The palladium-catalyzed cross-coupling reactions of trifluoroethyl iodide with aryl and heteroaryl boronic acid esters

Article abstract of DOI:10.1039/c2cc31651j

The cross-coupling reactions of 1,1,1-trifluoro-2-iodoethane with aryl and heteroaryl boronic acid esters have been successfully achieved. The new protocol allows for a convenient introduction of trifluoroethyl groups into a variety of aryl and heteroaryl moieties under mild conditions.

Full text of DOI:10.1039/c2cc31651j

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ARTICLE TYPE
The Palladium-Catalyzed Cross-Coupling Reactions of Trifluoroethyl
Iodide with Aryl and Heteroaryl Boronic Acid Esters
Apeng Liangb, Xinjian Lia, Dongfeng Liua, Jingya Lib, Dapeng Zou*a,b, Yangjie Wua and Yusheng Wu*b,c
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
50 longꢀterm storage makes them attractive intermediates for large
scale use. In addition, the coupling of arylboronic acid esters with
various alkyl halides including iodomethane had also been
achieved[13,16ꢀ19]. We have synthesized a series of functional
organoboronic acid derivatives and focused their application in
55 the construct of effective building blocks[20]. Here we report the
crossꢀcoupling of aryl and heteroaryl boronic acid esters with
trifluoroethyl iodide as a much simpler and efficient reaction
protocol for the synthesis of trifluoroethyl derivatives(Scheme 1).
The cross-coupling reactions of 1, 1, 1-trifluoro-2-iodoethane
with aryl and heteroaryl boronic acid esters has been
successfully achieved. The new protocol allows for
a
convenient introduction of trifluoroethyl groups into a variety
10 of aryl and heteroaryl moieties under mild condition.
Fluorine plays a privileged role in life science research as a
powerful modulator of bioactivity due to the atom´s high
electronegativity and small size.[1ꢀ8] In recent years, trifluoroethyl
has been shown to be an important substance in organic synthesis
15 and material science owing to its capacity of lipophilic electronꢀ
withdrawing[6,9]. However, the practical methods for the synthesis
of trifluoroethyl fragments are still limited to the crossꢀcoupling
O
B
O
Pd cat.
CF3
CF3CH2I
+
R
R
of TMSCF3 with benzyl bromide derivatives[10,11]
.
Y
Y
During the past decades, the palladium catalyzed crossꢀ
20 coupling reaction of organic halides with organometallic
compounds has been greatly progressed. Although trifluoroethyl
iodide is commercial available[12], the palladium catalyzed
reaction of trifluoroethyl iodide with organometallic compound
still remains difficult. The reluctance of inactivated trifluoroethyl
25 iodide to oxidatively add to palladium(0) and the pronounced
tendency of alkyl–palladium complexes to undergo βꢀ fluoride
ion of trifluoroethylꢀmetals elimination are generally believed to
be equally responsible for the difficulty in performing such
Y=C,N
60 Scheme 1 The crossꢀcoupling of aryl and heteroaryl boronic acid esters
with trifluoroethyl iodide
To evaluate the activity of the combination of different ligands
for catalysts, 6ꢀbenzyloxypyridineꢀ3ꢀboronic acid pinacol ester (1)
and trifluoroethyl iodide (2) were chosen as model reactions in
65 DMF at 65 ℃ in the presence of CsF as base (as shown in Table
1). Buchwald and coꢀworkers have shown that the dialkylbiaryl
phosphine ligands substantially accelerate the reductive
elimination[21]. The combination of Pd2(dba)3 with CyJohnPhos,
DavePhos, SPhos, XPhos or RuPhos (Scheme 2) ligands gave
70 different yields (Table 1, entries 1ꢀ5).
reactions[13,14]
.
