Versatile synthesis of isocoumarins and α-pyrones by Ruthenium-catalyzed oxidative C - H/O - H bond cleavages

Article abstract of DOI:10.1021/ol2034614

An inexpensive cationic ruthenium(II) catalyst enabled the expedient synthesis of isocoumarins through oxidative annulations of alkynes by benzoic acids. This C - H/O - H bond functionalization process also proved applicable to the preparation of α-pyrones and was shown to proceed by rate-limiting C - H bond ruthenation.

Full text of DOI:10.1021/ol2034614

ORGANIC
LETTERS
2012
Vol. 14, No. 3
930–933
Versatile Synthesis of Isocoumarins and
r-Pyrones by Ruthenium-Catalyzed
Oxidative CÀH/OÀH Bond Cleavages
Lutz Ackermann,* Jola Pospech, Karolina Graczyk, and Karsten Rauch
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received December 27, 2011
ABSTRACT
An inexpensive cationic ruthenium(II) catalyst enabled the expedient synthesis of isocoumarins through oxidative annulations of alkynes by
benzoic acids. This CÀH/OÀH bond functionalization process also proved applicable to the preparation of R-pyrones and was shown to proceed
by rate-limiting CÀH bond ruthenation.
Isocoumarins and R-pyrones are key structural motifs of
compounds with important biological activities.1 One of
the most general strategies for their synthesis involves
palladium-catalyzed annulations of alkynes by ortho-
halo-substituted carboxylic acid derivatives.2 While this
approach inherently requires prefunctionalized benzoic
acids as substrates, a more atom- and step-economical
access was elegantly devised by Miura and Satoh through
rhodium-catalyzed3 oxidative4 annulations of alkynes by
carboxylic acids.5,6 We, in contrast, reported recently on
the use of significantly less expensive ruthenium catalysts7
for oxidative CÀH/NÀH bond functionalizations.8
Further, Miura9 and we10 disclosed ruthenium-catalyzed
oxidative alkenylations of carboxylic acid derivatives
via twofold CÀH bond cleavages. In continuation of
our studies, we became interested in exploring cost-
effective ruthenium catalysts for oxidative annulations
of alkynes by carboxylic acids,11 on which we report
herein.
(1) (a) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L.
Tetrahedron 2003, 59, 2067–2081. (b) Mali, R. S.; Babu, K. N. J. Org.
€
Chem. 1998, 63, 2488–2492. (c) Powers, J. C.; Asgian, J. L.; Ekici, O. D.;
(5) (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 1407–1409.
(b) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362–5367.
(c) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009,
74, 3478–3483. (d) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2009, 74, 6295–6298.
(6) Reviews: (a) Satoh, T.; Miura, M. Synthesis 2010, 3395–3409.
(b) Satoh, T.; Ueura, K.; Miura, M. Pure Appl. Chem. 2008, 80, 1127–
1134.
James, K. E. Chem. Rev. 2002, 102, 4639–4750 and references cited
therein.
(2) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Black-
well Science Ltd.; Oxford, 2000. (b) Zeni, G.; Larock, R. C. Chem. Rev.
2004, 104, 2285–2310. A selected example: (c) Larock, R. C.; Doty,
M. J.; Han, X. J. Org. Chem. 1999, 64, 8770–8779.
(3) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–11222.
(4) Representative recent reviews on CÀH bond functionalizations:
(a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068–5083. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–
1292. (c) Wencel-Delord, J.; Droege, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740–4761. (d) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem.
2010, 292, 281–302. (e) Ackermann, L.; Potukuchi, H. K. Org. Biomol.
Chem. 2010, 8, 4503–4513. (f) Daugulis, O. Top. Curr. Chem. 2010, 292,
57–84. (g) Ackermann, L. Chem. Commun. 2010, 46, 4866–4877. (h)
Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (i) Giri, R.; Shi, B.-F.;
Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev 2009, 38, 3242–
3272. (j) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed.
2009, 48, 9792–9826. (k) Thansandote, P.; Lautens, M. Chem.;Eur. J.
2009, 15, 5874–5883. (l) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–
3039 and references cited therein.
(7) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–
229.
(8) (a) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int.
Ed. 2011, 50, 6379–6382. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278–3281. (c) Ackermann, L.; Fenner, S. Org. Lett.
2011, 13, 6548–6551. (d) Ackermann, L.; Wang, L.; Lygin, A. V. Chem.
Sci. 2012, 3, 177–180. (e) For oxidative arylations, see also: Ackermann,
ꢀ
L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K. Synthesis 2010,
2245–2253.
(9) For oxidative alkenylations of heteroarenes, see: Ueyama, T.;
Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
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(10) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–4155.
r
10.1021/ol2034614
Published on Web 01/24/2012
2012 American Chemical Society

