Controlled Heterocyclization/Cross‐Coupling Domino Reaction of β,γ‐Allendiols and α‐Allenic Esters: Method and Mechanistic Insight for the Preparation of Functionalized Buta‐1,3‐dienyl Dihydropyrans

Starting from β,γ‐allendiols and α‐allenic acetates, a chemo‐ and regiocontrolled palladium‐catalyzed methodology has provided access to enantiopure 3,6‐dihydropyrans that bear a buta‐1,3‐dienyl moiety. Thus, it has been demonstrated for the first time that the preparation of six‐membered heterocycles through cross‐coupling reactions of two different allenes can be accomplished. These heterocyclization/cross‐coupling reactions have been developed experimentally and their mechanisms have additionally been investigated by a computational study.     

Metal‐Catalyzed Cyclization of β‐ and γ‐Allenols Derived from D‐Glyceraldehyde—Synthesis of Enantiopure Dihydropyrans and Tetrahydrooxepines: An Experimental and Theoretical Study

Regiocontrolled metal‐catalyzed preparations of enantiopure dihydropyrans and tetrahydrooxepines have been synthesized starting from β‐ and γ‐allenols derived from D ‐glyceraldehyde. The Pd^II‐catalyzed cyclizative coupling reactions of β‐allenols 1 a and 1 b with allyl bromide effectively afforded enantiopure tetrafunctionalized dihydropyrans through a 6‐endo oxycyclization protocol, whereas the gold‐, platinum‐, and palladium‐mediated heterocyclization of γ‐allenol 2 furnished tetrahydrooxepines 13 – 16 through regioselective 7‐endo‐trig oxycyclization reactions. Moreover, density functional calculations were performed to predict the regioselectivity of the γ‐allenol cycloetherification to tetrahydrooxepines on the basis of both the tether nature and characteristics of the metals, and to gain an insight into the mechanism of the oxycyclization reactions.     

Metal‐Catalyzed Cyclization Reactions of 2,3,4‐Trien‐1‐ols: A Joint Experimental–Computational Study

Controlled preparation of tri‐ and tetrasubstituted furans, as well as carbazoles has been achieved through chemo‐ and regioselective metal‐catalyzed cyclization reactions of cumulenic alcohols. The gold‐ and palladium‐catalyzed cycloisomerization reactions of cumulenols, including indole‐tethered 2,3,4‐trien‐1‐ols, to trisubstituted furans was effective, due to a 5‐endo‐dig oxycyclization by attack of the hydroxy group onto the central cumulene double bond. In contrast, palladium‐catalyzed heterocyclization/coupling reactions with 3‐bromoprop‐1‐enes furnished tetrasubstituted furans. Also studied was the palladium‐catalyzed cyclization/coupling sequence involving protected indole‐tethered 2,3,4‐trien‐1‐ols and 3‐bromoprop‐1‐enes that exclusively generated trisubstituted carbazole derivatives. These results could be explained through a selective 6‐endo‐dig cumulenic hydroarylation, followed by aromatization. DFT calculations were carried out to understand this difference in reactivity.     

Chemo‐ and Regioselective Palladium‐Catalyzed Oxycyclization Reactions of Allendiols: Preparation of Five‐, Six‐, and Eight‐Membered Cycles

Positive discrimination : Chemo‐ and regioselective palladium‐catalyzed cycloetherification of allendiols, namely β,γ‐ and γ,δ‐allendiols, may occur by judicious choice of palladium‐catalyzed conditions owing to their potential ability to discriminate between both nucleophilic sites (see scheme).

