Ketenes Staudinger

Reactions of Imines with Ketenes (Staudinger Reaction)... 

The first synthetic route for isocyanates was reported in 1848 (10,11)- Subsequent efforts by Hofmann, Curtius, and Hentschel pioneered alternative synthetic approaches (12). These efforts highlighted the phosgene—amine approach. Staudinger presented the stmctural similarities between isocyanates and ketenes and stimulated interest in this class of compounds (13). However, it was not until 1945, when the world was pressed for an alternative to natural mbber, that synthetic routes to isocyanates became an area of great importance. Several excellent review articles covering the synthesis and chemistry of isocyanates have been presented (1 9). 

Asymmetric synthesis of 3-amino (3-lactams via Staudinger ketene-imine cycloaddition reaction 98KGS1448. 

Staudinger observed that the cycloaddition of ketenes with 1,3-dienes afforded cyclobutanones from a formal [2+2] cycloaddition [52] prior to the discovery of the Diels-Alder reaction. The 2+2 cycloadditions were classified into the symmetry-allowed 2+2 cycloaddition reactions [6, 7], It was quite momentous when Machiguchi and Yamabe reported that [4+2] cycloadducts are initial products in the reactions of diphenylketene with cyclic dienes such as cyclopentadiene (Scheme 11) [53, 54], The cyclobutanones arise by a [3, 3]-sigmatropic (Claisen) rearrangement of the initial products. 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

Staudinger H (1907) Zur Kenntnis der Ketene. Diphenylketen. Liebigs Ann Chem 356 51-123... 

Zhang YR, He L, Wu X, Shao PL, Ye S (2008) Chiral N-heterocyclic carbene catalyzed Staudinger reaction of ketenes with imines highly enantioselective synthesis of W-Boc P-lactams. Org Lett 10 277-280... 

In the fashion of the established German school of organic chemistry, Staudinger studied a wide range of materials we now know to be polymeric. His shift in research interest was quite courageous as it caused a stir in Germany. He was, as a result of his work which included the discovery of ketenes, an established, reputable synthetic organic chemist. 

This interesting derivative of ketene is also obtained from benzilic acid by the old process of Staudinger the add is converted, by the action of phosphorus pentachloride, into diphenylchloracetyl chloride from which the two chlorine atoms are removed by means of zinc. (Formulate this equation.) What is carbon suboxide For information about the ketenes see H. Staudinger, Die Ketene, Stuttgart, 1912. 

These building blocks can be obtained either by the Miller cyclization of (5-hydroxy-ct-amino acids or by the Staudinger reaction7 ([2+2] ketene-imine cycloaddition). The procedure reported here follows the second route and has the advantages of being diastereospecific and to proceed in high yield. For a large scale preparation, the harmful and toxic N-methylhydrazine can be replaced by N,N-dlmethyl-1,3-propanediamine. Further transformations of the key intermediate have been reported elsewhere.7 9... 

Thermolysis The thermolysis of diazomethane was studied by Staudinger 2) a long time ago. In the presence of CO some ketene was formed most probably by the reaction between methylene and CO. 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

Azetidinones on a solid support 49 have been prepared in high yield by Staudinger reaction of a supported imine with an acid chloride in the presence of a base. The liberated p-lactams were of high purity <99TL1249>. Cycloaddition of a ketene intermediate, derived fi"om an azo compound, to an imine having an oxidatively cleavable chiral auxiliary N-substituent was used to obtain p-lactams 50. The trans. cis ratio which varied between 69 31 and 93 7, depended on the nature of the substituents R and R <99S650>. 

Gonzalez et al. [104] have synthesized spiro-(3-lactams directly by employing Staudinger reaction using unsymmetrical ketenes. The (3-lactams 130-133 were prepared by reaction of either 2-tetrahydrofuroyl chloride or 3-tetrahydrofuroyl chloride with imines 129 resulting in the generation of a mixture of cis- and trans-spiro-(3-lactams (Scheme 33). 

Recently, they have synthesized enantiomerically pure 1,3-thiazolidine-derived spiro-(3-lactams [111] (Scheme 37) using Staudinger ketene-imine reaction starting from optically active lV-boc-1,3- thiazolidine-2-carboxylic acid derivatives and imines, thus confirming the generality of the earlier reported 1,3-thiazolidine-derived spiro-(3-lactams. 

Guama et al. [133] have employed unsymmetrical bicyclic ketene in the Staudinger reaction for diastereoselective synthesis of highly constrained... 

Deshmukh et al. [134] have investigated the use of D-(+)-glucose derived chiral ketenes in the stereoselective synthesis of spiro-(3-lactams 226-227. The D-(+)-glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-(3-lactams 226-227 in 70 30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four... 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

Staudinger-reaction. The Staudinger reaction consists in the coupling of ketenes with imines. The ketene could be also prepared in situ in different ways (Scheme 1). 

Planar-chiral derivatives of 4-(pyrrolidino)pyridine (PPY) have been reported as efficient catalysts for enantioselective Staudinger reactions [75]. These chiral derivatives catalyzed the reactions between a range of symmetrical and unsymmet-rical disubstituted ketenes and a wide imine array leading to (3-lactams with good stereoselections and yields. 

Alkylideneamido complex [Re(N=CPh2)(CO)3(bpy)] [80] has been reported to react with ketene to afford, via Staudinger reaction, a single (3-lactam complex whose structure was determined by X-ray diffraction [75]. The fi-lactam complex reacted with methyl triflate (CH3OTf), affording the free /V-methyl-fi-lactam and the complex used as precursor (Scheme 21), [81]. 

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