A wide array of readily prepared pivalates of ketoximes can be converted to the corresponding ketones in good yields by treatment with iron powder in THF containing catalytic amounts of both trimethylsilyl chloride and glacial acetic acid at room temperature for 30 minutes, followed by a brief aqueous workup. Keywords Oximes; ReductionWe have recently been actively involved in developing methodology for effecting both interand intramolecular Michael-type conjugate additions of carbon nucleophiles to in situproduced vinylnitroso compounds. 1,2 Thus, we have found that nitrosoalkene species 2 can easily be generated from α-chloro-O-TBS-oximes 1 using a fluoride source in the presence of a carbon nucleophile to form α-alkylated oximes 3 (Scheme 1). For many of our intended purposes, however, it was necessary to regenerate the carbonyl compounds 4 from the resulting oximes 3.Numerous methods have previously been described for converting oximes and their O-acyl derivatives to carbonyl compounds. 3 These procedures generally involve either hydrolytic, oxidative or reductive conditions. After some disappointing results using a few of the more common literature cleavage procedures (e.g. TiCl 3 , 4 Dess-Martin periodinane, 5 etc.), we decided to explore new methodology for this transformation. In particular, we were interested in developing a mild general procedure which would utilize inexpensive, commercially available reagents having long shelf lives. Moreover, since hydrolytic methods usually involve stringent reaction conditions, and oxidative procedures are often incompatible with functionality in some of our systems (e.g. amines, indoles, etc.), we primarily focussed on devising a reductive protocol.In 1998, Burk and coworkers discovered that N-acetyl enamides can be prepared in moderate to good yields directly from ketoximes by heating at 70 °C in toluene/acetic anhydride in the presence of iron powder.6a In an improvement of this methodology, Zhang et al. found that these reactions can be effected at room temperature if DMF is used as solvent, and also that * Corresponding author. Tel.: +1 814 863 0189; fax +1 814 865 3292; smw@chem.psu.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptTetrahedron Lett. Author manuscript; available in PMC 2011 July 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the reaction is initiated by the addition of a catalytic amount of trimethylchlorosilane.6b More recently, we reported that other acylating reagents can be used in this process. 6c We considered the possibi...
A diverse array of nitrosoalkenes derived from both acyclic and cyclic ketones, as well as aldehydes, via the Denmark protocol using α-chloro-O-TBS-oximes can be trapped efficiently in situ by a wide variety of potassium ester enolates to afford conjugate addition products in good yields. KeywordsConjugate additions; Oximes; Nitrosoalkenes Vinylnitroso compounds are highly reactive, generally unstable species which have only found sporadic use in organic synthesis. 1 There are presently two procedures most commonly used to generate nitrosoalkenes (Scheme 1). The most widely applied method involves basepromoted 1,4-elimination of an α-halo oxime 1 to produce the vinylnitroso species 3. These transient intermediates are known to undergo rapid conjugate additions with a variety of hetero and carbon nucleophiles in a Michael-type reaction to produce adducts 4 in good yields. When forming the vinylnitroso species via this process it is common to utilize at least two equivalents of a nucleophile, one of which acts as the base for the initial elimination step. Such a procedure, however, is inefficient when using valuable nucleophiles.A second, less widely used method for nitrosoalkene generation developed by Denmark, et al. relies on treatment of an O-silyl-α-halo oxime 2 with a fluoride source to form 3. 2 Several scattered examples have appeared describing the production of vinylnitroso compounds via this procedure in the presence of a nitrogen or oxygen heteronucleophile to afford the corresponding conjugate addition products. 3 In addition, two reports exist of the generation and intermolecular trapping of carbon nucleophiles starting from silyl-α-halo oximes like 2. 4 Recently we have used the Denmark procedure to effect the first examples of intramolecular conjugate additions of enolates to vinylnitroso compounds. 5 In view of our interest in exploring the potential of nitrosoalkenes as enolonium ion equivalents in organic synthesis, 7 we have studied effecting intermolecular conjugate additions of a number of vinylnitroso compounds formed by the Denmark strategy with a wide variety of ester enolates. It should be noted that vinylnitroso compounds derived from cyclic ketones 6 as well © 2010 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: +1 814 863 0189; fax +1 814 865 3292; smw@chem.psu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. as aldehydes 4a are still relatively rare and therefore we have opted to explore reactions involving such systems to probe the scope of the methodology. NIH Public AccessWe have developed a general experimenta...
