Reductive α-borylation of α,β-unsaturated esters using NHC-BH3 activated by I2 as a metal-free route to α-boryl esters

Article abstract of DOI:10.1039/c8sc04305a

Useful α-boryl esters can be synthesized in one step from α,β-unsaturated esters using just a simple to access NHC-BH₃ (NHC = N-heterocyclic carbene) and catalytic I₂. The scope of this reductive α-borylation methodology is excellent and includes a range of alkyl, aryl substituted and cyclic and acyclic α,β-unsaturated esters. Mechanistic studies involving reductive borylation of a cyclic α,β-unsaturated ester with NHC-BD₃/I₂ indicated that concerted hydroboration of the alkene moiety in the α,β-unsaturated ester proceeds instead of a stepwise process involving initial 1,4-hydroboration; this is in contrast to the recently reported reductive α-silylation. The BH₂(NHC) unit can be transformed into electrophilic BX₂(NHC) moieties (X = halide) and the ester moiety can be reduced to the alcohol with the borane unit remaining intact to form β-boryl alcohols. The use of a chiral auxiliary, 8-phenylmenthyl ester, also enables effective stereo-control of the newly formed C-B bond. Combined two step ester reduction/borane oxidation forms diols, including excellent e.e. (97%) for the formation of S-3-phenylpropane-1,2-diol. This work represents a simple transition metal free route to form bench stable α-boryl esters from inexpensive starting materials.

Full text of DOI:10.1039/c8sc04305a

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Reductive a-borylation of a,b-unsaturated esters
using NHC–BH3 activated by I2 as a metal-free
route to a-boryl esters†
Cite this: DOI: 10.1039/c8sc04305a
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
James E. Radcliffe, Valerio Fasano,
Ralph W. Adams,
Peiran You
*
and Michael J. Ingleson
Useful a-boryl esters can be synthesized in one step from a,b-unsaturated esters using just a simple to
access NHC–BH3 (NHC ¼ N-heterocyclic carbene) and catalytic I2. The scope of this reductive
a-borylation methodology is excellent and includes a range of alkyl, aryl substituted and cyclic and
acyclic a,b-unsaturated esters. Mechanistic studies involving reductive borylation of
a cyclic
a,b-unsaturated ester with NHC–BD3/I2 indicated that concerted hydroboration of the alkene moiety in
the a,b-unsaturated ester proceeds instead of a stepwise process involving initial 1,4-hydroboration; this
is in contrast to the recently reported reductive a-silylation. The BH2(NHC) unit can be transformed into
electrophilic BX2(NHC) moieties (X ¼ halide) and the ester moiety can be reduced to the alcohol with the
borane unit remaining intact to form b-boryl alcohols. The use of a chiral auxiliary, 8-phenylmenthyl
ester, also enables effective stereo-control of the newly formed C–B bond. Combined two
step ester reduction/borane oxidation forms diols, including excellent e.e. (97%) for the formation of
S-3-phenylpropane-1,2-diol. This work represents a simple transition metal free route to form bench
stable a-boryl esters from inexpensive starting materials.
Received 27th September 2018
Accepted 17th November 2018
DOI: 10.1039/c8sc04305a
rsc.li/chemical-science
multi-step nature and oxidising conditions indicate that there is
a need for other routes. This is particularly the case if the new
Introduction
a-boryl carbonyls use boron protecting groups complementary
to MIDA (in terms of stability/reagent compatibility).
Organoboranes are ubiquitous in synthetic chemistry due to the
wide range of C–Y (Y ¼ C, N, O, etc.) bond forming reactions that
can be carried out using these species.1,2 To this end, the
discovery of new C–B bond forming reactions remains of
importance and topical interest. The ability to form a-boryl
carbonyl compounds is desirable as they are functionality rich
amphoteric molecules that contain nucleophilic organoborane
and electrophilic carbonyl moieties. Until recently, these
compounds were largely overlooked in synthetic endeavours
due to their instability with respect to formation of the O-boron
enolate isomer. However, this has started to change in the last
decade due to the quaternized at B stabilization approach which
has enabled access to stable (with regard to C / O boryl
migration) a-boryl-carbonyls thereby facilitating a range of
subsequent transformations.3,4 MIDA-protected (MIDA ¼ N-
methyliminodiacetate) a-boryl carbonyls are the most explored
to date and are accessed by a hydroboration–oxidation-
rearrangement procedure (Scheme 1a).3,4 While notable, the
School of Chemistry, University of Manchester, Manchester, M13 9PL, UK. E-mail:
michael.ingleson@manchester.ac.uk
† Electronic supplementary information (ESI) available: Full synthetic methods and
characterization details (.PDF), computational details (.xyz) and crystallographic
data (.cif). CCDC 1864774–1864779. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c8sc04305a
Scheme 1 Previous main routes to quaternized a-boryl carbonyls and
this work.
