Asymmetric Hydroboration of Heteroaryl Ketones by Aluminum Catalysis

Article abstract of DOI:10.1021/jacs.9b10364

A series of methyl aluminum complexes bearing chiral biphenol-type ligands were found to be highly active catalysts in the asymmetric reduction of heterocyclic ketones (S/C = 100-500, ee up to 99%). The protocol is suitable for a wide range of substrates and has a high tolerance to functional groups. The formed 2-heterocyclic-alcohols are valuable building blocks in drug discovery or can be used as ligands in asymmetric catalysis. Isolation and comprehensive characterization of the reaction intermediates support a catalysis cycle proposed by DFT calculations.

Full text of DOI:10.1021/jacs.9b10364

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Article
Asymmetric Hydroboration of Heteroaryl Ketones by Aluminum Catalysis
Yury N. Lebedev, Iuliia Polishchuk, Bholanath Maity, Luigi Cavallo, and Magnus Rueping
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10364 • Publication Date (Web): 08 Nov 2019
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Asymmetric Hydroboration of Heteroaryl Ketones by Aluminum Catal-
ysis
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*
Yury Lebedev,a,b Iuliia Polishchuk,a,b Bholanath Maity,a* Luigi Cavallo,a* Magnus Ruepinga,b*
a King Abdullah University of Science and Technology (KAUST) KAUST Catalysis Center (KCC) Thuwal, 23955-6900 (Saudi Arabia)
b Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen (Germany)
KEYWORDS: asymmetric hydroboration, aluminum catalysis, chiral heteroaromatic alcohols, DFT
ABSTRACT: A series of methyl aluminum complexes bearing chiral biphenol-type ligands were found to be highly active
catalysts in the asymmetric reduction of heterocyclic ketones (S/C = 100 – 500, ee up to 99%). The protocol is suitable for a
wide range of substrates and has a high tolerance to functional groups. The formed 2-heterocyclic-alcohols are valuable
building blocks in drug discovery or can be used as ligands in asymmetric catalysis. Isolation and comprehensive charac-
terization of the reaction intermediates support a catalysis cycle proposed by DFT calculations.
◼ INTRODUCTION
Chiral 2-pyridine alcohols and related heterocyclic com-
pounds are valuable structural units in the pharmaceutical
and agrochemical industries1 as well as important ligands
in transition metal catalysis.2 For example, 7-(1-pyrinda-
nyl)propargyl ether1h is a rasagiline analogue and carbinox-
amine and bepotastine besilate are useful histamine H1 an-
tagonists (Figure 1).3 Furthermore, reaction with amines al-
lows a ready access to the corresponding chiral amines
with the inversion of configuration.4 Access to this class of
compounds is provided via bio-enzymatic5 as well as or-
gano-6 and transition metal catalyzed enantioselective re-
ductions.7 Despite the significant progress achieved several
drawbacks including the relatively high catalyst loading,
the necessity to protect the nitrogen atom or narrow sub-
strate scope usually limited to ortho-substituted aryl
groups, must be considered. Hence, the development of
improved protocols for the challenging highly asymmetric
catalytic reduction of 2-pyridine ketones and analogues is
desirable. Although significant progress has been achieved
in substitution of transition metal catalysts by their main
group congeners, the highly enantioselective reduction of
C=X (X = O, NR, CR2) bonds remains relatively scarce.8 In
the last few years considerable attention was devoted to
aluminum hydride and alkyl complexes9 as they were
found to be highly active catalysts in the hydrosilylation
and hydroboration of aldehydes and ketones.10 The latter
findings prompted us to develop an Al-based catalyst for
the asymmetric reduction of ketones.
Figure 1. Bioactive compounds containing 2-pyridine alcohol
structural fragment.
◼ RESULTS AND DISCUSSION
Initially we tested a number of aluminum complexes gen-
erated in situ by reacting stoichiometric amounts of AlMe3
and commercially available chiral diols (Table 1). Toluene
was the solvent of choice due to its non-coordinating na-
ture and good solubilizing properties for all components.
