Regiodivergent Hydroborative Ring Opening of Epoxides via Selective C-O Bond Activation

Article abstract of DOI:10.1021/jacs.0c05917

A magnesium-catalyzed regiodivergent C-O bond cleavage protocol is presented. Readily available magnesium catalysts achieve the selective hydroboration of a wide range of epoxides and oxetanes yielding secondary and tertiary alcohols in excellent yields and regioselectivities. Experimental mechanistic investigations and DFT calculations provide insight into the unexpected regiodivergence and explain the different mechanisms of the C-O bond activation and product formation.

Full text of DOI:10.1021/jacs.0c05917

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Article
Regiodivergent Hydroborative Ring Opening
of Epoxides via Selec-tive C-O Bond Activation
Marc Magre, Eva Paffenholz, Bholanath Maity, Luigi Cavallo, and Magnus Rueping
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05917 • Publication Date (Web): 13 Jul 2020
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Marc Magre,a Eva Paffenholz,a Bholanath Maity,b Luigi Cavallo*b and Magnus Rueping*b
a Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany.
b KAUST Catalysis Center (KCC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Supporting Information Placeholder
certain cases, even low-cost and readily available dialkyl-
magnesium could be applied as catalyst.[11] Given the current
limitations in the catalytic regiodivergent ring opening of epox-
ides we decided to explore whether simple magnesium cata-
lysts would allow for the selective C-O bond activation leading
to either branched or linear alcohols in good yields and with
broad functional group tolerance (Scheme 1b). We here report
the development of such a regiodivergent reaction and explain
the mechanism supported by experiment and computation.
ABSTRACT: A magnesium-catalyzed regiodivergent C-O bond
cleavage protocol is presented. Readily available magnesium
catalysts achieve the selective hydroboration of a wide range of
epoxides and oxetanes yielding secondary and tertiary alcohols
in excellent yields and regioselectivities. Experimental mecha-
nistic investigations and DFT calculations provide insight into
the unexpected regiodivergence and explain the different
mechanisms of the C-O bond activation and product formation.
Scheme 1. Catalytic methods for the regioselective ring
opening of epoxides
The broad presence of hydroxyl moieties in pharmaceuticals,
agrochemicals and fragrance chemistry have led to the devel-
opment of efficient protocols for their synthesis.[1] In this re-
gard, epoxides can be easily converted to alcohols via a ring-
opening reaction. It is well known that non-symmetrical epox-
ides afford mixtures of regioisomers, where ratios between lin-
ear and branched alcohols are strongly dependent on the re-
ducing agent employed.[2] In the last decades, great efforts have
been made to overcome regioselectivity problems of the ring
opening reaction of epoxides.[2] The catalytic C-O bond cleav-
age is limited due to the high stability of the corresponding
metal-alkoxide products, which impedes the regeneration of
the metal hydride intermediate.[3] One of the most employed
catalytic methods for the ring-opening of epoxides is the tran-
sition metal-catalyzed hydrogenation, either by using hetero-
geneous or homogeneous catalysts.[4] In all cases, high temper-
atures and H2 pressures are required, leading to poor selectiv-
ity along with the generation of oligomers or saturated hydro-
carbons as by-products (Scheme 1a). In recent years, the tran-
sition metal-catalyzed hydroboration has appeared as a plausi-
ble alternative to the hydrogenation protocols. The use of the
mild reductant pinacolborane resulted in good selectivities;
however, exclusively towards linear alcohols (Scheme 1a).[5]
We began our investigations with the magnesium-catalyzed
hydroboration of styrene oxide 1a by evaluating the activity
and selectivity of readily available MgBu2 (Table 1). By decreas-
ing the catalyst loading the activity was maintained (Table 1
entry 1 vs 2). Whereas all catalytic methods for the hydrobora-
tion of epoxides provided the linear regioisomer,[5] the magne-
sium catalyst provided the branched product. The regioselec-
tivity could be improved by decreasing the reaction tempera-
ture (Table 1 entry 2 vs 3). Testing different solvents led to a
small in increase in regioselectivity when THF was used (Table
1, entry 4). Finally, by decreasing the reaction concentration
(Table 1, entry 5), we reached better results. It should be
Alkaline-earth metals are among the most abundant metals
in the crust of the earth. Despite their abundance and low tox-
icity, their application has been mainly focused on the hydro-
functionalization of polarized unsaturated bonds.[6,7] Since the
first structurally characterized magnesium-hydride complex
by Jones and Stasch,[8] great efforts have been carried out to
understand the Mg-H reactivity and its application as valuable
alternative to transition-metal hydride species.[6] As a result,
magnesium complexes, mostly containing anionic -diketimi-
nate ligands[9] have been successfully applied to the hydrobo-
ration of polarized and unpolarized unsaturated bonds.[10] In
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pointed out that performing the catalytic reaction in neat con-
ditions (Table 1, entry 6) resulted in a lower regioselectivity.
