Iron(II)-Catalyzed Intermolecular Aminofluorination of Unfunctionalized Olefins Using Fluoride Ion

Article abstract of DOI:10.1021/jacs.6b07221

We herein report a new catalytic method for intermolecular olefin aminofluorination using earth-abundant iron catalysts and nucleophilic fluoride ion. This method tolerates a broad range of unfunctionalized olefins, especially nonstyrenyl olefins that are incompatible with existing olefin aminofluorination methods. This new iron-catalyzed process directly converts readily available olefins to internal vicinal fluoro carbamates with high regioselectivity (N vs F), many of which are difficult to prepare using known methods. Preliminary mechanistic studies demonstrate that it is possible to exert asymmetric induction using chiral iron catalysts and that both an iron-nitrenoid and carbocation species may be reactive intermediates.

Full text of DOI:10.1021/jacs.6b07221

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Article
Iron(II) Catalyzed Intermolecular Aminofluorination
of Unfunctionalized Olefins Using Fluoride Ion
Deng-Fu Lu, Cheng-Liang Zhu, Jeffrey D. Sears, and Hao Xu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07221 • Publication Date (Web): 16 Aug 2016
Downloaded from http://pubs.acs.org on August 16, 2016
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Journal of the American Chemical Society
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Iron(II)-Catalyzed Intermolecular Aminofluorination of Unfunctional-
ized Olefins Using Fluoride Ion
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‡
‡
Deng-Fu Lu, Cheng-Liang Zhu, Jeffrey D. Sears, and Hao Xu*
Department of Chemistry, Georgia State University, 100 Piedmont Avenue SE, Atlanta, Georgia 30303, United States
ABSTRACT: We herein report a new catalytic method for intermolecular olefin aminofluorination using earth-abundant
iron catalysts and nucleophilic fluoride ion. This method tolerates a broad range of unfunctionalized olefins, especially
non-styrenyl olefins that are incompatible with existing olefin aminofluorination methods. This new iron-catalyzed pro-
cess directly converts readily available olefins to internal vicinal fluoro carbamates with high regio-selectivity (N vs F),
many of which are difficult to prepare using known methods. Preliminary mechanistic studies demonstrate that it is pos-
sible to exert asymmetric induction using chiral iron catalysts and that both an iron-nitrenoid and carbocation species
may be reactive intermediates.
lecular aminofluorination of unfunctionalized olefins has
not yet been demonstrated. Additionally, the use of
INTRODUCTION
5
Selective incorporation of fluorine into organic mole-
cules is an emerging area with increasing importance in
organic synthesis because fluorine atoms are present in
earth-abundant iron catalysts to promote olefin amino-
fluorination with simple nucleophilic fluoride ion is desir-
6
18
able, especially considering potential applications in
F
1
numerous pharmaceuticals and biological probes. In par-
PET imaging; however, iron-catalyzed intermolecular ole-
ticular, intermolecular olefin functionalization via fluo-
rine atom transfer represents a convenient approach to
synthesize high-value building blocks with fluorine-
fin fluorination using nucleophilic fluoride remains unre-
7
ported, presumably because of the high BDE of the Fe−F
8
bond, the low solubility of iron fluoride species, and low
2
containing stereogenic centers. Among a variety of olefin
nucleophilicity of solvated fluoride ion in organic sol-
9
fluorination reactions, the intermolecular aminofluorina-
tion of unfunctionalized olefins is of great value since it
can directly convert simple olefins to vicinal fluoro prima-
ry amines which are important structural motifs in medic-
vents.
Scheme 1. Iron-catalyzed intermolecular olefin amino-
fluorination using fluoride ion
3
inal chemistry. However, development of this catalytic
reaction has been challenging; only a few methods were
reported and most of them are exclusively compatible
4
with styrenyl olefins.
