Allenic Carbon Research Articles

DABCO-catalyzed [3 + 4] annulations of Schiff bases with α-substituted allenes: Construction of functionalized benzazepine derivatives

A [3 + 4] annulation of α-substituted allenes and Schiff bases is reported. This methodology serves as a conduit for the construction of a series of biologically important benzazepine derivatives in good to excellent yields under mild conditions by an unprecedented mode involving β′-carbon of α-substituted allenes and the proposed mechanism is supported by capturing the intermediate. Moreover, this class of benzazepine derivatives exhibited potential ability of cytotoxicity toward cancer cells.

Phosphine-Catalyzed [3 + 4] Annulations of Salicylaldehyde Schiff Bases with α-Substituted Allenes: Construction of Functionalized Benzoxepine Fused Succinimide Derivatives.

Herein we reported a novel strategy for constructing benzoxepine fused succinimide derivatives via a phosphine-catalyzed [3 + 4] cyclization of α-substituted allenes and salicylaldehyde Schiff bases. This methodology serves as a conduit for the construction of benzoxepine derivatives in good yields under mild conditions by an unprecedented mode involving the β'-carbon of allenes. Density functional theory calculations were conducted to study the possible mechanism. Moreover, this class of compounds exhibited the potential ability of cytotoxicity toward cancer cells.

Experimental and Theoretical Study of Phosphine-Catalyzed Reaction Modes in the Reaction of α-Substituted Allenes with Aryl Imines.

A new phosphine-catalyzed reaction of α-substituted allenes with aryl imines, in stark contrast to classic cycloaddition reactions, has been developed. This reaction delivers valuable highly functionalized itaconimides with excellent stereoselectivities by a new uncyclized reaction mode involving β'-carbon of α-substituted allenes. Moreover, the present uncyclized reaction can also be carried out in a one-pot fashion and scaled up to the gram scale by using aryl aldehydes, without the need to isolate the aryl imines. Mechanistic studies and control experiments reveal the crucial role of H2CO3 for the present reaction mode. In addition, density functional theory (DFT) calculations were performed to understand the possible mechanism.

Five Bonds to Carbon through Tri-Coordination in 
 Al3C3−/0

Here, five bonds to carbon through tri-coordination are theoretically established in the global minimum energy isomers of Al3C3− anion (1a) and Al3C3 neutral (1n) for the first time. Various isomers of Al3C3−/0 are theoretically identified using density functional theory at the PBE0-D3/def2-TZVP level. Chemical bonding features are thoroughly analyzed for these two isomers (1a and 1n) with different bonding and topological quantum chemical tools, such as adaptive natural density partitioning (AdNDP), Wiberg Bond Indices (WBIs), nucleus-independent chemical shifts (NICS), and atoms in molecules (AIM) analyses. The structure of isomer 1a is planar with C2v symmetry, whereas its neutral counterpart 1n is non-planar with C2 symmetry, in which its terminal aluminum atoms are out of the plane. The central allenic carbon atom of isomers 1a and 1n exhibits tri-coordination and thus makes it a case of five bonds to carbon, which is confirmed through their total bond order as observed in WBI. Both the isomers show σ- and π-aromaticity and are predicted with the NICS and AdNDP analyses. Further, the results of ab initio molecular dynamics simulations reveal their kinetic stability at room temperature; thus, they are experimentally viable systems.

A Distinct Mode of Strain-Driven Cyclic Allene Reactivity: Group Migration to the Central Allene Carbon Atom.

Strained cyclic allenes are reactive species that can be trapped in a variety of complementary fashions that capitalize on their inherent high potential energy. 1,2,4-Cyclohexatrienes represent a subclass of allenes that, notably, can be conveniently generated by a net [4 + 2] cycloaddition within a 1,3-enyne bearing a tethered alkyne via a tetradehydro-Diels-Alder reaction. A limitation to the use of this type of thermally generated cyclic allene as a construct for the introduction of molecular complexity is their propensity to isomerize to benzenoids via a simple net 1,5-hydrogen atom migration. We have discovered that when the enyne component of the substrate is modified as an enol silyl ether (or an enol ester), migration of the silyl (or acyl) group can become the predominant event. Specifically, an appropriately electrophilic group can migrate from the O atom to the central allene carbon adjacent to the 1-siloxy(acyloxy) substituent. This process leads to highly substituted phenolic products (e.g., o-silyl phenols) following tautomerization of the intermediate cyclohexa-2,4-dienone. Experimental studies show that this novel mode of reactivity is general; DFT studies reveal the unimolecular nature of the group migration.

