Transition-metal-free synthesis of fluorinated nitriles and diaryl ketones through a selective C-F bond functionalization under mild conditions

Article abstract of DOI:10.1002/ejoc.201403354

A highly efficient and simple procedure was developed to synthesize substituted fluorinated nitriles and diaryl ketones under mild conditions from polyfluorobenzenes and phenylacetonitriles. This coupling process was achieved by using a selective C-F bond functionalization without a transitionmetal catalyst. The reactions had good functional group tolerance and provided the products in moderate to excellent yields.

Full text of DOI:10.1002/ejoc.201403354

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FULL PAPER
DOI: 10.1002/ejoc.201403354
Transition-Metal-Free Synthesis of Fluorinated Nitriles and Diaryl Ketones
Through a Selective C–F Bond Functionalization Under Mild Conditions
Guang-Hui Yang,[a] Ming Liu,[a] Na Li,[a] Ran Wu,[a] Xu Chen,[a] Ling-Ling Pan,[a]
Shang Gao,[a] Xing Huang,[a] Chen Wang,[a] and Chuan-Ming Yu*[a]
Keywords: Synthetic methods / Oxidation / C–F bond functionalization / Fluorine / Nitriles / Ketones
A highly efficient and simple procedure was developed to
synthesize substituted fluorinated nitriles and diaryl ketones
selective C–F bond functionalization without a transition-
metal catalyst. The reactions had good functional group tol-
under mild conditions from polyfluorobenzenes and phenyl- erance and provided the products in moderate to excellent
acetonitriles. This coupling process was achieved by using a
yields.
Introduction
biological activity, the bioavailability, and the potency of
biologically active molecules,[10] and now fluorine is com-
monly used in new drug discovery and development pro-
grams.[9]
Aryl ketones are important subunits and skeletons of
pharmaceutical intermediates, bioactive compounds, dyes,
and functional materials[1] such as mebendazole and tricor.
To date, the classical Friedel–Crafts reaction,[2] the Pd-cata-
lyzed β-aryl elimination of triarylmethanols,[3] and the tran-
sition-metal-catalyzed ortho-C–H bond functionalization[4]
have been the main methods for their synthesis. Substituted
nitriles are precursors to carboxylic acids, primary amines,
esters, lactones, and aldehydes as well as important interme-
diates in the syntheses of biologically active compounds,[5]
the drugs saxagliptin and verapamil, and PvdQ inhibitors[6]
(see Scheme 1). Most of the reported coupling reactions to
synthesize nitrile compounds occur between aryl halides
and nitriles under palladium or copper catalysis.[7] However,
the catalytic cross-coupling reaction of aryl fluorides has
received less attention than that of other aryl halides.[8] The
fluorine atom plays an important role in pharmaceutical,
veterinary, agrochemical, and material sciences.[9] The intro-
duction of a fluorine atom into a molecule can increase the
In past decades, fluorinated arenes received much atten-
tion with regard to materials science and drug discovery
because of the unique effects of fluoro substituents.[11]
These compounds are, however, synthetically difficult to
prepare because neither the selective fluorination of aro-
matic compounds[12] nor the partial C–F bond activation
of polyfluoroaromatics[13] is easy to achieve. It has been re-
ported that bromopentafluorobenzene[14] and hexachloro-
benzene[15] can be treated with phenylacetonitrile to synthe-
size diaryl nitriles, but the use of nBuLi limits the broad
application of this method. In 2000, Caron and co-workers
reported the coupling of nitrile anions with aryl fluorides to
prepare tertiary benzylic nitriles.[16] Nevertheless, primary
nitriles did not undergo substitution, and the reactions that
used either phenylacetonitrile or isovaleronitrile with aryl
fluoride led to decomposition. Recently, Nakamura,[17a]
Cao[17b] and Shen[17c] have reported some methods for the
selective activation of the C–F bond with coupling partners.
These protocols suffer from drawbacks, such as the need of
an expensive transition-metal catalyst or a stoichiometric
amount of alkali metal and tedious experimental pro-
cedures. As mentioned above, the development of a highly
efficient and mild method for the synthesis of fluorinated
diaryl ketones and substituted nitriles is a significant
achievement.
Scheme 1. Representative drug and active compounds for fluori-
nated nitriles and diaryl ketones.
Pentafluorobenzene is a representative class of fluorin-
ated compounds that can be converted into other fluorine-
[a] Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, College of Pharmaceutical Sciences,
Zhejiang University of Technology,
containing compounds through
a
series of reac-
tions.[11a,11b,11d,18] Research on pentafluorobenzene has
been made great progress during the past few years.[8a,19]
Our group has successfully developed useful methods to
synthesize fluorinated thioethers, tetrafluorophenoxthiines,
Chao Wang Road 18th, 310014 Hangzhou, China
E-mail: ycm@zjut.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403354.
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FULL PAPER
and biphenyl compounds by using copper catalysis.[20] results of the reaction were also unsatisfactory (see Table 1,
Herein, we report the uncatalyzed coupling reaction of po- Entries 14 and 15).
lyfluorobenzenes and phenylacetonitriles to give nitriles and
Next, the scope of substituted aromatic nitriles was ex-
diaryl ketones. This reaction occurs under mild conditions amined under the optimal reaction conditions (see Table 1,
and proceeds through a selective C–F bond functionaliza- Entry 2), and the representative results are summarized in
tion.
