Reactivity and selectivity of the InNPs mediated allylation of carbonyl compounds : a DFT study

Introduction Metal-mediated allylation of carbonyl compounds with allyl bromides is an interesting and convenient method to form C-C bond and to obtain homoallylic alcohols, which are significant building blocks in organic synthesis. Besides the reactivity, the diastereoselectivity in the addition of an allyl-metal to a carbonyl compound is a fundamental parameter to consider, and could be explained by steric and stereoelectronic or chelating effects. In this sense, in our group, we have synthesized indium nanoparticles (InNPs) of 4.0 ± 0.5 nm, through the reducing system InCl3-Li-DTBB(cat.) in THF at room temperature and in the absence of any additives or anti-caking ligand. The catalytic efficiency of these InNPs was evaluated by the allylation reaction of carbonyl compounds, giving excellent yields of the corresponding homoallylic alcohols. The reagents were selected rationally in order to complete an appropriate mechanistic knowledge of the system. Substituted allyl bromides allowed us to establish that the reaction products come from a γ-coupling, via a six-membered cyclic transition state, type Zimmerman-Traxler. In order to extend the scope of this indiummediated allylating methodology, we employ different ortho-substituted carbonyl compounds and crotyl bromide as allylating agent to study their effect over the diastereoselectivity in this C-C bond formation. Additionally, and in order to give an explanation to the reactivity and the syn-anti selectivity observed from the experimental results, computational studies have been applied by the Gaussian09 program.


Introduction
Metal-mediated allylation of carbonyl compounds with allyl bromides is an interesting and convenient method to form C-C bond and to obtain homoallylic alcohols, which are significant building blocks in organic synthesis.Besides the reactivity, the diastereoselectivity in the addition of an allyl-metal to a carbonyl compound is a fundamental parameter to consider, and could be explained by steric and stereoelectronic or chelating effects. 1 In this sense, in our group, we have synthesized indium nanoparticles (InNPs) of 4.0 ± 0.5 nm, through the reducing system InCl 3 -Li-DTBB(cat.)in THF at room temperature and in the absence of any additives or anti-caking ligand.The catalytic efficiency of these InNPs was evaluated by the allylation reaction of carbonyl compounds, giving excellent yields of the corresponding homoallylic alcohols.The reagents were selected rationally in order to complete an appropriate mechanistic knowledge of the system.Substituted allyl bromides allowed us to establish that the reaction products come from a γ-coupling, via a six-membered cyclic transition state, type Zimmerman-Traxler. 2 In order to extend the scope of this indiummediated allylating methodology, we employ different ortho-substituted carbonyl compounds and crotyl bromide as allylating agent to study their effect over the diastereoselectivity in this C-C bond formation.Additionally, and in order to give an explanation to the reactivity and the syn-anti selectivity observed from the experimental results, computational studies have been applied by the Gaussian09 program.
trifluoromethyl or nitro, gave the corresponding 1-(2-(trifluoromethyl)phenyl)-2-methyl-3buten-1-ol (2h) and 1-(2-nitrophenyl)-2-methyl-3-buten-1-ol (2i) with a syn:anti relation of 60:40 and 69:31, respectively.It should be mentioned that ortho-propoxybenzaldehyde yield the expected homoallylic alcohol with a 75:25 diastereoselectivity determined by 1 H-RMN.While we suppose that the syn-diastereomer would be the major product, this could not be determined yet.With the aim to explain and understand these experimental results, we performed a computational analysis using DFT 4 methods with the Gaussian09 program. 5The initial conformational analysis was performed using the semiempirical PM3 method, then we work with the B3LYP 6 functional, applying the LanL2DZ pseudopotential for the indium and the 6-31+G* basis set for all the other atoms and the solvent effect was evaluated with the PCM model.To simplify the reactive system and considering results reported by other authors, we evaluated the potential energy surfaces (PES) for the mentioned process by considering the formation of an initial complex between the carbonyl compound and the allyl-indium intermediate, a six member cyclic chair-like transition state (TS) and a final complex, as can be seen in Scheme 1 for 2a as representative compound.An auxiliary bromide atom was used as ligand for the indium atom to obtain a simplified neutral model system. 7 a Reaction conditions: Li (3.5 mmol), DTBB (0.1 mmol), InCl 3 (1.0 mmol) in THF (2 mL), crotyl bromide (1.5 mmol) in THF (1 mL), stirred for 30 min, carbonyl compound (0.5 mmol) in THF (1 ml), at 25 ºC, 1 h reaction time.b Quantified by GC analysis using internal standard method.c Syn:anti relation determined by 1 H NMR. d Stereoisomers undefined yet.

