Imines reaction with cyanide

Figure 6-14. The reduction of co-ordinated macrocyclic imines provides a method for the preparation of macrocyclic amines. The reaction above illustrates one of the standard methods for the preparation of cyclam. The metal ion may be removed from the nickel(n) complex by prolonged reaction with cyanide.

The standard synthesis for cyclam was developed by Barefield and Wagner in 1976.29 They used similar starting materials to the van Alphen procedure but the cyclisation yield is improved through the use of a nickel (II) template. Glyoxal completes the macrocycle by a Schiff base condensation reaction. The resulting imine functionalities are reduced with sodium borohydride to leave the complexed macrocycle. The metal ion is then removed by reaction with cyanide and the free ligand extracted with chloroform (Scheme 3.19). Yields are typically in the region of 60%. 

In the Strecker synthesis, an aldehyde reacts with ammonia to form an imine. An addition reaction with cyanide ion forms an intermediate, which, when hydrolyzed, forms the amino acid (Section 16.19). Compare this reaction with the Kiliani-Fischer synthesis of aldoses in Section 21.7. 

Some imine-forming reactions are shown in Figure 14.30—all of these were part of longer synthetic sequences. Imines undergo many of the same types of addition reactions as aldehydes and ketones. A particularly useful example of this is their reaction with cyanide ion, the Strecker reaction (Figure 14.31). When a carbonyl compound is treated with ammonia and sodium or KCN, the ammonia adds to the carbonyl to give an unstable imine. This is attacked by cyanide to give the a-aminocyanide. Since the cyanide can be hydrolyzed to a carboxylic acid, this constitutes a simple amino acid synthesis. 

Palladium complexes also catalyze the carbonylation of halides. Aryl (see 13-13), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex. Similar reactivity was reported with vinyl triflates. Use of an amine instead of the alcohol or alkoxide leads to an amide. Reaction with an amine, AJBN, CO, and a tetraalkyltin catalyst also leads to an amide. Similar reaction with an alcohol, under Xe irradiation, leads to the ester. Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a cobalt imine complex. Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions. ... 

Catalytic asymmetric cyanide addition to imines constitutes an important C—C bondforming reaction, as the product amino nitriles may be converted to non-proteogenic a-amino acids. Kobayashi and co-workers have developed two different versions of the Zr-catalyzed amino nitrile synthesis [73]. The first variant is summarized in Scheme 6.22. The bimetallic complex 65, formed from two molecules of 6-Br-binol and one molecule of 2-Br-binol in the presence of two molecules of Zr(OtBu)4 and N-methylimidazole, was proposed as the active catalytic species. This hypothesis was based on various NMR studies more rigorous kinetic data are not as yet available. Nonetheless, as depicted in Scheme 6.22, reaction of o-hydroxyl imine 66 with 5 mol% 65 and 1—1.5 equiv. Bu3SnCN (CH2C12, —45 °C) leads to the formation of amino nitrile 67 with 91 % ee and in 92 % isolated yield. As is also shown in Scheme 6.22, electron-withdrawing (— 68) and electron-rich (—> 69), as well as more sterically hindered aryl substituents (— 70) readily undergo asymmetric cyanide addition. 

An efficient primary amine synthesis via iV-diisobutylaluminium imines has been described. A cyanide R CN (R1 = Bu, CsHn, Ph, 2-furyl or 2-thienyl) is treated with diisobutylaluminium hydride and the product is converted into the amine by reaction with an organomagnesium or organolithium compound R2M (R2 = Bu, t-Bu, allyl or benzyl)... 

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

Nucleophiles attack DISN at the imine carbon with subsequent loss of either ammonia or hydrogen cyanide (72JOC4136). Neutral or basic conditions favor the loss of cyanide ion. A small amount of a strong acid catalyzes the addition, after which cyanide is lost. However strong acids not only catalyze the reaction, but when they are present in larger amounts, they can... 

In addition to their thermodynamic stability, complexes of macrocyclic ligands are also kinetically stable with respect to the loss of metal ion. It is often very difficult (if not impossible) to remove a metal from a macrocyclic complex. Conversely, the principle of microscopic reversibility means that it is equally difficult to form the macrocyclic complexes from a metal ion and the free macrocycle. We saw earlier that it was possible to reduce co-ordinated imine macrocycles to amine macrocyclic complexes in order to remove the nickel from the cyclam complex that is formed, prolonged reaction with hot potassium cyanide solution is needed (Fig. 6-24). 

Sigman and Jacobsen reported the first example of a metal-catalyzed enantioselective Strecker-type reaction using a chiral Alnl-salen complex (salen = N,N -bis(salicyhdene)-ethylenediamine dianion) [4]. A variety of N-allylimines 4 were evaluated in the reaction catalyzed by complex 5 to give products 6, which were isolated as trifluoroacetamides in good yields and moderate-to-excellent enantioselectivities (Scheme 3). Substituted arylimines 4 were the best substrates, while alkyl-substituted imines afforded products with considerably lower ee values. Jacobsen and co-workers also reported that non-metal Schiff base catalysts 8 and 9 proved to be effective in the Strecker reaction of imines 7 with hydrogen cyanide to afford trifluoroacetamides 10 after reaction with trifluoroacetic anhydride, since the free amines were not stable to chromatography (Scheme 4) [5]. 

Shibasaki and co-workers disclosed a general asymmetric Strecker-type reaction that was controlled by bifunctional Lewis acid-Lewis base catalyst 14 [10], N-Fluorenylimines 15 underwent catalytic asymmetric Strecker-type reactions with binaphthol catalyst 14 to give a-aminonitriles 16 in good to excellent enantioselectivities and yields (Scheme 6). a-Aminonitrile 16 (R = Ph) could then be converted to a-aminoamide 17 in several steps. Aromatic, aliphatic, heterocyclic and a,/f-unsaturated imines 15 were used as general substrates in these reactions. The origin of the highly enantioselective cataylsis by 14 is believed to be attributed to the simultaneous activation of imines and trimethylsilyl cyanide by the... 

The Strecker reaction is a way to make a-amino acids 7 from aldehydes 1 with cyanide and ammonia. Cyanide adds to the unstable imine 5 to give the stable amino nitrile 6 that can easily be hydrolysed to the inevitably racemic a-amino acid 7. 

Reaction with carbonyl compound 8 produced optically active imine 48 that could add cyanide to afford the chiral a-aminonitrile 49. 

Imine surrogates. In the Mtinnich reaction and cyanide addition, the use of these hydrazones instead of unstable imines is advantageous. Allylation may also be performed with allyltrichlorosilanes."... 

Reaction of indolemagnesium bromide with the chloroethylpyridine 664 gave the 3-ethylindole derivative (665) in 50% yield. Following the procedure of Suzue (267), 665 was converted into the salt 666 by successive reaction with o-mesitylsulfonylhydroxylamine, acetic anhydride, and methyl iodide, and then treated with potassium cyanide in the presence of ammonium chloride to afford the nitrile 667. Deacetylation by passage over alumina was followed by reaction with methyllithium, and the intermediate imine 668 was hydrolyzed and cyclized to ellipticine (267 Scheme 46). Overall yield for the latter steps is on the order of 25-30%. A similar procedure was used to prepare 8,9-methylenedioxyellipticine (660). 

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