Photochemical direct perfluoroalkylation of phenols

Article abstract of DOI:10.1016/j.tet.2015.02.034

A metal-free photochemical strategy for the direct aromatic perfluoroalkylation of phenols is reported. This operationally simple approach occurs at ambient temperature and under illumination by a fluorescent light bulb. The chemistry is driven by the ability of phenolate anions, transiently generated upon deprotonation of phenols, to directly reach an electronically excited state upon light absorption while successively triggering the formation of reactive radical species from perfluoroalkyl iodides. Preliminary mechanistic studies are reported.

Full text of DOI:10.1016/j.tet.2015.02.034

Tetrahedron xxx (2015) 1e8
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Tetrahedron
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Photochemical direct perfluoroalkylation of phenols
,
,
,b,
Giacomo Filippini a y, Manuel Nappi a y, Paolo Melchiorre a
*
a ICIQdInstitute of Chemical Research of Catalonia, Avenida Països Catalans 16, Tarragona 43007, Spain
b ICREAdCatalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23, 08010 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A metal-free photochemical strategy for the direct aromatic perfluoroalkylation of phenols is reported.
This operationally simple approach occurs at ambient temperature and under illumination by a fluo-
rescent light bulb. The chemistry is driven by the ability of phenolate anions, transiently generated upon
deprotonation of phenols, to directly reach an electronically excited state upon light absorption while
successively triggering the formation of reactive radical species from perfluoroalkyl iodides. Preliminary
mechanistic studies are reported.
Received 2 February 2015
Accepted 7 February 2015
Available online xxx
Keywords:
Photochemistry
Perfluoroalkylation
CeH functionalization
Phenols
Ó 2015 Elsevier Ltd. All rights reserved.
Synthetic methods
Axial chirality
1. Introduction
transition metals (especially copper and palladium) have been
successfully realized.3
Fluorine-containing functional groups can profoundly alter the
intrinsic properties of organic compounds. For this reason, in-
corporating perfluoroalkyl groups into aromatic scaffold is
a chemical strategy often exploited in medicinal chemistry to
modulate the biological activity of drug candidates.1 Since 1957,
over 150 fluorinated drugs have come to market (Fig. 1),1a justifying
the profuse efforts made by the synthetic community to develop
effective methodologies for directly incorporating perfluoroalkyl
groups into aromatic compounds. To achieve this synthetic goal,
cross-coupling methodologies that use stoichiometric amount of
metals have been developed.2 This approach requires that the
fluorinated fragments are installed in place of halides or boronic
acid derivatives. More recently, catalytic variants based on
The direct functionalization of simple arenes, by avoiding the
need for the pre-installation of a leaving group on the aromatics,
provides a more straightforward approach. However, the direct
introduction of perfluoroalkyl groups into a non-activated CeH
bond of aromatic rings is a challenging transformation for which
few strategies are available.4 Typically, direct functionalization
methodologies are based on radical reactivity. They capitalize upon
the strongly electrophilic nature of the perfluoroalkyl radicals,5
which are eager to react with arenes through the classical homo-
lytic aromatic substitution (HAS) pathway.6 Generating such radi-
cals generally require harsh reaction conditions, including the use
of high reaction temperature,7a,b stoichiometric amounts of radical
initiators and/or metals,7cei and potentially explosive oxidants.7kem
Recently, metal-based photoredox catalysis driven by visible light
has been identified as a suitable approach to generate fluorinated
radicals (RꢀF) from perfluroalkyl iodidies (RFI, 1, RF indicates the
perfluoroalkyl fragment) under mild reaction conditions (Scheme
1a).8 In 2014, our research group developed an operationally sim-
ple strategy for the direct aromatic perfluoroalkylation of a-cyano
arylacetates I that proceeded without the need for an external
photosensitizer (Scheme 1b).9 The metal-free process relied upon
the formation of photon-absorbing electron donor-acceptor (EDA)
complexes II,10 generated in the ground-state upon association of
Fig. 1. Examples of major fluorinated drugs.
RFI with the electron-rich enolate, formed by deprotonating a-cy-
ano arylacetates I. Visible light irradiation of the colored EDA
complex II induced a single electron transfer (SET), allowing access
to perfluoralkyl radicals under mild conditions. This served as the
* Corresponding author. Tel.: þ34 977 920 807; e-mail address: pmelchiorre@
iciq.es (P. Melchiorre).
y
These authors contributed equally.
http://dx.doi.org/10.1016/j.tet.2015.02.034
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
G. Filippini et al. / Tetrahedron xxx (2015) 1e8
Table 1
initiation step of a radical chain mechanism occurring trough
a classical HAS pathway, and leading to product III.
Reaction optimizationa
Entry
Base (n)
Solvent
% Yieldb
o-4
p-4
o,p-4%c
1
TMG (1)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
31
77
0
0
68
0
52%
32%
d
9%
8%
d
39%
60%
d
2
TMG (2.5)
TMG (2.5)
None
3d
4
d
d
d
5e
6
TMG (2.5)
KOH (2.5)
NaHCO3 (2.5)
K2CO3(2.5)
Cs2CO3 (2.5)
TMG (2.5)
TMG (2.5)
TMG (2.5)
TMG (2.5)
TMG (2.5)
35%
d
6%
d
59%
d
7
8
9
10
11
12
13
14
0
d
d
d
32
21
62
36
65
26
70
28%
5%
0%
0%
13%
8%
6%
30%
11%
72%
95%
48%
60%
68%
16%
51%
39%
32%
28%
54%
38%
Toluene
DMF
MeOH
EtOAc
Scheme 1. a & b: Previous photochemical strategies to generate perfluoroalkyl radicals
(RꢀF). c: the present metal-free strategy, which serves for the direct perfluoroalkylation
of phenols 2 at ambient temperature.
a
TMG: 1,1,3,3-tetramethylguanidine. Reactions performed on a 0.1 mmol scale
using 3 equiv of 1a, [2a]0¼0.5 M, and a 23 W CFL bulb to illuminate the reaction
vessel.
