A practical method for metal-free radical trifluoromethylation of styrenes with NaSO2CF3

Article abstract of DOI:10.1055/s-0033-1341057

A mild and practical protocol for the metal-free trifluoromethylation of styrenes using NaSO₂CF₃ (Langlois reagent) and TBHP was developed. The approach provides efficient access to α-trifluoromethylated ketones and alcohols in moderate to good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341057

LETTER
▌1307
lAettePr ractical Method for Metal-Free Radical Trifluoromethylation of Styrenes
with NaSO2CF3
Metal-Free Radical Trifluoromethylation of Styrenes
Hai-Qing Luo,* Zhi-Peng Zhang, Wen Dong, Xu-Zhong Luo*
Department of Chemistry & Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi, 341000, P. R. of China
Fax +86(797)8393670; E-mail: luohaiq@sina.com; E-mail: luoxuzhong@hotmail.com
Received: 18.01.2014; Accepted after revision: 02.03.2014
was developed for the preparation of α-trifluoromethyl
Abstract: A mild and practical protocol for the metal-free trifluo-
ketones from propiolic acids.11 However, most of the de-
romethylation of styrenes using NaSO2CF3 (Langlois reagent) and
veloped methods suffer from the need to use metal cata-
lysts and/or expensive trifluoromethylating reagents.
TBHP was developed. The approach provides efficient access to
α-trifluoromethylated ketones and alcohols in moderate to good
yields.
In this paper, a mild and practical protocol is described for
the metal-free trifluoromethylation of styrenes by using
NaSO2CF3 (Langlois’ reagent) and tert-butyl hydroperox-
ide (TBHP). The approach enables efficient access α-tri-
fluoromethylated ketones and/or alcohols.12 To the best of
our knowledge, only a few examples of the trifluorometh-
ylation of styrenes have been published so far (Scheme
1).13 Since the Langlois reagent was first developed in the
1980s as a convenient and inexpensive source of trifluo-
romethyl radicals, several reports have shown its synthetic
usefulness for the construction of C–CF3 bonds.14–16
Key words: metal-free, trifluoromethylation, ketones, alcohols,
Langlois reagent, styrenes
Organofluorine compounds bearing a CF3 group are im-
portant materials in pharmaceuticals, agrochemicals, and
material science.1 This is because the introduction of flu-
orine atoms into organic molecules often significantly al-
ters the biological activity, metabolism, solubility,
hydrophobicity or bulk properties of such organofluorine
compounds.2
Our initial investigation focused on the metal-free reac-
tion of styrene (1a) with NaSO2CF3, benzoquinone (BQ),
and TBHP at 80 °C in different solvents. The desired tri-
fluoromethylated products 2a and 3a (Table 1) were
formed in 54% yield by using the mixed solvent MeCN–
H2O (Table 1, entry 6). Other solvent systems such as
CH2Cl2–H2O, DMF–H2O, acetone–H2O, MeOH–H2O, or
MeCN–CH2Cl2–H2O (Table 1, entries 1–5) afforded the
product either in lower yield or not at all. It was found that
the use of a mixture of MeCN–H2O (4:1 v/v) resulted in
During the past several years, a series of methods have
been reported that allow transition-metal-mediated/cata-
lyzed or photoredox-catalyzed construction of C–CF3
bonds.3–8 In this context, the synthesis of α-trifluorometh-
yl ketones has commonly been achieved by the radical
and electrophilic CF3 addition to enolates and silyl enol
ethers.9 In 2012, Grushin and co-workers developed a nu-
cleophilic trifluoromethylation of α-halogenated ketones
by using fluoroform-derived CuCF3.10 Very recently, a
copper-mediated decarboxylative trifluoromethylation
previous work
O
HOCH2SO2Na
H2O (2 equiv)
CF3
1)
2)
+
R
R
+
S
Zhang et al. 2011
OTf–
CF3
CF3
photochemical
oxidation
H
R1
R1
R3
CF3SO2Na
R3
+
Nicewicz et al. 2013
R2
R2
this work
R
OH
O
BQ (1.0 equiv)
TBHP
CF3
CF3
+
CF3SO2Na
+
R
R
Scheme 1 Trifluoromethylation of styrenes; previous work by Zhang et al.13a and Nicewicz et al.,13b and current work
SYNLETT 2014, 25, 1307–1311
Advanced online publication: 27.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341057; Art ID: ST-2014-W0053-L
© Georg Thieme Verlag Stuttgart · New York

1308
H.-Q. Luo et al.
