Carbamoyl Radicals Research Articles

Site‐Selective Construction of N‐Linked Glycopeptides through Photoredox Catalysis

AbstractThe glycosylation of peptides and proteins can significantly impact their intrinsic properties, such as conformation, stability, antigenicity, and immunogenicity. Current methods for preparing N‐linked glycopeptides typically rely on amide bond formation, which can be limited by the presence of reactive functional groups like acids and amines. Late‐stage functionalization of peptides offers a promising approach to obtaining N‐linked glycopeptides. In this study, we demonstrate the preparation of N‐linked glycopeptides through a photoredox‐catalyzed site‐selective Giese addition between N‐glycosyl oxamic acid and peptides containing dehydroalanine (Dha) under visible light conditions. Unlike traditional methods that rely on the coupling of aspartic acid and glycosylamine, this approach utilizes the conjugation of N‐glycosylated carbamoyl radicals with Dha, facilitating the straightforward modification of complex peptides.

Site-Selective Construction of N-Linked Glycopeptides through Photoredox Catalysis.

The glycosylation of peptides and proteins can significantly impact their intrinsic properties, such as conformation, stability, antigenicity, and immunogenicity. Current methods for preparing N-linked glycopeptides typically rely on amide bond formation, which can be limited by the presence of reactive functional groups like acids and amines. Late-stage functionalization of peptides offers a promising approach to obtaining N-linked glycopeptides. In this study, we demonstrate the preparation of N-linked glycopeptides through a photoredox-catalyzed site-selective Giese addition between N-glycosyl oxamic acid and peptides containing dehydroalanine (Dha) under visible light conditions. Unlike traditional methods that rely on the coupling of aspartic acid and glycosylamine, this approach utilizes the conjugation of N-glycosylated carbamoyl radicals with Dha, facilitating the straightforward modification of complex peptides.

Versatile, Modular, and General Strategy for the Synthesis of α-Amino Carbonyls.

Modulating the basicity of alkylamines is a crucial factor in drug design. Consequently, alkylamines with a proximal amide, ester, or ketone have become privileged features in many pharmaceutical candidates. The impact of α-amino carbonyls has made the development of new methods for their preparation a continuous challenge in synthesis. Here, we describe a practical strategy that provides a modular and programmable synthesis of a wide range of α-amino carbonyls. The generality of this process is made possible by an extremely mild method to generate carbamoyl radicals, proceeding via a Lewis acid-visible-light-mediated Norrish type-I fragmentation of a tailored carboxamide reagent and intercepted through addition to in situ generated unbiased imines. Aside from the reaction's broad scope in each component, its capacity to draw on plentiful and diversely populated amine and carbonyl feedstocks is showcased through a two-dimensional array synthesis that is used to construct a library of novel, assay-ready, α-amino amides.

Unveiling the gas phase H2NCO radical: Laboratory rotational spectroscopy and interstellar searches in the direction of IRAS 16293-2422

Context. The carbamoyl radical (H2NCO) is believed to play a central role in the ice-grain chemistry of crucial interstellar complex organic molecules such as formamide and acetamide. Yet, little is known about this radical, which remains elusive in laboratory gasphase experiments. Aims. In order to enable interstellar searches of H2NCO, we have undertaken a mandatory laboratory characterisation of its pure rotational spectrum. Methods. We report the gas-phase laboratory detection of H2NCO, produced by H-atom abstraction from formamide, using pure rotational spectroscopy at millimetre and submillimetre wavelengths. Millimetre-wave data were acquired using chirped-pulse Fourier-transform spectroscopy, while submillimetre-wave ones were obtained using Zeeman-modulated spectroscopy. Experimental measurements were guided by quantum-chemical calculations at the ωB97X-D/cc-pVQZ level of theory. Interstellar searches for the radical have been undertaken in the Protostellar Interferometric Line Survey (PILS) towards the solar-type protostar IRAS 16293-2422. Results. From the assignment and fit of experimental transitions up to 660 GHz, reliable spectroscopic parameters for H2NCO in its ground vibrational state have been derived, enabling accurate spectral predictions. No transitions of the radical were detected in the PILS survey. The inferred upper limit shows that the H2NCO abundance is at least 60 times below that of formamide and 160 times below that of HNCO in this source; a value that is in agreement with predictions from a physico-chemical model of this young protostar.

