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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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... 4-Methoxybenzyl bromide 1 and trifluoromethyl diazo 2 were chosen as parent substrates for reaction discovery and optimization. After surveying a series of Lewis acids under different reaction conditions, it was found that SnBr 4 (50 mol %) in CH 2 Cl 2 at −78 °C afforded bromide 3a in 75% isolated yield (Figure 2A). 17 With the optimized conditions in hand, the scope of the reaction was evaluated with respect to both substituents on the diazo and the benzyl bromide derivative. ...
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... With the optimized conditions in hand, the scope of the reaction was evaluated with respect to both substituents on the diazo and the benzyl bromide derivative. Several different electron-withdrawing groups worked well in this process ( Figure 2A). Alkyl-substituted diazo derivatives containing an ethyl ester (3b), benzyl ester (3c), redox-active ester (3d), and a nitrile (3e) were all effective in this reaction. ...
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... completeness, the ratio of 3:3′ in the isolated material is quoted in parentheses, and the ratio in the crude reaction mixture is quoted in brackets below. The use of monosubstituted diazo derivatives to generate tertiary benzylic centers is also possible and further highlights the range of electron-withdrawing substituents amenable in this reaction ( Figure 2B). An ethyl ester (3f), benzyl ester (3g), tert-butyl ester (3h), amide (3i), ketone (3j), trifluoromethyl group (3k), and a sulfone (3l) all worked well to give the requisite tertiary benzylic centers. ...
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... diazo 2 was employed to evaluate a number of electron-rich benzyl bromide derivatives in the homologation reaction ( Figure 2C). In all cases, the regioselectivity of phenonium ion opening was high (>20:1). ...
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... these conditions, the use of benzyl bromide itself resulted in no reaction and recovered bromide (vide infra). 19 Next, attention was turned to exploring the functional group tolerance of the reaction with respect to the alkyl substituent on the diazo derivative ( Figure 2D). 20 Here, benzyl diazoacetate derivatives were employed to facilitate substrate synthesis and handling. ...
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... One enabling feature of this reaction is the retention of the alkyl bromide as a functional handle for further manipulation. For example, substitution of the bromide with azide delivers β 2,2 -amino acid derivative 4 in 68% yield ( Figure 2E). 22 Displacement with 1,2,4-triazole gave 5 in 55% yield. ...
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... 4-Methoxybenzyl bromide 1 and trifluoromethyl diazo 2 were chosen as parent substrates for reaction discovery and optimization. After surveying a series of Lewis acids under different reaction conditions, it was found that SnBr 4 (50 mol %) in CH 2 Cl 2 at −78 °C afforded bromide 3a in 75% isolated yield (Figure 2A). 17 With the optimized conditions in hand, the scope of the reaction was evaluated with respect to both substituents on the diazo and the benzyl bromide derivative. ...
Context 8
... With the optimized conditions in hand, the scope of the reaction was evaluated with respect to both substituents on the diazo and the benzyl bromide derivative. Several different electron-withdrawing groups worked well in this process ( Figure 2A). Alkyl-substituted diazo derivatives containing an ethyl ester (3b), benzyl ester (3c), redox-active ester (3d), and a nitrile (3e) were all effective in this reaction. ...
Context 9
... completeness, the ratio of 3:3′ in the isolated material is quoted in parentheses, and the ratio in the crude reaction mixture is quoted in brackets below. The use of monosubstituted diazo derivatives to generate tertiary benzylic centers is also possible and further highlights the range of electron-withdrawing substituents amenable in this reaction ( Figure 2B). An ethyl ester (3f), benzyl ester (3g), tert-butyl ester (3h), amide (3i), ketone (3j), trifluoromethyl group (3k), and a sulfone (3l) all worked well to give the requisite tertiary benzylic centers. ...
Context 10
... diazo 2 was employed to evaluate a number of electron-rich benzyl bromide derivatives in the homologation reaction ( Figure 2C). In all cases, the regioselectivity of phenonium ion opening was high (>20:1). ...
Context 11
... these conditions, the use of benzyl bromide itself resulted in no reaction and recovered bromide (vide infra). 19 Next, attention was turned to exploring the functional group tolerance of the reaction with respect to the alkyl substituent on the diazo derivative ( Figure 2D). 20 Here, benzyl diazoacetate derivatives were employed to facilitate substrate synthesis and handling. ...
Context 12
... One enabling feature of this reaction is the retention of the alkyl bromide as a functional handle for further manipulation. For example, substitution of the bromide with azide delivers β 2,2 -amino acid derivative 4 in 68% yield ( Figure 2E). 22 Displacement with 1,2,4-triazole gave 5 in 55% yield. ...

Citations

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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.