LETTER
an increased yield of 2a (37%) and 3a (21%) (Table 1, en- sired products in only 34 and 54% combined yields, re-
tries 6–9). The addition of oxidant was very important to spectively (Table 1, entries 16 and 17). The reaction
increase the yields of the trifluoromethylated products. temperature was also changed to 60 or 80 °C, however,
Without oxidant, only 21% combined yield of the desired neither the yields nor the ratios of the products changed
products were obtained (Table 1, entry 10). By using other significantly (Table 1, entries 18 and 19). In an attempt to
quinoid oxidants such as 2,3-dichloro-5,6-dicyano-1,4- make the trifluoromethylation more efficient, the amounts
benzoquinone (DDQ), 1,4-naphthoquinone, tetrachloro- of NaSO2CF3 and TBHP were reduced, however, under
1,4-benzoquinone, or methyl-p-benzoquinone, lower these conditions the product was obtained in lower yield
yields were obtained. When CuSO4 was used as the oxi- (41%; Table 1, entry 20). It is notable that none of the de-
dant (Table 1, entry 15), only trace quantities of the de- sired product was obtained when this reaction was carried
sired products were detected by 19F NMR analysis. out under an N2 atmosphere (Table 1, entry 21).
Therefore, BQ was established as the best choice for this
With these results in hand, we then investigated the sub-
trifluoromethylation of styrenes (Table 1, entries 11–14).
strate scope of this metal-free trifluoromethylation with
The addition of 0.5 or 2.0 equivalents BQ afforded the de-
Table 1 Optimization of the Trifluoromethylation of Styrene 1aa
t-BuOOH
(8.0 equiv)
oxidant
O
OH
CF3
CF3
+
CF3SO2Na
(6.0 equiv)
+
under O2
solvent, 16 h
1a
2a
3a
(1.0 equiv)
Entry
Oxidant (equiv)
Solvent (v/v)
Temp (°C)
Yield (2a + 3a) (%)b
1
2
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
none
CH2Cl2–H2O (2.5:1)
DMF–H2O (2.5:1)
acetone–H2O (2.5:1)
MeOH–H2O (2.5:1)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
trace
0
3
29 (20 + 9)
15 (4 + 11)
53 (31 + 22)
54 (30 + 24)
52 (8 + 44)
55 (36 + 19)
58 (37 + 21)
21 (10 + 11)
trace
4
5
MeCN–CH2Cl2–H2O (2.5:0.5:1)
MeCN–H2O (2.5:1)
MeCN–H2O (1:1)
MeCN–H2O (7:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
MeCN–H2O (4:1)
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20c
21d
DDQ (1.0)
1,4-naphthoquinone (1.0)
tetrachloro-1,4-benzoquinone (1.0)
methyl-p-benzoquinone
CuSO4 (1.0)
11 (7 + 4)
27 (16 + 11)
49 (36 + 13)
trace
BQ (0.5)
34 (21 + 13)
54 (35 + 19)
47 (31 + 16)
53 (26 + 27)
41 (28 + 13)
0
BQ (2.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
BQ (1.0)
a Reaction conditions: styrene 1a (0.3 mmol), NaSO2CF3 (1.8 mmol), TBHP (70% aqueous), solvent (4 mL), sealed tube under 1 atm O2.
b Yield was determined by 19F NMR spectroscopic analysis using benzotrifluoride as internal standard.
c Reactions were performed with styrene 1a (0.3 mmol), NaSO2CF3 (3.0 equiv), TBHP (5.0 equiv).
d Reaction performed under a nitrogen atmosphere.
