Cross-Coupling of [2-Aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes with Aryl Halides

Article abstract of DOI:10.1021/acs.orglett.5b01510

The synthesis of arylCF₂CF₂SiMe₃ and their reactivity in cross-coupling reactions with aryl iodides and aryl bromides to afford a range of 1,1,2,2-tetrafluoro-1,2-arylethanes is reported. The use of pyridine as an alternat

Full text of DOI:10.1021/acs.orglett.5b01510

Letter
pubs.acs.org/OrgLett
Cross-Coupling of [2-Aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes
with Aryl Halides
Miriam O’Duill, Emmanuelle Dubost, Lukas Pfeifer, and Veronique Gouverneur*
́
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, U.K.
S
* Supporting Information
ABSTRACT: The synthesis of arylCF2CF2SiMe3 and their
reactivity in cross-coupling reactions with aryl iodides and aryl
bromides to afford a range of 1,1,2,2-tetrafluoro-1,2-aryl-
ethanes is reported. The use of pyridine as an alternative to
phenanthroline, and the ability to carry out the reaction at 60
°C or room temperature are the key features of this Cu−Ag mediated cross-coupling methodology. The chemistry is compatible
with (hetero)aryl halides, offering a platform to develop products of interest in material and medicinal chemistry.
he Ruppert−Prakash reagent (CF3TMS) is a stable and
has encouraged the development of a range of alternative
methods for their synthesis, using precursors other than [2-aryl-
1,1,2,2-tetrafluoroethyl](trimethyl)silanes. Strategies featuring
late stage fluorination are known but suffer from harsh reaction
conditions.7 More recently, 2-bromo-1,1,2,2-tetrafluoroethylar-
enes were found to be suitable for cross-coupling reactions with
aryl iodides in the presence of an excess of copper, but these
couplings require temperatures higher than 130 °C and extended
reaction times (Scheme 1, eq 2).8 Ogoshi et al. disclosed an
elegant alternative strategy based on the generation of 2-aryl-
1,1,2,2-tetrafluoro-ethylcopper complexes from [CuOtBu]4,
tetrafluoroethylene (TFE), and arylboronic esters (Scheme 1,
eq 3). These complexes were successfully used in cross-coupling
reactions with aryl iodides; the use of gaseous TFE is not ideal for
common research laboratory settings, and the sensitivity of the
[CuOtBu]4 precursor may be limiting as a glovebox is preferable
for handling.9 Our research program on Cu-mediated 18F-
radiochemistry for positron emission tomography applications is
currently expanding with the development of new method-
ologies for the labeling of perfluorinated arenes.10 This program
led us to prepare [2-aryl-1,1,2,2-tetrafluoroethyl](trimethyl)-
silanes and develop an efficient protocol for the synthesis of
1,1,2,2-tetrafluoro-1,2-arylethanes via copper/silver-mediated
cross-coupling with a range of aryl halides (Scheme 1). Herein,
we disclose this operationally simple and mild reaction and
exemplify its scope on a range of (hetero)aryl iodides and
bromides.
T
easy to handle commercially available reagent widely
employed for late stage trifluoromethylation.1 Metal-mediated
cross-coupling strategies with this reagent have been extensively
studied,2 more recently with a focus on copper-mediated
processes with aryl halides.3,4 The use of this class of reagents
to install extended perfluoroalkyl chains is limited to
(pentafluoroethyl)trimethylsilane (C2F5TMS) and some se-
lected studies employing more functionalized perfluorinated
trimethylsilane derivatives (Scheme 1).4a,g−i We noted a single
Scheme 1. Synthesis of 1,1,2,2-Tetrafluoro-1,2-arylethanes
This study began with the synthesis of the model [2-aryl-
1,1,2,2-tetrafluoroethyl](trimethyl)silane 1a, which was pre-
pared from the parent aryl bromide following a three-step
procedure (Scheme 2). First, the Schlosser Grignard reagent
derived from 4-bromo-1,1′-biphenyl was reacted with methyl
chlorodifluoroacetate at −40 °C in THF. Treatment of the
resulting ketone with DAST at 60 °C afforded 4-(2-chloro-
1,1,2,2-tetrafluoroethyl)-1,1′-biphenyl in 65% overall yield after
example of a copper-mediated cross-coupling reaction of [2-aryl-
1,1,2,2-tetrafluoroethyl](trimethyl)silane (arylCF2CF2-TMS)
with 1-iodo-4-nitrobenzene, a reaction affording 1-(1,1,2,2-
tetrafluoro-2-(4-nitrophenyl)ethyl)-1H-pyrazole in 25% yield.5
The product formed in this reaction belongs to a class of highly
valuable 1,1,2,2-tetrafluoro-1,2-arylethane derivatives presenting
with a CF2CF2 unit flanked by two aryl (or heteroaryl) groups;
however, the low yield for this isolated reaction implies narrow
applicability. The usefulness of these compounds to access novel
perfluorinated materials such as liquid-crystalline compounds6
Received: May 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We focused next on the Cu-mediated cross-coupling of 1a with
Scheme 2. Synthesis and X-ray Structure of [2-(Biphenyl-4-
yl)-1,1,2,2-tetrafluoroethyl](trimethyl)silane 1a
1-iodo-2-methoxy-4-nitrobenzene (Table 1).