Silver-Catalyzed Carbofluorination of Olefins and α-Fluoroolefins with Carbamoyl Radicals.

The reactivity of carbamoyl radicals, generated in situ from sodium oxamate salts, has been investigated in the context of radical carbofluorination reactions of olefins and α-fluoroolefins, respectively. Both transformations are catalyzed by silver salts and required the presence of potassium persulfate (K2S2O8) and SelectfluorTM as a radicophilic fluorine source. The reported methods provide a direct access to β-fluoroamides and β,β-difluoroamides.

Generation of Carbamoyl Radicals and 3,4-Dihydroquinolin-2(1H)-ones Enabled by Iron Photoredox Catalysis

AbstractA new protocol for accessing 3,4-dihydroquinolin-2(1H)-ones was established through a sequence of iron-catalyzed photoredox generation of carbamoyl radicals from oxamic acids, addition of the carbamoyl radicals to electron-deficient alkenes, intramolecular cyclization, and aromatization. The process is compatible with a variety of N-phenyloxamic acids and monosubstituted, 1,1-disubstituted, and trisubstituted electron-deficient alkenes. Employing cheap, readily available, and environmentally benign iron as the catalyst, the protocol provides an excellent alternative for synthesis of 3,4-dihydroquinolin-2(1H)-ones.

Direct Amide Formation via Carbamoylation of Aromatic Bromides using Heteropoly Acid and UV‐Light

AbstractWe performed direct carbamoylation using heteropoly acid (HPA) photocatalysts with a Keggin structure under UV‐light. Carbamoyl radicals were generated via the decarboxylation of N,N‐disubstituted dimethyloxamic acid under these conditions. The HPA catalyst functioned as a photocatalyst when the dicarbonyl bond was broken, generating carbon dioxide. We found that disubstituted carbamoyl radicals readily coupled with aromatic bromides to generate diverse benzoic amides. In particular, using a homogeneous HPA photocatalyst improved the reaction's transmittance, which had been a problem of the existing heterogeneous photocatalyst. This reaction condition can be easily handled, mild, and safer than the traditional benzoic amide synthesis. This method can be scaled up efficiently, is eco‐friendly, and can be applied to producing active pharmaceutical ingredients.

Organophotocatalytic Carbamoylation of Morita‐Baylis‐Hillman Carbonates

AbstractHerein, we demonstrate that carbamoyl radicals generated through an organophotocatalytic protocol from 4‐carbamoyl‐dihydropyridines (carbamoyl‐DHPs) can be incorporated into Morita‐Baylis‐Hillman (MBH) carbonates, affording a range of polyfunctionalized scaffolds with yields ranging from 63–98%. Reaction monitoring experiments, scale‐up, reuse of the organophotocatalyst, and the hydrogenation of the succinamic ester's alkene moiety was also conducted, in order to showcase the mechanistic features and the robustness of this photochemical protocol.

Persulfate-Promoted Carbamoylation/Cyclization of Alkenes: Synthesis of Amide-Containing Quinazolinones.

The incorporation of amide groups into biologically active molecules has been proven to be an efficient strategy for drug design and discovery. In this study, we present a simple and practical method for the synthesis of amide-containing quinazolin-4(3H)-ones under transition-metal-free conditions. This is achieved through a carbamoyl-radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. Notably, the carbamoyl radical is generated in situ from the oxidative decarboxylative process of oxamic acids in the presence of (NH4)2S2O8.

