Rhodium-catalyzed benzylic fluorination of trichloroacetimidates

Article abstract of DOI:10.1016/j.tet.2015.04.066

Abstract Benzylic fluorides were synthesized via rhodium-catalyzed nucleophilic fluorination of benzylic trichloroacetimidates. A variety of naphthyl, phenyl, and pyridinyl trichloroacetimidates were fluorinated with Et₃N·3HF reagent to provide fluorine-containing compounds in moderate to high yields under mild and operationally simple conditions. Preliminary mechanistic studies suggest that benzylic fluorination of trichloroacetimidate substrates are more likely to proceed through a discrete benzylic cation, generated by rhodium catalyst.

Full text of DOI:10.1016/j.tet.2015.04.066

Tetrahedron 71 (2015) 5932e5938
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rhodium-catalyzed benzylic fluorination of trichloroacetimidates
y
y
*
Qi Zhang , Jason C. Mixdorf , Gilbert J. Reynders, III, Hien M. Nguyen
Department of Chemistry, University of Iowa, Iowa City, IA 52246, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzylic fluorides were synthesized via rhodium-catalyzed nucleophilic fluorination of benzylic tri-
chloroacetimidates. A variety of naphthyl, phenyl, and pyridinyl trichloroacetimidates were fluorinated
with Et3N$3HF reagent to provide fluorine-containing compounds in moderate to high yields under mild
and operationally simple conditions. Preliminary mechanistic studies suggest that benzylic fluorination
of trichloroacetimidate substrates are more likely to proceed through a discrete benzylic cation, gener-
ated by rhodium catalyst.
Received 25 March 2015
Received in revised form 19 April 2015
Accepted 20 April 2015
Available online 30 April 2015
This manuscript is dedicated to Professor
Barry Trost on the occasion of his receiving
the 2015 Tetrahedron Award
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Fluorination
Trichloroacetimidate
Rhodium
Benzylic Fluorides
Catalysis
1. Introduction
Organic compounds containing carbon-fluoride bonds are
common building blocks for the synthesis of pharmaceutical drug
candidates and can be used as radiotracers for medical imaging.1
The introduction of such CeF bonds can lead to the improved
bioavailability, and in turn the efficacy, of a substrate over its non-
fluorinated parent compound by affecting a wide variety of prop-
erties including pKa, lipophilicity, and binding affinity.1,2 In partic-
ular, benzylic fluorides have been the targets of much research due
to their presence in a number of biologically active pharmaceuticals
and radiotracers (Fig. 1).3e5 For example, benzylic fluorides are
motifs present in important pharmaceutical targets such as cho-
Fig. 1. Biologically relevant compounds and PET radiotracers containing benzylic
fluoride functionality.
manganese.9 Transition-metal-free benzylic fluorination has been
reported through the utilization of Lewis-acid-catalyzed epoxide
opening10 photochemical CeH activation,11 and several other
methods.12 Synthetic transformations that utilize rapid, late-stage
benzylic fluorination procedures may be suitable for the synthesis
of radiotracers by introducing radioactive fluorine-18 into the
benzylic position of bioactive target molecules. Benzylic 18F-fluo-
rination13 utilizing Mn-salen catalysts has been recently reported
by Groves5 and Carroll.14
Recently, our group has reported an iridium-catalyzed allylic
substitution of trichloroacetimidates and a rhodium-catalyzed se-
lective opening of vinyl epoxides with Et3N$3HF to produce the
desired allylic fluorides and fluorohydrins, respectively, in good
yields and with excellent branched selectivity.15,16 The efficient and
rapid fluorination of that work inspired us to hypothesize that the
lesteryl ester transfer protein (CETP) inhibitor 1,3 N-methyl-
D-as-
partate receptor antagonist 2,4 and
[
18F]benzylic fluoride-
containing COX inhibitor 3.5a
Traditionally, benzylic fluorides are prepared by the exchange of
halides with tetrabutylammonium fluoride and displacement of
benzylic hydroxyl groups with (diethylamino)sulfur trifluoride.2a
Recent reported efforts toward benzylic fluorination have also in-
cluded metal catalysis involving palladium,6 platinum,7 iron,8 and
* Corresponding author. Tel.: þ1 319 384 1887; fax: þ1 319 335 1270; e-mail
address: hien-nguyen@uiowa.edu (H.M. Nguyen).
y
The authors contributed equally to the present work.
http://dx.doi.org/10.1016/j.tet.2015.04.066
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

Q. Zhang et al. / Tetrahedron 71 (2015) 5932e5938
5933
combination of trichloroacetimidates with Et3N$3HF reagent, me-
diated by transition-metal catalysis, could potentially allow rapid
and efficient incorporation of fluorine ion into the benzylic position
of organic compounds. Herein, we report an effective methodology
for the synthesis of benzylic fluorides via rhodium-catalyzed nu-
cleophilic fluorination of trichloroacetimidates. A wide variety of
naphthyl, phenyl, and pyridinyl substrates were fluorinated with
Et3N$3HF to provide the corresponding fluorine-containing com-
pounds in moderate to high yields under mild and operationally
simple conditions (Scheme 1).
We continued our optimization studies by varying the nature
of the ligands (Table 1, entries 4 and 5) on rhodium catalysts and
found that these rhodium catalysts are not as effective as was
[Rh(COD)2]BF4 (entry 3) to activate trichloroacetimidate 4a. We
hypothesized that this is likely due to the effect of the ligand
bite angle that imparts both steric and electronic influence on
metal catalysts.19 We also examined the fluorination of 4a with
5 mol % of [Rh(COD)2]OTf (entry 6), and only 62% NMR con-
version of naphthylic fluoride 5a was observed in the reaction.
This experiment illustrated the effect of counterions on the re-
activity of the fluorination reaction (entry 3 vs entry 6). Rho-
dium with a more strongly coordinating counterion (ꢀOTf, entry
6) gave the fluorine-containing product with lower conversion
than rhodium with a weaker coordinating counterion (BFꢀ4 ,
entry 3).20
Next, we turned our attention to investigating the effects of
solvent (Table 1, entries 7e10). While dioxane (entry 9) was also an
effective solvent for the synthesis of benzylic fluoride 5a with
slightly lower NMR yield (92%) than Et2O, other solvents were not
suitable. We have previously examined the reaction of allylic tri-
chloroacetimidates and vinyl epoxides with a series of fluoride
reagents (CsF, AgF, TBAT, KF, and pyridine$HF)15,16 and found that
these fluoride sources proved ineffective in comparison to
Et3N$3HF under both iridium- and rhodium-catalyzed conditions.
As a result, we did not attempt to investigate these fluoride ions
with naphthylic substrate 4a.
