Asymmetric metal free β-boration of α,β-unsaturated imines assisted by (S)-MeBoPhoz

Article abstract of DOI:10.1039/c4ob02478h

The adduct [MeO → Bpin-Bpin]^- efficiently mediates the β-boration of α,β-unsaturated imines formed in situ. The use of chiral phosphines as additives, and in particular the chiral phosphine (S)-MeBoPhoz, enables the catalytic asymmetric reactio

Full text of DOI:10.1039/c4ob02478h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Asymmetric metal free β-boration of
α,β-unsaturated imines assisted by (S)-MeBoPhoz†
Cite this: Org. Biomol. Chem., 2015,
13, 1328
Enrico La Cascia,a,b Xavier Sanz,a,c Carles Bo,c Andrew Whiting*b and
Received 25th November 2014,
Accepted 10th December 2014
Elena Fernandez*a
DOI: 10.1039/c4ob02478h
www.rsc.org/obc
The adduct [MeO → Bpin–Bpin]− efficiently mediates the β-bora-
tion of α,β-unsaturated imines formed in situ. The use of chiral
phosphines as additives, and in particular the chiral phosphine (S)-
MeBoPhoz, enables the catalytic asymmetric reaction to proceed
with higher enantioselectivity than the analogue copper(I)
mediated reaction.
Metal-free activation of diboron reagents has gained signifi-
cant momentum, particularly to generate C–B bonds in an
organocatalytic context.1–3 However, the development of a
general, highly efficient asymmetric version of this reaction
is still an important goal4 with only limited successful
examples.2,3 Therefore, Cu(I) catalysts have become the most
widely used for inducing asymmetry in β-boration, since Yun
et al.5 discovered that copper catalysts modified with chiral
phosphines can activate diboron reagents, such as bis(pinaco-
lato)diboron (B2pin2), and catalyze the borylation of α,β-unsa-
turated carbonyl compounds with high levels of
enantioselectivity, in the presence of MeOH.6 In this context,
we have found that this approach might enable efficient access
to γ-aminoalcohols from the corresponding α,β-unsaturated
imines.7 The optimal combination an amine (for imine for-
mation), a copper source and a chiral ligand, followed by
careful selection of a reducing reagent has provided a con-
venient methodology to obtain γ-aminoalcohols in a highly
diastereo- and enantioselective manner (Scheme 1, pathways A
and B).7 The unique attempt to perform the β-boration of
(E)-1-phenyl-N-(4-phenylbutan-2-ylidene)-methanamine, in the
absence of Cu(I) salts as precatalysts, required the substrate
preactivation by Lewis acidic Fe(II) and Fe(III) salts (Scheme 1,
pathway C).8
Scheme 1 (A) Cu catalyzed β-boration of α,β-unsaturated imines (ref.
7a,b,c); (B) Cu catalyzed β-boration of in situ formed α,β-unsaturated
imines (ref. 7d,e,f); (C) Fe(II) activation of α,β-unsaturated imines towards
the β-boration reaction (ref. 8); (D) organocatalytic β-boration reaction
(this work).
Here, we have developed an asymmetric organocatalytic
approach to generate C–B bonds at the β-position of an unsatu-
rated imine, i.e. Scheme 1, pathway D, as an alternative strat-
egy to synthesize γ-aminoalcohols. Towards this end, we focus
our efforts on the in situ generation of a model α,β-unsaturated
imine, i.e. (E)-1-phenyl-N-(4-phenylbutan-2-ylidene)methan-
amine, from 4-phenyl-3-buten-2-one (1) and benzylamine in
THF with the dehydrating reagent, MK10.7a,dAfter 6 hours, the
aDepartment Química Física i Inorgànica, University Rovira i Virgili C/Marcellí
Domingo s/n, Tarragona, Spain. E-mail: mariaelena.fernandez@urv.cat
bCentre for Sustainable Chemical Processes, Dept. of Chemistry, Durham University,
South Road, Durham DH1 3LE, UK. E-mail: andy.whiting@durham.ac.uk
cICIQ, Tarragona, Spain
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob02478h
1328 | Org. Biomol. Chem., 2015, 13, 1328–1332
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Communication
Isolated yields were obtained for the corresponding γ-amino
alcohols by reduction with NaBH4 in methanol and oxidation
with H2O2 in NaOH.
