Ritter reaction concentration

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. 

Ionic hydrogenation of the same bicyclic diene 382 by Et3SiH in the presence of CF3COOH at room temperature or at 80 °C via ions 387 and 388 is accompanied by transannular cyclizations (equation 139)192. The behavior of diene 382 under Ritter reaction conditions (MeCN, H2SO4) reveals new possibilities to control the transannular cyclizations (equation 140)193. Depending on the sulfuric acid concentration, the reaction temperature and the presence of a nucleophilic solvent, these transformations can be directed to the formation of either the bicyclic amides 389 and 390 having the precursor structure or the tricyclic products 391193. 

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]. 

Mecamylamine Mecamylamine, M2,3,3-tetramethylnorboman-2-ylamine (14.2. 2), is synthesized from 2,3,3-trimethylnorbomen-2, which is reacted in a Ritter reaction conditions with hydrogen cyanide in concentrated snlfuric acid, giving 2,3,3-trimethylnorbor-nan-2-ylformylamine (14.2.1), the reduction of which by lithium aluminum hydride leads to mecamylamine (14.2.2) [32,33]. 

Exercise 15-24 It is possible to prepare amides from tertiary alcohols and alkane-nitriles, RCN, in concentrated sulfuric acid as the catalyst (Ritter reaction), as illustrated in the equation for the synthesis of W-fe/f-butylethanamide ... 

Meyers and Garcia-Munoz64 assume that the cyclization of the -ketonitriles 67 by the action of concentrated sulfuric acid may be regarded as a still further extension of the Ritter reaction to the reactions of carbonyl compounds in the synthesis of nitrogen-containing heterocycles (equation 25). In this case the cyano-group reacts as a nucleophile with the positively charged center of the carboxonium intermediate J L... 

In the laboratory of T.-L. Ho, the total synthesis of the novel marine sesquiterpene (+)-isocyanoallopupukeanane was completed." In the endgame of the synthesis, it was necessary to install the isocyano group onto the tricyclic trisubstituted alkene substrate so that it will occupy the more substituted carbon atom (according to Markovnikov s rule). The Ritter reaction was chosen to form the required carbon-nitrogen bond. The alkene substrate was dissolved in glacial acetic acid and first excess sodium cyanide followed by concentrated sulfuric acid was added at 0 °C. The reaction mixture was stirred at ambient temperature for one day and then was subjected to aqueous work-up. The product A/-alkyl formamide was subsequently dehydrated with tosyl chloride in pyridine to give rise to the desired tertiary isocyanide which indeed was identical with the natural product. 

The reaction of nitriles with aromatic aldehydes is carried out at heating the reactants to 50-70°C with a 1 -h 10 (v/v) mixture of concentrated sulfuric acid and glacial acetic acid. The cycloaddition reaction is regiospecific. The oxazines 21 (equation 10) are formed as diastereoisomeric pairs which are free from their regioisomeric products in the limit of the NMR analysis. Precursors used were benzonitrile and acetonitrile as well as acetaldehyde, benzaldehyde and its substituted derivatives, and a number of the olefins having various structures. Until now, the reaction of aldehydes with nitriles was interpreted as an extension of the Ritter reaction. The initial O-protonation of aldehyde 22 is postulated to form in the presence of acid the hydroxycarbenium ion 23 which then reacts as a cationoid electrophile with the nitrile (equation 11) giving the nitrilium ion 24. 

Carbenium ions can be produced from numerous different functionalities via many different techniques, and consequently the Ritter reaction represents an extremely versatile technique for the formation of amides. For example, we have above illustrated the formation of a stable carbenium ion from alcohols and alkenes, and Reddy has reported the use of an ester as a source of the necessary carbenium ion.5 In this case, t-butyl acetate (12) was converted to the corresponding cation with catalytic concentrated sulphuric acid and was reacted with a wide variety of aromatic nitriles 11 with commendable success. 

Addition of hydrogen cyanide or nitriles to olefins in the presence of concentrated sulfuric acid or some other strong acid is a preparatively important method of synthesizing alkylated amides containing secondary or tertiary alkyl groups on the nitrogen atom (the Graf-Ritter reaction) 20-26... 

Recent research into the Ritter reaction has concentrated on alternative means of generating the carbocation. Radiolytically formed carbocations have been reacted in the gas phase with aromatic and aliphatic cyanides yielding the corresponding nitrilium ions, which undergo condensation with water to yield A -alkylamides. 

The development of carbocations of organometallic complexes of transition metals offers an alternative method of carrying out the Ritter reaction with primary and secondary alcohols, which normally give poor yields. Reaction of the complex 114 with concentrated sulphuric acid at -15 °C in the presence of acetonitrile gives the amide complex in good yield. ... 

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. 

Other acid-catalysed addition reactions include reaction with nitriles (Ritter reaction), formaldehyde (Prins reaction) and carbon monoxide and water (Koch reaction). These reactions are normally catalysed by concentrated sulphuric acid. Extensive isomerization occurs and may even lead to quaternary compounds of the type RC(CH3)XR where X is the new functional group introduced into the molecule. Homogeneous catalysts have been developed which give simpler products without extensive isomerization. 

Regio- (Markovnikov) and stereo-specific (anti) incorporation of MeCN (a Ritter-type reaction) has been observed upon bromination of a series of olefins, carried out in this solvent187. The degree of this incorporation depends on the olefin structure and on the initial reagent concentrations and ratios. Thus, when performed at low initial concentrations and with the initial B /alkene ratio >2, this reaction can be used preparatively187. 

The participation of nitrilium salts has also been postulated42 in the Schmidt reaction and in some Beckmann rearrangements when concentrated sulfuric acid is employed. Hill43 has demonstrated recently that some Beckmann rearrangements carried out in a concentrated sulfuric acid medium are Ritter-type reactions in which the nitrile formed in situ from the oxime combines with a carbonium ion to yield a nitrilium salt, which, when diluted with water, leads to the N-alkylamide. 

In 1948, Ritter and his student Minieri reported that the reaction of alkenes 4 with mononitriles 2 in the presence of concentrated sulfuric acid, followed by aqueous workup gave amides 3.1 The report was illustrated with many examples, indicating a reaction of high reproducibility and wide applicability. In the paper immediately following this one, Ritter expanded on this report and detailed the mechanism further.2... 

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