A computational mechanistic study on the chemo-, regio- and stereoselectivity of cycloaddition reactions leading to γ-dihydropyran and tetrahydrocarbazol compounds

Accepted Manuscript A computational mechanistic study on the chemo-, regio- and stereoselectivity of cycloaddition reactions leading to ɤ-dihydropyran and tetrahydrocarbazol compounds Mina. Haghdadi, Fatime. Nikjoo PII: DOI: Reference:

S2210-271X(17)30408-5 http://dx.doi.org/10.1016/j.comptc.2017.09.010 COMPTC 2625

To appear in:

Computational & Theoretical Chemistry

Received Date: Revised Date: Accepted Date:

14 May 2017 10 September 2017 10 September 2017

Please cite this article as: Mina. Haghdadi, Fatime. Nikjoo, A computational mechanistic study on the chemo-, regioand stereoselectivity of cycloaddition reactions leading to ɤ-dihydropyran and tetrahydrocarbazol compounds, Computational & Theoretical Chemistry (2017), doi: http://dx.doi.org/10.1016/j.comptc.2017.09.010

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A

computational

mechanistic

study

on

the

chemo-,

regio-

and

stereoselectivity of cycloaddition reactions leading to ɤ-dihydropyran and tetrahydrocarbazol compounds Mina. Haghdadi*and Fatime. Nikjoo Department of Chemistry, Islamic Azad University, P.O. box 755, Babol branch, Babol, Iran *[email protected] Abstract The reaction mechanisms of Danishefsky’s diene (1) with 3- and 2-substituted indoles (2 and 3) were investigated using the DFT method. Two possible approaches of the carbonyl and carbon-carbon double bond of the dienophile to Danishefsky’s diene (1) yield two types of compound, arising from the sequential [4+2] cycloaddition reaction. and hydrolysis of the silyl enol ether. Also, an acyclic hydroxyl product indicates that a stepwise mechanism of the Mukaiyama-type may be involved, when the reaction takes place in the presence of zinc chloride catalyst. In the cycloaddition reactions, while 3-substituted indole (2) tended to participate as the dienophile, 2-substituted indole (3) can react through a hetero Diels-Alder reaction. Then the chemoselectivity completely reverse in 2- and 3- substituted indoles, which energetical aspects and analysis of the Parr functions explained the chemoselectivity experimentally observed. The reactions were completely ortho regioselective with endo stereoselectivity in the zinc chloride catalyzed process. The Mukaiyama aldol reaction, as a stepwise mechanism, had a low activation energy relative to the concerted cycloaddition reactions. Moreover, analysis of the conceptual DFT reactivity indices allows the explanation of the reactivity, and the chemo- and regioselectivity.

Keywords: Mukaiyama aldol reaction, indole, chemoselectivity, regioselectivity, Diels-Alder, Danishefsky’s diene.

1. Introduction One of the most useful organic reactions is the Diels-Alder (DA) reaction [1] which produces a six-membered ring [2] in at least one step. The use of five-membered aromatic heterocyclic compounds in the DA reactions is well established, and different possibilities have been described depending on the substrate [3]. Heterocyclic aromatic compounds with electron-withdrawing groups (EWG) can participate as active dienophile components in these cycloaddition reactions. They have been widely studied using theoretical methods [4]. DA reactions [5] involving electrophilic aromatic heterocyclic compounds and nucleophilic dienes usually take place through a one-step mechanism [6], with highly asynchronous TSs and of high polar character [7]. In regard to this, Wenkert et al. indicated that β-substituted five-membered aromatic heterocycles acting as dienophiles [8] were more reactive than α-substituted ones [9]. They investigated cycloaddition reactions of some compounds such as benzene sulfonyl pyrroles, furans and N-benzenesulfonyl indoles with some dienes, leading to mixtures of regioisomers in moderate to high yields. Their observations indicated that these reactions usually require the presence of two EWG on the fivemembered aromatic heterocycle [10]. They have shown that the presence of a sulfonyl group on the nitrogen and a carboxaldehyde functional group in position 3 of the indole nuclei accelerates the dienophilic behavior of indole compounds toward electron-rich dienes. Two reactive sites, namely the C=C double bond and C=O carbonyl group on indole, can make indole effective in the role of heterodienophile or dienophile in

cycloaddition

reactions.

The

heterocyclic

fragments

with

dihydropyran

or

tetrahydrocarbazol cores can be formed through indole acting as a heterodienophile or dienophile, respectively [11]. These compounds can act as heterocyclic segments of various biologically relevant molecules [11,12]. There are some reports of heterodienophiles competing with all-carbon dienophiles in [4+2] processes [12,13], where the all carbon dienophilic compounds were found to be deactivated. In the course of studies on the dienophilicity of five-membered aromatic heterocycles, complete and sometimes unexpected inversion of the chemoselectivity in reactions of indoles with electron-rich dienes was observed [14]. Furthermore, there is a competition between HDA and DA reactions of indole components. In 2001, Chataigner et al. experimentally reported results regarding the chemoselectivity and show the extent to which the reactivity of the aromatic dienophile can be modulated to favor either the classical process or the HDA reaction [14]. They studied the cycloaddition

reaction

of

1-methoxy-3-trimethyl

silyloxy-1,3-butadiene

(Danishefsky’s diene) (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde (2) demonstrating efficient formation of the desired DA cycloadduct 5 in a 75:25 ratio of endo/exo and an overall 57% yield (Scheme 1) [14]. New data was gathered in 2003, which revised the structure of the products [13]. They isolated cycloadducts 4, 6 and 7 through a hetero-DA (HDA) reaction. Their observations indicated that the presence of a zinc-based Lewis-acid (LA) caused the heterocycloaddition to go through a stepwise mechanism, via a Mukaiyama aldol reaction pathway. The experimental results revealed that in the presence of zinc-chloride catalyst the acyclic intermediate 7 and product 4 were observed in 36:64 ratio. The addition of silyl enol ether to the carbonyl group - the Mukaiyama aldol reaction - has been the subject of extensive investigation [15,16], due to the products containing one new C-C bond and up to two new

