Julien Braire

Aurélie Macé

Rania Zaier

Marie Cordier

Joëlle Vidal

Claudia Lalli

Arnaud Martel

François Carreaux

Raina Zaier

Catalytic Enantioselective Allylboration and Related Reactions of Isatins Promoted by Chiral BINOLs: Scope and Mechanistic Studies

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INTRODUCTION

Among the existing allylation reactions of carbonyl compounds, the asymmetric allylboration constitutes probably one of the most reliable and predictable stereoselective methods for the formation of homoallylic alcohols via a Zimmerman-Traxler transition state. 1 Moreover, a simple implementation coupled with non-toxic and easily accessible enantioenriched allylboron reagents has made this non-metal approach very popular. [START_REF] Brown | Asymmetric Carbon-Carbon Bond Formation via B-Allyldiisopinocampheylborane. Simple Synthesis of secondary Homoallylic Alcohols with Excellent Enantiomeric Purities[END_REF] Unfortunately, this approach requires stoichiometric amounts of chiral auxiliaries for which the recovery and recycling can hardly be applied. As a response to environmental sustainability requirements, the discovery of chiral catalysts to promote the allylboration reaction became a research topic incrementally important over time. [START_REF] For | Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones[END_REF] The pioneering results in this area have mainly been described by Miyura, and Hall based on Lewis and Brønsted acidcatalyzed allylboration. 4 Since the seminal work of Antilla's group on the highly enantioselective TRIP catalyzed allylboration of aldehydes, 5 a great number of work have been reported highlighting the significant interest of chiral phosphoric acids as Brønsted acid catalysts. [START_REF] Sedgwick | Recent Developments and Applications of the Chiral Brønsted Acid Catalyzed Allylboration of Carbonyl Compounds[END_REF] Examples with ketones are less common, because they are less electrophilic and sterically more hindered than aldehydes. 7 The Schaus group was one of the first to develop an efficient catalytic enantioselective synthesis of tertiary homoallylic alcohols from -aryl ketones using allyldiisopropoxyborane as allyl reagent and in the presence of chiral diols such as BINOL derivatives. 8 The method is based on the transient formation of a chiral allylboronate via reversible exchange of the boron's achiral alkoxy ligand with the chiral diol catalyst. [START_REF] Lou | Asymmetric Allylboration of Acyl Imines Catalyzed by Chiral Diols[END_REF] As a result of those outcomes, several research works in this area have been disclosed employing different allylic boron reagents such as boronic acids or dioxaborinanes to non-activated ketones using chiral biphenol catalysts. 10 This mode of catalysis can be extended to the enantioselective preparation of homopropargylic alcohols from ketones using allenylboronates under solvent-free microwaves conditions. 11 For substrates containing an activated ketone group, such as N-protected isatins, a chiral catalyst based on 1,3-amino alcohols incorporating an acidic phenol functionality was designed by the Hoveyda's group 12 (Figure 1a) while Li's group has reported the use of SPINOL-derived phosphoric acid with Bi(III) salt 7a (Figure 1b). Recently, we have shown that commercially available chiral BINOL derivatives can also catalyze an asymmetric allylboration of these substrates with 2-allyl-1,3,2-dioxaborolane under optimized conditions (Figure 1c). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] The choice to use a fivemembered cyclic boronic ester, more stable than an acyclic boronate but more reactive than a six-membered cyclic analog, [START_REF] Brown | A High-Field Variable-Temperature 1 H and 11 B NMR Study of the effects of Solvent and Structure on Reactivity in Allylboration[END_REF] was crucial to produce the expected chiral tertiary homoallylic alcohols in good yields and with excellent enantiomeric ratios. Unfortunately, an experimental limitation was observed with the N-unprotected isatins since these starting materials need an additional reaction time compared to their corresponding N-substituted compounds (6 days instead of 24 h). Due to our interest toward allylboration methodologies 15 and considering the 3-allyl-3-hydroxy-2-oxindole moiety as a privileged scaffold for the synthesis of natural or biologically active products (Figure 1d), 16 we planned to refine the experimental conditions of this organocatalytic method to further increase the scope. Moreover, in light of the stereochemical outcome obtained with cyclic non-activated ketones such as indan-1-one, 8,[START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] we considered that a computational study of this catalytic process was crucial to rationalize the face differentiation of the carbonyl group in the case of isatins. Herein, we report the improvements of BINOL derivatives-catalyzed allylboration of isatins, in particular with N-unprotected substrates. We also show that this catalytic process is effective for the crotylboration reaction with excellent enantiomeric ratios as well as for the asymmetric synthesis of tertiary homopropargylic alcohols through the addition of an ethylene glycol allenylboronate to isatins (Figure 1e). Results of DFT calculations of this allylboration reaction are also described and suggest the formation of a favored transition state, in agreement with the experimentally observed stereoselectivity, resulting from an internal hydrogen bonding involving the ethylene glycol of the chiral mixed boronate ester and the oxygen of the carbonyl group at position 2 of isatin. The role of the alcohol additive (t-BuOH or t-AmOH) on the reaction rate and enantioselectivity was also investigated via kinetic studies and computational calculations.

RESULTS AND DISCUSSION

Experimental studies. In order to find better experimental conditions for the enantioselective allylboration of N-unprotected isatins with 2-allyl-1,3,2-dioxaborolane 1, indoline-2,3-dione 3a was chosen as model substrate (Table 1). Our previous works using (R)-3,3'-Br 2 -BINOL 2a as catalyst (5 mol%) at -10 °C in toluene have shown that the reaction was almost completed after 6 days with an excellent enantiomeric ratio (Entry 1). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] In this context, the goal was to reduce the reaction time while maintaining a high enantioselectivity. Due to the negative impact on the enantiomeric ratio by increasing the temperature (Entry 2), we decided to examine the effect of the solvent. 17 Inspired by Schaus findings, 8 we first tested a mixture of toluene (PhCH 3 ) and ,,-trifluorotoluene (PhCF 3 ), this latter being considered as an environmentally friendly solvent. 18 A 1:2 solvent ratio in favor of PhCF 3 at -10 °C gave a lower enantioselectivity (Entry 3). When PhCF 3 was used as sole solvent at the same temperature, a higher enantiomeric ratio (94.5:5.5 er) was obtained (Entry 4). It is interesting to note that, in both cases, the reaction time is roughly 4 times shorter than employing only toluene as solvent. At this stage, we cannot assign this positive effect to a better solubility of 3a in PhCF 3 [START_REF]Solubility of 3a in PhCF 3 at room temperature was estimated at 0[END_REF] but probably other physical properties of this solvent such as polarity have to be considered. Encouraged by this outcome, we evaluated (R)-3,3'-F 2 -BINOL organocatalyst 2b which was described as efficient as 2a in the asymmetric allylboration reaction of ketones. 10a After 36 h, the use of (R)-2b (5 mol%) led to a lower yield of 4a accompanied by a significant drop in the enantioselectivity (Entry 5). Further optimizations were focused on tuning the reaction temperature as well as the nature of the alcohol additive (Entries 6-8).

Using catalyst 2a, the best conditions were found at room temperature in PhCF 3 by replacing tert-butyl alcohol (t-BuOH) with tert-amyl alcohol (t-AmOH), that has a lower melting point (Entry 7). Thanks to these easy-to-implement modifications, the 3-allyl-3-hydroxyindole 4a

was obtained after purification in 94% yield and 94.5:5.5 er in a shorter reaction time (5 h).

Moreover, a simple recrystallization of 4a using CH 2 Cl 2 allowed to obtain the (S)-enantiomer in a higher optical purity and with a moderate drop in yield (73%, >99:1 er, Entry 7).

Reaction of 3a at a ten times greater scale provided the homoallyl alcohol 4a with similar yield and enantioselectivity demonstrating the good reproducibility of this process (Entry 8).

The enantioselective allylboration starting from 2 mmol of 3a was repeated twice with similar results (Entry 8). Compared to the initial conditions, significant improvements in terms of reaction time and temperature have been brought offering the prospect of a convenient and large-scale access to chiral N-unprotected 3-allyl-3-hydroxyoxindoles. With the aim to define the substrate-scope of this asymmetric organocatalytic methodology, a set of diversely substituted NH isatins 3a-m has been evaluated under these optimized reaction conditions (Table 2). Whatever their electronic nature, the presence of substituents at C5, C6 and/or C7 positions on the aromatic ring was not a barrier to obtain the expected products 4a-l with excellent yields. In some instances, the reaction time was shorter (2 h 30, 4d-e) or longer (12 h, 4f, 4h, 4k) to reach a complete conversion at room temperature. In all cases, high enantioselectivities were obtained which could be sometimes enhanced by a simple recrystallization using CH 2 Cl 2 . As expected, yields and enantiomeric ratios in the same order of magnitude have been achieved for the synthesis of (R)-3-allyl-3-hydroxyoxindoles 4g-l employing the (S)-2a catalyst. The single-crystal X-Ray diffraction of 4h and 4k confirmed their absolute configuration and by inference, those of all of the products of the allylboration. 20 Significant limitations in terms of reaction time and stereoselectivity were observed starting from the C4substituted isatin 3m. The expected product 4m was isolated with a poor yield after 6 days (38%) and in an almost racemic form. This negative impact on the reaction suggests a steric hindrance between the substituent on the aromatic ring and the organocatalyst grafted on the boron atom. This point will be further discussed in the mechanistic study.

