A. Kena Diba et al. / Tetrahedron Letters 53 (2012) 6629–6632
6631
Table 3
Cyclization of 1 by Lewis vs. Brønsted acid
Entrya
(Lewis) acid (mol-%)
Additive 1 (mol-%)
Additive 2 (mol-%)
t
Yieldb (%)
1
2
3
4
5
6
7
Ca(NTf2)2 (5)
Ca(NTf2)2 (5)
HNTf2 (5)
HNTf2 (5)
HNTf2 (5)
HNTf2 (5)
HNTf2 (5)
Bu4NPF6 (5)
Bu4NPF6 (5)
—
—
Bu4NPF6 (5)
—
Bu4NPF6 (5)
—
1 h
20 h
1 h
1.5 h
5.5 h
5 d
98
53
81
93
97
—
2,6-t-Butyl pyridine (5)
—
—
—
2,6-t-Butyl pyridine (5)
2,6-t-Butyl pyridine (5)
5 d
—
a
Additives and (Lewis) acid were added at room temperature to alcohol 1 (0.25 mmol) in CH2Cl2 (2 mL) and stirred for the time indicated.
Isolated yield.
b
hypothesis is sustained by the fact that the reaction slows down
significantly in the presence of 2,6-t-butyl pyridine, as under these
conditions the protodemetallation event is no longer enhanced by
the presence of minor amounts of acid.
OH
1a
OH
OH
Ca2+
H+
- Ca2+
O
Ca+
1
- H+
1b
2a
A coordination of the calcium catalyst to the hydroxyl moiety,
which thereby enhances the acidity of the hydroxyl hydrogen atom
by several orders of magnitude followed by intramolecular proton-
ation of the double bond was confirmed as the olefin activation
mechanism for the aluminum triflate catalyzed hydroalkoxyla-
tion.8 However, in our case, experiments carried out with 6-
methylhept-5-en-2-ol-d2 show no incorporation of deuterium in
the cyclized product.12
In summary, we have demonstrated the suitability of our cal-
cium based catalyst system for the intramolecular hydroalkoxyla-
tion reaction, and thus developed a transition metal and acid
free, inexpensive, and very mild process for the highly atom eco-
Scheme 1. Mechanistic proposals for the cyclization of 1.
It is known that the cationic intramolecular hydroalkoxylation
of highly reactive substrates, such as alcohol 1, is promoted by cat-
alytic amounts of super Brønsted acids and proceeds in strongly
acidic media.3,4,10,11 However, apart from the apparent incompati-
bility of these protocols with many functional groups, the super-
acid catalyzed cycloisomerizations were reported to be difficult
to handle, since highly accurate control of acid concentration is
oftentimes crucial for obtaining synthetically useful product
yields.7,10 For a better understanding of the role of the calcium cat-
alyst in the presented hydroalkoxylation protocol a comparative
study of the cyclization of 1 with different additives was carried
out in the presence of catalytic amounts of the Ca(NTf2)2 catalyst
or HNTf2. The latter could be formed in situ by the protonation of
minor amounts of Ca(NTf2)2 with alcohol.
