Aldehydes imine derivatives

Aldehyde imines derived from alkoxyamines are metalated by LDA (0 °C, TIIF, 1 h6 or —23 °C, THF, 0.5 h13) and by potassium diethylamide, lithium bis(trimethylsily])amide and lithium 2,2,6,6-tetramethylpiperidide (—23 °C, THF, 2-4 h)1J. Nucleophilic bases such as alkyl- and aryllithium derivatives and, in some cases, alkylmagnesium bromides add to aldehyde imines. Best enantioselectivities are achieved with lithium 2,2,6,6-tetramethylpiperidide (LTMP)13. The... 

In the case of aldehyde imines derived from 1-phenyl-1-ethanamine optimum enantioselec-tivities (70 % ee) and good yields were achieved using magnesium azaenolates and HMPA as additive (see Table 5)6. 

A number of imine derivatives have been prepared as amine protective groups, but most of these have not seen extensive use. The most widely used are the ben-zylidene and diphenylmethylene derivatives. The less used derivatives are listed, for completeness, with their references at the end of this section. For the most part, they are prepared from the aldehyde and the amine by water removal cleavage is effected by acid hydrolysis. 

A range of electron-withdrawing groups on the nitrogen - N-P(0)Ph2, N-tosyl, and N-SES, for example - were tolerated. Imines derived from aromatic, heteroaromatic, unsaturated, and even aliphatic aldehydes and ketones were employed... 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

The reaction can be applied to aldehydes, indirectly, by alkylating an imine derivative of the aldehyde.The derivative is easily prepared (16-12) and the product easily hydrolyzed to the aldehyde (16-2). Either or both R groups may... 

In the future, further studies should be addressed to improve the chemose-lectivity and diastereoselectivity of the reductive coupling process, especially searching for novel reagents and milder experimental conditions. As a matter of fact, a few novel reductive couphng procedures which showed improved efficiency and/or stereoselectivity have not been further apphed to optically active imines. For example, a new electrochemical procedure which makes use of the spatially addressable electrolysis platform with a stainless steel cathode and a sacrificial aluminum anode has been developed for imines derived from aromatic aldehydes, and the use of the N-benzhydryl substituent allowed 1,2-diamines to be obtained with good yields and dl-to-meso ratios... 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

Amines can react with various carbonyl compounds and their derivatives in aqueous media to give the corresponding imine derivatives. These reactions have been discussed in related chapters. The synthetically most useful reaction of this type is the formation of imines and imine derivatives from the condensation of amines with aldehydes and ketones. Water is an excellent solvent for such condensation reactions. For example, water was found to be an ideal solvent for a high-yield, fast preparation of easily hydrolyzable 2-pyrrolecarbaldimines.23 In the presence of Cu2+, the reaction afforded the corresponding Cu(II) chelates (Eq. 11.19). 

Possible racemisation of imines, derivatives of amino acids and R(—)-myrtenal, has been examined by Dufrasne et al.1 After 72 h, no significant effect on chiral purity was observed. For imines being derivatives of chiral primary amines and the a-substituted 8-keto-aldehydes, no evidence of epimerisation has been indicated by the NMR measurements.3 For a series of imines, being derivatives of amino acids or amino acid esters and (R)-BINOL reagents, Chin et al.5 have tested the possibility of epimerization under experiment conditions. It was shown that R S ratio has changed only slightly, and after 24 h, the difference was lower than 10%. 

These authors also found that the addition of excess MgO during the in situ preparation of allyltantalum species improved reaction outcomes, even allowing for the first example of allylation of imines derived from aliphatic amines and aliphatic aldehydes (prepared in situ at room temperature in the presence of molecular sieves) (Equation (18)). The selective addition to imines permitted three-component reactions. 

An extension of the strategy described for the reaction with aldehydes (Section 5.4.2) to imine derivatives might be expected to yield a-amino ketone compounds (Scheme 5.14), which are the constituents of a variety of biologically important molecules. 

The heteroatom version of the vinylcyclopropane rearrangement serves to facilitate alkaloid construction. Scheme 13 outlines a strategy for the pyrrolizidine alkaloid isoretronecanol 211 90). Use of a carboxaldehyde (i.e. 213) as a synthon for the primary alcohol provides an ability to adjust stereochemistry. It also sets up formation of the pyrrolidine ring bearing the aldehyde by an aldol-type condensation of an enol of the aldehyde onto an imine derived from 214. Because of the lability of such systems, introduction of X=PhS imparts stability. The resultant azacyclopentene translates to an imine 215 using the iminocyclopropane rearrangement methodology. Simple condensation of the primary amine 216 with aldehyde 37a then initiates this... 

