Ir-catalyzed preparation of SF5-substituted potassium aryl trifluoroborates via C-H borylation and their application in the Suzuki-Miyaura reaction

Article abstract of DOI:10.1021/ol4025666

The preparation of new pentafluorosulfanyl-substituted potassium aryltrifluoroborates via Ir-catalyzed C-H borylation is reported. The utility of these novel building blocks was demonstrated in the Suzuki-Miyaura cross-coupling reaction, giving access to

Full text of DOI:10.1021/ol4025666

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ir-Catalyzed Preparation of
SF5‑Substituted Potassium Aryl
Trifluoroborates via CꢀH Borylation and
Their Application in the SuzukiꢀMiyaura
Reaction
Adrien Joliton and Erick M. Carreira*
Laboratory of Organic Chemistry, ETH-Zu€rich, HCI H335, Wolfgang-Pauli-Strasse 10,
8093 Zu€rich, Switzerland
carreira@org.chem.ethz.ch
Received September 5, 2013
ABSTRACT
The preparation of new pentafluorosulfanyl-substituted potassium aryltrifluoroborates via Ir-catalyzed CꢀH borylation is reported. The utility of
these novel building blocks was demonstrated in the SuzukiꢀMiyaura cross-coupling reaction, giving access to 3,5-disubstituted penta-
fluorosulfanylbenzenes.
In recent years, the pentafluorosulfanyl group has gained
increasing attention because of its particular combination of
properties. The SF5 is often compared to trifluoromethyl;
however it is more electronegative (Hammett substituent
constants: for SF5 σI = 0.55, for CF3 σI = 0.39)1 and
possesses higher intrinsic lipophilicity (Hansch hydropho-
bicity constants: for SF5 π = 1.51, for CF3 π = 1.09).2
Moreover, the SF5 displays higher chemical and thermal
stability.3 These assets make the pentafluorosulfanyl group
increasingly attractive, and several examples of its potential
for various applications have been reported, such as for agro-
chemicals and pharmaceuticals, and also in material sciences,
including polymers, liquid crystals, and energetic materials.4
The first synthesis of pentafluorosulfanylbenzene was
reported by Sheppard 50 years ago by oxidative fluorination
of aryl disulfides with silver difluoride.5 However, yields
were low and the substrate scope was limited to a few nitro-
substituted phenylsulfur pentafluorides. Improvements
in the preparation of SF5-aryl compounds were achieved
recently. Notably, Umemoto developed an efficient two-
step procedure, involving the synthesis of SF4Cl-substituted
aromatics, which were treated with a fluoride source, such as
zinc difluoride or even hydrofluoric acid in pyridine to give
ArSF5.6
More expansive applications of the pentafluorosulfanyl
group are limited by the paucity of building blocks that are
generally available. Herein, we document the implementa-
tion of the Ir-catalyzed CꢀH borylation reaction of Hartwig,
Ishiyama, and Miyaura with simple pentafluorosulfanylar-
enes to provide access to an expanded set of SF5-building
blocks from the parent hydrocarbon. Given that the
chemistry of SF5-substituted arenes is relatively unex-
plored, we showcase that they can be subjected to Suzukiꢀ
Miyaura cross-coupling reactions (Scheme 1).
(1) Sheppard, W. A. J. Am. Chem. Soc. 1962, 84, 3072–3076.
(2) Hansch, C.; Muir, R. M.; Fujita, T.; Maloney, P. P.; Geiger, F.;
Streich, M. J. Am. Chem. Soc. 1963, 85, 2817–2824.
(3) (a) Sheppard, W. A. J. Am. Chem. Soc. 1962, 84, 3064–3072. (b)
Bowdem, R. D.; Comina, P. J.; Greenhall, M. P.; Kariuki, B. M.;
Loveday, A.; Philp, D. Tetrahedron 2000, 56, 3399–3408.
