Chiral molecular tweezers: Synthesis and reactivity in asymmetric hydrogenation

Article abstract of DOI:10.1021/ja512658m

We report the synthesis and reactivity of a chiral aminoborane displaying both rapid and reversible H₂ activation. The catalyst shows exceptional reactivity in asymmetric hydrogenation of enamines and unhindered imines with stereoselectivities of up to 99% ee. DFT analysis of the reaction mechanism pointed to the importance of both repulsive steric and stabilizing intermolecular non-covalent forces in the stereodetermining hydride transfer step of the catalytic cycle.

Full text of DOI:10.1021/ja512658m

Communication
pubs.acs.org/JACS
Chiral Molecular Tweezers: Synthesis and Reactivity in Asymmetric
Hydrogenation
†
†
,†
†
‡
†
†
Markus Lindqvist, Katja Borre, Kirill Axenov, Bianka Kot
́
ai, Martin Nieger, Markku Leskela,
̈
,
‡
́
Imre Papai,* and Timo Repo*
†Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, P.O. Box 55, FIN-00014 Helsinki, Finland
‡Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, P.O. Box 286, H-1519
Budapest, Hungary
*
S Supporting Information
ABSTRACT: We report the synthesis and reactivity of a
chiral aminoborane displaying both rapid and reversible H2
activation. The catalyst shows exceptional reactivity in
asymmetric hydrogenation of enamines and unhindered
imines with stereoselectivities of up to 99% ee. DFT
analysis of the reaction mechanism pointed to the
importance of both repulsive steric and stabilizing
intermolecular non-covalent forces in the stereodetermin-
ing hydride transfer step of the catalytic cycle.
Figure 1. FLP catalysts for asymmetric hydrogenation of imines.
boranes, the Lewis acid and base are in close vicinity, but bulky
substituents hinder dative bond formation. Such structures
generate high FLP reactivity, allowing the substrate scope to be
ne of the most efficient and atom-economical ways to
prepare chiral amines is by transition metal (TM)-
O
5d,11
expanded to enamines and N-alkyl imines.
However,
catalyzed asymmetric hydrogenation of prochiral imines and
1
previous attempts to incorporate the high reactivity of ansa-
aminoboranes and asymmetric hydrogenation, namely, the
introduction of chiral amines into linked systems via
straightforward synthetic approaches (3 in Figure 1), have
enamines. The products, having chiral α-carbons, are important
in synthetic chemistry because of their applications as ligands,
resolving agents, chiral auxiliaries, and building blocks. Also, the
chiral information and tendency to form H-bonds are essential
features in molecular recognition, making them potential
1
1
resulted in only moderate enantioselectivities. Herein we
report the synthesis of a chiral binaphthyl-linked aminoborane,
its unique reactivity in enantioselective asymmetric hydro-
genation of unhindered imines and enamines, and a computa-
tional study of the mechanism of these reactions.
2
pharmaceuticals. Preparation of drugs via TM catalysis requires
tedious product purification because of strict demands on heavy-
3
metal residuals in the products.
Recently, main-group systems combining sterically hindered
Lewis acids and bases have been reported to cleave molecular
In our catalyst design, the main objective was to introduce the
Lewis acid and base groups at the 2- and 2′-positions of the rigid
asymmetric binaphthyl core, fixing their positions next to the
asymmetric axis and ensuring the close proximity of the amine
and boron centers [(S)-8 in Scheme 1]. Another clear benefit of
the design is the stability of the arene C−B bond, which impedes
retro-hydroboration and decomposition to olefins and amino-
4
hydrogen heterolytically under mild reaction conditions. The
chemistry of these “frustrated Lewis pairs” (FLPs) has attracted
increased scientific and practical interest, mainly because of their
applicability as catalysts in homogeneous metal-free hydro-
5
6
genations of imines, enamines, N-heterocycles, and carbonyl
7
compounds. In this regard, it is surprising that reports of the
12
boranes, unlike the alkyl-linked analogues. This is an evident
advantage, yet few reported examples of chiral biaryls with
corresponding asymmetric reactions are still few. Intermolecular
FLP systems involving chiral boranes have been successfully
utilized for enantioselective imine hydrogenation. The use of
inherently chiral terpene groups (e.g., α-pinene and camphor) on
boron (1 in Figure 1) has proven to be effective for
1
3
−
B(C F ) groups at the 2-position exist.
