Regiospecific Three-Component Aminofluorination of Olefins via Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b01760

Direct visible-light-mediated aminofluorination of styrenes has been developed with high regioselectivity. Shelf-stable N-Ts-protected 1-aminopyridine salt was used as the nitrogen-radical precursor, and the commercially available hydrogen fluoride-pyridi

Full text of DOI:10.1021/acs.orglett.8b01760

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regiospecific Three-Component Aminofluorination of Olefins via
Photoredox Catalysis
Jia-Nan Mo, Wan-Lei Yu, Jian-Qiang Chen, Xiu-Qin Hu,* and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P. R. China
S
* Supporting Information
ABSTRACT: Direct visible-light-mediated aminofluorination of styrenes has been developed with high regioselectivity. Shelf-
stable N-Ts-protected 1-aminopyridine salt was used as the nitrogen-radical precursor, and the commercially available hydrogen
fluoride-pyridine was used as the nucleophilic fluoride source. The synthesis of an analogue of LY503430 was performed to
demonstrate the synthetic value of this strategy.
Scheme 1. Direct Aminofluorination of Alkenes for the
Construction of the C(sp3)−F Bond
lkenes are fundamental building blocks for the synthesis
of complex molecules. Over the past several decades,
A
vicinal difunctionalization of alkenes has become one of the
most versatile approaches to install two functional groups
simultaneously to a carbon−carbon double bond.1 Much
attention has been paid to the direct aminofluorination of
olefins2 since the molecules containing the 1,2-aminofluoro
moiety constitute the key building blocks for the synthesis of
anticancer,3 anticholinergic, and anti-inflammatory drugs, as
well as therapeutic β-peptides.4
To synthesize the compounds possessing vicinal amino and
fluorine moieties efficiently, a wide variety of olefin amino-
fluorination approaches have been developed.5 For example,
one of the most widely used methods is tandem intramolecular
amination cyclization followed by intermolecular fluorination.6
In contrast, only a few methods are currently available to
generate β-fluoroamines in an intermolecular three-component
fashion.7 Recently, Liu and co-workers reported an efficient
intermolecular aminofluorination of styrenes using N-fluoro-
benzenesulfonimide (NFSI) as both an amino8 and a fluorine
source by fluoropalladation (Scheme 1a).9 In addition, Zhang
developed a highly regioselective copper-catalyzed radical
aminofluorination of styrenes with NFSI, wherein the
regioselectivity was complementary to that of palladium
catalysis (Scheme 1b).10 However, significant challenges still
exist in the nucleophilic fluorination process because of the
high electronegativity and low nucleophilicity of the solvated
fluoride ion in organic solvents.11 We herein describe an
efficient visible-light-mediated aminofluorination reaction of
styrenes with the fluoride ion (Scheme 1d).
For the past several years, photoredox catalysis has become
one of the fastest growing fields in organic chemistry.12
Particularly, extensive research efforts have been directed
toward visible-light photocatalytic olefin difunctionalization
reactions.13 More recently, the Akita group14 and our group15
have developed a series of reactions using shelf-stable N-Ts-
protected 1-aminopyridine salt as the nitrogen-radical
precursor by photoredox catalysis. The precursor, which was
Received: June 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
different from the other N-radical precursors, could only
generate pyridine with concomitant formation of N-radicals.16
Due to the poor nucleophilicity of pyridine, these methods
inspired us to construct the C−F bond using hydrogen
fluoride-pyridine (Olah’s reagent) as the nucleophilic fluorine
source.17
Scheme 2. Scope of Alkenes in the Intermolecular
Aminofluorination Reaction
a
Initially, the aminofluorination reaction was carried out with
styrene (1a), N-Ts-protected 1-aminopyridine salt (2), and
pyr·9HF (Olah’s reagent) as model substrates. The represen-
tative results are summarized in Table 1. When the reaction
a
Table 1. Optimization of the Reaction Conditions
b
entry
photocatalyst
Ir(ppy)3
Ru(bpy)3(PF6)2
1a/2
solvent
yield (%)
1
2
3
4
5
6
7
8
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CHCl3
EA
toluene
THF
37
trace
trace
79
13
23
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6
Ir(ppy)2(dtbbpy) PF6

14
N.R.
