Ferrocenes directed lithiation

The directed metalation reaction—lithiation with n-butyl-lithium of a position ortho to a substituent on an aromatic ring—is described. Aromatic systems in which the reaction has been studied are benzene, thiophene, naphthalene, and ferrocene. A systematic listing of the bond types that can be formed at the site of metalation is provided. Also of interest is the assessment of the relative directing abilities of directing substituents and comments and observations on the mechanism of the reaction. Utility of the reaction is indicated by the results from asymmetric-directed lithiation and the synthesis of heterocycles. 

Sulphoxide removal using sulphoxide-lithium exchange is also effective. It was employed in tandem with a sulphoxide-directed stereoselective ortholithiation of the ferrocene 105 in the synthesis of the phosphine ligand 106 (Scheme 45). Ferrocene lithiation is discussed further in Section III. 

Ferrocene is best deprotonated by f-BuLi/f-BuOK in THF at 0 since BuLi alone will not lithiate ferrocene in the absence of TMEDA and leads to multiple lithiation in the presence of TMEDA. In the example in Scheme 134, a sulphur electrophile and a Kagan-Sharpless epoxidation lead to the enantiomerically pure sulphinyl ferrocene 278. The sulphinyl group directs stereoselective ortholithiation (see Section I.B.2), allowing the formation of products such as 279. Nucleophilic attack at sulphur is avoided by using triisopropylphenyllithium for this lithiation. 

Attempts to make C2-symmetric ferrocenes by double lithiation of a bis-acetal met with only limited success . A second lithiation of the ferrocenylacetal 298 leads to functionalization of the lower ring of the ferrocene, in contrast with the second adjacent lithiation of the oxazolines described below. This can be used to advantage if, for example, the first-formed aldehyde 301 is protected in situ by addition of the lithiopiperazine 53 °, directing f-BuLi to the lower ring (Scheme 139) °. The same strategy can be used to introduce further functionalization to products related to 302. For example, silane 303, produced in enantiomerically pure form by the method of Scheme 138, may be converted to the ferrocenophane 304 by lithiopiperazine protection, lithiation and functionalization (Scheme 140) . 

A ferrocenyloxazoline with only one adjacent position available for deprotonation will lithiate at that position irrespective of stereochemistry. This means that the same oxazoline can be used to form ferrocenes with either sense of planar chirality. The synthesis of the diastereoisomeric ligands 311 and 313 illustrates the strategy (Scheme 143), which is now commonly used with other substrates to control planar chirality by lithiation (see below). Ferrocene 311 is available by lithiation of 305 directly, but diastereoselective silylation followed by a second lithiation (best carried out in situ in a single pot) gives the diastereoisomeric phosphine 313 after deprotection by protodesilylation ". ... 

Some headway has been made using sulphoxides to direct the lithiation of arenechromium tricarbonyls in the manner of Kagan s work with ferrocenes . Diastereoselectiv-ities in the lithiation-quench of 392 are excellent, though yields are poor with most electrophiles. Diastereoselectivity reverses on double lithiation, because the last-formed anionic site in 394 is the most reactive (Scheme 163). 

Bidentate ferrocene ligands containing a chiral oxazoline substituent possess both planar chiral and center chiral elements and have attracted much interest as asymmetric catalysts.However, until recently, preparation of such compounds had been limited to resolution. In 1995, four groups simultaneously communicated their results on the asymmetric synthesis of these structures using an oxazoline-directed diastereoselective lithiation (Scheme 8.141). " When a chiral oxazolinylferrocene 439 was metalated with butyllithium and the resulting aryllithium species trapped with an electrophile, diastereomer 442 was favored over 443. The structure of the major diastereomer 442 was confirmed, either by conversion to a compound of known stereochemistry or by X-ray crystallography of the product itself or of the corresponding palladium complex. ... 

Metalated ferrocenes also serve as convenient precursors to ferrocenylboranes. Lithiated ferrocenes have been ntilized for the preparation of ferrocenylboronates FcB(OR)2 and l,T-fc(B(OR)2)2 and are especially suitable in the presence of ort/ o-directing donor-substituents. The borylation of disilylated ferrocenes with excess BCI3 on the other hand was reported to yield varying amounts of 1,3-diborylated prodnct (82 M = Fe, X = Cl) in addition to the l,F-diborylated species (83 M = Fe, X = Cl). In contrast, when 1,F-distannylated ferrocenes were treated with equimolar amounts of boron halides, l-stannyl-2-borylferrocenes (86) were formed as the major product rather than the expected... 

A number of other metalated ferrocene derivatives containing a M-C bond (M = B, Cu, Si, P, Ge, As, Sn) can be prepared from (322) and (323)." Lithiation of alkyl-substituted ferrocenes occurs both homo- and heteroannularly, while the lithiation of A,A-dimethylaminomethylferrocene (289, R = H) is directed to the 2-position by chelation with the nitrogen lone pair see Lone Pair), to give... 

Three routes have been preferentially used to prepare ferrocene compounds that contain heteroelements directly attached to the metallocene unit borylation, mercuration, and lithiation. 

Carrying the concept of asymmetric lithiation one step further, Nozaki and co-workers incorporated the asymmetry-inducing complexing reagent with the metalated molecule (ferrocene) itself (37, 38). 1-Ferro-cenylmethyl-2-methylpiperidine was resolved and treated with n-butyl-lithium to give a mixture of diastereomeric lithio intermediates by directed metalation (Reaction 34). An optical yield of 93% was initially claimed for this reaction, but subsequent work by Ugi and co-workers (39) resulted in the suggestion that only a 67% optical yield was obtained. 

SAMP hydrazones derived from acylferrocenes will direct the diastereoselective lithiation of the ferrocene ring (Scheme 14). For example, treating benzoylfer-rocene 50 with (S)-N-amino-O-methylproUnol 51 generates 52 after siHca-cata-lysed equilibration to the more stable -hydrazone [42]. Lithiation of 52 gives or-ganolithium 53 selectively after electrophihc quench, products 54 were obtained in 80-95% yield and with <2% of a minor diastereoisomer. Removal of the auxiliary is achieved by oxidative or reductive means. 

Product 27 of entry 31 also deserves some comment since it was found that the oxazaphospholidine oxide group turns out to be an excellent ortho directing group for the diastereoselective lithiation of ferrocene (Scheme 3.15). 

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