Aryl Silyl Research Articles

Rhodium-Catalyzed Regioselective Silylation of Alkyl C-H Bonds for the Synthesis of 1,4-Diols.

A rhodium-catalyzed intramolecular silylation of alkyl C-H bonds has been developed that occurs with unusual selectivity for the C-H bonds located δ to the oxygen atom of an alcohol-derived silyl ether over typically more reactive C-H bonds more proximal to the same oxygen atom. (Hydrido)silyl ethers, generated in situ by dehydrogenative coupling of tertiary alcohols with diethylsilane, undergo regioselective silylation at a primary C-H bond δ to the hydroxyl group in the presence of [(Xantphos)Rh(Cl)] as catalyst. Oxidation of the resulting 6-membered oxasilolanes generates 1,4-diols. This silylation and oxidation sequence provides an efficient method to synthesize 1,4-diols by a hydroxyl-directed, aliphatic C-H bond functionalization reaction and is distinct from the synthesis of 1,3-diols from alcohols catalyzed by iridium. Mechanistic studies show that the rhodium-catalyzed silylation of alkyl C-H bonds occurs with a resting state and relative rates for elementary steps that are significantly different from those for the rhodium-catalyzed silylation of aryl C-H bonds. The resting state of the catalyst is a (Xantphos)Rh(I)(SiR3)(norbornene) complex, and an analogue was synthesized and characterized crystallographically. The rate-limiting step of the process is oxidative addition of the δ C-H bond to Rh. Computational studies elucidated the origin of high selectivity for silylation of the δ C-H bond when Xantphos-ligated rhodium is the catalyst. A high barrier for reductive elimination from the six-membered metalacyclic, secondary alkyl intermediate formed by cleavage of the γ C-H bond and low barrier for reductive elimination from the seven-membered metalacyclic, primary alkyl intermediate formed by cleavage of the δ C-H accounts for the selective functionalization of the δ C-H bond.

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies.

Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC50) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC50 values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.

1-Bromoethene-1-sulfonyl fluoride (BESF) is another good connective hub for SuFEx click chemistry.

We demonstrate 1,2-dibromoethane-1-sulfonyl fluoride (DESF) as a bench-stable and readily accessible precursor to the robust SuFEx connector, 1-bromoethene-1-sulfonyl fluoride (BESF). The in situ generation of BESF from DESF opens up several new reaction profiles, including application in the syntheses of unprecedented 3-substituted isoxazole-5-sulfonyl fluorides, 1-substituted-1H-1,2,3-triazole-4-sulfonyl fluorides, 2-amino-1-bromoethane-1-sulfonyl fluorides and 4-bromo-β-sultams in good to excellent yields. These new modules comprise a pendant sulfonyl fluoride handle, which further undergoes facile and selective SuFEx reactions with a selection of aryl silyl ethers to generate stable and useful sulfonate connections.

Synthesis of 1,2-Bis(trifluoromethylthio)arenes via Aryne Intermediates.

A general method for synthesis of 1,2-bis-trifluoromethylthioarenes has been developed. Arynes generated from silyl aryl triflates or halides react with bis(trifluoromethyl)disulfide to afford 1,2-bis-trifluoromethylthioarenes. Aryl, alkyl, ester, halide, and methoxy functionalities are compatible with reaction conditions. Use of bis(perfluoroaryl)disulfides gave moderate yields of aryne disulfenylation or cyclization to fluorinated dibenzothiophenes.

Silyloxyarenes as Versatile Coupling Substrates Enabled by Nickel-Catalyzed C–O Bond Cleavage

Silyloxyarenes are demonstrated to be a versatile substrate class in a variety of nickel-catalyzed coupling processes. The C(sp2)–O bond of aryl silyl ethers is directly transformed into C–H or C–Si bonds using Ti(O-i-Pr)4 or trialkylsilanes as reagents using nickel catalysts with N-heterocyclic carbene (NHC) ligands. Paired with the useful characteristics of silyl protecting groups, these methods enable protected hydroxyls to directly participate in high-value bond-forming steps rather than requiring deprotection-activation strategies that conventional approaches require. These processes of silyloxyarenes provide reactivity complementary to widely used phenol derivatives such as aryl pivalates, carbamates, and methyl ethers, thus enabling a powerful strategy for sequential chemoselective derivatization of complex substrates without protecting group and activating group manipulations.

