“…The group of Tidwell reported a number of studies that looked at the addition reaction of aminoxyl radicals, such as TEMPO, with ketenes, the latter generated either by a Wolff rearrangement or by dehydrochlorination of acyl chlorides. [19][20][21][22][23] In all cases, the results were consistent with addition of the aminoxyl radical occuring at the carbonyl carbon of the ketene to generate an α-acyl radical species. The reactivity of the latter radical was dependent on the particular system.…”
Section: Roh Et Al Reported the Polymerization Of N3-[bis(trans-1-pro...supporting
confidence: 68%
“…Tidwell's group also reported that a series of ketenes were generated by reaction of the appropriate acyl chloride with 1,8-bis(dimethylamino)naphthalene. 20 These ketenes are long-lived in solution at room temperature and can be adequately characterized by their distinct bands in IR spectroscopy. The ketenes react with TEMPO, initially at the carbonyl carbon, though due to the delocalization of the subsequently formed radical, give products derived from radical coupling or rearrangement with a second TEMPO addition, as illustrated for heptafulvenone (45) in Scheme 19.…”
“…The group of Tidwell reported a number of studies that looked at the addition reaction of aminoxyl radicals, such as TEMPO, with ketenes, the latter generated either by a Wolff rearrangement or by dehydrochlorination of acyl chlorides. [19][20][21][22][23] In all cases, the results were consistent with addition of the aminoxyl radical occuring at the carbonyl carbon of the ketene to generate an α-acyl radical species. The reactivity of the latter radical was dependent on the particular system.…”
Section: Roh Et Al Reported the Polymerization Of N3-[bis(trans-1-pro...supporting
confidence: 68%
“…Tidwell's group also reported that a series of ketenes were generated by reaction of the appropriate acyl chloride with 1,8-bis(dimethylamino)naphthalene. 20 These ketenes are long-lived in solution at room temperature and can be adequately characterized by their distinct bands in IR spectroscopy. The ketenes react with TEMPO, initially at the carbonyl carbon, though due to the delocalization of the subsequently formed radical, give products derived from radical coupling or rearrangement with a second TEMPO addition, as illustrated for heptafulvenone (45) in Scheme 19.…”
“…We found that simply mixing 1 equiv of 3b and acid chlorides 1 at low temperature usually does not produce detectable amounts of ketene. Although 3b is a strong thermodynamic base, it is hindered and in most cases kinetically slow at deprotonating carbon-based acids …”
Section: Resultsmentioning
confidence: 99%
“…Consequently, the isotope effect of 1.1 that we measured is more likely a normal equilibrium effect than a KIE (involving formation of an sp 2 -bound H or D) and scenario 2 cannot be ruled out on this basis. Precedent suggests that acylammonium salt intermediates are involved in the synthesis of the majority of ketenes; however, for acid halides possessing certain electron-withdrawing groups in the α-position, direct dehydrohalogenation (scenario 2) may operate. , …”
We report practical methodology for the catalytic, asymmetric synthesis of beta-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the beta-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.
“…Initially, TEMPO adds to the carbonyl group of the ketene moiety, generating an enoyl radical. This radical either can be directly trapped by TEMPO, forming the corresponding α-aminoxylated TEMPO ester, or can engage in typical radical reactions before being trapped by a second equivalent of TEMPO. − A similar reactivity was observed in the oxidation of ynamides. When treated with triflic acid, the ynamide undergoes a transformation into the corresponding ketene iminium cation, which readily reacts with TEMPO to yield an α-imidate radical.…”
Nitroxides, also known as nitroxyl radicals, are long-lived or stable radicals with the general structure R 1 R 2 N−O • . The spin distribution over the nitroxide N and O atoms contributes to the thermodynamic stability of these radicals. The presence of bulky N-substituents R 1 and R 2 prevents nitroxide radical dimerization, ensuring their kinetic stability. Despite their reactivity toward various transient C radicals, some nitroxides can be easily stored under air at room temperature. Furthermore, nitroxides can be oxidized to oxoammonium salts (R 1 R 2 N�O + ) or reduced to anions (R 1 R 2 N−O − ), enabling them to act as valuable oxidants or reductants depending on their oxidation state. Therefore, they exhibit interesting reactivity across all three oxidation states. Due to these fascinating properties, nitroxides find extensive applications in diverse fields such as biochemistry, medicinal chemistry, materials science, and organic synthesis. This review focuses on the versatile applications of nitroxides in organic synthesis. For their use in other important fields, we will refer to several review articles. The introductory part provides a brief overview of the history of nitroxide chemistry. Subsequently, the key methods for preparing nitroxides are discussed, followed by an examination of their structural diversity and physical properties. The main portion of this review is dedicated to oxidation reactions, wherein parent nitroxides or their corresponding oxoammonium salts serve as active species. It will be demonstrated that various functional groups (such as alcohols, amines, enolates, and alkanes among others) can be efficiently oxidized. These oxidations can be carried out using nitroxides as catalysts in combination with various stoichiometric terminal oxidants. By reducing nitroxides to their corresponding anions, they become effective reducing reagents with intriguing applications in organic synthesis. Nitroxides possess the ability to selectively react with transient radicals, making them useful for terminating radical cascade reactions by forming alkoxyamines. Depending on their structure, alkoxyamines exhibit weak C−O bonds, allowing for the thermal generation of C radicals through reversible C−O bond cleavage. Such thermally generated C radicals can participate in various radical transformations, as discussed toward the end of this review. Furthermore, the application of this strategy in natural product synthesis will be presented.
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