Methylenation with Dimethyltitanocene

Methylenation of ketones and aldehydes Similarly to the Tebbe reagent, dimethyltitanocene 30 is compatible with hydroxyl groups, and its low basicity also ex- 

Entry Carbonyl compound Yield R. Entry Carbonyl compound rield R.  

A valuable application of dimethyltitanocene 30 is in the methylenation of small-ring diones, lactones, and lactams (Table 4.10). Selective monocarbonyl methylenation is achieved when cyclobutenediones having one alkoxy and one C-substituent are treated wdth dimethyltitanocene 30 (entry 1) [75). The methylena- 

Remarkably high selectivity over various functional groups, including ester, carbamate, ketone, and alkene, is observed when yS-lactones are treated with 30 (see entry 2) [76]. Similarly, the reactions of 30 with yS-lactams having an ester or a carbamate moiety proceed with selective methylenation of the lactam carbonyl to afford methyleneazetidines (see entry 4) [77]. It should be noted that the chemo-selectivity of these reactions is not the same as that observed in the methylenation of acyclic or larger ring compounds as described above. 

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Reactions of titanocene-methylidene generated from titanacyclobutanes with acyl chlorides 55 [46] or acid anhydrides 56 [47] lead initially to the titanium enolates 57 (Scheme 14.24), which then afford aldols upon treatment with the carbonyl compounds. On the other hand, five-membered cyclic anhydrides are methylenated with dimethyltitanocene (Table 14.5, entry 7) [45]. 

An inseparable mixture of 51 and 54 (3 2 ratio) was methylenated with dimethyltitanocene reagent to furnish enol ethers 52 and 55 in 90% yield (Scheme 3.1.4). Thermal rearrangement of the mixture in a sealed tube produced the desired cyclooctenone 53 and the isomeric 6-5 system 58. The Claisen rearrangement of 52 proceeded with high stereoselectivity. The formation of 58 is a result of the partial isomerization of 52 to 57 followed by an alternative Claisen rearrangement Another product obtained was the enol ether 56, formed by the isomerization of 55. It was too hindered to perform the Claisen rearrangement of 55 and 56. Molecular models indicated that the chairtransition state R should be more favored over the chair-boat transition state [50]. 

As shown in Scheme 4.28, the stereocontrolled transformation of l,3-dioxolan-4-ones into substituted tetrahydrofurans involves initial methylenation with dimethyltitanocene 30, subsequent aluminum-mediated rearrangement of the cyclic... 

The mechanism of carbonyl methylenation with dimethyltitanocene 30 is one of the major subjects of discussion in titanium-carbene chemistry. Two reaction pathways have been proposed. Based on the observation of H/D scrambling in reactions using a deuterated ester and Cp2Ti(CD3)2, Petasis proposed that the reaction proceeds by methyl transfer to form the adduct 31 and subsequent elimination of methane and titanocene oxide (Scheme 4.29, Path A) [64]. Later, a detailed study by Hughes and co-workers using and D-labeled compounds showed that the methylenation of esters with 30 proceeds via a titanium carbene mechanism (Path B) [82]. 

Scheme 4.29. Plausible mechanisms for carbonyl methylenation with dimethyltitanocene.

In this reaction, acetals are used as dication equivalent of one-carbon unit 72, whereas 71 provides a dianion 73 <95TL5581>. A new stereocontrolled synthesis of substituted tetrahydrofiirans starts with dioxalones 74. A titanium-mediated methylenation using dimethyltitanocene (THF, 60 C) with subsequent treatment of 75 with trialkylaluminium reagents results in the formation of tetrahydrofiirans 76 <95JA6394>. 

Petasis, N. A., Bzowej, E. I. Titanium-mediated carbonyl olefinations. 1. Methylenations of carbonyl compounds with dimethyltitanocene. J. Am. Chem. Soc. 1990,112, 6392-6394. 

Moreover, the methylenation of lactones 210 with dimethyltitanocene was examined to synthesize 3-alkylidene-2-methyleneoxetanes 212. The yields of 212 depended strongly on the steric hindrance at C4. Bulkier substituents at C4 led to higher yields, and up to 75% yield was acquired with lactones 210d. Preliminary investigations of the reactivity of these unusual, strained hetero-cycUc compounds have been carried out. Using 212a as a model substrate, several potential applications of such 3-alkylidene-2-methyleneoxetanes as synthetic scaffolds were demonstrated (Scheme 4.64). 

A variety of carbonyl compounds, including esters, lactones, amides, and anhydrides, are methylenated upon heating with dimethyltitanocene 30 at 60-80 °C (Scheme 4.23). Generally, at least two equivalents of dimethyltitanocene are required for complete conversion. 

Tab. 4.9. Methylenation of carboxylic acid derivatives with dimethyltitanocene 30.

Tab. 4.10. Methylenation of small-ring carbonyl compounds with dimethyltitanocene 30.

Petasis and co-workers extended the above methylenation procedure to the alkylidenation of carbonyl compounds by using dialkyltitanocenes [lie, 62]. Like methylidenation with dimethyltitanocene, the Petasis alkylidenation is believed to proceed via the formation of titanocene-alkylidenes through a-elimination of dialkyltitanocenes. This assumption is supported by the isolation of the cy-clometalated product 32, which is indicative of the intermediary formation of titanocene-benzylidene 34 by thermolysis of dibenzyltitanocene 33 bearing a tert-butyl group on the Cp ring (Scheme 4.30) [83]. 

Methylenation of carboxylic acid derivatives A variety of carboxylic acid derivatives can be transformed into heteroatom-substituted olefins (Table 4.9). The C-glycoside congeners are easily prepared by the direct methylenation of aldono-lactones with 30 (entry 2) [67]. Since the generation of titanocene-methylidene 4 from 30 only produces methane as a by-product, 30 can be employed for the olefination of acid-sensitive substrates such as silyl esters and acylsilanes (entries 4 and 6). The tolerance toward acid-sensitive functional groups also allowed the application of dimethyltitanocene 30 in the conversion of a lactone bearing an acetal moiety into the corresponding cyclic vinyl ether, which was further transformed into the spiroketal ketone upon oxidation and rearrangement (Scheme 4.24) [69]. 

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