Cobalt-catalyzed regioselective [3+2] annulation of ortho -formyl and acetyl substituted phenylboronic acids with alkynes

Treatment of alkynes with ortho-formyl and acetyl phenylboronic acids in the presence of a cobalt catalyst resulted in the formation of 2,3-disubstituted indenols in good yields. When aryl silyl alkynes were used, 2-aryl-3-silyl indenols were obtained regioselectively in good yields.

Bifluoride-catalysed sulfur(VI) fluoride exchange reaction for the synthesis of polysulfates and polysulfonates.

Polysulfates and polysulfonates possess exceptional mechanical properties making them potentially valuable engineering polymers. However, they have been little explored due to a lack of reliable synthetic access. Here we report bifluoride salts (Q+[FHF]-, where Q+ represents a wide range of cations) as powerful catalysts for the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl silyl ethers and aryl fluorosulfates (or alkyl sulfonyl fluorides). The bifluoride salts are significantly more active in catalysing the SuFEx reaction compared to organosuperbases, therefore enabling much lower catalyst-loading (down to 0.05 mol%). Using this chemistry, we are able to prepare polysulfates and polysulfonates with high molecular weight, narrow polydispersity and excellent functional group tolerance. The process is practical with regard to the reduced cost of catalyst, polymer purification and by-product recycling. We have also observed that the process is not sensitive to scale-up, which is essential for its future translation from laboratory research to industrial applications.

Metal‐Catalyzed Synthesis of Functionalized 1,2,4‐Oxadiazoles from Silyl Nitronates and Nitriles

AbstractThe metal‐catalyzed cycloaddition of silyl nitronates and nitriles leading to 1,2,4‐oxadiazoles is described. Silver(I) triflate (AgOTf) and and ytterbium(III) triflate [Yb(OTf)3] are suitable catalysts. A variety of functional groups is tolerated in the nitrile. The reaction works well for alkenyl and aryl silyl nitronates while the use of alkyl silyl nitronates is less efficient. Mechanistic studies are in favour of an elimination of tert‐butyl(dimethyl)silanol (TBSOH) after the cycloaddition step. The new approach has also been applied for the synthesis of the drug ataluren.magnified image

Mechanistic Studies on Rhodium-Catalyzed Enantioselective Silylation of Aryl C-H Bonds.

Several classes of enantioselective silylations of C-H bonds have been reported recently, but little mechanistic data on these processes are available. We report mechanistic studies on the rhodium-catalyzed, enantioselective silylation of aryl C-H bonds. A rhodium silyl dihydride and a rhodium norbornyl complex were prepared and determined to be interconverting catalyst resting states. Kinetic isotope effects indicated that the C-H bond cleavage step is not rate-determining, but the C-H bond cleavage and C-Si bond-forming steps together influence the enantioselectivity. DFT calculations indicate that the enantioselectivity originates from unfavorable steric interactions between the substrate and the ligand in the transition state leading to the formation of the minor enantiomer.

ChemInform Abstract: Silylaryl Halides Can Replace Triflates as Aryne Precursors.

Silylaryl bromides and iodides can be prepared in one step from commercially available starting materials. Arynes can be generated from these compounds under conditions nearly identical to those employed for silylaryl triflates. Three distinct transformations, ortho-arylation of N-tritylanilines, intermolecular addition of arynes to amides, and reaction of ureas with arynes, were shown to be successful for the new aryne precursors. The main advantage of silylaryl halides relative to silyl aryl triflates is their one-step preparation from commercially available starting materials.

ChemInform Abstract: Trifluoromethylation of Arylsilanes with [(phen)CuCF3

A method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF3] as the CF3 source under mild, oxidative conditions with high functional-group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C−H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C−H bond into a C−CF3 bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation.

Silylaryl Halides Can Replace Triflates as Aryne Precursors.

Silylaryl bromides and iodides can be prepared in one step from commercially available starting materials. Arynes can be generated from these compounds under conditions nearly identical to those employed for silylaryl triflates. Three distinct transformations, ortho-arylation of N-tritylanilines, intermolecular addition of arynes to amides, and reaction of ureas with arynes, were shown to be successful for the new aryne precursors. The main advantage of silylaryl halides relative to silyl aryl triflates is their one-step preparation from commercially available starting materials.

Visible-Light-Promoted Oxidative [4 + 2] Cycloadditions of Aryl Silyl Enol Ethers.

