A Frustrated Lewis Pair Catalyzed Asymmetric Transfer Hydrogenation of Imines Using Ammonia Borane

Article abstract of DOI:10.1021/jacs.6b07245

Inspired by the zwitterion species generated from the splitting of H₂ by frustrated Lewis pairs, we put forward a novel frustrated Lewis pair by the combination of H^δ and H^δ incorporated Lewis acid and base together. Piers

Full text of DOI:10.1021/jacs.6b07245

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Article
A Frustrated Lewis Pair Catalyzed Asymmetric Transfer
Hydrogenation of Imines Using Ammonia Borane
Songlei Li, Gen Li, Wei Meng, and Haifeng Du
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07245 • Publication Date (Web): 08 Sep 2016
Downloaded from http://pubs.acs.org on September 9, 2016
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A Frustrated Lewis Pair Catalyzed Asymmetric Transfer Hydrogenation of Imines
Using Ammonia Borane
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Songlei Li, Gen Li, Wei Meng, * and Haifeng Du *
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Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, University of Chinese Academy of Sciences, Beijing 100049, China
ABSTRACT
Inspired by the zwitterion species generated from the splitting of H2 by frustrated
Lewis pairs, we put forward a novel frustrated Lewis pair by the combination of Hδꢀ and
Hδ+ incorporated Lewis acid and base together. Piers’ borane and chiral
tertꢀbutylsulfinamide were chosen as the FLP, and a metalꢀfree asymmetric transfer
hydrogenation of imines was realized with high enantioselectivities. Significantly, with
ammonia borane as hydrogen source, a catalytic asymmetric reaction using 10 mol % of
Piers’ borane, chiral tertꢀbutylsulfinamide, and pyridine additive, has been successfully
achieved to furnish optically active amines in 78ꢀ99% yields with 84ꢀ95% ees.
Experimental and theoretical mechanistic studies reveal an interesting 8ꢀmembered ring
hydrogen transfer transition state and an expected regeneration of reactive species with
ammonia borane. Accordingly, a plausible catalytic pathway for this reaction is depicted.
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INTRODUCTION
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The chemistry of frustrated Lewis pairs (FLPs) has witnessed an extremely rapid
growth in the past decade, and has become one of the most useful methodologies for the
metalꢀfree hydrogenations.1,2 The H2 splitting mechanism of FLPs involves an interaction
between vacant orbital of Lewis acid and the HꢀH σꢀbonding orbital, and a synergic
interaction of the lone pair of Lewis base with the HꢀH σ* antiꢀbonding orbital,
generating proton and hydride, which can be transferred to unsaturated compounds
(Figure 1). Since the first FLPs catalyzed metalꢀfree hydrogenations reported by Stephan
and coworkers in 2007,3 a wide range of unsaturated compounds have been successfully
hydrogenated under the catalysis of FLPs.2 Significantly, in recent years, some important
progresses have also been achieved for the challenging asymmetric hydrogenations.4,5 As
part of our general interest in exploring readily accessible FLPs, we developed an in situ
borane generation strategy by the hydroboration of commercially available alkenes, chiral
dienes, and chiral diynes with Piers’ borane HB(C6F5)2.6 These boranes were highly
effective for the stereoselective and/or enantioselective metalꢀfree hydrogenations.7
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Based on our previous work, and inspired by the zwitterion species A containing
both proton and hydride, we put forward a hypothesis to use species B instead of species
A for the metalꢀfree hydrogenation (Figure 1). In species B, Hδꢀ and Hδ+ are originally
incorporated in Lewis acid and base, respectively. After the hydrogen transfer, a covalent
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bond will form between Lewis acid and base. To realize this hypothesis, two key issues
await to be fulfilled including the matched Lewis pair without rapid releasing of H2 itself,
and the regeneration of reactive species from the bonding Lewis acid and base with
hydrogen sources. Moreover, the choice of effective chiral Lewis acid or base is also
crucial for the asymmetric hydrogenation.
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Figure 1. Our hypothesis for the FLP catalysis.
