Trifluoromethylation of Arylsilanes with [(phen)CuCF3]

Article abstract of DOI:10.1002/anie.201601163

A method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF₃] as the CF₃source under mild, oxidative conditions with high functional-group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C?H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C?H bond into a C?CF₃bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation.

Full text of DOI:10.1002/anie.201601163

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201601163
German Edition: DOI: 10.1002/ange.201601163
Cross-Coupling
Trifluoromethylation of Arylsilanes with [(phen)CuCF3]
Johannes Morstein+, Haiyun Hou+, Chen Cheng, and John F. Hartwig*
Abstract: A method for the trifluoromethylation of arylsilanes
is reported. The reaction proceeds with [(phen)CuCF3] as the
CF3 source under mild, oxidative conditions with high func-
tional-group compatibility. This transformation complements
prior trifluoromethylation of arenes in several ways. Most
important, this method converts arylsilanes formed by the
arenes have greatly expanded the accessibility of arylsi-
lanes.[16–19] The silylation of C H bonds forms arylsilanes with
regioselectivities that are enhanced or distinct from those of
À
the borylation of C H bonds.[17,20] The greater selectivity and
À
stability enables the late-stage functionalization of arenes and
heteroarenes in complex molecules to form arylsilane inter-
mediates when the arylboronate analogues are unstable.
Thus, if a method to convert arylsilanes into trifluoromethyl
arenes could be developed, a method to prepare trifluoro-
methylarenes from a wide range of arenes and heteroarenes,
À
silylation of aryl C H bonds to trifluoromethylarenes, thereby
allowing the conversion of arenes to trifluoromethylarenes.
The unique capabilities of the reported method are demon-
À
À
strated by the conversion of a C H bond into a C CF3 bond in
active pharmaceutical ingredients which do not undergo this
overall transformation by alternative functionalization pro-
cesses, including a combination of borylation and trifluoro-
methylation.
À
via the products of C H bond silylation, would result.
We report the trifluoromethylation of readily accessible,
stable arylsilanes. These reactions occur with [(phen)CuCF3]
as the CF3 source and air as the oxidant. The reactions occur
with a broad scope of arenes, heteroarenes, and active
À
F
luoroalkyl substituents modulate physicochemical proper-
pharmaceutical ingredients and, when combined with C H
bond silylation, provide access to trifluoromethylarenes
directly from both simple and complex arenes.
ties, metabolic stability, and protein–ligand interactions.[1] For
this reason, approximately 30% of the most recently
approved drugs contain fluorine, and nearly half of these
fluorinated molecules contain a trifluoromethyl group.[2] Yet,
most commercial syntheses of trifluoromethylarenes still rely
on Swarts reactions[3] of benzotrichlorides with HF and SF5
under harsh conditions, and are unsuitable for transforma-
tions of molecules containing most functional groups. Most
commercial syntheses of trifluoromethyl heteroarenes are
conducted by condensation reactions of trifluoroacetic acid
derivatives.[4] Although milder than the Swarts reactions,
these methods limit the position on the heteroarene at which
a trifluoromethyl group can be installed. In both cases, these
methods require that the trifluoromethyl group be installed
early in a synthetic sequence.
To initiate our search for reagents and conditions which
lead to the trifluoromethylation of arylsilanes, we investigated
reaction conditions reported for the trifluoromethylation of
arylboranates.[5–11]
We
tested
this
reaction
with
PhSiMe(OSiMe3)2 (Ph-HMTS for phenyl heptamethyltrisi-
loxane) because Ar HMTS compounds can be formed by the
silylation of aryl and heteroaryl C H bonds. A range of
À
À
common trifluoromethylation reagents, including both elec-
trophilic CF3 sources (Togniꢀs reagent[21] and Umemotoꢀs
reagent[22]
)
and nucleophilic CF3 sources (Ruppertꢀs
reagent,[23] Langloisꢀ reagent,[24] Chenꢀs reagent,[25] and
[(phen)CuCF3][26]; Scheme 1) were tested as the source of
the CF3 group. We conducted reactions with a series of
fluoride sources to activate the arylsilane by forming a hyper-
valent silicon species. The identity of the source of fluoride is
likely to be crucial for the activation of the silane. The
fluoride must be sufficiently nucleophilic to add to the silicon,
but it must not trigger rapid cleavage of the carbon–silicon
bond. Most combinations of the sources of trifluoromethyl
groups and fluoride we tested yielded either trace amounts or
More recently, arylboron reagents have been shown to
undergo copper-mediated, oxidative trifluoromethylation
reactions.[5–11] The ability to form trifluoromethylarenes
from arylboronates is important because the arylboronates
can be formed by metal-catalyzed borylation of aryl C H
bonds, which occurs with regioselectivities that are controlled
À
[12,13]
À
by the steric environment at the aryl C H bonds.