Table 1. Reaction optimization.a
results, we decided to test the MgBu2-catalyzed hydroboration
protocol for both, (R)- and (S)-enantiomers of 2,2-disubsti-
tuted epoxides 1m-n and 1q. Importantly, no loss of enanatio-
meric excess was observed and the tertiary alcohols were in
optically pure form. This good performance was also extended
when chiral epoxides derived from natural products or drug
derivatives were tested under the same reaction conditions.
When D-camphor (1w), -thujone (1x) and L-menthone (1y)
derived epoxides were studied, good yields and excellent regio-
and diastereoselectivities were obtained. We were also pleased
to see that sterol-derived epoxides 1z and 1aa also underwent
hydroboration effectively with excellent yields, regio- and dia-
stereoselectivities.
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Entry
MgBu2
T (°C) Solvent
2a:3a
(b:l)c
Conv.
(%)d
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(mol%)
The findings let us wonder whether less reactive oxacylic rings,
such as oxetanes and oxolanes could also be applied in the Mg-
catalyzed ring opening. To the best of our knowledge, there is
no catalytic method reported for the hydroboration reaction
involving these unreactive compounds. To our delight the hy-
droboration could also be applied and mono-substituted ox-
etanes containing aryl substituents (1ab-af) underwent ring
opening to give the corresponding branched alcohols 2ab-af in
good yields and excellent regioselectivities. This good perfor-
mance was also maintained when alkyl substituents are pre-
sent at the 2-position (1ag-ah), although lower conversions
were observed. When symmetrical oxetanes 1ai-aj were
tested, the corresponding alcohols 2ai-aj were also isolated in
moderate to good yields. Encouraged by these results, we de-
cided to study the MgBu2-catalyzed hydroboration of 2-phe-
nyloxolane. Unfortunately, even under harsher reaction condi-
tions, no conversion was observed for these less reactive
oxacycles. Thus, we wondered if the replacement of the ligand
(ie. butyl) would have an effect on the catalytic activity. In-
spired by our recent findings in which (i) Mg(OR)2 (where
(OR)2= BINOL) was shown to activate HBPin towards ketone
reduction via a cooperative magnesium-ligand activation,[15a]
and (ii) Mg(NTf2)2 acting as an efficient Lewis acid towards al-
kyne activation,[15b] we decided to replace MgBu2 by Mg(NTf2)2
and to evaluate the influence on both, the activity or selectivity.
To our surprise the application of Mg(NTf2)2 in the hydrobora-
tion of 2,2-disubstituted epoxide 1i resulted in the linear alco-
hol product 4a (2ai) (Scheme 3).
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5b
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-
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Toluene 80:20 99
Toluene 80:20 99
Toluene 84:16 99
THF
THF
neat
THF
87:13 99
89:11 99 (95)
66:33 99
n.d.
<5
a
1a (1 mmol), HBpin (1.5 equiv.), MgBu2 (0.5 M in heptane),
solvent [1 M] for 24 hours. THF [0.5 M]. c Selectivities deter-
b
mined by 1H NMR. Conversions determined by GC. Isolated
d
yield in parenthesis.