stereogenic centers. Moreover, 3-substituted indoles are known to be more reactive toward electron rich dienes in classical DA cycloaddition reactions than their 2substituted counterparts [9]. When Danishefsky’s diene (1) reacts with 1-ptoluenesulfonylindole-2-carboxaldehyde (3), it does so as a heterodienophile rather than an all-carbon dienophile [13,17]. The faster zinc-chloride catalyzed reaction leads to the sole HDA adduct 8 with 84% yield [13]. Hence, their studies on the dienophilicity of indoles indicated a complete unexpected inversion of the chemoselectivity in the reactions of 3-substituted and 2-substituted indoles with Danishefsky’s diene. So it would be interesting to investigate inversion of the chemoselecttivity of these reactions mechanistically. Insert Scheme 1 The regio-and stereoselectivity of five membered aromatic heterocyclic compounds in DA reactions has been widely studied using theoretical methods [18-21] but there hasn’t been a theoretical study on the chemoselectivity of these reactions. In the course of our studies on the mechanism of HDA and DA reactions [22-24], we report herein a DFT study on the chemo-, regio- and stereoselectivity of the cycloaddition reactions of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde (2) and 1-ptoluenesulfonylindole-2-carboxaldehyde (3), at the B3LYP and MPWB1K levels of theory. The experimental reports [13-14] indicate that the reactions of Danishefsky’s diene (1) with 2 and 3 yield 2-methoxy-6-[1-(toluene-4-sulfonyl)-1H-indol-3yl]tetrahydropyran-4-one

(4),

1-methoxy-9-tosyl-3-((trimethylsilyl)oxy)-4,4a,9,9a-

tetrahydro-1H-carbazole-9a-carbaldehyde (5), 5-Hydroxy-1-methoxy-5-[1-(toluene-4sulfonyl)-1H-indol-3-yl]pent-1-en-3-one, (6), 2-[1-(toluene-4-sulfonyl)-1H-indol-3yl]-2,3-dihydropyran-4-one (7), 2-methoxy-6-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]2,3-dihydropyran-4-one (8) and 4-methoxy-9-tosyl-2-((trimethylsilyl)oxy)-4,4a,9,9a-

tetrahydro-1H-carbazole-4a-carbaldehyde (9) through HDA, DA and Mukaiyama aldol reactions (Scheme 1). These are domino processes and comprise several consecutive steps. A possible explanation for these results may be related to energy barriers. Therefore to characterize the reaction mechanism of these processes, the potential energy surfaces corresponding to all possible chemo-, regio- and stereoselective pathways were investigated. Then, the global indices were defined within the conceptual DFT, and these were used to find the reactivity of electron-rich dienes toward indole derivatives via HDA and DA cycloaddition reactions. Finally, analysis of the Parr functions was studied to explain the chemoselectivity of these processes.

2. Computational methods The ubiquitous B3LYP [25] hybrid functional has been the workhorse of quantum chemical studies on organic molecules for years [26]. It is well known that B3LYP can be used to successfully describe interactions in the Diels-Alder reactions. Recently, some functionals, such as the MPWB1K, [27] have been proposed to investigate reaction energies, barrier heights and intermediates for the Diels-Alder reactions. For a comprehensive comparison of geometries, we were prompted to optimize all species of the aforementioned HDA reactions using both B3LYP and MPWB1K exchangecorrelation functionals. The cc-pVDZ basis set was used for full optimization with the B3LYP and MPWB1K methods. All calculations were performed using Gaussian09 [28]. The values of the relative energies, ∆E, have been calculated on the basis of total energies of stationary points. Relative enthalpies, ∆H, entropies, ∆S, and Gibbs free energies, ∆G, were calculated with the standard statistical thermodynamics at 298 and 400 K [29]. Consequently, implicit solvent effects of toluene on energies were taken

into account through energy calculations using the polarizable continuum model (PCM) which was reported by Tomasi’s group [30] in the framework of the selfconsistent reaction field (SCRF).[31] The global electron density which was transferred (GEDT) [32] at the TSs was computed through a natural population analysis (NPA).[33] The electronic structures of stationary points were analyzed by the natural bond orbital (NBO) method [33]. Global reactivity indices were estimated according to the equations proposed by Parr and Yang [34]. The global electrophilicity index, ω, is given by the following simple expression, [35] in terms of the electronic chemical potential, μ, and the chemical hardness, η. ω=μ2/2η

(1)

Both quantities may be evaluated in terms of the one-electron energies of the frontier molecular orbitals HOMO and LUMO, ɛH and ɛL, [34] using: μ=(ɛH+εL)/2

(2)

η=εL˗ɛH

(3)

Recently, Domingo introduced an empirical (relative) nucleophilicity index, N, [36] based on the HOMO energies obtained within the Kohn Sham scheme, [37] defined as: N=ɛH(NU)-ɛH(TCE)

(4)

Nucleophilicity is referenced to tetracyanoethylene (TCE), because this has the lowest HOMO energy in a large series of molecules already investigated in the context of polar cycloadditions. This choice allows us to conveniently handle a nucleophilicity scale of positive values. In 2013, Domingo proposed the Parr functions p(r) [38], which are given by the following equations: P-(r)=ρsrc(r)

for electrophilic attacks

(5)

and P+(r)=ρsra(r)

for nucleophilic attacks

(6)

where ρsrc(r) is the atomic spin density (ASD) at the r atom of the radical cation of the molecule under consideration and ρ sra(r) is the ASD at the r atom of the radical anion. The ASDs gathered at each of the atoms of the radical cation and radical anion of a molecule provides the local nucleophilic, Pkˉ, and electrophilic, Pk+, Parr functions of the corresponding neutral molecule. The local electrophilicity indices, ω k [38], and the local nucleophilicity indices, N k [37], were calculated using the following expressions, where Pk+ and Pkˉ are the electrophilic and nucleophilic Parr functions [38], respectively. ωk = ω Pk+

(7)

Nk = N Pkˉ

(8)

All stationary points were characterized as true minima or transition states by frequency calculations. The transition states were further characterized by analysis of the intrinsic reaction coordinates (IRC) for both forward and reverse directions [39].