Amid these discoveries, Stavber reported Ritter-type
electrophilic olefin vicinal fluoro acetamidation in ace-
tonitrile using electrophilic fluorination reagent Ac-
Herein, we report an iron-catalyzed intermolecular
aminofluorination method for a broad range of unfunc-
tionalized olefins, including non-styrenyl olefins, using
fluoride ion (Scheme 1). This new reaction readily affords
a variety of synthetically valuable vicinal fluoro carba-
mates with high regio-selectivity (N vs F), many of which
TM
cufluor NFTh, through β-fluorocarbenium intermedi-
ates, to afford terminal fluorides; however, the substrate
4
a
scope was predominately limited to styrenyl olefins. Liu
reported palladium-catalyzed styrene aminofluorination
using electrophilic NFSI, which affords terminal sulfon-
10
are difficult to prepare using existing methods. We fur-
4
b
amido fluorides; the same group later documented a
related styrene aminofluorination using AgF that provides
ther demonstrate that it is possible to modulate the enan-
tioselectivity for aminofluorination of cyclic olefins. Addi-
tionally, preliminary mechanistic studies suggest a possi-
ble new olefin aminofluorination pathway in which both
an iron-nitrenoid and carbocation species may be in-
volved in a stepwise nitrogen and fluorine atom-transfer.
4
e
internal sulfonamido fluorides.
The existing intermolecular olefin aminofluorination
methods are mechanistically illuminating; however, there
still exists significant gaps for this important transfor-
mation. First, there has yet to be developed a method for
catalytic aminofluorination of a broad range of unfunc-
tionalized olefins (especially for non-styrenyl olefins).
Next, the feasibility of asymmetric catalysis for intermo-
RESULTS AND DISCUSSION
We previously reported an iron-catalyzed method for
intramolecular olefin aminofluorination using fluoride ion
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in which iron(II)−bi-dentate ligand complexes catalyze
analysis revealed its structure as Fe(L1)
surprisingly, is inactive for styrene aminohydroxylation.
This result suggests that fluoride species may disrupt the
(BF ) , which,
2 4 2
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the reaction in the presence of Et N·3HF (Scheme 2A);
3
however, this type of catalysts were ineffective to catalyze
the intermolecular olefin aminofluorination because of
lack of reactivity (Scheme 2B). We also reported an iron-
catalyzed method for intermolecular olefin aminohydrox-
Fe(BF ) −L1 complex through iron sequestering and
4
2
therefore lead to the inactive Fe(L1) (BF ) catalyst for-
2
4 2
mation.
12
ylation using iron(II)−tri-dentate ligand complexes;
During the discovery of the aforementioned iron-
catalyzed intramolecular olefin aminofluorination, we
however, these catalysts were unable to promote the in-
termolecular olefin aminofluorination in the presence of
14
identified that electrophilic XtalFluor-E effectively sup-
Et N·3HF, possibly due to catalyst deactivation (Scheme
3
presses the competing olefin aminohydroxylation, pre-
sumably by sequestering the benzoate generated during
0
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2B). We therefore explored a range of catalysts, oxidants,
11,14
and fluorination reagents to search for a stable yet reac-
tive catalyst in the presence of the nucleophilic fluoride
ion.
the N−O bond cleavage (eq 1).
Scheme 2. Iron-catalyzed intramolecular olefin amino-
fluorination and early attempts for intermolecular olefin
aminofluorination
We also noted, through NMR titration experiments,
1
5
that XtalFluor-E and Et N·3HF may form dynamic com-
3
1
6
plexes (Scheme 4), which could attenuate the concentra-
tion of Et N·3HF and therefore significantly slow down
3
the putative fluoride-induced catalyst deactivation.
Scheme 4. Proposed complex formation from Et N·3HF
and XtalFluor-E
3
Scheme 3. Experiments to explore the putative fluoride-
induced catalyst deactivation
Table 1. Catalyst discovery for the intermolecular olefin
aminofluorination
To determine the possible cause of the aforementioned
catalyst deactivation (Scheme 2B), we exposed an in situ
generated Fe(BF ) −L1 catalyst (1:1 ratio), previously dis-
4
2
covered for styrene aminohydroxylation, to an intramo-
lecular aminofluorination condition in the absence of any
olefin or oxidant (Scheme 3). Insoluble FeF and a soluble
2
iron complex were obtained and X-ray crystallographic
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Journal of the American Chemical Society
outside of a glove-box (Figure 1), was found to effectively
a
Reactions were carried out under N at -15 °C in 2 h and 4
2
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Å activated molecular sieves (powder) were used to remove
catalyze styrene aminofluorination in the absence of the
MeCN co-solvent; 3 was isolated in an excellent yield
without using an excess amount of fluorination reagent
deleterious moisture, unless stated otherwise. The reaction
b
was quenched with saturated NaHCO3 solution. Isolated
c
d
1
3
yield. No reaction; 1 and 2a were recovered. The yield of 5 is
(
entry 11, 88%).
e
8−12%. No desired product observed and 5 (42%) was isolat-
ed. Pre-formed complex 6 was used as the catalyst in CH Cl
f
To better understand the structure–reactivity relation-
2
2
ship of fluoride donors, we explored a range of variations
using other nucleophilic fluorination reagents under the
optimized condition (Table 2). First, replacements of
in the absence of MeCN; -15 °C, 2 h; the yield of 5 is less than
%.
