An I(I)/I(III) Catalysis Route to the Heptafluoroisopropyl Group: A Privileged Module in Contemporary Agrochemistry

Article abstract of DOI:10.1055/a-1485-4916

The heptafluoroisopropyl group is emerging as a privileged chemotype in contemporary agrochemistry and features prominently in the current portfolio of leading insecticides. To reconcile the expansive potential of this module with the synthetic challenges

Full text of DOI:10.1055/a-1485-4916

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–J
special topic
A
Special Issue dedicated to Prof. Sarah Reis-
V. Martín-Heras et al.
Special Topic
Synthesis
An I(I)/I(III) Catalysis Route to the Heptafluoroisopropyl Group:
A Privileged Module in Contemporary Agrochemistry
Víctor Martín-Heras
Direct Vicinal Difluorination
Nicofluprole (Bayer)
Privileged discovery module for contemporary agrochemistry
Constantin G. Daniliuc
N
Ryan Gilmour*
0
0
0
0
-0
0
0
2
-
3
1
5
3
-
6
0
6
5
F
F
p-TolIF2 (in situ)
F
F
N
F
F
Cl
Cl
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Münster, Corrensstraße 36, 48149 Münster, Germany
ryan.gilmour@uni-muenster.de
CF3
CF3
Ar
Ar
Common chemotype
amine·HF
coplanar
F3C
F
F3C
Simple substrate
Published as part of the Special Topic
Special Issue dedicated to Prof. Sarah Reisman, recipient of the 2019
Dr. Margaret Faul Women in Chemistry Award
ROeMyrgaaaniCnlGoirsyirclramhen-so.Cpguhoirlenmmdoiinusgrc@hAeuusntIih-nomsrtuiteunt,stWere.dstefälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
Received: 31.03.2021
Accepted after revision: 19.04.2021
Published online: 19.04.2021
Mirroring the prominence of the trifluoromethyl group
in pharmaceutical chemistry,2 the evolution of the hepta-
fluoroisopropyl group as a privileged component in active
ingredients for insecticide development is conspicuous
(Figure 1).7 This structural unit is highly preorganised and
adopts a conformation in which the C(sp3)–F bond is copla-
nar with the aryl ring, thereby mitigating 1,3-allylic strain.8
Pertinent examples include flubendiamide9 and pyri-
fluquinazon,10 where the heptafluoroisopropyl unit is cru-
cial to efficacy. The X-ray crystal structure of flubendiamide
has been reported and clearly shows a conformation in
which A1,3-strain is minimised.11 The aniline unit that is
common in these agents is also found in cyhalodiamide,
which displays enhanced performance towards lepidoptera
parasites compared to flubendiamide.12 Similarly, the phen-
ylpyrazole insecticide nicofluprole also has this core struc-
tural unit,13 as do the broflanilides: these classes of agro-
chemicals have proven to be highly effective against a ple-
num of species including lepidopteran, coleopteran, and
thysanopteran.14 Intriguingly, this motif also features prom-
inently in List’s Diels–Alder catalyst15 and the retinoic acid
related orphan receptor RORt agonist BMT-362265 (Figure
1, lower left box).16 This latter example underscores the po-
tential of fluorinated tetralins in biomolecule design.17
From an agrochemical design context, the positive im-
pact of the heptafluoroisopropyl group on metabolic stabil-
ity18 has led to methods for its installation being intensively
pursued.7 Metal-mediated cross-coupling protocols have
proven to be particularly proficient in unifying aromatic
precursors with the respective perfluoroalkyl organometal-
lic reagent.19 Seminal studies by Mcloughlin and co-work-
ers established that the coupling of iodofluoroalkanes and
haloarenes with copper at elevated temperatures generates
the product in moderate yields.19a Gong and co-workers
DOI: 10.1055/a-1485-4916; Art ID: ss-2021-m0189-st
Abstract The heptafluoroisopropyl group is emerging as a privileged
chemotype in contemporary agrochemistry and features prominently
in the current portfolio of leading insecticides. To reconcile the expan-
sive potential of this module with the synthetic challenges associated
with preparing crowded, fluorinated motifs, I(I)/I(III) catalysis has been
leveraged. Predicated on in situ generation of p-TolIF2, this route en-
ables the direct difluorination of -trifluoromethyl--difluorostyrenes in
a single operation. This formal addition of fluorine across the alkene -
bond is efficient (up to 91% yield) and is compatible with a broad range
of functional groups. The ArCF(CF3)2 moiety is conformationally preor-
ganised, with the C(sp3)–F bond coplanar to the framework of the aryl
ring, thereby minimising 1,3-allylic strain. Moreover, orthogonal multi-
polar C–F···C=O interactions have been identified in a phthalimide de-
rivative. It is envisaged that this programmed vicinal difluorination en-
abled by a hypervalent iodine species will find application in functional
molecule design in a broader sense.
Key words agrochemistry, catalysis, conformational analysis, fluo-
rine, hypervalent iodine, vicinal oxidation
Fluorinated motifs have a venerable history in focussed
molecular design,1 and continue to manifest themselves in
the current portfolio of leading drugs,2 agrochemicals,3 and
performance materials.4 This success is predicated on H to F
bioisosterism, in which localised partial charge inversion
(H+ → F–) can be leveraged without straining the steric tol-
erance of the system. Harnessing fluorinated modules to
augment physicochemical parameters in functional small
molecule development5 continues to provide a strong im-
petus for sustained innovation in the conception of new
structural motifs, and to access validated motifs in a more
efficient manner.6 This latter consideration is particularly
relevant in agrochemistry, where consideration of the scale
of the enterprise is inescapable.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
V. Martín-Heras et al.
Special Topic
Synthesis
have reported a copper-mediated strategy to convert aryl-
boronic acids into the target scaffold using hexafluoropro-
pene and silver fluoride (Scheme 1a).20
a) Gong and co-workers (stoichiometric)
CuOAc (1 equiv), DMF, rt
F3C
CF3
Ar B(OH)2
+
Ag
F
Recently, Mikami and co-workers developed a copper-
mediated coupling of aryl halides with a perfluorinated or-
ganozinc reagent. Importantly, the group have validated a
process that is catalytic in the copper salt. It does, however,
require the addition of a stochiometric quantity of silver ac-
etate (Scheme 1b).21
To complement these innovative advances, a main
group catalysis approach based on the formal vicinal fluori-
nation of -trifluoromethyl--difluorostyrenes was envis-
aged (Scheme 1c). Confidence in this strategy was based on
our experience of exploiting I(I)/I(III) catalysis manifolds,
b) Mikami and co-workers (stoichiometric, example of catalysis)
CuTC (1.5 equiv)
F
Zn(i-C3F7)2(dmf)2
Ar
I
+
F3C
CF3
1,4-dioxane
70 °C
Ar
c) This work (organocatalytic)
I
H3C
H3C
I(I)/I(III)
catalysis
F
F
F
I
amine·HF
Ar
CF3
F
Scheme 1 Selected routes to introduce the heptafluoroisopropyl
group and the catalysis-based route described in this study based on an
I(I)/I(III) catalysis platform.
Heptafluoroisopropyl Group in Agrochemistry
utilising Selectfluor as an oxidant, to generate ArIF2 species
in situ.22–25 In the presence of simple amine·HF complexes,
these I(III) systems productively engage with alkenes to fa-
cilitate the formal addition of fluorine across a -bond. In
contrast to electron-rich styrenes, in which uncatalysed
background reactions dominate,26 the highly electron-defi-
cient nature of the alkene may present a challenge. Howev-
er, it was reasoned that through regulation of parameters
such as temperature and Brønsted acidity/amine:HF ratio,27
this issue may be overcome.
