Regio- and enantioselective aminofluorination of alkenes

Article abstract of DOI:10.1002/anie.201208471

Enantio- and regioselective: The intramolecular enantioselective aminofluorination of unactivated olefins was achieved by using a chiral iodo(III) difluoride salt. A highly regioselective aminofluorination of styrenes to access 2-fluoro-2-phenylethanamines was also developed. Copyright

Full text of DOI:10.1002/anie.201208471

Angewandte
Chemie
DOI: 10.1002/anie.201208471
Asymmetric Synthesis
Regio- and Enantioselective Aminofluorination of Alkenes**
Wangqing Kong, Pascal Feige, Teresa de Haro, and Cristina Nevado*
À
Compounds containing a C F bond present improved
properties (i.e. hydrophobicity, solubility, metabolic stability)
Initially, we studied the reaction of N-tosyl-2,2-diphenyl-
4-pentenyl amine (1a) with
a
catalytic amount of
compared to their corresponding C H counterparts, thus
[(Ph3P)AuNTf2] in the presence of Selectfluor (4).[17] The
starting material was partially converted into a complex
mixture of products, but the desired fluoropiperidine 2a could
not be detected (Table 1, entry 1). Inspired by the Pd-
À
explaining why approximately 25% of the current preclinical
drugs contain at least one fluorine atom.[1,2] In this context,
molecules that contain a vicinal aminofluorine moiety play
a relevant role, as they constitute key building blocks for the
synthesis of anticancer,[3] anticholinergic, and anti-inflamma-
tory drugs,[4] as well as therapeutic b-peptides.[5] However, in
spite of their importance, few methods are currently available
to generate b-aminofluorinated compounds,[6] particularly in
a stereocontrolled manner. Organocatalysis has been applied
in this context[7] although reactivity always relies on the a-
fluorination of carbonyl compounds through their enol
forms.[8] Recently, Lewis base[9] and anionic phase-transfer[10]
catalysts in combination with Selectfluor have been success-
fully employed in the stereocontrolled fluorination of nitro-
gen-containing activated olefins, such as indoles and enam-
ides, respectively. The Ritter-type amidofluorination of sty-
renes is a prototype example of the use of electrophilic
fluorine sources (e.g. Selectfluor) to activate alkenes towards
the attack of nitrogen-nucleophiles, although the reaction
scope is rather limited.[11] Other metal-free methods have also
been recently developed for the intramolecular aminofluori-
nation of unactivated olefins.[12] In addition, palladium
catalysis in combination with strong oxidants has been
successfully applied in both the intra- and intermolecular
aminofluorination of alkenes.[13] These processes rely on the
Table 1: Discovery and optimization of the intramolecular metal-free
aminofluorination of pentenamines.[17]
Entry Conditions
Product
ee
(yield [%])[a] [%][b]
[c]
1
2
[(Ph3P)AuNTf2] (5 mol%), 4 (2 equiv),
–
MeNO2, 808C, 17 h
[(Ph3P)AuNTf2] (5 mol%),
PhI(OPiv)2 (2 equiv), AgF (2 equiv),
MeNO2, 808C, 17 h
PhI(OAc)2 (2 equiv), TBAF (2 equiv),
NaHCO3 (1 equiv), CH3CN, 808C, 17 h
[(Ph3P)AuNTf2] (5 mol%), 5 (2 equiv),
MeNO2, 808C, 1.5 h
3a
1a
–
3
4
–
–
2a/3a
1:1[d]
5
6
7
8
9
10
5 (2 equiv), CH2Cl2, M.S. (4 ꢀ), 258C, 17 h 2a (93)
(R,R)-6a (2.5 equiv), CH2Cl2, 258C, 17 h 2a (76)
–
56
(R,R)-6a (2.5 equiv), toluene, 258C, 17 h 2a (62)
(R,R)-6b (2.5 equiv), toluene, 258C, 17 h 2a
(R,R)-6c (2.5 equiv), toluene, 258C, 17 h 2a (70)
(R,R)-6d (2.5 equiv), toluene, 258C, 17 h 2a (71)
67
45
62
81 (99)
oxidation of PdII to PdIV species to facilitate the C F bond
À
formation.[14] However, to the best of our knowledge, an
asymmetric variant of these transformations is not yet
reported.
