Eschenmoser salt

With an unsymmetrical ketone as CH-acidic substrate, two regioisomeric products can be formed. A regioselective reaction may in such cases be achieved by employing a preformed iminium salt instead of formaldehyde and ammonia. An iminium salt reagent—the Eschenmoser salt—has also found application in Mannich reactions. ... 

Diels-Alder and hetero [4 -I- 2] cycloadditions of l-(l,3-butadien-l-yl)benzotriazole (638) with N-phenylmaleimide, maleic anhydride, ethyl acrylate, Eschenmoser salt, and nitrosobenzene give a... 

The observed exclusive cis fusion and the predominance of the product 355 over 356 was ascribed to the reaction occurring via the preferred transition state 354, wherein steric repulsion between one of the methyl groups of the dioxolane ring and the methylene group f) to nitrogen is minimised. Final introduction of one carbon atom to achieve the crinane skeleton was accomplished with Eschenmoser salt. The product, the O-isopropylidene derivative of the alkaloid, on acid catalysed deketalisation furnished (-)-amabiline with an impressive overall yield of 43%. 

The secondary reduction of the terminal radical by Sml2 generates samarium alkyl species which are suitable for classical organometallic reactions, e.g. protonation, acylation, reactions with carbon dioxide, disulfides, diselenides, or the Eschenmoser salt. A broad variety of products is available (hydroxy-substituted alkanes, esters, carboxylic acids, thioethers, selenoethers, tertiary amines) by use of the double-redox four-step (reduction-radical reaction-reduction-anion reaction) route (Scheme 20) [73]. 

Utilization of preprepai ed A,A-dimethylmethyleneammonium iodide (Eschenmoser salt) or chloride gives higher yields of (3-amino ketones than does the classical Mannich reaction. Silyl enol ethers also react with the Eschenmoser salt to give Mannich bases, as exemplified below. 

Aminomethylation of lactone enolates with the Eschenmoser salt followed by neutralization (workup) yields the corresponding Mannich bases. Their conversion to quaternary ammonium iodides followed by treatment with DBU (1,5-diazabicy-clo[5.4.0]undec-5-ene) leads to a-methylene lactones. 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

As a final example to close this section, further advances in free radical chemistry will be explored. Unlike the examples presented earlier in this chapter, the radical acceptors used by Bimwala, et ai.,31 were derived from sugar synthons. Specifically, as shown in Scheme 8.9.5, treatment of the bicyclic ketone, shown, with tert-butyl-dimethylsilyltriflate followed by the Eschenmoser salt provided the desired conjugated ketone.32 34 The nature of the actual coupling reaction, which proceeded in a 48% yield, will be further elaborated upon in the next section. 

Acetonide 141 has also been used in a short synthesis of (— )-tulipalin B (148), a naturally occurring lactone with cutaneous allergenic activity (Scheme 19) [22]. Methylenation of 141 is accomplished by treatment of the enolate anion with Eschenmoser salt, followed by per-methylation and elimination of the resulting trimethylammonium salt. Unfortunately, the yield is rather low, but unreacted 141 can be recovered in 80% yield. Saponification of the ester and subsequent acid-catalyzed deprotection with concomitant lactonization furnishes 148. 

Mc2 I ), called Eschenmoser s salt, has also been used in Mannich reactions. ... 

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. 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

Scheme 7-39. Reagents and conditions a PI13PCIIOMC, THF, —78°C (91%). b 1 N HC1 (aq), Nal, dioxane (94% at 90% conversion), c TESC1, pyridine, CH2C12, -30°C (92%). d Dess-Martin periodinane, CH2C12. e Et3N, Eschenmoser s salt (97%).

When R = H, the TvIe2N=CH2 salt is known as Eschenmoser s salt... 

A/V- Di methylmethyleneammonium iodide is commercially available and is known as Eschenmoser s salt .96 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.97 The reagent can be added to a solution of an enolate... 

Eschenmoser s salt at 50 °C in THE, the imine 297 gave the target molecule 298 in 77% overall yield. 

Pictet-Spengier cyclization. The final step in a recent synthesis of the alkaloid crinane (2) from 1 involved insertion of the final carbon to form the isoquinoline moiety.1 Heating 1 with aqueous HCIIO and cone. IICI at 60° resulted in 2 in 53% yield. Use of Eschenmoser s salt resulted in 2 in 90% yield. 

Thioamides are strongly electrophilic and easily alkylated [368] at sulfur, yielding iminium salts in a quantitative yield. This property has often been used, notably for the Eschenmoser reaction (see Section 4.3.5). 

In an attempt to achieve an enantioselective Eschenmoser-Claisen rearrangement with amide salts 6, (2R,5R)-l-(fluoroacetyl)-2,5-dimethylpyrrolidine was methylated to give chiral 6d. 5 Reaction of 6d with the lithium salt of (fj-crotyl alcohol gives amide 7d as a mixture of diastereomers, in which the. vj rt-isomers predominate. 

---