Silyl Ethers - Thieme Chemistry

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ly common with tert-butyldimethylsilyl ethers, [9] but less so with triisopropylsilyl and tertbutyldiphenylsilyl ethers. Silyl migration of this type is most frequently seen where oxygens bear a 1,2-relationship [10] or a 1,3-relationship, [11] although more distant migrations are known. This aspect of silyl ether chemistry has sometimes presented problems in complex syntheses where a specific hydroxy protection is desired. It can pose severe difficulties for researchers in the fields of carbohydrate [12] and ribooligonucleotide [13] synthesis where unwanted silyl migrations often occur quite readily. Silyl migration between carbon and oxygen has long been recognized as an important feature of silicon chemistry; in fact, the rearrangement can be used as a preparative method for silyl ethers. [14] The transfer of a silyl group from carbon to oxygen was first described in the context of a [1,2]shift by Brook, [15] for whom the rearrangement is named. It was subsequently found that migration can occur between nonadjacent atoms, leading to [1,n]-Brook rearrangements where n £5. [16] It has been shown that silicon retains its configuration in the course of a Brook rearrangement. [17] The rearrangement requires the presence of a strong base and is synthetically most useful when the carbanion resulting from silyl migration is stabilized. [18] The reverse migration of silyl groups from oxygen to carbon (retro-Brook rearrangement) was discovered by West, initially as a [1,3]shift [19] and later as a [1,2]migration. [20] Longer range retro-Brook rearrangements have also been noted. [21] These reactions take place when silyl ethers are exposed to a strong base, such as an alkyllithium, which may be used to effect halogen±metal or metal±metal exchange. Silyl migration to the resultant carbanion is driven by the formation of a more stable alkoxide species. 4.4.17.1 Trimethylsilyl Ethers As the least stable of the family of silyl ethers, trimethylsilyl (TMS) ethers have found only limited utility as protecting groups in complex synthesis. Their sensitivity toward mild acids (e.g., acetic acid) and bases (potassium carbonate in methanol) makes their survival through multistep operations in a synthetic sequence problematic. Even chromatography on silica gel can suffice to cleave a trimethylsilyl ether. The most frequent use made of trimethylsilyl ethers is to mask polar functional groups, primarily hydroxy and carboxy groups, for the purpose of increasing the volatility of an otherwise nonvolatile compound. Since trimethylsilyl ethers are thermally quite stable, the resultant (poly)silyl ether can be subjected to gas chromatography and mass spectrometry without fear of decomposition. This technique has been widely applied in the carbohydrate area where exhaustive silylation, for example with N-(trimethylsilyl)acetamide, leads to a persilylated sugar. [22] Formation FOR PERSONAL USE ONLY 372 Science of Synthesis 4.4 Silicon Compounds 4.4.17.1.1 Method 1: Silylation ofAlcohols with Chlorotrimethylsilane A variety of silylating agents is available for the preparation of trimethylsilyl ethers, but chlorotrimethylsilane (TMSCl) is perhaps the most frequently employed. It is used in the presence of a base, typically imidazole or triethylamine, which removes hydrogen chloride formed during the silylation. There is very little difference in the rate of silylation of primary, secondary, and tertiary alcohols with this reagent, and selectivity in protection of alcohols is not usually possible. A typical silylation with chlorotrimethylsilane is that of alcohol 1 to give silyl ether 2 (Scheme 1); it is noteworthy that the terminal alkyne of 1 does not undergo silylation under these conditions. [23] White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg Thieme Verlag KG