Synlett 2014, 25, 1307–1311
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metal-Free Radical Trifluoromethylation of Styrenes
1309
NaSO2CF3, TBHP, and a range of styrenes. As shown in tion was also tested with other alkenes such as indene
Table 2, styrenes with either electron-withdrawing or (Table 2, entry 14), an internal olefin (Table 2, entry 15),
electron-donating groups on the phenyl ring could be and an aliphatic olefin (Table 2, entry 16), but they were
transformed into the corresponding oxidative-trifluoro- not suitable substrates for this reaction.
methylation products in moderate to good yields (Table 2,
To obtain the single trifluoromethylated product ketone or
entries 1–12), except in the case of 2,4,6-trimethylstyrene
alcohol, after the metal-free radical trifluoromethylation,
(Table 2, entry 13), which was deactivated due to its high
either an oxidative or a reductive reaction was conducted
steric bulk. The position of the substituent had some influ-
by applying two-step successive reactions. To our delight,
both the trifluoromethylated ketone and alcohol could be
independently obtained in moderate yields by these meth-
ods (Scheme 2).
ence on the reaction. On replacement of ortho-chlorosty-
rene
with
the
para-chloro
analogue,
the
trifluoromethylated products in the latter case were ob-
tained in higher yields (Table 2, entries 4 vs. 5). The reac-
O
DMP
(0.2 mmol)
CF3
BQ (1.0 equiv)
CF3SO2Na (6.0 equiv)
TBHP (8.0 equiv)
CH2Cl2, r.t., 3 h
50% yield
MeCN–H2O
OH
(4:1)
NaBH4
0.3 mmol
CF3
(0.3 mmol)
CH2Cl2–MeOH
r.t., 1 h
55% yield
Scheme 2 Synthesis of α-trifluoromethyl ketone or alcohol
Table 2 Substrate Scope of Metal-Free Trifluoromethylation of Styrenesa
t-BuOOH (8.0 equiv)
O
OH
BQ(1.0 equiv)
CF3
CF3
CF3SO2Na
(6.0 equiv)
R
+
+
R
R
MeCN–H2O (4:1)
80 °C, 16 h
1
2
3
(1.0 equiv)
Entry
Styrene
Products 2 + 3
2a + 3a
Yield (%)b
Ratio 2/3
1
57
63:37
2
3
2b + 3b
2c + 3c
59
53
31:69
61:39
MeO
Me
Cl
4
2d + 3d
57
44:56
5
6
7
8
2e + 3e
2f + 3f
2g + 3g
2h + 3h
67
58
58
45
55:45
61:39
60:40
65:35
Cl
Br
F
F3C
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1307–1311

1310
H.-Q. Luo et al.
LETTER
Table 2 Substrate Scope of Metal-Free Trifluoromethylation of Styrenesa (continued)
t-BuOOH (8.0 equiv)
O
OH
BQ(1.0 equiv)
CF3
CF3
CF3SO2Na
(6.0 equiv)
R
+
+
R
R
MeCN–H2O (4:1)
80 °C, 16 h
1
2
3
(1.0 equiv)
Entry
Styrene
Products 2 + 3
2i + 3i
Yield (%)b
58
Ratio 2/3
9
62:38
O2N
NC
10
11
12
2j + 3j
2k + 3k
2l + 3l
70
56
53
54:46
56:44
66:34
Ph
Me
13
14
2m + 3m
2n + 3n
18c
0
31:69c
–
Me
Me
O
15
16
OMe
2o + 3o
2p + 3p
0
0
–
–
a Reaction conditions: styrene 1a (0.3 mmol), NaSO2CF3 (1.8 mmol), TBHP (70% aqueous), MeCN–H2O (4:1; 4 mL), sealed tube under 1 atm
O2 atmosphere.
b Isolated combined yield.
c Yields and ratio of 2m and 3m were determined by 19F NMR spectroscopic analysis using benzotrifluoride as internal standard.