Following this optimization, we explored the scope and limi-
tations of the MgBu2-catalyzed regioselective hydroboration of
epoxides (Scheme 2) starting with mono-substituted terminal
epoxides, which lead to secondary alcohols (2a-2h). When ar-
omatic substituents are present, good to excellent regioselec-
tivities were obtained, regardless the electronic nature of the
aromatic moiety. Use of epoxides bearing an alkyl substituent
(1d-1h) showed full regioselectivity and good yields. Based on
the good performance observed also substrates with alkenyl
moieties (1e-1f) were tested. Fortunately, no influence on the
chemoselectivity towards the C-O cleavage was observed and
the products were isolated in good yields. Encouraged by these
results, we decided to test di-substituted terminal epoxides
(1i-1s). In this case, tertiary alcohols important synthesis
building blocks also found in several natural products,[12] were
obtained in excellent yields and regioselectivities. Again, differ-
ent electronic and steric properties on the aryl group (2i-2l)
did not influence either the activities or selectivities. When ap-
plying different alkyl substituted substrates (2m-2o) the excel-
lent results were preserved. Interestingly, diphenyl epoxide 1p
also underwent hydroboration regioselectively. In a similar
manner, the MgBu2-catalyzed hydroboration of trifluorome-
thyl-containing epoxide 1q also provided exclusively the
branched alcohol 2q in excellent yields and regioselectivities.
We were also delighted to see that this good performance could
be also extended to epoxides present in macrocycles, affording
in all cases the tertiary alcohols 2r and 2s in excellent yields
and regioselectivities. When symmetrical disubstituted epox-
ides were studied (1t-1v), the corresponding alcohols 2t-2v
could be isolated in good yields, although higher temperatures
were required.
Scheme 3. Regiodivergent magnesium-catalyzed hy-
droboration of epoxides.
Tertiary alcohols are present in several natural products or
drug derivatives.[12] Thus, the synthesis of enantiomerically
pure tertiary alcohols is of great interest. In this regard a few
catalytic asymmetric reactions are known,[13] with the catalytic
asymmetric addition of carbon-nucleophiles to ketones as the
most synthetically used approach.[14] Motivated by the above
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Scheme 2. Scope of the MgBu2-catalyzed hydroboration of epoxides and oxetanes.a
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a
b
1a-aj (1 mmol), HBpin (1.5 equiv.), MgBu2 (5 mol %, 0.5 M in heptane), THF [0.5 M], 40 °C for 24 hours. Isolated yields.
Toluene [1 M], 10 mol % MgBu2, 90 °C. c Enantioselectivities were determined by HPLC. Diastereoselectivities were determined
by 1H NMR. (R)- and (S)-1m, (S)-1n and (R)- and (S)-1o epoxides were used in 99% ee purity. (R)-1n epoxide was used in 97%
ee purity (all isolated from preparative HPLC. For more information, see Supporting Information). Epoxides 1w, 1x, 1y, 1z and
1aa were diasteriomerically pure. d MgBu2 (5 mol %, 0.5 M in heptane), toluene [1 M], 75 °C for 24 hours.
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This complete regioselectivity switch is very interesting and
points to a different HBpin activation and ring opening mecha-
nism. Several 2,2-disubstituted terminal epoxides with steri-
cally hindered or polyaromatic ring substitutions (4b-4c) as
well as linear and cyclic alkyl substituents (4d-4l) were then
applied (Scheme 4). The scope could also be extended diaryl-
substituted substrate and 2,2-diphenylethan-1-ol 4m was ob-
tained quantitatively. Overall the Mg(NTf2)2-catalyzed hydrob-
oration results in good yields and complete selectivity towards
linear alcohols.
