Ruthenium-catalyzed oxidative synthesis of 2-pyridones through C-H/N-H bond functionalizations

Article abstract of DOI:10.1021/ol201244s

An inexpensive ruthenium catalyst enabled oxidative annulations of alkynes by acrylamides with ample scope, which allowed for the preparation of 2-pyridones employing various electron-rich and electron-deficient acrylamides as well as (di)aryl- and (di)alkyl-substituted alkynes.

Full text of DOI:10.1021/ol201244s

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3278–3281
Ruthenium-Catalyzed Oxidative Synthesis
of 2-Pyridones through CꢀH/NꢀH Bond
Functionalizations
Lutz Ackermann,* Alexander V. Lygin, and Nora Hofmann
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received May 10, 2011
ABSTRACT
An inexpensive ruthenium catalyst enabled oxidative annulations of alkynes by acrylamides with ample scope, which allowed for the preparation
of 2-pyridones employing various electron-rich and electron-deficient acrylamides as well as (di)aryl- and (di)alkyl-substituted alkynes.
Pyridones are key structural motifs in compounds with
important activities of relevance to biology.1 As a result,
different methods for the selective preparation of these
heterocycles were devised,1 among which transition-metal-
catalyzed transformations have received significant recent
attention.2 Particularly, catalyzed direct functionalizations
of CꢀH bonds have emerged as economically and ecolo-
gically benign tools for the synthesis of substituted
heterocycles.3 Thus, cross-dehydrogenative reactions have
proven valuable, since they avoid the use of prefunctiona-
lized starting materials and thereby allow for a streamlin-
ing of organic synthesis.3,4 Based on pioneering reports on
rhodium-catalyzed oxidative annulation reactions by the
research groups of Miura and Satoh5 as well as Fagnou,6ꢀ8 Li
and co-workers recently disclosed a useful rhodium-catalyzed
synthesis of 2-pyridones through oxidative couplings be-
tween acrylamides and alkynes.9 While this report
represented remarkable progress, the rhodium catalyst
(3) Selected recent reviews on metal-catalyzed CꢀH bond functio-
nalizations: (a) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992–2002.
(b) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–1991.
(c) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885–1898. (d) Willis, M. C. Chem. Rev. 2010, 110, 725–748.
(e) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8,
4503–4513. (f) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84.
(g) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685.
(h) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624–655. (i) Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (j) Jazzar,
R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;
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(n) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087–4109. (o) Bellina,
F.; Rossi, R. Tetrahedron 2009, 65, 10269–10310. (p) Ackermann, L.;
Vicente, R; Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
(q) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874–5883.
(r) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–3039. (s) Satoh, T.;
Miura, M. Chem. Lett. 2007, 36, 200–205. (t) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174–238 and references cited therein.
(4) Representative recent reviews: (a) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215–1292. (b) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
Chem. Rev. 2011, 111, 1780–1824. (c) Yoo, W.-J.; Li, C.-J. Top. Curr.
Chem. 2010, 292, 281–302 and references cited therein.
(1) (a) Jessen, H. J.; Gademann, K. Nat. Prod. Rep. 2010, 27, 1168–
1185. (b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd
ed.; Wiley-VCH: Weinheim, 2003. (c) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell Science Ltd.: Oxford, 2000. (d) Gilchrist, T. L.
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2007, 36, 1085–1094. (b) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103,
3787–3801 and references cited therein. (c) For a pertinent example of
ruthenium-catalyzed [2 þ 2 þ 2] cycloaddition for the synthesis of
2-pyridones, see: Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi,
H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127,
605–613. (d) A recent representative example of ruthenium-catalyzed
[2 þ 2 þ 2] cycloaddition for the synthesis of arenes: Kawatsura, M.;
Yamamoto, M.; Namioka, J.; Kajita, K.; Hirakawa, T.; Itoh, T. Org.
Lett. 2011, 13, 1001–1003 and references cited therein.
(5) For early examples, see: (a) Ueura, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2007, 72, 5362–5367. (b) Ueura, K.; Satoh, T.; Miura, M.
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r
10.1021/ol201244s
Published on Web 05/25/2011
2011 American Chemical Society

