Moderated ylides

The reaction rates and the ratio of E and Z isomers are modified when the reaction involves a stabilized or moderated" ylide and an aromatic aldehyde. 

Because the geometry of the 9-double bond was not clear at that time, Corey et al. 75> tried to prepare the (Z)-9-isomer as well as the ( )-9-isomer of leukotriene-A (78 and 86). In the synthesis of the former isomer the tribenzoyl derivative of D-(—)-ribose (79) was converted in 8 stepy into the optically active epoxyaldehyde 71 and the latter to 72. 72 was olefmated with ylide 82, generated by treatment of the corresponding phosphonium mesylate with lithium diisopropylamide in THF/ HMPA75) (Scheme 15). In the first olefination step 72+82- 78, however, similar to the first method, a A9-isomer mixture was formed. The loss of (Z)-selectivity of the Wittig reaction is due to the use of conjugated unsaturated, i.e. moderate ylides of type 82, and had to be expected because of the mechanism of the Wittig reaction (see Sect. 2). 

Nearly all of the results available through 1967 could be interpreted to tell a consistent story. Betaines corresponding to carbonyl-stabilized ylides or to benzylic ( moderated ) ylides apparently were capable of extensive reversal, at least in hydroxylic solvents. Betaines corresponding to nonstabi-... 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

Phosphonium salts containing a benzyl group may be converted into ylides by the use of only moderately strong bases such as sodium ethoxide. The preparation of benzyli-dene derivatives of aldehydes and ketones is therefore easily done. The procedure below is for the preparation of a substituted butadiene, which in turn is ideally suited for use in the Diels-Alder reaction (see Chapter 8, Section I). 

The aldehyde structures and the tosylhydrazone salts were varied in an extensive study of scope and limitations, with use of both achiral and chiral sulfur ylides [73]. Aromatic aldehydes were excellent substrates in the reaction with benzaldehyde-derived ylides, whereas aliphatic aldehydes gave moderate yields and transxis ratios. 

When ot, 3-unsaturated aldehydes were employed, vinylepoxides were obtained with excellent transxis ratios but in poor yields. When benzaldehyde was treated with a, 3-unsaturated tosylhydrazone salts, the yields of vinylepoxides were improved but the transxis ratios dropped. When chiral sulfides were utilized, the ees were high with a, 3-unsaturated aldehydes, whereas unsaturated, chiral sulfur ylides gave moderate ees, poor yields, and modest transxis ratios. 

Whereas the nucleophilic addition of vinylmagnesium bromide to a-alkoxy aldehydes (12, 16) proceeds with a low to moderate chelation-controlled diastereoselectivity, a remarkably high preference for the opposite stereochemical behavior is found with the jS-silyl phosphorus ylide 1477. Due to the electron-donating 4-methoxyphenyl substituents at the phosphorus atom, as well as the /i-methyldiphenylsilyl group, 14 is an excellent vinylation reagent which does not lead to any Wittig olefination products. 

A second example of step-growth polycondensations with formation of the ole-finic double-bond are Wittig- and Wittig-Horner-type condensations. The Wittig-type polycondensations involve AA/BB-type reactions of aromatic bisal-dehydes with bisphosphonium ylides [99,100] with formation of PPV derivatives (75) and lead to products of only moderate molecular weight (DP 10-20). 

Hori and co-workers accomplished the first synthesis of azathianaphthalene and azathiaphenanthrene in 1979 <79TL3969>. Their approach began with the formation of an olefin from o rt/20 -ni t ro b e n za 1 dehyde 43, via a Wittig reaction with an ylide and a subsequent reduction with zinc to afford cis and trans ortho-aminostyryl methyl sulfide 45. The cis-olefin was then treated with NCS, AgCKAi and KOH to yield 2-methyl- l-aza-2-thianaphthalene 47 in 41% yield. 9-Methyl- 10-aza-9-thiaphenanthrene 48a and 9-ethyl-10-aza-9-thiaphenanthrene 48b were obtained in a similar fashion in almost quantitative yields, whereas 6-benzyl-67/-d i b e n zo [ c, e] [ 1,2 J t h i azi n cs 50 were isolated in moderate yields via a 1,2-rearrangement (Scheme 13) <90TL7021>. 

Iodonium ylides reacted with electron-deficient alkynes or conjugated Rh-catalyst to form trisubstituted furans in moderate yields as depicted in the... 

