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Arndt-Eistert Synthesis

Wolff Rearrangement

The Wolff Rearrangement allows the generation of ketenes from α-diazoketones. Normally, these ketenes are not isolated, due to their high reactivity to form diketenes.

Wolff rearrangements that are conducted in the presence of nucleophiles generate derivatives of carboxylic acids, and in the presence of unsaturated compounds can undergo [2+2] cycloadditions (for example Staudinger Synthesis).

The formation of α-diazoketones from carboxylic acids (via the acyl chloride or an anhydride) and the subsequent Wolff Rearrangement in the presence of nucleophiles results in a one-carbon homologation of carboxylic acids. This reaction sequence, which first showed the synthetic potential of the Wolff-Rearrangement, was developed by Arndt and Eistert.

Mechanism of the Wolff Rearrangement

α-Diazoketones undergo the Wolff Rearrangement thermally in the range between room temperature and 750 °C in gas phase pyrolysis. Due to competing reactions at elevated temperatures, the photochemical and metal-catalyzed variants that feature a significantly lowered reaction temperature are often preferred (Zeller, Angew. Chem. Int. Ed., 1975, 14, 32. DOI).

Nitrogen extrusion and the 1,2-shift can occur either in a concerted manner or stepwise via a carbene intermediate:

Silver ion catalysis fails with sterically hindered substrates, pointing to the requisite formation of a substrate complex with the ion. In these cases, photochemical excitation is the method of choice.

The solvent can affect the course of the reaction. If Wolff-Rearrangements are conducted in MeOH as solvent, the occurrence of side products derived from an O-H insertion point to the intermediacy of carbenes:

The course of the reaction and the migratory preferences can depend on the conditions (thermal, photochemical, metal ion catalysis) of the reaction. Analysis of the product distribution helps to determine different degrees of concertedness or the migratory aptitude of the group that rearranges. If R is phenyl, the main product comes from the rearrangement, whereas the methyl group gives more of the insertion side product.

The reactions of 2-diazo-1,3-diones also help to determine the migratory aptitude:

In a photolysis, methyl is preferred for rearrangement, whereas under thermolysis conditions the phenyl substituent migrates preferentially. Hydrogen always exceeds the migratory aptitude of phenyl groups. The alkoxy group in aryl or alkyl 2-diazoketocarboxylates never migrates.

More detailed explanations and additional examples can be found in a recent review by Kirmse (Eur. J. Org. Chem., 2002, 2193-2256. DOI).

Recent Literature

Combination of Enabling Technologies to Improve and Describe the Stereoselectivity of Wolff-Staudinger Cascade Reaction
B. Musio, F. Mariani, E. P. Śliwiński, M. A. Kabeshov, H. Odajima, S. V. Ley, Synthesis, 2016, 48, 3515-3526.

Synthesis of Fmoc-β-Homoamino Acids by Ultrasound-Promoted Wolff Rearrangement
A. Müller, C. Vogt, N. Sewald, Synthesis, 1998, 837-841.

Photochemical Wolff Rearrangement Initiated Generation and Subsequent α-Chlorination of C1 Ammonium Enolates
D. Weinzierl, M. Piringer, P. Zebrowski, L. Stockhammer, M. Waser, Org. Lett., 2023, 25, 3126-3130.

Synthesis of Chiral Esters via Asymmetric Wolff Rearrangement Reaction
J. Meng, W.-W. Ding, Z.-Y. Han, Org. Lett., 2019, 21, 9801-9805.

Synthesis of β-Lactams from Diazoketones and Imines: The Use of Microwave Irradiation
M. R. Linder, J. Podlech, Org. Lett., 2001, 3, 1849-1851.

A Tandem Approach to Isoquinolines from 2-Azido-3-arylacrylates and α-Diazocarbonyl Compounds
Y.-Y. Yang, W.-G. Shou, Z.-B. Chen, D. Hong, Y.-G. Wang, J. Org. Chem., 2008, 73, 3928-3930.

In an asymmetric [4+2] cycloaddition of vinyl benzoxazinanones with a variety of ketene intermediates via sequential visible-light photoactivation and palladium catalysis, the traceless and transient generation of ketenes from α-diazoketones through visible-light-induced Wolff rearrangement is important for the success of the palladium catalysis.
M.-M. Li, Y. Wei, J. Liu, H.-W. Chen, L.-Q. Lu, W.-J. Xiao, J. Am. Chem. Soc., 2017, 139, 14707-14713.