In the presence of 5 mol-% HNTf2 alcohol 1 cyclizes to tetrahy-
dropyran 2a in almost quantitative yield in a slightly longer reac-
tion time compared to the reaction in the presence of our
calcium based catalyst system (1.5 h vs 1 h, Table 3, entries 1/3/
4). Despite this very similar result for the conversion of the highly
reactive alcohol 1 in the presence of the acid HNTf2 and the cal-
cium catalyst, it shall be emphasized at this point that alcohols 7,
11 and 22, which are less reactive than 1, were found unreactive
under acid catalysis. Upon addition of 5 mol-% of Bu4NPF6 to the
acid catalyzed cyclization the reaction rate slowed down
significantly and 5.5 h was required to achieve complete conver-
sion (Table 3, entry 5). In the presence of an equimolar amount
of 2,6-t-butyl pyridine, as a sterically hindered base, the acid cata-
lyzed reaction ceased (Table 3, entries 6/7), whereas the calcium
catalyzed reaction yielded 53% of the desired product after 20 h
reaction time (Table 3, entry 2). This notable drop of the reaction
rate indicates for a cooperative effect of the calcium based catalyst
system and minor amounts of in situ formed acid, which is pre-
sumably no longer operative in the presence of base. These inves-
tigations clearly indicate that the acid catalyst shows a different
behavior than the calcium based catalyst system. Even though it
cannot be fully excluded at this point that in situ formed superacid
represents the only active catalytic species, as it is known to have
different properties than an acid catalyst that is directly added to
the reaction mixture, the reaction proceeds presumably through
the above mentioned cooperative catalyst system. A proposed
mechanistic pathway (Scheme 1) is initiated by the coordination
of the calcium catalyst to the double bond leading to the interme-
diate Lewis acid bound carbocation 1a, that is subjected to imme-
diate protodemetallation, leading to the carbocationic
intermediate 1b, cyclization of which leads to product 2a. This
nomic formation of cyclic ethers from
c,d-unsaturated alcohols.
In contrast to most of the previously reported procedures, room
temperature conditions were fully sufficient in most cases for a
high yielding cycloisomerization in the presence of a combination
of 5 mol-% Ca(NTf2)2 and 5 mol-% Bu4NPF6. Full selectivity to the
Markovnikov products was observed for mono-, 1,1-di-, and trisub-
stituted double bonds. The regioselectivity of the attack of the hy-
droxyl moiety to 1,2-disubstituted olefins was governed by angle
compression effects induced by the substituents in the a-position
of the alcohol functionality. Both, the double bond substitution
pattern and the degree of angle compression exerted by the chain
substituents affect the reactivity of the unsaturated alcohol.
Supplementary data
Supplementary data (general procedure and spectral data) asso-
ciated with this article can be found, in the online version, at
References and notes
1. (a) Elliott, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 2001, 1, 2303–2340; (b)
Narula, A. P. S. Perfum. Flavor. 2003, 28, 62–73.
2. (a) Inoue, M. Chem. Rev. 2005, 105, 4379–4405; (b) Tanaka, S.; Seki, T.;
Kitamura, T. Angew. Chem., Int. Ed. 2009, 48, 8948–8951; (c) Bandini, M.;
Monari, M.; Romaniello, A.; Tragni, M. Chem. Eur. J. 2010, 16, 14272–14277; (d)
Guerinot, A.; Serra Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.; Cossy, J.
Org. Lett. 2010, 12, 1808–1811; (e) Aponick, A.; Biannic, B. Synthesis 2008,
3356–3359; (f) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669–671; (g)
Korber, K.; Rominger, F.; Muller, T. J. J. Synlett 2010, 782–786.
3. Larrosa, I.; Romea, P.; Urpi, F. Tetrahedron 2008, 64, 2683–2723.
4. (a) Coulombel, L.; Dunach, E. Green Chem. 2004, 6, 499–501; (b) Jeong, Y.; Kim,
D.-Y.; Choi, Y.; Ryu, J.-S. Org. Biomol. Chem. 2011, 9, 374–378; (c) Linares-
Palomino, P. J.; Salido, S.; Altarejos, J.; Sanchez, A. Tetrahedron Lett. 2003, 44,
6651–6654.
5. (a) Dzudza, A.; Marks, T. J. Chem. Eur. J. 2010, 16, 3403–3422; (b) Kamiya, I.;
Tsunoyama, H.; Tsukuda, T.; Sakurai, H. Chem. Lett. 2007, 36, 646–647; (c) Kelly,
B. D.; Allen, J. M.; Tundel, R. E.; Lambert, T. H. Org. Lett. 2009, 11, 1381–1383;
(d) Marotta, E.; Foresti, E.; Marcelli, T.; Peri, F.; Righi, P.; Scardovi, N.; Rosini, G.
Org. Lett. 2002, 4, 4451–4453.