30
a The College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou, PR China.
b Tetranov Biopharm, LLC,75 Daxue Road, Zhengzhou, PR China
c Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New
PCy2
PCy2
PCy2
PCy2
OMe
PCy2
OiPr
i-Pr
i-Pr
N
MeO
iPrO
35 Brunswick, NJ 08901, USA.
*Corresponding Authors: Yusheng Wu; Email:
yusheng.wu@tetranovglobal.com, Tel. 001 732 253 7326, Fax 001 732
253 7327; Dapeng Zou, Email: Dapeng.zou@tetranov.com, Tel. 86 371
6776 1680, Fax 86 371 6776 1837.
i-Pr
CyJohnPhos
DavePhos
SPhos
XPhos
RuPhos
Scheme 2 The structure of biarylphosphine ligands
40
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
The XPhos was seen to be a more effective ligand than
DavePhos,
Palladiumꢀcatalyzed crossꢀcoupling reactions of organoboron
45 reagents have been found and widely applied in organic
synthesis, since they were easily performed and showed excellent
tolerance of functional groups[15]. Due to the great effort of
chemists, the boronic acid esters can be prepared easily by
different routes. The ease of isolation, purification, handling, and
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Table 1 Effects of the reaction conditions of 6ꢀbenzyloxypyridineꢀ3ꢀ
boronic acid pinacol ester with trifluoroethyl iodide on the product
distributiona
1ꢀ5). When XPhos was used, 53% yield was offered (Table 1,
20 entry 2). When switching the Pd source to Pd(OAc)2, a lower
yield (26%) was given (Table 1, entry 6). Liu and coꢀworkers had
reported copperꢀcatalyzed crossꢀcoupling reaction of organoboron
compounds with primary alkyl halides and pseudohalides[15g]
.
But The reaction of 6ꢀbenzyloxypyridineꢀ3ꢀboronic acid pinacol
25 ester with trifluoroethyl iodide did not work without Pd under the
single metal, CuCl as the catalyst (Table 1, entry 7). As a result
the combination of Pd2(dba)3/ XPhos was fixed.
Entry
Catalyst
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
—
Ligand
DavePhos
XPhos
Yieldb (%)
48
To further study the effect of solvents and bases on the crossꢀ
coupling reaction, 6ꢀbenzyloxypyridineꢀ3ꢀboronic acid pinacol
30 ester (1) and trifluoroethyl iodide (2) were chosen as the model
reactants by fixing 2.5 mol % Pd2(dba)3 as catalyst and 10 mol %
Xphos as ligand (as shown in Table 2). Several bases such as
K2CO3, Cs2CO3, K3PO4, CsF, tꢀBuOK, NEt3 and KOAc were
examined in the reaction. A good yield was obtained when CsF
35 was used as the base (Table 2, entry 4). It was also found that the
addition of a certain amount of water could encourage the
reaction. Increasing or decreasing the amount of water both gave
lower yield. Changing the solvent to toluene or THF did not favor
the reaction. The combination of 2.5 mol % Pd2(dba)3 and 10 mol
40 % XPhos in DMF, in the presence of CsF and CuCl at 65 ℃ was
chosen as the optimum condition.
1
2
3
4
5
6
7
53
SPhos
trace
15
RuPhos
CyJohnPhos
XPhos
25
26
—
trace
a Reaction conditions: 0.5 mmol 1, 1 mmol trifluoroethyl iodide, 2.5
mol% catalyst, 10 mol% ligand, 1.5 mmol CsF, 2.0 mL DMF, 4 mmol
H2O, 0.5 mmol CuCl, 65 ℃, 16 h, nitrogen atmosphere.
5
b Isolated yields based on 1.
Under these optimized reaction conditions, a wide range of
heteroaryl boronic acid esters were investigated for this reaction.
The optimized system of catalysis is also suitable for the other
45 heteroaryl boronic acid esters to give the trifluoroethylated
product in a moderate yield. These results are summarized in
Table 3.
