Iron(II)-catalyzed intramolecular olefin aminofluorination

Article abstract of DOI:10.1021/ol501051p

An iron(II)-catalyzed diastereoselective olefin aminofluorination is reported (dr up to >20:1). This new transformation applies a functionalized hydroxylamine and Et₃N·3HF as the nitrogen and fluorine source, which facilitates the efficient synthesis of β-fluoro primary amines and amino acids from allylic alcohol derivatives. Preliminary mechanistic studies reveal that an iron-nitrenoid is a possible intermediate and that its reactivity and enantioselectivity can be efficiently modulated by ligands.

Full text of DOI:10.1021/ol501051p

Letter
pubs.acs.org/OrgLett
Iron(II)-Catalyzed Intramolecular Olefin Aminofluorination
Deng-Fu Lu, Guan-Sai Liu, Cheng-Liang Zhu, Bo Yuan, and Hao Xu*
Department of Chemistry, Georgia State University, 100 Piedmont Avenue SE, Atlanta, Georgia 30303, United States
S
* Supporting Information
ABSTRACT: An iron(II)-catalyzed diastereoselective olefin
aminofluorination is reported (dr up to >20:1). This new
transformation applies a functionalized hydroxylamine and
Et3N·3HF as the nitrogen and fluorine source, which facilitates
the efficient synthesis of β-fluoro primary amines and amino
acids from allylic alcohol derivatives. Preliminary mechanistic
studies reveal that an iron−nitrenoid is a possible intermediate and that its reactivity and enantioselectivity can be efficiently
modulated by ligands.
Scheme 1. Iron-Catalyzed Intramolecular Olefin
Aminofluorination
luorinated organic molecules are valuable in medicinal
Fchemistry because they are often associated with unique
lipophilic and metabolic properties that are desirable in drug
discovery.1 More than 20% of the currently available
pharmaceuticals contain at least one fluorine atom.2 Therefore,
an extensive amount of research has been devoted to the selective
incorporation of fluorine atoms into medicinally relevant
molecules. In addition to alcohol deoxyfluorination protocols,3
a tremendous amount of progress has been made in the
development of methods for sp2 and sp3 C−F bond
formation.4−6 Among those developments, methods for selective
fluorine atom transfer via direct olefin aminofluorination have
recently emerged. Liu reported palladium-catalyzed intra-
molecular olefin aminofluorination methods with hypervalent
iodine and silver fluoride which afford fluorinated piperidines
and (fluoromethyl)pyrrolidines.7a,b An intermolecular styrene
aminofluorination method was reported by the same author.7c Li
disclosed a silver-catalyzed intramolecular olefin aminofluorina-
tion method with Selectfluor, which yields fluorinated N-
phenylpyrrolidinones.7d Recently, Toste developed an organo-
catalytic method for intramolecular 1,4-aminofluorination of
conjugated dienes with Selectfluor.7e Despite these important
discoveries, a method for direct olefin aminofluorination which
yields β-fluoro primary amines, especially those with a tertiary
fluoride moiety, has not been developed.8 In addition, methods
of iron-catalyzed or mediated selective fluorine atom transfer for
olefin difunctionalization have been underexplored.9
We have recently reported an iron(II)-catalyzed intra-
molecular olefin aminohydroxylation that affords 1,2 anti-
amino alcohols from trans-olefins.10 Herein, we describe an
iron(II)-catalyzed diastereoselective intramolecular olefin ami-
nofluorination with a functionalized hydroxylamine and Et3N·
3HF (dr up to >20:1, Scheme 1). This reaction readily affords
fluoro oxazolidinones which can then be conveniently converted
to β-fluoro amines and amino acids. We also demonstrated that
chiral ligands are effective in asymmetric induction (ee up to
81%). This method presents an expedient alternative to currently
available β-fluoro amino acid synthesis methods that mostly rely
on nucleophilic fluorination of alcohols and aziridines, and
electrophilic fluorination of α-carbonyl compounds.11
A cinnamyl alcohol-derived acyloxyl carbamate 112 was
selected as the model substrate for catalyst discovery (Table
1). Extensive experimentation revealed that both the benzoyl
activating group and the iron catalysts with noncoordinating
anions are crucial for the desired reactivity.13 Among the iron
catalysts examined, Fe(BF4)2·6H2O exemplifies superior reac-
tivity.13 The Fe(BF4)2−1,10-phenanthroline (L1) complex alone
catalyzes efficient aminohydroxylation of 1 and simultaneously
leads to a small amount of fluoro oxazolidinone 2 (eq 1, entry 1,
9% yield, dr 1.8). However, in the presence of Et3N·3HF,14 the
same catalyst evidently promotes the aminofluoroination of
olefin 1 (entry 2, 43% yield of 2, dr 3.1). Concordantly, an
aminohydroxylation product 3 was also detected (22% yield, dr
>20:1). We subsequently applied Olah’s reagent (HF−
pyridine)14 as the fluoride source and observed a similar result
(entry 3, 37% yield, dr 3.0). We also noted that other slightly
basic and more nucleophilic fluorine reagents lead to either rapid
aziridination or substrate decomposition.15
These experimental results (entries 1−3) suggest that there
are aminofluorination and aminohydroxylation pathways com-
peting for a same reactive intermediate. We hypothesized that
sequestering carboxylates may minimize the competing amino-
hydroxylation pathway. To our delight, the introduction of
carboxylate trapping reagents such as XtalFluor-E indeed
suppresses the competing aminohydroxylation and evidently
Received: April 10, 2014
Published: May 14, 2014
© 2014 American Chemical Society
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Letter
Table 1. Catalyst Discovery for the Iron-Catalyzed Olefin
Aminofluorination
Table 2. Substrate Scope for the Iron-Catalyzed Olefin
Aminofluorination
a
Molecular sieves are necessary for catalyst activation; see the
b
Supporting Information. Reactions were carried out under argon at
c
23 °C. Fe(BF4)2·6H2O or Fe(NTf2)2 was applied as the catalyst.
