Geminal difluorination of α,α’- disubstituted styrenes using fluoro-benziodoxole reagent. Migration aptitude of the α-substituents

Article abstract of DOI:10.1016/j.jfluchem.2017.07.006

α,α’-Disubstituted styrenes undergo a difluorination-rearrangement reaction with fluoro-benzoiodoxole reagent 1. The reaction is catalyzed by Pd(MeCN)₄(BF₄)₂ and Cu(MeCN)₄PF₆. We have studied the rear

Full text of DOI:10.1016/j.jfluchem.2017.07.006

Accepted Manuscript
Title: Geminal difluorination of ␣,␣’-Disubstituted styrenes
using fluoro-Benziodoxole reagent. migration aptitude of the
␣-Substituents
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´
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Authors: Nadia O. Ilchenko, Kalman J. Szabo
PII:
S0022-1139(17)30274-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.07.006
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13-7-2017
14-7-2017
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Please cite this article as: Nadia O.Ilchenko, Kalman J.Szabo, Geminal
difluorination of ␣,␣’-Disubstituted styrenes using fluoro-Benziodoxole
reagent.migration aptitude of the ␣-Substituents, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.07.006
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Geminal Difluorination of ’-Disubstituted Styrenes using Fluoro-
Benziodoxole Reagent. Migration Aptitude of the -Substituents
Nadia O. Ilchenko and Kálmán J. Szabó*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden.
Dedicated to Professor Antonio Togni on the occasion of receiving the ACS Award for Creative Work
in Fluorine Chemistry
Graphical abstract
Highlights (see also cover letter):

-substituted styrenes.
 The fluorination reaction was carried out with fluoro-benzoiodoxole reagent 1 in the presence of
copper or palladium-catalyst.

-substituent.
 We studied the electronic effects of the aryl substituents on the migration aptitude in this reac-
tion.

-
-alkyl type of disubstitution the alkyl group underwent migration. In
case of cyclic styrenes ring expansion and ring contraction reactions could be performed.
ABSTRACT: ,’-Disubstituted styrenes undergo a difluorination-rearrangement reaction with fluoro-
benzoiodoxole reagent 1. The reaction is catalyzed by Pd(MeCN)4(BF4)2 and Cu(MeCN)4PF6. We have
studied the rearrangement of ,’-diaryl substituted styrenes, in which the aryl groups have different
electronic character. In the case of -aryl, ’-alkyl substituted styrenes, the aryl substituent has a higher
migratory aptitude than the alkyl group. We have also extended the reactions to cycloalkyl styrenes,
which underwent interesting ring contraction/expansion reactions. The regioselectivity of the migration
can be explained on the basis of the formation of a phenonium intermediate.
KEYWORDS: difluorination, rearrangement, hypervalent fluoroiodine.
1. Introduction
Fluorine substituents have specific effects on the physical, chemical and biological properties of or-
ganic molecules [1-4]. Organofluorine compounds are particularly important in pharmaceutical [2, 5, 6]
and agrochemical products [4, 7, 8], as well as in medical diagnostics, such as Positron Emission To-
mography [9, 10] and Magnetic Resonance Imaging [11]. Although monofluoro- and trifluomethyl
compounds have found the widest application in the life sciences, the synthesis and application of
difluoromethyl derivatives have received increasing attention, as of late. Difluoromethyl compounds are
bioisosters of hydroxyl groups and have the ability to form hydrogen bonds [12] with enzymes and re-