     

Protecting‐Group‐Free Enantioselective Synthesis of (−)‐Pallavicinin and (+)‐Neopallavicinin

The first enantioselective synthesis of (?)‐pallavicinin and (+)‐neopallavicinin has been achieved in 15 steps. The described synthesis avoids protecting‐group manipulations by synthesis designs predicated on highly chemo‐ and stereoselective transformations. Highlights of the synthesis include a palladium‐catalyzed enantioselective decarboxylative allylation to form the chiral all‐carbon quaternary stereocenter, a palladium‐catalyzed oxidative cyclization to assemble the [3.2.1]‐bicyclic moiety, and an unprecedented LiBHEt₃‐induced fragmentation/protonation of an α‐hydroxy epoxide to form the α‐furan ketone with the desired configuration.     

PdII‐Catalyzed Domino Heterocyclization/Cross‐Coupling of α‐Allenols and α‐Allenic Esters: Efficient Preparation of Functionalized Buta‐1,3‐dienyl Dihydrofurans

A mild, palladium(II)‐catalyzed reaction of α‐allenols with α‐allenic esters in a heterocyclization/cross‐coupling sequence, applicable to a wide range of substitution patterns, has been developed for the preparation of 2,3,4‐trifunctionalized 2,5‐dihydrofurans. Our studies indicate high levels of chemo‐ and regiocontrol. The possibility of using optically active substrates as well as substrates of increased steric demand, such as tertiary α‐allenols, makes this novel sequence of heterocyclization/cross‐coupling an attractive method in organic synthesis. The current mechanistic hypothesis invokes a regiocontrolled palladium(II)‐mediated intramolecular oxypalladation of the free allenol component, that then undergoes a cross‐coupling reaction with the allenic ester partner, followed by a trans‐β‐deacyloxypalladation with concomitant regeneration of the Pd^II species.     

Preparation of C3‐Symmetric Homochiral syn‐Trisnorbornabenzenes through Regioselective Cyclotrimerization of Enantiopure Iodonorbornenes

C₃‐symmetric homochiral (?)‐syn‐trisoxonorbornabenzene 1 possessing a rigid cup‐shaped structure was synthesized through a novel regioselective cyclotrimerization of enantiopure iodonorbornenes catalyzed by palladium nanoclusters. The yield of the cyclotrimerization was dependent on the stability of the palladium clusters, which was ascertained from the appearance and TEM images of the reaction mixtures. The efficient preparation of (?)‐syn‐ 1 was established in short steps, including the newly developed cyclotrimerization reaction. The thus‐prepared homochiral (?)‐syn‐ 1 can serve as a key intermediate for the synthesis of C₃‐symmetric homochiral cup‐shaped molecules with a helical arrangement of substituents. Introduction of several types of substituents was well demonstrated through palladium‐catalyzed coupling reactions with the corresponding phosphate and triflate of (?)‐syn‐ 1 .     

Catalytic Asymmetric Prins Bicyclization for the endo‐Selective Formation of 2,6‐dioxabicyclo[2.2.2]octanes

A new Lewis acid‐catalyzed endo‐selective Prins bicyclization of γ,δ‐unsaturated aldehydes or ketones with a broad range of aldehydes to dioxabicyclo[2.2.2]octanes is disclosed. When using a chiral BINOL‐derived N‐triflylphosphoramide (NTPA) as catalyst and glyoxylate esters as substrates, the cross‐dimerization afford functionalized bicyclic acetals with excellent diastereo‐ and enantioselectivities.     

A General Synthesis of Alkenyl‐Substituted Benzofurans,Indoles, and Isoquinolones by Cascade Palladium‐Catalyzed Heterocyclization/Oxidative Heck Coupling

Structurally diverse C3‐alkenylbenzofurans, C3‐alkenylindoles, and C4‐alkenylisoquinolones are efficiently prepared by using consecutive Sonogashira and cascade Pd‐catalyzed heterocyclization/oxidative Heck couplings from readily available ortho‐iodosubstituted phenol, aniline, and benzamide substrates, alkynes, and functionalized olefins. The cyclization of O‐ and N‐heteronucleophiles follows regioselective 5‐endo‐dig‐ or 6‐endo‐dig‐cyclization modes, whereas the subsequent Heck‐type coupling with both mono‐ and disubstituted olefins takes place stereoselectively with exclusive formation of the E isomers in most cases.     

