Desilylation 3 + 2 cycloaddition reactions

Dipolar cycloaddition of 2,4-(trimethylsilyl)- and 2,4-(trimethylgermyl)-substituted thiophene-1,1-dioxides as well as silylated 2,2 -bithiophene-1,1-dioxides was investigated. It was shown that only the C(4)=C(5) double bond of 2,4-disubstituted thiophene-1,1-dioxides interacts with acetonitrile oxide to give thienoisoxazoline dioxides. Bithiophene derivatives were inactive or their reaction with nitrile oxide was accompanied by desilylation. Cycloaddition of benzonitrile oxide with all mentioned sulfones did not occur. The molecular structure of 3a-methyl-5.6a-bis(trimethylgermyl)-3a,6a-dihydrothieno 2.3-c/ isoxazole 4,4-dioxide was established by X-ray diffraction (263). ... 

Cycloadditions. Desilylation of 1 in CH,CN with LiF results in an azomethine ylide (a), which undergoes cycloaddition reactions with dipolarophiles and activated alkenes to give pyrrolidines. 

The addition of simple ester or ketoenolates to TT-allylpalladium complexes may constitute the second step of an ingenious [3 + 2] cycloaddition reaction. One substrate that undergoes this process is 2-(tri-methylsilylmethyl)allyl acetate (5). The mechanism proposed involves initial formation of a 2-(tri-methylsilylmethyl)allylpalladium cation followed by desilylation by the acetate liberated in the oxidative addition (Scheme 1). The dipolar intermediate can be envisioned as an T]3-trimethylenemethane-PdL2 species (6) or, less likely, an -complex (7). 

Triazines are trimers of unstable imines and may serve as imine precursors. Treatment of trimer of A1-pyrrol ine with a trimethylsilylmethyl triflate gives trimethylsilylmethyl-imonium triflate which may be desilylated by cesium fluoride, providing an ylid suitable for 1,3-dipolar cycloaddition reactions and constmction of the hexahydro-pyrrolizine framework.386 This strategy has been applied to prepare trachelanthamidine, supinidine and isoretronecanol alkaloids.387... 

In the presence of two equivalents of silver fluoride, N-protected bis[(trimethylsi-lyl)methyl]amines lead also to azomethine ylids which can be trapped by dipolarophiles. The mechanism of the cycloaddition reaction involves sequential electron-Me3Si+-electron transfer process from the amine to silver fluoride, which forms silver metal, ruling out a fluoride-induced desilylation process. Although silver is recovered at the end of the reaction, a cheaper oxidizing reagent is still lacking.448,449... 

The generation of nonstabilized azomethine ylide 256 via PET-initiated sequential double desilylation and [3 + 2]-cycloaddition reaction with various dipolarophiles to generate five-membered heterocycles 257, has also been established by Pandey et al., as shown in Table 8.5 [110]. 

The acceptor quality of vinyl ketones liberated from methyl 2-alkenyl 2-siloxycyclo-propanecarboxylates can also be used in cycloaddition reactions. Thus y-oxoester 147 adds smoothly to 2-siIoxybutadien 146 affording a cyclohexene derivative which after desilylation gives the tricarbonyl compound 148. This crucial intermediate can be obtained from vinyl cyclopropane 132 as a precursor of 147 in 72 % overall yield 85). Its chemoselective methylation, lactonization, and dehydration make norbisabolid available — a constituent of the root bark of atalantia monophylla. 

The [2 -I- 2] cycloaddition reaction of l-(trimethylsilyloxy)cyclopentene (63) and acet-ylenecarboxylate, in the presence of ZrCU, was accompanied with desilylation to afford bicyclo[3.2.0]heptene carboxylate 64 (Eq. 27) [28],... 

The vinyl and allyl trimethylsilanes obtained in the course of these cycloaddition reactions can be readily desilylated by protolysis, e.g. using excess trifluoroacetic acid (TFA) in di-chloromethane at 0°C. The corresponding desilylated alkenes are formed in high yield along with minor amounts of isomerization products, as exemplified for the isomeric hexahydropcn-talen-l(2//)-one derivatives 14 and 15. The silyl-substituted MCP can thus be employed as a synthetic equivalent for the parent MCP. 

Pyrrolidines from [3+2]cycloaddition. Using BFj OEt2 as catalyst, N-Cbz-a-amino aldehydes react with allyltrimethylsilane stereoselectively to give the N-protected cis, cis-2-alkyl-3-hydroxy-5-trimethylsilylmethylpyrrolidines. Interestingly, similar reactions of 2-chloromethylallyltrimethylsilane with N-Boc amino aldehydes proceed by the desilylative ene reaction pathway... 

Assembly of the lipstatin framework is effectively accomplished by a diastereoselective Lewis acid-promoted [2 + 2] cycloaddition reaction between silylketene 1152 and aldehyde 1151. The reaction occurs between —45 °C and —20 °C to give a 9 1 mixture of 1153 and the corresponding C-4 epimer. After desilylation and column chromatography, esterification with ( S)-A-formylleucine under Mitsunobu conditions furnishes (— )-lipstatin (1144). 

