Betaine equilibration

Stabilized sulfonium ylides react with cyclopentenone to give the corresponding cyclopropane with high diastereoselectivity as a result of base- or ylide-mediated (g) equilibration of the intermediate betaine.38 When using chiral sulfonium ylides, betaine equilibration compromises enantioselectivity, because whereas one diastereomer ring closes rapidly, the other diastereomer undergoes epimerization at the ester stereocentre, ultimately leading to the opposite enantiomer of the cyclopropane. 

Methods A, D, and E suffer from the inherent limitation that they deliberately generate a betaine as the precursor of the oxaphosphetane. Since there is no assurance that the reaction of an ylide with an aldehyde would involve the same ionic intermediate (19,21) these control experiments may provide opportunities for stereochemical equilibration that may not be available to the corresponding Wittig reactions. If the oxaphosphetane generated by methods A or E is stable enough to observe directly, then it is usually possible to distinguish between oxaphosphetane equilibration, betaine equilibration, and other mechanisms for loss of stereochemistry (21 c). However, this is not possible for oxaphosphetanes that contain unsaturated substituents at Cj because oxaphosphetane decomposition is fast at — 78°C (21c). In these examples, method A (like method D or E) can only establish an upper limit for equilibration of all of the conceivable intermediates betaines, betaine lithium halide adducts, oxaphosphetanes, and so on. 

A variety of anionic ylides reacts with high E selectivity with the reversal-prone aromatic aldehydes. On the other hand, aliphatic aldehyde adducts are more resistant to Li -induced betaine equilibration. The y-oxido ylides appear to have the optimal substitution pattern for betaine reversal, and these reagents afford useful ( )-alkene selectivity with aliphatic as well as aromatic aldehydes, results that are tabulated later. Only the aromatic aldehyde example (Table 7, entry 4) has been studied in depth, but it seems safe to conclude that all of the E-selective y-oxido ylide reactions are dominated by betaine reversal (23b). Other anionic ylides react with aliphatic aldehydes to give lower, less predictable ( )-alkene selectivity (for example. Table 7, entry 5 42 58 Z E). 

Fig. 3. Equilibration of meso-ionic isomers in protic solvents (e.g., EtOH) involving a betaine intermediate.

Ring closure after rotation of the bonds of the open chain betaine can lead to stereoisomers (71JA4004). Two examples are shown in Scheme 28. 31P NMR shifts are useful for the identification of the different species. In the case of (178) and (179), prepared by the reaction of benzil with trisdimethylaminophosphine, two crystalline forms were isolated. They equilibrate in solution. 

In aqueous solution 3-hydroxypyridine 176 equilibrates with the mesomeric betaine 177a for which no uncharged structure can be written. Since these pyridinium-3-olates 177a undergo 1,3-dipolar cycloadditions, it is reasonable to assume that there is also a contribution of the one form 177b to the overall structure. 

The normal preference for (Z) alkenes in reactions of non-stabilized phos-phoranes can be reversed by employing the Schlosser modification of the Wittig reaction (Scheme 6).19 Here, equilibration of the initially formed erythro and threo betaine intermediates is achieved by reaction with additional strong base, usually an alkyl lithium. The resulting betaine ylide then gives the (E) alkene on treatment with a proton source followed by potassium tert-butoxide. 

When a 1,2-diol reacts with DTPP, the replacement of two equivalents of ethanol by bis(transoxyphosphoranylation) of the diol is rapid at ambient temperature affording dioxaphosphoranes B (79). Assuming that Berry polytopal isomerization of dioxaphosphoranes B as well as equilibration with the regioisomeric oxyphosphonium betaines C are also facile (79), the chain closure to the cyclic ether by intramolecular displacement (i.e., 3-exo-tet) 20) of TPPO from betaines C is expected to be ratelimiting (Scheme 1). 

