Triazole-Enabled Ruthenium(II) Carboxylate-Catalyzed C-H Arylation with Electron-Deficient Aryl Halides

Article abstract of DOI:10.1055/a-1495-6994

A triazole-directed direct C H arylation of arenes with electron-deficient aryl halides or a synthetically useful pyrimidyl chloride was achieved through ruthenium catalysis. Our novel strategy provides operationally simple and environmentally benign access to highly functionalized hetarenes, avoiding the use of strong organometallic bases. Detailed studies revealed a significant effect of the phosphine ligand, thereby permitting the reaction to occur with excellent levels of chemoand position selectivity.

Full text of DOI:10.1055/a-1495-6994

Submission Date:
Accepted Date:
Publication Date:
2021-04-14
2021-04-30
2021-04-30
Accepted Manuscript
Synlett
Triazole-Enabled Ruthenium(II)carboxylate-Catalyzed C–H Arylation with Elec-
tron-deficient Aryl Halides
Torben Rogge, Thomas Müller, Hendrik Simon, Xiaoyan Hou, Simon Wagschal, Diego Broggini, Lutz Ackermann.
Affiliations below.
DOI: 10.1055/a-1495-6994
Please cite this article as: Rogge T, Müller T, Simon H et al. Triazole-Enabled Ruthenium(II)carboxylate-Catalyzed C–H Arylation with
Electron-deficient Aryl Halides. Synlett 2021. doi: 10.1055/a-1495-6994
Conflict of Interest: The authors declare that they have no conflict of interest.
This study was supported by Deutsche Forschungsgemeinschaft (http://dx.doi.org/10.13039/501100001659), SPP1807
Abstract:
The triazole-directed direct C–H arylation of arenes with electron-deficient aryl halides and a synthetically-useful pyrimidyl
chloride was achieved via ruthenium catalysis. Our novel strategy provides operationally-simple and environmentally-benign
access to highly functionalized heteroarenes, avoiding the use strong organometallic bases. Detailed studies revealed a signifi-
cant effect of the phosphine ligand, thus allowing for the reaction to occur with excellent levels of chemo- and position-selecti-
vity.
Corresponding Author:
Lutz Ackermann, Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Tammannstr. 2, 37077 Göt-
tingen, Germany, lutz.ackermann@chemie.uni-goettingen.de
Affiliations:
Torben Rogge, Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Göttingen, Germany
Thomas Müller, Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Göttingen, Germany
Hendrik Simon, Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Göttingen, Germany
[…]
Lutz Ackermann, Georg-August-Universität Göttingen, Institut für Organische und Biomolekulare Chemie, Göttingen, Germany
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will
undergo copyediting, typesetting, and review of the resulting proof before it is published in its
final form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.

Synlett
Letter / Cluster / New Tools
Triazole-Enabled Ruthenium(II)carboxylate-Catalyzed C–H Arylation with
Electron-deficient Aryl Halides
Torben Roggea,†
Thomas Müllera
Hendrik Simona
Xiaoyan Houa
Simon Wagschalb
Diego Broggini*b
Lutz Ackermann*a,c
a Institut für Organische und Biomolekulare Chemie, Georg-
August-Universität Göttingen, Tammannstraße 2, 37077
Göttingen (Germany)
b Discovery Product Development and Supply, Janssen
Pharmaceutica, Hochstrasse 201, 8200 Schaffhausen
(Switzerland)
c Wöhler Research Institute for Sustainable Chemistry, Georg-
August-Universität Göttingen, Tammannstraße 2, 37077
Göttingen (Germany)
* indicates the main/corresponding author.
† these authors contributed equally.
dbroggin@its.jnj.com
Lutz.Ackermann@chemie.uni-goettingen.de
Received:
Accepted:
Published online:
DOI:
Abstract The triazole-directed direct C–H arylation of arenes with electron-
deficient aryl halides and a synthetically-useful pyrimidyl chloride was
achieved via ruthenium catalysis. Our novel strategy provides operationally-
simple and environmentally-benign access to highly functionalized
heteroarenes, avoiding the use strong organometallic bases. Detailed studies
revealed a significant effect of the phosphine ligand, thus allowing for the
reaction to occur with excellent levels of chemo- and position-selectivity.
Key words C–H activation, arylation; ruthenium; heteroarenes
During the last decade, transition metal-catalyzed C–H
activation has emerged as an increasingly powerful tool in
molecular syntheses,1 with notable applications to late-stage
diversification,2 drug discovery3 and material sciences,4 among
others. In contrast to traditional cross-coupling reactions, C–H
activation does not require the use of pre-functionalized
substrates, thereby reducing the number of synthetic
operations and minimizing the generation of potentially toxic
chemical waste. Very recently, Knochel and Wagschal disclosed
an elegant approach for the synthesis of aryl triazole 3a, which
was evaluated in the synthesis of a novel Active Pharmaceutical
Ingredient (API).5 Despite this indisputable advance, this
Scheme 1 Direct C–H arylation by ruthenium catalysis.
strategy relied on highly reactive and costly 2,2,6,6-
tetramethylpiperidinyl butyl magnesium (TMPMgBu), ZnCl2 in
overstoichiometric amounts and a precious palladium catalyst.
Within our continued interest in cost-efficient6 ruthenium-
catalyzed7 C–H activation,8 we have now developed a novel
strategy to access triazole9 3a, thus providing user-friendly
access to a novel drug currently in development. Notable
features of our approach include i) cost-efficient ruthenium
catalysts, ii) a user-friendly one-step approach, and iii) K2CO3 as
a mild base (Scheme 1).
We initiated our studies by probing various phosphine ligands
for the direct C–H arylation of TMS-substituted triazole 1a
bearing
a sensitive chloro substituent (Figure 1). While
electron-rich alkyl phosphines L1, L3 and L4 as well as
methoxy-substituted phosphine L5 resulted in the formation of
significant amounts of de-silylated compounds 1b and 3b
(entries 1, 3-5), the de-silylation process could be suppressed,
when electron-deficient ligands were employed (entries 9-11).
The use of ligand L12 featuring a strongly electron-withdrawing
Template for SYNLETT © Thieme Stuttgart · New York
2021-04-30
page 1 of 4

