1 REACTIVITY , STEREO-AND REGIOSELECTIVITY OF DIELS-ALDER REACTIONS BETWEEN FIVE-MEMBERED HETEROCYCLES AND DANISHEFSKY ’ S DIENE

Conceptual density functional theory (chemical hard ness η, electronic chemical potential μ, global and local electrophilicity index ω and ωk, Fukui function fk) is used to predict reactivity, stereoand regioselectivity of the Diels-Alder (DA ) reaction between 2-nitropyrrole and its 1tosylated derivative with Danishefsky’s diene to yi eld 5-hydroxyindoles. A detailed mechanistic study of various possible reaction channels is done by DFT [B3LYP/6-31G(d)] calculations. Solvent effects (benzene) are taken into account by the CPCM bulk solvation model. In principle, the nitropyrrole can either act as diene involving the nitro group (hetero Diels-Alder reaction, HAD) or alternatively as alkene in a “normal” Diels -Alder reaction. The experimentally observed product 5-hydroxy-1-tosylindole can be formed eithe r directly by Diels-Alder reaction of the nitropyrrole acting as alkene or by rearrangement o f the dihydrooxazine N-oxides. The primary cycloadduct with the nitropyrrole acting as alkene is found to be unstable reacting further by extrusion of nitrous acid to 5-hydroxyindole. Final ly, the results are compared with those obtained for the analogous furans, thiophenes, and selenophenes.


Introduction
Due to their electron-rich character five-membered heterocycles like furans or pyrroles usually take part in Diels-Alder type reactions as dienes.Substitution by electron-withdrawing groups sufficiently increases the electrophilic character to make possible their reaction as dienophiles with electron-rich dienes, e.g.Danishefsky's diene. 1 For instance, 3-acylfurans and 1-tosylated 3acylpyrroles have been shown to undergo cycloaddition reactions even with isoprene in high yields. 2In continuation of our previous computational studies concerning Diels-Alder reactions of nitro-substituted furans and thiophenes here we want to present the results of the analogous reaction of 2-nitro-1-tosylpyrrole 2c with Danischefsky's diene 5. [3][4][5] Experimentally, the sole product found in this reaction is 5-hydroxy-1-tosylindole (Scheme 1).

Scheme 1
First, we will present DFT based reactivity indices to obtain information about the most likely site of attack by the diene.This will be used as a guideline for more detailed mechanistic investigations by quantum chemical calculations.In addition, comparison of these reactivity indices, especially the global electrophilicity ω as a indicator of the overall reactivity of the molecule under consideration, with related five-membered heterocycles (Scheme 2) will be made to put the results into scale.

Computational procedures
Geometries of all stationary states (reactants, transition structures, intermediates, products) were completely optimized using the B3LYP hybrid density functional 6,7 with the 6-31G(d) basis set (for selenium the Binning-Curtiss VTZP 8 basis set was used) and verified as true minima or transition structures by frequency calculations.Transition structures were further characterized by intrinsic reaction coordinate calculations along both modes corresponding to the imaginary frequency.Thermal corrections to Gibbs free energies were computed by the standard rigid-rotor harmonic oscillator approximation at T = 298, 393, and 438 K. To all structures the geometrical counterpoise and dispersion corrections (gCP-D3) of Grimme et al. [9][10][11][12] were added.Solvent effects (benzene) were treated by the CPCM solvation model 13 using the 6-31G(d,p) basis set.

Results and Discussion
DFT based reactivity indices.The global electrophilicity ω, defined as where the chemical hardness η and the electronic chemical potential µ are evaluated from the frontier orbital energies (ε HOMO and ε LUMO) as is a useful descriptor of the reactivity of a dienophile towards electron-rich dienes (e.g. Danishefsky's diene 5, Scheme 1).Local electrophilicities ω k , derived from the global electrophilicity and the respective condensed Fukui function indicate the preferred site of attack of the dienophile by the most nucleophilic atom of the diene (C4 of Danishefsky's diene).

