Other Reactions of Imines

Synthesis of 1,2-aminoalcohols via cross-coupling of imines with ketones or aldehydes can be achieved using TifOPr-r /c-CsHgMgCl in Et20, although some ketones form cm-2,3-dialkyl aziridines predominantly.  

NHCs have been used to promote reactions of enals with A -substimted isatini-mines ° ° and oxindole-derived a, -unsaturated imines to form spirocyclic y-lactam oxindoles. Asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with A-Boc-protected aryl imines to form RCOCH(Ar)NHBoc have also been NHC catalysed.  

The ambivalent role of metal chlorides, which may act as Lewis acids or electron donors, in ring-opening reactions of 2//-aziridines by imines, enaminones, and enam-inoesters to form imidazoles, pyrroles, and pyrrohnones has been discussed. Experimental and theoretical mechanistic studies of the Davis-Beirut reaction, whereby 2//-indazolenes are obtained from o-nitrosobenzaldehydes and primary amines, implicate o-nitrosobenzylidine imine as a pivotal intermediate in the Nfl-bond formation. 

The mechanism of Schiff base hydrolysis continues to receive attention. Direct spectroscopic observation of the decay of two protonated imines, A-methylisobutylidene and A-isopropylethylidene, has enabled kinetic monitoring of the carbinolamine as a non-steady-state intermediate. The kinetics and activation parameters for hydrolysis of the A-salicylidenes of m-methylaniline and p-chloroaniline have been monitored in the pH range 2.86-12.30 and 293-308 K a mechanism has been suggested to account for the rate minimum in the pH range 5.21-10.22 and subsequent plateau (found at pH 10.73 and 11.15, respectively). 

The mechanism of action of a type I dehydroquinate dehydratase has been explored theoretically by MD and DFT methods.  

Several of preparations of aziridines have been reported. The aza-Darzens reaction of an fV-bromoacylcamphorsultam with iV-diphenylphosphinylimines, ArCH=N—P-(=0)Ph2, gives cz s-aziridine derivatives, except if the aryl is o-substituted, which gives significant trans product, and even 100% trans- with o-CF3.61 While steric (g) factors play a role in this inversion of selectivity, electronic effects are also important o-methyl gives a 50 50 ratio of products. 

A computational study has probed the origin of the diastereoselectivity in aziridine formation from sulfur ylides, Me2S+-CH -R, and imines.62 For semi-stabilized cases (R = Ph), betaine formation is non-reversible, so that selectivity is determined in the (g) initial addition step. In contrast, for stabilized ylides (R = C02Me), betaine formation is endothermic, and the elimination step becomes rate and selectivity determining. 

Allylaziridines have been prepared in good yield by the action of allylindium reagents on azirines (e.g. 25).63 The C(3) substituent can control stereochemistry hydroxy- (or acetoxy-) -methyl gives d.v-allylalion (via chelation with the indium (g) reagent), whereas R = Me/Ph/C02Et gives a trans result, presumably due to steric repulsion. 

Enantioselective nucleophilic addition to imines has been carried out with a planar-chiral Lewis acid based on a 1,2-azaborolyl framework. 64  

Addition and cyclization reactions of imines, catalysed by IS r0 ns led acids, have been reviewed, including examples in water solvent and enantioselective cases.65 Another review examines stereoselective nucleophilic additions to the C=N bond of aromatic azines (60 references).66 (g) 

Salicyl A-thiophosphinyl imines (39) undergo novel domino annulations with certain sulfur ylides (40, R = C02R/C0R/CH=CHC02H, R typically = H) to give highly substituted fra 5-2,3-dihydrobenzofurans (41) in high yield and rfe. After formation 0 of the N-C bond, an otherwise likely kinetic preference for aziridine formation is suppressed by steric hindrance. 

The kinetics of hydrolysis of l,l-bis(l//-imidazol-l-yl)methammine and its methyl derivatives have been studied. The rates of hydrolysis of several pyridyl imines have been measured in buffered aqueous methanol.  

Aldimines (R -CH=N-R ) have been phosphinated with diphenylphosphine oxide to give a-amino phosphine oxides (42) in up to 99% ee, using a chiral magnesium phosphate catalyst.  

