Diastereoselective addition of lithiated N,N-diethyl-o-toluamide to chiral isopropylidine glyceraldehyde lmines. Asymmetric synthesis of 3-substituted 3,4-dihydro-1(2H)-isoquinolones

Clark, Robin D.; Jahangir, _; Souchet, Michel; Kern, John R.

doi:10.1039/c39890000930

Cited by 25 publications

(12 citation statements)

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“…Furthermore, our mechanistic studies suggest that configurational stability in this series is independent of the steric environment surrounding the DMG and the lithiated center. The lithiated species are configurationally stable regardless of ortho (9) or meta (23,24) silyl substituion. This is in contrast with the results of Clayden, 47 which demonstrate that lithiated ortho-ethyl-N,N-diisopropyl benzamides are less configurationally stable than their more hindered lithiated 2-ethyl-N,N-diisopropyl-1-naphthylamide analogs.…”

Section: Scheme 7 Tms As a Remote Protecting Groupmentioning

confidence: 99%

“…If the benzyllithium species(23) is configurationally stable on the timescale of the electrophilic quench reaction, this er reflects the relative population of diastereomeric complexes in solution; on the other hand, if 23 is configurationally unstable on this timescale, the ee reflects the difference in reaction rates of the two diastereomeric complexes. When 0.2 equiv of MeSSMe was used, 21a was obtained with 63:37 er.…”

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confidence: 99%

“…16 Subsequent to the initial observations of Nozaki 1 and the seminal studies of Hoppe 3 and Beak,4 (-)-sparteine-mediated benzylic metalation has been investigated on several types of derivatives 1-4 (Scheme 1), which take advantage of an α-heteroatom 1a-f, 17 an orthoheteroatom 2, 18 a styryl α-amino moiety 3, 19 a β-heteroatom 4 20 Stimulated by these findings, we had previously investigated the (-)-sparteine-induced, highly enantioselective preparation of planar chiral ferrocenes and their application in an asymmetric alkylation and Pd(0)-catalyzed allylic substitution. 22 The original studies of Clark 23 To determine the influence of solvent, the N,N-dialkyl aryl O-carbamates 5 and 6 were metalated under the optimized conditions in single and mixed solvent systems and the resulting benzyllithium species were quenched with TMSCl or dimethyl disulfide (MeSSMe) to afford compounds 11a and 12b and 11b and 13a respectively (Table 1). As gleaned from Table 1, no enantioenrichment was observed when the metalation of 6-MeOsubstituted N,N-dialkyl aryl O-carbamate 5 was carried out in THF (entry 1).…”

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confidence: 99%

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Highly Enantioselective (−)-Sparteine-Mediated Lateral Metalation-Functionalization of Remote Silyl Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates

et al. 2015

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We report the enantioselective, lateral deprotonation of ortho-protected or functionalized tertiary N,N-dialkyl aryl O-carbamates 5-7 (Scheme 2 ) and meta-protected carbamates 14, 15, and 20 (Schemes 5 and 7 ) by s-BuLi/(-)-sparteine and subsequent quench with a variety of electrophiles to give products 11-13 and 16, 17, and 21 in yields up to 96% and enantiomeric ratios up to 99:1. The influence of organolithium reagents, ratio of organolithium/(-)-sparteine pair versus N,N-dialkyl aryl O-carbamate starting materials, temperature, solvents, electrophiles, substituents located ortho or meta to the O-carbamate moiety, and O-carbamate N-substituents was investigated. The identical absolute configuration of the stereogenic center of the major enantiomers of the products, as established by single-crystal X-ray analysis for substrates (S)-11c, (S)-19, and (S)-21a, provides evidence for a consistent stereochemical course in the enantioselective deprotonation. Mechanistic investigations, including an estimate of the configurational stability of the benzyllithium species 9 (starting from 12e; Scheme 8 ) and 23 (starting from 17e; Scheme 9 ), both derived by tin-lithium exchange, and 24 (starting from 20; Scheme 9 ) are reported. The experimental results, together with semiempirical molecular orbital calculations (PM3/SMD), are consistent with a process in which enantioinduction occurs in the deprotonation step (Scheme 11 ).

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Section: Scheme 7 Tms As a Remote Protecting Groupmentioning

confidence: 99%

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confidence: 99%

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Highly Enantioselective (−)-Sparteine-Mediated Lateral Metalation-Functionalization of Remote Silyl Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates

et al. 2015

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“…Nevertheless, the most widely used method for deprotection involves the oxidative cleavage of the N-PMB moiety using ceric ammonium nitrate (CAN). [2][3][4][5][6][7][8][9][10][11][13][14][15][16][17][19][20][21]23,32,33 Factors such as the mild reaction conditions that are generally tolerant towards many different functional groups, the experimental simplicity, and the relatively low cost of CAN make this a method of choice.…”

