An Anion-Induced Regio- and Chemoselective Acylation and Its Application to the Synthesis of an Anticancer Agent

Poirier, Marc; Chen, Fanglin; Bernard, Charles; Wong, Yee-Shing; Wu, Guoli

doi:10.1021/ol016809d

Cited by 32 publications

(18 citation statements)

References 19 publications

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“…The reaction was complete within 30 min at À20 8C and led to the cyclized product 68 in 78 % yield (Scheme 12). [37] Functionalized aryl magnesium compounds allow direct aminomethylation reactions with various carbonyl compounds. Thus, the Grignard reagent 69 adds to the iminium trifluoroacetate 70 in THF/CH 2 Cl 2 at À60 8C within 30 min, providing the diallylamine 71 in 76 % yield.…”

Section: Functionalized Aryl Magnesium Reagentsmentioning

confidence: 99%

Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange

et al. 2003

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Organomagnesium reagents occupy a central position in synthetic organic and organometallic chemistry. Recently, the halogen-magnesium exchange has considerably extended the range of functionalized Grignard reagents available for synthetic purposes. Functional groups such as esters, nitriles, iodides, imines, or even nitro groups can be present in a wide range of aromatic and heterocyclic organomagnesium reagents. Also various highly functionalized alkenyl magnesium species can be prepared. These recent developments as well as new applications of organomagnesium reagents in cross-coupling reactions and amination reactions will be covered in this Review.

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Section: Functionalized Aryl Magnesium Reagentsmentioning

confidence: 99%

Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange

et al. 2003

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“…This powerful, but seldom-used strategy relies on the metal-halogen exchange of 9 occurring faster than the rate at which undesired addition of the hindered Grignard reagent to the electrophile occurs. 12 When 2-mesityl- The 'in situ Mg' method is indicated when greater reaction temperatures and functional-group tolerance are desired. Grignard reagent 10c is considered to be milder and less basic than potassium reagent 10b, but it is also less convenient to use.…”

Section: Scheme 6 Tetrazole Substrate Scope Of the 'In Situ K' Methodsmentioning

confidence: 99%

Some Practical Methods for the Application of 5-Metallo-1-benzyl-1H-tetrazoles in Synthesis

Wiedemann

Bio

Brown

et al. 2012

Synlett

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Nucleophilic reagents such as 5-lithiotetrazoles are synthetically powerful tools for the installation of tetrazole functional groups, but they are of limited utility due to the instability of tetrazole-derived carbanions. Herein, we report practical methods for the generation and use of new 5-metallo-1-benzyl-1H-tetrazoles (M = K, MgX, ZnX) derived from either 1-benzyl-1H-tetrazole or 1-benzyl-5-bromo-1H-tetrazole. By varying the metal counterion, the tetrazole carbanion stability was improved. Potassium-and magnesium-derived reagents underwent additions to carbonyl compounds at -30 and -20°C, respectively. The isolated yields (41-85%) from these and other reactions were comparable to those reported for 5-lithiotetrazoles at much lower temperatures (-78 to -98 °C).The tetrazole functional group, by virtue of its ability to act as a carboxylic acid isostere, has been incorporated into a number of drug-candidate structures. 1 Our research group recently became interested in methods for the formation of tetrazoles 2 with the generic structure 1, where R 1 and R 2 are generally aryl groups. Initial routes to 1 called for reacting an elaborated nitrile 2 with an azide species via [3+2] cycloaddition (Scheme 1). 3 Due to safety concerns and problems of efficiency on larger reaction scales, we sought alternatives to this strategy. 4 Scheme 1 Typical tetrazole synthesis via [3+2] cycloadditionOther common approaches to the synthesis of 5-substituted tetrazoles include multicomponent coupling reactions and the transformation of carboxylic acid derivatives into tetrazoles via imidoyl azides. 5 Ultimately, we were attracted to the idea of preparing 1 from an advanced tetrazolylcarbinol intermediate 3, which could be further traced back to a tetrazole carbanion synthon 4 and a ketone 5 (Scheme 2). 6 This approach offered the advantage of allowing the tetrazole moiety to be installed at a late stage in a complex setting while avoiding the use of azide reagents 7 .Scheme 2 Retrosynthetic analysis of drug candidate 1 A number of tetrazole synthetic equivalents (Figure 1) are capable of participating in C-C bond-forming reactions. 8 These reagents operate through reactive 5-metallotetrazole intermediates that are formed either by metal insertion into the C5-X bond or by selective deprotonation at the C5 position. Figure 1 Tetrazole synthetic equivalents with developed methodologyThe greatest limitation to the application of 5-metallotetrazoles in synthesis to date has been their susceptibility to spontaneous decomposition (Scheme 3). 9 The tetrazole ring can undergo [3+2] cycloreversion with loss of N 2 . This process is irreversible, and the metallocyanamide byproduct 12 that it generates can interfere with desired reactivity. Very low reaction temperatures (≤-78°C) do effectively suppress metallotetrazole decomposition, but such conditions can be impractical on large scales. In an effort to extend the range and practicality of transformations available for direct tetrazole installation, we explored the properties of some avai...