A control experiment was then conducted in the absence of the
rhodium catalyst (Table 1, entry 11), and the fluorination reaction
was stopped at 1 h in order to compare to the optimized rhodium-
catalyzed conditions (entry 3); only 23% NMR conversion was ob-
served under the identical conditions absent the catalyst (entry 11).
In a separate reaction, the catalyst-free reaction only reached
completion after 24 h. To determine if Lewis acid or Brønsted acid
behavior alone was responsible for the reactivity of the rhodium
species, other control experiments were performed with BF3$OEt2
(entry 12) and camphorsulfonic acid (CSA, entry 13), commonly
used reagents to activate trichloroacetimidates. The desired naph-
thylic fluoride 5a was observed with moderate conversion
(67e74%). While both Lewis and Brønsted acids did not provide
superior results to [Rh(COD)2]BF4, these data offered mechanistic
insight into the reaction (vide infra).
Scheme 1. Rhodium-catalyzed benzylic fluorination reaction.
2. Results and discussion
2.1. Optimization studies
We hypothesized that benzylic trichloroacetimidates would be
suitable electrophiles for fluorination reactions because CeO bonds
are likely to undergo heterolytic cleavage and generate h
3-benzyl-
metal complexes.17 The well-documented literature of metal-
catalyzed nucleophilic substitution reactions of benzylic electro-
philes is consistent with this hypothesis.17 We first tested our hy-
pothesis with naphthylic trichloroacetimidate 4a (Table 1) because
the extended aromaticity of the naphthyl ring is likely to stabilize
an h
3-benzyl-metal intermediate.18 At the outset of our studies, we
investigated the reaction of 4a with Et3N$3HF under both iridium-
and rhodium-catalyzed conditions.15 We observed low conversion
to benzylic fluoride 5a (Table 1, entry 1). The by-product tricho-
loroacetamide was also observed in the reaction by 1H NMR anal-
ysis. Switching to the rhodium dimer catalyst [RhCl(COD)]2 (entry
2) further improved conversion (33%/55%). We hypothesized that
utilization of a more reactive cationic rhodium catalyst could fur-
ther accelerate the rate of fluorination.16 As expected, reaction of
imidate 4a with 5 mol % of [Rh(COD)2]BF4 (entry 3) reached 100%
conversion in 1 h.
2.2. Substrate scope
With the optimized catalytic protocol in hand, we next sought to
examine the scope of the fluorination (Table 2). We designed
a number of naphthyl substituted trichloroacetimidate substrates
4aeg bearing varying electronic properties and degrees of steric
congestion. All naphthlyic fluorides were monitored by 19F NMR
spectroscopy for conversion and subsequently isolated for full
characterization and yield determination. For example, although
quantitative conversion was seen via 19F NMR analysis (entry 1), the
isolated yield of the desired fluoride product 5a was only 84% (entry
1) due to its volatility.24 The fluorination was slightly slower with
bulky substrate 4b (entry 2), yet the isolated yield of benzylic
fluoride 5b (entry 2) was not significantly affected (88%). In addi-
tion, steric bulk at the ortho-position of aryl groups was feasible
under rhodium conditions (entries 3 and 4), and the fluorination
proceeded smoothly to produce benzylic fluorides 5c and 5d in
68e73% yield.
Table 1
Optimization of fluorination of benzylic trichloroacetimidatesa
Entry
Catalyst
Solvent
NMR yieldb (%)
1
2
3
4
5
6
7
8
[IrCI(COD)]2
[RhCI(COD)]2
[Rh(COD)2]BF4
[Rh(NBD)2]BF4
[Rh(COD)(dppb)]BF4
[Rh(COD)2]OTf
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)2]BF4
None
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
MTBE
Dioxane
Toluene
Et2O
33
55
100
68
61
62
61
43
92
50
23
67
74
9
10
11
12
13
To further highlight the synthetic advantage of our method,
we next focused on the synthesis of 1,1-diaryl fluorides 5eeh
(Table 2, entries 5e8), where the arenes have similar steric
properties and are only differentiated by the para-substituents.
Although the fluorination reactions reached completion after
4e8 h, electron-withdrawing groups on the aryl rings of imidates
BF3$OEt2
Et2O
CSA
Et2O
a
All benzylic fluorination reactions were conducted at 0.3 M with 3 equiv of
Et3N$3HF.
b
Determined by 19F NMR analysis using PhCF3 as an internal standard.

5934
Q. Zhang et al. / Tetrahedron 71 (2015) 5932e5938
Table 2
Table 3
Fluorination of naphthylic trichloroacetimidatesa
Reactivity of mono-cyclic benzylic trichloroacetimidatesa
Time (h) NMR yieldb (%) Isolated yieldc (%)
Entry
Imidate
Time (h)
NMR yieldb (%)
Isolated yieldc (%)
Entry Imidate
1
1
4
5a (100)
5b (85)
5a (84)
5b (88)
1
2
6c (R¼H)
4
4
7c (85)
7d (100)
7c (74)
7d (83)
6d (R¼Me)
2
3
4
5
6
6e (X¼H)
6f (X¼F)
2
8
8
4
7e (84)
7f (95)
7g (97)
7h (98)
7e (36)
7f (73)
7g (50)
7h NDd
6g (X¼CI)
6h (X¼OMe)
a
All reactions were conducted at 0.3 M with 3 equiv of Et3N$3HF.
Determined by 19F NMR using PhCF3 as an internal standard.
Isolated yield determined after column chromatography.
ND¼not determined due to its rapid decomposition after isolation.
3
4
4c (R¼H)
1
1
5c (95)
5d (95)
5c (68)
5d (73)
b
c
4d (R¼Me)
d
N-Heterocyclic trichloroacetimidates (Table 4) are another
challenging class of substrates that we envisioned could undergo
fluorination reactions. N-Heterocyclic motifs are often found in
a variety of bioactive molecules and thus represent important tar-
gets.22 Our original fluorination conditions were not suitable for
these N-heterocyclic substrates. We also investigated the fluori-
nation of pyridinyl substrates with BF3$OEt2 and CSA, but only poor
5
6
7
8
4e (X¼H)
4f (X¼F)
4
8
4
4
5e (76)
5f (87)
5g (95)
5h (98)
5e (78)
5f (76)
5g (89)
5h NDd
4g (X¼CI)
4h (X¼OMe)
a
b
c
All reactions were conducted at 0.3 M with 3 equiv of Et3N$3HF.
Determined by 19F NMR using PhCF3 as an internal standard.
Isolated yield determined after column chromatography.
