Imines equilibration

The reduction of imines/enamines 10j-10n/36j-36n generated from p keto esters can be regarded as an interesting method for the preparation of p amino acids. This approach has been extended to the reduction ofthe imines/enamines derived from a substituted P keto esters 37 (Scheme 4.4). In this case, the fast enamine imine equilibration 38 39 is the key point since imines 39 are chiral but racemic, so that... 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

Imine metathesis has continued to be a popular exchange reaction for DCLs. Various groups have found novel systems in which the reaction can be applied, as well as interesting ways to halt the equilibration. For example, Wessjohann and coworkers have demonstrated that Ugi reactions can efficiently halt equilibration of an imine DCL, combining an irreversible diversification process with areversible library selection [24]. Xu and Giusep-pone have integrated reversible imine formation with a self-duplication process [25], and Ziach and Jurczak have examined the ability of ions to template the synthesis of complex azamacrocycles [26]. The mechanistically related reactions of hydrazone [27] and oxime [28] exchange have also been explored as suitable foundations for DCL experiments. 

Another process mechanistically related to imine exchange is the dynamic production of pyrazolotriazinones reported in 2005 by Wipf and coworkers [29]. After first verifying that reaction of either 16 or 17 with equimolar quantifies of isobutyraldehyde and hydrocinnamaldehyde at 40°C in water (pH 4.0) resulted in the same 3 7 mixture of 16 and 17 at equilibrium (Fig. 1.6, Eq. 1), the authors demonstrated that a library could be generated by reaction of pyrazolotriazinone 16 with a series of aldehydes (Fig. 1.6, Eq. 2). Direct metathesis of pyrazolotriazinones was also demonstrated, as was reaction with ketones. Importantly, equilibration was halted by raising the pH to 7. 

Ziach, K. Jurezak, J. Controlling and measuring the equilibration of dynamic combinatorial libraries of imines. Org. Lett. 2008,10, 5159-5162. 

The DCL was first composed in the absence of the CA template, a so-called blank DCL. Equilibration was complete in 24 hours, with each of the expected imine reduction products being observed in the HPLC trace (Fig. 2.2). Reconstitution of the DCL in the presence of a stoichiometric quantity of enzyme afforded the second trace. Equilibration was significantly retarded in the presence of the protein, 2 weeks being necessary for a dynamic equilibrium to be realized. A thermal denaturation step preceded HPLC analysis. 

In 2004, Rayner and coworkers reported a dynamic system for stabilizing nucleic acid duplexes by covalently appending small molecules [34]. These experiments started with a system in which 2-amino-2 -deoxyuridine (U-NH ) was site-specifically incorporated into nucleic acid strands via chemical synthesis. In the first example, U-NH was incorporated at the 3 end of the self-complementary U(-NH2)GCGCA DNA. This reactive amine-functionalized uridine was then allowed to undergo imine formation with a series of aldehydes (Ra-Rc), and aldehyde appendages that stabilize the DNA preferentially formed in the dynamic system. Upon equilibration and analysis, it was found that the double-stranded DNA modified with nalidixic aldehyde Rc at both U-NH positions was amplified 34% at the expense of Ra and Rb (Fig. 3.16). The Rc-appended DNA stabilizing modification corresponded to a 33% increase in (melting temperature). Furthermore, imine reduction of the stabilized DNA complex with NaCNBH, resulted in a 57% increase in T. ... 

Figure 3.19 Schematic of the DCC SELEX system. Upper left A library of random 2 -amino RNAs are allowed to equilibrate via imine formation with aldehydes in the presence of target. Bottom left Modified RNAs are bound to the target. Bottom center Modified RNAs bound to the target are separated from unbound RNAs. Bottom right Selected RNAs are eluted and reverse transcribed and amplified to corresponding double-stranded DNA. Upper right The selected double-stranded DNA is transcribed to the 2 -amino RNAs. The selection process is repeated n-cycles and selected conjugated aptamers are identified.

Preliminary studies of nitrogen substituent inversion processes have been reported for several naphthalen-l,4-imine derivatives. The syn and anti invertomers of the A-chloroamine (117) equilibrate in solution to a mixture in proportion 3 2. The process can be followed kinetically by NMR spectroscopy starting from the pure anti compound the inversion is relatively slow ki = 2.6 x 10 sec at 23°), and the free-energy barrier to inversion is as high AF = 23.5 kcal mole ) as values found for inversion in aziridines. (A-Chloroaziridine derivatives, for which the energy barrier is even higher, have also been resolved into diastereoisomeric invertomers. )... 

A preliminary study by NMR spectroscopy has been made of the equilibration of N-invertomers for the anthracen-9,10-imine (195). ... 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

By this process phenylglycine derivatives have been resolved by crystallization of the tartaric acid ammonium salts. The equilibration is induced at the amino ester stage by forming the configurationally labile imines with a catalytic amount of benzaldehyde or acetone (Table 11). 

