Facile synthesis of trifluoroethyl compounds by the Suzuki cross-coupling reactions of CF3CH2OTs with arylboronic acids

Article abstract of DOI:10.1039/c3cc46601a

This research provides a novel approach for introducing a CF ₃CH₂ group onto aromatic rings using Pd(OAc) ₂/palladacycle as a catalyst for the Suzuki cross-coupling reaction of CF₃CH₂OTs (OTs = 4-methylbenzene sulfonate) with arylboronic acids.

Full text of DOI:10.1039/c3cc46601a

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Facile Synthesis of Trifluoroethyl Compounds by the Suzuki Cross-Coupling
Reactions of CF3CH2OTs with Arylboronic Acids
Faqiang Lenga, Yaping Wanga, Hui Lia, Jingya Lib, Dapeng Zoua, b*, Yangjie Wua and Yusheng Wub, c*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
† Electronic
DOI: 10.1039/b000000x/
Supplementary
Information
(ESI)
available:See
This research provides a novel approach for introducing a
CF3CH2 group onto aromatic rings using Pd(OAc)2/ palla-
dacycle as a catalyst for the Suzuki cross coupling reaction of
CF3CH2OTs (OTs= 4-methylbenzene sulfonate) with arylbo-
45 on, we found that CF3CH2I is very hard to handle because of its
low boiling point (bp 54.8 °C) and volatility. Building upon our
earlier publication7, our ongoing research program toward the
development of efficient trifluoroethyl reagents instead of
CF3CH2I was found to be crucial to solve this issue. As an
50 important alternative to alkyl/aryl halides in transition metal
catalyzed crossꢀcoupling reactions, alkyl/aryl tosylate are often
more stable and easier to handle both in the solid state and in
solution8. In recent years, Fu et al. have exploited different steric
and electronic properties of various ligands to design successful
55 catalytic systems for the coupling of alkyl tosylate9 and halides10
with organoboranes by means of Suzuki coupling
reaction(Scheme 2, eq 1). Liu11 had shown Cuꢀcatalyzed cross
coupling reaction on nonꢀactivated alkyl tosylate/ halides with
arylboronate ester(Scheme 2, eq 2). These researches indicated
10 ronic acids.
The incorporation of fluorineꢀcontaining functional groups into
organic molecules can often bring about many profound changes
in their physical, chemical, and biological properties1. It has been
known that many distinct methods for the preparation of trifluorꢀ
15 omethyl compounds have been developed in recent years2ꢀ4
.
However, the process for the synthesis of trifluoroethyl
compounds is still limited. Recently, Baran et al. have described a
direct and freeꢀradicalꢀbased approach for the introduction of
CF3CH2 group5. A similar catalytic crossꢀcoupling method to
20 synthesize trifluoroethyl compounds has been reported by Hu6
and our group7 in 2012. It presented a Suzuki cross coupling
reaction by using CF3CH2I and aryl boron reagents and catalyzed
by Pd(0)(Scheme1).
60 that CF3CH2OTs may be
trifluoroethylation reaction.
a
good substrate for the
25
Scheme 1 The trifluoroethylation of organoboron compounds
by using CF3CH2I
Scheme 2 The Suzuki cross coupling reaction of alkyl tosylate/ halides
and organoboron compounds
It is the above straightforward synthesis of trifluoroethyl compꢀ
ounds via the trifluoroethylation of aryl that makes CF3CH2I to be
an attractive coupling partner. Previously, our laboratory was
30 involved in the development of Pdꢀcatalyzed process to provide
the trifluoroethyl compounds. However, during the actual operatiꢀ
65 In this paper, we report that CF3CH2OTs could be used as an
effective reagent to produce trifluoroethyl compounds in Suzuki
cross coupling reaction using Pd(OAc)2 and palladacycle as
catalyst (Figure 1).
a
The College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou, P. R. China.
35
40
Eꢀmail: zdp@zzu.edu.cn; Fax: +86 371 6776 3390;
Tel: +86 371 6776 6865
Tetranov Biopharm, LLC., No.75 Daxue Road , Zhengzhou, P. R.
b
China.
70
Figure 1. Palladacycle catalysts
c Tetranov International, Inc., 100 Jersey Avenue, Suite A340,
New Brunswick, NJ 08901, USA
Firstly, the reaction of 2ꢀ naphthyl boronic acid with CF3CH2OTs
was chosen as model reaction to optimize the reaction condition.
