Salt-free condition

This accounts for the considerable discrepancy between the alkene Z/E ratio found on work-up and the initial oxaphosphetan ais/trans ratio. By approaching the problem from the starting point of the diastereomeric phosphonium salts (19) and (20), deprotonation studies and crossover experiments showed that the retro-Wittig reaction was only detectable with the erythreo isomer (19) via the cis-oxaphosphetan (17). Furthermore, it was shown that under lithium-salt-free conditions, mixtures of (19) and (20) exhibited stereochemical drift because of a synergistic effect (of undefined mechanism) between the oxaphosphetans (17) and (18) during their decomposition to alkenes. 

Addition of lithium chloride is necessary for the reaction to proceed. Whereas no reaction was observed under salt-free conditions, the lactone is obtained in 90% yield within 5 min in the presence of LiCl impregnated with KF on alumina (KF-LiCl-Al203 = 1 1 4 by weight) under the action of focused microwave irradiation at 150 W. With conventional heating no reaction occurred. 

Scheme 12 Allylic alkylation with activated catalyst before and after applying salt-free conditions...

Anodic and cathodic limits, potential referred to LP/Li. The salt-free condition was realized via an ultramicroelectrode... 

Commercially available ethyl nitroacetate is an interesting pronucleophile, because it can serve as the synthetic equivalent of either nitromethane or glycine. The ethoxycarbonyl group can also be considered as a protecting group against dialkylation. The allylic alkylation with ethyl nitroacetate did not require an additional base (salt-free conditions). As a consequence of the high acidity of the chirality center a to N, 1 1 mixtures of epimers were formed. 

Substitutions with N,N-diacylamines are best carried out under salt-free conditions in order to minimize the concentration of base in the reaction medium and to circumvent the low solubility of salts in THF. For example, potassium phthalimide could not be reacted in THF because of its insolubility. The reaction under salt-free conditions proceeded smoothly even with LI as the ligand (Table 9.3). 

N-Boc-N-(but-2-enoyl)amine is an excellent pronucleophile for the Ir-catalyzed allylic amination under salt-free conditions (cf. Table 9.3, entries 15-18). The products were subjected to RCM with good results, even upon application of the Grubbs I catalyst (Scheme 9.29) [27bj. The resultant N-Boc protected a,P-unsaturated y-lactams are valuable chiral intermediates with appUcations in natural products synthesis and medicinal chemistry. 

Tellurophosphoranes, obtained through a transylidation reaction between tellurenyl halides and phosphoranes, react with aldehydes to give the expected vinylic tellurides as an E Z isomeric mixture (method a). One other methodology involves the treatment of equimolar amounts of phenyl tellurenyl bromide and phosphonium salts with t-BuOK followed by an aldehyde (method b). Under these lithium-salt-free conditions, (Z)-vinylic tellurides are the main products. ... 

In Hght of the hahde effects, the role of the copper afkoxide and the lithium halide, derived from the transmetaUation, was probed by preparing the copper afkoxide under salt-free conditions (Tab. 10.10) [24, 51, 52]. Initially, mesityl copper, from which the metal hahde salts are removed during preparation [53], was chosen to provide the copper(I) afkoxide. Interestingly, only a trace of product was observed in the absence of hthium... 

Anhydro-5-hydroxy-1,2,3,4-oxatriazolium hydroxides (4) are relatively stable at elevated temperatures under neutral and salt-free conditions. However, prolonged heating of (17) in the presence of lithium chloride gives rise to elimination of carbon dioxide with formation of an azide which can be trapped by 1,3-dipolar cycloaddition to an alkyne (Scheme 2) <68CB536>. 

The thus-formed peroxide then adds to the end of the eneone. Ozonization of the terminal olefin then leads to the aldehyde (63-5). The newly formed carbonyl group is then reacted with the ylide from phosphonium salt (63-6) under salt-free conditions. This results in the addition of the f7W-trifluoromethylbenzyl moiety with cis geometry about the double bond. There is thus obtained arteflene (63-7) [72]. 

The overall sequence of three steps may be called the Wittig reaction, or only the final step. Phosphonium salts are also prepared by addition of phosphines to Michael olefins (like 5-7) and in other ways. The phosphonium salts are most often converted to the ylides by treatment with a strong base such as butyllithium, sodium amide,640 sodium hydride, or a sodium alkoxide, though weaker bases can be used if the salt is acidic enough. For (PhjP CHj, sodium carbonate is a strong enough base.641 When the base used does not contain lithium, the ylide is said to be prepared under "salt-free conditions.642... 

Sulphur ylids also react with acyl silanes by two different, competing pathways, to give either silyl enol ethers, formed under salt-free conditions, or /1-ketosilanes, formed in the presence of soluble inorganic salts (Scheme 76)186. 

In contrast, the nonstabilized ylids (C6H5)3P=CH2 and (C6H3)3P=C(CH3)2 and even the moderately stabilized ylid (C6H5)3P=CHC6H5 react preferentially with the foemyl group of 2, even under salt-free conditions.4 Inverse addition is desirable to avoid presence of excess ylid. 

Under salt-free conditions, the cw-oxaphosphetanes formed from nonstabilized ylides can be kept from participating in the stereochemical drift and left intact until they decompose to give the alkene in the terminating step. This alkene is then a pure ci.s-isomer. In other words, salt-free Wittig reactions of nonstabilized ylides represent a stereoselective synthesis of cis-alkenes. 

Fig. 11.4. Optimum cis-selec-tivities of Wittig olefinations of different aldehydes with nonstabilized ylides under "salt-free" conditions.

A different reaction mode of lithiobetaines is used in the Schlosser variant of the Wittig reaction. Here, too, one starts from a nonstabilized ylide and works under non-salt-free conditions. However, the Schlosser variant is an olefination which gives a pure frans-alkene rather than a trans.cis mixture. The experimental procedure looks like magic at first ... 

Currently accepted mechanism of the Wittig reaction of aldehydes with non-stabilized ylides involves the formation of oxaphosphetanes through a [2-I-2]-cycloaddition-like reaction . The oxaphosphetanes are thermally unstable and collapse to alkene and phosphine oxide below room temperature. Under salt-free conditions there is no formation of betaine intermediates. The salt-free ylides can be prepared by the reaction of phosphines with carbenes generated in situ. Vedejs etal proposed a puckered 4-centre cyclic transition state I for sy -oxaphosphetane and planar structure J for anff-oxaphosphetane. In general, the flnfi-oxaphosphetane J is more stable than the syn-oxaphosphetane I, and under equilibrium conditions (when stabilized ylides are used) the E-alkene product is favoured (Scheme 4.24). However, kinetic control conditions, which appear to dominate when non-stabilized ylides are used, would lead to Z-alkene. 

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