Expedient C-H amidations of heteroaryl arenes catalyzed by versatile ruthenium(II) catalysts

Article abstract of DOI:10.1021/ol401321q

Heteroaryl-substituted arenes and heteroarenes were efficiently amidated through ruthenium-catalyzed C-H bond functionalizations with a variety of sulfonyl azides. Particularly, cationic ruthenium(II) complexes proved to be most effective and allowed nitrogenations of electron-rich and electron-deficient arenes with ample substrate scope.

Full text of DOI:10.1021/ol401321q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Expedient CÀH Amidations of Heteroaryl
Arenes Catalyzed by Versatile
Ruthenium(II) Catalysts
Vedhagiri S. Thirunavukkarasu, Keshav Raghuvanshi, and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstr. 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received May 12, 2013
ABSTRACT
Heteroaryl-substituted arenes and heteroarenes were efficiently amidated through ruthenium-catalyzed CÀH bond functionalizations with a
variety of sulfonyl azides. Particularly, cationic ruthenium(II) complexes proved to be most effective and allowed nitrogenations of electron-rich
and electron-deficient arenes with ample substrate scope.
Transition-metal-catalyzed CÀH bond functionalizations
are attractive tools for improving the atom- and step-
economyoforganicsyntheses.1 Inrecentyears, ruthenium-
(II) complexes have been identified as powerful catalysts
for the direct transformation of otherwise unreactive CÀH
bonds into CÀC bonds.2 On the contrary, ruthenium(II)-
catalyzed C(sp2)Àheteroatom bond forming processes
continue to be scarce. Given the recent success in ruthenium-
catalyzed direct arene oxygenations,3 along with the practical
importance of substituted anilines in medicinal chemistry,
crop protection and material sciences,4 we became intrigued
by devising ruthenium-catalyzed5,6 intermolecular CÀN
bond forming arene functionalizations. A very recent
independent report from Sahoo7 on functionalizations of
amides prompted us to disclose herein our results on the
development of versatile ruthenium(II) catalysts for expe-
dient amidations of heteroaryl arenes with sulfonyl azides.
(5) Selected examples of direct palladium, rhodium- or copper-
catalyzed chelation-assisted CÀN bond formations: (a) Tang, R.-J.;
Luo, C.-P.; Yang, L.; Li, C.-J. Adv. Synth. Catal. 2013, 355, 869–873. (b)
Tang, C.; Jiao, N. J. Am. Chem. Soc. 2012, 134, 18924–18927. (c) Jiang,
T.-S.; Wang, G.-W. J. Org. Chem. 2012, 77, 9504–9509. (d) Shi, J.; Zhou,
B.; Yang, Y.; Li, Y. Org. Biomol. Chem. 2012, 10, 8953–8955. (e) Kim,
J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am.
Chem. Soc. 2012, 134, 9110–9113. (f) Ryu, J.; Shin, K.; Park, S. H.; Kim,
J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904–9908. (g)
Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656–659.
(h) John, A.; Nicholas, K. M. J. Org. Chem. 2011, 76, 4158–4162. (i)
Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem.
Soc. 2011, 133, 7652–7655. (j) Xiao, B.; Gong, T.-J.; Liu, Z.- J.; Liu, L.
J. Am. Chem. Soc. 2011, 133, 1466–1474. (k) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048–9049. Selected reviews: (l)
Song, W.; Kozhushkov, S. I.; Ackermann, L. Angew. Chem., Int. Ed.
2013, DOI: 10.1002/anie.201302015. (m) Zhang, X. P.; Lu, H. Chem. Soc.
Rev. 2011, 40, 1899–1909. (n) Zalatan, D. N.; Du Bois, J. Top. Curr.
Chem. 2010, 292, 347–378. (o) Collet, F.; Dodd, R. H.; Dauban, P.
Chem. Commun. 2009, 5061–5074 and references cited therein.
(6) Selected ruthenium-catalyzed CÀN bond forming reactions: (a)
Louillat, M.-L.; Patureau, F. W. Org. Lett. 2013, 15, 164–167. (b) Hu, J.;
Chen, S.; Sun, Y.; Yang, J.; Rao, Y. Org. Lett. 2012, 14, 5030–5033. (c)
Harvey, M. E.; Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc. 2011, 133,
17207–17216. (d) Du Bois, J. Org. Process Res. Dev. 2011, 15, 758–762.
(e) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47,
6825–6828. (f) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che,
C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465–3468 and references cited
therein.
(1) Representative reviews on oxidative CÀH bond functionaliza-
tions: (a) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886–896.
(b) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236–10254. (c) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 788–802. (d) Hickman, A. J.;
Sanford, M. S. Nature 2012, 484, 177–185. (e) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–5083. (f) Satoh, T.;
Miura, M. Chem.;Eur. J. 2010, 16, 11212–11222.
(2) Recent reviews: (a) Ackermann, L. Acc. Chem. Res. 2013, 46,
DOI: 10.1021/ar3002798. (b) Arockiam, P. B.; Bruneau, C.; Dixneuf,
P. H. Chem. Rev. 2012, 112, 5879–5918. (c) Ackermann, L.; Vicente, R.
Top. Curr. Chem. 2010, 292, 211–229.
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Thirunavukkarasu, V. S.; Ackermann, L. Org. Lett. 2012, 14, 6206–
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(4) Ricci, A. Amino Group Chemistry; Wiley-VCH: Weinheim, 2008.
r
10.1021/ol401321q
XXXX American Chemical Society