6 5 2
Following the reported synthetic procedure for (R)-2′-iodo-
1
4
N-isopropyl-N-methyl-[1,1′-binaphth-2-yl]amine [(R)-7]
yielded the product with 82% ee (Scheme 1b,c), as compound
hydrogenation of acetophenone N-arylimines, and ee’s of up to
1
5
8
4 has a tendency to racemize during Pd-catalyzed reactions.
Therefore, a synthetic route via (R)-5, which could be isolated in
good yield and enantiopurity, was designed. Removal of the
acetyl group of (R)-5 with concentrated hydrochloric acid
followed by consecutive primary amine alkylations with i-PrI and
8
3% were reported. A recent development was achieved by
introducing chirality through a binaphthyl backbone (2),
enabling hydrogenation of imines, silyl enol ethers, and 2,3-
disubstituted quinoxalines at room temperature with high
16
9
asymmetric induction.
In intramolecular FLP systems, appropriate linking of the
Lewis acid and base has proven to be crucial for H activation as
well as for the hydrogen transfer process. In ansa-amino-
Received: December 22, 2014
2
10
©
XXXX American Chemical Society
A
DOI: 10.1021/ja512658m
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Synthetic Routes to Enantiopure Catalyst (S)-9
sterically well-protected by the diastereotopic pentafluorophenyl
groups, which are oriented edge-to-face and adapt pseudoaxial
and pseudoequatorial configurations, an arrangement thought to
induce high enantioselectivity in chiral biphenyl diphosphine
18
ligand systems. The −N(i-Pr) moiety forms a 80.9° angle with
the naphthyl plane, resulting in an N−H···H−B torsional angle
1
9
of 142° yet maintaining a short H···H distance of 1.86 Å.
The formation of colorless (S)-9 upon exposure of deep-red
(
S)-8 to H was rapid, with quantitative conversion occurring in
2
less than 1 min, making it one of the fastest reactions we have
studied in FLP H2 activation (Scheme 1e). Quantitative
dehydrogenation of (S)-9 occurred within 15 min at 80 °C
20
(
Scheme 1f). The catalytic activity of (S)-9 was studied, and the
reaction conditions were optimized in a series of hydrogenation
experiments with substrate 10 (Table 1). With a catalyst loading
(
a) EtOH, conc. HCl, 2 h, reflux. (b) Ph CNH, NaOt-Bu, cat.
2
Pd (dba) + dppe, PhMe, 16 h, 100 °C. (c) (1) i-PrI (2 equiv), K CO
2
3
2
3
(2 equiv), ACN, 48 h, 120 °C; (2) MeI (2 equiv), K CO (2 equiv),
2 3
ACN, 16 h, 60 °C. (d) (1) −78 °C to RT, PhMe, n-BuLi (1 equiv), 3
Table 1. Catalytic Hydrogenation of Imine 10 by (S)-9 under
Different Reaction Conditions
h; (2) −78 °C to RT, B(C F ) Cl (1 equiv), PhMe, 16 h. (e) H (2
6
5
2
2
bar), PhMe, 1 min, RT. (f) C D , 15 min, 80 °C.
6
6
CH I afforded the desired product (R)-7 with high enantiopurity
3
(
99% ee according to HPLC). Finally, aminoborane (S)-8 was
a
b
entry
1
cat. mol %
solvent
conv. [%]
ee [%]
synthesized by straightforward lithiation and reaction with
B(C F ) Cl and isolated as its ammonium borohydride salt (S)-9
after heterolytic splitting of H2.
NMR spectroscopic data for (S)-9 revealed a single species
with a B NMR signal at −19.3 ppm (doublet, J = 80.8 Hz),
typical for four-coordinate borates. Two different sets of peaks
were detected in the F NMR spectrum arising from the
diastereotopic pentafluorophenyl groups, both having typical
10
5
PhMe
PhMe
PhMe
28
48
99
99
34
56
94
n.d.
n.d.
