Aqueous aza-Diels-Alder reaction

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 origin of the acceleration of the aqueous aza-Diels-Alder reaction comes from a large decrease in the Gibbs energy of the activated complex, since cycloreversion smoothly occurs when 2-azanorbornene hydrochlorides are kept in water at room temperature in the presence of N-methylmaleimide as a trapping agent for cyclopentadiene formed in the process (Scheme 11) [67]. 

Aqueous aza Diels-Alder reactions were first described in cycloadditions of imini-um salts and dienes [38], Likewise, iminium salts derived from amino acids react in excellent yields in aqueous medium [39]. Such an aqueous aza Diels-Alder reaction was found to be catalyzed by lanthanide(III) trifluoromethanesulfonates [40]. 

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. 

This seminal work set the stage for further improvements and extensions of the aqueous aza Diels-Alder reaction as well as providing practical methodological alternatives for the synthesis of heterocycles and alkaloids (section 2.3). The following reactions highlight additional straightforward examples of this methodology. 

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] ... 

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] ... 

Synthetic exploitation of the aqueous aza Diels-Alder reaction... 

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... 

Another example of the use of Lewis acids in organic reactions in water is the lan-thanide(III) triflate catalysed aza-Diels-Alder reaction, exemplified in Scheme 14. In this reaction the hetero-dienophile is formed in situ from a primary ammonium hydrochloride and a carbonyl compound followed by the actual Diels-Alder reaction288,289. This type of reaction proceeds readily in aqueous media290-296, and a dramatic increase in the yield upon addition of lanthanide triflates was observed288,289. The exact role of the catalyst, however, is not entirely clear. Although it was suggested that the catalyst binds to the dienophile, other mechanisms, such as simple proton catalysis, are also plausible. Moreover, these reactions are further complicated since they are often heterogeneous. 

Savitha G, Perumal PT (2006) An efficient one-pot synthesis of tetrahydroquinoline derivatives via an aza Diels-Alder reaction mediated by CAN in an aqueous medium and oxidation to heteroaryl quinolines. Tetrahedron Lett 47 3589-3593... 

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]. 

L. Yu, J. Li, J. Ramirez, D. Chen, and P. G. Wang, Synthesis of aza-sugars via lanthanide-promoted aza-Diels-Alder reactions in aqueous solutions, J. Org. Chem., 62 (1997) 903-907. 

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