Herein, we describe a novel photochemical strategy for the di-
rect perfluoroalkylation of phenols11 with RFI, which occurs under
mild conditions, since it requires ambient temperature and illu-
mination by a compact fluorescent light (CFL) bulb in order to
proceed. The chemistry does not rely on the use of any external
photoredox catalyst nor on the formation of ground-state EDA
complexes to access radical reactivity patterns. Instead, the process
is driven by the ability of phenolate anions 3,12 generated upon
base-mediated deprotonation of phenols 2, to directly reach an
electronically excited state by light absorption while successively
triggering the formation of the perfluoralkyl radicals from RFI, 1
(Scheme 1c). Despite the propensity of excited phenolates to un-
dergo a photo-induced electron ejection has been established in
the 40’s of the last century,12,13 this mechanism has not found ap-
plication in synthetic organic chemistry so far.
b
Total yield determined by 1H and 19F NMR analysis using 1-fluoro-2-
nitrobenzene as the internal standard.
c
Percent distribution of the para (p-4), ortho (o-4) and ortho, para (o,p-4) func-
tionalized products.
d
Reactions performed i) in the dark, or ii) in air, or iii) in the presence of 2 equiv of
TEMPO, were all completely inhibited.
e
Reaction performed using a 300 W Xenon lamp, equipped with a cut-off filter at
385 nm.
noting that, upon addition of TMG, the solution of salicylaldehyde
2a, which was almost colorless, immediately turned to a bright
yellow color, indicating the ability of the phenolate 3a of absorbing
in the visible spectral region (blue line in Fig. 2). Addition of the
iodide 1a did not bring about any appreciable change of the
It is worth noting that, recently, Matsugi and co-workers de-
veloped a method for the direct perfluoroalkylation of phenols,
which relied upon the use of stoichiometric amounts of a radical
initiator while requiring a large excess of base (8 equiv of cesium
carbonate) to deprotonate the phenols.14 Our methodology, al-
though is characterized by a similar reactivity, allows for a wider
substrate scope. In addition, the systems are mechanistically dis-
tinguished by the way in which the perfluoroalkyl radical genera-
tion is achieved.
2. Results and discussion
Our initial explorations focused on the reaction between sali-
cylaldehyde 2a and perfluorohexyl iodide 1a (Table 1). The exper-
iments were conducted in CH3CN under irradiation by a 23 W CFL
lamp. Performing the reaction in the presence of a base such as
1,1,3,3-tetramethyl guanidine (TMG, 1 equiv), so as to favor the
formation of the corresponding phenolate 3a, provided both the
ortho and para functionalized products 4a in a roughly 5:1 ratio,
along with the ortho-para bifunctionalized adduct o,p-4a (entry 1,
total yield of 31%). Increasing the amount of TMG (2.5 equiv, entry
2) resulted in a higher reactivity (77% total yield), while the adduct
o,p-4a was formed as the major product. A control experiment
revealed how the careful exclusion of light completely suppressed
the process, thus establishing the photochemical nature of the re-
action (entry 3). In addition, we confirmed that the photochemical
activity of the phenolate 3a, formed in situ upon deprotonation of
2a, was essential for reactivity, since in the absence of a base the
starting substrates were completely recovered (entry 4). It is worth
Fig. 2. Optical absorption spectra recorded in CH3CN in quartz cuvettes (1 cm path)
using
a
Shimadzu 2401 PC UV-visible spectrophotometer. [2a]¼0.0025 M, [1a]¼
0.0075 M; [TMG]¼0.00625 M. While the substrates 1a, 2a, and TMG are almost col-
orless, the formation of the phenolate anion 3a, generated upon TMG addition, de-
termines a strong bathochromic shift (blue line). Its combination with perfluorohexyl
iodide 1a does not lead to any appreciable change of the absorption spectrum (red line
perfectly overlays the blue line).
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G. Filippini et al. / Tetrahedron xxx (2015) 1e8
3
absorption spectrum (red line in Fig. 2, perfect overlap with the
absorption of 3a), which excluded the formation of an EDA complex
ground-state association with the phenolate 3a.
observed when running the reaction in air (Table 1, entry 3). As
a final comment, the yield of the mono-perfluoralkylated products
o-4a and p-4a reached a maximum to then decrease during the
time. In contrast, the formation of the bifunctionalized adduct o,p-
4a uniformly increased with the reaction progression, indicating
that both o-4a and p-4a are reactive intermediates, which were
continuously transformed into o,p-4a.
While further insights on the photo-activity12 of the phenolate
anion of type 3 are discussed in a following section of the manu-
script, the observed reactivity deserves some comments. The
product distribution is congruent with the ability of the phenolate
intermediate 3a of acting, by means of mesomeric effects, as
a powerful electron releasing group, thus increasing the electronic
density on both the ortho and para positions of the aromatic ring.
This scenario is supported by the reactivity resonance parameter
Next, we evaluated the synthetic potential of the photochemical
perfluoroalkylation strategy, reacting differently substituted phe-
nols with perfluorohexyl iodide 1a. As shown in Fig. 4b, a variety of
electron-withdrawing substituents at the ortho-position, including
aldehyde, ester, bromine, and ketone moieties, was well tolerated.
The resulting perfluoroalkylation took place with moderate regio-
selectivity, favoring the formation of the bi-functionalized ortho,
para-adducts o,p-4aed. Notably, the major positional isomers could
be easily isolated by simple chromatography on silica gel, in-
creasing the synthetic utility of the approach. In consonance with
(
sR) of the phenolate anion, derived from simple phenol, which is
reported to be ꢁ0.6015 (for comparison, an N,N-dimethyl amino
substituent has a sR¼ꢁ0.56). Mechanistically, the mesomeric effect
within 3a facilitates the trapping of the electrophilic perfluorohexyl
radical through the classical HAS pathway,6 which is generally
characterized by a low level of regioselectivity.7c,14
We then conducted further control experiments to better un-
derstand the reactivity. The inhibition of the reaction observed
under aerobic atmosphere was consonant with a radical mecha-
nism occurring. This was further corroborated by the experiment
conducted in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO, 2 equiv), since the product 4a was not detected after
prolonged exposure to light (entry 3 in Table 1). An additional ex-
periment revealed how the use of a 300 W Xenon lamp, equipped
with a cut-off filter at 385 nm, did not significantly alter the re-
action efficiency (entry 5). This results is mechanistically relevant
since it excluded a possible homolytic cleavage of the CeI bond in 1
(not feasible upon irradiation with such low-energy photons) as
responsible for the RꢀF generation.
A cycle of optimization studies did not bring about any im-
provement in the efficiency of the model perfluoroalkylation. In-
organic bases were not suitable for the reaction (entries 6e9). We
also tested different solvents (entries 10e14). Although DCM, ethyl
acetate, and DMF provided a good reactivity, none of them could
parallel the performance offered by CH3CN (entry 2).
With the best conditions in hand (CH3CN, 2.5 equiv of TMG), we
studied the evolution of the product formation during time (Fig. 3).
After an apparent induction period, the perfluoroalkylation be-
came fast and the total yield of 4a increased rapidly reaching
a standstill at about 80% of conversion. To account for this reactivity
profile, we propose that molecular oxygen (present in trace quan-
tities despite the applied freeze-pump-thaw procedure) retards the
initiation of the reaction by quenching the phenolate triplet
state.12d,13b This is congruent with the complete loss of reactivity
the classic HAS reactivity,6 the use of
a strongly electron-
withdrawing nitro group greatly reduced the efficiency of the re-
action, because of the reduced electron density on the arene (4e).
