Malonates additions

This work was repeated by several groups7 11 in the reaction of sodium dimethyl-malonate with methyl sorbate, Farmer and Metha9 observed small amounts of the 1,4-adduct besides the 1,6-addition product. Difficulties in conducting the transformations and analyzing the products are evident from reports on malonate additions to ethyl muconate12-14 depending on the reaction conditions, the expected 1,4-adduct (equation 4) or isomerization products formed by double bond displacement were isolated. Nucleophilic 1,4- and 1,6-addition reactions to 2,4-pentadienenitrile were also reported15-17. 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

Substituted cyclopropyl rings conjugated with a triple bond system have recently received attention as C5 building blocks. The procedure described here is a modification of the decarboxylation-elimination reaction for the preparation of a.3 acetylenic acids from enol sulfonates of acyl malonates. Addition of aqueous alkali to the enol sulfonate of diethyl cyclopropyl carbonyl malonate gives cycl opropyl propiol ic acid, but the yield is 1 ow. 

Three new syntheses of fro-condensed heteroaromatic pyrroles and their derivatives were described <1995T193, 2003T1477> using retro-malonate addition and/or 1,3-dipolar cycloaddition-cycloreversion methods. 

In contrast to the malonate additions to methylenecycloalkane-derived ir-allyl complexes, where substantial endocyclic addition has been observed with the cyclohexyl analog, essentially exclusive exocy-clic addition occurs for both the five- and six-membered ring cases with PhS02Na (equations 282 and 283)219... 

Tandem intramolecular 1,3-dipolar cycloadditions and cycloreversion, phosphinimine alkylidenemalonate cyclization, and retro-malonate additions have been reviewed.52 The origins of the stereoselection in the 1,3-dipolar cycloadditions to chiral alkenes53 and the 3 + 2-cycloadditions of fullerene, Cea, have been reviewed.54 The selectivity of the double 3 + 2-cycloaddition of tethered double vinyl carbene species in die presence of C6o varies witii the nature of the tether.55... 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system 99 [27] and its derivatives was accomplished using the same synthetic sequence (Scheme 16). Starting with 2-mcthyl benzolb thiophcnc-3-carbaldehyde 100, an intermediate 101 was obtained. Treatment of bromo compound 101 with sodium azide in ethanol led to the stable triazoline 102.1,3-Dipolar cycloreversion of 102 was induced by a catalytic amount of p-TsOH to give the parent 27/-benzo [4,5]thieno[2,3-c]pyrrole 99. Alternatively, direct treatment of bromo compound 101 with excess ammonia furnished 99 in one step. Compound 99 was treated with Boc20 and DMAP to give the /V-Boc derivative 103. Reaction of 101 with alkyl- and arylamines, respectively, afforded the N-substituted benzo[4,5]thieno[2,3-c]pyrroles 105 via a retro-malonate addition from intermediate 104. 

In the chapter we suggested that you could detect an acetate starter unit and seven malonate additional units in the skeleton of brefeldin. Give the mechanism of the addition of the first malonyl CoA unit to acetate. Draw out the structure of the complete acyl polymalonate chain and state dearly what must happen to each section of it (reduction, elimination, etc.) to get brefeldin A. 

According to the local curvature model used in predicting bond reactivities, the minor Cy-symmetrical diastereoisomeric pair (67/68) most probably results from malonate addition across the apical a-type bond C( 1) - C(6) intersected by... 

Entry Enone n Malonate Additive Temperature (°C) Time (h) Yield (%) ee (%)... 

Isoxazole is ring-opened by NaOEt in EtOH to cyanoacetaldehyde (28), which condenses in situ with diethyl aminomalonatehydrochloride in EtOH in the presence of NaOAc/AcOH to afford the enamine 29. Ring-closure by base-induced intramolecular malonate addition to the cyano function leads to the iminodiester 31, which on treatment with NaOEt undergoes Krapcho cleavage and tautomerization to give the 3-aminopyrrole-2-carboxylate 30. 

Scheme 33.26 Malonate addition to enones reported by Jorgensen.

Paroxetine is another serotonin reuptake inhibitor used to treat depression and panic disorders. The group led by J0rgensen reported on a concise four-step synthesis of this drug containing a piperidine unit (Scheme 11.7). Crucial stereogenic center construction was achieved via malonate addition to the activated a, 3-unsaturated aldehyde 18 in... 

SCHEME 31.30. 1,4-Malonate addition followed by asymmetric protonation of chiral calcium... 

Yan B, Spilling CD. Stereospeciiic Pd(0)-catalyzed malonate additions to allylic hydroxy phosphonate derivatives a formal synthesis of (—)-enterolactone. J. Org. Chem. 2004 69 2859-2862. 

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