Table 1 In situ α,β-unsaturated imines formation followed by organo-
catalytic β-boration with B2pin2
a
With these preliminary results in hand, we extended this
observation to other ketone and amine combinations, to
develop a general organocatalytic methodology for the β-bora-
tion of α,β-unsaturated imines. Interestingly, nBuNH2 was also
a versatile amine for the imine formation with 1, and was com-
patible with the organocatalytic β-boration to produce quanti-
tatively the β-borated imine 2b (Table 1, entry 5). Electron
accepting and electron releasing substituents at the para-posi-
tion of the phenyl group of the ketone substrates 3 and 5,
respectively, did not change the reaction outcome (Table 1,
entries 6 and 7). Even α,β-unsaturated ketones with alkyl moi-
eties at the β-position were equally susceptible to quantitative
β-boration, whether cyclic or acyclic (Table 1, entries 8–10).
Hence, it can be seen that the organocatalytic β-boration of
in situ formed α,β-unsaturated imines is a general and indeed
new methodology for the formation of β-borylated imines in a
one-pot reaction.
% Conv.b
Entry Substrate
1
Additives
Product
[IY]c
—
—
2
3
″
″
Cs2CO3/
MeOH
PCy3/
Cs2CO3/
MeOH
PCy3
PCy3/
Cs2CO3/
MeOH
″
″
—
99 [56]
4
″
″
″
—
90 [66]
5d
In the next step we considered the possibility of inducing
asymmetry into the formation of the new C–B bond using this
organocatalytic approach. Hence, we proposed that chiral
phosphine additives might interact with the substrate and
provide an asymmetric environment for the β-boration with
the Lewis acid–base adduct [i.e. MeO− → Bpin–Bpin]. This
6
PCy3/
Cs2CO3/
MeOH
99 [47]
96 [37]
95 [51]
99 [68]
97 [30]
7
PCy3/
Cs2CO3/
MeOH
8
PCy3/
Cs2CO3/
MeOH
concept had already been successfully demonstrated in the
2a,d
β-boration of α,β-unsaturated ketones with B2pin2
or
BpinBdan (dan = 1,8-diaminonaphthalene) (Scheme 2),2e and
the hypothesis of the role of the phosphine in the asymmetric
induction has also been postulated from both an experimental
and theoretical point of view.9
9
PCy3/
Cs2CO3/
MeOH
10
PCy3/
Cs2CO3/
MeOH
However, since imine functionality is more sterically hin-
dered and less polarized than the carbonyl group, we were
interested to ascertain whether asymmetric induction would
a Standard conditions: ketone (0.5 mmol), NH2Bn (0.5 mmol), THF be more or less efficient. Hence, we initiated our studies with
(2 mL), MK-10 (140 mg), B2pin2 (1.1 eq.), Cs2CO3 (15 mol%), MeOH
substrate 1 and conducted the imine formation with benzyl-
(2.5 eq.), PCy3(10 mol%). b Conversion determined by 1H NMR
amine, followed by β-boration with the Lewis acid–base [MeO−
→ Bpin–Bpin] adduct in the presence of a series of chiral
diphosphines. Preliminary results using chiral Josiphos-type of
diphosphines did not provide any significant asymmetric
induction, which contrasts with the efficient trends observed
with the corresponding ketones.2a Remarkably, however, when
the [MeO− → Bpin–Bpin] adduct was used with the dipho-
spectroscopy. c Isolated yield calculated for syn-γ-amino alcohol (see
ESI for reaction conditions). d NH2Bu (0.5 mmol).
boron reagent bis(pinacolato)diboron (B2pin2) is added to the
intermediate α,β-unsaturated imine; however, even when the
reaction was performed at 70 °C, no β-borated product 2a was
observed (Table 1, entry 1). The addition of a base and MeOH
to activate the diboron, via quaternization, was also insuffi-
cient at promoting the β-boration (Table 1, entry 2), unless a
small amount of phosphine (10 mol% PCy3) was added to the
reaction (see Table 1, entry 3). However, the replacement of the
base by the phosphine alone was not enough to activate the
diboron (Table 1, entry 4). It seems, therefore, that the base/
MeOH combination is essential for the diboron activation and
that the role of the phosphine could be related to a similar
pre-activation of the substrate as we have previously observed
in the analogue metal-free β-boration of α,β-unsaturated carbo-
nyl compounds, which is also assisted by phosphines.9
Scheme 2 β-Boration of α,β-unsaturated ketones with B2pin2 and
BpinBdan (dan
=
1,8-diaminonaphthalene), assisted by chiral
phosphines.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 1328–1332 | 1329

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Asymmetric organocatalytic versus asymmetric Cu(I) catalyzed
β-boration of in situ formed α,β-unsaturated imines with (S)-MeBoPhoza
Entry
β-Borated imine
Method
% Conv.b
% eec
% I.Y.d
1
2
A
B
90
99
54
32
59
40
Fig. 1 Comparison of the chiral phosphine additives P2–P4 for asym-
metric β-boration of α,β-unsaturated imines 4, 6 and 8.
