Ritter intermediate

As an extension of the amidoseleniation processes discussed previously, imidates (the third Ritter intermediate) may be utilized as precursors for the synthesis of cyclic amides (Scheme 67) and lactams (equation 52). Such combination of imidate and onium ion processes has much potential for further extension of Ritter-type chemistry. 

Indeed, Pougny and Sinay had shown that Ritter products could be captured by an in situ carboxylic acid [77]. In keeping with this precedent (Scheme 10a) the glucoside 59 was treated with NBS in very dry acetonitrile, and the Ritter intermediate 60 was captured by the in situ aspartic acid 61 [78], leading to the rearranged a-imide 62a. In view of the three acyl residues, it took several experiments before finding that smooth Af-deacylation could be effected by piperidine to give 62b [79]. 

This method was designed to produce an acetyl intermediate just like that in the failed recipe a few paragraphs above using only sulfuric acid and acetonitrile [93]. This reaction works, in theory, in a so-so manner on allylbenzene but not on safrole. This method will not make X for many reasons. So why does underground literature and DEA forensic scientists keep claiming that it does Strike doesn t know either. Let s see what the man who invented this. Dr. Ritter, had to say back in 1952 "several attempts to obtain amides from...safrol (sic) were fruitless. [94]. What makes all these people think that this will work unless no one did their homework. This is another sore spot of Strike s and... 

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). ... 

In addition, Hegedus and co-workers extended this chemistry to the /V-alkylation of 1-lithioindole with alkenes (PdC MeCN /THF/HMPA/EtsN/then H2) to afford A/-alkylindoles in 28-68% yields [411], Moreover, a similar reaction of N-allylindole 343 with nitriles leads either to 344a, 344b, or 344c depending on how the intermediate Pd-alkyl (or acyl) complexes are treated [431]. The formation of these pyrazino[ 1,2-a]indoles is similar to a nitrile-Ritter reaction. 

The formation of the tetrazoles 66 and 67 from 62 and 63, respectively, has been rationalized on the basis of the solvent-assisted opening of the initially formed iodonium ion to give the Ritter reaction intermediate 68, which undergoes cycloaddition with azide... 

The I2 addition to 3 in chlorinated solvents yields a mixture of isomeric 2,6-diiodobicy-clo[3.3.0]octanes (endo.exo-69 and endo,endo-7tt) (equation 71)22. When the reaction was carried out in aqueous acetonitrile under similar conditions, the formation of a mixture of acetamido derivatives 71 and 72, arising from iodocyclization followed by the capture of the iodonium ion by the solvent to give a Ritter reaction intermediate, accompanied the formation of products 69 and 70 (equation 72)22. 

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]. 

Epoxides also participate in the Ritter reaction with nitriles. An investigation of the ring opening of several alkyl-substituted glycidic esters and amides 181 showed that this transformation occurs with inversion and is completely regiospecific. ° Esters appeared to be somewhat more reactive than amides. However, phenyl-substituted glycidic esters and amides 184 are almost totally nonstereoselective. In addition, the oxazolines 186 are isolated in low yield due to the propensity of intermediate 185 to generate an aldehyde byproduct 187 (Scheme 8.53). 

Epoxides also undergo the Ritter reaction in good yields with retention of configuration via a episulfonium intermediate 190a (double-inversion process). For monosubstituted epoxides, the yields of oxazolines are lower due to nondis-criminatory attack of the nitrile on both the primary and the secondary carbon atom of the episulfonium intermediate. Complete retention of configuration is still observed despite the lower yield (Scheme 8.54). 

In the mechanistic outline to Scheme 2, the intermediate oxocarbenium ion was trapped by an oxygen nucleophile to give an O-glycoside. Further experimentation has revealed that Af-nucleophiles can also be applied, leading to Af-glycosyl products [26]. Thus, if the reactions are carried out in the presence of acetonitrile, a Ritter reaction ensues affording nitrilium ion 49 (Scheme 12). This relatively unstable intermediate can be trapped... 

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. 

Reaction intermediates formed in the nitration of a series of a,/i-unsaturatcd esters, such as (47), with N02BF4 have been reported to exhibit the expected behaviour of a-carbonyl cations. Three diagnostic reaction types were observed (1) Ritter reaction (2) cyclopropane formation from propyl cations (3) Wagner-Meerwein migration of alkyl groups. Semi-empirical calculations of the relative gas-phase stabilities of the proposed intermediate cations have also been performed.53... 

Cyclic imines are obtained in the related transformation of methylenecyclpropanes with nitriles mediated by triflic acid700 (Scheme 5.68). The reaction pathway suggested to interpret product formation is similar to that in Scheme 5.67. The reaction of intermediate 162 with water may give Ritter products (carboxamides) isolated in some cases. 

Similar carbocationic intermediates may be involved in the transformation of substituted ethyl pentadienoates under Ritter conditions in excess triflic acid (3 equiv.) to furnish the bicyclic aza compounds 163 [Eq. (5.254)].701... 

Fused or spiro sugar oxazolines have been synthesized by treating D-fructopyranose or D-fructofuranose 1,2-0-acetonides with nitriles in triflic acid773 (Scheme 5.73). First the activation of the anomeric center takes place with simultaneous isopropy-lidene cleavage to form the oxocarbenium ion intermediate, which is attacked by the nitrile. The resulting nitrilium ion is then trapped by the hydroxyl group in an intramolecular Ritter-like reaction to yield the final product. 

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. 

A complementary approach to the synthesis (1R,2S)-1 has been developed by Merck using (.S, .S )-Mnl.CI catalyst in a hypochlorite medium to provide (IS, 2/0-indene oxide 26. This intermediate was converted without isolation to r/.v-aminoindanol in a stereoselective and regioselective manner using Ritter technology (Scheme 24.2). Several key issues, detailed later in this chapter, have been addressed and resolved in both Jacobsen s AE52 and Ritter technology50 to develop a reproducible and practical large-scale process for the synthesis of enantiopure d.s-aminoindanol. 

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 first of these approaches stems from the Ritter reaction, whereas the second utilizes nitrilium salt intermediates. These reactions are probably different in degree rather than in kind since they are regarded as involving similar intermediates. 

Although the term nitrilium salt was used for the first time in 1931,26 the actual existence of these interesting compounds was not established until 1955 as a result of the work of Klages27,28 and Meerwein.29-30 Nevertheless, long before this last date it was common knowledge that non-isolable intermediate nitrilium salts are formed in numerous reactions. This is specifically the case in the Ritter reaction (Section II, A), as well as in many cognate reactions between nitriles and alkyl halides,31 isoparaffins,32 or a-trisubstituted acids,33 all of which yield a carbonium ion in the presence of sulfuric acid. 

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