Catalytic Diastereo- and Enantioselective Fluoroamination of Alkenes

Article abstract of DOI:10.1021/jacs.8b02143

The stereoselective synthesis of syn-β-fluoroaziridine building blocks via chiral aryl iodide-catalyzed fluorination of allylic amines is reported. The method employs HF-pyridine as a nucleophilic fluoride source together with mCPBA as a stoichiometric oxidant, and affords access to arylethylamine derivatives featuring fluorine-containing stereocenters in high diastereo- and enantioselectivity. Catalyst-controlled diastereoselectivity in the fluorination of chiral allylic amines enabled the preparation of highly enantioenriched 1,3-difluoro-2-amines bearing three contiguous stereocenters. The enantioselective catalytic method was applied successfully to other classes of multifunctional alkene substrates to afford anti-β-fluoropyrrolidines, as well as a variety of 1,2-oxyfluorinated products.

Full text of DOI:10.1021/jacs.8b02143

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Communication
Catalytic Diastereo- and Enantioselective Fluoroamination of Al-kenes
Katrina Mennie, Steven M. Banik, Elaine C. Reichert, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02143 • Publication Date (Web): 27 Mar 2018
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Katrina M. Mennie, Steven M. Banik, Elaine C. Reichert, Eric N. Jacobsen*
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Supporting Information Placeholder
tive metal-free approach involves the fluoroamination of
alkenes promoted by hypervalent iodine compounds.7 For
example, a method to generate fluorinated piperidines enan-
tioselectively using stoichiometric iodine(III) reagents has
been reported by Nevado and coworkers.7a Other notable
approaches include the use of anionic phase-transfer8 and
Lewis basic9 catalysts together with Selectfluor in the stere-
oselective fluorination of enamides and indoles, respectively.
Transition-metal catalysis has also been applied to fluoroam-
ination reactions.10 In a particularly significant advance, an
enantio- and regioselective iron(II)-catalyzed intermolecular
fluoroamination of alkenes was described recently by Xu et
al. 10d These examples highlight the significant progress made
toward accessing -fluoroamines, as well as the continuing
need for general catalytic methods for their stereocontrolled
synthesis.
ABSTRACT: The stereoselective synthesis of syn-β-
fluoroaziridine building blocks via chiral aryl iodide-
catalyzed fluorination of allylic amines is reported. The
method employs HF-pyridine as a nucleophilic fluoride
source together with mCPBA as a stoichiometric oxidant,
and affords access to arylethylamine derivatives featuring
fluorine-containing stereocenters in high diastereo- and en-
antioselectivity. Catalyst-controlled diastereoselectivity in
the fluorination of chiral allylic amines enabled the prepara-
tion of highly enantioenriched 1,3-difluoro-2-amines bearing
three contiguous stereocenters. The enantioselective catalyt-
ic method was applied successfully to other classes of multi-
functional alkene substrates to afford anti-β-
fluoropyrrolidines, as well as a variety of 1,2-oxyfluorinated
products.
The unique ability of fluorine substituents to modulate the
physical and biological properties of organic molecules1 has
inspired widespread efforts to develop methods for the selec-
tive construction of C–F bonds.2 Given the crucial im-
portance of basic nitrogen groups in bioactive compounds,
the stereoselective construction of fluoroamines has
emerged as a particularly promising direction in organofluo-
rine chemistry. For example, introduction of a stereodefined
β-fluorine in the piperidine ring of MK-0731 was found to
attenuate the basicity of the amine while reducing cellular
efflux by P-glycoprotein and improving metabolic stability
(Figure 1a).3 Strategic incorporation of fluorine-bearing ste-
reocenters into β-peptide structures has been demonstrated
to induce powerful and predictable conformational effects
(Figure 1b).4
Figure 1. Fluoroamination of alkenes. a, Examples of compounds
where incorporation of a stereodefined C–F bond in a β-
relationship to a nitrogen has been shown to impart beneficial
properties to the molecule. b, β-Fluoroaziridination via sulfona-
mide trapping of a C(sp3)–I(III) intermediate.
