Enantioselective, Catalytic Vicinal Difluorination of Alkenes

Article abstract of DOI:10.1002/anie.201810328

The enantioselective, catalytic vicinal difluorination of alkenes is reported by I^I/I^III catalysis using a novel, C₂-symmetric resorcinol derivative. Catalyst turnover via in situ generation of an ArI^IIIF₂ species is enabled by Selectfluor oxidation and addition of an inexpensive HF–amine complex. The HF:amine ratio employed in this process provides a handle for regioselective orthogonality as a function of Br?nsted acidity. Selectivity reversal from the 1,1-difluorination pathway (geminal) to the desired 1,2-difluorination (vicinal) is disclosed (>20:1 in both directions). Validation with electron deficient styrenes facilitates generation of chiral bioisosteres of the venerable CF₃ unit that is pervasive in drug discovery (20 examples, up to 94:06 e.r.). An achiral variant of the reaction is also presented using p-TolI (up to >95 % yield).

Full text of DOI:10.1002/anie.201810328

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Accepted Article
Title: Enantioselective, Catalytic Vicinal Difluorination of Alkenes
Authors: Felix Scheidt, Michael Schäfer, Jérôme Sarie, Constantin
Daniliuc, John Molloy, and Ryan Gilmour
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810328
Angew. Chem. 10.1002/ange.201810328
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Enantioselective, Catalytic Vicinal Difluorination of Alkenes
Felix Scheidt, Michael Schäfer, Jérôme C. Sarie, Constantin G. Daniliuc, John J. Molloy, Ryan
Gilmour*
Abstract: The enantioselective, catalytic vicinal difluorination of
alkenes is reported via I(I)/I(III) catalysis using a novel, C2-symmetric
resorcinol derivative. Catalyst turnover via in situ generation of an
ArI(III)F2 species is enabled by Selectfluor® oxidation and addition of
an inexpensive HF•amine complex. The HF•amine ratio employed in
this process provides a handle for regioselective orthogonality as a
function of Brønsted acidity. Selectivity reversal from the 1,1-
difluorination pathway (geminal) to the desired 1,2-difluorination
(vicinal) is disclosed (>20:1 in both directions). Validation with
electron deficient styrenes facilitates generation of chiral bioisosteres
of the venerable CF3 unit that is pervasive in drug discovery (20
examples, up to 94:6 e.r.). An achiral variant of the reaction is also
presented using p-TolI (up to >95% yield).
enantioselective catalytic vicinal difluorination of styrenes via an
I(I)/I(III) manifold.[15] This catalysis platform has proven to be
particularly competent for the direct fluorination of π-bonds,
often enantioselectively.[16-18]
Herein, an enantioselective, catalytic vicinal difluorination
of electron deficient styrenes employing a novel C2-symmetric,
resorcinol derived aryl iodide is reported. I(I)/I(III) catalysis
turnover is enabled by Selectfluor®-mediated oxidation in the
presence of an inexpensive HF source. Decisively, the Brønsted
acidity of the HF•amine is harnessed to (a) activate the ArIF2
species generated in situ, and (b) achieve regioselective
orthogonality thereby allowing the intrinsic geminal-pathway to
be diverted to favour vicinal-selectivity (Figure 1, bottom).
Reconciling the prominence of vicinal oxidation patterns in
bioactive small molecules with the heterogeneity of the
enantioselective, catalytic dihalogenation arsenal is a strategic
exigency.[1] This imbalance is particularly acute in the direct 1,2-
difluorination of terminal C(sp2)-C(sp2) π-bonds, where general,
catalysis-based strategies are noticeable by their absence.[2]
Comparison with the venerable Sharpless dihydroxylation of α-
olefins[3] serves to underscore this disparity in vicinal oxidation
technologies (Figure 1, top): It is also a compelling impetus for
continued innovation in the programmed difunctionalisation of
terminal alkenes in the broadest sense.[4] A cogent bioisostere of
vicinal diols (Figure 1, right), this motif displays an inverse
temperature dependent dipole moment (d/dT<0)[5] that is
inextricably linked to the stereoelectronic gauche effect
(σC-H→σC-F*),[6] and is a powerful physicochemical modulator in
drug discovery.[7] Despite its palpable value in molecular design,
an asymmetric, catalytic 1,2-difluorination of mono-substituted
alkenes remains an intractable problem.[8] Consequently,
stoichiometric strategies are employed that are predicated on
stereoselective oxidation / deoxyfluorination sequences[9] where
efficiency is frequently compromised by the loss of
configurational integrity. Reagent cost, tempered nucleophilicity,
Figure 1. The vicinal dihydroxylation and difluorination of terminal alkenes.