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In notable previous work, the use of base-stabilized boranes that on appropriate activation NHC–boranes can react with p
and a-diazo carbonyls enabled catalysed formation of alterna- nucleophiles in an analogous manner to silanes/B(C6F5)3.18
tive (to MIDA) quaternized at boron a-boryl carbonyls (Scheme Therefore we hypothesised that NHC–BH3, upon activation, will
1b).5,6 In this area Curran et al. pioneered the use of NHC–BH3 react with a,b-unsaturated esters to generate NHC-stabilized
(NHC ¼ N-heterocyclic carbene) compounds to afford a-boryl a-boryl esters (Scheme 1d). Herein, we demonstrate that
carbonyls under transition metal or I2 catalysis.7,8 Base stabi- a wide range of a,b-unsaturated esters undergo highly selective
lised a-BH2-carbonyl products are bench stable and stable to reductive a-borylation using a simple NHC–BH3 compound and
strong bases/nucleophiles,5,6 and thus are complementary to catalytic I2 as an activator. This represents a facile, metal free
MIDA-boronates which while being bench/acid stable are route to bench stable a-boryl-esters (including quaternary
sensitive to strong bases.9 In comparison, a-Bpin esters and organoborane and diastereoselective examples) that are
amides (produced via a novel Cu catalyzed 1,4-hydroboration/ amenable to further functionalisation, for example to afford
isomerization process) are not bench stable and are highly enantiopure diols.
sensitive to protodeboronation due to their non-quaternized at
B nature.10 Base stabilised organoboranes, including a-BH2-
esters, can be utilised in a range of functional group trans-
Results and discussion
formations including the Suzuki–Miyaura reaction on appro-
priate activation.5–11 However, the current synthetic approaches
to base stabilised a-BH2 carbonyls generally require diazo
compounds (of which extremely limited examples are
commercially available), precluding the formation of quater-
nary a-boryl carbonyls, while their more hazardous nature
provides an additional drawback. Very recently, Zhu and co-
workers demonstrated that a-boryl carbonyls also can be
accessed by gold-catalysed oxidative coupling of terminal
alkynes with Lewis base–borane adducts (Scheme 1c), while
notable this is limited to forming primary a-boryl carbonyls.12
Therefore the formation of a wide range of bench stable a-boryl-
carbonyl derivatives in one-pot from simple starting materials
without using transition metal catalysis was an unsolved
problem before this work.
An attractive route to a-boryl carbonyls that is the focus of
this work is 3,4-hydroboration of a,b-unsaturated carbonyls,
where the boryl group is selectively added at the 3 position,
termed reductive a-borylation (Scheme 1d). While the reductive
b-borylation of a,b-unsaturated carbonyl species has been re-
ported,13,14 we are aware of no previous examples of selective
reductive a-borylation of substrates such as cinnamates and
crotonates. It should be noted that NHC–BH3 can reductively
borylate strong Michael acceptors (Mayr E values > ꢀ18);
however, the direct reaction between NHC–BH3 and a,b-unsat-
urated carbonyl derivatives that are weaker Michael acceptors
does not proceed (ethyl cinnamate has an E value of ꢀ24.5 for
example, Scheme 2).15 Furthermore, the catalysed hydro-
boration of a,b-unsaturated carbonyl compounds using
common boranes (e.g. CatBH and PinBH) proceeds via 1,4-
hydroboration.16 Recently, the Chang group reported the
reductive a-silylation of a,b-unsaturated carbonyls, using
silanes/B(C6F5)3.17 Previous work from some of us has indicated
This work commenced with the assessment of the relative
stability of the O- and C-boron bound isomers derived from
reductive borylation of a,b-unsaturated carbonyls using NHC–
BH3. Notably, previous work calculated that a-boryl esters are
thermodynamically favored compared to the O-boron enolate
isomer when the boron moiety is B(diol), whereas when it is
BMe2 the two isomers are effectively isoenergetic (DG <
1 kcal molꢀ1). The BMe2 analogue is more Lewis acidic at boron
and thus also had a low energy barrier to interconversion
between the O- and C-boron bound isomers.19 Reductive bor-
ylation will require electrophilic NHC–BH2Y (Y ¼ I, NTf2 etc.)
species, which will possibly form NHC–BHY(R) on reaction with
a,b-unsaturated esters before hydride transfer from NHC–BH3
occurs.20,21 Thus it was feasible that there would be a low barrier
to interconversion between O- and C-BH2(NHC) bound isomers
mediated by NHC–BHY(R). In this case the relative stability of
the two isomers would dramatically affect the product distri-
bution. Calculations therefore were carried out at the M06-2X/6-
311G(d,p) level with a CH2Cl2 solvation model (polarizable
continuum model, PCM). The a,b-unsaturated carbonyls
analyzed were butenal, pentenone, 2,2-dimethylhexenone, N,N-
dimethyl buteneamide and methyl crotonate (Scheme 3). The
NHC–borane adduct used was IMe–BH3 (IMe ¼ 1,3-dimethyl-
imidazol-2-ylidene), as it is the smallest and most readily
accessed NHC–borane.12 For the ketones and aldehydes it was
found that the O-boron enolates were favored over the a-boryl
carbonyl isomers. In contrast, it was found that for the ester and
amide substrates, the a-boryl carbonyl products were more
stable (by 12.1 and 7.8 kcal molꢀ1, respectively). Based upon
these ndings we investigated the borylation of unsaturated
esters and amides using NHC–BH3/activator.