Scheme 1.
Representative structures for 2a utilized in the computational analysis.
Regarding the reactivity, as already mentioned above, the allylation of benzaldehyde with allyl bromide gave 98% of 2a after 1 h reaction time, while the allylation of acetophenone, after 20 h, gave 2b in 67% yield.The computational modeling showed a very good agreement with the experimental results, thus, the activation energy (Ea) for the first process (exothermic in 3.4 kcal/mol) was 6.9 kcal/mol, while the Ea for the allylation of acetophenone was 10.2 kcal/mol, being an endothermic process (+0.94 kcal/mol) (Figure 1).On another hand, reactivity of the allyl-and prenyl bromides was very different, both giving the corresponding homoallylic alcohol in excellent yields (98 and 95%) but the allylation with prenyl bromide being notably slower, 1h vs 4 h reaction time respectively.As shown in Figure 2 the formation of the final complex of 2c takes place with higher Ea that 2a (11.4 and 6.9 kcal/mol, respectively).In addition, for 2a the process occurs exothermically (-3.4 Kcal/mol), while for 2c the corresponding final complex requires +3.6 kcal/mol.These energetic  Besides, the allylation of ortho-methoxy benzaldehyde showed to be faster than paramethoxy benzaldehyde, and we found that the Eas for 2e and 2f were 8.5 and 9.6 kcal/mol respectively, moreover, the first process was exothermic while the second was slightly endothermic (-1.7 vs +0.3 kcal/mol respectively).
Relative the selectivity, when we employed crotyl bromide as allylating agent and benzaldehyde, a mixture of diastereomer alcohols (2d) were obtained, with a higher proportion of syn regarding to anti (67:33).The computational analysis was agreed with these results, being the Eas 8.0 and 9.6 kcal/mol respectively (Figure 3).Besides, we studied the syn:anti selectivity for the crotylation of ortho-substituted benzaldehydes, thus, for ortho-OMe derivative (2f) a obtained relation syn:anti of 50:50, and the computational modeling showed very similar Eas, 12 and 11 kcal/mol respectively, while the process were endothermic (+3.5 vs +1.5 kcal/mol respectively).Ortho-Cl derivative (2g) showed a syn:anti diastereoisomers relation of 58:42, and the computational modeling indicates that 8.1 kcal/mol are required to give the anti diastereomer while only 5.7 kcal/mol for the syn product; moreover, the anti-process is less exothermic than the syn-process (-2.7 vs -4.0 kcal/mol respectively).For ortho-CF 3 derivative (2h) the relation syn:anti was 60:40, and the computational modeling was agreed with these results, being the Eas 5.7 and 8.0 kcal/mol respectively, while the process were both exothermic (-4.3 and -4.0 kcal/mol respectively).Ortho-NO 2 derivative (2i) showed a syn:anti diastereoisomers relation of 69:31, in agreed with the computational results, that indicates that 4.8 kcal/mol are required to give the anti diastereomer while only 2.6 kcal/mol for the syn product, and the process were exothermic (-7.7 (syn) vs -7.5 (anti) kcal/mol).On another hand, as can be seen from Figure 4, the TS geometries of the syn-anti diastereomers of 2f and 2i derivatives showed remarkable interactions, thus, an stabilizing interaction between the H-C atom and O-Me atom for the anti-2f could increased the proportion of this diastereomer in the mixture (50:50).Moreover, a destabilizing interaction between the O=C atom and O-NO atom was observed for the anti-2i, that could reduced the proportion of this diastereomer in the mixture (69:31).With the aim to extent the scope of the diastereolectivity for the InNPs-mediated crotylations, we synthesized ortho-propoxy benzaldehyde and obtained a diastereoisomeric relation of 2j 75:25 (by 1 H-RMN), but we could not distinguish each other yet.We are now making additional RMN experiments and computational calculations to elucidate the major diastereomer in the mixture.
Although the exact mechanistic pathway is difficult to ascertain, based on the stoichiometry of the reaction, our experimental observations and DFT studies, we propose plausible reaction pathway for the studied transformation.As can be seen from Scheme 2, the first step in the reaction would be the formation of InNPs by electron transfer (SET) from the arene radical anion to the indium salt.The addition of the allyl bromide to the InNPs suspension, could led to the formation of an allyl indium(III) intermediate, which by reaction with the activated carbonyl compound (probably adsorbed to the InNPs surface) could led to the corresponding γ-coupling homoallylic alcohol through a Zimmerman-Traxler type transition state.

Conclusion
The in situ prepared InNPs have demonstrated to be efficient for the synthesis of homoallylic alcohols almost quantitatively and at shorter reaction times.Besides the methodology allowed us to study experimentally the syn-anti selectivity of the reaction and DFT calculations have shown to be a successful approach for studying the allylindium intermediates as well as to explain the experimental results.Based on the experimental data and DFT studies, we have proposed a possible reaction mechanism that implies the formation of -coupling products via a cyclic six-membered Zimmermann-Traxler-type transition state.
We appreciate the support received from SGCyT-UNS, CONICET and ANPCyT.
to steric hindrance by methyl group of prenyl bromide in 2c and could explain the difference found in the reactivity with 2a.