Nonstabilized ylides

Generation and reactions of carbonyl ylides, nonstabilized 1,3-dipolar reagents 98YGK681. 

These newly discovered methods have found wide synthetic application. Examples include the generation and cycloaddition of stabilized N-unsubstituted azomethine ylides, nonstabilized N-substituted azomethine ylides, and even the parent azomethine ylides bearing no carbon substituents (19). However, these modem procedures often require severe reaction conditions such as high reaction temperatures, the use of polar solvents, and the use of strong bases, among others. The poor stereo- and regioselectivities that are often observed in the cycloadditions of nonstabilized azomethine ylides have discouraged their use in the stereocontrolled synthesis of complex molecules. 

Ditluoromeihylenaiion reactions may be effected also by the addition of chlorodifluoromethanc to a solution of nonstabilized phosphorus ylide [45, 46] (equation 44) (Table 17)... 

With the co side chain at C-12 in place, we are now in a position to address the elaboration of the side chain appended to C-8 and the completion of the syntheses. Treatment of lactone 19 with di-isobutylaluminum hydride (Dibal-H) accomplishes partial reduction of the C-6 lactone carbonyl and provides lactol 4. Wittig condensation8 of 4 with nonstabilized phosphorous ylide 5 proceeds smoothly and stereoselectively to give intermediate 20, the bistetra-hydropyranyl ether of ( )-1, in a yield of -80% from 18. The convergent coupling of compounds 4 and 5 is attended by the completely selective formation of the desired cis C5-C6 olefin. 

Retrosynthetic cleavage of the trans A8,9 disubstituted double bond in intermediate 11, the projected precursor of diketone 10, provides phosphorus ylide 12 and aldehyde 13 as potential precursors. In the forward sense, a Wittig reaction could conceivably achieve a convergent coupling of intermediates 12 and 13 with concomitant formation of the requisite trans C8-C9 olefin. Ordinarily, the union of a nonstabilized ylide, such as 12, with an aldehyde would be expected to afford an alkene with a cis geometry.8 Fortunately, however, the Schlosser modification of the Wittig reaction permits the construction of trans olefins from aldehydes and nonstabilized phosphorus ylides.9... 

The adjacent iodine and lactone groupings in 16 constitute the structural prerequisite, or retron, for the iodolactonization transform.15 It was anticipated that the action of iodine on unsaturated carboxylic acid 17 would induce iodolactonization16 to give iodo-lactone 16. The cis C20-C21 double bond in 17 provides a convenient opportunity for molecular simplification. In the synthetic direction, a Wittig reaction17 between the nonstabilized phosphorous ylide derived from 19 and aldehyde 18 could result in the formation of cis alkene 17. Enantiomerically pure (/ )-citronellic acid (20) and (+)-/ -hydroxyisobutyric acid (11) are readily available sources of chirality that could be converted in a straightforward manner into optically active building blocks 18 and 19, respectively. 

The major limitation of asymmetric sulfur ylide epoxidations is that only aromatic vinylepoxides can be formed efficiently and with high selectivity. When an aliphatic aldehyde is allowed to react with a semistabilized or nonstabilized sulfur ylide, poor diastereoselectivities and yields are observed, due to problems in controlling the ylide conformation and competing ylide rearrangement reactions [71]. However, some racemic, aliphatic vinylepoxides have been successfully formed by sulfur ylide epoxidations, although varying diastereoselectivities were observed [78-80],... 

Activated alcohols can be converted into olefins with Mn02 and nonstabilized ylides, see Blackburn, L. Pei, C., Taylor,... 

Nonstabilized carbonyl ylides (41) prepared by reaction of a-iodosilyl ethers with Smlj, can be trapped with various alkenes, alkynes and allenes to form furans of type 42, 43, and 44... 

Dipolar cycloaddition reaction of benzo(A)thiophene-l,1-dioxide 282 with nonstabilized azomethine ylides gave high overall yield of new pyrrolo derivatives 5 and 6 with low stereoselectivity (Scheme 50) <2006TL5139>. 

Organometallic betaines of type I can be considered as the closest structural analogs of carbon betaines of the (+ )P-C-C-X( ) type (IV), which were regarded for a long time as possible intermediates in classical reactions of carbonyl and thiocarbonyl compounds with phosphorus ylides (Wittig and Corey-Chaykovsky reactions and related processes,5,6 Scheme 1). Vedejs and coworkers7,8 proved unambiguously that oxapho-sphetanes (III) are true intermediates in the reactions of nonstabilized phosphorus ylides with carbonyl compounds. The formation of oxabetaines (+)p-c-c-o(-> was detected only in the form of their adducts with lithium salts.9,10... 

Syntheses of (l )-frans-isomers were reported by Crombie [24] and Elliott [25] starting from (1 /t Wran.v-chrysanthemic acid by means of the Wittig reaction. Their method were convenient to obtain (Z)-isomer (Scheme 10, step a) but not appropriate for the synthesis of ( )-isomer because of the (Z)-selective nature of the Wittig reaction in the case of nonstabilized ylides. It was very difficult to separate the pure ( )-isomer out of the (E)- and (Z)-mixture. This problem was overcome by use of the Takai s method (Scheme 10, step b) [26]. The ( )-selectivity of the double bond was fairly high (E Z = 89 11) (Scheme 10). 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefms. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes f-olefins instead. 

