Synthetic applications of lithiation reactions—V

Narasimhan, N. S.; Bhide, B. H.

doi:10.1016/s0040-4020(01)91782-x

Cited by 35 publications

(9 citation statements)

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“…The reaction with the fused system (L) also failed in the reaction despite the success of similar reactions in solution, 36 and the epoxide (M) did not yield the desired isocoumarin. 30 While anisaldehyde (R) produce a reasonable yield (23%), the tertiary aminobenzaldehydes (P and Q) reacted poorly, providing on average 12% yield (Table 5). Interestingly, several acetophenones were successful in yielding the desired phthalides, indicating that the addition reaction is faster than the enolization.…”

Section: Resultsmentioning

confidence: 99%

“…Most interesting was the failure of 10 because 3-methoxy benzamides have been shown to lithiate at the 2-position in solution 29 and have been used to synthesize phthalides. 30 The fine line between steric hindrance and cooperative lithiation can be seen by comparing the products obtained from benzamides 9 and 17 (Scheme 2). Benzamide 9 is sterically less hindered than 10 at the 2-position, and the oxygens in the benzo [1,3]dioxole system direct the lithiation to the 2 and 5 positions, though the cooperative effects of the benzamide should lead to a mostly 2-lithiated species.…”

Section: Resultsmentioning

confidence: 99%

“…However, the failure of benzamides 3 and 18 was less expected because they are not especially hindered. Most interesting was the failure of 10 because 3-methoxy benzamides have been shown to lithiate at the 2-position in solution and have been used to synthesize phthalides . The fine line between steric hindrance and cooperative lithiation can be seen by comparing the products obtained from benzamides 9 and 17 (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…An attempt to use tetrahydroxybenzophenone ( J ) as its tetralithium salt failed to yield any product, and the tetra-TBDMS-protected version of ( J ) also failed to react most likely because of steric hindrance. The reaction with the fused system ( L ) also failed in the reaction despite the success of similar reactions in solution, and the epoxide ( M ) did not yield the desired isocoumarin . While anisaldehyde ( R ) produce a reasonable yield (23%), the tertiary aminobenzaldehydes ( P and Q ) reacted poorly, providing on average 12% yield (Table ).…”

Section: Resultsmentioning

confidence: 99%

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Solid-Phase Directed Ortho-Lithiation and the Preparation of a Phthalide Library

et al. 2001

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An efficient solid-phase synthesis of phthalides is described in which aromatic carboxylic acids or acid chlorides and ketones are used as building blocks. The carboxylic acid or acid chloride is tethered to aminomethylated polystyrene resin, forming a secondary amide, which functions as both the linker and the directing metalation group. This allows the resin-bound benzamides to be ortho-lithiated at 0 degrees C. The ortho-lithiated species can be quenched with benzaldehydes, benzophenones, and even acetophenones, affording resin-bound alcohols. A cyclative cleavage is induced by simply warming the resin in toluene or dioxane, yielding the desired phthalide compounds in exceptionally high purity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Solid-Phase Directed Ortho-Lithiation and the Preparation of a Phthalide Library

et al. 2001

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“…The sodium salt of o-anisic acid was hardly cleaved (Entries 2,3,6,21,22). The presence of acidic proton was necessary at the heteroatom adjacent to the ortho-carbonyl group to cleave the methoxy group.…”

Section: Methodsmentioning

confidence: 99%

Regioselective Dealkylation of 2-Alkoxybenzoic Acid and Its Amide Derivatives with Aliphatic Amines