[a] The value in brackets is the yield after column chromatography on
neutral alumina. [b] Determined by HPLC on a chiral stationary phase.
The value in brackets corresponds to the ee value after crystallization.
[c] A complex mixture of products was obtained together with some
recovered 1a. [d] Ratio determined by 1H NMR spectroscopy.
Our group has recently combined the unique carbophi-
licity of gold complexes with Selectfluor to trigger the
[15]
À
formation of Csp3 and Csp2 F bonds.
In addition we
showed that gold can catalyze the selective oxidative difunc-
tionalization of alkenes to give 1,2-aminoalcohols, amino-
ethers, and aminoamides.[16] We envisaged that this protocol
could also be applied to the synthesis of 1,2-aminofluoro
compounds under the right set of conditions.
M.S.=molecular sieves, Piv=trimethylacetyl, TBAF=tetrabutylammo-
nium fluoride, Tf=trifluoromethanesulfonyl, Ts=p-toluenesulfonyl.
[*] Dr. W. Kong, P. Feige, T. de Haro, Prof. Dr. C. Nevado
Organic Chemistry Institute, Universitꢁt Zꢂrich (Switzerland)
E-mail: nevado@oci.uzh.ch
[**] The European Research Council (ERC Starting grant agreement no.
307948), the Forschungskredit of the University of Zꢂrich, and the
Novartis Foundation are kindly acknowledged for financial support.
Prof. Anthony Linden is kindly acknowledged for performing the X-
ray crystal structure determination of (R)-2a (CCDC 905602) and
(S)-8 a (CCDC 905603).
catalyzed alkene aminofluorination reported by Liu and co-
workers,[13] we attempted the reaction in the presence of
PhI(OPiv)2 as oxidant and silver fluoride as external source of
fluorine. In this case, aminoalcohol 3a was obtained, probably
owing to the presence of adventitious water in the reaction
(Table 1, entry 2). We then decided to use a phenyl difluoro-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208471.
Angew. Chem. Int. Ed. 2013, 52, 2469 –2473
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2469

.
Angewandte
Communications
Table 2: Scope of the metal-free intramolecular aminofluorination
iodonium salt generated in situ by treatment of phenyliodo-
diacetate with TBAF. However, only starting material was
recovered (Table 1, entry 3). As PhIF2 is unstable, we decided
to investigate the ability of a more stable analogue.[18]
Iodoarene difluorides are well-recognized fluorinating
agents of alkenes,[19] alkynes,[20] and ketones[21] and have
only been used with moderate success in fluorocyclizations of
alcohols and carboxylic acids in the presence of additional
amine-HF complexes.[22] When p-xylene-iodoniumdifluoride
(5) was used under the reaction conditions shown in entry 4,
we observed, for the first time, the formation of amino-
fluorination product 2a together with alcohol 3a. A control
experiment in the absence of gold and in the presence of
molecular sieves (4 ꢀ) in dichloromethane at room temper-
ature, showed the clean formation of the b-fluorinated
piperidine 2a, which could be isolated in 93% yield
(Table 1, entry 5).
Notably, the reaction was highly regioselective affording
exclusively the 6-endo-cyclization product. Inspired by the
widespread use of chiral iodine(III) reagents,[23] and their
recent successful application to the asymmetric functionali-
zation of alkenes,[24] we decided to target an enantioselective
version of this aminofluorocyclization. After some experi-
mentation,[17] we found that the use of (R,R)-dimethyl lactate
based hypervalent iodine (R,R)-6a afforded b-piperidine 2a
in 76% yield and 56% ee without the need of exhaustive
anhydrous conditions (Table 1, entry 6). A slight increase in
selectivity (67% ee) was observed when toluene was used as
solvent (Table 1, entry 7). Oxidants (R,R)-6b and (R,R)-6c,
bearing an iso-propyl and a 2,5-dimethylphenyl lactate unit,
respectively, were tested but significant improvement in the
selectivity was not achieved (Table 1, entries 8 and 9).