N.R.
N.R.
67
84
72
9
a
10
11
12
13
14
15
DMF
Reaction conditions: 1 (0.1 mmol), 2 (0.175 mmol), [Ir-
(ppy)2(dtbbpy)][PF6] (1 mol %), CH2Cl2 (2 mL), 25 °C, 25 W
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
b
c
d
e
1:1.75
1:2
blue LEDs. Isolated yield. 8 h. 12 h. Diastereomeric ratio was
determined by 19F NMR analysis of the mixture.
c
1:1.75
1:1.75
1:1.75
1:1.75
1:1.75
1:1.75
28
d
9
e
16
17
60
73
N.R.
N.R.
were explored. A range of styrenes with various electronic
properties were compatible with the reaction, and the
corresponding fluorosulfonamides 3a−3t were produced in
yields ranging from 34% to 84% with complete regioselectivity.
Styrene derivatives carrying halogen substituents at the para-
position of the arene such as F, Cl, Br, and I were successfully
converted to the corresponding aminofluorination products
(3b−3d, 3l) in good yields (73%−86%). In addition,
dihalosubstituted and trimethyl-substituted styrene also
smoothly afforded 3p and 3o in 34% and 47% yields,
respectively. The substrate bearing an electron-withdrawing
CF3 group provided the corresponding products 3e in 64%
yield. Furthermore, styrene derivatives bearing electron-
donating substituents at the p-position of the arene ring
provided the vicinal fluoroamines (3f−3h) in moderate to high
yields (57−78%). Ortho- and meta-substituted styrene
derivatives were well tolerated in this conversion (3i−3k). It
is worth mentioning that 2-vinylnaphthalene afforded 3n in a
slightly lower yield (41%). Additionally, α-methylstyrene was
also a good substrate (3m, 76%).
To gain more insight into the diastereoselectivity of the
reaction, we investigated the aminofluorination of internal
alkenes. With internal alkenes such as indene (1q), 1,2-
dihydronaphthalene (1r), β-methylstyrene (1s), and cyclo-
hexylbenzene (1t), the reactions also proceeded in a
regiospecific manner, but the products were obtained as
mixtures of two diastereomers (3q−3t). In addition, we also
investigated trisubstituted unsymmetric alkenes such as but-2-
en-2-yl benzene, but the reaction did not afford the desired
product (see Supporting Information).
f
18
19
g
Ir(ppy)2(dtbbpy) PF6
a
Reaction conditions are as follows: 1a (0.1 mmol), 2 (1−2 equiv),
photocatalyst (1 mol %), solvent (2 mL), 25 °C, 25 W blue LEDs
b
c
under N2 atmosphere in a sealed plastic vial for 5 h. Isolated yield. 5
equiv of HF. 15 equiv of HF. 4 mL of CH2Cl2. 2 mol %
photocatalyst. In the absence of a light source.
d
e
f
g
was performed using Ir(ppy)3 as the photocatalyst at room
temperature under irradiation with 25 W blue LED for 5 h, the
reaction proceeded to give the expected product 3a in 37%
yield (entry 1). A simple screening of reaction showed that
[Ir(ppy)2(dtbbpy)][PF6] gave rise to superior results with 3a
being obtained in yield of 79% (entries 2−4). Encouraged by
this result, we continued to optimize the reaction conditions to
improve the yield. Solvent screening showed that CH2Cl2 was
an optimal solvent for this transformation (Table 1, entries 5−
10). Modulating the ratio of 1a to 2 led to higher yields (Table
1, entries 11−13). Whether we increased or decreased the
amount of pyr·9HF, the yields were significantly reduced
(Table 1, entries 14 and 15). Either slight dilution of the
reaction mixture or more catalyst loading resulted in a slight
decrease of the yield (Table 1, entries 16 and 17). Control
experiments clearly confirmed that both the photocatalyst and
visible-light irradiation were critical for this process (Table 1,
entries 18 and 19).
