Angewandte
Communications
Chemie
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C(sp ) H Bromination
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Copper-Catalyzed Bromination of C(sp ) H Bonds Distal to
Functional Groups
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Abstract: Selective bromination of g-methylene C(sp ) H
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bonds of aliphatic amides and d-methylene C(sp ) H bonds of
nosyl-protected alkyl amines are developed using NBS as the
brominating reagent and catalytic amount of CuII/phenanthro-
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line complexes as the catalyst. Aryl and benzylic C H bonds at
other locations remain intact during this directed radical
abstraction reaction.
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T
ransition metal-catalyzed functionalizations of C(sp ) H
bonds that are b to carbonyl and carboxyl groups or g to
amino groups have the potential to provide new synthetic
disconnections, largely owing to the predictable and com-
monly encountered structural patterns generated by these
transformations.[1] Following the same considerations, func-
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tionalizations of C(sp ) H bonds that are further away will
afford new sets of strategic tools for organic synthesis. To
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date, Pd-catalyzed functionalizations of distal C H bonds are
generally rare[2] due to the predominant five-membered
cyclometallation reactions. In light of this limitation, we
initiated efforts to exploit the possibility of combining
directed radical 1,5 and 1,6-H-abstraction[3–5] with metal
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catalysis to achieve diverse C H functionalizations. The
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Scheme 1. Remote C(sp ) H functionalization. IBDA=iodobenzene
diacetate, TFA=trifluoroacetic acid, NIS=N-iodosuccinimide,
NBS=N-bromosuccinimide, phen=phenanthrolin,
interception of the remote carbon radical center by suitable
metal catalysts to mediate the subsequent carbon–carbon and
carbon–heteroatom bond formation has proved challenging.
Early investigations demonstrated the potential of metal-free
TMSN3 =trimethylsilyl azide, EWG=electron-withdrawing group.
1,5-H-abstraction reactions for functionalizations of remote
[6]
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C H bonds (Scheme 1B).
to other intermolecular C H functionalizations has met with
limited success due to the predominant cyclization pathway.
Herein we report CuII/phenanthroline-catalyzed bromi-
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nation of g-C H bonds of aliphatic amides and d-C H bonds
of alkyl amines (Scheme 1C). Both CuII catalyst and phenan-
throline ligands are essential for the observed reactivity.
Important examples of photochemical halogenation of
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remote C(sp ) H bonds of amine substrates have been
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achieved by preforming N Cl or N Br precursors (Sche-
Although photo-induced chlorination and bromination of C
H bonds by using preformed stoichiometric N Cl or N Br
me 1A).[7] Non-directed radical halogenation of C(sp ) H
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bonds has also been developed with synthetically useful site
selectivity.[8] Guided by our previous work on H-abstraction
and subsequent cyclization of amides (Scheme 1B) and other
reports,[3–6] we began to develop a catalytic system to intercept
the carbon radical of both amine and amide substrates
precursors have been reported with alkyl amine substrates
(Scheme 1A),[7] analogous g-C H halogenation of amide
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substrates have not been demonstrated.
1,5-H-abstraction has been successfully utilized for
remote C H nitration by Barton.[3d,f] Extending this approach
thereby achieving intermolecular C H functionalization.
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Our experimental efforts began with finding conditions
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for C(sp ) H bromination of readily prepared electron
[*] T. Liu, Prof. Dr. J.-Q. Yu
deficient N-nosyl pentanamide 1a. We found that the reaction
of amide 1a with 3.0 equivalent of NBS in the presence of
10 mol% of CuBr2, 10 mol% of 2,2’-bipyridine, and 3.0 equiv-
alent of NaN3 (in DCE at 608C under air for 18 h) gave
exclusively the g-bromo pentanamide 2a in 7% yield
(Table 1, entry 4). Replacing NaN3 with TMSN3 improved
the yield to 11% (entry 5). In the absence of azide additives,
no desired product was detected. The use of catalytic amounts
of 1,10-phenanthroline afforded the brominated product 2a
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Dr. M. C. Myers
Department of Discovery Chemistry, Bristol-Myers Squibb
P.O. Box 5400, Princeton, NJ 08543-5400 (USA)
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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