Cyanation of Aldehydes

Catalytic Asymmetric Cyanation with (R]-BINOLi/-PrOLi (10mol%) [87] 

A mixture of (R)-BINOL (97) (28.6mg, O.lmmol) and i-PrOLi (6.6mg, 0.1 mmol) in toluene (2 ml) was stirred at room temperature for 20 min under a nitrogen 

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In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

Lundgren, S. Wingstrand, E. Penhoat, M. Moberg, C. Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide and cyanoformate as cyanide sources. J. Am. Chem. Soc. 2005,127, 11592-11593. 

Cyanation of aldehydes and ketones is an important chemical process for C C bond formation." " Trimethylsilyl cyanide and/or HCN are commonly used as cyanide sources. The intrinsic toxicity and instability of these reagents are problematic in their applications. Acetyl cyanide and cyanoformates were used as cyanide sources in the enantioselective cyanation of aldehydes catalyzed by a chiral Ti complex and Lewis base (Scheme 5.31)." The Lewis base was necessary for the good yields and selectivities of these reactions. The desired products were obtained in the presence of 10mol% triethyl amine and 5mol% chiral titanium catalyst (Figure 5.14). Various aliphatic and aromatic aldehydes could be used in these reactions. 

Scheme 5.32. Catal3Tic heterobimetallic asymmetric cyanation of aldehydes.

Scheme 49 Representative products formed via cyanation of aldehydes...

Cyanation of carbonyl compounds has one of the richest histories of any transformation in the field of asymmetric catalysis, and intensive research efforts have continued unabated since the editorial deadline for the first edition of Comprehensive Asymmetric Catalysis in 1998. This chapter will summarize all efforts in this area from 1998 to date, highlighting the most important catalytic systems from a synthetic and/or mechanistic standpoint. Significant advances in both the cyanation of aldehydes (formation of secondary cyanohydrins Section 28.2.1) and the cyanation of ketones (formation of tertiary cyanohydrins Section 28.2.2) will be addressed [1,2]. 

Shibasaki and co-workers applied (BINOL)Al(III)-derived catalyst 5a, previously developed for the cyanation of aldehydes [28], to the asymmetric Strecker reaction. This catalyst proved to be highly enantioselective for both aromatic and a,p-unsaturated acyclic aldimines (>86% ee for most substrates) (Scheme 8) [63-65]. Aliphatic aldimines underwent cyanide addition with lower levels of enantioselectivity (70-80% ee). A significant distinction of 5 relative to other catalysts is, undoubtedly, its successful application to the hydrocyanation of quinolines and isoquinolines, followed by in situ protection of the sensitive cx-amino nitrile formed (this variant of the Strecker reaction is also known as the Reissert reaction [66]). Thus, Shibasaki has shown that high enantioselectivities (>80% ee for most substrates) and good yields are generally obtainable in the Reissert reaction catalyzed by 5b [67,68]. When applied to 1-substituted... 

For an earlier report on the use of box-ligands for cyanation of aldehydes, see Corey EJ, Wang Z (1993) Tetrahedron Lett 34 4001... 

Aldehydes, ketones, and acetals react with allyltrimethylsilane in the presence of a catalytic amount of BiX3 (X = C1, Br, OTf) to give homoallyl alcohols or homoallyl alkyl ethers (Equation (52)).91-93 The BiX3-catalyzed allylation of aldehydes and sequential intramolecular etherification of the resulting homoallylic silyl ethers are involved in the stereoselective synthesis of polysubstituted tetrahydropyrans (Equation (53)).94,95 Similarly, these Lewis acids catalyze the cyanation of aldehydes and ketones with cyanotrimethylsilane. When a chiral bismuth(m) catalyst is used in the cyanation, cyanohydrines are obtained in up to 72% ee (Equation (54)). a-Aminonitriles are prepared directly from aldehydes, amines, and cyanotrimethysilane by the BiCl3-catalyzed Strecker-type reaction. 

The cyanation of aldehydes with commercially available acetone cyanohydrin as cyanide source also appears feasible. For example, treatment of 2,2-dichlorodecanal (20) with acetone cyanohydrin under the influence of aluminum reagent 26a or 26b afforded the corresponding cyanohydrin 30 in high yield (Sch. 14) [34]. 

Asymmetric cyanation of aldehydes is important in organic synthesis. Mukaiyama and Minowa have developed a new chiral Lewis acid catalyst which is readily prepared from l,l -dimethylstannocene, triflic acid, and (+)-cinchonine [49]. In the presence of this Lewis acid reaction of TMSCN with aldehydes proceed smoothly at -78 °C in dichloromethane to give the corresponding cyanohydrin trimethylsilyl ether in high yield with good to excellent ee. In this reaction the products are isolated as trimethylsilyl ethers and the reaction proceeds smoothly in the presence of 30 mol % tin(II) Lewis acid (Eq. 31). The catalyst, Sn(II) monoalkoxymonotriflate, is assumed to be regenerated from the initially produced Sn(II) alkoxide and trimethylsilyl triflate. 

Optically pure cyanohydrins serve as highly versatile synthetic building blocks [24], Much effort has, therefore, been devoted to the development of efficient catalytic systems for the enantioselective cyanation of aldehydes and ketones using HCN or trimethylsilyl cyanide (TMSCN) as a cyanide source [24], More recently, cyanoformic esters (ROC(O)CN), acetyl cyanide (CH3C(0)CN), and diethyl cyanophosphonate have also been successfully employed as cyanide sources to afford the corresponding functionalized cyanohydrins. It should be noted here that, as mentioned in Chapter 1, the cinchona alkaloid catalyzed asymmetric hydrocyanation of aldehydes discovered... 