Table 2. The electronic nature of different substituents on
the phenyl group showed no pronounced effect on the yield
of the overall reaction. When the phenylacetonitriles con-
tained electron-donating substituents such as p-Me, p-OMe,
or 3,4-di-OMe, the reactions proceeded smoothly, and the
Results and Discussion
At the outset of our investigation, we focused on the cou-
pling of pentafluorobenzene (1a) with phenylacetonitrile
(2a). When tBuOLi (2 equiv.) was used as the base with
N,N-dimethylformamide (DMF) as the solvent under nitro-
gen, the reaction reached completion in 0.5 h, and coupling
product 3a was obtained in 62% yield (see Table 1, En-
try 1). Performing the reaction under an inert environment
was crucial for this process. When the quantity of base was
increased to 3 equiv., the yield increased to 93% (see
Table 1, Entry 2). However, there was no obvious change
with the addition of more base (see Table 1, Entry 3). Reac-
tions that were carried out with weaker bases such as
K2CO3, and Cs2CO3 afforded none of the desired product
(see Table 1, Entries 5 and 6). After screening a variety of
bases (e.g., NaOH, NaH, and tBuONa), we found that
tBuOLi gave the best results. Moreover, the choice of the
solvent was vitally important. Employing DMF, N,N-di-
Table 2. Cross-coupling reaction of polyfluorobenzenes with nitrile
compounds.[a]
methylacetamide
(DMA),
hexamethylphosphoramide
(HMPA), and N-methylpyrrolidone (NMP) as the solvent
afforded the corresponding product in 93, 73, 85, and 68%
yield, respectively (see Table 1, Entries 2, 9, 10, and 11).
When CH3CN or acetone was used as the solvent, only a
trace amount of product was observed. In moderately polar
solvents [e.g., tetrahydrofuran (THF) or 1,4-dioxane], the
Table 1. Optimization of the reaction conditions.[a]
Entry
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
tBuOLi
tBuOLi
tBuOLi
tBuONa
K2CO3
Cs2CO3
NaOH
NaH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
62[c]
93
94[d]
88
n.d.[e]
n.d.
65
90
9
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
DMA
HMPA
NMP
CH3CN
acetone
THF
73
85
68
trace
trace
8
10
11
12
13
14
15
1,4-dioxane
trace
[a] Unless otherwise noted, reaction conditions were as follows: 1a
(2 mmol), 2a (1 mmol), base (3 equiv.), solvent (4 mL), room temp., [a] Reagents and conditions: 1 (2 mmol), 2 (1 mmol), tBuOLi
0.5 h, N2. [b] Isolated yield. [c] Base (2 equiv.) was used. [d] Base
(4 equiv.) was used. [e] n.d.: not detected.
(3 equiv.), DMF (4 mL), room temp., 0.5 h, N2. [b] Reaction was
carried out at 40 °C. [c] Isolated yield.
2
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Metal-Free Synthesis of Fluorinated Nitriles and Diaryl Ketones
corresponding products were obtained in excellent yields nitrobenzene had enormous influence on the reactivity, and
[see Table 2, compounds 3b (92%), 3c (94%), and 3e the yield increased to 86% (see Table 2, compound 3r). Im-
(97%)]. Phenylacetonitriles with electron-withdrawing portantly, when 1-bromo-3-chloro-5-fluorobenzene was
groups such as p-F, p-Cl, or p-Br on the phenyl ring also used as the substrate, a selective C–F bond functionaliza-
afforded good isolated yields [see Table 2, compounds 3g tion occurred to give the product in 57% (see Table 2, com-
(90%), 3h (90%), and 3i (92%)]. However, the phenylaceto- pound 3s).
nitrile with a p-NO2 group had poor reactivity, and only
To our surprise, oxidative decyanation product 4a was
55% yield of the isolated product was obtained when the produced when we changed the solvent from DMF to
reaction was conducted at 40 °C (see Table 2, com- DMSO. Further efforts were directed towards evaluating
pound 3j). In addition, the reaction tolerated sterically hin- the influence of solvent, base, and oxidant on the oxidative
dered substrates such those that contain o-Me, o-Cl, 2,5- decyanation reaction, and the results of this study revealed
di-Cl, and 1-naphthyl groups to provide the corresponding that DMSO and CH3ONa were the suitable solvent and
product [see Table 2, compounds 3d (93%), 3k (83%), 3l base (see Table 3, Entries 1–8). To further improve the
(87%), and 3n (89%), respectively]. To expand the scope of product yield, various oxidants were added to the reaction
the substrates, heterocyclic 2-pyridylacetonitrile was further system (see Table 3, Entries 9–15), and DTBP was found to
examined, and an excellent product yield was obtained [see be the most effective oxidant. We then examined the opti-
Table 2, compound 3m (96%)]. Having examined the scope mal amount of DTBP and found that the yield reached
of a broad spectrum of nitriles, we proceeded to examine a 82% by using 6 equiv. of DTBP (see Table 3, Entry 18).
diverse set of polyfluorobenzenes. When 1,2,3,4-tetra- When additional oxidant was employed, there was not
fluorobenzene was used, a selective C-2–F bond function- much change in the yield (see Table 3, Entry 19).
alization occurred to give coupling product 3o in 83% yield.
To extend the substrate scope, the optimized protocol
The activity of 1,3,5-trifluorobenzene decreased somewhat, was employed, which afforded various substituted diaryl
and a moderate yield of product was obtained (see Table 2, ketones (see Table 4). Both electron-rich (see Table 4, com-
compound 3p). 1-Bromo-3,4,5-trifluorobenzene could also pounds 4b–4d) and electron-deficient phenylacetonitriles
undergo the reaction with phenylacetonitrile to afford the (see Table 4, compounds 4e and 4f) could be employed to
corresponding product 3q in 62% yield. However, the afford the corresponding products in moderate to good
strong electron-withdrawing group (NO2) in 3,4-difluoro-
Table 4. Substrate scope of oxidative decyanation reaction.[a]
Table 3. Optimization of oxidative decyanation reaction.[a]
Entry Base
Solvent
Gas
Oxidant Yield [%][b]
1
2
3
4
5
6
7
8
tBuOLi
DMSO[c]
DMSO
THF
1,4-dioxane
DMF
N2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
–
–
–
–
–
–
–
–
12
45
9
n.d.