Table 2 Effects of the reaction conditions of 6ꢀbenzyloxypyridineꢀ3ꢀ
10 boronic acid pinacol ester with trifluoroethyl iodide on the product
distributiona
Table 3 Palladiumꢀcatalyzed crossꢀcoupling of heteroaryl boronic acid
esters with trifluoroethyl iodidea
Entry
Base
K2CO3
Cs2CO3
K3PO4
CsF
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
Yieldb (%)
35
1
2
38
3
32
CF3
CF3
CF3
4
53
N
N
N
BnO
N
O
5
tꢀBuOK
NEt3
no
3a, 53%
3b, 40%
3c, 55%
6
no
CF3
7
KOAc
CsF
no
CF3
CF3
N
N
8
trace
trace
28c
Ph
N
N
3d, 51%
3e, 57%
3p, 28%c
9
CsF
Toluene
DMF
DMF
10
11
CsF
22d
50 a Reaction conditions: 0.5 mmol 1, 1 mmol trifluoroethyl iodide, 2.5
mol%Pd2(dba)3, 10 mol% XPhos, 1.5 mmol CsF, 2 ml DMF, 4 mmol
H2O, 0.5 mmol CuCl, 65 ℃, 16 h, nitrogen atmosphere.
CsF
a Reaction conditions: 0.5 mmol 1, 1 mmol trifluoroethyl iodide, 2.5
mol% Pd2(dba)3, 10 mol% XPhos, 1.5 mmol base, 2.0 ml solvent, 4 mmol
H2O, 0.5 mmol CuCl, 65 ℃, 16 h, nitrogen atmosphere.
b Isolated yields based on 1.
c Yields based on 1, determined by GC/MS.
15 b Isolated yields based on 1.
c
55 We proceeded to study the crossꢀcoupling reactions of various
aryl boronic acid esters with trifluoroethyl iodide under the
optimized reaction conditions. As shown in Table 4, the
conditions could compatible a wide range of functional groups
2.0 ml solvent without H2O.
d 2.0 ml solvent with 8mmol H2O.
CyJohnPhos, RuPhos and SPhos in this reaction (Table 1, entries
2
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such as ketones, ester, nitriles and nitro groups. Generally, both
electronꢀrich and electronꢀdeficient aryl boronic acid esters
worked well, providing the corresponding coupling products in
Notes and references
1
2
3
J. T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
John Wiley & Sons, New York, 1991.
Organofluorine Compounds: T. Hiyama, Chemistry and Applications,
Springer, New York, 2000.
Organofluorine Chemistry: R. E. Banks, B. E. Smart and J. C. Tatlow,
Principles and Commercial Applications, Plenum, New York, 1994.
W. K. Hagmann, J. Med. Chem, 2008, 51, 4359.
K. L. Kirk, Org. Process Res. Dev, 2008, 12, 305.
T. Yamazaki, T. Taguchi, I. Ojima, Fluorine in Medicinal Chemistry
and Chemical Biology, Wiley-Blackwell, Chichester, 2009, p. 3.
D. BonnetꢀDelpon, Bioorganic and Medicinal Chemistry of Fluorine,
WileyꢀVCH, Weinheim, 2008.
35
40
45
moderate yields.
(Table 4, entries 1–9).
5
Table 4 Palladiumꢀcatalyzed crossꢀcoupling of aryl boronic acid esters
with trifluoroethyl iodidea.
4
5
6
7
8
9
D. O’Hagan, Chem. Soc. Rev, 2008, 37, 308.
G. G. Dubinina, H. Furutachi, D. A. Vicic, J. Am. Chem. Soc, 2008,
130, 8600.
CF3
CF3
CF3
O
CF3
CF3
CF3
O2N
NC
10 H. Urata, D. Goto, T. Fuchikami, Tetrahedron Lett., 1991, 32, 3091.
O
50 11 R. P. Singh, J. M. Shreeve, Tetrahedron, 2000, 56, 7613.
12 L. C. Krogh, T. S. Reid, H. A. Brown, J. Org. Chem, 1954, 19, 1124.
13 M. R. Netherton, C. Y. Dai, G. C. Fu, J. Am. Chem. Soc, 2001, 123,
10099.
14 L. J. Gooßen, Appl. Organometal. Chem, 2004, 18, 602.
55 15 a) N. Miyaura, A. Suzuki, Chem. Rev, 1995, 95, 2457; b) N. Miyaura,
Top. Curr. Chem, 2002, 219, 11; c) A. F. Littke, G.C. Fu, Angew.
