Imine-condensation

A highly diasteieoselective synthesis of substituted 1,2,3,4,4a,9,9a, 10-octahydroacridines 95 with five stereogenic centers has been achieved by domino imine condensation/intramolecular polar [4ti + 2k] cycloaddition of anilines and oo-unsaturated aldehydes 94 <96JPR(338)468>. 

A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

The ultimate evidence for the nucleation-elongation mechanism is the effect of imbalanced stoichiometry on the MW of the polymerization. In standard step-growth polymerizations the MW is dependent upon the ratio of the monomer concentrations where almost exact 1 1 stoichiometry is necessary to bring about high MW [90]. An irreversible imine condensation of 67 and 68 was performed under imbalanced stoichiometry ([67]/[68]=0.5) and nonfolding conditions (Fig. 40) [93]. The starting material was completely consumed and... 

Imines and iminium ions are nitrogen analogs of carbonyl compounds, and they undergo nucleophilic additions like those involved in aldol condensations. The reactivity order is C=NR < C=0 < [C=NR2] + < [C=OH] +. Because iminium ions are more reactive than imines, condensations involving imines are frequently run under acidic conditions where the imine is protonated. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

The synthetic routes may often involve template directed condensations, a widely used reaction being the (carbonyl + amine) to imine condensation that efficiently leads to a variety of Schiff-base macrocycles [2.58-2.60, A.7, A.14], macrobicyclic cryptands [2.61-2.63] and lacunar cyclidene ligands [2.60, 2.64]. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Scheme 49 Solid-phase synthesis of P-lactams via ester enolate-imine condensation...

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

The ester enolate-imine condensation, also called Gilman-Speeter reaction, is another well-accepted method for (3-lactam synthesis (Scheme 4) [67-69]. In 1997, Tomioka reported the first example of a direct catalytic enantioselective synthesis of (3-lactam by using this method [70]. The active reagent is a ternary complex (comprising LDA, the ester enolate, and tridentate amino diether), which finally affords the (3-lactam compounds in high yields and good ee values. 

Schunk and Enders [134] disclosed the first solid-phase synthesis of (5-1 actants via ester enolate-imine condensation employing an immobilized ester enolate in a simple three-step procedure (Scheme 31). The protocol showed high purity, excellent diastereoselectivity, and good yields of the product. The substrates were attached to the polymer with a Tl-triazene linker, which was cleaved traceless. The... 

The possibility of the triazene linking system for the ester-enolate imine condensation was initially investigated on model compounds 110 and 111 (Scheme 35). Dibenzyltriazene 110 was used as a model compound for monobactam derivatives and prepared by diazotization of hippuric acid methyl ester. Dibenzyltriazene 111 was used as a model compound for 3-phenyl-substituted azetidin-2-ones and prepared by diazotization of 2-(4-aminophenyl)-propionic acid methyl ester and conversion with dibenzylamine in 64% overall yield. The low yields of /V-unsub-stituted lactams, during the model studies, hint at a problematic transfer to solid support. 

Fig. 23 The outcome of thermodynamically controlled imine condensations was suggested to be a function of the conformational preference of the diimine linker that predisposes the bowl-shaped reactants with a minimal amount of strain.134 Reprinted with permission from Ref.134 (For color version of this figure, the reader is referred to the web version of this book.)...

Lactams. z Carboxylic acids and imines condense to form 9-lactams when treated with 2-chloro-N-methylpyridinium iodide (1 equiv.) and tripropylamine (3 equiv.) in CH2C12. The stereoselectivity depends upon the temperature. Reactions conducted at 25° favor formation of cw-3-lactones. Yields are increased when the reactions are conducted for 12 hours at reflux, but the ris-selectivity decreases. Compared with triethylamine, tributylamine improves the yield and the c/ j-selectiv-... 

In the catalytic presence of tetrakis(triphenylphosphine)palladium imines condenses with disilanes in toluene after 5 h at 120 °C in a sealed tube to give high yields of the corresponding a-silyl-iV-silylamine.216... 