As a result of the strong interest in accessing compounds
possessing the vicinal fluoroamine substructure, a variety of
approaches have been devised for their synthesis. Thanks to
the availability of effective organocatalytic methods for -
fluorination of carbonyl compounds,5 one-pot -
fluorination/reductive amination protocols are possible for
accessing enantioenriched vicinal fluoroamines. 6 An alterna-
We and others have developed a variety of oxidative fluoro-
functionalization reactions of alkenes based on aryl iodine(I–
III) catalysis.11 In the presence of even weakly nucleophilic
groups proximal to the alkene, the C(sp3)–I(III) intermedi-
ate that is proposed to be generated after initial fluoride addi-
tion (e.g., A, Figure 1b) can be intercepted either temporari-
ly or permanently to give rise to a variety of different path-
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ways and products. This principle has been exploited with
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substituents by employing triflate-protected derivatives (3e
and 3h). This result bears significance given the prevalence
of 3- and 4-hydroxy-substitution patterns in biologically im-
portant arylethylamines. Trisubstituted cinnamyl tosyla-
mides proved less effective as substrates, as reflected by the
tertiary fluoride 3n being isolated in moderate yield and en-
antioselectivity.
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C2-symmetric aryl iodide catalysts in the highly enantioselec-
tive syntheses of anti-1,2-difluorinated cinnamamides,11g
chiral
,-difluoroarylethanes11m
and
4-
fluoroisochromanones.11j We hypothesized that enantioen-
riched syn-β-fluoroaziridines might be generated in an anal-
ogous manner by trapping the key ArI(III) intermediate A
with appropriately positioned nitrogen nucleophiles (Figure
1b). This methodology would provide access to versatile
precursors to β-fluoroamines, as the strained aziridine may
be engaged in regioselective ring opening with a wide variety
of nucleophiles.12 We describe here the successful develop-
ment and application of this principle to the highly stereose-
lective fluoroaziridination of cinnamyl amine derivatives, and
elaboration of the products to a variety of novel fluorinated
phenethylamine derivatives.13
Substrates lacking electron-withdrawing substituents were
found to undergo a phenonium ion rearrangement pathway
to afford 1,1-difluoromethylated products in competition
with the desired fluoroaziridination reaction (Figure 2b).11m
For example, nearly exclusive formation of the 1,1-
difluoromethylated product was observed in the case of the
unsubstituted phenyl substrate (R = H). Indeed, a good cor-
relation between the electronic properties of the substituents
(+) and the selectivity for the desired product was ob-
served.14
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Cinnamyl tosylamide derivative 2a was evaluated as a model
substrate in the proposed fluoroaziridination reaction. Eval-
uation of a variety of reagent combinations and experimental
protocols led to the identification of optimal conditions simi-
lar to those reported in our previously described alkene 1,1-
difluorination and fluorolactonization reactions (see Sup-
plementary Information).11j,m Thus, in the presence of chiral
aryl iodide catalysts, mCPBA as a stoichiometric oxidant and
HF-pyridine as a nucleophilic fluoride source and acid pro-
moter, 2a was observed to undergo selective oxidation to
generate the corresponding β-fluoroaziridine product (3a) as
a single detectable diastereoisomer. Catalyst 1a proved su-
perior with respect to both yield and enantioselectivity (94%
ee) among all chiral aryl iodides that were evaluated (see
Supplementary Information). Judicious optimization of HF
loading (15 equiv. HF) and temperature (–30 ˚C) proved
crucial for obtaining the desired aziridine product in high
yield; at higher HF loadings and/or temperatures, the 1,3-
difluoride product resulting from opening of the putative
aziridinium ion intermediate was obtained. Sulfonamides
proved to be uniquely effective in the fluoroaziridination
reaction, as carbonyl-based protecting groups (amides, car-
bamates) led to the formation of 1,2-oxy-fluorinated prod-
ucts instead. Variation of the sulfonyl protecting group had
no effect on the enantioselectivity of the reaction, but the
toluenesulfonamides generally afforded the highest yields
(see Supplementary Information) and were therefore select-
ed for investigation of substrate scope.
