Copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids using (trifluoromethyl)trimethylsilane

Article abstract of DOI:10.1021/jo202566h

Trifluoromethylated acetylenes and arenes are widely applicable in the synthesis of pharmaceuticals and agrochemicals. In 2010, our group has reported the copper-mediated oxidative trifluomethylation of terminal alkynes and aryl boronic acids. This method allows a wide range of functional group tolerant trifluoromethylated acetylenes and arenes to be easily prepared. After the preliminary mechanistic studies of the oxidative trifluoromethylation of terminal alkyne, an efficient copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids has been developed. The catalytic protocol is successfully achieved by adding both the substrate and a portion of CF₃TMS slowly using a syringe pump to the reaction mixture.

Full text of DOI:10.1021/jo202566h

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Copper-Catalyzed Oxidative Trifluoromethylation of Terminal
Alkynes and Aryl Boronic Acids Using
(Trifluoromethyl)trimethylsilane
Xueliang Jiang,† Lingling Chu,† and Feng-Ling Qing*,†,‡
†Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai 200032, China
‡College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620,
China
S
* Supporting Information
ABSTRACT: Trifluoromethylated acetylenes and arenes are
widely applicable in the synthesis of pharmaceuticals and
agrochemicals. In 2010, our group has reported the copper-
mediated oxidative trifluomethylation of terminal alkynes and
aryl boronic acids. This method allows a wide range of
functional group tolerant trifluoromethylated acetylenes and
arenes to be easily prepared. After the preliminary mechanistic
studies of the oxidative trifluoromethylation of terminal alkyne,
an efficient copper-catalyzed oxidative trifluoromethylation of terminal alkynes and aryl boronic acids has been developed. The
catalytic protocol is successfully achieved by adding both the substrate and a portion of CF3TMS slowly using a syringe pump to
the reaction mixture.
Scheme 1. Copper-Based Trifluoromethylation Protocols
INTRODUCTION
■
The introduction of trifluoromethyl (CF3) groups into organic
molecules can substantially alter their chemical and metabolic
stability, lipophilicity, and binding selectivity because of the
strongly electron withdrawing nature and large hydrophobic
domain of trifluoromethyl groups.1 Notably, many biologically
active compounds, including the antidepressant Prozac and the
herbicide Fusilade, contain the CF3 groups as the essential
motif.1 As a result, much attention has been paid to the
development of new synthetic methods for the introduction of
the CF3 groups into diverse organic compounds.1,2 In the past
few years, promising progress has been made in the area of
transition-metal-mediated trifluoromethylation.3−9 Among
these transition-metal-based protocols for the introduction of
the CF3 group to organic molecules, the most utilized protocol
should be copper-mediated trifluoromethylation of aromatic
substrates.6−9 Pioneering investigations by Burton identified
the CuCF3 complex by NMR.6a Further developments by
Vicic,6f Hartwig,6i and Grushin6j documented the high reactivity
of well-defined CuCF3 complex toward aryl halides. Moreover,
the groups of Chen,7a Amii,7b and Gooβen7c reported copper-
catalyzed trifluoromethylation of aryl iodides with in situ
generated CuCF3 species. While substantial progress has been
made, current copper-mediated trifluoromethylation methods
have been limited almost entirely to the cross-coupling reaction
between the nucleophilic trifluoromethylating reagents and the
electrophiles such as aryl iodides and bromides (Scheme 1a).6,7
The development of an alternative coupling manner involving
suitable coupling partners for these trifluoromethylations is
certainly desirable.
In 2010, our group reported the first copper-mediated
oxidative trifluoromethylation of terminal alkynes with
Received: December 17, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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(trifluoromethyl)trimethylsilane (CF3TMS) (Scheme 1b).8a
This is the first report of oxidative cross-coupling between
the nucleophilic substrate and the nucleophilic trifluoromethy-
lating reagent in the presence of copper, providing a new
viewpoint to construction of C−CF3 bonds. Soon afterward,
we8b and Buchwald8c independently applied this oxidative
trifluoromethylation protocol to aryl boronic acids, allowing
access to a variety of trifluoromethylated arenes (Scheme 1c).
However, stoichiometric amounts of copper reagents are
required to complete the oxidative trifluoromethylation
reactions of alkynes and boronic acids. Recently, copper-
catalyzed electrophilic trifluoromethylation of aryl boronic
acids9a,b and terminal olefins9c−e have been successively
reported, while the use of expensive electrophilic trifluorome-
thylating reagents is a significant limitation (Scheme 1d,e).
Clearly, the development of alternative copper-catalyzed
trifluoromethylations with more convenient and more inex-
pensive trifluoromethylating reagent remains an attractive goal.