Scheme 2 Previous work on reductive borylation of Michael accep- Scheme 3 Calculated relative energies of O- and C-BH2(IMe) bound
tors using NHC–BH3.
isomers.
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For reaction optimisation IMe–BH3 and I2 were selected due
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to their low cost (or simple synthesis), ease of handling (IMe–
BH3 is bench stable) and facile reactivity to give electrophilic
IMe–BH2I.7,20,21 Methyl crotonate, 1a, was mixed with IMe–BH3
in CDCl3 followed by addition of 10 mol% I2 (Fig. 1, top). NMR
spectroscopic analysis aer 2 h showed a new triplet 11B reso-
nance at ꢀ25.4 ppm (1JBH ¼ 90 Hz) consistent with the desired
reductive a-borylation product, 2a (Fig. 1). However, under
these conditions longer reaction times did not lead to accept-
able conversion, with the retention of a signicant amount of
methyl crotonate even aer 2 days. Optimization studies (see
ESI†) identied increasing the concentration as key, as previ-
ously observed by Curran and co-workers,7 with a 1 M reagent
concentration leading to the highest yield in a reasonable
timeframe (ca. 70% conversion aer 20 hours at room temper-
ature). It should be noted that other electrophilic activators
previously used with NHC–BH3, e.g. HNTf2 and B(C6F5)3, led to
poorer outcomes.22 Recent work has demonstrated that radical
initiators can enable alkyne cyclisation reactions and alkyne
trans-hydroboration using NHC–BH3.23,24 Therefore the use of
tert-butylhydroperoxide (TBHP) was explored under comparable
conditions to those reported for trans-hydroboration. However,
heating a mixture of IMe–BH3, 1a and 20 mol% TBHP in
benzene for 18 hours led to no reductive a-borylation.
Fig. 2 Substrate scope of the reductive a-borylation reaction. (a) ¼
20 mol% I2. (b) ¼ diastereomeric ratios obtained by 1H NMR analysis of
the reaction mixture. (c) ¼ yields from in situ 1H NMR spectroscopy
versus an internal standard. Isolated yields are provided in parentheses.
(d) ¼ isolated yield of the d2 isotopomer.
In order to probe the effect of varying the NHC, iPr–BH3 and
BenzIMe–BH3 were explored (Fig. 1). While both of these NHC–
boranes successfully led to reductive a-borylation of 1a upon
activation with I2, the conversions were lower than when using
IMe–BH3 under identical conditions (70% versus 43 and 34%, 2e). Increasing the substitution at the a or b position was viable
respectively), thus in further reactions IMe–BH3 was used. X-ray (e.g. 2f and 2g), with the formation of 2g being notable as it
diffraction studies (Fig. 1, inset) further conrmed the formu- contains a quaternary center and thus cannot be accessed via
lation of 2a and 4a. A substrate screening study revealed that procedures starting from the a-diazo-ester. Cyclic esters were
a wide range of acyclic and cyclic a,b-unsaturated esters gave also amenable (2h, 2i, and 2j), with the reductive borylation of
good-to-moderate yields of the reduced a-boryl ester products furanone proceeding with a yield of 61%, and 2i successfully
2a–r (Fig. 2). Generally, it was found that a,b-unsaturated esters crystallized, with the solid-state structure from X-ray diffraction
with b-alkyl substituents gave good yields (e.g. 2a, 2b, 2d and studies demonstrating the expected connectivity. The diaster-
eoselectivity in the formation of 2j was moderate (d.r. ¼ 77 : 23).
Cinnamates were also viable substrates and were borylated in
moderate yields of 40–55% (2k–2n). Functionalisation at the
para-position of the cinnamate phenyl ring with electron with-
drawing groups and electron donating groups (–Cl, –Br, –NO2,
and –Me) was possible with comparable yields (2o–2r). It should
be noted that attempts with a,b-unsaturated ketones led to no
signicant a-borylated carbonyl products, in line with our
calculations and previous work where C]O hydroboration
occurs for similar compounds.25 Using the optimized condi-
tions the reaction was amenable to scaling up to produce 0.9 g
of 2a and 1.0 g of 2k.
Attempts to extend the optimized procedure to a,b-unsatu-
rated amides led to complete amide consumption but with the
formation of complex mixtures in which the desired a-boryl
amide was only a minor intractable component (with N,N-diethyl-
crotonamide, 5a, and N,N-dimethylprop-2-enamide, 5b). This is
in contrast to reductive a-silylation which proceeds with both a,b
unsaturated esters and amides (including 5a).17 Compound 1b
Fig. 1 Top: formation of a-boryl carbonyls 2a–4a. Inset left: solid-
which undergoes reductive borylation and 5b have effectively
identical E parameters on the Mayr electrophilicity scale
state structure of 2a, inset right: solid-state structure of 4a, ellipsoids at
the 50% probability level. Most hydrogens omitted for clarity.
