In the Ritter reaction

Ritter Reaction (Method 4). A small but important class of amines are manufactured by the Ritter reaction. These are the amines in which the nitrogen atom is adjacent to a tertiary alkyl group. In the Ritter reaction a substituted olefin such as isobutylene reacts with hydrogen cyanide under acidic conditions (12). The resulting formamide is then hydroly2ed to the parent primary amine. Typically sulfuric acid is used in this transformation of an olefin to an amine. Stoichiometric quantities of sulfate salts are produced along with the desired amine. 

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

Epoxides also participate in the Ritter reaction with nitriles. An investigation of the ring opening of several alkyl-substituted glycidic esters and amides 181 showed that this transformation occurs with inversion and is completely regiospecific. ° Esters appeared to be somewhat more reactive than amides. However, phenyl-substituted glycidic esters and amides 184 are almost totally nonstereoselective. In addition, the oxazolines 186 are isolated in low yield due to the propensity of intermediate 185 to generate an aldehyde byproduct 187 (Scheme 8.53). 

The acid used in the Ritter reaction is usually sulfuric acid, although other acids such as perchloric, phosphoric, polyphosphoric, formic and sulfonic acids have been used. Lewis acids such as aluminum trichloride and boron trifluoride are also occasionally used. However, high yields are generally best obtained with sulfuric acid. The choice of solvents varies among sulfuric acid, glacial acetic acid, acetic an-... 

Recently, nonconjugated dienes have been successfully used in the Ritter reaction for the preparation of bridgehead amides238 and azatricycloundecane amides (equations 171 and 172).239... 

Nafion-H has also been shown to be active in the Ritter reaction. Treatment of alcohols, such as benzyl alcohols, 1-adamantanol [Eq. (5.346)], and 2-norborneols with acetonitrile or benzonitrile in the presence of Nafion-H under forcing conditions (140-145°C, 18—48h), affords the corresponding carboxamides in moderate to excellent yields (40-99%).652 Nafion-H can be reused after a simple activation (washing with deionized water and acetone followed by drying at 105°C). 

Nafion beads, Nafion—Si02, and Aciplex-Si02 were tested by Okuhara and coworkers923 924 in the Ritter reaction between 1-adamantanol and acrylonitrile [Eq. 

Although the term nitrilium salt was used for the first time in 1931,26 the actual existence of these interesting compounds was not established until 1955 as a result of the work of Klages27,28 and Meerwein.29-30 Nevertheless, long before this last date it was common knowledge that non-isolable intermediate nitrilium salts are formed in numerous reactions. This is specifically the case in the Ritter reaction (Section II, A), as well as in many cognate reactions between nitriles and alkyl halides,31 isoparaffins,32 or a-trisubstituted acids,33 all of which yield a carbonium ion in the presence of sulfuric acid. 

Another collection of related intermediates occurs in the Ritter reaction and the Beckmann fragmentation. The Ritter reaction involves the combination of a tertiary alcohol and a nitrile in acid solution and the proposed mechanism involves a series of intermediates. 

In the Ritter reaction a rather different kind of evidence for the cation is the fact that families of isomeric alcohols all give the same product. In all these cases, rearrangements of the first formed carbocation (Chapter 37) can easily account for the products. Another example in the decalin series is this Ritter reaction with KCN as the nitrile in acidic solution so that HCN is the reagent. The starting material is a spirocyclic tertiary alcohol but the product is a frans-decalin formed by... 

The chirality conies from the diamine and the oxidation from ordinary domestic bleach (NaOCl), which continually recreates the Mn=0 bond as it is used in the epoxidation. Only 0.7% catalyst is needed to keep the cycle going efficiently. The epoxide is as good as the diol in the Ritter reaction and the whole process gives a 50% yield of enantiomerically pure cis-ami no-indanol on a very large scale. 

On the other hand, our own group and Jochims and coworkers in Germany found recently and independently another pathway for formation of the A -acyliminium ions from aldehydes and nitriles in which the order of activation of the reagents differs from that in the Ritter reaction. The method involves an initial electrophilic activation of the... 

However, only recently the acid-catalyzed reaction of the keto and cyano functional groups have been reported. In these articles the unreactivity of ketones in the Ritter reaction was noted and the search for conditions to overcome this lack of reactivity was described. The reactions of camphor 110a81, isocamphanone 110b82 and their structural analogs isofenchone 110c and 5-exo-ethyl norcamphor 110d83 with acetonitrile in the... 

Kozlov and coworkers81-83 suggested that the formation of V,V -diacetamides 114a-d is promoted by the nonclassical stabilization of the cationoid intermediates 111 and 113. At the time that their work was published the reports on the participation of other ketones in the Ritter reaction had appeared. Vartanyan and coworkers have described the synthesis of bis-amides 116 from cycloalkanones 11584 (equation 40). 

Acidic hydrolysis of isonitriles proceeds in two steps to the N-formamide and subsequently to the amine derivatives in common with nitrilium ions produced in the Ritter reaction using hydrogen... 

For the same reason of relative molecular weight, if safrole is used in either the phenylacetone from allylbenzene method or in the Ritter reaction, the amount of safrole used is greater by a factor of about 1.35 as compared to allylbenzene. 

Most tertiary butylamine (and other tertiary alkyl amines) is produced using hydrogen cyanide in the Ritter reaction. Isobutylene [97] or methanol [98] is reacted with hydrogen cyanide under acidic conditions to generate r-butylamine ( 1.46/lb) ... 

The first step in the Ritter reaction is the formation of a carbenium ion 1. Thus any substrate capable of generating a stable carbenium ion is a suitable starting material. In the case of tertiary alcohols 5, the mechanism begins with an acid mediated El elimination of the hydroxyl to give the requisite carbenium ion 1. Nucleophilic attack by the nitrogen lone pair on the nitrile 2 leads to the formation of a nitrilium ion intermediate 7 and hydrolysis by simple aqueous workup then produces the amide 3. 

It is also worthwhile to note that the hydrolysis of amides produced in the Ritter reaction leads to amines, and thus the Ritter reaction provides a synthetically useful way to convert tertiary alcohols to tertiary amines. 

Explain why in the Ritter reaction with hydrogen cyanide and t-butyl alcohol, the product is t-butylamine and not t-butyl cyanide (or trimethylacetic acid). 

More important than proton additions are additions of electrophilic carbon by which a new carbon-carbon bond is formed. Carbon-carbon bond formation is a major goal in the synthesis of organic compounds. For instance, from a carboxylic acid chloride an a-oxoimidoyl chloride (70) is prepared Addition of a carbocation to an isocyanide gives a species that is identical to the ion obtained in the Ritter reaction " cf. Section III. 

Iminium halides are intermediates in the hydrolysis of nitriles and in a variety of chemical reactions. For example, in the Ritter reaction addition of a nitrile or hydrogen cyanide to a carbonium ion occurs, leading to the intermediate formation of a nitrilium salt. Nitrilium salt intermediates have also been postulated in the Schmidt reaction and in the Beckmann rearrangement, provided the latter was performed in concentrated sulfuric acid. However, since we are predominantly concerned with imidoyl halides, these reactions are not discussed in this monograph. 

Khalafi-Nezhad, A., Foroughi, H., Doroodmand, M. M. and Panahi, F. 2011. Silica boron-sulfuric acid nanoparticles (SBSANs) Preparation, characterization and their catalytic application in the Ritter reaction for the synthesis of amide derivatives. J. Mater. Chem. 21 12842-12851. 

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