unfortunately displayed significant limitations. For in-
stance, (i) dialkyl-substituted alkynes gave complicated
reaction mixtures, (ii) superstoichiometric amounts (2.2
equiv) of the terminal oxidant Cu(OAc)2 proved mandatory,
and (iii) the use of acrylamides bearing electron-deficient
N-substituents resulted in unsatisfactory selectivities. Based
on mechanistic studies on carboxylate assistance in
ruthenium-catalyzed CꢀH bond transformations,10,11
we recently devised a first ruthenium-catalyzed12 oxidative13,14
annulation process through CꢀH bond cleavages.15 Since
inexpensive16 ruthenium complexes have thus far been
underexplored for oxidative annulation processes, we
became interested in probing their use for an oxidative
synthesis of 2-pyridones through cleavages of CꢀH and
NꢀH bonds, on which we wish to report herein. Impor-
tantly, the inexpensive ruthenium catalyst displayed a
significantly improved substrate scope as compared to
the previously reported rhodium9 complex, which inter alia
set the stage for high-yielding 2-pyridone syntheses with
dialkyl-substituted alkynes and acrylamides with electron-
deficient N-substituents.
At the outset of our studies, we optimized reaction
conditions for the oxidative annulation of alkyne 2a
by acrylamide 1a for the synthesis of 2-pyridone 3aa.
Optimal reaction conditions involved the use of Cu(OAc-
)2•H2O as the terminal oxidant in t-AmOH as the solvent.
Other sacrificial oxidants, such as benzoquinone (0%), air
(5%), or AgOAc (65%), provided less satisfactory results.
Representative alternative solvents, including DME
(<5%) or MeOH (44%), gave inferior yields of the desired
product 3aa. Notably, 1 equiv of the terminal oxidant
Cu(OAc)2•H2O turned out to be sufficient, which compares
favorably with a rhodium-catalyzed9 process that required
superstoichiometric amounts of the oxidant (2.2 equiv).
With optimized reaction conditions in hand, we ex-
plored the scope of the ruthenium-catalyzed pyridone
(8) For important recent progress in catalyzed oxidative annulation
reactions, see: [Rh] (a) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2011, 50, 4169–4172. (b) Huestis, M. P.; Chan,
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Scheme 1. Scope of the Ruthenium-Catalyzed Oxidative An-
nulation of Alkyne 2aa
(9) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12,
5462–5465.
(10) (a) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V.
Org. Lett. 2010, 12, 5032–5035. (b) Ackermann, L. Pure Appl. Chem.
2010, 82, 1403–1413. (c) Ackermann, L. Chem. Commun. 2010, 46, 4866–
4877. (d) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13,
1875–1877.
(11) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
(12) A review on ruthenium-catalyzed CꢀH bond arylations:
Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–229.
(13) For pioneering ruthenium-catalyzed cross-dehydrogenative
coupling with alkenes, see: (a) Weissman, H.; Song, X.; Milstein, D.
J. Am. Chem. Soc. 2001, 123, 337–338. (b) Ueyama, T.; Mochida, S.;
Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–
708. For oxidative couplings of boronic acids with alkenes, see:
(c) Farrington, E. J.; Barnard, C. F. J.; Rowsell, E.; Brown, J. M. Adv.
Synth. Catal. 2005, 347, 185–195. (d) Farrington, E. J.; Brown, J. M.;
Barnard, C. F. J.; Rowsell, E. Angew. Chem., Int. Ed. 2002, 41, 169–171.
(14) For an example of carboxylate-assisted ruthenium-catalyzed
dehydrogenative CꢀH bond functionalizations, see: Ackermann, L.;
ꢀ
Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K. Synthesis 2010,
2245–2253.
a Reaction conditions: 1 (1.0 mmol), 2a (0.5 mmol), [RuCl2(p-cym-
ene]2 (5.0 mol %), Cu(OAc)2•H2O (0.5 mmol), t-AmOH (2.0 mL),
120 °C, 20 h; isolated yields. b Cu(OAc)2•H2O (1.0 mmol), 100 °C, 48 h.
(15) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int.
