Barton Esters Research Articles

Radical Decarboxylative Carbon-Nitrogen Bond Formation.

The carbon-nitrogen bond is one of the most prevalent chemical bonds in natural and artificial molecules, as many naturally existing organic molecules, pharmaceuticals, agrochemicals, and functional materials contain at least one nitrogen atom. Radical decarboxylative carbon-nitrogen bond formation from readily available carboxylic acids and their derivatives has emerged as an attractive and valuable tool in modern synthetic chemistry. The promising achievements in this research topic have been demonstrated via utilizing this strategy in the synthesis of complex natural products. In this review, we will cover carbon-nitrogen bond formation via radical decarboxylation of carboxylic acids, Barton esters, MPDOC esters, N-hydroxyphthalimide esters (NHP esters), oxime esters, aryliodine(III) dicarboxylates, and others, respectively. This review aims to bring readers a comprehensive survey of the development in this rapidly expanding field. We hope that this review will emphasize the knowledge, highlight the proposed mechanisms, and further disclose the fascinating features in modern synthetic applications.

Red-light-mediated Barton decarboxylation reaction and one-pot wavelength-selective transformations.

In organic chemistry, selecting mild conditions for transformations and saving energy are increasingly important for achieving sustainable development goals. Herein, we describe a red-light-mediated Barton decarboxylation using readily available red-light-emitting diodes as the energy source and zinc tetraphenylporphyrin as the catalyst, avoiding explosive or hazardous reagents or external heating. Mechanistic studies suggest that the reaction probably proceeds via Dexter energy transfer between the activated catalyst and the Barton ester. Furthermore, a one-pot wavelength-selective reaction within the visible light range is developed in combination with a blue-light-mediated photoredox reaction, demonstrating the compatibility of two photochemical transformations based on mechanistic differences. This one-pot process expands the limits of the decarboxylative Giese reaction beyond polarity matching.

Miquel Costas.

"The secret of being a successful scientist is, I guess, a combination of intelligence, hard work, perseverance, and serendipity. I admire intelligent originality …" Find out more about Miquel Costas in his Author Profile.

Formation of Enol Ethers by Radical Decarboxylation of α-Alkoxy β-Phenylthio Acids.

Enol ethers are formed by radical decarboxylation of α-alkoxy β-phenylthio acids via the corresponding Barton esters. The phenylthio acids were usually made by the known regioselective reaction of α,β-epoxy acids with PhSH in the presence of InCl3, followed by O-alkylation of the resulting alcohol. In one case, thiol addition to an α,β-unsaturated ethoxymethyl ester was used.

Boronate, trifluoroborate, sulfone, sulfinate and sulfonate congeners of oseltamivir carboxylic acid: Synthesis and anti-influenza activity

Tamiflu readily undergoes endogenous hydrolysis to give oseltamivir carboxylic acid (OC) as the active anti-influenza agent to inhibit the viral neuraminidase (NA). GOC is derived from OC by replacing the 5-amino group with a guanidino group. In this study, OC and GOC congeners with the carboxylic acid bioisosteres of boronic acid, trifluoroborate, sulfone, sulfinic acid, sulfonic acid and sulfonate ester were first synthesized, starting with conversion of OC to a Barton ester, followed by halodecarboxylation to give the iodocyclohexene, which served as a pivotal intermediate for palladium-catalyzed coupling reactions with appropriate diboron and thiol reagents. The enzymatic and cell-based assays indicated that the GOC congeners consistently displayed better NA inhibition and anti-influenza activity than the corresponding OC congeners. The GOC sulfonic acid congener (7a) was the most potent anti-influenza agent, showing EC50 = 2.2 nM against the wild-type H1N1 virus, presumably because the sulfonic acid 7a was more lipophilic than GOC and exerted stronger interactions on the three arginine residues (R118, R292 and R371) in the NA active site. Although the trifluoroborates, sulfones and sulfonate esters did not have acidic proton, they still exhibited appreciable NA inhibitory activity, indicating that the polarized B−F and S→O bonds still made sufficient interactions with the tri-arginine motif.

