Allylic Carbamates Research Articles

Computational Study of the Ir-Catalyzed Formation of Allyl Carbamates from CO2.

We have employed computational methods to investigate the iridium-catalyzed allylic substitution leading to the formation of enantioenriched allyl carbamates from carbon dioxide (CO2). The reaction occurs in several steps, with initial formation of an iridium-allyl, followed by nucleophilic attack by the carbamate formed in situ from CO2 and an amine. A detailed isomeric analysis shows that the rate-determining step differs for the (R)- and (S)-pathways. These insights are essential for understanding reactions involving enantioselective formation of allyl carbamates from CO2.

Fluorescent probes for investigating the internalisation and action of bioorthogonal ruthenium catalysts within Gram-positive bacteria.

Bioorthogonal reactions are extremely useful for the chemical modification of biomolecules, and are already well studied in mammalian cells. In contrast, very little attention has been given to the feasibility of such reactions in bacteria. Herein we report modified coumarin dyes for monitoring the internalisation and activity of bioorthogonal catalysts in the Gram-positive bacterial species Bacillus subtilis. Two fluorophores based on 7-aminocoumarin were synthesised and characterised to establish their luminescence properties. The introduction of an allyl carbamate (R2N-COOR') group onto the nitrogen atom of two 7-aminocoumarin derivatives with different solubility led to decreased fluorescence emission intensities and remarkable blue-shifts of the emission maxima. Importantly, this allyl carbamate group could be uncaged by the bioorthogonal, organometallic ruthenium catalyst investigated in this work, to yield the fluorescent product under biologically-relevant conditions. The internalisation of this catalyst was confirmed and quantified by ICP-OES analysis. Investigation of the bacterial cytoplasm and extracellular fractions separately, following incubation of the bacteria with the two caged dyes, facilitated their localisation, as well as that of their uncaged form by catalyst addition. In fact, significant differences were observed, as only the more lipophilic dye was located inside the cells and importantly remained there, seemingly avoiding efflux mechanisms. However, the uncaged form of this dye is not retained, and was found predominantly in the extracellular space. Finally, a range of siderophore-conjugated derivatives of the catalyst were investigated for the same transformations. Even though uptake was observed, albeit less significant than for the non-conjugated version, the fact that similar intracellular reaction rates were observed regardless of the iron content of the medium supports the notion that their uptake is independent of the iron transporters utilised by Gram-positive Bacillus subtilis cells.

Regioselective tungsten-catalyzed decarboxylative amination of allylic alcohols with isocyanates.

Highly regioselective tungsten (W)-catalyzed decarboxylative allylic amination of allylic carbamates has been developed. Allylic carbamates can be generated in situ from readily available allylic alcohols and commercially available isocyanates. In the presence of a tungsten catalyst, branched allylic amines could be obtained in moderate to good yields with excellent regioselectivities (b/l > 20 : 1), and CO2 is the only byproduct. This reaction features mild conditions and a broad substrate scope, and aryl- and aliphatic-substituted allylic alcohols and isocyanates are suitable substrates.

Nitrogen Heterocycle Synthesis through Hydride Abstraction of Acyclic Carbamates and Related Species: Scope, Mechanism, Stereoselectivity, and Product Conformation Studies.

Acyliminium ions and related species are potent electrophiles that can be quite valuable in the synthesis of nitrogen-containing molecules. This manuscript describes a protocol to form these intermediates through hydride abstractions of easily accessible allylic carbamates, amides, and sulfonamides that avoids the reversibility that is possible in classical condensation-based routes. These intermediates are used in the preparation of a range of nitrogen-containing heterocycles, and in many cases high levels of stereocontrol are observed. Specifically areas of investigation include the impact of chemical structure on oxidation efficiency, the geometry of the intermediate iminium ions, the impact of a substrate stereocenter on stereocontrol, and an examination of transition state geometry.

Silver-Catalyzed Cascade Radical Bicyclization Reaction: An Atom- and Step-Economical Strategy Accessing γ-Lactam Containing Isoquinolinediones.

