Copper-catalyzed nucleophilic trifluoromethylation of propargylic halides

Article abstract of DOI:10.1039/c3cc44434a

Reactions of propargylic halides with trifluoromethyltrimethylsilane in the presence of a catalytic amount of copper(i) thiophene-2-carboxylate (CuTC) have been found to give the corresponding trifluoromethylated products in good to high yields with a hig

Full text of DOI:10.1039/c3cc44434a

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Copper-catalyzed nucleophilic trifluoromethylation of
propargylic halides†
Cite this: Chem. Commun., 2013,
49, 7809
Yoshihiro Miyake, Shin-ichi Ota, Masashi Shibata, Kazunari Nakajima and
Yoshiaki Nishibayashi*
Received 13th June 2013,
Accepted 3rd July 2013
DOI: 10.1039/c3cc44434a
www.rsc.org/chemcomm
Reactions of propargylic halides with trifluoromethyltrimethyl-
silane in the presence of a catalytic amount of copper(I) thiophene-
2-carboxylate (CuTC) have been found to give the corresponding
trifluoromethylated products in good to high yields with a high
selectivity.
Trifluoromethylation of organic compounds is one of the most
important methodologies in organic synthesis1 because a wide
range of organic molecules bearing a trifluoromethyl (CF3)
group have attracted considerable attention as highly promis-
ing skeletons in the field of pharmaceuticals and materials.2 In
this context, the development of methods for the formation of
C(sp2)–1 and C(sp3)–CF33–6 bonds has been expected and exten-
sively studied for the last several years. Recently, we have also
Scheme 1 (a) Copper-catalyzed nucleophilic trifluoromethylation of allylic
halides. (b) Copper-catalyzed nucleophilic trifluoromethylation of propargylic
halides (this work).
succeeded in the development of copper-catalyzed nucleophilic As an extension of our study, we have now envisaged copper(I)-
trifluoromethylation of allylic halides, where the introduction catalyzed nucleophilic trifluoromethylation of propargylic halides
of a CF3 group occurred at the a-position of the carbon–halogen with trifluoromethyltrimethylsilane (Ruppert–Prakash reagent;
bond with complete regioselectivity (Scheme 1a).7,8
CF3SiMe3).13 In fact, we have succeeded in the introduction of a
Transition metal-catalyzed propargylic substitution reac- CF3 group at the propargylic- (R2 = H) and allenylic- (R2 a H)
tions of propargylic alcohol derivatives and halides are expected positions from reactions of primary and secondary propargylic
to be simple methods for constructing carbon–carbon and halides, respectively (Scheme 1b). Preliminary results are described
carbon–heteroatom bonds at the propargylic position.9 We herein.
have continuously studied ruthenium-10 and copper-catalyzed11
Treatment of 3-phenylpropargyl chloride (1a) with 3.0 equiv.
propargylic substitution reactions of propargylic alcohols and of CF3SiMe3 in the presence of a catalytic amount of copper(I)
derivatives with a variety of nucleophiles to give the corre- thiophene-2-carboxylate (CuTC) (5 mol%) and a stoichiometric
sponding propargylic substituted products in good to high amount of potassium fluoride (KF) (3.0 equiv.) in tetrahydro-
yields with complete selectivity. In sharp contrast, successful furan (THF) at 60 1C for 20 h gave 1,1,1-trifluoro-4-phenylbut-
examples of nucleophilic trifluoromethylation of propargylic 3-yne (2a) in 72% yield with complete regioselectivity, where no
halides using transition metal complexes are quite limited.8b,12 formation of 1,1,1-trifluoro-2-phenylbuta-2,3-diene (3a) was
In these reactions, stoichiometric amounts of copper metal observed at all (Table 1, entry 1). The choice of leaving groups
or copper salts are required to obtain the trifluoromethylated is one of the most important factors to promote this trifluoro-
products in good yields.12b,c To the best of our knowledge, there is methylation effectively. In fact, when 3-phenylpropargyl bromide
no report on catalytic trifluoromethylation of propargylic halides. was used in place of 1a, a mixture of 2a and 3a was obtained in
35% and 16% yields, respectively (Table 1, entry 2). Other
substrates such as 3-phenylpropargyl iodide, mesylate (OMs =
OSO2Me), and alcohol were ineffective (Table 1, entries 3–5).
Use of a smaller amount of CF3SiMe3 afforded 2a effectively.
Institute of Engineering Innovation, School of Engineering, The University of Tokyo,
Yayoi, Bunkyo-ku, Tokyo, 113-8656, Japan. E-mail: ynishiba@sogo.t.u-tokyo.ac.jp;
Fax: +81 3-5841-1175; Tel: +81 3-5841-1175
In fact, the reaction of 1a with 1.5 equiv. of CF3SiMe3 took
place smoothly to give 2a in 78% yield (Table 1, entry 6).
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc44434a
c
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Table 1 Copper-catalyzed trifluoromethylation of 3-phenylpropargyl substrates
with trifluoromethyltrimethylsilanea
CF3SiMe3 and KF
(equiv.)