1. Control experiments
We assumed that the regiodivergency is caused by the nature
of the different magnesium catalysts. However, given that BH3
is capable of catalyzing the hydroboration of olefins,[16] and due
to examples in literature which describe the decomposition of
HBpin to BH3 by alkali salts,[17] we decided to investigate if BH3
could catalyze the hydroboration of epoxides to either linear or
branched alcohol. Therefore, BH3·THF and BH3·SMe2 were
tested in the reaction. However, both did not efficiently cata-
lyze the hydroboration (Scheme 5a), providing low conver-
sions and a mixture of branched and isomerization by-product
(For more detail, see Supporting Information). Subsequently,
we investigated the deuterium incorporation by using DBpin
(Scheme 5b).
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Scheme 4. Mg(NTf2)2-catalyzed hydroboration of epox-
ides.[a]
Scheme 5. Control experiments.
a 1 (1 mmol), Mg(NTf2)2 (5 mol%), HBpin (1.5 equiv.) in THF
[0.5 M] at 40 °C for 24 hours. b Mg(NTf2)2 (10 mol%).
Thus, we successfully developed a regiodivergent ring opening
of epoxides by applying two readily available and low-cost
magnesium catalysts. On one hand, our MgBu2-HBPin catalytic
system can be applied to a broad range of substrates providing
the branched alcohols with excellent chemo- and regioselectiv-
ities without the loss of enantioselectivity. On the other hand,
the use of Mg(NTf2)2 catalyst provides the complementary ring
opening reaction leading to the linear alcohols. Considering the
unexpected regiodivergence observed by using either MgBu2
or Mg(NTf2)2, we decided to conduct several experiments to
gain insight into the different reaction mechanisms (Scheme 5).
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When the MgBu2-catalytic system was tested, the secondary al-
cohol 2d-d1 was isolated with full D-incorporation at the -me-
thyl moiety. This result suggested that the BuMg-D species in
situ formed would attack the least substituted carbon of the
epoxide ring (Scheme 5b1). Moreover, no isomerization was
observed. We also carried out the same D-incorporation exper-
iments by using Mg(NTf2)2. In this case, quantitative D-incor-
poration was observed at the less substituted carbon (Scheme
5b2). This result, together with the complete regiodivergence
observed suggests that the latter mechanism operates via a 1,2-
H shift,[18a] producing an aldehyde intermediate, which finally
undergoes reduction via a D-addition. This epoxide isomeriza-
tion is in agreement with the work reported by Weinwald[18a]
and Mazet using Pd or Ir-catalysts.[18b,c] Consequently, we car-
ried out an isomerization experiment (Scheme 5c). When epox-
ide 1i was mixed with catalytic amounts of Mg(NTf2)2 complex,
we observed the formation of aldehyde 5. This result supports
the notion that Lewis acidic Mg(NTf2)2 is an efficient catalyst
for the Meinwald rearrangement (1,2-H shift)[18a] of terminal
disubstituted epoxides to the corresponding aldehyde which is
in agreement with the control experiments (Scheme 5b2). Fi-
nally, we conducted a racemization experiment (Scheme 5d).
As shown above, MgBu2 catalyzes the ring opening of enanti-
opure epoxide without loss of enantioselectivity (Scheme 2,
compounds 2m, 2n and 2q). When enantiopure epoxide 1m
was tested in the presence of Mg(NTf2)2 catalyst, rac-4h was
obtained which can be explained by the formation of a carbo-
cation intermediate.
facile (∆G‡ = 9.0 kcal/mol) than that via TS1 (∆G‡ = 24.0
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kcal/mol). The reason for this observation is the attractive elec-
trostatic interaction between the two oppositely charged A10
and A11. The resulting two molecules of A12 are highly stable,
laying at -108.3 kcal/mol with respect to starting A7. Interme-
diate A12, having two THF coordinated to the Mg, is the most
stable over other possibilities (see Figure S3 in SI). The next
step, metathesis of the Mg‒O and B‒H bonds, starts with the
replacement of one THF of intermediate A12 by HBpin to gen-
erate A12h, a step endergonic by 3.4 kcal/mol (Figure 2). Then,
the alkoxide group migrates to the boron atom via transition
9
state TS3 and a total energy barrier of 5.6 kcal/mol from A12
.
