Reductive Desulfonylation Research Articles

Solution-Phase Late-Stage Chemoselective Photocatalytic Removal of Sulfonyl and Phenacyl Groups in Peptides.

Herein, BPC catalyzed visible-light-triggered target-specific late-stage solution phase desulfonylation from tryptophan in oligopeptides is portrayed by overcoming the isolation issue up to octamers. This robust and mild method is highly predictable and chemoselective, tolerating myriad of functional groups in aza-heteroaromatics and peptides. Interestingly, reductive desulfonylation is also amenable to biologically significant reactive histidine and tyrosine side chains, signifying the versatility of the strategy. Additional efficacy of BPC is demonstrated by solution phase phenacyl deprotection from C-terminal in peptides. Furthermore, excellent catalyst loading of 0.5 mol% and recyclability demonstrate the practical utility and applicability of this strategy.

Palladium-catalyzed carbomonofluoromethylation of unactivated alkenes: rapid access to γ-monofluoromethyl carboxylic acid derivatives.

Herein, we report a palladium-catalyzed regioselective carbomonofluoromethylation of unactivated alkenes. The reaction uses easily available fluorobis(phenylsulfonyl)methane (FBSM) as a fluoromethylating reagent, and proceeds smoothly with a wide variety of carbon electrophiles, including (hetero)aryl iodides, styrenyl iodides and TIPSBr. A range of remote γ-CH2F/CD2F carboxylic acid derivatives were constructed rapidly after a simple reductive desulfonylation step. The reaction features high regioselectivity, mild and simple reaction conditions and a broad substrate scope, and is easy to scale up.

A toolbox approach to revealing a series of naphthocarbazoles to showcase photocatalytic reductive syntheses.

The development of highly reducing photocatalysts to functionalize arenes via the generation of reactive aryl radicals under mild and environmentally benign reaction conditions has emerged as a noteworthy approach in the realm of organic synthesis. Herein, we report a readily synthesized series of novel naphthocarbazole derivatives (NCs) as organo-photocatalysts, which, upon irradiation under 390 nm light, acquire high reducing power to catalyze several reductive transformations. The promising properties revealed by in depth photophysical and electrochemical studies ( = -1.9 V to -2.07 V vs. SCE, τ = 5.59 to 7.12 ns) demonstrate NCs to be versatile catalysts, and notably, rational variation of the substituents (NC1-NC6) modulates their success as efficient photoreductants. Detailed DFT calculations of the frontier MO diagrams and energy levels revealed them to be non-donor-acceptor type molecular scaffolds. The applicability of the NCs as catalysts was demonstrated in reductive dehalogenative borylation, phosphorylation, and dehydrohalide intramolecular C-C coupling reactions, as well as the dimerization of carbonyls and imines. Visible-light-irradiated selective reductive desulfonylation from heteroaromatics and peptides further enhances their synthetic utility.

Effective synthesis of 1,4-diarylbutadienes via reductive desulfonylation of 1,3-butadienyl sulfones by proper choice of regioisomeric π-expanded pyrene photocatalysts

Abstract For the reductive desulfonylation of 1,3-butadienyl sulfones, we synthesized 1,3,6,8-tetra(phenylethynyl)pyrenes possessing (S)-citronellyloxy groups on the terminal phenyl rings at the ortho-, meta-, and para-positions to serve as photocatalysts. All of these pyrenes exhibited catalytic activity in the reductive desulfonylation of butadienyl sulfones when exposed to either green (514 nm) or blue LEDs (447 nm) in the presence of the sacrificial reducing agent i-Pr2NEt. The photocatalytic activities of these compounds could be fine-tuned by altering the position of the (S)-citronellyloxy group. Under green LEDs illumination, the ortho-(S)-citronellyloxy pyrene photocatalyst (S)-1 proved to be the most effective in the reductive desulfonylation of 1,4-diphenylbutadien-1-yl sulfone 4b to produce 1,4-diphenylbutadiene (5b) with an 88% yield. On the other hand, in the reductive desulfonylation of 1,2-diphenyethen-1-yl sulfone 4a, the para-(S)-citronellyloxy photocatalyst (S)-3 demonstrated high performance, producing stilbene (5a) with a 92% yield. Furthermore, the trio of pyrene photocatalysts proved to be highly efficient in promoting the reductive desulfonylation of functionalized dienyl sulfones as well as π-expanded dienyl sulfones. By judiciously selecting the suitable photocatalyst from the trio of (S)-1-3, these desulfonylation reactions could be rapidly and effectively accomplished.

Monofluoromethylation of Cyclic Sulfamidates and Sulfates with α‐Fluorocarbanions of Fluorobis(phenylsulfonyl)methane and Ethyl 2‐Fluoroacetoacetate

AbstractA regioselective fluoromethylation by ring‐opening of cyclic sulfamidates and sulfates with α‐fluorocarbanions and subsequent reductive desulfonylation is developed. Fluorobis(phenylsulfonyl)methane (FBSM) was explored as fluoromethide equivalent and the reaction was extended to the α‐fluorocarbanion of ethyl 2‐fluoroacetoacetate. This approach allows access to γ‐ and δ‐fluoroamines as well as γ‐ and δ‐fluoroalcohols in high yields.