Using the electron withdrawing effect of the pentafluor-
osulfanyl group, nucleophilic substitutions of halogens,7
(4) (a) Welch, J. T. Fluorine in Pharmaceutical and Medicinal Chem-
istry. From Biophysical Aspects to Clinical Applications; Gouverneur, V.,
M€uller, K., Eds.; Imperial College Press: London, 2012; pp 175ꢀ207. (b)
Winter, R. W., Dodean, R. A., Gard, G. A. Fluorine-Containing Syn-
thons; ACS Symposium Series 911; Soloshonok, V. A., Ed.; American
Chemical Society: Washington DC, 2005; pp 87ꢀ118.
(5) (a) Sheppard, W. A. J. Am. Chem. Soc. 1960, 82, 4751–4752. (b)
Sheppard, W. A. J. Am. Chem. Soc. 1962, 84, 3064–3072.
(6) Umemoto, T.; Garrick, L. M.; Saito, N. Beilstein J. Org. Chem.
2012, 8, 461–471.
r
10.1021/ol4025666
XXXX American Chemical Society

4,40-di-tert-butyl-2,20-bipyridine (dtbpy).12 This reaction
allowed the access to various functionalities via one-pot seq-
uences, such as halogenation, cyanation, alkylation, hydro-
xylation, or amination.13 Additionally, one-pot synthesis
of 3,5-disubstituted potassium aryltrifluoroborates via Ir-
catalalyzed CꢀH borylation followed by treatment with
KHF2 has been reported, but not for SF5-aryl substrates.14
Compared to other boron reagents, organotrifluorobo-
rate salts are exceptionally stable toward air and moisture.
Moreover, they are easily isolated, usually by simple
precipitation or recrystallization from acetone with diethyl
ether, and they show comparable reactivity to boronic
acids in many reactions, such as SuzukiꢀMiyaura cross-
coupling.15,16 Consequently, we decided to examine the
borylation reaction for the introduction of trifluorobo-
rates onto SF5-containing scaffolds.
In prospecting experiments we were delighted to note
that the pentafluorosulfanyl group displayed excellent
compatibility with Ir-catalyzed CꢀH borylation condi-
tions of Hartwig, Ishiyama, and Miyaura. After complete
conversion of the precursor, direct addition of water and
KHF2 to the reaction mixture converted the resulting
boronic ester into the corresponding aryltrifluoroborate
(Table 1). To the best of our knowledge, this is the first
example of the CꢀH activation reaction with a pentafluor-
osulfanyl-containing aryl system. Thus, from readily
available meta-substituted SF5-aryl compounds,17 we were
able to provide access to this novel class of buildings
blocks. Several examples with various substituents in
meta-position of the SF5-group were obtained in good to
high yields, such as methoxy, methyl ester, or halogens.
Interestingly, contrary to most of the potassium organotri-
fluoroborates, SF5ꢀArBF3K are soluble in diethyl ether,
emphasizing the lipophilicity of the pentafluorosulfanyl
group. Therefore, isolation was achieved by precipitation
from acetone with chloroform or dichloromethane. The
pinacol coproduct could be removed by additional wash-
ing of the solids to afford the SF5-substituted potassium
aryltrifluoroborates in high purity, according to 19F and
1H NMR spectra. The simplicity of the approach is under-
scored in a preparative scale reaction that was conducted
to give more than 3 g of 2a from a meta-methoxy precursor
in 92% yield.
Scheme 1. Access to SF5ꢀArBF3K via CꢀH Borylation
nitro group,8 or hydrogen9 have been described. Despite
the increasing interest in exploring and diversifying the
chemistry of aryl-SF5 compounds, their utility as sub-
strates in a number ofmodernmetal-catalyzed transforma-
tions remains underexplored. Knochel prepared mag-
nesium reagents, by Br/Mg exchange using iPrMgCl LiCl
3
and by directed metalation using TMP2Mg 2LiCl. The
3
handful of examples underwent further transformations,
such as cross-coupling reactions.10 However, the current
portfolio of basic building blocks incorporating SF5 re-
mains limited. Indeed, in most of the synthesis work, the
routes can be traced back to the same set of starting
materials: para-ormeta-(pentafluorosulfanyl)nitrobenzene.
Because of our interest in providing greater access to
novel building blocks for drug discovery,11 we have been
exploring ways of developing new approaches to SF5
compounds.
