Ritter reaction Acetamidation

By analogy with their behavior in mass spectrometry, branched hydrocarbons are cleaved when oxidized in CH3 CN/TEABF4 at —45 °C. The resulting acetamides of the fragments (Table 6) are formed by cleavage of the initial radical cation at the C,C bond between the secondary and tertiary C atom, to afford after a second electron transfer, carbocations, which react in a Ritter reaction with acetonitrile [29]. 

The Ritter reaction [6] proceeds by the electrooxidation of alkyl iodides (56) in an MeCN-(Pt) system to form Ai-alkyl acetamides (58) (Scheme 21). Attack of carbenium ion intermediate - from dissociation of the initially formed alkyl cation radical - to acetonitrile would give the iminium cation (57). However, a different mechanism is proposed, whereby the alkyl iodide reacts with the electrogenerated iodo cation [I]" " [73]. 

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. 

DFT calculations on the Mg(L—H)(L) complex reveal how water and acetonitrile can be lost (Scheme 9). Thus intramolecular proton transfer tautomerizes the neutral acetamide ligand in 48 into the hydroxyrmine form in 49, which can then dissociate via another intramolecular proton transfer to yield the four-coordinate adduct 50, which now contains both water and acetonitrile ligands. It is this complex that is the direct precursor to water and acetonitrile loss. Note that the reaction shown in Scheme 9 is a retro-Ritter reaction and involves fragmentation of the neutral rather than the anionic acetamide ligand, which is a bidentate spectator ligand. 

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)]. 

In its utilization of acetonitrile, the oxazoline synthesis shown in Scheme 56 resembles a Ritter reaction.The procedure is convenient, but yields are variable the pyrolysis gives starting alkene plus acetamide as by-products. Another oxazoline synthesis and subsequent conversion to a cif-amino alcohol is discussed later (Scheme 85). A recent y-hydroxy-a-amino acid synthesis incorporates the following type of transformation (Scheme 57).If a three-day equilibration with anhydrous HBr was introduced iMtween stages i and ii, almost pure trans product was obtained. The paper has many usefol references. Yet another modified Ritter reaction is shown in Scheme 58. ... 

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-... 

The anodic oxidation of substituted (4-hydroxy-3-coumarinyl) phenylthiomethanes in MeCN-LiC104 on a Pt electrode results in a C-S bond cleavage to give N-substituted acetamides by a Ritter reaction with MeCN [123] ... 

To favor the coupling reaction, the competing side reaction of the radical cation with nucleophiles must be suppressed by the use of a medium of low nucleophilicity. The solvent of choice is dichloromethane. Especially in electroanalytic studies, neutral alumina is frequently added to suppress hydroxylation of the radical cation [20]. The reversible cyclic voltammetric behavior of radical cations is also enhanced in mixtures of methylene dichloride, trifluoroacetic acid, and trifluoroacetic anhydride (TFAn) with TBABF4 as supporting electrolyte. With acetonitrile as solvent, acetamides, formed in a Ritter reaction, are often the major products. The selective dimerization of mesitylene in acetonitrile is exceptional (Table 1, number 3). Dichloromethane, however, is reducible at the cathode. 

Magat first reported the use of r-alkyl halides as Ritter reaction substrates but, in general, these were less satisfactory than the use of the corresponding alcohol or alkene analogs. This process has since come into its own for polycyclic systems, where simple methods of generating bridgehead halides are often available. An early example is Stetter s conversion of 1-bromoadamantane to the acetamide (30), there-... 

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). 

Earlier mention has been made of the use of Lewis acid and Friedel-Crafts reagents as initiators of carbenium ion formation. Another versatile device is to employ a metal to assist in generation of the carbenium ion. In its simplest form, addition of silver(I) ion to an alkyl halide is an excellent technique for encouraging reaction by means of the 5n 1 pathway. This process was first applied to the Ritter reaction by Cast and Stevens, but yields obtained were modest. A recent elegant application of this technique is the two-step conversion of dodecahedrane into its acetamide derivative (Scheme 45). ... 

