Facile Deprotection Research Articles

Palladium-Catalyzed One-Step Synthesis of Stereodefined Difunctionalized Glycals

Palladium-Catalyzed One-Step Synthesis of Stereodefined Difunctionalized Glycals

The Sulfolene Protecting Group: Observation of a Direct Photoinitiated Cheletropic Ring Opening

AbstractPhotolabile protecting groups offer synthetic routes with facile deprotection by photolysis, providing higher yields with less workup. Protecting groups producing only gaseous byproducts upon removal are particularly desirable as sustainable reagents. Cheletropic reactions provide just this combination of photocleavable groups with gaseous byproducts. However, only few protecting groups for cheletropic reactions have been described and little is known about their photochemistry and associated stereochemistry. Here we show that the sulfolene protecting group, used for diene protection and functionalization, can be photochemically removed. First, using TD‐DFT, we conclude that the photochemical ring‐opening occurs conrotatorily in a concerted process, consistent with the Woodward‐Hoffmann rules. Experimentally, we demonstrate that this process can be photoinitiated by radiation between 180 and 300 nm and confirm the proposed stereochemistry in solution. Using time‐resolved photoelectron spectroscopy, we determine that the first steps in the photochemical ring‐opening of sulfolene occur on ultrafast timescales (≤84 fs), consistent with a fully concerted process. Our findings expand applications of the sulfolene protecting group and promise an easy strategy for control of cis‐trans isomerization.

Glycidyl ether of naturally occurring sesamol in the synthesis of mussel-inspired polymers

The objective of this work is to synthesize the mussel-mimicking ionic polymers bearing electron-rich 1,3,4-triphenoxy motifs of naturally occurring sesamol [3,4-(methylenedioxy)phenol] I. To our knowledge, the work would represent, for the first time, the ring-opening reaction of epoxide built upon the triphenoxy motifs of hydroxyhydroquinone. Sesamol I upon O-alkylation using epibromohydrin has been converted to its epoxy monomer II in 77% yield. Monomer II under ring-opening polymerization using basic Bu4NOH and Bu4NF as well as by Lewis acid initiator/catalyst MePh3PBr/iBu3Al led to polyether III in 80–99% yields. Monomer II and allyl glycidyl ether (i.e. allyl 2,3-epoxypropyl ether) IV upon polymerization gave random copolymer V of number average molar mass of 9570 g mol−1, which upon thiol-ene reaction with HSCH2CH2NH3+Cl− and HSCH2CO2H afforded cationic (^^^NH3+) VI and anionic (^^^CO2−) VII copolymers, respectively. For facile deprotection, the methylenedioxy (OCH2O) motifs in VI was activated by its conversion to labile acetoxymethylenedioxy [OCH(OAc)O] unit to obtain VIII in 80% yields. The pendant allyl groups in VIII upon elaboration via thiol-ene reaction using cysteamine hydrochloride and subsequent hydrolysis of [OCH(OAc)O] under a mild condition led to a mussel-inspired cationic copolymer IX (78%) having catechol motifs-embedded pendants of 3,4-dihydroxyphenoxy groups.

Aggregation-Induced Emission Active Polyacrylates via Cu-Mediated Reversible Deactivation Radical Polymerization with Bioimaging Applications.

The introduction of aggregation-induced emission (AIE) moieties into polymers results in smart materials with AIE characteristics, expanding their scope of applications. Herein, well-defined polymers with controlled molecular weight, low dispersity, and high end-group fidelity areproducedvia copper(0)-mediated reversible-deactivation radical polymerizations (Cu(0)-RDRPs). An AIE-containing initiator tetraphenylethene bromoisobutyrate (TPEBIB) has been synthesized, fully characterized, and utilized for the construction of different polyacrylate homopolymers and block copolymers bearing the TPE group with a range of molecular weights and architectures. All of the polymers exhibited AIE behavior. Notably, the hydrophobic TPE-poly(tert-butyl acrylate) (TPE-PtBA)-containing block copolymers are transformed to TPE-poly(acrylic acid) (TPE-PAA)-based amphiphilic copolymers by facile deprotection, enabling pH-tunable self-assembly in aqueous media to give fluorescent nanoparticles with various sizes. The low cytotoxicity, high specificity, and excellent photostability render them promising candidates as lysosome-specific probes in biological imaging applications.