40
50
7
25
32
56
40
54
66
39
tBuOLi
tBuOLi
tBuOLi
tBuOLi
CH3ONa DMSO
K2CO3 DMSO
tBuONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
CH3ONa DMSO
9
DDQ[c]
K2S2O8
TBHP[c]
CuO
DTBP
MnO2
H2O2
DTBP
DTBP
DTBP
DTBP
10
11
12
13
14
15
16
17
18
19
52
72[d]
78[e]
82[f]
83[g]
[a] Unless otherwise noted, reaction conditions: 1a (2 mmol), 2a
(1 mmol), base (3 equiv.), solvent (4 mL), room temp., 1 h. [b] Iso-
lated yield; n.d.: not determined. [c] DMSO = dimethyl sulfoxide,
DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBHP = tert-
butyl hydroperoxide. [d] Di-tert-butyl peroxide (DTBP, 2.0 equiv.)
was used. [e] DTBP (4.0 equiv.) was used. [f] DTBP (6.0 equiv.) was [a] Reagents and conditions: 1 (2 mmol), 2 (1 mmol), CH3ONa
used. [g] DTBP (10.0 equiv.) was used.
(3 equiv.), DTBP (6 equiv.), DMSO (4 mL), O2, room temp., 1 h.
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yields. Small steric factors influenced the reactions of o-Me- When heterocyclic 2-pyridylacetonitrile was used as the
and 1-naphthyl-substituted substrates, and the yields substrate, the yield was much lower at only 48% (see
reached 67 and 68% (see Table 4, compounds 4c and 4g). Table 4, compound 4h). Other polyfluorobenzenes such as
Figure 1. HPLC chromatograms for monitoring the reaction process.
4
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Metal-Free Synthesis of Fluorinated Nitriles and Diaryl Ketones
Scheme 2. Possible mechanism for oxidative decyanation reaction.
1,2,3,4-tetrafluorobenzene,
1,3,5-trifluorobenzene,
1-
Conclusions
bromo-3,4,5-trifluorobenzene were also examined, and
moderate yields of product were obtained (see Table 4, com-
pounds 4i–4k). When1-bromo-3,4,5-trifluorobenzene was
used as the substrate, the reaction selectively occurred at
the C-3–F bond. To our delight, this selective C–F bond
functionalization of polyfluorobenzenes can provide unique
unsymmetrical diaryl ketones even in the presence of a
chloro and bromo group (see Table 4, compound 4l). This
process is different from that reported by Wang,[21a] in
which the C–Cl bond was selectively activated when both
C–Cl and C–F bonds were present.
In summary, we have developed a rapid route to synthe-
size a series of fluorinated diaryl ketones and nitriles by
using a selective C–F bond functionalization reaction that
occurs under mild conditions without a transition-metal
catalyst. This method has excellent functional group toler-
ance and provides the products in good to excellent yields.
Further investigations and applications of this strategy are
underway in our laboratory.
Experimental Section
By using this system, compound 3a could also be oxid-
ized alone to give the corresponding decyanation product General Methods: Unless otherwise noted, all materials were pur-
chased from commercial suppliers and used without further purifi-
cation. TLC analysis was carried out by using precoated glass
plates. Silica gel for column chromatography was purchased from
Qingdao Haiyang Chemical Co., Ltd. Flash column chromatog-
raphy was performed by using 200–300 mesh silica gel. The 1H,
13C, and 19F NMR spectroscopic data were recorded at 400, 100,
and 376 MHz, respectively The abbreviations (or combinations
thereof) that are used to report the multiplicity of the NMR signal
are s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br.
(broad). Coupling constants (J) are reported in Hertz (Hz). The
4a. To determine whether the reaction first afforded 3a and
then underwent the oxidative decyanation reaction, HPLC
analysis was used to monitor the process (see Figure 1). We
found that both products 3a and 4a existed in the reaction
mixture within 30 min, and then the amount of 3a de-
creased as time progressed. In addition, we carried out
some control experiments to determine the source of the
oxygen atom in the ketone derivatives (see Supporting in-
formation). The experiments show that dioxygen is not the
only source of the oxygen atom and other oxidants, such as progress of the reactions was monitored by using high performance
liquid chromatography (HPLC) with an Aglient Eclipse XDB-C18
column.
DMSO, could also be the source of the oxygen atom in
the ketone derivatives. Dioxygen plays a leading role in the
oxidative decyanation reaction, whereas DMSO and DTBP
General Procedure for the Preparation of Compounds 3a–3s: In a
promote this oxidative procedure by increasing the yield dry flask (25 mL), tBuOLi (0.24 g, 3 mmol) was dissolved in DMF
(4 mL) at room temperature under N2. After 10 min, phenylaceto-
nitrile and polyfluorobenzene were added in one portion. The reac-
tion mixture was stirred for 0.5 h (monitored by TLC) and then
poured into water (10 mL). The resulting mixture was extracted
with EtOAc (3ϫ 10 mL). The combined organic phases were
washed with saturated aqueous NaCl, dried with anhydrous
Na2SO4, and concentrated. The crude product was purified by
flash chromatography on a silica gel column (petroleum ether/
EtOAc, 32:1 v/v) to afford the desired pure products.
and shortening the reaction time.
On the basis of these results and those that are reported
in the literature,[21] a possible reaction mechanism is pro-
posed in Scheme 2. This process relies on the sequential
SNAr substitution of polyfluorobenzenes and the in situ
oxidation of secondary nitrile 3a. Initially, phenylaceto-
nitrile 2a is converted into phenylacetonitrile carbanion I in
the presence of base. This benzonitrile anion attacks the C–
F bond of pentafluorobenzene to form nitrile compound
3a, which upon treatment with base gives nitrile carbanion
II. In the oxidation system, II is transformed into per-
oxyanion III, which continues through an intramolecular
cyclization to give four-membered peroxide IV. After losing
a cyanate group, the fluorinated diaryl ketone is obtained.