Synlett
Letter / Cluster / New Tools
trifluoromethyl substituent delivered the desired product 3a in
an improved yield (entry 12).
40
30
20
10
0
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
3a 3b 1b
Figure 1 Effect of the phosphine ligand L. The conversion was determined by 1H NMR with 1,3,5-trimethoxybenzene as the internal standard. Unreacted 1a accounts
mostly for the remaining mass balance.10 [a] Isolated yield.
delivering the desired product 3a (Table 1, entries 8-10).12 The
obtained yield could be further increased by adjusting the
Next, the effect of the triazole C-4 substituent on the reaction
[Ru]/phosphine ratio from 1:2 to 1:1 (entry 13).13 In contrast,
outcome was tested (Scheme 2). A comparable efficiency was
varying the reaction temperature and the concentration did not
observed when the TMS group was replaced with
a
prove beneficial (entries 2-6).
triisopropylsilyl (TIPS) substituent. In contrast, the yield of
product 3 dropped significantly when triethylsilyl-substituted
(TES) compound 1d was employed. Replacing the silyl-group
with a chloro substituent resulted in an unsatisfactory reaction
outcome.
Table 1 Optimization of reaction parameters.[a]
Ligand (y
mol %)
Entry
1
[Ru] (x mol %)
T / °C
120
120
120
100
120
140
Yield / %
40
[Ru(O2CMes)2(p-cymene)]
L12 (10)
L12 (20)
L12 (30)
L12 (10)
L12 (10)
L12 (10)
(5.0)
[Ru(O2CMes)2(p-cymene)]
2
37
(10)
Scheme 2 Influence of the Triazole 1 substitution pattern.
[Ru(O2CMes)2(p-cymene)]
3[b]
4
34
(15)
[Ru(O2CMes)2(p-cymene)]
33
Among
a variety of solvents and bases, orienting studies
(5.0)
identified toluene and K2CO3, respectively, as being optimal. A
careful analysis of various reaction parameters revealed
[Ru(O2CMes)2(p-cymene)] to be the optimal catalyst for this
transformation, while cationic [Ru(NCMe)6][BF4]2 as well as
cyclometallated complexes Ru-I and Ru-II11 fell short in
[Ru(O2CMes)2(p-cymene)]
5[b,c]
6[d]
47
(5.0)
[Ru(O2CMes)2(p-cymene)]
33
(5.0)
Template for SYNLETT © Thieme Stuttgart · New York
2021-04-30
page 2 of 4

Synlett
Letter / Cluster / New Tools
Nitro-substituted aryl iodides 4a and 4b were hence efficiently
transformed under the reaction conditions, delivering the
arylated products 5a and 5b in a similar yield and with an almost
identical mono/diarylation ratio, indicating no pronounced
influence of the position of the substituent on the reaction
outcome (Scheme 4). Interestingly, a notable decrease in yield
was observed, when less electron-deficient arene 4c or electron-
rich aryl iodide 4d was subjected to the C–H arylation,
highlighting a preference of the optimized ruthenium catalyst for
electron-deficient electrophiles. Compound 4e bearing two
trifluoromethyl substituents exclusively led to the formation of
the diarylated product 5e.
7
[Ru(OAc)2(p-cymene)] (5.0)
L12 (10)
L11 (10)
L12 (10)
L12 (10)
L12 (10)
L12 (10)
L12 (5.0)
L12 (2.5)
120
120
120
120
120
120
120
120
40
--
8
[Ru(NCMe)6][BF4]2 (5.0)
9[e]
10[e]
11[f]
12[g]
13
Ru-I
--
Ru-II
--
[Ru(O2CMes)2(p-cymene)]
41
--
(5.0)
[Ru(O2CMes)2(p-cymene)]
(5.0)
[Ru(O2CMes)2(p-cymene)]
50
44
(5.0)
[Ru(O2CMes)2(p-cymene)]
14
(5.0)
[a] 1a (0.3 mmol), 2a (0.45 mmol), [Ru] (x–x mol %), L (x–x mol %), K2CO3 (2.0 equiv.),
PhMe (1.2 mL), 120 °C, 18–21 h, yield of isolated product. [b] 2a (0.6 mmol), PhMe
(2.0 mL). [c] for 48 h. [d] in m-xylene (1.2 mL). [e] with or without KOAc (10 mol %).
[f] in PhMe (0.6 mL). [g] Pd(OAc)2 (5.0 mol %) added.
Intrigued by the considerable influence of the phosphine ligand
on the catalyst’s efficacy, we became interested in probing the
phosphine ligand effect also with the C–H arylations of aryl
triazole 1a with electron-deficient arene 4a. When the reaction
was performed in the absence of an additional ligand, only traces
of the arylated compound 5a could be observed (Scheme 3). In
contrast, the use of ligand L12 led to the formation of 76% of the
mono- and diarylated products, thus clearly outperforming PPh3.
Scheme 4 Ruthenium-catalyzed C–H arylation with aryl iodides 4. [a] The ratio
of mono- and diarylated products is given in parenthesis.
In summary, we have developed a novel approach for the
triazole-enabled ruthenium-catalyzed C–H arylations under
carboxylate assistance with electron-deficient pyrimidyl and aryl
halides, thus representing a user-friendly, concise strategy of
interest to drug development. Key to success was the use of a
well-defined ruthenium(II)carboxylate complex in combination
with an electron-deficient phosphine ligand.
Funding Information
Generous support by the DFG (SPP1807 and Gottfried-Wilhelm-Leibniz
award to L.A.) and Janssen Pharmaceutica is gratefully acknowledged.
Scheme 3 Performance of phosphine ligands with different electrophiles. [a]
The ratio of mono- and diarylated products is given in parenthesis. n.d. = not
determined.
Acknowledgment
We thank Janssen Pharmaceutica and Bristol-Myers Squibb for funding
the project and for supplying compounds 1 and 2. We thank Dr. Yann
Bourne-Branchu for orienting experiments.
Finally, we employed representative aryl iodides 4 bearing
various substituents for the C–H arylation of triazole 1a.
Gratifyingly, and in contrast to previously reported
approaches,8g, 14 sensitive nitro substituents were found to be
fully tolerated under the reaction conditions. meta- or para-
Supporting Information
YES (this text will be updated with links prior to publication)
Primary Data
Template for SYNLETT © Thieme Stuttgart · New York
2021-04-30
page 3 of 4

