Asymmetric organocatalytic diboration of alkenes

Article abstract of DOI:10.1039/c2ob26079d

The use of chiral alcohols to form the Lewis acid-base *RO ^- → bis(pinacolato)diboron adduct, in situ, provides an opportunity to induce asymmetry in the organocatalytic diboration of alkenes and complements the well established transition metal-mediated enantioselective diboration.

Full text of DOI:10.1039/c2ob26079d

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COMMUNICATION
Asymmetric organocatalytic diboration of alkenes†‡
Amadeu Bonet, Cristina Sole, Henrik Gulyás* and Elena Fernández*
Received 4th June 2012, Accepted 5th July 2012
DOI: 10.1039/c2ob26079d
The use of chiral alcohols to form the Lewis acid–base *RO−
→ bis(pinacolato)diboron adduct, in situ, provides an oppor-
tunity to induce asymmetry in the organocatalytic diboration
of alkenes and complements the well established transition
metal-mediated enantioselective diboration.
The activation of diboron reagents had generally been attributed
to a direct interaction between the reagent and transition metal
complexes,1 until Miyaura and coworkers observed that AcO−
activated diborons by Lewis acid–base interactions.2 The result-
ing AcO− → diboron adduct facilitated the heterolytic cleavage
of the B–B bond and the transfer of one boryl moiety to a
copper(I) salt (Scheme 1a). Recently, it has been demonstrated
that it is possible to activate diboron reagents in the absence of
metals, by the sole addition of electron donor reagents
(Scheme 1b), such as amines,3 N-heterocyclic carbenes4 and alk-
oxides.5,6 This pre-activation increases the reactivity of the
Scheme 2 Plausible catalytic cycle for the asymmetric organocatalytic
diboration reaction.
reagent towards both inorganic and organic electrophiles.7
We have recently explored the addition of the MeO− → bis-
(pinacolato)diboron adduct to non-activated olefins. This was
achieved by activation of the diboron reagent by the in situ
formation of a nucleophilic boryl moiety and represented the
first example of a metal free diboration reaction.8
became interested in the extension of this methodology to permit
an asymmetric variant by using chiral alcohols as additives
(Scheme 2). Chiral alcohols are frequently good “chiral pool”
materials due to their ready accessibility from nature. Hitherto
the enantioselective diboration reaction has elegantly been
accomplished by Morken and coworkers,9,10 using rhodium and
platinum complexes modified with chiral bidentate and mono-
dentate ligands. But, to the best of our knowledge, the asym-
metric metal free version has not yet been reported.
Since the catalytic system for the organocatalytic diboration of
non-activated olefins is a combination of base and alcohol, we
To initiate the study on the asymmetric organocatalytic dibora-
tion reaction, a small but representative library of alcohols
(1–10) was selected to induce asymmetry in the addition of bis
(pinacolato)diboron to vinylcyclohexane as a model substrate
(Scheme 3). The use of 2 equiv. of chiral alcohols 1, 3, 4, 6 and
7 afforded negligible conversion (<10%). Chemoselectivity
towards the diborated product versus the hydroborated product
was expected to be high in accordance with the use of the MeO−
→ bis(pinacolato)diboron adduct,8 however none of the chiral
alcohols tested provided quantitative chemoselectivity on the
diborated product. The primary alcohol 5, a pyranose derivative,
was rather efficient in transforming the vinylcyclohexane into the
diborated product, but the enantioselectivity was low (Table 1,
entry 2). Only (S)-1-phenylethanol (10) induced enantioselec-
tivity up to 24%, although the conversion was low and the
chemoselectivity was only moderate (Table 1, entry 5).
Scheme 1 Lewis acid–base adducts: (a) Miyaura first observation,
(b) current versions.
Dept. Química Física i Inorgànica, University Rovira i Virgili,
C/Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
E-mail: mariaelena.fernandez@urv.cat;
http://argo.urv.es/tecat/catalytic_organoborane_chemistry.php
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26079d
‡This paper is dedicated to Prof. Sergio Castillon on his 60th birthday.
This journal is © The Royal Society of Chemistry 2012
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Table 2 Optimisation of the reaction conditions in asymmetric metal
free diboration of vinylcyclohexane with bis(pinacolato)diboron and
alcohol 10a
Conv. (%)b Diboronb eed
Entry Base (mol%) t (h) T (°C) [%]c
(%)
(%)
1
2
3
4
Cs2CO3(15)
Cs2CO3(15)
Cs2CO3(80)
Cs2CO3(100) 16
NaOtBu(100) 16
NaOMe(100) 16
Cs2CO3(100) 16
Cs2CO3(100) 16
16
16
16
70
45
45
45
45
45
45
45
66
49
78
91
87
88
83
96[72]
61
86
85
83
96
96
89
91
21 (S)
23 (S)
22 (S)
24 (S)
17 (S)
10 (S)
27 (S)
24 (S)
5
6
7e
8f
a Standard conditions: substrate (0.25 mmol), B2pin2 (1.1 equiv.),
alcohol (2 equiv.), THF (1 mL), 70 °C, 16 h. b Conversion and
chemoselectivity of the diborated product determined by GC and
1H NMR spectroscopy. c Isolated yield. d Enantioselectivity was
determined from the ketal product by GC-MS. e Solvent: toluene.
f Solvent: DCM.