A variety of electron-deficient cinnamyl tosylamides were
found to undergo clean conversion to the corresponding β-
fluoroaziridine products (3a–m) as single diastereoisomers
and with high enantioselectivity (Figure 2a). The syn relative
stereochemistry of the products was established by X-ray
crystallographic analysis of 3b, and is consistent with the
intermediacy of a fluoroiodinated adduct (A, Figure 1b).
Substrates bearing electron-donating substituents were poor
substrates for the fluoroaziridination reaction (see below),
but it proved possible to generate products bearing O-aryl
Figure 2. Evaluation of substrate scope for syn-β-
fluoroaziridination. a, Substrate scope evaluation for electron-
deficient cinnamyl tosylamides. Isolated yields are indicated below
each product (3); conditions: substrate (0.52 mmol), catalyst
(10 mol%), mCPBA (0.6 mmol), pyr9HF (7.5 mmol HF) in
DCM (3.0 mL) cooled to –30 ˚C, 18 h. b, Product selectivity as a
function of substituent. The ratio of fluoroaziridine product yield
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to the sum of fluoroaziridine and 1,1-difluoromethylated product
to chiral substrates bearing an aliphatic allylic substituent, as
in 5a (Figure 4a). Higher HF loadings (25–50 equiv. HF)
were required to achieve full conversion of the starting mate-
rial, and under these conditions the fluoride addition prod-
ucts were obtained exclusively. Completely regioselective
ring opening of the putative 1,2-disubstituted aziridinium ion
intermediate was observed, presumably due to the β-fluorine
inductively deactivating ring opening at the homobenzylic
position. The degree and sense of diastereoselectivity in the
reaction was found to be subject to high levels of catalyst
control. In the presence of an achiral catalyst such as iodo-
benzene, subjection of enantiopure 5a to the fluoroaziridina-
tion protocol resulted in generation of the 1,3-difluoride 6a
in low, 1.7:1 d.r. (anti/syn). In contrast, chiral catalyst 1a
promoted formation of either diastereomer of 6a with high
selectivity depending on the enantiomer of catalyst em-
ployed. Consistent results were obtained in the catalyst-
controlled difluorination of other substituted cinnamyl sul-
fonamides (5b–5e). X-Ray crystal structure analyses of both
diastereomers of 6a revealed that the alkyl chains adopt dra-
matically different conformations in the solid state to mini-
mize unfavorable dipolar interactions between the 1,3-
difluoro substituents. These observations add to the increas-
ing body of evidence that 1,3-difluorides can serve as poten-
tially valuable conformational control elements.
was determined by 19F NMR analysis of the crude mixture.
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The β-fluoroaziridine product 3c was selected as a model
for synthetic elaboration studies. We found that ring open-
ing with different classes of nucleophiles could be effected
smoothly to yield a variety of -fluoro-arylethyl amine prod-
ucts in excellent yields and without compromise of enantio-
meric integrity (Figure 3a). Fluoride opening could be ac-
complished by simply subjecting 3c to HF-pyridine at room
temperature to yield the corresponding 1,3-difluoride (4a).
Treatment of 3c with other strong Brønsted acids such as
hydrobromic and trifluoroacetic acid also resulted in clean
ring opening, affording 4b and 4c respectively. In contrast,
strongly basic nucleophiles were found to promote elimina-
tion pathways predominantly. In accordance with literature
precedent, regioselective ring opening of 3c with trimethylsi-
lyl azide and trimethylsilylcyanide in the presence of catalytic
base was observed to yield 4d and 4e respectively,15 while 4f
was obtained in quantitative yield by heating 3c with thio-
phenol in dimethyl sulfoxide.16 While removal of tosyl pro-
tecting groups is generally challenging, preparation, elabora-
tion and deprotection of the analogous nosyl derivatives (e.g.
3o) proved straightforward (Figure 3b).17 While the fluoro-
aziridination reaction was found to be restricted to cinnamyl
amine derivatives, the aromatic group in 3h could be degrad-
ed oxidatively to a functional carboxylic acid handle in a sim-
ple two-step sequence (Figure 3c).
