Aqueous aza Diels-Alder reaction with

Synthetic applications of the asymmetric aqueous aza Diels-Alder reaction with simple protonated iminium ions... 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

As in the case of Diels-Alder reactions, aqueous aza-Diels-Alder reactions are also catalyzed by various Lewis acids such as lanthanide triflates.113 Lanthanide triflate-catalyzed imino Diels-Alder reactions of imines with dienes or alkenes were developed. Three-component aza-Diels-Alder reactions, starting from aldehyde, aniline, and Danishefsky s diene, took place smoothly under the influence of HBL4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields (Eq. 12.46).114... 

Aqueous aza-Diels-Alder reactions of chiral aldehydes, prepared from carbohydrates and with benzylamine hydrochloride and cyclopentadiene, were promoted by lanthanide triflates (Eq. 12.65).137 The nitrogen-containing heterocyclic products were further transformed into aza sugars, which are potential inhibitors against glycoprocessing enzymes. 

The aqueous aza-Diels-Alder reaction of imines has recently been developed. (S)-Phenyleth-ylamine hydrochloride (1) reacts with aqueous formaldehyde (2) and the resulting imine 3 undergoes a [4 + 2] cycloaddition with cyclopentadiene (4) to give adduct 5 with d.r. 70 3067. 

It was demonstrated that fH]-diethoxymethane could be used as a deuteroformaldehyde equivalent with benzylamine hydrochloride and cyclo-hexadiene in the aqueous aza Diels-Alder reaction. The monolabelled 3-fH]-2-benzyl-2-azabicyclo[2.2.2]oct-5-ene is obtained in 32% yield [2] ... 

Asymmetric aza Diels-Alder reactions with simpleprotonated iminium ions in aqueous media... 

Grieco et al. demonstrated the potential for asymmetric induction in the aqueous aza Diels-Alder reaction by treatment of aqueous formaldehyde at 0°C with (-)-a-methylbenzylamine hydrochloride in the presence of cyclopentadiene [1]. After 20 h at 0°C, a 4/1 mixture of diastereomers was obtained in 86% yield. The absolute configurations of the diastereomers were later established to correspond to adducts 14 and 15 [6] ... 

A novel acid-induced rearrangement of 7V-acylated 2-azabicyclo[2.2.1]-hept-5-ene-3-carboxylic acid into the 2-oxabicyclo[3.3.0]oct-7-en-3-one skeleton has been reported by Kobayashi et al [30]. The requisite starting azanorbornene was formed in 84% yield via the aqueous aza Diels-Alder reaction of iminium ion 83, generated from saturated ammonium chloride and ethyl glyoxylate, and cyclopentadiene. Acylation of the nitrogen with benzoyl- or / -nitrobenzoyl chloride followed by alkaline hydrolysis of the... 

Aza-Diels-Alder reactions in aqueous soiutions cycioaddition of dienes with simpie iminium salts generated under Mannich conditions [22]... 

Bronsted acid catalyzed aza-Diels-Alder reaction of Danishefsky s diene with aidimine generated in situ from aldehyde and amine in aqueous media [107]... 

The montmorillonite KlO-catalyzed aza-Diels-Alder reaction of Danishefsky s diene with aldimines, generated in situ from aliphatic aldehydes and p-anisidine, proceeded smoothly in H20 or in aqueous CH3CN to afford 2-substituted 2,3-dihydro-4-pyridones in excellent yields (Eq. 12.47).115 Also, complex [(PPh3)Ag(CBiiH6Br6)] was shown to be an effective and selective catalyst (0.1 mol% loading) for a hetero-Diels-Alder reaction with Danishefsky s diene and the reaction showed a striking dependence on the presence of trace amounts of... 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

A novel Mannich reaction between A -alkoxycarbonylpyrroles 739, formaldehyde, and primary amine hydrochlorides catalyzed by Y(OTf)3 gave a monoaminoalkylation product 741 some times in good yield (14-81%) in aqueous media (Scheme 146) <2001TL461>. When formaldehyde was replaced by acetaldehyde or benzaldehyde, no reaction occurred. There was no formation of the 2,7-diazabicyclo[2.2.1]hept-5-ene 740 (through the aza-Diels-Alder reaction of an N-protected pyrrole with an aldehyde and amine salts by catalysis with triflate). 

