Copper-mediated radical trifluoromethylation of unsaturated potassium organotrifluoroborates

Article abstract of DOI:10.1021/jo4023233

Copper-mediated trifluoromethylation of unsaturated organotrifluoroborates with the Langlois reagent (NaSO₂CF₃) and TBHP allows the introduction of trifluoromethyl groups into a variety of organic substructures. The reactions are easy to set up, the conditions are mild and general, and the process provides access to trifluoromethylated alkynes, alkenes, arenes, and heteroarenes in fair to good yields.

Full text of DOI:10.1021/jo4023233

Note
pubs.acs.org/joc
Copper-Mediated Radical Trifluoromethylation of Unsaturated
Potassium Organotrifluoroborates
Marc Presset,†,‡ Daniel Oehlrich,† Frederik Rombouts,*,† and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
‡Neuroscience Medicinal Chemistry, Research & Development, Janssen Pharmaceutical Companies, Turnhoutseweg 30, 2340 Beerse,
Belgium
S
* Supporting Information
ABSTRACT: Copper-mediated trifluoromethylation of unsaturated organotri-
fluoroborates with the Langlois reagent (NaSO2CF3) and TBHP allows the
introduction of trifluoromethyl groups into a variety of organic substructures. The
reactions are easy to set up, the conditions are mild and general, and the process
provides access to trifluoromethylated alkynes, alkenes, arenes, and heteroarenes in
fair to good yields.
he unique properties of the trifluoromethyl group have
electrophilic Togni reagent [3,3-dimethyl-1-(trifluoromethyl)-
1
Tbeen appreciated in diverse fields of chemistry. The CF 1,2-benziodoxole] was found to be more general because it
3
could be used for arylboronates,19 aryltrifluoroborates,20 or
group is notably popular with medicinal chemists as a compact,
lipophilic group that slows the metabolic breakdown of
alkenyltrifluoroborates.21
aromatics.2 This has led to the development of many new
Sanford recently made a very interesting contribution to the
field.22 Her group reported the conversion of aryl- and
heteroarylboronic acids by trifluoromethyl radicals generated
in situ from the inexpensive Langlois reagent (NaSO2CF3) and
tert-butyl hydroperoxide (THBP).23 This reagent was already
used for the C−H trifluoromethylation of heterocycles,24 and
similar copper-mediated conditions were subsequently reported
by Beller with an extension to alkenylboronic acids.25
Importantly, Sanford’s protocol is very practical because the
reaction proceeds under ambient conditions and isolation of
the products is straightforward. Owing to their added value
compared to their boronic acid and -ester counterparts,26−28 an
extension of this method to organotrifluoroborates was
envisioned because only two examples had been reported in
a study published during the course of our investigation.25
Herein, efforts toward the development of such a general
trifluoromethylation method are revealed.
Potassium organotrifluoroborates can be efficiently used in
radical reactions,29 even under aqueous conditions.30 There-
fore, in a quest for a general protocol, investigations were
initiated under the previously reported conditions for boronic
acids: NaSO2CF3 (3.0 equiv), TBHP (5.0 equiv), and CuCl
(1.0 equiv) in CH2Cl2/MeOH/H2O (1:1:0.8) at rt for
electron-rich substrates and NaSO2CF3 (3.0 equiv), TBHP
(4.0 equiv), (CH3CN)CuPF6 (1.0 equiv), and NaHCO3 (1.0
equiv) in MeOH at rt for electron-poor substrates. Although an
excess of the Langlois reagent was required, the overall process
remains one of the more cost-effective owing to the lower cost
of this reagent compared to other trifluoromethylation reagents.
reagents and methods for its introduction.3,4 Among the
substrates used for these trifluoromethylations, organoboron
compounds have emerged as precursors of choice because of
their increasing and pivotal role in synthetic organic chemistry.5
Indeed, the past years have witnessed the emergence of new
methods involving different classes of borylated starting
materials reacting with nucleophilic, electrophilic, and radical
CF3 species, all of which can be mediated or catalyzed by
copper sources (Scheme 1).
