10.1002/anie.201706341
Angewandte Chemie International Edition
COMMUNICATION
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key feature leading to atropisomerism. The enantiomers of
diarylamine 6m were resolved by HPLC, and by following the
first order decay of enantiomeric excess we evaluated a
barrier to C–N rotation of 106.5 kJ mol–1 at 333 K in toluene
(Scheme 5, see SI for details).
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The only previous example of an atropisomeric diarylamine 4
featured an intramolecular hydrogen bond, locking rotation
about one of the Ar–N bonds.[9] To confirm that the
atropisomerism of 6m results solely from steric hindrance
and not intramolecular hydrogen bonding, compound 10 was
made by alkylation of the secondary amide of 6m. As a
result, the barrier to rotation decreased only marginally to
104.4 kJ mol–1. By contrast, methylation of 4 reduced the
barrier to rotation by 15.5 kJ mol–1.[9b]
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R. Vardanyan, V. Hruby, in Synthesis of Best-Seller Drugs, Academic
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NaH (2.0 equiv)
O
O
Me
N
Me
N
Me2N
MeHN
MeI (3.0 equiv)
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THF (0.2 M)
0 °C - rt, 20 h
10
6m
[9]
75%
ΔG‡333 = 104.4 kJ mol–1
ΔG‡333 = 106.5 kJ mol–1
t1/2 (333 K) = 40 min
t1/2 (333 K) = 84 min
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Scheme 5. (a) Atropisomeric diarylamines 6m and 10 and (b) their resolution
by HPLC on chiral stationary phase (Chiralpak OD-H, eluent 95:5 hexane–
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In conclusion, sterically hindered diarylamines can display
atropisomerism as a consequence of restricted rotation
around highly encumbered Ar–N bonds. Both hindered and
unhindered diarylamines may be made using an
unprecedentedly versatile Smiles rearrangement in which the
migrating ring requires no electronic activation. This
transition metal-free route to diarylamines is particularly
remarkable for its tolerance of a range of functionalities and
its compatibility even with the very hindered aryl rings, and
provides a valuable alternative to metal-catalysed coupling
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Acknowledgements
This work was supported by the EPSRC (EP/L018527), and
the University of Bristol. We thank Hazel Sparkes and
Natalie Pridmore for X-ray crystallographic assistance and
the Bristol Centre for Computational Chemistry for computing
resources and support.
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Keywords: diarylamine • Smiles rearrangement • atropisomer
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