Concerted Diels-Alder Reaction Research Articles

Diastereoselective synthesis and structure-affinity relationships of σ1 receptor ligands with spirocyclic scaffold.

Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different α,β-unsaturated amides 6 and 13-16 with methyl acrylate in the presence of TBDMSOTf. DFT calculations explain the mechanism of this transformation as concerted Diels-Alder reaction (functionals B3LYP and TPSS) or double (aza)-Michael addition (functionals PBE and wB97X-D). After separation of the diastereomeric spirocyclic products 8 and 17-20, LiAlH4 reduction provided the spirocyclic hydroxymethyl piperidines 21a,b-25a,b showing low nanomolar σ1 affinity (Ki < 100 nM). trans-Configured ligands (a-series) showed higher or equal σ1 affinity and higher selectivity over σ2 receptors and GluN2B-NMDA receptors than their cis-configured analogs (b-series). The additional hydroxymethyl moiety brings the log D7.4 value in a promising range. The high σ1 affinity (Ki = 3.6 nM) and the low lipophilicity result in the highest lipophilic ligand efficiency for the dispiro compound 23a (LLE = 6.0). The spirocyclic compounds reported herein and in particular the dispiro compound 23a demonstrate that ligands containing a large number of sp3 C-atoms possess favorable pharmacological (σ1 receptor affinity, receptor selectivity) and physicochemical properties (log D7.4 value) resulting in promising LLE.

Polycyclic Aromatic Hydrocarbon Growth by Diradical Cycloaddition/Fragmentation.

The recent theoretical and experimental investigations on the growth of polycyclic aromatic hydrocarbons in pyrolytic environments highlight the possible role of the 1,4-cycloaddition/fragmentation (1,4-CAF) steps in the formation of PAH intermediates and consequently soot. The present theoretical study explores the possibility to generalize such mechanism to reactions involving various diradical compounds and stable multiring structures. The calculations were performed using the uB3LYP/6-311G(d,p) method and different composite methods, when possible, for more accurate energy estimates. First, the complex potential energy surface for the reactions between o-benzyne and naphthalene was investigated, including the 1,4-CAF mechanism to form anthracene and acetylene through the dibenzobicyclo[2.2.2]octatriene intermediate. Moreover, the products of the addition reactions to the α- and β-carbons and to the ring-junction atoms were determined. The energies for the optimized CAF structures, which constitute the most-favorable pathway from an energetic point of view, were calculated using CBS-QB3, G3(MP2)B3, and G3B3 methods and compared to the corresponding values for the o-benzyne + benzene reactions. Additional calculations were focused on the possible CAF reactions between o-benzyne and larger multiring structures, such as anthracene, phenanthrene, pyrene, and the four-ring PAHs. The results indicate how the energetics of such reactions is influenced by both the size of the PAH compound and the position of the carbon atoms involved. In the second part of the study, the energy barriers necessary to form multiring diradicals from the corresponding radical molecules were analyzed at a G3(MP2)B3 level of theory. Such calculations are preliminary for the subsequent study on the CAF reactions between the different diradical intermediates and benzene. While the size of the diradical does not affect significantly the energy barriers, the position of the diradical site is critical. The concerted Diels-Alder reactions between the naphthynes and naphthalene were also studied in order to further clarify the analogies between the reactions involving different diradicals. Based on these results, kinetic considerations were provided based on the comparison with the simpler o-benzyne + benzene system, although further higher-level calculations and master equation kinetic analyses will be required to derive the general kinetic rules.

ChemInform Abstract: Expanding the Scope of Primary Amine Catalysis: Stereoselective Synthesis of Indanedione‐Fused 2,6‐Disubstituted trans‐Spirocyclohexanones.

AbstractMechanistic investigation of these organo‐catalytic spirocyclizations reveals two competing pathways: a concerted Diels—Alder reaction and a stepwise Michael addition.

Expanding the Scope of Primary Amine Catalysis: Stereoselective Synthesis of Indanedione-Fused 2,6-Disubstituted trans-Spirocyclohexanones.

A cinchona-alkaloid-derived chiral primary-amine-catalyzed enantioselective method for the synthesis of the thermodynamically less stable indanedione-fused 2,6-trans-disubstituted spirocyclohexanones is demonstrated. Both the enantiomeric forms of the trans isomer are obtained in excellent yields and enantioselectivities. Furthermore, one of the enantiopure trans-spiranes bearing an additional α-substitution on the cyclohexanone ring was then epimerized into its thermodynamically stable cis counterpart, with little loss of enantioselectivity to demonstrate the feasibility of such a transformation. Mechanistic investigations revealed two competing pathways, a concerted Diels-Alder reaction and a stepwise Michael addition, for the formation of corresponding products.