As shown in Table 1, the effect of the ligand on the conver-
sion of the ketone 1a to alcohol 3a and asymmetric induc-
tion was significant. The relatively unhindered BINOL and
TADDOL as well as the hindered SiPh3-BINOL (entries 1–
3) resulted in poor to moderate performance of the cata-
lytic system. In contrast, moderately bulky VANOL,
VAPOL and CF3-BINOL showed superior results (entries 4-
6). (R)-CF3-BINOL was selected for further development as
it provided excellent ee. Furthermore, the flanking substit-
uents of the BINOL scaffold can be easily tuned to adjust
the reactivity and selectivity for different substrates.
Screening of solvents confirmed toluene to provide the
highest performance for the catalyst (SI, Table S5). It is im-
portant to note that HBPin was the borane of choice and
another commonly utilized catecholborane, gave only ra-
cemic products with good conversion. Furthermore, for 9-
BBN no product was detected (SI, Table S1).
Herein, we report a highly enantioselective protocol for the
hydroboration of a wide range of 2-pyridine and analogous
heterocyclic ketones utilizing a low loading of a well-de-
fined aluminum catalyst.
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Table 1. Ligand screening for the aluminum catalyzed
asymmetric hydroboration of 2-acetylpyridine.
Table 2. Asymmetric Al – catalyzed hydroboration of
ketones.
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5
6
7
8
9
Entry
Ligand
Conversion
ee (%)
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(R)-BINOL
>36
43
80 (R)
60 (R)
2
(R,R)-TADDOL
3
(R)-SiPh3-BINOL
28
10 (R)
4
5
6
(S)-VANOL
(R)-VAPOL
98
99
99
98 (S)
98 (R)
98 (R)
(R)-CF3-BINOL
Reaction conditions: 1a (1 mmol), toluene (1.5 mL), HBPin
(1.05 mmol), 1 mol % Al-catalyst (0.01 mmol AlMe3 + 0.01 mmol
ligand in 0.5 mL of toluene). Conversion was determined by
GC after hydrolysis, ee was determined by HPLC analysis us-
ing a chiral stationary phase.
Under the optimized reaction conditions, we extended the
substrate scope to different 2-pyridine ketones as well as
pyrazine, imidazole and thiazole derivatives 1a-z (Table 2).
To our delight the reaction was found to be highly tolerant
to a variety of aryl and alkyl substituents, functional
groups, cyclic substrates and additional donor atoms. The
hydroboration was performed on a 4 mmol scale with 1 M
concentration of the substrate. For 2-acetylpyridine (1a),
the protocol was scaled up to 10 mmol using 0.2 mol % cat-
alyst loading without loss of yield and ee (96%, 98% ee).
Stereochemical analysis of the isolated -methyl-2-pyri-
dinemethanol (3a) was performed by comparing its optical
rotation and retention time on a chiral stationary phase
with those of commercial (R)--methyl-2-pyridinemetha-
nol demonstrating that (R)-configured CF3-BINOL pro-
vides the (R)-configurated product.
Reaction conditions: 1 (4 mmol), 4.05 mmol HBPin, 1 mol %
catalyst (0.04 mmol AlMe3 + 0.04 mmol (R)-CF3-BINOL), 1 M
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toluene concentration, ambient temperature, 2 h. (a)(R)-
structure is presumably retained in solution, as indicated
BINOL was used. (b)(R)-VAPOL was used. (c)(S)-VANOL was
used.
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by the three signals in a 12:6:6 ratio for the CF3 groups in
the 19F NMR spectrum in benzene-d6 (SI, Figure S9).
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Although 2-acethyl-5-methyl thiazole (1s) afforded very
high yield and ee for the corresponding alcohol 3s, the per-
formance of the catalyst bearing the CF3-BINOL ligand was
found to be sensitive to ortho- substitution in the hetero-
cyclic ring and bulky alkyl groups at the carbonyl position.
Nevertheless, switching to (R)-BINOL, (S)-VANOL or (R)-
VAPOL provided excellent yields and ee’s for the isolated
alcohols 3u-3z. However, the screening of ligands and sol-
vents for acetophenone and several imines did not allow to
achieve a similar performance (SI, Tables S2 -S3).
