Homoallylic Alcohols Research Articles

Indium mediated barbier-type allylation: Synthesis of highly functionalized homoallylic difluorohydrins

Indium-mediated Barbier-type allylation of halogenated difluoroacetophenone is reported for the first time. This method can directly and conveniently access homoallylic difluorohydrin alcohol blocks from halogenated difluoroacetophenones, and has good functional group compatibility. As a novel difluoromethylation reagent, the block has potential in the synthesis of fluorinated compounds.

Switchable Brønsted Acid‐Catalyzed Ring Contraction of Cyclooctatetraene Oxide Towards the Enantioselective Synthesis of Cycloheptatrienyl‐Substituted Homoallylic Alcohols and Oxaborinanes

AbstractThe ability of cyclooctatetraene oxide to undergo two sequential ring contraction events under mild conditions, using Brønsted acid catalysis, has been studied in detail. We have found that the selectivity can be controlled by the acidity of the catalyst and by the temperature, being able to obtain selectively either the cycloheptatriene carbaldehyde product, arising from a single ring‐contraction event, or phenylacetaldehyde that is formed after a second ring contraction process. A complete mechanistic picture of the reaction and a rationale behind the influence of the catalyst is provided based on both experimental and computational data. Finally, this acid‐catalyzed ring contraction has been coupled with an in situ enantioselective allylation reaction, delivering enantioenriched cycloheptatrienyl‐substituted homoallylic alcohols when it is carried out in the presence of a chiral phosphoric acid catalyst. These homoallylic alcohols have also been converted into enantioenriched oxaborinanes through copper‐catalyzed nucleophilic borylation/cyclization protocol.magnified image

Cobalt-Catalyzed Regiodivergent and Enantioselective Intermolecular Coupling of 1,1-Disubstituted Allenes and Aldehydes.

Catalytic enantioselective coupling of 1,1-disubstituted allenes and aldehydes through regiodivergent oxidative cyclization followed by stereoselective protonation or reductive elimination promoted by chiral phosphine-Co complexes is presented. Such processes represent unprecedented and unique reaction pathways for Co catalysis that enable catalytic enantioselective generation of metallacycles with divergent regioselectivity accurately controlled by chiral ligands, affording a wide range of allylic alcohols and homoallylic alcohols that are otherwise difficult to access without the need of pre-formation of stoichiometric amounts of alkenyl- and allyl-metal reagents in up to 92 % yield, >98 : 2 regioselectivity, >98 : 2 dr and >99.5 : 0.5 er.

Cobalt‐Catalyzed Regiodivergent and Enantioselective Intermolecular Coupling of 1,1‐Disubstituted Allenes and Aldehydes

AbstractCatalytic enantioselective coupling of 1,1‐disubstituted allenes and aldehydes through regiodivergent oxidative cyclization followed by stereoselective protonation or reductive elimination promoted by chiral phosphine‐Co complexes is presented. Such processes represent unprecedented and unique reaction pathways for Co catalysis that enable catalytic enantioselective generation of metallacycles with divergent regioselectivity accurately controlled by chiral ligands, affording a wide range of allylic alcohols and homoallylic alcohols that are otherwise difficult to access without the need of pre‐formation of stoichiometric amounts of alkenyl‐ and allyl‐metal reagents in up to 92 % yield, >98 : 2 regioselectivity, >98 : 2 dr and >99.5 : 0.5 er.

Transition-Metal-Free Unusual Oxidative Cleavage of Homoallylic Alcohol and Its Application in the Upcycling of Terpene to Value-Added Chemicals.

A NaOtBu-O2 -mediated oxidative dehomologation of homoallylic alcohols into structurally different carboxylic acids through direct oxidative cleavage of either the C(sp2 )-C(sp2 ) or C(sp3 )-C(sp3 ) bond utilizing enolate chemistry was demonstrated. Furthermore, under transition-metal-free conditions, this protocol has been applied to convert terpene as biomass feedstock into value-added chemicals.

