The hetero Diels-Alder reaction is one of the most important methods for the synthesis of heterocycles. In this article an overview is given for the period since 1989 describing the reaction of heterobutadienes such as oxabutadienes, thiabutadienes, azabutadienes, diaazabutadienes, nitroso-alkenes and nitroalkenes as well as of heterodienophiles such as carbonyls, thiocarbonyls, imines, iminium salts, azo- and nitroso compounds. In addition, several other less common hetero Diels-Alder reactions such as cycloadditions of thiaazabutadienes, oxaazabutadienes, dioxabutadienes, dithiabutadienes, oxathiabutadienes, diazaoxabutadienes as well as the use of N-sulfinyl-phosphaalkynes and other dienophiles are mentioned. A main point of discussion is the stereoselectivity of the reactions and the preparation of enantiopure compounds either using dienes and dienophiles carrying a chiral auxiliary or employing chiral Lewis acids. A point stressed is the synthesis of natural products using hetero Diels-Alder reactions leading to carbohydrates, alkaloids, terpenes, antibiotics, mycotoxins, cytochalasans, antitumor agents and several other classes of natural products.

Hetero diels-alder reactions in organic chemistry

C2-symmetric bis(oxazoline)−Cu(II) complexes 1 and 2 catalyze the inverse electron demand hetero Diels−Alder reaction of α,β-unsaturated carbonyl compounds (heterodiene) with electron-rich olefins (heterodienophile) in high diastereo- and enantioselectivity. α,β-Unsaturated acyl phosphonates and β,γ-unsaturated α-keto esters and amides are effective heterodienes, while enol ethers and sulfides function as heterodienophiles. A range of substitution patterns is possible on the heterodiene:  terminal alkyl, aryl, alkoxy, and thioether substituents are all tolerated. The enantioselective synthesis of dihydropyrans by this method has been shown to be straightforward:  cycloadditions may be conducted with as little as 0.2 mol % of the chiral catalyst and are readily run on multigram scale. The reactions exhibit a favorable temperature−enantioselectivity profile, with selectivities exceeding 90% even at room temperature. A simple reaction protocol that employs a solid air-stable catalyst, convenient reaction tem...

Enantioselective Synthesis of Dihydropyrans. Catalysis of Hetero Diels−Alder Reactions by Bis(oxazoline) Copper(II) Complexes

Domino-reactions: The tandem-knoevenagel-hetero-diels-alder reaction and its application in natural product synthesis

In 1894 Knoevenagel published a paper in the journal Chemisehe Berichte on the reaction of formaldehyde and diethyl malonate in the presence of diethylamine as catalyst.1 He obtained the bis adduct (1). Two years later he was able to show that the reaction of benzaldehyde and ethyl acetoacetate in the presence of piperidine gives the bis adduct (2) at room temperature and at 0 °C the benzylidene-1,3-di- carbonyl (3; Scheme 1).2

1.11 – The Knoevenagel Reaction

The synthesis, spectroscopic and structural characterization, linear and nonlinear optical properties, as well as the electrochemical behavior of a series of robust neutral binuclear M[Fc-C(O)CH=C(CH(3))N-X-N=CH-(2-O,5-R-C(6)H(3))] (M = Ni (4), Cu (5), X = o-C(6)H(4), R = H; M = Ni (9), X = CH(2)CH(2), R = OH), and their corresponding ionic trinuclear [M{Fc-C(O)CH=C(CH(3))N-X-N=CH-(eta(6)-2-O,5-R-C(6)H(3))RuCp*}][PF(6)] (6, 7, 10), M[ONNO]-type unsymmetrical Salophen and salen complexes featuring ferrocenyl (Fc) donor and the mixed sandwich acceptor [Cp*Ru(eta(6)- salicylidene)](+) as a push-pull moiety are reported in this paper (Fc = CpFe(eta(5)-C(5)H(4)); Cp = eta(5)-C(5)H(5); Cp* = eta(5)-C(5)Me(5)). The single-crystal X-ray structure of the bimetallic iron-nickel derivative 4 indicates a bowed structure of the unsymmetrical Schiff base skeleton. The Ni(II) ion is tetracoordinated in a square planar environment, with two nitrogen atoms and two oxygen atoms as donors. The new metalloligand [Fc-C(O)CH=C(CH(3))N(H)CH(2)CH(2)N=CH-(2,5-(OH)(2)C(6)H(3))] (8) obtained from the Schiff base condensation of 2,5-dihydroxobenzaldehyde with the half-unit precursor, Fc-C(O)CH=C(CH(3))N(H)CH(2)CH(2)NH(2) (2), is reported with its crystal structure showing partial delocalization of the heteroconjugated [O-C-C-C-N] frameworks with a dihedral angle between the respective planes of 60.76 degrees. Second order nonlinear optical (NLO) measurements were achieved using the Harmonic Light Scattering technique to probe the role of the M[ONNO] chromophores and of the pi-complexation of the salicylidene ring in the nonlinearity. All the complexes exhibit a second-order nonlinear response increasing with the nuclearity, the hyperpolarizability (beta) value of the trinuclear complex 10 being 1.5 time larger than that of the metalloligand 8 (beta = 155 x 10(-30) esu). A rationalization of the structural, electronic, and redox properties of the title compounds is provided, based on a theoretical investigation at the density functional theory (DFT) level. Their UV-visible spectra has been assigned with the help of time-dependent (TD) DFT calculations. They are dominated by LMCT, MLCT, and pi-pi* transitions.