Synlett
Letter / Cluster / New Tools
NO (this text will be deleted prior to publication)
M.; Ackermann, L. Angew. Chem. Int. Ed. 2020, 59, 18795-18803;
b) Rogge, T.; Ackermann, L. Angew. Chem. Int. Ed. 2019, 58,
15640-15645; c) Li, J.; Korvorapun, K.; De Sarkar, S.; Rogge, T.;
Burns, D. J.; Warratz, S.; Ackermann, L. Nat. Commun. 2017, 8,
15430; d) Schischko, A.; Ren, H.; Kaplaneris, N.; Ackermann, L.
Angew. Chem. Int. Ed. 2017, 56, 1576-1580; e) Ackermann, L.;
Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12,
5032–5035; f) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.;
Novák, P.; Büttner, L. Org. Lett. 2010, 12, 2056-2059; g)
Ackermann, L.; Born, R.; Vicente, R. ChemSusChem 2009, 2, 546-
549; h) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem. Int.
Ed. 2006, 45, 2619-2622; i) Ackermann, L. Org. Lett. 2005, 7,
3123-3125.
References and Notes
1. a) Rej, S.; Ano, Y.; Chatani, N. Chem. Rev. 2020, 120, 1788-1887;
b) Ackermann, L. Acc. Chem. Res. 2020, 53, 84-104; c) Khake, S.
M.; Chatani, N. Trends Chem. 2019, 1, 524–539; d) Gandeepan, P.;
Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. Chem. Rev.
2019, 119, 2192–2452; e) Wang, C. S.; Dixneuf, P. H.; Soule, J. F.
Chem. Rev. 2018, 118, 7532–7585; f) Chu, J. C. K.; Rovis, T. Angew.
Chem. Int. Ed. 2018, 57, 62–101; g) Park, Y.; Kim, Y.; Chang, S.
Chem. Rev. 2017, 117, 9247–9301; h) Hartwig, J. F.; Larsen, M. A.
ACS Cent. Sci. 2016, 2, 281–292; i) Colby, D. A.; Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814-825.
2. a) Friis, S. D.; Johansson, M. J.; Ackermann, L. Nat. Chem. 2020, 12,
511-519; b) Wang, W.; Lorion, M. M.; Shah, J.; Kapdi, A. R.;
Ackermann, L. Angew. Chem. Int. Ed. 2018, 57, 14700–14717; c)
Jbara, M.; Maity, S. K.; Brik, A. Angew. Chem. Int. Ed. 2017, 56,
10644-10655; d) Noisier, A. F. M.; Brimble, M. A. Chem. Rev. 2014,
114, 8775-8806.
9. For a review on C–H activations on triazoles, see: Ackermann, L.;
Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503-4513.
10. For detailed information, see the Supporting Information.
11. a) Korvorapun, K.; Struwe, J.; Kuniyil, R.; Zangarelli, A.; Casnati,
A.; Waeterschoot, M.; Ackermann, L. Angew. Chem. Int. Ed. 2020,
59, 18103-18109; b) Korvorapun, K.; Kuniyil, R.; Ackermann, L.
ACS Catal. 2020, 10, 435-440; c) Simonetti, M.; Cannas, D. M.;
Just-Baringo, X.; Vitorica-Yrezabal, I. J.; Larrosa, I. Nat. Chem.
2018, 10, 724–731; d) Simonetti, M.; Perry, G. J.; Cambeiro, X. C.;
Julia-Hernandez, F.; Arokianathar, J. N.; Larrosa, I. J. Am. Chem.
Soc. 2016, 138, 3596–3606.
3. a) Moir, M.; Danon, J. J.; Reekie, T. A.; Kassiou, M. Expert Opin. Drug
Discovery 2019, 14, 1137-1149; b) Caro-Diaz, E. J. E.; Urbano, M.;
Buzard, D. J.; Jones, R. M. Bioorg. Med. Chem. Lett. 2016, 26, 5378-
5383; c) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.;
Krska, S. W. Chem. Soc. Rev. 2016, 45, 546-576.
12. The mass balance largely accounted for unreacted starting
material 1, while only minor amounts of the corresponding
desilylated triazole were observed.
4. a) Bura, T.; Blaskovits, J. T.; Leclerc, M. J. Am. Chem. Soc. 2016,
138, 10056-10071; b) Schipper, D. J.; Fagnou, K. Chem. Mater.
2011, 23, 1594-1600.
13. Under an atmosphere of N2, a Schlenk-tube was charged with
triazole 1a (0.30 mmol, 1.00 equiv), 2-chloro-6-methoxy