A plausible mechanism is proposed as shown in Scheme
CF3SO2Na
+
CF3
+
CF3
3. From the control reaction (Table 1, entry 20), it is clear
that O2 is necessary to form intermediate I, however, the
role of BQ in this reaction is not clear. A detailed study of
the mechanism of this reaction is in progress.
TBHP
O2
1a
In conclusion, we have demonstrated a mild, metal-free
trifluoromethylation reaction of various styrenes with the
stable solid NaSO2CF3.17 Based on these results, a conve-
nient method for the synthesis of α-trifluoromethylated
ketones and alcohols has been developed.
O
CF3
OO
CF3
2a
+
OH
Acknowledgment
I
CF3
The authors are grateful for financial support by NSF of Jiangxi
Provincial Education Department (GJJ12570, KJLD13081), we
also thank the research fund of the China Scholarship Council.
3a
Scheme 3 Proposed mechanism
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Synlett 2014, 25, 1307–1311
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metal-Free Radical Trifluoromethylation of Styrenes
1311
A.; Martin, E.; Benet-Buchholz, J.; Grushin, V. V. J. Am.
Chem. Soc. 2011, 133, 20901.
(11) He, Z.; Zhang, R.; Hu, M.; Li, L.; Ni, C.; Hu, J. Chem. Sci.
2013, 4, 3478.
(12) While this manuscript was in preparation, a silver-catalyzed
oxidative trifluoromethylation of unactivated olefins was
reported, see: Deb, A.; Manna, S.; Modak, A.; Patra, T.;
Maity, S.; Maiti, D. Angew. Chem. Int. Ed. 2013, 52, 9747.
(13) (a) Zhang, C. P.; Wang, Z. L.; Chen, Q. Y.; Zhang, C. T.; Gu,
Y. C.; Xiao, J. C. Chem. Commun. 2011, 47, 6632.
(b) Wilger, D. J.; Gesmundo, N. J.; Nicewicz, D. A. Chem.
Sci. 2013, 4, 3160.
(14) (a) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron
Lett. 1991, 32, 7525. (b) Langlois, B. R.; Laurent, E.;
Roidot, N. Tetrahedron Lett. 1992, 33, 1291.
(15) (a) Ye, Y.; Künzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14,
4979. (b) Yang, Y.-D.; Iwamoto, K.; Tokunaga, E.; Shibata,
N. Chem. Commun. 2013, 49, 5510.
(16) (a) Li, Z.; Cui, Z.; Liu, Z.-Q. Org. Lett. 2013, 15, 406.
(b) Lu, Q.; Liu, C.; Peng, P.; Liu, Z.; Fu, L.; Huang, J.; Lei,
A. Asian J. Org. Chem. 2014, 3, 273.
(17) Typical Procedure: To a septum-capped 25 mL sealed tube
with a magnetic stirring bar were added CF3SO2Na (1.8
mmol) and BQ (0.3 mmol) in MeCN–H2O (4:1; 4 mL) under
O2, followed by the addition of styrene 1a (0.3 mmol) and
tBuOOH (2.4 mmol). The sealed tube was screw capped and
heated at 80 °C for 16–24 h (oil bath). Upon completion, the
mixture was cooled to room temperature and diluted with
H2O (10 mL). The aqueous layer was extracted with EtOAc
(3 × 10 mL) and the combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel
References and notes
(1) (a) Banks, R. E. Organofluorine Chemicals and their
Industrial Applications; Ellis Horwood: West Sussex, 1979.
(b) Ojima, I. Fluorine in Medicinal Chemistry and Chemical
Biology; Wiley-Blackwell: Chichester, 2009. (c) Muller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Hird,
M. Chem. Soc. Rev. 2007, 36, 2070. (e) Kirk, K. L. Org.
Process Res. Dev. 2008, 12, 305.
(2) (a) For an important early review on the subject, see: Welch,
J. T. Tetrahedron 1987, 43, 3123. (b) Special Issue on
‘Fluorine in the Life Sciences’: ChemBioChem 2004, 5, 557.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320.
