Imine nucleophilic addition

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

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... 

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 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 ... 

Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form carbinol-amines. These carbinolamines dehydrate under the conditions of their formation to give A/-substituted imines. Secondary amines yield enamines. 

Carbinolamines are formed by nucleophilic addition of an amine to a carbonyl group and are intermediates in the formation of imines and enamines. 

The mechanism for the formation of ( )-169 is explained in terms of an intermolecular nucleophilic dimerization. Nucleophilic addition of C-3 of 19 to the 3 position of the initially generated cation 168 gives an imine-nitrone... 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

Nucleophilic Addition of Amines Imine and Enamine Formation... 

Imine formation and enamine formation appear different because one leads to a product with a C=N bond and the other leads to a product with a C=C bond. Actually, though, the reactions are quite similar. Both are typical examples of nucleophilic addition reactions in which water is eliminated from the initially formed tetrahedral intermediate and a new C=Nu bond is formed. 

The key step is nucleophilic addition to yield a carbinolamine intermediate, which then loses water to give the imine. 

We can explain the observed pH dependence of imine formation by looking at the individual steps in the mechanism. As indicated in Figure 19.8, an acid catalyst is required in step 3 to protonate the intermediate carbinolamine, thereby converting the —OH into a better leaving group. Thus, reaction will be slow if not enough acid is present (that is, at high pH). On the other hand, if too much acid is present (low pH), the basic amine nucleophile is completely protonated, so the initial nucleophilic addition step can t occur. 

Each of the following substances can be prepared by a nucleophilic addition reaction between an aldehyde or ketone and a nucleophile. Identify the reactants from which each was prepared. If the substance is an acetal, identify the carbonyl compound and the alcohol if it is an imine, identify the carbonyl compound and the amine and so forth. 

Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with nucleophiles to yield 5p2-hybridized imine anions in a reaction analogous to the formation of an sp3-hybridized alkoxide ion by nucleophilic addition to a carbonyl group. 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

O Nucleophilic addition of hydroxide ion to the CN triple bond gives an imine anion addition product. 

Reduction Conversion of Nitriles into Amines Reduction of a nitrile with LiAIH4 gives a primary amine, RNH . The reaction occurs by nucleophilic addition of hydride ion to the polar C=N bond, yielding an imine anion, which still contains a C=N bond and therefore undergoes a second nucleophilic addition of hydride to give a dianion. Both monoanion and dianion intermediates are undoubtedly stabilized by Lewis acid-base complexafion to an aluminum species, facilitating the second addition that would otherwise be difficult Protonation of the dianion by addition of water in a subsequent step gives the amine. 

Reductive amination takes place by the pathway shown in Figure 24.4. An imine intermediate is first formed by a nucleophilic addition reaction (Section 19.8), and the C=N bond of the imine is then reduced. 

Reductive animations also occur in various biological pathways, fn the biosynthesis of the amino acid proline, for instance, glutamate 5-semjaldehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the C=N bond. 

Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

Q An amino acid reacts with the enzyme-bound PLP inline by nucleophilic addition of its -NH2 group to the C=N bond of the imine, giving a PLP-amino acid imine and releasing the enzyme amino group. 

Hydrolysis of the a-keto acid imine by nucleophilic addition of water to the C=M bond gives the transamination products pyridoxamine phosphate (PMP) and a-keto acid. 

In spite of the steric and electronic differences, the nucleophilic addition of enolates to imines (aza aldoi reaction) proceeds probably through similar pericyclic transition states as the carbonyl compounds do. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

The aza-Henry reaction is the nucleophilic addition of nitroalkanes to imines to give nitroamine derivatives. This reaction was also studied with metal-based catalysts [164]. 

The addition of terminal acetylenes to imines is an important reaction because of the importance of these products as building blocks. Conventionally, the addition reaction shown in Scheme 5.2 is performed with stoichiometric amounts of butyllithium in a step that is, separate from the subsequent nucleophilic addition reaction (see (b)). Carreira has recently developed a procedure that utilizes an iridium catalyst to effect the addition reaction to a wide range of aldimines and ketimines (see (a)). ... 

Imines and iminium ions are nitrogen analogs of carbonyl compounds and they undergo nucleophilic additions like those involved in aldol reactions. The reactivity order is C=NR < C=0 < [C=NR2]+ < [C=OH]+. Because iminium ions are more reactive than imines, the reactions are frequently run under mildly acidic conditions. Under some circumstances, the iminium ion can be the reactive species, even though it is a minor constituent in equilibrium with the amine, carbonyl compound, and unprotonated imine. 

The selectivity of RNH2 on M/A1203 and Raney catalysts decreased in the order Co Ni Ru>Rh>Pd>Pt. This order corresponds to the opposite sequence of reducibility of metal-oxides [8] and standard reduction potentials of metalions [9], The difference between Group VIII metals in selectivity to amines can probably been explained by the difference in the electronic properties of d-bands of metals [3], It is interacting to note that the formation of secondary amine, i.e. the nucleophilic addition of primary amine on the intermediate imine can also take place on the Group VIII metal itself. Therefore, the properties of the metal d-band could affect the reactivity of the imine and its interaction with the amine. One could expect that an electron enrichment of the metal d-band will decrease the electron donation from the unsaturated -C=NH system, and the nucleophilic attack at the C atom by the amine [3], Correlation between selectivity of metals in nitrile hydrogenation and their electronic properties will be published elsewhere. 

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