Chemoselective Deprotonations

Since the Ireland-Claisen rearrangement typically begins with deprotonation of an allyhc ester, the scope of the reaction is potentially Hmited by the presence of other acidic protons in the molecule. Several examples of selective deprotonation of esters in the presence of other carbon acids have been reported. 

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Aldol addition of aliphatic aldehydes to 105 [50] yielded the expected syn-aldol adducts 106, which spontaneously lactonized upon warming to 0 °C to give the y-butyrolactones 107 in good yields and excellent optical purities. The chemoselective deprotonation of 105 in a-position to the im-... 

The iodination of pyridine, quinoline, and isoquinoline via a-metalation using lithium di-fert-butyltetramethylpi-peridinozincate (TMP-zincate) proceeds smoothly at room temperature using iodine as the electrophile. The chemoselective deprotonative zincation generated 2-iodopyridine 70 and 1-iodoisoquinoline 71 in 76% and 93% yield, respectively. Quinoline metalated preferentially at the 8-position to give 61% yield of the 8-iodo derivative 72 and 26% yield of 2-iodoisoquinoline 73 (Equations 25-27) <1999JA3539>. 

Paterson and Hulme used a chemoselective deprotonation of a ketoester to generate a silyl ketene acetal in a Claisen approach to (-)-ebelactones A and B (Scheme 4.120) [49]. The reaction of the T-silyl ketene acetal proceeded via the expected chair transition state to afford the pentenoate ester with very high dia-stereoselectivity. 

The sulfone moiety was reductively removed and the TBS ether was cleaved chemoselectively in the presence of a TPS ether to afford a primary alcohol (Scheme 13). The alcohol was transformed into the corresponding bromide that served as alkylating agent for the deprotonated ethyl 2-(di-ethylphosphono)propionate. Bromination and phosphonate alkylation were performed in a one-pot procedure [33]. The TPS protecting group was removed and the alcohol was then oxidized to afford the aldehyde 68 [42]. An intramolecular HWE reaction under Masamune-Roush conditions provided a macrocycle as a mixture of double bond isomers [43]. The ElZ isomers were separated after the reduction of the a, -unsaturated ester to the allylic alcohol 84. Deprotection of the tertiary alcohol and protection of the prima-... 

The RLi homochiral ligand complexes are seldom used for the base-promoted isomerization of oxiranes into allylic alcohols because their poor chemoselectivity lead to complex mixtures of products. As examples, the treatment of cyclohexene oxide by a 1 1 i-BuLi/(—)-sparteine mixture in ether at low temperature provides a mixture of three different products arising respectively from -deprotonation (75), a-deprotonation (76) and nucleophilic addition (77) (Scheme 32) . When exposed to similar conditions, the disubstituted cyclooctene oxide 78 affords a nearly 1 1 mixture of a- and -deprotonation products (79 and 80) with moderate ee (Scheme 32, entry 1). Further studies have demonstrated that the a//3 ratio depends strongly on the type of ligand used (Scheme 32, entry 1 vs. entry 2) . ... 

The oxidation of sulfides to sulfoxides (1 eq. of oxidant) and sulfones (2 eq. of oxidant) is possible in the absence of a catalyst by employing the perhydrate prepared from hexafluoroacetone or 2-hydroperoxy-l,l,l-trifluoropropan-2-ol as reported by Ganeshpure and Adam (Scheme 99 f°. The reaction is highly chemoselective and sulfoxidation occurs in the presence of double bonds and amine functions, which were not oxidized. With one equivalent of the a-hydroxyhydroperoxide, diphenyl sulfide was selectively transformed to the sulfoxide in quantitative yield and with two equivalents of oxidant the corresponding sulfone was quantitatively obtained. 2-Hydroperoxy-l,l,l-fluoropropan-2-ol as an electrophilic oxidant oxidizes thianthrene-5-oxide almost exclusively to the corresponding cw-disulfoxide, although low conversions were observed (15%) (Scheme 99). Deprotonation of this oxidant with sodium carbonate in methanol leads to a peroxo anion, which is a nucleophilic oxidant and oxidizes thianthrene-5-oxide preferentially to the sulfone. 

Iron acyl complexes bearing an a,/ -unsaturated acyl ligand possess multiple sites of electrophilic reactivity. Strong bases may be induced to react with the acyl ligand, and in Section 1.1.1.3.4.1.1. the chemoselective y-deprotonation of Z-a,/i-unsaturated acyl ligands to generate enolate species was addressed. The profoundly different reactivity of the unsubstituted complex 1 and E-a,/ -unsaturated acyl complexes, such as 2, is discussed here. 