41
6
5 2
17
c
2
d
3
10
10
5
11
1
4
5
6
Et
Et
O
O
74
BH
2
75
2
1
9
5
MTBE
MTBE
77
e
7
7.5
83
borate pattern and thus confirming the assigned structure (Δδ
Conditions: (S)-9 (0.01−0.02 mmol), 10 (42 mg, 0.2 mmol), solvent
1
a b
p,m
1
=
2.98 ppm; Δδ
= 3.43 ppm). In the H NMR spectrum, B−
(1 mL). By H NMR spectroscopy. By HPLC (Chiralcel OD-H
c d
p′,m′
H was observed as a broad quartet in the region 3.50−2.75 ppm
and the ammonium group as a broad singlet at 8.68 ppm, also
column). Reaction time 64 h. Reaction temperature 80 °C.
e
Reaction time 20 h.
giving rise to doublet splitting on the N−Me group (δ = 1.18
H
1
ppm, J = 6.8 Hz). As a result of diastereotopism, the isopropyl
HH
of 10 mol % in toluene, the reaction at room temperature under
group was detected as two methyl doublets separated by 0.49
ppm. Formation of a chiral center on the ammonium nitrogen is
possible, yet no evident diastereomers or epimerization was
detected spectroscopically.
The X-ray crystallographic study of (S)-9 showed a twisted
binaphthyl core with a dihedral angle of 74.3° (Figure 2). This
sets the Lewis acid and base close to each other in space, even
though they are separated by five bonds. The boron center is
H at 2 bar gave 28% conversion in 16 h (entry 1). Prolonging the
2
reaction time by a factor of 4 and simultaneously halving the
catalyst loading nearly doubled the conversion, confirming the
catalyst’s stability (entry 2). Quantitative hydrogenations were
observed at elevated temperatures, but with only moderate ee
(
entry 3). Aiming for higher reaction rate and enantioselectivity,
11
we varied the solvent. As shown earlier, a remarkable increase
in activity and enantioselectivity was detected in ethereal solvents
(
(
cf. entries 1 and 4). The reaction rate in methyl tert-butyl ether
MTBE) was superior relative to diethyl ether, while the
enantioselectivity remained unchanged (cf. entries 5 and 6).
Finally, a conversion of 94% with 83% ee could be obtained with
substrate 10 using 7.5 mol % catalyst (entry 7).
To continue our experimental investigation, we studied the
reactivity of (S)-9 with a range of different substrates (Table 2).
Various N-alkyl and N-benzyl alkyl aryl ketimines were
hydrogenated with 75−83% ee, independent of the size of the
N substituent (11−13). The FLP activity was remarkably high
with small N-methyl imines, despite the production of small
amines that commonly reduce the activity by forming
deactivating B−N adducts (12 and 15). Bulkier N-benzyl
imine substrates, requiring increased catalyst loading and longer
reaction times, also gave products in high yield and enantiopurity
(
11, 13, and 14). The most sterically encumbered and least basic
Figure 2. Crystal structure of (S)-9 (50% probability ellipsoids, solvent
molecule omitted for clarity).
imine in our series [N-(p-methoxyphenyl) acetophenone imine]
was not reduced quantitatively even at elevated temperatures,
B
DOI: 10.1021/ja512658m
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Catalytic Asymmetric Hydrogenations of Imines and Enamines Catalyzed by (S)-9
1
H NMR conversion [%], (isolated yield [%]), ee by HPLC (Chiralcel OD-H or OD-J column). Conditions: H (2 bar), substrate (200 μmol),
2
a
b
c
d
e
f
MTBE (1 mL), 25 °C. (S)-9 (15 μmol), 20 h. (S)-9 (5 μmol), 16 h. (S)-9 (10 μmol), 20 h. (S)-9 (5 μmol), 0.5 h. (S)-9 (10 μmol), 16 h. ee by
1
g
h
H NMR as diastereomers with O-acetylmandelic acid. (S)-9 (20 μmol), 60 °C, 64 h, PhMe solvent. ee by optical rotation.
and product 16 was obtained in 53% conversion. These results
describe an interesting reverse substrate preference of (S)-9 in
comparison to previous FLP catalysts and are a fingerprint of an
was found to be clearly exergonic under standard conditions, but
the reverse process (H elimination) becomes feasible at higher
2
22
temperatures using nonpolar solvents.
