Oxazolines directed lithiation

There is one example, unique for several reasons, of the formation of a four-membered ring by anionic cyclisation onto an oxazoline. Attempted oxazoline-directed lithiation of the styrene 122 gave, instead, the cyclobutane 124 via addition of the alkyllithium to give a benzylic organolithium 123 which cyclises stereoselectively.63 The initial intermolecular carbolithiation proceeds remarkably easily - no additives (such as TMEDA) are required, even with MeLi. 

The cooperative effect of MeO and the oxazoline directs the lithiation of 60 in this synthesis of a lipoxygenase inhibitor AC-5-1 61 (Scheme 30) °. ... 

No heterocycle containing a C=N bond is as powerful a director as the oxazolines or tetrazoles described above, but their imidazoline analogues 132 direct well if deprotonated to the amidine equivalent 133 of a secondary amide anion (Scheme 61). Pyrazoles 134 also direct lithiation, but need protecting with a bulky Af-substituent to prevent nucleophilic attack by the base (Scheme 62). ... 

Examples of the direct lithiation of sites more remote from heterocyclic 5/ 2-nitrogen are much less common, although evidence for direct 8-lithiation has been seen with 2-phenylthio-4,4-dimethyloxazoline, where migration of the oxazoline ring occurred as a result of nucleophilic attack by the initially formed 8-carbanion (Scheme 143) (83JOC2610). 

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. ... 

In benzene rings, reaction at the ort/io-position can be induced by a group that will chelate with Li and thus direct the lithiation reaction. The oxazoline group has been used extensively for this purpose in recent years. However, a recent paper has highlighted the importance of the reagent and of reaction conditions in such lithiation-alkylations." For instance, in the oxazoline (14) lithiation and alkylation at the o-position (to the oxazoline) is favoured by Bu Li-ether, whereas if Bu"Li-THF is used alkylation occurs at the p-position (78%). 

Meyers and coworkers have exploited both the lithiation-directing and benzyne-forming abilities of a chloro substituent to form the benzyne 167 from oxazoline 166 (Scheme 84). Excess organolithium adds regioselectively to the 2-position of the benzyne (probably directed by coordination to the oxazoline) to give 168 . 

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 ". ... 

Bis-oxazoline ligands can also be produced by oxidative coupling of the copper derivative of diastereoisomerically pure 306 (Scheme 145) . Further lithiations of the product 317, which was produced as single diastereoisomer, occur (as in Scheme 143) at the second site adjacent to the oxazoline, giving, for example, 318, despite the (presumably) less favourable stereochemistry of the lithiation step. Bisoxazolines 318 direct the asymmetric copper-catalysed cyclopropanation of styrene using diazoacetate. 

For conversion of functionalized diorganozincs into tertiary amines, aromatic compounds which contain a directed metallation group, such as Af,Af-dialkylbenzamides, methoxymethyl phenyl ether, phenyl oxazolines and phenyl Af,Af-dialkylcarbamates, were ortho-lithiated, transmetallated and then aminated with 2a in good yields, but with a slower reaction rate (Scheme 19). 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

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