Cyano aldehydes, formation

The (5)-hydroxynitrile lyase from Hevea brasiliensis has been made available in sufficient quantities by cloning and overexpressirai to allow industrial-scale applications [1563]. It should be noted that also a,p-unsaturated aliphatic aldehydes were transformed into the corresponding cyanohydrins in a clean reaction. No formation of saturated p-cyano aldehydes through Michael-type addition of hydrogen cyanide across the C=C double bond occurred. The latter is a common side reaction using traditional methodology. 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

Amino acid formation in the Urey-Miller experiment and almost certainly in the prebiotic environment is via the Stecker synthesis shown in Figure 8.3. This reaction mechanism shows that the amino acids were not formed in the discharge itself but by reactions in the condensed water reservoir. Both HCN and HCO are formed from the bond-breaking reactions of N2 and H2O in a plasma, which then react with NH3 in solution. The C=0 group in formaldehyde or other aldehydes is replaced by to form NH and this undergoes a reaction with HCN to form the cyano amino compound that hydrates to the acid. The Strecker synthesis does not provide stereo-control over the carbon centre and must result in racemic mixtures of amino acids. There is no room for homochirality in this pathway. 

The modem concept of asymmetric induction is illustrated by the formulas in Fig. 1. As shown, the addition of hydrogen cyanide to the optically active aldehyde can lead to two diastereomers (1 and 2). If the process is under thermodynamic control, the formation of the more stable isomer will be favored that is, that isomer for which the non-bonded interactions between the newly formed cyano and the hydroxyl groups with the dissymmetric R group are weakest. On the other hand, the difference in the yields of 1 and 2 can be the result of kinetic control arising from a difference in the energies of the transition states—that state with the lower energy will form faster and lead to the product of higher yield. It is noteworthy that the tenets... 

Suzuki and co-workers achieve aromatic substitution of fluoroarenes with a variety of aldehydes in good yields [91, 92], Imidazolilydene carbene formed from 143 catalyzes the reaction between 4-methoxybenzaldehyde 22a and 4-fluoroni-trobezene 141 to provide ketone 142 in 77% yield (Scheme 20). Replacement of the nitro group with cyano or benzoyl results in low yields of the corresponding ketones. The authors propose formation of the acyl anion equivalent and subsequent addition to the aromatic ring by a Stetter-like process forming XXVIII, followed by loss of fluoride anion to form XXIX. 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

Microwave irradiation, for 15-20 min under solvent-free conditions, promoted the regiospecific three-component one-step cyclocondensation of benzoylacetonitrile, an aromatic aldehyde, and aminopyrimidinones 460 to give 6-cyano-5,8-dihydropyrido[2,3-, pyrimidin-4(3/7)-ones 461 rather than the isomers 462. The formation of 461 proceeds via a Michael-type addition of C-5 in aminopyrimidine 460 to the activated double bond of the arylidene-benzoylacetonitrile intermediate followed by cyclization with the removal of a water molecule. Compounds 461 were also prepared conventionally by refluxing the reactants in absolute ethanol for 40 8 h <2001TL5625>. 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

Amino and cyano-bonded columns have mainly been used for separation of carbohydrates. Aminophases should not be used with aldehydes or ketones, because they react with the formation of a Schiff s base. 

The Strecker synthesis is used to prepare amino acids in the laboratory. As shown in the following equation, an aldehyde is reacted with sodium cyanide and ammonium chloride in water to produce a cyanoamine. Conversion of the cyano group to a carboxylic acid completes the synthesis. Show the structure of the intermediate, A, in the following synthesis, and show the steps in the mechanism for the formation of A and for the conversion of A to the cyanoamine. (Hint Remember that NH4+ and H,0 are in equilibrium with NH3 and H-0+.)... 

Formation of the pyridazine ring occurs in a straightforward way from a suitably substituted pyrrole. Thus the pyrrole nucleoside (95) forms the pyrrolo[2,3-rf]pyridazine (96) on treatment with hydrazine <93JMC3834>. Another report describes the preparation of 4-amino-1 -(/i-o-ribo-furanosyl)pyrrolo[2,3-< /]pyridazine (Equation (30)) <91BMClll>. Similar pyrrole nucleosides, with an ester function at position 3 and an aldehyde at position 2, lead to 4-oxo derivatives upon treatment with hydrazine <90JHC1989>, or 4-amino derivatives with a cyano group at position 3 (92JMC526). 

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a (3-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a (3-ketoester and urea to afford dihydropyrimidines 4. 

As a preparative method the direct decarboxylation of olefinic acids is almost limited to the formation of styrenes and stilbenes from substituted cinnamic acids. Thermal decomposition of cinnamic acid gives styrene (41%). The yield is nearly quantitative if the reaction is carried out in quinoline at 220° in the presence of a copper catalyst. The yields of substituted styrenes where the aryl radical contains halo, methoxyl, aldehyde, cyano, and nitro groups are in the range of 30-76%. cis-Stilbene and cis-p-nitrostilbene are prepared in this way from the corresponding a-phenylcinnamic acids (65%). One aliphatic compound worthy of mention is 2-ethoxypropene, prepared by heating -ethoxycro-tonic acid at 165° (91% yield). The mechanism of acid-catalyzed decarboxylations of this type has been studied. Isomerization of the double bond from the a,/5- to the /5, y-position before decarboxylation very likely occurs in many instances. ... 

The condensation equilibrium is displaced to the right by removing the unsaturated cyano ester as it is formed by the addition of hydrogen cyanide The effect is analogous to the single-step formation and hydrogenation of a,/S-unsaturated cyanoacetic esters (method 394). The yields are good with most aliphatic ketones and aldehydes (49 75%), but poor results are obtained with aromatic carbonyl compounds and diisopropyl ketone. 

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