MacLachlan and coworkers have formed large SPMs 91-93 using a simple, one-pot, template-free, [3 + 3] Schiff-base condensation procedure (Scheme 6.21). The yields of the macrocycles were 40-68%, and no evidence of acyclic oligomer or polymer formation was observed. This is presumably due to the reversibility of the imine condensation, which allows the most thermodynamically stable product to... 

Stoddart and coworkers have used imine condensation in two different contexts to form interlocked molecules. The authors have modified the crown ether component of their dialkylammonium / D B24C8 system to incorporate reversible imine subunits which allow for dynamic clipping around dialkylammonium cation 91 [60], Three diformyl spacers (92-94) have been investigated with the same acyclic diamine 95 for their thermodynamic stability and kinetics of macrocyclization (96). However, reduction with BH3 to the kinetically trapped macrocyclic secondary diamine has only been reported for reaction of the 2,6-diformylpyridine derivative (Scheme 10.19 97) [60a]. 

Polymer-bound P-lactams have been prepared via the ester enolate imine condensation route <02JOC8034>. On the other hand, an efficient asymmetric synthesis of 2-azetidinones was accomplished when chiral acid chlorides or chiral aldehydes were used in the polymer-supported Staudinger reaction <02TA905>. 

This example clearly demonstrates that it is possible to self-amplify one product in a DCL, namely the one that can self-complementarily direct its own formation. It was shown that the expression of the components in the library evolves along both kinetic and thermodynamic biases that both lead to the amplification of the best duplicator. Importantly, because of the double reversibility of the system (supra-molecular H-bonds and molecular imine condensation), the competition is ruled not only by the differential rates of formation of the components, but also by the possible takeover of the building blocks of the antagonistic competitors, thus leading to the decrease of their absolute concentration. Such a system illustrates the spontaneous screening and selection of the most efficient self-duplicator by the destruction of the entities which are not (or less, such as Al, Am2) able to duplicate themselves. 

In the early 1960s, seminal work by Jencks and coworkers demonstrated that formation and hydrolysis of C=N bonds were proceeding via a carbinolamine intermediate, thus leading to a more general mechanism of addition reactions on carbonyl groups [17-19]. The dynamic nature of the reaction of imine formation can be exploited to drive the equilibrium either forward or backwards. Since the reaction involves the loss of a molecule of water, adding or removing water from the reaction mixture proved an efficient way to shift the equilibrium in either direction. The responsive behavior of imines to external stimuli makes the reversible reaction of imine formation perfectly suited for DCC experiments [20], Thermodynamically controlled reactions based on imine chemistry include (1) imine condensation/hydrolysis, (2) transiminations, and (3) imine-metathesis reactions... 

In 1992, Goodwin and Lynn reported the first example of template-directed synthesis of DNA analogs via formation of a reversible imino linkage [21]. Five years later, Hue and Lehn described the first use of the reaction of imine condensation for the selection, by DCC, of carbonic anhydrase inhibitors from a library of amines and aldehydes [8], Upon addition of the enzyme, the formation of one library component was strongly amplified when compared to a similar reaction carried out in the absence of template. Since then, imine exchange reaction has been applied... 

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... 

Reduction with alkali metals The solvents used for alkali metal reductions include hydrocarbons, ethers and, most commonly, liquid ammonia. Alcohols may also be used, but usually as co-solvents, since they react vigorously with these metals. Aldehydes are not usually reduced in this manner, because they react with ammonia to form unreactive imine condensation products. 

Electrochemical transformations of /3-lactams 90YZ463. Ester-enolate-imine condensation in the synthesis of /3-lactams 89CRV1447, 89H(29)2225. 

Imine Condensation (Acyl Species to -Lactam). Lithium enolates of acyl 10-diisopropylsulfonamidoisobomeols condense with A-aryl aldimines to give cw-disubstituted (3-lactams with 56-92% ee, accompanied by 2.5-9% of their trans isomers (in... 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

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