A clear-cut example of selective Bpin-Bdan activation and precise Bdan transfer on boron conjugate addition

Article abstract of DOI:10.1002/chem.201304615

Activating the non-symmetrical Bpin-Bdan diboron reagent with alkoxide leads to the formation of two possible adducts: MeO^-→Bpin-Bdan or MeO^-→Bdan-Bpin. Experimental and theoretical investigation confirms that the MeO^-→Bpin interaction is preferred and thus selective formation of a C-Bdan bond upon reaction with an activated C=C bond.

Full text of DOI:10.1002/chem.201304615

DOI: 10.1002/chem.201304615
Communication
&
Boron
A Clear-Cut Example of Selective BpinꢀBdan Activation and
Precise Bdan Transfer on Boron Conjugate Addition**
Jessica Cid, Jorge J. Carbꢀ,* and Elena Fernꢁndez*[a]
Abstract: Activating the non-symmetrical BpinꢀBdan di-
boron reagent with alkoxide leads to the formation of two
possible adducts: MeOꢀ!BpinꢀBdan or MeOꢀ!Bdanꢀ
Bpin. Experimental and theoretical investigation confirms
that the MeOꢀ!Bpin interaction is preferred and thus se-
lective formation of a CꢀBdan bond upon reaction with
an activated C=C bond.
The Lewis acidity of the boron atom is the key factor govern-
ing the reactivity of organoboron compounds. The vacant p or-
bital of the boron atom can be partially filled with the electron
lone pair of adjacent atoms, tuning the Lewis acid property. Ni-
trogen atoms donate their lone pair of electrons, thus lowering
the acidity significantly in comparison with that of the corre-
sponding oxygen atoms of boronic acids and their esters.[1] Di-
Scheme 1. Synthesis of CbꢀBdan carbonyl compounds.
amines, which form cyclic diaminoboranes, increase the overall
stability of the boryl species, thus reducing the reactivity.[2] In-
terestingly, organoboranes with CꢀBdan moieties (dan=1,8-di-
aminonaphthalene) are particularly easy to handle because the
only one example in the literature in which BpinꢀBdan has
dan moiety act as a masking group on the boron atom.[3–5] So
been used to diborate alkynes in a regioselective manner, and
far, Bpin moieties have been exclusively transferred from sym-
metric reagent, B2pin2 (1), to unsaturated substrates, but the
pinacol substituent on the boron center does not mask the
boron atom towards further interactions. In that context, the
interest of generating CbꢀBdan enoates 2 was justified because
they have served as intermediates towards the copper-mediat-
ed asymmetric conjugate borylation (Scheme 1, pathway b)[6]
or alkylation (Scheme 1, pathway c)[7] with total efficiency.
However, nowadays, the synthesis of CbꢀBdan enoates requires
a multistep synthetic methodology (Scheme 1, pathway a).[8]
We became interested in developing a method to access di-
rectly chiral alkylboronate derivatives containing the Bdan
moiety from commercially accessible a,b-unsaturated esters
the activation of the diboron by transition-metal complexes
was required.[11]
Initially, we computationally explored the potential reactivity
of the BpinꢀBdan reagent. Previous DFT studies by Bo et al.
have already demonstrated the nucleophilic character of the
B(sp2) moiety of MeOꢀ!BpinꢀBpin adducts.[10b,12] Subsequent-
ly, a tendency map was constructed based on DFT calculations
and NBO analysis of ground-state structures in order to estab-
lish a gradient in the nucleophilic character of trivalent boron
moieties.[13a] An approach based on structure–activity relation-
ships (SAR) can be used to screen a large and varied dataset of
compounds for homogeneous catalysis.[14] The boron p/s ratio
in the MꢀB s bond was considered an indicator of the intrinsic
nucleophilicity of the boryl fragment, based on a previous
work of Lin and Marder.[13b] For diboron reagents that are acti-
vated with Lewis bases, the p/s ratio of the B(sp2) atom is rela-
tively low with respect to the corresponding fragment bonded
to Pt (Figure 1). This indicated the greater polarizability of the
B(sp2) moiety in the BꢀB bond, and consequently, its propensi-
ty to react with soft electrophiles. Moreover, the MeOꢀ ion in-
duced greater polarization of the BꢀB bond than the nitrogen-
and carbon-donor Lewis bases.[13a] Thus, we initially calculated
the p/s ratio of the boron atom, from the Bdan(sp2) moiety, in
the MeOꢀ!Bpin-Bdan adduct in other to evaluate the poten-
tial of Bdan as a nucleophilic boryl moiety.[15] The computed
and ketones, following
a
catalytic b-boration reaction
(Scheme 1, pathway d).[9] Towards this new strategy, we envis-
aged the activation of the mixed diboron reagent, BpinꢀBdan
(3), with an alkoxide.[10] To the best of our knowledge, there is
[a] J. Cid, Dr. J. J. Carbꢀ, Dr. E. Fernꢁndez
Department Quꢂmica Fꢂsica i Inorgꢃnica
University Rovira i Virgili, C/Marcel·li Domingo s/n
E-mail: j.carbo@urv.cat
maraielena.fernandez@urv.cat
[**] pin=Pinacol; dan=1,8-diaminonaphthalene.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304615.