3. Results and discussion In order to compare the B3LYP energy results with those from the MPWB1K method, the stationary points were optimized at B3LYP/cc-pVDZ and MPWB1K/cc-pVDZ levels of theory. The relative energies and thermodynamic parameters are given in Tables 1-2 and S1-S3. A comparison of the relative energies indicated that the MPWB1K activation energies were lower than the B3LYP activation energies as a consequence of a lower stabilization of reagents than TSs, but there were no great differences in the activation and relative Gibbs free energies of B3LYP and MPWB1K results. Moreover, MPWB1K energies did not modify the selectivity. Therefore, we

discuss only B3LYP/cc-pVDZ results in the gas phase; the MPWB1K energies for some reactions are given in supporting information (Table S1). To investigate the solvent effect on regio- and stereoselectivity of these reactions, the gas phase stationary points were studied in toluene through single-point energy calculations at the B3LYP/cc-pVDZ level of theory. As can be seen in Table S4, the activation energies in toluene associated with the studied cycloaddition reactions are not substantially different from the gas phase results but increase slightly the exothermic character. The inclusion of solvent effects does not affect the regio- and stereoselectivity of the reactions, and the selectivity found in the gas phase is not modified. Thus the incorporation of solvent effects does not lead to any significant enhancement of regio- and stereoselectivity for all studied cycloaddition reactions. Therefore, the gas phase optimization using the B3LYP functional in combination with the cc-pVDZ basis set is accurate enough to address the selectivity and mechanistic details. The present DFT study has been divided into three parts; (I) the regio- and stereoselectivity of two competitive reactions, HDA and DA reactions of diene 1 with 2- and 3- substituted indoles (2-3) were studied and the chemoselectivity for these reactions were investigated using relative energies and Parr functions in presence and absence of LA (ZnCl 2); (II) the mechanism of the Mukaiyama aldol reaction were investigated; (III) the DFT reactivity of reactants were analyzed.

3.1. Mechanistic details of the HDA and DA reactions of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde carboxaldehyde (3)

(2)

and

1-p-toluenesulfonylindole-2-

The cycloaddition reactions of the C=O carbonyl and C=C double bond of 2 and 3 with diene 1 are shown in Scheme 2. While the corresponding cycloadducts (CAs) of the HDA reactions are 4 and 8, the DA reactions produced compounds 5 and 9. These stereoisomers can then undergo elimination reactions. This hydrolytic conversion of the silyl enol ether to ketone accompanied by the elimination of the methoxy group has been shown for such cycloaddition reactions. Due to the asymmetry of both reagents, four competitive pathways are feasible for each reaction, namely two stereoisomeric and two regioisomeric pathways. The two stereoisomeric approach modes of the methoxy group of diene 1 relative to the indole in HDA reactions and formyl groups in DA reactions are endo and exo. The two regioisomeric approach modes of the C 1 or C4 carbon atoms of diene 1 toward the O5 oxygen atom or C 7 carbon atom of 2 and 3 are named ortho (o) and meta (m). For easier comparison, identical atom numbering is used for all cycloaddition reactions. As can be seen in Scheme 2, two different main conformations, anti and syn (the direction of carbonyl group with respect to the N-C=C moiety) exist for the dienophile, which in the HDA reaction involving the carbonyl moiety can be approached by diene 1 on two faces, namely the Si-face and the Re-face. Theoretical results indicate that the most stable CAs along HDA reactions are produced by approach of the diene from the least hindered side opposite the –SO2Ar group, with preference to the syn conformation (Scheme 2). Insert Scheme 2 3.2. Study of the reaction paths involved in the competitive HDA and DA reactions of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde (2) In order to find the regio-, stereo- and chemoselectivity of two completive HDA and DA reaction of 1 and 2, the mechanism of these reactions was studied. The results of

calculations indicated that the HDA and DA reactions of Danishefsky’s diene (1) with 2 can proceed via four reaction pathways, two regioisomeric ortho and meta and two stereoisomeric endo and exo pathways, involving four transition states and four CAs (Scheme 2). The relative energies and thermodynamic parameters, including activation enthalpies, Gibbs free energies and entropies, as well as the reaction enthalpies, Gibbs free energies and entropies for the stationary points are given in Tables 1 and S1. As can be seen from Table 1, the ortho regioisomeric approach modes are more favorable than meta ones and the ortho-endo reactive pathways are lower than the ortho-exo ones. An analysis of the Parr functions [38] also allows us to rule out the meta regioisomeric paths associated with the nucleophilic attack of the C 1 carbon atom of 1 to the O5 and C8 carbon atoms of 3 in the HDA and DA reactions, respectively (see next sections). Insert Table 1 The following conclusions can be drawn from the energy results of the HDA and DA reactions of Danishefsky’s diene (1) with 2: I) The HDA and DA reactions are highly regio- and moderately stereoselective, leading to the formation of 10o-endo and 5o-endo, respectively. (The differences of energy between the endo and exo pathways are about 3 kcal mol-1). II) The computed energy barriers, activation enthalpies and entropies are lowest at the ortho-endo pathways of the HDA and DA reactions, so the ortho-endo reactive pathways are preferred from kinetic and thermodynamic perspectives. III) All of these reactions (HDA and DA) are exothermic by between -9.32 and -16.87 kcal mol-1 and so they can be considered irreversible. IV) The energy barriers for the DA reaction in the more favorable pathways (ortho) are lower than those for the HDA reaction (about 3 kcal mol -1). Then, the DA adduct