ND¼not determined due to its rapid decomposition after isolation.
d
Table 4
Reactivity of N-heterocyclic trichloroacetimidatesa
were well-tolerated (76e89%, entries 6 and 7). The aryl chloride
moiety of the fluoride product 5g (entry 7) provides functionality
for further chemical modification. In contrast, a strong electron-
donating para-OMe group demonstrated high transformation by
19F NMR analysis yet decomposed upon purification (entry 8).
This was most likely caused by elimination of fluoride due to the
electron-donating properties of the aromatic ring. The leaving
group ability of fluoride has been recently demonstrated by
Gouverneur and co-workers in palladium-catalyzed substitution
and cross-coupling of benzylic fluorides with a wide variety of
nucleophiles.21 Nevertheless, the crude product 5h possessing an
electronic-rich para-OMe group was confirmed by 1H and 19F
NMR analyses.
Entry Imidate
Time (h) NMR yieldb (%) Isolated yieldc (%)
1
2
8c (R¼H)
24
24
9c (83)
9d (74)
9c (78)
9d (69)
After successfully fluorinating a range of naphthyl-substituted
compounds, we tested our method on the less extended aromatic
substrates to determine the generality of the fluorination (Table
8d (R¼Me)
3). Due to attenuation of aromaticity upon
p-benzyl-metal or
cationic formation, mono-cyclic benzylic trichloroacetimidates
6ceh (Table 3) are expected to be challenging substrates. Grati-
fyingly, the desired benzyl fluoride products showed similar yields
to their naphthyl counterparts except for the biphenyl-substituted
fluoride 7e (entry 3); its isolated yield was only 36%. As observed
with the naphthyl fluoride 5h (Table 2, entry 8), the desired phenyl
product 7h (Table 3, entry 6) was not isolated due to
decomposition.
3
4
5
8e (R¼H)
8f (R¼F)
8g (R¼CI)
24
24
24
9e (77)
9f (70)
9g (39)
9e (71)
9f (48)
9g (39)
a
b
c
All reactions were conducted at 0.3 M with 3 equiv of Et3N$3HF.
Determined by 19F NMR using PhCF3 as an internal standard.
Isolated yield determined after column chromatography.

Q. Zhang et al. / Tetrahedron 71 (2015) 5932e5938
5935
conversion was observed in the reaction. Ultimately, it was found
that the pyridinyl imidates 8ceg could be fluorinated under
rhodium-catalyzed conditions, but required longer reaction times
(24 h) and higher temperatures (45 ꢁC). Nevertheless, the desired
fluoride products 9ceg (Table 4) were isolated with comparable
yields to the phenyl and naphthyl counterparts.24 We hypothesize
that coordination of rhodium to the pyridine nitrogen slows down
the rate of fluorination.
To further support the cationic intermediate notion, another
series of control experiments were performed with mono-cyclic
benzylic trichloroacetimidate substrate 6a (Scheme 4). If the fluo-
rination does go through a benzylic cation intermediate, one would
expect to observe similar conversions under both Lewis acid and
rhodium conditions. As illustrated in Scheme 4, both [Rh(COD)2]BF4
and BF3$OEt2 provided benzylic fluoride 7a with almost identical
conversion.
2.3. Preliminary mechanistic study
To evaluate the unique reactivity and efficiency of benzylic tri-
chloroacetimidate, both naphthylic acetate 10 and carbonate 11
(Scheme 2) were subjected to our fluorination conditions. Less than
1% conversion was observed for both substrates after 12 h, sug-
gesting that the trichloroacetimidate group is much more reactive
than both the acetate and carbonate groups.
Scheme 4. Fluorination of mono-cyclic benzylic trichloroacetimidate.
Overall, the above experiments allow us to gain insight into the
possible mechanism of the rhodium-catalyzed fluorination of
benzylic trichloroacetimdiates. It appears that the fluorination of
both naphthyl and phenyl trichloroacetimidate starting materials is
more likely to proceed through a benzylic intermediate as the op-
erative reaction pathway. The differences in naphthyl and phenyl
substrate conversions suggest that the formation of the benzylic
intermediate would completely break the aromaticity of the phenyl
ring but not the naphthyl ring due to the extended conjugation of
the naphthyl system.
Scheme 2. Fluorination of naphthylic acetate and carbonate.
To elucidate the mechanism of the benzylic fluorination re-
actions, enantiopure trichloroacetimidate 4a (99% ee Scheme 3)
was synthesized from commercially available enantiopure alcohol.
When enantioenriched substrate 4a was exposed to our catalytic
conditions, the fluorinated product 5a was isolated with significant
loss of enantiomeric excess (Scheme 3a). This result suggests that
the reaction does not go through a concerted SN2 mechanism, but
may involve a discrete benzylic cation through, which complete
racemization would be observed. However, an alternative reaction
3. Conclusion
In summary, we have developed a new methodology for the ef-
ficient synthesis of benzylic fluorides possessing a wide variety of
mono-cyclic aromatic, naphthlyic, and N-heterocyclic rings in mod-
erate to good yields under mild and operationally simple conditions.
This fluorination methodology relies on the ability of the tri-
chloroacetimidate to act as the efficient leaving group in the presence
of trimethylamine trihydrofluoride and 5 mol % of [Rh(COD)2]BF4
catalyst. The use of the rhodium catalyst allows to distinguish be-
tween the two possible mechanisms (the discrete cationic in-
pathway that proceeds through an
h
3-benzyl-rhodium in-
termediate,17,18,23 could also be likely to take place. To distinguish
between the two reaction pathways, fluorination studies conducted
with BF3$OEt2 (Scheme 3b), and the fluoride product 5a was ob-
served in 69% NMR yield with a complete racemization (7% ee). This
result suggests that the fluorination is likely to involve a discrete
benzylic cation intermediate. Under the catalyst-free conditions,
the reaction of trichloroacetimidate 4a with Et3N$3HF resulted in
39% NMR conversion of 5a with 27% ee (Scheme 3c), indicating that
the fluorinating reagent itself could be acidic enough to promote
the formation of a benzylic cation.
termediate vs the
h
3-benzyl-rhodium complex) of the benzylic
fluorination of trichloroacetimidates. Initial mechanistic studies
suggest that the fluorination is more likely to proceed through
a discrete benzylic cation intermediate, generated by rhodium acting
as a Lewis acid. Overall, this mild, rapid, and operationally simple
fluorination methodology provides the foundation for further in-
vestigations of the utility of benzylic trichloroacetimidate substrates
in radiofluorination.5,14 The use of the rhodium catalyst and/or
Brønsted acid25 to promote the incorporation of radioactive fluorine-
18 into benzylic systems of radiotracers for use in PET imaging
studies will be reported in due course.
