Enantioselective Rhodium(III)-Catalyzed Markovnikov Hydroboration of Unactivated Terminal Alkenes

We report the first enantioselective Rh-catalyzed Markovnikov hydroboration of unactivated terminal alkenes. Using a novel sp2–sp3 hybridized diboron reagent and water as a proton source, a broad range of alkenes undergo hydroboration to provide secondary boronic esters with high regio- and enantiocontrol.

S8 Crystallography Figure S1. Structure of 4b with atomic numbering scheme depicted. Anisotropic displacement parameters are depicted at the 50% probability level. Hydrogen atoms and DCM solvent molecule are omitted for clarity.
X-ray diffraction data for 4b were collected at 100(2) K on a Bruker APEX II diffractometer using Mo-Kα radiation (λ = 0.71073 Å). Data collections were performed using a CCD area detector. Intensities were integrated in SAINT 10 and absorption corrections were based on equivalent reflections using SADABS. 11 The structure was solved using olex2.solve 12 and the structure was refined against F 2 in SHELXL 13-14 using Olex2. 12 All of the non-hydrogen atoms were refined anisotropically. While all of the hydrogen atoms were located geometrically and refined using a riding model. The solvent DCM molecule in the lattice displayed disorder, the occupancies of the fragments was determined by refining them against a free variable with the sum of the two sites set to equal 1, the occupancies were then fixed at the refined values, restraints were used to maintain sensible geometries and thermal parameters. Crystal structure and refinement data are given in Table S1. Crystallographic
Phenyl lithium (1.9 M in Bu2O, 10.1 mL, 19.3 mmol, 2.2 eq.) was added dropwise over 2 h at RT. The reaction was stirred for a further 1 h at RT and then quenched by cautious addition of H2O (50 mL). The layers were seperated and the aqueous layer was extracted with Et2O (2 x 50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (0:100 to 10:90 EtOAc:petroleum ether) to provide the title compound as a colourless oil (566 mg, 37%).
Analytical data were consistent with those reported in the literature. 16

N-(But-3-en-1-yl)benzamide (2i)
Amide 2i was synthesised according to the literature procedure. 17 Analytical data were consistent with those reported in the literature. 17
Analytical data were consistent with those reported in the literature. 18 N,N-Diethylhept-6-enamide (2k) S12 Amide 2k was synthesised according to the literature procedure. 19 Analytical data were consistent with those reported in the literature. 19

Phenyl but-3-enoate (2m)
Ester 2m was synthesised according to the literature procedure. 20 Analytical data were consistent with those reported in the literature. 20
[The racemate (±)-2u-ox was obtained using racemic boronic ester (±)-2u in place of boronic ester (−)-2u for analysis by chiral SFC].  An expanded optimization table based on the optimization table presented in the main   manuscript (Table 1) is given below (Table S2). The conversion refers to the amount of starting material consumed in the reaction to furnish either product 3a or the resulting products from the isomerisation or reduction of 2a. We believe that the isomerization and reduction products derive from the presence of a rhodium-hydride species. A catalytic quantity of a rhodiumhydride species is sufficient to provide considerable isomerization via an insertion --hydride  1a 0 0 N/A N/A Reactions conducted with 0.38 mmol 2a. a Conversion determined by GC analysis using biphenyl as an internal standard b Yields determined by GC analysis by using biphenyl as an internal standard; yields of isolated product in parentheses. c The branched/linear ratio (rr) was determined by GC analysis of the crude reaction mixture. d Determined by chiral SFC analysis following oxidation of 3a. e 5 mol% NaOt-Bu was used as an additive; reaction conducted at 60 °C; 5 was isolated in 86% yield, 98:2 er. f Determined by 1 H NMR analysis of the crude reaction mixtures. g Reaction conditions: 5 mol% catalyst 1a, 1.5 eq. boron source 4, 6 eq. proton source, 1 M concentration, 40 °C, 16 h. h 5 was isolated in 6% yield, 81:19 er.