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Characterization of the catalyst and mechanistic con-
siderations
To gain an insight into the mechanism we first tested if an
adduct between HBPin and 2-acethylpyridine (1a) forms in
aromatic solvents. In the 1H, 13C and 11B NMR spectra (ben-
zene-d6), the positions of the peaks of an equimolar 0.25 M
mixture were identical to those of the individual com-
pounds, indicating that no complexation occurred in solu-
tion. Also no significant product formation was achieved
and traces of product were observed after stirring the reac-
tion for 10 days at ambient temperature.
Figure 3. MERCURY plot of the molecular structure of
[(R)-CF3-BINOL-AlMe]2. Hydrogen atoms are omitted for
clarity. Selected bond lengths [Å]: Al1-O1 1.856(3), Al1-O2
1.855(3), Al1-C1 1.896(3).
In a subsequent experiment, 0.5 equiv. of in situ generated
[(R)-CF3-BINOL-AlMe]2 was added dropwise to 4 equiv. 2-
acethylpyridine in n-hexane. A voluminous precipitate for-
mation was observed thereby. The filtrate was determined
to contain only 2 equivalents of the unreacted ketone. The
1H, 13C, 19F NMR spectra in benzene-d6 of the isolated solid
amorphous material were inconclusive, and, upon hydrol-
ysis on silica, (R)-CF3-BINOL was recovered. This result
can be attributed to the known formation of oligomers for
aluminum phenoxides. It is worth noting that despite its
ill-defined nature, the isolated material has the same per-
formance in the hydroboration of 2-acethylpyridine as in
situ formed [(R)-CF3-BINOL-AlMe]2, giving 98% conver-
sion with 97% ee at 1 mol % loading.
Next, adduct 2a isolated from the reaction of 1a with HBPin
in the presence of [(R)-CF3-BINOL-AlMe]2 was subjected
to single crystal XRD analysis, rendering the (R) configura-
tion of the product (Figure 2). The boron center coordi-
nates to the pyridine nitrogen atom with the B-N bond
(1.633(3) Å) slightly longer than the sum of single bond co-
valent radii of the elements (1.56 Å)11 and falls in the range
of B-N distances (1.655(3) – 1.611(3) Å) in previously charac-
terized Py-B(OAr)3 adducts.12 The N-B-O1 angle (98.0(2)°)
is distorted from the ideal sp3-hybridized one.
Thus, we assumed that a more sterically hindered substrate
can provide a monomeric, well defined adduct. Upon ad-
dition of 1 equiv. of [(R)-CF3-BINOL-AlMe]2 to an n-hexane
solution of (4-fluorophenyl)(2-pyridinyl) methanone (1k, 3
equiv.) a grayish precipitate was formed. Upon filtration
and according to the mass balance, a 1:1 adduct 4 was
formed (Scheme 1). The complex was characterized by liq-
1
uid state H, 13C, 19F NMR and solid-state IR spectroscopy.
Figure 2. MERCURY plot of the molecular structure of 2a.
Hydrogen atoms are omitted for clarity. Selected bond
lengths [Å] and angles [°]: N-B 1.633(3), O1-B 1.468(3), O2-
B 1.431(3), O3-B 1.435(3), C1-O1 1.401(3). N-B-O1 98.0(2), O2-
B-O3 107.7(2).
The adduct is stable in a solution of benzene-d6 and in the
solid state for several days. Integration of the 19F NMR spec-
trum shows a 1:12 ratio for the Ph-F and the −CF3 groups,
respectively (SI, Figure S10). The resonance signals of the
trifluoromethyl groups appear as two singlets, pointing to
a dynamic behavior of the molecule in solution.