3
4
A
B
94
80
53
32
47
40
Since (S)-MeBoPhoz has been shown to be the most active
and enantioselective additive for accessing β-boryl imines, in
this metal free context, we extended this study to other similar
chiral phosphines, i.e. P2–P4. We concluded that (R)-PhEt-(R)-
BoPhoz (P4) provides comparable asymmetric induction than
the close phosphine P1, and higher than the enantioselecti-
vities provided by the other analogues, i.e. P2 and P3, in which
the amine is either mono- or di-substituted (Fig. 1).
5
6
A
B
98
95
50
45
49
43
7
8
A
B
96
88
70
61
61
57
To gain a deeper insight into the reaction mechanism and
compare with other substrates that we reported previously,1b
we conducted DFT-based theoretical studies (Scheme 3).
Initially, we postulated that the methoxide ion can quater-
nize a boron atom of the B2pin2 molecule forming the acti-
vated adduct [MeO → Bpin–Bpin]− (chosen as the origin of the
9
10
A
B
99
92
51
33
48
57
11
12
A
B
99
95
57e
29e
73
52
a Conditions for method A: ketone or aldehyde (0.5 mmol), amine
(0.5 mmol), THF (2mL), MK-10 (140 mg), B2pin2 (1.1 eq.), Cs2CO3
(15 mol%), MeOH (2.5 eq.), (S)-MeBoPhoz (10 mol%), 70 °C; for
method B: same as method A + CuCl (3 mol%), 25 °C. b Conversion
determined by 1H NMR spectroscopy. c Enantioselectivity determined
from HPLC-MS. d Isolated yield for the corresponding syn
γ-aminoalcohol (see ESI for reaction conditions). e ee calculated on the
4-(N-benzhydrylacetamido)butan-2-yl acetate derivative.
sphine (S)-MeBoPhoz (P1), total conversion was observed
together with moderate enantioselectivity of the β-borated
product (54% ee, Table 2, entry 1). When subtle changes were
made to the reaction conditions, such as a lower base loading
or a different reaction temperature, conversions and enantio-
selectivities remained essentially unchanged. However, when
the β-boration was carried out in the presence of CuCl
(3 mol%), conversions from 1 to 2a were high but lower ees
were observed (32% ee, Table 2, entry 2). Note that the isolated
yields of the product are given for the final syn-γ-aminoalcohol
after a highly stereoselective reduction protocol with NaBH4 in
MeOH, as reported previously,7b followed by oxidation with
H2O2 in NaOH.
Scheme 3 Mechanistic proposal on the organocatalytic β-boration of
imines. Electronic energies and Gibbs free energies (in parentheses) of
the involved species in relation to the [MeO → Bpin–Bpin]− adduct are
shown. All energies are in kcal mol−1
.
1330 | Org. Biomol. Chem., 2015, 13, 1328–1332
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Communication
energies). This adduct can then react with the model α,β-unsatu-
rated imine through a transition state TS, which corresponds
to the nucleophilic attack of the sp2 boron atom on the
β-carbon of the α,β-unsaturated imine. The structural features
of the TS show the cleavage of the B–B bond (ΔdB–B = 0.257 Å)
and the formation of the new B–C bond (dB–C = 2.078 Å). After
this transition state (TS), a negatively charged intermediate I is
formed. Also in this step, a molecule of (pin)B–OMe is
released as the by-product. The anionic intermediate I is then
protonated in the presence of an excess of B2pin2 and MeOH,
regenerating again the active species [MeO → Bpin–Bpin]− and
hence the β-borated product. At this point, it is interesting to
compare energy values computed herein, with those obtained
for the metal-free β-boration of ketones, esters and alde-
hydes.1b For the model imine (E)-1-phenyl-N-(4-phenylbutan-2-
ylidene)methanamine, (2a), the transition state TS is higher
Scheme 4 Suggested formation of the ion pair ([α-H,β-PR3-4-phenyl-
butylaldimine]+[B2pin2·MeO]−).