4. Experimental
4.1. General information
All reactions were performed in oven-dried Schlenk flasks fitted
with glass stoppers under positive nitrogen/argon pressure. Or-
ganic solutions were concentrated by rotary evaporation below
40 ꢁC at 25 Torr. Analytical thin-layer chromatography (TLC) or 19F
NMR analysis was routinely used to monitor the progress of the
Scheme 3. Fluorination of enantiopure naphthylic trichloroacetimidate.

5936
Q. Zhang et al. / Tetrahedron 71 (2015) 5932e5938
reactions. TLC was performed using pre-coated glass plates with
230e400 mesh silica gel impregnated with a fluorescent indicator
(250 nm). Visualization was accomplished using UV light, potas-
sium permanganate, and/or phosphomolybdic acid. Dry organic
solvents were obtained from an SG Waters solvent system utilizing
activated alumina columns under argon pressure or purchased
from SigmaeAldrich in Sure/SealÔ bottles. The rhodium and irid-
ium catalysts were handled and transferred to Schlenk flasks
within a glovebox under a nitrogen atmosphere. Lewis acid
BF3$OEt2 and all chemicals and reagents were obtained from
commercial vendors and used without further purification. Flash
chromatography was performed on a Teledyne Isco Combi-Flash Rf
system utilizing normal phase pre-column cartridges and gold high
performance columns. The ees were determined on an Agilent
1200 series HPLC using a Diacel Chiralcel OJ-3 4.6ꢂ150 mm column
fitted with guard columns with flow rates and mobile phases as
indicated. All proton (1H) nuclear magnetic resonance spectra were
recorded on a 400 MHz or 500 MHz spectrometer. All carbon (13C)
nuclear magnetic resonance spectra were recorded on a 101 MHz or
126 MHz NMR spectrometer with proton decoupling. All fluorine
residue was loaded directly onto a RediSep load cartridge. Purifi-
cation by silica gel flash column chromatography resulted in 5a
(29 mg, 84%) as a white solid.
4.4. General procedure for fluorination of pyridinyl
substrates
An oven-dried 10 mL Schlenk flask was charged with
[Rh(COD)2]BF4 (4.1 mg, 0.01 mmol, 5 mol %) within glovebox and
then THF (1.0 mL) at room temperature. A solution of tri-
chloroacetimidate (8c) (69 mg, 0.20 mmol, 1 equiv) and
a,a,a-tri-
fluorotoluene (8.2 L, 0.067 mmol, 0.33 equiv) in THF (1.00 mL) was
m
then added. After the mixture had been stirred for 5 min, Et3N$3HF
(0.1 mL, 0.60 mmol, 3.0 equiv) was added dropwise. The resulting
mixture was then heated to 45 ꢁC and stirred for 24 h. Upon
completion, the reaction mixture was concentrated in vacuo and
loaded directly onto a RediSep load cartridge. Purification by silica
gel flash column resulted in 9c (31 mg, 78%) as a light yellow solid.
4.5. Structural data
(
19F) nuclear magnetic resonance spectra were recorded on
a 282 MHz, 376 MHz or 471 MHz spectrometer with proton
decoupling. All deuterated solvents were used as received from
Cambridge Isotope Laboratories. 1H NMR, 13C NMR, and 19F NMR
4.5.1. 2-(1-Fluoroethyl)naphthalene (5a). Yield 84%, 29.20 mg. 1H
NMR (500 MHz, CDCl3):
7.55e7.48 (m, 3H), 5.82 (dq, J¼47.6, 6.4 Hz, 1H), 1.76 (dd, J¼23.9,
6.5 Hz, 3H); 13C NMR (126 MHz, CDCl3):
d¼7.94e7.84 (m, 3H), 7.83 (s, 1H),
chemical shifts are expressed in parts per million (
d
scale) relative
d
¼139.0 (d, J¼19.5 Hz),
to the chemical shift of residual solvent. Reference peaks for CDCl3
in 1H NMR and 13C NMR spectra were set at 7.26 ppm and
77.16 ppm, respectively. The 19F NMR reference peak was set at
133.3, 133.2, 128.5, 128.2, 127.9, 126.4 (d, J¼15.0 Hz), 124.3, 124.3,
123.3 (d, J¼5.8 Hz), 91.2 (d, J¼167.8 Hz), 23.1 (d, J¼25.2 Hz); 19F
NMR (471 MHz, CDCl3):
d
¼ꢀ167.0; HRMS (TOF EIþ): calculated for
ꢀ63 ppm for
a
,
a
,
a
-trifluorotoluene in CDCl3 as an internal standard.
C
12H11F (M)þ: 174.0845; found: 174.0858.
Data are presented as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, and br
s¼broad singlet), integration, and coupling constant in hertz (Hz).
High-resolution TOF mass spectrometry utilizing electrospray
ionization in positive mode was performed to confirm the identity
of the compounds.
4.5.2. 2-(1-Fluoro-2-methylpropyl)naphthalene (5b). Yield 88%,
35.80 mg. 1H NMR (500 MHz, CDCl3):
d
¼7.91e7.83 (m, 3H), 7.77 (s,
1H), 7.56e7.48 (m, 2H), 7.45 (dd, J¼8.6, 1.7 Hz, 1H), 5.29 (dd, J¼47.0,
6.8 Hz, 1H), 2.36e2.04 (m, 1H), 1.09 (dd, J¼6.6, 1.0 Hz, 3H), 0.91 (d,
J¼6.9 Hz, 3H); 13C NMR (126 MHz, CDCl3):
¼137.0 (d, J¼20.3 Hz),
d
133.3, 133.1, 128.2, 128.2, 127.8, 126.4, 126.2, 125.6 (d, J¼8.4 Hz),
123.9 (d, J¼6.2 Hz), 99.6 (d, J¼174.0 Hz), 34.5 (d, J¼22.8 Hz), 18.2
4.2. General procedure of trichloroacetimidate formation
(dd, J¼103.4, 5.4 Hz); 19F NMR (471 MHz, CDCl3):
¼ꢀ179.7. HRMS
d
Trichloroacetonitrile (1.1 mL,10.8 mmol, 3.0 equiv) was added to
(TOF EIþ): calculated for C14H15F (M)þ: 202.1158; found: 202.1168.
a solution of a-methyl-2-naphthalenemethanol (0.62 g, 3.6 mmol,
1.0 equiv) in CH2Cl2 (7.2 mL) at 0 ꢁC in an oven-dried Schlenk flask.
After the solution had been stirring for 5 min, DBU (0.27 mL,
0.25 mmol, 0.5 equiv) was then added dropwise. The resulting
mixture was allowed to warm slowly to room temperature over-
night. Upon completion, the reaction mixture was concentrated in
vacuo and loaded directly onto a RediSep load cartridge containing
pre-equilibrated and dried silica. Purification by silica gel flash
column chromatography (pre-equilibrated 10 g RediSep column,
10% ethyl acetate/hexaneþ3% triethylamine) resulted in 4a (0.93 g,
82%) as a white solid.