of 5 is expected to be the major product with the mixture of endo and exo ratio, consequently the HDA adduct of 10 is produced as the minor product. So the HDA reaction is slower than the classical all-carbon DA cycloaddition, yet it may become competitive (or even exclusive) when the C=C double bond of the dienophile is less reactive. These results are in agreement with the experimental data [13,14]. In order to obtain the most stable CAs, conformational analysis were carried out on the HDA and DA cycloadducts. The conformational analysis indicated a half-chair conformation for the HDA cycloadducts of 10 with the O5 oxygen atom and C 6 carbon atom at the mean plane through the other four atoms and boat-shape conformation for DA cycloadducts of 5. The geometries of the TSs involved in the HDA and DA reaction of diene 1 with 2 are given in Figure 1 and S1. Also, the lengths of the forming bonds and bond order (BO) values, which are a further measure of bond-formation at the TSs [33], are given in Figure 1 and S1. In the ortho regioisomeric TSs the lengths of the forming bonds and BO values indicate that formation of bonds C 1-C6 and C1-C8 is more advanced than that of bonds C 4-O5 and C4-C7 in the HDA and DA reactions, respectively. Insert Figure 1 As can be seen in Figure 1, the TSs involved in the HDA reaction are asynchronous and can take place through a one-step mechanism. Formation of bonds C 1-C8 and C4C7 in TS5 and TS6 of the DA reactions corresponds to a highly asynchronous process which takes place through a two-stage one-step mechanism [40,41]. The lower energy barrier of the ortho pathway originates from it being the more asynchronous TSs [42]. The high asynchronicity of this process is also supported by an analysis of the evaluation of the bond formation along the IRC. Thus, the geometry of the “halfway” point between the saddle point TS5 and the cycloadduct 5o-endo shows that while the

C1-C8 bond is already formed, C 4-C7 bond formation is very delayed (see Figure 2). Moreover, these points are located at a smooth drop in energy after the maximum, explaining the unfeasibility of finding the corresponding acyclic intermediate as a stationary point [43,44]. The electronic nature of the HDA and DA reactions of 1 with 2 was evaluated by computing the global electron density transfer (GEDT) at the TSs associated with the four reactive pathways. Recently Domingo et al. proposed use of the GEDT concept [32] at the TSs to analyze the polar nature of cycloaddition reactions. The GEDT concept is related to the electron density transfer that takes place from a nucleophile to an electrophile along a polar reaction. [32,45] The GEDT values at the TSs are given in Figures 1 and S1. The values of the GEDT that fluxes from the diene framework to the indole are 0.33 e (TS1), 0.36 e (TS2), 0.33 e (TS5) and 0.35 e (TS6). These high GEDT values point to the polar character of the HDA and DA reactions [45]. The GEDT along the more favorable regioisomeric ortho pathways is larger than along meta pathways. 3.3. Study of the reaction paths involved in the competitive HDA and DA reactions of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-2-carboxaldehyde (3) in the absence and presence of LA The experimental results have shown a complete unexpected inversion of the chemoselectivity in the cycloaddition reactions of 3-substituted and 2-substituted indoles (2 and 3) with Danishefsky’s diene (1) [13]. So to better understand the reactivity of 3-substituted formyl indole (2) compared to 2-substituted formyl indole (3) toward diene 1, we investigated the chemo- and stereoselectivity of the HDA and DA reactions between Danishefsky’s diene 1 and 3. As noted earlier, the HDA and

DA reactions of 1 with 2 are completely regioselective, consequently only the ortho regioisomeric pathways were studied. An exploration of the PES for two competitive HDA and DA reactions of 1 with 3 found four TSs, TS9, TS10, TS11 and TS12 and corresponding CAs, 11o-endo, 11oexo, 9o-endo and 9o-exo, respectively. As can be seen from the relative energies and the thermodynamic parameters in Table 1 and S3, the reactions are moderately endo selective and the cycloaddition reactions are exothermic by -16.26 and -9.86 kcal mol1

, respectively. Addition of the entropic contribution to the enthalpy of HDA and DA

reactions increases the activation Gibbs free energies to 28.71 and 31.65 kcal mol -1 as a consequence of the unfavorable negative activation entropy associated with these reactions, ΔS= -53.58 and -59.37 cal mol-1K-1.These results are close to those obtained from the potential energies. Due to the high activation energies required for the HDA and DA reactions of 1 with 3, the corresponding reactions must be experimentally LA catalyzed [13]. Hence, these cycloaddition reactions in the absence of a LA catalyst are not favored via the mild conditions which were reported by Chretien [13]. Thus coordination of the ZnCl 2 LA to the carbonyl oxygen atom of 3 (3-LA) strongly increases the electrophilic character of 3. We next computationally examined the stereo- and chemoselectivity of the HDA and DA reactions of 1 with 3 in the presence of a LA (3-LA) (Scheme 3). The relative energies along two competitive pathways, endo and exo are given in Table 1. An analysis of the energetic results indicated that the energy barriers for the HDA and DA reactions of 3-LA with 1 were decreased dramatically and the endo pathways are preferred with very low energy barriers relative to the uncatalyzed reactions. These reactions are exothermic by -12.67 and -7.94 kcal mol-1. So we can state that

