Imine additions hetero-Diels-Alder reaction

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Arylimines can be obtained by the addition of N-silylated amides to aryl-lithium compounds (Scheme 200) 44 the imines may be isolated or reduced in situ to amines, or hydrolysed to carbonyl compounds. a-Ketodicarboxylic acid chloride imine chlorides, which readily undergo cyclization to N-heterocycles, have been prepared by -addition of dicarboxylic acid chlorides to isocyanides (Scheme 201).444 Two new formimidoylamino-substituted carbapenems (4) have been prepared by a route involving a hetero Diels-Alder reaction (Scheme 4).14... 

The Zr-BINOL complexes were effectively utilized for asymmetric aza- and hetero Diels-Alder reactions [lb]. The reaction of imine (27) with Danishefsky diene (113) afforded optically active dihydropyridone (114) in high yield (Equation 52) [7, 57]. A similar reaction was also possible for benzaldehyde and diene (115) (Equation 53), [7, 58] and the corresponding dihydropyranone was obtained in excellent yield with excellent enantioselectivity. In addition, the reaction was applied for total synthesis of natural products [58b]. 

In addition to aldehydes, ketones, and imines, a number of additional het-erodienophiles have been utilized in enantioselective copper-catalyzed hetero Diels-Alder reactions (Scheme 17.67). Yamamoto and Yamamoto reported highly... 

In 2009, Feng and coworkers developed new guanidine catalysts with an amino amide skeleton [139]. Among the various catalysts tested, guanidine 49 was found to be the most active for the enantioselective Michael reaction of a (i-ketoester with nitroolefins (Scheme 10.46). The conjugate addition products were obtained in high yields and excellent diastereo- and enantioselectivities. The same researchers used bis-guanidine catalysts for the enantioselective inverse-electron-demand hetero-Diels-Alder reaction of chalcones with azlactones (Scheme 10.47) [140] and enantioselective Mannich-type reaction of a-isothiocyanato imide and sulfonyl imines (Scheme 10.48) [141]. 

The enantioselective hetero-Diels-Alder reaction of siloxydienes, such as Danishefsky s and Brassard s dienes, with imines provides an efficient route for the preparation of functionalized nitrogen-containing heterocycles in optically active forms. Akiyama and coworkers reported the first catalytic enantioselective hetero-Diels-Alder reaction of Danishefsky s diene (21) with aromatic imines 20 using chiral phosphoric acid catalyst la (Scheme 11.7a) [14]. The desired dihydropyridi-nones 22 were obtained in good yields with high enantioselectivities. Notably, the addition of an equimolar amount of acetic acid was effective in improving the enantioselectivity. Akiyama and coworkers also reported an enantioselective... 

Another recent exciting addition to the catalyst armamentarium has resulted from studies of chiral N-heterocyclic carbenes. Bode utilized the steri-cally encumbered N-heterocyclic carbene 270 as a chiral catalyst to effect inverse-electron-demand hetero-Diels-Alder reactions of a,j8-unsaturated imines and unsaturated aldehyde 268 (Equation 28) [136, 137]. The addition of carbene 270 to aldehyde 268 in a 1,2-manner, followed by a critical proton-transfer step, leads to the formation of an enolate. This enolate possesses well differentiated diastereofaces as depicted in the proposed endo transition state assembly 272. A range of unsaturated imines participated in the reaction to give the product dihydropyridinones in excellent optical purity, as exemplified by the formation of 271 in 99% ee and 90% yield [136]. 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

FIGURE 2.32. Representative processes mediated by hydrogen-bond donors nucleophilic additions to (a) carbonyls, (b) imines, (c) epoxide, (d) hetero-Diels-Alder, (e) Claisen rearrangement reactions, and (f) Michael additions. 

Some other highly efficient cycloaddition reactions have been used for polymer end-group modification and polymer-polymer conjugation. These include an additive-free version of the hetero Diels-Alder (HDA) reaction or the nitrile-imine-mediated tetrazole-ene cycloaddition (NITEC), the latter only requiring photoirradiation. Both techniques meet the criteria to be considered bioorthogonal reactions and can be performed under mild reaction conditions. As such, these reactions should also be applicable for the preparation of bioconjugates. 

---