Tributyltin hydride is the reagent of the choice for the reduction of functional groups after a radical mechanism. But organotin compounds are toxic and can sometimes only be separated laboriously from nonpolar reaction products. It was necessary to find new reagents which made the adaption of these radical methods possible in (pharmaceutical) production, without having fear of toxic impurities.
Silanes are often an alternative. But the Si-H - bond in silanes is relatively strong compared to the appropriate bond in tributyltin hydride. The discoveries gained from the 80's, that replacement of alkyl by silyl groups weakens the Si-H bond at the central silicon atom, were very important for the discovery of tris(trimethylsilyl)silane as reducing agent. (bond strengths: Bu3Sn-H 74 kcal/mol, Et3Si-H 90 kcal/mol, TMS3Si-H 79 kcal/mol).
Tris(trimethylsilyl)silane was already described in the literature in 1965. But It was not rediscovered before the middle of the 80's as a reagent by Chryssostomos Chatgilialoglu, and its synthetic capabilities were developed. The first publication in 1988 of C. Chatgilialoglu describes the reduction of halides. Not without a reason: as the working group synthesized the reagent for the first time, no signal for Si-H could be determined in the 1H-NMR. A part of the solvent - CCl4 - was reduced to CHCl3 directly inside the NMR tube!
Tris(trimethylsilyl)silan - A New Reducing Agent. C. Chatgilialoglu, J. Org. Chem. 1988, 53, 3641-3642.
Meanwhile many tin-hydride-based reactions can be accomplished with tris(trimethylsilyl)silane. However, in many cases the reaction time must be adapted.
When treated with a radical initiator selenophosphates, selenophosphorodithioates, selenophosphorothioates and selenophosphorotrithioates undergo homolytic cleavage of the P-Se bond to generate radicals. Addition onto electron-rich and electron-poor alkenes in the presence of a hydrogen donor delivers the expected adducts in good yields.
C. Lopin, G. Gouhier, A. Gautier, S. R. Piettre, J. Org. Chem., 2003, 68, 9916-9923.
(Me3Si)3SiH was successfully used in various radical-based transformations in water. The system comprising substrate, silane, and initiator (ACCN) mixed in aqueous medium at 100°C worked well for both hydrophilic and hydrophobic substrates. In case of water-soluble water-soluble substrates, an amphiphilic thiol was also needed.
A. Postigo, S. Kopsov, C. Ferreri, C. Chatgilialoglu, Org. Lett., 2007, 9, 5159-5162.
Photoredox catalysis achieves a hydroacylation reaction of alkenes using readily available carboxylic acids as the acyl source and hydrosilanes as a hydrogen source. The protocol offers extremely mild conditions, broad substrate scope, and good functional group tolerance.
M. Zhang, R. Ruzi, J. Xi, N. Li, Z. Wu, W. Li, S. Yu, C. Zhu, Org. Lett., 2017, 19, 3430-3433.
Alkyl bromides can be coupled with aryl or heteroaryl bromides in excellent yields in the presence of commercially available tris(trimethylsilyl)silane and a metallaphotoredox catalyst. It is hypothesized that a photocatalytically generated silyl radical species can perform halogen-atom abstraction to activate alkyl halides as nucleophilic cross-coupling partners.
P. Zhang, C. Le, D. W. C. MacMillan, J. Am. Chem. Soc., 2016, 138, 8084-8087.
Visible light promotes a Ni-catalyzed cyanation of aryl halides with 1,4-dicyanobenzene as a cyanating agent. A broad array of aryl bromides, chlorides, and druglike molecules could be converted into their corresponding nitriles.
Y. Yan, J. Sun, G. Li, L. Yang, W. Zhang, R. Cao, C. Wang, J. Xiao, D. Xue, Org. Lett., 2022, 24, 2271-2275.
Intermolecular addition of perfluoroalkyl radicals on electron rich alkenes and alkenes with electron withdrawing groups in water, mediated by silyl radicals gives perfluoroalkyl-substituted compounds in good yields. The radical triggering events employed consist of thermal decomposition of 1,1′-azobis(cyclohexanecarbonitrile) (ACCN) or dioxygen initiation.
S. Barata-Vallejo, A. Postigo, J. Org. Chem., 2010, 75, 6141-6148.
The use of visible light and a silane reductant enables a carbonyl alkylative amination reaction that combines a wide range of primary amines, α-ketoesters, and alkyl iodides to form functionally diverse all-alkyl α-tertiary amino esters. A Brĝnsted acid-mediated formation of a ketiminium species is followed by rapid 1,2-addition of an alkyl radical (generated from an alkyl iodide).
J. H. Blackwell, R. Kumar, M. J. Gaunt, J. Am. Chem. Soc., 2021, 143, 1598-1609.
Sulfamoyl chlorides can be easily activated by Cl-atom abstraction in the presence of a silyl radical. This mode of activation can be used for a single-step hydrosulfamoylation using inexpensive olefins, tris(trimethylsilyl)silane, and photocatalyst Eosin Y.
S. M. Hell, C. F. Meyer, G. Laudadio, A. Misale, M. C. Willis, T. Noël, A. A. Trabanco, V. Gouverneur, J. Am. Chem. Soc., 2020, 142, 720-725.
Reductive radical cyclization of N-allyl-N-dimethylphosphinoyl-2-aminopropyl phenyl selenide using tris(trimethylsilyl)silane (TTMSS) / AIBN under UV irradiation gave the corresponding pyrrolidine in 74% yield and a cis/trans ratio of 10/1 which was superior to thermal cyclization.
D. Shanks, S. Berlin, M. Besev, H. Ottosson, L. Engman, J. Org. Chem., 2004, 69, 1487-1491.
A novel approach to 2,4-disubstituted piperidines involves the radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. An enhancement in diastereoselectivity using tris(trimethylsilyl)silane instead of tributyltin hydride is discussed.
L. A. Gandon, A. G. Russel, T. Güveli, A. E. Brodwolf, B. M. Kariuki, N. Spencer, J. S. Snaith, J. Org. Chem., 2006, 71, 5198-5207.
Bis-O-thioxocarbamate derivatives of vicinal diols are reduced with tris(trimethylsilyl)silane in the presence of azobisisobutyronitrile to afford the corresponding olefins in good yields. 2',3'-didehydro-2',3'-dideoxy analogs of adenosine, guanosine, inosine, cytidine and uridine were prepared.
M. Oba, M. Suyama, A. Shimamura, K. Nishiyama, Tetrahedron Lett., 2003, 44, 4027-4029.
A photochemical cross-coupling between N-amidopyridinium salts and various alkyl bromides under photocatalyst-free conditions provides various C4-alkylated pyridines. The photochemical activity of electron donor-acceptor (EDA) complexes between N-amidopyridinium salts and bromide generates silyl radicals and drives the alkylation process.
S. Jung, S. Shin, S. Park, S. Hong, J. Am. Chem. Soc., 2020, 142, 11370-11375.