Eschenmoser Sulfide Contraction Research Articles

Synthesis of hybrid molecules based on thioglycolurils and 1,2,5-oxadiazoles via the Eschenmoser sulfide contraction

A simple synthesis of novel hybrid molecules containing methylidenehexahydroimidazo[4,5-d]imidazol-2(1H)-one and 1,2,5-oxadiazole moieties is based on the Eschenmoser sulfide contraction involving alkylative precoupling of thioglycolurils with 3(4)-bromoacetyl-1,2,5-oxadiazoles. The proposed method does not require using toxic PPh3 for sulfur extrusion. The synthesized compounds may serve as platforms for constructing both new bioactive and new high- energy compounds.

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones.

A wide range of N-(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between N-(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1H-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower temperature and microwave power, although requiring much longer time. A possible mechanism for the cyclization is presented, and further functionalization of the newly created pyrrole ring in the dihydropyrrolizine core is described.

A Direct, Versatile, and Chemoselective Synthesis of Vinylogous Bis‐ and Monourethanes/amides and β‐Keto Esters by Aza‐Knoevenagel‐Type Reactions of Tertiary Amides with Enolates

Full details of our investigations into aza‐Knoevenagel‐type reactions with common tertiary amides as the electrophilic partner are reported. The method is based on the addition of stabilized carbanionic nucleophiles to the amides, which are activated in situ with triflic anhydride (Tf2O). The reaction proceeds under mild conditions and tolerates several sensitive functional groups including enamide and tert‐butyldimethylsilyloxy (TBSO) groups. Significantly, with amides bearing more reactive ester, cyano, and aldehyde groups, the reaction occurs chemoselectively at the least reactive amide group. Such “umpolung” of the chemoselectivity in C=C bond formation is challenging, rare, and of synthetic value. Vinylogous bis‐urethanes (aza‐Knoevenagel‐type condensation products), vinylogous urethanes, and vinylogous amides can be synthesized by employing enolates/carbanions generated from methyl ketones, malonic acid monoester, 2‐phenylacetate, or (benzylsulfonyl)benzene. Moreover, when higher homologues of acetate were used, β‐keto esters were obtained directly from amides. The method has been applied to the one‐step syntheses of several known key intermediates in the total syntheses of alkaloids and 4‐quinolone antibiotics. An efficient and mild intramolecular Friedel–Crafts‐type cyclization of an anilinyl ester has also been achieved with Tf2O as an effective promoter. This amide‐based method is a direct and umpoled alternative to the versatile but stepwise one based on thionation and the Eschenmoser sulfide contraction.

ChemInform Abstract: Yb(OTf)3‐Mediated Access to Furans from β‐Ketothioamides via Eschenmoser Sulfide Contraction Reaction.

AbstractVarious β‐ketothioamides are treated with arylglyoxals under conditions A) to produce highly substituted furan structures as important synthons in natural product and medicinal chemistry.

Yb(OTf)3-Mediated Access to Furans from β-Ketothioamides via Eschenmoser Sulfide Contraction Reaction.

A mild and straightforward synthetic protocol for construction of a furan skeleton promoted by Yb(OTf)3 from β-ketothioamides and arylglyoxals has been developed at room temperature. Importantly, this protocol involves a tandem sequence that includes aldol condensation, N-cyclization, ring opening, O-cyclization, S-cyclization, and Eschenmoser sulfide contraction.

ChemInform Abstract: The Eschenmoser Sulfide Contraction Method and Its Application in the Synthesis of Natural Products

AbstractReview: [173 refs.

Tertiary amide-based Knoevenagel-type reactions: a direct, general, and chemoselective approach to enaminones.

We report one-pot and chemoselective Knoevenagel-type reactions using highly stable amides and lactams as the electrophilic substrates. The method is based on the in situ activation of amide carbonyl with triflic anhydride and a subsequent reaction with carbanions generated in situ from carbonyl compounds. The amide-based method is an alternative to the versatile thioamide-based Eschenmoser sulfide contraction.

Unexpected Formation of Thiophene-annulated Tetrahydro-3- benzazepines by Alkylation of Thiolactams with Ethyl Bromoacetate

In order to synthesize enantiomerically pure tetrahydro-3-benzazepines with diverse substitution patterns, the lactams 3 were converted into thiolactams 4 upon treatment with Lawesson’s reagent. Instead of an Eschenmoser sulfide contraction a thiophene annulation reaction occurred, when the thiolactams 4 were reacted with ethyl bromoacetate. Altogether, enantiomerically pure thiopheneannulated 3-benzazepines 7 were prepared in a very short reaction sequence (five reaction steps) starting from commercially available o-phenylenediacetic acid

Development of a Second-Generation Process to Antibacterial Candidate Sulopenem

The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with the first-generation synthesis were partially addressed in an improved second-generation synthesis of the target molecule where the penem ring is constructed via a modified Eschenmoser sulfide contraction sequence. Other highlights of the second-generation process include an improved synthesis of an important trithiocarbonate intermediate and a superior process for Pd-catalyzed deallylation of the penultimate ester to obtain low levels of residual palladium.