Moberg and coworkers also achieved the highly enantioselective cyanation of aldehydes by using the dual activation concept (Table 4.5) [30]. It is known that the Lewis acidic dimeric salen-Ti complex 8 catalyzes the cyanation of benzaldehyde with... 

Scheme 4.10 Enantioselective cyanation of aldehydes with cyanoformic esters catalyzed by (S)-ALB (7) and cinchonine.

Table 4.5 Dual Lewis acid-Lewis base activation in enantioselective cyanation of aldehydes using acetyl cyanide.

The allylation and cyanation of aldehydes and ketones are mediated by BiCl3 and BiBr3 [174, 175]. When a chiral bismuth(lll) catalyst is used for cyanation, cyanohydrins are obtained in up to 72% ee (Scheme 14.85) [175]. The Bi(OTf)3-promoted intramolecular Sakurai cyclization of homoallylic alcohols is involved as a key step in the stereoselective synthesis of polysubstituted tetrahydropyrans (Scheme 14.86) [176]. In the presence of the BiCl3-xMl binary catalyst, allyltrimethylsilane [177] and silyl enolates [178] are acylated to give aUyl ketones and /l-dikelories, respectively. 

Chiral haloboranes such as diisopinocampheylchloroborane 2.16 (R = Cl) or cyclic borane 2.61 have been used as catalysts in Diels-Alder reactions or in hydro-cyanation of aldehydes, but poor enantioselectivities were observed [778], Cata-... 

Cyanations. Aluminum complexes with diarylphosphine oxide groups possev cyanation of aldehydes and imines- with in a manner analogous to the Reisser asymmetric Strecker synthesis is applic reactivity of Me SiCN than HCN in the p catalytic amount while supplying stoichica... 

Cyanadons. Aluminum complexes of BINOLs (1) that are armed at C-3 and C-3 with diarylphosphine oxide groups possess both Lewis acid and base centers. Asymmetric cyanation of aldehydes and mines with MeaSiCN, and of quinolines and isoquinolines in a manner analogous to the Reissert reaction is successful (ee 70-90%). The asymmetric Strecker synthesis is applicable to conjugated aldimines and the higher reactivity of Me SiCN than HCN in the presence of 10 mol% of PhOH enables its use in catalytic amount while supplying stoichiometric HCN as the cyanide source. 

Table 4.3 Asymmetric TMS cyanation of aldehydes catalysed with guanidine 13...

The bifunctional catalysts developed by Shibasaki and coworkers effective in the asymmetric cyanation of aldehydes and ketones (see Section 6.2) have been applied to good effect in the cyanation of imines. For instance, aluminium BINOL (6.65) catalyses the cyanation of aromatic and a,p-unsaturated N-fluorenylaldimines using TMSCN in good ee, while gadolinium complexes of the glucose-derived ligand (6.71) and derivatives have been used in the enantioselective cyanation of ketimines. ... 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

Khan and coworkers prepared the ligand 23, which led to complex 24 bearing four titanium atoms after the addition of titanium tetraisopropoxide and water (Scheme 7.17). The cyanation of aldehydes with KCN/AC2O works similarly to complex 19, giving acylated cyanohydrins in nearly quantitative yields and 85-95% enantiomeric excesses. Importantly, complex 24 precipitated after addition of hexane to the reaction mixture, and the filtrated catalyst was reused without affecting the enantiomeric excess (the yield decreases to 88% after 4 runs). 

I. V. P. Raj, G. Suryavanshi, A. Sudalai, Tetrahedron Lett. 2007, 48, 7211—7214. Organocatalytic activation of TMSCN by basic ammonium salts for efficient cyanation of aldehydes and imines. 

After bimetallic [(salen)Al]20 4 was reported in the asymmetric cyanation of aldehydes, the bimetallic [(salan)Al]20 5 was developed by the North group to catalyse the asymmetric addition of trimethylsilyl cyanide to aldehydes. The corresponding cyanohydrins were afforded in 32-78% enantiomeric excess (Scheme 19.2). ... 

Scheme 19.15 Asymmetric cyanation of aldehydes with CNPO(OEt)2 catalysed by an Al-BINOLAM complex.

Table 13.13 Cyanation of aldehydes and ketones catalyzed by Yb(OTf)3 O wu/ -rxx o. OTMS...

A multicomponent bifunctional catalytic system based on a titanium complex was also used for the efficient enantioselective cyanation of aldehydes with ethyl cyanoformate [221]. The catalyst was readily prepared by the reaction of Ti(O Pr)4 with (S)-6,6 -Br2BINOL in combination with cinchonine and (lR,2S)-(—)-N-methylephedrine. As shown in Scheme 14.91, the optimized catalyst combination (10 mol%) promotes the reaction smoothly to afford the desired cyanohydrins ethyl carbonates in moderate to excellent isolated yields (up to 95%) with high enantioselectivities (up to 94% ee). Although the mechanistic aspects... 

Sansano reported the enantioselective cyanation of aldehydes with benzoyl cyanide using BINOLAM-Ti(IV) complex as a catalyst without the presence of additives, good chemical yields and moderate enantioselectivities of the reaction have been achieved (Scheme 14.92) [222]. The Lewis basic side chains at 3,3 -positions of BINOL ligand are believed to play an important role and a bifunctional mechanism has been proposed. 

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