ceptors [13, 14]. The demand for a large variety of new organodifluorides provides an impetus for de-
veloping new methodologies for the selective synthesis of geminal difluoroalkanes. Early methodolo-
gies for introducing the CF2 moiety were primarily based on highly reactive fluorinating reagents, such
as XeF2 [15] and DAST [16]. However, application of these reagents may lead to problems with func-
tional group tolerance, selectivity issues, low yields and hazardous HF development upon contact with
water. Recently, stable and safe reagents have been utilized, often in the presence of catalysts for
difluorination reactions. Typical methods involve cross-coupling reactions with suitable CF2 carriers
[17-22], radical-[23-25], photoredox-difluorination [26] and application of hypervalent iodine reagents
[27-30] as the fluorine source. Recently, we employed fluoro-benziodoxole 1 [31-33] as the fluorine
source for the difluorination of alkenes [27] and cyclopropane derivatives [34]. Reagent 1 is closely
related with the privileged trifluoromethylation reagents, Togni-I and II [31, 35-40], which were em-
ployed very successfully in selective introduction of the CF3 group [41-43].
According to our previous studies [27] into the difluorination of styrenes with 1 and AgBF4, the reaction
leads to geminal difluorination with rearrangement of the  and -carbons of the alkene (Figure 1). The
reason for the apparent rearrangement is the formation of a fluoro-phenonium intermediate, which sub-
sequently undergoes a second fluorination mediated by the BF4 counterion [44] of the silver catalyst.
When the reaction was performed with -methyl styrene (R’ = Me), the methyl group was directly
bonded to the difluorinated (yellow colored) carbon of the product, indicating that the aryl group prefer-
entially migrated (and not the methyl group). In the present study, we investigated the migratory apti-
tude of different R’ substituents in this reaction, and explored the possibility of employing the above
rearrangement for both ring expansion and contraction reactions.
2. Results and discussion
First we directed our studies towards ,’-diaryl styrenes, with the intention of unearthing any sub-
stituent effects of the aryl groups migratory aptitude. Therefore, we first optimized the reaction condi-
tions for the difluorination of 2a.
2.1 Variation of the reaction conditions for the difluorination of 2a. After careful optimization, we
found that 2a undergoes difluorination and rearrangement using 1 and catalytic amounts (20 mol%) of
Pd(MeCN)4(BF4)2 as the catalyst affording 4a in 64% yield (Table 1, header). We employed CDCl3 as
the solvent instead of CHCl3, in order to analyze the crude reaction mixture and monitor the conversion
of 2a with 1H NMR. In this process, we used the same amount (0.1 mmol) of 2a and 1. As the isolated
yield is higher than 50%, the second fluoride, at least in part, arises from the BF4 counterion of Pd. We
have found a similar secondary fluorination process in our previous studies with styrene derivatives
(Figure 1) [27]. When we replaced the Pd-catalyst with AgBF4, only traces of products were observed
from 2a and 1 (Table 1, entry 1). In fluorocyclization reactions [45] with 1, Zn(BF4)2 proved to be a
very efficient catalyst. However, Zn(BF4)2 proved to be inefficient as the catalyst in this reaction (entry
2). When the amount of Pd(MeCN)4(BF4)2 was reduced to 10% the yield decreased from 64% to 27%.
When we replaced 3 with 20 mol% of Cu(MeCN)4PF6, we obtained 4a in 32% yield (entry 3). Alt-
hough, this yield is apparently lower than with the analogous Pd-catalyst, in some other reactions (see
below) the Cu-catalyst outperformed 3. Cu(MeCN)4BF4 proved to be less efficient than the PF6 analog
(c.f. entries 3 and 4). When we performed the reactions in MeCN or dioxane the yields dropped substan-
tially to 37% and 17%, respectively (entries 5-6). Only traces of product were observed in DCM or THF
(entry 7).
2.2 Rearrangements of diaryl substrates. First we studied the migratory aptitude of differentially sub-
stituted ,’-diaryl compounds 2b-e (Table 2, entries 2-5). In 2b-2d one of the aryl groups was the
simple unsubstituted phenyl group, while the others had one electron donating substituent (entries 2-4).