4.5.3. 2-(Fluoro(o-tolyl)methyl)naphthalene
31.40 mg. 1H NMR (400 MHz, CDCl3):
(5c). Yield
¼7.86e7.77 (m, 4H), 7.76 (s,
68%,
d
1H), 7.52e7.45 (m, 2H), 7.45e7.37 (m, 2H), 7.31e7.21 (m, 2H),
7.21e7.15 (m, 1H), 6.78 (d, J¼47.1 Hz, 1H), 2.27 (s, 3H); 13C NMR
(101 MHz, CDCl3):
d
¼137.6 (d, J¼20.2 Hz), 136.5 (d, J¼21.7 Hz), 135.9
(d, J¼4.4 Hz), 133.4 (d, J¼1.6 Hz), 133.2, 130.8, 128.7 (d, J¼2.1 Hz),
128.5, 128.4, 127.8, 127.05 (d, J¼8.6 Hz), 126.53 (d, J¼11.5 Hz), 126.41
(d, J¼7.3 Hz), 126.2, 124.9, 124.8, 92.7 (d, J¼171.6 Hz), 19.5; 19F NMR
(376 MHz, CDCl3):
d
¼ꢀ166.8. HRMS (TOF EIþ): calculated for
C
18H15F (M)þ: 250.1158; found: 250.1167.
4.3. General procedure for fluorination of both naphthyl and
phenyl substrates
4.5.4. 2-((2,6-Dimethylphenyl)fluoromethyl)naphthalene (5d). Yield
73%, 37.20 mg. 1H NMR (400 MHz, CDCl3):
d
¼7.85 (d, J¼8.5 Hz, 2H),
7.83e7.75 (m, 1H), 7.63 (s, 1H), 7.50 (dd, J¼6.4, 2.9 Hz, 2H), 7.43 (d,
J¼8.6 Hz, 1H), 7.29e7.20 (m, 1H), 7.13 (d, J¼47.8 Hz, 1H), 7.12 (d,
J¼7.6 Hz, 2H), 2.32 (s, 6H).
An oven-dried 10 mL Schlenk flask was charged with
[Rh(COD)2]BF4 (4.1 mg, 0.01 mmol, 5 mol %) within glovebox and
then Et2O (0.40 mL) at room temperature. A solution of tri-
13C NMR (101 MHz, CDCl3):
d
¼137.6 (d, J¼3.6 Hz), 137.0 (d,
chloroacetimidate (4a) (63 mg, 0.20 mmol, 1 equiv) and
a,
a,
a-tri-
J¼22.0 Hz), 135.0 (d, J¼16.6 Hz), 133.2, 133.0, 129.3, 128.8 (d,
J¼1.9 Hz), 128.4 (d, J¼7.6 Hz), 127.8, 126.4 (d, J¼6.8 Hz), 124.6 (d,
J¼6.4 Hz), 123.9 (d, J¼5.5 Hz), 91.4 (d, J¼170.8 Hz), 20.6 (d,
fluorotoluene (8.2 L, 0.067 mmol, 0.33 equiv) in Et2O (0.35 mL)
m
was then added under N2. After the resulting mixture had been
stirred for 5 min, Et3N$3HF (0.1 mL, 0.60 mmol, 3 equiv) was added
dropwise. The reaction mixture was monitored by 19F NMR analysis
at 30-min intervals. Upon completion, the biphasic reaction mix-
ture was diluted with Et2O (1 mL). The two layers were separated,
and the aqueous layer was back extracted with Et2O (3ꢂ1 mL). The
combined organic extracts were concentrated in vacuo, and the
J¼2.6 Hz). 19F NMR (376 MHz, CDCl3):
d
¼ꢀ175.5. HRMS (TOF EIþ):
calculated for C19H17F (M)þ: 264.1314; found: 264.1310.
4.5.5. 2-(Fluoro(phenyl)methyl)naphthalene
(5e). Yield
¼7.92e7.82 (m, 4H),
78%,
35.40 mg. 1H NMR (500 MHz, CDCl3):
d
7.57e7.50 (m, 2H), 7.49e7.34 (m, 6H), 6.67 (d, J¼47.4 Hz, 1H); 13C

Q. Zhang et al. / Tetrahedron 71 (2015) 5932e5938
5937
NMR (126 MHz, CDCl3):
d
¼139.9 (d, J¼21.7 Hz), 137.3 (d, J¼21.6 Hz),
J¼47.4 Hz, 1H); 13C NMR (101 MHz, CDCl3):
d
¼139.5 (d, J¼21.8 Hz),
133.4, 133.1, 128.7, 128.6 (d, J¼2.2 Hz), 128.6, 128.4, 127.9, 126.9 (d,
138.5 (d, J¼22.4 Hz), 134.5 (d, J¼2.3 Hz), 128.8, 128.8 (d, J¼2.3 Hz),
128.7, 128.1 (d, J¼6.3 Hz), 126.7 (d, J¼6.2 Hz), 93.9 (d, J¼173.7 Hz);
J¼6.2 Hz), 126.6, 126.5, 125.81 (d, J¼7.7 Hz), 124.3 (d, J¼5.2 Hz), 94.8
(d, J¼173.1 Hz); 19F NMR (376 MHz, CDCl3):
d¼ꢀ167.0. HRMS (TOF
19F NMR (376 MHz, CDCl3):
d
¼ꢀ166.7. HRMS (TOF EIþ): calculated
EIþ): calculated for C17H13F (M)þ: 236.1001; found: 236.0990.
C
13H10ClF (M)þ: 220.0455; found: 220.0465.
4.5.6. 2-(Fluoro(4-fluorophenyl)methyl)naphthalene (5f). Yield 76%,
4.5.14. 1-(Fluoro(phenyl)methyl)-4-methoxybenzene
(7h). Yield:
40.40 mg. 1H NMR (500 MHz, CDCl3):
d
¼7.87 (d, J¼8.8 Hz, 4H),
not isolated due to instability; crude 1H NMR and 19F NMR data are
7.59e7.50 (m, 2H), 7.47e7.34 (m, 3H), 7.13e7.03 (m, 2H), 6.64 (d,
provided in spectrum file. 1H NMR (500 MHz, CDCl3):
d
¼6.33 (d,
J¼47.3 Hz, 1H); 13C NMR (126 MHz, CDCl3):
d¼162.8 (d, J¼247.4 Hz),
J¼47.8 Hz, 1H, HCeF); 19F NMR (471 MHz, CDCl3):
d
¼ꢀ163.6.