Rf
The GC spectrum obtained from the reaction outlined in Table S2 (entry 17) is shown as representative example ( Figure S2). The side-products resulting from the isomerization and reduction of 2a were assigned by analogy to the corresponding signals observed by GCMS (parent mass ions for each compound were observed by EI). The extent of the isomerization or reduction of 2a could be further investigated by 1 H NMR analysis of the resulting mixture isolated from the reaction by column chromatography. A 1 H Biphenyl (internal standard) 3a (major regioisomer)

3a (minor regioisomer) 2a
Isomers/ reduction of 2a S17 NMR spectrum of a complex mixture of isomers isolated from an archetypal hydroboration reaction is shown ( Figure S3). The key characteristic signals for alkene isomers and the reduction product have been expanded and labelled correspondingly.

Optimization by Design of Experiments (DoE)
The experiment design, data analysis and the generation of a predictive model from the DoE study was assisted by a DoE software package (MODDE® Design of Experiments Solution version 11).
Having determined the most suitable reagents for the hydroboration reaction (see Table 1 in the main manuscript), the reaction was further optimized through a DoE study to ascertain the optimal reaction conditions by developing a predictive model of the reaction yield.
The predictive model was developed through gaining an understanding of the impact on the reaction yield of each of the reaction variables, and the interactions between each of the variables (i.e. the dependency of one factor on another). The study involved the investigation of five factors (variables): concentration, temperature, catalyst loading, and the stoichiometry of water and the mixed diboron species 4b. Each of these factors were set at two levels (high and low), and three centre points were used to provide reproducibility information. A total of S18 factor . The parameters for each of the factors and the results for each of the 19 experiments are   outlined in Table S3. Interestingly, two of the experiments lead to improved yields of 79% and 75% (entries 6 and 8, respectively, Table S3), and high levels of enantioselectivity (90:10 er). However, both of these experiments were conducted using an undesirably high two equivalents of the diboron S19 species 4b. The results of the DoE study were then fitted to generate a predictive model for the reaction yield and enantioselectivity. This model was then manually refined by removing nonsignificant factor and factor interaction terms. This is achieved through analysis of the coefficient plota positive bar represents a positive factor on the response when the factor level is increased (i.e. increasing the catalyst loading has a positive impact on the yield), whilst a negative bar represents the opposite effect ( Figure S4, A). Terms are considered statistically significant (at the 95% confidence level) when the error bar maximum and minimum values are on the same side of the X-axis. The Q2 value is a measure of how precise the predictive capabilities of the model arethe removal of terms was performed in a systematic manner in order to maximise the Q2 value. The R2 value is a measure of how well the experiment data fits the generated model. The reproducibility value is calculated from the variation observed from the three centre point experiment repeats ( Figure S4, B).

S20
From the model it was clear that improved yields and could be achieved when using 5 mol% catalyst and a reaction temperature of 40 °C. The reaction was further optimised through assistance of the DoE model to determine the most suitable loadings for water and 4b, and the reaction concentration. Reaction conditions were chosen for investigation based on high predictive yields generated by the model. Excellent yields of 78%, 76% and 79% were achieved when using 2.0, 2.5 and 3.0 equivalents of diboron compound 4b, respectively (entries 1-3, Table S4). Despite achieving high reaction yields, further optimisation was undertaken with the effort focused towards reducing the equivalents of diboron compound 4b. A comparably high 76% yield was achieved when using 1.5 equivalents of 4b, 6.0 equivalents of water, and a reaction concentration of 1 M (entry 4, Table S4). No further improvement to the reaction yield could be obtained following variation of the equivalents of water used or the reaction concentration (entries 5-8, Table S4). The following reaction conditions were therefore selected as the most appropriate for initially exploring the substrate scope of the hydroboration reaction (see entry 4, Table S4):

Hydroboration Products -Experimental and Characterization
The absolute stereochemical outcome of the hydroboration reaction was found to be the same as Nishiyama's diboration reaction. 24 The absolute stereochemistry for boronic esters 3 was generally determined by comparing their αD values (or in some cases, the αD values obtained for their derivatives) to the literature reported αD values. The absolute stereochemistry was assigned by analogy where literature reported αD values were not available. and water (40.9 μL, 2.27 mmol, 6.0 eq) were added followed by n-heptane (0.40 mL). The reaction was then heated to 40 °C and stirred vigorously iv for 16 h under Ar. The reaction was allowed to cool to RT and diluted with EtOAc (10 mL). 1 M aq. HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The product was then purified as specified.

General Procedure A -Hydroboration
iii Or a similarly sized Schlenk tube. iv 1400 rpm.