Table 2. Asymmetric allylboration of various

In order to demonstrate the synthetic value of chiral N-unprotected 3-allyl-3hydroxyindolin-2-ones, selective O-and N-functionalizations of compound 4a have been carried out (Scheme 1). N-acetylation was performed using acetic anhydride and Et 3 N at 40 °C for 18 h using an oil bath. The formation of the desired product 5 was accompanied by the presence of another compound 6 in a respective ratio 7:3, resulting from a subsequent Oacetylation of the tertiary hydroxyl group. Nevertheless, the N-acetyl-3-allyl-3hydroxyindolin-2-one 5 was isolated with a good yield (55%) and a high enantioselectivity (95.5:4.5 er). Recrystallization from CH 2 Cl 2 allowed to obtain single crystals of 5 which were subjected to X-ray diffraction. 21 This strategy in two steps thus permitted to circumvent the drawback associated to the low enantioselectivity of the direct asymmetric allylboration of Nacetyl isatin (57.5:42.5 er). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] Copper-mediated coupling methods were used to prepare the Naryl oxindoles 7 and 8. 22 Treatment of 4a with phenyl boronic acid and cupric acetate in the presence of triethylamine afforded the N-phenyl compound 7 in 49% yield. [START_REF]Direct allylboration of N-phenyl isatin lead to compound 7 with a lower enantioselectivity[END_REF] For the introduction of the p-methoxyphenyl (PMP) protecting group, an Ullmann-type reaction was chosen.

Scheme 1. Chemoselective O-and N-functionalization of (S)-3-allyl-3hydroxyindolin-2-one 4a and ORTEP diagram of compound 5

The coupling of 4-iodoanisole with 4a using a copper iodide/N,N'-dimethylbenzene-1,2diamine system provided the compound 8 in a good yield (83%). At last, silylation of 4a with the tert-butyldimethysilyl trifluoromethanesulfonate reagent (TBSOTf) at room temperature followed by an acid work-up led to the selective formation of the TBS ether 9 in a good yield and a high enantioselectivity.

For the purpose of determining if the positive effect of solvent, PhCF 3, on the reaction time can be extended to N-protected isatins, some modifications (solvent, temperature, additive alcohol) of our previously described procedure related to the asymmetric allylboration of 1-benzylindoline-2,3-dione 10a (X = H, Entry 1, Table 3) have been made. [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] The replacement of toluene by PhCF 3 led to a shorter reaction time for the formation of 11a at -10 °C (12 h instead of 24 h) with a slight decrease of the enantioselectivity (Entry 2).

Unfortunately, this drop was significantly enhanced when the reaction was performed at room temperature rendering the use of PhCF 3 as solvent for the N-substituted substrates less interesting (Entries 3-4). The use of t-AmOH as additive in toluene at -10 °C did not bring any improvement compared to t-BuOH in terms of reaction time and enantioselectivity (Entry 5 compared to Entry 1). In the case of hexafluoroisopropanol (HFIP) at the same temperature (-10 °C), the complete conversion was much faster but 11a was obtained in racemic form (Entry 6). This result can be explained by the high propensity of HFIP to form hydrogen bond (H-bond) clusters 24 and the mechanistic aspects derived from this experimental observation shall be discussed in the following section. Subsequently, we examined if the presence of a substituent at C4 position on the aromatic ring could also be problematic for N-protected substrates (Entries 7-9, Table 3) as it was for NH isatins (4m, Table 2). Therefore, halogen-substituted compounds 10b-d have been screened. In all cases, a very low conversion was observed compared to the unsubstituted compound 10a. However, a slight difference can be noted between 10d and 10b-c since after 24 h at -10 °C, a lower conversion was observed (around 9%). Three days have been necessary to isolate 11d in 30% yield (Entry 9). This difference in reactivity could be ascribed to the increased radius of halogen atoms then highlighting the argument of steric hindrance. This decrease reaction rate was also accompanied by a drastic drop of the enantioselectivity whatever halogen atom in C4 substituted isatins.

Mechanistic studies.

With the aim of identifying the most probable activation mode involved in this enantioselective allylboration reaction catalyzed by (R)-3,3'-Br 2 -BINOL 2a (Table 3, Entry 1), several possible activation modes were considered in our DFT calculations (Figure 2). The first activation mode with (R)-2a, taken into account in this article, was based on the mechanism previously proposed by S. C. Pellegrinet and J. M. Goodman (Figure 2, pathway 2) 9c and applied to allenylboronates [START_REF] Grayson | Acid Catalysis and Ligand Exchange in the Asymmetric Binaphthol-Catalyzed Propargylation of Ketones[END_REF] or trifluoromethyl allylboronic acids [START_REF] Jonker | Organocatalytic Synthesis of α-Trifluoromethyl Allylboronic Acids by Enantioselective 1,2-Borotropic Migration[END_REF] or with crotylboronates. [START_REF] Huang | Mechanism and Stereoselectivity of the BINOL-Catalyzed Allylboration of Skatoles[END_REF] These DFT studies suggested that a macrocyclic allylboronate was formed in situ. The authors proposed that this cyclic boronate could be responsible for the enantioselectivity of the reaction despite its higher free energy. [START_REF] Grayson | Acid Catalysis and Ligand Exchange in the Asymmetric Binaphthol-Catalyzed Propargylation of Ketones[END_REF] Then, we considered the possible activation of the allyboronate and/or isatin by the formation of H-bonds with (R)-2a

(Figure 2, pathway 3). Indeed, Grayson et al. have already proposed an activation of oxygen atoms of the boronate (in green, pathway 3, Figure 2). 6g Simultaneously, the reactive carbonyl group of 10 would be further stimulated through a second H-bond with the amide carbonyl group of isatin (in red, pathway 3, Figure 2). Finally, a modified version of the mechanism proposed by Schaus involving the mono-transesterification of the allylboronate 9a,b by chiral BINOL 2a was next studied (Figure 2, pathway 4). Based on NMR data that proved the formation of the mono-transesterification product from diisopropyl allylboronate, these authors proposed a transition state involving an intramolecular H-bond between the catalyst and the alkoxy ligand with opposite facial selectivity compared to isatin. In the present case, additional H-bonds with the amide carbonyl group will be studied (in red, pathway 4, Figure 2). As we used 2-allyl-1,3,2-dioxaborolane 1, we speculated about the presence of an additional intramolecular H-bond which could favor the Re facial attack on the carbonyl group of isatin 10 (in red, pathway 4, Figure 2). Considering pathways 4 and 2 that require prior formation of the allylboronates 12 and 13 resulting from the mono or double transesterification of allylboronate 1, it was decided to calculate by DFT these intermediates and to compare their relative stability to the starting materials (Figure 3). The role played by the additive (t-BuOH) in these reactions was also one of the main objectives of the present study. Therefore, the intermediates 14, 15 resulting from the possible transesterification with the additive (t-BuOH) were also studied (Figure 3). The DFT calculations were performed at the M06-2X/6-311+G (d,p) [START_REF] Zhao | The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals[END_REF] using the SMD [START_REF] Marenich | Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions[END_REF] model for the description of the solvent (toluene) at 298 K and atmospheric pressure. ΔΔE describes the electronic energy compared to the starting materials. ΔΔH 298 and ΔΔG 298 are respectively the relative enthalpies and Gibbs free energies at 298K compared to the starting materials. If the transesterification of the boronate 1 by BINOL 2a or even tert-butanol leads to the electronic stabilization of the products formed (12, 14 and 15), the corresponding free Gibbs energies are higher than the starting materials. Among those species, 12 is the most stable, but the Gibbs free energy is sufficiently high to prevent its identification by NMR from the reaction mixture. [START_REF]The 1 H NMR reaction monitoring of 1 with (R)-3,3'-Br 2 -BINOL 2a at -78 °C did[END_REF] Interestingly, the cyclic boronate 13 appears significantly less stable than the starting boronate 1, both electronic and Gibbs free energies suggesting that this mechanistic pathway 2 should be disfavored in the present case with allylboronate 1 9c even if the Lewis acidity of the boron atom should be enhanced as proposed by Grayson and Goodman. [START_REF] Grayson | Acid Catalysis and Ligand Exchange in the Asymmetric Binaphthol-Catalyzed Propargylation of Ketones[END_REF] Indeed, while the torsion angle between the aromatic rings in 2a from a crystal structures 31 can be measured to 87.7°, the same dihedral angle is constrained to 50.7° in the calculated structure of 13. This cycle strain contributes largely to the lower stability of 13 (+ ethylene glycol) compared to 12.

At this stage the possible transition states corresponding to each pathway involved in the allylboration reaction were calculated (Figure 2). The N-Me derivative of isatin 10e was considered as a good model to limit the computation cost compared to the benzyl derivative 10a (similar yield and enantioselectivity). Being by far the most stable reaction course, 32 only the chair-like transition states were calculated and are presented (Figures 4-8). Interestingly, the uncatalyzed reaction (TS-A)

presents an energy gap similar to that of TS-B considering the enthalpy and even greater considering the free energy, even for the most favored approach from the Si face of isatin (TS-B-Si) (Figure 4). It should also be noted that this transition state leads to a selectivity opposite to the experimentally observed one. Hence, in the current case, contrary to the previous DFT calculations, 9c,25-27 a mechanism involving a cyclic boronate like 13 is most likely not involved in the present reaction with the allylboronate 1 due to the enhanced reactivity of the carbonyl group of isatin compared to alkyl and aryl ketones. The next possible mode of activation of the boronate (pathway 3) proceeds via the formation of H-bonds. The four most stable TS-C were calculated (Figures 5 and6), and the most stable transition state found corresponds to an approach from the Si face of isatin to form the experimentally unfavored (R) product. These transition states corresponding to the two approaches on isatin (face Re and Si) reveal low energy gaps and subsequently weak expected selectivities. These reactions are almost certainly responsible of the background reaction lowering the selectivity at higher temperature and in the absence of t-BuOH. In these transition states, 2a forms H-bonds with both reagents to enhance the reactivity (Figure 6). One of the hydroxy groups of 2a is linked to the oxygen atom of amide, and the other hydroxyl group plays a role in the activation of the boron atom via the formation of a H-bond with one of the oxygen atoms of the boronate. Interestingly, TS-C-Si1 displays the lowest free energy and contribute evidently to the background reaction that reduces the selectivity of the reaction. Nevertheless, it should be considered that DFT calculations fail to calculate accurately the real entropic contribution in a reaction mixture that contains 5 eq of t-

BuOH due to the numerous states generated. In addition, the presence of t-BuOH will strongly contribute to disturb the hydrogen bonds involved in TS-C transition states providing a first explanation of the role played by t-BuOH as additive. The stabilization of the partial charges in the transition states by the formation of Hbonds with BINOL 2a, and hence the catalytic effect associated are consistent with the increase in the kinetic of the reaction described previously in the presence of HFIP (Table 3, Entry 6). These polar solvents contribute to even stabilize the transition state in the background reaction explaining the complete drop of selectivity observed in the presence of HFIP.

