Ruthenium-catalyzed C-H functionalization of arylpyrazoles: Regioselective acylation with acid chlorides

Article abstract of DOI:10.1021/ol402936c

A ruthenium-catalyzed C-H acylation of arylpyrazoles with a variety of acyl chlorides is described. The acylation reaction exhibits good regioselectivity and both aromatic and aliphatic acyl chlorides can be effectively coupled to the arylpyrazoles at the

Full text of DOI:10.1021/ol402936c

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5862–5865
Ruthenium-Catalyzed CÀH
Functionalization of Arylpyrazoles:
Regioselective Acylation with
Acid Chlorides
Po Man Liu and Christopher G. Frost*
Department of Chemistry, University of Bath, Bath, BA2 7AY, U.K.
c.g.frost@bath.ac.uk
Received October 11, 2013
ABSTRACT
A ruthenium-catalyzed CÀH acylation of arylpyrazoles with a variety of acyl chlorides is described. The acylation reaction exhibits good regioselectivity
and both aromatic and aliphatic acyl chlorides can be effectively coupled to the arylpyrazoles at the ortho-position.
Pyrazoles are important structural motifs that are
frequently featured at the core of biologically active
molecules.1 Thus, the development of new synthetic methods
for the preparation of functionalized pyrazole derivatives is
of broad interest to the pharmaceutical and agrochemical
industry. Transition-metal catalyzed CÀH functionalization
has emerged as fundamental methodology for the straight-
forward elaboration of organic molecules.2 In this context,
pyrazole serves as an effective directing group for CÀH
functionalization methods involving cyclometalation.3
Herein we describe an effective catalytic CÀH acylation of
arylpyrazoles that proceeds via cyclometalation to af-
ford the ortho product with excellent selectivity. To our
knowledge, this transformation represents the first in-
termolecular transition-metal catalyzed CÀH acylation
of 1-arylpyrazoles with both aromatic and aliphatic acyl
chlorides as the coupling partner. At present, methods
for acylating 1-arylpyrazole are relatively scarce. This
study complements the classic FriedelÀCrafts reactions
where the acyl chloride is substituted on the 4-position
of the pyrazole ring4 (Scheme 1 a) and the known direct
catalytic CÀH carbonylation process that also affords
the ortho product but is limited to alkyl substituents
(Scheme 1 b).5
ꢀ
ꢀ
(1) (a) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes,
A. Chem. Rev. 2011, 111, 6984–7034. (b) Janin, Y. L. Chem. Rev. 2012,
112, 3924–3958.
(2) For selected recent reviews: (a) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147–1169. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (c) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010,
16, 2654–2672. (d) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010,
46, 677–685. (e) Ackermann, L. Chem. Rev. 2011, 111, 1314–1345. (f)
The recent significant achievements of selective catalytic
CÀH bond functionalizations with Ru(II) species
prompted us to explore the catalytic directed cyclometala-
tion and subsequent acylation of 1-phenylpyrazole 1 with
acyl chlorides.6 The successful introduction of carbonyl
functionality to the ortho site of 2-arylpyridine deri-
vatives employing catalytic Ru(II) complexes has been
€
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
40, 4740–4761. (g) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215–1292. (h) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976–1991.
r
10.1021/ol402936c
Published on Web 11/06/2013
2013 American Chemical Society