Boronic acids were the first class of compounds studied, and
in a pioneering study, Qing described the oxidative
trifluoromethylation of aryl-, heteroaryl-, and alkenylboronic
acids by the nucleophilic Ruppert−Prakash reagent
(TMSCF3)6 in a process similar to Chan−Lam−Evans
coupling.7−9 Shortly thereafter, Buchwald developed a related,
but more practical, catalytic version of this reaction,10 also
achieved by Qing 1 year later.11 Importantly, Grushin
developed a protocol using simple fluoroform12 together with
alkylboronic acids that could be used in a strategy similar to
that reported by Fu.13
The complementary use of electrophilic trifluoromethylation
reagents has also been intensively studied in the case of boronic
acids. Whereas Liu14 and Xiao15 described the use of
trifluoromethylsulfonium salts, Shen expanded this reactivity
to Togni’s reagent.16 Because protodeborylation of the boronic
acid starting material was observed as the main side reaction in
all of these examples, the trifluoromethylation of protected
boron species was also investigated. Hartwig and Gooßen
reported the oxidative nucleophilic trifluoromethylation of aryl
pinacol boronates, but these required the use of either
[(phen)CuCF3] or K[CF3B(OMe)3].17,18 The use of the
Received: October 17, 2013
© XXXX American Chemical Society
A
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Note
Scheme 1. Trifluoromethylations of Organoboron Compounds
The results obtained with aryl- and heteroaryltrifluoroborates
are summarized in Table 1. In all of these examples and similar
to the case of boronic acids, isolation of the desired products is
very easy, as these materials can be obtained with good purity
by a simple aqueous workup. As expected, electron-rich
substrates such as 1a and 1c were efficiently trifluoromethy-
lated, but a decreased yield was observed in the case of ortho-
substituted products such as 2c, which may be attributed to
steric hindrance. Additionally, the reaction performed with 1b
led to a poor yield (21%). The case of unactivated substrates
was less straightforward. The simple trifluoromethylbenzene 2d
was generated from the corresponding trifluoroborate in 28%
yield under the same conditions, and electron-poor arenes such
as 1e and 1f required the use of modified conditions B. Under
these conditions, 2e and 2f were obtained in yields of 61 and
27%, respectively. We next turned our attention to the case of
heteroaryl substrates. Five- and six-membered heteroaryltri-
fluoroborates afforded the corresponding trifluoromethylated
products in 6−67% yields, and the observed trend was the same
as that seen for simple arenes. A broad variety of electron-rich
substrates such as indole 1g, pyrazole 1h, thiazole 1i, and
benzofuran 1j afforded the desired products in good yields
under generic conditions A. However, the case of electron-poor
quinoline was once again problematic, and 2k was obtained in a
poor 6% yield. Even though the yields obtained with electron-
poor potassium organotrifluoroborates are, in general, lower
than the ones observed with the corresponding boronic acids,22
the increased stability of the trifluoroborate salts as compared
to boronic acids makes the use of the former reagents very
attractive.
To investigate the scope of the reaction further, we also
evaluated the case of alkynyl- and alkenyltrifluoroborates
(Table 2). Owing to the electron-rich nature of these
substrates, only conditions A were applied. Alkynyltrifluor-
oborates 3a and 3d afforded the desired products in fair yields,
opening a new route to the preparation of trifluoromethyl-
substituted alkynes. The case of alkenyltrifluoroborates 4a−d
afforded valuable information. Under exactly the same
conditions, simple styrene derivatives 6a and 6b were obtained
in fair to good yields similar to those reported by other
methods,21,25 and only a small amount (∼5%) of isomerization
was detected. Moreover, the substitution pattern of the olefin
was found to be crucial. When the trifluoroborate group was
placed at the β-position of the aryl ring, the trisubstituted olefin
6c was obtained in a similarly good yield of 70%, but in the case
where CF3 resides in the α-position, the yield in 6d decreased
to 12%. Ultimately, no product was observed in the case of
cyclic olefins such as 4e, even using specifically designed
conditions for alkenyltrifluoroborates.21
In conclusion, the copper-mediated radical trifluoromethyla-
tion of unsaturated potassium organotrifluoroborates is
described. The conditions previously reported were successfully
extended to various trifluoroborato-containing arenes and
heteroarenes. Additionally, the trifluoromethylation of alkynyl-
trifluoroborates as well as mono- and disubstituted alkenyltri-
fluoroborates was achieved. These results, in conjunction with
the simplicity of this protocol, demonstrate the usefulness of
the radical trifluoromethylation of boronated substrates toward
a generic trifluoromethylation protocol.
EXPERIMENTAL SECTION
■
Preparation of Starting Materials 1, 3, and 4. General
Procedure C from Commercially Available Boronated Derivatives.
In air, the boronated starting material (1.0 mmol, 1.0 equiv) was
weighed in a round-bottomed flask and solubilized in MeOH (5 mL,
[SM] = 0.2 M). Saturated KHF2(aq) (0.9 mL, 4.5 M, 4.0 equiv) was
added. The flask was closed with a septum, and the resulting mixture
was stirred at rt for 1 h. The reaction mixture was evaporated to
dryness, and the resulting salt was extracted with hot acetone using a
Soxhlet apparatus overnight. The filtrate was concentrated to ca. 5 mL,
and precipitation was achieved by dropwise addition of the filtrate to
Et2O (100 mL) at 0 °C. The product was collected by gravity filtration
on a fritted funnel and dried to afford the corresponding potassium
organotrifluoroborate.
Potassium 3-Benzyloxyphenyltrifluoroborate 1b. Following gen-
eral procedure C, the reaction performed with 3-benzyloxyphenylbor-
onic acid (2.0 g, 8.77 mmol) afforded 1b (2.24 g, 88%) as a white
solid. mp > 200 °C (dec). HRMS (ESI): m/z calcd for C13H11BF3O
1
(M − K)−, 251.0861; found, 251.0854. H NMR (400 MHz/DMSO-
d6): δ 7.46−7.41 (m, 2H), 7.41−7.34 (m, 2H), 7.34−7.27 (m, 1H),
7.03−6.89 (m, 3H), 6.65 (ddd, J = 8, 3, 1 Hz, 1H), 5.02 (s, 2H). 13C
NMR (100 MHz/DMSO-d6): δ 157.2 (C), 138.0 (C), 128.3 (2 CH),
127.5 (CH), 127.4 (2 CH), 127.1 (CH), 124.1 (CH), 117.3 (CH),
111.5 (CH), 68.64 (CH2). 11B NMR (128 MHz/DMSO-d6): δ 3.08
(br). 19F NMR (376 MHz/DMSO-d6): δ −139.2 (br).