When, these compounds underwent the difluorination-rearrangment reaction the phenyl group was di-
rectly bonded to the difluorinated carbon in products 4b-d. In these reactions the formation of regioiso-
meric compounds to 4b-d was not observed. The regioselectivity of the rearrangement indicates that the
electron-rich aryl group bearing the Me (entry 2) and OR (entries 3-4) groups forms the fluorinated phe-
nonium ion and therefore also migrates (see also Figure 1). We have also carried out the reaction be-
tween electron deficient, fluoro substituted 2e and an electron-rich OMe substituted aryl group (entry 5).
The fluoro substituted aryl group appeared at the difluorinated carbon in 4e, indicating that the anisyl
group underwent migration and not the fluoro-aryl moiety. The structure of 4e was determined on the
13
basis of the C spectrum of 4e (see Figure 4 in the experimental part). The position of the fluorine at-
oms could be assigned on the basis of the coupling constants and multiplicity of the C-F couplings.
Considering the structural similarity of 4b-4d to 4e, we used also used this information for structural
assignment of 4b-d.
2.3 Rearrangement of -phenyl-’-alkyl substututed substrates. Similar to the AgBF4 mediated reac-
tion of -methyl styrene (Figure 1) ethyl (2f), propyl (2g), butyl and isopropyl (2i) moieties appeared at
the difluorinated carbon (entries 6-9) using Pd(MeCN)4(BF4)2 as the catalyst. As we reported previously
[34], cyclopropanes bearing alkyl substuents undergo difluorinative ring opening using AgBF4 as the
mediator. When we used cyclopropane derivative 2j as the substrate with 1 and Pd(MeCN)4(BF4)2 as the
catalyst a complex reaction mixture was obtained. However, when we replaced Pd(MeCN)4(BF4)2 with
Cu(MeCN)4PF6 as the catalyst, the reaction gave 4j with 58% yield (entry 10). In this reaction the aryl
ring migrated and the cyclopropane remained unopened. When benzyl derivative 2k reacted in the pres-
ence of Pd(MeCN)4(BF4)2, we obtained an inseparable mixture mixture of 4k and most likely its regioi-
somer. However, when the catalyst was changed to Cu(MeCN)4PF6, 4k formed as the sole product (en-
try 2k) in high yield (70%).
a
A mixture of styrene 2 (0.1 mmol), 1 (0.1 mmol), 3 (0.02 mmol, 20 mol%) was dissolved in CDCl3
o
under Ar. The reaction mixture was stirred at 40 C for 18h. The yields refer to isolated yields after
b
c
chromatography. Cu(MeCN)4PF6 (0.02 mmol, 20 mol%) was used instead of 3. 1 (0.2 mmol) was
used. d The reaction mixture was stirred at 40 oC for 4 h.
2.4 Ring expansion and contraction. We also wanted to study how this migration process would pro-
ceed with styrene derivateves embedded within benzofused-cyclic substrates. Dihydronaphthalene
(bearing an endocyclic alkene), 2l underwent an interesting ring contraction to 4l in a difluorination-
rearrangment sequence. The best yield (48%) was obtained using Cu(MeCN)4PF6 as the catalyst and
two equivalents of 1 (entry 12). On the other hand, when exocyclic alkenes 2m and 2n were used as
substrates, ring expansion products 4m-n were obtained. In these cases, the Cu(MeCN)4PF6 catalyst
gave the best yields (61 and 50%), when the reaction was carried out at 40 °C for 4 hours (entries 13-
14).
2.5. Plausible mechanism for the difluorination-rearrangement reaction. Considering our previous
mechanistic studies [27, 46] and recently reported DFT modeling studies [47, 48] for the fluorination of
alkenes with 1, we suggest the mechanism given in Figure 2.
Fluorobenzoiodoxole 1 is activated by coordination of palladium to the fluorine atom. Then, 1 under-
goes isomerization providing the more electrophilic complex 5. Our DFT studies on the mechanism of

fluorination reactions with 1 showed that this metal catalyzed isomerization is a pre-requisite of the effi-
cient fluor transfer from the hypervalent iodine to the organic substrate [47]. The I-F bond undergoes
metathesis to form 7 [47]. A possible intermediate or TS of the reaction is iodocyclopropane 6 [48]. Two
-electrons of the aryl group form one of the C-C -bond in phenonium ion 8 by displacement of the
iodine [48]. If there are two arenes available, as in 2e the electron-rich arene (i.e. the OMe substituted)
will preferentially form the phenonium ion. The next step is nucleophilic attack of the fluoride of the
BF4 counterion at the fluorinated carbon. This attack proceeds with a high level of regioselectivity prob-
ably due to the high electrophilicity of the fluorinated carbon atom. This second fluorination leads to
formation of product 4e.
3. Conclusions
In summary, we have studied the difluorination-rearrangement reactions of ,’-disubstituted sty-
renes. We have found that the reactions proceed with high selectivity at room temperature using 1 and
Pd(MeCN)4(BF4)2 or Cu(MeCN)4PF6 catalysts. In the case of electronically biased ,-diarylalkenes, the
electron-rich aryl substituent will preferentially undergo migration. Aryl groups have a higher migration
aptitude than alkyl groups, which can also be employed for ring contraction and expansion reactions.
The reactions outcome can be explained by catalytic activation of 1 followed by selective formation of a
phenonium intermediate.
4. Experimental
4.1.General information
Hypervalent iodine 1 [31, 32] and α-substituted styrenes[49] 4a-n were prepared according to literature
procedures. All other chemicals were obtained from commercial sources and used as received. 1H NMR,
19
1
13C NMR and F NMR spectra were recorded in CDCl3 (internal standard: 7.26 ppm, H; 77.2 ppm,
13C) using 400 MHz spectrometers. For column chromatography, silica gel (35-70 microns) was used.
Unless otherwise stated, all the reactions were performed under Ar atmosphere. We were not able to
obtain proper high-resolution mass data for products 4a-n, therefore, we provide EI mass data in the
characterization.
4.2. General procedure
Reagent 1 (28.0 mg, 0.1 mmol), the corresponding α,’-substituted styrene 2 (0.1 mmol)
Pd(MeCN)4(BF4)2 (3) (8.9 mg, 0.02 mmol) were mixed in CDCl3 (0.5 ml). This reaction mixture was
o
stirred at 40 C for 18 h. The products 4a-n were isolated by silica gel column chromatography using
petroleum ether: ether (100:1) system.
4.2.1. (1,1-difluoroethane-1,2-diyl)dibenzene (4a)
This product was prepared according to the above general procedure. Compound 4a appeared as a white
solid (14 mg, 64%). 1H-NMR (400 MHz, CDCl3) δ 7.42-7.31 (m, 5H), 7.25-7.22 (m, 3H), 7.14-7.07 (m,
2H), 3.40 (t, JHF = 15.8 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 137.0 (t, JCF = 26.4 Hz), 132.8 (t, JCF
=
4.3 Hz), 130.8, 129.8 (t, JCF = 1.5 Hz), 128.3, 128.3, 127.4, 125.4 (t, JCF = 6.2 Hz), 122.1 (t, JCF = 244.3
Hz), 46.1 (t, JCF = 28.7 Hz). 19F-NMR (377 MHz, CDCl3) δ -94.9 (t, JHF = 15.9 Hz). (EI) m/z (rel intens)
218 (M+, 32), 128 (10), 127 (100), 91 (43), 77 (10). Mp: 63-66 oC.
4.2.2. 1-(2,2-difluoro-2-phenylethyl)-4-methylbenzene (4b)
This product was prepared according to the above general procedure. Compound 4b appeared as a yel-
low oil (9 mg, 54%). 1H-NMR (400 MHz, CDCl3) δ 7.44-7.29 (m, 5H), 7.10-6.90 (m, 4H), 3.36 (t, JHF
=
15.8 Hz, 2H), 2.31 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 137.1 (t, JCF = 26.2 Hz), 137.0, 130.6, 129.7
(t, JCF = 1.9 Hz), 129.7, 129.0, 128.3, 125.4 (t, JCF = 6.2 Hz), 122.1 (t, JCF = 244.4 Hz), 45.6 (t, JCF
=