Modified
physicochemistry
Facile
synthesis
F3C
F
Ar
Ar
Conformational
pre-organisation
(allylic strain)
iPr
CF3
Metabolic
instability
H
ZJ5337
Fungicide
Flubendiamide
Insecticide
(Nihon Nohyaku)
Broflanilide
Insecticide
F3C
F
CF3
PhOC(Me)N
CF3
N
Me
CF3
CF3
MeO2S
Me
O
Me
F
O
F3C
F3C
HN
NH
O
To identify conditions that would enable the transfor-
mation of interest, a process of reaction optimisation was
conducted (Table 1, 1a → 2a). Inexpensive p-TolI was used
as the main group catalyst of choice in the presence of an
amine·HF complex. Catalysis was contingent on Selectfluor
enabling an I(I)/I(III) cycle to generate p-TolIF2 in situ, and
reactions were conducted in chloroform at the specified
temperature (Table 1). An investigation of the influence of
Brønsted acidity revealed that an amine:HF ratio of 1:9.23
was necessary to ensure turnover at ambient temperature
(entries 1–4). For the remainder of the study, Olah’s reagent
(pyridine:HF, 1:9.23) was utilised, enabling formation of
compound 2a in 58% yield (entry 4). Increasing the tem-
perature to 40 °C was found to have a positive impact on re-
activity (76% yield, entry 5). Despite this increase in tem-
perature, Olah’s reagent was found to be essential and any
reduction of the amine:HF ratio was detrimental (entry 6).
Further increasing the temperature to 50 °C generated
product 2a in 87% (entry 7). Solvent changes were generally
not tolerated (entries 8–10), but reactions in DCE delivered
the product, albeit in lower yield than chloroform (entry
11). Control reactions in the absence of p-TolI are fully in-
line with an I(I)/I(III) catalysis cycle (entry 12). Further-
more, both Olah’s reagent and Selectfluor were found to be
essential for difluorination to occur (entries 13 and 14).
Lowering the catalyst loading to 10% was detrimental (en-
try 15), as were electronic changes to the catalyst (entries
16 and 17).
F
O
O
Br
NH
I
OBn
CF3
Cl
F
CF3
N
N
Me
N
F3C CF3
F
Nicofluprole
Insecticide
(Bayer crop)
CF3
O
Cl
N
F3C CF3
Cl
F
Me
F
HN
N
List
Catalyst
F3C
CF3
N
HN
O
CF3
O
N
F
O
CF3
O
CF3
Me
Me
Me
CF3
HN
SO2
NH
SO2
F
F
Cl
CN
Pyrifluquinazon
Insecticide
(Nichino America)
Cyhalodiamide
Insecticide
CF3
CF3
O
N
F
F3C
CF3
F
O
F
Br
HN
F3C
F
H
N
O
F3C
F3C
F
CF3
PhO2S
CO2H
F3C
F
Cyproflanilide
BMT-362265 RORγt Inverse Agonist
Insecticide
Figure 1 The heptafluoroisopropyl group in contemporary agrochem-
istry. Inset: examples of the ArCF(CF3)2 motif in catalysis and medicinal
chemistry.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

C
V. Martín-Heras et al.
Special Topic
Synthesis
Having identified optimised conditions for the vicinal
difluorination (Table 1, entry 7), the scope of the transfor-
mation was explored (Scheme 2). To that end, the influence
of the para-substituent on reaction efficiency was explored.
It is pertinent to note that several of the products are vola-
tile and care must be taken during product isolation.
Switching the p-Br to p-Cl or p-OMe was well tolerated (2b
and 2c, 91% and 71% yield, respectively). Dihydrobenzo-
furan 2d was smoothly generated in 63% yield, as were the
alkyl derivatives 2e–2h (up to 81% yield). Given the promi-
nence of aniline derivatives in contemporary agrochemistry
(Figure 1), phthalimide 2i was prepared in 90% yield (1
mmol scale reaction in 79% isolated yield). The extended -
system 2j was also generated in 76% yield. Finally, exposure
of sulfonamide 1k to the standard conditions led to vicinal
difluorination with concomitant hydrolysis to generate me-
thylamine 2k (72% yield).28 In all cases, control experiments
that were conducted in the absence of the catalyst led to
<5% yield of the expected product.
Finally, a comparison of the van der Waals volumes of
common alkyl and fluoroalkyl fragments (Figure 2, lower)
t
indicates that the CF(CF3)2 group is notably larger than Bu
(73.5 versus 98.6 Å3).22d,29,30
Gratifyingly, compound 2i was crystalline thereby en-
abling the structure to be unequivocally established by sin-
gle crystal X-ray analysis (Figure 2, CCDC 2072566). Inspec-
tion of the structure revealed a dihedral angle () of 16.8°,
which mitigates 1,3-allylic strain. This necessarily places
one C–CF3 bond orthogonal to the plane of the -system
( = 98.8° and 78.7°), thereby enabling stabilising hyper-
conjugative →* interactions.31 The benzylic C(sp3)–F
bond distance (1.38 Å) was found to be slightly longer than
that of the constituent C–F bonds of the trifluoromethyl
groups (e.g., 1.33 Å). Interestingly, inspection of the ex-
panded structure revealed orthogonal interactions between
the C–F bonds and carbonyl units of the phthalimide unit
(Figure 3; F4···C9–O1 = 90.3° bond F7···C16–O2 = 83.9°).32
These orthogonal C–F···C=O effects are finding increasing
Table 1 Reaction Optimisationa
p-iodotoluene (20 mol%)
Selectfluor (1.5 equiv)
Olah's reagent (0.5 mL)
F
F
F
F
F
F
F
F
p-iodotoluene (20 mol%)
Selectfluor (1.5 equiv)
amine·HF (0.5 mL)
F
F
F
F
CF3
CF3
CHCl3 (0.5 mL)
50 °C
Ar
CF3
CF3
Ar
CHCl3 (0.5 mL)
Temp (°C)
Br
Br
1a
2a
F
F
F
F
F F
F
F
F
F
F
F
Yield (%)b
CF3
CF3
CF3
Entry Amine:
Temp Modified conditions
(°C)
HF ratio
Br
Cl
MeO
2a
87% (61%)
No catalyst <5%
2b
91% (62%)
No catalyst <5%
2c
71% (65%)
No catalyst <5%
1
2
1:3.0
25
25
25
25
40
50
50
50
50
50
50
50
50
50
50
50
50
–
<5
1:4.5
–
<5
3
1:7.5
–
<5
F
F
F
F
F F
F
F
F
F
F
F
4
1:9.23
1:9.23
1:7.5
–
58
CF3
CF3
CF3
5
–
76
O
Me
n-Pr
6
–
<5
2d
63% (59%)
No catalyst <5%
2e
68% (52%)
No catalyst <5%
2f
7
1:9.23
1:9.23
1:9.23
1:9.23
1:9.23
1:9.23
1:9.23
–
–
87 (61)c
<5
76% (64%)
No catalyst <5%
8
MeCN as solvent
toluene as solvent
F
F
F
F
F F
9
<5
F
F
F
F
F
F
10
11
12
13
14
15
16
17
ethyl trifluoroacetate as solvent
DCE as solvent
<5
CF3
CF3
CF3
Me
65
tBu
PhthN
no catalyst
<5
2g
2h
76% (54%)
No catalyst <5%
2i
90% (83%)
No catalyst <5%
81% (62%)
No catalyst <5%
no oxidant
<5
1k
no amine:HF
<5
F
F
F
F
R = NMeTs
F
F
F
F
1:9.23
1:9.23
1:9.23
10% catalyst loading
4-iodoanisole as catalyst
18
CF3
CF3
2j
2k
38
76% (66%)
No catalyst <5%
R = NHMe, 72% (58%)
No catalyst <5%
R
Ph
methyl 4-iodobenzoate as catalyst 27
a Standard reaction conditions: substrate (0.2 mmol), p-iodotoluene (20
mol%), Selectfluor (1.5 equiv), amine:HF source (0.5 mL), solvent (0.5 mL)
(concentration 0.2 M), 24 h.
Scheme 2 Establishing the scope of vicinal difluorination of the perflu-
oroalkenyl motif to generate a highly fluorinated isopropyl group. Yields
were determined by 19F NMR spectroscopy using ,,-trifluorotoluene
as internal standard. Isolated yields are given in parentheses. The prod-
ucts are often highly volatile and care must be taken during product
isolation.
b Determined by 19F NMR spectroscopy using ,,-trifluorotoluene as in-
ternal standard.
c Isolated yield is given in parentheses and is the average of two experi-
ments.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

D
V. Martín-Heras et al.
Special Topic
Synthesis
application in drug discovery,33 and contribute to the grow-
ing interest in bonding interactions involving C(sp3)–F
bonds.34
this group in agrochemistry and medicinal chemistry, it is
envisaged that this method will find application in the dis-
covery process.