2-Phenyl-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3a): White solid;
m.p. 78–79 °C; CAS: 58432-65-8.[14] 1H NMR (400 MHz, CDCl3):
δ = 7.49–7.33 (m, 5 H), 7.11 (tt, J = 9.4, 7.4 Hz, 1 H), 5.58 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.7 (dm, J =
247.8 Hz), 143.9 (dm, J = 248.4 Hz), 132.2, 129.2, 128.6, 126.8,
116.2, 115.8 (t, J = 15.2 Hz), 106.6 (t, J = 22.4 Hz), 31.4 ppm. 19F
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NMR (376 MHz, CDCl3): δ = –136.99 to –137.18 (m, 2 F), –141.47 2-(4-Chlorophenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3h):
to –141.66 (m, 2 F) ppm. MS (ESI): m/z = 264.1 [M – H]–.
White solid; m.p. 86–88 °C. 1H NMR (400 MHz, CDCl3): δ = 7.39
(s, 4 H), 7.13 (tt, J = 9.4, 7.4 Hz, 1 H), 5.54 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 146.0 (dm, J = 248.5 Hz), 144.1
(dm, J = 248.4 Hz), 134.9, 130.8, 129.4, 128.3, 115.7, 115.4 (t, J =
15.0 Hz), 106.9 (t, J = 22.5 Hz), 31.0 ppm. 19F NMR (376 MHz,
CDCl3): δ = –136.50 to –136.68 (m, 2 F), –141.41 to –141.58 (m, 2
F) ppm. HRMS (ESI): calcd. for C14H5ClF4N [M – H]– 298.0052;
found 298.0050.
2-(2,3,5,6-Tetrafluorophenyl)-2-(p-tolyl)acetonitrile (3b): White so-
lid; m.p. 117–118 °C; CAS: 175469-43-9.[14] 1H NMR (400 MHz,
CDCl3): δ = 7.33 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.2 Hz, 2 H),
7.10 (tt, J = 9.4, 7.4 Hz, 1 H), 5.54 (s, 1 H), 2.36 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 145.9 (dm, J = 247.6 Hz), 143.9
(dm, J = 248.2 Hz), 138.7, 129.8, 129.3, 126.7, 116.4, 116.1 (t, J =
15.3 Hz), 106.5 (t, J = 22.3 Hz), 31.1, 21.0 ppm. 19F NMR
(376 MHz, CDCl3): δ = –137.05 to –137.28 (m, 2 F), –141.51 to
–141.82 (m, 2 F) ppm. MS (ESI): m/z = 278.1 [M – H]–.
2-(4-Bromophenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3i):
White solid; m.p. 102–103 °C. 1H NMR (400 MHz, CDCl3): δ =
7.54 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.19–7.08 (m,
1 H), 5.52 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.8
(dm, J = 248.2 Hz), 143.80 (dd, J = 248.5, 14.6 Hz), 132.4, 131.3,
128.5, 123.0, 115.7, 115.4 (t, J = 15.2 Hz), 106.9 (t, J = 22.5 Hz),
31.0 ppm. 19F NMR (376 MHz, CDCl3): δ = –136.46 to –136.63
(m, 2 F), –141.37 to –141.53 (m, 2 F) ppm. HRMS (ESI): calcd.
for C14H5BrF4N [M – H]– 341.9547; found 341.9543.
2-(4-Methoxyphenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3c):
White solid; m.p. 86–87 °C; CAS: 175469-37-1.[14] 1H NMR
(400 MHz, CDCl3): δ = 7.36 (d, J = 8.6 Hz, 2 H), 7.09 (tt, J = 9.4,
7.4 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2 H), 5.51 (s, 1 H), 3.81 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7, 145.8 (dm, J =
247.4 Hz), 143.7 (dd, J = 248.1, 14.6 Hz), 128.1, 124.2, 116.4, 116.2
(d, J = 15.2 Hz), 114.6, 106.4 (t, J = 22.3 Hz), 55.3, 30.8 ppm. 19F
NMR (376 MHz, CDCl3): δ = –136.97 to –137.15 (m, 2 F), –141.73 2-(4-Nitrophenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3j): Yel-
to –141.90 (m, 2 F) ppm. MS (ESI): m/z = 294.1 [M – H]–.
low solid; m.p. 96–98 °C. 1H NMR (400 MHz, CDCl3): δ = 8.28
(d, J = 8.4 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 7.23–7.14 (m, 1 H),
5.67 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.9, 146.2
(dm, J = 248.7 Hz), 143.8 (dd, J = 250.0, 15.1 Hz), 138.8, 128.1,
124.4, 115.1, 114.5 (t, J = 14.9 Hz), 107.5 (t, J = 22.3 Hz),
31.2 ppm. 19F NMR (376 MHz, CDCl3): δ = –136.13 to –136.34
(m, 2 F), –141.17 to –141.36 (m, 2 F) ppm. HRMS (ESI): calcd.
for C14H5F4N2O2 [M – H]– 309.0293; found 309.0280.
2-(2,3,5,6-Tetrafluorophenyl)-2-(o-tolyl)acetonitrile (3d): White so-
1
lid; m.p. 99–101 °C. H NMR (400 MHz, CDCl3): δ = 7.65 (dd, J
= 4.0, 1.8 Hz, 1 H), 7.31–7.25 (m, 2 H), 7.21–7.15 (m, 1 H), 7.15–
7.06 (m, 1 H), 5.58 (s, 1 H), 2.31 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 145.77 (dm, J = 247.5 Hz), 144.09 (dm, J
= 248.7 Hz), 135.3, 131.0, 129.8 128.9, 128.1, 126.7, 116.5, 114.6
(t, J = 14.9 Hz), 107.2–106.2 (m), 29.4, 19.1 ppm. 19F NMR
(376 MHz, CDCl3): δ = –136.92 to –137.13 (m, 2 F), –140.04 to
–140.24 (m, 2 F) ppm. HRMS (ESI): calcd. for C15H8F4N
[M – H]– 278.0598; found 278.0597.