Yet, organosilanes would be attractive alternatives to
arylboronates as precursors to trifluoromethylarenes because
silanes are inexpensive[14] and because arylsilanes and heter-
oarylsilanes are more stable than their boronate counter-
parts.[15] Recent advances in the regioselective, catalytic
À
silylation of C H bonds in unactivated arenes and hetero-
[*] J. Morstein,[+] H. Hou,[+] C. Cheng, Prof. Dr. J. F. Hartwig
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
E-mail: jhartwig@berkeley.edu
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601163.
Scheme 1. Common reagents for the trifluoromethylation of prefunc-
tionalized arenes. Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
no desired product (see the Supporting Information for a list
of these reaction conditions).
oxidant in this system.[29] Finally, an evaluation of these
reaction conditions with a series of arylsilanes, including
phenyl trimethylsilane, triphenyl silanol, and both dimethoxy-
methyl and trimethoxy phenylsilane (see the Supporting
Information) showed that the yield of trifluoromethylbenzene
was highest from the reaction of phenyl hepatmethyltrisilox-
ane.
With these reaction conditions in hand, we explored the
scope of the trifluoromethylation of arylsilanes bearing the
HMTS group (Table 2). The reaction of arylsilanes with
À
However, reactions of Ph HMTS with [(phen)CuCF3] (1)
and KF in air formed the trifluoromethylarene product in
a measurable yield (20%).[27] The [(phen)CuCF3] is commer-
cially available and is a free-flowing solid, which can be stored
indefinitely under nitrogen and weighed in air. Our group
previously reported the trifluoromethylation of aryl
iodides,[26] aryl boronates,[27] and heteroaryl bromides[28] with
1 (Scheme 2a,b). Thus, a convenient method to convert
arylsilanes into trifluoromethylarenes would be created if the
yields of this initial reaction could be improved.
Table 2: Trifluoromethylation of arylsilanes.[a,b]
Scheme 2. Copper-mediated trifluoromethylation of arylsilanes.
DMF=N,N-dimethylformamide.
Further studies showed that the trifluoromethylation of
À
Ph HMTS (Table 1) can occur in high yields with the proper
fluoride source and solvent. The reactions with AgF under air
occurred in higher yields than those with either KF, KHF2, or
TBAF. Interestingly, reactions in the presence of benzoqui-
none formed trifluoromethylbenzene in a higher yield (71%)
than with air as an oxidant alone (62% yield). The same
reaction with benzoquinone under nitrogen gave the product
in 42% yield, thus suggesting that oxygen serves as the
[a] Reactions run on a 0.1 mmol scale to determine yields by 19F NMR
spectroscopy and run on a 0.3 mmol scale to obtain yields of the isolated
products. Yields determined by 19F NMR spectroscopy are listed first
followed by yields of isolated products within parentheses. [b] Deter-
mined by 19F NMR spectroscopy with 4-trifluoromethoxyanisole as the
internal standard. [c] Reaction run without benzoquinone.