Fragmentation of a dioxolanyl radical via nonstatistical reaction dynamics: characterization of the vinyloxy radical by ns time-resolved laser flash photolysis.

The photochemistry of two Barton esters, one derived from a dioxolane carboxylic acid and the other from pivalic acid, was investigated by product analysis and nanosecond laser flash photolysis (LFP). As expected, photolysis of the pivalate ester resulted in formation of the pyridine-2-thiyl and the t-butyl radical. Photolysis of the Barton ester of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid, on the other hand, revealed a complex multi-step fragmentation. In addition to the pyridine-2-thiyl and dioxolanyl radical, we gained evidence for the formation of the vinyloxy radical, CH2[double bond, length as m-dash]CHO˙. The latter was identified in the LFP by its π-complexes with benzene and diphenylether, its rapid quenching by electron-rich arenes and tri-n-butyl tin hydride, and its oxidative power in presence of trifluoroacetic acid as demonstrated by the oxidation of ferrocene to ferrocenium. Formation of CH2[double bond, length as m-dash]CHO˙ can be rationalized via fragmentation of the dioxolanyl radical. As the calculated barriers are too high for the reaction sequence to occur on the LFP time scale, we investigated the fragmentation of the photoexcited Barton ester via Born-Oppenheimer molecular dynamics simulations. In one trajectory, we could observe all reaction steps including ring opening of the dioxolanyl radical, suggesting that the excess energy gained in the ester cleavage and decarboxylation may lead to fragmentation of the hot dioxolanyl radical.

ChemInform Abstract: A New Era for Homolytic Aromatic Substitution: Replacing Bu3SnH with Efficient Light‐Induced Chain Reactions

AbstractReview: 113 refs.

ChemInform Abstract: Tandem Reactions via Barton Esters with Intermolecular Addition and Vinyl Radical Substitution onto Indole.

A one-pot initiator-free Barton ester decomposition with tandem radical addition onto alkyl propiolates or phenylacetylene with aromatic substitution of the resultant vinyl radical allows convenient access to new 9-substituted 6,7-dihydropyrido[1,2-a]indoles. Propyl radical cyclizations compete when forming the expanded 7,8-dihydro-6H-azepino[1,2-a]indole system. 2-Thiopyridinyl S-radical is incorporated into aromatic adducts when using unsubstituted indole-1-alkanoic acid precursors. X-ray crystallography on substitution products allows selectivity of the radical addition onto less reactive internal alkynes to be determined.

Tandem reactions via Barton esters with intermolecular addition and vinyl radical substitution onto indole.

A one-pot initiator-free Barton ester decomposition with tandem radical addition onto alkyl propiolates or phenylacetylene with aromatic substitution of the resultant vinyl radical allows convenient access to new 9-substituted 6,7-dihydropyrido[1,2-a]indoles. Propyl radical cyclizations compete when forming the expanded 7,8-dihydro-6H-azepino[1,2-a]indole system. 2-Thiopyridinyl S-radical is incorporated into aromatic adducts when using unsubstituted indole-1-alkanoic acid precursors. X-ray crystallography on substitution products allows selectivity of the radical addition onto less reactive internal alkynes to be determined.

Bu3SnH-mediated cyclopropyl radical cyclizations onto indole-3-carbaldehyde

Bromocyclopropyl)alkyl)-1H-indole-3-carbaldehydes and benzimidazole analogues were obtained in ~80% yield via the decomposition of Barton ester intermediates. The bromo- indolecarbaldehydes were precursors for Bu 3SnH-mediated five- and seven-membered cyclopropyl radical intramolecular aromatic substitutions giving cyclopropane-fused adducts in ~55% yields. The cyclization yields are greater than via the direct decomposition of the Barton esters. X-ray crystal structures of 1-((2-bromocyclopropyl)-trans -methyl)-1H-benzimidazole , and cyclopropyl radicals onto the 2-position of indole-3-carbaldehyde, indole-3-carbonitrile, and benzimidazoles were accomplished. The radicals were generated via the combined thermal and photochemical decomposition of Barton ester {pyridine-2-thione-N-oxycarbonyl (PTOC) or O- acyl thiohydroxamate} 2 intermediates formed from carboxylic acids using the Garner coupling reagent, HOTT ( S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate). 3 All six-membered radical cyclizations were high yielding (~80%), but the more challenging five and seven-membered cyclizations were found to give lower yields (<50%), with the exception of (i) the five-membered alkyl and cyclopropyl radical cyclizations onto indole-3-carbonitrile, which occurred in 75 and 78% yields respectively, and (ii) the seven-membered alkyl radical cyclization onto indole-3-carbonitrile gave a 61% yield. The structures of the indole five- membered cyclization adducts correspond to the skeleton of Moody's cyclopropamitosene, a hypoxic tumor cell selective cytotoxin, 4 which was previously prepared using intramolecular 1,3-