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“…On the contrary, the benzyllithium derivatives 176 were generated by carbolithiation of o-vinyl substituted N-Boc protected aniline with n-BuLi in diethyl ether at ±78 C. Further reaction with DMF followed by final acidic hydrolysis yielded functionalized indoles in a one-pot process [140]. Dianions 177 [141] and 178 [142] were prepared by double deprotonation with LDA and n-BuLi, respectively, the first one being used in the synthesis of b-resorcylic acid derivatives [141]. …”

Section: C-functionalized Benzyllithium Compoundsmentioning

confidence: 99%

Polyfunctional Lithium Organometallics for Organic Synthesis

Yus¹,

Foubelo²

2005

Handbook of Functionalized Organometallics

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Multifunctional organic molecules can be achieved by reacting functionalized organolithium compounds [1] with electrophilic reagents, this fact makes these intermediates of relevant interest in synthetic organic chemistry [2]. Another remarkable fact concerning organolithium compounds, compared with other organometallic compounds is that they can be prepared following a great number of different methodologies [3]: hydrogen±lithium exchange (deprotonation), halogen±lithium exchange, transmetallation reactions, carbon±heteroatom bond cleavage and carbolithiation of multiple carbon±carbon bonds. However, the highly ionic character of the carbon±lithium bond [4] makes these compounds extremely reactive and also unstable, so the synthetic processes should be carried out in some cases under very mild reaction conditions.Regarding the stability of functionalized organolithium compounds, it depends mainly on three factors, the most important one being the compatibility of the functional group with the carbon±lithium bond, so in some cases the functionality should be protected. The hybridization of the carbon atom bonded to the lithium atom is also important, so sp derivatives are more stable than the corresponding sp 2 and these are more stable than the sp 3 ones as it happens to the corresponding carbanions. Finally, the relative position of the functionality and the carbanionic center is also relevant, probably the b-functionalized derivatives being the most unstable species due to the existence of two consecutive carbon atoms with opposite polarities, the b-elimination process to give an olefin is extremely favored. Stabilized organolithium compounds, such as lithium enolate intermediates [5], a-organolithium compounds bearing electron-withdrawing groups (RSO, RSO 2 , CN, NO 2 , etc.) and heteroatoms such as sulfur [6], selenium and phosphorus as well as functionalized aryllithium compounds will not be consider in depth in this chapter due to the limited length of this review.The following study is ordered based on the relative position of the functionality and the carbanionic center, as well as on the hybridization of that center.

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An Anion-Induced Regio- and Chemoselective Acylation and Its Application to the Synthesis of an Anticancer Agent

Cited by 32 publications

References 19 publications

Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange

Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange

Some Practical Methods for the Application of 5-Metallo-1-benzyl-1H-tetrazoles in Synthesis

Polyfunctional Lithium Organometallics for Organic Synthesis

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