Potassium 2-Benzyloxyphenyltrifluoroborate 1c. Following gen-
eral procedure C, the reaction performed with 2-benzyloxyphenylbor-
onic acid (0.5 g, 2.19 mmol) afforded 1c (597 mg, 94%) as a white
solid. mp > 200 °C (dec). HRMS (ESI): m/z calcd for C13H11BF3O
1
(M − K)−, 251.0861; found, 251.0856. H NMR (400 MHz/DMSO-
d6): δ 7.54 (d, J = 7 Hz, 2H), 7.40−7.29 (m, 3H), 7.29−7.22 (m, 1H),
6.98 (td, J = 8, 2 Hz, 1H), 6.75−6.65 (m, 2H), 4.99 (s, 2H). 13C NMR
(100 MHz/DMSO-d6): δ 161.5 (C), 138.9 (C), 133.4 (CH), 133.4
(CH), 127.9 (2 CH), 126.8 (2 CH), 126.3 (CH), 119.4 (CH), 111.7
(CH), 68.8 (CH2). 11B NMR (128 MHz/DMSO-d6): δ 3.09 (br). 19
NMR (376 MHz/DMSO-d6): δ −136.8 (br).
F
Potassium 1-Boc-6-(methoxycarbonyl)indolyl-2-trifluoroborate
1g. Following general procedure C, the reaction performed with 1-
Boc-6-(methoxycarbonyl)indole-2-boronic acid (1.0 g, 3.13 mmol)
afforded 1g (903 mg, 76%) as a white solid. mp > 200 °C (dec).
HRMS (ESI): m/z calcd for C15H16BF3NO4 (M − K)−, 342.1130;
1
found, 342.1130. H NMR (400 MHz/DMSO-d6): δ 8.71 (s, 1H),
7.69 (dd, J = 8, 1 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 6.51 (d, J = 1 Hz,
B
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Note
a
Table 1. Scope of the Trifluoromethylation of Aryl- and Heteroaryltrifluoroborates
a
Conditions A: NaSO2CF3 (3.0 equiv), TBHP (5.0 equiv), CuCl (1.0 equiv), CH2Cl2/MeOH/H2O 1:1:0.8 ([1] = 0.1 M), open flask, rt, 12 h;
conditions B: NaSO2CF3 (3.0 equiv), TBHP (4.0 equiv), (CH3CN)CuPF6 (1.0 equiv), NaHCO3 (1.0 equiv), MeOH ([1] = 0.1 M), open flask, rt,
b
12 h. Yields were determined by 19F analysis; isolated yields are reported in brackets.
C
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Note
Table 2. Scope of the Trifluoromethylation of Alkynyl- and Alkenyltrifluoroborates
a
Conditions A: NaSO2CF3 (3.0 equiv), TBHP (5.0 equiv), CuCl (1.0 equiv), CH2Cl2/MeOH/H2O 1:1:0.8 ([3 or 4] = 0.1 M), open flask, rt, 12 h.
b
c
Yields were determined by 19F analysis; isolated yields are reported in brackets. With ∼5% of the (Z) product.
1H), 3.85 (s, 3H), 1.58 (s, 9H). 13C NMR (100 MHz/DMSO-d6): δ
(100 MHz/DMSO-d6): δ 140.1 (C), 139.5 (C), 137.5 (C), 132.5
(CH), 128.9 (2 CH), 127.0 (CH), 126.5 (2 CH), 126.3 (2 CH), 125.9
(2 CH). 11B NMR (128 MHz/DMSO-d6): δ 2.67 (br). 19F NMR (376
MHz/DMSO-d6): δ −137.8 (br).
167.2 (C), 151.1 (C), 136.9 (C), 134.6 (C), 122.6 (C), 122.3 (CH),
119.0 (CH), 115.9 (CH), 111.4 (CH), 82.0 (C), 51.7 (CH3), 27.5 (3
CH3). 11B NMR (128 MHz/DMSO-d6): δ 1.29 (br). 19F NMR (376
MHz/DMSO-d6): δ −136.7 (br).
Potassium N-Boc-1,2,5,6-tetrahydropyridinyl-4-trifluoroborate
4e. Following general procedure C, the reaction performed with N-
Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.5 g,
1.62 mmol) afforded 4e (396 mg, 85%) as a white solid. mp > 200 °C
(dec). HRMS (ESI): m/z calcd for C10H16BF3NO2 (M − K)−,
Potassium 4-Methyl-2-phenyl-5-(trifluoroborato)-1,3-thiazole 1i.