Table 1: Optimization of trifluoromethylation of PhSiMe(OSiMe3)2.[a]
1 tolerates a wide range of functional groups. Substrates
bearing a chloride, ether, ketone, ester, amide, nitrile, or
trifluoromethyl functionality (3a–f) gave the trifluoromethyl-
arene in good yields. In general, the reactions of more
electron-deficient arenes (3a–e) formed the trifluoromethyl-
arene products in higher yields than did reaction with
electron-rich arenes (3g). More specifically, the 3,4-dimethyl-
phenylsilane gave the corresponding trifluoromethylxylene in
a yield (34%) which was lower than that of most other
examples. Reaction of a substrate containing a bromide
substituent (3h) also gave the product in a moderate yield
(39%), most likely because of competing trifluoromethyla-
tion at the aryl bromide.[30]
Entry Oxidant Additive
Fluoride
(2.0 equiv)
Solvent Yield [%][b]
1
2
3
4
5
6
7
8
9
air
air
air
air
air
–
air
air
–
–
–
–
–
KF
DMF
DMF
DMF
DMF
DMF
DMF
20
38
62
17
–
KHF2
AgF
TBAF
–
KHF2
AgF
AgF
AgF
KOTMS (2.0 equiv)
–
–
BQ (3.0 equiv)
BQ (3.0 equiv)
8
DMSO 58
DMF
DMF
71
42
We subsequently explored the scope of the trifluorome-
thylation of heteroarylsilanes (Table 3). The reaction occurs
with five-membered ring heteroarylsilanes, including benzo-
fused examples, such as silylindoles. The reaction also occurs
[a] Reactions run on a 0.1 mmol scale. [b] Determined by 19F NMR
spectroscopy with 4-trifluoromethoxyanisole as the internal standard.
BQ=p-benzoquinone, TBAF=tetra-n-butylammonium fluoride.
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 3: Trifluoromethylation of heteroarylsilanes.[a,b]
Scheme 3. Late-stage trifluoromethylation of pharmaceutically active
molecules. Yields determined by 19F NMR spectroscopy (using 4-
trifluoromethoxyanisole as an internal standard) are listed first fol-
lowed by yields of isolated products given within parentheses.
cod=1,5-cyclootadiene.
[a] Reactions run on a 0.1 mmol scale to determine yields by 19F NMR
spectroscopy and run on a 0.3 mmol scale to obtain yields of the isolated
products. Yields determined by 19F NMR spectroscopy are listed first
followed by yields of isolated products within parentheses. [b]
thylthiophene in good yield (89%), tolerating all four func-
tional groups present, with only minor epimerization of the
stereocenter (3.8% of 7 epimerized). The overall yield of 8
for the two-step sequence comprising silylation and trifluoro-
methylation was 77% (68% isolated, 95.1% ee). Likewise,
reaction of the silylated aripiprazole gave the corresponding
trifluoromethylarene in 53% yield (41% isolated). The
compounds 8 and 10 are not accessible by an analogous
sequence comprising borylation and trifluoromethylation.
The borylation of clopidogrel gave a mixture of constitutional
isomers, as determined by GC and 11B NMR spectroscopy.
The borylated aripiprazole is unstable; this arylboronate
decomposed during purification on silica gel.
In conclusion, we report the first method for the
trifluoromethylation of arylsilanes. Trifluoromethylation of
the arylsilanes with 1 proceeds with high functional-group
compatibility, broad scope of arenes and heteroarenes, and is
suitable for the functionalization of pharmaceutically active
molecules. Furthermore, the trifluoromethylation of arylsi-
lanes gives access to complex, trifluoromethylated molecules
which are inaccessible by the sequence of borylation and
trifluoromethylation.
Determined by 19F NMR spectroscopy with 4-trifluoromethoxyanisole as
an internal standard. [c] Reaction run at 808C. Boc=tert-butoxycarbonyl.
with six-membered ring heteroarylsilanes, including those
derived from pyridines, pyrazines, and quinolines. The ability
to conduct the reaction with both electron-rich and electron-
poor heteroarenes demonstrates the exceptionally broad
scope of the reaction conditions we developed.