5
t
To test this hypothesis, we selected styrene 1 as a model
substrate for catalyst discovery (Table 1). We first ob-
Et N·3HF with Et N·HF, Et N·2HF, TBAF·( BuOH) , KF, or
3
3
3
4
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AgF all lead to unproductive decomposition of 2d (entry
17
served that the Fe(NTf ) −L1 complex, a catalyst for sty-
1). Next, replacement of XtalFluor-E with XtalFluor-M
2
2
rene amino-oxygenation, led to inefficient aminofluorina-
also affords 3d, albeit in a lower yield (entry 2, 65% yield).
Furthermore, using benzoyl fluoride instead of
tion when a 1:1 mixture of XtalFluor-E and Et N·3HF was
3
used: vicinal amino fluoride 3 was obtained in a low yield
Et N·3HF/XtalFluor-E does not afford the desired product
3
(
(
16%) together with the amino-oxygenation product 4
entry 1). Notably, there was no reaction in the absence of
3, but rather leads to benzoylation of 2d (entry 3). Fur-
18
19
20
thermore, using DFI, PhenoFluor, or DAST, reagents
that can presumably sequester benzoates, all lead to un-
productive decomposition of 2d (entries 4–5). Surprising-
ly, the DAST/XtalFluor-E (1:1) combination can lead to full
conversion of 1 and generation of amino fluoride 3d (en-
try 6, 51% yield). This result corroborates the proposal
an iron catalyst; both 1 and 2a were stable towards
XtalFluor-E and Et N·3HF and they were fully recovered
3
(
entry 2).
We also observed a higher yield of 3 when the XtalFlu-
or-E/Et N·3HF ratio was increased to 1.6:1 (entry 3,
3
that Et N·3HF and XtalFluor-E may form dynamic com-
XtalFluor-E (2.5 equiv), Et N·3HF (1.5 equiv), 42% yield).
3
3
plexes, which are compatible with the iron catalyst
Suspecting that an extra equivalent of XtalFluor-E may
sequester the carboxylate generated during the N−O bond
cleavage, we replaced 2a with 2b, from which we expected
a more nucleophilic benzoate to be generated. A similar
yield of 3 and a better mass balance were observed (entry
(
Scheme 4).
Table 2. Structure−reactivity relationship studies of nu-
cleophillic fluorination reagents
4
). Interestingly, a 2:1 mixture of XtalFluor-E/Et N·3HF
3
resulted in a decreased yield of 3 and isolation of imidazo-
line 5, presumably through MeCN (co-solvent) incorpora-
tion (entry 5). Notably, no desired product was observed
in the absence of Et N·3HF and only 5 was isolated (entry
3
6
).
Figure 1. Crystal structure of Fe(L1)(MeCN)(H O) (BF ) (6)
2
2
4 2
In order to attenuate the neighboring carbamate
group’s participation, we switched 2b to more electro-
philic 2c and 2d and observed further improved yield of 3
(entries 7−8, 46−73% yield). Furthermore, an excess
a
Reactions were carried out under N at -15 °C in 2 h and 4
2
Å activated molecular sieves (powder) were used to remove
b
deleterious moisture, unless stated otherwise. Amino-
oxygenation product 4d (42%) and benzoylated 2d (24%)
were isolated.
amount of both XtalFluor-E and Et N·3HF is beneficial to
3
the yield of 3 (entry 9, 81% yield) and the Fe(NTf )−L2
2
complex provides essentially the same yield (entry 10, 78%
Upon discovering the optimal catalytic conditions, we
explored the substrate scope of this new reaction (Table
3). First, a range of styrenes with various electronic prop-
yield). To our surprise, Fe(L1)(MeCN)(H O) (BF ) (6), a
2
2
4 2
crystalline solid that was easily prepared and handled
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erties are compatible with this method and they were
loading: 30 mol %, XtalFluor-E (1.5 equiv)/Et N·3HF (0.9
3
1
2
3
4
5
6
7
8
9
1
1
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1
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1
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6
equiv).
converted to internal amino fluorides with excellent
yields (entries 1a–1d). Additionally, an ene-yne and α-
methyl styrene are both excellent substrates (entries 2−3).