Similarly, several nitriles (such as CICH2CN and o-MeCsHtCN) which tend to react poorly in the conventional reaction now reacted most efficiency (98 and 83%, respectively) with the stabilized benzyl cation. Tertiary carbenium ions were so stabilized that no Ritter reaction took place and the behavior of secondary ions depended on the particular case (Scheme S3). Complexed propargyl alcohol (111) was converted into the complexed acetamide (112) without encountering the customary acid-catalyzed rearrangement problems (equation 48). 

The anodic conversion of tertiary C—H functions (without any specific activation) is possible, yet it needs rather high potentials. One typical example is certainly that of adamantane [42], the oxidation of which can be achieved in acetonitrile. Under these conditions, the corresponding acetamide (via Ritter reaction) was obtained. 

This led to the interesting suggestion that the azo compound underwent one-electron oxidation to the then little known azoalkane radical cation. This species subsequently lost dinitrogen to form 1-adamantyl cation and 1-adamantyl radical. This latter species was then oxidized by thianthrene radical cation to 1-adamantyl cation. The 1-adamantyl cation thus formed underwent Ritter reaction to produce AT-adamantyl acetamide 20. 

The N-alkylation of nitriles with aralkyl alcohols, a special case of the Ritter reaction,6 is a novel general reaction. The following compounds were prepared by this procedure in the corresponding yields N-benzylacetamide (48%), N-(2,4-di-methylbenzyl)-acetamide (40%), N-(4-methoxybenzyl)-acetam-ide (60%), NjN -diacrylyl-p-xylene-a-a -diamine (64%), N,N -diacetyl-4,6-dimethyl- w-xyleiie-a,a,-diamine (62 %). 

Although the conformational studies in Figs. 5 and 6 relate to mechanistic issues, the product of the hydrolyses also drew our attention. Thus, the a-acetamide 54 (n = 1 or 2) was the major product from hydrolyses of the restrained precursors 50 (a/P) and 51 (a/p) shown in Fig. 5, and reproduced in Scheme 9a [70]. Such compounds result from a Ritter reaction [71, 72] to give a nitrilium intermediate, e.g., 53, which rapidly scavenges water. 

A variation on the Ritter reaction, suitable for the transformation of primary secondary, and tertiary alcohols to acetamides, involves thionyl chloride in acetonitrile. Reduction of the crude products (Scheme 17) with zinc-acetic acid converts any chloroacetamide product into the acetamide, and overall yields are moderate to good. 

Since the solvolysis of intermediates occurred so easily in moist acetone, the stoichiometric reaction of la was repeated in methanol as solvent, resulting in the methyl ether 5a being isolated. More importantly, when the reaction was performed in dry acetonitrile, the corresponding acetamide (6a) was produced indicating that a Ritter-type reaction had occurred. Hence, C-N as well as C-0 bonds can be formed by this process. In a further development of this reaction, the intermediate nitrilium salts have been intercepted by azide ion, giving good yields of tetrazoles. 

It was also found recently that direct selective substitution of aliphatic hydrocarbons via a supposedly electrophilic mechanism can be achieved by use of F-TEDA-BF4 [202]. Depending on the exact reaction conditions, either alkyl fluorides or Ritter-type products are obtained (Scheme 2.91). Relatively short reaction times favor the formation of the fluorides, longer heating with F-TEDA-BF4 in acetonitrile favors the formation of acetamides, especially in the presence of additional BF3 OEt2 as Lewis acid catalyst [203]. 

In a first proof-of-principle study, we chose benzhydryl bromide 21 as a test substrate, since this compound features a relatively weak C-Br bond. If the corresponding benzhydryl carbocation is formed (see Scheme 16) and no further nucleophiles are added, the solvent (acetonitrile) will attack the cation and form a nitrilium ion intermediate. Finally, traces of water in the solvent will hydrolyze this species to from W-benzhydryl acetamide 22 in an overall Ritter-like reaction. The formation of this product from benzhydryl bromide can easily be followed by H-NMR spectroscopy. 

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