In conclusion, a main group catalysis strategy has been
developed to generate the heptafluoroisopropyl group
through a formal addition of fluorine across the highly elec-
tron-deficient alkene of -trifluoromethyl--difluorosty-
renes. Inexpensive p-TolI functions as an effective organo-
catalyst to enable transient generation of p-TolIF2 in situ:
this species, together with Olah’s reagent, facilitates effi-
cient vicinal difluorination and is compatible with a broad
range of functional groups (up to 91% yield). Structural
analysis of a representative example reveals that the hepta-
fluoroisopropyl group adopts a conformation in which 1,3-
allylic strain is mitigated. In view of the privileged status of
Commercially available reagents were purchased as reagent grade
from Sigma-Aldrich, Merck, Alfa Aesar, TCI, Fluorochem, or abcr and
were used without further purification unless otherwise stated.
Where indicated DMF was dried over activated molecular sieves and
stored under Argon. All reactions with HF were run in Teflon vials.
Solvents for extractions or chromatographic purifications were
bought as technical grade and distilled on a rotary evaporator prior to
use. For analytical TLC, glass plates coated with silica gel 60 F254
(Merck) were used. They were visualised with UV light (254 nm) or
with KMnO4 or PMA solution. Column chromatography was per-
formed using silica gel (40–63 m, VWR Chemicals). Due to the vola-
tility of the products, care must be taken during product isolation.
NMR measurements were performed on a Bruker AV300, Bruker
AV400, Agilent DD2 500, or Agilent DD2 600 spectrometer by the
NMR service of the Organisch-Chemisches Institut, Westfälische Wil-
helms-Universität Münster. Chemical shifts were referenced to the
residual solvent peak as the internal standard (7.26 ppm for CDCl3 for
1H NMR and 77.16 ppm for CDCl3 for 13C NMR). Multiplicity is abbre-
viated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p
(pentet), h (hextet), hept (heptet), m (multiplet), br (broad). Melting
points were determined on a Büchi B-545 melting point apparatus
with open glass capillaries. IR measurements were performed on a
Perkin-Elmer 100 FT-IR spectrophotometer and the intensities of the
bands are assigned as follows: w (weak), m (medium), s (strong).
High-resolution mass spectrometry was performed by the MS service
of the Organisch-Chemisches Institut, Westfälische Wilhelms-Univer-
sität Münster on a Bruker Daltonics micrOTOF (HRMS-ESI), Triple
Quad TSQ 7000 (MS-EI), Triple Quad Quattro Micro GC (GC-EI-MS), or
Shimadzu QP5050 Single Quad (GC-EI-MS) system.
Selected X-ray Data
F
1.38 Å
F3C
CF2
F
1.33 Å
FCCC 45.5°
F3C
π
σ*
2i
CF3
F
φ
FCCC 16.8°
φ
O
CF3
HA
F
N
π-system
A1,3-minimised
φCCCC
78.7°
φCCCC
98.8°
O
CF3
-Trifluoromethyl--difluorostyrenes 1; General Procedure A
VvdW [Å3]
Sodium 2-chloro-2,2-difluoroacetate (1.2 equiv) was added to a mix-
ture of the corresponding ketone (1.0 equiv) and triphenylphosphine
(1.5 equiv) in dried DMF (20 mL). The reaction was heated to 105 °C
for 30 min. Water was added slowly to the reaction mixture and the
mixture was extracted with Et2O. The combined organic layer was
washed with water (6 ×), dried over Na2SO4, filtered, and concentrat-
ed in vacuo. The residue was purified by column chromatography to
afford the -trifluoromethyl--difluorostyrene 1.
F
H
F
F
F
CH2F
iPr
F3C
F3C
CF3
Et
tBu
CF3
38.9 39.8
51.0
56.2
73.5
86.5
98.6
Figure 2 X-ray crystal structure analyses of compound 2i (CCDC
2072566)
1-Bromo-4-(perfluoroprop-1-en-2-yl)benzene (1a)
Prepared according to General Procedure A using 1-(4-bromophenyl)-
2,2,2-trifluoroethan-1-one (1.77 g, 7.0 mmol, 1.0 equiv). The crude
residue was purified by column chromatography (100% n-pentane) to
yield 1a as a colourless oil (1.34 g, 4.7 mmol, 67%).
Rf = 0.85 (100% n-pentane).
1H NMR (500 MHz, CDCl3):  = 7.57 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 8.5
Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 156.4 (ddq, J = 307.4, 293.4, 3.7 Hz),
132.3, 131.7 (dd, J = 3.0, 2.0 Hz), 125.0 (m), 124.1, 122.3 (qdd, J =
271.6, 11.7, 6.1 Hz), 89.4 (qdd, J = 35.2, 27.6, 13.1 Hz).
19F NMR (376 MHz, CDCl3):  = –59.3 (dd, J = 23.8, 10.9 Hz), –74.5 (qd,
J = 23.9, 9.6 Hz), –76.5 (p, J = 10.9 Hz).
O
Multipolar
C–F···C=O
Interaction
90°
F
HRMS (EI): m/z [M]+ calcd for C9H4BrF5
285.94082.
: 285.94111; found:
Figure 3 Packing of compound 2i (CCDC 2072566) showing C–F to
C=O interactions
+
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

E
V. Martín-Heras et al.
Special Topic
Synthesis
+
Analytical data in agreement with the literature data.35
HRMS (EI): m/z [M]+ calcd for C11H7OF5
:
250.04116; found:
250.04076.
1-Chloro-4-(perfluoroprop-1-en-2-yl)benzene (1b)
1-Methyl-4-(perfluoroprop-1-en-2-yl)benzene (1e)
Prepared according to General Procedure A using 1-(4-chlorophenyl)-
2,2,2-trifluoroethan-1-one (1.46 g, 7 mmol, 1.0 equiv). The crude res-
idue was purified by column chromatography (100% n-pentane) to
yield 1b as a colourless oil (1.22 g, 5.0 mmol, 72%).
Prepared according to General Procedure A using 2,2,2-trifluoro-1-(p-
tolyl)ethan-1-one (1.32 g, 7.0 mmol, 1.0 equiv). The crude residue
was purified by column chromatography (100% n-pentane) to yield 1e
as a colourless oil (865 mg, 3.9 mmol, 56%).
Rf = 0.85 (100% n-pentane).
Rf = 0.85 (100% n-pentane).
1H NMR (500 MHz, CDCl3):  = 7.29 (m, 4 H), 2.44 (s, 3 H).
1H NMR (500 MHz, CDCl3):  = 7.41 (d, J = 8.6 Hz, 2 H), 7.28 (d, J = 8.6
Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 156.4 (ddq, J = 307.3, 293.2, 3.7 Hz),
135.9, 131.5 (dd, J = 3.0, 2.0 Hz), 129.3, 124.5 (m), 122.4 (qdd, J =
271.5, 11.8, 6.2 Hz), 89.3 (qdd, J = 35.3, 27.7, 13.1 Hz).
13C NMR (126 MHz, CDCl3):  = 156.4 (ddq, J = 306.4, 291.9, 3.7 Hz),
139.6, 130.0 (m), 129.6, 123.1 (qt, J = 2.0, 0.8 Hz), 122.7 (qdd, J =
271.4, 11.9, 6.1 Hz), 89.9 (qdd, J = 35.0, 28.3, 12.3 Hz), 21.4.
19F NMR (376 MHz, CDCl3):  = –59.3 (dd, J = 23.9, 10.9 Hz), –74.6 (qd,
J = 23.9, 9.8 Hz), –76.6 (p, J = 10.8 Hz).
19F NMR (376 MHz, CDCl3):  = –59.4 (dd, J = 24.0, 11.0 Hz), –76.0 (qd,
J = 24.1, 12.6 Hz), –77.8 (p, J = 11.1 Hz).
+
HRMS (EI): m/z [M]+ calcd for C9H4ClF5
:
241.99162; found:
HRMS (EI): m/z [M]+ calcd for C10H7F5+: 222.04624; found: 222.04609.
241.99210.
Analytical data in agreement with the literature data.35
Analytical data in agreement with the literature data.36
1-(Perfluoroprop-1-en-2-yl)-4-propylbenzene (1f)
1-Methoxy-4-(perfluoroprop-1-en-2-yl)benzene (1c)
Prepared according to General Procedure A using 2,2,2-trifluoro-1-(4-
propylphenyl)ethan-1-one (600 mg, 2.8 mmol, 1.0 equiv). The crude
residue was purified by column chromatography (100% n-pentane) to
yield 1f as a colourless oil (455 mg, 1.8 mmol, 65%).
