent for a variety of O-, S-, and N-nucleophiles. The reaction is not sensitive to the radical scavenger such as nitrobenzene, which strongly supports an S_N2 mechanism rather than an SET mechanism. Although most of these products (fluoromethyl ethers, sulfides, and amines) can be isolated with good purity, some of these compounds do intend to decompose (via defluorination) during storage. The electrophilic monofluoromethylation of carbon-nucleophiles was attempted with CH₂ClF, CH₂FI, or FCH₂OTs as monofluoromethylating agents, but with no success.     

Concise synthesis of trans- and cis-3,4-disubstituted piperidines based on regio- and stereoselective allylation of cyclopentenyl esters

3,4-Disubstituted piperidines were synthesized through anti S_N2′ allylation of 4-substituted 2-cyclopentenyl esters with reagents based on RMgX and CuX, thus allowing equal access to both trans- and cis-isomers. As an application, the paroxetine intermediate was synthesized efficiently. During the investigation, the MeOCH₂CO₂ group was found to show high reactivity in the pivotal anti S_N2′ type reaction using the reagent derived from (i-PrO)Me₂SiCH₂MgCl and CuCN.     

Preparation of N-protected allylic amines and α-methylene-β-amino acids from vinylalumination/Baylis-Hillman products via tandem SN2′ substitution-Overman rearrangement

S_N2′ reaction on the acetates obtained from vinylalumination or Baylis-Hillman products, followed by in situ reduction afforded allylic alcohols. Upon conversion to trichloroacetimidates and [3,3]-sigmatropic rearrangement, the corresponding N-protected β-substituted allylic amines were obtained in good yields. Utilization of hydroxy group as the nucleophile furnished allylic hydroxy esters, which were converted to protected α-methylene-β-amino acids via Overman rearrangement.     

Stereoselective synthesis of anti-2-oxazolidinones by Ph3P-CCl4-Et3N mediated SN2 cyclization of N-Boc-β-amino alcohols

Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent yields using the Ph₃P-CCl₄-Et₃N system by S_N2 cyclization of N-Boc-β-amino alcohols. syn to anti conversion of ethyl 4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates using DBU as base is also described.     

Nucleophilic vinylic substitutions of (Z)-(2-aroyloxyvinyl)phenyl-λ-iodanes with tetrabutylammonium halides: vinylic SN2 reactions and ligand coupling on iodine(III)

Treatment of (Z)-(β-benzoyloxyvinyl)phenyl-λ³-iodanes, readily prepared from ethynyl(phenyl)(tetrafluoroborato)-λ³-iodane via stereoselective Michael-type addition of benzoic acids in methanol in the presence of sodium benzoates, with tetrabutylammonium halides in THF at 65 °C results in a vinylic S_N2 reaction to give the inverted (E)-β-benzoyloxyvinyl halides in high yields.     

Effects of stereochemistry and β-substituents on the rates of vinylic SN2 reaction of hypervalent vinyl(phenyl)-λ-iodanes with tetrabutylammonium halides

Both stereoisomers of β-(2-phenylethoxy)vinyl-λ³-iodane and (Z)-β-aroyloxyvinyl-λ³-iodane were prepared stereoselectively. These substituted vinyl-λ³-iodanes undergo nucleophilic vinylic substitutions with n-Bu₄NX (X=Cl, Br, I) under mild conditions, yielding vinyl halides. The observed inversion of configuration at the ipso vinylic carbon atom is compatible with a concerted vinylic S_N2 mechanism. Kinetic measurements indicated that the rates for vinylic S_N2 reaction of (Z)-vinyl-λ³-iodane are greater than those of the E-isomer, probably because of the higher ground state energy of the Z-isomer. Electronic effects of β-substituents of vinyl-λ³-iodanes in the vinylic S_N2 reaction are also discussed.     

One-pot synthesis of N-alkyl purine and pyrimidine derivatives from alcohols using TsIm: a rapid entry into carboacyclic nucleoside synthesis

A convenient and efficient one-pot N-alkylation of nucleobases from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, treatment of alcohols with a mixture of purine or pyrimidine nucleobase, TsIm, K₂CO₃, and triethylamine in refluxing DMF regioselectively furnishes the corresponding N-alkyl nucleobases in good yields. This methodology is highly efficient for various structurally diverse primary alcohols.     