Next, we evaluated olefins that are incompatible with ex-
isting aminofluorination methods. An allyl silane with a
labile C–Si bond in the presence of fluoride ion was con-
verted to an internal amino fluoride, which has a nitro-
gen, fluorine, and silicon-based triad with excellent yield
and regio-selectivity (entry 4, 82% yield). A silyl dienol
and an ethyl dienoate, both with labile functional groups,
were also tolerated by this method to produce amino al-
lylic fluorides in reasonable yields (entries 5−6). Isoprene
aminofluorination provided a pair of vicinal amino allylic
fluorides with an excellent yield and good regio-selectivity
Table 3. Substrate scope for the iron-catalyzed olefin
aminofluorination
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(
entry 7, 84% yield). Furthermore, a linear aliphatic diene
was converted to both 1,2- and 1,4-amino fluorides with
excellent combined yield (entry 8, 91% yield).
We subsequently explored indene aminofluorination
using the Fe(NTf ) −L1 complex: an anti-2-amino fluoride
was isolated with excellent regio-selectivity and signifi-
cant diastereoselectivity (entry 9, 72% yield, dr: 6.2:1).
2
2
23
Moreover, we evaluated isolated olefins, including 1,1-
disubstituted and mono-substituted olefins, both of
which are significantly less-reactive. With increased cata-
lyst loading and the amount of fluorination reagents, both
of them were converted to internal amino fluorides with
reasonable yields and high regio-selectivity (entries 10−11,
62−71% yield). Notably, this new method enables the syn-
thesis of a range of structurally diverse vicinal amino fluo-
rides for the first time (described in entries 4, 5, 7, 10, and
11).
Scheme 5. Derivatization of olefin aminofluorination
products to N-Boc protected vicinal fluoro amines
The furnished vicinal fluoro carbamates, both from
styrenyl and aliphatic olefins, such as 7 and 9, can be easi-
ly derivatized to N-Boc protected vicinal fluoro amines 8
and 10 in excellent yields under mild conditions (Scheme
1
).
3
5
Scheme 6. Iron-catalyzed aminofluorination of myrence
and (-)-β-pinene
a
Reactions were carried out under N2 with pre-formed
iron(II)−L1 catalysts (10 mol %), unless stated otherwise.
b
21
c
XtalFluor-E (3.0 equiv)/Et N·3HF (1.8 equiv).
Catalyst
3
d
loading: 15 mol %. XtalFluor-E (4.0 equiv)/Et N·3HF (2.4
equiv). Catalyst loading: 20 mol %. Additional XtalFluor-E
3
21 e
f
22
(
2.5 equiv)/Et N·3HF (2.5 equiv) were added after 1 h.
3
g
21
h
XtalFluor-E (5.0 equiv)/Et N·3HF (3.0 equiv).
Catalyst
3
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With the success of this aminofluorination method for
In order to demonstrate the potential practicality of
this reaction, we explored the aminofluorination of in-
dene and isoprene on a large scale (Scheme 8). To our
pleasure, both catalytic reactions can be scaled up to
gram scale with consistent yield, regio-, and stereoselec-
1
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9
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6
simple unfunctionalized olefins, we further explored this
new reaction with complex olefins, including myrcene
which contains both a tri-substituted olefin and a conju-
gated diene, and (-)-β-pinene (Scheme 6). The amino-
fluorination of myrcene readily affords both a standard
1
3
tivity.
1
,2-addition product 11b and a 1,6-addition product 11a
Table 4. Catalytic asymmetric indene aminofluorination
presumably through cyclization. We also note that the
nitrogen atom was selectively transferred to the same
terminal positions in both 11a and 11b. To our surprise,
the aminofluorination of (-)-β-pinene does not afford any
,2-addition product, but rather the same 1,6-addition
product 11a presumably through rearrangement. Notably,
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complete stereochemistry retention is observed in this
24
aminofluorination–rearrangement cascade.
