Palladium-catalyzed intramolecular aminofluorination of unactivated alkenes

Article abstract of DOI:10.1021/ja9076588

(Chemical Equation Presented) A novel palladium-catalyzed intramolecular oxidative aminofluorination of unactivated alkenes has been developed, in which AgF was used as a key fluorinating reagent and PhI(OPiv)₂ as oxidant. The reaction afforded

Full text of DOI:10.1021/ja9076588

Published on Web 10/26/2009
Palladium-Catalyzed Intramolecular Aminofluorination of Unactivated Alkenes
Tao Wu, Guoyin Yin, and Guosheng Liu*
State Key Laboratory of Organometallics Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Science, 354 Fenglin Road, Shanghai, China, 200032
Received September 9, 2009; E-mail: gliu@mail.sioc.ac.cn
Molecules bearing a vicinal aminofluorine moiety have been extensively
used as important building blocks for anticholinergic, antiemetic, and
antispastic drugs as well as enzyme inhibitors.1 However, very few
effective approaches are available for the synthesis of these fluorinated
molecules, and transition metal catalyzed methods are particularly rare.2,3
Several groups recently described methods for Pd-catalyzed fluorination
of aromatic compounds,4,5 in which the formation of C-F bonds have
been demonstrated via Pd(II/IV) catalytic cycles, involving oxidative
addition of Pd(II) to F+ reagents (Scheme 1).4a-d For instance, Sanford4a
and Yu4b have reported the use of 1 as an F+ source in the directed
fluorination of C-H bonds, and Ritter has explored the stoichiometric
fluorination of arylboronates with 2 (Scheme 1).5a Meanwhile, similar
Pd(II/IV) catalytic cycles have been successfully employed to achieve
palladium-catalyzed difunctionalization of olefins,6 such as aminooxy-
genation,7 diamination,8 and chloroamination,9 which provide versatile
strategies to prepare molecules with vicinal amino-heteroatom function-
alities. We reasoned that if F+ reagents, such as 1 and 2, were used as an
oxidant, an aminofluorination product could be expected (Scheme 2, top).
The same strategies have been studied using N-fluorobenzenesulfonimide
(NFSi) as an oxidant by Michael and co-workers; however, the reaction
exclusively afforded diamination8c or carboamination10 products (Scheme
2A). Here, we describe a novel and highly regioselective palladium-
catalyzed intramolecular aminofluorination of alkenes using AgF as the
fluorinating reagent in the presence of PhI(OPiv)2 (Scheme 2B).
to be the best oxidant, affording 4a in 77% yield (entry 6). An
aminocarboxylation side reaction generates small amounts of 5b. No
aminofluorination product was observed in the absence of I(III) oxidants
(entry 9). Furthermore, other strong oxidants, such as oxone, NCS, and
Table 1. Palladium-Catalyzed Intramolecular Aminofluorination of
Alkene 1aa
yield (%)b
entry
[Pd]
[O] (2 equiv)/MF (2.5 equiv)
4a
5c
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
--
1
0
0
0
--
--
--
--
2
NFSif
PhIF2
0
PhI(OAc)2/AgF
PhI(OCOtBu)2/AgF
PhI(OCOCF3)2/AgF
PhI(OCOPh)2/AgF
-- /AgF
Oxone/AgF
NCS/AgF
H2O2/AgF
38
77
0
34
0
0
0
0
69
0
24 (5a)
17 (5b)
40 (5c)
40 (5d)
--
--
--
--
25 (5b)
0 (5b)
20 (5b)
9 (5b)
20 (5b)
0 (5b)
10 (5b)
9d
10
11
12
13e
14
15
16
17
18
19d
PhI(OCOtBu)2/AgF
PhI(OCOtBu)2/AgF
PhI(OCOtBu)2/AgF
PhI(OCOtBu)2/AgF
PhI(OCOtBu)2/AgF
PhI(OCOtBu)2/Bu4NF
PhI(OCOtBu)2/AgF
Scheme 1. Palladium-Catalyzed Fluorination of Arenes via Pd(IV)F
Complexes
PdCl2
65
33
45
0
Pd(OCOCF3)2
PdCl2(CH3CN)2
Pd(OAc)2
Pd(OAc)2
86
a Reaction condition: 3a (0.1 mmol), [Pd] (0.01 mmol), AgF (0.25 mmol),
[O] (0.2 mmol), MgSO4 (50 mg) in 0.5 mL of CH3CN at room temperature.
b
1H NMR yield with 1,3,5-trimethoxybenzene as internal standard. c 5a:
R ) Me, 5b: R ) Bu, 5c: R ) CF3, 5d: R ) Ph. d AgF (5 equiv).
t
e Without MgSO4. f NFSi ) N-fluorodibenzene-sulfonimide.
Scheme 2. Hypthesis of Palladium-Catalyzed Aminofluorination of
Alkenes
H2O2, failed to result in product 4a (entries 10-12). The additive of
MgSO4 is helpful to increase the yield of 4a (entry 13). Control
experiments indicated that no reaction occurred in the absence of Pd
catalyst (entry 14). Among the palladium sources tested, Pd(OAc)2 was
the most effective catalyst (entries 6, 15-17). Screening of fluoride salts
indicated that AgF is the only efficient reagent (entry 18).11 Finally, the
highest yield (86%) was obtained with 5 equiv of AgF (entry 19).