Computational Investigation of the Competition between the Concerted Diels–Alder Reaction and Formation of Diradicals in Reactions of Acrylonitrile with Nonpolar Dienes

The energetics of the Diels-Alder cycloaddition reactions of several 1,3-dienes with acrylonitrile, and the energetics of formation of diradicals, were investigated with density functional theory (B3LYP and M06-2X) and compared to experimental data (Hall et al., J. Org. Chem.1993, 58, 7049-7058). For the reaction of 2,3-dimethyl-1,3-butadiene with acrylonitrile, the concerted reaction is favored over the diradical pathway by 2.5 kcal/mol using B3LYP/6-31G(d); experimentally, this reaction gives both cycloadduct and copolymer. The concerted cycloaddition of cyclopentadiene with acrylonitrile is preferred computationally over the stepwise pathway by 5.9 kcal/mol; experimentally, only the Diels-Alder adduct is formed. For the reactions of (E)-1,3-pentadiene and acrylonitrile, both cycloaddition and copolymerization were observed experimentally; these trends were mimicked by the computational results, which showed only a 1.2 kcal/mol preference for the concerted pathway. For the reactions of (Z)-1,3-pentadiene and acrylonitrile, the stepwise pathway is preferred by 3.9 kcal/mol, in agreement with previous experimental findings that only polymerization occurs. M06-2X is known to give more accurate activation and reaction energetics (Pieniazek, et al., Angew. Chem. Int.2008, 47, 7746-7749), but the energies of diradicals are too high.

Chemistry at the Dirac Point: Diels–Alder Reactivity of Graphene

Most of the interesting physics of graphene results from the singular electronic band structure at the so-called Dirac point, where the conduction and valence bands cross in momentum space. Although graphene is very stable thermodynamically, the electronic structure at the Dirac point facilitates basal plane chemistry including pericyclic reactions such as the Diels-Alder reaction. We have discovered a series of facile Diels-Alder reactions in which graphene can function either as a diene when paired with tetracyanoethylene and maleic anhydride or as a dienophile when paired with 2,3-dimethoxybutadiene and 9-methylanthracene. In this Account, we seek to rationalize these findings using simple arguments based on considerations of orbital symmetry and the frontier molecular orbital theory. The graphene conduction and valence bands (HOMO and LUMO) cross at the Dirac point, which defines the work function (W = 4.6 eV). Thus, the HOMO and LUMO form a degenerate pair of orbitals at this point in momentum space with the same ionization potential (IP) and electron affinity (EA). Based on the importance of the energies of the HOMO (-IP) and LUMO (-EA) in frontier molecular orbital (FMO) theory, graphene should be a reactive partner in Diels-Alder reactions due to the very high-lying HOMO and low-lying LUMO (energies of -4.6 eV). Inspection of the orbital symmetries of the degenerate pair of half-occupied band orbitals at the Dirac point confirms that with the appropriate orbital occupancies, both diene and dienophile reaction partners should undergo concerted Diels-Alder reactions with graphene that are allowed based on the Woodward-Hoffmann principles of orbital symmetry.

THEORETICAL STUDY OF CONCERTED DIELS-ALDER REACTIONS BETWEEN DIMETHYL 1,2,4,5-TETRAZINE-3,6-DICARBOXYLATE AND DIENOPHILES

Computational study at different levels of quantum calculations (AM1, PM3 and ab initio (HF/3-21G)) where preformed on the inverse-demand synchronous concerted Diels-Alder reactions between dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate as a diene and a variety of dienophiles (ethylene, cyclopentadiene, 1 -hexene, cyclohexene). All the molecular structures (reactants, transition states, intermediates and adducts) were optimized by AM1 method. The calculated energies and volumes showed that the cycloaddition systems followed a mechanism by formation an intermediate and proceed to eject N 2 molecule and ended by 1,2 -hydrogen shift adduct. The prediction of the reaction energies of modeling of the cycloaddition reactions under-study by semiempirical AM1 method showed a good agreement with the experimental data comparing with PM3 and HF/3-21G. whereas, the prediction of activation energies by (AM1, PM3 and ab initio (HF/3-21G)) showed overestimated values comparing with experimental data.

Study of Solvent Effects in Diels-Alder Reaction through Charge Transfer Formation by Using Semi-empirical Calculations

Study of computational model of the concerted Diels-Alder reaction between 9,10-dimethyl anthracene (as donor) and tetracyanoethylene (as acceptor) in absence and in presence of aromatic solvents (benzene, mesitylene and hexamethylbenzene, as donors) using an AM1 semi-empirical method. AM1 method used to study the neutral charge transfer complex models that could be expected between donor and acceptor during the course of the concerted Diels-Alder reaction. Calculated enthalpies of reaction of the charge transfer complexes models showed physical and chemical meaning for explain the effect of aromatic solvents on the kinetic process of concerted Diels-Alder reaction that contains tetracyanoethylene.

