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 Weinreb–Nahm ketone synthesis
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.
Overaddition of nucleophiles
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]
^Nahm, S.; Weinreb, S. M. (1981), "N-methoxy-n-methylamides as effective acylating agents", Tetrahedron Letters, 22 (39): 3815–3818, doi:10.1016/s0040-4039(01)91316-4
^Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.; Jung, J.-W.; Lee, Y.-S.; Jung, J.-K.; Suh, Y.-G. (2005), "Concise Syntheses of (+)-Macrosphelides A and B", Organic Letters, 7 (15): 3159–3162, doi:10.1021/ol0508429, PMID 16018610
^Barbazanges, M.; Meyer, C.; Cossy, J. (2008), "Total Synthesis of Amphidinolide J", Organic Letters, 10 (20): 4489–4492, doi:10.1021/ol801708x, PMID 18811171
^Shimizu, T.; Satoh, T.; Murakoshi, K.; Sodeoka, M. (2005), "Asymmetric Total Synthesis of (−)-Spirofungin A and (+)-Spirofungin B", Organic Letters, 7 (25): 5573–5576, doi:10.1021/ol052039k, PMID 16320994
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The Weinrebketonesynthesis or Weinreb–Nahm ketonesynthesis is a chemical reaction used in organic chemistry to make carbon–carbon bonds. It was discovered...
the Weinrebketonesynthesis, an acyl chloride is first converted to the Weinreb amide, then treated with an organometallic reagent to form a ketone, or...
a ketone /ˈkiːtoʊn/ is an organic compound with the structure R−C(=O)−R', where R and R' can be a variety of carbon-containing substituents. Ketones contain...
Chemistry Professor Tzvi Hersh Weinreb (born 1940), Rabbi and Executive Vice President of the Orthodox Union Weinrebketonesynthesis Weinrib (disambiguation)...
compounds to give, on protonation, ketones (see Weinrebketonesynthesis). It is generally accepted that the high yields of ketones are due to the high stability...
to proceed via a radical pathway. The Weinrebketonesynthesis can also be used to convert acid halides to ketones. In this reaction, the acid halide is...
140 °C) in monoester 4. A C2 fragment was added as Weinreb amide 5 to form PMB ether 6 using LDA. The ketone was then reduced to the alcohol (NaBH3CN, TiCl4)...
vitro. An alternative industrial synthesis of paracetamol developed by Hoechst–Celanese involves the conversion of ketone to a ketoxime with hydroxylamine...
emerged as reagents in organic synthesis. Tebbe's reagent, which is used for the methylenation of esters and ketones, is prepared from TMA and titanocene...
5920–5922. doi:10.1021/jo070814z. PMID 17602594. Wood, J. L.; Khatri, N. A.; Weinreb, S. M. (1979). "A direct conversion of esters to nitriles". Tetrahedron...
determination of ketones, cobalt and in organic synthesis. Sigma-Aldrich Chemical Catalogue "Acetone Oxime". Retrieved 2 September 2016. Steven M. Weinreb, Kristina...
resulting alpha-hydroxy ester into the corresponding methyl ester, free acid, Weinreb amide and alpha-azido ester, without any racemization, as shown in Figure...
synthesize ketones is through the addition of organolithium reagents to Weinreb amides (N-methoxy-N-methyl amides). This reaction provides ketones when the...
aliphatic aldehydes with a tethered α,β-unsaturated ester, ketone, thioester, malonate, nitrile or Weinreb amide. It has been shown that α,β-unsaturated nitros...
Terrell, Ross; Szmuszkovicz, Jacob (April 1954). "A New Synthesis of 2-Alkyl and 2-Acyl Ketones". Journal of the American Chemical Society. 76 (7): 2029–2030...
Heintzelman, G.R.; Weinreb, S.M.; Parvez, M. (1996). "Imino Diels-Alder-Based Construction of a Piperidine A-Ring Unit for Total Synthesis of the Marine Hepatotoxin...
expensive starting materials such as the Weinreb amide. In 2018, Han et al. reported on a one-pot procedure for the synthesis of a variety of functionalized tellurophenes...
(i.e. carbon-based) compounds, such as alcohols, acids, aldehydes, and ketones. One of the most abundant interstellar molecules, and among the easiest...
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