The Cu(I)-catalyzed cyclization for the formation of ethyl ( )-tetrahydro-4-methylene-2-phenyl-3-(phenylsulfonyl)furan-3-carboxylate 82 has been accomplished starting from propargyl alcohol and ethyl 2-phenylsulfonyl cinnamate. Upon treatment with Pd(0) and phenylvinyl zinc chloride as shown in the following scheme, the methylenetetrahydrofuran 82 can be converted to a 2,3,4-trisubstituted 2,5-dihydrofuran. In this manner, a number of substituents (aryl, vinyl and alkyl) can be introduced to C4 <00EJO1711>. Moderate yields of 2-(a-substituted N-tosyIaminomethyl)-2,5-dihydrofurans can be realized when N-tosylimines are treated with a 4-hydroxy-cis-butenyl arsonium salt or a sulfonium salt in the presence of KOH in acetonitrile. The mechanism is believed to involve a new ylide cyclization process <00T2967>. 

It is assumed that the mechanism proceeds via activation of the imine by the ruthenium catalyst (structure 169), followed by reaction with ethyl diazoacetate to generate a metal-bound ylide intermediate. Intramolecular ruthenium- assisted attack of the carbanion 170 onto the iminium ion provides the corresponding aziridine with moderate to high // selectivity. Imines bearing electron-donating groups (R2) showed significant rate enhancement. 

Finn and co-workers [87], who treated aromatic aldehydes with a mixed titanium-phosphorus ylide formed from iPrOTiCl3, (Me2N)3P=CH2 and an excess of sodium hexamethyldisilazide as base (Scheme 2.52). Symmetrical allenes 167 were thereby obtained with moderate to good yield. 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

Some thioketones are reported to give 1,3,2-dithiastannolanes in moderate to high yields in reactions with a stannylene Dis2Sn [Dis = CH(SiMc3)2] <930M4>. The key difference with the process discussed above is inversed polarization of intermediate ylide (380) which can exist in an equilibrium with a thiastannirane (381). 

The thermolytic preparation by De Shong et al. (74) of azomethine ylides from aziridines and their intermolecular reactions are the first examples of singly stabilized ylides of this type. However, the protocol has been further extended to include intramolecular processes. Aziridines tethered to both activated and unactivated alkenes were subjected to flash vacuum thermolysis generating cycloadducts in moderate-to-excellent yields. While previously singly activated alkenes had furnished low material yields via an intermolecular process, the intramolecular analogue represents a major improvement. Typically, treatment of 222 under standard conditions led to the formation of 223 in 80% yield as a single cis isomer. Similarly, the cis precursor furnished adduct 224 in 52% yield, although as a 1 1 diastereomeric mixture (Scheme 3.77). 

At about the same time, Wenkert and c-workers (75) reported a similar smdy into the intramolecular 1,3-dipolar cycloaddition of 2-alkenoyl-aziridine derived azomethine ylides. Thermolysis of 231 at moderate temperature (85 °C) produced 232 as a single isomer in 58% yield. Similarly, 233 furnished 234 in 67% yield. In each case, the same stereoisomers were produced regardless of the initial stereochemistry of the initial aziridine precursors. However, the reaction proved to be sensitive to both the substituents of the aziridine and tether length, as aziridines 235 and 236 furnished no cycloadducts, even at 200 °C (Scheme 3.79). 

Nair et al. (87,88) achieved a synthesis of spirooxindole-containing molecules by adding isatins to various carbonyl ylides (Scheme 4.46). There has been relatively little research regarding the efficiency of C=0 of 1,2-dicarbonyl compounds as dipolarophiles relative to their olefinic counterparts. As anticipated, Nair found that the more electrophilic carbonyl of the isatin 187 (non-amide carbonyl) reacted smoothly with the carbonyl ylide formed from diazoketone 186 to give the spirocyclic adduct 188. Nair s yields were moderate to good (44—83%), but were based on recovered isatin. 

One novel and interesting method of generating a silacarbonyl ylide occurred through the addition of a carbonyl species with a silylene formed under photolytic conditions. Komatsu and co-workers (177) found that photolysis of trisilane (315) in solution with a bulky carbonyl species led initially to the formation of a silacarbonyl ylide followed by a dipolar cycloaddition of an olefinic or carbonyl substrate. Reaction of simple, nonbulky aldehydes led to only moderate yields of cycloadduct, the siladioxolane. One lone ketone example was given, but the cycloadduct from the reaction was prepared in very low yield (Scheme 4.89). 

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. 

Nitrile ylides, generated by the imidoyl chloride-base route, have been added to 1-azetines (185) (X = 0, S) to give the adducts 186 in moderate to good yields (42-68%) (94,95). These examples are among the first cycloadditions to 1-azetines. In the case where Ar = Ph, the NMR spectrum of the product showed only one set... 

---