2-(2-Chlorophenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3k):
White solid; m.p. 110–112 °C. 1H NMR (400 MHz, CDCl3): δ =
7.88 (dd, J = 8.0, 1.2 Hz, 1 H), 7.44–7.33 (m, 3 H), 7.13 (tt, J =
9.4, 7.4 Hz, 1 H), 5.84 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.8 (dm, J = 247.1 Hz), 143.8 (dm, J = 249.9 Hz), 132.7,
130.4, 130.0, 129.4, 127.4, 115.8, 114.0 (t, J = 14.2 Hz), 107.0 (td,
J = 22.3, 6.1 Hz), 29.9 ppm. 19F NMR (376 MHz, CDCl3): δ =
–137.20 to –137.40 (m, 2 F), –139.57 to –139.77 (m, 2 F) ppm.
HRMS (ESI): calcd. for C14H5ClF4N [M – H]– 298.0052; found
298.0050.
2-(3,4-Dimethoxyphenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile
(3e): White solid; m.p. 125–127 °C; CAS: 175469-38-2.[14] 1H NMR
(400 MHz, CDCl3): δ = 7.10 (tt, J = 9.4, 7.4 Hz, 1 H), 7.00–6.94
(m, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 5.51 (s, 1 H), 3.91 (s, 3 H),
3.88 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.2 (d, J
= 8.9 Hz), 145.8 (dm, J = 247.7 Hz), 143.6 (dd, J = 249.4, 14.7 Hz),
124.4, 119.63–119.00 (m), 116.4, 116.0 (t, J = 15.2 Hz), 111.6–110.9
(m), 109.8 (d, J = 19.9 Hz), 106.5 (q, J = 22.0 Hz), 55.8, 31.0 (d, J 2-(2,5-Dichlorophenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3l):
= 16.9 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –136.87 to White solid; m.p. 113–115 °C. 1H NMR (400 MHz, CDCl3): δ =
–137.05 (m, 2 F), –141.72 to –141.90 (m, 2 F) ppm. MS (ESI): m/z
7.88–7.85 (m, 1 H), 7.36–7.33 (m, 2 H), 7.16 (tt, J = 9.4, 7.4 Hz, 1
H), 5.79 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.9
(dm, J = 247.7 Hz), 144.3 (dm, J = 249.7 Hz), 133.5, 131.1, 130.9,
130.6, 129.9, 115.3, 113.2 (t, J = 14.6 Hz), 107.4 (td, J = 22.2,
8.6 Hz), 29.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –136.77 to
–136.95 (m, 2 F), –139.39 to –139.57 (m, 2 F) ppm. HRMS (ESI):
calcd. for C14H4Cl2F4N [M – H]– 331.9662; found 331.9663.
= 324.0 [M – H]–.
2-([1,1Ј-Biphenyl]-4-yl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3f):
White solid; m.p. 137–138 °C. 1H NMR (400 MHz, CDCl3): δ =
7.66–7.59 (m, 2 H), 7.59–7.49 (m, 4 H), 7.49–7.41 (m, 2 H), 7.41–
7.35 (m, 1 H), 7.13 (tt, J = 9.4, 7.4 Hz, 1 H), 5.62 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 145.9 (dm, J = 247.9 Hz), 143.8
(ddt, J = 249.8, 14.8, 4.3 Hz), 141.6, 139.5, 131.1, 128.7, 127.8,
2-(Pyridin-2-yl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3m): Yel-
1
127.6, 127.3, 126.8, 116.2, 115.8 (t, J = 15.2 Hz), 107.2–106.2 (m), low solid; m.p. 68–70 °C. H NMR (400 MHz, CDCl3): δ = 8.56–
31.2 ppm. 19F NMR (376 MHz, CDCl3): δ = –136.73 to –136.91
(m, 2 F), –141.32 to –141.51 (m, 2 F) ppm. HRMS (ESI): calcd.
for C20H10F4N [M – H]– 340.0755; found 340.0755.
8.53 (m, 1 H), 7.80 (td, J = 7.6, 1.8 Hz, 1 H), 7.70 (d, J = 7.9 Hz,
1 H), 7.32–7.28 (m, 1 H), 7.13 (tt, J = 9.6, 7.4 Hz, 1 H), 5.72 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.5, 149.7 (d, J =
6.4 Hz), 145.6 (dm, J = 247.7 Hz), 144.2 (dd, J = 250.1, 14.7 Hz),
137.4, 123.3, 121.2, 115.7, 114.6 (t, J = 15.4 Hz), 106.7 (td, J =
22.4, 6.5 Hz), 33.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –137.29
to –137.45 (m, 2 F), –140.95 to –141.12 (m, 2 F) ppm. HRMS
(ESI): calcd. for C13H6F4N2Na [M + Na]+ 289.0359; found
289.0354.
2-(4-Fluorophenyl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3g):
White solid; m.p. 62–64 °C. 1H NMR (400 MHz, CDCl3): δ = 7.44
(dd, J = 8.4, 5.0 Hz, 2 H), 7.18–7.06 (m, 3 H), 5.55 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 162.5 (d, J = 248.5 Hz), 145.9
(dm, J = 247.9 Hz), 143.9 (dm, J = 248.4 Hz), 128.8 (d, J = 6.6 Hz),
128.1, 116.3 (d, J = 21.8 Hz), 116.0, 115.7 (t, J = 15.3 Hz), 107.5–
106.3 (m), 30.8 ppm. 19F NMR (376 MHz, CDCl3): δ = –112.40 to
–112.53 (m, 1 F), –136.57 to –136.76 (m, 2 F), –141.55 to –141.74
(m, 2 F) ppm. HRMS (ESI): calcd. for C14H5F5N [M – H]–
282.0348; found 282.0346.
