Stereospecific conversion of alcohols into pinacol boronic esters using lithiation-borylation methodology with pinacolborane

Article abstract of DOI:10.1039/c4cc00993b

The synthesis of primary and secondary pinacol boronic esters via lithiation-borylation of carbamates and benzoates with pinacolborane is described. This new protocol enables the highly selective synthesis of enantioenriched and geometrically defined boronic esters that cannot otherwise be accessed by alternative methodologies. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00993b

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Stereospecific conversion of alcohols into pinacol
boronic esters using lithiation–borylation
methodology with pinacolborane†
Cite this: Chem. Commun., 2014,
50, 4053
Received 6th February 2014,
Accepted 26th February 2014
Stefan Roesner, Christopher A. Brown, Maziar Mohiti, Alexander P. Pulis,
Ramesh Rasappan, Daniel J. Blair, Stephanie Essafi, Daniele Leonori and
Varinder K. Aggarwal*
´
DOI: 10.1039/c4cc00993b
www.rsc.org/chemcomm
The synthesis of primary and secondary pinacol boronic esters via
lithiation–borylation of carbamates and benzoates with pinacol-
borane is described. This new protocol enables the highly selective
synthesis of enantioenriched and geometrically defined boronic esters
that cannot otherwise be accessed by alternative methodologies.
Organoboron compounds are versatile functional groups
which, in addition to cross-coupling reactions, undergo a host
of useful functional group transformations. The most common
and indeed archetypal of these transformations is their stereo-
specific conversion into alcohols.1 The reverse process, the
stereospecific conversion of an alcohol into a boronic ester,
would itself be very useful since chiral alcohols are readily
available, but such a transformation is unknown (Scheme 1A).
Related, but non-selective processes have recently been reported.
For example, alcohols have been converted into halides or
tosylates and subsequently reacted with B2(pin)2 in the presence
of Cu,2a,b Pd2c or Ni2d,e salts. These reactions are believed to
involve the metal–boryl species and occur via radical intermediates,
rendering them non-stereospecific (Scheme 1B).2
Scheme 1
that treatment of 1,1-dibromocyclopropanes with n-BuLi and
Our strategy for the conversion of alcohols into boronic esters H–B(cat) gave the cyclopropyl boronic esters via an intermediate
is based on lithiation of carbamates or hindered benzoates3 and boronate complex, followed by 1,2-hydride migration (Scheme 1C).5
subsequent borylation with H–B(pin). Related reactions had been
In this communication we show that this strategy can also
described with aryl and alkyl boronic esters in which aryl and alkyl be applied to a range of carbamates and hindered benzoates
groups migrated with expulsion of the carbamates or hindered enabling the near stereospecific conversion of readily accessible
benzoates.3 In the current strategy, a hydride would be required to chiral, non-racemic alcohols into chiral boronic esters with
migrate, a very different migrating group with very few reports high enantiomeric ratios (Scheme 1D).
in the literature.4,5 Uguen initially reported the conversion of
Initial studies focused on the benzylic carbamate 1, which
phenylsulfones to primary alcohols by reaction of a lithiated can be prepared in very high enantiopurity and on gram scale
sulfone with 9-BBN followed by oxidation.4 In this case the (ee 99%). Thus, after stereospecific lithiation6 two different
hydride migrates from a borane–ate complex, a much more facile boranes [H–B(pin) and H–B(cat)] were added leading to the corre-
process than from a boronic ester–ate complex. Danheiser showed sponding ‘boron–ate’ complexes 2 and 3. We were delighted to
find that upon warming boronic ester 4 [using H–B(pin)] was
formed in high yield and enantiospecificity (92% yield, 98% ee,
School of Chemistry, Cantock’s Close, Bristol, BS8 1TS, UK.
98% es). Despite Danheiser’s report (Scheme 1C),5 the use of
E-mail: v.aggarwal@bristol.ac.uk
H–B(cat) resulted in a very low yield of the boronic ester 40 (11%)7
(Scheme 2). This method represents a valid alternative for the
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, 1H and 13C NMR spectra of all new compounds, chiral HPLC and SFC
traces. See DOI: 10.1039/c4cc00993b
synthesis of 4 in very high enantiopurity as the metal-catalysed
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Table 1 Scope of the lithiation–borylation methodology with H–B(pin)
Entry Carbamate/benzoate Product
1
Yield (%) [es (%)]
65
83
Scheme 2
2
3
7
hydroboration of styrene proceeds with lower levels of enantio-
selectivity (98% ee vs. 92% ee).8a
69
To probe the scope of this new 1,2-metallate rearrangement
we then evaluated a selection of structurally different carb-
amates and benzoates with particular emphasis on accessing
boronic esters that are difficult to prepare using other methods
(Table 1). With primary aliphatic substrates 5 and 6, the
benzoate derivative 6 was found to be better providing the
desired product 7 in 83% yield (compare entries 1 and 2). Allylic
boronic esters are very useful intermediates in organic synthesis
that can undergo a broad range of reactions with aldehydes,9a,b