Scheme 7. Iron-catalyzed aminofluorination of trans-β-
methyl-styrene
a
Unless stated otherwise, the reactions were carried out un-
b
der a nitrogen atmosphere with 4 Å molecular sieves. Isolat-
c
1
d
a
ed yield. Dr was determined by H NMR. Enantiomeric ex-
cess (ee) was measured by HPLC with chiral columns; the
absolute stereochemistry was determined by X-ray crystallo-
Reaction condition: Fe(NTf ) (15 mol %), L2 (15 mol %),
2
2
XtalFluor-E (2.5 equiv)/Et N·3HF (1.5 equiv), 4 Å MS,
3
CH Cl /MeCN, -15 °C, 1 h; then another portion of XtalFluor-
2
2
graphic analysis of 7d (R: (CF ) CH).
E (1.5 equiv)/Et N·3HF (1.5 equiv), 0 °C, 3 h.
3 2
3
The catalytic enantioselective aminofluorination of un-
functionalized olefins has been an unsolved synthetic
Fluorinated amphetamines are of great interest to bio-
logical studies of central nervous system; therefore, we
evaluated the aminofluorination of trans-β-methyl sty-
2
6
challenge; therefore, we explored the feasibility of
achieving asymmetric induction using chiral iron cata-
lysts. As a first step, we studied asymmetric indene ami-
nofluorination as a proof of concept, which may provide
valuable mechanistic insights (Table 4). The
Fe(NTf ) −chiral ligand L3 complex catalyzes indene ami-
25
rene (Scheme 7). Interestingly, although the Fe(BF ) −L1
4
2
complex 6 promotes undesirable C−H abstraction, a less
sterically hindered Fe(NTf ) −L2 complex catalyzes effi-
2
2
cient aminofluorination to afford 12 (Scheme 7, 72% yield,
13
2
2
dr: 2.0:1).
nofluorination with 2d and affords anti-2-amino fluoride
7d with significant ee (entry 1, 60% ee). Although less ste-
rically hindered acyloxyl carbamates (2b and 2c) lead to
further increased ee for indene aminofluorination, both
reactions evidently suffer from lower reactivity (entries 2–
3, 78–83% ee). In order to achieve enhanced reactivity, the
benzoyl activating group in 2c was switched to 3,5-
bis(trifluoromethyl)-benzoyl group in 2e. To our surprise,
a dramatically decreased ee was observed (entry 4, 55%
ee). Fortunately, indene aminofluorination with acyloxyl
carbamate 2f, which has a 2,4-dichloro-benzoyl activating
group, provides 7 with a synthetically useful yield and
high ee (entry 5, 59% yield, 84% ee). Other chiral ligands,
including tri-dentate L4 and L5, were also evaluated and
they all provided inferior results.
Scheme 8. Iron-catalyzed gram-scale aminofluorination
of indene and isoprene
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These results also provide valuable mechanistic insight. shift from a carbocation (eq 4). This result suggests that a
1
2
3
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5
6
7
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9
1
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6
The acyloxyl moiety on 2 proves crucial for stereo-
chemical communication in the iron-catalyzed indene
aminofluorination (Table 4, entries 3–5). This observation
suggests that the benzoate generated during N−O bond
cleavage may be involved in the ee-determining step. Ad-
ditionally, since the same ee was observed for both dia-
stereomers of 7, it is likely that the C−N bond forming
step is ee-determining.
carbocation may also be involved in the reaction pathway.
Furthermore, benzoylated morpholine 21 was identified
as a side product in styrene aminofluorination using
Et N·3HF/XtalFluor-M (eq 5). We suspected that 21 might
3
be derived from the interaction between XtalFluor-M and
the benzoic acid that was generated during the iron-
catalyzed N−O bond cleavage; therefore, a control exper-
iment between benzoic acid and XtalFluor-M was con-
ducted, from which 21 was indeed isolated (eq 6). These
results suggest that and XtalFluor-E or XtalFluor-M se-
questers benzoic acids to promote efficient fluorine atom
transfer.
Scheme 9. Control experiments to probe for mechanistic
insight
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7
8
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9
0
Based upon a range of mechanistic evidence presented
in Scheme 9, a mechanistic working hypothesis for the
iron-catalyzed olefin aminofluorination is proposed in
Scheme 10. First, the iron catalyst may reductively cleave
the N−O bond in 2, which can possibly be converted to an
iron-nitrenoid A. The iron-nitrenoid may initiate a radical
addition with olefin 1 to afford a carbo-radical species B.