The trifluoromethylation of heteroarylsilanes is particu-
larly valuable because heteroarylsilanes are less prone to
oxidation and protodemetalation than are heteroarylboro-
nates. For example, trifluoromethyl pyrazines (6c) cannot be
prepared from an isolated heteroarylboronate because of
rapid protodeborylation.[31] Moreover, the combination of
À
C H bond silylation and trifluoromethylation of the hetero-
arylsilane provides isomers which complement those gener-
ated from direct trifluoromethylation. For example, the
reaction of 5a gave 3-trifluoromethylpyrrole in an excellent
yield (96%), whereas direct trifluoromethylation with
common trifluoromethylation reagents, such as Togniꢀs
reagent,[32]
trifluoromethyliodide,[33]
and
Umemotoꢀs
reagent,[34] form the product from reaction at the 2’ position
of pyrrole. Although the borylation of the Boc-protected
pyrrole occurs at the 3’ position, the yields of trifluoromethyl
pyrroles from the corresponding heteroarylboronates are
below 50%.[35]
Encouraged by the high functional-group tolerance and
broad substrate scope of the trifluoromethylation of arylsi-
lanes, we evaluated the applicability of our conditions to the
late-stage trifluoromethylation of pharmaceutically active
molecules (Scheme 3). We prepared analogues of clopidogrel
(antiaggregant) and aripiprazole (antipsychotic) containing
HMTS groups under the reaction conditions we reported
previously.[18] Most striking, the trifluoromethylation of the
silylated clopidogrel gave the corresponding trifluorome-
Experimental Section
General procedure for the synthesis of trifluoromethyl arenes from
arylsilanes with 1: To an oven-dried 20 mL vial was added
1 (0.36 mmol, 1.2 equiv), anhydrous DMF (3.0 mL, stored under
nitrogen), AgF (0.60 mmol, 2.0 equiv), p-benzoquinone (0.90 mmol,
3.0 equiv), and arylsilane (0.30 mmol, 1.0 equiv) under air. The
suspension was purged with dry air for 30 seconds, and the vial was
sealed with a Teflon-lined cap and heated at 508C for 16 h under
vigorous stirring. The suspension was allowed to cool to room
temperature. Water was added to the reaction mixture (5 mL), and
the aqueous layer was extracted with diethylether (3 ꢁ 5 mL). The
organic layers were combined, washed with a saturated NaCl solution
(1 ꢁ 2 mL), dried over anhydrous MgSO4, and concentrated. The
residue was purified by flash column chromatography or preparative
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
thin layer chromatography. See the Supporting Information for
detailed procedures.
[16] C. Cheng, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 12064 –
12072.
[17] C. Cheng, J. F. Hartwig, Science 2014, 343, 853 – 857.
[18] C. Cheng, J. F. Hartwig, J. Am. Chem. Soc. 2015, 137, 592 – 595.
[19] A. A. Toutov, W.-B. Liu, K. N. Betz, A. Fedorov, B. M. Stoltz,
R. H. Grubbs, Nature 2015, 518, 80 – 84.
Acknowledgments
[20] C. Cheng, J. F. Hartwig, Chem. Rev. 2015, 115, 8946 – 8975.
[21] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12,
2579 – 2586.
[22] U. Teruo, I. Sumi, Tetrahedron Lett. 1990, 31, 3579 – 3582.
[23] I. Ruppert, K. Schlich, W. Volbach, Tetrahedron Lett. 1984, 25,
2195 – 2198.
[24] B. R. Langlois, E. Laurent, N. Roidot, Tetrahedron Lett. 1991, 32,
7525 – 7528.
[25] Q.-Y. Chen, S.-W. Wu, J. Chem. Soc. Chem. Commun. 1989, 705 –
706.
We thank the NIH (GM-115812) for support of this work.
J.M. thanks the German National Academic Foundation
(Studienstiftung) for supporting his research in the Hartwig
lab. We thank Michael Mormino for a sample of (phen)-
CuCF3, Jeff Pelton (UC Berkeley NMR facility) for expert
technical assistance, and Johnson-Matthey for a gift of
[{Ir(cod)Cl}2].
Keywords: arenes · copper · cross-coupling · fluorine · silanes
[26] H. Morimoto, T. Tsubogo, N. D. Litvinas, J. F. Hartwig, Angew.
Chem. Int. Ed. 2011, 50, 3793 – 3798; Angew. Chem. 2011, 123,
3877 – 3882.
[27] N. D. Litvinas, P. S. Fier, J. F. Hartwig, Angew. Chem. Int. Ed.
2012, 51, 536 – 539; Angew. Chem. 2012, 124, 551 – 554.