coordination of ZnCl 2 to the carbonyl group of 3 accelerates the HDA and DA reactions but does not significantly alter its exothermic character. Insert Scheme 3 Some appealing conclusions can be drawn from the energy results: I) The energy barriers of the HDA and DA reactions of 1 with 3-LA are lower than associated with the uncatalyzed reactions. II) The activation energies in the DA reactions are higher than the HDA reactions, so it can be used to show that 3 and 3-LA do indeed participate as a heterodienophile rather than an all-carbon dienophile. II) Interestingly, the energy results indicate a complete inversion of the chemoselectivity in the cycloaddition reactions of 1 with 2-substituted indoles, (3 and 3-LA), which is in agreement with the experimental findings [13]. III) The faster zinc chloride catalyzed reaction leads to the product under mild conditions, in which is in complete agreement with the experimental results [13]. The optimized geometries of the TSs involved in the HDA and DA reactions are given in Figure 1. As can be seen from this Figure the length of forming bonds in catalyzed reactions are longer than in their corresponding uncatalyzed cycloaddition reactions. The lengths of the forming bond and BO values indicate that the TSs associated with these cycloaddition reactions correspond to highly asynchronous processes. The high GEDT values in the HDA and DA reactions indicate a highly polar character for these reactions. Moreover, the GEDT values increased in catalyzed processes. Therefore, coordination of LA-ZnCl2 to indole 3 causes the reaction to be faster via highly asynchronous and polar TSs, as a consequence of the increased electrophilicity of 3-LA.

3.4. Study of the reaction paths involved in the Mukaiyama aldol reaction of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-2-carboxaldehyde (3) in the presence of LA As pointed out in the experimental results [13], the reaction of Danishefsky’s diene (1) with 3 in the presence of ZnCl 2 at room temperature leads to compound 4 and acyclic intermediate 6 in a 64:36 ratio, whereas in the absence of Lewis acid only the cyclized compounds 4 and 7 are observed. These observations suggest that when the reaction is catalyzed by a zinc-based Lewis acid, the heterocycloaddition may also go through a stepwise mechanism via a Mukaiyama aldol reaction pathway. In order to understand the experimental findings and the energetic aspects of these reactions, the mechanism of the Mukaiyama aldol reaction of trans and cis Danishefsky’s diene, (E)-1 and (Z)-1 with a ZnCl 2 complex of 2 (2-LA) were investigated. As it was expected based on the experimental observations, in the reaction of (Z)-1 with 2-LA two stereoisomers of 10o-endo and 10o-exo were produced, while in the case of (E)-1, the reaction proceed via the pathway leading to acyclic intermediate 6 (Scheme 4). Insert Scheme 4 The first step in our study of the Mukaiyama aldol reaction was to calculate the possible conformations for the transition structures of the relevant mechanistic steps. For the sake of direct comparison, the possible conformations of transition structures were calculated for (E)-1 and (Z)-1 with 2. The dihedral angle along two carboncarbon forming bonds is varied in the same way for all transition states, where the carbonyl group is positioned to the left and the –SiMe3 group is in front of it. In our calculations, the relative orientations of -SiMe3 and CO groups can lead to syn and anti-conformation transition structures. We also found that in the reactions of both

(E)-1 and (Z)-1, the synclinal transition structures are more favorable than antiperiplanar ones. The most stable synclinal transition structures for (E)-1 and (Z)-1 as the starting structure in the Mukaiyama aldol reaction are shown in Scheme 5. This observation is supported by the experimentally observed preference for the syn transition states. The syn pathway for (E)-1 and (Z)-1 shows similar dihedral angle values in their transition states (Scheme 5). Insert Scheme 5 As indicated by the experimental results, two reaction pathways were considered for the stepwise mechanism of the Mukaiyama aldol reaction; I) involved the formation of the cycloadduct 10, via heterocycloaddition and II) is associated with the formation of an acyclic compound 6 (Scheme 4). The relative energies for these processes are given in Tables 2 and S2. The first step of pathway I involved the nucleophilic attack of (Z)1 to 2-LA and the formation of zwitteronic intermediate 12, while along pathway II intermediate 14 is produced through the nucleophilic addition of (E)-1 to 2-LA (Scheme 4). The energy barriers for these processes are 2.65 and 3.97 kcal mol -1 through TS13 and TS17, respectively. Insert Table 2 In pathway I, zwitterionic intermediate 12 can subsequently follow two reaction modes (a) and (b). Along mode (a) a ring closing process allows the formation of formal [4+2] CA 10o-exo-LA via TS16 with an energy barrier of 6.60 kcal mol-1. On the other hand, along mode (b), a bond rotation occurs around the C2-C3 bond with an energy barrier of 2.39 kcal mol -1, via TS14, and a ring-closure process takes place through TS15, by 1.90 kcal mol-1, yielding CA 10-oe-LA. In pathway II, a hydroquinone molecule binds to the oxygen atom of 14 to produce species 15 with -7.07 kcal mol-1. Then a proton transfer takes place through TS18,

resulting in 16 by -8.74 kcal mol-1. The next step is dissociation of the –SiMe3 group which leads to the hydroxyl intermediate 6. The energy barrier for this process is 9.26 kcal mol-1. Considering the activation energies of the two pathways I and II, it can be concluded that the stepwise Mukaiyama aldol reactions with low energy barriers are more favorable than the corresponding HDA reactions, which is in agreement with the experimental results [13]. The thermodynamic calculations are given in Tables 2 and S2. Inclusion of thermal corrections to the energies raises the activation enthalpies to 2.45 (TS13) and 3.09 (TS17) kcal mol-1, and TS13 remains 1.32 kcal mol-1 more stable than TS17. The addition of the activation entropies to the enthalpies raises the activation Gibbs free energies, as a consequence of the large negative activation entropy associated with this process. These results are in agreement with those obtained from the potential energies. The optimized geometries of the TSs involved in the Mukaiyama aldol reaction are given in Figure 3. At the TSs associated with the nucleophilic approach of (Z)-1 and (E)-1 to 2-LA, the length of the C 1-C6 forming bond is 2.229 Å at TS13 and 1.914 Å at TS17, while the distance between C 4 and O5 is 3.143 Å at TS13 and 4.397 Å at TS17. At the TSs associated with ring closure steps, the length of the C 4-O5 forming bond is 2.768 Å at TS16 and 3.042 Å at TS15. These values indicate that while the C 1C6 bond is already partially formed, the O 5-C4 distance is more advanced than those involving intermediates 12 and 13. At TS18, the lengths of the O-H breaking and forming bonds are 1.026 and 1.518 Å respectively. Insert Figure 3 3.4. Analysis of the global Reactivity indices of the ground states of the reagents

