Organic Letters
Letter
contrast to the p-methoxy analogue (2k), the major product 3cc
occurred from azidation at the SMe group (50%), with only 10%
azidation taking place at the tolyl position. The radical-stabilizing
effect of sulfur was exemplified through azidation of thioanisole
3dd and p-bromo-thioanisole 3ee, compounds previously
prepared by Pummerer-type chlorination and azide addition.
Experimental procedures and characterization data for all
AUTHOR INFORMATION
Corresponding Author
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The N3CH2SAr moiety has been reported as a synthon for NH2 ,
reacting with aryl Grignard reagents to give anilines after
Notes
hydrolysis.14
The authors declare no competing financial interest.
We could apply the direct azidation methodology in the
synthesis of a drug, rufinamide (4), an antiepileptic medication
from Novartis. Previous routes utilize benzylic halogenation and
displacement with sodium azide, both at elevated temper-
atures.15 Here, we could effect direct benzylic azidation of 1,3-
difluorotoluene 2ff under benign conditions to give the azide 3ff
in 38% yield, which underwent Cu-catalyzed 1,3-dipolar addition
and aminolysis in quantitative yield to afford rufinamide 4,
without recourse to halogenation reagents or sodium azide in the
synthetic sequence.
ACKNOWLEDGMENTS
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We thank the EPSRC and AstraZeneca for funding. Mr.
Christopher Teskey (University of Manchester) is thanked for
helpful discussions.
REFERENCES
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Radical chain reactions have been implicated in C−H
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To conclude, we have described a direct azidation of benzylic
C−H positions that occurs at room temperature, under mild
conditions, using an earth-abundant first row transition metal
photoredox catalyst. The scope of the reaction is broad and
tolerant of many functional groups, encompassing primary,
secondary, and tertiary benzylic positions, and a formal azido-
Pummerer pathway has been identified for thioanisole
derivatives. Further photoredox-catalyzed azidation transforma-
tions are being investigated in our laboratory.
ASSOCIATED CONTENT
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