Prepared according to General Procedure A using 2,2,2-trifluoro-1-(4-
methoxyphenyl)ethan-1-one (1.40 g, 7 mmol, 1.0 equiv). The crude
residue was purified by column chromatography (n-pentane/Et2O,
95:5) to yield 1c as a colourless oil (1.05 g, 4.4 mmol, 63%).
Rf = 0.85 (100% n-pentane).
Rf = 0.70 (n-pentane/Et2O, 95:5).
1H NMR (500 MHz, CDCl3):  = 7.28 (d, J = 8.5 Hz, 2 H), 6.96 (d, J = 8.8
Hz, 2 H), 3.84 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 160.5, 156.4 (ddq, J = 306.6, 291.4, 3.7
Hz), 131.5 (dd, J = 2.9, 1.9 Hz), 122.7 (qdd, J = 271.4, 11.7, 6.2 Hz),
118.1 (m), 114.4, 89.6 (qdd, J = 35.0, 28.3, 12.7 Hz), 55.3.
FT-IR: 2964 (w), 2936 (w), 2875 (w), 1730 (m), 1615 (w), 1515 (w),
1466 (w), 1416 (w), 1352 (s), 1280 (w), 1254 (m), 1170 (m), 1127 (s),
1026 (m), 1010 (s), 955 (m), 839 (w), 802 (w), 761 (w), 736 (w), 702
cm–1 (w).
1H NMR (500 MHz, CDCl3):  = 7.30–7.20 (m, 4 H), 2.63 (t, J = 7.6 Hz, 2
H), 1.68 (h, J = 7.4 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).
19F NMR (376 MHz, CDCl3):  = –59.6 (dd, J = 24.2, 11.0 Hz), –76.0 (qd,
J = 24.2, 12.9 Hz), –78.2 (dq, J = 13.6, 11.1 Hz).
13C NMR (126 MHz, CDCl3):  = 156.4 (ddq, J = 306.5, 292.1, 3.8 Hz),
144.3, 130.0 (dd, J = 2.9, 1.9 Hz), 129.0, 123.33 (m), 122.7 (qdd, J =
271.5, 11.9, 6.1 Hz), 90.0 (qdd, J = 34.8, 28.0, 12.2 Hz), 37.9, 24.5, 13.9.
+
HRMS (EI): m/z [M]+ calcd for C10H7OF5
: 238.04116; found:
238.04160.
19F NMR (376 MHz, CDCl3):  = –59.4 (dd, J = 24.1, 11.1 Hz), –76.2 (qd,
J = 24.1, 12.8 Hz), –78.0 (dq, J = 12.7, 11.0 Hz).
HRMS (EI): m/z [M]+ calcd for C12H11F5
Analytical data in agreement with the literature data.35
+
: 250.07809; found:
250.07751.
5-(Perfluoroprop-1-en-2-yl)-2,3-dihydrobenzofuran (1d)
Prepared according to General Procedure A using 1-(2,3-dihydroben-
zofuran-5-yl)-2,2,2-trifluoroethan-1-one (605 mg, 2.8 mmol, 1.0
equiv). The crude residue was purified by column chromatography
(n-pentane/Et2O, 97:3) to yield 1d as a colourless oil (399 mg, 1.6
mmol, 57%).
1-(tert-Butyl)-4-(perfluoroprop-1-en-2-yl)benzene (1g)
Prepared according to General Procedure A using 1-(4-(tert-bu-
tyl)phenyl)-2,2,2-trifluoroethan-1-one (1.0 g, 4.3 mmol, 1.0 equiv).
The crude residue was purified by column chromatography (100% n-
pentane) to yield 1g as a colourless oil, which solidifies at –20 °C (735
mg, 2.8 mmol, 65%).
Rf = 0.55 (n-pentane/Et2O, 98:2).
FT-IR: 2901 (w), 1730 (m), 1615 (w), 1493 (m), 1444 (w), 1347 (s),
1302 (w), 1290 (m), 1259 (m), 1234 (m), 1172 (m), 1122 (s), 1107 (s),
1011 (s), 979 (s), 942 (m), 891 (w), 818 (m), 738 (m), 700 cm–1 (w).
Rf = 0.90 (100% n-pentane).
1H NMR (500 MHz, CDCl3):  = 7.47 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.2
Hz, 2 H), 1.37 (s, 9 H).
1H NMR (500 MHz, CDCl3):  = 7.15 (s, 1 H), 7.08 (d, J = 8.9 Hz, 1 H),
6.82 (d, J = 8.3 Hz, 1 H), 4.61 (t, J = 8.8 Hz, 2 H), 3.24 (t, J = 8.7 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 161.2, 156.4 (ddq, J = 306.8, 290.9, 3.6
Hz), 130.4 (dd, J = 3.1, 1.9 Hz), 128.0, 126.8 (dd, J = 3.2, 1.8 Hz), 122.7
(qdd, J = 271.3, 11.7, 6.3 Hz), 117.7 (d, J = 2.3 Hz), 109.7, 89.8 (qdd, J =
34.9, 28.4, 12.4 Hz), 71.7, 29.6.
13C NMR (126 MHz, CDCl3):  = 156.5 (ddq, J = 306.4, 292.2, 3.8 Hz),
152.7, 129.9–129.6 (m), 125.9, 123.2–123.1 (m), 122.78 (qdd, J =
271.4, 11.8, 6.0 Hz), 89.9 (qdd, J = 35.0, 28.0, 12.4 Hz), 34.9, 31.3.
19F NMR (376 MHz, CDCl3):  = –59.3 (dd, J = 24.2, 11.1 Hz), –76.1 (qd,
J = 24.2, 12.7 Hz), –77.9 to –78.1 (m, J = 11.4 Hz).
+
19F NMR (376 MHz, CDCl3):  = –59.8 (dd, J = 24.4, 11.1 Hz), –76.5 (qd,
J = 24.4, 13.7 Hz), –78.1 (dq, J = 13.7, 11.0 Hz).
HRMS (EI): m/z [M]+ calcd for C13H13F5
264.09317.
:
264.09319; found:
Analytical data in agreement with the literature data.37
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

F
V. Martín-Heras et al.
Special Topic
Synthesis
1-Methyl-3-(perfluoroprop-1-en-2-yl)benzene (1h)
N,4-Dimethyl-N-(4-(perfluoroprop-1-en-2-yl)phenyl)benzenesul-
fonamide (1k)
Prepared according to General Procedure A using 2,2,2-trifluoro-1-
(m-tolyl)ethan-1-one (1.98 g, 10.5 mmol, 1.0 equiv). The crude resi-
due was purified by column chromatography (100% n-pentane) to
yield 1h as a colourless oil (1.59 g, 7.1 mmol, 68%).
Prepared according to General Procedure A using N,4-dimethyl-N-(4-
(2,2,2-trifluoroacetyl)phenyl)benzenesulfonamide (500 mg, 1.4
mmol, 1.0 equiv). The crude residue was purified by column chroma-
tography (n-pentane/Et2O, 90:10) to yield 1k as a yellowish oil (433
mg, 1.1 mmol, 79%).
Rf = 0.85 (100% n-pentane).
FT-IR: 2930 (w), 1731 (s), 1610 (w), 1588 (w), 1490 (w), 1348 (s),
1267 (s), 1191 (w), 1164 (s), 1125 (s), 1024 (s), 1007 (s), 976 (m), 909
(w), 884 (w), 827 (m), 785 (m), 735 (m), 701 (m), 665 cm–1 (w).
1H NMR (500 MHz, CDCl3):  = 7.32 (t, J = 7.6 Hz, 1 H), 7.24 (d, J = 7.7
Rf = 0.35 (n-pentane/Et2O, 90:10).
FT-IR: 2931 (w), 1732 (m), 1598 (w), 1508 (w), 1453 (w), 1348 (s),
1306 (w), 1282 (m), 1253 (m), 1170 (s), 1155 (m), 1125 (s), 1089 (m),
1063 (m), 1010 (s), 956 (m), 865 (m), 837 (m), 814 (m), 750 (m), 737
(w), 712 (s), 700 (m), 660 cm–1 (s).
1H NMR (500 MHz, CDCl3):  = 7.43 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.0
Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 3.17 (s, 3 H),
2.42 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 156.4 (m), 144.0, 142.8, 133.4, 130.6
(m), 129.6, 127.9, 126.6, 124.6 (m), 122.4 (qdd, J = 271.6, 11.8, 6.1 Hz),
89.4 (qdd, J = 34.9, 27.4, 13.1 Hz), 37.85, 21.6.
