Nucleophiles imine addition

The majority of chemical commodities (plastics, foams, pharmaceuticals, agrochemicals) are made from rapidly depleting petrochemical feedstocks. Consequently, there is a growing need to develop catalytic methods for the direct manufacture of chemical products from abundant renewable resources in the absence of stoichiometric byproducts [1], In the specific case of carbonyl and imine addition, a departure from the use of premetallated nucleophiles represents a particularly important focus. Progress in this area will depend largely upon the discovery of new chemical reactivity. 

Scheme 14.7 General mechanism for the nucleophilic radical addition to imines mediated by Ti (IV).

Compared with aldehydes and ketones, aldimines and ketimines are less reactive towards nucleophilic addition. Furthermore, imine additions are subject to steric constraints, and rapid deprotonation proceeds with imines bearing ot-hydrogen atoms. The Lewis acid promoted addition methodology has provided a solution to these problems. 

While the abstraction of protons adjacent to the carbon-nitrogen double bond of imines/imine derivatives has been utilized for tiie regioselective generation of azaallyl anions (which are useful in asymmetric ketone synthesis), it competes with and often prevents the addition of nucleophiles to imines. For this reason, imine additions often involve azomethines (e.g. benzylidineanilines) which are not capable of enolization. Many potentially useful additions, however, involve substrates capable of proton abstraction. By avoiding in certain instances some of the structural features of imines/imine derivatives and the reaction conditions responsible for proton abstraction, products resulting from this serious side reaction can be minimized. 

EAN in Addition Reactions of Carbonyl Compound with Nitrogen Nucleophile Imine Formation... 

Tomioka and co-workers have also disclosed a catalytic enantioselective process for the alkylation reaction described just above, by the use of a substoichio-metric amount of the chiral tridentate ligand la [19bj. To compare the data obtained from both stoichiometric and substoichiometric processes, MeLi and n-BuLi were used as the carbon nucleophiles in additions to the imines 2a-d. Sub-... 

Ir -aUyl complexes can also act as nucleophiles in additing to various electrophiles such as aldehydes, ketones, or imines. Krische et al. [143d] have developed a broad new family of enantioselective allylations via hydrogenations and transfer... 

The gold-catalyzed inter- and intramolecular addition of carbon- and heteronucleophiles to alkynes leads to a wide variety of products [6]. In the case of nitrogen nucleophiles, the addition of amines, anihnes [67, 68], imines [69], pyridines and azides [72] is possible (Scheme 1.1). 

Povarov-type imine addition followed by trapping the oxocarbenium ion intermediate with an internal nucleophile, particularly electron-rich aromatic systems. 

Activation of Carbon-Carbon r-Bonds. The title compound can form adducts with unpolarized jr-systems, allowing the addition of soft nucleophiles. The addition of /3-dicarbonyls onto alkynes is the most reported instance of this type of reaction, with both intramolecular and intermolecular examples. Welding grade acetylene can even be used as the alkene substrate (eq 35). Imines can also be used as nucleophiles, and then a second nucleophile such as an allylstannane can react with the intermediate iminiumto yield dihydroisoquinolines (eq 36). ... 

The carbinolamine is formed by nucleophilic addition of the amine to the carbonyl group Its dehydration gives the imine product... 

Imines are formed by nucleophilic addition of a primary amine to the carbonyl group of an al dehyde or a ketone The key step is formation of a carbinolamine intermedi ate which then dehy drates to the imine... 

Carbinolamines are formed by nucleophilic addition of an amine to a carbonyl group and are intermediates in the for mation of imines and enamines Carbocation (Section 4 8) Positive ion in which the charge re sides on carbon An example is tert butyl cation (CH3)3C Carbocations are unstable species that though they cannot normally be isolated are believed to be intermediates in certain reactions... 

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

The other C=N systems included in Scheme 8.2 are more stable to aqueous hydrolysis than are the imines. For many of these compounds, the equilibrium constants for formation are high, even in aqueous solution. The additional stability can be attributed to the participation of the atom adjacent to the nitrogen in delocalized bonding. This resonance interaction tends to increase electron density at the sp carbon and reduces its reactivity toward nucleophiles. 

As with simple imines, the identity of the rate-limiting step changes with solution pH.. s the pH decreases, the rate of the addition decreases because protonation of the amino compound reduces the concentration of the nucleophilic unprotonated form. Thus, whereas the dehydration step is normalfy rate-determining in neutral and basic solution, addition becomes rate-determining in acidic solutions. 

The kinetics of the hydrolysis of some imines derived from benzophenone anc primary amines revealed the normal dependence of mechanism on pH with ratedetermining nucleophilic attack at high pH and rate-determining decomposition of the tetrahedral intermediate at low pH. The simple primary amines show a linear correlation between the rate of nucleophilic addition and the basicity of the amine Several diamines which were included in the study, in particular A, B, and C, al showed a positive (more reactive) deviation from the correlation line for the simple amines. Why might these amines be more reactive than predicted on the basis of thei ... 

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