Phase Strecker reaction

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Figure 6.13 Diaminocyclohexane-derived Schiff base catalyst 10 representing the optimized structure identified from parallel catalyst screening and its polymer-free (solution-phase) counterpart 11 prepared for application in asymmetric Strecker reactions.

This phase-transfer-catalyzed asymmetric Strecker reaction is further elaborated by the use of a-amido sulfone as a precursor of N-arylsulfonyl imine. In this system, the reaction can be conducted with a slight excess of potassium cyanide (1.05 equiv.), and the reaction leads to completion within 2h (Table 5.15) [46b],... 

Table 5.15 Direct asymmetric Strecker reaction of a-amido sulfones under phase-transfer conditions.

Ooi, T., Uematsu, Y. and Maruoka, K. (2006) Asymmetric Strecker reaction of aldimines using aqueous potassium cyanide by phase-transfer catalysis of chiral quaternary ammonium salts with a tetranaphthyl backbone. J. Am. Chem. Soc., 128, 2548. 

Table 11.9 Phase-transfer-catalyzed asymmetric Strecker reaction.

Van der Eycken and coworkers have demonstrated an interesting solid-phase synthesis of 2(l//)-pyrazinones " based on the Strecker reaction" of the resin-bound amine with an appropriate aldehyde and a cyanide, allowing a wide diversity at the C6 position of the pyrazinone ring (Scheme 8.29). The authors investigated a number of interesting decorations on the resin-bound 2(lJ/)-pyrazinones, using a variety of microwave-assisted, transition metal-mediated cross-coupling reactions (Scheme 8.29). 

Through the synthesis of parallel combinatorial libraries, Jacobsen and coworker discovered a new dass of catalysts for the Strecker reaction [15]. Because of its modular assembly, the new catalyst type was amenable to solid-phase synthesis and fast preparation, screening, and lead optimization were feasible. The best catalyst candidate afforded the Strecker product from N-allylbenzaldimine in 78% yield and 91% ee. Catalyst 21 was prepared as the soluble variant of the optimized candidate and proved to be an effective catalyst for a range of imine derivates 20, affording aromatic amino nitriles 22 in moderate to good yields (65-92%) and high enantioselectivities (70-91% ee) (Scheme 30.4). In addition, aliphatic aldimines 20... 

For better enantiopurities with aliphatic substrates, structural elements crucial for a high stereoinduction were revised by library screening on a solid phase. It was found that the presence of a bulky substituent at both the amino acid and at the 3-position of the salicylimine moiety were key elements responsible for high enantioselectivity. By employing of a pivaloyl substituent at the 5-position of the salicylaldehyde moiety, 24 was found to be a superior catalyst for the Strecker reaction of aliphatic imines 23 (Scheme 30.5) [16]. By adaptation of solid-supported 24 to homogenous conditions, the thiourea was replaced with a urea moiety because of the more convenient synthesis. By applying the so-synthesized catalyst 25, Strecker adducts 26 were obtained in high ee s and yields. Transformation of 3,4-dihydroisoquinoline, a fixed (Z)-imine, into the Strecker adduct (in 88% yield ... 

In 2006, Ooi conducted an asymmetric Strecker reaction under phase-transfer conditions (PTC) employing a chiral quaternary ammonium salt 76 with a tetrana-phthyl backbone (Scheme 30.18) [43]. Under biphasic conditions, aqueous KCN could be used as an inexpensive and safe surrogate for HCN. With lmol% of catalyst 76 the reaction in toluene-water at 0°C proceeded smoothly in relatively short reaction times (2-8h). In doing so, a-branched and a-unbranched aUphatic N-mesitylenesulfonyl imines 75 were transformed in high yields and good to high... 

Scheme 30.18 Asymmetric Strecker reaction with 76 under phase-transfer conditions.

Herrera RP, Sgarzani V, Bernard L, Fini F, Pettersen D, Ricci A. Phase transfer catalyzed enantioselective Strecker reactions of a-amido sulfones with cyanohydrins. J. Org. Chem. 2006 71 9869-9872. 

Ooi T, Uematsu Y, Fujimoto J, Fukumoto K, Maruoka K. Advantage of in situ generation of A-arylsulfonyl imines from alpha-amide sulfones in the phase-transfer-catalyzed asymmetric Strecker reaction. Tetrahedron Lett. 2007 48... 

Asymmetric phase-transfer catalytic addition of cyanide to C=N, C=0, and C=C bonds has been recently explored, which has been demonstrated to be an efficient method toward the synthesis of a series of substituted chiral nitriles. In this context, Maraoka and coworkers disclosed an enantioselective Strecker reaction of aldimines by using aqueous KCN [140]. In this system, the chiral quaternary ammonium salts (R)-36e bearing a tetranaphthyl backbone were found to be remarkably efficient catalysts (Scheme 12.25). Subsequently, this phase-transfer-catalyzed asymmetric Strecker reaction was further elaborated by use of a-amidosulfones as precursor of N-arylsulfonyl imines. Interestingly, the reaction could be conducted with a slight excess of potassium cyanide [141] or acetone cyanohydrin [40] as cyanide source, and good to high enantioselectivities were observed. In contrast, the asymmetric phase-transfer-catalytic cyanation of aldehydes led to the cyanation products with only moderate enantioselectivity [142]. 

Scheme 12.25 Asymmetric phase-transfer catalytic Strecker reaction...

Aromatic and aliphatic aldehydes in the presence of dialkylamines and an equivalent of acid such as hydrochloric, perchloric or p-toluenesulfonic acid give iminium salts, which add cyanide ion to form a-(dialkylamino)nitriles. An alternative preparation involves the reaction of the aldehyde with dialkylamines in the presence of acetone-cyanohydrin, a-(A, -dialkylamino)isobutyronitiiles, diethyl phosphorocyanidate or TMS-CN. Another route to a-aminonitrile starts with an aldehyde, the salt of an amine and KCN in organic solvents under solid-liquid two-phase conditions by combined use of alumina and ultrasound. Chiral a-aminonitriles were prepared by Strecker-type reactions, cyano-silylation of Schiffs bases, amination of a-siloxynitriles or from an A -cyanomethyl-l,3-oxazolidine synthon. Reaction of tertiary amines with CIO2 in the presence of 5.1 mol equiv. of aqueous NaCN as an external nucleophile affords a-aminonitrile. °... 

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