As a limitation of the system (Fig. 4c), our attempts to react the
unsubstituted phenol or a substrate bearing an electron donating
methoxy moiety have met with failure (products 4f and 4g). In-
terestingly, the perfluoroalkylation of a O-methyl protected phenol
did not proceed at all (4h), further highlighting the need for the
phenolate formation in order for the photochemical reaction to
occur.
Phenols bearing moderate electron-withdrawing group at the
para position were also suitable substrates, affording the bifunc-
tionalized ortho-adducts o,o0-4iej in synthetically useful yield
(Fig. 4d). The photochemical method was also useful to directly
functionalize paracetamol, a widely prescribed pharmaceutical
agent used as a mild analgesic. Albeit paracetamol bears a phenol
moiety decorated with a weak electron-donating amide group, the
corresponding product o,o0-4k was obtained in moderate yield
using an excess of 1a (6 equiv). Also an indanone derivative was
a suitable substrate, the resulting adduct 4l being obtained in
moderate yield.
We also found that the system is amenable to the use of other
perfluoralkyl iodides (Fig. 4e). We focused on a phenol adorned
with two electron-withdrawing groups (o-ester and p-ketone),
since the photochemical perfluoroalkylation led to the regiose-
lective formation of the sole ortho-adducts in high chemical yield.
In addition to the perfluorohexyl chain (product o-4m), either
a shorter or a longer perfluorinated chain were installed in a fairly
good yield to afford o-4n and o-4o, respectively. Notably, the tri-
fluoromethyl moiety could be easily installed starting from CF3I (o-
4p).
We then evaluated the possibility of applying our photochemi-
cal perfluoroalkylation strategy to meta-aryl substituted phenols
(Fig. 5a). The ortho-adduct o-5a was produced as the major isomer,
while only a minor amount of the ortho-para-bifunctionalized
compound was formed. This product distribution was probably
dictated by steric effects of the meta-aryl substituent, which fa-
vored a single perfluoroalkylation event. Interestingly, the per-
fluoroalkylated adducts o-5bed exhibited axial chirality.16 This was
due to the steric interactions between the ortho-methyl substituent
on the pendant aryl moiety and the perfluoralkyl fragment, which
precluded the possibility for the arylearyl single bond to freely
rotate. Rotationally hindered biaryl axes are important stereogenic
elements found in a number of natural products, chiral auxiliaries,
and catalysts.17 In particular, the antibiotic vancomycin contains
three stable chiral axes, including one that features a tri-hydroxyl
substituted bi-aryl system.18
The configurational stability of the chiral axis in o-5b was
Fig. 3. Evolution of the product distribution during the reaction progress.
established by means of variable temperature (VT)-19F NMR
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G. Filippini et al. / Tetrahedron xxx (2015) 1e8
Fig. 4. Metal-free photochemical aromatic perfluoroalkylation of substituted phenols. The yields refer to the major isolated regioisomeric compounds; for 4a, since two positional
[
isomers could be isolated by chromatography, individual yields are also given.
*
]19F NMR yields of the minor positional isomers, as inferred by analysis of the crude reaction. (a)
General conditions: reactions performed on a 0.2 mmol scale using 3 equiv of perfluoroalkyl iodides 1, 2.5 equiv of TMG, 0.4 mL of MeCN and a 23 W CFL bulb; an acidic work-up
(HCl 1N) is required to isolate the products. For the synthesis of compounds 4c, 4i, 4j, and 4k, 6 equiv of 1 have been used. (b) Scope of the perfluorohexylation of o-substituted
phenols. (c) Limitations of the system. (d) Perfluorohexylation of p-substituted phenols and of an indanone derivative. (e) Scope of the perfluoroalkylating agents.
Fig. 5. (a) Metal-free photochemical aromatic perfluoroalkylation of biaryl phenols. The yields refer to the major isolated regioisomeric compounds. [*]19F NMR yields of the minor
positional isomers, as inferred by analysis of the crude reaction. (b) (VT)-19F NMR studies (376 MHz) of o-5b in dimethyl sulfoxide-d6. Red spectrum: 298 K; green spectrum: 348 K;
blue spectrum: 398 K. The red arrows identify the diastereotopic CF2 signals. (c) Chromatographic trace of the two enantiomers of o-5d (chiral stationary phase column: IC-3;
eluent: hexane/dichloromethane 98:2; flux: 0.5 mL/min).
analyses, conducted in dimethyl sulfoxide-d6. The presence of the
axial stereogenic element rendered the two fluorine nuclei of the
CF2 group adjacent to the arene diastereotopics (Fig. 5b). Even at
a temperature as high as 398 K, we could not observe coalescence of
the diastereotopic CF2 signals, which confirmed the high stability of
the chiral axis against rotation. In addition, we found that a per-
fluorobutyl fragment was bulky enough to block the rotation
between the two aromatic systems (product o-5c). A bi-aryl phenol
bearing an ester substituent was also a suitable substrate, since
compound o-5d was isolated in a moderate yield. In this case, the
configurational stability of the chiral axis has allowed the separa-
tion of the atropoisomers by HPLC analysis on a chiral stationary
phase (Fig. 5c). All our attempts to perform an enantioselective
variant of the process, i.e. a dynamic kinetic resolution of the biaryl
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G. Filippini et al. / Tetrahedron xxx (2015) 1e8
5
atropisomers via photochemical perfluoroalkylation driven by
a chiral phase transfer catalyst or a chiral base, have met with
failure.19
2.1. Mechanistic considerations
Our initial explorations, detailed in Table 1, indicated that the
photochemical activity of the phenolate 3a, formed in situ upon
deprotonation of 2a, was essential for reactivity. To further examine
the possible implication of the phenolate within the photochemical
regime, we investigated the photo-physical behaviour of the in-
termediate 3a, prepared by dissolving salicylaldehyde 2a in
a freshly distilled solution of TMG.20 Fig. 6a shows the absorption
spectrum of 3a. More importantly, we have recorded the emission
spectra of 3a upon excitation at 460 nm (Fig. 6b, maximum emis-
sion at 490 nm). A series of Stern-Volmer quenching studies was
performed, which revealed that perfluorohexyl iodide 1a effec-
tively quenched the excited state of 3a.
