TMSCN addition

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

Jacobsen developed a method employing (pybox)YbCl3 for TMSCN addition to meso-epoxides (Scheme 7.22) [46] with enantioselectivities as high as 92%. Unfortunately, the practical utility of this method is limited because low temperatures must be maintained for very long reaction times (up to seven days). This reaction displayed a second-order dependence on catalyst concentration and a positive nonlinear effect, suggesting a cooperative bimetallic mechanism analogous to that proposed for (salen)Cr-catalyzed ARO reactions (Scheme 7.5). 

Addition of CN Anion Stereoselective addition of the CN-group to nitrones has received considerable attention for the synthesis of optically active a-hydroxyamino nitriles which can be further transformed into a-hydroxyamino acids and a-amino acids. Me SiCN (TMSCN), Et2AlCN, BU4NCN, and LiCN... 

The stereocontrolled addition of TMSCN to chiral 3.4-dihydro-277 - pyrroline N - oxides (394) is being used to prepare enantiopure 2-aminomethylpyrrolidines (395) and (396) (Scheme 2.172) (631). 

Cyanohydrination (addition of a cyano group to an aldehyde or ketone) is another classic reaction in organic synthesis. Enantioselective addition of TMSCN to aldehyde, catalyzed by chiral metal complexes, has also been an active area of research for more than a decade. The first successful synthesis using an (5,)-binaphthol based complex came from Reetz s group142 in 1986. Their best result, involving Ti complex, gave 82% ee. Better results were reported shortly thereafter by Narasaka and co-workers.143 They showed that by... 

TMSCN (1.8 equiv) was added over 10 h via syringe pump unless otherwise mentioned. 4 Isolated yield.c Determined by HPLC analysis. Configuration assigned by comparison to literature values of optical rotation. d 20 mol % of 123 and 80 mol % of the addtive were used. 1.2 equiv of TMSCN was used. e TMSCN (1.2 equiv) was added dropwise over 1 min. f 18 mol % of 123 and 72 mol % of the additive waer used. The absolute configuration was not determined. 

Belokon, Y. N. Chusov, D. Borkin, D. A. Yashkina, L. V. Dmitriev, A. V. Katayeva, D. North, M. (2006) Chiral Ti(lV) complexes of hexadentate Schiff bases as precatalysts for the asymmetric addition of TMSCN to aldehydes and the ring opening of cyclohexane oxide.. Tetrahedron Asymmetry, 17, 2328-2333. 

Furthermore, phosphonium salts have been applied as catalysts in the TMSCN addition to aldehydes [118] and ketones [119]. Methyltriphenylphosphonium iodide [118] was fonnd to be a reasonably active catalyst for the addition of TMSCN to aldehydes at room temperatnre by the gronp of Plumet. In general, the yields varied between 70% and 97% in 24 h, depending on the aldehyde, applied in the reaction (Scheme 46). However, the salt did not support the addition of TMSCN to ketones, with one exception, when the highly reactive cyclobutanone was applied in the reaction [120]. 

In the phosphonium iodide and chloride salt catalyzed TMSCN addition on aldehydes and ketones, a double activation should exist. Not only the activation of the ketones or aldehydes with the phosphonium cation is necessary, but also the activation of the TMSCN by the soft Lewis base [I] or the harder Lewis base [Cl], which can form a pentavalent silicon intermediate [121]. 

The TMSCN addition on aldehydes has been reported to be catalyzed by the ionic liquid [omim][PFJ [202]. The influence of the counter anion in activating the TMSCN cannot be neglected, since the TMSCN addition on aldehydes can be also catalyzed by a Lewis base. The imidazolinium-dithiocarboxylate 72 has been recently shown to catalyze the reaction also in good yields up to 99% (Scheme 80) [203]. One could assume, that the zwitterion incorporates a Lewis acid and Lewis base center. The reaction did not proceed in the absence of the catalyst. 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

The technology was further extended with formation of the ylide by nucleophiles other than the PhaSiH/CsF derived hydride addition (18,19). Cyanide anion, generated from TMSCN/CsF, underwent nucleophilic addition and opening to the... 

To a soln of aldehyde 41 xg (1.00 g, 3.97 mmol) in CH2C12 (27 mL) was added (.S )-2-phenylglycinol (0.65 g, 4.76 mmol) at rt. After being stirred at rt for 2h, the mixture was cooled to 0°C, and MeOH (3.3 mL) and TMSCN (0.79 mL, 5.96 mmol) were then introduced successively. After being stirred at 0°C for 1 h and at rt for 12 h, the mixture was carefully quenched by the addition of aq citric acid soln (CAUTION HCN perform in an efficient fume hood) and stirring was continued for another 30 min. The aqueous phase was then neutralized with pH 7 phosphate buffer and extracted with CH2C12. The combined... 

A range of Lewis bases catalyse the addition of TMSCN to aldehydes, with phosphines and amines the most efficient.247 Kinetic studies indicate that the orders of aldehyde, Lewis base (LB), and TMSCN are 1, 1, and 0, suggesting an Me3Si-LB+ CN ion pair as an intermediate. However, chiral phosphines and amines gave very... 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

A simple ionic liquid, octylmethylimidazolium (with PI >> counterion), promotes TMSCN addition to aldehydes in yields up to quantitative, in 1 day at room temperature. Environmentally friendly and recyclable, the solvent requires no Lewis acid or other activation.268 The long-chain substituent and the nature of the counterion are important contributors to the high yield. Deprotection to give the product as cyanohydrin just requires an HC1-THF workup. 

A BINOL-salen ligand catalyses the enantioselective addition of TMSCN to aldehydes at room temperature, in the presence of titanium(IV) isopropoxide.269... 

Lewis acidity of hiBr3 toward coordination and acid nucleophiles was not affected. Cozzi et al. described a sequential, one-pot InBr3-catalyzed 1,4-then 1,2-addition to enones, indicating that this is a versatile catalyst for the Michael additions [56]. When InBr3 (10 mol%) catalyst is used together with trimethylsilylcyanide (TMSCN), the reactions start by the 1,4-conjugate addition of indoles to a,fl-ketones and then finish by the 1,2-addition of TMSCN to the -substituted ketones in one pot (Scheme 12). 

Cole BM, Shimizu KD, Krueger CA, Harrity JPA, Snapper ML, Hoveyda AH, Discovery of chiral catalysts through ligand diversity Ti-catalyzed enantiose-lective addition of TMSCN to meso epoxides, Angew. Chem., Int. Ed. Engl., 35 1668-1671, 1996. 

Although there is some experimental evidence for the formation of hypervalent silicon species (Fukada et al. 2006) an alternative reaction pathway via preliminary carbene-mediated activation of the carbonyl or imine species respectively (1,2-addition), and subsequent reaction of the anionic species with TMSCN etc. (electrophilic trapping of the alkoxide) has been proposed (Suzuki et al. 2006b Marion et al. 2007). 

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