Weinreb amides from carboxylic acids

In 2001, De Luca and GiacomeUi " reported a new simple and high-yielding one-flask synthesis of Weinreb amides from carboxylic acids and A-protected amino acids that uses different 1,3,5-triazine derivatives (such as 236) as the coupling agents (Scheme 104). The method allows the preparation of Weinreb amides 237 and hydroxamates as O-benzyl and 0-silyl hydroxamates that can be easily transformed into hydroxamic acids. 

Tunoori, A. R., White, J. M., Georg, G. I. A One-Flask Synthesis of Weinreb Amides from Chiral and Achiral Carboxylic Acids Using the Deoxo-Fluor Fluorinating Reagent. Org. Lett. 2000, 2, 4091-4093. 

The so-called Weinreb amides (or Af-methoxy-A-methylamides) are versatile building blocks in organic synthesis . Their preparation can be accomplished by coupling carboxylic acids and Af,0-dimethylhydroxylamme. The majority of the methods reported use peptide coupling reagents such as chloroformates , BOP , DCC and others "" or phosphonic derivatives ". These reactive reagents are expensive in some cases, and the removal of their excess (and/or the removal of byproducts) from the reaction mixtures may be difficult. Additional purification of the reaction product is often required. 

Polymer-bound reagents have also been used. The synthetically important Weinreb amides [RCON(Me)OMe, see 16-82] can be prepared from the carboxylic acid and MeO(Me)NH HCl in the presence of tributylphosphine and 2-pyridine-A -oxide disulfide. Di(2-pyridyl)carbonate has been used in a related reaction that generates amides directly. The reaction of a carboxylic acid and imidazole under microwave irradiation gives the amide. Microwave irradiation of a secondary amine, formic acid, 2-chloro-4,6-dimethoxy[l,3,5]tria-zine, and a catalytic amount of DMAP (4-dimethylaminopyridine) leads to the formamide. ° Ammonium bicarbonate and formamide converts acids to amides with microwave irradiation. Lactams are readily produced from y- or 8-amino acids, for example. 

An important innovation in the Parham cyclization leading to cyclic ketones is the use of Weinreb amides as the electrophile, rather than carboxylic acids or esters. For example, compoimd 23 is converted to 24 in excellent yield,and benzocyclobutenones 26 are readily available from Weinreb amides 25. Lower yields of 26 are obtained using n-butyllithium. 

Although this methodology is not successful with acyclic carboxylic acid derivatives (e.g. Weinreb amides, A-acyloxazolidinones, carboxylic esters or thioesters), it is possible to reach this kind of valuable enantiomerically enriched products by a simple oxidation with commercial bleach from the corresponding ketone (Scheme 29, top). If the ketone possesses a substituent prone to oxidation, an alternative procedure, involving the formation of a silyl enol ether (which does not need isolation/purification), can be followed instead (Scheme 29, bottom). 

Aside from the outstanding and reliable diastereoselectivity, two more advantageous features helped the method to success the easy, one-step preparation of various N-acylated derivatives from the parent oxazolidinones and the cleavage of the auxiliary by hydrolysis, transamidation to the Weinreb amide, esterification, and reduction, as outlined in Section 4.1. A typical Evans aldol procedure with phenylalanine-derived oxazolidinone (S)-47, including the preparation of propionic imide 73 and cleavage of the auxiliary, is shown in Scheme 4.47. Typically, the boron aldolate resulting from the addition to the aldehyde has to be cleaved by an oxidative work-up. The hydrolysis of the aldol adduct 211 occurs without detectable epimerization that liberates diastereomerically and enantiomerically pure carboxylic acid 212 besides the auxiliary (S)-47 [110]. 

Scheme 40 presents a synthetic route to polymer-supported Weinreb amides starting from commercially available BAL-linker [216]. Whilst most approaches to Weinreb linkers start with the conversion of alcohol functionalities (and following Mitsunobu approach), the BAL linker 260 has to be reacted via reductive amination into the desired methoxyamines 261. Afterwards resin 261 is treated with carboxylic acids 262 in the presence of coupling reagents to give amides 263 containing the target structure. 

Acyl oxazolidinones 50-52 are easily prepared from commercially available chiral starting materials. As shown in Scheme 4.6, treatment of the amino-acid-derived amino alcohols with diethyl carbonate, followed by N-acylation, affords 54 [6, 46], The removal of the auxiliary following the aldol addition reactions proceeds smoothly under a variety of mild conditions to afford carboxylic acids 56 (UO2H) [47, 50], primary alcohols 57 (LiBH,) [51], esters 58 (Ti(OBn)4) [52], or Weinreb amides 59 [51]. 

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