For imine formation

The Staudinger-aza-Wittig cyclization methodology for imine formation can also be applied to the synthesis of oxazolines under essentially neutral conditions.Thus, an azido ester such as 281 reacts with triphenylphosphine to give the oxazoline 283 in excellent yield. There was no evidence for cychzation at the benzoate presumably because cyclization to a five-membered ring is faster than... 

Secondary amine reacts with aldehyde and ketone to produce enamine. An enamine is an a,P-unsaturated tertiary amine. Enamine formation is a reversihle reaction, and the mechanism is exactly the same as the mechanism for imine formation, except the last step of the reaction. 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

The mechanism for imine formation proceeds through the following steps ... 

The synthesis of enantiopure amino-functionalized compounds such as a- and (3-amino acids or nonfunctionalized amines can be envisaged by the use of aldehydes, ketones, a- or (3-keto acids, or derivatives thereof as substrates for imine formation followed by, for example, diastereoselective Strecker reactions, reductions, or organometallic addition reactions. In the literature, diastereoselective syntheses based on a large variety of chiral auxiliaries, such as a-arylethylamines,4... 

The mechanism for formation of the hydrazone is the same as the mechanism for imine formation (Key Mechanism 18-5 in Section 18-15). The actual reduction step involves two tautomeric proton transfers from nitrogen to carbon (Mechanism 18-7). In this strongly basic solution, we expect a proton transfer from N to C to occur by loss of a proton from nitrogen, followed by reprotonation on carbon. A second deprotonation sets up the intermediate for loss of nitrogen to form a carbanion. This carbanion is quickly reprotonated to give the product. 

Notice that an acid catalyst is normally added for imine formation. Without an acid catalyst, the reaction is veiy slow, though in some cases it may still take place (oximes, for example, will form without acid catalysis, but form much faster with it). It s important to notice that acid is not needed for the addition step in the mechanism (indeed, protonation of the amine means that this step is very slow in strong acid), but is needed for the elimination of water later on in the reaction. Imine formation is in fact fastest at about pH 4-6 at lower pH, too much amine is protonated and the rate of the first step is slow above this pH the proton concentration is too low to allow protonation of the OH leaving group in the dehydration step, Imine formation is like a biological reaction it is fastest near neutrality. 

The original Kabachnik-Fields procedure employing ammonia as the amine component used ammonia in ethanol and the reactions were performed in sealed vessels at circa 100°C.90,123 This method avoids such conditions by using ammonium acetate as the source of ammonia, and it is also thought to act as an acid catalyst for imine formation other ammonium salts were unsatisfactory. Addition of water to produce a homogeneous reaction mixture resulted in diethyl 1-hydroxy-1-benzylphosphonate formation (i.e. from direct attack of diethyl phosphite 25 on benzaldehye, a common side reaction in the Kabachnik-Fields reaction). The yields of this reaction are serviceable, and better for aromatic than aliphatic aldehydes. The product 58 may be further purified by crystallization as the hydrochloride salt by treatment of 58 with hydrogen chloride in ethanol/diethyl ether.122... 

The mechanism for enamine formation (Mechanism 21.6) is identical to the mechanism for imine formation except for the last step, involving formation of the n bond. The mechanism can be divided into two distinct parts nucleophilic addition of the 2° amine, followed by elimination of H2O. Each step involves a reversible equilibrium once again, so that the reaction is driven to completion by removing HpO. 

The imines thus formed are often not isolated but are, instead, reduced directly to amines. Although NaBH3(CN) is a very common reducing agent, NaBH4 or other reagents shown in Table 23 can also be used. When preparation and reduction of the imine are performed successively in the same apparatus, Ti(0-/-Pr)4 seems to be a more suitable reagent than TiCU for imine formation (Eq. 249) [573]. Preparation of several amines by use of this sequence is shown in Table 23. 

The pathway involving cyclization of a protonated migrating group provides a very appealing alternative to the fragmentation-recombination pathway. Given the lack of evidence for imine formation, it is interesting to note that the formation of a protonated imine (14-H ) in the model system can alternatively arise formally as the result of removal of a hydride ion from the parent (saturated) system (12), aminopropyl (path e. Scheme 9). 

Figure 10.3 Simplified problem space for imine formation, example 10.5.2.

Imine formation is a very important biochemical process. It has an interesting behavior that shows a maximum in the pH rate profile (Fig. 10.5). Using the previous mechanism postulated for imine formation, examine extremes in pH to understand the figure. What would you expect to happen in strong acid to slow the reaction down How about in strong base ... 

Commercially available diamine-functionalized trityl-based resins were found to be unsuitable starting materials due to their poor swelling in trimethyl orthoformate, the solvent of choice for imine formation. 