ketones,9b imines9c and as Suzuki coupling partners.9d However,
metal-catalysed conversion of allylic alcohols or related deriva-
tives to allylic boronic esters is often accompanied by iso-
merisation of variable amounts of olefin.2 Thus, geraniol was
converted into the corresponding carbamate 8 and benzoate 9
and subsequent lithiation–borylation gave the desired allylic
boronic ester 10 in good yields and as a single isomer in both
cases (entries 3 and 4).10 This method was extended to tri-
substituted allylic boronic esters, a class of substrates that are
especially problematic to be prepared using the metal-catalysed
process.2c,d Thus, deprotonation of substrates 11 and 12 followed
by addition of H–B(pin), gave the allylic boronic ester 13 in
moderate yields but as a single isomer (entries 5 and 6).10 We
then investigated the scope of secondary alcohol derivatives.
This class of compounds is particularly relevant as they are
readily available in high enantiomeric ratios. Enantioenriched
chiral benzylic boronic esters can be accessed by the asymmetric
metal-catalysed hydroboration of styrenes but certain derivatives
give low selectivities.8 For example, the Cu(I)-TangPhos catalysed
asymmetric hydroboration of p-chlorostyrene gives the boronic
ester 19 in 87% ee.8a We started our investigations using the
p-MeO substituted carbamate 14 that underwent the desired
lithiation–borylation in a good yield and 95% es (15, entry 7).
When the readily available ethyl-substituted and Cl-functionalised
4
5
6
10
13
66
49
34
7
62 [95]
64 [98]
43 [99]
76 [91]
8
9
10
11
12
53 [98]
79
carbamates 16 and 18 were exposed to the reaction conditions, and borylation gave the desired boronic ester 25 in high yield
the desired boronic esters 17 and 19 were obtained with very (entry 12).11
high levels of enantiospecificity (98 and 99% respectively,
The lithiation–borylation reactions of secondary benzylic
entries 8 and 9). Reaction of the 2-naphthyl substituted carb- carbamates are usually completely stereospecific.3c,d We were
amate 20 gave the desired boronic ester 21 in good yield surprised by the slight erosion in enantiospecificity observed
and high ee (entry 10). Non-benzylic secondary alcohol for the reaction of carbamates 14 and 20 (Table 1, entries 7
derivatives can also be employed. Thus, lithiation of chiral and 10). One possibility was that if 1,2-migration was slow then
benzoate 223e followed by addition of H–B(pin), gave dialkyl upon warming competing dissociation of the ate-complex back
secondary boronic ester 23 with high ee (96%) and good yield. to the starting Li-carbamate might take place, which could be
This methodology can also be applied to achiral secondary followed by racemisation of the Li-carbamate (Scheme 3A),
alcohols. For example, deprotonation of diaryl carbamate 24 a process we had observed with hindered boronic esters.3d
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Notes and references
1 A. Pelter and K. Smith, ‘‘Oxidation of Carbon-Boron Bonds’’ Compre-
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`
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Scheme 3
In order to probe reversibility, we added Et–B(pin) after
formation of the boron–ate complexes 26 but none of the
Et-incorporated boronic ester 27 was observed (Scheme 3B). In a
control experiment, reaction of Li-20 with a 1 : 1 mixture of HB(pin)
and EtB(pin) gave a 63 : 37 ratio of 21 :27 showing that both boronic
esters had similar reactivity towards Li-20 (see the ESI†). These
experiments ruled out reversibility as a source of the erosion in ee.
Instead, we believe that the small erosion in ee arises from a
strong preference of the boron–ate complex to adopt a con-
formation in which one of the oxygens of the pinacol ester is
positioned anti-periplanar to the carbamate. Subsequent
oxygen-assisted expulsion of the carbamate followed by hydride
migration would then occur with overall retention of configu-
ration.12 Initial computational studies support this hypothesis
(Scheme 3C). The degree to which this minor pathway occurs is
substrate dependent, but the dominant pathway remains the
stereospecific 1,2-migration with inversion.
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In conclusion we have reported the facile migration of hydride
in lithiation–borylation reactions and we have applied it to the
preparation of a variety of primary and secondary boronic esters. 10 (a) Pd-catalyzed borylation of geraniol and the mono-carbamate
analog of 11 with B2(pin)2 was also possible but 10 and 13 were
obtained as inseparable mixtures of isomers [see ESI†]; (b) For
an electrochemical approach to 10, see: J. Godeau, C. Pintaric,
Using this protocol variously substituted boronic esters can now
be obtained with very high levels of enantioselectivity and double
˜
S. Olivero and E. Dunach, Electrochim. Acta, 2009, 54, 5116–5119.
bond geometry, where current methodology is limited.
We thank EPSRC and the European Research Council (FP7/
2007-2013, ERC grant no. 246785) for support. R. R. thanks the
Marie Curie Fellowship program (EC FP7, no. 329578).
˜
11 C. Pintaric, C. Laza, S. Olivero and E. Dunach, Tetrahedron Lett.,
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