Esters from iminium salts

The iminium salt 132, generated from benzylamine hydrochloride and aqueous formaldehyde, reacts with cyclopentadiene during 3 h at room temperature to give, after basification, the cycloadduct 133 in nearly quantitative yield (equation 70). Other examples of this reaction are shown in equations 71-75. The separable diastereomers 134 and 135 are formed in the ratio 4 1 from cyclopentadiene, (—)-a-methylbenzylamine hydrochloride and aqueous formaldehyde in a combined yield of 86% (equation 75)62. Hydrochlorides 136 of methyl esters of natural amino acids [(S )-valine, (S )-isoleucine] react with cyclopentadiene and formaldehyde in aqueous THF to produce mixtures of the diastereomers 137 and 138, in which the former predominate (equation 76)63. 

RCOOH — RCHO. The iminium salt (1) formed on reaction of a carboxylic acid with the Vilsmeier reagent (formed from DMF and oxalyl chloride) is reduced by lithium tri-/-butoxyaluminum hydride (1 equiv.) to an aldehyde. The chemo-selectivity is noteworthy ester, nitrile, keto, and halide groups are not affected.3... 

The Pictet-Spengler cyclization of iminium salts, generated in situ from 3-indolyl)ethyl substituted amino acid esters 257 and various aldehydes, has been found to proceed with high stereoselectivity (up to 98.5 1.5)392. 

The iminium salts of 2,3-dihydropyridines are far more stable than the free bases and have been used extensively in the synthesis of alkaloids. N-Benzyl iminium salt 26, formed from the Polonovski-Potier reaction of V-oxide 25, was transformed into enol ether 27, which is a synthon for the unstable AT-benzvl-l, 2-dihvdropyridine 28 (Scheme 5) <2004LOC168>. The same transformation on a similar iminium salt has been used in the formation of macrocyclic marine alkaloids <1995TL2059>. Carbon nucleophiles, such as the silylenol ethers of esters, have been shown to undergo 1,2-addition rather than 1,4-addition to 2,3-dihydropyridinium salts <1999T14995>. 

Reaction of halides with silver nitrate to give nitrate esters has been known for years, but its synthetic application is more recent. Komblum showed that the nitrate esters derived from a-bromo ketones and esters decompose smoothly with catalytic sodium acetate in DMSO to give the a-dicarbonyl compounds in high yield. It was found unnecessary to isolate the nitrate ester after reaction of the halide with silver nitrate the solution was filtered to remove AgBr, concentrated, and added to DMSO containing catalytic sodium acetate. The method complements the others for the synthesis of a-dicarbonyl compounds since it employs nonacidic, nonbasic conditions. Unfortunately, the method gave variable results with benzyl halides. The application of the method to bromo esters other than bromoacetates was not reported. Some related oxidations are shown in equations (41) and (42), and Schemes 9 and 10. The oxidation of an iminium salt is notable. 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

In a similar manner, iminium salts derived from a, -unsaturated aldehydes and ketones are reduced by Hantzsch ester (Scheme 79). The ratio between the 1,4- and 1,2-reduction products depends upon the p/(a of the amine component. a-Keto-P,y-unsaturated esters are reduced by NAD(P)H models in the presence of Mg(Cl04)2- At room temperature 1 equiv. of the reducing agent effects 1,4-reduction of the... 

The action of oxonium salts on vinylogous amides affords iminium salts (71 equation 44), which are useful for synthetic purposes in heterocyclic chemistry. ° " - Alkyldiphenylsulfonium tetrafluoro-borates (72 equation 45) were recommended as reagents which alkylate amides and lactams under smooth conditions.2 2 With the aid of fluorosulfonic acid esters as well as with trifluorometh-anesulfonic acid esters, - - which have alkylation power comparable to oxonium salts, iminium salts, e.g. (73) and (74 Scheme 5), could be synthesized from amides, - vinylogous amides and lactams. Trimethylsilyloxymethyleneiminium salts (75 equation 46) are accessible by reacting tri-methylsilyltrifluoromethanesulfonate with amides. - ... 

Not only the Pinner synthesis provides alkoxymethyleneiminium salts the action of chloroformic acid esters on primary or secondary amides or thioamides ° as well as on lactams is a versatile method to get these salts and from them the imino esters, e.g. (230 equation 125). Primary and secondary amides have been alkylated by several reagents and the iminium salts thus formed were converted to imino esters with the aid of bases. A collection of imino esters prepared by this method can be found in a review the more recent results listed in Table 5 demonstrate the scope of this procedure. 

Reduction of iminium salts. 1,3-Diamines can be elaborated via reduction of the monoiminium species which arise from condensation of enamines with aldiminium salts. The subsequent reduction is carried out with NaBH, in methanol. Oximes of a-aminocycloalkanones undergo fragmentation and reduction, furnishing co-amino nitriles. A route to substituted ureas involves reductive alkylation, condensation with aldehydes in the presence of MejSiCl followed by treatment with NaBH. The borohydride reduction of P-amino-a,P-unsaturated esters in the presence of isobutanoic acid may also proceed via iminium species. 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of y -amino ketones and esters [46]. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have improved the process. Some of these materials are, however, unstable and difficult to isolate, and deaminations of the products that occur under the reaction conditions still remain as problems. The direct synthesis of /5-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view [47, 48]. Our working hypothesis is that aldehydes could react with amines in the hydrophobic micellar system in the presence of a catalytic amount of lanthanide triflate and a surfactant to produce imines, which could react with hydrophobic silyl enolates [49]. 

A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,P-unsaturated esters followed by in situ cyclisation. Other asymmetric syntheses include those of (/ )- and (S)-piper-idin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiazoline. In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used. 

The classical Mannich reaction converts phenols to aminomethylated phenols. The reaction involves the addition of phenols to C=N bonds of imines or iminium salts formed from formaldehyde and primary or secondary amines, respectively . Recent modifications employ the reaction of an aminal in the presence of SO3, which gives a sulfonate ester, followed by o-aminomethylation (equation Sc(OTf)3 catalyzed... 

In 1987, Hill and co-workers (75) reported a clever synthesis of the pentacyclic cephalotaxine analog 246 starting from the nitrostyrene derivative 98 (Scheme 42). The Diels-Alder adduct 244, obtained by the reaction of butadiene sulfone with 98, was treated with methyl acrylate to give a single stereoisomer of the nitro ester, which was reduced with zinc in etha-nolic HCl to yield the lactam 245 and further reduced by Red-AI to the corresponding pyrrolidine. Pictet-Spengler cyclization with formaldehyde gave the pentacyclic amine 246. Alternatively, the reduced pyrrolidine obtained from 245 could be formylated, cyclized to the iminium salt by a Bischler-Napieralski protocol, and finally reduced with sodium borohy-dride to 246. Nearly identical sequences have also been reported by Bryce... 

The first step is probably the Michael addition 115 of the enamine 112 to the unsaturated ester 113. The resulting iminium salt 116 loses a proton to regenerate an enamine. But it does so on the side away from the first reaction to avoid forcing the side chain into the same plane as the pyrrolidine ring. The new enamine is 117. 

Loss of water from 103 gives the iminium salt that undergoes the [3,3]-sigmatropic rearrangement 105 to give 106 with two of the new chiral centres already fixed. An ionic cyclisation 106 fixes the third and the cation 107 picks up water to give 104 or formic acid to give its formate ester. 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

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