Bis-ketoesters

A double tethered Biginelli reaction was carried out on the simple five-membered urea aldehyde 305 that reacted with the aliphatic and aromatic bis-ketoesters 306 and 307 giving compounds 308 and 309, respectively, in good yield, albeit with a diasteromeric ratio of 1 3. A series of different polycyclic bis-guanidines resembling betzelladine alkaloids were prepared <2003OL4485>. 

The [Cu(acac)2]-catalysed reactions of conjugated bisketones/conjugated bisesters/ conjugated bis[ketoesters], and dimethyl diazomalonate/ethyl diazocetate have been reported to give dihydrofiiran and dihydrobenzoxepine/dihydrooxepine derivatives by l,5-/l,7-electrocyclic reactions of related conjugated carbonyl ylides (Scheme 105). 

The power of Noyori s Ru -BINAP system in ketone reductions has been amply demonstrated in numerous complex molecule syntheses. Schreiber, for example, has disclosed a route to the macrolide antibiotic mycoticin A (221, Scheme 2.27) [139] that relies on a strategy involving two-directional chain synthesis [140]. Catalytic asymmetric reduction of diketone 216 affords the C2-symmetric diol 217. Conversion of 217 into bis(ketoester) 218 then allows double ketone reduction to furnish 219, which was subsequently elaborated into the skipped polyol chain 220 of mycoticin A (221). 

P-Ketoester Chelates. p-Ketoesters react in a fashion similar to the p-diketones. TYZOR DC [27858-32-8] is the hght-yeUow Hquid from TYZOR TPT and two moles of ethyl acetoacetate (eaa) after removal of the isopropyl alcohol. TYZOR BEAT, the bis-ethylacetoacetate [20753-28-0] derived from the tetra- -butyl titanate, and TYZOR IBAY [83877-91-2] the isobutoxy analogue, perform similarly to TYZOR DC. Both, however, have better cold-storage stabiHty. 

The fluorination of P-diketones and p-ketoesters with N-/luorobis(trifluo-romethanesulfonyl)imide (Table 3a, B) can be controlled to give either mono-fluorination or difluorination. Monofluorination occurs when the strong acid, bis(trifluoromethanesulfonyl)imide, a reaction product, is removed by addition of water, which prevents further enolization and fluormation of the monofluoro adduct [83] (equation 38)... 

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

Similar transformations have been performed with Danishefsky s diene and glyoxylate esters [85] catalyzed by bis (oxazoHne)-metal complexes to afford the hetero Diels-Alder product in 70% isolated yield and up to 72% ee. Jorgensen [86,87] reported a highly enantioselective, catalytic hetero Diels-Alder reaction of ketones and similar chiral copper(II) complexes leading to enantiomeric excesses up to 99% (Scheme 31, reaction 2). They also described [88] a highly diastereo- and enantioselective catalytic hetero Diels-Alder reaction of /I, y-imsaturated a-ketoesters with electron-rich alkenes... 

The penicillin-N,S-acetal 479 reacts with N,N-bis(trimethylsilyl)formamide 22c and Hg(OAc)2, apparently via the iminium salt 480, to give the penicillin-N,N-acetal 481 in 65% yield [64]. On treatment of racemic y-ketoesters such as 482 with chiral silylated 1,3-mercaptoalcohols such as 483, in the presence of TMSOTf 20, at room temperature a kinetically controlled 2 1 mixture of the 0,S-acetals... 

Amides such as DMF or ureas such as N,N-tetramethylurea react with bis(trimethylsilyl)selenide 604 in the presence of BF3-OEt2 to give selenoamides, for example 617, or selenoureas whereas esters such as n-butyl benzoate react with 604 in the presence of Bp3-Et20 and 2,3-dimethylbutadiene to give 619 via 618 [157]. On heating with P4Sio/sulfur and hexamethyldisiloxane 7 y9-ketoesters such as ethyl acetoacetate are converted to 3H-l,2-dithiole-3-thiones such as 620 in high yields [158] (Scheme 5.51 cf. also Section 8.6). 

