Ritter reaction acids

Method 4. Ritter reaction reaction of hydrogen cyanide with an olefin in an acidic medium to produce a primary amine. 

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. 

Alkenes of the form RCH=CHR and RR C=CH2 add to nitriles in the presence of mercuric nitrate to give, after treatment with NaBHj, the same amides that would be obtained by the Ritter reaction. This method has the advantage of avoiding strong acids. 

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. 

In addition to the present method,2 1-amino-1-methylcyclo-hexane has been synthesized by the following procedures Ritter reaction, e.g., with 1-methylcyclohexanol (76%, 67%)3i 4 or 1-methylcyclohexene (35%,) 4 5 Hofmann reaction with 1-methyl-cyclohexanecarboxamide (80% as hydrochloride) 6 reduction of 1-methyl-l-nitrocyclohexane (63%) 6 Schmidt reaction with 1-methylcyclohexanecarboxylic acid (42%).6... 

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. 

Ritter reaction org chem A procedure for the preparation of amides by reacting alkenes or tertiary alcohols with nitriles in an acidic medium. rid-ar re,ak-sh3n ) Ritz s combination principie spect The empirical rule that sums and differences of the frequencies of spectral lines often equal other observed frequencies. Also known as combination principle. rit-soz, kam-b3 na-sh3n. prin-sa-pal )... 

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]. 

Br prevents side reactions and makes BiBr3 a better Lewis acid catalyst, which is in accordance with our work BiBr3 affords only Ritter reaction products in the high dielectric constant solvent CH3CN, while BiCl3 originates a mixture of both v7 -/V-acylamino-hydroxy compounds and chlorohydrins. 

Reactions with secondary or tertiary alcohols in strongly acidic media yield amides (Ritter reaction) ... 

Olefins also undergo the Ritter reaction with nitriles in the presence of diphenyl diselenide, ammonium persulfate, and trifluoromethanesulfonic acid to produce oxazolines.When cyanamide is used, 2-aminooxazolines are obtained. The active electrophilic agent is phenylselenyl sulfate formed by oxidation of diphenylselenide with ammonium persulfate. The reaction is trans-stereospecific. 

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 ... 

The treatment of 3-cyano-4-styrylpyridine (109) with polyphos-phoric acid gave substance 110. This cyclization represents a rare example of an intramolecular Ritter reaction.128 This derivative was converted into compound 111 by the steps outlined. A similar condensation involving the treatment of compound 112 with polyphosphoric acid afforded l,8-dihydroxy-3,6-diphenyl-2,7-naph-thyridine (113) in 65% yield.129... 

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. 

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-... 

Ritter reaction of the triene 287 in triflic acid, performed to accomplish the synthesis of a marine sesquiterpene, gave the product acetamide derivative via a predominant trans antiparallel addition of H+ and acetonitrile to the endocyclic double bond920 [Eq. (5.343)]. 

Tertiary hydroxyls can undergo several reactions under acidic conditions to form artifacts in degradation experiments. In acidic acetonitrile/ water solutions, primary, secondary and tertiary alcohols can undergo a Ritter reaction to form amides (Fig. 83). 

Figure 83 Ritter reaction of tertiary alcohols to form amides under acidic conditions in acetonitrile.

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