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(E ¼ ꢀ23.59 and ꢀ23.54, respectively),26 and thus they would be
expected to react at similar rates with unhindered nucleophiles,
in contrast to what is observed here. Notably, while the E
parameters are similar there is a signicant difference in the
nucleophilicity of esters and amides as Lewis bases towards
boron electrophiles, with amides being signicantly more Lewis
basic than esters towards B(C6F5)3.27 Therefore the in situ NMR
spectra were analyzed for any disparities between these esters
and amides on addition to IMe–BH2I/IMe–BH3 mixtures. On
combining a range of a,b-unsaturated esters/IMe–BH3/I2 (at
various I2 loadings) in chloroform IMe–BH2I is observed (d11B
ꢀ31 ppm) as the only new boron-containing species at short
reaction times (at longer times the a-boryl esters are also
observed with no intermediates detected). Thus these esters do
not displace the iodide from boron in IMe–BH2I to any observ-
able extent. In contrast, on combining IMe–BH3/I2 and 5a or 5b
minimal IMe–BH2I is observed (even when using 50 mol% I2).
Instead, a new broad 11B resonance (at ꢀ10.6 and ꢀ11.4 ppm
when using 5a and 5b, respectively) is observed (Scheme 4). These
products are assigned as the products from amide coordination
to {IMe–BH2}+, with the d11B being consistent with [IMe–BH2(L)]+
boronium cations,18 and NHCBH2(OR) species.28 Furthermore,
the NMR spectra obtained immediately aer combining stoi-
chiometric 5a and IMe–BH2I revealed that the d11B ꢀ10.6 ppm
species forms concomitantly with two new vinylic resonances in
the 1H NMR spectrum indicating the persistence of the a,b-
unsaturated moiety and the absence of any observable hydride
transfer to form the O-boron enolate (which only has one vinylic
proton). Aer longer reaction times (24 h) this stoichiometric
reaction produced the a-boryl amide as only a minor product.
The reactivity disparity between amides and esters suggested
that coordination of carbonyl moieties to [IMe–BH2]+ does not
lead to effective reductive a-borylation, at least for amide
derivatives. This suggested that pathway (i) (Scheme 5, top) may
not be operating for the reductive a-borylation of esters and that
an alternative mechanism needs to be considered. Specically,
we considered a concerted addition of a B–H unit of IMe–BH2I
across the double bond, prior to hydride transfer from another
IMe–BH3 molecule (Scheme 5, bottom) as proposed for the
hydroboration of simple alkenes.21,22 Mechanistic insight
initially was sought via reductive borylation using a mixture of
BenzIMe–BH3 and IMe–BD3; however, this was inconclusive as
combining IMe–BD3 and BenzIMe–BH3 in CDCl3 solution with
catalytic I2 led to rapid H/D exchange. Next the KIE was deter-
mined to be approximately 1.0 when using IMe–BD3 and IMe–
BH3 in the reductive a-borylation of 1a (initial KIE values ranged
Scheme 5 Pathways (i) and (ii) for reductive a-borylation of a,b-
unsaturated esters.
from 0.95 to 1.1). However, the absence of a signicant KIE does
not discriminate between either of the pathways, as a p complex
(where the alkene has displaced the iodide) is potentially an
intermediate in the hydroboration pathway using NHC–BH2I.21
Thus iodide displacement (by the carbonyl or by the alkene)
is potentially the rate limiting step in both pathways. Finally,
the reduction of cyclic ester 1i with IMe–BD3/catalytic I2 was
used to probe the stereoselectivity of reductive borylation, with
a concerted hydroboration mechanism (pathway (ii)) leading to
D and IMe–BD2 addition to the same face while pathway (i) is
expected to give a mixture of isomers due to the lack of any
facial discrimination during isomerization of the O-boron
3
enolate to the a-boryl ester. The JHH coupling constant
between HA and HB (Scheme 6) for the d3-isotopomer of 2i
(d3-2i) allowed for assignment of a syn-conguration for the
3
IMe–BD2 and D groups.29–33 Specically, the JHH coupling was
8.2 Hz, in good agreement with the 7.1 Hz (Karplus) and 9.7 Hz
(Altona) values predicted for the syn-conguration of IMe–BD2
and D for 2i (calculated based upon the solid-state structure of
2i). The alternative isomer (see the inset in Scheme 6) had
a calculated 3JHH of <2 Hz and no d3-2i product containing this
arrangement of D and IMe–BD2 was observed. Based upon these
observations we conclude that a-borylation of this unsaturated
ester using IMe–BH3/I2 occurs via a concerted addition mech-
anism (pathway (ii)).
Scheme 4 Reactivity disparity on combining a,b-unsaturated amides
and esters with NHCBH2I.
Scheme 6 . Reductive borylation of 2i with IMe–BD3.
