Silver-catalyzed radical aminofluorination of unactivated alkenes in aqueous media

Article abstract of DOI:10.1021/ja400124t

We report herein a mild and catalytic intramolecular aminofluorination of unactivated alkenes. Thus, with the catalysis of AgNO₃, the reactions of various N-arylpent-4-enamides with Selectfluor reagent in CH ₂Cl₂/H₂

Full text of DOI:10.1021/ja400124t

Communication
pubs.acs.org/JACS
Silver-Catalyzed Radical Aminofluorination of Unactivated Alkenes in
Aqueous Media
Zhaodong Li, Liyan Song, and Chaozhong Li*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: We report herein a mild and catalytic
intramolecular aminofluorination of unactivated alkenes.
Thus, with the catalysis of AgNO3, the reactions of various
N-arylpent-4-enamides with Selectfluor reagent in
CH2Cl2/H2O led to the efficient synthesis of 5-
fluoromethyl-substituted γ-lactams. A mechanism involv-
ing silver-catalyzed oxidative generation of amidyl radicals
and silver-assisted fluorine atom transfer was proposed.
he introduction of fluorine atoms into organic molecules
Tsignificantly changes their physical, chemical and bio-
logical properties, and thus, organofluorine compounds have
found widespread and growing use in agrochemicals,
pharmaceuticals, materials, and other industries.1 Moreover,
Figure 1. Proposed mechanism of radical aminofluorination of
18F-labeled organic compounds are clinically used as contrast
unactivated alkenes.
agents for positron emission tomography (PET).2 The
development of new methods for C−F bond formation under
mild conditions has therefore received an increasing attention
in the past four years.3−11 In particular, free radical
fluorination7−11 is emerging as a powerful tool for C(sp3)−F
bond formation, especially under the catalysis of transition
metals.8−11 Lectka and co-workers8 reported the copper-
catalyzed aliphatic C−H fluorination with Selectfluor12 (1-
chloromethyl-4-fluorodiazoniabicyclo-[2,2,2]octane bis-
(tetrafluoroborate)). Groves et al. successfully developed the
manganese-catalyzed oxidative aliphatic C−H fluorination with
fluoride ion.9 We introduced the Ag(I)-catalyzed decarbox-
ylative fluorination of aliphatic carboxylic acids with Selectfluor
in aqueous solution.10 In addition, Boger and Barker reported
the Fe(III)/NaBH4-mediated free radical hydrofluorination of
unactivated alkenes.11 It is certainly desirable to further explore
the versatility and efficiency of radical fluorination. Herein, we
report the Ag(I)-catalyzed radical aminofluorination13,14 of
unactivated alkenes in aqueous media.
subsequent fluorine atom transfer from Ag(II)F to C produces
the aminofluorination products 2 and regenerates Ag(I), which
enters into the next catalytic circle. Driven by our interest in the
reactivities of amidyl radicals17 and in Ag(I)-catalyzed radical
reactions,10,18 we set out to explore this possibility.
Thus, N-phenylpent-4-enamide 1a was chosen as the model
substrate for the optimization of reaction conditions (Table 1).
With 10 mol % AgNO3 as the catalyst, the reaction of 1a with
Selectfluor (2 equiv) in organic solvents such as CH3CN, DMF,
acetone or CH2Cl2 at ambient temperature failed to give any
desired product. However, when the aminofluorination was
carried out in water at around 45 °C for 12 h, we were
delighted to see that the expected lactam 2a was observed in
76% yield. To improve the result, an organic cosolvent was
used to increase the solubility of substrate 1a. With CH3CN or
acetone as the cosolvent, the reaction was somehow
complicated and no 2a could be detected. On the other
hand, the use of CH2Cl2 as the cosolvent led to a higher yield of
2a (91% yield). Benzene showed a behavior similar to CH2Cl2.