2-(Naphthalen-1-yl)-2-(2,3,5,6-tetrafluorophenyl)acetonitrile (3n):
White solid; m.p. 137–139 °C; CAS: 175469-40-6.[14] 1H NMR
(400 MHz, CDCl3): δ = 7.99–7.83 (m, 4 H), 7.61–7.49 (m, 3 H),
7.14–7.02 (m, 1 H), 6.17 (s, 1 H) ppm. 13C NMR (100 MHz,
6
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/KAP1
Date: 11-12-14 11:28:03
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Metal-Free Synthesis of Fluorinated Nitriles and Diaryl Ketones
CDCl3): δ = 145.7 (dm, J = 247.6 Hz), 144.4 (dm, J = 248.5 Hz), J = 7.8 Hz, 2 H), 7.67 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 2
133.8, 129.9, 129.7, 129.2, 127.3, 126.9, 126.1, 125.1, 121.2, 116.6,
H), 7.25–7.17 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
115.1 (t, J = 14.7 Hz), 106.8 (t, J = 22.3 Hz), 29.3 ppm. 19F NMR 185.8, 145.6 (dm, J = 248.6 Hz), 143.2 (dm, J = 248.8 Hz), 135.9,
(376 MHz, CDCl3): δ = –136.78 to –136.96 (m, 2 F), –140.02 to
134.6, 129.5, 128.8, 119.8 (t, J = 20.3 Hz), 107.5 (t, J =
22.3 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –137.12 to
–137.28 (m, 2 F), –140.90 (tdd, J = 15.1, 7.1, 2.8 Hz, 2 F) ppm.
MS (EI): m/z = 254 [M]+.
–140.20 (m, 2 F) ppm. MS (ESI): m/z = 314.1 [M – H]–.
2-Phenyl-2-(2,3,6-trifluorophenyl)acetonitrile (3o): White solid; m.p.
69–70 °C. 1H NMR (400 MHz, CDCl3): δ = 7.48–7.32 (m, 5 H),
7.17 (qd, J = 9.0, 4.8 Hz, 1 H), 6.93 (tdd, J = 9.0, 3.6, 2.2 Hz, 1
H), 5.56 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.1 (d,
J = 247.7 Hz), 148.0 (dm, J = 250.4 Hz), 147.3 (dm, J =
1244.5 Hz), 132.9, 129.0, 128.4, 126.8, 117.4 (dd, J = 19.1, 9.8 Hz),
116.7, 114.8–114.2 (m), 111.4 (d, J = 23.1 Hz), 31.2 ppm. 19F NMR
(376 MHz, CDCl3): δ = –118.15 to –118.28 (m, 1 F), –135.70 (dd,
J = 20.3, 8.6 Hz, 1 F), –140.18 to –140.36 (m, 1 F) ppm. HRMS
(ESI): calcd. for C14H7F3N [M – H]– 246.0536; found 246.0529.
(2,3,5,6-Tetrafluorophenyl)(p-tolyl)methanone (4b): White solid;
m.p. 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J =
8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.20 (tt, J = 9.4, 7.2 Hz, 1
H), 2.47 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.3,
146.1, 145.7 (dm, J = 248.7 Hz), 142.9 (dm, J = 247.9 Hz), 133.4,
129.7, 129.5, 119.90 (t, J = 20.5 Hz), 107.34 (t, J = 22.4 Hz),
21.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –137.25 to –137.42
(m, 2 F), –141.06 (tdd, J = 15.0, 7.1, 2.7 Hz, 2 F) ppm. HRMS
(EI): calcd. for C14H8OF4 [M]+ 268.0511; found 268.0520.
2-(3,5-Difluorophenyl)-2-phenylacetonitrile (3p): White solid; m.p.
69–71 °C. 1H NMR (400 MHz, CDCl3): δ = 7.48–7.27 (m, 5 H),
6.94–6.82 (m, 2 H), 6.78 (tt, J = 8.6, 2.2 Hz, 1 H), 5.11 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 163.0 (dd, J = 250.3, 12.6 Hz),
139.3 (t, J = 7.4 Hz), 134.3, 129.3, 128.6, 127.5, 118.4, 110.9 (d, J
= 26.5 Hz), 103.8 (t, J = 25.2 Hz), 42.2 ppm. 19F NMR (376 MHz,
CDCl3): δ = –107.87 to –108.00 (m, 2 F) ppm. HRMS (ESI): calcd.
for C14H8F2N [M – H]– 228.0630; found 228.0631.
(2,3,5,6-Tetrafluorophenyl)(o-tolyl)methanone (4c): White solid;
1
m.p. 65–67 °C. H NMR (400 MHz, CDCl3): δ = 7.53–7.44 (m, 2
H), 7.38–7.34 (m, 1 H), 7.30–7.25 (m, 1 H), 7.19 (tt, J = 9.4, 7.2 Hz,
1 H), 2.69 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.5,
145.9 (dm, J = 248.7 Hz), 142.9 (dm, J = 247.5 Hz), 140.6, 135.2,
133.3, 132.3, 131.9, 126.0, 121.3 (t, J = 19.9 Hz), 107.4 (td, J =
22.6, 5.4 Hz), 21.7 ppm. 19F NMR (376 MHz, CDCl3): δ = –137.37
to –137.54 (m, 2 F), –141.59 to –141.75 (m, 2 F) ppm. HRMS (EI):
calcd. for C14H8OF4 [M]+ 268.0511; found 268.0501.
2-(5-Bromo-2,3-difluorophenyl)-2-phenylacetonitrile (3q): White so-
lid; m.p. 71–72 °C. 1H NMR (400 MHz, CDCl3): δ = 7.45–7.31 (m,
7 H), 5.41 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.2
(dd, J = 254.8, 13.4 Hz), 147.0 (dd, J = 251.0, 13.7 Hz), 133.1,
129.3, 128.7, 127.2, 127.1, 126.7 (d, J = 3.0 Hz), 121.1 (dd, J = 19.7,
7.0 Hz), 117.6, 116.5 (dd, J = 7.5, 4.6 Hz), 35.9 ppm. 19F NMR
(376 MHz, CDCl3): δ = –132.83 to –132.95 (m, 1 F), –142.30 (dt,
J = 20.1, 6.1 Hz, 1 F) ppm. HRMS (ESI): calcd. for C14H7BrF2N
[M – H]– 305.9735; found 305.9725.
