molecular quantities of reducing systems such as Ni,5 Mg,6
In,7 Mn/CuCl2,8 Zn/Cu,9 SmI2,10 CrCl2,11 Ti(III)citrate/vitamin
B
Couplings of Benzylic Halides Mediated
by Titanocene Chloride: Synthesis
of Bibenzyl Derivatives
12 cat.,12 and salts and carbonyl complexes of Ni, Mn, or Fe.13
The Pd/C-catalyzed14 coupling of benzylic chloride, 1-(dichlo-
romethyl)-, and 1-(trichloromethyl)benzene leading to the cor-
responding bibenzyl systems with uneven yields has also been
described. McMurry coupling reaction of different benzalde-
hydes was used to synthesize a series of stilbenoids.15 There
has also been a very recent description of the stereoselective
synthesis of hydroxystilbenoids by ruthenium-catalyzed cross-
metathesis.16 One precedent of the reaction of benzylic and
allylic halides using equimolecular quantities of Ti(III) to give
the corresponding homocoupling products has been reported by
Yanlong et al.17 Heterocoupling of benzylic halides with
benzaldehyde or derivatives has also been reported to be
achieved using conventional methods such as Wittig synthesis,18
condensation via sulfones,19 and either SmI2-,10 CrCl2-,11 or
Mn-mediated20 carbon-carbon bond forming processes, among
others.
Alejandro F. Barrero,*,† M. Mar Herrador,†
Jose´ F. Qu´ılez del Moral,† Pilar Arteaga,†
Mohammed Akssira,‡ Fadwa El Hanbali,‡
Jesu´s F. Arteaga,† Horacio R. Die´guez,†
and Elena M. Sa´nchez†
Department of Organic Chemistry, Institute of Biotechnology,
UniVersity of Granada, AVda. FuentenueVa,
18071 Granada, Spain, and Laboratoire de Chimie
Bioorganique et Analytique, UniVersite´ Hassan II,
B.P. 146-20650 Mohammedia, Morocco
ReceiVed December 5, 2006
As a result of our research into the use of Cp2TiCl in the
synthesis of bioactive natural products, we have recently
developed novel processes of homocoupling of allylic halides21
and vinylepoxides catalyzed by titanocene chloride.22 Subse-
quently, we wanted to explore the feasibility of accomplishing
Ti(III)-mediated homo- and heterocoupling of benzylic halides.
Thus, considering the mechanism proposed for the reaction with
allylic halides and vinylepoxides, we surmised that titanocene
could well intervene efficiently in the homocoupling of benzylic
halides (Scheme 1). Following this mechanistical proposal,
(5) Inaba, S.; Matsumoto, H.; Rieke, R. D. J. Org. Chem. 1984, 49,
2093-2098.
(6) Aitken, R. A; Hodgson, P. K. G.; Morrison, J. J.; Oyewale, A. O. J.
Chem. Soc, Perkin Trans. 1 2002, 3, 402-415.
Titanocene monochloride catalyzes the homocoupling of
benzylic halides and benzylic gem-dibromides to give the
corresponding bibenzyl and stilbenyl systems. Exposure of
benzylic bromides to Ti(III) in the presence of aldehydes
gave rise to the Barbier-type products. Examples of the utility
of the herein described processes are included.
(7) Ranu, B. C.; Dutta, P.; Sarkar, A. Tetrahedron Lett. 1998, 39, 9557-
9558.
(8) Ma, J.; Chan, T.-H. Tetrahedron Lett. 1998, 39, 2499-2502.
(9) De Sa, A. C. P. F.; Pontes, G. M. A.; Dos Anjos, J. A. L.; Santana,
S. R.; Bieber, L. W.; Malvestiti, I. J. Braz. Chem. Soc. 2003, 14, 429-
434.
(10) Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745-777.
(11) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
(12) Shey, J.; McGinley, C. M.; Mcauley, K. M.; Dearth, A. S.; Young,
B.; van der Donk, W. A. J. Org. Chem. 2002, 67, 837-846.
(13) (a) Corey, E. J.; Semmelhack, M. F. J. Am. Chem. Soc. 1967, 89,
2755-2757. (b) Huther, N.; McGrail, P.; Parsons, A. F. Tetrahedron Lett.
2002, 43, 2535-2538. (c) Li, H.; Turnbull, M. M. Synth. React. Inorg.
Met.: Org. Chem. 1993, 23, 797-807.
Compounds containing the bibenzyl moiety as the core of
their structure constitute an interesting group of molecules.
These molecules have been used as key intermediates both for
the synthesis of dyes, paints, and resins, and for the preparation
of a number of natural products as stilbenyl or bibenzyl
derivatives. A number of biologically important compounds such
as the well-known resveratrol and derivatives,1 combretastatins2
and isocombretastatins,3 or lunularic acid4 are included among
this group of compounds.
(14) Joshi, A. V.; Baidossi, M.; Taha, N.; Mukhopadhyay, S.; Sasson,
Y. Synth. Commun. 2005, 35, 2715-2722.
(15) (a) Shadakshari, U.; Rele, S.; Nayak, S. K.; Chattopadhyay, S. Ind.
J. Chem., Sect., B: Org. Chem. Incl. Med. Chem. 2004, 43B, 1934-1938.
(b) Ramana, M. M. V.; Singh, B. K. D.; Parihar, J. A. J. Chem. Res. 2004,
760-761.
(16) (a) Ferre´-Limon, K.; Delaude, L.; Demonceau, A.; Noels, A. F. Eur.
J. Org. Chem. 2005, 3319-3325. (b) Velder, J.; Ritter, S.; Lex, J.; Schmalz,
H.-G. Synthesis 2006, 2, 273-278.
Different methods have already been developed to achieve
the synthesis of compounds of this type, among them, the
homocoupling of benzylic halides mediated mostly by equi-
(17) Yanlong, Q.; Guisheng, L.; Huang, Y. J. Organomet. Chem. 1990,
381, 29-34.
(18) Warner, P.; Sutherland, R. J. Org. Chem. 1992, 57, 6294-6300.
(19) Alonso, D. A.; Fuensanta, M.; Na´jera, C.; Varea, M. J. Org. Chem.
2005, 70, 6404-6416.
† University of Granada.
‡ Universite´ Hassan II.
(1) Baur, J. A.; Sinclair, D. A. Nat. ReV. Drug DiscoVery 2006, 5, 493-
506.
(2) Cirla, A.; Mann, J. Nat. Prod. Rep. 2003, 20, 558-564.
(3) Singh, S. B.; Pettit, G. R. Synth. Commun. 1987, 17, 877-892.
(4) Bracher, F.; Kreauss, J.; Bornatsch, A. Nat. Prod. Lett. 2000, 14,
305-310.
(20) Kim, S. H.; Rieke, R. D. J. Org. Chem. 2000, 65, 2322-2330.
(21) Barrero, A. F.; Herrador, M. M.; Qu´ılez del Moral, J. F.; Arteaga,
P.; Arteaga, J. F.; Piedra, M.; Sa´nchez, E. M. Org. Lett. 2005, 7, 2301-
2304.
(22) Barrero, A. F.; Qu´ılez del Moral, J. F.; Sa´nchez, E. M.; Arteaga, J.
F. Org. Lett. 2006, 8, 669-672.
10.1021/jo062492p CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/20/2007
J. Org. Chem. 2007, 72, 2251-2254
2251