The reagent for the vinyl anion needs to be compatible with the conditions for imine formation and the choice fell on a vinyl silane 132. The stereogenic centres in the ring can be controlled by an epoxide 133 in combination with some other vinyl silane reagent 134. 

The catalytic efficiency was at least partially due to the depression of lysine pfC values caused by the presence of neighboring protonated lysines in the folded helix, and the resulting increased propensity for imine formation. Although the peptide was partially disordered there appeared to be a correlation between helical content and catalysis and specific acid catalysis was an important feature of the reaction mechanism. Follow up publications by Allemarm in ordered polypeptide scaffolds showed enhanced activity [25]. 

For simple alkyl amines, the K for imine formation in aqueous solution is defined as... 

Equilibrium Constants for Imines Formation with 2-Methylpropanal... 

In the first step of the mechanism for imine formation, the amine attacks the carbonyl carbon. Gain of a proton by the alkoxide ion and loss of a proton by the ammonium ion forms a neutral tetrahedral intermediate. The neutral tetrahedral intermediate, called a carbinolamine, is in equilibrium with two protonated forms. Protonation can take place on either the nitrogen or the oxygen atom. Elimination of water from the oxygen-protonated intermediate forms a protonated imine that loses a proton to yield the imine. 

The mechanism for enamine formation is exactly the same as that for imine formation, until the last step of the reaction. When a primary amine reacts with an aldehyde or a ketone, the protonated imine loses a proton from nitrogen in the last step of the reaction, forming a neutral imine. However, when the amine is secondary, the positively charged nitrogen is not bonded to a hydrogen. A stable neutral molecule is obtained by removing a proton from the a-carbon of the compound derived from the carbonyl compound. An enamine is the result. 

Nucleophilic reactions. Chiral epoxides are converted into 2,2-dimethyl-l,3-dioxolanes with inversion of configuration by reaction with acetone. An efficient procedure for imine formation from ketones and amines specifies TiCU as promoter. Hydrolysis (or alcoholysis) of RCONH2 is achieved in the presence of TiCU in acidic media. 

The direct observation of this reaction is difficult because of the small equilibrium constant for imine formation. This type of reaction is therefore commonly studied by trapping the imine as it is formed with hydroxylamine, which reacts rapidly to form an oxime. Because the equilibrium constant for formation of the imine between methyl amine and acetone is so small, the equilibrium is established very rapidly. (The observed rate constant for a reaction proceeding to an equilibrium position is larger than the first-order rate constant for the forward reaction [7].) Thus the addition of methylamine and acetone to an aqueous solution results in the establishment of an equilibrium concentration of imine (and iminium ion) in several seconds. In several studies described below wherein reactions subsequent to imine formation occur, it is common to find a presumption of rapid imine equilibria prior to the slower o-proton abstraction or decarboxylation events that occur subsequently. 

A parallel solution-phase asymmetric synthesis of a-branched amines based on stereoselective addition of organomagnesium reagents to enantiomerically pure fert-butanesulfinyl imines has been reported [141]. Microwave heating was used in two of the steps for synthesis of asymmetric amines, both for imine formation and for resin capture (Scheme 16.91). After the Grignard addition step, microwave... 

Revision of the often forgotten mechanism for imine formation. 

For these reasons, the pH-rate profile for imine formation looks like this there is a maxi- Interactive mechanism for mum rate around pH 6, and either side the reaction goes more slowly. 

Just [50] described a survey of the amine component of the cycloaddition in a search for reagents that would allow deprotection of the resulting azetidin-ones. Azidoacetyl chloride was the ketene source, with acetaldehyde or cinnam-aldehyde employed for imine formation. Hydroxylamine and 0-benzylhydrox-ylamine formed oximes which did not undergo the cycloaddition. Tritylamine and tertbutyldimethylsilylamine would not form imines. Trimethylsilylethyl-amine and allylamine reacted well with cinnamaldehyde, but the p-lactams could not be deprotected. L-phenylethylamine, benzhydrylamine, and p,p -... 

The mechanism for the acidic hydrolysis step is the reverse of one that we shall study for imine formation in Section 16.8A. 

These derivatives are called oximes, hydrazones, phenylhydrazones, and 2,4-dinitro-phenylhydrazones, respectively. The mechanisms by which these C = N derivatives form are similar to the mechanism for imine formation from a primary amine. As with imines, the formation of ( ) and (Z) isomers is possible. 

A mechanism for the reaction is given in the following box. Note the difference between the previously described mechanism for imine formation and this mechanism for enamine formation. In enamine formation, which involves a secondary amine, there is no proton for removal from the nitrogen in the iminium cation intermediate. Hence, a neutral imine cannot be formed. A proton is removed from a carbon adjacent to the former carbonyl group instead, resulting in an enamine. We shall see in Chapter 18 that enamines are very useful for carbon—carbon bond formation (Section 18.9). 

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