Fig. 7. Proposed mechanism: exploiting the dichotomous reactivity profile of pheno-
lates 3 in the ground- and excited-states. For simplicity, only the ortho-alkylation
pathway is shown.
triggering the formation of the electron-deficient radical RꢀF through
the reductive cleavage of the perfluorohexyl iodide CeI bond via
a single electron transfer (SET) mechanism. Consistently with a SET
pathway, the model reaction was strongly inhibited when per-
formed in the presence of 0.2 equiv of a redox trap such as 1,4-
dinitrobenzene (30% yield, 16 h). RꢀF is then trapped by the
ground-state phenolate 3 to form the new CeC bond. The meso-
meric effect of the phenolate anion facilitates the CeC bond for-
mation leading to the cyclohexadienyl radical IV. As for the chain
propagation step, IV is oxidized by RFI through a SET mechanism to
give the cyclohexadienyl intermediate V along with RꢀF and the io-
dide anion. V is eventually deprotonated to form the final product 4
(upon acidic work-up).
3. Conclusions
In summary, we have developed a direct and effective way to
install perfluoroalkyl and trifluoromethyl groups within the aro-
matic ring of substituted phenols. The reaction protocol is opera-
tionally simple, conducted at ambient temperature with readily
available substrates and reagents, and using household CFL bulbs as
the light source. The chemistry is driven by the ability of phenolate
anions to act as photosensitizers upon excitation by simple light
irradiation, and to trigger the formation of perfluoroalkyl radicals
under mild conditions.
4. Experimental section
4.1. General information
All reactions were set up under an argon atmosphere in oven-
dried glassware using standard Schlenk techniques, unless other-
wise stated. Synthesis grade solvents were used as purchased and
the reaction mixtures were deoxygenated by three cycles of freeze-
pump-thaw. Chromatographic purification of products was ac-
complished using force-flow chromatography (FC) on silica gel
(35e70 mesh). For thin layer chromatography (TLC) analysis
throughout this work, Merck precoated TLC plates (silica gel 60
GF254, 0.25 mm) were employed, using UV light as the visualizing
agent and an acidic mixture of para-anisaldehyde or basic aqueous
potassium permanganate (KMnO4) stain solutions, and heat as
Fig. 6. (a) Optical absorption spectra of neat TMG (blue line) and of the phenolate 3a in
neat TMG ([3a]¼0.007 M, red line). (b) Quenching of the phenolate 3a emission ([3a]¼
7$10ꢁ3 M in TMG, excitation at 460 nm) in the presence of increasing amounts of
perfluorohexyl iodide 1a.
On the basis of these observations, we propose a radical chain
mechanism, which follows a classical HAS pathway6 (Fig. 7). The
reaction is initiated by the photochemical activity of the phenolate
anion of type 3, formed by deprotonation of the phenol 2. Upon
light absorption, 3 can reach an electronically excited state (3*)
developing agents. Organic solutions were concentrated under re-
1
duced pressure on a Buchi rotatory evaporator. The H and 13C NMR
€
spectra were recorded at 400 MHz or 500 MHz for 1H and at
100 MHz or 125 MHz for 13C, respectively. The chemical shifts (
d)
for 1H and 13C are given in parts per million relative to residual
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6
G. Filippini et al. / Tetrahedron xxx (2015) 1e8
signals of the solvents (CHCl3 @ 7.26 ppm 1H NMR, 77.0 ppm 13C
NMR). Coupling constants are given in Hertz. The following ab-
breviations are used to indicate the multiplicity: s, singlet; d,
doublet; t, triplet; q, quartet; qn, quintet; m, multiplet; bs, broad
signal. Mass spectra (high and low resolution) were obtained from
the ICIQ High Resolution Mass Spectrometry Unit on a Bruker Maxis
Impact (QTOF) or Waters Micromass LCT-Premier (TOF) in Elec-
trospray Ionization (ESI) by direct infusion. Optical rotations Optical
rotations were measured on a Polarimeter Jasco P-1030 and are
2F), ꢁ122.82 (m, 2F), ꢁ126.21 (m, 2F); 13C NMR (101 MHz, CDCl3)
d
196.75, 161.21, 138.49, 136.82 (t, J¼8.4 Hz), 121.84, 121.65, 119.82;
HRMS calculated for
439.0016.
C13H4F13O2 (MeH): 439.0009, found:
4.3.3. Methyl
2-hydroxy-3,5-bis(perfluorohexyl)benzoate
(o,p-
4b). The title compound was isolated in 50% yield as a white solid
by chromatography using a gradient eluent of hexane/ethyl acetate
(Rf¼0.30 hexane/ethyl acetate 24:1). 1H NMR (400 MHz, CDCl3)
reported as follows: [
a
]
D
rt (c in g per 100 mL, solvent). UVevis
d
12.09 (s, 1H), 8.30 (d, J¼2.08 Hz, 1H), 7.87 (d, J¼2.00 Hz, 1H), 4.05
measurements were carried out on a Shimadzu UV-2401PC spec-
trophotometer equipped with photomultiplier detector, double
beam optics and D2 and W light sources. The emission spectra were
recorded in a Fluorolog Horiba Jobin Yvon spectrofluorimeter
equipped with photomultiplier detector, double monochromator
and 350 W xenon light source. Cut-off and band-pass photo-
chemical experiments have been performed using a 300 W xenon
lamp (Asashi Spectra Co., Ltd.) to irradiate the reaction mixture.
Reagents were purchased at the highest commercial quality and
used without further purification, unless otherwise stated.
(s, 3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
ꢁ80.92 (m, 6F),
ꢁ109.22 (t, J¼14.60 Hz, 2F), ꢁ110.68 (t, J¼14.30 Hz, 2F), ꢁ121.47 (m,
4F), ꢁ121.95 (m, 4F), ꢁ122.89 (m, 4F), ꢁ126.27 (m, 4F).13C NMR
(100 MHz, CDCl3)
d 164.44, 163.29, 133.70, 133.31, 119.59 (t,
J¼26.04 Hz), 118.12 (t, J¼23.87 Hz), 114.36, 53.55. HRMS calculated
for C20H6F26NaO3 (MþNa): 810.9794, found: 810.9824.
