Directed ortho-metallation, preparation

The Henegar modification of the Friedlander reaction has been recently reported. The A-Boc protected derivative of o-aminobenzaldehyde (25, in this case prepared via directed ortho metallation of 24) is a stable, crystalline compound that can be stored for extended periods (in contrast with 4, which typically is freshly prepared). Treatment of 25 with ketone 26 in acetic acid results in deprotection of the aniline in situ and subsequent formation of 27, an intermediate in the synthesis of mappicine. 

Magnesium 2-ethaxye(hoxide, Mg(OCHjCHJ)CJIs)2. Preparation.3 This metal alkoxide (1) decreases the activity of RLi reagents to such an extent that they can be prepared in THF in the presence of 0.5 equiv. of 1. The advantages of this fact are that some unstable organolithiums can be generated by this technique and that directed ortho-metallation can be suppressed if desired.4... 

Victor Snieckus is well known for having developed powerful methodological tools for the synthesis of polysubstituted aromatics, in particular heteroaromatic directed ortho-metalation. Thus, in his chapter (No. 10), prepared with his co-author Christian Hartung, directed ortho-metalation is taken as a starting point for new synthetic aromatic chemistry. 

V. Snieckus and co-workers developed a new carbamoyl Baker-Venkataraman rearrangement, which allowed a general synthesis of substituted 4-hydroxycoumarins in moderate to good overall yields. The intermediate arylketones were efficiently prepared from arylcarbamates via directed ortho metallation and Negishi cross coupling. The overall sequence provided a regiospecific anionic Friedel-Crafts complement for the construction of ortho-acyl phenols and coumarins. 

When pyridine is heated to 165 °C in MeONa-MeOD, H-D exchange occurs at all positions via small concentrations of deprotonated species, at the relative rates a (3 7, 1 9.3 12. However, using the combination n-butyllithium/potassium t-butoxide, efficient formation of 2-pyridylpotassium or 4-pyridylpotassium has been achieved." Some pyridines have been selectively lithiated at C-2 via complexes with hexafluoroacetone " complexation removes the lone pair (cf. section 5.5.1) and additionally provides inductive and chelation effects to assist the regioselective metallation. In practice, simple lithiopyridines are generally prepared by metal-halogen exchange, however the presence of chlorine or fluorine, or other substituents which direct ortho metallation, allows direct lithiation (section 5.5.1). 

Alternatively, the directed ortho metalation strategy has been applied to the regioselective fluorination with NFSi. 4-Fluoro-7-azaindoles were functionalized at C-5 without any halogen scrambling or competitive lithiation at C-2 (eq 37). The orf/io-fluoro derivative of [(/ )-(l-phenyl)ethyldimethylamine]chromium tricarbonyl was prepared diastereoselectively by electrophilic fluorination employing NFSi (eq 38). ... 

The tetracyclic A/B/C/D ring core of (205)-camptothecin, one of the most potent antitumor natural products isolated from Camptotheca acuminate, was prepared by a combined directed ortho metallation/cross-coupling strategy. Snieckus showed that 2-bromo-6-methoxypyridine (152) could be sequentially treated with ter/-butyllithium (2 equiv) at -78 °C and anhydrous zinc bromide. The resulting organozinc species was then subjected to palladium-catalyzed cross-coupling reaction with triflate 153 to afford the biaryl 154, a precursor to the tetracyclic A/B/C/D ring core 155. 

Figure 8.18 Directed ortho metallation in the preparation of functionalized [ring-U- " C] benzoic acid derivatives...

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules with biological relevance. The ability to prepare haloarenes selectively by an ortho-metallation halogenation sequence allows for the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metallation to form aryl halides that were subsequently reacted with anilines to prepare diarylamines (Eq. 34)) [156]. Frost and Mendon a have reported an iterative strategy to prepare (by palladium-catalyzed chemistry) amides and sulfonamides that may act as peptidomimetics. Diarylamine units are constructed using the DPPF-ligated palladium catalysts, and the products are then acylated or sulfo-nated with 4-bromo benzoyl or arylsulfonyl chlorides [157]. 

The preparation of functionalized aryl boronic reagents can be achieved by directed metallation followed by a transmetallation of aryllithiums with organoboron compounds. Thus, Caron and Hawkins have described a directed ortho-metalla-tion of aryl neopentyl esters such as 1 for the synthesis of substituted ortho-horo-nyl neopentyl benzoates using lithium diisopropylamide (LDA) as the base and B(OiPr)3 as an in situ trap [3]. The crude boronic acids obtained by acidic hydrolysis were subsequently treated with ethanolamine and converted to stable diethanolamine complexes such as 2. This methodology allows the preparation of a new class of boronic acids with ortho-carbonyl substituents and other functionalities... 

Boron trioxide is not particularly soluble in water but it slowly dissolves to form both dioxo(HB02)(meta) and trioxo(H3B03) (ortho) boric acids. It is a dimorphous oxide and exists as either a glassy or a crystalline solid. Boron trioxide is an acidic oxide and combines with metal oxides and hydroxides to form borates, some of which have characteristic colours—a fact utilised in analysis as the "borax bead test , cf alumina p. 150. Boric acid. H3BO3. properly called trioxoboric acid, may be prepared by adding excess hydrochloric or sulphuric acid to a hot saturated solution of borax, sodium heptaoxotetraborate, Na2B407, when the only moderately soluble boric acid separates as white flaky crystals on cooling. Boric acid is a very weak monobasic acid it is, in fact, a Lewis acid since its acidity is due to an initial acceptance of a lone pair of electrons from water rather than direct proton donation as in the case of Lowry-Bronsted acids, i.e. 

One method for preparing imidazolylstannanes is direct metalation followed by treatment with RjSnCl [21]. l-Methyl-2-tributylstannylimidazole, derived in such manner, was coupled with 3-bromobenzylphosphonate (26) to furnish heterobiaryl phosphonate 27 [22], Under the same reaction conditions, 4-bromobenzylphosphonate led to the adduct in 69% yield, whereas only 24% yield was obtained for 2-bromobenzylphosphonate. The low yield encountered for the ortho derivative may be attributed to the steric factors to which the Stille reaction has been reported to be sensitive [23]. Heterobiaryl phosphonates such as 27 are not only substrates for the Wadsworth-Homer-Emmons reaction, but also bioisosteric analogs of the carboxylic acid group. 

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