Asymmetric synthesis of α-amino boronate esters via organocatalytic pinacolboryl addition to tosylaldimines

Article abstract of DOI:10.1039/c2cc00020b

Organocatalytic nucleophilic pinacolboryl addition from in situ generated MeO^- → B₂pin₂ to CN double bond can be performed enantioselectively with the aid of chiral phosphines, which promote enantiofacial differentiation in the course of the C-B bond formation. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc00020b

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COMMUNICATION
Asymmetric synthesis of a-amino boronate esters via organocatalytic
pinacolboryl addition to tosylaldiminesw
´ ´ ´
Cristina Sole, Henrik Gulyas and Elena Fernandez*
Received 2nd January 2012, Accepted 16th February 2012
DOI: 10.1039/c2cc00020b
Organocatalytic nucleophilic pinacolboryl addition from in situ
generated MeOÀ - B2pin2 to C N double bond can be performed
Q
enantioselectively with the aid of chiral phosphines, which promote
enantiofacial differentiation in the course of the C–B bond formation.
The catalytic addition of diboron reagents to CQN has been
attempted using transition metal complexes as catalysts. The
activation of bis(catecholato)diboron (B2cat2) by [Pt(cod)Cl2]
allowed the diboration of aldimines providing the first
synthetic route towards rac-a-aminoboronate esters (Scheme 1,
path a).1 However, the same catalytic system was unable to
mediate the diboration of N-tert-butanesulfinyl aldimines
(Scheme 1, path b).2 Recently, copper-alkoxide complexes
modified with N-heterocyclic carbenes have efficiently been
used to activate bis(pinacolato)diboron (B2pin2), and to form
(NHC)CuBpin complexes, which catalyse the pinacolboryl
addition to unsaturated molecules.3,4 Ellman and co-workers2
successfully promoted diastereoselective Bpin addition to
N-tert-butanesulfinyl aldimines with the catalytic system
Scheme 2
In our ongoing research, we focus on the enantioselective
introduction of boryl moieties into unsaturated substrates.
Recently, we have found that the methoxide anion activates
B2pin2 to promote a nucleophilic boron addition to both
activated5,6 and non-activated olefins.7 We have also observed
that the use of chiral phosphines has been essential to induce
asymmetry in the organocatalytic b-boration of a,b-unsaturated
carbonyl compounds.5 Based on the experience we have
accumulated in the asymmetric organocatalytic boron addition
reactions, we describe here a synthetic route towards a-amino-
boronate esters via metal-free nucleophilic boryl addition to
(ICy)CuOtBu (ICy
= 1,3-dicyclohexylimidazol-2-ylidene)
tosylaldimines. We planned to use the in situ formed MeOÀ
-
(Scheme 1, path c). However, it was also reported that in the
absence of transition metal complexes, the N-tert-butanesulfinyl
aldimines could not be transformed into the desired N-sulfinyl
a-amino pinacolboronate esters (Scheme 1, path d).2
bis(pinacolato)diboron adduct, and to induce asymmetry with
catalytic amounts of chiral phosphines (Scheme 2).
We used N-benzylidene-benzenesulfonamide (1a) as a model
substrate, and we activated B2pin2 with an excess of MeOH
and catalytic amount of base to guarantee the in situ formation
of the MeOÀ - B2pin2 adduct.5–7 Within 15 h, at reflux
temperature, 70% of the substrate was transformed into the
corresponding a-amino boronate ester (Table 1, entry 1).
The addition of phosphine (PPh3) resulted in higher
conversion (up to 91%), but only when base and methanol
were also present in the medium, otherwise no activity was
observed (Table 1, entries 2–4). The obvious beneficial effect of
PPh3 prompted us to complement our catalytic system
with the phosphine. To further optimise the methodology, a
number of bases and protic additives were screened. We found
that MOMe (M = Li, Na, K) could be reasonable alternatives
to Cs2CO3 (Table 1, entries 5–10). The nature of the alcohol as
additive could be considered to have a more direct influence on
the reaction outcome as it is assumed that the alcohol
generates the alkoxide ion which interacts with the B2pin2.
We examined alcohol additives of different pKa values and
steric properties but none of them could outperform the
originally chosen MeOH (Table 1, entries 11–13). It is important
Scheme 1
´
´
`
Dept. Quımica Fısica i Inroganiac, Universitat Rovira i Virgili,
C/Marcel.lı Domingo, s/n, 43007 Tarragona, Spain.
E-mail: mariaelena.fernandez@urv.cat; Fax: +34 977 559563;
Tel: +34 977 558046
´
w Dedicated to Prof. Carmen Claver on her 60th birthday.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3769–3771 3769

