Nitriles, conjugated, reaction with ammonia

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

At temperatures between -33and 0°C, l-cyano-l,2-allenes 574 can react with primary or secondary amines to afford unconjugated enaminic nitriles 575, which can be converted to conjugated enamines 576 at 200 °C [264, 265], The corresponding reaction of ammonia is relatively slow and was conducted at 60-70 °C to afford 3-amino-4-ethyl-2-hexenenitrile 577 together with a small precentage of iminyl nitrile 578 [264, 265],... 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

The reaction of aliphatic, aromatic, heterocyclic, conjugated, and polyhydroxy aldehydes with NBS and ammonia gave the corresponding nitriles in high yields at 0°C in water (Eq. 9.18).39 Ceric ammonium nitrate (CAN)40 and iodine41 are also effective as the oxidizing reagents. 

Pyridines form stable salts with strong acids. Yellow ionic picrates were used for characterization in the past. Pyridine itself is often used to neutralize acid formed in a reaction and as a basic solvent. The basicity of pyridine (as measured by the dissociation constant of its conjugate acid, pKa 5.2) is less than that of aliphatic amines (cf. NH3, pA"a 9.5 NMe3, pKd 9.8). This reduced basicity is probably due to the changed hybridization of the nitrogen atom in ammonia the lone electron pair is in an sp3-orbital, but in pyridine it is in an s/r-orbital. The higher the s character of an orbital, the more it is concentrated near the nucleus, and the less available for bond formation. Nitriles, where the lone electron pair is in an. vp-orbital, are of even lower basicity. 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

So far we have shown you conjugate additions mainly of a,P-unsaturated aldehydes and unsaturated a,P-ketones. You won t be at all surprised to learn, however, that unsaturated acids, esters, amides, and nitriles—in fact all carboxylic acid derivatives—can also take part in conjugate addition reactions. Two examples, an amide and an ester, are shown on the right below. But notice how the selectivity of these reactions depends on the structure of the unsaturated compound compare the way butyllithium adds to this a,P-unsaturated aldehyde and a,P-unsaturated amide. Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives from direct... 

Conjugated and unconjugated unsaturated nitriles are both susceptible to hydroformylation. Few examples are found in the literature and most of the work has been with acrylonitrile (table 21). The aldehyde group is incorporated mainly in the -position, but the reaction is strongly solvent dependent and byproducts are frequently produced, mainly propionitrile, acrolein, propyl amine and ammonia (see also ref. [972, 973] and [985]). 

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