Ed. 2011, 50, DOI: 10.1002/anie201101943.
(16) [Cp*RhCl2]2: 2545 h versus [RuCl2(p-cymene)]2: 257 h (5.0 g,
Sigma-Aldrich, 2011).
Org. Lett., Vol. 13, No. 12, 2011
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synthesis using alkyne 2a (Scheme 1). We were delighted to
observe that the catalytic system turned out to be broadly
applicable. Hence, acrylamides 1 bearing various N-alkyl
or N-aryl substituents were efficiently converted to 2-pyr-
idones 3aaꢀ3da and 3eaꢀ3ja, respectively. It is particu-
Scheme 3. Annulation with Diaryl-Substituted Alkynes 2bꢀ2g
larly noteworthy that amides
1 bearing electron-
withdrawing N-substituents chemoselectively delivered
products 3haꢀ3ja, a notable difference compared to a
rhodium-catalyzed9 transformation in which a mixture of
products was obtained. Moreover, acrylamides 1 bearing
different substituents in the R- or β-position could be
employed in the ruthenium-catalyzed oxidative annula-
tion. Interestingly, β-phenyl substituted acrylamide 1l
proved also to be a viable substrate, while no coupling
product could be detected when using this starting material
in the rhodium-catalyzed oxidative coupling.9
Scheme 2. Ruthenium-Catalyzed Oxidative Annulations with
R,β-Disubstituted Amides 1m and 1n
Scheme 4. Ruthenium-Catalyzed Annulation with Unsymme-
trically Substituted Alkynes 2h and 2i
Furthermore, our new ruthenium-based annulation
method allowed for the first use of R,β-disubstituted
acrylamides in oxidative 2-pyridone syntheses, which pro-
vided direct access to products 3ma and 3na (Scheme 2).17
The inexpensive ruthenium catalyst was not limited to
the oxidative annulation of tolane (2a) but also enabled the
efficient conversion of functionalized diaryl-substituted
alkynes 2bꢀ2g (Scheme 3).
Scheme 5. Oxidative Annulation with Dialkyl-Substituted
Alkynes 2
Likewise, unsymmetrically substituted alkynes 2 proved
to be viable substrates (Scheme 4). Importantly, the oxi-
dative annulations with alkynes 2h and 2i occurred with
remarkably high regioselectivity, which set the stage for the
preparation of 2-pyridones 3lh and 3li.
In contrast to a recently reported rhodium catalyst,9
the ruthenium-based protocol allowed for the use of
dialkyl-substituted alkynes as well (Scheme 5).18 Notably,
even the more challenging amides 1h and 1i displaying
(17) Products stemming from hydroarylations of alkyne 2a were
isolated here as a minor byproduct. For detailed information, see the
Supporting Information.
(18) Intermolecular competition experiments between diaryl- and
dialkyl-substituted alkynes (2a versus 2k, and 2b versus 2c) revealed
that electron-deficient tolane derivatives are preferentially converted
(see Supporting Information).
3280
Org. Lett., Vol. 13, No. 12, 2011

electron-deficient N-substituents furnished the desired
products 3hk and 3ik, respectively, in high yields.
illustrate the beneficial features and remarkable potential
of thus far underexplored ruthenium catalysts in oxidative
annulative CꢀH bond functionalization processes.
As to the reaction mechanism, our preliminary studies15
indicate a reaction manifold involving initial intermolecu-
lar carboruthenation of alkyne 2, along with a subsequent
intramolecular CꢀN bond formation.
Acknowledgment. Support by the DFG and the
CaSuS PhD program (fellowship to N.H.) is gratefully
acknowledged.
In summary, we have disclosed a novel ruthenium-
catalyzed oxidative synthesis of 2-pyridones. Importantly,
the inexpensive ruthenium catalysts displayed a notable
chemo- and regioselectivity, which resulted in a signifi-
cantly improved substrate scope as compared to a related
rhodium-catalyzed transformation. These results clearly
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
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