Following general procedure C, the reaction performed with 4-methyl-
2-phenyl-5-boronic-1,3-thiazole acid pinacol ester (0.5 g, 1.66 mmol)
afforded 1i (386 mg, 83%) as a white solid. mp > 200 °C (dec).
HRMS (ESI): m/z calcd for C10H8BF3NS (M − K)−, 242.0428;
1
250.1232; found, 250.1237. H NMR (400 MHz/acetone-d6): δ 5.56
1
(br, 1H), 3.72 (br, 2H), 3.33 (t, J = 6 Hz, 2H), 2.07 (br, 2H), 1.42 (s,
9H). 13C NMR (100 MHz/acetone-d6): δ 155.4 (C), 121.3 (CH),
78.7 (C), 44.7 (CH2), 42.3 (CH2), 28.8 (3 CH3), 27.6 (CH2). 11B
NMR (128 MHz/acetone-d6): δ 2.91 (br). 19F NMR (376 MHz/
acetone-d6): δ −146.7 (br).
found, 242.0421. H NMR (400 MHz/DMSO-d6): δ 7.86−7.79 (m,
2H), 7.45−7.37 (m, 2H), 7.37−7.31 (m, 1H), 2.35 (s, 3H). 13C NMR
(100 MHz/DMSO-d6): δ 163.4 (C), 152.5 (C), 134.5 (C), 128.8 (2
CH), 128.5 (CH), 125.5 (2 CH), 16.8 (CH3). 11B NMR (128 MHz/
DMSO-d6): δ 2.25 (br). 19F NMR (376 MHz/DMSO-d6): δ −132.3
(br).
Preparation of 3b:31 In air, 4-ethynylbiphenyl (1.0 g, 5.61 mmol,
1.0 equiv) was weighed in a 50 mL round-bottomed flask equipped
with a stir bar. The flask was closed with a septum, evacuated, and
backfilled with N2. THF (10 mL, [SM] = 0.5 M) was added, and the
mixture was cooled to −78 °C. n-BuLi (2.2 mL, 2.5 M in hexanes, 5.61
mmol, 1.0 equiv) was added slowly, and the reaction was stirred 1 h at
−78 °C. Triisopropyl borate (1.9 mL, 8.42 mmol, 1.5 equiv) was
added, and the reaction was stirred 1 h at −78 °C and then warmed to
Potassium (E)-4-Phenylstyryltrifluoroborate 4b. Following general
procedure C, the reaction performed with (E)-4-phenylstyrylboronic
acid (535 mg, 2.39 mmol) afforded 4b (292 mg, 43%) as a white solid.
mp > 200 °C (dec). HRMS (ESI): m/z calcd for C14H11BF3 (M −
1
K)−, 247.0911; found, 247.0904. H NMR (400 MHz/DMSO-d6): δ
7.67−7.62 (m, 2H), 7.56 (d, J = 8 Hz, 2H), 7.48−7.37 (m, 4H), 7.36−
7.29 (m, 1H), 6.52 (d, J = 18 Hz, 1H), 6.30−6.20 (m, 1H). 13C NMR
D
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Note
−20 °C in 1 h. Saturated KHF2(aq) (7.5 mL, 4.5 M, 6.0 equiv) was
added, and the reaction was stirred at rt for 2 h. The reaction mixture
was evaporated to dryness, and the resulting salt was extracted with
hot acetone using a Soxhlet apparatus overnight. The filtrate was
concentrated to ca. 5 mL, and precipitation was achieved by dropwise
addition of the filtrate to Et2O (100 mL) at 0 °C. The resulting
product was collected by gravity filtration on a fritted funnel and dried
to afford 3b (280 mg, purity = 95%, 17%) as a white solid. mp > 200
°C (dec). HRMS (ESI): m/z calcd for C14H9BF3 (M − K)−, 245.0755;
found, 245.0750. 1H NMR (400 MHz/DMSO-d6): δ 7.66 (d, J = 7 Hz,
2H), 7.59 (d, J = 8 Hz, 2H), 7.46 (dd, J = 8, 8 Hz, 2H), 7.40−7.33 (m,
3H). 13C NMR (100 MHz/DMSO-d6): δ 139.5 (C), 138.2 (C), 131.5
(2 CH), 128.9 (2 CH), 127.4 (CH), 126.4 (2 CH), 126.4 (2 CH),
124.7 (C), 89.0 (C). 11B NMR (128 MHz/DMSO-d6): δ −1.56 (br).
