Titanium homoenolates reactions

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

An exothermic reaction between cyclopropane 1 and TiCl in methylene chloride produces a wine-red solution of a mixture of titanium homoenolate 2 and chlorotrimethylsilane [10, 19]. When the reaction is performed in hexane, the titanium species precipitates in the form of fine violet needles (approx 90% isolated yield, Eq. (9)). 

The chemical reactivities of such titanium homoenolates are similar to those of ordinary titanium alkyls (Scheme 2). Oxidation of the metal-carbon bond with bromine or oxygen occurs readily. Transmetalations with other metal halides such as SnCl4, SbClj, TeCl4, and NbCls proceed cleanly. Reaction with benzaldehyde gives a 4-chloroester as the result of carbon-carbon bond formation followed by chlorination [9]. Acetone forms an addition complex. No reaction takes place with acid chloride and tm-alkyl chlorides. 

The cyclopropane 1 reacts with none of the group 1 and 2 metal chlorides. Among early transition metal chlorides, NbCl reacted with i in moderate yield to give the same homoenolate obtained by the reaction of equimolar amounts of titanium homoenolate 2 and NbCl (Scheme 2). TaCl5, CrCl3, MoCls, and WC15 did not give any characterizable products. 

Two groups independently reported the formation of titanium homoenolates by the transmetalation reaction of 3-stannyl-propionate esters with TiCl, Eq. (48) [45, 46]. Amide homoenolates become available along this route [47], The trichlorotitanium species thus obtained have been shown ( H NMR) to be similar to that generated along the siloxycyclopropane route and indeed exhibit very similar reactivities. This method does provide a conventient alternative to the siloxycyclopropane route. 

The reaction of 1-isopropoxy-l-trimethylsiloxycyclopropane (1, R = i-Pr) with TiCl yields the titanium homoenolate of isopropyl propionate 2 (R = i-Pr) and Me3SiCl (Eq. see 9). That of 23, in contrast, yields a considerable fraction of the homoenolate of silyl propionate as well, Eq. (66) [19]. Apparently, the loss of an isopropyl group from an oxygen-stabilized cationic intermediate competes with that of the silyl group with bulky substituents. 

Ring-opening reactions of cyclopropanone hemiketals are well known. Under appropriate conditions, cleavage of trimethylsilyl protected hemiketals can provide a synthetically useful route to homoenolate anions as noted earlier (Scheme 20). The reaction of an isopropoxy-titanium homoenolate (128) derived from 127 with an aldehyde has recently been used as the key step in the stereocontrolled construction of the steroidal side-chain of depresosterol (Scheme 49) ... 

TMS-Cl or TMS-I, formed in situ, worics as the promoter in addition reactions of zinc homoenolates ((3-metallocarbonyl compounds), generated from 1-alkoxy-l-siloxycyclopropanes and ZnXz (equation 7). No reaction t es place with the purified zinc homoenolates. In contrast, titanium homoenolates are reactive enough to add to aldehydes in the absence of the Lewis acid promoter.Related reactions of zinc esters with aldehydes in the presence of (lVO)3TiCl have been reported (equation 8). ... 

Ester homoenolates can be made from 3-chloroesters 20 with sodium in the presence of Me3SiCl which traps them as the cyclopropyl silyl ethers4 21, analogues of silyl enol ethers, in a step reminiscent of the acyloin condensation.5 Reaction with aldehydes and ketones again gives y-lactones 19 and Kuwajima has shown that the titanium homoenolate 22 is a true intermediate in this reaction.6... 

The reaction of the siloxycyclopropane with titanium(IV) chloride produces the titanium homoenolate (3-titaniopropionate) in good yield this, however, is relatively unreactive (eq 2). Addition of one equivalent of Ti(OR )4 generates a more reactive RTiChOR species, which smoothly reacts with carbonyl compounds below room temperature. The y-hydroxy ester adducts are useful synthetic intermediates and serve as precursors to y-lactones and cyclopropanecarboxylates. A useful variation involves the use of the cyclopropanecarboxylate ester as a functionalized homoenolate precursor to obtain levulinic acid derivatives (eq 3). ... 

