From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes

Li, Zhen; Mayer, Robert J.; Ofial, Armin R.; Mayr, Herbert

doi:10.1021/jacs.0c01960

Cited by 72 publications

(72 citation statements)

References 124 publications

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“…Arylacetates substituted with a-alkyl, a-alkoxy, and a-NH benzoyl groups were productive substrates (23)(24)(25), as were molecules featuring an alkene or terminal alkyne (26)(27). Alkylated or heteroatom containing b-carboxy amides, b-carboxy lactams, malonate half-esters, and b-carboxy nitriles were compatible substrates (30)(31)(32)(33). The labelling of complex molecules featuring malonate half-esters was possible (34)(35).…”

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confidence: 99%

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

et al. 2021

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Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp 3 )-acids with labelled CO2. Substrates that are not compatible with transition metal catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabelling of drug molecules and precursors with [ 11 C]CO2 is demonstrated.The synthesis of isotopically labelled molecules is essential to drug development and nuclear medicine. As drug candidates move towards clinical research and human trials, absorption, distribution, metabolism, and excretion (ADME) studies require compounds enriched with long-lived radioisotopes like 3 H and 14 C. 1 Positron emission tomography (PET) techniques that probe the advance of disease states and can determine the efficacy of drug treatment require molecular targets radiolabelled with short-lived positron-emitting isotopes such as 11 C or 18 F. 2 The limited availability and high cost of isotopically enriched precursors make the preparation of complex targets challenging. For PET studies, compounds must be synthesized and purified within a few half-lives of the radiolabel ( 11 C t1/2 = 20.3 minutes). Approaches that selectively introduce isotopic labels from feedstock sources with compatibility towards common structural motifs found in clinical candidates will have a positive impact on both drug discovery efforts and medical imaging.Metal-catalyzed 1 H/ 3 H exchange is widely used in drug development to introduce long-lived radiolabels into target molecules. [3][4][5][6][7][8][9] The loss of 3 H labels through (bio)chemical reactions and metabolic shifting due to primary kinetic isotope effects are liabilities of 3 H-labelling approachs. 10-11 ADME tracer compounds with greater stability can be obtained by using 14 C radiolabels. 12 Similarly, 11 C-isotopologues of native bioactive molecules enable PET probe generation without changes to their biological or pharmacological properties. 13 The incorporation of 14 C, 13 C or 11 C (*C) units into drug molecules or precursors by the formation of a *C-C bond is challenging and often requires revised synthetic pathways to introduce the label from *CO, 14-18 *CH3I, [19][20] or other small molecules derived by reduction of *CO2. [21][22][23][24][25] The direct exchange of carboxylate groups with CO2 offers the potential for simple and cost-effective syntheses of C-labelled small molecules, particularly as CO2 (or BaCO3) is the feedstock for all radiolabelled carbon-based precursors. 26 The easy conversion of carboxylic acids into other common functionalities (esters, amides, ketones, alcohols) makes this an attractive tactic for isotope incorporation.The use of redox active hydroxyphthalimide ester substrates in combination with Ni-based mediators and stoichiometric metal reductants enables carboxylate groups to undergo net exchange with CO2 (Fig 1A ). [27][28] These reactions are limited to primary alkyl or cyclic secondary a...

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confidence: 99%

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

et al. 2021

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“…Among commercially available isocyanates, p ‐tosyl isocyanate (TSI) bearing a strong electron‐withdrawing group was selected for the copolymerization with epoxides (Scheme 2 A). TSI is highly electrophilic, [18] and the generated negative charge upon attack by nucleophiles can be delocalized due to the presence of the toluene sulfonyl group, giving rise to anionic species of low nucleophilic character. We reasoned that this might prevent the homopolymerization of TSI.…”

Section: Methodsmentioning

confidence: 99%

Polyurethanes from Direct Organocatalytic Copolymerization of p‐Tosyl Isocyanate with Epoxides

et al. 2020

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The direct copolymerization of p-tosyl isocyanate (TSI) with epoxides, initiated by onium salts in the presence of trialkylborane, to produce polyurethanes is reported. The rate of copolymerization and the (regio)selectivity were investigated in relation to the trialkylborane and the initiator used. Under optimized conditions such copolymerizations have been successfully performed for a wide range of epoxides, including ethylene oxide, propylene oxide, 1-octene oxide, cyclohexene oxide, and allyl glycidyl ether. These copolymerizations afford a new category of polyurethanes, clear of side products such as cyclic oxazolidinone, isocyanurate, and poly(isocyanate) linkages. The experimental conditions used in this work are compatible with those for the organocatalytic (co)polymerization of other oxygenated monomers and CO 2 , holding the potential for their terpolymerization with p-tosyl isocyanate and the development of new materials with unprecedented properties.Scheme 1. Trialkylborane-mediated polymerization route to oxygenated polymers.

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“…The radical-polar crossover process combines the advantages of low barrier C-CO2 bond cleavage initiated by carboxylate single electron oxidation with the efficient, uncatalyzed recombination of carbanion intermediates with CO2. 33 Tertiary carboxylic acid substrates not compatible with either Nicatalysis or thermal reactions can be labelled to useful levels. The kinetics of CO2 exchange are compatible with 11 C labelling of nonsteroidal anti-inflammatory drugs (NSAIDs) and precursors to other bioactive molecules.…”

Section: Incorporationmentioning

confidence: 99%

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Kong¹,

Munch²,

Qiqige³

et al. 2020

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From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes

Cited by 72 publications

References 124 publications

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Polyurethanes from Direct Organocatalytic Copolymerization of p‐Tosyl Isocyanate with Epoxides

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

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