TS-C-

We tried to evaluate the role played by the H-bonds in the energy of these calculated transition states. Emamian and Lu proposed a correlation between the H-bond energy and the electron density at the critical point (r) for neutral complexes. [START_REF] Emamian | Exploring Nature and Predicting Strength of Hydrogen Bonds: A Correlation Analysis Between Atoms-in-Molecules Descriptors, Binding Energies, and Energy Components of Symmetry-Adapted Perturbation Theory[END_REF] A single point calculation of the TSs was performed at the B3LYP-D3(BJ)/ma-TZVPP level as described by Emamian et al. The electron density was calculated using MultiWfn [START_REF] Lu | A Multifunctional Wavefunction Analyzer[END_REF] and the equation applied to neutral complexes (bond energy in kcal/mol = -223.08*+0.7423) was applied. Then, the energies of the two H-bonds were converted to kJ/mol and the sums are collected in Table 4. These results highlight the fact that other interactions play a crucial role in the relative energy of these transition states. The TS-D transition states were then calculated at the same level and the two most stable transition states corresponding to each approach could be calculated (Figure 7, pathway 4); two leading to the S and two to the R product, from the approaches of the allyl group on the Re and Si face of the isatin, respectively. In the most favored transition state TS-D-Re1, two H-bonds are formed (Figure 8), one between the ethylene glycol and the oxygen atom of the amide C=O group of isatin, which plays a key role in the creation of the oxygen-boron bond prior to the transition state. A second H-bond exists between the residual OH of BINOL 2a and one of the oxygens of the boronate. Owing to its energy gap compared with the three other transition states, this approach is most likely responsible for the observed selectivity. In order to identify the non-covalent interactions (NCI) occurring in TS-D-Re1, an NCI plot using Multiwfn 34 was performed (Figure 9). This representation confirms the presence of two H-bonds in this transition state. It also displays a large surface of noncovalent interactions existing between one of the naphthol moiety and isatin due to π-π interactions. Considering the importance of these interactions in the present case, this is mandatory to model the reaction with a full BINOL molecule in order to avoid to set aside some critical interactions. As previously described, the contribution of H-bonds in these transition states was calculated and contrary to TS-Cs, the stabilization of the TSs by the H-bonds follows approximately the same trend as the relative energies of the TSs (Table 5 and Figure 8). That

illustrates the important role played by the ability to create intramolecular H-bonds in these transition states. It should also be noted that the poor reactivity and selectivity observed with 10b-d (Table 3, Entries 7-9) can easily be explained by the structure of all these calculated transition states TS-B and TS-D. Indeed, in all these structures, the atom in 4 position of the indoline-2,3-dione is pointing toward one of the oxygen atoms of the boronate. Hence, changing the hydrogen by a halogen creates an important steric bulk that contributes to dramatically decrease the reactivity of the corresponding isatin.

Kinetics study. In order to better understand the key role played by the alcohol additive, a kinetics study of the reaction of N-methyl isatin 10e with 1.5 equivalent of allylboronate 1 was performed at 25 °C in toluene (Scheme 2). ). With 1 equivalent of t-BuOH, the reaction was 1.6 times faster than without t-BuOH. The rate steadily increased with the tertiary alcohol quantity, the initial rate V 0 in the presence of 5 equiv. t-BuOH being 2.2 times higher than the one without. The alcohol additive had also an effect on the enantiomeric ratio of 11e: an important improvement was observed as soon as one equivalent was added but was nearly not dependent on the quantity of t-BuOH (er from 83:17 for 1 and 2 equiv. to 86:14 for 3 to 5 equiv., Figure 10A). The additive t-BuOH favored only the rate of the catalyzed reaction, since the initial rate of the uncatalyzed reaction with 5 equivalents of added t-BuOH (V 0 = 0.9 10 -4 mol L -1 min -1 ) was identical to that of the uncatalyzed one without t-BuOH. The reaction in the presence of 5 equiv. t-BuOH and 10 mol% catalyst was monitored at 25 °C until conversion of 10e reached 65% by recording absorbance (A) at 428 nm as a function of time (t). Fitting of the data according to equation 1 (Eq. 1) [START_REF] Laidler | Chemical Kinetics[END_REF] proved a second order mechanism (Figure 10B), with an apparent rate constant k app = 0.12 mol -1 L min -1 (25 °C, 10 mol% (R)-2a, 5 eq t-BuOH, toluene).

(Eq. 1)

This result is consistent with the hypothesis that the formation of the carbon-carbon bond between 10e and 1 is the rate-limiting step in all mechanisms or catalytic cycles involved in these reaction conditions.

The effect of the catalyst on initial rate V 0 was also measured in the presence of 5 equivalent of t-BuOH (Figure 10C). At 25 °C, the uncatalyzed reaction was 10.5 times slower than the reaction in the presence of 10 mol% of (R)-2a. Data treatment furnished a first order of the reaction related to the catalyst (see supporting information). If we assume that the catalyzed reaction only gives enantiopure product (S)-11e and is 10.5 times faster than the uncatalyzed reaction at 25 °C, then the proportion of enantiopure (S)-11e and racemic 11e formed under kinetic control would be 91. 3:8.7 (95.6:4.4 er). We can conclude that in the studied catalytic conditions at 25 °C (86:14 er), the minor enantiomer is also produced by the catalyzed reaction. So, it is mandatory to work at lower temperature in order to obtain 11e in higher er. [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] The influence of added hexafluoropropanol (5 equiv.) on the initial rate of the reaction in the presence of 10 mol% (R)-2a was also measured and was 1.2 times higher than the one observed with added t-BuOH (5 equiv.). As already observed (entries 6 and 1, Table 3) this faster reaction unfortunately led to a quasi-racemic mixture of 11e (53.3:46.7 er).

Role of the alcohol additive. Tert-butanol is assumed to play a key role in the turn-over of the catalyst by favoring the transesterification of the allylboronate 1 by (R)-3,3'-Br 2 -BINOL 2a. Indeed, the mechanism proposed previously (pathway 4) requires, in the first instance, the mono-transesterification of the cyclic boronate by BINOL 2a to furnish 12 that reacts more rapidly to form the expected allylation product 19 (Scheme 3). Then, 2-alkoxy-1,3,2dioxaborolane 17 has to be formed to release BINOL catalyst 2a that will continue to promote the allylation reaction.

Scheme 3. Catalytic cycle according to pathway 4

However, these reactions are not as fast as expected due to the required prototropy in these steps. It is often assumed in organic chemistry that steps involving prototropy occur easily and quickly. Nevertheless, in the absence of additive, the prototropy has to proceed via a 4-membered ring transition state (TS--4, Figures 11a and12). This type of transition state is located quite high compared to the energy of the starting materials and the energy gap (ΔH 298 ) to overcome is significant (102.9 kJ/mol) compared to that of the allyboration step (Figure 11a). TS-4 (Figure 12) corresponds exactly to the transfer of the hydrogen from one of the hydroxyl groups of 2a to one of the oxygens of the boronate. The IRC calculations then highlight that the formation and cleavage of the B-O bonds occur along the path without any additional transition state. 12' correspond to the conformations of 12 obtained from the IRC calculations. b) 6-Membered ring mechanism assisted by the additive. 12" correspond to the conformations of 12 obtained from the IRC calculations.

The presence of a few equivalents of a protic solvent such as t-BuOH promotes the prototropic step to proceed via a six-membered ring transition state (TS--6, Figures 11b and12). Obviously, this role can also be played by catalyst 2a or 12, but considering the small amounts of these compounds in solutions, the kinetic of the catalytic cycle is significantly hampered in the absence of t-BuOH. In the presence of t-BuOH, the transesterification of the allylboronate proceeds via a two steps mechanism and via an intermediate revealing a tetrahedral boron atom (Figure 11b). The first step (TS--6-1, Figure 12) corresponds to the attack of the oxygen of BINOL on the boron atom with simultaneous transfer of the OH hydrogen from BINOL to the oxygen of t-BuOH, and the transfer of the tert-butanol hydrogen 6-Membered ring mechanism assisted by the additive. 17" correspond to the conformations of 17 obtained from the IRC calculations.

Then, as previously, the 6-membered ring mechanism involving the presence of tertbutanol proceeds with a significantly lower energy barrier (24.8 kJ/mol, Figure 13b). The presence of tert-butanol facilitates greatly the transfer of the hydrogen from the CH 2 OH to the BINOL 2a (TS--6, Figure 14). In this case, the sequence proceeds with only one located transition state [TS--6] and one intermediate 23 with a tetrahedral boron atom. The first transition state corresponding to the cyclization of the boronate stands too low to be located.

Interestingly, in TS--6 (Figure 14), the hydrogen from the boronate is already transferred to that chiral (R)-3,3'-Br 2 -BINOL 2a can be a suitable organocatalyst for the enantioselective crotylboration of isatins, we selected the Z-2-(but-2-en-1-yl)-1,3,2-dioxoborolane 24 as reference reagent to evaluate this reaction (Table 6). We first examined the addition of 24 to N-benzyl isatin 10a in the absence of chiral catalyst in order to evaluate the reaction time and determine the diastereoselectivity. A complete conversion of 10a into the expected -adducts 25 was observed at room temperature in toluene after 24 h. No -adducts resulting from a 1,3borotropic shift was detected in the crude reaction mixture. [START_REF]-adducts are mainly formed using crotylboronates as reagents when the reaction is performed in the presence of transition metal-based Lewis acids[END_REF] 25 was isolated in 95% yield with a corresponding diastereomeric ratio of 81:19 (Entry 1). As expected due to the isomeric purity of crotyl boron reagent 24 (≥ 95% (Z), see Supporting information), the relative configuration of the predominantly diastereomer formed was confirmed to be the syn isomer by a single crystal X-Ray analysis of 25 (see supporting information). 37 When the catalyzed reaction was performed at -10 °C in the presence of (R)-2a (5 mol%) and tert-butanol additive (5 equiv), the diastereoselectivity was improved and 25 was isolated in 92% yield and 97.5:2.5 er (Entry 2). An increased loading of catalyst to 10 mol% led to a better enantioselectivity (Entry 3).