Synthesis of Indeno‐Fused Derivatives of Quinolizinium Salts, Imidazo[1,2‐a]pyridine, Pyrido[1,2‐a]indole, and 4H‐Quinolizin‐4‐one via Benzannulated Enyne—Allenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Concerted Diels–Alder reaction between anthracene and C60

The Diels–Alder reaction of anthracene with C60 has been investigated experimentally by using secondary isotope effects. The inverse α-secondary isotope effect in conjunction with the unity value of the β-secondary isotope effect indicates a concerted mechanism for the title reaction.

Quest For Natural Diels-Alderases Yields Two Likely Candidates

To create carbon-carbon bonds, synthetic chemists often turn to the Diels-Alder reaction, in which a double bond adds to a conjugated diene to form a six-membered ring. That nature also makes use of this reaction has been proposed on the basis of the structures of many secondary metabolites. The isolation of precyclization substrates from organisms has bolstered this proposal, as has the conversion to the Diels-Alder product of precyclization substrates that have been fed to organisms. Two groups now have independently purified naturally occurring proteins that appear to catalyze Diels-Alder reactions in the biosynthesis of natural products. But more experiments are necessary to prove that these proteins are truly Diels-Alderases—that is, the reactions they catalyze are concerted Diels-Alder reactions and not some other reactions that lead to Diels-Alder-type products. John C. Vederas, a chemistry professor at the University of Alberta, Edmonton; C. Richard Hutchinson, an emeritus medicinal chemistry prof...

Are Charge‐Transfer Complexes Intermediates in Diels‐Alder Reactions? A Case Study of the Reaction of 1,2‐Dimethylenecyclopentane with Tetracyanoethylene

The Diels‐Alder reaction of 1,2‐dimethylenecyclopentane (1) and tetracyanoethylene (TCNE) is kinetically studied by conventional and stopped‐flow UV/Vis absorption‐spectroscopic techniques. A transient charge‐transfer (CT) absorption band with λmmax=490 nm (half‐life at 20°C ca. 3.4 × 10‐2 s) is detected in dichloromethane solution. For the molar extinction coefficient a value of e490=310 M‐1 cm‐1 has been determined from measurements of the optical densitity at zero time as a function of excess diene concentration. With the aid of computer simulation the combined kinetic analysis of the disappearance of reactants and CT complex reveals that the data obtained from experiments at equimolar concentration and at a single temperature (20°C) can be interpreted equally well by both the model where the CT complex is an intermediate on the reaction path and where it is in a nonreactive side equilibrium with the reactants. Activation parameters have been determined for the disappearance of the starting compounds and of the CT complex. Contrary to what is expected for a CT complex being an intermediate in a concerted Diels‐Alder reaction a more negative activation entropy for the decay of the CT complex than for the disappearance of the reactants is found. This suggests that the CT complex is unlikely to exhibit a transition‐state‐like structure as is required for a concerted cycloaddition. Experiments under pseudo‐first‐order conditions have led to an extension of the reaction scheme by a second‐order reaction of the CT complex with the excess diene, the rate constant of which is virtually identical to that for the direct bimolecular cycloaddition. The conclusion is drawn for our case that there are more arguments against than arguments for the CT complex being a preorientation complex in the [4 + 2] cycloaddition.

Nevv Reactions of Vinylindoles as Heterocyclic Dienes with 4-Phenyl-1,2,4-triazoline-3,5-dione: Non-Concerted versus Concerted Processes

The reactions of some 3-vinylindoles and one 2-vinylindole with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) were investigated. In dependence on the structure of the vinylindole, the experimental results revealed the occurrence in some cases of a non-concerted step to furnish Michael-type adducts and in other cases of a probably concerted Diels-Alder reaction to furnish novel pyridazino[b]indoles, respectively. In one particular case, PTAD-catalysed dimerisation of the 3-vinylindole took place.

ChemInform Abstract: Base‐Catalyzed Reactions of Anthrones with Dienophiles.

AbstractDiels‐Alder reaction of the anthrone (I) with the dienophiles (II) in the presence of triethylamine produces the cycloadducts (III).

Base-catalyzed reactions of anthrones with dienophiles

Anthrone in the presence of an amine functions as a reactive diene in [4+2] cycloadditions. Dienophiles which differ in reactivity over a range of ca. 10 5 give products at 25°C. Thus N-methylmaleimide (NMM) gives cycloadduct within minutes in various solvents containing catalytic triethylamine. The product with NMM is deuterated stereoselectively trans to the anthracenyl ring, implying sterically controlled intermolecular reaction. Similar stereoselectivity was observed for the conversion of anthrone-NMM cycloadduct to Michael adduct in MeOD cosolvent. Cycloadducts may be formed either by stepwise (Michael+aldol) reactions, or by oxyanion accelerated concerted Diels-Alder reactions. Arguments favoring the latter mechanism are presented. The reaction is discussed in the context of other base-induced and base-catalyzed cycloadditions of 1-oxido and 2-oxido 1,3-dienes