Electron and hydrogen atom donor photocatalysts in situ generated from benzimidazolium salts and hydride reagents

Photocatalytic systems consisting of 2-substituted benzimidazoliums (BI+–R, R = polycyclic aryl, triarylamine or phenyl-sulfate) and stoichiometric hydride donor reagents were developed. Light emitting diode irradiation of these photocatalysts in the presence of NaBH4 or picoline borane promotes desulfonylation reactions of an N-sulfonyl indole, N-sulfonyl amide and α-sulfonyl ketone. Absorption spectroscopic and redox potential measurements as well as density functional theory calculations were carried out to gain mechanistic information. Benzimidazolines (BIH–R), generated in situ by hydride reduction of BI+–R, serve as both an electron and hydrogen atom donor photocatalysts in these reductive desulfonylation reactions, which contrasts to ordinary reducing photocatalysts that simply donate electrons.

Rigidified Bis(sulfonyl)ethylenes as Effective Michael Acceptors for Asymmetric Catalysis: Application to the Enantioselective Synthesis of Quaternary Hydantoins.

The catalytic, enantio- and diastereoselective addition of hydantoin surrogates II to "rigidified" vinylidene bis(sulfone) reagents is developed, thus overcoming the inability of commonly employed β-substituted vinylic sulfones to react. Adducts are transformed in enantioenriched 5,5-disubstituted hydantoins through hydrolysis and reductive desulfonylation processes providing new structures for eventual bioassays. Density functional theory studies that rationalize the observed reactivity and stereoselectivity trends are also provided.

Aromatic C-H Methylation and Other Functionalizations via the Rh(III)-Catalyzed Migratory Insertion of Bis(phenylsulfonyl)carbene and Subsequent Transformations.

The Rh(III)-catalyzed migratory insertion of bis(phenylsulfonyl)carbene into aromatic C-H bonds has been developed. A variety of bis(phenylsulfonyl)methyl derivatives were prepared with good yields under mild conditions. The methylated products were readily obtained after reductive desulfonylation. Furthermore, the diverse transformations of bis(phenylsulfonyl)methyl to trideuteriomethyl, aldehyde, and other functional groups were demonstrated.

Custom-Made Pyrene Photocatalyst-Promoted Desulfonylation of Arylethenyl Sulfones Using Green-Light-Emitting Diodes

AbstractThe Sonogashira coupling of 1,3,6,8-tetrabromopyrene with 4-[(–)-β-citronellyloxy]phenylethyne was employed to synthesize 1,3,6,8-tetra[4-(citronellyloxy)phenylethynyl]pyrene. The pyrene derivative catalyzed the reductive desulfonylation of ethenyl sulfones via visible-light irradiation (514 nm green light-emitting diodes) in the presence of i-Pr2NEt. The β-citronellyloxy groups provided the sufficient solubility to the highly π-expanded pyrene catalyst, and their polar oxygen functionalities enabled the easy separation of the catalyst from the products via column chromatography.

Electron Transfer Photoredox Catalysis: Development of a Photoactivated Reductive Desulfonylation of an Aza‐Heteroaromatic Ring

AbstractHerein, we report a protocol for desulfonylation of aza‐heteroaromatic rings via photoinduced electron transfer and hydrogen atom transfer. This general protocol has a wide substrate range and moderate to good yields. The utility of the method was demonstrated by the chemoselective desulfonylation of a molecule containing both an aliphatic and an aromatic sulfonamide.magnified image

Radical Addition to Strained σ-Bonds Enables the Stereocontrolled Synthesis of Cyclobutyl Boronic Esters.

While radical additions to π-bonds are well established, additions to σ-bonds are far less explored. We have found that electron deficient radicals derived from alkyl iodides under visible light irradiation add to the central strained bond of bicyclobutyl (BCB)-boronate complexes and lead to 1,3-alkyl disubstituted cyclobutyl boronic esters in high yields, with full stereospecificity and high levels of stereoselectivity. Novel cyclobutyl-substituted structures, including peptide and steroid boronic ester derivatives can be accessed. Additionally, although the use of electron-rich alkyl iodides as radical precursors was found to be ineffective, an alternative route involving alkylsulfonylation of the BCB-boronate followed by reductive desulfonylation provided access to simple alkyl substituted cyclobutane products.

Stereospecific Synthesis of Fluorinated Pyrazolidinones and Isoxazolidines via a Catalyst‐Free 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones

AbstractA highly atom‐economic, regio‐ and stereospecific synthesis of fluorinated pyrazolidinones and isoxazolidines is disclosed under catalyst‐ and additive‐free mild conditions. The diastereoselectivity with different type of 1,3‐dipoles is elucidated by using DFT calculations in CH3CN. Furthermore, a reaction using a chiral azomethine imine, a gram‐scale synthesis, and a reductive desulfonylation are also presented.

Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-diaryloxazoles.