Table 1. Optimization Studies for the Cross-Coupling of 1a
a
with 1-Iodo-2-methoxy-4-nitrobenzene
b
entry fluoride source solvent
additive
NMR ratio 3aa/4a/5a/6a
1
2
3
4
5
6
7
8
9
KF
DMF
26:35:31:8
16:33:28:22
31:38:18:13
36:38:15:11
0:100:0:0
KF
NMP
two steps. The subsequent reaction, a magnesium-mediated
trimethylsilylation, was less efficient, but this process was readily
scalable, delivering more than two grams of [2-(biphenyl-4-yl)-
1,1,2,2-tetrafluoroethyl](trimethyl)silane 1a; this compound is a
white crystalline solid found suitable for single crystal X-ray
diffraction analysis.11,12 The additional [2-aryl-1,1,2,2-
tetrafluoroethyl](trimethyl)silanes 1b and 1c used in this study
were prepared following a similar reaction sequence. For 1c,
lithium halogen exchange was preferable to Grignard formation
for the trimethylsilylation step.12
KF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CsF
TBAF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
53:18:19:10
8:53:21:14
48:16:26:11
44:24:21:11
37:25:25:12
2:92:4:2
c
d
e
10
11
12
13
14
15
16
17
18
19
B(OMe)3
TMEDA
Phen
50:26:12:13
47:10:30:13
64:14:5:16
63:11:21:3
73:5:19:1
In the first instance, the reactivity of 1a was probed with a
benchmark reaction, a fluoride-mediated addition to enolizable
and nonenolizable aldehydes (Scheme 3).
Bipy
tBu2-Bipy
Py
f
Py
g
h
e
f
Scheme 3. Reactivity of [2-(Biphenyl-4-yl)-1,1,2,2-
tetrafluoroethyl](trimethyl)silane 1a with Aldehydes
Py
63:6:27:4
a
f
Py
76:5:13:5
f
Py
60:20:18:2
a
Standard conditions: 1.0 equiv of 1-iodo-2-methoxy-4-nitrobenzene,
1.2 equiv of 1a, 1.5 equiv of fluoride source, 1.5 equiv of CuI, 1.5 equiv
of additive (if applicable), 0.25 M in solvent, 60 °C, 16 h. TMEDA =
N,N,N′,N′-tetramethyl-1,2-ethylenediamine; Phen = 1,10-phenanthro-
line; Bipy = 2,2′-bipyridine; tBu2-Bipy = 4,4′-di-tert-butyl-2,2′-
b
bipyridine; Py = pyridine. Determined by 19F NMR by integration
c
of the product peak(s) using PhCF3 as the internal standard. Reaction
d
e
f
with CuCl. Reaction with CuBr. 20 mol % of CuI. 5.0 equiv of
g
h
pyridine. rt for 6 h. 6 h reaction time.
a
Our investigation began with the coupling of 1a and our model
aryl iodide in DMF with 1.5 equiv of KF and CuI at 60 °C for 16 h
(Table1, entry 1). These conditions led to the desired product
3aa in 26% yield along with 35% of 4-(1,1,2,2-tetrafluoroethyl)-
1,1′-biphenyl 4a resulting from competitive protodesilylation.