As described previously, we have reported the copper-
mediated oxidative trifluoromethylation of terminal alkynes8a
and aryl boronic acids8b using CF3TMS as a convenient
trifluoromethylating agent (Scheme 1b,c). Although various
trifluoromethylated alkynes and aromatics were obtained in
high yields using this oxidative trifluoromethylation protocol, a
significant limitation of the protocol is that a stoichiometric
amount of copper was needed to complete the transformation.
Herein, we describe that the oxidative trifluoromethylations of
terminal alkynes and aryl boronic acids is successfully achieved
under the catalysis of copper.
oxidative trifluoromethylation process.8a To investigate the
intermediates of the present oxidative trifluoromethylation, the
complex [(phen)CuCF3] I was prepared according to the
literature6i and then used for oxidative trifluoromethyaltion of
terminal alkyne. The reaction of phenylacetylene (1a) with
complex [(phen)CuCF3] I under air gave the desired product
2a in 57% yield (Scheme 2). This result showed that copper-
mediated oxidative trfluoromethylation proceeded through
CuCF3 species.
Scheme 2. Mechanistic Study
On the basis of these experimental results, we proposed that
the oxidative trifluoromethylation of terminal alkynes proceeds
by the formation of trifluoromethyl anion, which undergoes
generation of CuCF3 B. The subsequent transmetalation with
phenylacetylene to afford Cu(alkynyl)(trifluoromethyl) com-
plex C. Oxidation of complex C to a Cu(III) intermediate10 and
followed by reductive elimination delivered the desired product
and regenerated copper catalyst (Scheme 3).
Scheme 3. Proposed Mechanism of Oxidative
Trifluoromethylation of Terminal Alkyne
RESULTS AND DISCUSSION
■
In the hope of developing a catalytic process, we initially turned
our attention to the preliminary mechanistic studies to acquire
a deeper understanding of copper-mediated oxidative trifluor-
omethylation. In the case of copper-mediated oxidative
trifluoromethylation of 1-tert-butyl-4-ethynylbenzene, we no-
ticed that the 19F NMR spectrum of the reaction mixture clearly
shows two CuCF3 species: [(phen)CuCF3] (resonates at δ =
−23.6 ppm) and [(phen)2Cu][Cu(CF3)2] (resonates at δ =
−34.9 ppm), which is similar to the literature data for the
CuCF3 intermediate (Figure 1).6a,f,i,j This phenomenon
In view of the inherent instability of the trifluoromethyl
anion,2a the decomposition rate of the trifluoromethyl anion
under the oxidative reaction condition would be much higher
than the reductive elimination rate for regeneration copper
catalyst. As a result, there was no sufficient amount of the
regenerated copper A to combine with trifluoromethyl anion
before its decomposition, directly impeding the formation of
the key CuCF3 intermediate B. This is why a stoichiometric
amount of copper is needed for the oxidative trifluoromethy-
lation of terminal alkynes (Scheme 1b). Actually, by simply
reducing the loading of copper to 20 mol % under the
optimized reaction conditions of oxidative trifluoromethylation
of terminal alkyne,8a the yield of the desired product 2a was
dramatically decreased to 13% yield (Scheme 4a). To obviate
the problem of quick decomposition of trifluoromethyl anion
under the oxidative reaction conditions, we reasoned that
CF3TMS should be added slowly to the reaction mixture other
than in one portion. On the other hand, phenylacetylene (1a)
should be also added slowly to a pregenerated CuCF3 to inhibit
the homocoupling of phenylacetylene.8a Combined with the
above considerations, the following addition method was
Figure 1. 19F NMR of the reaction mixture of the oxidative
trifluoromethylation of 1-tert-butyl-4-ethynylbenzene (PhCF3 was
added to reaction mixture as an internal standard).
indicated that CuCF3 was generated in situ in the reaction
and might be the key intermediate for the Cu-mediated
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Scheme 4. Catalytic Process of Oxidative Trifluoromethylation
conducted: a portion of CF3TMS was added to the mixture of
CuI, phenanthroline, and KF in DMF to ensure the
pregeneration of CuCF3, and the rest of CF3TMS was added
slowly to the reaction mixture to avoid the quick decom-
position of CF3TMS, accompanying with the slow addition of
phenylacetylene to inhibit the homocoupling side product.
Indeed, when phenylacetylene (1.0 equiv) and CF3TMS (3.0
equiv) were added slowly by using a syringe pump over a
period of 4 h to the mixture of CF3TMS (2.0 equiv), KF (5.0
equiv), CuI (20 mol %), and phenanthroline (20 mol %), the
copper-catalyzed oxidative trifluoromethylation of terminal
alkyne proceeded smoothly to give the desired product 2a in
79% yield (Scheme 4b).
yield. In contrast, the reaction of 1e under the stoichiometric
copper reaction afforded compound 1e in only 47% yield,
together with some unidentified side products.
The modified methodology was further found to be
successfully applied to copper catalyze the oxidative trifluor-
omethylation of a range of aryl boronic acids with CF3TMS.