These different solvent effects might be rationalized by the fact
that the biphasic system (such as CH2Cl2/H2O) keeps the
product from further oxidation. In this respect, increasing the
ratio of CH2Cl2/H2O from 1:1 to 2:1 helped for most
substrates (vide infra), although no difference was observed for
1a. Reducing the amount of AgNO3 slowed down the
aminofluorination while no expected product could be detected
without AgNO3. Changing AgNO3 to AgOAc or AgOTf did
Our idea was based on our recent finding10 that the
combination of Selectfluor and Ag(I) catalyst served not only as
an oxidant, but also as a fluorine atom transfer agent in
fluorodecarboxylation of aliphatic carboxylic acids, presumably
via the intermediacies of Ag(III)F and Ag(II)F. We envisioned
that such a combination might be utilized to allow the catalytic
oxidative generation of amidyl radicals.15,16 As depicted in
Figure 1, N-arylpent-4-enamides (1) might be oxidized by the
proposed intermediate Ag(III)F to generate Ag(II)F and arene
radical cations A. The deprotonation of A gives amidyl radicals
B, which then add intramolecularly to CC double bonds in a
5-exo mode to afford carbon-centered radicals C. The
Received: January 5, 2013
Published: March 18, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Optimization of Reaction Conditions
Scheme 2. Silver-Catalyzed Aminofluorination of
a,b
,c,d,e
Unactivated Alkenes
a
Conditions: 1a (0.3 mmol), fluorine source (0.6 mmol), organic
solvent (3 mL) if applied, H2O (3 mL) if applied, Ag source, 40−45
b
c
°C, 12 h. Isolated yield based on 1a. The ratio is 1:1 (v:v).
not show much difference. However, no reaction occurred
when the fluorine source was switched to N-fluorobis-
(benzenesulfonyl)imide (NFSI).
With the optimized conditions in hand, we then explored the
scope and limitations of the above radical aminofluorination,
and the results are summarized in Schemes 1 and 2. The para-
Scheme 1. para-Substituent Effect in the Aminofluorination
a,b,c
of N-Arylpent-4-enamides
a,b
c
d
See Scheme 1. Thirty mole percent AgNO3 was used. Two
e
stereoisomers in 1:1 ratio. CH2Cl2 (3 mL) and H2O (3 mL) was used
as the solvent.
failed to give the desired product 2n. Instead, the formation
of benzoquinone was observed in about 30% yield. Presumably
the oxidation of 1n to radical cations A was followed by
nucleophilic attack (by water) rather than deprotonation (to
give amidyl radicals B), a procedure similar to CAN (cerium
ammonium nitrate)-mediated deprotection of N-(p-methox-
yphenyl)-protected amides.19 In the meantime, primary or N-
alkyl-substituted amides did not undergo aminofluorination
under the optimized conditions. These results were in
accordance with the proposed mechanism illustrated in Figure
1.20 The above results also demonstrated the excellent
functional group compatibility of the radical aminofluorination.
Next, substrates 3a−3q with various substitution patterns
were screened (Scheme 2). The reactions of meta- or ortho-
substituted aromatic amides (3a−3g) all proceeded nicely.
Substrates with different substitution on the alkenyl chain also
underwent smooth 5-exo cyclization. Di- and trisubstituted
alkenes (such as 3j, 3l and 3m) were also applicable for the
aminofluorination. Other than amides, N-arylcarbamates and
a
Reaction conditions: alkene (0.3 mmol), AgNO3 (0.03 mmol),
Selectfluor (0.6 mmol), CH2Cl2 (1.5 mL), H2O (0.75 mL), reflux.
b
c
Isolated yield based on the starting alkene. CH2Cl2 (3 mL) and H2O
(3 mL) was used as the solvent.
substituent effect was first examined (Scheme 1). The
aminofluorination proceeded smoothly not only for the N-
arylamides bearing an electron-donating group on the aryl ring
(1b−1e), but also for those substrates having a strong electron-
withdrawing substituent (2g−2m) such as CN, NO2, CF3,
CO2H, although a longer reaction time was required in the
latter cases. Nevertheless, N-(p-methoxyphenyl)-amide 1n
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Communication
ureas could also be utilized to participate in the transformation,
as exemplified by the synthesis of 4n−4p from the
corresponding substrates 3n−3p. It is conceivable that the
hydrolysis of 4n−4p would produce the corresponding
fluorinated 1,2-diamines or aminoalcohols, which should serve
as useful building blocks in the synthesis of fluorinated
molecules.