Regioselectivity Switch Based on the Stoichiometry: Stereoselective Synthesis of Trisubstituted Vinyl Epoxides by Cu‐Catalyzed 3‐exo‐trig Cyclization of α‐Allenols

AbstractTypical transition metal‐catalyzed oxycyclization of allenols takes place at the terminal allene carbon via a 5‐endo path and forms dihydrofurans. A copper‐catalyzed protocol brought about a reversed regioselectivity, generating a series of trisubstituted epoxides through a 3‐exo‐cyclization/sulfonylation cascade. The current stoichiometry control of regioselectivity may open singular opportunities in chemical transformations.magnified image

Photochemical Deracemization of Primary Allene Amides by Triplet Energy Transfer: A Combined Synthetic and Theoretical Study.

The photochemical deracemization of 2,4-disubstituted 2,3-butadienamides (allene amides) was investigated both experimentally and theoretically. The reaction was catalyzed by a thioxanthone which is covalently linked to a chiral 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one skeleton providing a U-shaped arrangement of the sensitizing unit relative to a potential hydrogen-bonding site. Upon irradiation at λ = 420 nm in the presence of the sensitizer (2.5 mol %), the amides reached at -10°C a photostationary state in which one enantiomer prevailed. The enantioenriched allene amides (70-93% ee) were isolated in 74% to quantitative yield (19 examples). Based on luminescence data and DFT calculations, energy transfer from the thioxanthone to the allene amides is thermodynamically feasible, and the achiral triplet allene intermediate was structurally characterized. Hydrogen bonding of the amide enantiomers to the sensitizer was monitored by NMR titration. The experimental association constants (Ka) were similar (59.8 vs 25.7 L·mol-1). DFT calculations, however, revealed a significant difference in the binding properties of the two enantiomers. The major product enantiomer exhibits a noncovalent dispersion interaction of its arylmethyl group to the external benzene ring of the thioxanthone, thus moving away the allene from the carbonyl chromophore. The minor enantiomer displays a CH-π interaction of the hydrogen atom at the terminal allene carbon atom to the same benzene ring, thus forcing the allene into close proximity to the chromophore. The binding behavior explains the observed enantioselectivity which, as corroborated by additional calculations, is due to a rapid triplet energy transfer within the substrate-catalyst complex of the minor enantiomer.

Kinetics and Mechanism of the Gold-Catalyzed Hydroamination of 1,1-Dimethylallene with N-Methylaniline.

The mechanism of the intermolecular hydroamination of 3-methylbuta-1,2-diene (1) with N-methylaniline (2) catalyzed by (IPr)AuOTf has been studied by employing a combination of kinetic analysis, deuterium labelling studies, and in situ spectral analysis of catalytically active mixtures. The results of these and additional experiments are consistent with a mechanism for hydroamination involving reversible, endergonic displacement of N-methylaniline from [(IPr)Au(NHMePh)]+ (4) by allene to form the cationic gold π-C1,C2-allene complex [(IPr)Au(η2 -H2 C=C=CMe2 )]+ (I), which is in rapid, endergonic equilibrium with the regioisomeric π-C2,C3-allene complex [(IPr)Au(η2 -Me2 C=C=CH2 )]+ (I'). Rapid and reversible outer-sphere addition of 2 to the terminal allene carbon atom of I' to form gold vinyl complex (IPr)Au[C(=CH2 )CMe2 NMePh] (II) is superimposed on the slower addition of 2 to the terminal allene carbon atom of I to form gold vinyl complex (IPr)Au[C(=CMe2 )CH2 NMePh] (III). Selective protodeauration of III releases N-methyl-N-(3-methylbut-2-en-1-yl)aniline (3 a) with regeneration of 4. At high conversion, gold vinyl complex II is competitively trapped by an (IPr)Au+ fragment to form the cationic bis(gold) vinyl complex {[(IPr)Au]2 [C(=CH2 )CMe2 NMePh]}+ (6).