19F NMR (376 MHz, CDCl3):  = –59.1 (dd, J = 24.0, 11.0 Hz), –74.7 (qd,
J = 24.0, 10.0 Hz), –76.6 to –76.9 (m).
Hz, 1 H), 7.14 (m, 2 H), 2.39 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 156.4 (ddq, J = 306.4, 292.3, 3.8 Hz),
138.7, 130.7 (dd, J = 3.0, 1.9 Hz), 130.3, 128.8, 127.2 (dd, J = 2.9, 2.0
Hz), 126.0, 122.7 (qdd, J = 271.5, 11.9, 6.0 Hz), 90.1 (qdd, J = 35.2, 27.6,
13.1 Hz), 21.4.
19F NMR (376 MHz, CDCl3):  = –59.3 (dd, J = 23.9, 11.0 Hz), –75.9 (qd,
J = 23.8, 12.1 Hz), –77.5 (p, J = 11.1 Hz).
HRMS (EI): m/z [M]+ calcd for C10H7F5+: 222.04624; found: 222.04617.
2-(4-(Perfluoroprop-1-en-2-yl)phenyl)isoindoline-1,3-dione (1i)
HRMS (ESI): m/z [M + Na]+ calcd for C17H14NO2SF5Na+: 414.05576;
found: 414.05508.
Prepared according to General Procedure A using 2-(4-(2,2,2-trifluo-
roacetyl)phenyl)isoindoline-1,3-dione (1.98 g, 6.2 mmol, 1.0 equiv).
The crude residue was purified by column chromatography (n-pen-
tane/Et2O, 80:20) to yield 1i as a white solid (1.31 g, 3.7 mmol, 60%);
mp 123–125 °C.
Synthesis of Heptafluoroisopropyl Groups; General Procedure B
Unless stated otherwise, a Teflon vial was equipped with a 1 cm stir-
ring bar followed by the addition of the -trifluoromethyl--difluoro-
styrene 1 (0.2 mmol, 1.0 equiv), p-iodotoluene (9 mg, 0.04 mmol, 20
mol%), and CHCl3 (0.5 mL). The mixture was stirred and Olah’s reagent
(0.5 mL) was added via syringe. After stirring for 1 min at ambient
temperature, Selectfluor (106 mg, 0.3 mmol, 1.5 equiv) was added in
one portion. The reaction vessel was then sealed with a Teflon screw
cap. After stirring (350 rpm) at 50 °C for 24 h, the reaction was cooled
to ambient temperature then CH2Cl2 (1 mL) was added to dilute the
mixture. Saturated aqueous NaHCO3 (1 mL) was then added via a long
glass pipette to pre-quench the reaction. The mixture was poured into
an Erlenmeyer flask charged with saturated aqueous NaHCO3 (100
mL) (CAUTION: generation of CO2!). The Teflon vial was rinsed with
CH2Cl2 and placed into another flask with saturated aqueous NaHCO3
to ensure that excess HF was neutralised. The organics were extracted
with CH2Cl2 (3 × 30 mL), and the combined organic layers were dried
over MgSO4 and solvent was carefully removed under reduced pres-
sure. An internal standard (,,-trifluorotoluene) was added to the
crude residue and the NMR yield was determined by 19F NMR spec-
troscopy against the internal standard. The NMR sample was recom-
bined with the crude residue and purification by column chromatog-
raphy yielded the desired product. We have observed that the pres-
ence of water is highly detrimental for the reaction and best results
are obtained with fresh Olah’s reagent (25 mL, Sigma-Aldrich). This
bottle was stored at –20 °C and allowed to warm to room temperature
prior to use.
Rf = 0.60 (n-pentane/Et2O, 80:20).
FT-IR: 1792 (w), 1772 (w), 1743 (s), 1709 (s), 1520 (w), 1469 (w),
1395 (m), 1349 (s), 1293 (w), 1273 (w), 1249 (m), 1173 (m), 1116 (s),
1098 (m), 1084 (m), 1025 (w), 1012 (s), 956 (m), 949 (m), 888 (m),
852 (w), 829 (s), 787 (w), 745 (w), 734 (w), 716 (s), 703 (m), 656 cm–1
(w).
1H NMR (500 MHz, CDCl3):  = 7.96 (dd, J = 5.4, 3.0 Hz, 2 H), 7.80 (dd, J
= 5.5, 3.0 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 167.0, 156.5 (ddq, J = 307.2, 293.5, 3.6
Hz), 134.7, 133.0, 131.7, 130.9 (m), 126.6, 125.5 (m), 124.0, 122.5
(qdd, J = 271.8, 11.8, 6.1 Hz), 89.5 (qdd, J = 35.2, 27.5, 13.0 Hz).
19F NMR (376 MHz, CDCl3):  = –59.1 (dd, J = 24.0, 10.9 Hz), –74.6 (qd,
J = 24.0, 9.4 Hz), –76.5 (p, J = 10.7 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C17H8NO2F5Na+: 376.03674;
found: 376.03694.
4-(Perfluoroprop-1-en-2-yl)-1,1′-biphenyl (1j)
Prepared according to General Procedure A using 1-([1,1′-biphenyl]-
4-yl)-2,2,2-trifluoroethan-1-one (1.5 g, 6.0 mmol, 1.0 equiv). The
crude residue was purified by column chromatography (100% n-pen-
tane) to yield 1j as a white solid (1.26 g, 4.4 mmol, 74%).
Rf = 0.75 (100% n-pentane).
1H NMR (500 MHz, CDCl3):  = 7.73–7.68 (m, 2 H), 7.68–7.64 (m, 2 H),
7.55–7.49 (m, 2 H), 7.49–7.42 (m, 3 H).
1-Bromo-4-(perfluoropropan-2-yl)benzene (2a)
13C NMR (126 MHz, CDCl3):  = 156.4 (ddq, J = 306.9, 292.7, 3.7 Hz),
142.4, 140.2, 130.4, 128.9, 127.9, 127.5, 127.2, 124.9, 122.6 (qdd, J =
271.6, 11.8, 6.1 Hz), 89.8 (m).
19F NMR (376 MHz, CDCl3):  = –59.1 (dd, J = 24.0, 11.0 Hz), –75.3 (qd,
J = 24.0, 11.5 Hz), –77.3 (p, J = 11.1 Hz).
Prepared according to General Procedure B using 1a (57.4 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (100% n-pentane) to yield 2a as a colourless
oil (39.7 mg, 0.12 mmol, 61%).
HRMS (EI): m/z [M]+ calcd for C15H9F5+: 284.06189; found: 284.06189.
Rf = 0.85 (100% n-pentane).
Analytical data in agreement with the literature data.36
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

G
V. Martín-Heras et al.
Special Topic
Synthesis
1H NMR (599 MHz, CDCl3):  = 7.65 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 9.0
Rf = 0.55 (n-pentane/Et2O, 98:2).
Hz, 2 H).
FT-IR: 2907 (w), 1618 (w), 1497 (m), 1446 (w), 1366 (w), 1278 (m),
1203 (s), 1164 (m), 1147 (m), 1127 (m), 1110 (m), 1094 (s), 992 (m),
975 (s), 943 (m), 892 (w), 819 (m), 753 (w), 734 (m), 711 (m), 661 cm–
1 (w).
13C NMR (151 MHz, CDCl3):  = 132.4 (d, J = 2.2 Hz), 127.5 (dhept, J =
10.5, 1.5 Hz), 126.1 (d, J = 1.4 Hz), 126.0 (d, J = 20.8 Hz), 121.5 (qd, J =
287.7, 27.9 Hz), 91.5 (dhept, J = 202.6, 33.2 Hz).
19F NMR (564 MHz, CDCl3):  = –75.9 (d, J = 7.3 Hz), –182.5 (hept, J =
7.3 Hz).
1H NMR (500 MHz, CDCl3):  = 7.41 (s, 1 H), 7.36 (d, J = 8.5 Hz, 1 H),
6.86 (d, J = 8.5 Hz, 1 H), 4.65 (t, J = 8.8 Hz, 2 H), 3.27 (t, J = 8.7 Hz, 2 H).
HRMS (EI): m/z [M]+ calcd for C9H4BrF7
323.93791.
