Swern Oxidation Research Articles

Selective Oxidation of Lignin Model Compounds.

Lignin, the planet's most abundant renewable source of aromatic compounds, is difficult to degrade efficiently to welldefined aromatics. We developed a microwave-assisted catalytic Swern oxidation system using an easily prepared catalyst, MoO2 Cl2 (DMSO)2 , and DMSO as the solvent and oxidant. It demonstrated high efficiency in transforming lignin model compounds containing the units and functional groups found in native lignins. The aromatic ring substituents strongly influenced the selectivity of β-ether phenolic dimer cleavage to generate sinapaldehyde and coniferaldehyde, monomers not usually produced by oxidative methods. Time-course studies on two key intermediates provided insight into the reaction pathway. Owing to the broad scope of this oxidation system and the insight gleaned with regard to its mechanism, this strategy could be adapted and applied in a general sense to the production of useful aromatic chemicals from phenolics and lignin.

Synthesis of Substrates for Aldolase-Catalysed Reactions: A Comparison of Methods for the Synthesis of Substituted Phenylacetaldehydes

Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic acid (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydro­lysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

Stereocontrolled Synthesis of Resolvin D4.

The stereoselective synthesis of resolvin D4 (RvD4) was achieved using the Wittig reaction of the C1-C10 dienal with the known C11-C22 phosphonium salt. The ( S, E)-enantiomer ( S)-10, corresponding to the C1-C8 part, was synthesized in 95% ee by the asymmetric transfer hydrogenation reaction of the corresponding acetylenic ketone followed by Red-Al reduction. Sharpless epoxidation of this alcohol using Ti(O- i-Pr)4/l-(+)-DIPT as a catalyst produced anti epoxy alcohol with >99% ee as the sole product in 82% yield. A subsequent functional group manipulation, including removal of the PMB group, produced the alcohol, which upon Swern oxidation afforded anti 4-hydroxy-5-TBS-oxy enal via epoxide ring opening of the resulting aldehyde. The Horner-Wadsworth-Emmons reaction was used to add the C9-C10 enal part to this aldehyde, and the resulting dienal was subjected to the Wittig reaction with C11-C22 phosphonium salt to furnish the entire structure of RvD4. Conversion of the primary alcohol to the methyl ester and deprotection of the three TBS groups with TBAF afforded 5,17-dihydroxy-γ-lactone, which was hydrolyzed to RvD4. Additionally, anti-4,5-dihydroxydodecanoic acid, a model compound of RvD4, in CD3OD was observed to be stable at room temperature for several weeks, whereas 20% of the acid in CDCl3 was converted into the γ-lactone after 24 h at rt.

Synthesis of benzaldehyde by Swern oxidation of benzyl alcohol in a continuous flow microreactor system

Preparation of benzaldehyde by Swern oxidation of benzyl alcohol was carried out in a continuous flow microreactor system. Dimethyl sulfoxide (Me2SO) was used as oxidizing agent and oxalyl chloride or p-toluenesulfonyl (p-TsCl) chloride was used as the activating agent. Benzyl alcohol was oxidized to benzaldehyde by the Me2SO-activating agent mixture in the continuous flow microreactor system. The optimized reaction conditions of the Swern oxidation were as follows: oxalyl chloride was used as the activating agent; the mole ratio of Me2SO, oxalyl chloride, and benzyl alcohol was 4:2:1; the ow rate of Me2SO was 1.5 mL/min; the reaction temperature was 15 length of delay loop was 1.5 m; a Caterpillar Split-Recombine Micro Mixer was used; and all of the experiments were completed at atmospheric pressure. The yield of benzaldehyde can reach 84.7% with selectivity of 98.5%. Due to the small reactor volume and short residence times, the Swern oxidation of benzyl alcohol in a continuous flow microreactor system can be operated at nearly room temperature (5–19 ℃) instead of –70 ℃ in a batch reaction, with residence time of reactants in microreactors in milliseconds instead of several hours in a batch reaction.

Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (−)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO3-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.

Studies on the 6-homologation of β-D-idopyranosides

β-D-Idopyranosides are interesting sugars because of their unusual conformational flexibility in the pyranosyl ring, and also their β-1,2-cis-anomeric configuration. Here we report our studies of the regioselective opening of 4,6-O-benzylidene-protected β-D-idopyranosides under reducing conditions, and the subsequent 6-homologation via Swern oxidation and Wittig olefination to afford a 6,7-dideoxy-β-D-ido-hept-6-enopyranoside. This olefination product was found to adopt predominantly 1C4 conformation in solution by NMR experiments, which places the vinyl group at a more sterically hindered axial position and creates difficulty in subsequent hydroborations.

Utilization of a Trimethylsilyl Group as a Synthetic Equivalent of a Hydroxyl Group via Chemoselective C(sp3)-H Borylation at the Methyl Group on Silicon.