Yield of 2ab
(%)
Yield of 3ab
(%)
Entry
X
1
2
3
4
5
6
Cl (1a)
Br
I
OMs
OH
Cl (1a)
3.0
3.0
3.0
3.0
3.0
1.5
72
35
48
47
0
16
8
2
0
7
78 (73)c
1
a
All reactions of the phenylpropargyl substrate (0.50 mmol) with
CF3SiMe3 were carried out in the presence of CuTC (0.025 mmol) and
Scheme 2 Copper-mediated and catalyzed propargylic trifluoromethylation of 1l.
KF in THF (3 mL) at 60 1C for 20 h. Determined by 1H NMR. Isolated
b
c
yield.
(1j and 1k) were also applicable to this reaction system, giving
the corresponding propargylic trifluoromethylated products
Unfortunately, when reactions of 3-phenylpropargyl acetate and (2j–2k) in high yields (Table 2, entries 9 and 10).
´
Recently, Szabo’s group has reported the copper-mediated
trifluoroacetate were carried out, only a small amount of 2a was
obtained in both cases (4% and 3%, respectively). Separately, trifluoromethylation of propargylic halides.12c In their reaction
we confirmed that no formation of 2a was observed in the system, the reaction of 1l with a stoichiometric amount of
absence of CuTC or KF.
Cu(CF3)(PPh3)3 at room temperature gave the corresponding
Propargylic trifluoromethylation of a variety of 3-arylpro- trifluoromethylated allene 3l in good yield, while the formation
pargyl chlorides in the presence of a catalytic amount of CuTC of the propargylic trifluoromethylated product 2l was observed
´
proceeded smoothly to give the corresponding propargylic when the reaction was carried out at 50 1C (Scheme 2; Szabo’s
trifluoromethylated products 2 in good to high yields. Typical system).12c In sharp contrast to the result obtained by Szabo’s
´
results are shown in Table 2. The introduction of a substituent group, only 2l was obtained from the reaction of 1l in the
such as methyl, chloro, or methoxy at the para-position in the presence of 5 mol% of CuTC even at room temperature
benzene ring of 1a did not affect the yields of 2 much (Table 2, (Scheme 2; our system). These results indicate that our catalytic
´
entries 1–3). The reaction of p-trifluoromethylphenylpropargyl reaction proceeds via a different pathway from that of Szabo’s
chloride (1e) for 48 h gave 2e in 75% yield although a larger system.
amount (10 mol%) of CuTC was required (Table 2, entry 4).
Next, nucleophilic trifluoromethylation of a variety of
Reactions of 3-tolylpropargyl chlorides (1f and 1g) and secondary propargylic chlorides in the presence of a catalytic
3-naphthylpropargyl chlorides (1h and 1i) also took place to amount of CuTC was investigated. Typical results are shown in
give the corresponding propargylic trifluoromethylated pro- Table 3. When we carried out the reaction of 2-chloro-4-
ducts (2f–2i) in good to high yields (Table 2, entries 5–8). phenylbut-3-yne (1m) with 1.5 equiv. of CF3SiMe3, the corre-
Propargylic chlorides bearing no conjugated aromatic rings sponding trifluoromethylated allene (3m) was obtained in 89%
isolated yield (Table 3, entry 1). The introduction of a substi-
tuent such as methyl and chloro groups at the para-position in
the benzene ring of 1m did not affect the yields of 3 much
Table 2 Copper-catalyzed trifluoromethylation of primary propargylic chlorides
(1) with trifluoromethyltrimethylsilanea
Table 3 Copper-catalyzed trifluoromethylation of secondary propargylic chlor-
ides (1) with trifluoromethyltrimethylsilanea
Entry
Propargylic chloride (1)
Yield of 2b (%)
1
2
R1 = p-MeC6H4 (1b)
R1 = p-ClC6H4 (1c)
R1 = p-MeOC6H4 (1d)
R1 = p-CF3C6H4 (1e)
R1 = o-MeC6H4 (1f)
R1 = m-MeC6H4 (1g)
R1 = 1-naphthyl (1h)
R1 = 2-naphthyl (1i)
R1 = PhCH2 (1j)
83 (2b)
71 (2c)
79 (2d)
75 (2e)
84 (2f)
62 (2g)
86 (2h)
72 (2i)
80 (2j)
93 (2k)
3
4c,d
5
Entry
Propargylic chloride (1)
Yield of 3b (%)
6
7
8
9
1
2
R1 = Ph (1m)
89 (3m)
79 (3n)
81 (3o)
77 (3p)
71 (3q)
R1 = p-MeC6H4 (1n)
R1 = p-ClC6H4 (1o)
R1 = p-MeOC6H4 (1p)
R1 = PhCH2CH2 (1q)
3
4c
5
10
R1 = PhCH2CH2 (1k)
a
a
All reactions of 1 (0.50 mmol) with CF3SiMe3 (0.75 mmol) were carried
All reactions of 1 (0.50 mmol) with CF3SiMe3 (0.75 mmol) were carried
out in the presence of 5 mol% of CuTC (0.025 mmol) in THF (3 mL) at out in the presence of 5 mol% of CuTC (0.025 mmol) in THF (3 mL) at
b
c
d
b
c
60 1C for 20 h. Isolated yield. 10 mol% of CuTC was used. For 48 h. 60 1C for 20 h. Isolated yield. At 40 1C for 48 h.
c
7810 Chem. Commun., 2013, 49, 7809--7811
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D. Cahard, Angew. Chem., Int. Ed., 2012, 51, 5048; (e) A. Studer,
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3 For reviews on trifluoromethylation of carbonyl compounds, see:
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Scheme 3 Copper-catalyzed trifluoromethylation of (R)-1m with trifluoromethyl-
trimethylsilane.