(>98) g

a Reactions were performed with isatin 10a, 10e or 3a (0.2 mmol), boronate 23 (1.5 equiv), solvent (1 mL) under Ar. b Isolated yield after chromatography purification on silica. c Ratio syn/anti was determined by 1 H NMR of the crude product. d Determined by HPLC analysis using a chiral column. e Reaction was performed at room temperature. f Reaction was performed at 50 °C using an oil bath for 36 h. g Obtained after a single recrystallization using CH 2 Cl 2 .

These optimized conditions were applied to N-methyl isatin 10e to furnish solely the addition product with an excellent diastereoselectivity (94:6 dr) in favor of syn isomer 26 and a high enantioselectivity (98:2 er) (Entry 4). As expected, the uncatalyzed crotylboration of N-unprotected isatin 3a was more sluggish (Entry 5 relative to Entry 1). The completion of the reaction required to heat at 50 °C in toluene for 36 h compared to 24 h at room temperature for 10a. In contrast, a higher level of diastereoselectivity was determined by 1 H NMR analysis and compound 27 was isolated in 80% yield (Entry 5). Using previously optimized conditions for the catalyzed allylboration of NH isatins (t-AmOH, PhCF 3 , Table 2), the crotylboration of 3a at -10 °C proved to be much slower than anticipated since the reaction was incomplete after 6 days. Fortunately, by working at room temperature, the reaction time was greatly reduced (24 h) and compound 27 was isolated in 82% yield with a good diastereoselectivity and high enantioselectivity (Entry 6). A simple recrystallization in CH 2 Cl 2 allowed to enhance significantly stereoselectivity (97:3 dr, >99:1 er) with a relatively limited impact on the yield.

Eventually, as an obvious extension of asymmetric allylboration of isatins, we studied the reactivity of allenylboronate reagent 28 in our organocatalytic method in view of the importance of homopropargylic alcohols in synthesis (Table 7). [START_REF] For | Catalytic Asymmetric Propargylation[END_REF] To the best of our knowledge, only one example of asymmetric propargylation of isatins using allenylboronates was reported in the literature to date. 39 This metal-mediated method needed copper as a Lewis acid catalyst and chiral ligands to afford the corresponding homopropargylic alcohols with excellent yields but moderate to good enantioselectivity (er up to 88:12). Based on the reactivity of allenylboronates towards ketones, 11 our study began with the addition of 28 to isatin 10a in toluene at 50 °C in the absence of catalyst. Under these conditions, the conversion was completed after 24 h and compound 29 was isolated in 90% yield (Entry 1).

No formation of the allenyl alcohol 30 was detected by 1 H NMR analysis of the crude reaction mixture. 40 In the presence of catalyst (R)-2a (10 mol%) at the same temperature ( 50°C), the reaction time was significantly reduced (1 h instead of 24 h) giving the homopropargyl alcohol 29 in 92% yield and 94:6 er (Entry 2). The (S) absolute configuration of the new stereocenter created was ascertained by the single crystal X-Ray diffraction analysis of 29. 41 The use of an alcohol additive such as t-BuOH (2 equiv) in the procedure had a negative impact on reaction time, selectivity (propargylation vs allenylation) and enantioselectivity (Entry 3). This outcome can be explained by the fact that the origins of stereoselectivities for the addition of allenyl-and allylboronates to carbonyl compounds could be different due to a different transition state involved in this specific case. Finally, the best results were obtained working at room temperature (Entry 4). Despite a longer reaction time, the reaction occurred with a complete selectivity in favor of propargylation adduct providing 29 with an excellent yield and in high enantiomeric ratio (95.5:4.5). Concerning propargylation of the N-unprotected isatin 3a, the reaction in the absence of catalyst is drastically much slower than could have been expected if we compare with the corresponding N-substituted substrate 10a (Entries 1 and 5). After 7 days at 50 °C in toluene, the conversion of the reaction into the expected product 31 was only 25%. In view of this result, the catalytic enantioselective allylboration was performed at the same temperature. Under these conditions, the reaction was completed after 24 h and 31 was isolated in 96% yield (Entry 6).

Unfortunately, the enantiomeric ratio obtained was modest. In this case, the drop of enantioselectivity cannot be attributed to a negative effect of the temperature (if we compare with entries 2-4) since when the reaction was performed at room temperature, in spite of a low conversion after 7 days, a similar enantiomeric ratio was obtained (75:25) (Entry 7). An additional study for the propargylation of N-unprotected isatins should be necessary to improve these results. a All reactions were performed with isatin 10a (0.2 mmol), allenylboronate 28 (1.5 equiv), 1 mL solvent under Ar at the indicated temperature and reaction time. b Reactions at 50 °C were performed using an oil bath c Isolated yield after chromatographic purification on silica. d Determined by HPLC analysis using a chiral column.

CONCLUSIONS

We have developed an efficient protocol at room temperature for BINOL derivativescatalyzed allylboration of N-unprotected isatins, subsequently enhancing the scope of the reaction. This approach also opens the way towards N-substituted-3-allyl-3-hydroxyindolin-2ones which cannot be prepared with a high enantioselectivity by direct allylboration of the corresponding N-protected isatins such as N-acetyl substrates. The reaction catalyzed by (R)-3,3'-Br 2 -BINOL 2a follows a specific stereochemical course induced by the presence of the amide function. A complete DFT study of the possible mechanisms involved in these reactions proved the crucial role played by the H-bonds and the π-π interactions existing between the substrate and the catalyst. Kinetics experiments confirmed the key role played by tert-butanol as additive. Then, the DFT study explained how it increases the catalyst turn-over by enhancing prototropy in the transesterification steps of the catalytic cycle. This activation reduces significantly the energy barrier for the formation of the reactive species 12 and facilitates even more the release of the catalyst. This organocatalytic process can also be extended to other 1,3,2-dioxabolorane reagents such as crotylboronates and allenylboronates with high stereoselectivities. Based on this mechanistic study, we speculate that other substrates such as acyclic -ketoamides and esters could be used efficiently with this methodology. The work is underway in our laboratory.

EXPERIMENTAL SECTION

General Information and Materials. Toluene was distilled over sodium and tert-butyl alcohol (t-BuOH), tert-amylalcohol (t-AmOH) were distilled over CaH 2. Molecular sieve was activated by flame heating under Ar and vacuum. All other solvents and commercially available chemicals were used without further purification. TLC analyses were performed using precoated Merck TLC Silica Gel 60 F254 plates. Column chromatography purifications were performed over silica gel (Merck Geduran 60, 0.063-0.200 mm). Flash chromatography purifications were performed on a Grace Reveleris with packed columns (40 μm granulometry).

NMR spectra were recorded at 300 or 400 MHz for 1 H, 75 or 101 MHz for [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] C, 282 or 471 MHz for [START_REF]Solubility of 3a in PhCF 3 at room temperature was estimated at 0[END_REF] F. Data are represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad singlet), coupling constant J (Hz) and integration. High-resolution mass spectra (HRMS) were recorded on a Micro-Tof-Q II or on a Q-Tof 2 using positive ion electrospray. X-ray crystallographic data were collected on a D8 VENTURE Bruker AXS diffractometer. Infrared spectra were recorded on a FT-IR spectrometer equipped with a diamond detection and an ATR unit or a single reflection ATR module; wavenumbers are given in cm -1 . Optical rotations were measured using 10-cm cell at 22 °C (sodium D-line: 589 nm), and the concentration is expressed in g/dL. UV-visible spectra were recorded on a JASCO-V570 spectrometer. Melting points were measured without correction on a digital melting point apparatus. All analytical high-performance liquid chromatography (HPLC) were performed, using Daicel Chiralpak IA, IB and IC columns. Isatins 3 and chiral catalysts 2 are commercially available compounds. Isatins 3 were purified before reaction. The known isatins 10a, 42 10b, 43 10c, 43 10d 44 and 10e [START_REF] Ošeka | Asymmetric Organocatalytic Wittig [2,3]-Rearrangement of Oxindoles[END_REF] were prepared according to literature procedures. The known boron reagents, crotylboronate 24 46 and 2-(Propa-1,2-dien-1-yl)-1,3,2dioxaborolane 28 11 were prepared according to modified literature procedure (see supporting information).

General procedure for the synthesis of homoallylic alcohols 4. To a dried 20 mL Schlenk flushed with Ar, were successively added activated 5 Å molecular sieve (100 mg), isatin 3 (0.2 mmol), ,,-trifluorotoluene (0.7 mL), catalyst (R) or (S)-2a (4.5 mg, 0.01 mmol, 0.05 equiv), t-AmOH (110 µL, 5 equiv) and allylboronate 1 (1 M solution in trifluorotoluene, 0.3 mL, 0.3 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature until discoloration, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the corresponding enantioenriched 3-allyl-3-hydroxy-2-oxindole

4.

(S)-3-Allyl-3-hydroxyindolin-2-one (4a). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] Prepared from isatin 3a and using (R)-2a catalyst (5 h).

Purified using a CH 2 Cl 2 /acetone mixture (90/10, R f 0.15) as eluent. The product was isolated as a white solid (33 mg) in 94% yield. After recrystallization from CH 2 Cl 2 , yield was 73% ( 26 2.75 (dd, J = 13.4, 6.4 Hz, 1H), 2.62 (dd, J = 13.4, 8.3 Hz, 1H). The reaction was also performed starting from 2 mmol of 3a and (R)-2a catalyst (0,1 mmol) to give, after purification, the desired product 4a (374 mg) in 99% yield and with a high enantioselectivity (5:95 er, 90% ee).

