Petasis methylenation

Not surprisingly, an attempt at direct Mitsunobu inversion of (3-hydroxyketone 14 led only to elimination, yielding the corresponding a,(3-unsaturated ketone. To circumvent this problem, 14 was converted to homoallylic alcohol 15 by Petasis methylenation via the corresponding TES ether. Attempts to methylenate (3-hydroxyketone 14 directly under Petasis conditions led to substantial decomposition via elimination and retro-aldol pathways. Alcohol 15 underwent smooth Mitsunobu inversion to give, following methanolysis and TES ether formation, the desired 1,4-anti compound 16 (Scheme 3). This was then converted in three straightforward steps to aldehyde 17, ready for the proposed aldol union with ketone 10. 

The common element between Tebbe and Petasis methylenation is that both share the same reactive intermediate, titanocene methylidene 5, in the reaction pathway. Hughes has provided a strong evidence that the Petasis reaction proceeds by the rate-determining generation of titanocene methylidene 5 via an a-elimination to remove of methane, followed by a rapid reaction with the carbonyl compound. ... 

Scheme 6.77 (a) Methylenation of ketones with the Petasis reagent,... 

Petasis, et al. have discovered that dimethyltitanocene is an excellent substitute for the Tebbe reagent" for the methylenation of heteroatom-substituted carbonyl compounds. ... 

Scheme 3. Carbonyl methylenation with the titanium-methylene species 4 prepared from the Tebbe, Grubbs, or Petasis reagents (1 - 3).

The Petasis reagent, dimethyl titanocene (4.93) can also be used for the methylenation of carbonyl compounds. The Petasis reagent (4.93) is prepared by the reaction of methyl magnesium chloride or methyllithium with titanocene dichloride (Cp2TiCl2). Carbonyl compounds on heating with 4.93 at 60-65° C in a toluene solution give the corresponding alkenes or enol ethers. 

Tebbe, Petasis and Alternative Alkenylations Methylene-de-oxo-bisubstitution... 

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. 

Petasis, N. A., Lu, S.-P. Methylenations of heteroatom-substituted carbonyls with dimethyl titanocene. Tetrahedron Lett. 1995, 36, 2393-2396. 

Petasis and co-worker reported that methylenation of selenol and thio esters with dimethyl titanocene led to the formation of the corresponding vinyl se-lenides and sulfides (Eq. 58) [111]. Dimethyl titanocene can be easily prepared from titanocene dichloride and methyllithium [112]. The methylenation reactions involve simply heating a mixture of dimethyl titanocene and chalcogeno esters at 60-75 °C. 

Smith utilized Petasis-Ferrier rearrangement [17] in the total syntheses of zampanoUde (Sect. 3.2.1) and phorboxazole [18,19]. The l,3-dioxan-4-ones 11 are transformed into 4-methylene-1,3-dioxanes 12, which are treated with Lewis acids to give oxonium intermediates 13. like the Prins reaction described above, the cfs-2,6-disubstituted tetrahydropyran-3-ones 14 are preferentially synthesized via the C - C bond formation (Scheme 5). 

Table 2.1 lists some of the mechanistic studies of organic and organometallic reactions reported in the literature by ESI-MS. All sorts of reactions have been successfully explored in the gas phase, such as the Baylis-Hillman reaction [211-213], C-H or N-H activation [214—219], cydopropanation reaction [220], Diels-Alder reactions [221], displacement reactions [222], electrophilic fluorination [223, 224], Fischer indole synthesis [225], Gilman reaction [226, 227], Grubbs metathesis reaction [228-231], Heck reaction [194], methylenation [232], oxidation [233, 234], Petasis olefination reaction [235], Raney Nickel-catalyzed coupling [236], ruthenium... 

Grigg and co-workers have used a sequential, one-pot Petasis borono-Mannich reaction with either Pd(0)-catalyzed carbonylative amination cyclization or Pd(0)-cat-alyzed allenylation/amination cyclization (Scheme 7.7) [46]. The overall approach results in the formation of a-amino acid derivatives of isoindolone 25 and 4-methylene-3,4 -dihydroisoquinoline 26. While this is the only reported example of a combination of a Petasis borono-Mannich reaction with a Pd(0)using other Pd(0) or transition metal catalyzed reactions is a very attractive strategy for the synthesis of complex molecules or combinatorial libraries. 

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]. 

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]. 

The a,P-unsaturated esters 12 and 14, spirobislactone 16, and vinylogous lactone 18 are smoothly methylenated by Petasis reagent. Silyl esters 22 and 24 are converted to silyl enol ethers 23 and 25. Carbonate 20 can be methylenated to give ketene acetal 21. Amide 26 and lactams can be methylenated, however the reaction is generally sluggish and the complete separation of Ti species is usually difficult. In a similar manner, thioester 28 and selenoester 30 are converted to alkenyl sulphide 29 and alkenyl selenide 31, respectively. Additionally it has been demonstrated that acyl silanes can be converted to the corresponding alkenyl silanes. 

An elegant example of the preparation, storage, and use of the Petasis reagent for methylenation in multikilogram scale (250 kg, 474 mole) was provided by Payack and co-workers at Merck Process Chemistry Department in 2004. The Petasis reagent should be stored refrigerated as a solution (in... 

The Petasis reagent has been demonstrated to methylenate base-sensitive substrates without epimerization of sensitive stereoeenters. For example the easily enolizable cyclopentanones 73 and 75 were converted to alkenes 74 and 76 in 77% and 81% isolated yield respectively... 

Methylenation of tertiary amides utilizing Petasis reagent, including A -acyl heterocycles, gives enamines. From the corresponding a-lactam 92, and P-lactams 89, methyleneaziridine 93 and methylenetidine 91 were synthesized via Petasis olefination. ... 

Petasis reagent was also effective for the methylenation of aldonolactones, 96" and 98."" Petasis olefmation of unsymmetrical oxalates and oxalate monoesters or monoamides 100 under microwave-assisted, provides pyruvate-based enol ethers and enamines 101 in higher yields... 

Depending on the number of equivalents of Petasis reagent used, anhydrides, as well as thioanhydrides and imides can be methylenated one or both carbonyl groups. In the case of cyclic substarates, the bis-methylenation provides a novel method for accessing functionalized fiirans or thiophenes, such as 104 via subsequent isomerization of the newly generated olefin. ... 

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