Trimethylsilyl deprotection

Efficiency of the deprotection and coupling reactions are critical to the success of any iterative solid-phase synthesis. Shown in Scheme 1 is a triad of reactions for phenylacetylene oligomer synthesis trimethylsilyl deprotection,28 29 triazene unmasking of an iodobenzene,30 and the Sonogashira coupling of a terminal acetylene with an aryl iodide.31-33 Representative procedures for each step in this sequence are included at the end of this chapter. 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Aryl and alkyl trimethylsilyl ethers can often be cleaved by refluxing in aqueous methanol, an advantage for acid- or base-sensitive substrates. The ethers are stable to Grignard and Wittig reactions and to reduction with lithium aluminum hydride at —15°. Aryl -butyldimethylsilyl ethers and other sterically more demanding silyl ethers require acid- or fluoride ion-catalyzed hydrolysis for removal. Increased steric bulk also improves their stability to a much harsher set of conditions. An excellent review of the selective deprotection of alkyl silyl ethers and aryl silyl ethers has been published. ... 

Trimethylsilylethynylpyrazole was deprotected by treatment with tetrabutyl-ammonium fluoride (TBAF) to give monosubstituted acetylene in 90% yield. (96ADD193). The same conditions were used to cleave the trimethylsilyl group in l-tetrahydropyranyl-3-carboxyethyl-4-[2-(trimethylsilyl)ethynyl]pyrazole (96INP 9640704). 

Ceftiofur (57) differs from the preceding cephalosporin derivatives in that it ha.s a thioester moiety at C-3. This can be introduced by displacement of the C-3 acetyl group of 7-aminocepha-losporanic acid (40) with hydrogen sulfide and esterification with 2-furylcarboxylic acid to give synthon 5reacted with trimethylsilylated oximinoether derivative 55 (itself obtained from the corresponding acid by reaction with dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole) to produce, after deprotecting, ceftiofur (57) [18]. 

The trimethylsilyl protecting group can be removed by routine deprotection with triethylamine -hydrogen fluoride complex. 

The related planar pyrrole analog 118 has also been prepared (2) from either ethyl or benzyl pyrrole-2-carboxylate 116. Direct alkylation with diethyl phosphonomethyl triflate (70) and base produced the N-phosphonomethylpyrrole 2-carboxylate 117, which was deprotected with trimethylsilyl bromide and saponified to the corresponding phosphonic acid 118. 

The synthesis of S-phosphonothiazolin-2-one 133 started with 2-bromothiazole 129. Nucleophilic displacement of the 2-bromide proceeded cleanly with hot anhydrous sodium methoxide to give 2-methoxythiazole 130. Low-temperature metalation of 130 with n-butyl lithium occurred selectively at the 5-position (76), and subsequent electrophilic trapping with diethyl chlorophosphate produced the 5-phosphonate 131. Deprotection of 131 was accomplished either stepwise with mild acid to pn uce the thiazolin-2-one intermediate 132, or directly with trimethylsilyl bromide to give the free phosphonic acid 133, which was isolated as its cyclohexylammonium salt. 

The 2-(trimethylsilyl)ethoxymethyl group (SEM) can be removed by various fluoride sources, including TBAF, pyridinium fluoride, and HF.165 This deprotection involves nucleophilic attack at silicon, which triggers (3-elimination. 

In an earlier study the authors proposed a [3.2.0] bicyclic sulfonium salt 8 as the reactive intermediate in the trimethylsilyl iodide mediated ring contraction of 4-methoxythiephane <1996T5989>. Enantiomerically pure thio-lane derivatives were synthesized via a ring contraction of a seven-membered sulfur heterocycle by nucleophilic transannular substitution <2000TA1389>. The thiepane derivative 15, derived from d-sorbitol, was converted into the dimesyl derivative 16 following deprotection under acidic conditions. Treatment of 16 with sodium azide in DMSO at 120°C yielded the corresponding thiolane as a mixture of two diastereoisomers, 17a and 17b, in a 5 1 ratio (see Scheme 1). 

The Baran group has reported an unusual deprotection of allyl esters in micro-wave-superheated water. A diallyl ester structurally related to the sceptrin natural products (see Scheme 6.87) was cleanly deprotected at 200 °C within 5 min (Scheme 6.168) [181]. Other standard deprotection transformations carried out under microwave conditions, specifically N-detosylations [317], trimethylsilyl (TMS) removal [318, 319], and N-tert-butoxycarbonyl (Boc) deprotection [231], are summarized in Scheme 6.169. 

Deprotection of N-2 by ozonolysis furnishes triazoles 1225 (Scheme 202) <2003JA7786>. Finding that 1,3-dipolar cycloaddition of alkynes 1222 to trimethylsilyl azide, carried out in DMF/MeOH in the presence of Cul as a catalyst, leads directly to products 1225 with much higher yields provides a significant progress to the synthesis of N-unsubstituted 1,2,3-triazoles <2004EJO3789>. 

The potentiality of the present methodology is demonstrated by the synthesis of y-undecalactone, as shown in Scheme 18 [37,47], The treatment of the THP-protected cu-hydroxyalkyl iodide with the anion of methoxybis(trimethylsilyl) methane gave the corresponding alkylation product. Acidic deprotection of the hydroxyl group followed by Swern oxidation produced the aldehyde. The aldehyde was allowed to react with heptylmagnesium bromide, and the resulting alcohol was protected as tm-butyldimethylsilyl ether. The electrochemical oxidation in methanol followed by the treatment with fluoride ion afforded the y-undeealactone. 

Hydroboration of allylic amines.1 Hydroboration of primary and secondary allylic amines presents problems because amino groups interact with boron reagents. Hydroboration proceeds normally when the amino group is protected by trimethylsilyl groups, and deprotection can be effected by protonolysis in CH,OH. 

Scheme 9.8 The synthesis of methyl pentamannoside 2. The numerals indicate reagents used in the synthetic sequence (1) trimethylsilyl triflate, methylene chloride, 4 A molecular sieves (2) DBU, methanol. The final deprotection conditions shown in Scheme 9.7 were employed.

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