19F NMR (376 MHz/DMSO-d6): δ −131.7 (br).
mixture stirred at rt for 5 min. A solution of 4-(propyn-1-yl)-biphenyl
(171 mg, 0.89 mmol, 1.0 equiv) in toluene (1 mL) was added, and the
reaction was stirred at rt for 3 days. The reaction mixture was diluted
with EtOAc (10 mL) and filtered through a pad of Celite. The filtrate
was evaporated to afford the crude boronate intermediate. In air, this
boronate was charged in a round-bottomed flask and solubilized in
THF (10 mL). Saturated KHF2(aq) (0.8 mL, 4.5 M, 3.6 mmol, 4.0
equiv) was added. The flask was closed with a septum, and the
resulting mixture was stirred at rt for 2 h. The reaction mixture was
evaporated to dryness, and the resulting salt was extracted with hot
acetone using a Soxhlet apparatus overnight. The filtrate was
concentrated to ca. 5 mL, and precipitation was achieved by dropwise
addition of the filtrate to Et2O (100 mL) at 0 °C. The product was
collected by gravity filtration on a fritted funnel and dried to afford 4d
(69 mg, 26%) as a white solid. mp > 200 °C (dec). HRMS (ESI): m/z
1
Preparation of 4c and 4d. 4-(Propyn-1-yl)-biphenyl. In air, 4-
ethynylbiphenyl (1.0 g, 5.61 mmol, 1.0 equiv) was weighed in a round-
bottomed flask equipped with a stir bar. The flask was closed with a
septum, evacuated, and backfilled with N2. THF (20 mL, [SM] = 0.25
M) was added, and the mixture was cooled to −78 °C. n-BuLi (2.5
mL, 2.5 M in hexanes, 6.17 mmol, 1.1 equiv) was slowly added (by
syringe), and the reaction was stirred 15 min at −78 °C. MeI (0.4 mL,
6.17 mmol, 1.1 equiv) was added, and the reaction was allowed to
warm to rt over 2 h and then stirred at rt for 4 h. Subsequently, the
reaction mixture was poured into saturated NH4Cl(aq) (20 mL), and
the resulting solution was extracted twice with EtOAc (20 mL). The
combined organic layers were washed with brine (50 mL), dried
(MgSO4), and evaporated to afford the crude product. Purification by
flash column chromatography (80 g SiO2, heptane to EtOAc/heptane
1:9) afforded the title compound (654 mg, 60%) as a white solid. mp
69−70 °C. 1H NMR (400 MHz/CDCl3): δ 7.63−7.58 (m, 2H), 7.57−
7.53 (m, 2H), 7.51−7.43 (m, 4H), 7.40−7.34 (m, 1H), 2.10 (s, 3H).
Spectral data were consistent with that previously reported.32
calcd for C15H13BF3 (M − K)−, 261.1068; found, 261.1058. H NMR
(400 MHz/DMSO-d6): δ 7.63 (dd, J = 8, 1 Hz, 2H), 7.50−7.40 (m,
4H), 7.33−7.27 (m, 1H), 7.12 (d, J = 8 Hz, 2H), 5.69 (q, J = 7 Hz,
1H), 1.48 (t, J = 7 Hz, 3H). 13C NMR (100 MHz/DMSO-d6): δ 145.2
(C), 140.8 (C), 135.4 (C), 128.9 (2 CH), 128.7 (2 CH), 126.6 (CH),
126.2 (2 CH), 125.2 (2 CH), 122.6 (CH), 15.0 (CH3). 11B NMR
(128 MHz/DMSO-d6): δ 2.73 (br). 19F NMR (376 MHz/DMSO-d6):
δ −139.4 (br).
Radical Trifluoromethylation of Unsaturated Potassium
Organotrifluoroborates. General Procedure A for the Preparation
of Trifluoromethylated Compounds 2, 5, and 6. In air, potassium
organotrifluoroborates 1, 3, or 4 (0.5 mmol, 1.0 equiv), NaSO2CF3
(234 mg, 1.5 mmol, 3.0 equiv), and CuCl (50 mg, 0.5 mmol, 1.0
equiv) were weighed in a 2−5 mL MW vial equipped with a stir bar.
MeOH (1 mL), CH2Cl2 (1 mL), and distilled H2O (0.8 mL) were
successively added, and the tube was sealed with a tap open to air by a
needle. This solution was cooled to 0 °C, and TBHP (0.35 mL, 70% in
H2O, 2.5 mmol, 5.0 equiv) was slowly added. The reaction was
allowed to warm to rt and stirred at rt for 12 h. The reaction mixture
was diluted with Et2O (10 mL), and this solution was washed
successively with saturated NaHCO3(aq) (5 mL) and 5%
Na2S2O3(aq) (5 mL). The organic layer was dried (MgSO4), and
1,3,5-trifluorobenzene (51.7 μL, 0.5 mmol, 1.0 equiv) was added as an
internal standard. The solution was analyzed by 19F NMR and GCMS.
Additionally, this solution can be evaporated and purified by flash
column chromatography (SiO2, mixtures of EtOAc and heptane) to
afford the pure compounds 2, 5, or 6.
33
Compound 4c. In air, CuCl (5 mg, 0.05 mmol, 5 mol %), Ph3P
(27 mg, 0.10 mmol, 10 mol %), and NaOt-Bu (20 mg, 0.21 mmol, 20
mol %) were weighed in a 2−5 mL MW vial equipped with a stir bar.