Ammonia borane NH3 BH3 is an ideal hydrogen source which has been intensively
ꢀ
studied as hydrogen storage materials for its high storage capacity (19.6 % weight H) and
small molecular weight (30.87 g/mol).8 Notably, ammonia borane is also widely used in
synthetic chemistry as a reagent due to its stability and easy handling, which can provide
both proton and hydride.9 For example, with ammonia borane, Stephan and coworkers
reported a FLPs catalyzed reduction of CO2,9a Berke and coworkers described the
hydrogenation of imines, polarized olefins, and carbonyl compounds,9bꢀe Kinjo, Hirao,
and coworkers reported a 1,3,2ꢀdiazaphospholene catalyzed transfer hydrogenation of
N=N bond,9g and Liu, Luo, and coworkers reported a cobaltꢀcatalyzed transfer
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hydrogenation of alkynes.9i Despite these advances, to the best of our knowledge, the
asymmetric reduction reactions with ammonia borane as a hydrogen source has rarely
been reported. In 1984, Williams and coworkers described an asymmetric reduction of
imines with complexes of ammonia borane and chiral 18ꢀcrownꢀ6 derivatives to give up
to 67% ee.10 The development of highly enantioselective reactions with ammonia borane
is therefore a challenging and interesting subject.
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Chiral tertꢀbutylsulfinamide has a wide application as auxiliaries11 or coordinating
moieties in chiral ligands12. It possesses adjacent N, O, and S Lewis base centers,
appropriate steric hindrance, and weak NꢀH acidity, which will well fulfill the
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requirements of Lewis base in the proposed FLP. Piers’ borane HB(C6F5)2 is a suitable
Lewis acid candidate due to its strong Lewis acidity, good hydride nucleophilicity, and
appropriate steric hindrance. Herein, we wish to report our efforts on the asymmetric
transfer hydrogenation14 of imines using chiral tertꢀbutylsulfinamide and Piers’ borane as
a FLP with ammonia borane as a hydrogen source.
RESULTS AND DISCCUSSION
Stoichiometric asymmetric transfer hydrogenation of imines
Initially, the transfer hydrogenation of imine 1a was carried out using Piers’ borane 2
(1.1 equiv) and (S)ꢀtertꢀbutylsulfinamide (3) (1.1 equiv) in CH2Cl2 at room temperature
for 14 h (Scheme 1). To our pleasure, the desired product 4a was obtained in a
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quantitative conversion with 90% ee. Using BH3
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SMe2 or catecholborane instead of
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Piers’ borane led to racemic products. When a benzyl group was introduced to
sulfinamide 3, amine 4a was obtained as a racemate in 86% conversion.
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Scheme 1. Initial study on the asymmetric transfer hydrogenation of imine
Scheme 2. Asymmetric transfer hydrogenation of imines using FLPs
A variety of imines 1aꢀm were next subjected to the stoichiometric asymmetric
transfer hydrogenations. As shown in Scheme 2, all these reactions proceeded smoothly
to furnish products 4aꢀm in 78ꢀ96% yields with 73ꢀ96% ees. Both electronꢀwithdrawing
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and donating substituents at the paraꢀ and meta- positions were well tolerant. But
orthoꢀsubstituted imine 1i gave an obvious lower yield and ee. Imines 1kꢀm with
different protecting groups on the nitrogen atoms were also effective substrates.
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Catalytic asymmetric transfer hydrogenation of imines
After accomplishment of the stoichiometric reaction, we further devoted our efforts
to the catalytic asymmetric transformation. The transfer hydrogenation of imine 1a was
reꢀexamined using Piers’ borane 2 (10 mol %) and (R)ꢀtertꢀbutylsulfinamide 3 (10 mol %)
in toluene with H2 (20 bar) and ammonia borane (1.0 equiv) as hydrogen sources,
respectively (Scheme 3). Only 10% conversion was obtained with H2. Further raising the
temperature to 100 °C and the H2 pressure to 60 bar led a similar conversion, which
suggests that H2 was not an effective hydrogen source for the regeneration of reactive
species. In contrast, the reaction with ammonia borane as a hydrogen source went well to
give amine 4a in 96% conversion with a dramatic loss of enantioselectivity, indicating
there involved other pathways besides the chiral catalystꢀcontrolled transformation.