4.3.4. 2-Bromo-4,6-bis(perfluorohexyl)phenol (o,p-4c). The title
compound was isolated in 40% yield as a colorless oil by chroma-
tography using a gradient eluent of hexane/ethyl acetate (Rf¼0.35
hexane/ethyl acetate 24:1). 1H NMR (400 MHz, CDCl3)
7.67 (s, 1H). 19F NMR decoupled 1H (376 MHz, CDCl3)
d
d
7.93 (s, 1H),
ꢁ80.96 (m,
4.2. General procedures for the light-driven perfluoroalkyla-
tion of phenols
6F), ꢁ109.15 (t, J¼14.67 Hz, 2F), ꢁ110.54 (t, J¼14.41 Hz, 2F), ꢁ121.52
(m, 4F), ꢁ121.89 (m, 4F), ꢁ122.90 (m, 4F), ꢁ126.28 (m, 4F); 13C NMR
A 10 mL Schlenk tube was charged with the appropriate phenol
2 (0.2 mmol), acetonitrile (0.4 mL, 0.5 M referring to 2), per-
fluoroalkyl iodide 1 (0.6 mmol, 3 equiv) and N,N,N0,N0-tetrame-
thylguanidine (0.063 mL, 0.5 mmol, 2.5 equiv). The reaction
mixture was thoroughly degassed via 3 cycles of freeze pump thaw,
and the vessel was refilled with argon, sealed, and positioned ap-
proximately 5 cm away from a household full spectrum 23 W
compact fluorescent light (CFL). For the preparation of the tri-
fluoromethylated phenol 4p, the trifluoroiodomethane (0.6 mmol,
15 mL, gas) was added via gas syringe at ꢁ196 ꢂC (nitrogen bath)
after freeze pump thaw of the reaction mixture.
After stirring for the indicated time, the reaction was diluted
with DCM, quenched with aqueous HCl 1 M solution and extracted
3 times with DCM. The organic phase was then dried and the sol-
vent removed under reduced pressure. The residue was purified by
flash column chromatography on silica gel to afford the title com-
pounds 4 and 5.
(100 MHz, CDCl3)
116.73 (t, J¼24.12 Hz), 113.28. HRMS calculated for C18H2BrF26
(MeH): 806.8879, found: 806.8883.
d
154.33, 134.66, 128.13, 122.36 (t, J¼25.88 Hz),
O
4.3.5. 1-(2-Hydroxy-3,5-bis(perfluorohexyl)phenyl)ethan-1-one (o,p-
4d). The title compound was isolated in 35% yield as a colorless oil
by chromatography using a gradient eluent of hexane/ethyl acetate
(Rf¼0.30 hexane/ethyl acetate 15:1).1H NMR (500 MHz, CDCl3)
d
13.55 (s,1H), 8.14 (d, J¼1.66 Hz,1H), 7.90 (d, J¼1.67 Hz,1H), 2.75 (s,
3H); 19F NMR decoupled 1H (376 MHz, CDCl3)
d
ꢁ80.89 (m, 6F),
ꢁ109.25 (t, J¼14.51 Hz, 2F), ꢁ110.64 (t, J¼14.67 Hz, 2F), ꢁ121.38 (m,
4F), ꢁ121.87 (m, 4F), ꢁ122.86 (m, 4F), ꢁ126.25 (m, 4F); 13C NMR
(126 MHz, CDCl3)
d 204.26, 164.32, 134.31, 133.61, 120.51, 119.11 (t,
J¼26.03 Hz), 118.90 (t, J¼23.83 Hz); HRMS calculated for
C20H6F26NaO2 (MþNa): 794.9845, found: 794.9878.
4.3.6. 4-Hydroxy-3,5-bis(perfluorohexyl)benzaldehyde (o,o0-4i). The
title compound was isolated in 40% yield as a white solid by
chromatography using a gradient eluent of hexane/DCM (Rf¼0.3
4.3. Characterization of products
hexane/DCM 2:1). 1H NMR (400 MHz, CDCl3):
2H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
d
9.98 (s, 1H), 8.22 (s,
ꢁ80.89 (t, J¼9.9 Hz,
4.3.1. 2-Hydroxy-3,5-bis(perfluorohexyl)benzaldehyde (o,p-4a). The
title compound was isolated in 40% yield as a colorless oil by
chromatography using a gradient eluent of hexane/ethyl acetate
(Rf¼0.25 hexane/ethyl acetate 20:1). The characterization of com-
pound (o,p-4a) matches with the data reported in the literature.13
6F), ꢁ108.25 (t, J¼14.5 Hz, 4F), ꢁ121.38 (m, 4F), ꢁ121.74 (m, 4F),
ꢁ122.79 (m, 4F), ꢁ126.21 (m, 4F). 13C NMR (101 MHz, CDCl3)
d
188.16, 158.37, 135.09, 129.46, 118.12 (t, J¼23.0 Hz). HRMS calcu-
lated for C19H3F26O2 (MeH): 756.9723, found: 756.9749.
1H NMR (400 MHz, CDCl3)
d 12.20 (s, 1H), 10.02 (s, 1H), 8.03 (d,
J¼2.28 Hz, 1H), 7.93 (d, J¼2.29 Hz, 1H); 19F NMR decoupled 1H
4.3.7. 1-(4-Hydroxy-3,5-bis(perfluorohexyl)phenyl)ethan-1-one
(o,o0-4j). The title compound was isolated in 50% yield as a white
solid by chromatography using a gradient eluent of hexane/DCM
(376 MHz, CDCl3)
d
ꢁ81.00 (m, 6F), ꢁ109.42 (t, J¼14.61 Hz, 2F),
ꢁ110.75 (t, J¼14.42 Hz, 2F), ꢁ121.47 (m, 4F), ꢁ121.88 (m, 4F),
ꢁ122.88 (m, 4F), ꢁ126.26 (m, 4F). 13C NMR (101 MHz, CDCl3)
(Rf¼0.35 hexane/DCM 2:1). 1H NMR (400 MHz, CDCl3):
d
8.28 (s,
ꢁ80.97
d
195.72, 163.31, 136.70, 134.6, 121.34, 120.65 (t, J¼26.26 Hz), 118.56
2H), 2.62 (s, 3H). 19F NMR decoupled 1H (376 MHz, CDCl3):
d
(t, J¼24.13 Hz). HRMS calculated for C19H3F26O2 (MeH): 756.9723,
(t, J¼10.0 Hz, 6F), ꢁ108.19 (t, J¼14.6 Hz, 4F), ꢁ121.45 (m, 4F),
found: 756.9735.
