Iminium trifluoroacetate

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

Entries 1 and 2 in Scheme 2.11 show the preparation of Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as bis(dimethylamino)methane in entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. 

Table 5 Regioselective Mannich Reactions of Methyl Ketones (39) Using A -Dimethyl(methylene)iminium Trifluoroacetate (32) in Trifluoroacetic Acid versus Acetonitrile ...

Laboratory transformations took advantage of fragmentation of dregamine (30), tabemaemontanine (31), and vobasine (32) as N4 oxide induced by treatment with trifluoroacetic anhydride (Polonovski-Potier reaction) (192) and reductive capture of the intermediate iminium ion (Scheme 1). 

In 2004, List reported that several ammonium salts including dibenzylammonium trifluoroacetate catalyzed the chemoselective 1,4 reduction of a, 5-unsaturated aldehydes with Hantszch esters as hydride sources [40]. It is assumed that substrate activation via iminium ion formation results in selective 1,4 addition of hydride. Subsequently, List [41] and MacMillan [42] reported asymmetric versions of this reaction promoted by chiral imidazoUdinone salts. In this context, several reports of this metal-free reductive process catalyzed by chiral phosphoric acids have appeared in the recent literature. 

Another example is provided by the application of the modified Polonovski reaction to A3-piperideines. Treatment of amine oxides (141) with trifluoroacetic anhydride results in the formation of iminium ion (142). These compounds can behave as useful synthetic intermediates, reacting with a number of nucleophiles such as cyanide ion (80JA1064). 

Tadalafil (3, IC-351) was discovered at ICOS and is being developed and marketed as a joint venture with Eli Lilly, D-tryptophan methyl ester (21) was condensed with piperonal by means of trifluoroacetic acid and the C2 carbon of the indole adds to the resulting iminium ion to give a mixture of cis (3-carboline 22 and trans isomer 23 (Scheme 5). The desired cis isomer 22 can be isolated by chromatography or crystallization in 42% yield. Compound 22 was acylated with chloroacetyl chloride to... 

X = CF3COO) were formed but within minutes to hours, they underwent quantitative isomerization (recyclization) to 1,3,4-thiadiazolidin-2-iminium cations 89B. The same cations were formed from the open-chain aldehyde thiosemicarbazones in trifluoroacetic acid solution. Deprotonation of the salts 89B with C5D5N yielded the open-chain thiosemicarbazones 88A and not the cyclic isomers 88B. The open-chain isomers of ketone 2-methyl- or 2,4-dialkylthiosemicarbazones obtained in this way (89B —> 88A) are unstable and readily cyclize into 88C when their solutions are stored or when they undergo a recrystallization or thin-layer chromatography procedure. 

Evidence that this reduction proceeds mainly via an N-acyl iminium ion intermediate 120 was obtained by carrying out the triethylsilane reduction of 108 in deuterated trifluoroacetic acid (Scheme 49). As before, two C-4 epimeric protected kainoid analogues 121 and 122 were obtained, H NMR showing loss of the C-4 proton in both products accompanied by a simplification in the spin-spin coupling pattern of the C-5 protons.73 A close examination of the 2H NMR spectrum of each diastereoisomer did, however, reveal a trace of deuteration at C-5 indicating that a small percentage of the reduction also occurs via a benzylic carbocation intermediate 123 (Figure 12). 

Tetrahydrofuran was distilled from the ketyl prepared from benzophenone and sodium, but the reaction does not suffer from moisture. Dioxane can also be used, but the iminium salt polymerizes rapidly at the reflux temperature of this solvent (101°C). To avoid polymerization the N-methylanilinium trifluoroacetate should be added in portions to the reaction mixture. 

The amine-oxide (316) reacts with trifluoroacetic anhydride in the manner depicted in Scheme 13. The iminium ion (317) has the properties of a Mannich reagent, and alkylates a second steroid molecule in the enamine form (318) to give the 2-methylene-3-ketone (31-9) after hydrolysis. The demethylated amine was formed at the same time. Different behaviour of the A -unsaturated amine oxide (320) results from participation of the olefinic bond in a novel type of Grob... 

Upon addition of excess trifluoroacetic acid to the crude Heck product, an iminium ion cyclization furnishes the tetracyclic core of minfiensine (1) without cleavage of the Boc group. 

Preformed iminium salts have been used extensively in organic synthesis. The facility of the condensation is a function of iminium salt substitution. Treatment of formaldehyde-derived methyl(methylene)ammonium halides (or trifluoroacetates) (46) with Grignard and lithium reagents results in the high yield formation of dimethylaminomethyl-containing compounds (47). Subsequent oxidation or alkylation of these products has been employed to generate terminal alkenes (48 Scheme 7). As expected, addition yields are modest for the mote-hindered iminium salts derived frrom other aldehydes and are somewhat lower for those derived from cyclic ketones. ... 

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