A Facile, Efficient and Selective Deprotection of P - Methoxy Benzyl Ethers Using Zinc (II) Trifluoromethanesulfonate

: Deprotection is significant and conducted over mild reaction conditions, in order to restrict any more side reactions with sensitive functional groups as well as racemization or epimerization of stereo center because the protective groups are often cleaved at last stage in the synthesis. P - Methoxy benzyl (PMB) ether appears unique due to its easy introduction and removal than the other benzyl ether protecting groups. A facile, efficient and highly selective cleavage of P - methoxy benzyl ethers was reported by using 20 mole% Zinc (II) Trifluoromethanesulfonate at room temperature in acetonitrile solvent over 15-120 min. time period. To study the generality of this methodology, several PMB ethers were prepared from a variety of substrates having different protecting groups and subjected to deprotection of PMB ethers using Zn(OTf)2 in acetonitrile. In this methodology, zinc triflate cleaves only PMB ethers without affecting acid sensitivity, base sensitivity and also chiral epoxide groups.

(S)-(−)-Fluorenylethylchloroformate (FLEC); preparation using asymmetric transfer hydrogenation and application to the analysis and resolution of amines

Fluorenylethylchoroformate (FLEC) is a valuable chiral derivatisation reagent that is used for the resolution of a wide variety of chiral amines. Herein, we describe an improved preparation of (S)-(−)-FLEC using an efficient asymmetric catalytic transfer hydrogenation as the key step. We also demonstrate the application of FLEC as a chiral Fmoc equivalent for chiral resolution, with facile deprotection, of tetrahydroquinaldines, and its capacity for inducing regioselective outcomes in nitration reactions.

Hydrosilane‐Promoted Facile Deprotection of tert‐Butyl Groups in Esters, Ethers, Carbonates, and Carbamates

AbstractCombination of PdCl2 with 1,1,3,3‐tetramethyldisiloxane in the presence of activated carbon was found to be an effective catalyst system for the cleavage reaction of C−O bond of O−t‐Bu moieties. The present catalytic reaction offers a practical method for the deprotection of tert‐butyl esters, tert‐butyl ethers, O‐Boc, and N‐Boc derivatives under mild conditions. The addition of activated carbon in the reaction mixture was proved to be crucial for not only sustaining the catalytic activity but also trapping the palladium species after the reaction.magnified image

Synthetic Insights into Surface Functionalization of Si(111)–R Photoelectrodes: Steric Control and Deprotection of Molecular Passivating Layers

We report the utility of controlled spacing of molecular monolayers on Si(111) surfaces by the use of sterically bulky silanes. The steric bulk of a 3,5-diphenolic linker of type Ph-diO-SiR3 (R = hexyl, phenyl, iPr)-as well as the smaller Ph-diOMe-is shown to control the surface coverage on Si(111). The para substituent was also changed from -F (small) to -OTf (triflate, large) to modulate the conformation of a selected bulky silane (SiR3; R = hexyl) to further control the steric environment of the monolayer. The surface coverage values are found to vary systematically from 57 → 21 → 15 → 11% for the series CH3 → hexyl → iPr → phenyl. Substitution at the para position (F → OTf) decreased the packing density for R = hexyl to as low as 8% (from 21%). The molecular coverage was also found to control the rate and extent of surface oxidation when unfunctionalized sites were allowed to oxidize. Following attachment, facile deprotection of the silanes was achieved by treatment with BBr3 to afford the diphenolic -OH groups. To electronically characterize the monolayers, voltammetry was performed in contact with liquid Hg to determine the barrier height, which was decreased by 70 mV as the coverage is increased. This study provides a synthetic rationale for controlling the packing density of surface linkers using electroless chemistry at semiconductor interfaces, thus providing further tunability and functionality of photoelectrochemical devices.

Deprotection of durable benzenesulfonyl protection for phenols — efficient synthesis of polyphenols

ABSTRACTA robust protection method for phenol was demonstrated by the use of durable benzenesulfonyl group, which survives various harsh reaction conditions using Grignard reagent, organolithium reagent, metal alkoxide, phosgene, mineral, and Lewis acids. A facile deprotection condition utilizing pulverized KOH (5 equiv) and t-BuOH (10 equiv) in hot toluene makes this protocol as a practical method, which can be applied to the multistep synthesis of biologically and medicinally important polyphenol compounds.

