final compound, which would be reminiscent of a Heck-
type reaction using alkyl halides as reactants. It is worth
noting that despite the enormous effort carried out in the
development of Heck-type reactions, the use of alkyl halides
presenting β-hydrogens as organic electrophiles6 is con-
siderably less advanced.7 The success of this new approach
is also based on the chemical compatibility of titanocene-
(III) complexes withpalladium and nickel catalysts8 and its
facility to oxidize different carbon-center radicals type-II
under highly reductive reaction conditions.9
In this work, we report new cyclization reactions of
primary and secondary alkyl iodides and simple alkenes
with different substitution patterns based on the combina-
tion of Ti and Ni catalysts. Control toward the final ending
step is obtained just by carrying out the reaction in the
presence of water or in anhydrous media, yielding tin-free
reductive radical cyclizations or Heck-type reactions re-
spectively. This protocol expands significantly the scope of
both reactions and improves considerably the reaction
conditions reported to date, also showing that free radical
and transition metal chemistries are complementary, re-
ducing the limitations of both methodologies and giving
rise to new reactivities.
To check our working hypothesis we initially treated the
prenyl derivative 1 (1 mmol) with a mixture of different Ni
catalysts (20 mol %) and phosphorated ligands (40 mol %)
with diverse electronic and steric characteristics (PPh3,
P(2-furyl)3, P(p-F-Ph)3, P(tBu)3, P(Me)2Ph, P(p-MeO-
Ph)3, P(C6F5)3, P(Cy)3, P(Ph)2tBu, P(Ph)2Me, P(OPh)3,
P(OEt)3) and in situ generated Cp2TiCl (2 mmol)10À12 in
THF (0.02 M) at room temperature in the presence
(10 mmol) and absence of water (Scheme 2). In this latter
case, we found that the addition of trimethylsilyl chloride
(4 mmol) also improved the reaction yields. Finally, our work-
ing hypothesis could be verified. After 16 h, the Heck-type
product 2 was isolated in high yield (84%) using simple
PPh3 as a ligand. Only minor amounts of 3 could be
obtained under these reaction conditions (9%), which
presumably derived from a HAT reaction from the solvent
(THF).13 This side reaction was also observed in the Co-
catalyzed Heck-type reaction of closely related alkyl
iodides.7c In the presence of water the excellent HAT
capability of the complex Cp2TiClÀH2O ensured a reduc-
tive ending, thus selectively obtaining the corresponding
alkane 3 in high yield (91%).14 In this latter case, P(Cy)3
gave the best yields.
Scheme 2. Reductive- and Heck-Type Cyclization of 1
Scheme 1. Working Hypothesis
Remarkably, these reaction conditions could be success-
fully applied to other starting materials. The wide variety
of products obtained for the reductive-type cyclization are
summarized in Table 1.
The reductive cyclizations took place in moderate to
excellent yieldscoveringa broadrangeof starting materials
yielding the corresponding cyclic structures. Therefore, the
radical cyclization is faster than the HAT from Ti(III)-
aqua complexes to the acyclic transient radicals, even despite
the fact that those complexes are present in stoichiometric
(6) Heck-type reactions using alkyl halides that lack β-hydrogens are
known: Matsubara, R.; Gutierrez, A. C.; Jamison, T. F. J. Am. Chem.
Soc. 2011, 133, 19020–19023 and references cited therein.
(7) (a) Levedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P.
J. Organomet. Chem. 1988, 344, 253–259. (b) Terao, J.; Watanabe, H.;
Miyamoto, M.; Kambe, N. Bull. Chem. Soc. Jpn. 2003, 76, 2209–2214.
(c) Affo, W.; Ohmiya, H.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.;
Oshima, K.; Imamura, Y.; Mizuta, T.; Miyoshi, K. J. Am. Chem. Soc.
2006, 128, 8068–8077. (d) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 11340–11341. (e) Bloome, K. S.; Alexanian, E. J. J. Am. Chem.
Soc. 2010, 132, 12823–12825. (f) Bloome, K. S.; McMahen, R. L.;
Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146–20148. (g) Weiss,
M. E.; Kreis, L. M.; Lauber, A.; Carreira, E. M. Angew. Chem., Int. Ed.
2011, 50, 11125–11128. (h) Zhou, W.; An, G.; Zhang, G.; Han, J.; Pan,
Y. Org. Biomol. Chem. 2011, 9, 5833–5837. (i) Liu, C.; Tang, S.; Liu, D.;
Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem., Int. Ed. 2012, 51,
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(9) Justicia, J.; Alvarez de Cienfuegos, L.; Campana, A. G.; Miguel,
~
€
D.; Jakoby, V.; Gansauer, A.; Cuerva, J. M. Chem. Soc. Rev. 2011, 40,
3525–3537.
(10) For seminal papers, see: (a) RajanBabu, T. V.; Nugent, W. A.
€
J. Am. Chem. Soc. 1994, 116, 986–997. (b) Gansauer, A.; Bluhm, H.;
Pierobon, M. J. Am. Chem. Soc. 1998, 120, 12849–12859.
(11) Titanocene(III) chloride exists in THF as an equilibrium mixture
of Cp2TiCl and (Cp2TiCl)2; see: Enemærke, R. J.; Larsen, J.; Skrydstrup,
T.; Daasbjerg, K. J. Am. Chem. Soc. 2004, 126, 7853–7864. For clarity’s
sake we usually represent this complex as Cp2TiCl.
€
3638–3641. (j) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.;
Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773–8787.
(12) The corresponding control experiments showed that the nickel
catalyst, the titanium catalyst, and the manganese dust are indispensable
for the success of both types of reactions.
(13) We explored other solvents and obtained the Heck-type product
2 (71%) in benzene, but it resulted in being nonreproducible.
(14) Noteworthy, when deuterium oxide is used instead of water the
isotopomer 3d can be isolated in excellent yield (93%), confirming that
the hydrogen atom comes from the added water. See Supporting
Information for details.
~
(8) (a) Campana, A. G.; Bazdi, B.; Fuentes, N.; Robles, R.; Cuerva,
J. M.; Oltra, J. E.; Porcel, S.; Echavarren, A. M. Angew. Chem., Int. Ed.
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~
2008, 47, 7515–7519. (b) Millan, A.; Campana, A. G.; Bazdi, B.; Miguel,
D.; Alvarez de Cienfuegos, L.; Echavarren, A. M.; Cuerva, J. M.
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Chem.;Eur. J. 2011, 17, 3985–3994. (c) Millan, A.; Alvarez de
~
Cienfuegos, L.; Martın-Lasanta, A.; Campana, A. G.; Cuerva, J. M.
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Adv. Synth. Catal. 2011, 353, 73–78. (d) Millan, A.; Martın-Lasanta, A.;
Miguel, D.; Alvarez de Cienfuegos, L.; Cuerva, J. M. Chem. Commun.
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Org. Lett., Vol. 14, No. 23, 2012
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