General ether synthesis under mild acid-free conditions. Trimethylsilyl iodide catalyzed reductive coupling of carbonyl compounds with trialkylsilanes to symmetrical ethers and reductive condensation with alkoxysilanes to unsymmetrical ethers

Abstract

Facile synthesis of symmetrical ethers is achieved by either trimethylsilyl triflate or trimethylsilyl iodide catalyzed reductive coupling of carbonyl compounds (aldehydes and ketones) with trialkylsilanes. The method was also extended to the trimethylsilyl iodide catalyzed preparation of unsymmetrical ethers by reductive condensation (of carbonyl compounds) with alkoxysilanes. The scope and limitations of the reactions are discussed with emphasis on diastereoselectivity.

First Synthesis and Characterization of Stereoisomers of Choleretic Drug Dihydroxydibutylether

“…[26,27] Protection of the hydroxyl group with TMSCl gave the key intermediate 9a, whose spectral data and optical rotation were consistent with those reported. [23,28] Then using Olah's method, [29] 4a and 9a were treated with trimethylsilyl triflate and triethylsilane in dry CH 2 Cl 2 at 0 ℃. The stirring was continued at 0 ℃ for 10 min, then at room temperature for 5 h to give 10a (39%) along with 11 in 12% yield.…”

A Concise Synthesis of a Very Late Antigen-4 Antagonist <i>trans</i>-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4<i>S</i>)-methoxy-(2<i>S</i>)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid <i>via</i> Reductive Etherification

“…Reductive etherification [6][7][8][9][10][11][12][13][14][15][16] of silyl ethers with carbonyl compounds using triethylsilane as a reductive agent and Lewis acids such as trimethylsilyl trifluoromethanesulfonate (TMSOTf), 6,7) trimethyl iodosilane (TMSI), 8,9) TrClO 4 , 10) BiBr 3 , 11) BiCl 3 , 12) CuOTf, 13) InCl 3 , 14) FeCl 3 15,16) as a catalyst, is a useful transformation reaction in organic synthesis. It is well known that the etherification works well even in case of a secondary alkoxy silyl ethers with ketone in Chart 2.…”

“…It is well known that the etherification works well even in case of a secondary alkoxy silyl ethers with ketone in Chart 2. 9,16) At this point, we considered that compound 2b could be efficiently synthesized by using the etherification reaction. Thus, we envisioned applying it in the synthesis of 2b from silyl ether 10 and ketone 11 via Route C-1 or aldehyde 12 and silyl ether 13 via Route C-2 as shown in Chart 3.…”

“…In the case of FeCl 3 15,16) as a Lewis acid, the reaction of 10b with 11 afforded only trace amount of 17 (entry 3). On the other hand, treatment of 10a with 11 under 0.5 eq TMSI and 1.5 eq Et 3 SiH condition 8,9) in dichoromethane (DCM) provided a mixture of 17a and 17b in 46% yield in a ratio of 1 : 1 (entry 4).…”

“…However, Route B needed a total of 13 steps to 2c. In continuation of our work on the synthesis of 1, we have now developed a more concise synthetic route to 1 than Route A and B. Herein, we describe the new approach to 1 via the synthesis of ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy] cyclohexanecarboxylate (2b) based on a stereo defined method using reductive etherification.Reductive etherification 6-16) of silyl ethers with carbonyl compounds using triethylsilane as a reductive agent and Lewis acids such as trimethylsilyl trifluoromethanesulfonate (TMSOTf), 6,7) trimethyl iodosilane (TMSI), 8,9) TrClO 4 , 10) BiBr 3 , 11) BiCl 3 , 12) CuOTf, 13) InCl 3 , 14) FeCl 3 15,16) as a catalyst, is a useful transformation reaction in organic synthesis. It is well known that the etherification works well even in case of a secondary alkoxy silyl ethers with ketone in Chart 2.…”