Disubstituted Allenes Research Articles

Highly efficient synthesis of di-substituted allenes via copper-catalyzed SN2′- substitution reaction of organotitanium reagents with propargyl bromides

A simple and mild catalytic SN2′-type displacement of propargyl halides with organotitanium reagents is reported. The SN2′-type displacement of propargyl bromides with organotitanium reagents mediated by CuI (2 mol%)/MePPh2(4 mol%) in dichloro methane afforded multi-substituted allenes in good yields (up to 95 %) at 40 °C for 5 h. The aryls bearing electron-donating or electron-withdrawing groups in aryltitanium reagents gave multi-substituted allenes in good yields. In addition, the di-substituted allenes bearing a naphthyl group was obtained in 54–99 % selectivities with isolated yields of 43–83 %. The process was simple and easily performed, and it provides an efficient method for the synthesis of di-substituted allene derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Post-Transition State Bifurcation Controls Torsional Selectivity in Radical Addition of Allenes.

Post-transition state bifurcation (PTSB) has received wide attention in the field of reaction mechanism research due to its role in producing nonstatistical reaction selectivity, which cannot be solely explained by transition state theory. Particularly, even subtle molecular motions such as bond torsion can precipitate PTSB, thereby significantly complicating the quantitative understanding of dynamic selectivity. In this work, we found that the radical addition of allenes is an elementary transformation that generally exhibits PTSB stereoselectivity, where a single radical addition transition state can lead to both Z- and E-allylic radicals via the post-transition state allylic single bond torsion. Interestingly, dynamic Z/E-selectivity favors the Z-allylic radicals, which contrasts the thermodynamic preference. Based on the dynamics study of twenty-five radical additions of mono-substituted allenes with diverse electronic and steric effects, we have identified that this dynamic stereoselectivity is synergistically controlled by the transition state structure and the differential trends within specific dimensions of the bifurcating reaction coordinates, which also holds true for di-substituted allene substrates. This study refines the mechanism of radical addition of allenes and underscores the importance of the differential trend of the reaction coordinates in controlling dynamic selectivity, offering a deeper insight into PTSB selectivity factors.

Photoexcited Palladium-Catalyzed Deracemization of Allenes.

The different enantiomers of specific chiral molecules frequently exhibit disparate biological, physiological, or pharmacological properties. Therefore, the efficient synthesis of single enantiomers is of particular importance not only to the pharmaceutical sector but also to other industrial sectors, such as agrochemical and fine chemical industries. Deracemization, a process during which a racemic mixture is converted into a nonracemic product with 100% atom economy and theoretical yield, is the most straightforward method to access enantioenriched molecules but a challenging task due to a decrease in entropy and microscopic reversibility. Axially chiral allenes bear a distinctive structure of two orthogonal cumulative π-systems and are acknowledged as synthetically versatile synthons in organic synthesis. The selective creation of axially chiral allenes with high optical purity under mild reaction conditions has always been a very popular and hot topic in organic synthesis but remains challenging. Herein, a photoexcited palladium-catalyzed deracemization of nonprefunctionalized disubstituted allenes is disclosed. This method provides an efficient and economical strategy to accommodate a broad scope of allenes with good enantioselectivities and yields (53 examples, up to 96% yield and 95% ee). The use of a suitable chiral palladium complex with visible light irradiation is an essential factor in achieving this transformation. A metal-to-ligand charge transfer mechanism was proposed based on control experiments and density functional theory calculations. Quantum mechanical studies implicate dual modes of asymmetric induction behind our new protocol: (1) sterically controlled stereoselective binding of one allene enantiomer under the ground-state and (2) facile, noncovalent interaction-driven excited-state isomerization toward the opposite enantiomer. The success of this newly established photochemical deracemization strategy should provide inspiration for expansion to other multisubstituted allenes and will open up a new mode for enantioselective excited-state palladium catalysis.

Copper-Catalyzed Radical Allene C(sp2 )-H Cyanation.

