Cu(ii)-Catalyzed asymmetric boron conjugate addition to α,β-unsaturated imines in water

Article abstract of DOI:10.1039/c4cc04062g

Enantioselective conjugate addition of bis(pinacolato)diboron to α,β-unsaturated imines proceeds smoothly in water in the presence of a chiral copper(ii) complex consisting of Cu(OAc)₂ and chiral 2,2′-bipyridine. The corresponding β-boryl imines, which were oxidized to β-hydroxy imines, further leading to γ-amino alcohols, were obtained in high yields and high enantioselectivities.

Full text of DOI:10.1039/c4cc04062g

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Cu(II)-Catalyzed asymmetric boron conjugate
addition to a,b-unsaturated imines in water†
Cite this: Chem. Commun., 2014,
50, 9336
Taku Kitanosono, Pengyu Xu, Satoshi Isshiki, Lei Zhu and Shu Kobayashi*
¯
Received 27th May 2014,
Accepted 24th June 2014
DOI: 10.1039/c4cc04062g
www.rsc.org/chemcomm
Enantioselective conjugate addition of bis(pinacolato)diboron to out in organic solvents, it is becoming apparent that some
a,b-unsaturated imines proceeds smoothly in water in the presence reactions proceed smoothly in water and that unique reactivity
of a chiral copper(II) complex consisting of Cu(OAc)2 and chiral and selectivity can be induced in reactions in water compared
2,20-bipyridine. The corresponding b-boryl imines, which were oxidized with the same reactions in organic solvents. In general, organic
to b-hydroxy imines, further leading to c-amino alcohols, were obtained reactions in water are less explored and much less information
in high yields and high enantioselectivities.
is available on reactions in aqueous medium compared with
reactions in organic solvents.
Enantiopure b-hydroxy imines are useful precursors of optically
In this context, we have recently disclosed Cu(II)-catalyzed
active g-amino alcohols, and compounds with backbones composed asymmetric boron conjugate additions to a,b-unsaturated
of the latter are often observed in natural products including ketones, esters, and amides in water.14 While boron conjugate
antibiotics1 as well as in chiral auxiliaries2 and chiral ligands3 for addition reactions have previously been reported, in most cases
asymmetric synthesis. Asymmetric synthesis of g-amino alcohols has Cu(I) catalysts have been used in organic solvents and, to our
received much attention in recent years because of the versatility of knowledge, no asymmetric examples of the reaction in water
such compounds in chemical transformations and because of their have been disclosed before our report. Because unique reactivities
anticipated pharmacology in areas such as development of ‘‘second- and selectivities can be obtained in asymmetric catalysis in water,
generation’’ serotonin-norepinephrine reuptake inhibitor (SNRI) we became interested in the application of such chiral Cu(II)
antidepressants4 and m-opioid receptor agonist analgesics.5 Intensive catalysis to other aqueous systems. We were particularly intrigued
work over the past decade on developing efficient protocols to by the use of imines in water. While imines (Schiff bases) are
furnish enantioenriched g-amino alcohols has led to the emergence versatile intermediates in organic transformations, their use in
of asymmetric catalysts for the construction of suitable precursors. water is very limited because they readily decompose in the
A widely implemented technique is based on asymmetric synthesis presence of even a small amount of water.
of precursors such as b-hydroxy imines,6,7 b-amino carbonyl
We now report Cu(II)-catalyzed asymmetric boron conjugate
compounds,8 and isoxazolidines,9 or other cyclic compounds,10 additions to a,b-unsaturated imines in water. Remarkably, the
followed by appropriate selective reduction. A limited number of reactions proceed smoothly without decomposition of the imines, to
reports on b-hydroxy imines have been published7,11 where chiral afford the desired b-boryl imines, which were oxidized to b-hydroxy
Cu(I) catalysts were used for asymmetric b-borylation of electron- imines, in high yields and with high enantioselectivities.15
deficient alkenes.12 These protocols entailed the use of air-sensitive
phosphine ligands as well as the addition of strong bases such as the reaction of benzalacetone-derived imines with bis(pinacolato)-
sodium tert-butoxide to activate bis(pinacolato)diboron.13 diboron in water (Table 1). As reported previously,14a,d despite the
At the outset, Cu(OH)2 with chiral 2,20-bipyridine16 was applied to
On the other hand, organic reactions in water are now of insolubility of all materials (both substrates, Cu(OH)2 and chiral
great interest. Water is a safe, inexpensive, and environmentally ligand) in water, the reaction of benzalacetone proceeded smoothly
benign solvent. While most organic reactions tend to be carried to afford the desired product in high yield with moderate enantio-
selectivity after subsequent oxidation (entry 1). We then examined
the reaction of a,b-unsaturated imines. Whereas the reactions of
a,b-unsaturated imines derived from isopropylamine or aniline gave
low yields with low enantioselectivities (entries 2 and 3), the use
Deparment of Chemistry, School of Science, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo, Japan. E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp;
Fax: +81-3-5684-0634; Tel: +81-3-5841-4790
of the a,b-unsaturated imines derived from benzylamine resulted
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04062g
in high reactivity and excellent enantioselectivity (entry 4).
9336 | Chem. Commun., 2014, 50, 9336--9339
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Table 1 Comparative reaction of benzalacetone and the corresponding imines
Entry
R
Yielda (%)
eeb (%)
1c
2
3
4
5
6
—
84
20
19
65
43
Trace
65
32
35
499
17
iPr
Ph
Bn
OH
NHPh
Scheme 1 Enantioselective b-borylation of a,b-unsaturated imines.
—
a
c