19
28.5 Hz), 21.3. F-NMR (377 MHz, CDCl3) δ -95.0 (t, JHF = 15.9 Hz). (EI) m/z (rel intens) 232 (M+,
42), 127 (27), 106 (10), 105 (100), 77 (10).
4.2.3. 1-(2,2-difluoro-2-phenylethyl)-4-methoxybenzene (4c)
This product was prepared according to the above general procedure. Compound 4c appeared as a white
solid (13 mg, 52%). 1H-NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 7.02-6.95 (m, 2H), 6.81-6.73 (m,
2H), 3.78 (s, 3H), 3.34 (t, JHF = 15.8 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 159.0, 137.1 (t, JCF = 26.6
Hz), 131.8, 129.7 (t, JCF = 1.9 Hz), 128.3, 125.4 (t, JCF = 6.0 Hz), 124.9 (t, JCF = 4.3 Hz), 122.2 (t, JCF
=
243.9 Hz), 113.8, 55.4, 45.2 (t, JCF = 28.6 Hz). 19F-NMR (377 MHz, CDCl3) δ -95.2 (t, JHF = 15.8 Hz).
(EI) m/z (rel intens) 248 (M+, 29), 127 (6), 122 (12), 121 (100), 77 (9). Mp: 90-93 oC.
4.2.4. 1-(2,2-difluoro-2-phenylethyl)-4-phenoxybenzene (4d)
This product was prepared according to the above general procedure. Compound 4d appeared as a white
solid (18 mg, 66%). 1H-NMR (400 MHz, CDCl3) δ 7.44-7.27 (m, 7H), 7.19-6.95 (m, 5H), 6.92-6.85 (m,
2H), 3.38 (t, JHF = 15.8 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 157.3, 156.7, 137.0 (t, JCF = 26.8 Hz),
132.1, 129.9, 129.8 (t, JCF = 2.1 Hz), 128.4, 127.6 (t, JCF = 4.5 Hz), 125.4 (t, JCF = 6.6 Hz), 123.5, 122.1
19
(t, JCF = 244.0 Hz), 119.1, 118.7, 45.3 (t, JCF = 28.7 Hz). F-NMR (377 MHz, CDCl3) δ -95.3 (t, JHF
=
15.7 Hz). (EI) m/z (rel intens) 310 (M+, 40), 311 (9), 184 (14), 183 (100), 77 (14). Mp: 76-79 oC.
4.2.5. 1-(2,2-difluoro-2-(4-fluorophenyl)ethyl)-4-methoxybenzene (4e)
This product was prepared according to the above general procedure. Compound 4e appeared as a yel-
1
low oil (18 mg, 67%). H-NMR (400 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 7.05-6.95 (m, 4H), 6.82-6.72
(m, 2H), 3.78 (s, 3H), 3.32 (t, JHF = 15.8 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ 163.7 (dt, JCF = 248.7,
1.9 Hz), 159.1, 133.1 (td, JCF = 27.5, 3.1 Hz), 131.8, 127.6 (dt, JCF = 8.6, 6.2 Hz), 124.6 (t, JCF = 4.6
19
Hz), 122.0 (t, JCF = 243.6 Hz), 115.5 (d, JCF = 22.0 Hz), 113.8, 55.4, 45.2 (t, JCF = 28.9 Hz). F-NMR
(377 MHz, CDCl3) δ – 94.1 (t, JHF = 15.6 Hz), -111.6--111.7 (m). (EI) m/z (rel intens) 266 (M+, 64),
145 (18), 122 (51), 121 (100), 77 (21).
The position of the fluorine atoms were determined on the basis of the 13C NMR spectrum of 4e by
analysis of the coupling constants and their multiplicity (Figure 3). The aromatic C1 carbon has a large
doublet C-F coupling of 248.7 Hz and a triplet coupling of 1.9 Hz. In C2 and C3 the doublet C-F cou-
plings are successively decreased (22 Hz and 8.6 Hz) At C4 and C5 the C-F triplet couplings are in-
creasing (27.5 Hz and 243.6 Hz). The benzylic carbon C6 has a C-F triplet coupling of 28.9 Hz and C7
still displays a minor C-F triplet coupling of 4.6 Hz. The other carbons of the anisyl ring do not display
any C-F couplings.
4.2.6. (2,2-difluorobutyl)benzene (4f)
This product was prepared according to the above general procedure. Compound 4f appeared as a color-
1
less oil (13 mg, 76%). H-NMR (400 MHz, CDCl3) δ 7.36-7.27 (m, 5H), 3.14 (t, JHF = 15.8 Hz, 2H),
1.88-1.68 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 133.8 (t, JCF = 5.0 Hz),
130.4, 128.6, 127.4, 124.7 (t, JCF = 242.0 Hz), 42.8 (t, JCF = 26.6 Hz), 29.1 (t, JCF = 25.7 Hz), 6.6 (t, JCF
= 5.5 Hz). 19F-NMR (377 MHz, CDCl3) δ – 98.6 (tt, JHF = 16.4, 16.3 Hz). (EI) m/z (rel intens) 170 (M+,
22), 92 (11), 91 (100), 79 (2), 65 (6).
4.2.7. (2,2-difluoropentyl)benzene (4g)
This product was prepared according to the above general procedure. Compound 4g appeared as a color-
1
less oil (16 mg, 75%). H-NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 5H), 3.13 (t, JHF = 16.4 Hz, 2H),
1.81-1.64 (m, 2H),1.54-1.44 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 133.7 (t,
JCF = 4.6 Hz), 130.4, 128.6, 127.4, 124.4 (t, JCF = 242.8 Hz), 43.0 (t, JCF = 25.7 Hz), 37.9 (t, JCF = 25.3