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These results prompted us to use the BpinꢀBdan
reagent in the organocatalyic b-boration reation of
a,b-unsaturated carbonyl compounds. We adapted
the synthetic protocol from Suginome’s method,[11]
by
mixing
tetrakis(dimethylamino)diboron,
B2(NMe2)4,[17] with 1,8-diaminonaphthalene and pina-
col in a 1:1:1 ratio. In the presence of a base and
MeOH, some spectroscopic evidences demonstrated
the formation of the Lewis acid–base adduct [ROꢀ!
BpinꢀBdan]. The original 11B NMR spectra of the
mixed diboron reagent BpinꢀBdan, in MeOH as sol-
vent, shows signals at 28.5 and 25.2 ppm owing to
the sp2 Bpin and sp2 Bdan fragments, respectively.
After the addition of 1 equiv of NaOtBu, one of the
signals completely shifted to higher fields (1.59 ppm),
Figure 1. Relative distribution of p/s ratio of the orbital population of the boron atom in
B-Pt(PMe3)2Cl moieties and Lewis acid–base adducts.
p/s value, 1.15, is within the range (1.03–1.19) of other tested
diboron compounds activated with Lewis bases (Figure 1).[13a]
Although the tendency map identifies Bdan as a potential
nucleophilic boryl moiety,[13a] its semi-quantitative nature does
not allow discerning whether the Bdan moiety is more or less
reactive than the Bpin moiety. Therefore, we performed
a more detailed DFT study in order to compare the reactivity
of both adducts (Figure 2).[15] Using the CH2CHCHO substrate
as the simplest model of a,b-unsaturated carbonyl compound,
we located the transition states (TSs) corresponding to the nu-
with one signal remaining at low field (33.2 ppm). The new
signal might correspond to the sp3 Bpin moiety of the adduct
[ROꢀ!BpinꢀBdan] in agreement with previous spectroscopic
evidences of [ROꢀ!BpinꢀBpin].[10] This finding is also in agree-
ment with the DFT calculations that suggested the preferred
formation of the Lewis acid–base adduct [MeOꢀ!Bpin-Bdan].
With the aim of activating organocatalytically BpinꢀBdan (3)
and selectively transfer the Bdan moiety to activated olefins,
we first attempted to find the optimal conditions for the b-bo-
ration of 4-hexen-3-one with BpinꢀBdan (Table 1). When the
reaction was carried out in MeOH as solvent at 708C, no b-bo-
rated product was observed. The sole addition of 9 mol% of
Table 1. Optimization of reaction conditions for the organocatalytic b-bo-
ration of 4-hexen-3-one (4) with BpinꢀBdan (3).[a]
Entry
Additive Base
Conv CbꢀB(dan) (5) CbꢀOMe (5-OMe)
[%][b]
[%][c]
[%][c]
1
2
3
4[d]
5
—
NaOtBu 72
—
99
99
99
60
99
99
—
—
—
40
—
PCy3
PCy3
PCy3
PPh3
PPh3
—
99
NaOtBu 99
NaOtBu 23
NaOtBu 99
Figure 2. Relative MeOꢀ!BpinꢀBdan and MeOꢀ!BdanꢀBpin adduct forma-
tion and relative reactivity with CH2CHCHO. Electronic energies in kcalmolꢀ1
.
