Unsymmetrical 1,1-diborated multisubstituted sp3-carbons formed via a metal-free concerted-asynchronous mechanism

Article abstract of DOI:10.1039/c5ob01523e

We have experimentally proved the unsymmetrical 1,1-diboration of diazo compounds, formed in situ from aldehydes and cyclic and non-cyclic ketones, in the absence of any transition metal complex. The heterolytic cleavage of the mixed diboron reagent, Bpin-Bdan, and the formation of two geminal C-Bpin and C-Bdan bonds has been rationalised based on DFT calculations to occur via a concerted-asynchronous mechanism. Diastereoselection is attained on substituted cyclohexanones and DFT studies provide understanding on the origin of the selectivity. The alkoxide-assisted selective deborylation of Bpin from multisubstituted sp³-carbon and generation of a Bdan stabilized carbanion, easily conducts a selective protodeboronation sequence.

Full text of DOI:10.1039/c5ob01523e

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Unsymmetrical 1,1-diborated multisubstituted
sp3-carbons formed via a metal-free
Cite this: DOI: 10.1039/c5ob01523e
concerted-asynchronous mechanism†
Ana B. Cuenca, Jessica Cid, Diego García-López, Jorge J. Carbó* and
Elena Fernández
We have experimentally proved the unsymmetrical 1,1-diboration of diazo compounds, formed in situ
from aldehydes and cyclic and non-cyclic ketones, in the absence of any transition metal complex. The
heterolytic cleavage of the mixed diboron reagent, Bpin–Bdan, and the formation of two geminal C–Bpin
and C–Bdan bonds has been rationalised based on DFT calculations to occur via a concerted-asynchro-
nous mechanism. Diastereoselection is attained on substituted cyclohexanones and DFT studies provide
understanding on the origin of the selectivity. The alkoxide-assisted selective deborylation of Bpin from
multisubstituted sp3-carbon and generation of a Bdan stabilized carbanion, easily conducts a selective
protodeboronation sequence.
Received 23rd July 2015,
Accepted 29th July 2015
DOI: 10.1039/c5ob01523e
www.rsc.org/obc
Introduction
1,1-Diborylalkanes are attracting the attention of synthetic
researchers since Shibata and co-workers demonstrated in
2010 that two consecutive Suzuki–Miyaura cross-coupling
(SMC) reactions can be performed in a chemo and regiospeci-
fic manner, even at room temperature.1 This new concept,
based on the protection-free selective cross-coupling on a
multisubstituted sp3-carbon, succeeded by virtue of the adja-
cent B atom in 1,1-diborylalkanes (Scheme 1). When chiral
ligands modify the Pd complex, the reaction can take place
Scheme 1 Protection-free cross-coupling on
sp3-carbon.
a
multisubstituted
through
a
stereochemical-determining transmetallation
with inversion of configuration at carbon.2 The accomplish-
ment of a second cross-coupling reaction guarantees the for-
mation of unsymmetrical diarylated compounds from simple
1,1-dibromoalkanes.3
The unsymmetrical formation of 1,1-diborylalkane com-
pounds has been elegantly performed by the groups of Hall4a
and Yun,4b through copper mediated asymmetric borylation of
β-boronylacrylates (Scheme 2a) and asymmetric hydroboration
of borylalkenes (Scheme 2b), respectively. Both strategies
share the fact that the substrate already contains the C–Bdan
functionality (Bdan = 1,8-naphthalenediaminatoboryl) and
the Bpin moiety (Bpin = pinacolboryl) is stereoselectively intro-
Scheme 2 Copper mediated unsymmetrical step wise formation of
1,1-diborylalkane compounds and further functionalization.
Department Química Física i Inorgànica, University Rovira i Virgili, C/Marcel lí
Domingo s/n, Tarragona, Spain. E-mail: j.carbo@urv.cat
†Electronic supplementary information (ESI) available. CCDC 1409206–1409208.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5ob01523e
duced using a copper catalyst modified with a chiral ligand.
Interestingly, although in both cases the enantioselection is
transferred along the Suzuki–Miyaura cross-coupling5 (via
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Table 1 1,1-Diboration of aldehydes and ketones with Bpin–Bdan, via
N-tosylhydrazone/diazo intermediate formationa
NMR yieldb Isolated yieldc
Entry Substrate
1
Product
(%)
(%)
Scheme 3 Metal-free carbon insertion of N-tosylhydrazones into
Bpin–Bdan.
75
71
2
3
4
81
68
83
75
49
71
the trifluoroborate salt), the configuration is inverted for β,β′-
diboronylacrylates and retained for 1,1′-diborylalkanes.