19
Hz), 15.7 (t, JCF = 4.9 Hz), 14.1. F-NMR (377 MHz, CDCl3) δ - 96.5 (tt, JHF = 16.0, 15.8 Hz). (EI)
m/z (rel intens) 184 (M+, 31), 169 (4), 92 (20), 91 (100), 65 (11).
4.2.8. (2,2-difluoroheptyl)benzene (4h)
This product was prepared according to the above general procedure. Compound 4h appeared as a col-
1
orless oil (15 mg, 68%). H-NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 3.13 (t, JHF = 15.9 Hz, 2H),
1.82-1.64 (m, 2H), 1.53-1.45 (m, 2H), 1.34-1.22 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H). 13C-NMR (100 MHz,
CDCl3) δ 133.8 (t, JCF = 4.6 Hz), 130.5, 128.6, 127.4, 124.5 (t, JCF = 241.8 Hz), 43.1 (t, JCF = 26.6 Hz),
35.9 (t, JCF = 24.8 Hz), 31.7, 22.6, 22.0 (t, JCF = 4.4 Hz), 14.1. 19F-NMR (377 MHz, CDCl3) δ - 96.5 (tt,
JHF = 16.5, 16.1 Hz). (EI) m/z (rel intens) 212 (M+, 19), 169 (5), 92 (19), 91 (100), 65 (4).
4.2.9. (2,2-difluoro-3-methylbutyl)benzene (4i)
This product was prepared according to the above general procedure. Compound 4i appeared as a color-
1
less oil (12 mg, 62%). H-NMR (400 MHz, CDCl3) δ 7.36-7.27 (m, 5H), 3.14 (t, JHF = 17.1 Hz, 2H),
13
2.06-1.90 (m, 1H), 1.04 (d, J = 6.9 Hz, 6H). C-NMR (100 MHz, CDCl3) δ 133.7 (t, JCF = 4.2 Hz),
130.5, 128.5, 127.3, 125.6 (t, JCF = 245.3 Hz), 40.6 (t, JCF = 26.4 Hz), 33.8 (t, JCF = 24.2 Hz), 16.0 (t,
JCF = 4.9 Hz). 19F-NMR (377 MHz, CDCl3) δ -105.1 (td, JHF = 16.8, 13.8 Hz). (EI) m/z (rel intens) 184
(M+, 24), 93 (5), 92 (28), 91 (100), 65 (13).
4.2.10. (2-cyclopropyl-2,2-difluoroethyl)benzene (4j)
This product was prepared according to the above general procedure. Cu(MeCN)4PF6 (7.5 mg, 0.02
mmol) was used instead of Pd(MeCN)4(BF4)2 (3). Compound 4j appeared as a colorless oil (14 mg,
58%). 1H-NMR (400 MHz, CDCl3) δ 7.35-7.28 (m, 5H), 3.21 (t, JHF = 15.6 Hz, 2H), 1.21-1.05 (m, 1H),
0.67-0.41 (m, 4H). 13C-NMR (100 MHz, CDCl3) δ 133.7 (t, JCF = 4.6 Hz), 130.6, 128.5, 127.4, 122.9 (t,
19
JCF = 244.5 Hz), 44.3 (t, JCF = 25.2 Hz), 15.5 (t, JCF = 29.5 Hz), 1.5 (t, JCF = 4.6 Hz). F-NMR (377
MHz, CDCl3) δ – 101.8 (dt, JHF = 15.1, 13.1 Hz). (EI) m/z (rel intens) 182 (M+, 14), 147 (17), 117 (11),
91 (100), 65 (11).
4.2.11. (2,2-difluoropropane-1,3-diyl)dibenzene (4k)
This product was prepared according to the above general procedure. Cu(MeCN)4PF6 (7.5 mg, 0.02
mmol) was used instead of Pd(MeCN)4(BF4)2 (3). Compound 4k appeared as a colorless oil (15 mg,
70%). 1H-NMR (400 MHz, CDCl3) δ 7.36-7.28 (m, 6H), 7.25-7.23 (m, 4H), 3.10 (t, JHF = 16.2 Hz, 4H).
13C-NMR (100 MHz, CDCl3) δ 133.4 (t, JCF = 4.2 Hz), 130.7, 128.6, 127.5, 123.3 (t, JCF = 243.6 Hz),
42.6 (t, JCF = 25.8 Hz). 19F-NMR (377 MHz, CDCl3) δ – 94.8 (tt, JHF = 16.5, 16.2 Hz). (EI) m/z (rel in-
tens) 232 (M+, 51), 141 (16), 92 (35), 91 (100), 65 (11).
4.2.12. 1-(difluoromethyl)-2,3-dihydro-1H-indene (4l)
This product was prepared according to the above general procedure using fluoroiodane reagent 1 (56
1
mg, 0.2 mmol). Compound 4l appeared as a colorless oil (8 mg, 48%). H-NMR (400 MHz, CDCl3) δ
7.39-7.31 (m, 1H), 7.25-7.17 (m, 3H), 5.79 (td, JHF = 57.1, 5.5 Hz, 1H), 3.71-3.51 (m, 1H), 3.09-2.80
(m, 2H), 2.37-2.23 (m, 1H), 2.18-1.95 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ 145.1, 128.1, 126.7,
125.6, 125.5, 124.9, 118.3 (t, JCF = 245.2 Hz), 49.2 (t, JCF = 20.1 Hz), 31.6, 25.5 (t, JCF = 4.3 Hz). 19F-
NMR (377 MHz, CDCl3) δ – 118.8 (ddd, JHF =56.9, 38.3, 14.2 Hz). (EI) m/z (rel intens) 168 (M+, 27),
118 (9), 117 (100), 115 (30), 91 (6).
4.2.13. 6,6-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulene (4m)
This product was prepared according to the above general procedure. The reaction mixture was stirred at
1
40oC for 4 h. Compound 4m appeared as a colorless oil (10 mg, 61%). H-NMR (400 MHz, CDCl3) δ
7.23-7.13 (m, 3H), 7.12-7.06 (m, 1H), 3.32 (t, JHF = 13.4 Hz, 2H), 2.86-2.76 (m, 2H), 2.28-2.15 (m,
2H), 1.82-1.71 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 142.2, 132.6 (t, JCF = 7.3 Hz), 131.4, 129.3,