ꢁ121.81 (m, 4F), ꢁ122.85 (m, 4F), ꢁ126.28 (m, 4F); 13C NMR
(100 MHz, CDCl3):
117.41 (t, J¼22.9 Hz), 26.26; HRMS calculated for C20H5F26O2
(MeH): 770.9880, found: 770.9875.
d
194.27, 157.50, 133.90 (t, J¼8.0 Hz), 130.12,
4.3.2. 2-Hydroxy-3-(perfluorohexyl)-benzaldehyde (o-4a). The title
compound was isolated in 20% yield as a colorless oil by chroma-
tography using a gradient eluent of hexane/ethyl acetate (Rf¼0.33
hexane/ethyl acetate 20:1). The characterization of the compound
matches with the data reported in the literature.13 1H NMR
4.3.8. N-(4-Hydroxy-3,5-bis(perfluorohexyl)phenyl)acetamide (o,o0-
4k). The title compound was isolated in 35% yield as a white solid
(400 MHz, CDCl3)
d
11.84 (s, 1H), 9.96 (s, 1H), 7.83e7.72 (m, 2H), 7.16
by chromatography using a gradient eluent of hexane/DCM
(t, J¼7.8 Hz, 1H); 19F NMR decoupled 1H (376 MHz, CDCl3)
d
ꢁ80.88
(Rf¼0.40 hexane/DCM 2:1). 1H NMR (400 MHz, acetonitrile-d3);
(m, 3F), ꢁ109.03 (t, J¼28.95 Hz, 2F), ꢁ121.48 (m, 2F), ꢁ121.88 (m,
d
8.55 (s, 1H), 7.98 (s, 2H), 2.06 (s, 3H); 19F NMR (376 MHz,
Please cite this article in press as: Filippini, G.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.034

G. Filippini et al. / Tetrahedron xxx (2015) 1e8
7
acetonitrile-d3):
ꢁ121.77 (m, 4F), ꢁ122.33 (m, 2F), ꢁ123.30 (m, 4F), ꢁ126.7 (m, 4F);
13C NMR (101 MHz, acetonitrile-d3):
170.03, 150.53, 133.85,
d
ꢁ81.70 (m, 6F), ꢁ107.84 (t, J¼14.8 Hz, 4F),
eluent of hexane/toluene (Rf¼0.35 hexane/toluene 4:1). 1H NMR
(400 MHz, CDCl3):
d
12.17 (s, 1H), 9.98 (s, 1H), 8.05 (d, J¼8.5 Hz, 2H),
d
7.74 (d, J¼7.9 Hz, 1H), 7.28 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼7.9 Hz, 1H),
126.05e123.98 (m), 119.38 (t, J¼22.0 Hz), 24.15; HRMS calculated
3.95 (s, 3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
ꢁ80.91 (m,
for C20H6F26NO2 (MeH): 785.9989, found: 785.9983.
3F), ꢁ100.59 (m, 2F), ꢁ118.88 (m, 2F), ꢁ122.11 (m, 2F), ꢁ122.78 (m,
2F), ꢁ126.22 (m, 2F); 13C NMR (100 MHz, CDCl3):
d 195.96, 166.68,
4.3.9. 7-Hydroxy-6-methyl-4-(perfluorohexyl)-2,3-dihydro-1H-in-
den-1-one (p-4l). The title compound was isolated in 30% yield as
a yellow solid by chromatography using a gradient eluent of hex-
ane/ethyl acetate (Rf¼0.35 hexane/ethyl acetate 24:1). 1H NMR
161.97, 151.23, 144.80, 136.25, 129.61, 128.73, 127.76, 123.54, 120.4;
52.40; HRMS calculated for C21H10F13O4 (MeH): 573.0377, found:
573.0376.
(400 MHz, CDCl3):
d
9.93 (s, 1H), 7.48 (s, 1H), 3.36e3.12 (m, 2H),
4.3.15. 3-Hydroxy-20-methyl-2-(perfluorohexyl)-[1,10-biphenyl]-4-
carbaldehyde (o-5b). The title compound was isolated in 38% yield
as a yellow oil by chromatography using a gradient eluent of hex-
ane/toluene (Rf¼0.3 hexane/toluene 4:1). 1H NMR (400 MHz,
2.82e2.70 (m, 2H), 2.29 (s, 3H); 19F NMR decoupled 1H (376 MHz,
CDCl3):
ꢁ80.86 (m, 3F), ꢁ108.61 (m, 2F), ꢁ121.67 (m, 4F), ꢁ122.84
(m, 2F), -126.18 (m, 2 F). 13C NMR (101 MHz, CDCl3):
209.88,
d
d
158.97, 152.17, 137.27 (t, J¼7.2 Hz), 124.62, 122.72, 116.86 (t,
J¼25.0 Hz), 35.85, 25.38, 14.37. HRMS calculated for C16H8F13O2
(MeH): 479.0322, found: 479.0325.
CDCl3):
d
12.20 (s, 1H), 9.99 (s, 1H), 7.75 (d, J¼7.9 Hz, 1H), 7.38e7.17
(m, 3H), 7.04 (dd, J¼7.4, 3.0 Hz, 1H), 6.86 (d, J¼7.9 Hz, 1H), 2.08 (s,
3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
ꢁ101.49 (m, 3F),
ꢁ104.79 (dd, J¼722.1, 282.2 Hz 2F), ꢁ118.95 (dd, J¼581.7, 292.2 Hz,
4.3.10. Methyl 5-acetyl-2-hydroxy-3-(perfluorohexyl)benzoate (o-
4m). The title compound was isolated in 72% yield as a white solid
by chromatography using a gradient eluent of hexane/ethyl acetate
2F), ꢁ122.17 (m, 2F), ꢁ122.80 (m, 2F), ꢁ126.22 (m, 2F); 13C NMR
(100 MHz, CDCl3):
d
196.11, 162.39, 152.25, 139.81 (d, J¼3.0 Hz),
136.55, 134.91 (d, J¼3.9 Hz), 129.55, 128.04, 127.50, 124.93, 123.81,
120.26, 115.78 (t, J¼21.3 Hz), 20.12; HRMS calculated for
(Rf¼0.3 hexane/ethyl acetate 4:1). 1H NMR (400 MHz, CDCl3):
d 8.68
(s, 1H), 8.31 (s, 1H), 4.04 (s, 3H), 2.61 (s, 3H); 19F NMR decoupled 1H
C20H10F13O2 (MeH): 529.0479, found: 529.0468.
(376 MHz, CDCl3):
2F), ꢁ121.18 (m, 2F), ꢁ121.90 (m, 2F), ꢁ122.85 (m, 2F), ꢁ126.22 (m,
2F); 13C NMR (101 MHz, CDCl3):
194.74, 169.94, 164.09, 135.43 (t,
d
ꢁ80.95 (t, J¼10.0 Hz, 3F), ꢁ108.97 (t, J¼14.3 Hz,
4.3.16. 3-Hydroxy-20-methyl-2-(perfluorobutyl)-[1,10-biphenyl]-4-
carbaldehyde (o-5c). The title compound was isolated in 40% yield
as a yellow oil by chromatography using a gradient eluent of hex-
ane/toluene (Rf¼0.25 hexane/toluene 4:1). 1H NMR (400 MHz,
d
J¼8.4 Hz), 134.89, 128.30, 117.53 (t, J¼23.8 Hz), 113.78, 53.39, 26.33.