In this section, reactions of zinc dienolates with carbonyl compounds, imines and conjugated enones will be considered all of these reactions have been proved to be reversible, and, hence, conditions favouring either kinetic or thermodynamic control will drive the reaction towards the formation of different regioisomers. Generally, equilibrating conditions lead to attack at the position of 190, as a thermodynamically more stable conjugated carbonyl or carboxylic compound is formed on the other hand, kinetic control leads to attack at the electron richer a-position. 

The postulated 1-aminoalkylarsonic acids have something in common with 1-hydroxyalkanesulfonic acids, R—CHOH—S03-. These are not usually known as such, but as bisulfite addition compounds of aldehydes. They are not usually isolable, because of the ease of the reaction shown in Fig. 14. In just the same way we might expect R— CH(—NH3+)—As03H to lose arsenite as H2As03" and H+, i.e., H2As03" overall, leaving the imine R—CH=NH2+, which would equilibrate with R—CH=0 and NH4+. So this would explain why 1-amino-alkylarsonic acids may not exist as stable compounds. 

The profound influence of base on the course of the reaction led to the postulate that at high methoxide molarity it is the anion of the imine (306) which is in equilibrium with the ester anion (305). The former ionic species is readily hydrolyzed by acid to the pyran-2-one. However, at low molarities the unionized imine (307) is the equilibrating species and this is susceptible to nucleophilic attack at C-6 which occurs with ring opening. Subsequent cyclization gives the pyridone (Scheme 87). 

Nitrile imines can cyclize to 1,1-cycloadducts if the dipole-dipolarophile parallel plane approach is unfavorable. Thus, cyclopropanes (175a-b) were independently obtained on short-term reaction of the chlorohydrazone precursors with silver carbonate (Scheme 55).93 Longer reaction times afforded a 3 1 b a ratio from either precursor the products were shown to equilibrate. Heating of cyclopropanes (175a-b) afforded a benzodiazepine. 

The oxidation of imines derived from substituted cyclohexanones occurs predominantly from the equatorial direction. However, the product oxaziridines can undergo subsequent equilibration to favor a more stable conformation which places the bulkier nitrogen substituent in an equatorial conformation (equation 44)219. 

Functionalization of tiglaldehyde. Anions of a,/5-unsaturated aldimines are known to react with electrophiles at both the a- and y-position. Thus, the lithium salt (1) of tiglaldehyde cyclohexylimine reacts with aldehydes to give, after acid hydrolysis of the imine, mainly the product of a-substitution. Addition of HMPT (1 equiv.) to the reaction followed by equilibration at 0° (2 hours) results mainly in formation of the product of y-subsitution. 

A three-component reaction of aryl diazoacetates, alcohols, and araldehydes (or araldimines) has been investigated, using a rhodium(II) catalyst.283 The first two components combine in the presence of catalyst to produce a zwitterion (72a). Evidence for equilibration with an alcoholic oxonium ylide intermediate (72b) is presented. It is proposed that this species is trapped by electron-deficient araldehyde (or imine) to give new C-C bond formation. 

One equivalent each of unsubstituted aniline, substituted aniline, and pyridine-2-carbaldehyde were mixed in DMSO. Following equilibration, no free aldehyde could be detected An equilibrium mixture of imines and free anilines was observed in each case. Once the equilibrium had stabilized, half of an equivalent of copper( I) was added, and the equilibrium population of the two free anilines was again measured. 

The actual cyclisation stage is not as imponderable as it appears. The first step is the acid-catalysed equilibration between hydrazone 7.8 and ene hydrazine 7.10. The next step, which is irreversible, is a concerted electrocyclic reaction, forming a strong carbon-carbon bond, and breaking a weak nitrogen-nitrogen bond. The resulting imine 7.11 immediately re-aromatises by tautomerisation to aniline 7.12. Finally, acid-catalysed elimination of ammonia forms indole 7.9, reminiscent of the last step of the Knorr pyrrole synthesis (Chapter 2). 

Only limited success has been reported in the reduction of ketimines due to the low electrophilicity of the imine carbon and the rapid equilibration between the (E)- and (Z)-isomers. However, high enantioselectivity was achieved in catalytic reduction of imines of keto esters (Equation (261))1125 and oximes of acetophenone (Equation (262))1089,1125-1131 cyclic ketones (Equation (263)),1127 and a ketone possessing a boryl group (Equation (264)).1128... 

The question about which of the imine or enamine forms dominates in the gas phase when both tautomers can equilibrate has been examined in a series of articles dealing with more complex nitrogen-containing aromatic compounds21-25. 

Very recently, an enamine-imine tautomerism of ketene aminals has been reported by Huang and coworkers64-67. Due to competition by increased aromaticity, very stable enaminone isomers 63-65 equilibrate to their imine isomers 63-65 (equation 10). It is... 

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