Imines from nucleophilic addition

The reaction of primary amines with aldehydes and ketones do not give the products expected from nucleophilic addition alone. This is because of the further reaction taking place once nucleophilic addition occurs, e.g. consider the reaction of acetaldehyde (ethanal) with a primary amine methylamine (Following fig.). The product contains the methylamine skeleton, but there is no alcohol group and there is a double bond between the carbon and the nitrogen. This product is known as imine or a Scbiffbase. 

In some cases, vinylidene complexes undergo [2-t-2] reactions that are characteristic of Fischer and Schrock carbene complexes. However, these [2+2] reactions involving vinylidene complexes can result from nucleophilic addition at the central carbon, rather than a concerted [2+2] process. For example, the reaction of an imine with the iron-vinylidene complex in Equation 13.28 leads to formation the product of a [2+2] reaction between the carbon-nitrogen double bond and the carbon-carbon double bond. ° - This reaction is believed to occur by nucleophilic attack of the nitrogen at the central carbon, followed by ring closure at the p-carbon, instead of a concerted [2+2] process. 

A wide range of these subunits can be prepared from the corresponding carbonyl derivatives in typically three reaction steps that include imine formation, nucleophilic addition, and protecting group (PG) cleavage (Scheme 6.1). The importance of the PG in the imine moiety lies in its ability to activate the substrate for nucleophilic addition. 

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 ... 

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. 

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. 

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). 

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)). ... 

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. 

Fig. 6.25. Simplified mechanism of two degradation reactions between peptides and reducing sugars occurring in solids, a) Maillard reaction between a side-chain amino (or amido) group showing the formation of an imine (Reaction a), followed by tautomerization to an enol (Reaction b) and ultimately to a ketone (Reaction c). Reaction c is known as the Amadori rearrangement (modified from [8]). b) Postulated mechanism of the reaction between a reducing sugar and a C-terminal serine. The postulated nucleophilic addition yields an hemiacetal (Reaction a) and is followed by cyclization (intramolecular condensation Reaction b). Two subsequent hydrolytic steps (Reactions c and d) yield a serine-sugar conjugate and the des-Ser-peptide...

Finally, reaction of 2,4-diphenyl-5(4//)-oxazolone 322 with 4-phenyl-A -tosyl-1-azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-A-tosyl-1-azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6-triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324—327. The marked differences in reactivity of 4-phenyl-A-tosyl-l-azabuta-l,3-diene relative to A-alkyl- or A-aryl-1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107). ... 

Common reactions of the ylide include (i) [2,3]-sigmatropic rearrangement of allylic, propargylic, and allenic ylides (ii) [l,2]-shift (Stevens rearrangement) (iii) 1,3-dipolar cycloaddition of the ylide generated from carbonyl compounds or imines with dipolarophiles, usually G=G or C=C bonds and (iv) nucleophilic addition/elimination, leading to the formation of epoxides or cyclopropanes (Figure 2). 

The nucleophilic addition of organometallic reagents to imines provides an attractive route to amines [4]. Recendy, however, some completely different approaches to the synthesis of a-aryl amine were reported. Hayashi and Ishigeda-ni found a new catalytic system for the asymmetric addition of arylstannanes to imines derived from aromatic aldehydes (Scheme 11) [20]. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

The Mannich reaction [18, 19] is a widely applied means of producing /i-amino carbonyl compounds starting from cheap and readily available substrates. In this reaction an aldehyde 20, an amine 21, and a ketone 22 react in a three-component-one-pot synthesis (Scheme 5.12, pathway 1). As a synthetic alternative, the reaction can also be performed as a nucleophilic addition of a C-nucleophile 22 to a preformed imine 24 which is prepared starting from the aldehyde and an amine source (Scheme 5.12, pathway 2). 

Little is known with certainty in connection with the key step that involves the nucleophilic addition of the organic ligand from the boronate to the imine. One proposal is that the transfer is actually intramolecular, and takes place via the adduct pictured above ... 

The regioselectivity of the double nucleophilic addition of ketene silyl acetals to a,/3-unsaturated imines has been found to be highly dependent on the subtle difference in the reactivities of the ketene silyl acetals the factors are mainly derived from the ability of the ketene silyl acetals to undergo the silicon-aluminium exchange reaction, where the aluminium enolate preferentially undergoes 1,4-addition.209... 

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