Titanocene-catalyzed reduction

Generally, amine products can be obtained with 91-99% ee. It is noteworthy that the ee of the product does not correspond to the E Z ratio of the starting imines. Imines 103 and 104 exist as 2.5 1 and 1.8 1 (E)/(Z) isomers, but titanocene-catalyzed reduction produces amines with 93% and 97% ee, respectively.105... 

Titanocene-Catalyzed Reductive Epoxide Opening to Alcohols... 

Scheme 12.12. Planned titanocene-catalyzed reductive epoxide opening.

TiTANOCENE-CATALYZED reduction of ketones in the presence of WATER. 

TITANOCENE-CATALYZED REDUCTION OF KETONES IN THE PRESENCE OF WATER. A CONVENIENT PROCEDURE FOR THE SYNTHESIS OF ALCOHOLS VIA FREE-RADICAL CHEMISTRY... 

TITANOCENE-CATALYZED REDUCTION OF ACETOPHENONE IN THE PRESENCE OF WATER... 

The coupling of independent catalytic cycles for both radical generation and reduction has been realized by the combination of the titanocene catalyzed reductive epoxide opening [36—4-0] via electron transfer and the catalytic reduction of radicals after H2 activation by Wilkinson s complex [Rh(PPh3)3Cl] as shown in Scheme 16 [41—43],... 

Stoichiometric Opening of Epoxides by Electron Transfer 435 Titanocene-Catalyzed Epoxide Opening 439 Titanocene-Catalyzed Reductive Epoxide Opening to Alcohols 439... 

Scheme 7.11. Proposed catalytic cycle for the titanocene catalyzed reduction of imines [86].

Gansauer A, Bluhm H, Pierobon M. Emergence of novel catalytic radical reactions titanocene-catalyzed reductive opening of epoxides. J. Am. Chem. Soc. 1998 120(49) 12849-12859. 

The inter- and intramolecular catalytic reductive couplings of alkynes and aldehydes recently have experienced rapid growth and are the topic of several recent reviews.5 h-8k 107 With respect to early transition metal catalysts, there exists a single example of the catalytic reductive cyclization of an acetylenic aldehyde, which involves the titanocene-catalyzed conversion of 77a to ethylidene cyclopentane 77b mediated by (EtO)3SiH.80 This process is restricted to terminally substituted alkyne partners (Scheme 53). 

The very first example of the catalytic reductive cyclization of an acetylenic aldehyde involves the use of a late transition metal catalyst. Exposure of alkynal 78a to a catalytic amount of Rh2Co2(CO)12 in the presence of Et3SiH induces highly stereoselective hydrosilylation-cyclization to provide the allylic alcohol 78b.1 8 This rhodium-based catalytic system is applicable to the cyclization of terminal alkynes to form five-membered rings, thus complementing the scope of the titanocene-catalyzed reaction (Scheme 54). 

This titanocene-catalyzed procedure was immediately extended by Gansauer et al. to the enantioselective opening of meso-epoxides by employing substoichiometric quantities of titanocene complexes with chiral hgands [58-60]. It has also been applied by this group in racemic form not only for reductive epoxide openings and intermolecular additions to a,P-unsaturated carbonyl compounds, but also to achieve 3-exo, 4-exo, and 5-exo cycliza-tions, as well as tandem cyclization addition reactions featuring vinyl radicals (Scheme 9) [8,9,44,46,57,61-65]. 

Titanocene dichloride catalyzes the reduction of alkyl, aryl, and vinyl bromides, aryl chlorides, alkoxy- and halosilanes ketones, esters, and carboxylic acids with alkyl Grignard reagents. This Cp2TiCl2/RMgX system can also be used for the hydromagnesation of alkynes, dienes, and alkenes (Section 3.2.5). Kambe et al. have reported a new type of titanocene-catalyzed transformation with vinyl Grignard reagents and chlorosilanes to furnish l,4-disilyl-2-butenes, as shown in Scheme 3.43 [31]. 

Scheme 7.10. Titanocene catalyzed asymmetric reduction of imines [85], In the accompanying discussion, the catalyst shown is designated the S,S enantiomer, in accord with the CIP rules for describing metal arenes [88]. This is a different designation than that used by Buchwald, however. ...