The results were summarized in Table 1. By combining of
Eꢀmail: yusheng.wu@tetranovglobal.com; Fax: +1 732 253 7327;
Tel: +1 732 253 7326
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DOI: 10.1039/C3CC46601A
different phosphine ligands with Pd(OAc)2，trace to 20% of the 25 reaction. In the used Pd source, Pd(OAc)2 gives the desired result
desired product was detected. It was described by Buchwald that
the ligands of electronꢀrich and bulky phosphines were effective
for palladiumꢀcatalyzed Suzuki crossꢀcoupling reactions of arylꢀ
tosylate with organoboron compounds12. However, when some
electronꢀrich and bulky phosphines (XantꢀPhos, XꢀPhos, SꢀPhos,
(Table 1, entry 8ꢀ11). On the other hand, among palladacycle
Cat.1, Cat.2, Cat.3, Cat.4, Cat.5 that used in the reaction with
Pd(OAc)2, palladacycle Cat.1 was proved to be the most efficient
candidate (Table 1, entry 12ꢀ17). The synthesis and application
30 of palladacycle have been reported by Wu13. Moreover, we found
that the combination of Pd(OAc)2 and palladacycle Cat.1 were
essential for the reaction(Table 1, entry 12, 13). The result also
showed that the addition of 10 mol% of ligands will lead the
decrease of the yield (Table 1, entry 18, 19). Whereas, when
35 decreasing amount of PPh3 (1 mol%) was used in the cross
coupling reaction, the desired product was obtained in slightly
higher yield (Table 1, entry 20). Then the combination of
Pd(OAc)2 and palladacycle Cat.1 / PPh3 (1 mol%) was fixed.
5
Table 1. Screen of catalysts and ligands for the coupling reaction of 2ꢀ
naphthyl boronic acid with CF3CH2OTs a
Entry
1
Catalyst 1
PdX
Catalyst 2
Palladacycle
Ligand
Yieldb
(%)
Table 2. Effect of base and additive on the coupling reaction a
OH
Pd(OAc)2
XꢀPhos
SꢀPhos
12
5 mol% Pd(OAc)2, 4 mol% Cat.1
CF3
B
+
CF3CH2OTs
OH
1 mol% PPh3, 3.0 equiv Additive
3.0 equiv Base
2
3
Pd(OAc)2
Pd(OAc)2
Trace
15
DMSO, 150
℃, 4h, Ar
Xantꢀ
Phos
1
1a
Yield % b
57
40
Entry
Base
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NaOH
tꢀBuOK
K2CO3
KOAc
CsF
Additive
4
5
Pd(OAc)2
Pd(OAc)2
Daveꢀ
Phos
CyJohnꢀ
Phos
Trace
Trace
1
2
KI
KBr
(Bu)4NI
LiCl
NaI
23
3
50
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
PdBr2
PCy3
20
10
65
35
40
10
30
4
Trace
67
PEt3
5
8
Cat.1
Cat.1
Cat.1
Cat.1
6
NaI
28
9
7
NaI
18
10
11
12
8
NaI
29
PdCl2
9
NaI
Trace
35
Pd(OAc)2
PPh3
10
NaI
(10 mol%)
a Reaction conditions: 0.5 mmol 1, 1.5 mmol CF3CH2OTs, 5 mol%
Pd(OAc)2 , 4 mol% Cat.1, 1 mol% PPh3, 1.5 mmol Additive, 1.5 mmol
Base, 3 mL DMSO, 150°C, 4 h, Argon atmosphere.
13
Cat.1
(10 mol%)
Cat.2
12
14
15
16
17
18
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
50
40
Cat.3
Cat.4
Cat.5
Cat.1
b The yields were determined by GC (average of two GC runs) using nꢀ
45 dodecane as an internal standard.
41
31
According to the above condition, a series of additives were also
investigated. No product was detected in the absence of MX (MX
= NaI, KI, (Bu)4NI, KBr, LiCl), indicating the pivotal role of MX
in the reaction. Some evidence prompted that the presence of
50 halide ions was favorable for the Suzuki cross coupling
reaction14,15. Compared with KI, KBr, (Bu)4NI and LiCl, NaI was
more effective additive for the cross coupling reaction(Table 2,
entry 1ꢀ5). Therefore, NaI is the better choice. The effect of base
for the reaction was also discussed herein. Potassium phosphate is
55 reported as a remarkably active and selective solid base in phaseꢀ
transferꢀcatalyzed alkylation reactions of alkalineꢀsensitive
substrates such as esters and halides16. In contrast with K3PO4,
stronger (NaOH) or soft base (KOAc) was less effective for the
reaction even prolonged the reaction time (Table 2, entry 5ꢀ9).