Scheme 1. Catalytic Acylation of 1-Arylpyrazoles
Scheme 2. Ruthenium-Catalyzed Ortho Acylation of 1-Phenyl-
pyrazole
mechanism involving chelation-assisted cyclometalation
and oxidative addition of the acyl chloride rather than
σ-activation by ruthenium and electrophilic attack.
The optimized conditions for the catalytic ortho CÀH
acylation of 1-phenylpyrazole 1 employed 5 mol % of
[RuCl2(p-cymene)]2 in the presence of 10 mol % of PCy3
and 5 equiv of K2CO3.9 The reaction of 1-phenylpyrazole
with a range of acyl chlorides afforded ortho acylated
products in moderate-to-good yields (Scheme 2). In gen-
eral, acylation of 1-phenylpyrazole with aryl acid chlorides
gives both mono- and diacylated products that are difficult
to purify and isolated yields that are low (4aÀ8a). How-
ever, reproducible experiments indicated that the more
sterically hindered o-toluoyl chloride was more effective in
the ortho acylation of 1-phenylpyrazole than benzoyl
chloride.
We were pleased to discover that alkyl acid chlorides
were converted to the corresponding products 9aÀ19a
in predominantly respectable yields with recovery of un-
reacted 1-phenylpyrazole. Notably, the reaction proceeded
with acetyl chloride to afford 9a; although a modest
yield (28%) was obtained, this is the first example of 9a
being prepared via catalytic CÀH functionalization and it
provides evidence that the reaction proceeds through
established.7 More recently, the Ru(II)-catalyzed functio-
nalization of meta sites by remote para activation has
also been demonstrated for sulfonations and alkylations
(including 1-phenylpyrazole).8
Interestingly, with acyl chlorides (e.g., o-toluoyl chloride 2)
only the product from ortho CÀH functionalization is
observed under a broad range of conditions with no trace
of the meta product (Scheme 2). This is consistent with a
(3) Cu-catalyzed CÀH functionalization: (a) Zhang, L.; Liu, Z.; Li,
H.; Fang, G.; Barry, B.-D.; Belay, T. A.; Bi, X.; Liu, Q. Org. Lett. 2011,
13, 6536–6539. (b) Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Chem. Commun.
2012, 48, 9933–9935. Pd-catalyzed CÀH functionalization: (c) Dick,
A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300–
2301. (d) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
Tetrahedron 2006, 62, 11483–11498. (e) Chen, X.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 12634–12635. (f) Liu, Y.-K.; Lou,
S.-J.; Xu, D.-Q.; Xu, Z.-Y. Chem.;Eur. J. 2010, 16, 13590–13593. (g)
Lou, S.-J.; Xu, D.-Q.; Xia, A.-B.; Wang, Y.-F.; Liu, Y.-K.; Du, X.-H.;
Xu, Z.-Y. Chem. Commun. 2013, 49, 6218–6220. Rh-catalyzed CÀH
functionalization: (h) Miyamura, S.; Tsurugi, H.; Satoh, T.; Miura, M.
J. Organomet. Chem. 2008, 693, 2438–2442. (i) Umeda, N.; Hirano, K.;
Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7094–7099. (j) Umeda, N.;
Hirano, K.; Satoh, T.; Shibata, N.; Sato, H.; Miura, M. J. Org. Chem.
2011, 76, 13–24. (k) Li, X.; Yu, S.; Wang, F.; Wan, B.; Yu, X. Angew.
Chem., Int. Ed. 2013, 52, 2577–2580. (l) Huang, L.; Wang, Q.; Qi, J.; Wu,
X.; Huang, K.; Jiang, H. Chem. Sci. 2013, 4, 2665–2669. (m) Pan, F.; Lei,
Z.-Q.; Wang, H.; Li, H.; Sun, J.; Shi, Z.-J. Angew. Chem., Int. Ed. 2013,
52, 2063–2067. Ru-catalyzed CÀH functionalization: (n) Kakiuchi, F.;
Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani, N.; Murai, S. Chem.
Lett. 2002, 396–397. (o) Ackermann, L.; Althammer, A.; Born, R.
Synlett 2007, 18, 2833–2836. (p) Ackermann, L.; Vicente, R.; Althammer,
A. Org. Lett. 2008, 10, 2299–2302. (q) Ackermann, L.; Mulzer, M. Org.
(5) (a) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am.
Chem. Soc. 1996, 118, 493–494. (b) Asaumi, T.; Chatani, N.; Matsuo, T.;
Kakiuchi, F.; Murai, S. J. Org. Chem. 2003, 68, 7538–7540. (c) Asaumi,
T.; Matsuo, T.; Fukuyama, T.; Ie, Y.; Kakiuchi, F.; Chatani, N. J. Org.
Chem. 2004, 69, 4433–4440. (d) Imoto, S.; Uemura, T.; Kakiuchi, F.;
Chatani, N. Synlett 2007, 1, 170–172.
(6) Selected recent reviews on Ru(II)-catalyzed CÀH bond functio-
nalization: (a) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744–
5767. (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.
(7) (a) Kochi, T.; Urano, S.; Seki, H.; Mizushima, E.; Sato, M.;
Kakiuchi, F. J. Am. Chem. Soc. 2009, 131, 2792–2793. (b) Kochi, T.;
Tazawa, A.; Honda, K.; Kakiuchi, F. Chem. Lett. 2011, 40, 1018–1020.
(8) For recent ruthenium-catalyzed CÀH bond functionalizations of
meta sites: (a) Saidi, O.; Marafie, J.; Ledger, A. E. W.; Liu, P. M.;
ꢀ
Lett. 2008, 10, 5043–5045. (r) Ackermann, L.; Novak, P.; Vicente, R.;
Hofmann, N. Angew. Chem., Int. Ed. 2009, 48, 6045–6048. (s)
ꢀ
Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi,
H. K. Synthesis 2010, 13, 2245–2253. (t) Luo, N.; Yu, Z. Chem.;Eur.
J. 2010, 16, 787–791. (u) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.;
Dixneuf, P. H. Green Chem. 2011, 13, 3075–3078. (v) Li, W.; Arockiam,
P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2011,
13, 2315–2319. (w) Hashimoto, Y.; Ueyama, T.; Fukutani, T.; Hirano,
K.; Satoh, T.; Miura, M. Chem. Lett. 2011, 40, 1165–1166. (x)
Ackermann, L.; Kozhushkov, S. I.; Yufit, D. S. Chem.;Eur. J. 2012, 18,
12068–12077. (y) Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.;
Miura, M. Org. Lett. 2012, 14, 2058–2061. (z) Hashimoto, Y.; Hirano, K.;
Satoh, T.; Kakiuchi, F.; Miura, M. J. Org. Chem. 2013, 78, 638–646.
(4) (a) Kost, A. N. I.; Grandberg, I. Adv. Heterocycl. Chem. 1966, 6,
347–429. (b) Finar, I. L.; Foster, T. J. Chem. Soc. 1967, 1494–1497.
€
Mahon, M. F.; Kociok-Kohn, G.; Whittlesey, M. K.; Frost, C. G. J. Am.
Chem. Soc. 2011, 133, 19298–19301. (b) Hofmann, N.; Ackermann, L.
ꢀ
ꢀ
J. Am. Chem. Soc. 2013, 135, 5877–5884. (c) Julia-Hernandez, F.;
Simonetti, M.; Larrosa, I. Angew. Chem., Int. Ed. 2013, 52, 11458–11460.
(9) See Supporting Information for details.
Org. Lett., Vol. 15, No. 22, 2013
5863

