Aldehydes transmetallation

Allenyl trialkylsilyl ethers 771 can be a-deprotonated with f-BuLi in THF at — 78 °C to give the allenyllithiums 77210901091. They underwent reverse Brook rearrangement to afford the silaacrolein enolates 773, which react with aldehydes and ketones to yield the a,/9-unsaturated acyl silanes 774 (Scheme 200). For enolizable aldehydes transmetallation with ZnCl2-TMEDA, and MgBr2 for ketones, provided better yields. 

Isolated yield. Yields in parentheses are based upon homoenolate, the molarity of which was determined by HPLC, correcting for response factors, Yield based upon aldehyde. Transmetallation with TiCh. Based upon recovered aldehyde. SYield of major isomer only. 

A variety of 1,3-oxazolidines have been used as chiral formyl anion equivalents for addition to aldehydes. Thus, for example, reaction of N-protected norephedrine with Bu3Sn-CH(OEt)2 gives 48, and transmetallation with BuLi followed by addition of benzaldehyde affords the expected adduct 49. The selectivity at the newly formed alcohol center is poor, but the situation can be salvaged by oxidation and re-reduction, which affords the product 50 with >95% d.e. It is then a simple matter to hydrolyze off the oxazolidine, although the resulting hydroxyaldehydes... 

Before Ihe addilion of the aldehyde, the oxiranyllithi-uin reagenl was transmetalated with chloro(triisopro-poxy)litanium. 

The addition of aziridinyl anions to aldehydes gave the alcohols 31 in good yields15. As with the oxiranyl anions, the diastereoselectivity of the addition reaction could be substantially enhanced by transmetalation of the lithium reagent with chlorotris(dimethylamino)titanium. 

However, addition of (+ )-(7 )-l-methyl-4-(mcthylsulfinyl)benzene, to aldehydes and ketones proceeds with low stereoselectivity. An improvement of the 3-syn diaslereoselectivity was found with the zinc reagent obtained by transmetalation of the lithiated sulfoxide with anhydrous zinc chloride38. An improvement of the stereoselectivity was also attained by exchange of the 4-methylphenyl substituent for a 2-methoxyphenyl or 2-pyridinyl substituent. Thus, the introduction of an additional complexing site into the aromatic part of the sulfoxide reagent enhances the stereoselectivity35. 

Dimethylpropanoyl)-l, 2,3,4-tetrahydroisoquinolincs 16 form dipole-stabilized lithium carbanions on deprotonation, but their addition to aldehydes or methyl ketones proceeds nevertheless with low simple diastereoselectivity22 23. However, a high preference for the formation of the w-diastereomer is observed after transmetalation with magnesium bromide22"24. 

Lewis acids, particularly the boron trifluroride diethyl ether complex, are used to promote the reaction between allyl(trialkyl)- and allyl(triaryl)stannanes and aldehydes and ketones52-54. The mechanism of these Lewis acid promoted reactions may involve coordination of the Lewis acid to the carbonyl compound so increasing its reactivity towards nucleophilic attack, or in situ transmetalation of the allyl(trialkyl)stannane by the Lewis acid to generate a more reactive allylmetal reagent. Which pathway operates in any particular case depends on the order of mixing of the reagents, the Lewis acid, temperature, solvent etc.55- 58. 

Transmetalation to give l-methyl-2-propenylaluminum followed by isomerization to 2-butenyl isomers may be involved in reactions between aldehydes and 2-butenyl(tributyl)-stannane induced by aluminum(III) chloride in the presence of one mole equivalent of 2-propanol. Benzaldehyde and reactive, unhindered, aliphatic aldehydes give rise to the formation of linear homoallyl alcohols, whereas branched products are obtained with less reactive, more hindered, aldehydes66,79. 

Very high levels of induced diastereoselectivity are also achieved in the reaction of aldehydes with the titanium enolate of (5)-l-rerr-butyldimethylsiloxy-1-cyclohexyl-2-butanone47. This chiral ketone reagent is deprotonated with lithium diisopropylamide, transmetalated by the addition of triisopropyloxytitunium chloride, and finally added to an aldehyde. High diastereoselectivities are obtained when excess of the titanium reagent (> 2 mol equiv) is used which prevents interference by the lithium salt formed in the transmetalation procedure. Under carefully optimized conditions, diastereomeric ratios of the adducts range from 70 1 to >100 1. 

A more effective control of both simple diastereoselectivity and induced stereoselectivity is provided by the titanium enolate generated in situ by transmetalation of deprotonated 2,6-dimethylphenyl propanoate with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene-a-D-glucofuranos-3-0-yl)titanium. Reaction of this titanium enolate with aldehydes yields predominantly the. yyw-adducts (syn/anti 89 11 to 97 3). The chemical yields of the adducts are 24 87% while the n-u-products have 93 to 98% ee62. 