The two additional side products observed in the crude reaction
mixture were the iodo derivative 5a formed in 31% yield along
with 8% of alkene 6a. A similar product distribution was obtained
using NMP, but the use of DMSO proved beneficial (Table 1,
entries 2−3). AgF was the most efficient activator affording the
desired coupling product in 53% yield (Table 1, entry 6). The
cooperative effect of silver in the Cu-catalyzed trifluoromethy-
lation of aryl iodides with CF3TMS has been reported for other
systems by Weng and co-workers.4e Alternative sources of Cu(I)
such as CuBr or CuCl were less effective (Table 1, entries 7−
8).14 The reaction did proceed with a catalytic amount of CuI;
however, a substantial amount of byproduct formation was
observed (Table 1, entry 9). Several additives were considered
next. With the Ruppert−Prakash reagent CF3SiMe3, B(OMe)3
was shown to stabilize the CF3 anion in copper mediated cross-
coupling, thus minimizing the formation of protodesilylated
1.2 equiv of 1a and 1.0 equiv of aldehyde; yields of isolated product.
b
4-(1,1,2,2-Tetrafluoroethyl)-1,1′-biphenyl was formed as side-product
c
(40%). 4-(1,1,2,2-Tetrafluoroethyl)-1,1′-biphenyl (30%) and 4-
(1,2,2,2-tetrafluoroethyl)-1,1′-biphenyl (20%) were formed as side-
products.
The addition of 1a (1.2 equiv) to benzaldehyde (1.0 equiv)
was accomplished at room temperature in THF in the presence
of 10 mol % CsF. The resulting silylated alcohol was subjected to
deprotection using TBAF. The desired compound was isolated
in 90% yield. Electron poor and electron rich benzaldehydes are
tolerated, but the reaction proved less efficient with pyridine 2-
carboxaldehyde and hexanal, affording 2ad and 2ae in 48% and
50% yields, respectively. For reactions giving the desired
products in yields inferior to 70%, protodesilylation of 1a
leading to 4-(1,1,2,2-tetrafluoroethyl)-1,1′-biphenyl was ob-
served as a competitive side reaction, and an additional product
identified as 4-(1,2,2,2-tetrafluoroethyl)-1,1′-biphenyl was
formed when using hexanal.13 Only traces of 4-(1,2,2-
trifluorovinyl)-1,1′-biphenyl resulting from elimination were
detectable in the crude reaction mixtures.
B
DOI: 10.1021/acs.orglett.5b01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
byproduct;4j no beneficial effect was observed with 1a (Table 1,
entry 10). As anticipated, we found that 1,10-phenanthroline and
bipyridine were superior to TMEDA, but these ligands afforded
product 3aa in only low to moderate conversion (Table 1, entries
11−13); the more electron rich 4,4′-di-tert-butyl-2,2′-bipyridine
ligand gave 3aa in 64% (Table 1, entry 14) and pyridine afforded
3aa in 63% (Table 1, entry 15). Cost-effective pyridine was
identified as the best additive for cross-coupling (Table 1, entries
15−16). The use of pyridine as a preferential ligand for copper-
mediated cross-coupling methodologies for perfluoroalkylation
is not common, but its advantage over other ligands has been
documented in the context of flow chemistry.15 Monitoring the
reaction by NMR indicated that the starting material was
consumed after 6 h (Table 1, entry 17). Applying our best
conditions consisting of CuI (1.5 equiv), AgF (1.5 equiv), and
pyridine (5.0 equiv) in DMSO at 60 °C for 6 h, 3aa was isolated
in 78% yield (Table 1, entry 18). Similar conditions using 20 mol
% of CuI instead of 1.5 equiv led to inferior results, so these
conditions using substoichiometric amount of CuI were not
retained to study the scope of this cross-coupling reaction (Table
1, entry 19).
ents. This methodology can be extended to a vinyl iodide as well
as a range of heteroaryl iodides including thiophene, pyrazine,
indole, and pyridine derivatives. The reaction also proceeds with
alternative 2-substituted trimethyl(1,1,2,2-tetrafluoroethyl)-
silanes, as exemplified by the synthesis of 3bg, 3cg, and 3ce.