:
323.93754; found:
13C NMR (126 MHz, CDCl3):  = 162.4 (d, J = 1.2 Hz), 128.3 (d, J = 2.2
Hz), 126.4 (dp, J = 10.7, 1.6 Hz), 122.6 (dp, J = 10.8, 1.6 Hz), 120.9 (qd, J
= 287.0, 28.0 Hz), 118.5 (d, J = 20.5 Hz), 109.7, 91.8 (dp, J = 200.8, 33.0
Hz), 72.0, 29.6.
+
Analytical data in agreement with the literature data.19c
19F NMR (564 MHz, CDCl3):  = –76.0 (d, J = 7.3 Hz), –180.8 (hept, J =
7.3 Hz).
1-Chloro-4-(perfluoropropan-2-yl)benzene (2b)
Prepared according to General Procedure B using 1b (48.5 g, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (100% n-pentane) to yield 2b as a colourless
oil (35 mg, 0.12 mmol, 62%).
+
HRMS (EI): m/z [M]+ calcd for C11H7OF7
: 288.03825; found:
288.03796.
1-Methyl-4-(perfluoropropan-2-yl)benzene (2e)
Rf = 0.85 (100% n-pentane).
Prepared according to General Procedure B using 1e (44.4 g, 0.2 mmol,
1.0 equiv). The reaction was run twice on this scale and the crude
products were combined. The crude residue was purified by column
chromatography (100% n-pentane) to yield 2e as a colourless oil (27.1
mg, 0.10 mmol, 52%).
FT-IR: 2926 (w), 2856 (w), 1602 (w), 1497 (w), 1466 (w), 1411 (w),
1314 (m), 1302 (m), 1277 (m), 1208 (s), 1169 (m), 1132 (w), 1098
(m), 1019 (w), 983 (s), 952 (s), 824 (m), 762 (w), 733 (w), 699 cm–1
(m).
Rf = 0.85 (100% n-pentane).
1H NMR (500 MHz, CDCl3):  = 7.49 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.3
1H NMR (599 MHz, CDCl3):  = 7.56 (d, J = 9.1 Hz, 2 H), 7.49 (d, J = 8.3
Hz, 2 H).
Hz, 2 H), 2.41 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 137.8 (d, J = 1.4 Hz), 129.5 (d, J = 2.2
Hz), 127.3 (dhept, J = 10.7, 1.4 Hz), 125.4 (d, J = 20.8 Hz), 120.6 (qd, J =
287.0, 27.5 Hz), 91.4 (dhept, J = 200.7, 33.2 Hz).
19F NMR (564 MHz, CDCl3):  = –75.8 (d, J = 7.3 Hz), –182.3 (hept, J =
7.4 Hz).
13C NMR (126 MHz, CDCl3):  = 146.5 (d, J = 0.9 Hz), 129.7 (d, J = 2.0
Hz), 125.2 (dhept, J = 10.3, 1.4 Hz), 125.2 (d, J = 21.7 Hz), 120.6 (qd, J =
287.0, 28.0 Hz), 91.4 (dhept, J = 201.8, 32.0 Hz), 34.8.
19F NMR (376 MHz, CDCl3):  = –75.8 (d, J = 7.4 Hz), –182.6 (hept, J =
7.3 Hz).
+
HRMS (EI): m/z [M]+ calcd for C9H4ClF7
: 279.98836; found:
279.98843.
HRMS (EI): m/z [M]+ calcd for C10H7F7+: 260.04305; found: 260.04333.
Analytical data in agreement with the literature data.19c
1-Methoxy-4-(perfluoropropan-2-yl)benzene (2c)
Prepared according to General Procedure B using 1c (47.6 g, 0.2 mmol,
1.0 equiv). The reaction was run twice on this scale and the crude
products were combined. The crude residue was purified by column
chromatography (n-pentane/Et2O, 95:5) to yield 2c as a colourless oil
(35.9 mg, 0.13 mmol, 65%).
1-(Perfluoropropan-2-yl)-4-propylbenzene (2f)
Prepared according to General Procedure B using 1f (50.4 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (100% n-pentane) to yield 2f as a colourless
oil (36.9 mg, 0.13 mmol, 64%).
Rf = 0.70 (n-pentane/Et2O, 95:5).
1H NMR (500 MHz, CDCl3):  = 7.53 (d, J = 9.3 Hz, 2 H), 7.00 (d, J = 8.3
Rf = 0.85 (100% n-pentane).
Hz, 2 H), 3.85 (s, 3 H).
FT-IR: 2965 (w), 2936 (w), 2876 (w), 2365 (w), 1616 (w), 1518 (w),
1461 (w), 1308 (m), 1280 (s), 1206 (s), 1191 (s), 1166 (m), 1137 (w),
1104 (m), 981 (s), 951 (s), 840 (w), 801 (w), 755 (w), 738 (w), 708 cm–
1 (m).
13C NMR (126 MHz, CDCl3):  = 161.5 (d, J = 1.2 Hz), 127.2 (dhept, J =
10.5, 1.4 Hz), 120.7 (dq, J = 287.1, 27.9 Hz), 118.5 (d, J = 20.9 Hz),
114.2 (d, J = 2.1 Hz), 91.4 (dhept, J = 200.9, 33.1 Hz), 55.3.
19F NMR (376 MHz, CDCl3):  = –76.0 (d, J = 7.4 Hz), –181.7 (hept, J =
7.3 Hz).
1H NMR (599 MHz, CDCl3):  = 7.52 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.1
Hz, 2 H), 2.68–2.62 (m, 2 H), 1.68 (h, J = 7.4 Hz, 2 H), 0.97 (t, J = 7.4 Hz,
3 H).
13C NMR (151 MHz, CDCl3):  = 146.1 (d, J = 1.0 Hz), 129.1 (d, J = 2.1
Hz), 125.7 (dp, J = 10.4, 1.5 Hz), 124.2 (d, J = 20.7 Hz), 120.9 (qd, J =
287.1, 28.2 Hz), 91.9 (dp, J = 201.0, 33.2 Hz), 37.8, 24.35, 13.9.
+
HRMS (EI): m/z [M]+ calcd for C10H7OF7
: 276.03762; found:
276.03796.
Analytical data in agreement with the literature data.21
19F NMR (564 MHz, CDCl3):  = –75.9 (d, J = 7.3 Hz), –182.5 (hept, J =
7.3 Hz).
5-(Perfluoropropan-2-yl)-2,3-dihydrobenzofuran (2d)
Prepared according to General Procedure B using 1d (50 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (n-pentane/Et2O, 97:3) to yield 2d as a co-
lourless oil (34 mg, 0.12 mmol, 59%).
+
HRMS (EI): m/z [M]+ calcd for C12H11F7
: 288.07435; found:
288.07406.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

H
V. Martín-Heras et al.
Special Topic
Synthesis
1-(tert-Butyl)-4-(perfluoropropan-2-yl)benzene (2g)
19F NMR (564 MHz, CDCl3):  = –75.6 (d, J = 7.3 Hz), –182.2 (hept, J =
7.3 Hz).
Prepared according to General Procedure B using 1g (52.8 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (100% n-pentane) to yield 2g as a colourless
oil, which solidifies at –20 °C (37.5 mg, 0.12 mmol, 62%).
HRMS (ESI): m/z [M + Na]+ calcd for C17H8NO2F7Na+: 414.03355;
found: 414.03359.
4-(Perfluoropropan-2-yl)-1,1′-biphenyl (2j)
Rf = 0.90 (100% n-pentane).
1H NMR (599 MHz, CDCl3):  = 7.56–7.50 (m, 4 H), 1.36 (s, 9 H).
13C NMR (151 MHz, CDCl3):  = 154.5, 126.0 (d, J = 2.1 Hz), 125.8–
125.4 (m), 123.9 (d, J = 20.6 Hz), 120.7 (qd, J = 287.1, 27.8 Hz), 91.8
(dhept, J = 201.3, 33.0 Hz), 35.0, 31.3.
Prepared according to General Procedure B using 1j (56.8 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (100% n-pentane) to yield 2j as a white solid
(42.5 mg, 0.13 mmol, 66%).
Rf = 0.75 (100% n-pentane).
1H NMR (500 MHz, CDCl3):  = 7.75–7.70 (m, 4 H), 7.65–7.62 (m, 2 H),
19F NMR (564 MHz, CDCl3):  = –75.8 (d, J = 7.3 Hz), –182.6 (hept, J =
7.4 Hz).
7.53–7.48 (m, 2 H), 7.46–7.41 (m, 1 H).