In the solid-state IR spectrum (Figure S16 and S12 respec-
tively), the bathochromic shift ( = 53 cm−1) of the C=O
stretching vibration is observed for 4 ( = 1598 cm−1) com-
pared to the free ketone 1k ( = 1651 cm−1). The Al-Me res-
onances in 1H and 13C NMR spectra of 4 shift to downfield
Suitable single crystals of the in situ generated catalyst
were obtained upon cooling an n-hexane solution to −35 °C
and their XRD analysis showed a dimer [(R)-CF3-BINOL-
AlMe]2 formed via oxygen bridges (Figure 3). The dimeric
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The broad signals in the H and 13C NMR spectra for the
THF ligand and a sharp singlet for all −CF3 groups indicate
a fluctuating coordination environment at the aluminum
center. The central atom in 5 adopts a distorted trigonal
bipyramidal coordination geometry with the THF and pyr-
idine ligands occupying axial positions (Figure 4). In an
NMR experiment, where 2-acetylpyridine (1a) was added
directly to a solution of [(R)-BINOL-AlMe(THF)2]2 in THF-
d8 no reaction was observed at ambient temperature (SI,
Figures S7 and S8), demonstrating the importance of the
solvent coordinating ability.
 = −0.94/−11.7 ppm compared to those in the starting ma-
terial  = −1.32/−16.4 ppm (SI, Figures S10 and S9, respec-
tively). Previously reported data for AlMe(BHT)2 (BHT =
2,6-di-tert-butyl-4-methylphenolate) adducts with a num-
ber of diaryl, aryl-alkyl and dialkyl ketones show that Al-
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1
Me resonance peaks in H and 13C NMR spectra also un-
dergo similar downfield shifts upon complexation.13 How-
ever, the bathochromic shifts of the carbonyl stretching vi-
brations is significantly stronger (ca. 100 – 115 cm−1), which
is presumably due to the coordination number at the Al
center.
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Computational Study
To get further insight into the reaction mechanism and the
origin of enantioselectivity we have performed DFT calcu-
lations, which suggest that the active catalyst is generated
in situ, as described in Figure 5. The overall catalytic reac-
tion pathway is displayed in Figure 6. In these calculations
we considered the complex based on the (R)-CF3-BINOL
ligand.
Scheme 1. Reactivity of [(R)-CF3-BINOL-AlMe]2 towards
(4-fluorophenyl)(2-pyridinyl)methanone (1k).
Upon dissolving 4 in THF-d8, the Al-Me signal disappears
in the 1H and 13C NMR spectra and a singlet corresponding
to the Me group appears at  = 1.42 and 32.58 ppm, respec-
Catalyst Activation: In agreement with the experiments,
calculations revealed that the dimeric form of the [(R)-CF3-
BINOL-AlMe]2 complex (C1) is more stable compared to
the monomeric form by 19.9 kcal/mol. We thus considered
the dimeric species C1 as starting point of the activation
pathway shown in Figure 5. Coordination of two molecules
of 2-acetylpyridine (1a) converts the dimeric species C1 to
two monomeric species C2 by an exergonic step of 3.1
kcal/mol per C2 molecule. Coordination of a second mole-
cule of 1a to C2 facilitates the migration of the −Me group
from aluminum to the carbonyl group via transition state
[C3-C4]‡ and an activation barrier of 24.3 kcal/mol from C2,
leading to C4. In the absence of the second 1a molecule the
activation barrier for the migration of the −Me group to Al
in C2 amounts to 31.4 kcal/mol (see Figure S1). An indirect
experimental proof that an additional ligand facilitates the
migration of the Me group is the conversion of 4 to 5 upon
dissolving 4 in THF-d8 (Scheme 1).
1
13
tively. Only one set of signals was observed in H, C and
19F NMR spectra pointing to highly stereoselective methyl
transfer. The reaction was repeated on a preparative scale
and five-coordinate aluminum complex 5 was isolated in
60% yield after crystallization. This compound was spec-
troscopically and structurally characterized (Scheme 1, Fig-
ure 4).