Origins of Endo Selectivity in Diels–Alder Reactions of Cyclic Allene Dienophiles

AbstractStrained cyclic allenes, first discovered in 1966 by Wittig and co‐workers, have recently emerged as valuable synthetic building blocks. Previous experimental investigations, and computations reported here, demonstrate that the Diels–Alder reactions of furans and pyrroles with 1,2‐cyclohexadiene and oxa‐ and azaheterocyclic analogs proceed with endo selectivity. This endo selectivity gives the adduct with the allylic saturated carbon of the cyclic allene endo to the diene carbons. The selectivity is very general and useful in synthetic applications. Our computational study establishes the origins of this endo selectivity. We analyze the helical frontier molecular orbitals of strained cyclic allenes and show how secondary orbital and electrostatic effects influence stereoselectivity. The LUMO of carbon‐3 of the allene (C‐3 is not involved in primary orbital interactions) interacts in a stabilizing fashion with the HOMO of the diene in such a way that the carbon of the cyclic allene attached to C‐1 favors the endo position in the transition state. The furan LUMO, allene HOMO interaction reinforces this preference. These mechanistic studies are expected to prompt the further use of long‐avoided strained cyclic allenes in chemical synthesis.

Origins of Endo Selectivity in Diels-Alder Reactions of Cyclic Allene Dienophiles.

Strained cyclic allenes, first discovered in 1966 by Wittig and co-workers, have recently emerged as valuable synthetic building blocks. Previous experimental investigations, and computations reported here, demonstrate that the Diels-Alder reactions of furans and pyrroles with 1,2-cyclohexadiene and oxa- and azaheterocyclic analogs proceed with endo selectivity. This endo selectivity gives the adduct with the allylic saturated carbon of the cyclic allene endo to the diene carbons. The selectivity is very general and useful in synthetic applications. Our computational study establishes the origins of this endo selectivity. We analyze the helical frontier molecular orbitals of strained cyclic allenes and show how secondary orbital and electrostatic effects influence stereoselectivity. The LUMO of carbon-3 of the allene (C-3 is not involved in primary orbital interactions) interacts in a stabilizing fashion with the HOMO of the diene in such a way that the carbon of the cyclic allene attached to C-1 favors the endo position in the transition state. The furan LUMO, allene HOMO interaction reinforces this preference. These mechanistic studies are expected to prompt the further use of long-avoided strained cyclic allenes in chemical synthesis.

A computational investigation of the activation of allene (H2C = C = CHR; R = H, CH3, CN) by a frustrated phosphorous/boron Lewis pair

The activation of allene by a five-membered P/B frustrated Lewis pair (FLP) has been explored by DFT based computational study. It reveals the addition of allene to the FLP takes place via two thermodynamically favorable path. But, the attack of the P center of the FLP to the middle carbon of allene is kinetically more preferable. The reaction is further analysed by taking methyl-allene and cyano-allene and which produce four thermodynamically favorable regioisomers. However the attack of the P center of the FLP to the middle carbon is kinetically more preferable. The mechanism of the reactions are carefully analysed.

Mechanistic Aspects and Synthetic Applications of Radical Additions to Allenes.

More than 50 years have passed since Haszeldine reported the first addition of a trifluoromethyl radical to an allene; in the intervening years, both the chemistry of allenes and the reactivity of single-electron species have become topics of intense interest. In this Review, we provide an overview of the fundamentals of radical additions to allenes and highlight the emergence of theoretical and experimental evidence that reveals unique reactivity patterns for radical additions to allenes as compared with other unsaturated compounds. Factors capable of exerting control over the chemo-, regio-, and stereoselectivities of the attack of carbon- and heteroatom-based radicals at each of the three potential reactive sites in an allene substrate are described. These include reaction conditions, the nature of the attacking radical, the substitution pattern of the allene, and the length of the linker between the radical center and the proximal allene carbon in the substrate. Cycloaddition reactions between allenes and partners containing π-bonds, which are likely to proceed through radical pathways, are presented to highlight their ability to rapidly access complex polycyclic scaffolds. Finally, the synthetic utility of the products arising from these chemistries is described, including their applications to the construction of complex molecules.

Mechanistic Insights into the Reaction of N‐Propargylated Pyrrole‐ and Indole‐Carbaldehyde with Ammonia, Alkyl Amines, and Branched Amines: A Synthetic and Theoretical Investigation

The reaction of pyrrole‐ and indole‐carbaldehydes having a propargyl group attached to the nitrogen atom with various amines was studied. The reaction with ammonia formed pyrrolo[1,2‐a]pyrazine and pyrazino[1,2‐a]indole while the reaction with alkylamines such as methyl, ethyl, hexyl, and benzylamines formed the corresponding pyrazinone derivatives. Unexpectedly, the reaction with allylamine and propargylamine formed pyrazine derivatives in which the allyl and propargyl groups were removed from the molecule. On the other hand, the reaction of N‐propargylated pyrrole‐carbaldehyde formed indolizine derivatives upon reaction with sterically bulky adamantyl‐ and tert‐butylamines. To understand the main factors causing these differences in reactivity, the reaction mechanisms were studied by means of computational methods. Our calculations showed that bulky amines tend to attack the central carbon of allene formed by the isomerization of N‐propargyl functionality, while the attack on the carbonyl carbon by aliphatic amines is more profound.