pyrimidine (2) (0.45 mmol, 1.5 equiv), [Ru(O2CMes)2(p-
5. Lutter, F. H.; Grokenberger, L.; Perego, L. A.; Broggini, D.; Lemaire,
S.; Wagschal, S.; Knochel, P. Nat. Commun. 2020, 11, 4443.
6. On November 16, 2020, the prices of platinum, rhodium, iridium,
palladium, and ruthenium were 915, 14700, 1660, 2365, and 270
cymene)]
(8.4 mg,
15 μmol,
5.0 mol %),
tris(4-
trifluoromethylphenyl)phosphine (L12) (7.0 mg, 15 μmol,
5.0 mol %) and K2CO3 (82.9 mg, 0.60 mmol, 2.00 equiv). PhMe
(1.2 mL) was added and the mixture was stirred at 120 °C for
21 h. After cooling to ambient temperature, H2O (10 mL) was
added, the mixture was extracted with EtOAc (3 × 25 mL),
washed with brine (25 mL), dried over Na2SO4 and concentrated
in vacuo. Purification of the remaining residue by column
chromatography on silica gel (n-hexane:EtOAc = 5:1) yielded the
desired product 3a (53.6 mg, 50%). M.p. = 87–89 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.70 (d, J = 1.0 Hz, 1H), 7.82 (d, J = 2.2 Hz,
1H), 7.58 (dd, J = 8.5, 2.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 6.19 (d,
J = 1.1 Hz, 1H), 3.91 (s, 3H), 0.29 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ = 170.1 (CH), 161.9 (CH), 158.5 (Cq), 147.2 (CH); 136.2
(CH), 135.8 (CH), 133.9 (CH), 131.2 (Cq), 130.9 (Cq), 130.7 (Cq),
128.2 (Cq), 107.3 (Cq), 54.2 (CH3), -1.1 (CH3). IR (ATR): ṽ = 1584,
1500, 1468, 1202, 1032, 838, 823, 758, 632, 417 cm-1. MS (ESI)
m/z (relative intensity): 741 [2M+Na]+ (85), 559 (8), 382
[M+Na]+ (49), 360 [M+H]+ (100), 332 (16). HR-MS (ESI): m/z
calcd for C16H1935ClN5OSi+ [M+H]+ 360.1042, found 360.1028.
14. Ackermann, L.; Novák, P.; Vicente, R.; Pirovano, V.; Potukuchi, H.
K. Synthesis 2010, 2245–2253.
US$
per
troy
oz,
respectively.
See:
http://www.platinum.matthey.com/prices/price-charts.
7. For selected reviews on ruthenium-catalyzed C–H activations,
see: a) Leitch, J. A.; Frost, C. G. Chem. Soc. Rev. 2017, 46, 7145–
7153; b) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744–
5767; c) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292,
211–229; for selected examples, see: d) Greaney, M.; Sagadevan,
A. Angew. Chem. Int. Ed. 2019, 58, 9826–9830; e) Koseki, Y.;
Kitazawa, K.; Miyake, M.; Kochi, T.; Kakiuchi, F. J. Org. Chem. 2017,
82, 6503-6510; f) Biafora, A.; Krause, T.; Hackenberger, D.; Belitz,
F.; Gooßen, L. J. Angew. Chem. Int. Ed. 2016, 55, 14752-14755; g)
Huang, L.; Weix, D. J. Org. Lett. 2016, 18, 5432-5435; h) Li, B.;
Darcel, C.; Dixneuf, P. H. ChemCatChem 2014, 6, 127-130; i)
Chinnagolla, R. K.; Jeganmohan, M. Chem. Commun. 2014, 50,
2442-2444; j) Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664-670;
k) Dastbaravardeh, N.; Schnürch, M.; Mihovilovic, M. D. Org. Lett.
2012, 14, 1930-1933; l) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf,
P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161-10170; m)
Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H.
Angew. Chem. Int. Ed. 2010, 49, 6629-6632; n) Oi, S.; Aizawa, E.;
Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113-3119.
8. For representative examples on C–H activations by
ruthenium(II) catalysis from our laboratories, see: a)
Korvorapun, K.; Moselage, M.; Struwe, J.; Rogge, T.; Messinis, A.
Template for SYNLETT © Thieme Stuttgart · New York
2021-04-30
page 4 of 4