Beyond their ubiquitous role in organic synthesis, stabilized, semistabiUzed, or nonstabilized phosphonium ylides are fascinating ligands of transition metals. Their coordination chemistry is dominated by C-coordination to the metal center they are known to act exclusively as carbon-centered ligands rather than as v -C=P ligands. 

Some particular aspects of the chemistry of ylides as ligands have been reviewed throughout the years [15-27]. The topics are quite specific in most cases, and are mainly treated comprehensively nonstabilized ylides [15, 16], S-ylides [17], Au ylides and methanides [18], Li derivatives [19], Pd and Pt complexes [20-23], zwitterionic metallates [24], stabilized ylides [25], and applications [26, 27] have been reported upon. We will try in the following sections to give a basic complementary point of view about the chemistry of ylides as ligands. 

A different approach to synthesize nonstabilized ylide complexes is the reaction of halomethyl-metallic precursors with the corresponding nucleophile EZ . This method is quite general and usually occurs in very mild reaction conditions. Platinum, rhodium, iron, and palladium complexes (21)-(25) (Scheme 8) have been prepared, using phosphines [79-83], amines [84], or sulfides [85] as nucleophiles. Some of the most representative examples are shown in Scheme 8. 

Scheme 10 Carbene complexes obtained from nonstabilized ylides as CTR...

The 5,6-double bond in activated pyrimidines can participate in thermal [4-1-2] cyclization reactions as demonstrated by the 1,3-dipolar cycloaddition reactions of O-protected thymidine derivatives 483 with the nonstabilized azo-methine ylide 484, which is generated from trimethylamine AT-oxide by reaction with EDA <2002SC1977>. 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

The decarboxylative approach to the ylide formation generated cycloaddition products derived from cycloaddition of the ylide to the carbonyl moiety of the molecule, as opposed to the alkene as seen in previous examples. Kanemasa has reconciled this observation by consideration of the postulated transition state model of the reaction. It was assumed that the steric repulsion of the terminal olehnic substituent and the ylide would favor transition state 309 (Fig. 3.19). Additionally, nonstabilized azomethine ylides have a higher energy HOMO than stabilized ylides, and would therefore prefer the LUMO of the carbonyl than the lower lying alkene LUMO. Formation of fused hve-membered rings would also be kinetically favored over construction of six-membered ring (Scheme 3.103). 

Generation of Carbonyl Ylides from Nonstabilized Carbenes... 

Silyl substituted chloromethyl ethers such as 49 serve as a convenient precursor to nonstabilized carbonyl ylides. Treatment with a fluoride source promoted... 

Hosami and co-workers (12,173,174) prepared alternative forms of nonstabilized ylides (Scheme 4.87). They generated tailor-made carbonyl ylides from substituted 1,3-dichloroethers through a 1,3-elimination pathway mediated with a samarium reagent. These simple carbonyl ylide intermediates are valuable for preparing tetrahydro- and dihydrofurans. To a mixture of bis(chloromethyl) ethers and... 

This work has been extended from aryl and alkyl substituted systems (42) (R = aryl, alkyl) to analogues where R is an amino group, so giving access to synthetic equivalents of the nonstabilized amino nitrile ylides (45). Adducts were obtained in good-to-moderate yield with A-methyhnaleimide (NMMA), DMAD, electron-deficient alkenes and aromatic aldehydes (27,28), and with sulfonylimines and diethyl azodicarboxylate (29). Similarly the A-[(trimethylsilyl)methyl]-thiocarbamates (46) undergo selective S-methylation with methyl triflate and subsequent fluorodesilylation in a one-pot process at room temperature to generate the azomethine ylides 47. 

Thus, N-metalated azomethine ylides of the cyano-stabilized type are important in the stereoselective synthesis of pyrrohnes. These reactive intermediates are regarded as synthetic equivalents of nonstabilized nitrile ylides. 

Alkylthieno[2,3-4furans 414 and 4-alkylfuro[3,4-, ]furans 416 were obtained as unexpected side products from the reaction of 2-acetyl-5-bromothiophene and 2-acetyl-5-methylfuran with stabilized and nonstabilized ylides, along with the corresponding phosphoranes 415, pyrans 417, and dimeric products 418, respectively (Scheme 45) <2000T7573>. 

As illustrated in Section 4.1.1, the addition of nonstabilized carbenes to the oxygen atom of a carbonyl derivative can lead to the production of carbonyl ylides. However, these methods are not always practical for preparative scale since many side reactions can accompany the decomposition of alkyl diazo and diazirine derivatives. Landgrebe and co-worker (8) extensively studied the thermal decomposition of organomercurials in the presence of carbonyl compounds for the preparative generation of carbonyl ylides (Scheme 4.6). 

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