Ritter-type products

Direct anodic oxidation of aldehydes to acids has long been known, but has been largely neglected in recent years due to its limited preparative value [156,157]. Likewise, the anodic oxidation of ketones leads mainly to C-C bond cleavage reactions or to Ritter-type products when conducted in acetonitrile, though the reaction in the latter case is of some mechanistic interest [158-160]. 

Intramolecular reaction of a nitrile group and a carbenium ion can produce a cyclic nitrilium intermediate leading to Ritter-type products after reaction with an external nucleophile (Scheme 15). Geome-... 

Cristol has earned out photochemical studies on a range of cyclic halogenated substrates which yield Ritter-type products.Irradiation of the dihalides (80) in acetonitrile normally affords a mixture of the isomeric piquets (81) and (82 X = halogen), plus polar material. However, when the solvent was switched to 3% aqueous acetonitrile, significant amounts of the additional products (81 X = OH 13%) and (81 X = NHAc 16%), plus traces of (82 X = NHAc) were isolated (equation 40). These new substances are believed to result from nucleophilic attack by water or acetonitrile on a ground state carbe-nium ion-like intermediate. A number of further, closely related reactions of this type have been described.These photolyses consistently yield amide products but, unfortunately from the synthetic viewpoint, mixtures are often produced, and overall yields of the amides are not generally high. 

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]. 

Styrenes (1) have been reported to undergo head-to-tail dimerization in the presence of I2 and p-TsOH (Scheme 1), which is then followed by trapping the intermediate with nitriles (2) to afford the corresponding Ritter-type products (3). ... 

Triflic acid has been applied in a three-component condensation of phenols or 2-naphthol, aromatic aldehydes, and alkyl nitriles to form amidoalkylphenols under mild conditions in good to high yields922 [Eq. (5.345)]. The reaction involves a Ritter-type step, wherein the intermediate condensation product reacts with the nitrile component. 

When o-aminocarbonitriles 48 (R2 = R3 = Me) or 52 were reacted with jY-arylcyanamides in the presence of dry hydrogen chloride gas followed by aqueous workup, a mixture of 2-amino-3-aryl-4-iminothieno[2,3-d]-pyrimidines 65d and the corresponding thieno[2,3-d]pyrimidin-4(3//)-ones 66b was isolated. The formation of the latter as a minor product for each derivative was rationalized to proceed via the guanidine intermediate 67, which hydrolyzed through a Ritter-type reaction and then cyclized during workup (93JHC435). 

The addition to allyl nitrile also shows some preference for the anri-Markovnikov adduct (equation III). However, both products undergo a Ritter-type hydrolysis of the nitrile group to provide the same lactone. 

Bimolecular trapping of phenoxonium ions by nucleophilic yr-bonds can lead to cyclized products when attack occurs at the or /io-position. For instance, a Ritter-type reaction occurs when MeCN is used as solvent in the absence of other nucleophiles, leading to a useful synthesis of benzoxazoles (XLV) [48] ... 

The reactive intermediate is considered to be RS", which adds to the carbon-oarbon double bond, probably forming an intermediate episulfonium ion as in Eq. (18). This by a Ritter-type reaction followed by hydrolysis leads to the final products, as in Eqs. (19) and (20). 

The isolation of oxazole derivatives from Ritter-type reactions dates back to 1893, when Japp and Murray reported that benzoin and sulfuric acid reacted with nitriles (equation 33). Better yields of such products are obtained from reaction of chloro ketones (54) with nitrile-SnCU complexes (equation 34). Likely mechanisms for these processes have been discussed by Meyers and Sircar. ... 

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). 

Several other reactions involving C-N bond formation have been reported. A Ritter-type reaction of alkylbenzenes with nitriles has been achieved. Thus, the treatment of ethylbenzene with CAN in the presence of a catal3dic amount of N-hydroxy-phthalimide (NHPI) in EtCN produces the corresponding amide in good selectivity (eq 23). The reaction is also applicable to a number of unactivated hydrocarbons. As a comparison, the photolysis of admantane with CAN gives a mixture of products. In another case, the oxidation of monoterpenes such as pinene with CAN in acetonitrile affords the corresponding bisamides in good yields (eq 24). ... 

In a report describing acid-promoted Ritter reactions involving a-methylene-)5-hydroxyesters, an I -type process was found to be the preferred mechanism. For compound (104), both Ritter reaction products (105 and 106) are obtained. In order to rule out 5 2 or Sf 2 mechanisms, kinetic analysis was performed, kinetic isotope effects were evaluated, and both Hammett and Eyring plots were done. The mechanistic studies were consistent with an I -type process being preferred with initial formation of the oxonium cation, loss of water, and formation of the allylic acarbocation (107). DFT calculations indicated nucleophilic attack at the terminal carbon (107b, 5 10 was favored by about 2.6kcalmol over attack at the benzylic position (107a, 5 1) (Scheme 23). 

A Ritter-type alkylation has been used to alkylate benzopyrazole to form the corresponding (V-trifluoromethyl imines. The methodology uses electrophilic hypervalent iodines in the presence of catalytic amount of acid to activate acetonitrile, affording the N-2 alkylated trifluoromethyl imine in 57% yield as the kinetic product in the reaction. The N-2 substituted imine, when subjected to similar reaction conditions over longer reaction times, affords... 

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. ... 

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