Michael-type conjugate additions of γ-chiral aldehyde-derived acyclic nitrosoalkenes have been explored using a series of carbon and hetero nucleophiles. In all cases examined, these reactions are stereoselective, leading exclusively to the anti products.Vinylnitroso compounds 1 are highly reactive, short-lived species which have found only sporadic use in organic synthesis. 1 To date, very few of these intermediates have actually been isolated and characterized, and they are usually generated and trapped in situ. One potentially valuable reaction of nitrosoalkenes involves intermolecular conjugate additions of hetero and carbon nucleophiles in a Michael-type of transformation to produce adducts such as 2 (eq 1). By this process nitrosoalkenes 1 can act as enolonium ion equivalents, thereby allowing a simple method for the umpolung of the usual enolate reactivity. 2 However, these vinylnitroso species have been the object of surprisingly little systematic study and have not seen application to the synthesis of complex molecules. We have recently been exploring the scope of both inter-3 and intramolecular 4 conjugate additions of these reactive intermediates with a variety of nucleophiles. Recently, we have also begun to investigate various stereochemical issues relevant to these reactions which have never been addressed, and some of this work is the subject of this communication. Our initial studies were designed to probe the stereoselectivity of conjugate additions of acyclic aldehyde-derived nitrosoalkenes bearing a γ-stereogenic center (Cf 4, Scheme 1). It should also be noted that relatively few examples exist in the literature of reactions of nitrosoalkenes generated from aldehydes. 3,5 For this work, we have opted to generate the requisite nitrosoalkene by the Denmark method, which involves exposure of an O-TBS-α-chlorooxime to a fluoride source.6 Therefore, known α-chloro-γ-methyldihydrocinnamaldehyde 7 (racemic, mixture of diastereomers) was converted to O-TBS-oxime 3 with commercially available O-TBS-hydroxylamine (see Supporting Information). Conjugate additions to the vinylnitroso compound derived from 3 were then effected with a series of four malonate anions as the nucleophiles (Scheme 1). Thus, the malonate (2 equiv) was first deprotonated with potassium hexamethyldisilazide in THF at low temperature followed by addition of O-silyloxime 3 (1 equiv). Tetrabutylammonium fluoride (2 equiv) in THF was then added at −78 °C and the mixture was warmed to 0 °C to generate the nitrosoalkene 4. We were pleased to find that in each case the malonate enolate addition was completely stereoselective, producing only the anti stereoisomeric adducts 5-8. Oximes 7 and 8 appear to be single geometric isomers assumed to be (E), whereas 5 and 6 are ~9-10:1 (E/Z) mixtures. 8,9 In order to establish the configuration of these adducts, α-allylmalonate oxime 5 was heated in toluene at 190 °C (sealed tube) to generate nitrone 9, which then cyclizes via the conformation shown to afford cis-fused bicyclic isoxazolidin...
Intermolecular Michael-type conjugate additions of some in situ-generated ring-substituted nitrosocyclohexenes with both carbon- and heteronucleophiles have been found to be highly stereoselective, leading predominantly (or exclusively) to products resulting from axial attack on a half-chair conformation of the nitrosoalkene substrate.
Imaging of misfolded proteins implicated in neurodegenerative disorders using positron emission tomography (PET) imaging has revolutionized dementia research. In this viewpoint, the development of radiotracers for tau PET is highlighted. We draw attention to key innovations that were essential to development of radiotracers for imaging tau, from early imaging agents, through the structure−activity relationship (SAR) studies required to minimize off-target binding of the newer probes in use today. We also highlight development of Tauvid, the first tau PET radiotracer approved by the US FDA for tau imaging in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease.
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