Grignard with Weinreb amides

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

The diketoindoles 777 were prepared in three steps starting from indol-3-ylacetic acid (680) and 5-chloro indol-3-ylacetic acid (774) in 75% and 66% overall yield, respectively. The indole acids 680 and 774 were converted into Weinreb amides 775, followed by reaction with ethyl Grignard reagent to afford the corresponding indol-3-yl ketones 776. In order to introduce the second carbonyl moiety, the 3-substituted... 

Aldehydes and ketones have also been prepared by nucleophilic cleavage of resin-bound O-alkyl hydroxamic acids (Weinreb amides [744]) with lithium aluminum hydride [745] or Grignard reagents (Entries 1 and 2, Table 3.41). Similarly, support-bound thiol esters can be cleaved with Grignard reagents to yield ketones [272], or with reducing agents to yield aldehydes (Entry 3, Table 3.41). Polystyrene-bound sele-nol esters (RCO-Se-Pol) react with alkynyl cuprates to yield alkynyl ketones [746]. 

After exchange of the protecting group, the Weinreb amide 111 (an alternative to nitriles for the formation of ketones discussed in detail in Strategy and Control) reacted with the aryl Grignard reagent to give, after reduction, 112—the protected version of the alcohol 106 required for cyclisation. 

The first noncarbohydrate-based asymmetric synthesis of kedarosamine uses the A,0-protected D-threonine 166. It is first converted into the corresponding Weinreb amide via the acyl chloride. Subsequent coupling with the allyl Grignard reagent provides 167. The nonchelation controlled reduction of ketone 167 with NaBH4 is syn selective, whereas 1,2-chelation controlled reduction... 

When Grignard reagents, organolithium compounds, or complex metal hydrides add to amides, the elimination step is slow at —78 °C, especially when the amine component is -N(Me)OMe (Weinreb amides). When the tetrahedral intermediate is sufficiently long lived, quenching of the reaction mixture with water at —78 °C gives the ketone or aldehyde rather than the alcohol. 

The most popular method these days for the acylation of Grignard or organolithium reagents is the Weinreb amide (also discussed in chapter 8). Acylation of vinyl Grignard with the complex intermediate 60 was part of a synthesis of ( )-fumagillolB 62. 

Formylation. This Weinreb amide is prepared from methyl formate and N,( -dimethylhydroxylamine in the presence of NaOMe. It reacts with Grignard reagents, organolithium compounds, and enolates to furnish aldehydes. 

Methoxyamine solid supports 7x can be used to anchor carboxylic acids in the presence of BOP/DIEA as Weinreb amides [338,339]. The resultant anchor is compatible with peptide assembly using Boc or Fmoc strategies, and treatment of the final sequence with LiAlH4 in THF led to release of peptide aldehydes. A related support with RAM as the base resin has also been used to prepare resin-bound Weinreb amides, which afforded ketones on cleavage induced by reaction with Grignard reagents [340]. 

Modern alternatives for the assembly of the a-aminocarbonyl component include the reaction of a 2-bromoketone with sodium diformamide producing an a-formamido-ketone, " and the reaction of a Weinreb amide of an A-protected a-amino acid with a Grignard reagent, then release of the A-protection in the presence... 

Impressively short is a total synthesis by Ian Paterson [281], who uses a lactate ester as chiral auxiliary. This is subsequently converted into a ketone via a Grignard reaction with its Weinreb amide. The boron-mediated aldol reaction, after an oxidative work-up, gives the aldol with a diastereoselectivity of >98 %. Since also the reaction with propionaldehyde shows the same diastereoselectiv-... 

Good chemoselectivity has been observed in the reactions of substrates containing both nitrile and Weinreb amide functionalities with Grignard reagents Even in the presence of excess Grignard reagent, in most cases only the Weinreb amide group reacted at room temperature. 

This can, with primary amines, be extended to two electron-withdrawing groups, which lead to a complete change of the general reactivity as was demonstrated with the Weinreb amide 541. This carbonyl group behaves similar to a ketone, allowing DIBAH reduction to the aza-hemiacetal 542. This is the equivalent of an aldehyde, but via elimination and Grignard addition it can also lead to the branched alkylamine 543 [190]. 

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