Supporting Information
Triazole-Enabled Ruthenium(II)carboxylate-Catalyzed C–H
Arylation with Electron-deficient Aryl Halides
Torben Rogge, Thomas Müller, Hendrik Simon, Xiaoyan Hou, Simon Wagschal, Diego
Broggini,* and Lutz Ackermann*

Contents
General Remarks...................................................................................................................... S2
General Procedure A for the Ruthenium(II)carboxylate-Catalyzed C–H Arylation of Arenes 1
with Pyrimidyl Chloride 2........................................................................................................ S3
General Procedure B for the Ruthenium(II)carboxylate-Catalyzed C–H Arylation of Arenes 1
with Aryl Iodides 4................................................................................................................... S3
Characterization Data of Products 3 and 5............................................................................... S4
References .............................................................................................................................. S12
NMR Spectra.......................................................................................................................... S13
S1

General Remarks
Reactions involving air- or moisture-sensitive compounds were conducted under an atmosphere
of nitrogen using pre-dried glassware and standard Schlenk- or glovebox-techniques. PhMe was
dried over Na and distilled under an atmosphere of nitrogen. Ruthenium complexes
[Ru(O2CMes)2(p-cymene)],1 [Ru(OAc)2(p-cymene)],1 [Ru(NCMe)6][BF4]2,2 Ru-I3 and Ru-II4
were synthesized according to previously described methods. All other compounds were
obtained from commercial sources and were used without further purification. If not otherwise
noted, yields refer to isolated compounds, estimated to be >95% pure by GC and NMR.
Analytical thin layer chromatography (TLC) was performed on TLC Silica gel 60 F254 from
Merck with detection at 254 nm or 360 nm. Preparative chromatographic separations were
carried out on Merck Geduran SI 60 (40–63 μm, 70–230 mesh ASTM) silica gel. Infrared (IR)
spectra of pure compounds were measured on Bruker Alpha-P FT-IR spectrometer. Nuclear
magnetic resonance (NMR) spectra were recorded on Bruker Avance III 300, Avance III HD
300 and Avance III HD 500 spectrometers. Chemical shifts (δ) are referenced using the residual
proton or carbon solvent signal. 19F spectra were referenced using CFCl3 as external standard.
Electron-ionization (EI) mass spectra were recorded on Jeol AccuTOF instrument at 70 eV.
Electrospray-ionization (ESI) mass spectra were obtained on Bruker micrOTOF and maXis
instruments. All systems are equipped with time-of-flight (TOF) analyzers. The ratios of mass
to charge (m/z) are reported and the intensity relative to the base peak (I = 100) is given in
parenthesis.
S2

General Procedure A for the Ruthenium(II)carboxylate-Catalyzed
C–H Arylation of Arenes 1 with Pyrimidyl Chloride 2
Under an atmosphere of N2, a Schlenk-tube was charged with triazole 1 (0.30 mmol, 1.00
equiv), 2-chloro-6-methoxy pyrimidine 2 (0.45 mmol, 1.5 equiv), [Ru(O2CMes)2(p-cymene)]
(8.4 mg, 15 μmol, 5.0 mol %), tris(4-trifluoromethylphenyl)phosphine (L12) (7.0 mg,
15 μmol, 5.0 mol %) and K2CO3 (82.9 mg, 0.60 mmol, 2.00 equiv). PhMe (1.2 mL) was added
and the mixture was stirred at 120 °C for 18–21 h. After cooling to ambient temperature, H2O
(10 mL) was added, the mixture was extracted with EtOAc (3 × 25 mL), washed with brine (25
mL), dried over Na2SO4 and concentrated in vacuo. Purification of the remaining residue by
column chromatography on silica gel yielded the desired product 3.
General Procedure B for the Ruthenium(II)carboxylate-Catalyzed
C–H Arylation of Arenes 1 with Aryl Iodides 4
Under an atmosphere of N2, a Schlenk-tube was charged with triazole 1 (0.30 mmol, 1.00
equiv), aryl iodide 4 (0.45 mmol, 1.5 equiv), [Ru(O2CMes)2(p-cymene)] (8.4 mg, 15 μmol,
5.0 mol %), tris(4-trifluoromethylphenyl)phosphine (L12) (14.1 mg, 30 μmol, 10.0 mol %) and
K2CO3 (82.9 mg, 0.60 mmol, 2.00 equiv). PhMe (1.2 mL) was added and the mixture was
stirred at 120 °C for 18 h. After cooling to ambient temperature, H2O (10 mL) was added, the
mixture was extracted with EtOAc (3 × 25 mL), washed with brine (25 mL), dried over Na2SO4
and concentrated in vacuo. Purification of the remaining residue by column chromatography on
silica gel yielded the desired product 5.
S3

Characterization Data of Products 3 and 5
4-[5-Chloro-2-(4-trimethylsilyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (3a)
The General Procedure A was followed using 1-(4-chlorophenyl)-4-trimethylsilyl-1H-1,2,3-
triazole (1a) (75.5 mg, 0.30 mmol) and 4-chloro-6-methoxypyrimidine (2) (65.1 mg,
0.45 mmol) for 21 h. Purification by column chromatography on silica gel (n-hexane/EtOAc
5:1) yielded 3a (53.6 mg, 50%) as a yellow solid.
1
M.p. = 87–89 °C. H NMR (300 MHz, CDCl3): δ = 8.70 (d, J = 1.0 Hz, 1H), 7.82 (d, J = 2.2
Hz, 1H), 7.58 (dd, J = 8.5, 2.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 6.19 (d, J = 1.1 Hz, 1H), 3.91
13
(s, 3H), 0.29 (s, 9H). C NMR (75 MHz, CDCl3): δ = 170.1 (CH), 161.9 (CH), 158.5 (Cq),
147.2 (CH); 136.2 (CH), 135.8 (CH), 133.9 (CH), 131.2 (Cq), 130.9 (Cq), 130.7 (Cq), 128.2
(Cq), 107.3 (Cq), 54.2 (CH3), -1.1 (CH3). IR (ATR): ṽ = 1584, 1500, 1468, 1202, 1032, 838,
823, 758, 632, 417 cm-1. MS (ESI) m/z (relative intensity): 741 [2M+Na]+ (85), 559 (8), 382
[M+Na]+ (49), 360 [M+H]+ (100), 332 (16). HR-MS (ESI): m/z calcd for C16H1935ClN5OSi+
[M+H]+ 360.1042, found 360.1028.
The analytical data are in accordance with those reported in the literature.5
S4

