Weinreb ketone synthesis | |
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Named after | Steven M. Weinreb |
Reaction type | Coupling reaction |
Identifiers | |
Organic Chemistry Portal | weinreb-ketone-synthesis |
The Weinreb ketone synthesis or Weinreb–Nahm ketone synthesis is a chemical reaction used in organic chemistry to make carbon–carbon bonds. It was discovered in 1981 by Steven M. Weinreb and Steven Nahm as a method to synthesize ketones. [1] The original reaction involved two subsequent nucleophilic acyl substitutions: the conversion of an acid chloride with N,O-Dimethylhydroxylamine, to form a Weinreb–Nahm amide, and subsequent treatment of this species with an organometallic reagent such as a Grignard reagent or organolithium reagent. Nahm and Weinreb also reported the synthesis of aldehydes by reduction of the amide with an excess of lithium aluminum hydride (see amide reduction).
The major advantage of this method over addition of organometallic reagents to more typical acyl compounds is that it avoids the common problem of over-addition. For these latter reactions, two equivalents of the incoming group add to form an alcohol rather than a ketone or aldehyde. This occurs even if the equivalents of nucleophile are closely controlled.
The Weinreb–Nahm amide has since been adopted into regular use by organic chemists as a dependable method for the synthesis of ketones. These functional groups are present in a large number of natural products and can be reliably reacted to form new carbon–carbon bonds or converted into other functional groups. This method has been used in a number of syntheses, including macrosphelides A and B, [2] amphidinolide J, [3] and spirofungins A and B. [4]
Weinreb and Nahm originally proposed the following reaction mechanism to explain the selectivity shown in reactions of the Weinreb–Nahm amide. Their suggestion was that the tetrahedral intermediate (A below) formed as a result of nucleophilic addition by the organometallic reagent is stabilized by chelation from the methoxy group as shown. [1] This intermediate is stable only at low temperatures, requiring a low-temperature quench.
This chelation is in contrast to the mechanism for formation of the over-addition product wherein collapse of the tetrahedral intermediate allows a second addition. The mechanistic conjecture on the part of Weinreb was immediately accepted by the academic community, but it was not until 2006 that it was confirmed by spectroscopic and kinetic analyses. [5]
In addition to the original procedure shown above (which may have compatibility issues for sensitive substrates), Weinreb amides can be synthesized from a variety of acyl compounds. The vast majority of these procedures utilize the commercially available salt N,O-dimethylhydroxylamine hydrochloride [MeO(Me)NH•HCl], which is typically easier to handle than the free amine. [6]
Treatment of an ester or lactone with AlMe3 or AlMe2Cl affords the corresponding Weinreb amide in good yields. Alternatively, non-nucleophilic Grignard reagents such as isopropyl magnesium chloride can be used to activate the amine before addition of the ester. [7]
A variety of peptide coupling reagents can also be used to prepare Weinreb–Nahm amides from carboxylic acids. Various carbodiimide-, hydroxybenzotriazole-, and triphenylphosphine-based couplings have been reported specifically for this purpose. [6] [7]
Finally, an aminocarbonylation reaction reported by Stephen Buchwald allows conversion of aryl halides directly into aryl Weinreb–Nahm amides. [8]
The standard conditions for the Weinreb–Nahm ketone synthesis are known to tolerate a wide variety of functional groups elsewhere in the molecule, including alpha-halogen substitution, N-protected amino acids, α-β unsaturation, silyl ethers, various lactams and lactones, sulfonates, sulfinates, and phosphonate esters. [6] [7] A wide variety of nucleophiles can be used in conjunction with the amide. Lithiates and Grignard reagents are most commonly employed; examples involving aliphatic, vinyl, aryl, and alkynyl carbon nucleophiles have been reported. However, with highly basic or sterically hindered nucleophiles, elimination of the methoxide moiety to release formaldehyde can occur as a significant side reaction. [9]
Nonetheless, the Weinreb–Nahm amide figures prominently into many syntheses, serving as an important coupling partner for various fragments. Shown below are key steps involving Weinreb amides in the synthesis of several natural products, including members of the immunosuppressant family of macrosphelides, and the antibiotic family of spirofungins. [2] [3] [4]
Reaction of Weinreb–Nahm amides with Wittig reagents has been performed to avoid the sometimes harsh conditions required for addition of hydride reagents or organometallic compounds. This yields an N-methyl-N-methoxy-enamine that converts to the corresponding ketone or aldehyde upon hydrolytic workup. [10]
Additionally, a one-pot magnesium–halogen exchange with subsequent arylation has been developed, showcasing the stability of the Weinreb–Nahm amide and providing an operationally simple method for the synthesis of aryl ketones. [11]
More unusual reagents with multiple Weinreb–Nahm amide functional groups have been synthesized, serving as CO2 and α-diketone synthons. [12] [13]
Finally, Stephen G. Davies of Oxford has designed a chiral auxiliary that combines the functionality of the Weinreb amide with that of the Myers' pseudoephedrine auxiliary, allowing diastereoselective enolate alkylation followed by facile cleavage to the corresponding enantioenriched aldehyde or ketone. [14]
The Grignard reaction is an organometallic chemical reaction in which, according to the classical definition, carbon alkyl, allyl, vinyl, or aryl magnesium halides are added to the carbonyl groups of either an aldehyde or ketone under anhydrous conditions. This reaction is important for the formation of carbon-carbon bonds.
In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.
A tetrahedral intermediate is a reaction intermediate in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral. Tetrahedral intermediates result from nucleophilic addition to a carbonyl group. The stability of tetrahedral intermediate depends on the ability of the groups attached to the new tetrahedral carbon atom to leave with the negative charge. Tetrahedral intermediates are very significant in organic syntheses and biological systems as a key intermediate in esterification, transesterification, ester hydrolysis, formation and hydrolysis of amides and peptides, hydride reductions, and other chemical reactions.
The Bamford–Stevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong base gives alkenes. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis.
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Nucleophilic acyl substitution describes a class of substitution reactions involving nucleophiles and acyl compounds. In this type of reaction, a nucleophile – such as an alcohol, amine, or enolate – displaces the leaving group of an acyl derivative – such as an acid halide, anhydride, or ester. The resulting product is a carbonyl-containing compound in which the nucleophile has taken the place of the leaving group present in the original acyl derivative. Because acyl derivatives react with a wide variety of nucleophiles, and because the product can depend on the particular type of acyl derivative and nucleophile involved, nucleophilic acyl substitution reactions can be used to synthesize a variety of different products.
In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.
The Dakin oxidation (or Dakin reaction) is an organic redox reaction in which an ortho- or para-hydroxylated phenyl aldehyde (2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde) or ketone reacts with hydrogen peroxide (H2O2) in base to form a benzenediol and a carboxylate. Overall, the carbonyl group is oxidised, whereas the H2O2 is reduced.
In organic chemistry, a Grignard reagent or Grignard compound is a chemical compound with the general formula R−Mg−X, where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride Cl−Mg−CH3 and phenylmagnesium bromide (C6H5)−Mg−Br. They are a subclass of the organomagnesium compounds.
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Steven M. Weinreb is an American chemist and is a professor of chemistry at Pennsylvania State University in United States. Together with Steven Nahm, he developed the Weinreb ketone synthesis, which allows for mono-addition of an organometallic reagent such as a Grignard reagent or organolithium reagent to an amide.
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