We initiated our studies by optimizing reaction con-
ditions for the oxidative annulation of tolane (2a) by
carboxylic acid 1a (Table 1). Notably, the desired iso-
coumarin synthesis occurred with water12 as the reaction
medium, when using KPF6 as a cocatalytic additive
(entries 1 and 2). Yet, among a set of representative
solvents, t-AmOH was found to be optimal (entries
1À8). The oxidative annulation proceeded efficiently
under an atmosphere of ambient air (entry 9). It is
noteworthy that the cationic13 ruthenium(II) catalysts
derived from KPF6 proved to be more effective than the
corresponding complexes generated from cocatalytic
amounts of AgBF4, AgSbF6, AgOTf, CsOAc, HOPiv,
With an optimized catalytic system in hand, we probed
its scope in the ruthenium-catalyzed oxidative annulation
of aryl-substituted alkynes 2 by benzoic acids 1 (Scheme 1).
The cationic ruthenium(II) catalyst proved broadly appli-
cable and, thus, enabled the synthesis of diversely decorated
isocoumarins 3. Notably, also salicylic acid 1g bearing an
unprotected hydroxyl group was chemoselectively con-
verted to the desired product 3ga. The oxidative annula-
tion of electron-rich alkynes 2b and 2c occurred efficiently
as well.
or KOAc (entries 9À17). Furthermore, Cu(OAc)2 H2O
Scheme 1. Scope Using Aryl-Substituted Alkynes 2
3
turned out to be the sacrificial oxidant of choice (entries
18À20).
Table 1. Optimization of Ruthenium-Catalyzed Oxidative
Annulationa
The ruthenium catalysts were not limited to the use of
tolane derivatives but were also found to be applicable to
alkyl-substituted alkynes 2 (Scheme 2). Again, valuable
functional groups, such as free hydroxyl groups or
fluoro- and bromo-substituents, were well tolerated by
the catalytic system, the latter of which could be used for
the subsequent elaboration of the obtained isocoumar-
ins 3.
Moreover, heteroaromatic carboxylic acids 1 turned
out to be suitable substrates for the ruthenium-catalyzed
CÀH/OÀH bond functionalization process, thereby deliver-
ing valuable indole derivatives 3 (Scheme 3).
Notably, unsymmetrically substituted alkynes 2f and
2g were converted with remarkably high regioselectivity,
furnishing the desired isocoumarins 3 (Scheme 4).
The cationic ruthenium(II) catalyst further allowed the
oxidative annulation of alkynes by acrylic acid derivative
a Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), [RuCl2-
(p-cymene)]2 (2.5 mol %), additive (20 mol %), oxidant (2.0 equiv), solvent
(3.0 mL), 120 °C, 16 h; isolated yields, under N2. b GC conversion.
c Under air. d 5.0 mmol scale. e Cu(OAc)2 H2O (1.5 equiv).
3
(11) (a) Pospech, J. MSc thesis, Georg-August-Universitaet Goettin-
gen, 08.2011. (b) After submission of our manuscript a related transformation
was independently reported: Chinnagolla, R. K.; Jeganmohan, M. Chem.
Commun. 2012, 48, 2030–2032.
(12) For ruthenium-catalyzed direct arylations and alkylations in
the presence of water, see: (a) Ackermann, L.; Hofmann, N.; Vicente,
R. Org. Lett. 2011, 13, 1875–1877. (b) Arockiam, P. B.; Fischmeister,
C.; Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2010, 49, 6629–
6632. (c) Ackermann, L. Org. Lett. 2005, 7, 3123–3125. See also refs 8c
and 10.
(13) (a) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans.
ꢀ
1974, 233–241. (b) Fernandez, S.; Pfeffer, M.; Ritleng, V.; Sirlin, C.
Organometallics 1999, 18, 2390–2394.
Org. Lett., Vol. 14, No. 3, 2012
931

Scheme 2. Oxidative Annulation with Alkyl-Substituted
Alkynes 2
Scheme 4. Annulations of Unsymmetrically Substituted
Alkynes 2
Scheme 5. Oxidative R-Pyrone Synthesis
Scheme 6. Intramolecular Competition Experiment
As to the catalyst’s working mode, an intramolecular
competition experiment with meta-substituted arene 1n
exclusively delivered product 3nd through the site-selective
functionalization of the CÀH bond, displaying a higher
kinetic acidity (Scheme 6). Moreover, additional competi-
tion experiments between differently substituted starting
materials indicated aryl-substituted alkynes 2 and electron-
rich carboxylic acids 1 to be preferentially converted.
Mechanistic studies with isotopically labeled substrate
[D5]-1b revealed the CÀH bond metalation to be irreversible
in nature, with a kinetic isotope effect of kH/kD ≈ 7.3
(Scheme 7). These experimental findings are in good agree-
ment with a reaction manifold involving a rate-limiting
CÀH bond metalation through acetate assistance.14
Scheme 3. Oxidative Annulations with Heteroarenes 1
Thus, a proposed catalytic cycle initiates with an
acetate-assisted irreversible cycloruthenation (Scheme 8),
followed by coordination of alkyne 2. Subsequent
4, thus providing a step-economical access to R-pyrone 5a
(Scheme 5).
(14) A review: Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
Org. Lett., Vol. 14, No. 3, 2012
932

Scheme 7. Studies with Isotopically Labeled Compounds
Scheme 8. Proposed Catalytic Cycle
regioselective migratory insertion delivers key intermedi-
ate 5, which upon reductive elimination furnishes desired
isocoumarin 3.
In summary, we have developed an atom- and step-
economical synthesis of isocoumarins through oxidative
annulations of alkynes by carboxylic acids using an
inexpensive ruthenium catalyst. The optimized cationic
ruthenium(II) complex proved widely applicable and,
hence, allowed the direct preparation of R-pyrones via a
rate-limiting CÀH bond ruthenation as the key step.
Further studies on oxidative ruthenium-catalyzed CÀH
bond functionalizations are ongoing in our laboratories
and will be reported in due course.
Acknowledgment. Support by the DFG is gratefully
acknowledged.
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.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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