11
exceptionally hindered borane (see Figure 2).
The computational results support the view that hydrogen
transfer from the hydrogenated FLP to the enamine occurs in
two distinct steps: it is initiated by protonation of the substrate,
Although (S)-9 prefers small imines for hydrogenation,
stereoselective hydrogenation of alkyl imines remains challeng-
ing because of the chemically similar groups on both sides of the
CN carbon. Catalyst (S)-9 yielded alkyl amines 14 and 15 with
over 30% ee, which are noteworthy values compared with
23
which is followed by a hydride transfer process. The barrier for
the latter step was found to be slightly higher than that of the
protonation (23.5 and 21.8 kcal/mol, respectively) suggesting
that the hydride transfer is likely to be rate-determining in the
catalytic cycle. The most stable form of the hydridoborate/
iminium ion-pair intermediate formed upon protonation was
computed to have a free energy of −9.9 kcal/mol (see int in
Figure 3), but several other low-lying and easily interchangeable
forms could be identified for this species. These isomeric forms
differ in the orientation of the aryl substituents at the boron
center and also in the relative position of the interacting iminium
9a,11
previous FLP results.
Remarkably, N,N-symmetric enamines were quantitatively
converted to the corresponding amines with extremely high
optical purity (17 and 18). Alkyl amine 19 was also obtained with
high optical purity (85% ee). Unequal N-alkyl groups decreased
the enantioselectivity due to iminium intermediate formation
and the possibility of E/Z isomerism (20). The results with N,N-
dialkyl enamines are particularly important, as they are among
−
1b
ion. The BH unit of the hydridoborate species is embedded in a
the most challenging substrates for TM catalysts.
chiral environment, which enables stereoselective attack of the
iminium ion. Hydride transfer to the Re face of the iminium was
predicted to be kinetically favored (by 1.4 kcal/mol) over the
attack at the Si face, which is consistent with the observed
enantioselectivity (excess of the R product). Our analysis of the
origin of the stereoselectivity revealed that the energy difference
obtained for the competing transition states is a result of a subtle
balance between repulsive steric and attractive non-covalent
interactions in the stereoselectivity-determining hydride transfer
step (see Figure 4 and the Supporting Information).
To gain insight into the mechanism of the present hydro-
genation reactions and the origin of the observed stereo-
selectivity, we explored possible reaction pathways for the
formation of amine 17 in a computational study. We used density
functional theory (DFT) calculations to identify and characterize
relevant transition states and the corresponding reaction
intermediates. The results are summarized in terms of a free
energy diagram as depicted in Figure 3. In line with our
experimental observations, the calculations predicted a fairly low
2
1
barrier (14.7 kcal/mol) for the heterolytic H splitting induced
2
In summary, a chiral bridged binaphthyl aminoborane catalyst
for highly enantioselective hydrogenation is reported. A series of
imines and enamines react readily under mild conditions with
by aminoborane (S)-8 (denoted as cat in Figure 3). This reaction
Figure 4. Transition state of the hydride transfer yielding the major
product enantiomer. Intermolecular contacts are highlighted by blue
arrows. CH hydrogen atoms have been omitted for clarity.
Figure 3. Computed free energy diagram for the formation of 17.
C
DOI: 10.1021/ja512658m
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Journal of the American Chemical Society
Communication
enantioselectivities of up to 99% ee. Unhindered N-alkyl imines
are readily hydrogenated without catalyst−product adduct
formation, in contrast to what is typical for FLPs. Most
importantly, the first results on FLP-catalyzed asymmetric
hydrogenations of enamines are presented. Because the catalyst
itself can be synthesized from readily available starting materials
with high enantiopurity, the simplicity of the synthesis and
overall structure makes (S)-9 a good candidate for further
development in asymmetric metal-free hydrogenation.
