place at room temperature or below, under mild conditions.
Novel complex structures difficult to achieve by other meth-
odologies are obtained in one step by this procedure. Thus,
our method is an interesting tool in the context of organic
synthesis. Future work will be directed to the development of
an enantioselective version of this reaction using chiral tita-
nocene complexes.
Scheme 2 Mechanistic hypothesis.
a,b-g,d-unsaturated esters (entries 14 and 16) and ketones
(entry 15) are also suitable substrates. In those cases, a residual
non-conjugated E double bond is retained in the final cyclic
structure. Compounds presenting different substitutions in the
pronucleophile (entries 11 and 12) and the activated alkene
(entry 13) are also valid starting materials. In this case the
steric hindrance at the newly formed C–C bond correlates with
a decrease in the cyclization yield (entry 12). Although the
cis:trans stereoselectivity in the five-membered cycles is not high
at room temperature it can be improved at lower temperatures.
Thus for example, the initial 4 : 1 stereoselectivity (entry 1) can
be substantially improved by carrying out the reaction at
lower temperatures, yielding exclusively compound 2-cis
(61%) at À20 1C.
Notes and references
1 For a review of the advantages of these mixed systems, see: L. Ford
and U. Jahn, Angew. Chem., Int. Ed., 2009, 48, 6386–6389.
2 (a) A. Gansauer, C.-A. Fan and F. Piestert, J. Am. Chem. Soc.,
¨
¨
2008, 130, 6916–6917; (b) A. Gansauer, M. Otte and L. Shi, J. Am.
Chem. Soc., 2001, 133, 416–417.
3 For seminal works in titanocene(III) chemistry, see:
(a) T. V. RajanBabu and W. A. Nugent, J. Am. Chem. Soc.,
1994, 116, 986–997; (b) A. Gansauer, H. Bluhm and M. Pierobon,
¨
J. Am. Chem. Soc., 1998, 120, 12849–12859.
4 (a) A. G. Campana, B. Bazdi, N. Fuentes, R. Robles,
J. M. Cuerva, J. E. Oltra, S. Porcel and A. M. Echavarren, Angew.
´
Chem., Int. Ed., 2008, 47, 7515–7519; (b) A. Millan,
A. G. Campana, B. Bazdi, D. Miguel, L. Alvarez de Cienfuegos,
A. M. Echavarren and J. M. Cuerva, Chem.–Eur. J., 2011, 17,
´
3985–3994.
´
5 A. Millan, L. Alvarez de Cienfuegos, A. Martın-Lasanta,
´ ´
Concerning the proposed mechanism (path b) two other
alternative pathways may be operative (Scheme 2). The first
one (path a) has no precedent in the literature owing to no
examples of Oppolzer-type carbocyclizations of activated
alkenes having been described. Therefore, we carried out the
Oppolzer-type cyclization of compound 1 using two different
conditions. Under the original Oppolzer conditions (Pd(0)
catalyst, AcOH, reflux) we obtained minor amounts (14%)
of the carbocycle with an additional double bond derived from
a b-elimination process. Under our conditions (THF, rt) no
cyclization was observed. Only a diene arising from the
elimination of the ethyl carbonate group was isolated. These
two experiments ruled out a palladium-catalyzed Oppolzer-type
mechanism. A mechanism based on an in situ generation of
nucleophilic titanocene(IV)-complexes (path c) was ruled out
taking into account that an increase in the steric hindrance in
the titanocene(III)-complex ((t-Bu-Cp)2TiCl) was not correlated
with a variation in the 4 : 1 2-cis:2-trans relationship. Therefore,
a direct radical addition seems to be the only way to explain the
experimental results. It is worth noting that few examples of
allyl radical additions to a,b-unsaturated carbonyl compounds
have been described in the literature owing to their tendency to
dimerize.15 High dilution and/or slow addition using a syringe
pump are usually required. Accordingly, a control radical
cyclization was carried out using the corresponding bromide
of 1 in our standard concentrations (10 mM) and no cyclization
products were obtained. This fact suggests that this multimetallic
protocol generates tiny amounts of the allyl radicals decreasing
the amounts of undesired side dimerization products.
A. G. Campana and J. M. Cuerva, Adv. Synth. Catal., 2011, 353,
73–78.
6 See for example:(a) G. Majetich, R. W. Desmond and J. J. Soria,
J. Org. Chem., 1986, 51, 1753–1769; (b) C. Kuroda, H. Nogami,
Y. Ohnishi, Y. Kimura and J. Y. Satoh, Tetrahedron, 1997, 53,
839–858; (c) S. A. Rodgen and S. E. Schaus, Angew. Chem., Int.
Ed., 2006, 45, 4929–4932.
´
7 M. Paradas, A. G. Campana, R. E. Este
Cienfuegos, T. Jime
J. Org. Chem., 2009, 74, 3616–3619.
8 (a) J. Justicia, A. Rosales, E. Bunuel, J. L. Oller-Lo
M. Valdivia, A. Haıdour, J. E. Oltra, A. F. Barrero,
´
vez, L. Alvarez de
´
nez, R. Robles, J. M. Cuerva and J. E. Oltra,
´
pez,
¨
D. J. Cardenas and J. M. Cuerva, Chem.–Eur. J., 2004, 10,
´
1778–1788; (b) J. Justicia, J. L. Oller-Lopez, A. C. Campana,
J. E. Oltra, J. M. Cuerva, E. Bunuel and D. J. Cardenas, J. Am.
Chem. Soc., 2005, 117, 14911–14921.
9 Nickel complexes can be also used as catalysts but with lower
yields.
10 For a full list of conditions tried, see ESIw.
11 Control experiments also showed that the presence of 2,4,6-
collidine has little influence on the yield but it allows
smooth reaction conditions and it is recommended when labile
compounds are used. Moreover, it is easily recovered at the end of
the reaction.
12 We also tried different titanocene-based catalysts (see ESIw) with
different steric hindrance and we also obtained the corresponding
carbocycles in similar yields and in similar stereoselectivities.
13 The Cp2TiCl and Pd catalyst loadings can be smaller but, in some
cases, incomplete conversions are obtained. The reported loadings
have been optimized for complete conversions in almost all the
experiments. For example, the cyclization of compound 1 can be
carried out using 10 mol% of both Cp2TiCl and Pd catalyst with
similar yields (71%).
14 For details, see ESIw.
15 (a) N. J. G. Cox and G. Pattenden, Tetrahedron Lett., 1989, 30,
621–624; (b) S. K. Mandal, S. Jana and S. C. Roy, Tetrahedron
Lett., 2005, 46, 6115–6117; (c) T. Morikawa, J. Uchida, K. Imoto
and T. J. Taguchi, J. Fluorine Chem., 1992, 58, 119–125.
In conclusion we have developed a novel Ti/Pd mediated
intramolecular Michael-type allylation reaction, which takes
c
10472 Chem. Commun., 2011, 47, 10470–10472
This journal is The Royal Society of Chemistry 2011