A conversion of trimethylsilylalkanes into the corresponding alcohols is established based on an iridium-catalyzed, chemoselective C(sp3)-H borylation of the methyl group on silicon. The (borylmethyl)silyl group formed by C(sp3)-H borylation is treated with H2O2/NaOH, and the resulting (hydroxymethyl)silyl group is converted into a hydroxyl group by Brook rearrangement, followed by oxidation of the resulting methoxysilyl group under Tamao conditions. An alternative route proceeding through the formylsilyl group formed from a (hydroxymethyl)silyl group by Swern oxidation is also established. The method is applicable to substituted trimethylsilylcycloalkanes and 1,1-dimethyl-1-silacyclopentane for conversion into the corresponding stereodefined cycloalkyl alcohols and 1,4-butanediol.

Oxidations of chromene-annulated chlorins.

A chromene-annulated chlorin is a meso-pentafluorophenyl-2,3-dihydroxychlorin in which one of the hydroxy groups is linked to the ortho-position of a flanking meso-aryl group, thereby forming an annulated chromene moiety; the second hydroxy group is unprotected. This report illustrates the oxidation chemistry of the chromene-annulated chlorin under a number of different oxidation conditions. In some reactions, chromene annulation is retained and the non-protected alcohol is oxidized, generating chlorin-like chromophores carrying pyrroline β-carbons in oxidation states between those found in typical porphyrins and chlorins. Other products have lost the chromene moiety. The reactivity of the pyrroline carbon with respect to undergoing radical chemistry is shown with the formation of a number of products following a Swern oxidation, including the formation of two directly linked pyrroline-pyrroline and pyrroline-pyrrole chlorin dimers. This work contributes to the further understanding of the chemistry of chlorins. Selected compounds possess functionalities at their periphery susceptible to nucleophilic attack by MeOH, suggesting their use as chemosensors.

Burgess Reagent Facilitated Alcohol Oxidations in DMSO.

The Burgess reagent ([methoxycarbonylsulfamoyl]triethylammonium hydroxide) has historically found utility as a dehydrating agent. Herein we show that, in the presence of dimethyl sulfoxide, the Burgess reagent efficiently and rapidly facilitates the oxidation of a broad range of primary and secondary alcohols to their corresponding aldehydes and ketones in excellent yields and under mild conditions, and can be combined with other transformations (e.g., Wittig olefinations). A mechanism similar to those described for the Pfitzner-Moffatt and Swern oxidations is proposed.

ChemInform Abstract: Efficient and Mild Swern Oxidation Using a New Sulfoxide and Bis(trichloromethyl)carbonate.

ABSTRACTA new type of sulfoxide, 4-(2-(2-(methylsulfinyl) ethyl)-4-nitrophenyl)- morpholine (I), was designed and prepared in good yield. Upon the combination of I and bis(trichloromethyl)carbonate, the Swern oxidation of primary and secondary alcohols was significantly promoted under mild conditions, which afforded the corresponding aldehydes or ketones in good yields. It is noteworthy that the reoxidation of the isolated by-product sulfide V could be further recycled in Swern oxidation.

ChemInform Abstract: Sc(OTf)3‐Catalyzed Addition of Bromomagnesium 2‐Vinyloxy Ethoxide to Various Aldehydes Leading to Protected Aldol Products.

The addition of bromomagnesium 2-vinyloxy ethoxide to various aldehydes in the presence of 10 mol% Sc(OTf) 3 provides a broad range of functionalized protected aldol compounds. The enantioselective preparation of these aldols can be achieved via a Swern oxidation–CBS reduction sequence. Use of the dioxolane derived from 2-bromocyclohexanone provides the expected aldol product as the anti diastereoisomer (dr >99:1).

Multigram-scale synthesis of l,d-heptoside using a Fleming-Tamao oxidation promoted by mercuric trifluoroacetate

An efficient multigram-scale synthesis of methyl 2,3,4,6-tetra-O-benzyl-l-glycero-α-d-manno-heptopyranoside from methyl 2,3,4-tri-O-benzyl-α-d-mannopyranoside is reported. It involves a sequence of Swern oxidation, Grignard addition and Fleming-Tamao reactions. The resulting scaffold was used as a precursor to design a small library of clickable l-heptosides. This study shows that the use of mercuric bistrifluoroacetate is required both to accelerate and to cleanly perform the Fleming-Tamao oxidation, without side-reactions.

Multicomponent Coupling Reaction and Intramolecular Nitrile Oxide–Alkyne Cycloaddition towards Isoxazolo[3,4]‐pyrrolizines

AbstractThis study reports an efficient four‐step method to synthesize a series of new (4S,8aS)‐3,4‐diphenyl‐6,7,8,8a‐tetrahydro‐4H‐isoxazolo[3,4‐a]pyrrolizines. The first step involves a copper(II) acetylacetonate catalyzed three component coupling of aldehyde, (S)‐pyrrolidin‐2‐ylmethanol, and alkynes (A3 coupling) to form propargylamines (4 a–4 n). The coupling reaction is applicable to various aldehydes, amines, and alkynes and provides the propargylamines in good to excellent yields with excellent distereoselectivities. Products (4 a–4 n) were converted into aldehydes (5 a–5 n) by Swern oxidation, aldehydes (5 a–5 n) were reacted with hydroxyl amine hydrochloride to form aldoxime (6 a–6 n), respectively. Further aldoximes (6 a–6 n) underwent an intramolecular 1,3‐dipolar cycloaddition to form tricyclic‐fused isoxazoles (7 a–7 n). The 1,3‐dipolar cycloaddition reaction tolerates high structural diversity and generated desired products (7 a–7 n) in moderate to good yields and excellent diastereoselectivities. A proposed mechanism for synthesis of 7 a is reported.