The resulting intermediate C4 (36.7 kcal/mol below the re-
actant) can evolve by σ-bond metathesis between the Al‒
O and H‒BPin bonds. The most favorable reaction path-
way (see Figure S1 for an unfavored pathway) involves the
endergonic dissociation of 1a from C4 with almost ther-
moneutral coordination of HBPin to the Al‒O bond, lead-
ing to intermediate C6. Subsequent, σ-bond metathesis be-
tween the Al‒O and H‒BPin bonds occurs via transition
state [C6-C7]‡ with an energy barrier of 16.1 kcal/mol from
C4. The resulting Al−H intermediate C7, is 10.5 kcal/mol
higher in energy compared to the most stable intermediate
C4. Finally, the Al‒H species A, generated by coordination
of 1a to C7 with release of C8, is considered as the active
catalyst for the hydroboration reaction discussed in the
next section.
Figure 4. MERCURY plot of the molecular structure of 5.
Hydrogen atoms are omitted for clarity. Selected bond
lengths [Å] and angles [°]: Al-O1 1.764(5), Al-O2 1.792(6),
Al-O3 1.967(6), Al-O4 1.764(7), Al-N 2.065(7). O1-Al-O2
104.5(3), O1-Al-O4 121.8(3), O1-Al-O3 92.0(2), O1-Al-N
99.7(3), O2-Al-O4 133.7(3), O2-Al-N 89.4(3), O3-Al-O4
85.8(3), O3-Al-N 166.6(3), O4-Al-N 82.5(3).
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‡
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2
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4
‡
[C3-C4]‡
21.2
5
6
1a
7
8
9
C3
0.0
-3.1
0.8
[C6-C7]‡
C1
1a
C2
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19
-20.6
-26.2
A
1a
C7
-27.0
C5
-33.1
-33.8
C6
-36.7
C4
HBPin
=
C8
‒Ar
methyl migration
σ-bond metathesis of B-H and Al-O
Figure 5. Energy profile for the formation of the active catalyst. Free energies in solution (in kcal/mol) are calculated at the
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M06/TZVP//BP86/SVP level.
Catalytic Mechanism: The overall catalytic pathway is
strictly related to the activation pathway of Figure 5, with
the difference that a H-atom (instead of a Me group) mi-
grates to the aluminum atom. For this reason, the catalytic
pathway can be divided into two sections: i) hydride mi-
gration and ii) σ-bond metathesis between B−H and Al−O
bonds. The energy profile and the respective discussion re-
fer to formation of the favored R product (R)-2a (Figure 6).
Similarly to the Me migration step during catalyst activa-
tion, coordination of a second molecule of 1a to the alumi-
num center of A, leading to BR, facilitates hydride migra-
tion via the four-membered transition state [BR-CR]‡ and a
moderate energy barrier of 18.2 kcal/mol from A + 1a (see
Figure S2 for hydride transfer prior to coordination of a
second 1a molecule). The overall step BR→CR is exergonic
by 34.2 kcal/mol. The catalytic cycle evolves further by σ-
bond metathesis between the Al−O and the H‒BPin bonds.
This step starts with dissociation of 1a from CR and coordi-
nation of HBPin to the Al-O bond, leading to intermediate
ER, which is 2.1 kcal/mol lower in energy than DR. No tran-
sition state has been located for HBPin coordination to DR,
which is in agreement with previous reports.14 σ-bond me-
tathesis between the H−BPin and Al−O bonds via transi-
tion state [ER-FR]‡ and an activation barrier of 15.8 kcal/mol
from ER results in the formation of the Al−H species FR. Co-
ordination of a 1a molecule to FR releases product (R)-2a
and regenerate the starting catalytic species A.
transition state [BR-CR]‡, leading to formation of (R)-2a, is
favored by 3.7 kcal/mol compared to transition state [BS-
CS]‡, leading to formation of (S)-2a (for complete pathway
refer Figure S3 in SI).
To understand the origin of enantioselectivity we per-
formed an energy decomposition analysis (EDA) of the rel-
ative stability of transition states [BR-CR]‡ and [BS-CS]‡ (for
details refer to Table S6 in SI).15 Within the EDA the energy
difference between transition states [BS-CS]‡ and [BR-CR]‡
(E‡) can be decomposed as E‡ = Edef + Eint, where Edef
is the difference between the energies required to deform
A + 1a to the geometry of transition states [BR-CR]‡ and [BS-
CS]‡, and Eint is the difference between the interaction en-
ergies of the deformed A and 1a fragments in transition
states [BR-CR]‡ and [BS-CS]‡ (see Scheme 2).