this with the corresponding α,β-unsaturated ketone-derived
enolate species (Fig. 2). Interestingly, the imine-derived phos-
phonium enamide formed from PMe3 and 2a is higher in
energy than the corresponding ketone-derived phosphonium
enolate intermediate, which explains why that reaction has to
be carried out at 70 °C, and does not proceed readily at lower
temperature. Hence, the origin of the asymmetric induction
when using (S)-MeBoPhoz may result from the protonation of
the zwitterionic phosphonium enamide with MeOH, and for-
mation of a tight ion-pair between the resulting [B2pin2·MeO]−
adduct and the chiral phosphonium imine, i.e. as in 15
(Scheme 4), as we have postulated before.9
(ΔG≠ = 32.3 kcal mol−1) than that found for acrolein (ΔG≠
=
16.7 kcal mol−1), 3-buten-2-one (ΔG≠ = 18.7 kcal mol−1),
methyl acrylate (ΔG≠ = 21.5 kcal mol−1) and styrene (ΔG≠
25.1 kcal mol−1), but lower in energy than propylene (ΔG≠
=
=
35.9 kcal mol−1). This fact can be explained by the lower elec-
trophilicity of the Cβ of the α,β-unsaturated imine which
makes it less reactive towards the nucleophilic attack. More-
over, the intermediate I for the imine (ΔG = –17.2 kcal mol−1
)
is energetically more stable than the reactants, as expected,
but less stable than the corresponding analogues for the acti-
vated alkenes.1b This can be also rationalized by the fact that
the negative charge that is generated is more stabilized by the
oxygen atom than the nitrogen due to their different electrone-
gative characters. It is worth mentioning that the reaction
energies computed for this model α,β-unsaturated imine sub-
strate are in a similar range to those previously computed for
ketones, aldehydes and esters, thus justifying the similarity in
the reaction conditions (T = 70 °C) as described above.
Finally, we addressed the role of the chiral phosphine in
not only mediating the catalytic reaction but importantly,
guiding the asymmetric C–B bond formation. A possible inter-
action between a model phosphine of reduced steric conges-
tion PMe3, and the α,β-unsaturated imine 2a, is to form a
phosphonium enolate intermediate (Fig. 2).10–12 We compared
Conclusions
In conclusion, we have developed the first example of metal-
free β-boration of in situ formed α,β-unsaturated imines, high-
lighting the compatibility of the organocatalytic Bpin addition
with the imine formation in the presence of both ketone and
amine. The reaction shows little dependence upon substrate
electronics and shows consistently high conversion. Impor-
tantly, the use of chiral phosphines, such as the diphosphine
(S)-MeBoPhoz, enables the catalytic asymmetric version to be
realized with moderate asymmetric induction. Interestingly,
the enantioselectivity is higher than that induced by the same
chiral phosphines when modified using the corresponding
Cu(I)-based catalytic system. The mechanism of the organo-
catalytic β-boration of these α,β-unsaturated imines has been
postulated from a theoretical point of view, and seems to
necessarily involve quaternization of the diboron reagent with
methoxide. The role of the phosphine has been regarded to
the ion pair formation and further work to elucidate this issue
will be reported in due course.
Acknowledgements
This research has been supported by the Spanish Ministerio
de Economia
y Competitividad MINECO under projects
CTQ2013-43395-P, CTQ2011-29054-C02-02 and SEV-2013-0319,
by the Generalitat de Catalunya (2014SGR409) and by the ICIQ
Foundation. We thank Johnson Matthey for the gift of chiral
phosphines. E. La Cascia thanks URV and Durham University
Fig. 2 Reaction energy profile for the formation of phosphonium eno-
lates. Electronic and Gibbs free energies (in parentheses) are given in
kcal mol−1
.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 1328–1332 | 1331

View Article Online
Communication
Organic & Biomolecular Chemistry
for 2013PMF-PIPF-91grant and X. Sanz thanks URV-ICIQ for
the grant.
4 A. Berkessel and H. Gröger, Asymmetric Organocatalysis,
Wiley-VCH, Weinheim, 2005.
5 (a) S. Mun, J.-E. Lee and J. Yun, Org. Lett., 2006, 8, 4887;
(b) J.-E. Lee and J. Yun, Angew. Chem., Int. Ed., 2008, 47,
145; (c) H.-S. Sim, X. Feng and J. Yun, Chem. – Eur. J., 2009,
15, 1939.
6 Reviews on the asymmetric β-boration reaction:
(a) J. A. Schiffner, K. Müther and M. Oestreich, Angew.
Chem., Int. Ed., 2010, 49, 1194; (b) E. Hartmann, D. J. Vyas
and M. Oestreich, Chem. Commun., 2011, 7917; (c) V. Lillo,
A. Bonet and E. Fernández, Dalton Trans., 2009, 2899;
(d) L. Dang, Z. Lin and T. B. Marder, Chem. Commun., 2009,
3987; (e) L. Mantilli and C. Mazet, ChemCatChem, 2010, 2,
501; (f) A. D. J. Calow and A. Whiting, Org. Biomol. Chem.,
2012, 29, 5485.