Photocatalytic Carbamoyl Radical Transfer to Alkenyl Azaarenes

Abstract1-Phenyl-3-azaarenyl-propan-1-amine structural moieties have been widely incorporated in pharmaceuticals and biologically active compounds; however, current synthetic methods to access these compounds need multiple steps and proceed with low efficiency. Herein, we reported an efficient photocatalytic carbamoyl radical transfer approach that allows the preparation of these compounds in high yields (up to 88%). The reaction easily runs on a gram-scale and was applied for the preparation of pheniramine in two steps with 72% total yield.

Minisci‐Type Carbamoylation of Azauracils with Oxamic Acids

AbstractA Minisci‐type carbamoylation of azauracils was developed to afford 6‐carbamoyl azauracils in yields up to 94 %. In this transformation, oxamic acids were employed as the carbamoyl radical sources under metal‐free conditions. It features high atom economy, good functional group compatibility and convenient operation.

Metal-free photoinduced generation and alkynylation of carbamoyl radicals: a facile synthesis of alkynyl amides.

A metal-free photoinduced alkynylation of carbamoyl radicals with hypervalent iodine(III) reagents for a facile synthesis of alkynyl amides is described. This protocol features good functional group tolerance and a broad substrate scope for direct synthesis of alkynyl amide derivatives in good to excellent yields under mild and redox-neutral reaction conditions. The synthetic application is demonstrated by the late-stage installation of alkynyl amides into natural products and active pharmaceutical relevant molecules. The mechanistic studies indicated the simultaneous existence of photoredox catalytic and direct photoexcited processes, and the quantum yields confirmed the occurrence of the radical chain propagation process.

Visible light mediated iron-catalyzed addition of oxamic acids to imines.

Oxamic acids where shown to add to imines, providing a broad range of α-aminoacid amides in generally good yields. The process is efficient on pre-formed imines but may also be conducted using a 3-component strategy by simply mixing aldehydes, amines and oxamic acids in the presence of ferrocene, acting both as a photocatalyst under visible light and as a Lewis acid. The reaction proceeds through the addition onto the imine of a carbamoyl radical intermediate generated through a charge transfer from the carboxylate ligand to a Fe(iii) species (LMCT).

Carbonylative cyclization of biaryl enones with aldehydes and oxamic acids.

An oxidative radical-promoted carbonylative cyclization strategy for the synthesis of phenanthren-9-(10H)-one frameworks from biaryl enones using aldehydes as the carbonyl radical sources is disclosed. The reaction proceeds through a sequential addition of a carbonyl radical to the olefin followed by cyclization with an aryl ring. The method is further extended to carbamoyl radicals generated from oxamic acids to access the corresponding phenanthrenones with amide functionalities.

Visible-Light-Induced Three-Component Radical Coupling of Selenocarbamates, Enones, and Allylstannanes with Diphenyl (2,4,6-trimethylbenzoyl)phosphine Oxide

AbstractA blue LED-induced three-component coupling of a carbamoyl radical, cyclic enone, and allylstannane was developed. The use of blue LEDs and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO) as a radical initiator permitted the three-component radical coupling to proceed with a high chemoselectivity. An elucidation of the mechanism revealed a pathway for the formation of a tributyltin radical from TPO and allylstannane. This tandem radical reaction is expected to be applicable in natural-product synthesis.

Reactivity of Isocyanate Radical with Formic Acid in the Tropospheric and Outer Space Regions: A DFT and MP2 Investigation in Gaseous Phase