Gas phase
Benzene  According to the local electrophilicity ω k the preferred site of attack by electron-rich dienes in polar Diels-Alder reactions is C3 of 2-nitro-substituted five-membered heterocycles.Detailed calculations for all possible cycloaddition modes (site-and regioisomers) are completely in line with this prediction. 5Therefore, in the reaction of 2-nitro-1-tosyl-pyrrole with Danishefsky's diene we will concentrate on the following four channels (Scheme 3).
Mechanistic details of the Cycloaddition Reaction.The individual reactions considered here are depicted in Scheme 3. Calculated relative Gibbs free energies with respect to the separated reactants, 2-nitro-1-tosylpyrrole 2c and Danischefsky's diene 5 are collected in Table 3.While in our previous studies on the reactions of nitro-substituted furans and thiophenes with a variety of dienes, [3][4][5] only concerted albeit quite asynchronous reaction mechanisms (aka twostage one-step mechanisms 24 ) could be found, in the present case of the reaction between 2-nitro-1-tosylpyrrole 2c with Danishefsky's diene 5 both one-step (channels 2 and 4, Scheme 3) as well as two-step processes (channels 1 and 3, Scheme 3) could be found.The latter ones correspond to a hetero Diels-Alder reaction involving the endocyclic double and one N=O bond of the nitro group of 2c as diene and the C3=C4 double bond of 5 as dienophile, followed by a [3,3]   sigmatropic rearrangement to the "normal" Diels-Alder cycloadduct (Scheme 4).Such participation of the nitro group in hetero Diels-Alder reactions leading to nitronates has been observed experimentally in reactions of nitroalkenes or 4,6-dinitrobenzofuroxanes. 25,26 Moreover, the tandem hetero Diels-Alder/ [3,3] sigmatropic shift mechanism has also been considered in calculations on the reaction of 3-nitro-1-tosylpyrrole with various dienes. 27 Scheme 4 Reaction of 2c with 5 to the hetero Diels-Alder cycloadduct Int1 and rearrangement to the "normal" Diels-Alder cycloadduct P1.
Formation of the hetero Diels-Alder cycloadduct Int3 involves a significantly higher barrier (~ 6 kcal mol -1 ) than formation of Int1.Therefore, this reaction path will not be considered in more detail.Both barriers for formation as well as rearrangement of Int1 are nearly equal and, hence, the [3,3] sigmatropic shift to P1 easily should occur.The barrier for the one-step process according to channel 2 is essentially equal to both barriers of the two-step endo/syn mechanism (channel 1).However, irrespective of the mechanism (concerted or two-step) formation of the Diels-Alder adducts is endergonic.The driving force for the reaction is the strongly exothermic elimination of nitrous acid to yield intermediate P5 (Scheme 5).
The barrier for elimination is significantly lower (~10 kcal mol -1 ) than the barrier for formation of the Diels-Alder cycloadducts and hence formation of P5 should occur easily.Similarly, the irreversible extrusion of nitrous acid has been found to be responsible for the feasibility of the reaction of 1-nitronaphthalene with 5. 28 Ultimately, according to the experimental findings P5 reacts in analogy to nitrofurans and -thiophenes via extrusion of the trimethylsilyl group and methanol to yield the final product 5-hydroxy-1-tosylindole Pf. 1

Figure 1
Figure 1 Calculated [B3LYP/6-31G(d)] structures of transition states (TS1A, TS1B), Density functional calculations [B3LYP/6-31G(d)] with inclusion of solvent effects (benzene, CPCM model), dispersion and basis set superposition error corrections (gCP-D3) have been used to address the feasibility and mechanistic details of the Diels-Alder reaction between 2-nitro-1tosylpyrrole 2c and Danischefsky's diene 5.Both asynchronous concerted, i.e. two-stage one-step as well as stepwise mechanisms have been found.The stepwise mechanism consists in an initial hetero Diels-Alder reaction with the endocyclic double bond and one of the N=O bonds acting as heterodiene and the C3=C4 bond of 5 as dienophile.This primary hetero Diels-Alder adduct easily undergoes a[3,3] sigmatropic rearrangement to the "normal" Diels-Alder adduct.Like in the analogous reaction of nitronaphthalenes, -furans, and -thiophenes, the large electrophilic character of 2c as indicated by DFT based reactivity indices, is responsible for the participation of 2c in Diels-Alder reactions with electron-rich dienes.However, further transformations of the initial Diels-Alder adduct, namely extrusion of nitrous acid followed by elimination of methanol and the trimethylsilyl group, are the driving forces for this reaction to occur.References(1) Della Rosa, C.; Kneeteman, M.; Mancini, P. TetrahedronLett.2007, 48, 1435-1438.
23ectrophilic; introduction of a nitro substituent, especially at position 2, substantially increases the global electrophilicity and, hence, reactivity towards electron-rich dienes.According to the classification scheme of Domingo et al.,23the nitro-substituted derivatives 1b -4b and 2c can be considered as strong electrophiles.Concerning the effect of the heteroatom, the reactivity increases in the series O < S < Se; pyrrole derivatives are less reactive than furans.1-Tosylation slightly increases the electrophilicity.The effect of taking into account solvation by a bulk solvent model (CPCM) has only little effect on ω.

Table 3
Relative Gibbs free energies a ∆G T for transition structures, intermediates and products of the four reaction channels depicted in Scheme 3 in gas phase and benzene solution at T = 298,