An efficient and convenient method for the cascade radical bicyclization of N-phenyl-4-pentenamides with N-methyl-N-methacryloylbenzamides under silver-catalyzed conditions is described. Based on this newly developed strategy, a variety of valuable γ-lactam containing isoquinolinediones can be effectively synthesized in one step within 0.5 h, during which two C-C bonds, one C-N bond, and two new N-heterocycles were formed concurrently. With N-aryl allyl carbamates, similar 2-oxazolidinone substituted isoquinolinedione compounds can likewise be produced. The approach demonstrates wide functional group compatibility, high step- and atom-economy, and the ability to be scaled up to gram quantities in a satisfactory yield. It marks the first instance of introducing γ-lactams into isoquinoline-1,3(2H,4H)-diones to construct linked hybrid drug-like molecules, thereby making this strategy highly attractive to drug discovery.

Divergent reactivity of sulfoxonium ylide with allyl carbonate and allyl carbamate.

A divergent reactivity of sulfoxonium ylide with allyl carbonates and allyl carbamates is demonstrated. Rh(III)-catalyzed C-H activation and cyclization of sulfoxonium ylide with ally esters leads to the formation of a cyclopropane-fused tetralone derivative by cascade C-H activation, (4+2) annulation, and cyclopropanation. A similar reaction of sulfoxonium ylide with allyl carbamates forms a C3-substituted indanone derivative via a rare and interesting domino C-H activation and (4+1) annulation in which allyl carbamate is acting as a C1-synthon.

Palladium Nanoparticles on Chitosan-Coated Superparamagnetic Manganese Ferrite: A Biocompatible Heterogeneous Catalyst for Nitroarene Reduction and Allyl Carbamate Deprotection

Although metallic nanocatalysts such as palladium nanoparticles (Pd NPs) are known to possess higher catalytic activity due to their large surface-to-volume ratio, however, in nanosize greatly reducing their activity due to aggregation. To overcome this challenge, superparamagnetic chitosan-coated manganese ferrite was successfully prepared and used as a support for the immobilization of palladium nanoparticles to overcome the above-mentioned challenge. The Pd-Chit@MnFe2O4 catalyst exhibited high catalytic activity in 4-nitrophenol and 4-nitroaniline reductions, with respective turnover frequencies of 357.1 min-1 and 571.4 min-1, respectively. The catalyst can also be recovered easily by magnetic separation after each reaction. Additionally, the Pd-Chit@MnFe2O4 catalyst performed well in the reductive deprotection of allyl carbamate. Coating the catalyst with chitosan reduced the Pd leaching and its cytotoxicity. Therefore, the catalytic activity of Pd-Chit@MnFe2O4 was proven to be unrestricted in biology conditions.

A one-pot synthesis and X-Ray structural characterization of new highly substituted-allyl carbamates

A one-pot synthesis of new variously substituted γ-chloro-γ, β-allylic carbamates have been carried out starting from β-chloro-α, β-unsaturated aldehydes. The new carbamates and the corresponding intermediates, the γ-chloro-γ, β-allylic alcohols, were fully characterized by (1H and 13C) NMR, IR and HRMS spectroscopic techniques. The crystal structures of two allylic carbamates, were established by single-crystal X-ray diffraction.

Acid-mediated decarboxylative C–H coupling between arenes and O-allyl carbamates

Treatment of O-allyl N-tosyl carbamates with arenes in the presence of Cu(OTf)2 or TMSOTf as promoters affords N-substituted 1-arylpropan-2-amines, 1,2-diarylpropanes, 1,1-diarylpropanes, or indanes, depending on the nature of the promoter.

Silver-catalyzed cascade cyclization and functionalization of N-aryl-4-pentenamides: an efficient route to γ-lactam-substituted quinone derivatives.

The synthesis of γ-lactam-substituted quinone derivatives through a Ag2O-catalyzed cascade cyclization and functionalization of N-aryl-4-pentenamides has been developed. Related 2-oxazolidinone substituted quinone products can be also obtained with N-aryl allyl carbamates. The reactions proceed through an amidyl radical-initiated 5-exo-trig cyclization and followed radical addition to quinones. They provide an efficient route to various γ-lactam-substituted quinone derivatives with a wide range of substrate scope.