Hartwig, Ishiyama, and Miyaura developed a powerful
catalytic system for the meta-directed CꢀH borylation
of 1,3-disubstituted arenes using [{Ir(OMe)(cod)}2] and
(7) (a) Sipyagin, A. M.; Bateman, C. P.; Tan, Y. T.; Thrasher, J. S.
J. Fluorine Chem. 2001, 112, 287–295. (b) Sipyagin, A. M.; Enshov, V. S.;
Kashtanov, S. A.; Bateman, C. P.; Mullen, B. D.; Tan, Y. T.; Thrasher,
J. S. J. Fluorine Chem. 2004, 125, 1305–1316.
ꢀꢁ
´
ꢀ
(8) Beier, P.; Pastyrıkova, T.; Vida, N.; Iakobson, G. Org. Lett. 2011,
13, 1466–1469.
(9) (a) Beier, P.; Pastyrikova, T.; Iakobson, G. J. Org. Chem. 2011,
76, 4781–4786. (b) Beier, P.; Pastyrikova, T. Tetrahedron Lett. 2011, 52,
4392–4394. (c) Pastyrikova, T.; Iakobson, G.; Vida, N.; Pohl, R.; Beier,
P. Eur. J. Org. Chem. 2012, 2123–2126. (d) Vida, N.; Beier, P. J. Fluorine
Chem. 2012, 143, 130–134. (e) Beier, P.; Pastyrikova, T. Beilstein J. Org.
Chem. 2013, 9, 411–416.
In order to demonstrate the usefulness of these SF5-
building blocks, we set out to explore their reactivity in the
(10) Frischmuth, A.; Unsinn, A.; Groll, K.; Stadtmuller, H.; Knochel,
P. Chem.;Eur. J. 2012, 18, 10234–10238.
(11) (a) Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Fischer, H.;
€
(13) For a review, see: Mkhalid, I. A. I.; Barnard, J. H.; Marder,
T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931.
(14) Murphy, J. M.; Tzchucke, C. C.; Hartwig, J. F. Org. Lett. 2007,
9, 757–760.
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2006, 45, 7736–7739. (b) Wuitschik, G.; Rogers-Evans, M.;
€
Buckl, A.; Bernasconi, M.; Marki, M.; Godel, T.; Fischer, H.; Wagner,
B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.;
(15) (a) Molander, G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867–1870.
(b) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A.
€
Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4512–4515.
(c) Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.;
ꢀ
J. Am. Chem. Soc. 2008, 130, 9257–9259. (c) Sandrock, D. L.; Jean-Gerard,
€
Schuler, F.; Rogers-Evans, M.; Muller, K. J. Med. Chem. 2010, 53,
3227–3246. (d) For a review, see: Burkhard, J. A.; Wuitschik, G.;
L.; Chen, C. Y.; Dreher, S. D.; Molander, G. A. J. Am. Chem. Soc. 2010,
132, 17108–17110. For review, see: (d) Molander, G. A.; Ellis, N. Acc.
Chem. Res. 2007, 40, 275–286.
(16) (a) Darses, S.; Genet, J. P.; Brayer, J. L.; Demoute, J. P.
Tetrahedron Lett. 1997, 38, 4393–4396. (b) Darses, S.; Michaud, G.;
Genet, J. P. Tetrahedron Lett. 1998, 39, 5045–5048. (c) Darses, S.;
Michaud, G.; Genet, J. P. Eur. J. Org. Chem. 1999, 1875–1883. For a
review, see: (d) Darses, S.; Genet, J. P. Chem. Rev. 2008, 108, 288–325.
€
Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed.
2010, 49, 9052–9067. (e) Li, D. B.; Rogers-Evans, M.; Carreira, E. M.
Org. Lett. 2011, 13, 6134–6136. (f) Li, D. B.; Rogers-Evans, M.;
Carreira, E. M. Org. Lett. 2013, 15, 4766–4769.
(12) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi,
N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390–391. (b)
Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem.,
Int. Ed. 2002, 41, 3056–3058. (c) Boller, T. M.; Murphy, J. M.; Hapke,
M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
127, 14263–14278.