1‐Bromo‐2‐(cyclopropylidenemethyl)benzene: A Useful Building Block in the Palladium‐Catalyzed Reaction of 2‐Alkynylbenzenamine

A novel palladium‐catalyzed domino reaction of 1‐bromo‐2‐(cyclopropylidenemethyl)benzene and 2‐alkynylbenzenamine is reported, which generates 2‐(naphthalen‐2‐yl)benzenamines and 5H‐indeno[1,2‐c]quinolines via 6‐endo and 5‐exo cyclization, respectively. The regioselectivity for the final outcome can be affected by phosphine and N‐heterocyclic carbene ligands.     

Stereoselective Synthesis of Chiral Polycyclic Indolic Architectures through Pd0‐Catalyzed Tandem Deprotection/Cyclization of Tetrahydro‐β‐carbolines on Allenes

Enantioenriched N‐allyl tetrahydro‐β‐carbolines were prepared by chiral phosphoric acid‐catalyzed Pictet–Spengler reactions. The compounds undergo Pd⁰‐catalyzed cyclizations through a tandem deprotection/cyclization process. The regioselectivity of the attack is controlled by the chain length and by the substitution pattern of the allene function. Products resulting from 5‐exo‐ or 6‐exo‐attack were obtained with diastereoisomeric ratio up to 95:5. Azepinopyrrido[3,4‐b]indoles were obtained by 7‐endo‐cyclizations.     

Lewis Acid‐Assisted Ene Cyclization of 2‐Azetidinone‐Tethered Enals: Synthesis of Enantiopure Carbacepham Derivatives

Diastereocontrolled Lewis acid‐catalyzed preparation of enantiopure carbacepham derivatives have been developed starting from 2‐azetidinone‐tethered enals. The BF₃?Et₂O‐promoted reaction of alkenylaldehydes 1 and 16 is effective as carbocyclization protocol to afford 4‐substituted 5‐hydroxycarbacephams or 3‐substituted 4,5‐dihydroxycarbacephams, respectively, by a type I carbonyl‐ene reaction, while the BF₃?Et₂O or SnCl₄‐mediated type II carbonyl‐ene cyclization of alkenylaldehydes 2 furnishes 3‐methylene 5‐hydroxycarbacephams along with the corresponding 3‐halo 5‐hydroxycarbacepham. The stereochemical outcome of these carbonyl‐ene cyclizations leading to carbacepham derivatives can be explained in terms of six‐membered, cyclic chair‐like transition‐state models. The formation of halocarbacepham derivatives is proposed to proceed by a stepwise mechanism.     

Pd/C‐Catalyzed Cyclizative Cross‐Coupling of Two ortho‐Alkynylanilines under Aerobic Conditions: Synthesis of 2,3′‐Bisindoles

A palladium‐catalyzed cyclizative cross‐coupling of two o‐alkynylanilines to 2,3′‐bisindoles under aerobic oxidative conditions was developed. Mechanistic studies suggested that the two catalytic cycles, namely the formation of 3‐alkynylindoles 8 and their subsequent cyclization to bisindoles 5 , are temporally separated. The aminopalladation of 3‐alkynylindoles 8 occurred only after all the N,N‐dialkyl‐o‐alkynylanilines were consumed. The solid support (activated charcoal) played a crucial role in the second intramolecular aminopalladation process.     

One Stone for Three Birds‐Rhodium‐Catalyzed Highly Diastereoselective Intramolecular [4+2] Cycloaddition of Optically Active Allene‐1,3‐dienes

RhCl(PPh₃)₃‐catalyzed [4+2] intramolecular cycloaddition of optically active axially chiral allene‐dienes afforded cis‐fused [3.4.0]‐bicyclic products with three chiral centers in good yields with an excellent chemo‐ and diastereoselectivity. A pair of enantiomers of such products was generated highly selectively from both enantiomers of starting allene‐dienes, indicating that the axial chirality dictated the absolute configurations of the three in situ generated chiral centers with a very high efficiency of chirality transfer.     