Microwave‐Assisted 1,3‐Dioxa‐[3,3]‐Sigmatropic Rearrangement of Substituted Allylic Carbamates: Application to the Synthesis of Novel 1,3‐Oxazine‐2,4‐dione Derivatives

AbstractIn a first instance, the effect of the microwave irradiation on the 1,3‐Dioxa‐[3,3]‐sigmatropic rearrangement of aryl allylic carbamates was investigated. Under these new conditions, the reaction acceleration was clearly highlighted compared to conventional heating conditions. Depending on the electronic nature of substituents on the aromatic group, this type of rearrangement can be faster with similar or improved yields. Due to this experimental improvement, the diversity of aryl allylic carbamates able to undergo this rearrangement in a reasonable reaction time (30 min.) and with acceptable to high yields was greatly extended. Finally, an original synthetic way involving this microwave‐assisted process to access new six‐membered heterocyclic structures such as (E)‐5‐arylidene‐1,3‐oxazinane‐2,4‐diones was developed from Morita‐Baylis‐Hillman (MBH) adducts showing the interest of this molecular rearrangement approach. DFT and Fragment Distortion studies showed in general polar transition structures and connected high deformation and interaction energies with lower activation barriers.

Stereospecific Synthesis of Conjugated Dienes by Carbenoid Eliminative Cross‐Coupling Using Lithiated Allylic Carbamates

Abstract1,2,4‐Trisubstituted 1,3‐butadienes were prepared in a stereocontrolled manner by carbenoid eliminative cross‐coupling between stereodefined lithiated secondary allylic carbamates and α‐carbamoyloxyalkyl boronates. All four geometric isomers of 4,7‐dimethyl‐1‐phenylocta‐3,5‐diene were stereospecifically generated [yields 44–73 %, dr (Δ3,4)=84 : 16 to 97 : 3] by appropriate combinations of (S,E)‐ or (S,Z)‐i‐PrCH=CHCLi(Me)OCb with (R)‐Ph(CH2)2CH(Bneo)OCb. A conjugated cyclohexenylidene and a model diene representing the C5‐C12 domain of cytotoxin callystatin A, were similarly elaborated in a stereochemically programmed manner. The configuration of the 1,2‐disubstituted alkene within the Li‐carbenoid was preserved in the diene product and the newly generated trisubstituted alkene component of the diene could be selectively installed in either (E)‐ or (Z)‐configuration by variation in carbenoid stereochemical pairing (like or unlike) and/or the mode of the elimination stage (syn or anti).

Regio- and diastereoselective Pd-catalyzed aminochlorocyclization of allylic carbamates: scope, derivatization, and mechanism.

The regio- and diastereoselective synthesis of oxazolidinones via a Pd-catalyzed vicinal C-N/C-Cl bond-forming reaction from internal alkenes of allylic carbamates is reported. The oxazolidinones are obtained in yields of 44 to 95% with high to excellent diastereoselectivities (from 6 : 1 to >20 : 1 dr) from readily available precursors. This process is scalable, and the products are suitable for the synthesis of useful amino alcohols. A detailed theoretical and experimental mechanistic study was carried out to describe that the reaction proceeds through an anti-aminopalladation of the alkene followed by an oxidative C-Pd(ii) cleavage with retention of the carbon stereochemistry to yield the major diastereomer. The role of Cu(ii) in a C-Cl bond-forming mechanism step has also been proposed.

Exogenous Flupirtine as Potential Treatment for CLN3 Disease.

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3Δex7/8 mice. WT/Cln3Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3Δex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3Δex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3Δex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3Δex7/8 mice, paving the way for potential therapies for CLN3 disease.

The Synthesis of Chiral Allyl Carbamates via Merger of Photoredox and Nickel Catalysis

AbstractA mild, and versatile, organophotoredox/Ni‐mediated protocol was developed for the direct preparation of diverse, enantioenriched allyl carbamates. The reported approach represents a significant departure from classical step‐by‐step synthesis of allyl carbamates. This dual photoredox/Ni based strategy offers unrivalled capacity for convergent unification of readily available alkyl halides and chiral carbamates derived from 1‐bromo‐alken‐3‐ols with high chemoselectivity and efficiency. The reported photoredox/Ni catalyzed cross‐coupling reaction is not limited to carbamates, but also to other O‐derivatives such as esters, ethers, acetals, carbonates or silyl ethers. To demonstrate the utility of the reported protocol, the resulting allyl carbamates were transformed into functionalized non‐racemic allylamines through a sigmatropic rearrangement reaction in enantiospecific manner. This approach allowed for synthesis of enantiomeric allylamines by a simple control of the geometry of a double bond of allyl carbamates.magnified image

N-Allylation versus C-allylation of intermediates from aza-Michael adducts of arylideneisoxazol-5-ones.