A similar transformation results when trimethylsilyloxy-substituted allylic halides react with silver perchlorate in nitromethane. The resulting allylic cation gives cycloaddition reactions with dienes such as cyclopentadiene. The isolated products result from desilylation of the initial adducts. ... 

The use of Bu2BOTf or AICI3 led to increased yields of the cyclobutane product 2a, but production of the desilylated alcohol 2b was also observed with these catalysts (entries 2 and 3). Broad screening of a number of Lewis acids showed that EtAlCL and TiCL were the optimal catalysts, both serving to promote formation of cycloadduct 2a in 76 and 61% yields, respectively (entries 4 and 5). Diastereoselective formation of 2a occurred in these reactions, as was seen in the stoichiometric reactions reported earlier [10b]. Several Lewis acids, including Et2AlCl, Sn(OTf)2, SnCLt, TMSI, and InCL, were found to catalyze the formation of 2a and/or 2b, but in low yields (not shown in Table 4.1). On the contrary, no cyclobutane product is produced in reactions catalyzed by lanthanide Lewis acids and transition metal Lewis acids starting enol ether 1 or desilylated ketone 3 were recovered in these cases. Thus, these results indicated that EtAlCla is an efficient catalyst for catalytic [2+2] cycloaddition reaction. 

Diene 265, substituted by a bulky silyl ether to prevent cycloaddition before the metathesis process, produced in the presence of catalyst C the undesired furanophane 266 with a (Z) double bond as the sole reaction product in high yield. The same compound was obtained with Schrock s molybdenum catalyst B, while first-generation catalyst A led even under very high dilution only to an isomeric mixture of dimerized products. The (Z)-configured furanophane 266 after desilylation did not, in accordance with earlier observations, produce any TADA product. On the other hand, dienone 267 furnished the desired macrocycle (E)-268, though as minor component in a 2 1 isomeric mixture with (Z)-268. Alcohol 269 derived from E-268 then underwent the projected TADA reaction selectively to produce cycloadduct 270 (70% conversion) in a reversible process after 3 days. The final Lewis acid-mediated conversion to 272 however did not occur, delivering anhydrochatancin 271 instead. 

Azomethine ylides. The reaction of 1 with the oxime of an aldehyde results in an iminium salt 2. Desilylation of 2 (CsF) gives rise to an azomethine ylide (a) that undergoes 1,3-dipolar cycloaddition with electron-deficient alkenes (equation I). 

The reaction of allenylsilanes with a,/8-unsaturated acylsilanes presents a new [3 + 3]-cycloaddition approach to a six-membered carbocycle [189]. Lewis acid-promoted ring expansion of the [3 + 2]-annulation product 260 is followed by a second cationic 1,2-silyl migration to produce the cyclohexenone 261 after desilylation. 

A more recent report has outlined the use of a-silylimidates for the construction of aromatic pyrroles (7). Treatment of the precursor 29, with trifluorophenylsilane and DMAD furnished the adduct 30 in 97% yield after purification. The reaction was rationalized via quaternization of the imidate and subsequent intramolecular desilylation by fluorine to develop the ylide, which underwent in situ cycloaddition and subsequent aromatization delivering 30 (Scheme 3.7). 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

Other examples of functionalized thiocarbonyl ylides that have been generated by the desilylation method are those bearing an imino group (49) (see Scheme 5.7). These ylides readily undergo [3 + 2] cycloaddition with aromatic aldehydes to afford l,3-thioxolane-2-imines of type 24 (X = RiN). The reaction with ketones is sluggish, however, and the cycloadducts are obtained in very low yield. 

A -Silylmethyl-amidines and -thioamides (42) (X=NR or S) undergo alkylation at X with, for example methyl triflate, and then fluorodesilylation to give the azomethine ylides 43 (identical with 38 for the thioamides) (25,26). Cycloaddition followed by elimination of an amine or thiol, respectively, again leads to formal nitrile ylide adducts. These species again showed the opposite regioselectivity in reaction with aldehydes to that of true nitrile ylides. The thioamides were generally thought to be better for use in synthesis than the amidines and this route leads to better yields and less substituent dependence than the water-induced desilylation discussed above. 

The first effective enantioselective 1,3-dipolar cycloaddition of diazoalkanes catalyzed by chiral Lewis acids was reported in the year 20(X) (139). Under catalysis using zinc or magnesium complexes and the chiral ligand (R,/ )-DBFOX/Ph, the reaction of diazo(trimethylsilyl)methane with 3-alkenoyl-2-oxazolidin-2-one 75 (R = H) gave the desilylated A -pyrazolines (4S,5R)-76 (R =Me 87% yield, 99% ee at 40 °C) (Scheme 8.18). Simple replacement of the oxazohdinone with the 4,4-dimethyloxazolidinone ring resulted in the formation of (4R,5S)-77 (R = Me 75% yield, 97% ee at -78 °C). 

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