Notably, the reaction of (R,R)-tert-butyl lactate iododifluor-
ide ((R,R)-6d) gave 2a in 71% yield with a significantly
enhanced enantiomeric excess of 81%. Upon recrystalliza-
tion, enantiomerically pure fluoropiperidine 2a was obtained.
The structure of (R)-2a was unequivocally assigned by X-Ray
diffraction analysis.[25] It is worth mentioning that, although
2.5 equivalents of the chiral oxidant were used, 50–60% of the
corresponding iodide precursor with the initial enantiomeric
purity (99% ee) is recovered from the reaction mixture. To
the best of our knowledge, our discovery not only represents
one of the first examples of metal-free aminofluorination of
nonactivated alkenes[12] but also the first breakthrough in the
development of an asymmetric version of these highly
demanded transformations.
reaction.[a]
Entry
Substrate: R, R1, R2[b]
Product
ee [%][d]
(Yield [%])[c]
1
2
3
4
5
6
7
8
1a: R=Ts, R1 =Ph
(S)-2a (79)
(R)-2b (72)
(R)-2c (72)
(S)-2d (75)
(S)-2e (76)
(S)-2 f (75)
(S)-2g (69)
(S)-2h (73)
(S)-2i (69)
(S)-2j (63)
(S)-2k (70)
2l (71)[g]
81 (99)
67 (90)
79 (>99)
77 (93)
76 (99)
61 (98)[e]
69[f]
1b: R=o-MeC6H4SO2, R1 =Ph
1c: R=m-MeC6H4SO2, R1 =Ph
1d: R=PhSO2, R1 =Ph
1e: R=p-OMeC6H4SO2, R1 =Ph
1 f: R=MeSO2, R1 =Ph
1g: R=Cbz, R1 =Ph
1h: R=Ts, R1 =o-MeC6H4
1i: R=Ts, R1 =p-MeC6H4
1j: R=Ts, R1 =p-OMeC6H4
1k: R=Ts, R2 =Me
88
9
74 (98)
72 (99)
66
–
–
10
11
12
13
14
1l: R=Ts, R1 =Ph, H
1m: R=Ts, R1 =Me[h]
2m (90)
1n: R=Ns, R1 =Me[h]
2n (64)[i]
–
15
2o (84)
–
[a] Reaction conditions: Same as Table 1, entry 10 with either (R,R)-6d or
(S,S)-6d. Product configuration is indicated. [b] Unless otherwise stated
Rx =H. [c] Yield after column chromatography on alumina. [d] Deter-
mined by HPLC on a chiral stationary phase. The value in brackets
corresponds to the ee value after crystallization. [e] Reaction performed
in chlorobenzene as solvent. [f] The ee value was determined upon Cbz
removal and conversion into 2a. [g] The cis/trans ratio of isomers was
20:1. A 6:1 d.r. was obtained in the reaction of 1l with oxidant 5.
[h] Difluoride 5 was used as oxidant. [i] Reaction temperature=508C.
