Imines as electrophiles

The naphthalene-catalyzed (3%) lithiation of carbamoyl or thiocarbamoyl chlorides 91 in the presence of carbonyl componnds or imines as electrophiles in THF at temperatnres ranging between —78 to 20 °C led to the expected fnnctionalized amides or thioamides 92 after hydrolysis (Scheme 39) . ... 

The organolithium compounds, formed by deprotonation of Af-benzylic-Af-Boc p-anisole carbamates, react with imines to yield tran5-4,5-disubstituted 1,3-imidazolin-2-ones in good yield and excellent stereoselectivity (Scheme 52). Benzaldehydes gave poor stereoselectivity, and the nse of imines as electrophiles is critical. The stereoselectivity can be explained by the transition states shown, in which the aryl and R substituents on the 4-membered ring are trans to one another. 

Although asymmetric reactions using chiral Lewis acids are of great current interest as one of the most efficient methods for the preparation of chiral compounds, examples using imines as electrophiles are rare compared to those us-... 

A more direct way for the preparation of carbamoyl and thiocarbamoyllithiums started from carbamoyl and thiocarbamoyl chlorides 119 and used lithium powder and a catalytic amount of naphthalene (3 mol%)113,114. The lithiation was performed at —78°C in the presence of carbonyl compounds and imines as electrophiles to yield products 120 (Scheme 32). Phenyl isocyanate and DMF afforded oxamides in modest yields (21 and 42%, respectively). 

Using the hint, we have the dimerization step and then we have a number of options to get to the cyclic trimer. As long as you use amines as nucleophiles and imines as electrophiles, the precise order of events doesn t matter very much. Cyclization to form a six-membered ring will beat addition of a fourth cyanamide molecule and thermodynamically the trimerization is very favourable as melamine is aromatic. 

In addition to the imine as electrophilic reagent, N, O acetals were also employed for the aza MBH reaction. Using the camphor sulfonic add derivative, sulfide catalyst... 

Considerable effort has been made in developing iV-diphenylphosphinoyl (Dpp) aid- and keto-imines as electrophilic partners in copper-catalyzed 1,2-additions (Scheme 1-10). Thioamides and aldimines e.g., 123) in the presence of a soft Lewis acidic Cu(I) salt complexed by 6/5-phosphine 124, together with a hard base in the form of a lithium phenoxide, react to afford products in good-to-excellent ee s. Activation resulting from a likely Cu-S interaction increases the acidity of an a-proton and, hence, more facile deprotonation. With alkyinitriles as nucleophiles generated via an initial decarboxylative process e.g., from 125), a DTBM-SEGPHOS-coordinated copper complex arrives at C-C bond formation in usually >80% ee. 

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. 

Stereoselective addition of organometallics to C=N bond is not fully understood due to a number of difficulties. First, imines are not as electrophilic as... 

One possible solution of this problem is to differentiate a radical first as electrophilic or nucleophilic with respect to its partner, depending upon its tendency to gain or lose electron. Then the relevant atomic Fukui function (/+ or / ) or softness f.v+ or s ) should be used. Using this approach, regiochemistry of radical addition to heteratom C=X double bond (aldehydes, nitrones, imines, etc.) and heteronuclear ring compounds (such as uracil, thymine, furan, pyridine, etc.) could be explained [34], A more rigorous approach will be to define the Fukui function for radical attack in such a way that it takes care of the inherent nature of a radical and thus differentiates one radical from the other. 

Many other examples, even with less reactive imine precursors as electrophiles, demonstrate that this type of dihydropyrrole synthesis has a very broad range. Eqs 8.21-8.24 present selected examples of the addition of lithiated methoxyallene 42 to... 

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. 

Phenone imines 587 were lithiated with lithium and a catalytic amount of naphthalene (8%) in the presence of different carbonyl compounds as electrophiles in THF at temperatures ranging between —78 and room temperature, giving, after hydrolysis with water, the corresponding 1,2-aminoalcohols 588 (Scheme 154). ... 

Halogen-free JV-acyl aldimines and JV-acyl ketnmnes tautomenze readily to give enamides [36] In contrast, perfluonnated W-acyl imines are stable compounds These electron-deficient imines not only exhibit high thermal stability but also show unique properties both as electrophiles and as strongly polarized hetero-1,3-dienes... 

Because of their significant electrophilic character, aldehydes are often unstable and will react with nucleophiles. For example, a common reaction of aldehydes is the formation of a hemiaminal with amines. If the amine is a primary amine, the hemiaminal can dehydrate to form an imine as shown in Figure 21. The reaction of aldehydes with primary and secondary amines is a well-studied reaction pathway because it is a common reaction pathway of reducing sugars and amino acids, and this reaction pathway is known as the Maillard reaction (40). In the case of amino acids and sugars, this reaction leads to discoloration, or browning. This reaction will be discussed in greater detail in the Amines-Maillard Reaction section. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Scheme 2.1 The enamine catalytic cycle. An enamine derived from an amine- or amino acid-catalyst can react with a variety of electrophiles. The aldehyde and ketone reactants that form enamines and act as nucleophiles are often described as donors . Aldehyde and imine reactants that serve as electrophiles are described as acceptors for aldol and Mannich reactions, respectively. Ketones also serve as acceptors for aldol reactions.

Aldehydes, ketones, carboxylic esters, carboxylic amides, imines and N,A-disubstiluted hydrazones react as electrophiles at their s/ 2-hybridized carbon atoms. These compounds also become nucleophiles, if they contain an H atom in the a-position relative to their C=0 or C=N bonds. This is because they can undergo tautomerization to the corresponding enol as seen in Chapter 12. They are also C,H-acidic at this position, i.e., the H atom in the a-position can be removed with a base (Figure 13.1). The deprotonation forms the conjugate bases of these substrates, which are called enolates. The conjugate bases of imines and hydrazones are called aza enolates. The reactions discussed in this chapter all proceed via enolates. 

The obviously low electrophilicity of the C=N double bonds of aldimines precludes the addition of the azaenolate to remaining aldimine in the course of aldimine deprotonation. The aldimine enolate is obtained quantitatively and then reacted with the alkylating reagent. This step results cleanly in the desired product, again because of the low electrophilicity of imines as the alkylation progresses, azaenolate and the alkylation product coexist without reacting with each other, no aldol-type reaction, no proton transfer. All the azaenolate is thus converted... 

We made the point above that the difference in reactivity between an iminium ion and an oxonium ion is that an iminium ion can lose H+ and form an imine or an enamine, while an oxonium ion reacts as an electrophile. Iminium ions can, however, react as electrophiles provided suitable nucleophiles are present. In fact, they are very good electrophiles, and are significantly more reactive than... 

A more direct access to imidoyllithiums was to perform the lithiation of imidoyl chlorides 72 with lithium and substoichiometric amounts of naphthalene at low temperatures so that intermediates 73 were generated (Scheme 19)65,81. Aldehydes, ketones and acyl chlorides have been used as electrophilic reagents to afford imines 74 or the corresponding ketones, depending on the hydrolysis conditions. 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

Recently, the bis(methylthio)methylene imine of pseudoephedrine glycinamide was shown to undergo diastereoselective alkylation at 23 °C with lithium terf-butoxide or sodium ethoxide as base and various alkyl halides as electrophiles (eq 21 ). This procedure was used to prepare enantiomerically enriched a-amino acids. 

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