Lewis acid mediated SN2-type nucleophilic ring opening followed by [4+2] cycloaddition of N-tosylazetidines with aldehydes and ketones: synthesis of chiral 1,3-oxazinanes and 1,3-amino alcohols

A highly efficient strategy for Cu(OTf)₂ mediated S_N2-type nucleophilic ring opening followed by [4+2] cycloaddition reactions of enantiopure 2-phenyl-N-tosylazetidines with various aldehydes and ketones afforded a variety of substituted 1,3-oxazinanes and 1,3-amino alcohols in excellent yields, excellent de and good to excellent ee. The proposed S_N2-type mechanism of the cycloaddition reaction is supported by experimental evidence.     

The reaction of biphenyl radical anion and dianion with alkyl fluorides. From ET to SN2 reaction pathways and synthetic applications

The reaction of dilithium biphenyl (Li₂C₁₂H₁₀) with alkyl fluorides has been studied from the point of view of the distribution of products. Two main reaction pathways, the nucleophilic substitution (S_N2) and the electron transfer (ET), can compete to yield the same alkylation products in what is known as the S_N2-ET dichotomy. S_N2 seems to be the main mechanism operating with primary alkyl fluorides (n-RF). Alkylation proceeds in good yields, and the resulting alkylated dihydrobiphenyl anion (n-RC₁₂H₁₀Li) can be trapped with a second conventional electrophile (E⁺) affording synthetically interesting dearomatized biphenyl derivatives (n-RC₁₂H₁₀E). The reaction gives a higher amount of ET products as we move to secondary (s-RF) and to tertiary alkyl fluorides (t-RF), in which case the mechanism seems to be dominated by ET. In this case, alkylation by radical coupling is still feasible, giving access to the synthesis of t-RC₁₂H₁₀E, although in lower yields. A rational interpretation of this S_N2-ET dichotomy is given on the basis of the full distribution of products observed when 5-hexenyl fluoride and 1,1-dimethyl-5-hexenyl fluoride were are used as radical probes in their reaction with Li₂C₁₂H₁₀ and LiC₁₂H₁₀.     

Metal-organic chains constructed from pre-organized N2S2 donor ligands

Three new N₂S₂ donor ligands 1,1′-((2-(2-(phenylthio)phenylthio)phenyl)methylene)bis(3,5-R-1H-pyrazole), R = H (L^H), R = Me (L^Me), R = i-Pr (L^i-Pr) have been prepared and characterized. These bifunctional ligands incorporate two distinct chelate donor systems, by virtue of the presence of bispyrazole and bisthioether functions. The preferred conformation of these ligands is such that the N₂ and S₂ donor moieties may be oriented in opposite directions, thus favoring the formation of molecular chains when treated with AgBF₄. The X-ray structures of Ag(I) complexes show that, depending on the steric hindrance present on the pyrazole rings, these ligands behave as κ⁴-SSNN-μ bridging tetradentate (when R = H), or κ³-SNN-μ bridging tridentate (when R = Me, i-Pr). Interestingly, [Ag(L^H)]BF₄ crystallizes in the chiral space group P4₁, with the molecular chain that is folded around the 4₁ screw axis.     

Expedient synthesis of β,β-disubstituted α-methylenepropionates

Baylis-Hillman alcohols are excellent sources of the allylic halides ArCHCH(CH₂X)(CO₂R) (X=Br, Cl; R¹=Me, Et, Bu^t). The Z double bond isomers are attained in high isomeric purity (>14:1, Z/E). The halides are chemo- and regiospecifically transformed into the acrylates (ArCHR²)C(CH₂)(CO₂R¹) on treatment with Zn(R²)₂ (R²=Me, Et, CH₂TMS, CH₂SiMe₂OMe) or PrZnBr in the presence of catalytic amounts of copper(I) salts (0.5-20 mol%) in high yield.     