Nishioka¹,

Nagasawa²,

Yoshida³

2000

Synthesis

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The methoxy group of o-anisic acid was cleaved with aliphatic amines in aprotic dipolar solvents. This cleavage reaction was especially smooth when piperazine in dimethylacetamide was used. This method was applicable to a variety of dealkylations of o-alkoxybenzoic acid and ist amide derivatives with high regioselectivity.For the demethylation of o-anisic acid (o-methoxybenzoic acid) and amide derivatives, dealkylation methods used for the O-alkyl protective group of phenols 1 can generally be applied. A number of methods have been reported using reagents such as Brønsted acid, 2 Lewis acid, 3-7 alkali metals or organic metals. 8-12 However, the use of aliphatic amines as a nucleophile has not been reported in the dealkylation of the O-alkyl protective group of phenols.Buchanan and coworkers have succeeded in the specific demethylation of o-anisic acid using lithium iodide or pyridinium hydroiodide in boiling pyridine. 14,15 The reaction was explained in terms of nucleophilic attack of the iodide ion on the methyl group with activation of the ether oxygen by intramolecular hydrogen bonding. 16,17 In a preliminary investigation, we found that heating o-anisic acid and hexylamine in 2-methoxyethyl ether at 150°C led to a 30% of salicylic acid accompanied by 28% of N-hexyl-o-anisamide. In order to systematically investigate this interesting cleavage of the methoxy group, we attempted to find the optimal reaction conditions and to clarify the scope and limitations of this useful method for the dealkylation of o-alkoxybenzoic acid and amide derivatives. Table 1 shows the results of the reaction of o-anisic acid with various amines and solvents. In using hexylamine, the cleavage reaction proceeded predominantly in DMSO, DMF and dimethylacetamide (DMA) (Entries 1-3) although the amide formation was only observed in cumene (Entry 4). The results of various amines in DMA revealed that the use of secondary or tertiary amines was superior to that of primary amines in terms of yield and reaction time (Entries 3,8,9). Furthermore, diacidic bases (ethylenediamines) shortened the reaction time (Entries 13, 14) and cyclic amines (piperidine, morpholine) gave higher yields (Entries 15, 16). Consequently, the optimal condition was obtained using piperazine as a diacidic cyclic base in DMA at 150°C (Entry 17). Table 2 shows the results of the reaction of various alkoxybenzoic acids and amides with piperazine in DMA. The amide derivatives required a longer time for completion of this demethylation in comparison with acids. The benzyloxy, methoxymethoxy or even ethoxy group was cleaved at the ortho position, but the isopropoxy group was inactive (Entries 8-11). In addition, o-anisic acid or amide derivatives including a meta-or para-alkoxy group underwent the selective cleavage of the ortho-alkoxy group without affecting other substituents (17)(18)(19)(20). However, 2,6-dimethoxybenzoic acid failed to demethylate, and 6-methyl-o-anisic acid required a longer reaction time for completion (Entries 15, 16). Scheme 1 Scheme 2Ethyl ester ...

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Heteroatom‐Facilitated Lithiations

Gschwend¹,

Rodriguez²

1979

Organic Reactions

185

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Some 25 years have elapsed since the topic of metalation reactions was reviewed by Gilman and Morton. The intervening years have been notable for intensive explorations in this area, in part because many organolithium reagents are now commercially available. Specifically, research efforts have been characterized by the discovery of new functional groups that promote metalation, elaboration of novel heterocyclic and olefinic substrates as metalatable species, recognition of new types of lithiating agents, and the continuation of efforts to define accurately the mechanism of metalation. Accordingly, heteroatom‐facilitated lithiation has become recognized as an increasingly important tool, not only in the elaboration of carbocyclic aromatic and heteroaromatic systems, but also in synthetic aliphatic chemistry. A few recent reviews have covered the topic in a more limited or less specific sense. It is the purpose of this chapter to survey and classify the vast accumulation of heteroatom‐facilitated lithiations recorded since the first coverage in Organic Reactions . As outlined by Gilman and Morton, the terms “metalation” in general and “lithiation” in particular denote any replacement of a hydrogen atom by metal or lithium. In this review, however, lithiation is defined as the exchange of a hydrogen atom attached to an sp 2 ‐hybridized carbon atom by lithium to form a covalent lithium‐carbon bond. More specifically, discussion is limited to those metalations that, through the influence of a heteroatom, are characterized by rate enhancement and regioselectivity. In fact, lithiation reactions of this type are noted for an extraordinarily high degree of regioselectivity, metalation generally occurring on the sp 2 ‐carbon atom closest to the heteroatom. Based on the relative position of the heteroatom, such lithiations are conveniently classified into two principal categories: alpha and beta ( ortho ) lithiations. In alpha lithiations the metalating agent deprotonates the sp 2 ‐carbon atom alpha to the heteroatom to form a carbonlithium bond. This sp 2 ‐carbon atom may be part of an olefinic or heteroaromatic π system. In beta lithiations the metalating agent is directed to deprotonate the sp 2 ‐carbon atom beta to the heteroatom‐containing substituent. The sp 2 ‐carbon atom can be part of an aromatic or an olefinic π system. It should be noted that the designation “ ortho metalation” is used specifically for the beta metalation of carbocyclic aromatic systems. This chapter surveys all systems in which alpha and beta lithiations have been observed, with the exception of ferrocenes.

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Synthetic applications of lithiation reactions—V

Cited by 35 publications

References 3 publications

Solid-Phase Directed Ortho-Lithiation and the Preparation of a Phthalide Library

Solid-Phase Directed Ortho-Lithiation and the Preparation of a Phthalide Library

Regioselective Dealkylation of 2-Alkoxybenzoic Acid and Its Amide Derivatives with Aliphatic Amines

Heteroatom‐Facilitated Lithiations

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