Section: Introductionmentioning

confidence: 99%

“…The p-methoxybenzyl (PMB) group is often used for the N-protection 1 of amides, lactams and aza-heterocycles in the synthesis of natural [2][3][4][5][6][7][8][9][10][11][12] and non-natural products [13][14][15][16][17][18][19][20][21][22][23] because of its ease of removal. Many methods, such as Lewis 24 and Brönsted acid 18,22,[25][26][27] -mediated hydrolysis, benzylic anion oxidation, 12,28,29 catalytic hydrogenation, 30 and persulfate-mediated oxidative cleavage, 31 have been employed for the removal of the N-PMB group.…”

Section: Introductionmentioning

confidence: 99%

Ceric ammonium nitrate oxidation of N-(p-methoxybenzyl)lactams: competing formation of N-(hydroxymethyl)δ-lactams

Annadi¹,

Wee²

2014

Arkivoc

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The ceric ammonium nitrate mediated oxidative deprotection of N-(p-methoxybenzyl) δ-lactams leads to the formation of an unexpected N-(hydroxymethyl) δ-lactam along with the Ndeprotected δ-lactam. In comparison, N-(p-methoxybenzyl) γ-lactams are completely deprotected under the same reaction conditions. Further studies indicated that addition of an aqueous solution of ceric ammonium nitrate to an acetonitrile solution of N-(p-methoxybenzyl) δ-lactams in the presence of 2-amino-2-methyl-1-propanol as an additive promoted N-deprotection. Ceric ammonium nitrate oxidation of N- (α,α-dideuterio-p-methoxybenzyl)-6-allyl-δ-lactam (8), revealed that the methylene unit of the N-(hydroxymethyl) group is derived from the benzylic methylene unit of the N-protecting group. A plausible reaction pathway for the formation of the N-(hydroxymethyl) δ-lactams from an N-acyliminium ion intermediate is proposed.

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Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

Clark¹,

Jahangir²

1995

Organic Reactions

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Heteroatom‐facilitated lithiation reactions have assumed an increasingly important role in the elaboration of carbocyclic aromatic and heteroaromatic systems in the 40 years subsequent to the seminal review on metalation with organolithium reagents by Gilman and Morton. Of particular note has been the development of methodology for the lateral lithiation of alkyl‐substituted aromatic systems promoted by an extensive array of heteroatomic substituents. These lithiations involve deprotonation at a benzylic (side chain) position that is lateral to, or flanked by, a heteroatom‐containing substituent (G); this substituent facilitates lithiation relative to the parent system in which G is not present. The derived lithiated species have great synthetic utility for functionalization of benzylic sites, for chain extensions, and for the synthesis of fused carbocyclic and heterocyclic systems via annelation processes. This chapter summarizes the significant amount of work reported on heteroatom‐facilitated lateral lithiations and the synthetic applications thereof. The survey covers the substituents that promote these reactions, and the methods of formation, stability, reactivity, and synthetic utility of the lithiated species. Coverage is limited to examples in which the R 1 group in the representative equation is hydrogen (toluene derivatives), alkyl, or aryl. Examples that would be better classified as alpha ‐lithiations are not covered, for example, where R 1 is an anion‐stabilizing group such as cyano, carboxy, and so on. Rare examples of lithiations of alkyl groups that are meta or para to the facilitating group G are included in the chapter, although these are not, strictly speaking, lateral lithiations. Also included are a limited number of older lateral metalations that were originally effected with sodium or potassium bases but would now be more conveniently carried out with lithium dialkylamide bases. The aromatic nucleus may be carbocyclic or heterocyclic, but lateral lithiations of heterocycles lacking the heteroatomic substituent are not covered. For example, lithiation of nicotinamides (Eq. 2) are included; however, lithiations of picolines, and other heterocyclic systems, are considered beyond the scope of this chapter. The relationship of lateral lithiation reactions to heteroatom‐facilitated ortho lithiations is obvious and the two fields have developed, for the most part, in concert. With several notable exceptions, the same heteroatomic substituents (G) promote both types of lithiations. A number of reviews cover various aspects of ortho lithiation reactions, including the comprehensive chapter in Organic Reactions by Gschwend and Rodriguez that surveyed the literature to 1979. In the present chapter, the relationship of lateral lithiation and ortho lithiation reactions is discussed within the contexts of mechanism, reactivity, and synthetic utility. In addition, the sequential use of these two lithiation processes for the synthesis of complex aromatic and heteroaromatic systems is covered.

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Diastereoselective addition of lithiated N,N-diethyl-o-toluamide to chiral isopropylidine glyceraldehyde lmines. Asymmetric synthesis of 3-substituted 3,4-dihydro-1(2H)-isoquinolones

Cited by 25 publications

References 0 publications

Highly Enantioselective (−)-Sparteine-Mediated Lateral Metalation-Functionalization of Remote Silyl Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates

Highly Enantioselective (−)-Sparteine-Mediated Lateral Metalation-Functionalization of Remote Silyl Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates

Ceric ammonium nitrate oxidation of N-(p-methoxybenzyl)lactams: competing formation of N-(hydroxymethyl)δ-lactams

Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

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