reactivity. 1-Phenylindazole was found to be a suitable
substrate for catalytic CÀH acylation and afforded 28a in
45% yield, which is comparable to 13a.
Scheme 3. Scope of Catalytic Acylation of 1-Phenylpyrazole
Scheme 4. Catalytic Ortho Acylation of 1-Arylpyrazoles and
1-Phenylindazole
cyclometalation and oxidative addition and not via a
classic FriedelÀCrafts pathway. For both acyclic and
cyclic alkyl acid chlorides, there is a notable correlation
in which higher yields of acylation products are obtained
for the more sterically hindered acid chloride substrates.
One example is when trimethylacetyl chloride and ada-
mantanecarbonyl chloride were used as the electrophile
(13a and 19a, Scheme 3). This could arise from steric
acceleration in the reductive elimination step.10
To further evaluate the scope of this reaction, a range of
1-arylpyrazole derivatives were synthesized and coupled
with various acyl chlorides under identical conditions.11
The electronic properties of the 1-arylpyrazole substrate sig-
nificantly affected the feasibility of the reaction (Scheme 4).
The reaction was promoted by electron-donating groups
on the aryl ring and retarded by electron-deficient sub-
stituents. Theselectivity of catalytic mono-and diacylation
appears to be influenced by steric hindrance on the aryl
ring. Forthemajorityof examples showninScheme 4, only
the monoacylated product was obtained. In particular the
electron-rich meta substituted substrates in combination
with sterically hindered acyl chlorides afforded products in
high yields (for example, 26a and 27a). Interestingly,
changing the meta CH3 to a CF3 group switched off
the reactivity (no formation of 32a was observed) despite
the increased propensity of the substrate to undergo cyclo-
metalation. It appears that the reaction is sensitive to
substituent effects, and the introduction of any electron-
withdrawing groups to the substrate is detrimental to the
Scheme 5. Regioselectivity with Meta Substituted Substrates
(10) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936–1947and references
therein.
(11) General protocol for the synthesis of 1-arylpyrazole derivatives:
Correa, A.; Bolm, C. Adv. Synth. Catal. 2007, 349, 2673–2676.
5864
Org. Lett., Vol. 15, No. 22, 2013

Interestingly, an intramolecular competition experiment
with 1-(3-methoxyphenyl)pyrazole as the substrate re-
sulted in the formation of three products in the reaction
with cyclopropanecarbonyl chloride (Scheme 5). The ma-
jor product was the ortho monoacylated product 35a and
this is based on steric arguments for the cyclometalation.
The electron-rich OMe-substitutent would be expected to
promote acylations based on ortho-/para-directing effects.
In this case, formation of the alternative regioisomer of the
monoacylated product 35c was observed in low yield along
with the diacylatedproduct 35b. The lower yield was due to
increased steric interactions between the C-3 substituent
and the ruthenium fragment hindering cyclometalation in
the ortho position.
acylation of 1-arylpyrazoles with alkyl acid chlorides and
complements emerging catalytic methods for the site-
selective functionalization of heteroaromatics. Further stu-
dies are in progress to provide insight into the mechanism
and expand further the scope of catalytic CÀH acylation
processes, and these results will be reported in due course.
Acknowledgment. This work was supported by the
EPSRC. Dr. Anneke Lubben (Mass Spectrometry Service
at the University of Bath) and Dr. John Lowe (NMR) are
also thanked for valuable assistance.
Supporting Information Available. Experimental pro-
cedures, cif file, and full characterization for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have developed a new protocol for
ruthenium(II) catalyzed CÀH acylation of phenylpyrazole
with acyl chlorides. This useful transformation represents
the first intermolecular transition-metal catalyzed CÀH
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5865