(S)- 3-Allyl-6-bromo-3-hydroxyindolin-2-one (4b). [START_REF] Cao | A Highly Enantioselective Hg(II)-Catalyzed Sakurai-Hosomi Reaction of Isatins with Allyltrimethylsilanes[END_REF] Prepared from isatin 3b and using (R)-2a catalyst ( 5h). Purified using a CH 2 Cl 2 /acetone mixture (90/10, R f 0.20) as eluent. The product was isolated as a white solid (47 mg) 4, 136.4, 131.9, 131.4 (q, J = 31.9 Hz), 125.8, 125.1 (q, J = 271.3 Hz), 119.8, 119.6 (q, J = 4.3 Hz), 106.9 (q, J = 3.3 Hz), 76.4, 43.1. [START_REF]Solubility of 3a in PhCF 3 at room temperature was estimated at 0[END_REF] F NMR (282 MHz, Acetone-d 6 ) δ -63.1. IR (cm -1 ) 3325, 3160, 1718, 1673, 1640, 1514, 1465, 1436, 1404, 1362, 1320, 1273, 1255, 1218, 1191, 1159, 1125, 1099, 1058, 999, 973, 925, 879, 838, 830, 784, 767, 728 (S)- 3-Allyl-5-fluoro-3-hydroxyindolin-2-one (4d). [START_REF] Cao | A Highly Enantioselective Hg(II)-Catalyzed Sakurai-Hosomi Reaction of Isatins with Allyltrimethylsilanes[END_REF] Prepared from isatin 3d and using (R)-2a catalyst (2 h 30). Purified using a CH 2 Cl 2 /acetone mixture (90/10, R f 0.15) as eluent. The product was isolated as a white solid (36 mg) in 88% yield. Mp: 134-136 °C. The enantiomeric ratio was determined using a Daicel Chiralpak IA-3, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (S) = 9.90 min. (major), t (R) = 12.62 min. (minor), 93:7 er, 86% ee ([α] D = -10.1 (c 1.55, MeOH)). 1 H NMR (500 MHz, CDCl 3 )  7.81 -7.73 (br s, 1H), 7.12 (dd, J = 7.7, 2.7 Hz, 1H), 6.97 (ddd, J = 8.8, 8.8, 2.6 Hz, 1H), 6.80 (dd, J = 8.5, 4.1 Hz, 1H), 5.69 (dddd, J = 15.6, 11.9, 8.3, 6.5 Hz, 1H), 5.18 -5.11 (m, 2H), 3.05 -3.00 (br s, 1H), 2.72 (ddt, J = 13.5, 6.5, 1.2 Hz, 1H), 2.60 (ddt, J = 13.5, 8.3, 1.0 Hz, 1H). [START_REF]Solubility of 3a in PhCF 3 at room temperature was estimated at 0[END_REF] F NMR (471 MHz, CDCl 3 ) δ -119.41.

(S)- 3-Allyl-3-hydroxy-5-(trifluoromethoxy)indolin-2-one (4e). [START_REF] Hanhan | III)-Catalyzed Enantioselective Allylation of Isatins using Allylsilanes[END_REF] Prepared from isatin 3e and using (R)-2a catalyst (2 h 30). Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.40) as eluent. The product was isolated as a white solid (52 mg) in 95% yield. After recrystallization from CH 2 Cl 2 , yield was 60% (33 mg). Mp: 115-117 °C. Before recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IA-3, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (S) = 7.45 min. (major), t (R) = 10.17 min. (minor), 90.5:9.5 er, 81% ee; After recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IA-3, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (S) = 6.92 min. (major), t (R) = 9.33 min. (minor), >99:1 er, >98% ee ([α] D = -6.0 (c 0.95, MeOH)). 1 H NMR (300 MHz, CD 3 OD/CDCl 3 (1:4))  7.04 (dd, J = 2.4, 1.1 Hz, 1H), 6.92 (ddd, J = 8.5, 2.5, 1.1 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.47 -5.31 (m, 1H), 4.89 -4.80 (m, 2H), 2.53 (dd, J = 13.3, 6.6 Hz, 1H), 2.38 (dd, J = 13.3, 8.2 Hz, 1H). [START_REF]Solubility of 3a in PhCF 3 at room temperature was estimated at 0[END_REF] F NMR (282 MHz, CD 3 OD/CDCl 3 (1:4)) δ -54.95.

(S)- 3-Allyl-5,7-dibromo-3-hydroxyindolin-2-one (4f). [START_REF] Cao | A Hg(ClO 4 ) . 3H 2 O Catalyzed Sakurai-Hosomi Allylation of Isatins and Isatin Ketoimines using Allyltrimethylsilane[END_REF] Prepared from isatin 3f and using (R)-2a catalyst (12 h). Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.65) as eluent. The product was isolated as a white solid (61 mg) in 88% yield. Mp: 122-124 °C. The enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (S) = 9.03 min. (major), t (R) = 11.01 min. (minor), 94.5:5.5 er, 89% ee ([α] D = +15.4 (c 2.6, MeOH)). 1 H NMR (500 MHz, CDCl 3 ) δ 7.60 -7.56 (br s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 5.69 (dddd, J = 16.8, 10.2, 8.4, 6.5 Hz, 1H), 5.23 -5.14 (m, 2H), 2.99 -2.96 (br s, 1H), 2.71 (ddt, J = 13.6, 6.5, 1.4 Hz, 1H), 2.60 (ddt, J = 13.6, 8.4, 0.9 Hz, 1H).

(R) -3-Allyl-3-hydroxyindolin-2-one (4g). 12a Prepared from isatin 3a and using (S)-2a catalyst (5 h).

Purified using a CH 2 Cl 2 /acetone mixture (90/10, R f 0.15) as eluent. The product was isolated as a white solid (34 mg) 9, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, 16999, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 16669, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 16289, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 16039, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 15099, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 14529, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 14039, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 13459, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 13199, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 12819, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 12499, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 11929, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 11599, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 11339, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 10909, 161.8, 143.9, 132.8, 126.0, 124.0, 119.1, 107.1, 97.6, 76.3, 55.6, 43.4. IR (cm -1 ): 3340, 3169, , 1025, 995, 952, 930, 886, 834, 824, 789, 766, , 995, 952, 930, 886, 834, 824, 789, 766, 11.5, 8.4, 6.4 Hz, 1H), 5.18 -5.11 (m, 2H), 2.72 (dd, J = 13.5, 6.4 Hz, 1H), 2.59 (dd, J = 13.5, 8.4 Hz, 1H).

(R) -3-Allyl-3-hydroxy-5-methoxyindolin-2-one (4j). [START_REF] Hanhan | III)-Catalyzed Enantioselective Allylation of Isatins using Allylsilanes[END_REF] Prepared from isatin 3j and using (S)-2a catalyst (5 h). Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.30) as eluent. The product was isolated as a beige

(S)-1-acetyl-3-allyl-3-hydroxyindolin-2-one (5)

. [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] (S)-3-Allyl-3-hydroxyindolin-2-one (4a) (50 mg, 0.26 mmol, 1.0 equiv) was dissolved in DCM (3 mL). Triethylamine (77 µL, 0.56 mmol, 2.1 equiv) was introduced, followed by acetic anhydride (37 µL, 0.40 mmol, 1.5 equiv). The reaction mixture was stirred at 40°C using an oil bath for 39 h, diluted with DCM and washed with water. The combined organic phases were washed with brine, dried over MgSO 4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (100% DCM to 98/2 DCM/Acetone as eluent) to give the (S)-1-acetyl-3allyl-3-hydroxyindolin-2-one (5) (33 mg, 55% yield) as a white solid. R f = 0.70 (DCM/Acetone = 9:1). Mp: 108-110 °C. The enantiomeric ratio was determined using a Daicel Chiralpak IC-

(S)-3-allyl-3-hydroxy-1-(4-methoxyphenyl)indolin-2-one (8).

(S)-3-Allyl-3hydroxyindolin-2-one (4a) (50 mg, 0.26 mmol, 1.0 equiv), 4-iodoanisole (91 mg, 0.39 mmol, 1.5 eq.), copper (I) iodide (25 mg, 0.13 mmol, 0.5 equiv) and potassium carbonate (79 mg, 0.57 mmol, 2.2 equiv) were placed in a two-necked flask equipped with a condenser. After degassing with argon, repeated three times, the mixture was dissolved in degazed dioxane (1.75 mL) and N,N'-dimethylbenzene-1,2-diamine (41 µL, 0.26 mmol, 1.0 equiv).

The reaction mixture was stirred at 110 °C using an oil bath for 17 h, cooled to room temperature, filtered CHCl 3 )). 1 H NMR (300 MHz, CDCl 3 ) δ 7. 45 (dd, J = 7.3, 1.4 Hz, 1H), 7.31 -7.21 (m, 3H), 7.12 (ddd, J = 7.5, 7.3, 1.1 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 6.74 (d, J = 7.5 Hz, 1H), 5.66 (dddd, J = 16.6, 10.1, 8.4, 6.3 Hz, 1H), 5.21 -5.08 (m, 2H), 3.85 (s, 3H), 3.33 -3.24 (br s, 1H), 2.84 (ddt, J = 13.2, 6.3, 1.2 Hz, 1H), 2.73 (dd, J = 13.2, 0.86 (d, J = 6.9 Hz, 0.24H (anti)). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] C { 1 H} NMR (75 MHz, CDCl 3 ) δ 177. 8, 143.4, 137.2, 135.7, 129.8, 128.9, 128.8, 127.8, 127.5, 124.3, 123.1, 119.2, 109.5, 78.0, 47.2, 44.0, 14.4.