6
—
70
[a] Reaction conditions: substrate (0.25 mmol), BpinꢀBdan (0.275 mmol),
base (9 mol%), PR3 (6 mol%), MeOH (2 mL), 708C, 16 h. [b] Conversion
calculated by averaging GC-MS data from two reactions. [c] Selectivity
calculated by 1H NMR analysis. [d] 258C.
cleophilic attack of the Bpin(sp2) and Bdan(sp2) moieties at the
b-carbon atom of the olefinic group. The computed energy
barrier for the Bdan group (+12.0 kcalmolꢀ1) is higher than
that for the Bpin moiety, +4.2 kcalmolꢀ1, indicating that the
Bdan(sp2) has a lower nucleophilic character than Bpin(sp2).
However, owing to the p donation from nitrogen lone pair to
boron empty orbital, the acidity of the boron unit is weakened
NaOtBu favored the formation of 5-methoxy-hexan-3-one (5-
OMe) as the only product, with a conversion of 72% (Table 1,
and has less tendency to add the alkoxide. The MeOꢀ!Bpinꢀ entry 1). It seemed that the MeOH–base interaction provided
Bdan adduct is 7.4 kcalmolꢀ1 lower in energy than MeOꢀ!
BdanꢀBpin. In this scenario, the 1,8-diaminonaphtalene group
might protect the boron atom from alkoxide attack, forming
preferentially the MeOꢀ!BpinꢀBdan reagent, which only
needs to overcome a modest energy barrier to release Bdan as
a nucleophile.[16]
the methoxy group that directly attacked the substrate instead
of activating BpinꢀBdan. However, when no base was present
in the reaction media and PCy3 was added as additive
(6 mol%), the substrate was totally transformed into the b-bo-
rated product 5 with exclusive formation of the CbꢀBdan
bond, (Table 1, entry 2).
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The use of phosphines to assist the organocatalytic b-bora-
tion reaction of a,b-unsaturated carbonyl compounds was al-
ready demonstrated.[18] The presence of base and the use of
phosphine as an additive was beneficial (Table 1, entry 3), and
the reaction was observed even at 258C (Table 1, entry 4). The
nature of the phosphine is also important. When PPh3 was
used together with NaOtBu as base, selectivity towards the b-
borated product decreased to 60% with the generation of 5-
methoxy-hexan-3-one (5-OMe) as byproduct (Table 1, entry 5).
But once again, when no base was present and PPh3 assisted
the reaction, the b-borated product was exclusively formed,
but with lower conversion (Table 1, entry 6). Importantly, the
activation of BpinꢀBdan (3) with the alkoxide exclusively ren-
ders CbꢀBdan formation as no CbꢀBpin product has been de-
tected. The scope of substrates was also a subject of study.
Under optimized reaction conditions, we were able to general-
ize the selective transfer of the Bdan moiety to a variety of
a,b-unsaturated ketones and esters (Figure 3).
Scheme 2. Comparative asymmetric b-boration of 4 with B2pin2 and Bpinꢀ
Bdan assisted by (R)-(+)-MeO-BIPHEP diphosphine.
[PMe3!BpinꢀBdan] adduct. Similar conclusion was made from
the spectroscopic studies carried out in 11B NMR and 31P NMR
by mixing BpinꢀBdan and PMe3. Recently, Bo et al. computa-
tionally characterized the role of the phosphine in the organo-
catalytic b-boration of a,b-unsaturated ketones and esters with
the BpinꢀBpin reagent.[18] In that previous study, the role of
the phosphine was associated with the preactivation of the
substrate, by forming a phosphonium salt. Following previous
proposal,[18] we suggest a catalyt-
We recently pointed out that chiral phosphines can assist
the asymmetric organocatalytic b-boration of a,b-unsaturated
ic cycle that starts with the plau-
sible phosphine attack on the
electrophilic carbon atom of the
a,b-unsaturated carbonyl com-
pound, yielding the zwitterionic
phosphonium enolate, species B
in Figure 4. In the presence of an
excess of methanol, a MeOH
molecule might be hydrogen
bonded to the a-carbon atom of
intermediate B, species
C in
Figure 4. This species may act as
a Brçnsted base, deprotonating
directly the MeOH molecule;
however, the process is comput-
ed to be thermodynamically dis-
favored by 5.1 kcalmolꢀ1. From
C, two ion pairs can be also
formed by the interaction with
BpinꢀBdan: the [a-H,b-PMe3-pro-
Figure 3. Substrate scope of selective organocatalytic b-boration of a,b-unsaturated carbonyl compounds with
BpinꢀBdan under the conditions listed in Table 1 and PCy3 as additive. IY=isolated yield. [a] 18% of b-methoxy
byproduct was observed.
