Imine intermediates

There is an experimental variation in which an W-phenacylpyridinium salt is heated with an aniline[4]. This reaction can also be readily accommodated to the mechanism involving an imine intermediate. There are a few examples of use of other types of a-halokctoncs[5,6] but most of the synthetic applications have been to 2-arylindoles. 

Write an equation showing how you could prepare ethyl phenyl ketone from propanenitrile and a Grignard reagent What is the structure of the imine intermediate ... 

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

Preparation of (14) and treatment with A[,A[-bis(ttimethylsily)fomiamide (BSF) and triethylamine provided (16) in 84% yield via the putative imine intermediate (15). The trifliioromethyl group could be replaced by other moieties such as 2,4,5 trichlorophenyl, pentafluorophenyl, or nonafluorobutyl with increasing effectiveness. 

The above cycloaddition process consists of two separate [3-1-2] cycloaddition steps and represents a 1,3-2,4 addition of a multiple bond system to a hetero-1,3-diene [7S7]. The structure ot the azomethine imine intermediate has been proved unequivocally by X-ray analysis [195] Ethylene [194], acetylene [/iS2] . many alkyl- and aryl- as well sgemmal dialkyl- and diaryl-substituted alkenes [196,197, 198, 199], dienes [200], and alkynes [182, 201], certain cyclic alkenes [198, 199,... 

Many biological processes involve an "association" between two species in a step prior to some subsequent transformation. This association can take many forms. It can be a weak association of the attractive van der Waals type, or a stronger interaction such as a hydrogen bond. It can be an electrostatic attraction between a positively charged atom of one molecule and a negatively charged atom of another. Covalent bond formation between two species of complementary chemical reactivity represents an extreme kind of association. It often occurs in biological processes in which aldehydes or ketones react with amines via imine intermediates. 

One of the biological pathways by which an amine is converted to a ketone involves two steps (1) oxidation of the amine by N.AD+ to give an imine, and (2) hydrolysis of the imine to give a ketone plus ammonia. Glutamate, for instance, is converted by this process into a-ketoglutarate. Show the structure of the imine intermediate, and propose mechanisms for both steps. 

Reductive amination takes place by the pathway shown in Figure 24.4. An imine intermediate is first formed by a nucleophilic addition reaction (Section 19.8), and the C=N bond of the imine is then reduced. 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

As has been outlined for the Strecker synthesis, the Ugi reaction also proceeds via initial formation of a Schiff base from an aldehyde and an amine. The imine intermediate is attacked by the isocyanidc, a process which is supported by protonation of the imine by the carboxylic acid component. The resulting a-amino nitrilium intermediate is immediately trapped by the carboxylate to give an 6>-acyl imidiate. All steps up to this stage are reversible. Only the final oxygen to nitrogen acyl shift is irreversible and delivers the A-acyl-a-amino amide as the thermodynamically favored product which contains two amide groups. 

Until recently the products of all nitrile cyclizations by the Thorpe reaction had been formulated as imines, although the products were found in 1955 to be better written as the enamine structure. In order to verify the reaction mechanism of the Thorpe reaction, the solid-state reaction of 84 and Bu OK was monitored by measurement of IR spectra in Nujol mulls. As the reaction proceeds (Scheme 14), the CN absorption of 84 at 2250 cm" decreases and a new CN absorption of the imine intermediate (87) arises at 2143 cm As 87 is converted into 88 by a proton migration, the CN absorption of 87 at 2143 cm" disappears, and only the CN absorption of 88 at 2189 cm remains finally [13]. 

Decarboxylative condensations of this type are sometimes carried out in pyridine, which cannot form an imine intermediate, but has been shown to catalyze the decarboxylation of arylidene malonic acids.215 The decarboxylation occurs by concerted decomposition of the adduct of pyridine to the a, 3-unsaturated diacid. 

Another useful approach to aldehydes is by partial reduction of nitriles to imines. The reduction stops at the imine stage because of the low electrophilicity of the deprotonated imine intermediate. The imines are then hydrolyzed to the aldehyde. Diisobutylaluminum hydride seems to be the best reagent for this purpose.88,89... 

FIGURE 7.6 13C-NMR documentation of ene-imine intermediate. The 13C labels are designated with asterisks ( ). 

C-NMR, COSY, HMQC (heteronuclear multiple quantum coherence), and HMBC (heteronuclear multiple bond correlation).48 Furthermore, the structure of trimer was confirmed by X-ray crystallography.48 The incorporation of 13C into the indole 3a position proved valuable in these structural determinations and in documenting the ene-imine intermediate. For example, the presence of a trimer was readily determined from its 13C-NMR spectrum (Fig. 7.7). 

Reactions of selected metal complexes of multidentate amines with formaldehyde and a range of carbon acids (such as nitroethane) have led to ring-closure reactions to yield a series of three-dimensional cage molecules (see Chapter 3). Condensations of this type may also be used to produce two-dimensional macrocycles (Comba et al., 1986) - see [2.20], In such cases, it appears that imine intermediates are initially produced by condensation of the amines with formaldehyde as in the Curtis reaction. This is followed by attack of the conjugate base of the carbon acid on an imine carbon. The resulting bound (new) carbon acid then reacts with a second imine in a cis site to yield chelate ring formation. 

An alternative method of synthesizing the pyrazine compounds was described by Ghosh et al, and the synthesis is shown is Scheme 32 [78]. Reaction of a 1,2-dione (124) with a 1,2-diamine (125) to form an imine intermediate followed by spontaneous oxidation of the dihydropyrazine intermediate, formed the protected pyrazine compound 126. The free phenol 127 was obtained by removal of the methyl-protecting groups with a boron trifluoride-dimethyl sulfide complex. Similar compounds were prepared via the same method by Simoni et al. [79]. 

Other routes to the key imine intermediate of the Pictet-Spengler reaction have also been reported. For example, Molina and coworkers [34] generated imine intermediate 34 by reaction of azide 32 with aldehyde 33 in the presence of tributylphosphine, via the corresponding iminophosphorane (Fig. 11). Use of triphenylphosphine was unsuccessful in the formation of an iminophosphorane. Without isolation, the intermediate was heated at 165 °C in a sealed tube with palladium on carbon, giving /J-carboline 35 in 45% yield. This com-... 

Larock et al. reported the palladium-catalyzed reactions of alkynes and nitriles with 2-iodophenyl group (Equations (116)-(118)).473,473a 473c Ketones and naphthylamines are obtained presumably through the formation of vinylpalladium species followed by their addition to nitriles to afford palladium imine intermediates. 

Selectivities of about 2 1 are the best found for this type of hydrogenation and are highly dependent on the secondary amine used they seem to correlate with the nucleophilicity of the amine. Reductive amination of PhCHO with ben-zylamine can proceed through an imine intermediate, and thus gave better selectivities (12 1) but was found to be sluggish using this catalyst system. 

Indeed, the imine intermediate 142 in the synthesis of metolachlor has been reduced in 97% ee using an iridium complex of the phospholane-containing ligand 55 [80]. 

The Suzuki coupling of soluble polyethylene glycol (PEG)-bound bromothiophene 71 and p-formylphenylboronic acid provided biaryl 72 [56]. Due to the high solubilizing power of PEG, the reaction was conducted as a liquid-phase synthesis. Treatment of 72 with o-pyridinediaminc resulted in a two-step-one-pot heterocyclization through an imine intermediate. Nitrobenzene served as an oxidant in the ring closure step. Finally, transesterification with NaOMe in MeOH resulted in l//-imidazole[4,5-e]pyridine 73. 

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