ChemInform Abstract: Total Synthesis of (2S,3S,4R)-Plakoridine A.

Abstract The β-amino ester 6 is synthesized via the diastereoselective Michael addition of the lithium amide derived from amine 5 to methyl ( E )-2-hexenoate. This ester is converted to the pyrrolidinone 8 via an aldol condensation/deprotection/cyclization. Transformation of the lactam 8 into thiolactam 11 followed by Eschenmoser sulfide contraction provides (2 S ,3 S ,4 R )-plakoridine A.

Facile conversion of Biginelli 3,4-dihydropyrimidin-2(1 H)-thiones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidines via Eschenmoser coupling

A one-pot, two-step synthesis protocol for the conversion of Biginelli 3,4-dihydropyrimidin-2(1 H)-thiones to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidine (DHPM) derivatives via Eschenmoser sulfide contraction coupling is described. Solution phase as well as solid-supported protocol was carried out for the decoration of the Biginelli DHMP scaffold at the C-2 position. The scope of the optimized protocol is demonstrated for different DHMP precursors.

Rapid diastereocontrolled synthesis of 2,2,5-trisubstituted pyrrolidines

2,2,5-Trisubstituted pyrrolidines are available from allylic pyroglutamates by Ireland-Claisen ester rearrangement followed by Eschenmoser sulfide contraction and reduction in a highly diastereoselective and efficient sequence. Some of the products from this sequence exhibit activity against S. aureus, but are much less active against E. coli.

A Versatile Synthesis of (±)-Deoxyfebrifugine, an Antimalarial Alkaloid Analogue, and Related Compounds

The title compound was prepared by a simple route involving Eschenmoser sulfide contraction between 3-(3-bromo-2-oxopropyl)quinazolin-4(3H)-one (11) and piperidine-2-thione (13) followed by chemoselective catalytic hydrogenation. This short but flexible procedure also permitted access to N-alkyl analogues, and to analogues in which the piperidine ring was replaced by other ­saturated nitrogen-containing heterocycles.

Studies Towards the Total Synthesis of Batzelladine A.

Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction. An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the particular compounds required for this target.

Studies towards the total synthesis of batzelladine A.

Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction. An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the particular compounds required for this target.

Synthetic studies of carzinophilin. Part 1: Synthesis of 2-methylidene-1-azabicyclo[3.1.0]hexane systems related to carzinophilin

Synthesis of the model compounds of carzinophilin carrying 2-methylidene-1-aza-bicyclo[3.1.0]hexane systems was achieved. Formation of malonylidenes or N-acyl-glycinylidenepyrrolidines was carried out by utilizing Eschenmoser's sulfide contraction or Herdeis's condensation between the 2-methylthio-Δ 1-pyrrolone derivatives and ethyl nitroacetate, respectively. The 1-azabicyclo-[3.1.0]hexane systems were constructed by base-promoted aziridine formation.

A concise and stereoselective synthesis of (+/−)- erythro-methylphenidate

A concise and stereoselective synthesis of racemic erythro-methylphenidate ( 1 ) is described. The coupling reaction between piperidine-2-thione ( 3 ) and 2-bromo-2-phenylmethylacetate ( 4 ) afforded the β-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/−)- erythro-methylphenidate in good yields with dr >95%.

Influence of ring size on the outcome of sulfide contraction reactions with thiolactams. Isolation of bicyclic ketene S,N-acetals and thioisomünchnones

Reaction between diethyl bromomalonate and 3-phenylpyrrolidine-2-thione yielded a vinylogous urethane by the Eschenmoser sulfide contraction. However, with 3-substituted piperidine-2-thiones, sulfur was retained in the products, and a range of bicyclic heterocycles, including bicyclic ketene S,N-acetals (2-alkylidene-1,3-thiazolidin-4-ones) and stable thioisomunchnones, was isolated. A novel dimeric ketene S,N-acetal was characterised by X-ray crystallography.

Total synthesis of (2 S,3 S,4 R)-plakoridine A

The β-amino ester 6 is synthesized via the diastereoselective Michael addition of the lithium amide derived from amine 5 to methyl ( E)-2-hexenoate. This ester is converted to the pyrrolidinone 8 via an aldol condensation/deprotection/cyclization. Transformation of the lactam 8 into thiolactam 11 followed by Eschenmoser sulfide contraction provides (2 S,3 S,4 R)-plakoridine A.

Stereocontrolled Synthesis of a Nonracemic Vitamin B12 A−B-Semicorrin

The first synthesis of a vitamin B12 A−B-semicorrin 44 is described. Both A and B rings were prepared from the same precursor, enamide 40, which is obtained by a sequence of sigmatropic rearrangements and a biomimetic oxylactonization. The coupling has been achieved via Eschenmoser sulfide contraction. A−B-semicorrin 44 allows a new approach toward vitamin B12 and other uroporphinoids.