Metal-free intramolecular aminofluorination of alkenes mediated by PhI(OPiv)2/hydrogen fluoride-pyridine system

Article abstract of DOI:10.1039/c2ob26664d

A convenient, metal-free intramolecular aminofluorination of alkenes has been developed. Employing readily available PhI(OPiv)₂ and hydrogen fluoride-pyridine in the presence of BF₃·OEt₂, tosyl-protected pent-4-en-1-amines were converted to 3-F-piperidines in one step in good yields as well as high stereoselectivity.

Full text of DOI:10.1039/c2ob26664d

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Biomolecular
Chemistry
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Volume 10 | Number 43 | 21 November 2012 | Pages 8553–8740
ISSN 1477-0520
COMMUNICATION
Xiangbao Meng, Zhongjun Li et al.
Metal-free intramolecular aminofluorination of alkenes mediated by
PhI(OPiv)2/hydrogen fluoride–pyridine system
1477-0520(2012)10:43;1-8

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COMMUNICATION
Metal-free intramolecular aminofluorination of alkenes mediated by
PhI(OPiv)2/hydrogen fluoride–pyridine system†
Qing Wang, Wenhe Zhong, Xiong Wei, Maoheng Ning, Xiangbao Meng* and Zhongjun Li*
Received 23rd August 2012, Accepted 11th September 2012
DOI: 10.1039/c2ob26664d
A convenient, metal-free intramolecular aminofluorination of
alkenes has been developed. Employing readily available
PhI(OPiv)2 and hydrogen fluoride–pyridine in the presence
of BF3·OEt2, tosyl-protected pent-4-en-1-amines were
converted to 3-F-piperidines in one step in good yields as
Scheme 1 Palladium-catalyzed intramolecular aminofluorination.
well as high stereoselectivity.
Carbon–fluorine bond formation is an integral reaction in the
preparation of pharmaceuticals, agrochemicals, materials and
tracers for positron emission tomography.1 In recent years, many
metal-catalyzed fluorination reactions have been studied for the
efficient incorporation of fluorine.2 Vicinal amino-fluoro-com-
pounds, which contain a fluoro group adjacent to an amino
group, have been used as an important intermediate in the syn-
thesis of many pharmaceuticals.3 Direct aminofluorination of
alkenes could allow rapid access to this type of useful building
block, but only a few methods have been reported. For instance,
Liu and co-workers developed a palladium-catalyzed intramole-
cular aminofluorination of unactivated alkenes for the efficient
construction of fluoro-containing cyclic amines. A palladium cat-
alyst was crucial for this reaction and a Pd(II/IV) catalytic process
was proposed in the presence of PhI(OPiv)2/AgF (Scheme 1).4
Recently, hypervalent iodine reagents have been employed to
mediate the difunctionalization of alkenes without the use of a
noble metal catalyst. Lovick and Michael found that a highly
regioselective aminotrifluoroacetoxylation of an unactivated
alkene was achieved in the presence of hypervalent iodine(III).5
Meanwhile, Wardrop and co-workers developed a method for
the intramolecular oxamidation of unsaturated O-alkyl hydroxa-
mates mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA).6
Furthermore, hypervalent iodine(III) also has been used in the
stereoselective dioxygenation of alkenes and the mechanism has
been clarified.7 In addition, Muñiz et al. described a method for
the enantioselective diamination of styrenes by employing a
chiral iodine(III) reagent,8 and the diamination of other alkenes
Scheme 2 Metal-free aminofluorination of alkenes.
was reported by the same group.9 Gouverneur et al. reported an
enantioselective intramolecular aminofluorination reaction of
N-Ts indole derivatives by use of Selectfluor/(DHQ)2PHAL and
NFSI/(DHQ)2PHAL.10 The use of hypervalent iodine reagents,
which are less toxic and readily available, represents a useful