The titanocene catalyzed asymmetric imine reduction may be used in kinetic resolutions of racemic pyrrolines [96]. The most efficient kinetic resolution was observed for 5-substituted pyrrolines, and the mechanistic postulate outlined above readily accomodates the experimental results, as shown by the matched pair transition structure in Scheme 7.12 [96]. Pyrrolines substituted at the 3- and 4-positions were reduced with excellent enantioselectivity, but kinetic resolution of the starting material was only modest [96]. 

Titanocene derivatives catalyze reductive cyclization of an alkene with a hetero-atom-containing functional group and the cleavage of the titanium-oxygen bond in these metallacycles was promoted by reaction with silanes, with concomitant formation of Ti-H and Si-O bonds via a <7-bond metathesis process (Scheme 12.45) [65],... 

Although the titanium-based methods are typically stoichiometric, catalytic turnover was achieved in one isolated example with trialkoxysilane reducing agents with titanocene catalysts (Scheme 28) [74], This example (as part of a broader study of enal cyclizations [74,75]) was indeed the first process to demonstrate catalysis in a silane-based aldehyde/alkyne reductive coupling and provided important guidance in the development of the nickel-catalyzed processes that are generally more tolerant of functionality and broader in scope. 

The above-mentioned important and impressive applications of titanocene mediated and catalyzed epoxide opening have been achieved by using the already classical 5-exo, 6-exo and 6-endo cyclizations with alkenes or alkynes as radical acceptors. Besides these achievements, the high chemoselectiv-ity of radical generation and slow reduction of the intermediate radicals by Cp2TiCl has resulted in some remarkable novel methodology. 

It is also essential that competing radical pathways are excluded. The radical intermediates should therefore be relatively persistent. This is the case here, because tertiary radicals are relatively slowly trapped by hydrogen atom donors, e.g., THF, which is usually applied as solvent in titanocene-mediated or -catalyzed reactions, or a second equivalent of Cp2TiCl. Flowever, in the absence of other pathways this reduction, which was followed by a -hydride elimination, was observed [75,76]. Our results with 10 are summarized in Table 5. 

Since the introduction of the titanocene chloride dimer 67a to radical chemistry, much attention has been paid to render these reactions catalytic. This field was reviewed especially thoroughly for epoxides as substrates [123, 124, 142-145] so only catalyzed reactions using non-epoxide precursors and a few very recent examples of titanium-catalyzed epoxide-based cyclization reactions, which illustrate the principle, will be discussed here. A very useful feature of these reactions is that their rate constants were determined very recently [146], The reductive catalytic radical generation using 67a is not limited to epoxides. Oxetanes can also act as suitable precursors as demonstrated by pinacol couplings and reductive dimerizations [147]. Moreover, 5 mol% of 67a can serve as a catalyst for the 1,4-reduction of a, p-un saturated carbonyl compounds to ketones using zinc in the presence of triethylamine hydrochloride to regenerate the catalyst [148]. 

Radical A-exo cyclizations can also be catalyzed without recourse to the Thorpe-Ingold effect by applying the concept of template catalysis (Fig. 24) [157]. Here, 20 mol% of a cationic titanocene(IV) precatalyst 82 is applied, which contains a coordinating neutral tether. After reductive opening of epoxide 81, a cationic titanocene(III) complexed radical 83 is formed, in which both the epoxide and the xfi-un saturated carboxamide radical acceptor are coordinated. This provides the template to accelerate the slow A-exo radical cyclization step considerably. Cyclobutanes 84 were isolated in 46-84% yield with mostly good / / [Pg.145]

Radical cyclizations catalyzed by 67a require the regeneration of the titanocene catalysts by a stoichiometric reductant, such as manganese. When 10 mol% of substituted cyclopentadienyltitanium complex 47e is applied instead truly catalytic cyclization sequences of epoxides 86 are possible (Fig. 25) [160]. Reductive radical generation from 86 promoted by titanocene chloride 67e and subsequent 5-exo cyclization of radical 86A generates a titanoxy cyclopentylalkyl radical 86B. Since the electron-poor titanocene chloride 67e reduces the tertiary radical 86B only sluggishly, its extended lifetime allows for a 1,5-SHi affording the bicyclic tetrahy-drofuran ring system 87. At the same time catalyst 67e is liberated. The reaction... 

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