d
e
Isolated yield. dr was determined by 19F NMR analysis. NTf2 =
trifluoromethanesulfonimide.
increases the efficiency of aminofluorination (entry 4, 61% yield,
dr 3.1).16 We subsequently explored a range of carboxylate
trapping reagents and determined that XtalFluor-E is superior
than others.17 Interestingly, in the absence of Et3N·3HF, the
Fe(BF4)2−L1 complex and XtalFluor-E lead to decomposition of
1 (entry 5).
We thereby systematically examined a series of nitrogen-based
ligands. We first observed that the hybrid pyridine−oxazoline
ligand L2 induces aminofluorination with a decreased yield
(entry 6, 58% yield in 4 h, dr 3.7).18 Interestingly, the hybrid
ligand L3 derived from ( ) 1-amino indanol significantly
accelerates the aminofluorination and increases selectivity
(entry 7, 72% yield in 1.5 h, dr 3.9). Importantly, we discovered
that a decreased ligand/metal ratio correlates with enhanced
reactivity and dr (entry 8, 71% yield in 1 h, dr 4.2). Furthermore,
we observed a detectable ee (23%) when the optically pure L3
was applied as the chiral ligand. We also uncovered that
Fe(NTf2)2 catalyzes a slower reaction with decreased dr yet with
further increased yield (entry 9, 75% yield in 3.5 h, dr 3.4).
To explore the substrate scope of this transformation, we
examined a variety of olefins under optimized conditions. We
observed that trans-disubstituted styrenyl olefins are decent
substrates (Table 2, entries 1−6). Aminofluorination of styrenyl
olefins which have electron-donating groups affords anti-fluoro
oxazolidinones with further increased dr (entries 2−3, dr up to
9.5). We also determined that a naphthyl olefin is a suitable
substrate (entry 4, dr 10:1). However, substrates with electron-
withdrawing groups suffer from modest dr in the delivery of syn-
fluoro oxazolidinones (entries 5−6, dr 2.2−3.1).19 This unique
electronic effect is opposite to the effect we observed during the
iron-catalyzed aminohydroxylation.10 In addition to styrenyl
olefins, both enynes and aliphatic-substituted olefins were found
to be decent substrates (entries 7−8, dr 1.5−2.5). Following the
latter with a two-step procedure (entry 8) provides 3-deoxy-3-
fluoro safingol and sphinganine which are both fluorinated
analogues of biologically active molecules.20
a
b
Reactions were carried out under argon at 23 °C. Isolated yield; dr
c
was determined by 19F NMR analysis. Fe(NTf2)2 (10 mol %), L3 (20
d
mol %), Et3N·3HF (1.6 equiv), XtalFluor-E (1.4 equiv). R4: benzoyl;
Fe(BF4)2·6H2O (10 mol %), L3 (10 mol %); Et3N·3HF (1.8 equiv),
XtalFluor-E (2.0 equiv).