[28] M. G. Mormino, P. S. Fier, J. F. Hartwig, Org. Lett. 2014, 16,
1744 – 1747.
[1] S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320 – 330.
[29] Although some reactions without added benzoquinone form the
trifluoromethylarene in good yield, most reactions of arenes
which are not sensitive to oxidation occurred in about 20%
higher yield in the presence of benzoquinone than in the absence
of this oxidant. See the Supporting Information for a series of
comparisons in the presence and absence of benzoquinone.
[30] This assertion is supported by the observation of additional
[2] Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. AceÇa, V. A.
Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422 – 518.
[3] F. Swarts, Bull. Acad. R. Belg. 1892, 24, 309.
[4] V. A. Petrov, Flourinated Heterocyclic Compounds: Synthesis
Chemistry, and Applications, Vol. 1, Wiley, Weinheim, 2009.
[5] L. Chu, F.-L. Qing, Org. Lett. 2010, 12, 5060 – 5063.
[6] B. A. Khan, A. E. Buba, L. J. Gooßen, Chem. Eur. J. 2012, 18,
1577 – 1581.
[7] Y. Li, L. Wu, H. Neumann, M. Beller, Chem. Commun. 2013, 49,
2628 – 2630.
[8] T. Liu, X. Shao, Y. Wu, Q. Shen, Angew. Chem. Int. Ed. 2012, 51,
540 – 543; Angew. Chem. 2012, 124, 555 – 558.
[9] T. D. Senecal, A. T. Parsons, S. L. Buchwald, J. Org. Chem. 2011,
76, 1174 – 1176.
Aryl CF3 compounds by 19F NMR spectroscopy.
À
[31] S. A. Sadler, H. Tajuddin, I. A. I. Mkhalid, A. S. Batsanov, D.
Albesa-Jove, M. S. Cheung, A. C. Maxwell, L. Shukla, B.
Roberts, D. C. Blakemore, Z. Lin, T. B. Marder, P. G. Steel,
Org. Biomol. Chem. 2014, 12, 7318 – 7327.
[32] M. S. Wiehn, E. V. Vinogradova, A. Togni, J. Fluorine Chem.
2010, 131, 951 – 957.
[33] T. Kino, Y. Nagase, Y. Ohtsuka, K. Yamamoto, D. Uraguchi, K.
Tokuhisa, T. Yamakawa, J. Fluorine Chem. 2010, 131, 98 – 105.
[34] J.-J. Yang, R. L. Kirchmeier, J. M. Shreeve, J. Org. Chem. 1998,
63, 2656 – 2660.
[10] J. Xu, D.-F. Luo, B. Xiao, Z.-J. Liu, T.-J. Gong, Y. Fu, L. Liu,
Chem. Commun. 2011, 47, 4300 – 4302.
[11] Y. Ye, S. A. Kꢂnzi, M. S. Sanford, Org. Lett. 2012, 14, 4979 –
4981.
[12] J. F. Hartwig, Acc. Chem. Res. 2012, 45, 864 – 873.
[13] T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi, J. F.
Hartwig, J. Am. Chem. Soc. 2002, 124, 390 – 391.
[14] A. A. Yaroshevsky, Geochem. Int. 2006, 44, 48 – 55.
[15] S. E. Denmark, A. Ambrosi, Org. Process Res. Dev. 2015, 19,
982 – 994.
[35] Reaxys Search.
Received: February 1, 2016
Revised: April 10, 2016
Published online: && &&, &&&&
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Cross-Coupling
J. Morstein, H. Hou, C. Cheng,
J. F. Hartwig*
&&&& — &&&&
Trifluoromethylation of Arylsilanes with
[(phen)CuCF3]
All about the source: The first trifluoro-
methylation of arylsilanes occurs with
[(phen)CuCF3] as the CF3 source and AgF
as the activator under mild, oxidative
conditions; the choice of both reagents
was shown to be crucial for the reported
transformation. The method shows high
functional-group compatibility, and late-
stage functionalization of active pharma-
ceutical ingredients is possible. DMF=
N,N-dimethylformamide, phen=9,10-
phenanthroline.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!