Isolated yield. b Determined by HPLC analysis. Performed with 5 mol%
acetate resulted in higher yield of the desired product, which was
formed with 499% ee (entry 3). Whereas a similar result was
obtained by decreasing the catalyst loading from 10 to 5 mol%, the
yield and the enantioselectivity decreased slightly when 1 mol%
catalyst was used (entries 4 and 5). Copper salts with more
catalyst loading at 5 1C; ref. 14d.
Besides steric hindrance, the exocyclic CQN double bonds as
well as CQC bonds tend to undergo the isomerization,17
exerting an influence on the stereochemical outcomes. The
reactions of a,b-unsaturated oxime or hydrazone produced
poor results, presumably because of the strong coordination
between copper and the substrates (entries 5 and 6).
nucleophilic counteranions such as Clꢀ and SO4 exhibited lower
2ꢀ
enantioselectivity compared with Cu(OTf)2, and the use of Cu(OTf)2
gave a poor yield (entries 6–8). Performing the reaction with Cu(II)
acetylacetonate afforded similar results to those obtained with Cu(II)
acetate (entry 9).
A range of a,b-unsaturated imines underwent Cu(II)-catalyzed
enantioselective b-borylation to afford the desired enantioenriched
b-hydroxy imines in high yields with excellent enantioselectivities
(Scheme 1). It is noteworthy that imines bearing chalcone and
benzalacetone backbones gave b-hydroxy imines with outstanding
enantioselectivities (499% ee). The use of a substrate with an
electron-withdrawing substituent at the b-position resulted in lower
enantioselectivity.
The reaction profile of Cu(OAc)2-catalyzed b-borylation of an
a,b-unsaturated imine was compared with that of the reaction of the
corresponding ketone (Scheme 2, top). Although the b-borylation of
the a,b-unsaturated imine was slightly slower than that of the
corresponding ketone, the relatively rapid completion of the reaction
implied sufficient and efficient activation of the a,b-unsaturated
imine by Cu(OAc)2. On the other hand, when a 1 : 1 mixture of
chalcone and the corresponding imine was added to the catalyst
solution, chalcone was consumed almost quantitatively and the
competitive b-borylation of the imine was clearly hampered
(Scheme 2, bottom). Considering decomposition of the imine in
water, the amounts of the recovered imine and the ketone are
reasonable. The preferential consumption of the a,b-unsaturated
ketone over the corresponding imine under Cu(II) catalysis is inter-
esting, considering the preferential activation of an aldimine over an
aldehyde by a Cu(II) salt.18
In previous reports,14a,b,d b-borylation reactions of multifarious
unsaturated compounds were efficiently catalyzed by chiral
Cu(II) complexes formed from Cu(OH)2 or Cu(OAc)2 and chiral
2,20-bipyridine, irrespective of whether the catalyst was homo-
geneous or heterogeneous. The use of Cu(OH)2 renders the
catalysis heterogeneous, whereas Cu(OAc)2 is homogeneous.
The effect of Cu(II) salts on the outcome of the reaction was
then examined (Table 2). The addition of one equivalent of
AcOH to Cu(OH)2 increased the reactivity slightly while retaining
excellent enantioselectivity (entry 2). The catalytic system became
homogeneous under these conditions, which implied an exchange
of one hydroxide with an acetate group. Catalytic use of Cu(II)
Table 2 Effect of Cu salts
Entry
Cu salt
Yielda (%)
eeb (%)
1
Cu(OH)2
Cu(OH)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
CuSO4
Cu(OTf)2
Cu(acac)2
65
69
83
86
67
10
43
5
499
499
499
499
94
45
85
2c
3
4d
5e
6
7
8
9
We assume that the asymmetric boron conjugate addition to
a,b-unsaturated imines in water follows the catalytic cycle
shown in Scheme 3. In situ formation of a borylcopper(II) species 2
was confirmed by ESI-MS analysis, and this intermediate was
assumed to be a key component in the Cu(II) catalysis.14b,d
499
499
80
a
b
c
Isolated yield. Determined by HPLC analysis. 10 mol% of AcOH
d
e
was added as an additive. 5 mol% of catalyst loading. 1 mol% of
catalyst loading.
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activators in water, resulting in potentially base-free conditions.
Given the instability of the d9–p interaction due to its unpaired
electron, a nucleophilic addition would take place to produce
an N-enolate intermediate 3. The polarization of the Cu–B bond
toward the boron could facilitate the interaction. Steric bulk of
the two tert-butyl groups in the ligand may give rise to enantio-
facial preference toward the more accessible Si face, which is
consistent with the observed sense of chiral induction. Because
the proton-transfer rate in water is known to be in the order of
picoseconds, rapid protonation subsequent to the nucleophilic
addition would afford the product in water, lowering the
activation energy and facilitating the catalytic turnover.21
It was found that a chiral Cu(II) complex formed with chiral
2,20-bipyridine was suitable for use in the b-borylation of
a,b-unsaturated imines in water. The use of Cu(OAc)2 as the
Cu(II) source gave superior performance, affording enantioenriched
b-hydroxy imines after oxidation, which are known to be useful
precursors of g-amino alcohols. Excellent stereocontrol was
achieved with a range of substrates. In contrast to the known
Cu(I) catalyses in organic solvents, this Cu(II) protocol in water is
expedient and free from the use of air-sensitive phosphine ligands
and strong bases. The use of unstable imines in water is also
remarkable.
Scheme 2 Competitive reactivity against the a,b-unsaturated ketone and
the corresponding imine as an independent system (above) and as a mixed
system (below).
This work was partially supported by a Grant-in-Aid for
Science Research from the Japan Society for the Promotion of
Science (JSPS), Global COE Program, The University of Tokyo,
MEXT, Japan, Japan Science Technology Agency (JST). T.K.
thanks the JSPS for a Research Fellowship for Young Scientists.
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