Homoenolate Reactivity. Since the previous e-EROS report, a number of examples have been described using the cyclopropanone acetals. Thus, the zinc homoenolate, known to undergo a highly regioselective and stereoselective Sn2 allylation reaction (eq 6), is used in the synthesis of moenomycin analogues. The activated titanium homoenolate reacts with aldehydes or ketones to give y-hydroxy esters that serve as precursors to y-lactones. ... 

An alternative formation of titanated alkoxyallenes could be achieved by reaction of 3-alkoxy-2-propyn-l-yl carbonates 78 with (r/2-propene)titanium diisopropoxylate (79). Successive addition of 80 to benzaldehyde afforded the corresponding addition products 81 in high yield (Scheme 8.22) [70]. The results demonstrate that titanium species 75 and 80 can serve as easily available ester homoenolate equivalents. Notably, conversion of lithiated alkoxyallenes to the magnesium species by treatment with MgBr2 followed by addition to chiral carbonyl compounds resulted in a mixture of a- and y-products [71]. 

These alkoxytitanium homoenolates show high propensity for equatorial attack in their ir reactions with substituted cyclohexanones (Table 6). The basic trend of their chemical behavior is similar to that of simple titanium alkyls [35]. Chemo-selectivity of the reagent 19 is also noteworthy. The alkoxytitanium homoenolate reacts preferentially with an aldehyde even in the presence of a ketone Eq. (32). A notable difference of rate between the reaction with cyclohexanone and that with 2-methylcyclohexanone was also observed, the latter being far less reactive toward the homoenolate. 

Selective transfer of the homoenolate moiety characterizes the transmetalation from tin to titanium described in the previous section. A very facile transmetalation of the same kind occurs for 3-stannylketoxime, Eq. (50) [48]. Reaction of the ( )- 3-(tributyltin)ketoxime with dichlorobis(benzonitrile)palladium in CH2C12 at 0 °C for 30 min yields 78% of the transmetalation product. The... 

In place of a Grignard reagent, several homoenolate equivalents have also been employed. Kempt 1 7 reported the titanium-mediated addition of /V-alkylmethylacrylamide dianions to N-protected a-amino aldehydes (Scheme 8). Pyrolytic cyclization affords a 3-methylenetetrahydrofuran-2-one and the side chain of C3 is appended via conjugate addition. The resulting lactone can be converted into the 1-hydroxyethylene dipeptide by hydrolysis. The stereochemistry of the C6 atom is the same as that of the a-amino aldehyde. However, the stereoselectivities of the reactions regarding the C3 and C5 atoms are unsatisfactory. 

Addition of a homoenolate to a carbonyl compound, which may be called a homoaldol reaction , provides a straightforward route to 4-hydroxy esters and y-lactones. Only two classes of well-characterized homoenolates that undergo nucleophilic addition to carbonyl compounds are known, namely titanium and zinc homoenolates of esters. 

Baker described the transmetalation of 4,5-diphenyl-2-[2-(trimethylstannyl) ethyl]oxazole 962 with titanium tetrachloride in anticipation that it could function as a homoenolate equivalent. Reaction of 231a with LDA followed by alkylation with (iodomethyl)trimethyltin gave 962 in very good yield. Treatment of 962 with TiCU in the presence of benzaldehyde afforded a,4,5-triphenyl-2-oxazolepropanol 963 in 80% yield (Scheme 1.258). 

Terminal epoxides react slowly with sulfonyl carbanions such as the homoenolate equivalent (1) (eq 4). With disubstituted epoxides and cyclic epoxides the reactions are slower still. For example, reaction of the lithio derivative of ethyl phenyl sulfone with cyclopentene oxide occurs in excellent yield (98%) after 10 h reflux in toluene. It has been reported that, in some cases, the addition of a Lewis acid (magnesium bromide, boron trifluoride etherate, 4 titanium tetraisopropoxide, MeOAl(i-Bu)2 ) or HMPA iirproves the yield dramatically. 

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