Aldehydes directed lithiation

Propargylic ethers undergo directed lithiation and subsequent transmetallation to afford oxygenated allenyl titanium reagents. Subsequent addition of aldehydes gives rise to various homopropargylic alcohol adducts as mixtures favoring the anti dia-stereomers (Tables 9.18 and 9.19) [29, 30]... 

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

Thiophene is sufficiently acidic to be directly metallated upon treatment with n-BuLi (see Figure 4.1). This direct lithiation can also be realized with polystyrene-bound 3-(alkoxymethyl)thiophene [96]. The resulting organolithium compounds react as expected with several electrophiles, such as amides (to yield ketones), alkyl halides, aldehydes, and Me3SiCl [96]. 

During this reaction an aldehyde functionality is introduced selectively at C-6 of the piperidine. The advantages of the BOC group as activator and director of lithiation are its applicability to carbanion formation at otherwise inactivated or-positions and its convenience for addition and removal.6 Equatorially substituted 2-piperidines are well recognized to be less stable than their axially substituted isomers because of allylic 1,3-strain.7 Therefore 4 would be expected to undergo conformational equilibration to 4 . Directed lithiation via 16 and subsequent reaction with dimethylformamide finally yields 5 as an 8 1 mixture of trans and cis isomers. They can be separated by careful silica gel chromatography. 

Hydroxyisocoumarins are accessible from 3-hydroxybenzyl ketones using directed lithiation as the key step (95G 111) and isocoumarins have been prepared from 2-iodobenzoic acid and alkynes through a Pd-mediated annulation (95JOC3270, 3711). The cyclisation of tertiary alcohols derived from the reaction of o-cyanobenzyllithium with aldehydes and ketones yields 3,4-dihydroisocoumarins (95S1102). 

An orf/io-directed lithiation allows the conversion of 25 to aryl iodide 40. Reductive ether formation of aldehyde 40 with crotyl alcohol yields compound 41. Intramolecular Heck reaction of 41 affords a mixture of the olefins 42 and 43. The undesired alkene 42 can be isomer-ized quantitatively to the desired enol ether 43 with Wilkinson s catalyst. Sharpless dihydroxylation ee 94 %) of the enol ether 43 provides lactol 44, which is oxidized directly to lactone 45. Finally, the pyridone-O-methyl ester is cleaved under acid conditions (45 — 7). 

SYNTHESIS OF 7-SUBSTITUTED INDOLINES Via DIRECTED LITHIATION OF 1-(tert-BUTOXYCARBONYL)INDOLINE 7-IN DO LIN EC A R BOX ALDEHYDE... 

Masatomo Iwao and Tsukasa Kuraishi 85 SYNTHESIS OF 7-SUBSTITUTED INDOLINES via DIRECTED LITHIATION OF l-(tert-BUTOXYCARBONYL)-INDOLINE 7-INDOLINECARBOX-ALDEHYDE... 

A new method for the ortho hydroxylation of aromatic aldehydes via orrho-lithiated arcnnatic aminoal-koxides has recently been reported by Einhom et al Fonnation of the aminoalkoxide serves two purposes. Firstly, the aldehyde group is protected and, secondly, the aminoalkoxide directs lithiation to the ortho position. Oxidation of the lithio species was effected by either MoOPH or molecular oxygen, albeit in poor yield. Alternatively, a two-step, one-pot condensation of the lithio intermediate with tributyl borate followed by oxidation with hydrogen peroxide gave the ortho-hydroxy aldehydes (24) in slightly better yields (Scheme 9). 

As shown in Scheme 11.72, direct lithiation of protected glucal 346 using tBuLi to form 347 has been proposed [258]. From the lithium anion 347 it was also possible to prepare the vinyl stannane 348, which can be isolated and retreated with nBuLi to give the lithio derivative 347 [259,260]. This anion has been condensed with aldehydes and esters. Lithiation of 2-phenyl-thioglycal was also effective [261]. A good example of the use of such a dihydropyran anion could be found in a pederin synthesis [262]. 

Though anions of allyl ethers, the extra functionality allows regiospecific heteroatom-directed lithiation 160 in the manner of chapter 7. Hence reaction of 160 with an aldehyde goes through a six-membered cyclic transition state 161 to give the enol derivative 163 and hence the y-hydroxyaldehyde 164. 

Lithiation at a thiophene P-position, in the presence of a free a-position, can be achieved with the assistance of an ort/to-directing substituent at C-2. Thiophene-2-carboxylic acid lithiates at C-3, via ortho assistance, using n-butylhthium, but at C-5 using lithium diispropylamide. 3-(Hydroxyalkyl)thiophenes, again with orthx) assistance, are lithiated at C-2. The lithiation of 2-chloro-5-methoxythiophene at C-4 and C-3, in a ratio of 2 1, is instructive, as is the deprotonation of 2- and 3-bromothiophenes at 5- and 2-positions, respectively, with lithium diisopropylamide. The conversion of 3-isopropylthiophene into the 2-aldehyde by Vilsmeier formylation, but into the 5-aldehyde via lithiation, presents a nice contrast. Lithiation of 3-hexyloxythiophene can be carried out with thermodynamic control at C-2 using n-butyllithium and with kinetic control using lithium diisopropylamide at C-5. ... 

Directed lithiation of (9-aryl carbamates provides a method for the formation of 2-substituted phenols. For example, quenching with dimethylformamide (DMF) gave the aldehyde 130 (1.120). Interestingly, if no electrophile is added but the mixture is allowed to warm to room temperature, then a rearrangement takes place, in which the aryllithium species undergoes attack on the carbamate group (1.121). 

The addition of allylic organometallic reagents to aldehydes and ketones is another route to -unsaturated alcohols. A new preparation of allyl-stannanes, and hence of allyl-lithium species (Scheme 13), is useful where direct lithiation to... 

Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using Bu Li produces the vinyl-lithium species (355) which condenses with aliphatic aldehydes to give... 

The foregoing examples do not represent useful chiral formyl anion equivalents in a direct sense since the stereoselectivity of the initial addition to aldehydes is poor, although as has been explained, the situation is salvaged by oxidation and re-reduction. On the other hand, by lithiation at the 2 position of the achiral oxazo-lidine 53 in the presence of (-)-sparteine followed by addition of benzaldehyde, useful levels of d.e. and e.e. are achieved directly (98TA3125). For example, by adding MgBr2 before the benzaldehyde, the major product obtained is 54 in 80% d.e. and 86% e.e. 

Since the first reported directed aldol condensation using lithiated imines1. few methods concerning the diastereo- and enantioselectivity of their addition to aldehydes and ketones have been published. 

This is known as the directed aldol reaction. Similar reactions have been performed with oc-lithiated dimethylhydrazones of aldehydes or ketones and with a-lithiated... 

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