Overcoming the Usual Reactivity of β-Nitroenones: Synthesis of Polyfunctionalized Homoallylic Alcohols and Conjugated Nitrotriene Systems

Herein, we report a new application of β-nitroenones as valuable building blocks for the preparation of polyfunctionalized homoallylic alcohols; they can be used as key precursors of conjugated nitrotriene systems. The synthesis of homoallylic alcohols was performed exploiting the chemoselective addition of metal allylating agents to the ketone moiety vs the nitroalkenyl group. The conversion of alcohols into nitrotrienes was achieved under Lewis-acid-promoted conditions. Both classes of compounds were obtained in good to excellent yields.

Enantioselective Ir-Catalyzed Hydrogenation of Terminal Homoallyl Sulfones: Total Synthesis of (-)-Curcumene.

A novel methodology for the preparation of chiral methyl benzylic compounds is reported. Terminal homoallyl sulfones were prepared from homoallyl alcohols, which are easily accessible through the recently reported Lewis acid isomerization of oxetanes. The iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones afforded γ-chiral sulfones with excellent enantioselectivities (up to 98% ee). The synthetic potential of this novel methodology was demonstrated by the total synthesis of (R)-(-)-curcumene.

Iridium-Catalyzed 1,3-Rearrangement of Allylic Alcohols.

The allylic alcohol structural motif is prevalent in many important molecules and valuable building blocks. The rearrangement reaction is one of the most important transformations, however there are only a few reports for the 1,3-rearrangement of allylic alcohols. Herein, a 1,3-rearrangement of allylic alcohols catalyzed by an Ir(III) dihydride complex is described. This reaction could provide the corresponding less accessible allylic alcohols regio- and stereoselectively from readily available E/Z mixtures of the substrates. Furthermore, a tandem alkene isomerization followed by 1,3-rearrangement of homoallylic alcohols was also realized. In addition, this rearrangement reaction could be used to synthesize the natural product Navenone B. Mechanistic investigation indicated that the reaction pathway involved a π-allyl-Ir(V) intermediate and that the dihydride in the iridium catalyst acts as a hydrogen switch to modulate the valence of the iridium center.

Sterically Hindered and Deconjugative α-Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement-Intermediate.

Compared to γ-addition, the α-addition of α-branched β,γ-unsaturated aldehydes faces larger steric hindrance and disrupts the π-π conjugation, which might be why very few examples are reported. In this article, a highly diastereo- and enantioselective α-regioselective Mannich reaction of isatin-derived ketimines with α-, β- or γ-branched β,γ-unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N'-dioxide/ScIII catalysts. A series of chiral α-quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α-regioselectivity.

Sterically Hindered and Deconjugative α‐Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement‐Intermediate

AbstractCompared to γ‐addition, the α‐addition of α‐branched β,γ‐unsaturated aldehydes faces larger steric hindrance and disrupts the π–π conjugation, which might be why very few examples are reported. In this article, a highly diastereo‐ and enantioselective α‐regioselective Mannich reaction of isatin‐derived ketimines with α‐, β‐ or γ‐branched β,γ‐unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiralN,N′‐dioxide/ScIIIcatalysts. A series of chiral α‐quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellenteevalues. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α‐regioselectivity.

Generation of Allylmagnesium Reagents by Hydromagnesiation of 2-Aryl-1,3-dienes.

A protocol for the generation of allylmagnesium reagents from 2-aryl-1,3-dienes was developed using magnesium hydride (MgH2 ) that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI2 ) in tetrahydrofuran (THF). Downstream functionalization of the resulting allylmagnesium reagents with carbonyl compounds or alkyl (pseudo)halides delivers branched products having an allylic quaternary carbon center, whereas that with chlorosilanes resulted in formation of linear allylsilanes in regio and stereoselective manners. Further derivatizations of the homoallylic alcohols and allylsilanes were also demonstrated.

Generation of Allylmagnesium Reagents by Hydromagnesiation of 2‐Aryl‐1,3‐dienes

AbstractA protocol for the generation of allylmagnesium reagents from 2‐aryl‐1,3‐dienes was developed using magnesium hydride (MgH2) that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI2) in tetrahydrofuran (THF). Downstream functionalization of the resulting allylmagnesium reagents with carbonyl compounds or alkyl (pseudo)halides delivers branched products having an allylic quaternary carbon center, whereas that with chlorosilanes resulted in formation of linear allylsilanes in regio and stereoselective manners. Further derivatizations of the homoallylic alcohols and allylsilanes were also demonstrated.