Table 1. Optimization of CÀH Amidation of Pyrazole 1aa
Scheme 2. Ruthenium-catalyzed CÀH Amidation with
Substituted Pyrimidines 4
entry
[Ru] (mol %)
additive
yield (%)
1
2
3
4
5
6
7
8
9
[RuCl2(p-cymene)]2 (5.0)
À
À
À
À
AgSbF6
[RuCl2(p-cymene)]2 (5.0)
[RuCl2(p-cymene)]2 (5.0)
[RuCl2(p-cymene)]2 (5.0)
[RuCl2(p-cymene)]2 (5.0)
[RuCl2(p-cymene)]2 (5.0)
RuCl3(H2O)n (5.0)
KO2CMes
KPF6
8
À
AgAl(OCF3)4
AgBF4
AgSbF6/KOAcb
AgSbF6
21
37
À
2
[Ru(O2CMes)2(p-cymene)] (5.0) AgSbF6
3
10 [RuBr2(p-cymene)]2 (5.0)
11 [RuCl2(p-cymene)]2 (2.5)
12 [RuCl2(p-cymene)]2 (5.0)
AgSbF6
AgSbF6
AgSbF6
74
62
82
a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), [RuCl2-
(p-cymene)]2 (5.0 mol %), additive (20 mol %), THF (2.0 mL). b KOAc
(0.5 equiv).
Scheme 3. Acetate-assisted Ruthenium-catalyzed CÀH
Amidation with Pyridines 6
Scheme 1. Scope of Ruthenium-Catalyzed CÀH Amidation
with Pyrazoles 1
conditions for the direct amidation of substrate 1a utilizing
complex [RuCl2(p-cymene)]2 as the catalyst (Table 1). The
desired transformation was not accomplished in the ab-
sence of additives or the ruthenium complex (entries 1 and
2). While the use of a carboxylate or KPF6 as cocatalytic
additives only gave unsatisfactory results (entries 3 and 4),
silver salts of weakly coordinating anions proved to be more
promising (entries 5À12). Among a set of representative
silver(I) additives, AgSbF6 was identified as being most
effective, while [RuCl2(p-cymene)]2 was the optimal ruthe-
nium precursor (entries 8À12). Interestingly, the presence of
In consideration of the broad synthetic utility of sub-
stituted pyrazoles,8 we initially explored reaction
B
Org. Lett., Vol. XX, No. XX, XXXX