Barton esters for initiator-free radical cyclisation with heteroaromatic substitution

S-(1-Oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate (HOTT) facilitates the first examples of efficient radical cyclisation with (hetero)aromatic substitution via Barton ester intermediates. Cyclopropyl and alkyl radicals allow access to five, six and seven-membered alicyclic-ring fused heterocycles with and without an additional fused cyclopropane, including the skeleton of the anti-cancer agent, cyclopropamitosene, expanded, and diazole analogues. Radical initiators are not required for cyclisation from carboxylic acid precursors.

Barton radical reactions of 2-C-branched carbohydrates

Barton esters have been introduced into the side chain of carbohydrates with high yields in only a few steps from easily available glycals. Their radical reactions afford 2-C-methyl and 2-C-bromomethyl hexoses, pentoses and disaccharides in good yields in analytically pure form. Since the Barton esters have been synthesized by an oxidative radical addition and their transformations by reductive radical processes, our results demonstrate the power of such reactions in carbohydrate chemistry.

Non-resonant two-photon photochemistry of a Barton ester, N-phenylacetyloxy-2-pyridinethione

N-Acetyloxy-2-pyridinethiones, otherwise known as Barton esters, are a class of molecules that can be easily photolysed via single-photon excitation to facilitate the controlled release of carbon or oxygen-centred radicals. In the present work, we investigate the two-photon chemistry of a simple Barton ester, and show that this material can be photolysed via two-photon excitation, with a two-photon bleaching cross section value of 0.13 +/- 0.01 GM.

Investigation of Barton esters as radical photoinitiators

AbstractDifferent photoinitiators based on Barton thiohydroxamic esters,O‐acyl‐N‐hydroxy‐pyridine‐2(1H)‐thione andO‐acyl‐N‐hydroxy‐thiazole‐2(3H)‐thione derivatives, were tested in photopolymerization reactions through time‐resolved FTIR spectroscopy. Good rates of polymerization and final monomer conversion were obtained for some compounds. The excited state processes, investigated by time resolved absorption spectroscopy, lie on a fast singlet state cleavage leading to thiyl and alkyl radicals. Both the pyridine‐2(1H)‐thiyl and alkyl radicals are able to initiate a polymerization, in contrast with the thiazole‐2(3H)‐thiyl radical. A triplet state is observed for some derivatives. Computational studies help to describe the excited state properties and show a strong difference in the spin localization in the formed thiyl initiating radicals. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Decarboxylative Radical Azidation Using MPDOC and MMDOC Esters

An efficient radical-mediated decarboxylative azidation of aliphatic carboxylic acids has been developed. The success of this transformation hinges on the use of a new type of thiohydroxamate esters (MPDOC esters). These esters are more stable than the classical Barton esters and less prone to rearrange under radical conditions. In the case of alpha-alkoxy and alpha-amino acids, optimal results are obtained with the even more stable MMDOC esters developed recently by Kim.

Barton Esters as New Radical Photoinitiators for Flat Panel Display Applications

A new series of photoinitiators for free radical photopolymerization based on Barton ester derivatives is developed for flat panel display applications. The absorption spectra exhibit a broad band between 320 and 420 nm. The photolysis quantum yields are very high, a fact that underlines the capability of the photoinitiators to bleach during the irradiation and thereby to lead to a moderate yellowing. Compared to commercial photoinitiators, the Barton esters display a very good efficiency. As revealed by laser flash photolysis, the dissociation rate constants are very high. Quantum mechanical computations show that the photodissociation can occur from both the excited singlet and triplet states.

A synthetic strategy using Witkop's pyrroloindole for (−)-debromoflustramine B, (+)- ent-debromoflustramine B and (+)- ent-debromoflustramide B

While prenylation of (−)-Witkop's pyrroloindole ( 2), secured from l-tryptophan under standard N-alkylation conditions, led to a ca. 1:1 diastereoisomeric mixture of two C 3a-alkylated indolenines 3 and 4, use of phase-transfer conditions altered this to ca. 1:2. Reduction followed by N-prenylation of the resulting secondary amines gave C, N-dialkylated products. The derived separable diastereoisomeric (−)- and (+)-Barton esters 19a and 19b were then converted into (−)-debromoflustramine B and (+)- ent-debromoflustramine B, respectively. A novel reaction involving oxygen and the carbanion derived from Barton ester 19b led to (+)- ent-debromoflustramide B. Treatment of N 8-prenylated Witkop's pyrroloindole 5 with Lewis acid (BF 3·Et 2O) uncovered a new clean intramolecular cyclisation involving the prenyl unit.

Tin-free Radical Allylation of α-Acetoxy Alkyl Xanthates. Routes to Homoallyl Alcohols and α,β-Unsaturated Ketones

Radical allylations are most frequently used intermolecular radical carbon-carbon bond forming reactions and provide an easy access to introduce allyl groups into organic molecules under mild conditions. Allylating agents normally utilize simple allyl and 2-substituted allyl stannanes along with the corresponding sulfides and sulfones. Contrary to the radical allylations, radical-mediated aldol reactions have not been well developed due to the very high π-bond strength of C=O bonds. Thus, several indirect approaches for aldol-type products have been reported to date. We studied the possibility of indirect radicalmediated aldol reactions using α-acetoxy alkyl radicals along with reagent equivalents of the α-ketone acceptor synthon. In this regard, 2-acetoxy and 2-benzoyloxy substituted allyl sulfones seemed to be promising for our purpose. The combination of these new allylating agents together with the α-acetoxy alkyl radical precursors would provide α,β-unsaturated ketones after hydrolysis of the acetates and the following dehydration. Among several α-alkoxy alkyl radical precursors, αbromoalkyl acetate 1 seemed to be most attractive and promising to introduce an acetate group at the β-position of an alkenyl bond. Previously, radical allylation of 1 with allyl stannane was known to give a homoallyl acetate. Furthermore, chiral α-alkoxy alkyl radicals were generated from decarboxylation of α-alkoxy substituted Barton esters. The α-bromoalkyl acetate 1 was readily prepared by the addition of acetyl bromide to an aldehyde in the presence of zinc chloride in methylene chloride at 0 C (eq. 1).

Hyperbranched (Co)Polymers via Free Radical Polymerization of Polymerizable Barton Esters

The free radical synthesis of hyperbranched polymer architectures using a thermally and photochemically labile styrenic Barton ester monomer of the AB type, designed to combine the functions of initiator, monomer, and branch unit, is described. Highly branched poly(styrene)s were obtained in one step by copolymerizing this monomer with styrene. Residual Barton ester functionality in the hyperbranched products enabled their use as macroinitiators in subsequent polymerizations. Linear PMMA was thus successfully grafted from the hyperbranched poly(styrene) cores. This approach is a versatile route for the synthesis of hyperbranched homopolymers and copolymers via free radical polymerization chemistry.

Decarboxylative Allylation and Vinylation Approach of Thiohydroxamate Esters.

Barton's O-acyl thiohydroxamates are very useful to generate alkyl radicals from carboxylic acids via O-acyl thiohydroxamates 1,2 and have been used to form carboncarbon bonds by reacting with sulfonyl cyanides 3 and activated olefins. 4 However, Barton esters 1 have some limitations because they are very reactive, thereby yielding a byproduct resulting from attacking the thiocarbonyl group of Barton ester by alkyl radicals. This problem was solved to some extent by using less reactive O-acyl thiohydroxamates 6 in radical acylation approach. 5,6