Unprecedented Barbier-type reactions catalysed by titanocene( III) { Antonio Rosales, a Juan L. Oller-Lo ´pez, a Jose ´ Justicia, a Andreas Gansa ¨uer, b J. Enrique Oltra* a and Juan M. Cuerva* a a Department of Organic Chemistry, Faculty of Sciences, University of Granada, E-18071 Granada, Spain. E-mail: jmcuerva@platon.ugr.es; Fax: 134 958 248437; Tel: 134 958 248090 b Rheinische Friedrich-Wilhelms-Universita ¨t, Kekule ´-Institut fu ¨r Organische Chemie und Biochemie, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany Received (in Cambridge, UK) 22nd July 2004, Accepted 17th August 2004 First published as an Advance Article on the web 5th October 2004 Selective Barbier-type allylations, benzylations and propargylations of aldehydes and ketones can be carried out under extremely mild conditions employing titanocene( III) complexes as catalysts. In this way, chiral titanocene catalysts provided yields ranging from 50–80% of optically active products. Allylation, benzylation and propargylation of carbonyl compounds are useful C–C bond forming reactions in organic synthesis. These reactions can be carried out under Barbier-type conditions employing magnesium, chromium, samarium and other metals, 1 among which titanium complexes 2 showed an outstanding capacity of promoting enantioselective processes. 3 Nevertheless, the require- ment for stoichiometric proportions (often interpreted as consider- able excesses) of chiral titanium complexes is a serious drawback in the methods described to date. 4 Therefore, we decided to develop a convenient procedure catalysed by titanocene complexes. We have recently found that the combination Mn/Me 3 SiCl/ collidine can effectively regenerate Cp 2 Ti III Cl in situ. 5 This observation prompted us to attempt Barbier-type reactions of allyl bromide (1) catalysed by titanocene( III). To this end we treated different aldehydes and ketones with 1, a substoichiometric quantity of the commercial pre-catalyst Cp 2 TiCl 2 (0.2 equiv.), Mn dust, Me 3 SiCl and 2,4,6-collidine. 6 The results are summarised in Table 1. The reaction worked well with aliphatic, unsaturated and aromatic aldehydes and ketones but after treatment under our conditions ethyl benzoate and ethyl cinnamate were recovered unchanged. This chemoselectivity profile is considerably better than that shown by allyl–samarium complexes, which do not dis- criminate between esters and carbonyl compounds. 7 It should be noted that despite the fact that acetophenone and benzaldehyde are prone to undergo pinacol coupling reactions in the presence of single-electron-transfer reagents, both substrates gave satisfactory yields of the corresponding allylated products. 8 Moreover, when cyclopropyl phenyl ketone was used as a radical clock, 9 no rearranged products were obtained, indicating that ketyl radicals were not involved in the process. Therefore, we propose the mechanism depicted in Scheme 1 to rationalise the catalytic cycle. 10 If our mechanistic proposal is correct, our catalytic procedure should also work well with other activated alkyl halides. As we expected, the reaction of decanal with allyl chloride, and benzyl and propargyl bromides catalysed by Cp 2 TiCl gave the corresponding condensation products at yields ranging from 70 to 90% (Table 2). Under similar conditions, the propargylation of 2-decanone provided a 60% yield of the expected acetylenic alcohol (Table 2). It should be noted that, in contrast to what occurs in the chromium-promoted Nozaki–Hiyama–Kishi propargylations, 11 allenic by-products were not detected. Finally, we decided to use our method for asymmetric catalysis, one of the most powerful tools in organic synthesis. 12 For this purpose we selected the commercial Brintzinger complex 2 and the { Electronic supplementary information (ESI) available: Alternative experimental protocol for reactions with unsaturated carbonyl compounds. See http://www.rsc.org/suppdata/cc/b4/b411173g/ DOI: 10.1039/b411173g Table 1 Titanocene(III)-catalysed addition of allyl bromide to carbo- nyl compounds Carbonyl compound Product (yield) Carbonyl compound Product (yield) Decanal (90%) 4-tert-Butylcyclo- hexanone (52%, a 81% b ) Citral (75%) b-Ionone (50%, 67% b ) Benzaldehyde (80%) Acetophenone (86%) 2-Decanone (100%) 3,4,5-Trimethoxy- benzaldehyde (70%) a 2:1 Mixture of stereoisomers. b Based on recovered starting material. Scheme 1 Catalytic cycle for Ti(III)-mediated addition of allyl bromide to carbonyl compounds. 2628 Chem. Commun. , 2004, 2628–2629 This journal is ß The Royal Society of Chemistry 2004