(CF3CO)2O as scavenger, which gives moderate yields of
â-hydroxy esters.6 Here we extend the Ti-based procedure to
the Reformatsky-type coupling between R-halo ketones and
aldehydes to obtain â-hydroxy ketones (aldol-like products)
under neutral conditions. The reaction is catalyzed by substo-
ichiometric proportions of the titanium complex, using Mn dust
as stoichiometric reductant and a combination of Me3SiCl and
2,4,6-collidine, developed in our laboratory, as titanocene-
regenerating agent.7
Ti-Catalyzed Reformatsky-Type Coupling
between r-Halo Ketones and Aldehydes
Rosa E. Este´vez, Miguel Paradas, Alba Milla´n,
Tania Jime´nez, Rafael Robles,* Juan M. Cuerva,* and
J. Enrique Oltra*
Department of Organic Chemistry, UniVersity of Granada,
Faculty of Sciences, Campus FuentenueVa s/n,
E-18071 Granada, Spain
Because Mn dust (unlike Zn) does not promote Reformatsky
reactions,5,6,8 we chose this metal to generate Cp2TiCl for our
experiments to avoid Zn-derived competing processes, which
might generate misleading observations.5,6,9 Thus, on the basis
of our own experience with Ti-catalyzed reactions,10 we
anticipated the catalytic cycle depicted in Scheme 1.
joltra@ugr.es; jmcuerVa@ugr.es; rrobles@ugr.es
ReceiVed October 9, 2007
According to our hypothesis, an R-halo ketone such as 1
would react with 2 equiv of Cp2TiIIICl to give a titanium(IV)
enolate such as 2, releasing 1 equiv of Cp2TiIVCl2 (Scheme 1).
Enolate 2 could subsequently react with an aldehyde (3) to give
adduct 4. Titanocene-regenerating agent 5, presumably derived
from the Me3SiCl/collidine mixture used,7a would generate Cp2-
TiCl2 from 4, releasing 6, which after the final acidic quenching
would give the desired â-hydroxy ketone 7. Eventually the Mn
present in the medium would reduce Cp2TiIVCl2 to Cp2TiIIICl,
thus closing the catalytic cycle.
We describe the first Ti-catalyzed Reformatsky-type coupling
between R-halo ketones and aldehydes. The reaction affords
â-hydroxy ketones under mild, neutral conditions compatible
with ketones and other electrophiles. The catalytic cycle
possibly proceeds via bis(cyclopentadienyl)titanium enolates.
(4) Bis(cyclopentadienyl)titanium(III) chloride (Nugent’s reagent) can
be generated in situ by stirring commercial Cp2TiCl2 with Zn or Mn dust
in THF, where it exists as an equilibrium mixture of the monomer Cp2TiCl
and the dinuclear species (Cp2TiCl)2; see: (a) RajanBabu, T. V.; Nugent,
W. A. J. Am. Chem. Soc. 1994, 116, 986-997. (b) Enemærke, R. J.; Larsen,
J.; Skrydstrup, T.; Daasbjerg, K. J. Am. Chem. Soc. 2004, 126, 7853-
7864. (c) Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp, M.; Mu¨ck-
Lichtenfeld, C.; Gansa¨uer, A.; Barchuck, A.; Keller, F. Angew. Chem., Int.
Ed. 2006, 45, 2041-2044. (d) Gansa¨uer, A.; Barchuk, A.; Keller, F.;
Schmitt, M.; Grimme, S.; Gerenkamp, M.; Mu¨ck-Lichtenfeld, C.; Daasbjerg,
K.; Svith, H. J. Am. Chem. Soc. 2007, 129, 1359-1371. For the sake of
clarity, we represent this complex as Cp2TiCl.
As long ago as 1887, Reformatsky reported the coupling
between ethyl R-haloacetates and aldehydes or ketones promoted
by zinc dust, thus establishing the basis of the Reformatsky
reaction.1 Currently, the Reformatsky reaction is considered in
a broad sense as being the process that results from the insertion
of a metal into a carbon-halogen bond activated by a carbonyl-,
carbonyl-derived, or carbonyl-related group in a vicinal (or
vinylogous) position, followed by coupling of the enolate thus
formed with aldehydes, ketones, or other kinds of electrophile.2a
In recent years, the Reformatsky reaction has been the subject
of renewed interest, due largely to the replacement of hetero-
geneous zinc dust by homogeneous metals and metal derivatives,
which have helped to improve the poor stereochemical control
of the classic Reformatsky reaction and facilitated the develop-
ment of metal-catalyzed versions of the process, among other
advantages.2,3 In this context, Little and co-workers introduced
the use of Cp2TiCl, a mild, homogeneous, single-electron-
transfer reagent4 to promote the Reformatsky-type reaction
between R-halo esters and aldehydes.5 This method proceeds
at room temperature under mild conditions and affords good
yields (78-95%) of â-hydroxy esters but requires stoichiometric
proportions of Cp2TiCl. Subsequently, Cozzi and co-workers
developed a titanium-catalyzed version of the process, using
(5) Parrish, J. D.; Shelton, D. R.; Little, R. D. Org. Lett. 2003, 5, 3615-
3617.
