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The ability to manipulate C-C bonds for selective chemical transformations is challenging and represents a growing area of research. Here, we report a formal insertion of diazo compounds into the "unactivated" C-C bond of benzyl bromide derivatives catalyzed by a simple Lewis acid. The homologation reaction proceeds via the intermediacy of a phenon...

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... approaches to organic compounds are grounded in the combination of nucleophiles and electrophiles. 1 For example, benzyl halide derivatives may participate in classical reactions such as nucleophilic substitution and electrophilic aromatic substitution ( Figure 1A). 2 The advent of reactions that unlock "nonclassical" transformations of common building blocks provides opportunities to reimagine and/or streamline synthetic strategies. ...
Context 2
... approaches to organic compounds are grounded in the combination of nucleophiles and electrophiles. 1 For example, benzyl halide derivatives may participate in classical reactions such as nucleophilic substitution and electrophilic aromatic substitution ( Figure 1A). 2 The advent of reactions that unlock "nonclassical" transformations of common building blocks provides opportunities to reimagine and/or streamline synthetic strategies. "Nonclassical" reactions may be described as those reacting at a traditionally inert functionality, for example, insertion into the C(sp 2 )-C(sp 3 ) bond of a benzyl halide derivative ( Figure 1B). Cascade reactions that effect formal C-C bond insertion reactions via skeletal rearrangements represent an appealing approach toward such a goal. ...
Context 3
... reactions that effect formal C-C bond insertion reactions via skeletal rearrangements represent an appealing approach toward such a goal. 3,4 Herein, we describe the development of a homologation reaction of electron-rich benzyl bromide derivatives involving formal insertion of diazo compounds into the C(sp 2 )-C(sp 3 ) bond ( Figure 1C). 5 Cognizant of the ionic reactivity of diazo compounds with sp 2 -hybridized electrophiles (e.g., carbonyl derivatives), 6 we questioned whether electron-rich benzyl bromide A would react with diazo B, via the intermediacy of a stabilized benzylic carbocation, to generate alkyl diazonium ion C ( Figure 1C). ...
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... Herein, we describe the development of a homologation reaction of electron-rich benzyl bromide derivatives involving formal insertion of diazo compounds into the C(sp 2 )-C(sp 3 ) bond ( Figure 1C). 5 Cognizant of the ionic reactivity of diazo compounds with sp 2 -hybridized electrophiles (e.g., carbonyl derivatives), 6 we questioned whether electron-rich benzyl bromide A would react with diazo B, via the intermediacy of a stabilized benzylic carbocation, to generate alkyl diazonium ion C ( Figure 1C). 7 Loss of nitrogen would then trigger neighboring group participation of the aryl ring, resulting in phenonium ion D. 8,9 The bromide leaving group from the first step could then engage the putative spirocyclopropane at the less substituted position to afford the desired product E. 10 Tertiary bromide F was considered a potential side product accessible via competitive intermolecular displacement of nitrogen in diazonium C or nucleophilic opening of phenonium ion D at the more substituted position. ...
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... Loss of nitrogen would then trigger neighboring group participation of the aryl ring, resulting in phenonium ion D. 8,9 The bromide leaving group from the first step could then engage the putative spirocyclopropane at the less substituted position to afford the desired product E. 10 Tertiary bromide F was considered a potential side product accessible via competitive intermolecular displacement of nitrogen in diazonium C or nucleophilic opening of phenonium ion D at the more substituted position. The desired product E contains an acyclic, benzylic tertiary or quaternary center -motifs present in many pharmaceutical and agrochemical molecules ( Figure 1D) 11,12 while retaining the alkyl bromide as a functional handle for further derivatization. 13,14 This method enables programmable introduction of trifluoromethyl, ester, amide, ketone, and sulfone functional groups via a unified approach. ...