The yields of the desired trifluoromethylated aromatics were
comparable to those of the reaction of these boronic acids
under the stoichiometric copper reaction conditions (Table
Table 2. Catalytic Oxidative Trifluoromethylation of Aryl
a
Boronic Acids
With the copper-catalyzed oxidative trifluoromethylation
reaction conditions, the substrate scope was then investigated,
and the results are shown in Table 1. Similar to the previous
Table 1. Catalytic Oxidative Trifluoromethylation of
a
Terminal Alkynes
a
On a 0.2 mmol scale. Yield in parentheses is the yield under the
b
stoichiometric reaction described in ref 8b. Reaction temperature is
70 °C. Yield in parentheses reported in ref 8c.
c
2).8b Both electron-rich and electron-poor aryl boronic acids
were suitable substrates. Functional groups such as carbonyl,
nitro, and bromo could be compatible (4b, 4d, 4e). Different
from the stoichiometric copper reaction reported by us8b and
Buchwald,8c heteroaryl boronic acids under the catalytic copper
condition did not proceed well at room temperature or 45 °C.
To our delight, the corresponding trifluoromethylated hetero-
arenes could be obtained in moderate yields when the reaction
temperature was elevated to 70 °C (4f, 4g).
Notably, copper-catalyzed oxidative trifluoromethylation of
compound 12, prepared from commercially available 3-
chlorocinnamic acid 5 by multisteps, proceeded smoothly
under the optimized reaction conditions, affording the desired
a
Reaction was conducted in 0.2 mmol of terminal alkynes. Yield in
parentheses is the yield under the stoichiometric reaction described in
ref 8a. Reaction was conducted on a 0.4 mmol scale.
b
examples of oxidative trifluoromethylation of terminal alkynes
using stoichiometric amount of copper,8a the catalytic reaction
could be carried out with a series of electron-rich and electron-
poor aryl alkynes, as well as terminal alkyne containing a
pyridine skeleton. Notably, the copper-catalyzed oxidative
trifluoromethylation of 1e containing a nitro group on the
aromatic ring gave the trifluoromethylated product 2e in 74%
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Scheme 5. Synthesis of the Precursor of Cinacalcet
mixture was kept for another 2 h at 100 °C. At the conclusion of the
reaction, the mixture was allowed to cool to room temperature, and
water was added to the mixture at 0 °C. The resulting mixture was
extracted by ethyl ether, and the combined organic phase was washed
with a large amount of water threee times and with brine once and
then dried with sodium sulfate. The solvent was removed by rotary
evaporation in ice bath and purified by column chromatography on
silica gel with pentane to give the product.
product 13 in 56% yield (Scheme 5). Compound 13 is the
important precursor for the synthesis of the calcimimetic agent,
Cinacalcet.11
CONCLUSION
■
In summary, the preliminary mechanistic studies on the copper-
mediated oxidative trifluoromethylation of terminal alkynes had
been successfully used to design the copper-catalyzed oxidative
trifluoromethylation of aryl and heteroaryl terminal alkynes
protocol. An efficient catalytic oxidative trifluoromethylation
process was developed by adding both terminal alkynes and a
portion of CF3TMS slowly using a syringe pump to the
reaction mixture. The catalytic trifluoromethylation protocol
could also be applied to the oxidative trifluoromethylation of
aryl boronic acids.
1-Phenoxy-4-(3,3,3-trifluoroprop-1-ynyl)benzene (2b): 1H
NMR (300 MHz, CDCl3) δ ppm 7.50 (d, J = 8.7 Hz, 2H), 7.39 (t,
J = 7.8 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.96
(d, J = 8.7 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ ppm −49.3 (s,
3F).
Ethyl 4-(3,3,3-trifluoroprop-1-ynyl)benzoate (2c): 1H NMR
(300 MHz, CDCl3) δ ppm 8.07 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.1
Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 6H); 19F NMR
(282 MHz, CDCl3) δ ppm −49.9 (s, 3F).
1-Chloro-3-(3,3,3-trifluoroprop-1-ynyl)benzene (2d): 1H
NMR (300 MHz, CDCl3) δ ppm 7.51 (s, 1H), 7.25−7.42 (m, 3H);
19F NMR (282 MHz, CDCl3) δ ppm −49.9 (s, 3F).
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR (TMS as the internal
standard) and 19F NMR spectra (CFCl3 as the outside standard and
low field is positive) were recorded on a 300 or 400 MHz
spectrometer. 13C NMR was recorded on 400 MHz spectrometer.
Chemical shifts (δ) are reported in ppm, and coupling constants (J)
are in Hertz (Hz). The following abbreviations were used to explain
the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad. Substrates 1d, 1f, 1g, and 4a−g and compound
5 were purchased from commercial sources and used as received.