^
^
^
^
(17) Most of these starting materials are commercially available, but
in the present case, they were prepared in our laboratory. See Supporting
Information for detailed preparations.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. One-Pot Synthesis of SF5-Substituted Potassium
Aryltrifluoroboratesa
Table 2. Cross-Coupling Reactions of SF5ꢀArBF3K with Aryl
Halides
entry
R
2
yield (%)
1
2
3
4
5
6
7
OMe
CN
2a
2b
2c
2d
2e
2f
94
88
65
81
89
76
72b
CO2Me
NMe2
Cl
Br
I
2g
a Reaction conditions: 1, pin2B2 (0.7 equiv), {[Ir(OMe)(cod)]2} (0.75
mol %), dtbpy (1.5 mol %), THF, 80 °C, 24 h. Then KHF2 (5.7 equiv),
THF/H2O (5:3), rt, 6 h. b 48 h were needed for the CꢀH borylation.
SuzukiꢀMiyaura reaction. After screening of conditions
for the cross-coupling of aryl halides and organotrifluor-
oborates, we identified those of Molander as promising.18
In our case, slight modifications of these conditions were
necessary in order to obtain satisfying yields. The choice of
the method was dependent on the aryl halide used (Table 2).
Thus, employing 2 mol % of PdCl2(dppf) CH2Cl2 with 3
3
equivalents of triethylamine in EtOH at 85 °C (Method A)
allowed cross-coupling of the meta-methoxy derivative of
SF5ꢀArBF3K 2a with various functionalized aryl halides
(Table 2, entries 1ꢀ3). The use of substrates bearing
electron withdrawing groups under conditions A resulted
in a decrease in yield of product (Table 2, entries 4ꢀ5).
Attempts to improve the reaction by using Pd(OAc)2 with
K2CO3 in MeOH at 80 °C (Method B) failed with only
traces of the biaryl product being observed. However, with
heteroaryl halides, the conditions of method A were not
effective, whereas using method B afforded the desired
cross-coupling product. For example, when 3-bromopyridine
was submitted to reaction conditions B, the corresponding
biaryl was obtained in excellent yield (Table 2, entry 7),
whereas method A afforded less than 20% conversion.
Reaction of 2a with unprotected 4- and 5-bromoindoles
could be achieved in modest yield (Table 2, entries 8ꢀ9).
Diheteroaryl halide 5-bromopyrimidine also participated
in the reaction and gave the corresponding cross-coupling
product in excellent yield (Table 2, entry 10).
In conclusion, we have described the preparation of new
stable and versatile 3,5-disubstituted potassium aryltri-
fluoroborates bearing a pentafluorosulfanyl group. These
new compounds are potential important building blocks
for drug discovery and agrochemicals. Their synthesis was
achieved in one-pot, involving Hartwig, Ishiyama, and
Miyaura Ir-catalyzed CꢀH borylation. We also showed
their compatibility in the SuzukiꢀMiyaura cross-coupling
a Method A: ArꢀX, 2 (1.2 equiv), Et3N (3.0 equiv), PdCl2(dppf)
3
CH2Cl2 (2 mol %), EtOH, 85 °C, 12ꢀ16 h. Method B: ArꢀX, 2 (2.0 equiv),
K2CO3 (3.0 equiv), Pd(OAc)2 (5 mol %), MeOH, 80 °C, 16 h.
reaction with aryl and heteroaryl halides, allowing the
access to a library of unprecedented 3,5-disubstituted
SF5-aryl compounds.
Acknowledgment. We gratefully acknowledge financial
€
support from the ETH Zurich (ETH-23-11-1) and Spir-
ochem for supplying meta-(pentafluorosulfanyl)nitrobenzene.
We are also grateful to F. Hofmann-La Roche for generous
support of our research program and to Dr. Jean-Marc
Plancher, senior scientist at F. Hofmann-La Roche, for
fruitful discussions.
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds. This mate-
rial is available free of charge via the Internet http://pubs.
acs.org.
(18) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–
4314.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C