Scheme 2. Cartoon representation of the scheme used to
decompose the activation barrier, E‡, into a deformation
term, Edef, and an interaction term, Eint.
The reaction profile in Figure 6 reveals that hydride migra-
tion via transition state [BR-CR]‡ is the rate-controlling
step. Therefore, to rationalize the observed enantio-selec-
tivity we have investigated the hydride migration step to-
wards formation of the opposite enantiomer (S)-2a (red
line in Figure 6, complete energy profile in Figure S3). In
agreement with the experimentally observed selectivity,
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‡
1
2
3
1.85
4
5
6
7
1.63
‡
[BS-CS]‡
21.9
1.45
8
9
3.7
‡
18.2
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[BR-CR]‡
BS
[ER-FR]‡
7.9
3.2
0.0
BR
[ER-FR]‡
A + 1a
1a
-17.2
-24.3
-24.5
15.8
CS
-30.4
FR
A + (R)-2a
DR
A
-33.0
ER
-30.9
-31.0
CR
1a
HBPin
1a
(R)-2a
hydride migration
σ-bond metathesis of B-H and Al-O
Figure 6. Energy profile for the catalytic reaction. Blue line for selective (R)-2a product formation pathway and red line for
rate limiting step towards (S)-2a product. Bond lengths are in Å. Free energies in solution (in kcal/mol) at the
M06/TZVP//BP86/SVP level are displayed.
Calculations reveal that the higher stability of transition
state [BR-CR]‡, E‡ = 3.4 kcal/mol, is due to the smaller en-
ergy required to deform A + 1a to the geometry of transi-
tion state [BR-CR]‡, rather than to that of transition state
[BS-CS]‡, for a Edef = 10.7 kcal/mol. The positive Edef fa-
voring [BR-CR]‡ is not compensated by the higher interac-
tion energy between A and 1a in transition states [BS-CS]‡,
for a Eint = -7.3 kcal/mol. This suggests that transition
state [BS-CS]‡ is destabilized by steric repulsion between A
and 1a.
Inspection of the geometries of transition states [BR-CR]‡
and [BS-CS]‡ (see Figure 7) shows that the reacting groups
and the ancillary 1a molecule in [BR-CR]‡ are placed away
from the (R)-CF3-BINOL ligand, while in [BS-CS]‡ the aro-
matic ring of the reacting 1a molecule and the methyl
group of the ancillary 1a molecule, highlighted in yellow,
are at short (repulsive) distances from a CF3 substituted
ring and the binaphthol skeleton of the (R)-CF3-BINOL lig-
and, respectively. The repulsive interaction involving the
binaphthol skeleton explain the relatively high ee observed
in presence of the (R)-BINOL ligand (see Table 1), despite
it has no ortho substituents.
As the above analyses indicated that the main parameter
impacting enantioselectivity can be related to repulsive in-
teractions in the pro-(S) transition state, due to clashes be-
tween the reacting group and the (R)-CF3-BINOL ligand, to
rationalize the performance of the whole set of 6 catalysts
used experimentally we analyzed their steric properties. To
this end we analyzed the optimized geometry of interme-
diate A for the 6 ligands reported in Table 1 using the bur-
ied volume family of descriptors.16 Plotting both the con-
version and the ee versus the %VBur results in a volcano
plot, with highest conversion and enantio-selectivity in the
%VBur range of 34-38% (Figure 8a). Further increase of ste-
ric hindrance results in declining performances, see the
trend from (R)-CF3-BINOL to (R)-TADDOL and to (R)-
SiPh3-BINOL. Comparison of the steric maps of these com-
plexes (Figure 8b-c) shows the impact of the ligand skele-
ton on the catalytic pocket around the aluminum center.
