Inverse Electron Demand Diels-Alder Cycloaddition Research Articles

Synthesis and Crystal Structure of 2-Amino-4,6,6-trimethyl-cyclohex-2-en-1,1,3,4(S)-tetracarbonitrile

Crystal structure analysis of the novel 2-amino-4,6,6-trimethyl-cyclohex-2-en-1,1,3,4(S)-tetracarbonitrile, obtained in 70% yield, by the Bi(OTf)3 catalyzed reaction of acetone and malononitrile, at room temperature, is described. For the first time Bi(OTf)3–Et3N has been used in this inverse electron demand Diels–Alder cycloaddition reaction involving the participation of carbonitrile π-bond. The structure of the molecule was established by spectral analysis and X-ray diffraction studies. The compound crystallizes in the monoclinic space group P21/n with unit cell parameters: a = 8.0580 (17), b = 13.038 (3), c = 12.641 (3) A, β = 101.883 (4)°, Z = 4. The crystal structure was solved by direct methods and refined to R = 0.0506 for 2,456 observed reflections. The cyclohexene ring of the molecule adopts a distorted sofa conformation. The molecules in the unit cell are arranged in layers. The crystal structure in stabilized by C–H⋯N and N–H⋯N interactions. Crystal structure analysis of the novel 2-amino-4,6,6-trimethyl-cyclohex-2-en-1,1,3,4(S)-tetracarbonitrile.

Investigation of steric and functionality limits in the enzymatic dihydroxylation of benzoate esters. Versatile intermediates for the synthesis of pseudo-sugars, amino cyclitols, and bicyclic ring systems

A series of benzoate esters (methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl) were subjected to enzymatic dihydroxylation by E. coli JM 109(pDTG 601) strain in a whole-cell fermentation. The cis-cyclohexadienediols were obtained in yields of approximately 1g/L except for n-propyl- and i-propyl benzoate which were found to be poor substrates. n-Butyl and t-butyl benzoates were not oxidized at all. The absolute stereochemistry for all metabolites was determined by comparison with a standard prepared from (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol, whose absolute configuration is well established. The free diols were found to be quite stable compared to other cis-dihydrodiols of this type, however, their acetonides underwent a dimerization via a regio- and stereoselective Diels-Alder cycloaddition. The diol derived from ethyl benzoate was subjected to a stereo- and regioselective inverse electron demand Diels-Alder cycloadditions with several dienophiles. The new adducts were completely characterized. The hetero-Diels-Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols. The diol was also converted to carba-alpha-L-galactopyranose to demonstrate its potential utility as a source of pseudo sugars. Experimental and spectral data are provided for all new compounds.

Scandium triflate and secondary amine promoted AA′B 2:1 coupling and formal inverse electron demand Diels–Alder reactions of dienals

Reaction prospecting studies resulted in the discovery of a Sc(OTf) 3 promoted novel AA′B 2:1 coupling of imidazolone or benzofuran substituted enals with morpholine. A related Sc(OTf) 3/morpholine promoted reaction was demonstrated for the coupling of a benzofuran substituted enal with dihydrofuran. The formation of these adducts is consistent with formal inverse electron demand Diels–Alder cycloadditions, most likely in a stepwise manner via a domino Michael–Mannich annulation process, involving iminium ion activation of the diene. A purely amine promoted formal inverse electron demand Diels–Alder cycloaddition approach was also demonstrated in the 2:1 coupling of 2,4-hexadienal with methanol. These reactions demonstrate the concepts of dual metal/amine catalysis and amine promoted formal inverse electron demand Diels–Alder cycloadditions. They differ from known examples of organocatalyzed Diels–Alder reactions, in which iminium ion activation of the dienophiles or enamine activation of the dienes occur.

Silver(i) ions bridged by pyridazine: doubling the ligand functionality for the design of unusual 3D coordination frameworks

Nitrogen donor tetradentate ligands 4,4'-bipyridazine (bpdz) and pyridazino[4,5-d]pyridazine (pp) were prepared by inverse electron demand Diels-Alder cycloaddition reactions of 1,2,4,5-tetrazine. Examination of their behaviour towards silver(I) ions revealed a special potential of the ligands for the design of 3D coordination frameworks involving characteristic polynuclear and polymeric silver(I)-pyridazine motifs and multiple coordination of the ligands. Ag4(pp)5(ClO4)4 and Ag4(pp)5(SiF6)(BF4)(2).4H2O adopt a unique 3D trinodal 4,4,5-connected topology based upon five-fold coordination of the metal ions and tetradentate bridging function of the organic modules. Complexes Ag3(L)3(SO3CF3)3.nH2O and Ag4(L)3(X)4.nH2O (L = bpdz, pp; X = BF4-, 0.5SiF(6)(2-)) illustrate formation of highly-connected frameworks incorporating trinuclear clusters as an origin of the net connectivity. In the carboxylate complexes Ag2(L)(R(F)COO)2 (R(F) = CF3, C2F5, C3F7) the pyridazine and acido ligands act as complementary linkers for generation of 3D frameworks involving helicate motifs. Fused bicyclic pyridazine pp is a unique system combining very efficient sigmaN-donor ability and pronounced pi-acidity. The coordination frameworks commonly exhibit strong anion-pi interactions, including unprecedented examples of double anion-pi,pi binding that occur between pyridazino[4,5-d]pyridazine as a double pi,pi-receptor for geometry complementary SiF(6)(2-) anions.