The aza-Diels-Alder reaction combines three components (an aldehyde, an amine salt and a diene) to produce heterocyclic products which are useful synthetic intermediates. Grieco first reported that such a reaction could occur in water. Preliminary studies focused on the reaction of dienes with iminium ions generated by an amine hydrochloride and 37% aqueous formaldehyde solution [59]. When dienylamine hydrochlorides are treated with aqueous formaldehyde at 50 °C, bicyclic ring systems are formed (Scheme 9). 

Another intramolecular version of the aza-Diels-Alder reaction was realized with the condensation of a dienyl aldehyde and benzylamine hydrochloride at 70 °C in 50% aqueous ethanol (Scheme 10) [59]. This methodology was used in the synthesis of racemic dihydrocannivonine [60] and substituted octahydro-quinolines related to pumiliotoxin C [61]. 

The aza-Diels-Alder reaction of imines with diene of Danishefsky is an important route to 2,3-dihydro-4-pyridones. A number of Lewis acids have been used to catalyze the reaction in organic solvents. In water the reaction was realized by acid catalysis via iminium salts or by Bronsted acids. The montmorillonite K-10 catalyzed this cycloaddition in water or in aqueous acetonitrile in excellent yield. Recently Kobayashi has performed the reaction in water at room temperature under neutral conditions in two (imine - - diene) or three (aldehyde -b amine -b diene) component versions by using sodium triflate as catalyst. Imine intermediates from the indium-mediated reaction, in aqueous medium at 50° C, between aromatic nitro compounds and 2,3-dihydrofuran undergo aza-Diels-Alder cycloadditions to give tetrahydroquinoline derivatives in good overall yields. ... 

The reaction of amines with aqueous formaldehyde provides iminium salts, which are used in various processes. In the presence of cyclopentadiene, the aza Diels-Alder reaction can take place to yield the azabicycloheptene skeleton (Larsen and Grieco, 1985) ... 

The study of the aza-Diels-Alder reaction in aqueous media has been restricted in the past to the use of water-soluble dienes and iminium salts. AgOTf has been used to catalyze the reaction of Danishefsky s diene, a water-sensitive reagent, with various imines in aqueous media in good 3deld (eq 13). This process has been extended to the use of three-corrqionent systems that generate the imine in situ (eq 14). 

A one-pot, three-component asymmetric aza-Diels-Alder reaction using S-proline as the organocatalyst was developed by Cordova et al. 2-cyclohexene-1-one 313, aqueous formaldehyde 314, and / -anisidine 315 were mixed with catalytic amount of proline to get the aza-Diels-Alder adduct 316 with excellent enantiomeric excess (Scheme 40.68). 

A review of the use of iminium ions as dienophiles in inter- and intra-molecular aza-Diels-Alder reactions in aqueous solutions has been published. A radical-cation-mediated aza-Diels-Alder reaction between 2,3-dihydrofuran and imines yielded hexahydrofuro[3,2-c]quinoline derivatives with high stereoselectivity. " ... 

Costantino et al. [103] reported the direct aza-Diels-Alder reaction between 2-cyclohexen-l-one and benzaldimines in water, catalyzed by layered a-zirconium hydrogen phosphate (a-ZrP) in the presence of sodium dodecyl sulfate (SDS) at 30 ° C (Table 6.2). The yield of the product was good, and the reaction was faster and the exo-diastereoselectivity was higher than when an organic solvent was used. A Cr(III)(salen)Cl catalyst embedded into a self-assembled supramolecular aggregate displays substrate selectivity with an up to 3.5 fold increase in activity in favor of longer over shorter dienophiles in the reaction with cyclopentadiene under aqueous micellar conditions [104]. 

The model reaction to be mediated by hybrid catalysts comprised of 32/serum albumins, was the Diels-Alder reaction of the H O-soluble aza-chalcone 33 with cyclopentadiene 34 with formation of chiral adducts 35. This reaction had been originally devised by Engberts [123, 124], who used Cu -complexes of amino acids in aqueous medium ee up to 74%). Later it was employed by Feringa in the study of Cu -conjugates of DNA as catalysts [125]. 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have also been developed. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, the reaction of benzaldehyde with aniline and Danishefsky s diene produces the tetrahydropyridine derivative in 83% yield, while the reaction with cyclopentadiene instead of Danishefsky s diene produces the tetrahydroquinoline derivative. Various combinations of aldehydes, amines, and alkenes are possible in these reactions to produce diverse tetrahydroquinoline derivatives in high yield. Moreover, the three-component coupling reactions proceed smoothly in aqueous solution, and commercial formaldehyde-water solution can be used directly (eq 19). Sc(OTf)3-catalyzed three-component aza Diels-Alder cycloadditions also proceed smoothly in an ionic liquid. ... 

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