KOAc completely inhibited the CÀH bond amidation of
substrate 1a (entry 7), a striking difference to the recently
reported procedure.7 As to the reactions site-selectivity,
the sterically less congested CÀH bond was exclusively
functionalized, providing anilide 3a in all reactions as the
sole product.
With an optimized catalytic system in hand, we tested its
scope and limitations in the direct nitrogenation of differ-
ently substituted N-arylpyrazoles 1 (Scheme 1). A substi-
tuent inproximitytothe coordinating nitrogen insubstrate
1b significantly reduced the yield of the desired product
3b. Substituents in meta-, para- or even ortho-position
on the arenes 1 were well tolerated by the catalytic
system, as was heteroaromatic substrate 1f. Differently
decorated sulfonyl azides 2 with aromatic or alipha-
tic substituents could be successfully employed. The
cationic ruthenium(II) catalyst displayed a remarkable
chemo-selectivity in that valuable functional groups
were well tolerated, most notably chloro, bromo or nitro
substituents.
Likewise, pyridyl-substituted arenes were found to be
suitable substrates, provided that NaOAc was present as an
additive (Scheme 3). The carboxylate-assisted9 ruthenium-
catalyzed direct amidation thereby allowed for the conver-
sion of numerous substituted sulfonyl azides 2 as well as
para-, meta- or ortho-substituted arenes 6. Notably, the
electron-deficient substrate 6e furnished efficiently desired
product, as did the more hindered starting material 6f.
As to the catalysts working mode, we conducted a series
of competition experiments with substituted azides 2
highlighting a slight preference for the less electron-rich
derivative 2m (Scheme 4).
Scheme 6. Mechanistic Studies with Isotopically Labeled
Compounds
The optimized catalytic system was not limited to arenes
bearing electron-rich pyrazoles. Indeed, starting materials
with electron-deficient pyrimidine moieties were found to
be viable substrates for the chelation-assisted CÀH bond
amidation as well (Scheme 2).
Scheme 4. Competition Experiments with Azides 2
Scheme 7. Proposed Mechanism
Scheme 5. Intermolecular Competition Experiments with Arenes 1
Org. Lett., Vol. XX, No. XX, XXXX
C

Intermolecular competition experiments between pyrazolyl-
substituted substrates 1 revealed electron-rich arenes to be
converted preferentially (Scheme 5), which is suggestive of an
electrophilic-type ruthenation manifold.
In summary, we have reported on ruthenium(II)-catalyzed
direct amidations of arenes displaying heteroaromatic groups.
The chelation-assisted CÀH bond functionalization pro-
ceeded most efficiently with cationic complexes using various
alkyl and aryl sulfonyl azides, which enabled CÀN bond
formations on pyrazolyl-, pyrimidyl- or pyridyl-substituted
arenes and heteroarenes. The catalysts displayed an excellent
site- and chemo-selectivity as well as a remarkably broad
substrate scope.
Finally, we utilized D2O as a cosolvent, which indicated a
significant H/D scrambling exclusively in the ortho-position
of arene 1a (Scheme 6a). Moreover, an intermolecular
competition experiment with isotopically labeled [D5]-6a
was indicative of a reversible ruthenation event with a
kinetic isotope effect (KIE) of kH/kD ≈ 1.3 (Scheme 6b).
On the basis of these mechanistic studies, we pro-
pose the CÀH bond activation to occur by a reversible
electrophilic-type metalation, as illustrated for pyrazole 1c
in Scheme 7. This proposed working mode in turn ratio-
nalizes the high catalytic activity of cationic ruthenium
complexes.
Acknowledgment. Support by the Alexander von
Humboldt foundation (fellowship to V.S.T.), the DAAD
(fellowship to K.R.), and the European Research Council
under the European Community’s Seventh Framework
Program (FP7 2007À2013)/ERC Grant agreement no.
307535 is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
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Silva, A. M. S.; Tome, A. C. In Modern Heterocyclic Chemistry; Alvarez-
cedures, characterization data, and H and 13C NMR
ꢀ
Builla, J., Vaquero, J. J., Barluenga, J., Eds.; Wiley-VCH: Weinheim, 2011;
Vol. 2, pp 635À725. (c) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.;
Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984–7034.
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118–1126.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX