Scheme 1
.
Multicatalytic Strategies for Heterocycle Synthesis
Table 1. Bi(OTf)3-Catalyzed Intramolecular Hydroalkoxylation
of Unactivated Olefinsa
development of this process would be well attended by the
appropriate identification of a Lewis acidic catalyst.
Unfortunately, of the Lewis acidic hydroalkoxylation
catalysts that have been reported, we found each of them to
be either inconvenient to prepare or poorly efficient. We thus
sought to identify a more suitable alternative. Inspired by
the reports of Shibasaki6a and Rueping6b that Bi(OTf)3 is
capable of catalyzing the hydrofunctionalization of dienes
or styrenyl olefins, respectively, and by the increasing body
of work regarding Bi(OTf)3-catalyzed nucleophilic addition
reactions,7 we decided to examine this reagent for its
hydroalkoxylation proficiency. Thus, we found that 10 mol
% Bi(OTf)3 at 80 °C in DCE effectively catalyzed the
conversion of 1-phenyl-5-hexen-2-ol to 2-benzyl-5-meth-
yltetrahydrofuran in 94% yield after only 50 min (Table 1,
entry 1). A comparison study revealed that Bi(OTf)3 offers
reaction rates superior to those of other metal triflate based
hydroalkoxylation catalysts (see Supporting Information).
Before progressing to our multicatalytic goal, we decided
to examine the substrate scope of the Bi(OTf)3-catalyzed
hydroalkoxylation reaction, particularly in the context of the
highly functionalized substrates required by our reaction
design. Thus, we found that both terminal and internal olefins
underwent hydroalkoxylation to furnish tetrahydrofurans in
high yield with preference for the anti diastereomer (Table
1, entries 1 and 2). Not surprisingly, the presence of
additional biasing substituents increased the level of dias-
tereoselection (entry 3). Cyclization to form a pyran also
a Reactions were run in the presence of 10 mol % Bi(OTf)3 at a
concentration of 0.2 M in DCE at 80 °C. b Diastereomeric ratios were
determined by GC or 1H NMR analysis. c 2-Benzyl-6-methyltetrahydropyran
was also isolated in 5% yield. d Reaction run at 70 °C. e Reaction run in
benzene at 40 °C.
proved possible, as shown in entry 4. Notably, this styrenyl
substrate gave rise to a challenging 2,2,6-trisubstituted pyran
with good yield and diastereoselectivity. Importantly, we
have found that carboxylate ester functionality is well
tolerated, thus allowing for the production of cyclic ethers
bearing this useful functional handle (entries 4 and 5). Indeed,
even a ꢀ-hydroxyester substrate was found to undergo facile
hydroalkoxylation without any observable elimination of
water (entry 5). In addition, we have found that bisolefinic
and nitro substrates are well tolerated in this reaction,
allowing efficient access to substituted cyclic ether adducts
bearing these versatile functional motifs (entries 6 and 7).
Finally, although tertiary alcohols tend to be difficult to
employ in hydroalkoxylation processes because of their
propensity to undergo dehydration, we have found that in
certain circumstances this functionality can be successfully
employed. Thus, for example, eucalyptol could be prepared
in good yield by the treatment of R-terpineol with 10 mol
% Bi(OTf)3 in benzene at 40 °C (entry 8).
(3) (a) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536. (b) Ohta, T.; Kataoka, Y.; Miyoshi, A.; Oe, Y.; Furukawa, I.;
Ito, Y. J. Organomet. Chem. 2007, 692, 671. (c) Grant, V. H.; Liu, B.
Tetrahedron Lett. 2005, 46, 1237. (d) Komeyama, K.; Morimoto, T.;
Nakayama, Y.; Takaki, K. Tetrahedron Lett. 2007, 48, 3259. (e) Marotta,
E.; Foresti, E.; Marcelli, T.; Peri, F.; Righi, P.; Scardovi, N.; Rosini, G.
Org. Lett. 2002, 4, 4451. (f) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C.
Org. Lett. 2005, 7, 4553. (g) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005,
127, 6966.
(4) (a) Coulombel, L.; Rajzmann, M.; Pons, J.-M.; Olivero, S.; Dun˜ach,
E. Chem. Eur. J. 2006, 12, 6356. (b) Coulombel, L.; Favier, I.; Dun˜ach, E.
Chem. Commun. 2005, 2286.
Satisfied that the substrate scope allowed by Bi(OTf)3
catalysis was suitably broad, we next sought to actualize the
multicatalytic goal illustrated in Scheme 1B. After much
experimentation, we found that complex tetrahydrofurans can
be readily assembled by the coupling of a range of silylated
nucleophilic partners and aldehydes under the action of 10
(5) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.;
Hartwig, J. F. Org. Lett. 2006, 8, 4179.
(6) (a) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 1611. (b) Rueping, M.; Nachtsheim, B. J.; Kuenkel,
A. Synlett 2007, 1391.
(7) For reviews on the chemistry of Bi(OTf)3, see: (a) Leonard, N. M.;
Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58, 8373. (b) Gaspard-
Iloughmane, H.; Le Roux, C. Eur. J. Org. Chem. 2004, 2517.
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Org. Lett., Vol. 11, No. 6, 2009