127.7, 126.8, 121.8 (t, JCF = 243.6 Hz), 44.1 (t, JCF = 28.9 Hz), 39.6 (t, JCF = 26.4 Hz), 34.9, 22.9 (t, JCF =
19
5.9 Hz). F-NMR (377 MHz, CDCl3) δ – 89.4– -90.6 (m). (EI) m/z (rel intens) 182 (M+, 100), 148
(25), 147 (68), 134 (45), 117 (26).
4.2.14. 2,2-difluoro-1,2,3,4-tetrahydronaphthalene (4n)
This product was prepared according to the above general procedure. The reaction mixture was stirred at
1
40oC for 4 h. Compound 4n appeared as a colorless oil (9 mg, 50%). H-NMR (400 MHz, CDCl3) δ
7.23-7.13 (m, 3H), 7.11-7.04 (m, 1H), 3.26 (t, JHF = 15.0 Hz, 2H), 3.02 (t, JHF = 6.6 Hz, 2H), 2.30-2.03
13
(m, 2H). C-NMR (100 MHz, CDCl3) δ 134.2, 131.9 (t, JCF = 5.6 Hz), 129.3, 128.7, 126.8, 126.6,
123.3 (t, JCF = 240.0 Hz), 38.2 (t, JCF = 27.9 Hz), 31.3 (t, JCF = 24.0 Hz), 27.2 (t, JCF = 5.5 Hz). 19F-
NMR (377 MHz, CDCl3) δ – 95.6 (tt, JHF = 14.3, 14.0 Hz). (EI) m/z (rel intens) 168 (M+, 100), 149
(23), 147 (51), 104 (23), 78 (28).
ACKNOWLEDGMENT
The authors thank the financial support of the Swedish Research Council (VR) and the Knut och Alice
Wallenbergs Foundation.
REFERENCES
[1] K. Müller, C. Faeh, F. Diederich, Science, 317 (2007) 1881-1886.
[2] S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev., 37 (2008) 320-330.
[3] D. O’Hagan, J. Fluor. Chem., 131 (2010) 1071-1081.
[4] T. Fujiwara, D. O’Hagan, J. Fluor. Chem., 167 (2014) 16-29.
[5] J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. del Pozo, A.E. Sorochinsky, S. Fustero, V.A.
Soloshonok, H. Liu, Chem. Rev., 114 (2014) 2432-2506.
[6] Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Aceña, V.A. Soloshonok, K. Izawa, H. Liu, Chem.
Rev., 116 (2016) 422-518.
[7] F. Giornal, S. Pazenok, L. Rodefeld, N. Lui, J.-P. Vors, F.R. Leroux, J. Fluor. Chem., 152 (2013) 2-
11.
[8] P. Jeschke, R. Nauen, M.E. Beck, Angew. Chem. Int. Ed., 52 (2013) 9464-9485.
[9] P.W. Miller, N.J. Long, R. Vilar, A.D. Gee, Angew. Chem. Int. Ed., 47 (2008) 8998-9033.
[10] S. Preshlock, M. Tredwell, V. Gouverneur, Chem. Rev., 116 (2016) 719–766.
[11] J. Ruiz-Cabello, B.P. Barnett, P.A. Bottomley, J.W.M. Bulte, NMR in Biomedicine, 24 (2011) 114-
129.
[12] C.D. Sessler, M. Rahm, S. Becker, J.M. Goldberg, F. Wang, S.J. Lippard, J. Am. Chem. Soc.,
(2017) 10.1021/jacs.1027b04457.
[13] N.A. Meanwell, J Med Chem, 54 (2011) 2529-2591.
[14] F. Narjes, K.F. Koehler, U. Koch, B. Gerlach, S. Colarusso, C. Steinkühler, M. Brunetti, S.
Altamura, R. De Francesco, V.G. Matassa, Bioorganic & Medicinal Chemistry Letters, 12 (2002) 701-
704.
[15] T.B. Patrick, S. Qian, Org. Lett., 2 (2000) 3359-3360.
[16] W.J. Middleton, J. Org. Chem., 40 (1975) 574-578.
[17] Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang, X. Zhang, Angew. Chem. Int. Ed., 53 (2014) 1669-
1673.
[18] G.K.S. Prakash, S.K. Ganesh, J.-P. Jones, A. Kulkarni, K. Masood, J.K. Swabeck, G.A. Olah,
Angew. Chem. Int. Ed., 51 (2012) 12090-12094.
[19] P.S. Fier, J.F. Hartwig, J. Am. Chem. Soc., 134 (2012) 5524-5527.
[20] X.-L. Jiang, Z.-H. Chen, X.-H. Xu, F.-L. Qing, Organic Chemistry Frontiers, 1 (2014) 774-776.
[21] M.D. Kosobokov, V.V. Levin, A.A. Zemtsov, M.I. Struchkova, A.A. Korlyukov, D.E. Arkhipov,
A.D. Dilman, Org. Lett., 16 (2014) 1438-1441.