However, the more hindered, less basic lithium hexamethyldisilazamide reacts slowly with 1 at 0 °C to provide chemoselectively the desired enolate species 5. The a-protons of these rhenium-acyl complexes are believed to have a lower pKa than the cyclopentadienyl protons, but unless treated with hulky, selective hases the cyclopentadienyl protons exhibit greater kinetic acidity due to statistical factors and an earlier, reactant-like transition state since minimal rchybridiza-tion is required at the anionic center after cyclopentadienyl deprotonation. Equilibration of the cyclopentadienyl anion to the thermodynamically more stable enolate species cannot compete with the rapid acyl migration84. 

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Fig. 6.45. Chemoselective acylation of organolithium compounds with lithium-carboxylates (A). In order to generate the substrates the choice is between the deprotonation of the corresponding carboxylic acid and the addition of an organolithium compound to carbon dioxide, i.e. via C,C bond formation.

In the reaction of Figure 12.19, the alkoxide formed in this step deprotonates a carboxylic acid (cis-1 —> K), whereas in Figure 12.18 an iminium ion is deprotonated (B — C). Accordingly, different chemoselectivities are observed Figure 12.19 shows an enamine-mediated aldol addition, and Figure 12.18 presents an enamine-mediated aldol condensation. Hydrolysis of the iminium ion K in Figure 12.19 leads to the formation of the aldol addition products B and the amine which, together with the still unconsumed substrate A, forms the new enam-ine C, to start the catalytic cycle anew. 

Table 13.4 also shows that the deprotonation of isopropanol with LiHMDS is less than half as exothermic as the deprotonations with LDA or LTMP. Hence, LiHMDS is a much weaker base than the other two amides. This is due to the ability of the SiMe3 groups of LiHMDS to stabilize the negative charge in the a-position at the N atom. The mechanism of this stabilization might be the same as in the case of the isoelectronic triphenylphosphonium center in P ylides (Figure 11.1), that is, a combination of an inductive effect and anomeric effect. Because of its relatively low basicity, LiHMDS is employed for the preparation of enolates primarily when it is important to achieve high chemoselectivity. 

The aldimine of Figure 13.34 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde to be alkylated, and an enantiomerically pure hydrazine A, the S-proline derivative iS-aminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 13.34 is the Enders SAMP alkylation. The reaction of the aldehydrazone C with LDA results in the chemoselective formation of an azaenolate D, as in the case of the analogous aldimine A of Figure 13.33. The C=C double bond of the azaenolate D is fraws-configured. This selectivity is reminiscent of the -preference in the deprotonation of sterically unhindered aliphatic ketones to ketone enolates and, in fact, the origin is the same both deprotonations occur via six-membered ring transition states with chair conformations. The transition state structure with the least steric interactions is preferred in both cases. It is the one that features the C atom in the /3-position of the C,H acid in the pseudo-equatorial orientation. 

The converse of this idea is central to a useful bit of chemoselectivity that can be obtained in the reactions of dianions. 1-Propynol can be deprotonated twice by strong bases—first, at the hydroxyl group to make an alkoxide anion (the pIQ of the OH group is about 16) and, secondly, at the alkyne (pKa of the order of 25) to make a reacts with electrophiles it always reacts at the alkynyl anion and not at the alkoxide. 

It was mentioned in the discussion of equation 56 that the presence of certain amines leads to nearly perfect chemoselectivity in the hydrogenation of the C=0 group adjacent to a Mef group. It has also been shown that in solution the amine deprotonates the enol and generates an ammonium cation and an enolate anion. This was modeled by the interaction between the trimethylammonium ion and the enolate derived from 223 in the presence of... 

In an application of (Z)-selective alkene formation to enolizable aldehydes, it was noted that the combination of LiCl and DBU was effective for deprotonation by lithium complexation of the Still phosphonate. In this example, the cyclopropyl aldehyde (176) reacted chemoselectively in the presence of the ketone (equation 43). In addition, the ( )-alkene could be synthesized by lithium coordination with a standard HWE methyl phosphonate. As this example illustrates, the trifluoroethyl phosphonate can fill an important void by providing trisubstituted alkenes with sensitive substrates in go< selectivity. From the examples of Marshall and Oppolzer it appears that the application of the reaction to higher order trisubstituted alkenes is selective for the (Z)-isomer. The magnitude of the selectivity is substrate specific and dependent on the rapid rate of eo firo-a-oxyphosphonate decomposition. 

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