4-[5-Chloro-2-(4-triisopropylsilyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine
(3c)
The General Procedure A was followed using 1-(4-chlorophenyl)-4-triisopropylsilyl-1H-1,2,3-
triazole (1c) (101 mg, 0.30 mmol), 4-chloro-6-methoxypyrimidine (2) (65.1 mg, 0.45 mmol)
and tris(4-trifluoromethylphenyl)phosphine (L12) (14.1 mg, 30 μmol, 10.0 mol %) for 20 h.
Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1) yielded 3c
(46.3 mg, 35%) as a green solid.
M.p. = 113–116 °C. 1H NMR (400 MHz, CDCl3): δ = 8.71 (s, 1H), 7.80 (s, 1H), 7.59 (s, 2H),
7.46 (s, 1H), 6.16 (s, 1H), 3.88 (s, 3H), 1.33 (hept, J = 7.5 Hz, 3H), 1.04 (d, J = 7.5 Hz, 18H).
13C NMR (100 MHz, CDCl3): δ = l69.1 (Cq), 161.9 (Cq), 158.7 (CH), 142.5 (Cq), 136.2 (Cq),
135.8 (Cq), 134.0 (Cq), 132.4 (CH), 130.8 (CH), 130.7 (CH), 128.3 (CH), 107.5 (CH), 54.0
(CH3), 18.6 (CH3), 11.1 (CH). IR (ATR): ṽ = 2941, 2864, 1739, 1584, 1541, 1470, 1390, 1358,
1196, 1031 cm-1. MS (ESI) m/z (relative intensity): 466 [M+Na]+ (4), 444 [M+H]+ (100). HR-
MS (ESI): m/z calcd for C22H3135ClN5OSi + [M+H]+ 444.1981, found 444.1986.
4-[5-Chloro-2-(4-triethylsilyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (3a)
The General Procedure A was followed using 1-(4-chlorophenyl)-4-triethylsilyl-1H-1,2,3-
triazole (1d) (88.2 mg, 0.30 mmol), 4-chloro-6-methoxypyrimidine (2) (65.1 mg, 0.45 mmol)
S5

and tris(4-trifluoromethylphenyl)phosphine (L12) (14.1 mg, 30 μmol, 10.0 mol %) for 20 h.
Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1) yielded 3d
(34.3 mg, 28%) as a yellow solid.
1
M.p. = 84–86 °C. H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1H), 7.81 (d, J = 2.3 Hz, 1H),
7.61–7.50 (m, 2H), 7.46 (s, 1H), 6.15 (s, 1H), 3.88 (s, 3H), 0.93 (t, J = 7.7 Hz, 9H), 0.78 (q,
J = 7.7 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ = 170.0 (Cq), 161.8 (Cq), 158.5 (CH), 144.2
(Cq), 136.2 (Cq), 135.8 (Cq), 133.9 (Cq), 131.9 (CH), 130.8 (CH), 130.6 (CH), 128.3 (CH), 107.4
(CH), 54.1 (CH3), 7.29 (CH3), 3.49 (CH2). IR (ATR): ṽ = 3099, 2954, 2909, 2874, 1588, 1541,
1469, 1214, 1030, 718 cm-1. MS (ESI) m/z (relative intensity): 424 [M+Na]+ (6), 402 [M+H]+
(100). HR-MS (ESI): m/z calcd for C19H2535ClN5OSi+ [M+H]+ 402.1511, found 402.1509.
4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (3a)
The General Procedure A was followed using 1-(4-chlorophenyl)-4-chloro-1H-1,2,3-triazole
(1e) (64.2 mg, 0.30 mmol), 4-chloro-6-methoxypyrimidine (2) (65.1 mg, 0.45 mmol) and
triscyclohexylphosphine (L1) (8.4 mg, 30 μmol, 10.0 mol %) for 20 h. Purification by column
chromatography on silica gel (n-hexane/EtOAc 5:1) yielded 3e (16 mg, 17%) as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.69 (s, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.64–7.57 (m, 2H),
13
7.49 (d, J = 8.5 Hz, 1H), 6.52 (s, 1H), 3.97 (s, 3H). C NMR (100 MHz, CDCl3): δ = 170.2
(Cq), 161.8 (Cq), 158.6 (CH), 137.0 (Cq), 135.9 (Cq), 135.8 (Cq), 133.3 (Cq), 131.2 (CH), 130.8
(CH), 128.2 (CH), 123.1 (CH), 107.7 (CH), 54.3 (CH3). IR (ATR): ṽ = 3064, 2954, 2925, 2854,
1732, 1585, 1370, 1211, 1024, 815 cm-1. MS (ESI) m/z (relative intensity): 344 [M+Na]+ (100),
322 [M+H]+ (52). HR-MS (ESI): m/z calcd for C13H1035Cl2N5O+ [M+H]+ 322.0257, found
322.02360.
S6

1-(5-Chloro-4'-nitro-[1,1'-biphenyl]-2-yl)-4-trimethylsilyl-1H-1,2,3-triazole (5a)
The General Procedure B was followed using 1-(4-chlorophenyl)-4-trimethylsilyl-1H-1,2,3-
triazole (1a) (75.5 mg, 0.30 mmol), 1-iodo-4-nitrobenzene (4a) (112 mg, 0.45 mmol) for 19 h.
Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1) yielded 5a (62 mg,
55%) and 5a’ (31 mg, 21%) as black solids.
M.p. = 129–133°C. 1H NMR (400 MHz, CDCl3): δ = 8.15–8.07 (m, 2H), 7.58–7.50 (m, 3H),
7.28–7.18 (m, 3H), 0.22 (s, 9H). 13C NMR (100 MHz, CDCl3): δ = 147.7 (Cq), 147.3 (Cq),
142.9 (Cq), 136.9 (Cq), 136.1 (Cq), 133.7 (Cq), 130.9 (CH), 130.8 (CH), 129.9 (CH), 129.5 (CH),
128.3 (CH), 123.9 (CH), -1.19 (CH3). IR (ATR): ṽ = 3078, 2960, 2856, 1602, 1516, 1503, 1350,
1029, 840, 830 cm-1. MS (ESI) m/z (relative intensity): 395 [M+Na]+ (5), 373 [M+H]+ (100).
HR-MS (ESI): m/z calcd for C17H1835ClN4O2Si+ [M+H]+ 373.0882, found 373.0871.
1-(5'-Chloro-4,4''-dinitro-[1,1':3',1''-terphenyl]-2'-yl)-4-trimethylsilyl-1H-1,2,3-triazole
(5a’)
1
M.p. = 208–212°C. H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.8 Hz, 4H), 7.60 (s, 2H),
13
7.27 (d, J = 8.8 Hz, 4H), 7.09 (s, 1H), 0.11 (s, 9H). C NMR (100 MHz, CDCl3): δ = 147.8
(Cq), 147.6 (Cq), 142.5 (Cq), 140.0 (Cq), 136.7 (Cq), 131.9 (CH), 131.7 (Cq), 130.8 (CH), 129.5
(CH), 123.7 (CH), -1.22 (CH3). IR (ATR): ṽ = 2958, 1600, 1576, 1492, 1468, 1348, 1247, 1035,
S7