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The transformation of the BH2IMe group in 9 into BPin also
was explored briey. Compound 9 was combined with pinacol
in dry toluene, and then NCS was added to form the reactive
(towards ROH) –BCl2(NHC) congener in situ. 11B NMR spec-
troscopy displayed a major signal at 34 ppm consistent with an
alkyl-BPin, but upon work-up the desired product 10 (Scheme 8)
was only a minor component (31%). Two de-hydroxylated
products, 11 and 12, were produced alongside 10 (Scheme 8),
in a combined yield of 51%. The formation of 11 and 12 is
tentatively attributed to a Bora–Peterson reaction36 between the
alcohol moiety and an electrophilic boryl group (e.g. RBCl(H)–
IMe) derived from 9/NCS which would on B–O bond formation
eliminate the alkene (allylbenzene) and a reactive B–H species
that can effect hydroboration of allylbenzene (the subsequent
reaction with pinacol would then give 11 and 12). Any acid
initiated alcohol dehydration steps to form an alkene (for
hydroboration) are disfavored due to comparable outcomes
(formation of 10, 11 and 12) being observed in the presence and
absence of amine bases (HCl is the expected by-product from
addition of pinacol to B–Cl species). Due to the competitive
formation of 10, 11 and 12 and the greater step efficiency of
using the NHC–BH2R species directly the direct functionalisa-
tion of the C–B moiety in 9 was explored. Compound 9 could be
oxidized directly to 3-phenylpropane-1,2-diol using standard
oxidation conditions for organoboranes (H2O2/NaOH) con-
rming the utility of these NHC-organoboranes and obviating
the need for prior conversion to BPin (or other boron moieties).
With the feasibility of direct oxidation demonstrated this
process was extended to enantioenriched products by per-
forming reductive a-borylation on a,b-unsaturated esters con-
taining chiral auxiliaries. The reductive a-borylation of methyl
cinnamate with menthyl as the chiral auxiliary proceeded with
minimal diastereoselectivity (2s d.r. ¼ 57 : 43); however, the two
products could be readily separated by column chromatog-
raphy. Crystals of 2s were grown enabling characterization by
X-ray crystallography and unambiguous assignment of stereo-
chemistry for both products of the reaction (Fig. 3). The more
bulky 8-phenyl menthyl group was next utilized as a chiral
auxiliary as it has been successfully used to induce high
Scheme 7 Formation of dihalo derivatives. (i) ¼ selectfluor/MeCN and
(ii) ¼ NCS, toluene. Inset, solid state structure of 6, ellipsoids at 50%
probability (hydrogens omitted for clarity).
A series of reactions were carried out to functionalize these a-
boryl esters. Curran et al. have shown that NHC–BH2-(R) can be
converted to NHC–BX2(R) intermediates (X ¼ halide) that are
electrophilic at boron.11 Using the reported conditions IMe–BF2-
ester, 6, was synthesized (quantitatively by in situ NMR spec-
troscopy) and isolated in 46% yield aer purication by column
chromatography, with X-ray diffraction conrming the formu-
lation (Scheme 7). The IMe–BCl2-derivative, 7, was also acces-
sible (again quantitatively by in situ NMR spectroscopy) through
the reaction of 2a with N-chloro-succinimide (NCS). Attempts to
transform 2a into the a-BPin-ester derivative by addition of
NCS/pinacol under various conditions (with and without H2O/
triethylamine, the latter as a base to sequester the expected
HCl by-product) led instead to protodeboronation with no a-
BPin congener observed. Furthermore, attempts to use 6 or 7 in
a range of Suzuki–Miyaura cross coupling protocols were
unsuccessful in our hands, including conditions reported by
Chiu et al.10 for the cross-coupling of a-BPin esters, instead the
protodeborylated product dominated. These observations are
consistent with the sensitivity of non-quaternized a-boryl ester
derivatives to rapid protodeboronation,10 in contrast to bench/
column stable 2a–r.
Seeking transformations that cannot be achieved with a-
BPin ester analogues, the reduction of 2a to the alcohol was
explored next with b-boryl alcohols previously reported and
shown to be useful intermediates.34 Both LiAlH4 and DIBAL
were used with 2a to form the IMe–BH2-alcohol, 8 (Scheme 8),
with no aldehyde observed under a range of conditions/reagent
stoichiometry (lower equivalents of DIBAL instead led to a lower
conversion to the alcohol and unreacted starting material). A
phenyl analogue, 9, can also be accessed, e.g. by addition of
DIBAL to 2k. It should be noted that in contrast to 2a (or 2k)
organoBPin derivatives undergo transformation at boron with
LiAlH4, to form [RBH3]ꢀ species.35 Thus the successful conver-
sion of 2a (or 2k) to 8 (or 9) demonstrates the complementarity
of the a-BPin and a-BH2NHC ester congeners.
Fig. 3 a-boryl esters containing chiral auxiliaries. Left, solid state
structure of 2s (the major diastereomer) and right, 2t (the minor dia-
stereomer), ellipsoids at 50% probability and most hydrogens omitted
Scheme 8 Reduction of a-boryl esters and subsequent reaction with for clarity. Values shown are for isolated yields of the diastereomeric
NCS/pinacol.
mixtures.