Subsequently, the high-valent iron intermediate may fur-
ther oxidize the radical, presumably through single elec-
27
tron transfer (SET), to generate a carbocation C1. When
the concentration of a suitable fluoride donor is low, C1
may be efficiently intercepted by the neighboring carba-
mate group to afford amino-oxygenation product 4.
However, in the presence of a suitable nucleophilic flu-
oride and benzoate sequestering reagent (e.g.
Et N·3HF/XtalFluor-E), carbocation C1 may be rapidly
3
converted to C2, which can be captured and converted to
amino fluoride 3; therefore, the aminofluorination path-
way will override the competing amino-oxygenation
pathway. Since oxazoline 4 may also be converted to car-
bocation C1 under reaction conditions which are strongly
Lewis-acidic, it is possible that this additional pathway
may also operate, for certain type of substrates, to afford
the olefin aminofluorination product 3.
a
6
(15 mol %), XtalFluor-E (2.5 equiv)/Et N·3HF (1.5 equiv),
3
b
-
15 °C, CH Cl .
equiv)/Et N·3HF (2.4 equiv), -40 °C, CH Cl . 6 (15 mol %),
XtalFluor-E (3.0 equiv)/Et N·3HF (1.8 equiv), -35 to 0 °C,
CH Cl . R : 2,4-Cl -benzoyl, R : CF CH , R : (CF ) CH.
6
(15 mol %), XtalFluor-E (4.0
2
2
c
3
2
2
3
1
2
3
2
2
2
3
2
3 2
In order to formulate a mechanistic model, we carried
out several control experiments to gain more insight into
both the C−N and C−F bond forming steps (Scheme 9).
First, two analogues of 2 in which the N−H moiety was
replaced with either the N−Me or N−Ac groups were sub-
jected to standard reaction conditions (Scheme 9, eq 2).
Neither was reactive toward the aminofluorination, which
suggests that the N−H moiety in 2 is critical for its activa-
tion.
CONCLUSION
In conclusion, we reported a catalytic method for in-
termolecular olefin aminofluorination using earth-
abundant iron catalysts and nucleophilic fluoride ion.
This method tolerates a broad range of unfunctionalized
olefins, including non-styrenyl olefins that are incompati-
ble with existing aminofluorination methods. It also read-
ily affords a variety of synthetically valuable vicinal fluoro
carbamates with high regio-selectivity. Notably, many of
them are difficult to prepare using existing methods. We
systematically described the catalytic discovery, struc-
ture–reactivity relationship studies of fluoride donors,
substrate scope and limitation of this method, derivatiza-
tion of vicinal fluoro carbamates under mild conditions,
practical procedures for gram-scale olefin aminofluorina-
tion, chiral catalyst discovery for asymmetric olefin ami-
nofluorination, and preliminary mechanistic studies. The-
se studies demonstrate that it is feasible for asymmetric
induction using chiral iron catalysts for aminofluorination
Next, the aminofluorination of
a
cyclopropyl-
substituted olefin 15 afforded only the ring-opening prod-
ucts 16 and 17 (eq 3). This result, together with the ob-
served 1,6-myrcene aminofluorination, suggests that the
reaction may proceed through a stepwise process and that
a carbo-radical species may be an intermediate. To obtain
more mechanistic details beyond the C−N bond forming
step, we further evaluated a 1,1-disubstituted olefin 18 and
observed both 1,2-amino fluoride 19 and 1,3-aminofluoride
20 which is presumably obtained through 1,2-hydride
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of unfunctionalized olefins, in which both an iron
nitrenoid and a carbocation species may be possible reac-
tive intermediates. Our current efforts focus on both
mechanistic understanding and synthetic applications of
this new reaction.
1
2
3
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6
7
8
9
1
1
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6
Scheme 10. Mechanistic working hypothesis of the iron-catalyzed intermolecular olefin aminofluorination using fluoride
ion
0
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8
9
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9
0
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2
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9
0
(
3) For a selected reference of vicinal fluoro amines in me-
dicinal chemistry, see: Hagmann, W. K. J. Med. Chem.
2008, 51, 4359.
ASSOCIATED CONTENT
(
4) (a) Stavber, S.; Pecăn, T. S.; Papež, M.; Zupan, M.
Chem. Commun. 1996, 2247. In this report, the sub-
strate scope was predominately limited to styrenyl ole-
fins with two exceptions. First, tetramethylethylene.