alternative to the metal-catalyzed procedures. Herein, we report a
novel BF3·OEt2-catalyzed metal-free method for the intramole-
cular aminofluorination of unactivated alkenes mediated by a
PhI(OPiv)2/hydrogen fluoride–pyridine system (Scheme 2).
Compared with previous reports,4,11 this method is more regiose-
lective and stereoselective, and in the absence of a noble metal
catalyst.
Although difluoroiodoarenes (ArIF2) have been widely used
in fluorination reactions,12 the preparation of ArIF2 usually
needs the use of powerful fluorinating reagents such as F2,13
XeF2,14 or toxic HgO.15 Therefore, we initially used commer-
cially available PhI(OAc)2 (PIDA) as the oxidant and AgF as the
fluorine source. Based on our previous work,7 we chose
BF3·Et2O as the promoter. To our delight, the aminofluorination
product was obtained in the absence of palladium catalyst, albeit
in 18% yield. Meanwhile, an aminohydroxylation byproduct was
observed (Table 1, entry 1). We then used PhI(OPiv)2 (PIDP) for
its larger size to reduce the aminohydroxylation byproduct and
the aminofluorination yield increased to 29% (Table 1, entry 2).
Various fluorine sources were also tested to increase the ami-
nofluorination yield. However, the reaction failed to provide
desired product 2a when several fluorides were employed as the
The State Key Laboratory of Natural and Biomimetic Drugs,
Department of Chemical Biology, School of Pharmaceutical Sciences,
Peking University, Beijing 100191, P. R. China.
E-mail: xbmeng@bjmu.edu.cn, zjli@bjmu.edu.cn
†Electronic supplementary information (ESI) available: Detailed
experimental procedures and spectroscopic data. See DOI:
10.1039/c2ob26664d
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Table 1 Hypervalent iodine(III) mediated intramolecular amino-
fluorination of alkenes
Table 2 Hypervalent iodine(III) mediated intramolecular amino-
fluorination of alkenesa
Entry
1
Alkene
Product
Yieldb (%)
85
2
3
4
90
81
Hypervalent
Solvent iodine(III)
Yield
(%)
81 (cis : trans > 99 : 1)
Entry [F] Source
R
1
2
3
4
5
6
7
8
AgF (2.5 eq.)
AgF (2.5 eq.)
AgF (2.5 eq.)
HF/H2O (2.5 eq.)
CaF2 (2.5 eq.)
NH4HF2 (2.5 eq.)
DCM
DCM
DCM
DCM
DCM
DCM
PIDA
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDP
PIDA
PIFA
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
18
29
n.r.a
0
0
0
5
6
7
78 (cis : trans > 99 : 1)
75 (cis : trans > 99 : 1)
64 (cis : trans > 99 : 1)
NEt3·3HF (2.5 eq.) DCM
0
TBAF (2.5 eq.)
HF–Py (2 eq.)
HF–Py (3 eq.)
HF–Py (4 eq.)
HF–Py (5 eq.)
HF–Py (10 eq.)
HF–Py (15 eq.)
HF–Py (10 eq.)
HF–Py (10 eq.)
HF–Py (10 eq.)
HF–Py (10 eq.)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
n.r.
35
70
76
81
85
85
39
59
n.r.b
9
8
89 (cis : trans = 1.6 : 1)
10
11
12
13
14
15
16
17
18
9
63 (cis : trans > 99 : 1)
10
80
DMSO PIDP
DCM PIDP
Cbzc Complex
a Carried out without BF3·Et2O. b No desired product was obtained
when the reaction was carried out in DMSO, THF or MeCN. c The
reactions of N-Bz, N-Ac and N-Boc protected amines also produced a
complex mixture.
11
12
59
59 (cis : trans > 99 : 1)
13
14
Complex mixture
Complex mixture
fluorine sources (Table 2, entries 4–9). Fortunately we found that
the aminofluorination yield increased to 35% when HF–Py was
used as a fluorinating reagent (Table 1, entry 9). The aminofluor-
ination yield increased to 85% after we increased the amount of
HF–Py to 10 eq. (Table 1, entry 13). PhI(OAc)2 and PIFA were
not as good as PIDP (Table 1, entries 15 and 16) in this pro-
cedure. When the reaction was carried out in DMSO, THF or
MeCN, no desired product was obtained (Table 1, entry 17).
Compared with N-tosyl alkene 1a that produced 85% yield, the
reactions of other protected amines such as N-Cbz, N-Bz, N-Ac
and N-Boc produced a complex mixture (Table 1, entry 18).
The scope of the aminofluorination reaction was also investi-