[22] A.A. Zemtsov, N.S. Kondratyev, V.V. Levin, M.I. Struchkova, A.D. Dilman, J. Org. Chem.,
Submitted (2013).
[23] Q. Zhou, A. Ruffoni, R. Gianatassio, Y. Fujiwara, E. Sella, D. Shabat, P.S. Baran, Angew. Chem.
Int. Ed., 52 (2013) 3949-3952.
[24] Y. Fujiwara, J.A. Dixon, F. O'Hara, E.D. Funder, D.D. Dixon, R.A. Rodriguez, R.D. Baxter, B.
Herle, N. Sach, M.R. Collins, Y. Ishihara, P.S. Baran, Nature, 492 (2012) 95-99.
[25] P. Xu, S. Guo, L. Wang, P. Tang, Angew. Chem. Int. Ed., 53 (2014) 5955-5958.
[26] J.-B. Xia, C. Zhu, C. Chen, J. Am. Chem. Soc., 135 (2013) 17494-17500.
[27] N.O. Ilchenko, B.O.A. Tasch, K.J. Szabó, Angew. Chem. Int. Ed., 53 (2014) 12897-12901.
[28] S.M. Banik, J.W. Medley, E.N. Jacobsen, Science, 353 (2016) 51-54.
[29] T. Kitamura, K. Muta, J. Oyamada, J. Org. Chem., 80 (2015) 10431-10436.
[30] I.G. Molnár, R. Gilmour, J. Am. Chem. Soc., 138 (2016) 5004-5007.
[31] V. Matoušek, E. Pietrasiak, R. Schwenk, A. Togni, J. Org. Chem., 78 (2013) 6763–6768.
[32] G.C. Geary, E.G. Hope, K. Singh, A.M. Stuart, Chem. Commun., 49 (2013) 9263-9265.
[33] S.V. Kohlhepp, T. Gulder, Chem. Soc. Rev., 45 (2016) 6270-6288.
[34] N.O. Ilchenko, M. Hedberg, K.J. Szabo, Chem. Sci., 8 (2017) 1056-1061.
[35] I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem. Int. Ed., 46 (2007) 754-757.
[36] R. Koller, K. Stanek, D. Stolz, R. Aardoom, K. Niedermann, A. Togni, Angew. Chem. Int. Ed., 48
(2009) 4332-4336.
[37] M.S. Wiehn, E.V. Vinogradova, A. Togni, J. Fluor. Chem., 131 (2010) 951-957.
[38] K. Niedermann, N. Früh, E. Vinogradova, M.S. Wiehn, A. Moreno, A. Togni, Angew. Chem. Int.
Ed., 50 (2011) 1059-1063.
[39] E. Mejía, A. Togni, ACS Catal., 2 (2012) 521-527.
[40] N.O. Ilchenko, P.G. Janson, K.J. Szabo, J. Org. Chem., 78 (2013) 11087-11091.
[41] J. Charpentier, N. Früh, A. Togni, Chem. Rev., 115 (2015) 650–682.
[42] A. Studer, Angew. Chem. Int. Ed., 51 (2012) 8950-8958.
[43] E. Merino, C. Nevado, Chem. Soc. Rev., 43 (2014) 6598-6608.
[44] A.J. Cresswell, S.G. Davies, P.M. Roberts, J.E. Thomson, Chem. Rev., (2014).
[45] W. Yuan, K.J. Szabó, Angew. Chem. Int. Ed., 54 (2015) 8533-8537.
[46] N.O. Ilchenko, M.A. Cortés, K.J. Szabo, ACS Catal., 6 (2016) 447-450.
[47] J. Zhang, K.J. Szabo, F. Himo, ACS Catal., 7 (2017) 1093-1100.
[48] B. Zhou, T. Yan, X.-S. Xue, J.-p. Cheng, Org. Lett., 18 (2016) 6128-6131.
[49] D.H.T. Phan, K.G.M. Kou, V.M. Dong, J. Am. Chem. Soc., 132 (2010) 16354-16355.
8