AbstractThis work aims to investigate the nature of the structures, mechanisms and kinetics associated with the prototype reaction of formic acid (FA) with NCO radical in either the troposphere or outer space regions. The kinetic properties have been investigated to include temperature in the cold outer space molecular clouds populated regions (typically between 10 and 100 K), temperature in the warm outer space molecular cloud regions (between 90–200 K) and temperature in the troposphere region of the atmosphere (200–400 K). The study has been performed by means of selected Density Functional Theory (DFT), second order Møller–Plesset perturbation theory (MP2) and transition state theory approaches. The results of the investigation suggest that the H2NCO carbamoyl radical and carbon dioxide are the final fate for the reaction involving NCO radical and FA. HOCNH radical is considered the least formed product of the NCO+FA reaction because all pathways leading to its formation are unfavourable with regards to other competitive processes. Of all the investigated reaction channels, the thermodynamically preferred reaction pathways involve cases in which the starting isocyanate radical species has its unpaired electron on the nitrogen atom (N⋅) rather than on its oxygen atom (O⋅).

Decarboxylative Nickel- and Photoredox-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides.

An efficient methodology for the photoredox- and nickel-catalyzed aminocarbonylation of (hetero)aryl bromides was developed. The utilization of readily available oxamic acids, the application of a broadly used organic photoredox catalyst (4CzIPN), and mild reaction conditions make this transformation an appealing alternative to classical amidation procedures. The generation of carbamoyl radicals was supported by trapping reactions with a hydrogen atom transfer catalyst in the presence of D2O, yielding the deuterated formamide. The generality of this deuteration protocol was confirmed for various oxamic acids.

Photoinduced Five‐Component Radical Relay Aminocarbonylation of Alkenes

AbstractRadical single carbonylation reactions with CO constitute a direct and robust strategy toward various carbonyl compounds from readily available chemicals, and have been extensively studied over the past decades. However, realizing highly selective catalytic systems for controlled radical double carbonylation reactions has remained a substantial challenge, particularly for the more advanced multicomponent variants, despite their great potential value. Herein, we report a visible‐light‐driven radical relay five‐component radical double aminocarbonylation reaction of unactivated alkenes using CO under metal‐free conditions. This protocol provides direct access to valuable γ‐trifluoromethyl α‐ketoamides with good yields and high chemoselectivity. Crucial was the identification of distinct dual roles of amine coupling partners, sequentially acting as electron donors for the formation of photoactive electron donor‐acceptor (EDA) complexes with radical precursors and then as a CO acceptor via nitrogen radical cations to form carbamoyl radicals. Cross‐coupling of carbamoyl radicals with the acyl radicals that are formed in an alkene‐based relay process affords double aminocarbonylation products.

Photoinduced Five-Component Radical Relay Aminocarbonylation of Alkenes.

Radical single carbonylation reactions with CO constitute a direct and robust strategy toward various carbonyl compounds from readily available chemicals, and have been extensively studied over the past decades. However, realizing highly selective catalytic systems for controlled double radical carbonylation reactions has remained a substantial challenge, particularly for the more advanced multi-component variants, despite their great potential value. Herein, we report a visible light-driven radical relayed five-component radical double aminocarbonylation reaction of unactivated alkenes using CO under metal-free conditions. This protocol provides direct access to valuable γ-trifluoromethyl α-ketoamides with good yields and high selectivity. Crucial was the identification of distinct dual roles of amine coupling partners, sequentially acting as electron donors for the formation of photoactive electron donor-acceptor (EDA) complexes with radical precursors and then as a CO acceptor via nitrogen radical cations to form carbamoyl radicals. Cross-coupling of carbamoyl radicals with the acyl radicals that are formed in an alkene-based relay process affords double aminocarbonylation products.

Cascade Cyclizations Triggered by Photochemically Generated Carbamoyl Radicals Derived from Alkyl Amines.

We report on a visible light-mediated cascade carbamoylation/cyclization of acrylamides using dihydropyridyl carbamoyl donors derived from alkyl amines. Diversely selected acrylamides including 2-cyano-N-arylacrylamides, indolyl- and benzimidazolyl acrylamides, and 2-alkynyl-N-aryl acrylamides participate in this reaction, providing products in good yields. The highlights of this photochemical method include the application of alkyl amine-derived carbamoyl donors, peroxide-free reaction conditions, and a broad scope.