7 (a) C. Solé and E. Fernández, Chem. – Asian J., 2009, 4,
1790; (b) C. Solé, A. Whiting, H. Gulyás and E. Fernández,
Adv. Synth. Catal., 2011, 353, 376; (c) C. Solé, A. Tatla,
J. A. Mata, A. Whiting, H. Gulyás and E. Fernández, Chem.
– Eur. J., 2011, 17, 14248; (d) A. D. J. Calow, A. S. Batsanov,
E. Fernández, C. Solé and A. Whiting, Chem. Commun.,
2012, 48, 11401; (e) A. D. J. Calow, A. S. Batsanov, A. Pujol,
C. Solé, E. Fernández and A. Whiting, Org. Lett., 2013, 15,
4810; (f) A. D. J. Calow, C. Solé, A. Whiting and
Notes and references
1 (a) C. Kleeberg, L. Dang, Z. Lin and T. B. Marder, Angew.
Chem., Int. Ed., 2009, 48, 5350; (b) C. Pubill-Ulldemolins,
C. A. Bonet, C. Bo, H. Gulyás and E. Fernández, Chem. –
Eur. J., 2012, 18, 1121; (c) C. Kleeberg, A. G. Crawford,
A. S. Batsanov, P. Hodgkinson, D. C. Apperley, M. Cheung,
Z. Lin and T. B. Marder, J. Org. Chem., 2012, 77, 785;
(d) C. Kleeberg, Dalton Trans., 2013, 42, 8276;
(e) H. Braunschweig, A. Damme, R. D. Dewhurst,
T. Kramer, T. Kupfer, K. Radacki, E. Siedler, A. Trumpp,
K. Wagner and C. Werner, J. Am. Chem. Soc., 2013, 135,
8702; (f) H. Braunschweig, A. Damme, J. O. C. Jimenez-
Halla, T. Kupfer and K. Radacki, Angew. Chem., Int. Ed.,
2012, 51, 6267; (g) H. Braunschweig, A. Damme and
T. Kupfer, Chem. Commun., 2013, 49, 2774.
2 (a) A. Bonet, H. Gulyás and E. Fernández, Angew. Chem.,
Int. Ed., 2010, 49, 5130; (b) A. Bonet, C. Pubill-Ulldemolins,
C. Bo, H. Gulyás and E. Fernández, Angew. Chem., Int. Ed.,
2011, 50, 7158; (c) A. Bonet, C. Solé, H. Gulyás and
E. Fernández, Org. Biomol. Chem., 2012, 10, 6621;
(d) C. Sole, H. Gulyás and E. Fernández, Chem. Commun.,
2012, 48, 3769; (e) J. Cid, J. J. Carbó and E. Fernández,
Chem. – Eur. J., 2014, 20, 3616.
E.
Fernández,
ChemCatChem,
2013,
8,
2233;
(g) A. D. J. Calow, A. Whiting and E. Fernández, Org.
Biomol. Chem., 2014, 12, 6121.
8 C. Solé, A. Bonet, H. Gulyás and E. Fernández, Chem. –
Asian J., 2011, 6, 1011.
3 (a) K. Lee, A. R. Zhugralin and H. A. Hoveyda, J. Am. Chem.
Soc., 2009, 131, 7253; (b) I. Ibrahem, P. Breistein and
9 C. Pubill-Ulldemolins, A. Bonet, H. Gulyás, C. Bo and
E. Fernández, Org. Biomol. Chem., 2012, 10, 9677.
A. Córdova, Chem. – Eur. J., 2012, 18, 5175; (c) H. Wu, 10 J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346,
S. Radomkit, J. M. O’Brien and A. H. Hoveyda, J. Am. Chem. 1035.
Soc., 2012, 134, 8277; (d) Y. Nagashima, K. Hirano, 11 C. I. Stewart, G. R. Bergman and F. D. Toste, J. Am. Chem.
R. Takita and M. Uchiyama, J. Am. Chem. Soc., 2014, 136, Soc., 2003, 125, 8696.
8532; (e) T. P. Blaisdell, Th. C. Caya, L. Zhang, 12 (a) K. Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc.
A. Sanz-Marco and J. P. Morken, J. Am. Chem. Soc., 2014,
136, 9264.
Jpn., 1968, 41, 2815; (b) D. Basavaiah, A. J. Rao and
T. Satyanarayana, Chem. Rev., 2003, 103, 811.
1332 | Org. Biomol. Chem., 2015, 13, 1328–1332
This journal is © The Royal Society of Chemistry 2015