The vial was sealed, evacuated, and backfilled with N2 (×3). THF (0.5
mL) was added, and the resulting mixture stirred at rt for 30 min. A
solution of bis(pinacolato)diboron (290 mg, 1.14 mmol, 1.1 equiv) in
THF (1 mL) was added, and the mixture was stirred at rt for 5 min. A
solution of 4-(propyn-1-yl)-biphenyl (200 mg, 1.04 mmol, 1.0 equiv)
in THF (0.5 mL) and MeOH (84 μL, 2.08 mmol, 2.0 equiv) were
successively added, and the reaction stirred at rt for 14 h. Then, the
reaction mixture was diluted with Et2O (10 mL) and filtered through a
pad of Celite. The filtrate was evaporated and purified by flash column
chromatography (24 g SiO2, heptane to EtOAc/heptane 1:4). In air,
this boronate was charged in a round-bottomed flask and solubilized in
THF (10 mL). Saturated KHF2(aq) (0.9 mL, 4.5 M, 4.2 mmol, 4.0
equiv) was added. The flask was closed with a septum, and the
resulting mixture stirred at rt for 2 h. The reaction mixture was
evaporated to dryness, and the resulting salt was extracted with hot
acetone using a Soxhlet overnight. The filtrate was concentrated to ca.
5 mL, and precipitation was achieved by dropwise addition of the
filtrate to Et2O (100 mL) at 0 °C. The product was collected by
gravity filtration on a fritted funnel and dried to afford 4c (208 mg,
67%) as a white solid. mp > 200 °C (dec). HRMS (ESI): m/z calcd for
General Procedure B for the Preparation of Trifluoromethylated
Compounds 2. In air, potassium organotrifluoroborates 1 (0.5 mmol,
1.0 equiv), NaSO2CF3 (234 mg, 1.5 mmol, 3.0 equiv), and
(MeCN)4CuPF6 (157 mg, 0.5 mmol, 1.0 equiv) were weighed in a
2−5 mL MW vial equipped with a stir bar. MeOH (3 mL) was added,
and the tube was sealed with a tap open to air by a needle. This
solution was cooled to 0 °C, and TBHP (0.28 mL, 70% in H2O, 2.0
mmol, 4.0 equiv) was slowly added. The reaction was allowed to warm
to rt and stirred at rt for 12 h. The reaction mixture was diluted with
Et2O (10 mL), and this solution was washed successively with
saturated NaHCO3(aq) (5 mL) and 5% Na2S2O3(aq) (5 mL). The
organic layer was dried (MgSO4), and 1,3,5-trifluorobenzene (51.7 μL,
0.5 mmol, 1.0 equiv) was added as an internal standard. The solution
was analyzed by 19F NMR and GCMS. Additionally, this solution can
be evaporated and purified by flash column chromatography (SiO2,
mixtures of EtOAc and heptane) to afford the pure compound 2.
1-(Benzyloxy)-4-(trifluoromethyl)benzene 2a. Following general
procedure A, the reaction performed with 1a (145 mg, 0.5 mmol)
afforded 2a in 19F yield = 99% and, after purification, 117 mg (93%) as
1
C15H13BF3 (M − K)−, 261.1068; found, 261.1065. H NMR (400
MHz/DMSO-d6): δ 7.65 (d, J = 8 Hz, 2H), 7.57 (d, J = 8 Hz, 2H),
7.44 (dd, J = 8, 8 Hz, 2H), 7.36−7.30 (m, 1H), 7.27 (d, J = 8 Hz, 2H),
6.41 (s, 1H), 1.76 (s, 3H). 13C NMR (100 MHz/DMSO-d6): δ 140.2
(C), 139.9 (C), 136.1 (C), 129.0 (2 CH), 128.8 (2 CH), 126.9 (CH),
126.3 (2 CH), 126.0 (2 CH), 125.6 (CH), 16.7 (CH3). 11B NMR
(128 MHz/DMSO-d6): δ 3.08 (br). 19F NMR (376 MHz/DMSO-d6):
a white solid. mp 79−80 °C. GC−MS: 5.438 min (m/z 252 (M)+). 19
F
NMR (376 MHz/CDCl3): δ −61.4 (s). Spectral data were consistent
with that previously reported.16
δ −143.6 (br).
Compound 4d.
34
1-(Benzyloxy)-3-(trifluoromethyl)benzene 2b. Following general
procedure A, the reaction performed with 1b (145 mg, 0.5 mmol)
afforded 2b in 19F yield = 21% and, after purification, 18 mg (14%) as
a colorless oil. GC−MS: 5.241 min (m/z 252 (M)+). 19F NMR (376
MHz/CDCl3): δ −62.9 (s). Spectral data were consistent with that
previously reported.35
In air, CuCl (4 mg, 0.04 mmol, 5 mol %),
xantphos (51 mg, 0.09 mmol, 10 mol %), and NaOt-Bu (17 mg, 0.18
mmol, 20 mol %) were weighed in a 2−5 mL MW vial equipped with a
stir bar. The vessel was sealed, evacuated, and backfilled with N2 (×3).
Toluene (1 mL) was added, and the mixture stirred at rt for 15 min.