Figure 2 illustrates several reaction coordinate diagrams that allow exothermic oxaphosphetane formation. Option a (four-center process) and the kinetically equivalent b (transient betaine precursor of the oxaphosphetane two-step mechanism) are consistent with the observation that oxaphosphetanes are formed rapidly and decompose slowly when R = alkyl. Since the barrier AGjJgc decomposition to the alkene is smaller than AGJ y, there will be little reversal or loss of stereochemistry in option a. Reversal should become less likely if the a-substituent R is unsaturated (CH=CH2 or aryl), a situation that would decrease AG g by weakening the P—Cj bond (reaction profile c). If substituents are present that retard the rate of decomposition relative to reversal (as in options d or e), then oxaphosphetane reversal and equilibration of stereochemistry become possible, as discussed in a later section. However, this behavior has not been demonstrated for members of the Ph3P=CHR ylide family in the absence of lithium salts. 

The last item (S) may explain why the independent betaine generation control experiments gave contradictory results. If betaines are high-energy species that lie above the saddle point leading from the ylide to the oxaphosphetane, then experiments that deliberately generate betaines (Schemes 3-5) may encounter pathways for stereochemical equilibration that are not accessible to typical Wittig reactions. 

Subset 2. Equilibration In Experiments that Access Oxaphoshetanes via Deliberate Generation of Betaines. 

Tables 6 and 7 summarize results from stereochemical equilibration studies performed over the past decade by MaryanofT et al. (22,23), and Vedejs et al. (20, 21c, 39-42). A few other convincing examples are included to expand the scope of the systems covered. Table 6 lists those examples where control experiments establish at least 90% retention of stereochemistry from intermediates-to alkene products. As already discussed, the percentage of equilibration represents the upper limit for loss of stereochemistry from all possible pathways in the control experiments. No attempt has been made to determine whether the minor levels of stereochemical leakage in Table 6 occur at the stage of oxaphosphetanes, betaines, or other potential intermediates. Table 6 includes entries corresponding to all of the principal families of Wittig reagents nonstabilized ylides (entries 1-12, 24, 25, 29, and 30), benzylic ylides (entries 13-17 and 28), allylic ylides (entries 22, 23, 26, and 27), and ester-stabilized ylides (entries 18-21). The corresponding Wittig reactions must take place under dominant kinetic control.

There are also some examples where significant reversal and stereochemical equilibration of intermediates has been demonstrated in aldehyde Wittig reactions (Table 7, subset 1). Several additional examples of reversal from betaine generation experiments may also be relevant, depending on whether the same betaines play any role in the Wittig process (Table 7, subset 2). The following generalizations follow from the comparison of Tables 6 and 7. 

By the same logic, it is unlikely that the stabilized ylide reactions can be influenced by stereochemical equilibration. It would be difficult for any equilibration process to compete with the exceptionally rapid oxaphosphetane decomposition step. Partial loss of stereochemistry does occur in some of the high-temperature control experiments at the betaine stage, as listed in Table 7, but oxaphosphetane decomposition takes place with retention of stereochemistry (Table 6, entries 18-21) (21c). 

Thermal Equilibration of Salt-free cis-Disubstituted Oxaphosphetanes. Only three examples of this process are known. The reaction appears to occur spontaneously when certain oxaphosphetanes are warmed to temperatures near the decomposition point. Spontaneous equilibration is restricted to oxaphosphetanes derived from P-trialkyl ylides and aromatic or tertiary aliphatic aldehydes. A catalyzed process via betaine derivatives is not ruled out, but there is no direct evidence to implicate catalysis. 

A fifth category must be mentioned even though it may have no direct relevance to Wittig alkene synthesis. This is the equilibration of anti betaines under lithium-free conditions that was encountered in early attempts to design control experiments [Speziale and Bissing (12) and Trippett and Jones (13)]. As already discussed, strong evidence is now available that the... 

Several puzzling entries in Table 14 remain to be explained, including reactions where hydroxylic solvents or alkoxide bases are used (entries 11-14). Betaine reversal was demonstrated under hydroxylic conditions in the original Trippet-Jones experiment (Scheme 4) (13), and it is conceivable that interconversion between oxaphosphetanes and betaines could be fast enough in hydroxylic solvents to allow significant betaine reversal to the ylide and aldehyde in some cases. However, there is no clear evidence to implicate stereochemical equilibration of benzylide-derived Wittig intermediates in ether solvents. 

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