Transition‐Metal‐Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α‐Branched Amine Synthesis

Ong, Derek Yiren; Fan, Dongyang; Dixon, Darren J.; Chiba, Shunsuke

doi:10.1002/ange.202004272

Cited by 22 publications

(4 citation statements)

References 78 publications

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“…described a reductive functionalisation of carboxamides 160 for the synthesis of α‐branched amines 161 or 162 (Scheme 28). [57] Therein, a stable anionic hemiaminal intermediate 163 is formed through single hydride transfer from the sodium hydride/sodium iodide composite. This species is then captured by TMSCl and the resulting activated hemiaminal 164 .…”

Section: Other Strategies For Amide Functionalisationmentioning

confidence: 99%

Challenges and Breakthroughs in Selective Amide Activation

2022

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In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.

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Section: Other Strategies For Amide Functionalisationmentioning

confidence: 99%

Challenges and Breakthroughs in Selective Amide Activation

2022

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“…Within the scope of the latter approach, the reductive functionalization of ubiquitous amides is a powerful access point toward decorated α-branched amines. It is equally applicable for the elaboration of simple building blocks into valuable products and for expediting natural product synthesis. − To this end, Vaska’s complex (IrCl(CO)(PPh 3 ) 2 ), in conjunction with TMDS (1,1,3,3-tetramethyldisiloxane) as a terminal reductant, has come to the fore as an effective system for generating iminium ions in situ, via the hydrosilylation of tertiary amide and lactam reactants (Scheme A) . The mild reaction conditions, exquisite chemoselectivity, and broad functional group tolerance of this approach have contributed to its growing application as a synthetic strategy in the elaboration of simple building blocks and in late-stage functionalization of complex molecular architectures including alkaloid natural products …”

Section: Introductionmentioning

confidence: 99%

Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium-Catalyzed Hydrosilylation and Single Electron Transfer Strategy

et al. 2020

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A new strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska's complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction's efficiency. Scheme 1. α-Functionalization strategies for amine synthesis from tertiary amides Scheme 3. Optimization studies for (A) Vaska's catalyzed amide hydrosilylation. (B) The photocatalytic reductive coupling of the silyl hemiaminal intermediate with DHA derivative. stituted structures delivered tertiary amine products, although a steric increase vs. reaction efficiency trend was observed. 19 Intramolecular Cyclization. We recognized the opportunity that this tandem amide activation protocolthrough tethering an alkene acceptor to the alkyl chain of the amide starting material-could be suitably leveraged towards the synthesis of complex heterocyclic amine frameworks. Accordingly, model substrates bearing a pendant α,β-unsaturated ester (1s-1t) were prepared, but initial studies demonstrated that these motifs did not readily undergo hydrosilylation using Vaska's catalyst (only around 80% conversion was achieved after 8 hours of reaction time), and furthermore significant quantities of over reduction side-product were isolated following the photocatalytic step. 20 Nevertheless, these initial challenges were circumvented when a derivative of Vaska's complex bearing triphenylphosphite ligands-previously reported by Nagashima 21-was employed in the hydrosilylation step instead (Scheme 5). Pleasingly, clean conversion to a stable silyl hemiaminal species was achieved within one hour, and subsequent subjection to the optimized photoredox conditions delivered the desired cyclic pyrrolidine (4s) and piperidine (4t) products in good yields. Scheme 5. Extension of the Vaska-photoredox system for reductive cyclization of tertiary amides Secondary Amide Activation. Recent endeavors by Chida and Sato, and Huang have demonstrated the utility of [Ir(COE)2Cl]2 complex in conjunction with Et2SiH2 reductant for the nucleophilic reductive functionalization of secondary amide building blocks, affording the corresponding α-branched secondary amine products. 4e,f Scheme 6. Reverse polarity, photocatalytic reductive functionalization of seconda...

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“…In order to circumvent the difficulties associated with benzhydrylamine synthesis, methods for the reductive functionalization of amides have been a key area of advancement. − These reductive methods utilize either stoichiometric quantities of samarium or rely upon highly effective catalytic hydrosilylation processes. One such catalyst, Vaska’s complex (IrCl(CO)(PPh 3 ) 2 ), promotes generation of reactive iminium species that allow for the addition of various nucleophilic aryl metal species for benzhydrylamine synthesis (Figure a). ,− While these hydrosilylation systems allow for catalytic functionalization of amides, they often do require reactive aryl Grignard or zinc nucleophiles to access the branched amine products, demonstrating a need for milder amide arylation conditions.…”

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confidence: 99%

Deoxy-Arylation of Amides via a Tandem Hydrosilylation/Radical– Radical Coupling Sequence

Venditto,

Boerth

2024

Org. Lett.

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Vaska's complex is a prominent catalyst for the hydrosilylation of amides. The O-silyl hemiaminal intermediate formed in these processes has been demonstrated as an electrophile for nucleophilic additions. More recently, these intermediates have been shown to be suitable for single electron reduction to generate α-amino radicals. Leveraging the ability to generate α-amino radicals from these hemiaminals, we describe a two-step, one-pot, deoxy-arylation of amides utilizing iridium-catalyzed hydrosilylation and photoredox catalysis. This transformation can be tailored toward the late-stage functionalization of biologically relevant molecules, with drug discovery applications as shown in the streamlined synthesis of an NPY Y2 inhibitor.

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Transition‐Metal‐Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α‐Branched Amine Synthesis

Cited by 22 publications

References 78 publications

Challenges and Breakthroughs in Selective Amide Activation

Challenges and Breakthroughs in Selective Amide Activation

Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium-Catalyzed Hydrosilylation and Single Electron Transfer Strategy

Deoxy-Arylation of Amides via a Tandem Hydrosilylation/Radical– Radical Coupling Sequence

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