To complete the picture of the synthesis and application of
1,1-diborylalkane compounds,6,7 two parallel strategies have
proved their efficiency in formal 1,1-diboration with a sym-
metrical B–B bond: (a) Pt-catalysed diborylation of diazo-
alkanes with Bpin–Bpin8,9 and (b) metal-free carbon insertion
of N-tosylhydrazones into Bpin–Bpin.10
Inspired by the last strategy, we planned here to study the
heterolytic B–B bond cleavage, from the Bpin–Bdan diboron
reagent, employing N-tosylhydrazones derived from aldehydes
and ketones. In particular, for N-tosylhydrazones derived from
cyclic ketones, we looked at the potential of diastereoselection
when employing diazo precursors possessing diastereotopic
π faces (Scheme 3). We have also elucidated, by means of DFT
calculations, a plausible mechanism for the 1,1-diboration of
Bpin–Bdan as well as the diastereoselective preferences,
together with a prediction of the functionalization of the Bpin
unit.
5
6
82
95
73
77
7
8
55
44
43
27
a Reaction conditions for N-tosylhydrazone formation: substrate
(0.25 mmol), TsNHNH2 (0.25 mmol), MeOH, 2–3 h, rt; for hydrazone
sodium salt formation: NaH (1.2 eq.),
1 h, rt; for diazoalkane
generation and insertion: BpinBdan (1.2 eq.), 110 °C, 16 h. b Yield
calculated by NMR spectroscopy with ferrocene as the internal
standard. c Isolated yield calculated based on the aldehyde or ketone
substrate.
Results and discussion
We initiated our study by reacting hydrocinnamaldehyde (1)
with N-tosylhydrazine. After isolation and recrystallization of
the corresponding tosylhydrazone (2), the sodium salt of the
tosylhydrazone was generated in situ by treatment with NaH
(1.2 eq.) at rt. After 1 h, at this temperature, 1.2 eq. of Bpin–
Bdan was added and the reaction was heated to promote the
formation of the diazo intermediate and the subsequent
formal carbon insertion in the unsymmetrical B–B bond.
Upon workup, the target 1,1-diborylalkane compound (3) was
isolated in 71% yield (Table 1, entry 1). Interestingly, when
N-tosylhydrazone 2 was used without purification, the final
1,1-diborylalkane product 3 was isolated in a comparable iso-
lated yield, 75% (Table 1, entry 2). Encouraged by this promis-
ing streamlined 1,1-diboration with an unsymmetrical diboron
reagent, we sought to transform a series of aldehydes into 1,1-
diborylalkane compounds following this one-pot insertion
strategy. The aliphatic aldehydes were converted into the
desired products in comparable good yields (Table 1, entries
3–6). Particularly noteworthy was the conversion of substrates
4 and 6 featuring an increased steric bulkiness around the Cα.
Extension of the 1,1-diboration protocol to ketones, such as
benzylacetone (12) and 2-hexanone (14) resulted in a dimin-
ished reactivity towards the corresponding 1,1-diborylalkanes
13 and 15, respectively, most probably due to the steric
hindrance.
A plausible mechanistic pathway has been elucidated by
DFT calculations11 using Bpin–Bdan and CH3(H)CN2 as model
diazoalkane. Scheme 4 summarizes the outcome of these
calculations. We were able to locate a transition state for the
formation of the two carbon–boron bonds that indicate the
occurrence of a concerted, yet asynchronous mechanism with
a free energy barrier of 30.8 kcal mol−1 (Fig. 1). As the nucleo-
philic diazo carbon attacks at the electron deficient boron of
the Bpin moiety, the 1,2-boron migration of the Bdan moiety
occurs to yield the 1,1-diboron intermediate and concomitant
release of the dinitrogen. A similar mechanism has been
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Scheme 4 Proposed mechanism for diazo compound type insertion of
CH3(H)CN2 into Bpin–Bdan. Calculated free energies (and electronic
energies in brackets) in kcal mol−1
.
Scheme 5 1,1-Diboration of substituted cyclohexanones and trans-
decalone. a Yield determined by NMR spectroscopy with ferrocene as
the internal standard. b Isolated yield based on the ketone.
Fig. 1 Molecular structure and main geometric parameters of the tran-
sition state for diazo compound type insertion into the Bpin–Bdan
molecule. Distance in angstroms.