Following Hara and Yoneda’s seminal disclosure of a
stoichiometric vicinal difluorination of alkenes using p-TolIF2,[19]
contemporaneous studies by Jacobsen and co-workers[17a] and
and solubility issues must also be considered.[10] Whilst achiral
[11]
vicinal difluorination reactions of alkenes employing F2(g)
XeF2
or
[12]
have also been documented, their translation to an
this laboratory[8,17b] translated the reaction to
a catalytic
enantioselective paradigm is doubtful.
paradigm. Common to both strategies was the in situ generation
of ArIF2[20,21] using a terminal oxidant and an inexpensive fluoride
source. Encouraged by the efficiency of these closely similar
platforms, it was envisaged that a chiral resorcinol catalyst
would promote enantioselectivity due to the high degree of
symmetry inherent to these scaffolds.[22,23] Full details of the
catalyst and oxidant optimisation are provided in the SI. An
optimisation process on a model transformation (2 → 3 or 4,
Table 1) quickly revealed catalyst (R,R)-1 to be highly
competent in promoting enantioinduction. Electron deficient 4-
nitrostyrene (2) was employed as a model substrate for this
investigation. Since electron rich styrenes undergo 1,2-
difluorination with Selectfluor® / HF mixtures,[24] it was envisaged
that the deactivating nitro group would simultaneously mitigate
With the rapid expansion of drug discovery into 3-D chemical
space,[13] enabling technologies for the efficient generation of
stereochemically defined, fluorinated motifs from feedstock
precursors will be of increasing importance. Cognisant of the
prominence of trifluoromethylated aryl ring systems (ArCF3) in
contemporary medicinal chemistry,[14] we sought to validate an
M.Sc. F. Scheidt, B.Sc. M. Schäfer, M.Sc. J. C. Sarie, Dr. C. G. Daniliuc,
Dr. J. J. Molloy, Prof. Dr. R. Gilmour
Organisch Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
Homepage: www.uni-muenster.de/chemie.oc/gilmour
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this reactivity and supress the 1,2-phenyl shift that occurs en
route to the geminal product.
to 1:9.2 (Pyr•(HF)x) induced
a
complete reversal of the
regioselectivity thus favouring formation of 4 (gem:vic >20:1,
entry 6). Lowering the ratio to 1:7.5 led to a marginal bias in the
regioselectivity to favour the desired vicinal product (1:2 mixture
of gem:vic, Entry 7). Gratifyingly, further reducing the amine:HF
ratio to 1:4.5 provided the desired vicinal difluorination product
(>20:1 vic:gem) with high levels of enantioselectivity (94:06 e.r.)
albeit in modest yield (35%) (entry 8). Commercial Et3N•5HF
behaved similarly to the 1:7.5 amine:HF ratio and gave
encouraging levels of enantiocontrol (94:06 e.r.), but with
diminished regioselectivity (entry 9). Whereas lowering the
concentration to 0.1 M resulted in poor conversion (entry 10),
extending the reaction time to 48 hours resulted in near
consumption of starting material (entry 11). Acceptable levels of
regio- and stereo-selectivity were also observed (>20:1, 92:08
e.r.). It is interesting to note that the selectivity proved to be
essentially independent of the temperature (0 °C to 35 °C,
entries 12 and 13). Reducing the catalyst loading to 10 mol%
gave unsatisfactory results with respect to conversion and
enantiomeric ratio (entry 14). Finally, the control reaction in the
absence of (R,R)-1 unequivocally established catalysis.