Substrates 1b,12 1c,13 and 1e14 were prepared according to literature
procedures. Compounds 2b,8a 2c,8a 2d,8a 2e,8a 2f,8a 2g,8a 4a,8b 4b,8b
4c,8b 4d,8b 4e,8b 4f,8b and 4g8c are all known compounds.
1
1-Nitro-3-(3,3,3-trifluoroprop-1-ynyl)benzene (2e): H NMR
(300 MHz, CDCl3) δ ppm 8.43 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.89
(d, J = 7.5 Hz, 1H), 7.64 (t, J = 8.1 Hz, 2H); 19F NMR (282 MHz,
CDCl3) δ ppm −50.2 (s, 3F).
2-Methoxy-6-(3,3,3-trifluoroprop-1-ynyl)naphthalene (2f):
1H NMR (300 MHz, CDCl3) δ ppm 8.01 (s, 1H), 7.70 (d, J = 9.3
Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 9.1 Hz, 1H), 7.11 (s,
1H), 3.92 (s, 3H); 19F NMR (282 MHz, CDCl3) δ ppm −49.0 (s, 3F).
2-(3,3,3-Trifluoroprop-1-ynyl)pyridine (2g): 1H NMR (300
MHz, CDCl3) δ ppm 8.68 (d, J = 3.9 Hz, 1H), 7.77 (t, J = 7.8 Hz,
1H), 7.60 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 6.0 Hz, 1H); 19F NMR (282
MHz, CDCl3) δ ppm −51.0 (s, 3F).
General Procedure for the Copper-Catalyzed Oxidative
Trifluoromethylation of Boronic Acids with Me3SiCF3. In a
glovebox, [Cu(OTf)]2·C6H6 (0.02 mmol), phen (0.04 mmol), K3PO4
(0.6 mmol), and KF (1.0 mmol) were added to a reaction tube that
was equipped with a stirring bar. The tube was capped with a septum
and taken out. Ag2CO3 (0.2 mmol) and DMF (2.0 mL) were added.
Next, Me3SiCF3 (2.0 equiv) was added in one portion, and then the
resulting mixture was heated to 45 °C (70 °C for substrates 4f and
4g). Both the solution of boronic acid (0.2 mmol) in 1.0 mL of DMF
and the solution of Me3SiCF3 (2.0 equiv) in 1.0 mL of DMF were
added to the tube together over 2 h by using a syringe pump under N2
General Procedure for the Copper-Catalyzed Oxidative
Trifluoromethylation of Terminal Alkynes with Me3SiCF3. In a
glovebox, CuI (0.04 mmol), phen (0.04 mmol), and KF(1.0 mmol)
were added to a reaction tube that was equipped with a stirring bar.
The tube was capped with a septum and taken out. The vial was
evacuated and then refilled with air for three times. DMF (1.0 mL)
was added, and the mixture was stirred for 15 min at room
temperature. Next, Me3SiCF3 (2.0 equiv) was added in one portion,
and then the resulting mixture was heated to 100 °C. A solution of
terminal alkyne (0.2 mmol) and Me3SiCF3 (2.0 equiv) in 1.0 mL DMF
was added to the tube over 4 h by using a syringe pump under air
atmosphere (1 atom). After addition of the solution, the reaction
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atmosphere (1 atom). After addition of the solution, the reaction
mixture was kept for another 2 h at 45 °C (70 °C for substrates 4f and
4g). At the conclusion of the reaction, the mixture was allowed to cool
to room temperature, and water was added to the mixture at 0 °C. The
resulting mixture was extracted by ethyl ether, and the combined
organic phase was washed with a large amount of water three times
and with brine once and then dried over magnesium sulfate. The
solvent was removed by rotary evaporation and purified by column
chromatography on silica gel with pentane to give the product.
2-Methoxy-6-(trifluoromethyl)naphthalene (4a): 1H NMR
(300 MHz, CDCl3) δ ppm 8.05 (s, 1H), 7.80 (d, J = 12.0 Hz, 2H),
7.59 (d, J = 11.6 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 3.94
(s, 3H); 19F NMR (282 MHz, CDCl3) δ ppm −61.8 (s, 3F).
1-(4-(Trifluoromethyl)phenyl)ethanone (4b): 1H NMR (300
MHz, CDCl3) δ ppm 8.08 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz,
2H), 2.67 (s, 3H); 19F NMR (282 MHz, CDCl3) δ ppm −62.8 (s, 3F).
