SN2-type Process Research Articles

Copper-Catalyzed Enantioconvergent Radical Suzuki-Miyaura C(sp3)-C(sp2) Cross-Coupling.

A copper-catalyzed enantioconvergent Suzuki-Miyaura C(sp3)-C(sp2) cross-coupling of various racemic alkyl halides with organoboronate esters has been established in high enantioselectivity. Critical to the success is the use of a chiral cinchona alkaloid-derived N,N,P-ligand for not only enhancing the reducing capability of copper catalyst to favor a stereoablative radical pathway over a stereospecific SN2-type process but also providing an ideal chiral environment to achieve the challenging enantiocontrol over the highly reactive radical species. The reaction has a broad scope with respect to both coupling partners, covering aryl- and heteroarylboronate esters, as well as benzyl-, heterobenzyl-, and propargyl bromides and chlorides with good functional group compatibility. Thus, it provides expedient access toward a range of useful enantioenriched skeletons featuring chiral tertiary benzylic stereocenters.

HFIP-Promoted Synthesis of Substituted Tetrahydrofurans by Reaction of Epoxides with Electron-Rich Alkenes.

In the present work, the employment of fluorinated alcohols, specifically 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), as solvent and promoter of the catalyst-free synthesis of substituted tetrahydrofuranes through the addition of electron-rich alkenes to epoxydes is described. The unique properties of this fluorinated alcohol, which is very different from their non-fluorinated analogs, allows carrying out this new straightforward protocol under smooth reaction conditions affording the corresponding adducts in moderate yields in the majority of cases. Remarkably, this methodology has allowed the synthesis of new tetrahydrofuran-based spiro compounds as well as tetrahydrofurobenzofuran derivatives. The scope and limitations of the process are also discussed. Mechanistic studies were also performed pointing towards a purely ionic or a SN2-type process depending on the nucleophilicity of the alkene employed.

Carbon–Carbon Bond Formation by Activation of CH3F on Alumina

The reaction of CH3F on partially dehydroxylated Al2O3 yields isobutene and higher hydrocarbons along with dimethyl ether. In a combined experimental and computational study, we show that the reaction starts through the initial formation of a methoxy intermediate observed experimentally and formed via an SN2 type process between surface O atoms and the CH3F molecule, which undergoes C–F activation on the most acidic Lewis site of the 110 termination of the Al2O3 surface. Coordination of an additional CH3F molecule on adjacent Al Lewis acid sites generates methyl cation-like species, which abstract a hydride from the adjacent initially generated surface methoxy species, yielding a “AlOCH2+” oxonium-like transient structure and CH4. Both species can further react, forming the first carbon–carbon bond by producing an ethoxy intermediate in a process very exoergic and with accessible energy barriers. This ethoxy intermediate can further react in successive exoergic steps with additional “activated” CH3F on Al sites leading to higher alkoxy species, which are finally liberated as isobutene and higher hydrocarbons.

Practical synthesis of anti-β-hydroxy-α-amino acids by Pd(II) -catalyzed sequential C(sp(3) )-H functionalization.

An improved and practical procedure for the stereoselective synthesis of anti-β-hydroxy-α-amino acids (anti-βhAAs), by palladium-catalyzed sequential C(sp(3) )-H functionalization directed by 8-aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β-methyl C(sp(3) )-H of alanine derivative, β-acetoxylation of both alkylic and benzylic methylene C(sp(3) )-H bonds affords various anti-β-hydroxy-α-amino acid derivatives. As an example, the synthesis of β-mercapto-α-amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β-branched α-amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side-chain AAs, which could be explained by the competition of intramolecular C-OAc bond reductive elimination from Pd(IV) intermediates vs. intermolecular attack by an external nucleophile (AcO(-) ) in an SN 2-type process.

Diastereodivergent Hydroxyfluorination of Cyclic and Acyclic Allylic Amines: Synthesis of 4-Deoxy-4-fluorophytosphingosines

A diastereodivergent hydroxyfluorination protocol enabling the direct conversion of some conformationally biased allylic amines to the corresponding diastereoisomeric amino fluorohydrins has been developed. Sequential treatment of a conformationally biased allylic amine with 2 equiv of HBF(4)·OEt(2) followed by m-CPBA promotes epoxidation of the olefin on the face proximal to the amino group under hydrogen-bonded direction from the in situ formed ammonium ion. Regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF(4)(-) ion (an S(N)2-type process at the carbon atom distal to the ammonium moiety) then occurs in situ to give the corresponding amino fluorohydrin. Alternatively, an analogous reaction using 20 equiv of HBF(4)·OEt(2) results in preferential epoxidation of the opposite face of the olefin, which is followed by regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF(4)(-) ion (an S(N)2-type process at the carbon atom distal to the ammonium moiety). The synthetic utility of this methodology is demonstrated via its application to a synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingosine, each in five steps from Garner's aldehyde.