Reactions of Heterocumulenes with Organometallic Reagents: XXV. Quantum Chemical Study of the Substituent Effects in Alkyl [(Buta-2,3-dienimidoyl)sulfanyl]acetates on Their Cyclization to Thiophene Derivatives

Base-catalyzed low-temperature transformation of alkyl [(buta-2,3-dienimidoyl)sulfanyl]acetates [1-aza-1,3,4-trienes generated from lithiated alkoxy(or 1H-pyrrol-1-yl)allenes, isothiocyanates, and alkyl 2-bromoacetates] to tetrasubstituted thiophenes has been studied by B3LYP/6-311+G(d,p) quantum chemical calculations. Structural reorganization of 1-aza-1,3,4-trienes to thiophene derivatives involves deprotonation of the SCH2 group, followed by intramolecular addition of the resulting carbanion to the β-carbon atom of the allene fragment. Gradient paths leading to sulfur heterocycles have been analyzed assuming participation of most stable 1-aza-1,3,4-triene isomers with trans-gauche orientation of the N=C and C=C=C fragments that are conformationally favorable for thiophene ring closure. The nature of substituents on the allene carbon atom and nitrogen atom is the main factor responsible for the ability of 1-aza-1,3,4-trienes to rearrange to thiophene derivatives. In going from 3-methoxy- to 3-(1H-pyrrol-1-yl)-1-aza-1,3,4-triene, the barrier to the cyclization decreases more than twice (from 5.6 to 2.5 kcal/mol). A comparable effect is observed on replacement of methyl group on the nitrogen atom by phenyl: the barrier decreases from 5.6 to 3.1 kcal/mol. Change of substituent in the allene fragment from methoxy to ethoxy group reduces the barrier by 1.0 kcal/mol (from 5.6 to 4.6 kcal/mol). Variation of the alkyl group in the ester moiety almost does not affect the cyclization barrier.

Gold(I)-Catalyzed Intramolecular Diels–Alder Reaction: Evolution of Trappable Intermediates via Asynchronous Transition States

In recent years allenes have been shown to be capable of exhibiting several modes of cycloadditions in the presence of transition metal catalysts that are otherwise unattainable for ethylene and acetylene. Herein, we predict that the [1 + 2]-cycloaddition pathway is accessible in a Au(I)-catalyzed reaction of allene with cis-1,3-butadiene. The electrophilicity of the central carbon of allene can be harnessed using a Au(I)-catalyst and -COOMe mediated stereoelectronics. A potential energy modification approach is applied to stabilize the diradicaloid intermediates. Our simulations establish that the product selectivity of the [4 + 2]- and [2 + 2]-pathways are steered by dynamical effects. Furthermore, a bioinspired version of this reaction is shown to afford an alternative synthetic pathway for proline and azepine analogs indicating rich prospects for thermal allene-butadienereactions in drug discovery.

Access to thiopyrano[2,3-b]indole via tertiary amine-catalyzed formal (3+3) annulations of β'-acetoxy allenoates with indoline-2-thiones.

DABCO-catalyzed formal (3+3) annulations of β'-acetoxy allenoates with indoline-2-thiones are described, which provide facile access to thiopyrano[2,3-b]indole under mild reaction conditions. The reaction might proceed via the SN2'-SN2'-type process between β'-acetoxy allenoate and indole-2-thiolate with the assistance of the DABCO catalyst and K2CO3 additive, followed by intramolecular Friedel-Crafts reaction at the 3-position of indole and central carbon of allene.

Tunable Metal-Catalyzed Heterocyclization Reactions of Allenic Amino Alcohols: An Experimental and Theoretical Study.