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as an oily solid. The product was subsequently puried by
column chromatography (SiO2, 9 : 1 ethyl acetate : pet. ether) to
yield 897 mg of a white crystalline solid (56% yield). The identity
and purity of the title compound was conrmed by 1H, 13C{1H}
and 11B NMR spectroscopy. Crystals suitable for X-ray crystal-
lography were successfully grown by slow evaporation of
a chloroform solution conrming the molecular structure.
1H NMR (400 MHz, chloroform-d) d 6.82 (s, 2H), 3.74 (d, J ¼
1 Hz, 6H), 3.44 (d, J ¼ 1 Hz, 3H), 1.72 (m, 2H), 1.38 (t, J ¼ 8 Hz,
1H), 0.87 (t, J ¼ 7 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-
d) d 182.9, 120.4, 50.4, 41.6–38.7 (m), 36.1, 26.4, 15.1. 11B NMR
(128 MHz, chloroform-d) d ꢀ25.3 (t, J ¼ 90 Hz).
Scheme 9 Reduction of a single diastereomer of 2s and subsequent
oxidation to form S-3-phenylpropane-1,2-diol.
diastereoselectivity in Diels–Alder reactions using acrylates.37 In
this case, two diastereomeric products of 2t were isolated in
a 87 : 13 d.r. aer reductive a-borylation at room temperature
(again these were readily separable by column chromatog-
raphy). Conrmation of the major and minor components was
achieved by X-ray diffraction. Finally, we investigated the
possibility of transforming the enantiopure organoborane
products into the chiral diol in two steps without isolation of
any intermediates. A single diastereomer of 2s was reduced to
the alcohol using LiAlH4 and, aer extraction, the crude reac-
tion mixture was oxidized to yield S-3-phenylpropane-1,2-diol in
an overall 65% yield, with no observable reduction in enantio-
purity which was >97% (by chiral HPLC, Scheme 9).
Synthesis of d3-2i
A Young's ampule was charged with IMe–BD3 (137 mg,
1.2 mmol) and placed under an N2 atmosphere. CHCl3 (1 mL)
was added, followed by furanone (71 mL, 1 mmol) before the
mixture was cooled to 0 ꢁC. Iodine (25 mg, 0.1 mmol) was added
causing rapid effervescence, aer which the solution was
allowed to warm to room temperature and le to stir for 24
hours. The solvent was then removed under vacuum to yield
a crude product as an oily residue. The product was puried by
column chromatography (SiO2, 95 : 5 DCM : MeOH) to yield the
product (78 mg, 40% yield). The identity of the product was
conrmed as that of the title compound by 1H, 13C and 11B NMR
spectroscopy. Crystals of compound d3-2i suitable for X-ray
diffraction studies were grown by slow evaporation from
a chloroform solution, and the resulting structure was used as
an input to determine predicted H–H coupling constants via the
Karplus and Altona methods.
Conclusions
In conclusion, iodine activation of a bench stable borane, IMe–
BH3, enables reductive a-borylation of a range of readily
accessible (and in many cases commercially available) a,b-
unsaturated esters. This procedure represents a simple route to
bench stable quaternized (at B) a-boryl-esters that does not
require transition metal catalysis. It is applicable to a wide
range of ester substrates including cyclic, acyclic, and highly
substituted derivatives and chiral precursors, the latter enable
high diastereoselectivity in the reductive borylation step.
Mechanistic studies reveal that concerted hydroboration
proceeds in contrast to the mechanism for reductive a-silyla-
tion. The a-boryl ester products could be converted readily into
the B–X (X ¼ F and Cl) derivatives and b-boryl alcohols and
glycols, including an example proceeding with high enantio-
purity demonstrating the utility of this process and the
products.
1H NMR (400 MHz, chloroform-d) d 6.81 (d, J ¼ 2.0 Hz, 2H),
4.46–4.35 (m, 1H), 4.28–4.15 (m, 1H), 3.70 (s, 6H), 2.31 (s, 1H),
1.77 (s, 1H). 13C{1H} NMR (101 MHz, chloroform-d) d 187.9,
171.3–165.6 (m), 120.6, 67.6, 35.9, 33.5–28.2 (m).
11B NMR (128 MHz, chloroform-d) d ꢀ27.4 (br). 2H NMR
(61 MHz, chloroform-d) d 1.87 (s, br), 1.76–1.15 (m).