2-(Trifluoromethyl)biphenyl (4c): 1H NMR (300 MHz, CDCl3)
δ ppm 7.74 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.49 (d, J =
7.5 Hz, 1H), 7.45−7.40 (m, 3H), 7.36−7.35 (m, 3H); 19F NMR (282
MHz, CDCl3) δ ppm −56.6 (s, 3F).
reaction. Products were exacted with ethyl ether. The combined
organic layers were washed with water and brine, dried over sodium
sulfate, and concentrated to give a crude mixture, which was purified
by column chromatography on silica gel with a mixture of petroleum
ether and ethyl acetate (10:1) as the eluent to give the compound 8
(2.321 g, 76% yield) as a colorless liquid: 1H NMR (300 MHz,
CDCl3) δ ppm 7.79 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H),
6.96−7.17 (m, 4H), 4.02 (t, J = 6.0 Hz, 2H), 2.63(t, J = 7.4 Hz, 2H),
2.46 (s, 3H), 1.92−1.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
ppm 144.9, 142.5, 134.2, 133.0, 130.0, 129.8, 128.5, 127.9, 126.7,
126.4, 69.3, 31.1, 30.2, 21.7; IR (thin film) ν 3066, 2959, 1360, 1176,
1080 cm−1; MS (ESI): m/z 324.8 (M+ + H), 346.3 (M+ + Na); HRMS
calcd for C16H17ClO3SNa (M+ + Na) 347.0479, found 347.0485.
(R)-tert-Butyl 1-(Naphthalen-1-yl)ethylcarbamate (9). Com-
pound 9 was prepared following the procedure in the literature:15 1H
NMR (400 MHz, CDCl3) δ ppm 8.13 (d, J = 8.0 Hz, 1H), 7.84 (d, J =
7.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.40−7.54 (m, 4H), 5.61 (s,1H),
4.93 (d, J = 6.8 Hz, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.43 (s, 9H).
(R)-tert-Butyl-3-(3-chlorophenyl)propyl(1-(naphthalen-1-yl)-
ethyl)carbamate (10). To a suspension of NaH (0.180 g, 2.5 mmol)
in DMF (8 mL) was added compound 9 (0.813 g, 3.00 mmol) at
room temperature. After stirring 15 min, compound 8 (0.990 g, 3.10
mmol) was added dropwise. The reaction was stirred for 24 h at 35
°C, quenched with water (8 mL) and extracted with ethyl ether (3 ×
15 mL). The ether layers were washed with water and brine, dried over
sodium sulfate, and concentrated to give a crude mixture, which was
purified by column chromatography on silica gel with a mixture of
petroleum ether and ethyl acetate (12:1) as the eluent to give the
compound 10 (1.101 g, 79% yield) as a colorless liquid: [α]D 26 =
+56.4 (c 3.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (d, J
= 7.6 Hz, 1H), 7.85 (d, 8.0 Hz, 1H), 7.79 (t, J = 4.8 Hz, 1H), 7.46−
7.53 (m, 2H), 7.39 (d, J = 5.2 Hz, 2H), 6.99−7.06 (m, 2H), 6.63 (s,
1H), 6.55 (d, J = 6.8, 1H), 6.16−6.19 (m, 1H), 2.72−2.96 (m, 2H),
2.07 (t, J = 7.2 Hz, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.52(s, 9H), 1.21−
1.26 (m, 1H), 0.71−0.74 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
ppm 155.4, 143.8, 136.7, 134.0, 133.8, 132.4, 129.4, 128.8, 128.6,
128.3, 126.5, 126.4, 125.9, 125.8, 125.1, 124.3, 79.7, 49.4, 42.0, 33.0,
30.7, 28.6, 17.1; IR (thin film) ν 3048, 2974, 1682, 1407, 1154 cm−1;
MS (ESI) m/z 446.3 (M+ + Na); HRMS calcd for C26H30ClNO2Na
(M+ + Na) 446.1857, found 446.1860.
1
1-Nitro-3-(trifluoromethyl)benzene (4d): H NMR (300 MHz,
CDCl3) δ ppm 8.52 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.1
Hz, 1H), 7.74 (t, J = 8.1 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ
ppm −62.7 (s, 3F).
1-Bromo-4-(trifluoromethyl)benzene (4e): 1H NMR (300
MHz, CDCl3) δ ppm 7.65 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz,
2H); 19F NMR (282 MHz, CDCl3) δ ppm −62.1 (s, 3F).
2-(Trifluoromethyl)benzo[b]thiophene (4f): 1H NMR (300
MHz, CDCl3) δ ppm 7.85−7.89 (m, 2H), 7.69 (s, 1H), 7.41−7.49 (m,
2H); 19F NMR (282 MHz, CDCl3) δ ppm −56.0 (s, 3F).
3-(trifluoromethyl)quinoline (4g): 1H NMR (300 MHz, CDCl3)
δ ppm 9.11 (s, 1H), 8.47 (s, 1H), 8.21 (d, J = 8.4 Hz, 2H), 7.94 (d, J =
8.1 Hz, 1H), 7.88 (t, J = 8.4 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H); 19F
NMR (282 MHz, CDCl3) δ ppm −61.5 (s, 3F).