2-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The corresponding α-sulfonyl anion reacts smoothly with diverse alkyl halides giving monoalkylated (47-90%), dialkylated (50-97%), and cyclic (59-93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products in the range of 66-97%. The anti-inflammatory Oxaprozin was prepared using the α-sulfonyl carbanion strategy along with optimized desulfonylation.

A Straightforward Synthesis of 5‐Methylaaptamine from Eugenol, Employing a 6π‐Electrocyclization Reaction of a 1‐Azatriene

AbstractAaptamine, isolated from tropical marine sponges of the Demospongiae class, is the most prominent member of a growing family of natural products. Many aaptaminoids have been shown to have interesting biological activity. The efficient access to 5‐methylaaptamine, an unnatural analogue of aaptamine, was achieved by using economic and naturally‐occurring eugenol as the starting material. The synthesis involved the preparation of a 5‐aminoeugenol derivative through successive nitration, O‐methylation, and nitro group reduction reactions. An Elderfield–Johnson sequence was employed to synthesize the N‐tosyl‐5‐allyl‐7,8‐dimethoxydihydro‐1H‐quinolin‐4‐one ring system. A catalytic double‐bond isomerization followed by a carbonyl methoximation and 6‐π electrocyclization of the 1‐azatriene motif afforded the 2,3‐dihydro‐1H‐benzo[de][1,6]naphthyridine tricyclic intermediate, which underwent a reductive desulfonylation and catalytic dehydrogenation to afford the target product.

Reductive opening of carbohydrate phenylsulfonylethylidene (PSE) acetals

The phenylsulfonylethylidene (PSE) acetal is a relatively new protecting group in carbohydrate chemistry. However, carbohydrate-derived phenylsulfonylethylidene (PSE) acetals show a different behavior in reductive desulfonylation than simple symmetrical acetals. Here we have investigated various SET-type reaction conditions in order to open PSE acetals regioselectively and to produce chiral ω-hydroxyethenyl ethers. Whereas sodium amalgam leads to a mixture of regioisomeric vinyl ethers besides the ethylidene acetal, samarium iodide is suited for regioselective ring opening. This is shown with seven different carbohydrate PSE acetals, both of the 1,3-dioxane and the 1,3-dioxolane type.

Total Synthesis of (+)-Clavulatriene A

The protecting-group-free total synthesis of (+)-clavulatriene A has been achieved. Key features of the synthetic strategy include the development of a novel strategy for the practical synthesis of α-cyperone, and a one-pot palladium-catalyzed reductive desulfonylation and deacetoxylation reaction. Furthermore, the total synthesis described in this study allowed for the determination of the absolute configuration of (+)-clavulatriene A.

ChemInform Abstract: Synthesis of 2‐Substituted 9,10‐Anthraquinones.

AbstractRacemic 2‐triazolyl or 2‐alkylethyl 9,10‐anthraquinone derivatives [(V), (X), and (XI)] are efficiently synthesized in good yields by a three‐ or four‐step procedure involving bromination, nucleophilic substitution, and CuI‐promoted 1,3‐dipolar cycloaddition or alkylation and reductive desulfonylation, respectively.

Synthesis of Neu5Ac-α-C-galactopyranosyl-functionalized magnetic nanoparticles via click chemistry

A new type of glyco-nanoparticle has been accomplished through Cu(I)-catalyzed 1,3-dipolar cycloaddition of 6-azidohexyl Neu5Ac-α-C-galactoside and N-propargyl derivative, which was attached on a silica-wrapping magnetic nanoparticle. Neu5Ac-α-C-galactoside was stereo-selectively synthesized in 11 steps from isopropyl thiogalactopyranoside and per-acetylated Neu5Ac phenylsulfone using samarium-mediated reductive desulfonylation as the key step. Magnetic nanoparticles were prepared with one-step hydrothermal method and a subsequent coating with (N,N′-di-propargyl-3-aminopropyol) triethoxysilane derivative.

Copper-Catalyzed Debenzoylative Monofluoromethylation of Aryl Iodides Assisted by the Removable (2-Pyridyl)sulfonyl Group

A new method for aromatic monofluoromethylation was developed. Aryl iodides can be efficiently transformed into the corresponding monofluoromethylated products by a copper-catalyzed debenzoylative fluoroalkylation with 2-PySO2CHFCOR and subsequent reductive desulfonylation. The (2-pyridyl)sulfonyl moiety plays an important role in the copper-catalyzed cross-coupling, and it can be removed easily through Bu3SnH-mediated desulfonylation.

Iridium‐Catalyzed Enantioselective Allylic Alkylation of Methyl 2‐(4‐nitrophenylsulfonyl)acetate and Subsequent Transformations

AbstractHighly enantioselective allylic alkylation reactions of methyl 2‐(4‐nitrophenylsulfonyl)acetate were carried out in the presence of an iridium catalytic system. The subsequent transformations of the products including reductive desulfonylation and modified Julia olefination led to the allylic alkylation products of methyl acetate or methyl acrylate with good yields and high enantioselectivity.