+
HRMS (EI): m/z [M]+ calcd for C13H13F7
: 302.09000; found:
13C NMR (126 MHz, CDCl3):  = 144.1 (d, J = 1.0 Hz), 139.8, 129.2,
128.3, 127.7 (d, J = 2.4 Hz), 127.4, 126.3 (dhept, J = 10.4, 1.5 Hz), 125.7
(d, J = 20.6 Hz), 120.9 (qd, J = 287.1, 27.5 Hz), 91.76 (dhept, J = 201.6,
33.1 Hz).
19F NMR (470 MHz, CDCl3):  = –75.7 (d, J = 7.3 Hz), –182.4 (hept, J =
7.2 Hz).
302.09011.
Analytical data in agreement with the literature data.19c
1-Methyl-3-(perfluoropropan-2-yl)benzene (2h)
Prepared according to General Procedure B using 1h (44.4 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (100% n-pentane) to yield 2h as a colourless
oil (28.1 mg, 0.11 mmol, 54%).
HRMS (EI): m/z [M]+ calcd for C15H9F7+: 322.05870; found: 322.05860.
Analytical data in agreement with the literature data.19c
Rf = 0.85 (100% n-pentane).
N-Methyl-4-(perfluoropropan-2-yl)aniline (2k)
1H NMR (599 MHz, CDCl3):  = 7.44–7.40 (m, 2 H), 7.38 (ddd, J = 8.6,
7.2, 0.7 Hz, 1 H), 7.36–7.33 (m, 1 H), 2.43 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 139.0 (d, J = 2.3 Hz), 131.9 (d, J = 0.9
Hz), 128.9 (d, J = 2.3 Hz), 126.9 (d, J = 20.4 Hz), 126.3 (dhept, J = 10.6,
1.4 Hz), 122.9 (dhept, J = 10.4, 1.5 Hz), 120.8 (qd, J = 287.1, 28.1 Hz),
91.6 (dhept, J = 201.6, 33.0 Hz), 34.3.
Prepared according to General Procedure B using 1k (78.5 mg, 0.2
mmol, 1.0 equiv). The reaction was run twice on this scale and the
crude products were combined. The crude residue was purified by
column chromatography (n-pentane/Et2O, 90:10) to yield 2k as a co-
lourless oil (32.0 mg, 0.12 mmol, 58%).
Rf = 0.4 (n-pentane/Et2O, 90:10).
19F NMR (564 MHz, CDCl3):  = –75.8 (d, J = 7.1 Hz), –182.6 (hept, J =
7.2 Hz).
HRMS (EI): m/z [M]+ calcd for C10H7F7+: 260.04305; found: 260.04314.
Analytical data in agreement with the literature data.19c
FT-IR: 3437 (w), 2908 (w), 1616 (m), 1532 (m), 1491 (w), 1453 (w),
1326 (w), 1295 (m), 1276 (m), 1209 (s), 1190 (s), 1161 (s), 1132 (w),
1117 (w), 1094 (m), 1066 (w), 1012 (w), 976 (s), 949 (s), 936 (w), 819
(m), 753 (w), 735 (m), 705 cm–1 (m).
1H NMR (500 MHz, CDCl3):  = 7.38 (d, J = 8.5 Hz, 2 H), 6.64 (d, J = 8.4
Hz, 2 H), 4.03 (br, 1 H), 2.87 (s, 3 H).
2-(4-(Perfluoropropan-2-yl)phenyl)isoindoline-1,3-dione (2i)
13C NMR (126 MHz, CDCl3):  = 151.2 (d, J = 0.9 Hz), 127.0 (dp, J = 10.4,
1.5 Hz), 122.18 (qd, J = 287.1, 28.1 Hz), 114.2 (d, J = 21.0 Hz), 112.0 (d,
J = 2.1 Hz), 91.9 (dp, J = 199.5, 32.4 Hz), 30.3.
19F NMR (470 MHz, CDCl3):  = –76.1 (d, J = 7.5 Hz), –181.4 (hept, J =
7.5 Hz).
Prepared according to General Procedure B using 1i (70.6 g, 0.2 mmol,
1.0 equiv). The reaction was run twice on this scale and the crude
products were combined. The crude residue was purified by column
chromatography (n-pentane/Et2O, 80:20) to yield 2i as a yellowish
solid (64.9 mg, 0.17 mmol, 83%).
HRMS (ESI): m/z [M + H]+ calcd for C10H9NF7+: 276.06168; found:
276.06155.
Large-scale synthesis: Prepared according to General Procedure B us-
ing 1i (353 mg, 1.0 mmol, 1.0 equiv). Purification by column chroma-
tography (n-pentane/Et2O, 80:20) yielded 2i as a yellowish solid (308
mg, 0.79 mmol, 79%); mp 146–148 °C.
Conflict of Interest
Rf = 0.60 (n-pentane/Et2O, 80:20).
The authors declare no conflict of interest.
FT-IR: 2920 (w), 2850 (w), 1785 (w), 1743 (m), 1716 (s), 1611 (w),
1520 (w), 1468 (w), 1424 (w), 1376 (s), 1333 (w), 1305 (m), 1277 (s),
1226 (s), 1206 (s), 1196 (s), 1167 (s), 1105 (s), 1077 (m), 981 (s), 948
(s), 884 (m), 852 (m), 834 (s), 824 (m), 791 (m), 757 (m), 740 (m), 710
(s), 697 cm–1 (m).
Funding Information
We acknowledge financial support from the Westfälische Wilhelms-
Universität Münster, the Deutsche Forschungsgemeinschaft (SFB
858), and the Alexander von Humboldt Foundation (postdoctoral fel-
1H NMR (599 MHz, CDCl3):  = 7.97 (m, 2 H), 7.81 (m, 2 H), 7.76 (d, J =
8.5 Hz, 2 H), 7.69 (d, J = 8.5 Hz, 2 H).
13C NMR (151 MHz, CDCl3):  = 166.9, 134.9, 131.6, 126.7 (dhept, J =
10.7, 1.6 Hz), 126.5 (d, J = 2.2 Hz), 126.0 (d, J = 20.8 Hz), 124.1, 121.6
(qd, J = 287.6, 27.8 Hz), 91.5 (dhept, J = 202.3, 33.0 Hz).
lowship to V.M.-H.).Westfälicsh
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

I
V. Martín-Heras et al.
Special Topic
Synthesis
Acknowledgment
(16) Karmakar, A.; Nimje, R. Y.; Silamkoti, A.; Pitchai, M.; Basha, M.;
Singarayer, C.; Ramasamay, D.; Babu, G. T. V.; Samikannu, R.;
Subramaniam, S.; Anjanappa, P.; Vetrichelvan, M.; Kumar, H.;
Dikundwar, A. G.; Gupta, A.; Gupta, A. K.; Rampulla, R.; Dhar, T.
G. M.; Mathur, A. Org. Process Res. Dev. 2021, 25, 1001.
(17) Neufeld, J.; Stünkel, T.; Mück-Lichtenfeld, C.; Daniliuc, C.;
Gilmour, R. Angew. Chem. Int. Ed.. 2021, DOI: in press; DOI:
10.1002/anie.202102222.
We thank the analytical departments of the Organisch-Chemisches
Institut for technical support.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1485-4916. Su
(18) Lepri, S.; Goracci, L.; Valeri, A.; Cruciani, G. Eur. J. Med. Chem.
2016, 121, 658.
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
(19) (a) Mcloughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.
(b) Jiang, D.-F.; Liu, C.; Guo, Y.; Xiao, J.-C.; Chen, Q.-Y. Eur. J. Org.
Chem. 2014, 6303. (c) Wang, X.; Li, Y.; Zhu, Z.; Wu, Y.; Cao, W.
Org. Chem. Front. 2016, 3, 304. (d) Liu, X.-H.; Leng, J.; Jia, S.-J.;
Hao, J.-H.; Zhang, F.; Qin, H.-L.; Zhang, C.-P. J. Fluorine Chem.
2016, 189, 59.
References
(1) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Zimmer, L. E.;
Sparr, C.; Gilmour, R. Angew. Chem. Int. Ed. 2011, 50, 11860.
(c) Thiehoff, C.; Rey, Y. P.; Gilmour, R. Isr. J. Chem. 2017, 57, 92.