obtained as a major diastereoisomer in a (70/30) proportion
(Scheme 5). A similar diastereoselection has been observed for
the 1,1-diboration of 4-methyl-, 4-tert-butyl-, 4-isopropyl-, and
4-phenylcyclohexanones with a major diastereomeric ratio
observed for 20a/20b (75/25) (Scheme 5). Diastereoisomers
16a–20a could be isolated in a pure form. Through the X-ray
analysis of suitable single crystals of 16a (Fig. 2) the di-
equatorial (trans) position of the Bdan fragment and the CF3
group was unequivocally established. There is only one pre-
cedent in the literature that reports the 1,1-diboration of 4-Ph-
cyclohexanone (20) with B2pin2, with comparable yields but,
logically, without diastereoselection due to the symmetry of
the diboron reagent.10b When we conducted the 1,1-diboration
of 3-Ph-cyclohexanone (21) with BpinBdan, the diastereomeric
ratio 64/36 was in favor of the stereoisomer 21a with Bdan and
Ph in cis relative configuration (Scheme 5). Unfortunately, 2-
Ph-cyclohexanone did not undergo any insertion reaction,
likely due to steric hindrance. Interestingly, the analogue 2-
Me-cyclohexanone (22) did react with BpinBdan providing the
highest stereoselection of 96/4 in favor of the diastereomer
with Bdan and Ph in a trans configuration (Scheme 5). As a
postulated for the metal-free insertion of diazoalkanes into
HBpin, Me2PhSi–Bpin and Bpin–Bpin.10 In those cases, the
authors proposed a process that may initiate with the for-
mation of a Lewis acid–base interaction between the diazo-
alkanes and the Bpin moiety, prior to the 1,2-migration of the
H, Me2PhSi, or Bpin fragment. To further analyze the diboron
addition and the possible formation of a stable Lewis acid–
base adduct, we performed a relaxed potential surface scan
along different values of the C–Bpin bond (see Fig. S1†). Start-
ing at the transition state, only in the free-energy curve, we
could observe a very shallow minimum when the C–B distance
was increased (at ∼1.83 Å), and its estimated free energy
barrier for dissociation was very low, ∼1 kcal mol−1. Thus, we
can conclude that the nucleophilic attack and the 1,2-boron
migration occurs in a concerted but asynchronic manner. We
have also characterized an analogous pathway in which the
diazo carbon attacks at the other boron of the Bdan moiety. As
expected,12 the lower Lewis acidity of the Bdan fragment
increases the energy barrier by ∼2 kcal mol−1. For comparison,
we analyzed the diazoalkane insertion into symmetric Bpin-
Bpin, finding the same concerted, yet asynchronous, mechan-
ism and a very similar free energy barrier, 29.7 kcal mol−1 (see
the ESI†).
With the aim of exploring the diastereoselection in the multi-
substituted sp3-carbon formed, we selected a series of cyclic
ketones to in situ generate the diazo compound and promote
the insertion into the Bpin–Bdan molecule. Interestingly,
when 4-(trifluoromethyl)cyclohexanone (16) was subjected to
the diboration protocol, the corresponding insertion took
place in a diastereoselective manner and compound 16a was
Fig. 2 X-Ray structure determination for major product 16a.
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proof of concept, we selected trans-1-decalone (23) to be trans- (∼5 kcal mol−1) due to the destabilizing 1,3-diaxial interactions
formed into the corresponding diazo compound and explore with a cyclohexane structure (see Scheme 7 and Fig. S2†).
its insertion into the Bpin–Bdan molecule. To our delight, the Thus, the computed lowest energy path conducts the experi-
new multisubstituted sp3-carbon was formed with moderate mentally obtained diastereoisomer with Bdan and CF3 substi-
yield but outstanding diastereoselectivity, towards the isomer tuents in the equatorial position and trans to each other (16a,
with the Bdan moiety in the equatorial position 23a see the X-ray structure in Fig. 2).
(Scheme 6).
Starting at the diazo conformer with an axial CF3 (16Nax in
The DFT analysis of the origin of diastereoselective prefer- Scheme 7, right), we observed similar free energy barriers to
ences is summarized in Schemes 7 and S1 (ESI).† For 4-(tri- those from 16Neq, 33.9 and 37.7 kcal mol−1 for Bdan addition
fluoromethyl)cyclohexanone (16), we considered two possible in equatorial (16b) and axial positions (16a′), respectively. This
chair conformations with the CF3 substituent in the equatorial indicates that the substituent in the para position has little
or axial position, the equatorial conformer (16Neq) being influence on the reaction center. However, the axial CF3 shifts
1.7 kcal mol−1 lower than the axial one (16Nax). The species up the energy of both paths and the approach of Bdan through
16Neq can attack at the Bpin–Bdan substrate through its two the less hindered equatorial channel (16b) becomes 1–2 kcal
diastereofaces (Scheme 7, left) and the computed free energy mol−1 higher than the path conducting to 16a.
barriers are 33.9 and 38.9 kcal mol−1. The latter path, leading
Since the energy difference is not too large, we expect a
the Bdan in the axial position (16b′) is higher in energy non-negligible formation of diastereoisomer 16b with Bdan
and CF3 substituents in cis that agrees with the observed dia-
stereoisomeric ratio 70/30. For 2-Me-cyclohexanone (22) the
DFT analysis of the diastereoisomerism shows a similar
pattern to 16 (see Scheme S1 in the ESI†), but bringing the
substituent from the para to the ortho position has a direct
influence on the reaction center. Thus, the path leading to
the minor diastereoisomer (22b) is destabilized by the cis-1,2
interactions of Bdan and methyl substituents in ∼5 kcal mol−1
(see Fig. S3 and Scheme S1†), resulting in a significant
increase of diastereoselectivity for ortho-substituted cyclo-
hexanones.