Compound 3ce is an advanced precursor for the synthesis of a
liquid crystalline compound.6c We noted that this protocol
allowed for the coupling of CF3CF2TMS with 1-iodo-2-methoxy-
4-nitrobenzene and HCF2TMS with 1-tert-butyl-4-iodobenzene
affording the desired products in 82% (yield of isolated product)
and 59% (19F NMR yield), respectively. This is an improvement
over current methods reported in the literature because of the
mildness of our reaction conditions.4h,16 The cross-coupling of
1a with aryl iodides could also be performed at room
temperature, but the yields of the isolated products were
generally lower under these conditions (Scheme 4). The diaryl
derivatives 3ac, 3aq, and 3as stand out as candidates for further
derivatization via cross-coupling or metathesis.
The difference in availability and price of (hetero)aryl iodides
and bromides prompted us to study the coupling of
representative (hetero)aryl bromides (Scheme 5). These
The substrate scope was investigated next (Scheme 4).
Numerous functionalized aryl iodides underwent cross-coupling
with 1a. Ketone, nitro, cyano, ether, ester, and bromo
substituents are well tolerated with good conversions obtained
for both electron-donating and electron-withdrawing substitu-
Scheme 5. Copper-Mediated Cross Coupling of 1a with
(Hetero)aryl Bromides
a
Scheme 4. Copper-Mediated Cross Coupling of 1a with
a
(Hetero)aryl Iodides
a
1.2 equiv of 1a and 1.0 equiv of aryl iodide (0.2 mmol scale); yields of
b
isolated products unless stated otherwise. 19F NMR yields,
determined by integration of the product peak(s) using PhCF3 as
the internal standard.
reactions were performed using CuI (1.5 equiv), AgF (1.5
equiv), and pyridine (5.0 equiv) in DMSO at 60 °C for 6 h. We
found that this reaction does not proceed for electron rich cross-
coupling partners such as 1-bromo-4-methoxybenzene. For
electron deficient aryl bromides, cross-coupling proceeded under
the reaction conditions applied to aryl iodides with yields of
isolated products reaching up to 68%. 2-Bromopyridine was
more reactive than 3-bromopyridine, a reactivity order allowing
for the exclusive formation of product 3aq from 2,3-
dibromopyridine.
In summary, we have developed a simple synthetic procedure
for the generation of 1,1,2,2-tetrafluoro-1,2-arylethanes from the
reaction of stable arylCF2CF2SiMe3 Ruppert−Prakash type
reagents with (hetero)aryl iodides or bromides. These reactions
are an improvement over current fluoroalkylation reactions due
to the mildness of the reaction conditions applied. However,
improved routes toward arylCF2CF2SiMe3 will be necessary to
a
1.2 equiv of 1 and 1.0 equiv of aryl iodide (0.2 mmol scale); All yields
b
are for isolated products. Reaction performed at room temperature
for 6 h. Chemical purity 91%. 0.5 mmol scale. Chemical purity 90%.
c
d
e
C
DOI: 10.1021/acs.orglett.5b01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Chang, Y.; Tewari, A.; Adi, A.-I.; Bae, C. Tetrahedron 2008, 64, 9837.
(e) Gatenyo, J.; Rozen, S. J. Fluorine Chem. 2009, 130, 332.
(8) (a) Zhu, J.; Ni, C.; Gao, B.; Hu, J. J. Fluorine Chem. 2015, 171, 139.
(b) Watanabe, Y.; Konno, T. J. Fluorine Chem. 2015, 174, 102.
(9) Saijo, H.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2014, 136,
15158.
(10) (a) Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.; Zhang, X.;
Collier, T. L.; Gouverneur, V.; Passchier, J. Nat. Chem. 2013, 5, 941.
(b) Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M.;
progress this methodology from research to process. The use of
pyridine as an alternative to phenanthroline and the ability to
carry out the reaction at 60 °C or room temperature for aryl
iodides are the key features of this cross-coupling methodology.
An additional characteristic is the range of (hetero)aryl halides
amenable to cross-coupling under such mild reaction conditions.
We anticipate that this process will facilitate research programs
focusing on the discovery of high performance materials.
Passchier, J.; Mercier, J.; Gen
Ed. 2014, 53, 7751. (c) Emer, E.; Twilton, J.; Tredwell, M.; Calderwood,
S.; Collier, L. T.; Liegault, B.; Taillefer, M.; Gouverneur, V. Org. Lett.
2014, 16, 6004.
́
icot, C.; Gouverneur, V. Angew. Chem., Int.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and full spectroscopic data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01510.