Pinacolborane (0.2 mL, 1.33 mol, 1.5 equiv) was added, and the
E
dx.doi.org/10.1021/jo4023233 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1-(Benzyloxy)-2-(trifluoromethyl)benzene 2c. Following general
procedure A, the reaction performed with 1c (145 mg, 0.5 mmol)
afforded 2c in 19F yield = 66% and, after purification, 63 mg (50%) as a
colorless oil. GC−MS: 5.462 min (m/z 252 (M)+). HRMS (ESI): m/z
calcd for C14H11F3O (M)+, 252.0762; found, 252.0748. 1H NMR (400
MHz/CDCl3): δ 7.64 (dd, J = 8, 1 Hz, 1H), 7.52−7.46 (m, 3H),
7.46−7.40 (m, 2H), 7.39 - 7.33 (m, 1H), 7.11−7.00 (m, 2H), 5.22 (s,
2H). 13C NMR (100 MHz/CDCl3): δ 156.4 (C), 136.3 (C), 133.2
(CH), 128.6 (2 CH), 127.9 (CH), 127.1 (q, J = 5 Hz, CH), 126.8 (2
CH), 123.8 (q, J = 272 Hz, C), 120.2 (CH), 119.2 (q, J = 31 Hz, C),
113.2 (CH), 70.2 (CH2). 19F NMR (376 MHz/CDCl3): δ −62.3 (s).
Trifluoromethylbenzene 2d. Following general procedure A, the
reaction performed with 1d (92 mg, 0.5 mmol) afforded 2d in 19F
yield = 28%. GC−MS: 0.624 min (m/z 146 (M)+). 19F NMR (376
MHz/CDCl3): δ −62.9 (s). Spectral data were consistent with that
previously reported.22
1-Fluoro-2-phenyl-5-trifluoromethylbenzene 2e. Following gen-
eral procedure B, the reaction performed with 1e (139 mg, 0.5 mmol)
afforded 2e in 19F yield = 61% and, after purification, 41 mg (34%) as a
colorless oil. GC−MS: 4.151 min (m/z 240 (M)+). 19F NMR (376
MHz/CDCl3): δ −62.8 (s, 3F), 115.7 (s, 1F). Spectral data were
consistent with that previously reported.16
4-Acetyl-trifluoromethylbenzene 2f. Following general procedure
B, the reaction performed with 1f (113 mg, 0.5 mmol) afforded 2f in
19F yield = 27%. GC−MS: 2.437 min (m/z 188 (M)+). 19F NMR (376
MHz/CDCl3): δ −63.2 (s). Spectral data were consistent with that
previously reported.22
(376 MHz/CDCl3): δ −49.9 (s). Spectral data were consistent with
that previously reported.37
1′-Trifluoromethyl-1-biphenylacetylene 5b. Following general
procedure A, the reaction performed with 3b (149 mg, 0.5 mmol)
afforded 5b in 19F yield = 51% and, after purification, 56 mg (45%) as
a white solid. mp 82−83 °C. GC−MS: 5.471 min (m/z 246 (M)+). 19
F
NMR (376 MHz/CDCl3): δ −49.9 (s). Spectral data were consistent
with that previously reported.37
Compound 6a. Following general procedure A, the reaction
performed with 4a (105 mg, 0.5 mmol) afforded 6a in 19F yield = 54%
(contaminated by 5% of the isomerized (Z)-product). GC−MS: 1.806
min (m/z 172 (M)+). 19F NMR (376 MHz/CDCl3): δ −63.4 (s).
Spectral data were consistent with that previously reported.38
Compound 6b. Following general procedure A, the reaction
performed with 4b (143 mg, 0.5 mmol) afforded 6b in 19F yield = 77%
and, after purification, 101 mg (77%) as a white solid (contaminated
by 5% of the isomerized (Z)-product). GC−MS: 5.890 min (m/z 248
(M)+). 19F NMR (376 MHz/CDCl3): δ −63.4 (s). Spectral data were
consistent with that previously reported.16
Compound 6c. Following general procedure A, the reaction
performed with 4c (75 mg, 0.25 mmol) afforded 6c in 19F yield =
70% (in this case, 2.0 equiv of internal standard was used) and, after
purification, 39 mg (59%) as a white solid. mp 82−83 °C. GC−MS:
6.183 min (m/z 262 (M)+). HRMS (ESI): m/z calcd for C16H13F3
+
1
(M) , 262.0969; found, 262.0970. H NMR (400 MHz/CDCl3): δ
7.73−7.60 (m, 4H), 7.54−7.35 (m, 5H), 7.12 (s, 1H), 2.10 (s, 3H).