(3,4-Dimethoxyphenyl)(2,3,5,6-tetrafluorophenyl)methanone (4d):
White solid; m.p. 91–93 °C. 1H NMR (400 MHz, CDCl3): δ = 7.59
(d, J = 2.0 Hz, 1 H), 7.30–7.26 (m, 1 H), 7.20 (tt, J = 9.4, 7.2 Hz,
1 H), 6.89 (d, J = 8.4 Hz, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 184.0, 154.7, 149.3, 145.6 (dm,
J = 248.4 Hz), 142.9 (dm, J = 247.7 Hz), 128.8, 126.1, 125.9, 119.7
(t, J = 20.7 Hz), 110.5–109.4 (m), 107.1 (dd, J = 40.4, 22.1 Hz),
56.1, 55.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –137.27 to
–137.43 (m, 2 F), –141.06 to –141.22 (m, 2 F) ppm. HRMS (EI):
calcd. for C15H10O3F4 [M]+ 314.0566; found 314.0562.
2-(2-Fluoro-4-nitrophenyl)-2-phenylacetonitrile (3r): Yellow-brown
1
viscous oil. H NMR (400 MHz, CDCl3): δ = 8.08 (ddd, J = 8.4,
2.2, 1.0 Hz, 1 H), 7.97 (dd, J = 9.4, 2.2 Hz, 1 H), 7.68 (dd, J = 8.8,
7.2 Hz, 1 H), 7.42–7.32 (m, 5 H), 5.49 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.7 (d, J = 253.1 Hz), 148.4 (d, J =
8.6 Hz), 132.9, 130.4 (d, J = 14.3 Hz), 129.8 (d, J = 3.1 Hz), 129.3,
128.7, 127.2, 119.8 (d, J = 3.8 Hz), 117.5, 111.8 (d, J = 26.6 Hz),
36.3 (d, J = 3.1 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
–112.18 to –112.25 (m, 1 F) ppm. HRMS (ESI): calcd. for
C14H8FN2O2 [M – H]– 255.0575; found 255.0573.
(4-Fluorophenyl)(2,3,5,6-tetrafluorophenyl)methanone (4e): White
1
solid; m.p. 50–52 °C. H NMR (400 MHz, CDCl3): δ = 7.94–7.86
(m, 2 H), 7.28–7.17 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 184.2, 166.6 (d, J = 257.6 Hz), 145.4 (dm, J = 248.8 Hz), 143.0
(dm, J = 249.3 Hz), 132.3 (d, J = 9.7 Hz), 119.6–119.0 (m), 116.2
(d, J = 22.3 Hz), 107.7 (t, J = 22.8 Hz) ppm. 19F NMR (376 MHz,
CDCl3): δ = –101.75 to –101.84 (m, 1 F), –136.85 to –137.03 (m, 2
F), –140.75 to –140.92 (m, 2 F) ppm. HRMS (EI): calcd. for
C13H5OF5 [M]+ 272.0261; found 272.0268.
2-(3-Bromo-5-chlorophenyl)-2-phenylacetonitrile (3s): Colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.46 (t, J = 1.8 Hz, 1 H), 7.40–
7.29 (m, 6 H), 7.26 (td, J = 1.8, 0.6 Hz, 1 H), 5.06 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 139.1, 135.7, 134.3, 131.3, 129.4,
128.9, 128.7, 127.6, 126.6, 123.4, 118.5, 41.9 ppm. HRMS (ESI):
calcd. for C14H8BrClN [M – H]– 303.9534; found 303.9537.
(4-Chlorophenyl)(2,3,5,6-tetrafluorophenyl)methanone (4f): White
solid; m.p. 73–75 °C; CAS: 1356145-52-2.[23] 1H NMR (400 MHz,
CDCl3): δ = 7.81 (d, J = 8.5 Hz, 2 H), 7.54–7.47 (m, 2 H), 7.29–
7.19 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.6, 145.9
(dm, J = 249.4 Hz), 143.1 (dm, J = 248.9 Hz), 141.5, 134.2, 130.8,
129.3, 119.4–118.8 (m), 108.2–107.6 (m) ppm. 19F NMR
(376 MHz, CDCl3): δ = –136.85 to –137.01 (m, 2 F), –140.75 to
–140.92 (m, 2 F) ppm. MS (EI): m/z = 288 [M]+.
General Procedure for the Preparation of Compounds 4a–4l: Sodium
methylate (0.162 g, 3 mmol), 97% DTBP (0.903 g, 6 mmol), and
DMSO (4 mL) were added to a dry flask (25 mL) at room tempera-
ture under O2. After 10 min, phenylacetonitrile and polyfluoroben-
zene were added in one portion. The reaction mixture was stirred
for 1 h (monitored by TLC) and then poured into water (10 mL).
The resulting mixture was extracted with EtOAc (3ϫ 10 mL). The
combined organic phases were washed with saturated aqueous
NaCl, dried with anhydrous Na2SO4, and concentrated. The crude
product was purified by flash chromatography on a silica gel col-
umn (petroleum ether/EtOAc, 32:1 v/v) to afford the desired pure
product.
Naphthalen-1-yl(2,3,5,6-tetrafluorophenyl)methanone (4g): White
1
solid; m.p. 106–108 °C. H NMR (400 MHz, CDCl3): δ = 9.14 (d,
J = 8.4 Hz, 1 H), 8.13 (d, J = 8.2 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1
H), 7.79–7.71 (m, 2 H), 7.66–7.61 (m, 1 H), 7.53–7.48 (m, 1 H),
7.23 (tt, J = 9.4, 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 187.2, 145.7 (d, J = 255.2 Hz), 143.1 (d, J = 264.3 Hz), 135.6,
133.8, 133.3, 132.4, 130.5, 129.2, 128.5, 126.9, 125.5, 124.2, 121.5
Phenyl(2,3,5,6-tetrafluorophenyl)methanone (4a): Colorless oil; (t, J = 19.6 Hz), 107.4 (t, J = 22.4 Hz) ppm. 19F NMR (376 MHz,
CAS: 1225194-09-1.[22] 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, CDCl3): δ = –137.24 to –137.41 (m, 2 F), –141.26 to –141.46 (m, 2
Eur. J. Org. Chem. 0000, 0–0
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/KAP1
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Pages: 10
C.-M. Yu et al.