4 For examples of enantioselective a-trifluoromethylation of alde-
hydes, see: (a) D. A. Nagib, M. E. Scott and D. W. C. MacMillan,
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6 For recent examples, see: (a) P. G. Janson, I. Ghoneim,
(Table 3, entries 2 and 3). The reactions of 2-chloro-4-
(4-methoxyphenyl)but-3-yne (1p) at lower temperature (40 1C)
gave the good result (Table 3, entry 4). Secondary propargylic
chloride bearing no conjugated aromatic ring (1q) was also
applicable to this reaction system, giving the corresponding
trifluoromethylated allene (3q) in 71% yield (Table 3, entry 5).
Only a small amount (8%) of the corresponding trifluoromethyl-
ated allene was obtained from the reaction of 1-chloro-1-phenyl-
prop-2-yne under the same reaction conditions.
In order to obtain information on the reaction pathway, we
investigated the reaction of an optically active secondary pro-
pargylic chloride. Treatment of (R)-1m (94% ee) with 1.5 equiv.
of CF3SiMe3 under the same reaction conditions afforded 3m in
83% yield with a complete loss of optical purity (Scheme 3).
This result indicates that our catalytic reaction proceeds not via
an anti-SN20 pathway14 but via other pathways involving cationic
propargyl/allenyl–copper complexes as reactive intermediates.7,9c
In summary, we have found the copper-catalyzed nucleophilic
trifluoromethylation of propargylic chlorides with trifluoro-
methyltrimethylsilane. In our system, reactions of primary pro-
pargylic chlorides (1) afford the corresponding propargylic
trifluoromethylated products (2), while the trifluoromethylated
allenes (3) can be obtained from reactions of secondary pro-
pargylic chlorides. This is the first successful example of catalytic
trifluoromethylation of propargylic halides. We believe that the
method described here provides an efficient strategy for the
synthesis of CF3-containing compounds at the propargylic and
allenylic positions, which are useful building blocks in pharma-
ceuticals.12c,15 Further work is currently in progress to apply this
strategy to the enantioselective reactions and to clarify the
precise reaction mechanism.
´
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´
(b) J.-P. Bouillon, C. Maliverney, R. Merenyi and H. G. Viehe, J. Chem.
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(b) M. Ikeda, Y. Miyake and Y. Nishibayashi, Angew. Chem., Int. Ed.,
2010, 49, 7289; (c) M. Ikeda, Y. Miyake and Y. Nishibayashi,
Chem.–Eur. J., 2012, 18, 3321 and references therein.
11 For examples of copper-catalyzed reactions, see: (a) G. Hattori,
H. Matsuzawa, Y. Miyake and Y. Nishibayashi, Angew. Chem., Int.
Ed., 2008, 47, 3781; (b) G. Hattori, K. Sakata, H. Matsuzawa,
Y. Tanabe, Y. Miyake and Y. Nishibayashi, J. Am. Chem. Soc., 2010,
132, 10592; (c) A. Yoshida, G. Hattori, Y. Miyake and Y. Nishibayashi,
Org. Lett., 2011, 13, 2460 and references therein.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Advanced Molecular Transfor-
mations by Organocatalyst’’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan and the Fund-
ing Program for Next Generation World-Leading Researchers
(GR025). We thank Dr Shingo Ito and Prof. Dr Kyoko Nozaki at
The University of Tokyo for measurement of 19F NMR.
12 (a) D. J. Burton, G. A. Hartgraves and J. Hsu, Tetrahedron Lett., 1990,
31, 3699; (b) H. Kawai, T. Furukawa, Y. Nomura, E. Tokunaga and
´
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(b) R. P. Singh and J. M. Shreeve, Tetrahedron, 2000, 56, 7613.
14 For recent examples of copper-catalyzed reactions, see: (a) C. Zhong,
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Notes and references
1 For recent reviews on trifluoromethylation, see: (a) J.-A. Ma and
D. Cahard, Chem. Rev., 2008, 108, PR1; (b) O. A. Tomashenko and
V. V. Grushin, Chem. Rev., 2011, 111, 4475; (c) T. Furuya, A. S. Kamlet 15 Y. Matsuya, D. Ihara, M. Fukuchi, D. Honma, K. Itoh, A. Tabuchi,
and T. Ritter, Nature, 2011, 473, 470; (d) T. Besset, C. Schneider and
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c
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Chem. Commun., 2013, 49, 7809--7811 7811