Iminium salt, a,P-Unsaturated

Although the use of cyclic enals improved the overall product distribution by suppressing the 1,4-addition pathway,33 34 a general solution remained elusive. To solve the competing reaction pathway problem or to improve the pathway that would ultimately lead to the 2H-pyran 33 involved extensive experimental modifications. Our solution eventually involved the utilization of preformed a,P-unsaturated iminium salts instead of generating them in situ.35-38... 

The usage of a,P-unsaturated iminium salts clearly represents a general and efficient solution leading to 2//-pyranyl products exclusively via the C-1,2-addition pathway. The reaction of the pyrone 22 led to the pyran product 23 in a much-improved yield relative to Moreno-Manas s study, and also gave previously unknown products 30b and 30c under these reaction conditions [Scheme 5]. The significance of using preformed a,P-unsaturated iminium salts to control regioselectivity of this formal cycloaddition reaction was recently validated in an account reported by Cravotto.39... 

First, sterically congested a,P-unsaturated iminium salts such as 11 [Scheme 2] can impede the formal [3 + 3] cycloaddition.20 Secondly, and more significantly, there had been no successful stereoselective examples36... 

By using pyrone 5757 under the same conditions, pentacycle 58 was obtained in 72% yield with a diastereomeric ratio of 91 9 in favor of the same major isomer. The compound 58 contains the desired E-ring of territrem B [3]. This current formal [3 + 3] cycloaddition approach also proves to be superior to another related variation of this cycloaddition using acid chlorides58 instead of a,P-unsaturated iminium salts. 

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

In the initial report by MacMillan, use of the imidazolidinonium salt 12 HC1 to generate iminium ion intermediates identified a new catalytic strategy for the activation of a,P-unsaturated carbonyl compounds towards cycloaddition [3]. Inherent... 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

This chapter will be divided into sections according to the electrophiles aldehydes and ketones, imines and iminium salts, carboxylic acid derivatives and finally a,P-unsaturated carbonyl compounds, which undergo conjugate additions. Further subdivision will be made according to the nature of the nucleophile, i.e. 0-, N-, S-, P- or C-nucleophiles. Finally, multicomponent heterocyclic syntheses will be mentioned, if they consist at least of one iron-catalyzed addition step to a carbonyl compound. 

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... 

In alkoxymethyleneiminium salts the anions are exchangeable (Cl versus C104" or SbCU etc.). This procedure can be used to purify the iminium compounds for analytical purposes. Tetraphenylborates (105), which are easy to obtain from the iminium salt and sodium tetraphenylborate in d acetonitrile (equation 64), and which crystallize easily, are suitable reagents. The carbon skeleton of a,p-unsaturated alkoxymethyleneiminium compounds can be altered by cycloadditions, e.g. Diels-Alder reactions, to give compounds of type (106 equation 65). - °... 

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). 

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. 

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. 

N-Dimethylamides react with EtOTf to give iminium salts, which can be selectively reduced to aldehydes by Li(s-Bu)3BH in THF at —78°C [TR2]. This method can be applied to a,p-unsaturated amides and is compatible with isolated double bonds, nitriles, and esters. 

Other reactions are possible with iminium salts derived from a,p-unsaturated carbonyl compounds. The Baylis-Hillman reaction (chapter 18) also uses conjugate addition as a first step and we shall deal with that immediately. Much more work has been done on the Diels-Alder reaction that will follow. The Baylis-Hillman reaction between an electrophilic a,p-unsaturatcd carbonyl compound and an... 

A(, -Dimethyl(methylene)iminium salts have been the most widely used class of preformed iminium salts, mainly due to their applications in the synthesis of a,p-unsaturated carbonyl compounds, normally accomplished by subjecting the /V, -dimethyl Mannich base to quatemarization followed by base-induced elimination. Table 3 outlines various counterion forms of /V, -dimethyl(methylene)iminium salts that have been used in Mannich reactions as well as their synthetic precursors. The crystalline iodide (30), known also as Eschenmoser s salt , has seen the most widespread use and is prepared by thermal fragmentation of (iodomethyl)trimethylammonium iodide or, more conveniently, by a variant of the... 

The POClj-mediated reaction of acetamides with DMF followed by treatment with HCIO4 forms the iminium salts 102 (Eq. 37) [68]. The reaction of 102 with sodium selenide gives the p-amino-a,p-unsaturated selenoamides 103 as thermally stable compounds, although the yields of 103 are lower than those of thioamides derived by a similar reaction. 

In Diels-Alder reactions a,P-unsaturated oxazolines react with various dienes (1, 2, 12, 14) stereoselectively via the acyl iminium salts derived by A-acylation with trifluoroacetic anhydride. 

In 2000, MacMillan and his co-workers presented the first enantioselective organocatalytic 1,3-dipolar cycloaddition of nitrones 187 and a,p-unsaturated aldehydes 28 (dipolarphiles) to afford the e do-(45)-isoxazolidine adducts 188, Scheme 3.59 [75]. With the LUMO-lowering activation of a,p-unsaturated aldehydes 28 and enforced formation of (fi)-iminium isomer, the HClO -salt of catalyst 30 effectively promote cycloaddition of the dipolarphile. In addition, e do-cycloaddition effectively alleviated nonbonding interaction between the nitrone phenyl group and the neopentyl methyl substituent on the catalyst framework. Later, in 2002, Karlsson and Hbgberg reported the organocatalytic enantioselective 1,3-dipolar cycloaddition of... 

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