(S)-3-((S)-but-3-en-2-yl)- 3-hydroxy-1-methylindolin-2-one (syn-26). [START_REF] Tang | Diastereo-and Enantioselective Synthesis of 3-Allyl-3-hydroxyindoles via Allylation of Isatins[END_REF] Prepared from isatin 10e (-10 °C, 24h). The product was isolated as a white solid (41 mg) in 94% yield (94:6 dr (syn:anti)). R f = 0.50 ). 1 H NMR (300 MHz, CDCl 3 ) δ 7.37 (ddd, J = 7. 3, 1.3, 0.6 Hz, 1H), 7.32 (ddd, J = 7.8, 7.5, 1.3 Hz, 1H), 7.08 (ddd, J = 7.5, 7.3, 1.0 Hz, 1H), 6.80 (ddd, J = 7.8, 1.0, 0.6 Hz, 1H), 6.08 (ddd, J = 17.3, 10.5, 7.2 Hz, 0,06H (anti)), 5.61 (ddd, J = 17.1, 10.1, 9.1 Hz, 0.94H (syn)), 5.18 (ddd, J = 17.1, 1.9, 0.8 Hz, 1H), 5.08 (dd, J = 10.1, 1.9 Hz, 1H), 3.14 (s, 3H), 2.76 (dq, J = 9.1, 6.9 Hz, 1H), 1.02 (d, J = 6.9 Hz, 0.82H (syn)), 0.74 (d, J = 6.7 Hz, 0.18H (anti)). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] C { 1 H} NMR (75 MHz, CDCl 3 ) δ 177. 7, 144.1, 137.2, 129.8, 128.8, 124.3, 123.0, 118.7, 108.3, 78.2, 47.0, 26.1, 14.1. IR (cm -1 ): 3315, 2977, 1692, 1616, 1498, 1468, 1425, 1384, 1357, 1302, 1273, 1260, 1203, 1163, 1122, 1101, 1059, 1022, 995, 967, 945, 933, 864, 838, 760, 709, 693. HRMS (ESI): m/z calcd. for C 13 H 15 NO 2 Na [M+Na] + 240.0995; found 240.0996.

(
(S)-3((S)-but-3-en-2-yl)- 3-hydroxyindolin-2-one (syn-27). [START_REF] Higushi | Claisen Rearrangement through Enolization of 2-Allyloxyindolin-3-ones: Construction of Adjacent Carbon Stereocenters in 3-Hydroxyindolin-2-ones[END_REF] Prepared from isatin 3a (50 °C using an oil bath, 36h). The product was isolated as a white solid (33 mg) in 82% yield (82:18 dr (syn:anti)). R f = 0.10 (DCM/Acetone = 9:1). After recrystallization, yield was 61% (25 mg) (97:3 dr (syn:anti)). Mp 155-157 °C.

Before recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IA-3, heptane/i-PrOH = 98/2, 0.8 mL/min, 220 nm, t (syn S,S) = 107.68 min., t (anti R,S) = 124.92 min., t (syn R,R) = 151.65 min., t (anti S,R) = 188.37 min., 96:4 er, 92% ee. After recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak 3 )). 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 7.3 Hz, 1H), 7.27 (ddd, J = 7.8, 7.6, 1.3 Hz, 1H), 7.08 (ddd, J = 7.8, 7.6, 1.1 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.07 (ddd, J = 17.1, 10.4, 7.4 Hz, 0.03H (anti)), 5.73 (ddd, J = 17.1, 10.1, 9.1 Hz, 0.97H (syn)), 5.24 (ddd, J = 17.1, 1.9, 0.8 Hz, 1H), 5.17 (dd, J = 10.1, 1.9 Hz, 1H), 3.00-2.84 (br s, 1H), 2.74 (dq, J = 9.3, 6.9 Hz, 0.97H), 1.04 (d, J = 6.9 Hz, 2.91H (syn)), 0.87 (d, J = 6.8 Hz, 0.09H (anti)). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] C { 1 H} NMR (75 MHz, CDCl 3 ) δ 179. 7, 141.1, 137.1, 129.8, 129.4, 124.7, 123.3, 119.0, 110.1, 78.5, 47.1, 14.1. General procedure for the asymmetric propargylation. To a dried 5 mL tube flushed with Ar, were successively added activated 5 Å molecular sieve (400 mg/mmol), toluene (0.7 mL), catalyst (R)-2a (9.0 mg, 0.02 mmol, 0.1 equiv), and allenylboronate 28 (1 M solution in toluene, 0.3 mL, 0.3 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 15 minutes before addition of 10a or 3a (0.2 mmol, 1 equiv) was added. After complete starting material consumption, the reaction mixture was directly deposed on silica gel and a purification was performed via preparative liquid chromatography (100% DCM to 80% DCM, 20% acetone). The pure fractions were collected and the solvent was evaporated to give the expected enantio-enriched homopropargylic alcohol.

(S)- 1-benzyl-3-hydroxy-3-(prop-2-yn-1-yl)indolin-2-one (29). 39 Prepared from 10a (rt, 18h). The product was isolated as a white solid (52 mg) in 94% yield. R f = 0.65 (DCM/Acetone = 9:1). Mp 132-134 °C.

The enantiomeric ratio was determined using a Daicel Chiralpak IC-5, heptane/i-PrOH = 80:20, 1.0 mL/min, 254 description of toluene as the solvent. Frequency calculations were used to characterize stationary points by the number of negative eigenvalues of their analytic Hessian matrix. The imaginary frequencies were checked to exhibit the expected motion and transition states were verified using IRC calculation.

ASSOCIATED CONTENT

Figure 1 .

 1 Figure 1. Catalysts for the asymmetric allylboration of isatins. a) Catalytic process developed by Hoveyda's group. b) Catalytic process developed by Li's group. c) Our previous work describing BINOL derivatives as catalysts. d) Representative bioactive compounds containing the 3-substituted-3-hydroxyindole core. e) This work: improvement/extension to the methodology using BINOL catalysts and mechanistic study.

  N-unprotected isatins 3 and ORTEP diagram of compounds 4h and 4k a a All reactions were performed with 3 (0.2 mmol), boronate 1 (0.3 mmol), catalyst (R)-2a (5 mol%) in PhCF 3 (1 mL) under Ar. Isolated yields are shown. Enantiomeric excess was determined by chiral HPLC. b Catalyst (S)-2a was used. c 2 h 30 instead of 5 h. d 12 h instead of 5 h. e 144 h instead of 5 h. f In brackets, yield and enantiomeric ratio through a single recrystallization process using CH 2 Cl 2 .

Figure 2 .

 2 Figure 2. Different mechanistic pathways.

Figure 3 .

 3 Figure 3. Relative energy compared to the starting materials of the transesterification products in kJ/mol.

  [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] TS-A corresponds to the uncatalyzed allyboration reaction (pathway 1). TS-B involves the cyclic boronate formed by double transesterification with (R)-3,3'-Br 2 -BINOL 2a (pathway 2). TS-C corresponds to the activation of the boronate by the formation of H-bonds with the OH groups of 2a (pathway 3). Finally, TS-D involves the boronate issued from the monoesterification by BINOL 2a (pathway 4).

Figure 4 .

 4 Figure 4. Representation of TS-A and TS-B (pathway 1 and 2).

Figure 5 .

 5 Figure 5. Energy diagram of the allylboration step for pathway 3 in kJ/mol.

Figure 6 .

 6 Figure 6. TS-C transition state structures (kJ/mol).

Figure 7 .Figure 8 .

 78 Figure 7. Energy diagram of the allylboration step for pathway 4 (kJ/mol).

Figure 9 .

 9 Figure 9. NCI plot of TS-D-Re1.

Scheme 2 :

 2 Scheme 2: Reaction studied in the kinetics experiments

Figure 10 .

 10 Figure 10. Initial velocity V 0 () at 25 °C of the reaction between N-methyl isatin 10e and 1.5 equiv. of allylboronate 1 in the presence of different additives and % of the major enantiomer 11e () (A and C). Second order mechanism (B). See data in supporting information.

Figure 11 .

 11 Figure 11. Reaction path for the formation of 12 (TS-). a) 4-Membered ring mechanism.

9 Figure 12 .

 912 Figure12) figures the opening of the cyclic boronate to form 12. In this last transition state, the B-O bond is almost broken displaying a B-O distance of 2.16 Å (Figure12). The calculated energy gap (ΔΔH 298 ) for TS--6-1 appears significantly lower (57.1 kJ/mol) than TS--4 for the 4-membered ring mechanism.

Figure 13 .

 13 Figure 13. Reaction path for the release of the catalyst 2a (TS-). a) 4-Membered ring mechanism 17' correspond to the conformations of 17 obtained from the IRC calculations. b)

Figure 14 .