Scheme 3. Catalytic asymmetric transfer hydrogenation of imine with hydrogen sources
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Table 1. Optimization of reaction conditions a
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entry imine method additive
solvent
toluene
hexane
mesitylene
C6H5F
conc. (M) conv. (%)b ee (%)c
1
2
A
A
A
A
A
A
B
B
B
B
B
C
C
C
C
C
ꢀ
0.1
0.1
>99
56
56
42
51
43
42
60
69
69
74
78
83
90
89
67
91
92
1a
1a
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ꢀ
3
ꢀ
0.1
97
1a
4
ꢀ
0.1
>99
>99
>99
>99
>99
>99
>99
90
1a
5
ꢀ
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0.1
1a
6
ꢀ
0.2
1a
7
ꢀ
0.2
1a
8
ꢀ
ꢀ
0.2
1k
1l
9
0.2
10
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12
13
14
15d
16d,e
ꢀ
0.2
1m
1m
1m
1m
1m
1m
1m
ꢀ
0.05
0.05
0.05
0.05
0.05
0.05
pyridine
Et3N
aniline
pyridine
pyridine
96
95
83
87
99
a
All reactions were carried out with imines (0.10 mmol), Piers’ borane 2 (0.01 mmol),
(R)ꢀtertꢀbutylsulfinamide 3 (0.02 mmol), and ammonia borane (0.10 mmol) at room
temperature for 24 h according to the following methods: (A) all materials were subjected
in one portion; (B) imine, 2, and 3 were subjected and stirred for 12 h before addition of
ammonia borane; (C) imine, 2, and 3 were subjected and stirred for 12 h before addition
b
1
c
of ammonia borane and additive (10 mol %). Determined by crude H NMR.
d
e
Determined by chiral HPLC. (R)ꢀtertꢀbutylsulfinamide 3 (0.01 mmol) was used. At
30 °C.
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To avoid these side reactions, further optimization of reaction conditions was
conducted. Increasing the amount of sulfinamide 3 from 10 mol % to 20 mol % resulted
in a higher ee (Table 1, entry 1). Both solvents and reaction concentration had impacts on
the enantioselectivities, and toluene was the optimal solvent (Table 1, entries 1ꢀ6).
Interestingly, subjecting ammonia borane 12 h later to the reaction mixture of imine 1a, 2,
and 3 gave a little higher ee than that of addition of all materials in one portion (Table 1,
entry 6 vs 7). A possible explanation is that this process inhibited the racemic reaction of
imine with ammonia borane catalyzed the free Piers’ borane 2. The protecting groups on
the nitrogen atoms were also investigated, and the 4ꢀCNC6H4 protecting group gave 78%
ee (Table 1, entries 8ꢀ10), and the ee can be improved to 83% at the concentration of 0.05
M (Table 1, entry 11). The effect of additives (10 mol %) was subsequently studied
(Table 1, entries 12ꢀ15). It is noteworthy that 90% ee was obtained with pyridine as an
additive (Table 1, entry 12). Significantly, the loading amount of 3 can be reduced to 10
mol % without any loss of ee value (Table 1, entry 15). Overall, the reaction of imine 1m
using 10 mol % of Piers’ borane 2, sulfinamide 3, and pyridine was carried out at 30 °C
to produce amine 4m in 99% conversion with 92% ee (Table 1, entry 16).
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Under the optimal conditions, the substrate scope was studied for the catalytic
asymmetric transfer hydrogenations. As shown in Scheme 4, a variety of imines 1m, 5a-p
were suitable substrates to furnish the desired products in 78ꢀ99% yields with 84ꢀ95% ees.
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Both electronꢀwithdrawing and donating substituents were well tolerated. Imine 5p
containing 2ꢀfuryl was also effective for this reaction to give the corresponding product
6p in 99% yield with 86% ee.
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Scheme 4. Asymmetric transfer hydrogenation of imines: (a) with 20 mol % of 2 and 3
Mechanistic study
The interesting results for the transfer hydrogenation of imines encouraged us to
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investigate the mechanism by experiments and theoretical calculations. An NMR study
on the mixture of Piers’ borane 2 and sulfinamide 3 in C6D6 showed that a complex 7 was
formed completely with trace amount of dehydrogenation product 8 (Scheme 5). Notably,
the dehydrogenation process was slow, and a 60% conversion was observed after 18 h,
which well fulfills the requirement of our hypothesis.
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Scheme 5. NMR study on the mixture of 2 and 3
The interaction of Piers’ borane 2 and sulfinamide 3 may lead to three possible isomers
(Figure 2). Their thermodynamic stabilities are tested utilizing M06ꢀ2X method15 on the
6ꢀ31G(d) level.16 It is indicated that, in the toluene solution, the formation of
corresponding complexes 7 is exothermic in terms of enthalpy. After taking the solvent
effects into consideration, the computed free energies of B/S (I), B/N (II) species are ꢀ4.4
and ꢀ17.0 kcal/mol respectively, and the B/O coordinated specie III lies 5.3 kcal/mol
below, indicating the preference of forming the B/O complex (Figure 2). The BꢀO
distance is 1.56 Å, which is longer than the single bond (1.50 Å)17 but shorter than the
sum of corresponding van der Waals radius (3.41 Å)18. A quantitative Laplacian bond
order analysis,19 which is a definition of covalent bond order rather than total bond order
and noncovalent interactions thus have no contribution, depicts that the bond order of
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BꢀO is 0.041, suggesting a primary contribution of coordinate bonding. Moreover, the
electrostatic potential computation also supports the preference of forming the B/O
complex (see Supporting Information, Figure S3).