Reactions of arylidene-isoxazol-5-ones with intermediates from palladium-catalysed decarboxylation of allyl carbamates proceeded through aza-Michael addition and N-allylation to give the corresponding bis-adducts, β-amido-N-allylated products, in good yields. In similar reactions with 4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, a cyclic allyl carbamate, C-allylation took place to yield a series of spiro[isoxazole-4,3'-quinolin]-5-ones in high yields. Regio-selective N- versus C-allylation is illustrated to occur in an inter- versus intra-molecular fashion. The structure and stereochemistry of these products are determined by NMR spectroscopy and further confirmed by X-ray crystallography. This work offers an excellent method for the preparation of various substituted isoxazol-5-ones.

The synthesis of unnatural α-alkyl- and α-aryl-substituted serine derivatives.

The synthesis of α-aryl- and α-alkyl-substituted serine derivatives via [3,3]-sigmatropic rearrangement of allyl carbamates as a key step is reported. Allyl carbamates were obtained from the corresponding allyl alcohols. The former were prepared through three approaches. Aryl-substituted ones were synthesized via the Stille coupling reaction of aryl iodides with enantiomerically enriched vinyl stannanes. Conversely, alkyl-substituted allyl alcohols were prepared by an analogous strategy involving the Negishi coupling reaction of enantiomerically enriched vinyl iodides or by enzymatic kineric resolution of the corresponding racemic alcohols.

Comparison between Conventional and Nonconventional Methods for the Synthesis of Some 2-Oxazolidinone Derivatives and Preliminary Investigation of Their Inhibitory Activity Against Certain Protein Kinases

A series of propargyl and allyl carbamates were prepared directly from propargyl and allyl alcohols and phenyl or cyclohexyl isocyanate or indirectly by generating the isocyanates in situ from the corresponding Cbz-protected amines. The obtained carbamates underwent intramolecular nucleophilic cyclization in presence of cesium hydroxide monohydrate as a base catalyst under conventional and ultrasonic irradiation conditions to give the corresponding substituted 4-(benzylidene)methylidene-2-oxazolidinones in good to excellent yields. The use of ultrasonic irradiation provided remarkably improved yield of the cyclization products and significant shortening of the reaction time. In some cases the reaction was highly stereoselective, and (Z)-4-benzylideneoxazolidinones were formed as a single stereoisomer. A series of biological tests were performed to evaluate the inhibitory potential of all synthesized compounds against some protein kinases.

Dipicolylamino quinoline derivative as novel dual fluorescent detecting system for Hg2+ and Fe3+

Novel quinolinyl oxazolidinonyl dipicolylamine derivatives (QOD) were synthesized via halo-induced cyclization of t-butyl allyl(quinolinyl) carbamate followed by substitution of dipicolylamine (DPA). One of the quinoline derivatives, 6QOD, shows a remarkable fluorescent enhancement in both Hg2+ in aqueous media and Fe3+ in CH3CN over other metal ions with a detection limit of 1.01 and 0.22 μM, respectively. Moreover, the complexation was proved to be a 1:1 stoichiometric binding by Job's plot and MS data. 6QOD was confirmed to form a bidentate binding with Hg2+ (Ka = 6556 M−1) and Fe3+ (Ka = 27,700 M−1) as evidenced by the chemical shifts in 1H NMR experiments of the DPA protons and the oxazolidinonyl protons in an excellent agreement with the most stable complex structures for both metal ions revealed by the DFT study. Both sensing mechanisms probably involve PET inhibition between the DPA unit and quinoline. The advantage of this 6QOD probe is that it can effectively be applied as a selective Hg2+ and Fe3+ chemosensor by adapting the proper dual-sensing system.

Direct Synthesis of Diallyl Carbonate Via Urea Transesterification with Allyl Alcohol Over Metal Chlorides

A promising technique was studied towards diallyl carbonate (DAC) manufacture via urea transesterification with allyl alcohol over several metallic chlorides. It was revealed that the intermediate allyl carbamate (AC) was first generated via urea mono-alcoholysis with high yield, and subsequently AC further reacted with another allyl alcohol molecule to produce DAC. All the metal halides were evaluated for the overall reaction and the reaction of AC and allyl alcohol, respectively. This work found that the catalytic ability of catalysts originated from metal ions. Importantly, the highest yield of DAC could be achieved using LaCl3 as catalyst. In addition, the activation patterns of reactants were investigated using in situ FT-IR measurement. Based on the characterization results of X-ray power diffraction and elemental analysis of the lanthanum species, separated from the reaction conduced over LaCl3, a possible reaction mechanism was speculated.