Under the optimized reaction conditions, the substrate
scopes of the above aminofluorination reaction (Scheme 2)
B
DOI: 10.1021/acs.orglett.8b01760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the success of direct aminofluorination of styrenes, we
further explored the possibility of achieving aminochlorination
and aminobromination of olefins using nucleophilic halides. It
was found that intermolecular aminochlorination of alkenes
using pyridine hydrochloride as the Cl donor also demon-
strated good efficiency, regioselectivity, and functional group
tolerance, although the reactivities of these aminochlorination
reactions were slightly lower than those of the corresponding
aminofluorination reactions (Scheme 3). Additionally, we were
reported literature,21 a putative mechanism is illustrated in
Scheme 5. First, the photocatalyst Ir(ppy)2 (dtbbpy)PF6 (IrIII)
Scheme 5. A Proposed Mechanism
a
Scheme 3. Aminochlorination of Alkenes
a
Reaction conditions: 1 (0.1 mmol), 2 (0.175 mmol), [Ir-
(ppy)2‑(dtbbpy)][PF6] (1 mol %), CH2Cl2 (2 mL), 25 °C, 25 W
b
blue LEDs. Isolated yield.
pleased to find that this reaction system could also be
modulated to obtain β-bromoamines using pyridine hydro-
bromide as the bromide donor, albeit with a low yield of 17%
(10) (see Supporting Information). We speculated that the
strong acidity of hydrobromic acid caused the poor yield.
Having established this strategy for generating the β-
fluoroamine skeleton, we next sought to demonstrate the
utility of this method in the rapid synthesis of an analogue of
LY503430, which is a potential therapeutic agent for
Parkinson’s disease (Scheme 4).18 The synthesis began with
is excited by visible light to give the excited species (*IrIII),
which undergoes oxidative quenching with N-Ts-protected 1-
aminopyridine salt 2 to give the corresponding radical 7 along
with highly oxidizable Ir species IrIV. Subsequently, the N-
centered radicals react with the alkene in a regiospecific
manner to give stabilized radical intermediate 8, which is
oxidized by strongly oxidizing Ir species IrIV to a cationic
intermediate 9, which is trapped by hydrogen fluoride-pyridine
to form the final product (3). Alternatively, the N-Ts-protected
1-aminopyridine salt 2 can act as a chain carrier, whereby it
oxidizes benzyl radical intermediate 8 to provide the cationic
intermediate 9. Quantum yield measurements (Φ = 1.167)
suggest a chain mechamism is possible (see the Supporting
Information for further details).
Scheme 4. Synthetic Utility of the Method
To our knowledge, this is the first example employing
commercially available hydrogen fluoride-pyridine as the
nucleophilic fluorine source, thus making it an attractive
reagent for synthetic purposes. The practicability of this
transformation has also been demonstrated by the efficient
synthesis of an LY503430 analogue.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01760.
Experimental details on experimental procedures for the
catalytic reactions and spectroscopic data for the
products (PDF)
a Wittig olefination, which converted 4-iodoacetophenone into
the corresponding alkene. Under the optimized conditions,
product 3l was afforded through the aminofluorination process
as the key step.19 Product 3l was subsequently subjected to
Suzuki coupling and amide coupling to provide product 6,
which is an analogue of LY503430.20
TEMPO trapping experiments were carried out to prove
that the aminofluorination process was a radical one. On the
basis of the aforementioned control experiments and other
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: huxiuqin@lzu.edu.cn.
*E-mail: xupf@lzu.edu.cn.
ORCID
Peng-Fei Xu: 0000-0002-5746-758X
C
DOI: 10.1021/acs.orglett.8b01760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (21632003 and 21572087), the
Key Program of Gansu Province (17ZD2GC011), and the
“111” Project from the MOE of P. R. China for financial
support.
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