Having identified general conditions for the title
transformation, substrate scope was considered (Figure 2). An
achiral protocol exploiting p-TolI as the catalyst was developed
in parallel with enantioselective process (Methods A and B,
respectively, Figure 2). As a general trend, the racemic reactions
catalysed by p-iodotoluene require shorter reaction times, and
higher yields are obtained than with (R,R)-1. Initially, the three
regioisomers of nitrostyrene were investigated (3a-c). The para-
substituted compound (3a) gave the highest enantioselectivity of
the set (92:08 e.r.). The meta-substituted substrate (2b) was
formed with a reasonable e.r. (83:17), albeit as a 4:1 mixture
with the geminal adduct. Although the ortho-nitro group proved
detrimental to stereoselectivity (75:25 e.r.), complete
suppression of the geminal pathway was observed. Nitrile
substituted styrenes 3d and 3e were well tolerated (90:10 and
86:14 e.r., respectively), and constitute useful benzylic amine
precursors. The p-CF3 group also proved to be sufficiently
electron withdrawing to favour formation of the vicinal product 3f
(75:15 e.r.). Aryl triflates were viable substrates (3g and 3h,
83:17 and 82:18, respectively) and provide a useful handle for
downstream synthetic manipulations.[26] Methylsulfonyl styrenes
of varying substitution pattern were tolerated (3i-k) with
enantioselectivity following the trend para- (3i, 86:14 e.r.) >
meta- (3j, 75:25 e.r.) ≈ ortho- (3k, 77:23 e.r.). Investigation of
disubstituted styrenes began with the effect of ortho-halogen
substituents on meta-nitrostyrenes. Synthetically useful yields
and enantioselectivities were obtained for bromo-, chloro-, and
fluoro-substitution (3l, 3m and 3n, respectively) when the
reaction temperature was increased to 35 °C (up to 83%, >20:1,
86:14 e.r.). In the case of 3o and 3p, the highest regio- and
enantio-selectivities of the study were observed (>20:1, 94:6 and
93:07 e.r., respectively). Exposing 2-vinylanthraquinone to the
standard difluorination conditions afforded 3q in 86% yield and
82:18 e.r. The reaction conditions were sufficiently mild that the
bistriflimide unit was tolerated and 3r could be isolated in good
yields and 85:15 e.r. Trifluoromethyl containing substructures
such as those found in products 3s and 3t (94:6 and 86:14,
respectively) were also smoothly processed.
Table 1. Optimisation of the reaction conditions: Exploring the effect of
Brønsted acidity on regulating regioselectivity and efficiency.[a]
Amine:HF
source
Conversion
Yield %[c]
(gem:vic)
e.r.
(vic)
Entry
1
Solvent
CHCl3
ETFA
[b]
%
1:5
1:5
82
90
14
70
88
>95
47
54
60
30
90
95
70
54
-
71 (1:6)
57 (1:10)
-
87:13
87:13
-
2
3
MTBE
Toluene
MeCN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1:5
4
1:5
13 (1:6)
24 (1:5)
40 (>20:1)
33 (1:2)
35 (>1:20)
52 (1:2)
25 (>1:20)
63 (>1:20)
61 (>1:20)
43 (>1:20)
40 (>1:20)
-
75:25
94:06
-
5
1:5
6
1:9.2
1:7.5
1:4.5
Et3N•5HF
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
7
63:37
94:06
94:06
93:07
92:08
92:08
94:06
88:12
-
8
9
10[d]
11[e]
12[f]
13[g]
14[h]
15[i]
[a]Standard reaction conditions: 4-Nitrostyrene (0.2 mmol), (R,R)-1 (20 mol%),
Selectfluor® (1.5 eq.), amine:HF source (0.5 ml), solvent (0.5 ml)
(concentration 0.2 M), 24 h, ambient temperature. ETFA: Ethyl trifluoroacetate.
[b]Determined by 1H NMR using ethyl fluoroacetate as an internal standard.
[c]Determined by 19F NMR using ethyl fluoroacetate as an internal standard.
[d]Concentration 0.1 M. [e]Reaction time increased to 48 h. [f]Stirred for 24 h at
35 °C. [g]Stirred for 7 days at 0 °C. [h]Catalyst loading 10 mol%. [i]No catalyst.
The effects of the HF•amine ratio on Brønsted acid activation
and in determining regioselectivity (geminal versus vicinal) is
described in Table 1. The optimisation was initiated using
previously reported conditions from this laboratory[17b,25] with
commercially available Selectfluor® as the terminal oxidant and a
mixture of NEt3•3HF and Pyr•(HF)x as amine:HF sources. This
system, which permits careful tuning of the acidity, proved to be
instrumental in augmenting both conversion and selectivity.
Initially, an amine:HF ratio of 1:5 was explored whilst the effect
of reaction medium was examined (entries 1-5). Chloroform was
quickly identified as the solvent of choice with encouraging
enantioselectivity (87:13 e.r.), regioselectivity (1:6 gem:vic) and
yield (71%) being noted (entry 1). Increasing the amine:HF ratio
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100
95
90
85
80
75
70
136 137 138 139 140 141 142 143 144 145 146 147
(Cipso) / ppm
1.95
1.90
1.85
1.80
1.75
1.70
1.65
p-NO
2
p-SO Me
2
p-COCF
m-SO Me
3
m-NO
2
2
p-CF
3
R² = 0.8173
0.7 0.8
0.5
0.6
σ
Figure 2: Establishing the scope of the catalytic, enantioselective vicinal difluorination of electron-deficient styrenes. Method A (racemic) performed with p-TolI as
catalyst. Method B (enantioselective) performed with (R,R)-1. The yield is the sum of vicinal and geminal difluorination products (ratio vic:gem). Yields were
determined by 19F NMR spectroscopy using ethyl fluoroacetate as internal standard. Full experimental details are provided in the SI. Method A: Styrene
(200 µmol), p-Iodotoluene (20 mol%), Selectfluor® (1.5 eq.), CHCl3 (0.5 ml), Amine:HF 1:4.5 (0.5 ml) (concentration 0.2 M), 24–48 h, ambient temperature.