Table
1
Organocatalytic pinacolboryl addition from B2pin2 to
Table 2 Organocatalytic pinacolboryl addition from B2pin2 to
tosylaldiminesa
N-benzylidene-benzenesulfonamidea
Entry
Base
Phosphine
Additive
Convb (%)
Entry Substrate
Product
Time/h Convb (%) Yieldc (%)
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
—
K2CO3
KOH
KOMe
LiOMe
NaOMe
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
—
MeOH
MeOH
—
70
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
91 (78)c
—
—
1
6/15
80/84
62
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
PhOH
iPrOH
BuOH
83
58
88
89
88
85
89
83
2
3
4
6/15
6/15
95/99
99/99
79
82
9
10
11
12
13
6/15
6/15
31/40
61/90
20
68
78
a
Standard conditions: substrate (0.25 mmol), B2pin2 (1.2 eq.),
phosphine (4 mol%), base (15 mol%), MeOH (2.5 eq.), THF (1 mL),
5
70 1C, 15 h. Conversion calculated using 1H NMR spectroscopy.
Isolated yield from 1 mmol of substrate.
b
c
a
Standard conditions: substrate (0.25 mmol), B2pin2 (1.2 eq.), PPh3
(4 mol%), Cs2CO3 (15 mol%), MeOH (2.5 eq.), THF (1 mL), 70 1C.
b
c
Conversion calculated using 1H NMR spectroscopy. Isolated yield
from 1 mmol of substrate.
In search of asymmetric induction in the C–B bond
formation, we conducted a preliminary study with 2 mol%
of the chiral diphosphine Walphos (R)-(R)W001 (CF3) (2),
which allowed the transformation of 1a into the a-amino
boronate ester with 94% of ee at rt (Fig. 1, bar 5). The
enantioselectivity slightly decreased at higher temperatures
but the activity significantly increased (Fig. 1, bars 3–5). We
should also highlight that, under identical reaction conditions,
the metal free approach was more enantioselective than the
analogous Cu(I)/2 catalysed reaction (2 mol% loading) which
provided only 66% of ee at rt (Fig. 1, bars 1–2). Interestingly,
it has been reported that when Cu(I)/2 mediated the asymmetric
boration of a,b-unsaturated b-methyl sulfones, the conversion
and ee values were only moderate (76% and 40%, respectively)
despite the fact that 10 mol% of copper salt/chiral ligand and
15 mol% of base were required.8
Scheme 3
to note at this point that when the (E)-N-benzylidene-
1-phenylmethanamine was used as substrate in the organo-
catalytic boron addition reaction, the nucleophilic attack of
the pinacolboryl, from the MeOÀ - B2pin2 adduct, did not
take place. The fact that the pinacolboryl addition to the
tosylaldimines was efficient might indicate a beneficial electronic
influence of the tosyl substituent on N (Scheme 3).
With this hypothesis in mind, we performed organocatalytic
pinacolboryl addition to a series of tosylaldimines (1b–d),
achieving high to quantitative conversions into the corres-
ponding a-amino boronate esters, even within 6 h of reaction
time (Table 2). Interestingly, the presence of electron with-
drawing substituents on the aryl groups or lack of conjugation
in the case of aliphatic tosylaldimines clearly facilitated the
nucleophilic addition.
To identify alternative chiral catalysts we screened a small
library of phosphines and phosphoramidites. Therefore, the
enantioselective nucleophilic attack of Bpin from MeOÀ - B2pin2
adduct to N-benzylidene-benzenesulfonamide (1a) could be
Fig. 1 Enantioselective organocatalytic pinacolboryl addition from B2pin2, to 1a with 2 versus the Cu(I)/2 catalytic reaction. Substrate
(0.25 mmol), B2pin2 (1.2 eq.), 2 (2 mol%), Cs2CO3 (15 mol%), MeOH (2.5 eq.), THF (1 mL), CuCl (2 mol% when required).
c
3770 Chem. Commun., 2012, 48, 3769–3771
This journal is The Royal Society of Chemistry 2012