Chem. Int. Ed, 2002, 41, 4176; d) A. Suzuki, F. Diederich, P. J.
Stang, In Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH,
New York, 1998; chapter 2; e) A. Capretta, J. Org. Chem., 2004, 69,
3g, 53%
3k, 60%
3f, 34%
3h, 55%
O
3i, 58%
O
CF3
O
CF3
CF3
O
O
O
3j, 53%
O
3l, 54%
3m, 31%
CF3
60
7635; f) G. Lalic, Org. Lett., 2010, 12, 3216; g) Liu et al. Angew.
Chem. Int. Ed., 2011, 50, 3904.
3n, 30%
3o, 60%c
16 A. Suzuki, J. Organomet. Chem, 1999, 576, 147.
17 H. Doi, I. Ban, A. Nonoyama, K. Sumi, C. X. Kuang, T. Hosoya, H.
Tsukada, M. Suzuki , Chem. Eur. J., 2009, 15, 4165.
65 18 N. Miyaura, M. Satoh, A. Suzuki, Tetrahedron Lett., 1986, 27, 3745.
19 S. M. Zhou, Y. L. Yan, M. Z. Deng, Synlett, 1998, 2,198.
20 a) L. H. Wang, J. Y. Li, X. L. Cui, Y. S. Wu, Z. W. Zhu, Y. J. Wu,
Adv. Synth. & Catal, 2010, 352, 2002; b) D. P. Zou, H. M. Cui,L. J.
Qin, J. Y. Li, Y. J. Wu, Y. S. Wu, Synlett, 2011, 3, 349; c) L. H.
a Reaction conditions: 0.5 mmol 1, 1 mmol trifluoroethyl iodide, 2.5
mol%Pd2(dba)3, 10 mol% XPhos, 1.5 mmol CsF, 2 ml DMF, 4 mmol
H2O, 0.5 mmol CuCl, 65 ℃, 16 h, nitrogen atmosphere.
10 b Isolated yields based on 1.
c Yields based on 1, determined by GC/MS.
70
Wang, X. L. Cui, J. Y. Li, Y. S. Wu, Z. W. Zhu, Y. J. Wu, Eur. J.
Org. Chem, 2012, 2012, 595; d) M. Zhang, X. L. Cui, X. P. Chen,
L. H. Wang, J. Y. Li, Y. S. Wu, L. F. Hou, Y. J. Wu, Tetrahedron,
2012, 68, 900; e) W. Ren, J. Y. Li, D. P. Zou, Y. J. Wu, Y. S. Wu,
Tetrahedron, 2012, 68, 1351.
It should be noted that the multiꢀfluoro alkyl halides was also
employed as the substrates. For example, when the CF3CF2CH2I
was added as the substrates under the optimized reaction
15 conditions, 18% yield was obtained (Scheme 3).
75 21 R. Martin, S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461.
Scheme 3 The crossꢀcoupling of heteroaryl boronic acid esters with
1,1,1,2,2ꢀpentafluoroꢀ3ꢀiodopropane
20 In conclusion, we have developed an efficient new catalytic
system for Pdꢀcatalyzed crossꢀcoupling reaction of trifluoroethyl
iodide with aryl(het) boronic acid esters. The procedure possesses
several advantages when compared with other methods. The
catalyst and ligand used are commercially available, a wide range
25 of substrates can be used in this system, and a variety of
functional groups (ketones, ester, nitriles and nitro groups) are
tolerated in both coupling partners. This approach provides a
convenient route for the introduction of the CF3CH2 group into
organic molecules.
30 We are grateful to the Natural Science Foundation of China
(20772114, 21172200) and the Innovation Fund for Outstanding
Scholar of Henan Province (0621001100) for financial support.
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The cross-coupling reactions of 1, 1, 1-trifluoro-2-iodoethane with aryl and heteroaryl boronic acid
esters has been successfully achieved