While the hydrogen atom abstraction (HAA) from C(sp3 )-H bond has been well explored, the radical-mediated chemo- and regio-selective functionalization of allenic C(sp2 )-H bond via direct HAA from C(sp2 )-H bond of allene remains an unsolved challenge in synthetic chemistry. This is primarily due to inherent challenges with addition of radical intermediates to allenes, regioselectivity of HAA process, instability of allenyl radical toward propargyl radical et al. Herein, we report a copper catalyzed allenic C(sp2 )-H cyanation of an array of tri- and di-substituted allenes with exceptional site-selectivity, while mono-substituted allene was successfully cyanated, albeit with a low yield. In the developed strategy, steric N-fluoro-N-alkylsulfonamide, serving as precursor of hydrogen atom abstractor, plays a crucial role in achieving the desired regioselectivity and avoiding addition of N-centered radical to allene.

Lithium Triethylborohydride (LiHBEt3)-Promoted Hydrosilylation of Allenes to Prepare (E)-Allylsilanes.

A transition-metal-free hydrosilylation of allenes is reported herein by using commercially available lithium triethylborohydride (LiHBEt3) as the catalyst. Both mono- and disubstituted allenes could be hydrosilylated with primary or secondary silanes effectively. This reaction represents an environmental and economic method to prepare (E)-allylsilanes in good yields along with decent selectivities.

Correlation between Optical Activity and the Helical Molecular Orbitals of Allene and Cumulenes.

Helical frontier molecular orbitals (MOs) appear in disubstituted allenes and even-n cumulenes. Chiral molecules are optically active, but while these molecules are single-handed chiral, π-orbitals of both helicities are present. Here we computationally examine whether the optical activity of chiral cumulenes is controlled by the axial chirality or the helicity of the electronic structure. We exploit hyperconjugation with alkyl, silaalkyl, and germaalkyl substituents to adjust the MO helicity without altering the axial chirality. For the same axial chirality, we observe an inversion of the helical MOs contribution to the electronic transitions and a change of sign in the electronic circular dichroism and optical rotation dispersion spectra. While the magnitude of the chiroptical response also increases, it is similar to that of chiral cumulenes without helical π-orbitals. Overall, helical π-orbitals correlate with the big chiroptical response in cumulenes, but are not a prerequisite for it.

Copper Hydride Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes.

The general enantioselective synthesis of axially chiral disubstituted allenes from prochiral starting materials remains a long-standing challenge in organic synthesis. Here, we report an efficient enantio- and chemoselective copper hydride catalyzed semireduction of conjugated enynes to furnish 1,3-disubstituted allenes using water as the proton source. This protocol is sufficiently mild to accommodate an assortment of functional groups including keto, ester, amino, halo, and hydroxyl groups. Additionally, applications of this method for the selective synthesis of monodeuterated allenes and chiral 2,5-dihydropyrroles are described.

Carbon Atom as an Extremely Strong Nucleophilic and Electrophilic Center: Dendritic Allenes Are Powerful Organic Proton and Hydride Sponges.

Gas-phase proton affinities (PAs) and hydride affinities (HAs) of organic bases possessing an allene moiety and substituted with methyl, dimethylamino, cyano, and vinyl substituents were examined with the B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) model. It was shown that a number of superbases and hyperbases can be obtained, as well as the potent hydride sponges. Methyl or dimethylamino substituents increased the proton affinity of the parent molecule, and the cyano substituents increased its hydride affinity. When the vinyl substituents are placed on allene, both the hydride and the proton affinities increased. A disubstituted allene with two dimethylamino groups is the smallest studied superbase, whereas the allene tetrasubstituted with four vinyl groups gives the smallest superbase possessing only alkene substituents. By introducing the vinyl group as a repeating subunit, one can obtain dendritic structures with the investigated substituents determining its properties. By changing the dimethylamino with the cyano group, a dendrimeric molecule can change from a hyperbase with a proton affinity of 324.6 kcal mol-1 to a very strong hydride ion acceptor with a hydride affinity of 205.4 kcal mol-1, while possessing the same proton or hydride ion attachment site.

Cobalt-Catalyzed Intermolecular [2+2] Cycloaddition between Alkynes and Allenes.

