Cycloaddition reactions azetidinones from

Boedeker and Courault215 reacted Schiff bases (151) derived from 2-aminopyridine and aromatic aldehydes with diphenylketene. In benzene at room temperature 4-oxopyrido[l,2-a]pyrimidines (152) were obtained in a reversible [4 + 2] cycloaddition reaction, whereas upon boiling mesitylene, irreversible [2 + 2] cycloaddition yielded azetidinones (150). Previously Sakamoto et al.216 prepared the azetidinones (150) in boiling xylene. 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

Cycloaddition Reactions Across C—C Multiple Bonds. Cycloadducts derived from carbodiimides and olefins or allenes are not known. However, the [2+2] cycloaddition of ketenes, R2C=C=0, to carbodiimides affords 4-imino-2-azetidinones (/3-lactames) 239 in high yield. Aliphatic carbodiimides show higher reactivity in comparison to aromatic carbodiimides, and the reaction proceeds across the aliphatic C=N bond in N-alkyl-N -arylcarbodiimides. The cycloadducts obtained in this reaction are listed in Table 2.3. 

Optically active 3-amino-2-hydroxycarboxylic acid derivatives are often key components of medicinally important compounds. The synthesis of isopropyl (2i ,35)-3-amino-4-cyclo-hexyl-2-hydroxybutyrate (126) (Scheme 28) takes advantage of a [2 + 2]-cycloaddition reaction of the chiral imines 123, prepared from 63, to assemble the important diastereomeric azetidinone 124 as the crucial precursor for completion of this novel synthesis. Protection of the hydroxy group of 63 as either the TBS ether 119 or the tert-buty ether 120, followed by a DIBAL reduction at —78 °C, produces smoothly one of the aldehydes 121 or 122. Condensation of these aldehydes with either di-p-anisylmethylamine or benzylamine in the presence of anhydrous magnesium sulfate affords the four possible chiral imines 123a—d (Scheme 26). 

The relative basicity of the nitrogen atom of the imine seems to determine the stereochemistry of the azetidinones. If the p a of the nitrogen is greater than 2.05, cw-azetidinones are formed exclusively while at lower p/fa values, mixtures of both isomers are formed Instead of the azidoacetyl chloride, the anhydride, derived from azidoacetic acid and trifluoroaceticanhydride, can be used in the [2-f2] cycloaddition reaction to give the /3-lactames 271 . 

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