Second, 1-octene was converted to an inseparable mix-
ture of 1,2- and 1,3- terminal fluorides. For recent refer-
ences of intermolecular styrene aminofluorination, see:
Supporting Information
Experimental procedure, characterization data for all new
compounds, selected NMR spectra and HPLC traces. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(b) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am.
Chem. Soc. 2010, 132, 2856. (c) Zhang, H.; Song, Y.;
Zhao, J.; Zhang, J.; Zhang, Q. Angew. Chem., Int. Ed.
2014, 53, 11079. (d) Saavedra-Olavarria, J.; Arteaga, G.
C.; López, J. J.; Pérez, E. G. Chem. Commun. 2015, 51,
*
hxu@gsu.edu
Author Contributions
These authors contributed equally.
3379. (e) Chen, P.; Liu, G. Eur. J. Org. Chem. 2015, 4295.
‡
For a recent review of intramolecular olefin amino-
fluorination, see: (f) Serguchev, Y. A.; Ponomarenko,
M. V.; Ignat’ev, N. V. J. Fluorine Chem. 2016, 185, 1.
ACKNOWLEDGMENT
(5) For a reference of asymmetric fluoro aminoxylation of
enals using chiral diphenyl prolinol-type of organocat-
alysts, see: Appayee, C.; Brenner-Moyer, S. E. Org. Lett.
This work was supported by the National Institutes of Health
(
GM110382) and Georgia State University. H.X. is an Alfred P.
Sloan Research Fellow. We also thank a referee for insightful
comments and suggestions.
2010, 12, 3356.
(
6) The aminofluorination of terminal olefins using nucle-
ophilic fluorination reagents affords internal amino
fluorides with the inverse regio-selectivity obtained us-
ing electrophilic fluorination reagents.
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(
1) For a selected reference of fluorine in medicinal chem-
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(8) BDE for Fe−F is 447 kJ/mol, while BDEs for Fe−Cl and
Fe−Br are 336 and 243 kJ/mol, respectively. See: Luo,
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Y.-R. Comprehensive Handbook of Chemical Bond Ener-
(24) The ee for (-)-β-pinene is 92% and the ee for 11a is 91%.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
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gies; CRC Press: Boca Raton, FL, 2007; pp 803.
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Am. Chem. Soc. 2005, 127, 2050.
For experimental details, see the Supporting Infor-
mation.
(25) For a selected example of fluorinated amphetamine
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Org. Lett. 2010, 12, 2936.
(
10) For existing vicinal fluoro acetamide and sulfonamide
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(
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(13) For experimental details, see the Supporting Infor-
mation.
(
14) For synthesis of XtalFluor-E, see: L’Heureux, A.; Beau-
lieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme,
F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier,
M. J. Org. Chem. 2010, 75, 3401. XtalFluor-E is hygro-
scopic; see Supporting Information for correct han-
dling and storage. XtalFluor-E has no effect on the cat-
alytic activity of the iron–bi-dentate ligand complexes
in the intramolecular olefin aminofluorination. Full
conversion of the substrate was observed in the ab-
sence of XtalFluor-E (eq 1).
3
(15) For a reference describing the structure of Et N·3HF,
see: Wiechert, D.; Mootz, D.; Franz, R.; Siegemund, G.
Chem.-Eur. J. 1998, 4, 1043.
3 2
(16) XtalFluor-E is prepared using DAST and BF ·Et O. For
experimental details, see the Supporting Information.
For reactivity of these complexes, see entry 11 of Table 1
and entry 6 of Table 2.
(
17) Acyloxyl carbamate 2d decomposes under weakly basic
conditions. We suspect that the reaction medium may
be slightly basic due to solvation of fluoride ion with
deleterious moisture in these reagents.
(18) Hayashi, H.; Sonoda, H.; Fukumura, K.; Nagata, T.
Chem. Commun. 2002, 1618.
(19) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011,
133, 11482.
(
(
20) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
21) An excess amount of XtalFluor-E/Et N·3HF was ap-
3
plied to suppress the rapid competing olefin aminohy-
droxylation.
3
(22) An additional amount of XtalFluor-E/Et N·3HF was
used to convert oxazolines to corresponding amino
fluorides.
(23) For a diastereoselective indene aminofluorination to
afford 1-amino fluoride, which is the regio-isomer of 7,
see ref. 4e.
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