R)- and (,S )-1.1,2-Triphenyl-l,2-ethancdiol which are reliable and useful chiral auxiliary groups (see Section 1.3.4.2.2.3.) also perform ami-sclcctive aldol additions with remarkable induced stereoselectivity72. The (/7)-diastercomer, readily available from (7 )-methyl mandelate (2-hy-droxy-2-phcnylaeetate) and phenylmagnesium bromide in a 71 % yield, is esterified to give the chiral propanoate which is converted into the O-silyl protected ester by deprotonation, silylation, and subsequent hydrolysis. When the protected ester is deprotonated with lithium cyclohexyliso-propylamide, transmetalated by the addition of dichloro(dicyclopentadienyl)zirconium, and finally reacted with aldehydes, predominantly twm -diastereomers 15 result. For different aldehydes, the ratio of 15 to the total amount of the syn-diastereomers is between 88 12 and 98 2 while the chemical yields are 71 -90%. Furthermore, high induced stereoselectivity is obtained the diastereomeric ratios of ami-15/anti-16 arc between 95 5 and >98 2. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

Transmetalation of lithium enolate 1 a (M = Li ) by treatment with tin(II) chloride at — 42 °C generates the tin enolate that reacts with prostereogenic aldehydes at — 78 °C to preferentially produce the opposite aldol diastereomer 3. Diastereoselectivities of this process may be as high as 97 3. This reaction appears to require less exacting conditions since similar results are obtained if one or two equivalents of tin(ll) chloride arc used. The somewhat less reactive tin enolate requires a temperature of —42 C for the reaction to proceed at an acceptable rate. The steric requirements of the tin chloride counterion are probably less than those of the diethyla-luminum ion (vide supra), which has led to the suggestion26 44 that the chair-like transition state I is preferentially adopted26 44. This is consistent with the observed diastereoselective production of aldol product 3, which is of opposite configuration at the / -carbon to the major product obtained from aluminum enolates. 

Reaction of the lithium enolate 2 with prochiral aldehydes at low temperature proceeds with little selectivity, producing all four possible diastereomers 3, 4, 5, and 6 in similar amounts50. Transmetalation of the lithium enolate by treatment with three equivalents of diethylaluminum chloride or with one equivalent of copper cyanide generates the corresponding cthylaluminum and copper enolates which react at — 100°C with prochiral aldehydes to produce selectively diastereomers 1 and 2, respectively50. The reactivity of tin enolates of iron- propanoyl complexes has not been described. 

In contrast, transmetalation of the lithium enolate at —40 C by treatment with one equivalent of copper cyanide generated a species 10b (M = Cu ) that reacted with acetaldehyde to selectively provide a 25 75 mixture of diastereomers 11 and 12 (R = CH3) which are separable by chromatography on alumina. Other diastereomers were not observed. Similar transmetalation of 10a (M = Li0) with excess diethylaluminum chloride, followed by reaction with acetaldehyde, produced a mixture of the same two diastereomers, but with a reversed ratio (80 20). Similar results were obtained upon aldol additions to other aldehydes (see the following table)49. 

In contrast to the amt-selective reaction of lithiated imines with aldehydes, titanated imines, prepared by transmetalation of the corresponding lithium azaenolates, give predominantly. sFH-adducts2. 

Finely symmetrical divinyl tellurides 135, especially useful in transmetallation reactions, have been prepared in situ by sequential reaction of an excess of the ylide 134 with TeCl4 and aldehydes (Scheme 36) [134]. These compounds whatever their geometry lead in presence of -BuLi to the formation of -a,/l-unsat-urated aldehydes. 

Scheme 3.62 Zirconocene-ziiic transmetalations and in situ additions to aldehydes in the presence of amino thiol ligand.

The allenic stannanes can be transmetallated by treatment with SnCl4, a reaction that results in the formation of the a propargyl stannane. If the transmetallation reaction is allowed to equilibrate at 0°C, an allenic structure is formed. These reagents add stereospecifically to the aldehyde through cyclic TSs.194... 

The catalytic process is also achieved in the Pd(0)/Cr(II)-mediated coupling of organic halides with aldehydes (Scheme 33) [74], Oxidative addition of a vinyl or aryl halide to a Pd(0) species, followed by transmetallation with a chromium salt and subsequent addition of the resulting organo chromate to an aldehyde, leads to the alcohol 54. The presence of an oxophile [Li(I) salts or MesSiCl] allows the cleavage of the Cr(III) - 0 bond to liberate Cr(III), which is reduced to active Cr(II) on the electrode surface. 

The palladium-catalyzed cross-coupling reaction featured in this procedure occurs under neutral conditions in the presence of many synthetically useful functional groups (e.g. alcohol, ester, nitro, acetal, ketone, and aldehyde). The reaction works best in N,N-dimethylformamide with bis(triphenylphosphine)palladium(ll) chloride, PdCI2(PPh3)2, as the catalyst. Lithium chloride is added to prevent decomposition of the catalyst.143 13 It is presumed that conversion of the intermediate aryl palladium triflate to an aryl palladium chloride is required for the transmetallation step to proceed.9... 

A tandem enolate-arylation-allylic cyclisation, in which an essential z-butyldimethylsilyl ether protecting group delays the cyclisation step until the Pd-catalysed arylation is complete, enables 1-vinyl-l//-[2]benzopyrans 54 to be prepared from 2-bromobenzaldehyde (Scheme 32) <00CC1675>. 4-Substituted isochromans 55 are formed from aldehydes by a Pd-catalysed termolecular queuing cascade. The sequence involves cyclisation of an aryl iodide onto a proximate alkyne followed by an allene insertion. Transmetallation with indium then allows addition to the aldehyde (Scheme 33) . 

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