(6) Sgreccia, L.; Bandini, M.; Morganti, S.; Quintavalla, A.; Umani-
Ronchi, A.; Cozzi, P. G. J. Organomet. Chem. 2007, 692, 3191-3197.
(7) For the Me3SiCl/2,4,6-collidine combination as titanocene-regenerat-
ing agent, see: (a) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E.
Org. Lett. 2003, 5, 1935-1938. For pioneering work on collidine
hydrochloride and other pyridine hydrochloride derivatives, see: (b)
Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
12849-12859.
(8) In fact, after 6 h of stirring decanal (8) with 9 (2 equiv), Mn dust (8
equiv), 2,4,6-collidine (8 equiv), and Me3SiCl (4 equiv) in the absence of
Ti, an 81% yield of 8 was recovered unchanged and only a trace of coupling
product 10 was detected. Comparison of this result with that presented in
entry 1 of Table 1 (80% yield of 10 after the same reaction time) indicated
that under our conditions the potential Reformatsky reaction promoted by
Mn/Me3SiCl would be substantially slower than the Ti-catalyzed process.
(9) It may be presumed that not only Cp2TiCl but also Zn plays an
important role in Zn/Cp2TiCl2-promoted Reformatsky reactions; see: (a)
Ding, Y.; Zhao, Z.; Zhou, C. Tetrahedron 1997, 53, 2899-2906. (b) Chen,
L.; Zhao, G.; Ding, Y. Tetrahedron Lett. 2003, 44, 2611-2614.
(10) (a) Rosales, A.; Oller-Lo´pez, J. L.; Justicia, J.; Gansa¨uer, A.; Oltra,
J. E.; Cuerva, J. M. Chem. Commun. 2004, 2628-2629. (b) Justicia, J.;
Rosales, A.; Bun˜uel, E. Oller-Lo´pez, J. L.; Valdivia, M.; Ha¨ıdour, A.; Oltra,
J. E.; Barrero, A. F.; Ca´rdenas, D. J.; Cuerva, J. M. Chem. Eur. J. 2004,
10, 1778-1788. (c) Justicia, J.; Oltra, J. E.; Cuerva, J. M. J. Org. Chem.
2004, 69, 5803-5806. (d) Justicia, J.; Oller-Lo´pez, J. L.; Campan˜a, A. G.;
Oltra, J. E.; Cuerva, J. M.; Bun˜uel, E.; Ca´rdenas, D. J. J. Am. Chem. Soc.
2005, 127, 14911-14921. (e) Este´vez, R. E.; Oller-Lo´pez, J. L.; Robles,
R.; Melgarejo, C. R.; Gansa¨uer, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett.
2006, 8, 5433-5436.
(1) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210-1212.
(2) For a recent review, see: (a) Ocampo, R.; Dolbier, W. R., Jr.
Tetrahedron 2004, 60, 9325-9374. For recent reports on Reformatsky-
type reactions catalyzed by SmI2, [ClMn(salen)], low-valent Fe, and CoI,
see: (b) Lannou, M. I.; He´lion, F.; Namy, J. L. Tetrahedron 2003, 59,
10551-10565. (c) Orsini, F.; Lucci, E. M. Tetrahedron Lett. 2005, 46,
1909-1911. (d) Cozzi, P. G. Angew. Chem., Int. Ed. 2006, 45, 2951-
2954. (e) Durandetti, M.; Pe´richon, J. Synthesis 2006, 1542-1548. (f)
Lombardo, M.; Gualandi, A.; Pasi, F.; Trombini, C. AdV. Synth. Catal. 2007,
349, 465-468.
(3) Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568-2571.
10.1021/jo702189k CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/12/2008
1616
J. Org. Chem. 2008, 73, 1616-1619