Angewandte
Chemie
DOI: 10.1002/anie.201406797
Sythetic Methods
Regioselective Radical Aminofluorination of Styrenes**
Hongwei Zhang, Yongcheng Song, Jinbo Zhao, Jingping Zhang,* and Qian Zhang*
Abstract: The copper-catalyzed radical aminofluorination of
styrenes with N-fluorobenzenesulfonimide (NFSI) is realized
with high regioselectivity, thus affording aminofluorination
products with regioselectivities opposite that of the palladium-
catalyzed and noncatalyzed processes. Preliminary mechanis-
tic studies suggested the reaction went through a radical
pathway and was supported by DFT calculations. In these
reactions, NFSI is utilized as both a radical nitrogen source and
radical fluorine source, thus rendering it an attractive reagent.
Scheme 1. Aminofluorination of styrene with NFSI.
M
olecules containing vicinal amino and fluorine moieties
constitute key building blocks for the synthesis of anticancer,
anticholinergic, and anti-inflammatory drugs, as well as
therapeutic b-peptides.[1] Tandem intramolecular amination
cyclization followed by intermolecular fluorination of unsa-
turated carbon–carbon bonds has been proven to be an
efficient way to construct nitrogen-containing heterocycles
with vicinal amino and fluorine moieties.[2] In contrast, the
addition reaction between unsaturated carbon–carbon bonds
wherein the regioselectivity is complementary to that of
palladium catalysis (Scheme 1).
Novel synthetic methods for fluorine incorporation have
been significantly developed because of the widespread use of
fluorine-containing compounds in pharmaceutical and agro-
chemical industries.[1c,9] In comparison with nucleophilic or
electrophilic fluorination, radical fluorination under benign
conditions is far less explored. Very recently, the electrophilic
fluorine sources NFSI and Selectfluor were effectively used to
À
and compounds containing N F bonds might provide a highly
attractive strategy for direct and efficient construction, in an
intermolecular fasion, of molecules containing vicinal amino
and fluorine moieties.
À
construct C F bonds by radical fluorination, during which the
generation of a C(sp3)-centered radical was neccesary.[10]
Accordingly, intermolecular hydrofluorination,[10a] phospho-
nofluorination,[10f] as well as intramolecular aminofluorina-
tion[10h] of alkenes were realized. However, to the best of our
knowledge, intermolecular radical aminofluorination of
alkenes has not been documented, and might be attributed
to the lack of a convenient route for the generation of
relatively stable nitrogen-centered radical species.[11–14] More
recently, we developed copper-catalyzed aminocyanation and
diamination reaction of alkenes by the efficient generation of
nitrogen-centered radicals from NFSI, and subsequent radical
addition reactions with alkenes.[7a] With this methodology, six-
membered-ring sultams[7c] were consturcted and aminoazida-
tion reaction of alkenes were also developed.[7e] Therefore, we
reasoned that if fluorine transfer between the in situ gener-
ated C-centered radical intermediate and NFSI could occur,
a novel radical amination initiated aminofluorination of
styrenes would lead to a unique regioselectivity which
would be different from previous work[8] (Scheme 1).
À
N-Fluorobenzenesulfonimide (NFSI) contains a N F
bond and is widely used as an electrophilic fluorination
agent.[3] Radical fluorine atom transfer reactions of NFSI
have been also developed.[4] With NFSI as a nitrogen source,
interesting amination reactions were discovered through
possible nucleophilic,[5] electrophilic,[6] and radical[7] aminat-
ing processes. Given the multiple reaction modes of NFSI and
our work on employing NFSI as a nitrogen source,[5b–d,7a,b] we
were prompted to investigate the challenging regioselective
aminofluorination directly from unsaturated carbon–carbon
bonds and NFSI. Recently, Liu and co-workers developed an
efficient palladium-catalyzed aminofluorination of styrenes
with NFSI by fluoropalladation (Scheme 1).[8] Herein, we
report an efficient and highly regioselective copper-catalyzed
radical aminofluorination reaction of styrenes with NFSI,
[*] H.-W. Zhang,[+] Y. C. Song,[+] Dr. J. B. Zhao, Prof. J. P. Zhang,
Prof. Q. Zhang
Initially, the aminofluorination reaction between styrene
(1a) and NFSI was investigated without employing a cata-
lyst.[15] When the reaction of 1a (0.5 mmol) and NFSI
(1.2 equiv) was performed at 1358C in 1,2-dichloroethane
(DCE, 2 mL) for 10 hours, the aminofluorination product 2a
(same regioselectivity as with palladium as catalyst[8]) was
obtained in 23% yield upon isolation [Eq. (1)]. The amino-
fluorination product 3a was not detected. In contrast, the
reaction catalyzed by CuBr and bathocuproine (BC), as the
ligand, delivered the aminofluorination product 3a having the
opposite regioselectivity.
Department of Chemistry, Northeast Normal University
Changchun, 130024 (China)
E-mail: zhangjp162@nenu.edu.cn
[+] These authors contributed equally to this work.
[**] Financial support of this research from the SRFDP
(20110043110002) and the NNSFC (21172033, 21372041,
21302017) are greatly acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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