HRMS calculated for C16H8F13O4 (MeH): 511.0220, found: 511.0218.
CDCl3):
d
12.19 (s, 1H), 9.99 (s, 1H), 7.75 (d, J¼7.9 Hz, 1H), 7.40e7.09
4.3.11. Methyl 5-acetyl-2-hydroxy-3-(perfluorobutyl)benzoate (o-
4n). The title compound was isolated in 78% yield as a yellow solid
by chromatography using a gradient eluent of hexane/ethyl acetate
(Rf¼0.35 hexane/ethyl acetate 4:1). 1H NMR (400 MHz, CDCl3):
(m, 3H), 7.04 (dd, J¼7.4, 2.9 Hz, 1H), 6.86 (d, J¼7.9 Hz, 1H), 2.08 (s,
3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
ꢁ81.03 (m, 3F),
ꢁ102.90 (dd, J¼718.5, 286.2 Hz, 2F), ꢁ119.45 (dd, J¼593.8, 293.0 Hz,
2F), ꢁ126.32 (m, 2F); 13C NMR (101 MHz, CDCl3):
d 196.10, 162.32,
d
12.14 (s, 1H), 8.67 (d, J¼2.3 Hz, 1H), 8.30 (d, J¼2.3 Hz, 1H), 4.03 (s,
152.24,139.80, 136.54, 134.92, 129.55, 128.03, 127.51, 124.93, 123.80,
120.24, 115.70, 20.15; HRMS calculated for C18H10F9O2 (MeH):
429.0543, found: 429.0555.
3H), 2.60 (s, 3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
(m, 3F), ꢁ109.21 (t, J¼13.7 Hz, 2F), ꢁ122.11 (m, 2F), ꢁ126.06 (m, 2F);
13C NMR (101 MHz, CDCl3):
194.72, 169.93, 164.06, 135.37 (t,
d
ꢁ81.12
d
J¼8.4 Hz), 134.88, 128.29, 117.39 (t, J¼23.7 Hz), 113.75, 53.35, 26.25.
4.3.17. Methyl
3-hydroxy-20-methyl-2-(perfluorohexyl)-[1,10-bi-
HRMS calculated for C14H8F9O4 (MeH): 411.0284, found: 411.0292.
phenyl]-4-carboxylate (o-5d). The title compound was isolated in
25% yield as a yellow oil by chromatography using a gradient eluent
of hexane/toluene (Rf¼0.25 hexane/toluene 4:1). 1H NMR
4.3.12. Methyl 5-acetyl-2-hydroxy-3-(perfluorooctyl)benzoate (o-
4o). The title compound was isolated in 70% yield as a yellow solid
by chromatography using a gradient eluent of hexane/ethyl acetate
(Rf¼0.35 hexane/ethyl acetate 4:1). 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
d
11.91 (s, 1H), 8.02 (d, J¼8.2 Hz, 1H), 7.31e7.10
(m, 3H), 7.05e6.96 (m, 1H), 6.69 (d, J¼8.2 Hz, 1H), 4.01 (s, 3H), 2.05
(s, 3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
ꢁ80.92 (t,
d
12.16 (s, 1H), 8.69 (d, J¼2.2 Hz, 1H), 8.31 (d, J¼2.2 Hz, 1H), 4.04 (s,
J¼10.0 Hz, 3F), ꢁ102.75 (dd, J¼693.7, 279.6 Hz, 2F), ꢁ119.50 (dd,
J¼565.0, 287.7 Hz, 2F), ꢁ122.18 (m, 2F), ꢁ122.76 (m, 2F), ꢁ126.25
3H), 2.61 (s, 3H);19F NMR decoupled 1H (376 MHz, CDCl3)
d
ꢁ80.86
(t, J¼10.0 Hz, 3F), ꢁ108.92 (t, J¼14.1 Hz, 2F), ꢁ121.09 (m, 2F),
(m, 2F); 13C NMR (100 MHz, CDCl3):
d 170.41, 162.08, 150.91, 140.27,
ꢁ121.82 (m, 6F), ꢁ122.79 (m, 2F), ꢁ126.20 (m, 2F); 13C NMR
135.03, 132.96, 129.44, 127.78, 127.66, 124.85, 122.89, 121.62, 112.57,
52.99, 20.13; HRMS calculated for C21H12F13O3 (MeH): 559.0584,
found: 559.0593.
(101 MHz, CDCl3):
d
194.75, 169.94, 164.10, 135.44 (t, J¼8.4 Hz),
130.18, 128.43, 128.30, 113.78, 53.40, 26.35; HRMS calculated for
18H8F17O4 (MeH): 611.0157, found: 611.0167.
C
Acknowledgements
4.3.13. Methyl 5-acetyl-2-hydroxy-3-(trifluoromethyl)benzoate (o-
4p). The title compound was isolated in 44% yield as a white solid
by chromatography using a gradient eluent of hexane/ethyl acetate
(Rf¼0.35 hexane/ethyl acetate 5:1). 1H NMR (400 MHz, CDCl3):
This work was supported by the ICIQ Foundation, MICINN
(CTQ2013-45938-P) and by the European Research Council (ERC
278541 - ORGA-NAUT). We also thank MINECO for support through
the Severo Ochoa Excellence Accreditation 2014-2018 (SEV-2013-
0319). G.F. thanks the Severo Ochoa Excellence Accreditation for
a fellowship (Ref. SVP 2014-068818). M.N. is grateful to the MEC for
FPU fellowships (Ref. AP2010-1963).
d
12.03 (s, 1H), 8.66 (d, J¼2.2 Hz, 1H), 8.38 (d, J¼2.7 Hz, 1H), 4.04 (s,
3H), 2.61 (s, 3H); 19F NMR decoupled 1H (376 MHz, CDCl3):
d
ꢁ63.37
(s, 3F). 13C NMR (101 MHz, CDCl3):
d
194.83, 169.81, 163.20, 134.44,
133.10 (t, J¼5.0 Hz), 128.16, 122.77 (q, J¼273.1 Hz), 119.37 (q,
J¼32.5 Hz), 113.63, 53.35, 26.38. HRMS calculated for C11H8F3O4
(MeH): 261.0380, found: 261.0384.
Supplementary data
4.3.14. Methyl
40-formyl-30-hydroxy-20-(perfluorohexyl)-[1,10-bi-
phenyl]-4-carboxylate (o-5a). The title compound was isolated in
40% yield as a colorless oil by chromatography using a gradient
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.02.034.
Please cite this article in press as: Filippini, G.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.034

8
G. Filippini et al. / Tetrahedron xxx (2015) 1e8
10. (a) Mulliken, R. S. J. Phys. Chem. 1952, 56, 801e822; (b) Rosokha, S. V.; Kochi, J. K.