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Compared to (R)-BINOL, the catalytic pocket of (R)-CF3-
1
BINOL shows increasing steric hindrance around the
north-west and south-east borders, while the catalytic
pocket of (R)-SiPh3-BINOL is clearly more hindered than
that of (R)-CF3-BINOL. These insights offer an explanation
for the lower performance of the (R)-BINOL and (R)-SiPh3-
BINOL complexes. Specifically, the low steric hindrance in
(R)-BINOL suggests it can results in a very stable dimeric
aluminum complex C1. We thus calculated the energy for
the opening of C1 by 1a to give the monomeric complex C2
(see Figure 5), and we found that in presence of the (R)-
BINOL ligand this process is disfavored by 4.4 kcal/mol. In
contrast, opening of the dimeric complex C1 with (R)-CF3-
BINOL is favored by 3.1 kcal/mol (see Figure 5). The high
stability of the dimeric aluminum complex with the (R)-
BINOL ligand explains the experimentally observed re-
duced conversion promoted by this ligand (see Table 1). As
for (R)-SiPh3-BINOL, its high steric hindrance suggests it
can disfavor coordination of two 1a molecules to the alu-
minum center, needed to promote migration of both the –
Me group and the –H atom. We thus calculated the energy
for coordinating a 1a molecule to C2 to give complex C3 (see
Figure 5), and we found that in presence of the (R)-SiPh3-
BINOL ligand this process is disfavored by 10.9 kcal/mol.
In contrast, coordination of 1a to C2 with (R)-CF3-BINOL is
disfavored by 3.9 kcal/mol only (see Figure 5). The more
difficult coordination of the second 1a molecule with the
(R)-SiPh3-BINOL ligand explains the experimentally ob-
served reduced conversion promoted by this ligand (see
Table 1).
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Figure 7. Optimized geometries of transition states for hydride
migration step. Bond lengths are in Å. The emerging C–H bond
is colored in yellow. The methyl group of the ancillary 1a mol-
ecule is highlighted in yellow.
Figure 8. Part a, plots of the experimental conversion and ee versus the buried volume of the 6 binapthol ligands in the
optimized geometry of complex A. Part b), orientation of the A complex in the cartesian frame used to calculated the buried
volume and the steric maps. Part c), steric map of the (R)- BINOL, (R)-CF3-BINOL and (R)-SiPh3-BINOL ligands in the
optimized geometry of complex A.
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CONCLUSIONS
In summary, we have developed a versatile protocol for a
highly enantioselective hydroboration of 2-pyridine and
similar heterocyclic ketones utilizing an in situ formed alu-
minum complex bearing readily available VANOL, VAPOL
and BINOL based ligands. The ligand can be fully recov-
ered and reused. Short reaction times, as well as broad
scope of substrates make this protocol a valuable synthetic
tool in organic synthesis. The catalyst was isolated and
structurally as well as spectroscopically characterized. Sev-
eral intermediates which provide insight into the catalytic
cycle were spectroscopically or/and structurally identified.
A detailed reaction mechanism fully confirming our empir-
ical observations is proposed based on computational
studies. Steric analysis indicated that top performances can
only be achieved if appropriate tuning of the steric hin-
drance around the active center is performed.
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ASSOCIATED CONTENT
Supporting Information. This material is available free of
charge on the ACS Publication Website at DOI:
NMR and IR Spectra, HPLC traces and Computational De-
tails (PDF)
X-Ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Authors
* magnus.rueping@rwth-aachen.de
* yury.lebedev@kaust.edu.sa
* luigi.cavallo@kaust.edu.sa
* bholanath.maity@kaust.edu.sa
Author Contributions
The manuscript was written through contributions of all au-
thors. / All authors have given approval to the final version of
the manuscript.
ACKNOWLEDGMENT
B.M. and L.C. acknowledge King Abdullah University of Sci-
ence and Technology (KAUST) for support and the KAUST Su-
percomputing Laboratory for providing computational re-
sources of the supercomputer Shaheen II.
Miguel Dinis Veloso Guerreiro (KAUST) is acknowledged for
providing several starting materials.
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