13C NMR (100 MHz/CDCl3): δ 141.0 (C), 140.3 (C), 133.5 (C),
130.9 (q, J = 6 Hz, CH), 129.7 (2 CH), 128.9 (2 CH), 127.6 (CH),
127.1 (2 CH), 127.0 (2 CH), 126.2 (q, J = 29 Hz, C), 124.6 (q, J =
272 Hz, C), 12.3 (CH3). 19F NMR (376 MHz/CDCl3): δ −69.5 (s).
Compound 6d. Following general procedure A, the reaction
performed with 4d (62 mg, 0.21 mmol) afforded 6d in 19F yield = 12%
(in this case, 2.0 equiv of internal standard was used) and, after
purification, 6 mg (10%) as a white solid. mp 64−65 °C. GC−MS:
5.862 min (m/z 262 (M)+). HRMS (ESI): m/z calcd for C16H13F3
1-Boc-2-trifluoromethyl-6-(methoxycarbonyl)indole 2g. Follow-
ing general procedure A, the reaction performed with 1g (191 mg, 0.5
mmol) afforded 2g in 19F yield = 67% and, after purification, 110 mg
(64%) as a white solid. mp 83−84 °C. GC−MS: 7.321 min (m/z 343
(M)+). HRMS (ESI): m/z calcd for C11H8F3NO2 (M-Boc+H)+,
1
243.0507; found, 243.0533. H NMR (400 MHz/CDCl3): δ 8.99 (s,
1H), 7.99 (d, J = 8 Hz, 1H), 7.66 (d, J = 8 Hz, 1H), 7.16 (s, 1H), 3.97
(s, 3H), 1.70 (s, 9H). 13C NMR (100 MHz/CDCl3): δ 167.1 (C),
148.0 (C), 137.1 (C), 129.9 (C), 129.5 (q, J = 40 Hz, C), 128.6 (C),
124.5 (CH), 121.8 (CH), 120.4 (q, J = 268 Hz, C), 118.1 (CH), 112.8
(q, J = 5 Hz, CH), 86.1 (C), 52.2 (CH3), 27.8 (3 CH3). 19F NMR
(376 MHz/CDCl3): δ −58.4 (s).
1-Methyl-4-trifluoromethyl-1H-pyrazole 2h. Following general
procedure A, the reaction performed with 1h (47 mg, 0.25 mmol)
afforded 2f in 19F yield = 48% (in this case, 2.0 equiv of internal
standard was used). GC−MS: 0.882 min (m/z 150 (M)+). 19F NMR
(376 MHz/CDCl3): δ −56.4 (s). Spectral data were consistent with
that previously reported.36
+
1
(M) , 262.0969; found, 262.0963. H NMR (400 MHz/CDCl3): δ
7.68−7.57 (m, 5H), 7.54−7.42 (m, 2H), 7.42−7.30 (m, 2H) 6.58 (m,
1H), 1.74 (m, 3H). 13C NMR (100 MHz/CDCl3): δ 141.2 (C), 140.5
(C), 131.9 (C), 131.6 (q, J = 5 Hz, CH), 131.3 (q, J = 45 Hz, C),
130.1 (2 CH), 128.8 (2 CH), 128.6 (q, J = 275 Hz, C), 127.5 (CH),
127.1 (4 CH), 14.3 (CH3). 19F NMR (376 MHz/CDCl3): δ −65.7
(s).
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental considerations and copies of GCMS
monitoring and NMR spectra for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
4-Methyl-2-phenyl-5-trifluoromethyl-1,3-thiazole 2i. Following
general procedure A, the reaction performed with 1i (140 mg, 0.5
mmol) afforded 2i in 19F yield = 43% and, after purification, 37 mg
(24%) as a colorless oil (contaminated by 5% of the bis-
trifluoromethylated product). GC−MS: 4.642 min (m/z 243 (M)+).
HRMS (ESI): m/z calcd for C11H8F3NS (M)+, 243.0330; found,
243.0331. 1H NMR (400 MHz/CDCl3): δ 7.95−7.89 (m, 2H), 7.50−
7.43 (m, 3H), 2.62 (q, J = 2 Hz, 3H). 13C NMR (100 MHz/CDCl3): δ
168.4 (C), 155.2 (C), 132.5 (C), 131.0 (CH), 129.1 (2 CH), 126.7 (2
CH), 122.7 (q, J = 269 Hz, C), 119.7 (q, J = 37 Hz, C), 16.1 (CH3).
19F NMR (376 MHz/CDCl3): δ −53.0 (s).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: frombout@its.jnj.com (F.R.).
■
*E-mail: gmolandr@sas.upenn.edu (G.A.M.).
Notes
The authors declare no competing financial interest.
2-Trifluoromethylbenzofuran 2j. Following general procedure A,
the reaction performed with 1j (124 mg, 0.5 mmol) afforded 2j in 19
F
ACKNOWLEDGMENTS
■
yield = 53%. GC−MS: 1.902 min (m/z 186 (M)+). 19F NMR (376
MHz/CDCl3): δ −65.0 (s). Spectral data were consistent with that
previously reported.22
This research was supported by the NIH (NIGMS R01
GM081376) and by the Neuroscience Medicinal Chemistry
Department of Janssen. Michel Carpentier and Guy Winderickx
(Janssen) are acknowledged for obtaining HRMS data.
3-Trifluoromethylquinoline 2k. Following general procedure B, the
reaction performed with 1k (117 mg, 0.5 mmol) afforded 2k in 19F
yield = 6%. GC−MS: 3.277 min (m/z 197 (M)+). 19F NMR (376
MHz/CDCl3): δ −62.0 (s). Spectral data were consistent with that
previously reported.16
1′-Trifluoromethylphenylacetylene 5a. Following general proce-
dure A, the reaction performed with 1j (104 mg, 0.5 mmol) afforded
5a in 19F yield = 50%. GC−MS: 1.344 min (m/z 170 (M)+). 19F NMR
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