Rhodium‐Catalyzed Parallel Kinetic Resolution of Racemic Internal Allenes Towards Enantiopure Allylic 1,3‐Diketones

A rare case of a parallel kinetic resolution of racemic 1,3‐disubstituted allenes by means of a rhodium‐catalyzed addition to 1,3‐diketones furnishing enantiopure allylic 1,3‐diketones is described. Mechanistic experiments demonstrate that the different allene enantiomers react in parallel to either the diastereomeric E‐ or Z‐allylic 1,3‐diketones with the same absolute configuration of the newly formed stereogenic center. A broad substrate scope demonstrates the synthetic utility of this new method.     

Synthesis of 3,4‐Dihalogenated Furan‐2‐(5 H)‐ones by Electrophilic Cyclization of 4‐Hydroxy‐2‐alkynoates

Functionalized 3,4‐dihalogenated furan‐2(5 H)‐ones can be readily prepared in moderate to good yields by treating 4‐hydroxy‐4‐arylbut‐2‐ynoate derivatives with ICl, IBr, and I₂. Both halogen atoms of the electrophile are incorporated in the product. The resulting halides can further afford polycyclic aromatic compounds using known palladium‐catalyzed coupling reactions.     

Iron‐Catalyzed Aminomethyloxygenative Cyclization of Hydroxy‐α‐diazoesters with N,O‐Aminals

A new and efficient cyclization reaction has been developed to synthesize cyclic α,α‐disubstituted β‐amino esters via iron‐catalyzed intramolecular aminomethyloxygenative cyclization of diazo compounds with N,O‐aminal under mild reaction conditions. A broad range of hydroxy‐α‐diazoesters with different substituents and various N,O‐aminals were compatible with this protocol, affording the corresponding α,α‐disubstituted β‐amino esters bearing a five‐ to eight‐membered oxacycle in good yields.     

Palladium‐ and Rhodium‐Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazoles

A complementing Pd‐ and Rh‐catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N‐allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry as certified drugs and potential drug candidates. The new methods feature high chemo‐, regio‐ and enantioselectivities aside from displaying a broad substrate scope and functional group compatibility. A mechanistic rational accounting for allene racemization and trans‐alkene selectivity is discussed.     

Highly Selective Construction of Seven‐Membered Carbocycles by Olefin‐Assisted Palladium‐Catalyzed Oxidative Carbocyclization–Alkoxycarbonylation of Bisallenes

An olefin‐assisted palladium‐catalyzed oxidative carbocyclization–alkoxycarbonylation of bisallenes to afford seven‐membered carbocycles has been established. This dehydrogenative coupling reaction showed excellent substrate scope and functional group compatibility. The reaction exhibited high chemo‐ and regioselectivity, and ester 3 was the only product obtained. The olefin unit has been proven to be indispensable during the reaction. Moreover, intramolecular oxidative coupling suggests that the reaction proceeds via a (π‐allyl)palladium intermediate.     

Palladium(II)‐Catalyzed Aminotrifluoromethoxylation of Alkenes: Mechanistic Insight into the Effect of N‐Protecting Groups

An efficient palladium‐catalyzed regioselective 5‐exo aminotrifluoromethoxylation of alkenes has been established herein, which provides a practical route towards the synthesis of OCF₃‐containing pyrrolidines. tert‐Butyloxycarbonyl (Boc) as an amino protecting group plays a significant role in both the chemo‐ and regioselectivities. In addition, preliminary mechanistic studies reveal that the amino protecting group of substrates and the counter anion of palladium catalyst play critical roles in reaction efficiency presumably due to an isomerization of alkyl‐ Pd(II) intermediates. Moreover, the asymmetric 5‐exo aminotrifluoromethoxylation reaction has also been achieved by introducing a sterically bulky pyridinyl‐oxazoline ligand.