Recent studies devoted to DA reactions have shown that analysis of the reactivity indices defined within the context of the conceptual DFT [46-48] is a powerful tool to understand the reactivity in polar cycloadditions. DFT reactivity indices, namely electronic chemical potential, μ, hardness, η, electrophilicity, ω, and nucleophilicity, N, indices of all reagents are given in Table 3. Insert Table 3 The electronic chemical potential of the Danishefsky`s diene 1, is higher than indoles 2 and 3, indicating that along a polar cycloaddition reaction the GEDT will take place from the diene 1 towards indoles 2, 2-LA, 3 and 3-LA, in clear agreement with the GEDT analysis performed at the TSs associated with these polar reactions. According to the global electrophilicity index, ω, diene 1 with ω= 0.82 eV, will not participate as an electrophile in polar reactions. The nucleophilicity index, N, of 1 is 3.602 eV, and it is classified as a strong nucleophile [49] and so it will act as a nucleophile. As expected, 2 present a high electrophilicity value, ω, of 1.980 eV, classifying it as a strong electrophile on the electrophilicity scale [50]. Also, this dienophile has a high nucleophilicity value, N, of 2.809 eV, and thus it is classified as a strong nucleophile on the nucleophilicity scale [49]. Coordination of ZnCl 2 to the oxygen atom of 2 noticeably increases the electrophilicity of 2-LA, and slightly decreases its nucleophilicity. Moreover, by changing the location of the carbonyl group on the C=C double bond from the C7 of 2 to the C8 of 3, the electrophilicity increased. Thus, the high nucleophilic character of 1 together with the high electrophilic character of 2, 2-LA, 3 and 3-LA indicate that these cycloaddition reactions have highly polar character. The polar character also can be predicted using the electrophilicity differences of the reaction pairs, Δω [51]. In this sense, the electrophilicity differences for 1 with 2-LA, Δω2-ZnCl2/1=1.673 eV and 3-LA,

Δω3-ZnCl2/1=2.673 eV are higher than those for 1 with the isolated 2, Δω2/1=1.16 eV and 3 Δω3/1=1.376 eV. Therefore, LA catalyzed processes will be more polar than uncatalyzed ones. The most polar reaction occurs in the cycloaddition reaction of 1 with 3-LA, which has the highest GEDT and the largest chemical potential difference (Δµ=2.24 eV). Also, a simultaneous decrease in the chemical hardness of 3.75 eV was observed for this process, which is associated with a low resistance to charge transfer.

3.5. Prediction of the chemoselectivity of the studied cycloaddition reactions using Parr functions As mentioned in the previouse sections the chemselectivity can reverse from 3substituted indole (2) to 2-substituted indole (3). The energy barriers could explain these results but to better understand the observed chemoselectivity of the studied cycloaddition reactions, the Parr functions electrophilicity and nucleophilicity indices were inspected for reactants. Along a polar reaction, the most favorable reactive pathway will involve an initial two center interaction between the most electrophilic center of the electrophile and the most nucleophilic center of the nucleophile [52]. Recently, Domingo et al. proposed the electrophilic, Pk+, and nucleophilic, Pk–, Parr functions which are obtained from the ASDs of radical anions and radical cations of the reagents [36,38,52]. A simple analysis of the Parr functions allows us to characterize the most electrophilic and most nucleophilic centers in a molecule. Accordingly, the nucleophilic, Pk-, Parr functions for diene 1 and the electrophilic, Pk+, Parr functions for indoles 2, 2-LA, 3 and 3-LA are analyzed in order to explain the chemoselectivity in the studied reactions. Figure 4 shows the ASD of the radical cation of 1 and the radical anion of indoles 2, 2-LA, 3 and 3-LA. The Parr functions for the C 1, C2, C3 and C4 atoms of 1 and the O 5, C6, C7

and C8 atoms of 2, 2-LA, 3 and 3-LA are given in Table 4. As shown in Figure 4 and Table 4, while the nucleophilic, Pk–, Parr function of 1 is mainly concentrated at C 1, (Pk–=0.574), C3 and C4 present considerable nucleophilic, with Pk– Parr functions of 0.170 and 0.109, respectively, and C 2 has an insignificant value of -0.026. These results are similar to those found with the analysis of the ASD at the radical cation of Danishfsky's diene 1, which indicate the spin density is located mainly at C 1. On the other hand, analysis of the ASD of the radical anion of 3-substituted indole 2 indicated that spin density is located mainly at C 8, suggesting that C 8 of 2 will be the preferred position for a nucleophilic attack of C1 of 1. This behavior is similar to electrophilic, Pk+, Parr function, which indicate that C is the most electrophilic center of 2. So, the C8 of the ethylene framework has been more electrophilically activated than the carbonyl carbon (C 6) of indole 2. It can be predicted that the reactivity of the C 7=C8 ethylene framework of 2 toward diene 1 is higher than the carbonyl framework. On the other hand, analysis of the electrophilic, Pk+, Parr functions of 3 is contrary to that of 2. The oxygen atom, with Pk+=0.204, is more electrophilically activated than C 8 with Pk+=0.066. Therefore, O 8 of indole 3 will be the preferred position for a nucleophilic attack by C1 of 1. In the presence of LA (ZnCl 2), the electrophilic, Pk+, Parr functions of C 6 of 2-LA and 3-LA are increased to 0.352 and 0.335, respectively, which means they are now more electrophilically activated than O 5, with Pk+=0.144 and Pk+=0.163, respectively. This behavior is consistent with the analysis of the local electrophilicity indices of 3-LA, which indicates that C 6 is more electrophilically activated than O 5 along the HDA reaction. As can be seen in Figure 4 and table 4, the electrophilic, P k+, Parr functions of 2-LA and 3-LA are mainly concentrated at C 8 and C6, respectively, which will be the preferred positions for the nucleophilic attack of C 1 of 1. This behavior is similar to

