A wide variety of stabilized carbanions have been found to participate as nucleophiles in intramolecular Michael-type conjugate additions to in situ-generated nitrosoalkenes to form bridged carbocyclic systems. The vinylnitroso platforms for these cyclizations have been prepared via two key steps involving ring closing metathesis of vinyl chlorides and regioselective conversion of vinyl chlorides to α-chloroketones with sodium hypochlorite in glacial acetic acid/ acetone. An alternative approach to preparation of some cyclization substrates has involved use of more reactive enol ethers as precursors to the requisite α-chloroketones. A sulfonamide anion has also been found to be an effective nucleophile in this type of reaction, leading to formation of a 6-azabicyclo[3.2.1]octane.

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...

A wide variety of α-diazo-β-ketoesters can be prepared in good overall yields via a two-step sequence involving addition of ethyl lithiodiazoacetate to aliphatic, aromatic and conjugated aldehydes followed by mild oxidation with the Dess-Martin periodinane. Keywords ethyl diazoacetate; Dess-Martin periodinane; oxidationIn the course of some natural product syntheses currently ongoing in these labs, we needed to convert an aldehyde 1 into an α-diazo-β-ketoester 4 and two reasonable sequences seemed possible (Scheme 1). The most common methodology for this transformation would involve first homologating 1 to the corresponding β-ketoester 2, followed by a Regitz diazo transfer step to produce 4. 1 Alternatively, a potentially more attractive route would be to initially add ethyl lithiodiazoacetate to aldehyde 1 to produce an α-diazo-β-hydroxyester 3, which would be oxidized to the desired diazo compound 4. Although the addition of metallated ethyl diazoacetate to aldehydes is well precedented, 2 examples of the oxidation of adducts 3 to the corresponding ketones 4 are rare. In the few extant cases, the β-hydroxy-α-diazoesters 3 are derived only from aromatic or conjugated aldehydes. Moreover, the only reagents which have been used for alcohol oxidation in these few examples are limited to manganese dioxide, 3 IBX, 4 or barium permanganate. 5Since we were particularly interested in effecting this sequence starting with aliphatic aldehydes, and also required a mild oxidant for the second step which is compatible with sensitive functionality, we have explored this methodology further, particularly with regard to the oxidation process. Since there was good literature precedent that α-diazo-β-ketoesters are stable towards Dess-Martin periodinane (DMP), 6 we chose to investigate this reagent for oxidation of substrates like 3.As listed in Table 1, several α-diazo-β-hydroxyesters 3 were prepared from a variety of aliphatic, aromatic and unsaturated aldehydes and ethyl lithiodiazoacetate in THF using the experimental procedure of Padwa, et al. 2b It was found that exposure of these compounds to Dess-Martin periodinane in methylene chloride at room temperature indeed led to the formation of the corresponding α-diazo-β-ketoesters

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Oxidation O 0212A Mild, Efficient Method for the Oxidation of α-Diazo-β-hydroxyesters to α-Diazo-β-ketoesters. -A variety of α-diazo-β-ketoesters are prepared via a two-step sequence involving addition of lithiated diazoester (II) to aldehydes (I) followed by mild oxidation using Dess-Martin periodinane. -(LI, P.; MAJIRECK, M. M.; KORBOUKH, I.; WEINREB*, S. M.; Tetrahedron Lett. 49 (2008) 19, 3162-3164;