Scheme 3 Set of chiral alcohols used in the organocatalytic diboration
of vinylcyclohexane.
Table 3 Screening of secondary chiral alcohols for asymmetric metal
free diboration of vinylcyclohexane with bis(pinacolato)diborona
Conv.b
(%)
Diboronb
(%)
eec
(%)
Entry Alcohol
Table 1 Asymmetric metal-free diboration of vinylcyclohexane with
bis(pinacolato)diborona
1
11
83
84
18 (S)
Entry
Alcohol
Conv.b (%)
Diboronb (%)
eec (%)
2
3
12
13
50
90
70
86
3 (S)
1
2
3
4
5
2
5
8
9
47
85
34
36
33
73
87
67
63
65
13 (S)
10 (R)
9 (S)
9 (S)
24 (S)
33 (S)
10
4
5
14
15
70
75
87
80
40 (S)
20 (S)
a Standard conditions: substrate (0.25 mmol), B2pin2 (1.1 equiv.),
Cs2CO3 (15 mol%), alcohol (2 equiv.), THF (1 mL), 70 °C, 6 h.
b Conversion and chemoselectivity of the diborated product determined
by GC and H NMR spectroscopy. c Enantioselectivity was determined
1
from the ketal product by GC-MS.
6
16
18
89
35 (S)
a Standard conditions: substrate (0.25 mmol), B2pin2 (1.1 equiv.),
Cs2CO3 (1 equiv.), alcohol (2 equiv.), DCM (1 mL), 45 °C, 16 h.
b Conversion and chemoselectivity of the diborated product determined
These initial results prompted us to optimise the reaction con-
ditions in order to increase the yield of the diborated product. We
did a general screening of the reaction conditions, keeping con-
stant the amount of chiral alcohol for economical reasons. We
observed that 16 h of reaction time ensured synthetically useful
conversions (Table 2, entry 1). Interestingly, we found that the
temperature had a dramatic effect not only on the activity, but
also on the chemoselectivity of the reaction. Lower temperature
provided better selectivities towards the diborated product, unfor-
tunately without any significant increase of the enantioselectivity
(Table 2, entry 2). Increasing the amount of base resulted in a
steady increase of the conversion up to 91%, at 1 equiv. of base
(with respect to the substrate) (Table 2, entries 3, 4). Replace-
ment of Cs2CO3 with sodium alkoxides such as NaOMe or
NaOtBu did not affect the chemoselectivity but it decreased the
enantioselectivity (Table 2, entries 5, 6). This could be due to
the competitive formation of [MeO → Bpin–Bpin]− or [tBuO →
Bpin–Bpin]− which produces the racemic diborated product. The
non-polar and polar nature of the solvent hardly affected the
reaction outcome under the applied conditions (Table 2, entries
1
by GC and H NMR spectroscopy. c Enantioselectivity was determined
from the ketal product by GC-MS.
7, 8), although dichloromethane (DCM) provided the highest
conversion and chemoselectivity (Table 2, entry 8).
In order to tune the chiral reagent, we carried out the model
reaction using secondary alcohols structurally related to
1-phenyl-ethanol (10). These reactions were carried out in DCM,
which provided the optimal combination of activity, chemo- and
stereoselectivity in the course of the optimization phase. Impor-
tantly, α-substituted benzyl alcohols (11, 13–15) provided better
activities and enantioselectivities than 2-phenyl-ethanol deriva-
tive 12, confirming the beneficial effect of the benzylic position
of the hydroxyl group (Table 3). Increasing the steric bulk of the
alkyl substituents of the benzyl alcohol, such as the change of
the methyl for ethyl, also provided a slight increase of the
6622 | Org. Biomol. Chem., 2012, 10, 6621–6623
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work on the experimental and theoretical design of chiral Lewis
acid–base *RO− → bis(pinacolato)diboron adducts to promote
the organocatalytic reaction inducing higher levels of
asymmetry.
Acknowledgements
Fig. 1 Asymmetric metal free diboration of alkenes with chiral alcohol
14.
We thank MEC for funding (CTQ2010-16226), A. B. for an FPI
grant and C. S. for an FI grant. We thank AllyChem for the gift
of bis(pinacolato)diboron.
stereoselectivity (ee up to 40%, Table 3, entry 4). The use of
(S,S) syn-γ-amino alcohol provided similar enantioselectivity
(ee 35%) combined with high chemoselectivity and low conver-
sion (Table 3, entry 6).