3-(3-Chlorophenyl)propanoic Acid (6). A suspension of 3-
chlorocinnamic acid (1.092 g, 6.00 mmol) and Pt(IV) oxide (0.027 g,
0.12 mmol) was stirred in ethyl acetate (50 mL) under H2 (1 atm) at
room temperature for 48 h. The catalyst was removed by filtration, and
solvent from the filtrate was removed by rotary evaporation. The
residue was dried further in vacuo to give the compound 6 (1.030 g,
1
93% yield) as a white solid: H NMR (300 MHz, CDCl3) δ ppm
(R)-tert-Butyl-1-(naphthalen-1-yl)ethyl (3-(3-(4,4,5,5-Tetra-
methyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate
(11). In a glovebox, bis(pinacolato)diboron (0.852 g, 3.40 mmol),
Pd2(dba)3 (0.078 g, 0.09 mmol), PCy3 (0.057 g, 0.2 mmol), and KOAc
(0.430 g, 4.25 mmol) were added to a reaction tube that was equipped
with a stirring bar. The tube was capped with a septum and taken out.
Compound 10 (0.710 g, 1.70 mmol) and 1,4-dioxane (8 mL) were
added via syringe, and the resulting mixture was stirred for 12 h at 95
°C. After removal of solvent, water (10 mL) was added, and the
mixture was extracted with dichloromethane (3 × 10 mL). The
combined organic layers were washed with water and brine, dried over
sodium sulfate, and concentrated to give a crude mixture, which was
purified by column chromatography on silica gel with a mixture of
petroleum ether and ethyl acetate (9:1) as the eluent to give the
7.08−7.26 (m, 4H), 2.94 (t, J = 7.6 Hz, 2H), 2.68(t, J = 7.6 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ ppm 179.3, 142.2, 134.4, 129.9, 128.6,
126.7, 126.6, 35.3, 30.2; IR (neat) ν 3035, 2922, 1709 cm−1; MS (ESI)
m/z 182.9 (M− − H), 367.0 (2M− − H); HRMS calcd for C9H8ClO2
(M− − H) 183.0218, found 183.0223.
3-(3-Chlorophenyl)propan-1-ol (7). To a suspension of LiAlH4
(0.912, 24.00 mmol) in THF (20 mL) at 0 °C was added compound 6
(1.900 g, 10.30 mmol) slowly. The resulting mixture was allowed to
warm to room temperature and stirred for 45 min, and it was then
refluxed until the reaction was complete. The reaction mixture was
cooled to 0 °C, and H2O (0.9 mL), 15% NaOH solution (0.9 mL),
and H2O (7 mL) were added slowly to quench the reaction. The
resulting solid was removed by filtration through Celite. The obtained
filtrate was washed with water three times and with brine once and
then dried with sodium sulfate. The solvent was removed by rotary
evaporation and purified by column chromatography on silica gel with
a mixture of petroleum ether and ethyl acetate (3:1) as the eluent to
compound 11 (0.700 g, 80% yield) as a colorless liquid: [α]26
=
D
+38.2 (c 6.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (d, J
= 6.9 Hz, 1H), 7.84(d, J = 7.6, 1H), 7.78(t, J = 4.8 Hz, 1H), 7.38−
7.58(m, 5H), 7.32 (s, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 7.2 Hz,
1H), 6.16−6.18 (m, 1H), 2.74−2.87 (m, 2H), 2.16 (t, J = 7.5 Hz, 2H),
1.58 (d, J = 6.4 Hz, 3H), 1.50(s, 9H), 1.26−1.34 (m, 13H), 0.86−0.88
(m, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 155.5, 141.0, 136.9,
134.7, 133.8, 132.4, 132.2, 131.2, 128.7, 128.6, 127.7, 126.5, 125.9,
125.1, 124.3, 83.8, 79.6, 49.5, 42.3, 33.3, 31.0, 28.7, 25.0, 25.0, 17.4; IR
(thin film) ν 2976, 1741, 1682, 1364, 1151 cm−1; MS (ESI): m/z 537.8
(M+ + Na); HRMS calcd for C32H42BNO4Na (M+ + Na) 537.3135,
found 537.3147.
1
give the compound 7 (1.622 g, 93% yield) as a colorless liquid: H
NMR (300 MHz, CDCl3) δ ppm 7.06−7.23 (m, 5H), 3.66 (t, J = 6.3
Hz, 2H), 2.68(t, J = 7.6 Hz, 2H), 1.82−1.89 (m, 2H); 13C NMR (100
MHz, CDCl3) δ ppm 144.0, 134.1, 129.7, 128.6, 126.7, 126.0, 61.8,
33.9, 31.7; IR (thin film) ν 3345, 3066, 2939, 1080 cm−1; MS (EI) m/z
170 (M+); HRMS Calculated for C9H11ClO (M+) 170.0499, Found:
170.0498.
3-(3-Chlorophenyl)propyl 4-methylbenzenesulfonate (8).