Scheme 1 Silylation with Chlorotrimethylsilane [23] H OH 1 OPMB TMSCl, imidazole CH2Cl2, rt, 10 h 95% H OTMS 2 OPMB (4S,5R)-6-(4-Methoxybenzyloxy)-5-methyl-4-(trimethylsiloxy)hex-1-yne (2): [23] TMSCl (747 ìL, 5.92 mmol) followed by imidazole (619 mg, 9.10 mmol) were added to a stirred soln of alcohol 1 (1.129 g, 4.55 mmol) in CH 2Cl 2 (50 mL) at rt under N 2. A white precipitate formed immediately. The mixture was stirred for 10 h and was then diluted with EtOAc (100 mL). The organic phase, after washing with H 2O (15 mL) and sat. aq NaCl (15 mL), was dried (Na 2SO 4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc 7:1) of the residue gave 2 as a clear, colorless oil; yield: 1.384 g (95%). 4.4.17.1.2 Method 2: Silylation ofAlcohols with Trimethylsilyl Trifluoromethanesulfonate Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate, TMSOTf), a powerful silylating agent, [24] has gained popularity among synthetic chemists since it became readily available from commercial sources. Despite the highly electrophilic character of this reagent, it is remarkably tolerant of other functionalities providing it is used in the presence of a base such as a tertiary amine. All alcohols, regardless of their steric environment, are usually silylated with this reagent, an example being conversion of the ciguatoxin precursor 3 into its trimethylsilyl ether 4 (Scheme 2). [25] Scheme 2 Silylation with Trimethylsilyl Trifluoromethanesulfonate [25] I HO H H O BnO O H H 3 FOR PERSONAL USE ONLY 4.4.17 Silyl Ethers 373 OTBDMS OTBDPS TMSOTf, Et3N CH2Cl2, −10 98% oC I TMSO H H O BnO O H H 4 OTBDMS OTBDPS (1R,3S,4R,5S,6S,8R,9S)-5-Benzyloxy-9-(tert-butyldimethylsiloxy)-8-[2-(tert-butyldiphenylsiloxy)ethyl]-3-(2-iodoethyl)-4-(trimethylsiloxy)-2,7-dioxabicyclo[4.4.0]decane (4): [25] To a soln of alcohol 3 (68.4 mg, 82.3 ìmol) and Et 3N (45.9 ìL, 329 ìmol) in CH 2Cl 2 was added dropwise TMSOTf (31.8 ìL, 165 ìmol) at ±108C, and the mixture was stirred at that temperature for 10 min. The reaction was quenched with sat. aq NaHCO 3, and the aqueous layer was extracted repeatedly with Et 2O. The combined organic layers were washed with brine, dried (MgSO 4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc 15:1) to afford 4 as a pale yellow oil; yield: 72.8 mg (98%). 4.4.17.1.3 Method 3: Silylation ofAlcohols with Trimethylsilyl Cyanide CAUTION: All silyl cyanides should be treated as highly toxic in their own right, and are capable of generating hydrogen cyanide if exposed to water or moisture. Many silyl cyanide derivatives are also volatile. All reactions involving the preparation or use of these compounds should be carried out by appropriately trained personnel in a well-ventilated fume hood and in full compliance with all local safety regulations regarding the use of cyanides. for references see p 410 White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg Thieme Verlag KG
Page 1: 4.4.17 Product Subclass 17: Silyl E
Page 5 and 6: Scheme 4 Silylation with N,O-Bis(tr
Page 7 and 8: Scheme 8 Cleavage of a Trimethylsil
Page 9 and 10: Tri-tert-butyl {1S-[1á,3á,4â,5á
Page 11 and 12: Scheme 13 Cleavage of a Triethylsil
Page 13 and 14: Scheme 16 Cleavage of Triethylsilyl
Page 15 and 16: dazole has diminished solubility in
Page 17 and 18: Scheme 22 Selective Silylation of S
Page 19 and 20: Scheme 25 Cleavage of Primary and S
Page 21 and 22: 4.4.17.3.6 Method 6: Cleavage of te
Page 23 and 24: Scheme 30 Selective Cleavage of a t
Page 25 and 26: (2Z,4S,5R,6E,8S,9R,10S,12S,13R)-5-(
Page 27 and 28: 4.4.17.4.1.1 Variation 1: With Trii
Page 29 and 30: Scheme 38 Cleavage of a Triisopropy
Page 31 and 32: Scheme 40 Selective Cleavage of a T
Page 33 and 34: Scheme 43 Monosilylation of Butane-
Page 35 and 36: Scheme 47 Cleavage of a Bis(tert-bu
Page 37 and 38: Scheme 50 Selective Cleavage of a t
Page 39 and 40: 4.4.17.6 Other Silyl Ethers FOR PER
Page 41 and 42: FOR PERSONAL USE ONLY References 41

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