Allenylsilanes undergo intramolecular additions to appropriately positioned aldehydes, imines, conjugated esters and alkenes to afford various alkynylcyclopentane and cyclohexane derivatives (Eqs. 9.66-9.70) [66]. The reactions are promoted by SnCl4 or by thermolysis. The stereochemistry of these cyclization reactions is consistent with a concerted sigmatropic process as illustrated in Scheme 9.17. 

Aldehydes and imines derived from them can undergo electrophilic attack of activated aromatic systems under harsh hydroformylation conditions (Scheme 25). 

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

The action of the valine derivatives 87 on the diene 86 under EtAlCU catalysis resulted in a mixture of cycloadducts 88, which on hydrolysis with aqueous methanolic sodium carbonate furnished a mixture of the dihydro-2-pyridones 89 and 90 and the esters 91 and 92. In the case of imines derived from aliphatic aldehydes, e.g. 87 (R = Pr), all four types of product were isolated, whereas imines from aromatic aldehydes, 87 (R = Ph, 3-CIC6H4 etc.), gave only the esters 91 and 92 (equation 55). All products were formed in yields of 64-84% and in high de49. 

Miller and co-workers have reported the use of thiazolylalanine-derived catalyst 65 to render the aldehyde-imine cross-coupling enantioselective [56]. The authors comment on the time sensitivity of this transformation and found that racemization occurs when the reaction goes to complete conversion. Electron-deficient aldehydes are the most efficient couphng partners for various tosylamides leading to the corresponding products 66, 68, and 69 (Scheme 8). 

Scheme 8 Miller and co-workers aldehyde imine cross-coupling catalyzed by thiazolylalanine-derived catalysts...

Akiyama et al. disclosed an asymmetric hydrophosphonylation in 2005 (Scheme 32) [55], Addition of diisopropyl phosphite (85a) to A-arylated aldimines 86 in the presence of BINOL phosphate (R)-M (10 mol%, R = 3,5-(CF3)j-C Hj) afforded a-amino phosphonates 87 in good yields (72-97%). The enantioselectivities were satisfactory (81-90% ee) in the case of imines derived from a,(3-unsaturated aldehydes and moderate (52-77% ee) for aromatic substrates. 

Indole derivatives such as dihydroindolone are scaffolds of potentially biological interest. Thus, the development of such functionalized skeletons has been approached by a MCR involving cyclic 1,3-diketones, cyclohexyl isocyanide, aromatic aldehydes, and ammonium acetate in the presence of catalytic amount of KHSO4 in refluxing acetonitrile (Scheme 30) [117]. hi this strategy, the imine derived from the Knoevenagel adduct reacts with cyclohexyl isocyanide to give the... 

In contrast to the epoxides, preparative routes to the aziridines are fairly evenly split between the [C=N + C] and the [C=C + N] routes. Among contributions in the former category, aziridine carboxylate derivatives 110 can be prepared through the lanthanide-catalyzed reaction of imines with diazo compounds, such as ethyl diazoacetate (EDA). In this protocol, iV-benzyl aryl aldimines and imines derived from aromatic amines and hindered aliphatic aldehydes are appropriate substrates <99T12929>. An intramolecular variant of this reaction (e.g.. Ill —> 112) has also been reported <990L667>. 

Asymmetric alkylation of aldehydes is possible via enamines or azaenolates of imine derivatives (see Section D. 1.1.1.4.). Alkylation is also possible via enol ethers or esters (see Section 1.1.1.3.1.2.), although the use of these methods for asymmetric synthesis has not yet been explored. 

The most general method for synthesizing amines involves the reduction of oximes and imine derivatives obtained from aldehydes or ketones (see Sections 5.5.2 and 4.3.11). By catalytic hydrogenation or by LiAltLj reduction, while 1° amines are prepared from oxime or unsubstituted imine, 2° amines are obtained from substituted imine. Unsubstituted imines are relatively unstable, and are reduced in situ. 

Alkylation and deprotection of N-protected aminomethylphosphonate esters 6 are shown in Scheme 6. The nitrogen is protected as the imine derived from benzophenone or a benz-aldehyde, and a variety of conditions are used for deprotonation and alkylation (Table 2). The benzaldehyde imine of aminomethylphosphonate can be deprotonated with LDA and alkylated with electrophilic halides (entries 1 and 2). For the best yields, saturated alkyl bromides require an equivalent of HMPA as an additive. 36 Allylic esters can be added to the carbanion with palladium catalysis (entries 3-7). 37,38 For large-scale production, phase-transfer catalysis appears to be effective and inexpensive (entries 8-12). 39,40 ... 

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