To a solution of compound 7 (1.603 g, 9.40 mmol), DMAP (0.132
g, 1.10 mmol), and Et3N (1.8 mL, 13.20 mmol) in CH2Cl2 (10 mL)
was added TsCl (2.324 g, 12.2 mmol) at room temperature. After the
mixture was stirred overnight at 40 °C, water was added to quench the
(R)-3-(3-(tert-Butoxycarbonyl(1-(naphthalen-1-yl)ethyl)-
amino)propyl)phenylboronic Acid (12). To a solution of
compound 11 (0.381 g, 0.74 mmol) in acetone (8 mL) and water
(4 mmol) were added NH4OAc (0.231 g, 3.00 mmol) and NaIO4
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The Journal of Organic Chemistry
Featured Article
(0.642 g, 3.00 mmol), and the mixture was stirred overnight at room
temperature. The solution was concentrated, water was added to the
residue, and the resulting mixture was extracted with ethyl acetate (3 ×
8 mL). The combined organic extracts were washed with water and
brine, dried over sodium sulfate, and concentrated to give a crude
mixture, which was purified by column chromatography on silica gel
with a mixture of petroleum ether and ethyl acetate (3:1) as the eluent
to give the compound 12 (0.291 g, 91% yield) as a white, foam-like
solid: [α]26D = +48.0 (c 3.04, CHCl3); 1H NMR (300 MHz, CDCl3) δ
ppm 8.17 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.75−7.82 (m,
2H), 7.25−7.54 (m, 6H), 6.93 (s, 1H), 6.16−6.20 (m, 1H), 2.81−2.98
(m, 2H), 2.29 (t, J = 7.2 Hz, 2H), 1.52−1.61 (m, 13H), 0.91−0.94 (m,
1H); 13C NMR (100 MHz, CDCl3) δ ppm 155.5, 141.2, 136.8, 135.5,
133.7, 133.2, 132.6, 132.4, 130.1, 128.7, 128.6, 127.9, 127.7, 126.5,
125.9, 125.0, 124.3, 79.6, 49.5, 42.4, 33.4, 31.2, 28.7, 17.3; IR (thin
film) ν 3441, 3054, 2977, 1681, 1366, 1349, 1154 cm−1; MS (ESI) m/z
455.9 (M + Na)+; HRMS calcd for C26H32BNO4Na (M+ + Na)
455.2353, found 455.2364.
473, 470. (e) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.; Roy, S.
Tetrahedron 2011, 67, 2161.
(3) For selected examples of Pd-mediated trifluoromethylation, see:
(a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 4632.
(b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644.
(c) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010,
132, 2878. (d) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am.
Chem. Soc. 2010, 132, 14682. (e) Wang, X.; Truesdale, L.; Yu, J.-Q. J.
Am. Chem. Soc. 2010, 132, 3648. (f) Cho, E. J.; Senecal, T. D.; Kinzel,
T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679.
(g) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S. J. Am. Chem. Soc.
2011, 133, 7577. (h) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.Eur.
J. 2011, 17, 6039. (i) Loy, R. N.; Sanford, M. S. Org. Lett. 2011, 13,
2548. (j) Cho, E. J.; Buchwald, S. L. Org. Lett. 2011, 13, 6552.
(4) Ni-mediated trifluoromethylation: Dubinina, G. G.; Brennessel,
W. W.; Miller, J. L.; Vicic, D. A. Organometallics 2008, 27, 3933.
(5) Ag-mediated trfluoromethylation: Ye, Y.; Lee, S. H.; Sanford, M.
S. Org. Lett. 2011, 13, 5464.
(6) For selected examples of Cu-mediated nucleophilic trifluor-
omethylations of aryl halides, see: (a) Wiemers, D. M.; Burton, D. J. J.
Am. Chem. Soc. 1986, 108, 832. (b) Urata, H.; Fuchikami, T.
Tetrahedron Lett. 1991, 32, 91. (c) Chen, Q.-Y.; Duan, J.-X. J. Chem.
Soc., Chem. Commun. 1993, 1389. (d) Yang, Z.-Y.; Burton, D. J. J.
Fluorine Chem. 2000, 102, 89. (e) Cottet, F.; Schlosser, M. Eur. J. Org.
Chem. 2004, 3793. (f) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J.
Am. Chem. Soc. 2008, 130, 8600. (g) McReynolds, K. A.; Lewis, R. S.;
Ackerman, L. K. G.; Dubinina, G. G.; Brennessel, W. W.; Vicic, D. A. J.
Fluorine Chem. 2010, 131, 1108. (h) Zhang, C.-P.; Wang, Z.-L.; Chen,
Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Angew. Chem., Int. Ed. 2011,
50, 1896. (i) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J.
