Visible light mediated intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes

Visible-light mediated photoredox reactions have recently emerged as a powerful means for organic synthesis and thus have generated significant interest from the organic chemistry community. Although the reaction mechanisms have been probed by a number of techniques such as NMR, fluorescence quenching, and laser flash photolysis and various degree of success has been achieved, mechanistic ambiguity still exists (for instance, the involvement of the chain mechanism is still under debate) due to lack of structural information about the proposed and short-lived intermediates. Herein, we present the detection of transient amine radical cations involved in intermolecular [3+2] annulation reaction of N-cyclopropylaniline (CPA, 1) and styrene 2 by electrospray ionization mass spectrometry (ESI-MS) in combination with online laser irradiation of the reaction mixture. In particular, the reactive CPA radical cation 1+·, the reduced photocatalyst Ru(I)(bpz)3 +, and the [3+2] annulation product radical cation 3+· are all successfully detected and confirmed by high resolution MS. More importantly, the post-irradiation reaction with an additional substrate, the isotope-labeled CPA following photolysis of 1, 2 and Ru catalyst provide strong evidences to support the chain mechanism in the [3+2] annulation reaction. Furthermore, the key step of the proposed chain reaction, the oxidation of CPA 1 to amine radical cation 1+· by product radical cation 3+· (generated using online electrochemical oxidation of 3) is successfully established. Additionally, the coupling of ESI-MS with online laser irradiation has been successfully applied to probe the photostability of photocatalysts.

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“…We selected this pair of substrates because both were extensively studied in the initial development of the annulation reaction. 9,10 …”

Section: Resultsmentioning

confidence: 99%

“…The scope of this reaction was later expanded to include various pi bonds. 10 These results have opened new avenues for the use of aniline-substituted cyclopropanes as synthetic building blocks. 11 Mechanistically, these methods are all believed to proceed through ring opening of the amine radical cations of N- cyclopropylanilines.…”

Section: Introductionmentioning

confidence: 99%

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques

et al. 2017

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“…Homolytic decomposition modes are far less common, [43][44][45] although only small amounts of ring strain are necessary to drive C-C bond scission as seen in our efforts converting catharanthine (4.2 kcal/mol ring strain) into Aspidosperma and Iboga alkaloids. 46 Zheng and co-workers have demonstrated the viability of cyclopropane fragmentations within photoredox catalysis, coupling oxidized anilinocyclopropanes with a variety of styrenes, 47 arylacetylenes, 48 diynes, and enynes. 49 The goal of this work was to harness the unique capabilities of photoredox catalysis to generate 1-aminoNBs as a means of addressing the need for new, saturated building blocks in drug discovery.…”

Section: As Illustratedmentioning

confidence: 99%

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

Staveness

Sodano

et al. 2019

Chem

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The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO 2 Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. HIGHLIGHTSStrain-driven homolysis initiates radical cyclization sequence toward norbornane core Robust functional-group tolerance provides readily modifiable building blocks Unique modes of diastereocontrol afford enantiopure 1aminonorbornanes 1-Aminonorbornanes are shown to offer improved metabolic stability over anilines Staveness et al., Chem 5,[215][216][217][218][219][220][221][222][223][224][225][226] January 10, SUMMARYThis report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp 3 -rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.

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“…For instance, we have reported that 2 is uniquely capable of promoting radical cation mediated Diels–Alder cycloadditions [ 12 ], radical thiol–ene couplings [ 13 – 14 ], and photooxygenation reactions [ 15 – 16 ]. Similarly, Zheng has reported oxidatively initiated indole synthesis [ 17 ] and [3 + 2] cycloaddition [ 18 – 19 ] reactions using photocatalyst 2 . Finally, a variety of transition metal complexes bearing bipyrazyl ligands have been prepared and investigated for a wide range of applications in inorganic and organometallic chemistry [ 20 – 25 ].…”

Section: Resultsmentioning

confidence: 99%

An improved procedure for the preparation of Ru(bpz)₃(PF₆)₂ via a high-yielding synthesis of 2,2’-bipyrazine

Schultz¹,

Sawicki²

2015

Beilstein J. Org. Chem.

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SummaryThere has been a recent surge of interest in the use of transition metal polypyridyl complexes as visible light-absorbing photocatalysts for synthetic applications. Among the most attractive features of this approach is the availability of many known complexes with well-characterized photophysical and electrochemical properties. In particular, Ru(bpz)3 2+ is a powerful photooxidant that has proven to be uniquely suited for oxidatively induced photoredox transformations. We present here a straightforward and high-yielding route to Ru(bpz)3(PF6)2 that features an improved Pd-catalyzed synthesis of the 2,2’-bipyrazine ligand that is amenable to gram-scale preparations.

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Visible light mediated intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes

Cited by 54 publications

References 42 publications

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

An improved procedure for the preparation of Ru(bpz)₃(PF₆)₂ via a high-yielding synthesis of 2,2’-bipyrazine

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Visible light mediated intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes

Cited by 54 publications

References 42 publications

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes

An improved procedure for the preparation of Ru(bpz)3(PF6)2 via a high-yielding synthesis of 2,2’-bipyrazine

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An improved procedure for the preparation of Ru(bpz)₃(PF₆)₂ via a high-yielding synthesis of 2,2’-bipyrazine