■
́
S
(11) CCDC 1401715. (a) Cosier, J.; Glazer, A. M. J. Appl. Crystallogr.
1986, 19, 105. (b) Otwinowski, Z.; Minor, W. Macromolecular
Crystallography Part A; Carter, C. W., Jr.; Sweets, R. M., Eds.; Methods
in Enzymology; Academic Press: New York, 1997; Vol. 276, p 307.
(c) Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786.
(d) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487. (d) Cooper, R. I.; Thompson, A.
L.; Watkin, D. J. J. Appl. Crystallogr. 2010, 43, 1100. (e) Parois, P.;
Cooper, R. I.; Thompson, A. L. Chem. Cent. J. 2015, 9, 30. (f) Thompson,
A. L.; Watkin, D. J. J. Appl. Crystallogr. 2011, 44, 1017.
(12) For details, see the Electronic Supporting Information.
(13) 4-(1,2,2,2-Tetrafluoro-ethyl)-1,1′-biphenyl is likely formed by
regioselective addition of fluoride onto 4-(1,2,2-trifluorovinyl)-1,1′-
biphenyl, a product resulting from competitive elimination.
(14) The formation of side-product 5a for these reactions performed in
the absence of copper iodide indicates that the substrate can serve as the
source of iodine.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: veronique.gouverneur@chem.ox.a.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the BBSRC (studentship to
M.O’D.), the ARC (SAE20131200603, to E.D.), and the
European Union (H2020-MSCA-IF-2014-658405 for a Fellow-
ship to E.D. and FP7-PEOPLE-2012-ITN-316882 for a
studentship to L.P.). V.G. holds a Royal Society Wolfson
Research Merit Award. The authors thank Dr. Amber L.
Thompson, University of Oxford, for her assistance with the
single crystal X-ray diffraction analysis of 1a.
(15) Chen, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 11628.
(16) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
REFERENCES
■
(1) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(b) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683 and
references therein. .
(2) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
and references therein. (b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. -
Asian J. 2012, 7, 1744 and references therein. .
(3) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012, 2012, 6679.
(4) (a) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91.
(b) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008,
130, 8600. (c) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics
2008, 27, 6233. (d) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun.
2009, 1909. (e) Weng, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang, W.; Feng, X.;
Huang, K. Organometallics 2011, 30, 3229. (f) Tomashenko, O. A.;
́
Escudero-Adan, E. C.; Martínez Belmonte, M.; Grushin, V. V. Angew.
Chem., Int. Ed. 2011, 50, 7655. (g) Morimoto, H.; Tsubogo, T.; Litvinas,
N. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793. (h) Hafner,
A.; Brase, S. Adv. Synth. Catal. 2013, 355, 996. (i) Mormino, M. G.; Fier,
̈
P. S.; Hartwig, J. F. Org. Lett. 2014, 16, 1744. (j) Gonda, Z.; Kovac
Weber, C.; Gati, T.; Meszaros, A.; Kotschy, A.; Novak, Z. Org. Lett. 2014,
16, 4268.
́
s, S.;
́
́
́
́
́
(5) Petko, K. I.; Kot, S. Y.; Yagupolskii, L. M. J. Fluorine Chem. 2008,
129, 301.
(6) (a) Kirsch, P.; Bremer, M.; Huber, F.; Lannert, H.; Ruhl, A.; Lieb,
M.; Wallmichrath, T. J. Am. Chem. Soc. 2001, 123, 5414. (b) Kirsch, P.;
Huber, F.; Lenges, M.; Taugerbeck, A. J. Fluorine Chem. 2001, 112, 69.
(c) Kirsch, P.; Huber, F.; Krause, J.; Heckmeier, M.; Pauluth, D. U.S.
Patent 20030230737 A1, December 2003. (d) Kirsch, P.; Bremer, M.
ChemPhysChem 2010, 11, 357.
(7) (a) Zupan, M.; Pollak, A. J. Org. Chem. 1974, 39, 2646. (b) York, C.;
Prakash, G. K. S.; Olah, G. a. J. Org. Chem. 1994, 59, 6493. (c) Singh, R.
P.; Majumder, U.; Shreeve, J. M. J. Org. Chem. 2001, 66, 6263.
D
DOI: 10.1021/acs.orglett.5b01510
Org. Lett. XXXX, XXX, XXX−XXX