Hydrolysis Ritter reaction

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. 

Other sequences that transform primary alcohols to primary amines include (a) conversion of the alcohol to a cyanate, rearrangement to an isocyanate, and hydrolysis,3 and (b) conversion of the alcohol to an -V alkylformamide via the Ritter reaction, followed by hydrolysis.4... 

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

Amantadine Amantadine, 1-adamantanamine (10.1.12), is synthesized from adaman-tane. It is directly brominated to 1-bromadamantane (10.1.10), which in Ritter reaction conditions when heated with a mixture of acetonitrile and concentrated sulfuric acid transforms into 1-acetylaminoadamantane (10.1.11). Hydrolysis of this product using alkali leads to the formation of amantadine (10.1.12) [16,17]. 

Amantadine Amantadine, 1-adamantylamine (36.1.3), is synthesized from adamantane, which is first brominated with molecular bromine to make 1-bromoadamantane (36.1.1). Interacting this with acetonitrile in a Ritter reaction conditions gives 1-acetylaminoadaman-tane (36.1.2). Hydrolysis of the last with sodium hydroxide gives amantadine [1-6]. 

The preparation of amides by the addition of hydrogen cyanide or alkyl nitriles to alkenes in the presence of acids, known as the Ritter reaction, has been reviewed.229-232 The reaction may be considered simplistically as nucleophilic attack of a nitrile on a carbocation formed by the protonation of an alkene. Subsequent hydrolysis of the nitrilium intermediate gives the amide product (equation 164). The overall result is addition of a molecule of H—NHCOR to a C—C double bond. 

A -(2-Methylbut-3-yn-2-yl)acetamide (39) (prepared by the Ritter reaction of acetonitrile with 3-hydroxy-3-methylbut-l-yne) on hydrolysis with sulfuric or hydrochloric acid in methanol, basified and steam distilled, gave 2,2,3,5,5,6-hexamethyl-... 

Since the amides (especially the formamides) are easily cleaved under hydrolysis conditions to amines, the Ritter reaction provides a method for achieving the conversions R OH R NH2 (see 10-32) and alkene R NH2 (see 15-8) in those cases where R can form a relatively stable carbocation. The reaction is especially useful for the preparation of tertiary alkyl amines because there are few alternate ways of preparing these compounds. The reaction can be extended to primary alcohols by treatment with triflic anhydride ° or Ph2CCl" SbClg or a similar salt in the presence of the nitrile. 

The physical technique with the greatest potential for synthetic applications of Ritter-type reactions is electrochemistry. A selection only of examples is discussed here. Synthetic chemists unfamiliar with this technique will find the review by Eberson and Nyberg an informative and entertaining introduction to this area. Electrochemical Ritter reactions may be performed through anodic substitution of a hydrogen by the nitrile, followed by hydrolysis of the nitrilium ion intermediate, as shown in Scheme 42. The majority of reactions investigated have been anodic acetamidations using hydrocarbons, alkyl halides, esters or ketones as the substrate. In some cases, such as reaction of the adamantane derivatives (83), the yields of amide product are excellent (Scheme 43). 

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... 

The Ritter reaction proceeds by a nucleophilic addition of hydrogen cyanide followed by the hydrolysis of the intermediate formamide. Higher tertiary alkyl amines are produced using the same method with higher alkenes and alcohol. This is considered the most practical way to produce tertiary amines [99]. 

The alkylation and reduction of aliphatic nitro compounds is one route to t-AlkNH2 and is discussed in Chapter 22. Another route uses the Ritter reaction followed by hydrolysis of the amide. 

The Ritter reaction occurs when a stable carbenium ion 1 reacts with a nitrile 2 in the presence of an acid. Hydrolysis of the adduct then leads to an amide 3.1,2... 

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. 

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. 

In another vein, addition of sulfuric acid to an alkene in the presence of a nitrile (R-C=N) or hydrogen cyanide (HC N), either of which can react with the carbo-cation as a nucleophile, apparently leads to nitrilium ions. These ions, on hydrolysis, produce amides. As amides can be hydrolyzed in acid or basic medium to amines and carboxylic acids, the overall process (the Ritter reaction) of carbocation... 

Scheme 6.41. A representation of the Ritter reaction. Hydrolysis of the iminium ion produces either an amide (as shown for reaction with hydrogen cyanide [HCN] producing the formamide of 2-amino-2-methylpropane [At-ferf-butylformamide (CHslsCNHCHO]) or, further, past the amide to the amine (2-amino-2-methylpropane [2-methyl-2-propananiine, f-butylamine, (CH3)3CNH2] and the corresponding (unspecified and thus unnamed) carboxylic acid (R-CO2H).

---