Synthesis of Diastereo- and Enantioenriched Homoallylic Alcohols with a Chiral CF3- and F-Bound Carbon

Synthesis of Diastereo- and Enantioenriched Homoallylic Alcohols with a Chiral CF3- and F-Bound Carbon

Rh(III)-Catalyzed Stereoselective C–H Homoallylation of Indolines with 4-Vinyl-1,3-dioxan-2-ones

AbstractAn efficient and robust Rh(III)-catalyzed C–H homoallylation of indolines has been developed. Using 4-vinyl-1,3-dioxan-2-one as coupling partner, a range of homoallylic alcohols were prepared in excellent stereoselectivities. The current strategy features high efficiency, good yields, and exceptional functional group tolerance.

Asymmetric Ruthenium-Catalyzed Carbonyl Allylations by Gaseous Allene via Hydrogen Auto-Transfer: 1° vs 2° Alcohol Dehydrogenation for Streamlined Polyketide Construction.

Iodide-bound ruthenium-JOSIPHOS complexes catalyze the redox-neutral C-C coupling of primary alcohols 2a-2r with the gaseous allene (propadiene) 1a to form enantiomerically enriched homoallylic alcohols 3a-3r with complete atom-efficiency. Using formic acid as reductant, aldehydes dehydro-2a and dehydro-2c participate in reductive C-C coupling with allene to deliver adducts 3a and 3c with comparable levels of asymmetric induction. Deuterium labeling studies corroborate a mechanism in which alcohol dehydrogenation triggers allene hydroruthenation to form transient allylruthenium-aldehyde pairs that participate in carbonyl addition. Notably, due to a kinetic preference for primary alcohol dehydrogenation, chemoselective C-C coupling of 1°,2°-1,3-diols occurs in the absence of protecting groups. As illustrated by the synthesis of C7-C15 of spirastrellolide B and F (7 vs 17 steps), C3-C10 of cryptocarya diacetate (3 vs 7 or 9 steps), and a fragment common to C8'-C14' of mycolactone F (1 vs 4 steps) and C22-C28 marinomycin A (1 vs 9 steps), this capability streamlines type I polyketide construction.

Homoallyl alcohol as an allylation reagent for termination of the Catellani–Lautens reaction via retro-allylation

A palladium/norbornene-catalyzed ortho-amination/allylation of aryl iodides was developed for the construction of ortho-aminated allylbenzene by using N-benzoyloxyamine as the amination reagent and homoallyl alcohol as the allylation reagent.

Visible-light-promoted defluorinated alkylation of trifluoromethyl alkenes initiated by radical [1,2]-Brook rearrangement: facile synthesis ofgem-difluoro homoallylic alcohol derivatives

A photoinduced radical [1,2]-Brook rearrangement/defluorinated alkylation reaction of α-trifluoromethyl alkenes with α-silyl alcohols was developed for facile access togem-difluoro homoallylic alcohol derivatives.

Co(III)-Catalyzed three-component assembling of N-(2-pyrimidyl) indoles with dienes and formaldehyde.

A highly regio- and chemoselective three-component assembling of N-pyrimidyl indoles with dienes and formaldehyde in the presence of a Co(III) catalyst was demonstrated. The scope of the reaction was investigated with a variety of indole derivatives to synthesize substituted homoallylic alcohols. Both butadiene and isoprene units were compatible with the reaction. To understand the reaction mechanism, various investigations were carried out, and suggested the plausibility of a reaction mechanism involving C-H bond activation as a key step.

Palladium-catalyzed allylic allenylation of homoallyl alcohols with propargylic carbonates

A palladium-catalyzed reaction of homoallyl alcohols with propargylic carbonates was realized via oxidative addition/decarboxylation/retro-allylation.

Diastereodivergent and Enantioselective Synthesis of Homoallylic Alcohols via Nickel-Catalyzed Borylative Coupling of 1,3-Dienes with Aldehydes

Diastereodivergent and Enantioselective Synthesis of Homoallylic Alcohols via Nickel-Catalyzed Borylative Coupling of 1,3-Dienes with Aldehydes