Synthesis of 2k
A Schlenk ask was charged with IMe–BH3 (1.32 g, 12 mmol)
and methyl cinnamate (1.62 g, 10 mmol) before placing under
an N2 atmosphere. CHCl3 (10 mL) was added and the resulting
solution was cooled to 0 ꢁC. Iodine (506 mg, 2 mmol) was added
causing instant effervescence and the reaction was allowed to
warm to room temperature. The mixture was le to stir for 20
hours, aer which time the solvent was removed under vacuum
to yield a pale yellow oil as the crude product. The product was
puried by column chromatography (SiO2, 2 : 1 ethyl aceta-
te : pet. ether), yielding 1.01 g of a clear colourless oil (37%
yield). The identity of the product was conrmed as the title
compound by 1H and 11B NMR spectroscopic data matching
with those previously reported in the literature.8
Experimental
For general considerations see the ESI.†
Synthesis of 2a
A Schlenk ask was charged with IMe–BH3 (1.00 g, 9.1 mmol)
and placed under an N2 atmosphere before CHCl3 (7.5 mL) was
added. Methyl crotonate (0.80 mL, 7.6 mmol) was added to the
ask and the resulting reaction solution was cooled to 0 ꢁC.
Iodine (192 mg, 0.76 mmol) was added to the mixture causing
Synthesis of 2s
instant effervescence and the reaction was allowed to warm to A Young's ampule was charged with menthyl cinnamate
room temperature. Aer being le to stir for 24 hours the (286 mg, 1 mmol) and IMe–BH3 (132 mg, 1.2 mmol) before
solvent was removed under vacuum, yielding the crude product placing under an N2 atmosphere. CHCl3 (1 mL) was added and
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the resulting solution was cooled to 0 ꢁC prior to addition of successfully crystallised from slow cooling of a hot hexane
iodine (51 mg, 0.2 mmol). Effervescence was observed and the solution conrming the structure of the product, and allowing
solution was allowed to warm to room temperature before being for the assignment of the stereochemistry of the C–B bond as
le to stir for 20 hours. The solvent was removed under vacuum the S conguration for the minor component, conrming that
giving an oily white residue which was puried by column the major component has the R conguration at the C–B.
chromatography (SiO2, ethyl acetate : pet. ether 1 : 1 / 2 : 1
2t major diastereomer. 1H NMR (400 MHz, chloroform-d)
varying polarity). Two diastereomeric products were isolated d 7.25–7.03 (m, 8H), 6.99–6.93 (m, 2H), 6.74 (s, 2H), 4.41 (td,
(total yield 191 mg, 48%; major: 108 mg, minor: 83 mg, 57 : 43 J ¼ 11, 4 Hz, 1H), 3.59 (s, 6H), 3.07 (dd, J ¼ 14, 10 Hz, 1H), 2.61
d.r.). The identity of the products as that of the title compounds (dd, J ¼ 14, 4 Hz, 1H), 1.94–1.85 (m, 1H), 1.66–1.54 (m, 2H),
was conrmed by 1H, 13C{1H} and 11B NMR spectroscopy. 1.54–1.45 (m, 2H), 1.43–1.35 (m, 2H), 0.96 (d, J ¼ 5 Hz, 6H),
Crystals of the major diastereomer suitable for X-ray diffraction 0.93–0.77 (m, 2H), 0.73 (d, J ¼ 7 Hz, 3H), 0.70–0.56 (m, 1H), 0.09
were successfully grown by evaporation of a DCM solution (q, J ¼ 12 Hz, 1H).
conrming the molecular structure of the compound, and
allowing for the assignment of the stereochemistry at the C–B 129.1, 127.9, 127.8, 125.9, 125.2, 124.7, 120.4, 72.7, 51.0, 41.6,
13C{1H} NMR (101 MHz, chloroform-d) d 180.9, 152.3, 145.3,
bond as the R conguration.
39.7, 39.6, 36.3, 34.9, 31.0, 27.1, 26.6, 26.0, 22.1.
2s major diastereomer. 1H NMR (400 MHz, chloroform-d)
d 7.24–7.14 (m, 4H), 7.12–7.03 (m, 1H), 6.79 (s, 2H), 4.37 (td,
11B NMR (128 MHz, chloroform-d) d ꢀ25.0 (t, J ¼ 90 Hz).
2t minor diastereomer. 1H NMR (400 MHz, chloroform-d)
J ¼ 11, 4 Hz, 1H), 3.76 (s, 6H), 3.06 (dd, J ¼ 14, 11 Hz, 1H), 2.72 d 7.29–7.23 (m, 4H), 7.20–7.17 (m, 4H), 7.15–7.05 (m, 2H),
(dd, J ¼ 14, 4 Hz, 1H), 2.22 (s, 1H), 1.61–1.26 (m, 6H), 1.10–0.98 6.75 (s, 2H), 4.70 (td, J ¼ 10.5, 4.3 Hz, 1H), 3.73 (s, 6H), 2.96 (dd,
(m, 1H), 0.97–0.84 (m, 1H), 0.78 (d, J ¼ 6 Hz, 3H), 0.69 (d, J ¼ J ¼ 13.9, 9.0 Hz, 1H), 2.62 (dd, J ¼ 13.9, 6.0 Hz, 1H), 2.22–2.14
7 Hz, 3H), 0.51 (d, J ¼ 7 Hz, 3H), 0.36 (q, J ¼ 12 Hz, 1H).
(m, 1H), 1.78 (ddd, J ¼ 12.1, 10.4, 3.4 Hz, 1H), 1.68–1.60 (m, 1H),
13C{1H} NMR (101 MHz, chloroform-d) d 181.2, 145.1, 128.7, 1.43–1.35 (m, 2H), 1.28 (s, 3H), 1.20–1.17 (m, 3H), 1.08 (dq, J ¼
127.8, 125.0, 120.4, 71.3, 47.3, 41.2, 39.8, 39.7, 36.4, 34.5, 31.3, 13.3, 3.3 Hz, 1H), 0.97–0.84 (m, 2H), 0.80 (dd, J ¼ 12.6, 3.2 Hz,
25.7, 23.4, 22.3, 20.9, 16.3.