Likewise, we demonstrated that cis-disubstituted olefins
readily participate in this reaction and that essentially the same
dr is observed for both the cis and trans isomers (entries 1,7 vs 9−
10). The observed stereoconvergence suggests that the reaction
occurs in a stepwise fashion. Moreover, we observed that the
aminofluorination proceeds with trisubstituted olefins with
excellent dr to afford a syn-fluoro oxazolidinone (entries 11−
12, dr > 20:1).21 Additionally, we determined that a cyclic
substrate derived from a secondary allylic alcohol undergoes
highly diastereoselective aminofluorination to afford an anti-
fluoro oxazolidinone (entry 13, dr > 20:1).21 We also noted that
the corresponding acyclic substrate can be converted into an anti-
fluoro oxazolidinone with modest dr (entry 14).21
To demonstrate the unique synthetic utility of the olefin
aminofluorination method, we have converted anti-fluoro
oxazolidinone 2a to a protected anti-β-fluoro phenylalanine 4a
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Organic Letters
Letter
with excellent yield via a standard three-step procedure (Scheme
2). The same procedure has been applied to synthesize syn-β-
fluoro phenylalanine 4b and β-fluoro valine 6 in good overall
yield (71−77%).
olefin aminofluorination is shown in Scheme 4. First, the iron
complex can reductively cleave the N−O σ bond in the isomeric
Scheme 4. Mechanistic Working Hypothesis for the Iron-
Catalyzed Olefin Aminofluorination
Scheme 2. Synthetic Applications: β-Fluoro Amino Acid
Synthesis
a
b
c
Boc2O, Et3N, CH2Cl2, rt, 1 h. Cs2CO3, MeOH, rt, 2 h. TEMPO,
TBAB, NaClO, NaHCO3, 0 °C, 2 h. Boc = tert-butyloxycarbonyl;
TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy; TBAB = tetra-n-
butylammonium bromide.
olefinic substrates 1 and 10, possibly converting them to two
iron-nitrenoids A1 and A2, respectively.22 Presumably, a
competing aminohydroxylation can occur with A1 and A2 in
the absence of external fluoride source to deliver the benzyloxyl
oxazolidinone 3.10 However, in the presence of Et3N·3HF and
XtalFluor-E, a facile anion metathesis process may occur, which
can convert A1 and A2 to iron fluoride-based nitrenoids B1 and
B2. From there, a stepwise cycloamination might occur,
presumably converting B1 and B2 to two carbo-radical species
C1 and C2 that are in a fast equilibrium. Subsequently, an
oxidative fluoride ligand transfer can occur with either radical
species C1 or C2, affording the fluoro oxazolidinone 2.23
Alternatively, an electron transfer from the C1/C2 radical species
to the iron center followed by fluoride trapping of the generated
carbocation may also lead to the final product 2.
In order to gain further mechanistic insight of this iron-
catalyzed fluorine atom transfer process, we have performed
several experiments (Scheme 3). First, we subjected both
Scheme 3. Control Experiments To Probe the Possible
Mechanism
In summary, we have reported a new iron(II)-catalyzed
diastereoselective olefin aminofluorination reaction with func-
tionalized hydroxylamines and Et3N·3HF. This reaction readily
transforms allylic alcohol derivatives to β-fluoro primary amines
and amino acids after simple derivatization. Preliminary
mechanistic studies revealed that an iron nitrenoid is a possible
reactive intermediate for this stereoconvergent process. Our
current effort focuses on the mechanistic understanding of this
process and its applications in fluorinated nitrogen-containing
molecule synthesis.
a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedure, characterization data for all new
compounds, and selected NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Fe(BF4)2·6H2O (10 mol %), L3 (10 mol %); Et3N·3HF (1.4 equiv),
■
XtalFluor-E (1.2 equiv), CH2Cl2, rt, 4 Å molecular sieves, 24 h.
S
b
Fe(BF4)2·6H2O (20 mol %), L4 (20 mol %); Et3N·3HF (1.4 equiv),
XtalFluor-E (1.2 equiv), CH2Cl2, −30 °C, 4 Å molecular sieves, 12 h.
preformed aziridine 7 and β-benzyloxyl oxazolidinone 3 to
catalytically active conditions and did not detect the amino-
fluorination product 2 even after 24 h (eqs 2 and 3). These
observations suggest that the aminofluorination unlikely
proceeds through an aziridine or a β-benzyloxy oxazolidinone
intermediate.
Furthermore, we observed that the iron-catalyzed asymmetric
olefin aminofluorination is stereoconvergent: the isomeric
olefins 1 and 10 are converted to fluoro oxazolidinone 2 with
essentially the same ee (81%) and dr. These results and the
ligand-enabled diastereoselectivity suggest that the iron−ligand
complex is involved in the C−F and C−N bond formation
processes.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hxu@gsu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Georgia State University and the
American Chemical Society Petroleum Research Fund (ACS
PRF 51571-DNI1). We thank Dr. Siming Wang (Georgia State
U) for the help in ESI-TOF MS studies of catalysts and
Boehringer Ingelheim for the generous donation of chiral amino
indanol building blocks.
Based on these experiments, a working hypothesis that best
corroborates the mechanism of the iron-catalyzed intramolecular
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Letter
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