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... heterocycles such as a tetrahydropyran and piperidinecommonly found in medicinally relevant compounds-could be incorporated in the diazo starting material and afforded the desired products (3ag, 3ah) in good yield. Use of benzylsubstituted diazo compounds opens the possibility of competitive aryl migration at the stage of the putative alkyl diazonium C (see Figure 1C). In both cases, the reaction proceeds in high yield, and the more electron-rich arene migrated selectively (3ai, 3aj). ...
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... Displacement with 1,2,4-triazole gave 5 in 55% yield. 23 1,2,4-Triazoles are emerging as privileged scaffolds in medicinal chemistry 24 and also represent a core component of many agrochemical compounds (e.g., fenbuconazole, Figure 1D). Use of cyanide as the nucleophile afforded nitrile 6 in 92% yield. ...
Context 8
... approaches to organic compounds are grounded in the combination of nucleophiles and electrophiles. 1 For example, benzyl halide derivatives may participate in classical reactions such as nucleophilic substitution and electrophilic aromatic substitution ( Figure 1A). 2 The advent of reactions that unlock "nonclassical" transformations of common building blocks provides opportunities to reimagine and/or streamline synthetic strategies. ...
Context 9
... approaches to organic compounds are grounded in the combination of nucleophiles and electrophiles. 1 For example, benzyl halide derivatives may participate in classical reactions such as nucleophilic substitution and electrophilic aromatic substitution ( Figure 1A). 2 The advent of reactions that unlock "nonclassical" transformations of common building blocks provides opportunities to reimagine and/or streamline synthetic strategies. "Nonclassical" reactions may be described as those reacting at a traditionally inert functionality, for example, insertion into the C(sp 2 )-C(sp 3 ) bond of a benzyl halide derivative ( Figure 1B). Cascade reactions that effect formal C-C bond insertion reactions via skeletal rearrangements represent an appealing approach toward such a goal. ...
Context 10
... reactions that effect formal C-C bond insertion reactions via skeletal rearrangements represent an appealing approach toward such a goal. 3,4 Herein, we describe the development of a homologation reaction of electron-rich benzyl bromide derivatives involving formal insertion of diazo compounds into the C(sp 2 )-C(sp 3 ) bond ( Figure 1C). 5 Cognizant of the ionic reactivity of diazo compounds with sp 2 -hybridized electrophiles (e.g., carbonyl derivatives), 6 we questioned whether electron-rich benzyl bromide A would react with diazo B, via the intermediacy of a stabilized benzylic carbocation, to generate alkyl diazonium ion C ( Figure 1C). ...
Context 11
... Herein, we describe the development of a homologation reaction of electron-rich benzyl bromide derivatives involving formal insertion of diazo compounds into the C(sp 2 )-C(sp 3 ) bond ( Figure 1C). 5 Cognizant of the ionic reactivity of diazo compounds with sp 2 -hybridized electrophiles (e.g., carbonyl derivatives), 6 we questioned whether electron-rich benzyl bromide A would react with diazo B, via the intermediacy of a stabilized benzylic carbocation, to generate alkyl diazonium ion C ( Figure 1C). 7 Loss of nitrogen would then trigger neighboring group participation of the aryl ring, resulting in phenonium ion D. 8,9 The bromide leaving group from the first step could then engage the putative spirocyclopropane at the less substituted position to afford the desired product E. 10 Tertiary bromide F was considered a potential side product accessible via competitive intermolecular displacement of nitrogen in diazonium C or nucleophilic opening of phenonium ion D at the more substituted position. ...
Context 12
... Loss of nitrogen would then trigger neighboring group participation of the aryl ring, resulting in phenonium ion D. 8,9 The bromide leaving group from the first step could then engage the putative spirocyclopropane at the less substituted position to afford the desired product E. 10 Tertiary bromide F was considered a potential side product accessible via competitive intermolecular displacement of nitrogen in diazonium C or nucleophilic opening of phenonium ion D at the more substituted position. The desired product E contains an acyclic, benzylic tertiary or quaternary center -motifs present in many pharmaceutical and agrochemical molecules ( Figure 1D) 11,12 while retaining the alkyl bromide as a functional handle for further derivatization. 13,14 This method enables programmable introduction of trifluoromethyl, ester, amide, ketone, and sulfone functional groups via a unified approach. ...