Metal–organic frameworks exhibiting strong anion–π interactions

Coordination polymers offer a significant potential for applications in adsorption, guest and anion recognition and sensing. Their structure commonly provides binding sites for such specific interactions as pi-pi stacking and XH...pi hydrogen bonding. The latter reflects the ability of the pi-cloud to interact with positively polarized atoms. An electrostatic interaction between anionic species and electron deficient heterocycles, which parallels the above binding scheme, is also possible and very recently the existence of anion-pi interactions was proved in the solid state and in solution. This effect may be significant also for biomolecule/solution interfaces, as it occurs in protein structures. In fact, such interactions could be especially relevant for host-guest chemistry of coordination polymers, particularly for functionalization of hydrophobic crystal cavities and for the design of geometrically rigid anion receptors. However, typical electron deficient heterocycles such as 1,3,5-triazines and 1,2,4,5-tetrazines are very weak donors and they are hardly suitable for bridging metal ions and the generation of coordination frameworks. As a system that combines efficient donor properties towards transition metal ions and a pronounced ability for anion-pi interactions we have developed unsubstituted pyridazino[4,5-d]pyridazine, which was readily accessible by a novel one-pot synthesis involving inverse electron demand Diels-Alder cycloaddition (Scheme 1). Unusual anion binding properties of the ligand may be clearly related to its electron-deficiency (LUMO energy -1.591 vs. -0.288 eV for the parent pyridazine), influenced also by N-coordination to such Lewis acids as metal ions.

A New Cycloaddition Process Involving Nitro Group Participation in Polynitroaromatic Chemistry.

The reaction of ethyl vinyl ether (2 equiv) with 4,6-dinitrobenzofuroxan (DNBF, 1 equiv) in dichloromethane affords a mixture of two diastereomeric dihydrooxazine N-oxide adducts, 5a and 5b, in a 4:1 ratio. Further addition of the enol reagent to this mixture results in a second cycloaddition process with formation of a bis(dihydrooxazine N-oxide) product 6, which can also be obtained directly upon treatment of DNBF with excess ethyl vinyl ether. The observed condensations are accounted for in terms of inverse electron demand Diels-Alder cycloaddition processes between the enol ether dienophile and the heterodienyl moieties of DNBF, constituted first, by the 6-NO(2) group conjugated to the 6,7-double bond and then by the 4-NO(2) group and the 4,5-double bond of the carbocyclic ring. The configurations of the cycloadducts 5a and 5b have been determined on the basis of collected (1)H NMR parameters, as well as NOE experiments. It thus appears that the configuration of the major diastereomer corresponds to the endo product while that of the minor one corresponds to the exo product of the first cycloaddition process. The results obtained emphasize a low aromatic character for the DNBF molecule.

Catalytic, enantioselective, inverse electron-demand Diels-Alder reactions of 2-pyrone derivatives

Abstract

Normal and inverse electron demand Diels–Alder cycloaddition of protonated and methylated carbonyl compounds in the gas phase

AbstractProtonated and methylated quinones, α,β‐unsaturated ketones and aldehydes and saturated ketones all react to form cycloaddition products with butadiene. The reagent ions are generated by chemical ionization (CI) and react at nominally zero kinetic energy with butadiene in an r.f.‐only quadrupole of a pentaquadrupole mass spectrometer. In selected cases, the product ions were characterized by sequential product ion dissociation (triple stage mass spectrometry [MS3]). The activated dicarbonyl ions, such as protonated quinone and protonated 4‐cyclopentene‐1,3‐dione, are more reactive than the protonated α,β‐unsaturated carbonyl compounds and the protonated saturated ketones. The methylated ions are less reactive than their protonated analogs. MS3 spectra of the quinone and α,β‐unsaturated carbonyl adducts and ab initio calculations of product ion stability are interpreted as indicating Diels–Alder cycloaddition at the carbon–carbon double bond. Benzoquinones and the α,β‐unsaturated ketones are also good dienophiles in solution. The differences in reactivity between these two groups of reactant ions, between the protonated and methylated ions and between individual members of each of these groups are ascribed to differences between the HOMO and LUMO orbital energies (ΔE) of the diene and reactant ion, respectively. The correlations observed between the cycloaddition reactivity and the energy gap indicate that normal Diels–Alder reactions occur for the quinones and α,β‐unsaturated ions. Correlations between ion–molecule reactivity and the HOMO–LUMO energy gaps also extend to the protonated saturated ketones, where MS3 studies confirm that cycloaddition occurs at the carbon–oxygen double bond. In all cases, when the proton affinity of the conjugate base of the dienophile is close to that of the diene, proton transfer between the diene and the dienophile becomes a major competitive process; this in turn decreases the cycloaddition yield. Gas‐phase inverse electron demand Diels–Alder reactions are studied using methylated 2‐butenone as diene and several neutral alkenes as dienophile. Higher reactivity is achieved with electron‐donating alkenes as dienophiles, in agreement with observations made in solution chemistry on inverse electron demand Diels–Alder reactions.

Efficient Lanthanide Catalysis in the Diels-Alder Cycloaddition of Electron-Deficient 2-Pyrones

Lanthanide Shift Reagents have been shown to be efficient catalysts for the Inverse Electron Demand Diels-Alder (IEDDA) cycloaddition of 3-Carbomethoxy-2-pyrone (3-CMP) with a range of dienophiles.