Ritter reactions

The enantioselective biomimetic total synthesis of the alkaloid (+)-aristotelone was accomplished by C.H. Heathcock and co-workers. The synthetic sequence commenced with a Hg(N03)2-mediated Ritter reaction between (1S)-(-)-P-pinene and 3-indolylacetonitrile. Upon protonation, the pinene underwent a Wagner-Meerwein rearrangement to generate a tertiary carbocation which reacted with the cyano group. The initially formed imine product was reduced to the corresponding amine by sodium borohydride in methanol. 

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. 

NaCN (8 equiv) AcOH (glacial) H2SO4 (8 equiv) 

A modified Ritter reaction was used by Y.L. Janin et al. for the preparation of electron rich 1-aryl-3-carboxylisoquinolines, which are considered to be the eiectron-rich anaiogues of PK 11195, a faicipain-2 inhibitor. interestingiy, the standard Ritter reaction conditions (strong acid) ied to extensive decomposition of both starting materiais, but the use of HBF4 in ether gave rise to the desired dihydroisoquinoiine, aibeit in poor yieid. 

The intramolecular Ritter reaction was utiiized by F. Compernoiie and co-workers for the synthesis of a potentiai dopamine receptor iigand. The six-membered iactam ring was formed upon treatment of the tertiary benzyiic aicohoi substrate with methansuifonic acid. The benzyiic carbocation was captured by the nitrogen of the cyano group. 

Amides from nitriles and alcohols in strong acids. General scheme  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications y DOI 10.1007/978-3-319-03979-4 233, Springer International Publishing Switzerland 2014 

Example 6, A cascade of the Prins/Ritter amidation reaction  

Brewer, A. R. E. Ritter reaction. In Name Reactions for Functional Group Transformations, Li, J. J., Ed. Wiley Hoboken, NJ, 2007, pp 471-476. (Review). 

Michael addition of cyclohexanones to methyl vinyl ketone followed by intramolecular aldol condensation to afford six-membered a, p-unsaturated ketones. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 218, Springer-Verlag Berlin Heidelberg 2009 

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The last recipe deserves to be last The Ritter Reaction [not affiliated with the above Ritter]. 

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. 

CH3)2CH0H + CH2=C=0 CH3C00CH(CH3)2 and the Ritter reaction to prepare A/-isopropylacrylamide [2210-25-5] from acrylonitrile [107-13-1] and isopropyl alcohol ... 

The Ritter reaction with unsaturated carbenium ions under either silver-assisted solvolysis or photolytic conditions leads to excellent yields of isoquiaolines (173). The ease of preparation of the requited vinyl bromides makes an attractive route to highly substituted isoquiaolines. 

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. 

In contrast to the normal Ritter reaction, the reaction shown in equation 47 gives good results starting from primary and secondary alcohols Other advantages are the mild reaction conditions and easy workup [96]... 

Side reactions consistent with decomposition of intermediate nitrilium salt 7 have also been observed, including retro-Ritter reactions that afford alkenes (8), and VonBraun reactions that provide alkyl chlorides (9). ... 

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... 

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. 

The Ritter reaction can be applied to cyanamides RNHCN to give ureas (RNHCONHR ). ... 

In this modified Ritter reaction inversion at C-3 takes place, implying that the five-membered rings 40 have a czs-relationship between the alkyl substituent... 

PhentEimine (11),used in the treatment of obesity, is a t-alkyl amine. The Ritter reaction, using HCN as the nitrile (p T63), is ideal for this,... 

Attempts to replace the phenylsulfenyl group in 1239 with benzyloxytrimethyl-silane 13 c leads, via fragmentation of 1240 and 1241 and incorporation of acetonitrile in a Ritter reaction, to 82% of a 7 1 mixture of 1242 and 1243 [44]... 

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. 

Scheme 1.29. Domino acyliminium ion cyclization/Ritter reaction procedure in the synthesis of CPG 49823 (1-116).

Application of the Ritter reaction conditions on y-hydroxy-a,P-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or y-A-acylamino-P-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The y-A-acylamino-P-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCI3 <06TL4385>. 

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