136.9 (d, J¼21.7 Hz), 135.7 (dd, J¼22.2, 3.1 Hz), 133.3 (d, J¼1.4 Hz),
133.0, 129.2 (d, J¼8.2 Hz), 128.8 (dd, J¼8.3, 6.0 Hz), 128.5, 128.2,
127.8, 126.5 (d, J¼4.6 Hz), 125.6 (d, J¼7.7 Hz), 124.0 (d, J¼5.2 Hz),
115.5 (d, J¼21.7 Hz), 94.0 (d, J¼173.4 Hz); 19F NMR (471 MHz,
4.5.15. 2-(Fluoro(o-tolyl)methyl)pyridine (9c). Yield 78%, 39.30 mg.
1H NMR (400 MHz, CDCl3):
d
¼8.62e8.55 (m, 2H), 7.60 (dd, J¼8.0,
1.8 Hz, 1H), 7.37 (dd, J¼6.7, 2.4 Hz, 1H), 7.33e7.23 (m, 3H), 7.20 (dd,
CDCl3):
d
¼ꢀ113.2, ꢀ164.9. HRMS (TOF EIþ): calculated C17H12F2
J¼6.3, 2.2 Hz, 1H), 6.67 (d, J¼46.9 Hz, 1H), 2.24 (s, 3H); 13C NMR
(M)þ: 254.0907; found: 254.0914.
(101 MHz, CDCl3):
d
¼149.8, 148.7, 136.4 (d, J¼19.9 Hz), 135.5 (d,
J¼4.4 Hz), 134.8 (d, J¼22.4 Hz), 134.8 (d, J¼5.2 Hz), 131.0, 129.0,
4.5.7. 2-((4-Chlorophenyl)fluoromethyl)naphthalene
(5g). Yield
126.7 (d, J¼8.8 Hz), 126.4, 123.6, 90.7 (d, J¼172.4 Hz), 19.3; 19F NMR
89%, 49.90 mg. 1H NMR (500 MHz, CDCl3):
d
¼7.91e7.79 (m, 4H),
(471 MHz, CDCl3):
d
¼ꢀ169.6. HRMS (TOF EIþ): calculated for
7.57e7.48 (m, 2H), 7.43e7.30 (m, 5H), 6.62 (d, J¼47.3 Hz, 1H); 13C
C
13H12FN (M)þ: 201.0954; found: 201.0960.
NMR (126 MHz, CDCl3):
d
¼138.3 (d, J¼22.2 Hz), 136.6, 134.5 (d,
J¼2.6 Hz), 133.3 (d, J¼1.6 Hz), 133.0, 128.8, 128.6, 128.2, 128.1 (d,
J¼6.2 Hz), 127.8, 126.7, 126.6, 125.8 (d, J¼7.6 Hz), 124.1 (d, J¼5.0 Hz),
4.5.16. 2-((2,6-Dimethylphenyl)fluoromethyl)pyridine
(9d). Yield
69%, 29.70 mg. 1H NMR (400 MHz, CDCl3):
d
¼8.60e8.44 (m, 2H),
94.0 (d, J¼173.9 Hz); 19F NMR (471 MHz, CDCl3):
d
¼ꢀ166.5. HRMS
7.57e7.50 (m, 1H), 7.34e7.23 (m, 1H), 7.23e7.14 (m, 1H), 7.06 (t,
(TOF EIþ): calculated for C17H12ClF (M)þ: 270.0612; found:
270.0600.
J¼7.8 Hz, 2H), 6.98 (d, J¼47.6 Hz, 1H), 2.38 (s, 3H), 2.25 (s, 3H); 13
C
NMR (101 MHz, CDCl3):
d
¼149.0 (d, J¼48.4 Hz), 147.5, 138.2, 137.2
(d, J¼5.0 Hz), 133.5 (d, J¼2.6 Hz), 129.4, 129.3, 129.1 (d, J¼18.7 Hz),
4.5.8. 2-(Fluoro(4-methoxyphenyl)methyl)naphthalene (5h). Yield:
123.3, 89.5 (d, J¼165.1 Hz), 20.5 (d, J¼2.3 Hz); 19F NMR (471 MHz,
not isolated due to instability; crude 1H NMR and 19F NMR data are
CDCl3):
215.1110; found: 215.1126.
d
¼ꢀ178.2. HRMS (TOF EIþ): calculated for C14H14FN (M)þ:
provided in the spectrum file. 1H NMR (500 MHz, CDCl3):
d¼6.45 (d,
J¼47.6 Hz, 1H, HCeF); 19F NMR (471 MHz, CDCl3):
d¼ꢀ163.6.
4.5.17. 2-(Fluoro(phenyl)methyl)pyridine (9e). Yield 71%, 26.50 mg.
4.5.9. 1-(Fluoro(phenyl)methyl)-2-methylbenzene (7c). Yield 74%,
1H NMR (500 MHz, CDCl3):
d
¼8.65e8.54 (m, 2H), 7.68e7.61 (m,
28.70 mg. 1H NMR (400 MHz, CDCl3):
d
¼7.47e7.23 (m, 8H),
1H), 7.47e7.28 (m, 6H), 6.51 (d, J¼47.0 Hz, 1H); 13C NMR (126 MHz,
7.21e7.14 (m, 1H), 6.63 (d, J¼47.2 Hz, 1H), 2.25 (s, 3H); 13C NMR
CDCl3):
d
¼149.8, 148.2 (d, J¼6.8 Hz), 138.7 (d, J¼21.4 Hz), 135.6 (d,
(101 MHz, CDCl3):
d
¼139.1 (d, J¼21.5 Hz), 137.7 (d, J¼20.4 Hz), 135.7
J¼22.4 Hz), 134.4 (d, J¼5.9 Hz), 129.0, 128.9, 126.6 (d, J¼6.2 Hz),
(d, J¼4.6 Hz), 130.8, 128.6, 128.6, 127.3, 127.2, 126.8 (d, J¼9.0 Hz),
123.6, 92.6 (d, J¼173.8 Hz); 19F NMR (471 MHz, CDCl3):
¼ꢀ169.2.
d
126.2, 92.6 (d, J¼171.4 Hz), 19.4; 19F NMR (376 MHz, CDCl3):
HRMS (TOF EIþ): calculated for C12H10FN (M)þ: 187.0797; found:
187.0812.
d
¼ꢀ166.9. HRMS (TOF EIþ): calculated for C14H13F (M)þ: 200.1001;
found: 200.1007.
