esterification processes,5ꢀ7 the present system exploits the
molecular oxygen in air as the source of an oxygen atom instead
of alcohols.16,17 From a practical perspective, this newly
developed method offers a user-friendly entry to a variety
of lactones through oxidation of aldehydes under atmo-
spheric oxygen, thereby obviating any precautionary mea-
sures to rigorously exclude air and moisture from the reaction
mixture.
Scheme 1. NHC-Catalyzed Cyclization Reaction: Dual Acti-
vation of Two Functionalities
Before proceeding with the discussions, a few cursory
words of mechanistic considerations would be appropriate
at this juncture which provided the basis for our discovery.
In this context, generation of the NHC species through
deprotonation of the heterazolium salt followed by its
reaction with the aldehyde moiety renders an acyl anion
intermediate with its nucleophilicity toward internal (e.g.,
alkyne) or external (e.g., molecular oxygen) electrophiles.
Meanwhile, the so-obtained conjugate acid (BHþ) result-
ing from deprotonation of the heterazolium salt could
serve as a π-activator toward the alkyne moiety.12d,f,13a
Since both processes are well-documented, we envisaged a
reaction involving catalytic dual activation18 of a bifunc-
tional substrate containing both aldehyde and alkyne
functionalities at appropriate positions, to furnish a cy-
clized product. Indeed, along these lines of thoughts, the
following sections describe the results of our investigations
and realization of our hypothesis.
We began our studies on the proposed cyclization reac-
tion using 1a as the test substrate. We initially anticipated
that 1a would undergo an intramolecular hydroacylation
reaction involving the addition of the Breslow intermediate
to the proximal alkyne moiety (activated by BHþ) to afford
the corresponding indenone product (Scheme 1, path a).
Much to our surprise, instead of the expected 2-phenylin-
denone, phthalide 2a was obtained exclusively (for details,
see Supporting Information). Undaunted by this unex-
pected result, we set out to examine the reaction parameters
in order to further optimize this serendipitous transforma-
tion. Among the variety of heterazolium salts examined, 1,3-
bis(2,4,6-trimethylphenyl)imidazolinium chloride (A)
proved most superior for this reaction. DBU was revealed
as the most effective base among all the inorganic and
organic bases examined, while MeCN was the solvent of
choice at high concentrations (0.2 M). Lastly, control
experiments employing only either A or DBU gave no
conversions.
the context of NHC catalysis.8 Phthalides9 and isocoum-
arins10 are important classes of naturally occurring lactones
that have been found to exhibit a wide range of biological
indications and to be versatile building blocks for the synth-
esis of bioactive compounds.11 Consequently, a number of
synthetic strategies have been developed for their construc-
tions, generally involving 5-exo or 6-endo cyclizations of either
preformed12 or in situ generated13 o-alkynylbenzoic acids
through electrophilic activation of the alkyne moiety. Here,
we disclose the discovery of a highly effective, NHC-catalyzed
oxidative cyclization of o-alkynylbenzaldehydes that enabled
the easy preparation of a diverse array of phthalides and
isocoumarins (Scheme 1, path b). This is the first example of
an NHC-catalyzed oxidative lactonization of aldehydes under
aerobic conditions involving an unactivated alkyne as an internal
electrophile.14,15 In sharp contrast to the related oxidative
(11) (a) Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds; Academic Press: New York, 1975; Vol. 1, p 249. (b) Elderfield,
R. C. Heterocyclic Compounds; Wiley: New York, 1951; Vol. 2, Chapter 2.
(12) (a) Sashida, H.; Kawamukai, A. Synthesis 1999, 1145. (b)
Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron 2000, 56,
2533. (c) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett.
2005, 7, 5437. (d) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto,
Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517. (e)
Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.; van de Weghe, P.
Tetrahedron 2007, 63, 9979. (f) Kanazawa, C.; Terada, M. Tetrahedron
Lett. 2007, 48, 933.
(13) (a) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin
Trans. 1 1998, 561. (b) Liao, H.-Y.; Cheng, C.-H. J. Org. Chem. 1995, 60,
3711. (c) Subramanian, V.; Batchu, V. R.; Barange, D.; Pal, M. J. Org.
Chem. 2005, 70, 4778. (d) Zhou, L.; Jiang, H.-F. Tetrahedron Lett. 2007,
48, 8449. (e) Inack-Ngi, S.; Rahmani, R.; Commeiras, L.; Chouraqui,
^
G.; Thibonnet, J.; Duchene, A.; Abarbri, M.; Parrain, J.-L. Adv. Synth.
Catal. 2009, 351, 779.
With the optimized reaction conditions in hand, we
set out to explore the substrate scope of this newly
developed process, and the results are summarized in
Table 1. Both terminal and internal alkynes were well
tolerated for this reaction, and the regiochemical
(14) During our investigations, Glorius and co-workers reported an
example of NHC-catalyzed intramolecular cyclization of benzaldehydes
bearing an unactivated alkyne moiety; see: Biju, A. T.; Wurz, N. E.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 5970. However, this reported
reaction differs significantly from our work described herein in terms of
reactivity under the conditions described, the product obtained, and the
mechanistic pathway involved. The same group reported NHC-cata-
lyzed hydroacylation of unactivated alkenes and arynes; see: (a) Hirano,
K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 14190.
(b) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761.
(15) For the reactions of aldehydes with activated alkynes involving
NHCs as a reagent, see: (a) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E.
Org. Lett. 2005, 7, 2297. (b) Ma, C.; Ding, H.; Wu, G.; Yang, Y. J. Org.
Chem. 2005, 70, 8919 and references therein.
(17) For an example using CO2 as an oxidant for NHC-catalyzed
oxidation of aldehydes, see: (a) Gu, L.; Zhang, Y. J. Am. Chem. Soc.
2010, 132, 914. (b) Nair, V.; Varghese, V.; Paul, R. R.; Jose, A.; Sinu,
C. R.; Menon, R. S. Org. Lett. 2010, 12, 2653.
(18) Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566.
(19) For an example of anionic cyclizations that give a different
regiochemical outcome depending on the nature of alkyne substituents,
see: Vasilevsky, S. F.; Mikhailovskaya, T. F.; Mamatyuk, V. I.; Salni-
kov, G. E.; Bogdanchikov, G. A.; Manoharan, M.; Alabugin, I. V. J.
Org. Chem. 2009, 74, 8106.
(16) For examples of NHC-catalyzed reactions involving esterifica-
tion through a similar mechanism under aerobic conditions, see: (a) Liu,
Y.-K.; Li, R.; Yue, L.; Li, B.-J.; Chen, Y.-C.; Wu, Y.; Ding, L.-S. Org.
Lett. 2006, 8, 1521. (b) Lin, L.; Li, Y.; Du, W.; Deng, W.-P. Tetrahedron
Lett. 2010, 51, 3571.
Org. Lett., Vol. 13, No. 9, 2011
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Park, Jong Hyub
