Journal of the American Chemical Society
Page 4 of 5
(2042018kf0017), the NSF under the CCI Center for Selective
bromo- or iodo-precursors, a library of deuterated indoles
2a, and 2e 2h) were synthesized in moderate to good yield
(81 – 91%) with excellent deuterium incorporation (Scheme
4a). Similarly, quinolones (3a, and 3c
3h) were successfully
1
2
3
4
5
6
7
8
C−H Functionalization (CCHF), CHE-1700982, National
Program for 1000 Young Talents of China, Wuhan University,
and Caltech for financial support. Prof. Qiang-Hui Zhou and his
group are appreciated for generously sharing their lab space.
Profs. Martin Oestreich (T.U. Berlin), Nasri Nesnas (F.I.T.), and
Yong Liang (Nanjing Univ.) are thanked for helpful discussions.
We also thank Dr. Hongbing Liu (Wuhan Institute of Physics
and Mathematics, CAS) for the measurements of 2H NMR
spectra.
(
–
–
labeled (from C2 to C8) in 31 – 91% yield (Scheme 4b).
A number of synthetic methods with potassium alkoxides
and organosilanes have been reported involving the
intermediacy of either radicals or silyl anions.13,16 We first
considered the possibility of a radical pathway. The addition
of TEMPO, which is able to shut down the silyl radical
addition,16e has little effect to the deuteration reaction (see
Scheme S2a in SI). Moreover, when a radical probe substrate
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1-bromo-2-(but-3-en-1-yl)benzene
was
used, ipso-
debromination product was obtained in 54% yield
exclusively without the observation of radical cyclization
reaction (Scheme S2b).17 Those results indicate that a free
radical species is less possible. Inspired by previous studies
reporting silyl substitutions of aryl halides by Ito et al18 and
Strohmann et al,19 a putative mechanism involving an anionic
pathway is proposed to be active under our reation
conditions (Scheme S2c). The mixture of KOMe and
Me3SiSiMe3 may slowly generate trimethylsilyl anion or a
nucleophilic hypervalentsilane species,16 which attacks the
aryl bromide to form an aryl carbanion.18 The transient
carbanion is instantaneously trapped by the large excess of
CD3CN to provide the desired deuterated product. Detailed
studies aimed at understanding mechanism will be carried
out to further probe this hypothesis.
In summary, a general KOMe/disilane-mediated ipso-
dehalogenative deuteration reaction in CD3CN was
developed. This method features operationally simple
procedures, mild reaction conditions, readily available
reagents, and good functional group tolerance. A diverse
range of valuable deuterated (hetero)arenes, natural
products, and pharmaceuticals were isotopically labeled with
excellent deuterium incorporation and specificity. Further
mechanistic studies are currently ongoing.
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Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am.
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(b) Yus, M. Chem. Soc. Rev. 1996, 25, 155. (c) Yus, M. Synlett 2001, 8,
1197. (d) Reich, H. J. J. Org. Chem. 2012, 77, 5471.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization data and NMR
spectra for all new compounds (PDF)
(10) For a review of metal-mediated reductive hydrodehalogenation:
(a) Alonso, F.; Beletskaya, I. P; Yus, M. Chem. Rev. 2002, 102, 4009. For
selected examples of transition-metal catalyzed dehalogenative
deuteration: (b) Desmarets, C.; Kuhl, S.; Schneider, R.; Fort, Y.
Organometallics 22002, 21, 1554. (c) Janni, M.; Peruncheralathan, S. Org.
Biomol. Chem. 2016, 14, 3091. (d) Kuriyama, M.; Hamaguchi, N.; Yano,
G.; Tsukuda, K.; Sato, K.; Onomura, O. J. Org. Chem. 2016, 81, 8934. (e)
Donald, C. S.; Moss, T. A.; Noonan, G. M.; Roberts, B.; Durham, C. E.
Tetrahedron Lett. 2014, 55, 3305. (f) Johansen, S. K.; Sørensen, L.;
Martiny, L. J. Label Compd. Radiopharm. 2005, 48, 569. For selected
examples of radical mediated dehalogenative deuteration: (g) Mutsumi,
T.; Iwata, H.; Maruhashi, K.; Monguchi, Y.; Sajiki, H. Tetrahedron 2011,
67, 1158. (h) Miura, Y.; Oka, H.; Yamano, E.; Morita, M. J. Org. Chem.
1997, 62, 1188, and ref 8. For a recent example of hydrodehalogenation of
haloarenes by NaH/LiI: (i) Ong, D. Y.; Tejo, C.; Xu, K.; Hirao, H.; Chiba,
S. Angew. Chem. Int. Ed. 2017, 56, 1840.
AUTHOR INFORMATION
Corresponding Author
wenboliu@whu.edu.cn;
Notes
The authors declare no competing financial interest.
A
provisional patent has been filed.
ACKNOWLEDGMENT
We gratefully acknowledge the NSFC (21602160, 21772148),
the Fundamental Research Funds for the Central Universities
(11) Selected examples: (a) Klei, S. R.; Golden, J. T.; Tilley, T. D.;
Bergman, R. G. J. Am. Chem. Soc. 2002, 124, 2092. (b) Esaki, H.; Ito, N.;
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