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The resulting zwitterionic intermediate A13 is highly stable,
and is the lowest point in the potential energy surface. The re-
action is completed by hydride transfer from the electron rich
HBpin moiety to the electron deficient Mg center of A13, via
transition state TS4 and an energy barrier of 19.9 kcal/mol.
Liberation of product PA from the formed intermediate A14 re-
generates A7 for further catalysis. The overall reaction profile
(Figures 1 and 2) reveals that bimetallic hydride transfer via
TS1 is the rate-controlling step. Regarding the regioselectivity,
we checked the two epoxide opening transition states TS1 and
TS2. We thus investigated the hydride transfer step via TS1-R
and via TS2-R, where hydride transfer occurs to the substi-
tuted C atom of the epoxide (red lines in Figure 1). Consistently
with the experimental regioselectivity, transition states TS1
and TS2 are favored by 5.2 and 3.8 kcal/mol as compared to
transition states TS1-R and TS2-R (details in Figure S4 in SI).
The high regioselectivity towards H transfer to the unsubsti-
tuted C atom of the epoxide can be easily rationalized in terms
of steric effects. In fact, the steric map of the epoxide coordi-
nated intermediate A7h (Figure 3) shows that, as expected, the
western quadrants, hosting the unsubstituted C atom of the
epoxide, are less hindered than the eastern ones, hosting the
substituted C atom.
2. Computational Study
Supported by control experimental results, we performed DFT
calculations (Computational Details in Supporting Infor-
mation) to define possible reaction pathways for both catalytic
systems, MgBu2 and Mg(NTf2)2. Epoxide 1i was selected as pro-
totype substrate.
MgBu2 catalyzed mechanism: As previously reported, hy-
droboration reactions using MgBu2 as the catalyst occur via in
situ formation of the active catalytic species BuMg‒H.[11] The
energy profile for the formation of BuMg‒H by reaction of
MgBu2 with HBpin is discussed in Figure S1 (see SI). Within the
reaction conditions used in this work, BuMg‒H can be stabi-
lized by solvent molecules (THF), by HBpin, or by 1i, as shown
in Figure S2. Among all the possibilities the most stable geom-
etry is A7, in which two THF molecules are coordinated to Mg,
and we considered it as the starting state in the catalytic cycle.
The overall pathway is divided into two sections: ring opening
of the epoxide (Figure 1) and metathesis of the Mg‒O and H‒B
bonds (Figure2).
The catalytic pathway examined by the DFT calculations re-
veals an explicit role for the THF solvent molecules coordinated
to Mg. Therefore, we investigated the feasibility of this mecha-
nism with a non-coordinating solvent, e.g. toluene. In this case
the starting Mg‒H complex is A7e, in which two molecules of
HBpin are bound to the Mg (Figure S5 in SI). The resulting acti-
vation energy barrier for the hydride transfer step via TS1, 22.5
kcal/mol, is similar to that reported in Figure 1. Further, hy-
dride transfer to the substituted C atom of the epoxide, via tran-
sition state TS1-R, is unfavored by 2.3 kcal/mol relative to TS1.
Thus, the proposed mechanism can be considered operative
both in coordinating and non-coordinating solvents.
Mg(NTf2)2 catalyzed mechanism: Also in this case we started
by analyzing the most stable form of the Mg(NTf2)2 catalyst in
presence of substrate 1i and HBpin (for details refer to Figure
S6 in SI). The complex B1, having two THF molecules coordi-
nated to the Mg atom, is found to be the most stable form and
it is considered as the starting point of the reaction pathway.
Differently from the MgBu2 catalyzed mechanism, formation of
the Mg‒H complex is unfeasible because of the very high ender-
gonicity associated with the transfer of a hydride from HBpin
to Mg (∆G = 37.8 kcal/mol, Scheme S1 in SI). Thus, for
Mg(NTf2)2 catalyzed hydroboration we had to locate an alter-
native mechanism, devoid of a Mg‒H intermediate. The overall
reaction pathway is composed of two steps: isomerization of
epoxide to aldehyde, followed by hydroboration of the alde-
hyde (Figure 4).