4.5.18. 2-(Fluoro(4-fluorophenyl)methyl)pyridine (9f). Yield 48%,
4.5.10. 2-(Fluoro(phenyl)methyl)-1,3-dimethylbenzene (7d). Yield
22.30 mg. 1H NMR (500 MHz, CDCl3):
d
¼8.64e8.52 (m, 2H),
83%, 38.30 mg. 1H NMR (400 MHz, CDCl3):
d
¼7.36e7.25 (m, 3H),
7.65e7.62 (m, 1H), 7.41e7.28 (m, 3H), 7.15e7.00 (m, 2H), 6.49 (d,
7.24e7.13 (m, 3H), 7.05 (d, J¼7.6 Hz, 2H), 6.95 (d, J¼48.0 Hz, 1H),
J¼47.0 Hz,1H); 13C NMR (126 MHz, CDCl3):
¼163.0 (d, J¼239.2 Hz),
d
2.25 (d, J¼2.5 Hz, 6H); 13C NMR (101 MHz, CDCl3):
d¼139.6 (d,
149.9, 148.0 (d, J¼6.7 Hz), 135.4 (d, J¼22.5 Hz), 134.6 (dd, J¼21.8,
3.2 Hz), 134.3 (d, J¼5.9 Hz), 128.7 (dd, J¼8.4, 6.0 Hz), 123.6, 115.9 (d,
J¼21.8 Hz), 92.0 (d, J¼174.1 Hz); 19F NMR (471 MHz, CDCl3):
J¼22.1 Hz), 137.4 (d, J¼3.6 Hz), 135.1 (d, J¼16.7 Hz), 129.4e129.0
(m), 128.73 (d, J¼1.9 Hz), 128.5, 127.9 (d, J¼1.6 Hz), 125.7 (d,
J¼6.0 Hz), 91.2 (d, J¼170.4 Hz), 20.6 (d, J¼2.4 Hz); 19F NMR
d
¼ꢀ112.4, ꢀ167.5. HRMS (TOF EIþ): calculated for C12H9NF2 (M)þ:
(376 MHz, CDCl3):
d
¼ꢀ176.1. HRMS (TOF EIþ): calculated for
205.0703; found: 205.0718.
C
15H15F (M)þ: 214.1158; found: 214.1163.
4.5.19. 2-((4-Chlorophenyl)fluoromethyl)pyridine (9g). Yield 39%,
4.5.11. (Fluoromethylene)dibenzene (7e). Yield 36%, 13.60 mg. 1H
NMR (300 MHz, CDCl3):
¼7.47e7.27 (m, 10H), 6.49 (d, J¼47.3 Hz,
1H); 19F NMR (282 MHz, CDCl3):
¼ꢀ166.9.
19.10 mg. 1H NMR (400 MHz, CDCl3):
d
¼8.65e8.49 (m, 2H),
d
7.65e7.49 (m, 1H), 7.42e7.02 (m, 7H), 6.44 (d, J¼46.9 Hz, 1H); 13C
d
NMR (101 MHz, CDCl3):
d
¼150.2 (d, J¼2.1 Hz), 148.3 (d, J¼6.6 Hz),
137.3 (d, J¼22.0 Hz), 135.0 (d, J¼2.7 Hz), 134.3 (d, J¼5.6 Hz), 129.1,
4.5.12. 1-Fluoro-4-(fluoro(phenyl)methyl)benzene (7f). Yield 73%,
128.5, 128.0 (d, J¼6.1 Hz), 123.6, 92.0 (d, J¼174.6 Hz); 19F NMR
30.20 mg. 1H NMR (400 MHz, CDCl3):
d
¼7.54e7.29 (m, 7H),
(471 MHz, CDCl3):
d
¼ꢀ169.3. HRMS (TOF EIþ): calculated for
7.15e6.95 (m, 2H), 6.47 (d, J¼47.4 Hz, 1H); 13C NMR (101 MHz,
C
12H9ClFN (M)þ: 221.0408; found: 221.0405.
CDCl3):
d
¼162.9 (d, J¼247.3 Hz), 139.7 (d, J¼21.8 Hz), 135.9 (dd,
J¼22.2, 3.4 Hz), 129.5e128.1 (m), 126.6 (d, J¼6.2 Hz), 115.6 (d,
J¼21.6 Hz), 94.0 (d, J¼173.0 Hz); 19F NMR (376 MHz, CDCl3):
Acknowledgements
d
¼ꢀ113.5, ꢀ165.0. HRMS (TOF EIþ): calculated for C13H10F2 (MꢀF)þ:
185.0761; found: 185.0777.
We would like to thank the University of Iowa for financial
support. Q.Z. and G.J.R. thank the Graduate College for the Summer
Research Fellowship. J.C.M. thanks the University of Iowa for the
ICRU fellowship.
4.5.13. 1-Chloro-4-(fluoro(phenyl)methyl)benzene (7g). Yield 50%,
20.30 mg. 1H NMR (400 MHz, CDCl3):
d¼7.43e7.25 (m, 9H), 6.45 (d,

5938
Q. Zhang et al. / Tetrahedron 71 (2015) 5932e5938
2580e2585; (b) Bethell, D.; McDonald, K.; Rao, K. S. Tetrahedron Lett. 1977, 17,
Supplementary data
1447e1448; (c) Laurent, E.; Marquet, B.; Tardivel, R. J. Fluorine Chem. 1990, 49,
115e126; (d) Kuroboshi, M.; Hiyama, T. Chem. Lett. 1990, 9, 1607e1610; (e)
Laurent, E.; Marquet, B.; Tardivel, R. Tetrahedron 1991, 47, 3969e3980; (f)
Guijarro, D.; Yus, M. J. Organomet. Chem. 2001, 624, 53e57; (g) Gree, D.; Gree, R.
Tetrahedron Lett. 2007, 48, 5435e5438; (h) Pujari, S. A.; Kaliappan, K. P.; Valleix,
A.; Gree, D.; Gree, R. Synlett 2008, 2503e2507; (i) Bresciani, S.; O’Hagan, D.
Tetrahedron Lett. 2010, 51, 5795e5797; (j) Garcia, R.; Jose, L.; Fernandez-Salas, J.
A.; Maestro, M. C. J. Org. Chem. 2012, 77, 2893e2900; (k) Champagne, P. A.;
Drouin, M.; Legault, C. Y.; Audubert, C.; Paquin, J.-F. J. Fluorine Chem. 2015, 171,
113e119; (l) Ma, J.-J.; Yi, W.-B.; Lu, G.-P.; Cai, C. Org. Biomol. Chem. 2015, 13,
2890e2894.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.04.066.
References and notes
1. (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881e1886; (b) Gou-
verneur, V. Science 2009, 325, 1630e1631; (c) Qui, X.-L.; Xu, X.-H.; Qing, F.-L.
