Aldehydes Lewis base-catalyzed

These highly enantioselective Lewis-acid/Lewis-base-catalyzed dialkylzinc and phenylzinc addition reactions to imines give rise to arylalkylamides and diaryl-methylamides in excellent yields and enantioselectivities. Due to the simplicity of the process and the good availability of the imine precursors 23 from the corresponding aldehydes, wide applicability of the reported catalytic reaction can be expected. 

In a related study Denmark and Fan [22] investigated chiral Lewis base-catalyzed enantioselective a-additions of isocyanides to aldehydes in a Passerini-type reaction (Scheme 9.14). The development of the reaction was based on the concept of Lewis base activation of a weak Lewis acid such as SiCl4 forming a trichlorosilyl-Lewis base adduct which is capable of activating aldehydes towards nucleophilic attack. 

Scheme 7.2 Lewis base-catalyzed allylation of aldehydes 1 with allyl trichlorosilanes 2a-d.

Many noticeable examples of chiral Lewis base catalyzed allylation of carbonyl compounds have also appeared. Iseki and coworkers published a full paper on enantioselective addition of allyl- and crotyltrichlorosilanes to aliphatic aldehydes catalyzed by a chiral formamide 28 in the presence of HMPA as an additive [41]. This method was further applied to asymmetric allenylation of aliphatic aldehydes with propargyltrichlorosilane [40]. Nakajima and Hashi-moto have demonstrated the effectiveness of (S)-3,3 -dimethyl-2,2 -biquinoline N,AT-dioxide (29) as a chiral Lewis base catalyst for the allylation of aldehydes [42]. In the reaction of (fs)-enriched crotyltrichlorosilane (54 , E Z=97 3) with benzaldehyde (48), y-allylated anfi-homoallylic alcohol 55 was obtained exclusively with high ee while the corresponding syn-adduct was formed from its Z isomer 54Z (fs Z= 1 99) (Scheme 6). Catalytic amounts of chiral urea 30 also promote the asymmetric reaction in the presence of a silver(I) salt, although the enantioselectivity is low [43]. 

Catalytic asymmetric allylation of aldehydes and ketones with allylsilanes can be achieved by using chiral Lewis acids, transition metal complexes, and Lewis bases. In recent years, much attention has been paid for the chiral Lewis base-catalyzed system using allyltrichlorosilanes. Advances in catalytic asymmetric carbonyl allylation have been described in detail in recent reviews.116,117,117a... 

Mukaiyama and co-workers have reported a high-yielding Lewis base-catalyzed cyanosilylation of aldehydes [79]. The procedure was applied to the cyanosilylation of 22 (Table 2). Treatment of 22 with... 

Recent developments in the field have also identified novel mechanistic pathways for the development of catalytic, asymmetric aldol processes. Thus in addition to Lewis acid catalysts that mediate the Mukaiyama aldol addition by electrophilic activation of the aldehyde reactant, metal complexes that lead to enolate activation by the formation of a metalloenolate have been documented. Additionally, a new class of Lewis-base-catalyzed addition reactions is now available for the asymmetric aldol addition reaction. 

A second distinct process disclosed by Denmark involves the Lewis base-catalyzed addition of enol trichlorosilanes 36 to aldehydes (Eq. 3) [30b]. Remarkably, despite the fact that the imcatalyzed addition of such enol silanes to aldehydes is rapid at -78 C, the use of optically active phosphoramides substantially accelerates the addition reaction and leads to the formation of optically active products. As a consequence of stereochemical studies involving substituted enol trichlorosilanes, Denmark has proposed a hexacoordinated silicon atom as the organizational locus about which enolate and aldehyde are arranged in a cyclic array 37. 

In a novel departure from the traditional approach to the asymmetric Mukaiyama aldol, Denmark has reported a Lewis base-catalyzed aldol addition reaction of enol trichlorosilanes and aldehydes. These unusual silyl ketene acetals are readily prepared by treatment of the tributylstannyl enolates 246 with SiC (Eq. 51). In the initial ground-breaking studies, the methyl acetate-derived trichlorosilyl ketene acetal 247 was shown to add rapidly to a broad range of aldehydes at -80 C to give adducts (89-99% yield, Eq. 52). 

Transition metal-free hydrosilylation of carbonyl compounds can be realized with the use of Brpnsted or Lewis acids as well as Lewis bases. Alkali or ammonium fiuorides (CsF, KF, TBAF, and TSAF) are highly effective catalysts for the reduction of aldehydes, ketones, esters, and carboxylic acids with H2SiPh2 or PMHS. Lithium methoxide promotes reduction of esters and ketones with trimethoxysilane. A generally accepted mechanism of Lewis base-catalyzed hydrosilylation of carbonyl compovmds involves the coordination of the nucleophile to the silicon atom to give a more reactive pentacoordinate species that is attacked by the carbonyl compound giving hexacoordinate silicon intermediates (or transition states), in which the hydride transfer takes place (Scheme 30) (235). 

As a Carbon Nucleophile in Lewis Base-catalyzed Reactions. Allylation of alkyl iodides with allyltrimethylsilane proceeds in the presence of phosphazenium fluoride. Tetra-butylammonium triphenyldifluorosilicate (TBAT) is useful for allylation of aldehydes, ketones, imines, and alkyl halides with allyltrimethylsilane (eq 63). 55 Similarly, TBAHF2 is an effective catalyst for allylation of aldehydes. The homoallylamines are synthesized from allyltrimethylsilane and imines with a catalytic amount of TBAF (eq 64). The reactions of thioketones as well as sulfines with allyltrimethylsilane can be mediated by TBAF to give allylic sulfides and allyl sulfoxides, respectively. Besides fluoride ion, 2,8,9-triisopropyl-2,5,8,9-tetra-aza-1-phosphabi-cyclo[3.3.3]undecane promotes the allylation of aldehydes with allyltrimethylsilane as a Lewis base catalyst (eq 65). ... 

Cyanation. The addition of nitrile functionalities to molecules is a viable route for the introduction of carbonyl derivatives. An example of this approach can be seen in the Lewis base-catalyzed cyanomethylation of benzaldehyde with (trimethylsilyl)propio-nitrile. The Lewis base catalyst activates the Si-C bond of (trimethylsilyl)propionitrile, allowing the subsequent attack at the target aldehyde center, providing the substituted benzylic alcohol in good to excellent yields. However, upon treatment of the same starting materials with both Lewis base catalyst and TBAT, overall yields declined (eq 20). 

Thus in the aldol addition, just as in the case of epoxide-opening reactions, the chloride ion, formed as a necessary consequence of the mechanism of Lewis base catalysis with chlorosilanes, is not innocuous. In fact, it is a competent nucleophile that can attack an aldehyde or an epoxide activated by the Lewis base-coordinated silicenium cation in an intermolecular fashion. The desire to understand these two seemingly inconsistent results obtained in our study of the Lewis base-catalyzed reactions of trichlorosilanes presented an opportunity for the development of novel catalytic processes. For example, if a chloride ion can capture these activated electrophiles, could other exogenous nucleophiles be employed to intercept these reactive intermediates If so, a wide variety of bond-forming processes mediated by the phosphoramide-bound chiral Lewis acid [LB SiCls]" would be feasible. At this point it remained unclear if (1) an exogenous nucleophile could compete with the ion-paired chloride and (2) what kinds of nucleophiles could be compatible with the reaction conditions. 

A similar pattern is observed in the reactions of silyl enol ethers derived from aldehydes. Aldehyde-aldehyde aldol reactions had already been reduced to practice in the context of the Lewis base-catalyzed aldol reaction of trichlorosilyl enol ethers, thanks to the stabilizing effect of the trichlorosilyl chlorohydrin (Scheme 9) [25-27]. Because the product of the aldehyde-aldehyde aldol reaction is an aliphatic aldehyde, it can be quickly transformed into an umeactive chlorohydrin such... 

Denmark SE, Bui T (2005) Lewis base-catalyzed enantioselective aldol addition of acetaldehyde-derived silyl enol ether to aldehydes. J Org Chem 70 10190-10193... 

Denmark SE, Wilson TW, Burk MT, Heemstra JR (2(X)7) Enantioselective construction of quaternary stereogenic caarbons by the lewis base catalyzed additions of silyl ketene imines to aldehydes. J Am Chem Soc 127 14864-14865... 

New challenges were then made to develop useful Lewis base-catalyzed aldol reactions of trimethylsilyl enolates, simple and the most popular silicon enolates. It has recently been found that aldol reactions of trimethylsilyl enolates with aldehydes proceed smoothly under the action of a catalytic amount of lithium diphenylamide or lithium 2-pyrrilidone in DMF or pyridine (Eq. (38)) [57]. This Lewis base-catalyzed aldol reaction of trimethylsilyl enolates [58] has an advantage over acid-catalyzed reactions in that aldol reaction of carbonyl compounds with highly-coordinative functional groups with Lewis acid catalysts are smoothly catalyzed by Lewis bases to afford the desired aldol adducts in high yields. 

Scheme 3-113. Chiral Lewis-base catalyzed enantioselective allylation of aldehydes using allylsilanes.

Another example is the asymmetric cyanosilylation of aldehydes catalyzed by bifunctional catalyst 131.100 Compound 131 contains aluminum, the central metal, acting as a Lewis acid, and group X, acting as a Lewis base. The asymmetric cyanosilylation, as shown in Scheme 8-50, proceeds under the outlined... 

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. 

Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several highly enantioselective carbon-carbon bond forming reactions [92-98]. In these reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis acid component and only catalytic amount of chiral Lewis base were used. The chiral Lewis acid species desired for the transformations was generated in situ. The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good yield and high enantioselectivity and diastereoselectivity. 

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. 

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