Taking advantage of the potential diastereoselection on this
new metal-free 1,1-diboration of cyclic ketones, we selected
5-α-cholestan-3-one (24) to transform its carbonyl functional
group into a chiral multisubstituted sp3-carbon in a one-pot
protocol. Scheme 8 illustrates the formation of the chiral gem-
diborated product in 70% yield with a diastereomeric ratio
65/35, with the Bdan unit located in the equatorial position
and Bpin in the axial position, as the preferred isomer.
Scheme 6 1,1-Diboration of trans-1-decalone (23). a Yield determined
by NMR spectroscopy with ferrocene as the internal standard. b Isolated
yield based on the ketone. c X-ray structure determination of major
isomer 23a.
Scheme 7 Proposed diastereoisomeric pathways for the 1,1-diboration of 4-CF3-cyclohexanone with Bpin–Bdan. Relative Gibbs free energies in
kcal mol−1
.
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Fig. 4 Alkoxide-assisted protodeboronation process.
(Scheme S2†), but the reaction path is shifted up in energy by
∼4 kcal mol−1, and the resulting α-(pinacolato)boronate carba-
nion is less stable than the α-(1,8-naphthalenediaminato)boro-
nate by 12.3 kcal mol−1. According to NBO analysis, the Bpin
fragment supports a less negative charge (−0.14e) than the
Bdan fragment (−0.21e), as inferred from the corresponding
HOMO orbitals (Fig. 3). Thus, selective functionalization of the
Bpin position is expected.
Alike computational results, the exclusive diastereoisomer
22a was efficiently protodeboronated into the corresponding
trans-25(H) (Fig. 4) in the presence of 5 eq. KOtBu at rt. Simi-
larly we conducted the protodeboronation on the diastereo-
meric mixture of 17a/17b14 and 21a/21b to afford principally
the trans-26(H) and cis-27(H), respectively (Fig. 4). This is a
new approach towards the diastereoselective C–H bond for-
mation, which complements other efficient protodeborona-
tions on tertiary diarylalkyl boronic esters or tertiary
aryldialkyl boronic esters, with CsF–H2O or TBAF·3H2O,
respectively.15
Scheme 8 1,1-Diboration of 5-α-cholestan-3-one (24) and X-ray struc-
ture determination of major isomer 24a. a Yield determined by NMR
spectroscopy with ferrocene as the internal standard. b Isolated yield
based on the ketone.
Our next goal was to establish
a selective C–Bpin
functionalization from the enriched diastereoselective gem-
diborated products. It has been recently described that the alk-
oxide-assisted deborylation and generation of a boron-stabi-
lized carbanion, from 1,1-bis(pinacolboronate)esters, allow the
reactivity with alkyl halides.13 Initially, we analyzed computa-
tionally the reactivity of 1,1-diborylalkanes with alkoxides
using CH3(H)C(Bpin)(Bdan) and MeO− as model substrates
(Scheme S2†). As determined previously,12 the methoxy group
interacts preferentially with the Bpin moiety forming a stable
Lewis acid–base adduct. From this adduct, the deborylation to
give the carbanion occurs with a moderate free energy barrier
(21.9 kcal mol−1). Moreover, the stabilization of the carbanion
using the α-Bdan moiety is reflected in the HOMO orbital,
which shows strong delocalization of the carbanion p-type
electron density into the π-channel of the Bdan moiety
(Fig. 3, left). Analogously, the Bdan could be also activated
Conclusions
In summary, we proved the metal-free 1,1-diboration of an
unsymmetrical Bpin–Bdan diboron reagent to aldehydes and
ketones, via diazo compounds. We have disclosed that the
carbon–boron formation might occur in a concerted, yet asyn-
chronous, way. High diastereoselectivity can be achieved in
ortho substituted cyclohexanones due to a combination of
repulsive 1,3-diaxial and 1,2-cis interactions with the diboron
reagent. In addition, this synthetic strategy can be used to
obtain multifunctional chiral centers. Finally, it is possible to
deborate selectively the Bpin group via protodeboration in the
presence of bases since the Bdan moiety stabilize better than
the transient carbanion species.
Acknowledgements
Research supported by the Spanish Ministerio de Economia y
Competitividad (MINECO) through projects CTQ2013-43395P
and CTQ2011-29054-C02-01.
Notes and references
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carbanion lone pair, for α-(1,8-naphthalenediaminato)boronate anion
(left) and α-(pinacolato)boronate (right).
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