protected substrate (1g) proved to be amenable to the
reaction conditions as well (Table 2, entry 7). In all these
cases, high enantioselectivities (> 90% ee) were obtained
upon a single recrystallization of the products. We also
examined the effect of substituents on the backbone of the
aminopentene substrates. 2,2-Disubstituted substrates 1h–j
afforded aminofluorinated piperidines 2h–j in good yields
and selectivities (Table 2, entries 8–10). Substitution at the
C1-position of the pentenamine substrate (1k) was also
tolerated although the selectivity was slightly reduced
(Table 2, entry 11). High levels of cis-diastereoselectivity
were obtained in the reaction of 6d with substrate 1l;
a result that is in sharp contrast to previous Pd-catalyzed
examples (Table 2, entry 12).[13a] Our metal-free regioselec-
tive aminofluorination was applied to other pentenamine
substrates (Table 2, entries 13–15 and additional examples in
Table S3 of the Supporting Information); these results
showed that terminal alkenes and aromatic substituents
seem to be preferred for enantioselective induction.[17]
We then set out to explore the scope of this reaction
(Table 2). First, we decided to confirm that the product
configuration is defined by that of the chiral oxidant. Indeed,
(S,S)-6d afforded 2a in comparable yield but opposite
selectivity to that reported in Table 1 (Table 2, entry 1). We
then evaluated the influence of the N-protecting group in the
reaction. A series of different N-aromatic sulfonamides 1b–
e were converted into the corresponding b-fluoropiperidines
2b–e in high yields, with complete regioselectivity and good
levels of asymmetric induction (Table 2, entries 2–5). An N-
methylsulfonamide substrate (1 f) was also converted into the
corresponding aminofluorinated product 2 f with moderate
enantioselectivity (Table 2, entry 6). A carbobenzyloxy (Cbz)
Owing to the widespread presence of azepane scaffolds in
natural products as well as in synthetic bioactive molecules,
we envisioned the extension of this method to the stereocon-
trolled synthesis of b-fluorinated azepane heterocycles
(Table 3). N-(2,2-Diphenylhex-5-enyl)-4-tosyl amide 7a was
selected as benchmark substrate. To our surprise, under the
2470 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2469 –2473

Angewandte
Chemie
Table 3: Optimization of the intramolecular aminofluorination of hexenamines.[17]
conditions from Table 1 (entry 5) to
afford [D]-trans-2a and [D]-cis-2a,
respectively, as single diastereoiso-
mers (Scheme 1).[26] In addition,
N,N-tosylmethyl and N,N-tosyl-
fluoro-2,2-dimethyl-4-pentenyl
amines 9 and 10 proved to be
unreactive under the standard reac-
tion conditions.
Entry
Substrate
Conditions
Product
ee [%][b]
(yield [%])[a]
Based on these results, the fact
that no 5-exo products were
detected, and the observation of
a faster reaction rate for the N-tosyl
substrates compared to the N-nosyl
one (Table 2, entries 13 vs. 14), we
1
2
3
4
5
6
7
8
9
10
7a
toluene, RT, 7 days
7a
–
R=Ts, R1 =Ph
7a
[(Ph3P)AuNTf2] (5 mol%),
CH2Cl2, RT, 2 days
HNTf2 (5 mol%), CH2Cl2,
RT, 1 day
AgNTf2(5 mol%), CH2Cl2,
RT, 7 days
[2-PicAuNTf2] (5 mol%),
RT, CH2Cl2, 2 days
[2-PicAuNTf2] (5 mol%),
RT, CH2Cl2, 2 days
[2-PinAuNTf2] (5 mol%),
RT, CH2Cl2, 2 days
[2-PicAuNTf2] (5 mol%),
RT, CH2Cl2, 2 days
[2-PicAuNTf2] (5 mol%),
RT, CH2Cl2, 4 days
8a (46)
61
[c]
7a
7a
7a
–
[c]
–
propose
a
reaction mechanism
involving the oxidation of the sul-
fonamide in the first step
(Scheme 2, path A) rather than an
oxidation of the alkene (i.e. via
8a (62)
8b (59)
8c (60)
8d (61)
8e (50)
8 f (64)
73 (99)
76 (91)
77 (99)
77 (98)
75 (99)
72 (98)
7b
R=m-MeC6H4SO2, R1 =Ph
cyclopropyl
iodonium
salt,
7c
path B).[24d] The lack of reactivity
of 9 and 10 strongly suggests that
activation of the aryliododifluoride
reagent with the amine by H-bond-
ing precedes the ligand exchange on
the iodine(III) atom (intermediate
I).[19,27] The aminofluoro iodonium
intermediate II then reacts with the
olefin to give aziridinium inter-
R=p-OMeC6H4SO2, R1 =Ph
7d
R=PhSO2, R1 =Ph
7e
R=Ts, R1 =m-MeC6H5
7 f
[2-PicAuNTf2] (5 mol%),
RT, CH2Cl2, 4 days
R=Ts, R1 =p-MeC6H5
[a] Yield after column chromatography on neutral alumina. [b] Determined by HPLC on a chiral
stationary phase. The value in brackets corresponds to the ee value after crystallization. [c] A complex
mixture of products was obtained. Pic=2-pyridinecarboxylato.