To provide further evidence on the proposed radical
mechanism (Figure 1), (E)-5-cyclopropyl-N-phenylpent-4-
enamide (5) was prepared as the radical probe.21 The reaction
of 5 under the above optimized conditions turned out to be
unsatisfactory probably because of the instability of the
expected allylic amine product 6 under the oxidative conditions.
However, by using 1.5 equiv of AgOAc and shortening the
reaction time to 30 min, the ring-opening product 6 of (E)-
configuration was isolated in 23% yield along with the recovery
of 5 in 30% yield (eq 1). This experiment provides a solid
migration. These results provide a promising route for site-
specific C−H fluorination, which is currently under further
investigation in our laboratory.
In conclusion, we have developed the radical amino-
fluorination of unactivated alkenes in aqueous media with
AgNO3 as the catalyst and Selectfluor as both the fluorine
source and the oxidant. This new method further broadens the
scope of radical fluorination and features (1) the catalytic
oxidative generation of amidyl radicals and (2) the silver-
assisted fluorine atom transfer. In view of the mild conditions
and excellent functional group compatibility, this radical
procedure should find practical application in the synthesis of
fluorinated molecules.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details, characterizations of new compounds,
evidence for the intermediacy of amidyl radicals in the
aminofluorination. Moreover, treatment of amide 1a with
AgNO3 (20 mol %), K2S2O8 (2 equiv) and KF (2 equiv) in
CH2Cl2/H2O at reflux for 12 h led to the formation of 5-
methyl-1-phenylpyrrolidin-5-one (7, 23% yield) rather than 2a.
Apparently 7 resulted from the H-abstraction of cyclized radical
C. This implies that the H-abstraction is much faster than the
further oxidation for radical C. The reaction of 1a with
Ag(Phen)2S2O8 (2 equiv) and Selectfluor (2 equiv) in CH2Cl2/
H2O or CH3CN/H2O at refluxing temperature gave not 2a but
7 (10−30%) as the product, indicating that 2a is unlikely to be
formed via the direct trapping of radical C by Selectfluor. These
results, in combination with our previous finding in
decarboxylative fluorination,10 support the silver-assisted
fluorine atom transfer mechanism.
The above radical aminofluorination of unactivated alkenes
exhibits the behavior different from the reported palladium-
catalyzed processes, in which N-tosyl or N-nosyl-substituted 3-
fluoropiperidines was obtained via a 6-endo mode of cyclization
and the procedure was not applicable to amides.13a Other
reported nonradical aminofluorination processes also gave
endo-cyclization products.13c−e It is worth mentioning that
electrophilic halocyclizations22 of unsaturated amides typically
afford lactones or oxazolines6a rather than lactams. In addition,
the fact that amidyl radicals can be accessed directly from the
parent amides under silver catalysis should be valuable for the
design of a range of other reactions.15,16,23
As an extension of the above aminofluorination, the
following remote C−H fluorination could be designed based
on the intramolecular 1,5-H abstraction of amidyl radicals.23l
Our preliminary results showed that, under the conditions
identical to those of aminofluorination detailed above, the
reaction of 4-methyl-N-phenylpentanamide (8a) afforded the
fluorinated product 9a in 9% yield. However, with para-cyano-
substituted aromatic amide 8b as the substrate, the
corresponding fluorinated product 9b was achieved in 41%
yield (eq 2). The para-cyano-substitution effect might be
attributed to the higher N−H bond dissociation energy in 8b
than in 8a, which serves as a better driving force for 1,5-H
1
and copies of H, 13C and 19F NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
clig@mail.sioc.ac.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (Grant nos. 21072211, 21228202,
21272259 and 21290180) and by the National Basic Research
Program of China (973 Program) (Grant nos. 2011CB710805
and 2010CB833206).
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