Organocatalytic Asymmetric Allylic Alkylation of Morita-Baylis-Hillman Carbonates with Diethyl 2-Aminomalonate Assisted by In Situ Protection.

With the aid of in situ protection by N-(2-formylphenyl)-4-methyl-benzenesulfonamide, enantioselective allylic alkylation of Morita-Baylis-Hillman carbonates with diethyl 2-aminomalonate was successfully realized. The corresponding adducts can be obtained in up to 99% yield with up to 98% ee as well as excellent regioselectivity. Besides, the adducts with opposite configurations were readily prepared by utilizing easily available and inexpensive quinine or quinidine as organocatalyst. Facile deprotection of the resulting adduct provides straightforward access to enantiopure α-methylene-γ-lactam.

Kinetic Resolution of 2-Substituted Indolines by N-Sulfonylation using an Atropisomeric 4-DMAP-N-oxide Organocatalyst.

The first catalytic kinetic resolution by N-sulfonylation is described. 2-Substituted indolines are resolved (s=2.6-19) using an atropisomeric 4-dimethylaminopyridine-N-oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-4-nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

Kinetic Resolution of 2‐Substituted Indolines by N‐Sulfonylation using an Atropisomeric 4‐DMAP‐N‐oxide Organocatalyst

AbstractThe first catalytic kinetic resolution by N‐sulfonylation is described. 2‐Substituted indolines are resolved (s=2.6–19) using an atropisomeric 4‐dimethylaminopyridine‐N‐oxide (4‐DMAP‐N‐oxide) organocatalyst. Use of 2‐isopropyl‐4‐nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

ChemInform Abstract: Synthesis of 8‐Aminoquinolines by Using Carbamate Reagents: Facile Installation and Deprotection of Practical Amidating Groups.

Described herein is the development of practical routes to 8-aminoquinolines by using readily installable and easily deprotectable amidating reagents. Two scalable procedures were optimized under Rh(III) -catalyzed conditions: i) the use of pre-generated chlorocarbamates and ii) a two-step one-pot process that directly employs carbamates. Both approaches are highly convenient for the gram-scale synthesis of 8-aminoquinolines under mild conditions. Facile deprotection of the synthetically versatile amidating groups was achieved under the Pd-catalyzed transfer hydrogenation conditions with simultaneous deoxygenation of quinoline N-oxides, thus yielding 8-aminoquinolines in excellent overall efficiency.

Synthetic Reactions Using Low-valent Titanium Reagents Derived from Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) in the Presence of Me3SiCl and Mg.

In the presence of Me3SiCl, Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) is reduced by Mg powder in THF to gradually generate a specific low-valent titanium (LVT) species that mediates several synthetic reactions. The LVT-catalyzed C-O bond-cleaving reactions of allyl and propargyl ethers and esters generate parent alcohols and carboxylic acids, respectively. O-allyl and propargyl carbamates are also readily deprotected by the LVT to afford parent amines. In addition, the respective reductive N-S or O-S bond cleavage of sulfonamides or sulfonyl esters mediated by the LVT was developed as a novel facile deprotection method. The reagent catalyzes intra- and intermolecular alkyne or alkyne/nitrile cycloaddition to produce substituted benzenes and pyridines, while epoxides and oxetanes are reduced to alcohols via an LVT-mediated homolytic ring opening. The McMurry coupling of aryl aldehydes and ketones proceeds with the LVT under homogeneous and mild reaction conditions and is effective for the polymerization of aromatic dialdehydes, generating conjugated polymers. Finally, imino-pinacol coupling of imines is mediated by the LVT to provide 1,2-diamines.

Synthesis of 8-Aminoquinolines by Using Carbamate Reagents: Facile Installation and Deprotection of Practical Amidating Groups.

Described herein is the development of practical routes to 8-aminoquinolines by using readily installable and easily deprotectable amidating reagents. Two scalable procedures were optimized under Rh(III) -catalyzed conditions: i) the use of pre-generated chlorocarbamates and ii) a two-step one-pot process that directly employs carbamates. Both approaches are highly convenient for the gram-scale synthesis of 8-aminoquinolines under mild conditions. Facile deprotection of the synthetically versatile amidating groups was achieved under the Pd-catalyzed transfer hydrogenation conditions with simultaneous deoxygenation of quinoline N-oxides, thus yielding 8-aminoquinolines in excellent overall efficiency.