1H), 0.74 (d, J ¼ 6.4 Hz, 3H), 0.71–0.60 (m, 2H).
11B NMR (128 MHz, chloroform-d) d ꢀ25.1 (t, J ¼ 70 Hz).
13C{1H} NMR (101 MHz, chloroform-d) d 181.4, 151.2, 144.2,
2s minor diastereomer. 1H NMR (400 MHz, chloroform-d) 128.9, 128.0, 127.8, 125.9, 125.2, 125.1, 120.6, 73.7, 50.6, 42.0,
d 7.21–7.16 (m, 4H), 7.10–7.03 (m, 1H), 6.78 (s, 2H), 4.45 (td, J 40.7, 39.7, 36.3, 34.7, 31.3, 31.0, 27.7, 22.4, 21.9.
¼ 11, 4 Hz, 1H), 3.75 (s, 6H), 3.08 (dd, J ¼ 15, 10 Hz, 1H), 2.71
(dd, J ¼ 15, 5 Hz, 1H), 2.25 (s, 1H), 1.74–1.65 (m, 1H), 1.59–1.52
(m, 2H), 1.47–1.31 (m, 2H), 1.25–1.15 (m, 1H), 0.99–0.86 (m,
1H), 0.81 (d, J ¼ 7 Hz, 3H), 0.80–0.72 (m, 2H), 0.71 (d, J ¼ 7 Hz,
3H), 0.54 (d, J ¼ 7 Hz, 3H).
11B NMR (128 MHz, chloroform-d) d ꢀ25.8 (t, J ¼ 87 Hz).
General catalytic substrate screening protocol
An oven dried J. Young's NMR tube was equipped with a d6-
benzene lled capillary and charged with IMe–BH3 (0.6 mmol)
before placing under an N2 atmosphere. Chloroform (0.5 mL)
was added, followed by the desired a,b-unsaturated ester
(0.5 mmol). The resulting starting material solution was ana-
lysed by 1H, 11B and 11B{1H} NMR spectroscopy to provide
a comparison for reaction monitoring. Solid I2 (0.05 or
0.1 mmol) was added to the reaction mixture causing major
effervescence in the tube, and 1H, 11B and 11B{1H} NMR spectra
were recorded at t ¼ 0. Subsequently, the reaction was set to mix
for 20 hours, aer which time further NMR spectroscopic
analysis was undertaken. Mesitylene (0.5 mmol) was added to
13C{1H} NMR (101 MHz, chloroform-d) d 181.5, 144.6, 128.5,
127.9, 125.1, 120.5, 72.0, 47.1, 41.2, 39.6, 36.4, 34.5, 31.4, 25.2,
23.0, 22.2, 21.3, 15.9.
11B NMR (128 MHz, chloroform-d) d ꢀ25.2 (t, J ¼ 89 Hz).
Synthesis of 2t
A Young's ampule was charged with 8-phenyl-menthyl cinna-
mate (362 mg, 1 mmol) and IMe–BH3 (132 mg, 1.2 mmol) before
placing under an N2 atmosphere. CHCl3 (1 mL) was added and
the resulting solution was cooled to 0 ꢁC prior to addition of
iodine (51 mg, 0.2 mmol). Effervescence was observed and the
solution was allowed to warm to room temperature before being
le to stir for 20 hours. Subsequently, mesitylene (139 mL,
1 mmol) was added and an aliquot of the reaction solution was
removed and subjected to NMR spectroscopic analysis to
determine the degree of substrate consumption. This indicated
a combined conversion of 72%. The sample was returned to the
bulk solution before the solvent was removed under vacuum to
yield the crude product mixture as an oily white residue. Two
diastereomeric products were isolated by column chromatog-
1
the sample, and H NMR spectroscopy allowed for the in situ
reaction yield to be measured by integration of the product
signals relative to mesitylene.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
raphy (SiO2, ethyl acetate : pet. ether 1 : 1 / 2 : 1 varying This work was made possible by nancial support from the
polarity) as 167 mg and 26 mg (41% total yield, 87 : 13 d.r.). The EPSRC (EP/M023346/1 and EP/K039547/1) and the Horizon
identities of the products were conrmed by 1H, 13C{1H} and 11
B
2020 Research and Innovation Program (Grant No. 769599). Dr
NMR spectroscopy. Crystals of the minor diastereomer were Daniele Leonori is thanked for useful discussions. Additional
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