Method B: Styrene (400 µmol), catalyst (R,R)-1 (20 mol%), Selectfluor® (1.5 eq.), CHCl3 (1 ml), Amine:HF 1:4.5 (1 ml) (concentration 0.2 M), 48–96 h, ambient
temperature. [a]Temperature increased to 35 °C. Upper inset: Correlation of the enantioselectivity versus the (Cipso) / ppm. Lower inset: Correlation of the log (ee)
versus the Hammett σ parameter for meta- and para-substituted systems. N.B. The optical rotation values for all substrates are positive with the exception of 1-
(1,2-difluoroethyl)-2-nitrobenzene (3c) in which anchimeric assistance cannot be excluded.[17b]
plotting the log (ee) versus the Hammett σ-parameter (Figure 2,
Plotting the shift of the ipso carbon of the aryl ring (Cipso
against enantioselectivity reveals a loose trend correlating more
electron deficient systems with higher enantioselectivities. The
electronic effect of the substrate was further corroborated by
)
lower inset). Based on a tentative catalytic cycle (Figure 3),
predicated on in situ generation and activation of A, intermediate
B is processed to a common species C: A competition between
final displacement to generate the desired vicinal product, or the
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formation of phenonium ion D leading to the geminal product, is
established. Whilst the simple, C2-symmetric catalyst regulates
stereoselectivity (R- or S-3a, 94:06 and 92:08 e.r., respectively.
As proof of concept, the e.r. of S-3a could be enhanced to 98:02
after recrystallisation), the HF source governs regioselection:
Pyr•(HF)x complex activates the geminal pathway (4), whereas
employing an 1:4.5 amine:HF enables regiodivergence to
generate the desired vicinal products (3) (Figure 3, bottom).
established geminal pathway to favour formation of the desired
vicinal product. Understanding this phenomenon will be the
focus of future research efforts.[10b] Correlations of
enantioselectivity with the log (ee) and the Hammett σ-
parameter reveal the subtle interplay of electronic effects in
determining both the course and selectivity of the process. This
study is a tentative first step towards reconciling the importance
of the vicinal difluoro motif in structural chemistry with the
strategic exigency in the catalysis ordnance.
Experimental Section
Full experimental details are provided in the Supporting Information.
Acknowledgements
We acknowledge financial support from the WWU Münster, the
DFG: “Cells in Motion, Cluster of Excellence” (CiM, FF-2013-10)
and SFB 858, and the European Research Council (ERC-2013-
StG Starter Grant to RG - Project number 336376-ChMiFluorS).
Keywords: Brønsted acid
enantioselectivity • iodine
•
catalysis
•
difluorination
•
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In summary, the enantioselective, catalytic vicinal difluorination
of electron deficient styrenes is disclosed via I(I)/I(III) catalysis.
Brønsted acidity is
a critical parameter in diverting the
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[15] For
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Entry for the Table of Contents
COMMUNICATION
Felix Scheidt, Michael Schäfer, Jérôme
C. Sarie, Constantin G. Daniliuc, John J.
Molloy, Ryan Gilmour
Page No. – Page No.
Enantioselective, Catalytic, Vicinal
Difluorination of Alkenes
The enantioselective, catalytic vicinal difluorination of alkenes is reported via I(I)/I(III) catalysis using a novel, C2-symmetric resorcinol derivative. The
HF•amine ratio employed in this process provides a handle for regioselective orthogonality as a function of Brønsted acidity. Selectivity reversal from the
1,1-difluorination pathway (geminal) to the desired 1,2-difluorination (vicinal) is disclosed (>20:1 in both directions). Validation with electron deficient
styrenes facilitates generation of chiral bioisosteres of the venerable CF3 unit that is pervasive in drug discovery (20 examples, up to 94:6 e.r.). An achiral
variant of the reaction is also presented using p-TolI (up to >95% yield).
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