60 McClure had found that fluoride salts have positive affect on the
crossꢀcoupling reactions of arylboronic acids17. When CsF was
used as base, just 35% yield was obtained (Table 2, entry 10).
Finally, K3PO4 was found to be the optimal base. After
rescreening various solvents and temperature, the optimal
65 reaction conditions were identified as follows: 1.0 equiv of
arylboronic acid, 3.0 equiv of CF3CH2OTs in the presence of 5
Xantꢀ
Phos
PPh3
Trace
19
20
Pd(OAc)2
Pd(OAc)2
Cat.1
Cat.1
56
67
PPh3
(1mol%)
10 a Reaction conditions: 0.5 mmol 1, 1.5 mmol CF3CH2OTs, 5 mol%
Catalyst 1 , 10 mol% Ligand or 4 mol % Cat.1-5, 1.5 mmol NaI, 1.5
mmol K3PO4, 3 mL DMSO, 150°C, 4 h, Argon atmosphere.
b The yields were determined by GC (average of two GC runs)using nꢀ
dodecane as an internal standard.
15 CyJohnꢀPhos, DaveꢀPhos) were examined in the reaction; very
low yields were obtained (Table 1, entry 1ꢀ5). Fu9a reported that
Pd/alkyl phosphines could catalyze the Suzuki crossꢀcoupling
reaction of alkyl tosylate with organoboronic compounds. When
PCy3 or PEt3 was used as ligand, 1a was obtained in a low yield
20 (Table 1, entry 6ꢀ7). Fortunately, the combination of Pd(OAc)2
and palladacycle Cat.1(Figure 1) gave the desired product 1a in
65% yield(Table 1, entry 8). The combination of different PdX
(Pd(OAc)2, PdBr2, PdCl2, Pd2(dba)3) with palladacycle catalyst
(Cat.1, Cat.2, Cat.3, Cat.4, Cat.5) were also detected in the
2
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DOI: 10.1039/C3CC46601A
mol% Pd(OAc)2, 4 mol% Cat.1, 1 mol% PPh3, and 3.0 equiv
K3PO4 in dimethyl sulfoxide at 150°C for 4h under argon
atmosphere.
is very useful for the synthesis of trifluoroethylated products
which are potential pharmaceutical intermediates. The significant
advantages of this procedure are simple operation, not long (4h)
35 reaction time and the raw materials were commercial available.
On the basis of the observations reported in this and earlier
studies from our laboratory, we believe that the performance of
CF3CH2OTs in Pd/palladacycle catalyzed crossꢀcoupling
reactions will be fully developed and utilized.
Table 3. Pd(OAc)2/Palladacycleꢀcatalyzed crossꢀcoupling of heteroꢀ and
5
arylboronic aicds with CF3CH2OTs a
40 Acknowledgments
We are grateful to the Natural Science Foundation of China
(20772114, 21172200), the Innovation Fund for Outstanding
Scholar of Henan Province (0621001100) and Research Program
of Fundamental and Advanced Technology of Henan Province
45 (122300413203) for financial support.
Notes and references
1
(a) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem.
Soc. Rev.,2008, 37, 320; (b) K. L. Kirk, Org. Process Res. Dev.,
2008, 12, 305; (c) K. Müller, C. Faeh and F. Diederich, Science,
2007, 317, 1881; (d) G. K. S. Prakash and S. Chacko, Curr. Opin.
Drug. Discov. Devel., 2008, 11, 793.
50
55
60
65
70
2
3
O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475.
N. Kamigata, T. Ohtsuka, T. Fukushima, M. Yoshida and T. Shimizu,
J. Chem. Soc. Perkin Trans. 1, 1994, 1339.
(a) Y. D. Ye, S. H. Lee and M. S. Sanford, Org. Lett., 2011, 13, 5464;
(b) H. Kawai, T. Furukawa, Y. Nomura, E. Tokunaga and N.
Shibata, Org. Lett., 2011, 13, 3596.
Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder, D. D. Dixon, R. A.
Rodriguez, R. D. Baxter, B. Herlé, N. Sach, M. R. Collins, Y.
Ishihara, P. S. Baran, Nature, 2012, 492, 95.
Y. Zhao and J. Hu, Angew. Chem. Int. Ed., 2012, 51, 1033.
A. Liang, X. Li, D. Liu, J. Li, D. Zou, Y. Wu and Y. Wu, Chem.
Commun., 2012, 48, 8273.