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Synthesis, Spectral, Structural, Second-Order Nonlinear Optical Properties and Theoretical Studies On New Organometallic Donor−Acceptor Substituted Nickel(II) and Copper(II) Unsymmetrical Schiff-Base Complexes

The Hetero Diels-Alder reaction of the enamino ketones 5a–d and ethyl vinyl ether (2) to give the dihydropyrans 6a–d and 7a–d is studied in dichloromethane and in heptane/isodurene under high pressure up to 7 kbar at temperatures between 0.5 and 130°C. The kinetics is measured by on-line FT-IR spectroscopy. The cycloaddition shows a remarkable pressure-dependent increase of diastereoselectivity in favour of the cis adducts 6a–c with the largest effect found for the reaction of 5a and the smallest for 5c. The pressure-averaged overall activation volumes ΔV≠ in dichloromethane are determined to be between –(23.4± 1.0) and –(24.2±1.0) cm3/mol. The ΔΔV≠ values for the cycloaddition of 5a, 5b, and 5c are –(5.9±0.5), –(3.9±0.1), and –(2.4±0.2) cm3/mol, respectively, and the ΔΔH≠ values are –(8.1±1.7), –(8.7±2.7), and –(10.0±0.9 kJ/mol, respectively. Because of the favourable ΔΔV≠ and ΔΔH≠, the selectivity of the reaction of 5a to give 6a/7a can be increased from 1.67: 1.00 at 90°C and 1 bar to 13.6:1.0 at 0.5°C and 6 kbar. This example shows that a significant and synthetic useful increase of diastereoselectivity in chemical reactions is possible by applying high pressure.

Inter- and Intramolecular Hetero Diels-Alder Reactions, Part XXVI. Diastereoselectivity and Kinetics of Intermolecular Hetero Diels-Alder Reactions under High Pressure. A Significant Pressure-Induced Increase in Stereoselectivity

Synthesis of 3-amino sugars of the daunosamine type through hetero-Diels-Alder reaction of enaminones

Synthese des composes du titre par acylation d'enols ethers, par des chlorures d'acides acetique ou oxalique, par condensation de Claisen entre un orthoformiate d'ethyle et des pyruvates, par transacetalisation de diethoxy-3,3 propionate d'ethyle avec le dimethyl-2,2 propanediol-1,3

Highly Efficient Syntheses of Alkyl 3,3-Dialkoxypropanoates, Alkyl 4-Ethoxy-2-oxo-3-butenoates, and Monoprotected Malonaldehydes

The synthesis of enaminecarbaldehydes 1a–s and 17a–c as well as enamino ketones 2a–k, and their N-acyl derivatives 19a–k and 21–t with electron accepting substituents at C-2 and at the CO group, respectively, is described. Condensation of methyl 2-formyl-3-oxopropanoate (13) with ammonia and the amines 14b–s gave the enaminecarbaldehydes 1a and 1b–s, respectively, in 72–93% yield. The enaminecarbaldehydes 17 were obtained by formylation of 15 with acetic formic anhydride. The synthesis of the enamino ketones 2a–k was accomplished in 61–97% yield by reaction of ammonia and amines with the enol ethers 24a–f, which were formed by treatment of reactive acyl chlorides 23 with ethyl vinyl ether. The enaminecarbaldehyde 1a as well as the enamino ketones 2a–k could be acylated to give 19a–k and 2l–t, respectively, which can be used in the hetero Diels-Alder reaction.



Synthese und Struktur von Enaminecarbaldehyden und Enamino Ketonen



Die Synthese der Enamincarbaldehyde 1a–s und 17a–c sowie der Enamino-Ketone 2a–k und deren N-Acyl-Derivate 19a–k und 21–t mit Elektronenacceptor-Substituenten an C-2 bzw an der CO-Gruppe wird beschrieben. Kondensation von 2-Formyl-3-oxopropansaure-methylester (13) mit Ammoniak und den Aminen 14b–s ergab die Enamincarbaldehyde 1a bzw. 1b–s in einer Ausbeute von 72–93%. Die Enamincarbaldehyde 17 konnten durch Formylierung von 15 mit dem gemischten Ameisensaureessigsaureanhydrid erhalten werden. Die Synthese der Enamino-Ketone 2a–k erfolgte mit einer Ausbeute von 61–97% durch Kondensation von Ammoniak und Aminen mit den Enolethern 24a–f, die durch Umsetzung reaktiver Acylchloride 23 mit Ethylvinyl-ether dargestellt wurden. Die fur hetero-Diels-Alder-Reaktionen benotigten N-Acyl-Derivate 19a–k und 21–t wurden durch Acylierung des Enamincarbaldehyds 1a und der Enamino-Ketone 2a–k gebildet.

Synthesis and Structure of Enaminecarbaldehydes and Enamino Ketones

Inter‐ and intramolecular hetero‐Diels‐Alder reactions, 37. Syntheses of the 3‐amino sugar glycosides rac‐4‐deoxydaunosaminide rac‐4‐deoxyristosaminide, and rac‐acosaminide

Edgar Voß

Papers

Inter- and Intramolecular Hetero Diels-Alder Reactions, Part XXVI. Diastereoselectivity and Kinetics of Intermolecular Hetero Diels-Alder Reactions under High Pressure. A Significant Pressure-Induced Increase in Stereoselectivity

Synthesis of 3-amino sugars of the daunosamine type through hetero-Diels-Alder reaction of enaminones

Highly Efficient Syntheses of Alkyl 3,3-Dialkoxypropanoates, Alkyl 4-Ethoxy-2-oxo-3-butenoates, and Monoprotected Malonaldehydes

Synthesis and Structure of Enaminecarbaldehydes and Enamino Ketones

Inter‐ and intramolecular hetero‐Diels‐Alder reactions, 37. Syntheses of the 3‐amino sugar glycosides rac‐4‐deoxydaunosaminide rac‐4‐deoxyristosaminide, and rac‐acosaminide