An ab initio and DFT study has examined the mechanisms of and interactions present in radical additions of imidoyl and thioyl radicals to methanimine, H2C=NH. 2 

Sugar-derived imines have been converted to )8-lactams via a diastereoselective reaction with bromoesters mediated by indium and sonication.  

---

The most accepted mechanism for the Ugi-4CR is still the one proposed originally by Ugi (Scheme 7.15) [38], In the first step, the aldehyde (or ketone) and the amine react to form the corresponding imine. Then, the acid protonates the nitrogen atom of the imine to increase the electrophilicity of the C=N bond. As other reactions of imines, its electrophilicity can be also increased by the addition of Lewis acids such as TiCl, SclOTUj, or Yb(OTf)3 [39], Next, the addition of the isocyanate to the imine gives a nitrilium ion 37, which... 

Reactions of A-(/>-methoxyphenyl)imines 223a and 223b with diorganozincs result in the formation of chiral arylalkyl secondary amines 227, Scheme 130). Upon alkylation of three other types of imines 224b-226b, valuable amine precursors are obtained, which can be transformed in one step to the corresponding primary amines with a chiral center in the a-position. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Lactams are often formed by reaction of imines with dibromoketene. Such a compound can be readily singly or totally reduced using tributyltin hydride (TBTH) in a controlled fashion26 (equation 5) and this has been carried out in the presence of alkylthio and other groups50. 

Another recent innovation regarding the use of imine chemistry in DCC relies on an original way to freeze the equilibrating mixture by Ugi reactions [27]. In other words, this consists in conjugating a reversible reaction of imine condensation with an irreversible Ugi reaction. The latter step therefore represents an alternative to the more widespread reduction of imines with borohydrides. Wessjohann and coworkers recently prepared a library of macrocyclic oligoimines by condensation... 

Other Reactions of Chiral Titanocene Derivatives. Buch-wald has recently reported the catalytic asymmetric hydrogenation of imines and unfunctionalized alkenes using chiral titanocene catalysts. 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

In contrast to cycloaddition reactions of carbonyl compounds and olefins the related reactions of imines and nitriles have been less well documented. Some characteristic examples will be discussed here, further details, as well as the photoreactions of iminium salts, can be found mainly in reviews94,95 and other sources96-99. 

Pyridoxal is the reagent in other reactions of amino acids, all involving the imine as intermediate. The simplest is the racemization of amino acids by loss of a proton and its replacement on the other face of the enamine. The enamine, in the middle of the diagram below, can be reprotonated on either face of the prochiral imine (shown in green). Protonation on the bottom face would take us back to the natural amino acid from which the enamine was made in the first place. Protonation on the top face leads to the unnatural amino acid after hydrolysis of the imine (really transfer of pyridoxal to a lysine residue of the enzyme). 

O-acyl thiohydroxamates was initially thwarted by competing ionic reactions but eventually culminated in the introduction of 3-bromo or 3-(trifluoromethyl)-3-phenyl diazirine as extremely effective reagents [27]. In contrast to almost all of the other reactions of Barton esters described in this chapter, however, the reaction sequence does not involve a chain process. Thus, as outlined in Scheme 25, capture of the alkyl radical by the diazirine is followed by dimerization and subsequent loss of nitrogen to give the product imine from which the desired amide or amine is easily liberated by mild hydrolysis. Some typical yields are shown in the Scheme 26. 

In the reactions of imines, one drawback is their instability. It is desirable from a synthetic point of view that imines, generated in situ from aldehydes and amines, immediately react with TMSCN and provide a-amino nitriles in a one-pot reaction. However, most Lewis acids cannot be used in this reaction because they decompose or deactivate in the presence of the amines and water that exist during imine formation. On the other hand, it was reported that a-amino nitriles were prepared by simply mixing aldehydes, amines, and TMSCN without any catalysts (Leblanc and Gibson 1992, Chakraborty et al. 1991). The reports insisted that water which was produced in the imine formation catalyzed the reactions. It was assumed that water would react with TMSCN... 

This section deals with the reactions of amino compounds with phosgene generated from its common source or phosgene equivalents, by a direct transfer of the chlorocarbonyl group, giving carbamoyl chlorides. Reactions of imines and other unsaturated (cyclic) nitrogen compounds with phosgene will be discussed later. 

---