that found in the radical anion of 2-LA and 3-LA in ASD. Analysis of the Parr functions can clear explain the source of the chemoselectivities observed in the studied cycloaddition reactions. As can be seen in Figure 4, complexing LA to the carbonyl group increases the electrophilic activation of CO, which explains the high reactivity of the carbonyl framework of 2-LA toward 1 in the Mukaiyama aldol reaction. This is in clear agreement with the experimental results. These behaviors are also reflected through the local electrophilicity indices (ω k) and the local nucleophilicity indices (N k) which are shown in Table 4. Moreover, these findings suggest that the strong nucleophilic character of 1 and electrophilic character of 2, 2-LA, 3 and 3-LA along polar DA and HDA reactions will proceed with a large GEDT.

4. Conclusion The molecular mechanism of the domino reactions between Danishefsky’s diene (1) and 3- and 2-substituted formyl indoles 2 and 3 have been studied using the DFT method at the B3LYP/cc-pVDZ level of theory in the absence and presence of a LA catalyst. The HDA and DA reactions are completely regioselective and endo selective, yielding dihydropyrane and tetrahydrocarbazol compounds, respectively. The formation of these CAs takes place through a domino process that comprises three consecutive reactions; (i) a cycloaddition reaction between Danishefsky’s diene 1 with 2 and 3 to yield stereoisomeric CAs 5, 9, 10 and 11; (ii) the hydrolysis of the silyl enol ether under essentially neutral conditions through nucleophilic cleavage of the O-Si bond affording compound 4 and finally (iii) the elimination of methanol from this intermediate, yielding cyclic α,β-unsaturated ketone 7. The chemoselectivity of the

cycloaddition reactions indicate that while the DA reaction of 2 is faster than the HDA reaction, 2-substituted indole 3 participates as a heterodienophile rather than all-carbon dienophile. Therefore a complete inversion of the chemoselectivity is seen in the cycloaddition reactions of 1 with 2-substituted indoles, (3 and 3-LA) relative to 3substituted indoles (2 and 2-LA). Moreover, LA catalyzed reactions had lower energy barriers which led to them proceeding under milder conditions. The stepwise Mukaiyama aldol reaction can take place via two pathways (I and II), with a lower energy barrier than the concerted HDA cycloaddition reactions. Analysis of the global reactivity indices of the ground states of reagents correctly explains the reactivity of these reagents in polar cycloaddition reactions. Also, analysis of the electrophilic, Pk+, and nucleophilic, Pk-, Parr functions indicates that the most favorable two center interactions between the nucleophilic diene 1 and the electrophilic dienophiles 2 and 3 will take place between C 1 of 1 and C8 and O5 of 2 and 3, respectively. The Parr functions correctly explain the observed inversion chemoselectivity of these reactions.

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Table 1. Calculated activation energies (ΔE #/kcal mol-1), reaction energies (∆Er/kcal mol-1), activation Gibbs free energies (∆G#/kcal mol1

) and reaction Gibbs free energies (ΔGr/kcal mol-1) in the gas phase of

DA and HDA cycloaddition reactions between Danishefsky’s diene 1 and 2 and 3 in the absence and presence of Lewis-acid catalyst (LA) at the B3LYP/cc-pVDZ level of theory. (For a full comparison of energies see supporting information) Reaction 1+2→10o-endoa 1+2→10o-exoa 1+2→10m-endoa 1+2→10m-exoa 1+2→5o-endoa 1+2→5o-exoa 1+2→5m-endoa 1+2→5m-exoa 1+3→11o-endob 1+3→11o-exob 1+3→9o-endob 1+3→9o-exob 1+3→11o-endoLAb 1+3→11o-exo-LAb 1+3→9o-endo-LAb 1+3→9o-exo-LAb a

TSs TS1 TS2 TS3 TS4 TS5 TS6 TS7 TS8 TS9 TS10 TS11 TS12 TS9-LA TS10-LA TS11-LA TS12-LA

ΔE # 17.81 20.07 34.39 33.59 14.82 17.94 32.73 32.01 13.66 15.36 15.72 17.08 0.54 2.31 6.61 7.11

ΔG # 32.32 34.13 48.81 47.55 29.69 33.26 47.01 45.90 28.71 30.07 31.65 33.39 12.79 15.16 22.11 23.31

ΔEr -14.75 -16.87 -4.90 -5.04 -10.45 -9.32 -7.49 -10.19 -16.26 -14.55 -9.86 -11.51 -12.67 -11.36 -7.94 -9.52

thermodynamic functions calculated at 400 k, b thermodynamic functions calculated at 298

ΔGr 1.43 -1.23 10.49 9.86 4.45 5.73 8.94 5.28 -1.44 0.11 4.97 4.22 3.62 4.87 7.65 7.24