(a) G. P. Roth and C. E. Fuller, J. Org. Chem., 1991, 56, 3493; (b) H.
Zhang, C. Zhou, Q. Chen, J. Xiao and R. Hong, Org. Lett., 2011, 13,
560; (c) T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt, K. L. Jensen
and T. Skrydstrup, J. Org. Chem., 2008, 73, 3404.
(a) M. R. Netherton and G. C. Fu, Angew. Chem. Int. Ed., 2002, 41,
3910; (b) B. J. Stokes, S. M. Opra and M. S. Sigman, J. Am. Chem.
Soc., 2012, 134, 13408; (c) A. Y. He and J. R. Falck, J. Am. Chem.
Soc., 2010, 132, 2524.
4
5
6
7
8
a Reaction conditions: 0.5 mmol 1-15, 1.5 mmol CF3CH2OTs, 5 mol%
Pd(OAc)2 , 4 mol% Cat.1, 1 mol% PPh3, 1.5 mmol NaI, 1.5 mmol K3PO4,
10 3 mL DMSO, 150°C, 4 h, Argon atmosphere.
9
b Isolated yields base on 1-15
With this promising result in hand, the reaction scope was
extended to a variety of arylboronic acids to give corresponding
trifluoroethylated products in Table 3. Arylboronic acids with a
15 general range of substitutions were tolerated in this condition.
Obviously, αꢀ and βꢀ naphthaleneboronic acid can achieve a good
yield in the cross coupling reaction (1a, 2a). The substitute of
phenyl, methoxy, secondary amine group and acetyl of benzene
boron acids were tolerated in the reaction with a low to moderate
20 yield (3a-7a). The organoboron compounds containing
benzofuran and benzothiophene group can afford better yields in
the reaction (8a, 9a). The reaction condition was also suitable for
phenanthryl boronic acid with a 45% isolated yield (10a).
Furthermore, heteroꢀarylboronic acids with free amino (NH2 and
25 NH) and secondary amine group were also tolerated in the
reaction and no Nꢀtrifluoroethylated byproduct was monitored
(11a-13a). In addition, the product of 3ꢀ(2,2,2ꢀtrifluoroethyl)
quinoline (15a) was also obtained with a 37% yield.
10 (a) J. H. Kirchhoff, M. R. Netherton, I. D. Hills and G. C. Fu, J. Am.
Chem. Soc., 2002, 124, 13662; (b) P. M. Lundin and G. C. Fu, J. Am.
Chem. Soc., 2010, 132, 11027; (c) T. Brenstrum, D. A. Gerristma, G.
M. Adjabeng, C. S. Frampton, J. Britten, A. J. Robertson, J.
McNulty and A. Capretta, J. Org. Chem., 2004, 69, 7635.
11 C. Yang, Z. Zhang, Y. Liu and L. Liu, Angew. Chem. Int. Ed., 2011,
50, 3904.
75
80
12 H. N. Nguyen, X. H. Huang and S. L. Buchwald, J. Am. Chem. Soc.,
2003, 125, 11818.
13 (a) Y. Wu, S. Huo, J. Gong, X. Cui, L. Ding, K. Ding, C. Du, Y. Liu
and M. Song, J. Organomet. Chem., 2001, 637~639, 27; (b) B. Mu,
T. Li, W. Xu, G. Zeng, P. Liu and Y. Wu, Tetrahedron, 2007, 63,
11475; (c) M. Zhang, X. Cui, X. Chen, L. Wang, J. Li, Y. Wu, L.
Hou and Y. Wu, Tetrahedron, 2012, 68, 900.
14 T. Ohe, N. Miyaura and A. Suzuki, J. Org. Chem., 1993, 58, 2201.
15 M. Suzuki, H. Doi, M. Bjorkman, Y. Andersson, B. Llngstrom,Y.
Watanabe and R. Noyori. Chem. Eur. J., 1997, 3, 2039.
16 N. Qafisheh, S. Mukhopadhyay, A. V. Joshi, Y. Sasson, G. K. Chuah,
and S. Jaenicke, Ind. Eng. Chem. Res., 2007, 46, 3016.
17 S. W. Wright, D. L. Hageman and L. D. McClure, J. Org. Chem.,
1994, 59, 6095.
85
90
In summary, we reported for the first time that CF3CH2OTs could
30 be used as an efficient reagent to produce trifluoroethyl
compounds in Suzuki cross coupling reaction. This new process
This journal is © The Royal Society of Chemistry [year]
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