The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐Withdrawing Substituents

Abstract

The Krapcho reaction involves esters with α‐electron‐withdrawing substituents such as malonates, β‐keto esters, and α‐cyano esters, which undergo dealkoxycarbonylation on being heated in polar aprotic solvents (such as DMSO, DMF, or HMPT) in the presence of water, or in polar aprotic solvents with water in the presence of added salts (such as NaCN, NaCl, LiCl, LiI, or MgCl 2 ). This procedure avoids the use of strongly aqueous acidic and alkaline conditions and tolerates many functional and protecting groups. The chapter presents the mechanistic aspects of this procedure, which include reaction parameters such as solvents, salts, other additives, and the use of microwave irradiation. The diastereoselectivity of protonation of the enolate intermediate leading to the dealkoxycarbonylated products is discussed. Trapping of the intermediate enolate by electrophiles other than a proton is illustrated. Potential side reactions and same‐pot subsequent reactions of substrates are discussed along with functional‐group compatibility for halogens and nitrogen, oxygen, sulfur, selenium, and carbon functional groups. Several examples of applications of this methodology for the synthesis of natural products along with experimental conditions and procedures are presented. Closely related methods are discussed in the Comparison with Other Methods section. The tables, which consist of 371 pages, are grouped according to substrate structure. Selective entries for other methods (excluding classical aqueous acidic or basic methods) are included in the tabular survey for comparative purposes.

Total Synthesis of (±)‐Scopolamine: Challenges of the Tropane Ring

“…Next, the dealkoxycarbonylation of 7 was investigated. After a short screening of Krapcho-type conditions, [19] desired ketone 13a was obtained from 7a in a maximum yield of 34 % using LiCl in DMSO. Formation of pyrrole 14 resulting from a retro-Mannich reaction was also observed.…”

Synthesis of 3-benzylidene-dihydrofurochromen-2-ones: promising intermediates for biflavonoid synthesis

“…Instead, compound 14 was prepared by α-phosphorylation of lactone 13 , 13 obtained from compound 12 by decarboxylation with NaI in refluxing DMF. 14 …”

Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

“…Towards this end, the mixture of oximes 16 was cleaved, and the resulting aldehyde 17 was reduced, leading to a-carbomethoxylactone 18. This product was then subjected to a Krapcho decarboxylation [19] to afford butyrolactone 19.…”