Controlled preparation of 2,5-dihydro-1H-pyrroles, 3,6-dihydro-2H-pyrans, and pyrroles has been achieved through switchable chemo- and regioselectivity in the metal-catalyzed heterocyclization reactions of allenic amino alcohols. The gold-catalyzed cycloisomerization reaction of α-amino-β-hydroxyallenes was effective as 5-endo cyclization by addition of amino functionality to the distal allene carbon to yield enantiopure 2,5-dihydro-1H-pyrroles, whereas their palladium-catalyzed cyclizative coupling reactions furnished 3,6-dihydro-2H-pyrans through a chemo- and regioselective 6-endo cycloetherification. Conversely, the gold-catalyzed heterocyclization reaction of β-amino-γ-hydroxyallenes generated exclusively pyrrole derivatives. These results could be explained through a chemo- and regioselective 5-exo aminocyclization to the central allene carbon followed by aromatization. Chemo- and regioselectivity depend on both linker elongation as well as the type of catalyst. This behavior can be justified by means of density functional theory calculations.

Gold as Catalyst for the Hydroarylation and Domino Hydroarylation/N1-C4 Cleavage of β-Lactam-Tethered Allenyl Indoles.

Gold-catalyzed hydroarylation reaction of β-lactam-tethered allenyl indoles gives azeto-oxepino[4,5-b]indol-2-ones, tetrahydroazeto-azocino[3,4-b]indol-2-ones, and hexahydroazeto-azepino[3,4-b]indol-2-ones with very high levels of stereo- and regioselectivity, the 7-exo and 8-endo carbocyclization modes by attack of the indole group toward either the internal or the terminal allene carbon, respectively, being favored. Hydroarylation across the central carbon of the allene moiety has not been detected. The controlled gold-catalyzed annulations allowed the formation of fused β-lactams without harming the sensitive four-membered heterocycle. Besides, a novel gold-catalyzed domino process, namely, the allenic hydroarylation/N1-C4 β-lactam bond breakage to afford dihydro-oxepino[4,5-b]indole-4-carboxamides, has been discovered.

Cyclodiphosphazanes as synthetic probes: P-C/P-N bond formation from the reaction with functionalized propargyl alcohols and N-hydroxy substrates

Phosphano-indoles were synthesized in a fairly straightforward route from the reaction of simple cyclodiphosphazanes [XP(μ-N-t-Bu)2PY] [X = Y = NH-t-Bu (1a); X = Y = NH-i-Pr (1b)] with o-aminophenyl functionalized propargyl alcohols. The reaction occurs via an allene intermediate formed by P III-O-C → P V(O)-C rearrangement, followed by cyclization utilizing the central allenic carbon and the –NH2 functionality. In a similar way, cyclodiphosphazanes [XP(μ-N-t-Bu)2PY] [X = Y = Cl (1c); X = Cl, Y = NH-t-Bu (1d)] have been treated with N-hydroxy substrates to obtain novel P III-O-N → P V(O)-N rearranged products. X-ray structures of the four products, 2-(1-phenyl-ethyl)-3-[(t-Bu)NH)P(μ-N-t-Bu)2P(O)]-indole [14], cis-{[-C(=O)-C6 H 4-C(=O)-]-N-P(=O)-N-t-Bu}2 [cis-18], trans-{[-C(=O)-C6 H 4-C(=O)-]-N-P(=O)-N-t-Bu}2 [trans-18] and cis-[(t-BuNH)P(μ-N- t−Bu)2P(=O)-N{ -C(=O)-CH2-CH2-C(=O)-}] [cis- 19] are also reported. Novel phosphano-indoles and PIII-O-N → PV(O)-N rearranged products have been synthesized from the reaction of cyclodiphosph(III)azanes with functionalized propargyl alcohols and N-hydroxy substrates.

Theoretical Investigation on Rhodium(I)-Catalyzed Cycloisomerizations of 4-Allenal Species with Linked Alkyne: Ketone vs Alcohol Products

A density functional theory study was performed to understand the mechanisms and the origins leading to different products in the cycloisomerization reactions of 4-allenal species with linked alkyne when two types of Rh(I) catalysts were employed. With RhCl(PPh3)3 as the catalyst, the water present in the solvent promotes the H-migration from Rh to the allenic carbon and thus prompts formation of 5–8-fused bicyclic ketone (P1). When [Rh(dppe)]ClO4 was employed as the catalyst, the positive charge on the catalyst plays a key role in lowering the barriers of the oxidative coupling, β-H elimination, and O–H reductive elimination steps compared to the corresponding processes catalyzed by RhCl(PPh3)3. In addition, the water in solvent was found to assist the O–H reductive elimination and thus facilitates formation of the 6–7-fused bicyclic alcohol (P2). The predicted mechanisms provide a successful interpretation of the experimental observations.