conditions used in Table 2, no conversion of the starting
material was observed even after prolonged reaction times
(Table 3, entry 1). We hypothesized that the 7-endo-trig cy-
clization might be a less favorable process, and thus the
addition of a Lewis acid could facilitate the activation of the
olefinic moiety.[17] Pleasingly,
a
catalytic amount of
[(Ph3P)AuNTf2] was able to trigger the desired transforma-
tion to produce azepane 8a in 46% yield and 61% ee
(Table 3, entry 2). Control experiments with AgNTf2 and
HNTf2 showed the need of gold for a successful transforma-
tion
(Table 3,
entries 3–4).
Dichloro(pyridine-2-
carboxylato)gold(III) complex in combination with AgNTf2
proved to efficiently transform 7a into 8a with an increased
the enantiomeric excess of 73% ee (Table 3, entry 5). Upon
crystallization, the absolute configuration of enantiopure
fluoroazepane 8a was established to be S by X-Ray diffrac-
tion analysis.[25] As in the case of the penteneamine substrates,
variations in the protecting group on the nitrogen atom
(Table 3, entries 6–8) and on the substrate backbone
(entries 9–10) were well-tolerated, so that the corresponding
b-fluoroazepanes were obtained in synthetically useful yields
and high enantiomeric purity upon crystallization of the
reaction products.
Scheme 1. Control experiments. For the reaction conditions see
Table 1, entry 5.
mediate III, which undergoes nucleophilic attack by fluoride
onto the more substituted carbon atom to give the endo
cyclized products with anti selectivity.[28] The slower reaction
observed for N-nosyl-substituted substrate 1n versus the N-
tosyl-substituted 1m, strongly suggests that the nucleophilic
attack of the nitrogen atom onto the olefin in II leading to III
is the critical step in the reaction rather than the formation of
I, which would be favored in the case of 1n owing to the better
To gain a deeper insight into the mechanism of these
transformations the following control experiments were
designed. First, deuterium labelled alkenes [D]-E- and [D]-
Z-1a were prepared and subjected to the optimized reaction
À
H-bond donor properties of the nosyl-substituted N H bond.
Angew. Chem. Int. Ed. 2013, 52, 2469 –2473
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2471

.
Angewandte
Communications
Table 4: Scope of the metal-free intermolecular aminofluorination
reaction.
Entry Conditions[a] Product: R1, R2, R3, R4
Yield
[%][b,c]
1
2
3
4
5
6
7
8
A
B
B
B
B
B
B
B
B
B
B
11a: R1 =R2 =H, R3 =Ts, R4 =Me
11a: R1 =R2 =H, R3 =Ts, R4 =Me
11b: R1 =CF3, R2 =H, R3 =Ts, R4 =Me
11c: R1 =F, R2 =H, R3 =Ts, R4 =Me
11d: R1 =Cl, R2 =H, R3 =Ts, R4 =Me
11e: R1 =Br, R2 =H, R3 =Ts, R4 =Me
11 f: R1 =H, R2 =CF3, R3 =Ts, R4 =Me
11g: R1 =H, R2 =F, R3 =Ts, R4 =Me
11h: R1 =H, R2 =CH3, R3 =Ts, R4 =Me
11i: R1 =H, R2 =H, R3 =Ts, R4 =H
11j: R1 =F, R2 =H, R3 =p-MeOC6H4SO2,
R4 =Me
52[d]
77
68
68
66
66
72
70
Scheme 2. Mechanistic proposal. PG=protecting group.