An intermolecular [2+2] cycloaddition reaction between an alkyne and an allene is reported. In the presence of a cobalt(I)/diphosphine catalyst, a near equimolar mixture of the alkyne and allene is converted into a 3-alkylidenecyclobutene derivative in good yield with high regioselectivity. The reaction tolerates a variety of internal alkynes and mono- or disubstituted allenes bearing various functional groups. The reaction is proposed to involve regioselective oxidative cyclization of the alkyne and allene to form a 4-alkylidenecobaltacyclopentene intermediate, with subsequent C-C reductive elimination.

Cobalt‐Catalyzed Intermolecular [2+2] Cycloaddition between Alkynes and Allenes

AbstractAn intermolecular [2+2] cycloaddition reaction between an alkyne and an allene is reported. In the presence of a cobalt(I)/diphosphine catalyst, a near equimolar mixture of the alkyne and allene is converted into a 3‐alkylidenecyclobutene derivative in good yield with high regioselectivity. The reaction tolerates a variety of internal alkynes and mono‐ or disubstituted allenes bearing various functional groups. The reaction is proposed to involve regioselective oxidative cyclization of the alkyne and allene to form a 4‐alkylidenecobaltacyclopentene intermediate, with subsequent C−C reductive elimination.

Mechanistic Study of Manganese-Catalyzed C-H Bond Functionalizations: Factors Controlling the Competition between Hydroarylation and Cyclization.

The Mn-catalyzed C-H functionalization of indoles with allenes developed by Rueping and co-workers provides an efficient access to various alkenylated indoles and substituted pyrroloindolones. Herein, we present a systematic computational study to understand the mechanism and origins of substrate-controlled chemoselectivity of the C-H functionalization reactions (hydroarylation vs cascade cyclization). For the disubstituted allene system, the computed mechanism consists of three main phases: C-H activation, allene migratory insertion, and protonation giving the hydroarylation product. All of these steps are feasible, in agreement with the good yield under the mild experimental conditions. On the other hand, for the trisubstituted allene system, hydroarylation is suppressed due to the higher energy barrier for the protonation step arising from the disfavored ligand-substrate steric repulsions between the carboxide ligand and the substituent group in the allene substrate; our computational results demonstrate that, after the allene insertion leading to a seven-membered cyclometalated intermediate, it undergoes a reaction pathway involving sequential "ketone to enol" isomerization, a 1,4-heteroaryl shift, and β-methoxyl elimination giving the pyrroloindolone product. In contrast, this isomerization → heteroaryl shift → β-methoxyl elimination process is unworkable in the disubstituted allene system, because the protonation step takes place more favorably owing to the lack of ligand-substrate steric interactions. The findings taken together give an insight into the role of the ligand-substrate interactions in directing the competitive pathways and differentiating the energies of key transition states by steric repulsions.

Regioselective Annulation of Aryl Sulfonamides with Allenes through Cobalt-Promoted C-H Functionalization.

The development of an efficient method for the construction of biologically relevant sultams is described, which represents the first case of cobalt-promoted C-H/N-H functionalization of sulfonamides with allenes. This newly developed annulation reaction demonstrated good functional group tolerance and excellent regioselectivity. Both terminal monosubstituted allenes and internal disubstituted allenes can be employed to give the desired sultams in good yields. This strategy can be successfully used to build a unique sultam library with novel structural diversity.

Synthesis of Linear Allylsilanes via Molybdenum-Catalyzed Regioselective Hydrosilylation of Allenes

A simple molybdenum-based catalytic system for hydrosilylation of allenes has been developed. The reactions of mono- and disubstituted allenes with secondary and tertiary silanes proceeded smoothly and selectively to afford linear allylsilanes. The origin of the unprecedented linear selectivity was investigated by density functional theory studies to reveal that the reaction consists of the following steps: (1) concerted hydromolybdation/Si–H oxidative addition from a Mo(CO)4/allene/silane adduct to form (π-allyl)molybdenum, (2) allyl rotation from the initially formed (π-allyl)molybdenum to a thermodynamically more stable isomer, and (3) reductive elimination at the less-hindered allyl carbon to afford a linear allylsilane.

Gold(I)-Catalyzed Inter- and Intramolecular Additions of Carbonyl Compounds to Allenenes.