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Variation of the spacing between the alkene and the sulfon-
amide was examined with an interest in generating fluorinat-
ed N-heterocycles of varying size. Substrates bearing either
two or four methylene groups between the alkene and sul-
fonamide did not form the desired 4- or 6-membered N-
heterocycles. Instead, low reactivity and conversion of the
starting material to multiple uncharacterized fluorinated
products were observed. In contrast, the fluoroamination
protocol was applied successfully to the formation of 5-
membered N-heterocycles. For example, β-fluoropyrrolidine
8 was obtained in good yield and in high levels of diastereo-
and enantioselectivity (Figure 4b). The enantiomeric purity
of 8 was readily upgraded to >99% by recrystallization. While
a syn relationship is observed in the case of the fluoroaziri-
dine products (2a–n), anti-fluoroamination of the alkene in
7 was observed.7a The fluoroaziridination and fluoropyrroli-
dination reactions therefore must proceed by fundamentally
different mechanisms, yet both pathways can be promoted
with high enantioselectivity using the same aryl iodide cata-
lyst 1a.
Figure 3. Synthetic elaboration studies. a, Reactions of fluoroaziri-
dine 3c (upgraded from 97 to 99% ee by recrystallization). b, Reac-
tions of the nosyl-protected fluoroaziridine 3o. c, Oxidative degra-
dation of aromatic group in 3h to a carboxylic acid. Isolated yields
are indicated below each product (4); experimental details are
provided in the Supplementary Information. TBD, triazabicyclode-
cene; TBAF, tetrabutylammonium fluoride.
1,3-Difluorides (6a–e) bearing three contiguous stereocen-
ters were generated when the reaction protocol was applied
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Figure 5. Catalytic diastereo- and enantioselective 1,2-
Figure 4. Extension of the fluoroamination reaction protocol. a,
Formation of 1,3-difluoro-2-amines bearing three contiguous ste-
reocenters from enantioenriched allylic sulfonamides. b, Fluoroam-
ination of bis-homoallylic sulfonamide 7 results in formation of the
corresponding anti-β-fluoro-pyrrolidine. Isolated yields are indicat-
ed below all products; the yield in parentheses corresponds to re-
crystallized product. Full experimental details are provided in the
Supplementary Information.
oxyfluorination reactions. Isolated yields are indicated below each
product. Experimental details are provided in the Supplementary
Information.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
For several classes of cinnamyl derivatives, neighboring
group participation by O-centered functional groups was
found to result in stereoselective generation of oxyfluorinat-
ed products. Benzyl ether 9 underwent a fluorinative rear-
rangement reaction to generate the 1,3-difluoride 10, con-
sistent with formation and fluorinative ring opening of the
corresponding oxiranium ion intermediate. As noted above,
allylic amine substrates bearing carbonyl-containing nitrogen
protecting groups such as carbamates and acetamides were
found to undergo cyclization via reaction at the carbonyl
oxygen rather than the nitrogen, resulting in the formation of
a variety of novel 1,2-oxyfluorinated products (Figure 5). For
example, when the reaction protocol was applied to Cbz-
protected cinnamyl amine 11, formal 1,2-oxyfluorination of
the alkene was observed to generate the cyclic carbamate 12
as a single observable diastereoisomer in good yield and in
93% ee. Allylic acetates such as 13 were observed to undergo
reaction via an analogous pathway, resulting in the formation
of mixtures of hydroxy and acetoxy products that presumably
arise from hydrolytic ring opening of an acetoxonium ion
intermediate. Treatment of the product mixture with acetic
anhydride yielded the corresponding 1-fluoro-2,3-
diacetoxylated product 14 in good yield and as a single ob-
servable diastereoisomer in 94% ee.
Experimental procedures; characterization data (PDF) Crystal-
lographic data for 3b (CIF)
Crystallographic data for 4a (CIF)
Crystallographic data for syn-6a (CIF)
Crystallographic data for anti-6a (CIF)
Crystallographic data for 8 (CIF)
Crystallographic data for 12 (CIF)
Crystallographic data for 16 (CIF)
AUTHOR INFORMATION
Corresponding Author
*jacobsen@chemistry.harvard.edu .
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the NIH (GM043214), and by an
NSF pre-doctoral fellowship to S.M.B. We thank Dr. Shao-Liang
Zheng (Harvard University) for determination of all of the X-ray
crystal structures.
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