Probing O-dealkylation and deamination aging processes in tabun-conjugated AChE: a computational study

The mechanisms of the aging process of tabun-conjugated acetylcholinesterase were explored using density functional theory calculations. The free energy surfaces were calculated for O-dealkylation (C–O bond breaking) and deamination (P–N bond breaking) pathways for the aging process of tabun-conjugated acetylcholinesterase as suggested by mass and crystallographic studies. Initially, the calculations were performed using tabun-conjugated serine (SUN) molecule. O-dealkylation mechanism proceeds via one-step SN2 type process, whereas the deamination process proceeds via two steps addition–elimination reaction at the phosphorus center of SUN molecule. The recent proposal of another deamination mechanism using human butyrylcholinesterase (hBChE) conjugated with N-mono methyl analogue of tabun (TA4) has also been explored (Nachon et al. in Chem Biol Interact 187:44–48, 2010). The rate-determining activation barrier calculated for this deamination mechanism (26.3 kcal/mol) was comparable with O-dealkylation process (26.9 kcal/mol) with B3LYP/6-31+G* level of theory. To examine the influence of catalytic residue His447, additional calculations were performed with imidazole group of His447 residue. The incorporation of imidazole group of catalytic residue His447 showed marked decrease in the free energies of activation for all the studied aging processes of tabun-inhibited serine. The aging mechanisms have been explored with TA4-inhibited serine, and calculated results showed that the deamination with the rearrangement process is markedly preferred in this case, which supports the Nachon et al. proposal based on the crystallographic studies.

α‐Sulfinyl Carbanions as a New Source of Olefins.

AbstractFor Abstract see ChemInform Abstract in Full Text.

ChemInform Abstract: NUCLEOPHILIC SUBSTITUTION WITH PHOSPHIDE ANIONS PREPARED BY AN ACTION OF SODIUM DIHYDRIDOBIS(2‐METHOXYETHANOLATO)ALUMINATE ON PHOSPHORUS COMPOUNDS

AbstractBei Umsetzung des Phosphinoxids (I) mit Alkylhalogeniden (II) entstehen gemäß der Titelreaktion die Derivate (III) mit einer neu gebildeten P‐C‐Bindung.

Nucleophilic Substitution with Phosphide Anions Prepared by an Action of Sodium Dihydridobis(2-methoxyethanolato)aluminate on Phosphorus Compounds

Abstract Phosphide anions, prepared by an action of sodium dihydridobis(2-methoxyethanolato)aluminate on derivatives of phosphine, phosphine oxide, or phosphorus esters, react with primary and secondary alkyl halides to produce phosphine derivatives having a newly formed phosphorus-carbon bond. The reactivity increases in the order of chloride<bromide<iodide and of secondary<primary in alkyl halide. Reaction of phosphide anion is also feasible with p-toluenesulfonate. Reaction of an anion of diphenylphosphine oxide seems to proceed mainly as an SN2 type process.

ChemInform Abstract: FORMATION OF 5‐PHENYLTETRAZOLE FROM N2‐BENZOYL‐N4‐(PHENYLSULFONYL)BENZOHYDRAZIDE HYDRAZONE

AbstractDas aus dem Hydrazon (I) und Benzoesäurehydrazid erhältliche Hydrazidhydrazon (II) cyclisiert sich in Gegenwart von HgO/K,CO3 zu 5‐Phenyl‐tetrazol (III).

Formation of 5-Phenyltetrazole from N2-Benzoyl-N4-(phenylsulfonyl)benzohydrazide Hydrazone

Abstract 5-Phenyltetrazole is obtained in a moderate yield by the mercury(II) oxide oxidation of the title hydrazidine prepared from N-(phenylsulfonyl)benzohydrazonoyl chloride and benzohydrazide. The tetrazole formation is interpreted in terms of an intramolecular SN2 type process of the intermediate formazan with the removal of benzenesulfinic acid. In the absence of oxidizing agents, the hydrazidine gives 2,5-diphenyl-1,3,4-oxadiazole and 3,5-diphenyl-4-phenylsulfonylamino-4H-1,2,4-triazole.

Mechanism of Oxygen Exchange Reaction of Diaryl and Alkyl Aryl Sulfoxides in Sulfuric Acid

Abstract The mechanistic investigations of the concurrent oxygen exchange and racemization reactions of 18O-labeled and optically active methyl p-tolyl sulfoxide (I) and phenyl p-tolyl sulfoxide (II) in sulfuric acid of various concentrations have been carried out by the determination of detailed kinetics. The kinetic data were analyzed in the lights of kex⁄krac values, activation parameters, correlations between the rates and acidity functions, solvent isotope effects, polar effects of substituents, etc.. A gradual change of mechanism of the reaction from an SN2 type process to a predominant A-1 like one (in above 95% sulfuric acid) with the increase of the concentration of sulfuric acid was observed. All these observations suggest that the A-1 like reaction takes place through a cation radical (–\overset+·S–) or a dication (–\overset++S–) intermediate at higher concentrations of sulfuric acid, while the SN2 type reaction that involves a water molecule as nucleophile in the rate-limiting step is the predominant path in less concentrated sulfuric acid.

Acid and Basic Hydrolyses of p-Nitrophenyl Benzenesulfonate

Abstract The mechanisms of both the acid- and the alkaline-catalyzed hydrolyses of p-nitrophenyl benzenesulfonate have been investigated by means of the 18O-tracer technique. The acid-catalyzed hydrolysis apparently proceeds via a SN2-type process involving the nucleophilic attack of water on the sulfur atom, with a S–O bond cleavage. Much as with the earlier findings concerning other nucleophiles, the major portion of the alkaline hydrolysis was also found to proceed through a SN2 process which involves the nucleophilic attack of the hydroxide ion on the sulfur atom, with a S–O bond fission; only a small portion of the reaction appeared to proceed via an aromatic SN2-type process.