New synthetic method of 1,2-diaryl-1,2-dicarba-closo-dodecaboranes employing aromatic nucleophilic substitution (SNAr) reaction

Aromatic nucleophilic substitution (S_NAr) reaction of 1-phenyl-o-carborane with 4-nitrofluorobenzene in the presence of NaH or KO^tBu proceeded smoothly to give 1-(4-nitrophenyl)-2-phenyl-o-carborane; similar reaction affords various 1,2-diaryl-o-carboranes, which are useful precursors for macromolecular construction and drug design.     

Lewis acid mediated nucleophilic ring opening followed by cycloaddition of 2-aryl-N-tosylaziridines with carbonyl compounds: further support towards an SN2-type mechanism

A highly regioselective S_N2-type ring opening of 2-aryl-N-tosylaziridines with carbonyl compounds in the presence of a Lewis acid to afford various 1,3-oxazolidines and 1,2-amino alcohols in excellent yields and moderate to high enantioselectivity is described. The formation of non-racemic products provides convincing evidence for the S_N2-type ring opening mechanism.     

An efficient one-pot protocol for asymmetric bifunctionalization of 5,15-disubstituted porphyrins: direct access to meso activated alkenyl-substituted meso-formylporphyrins

An efficient one-pot protocol for the direct conversion of free base 5,15-disubstituted porphyrins into the corresponding meso activated alkenyl-substituted meso-formylporphyrins has been developed using a sequential S_NAr reaction with PyMe₂SiCH₂Li, conjugate addition to enones or alkenoates in the presence of TMSCl, and oxidation with DDQ.     

Aerobic alcohol oxidation using a PdCl2/N,N-dimethylacetamide catalyst system under mild conditions

A new and simple PdCl₂/DMA catalytic system for the alcohol oxidation has been developed using molecular oxygen as the sole oxidant under mild conditions. The catalytic system could be reused for three runs without significant loss of catalytic activity. A variety of active and non-active alcohols were oxidized to their corresponding carbonyl compounds in good to excellent yields. Gas-uptake kinetics for the catalytic system was also investigated. The ca. 1:1 molar ratio of O₂ uptake to product yield is observed, suggesting the in situ formation of H₂O₂.     

A practical and efficient procedure for reduction of carboxylic acids and their derivatives: use of KBH4-MgCl2

The use of KBH₄-MgCl₂ to reduce carboxylic acids and their derivatives to the corresponding alcohols or the respective reduced products is described. Methyl (S)-3,4-O-isopropylidene-3,4-dihydroxy butanoate 2 used as a reference substrate was reduced with KBH₄ and MgCl₂ in 1:1 mol ratio to (S)-1,2-O-isopropylidene-1,2,4-butanetriol 1.     

Versatile acenaphtho[1,2-b]pyrrol-carbonitriles as a new family of heterocycles: diverse SNAr reactions, cytotoxicity and spectral behavior

The diverse reactivity of highly electron-deficient 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile 1 is attractive for the preparation of derivatives bearing different substituents via S_NAr^H reaction with N, O, S nucleophiles. These derivatives were versatile, possessing potential antitumor activities and displaying tunable fluorescence spectral behavior.     

Regio- and stereoselective reactions of a rhodanine derivative with optically active 2-methyl- and 2-phenyloxirane

The reaction of a rhodanine derivative (=(Z)-5-benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one; 1) with (S)-2-methyloxirane (2) in the presence of SiO₂ in dry CH₂Cl₂ for 10 days led to two diastereoisomeric spirocyclic 1,3-oxathiolanes 3 and 4 with the Me group at C(2) (Scheme 2). The analogous reaction of 1 with (R)-2-phenyloxirane (5) afforded also two diastereoisomeric spirocyclic 1,3-oxathiolanes 6 and 7 bearing the Ph group at C(3) (Scheme 3). The structures of 3, 4, 6, and 7 were confirmed by X-ray crystallography (Figs. 1 and 2). These results show that oxiranes react selectively with the thiocarbonyl group (CS) in 1. Furthermore, the nucleophilic attack of the thiocarbonyl S-atom at the SiO₂-activated oxirane ring proceeds with high regio- and stereoselectivity via an S_N2-type mechanism.     

Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction with complete inversion of configuration

Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields at elevated temperatures (80-100°C). The S_N2 displacement pathway is evident by complete inversion of the (S)-alcohol to (R)-ether.