Visible-light-promoted oxidative [4 + 2] cycloadditions of ε,3-unsaturated silyl enol ethers have been developed to efficiently and diastereoselectively construct polycyclic skeletons under mild conditions. The diastereoselectivities were dependent on the stereoconfiguration of silyl enol ether, substitutions on the link, as well as electric properties of substitutions on aryl rings. The intermediates could be trapped by TEMPO, oxygen or methanol. Mechanistic studies indicated the reaction was initiated by one-electron oxidation of the silyl enol ether.

Trifluoromethylation of Arylsilanes with [(phen)CuCF3

A method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF3 ] as the CF3 source under mild, oxidative conditions with high functional-group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C-H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C-H bond into a C-CF3 bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation.

Trifluoromethylation of Arylsilanes with [(phen)CuCF3

AbstractA method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF3] as the CF3 source under mild, oxidative conditions with high functional‐group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C−H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C−H bond into a C−CF3 bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation.

DMF-mediated deprotection of bulky silyl esters under neutral and fluoride-free conditions

Bulky TBDPS and TIPS carboxylic esters were efficiently cleaved by a green and mild protocol using only DMF–H2O (20:1) at 70°C. The neutral conditions tolerate various common acid- and base-labile functionalities, including alkyl and aryl silyl ethers.

Iridium-catalyzed silylation of aryl C-H bonds.

A method for the iridium-catalyzed silylation of aryl C-H bonds is described. The reaction of HSiMe(OSiMe3)2 with arenes and heteroarenes catalyzed by the combination of [Ir(cod)(OMe)]2 and 2,4,7-trimethylphenanthroline occurs with the aromatic compound as the limiting reagent and with high levels of sterically derived regioselectivity. This new catalytic system occurs with a much higher tolerance for functional groups than the previously reported rhodium-catalyzed silylation of aryl C-H bonds and occurs with a wide range of heteroarenes. The silylarene products are suitable for further transformations, such as oxidation, halogenation, and cross-coupling. Late-stage functionalization of complex pharmaceutical compounds was demonstrated.

ChemInform Abstract: A Facile Chemoselective Deprotection of Aryl Silyl Ethers Using Sodium Hydride/DMF and in situ Protection of Phenol with Various Groups.

An efficient method for the selective removal of aryl silyl protection using NaH in DMF solvent is developed. The method is rapid, operationally simple and can be carried out at room temperature. Excellent chemoselectivity and high yields of phenol products are other advantages of this method. A one-pot desilylation and reprotection as aryl alkyl ethers and esters has also been demonstrated.

Reductive Degradation of Lignin and Model Compounds by Hydrosilanes

The exploitation of lignin, the second most abundant naturally occurring polymer on earth, has been hampered by its network structure, which makes it difficult to process. Hydrosilanes have previously been shown to convert aryl ethers to hydrolyzable silyl ethers in the presence of B(C6F5)3. We demonstrate that the process is general and can be used to convert model lignin compounds to both aryl silyl ethers and alkanes. The relative reactivity of functional groups on model lignin compounds was found to be phenol > primary alcohol > methoxybenzene > alkyl silyl ethers. The process thus leads to cleavage of β-O-4, α-O-4, and methoxybenzene groups with concomitant silylation of phenolic and secondary alcohol groups. At longer time points provided sufficient silane was present, the full reduction of primary and secondary alcohols to alkyl groups was observed. Softwood lignin itself could only be partially solubilized (∼30%) even using excess hydrosilane and high catalyst loadings; the products were not characterized in detail. The lack of further degradation was attributed to its highly branched network structure containing 5-5, β-5, 4-O-5, and other linkages derived from coniferyl alcohol monomers that are not susceptible to reductive silylation. By contrast, over 95% of hardwood lignin was efficiently reduced/degraded into organosoluble products by the monofunctional hydrosilane HMe2SiOSiMe3 over a few hours at 50 °C. The molecular weight of the silylated products was consistent with oligomeric structures comprised of 3–8 linked aryl groups. This process holds promise to increase the accessibility to value-added products using lignin as a starting material.

A facile chemoselective deprotection of aryl silyl ethers using sodium hydride/DMF and in situ protection of phenol with various groups

A facile method for chemoselective aryl silyl ether deprotection with NaH/DMF is developed and a one-pot desilylation/reprotection as different aryl silyl ethers/esters has also been realized.