I.; Rokob, T. A.; Kiral
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01.
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Welch, G. C.; Ullrich, M. Inorg. Chem. 2011, 50, 12338. (c) Eros, G.;
Nagy, K.; Papai, I.; Nagy, P.; Kiraly, G.; Tarkanyi, G.; Soos
, T. Chem.
(
4
̋
ASSOCIATED CONTENT
Supporting Information
́
́
́
́
́
■
Eur. J. 2012, 18, 574. (d) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Angew.
Chem., Int. Ed. 2014, 53, 10218. (e) Clark, E. R.; Ingleson, M. J. Angew.
Chem., Int. Ed. 2014, 53, 11306.
*
S
Procedures and additional data. This material is available free of
charge via the Internet at http://pubs.acs.org. Structure
parameters for (S)-9 (CCDC-1036946), (R)-9 (CCDC-
(7) (a) Mahdi, T.; Stephan, D. W. J. Am. Chem. Soc. 2014, 136, 15809.
(b) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. J. Am. Chem. Soc. 2014, 136,
1
036947), and (R)-17·HCl (CCDC-1036948) are available
15813.
from the Cambridge Crystallographic Data Centre.
(8) (a) Chen, D.; Klankermayer, J. Chem. Commun. 2008, 2130.
(b) Chen, D.; Wang, Y.; Klankermayer, J. Angew. Chem., Int. Ed. 2010,
AUTHOR INFORMATION
Corresponding Authors
papai.imre@ttk.mta.hu
timo.repo@helsinki.fi
49, 9475. (c) Ghattas, G.; Chen, D.; Pan, F.; Klankermayer, J. Dalton
Trans. 2012, 41, 9026.
■
(9) (a) Liu, Y.; Du, H. J. Am. Chem. Soc. 2013, 135, 6810. (b) Wei, S.;
*
Du, H. J. Am. Chem. Soc. 2014, 136, 12261. (c) Zhang, Z.; Du, H. Angew.
Chem., Int. Ed. 2015, 54, 623.
*
Notes
(10) (a) Rokob, T. A.; Hamza, A.; Pap
0701. (b) Rokob, T. A.; Papai, I. Top. Curr. Chem. 2013, 332, 157.
11) Sumerin, V.; Chernichenko, K.; Nieger, M.; Leskela, M.; Rieger,
B.; Repo, T. Adv. Synth. Catal. 2011, 353, 2093.
12) (a) Singaram, B.; Goralski, C. T.; Rangaishenvi, M. V.; Brown, H.
C. J. Am. Chem. Soc. 1989, 111, 384. (b) Sigaram, B.; Rangaishenvi, M.
V.; Brown, H. C.; Goralski, C. T.; Hasha, D. L. J. Org. Chem. 1991, 56,
1543. (c) Singaram, B.; Goralski, C. T.; Fisher, G. B. J. Org. Chem. 1991,
56, 5691. (d) Parks, D. J.; Piers, W. E.; Yap, G. P. A. Organometallics
́
ai, I. J. Am. Chem. Soc. 2009, 131,
1
(
́
The authors declare no competing financial interest.
̈
ACKNOWLEDGMENTS
This work was supported by the Academy of Finland (139550,
76586), the Inorganic Materials Chemistry Graduate Program,
■
2
(
COST Action CM0905, and the Hungarian Scientific Research
Fund (OTKA, K-81927).
1
998, 17, 5492. (e) Schwendemann, S.; Oishi, S.; Saito, S.; Fro
Kehr, G.; Erker, G. Chem.Asian J. 2013, 8, 212. (f) Lindqvist, M.;
Axenov, K.; Nieger, M.; Raisanen, M.; Leskela,
M.; Repo, T. Chem.
Eur. J. 2013, 19, 10412.
̈
hlich, R.;
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(
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̈
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D
DOI: 10.1021/ja512658m
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX