Imines electrophilic activation

After having proven that BINOL phosphates serve as organocatalysts for asymmetric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of electrophilic activation of imines by means of chiral phosphoric acids might be applicable to further asymmetric transformations. Other groups recognized the potential of these organocatalysts as well. They showed that various nucleophiles can be used. Subsequently, chiral phosphates were found to activate not only imines, but also other substrates. 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

Hydrogen bonding to substrates such as carbonyl compounds, imines, etc., results in electrophilic activation toward nucleophilic attack (Scheme 3.1). Thus, hydrogen bonding represents a third mode of electrophihc activation, besides substrate coordination to, for example, a metal-based Lewis acid or iminium ion formation (Scheme 3.1). Typical hydrogen bond donors such as (thio)ureas are therefore often referred to as pseudo-Lewis-acids. ... 

Although phosphoric acids have found broad applicability for a wide range of asymmetric transformations, most reactions are limited to electrophilic activation of imines. Expanding the scope of phosphoric acid catalysis to other classes of electrophiles, Akiyama and Terada subsequently reported activation of nitroalkene [38] and carbonyl [39] electrophiles, respectively (Scheme 5.23). 

Another important means of mediation of metal-free catalytic enantioselective Mannich-type reactions is via electrophilic activation of the preformed imines by chiral Bronstedt acids [7, 8, 46], By using this strategy Terada and coworkers performed chiral phosphoric acid-catalyzed direct asymmetric Mannich-type reactions between Boc-protected imines and acetoacetone that furnished aryl /3-amino... 

Intermolecular carbon-carbon bond formation of alkenylsilanes by electrophilic substitution is rather limited except for the reaction with acyl chlorides.1. The alkenylations of imines and epoxides are achieved with electronically activated alkenylsilanes (Equation (3)).2 a Alkynylsilanes have frequently been used for intermolecular alkynylation of carbon electrophiles activated by a Lewis acid.30 30a-30d... 

One entrance into the chemistry of sulfimide-based functional groups is electrophilic activation of the corresponding sulfoxides with triflic anhydride and subsequent reaction of the resulting sulfonium salts with trifluoromethane sulfonamide [39[ (Scheme 2.179). The other entrance is oxidative imination of a sulfoxide then trifluoromethanesulfonylation of the resulting imidosulfone [40]. 

Overall, the carbonylation of alkynes is rather complex, but it is possible to draw a general trend and to divide these processes into three classes depending on the alkyne (i) For most internal alkynes, the carbon-carbon bond-forming process can involve an acylpalladation step whether there is an isomerization or not. (ii) However, some of them may involve an electrophilic activation of the triple bond by the acylpalladium complex followed by nucleophilic attack and reductive elimination, (iii) On the other hand, terminal alkynes appear to undergo mostly cross-coupling for the first carbon-carbon bond formation. Aside from these mechanistic intricacies, it is important to point out that these processes usually involve incorporation of more than one molecule of CO and creation of two to three carbon-carbon bonds in one reaction, and they yield heterocycles in fair to good yields. Other multiple bond systems like alkenes, imines or dienes also provide nice entries to carbo- and heterocycles. The limitations are usually due to the necessary time balance between acylpalladation and the termination step to avoid polymeric or decarbonylation processes. 

In 1973, Mukaiyama and his co-workers reported the use of silyl enol ethers as ketone enolate equivalents. Silyl enol ethers react with aldehydes in the presence of a stoichiometric amount of TiCU as a Lewis acid (Scheme 3-78). The Lewis acid is considered to electrophilically activate aldehydes. Since this landmark discovery, many efforts have been made to improve the original protocol, especially focusing on the use of a catalytic amount of Lewis acid catalysts.A wide variety of metal complexes and nonmetallic cationic compounds is now applicable to this reaction as a catalyst. Not only aldehydes but also acetals, ketones, and imines have been extensively employed as electrophiles for the aldol reactions. The reaction generally proceeds via an acyclic transition state, in which the electron-rich double bond of enol silyl ethers approach carbonyls activated by a Lewis acid (Scheme 3-79). In most cases, acyclic transition state with an antiperiplanar orientation of reactants well accounts for observed diastereoselectivities. ... 

Dinitrogen-fused heterocycles have been formed in high yield by thermal 3-1-2-cycloadditions of two types of azomethine imines with allenoates. Rhodium-catalysed formal 3 -l- 2-cycloadditions of racemic butadiene monoxide with imines in the presence of a chiral sulfur-alkene hybrid ligand have furnished spirooxindole oxazolidines and 1,3-oxazolidines stereoselectively. ° Formation of 1,2-disubstimted benzimidazoles on reaction of o-phenylenediamine with aldehydes is promoted by fluorous alcohols that enable initial bisimine formation through electrophilic activation of the aldehyde. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

A-Acido imines (R R"C = N —X=0) like /V-acyl (X = CR) /V-sulfonyl [X = S(R)=0]2-7 or /V-diphenylphosphinoylimines [X = P(C6H5)2]3 are masked inline derivatives of ammonia. Compared to the imines themselves these activated derivatives are better electrophiles showing less tendency to undergo undesired deprotonation rather than addition of organometal-lics1812 The apparent advantages of these compounds have been exploited for asymmetric syntheses of amines, amides, amino acids and /J-lactams1-8 I6. 

The assumed mechanism includes the activation of acetonitrile by iV-coordination to the metal center, followed by deprotonation with DBU. The generated carbanion, iV-coordinated to the ruthenium atom, adds to the corresponding electrophile, while the presence of the sodium salt allows the regeneration of the ruthenium catalyst. Both various types of aldehydes as well as activated aromatic imines have been successfully employed as electrophiles, providing the corresponding adducts 171 in good to high yields. 

Equation 9.9 shows a remarkable example of the simultaneous asymmetric construction of three stereogenic centers by the aforementioned reaction of an enyne—titanium complex (see Scheme 9.4) [25], using imines derived from optically active phenylethylamine as the electrophile. 

The synthesis of optically active compounds by the diastereoselective reaction of allyltitanium reagents with chiral electrophiles has also been reported. The reaction of allyltitanium reagents with chiral imines proceeds with excellent diastereoselectivity, as shown in Eq. 9.28, thus providing a new method for synthesizing optically active homoallylic amines with or without a P-substituent [51,52],... 

Aldehydes and imines derived from them can undergo electrophilic attack of activated aromatic systems under harsh hydroformylation conditions (Scheme 25). 

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

This compound removes a proton from the carboxylic acid, producing a cation that is readily attacked by the carboxylate nucleophile across one of the C-N double bonds - the protonated imine behaves as a good electrophile (see Section 7.7.1). The product is now an activated ester (an O-acylisourea) that can be attacked by any available nucleophile. The amino group of the second amino acid derivative provides the nucleophile, resulting in expulsion of a very stable urea as the leaving group, and production of the... 

In enantioselective enamine catalysis, the enamine can control the approach of the electrophile either by the steric bulk of the enamine or by directing the electrophile with an activating group. As can be readily observed with relatively unreactive electrophiles, such as aldehydes, ketones or imines, additional assistance for catalysis can be provided by suitably positioned hydrogen bond donors and/or other acids (Scheme 6) [46]. 

Although imines are less electrophilic than carbonyl compounds, they are also more readily activated by acids or hydrogen bonding. For this reason, Mannich reactions are often faster than the corresponding aldol reactions. It is not even necessary to use preformed imines. In a typical three-component Mannich reaction, the acceptor imine is generated from an aromatic or otherwise protected primary amine. 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

In 2007, AntiUa and coworkers described the Brpnsted add-catalyzed desymmetrization of me yo-aziridines giving vicinal diamines [75]. hi recent years, chiral phosphoric acids have been widely recognized as powerful catalysts for the activation of imines. However, prior to this work, electrophiles other than imines or related substrates like enecarbamates or enamides have been omitted. In the presence of VAPOL-derived phosphoric acid catalyst (5)-16 (10 mol%) and azidotrimethylsilane as the nucleophile, aziridines 129 were converted into the corresponding ring-opened prodncts 130 in good yields and enantioselectivities (49-97%, 70-95% ee) (Scheme 53). 

Electrophilic aromatic substitution of 708 with the iron-coordinated cation 602 afforded the iron-complex 714 quantitatively. The iron-mediated quinone imine cyclization of complex 714, by sequential application of two, differently activated, manganese dioxide reagents, provided the iron-coordinated 4b,8a-dihydrocarbazole-3-one 716. Demetalation of the iron complex 716 with concomitant... 

Electrophilic substitution at the arylamine 709 using the complex salt 602, provided the iron complex 725 quantitatively. Sequential, highly chemoselective oxidation of the iron complex 725 with two, differently activated, manganese dioxide reagents provided the tricarbonyliron-complexed 4b,8a-dihydrocarbazol-3-one (727) via the non-cyclized quinone imine 726. Demetalation of the tricarbonyliron-complexed 4b,8a-dihydrocarbazol-3-one (727), followed by selective O-methylation, provided hyellazole (245) (599,600) (Scheme 5.70). 

Electrophilic aromatic substitution of the arylamine 780a using the iron-complex salt 602 afforded the iron-complex 785. Oxidative cyclization of complex 785 in toluene at room temperature with very active manganese dioxide afforded carbazomycin A (260) in 25% yield, along with the tricarbonyliron-complexed 4b,8a-dihydro-3H-carbazol-3-one (786) (17% yield). The quinone imine 786 was also converted to carbazomycin A (260) by a sequence of demetalation and O-methylation (Scheme 5.86). The synthesis via the iron-mediated arylamine cyclization provides carbazomycin A (260) in two steps and 21% overall yield based on 602 (607-609) (Scheme 5.86). 

---