In line with this hypothesis, an intermolecular reaction
with a monosubstituted olefin should deliver the fluoro group
onto the internal carbon atom of the alkene. Such a regiose-
lective reaction would provide access, for the first time, to 2-
fluoro-2-phenylethanamines if styrenes were used as sub-
strates. This class of compounds is currently not accessible,
because previously reported electrophilic amidofluorinations
of alkenes (metal or nonmetal catalyzed) provide 2-fluoro-1-
phenylethanamines as a result of the carbocation stabilization
at the benzylic position.[11,13] The realization of this hypothesis
is summarized in Table 4. Mixing styrene and N-methyl-N-4-
methylbenzenesulfonamide in a 2:1 ratio in the presence of
2 equivalents of iododifluoride 5 at 408C for two hours
afforded the aminofluorinated product 11a in 52% yield
(71% based on recovered starting material) together with
diamination product 12a in 12% yield (Table 4, entry 1). By
increasing the amount of styrene we were able to isolate the
desired fluoroaminated product in 77% yield, and the excess
of styrene could be almost completely recovered at the end of
the reaction (Table 4, entry 2). 4-Trifluoromethyl, 4-fluoro, 4-
chloro, and 4-bromo styrenes were transformed into the
corresponding aminofluorinated products 11b–e in good
yields under the reaction conditions (Table 4, entries 3–6).
Both, electron-withdrawing and electron-donating groups
were tolerated at the 3-position of the aromatic ring as
shown by examples summarized in entries 7 and 8.[29] Inter-
estingly, the reaction of 3-methylstyrene gave the desired
aminofluorinated product 11h together with aziridinium
intermediate 13,[30] thus supporting the mechanistic proposal
outlined in Scheme 2. We then decided to explore the
substitution pattern on the amine counterpart by studying
reactions with 1-fluoro-4-vinylbenzene. Under the optimized
reaction conditions, a tosylamide afforded the product in 11i
in 53% yield (77% yield based on recovered starting
material; Table 4, entry 10). 4-Methoxy-N-methylbenzenesul-
fonamide and N-methylmethanesulfonamide afforded the
corresponding aminofluorinated products 11j and 11k in 80
and 68% yield, respectively (Table 4, entries 11 and 12).
Diamination products 12 might arise from the competitive
ring opening of the aziridinium III with free amine still
present in the reaction media, as previously reported by
MuÇiz and co-workers.[24d]
9
10
11
80
53[e]
80
12
B
11k: R1 =F, R2 =H, R3 =SO2Me, R4 =Me 68
[a] Conditions A: Alkene (2 equiv), amine (1 equiv), CH2Cl2, M.S. (4 ꢀ),
608C, 2 h; conditions B: Alkene (6 equiv), amine (1 equiv), CH2Cl2, M.S.
(4 ꢀ), 608C, 17 h. [b] Yield of 11 after column chromatography on neutral
alumina; [c] Diamines 12a–g were isolated in less than 15% yield.
[d] 71% yield based on recovered starting material. [e] 77% yield based
on recovered starting material.
of unactivated alkenes by using difluoroiodonium salts. In
chiral form, these species provide access, for the first time, to
2-fluoropiperidines and azepanes in enantiomerically pure
form. In addition, an intermolecular regioselective metal-free
aminofluorination of styrenes has been developed enabling
the synthesis of unprecedented 2-fluoro-2-phenylethan-
amines. This regioselective reaction nicely complements the
previously available amidofluorination methods, which pro-
vide 2-fluoro-1-phenylethanamines, while expanding the
scope on the amine counterpart, thus reflecting the synthetic
utility of this method. Efforts towards an asymmetric variant
of this transformation are currently underway in our labo-
ratory.
Received: November 13, 2012
Published online: January 30, 2013
Keywords: alkenes · aminofluorination · asymmetric synthesis ·
.
fluorination · iodine(III) reagents
[1] a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reac-
tivity Applications, Wiley-VCH, Weinheim, 2004; b) I. Ojima,
Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-
Blackwell, Chichester, 2009.