The gold(I)-catalyzed intramolecular reaction of allenes with oxoalkenes leads to bicyclo[6.3.0]undecane ring systems, although in the case of terminally disubstituted allenes, seven-membered rings are formed. The related intermolecular addition of aldehydes to allenenes also gives seven-membered rings.

ChemInform Abstract: Catalytic Enantioselective Protoboration of Disubstituted Allenes. Access to Alkenylboron Compounds in High Enantiomeric Purity.

AbstractOptimized reaction conditions are developed for the proto‐boryl addition of (Bpin)2 up to 1,1‐disubstituted allenes to afford alkenyl boronic esters in good site selectivity.

Enantioselective Protoboration of Disubstituted Allenes

Enantioselective Protoboration of Disubstituted Allenes

Catalytic enantioselective protoboration of disubstituted allenes. Access to alkenylboron compounds in high enantiomeric purity.

Proto-boryl additions to 1,1-disubstituted allenes in the presence of 1.0–5.0 mol % of chiral NHC–Cu complexes, B2(pin)2, and t-BuOH proceed to afford alkenyl–B(pin) products in up to 98% yield, >98:2 site selectivity, and 98:2 er. The enantiomerically enriched alkenylboron products can be converted to otherwise difficult-to-access alkenyl bromides, methyl ketones or carboxylic acids. What’s more, the corresponding boronic acids may be used in highly stereoselective NHC−Cu-catalyzed allylic substitution reactions.

Enantioselective Synthesis of 5,7-Bicyclic Ring Systems from Axially Chiral Allenes Using a Rh(I)-Catalyzed Cyclocarbonylation Reaction

A transfer of chirality in an intramolecular Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) to access tetrahydroazulenones, tetrahydrocyclopenta[c]azepinones and dihydrocyclopenta[c]oxepinones enantioselectively (22-99% ee) is described. The substitution pattern of the allene affected the transfer of chiral information. Complete transfer of chirality was obtained for all trisubstituted allenes, but loss of chiral information was observed for disubstituted allenes. This work constitutes the first demonstration of a transfer of chiral information from an allene to the 5-position of a cyclopentenone using a cyclocarbonylation reaction. The absolute configuration of the corresponding cyclocarbonylation product was also established, something that is rarely done.

Theoretical study on intramolecular allene-diene cycloadditions catalyzed by PtCl2 and Au(i) complexes

The intramolecular [4C+3C] cycloaddition reaction of allenedienes catalysed by PtCl(2) and several Au(I) complexes has been studied by means of DFT calculations. Overall, the reaction mechanism comprises three main steps: (i) the formation of a metal allyl cation intermediate, (ii) a [4C(4π)+3C(2π)] cycloaddition that produces a seven-membered ring and (iii) a 1,2-hydrogen migration process on these intermediates. The reaction proceeds with complete diastereochemical control resulting from a favoured exo-like cycloaddition. Allene substituents have a critical influence in the reaction outcome and mechanism. The experimental observation of [4C+2C] cycloadducts in the reaction of substrates lacking substituents at the allene terminus can be explained through a mechanism involving Pt(IV)-metallacycles. With gold catalysts it is also possible to obtain [4C+2C] cycloaddition products, but only with substrates featuring terminally disubstituted allenes, and employing π-acceptor ligands at gold. However the mechanism for the formation of these adducts is completely different to that proposed with PtCl(2), and consists of the formation of a metal allyl cation, subsequent [4C+3C] cycloaddition and a 1,2-alkyl shift (ring contraction). Electronic analysis indicates that the divergent pathways are mainly controlled by the electronic properties of the gold heptacyclic species (L-Au-C(2)), in particular, the backdonation capacity of the metal center to the unoccupied C(2) (pπ-orbital) of the intermediate resulting from the [4C+3C] cycloaddition. The less backdonation, (i.e. using P(OR)(3)Au(+) complexes), the more favoured is the 1,2-alkyl shift.

ChemInform Abstract: Pauson—Khand Reaction of Allenic Hydrocarbons: Synthesis of 4‐Alkylidenecyclopentenones.

AbstractA comprehensive study of the reaction of in situ generated dicobalthexacarbonyl complexes of disubstituted alkynes, terminal alkynes, or acetylene with a variety of mono‐ and disubstituted allenes is presented yielding mainly the title cyclopentenones.