836, 820 cm-1. MS (ESI) m/z (relative intensity): 516 [M+Na]+ (6), 494 [M+H]+ (100). HR-MS
(ESI): m/z calcd for C23H2135ClN5O4Si+ [M+H]+ 494.1046, found 494.1042.
1-(5-Chloro-3'-nitro-[1,1'-biphenyl]-2-yl)-4-trimethylsilyl-1H-1,2,3-triazole (5b)
The General Procedure B was followed using 1-(4-chlorophenyl)-4-trimethylsilyl-1H-1,2,3-
triazole (1a) (75.5 mg, 0.30 mmol), 1-iodo-3-nitrobenzene (4b) (112 mg, 0.45 mmol).
Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1) yielded 5b as a
black oil (62 mg, 55%) and 5b’ (32 mg, 22%) as a black solid.
1H NMR (400 MHz, CDCl3): δ = 8.19–8.11 (m, 1H), 7.95 (d, J = 2.0, 2.0 Hz, 1H), 7.56 (s, 3H),
7.46–7.37 (m, 1H), 7.37–7.24 (m, 2H), 0.23 (s, 9H). 13C NMR (100 MHz, CDCl3): δ = 148.4
(Cq), 147.3 (Cq), 140.0 (Cq), 136.8 (Cq), 136.3 (Cq), 134.5 (CH), 133.8 (Cq), 130.9 (CH), 130.9
(CH), 129.8 (CH), 129.8 (CH), 128.3 (CH), 123.3 (CH), 123.3 (CH), -1.2 (CH3). IR (ATR):
ṽ = 3087, 2957, 1528, 1503, 1350, 1249, 1032, 838, 688, 632 cm-1. MS (ESI) m/z (relative
intensity): 395 [M+Na]+ (50), 373 [M+H]+ (100). HR-MS (ESI): m/z calcd for
C17H1835ClN4O2Si+ [M+H]+ 373.0882, found 373.0887.
1-(5'-Chloro-3,3''-dinitro-[1,1':3',1''-terphenyl]-2'-yl)-4-trimethylsilyl-1H-1,2,3-triazole
(5b’)
S8

M.p. = 208–212°C. 1H NMR (400 MHz, CDCl3): δ = 8.19–8.11 (m, 2H), 8.01–7.96 (m, 2H),
7.64 (s, 2H), 7.50–7.37 (m, 4H), 7.23 (s, 1H), 0.12 (s, 9H). 13C NMR (75 MHz, CDCl3):
δ = 140.2 (Cq), 147.6 (Cq), 139.7 (Cq), 137.7 (Cq), 136.9 (Cq), 134.4 (CH), 132.1 (Cq), 131.9
(CH), 130.8 (CH), 129.7 (CH), 123.5 (CH), 123.3 (CH), -1.3 (CH3). IR (ATR): ṽ = 2958, 1525,
1494, 1351, 1247, 1034, 842, 809, 740, 686 cm-1. MS (ESI) m/z (relative intensity): 516
[M+Na]+ (45), 494 [M+H]+ (100). HR-MS (ESI): m/z calcd for C23H2135ClN5O4Si+ [M+H]+
494.1046, found 494.1047.
1-(5-Chloro-3'-trifluoromethyl-[1,1'-biphenyl]-2-yl)-4-trimethylsilyl-1H-1,2,3-triazole
(5c)
The General Procedure B was followed using 1-(4-chlorophenyl)-4-trimethylsilyl-1H-1,2,3-
triazole (1a) (75.5 mg, 0.30 mmol), 1-iodo-3-trifluoromethylbenzene (4c) (122 mg,
0.45 mmol). Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1)
yielded 5c (51 mg, 43%) as a colorless oil.
1
Due to the presence of two rotamers, the H and 13C NMR spectra exhibit two partially
overlapping sets of resonances.
1H NMR (400 MHz, CDCl3): δ = 7.62–7.50 (m, 4H), 7.45–7.29 (m, 3H), 7.16 (d, J = 3.4 Hz,
1H), 0.25–0.07 (m, 9H). 13C NMR (100 MHz, CDCl3): δ = 147.0 (Cq), 140.5 (Cq), 137.4 (Cq),
137.1 (Cq), 136.4 (Cq), 136.0 (Cq), 133.9 (Cq), 132.0 (CH), 131.9 (CH), 131.8 (CH), 131.0 (q,
2JC–F = 32.7 Hz, Cq), 130.9 (CH), 130.8 (CH), 130.4 (CH), 129.4 (CH), 129.2 (CH), 128.2 (CH),
125.2 (q, 3JC–F = 3.9 Hz, CH), 125.0 (q, 3JC–F = 3.9 Hz, CH), 124.0 (q, 1JC–F = 272.6 Hz, Cq), -
1.3 (CH3), -1.4 (CH3). 19F NMR (376 MHz, CDCl3): δ = -62.8 (s). IR (ATR): ṽ = 2899, 1576,
1490, 1251, 1121, 1075, 1031, 839, 804, 702 cm-1. MS (ESI) m/z (relative intensity): 396
+
[M+H]+ (100). HR-MS (ESI): m/z calcd for C18H1835ClN3SiF3 [M+H]+ 396.0905, found
396.0901.
S9