ChemInform Abstract: Facile and Selective Deprotection of PMB Ethers and Esters Using Oxalyl Chloride.

Abstract Oxalyl chloride, (0.5 equiv) was found to cleave the PMB group from alkyl, aryl PMB ethers, and esters to give corresponding alcohol and acid in good yields. This method offers simple and efficient protocol for the selective deprotection of PMB ether and ester in DCE at ambient temperature.

Facile and Rapid Deprotection Conditions for the Cleavage of Synthetic Oligonucleotides from 1,4-Anhydroerythritol-Based Universal Polymer Support

In our previous report [Kumar, P.; Dhawan, G.; Chandra, R.; Gupta, K.C. Polyamine-assisted rapid and clean cleavage of oligonucleotides from cis-diol bearing universal support. Nucl. Acids Res. 2002, 30, e130 (1-8)], we demonstrated polyamine-mediated deprotection of oligonucleotides from cis-diol group bearing universal polymer support (I). However, vulnerability of the conventional dCbz to modifications under these conditions compelled us to employ dCac during synthesis of oligonucleotide using conventional synthons. Here, a new set of simple and rapid deprotection conditions has been developed for the complete cleavage of oligonucleotides from the 1,4-anhydroerythritol-based universal polymer support employing conventional dCbz synthon. Using manganese-imidazole complex in aqueous ammonium hydroxide (∼30%), fully deprotected oligonucleotide sequences were obtained in 40 min, which were analyzed on reverse phase-HPLC and compared with the standard oligomers in terms of their retention time. Finally, their biological compatibility was established by analyzing PCR amplified products of npsA gene of N. meningitidis.

Amine protection/α-activation with the tert-butoxythiocarbonyl group: application to azetidine lithiation-electrophilic substitution.

tert-Butoxythiocarbonyl (Botc), the long-neglected thiocarbonyl analogue of Boc, facilitates (unlike its alkoxycarbonyl cousin) α-lithiation and electrophile incorporation on N-Botc-azetidine. N,N,N',N'-endo,endo-Tetramethyl-2,5-diaminonorbornane proved optimal as a chiral ligand, generating adducts with er up to 92:8. Facile deprotection, under conditions that left the corresponding N-Boc systems intact, was achieved using either TFA or via thermolysis in ethanol.

Revisiting synthetic preparation of the quorum sensing substrate S-d-ribosyl-l-homocysteine (SRH)

Cleavage of the thioether bond of S-d-ribosyl-l-homocysteine (SRH) by the enzyme S-ribosylhomocysteinase (LuxS) serves as the final biosynthetic step in the generation of the quorum sensing autoinducer AI-2 by bacteria. Herein, a revised chemical synthesis of SRH is presented at convenient scale and purity for in vitro studies of LuxS. Potassium bis(trimethylsilyl)amide (KHMDS) is identified as a judicious base for the formation of the thioether of the target compound from readily-accessible precursors: a thiol nucleophile derived from l-homocystine and a sulfonate-activated d-ribosyl electrophile. The exclusive use of acid-labile protecting groups allows for facile deprotection to the final product, producing the TFA salt of SRH in five synthetic steps and 26% overall yield. The chemically-synthesized material is isolated at high purity and demonstrated to serve as the LuxS substrate by an in vitro assay.

Rhodium(III)‐Catalyzed Regioselective Direct C‐2 Alkenylation of Indoles Assisted by the Removable N‐(2‐Pyrimidyl) Group

AbstractThe C‐2‐alkenylindole unit is a key component of numerous natural products and pharmacophores. However, the intermolecular direct construction of the core structural motif remains challenging in organic synthesis. Here we report a new, efficient, and versatile methodology for the synthesis of C‐2‐alkenylindoles through rhodium(III)‐catalyzed direct CH functionalization of indoles with acrylates under air by employing a metal‐directing group strategy. This strategy gives a rare selectivity for the alkenylation N‐(2‐pyrimidyl)indoles at the C‐2 position and provides the functionalized C‐2‐ alkenylindoles under mild conditions with broad substrate tolerance. An expansion of the methodology has also been demonstrated to, for example, the direct alkenylation of pyrrole and facile deprotection of the pyrimidyl group. All the results suggest that this methodology could be served as a highly attractive alternative for the direct construction of biologically important C‐2‐alkenylindoles.magnified image