 14 Figure 14. TS- structures and energy (kJ/mol). a Energy relative to 19. b Energy relative to 19+tert-butanol. Asymmetric crotylboration and propargylation of isatins. With the aim to demonstrate

  mg). Mp 164-166 °C. Before recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (R) = 17.10 min. (minor), t (S) = 18.98 min. (major), 5.5:94.5 er, 89% ee. After recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (R) = 17.11 min. (minor), t (S) = 18.95 min. (major), >1:99 er, >98% ee ([α] D = -55.6 (c 0.45, CHCl 3 )).1 H NMR (400 MHz, CDCl 3 )  8.02 -7.94 (br s, 1H),7.38 (d, J = 7.4 Hz, 1H), 7.31 - 7.22 (m, 1H), 7.08 (dd, J = 7.8, 7.4 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.80 -5.58 (m, 1H), 5.19 -5.08 (m, 2H),

(S)- 3 -

 3 allyl-3-hydroxy-1-phenylindolin-2-one(7).[START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] (S)-3-Allyl-3-hydroxyindolin-2-one (4a) (50 mg, 0.26 mmol, 1.0 equiv) was dissolved in methanol(1.2 mL). Phenylboronic acid (70 mg, 0.58 mmol, 2.2 equiv) was introduced, followed by triethylamine(55 µL, 0.40 mmol, 1.5 equiv) and copper (II) acetate (47 mg, 0.26 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C using an oil bath for 24 h, diluted with DCM and washed with water. The combined organic phases were washed with brine, dried over MgSO 4 , and concentrated in vacuo. The crude product was purified by flash column chromatography (Eluent 100% DCM to 95/5 DCM/Acetone) to afford the (S)-3-allyl-3-hydroxy-1-phenylindolin-2-one (7) (34 mg, 49% yield) as a brown syrup. R f = 0.40 (DCM/Acetone 95/5). The enantiomeric ratio was determined using a Daicel Chiralpak OD-H, hexane/i-PrOH = 95/5, 0.7 mL/min, 254 nm, t (R) = 19.52 min. (minor), t (S) = 24.82 min. (major), 2.5:97.5 er, 95% ee ([α] D 20 = -32.5 (c 1.35, CHCl 3 )). 1 H NMR (300 MHz, CDCl 3 ) δ 7.58 -7.33 (m, 6H), 7.26 (td, J = 7.8, 1.4 Hz, 1H), 7.14 (td, J = 7.5, 1.1 Hz, 1H), 6.80 (dd, J = 7.7, 1.0 Hz, 1H), 5.67 (dddd, J = 16.6, 10.1, 8.4, 6.3 Hz, 1H), 5.22 -5.10 (m, 1H), 3.25 -3.21 (br s, 1H), 2.85 (ddt, J = 13.2, 6.3, 1.2 Hz, 1H), 2.75 (dd, J = 13.2, 8.4 Hz, 1H).

  through a pad of Celite with AcOEt and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (Eluent 100% DCM to 95/5 DCM/Acetone) to give (S)-3-allyl-3-hydroxy-1-(4methoxyphenyl)indolin-2-one (8) (64 mg, 83% yield) as a brown solid. R f = 0.35 (DCM/Acetone = 95:5). Mp: 72-74 °C. The enantiomeric ratio was determined using a Daicel Chiralpak IC, heptane/i-PrOH = 90:10, 1.0 mL/min, 254 nm, t (S) = 21.31 min. (major), t (R) = 27.84 min. (minor), 96.5:3.5 er, 93% ee ([α] D 20 = -34.2 (c 2.95,

  DCM/Acetone = 9:1). Mp 106-108 °C. The enantiomeric ratio was determined using a Daicel Chiralpak IB, heptane/i-PrOH = 98/2, 1.0 mL/min, 254 nm, t (syn R,R) = 81.47 min., t (anti, S,R) = 92.92 min., t (syn S,S) = 121.01 min., t (anti, R,S) = 133.92 min., 2:98 er, 96% ee (

IA- 3 ,

 3 hexane/i-PrOH = 98:2, flow rate = 0.8 mL/min, 220 nm, t (syn S,S) = 107.66 min., t (anti R,S) = 125.40 min., t (syn R,R) = 152.46 min., t (anti S,R) = 190.04 min., >99:1 er, >98% ee([α]

Table 1 . Optimization of the allylboration reaction with N-unprotected isatin 3a

 1

	Entry a	Cat.	additive	Solvent	T (°C)	Time (h) Yield (%) b	ee (%)

  All reactions were performed with isatin 3a (0.2 mmol), boronate 1 (0.3 mmol), solvent (1 mL) under Ar at the indicated temperature and reaction time.b Isolated yield after chromatography purification on silica.c Determined by chiral HPLC. d tert-Amyl alcohol. e Obtained after a single recrystallization using CH 2 Cl 2 . f Starting from 2 mmol of isatin 3a.

	5	2b	t-BuOH	PhCF 3	-10 °C	36	85	62
	6	2a	t-BuOH	PhCF 3	rt	5	97	85
	7	2a	t-AmOH d	PhCF 3	rt	5	94	89
							(73) e	(>98) e
	8 f	2a	t-AmOH d	PhCF 3	rt	5	99 (86) e	90 (>98) e
	a
	1	2a	t-BuOH	PhCH 3	-10 °C	144	87	94
	2	2a	t-BuOH	PhCH 3	rt	22	97	85
	3	2a	t-BuOH	PhCH 3 /PhCF 3	-10 °C	36	93	86
				(1:2)
	4	2a	t-BuOH	PhCF 3	-10 °C	36	95	89

Table 3 . Additional information on the asymmetric allylboration of N-protected isatins 10

 3

	Entry a Product	Solvent	Additive	T (°C)	Time (h) Yield (%) b	ee (%) c
	1	11a	PhCH 3	t-BuOH	-10	24	99	94
	2	11a	PhCF 3	t-BuOH	-10	12	98	90
	3	11a	PhCH 3	t-BuOH	r.t.	16	98	88
	4	11a	PhCF 3	t-BuOH	r.t.	2	96	79
	5	11a	PhCH 3	t-AmOH	-10	24	99	88
	6	11a	PhCH 3	HFIP	-10	3	91	0
	7	11b	PhCH 3	t-BuOH	-10	24	15	5
	8	11c	PhCH 3	t-BuOH	-10	24	18	0
	9	11d	PhCH 3	t-BuOH	-10	72	30	19
	a All reactions were performed with isatin 10 (0.2 mmol), boronate 1 (1.5 equiv), solvent (1 mL) under
	Ar at the indicated temperature and reaction time. b Isolated yield after chromatography purification on
	silica. c Determined by HPLC analysis using a chiral column.

Table 4 . Contribution of H-bonds in TS-C

 4

	Entry	TS	 H-bond stabilization	ΔΔE (kJ/mol)
			energy (kJ/mol)
	1	TS-C-Re1	-48.0	-49.0
	2	TS-C-Re2	-44.5	-29.1
	3	TS-C-Si1	-56.5	-57.2
	4	TS-C-Si2	-65.6	-39.5

Table 5 . Contribution of H-bonds in TS-D.

 5

	Entry	TS	 H-bond stabilization	ΔΔE (kJ/mol)
			energy (kJ/mol)
	1	TS-D-Re1	-43.3	-57.8
	2	TS-D-Re2	-16.4	-38.7
	3	TS-D-Si1	-32.3	-36.8
	4	TS-D-Si2	-18.0	-9.1

Table 6 . Asymmetric crotylboration of isatins

 6

	Entry a	Compound	Cat. (mol%) Additive Solvent Yield (%) b	dr c	ee (%) d
	1 e	10a	-	-	PhCH 3	95	81:19	-
	2	10a	(R)-2a (5)	t-BuOH	PhCH 3	92	91:9	95
	3	10a	(R)-2a (10)	t-BuOH	PhCH 3	95	92:8	98
	4	10e	(R)-2a (10)	t-BuOH	PhCH 3	94	94:6	96
	5 f	3a	-	-	PhCH 3	80	90.5:9.5	-
	6 e	3a	(R)-2a (10)	t-AmOH PhCF 3	82	82:18
						(61) g	(97:3) g

Table 7 . Asymmetric propargylation of isatins and ORTEP diagram of compound 29 Entry

 7

a Compound Catalyst Additive T (°C) b t (h) Yield (%) c Ratio 29/

30 or 31/32

									ee (%) d
	1	10a	-	-	50	24	90	>99:1	-
	2	10a	(R)-2a	-	50	1	92	>99:1	88
	3	10a	(R)-2a	t-BuOH	50	18	90	96:4	80
	4	10a	(R)-2a	-	rt	18	94	>99:1	91
	5	3a	-	-	50	168	19	>99:1	-
	6	3a	(R)-2a	-	50	24	96	>99:1	53
	7	3a	(R)-2a	-	rt	168	11	>99:1	50

  . HRMS (ESI): m/z calcd. for C 12 H 12 NO 2 F 3 Na [M+Na] +

	280.0556; found 280.0559.

  in 97% yield. After recrystallization from CH 2 Cl 2 , yield was 69% (24 mg). Mp 164-166 °C. Before Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.30) as eluent. The product was isolated as a white solid (41 mg) in 93% yield. After recrystallization from CH 2 Cl 2 , yield was 48% (21 mg). Mp 163-165 °C.

	recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH = 90/10,
	flow rate = 1 mL/min, 254 nm, t (R) = 17.22 min. (major), t (S) = 19.10 min. (minor), 92.5:7.5 er, 85% ee; After
	recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IA-3, hexane/i-PrOH = 90/10,
	flow rate = 1 mL/min, 254 nm, t (S) = 10.54 min. (minor), t (R) = 15.39 min. (major), >1:99 er, >98% ee ([α] D = +
	56.0 (c 0.54, CHCl 3 )). 1 H NMR (400 MHz, CDCl 3 )  8.01 -7.94 (br s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.31 -
	7.22 (m, 1H), 7.08 (dd, J = 7.8, 7.4 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.80 -5.58 (m, 1H), 5.19 -5.08 (m, 2H),
	2.75 (dd, J = 13.4, 6.4 Hz, 1H), 2.62 (dd, J = 13.4, 8.3 Hz, 1H).
	Before recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH =
	90/10, flow rate = 1 mL/min, 254 nm, t (R) = 26.57 min. (major), t (S) = 39.29 min. (minor), er 94.5:5.5, ee 89%;
	After recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC-3, hexane/i-PrOH =
	90/10, flow rate = 1 mL/min, 254 nm, t (R) = 37.44 min. (major), t (S) = 53.46 min. (minor), >99:1 er, >98% ee
	([α] D = +10.5 (c 0.90, MeOH)). 1 H NMR (500 MHz, Acetone-d 6 ) δ 9.24 -9.18 (br s, 1H), 7.24 (d, J = 8.2 Hz,
	1H), 6.54 (dd, J = 8.2, 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.58 (dddd, J = 16.9, 10.2, 8.1, 6.5 Hz, 1H), 5.02 -
	4.92 (m, 2H), 4.81 -4.79 (br s, 1H), 3.77 (s, 3H), 2.70 (ddt, J = 13.3, 6.5, 1.5 Hz, 1H), 2.56 (ddt, J = 13.3, 8.1,
	1.1 Hz, 1H).

(R)

-3-Allyl-3-hydroxy-6-methoxyindolin-2-one (4h)

. Prepared from isatin 3h and using (S)-2a catalyst (12 h).

