| Weinreb ketone synthesis | |
|---|---|
| Named after | Steven M. Weinreb |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | weinreb-ketone-synthesis |
TheWeinreb ketone synthesis orWeinreb–Nahm ketone synthesis is a chemical reaction used inorganic chemistry to makecarbon–carbon bonds. It was discovered in 1981 bySteven M. Weinreb and Steven Nahm as a method to synthesizeketones.[1] The original reaction involved two subsequent substitutions: the conversion of anacid chloride withN,O-dimethylhydroxylamine, to form aWeinreb–Nahm amide, and subsequent treatment of this species with anorganometallic reagent such as aGrignard reagent ororganolithium reagent. Nahm and Weinreb also reported the synthesis ofaldehydes byreduction of theamide with an excess oflithium aluminum hydride (seeamide 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, twoequivalents of the incoming group add to form analcohol 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. Thesefunctional groups are present in a large number ofnatural 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 followingreaction mechanism to explain the selectivity shown in reactions of the Weinreb–Nahm amide. Their suggestion was that thetetrahedral intermediate (A below) formed as a result ofnucleophilic addition by theorganometallic reagent is stabilized bychelation from themethoxy group as shown.[1] This intermediate is stable only at low temperatures, requiring a low-temperaturequench.
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 ofacyl compounds. The vast majority of these procedures utilize the commercially available saltN,O-dimethylhydroxylamine hydrochloride [MeO(Me)NH•HCl], which is typically easier to handle than the free amine.[6]
Treatment of anester orlactone 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 ofpeptide coupling reagents can also be used to prepare Weinreb–Nahm amides from carboxylic acids. Variouscarbodiimide-,hydroxybenzotriazole-, andtriphenylphosphine-based couplings have been reported specifically for this purpose.[6][7]
Finally, an aminocarbonylation reaction reported by Stephen Buchwald allows conversion ofaryl 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-protectedamino acids, α-β unsaturation,silyl ethers, variouslactams and lactones,sulfonates, sulfinates, and phosphonate esters.[6][7] A wide variety of nucleophiles can be used in conjunction with the amide.Lithiates andGrignard reagents are most commonly employed; examples involvingaliphatic,vinyl,aryl, andalkynyl carbonnucleophiles 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 theimmunosuppressant family of macrosphelides, and theantibiotic family of spirofungins.[2][3][4]
Reaction of Weinreb–Nahm amides withWittig 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-diketonesynthons.[12][13]
Finally,Stephen G. Davies ofOxford has designed achiral auxiliary that combines the functionality of the Weinreb amide with that of the Myers'pseudoephedrine auxiliary, allowing diastereoselectiveenolate alkylation followed by facile cleavage to the corresponding enantioenriched aldehyde or ketone.[14]