Calculations indicate that a bimolecular ring opening mecha-
nism is operative, see Figure 1. The reaction pathway starts
with the transfer of a hydride from A7 to an epoxide molecule
h
coordinated to the Mg of another A7 molecule, via transition
state of TS1. This bimolecular epoxide ring opening step is re-
quired to overcome a free energy span of 24.0 kcal/mol from
the reference state corresponding to two A7 molecules. The re-
sulting ionic intermediates, A8 and A9, are 27.5 kcal/mol lower
in energy than the starting two A7 molecules. The next two
steps, from A8+A9 to A10+A11, correspond to substantially ther-
moneutral dissociation of a THF molecule from A9 yielding A10
,
and to substitution of a THF molecule of A8 by an epoxide mol-
ecule, yielding A11. The reaction proceeds by another epoxide
opening by hydride transfer from A10 to A11 via another bime-
tallic transition state, TS2. This ring-opening is clearly more
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‡
‡
1
2
1.988
3
4
5
6
7
8
9
A10
A7
A7h
A11
TS1-R
29.2
TS1-R
= THF
‡
TS2-R
5.2
1.867
TS1-R (29.2)
1.811
24.0
TS1
‡
3.2
A7+A7h
0.0
2 A7
A7h
A7
A11
TS1
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TS2-R
-17.0
A10
1i
-25.4
1.817
-27.5
-20.8
TS2
-29.8
1i
A11+A10
TS2
A8+A9
A8+A10
3
1.727
-108.4
2 A12
1.822
TS1 (24.0)
A7
A7h
A8
A9
A10
A11
Figure 1. Computed energy profile for the ring opening step in MgBu2 catalyzed hydroboration of epoxide reaction. Free energy
values at M06-2X(SMD, THF solvent)/Def2-TZVPP//PBE0/Def2-SVP level of theory are presented.
‡
‡
= THF
TS4
-42.4
-48.1
TS3
-50.8
HBpin
-51.8
A14
-48.6
h
A12
A7+PA
-54.2
A12
-62.3
A13
PA
Figure 3. Steric map of the epoxide coordinated intermediate
A7h. The percent of buried volume is reported near to each of
the quadrants. For clarity, the 3D geometry of the coordinated
epoxide is overlapped to the steric map. The scale of the steric
contours is also reported. The middle point of the epoxide C-C
bond is placed at the origin, and the epoxide O atom is placed
on the Z-axis.
Figure 2. Computed energy profile for the metathesis of Mg‒O
and B‒H bonds in MgBu2 catalyzed hydroboration of epoxide
reaction. For energy convention refer Figure 1.
The reaction starts with the replacement of a THF in B1 by the
epoxide molecule 1i generating B1b, a step endergonic by 5.5
kcal/mol. The next step is ring opening of the epoxide by nucle-
ophilic attack via the SN2 type transition state TS5 (Figure 4).
This step requires the overcoming of a free energy barrier of
29.2 kcal/mol from B1, and leads to the formation of the inter-
mediate B2, a charge separated species. The high energy inter-
mediate B2 transforms rapidly to the aldehyde coordinated
species B3 via the 1,2-H transfer transition state TS6, with a
negligible activation barrier (∆G‡ = 2.2 kcal/mol). Coordination
of a THF molecule to B3 liberates the aldehyde 4, and regener-
ates B1.