[START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF]

C { 1 H} NMR (126 MHz, Acetone-d 6 ) δ 179.

  719 cm -1 . HRMS (ESI): m/z calcd. for C 12 H 13 NO 3 Na [M+Na] + 242.0788; found 242.0788.

	(R)-3-Allyl-6-chloro-3-hydroxyindolin-2-one (4i). 50 Prepared from isatin 3i and using (S)-2a catalyst (5
	h). Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.45) as eluent. The product was isolated as a white solid
	(40 mg) in 90% yield. Mp 196-198 °C. The enantiomeric ratio was determined using a Daicel Chiralpak IC-5,
	hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (R) = 13.47 min. (major), t (S) = 17.56 min. (minor),
	93.5:6.5 er, 87% ee ([α] D = +1.44 (c 2.0, MeOH)). 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 -7.46 (br s, 1H), 7.29 (d,
	J = 8.0 Hz, 1H), 7.06 (dd, J = 8.0, 1.8 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H), 5.68 (dddd, J = 15.0,

ACKNOWLEDGEMENTS

This work was supported by the University of Rennes 1 and the Centre National de la Recherche Scientifique (CNRS). One of us (J.B.) thanks "Ecole doctorale 3M" and University of Rennes 1 for a research fellowship. The authors would like to thank Marielle Blot for her technical assistance.

Data Availability Statement

The data underlying this study are available in the published article and its supporting information Supporting Information statement. This material is available free of charge via the Internet at http://pubs.acs.org.

 Copies of 1 H, 13 C{ 1 H}, [START_REF]Solubility of 3a in PhCF 3 at room temperature was estimated at 0[END_REF] F NMR spectra of all compounds as well as their corresponding HPLC chromatograms (PDF)

 Crystal data, CCDC 2127790 for 4h, CCDC 2127791 for 4k, CCDC 2127792 for 5, CCDC 2155726 for syn-25 , CCDC 2127789 for 29 (CIF)  DFT calculation data and IR spectra of 10e and 11e, visible spectrum of 10e, table of kinetics data (PDF)

solid (43 mg) in 98% yield. After recrystallization from CH 2 Cl 2 , yield was 51% (22 mg). Mp 162-164 °C.

Before recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (R) = 21.74 min. (major), t (S) = 28.47 min. (minor), 93:7 er, 86% ee. After recrystallization, the enantiomeric ratio was determined using a Daicel Chiralpak IC-3, hexane/i-PrOH = 90:10, flow rate = 1 mL/min, 254 nm, t (R) = 26.96 min. (major), t (S) = 33.78 min. (minor), 94:6 er, 88% ee ([α] D = -17.5 (c 1.10, MeOH)). 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.07 -10.00 (br s, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.76 (dd, J = 8.4, 2.5 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.98 -5.96 (br s, 1H), 5.52 -5.36 (m, 1H), 4.99 -4.88 (m, 2H), 3.70 (s, 3H), 2.59 (dd, J = 13.1, 6.6 Hz, 1H), 2.43 (dd, J = 13.1, 7.9 Hz, 1H).

(R) -3-Allyl-3-hydroxy-5-nitroindolin-2-one (4k). [START_REF] Cao | A Hg(ClO 4 ) . 3H 2 O Catalyzed Sakurai-Hosomi Allylation of Isatins and Isatin Ketoimines using Allyltrimethylsilane[END_REF] Prepared from isatin 3k and using (S)-2a catalyst (12 h). Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.35) as eluent. The product was isolated as a yellow solid (46 mg) in 98% yield. After recrystallization from CH 2 Cl 2 , yield was 60% (28 mg). Mp 114-116 °C. Before recrystallisation, the enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH = 90/10, flow rate = 1 mL/min, 254 nm, t (S) = 14.69 min. (minor), t (R) = 16.93 min. (major), 10.5:89.5 er, 79% ee. After recrystallisation, the enantiomeric ratio was determined using a Daicel Chiralpak IC-5, hexane/i-PrOH = 90:10, flow rate = 1 mL/min, 254 nm, t (S) = 14.38 min. (minor), t (R) = 16.11 min. (major), >1:99 er, >98% ee ([α] D = -65.8 (c 1.00, MeOH)). 1 HNMR (400 MHz, DMSO-d 6 ) δ 11.02 -10.94 (br s, 1H), 8.19 (dd, J = 8.6, 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.36 -6.34 (br s, 1H), 5.54 -5.41 (m, 1H), 5.01 -4.94 (m, 2H), 2.71 (ddt, J = 13.2, 6.5, 1.3 Hz, 1H), 2.53 -2.45 (m, 1H).

(R) -3-Allyl-7-bromo-3-hydroxyindolin-2-one (4l). Prepared from isatin 3l and using (S)-2a catalyst ( 5h). Purified using a CH 2 Cl 2 /acetone mixture (80/20, R f 0.60) as eluent. The product was isolated as a beige solid (53 mg) in 98% yield. After recrystallization from CH 2 Cl 2 , yield was 70% ( 38 2.74 (dd, J = 13.5, 6.4 Hz, 1H), 2.61 (dd, J = 13.5, 8.2 Hz, 1H). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] C { 1 H} NMR (75 MHz, CDCl 3 ) δ 179.0, 139. 8, 132.5, 131.8, 130.0, 124.4, 123.5, 121.1, 103.5, 77.6, 43.0. IR (cm -1 ): 3335, 3240, 1705, 1622, 1472, 1454, 1426, 1331, 1277, 1230, 1210, 1172, 1139, 1122, 1096, 994, 980, 932, 918, 879, 846, 795, 778, 737, 757 (R) -3-Allyl-4-chloro-3-hydroxyindolin-2-one (4m). [START_REF] Hanhan | III)-Catalyzed Enantioselective Allylation of Isatins using Allylsilanes[END_REF] Prepared from isatin 3m and using (S)-2a catalyst ). 1 H NMR (300 MHz, CDCl 3 ): δ 7.56 (ddd, J = 7.3, 1.4, 0.6 Hz, 1H), 7.38 -7.18 (m, 6H), 7.09 (ddd, J = 7.6, 7.3, 1.0 Hz, 1H), 6.73 (ddd, J = 7.9, 1.0, 0.6 Hz, 1H), 5.04 (d, J = 15.7 Hz, 1H), 4.75 (d, J = 15.7 Hz, 1H), 3.42 (s, 1H), 2.99 (dd, J = 16.4, 2.7 Hz, 1H), 2.85 (dd, J = 16.4, 2.7 Hz, 1H), 1.94 (t, J = 2.7 Hz, 1H). [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] C { 1 H} NMR ( 75MHz, CDCl 3 ) δ 176. 9, 142.7, 135.3, 130.2, 129.1, 128.9, 127.9, 127.5, 124.3, 123.4, 109.7, 77.8, 74.6, 71.7, 44.1, 29.0. (S)-3-hydroxy-3-(prop-2-yn-1-yl)indolin-2-one (31). 39 Prepared from 3a (50 °C using an oil bath, 24h).

The product was isolated as a white solid (36 mg) Kinetics experimental section. To a 3 mL test tube under argon and in a thermostat at 25.0 °C, were added molecular sieves (4 Å, 35 mg), anhydrous toluene (v 1 µL), (R)-3,3'-dibromoBINOL (0.0235 mol/L in toluene, v 2 µL), B-allyl-1,3,2-dioxaborolane (1.00 M in toluene, 100 µL, 0.100 mmol, 1.5 eq) and tert-butanol (8.36 mol/L in toluene, v 3 µL). Variable volumes v 1 , v 2 , and v 3 were chosen in order to set a constant total volume (v 1 + v 2 + v 3 = 340 µL). The resulting solution was stirred before N-methyl isatin 10e was added (0.150 mol/L in toluene, 440 µL, 0.066 mmol). The reaction was followed by quenching aliquots (50 µL) in toluene (2.80 mL) every minute. The absorbance of the resulting solution was measured in a 10 mm light path glass cuvette at 428 nm. The initial rate V 0 was then determined by measuring the slope of the N-methylisatin concentration curve versus time, the consumption of N-methylisatin being lower than 10 %. After overnight reaction and purification on a TLC silica plate, the enantiomeric excess of N-methyl 3-allyl-3-hydroxy-2oxindole 11e [START_REF] Braire | BINOL Derivatives-Catalysed Enantioselecive Allylboration of Isatins: Application to the Synthesis of (R)-Chimonamidine[END_REF] was measured by HPLC using a Daicel Chiralpak IC3 column, hexane/i-PrOH = 80/20, flow rate = 1 mL/min, 254 nm, t (R) = 9.10 min., t (S) = 11.52 min (major).

Computational Methods. Considering the numerous possible conformations for TS-C and the numerous possible orientations of the BINOL and the ethylene glycol moieties in TS-D, the most stable transition states were found from a conformational analysis performed with Spartan 10. For TS-Cs, the structure of TS-A was used as the starting geometry and a molecule of 2a was added. The B-O and C-C bonds formed during the reaction were then frozen, and it was submitted to a conformational analysis with MMFF molecular mechanics. For TS-D, a first transition state based on pathway 4 was found and optimized to B3LYP/6-31+G (d) level using Spartan 10. 57 Then, the B-O and C-C bonds formed during the reaction were frozen, and the structure was submitted to a conformational analysis with MMFF molecular mechanics. For both TS-C and TS-D, all the conformers were then optimized under the same constraint to the B3LYP/3-21G level. The two most stable transition states for each approach (Re and Si) were then optimized using Gaussian 16 58 to B3LYP/6-31+G (d) level, then with M062X/6-31+G (d) and finally with M062X/6-311+G (d,p) using the SMD solvent model for the

AUTHOR INFORMATION

Corresponding Author *E-mails: joelle.vidal@univ-rennes1.fr; claudia.lalli@univ-rennes1.fr; arnaud.martel@univlemans.fr; francois.carreaux@univ-rennes1.fr.

Notes

The authors declare no competing financial interest.