[2] S. Purser, P. R. Moore, S. Swallow, V. Governeur, Chem. Soc.
Rev. 2008, 37, 320 – 330.
[3] C. D. Cox et al., J. Med. Chem. 2008, 51, 4239 – 4252.
[4] J. T. Welch, S. Eswarakrishman, Fluorine in Bioorganic Chemis-
try, Wiley, New York, 1991.
In summary, we report here the first example of an
intramolecular, metal-free regioselective aminofluorination
[5] D. Seebach, et al., Helv. Chim. Acta 2008, 91, 1736 – 1786.
[6] J. M. Percy, Sci. Synth. 2005, 34, 379 – 416.
2472
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2469 –2473

Angewandte
Chemie
[7] a) O. O. Fadeyi, C. W. Lindsley, Org. Lett. 2009, 11, 943 – 946;
b) M. L. Schulte, C. W. Lindsley, Org. Lett. 2011, 13, 5684 – 5687;
c) C. Appayee, S. E. Brenner-Moyer, Org. Lett. 2010, 12, 3356 –
3359.
[8] a) T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Naka-
mura, T. Toru, M. Shiro, Angew. Chem. 2008, 120, 4225 – 4229;
Angew. Chem. Int. Ed. 2008, 47, 4157 – 4161; b) P. M. Marigo, D.
Fielenbach, A. Braunton, A. Kjaersgaard, K. A. Jorgensen,
Angew. Chem. 2005, 117, 3769 – 3772; Angew. Chem. Int. Ed.
2005, 44, 3703 – 3706; c) P. Kwiatkowski, T. D. Beeson, J. C.
Conrad, D. W. C. MacMillan, J. Am. Chem. Soc. 2011, 133, 1738 –
1741.
[9] O. Lozano, G. Blessley, T. Martinez del Campo, A. L. Thomp-
son, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V.
Governeur, Angew. Chem. 2011, 123, 8255 – 8259; Angew. Chem.
Int. Ed. 2011, 50, 8105 – 8109.
[10] a) T. Honjo, R. J. Phipps, V. Rauniyar, F. D. Toste, Angew. Chem.
2012, 124, 9822 – 9826; Angew. Chem. Int. Ed. 2012, 51, 9684 –
9688; b) R. J. Phipps, K. Hiramatsu, F. D. Toste, J. Am. Chem.
Soc. 2012, 134, 8376 – 8379.
[11] a) S. Stavber, T. S. Pecan, M. Papez, M. Zupan, Chem. Commun.
1996, 2247 – 2248; b) J. S. Yadav, B. V. S. Reddy, D. N. Chary, D.
Chandrakanthm, Tetrahedron Lett. 2009, 50, 1136 – 1138.
[12] During the preparation of this manuscript, a metal-free amino-
fluorination of unactivated alkenes using PhI(OPiv) and FÀ was
reported: Q. Wang, W. Zhong, X. Wei, M. Ning, X. Meng, Z. Li,
Org. Biomol. Chem. 2012, 10, 8566 – 8569.
[13] a) T. Wu, G. Yin, G. Liu, J. Am. Chem. Soc. 2009, 131, 16354 –
16355; b) S. Qui, T. Xu, J. Zhou, Y. Guo, G. Liu, J. Am. Chem.
Soc. 2010, 132, 2856 – 2857.
[20] a) M. Yoshida, D. Nagahara, T. Fukuhara, N. Yoneda, S. Hara, J.
Chem. Soc. Perkin Trans. 1 2001, 2283 – 2288; b) P. Conte, B.
Panuzi, M. Tingoli, Tetrahedron Lett. 2006, 47, 273 – 276.
[21] S. Sato, M. Yoshida, S. Hara, Synthesis 2006, 2602 – 2605.
[22] M. Sawaguchi, S. Hara, T. Fukuhara, N. Yoneda, J. Fluorine
Chem. 2000, 104, 277 – 280.