Context 13
... heterocycles such as a tetrahydropyran and piperidinecommonly found in medicinally relevant compounds-could be incorporated in the diazo starting material and afforded the desired products (3ag, 3ah) in good yield. Use of benzylsubstituted diazo compounds opens the possibility of competitive aryl migration at the stage of the putative alkyl diazonium C (see Figure 1C). In both cases, the reaction proceeds in high yield, and the more electron-rich arene migrated selectively (3ai, 3aj). ...
Context 14
... Displacement with 1,2,4-triazole gave 5 in 55% yield. 23 1,2,4-Triazoles are emerging as privileged scaffolds in medicinal chemistry 24 and also represent a core component of many agrochemical compounds (e.g., fenbuconazole, Figure 1D). Use of cyanide as the nucleophile afforded nitrile 6 in 92% yield. ...

Citations

Article
An electrochemical carbenoid insertion reaction of diazo compounds into C-S and C-O bonds with electricity as the oxidant has been reported in this work. In this protocol, this transformation proceeded smoothly under mild conditions at room temperature in the absence of a catalyst and a ligand. In addition, the yield of the S-H insertion product was up to 96% and the O-H product could be efficiently obtained in up to 80% yield. Of note is that this environmentally friendly strategy exhibited excellent applicability in gram-scale synthesis.
Article
The control of chemoselective insertions of diazoalkanes with 2-hydroxybenzothiazoles is challenging. Herein, the chemoselective N-H, O-H, C-O or C-H bond insertions of diazoalkanes with 2-hydroxybenzothiazoles are achieved using B(C6F5)3, Rh2(OAc)4...
Article
Full-text available
The “borrowing hydrogen” (BH) method for C‐alkylation reactions using alcohol as alkylating agents is an important synthetic transformation. In this respect, designing cheap and bench stable earth abundant metal catalyst for borrowing hydrogen transformation is a key challenge to be witnessed. Herein we have presented a synthesis of non‐phosphine, easily accessible and bench stable SNS‐Ni complexes. The Ni‐catalyst was successfully applied for the C‐alkylation of ketone enolates to α‐alkylated ketones. Primary alcohol with different functional groups and various heteroaromatic alcohols are well tolerated. The present catalyst system was efficiently applied to gram scale synthesis and also the green chemistry metrics of the reaction were calculated. The present protocol was also extended successfully for the synthesis of biologically important quinoline moieties. Finally, various control experiments and deuterium labelled experiments suggest that the reaction proceeds via borrowing hydrogen pathway.
Article
We report a formal carbon–carbon (C–C) bond insertion via the reaction of secondary benzylic halides (fluorides, chlorides, and bromides) with α‐diazo esters catalyzed by Lewis acid catalysts. Secondary benzylic halides underwent elongation to afford α,β‐diaryl‐β‐haloesters diastereoselectively. Density functional theory calculation revealed that the present formal C–C bond insertion was the result of Lewis acid‐promoted cleavage and the re‐formation of a carbon–halogen bond and that the aryl‐migration step determined the diastereoselectivity. Various diarylmethyl halides and α‐diazo esters were applicable to this reaction system. In addition, ring expansion in cyclic benzylic chlorides was accomplished.
Article
We report a formal carbon–carbon (C–C) bond insertion via the reaction of secondary benzylic halides (fluorides, chlorides, and bromides) with α‐diazo esters catalyzed by Lewis acid catalysts. Secondary benzylic halides underwent elongation to afford α,β‐diaryl‐β‐haloesters diastereoselectively. Density functional theory calculation revealed that the present formal C–C bond insertion was the result of Lewis acid‐promoted cleavage and the re‐formation of a carbon–halogen bond and that the aryl‐migration step determined the diastereoselectivity. Various diarylmethyl halides and α‐diazo esters were applicable to this reaction system. In addition, ring expansion in cyclic benzylic chlorides was accomplished.