Under standard conditions, the substrate scope of the aminofluorination
reaction was then investigated (Table 2). Compared to N-tosyl alkene 3a
with an 84% yield, the reaction of N-nosyl alkene 3b gave 4b in a slightly
lower yield, and N-Boc alkene 3c did not achieve aminofluorinaton (entries
1-3). The reactions of 3d and 3e still afforded products 4d and 4e in
80% and 83% yields, respectively (entries 4-5). Subtrates 3f and 3g, with
one substituent in the ꢀ-carbon position, underwent intramolecular
aminofluorination to afford the corresponding products with moderate to
good yields but poor diastereoselectivity (entries 6-7). The spiro-product
4h could be obtained under the standard conditions (entry 8). Furthermore,
substrates 3i and 3j bearing a methyl group at the internal carbon of the
Our initial investigation focused on the reaction of amino-alkene 3a
with various F+ reagents, such as 1, 2, and NFSi, using Pd(OAc)2 as the
catalyst. However, none of the desired product was observed under such
reaction conditions (Table 1, entries 1-3). When PhIF2 was used as the
oxidant, the reaction also failed to provide desired product 4a (entry 4).
Interestingly, a significant amount of aminofluorination product 4a was
observed with high regioselectivity when AgF was used as a fluorinating
reagent in the presence of I(III) oxidants (entries 5-8); PhI(OPiv)2 proved
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16354 J. AM. CHEM. SOC. 2009, 131, 16354–16355
10.1021/ja9076588 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Possible Mechanism for Aminofluorination of Alkenes
double bond exhibited high reactivity to form aminofluorination products
4i and 4j (entries 9-10). For the cyclic aminoalkenes, the reaction of trans-
3k afforded bicyclic product 4k at 87% yield with a 4:1 3,5-trans/cis
isomer ratio (entry 11). As a comparison, the opposite diastereoselectivity
(1:5 for 3,5-trans/cis) was achieved in the reaction of cis-3k with a similar
reaction yield (entry 12). Finally, the reaction of 3m, which has one more
carbon atom tethered between the amide and alkene, provided a mixture
of regioisomers 4m and 4m′ at a 5:1 ratio, in which the reaction favors
the 7-endo ring closures (entry 13). For the 1,2-disubstituted alkene N-tosyl
(Z)-4-hexenylamine, however, the reaction only afforded an aminopalla-
dation/ꢀ-hydride elimination product, rather than an aminofluorination
product (See Supporting Information Table S2).
Table 2. Palladium-Catalyzed Intramolecular Aminofluorination of
Alkenesa
(20821002, 20872155, and 20972175), the National Basic Research
Program of China (973-2009CB825300), and the Science and Technology
Commission of the Shanghai Municipality (08PJ1411600 and 08dj1400100).
G.L. thanks Prof. Jinbo Hu at SIOC for helpful discussions.
Supporting Information Available: Detail experimental procedures
and analytical data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a Reactions were conducted at 0.2 mmol scale. b Isolated yield (the ratio
of diastereoselectivity which determined by 19F NMR). c The ratio of
trans and cis isomers. d The ratio of 3,5-trans and 3,5-cis isomers. e The
ratio of 4m:4m′.
To gain some mechanistic insight into the aminofluorination process,
deuterium-labeled alkene E-3a-d1 was subjected to the standard reaction
condition, and a successful aminofluorination afforded the mixture of trans-
4a-d1 and cis-4a-d1 in 79% yield with a 72:28 ratio (Scheme 3). A possible
catalytic cycle based on our findings is shown below: Pd(II)-mediated
trans-aminopalladation of the alkene with attack at the terminal carbon
(6-endo)12 generates a Pd(II) intermediate that undergoes an oxidation
step by PhI(OPiv)2/AgF.4c,d Reductive elimination from the Pd(IV)
intermediate generates the C-F bond, where direct reductive elimination
is favored, but competing with SN2 type nucleophilic attack by fluorine.
In conclusion, a highly regioselective palladium-catalyzed intramo-
lecular oxidative aminofluorination of unactivated alkenes was reported,
in which AgF functioned as a fluorinating reagent in the presence of
PhI(OPiv)2. This transformation represents a very efficient method to
prepare fluoro-containing cyclic amine.
Acknowledgment. This work was supported by the Chinese
Academy of Science, the National Natural Science Foundation of China
JA9076588
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