carbonyl compounds with B2pin2.[10a] In the present study, we
explored this possibility and conducted a parallel b-boration of
model substrate 4, with B2pin2 and BpinꢀBdan in the presence
of (R)-(+)-MeO-BIPHEP diphosphine, (R)-(+)-(6,6’-dimethoxybi-
phenyl-2,2’-diyl)bis(diphenylphosphine). Scheme 2 shows that
the asymmetric induction in the organocatalytic CbꢀBdan for-
mation is much higher (ee=80%) than that observed in the
formation of the CbꢀBpin bond (ee=23%). Other chiral phos-
phines such as Josiphos-type ligands provided similar results
to the b-boration with B2pin2.
pionaldehyde]+[MeOꢀ!BdanꢀBpin], Da, (Figure 4, mechanis-
m a) and the [a-H,b-PMe3-propionaldehyde]+[MeOꢀ!Bpinꢀ
Bdan], Db, (Figure 4, mechanism b). The corresponding
energies associated to the formation of ion pair Da
(+5.6 kcalmolꢀ1) and Db (ꢀ7.5 kcalmolꢀ1), clearly shows the fa-
vored formation of ion pair Db, in which the Bpin moiety acts
as the preferred Lewis acid. Moreover, the energy barrier to
reach ion pair Db is significantly lower than that calculated to
reach ion pair Da, 4.0 and 13.9 kcalmolꢀ1, respectively. These
results are coherent with previous experimental findings in
which quantitative formation of the phosphonium species re-
quired the presence of the diboron reagent,[18] and indicate
that the Bdan moiety is not as good a Lewis acid as the Bpin
moiety.
To get more insight into the selective addition of Bdan
moiety in the presence of phosphines as additive, we per-
formed a systematic DFT study using PMe3 and CH2CHCHO as
model phosphine and substrate, respectively. First of all, DFT
studies related to the plausible interaction of PMe3 with Bpinꢀ
Bdan demonstrated the lack of stability of the corresponding
In the next step, it has been suggested that the enhanced
nucleophilic sp2 boryl unit in ion pairs Da and Db might trans-
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Figure 4. Suggested catalytic cycle for b-boration of acrylaldehyde with BpinꢀBdan diboron reagent in the presence of MeOH and PMe3. Mechanism a depicts
the CbꢀBpin formation and mechanism b illustrates the CbꢀBdan formation. Relative electronic energies in kcalmolꢀ1
.
fer the Bpin moiety or the Bdan moiety, respectively, to the b-
carbon atom of another molecule of substrate through transi-
tion state TSDꢀE. For both types of boryl units, the process is
strongly exothermic, ꢀ51.5 kcalmolꢀ1 for Bpin release in mech-
anism a and ꢀ41.9 kcalmolꢀ1 for Bdan release in mechanism b.
As it was found for the free anionic adducts depicted in the
Figure 2, the activated Bpin(sp2) moiety is more reactive than
duction in a more efficient way than the analogous borylation
with B2pin2. This new method allows the selective preparation
of CbꢀBdan carbonyl compounds in a selective and straightfor-
ward manner.
Acknowledgements
¼
the Bdan(sp2) one (DE =13.0 and 25.3 kcalmolꢀ1, respective-
Research supported by the Spanish Ministerio de Economia y
Competitividad (MINECO) through projects CTQ2010-16226
and CTQ2008-06549-C02-01/BQU and by the Direcciꢀ General
de Recerca (DGR) of the Autonomous Government of Catalonia
(grants 2009SGR462 and XRQTC). J. C. thanks URV for grant.
ly). However, if we look at the overall catalytic cycle, transition
state TSDꢀE is the most energetically demanding, and this is
higher in energy for Bpin release (TSaDꢀE) than for Bdan release
(TSbDꢀE) by ca. 1 kcalmolꢀ1. Thus, the computed overall catalyt-
ic cycle explains the observed selectivity from both the ther-
modynamic and the kinetic point of view. Thermodynamically,
the deprotonation of methanol requires the enhanced Lewis
acidity of the Bpin moiety in BpinꢀBdan by forming the
[MeOꢀ!BpinꢀBdan] adduct. Kinetically, the overall energy bar-
rier to transfer the Bdan moiety from the ion pair to acrylalde-
hyde is somewhat lower than that for Bpin transfer.
Keywords: boration · density functional theory · diboron
reagents · nucleophilic boron
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Received: November 25, 2013
Published online on February 24, 2014
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