gated under optimized conditions (Table 2).
Substrate 1b, without a substituent at the β-carbon of the
alkene, underwent an intramolecular aminofluorination to form
the corresponding product in an excellent yield, while substrate
1c with two phenyl groups at the β-carbon formed the corre-
sponding product in a slightly lower yield. Gratifyingly, the
monosubstituted product 2d in sole cis configuration was
obtained under the standard conditions in 81% yield (Table 2,
entries 2–4). Substrates 1e, 1f and 1g bearing a methylphenyl
group at the β-carbon exhibited lower reactivity to furnish pro-
ducts 2e, 2f and 2g, but maintained the high stereoselectivity
(Table 2, entries 5–7). Substrate 1h with one phenyl group and
one methyl group at the β-carbon afforded product 2h in 89%
yield with a 1.6 : 1 (cis : trans) isomer ratio (Table 2, entry 8).
Substrate 1i with a benzyl group at the β-carbon produced 2i in
15
33 (2o : 2p = 9.3 : 1)c
a Reactions were conducted at 0.25 mmol scale. b Isolated yield (the ratio
of diastereoselectivity was determined by 19F NMR). c Products 2o and
2p cannot be separated by column chromatography on silica gel.
63% yield with excellent stereoselectivity (Table 2, entry 9). The
spiro-product 2j was obtained in 80% yield (Table 2, entry 10).
The intramolecular aminofluorination of internal olefins 1m and
1n were unsuccessful (Table 2, entries 13 and 14); however, sub-
strates 1k and 1l with disubstituted terminal olefin produced 2k
and 2l in 59% yield (Table 2, entries 11 and 12). Lastly, the reac-
tion of 1o, which has one extra carbon between the amine and
the olefin, provided a mixture of regioisomers 2o and 2p in a
9.3 : 1 ratio, indicating that the reaction favored the 7-endo ring
closure (Table 2, entry 15).
Based on the reaction mechanism of PhI(OAc)2/TFA mediated
intramolecular aminotrifluoroacetoxylation of alkenes,5 two
possible pathways are proposed for the aminofluorination reac-
tion (Scheme 3). For pathway (a), the alkene is oxidized first to
generate an iodonium ion A. This intermediate is
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Scheme 4 Intramolecular aminopivaloylation of alkenes mediated by
PhI(OPiv)2/BF3·Et2O system.
In conclusion, we developed a highly regioselective and
stereoselective metal-free method for the intramolecular oxi-
dative aminofluorination of unactivated terminal alkenes, in
which HF–Py acted as the fluorine source in the presence of PhI
(OPiv)2 and BF3·Et2O. Without the use of metal reagents, this
new transformation represents an efficient method for the prep-
aration of fluorine containing cyclic amines.
This work was supported by grants from the National Basic
Research Program of China (Grant No. 2012CB822100) and the
National Natural Science Foundation of China (NSFC No.
21072017, 21072016, 20972012).
Notes and references
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Scheme 3 Possible mechanism of PhI(OPiv)2/BF3·OEt2 mediated
aminofluorination of alkenes.
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intramolecularly attacked by the sulfonamide nitrogen to form
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In order to understand the reaction mechanism further, we
carried out the reaction without the hydrogen fluoride–pyridine.
The substrate 1d underwent intramolecular aminopivaloylation
to provide the corresponding cis product 3 in 64% yield, indicating
a similar mechanism as the aminofluorination reaction. When the
aminopivaloylation product 3 was treated with HF–Py, no reaction
was observed. This phenomenon ruled out the aminopivaloxylation
product as an intermediate in the reaction (Scheme 4).
8568 | Org. Biomol. Chem., 2012, 10, 8566–8569
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8566–8569 | 8569