General Procedure B -H2O2/ NaOH oxidation
The corresponding boronic ester (0.15 mmol, 1.0 eq.) was dissolved in THF/Et2O (1:1 v/v, 4.5 mL) and cooled to 0 °C. A 2 M NaOH/30% H2O2 (2:1 v/v, 1.5 mL) mixture was added dropwise and the reaction was allowed to warm to RT and then stirred for 2 h. The reaction was diluted with Et2O/H2O (1:1 v/v, 15 mL) and the phases were separated. The aqueous layer was then extracted with Et2O (2 x 10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The product was then purified as specified.
The aqueous layer was then extracted with Et2O (2 x 10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The product was then purified as specified.

General Procedure D -Benzoylation
To a solution of the alcohol (1.0 eq.), triethylamine (3.0 eq.) and DMAP (0.1 eq.) in CH2Cl2 (~0.1 M) at 0 °C under N2 was added benzoyl chloride (1.5 eq.). The reaction was then allowed to warm to RT and stirred for 16 h. H2O (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The product was then purified as specified.
Analytical data were consistent with those reported in the literature. 30 The er was determined following benzoylation to benzoate (+)-3d-benz.
Analytical data were consistent with those reported in the literature. 31
The aqueous layer was then extracted with Et2O (2 x 10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure.
The crude reaction mixture was dissolved in CH2Cl2 (1 mL
Modified Work-up: following cooling to room temperature, the reaction was diluted with THF/Et2O (1:1 v/v, 11 mL) and cooled to 0 °C. A 2 M NaOH/30% H2O2 (2:1 v/v, 3.8 mL) mixture was added dropwise and the reaction was allowed to warm to RT and then stirred for
Rf: 0.54 (30:70 EtOAc:hexane). vi We suspect that the unknown impurity is a side-product resulting from a transfer of the benzyl ester from the C-4 to the C-6 position of hydroxy ester 3p-oxthis side product has not been characterised.   Analytical data were consistent with those reported in the literature. 35
Analytical data were consistent with those reported in the literature. 40 The er was determined after oxidation to alcohol (-)-3r-ox.
Analytical data were consistent with those reported in the literature. 32 The er was determined after oxidation to alcohol (+)-5-ox.
xii A known quantity of 1,3,5-trimethoxybenzene was added to the crude reaction mixture following work up. xiii The starting material was isolated with a small amount (~5% by GCMS) of alkene isomers.

C NMR measurements
Each of the three samples was analysed by 13 C NMR according to Singleton's protocol. 44 The 13 C NMR spectra were aquired using a Bruker Cryo 500 MHz spectrometer (~4.5 h acquisition time) at 25 °C with the following paramaters:  Inverse-gated decoupling;  1024 scans;  15 s relaxation delay;  π/6 pulse angle.
6 independent 13 C NMR spectra were obtained for each of the three samples. The NMR data were processed using MestreNova and each FID signal was Fourier transformed, zero-filled to 262144 points and apodized with a line broadening of 1.0 Hz (exponential). One spectrum was manually phase corrected and this was applied identically to the remaining 17 spectra.
The integrations were determined by integrating a ±5*ν1/2 region xiv of each of the peaks. C-5 was set to a standard integral of 1000 in each spectrum. The 13 C NMR integrals for each of the 6 spectra acquired for the three samples, along with the averages and standard deviations (ΔR) of those values, are reported for the unreacted alkene starting material 2f (Table S5), and the recovered alkene starting material 2f from Run 1 and Run 2 (Table S6 and Table S7, respectively).     (Table S8 and Table S9, respectively). The KIE and ΔKIE values were derived using the following equations (1-5): Where F = fractional conversion of the starting material; R = 13 C NMR integral from the recovered starting material; R0 = 13 C NMR integral from the standard starting material.  The gradients of these lines, and their average, are reported (Table S11).  Table S11. GC calibration gradients.
The GC data obtained for H2O Run 1-3 (Table S12-Table S14) and D2O Run 1-3 (Table S17-Table S17) are reported along with the processed data (using the gradient obtained for the GC were overlaid on each plot with a blue linethese differentials describe how the rate of reaction for each run varies with time.  The Vmax for each run was obtained mathematically by obtaining the second differential The Vmax values obtained for Runs 1-3 were averaged for H2O and D2O, and these values were used to calculate kH/kD (Table S18).