(3) (a) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem.
Int. Ed. 2012, 51, 536. (b) Cho, E. J.; Senecal, T. D.; Kinzel,
T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010,
328, 1679. (c) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.;
Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 3793.
(4) (a) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.;
Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.;
Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature
2012, 492, 95. (b) Ji, Y. N.; Brueckl, T.; Baxter, R. D.;
Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran,
P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 14411.
(5) (a) Novák, P.; Lishchynskyi, A.; Grushin, V. V. Angew.
Chem. Int. Ed. 2012, 51, 7767. (b) Wang, X.; Xu, Y.; Mo, F.;
Ji, G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S.; Zhang, Y.; Wang,
J. J. Am. Chem. Soc. 2013, 135, 10300.
(6) (a) Xu, J.; Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu,
Y.; Liu, L. Chem. Commun. 2011, 47, 4300. (b) Studer, A.
Angew. Chem. Int. Ed. 2012, 51, 8950.
(7) (a) Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342. (b) Liu, T.;
Shao, X.; Wu, Y.; Shen, Q. Angew. Chem. Int. Ed. 2012, 51,
540. (c) Feng, C.; Loh, T.-P. Chem. Sci. 2012, 3, 3458.
(d) Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu,
X.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436.
(8) (a) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134,
9034. (b) Nagib, D. A.; MacMillan, D. W. C. Nature 2011,
480, 224. (c) Qi, Q.; Shen, Q.; Lu, L. J. Am. Chem. Soc.
2012, 134, 6548.
(9) (a) Cahard, D.; Ma, J.-A. Chem. Rev. 2004, 104, 6119.
(b) Itoh, Y.; Mikami, Y. Org. Lett. 2005, 7, 649. (c) Kieltsch,
I.; Eisenberger, P.; Stanek, K.; Togni, A. Chimia 2008, 62,
260. (d) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem.
Res. 2008, 41, 817. (e) Matousek, V.; Togni, A.; Bizet, V.;
Cahard, D. Org. Lett. 2011, 13, 5762. (f) Pham, P. V.; Nagib,
D. A.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2011, 50,
6119. (g) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993,
115, 2156.
chromatography (hexane) to provide pure products 2a and
3a in 57% combined yield. Purification by flash column
chromatography on silica gel (hexanes–EtOAc, 20:1 v/v)
gave the pure products.
Compound 2a: Yield: 36%; white solid. 1H NMR (400
MHz, CDCl3): δ = 7.87 (d, J = 7.4 Hz, 2 H), 7.57 (t, J =
7.4 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 3.73 (q, J = 10.0 Hz,
2 H). 13C NMR (100 MHz, CDCl3): δ = 189.7 (q, J = 2.8 Hz),
135.7, 134.1, 128.9, 128.3, 124.0 (q, J = 276.7 Hz), 41.9
(q, J = 28.3 Hz). 19F NMR (376 MHz, CDCl3): δ = –62.1
(t, J = 10.0 Hz, 3F).
Compound 3a: Yield: 21%; colorless oil. 1H NMR (400
MHz, CDCl3): δ = 7.32–7.41 (m, 5 H), 7.08 (dd, J = 9.0,
3.6 Hz, 1 H), 2.56–2.70 (m, 1 H), 2.39–2.52 (m, 1 H), 2.25
(s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 142, 128.9, 128.4,
125.9 (q, J = 275.7 Hz), 125.7, 68.8 (d, J = 3.3 Hz), 42.9
(q, J = 26.9 Hz). 19F NMR (376 MHz, CDCl3): δ = –63.7
(t, J = 10.5 Hz, 3F). HRMS (EI): m/z [M + H]+ calcd. for
C9H10F3O: 191.0684; found: 191.0688.
(10) (a) Novák, P.; Lishchynskyi, A.; Grushin, V. V. J. Am.
Chem. Soc. 2012, 134, 16167. (b) Zanardi, A.; Novikov, M.
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