The reaction is completed by release of product PB, promoted
by coordination of a THF molecule to Mg, via transition state
TS9 and an energy barrier of 8.5 kcal/mol, regenerating the ac-
tive catalyst B1. To rationalize the experimentally observed
loss of enantioselectivity in the product, when the reaction is
catalyzed by Mg(NTf2)2, we have investigated racemization
(see Scheme 6). The reaction starts with the Mg-coordinated
alkoxide B2, which is predicted to be the structure from which
racemization starts. In B2, the THF is coordinated to the cati-
onic carbon, which is a chiral center. This THF can be replaced
with another THF via SN2 type transition state
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‡
‡
‡
1
2
δ+
δ‒
δ+
‡
‡
δ‒
3
4
5
6
7
TS5
= THF
TS6
23.1
29.2
25.3
B2
TS8
8
9
5.5
0.0
7.6
TS7
-0.3
B6
-2.1
b
B1
1i
B4+4
B1
B5
-1.0
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-4.6
-15.2
-17.4
B3
HBpin
B1+4
TS9
B8
-28.6
-37.1
-31.7
PB
B7
-50.8
B1+PB
epoxide ring opening to aldehyde
hydroboration of aldehyde
Figure 4. Computed energy profile for the Mg(NTf2)2 catalyzed ring opening hydroboration of epoxide. For energy convention refer
Figure 1.
By means of control experiments and DFT calculations, we
demonstrate that the different activation modes of HBpin are
crucial for the regiodivergency observed. Mechanistically, for
Scheme 6. Energetics for the step of racemization of
Mg(NTF2)2 catalyzed reaction.
the MgBu2 catalyzed procedure a bimolecular ring opening
mechanism is proposed in which the epoxide activation and the
hydride addition to the least substituted carbon occur simulta-
neously, providing the corresponding branched alcohols. On
the other hand, the Lewis acidic Mg(NTf2)2 facilitates the ring
opening of epoxides via an isomerization pathway, to give the
corresponding aldehyde, which subsequently undergoes hy-
droboration through a dual magnesium-ligand cooperative
HBpin activation. Due to the mild reaction conditions, the use
of readily available and non-toxic catalysts, the good chemo-,
regio- and stereoselectivities obtained for a wide range of
epoxides, the catalytic system presented can be considered a
green alternative to the existing ring opening protocols and
may be further applied to the late stage functionalizations.
+ thf
- thf
12.9
-16.0
B2
B2-TS
B2-I
Therefore, an inversion of configuration is observed at the
chiral center in the resulting intermediate, emerging a pathway
toward the formation of enantiomer of PB.
In summary, a new magnesium-catalyzed protocol has been
successfully applied to a wide range of terminal and internal
epoxides. Depending on the nature of the Mg-catalyst, a re-
giodivergent ring opening is observed. Whereas MgBu2 pro-
vides the corresponding branched alcohol, Mg(NTf2)2, allows
the formation of the linear regioisomer. To date, all transition
metal-catalyzed hydroborations of epoxides protocols provide
the linear alcohol. In contrast, the use of readily available
MgBu2 catalyzes the hydroboration of terminal and internal
epoxides in excellent regioselectivities towards the branched
isomer. Moreover, enantiopure alcohols can also be obtained
due to the enantiospecific ring opening of optically pure epox-
ides. Besides, good efficiency is also observed when less reac-
tive oxetanes are applied which again result in the branched al-
cohols in good yields and with excellent regioselectivities. To
the best of our knowledge, this is the first selective hydrobora-
tion of these unreactive compounds. On the other hand, the use
of readily available Mg(NTf2)2, containing trifluoromethanesul-
fonimide ligands, provides the linear isomer when 2,2-disub-
stituted terminal epoxides were tested.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and analytical data for all
compounds, detailed control experiments and DFT
calculations, and NMR spectra.
Luigi Cavallo: luigi.cavallo@kaust.edu.sa
Magnus Rueping: magnus.rueping@kaust.edu.sa
We would like to thank Frau Cornelia Vermeeren for the pre-
parative HPLC separation. The Deutsche Bundesstiftung Um-
welt (DBU) is acknowledged for financial support for E.
Paffenholz. We acknowledge King Abdullah University of Sci-
ence and Technology (KAUST) for support and the KAUST
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[9] Magnesium complexes containing β-Diketiminate ligands have also
Supercomputing Laboratory for providing computational re-
sources of the supercomputer Shaheen II.
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