1-(5-Chloro-4'-methoxy-[1,1'-biphenyl]-2-yl)-4-trimethylsilyl-1H-1,2,3-triazole (5d)
The General Procedure B was followed using 1-(4-chlorophenyl)-4-trimethylsilyl-1H-1,2,3-
triazole (1a) (75.5 mg, 0.30 mmol), 4-iodoanisole (4d) (105 mg, 0.45 mmol) for 17 h.
Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1) yielded 5d as a
colorless oil (40 mg, 37%) and 5d’ (14 mg, 10%) as a colorless solid.
1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.44 (dd,
J = 8.5, 2.3 Hz, 1H), 7.09 (d, J = 1.1 Hz, 1H), 6.95–6.89 (m, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.77
13
(s, 3H), 0.22 (s, 9H). C NMR (100 MHz, CDCl3): δ = 159.8 (Cq), 146.6 (Cq), 138.5 (Cq),
135.5 (Cq), 133.8 (Cq), 131.2 (CH), 130.8 (CH), 129.7 (CH), 128.5 (Cq), 128.2 (CH), 127.9
(CH), 114.2 (CH), 55.4 (CH3), -1.1 (CH3). IR (ATR): ṽ = 3118, 2956, 2899, 2838, 1609, 1516,
1495, 1247, 1033, 982 cm-1. MS (ESI) m/z (relative intensity): 380 [M+Na]+ (29), 358 [M+H]+
(100). HR-MS (ESI): m/z calcd for C18H2135ClN3OSi+ [M+H]+ 358.1137, found 358.1141.
The analytical data are in accordance with those reported in the literature.5
1-(5'-Chloro-4,4''-dimethoxy-[1,1':3',1''-terphenyl]-2'-yl)-4-trimethylsilyl-1H-1,2,3-
triazole (5d’)
S10

1
M.p. = 158–163°C. H NMR (400 MHz, CDCl3): δ = 7.45 (s, 2H), 7.09 (s, 1H), 6.98 (d, J =
8.8 Hz, 4H), 6.73 (d, J = 8.8 Hz, 4H), 3.74 (s, 6H), 0.15 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ = 159.5 (Cq), 146.1 (Cq), 141.6 (Cq), 135.6 (Cq), 132.4 (Cq), 131.8 (Cq), 129.6 (CH), 129.4
(CH), 129.0 (CH), 113.8 (CH), 55.3 (CH3), -1.1 (CH3). IR (ATR): ṽ = 3111, 3006, 2957, 2901,
2838, 1608, 1247, 1033, 826, 564 cm-1. MS (ESI) m/z (relative intensity): 486 [M+Na]+ (24),
464 [M+H]+ (100). HR-MS (ESI): m/z calcd for C25H2735ClN3O2Si+ [M+H]+ 464.1556, found
464.1559.
1-[5'-Chloro-3,3'',5,5''-tetrakis(trifluoromethyl)-[1,1':3',1''-terphenyl]-2'-yl]-4-
trimethylsilyl-1H-1,2,3-triazole (5e)
The General Procedure B was followed using 1-(4-chlorophenyl)-4-trimethylsilyl-1H-1,2,3-
triazole (1a) (75.5 mg, 0.30 mmol), 1-iodo-3,5-bis(trifluoromethyl)benzene (4e) (153 mg,
0.45 mmol). Purification by column chromatography on silica gel (n-hexane/EtOAc 5:1)
yielded 5e (91 mg, 45%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.81 (s, 1H), 7.58 (d, J = 2.9 Hz, 3H), 7.45 (s, 2H), 7.34 (s,
1H), 0.25 (s, 9H). 13C NMR (100 MHz, CDCl3): δ = 147.6 (Cq), 138.5 (Cq), 136.5 (Cq), 136.3
(Cq), 133.9 (Cq), 132.3 (q, 2JC–F = 33.8 Hz, Cq), 130.8 (Cq), 130.7 (Cq), 130.1 (CH), 128.5 (q,
1
3JC–F = 2.5 Hz, CH), 128.4 (CH), 122.9 (q, JC–F = 273.0 Hz, Cq), 122.2 (hept, 3JC–F = 3.1 Hz,
CH), -1.3 (CH3). 19F NMR (376 MHz, CDCl3): δ = -63.0 (s). IR (ATR): ṽ = 1503, 1367, 1275,
1182, 1131, 1059, 1034, 834, 707, 681 cm-1. MS (ESI) m/z (relative intensity): 395 [M+Na]+
+
(50), 464 [M+H]+ (100). HR-MS (ESI): m/z calcd for C19H1935ClN3SiF6 [M+H]+ 464.0779,
found 464.0780.
S11

References
1.
Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–
5035.
2.
Underwood, C. C.; Stadelman, B. S.; Sleeper, M. L.; Brumaghim, J. L. Inorg. Chim.
Acta 2013, 405, 470–476.
3.
a) Simonetti, M.; Cannas, D. M.; Just-Baringo, X.; Vitorica-Yrezabal, I. J.; Larrosa, I.
Nat. Chem. 2018, 10, 724–731; b) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A.
J. Am. Chem. Soc. 2011, 133, 10161-10170.
4.
5.
Korvorapun, K.; Kuniyil, R.; Ackermann, L. ACS Catal. 2020, 10, 435-440.
Lutter, F. H.; Grokenberger, L.; Perego, L. A.; Broggini, D.; Lemaire, S.; Wagschal, S.;
Knochel, P. Nat. Commun. 2020, 11, 4443.
S12

NMR Spectra
S13

S14

S15

S16

S17

S18

S19

S20

S21

S22

S23

S24