[23] For a review, see: a) M. Ngatimin, D. W. Lupton, Aust. J. Chem.
2010, 63, 653 – 658; for selected examples, see: b) T. Dohi, A.
Maruyama, N. Takenaga, K. Senami, Y. Minamitsuji, H. Fujioka,
S. B. Caemmerer, Y. Kita, Angew. Chem. 2008, 120, 3847 – 3850;
Angew. Chem. Int. Ed. 2008, 47, 3787 – 3790; c) M. Uyanik, T.
Yasui, K. Ishihara, Angew. Chem. 2010, 122, 2221 – 2223; Angew.
Chem. Int. Ed. 2010, 49, 2175 – 2177.
[24] For a review, see: a) G. F. Koser, Top. Curr. Chem. 2000, 208, 137;
for selected examples, see: b) M. Fujita, Y. Yoshida, K. Miyata,
A. Wakisaka, T. Sugimura, Angew. Chem. 2010, 122, 7222 – 7225;
Angew. Chem. Int. Ed. 2010, 49, 7068 – 7071; c) A. Y. Koposov,
V. V. Boyarskikh, V. V. Zhdankin, Org. Lett. 2004, 6, 3613 – 3615;
d) M. Fujita, W. Wakita, T. Sugimura, Chem. Commun. 2011, 47,
3983 – 3985; e) C. Rçben, J. A. Souto, Y. Gonzꢂlez, A. Lish-
chynskyi, K. MuÇiz, Angew. Chem. 2011, 123, 9650 – 9654;
Angew. Chem. Int. Ed. 2011, 50, 9478 – 9482; f) U. Farid, T.
Wirth, Angew. Chem. 2012, 124, 3518 – 3522; Angew. Chem. Int.
Ed. 2012, 51, 3462 – 3465.
[25] CCDC 905602 ((R)-2a) 905603 ((S)-8a) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[26] Relative configuration was assigned based on NOE analysis. See
Ref. [17] and Ref. [13a].
[14] a) K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc.
2006, 128, 7134 – 7135; b) T. Furuya, H. M. Kaiser, T. Ritter,
Angew. Chem. 2008, 120, 6082 – 6085; Angew. Chem. Int. Ed.
2008, 47, 5993 – 5996; c) D. A. Watson, M. Su, G. Teverovskiy, Y.
Zhang, J. Garcꢁa-Fortanet, T. Kinzel, S. L. Buchwald, Science
2009, 325, 1661 – 1664.
[15] a) T. de Haro, C. Nevado, Adv. Synth. Catal. 2010, 352, 2767 –
2772; b) T. de Haro, C. Nevado, Chem. Commun. 2011, 47, 248 –
249.
[27] As shown in Ref. [19], the activation of the iodonium difluoride
salt can also be carried out by the HF-amine complex that was
generated in the first step of the reaction.
[28] The role of gold in the reaction of hexenamines is not entirely
clear, but we hypothesized that it might affect the conformation
of the substrate upon coordination to the olefin enabling the
formation of an aziridinium intermediate related to III.
[29] 4-Methoxystyrene underwent decomposition
under these conditions. For further examples,
[16] T. de Haro, C. Nevado, Angew. Chem. 2011, 123, 936 – 940;
Angew. Chem. Int. Ed. 2011, 50, 906 – 910.
[17] For further examples and detailed information, see the Support-
ing Information.
see Ref. [17].
[30] Compound 13 could be characterized by
1H NMR spectroscopy and HRMS–ESI. See
Ref. [17].
[18] C. Ye, B. Twamley, J. M. Shreeve, Org. Lett. 2005, 7, 3961 – 3964.
[19] S. Hara, J. Nakahigashi, K. Ishi-i, M. Sawaguchi, H. Sakai, T.
Fukuhara, N. Yoneda, Synlett 1998, 495 – 496.
Angew. Chem. Int. Ed. 2013, 52, 2469 –2473
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2473