Tetrahedron 2010, 66, 789e843; (d) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470e477; (e) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012,
2929e2942.
2. (a) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008, 108, 1943e1981;
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320e330; (c) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108,
1501e1516; (d) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem., Int. Ed.
2008, 47, 8998e9033; (e) Pimlott, S. L.; Sutherland, A. Chem. Soc. Rev. 2011, 40,
149e162.
13. Liang, S. H.; Vasdev, N. Angew. Chem., Int. Ed. 2014, 53, 11416e11418.
14. Carroll, L.; Evans, H. L.; Spivey, A. C.; Aboagye, E. O. Chem. Commun. 2015, http://
dx.doi.org/10.1039/c4cc05762g
15. Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. J. Am. Chem. Soc. 2011, 133,
19318e19321.
16. Zhang, Q.; Nguyen, H. M. Chem. Sci. 2014, 5, 291e296.
17. Trost, B. M.; Czabaniuk, L. C. Angew. Chem., Int. Ed. 2014, 53, 2826e2851.
18. For representative examples of an h
3-benzyl-metal complex, see: (a) Taylor, B.
3. Paulsen, H.; Antons, S.; Brandes, A.; Logers, M.; Muller, S. N.; Naab, P.; Schmeck,
C.; Schneider, S.; Stoltefuss, J. Angew. Chem., Int. Ed. 1999, 38, 3373e3375.
4. Bio, M. M.; Waters, M.; Javadi, G.; Song, Z. J.; Zhang, F.; Thomas, D. Synthesis
2008, 891e896.
5. (a) Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.; Groves, J. T. J. Am.
Chem. Soc. 2014, 136, 6842e6845; (b) Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.;
Sanford, M. S.; Scott, P. J. H. Chem. Sci. 2014, 5, 4545e4553.
6. (a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128,
7134e7135; (b) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett. 2012,
14, 4094e4097; (c) Emer, E.; Pfeifer, L.; Brown, J. M.; Gouverneur, V. Angew.
Chem., Int. Ed. 2014, 53, 4181e4185; (d) Yuan, Z.; Wang, H.-Y.; Mu, X.; Chen, P.;
Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2015, 137, 2468e2471.
L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389e391;
(b) Greene, M. A.; Yonova, I. M.; Williams, F. J.; Jarvo, E. R. Org. Lett. 2012, 14,
4293e4294; (c) Taylor, B. L. H.; Harris, M. R.; Jarvo, E. R. J. Am. Chem. Soc. 2012,
51, 7790e7793; (d) Yonova, I. M.; Johnson, A. G.; Osborne, C. A.; Moore, C. E.;
Morrissette, N. S.; Jarvo, E. R. Angew. Chem., Int. Ed. 2014, 53, 2422e2427; (e)
Tollefson, E. J.; Dawson, D. D.; Osborne, C. A.; Jarvo, E. R. J. Am. Chem. Soc. 2014,
136, 14951e14958; (f) Harris, M. R.; Konev, M. O.; Jarvo, E. R. J. Am. Chem. Soc.
2014, 136, 7825e7828; (g) Zhu, Y.; Rawal, V. R. J. Am. Chem. Soc. 2012, 134,
111e114.
19. Freixa, Z.; van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton Trans. 2003, 1890e1891.
20. Macchioni, A. Chem. Rev. 2005, 105, 2039e2074.
21. Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.; Gouverneur, V. Org. Lett. 2012,
7. (a) Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2008, 130, 10060e10061; (b) Wang, T.;
14, 2754e2757.
Love, J. A. Organometallics 2008, 27, 3290e3296; (c) Zhao, S.-B.; Becker, J. J.;
Gagne, M. R. Organometallics 2011, 30, 3926e3929; (d) Yahav-Levi, A.; Goldberg,
22. Mukherjee, P.; Cinelli, M. A.; Kang, S.; Silverman, R. B. Chem. Soc. Rev. 2014, 43,
6814e6838.
ꢀ
23. Recent studies demonstrate that the
rationally stable, see: Bleuel, E.; Schwab, P.; Laubender, M.; Werner, H. J. Chem.
Soc., Dalton Trans. 2000, 266e273 Thus, if the
3-benzyl-rhodium complex is
h
3-benzyl-rhodium complex is configu-
I.; Vigalok, A. J. Fluorine Chem. 2010, 131, 1100e1102; (e) Zhao, S.-B.; Wang, R.-Y.;
ꢀ
Nguyen, H.; Becker, J. J.; Gagne, M. R. Chem. Commun. 2012, 443e448; (f) Co-
ꢀ
chrane, N. A.; Nguyen, H.; Gagne, M. R. J. Am. Chem. Soc. 2013, 135, 628e631.
h
8. (a) Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.; Lectka, T. Org.
Lett. 2013, 15, 1722e1724; (b) Bloom, S.; Sharber, S. A.; Holl, M. G.; Knippel, J. L.;
Lectka, T. J. Org. Chem. 2013, 78, 11082e11086.
9. Liu, W.; Groves, J. T. Angew. Chem., Int. Ed. 2013, 52, 6024e6027.
10. (a) Islas-Gonzalez, G.; Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Riera, A.;
Pericas, M. A. Tetrahedron Lett. 2004, 45, 6337e6341; (b) Cresswell, A. J.; Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Tyte, M. J. Org. Lett.
2010, 12, 2936e2939.
11. (a) Xia, J. B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494e17500; (b)
Bloom, S.; McCann, M.; Lectka, T. Org. Lett. 2014, 16, 6338e6341; (c) Cantillo, D.;
de Frutos, O.; Rincon, J. A.; Mateos, C.; Kappe, C. O. J. Org. Chem. 2014, 79,
8486e8490.
the operative reaction pathway, it is anticipated that fluorination of enantio-
pure substrate 4a would proceed with the conservation of stereochemistry in
the product 5a. However, fluorination of enantiopure 4a proceeded with al-
most complete racemization under rhodium conditions, suggesting that the
reaction is more likely to proceed via the discreet benzylic cation intermediate.
24. A significant lower yield (<50%) of 5a was isolated under both BF3$OEt2 and
CSA conditions. We also investigated these Lewis and Brønsted acids conditions
with other naphthylic substrates, and the fluorination proceeded with much
lower conversions in compared to the rhodium catalyst.
25. Preliminary studies showed that Brønsted acid, such as CSA (Table 1, entry 13),
is capable of promoting the fluorination of naphthylic trichloroacetimidate 4a
in good NMR conversion, but moderate isolated yield.
12. For representative examples of other approaches for the synthesis of benzylic
fluorides, see: (a) Zieger, H. E.; Angres, I.; Mathisen, D. J. Am. Chem. Soc. 1976, 98,