References and notes
Acc. Chem. Res. 2008, 41, 641e653; (c) Kandukuri, S. R.; Bahamonde, A.; Chat-
ꢀ
terjee, I.; Jurberg, I. D.; Escudero-Adan, E.-D.; Melchiorre, P. Angew. Chem., Int.
€
1. (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881e1886; (b) Purser,
Ed. 2015, 54, 1485e1489.
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320e330.
11. Since phenols represent a common structural motif in natural products and
organic materials, methods that allow for their direct functionalization are
synthetically relevant. For overviews on phenols in polymer chemistry, see: (a)
Marder, S. R.; Kippelen, B.; Jen, A. K. Y.; Peyghambarian, N. Nature 1997, 388,
845e851; (b) Grimsdale, A. C.; Chan, K. L.; Martin, R. E.; Jokisz, P. G.; Holmes, A.
B. Chem. Rev. 2009, 109, 897e1091 For examples of phenols as bioactive com-
pounds or in total synthesis, see: (c) Kurosawa, W.; Kan, A. T.; Fukuyama, T. J.
Am. Chem. Soc. 2003, 125, 8112e8113; (d) Yoshinari, T.; Ohmori, K.; Schrems, M.
G.; Pfaltz, A.; Suzuki, K. Angew. Chem., Int. Ed. 2010, 49, 881e885.
2. Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475e4521.
3. For a review, see: (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473,
470e477 For selected examples, see: (b) Oishi, M.; Kondo, H.; Amii, H. Chem.
Commun. 2009, 1909e1911; (c) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.;
Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679e1681; (d) Tomashenko,
O. A.; Escudero, E. C.; Belmonte, M. M.; Grushin, V. V. Angew. Chem., Int. Ed.
2011, 50, 7655e7659; (e) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2012, 51, 536e539; (f) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134,
9034e9037.
4. Another direct strategy is via metal-catalyzed C-H activation, which requires
the presence of a directing group on the arene, see: (a) Wang, X.; Truesdale, L.;
Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 3648e3649; (b) Zhang, X.-G.; Dai, H.-X.;
Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 11948e11951; (c) Miura, M.; Feng,
C.-G.; Ma, M.; Yu, J.-Q. Org. Lett. 2013, 15, 5258e5261.
12. For studies on the photo-induced oxidation of phenolate anions, see: (a) Lewis,
G. N.; Lipkin, D. J. Am. Chem. Soc. 1942, 64, 2801e2808; (b) Fessenden, R. W.;
Verma, N. C. J. Am. Chem. Soc. 1976, 98, 243e244; (c) Ichino, T.; Fessenden, R. W.
J. Phys. Chem. A 2003, 107, 9257e9268; (d) Chen, X.; Larsen, D. S.; Bradforth, S. E.
J. Phys. Chem. A 2011, 115, 3807e3819 and references therein.
13. Studies on electron photo-ejection from phenols and phenolates have bi-
ological relevance because of the structural analogies with tyrosine, see: (a)
Itoh, S.; Taki, M.; Fuku, S. Coord. Chem. Rev. 2000, 198, 3e20; (b) Bent, D. V.;
Hayon, E. J. Am. Chem. Soc. 1975, 97, 2599e2606.
5. Dolbier, W. R., Jr. Chem. Rev. 1996, 96, 1557e1584.
6. Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950e8958.
7. (a) Tiers, G. V. D. J. Am. Chem. Soc. 1960, 82, 5513; (b) Cowell, A. B.; Tamborski, C.
J. Fluorine Chem. 1981, 17, 345e356; (c) Bravo, A.; Bjørsvik, H.-R.; Fontana, F.;
Liguori, L.; Mele, A.; Minisci, F. J. Org. Chem. 1997, 62, 7128e7136; (d) Naumann,
D.; Wilkes, B.; Kischkewitz, J. J. Fluorine Chem. 1985, 30, 73e87; (e) Tanabe, Y.;
Matsuo, N.; Ohno, N. J. Org. Chem. 1988, 53, 4582e4585; (f) Lai, C.; Mallouk, T. E.
J. Chem. Soc., Chem. Commun. 1993, 1359e1361; (g) Kamigata, N.; Fukushima, T.;
Yoshida, M. Chem. Lett. 1990, 649e650; (h) Ye, Y.; Lee, S. H.; Sanford, M. S. Org.
Lett. 2011, 13, 5464e5467; (i) Mejía, E.; Togni, A. ACS Catal. 2012, 2, 521e527; (j)
Sawada, H.; Nakayama, M.; Yoshida, M.; Yoshida, T.; Kamigata, N. J. Fluorine
Chem. 1990, 46, 423e431; (k) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron
Lett. 1991, 32, 7525e7528; (l) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple,
I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411e14415; (m) O’Hara, F.; Blackmond, D. G.; Baran, P. J. Am. Chem. Soc. 2013,
135, 12122e12134.
8. (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224e228 For a related
approach, see: (b) Cui, L.; Matusaki, Y.; Tada, N.; Miura, T.; Uno, B.; Itoha, A. Adv.
Synth. Catal. 2013, 355, 2203e2207 See also: (c) Nagib, D. A.; Scott, M. E.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875e10877.
9. Nappi, M.; Bergonzini, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2014, 53,
4921e4925.
14. Matsugi, M.; Hasegawa, M.; Hasebe, S.; Takai, S.; Suyama, R.; Wakita, Y.; Kudo,
K.; Imamura, H.; Hayashi, T.; Haga, S. Tetrahedron Lett. 2008, 49, 4189e4191.
15. (a) Taft, R. W.; Price, E.; Fox, I. R.; Lewis, I. C.; Andersen, K. K.; Davis, G. T. J. Am.
Chem. Soc. 1963, 85, 3146e3156; (b) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev.
1991, 91, 165e195.
16. Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning,
M. Angew. Chem., Int. Ed. 2005, 44, 5384e5427.
17. (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992, 503e517; (b)
McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809e3844.
18. (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38, 1172e1193; (b)
€
Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2096e2152.
19. For a recent successful example, see: Gustafson, J. L.; Lim, D.; Miller, S. J. Science
2010, 328, 1251e1255.
20. The use of neat TMG to conduct the Stern-Volmer quenching studies secured
a full deprotonation of the phenol 2a into the corresponding phenolate 3a.
Performing the model reaction in neat TMG ([2a]¼0.5 M) over 16 hours did not
affect the efficiency of the photochemical perfluoroalkylation, providing a high
conversion (about 90%) into the corresponding product 4a.
Please cite this article in press as: Filippini, G.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.034