F. Angew. Chem., Int. Ed. 2011, 50, 3793. (j) Tomashenko, O. A.;
Escudero-Adan, E. C.; Belmonte, M. M.; Grushin, V. V. Angew. Chem.,
Int. Ed. 2011, 50, 7655. (k) Kawai, H.; Furukawa, T.; Nomura, Y.;
Tokunaga, E.; Shibata, N. Org. Lett. 2011, 13, 3596. (l) Zanardi, A.;
Novikov, M. A.; Martin, E.; Benet-Buchholz, J.; Grushin, V. V. J. Am.
Chem. Soc. 2011, 133, 20901.
( R ) - t e r t - B u t y l 1 - ( n a p h t h a l en - 1 - y l ) e t h y l ( 3 - ( 3 -
(trifluoromethyl)phenyl)propyl)carbamate (13): [α]26 = +42.9
D
(c 2.58, CHCl3); 1H NMR (300 MHz, CDCl3) δ ppm 8.17 (d, J = 6.9
Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.20−7.55
(m, 6H), 6.82−6.90 (m, 2H), 6.12−6.20 (m, 1H), 2.74−3.00 (m, 2H),
2.14 (t, J = 7.5 Hz, 2H), 1.60 (d, J = 6.9 Hz, 3H), 1.50(s, 9H), 1.23−
1.25 (m, 1H), 0.71−0.73 (m, 1H); 19F NMR (282 MHz, CDCl3) δ
ppm −62.2 (s, 3F); 13C NMR (100 MHz, CDCl3) δ ppm 155.4, 142.7,
136.8, 133.8, 132.5,131.6, 130.6 (q, J = 31.4 Hz), 128.8, 128.7, 128.6,
126.1, 126.0, 125.7, 125.1, 124.9 (q, J = 3.6 Hz), 124.3 (q, J = 270.5
Hz), 124.3, 122.6, 79.8, 49.6, 42.1, 33.2, 30.9, 28.7, 17.2; IR (thin film)
ν 3051, 2975, 1683, 1408, 1329, 1160, 1124 cm−1; MS (ESI) m/z
479.8 (M+ + Na); HRMS calcd for C27H30F3NO2Na (M+ + Na)
480.2121, found 480.2130.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 19F NMR spectra for the compounds 2b−g and 4a−g.
1
Copies of H and 13C NMR spectra for all new compounds.
(7) For examples of Cu-catalyzed nucleophilic trifluoromethylations
of aryl halides, see: (a) Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Chem.
Commun. 1989, 705. (b) Oishi, M.; Kondo, H.; Amii, H. Chem.
These material are available free of charge via the Internet at
http://pubs.acs.org.
Commun. 2009, 1909. (c) Knauber, T.; Arikan, F.; Roschenthaler, G.-
̈
V.; Gooßen, L. J. Chem.Eur. J. 2011, 17, 2689. (d) Kondo, H.; Oishi,
M.; Fujikawa, K.; Amii, H. Adv. Synth. Catal. 2011, 383, 1247. (e) Li,
Y.; Chen, T.; Wang, H.; Zhang, R.; Jin, K.; Wang, X.; Duan, C. Synlett
2011, 1713. (f) Wang, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang, W.; Feng,
X.; Huang, K. W. Organometallics 2011, 30, 3229.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: flq@mail.sioc.ac.cn.
(8) For Cu-mediated (catalyzed) oxidative trifluoromethylation, see:
(a) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262. (b) Chu,
L.; Qing, F.-L. Org. Lett. 2010, 12, 5060. (c) Senecal, T. D.; Parsons, A.
T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174. (d) Chu, L.; Qing, F.-
L. J. Am. Chem. Soc. 2012, 134, 1298. (e) Litvinas, N. D.; Fier, P. S.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 536.
(9) For Cu-catalyzed eletrophilic trifluoromethylation, see: (a) Liu,
T.; Shen, Q. Org. Lett. 2011, 13, 2342. (b) Xu, J.; Luo, D.-F.; Xiao, B.;
Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem. Commun. 2011, 47, 4300.
(c) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50,
9120. (d) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.;
Gong, T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300. (e) Wang, X.;
Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011,
133, 16410. (f) Liu, T.; Shao, X.; Wu, Y.; Shen, Q. Angew. Chem., Int.
Ed. 2012, 51, 540.
(10) (a) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahia, J.; Parella,
T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P.
Angew. Chem., Int. Ed. 2002, 41, 2991. (b) Huffman, L. M.; Stahl, S. S.
J. Am. Chem. Soc. 2008, 130, 9196. (c) King, A. E.; Brunold, T. C.;
Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044. (d) King, A. E.;
Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am.
Chem. Soc. 2010, 132, 12068. (e) Ribas, X.; Calle, C.; Poater, A.;
ACKNOWLEDGMENTS
■
The National Natural Science Foundation of China (21072028,
20832008) and the National Basic Research Program of China
(2012CB21600) are greatly acknowledged for funding this
work.
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