(d) Aufiero, M.; Gilmour, R. Acc. Chem. Res. 2018, 51, 1701.
(2) (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (c) Wang, J.; Sánchez-Roselló, M.;
Acenaña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(3) For selected reviews on fluorine in contemporary agrochemis-
try, see: (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Fujiwara,
T.; O’Hagan, D. J. Fluorine Chem. 2014, 167, 16. (c) Pazenok, S.;
Leroux, F. R. In Frontiers of Organofluorine Chemistry; Ojima, I.,
Ed.; World Scientific: London, 2020, 695. (d) Ogawa, Y.;
Tokunaga, E.; Kobayashi, O.; Hirai, K.; Shibata, N. iScience 2020,
23, 101467.
(4) (a) Pagliaro, M.; Ciriminna, R. J. Mater. Chem. 2005, 15, 4981.
(b) Ragni, R.; Punzi, A.; Babudri, F.; Farinola, G. M. Eur. J. Org.
Chem. 2018, 3500.
(5) (a) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.;
Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K.
J. Med. Chem. 2015, 58, 9041. (b) Erdeljac, N.; Kehr, K.; Ahlqvist,
M.; Knerr, L.; Gilmour, R. Chem. Commun. 2018, 54, 12002.
(6) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013,
52, 8214.
(20) Li, Y.; Wang, X.; Guo, Y.; Zhu, Z.; Wu, Y.; Gong, Y. Chem.
Commun. 2016, 52, 796.
(21) Ono, S.; Yokota, Y.; Ito, S.; Mikami, K. Org. Lett. 2019, 21, 1093.
(22) (a) Molnár, I. G.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 5004.
(b) Scheidt, F.; Schäfer, M.; Sarie, J. C.; Daniliuc, C. G.; Molloy, J.
J.; Gilmour, R. Angew. Chem. Int. Ed. 2018, 57, 16431.
(c) Erdeljac, N.; Bussmann, K.; Schöller, A.; Hansen, F.; Gilmour,
R. ACS Med. Chem. Lett. 2019, 10, 1336. (d) Meyer, S.; Häfliger, J.;
Schäfer, M.; Molloy, J. J.; Daniliuc, C. G.; Gilmour, R. Angew.
Chem. Int. Ed. 2021, 60, 6430.
(23) (a) Weinland, R. F.; Stille, W. Ber. Dtsch. Chem. Ges. 1901, 34,
2631. (b) Edmunds, J. J.; Motherwell, W. B. J. Chem. Soc., Chem.
Commun. 1989, 881. (c) Sarie, J. C.; Thiehoff, C.; Mudd, R. J.;
Daniliuc, C. G.; Kehr, G.; Gilmour, R. J. Org. Chem. 2017, 82,
11792. For the analogous chlorinated system, see: (d) Sarie, J. C.;
Neufeld, J.; Daniliuc, C. G.; Gilmour, R. ACS Catal. 2019, 9, 7232.
(24) For examples from other laboratories, see: (a) Banik, S. M.;
Medley, J. W.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 5000.
(b) Haj, M. K.; Banik, S. M.; Jacobsen, E. N. Org. Lett. 2019, 21,
4919. (c) Doobary, S.; Sedikides, A. T.; Caldora, H. P.; Poole, D. L.;
Lennox, A. J. J. Angew. Chem. Int. Ed. 2020, 59, 1155.
(25) For selected reviews, see: (a) Kohlhepp, S. V.; Gulder, T. Chem.
Soc. Rev. 2016, 45, 6270. (b) Arnold, A. M.; Ulmer, A.; Gulder, T.
Chem. Eur. J. 2016, 22, 8728. (c) Doobary, S.; Lennox, A. J. J.
Synlett 2010, 1333. (d) Wang, Y.; Yang, B.; Wu, X.-X.; Wu, Z.-G.
Synthesis 2020, 52, 889.
(7) Qacemi, M. El.; Rendine, S.; Mainfisch, P. In Fluorine in Life Sci-
ences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemi-
cals; Haufe, G.; Leroux, F., Ed.; Elsevier Inc: London, 2019, 607–
623.
(26) Lal, G. S. J. Org. Chem. 1993, 58, 2791.
(8) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(27) For a study on the effect of Brønsted acidity on the activation of
PhICl2 by TFA, see: Cotter, J. L.; Andrews, L. J.; Keefer, R. M. J. Am.
Chem. Soc. 1962, 84, 793.
(28) (a) Oppolzer, W.; Bienaymé, H.; Genevois-Borella, A. J. Am.
Chem. Soc. 1991, 113, 9661. (b) Yajima, H.; Takeyama, M.;
Kanaki, J.; Nishimura, O.; Fujino, M. Chem. Pharm. Bull. 1978, 26,
3752.
(9) Tohnishi, M.; Nakao, H.; Furuya, T.; Seo, A.; Kodama, H.; Tsubata,
K.; Fujioka, H.; Hirooka, T.; Nishimatsu, T. J. Pestic. Sci. 2005, 30,
354.
(10) Nesterov, A.; Spalthoff, C.; Kandasamy, R.; Katana, R.; Rankl, N.
B.; Andrés, M.; Jähde, P.; Dorsch, J. A.; Stam, L. F.; Braun, F.-J.;
Warren, B.; Salgado, V. L.; Göpfert, M. C. Neuron 2015, 86, 665.
(11) Tsubata, K.; Tohnishi, H.; Kodama, H.; Seo, A. Pflanzenschutz-
Nachrichten Bayer 2007, 60, 105.
(29) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822.
(30) van der Waals volumes were calculated according to: (a) Zhao,
Y. H.; Abraham, M. H.; Zissimos, A. M. J. Org. Chem. 2003, 68,
7368. See: (b) Bondi, A. J. Phys. Chem. 1964, 68, 441. In order to
calculate the volume of a specific fragment, the number of
atoms was doubled and the resulting volume was divided by 2
(31) Schaefer, T.; Schurko, R. W.; Sebastian, R.; Hruska, F. E. Can.
J. Chem. 1995, 73, 816.
(32) (a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Sander, U. O.; D’Arcy, A.;
Stihle, M.; Müller, K.; Diederich, F. Angew. Chem. Int. Ed. 2003,
42, 2507. (b) Hof, F.; Scofield, D. M.; Schweizer, W. B.; Diederich,
F. Angew. Chem. Int. Ed. 2004, 43, 5056.
(12) Liu, Y.; Zhang, Y.; Liu, S.; Lü, Y.; Lin, R.; Li, M.; Liao, X.; Li, X. Chin.
J. Chem. Eng. 2018, 26, 2185.
(13) Hallenbach, W.; Schwarz, H.-G.; Ilg, K.; Görgens, U.; Köbberling,
J.; Turberg, A.; Böhnke, N.; Maue, M.; Velten, R.; Harschneck, T.;
Hahn, J. J.; Horstmann, S. WO 2015067646A1, 2015.
(14) Katsuta, H.; Nomura, M.; Wakita, T.; Daido, H.; Kobayashi, Y.;
Kawahara, A.; Banba, S. J. Pestic. Sci. 2019, 44, 120.
(15) Guin, J.; Rabalakos, C.; List, B. Angew. Chem. Int. Ed. 2012, 51,
8859.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J

J
V. Martín-Heras et al.
Special Topic
Synthesis
(33) (a) Paulini, R.; Müller, K.; Diederich, F. Angew. Chem. Int. Ed.
2005, 44, 1788. (b) Pollock, J.; Borkin, D.; Lund, G.; Purohit, T.;
Dyguda-Kazimierowicz, E.; Grembacka, J.; Cierpicki, T. J. Med.
Chem. 2015, 58, 7465.
(34) (a) Struble, M. D.; Scerba, M. T.; Siegler, M.; Lectka, T. Science
2013, 340, 57. (b) Pitts, C. R.; Holl, M. G.; Lectka, T. Angew. Chem.
Int. Ed. 2018, 57, 1924. (c) Holl, M. G.; Pitts, C. R.; Lectka, T. Acc.
Chem. Res. 2020, 53, 265.
(35) Morken, P. A.; Burton, D. J. J. Org. Chem. 1993, 58, 1167.
(36) Wang, F.; Li, L.; Ni, C.; Hu, J. Beilstein J. Org. Chem. 2014, 10, 344.
(37) Loska, R.; Bukowska, P. Org. Biomol. Chem. 2015, 13, 9872.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–J