FULL PAPER
F) ppm. HRMS (EI): calcd. for C17H8OF4 [M]+ 304.0511; found
304.0511.
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4.4 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.93 (t, J = 7.6 Hz, 1 H),
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107.6 (t, J = 22.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
–138.29 to –138.45 (m, 2 F), –140.48 to –140.63 (m, 2 F) ppm.
HRMS (EI): calcd. for C12H5NOF4 [M]+ 255.0307; found
255.0314.
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65; b) S. S. Laev, V. U. Evtefeev, V. D. Shteingarts, J. Fluorine
Chem. 2001, 110, 43; c) A. O. Miller, V. I. Krasnov, D. Peters,
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H. M. Refat, A. A. Faddo, E. Biehl, J. Fluorine Chem. 1996,
76, 99.
Phenyl(2,3,6-trifluorophenyl)methanone (4i): Colorless oil; CAS:
239135-56-9. 1H NMR (400 MHz, CDCl3): δ = 7.90–7.85 (m, 2 H),
7.68–7.62 (m, 1 H), 7.55–7.47 (m, 2 H), 7.34–7.24 (m, 1 H), 7.00–
6.92 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.2, 154.4
(d, J = 246.1 Hz), 147.1 (ddd, J = 251.5, 15.0, 8.0 Hz), 146.7 (dm,
J = 245.3 Hz), 136.0, 134.4, 129.4, 128.7, 128.6, 119.0–117.9 (m),
112.0–110.9 (m) ppm. 19F NMR (376 MHz, CDCl3): δ = –117.21
to –117.37 (m, 1 F), –135.34 (dd, J = 21.6, 8.2 Hz, 1 F), –140.97
to –141.22 (m, 1 F) ppm. MS (EI): m/z = 236 [M]+.
[5]
(3,5-Difluorophenyl)(phenyl)methanone (4j): White solid; m.p. 51–
53 °C; CAS: 179113-89-4.[24] 1H NMR (400 MHz, CDCl3): δ =
7.82–7.77 (m, 2 H), 7.66–7.60 (m, 1 H), 7.55–7.48 (m, 2 H), 7.35–
7.28 (m, 2 H), 7.04 (tt, J = 8.4, 2.4 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 193.5, 162.5 (dd, J = 250.6, 11.8 Hz), 140.4
(t, J = 7.1 Hz), 136.2, 132.9, 129.8, 128.4, 112.8 (d, J = 25.9 Hz),
107.6 (t, J = 25.3 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
–108.45 to –108.56 (m, 2 F) ppm. MS (EI): m/z = 218 [M]+.
[6]
[7]
[8]
(5-Bromo-2,3-difluorophenyl)(phenyl)methanone (4k): Colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.79 (m, 2 H), 7.65 (tt, J =
7.2, 1.6 Hz, 1 H), 7.56–7.48 (m, 3 H), 7.46–7.41 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 189.9, 150.1 (dd, J = 255.5,
13.9 Hz), 147.2 (dd, J = 254.6, 13.5 Hz), 135.9, 134.2–133.6 (m),
129.9 (d, J = 13.4 Hz), 129.6 (d, J = 7.1 Hz), 128.5 (d, J = 11.7 Hz),
127.7 (d, J = 17.6 Hz), 123.0 (dd, J = 19.8, 14.3 Hz), 116.0 (dd, J
= 6.4, 4.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –132.99
(ddd, J = 21.4, 9.1, 1.9 Hz, 1 F), –137.91 (dt, J = 21.4, 5.7 Hz, 1
F) ppm. HRMS (EI): calcd. for C13H7OF2Br [M]+ 295.9648; found
295.9655.
[9]
[10]
(3-Bromo-5-chlorophenyl)(phenyl)methanone (4l): White solid; m.p.
62–64 °C. 1H NMR (400 MHz, CDCl3): δ = 7.80–7.76 (m, 2 H),
7.76–7.74 (m, 1 H), 7.72–7.70 (m, 1 H), 7.68–7.66 (m, 1 H), 7.65–
7.59 (m, 1 H), 7.54–7.47 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 192.9, 140.1, 136.0, 135.1, 134.6, 133.0, 130.8, 129.8,
128.4, 122.7 ppm. HRMS [atmospheric pressure chemical ioniza-
tion (APCI)]: calcd. for C13H9BrClO [M + H]+ 294.9520; found
294.9522.
[11]
HPLC Conditions for Monitoring Reaction Process: Column: Agli-
ent Eclipse XDB-C18 (4.6ϫ150 mmϫ5 μm); CH3CN/H2O, 55:45;
flow rate: 1.0 mLmin–1; T = 30 °C; 257 nm; tR = 8.26 min (for 3a)
and tR = 9.12 min (for 4a).
[12]
[13]
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (grant number 21176222) and the Public
Projects of Zhejiang Province (grant number 2014C31133).
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Metal-Free Synthesis of Fluorinated Nitriles and Diaryl Ketones
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Received: October 15, 2014
Published Online: ᭿
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Date: 11-12-14 11:28:03
Pages: 10
C.-M. Yu et al.
FULL PAPER
C–F Bond Functionalization
G.-H. Yang, M. Liu, N. Li, R. Wu,
X. Chen, L.-L. Pan, S. Gao, X. Huang,
C. Wang, C.-M. Yu* ....................... 1–10
Transition-Metal-Free Synthesis of Fluori-
nated Nitriles and Diaryl Ketones Through
a Selective C–F Bond Functionalization
Under Mild Conditions
A highly efficient and simple procedure was
developed to synthesize substituted fluori-
nated nitriles and diaryl ketones under mild
conditions from polyfluorobenzenes and
phenylacetonitriles. This coupling process
proceeded through a selective C–F bond
functionalization without the use of a tran-
sition-metal catalyst and afforded the prod-
ucts in moderate to excellent yields.
Keywords: Synthetic methods / Oxidation /
C–F bond functionalization / Fluorine /
Nitriles / Ketones
10
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