Notes and references
1 (a) T. B. Marder and N. C. Norman, Top. Catal., 1998, 5, 63;
(b) T. Ishiyama and N. Miyaura, Chem. Rec., 2004, 3, 271;
(c) I. Beletskaya and C. Moberg, Chem. Rev., 2006, 106, 2320.
2 (a) K. Takahashi, T. Isiyama and N. Miyaura, Chem. Lett., 2000, 982;
(b) K. Takahashi, T. Isiyama and N. Miyaura, J. Organomet. Chem.,
2001, 625, 47.
3 (a) M. Gao, S. B. Thorpe and W. L. Santos, Org. Lett., 2009, 11, 3478;
(b) S. B. Thorpe, X. Guo and W. L. Santos, Chem. Commun., 2011, 424;
(c) M. Gao, S. B. Thorpe, Ch. Kleeberg, C. Slebodnick, T. B. Marder and
W. L. Santos, J. Org. Chem., 2011, 76, 3997.
To extend this methodology to other alkenes, we selected the
chiral alcohol 14 on the basis of its beneficial influence on the
chemo- and stereoselectivity. The substrates tested included a
terminal aliphatic alkene (1-octene), a cyclic alkene (indene) and
allylbenzene. In the case of the diboration of indene, in THF at
70 °C after 20 h of reaction time, the diborated product was
formed in 40% enantiomeric excess, but both the conversion and
the chemoselectivity were low (Fig. 1). Temperatures up to
70 °C were required for moderate conversion. Under the same
reaction conditions described in Table 3 (45 °C, 16 h), the asym-
metric organocatalytic diboration of 1-octene and allylbenzene
provided high conversions and chemoselectivities, and enantio-
selectivities up to 42% ee (Fig. 1).
4 K. Lee, A. R. Zhugralin and A. H. Hoveyda, J. Am. Chem. Soc., 2009,
131, 7253.
5 (a) C. Kleeberg, L. Dang, Z. Lin and T. B. Marder, Angew. Chem., Int.
Ed., 2009, 48, 5350; (b) T. B. Marder lecture at Euroboron 5, Edinburgh
2010; (c) C. Kleeberg lecture at Imeboron XIV, Niagara 2011.
6 (a) A. Bonet, H. Gulyás and E. Fernández, Angew. Chem., Int. Ed., 2010,
49, 5130; (b) C. Pubill-Ulldemolins, A. Bonet, C. Bo, H. Gulyás and
E. Fernández, Chem.–Eur. J., 2012, 18, 1121.
7 J. Cid, H. Gulyás, J. J. Carbó and E. Fernández, Chem. Soc. Rev., 2012,
41, 3558.
8 A. Bonet, C. Pubill-Ulldemolins, C. Bo, H. Gulyás and E. Fernández,
Angew. Chem., Int. Ed., 2011, 50, 7158.
Conclusions
9 (a) J. B. Morgan, S. P. Miller and J. P. Morken, J. Am. Chem. Soc., 2003,
125, 8702; (b) H. E. Burks and J. P. Morken, Chem. Commun., 2007,
4717; (c) S. Trudeau, J. B. Morgan, M. Shrestha and J. P. Morken,
J. Org. Chem., 2005, 70, 9538; (d) L. T. Kliman, S. N. Mlynarski and
J. P. Morken, J. Am. Chem. Soc., 2009, 131, 13210; (e) H. E. Burks,
L. T. Kliman and J. P. Morken, J. Am. Chem. Soc., 2009, 131, 9134;
(f) K. Hong and J. P. Morken, J. Org. Chem., 2011, 76, 9102;
(g) C. H. Schuster, B. Li and J. P. Morken, Angew. Chem., Int. Ed., 2011,
50, 7906.
10 Other examples of metal mediated asymmetric induction in the diboration
reaction: (a) T. B. Marder, N. C. Norman and C. R. Rice, Tetrahedron
Lett., 1998, 39, 155; (b) J. Ramirez, A. M. Segarra and E. Fernández,
Tetrahedron: Asymmetry, 2005, 16, 1289.
As a conclusion, we state that the described methodology rep-
resents a new concept for inducing enantioselectivity in the
diboration of alkenes, in the absence of any transition metal
complex, and as such it can potentially be applied in the enantio-
selective difunctionalization of unsaturated molecules. The sim-
plicity of the method using economically accessible chiral
alcohols combined with the obvious advantages in the purifi-
cation of the products, due to the absence of transition metals,
open new perspectives for organic synthetic purposes. The asym-
metric induction needs to be improved, therefore we currently
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6621–6623 | 6623