Figure 1. Previously studied difluorination of styrenes [27].
Figure 2. Plausible reaction mechanism exemplified with 2e.
Figure 3. Coupling pattern in 13C-NMR for 4e
9

Table 1. Variation of the reaction conditions for β-difluorination reaction.
Entry
1
Deviation from standard conditions
Product 4a (%)
AgBF4 or Zn(BF4)2 x H2O 1 equiv. instead of 3
<5
2
3
4
5
6
7
Pd(MeCN)4(BF4)2 10 mol%
27
32
18
37
17
<5
Cu(MeCN)4PF6 20 mol% instead of 3
Cu(MeCN)4BF4 30 mol% instead of 3
MeCN instead of CDCl3
Dioxane instead of CDCl3
DCM or THF instead of CDCl3
10

Table 2. β-Difluorination of various α-substituted styrene derivatives.a
Entrya
Substrate
Product
Yield (%)
1
64
2a
4a
2
3
54
52
2b
2c
4b
4c
4
5
66
67
4d
2d
2e
4e
4f
6
7
8
9
76
75
68
62
2f
4g
4h
2g
2h
2i
4i
11

10b
11b
58
70
4j
2j
4k
2k
2l
12b,c
48
4l
13b,d
61
50
2m
2n
4m
4n
14b,d
12