Ritter reaction synthesis

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

Dorzolamide contains two chiral centers, and is therefore capable of existing in four diastereomers. The stereochemistry at the C-6 position of the starting material is preserved during the various chemical reactions which take place during the synthesis. The stereochemistry at the C-4 position (absolute configuration being 5) results from the Ritter substitution reaction (Scheme 1, Steps I-II) used to transform the alcohol to an acetamide. The Ritter reaction yields mostly the rra j-diastereomer, and the c/s-diastereomers are easily separated as their maleate salts. The potential sulfonamide positional isomer (3-sulfonamide) has not been observed at levels greater than 0.1% in HPLC analyses. 

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 synthetic utility of the Ritter reaction is evident from surveying the literature. An early example of the Ritter reaction is found in the synthesis of in vivo metabolites of the drug mephentermine (equation... 

The synthesis of heterocycles is another common application of the Ritter reaction. Equations (168 -(170) illustrate the preparation of a lactam,236 oxazoline237 and dihydroisoquinoline,235 respectively. 

Extension of the Ritter reaction to conjugated dienes, however, has been less successful. The reaction is often met with competing Diels-Alder reactions or extensive polymerization. The polymerization that occurs during the reaction of 1,3-dienes and nitriles has been used in the synthesis of linear... 

The experimental support for such a conclusion is the synthesis of isoquinolines 33 from benzyl ketones 25, which obviously takes place by a new version of the Ritter reaction [7IJCS(C)3590 78CPB245 82MII 89TH1]. Detailed discussion of this conversion is outside the scope of this review. 

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)]. 

One of the earliest heterocyclic applications of the Ritter reaction was to the synthesis of dihydro-1,3-oxazines.9 It was found that the reaction of the dialcohol (1) with nitriles leads to the oxazines (2) rather than the expected bis-amides (Table I). The yields are only fair... 

A novel application of the Ritter reaction to the synthesis of 2-hydroxythiazoles was reported recently by Yura,19 using acetylenic thiocyanates. 

The most useful application of the Ritter reaction in heterocyclic synthesis appears to be the preparation of 1-pyrrolines17 (7). These... 

The first synthesis of a heterocyclic system (22) by the Ritter reaction was reported24 in 1952, from the reaction of nitriles with methyleugenol (19). The reactions succeed only when the benzene ring is activated and allylbenzene itself gives the expected amide. 

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... 

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). 

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