Table 3 Enantioselective organocatalytic pinacolboryl addition to
N-benzylidene-benzenesulfonamide (1a)a
Scheme 4
The scope of the enantioselective organocatalytic reaction
was established with the related tosylaldimines 1b–d, using 2
and 4 as chiral phosphines (Table 4). At 45 1C, the aliphatic
tosylaldimine was transformed into the corresponding a-amino
boronate ester with lower enantioselectivity.
It is well known that chiral a-amino boronate esters have a
tremendous scope of applications in pharmacology,9 and here
we have described a new methodology for the direct asymmetric
synthesis of this type of interesting organoboranes. But we have
also envisaged a simple one-pot transformation from the
tosylaldimines towards chiral 1,2-amino alcohols by using
the enantioselective organocatalytic boryl addition to CQN
followed by homologation/oxidation. In this reaction sequence,
the treatment of the a-amino boronate ester intermediate
(achieved in 99% ee, Table 3, entry 12) with CH2BrCl/nBuLi
and NaOH/H2O210 allowed the formation of the corresponding
1,2-amino alcohol with 99% ee indicating that the optical purity
was completely preserved during the derivatisation process
(Scheme 4). This new synthetic procedure opens a new strategic
avenue towards the asymmetric synthesis of the very versatile
1,2-amino alcohols11 and complements the current metal- and
organocatalysed synthetic strategies.12
Entry
T/1C
Aux. (mol%)
t/h
Convb (%)
eec (%)
1
2
3
4
5
6
7
8
45
45
45
45
45
45
45
45
45
25
25
25
25
3 (2)
4 (2)
5 (2)
6 (2)
7 (2)
8 (2)
9 (2)
10 (2)
11 (2)
2 (4)
3 (4)
4 (4)
6 (4)
15
15
15
15
15
15
15
15
15
24
24
24
24
88
99
63
19
35
23
33
40
55
56
80
45
47
67 (+)
41 (+)
72 (+)
85 (+)
60 (+)
70 (+)
86 (+)
90 (+)
79 (+)
99 (+)
65 (+)
99 (+)
80 (+)
9
10
11
12
13
a
Standard conditions: substrate (0.25 mmol), B2pin2 (1.2 eq.), chiral
phosphine (2 or 4 mol%), Cs2CO3 (15 mol%), MeOH (2.5 eq.), THF
(1 mL). Conversion calculated using 1H NMR spectroscopy. ee
determined by HPLC-TOF.
b
c
Based on this preliminary study, we claim that the in situ
generated MeOÀ - bis(pinacolato)diboron adduct combined
with chiral phosphines, at 2–4 mol% loading, allows the
asymmetric synthesis of a-amino boronate esters via enantio-
selective nucleophilic boron addition to tosylaldimines (ee up
to 99%). The homologation/oxidation work up of the chiral
a-amino boronate esters provides a direct access to chiral 1,2-
amino alcohols.
Table 4 Enantioselective organocatalytic pinacolboryl addition to
tosylaldiminesa
Entry
R
Chiral phosphine
Convb (%)
eec (%)
We thank MEC for funding (CTQ2010-16226) and C. S. for
FPU grant. We thank AllyChem, Solvias and DSM for the gift
of diboron reagents and chiral phosphines.
1
2
3
4
5
6
p-OMe–C6H4
p-OMe–C6H4
p-CF3–C6H4
p-CF3–C6H4
C6H13
2
4
2
4
2
4
83
74
95
90
97
99
75
55
71
52
24
14
Notes and references
C6H13
1 G. Mann, K. D. John and R. T. Baker, Org. Lett., 2000, 2, 2105.
2 M. A. Beenen, Ch. An and J. A. Ellman, J. Am. Chem. Soc., 2008,
130, 6910.
a
Standard conditions: substrate (0.25 mmol), B2pin2 (1.2 eq.), chiral
phosphine (4 mol%), Cs2CO3 (15 mol%), MeOH (2.5 mmol), THF
(1 mL), 45 1C, 15 h. Conversion calculated using 1H NMR spectro-
scopy. ee determined by HPLC–TOF.
b
3 D. S. Laitar, P. Muller and J. P. Sadighi, J. Am. Chem. Soc., 2005,
127, 17196.
¨
c
4 A. Bonet, V. Lillo, J. Ramı
E. Fernandez, Org. Biomol. Chem., 2009, 7, 1533.
5 A. Bonet, H. Gulyas and E. Fernandez, Angew. Chem., Int. Ed.,
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6 C. Pubill-Ulldemolins, A. Bonet, C. Bo, H. Gulya
E. Fernandez, Chem.–Eur. J., 2012, 18, 1121.
7 A. Bonet, C. Pubill-Ulldemolins, C. Bo, H. Gulya
E. Fernandez, Angew. Chem., Int. Ed., 2011, 50, 7158.
8 A. L. Moure, R. G. Arrayas and J. C. Carretero, Chem. Commun.,
2011, 47, 6701.
rez, M. Mar Dıaz Requejo and
´ ´
´
´
´
performed in the presence of 2 mol% of (R)-Binap, and
(S)-Quinap (Table 3, entries 1 and 2), but particularly successful
was the use of chiral ferrocenyl type diphosphines and
phosphoramidite ligands 10 and 11(Table 3, entries 3–9). In
order to find a compromise between the activity and the enantio-
selectivity of the organocatalytic system, we performed the
reactions at room temperature with 4 mol% loading of chiral
phosphines and 24 h of reaction time. Moderate conversions
were observed but a significant increase in enantioselectivity up
to 99% was achieved when Walphos (R)-(R)W001 (CF3) (2) and
(S)-Quinap (4) were involved (Table 3, entries 10–13).
´
s
s
and
and
´
´
´
´
9 D. S. Matteson, Med. Res. Rev., 2008, 28, 233; R. Snow, J. Am.
Chem. Soc., 1994, 116, 10860.
10 Y. Fujiota and H. Amii, Org. Lett., 2008, 10, 769.
11 (a) D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996,
96, 835; (b) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561.
12 S. Wei, R. Messerer and S. B. Tsogoeva, Chem.–Eur. J., 2011,
17, 14380.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3769–3771 3771