Ketoesters from Imidazolides and Magnesium Bis(alkyl malonates) or Bis(alkyl thiomalonates)... 

In an approach toward substituted guanidines, Louwrier and co-workers observed an unusual reaction whereby reaction of the /3-ketoester 310 with bis-BOC-thiourea 311 in the presence of HgCl2 and triethylamine gave the tricyclic product 312 in excellent yield <1996T2629>. The mechanism that the authors suggest to account for this product, via intermediates 314-316, is outlined in Scheme 23. 

Bei der thermischen Decarbonylierung des Brenztraubensaureiithyl-esters bei HO bis 130° fanden Calvin und Lemmon (31 ), daB das Kohlen-oxyd aus der Carboxylgruppe des a-Ketoesters stammt. 

It has been reported that a cationic iridium such as [Ir(cod)2]BARF (BARF = 3,5-(CF3)2C6H3 4B), when combined with l,l -bis(diphenylphosphino)ferrocene (DPPF), catalyzed a hydrogen-mediated reductive carbon-carbon bond formation [68]. Thus, the reaction of alkynes 150 with a-ketoesters 151 produces p.y-unsaturated-a-hydroxy ketones 152 (Equation 10.40). 

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

Furthermore, for the first time this procedure has been extended to (i-ketoesters, although only an intramolecular reaction was feasible. However, with 5 mol% of Bi(OTf)3, the styrene-substituted ketoester 41 was converted into the 2,3-disubsti-tuted cyclohexanone 42 in 72% yield (Scheme 32). 

In a similar fashion 2-aminothiophenol can be reacted with 1,3-bis carbon electrophiles to give various types of 1,5-benzothiazepine. Thus the benzo analogues of (408) and (409), e.g. (410), are prepared by parallel routes, reaction with 1,3-diphenylpropynone gives (411), reaction with /3-ketoesters gives products of type (412), reaction with diketene gives (413), and the reaction with methyl 3-arylglycidates gave (414) which could not be dehydrated. 

The photochemical reaction of 2,6-bis-(trimethylsilyl)-4//-pyran 148 with various ketoesters results in functionalization at the 4-position in moderate to good yields (61-73%) (Equation 9) <2000TL5199>. 

Phenylation and arylation have also been performed in bifunctional compounds such as malonates, /1-diketones and /1-ketoesters (Table 8.4). Diethyl malonate was arylated at room temperature affording mixtures of mono- and bis-arylated products, whereas isopropylidene malonate (Meldrum s acid) underwent bis arylation directly. Dimedone, the all carbon analogue of Meldrum s acid, was also mono-and bis-phenylated, with some concomitant O-phenylation [33], Generally, / -diketones show often ambident reactivity but the O-arylated product is normally the minor one an exception was noted in the triketone (PhCO)2CHCOPh which underwent mainly O-phenylation (68%) [33], Several dianions from /1-diketones have been arylated in high yields at the a-position, in a procedure superior to other methods [35]. 

The reactions of arylation of heterocyclic /3-ketoesters were employed in the synthesis of a number of isoflavanones and isoflavones.27,28 cr-Methylene cr-arylketones can be easily and selectively obtained by arylation of allyl /3-ketoesters which are eventually deprotected by the Tsuji s procedures. a Deallyloxycarbonylation was performed by treatment of the allyl cr-aryl-/3-ketoesters with catalytic amounts of palladium(n) acetate, triethylammo-nium formate and triphenylphosphane in THF at room temperature and afforded the a-arylketones in 75-97% yield.27 Deallyloxycarbonylation-dehydrogenation can be realized with the same allyl esters by treatment with catalytic amounts of palladium(n) acetate and l,2-bis(diphenylphosphino)ethane (DPPE) in acetonitrile under reflux and affords the ct-aryl cr,/3-unsaturated ketones in 60-90% yield (Scheme 4).28 In particular, this reaction was used in a direct convergent synthesis of 2 -hydroxyisoflavones involving arylation of an appropriate allyl /3-ketoester with the MOM-protected (2-methoxymethoxyphenyl)lead triacetate derivative (Scheme 4). The reaction of the isomeric... 

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