Efficient and mild swern oxidation using a new sulfoxide and bis(trichloromethyl)carbonate

ABSTRACTA new type of sulfoxide, 4-(2-(2-(methylsulfinyl) ethyl)-4-nitrophenyl)- morpholine (I), was designed and prepared in good yield. Upon the combination of I and bis(trichloromethyl)carbonate, the Swern oxidation of primary and secondary alcohols was significantly promoted under mild conditions, which afforded the corresponding aldehydes or ketones in good yields. It is noteworthy that the reoxidation of the isolated by-product sulfide V could be further recycled in Swern oxidation.

21,21,21‐Trifluorothevinone: the Straightest Way to Fluorinated Thevinols and Orvinols

AbstractThevinone is the key starting material for preparations of thevinols and orvinols, the well‐known opioid receptor ligands. Some of them have found applications both in human medicine and veterinary. Herein we disclose the convenient multigram‐scale preparation of 21,21,21‐trifluorothevinone that opens the straightest way to the relative C(21)‐fluorinated thevinols and orvinols, the putative opiod receptor ligands as well as the valuable objects for investigations of the structure‐activity relationship in the thevinol/orvinol series. 21,21,21‐Trifluorothevinone was prepared by a reaction of the thebaine‐based [4+2]‐adduct of acroleine with CF3SiMe3 followed by the Swern oxidation of the fluorinated alcohol thus obtained.

Sc(OTf)3-Catalyzed Addition of Bromomagnesium 2-Vinyloxy Ethoxide to Various Aldehydes Leading to Protected Aldol Products

The addition of bromomagnesium 2-vinyloxy ethoxide to various aldehydes in the presence of 10 mol% Sc(OTf)₃ provides a broad range of functionalized protected aldol compounds. The enantioselective preparation of these aldols can be achieved via a Swern oxidation–CBS reduction sequence. Use of the dioxolane derived from 2-bromocyclohexanone provides the expected aldol product as the anti diastereoisomer (dr >99:1).

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics Bearing a Hydroxyl Group, 3-Hydroxypyridinium Salts

A highly enantioselective hydrogenation of heteroaromatics bearing a hydroxyl group, 3-hydroxypyridinium salts, has been successfully developed using chiral iridium catalyst, providing a direct access to trans 6-substituted piperidin-3-ols with up to 95% ee. Swern oxidation of the hydrogenation products affords chiral 6-substituted piperidin-3-ones, which are easily reduced to cis 6-substituted piperidin-3-ols using K-selectride.

ChemInform Abstract: mCPBA‐Mediated Metal‐Free Intramolecular Aminohydroxylation and Dioxygenation of Unfunctionalized Olefins.

AbstractAminohydroxylation product (IVb) can be carried out at gram‐scale and the hydroxyl group can be further converted to a variety of different functional groups via conventional group transformation reactions such as azidation, bromination, acetylation, carboxylation and Swern oxidation.

A Facile and Efficient Synthesis of (15R)-Latanoprost from Chiral Precursor Corey Lactone Diol

An efficient asymmetric synthetic route for the synthesis of anti-glaucoma agent, (15R)-latanoprost using Corey lactone diol as chiral substrate under Swern oxidation, allylic reduction and Wittig reaction conditions has been developed. In this method, reduction of keto and alkene functional groups has been achieved in a single step using low cost catalyst NiCl2/NaBH4 in methanol. This new synthetic protocol is a good alternative for the synthesis of latanoprost with high stereo selectivity and improved yield. A simple, convenient and convergent approach for the synthesis of (15R) latanoprost is reported with high stereo selectivity and improved yield from chiral precursor Corey lactone diol using Swern oxidation, allylic reduction and Wittig reaction conditions.

Intramolecular Carbolithiation of 3-Lithioxy-5-alkenyllithiums as a Platform for Cyclopentanols and Cyclopentanones

Intramolecular carbolithiation of 3-lithioxy-5-hexenyllithiums was studied. Unlike the case of 5-hexenyllithium, the cyclization of 3-lithioxy-5-hexenyllithium was very sluggish. Acceleration was observed when lithium chloride was added, suggesting that intramolecular lithioxy coordination would hinder the cyclization. Introduction of a silyl or thiophenyl group at the olefin terminus caused smooth cyclization. The resulting dianions having a cyclopentane framework are subjected to C–C bond-forming reaction with electrophiles to give 3-substituted cyclopentanols. Coupled with the Swern oxidation, the overall protocol served as a platform for 3-substituted cyclopentanones.