Table 2. Calculated activation energies (ΔE#/kcal mol-1), reaction energies (∆Er/kcal mol-1), activation Gibbs free energies (∆G#/kcal mol-1) and reaction Gibbs free energies (ΔGr/kcal mol-1) at 298 K in the gas phase of the Mukaiyama aldol reactions in the presence of Lewis-acid catalyst between Danishefsky’s diene 1 and 2 at the B3LYP/cc-pVDZ level of theory Reaction (Z)-1+(2-LA)→12 12→13 13→10o-endo-LA 12→10o-exo-LA (E)-1+(2-LA)→14 14 →15 15 →16 16→6

TSs TS13 TS14 TS15 TS16 TS17 TS18 TS19

ΔE# 2.65 2.39 1.90 -3.43 3.97 -5.73 0.52

ΔG# 16.45 15.69 18.36 12.29 20.43 12.45 14.31

ΔEr -1.88 -4.48 -10.19 -12.58 2.72 -7.07 -8.74 -20.81

ΔGr 12.95 11.69 5.84 3.52 19.24 20.24 15.35 7.49

Table 3. HOMO energies/au, LUMO energies/au, electronic chemical potential (µ/eV), chemical hardness (η/eV), global electrophilicity (ω/eV) and nucleophilicity (N/eV) for the reactants obtained at the B3LYP/cc-pVDZ level of theory . Species 1 2 2-LA 3 3-LA

EHOMO -0.20409 -0.23325 -0.25790 -0.23545 -0.25815

ELUMO -0.00948 -0.07270 -0.10296 -0.05072 -0.12052

µ -2.912 -4.163 -4.607 -4.301 -5.152

η 5.170 4.354 4.216 4.210 3.745

ω 0.820 1.980 2.193 2.196 3.543

N 3.602 2.809 2.138 2.749 2.132



 Table 4. The Parr functions ( Pk /au), local electrophilicity

indices (ωk /eV), and local nucleophilicity indices (Nk/eV) at the reactive sites of the reactants calculated at the B3LYP/cc-pVDZ level of theory. OCH3 3 2

TMSO

H

7

4

6

N

1

8

O

5

SO2Ar

1 Species 1

2

2-LA

3

3-LA

k C1 C2 C3 C4 O5 C6 C7 C8 O5 C6 C7 C8 O5 C6 C7 C8 O5 C6 C7 C8

2, 2-LA, 3, 3-LA Pk+ 0.259 0.109 0.091 0.429 0.085 0.075 0.011 0.226 0.144 0.352 -0.065 0.363 0.204 0.109 0.121 0.066 0.163 0.335 0.270 -0.013

Pkˉ 0.547 -0.026 0.170 0.109 0.114 -0.063 0.281 0.032 0.092 -0.043 0.225 0.009 0.127 -0.077 0.295 0.014 0.034 -0.015 0.173 0.042

ωk 0.156 0.217 0.181 0.848 0.069 0.059 0.008 0.185 0.287 0.516 -0.076 0.532 0.447 0.239 0.266 0.145 0.555 1.187 0.657 -0.046

Nk 1.538 -0.073 0.478 0.307 0.410 -0.227 1.011 0.116 0.241 -0.089 0.593 0.018 0.349 -0.212 0.816 0.038 0.311 0.139 0.158 0.382

Scheme Captions Scheme 1. The overal cycloaddition reactions of DA and HDA of Danishefsky’s diene (1) with 1-ptoluenesulfonylindole-3-carboxaldehyde (2) and 1-p-toluenesulfonylindole-3-carboxaldehyde ( 3).

Scheme 2. The possible regio-, stereo- and chemoselectivity pathways for the cycloaddition reactions of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde (2).

Scheme 3. The possible stereo- and chemoselectivity pathways for the cycloaddition reactions of Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde (3) in absence and presence of LA.

Scheme 4. The stepwise mechanism of the Mukaiyama aldol reaction of (E)- and (Z)-Danishefsky’s diene (1) with 1-p-toluenesulfonylindole-3-carboxaldehyde (2) in the presence of LA.

Scheme 5. The most stable synclinal transition structures for (E)-1 and (Z)-1 as the starting structure with 1-p-toluenesulfonylindole-3-carboxaldehyde (2) in the Mukaiyama aldol reaction.

Figure Captions Fig. 1 The geometry optimized transition states for ortho pathways of the DA and HDA reactions of 1 with 2 and 3 at the B3LYP/cc-pVDZ level of theory. Bond distances are given in Å, wiberg bond indices are given in parentheses and the natural charges (GEDT) of TSs are also given (For a full comparison of geometries see supporting information).

Fig. 2 The structure of an IRC point “halfway” between the saddle point TS5 and the cycloadduct 5o-endo. The lengths of the bonds involved in the reaction show that while the C1-C8 bond is advanced, the C4-C7 bond formation is delayed

Fig. 3 The geometry optimized transition states of the Mukaiyama aldol reactions of 1 with 2 and 3 at the B3LYP/cc-pVDZ level of theory. Bond distances are given in Å, wiberg bond indices are given in parentheses and the natural charges (GEDT) of TSs are also given.

Fig. 4 Maps of (a) ASD of the radical cation Danishefsky’s diene 1, (b) ASD of the radical anion indole 2, (c) ASD of the radical anion indole 3, (d) ASD of the radical anion ZnCl2-indole 2LA, (e) ASD of the radical anion ZnCl2-indole 3-LA.

  

Chemoselectivity of the cycloaddition reactions of some indole derivatives is investigated. The mechanism of the Mukaiyama aldol reactions is investigated To evaluate the regioselectivity of reactions reactivity indices were performed

A computational mechanistic study on Chemo-, Regio- and Stereoselectivity of cycloaddition reactions leading to ɤ-dihydropyran and tetrahydrocarbazol compounds Mina. Haghdadi*and Fateme. Nikjoo

Department of Chemistry, Islamic Azad University, P.O. box 755, Babol branch, Babol, Iran *[email protected]