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Figure 2. Thermodynamic stabilities of complexes 7: selected bond distances are given
in Å; relative Gibbs free energies and enthalpies calculated at 298.15 K and 1.0 atm in
toluene (with respect to that of the reactants) are given.
To explore the possible reactive species, the reaction process of imine 1a with Piers’
borane 2 (1.0 equiv) and sulfinamide 3 (1.0 equiv) in C6D6 was monitored by 11B NMR
spectroscopy (Figure 3). It was found that the signal for complex 7 gradually decreased,
while the signal for compound 8 gradually increased with extension of time, which
indicates that complex 7 is likely a reactive species and compound 8 is generated from
the reaction of imine and complex 7. Moreover, a complex of imine 1a and Piers’ borane
2 was also observed, which may lead a racemic reaction.
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Figure 3. NMR study on stoichiometric reaction of imine 1a (0.05 mmol), HB(C6F5)2 2
(0.05 mmol) and (R)ꢀtertꢀbutylsulfinamide 3 (0.05 mmol) in C6D6 (0.5 mL) at room
temperature: ꢁ compound 8 (δ = 1.3 ppm); ꢀ complexes 7 (δ = ꢀ4.8 ppm); ꢂ complexes
of HB(C6F5)2 2 and imine (δ = ꢀ11.2 ppm).
DFT calculation is next conducted for the stoichiometric asymmetric transfer
hydrogenation. As shown in Figure 4, (R)ꢀtertꢀbutylsulfinamide 3 complexes with Piers’
borane 2 to form complex 7 with a reaction enthalpy of ꢀ34.3 kcal/mol in gas phase and a
reaction free energy of ꢀ22.3 kcal/mol in toluene, which indicates that this process is
thermoꢀ dynamically favorable. Then complex 7 binds with imine 1a, and hydrogen
transfer occurs via a 8ꢀmembered ring transition state TS1 to generate amine 4a and
compound 8, which is very similar to the concerted mechanism involving a
sixꢀmembered transition state in the transfer hydrogenation of imines with ammonia
borane reported by Berke and coworkers.9b A 1.5 kcal/mol energy difference between
TS1ꢀ(S) and TS1ꢀ(R) predicts a 86% ee favored for (S)ꢀisomer, which is well in
accordance with the experiment result (90% ee). An atomsꢀinꢀmolecules (AIM) analysis20
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shows that there involve some weak interactions, for example, HꢀF interactions between
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8
t
hydrogens of Me or Bu, and fluorines of C6F5 in TS1 (for detailed analysis, see
9
Supporting Information). Moreover, the πꢀπ stacking between Ph and C6F5 is also likely
to exist. These weak interactions make the conformations of TS1 rigid enough for the
enantiofacial discrimination despite that the tBu group is remote from the C=N bond.
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Figure 4. DFT calculated reaction profile for the stoichiometric asymmetric transfer
hydrogenation of imines. Relative Gibbs free energies and enthalpies are calculated at
298.15 K and 1.0 atm in toluene.
11
A B NMR study was carried out by treating compound 8 with one equivalent of
ammonia borane in C6D6. As shown in Figure 5, the signal of compound 8 gradually
decreased, and the signal of complex 7 gradually increased with extension of time, which
suggests that species 7 can be regenerated by the reaction of compound 8 with ammonia
borane. Further DFT computational study indicates that the reaction of compound 8 with
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ammonia borane occurs in a concerted mechanism involving a sixꢀmembered transition
state TSꢀ1 with an activating Gibbs free energy of 14.4 kcal/mol (Figure 6). The B/N
complex is formed and then converted to the more stable B/O complex 7. The calculation
agrees with the observation on 11B NMR spectra.
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Figure 5. NMR study on reaction of ammonia borane (0.05 mmol) with 8 (0.05 mmol) in
C6D6 at room temperature:
ꢁ
compound 8 (δ = 1.5 ppm);
ꢀ complexes 7 (δ = ꢀ3.4 ppm);
ꢂ
undetermined compounds;
ꢀ ammonia borane (δ = ꢀ21.0 ppm).
Figure 6. DFT computation on the reaction of 8 with ammonia borane. Free energies and
enthalpies are calculated at 298.15 K and 1.0 atm in toluene.
Then compound 8 (10 mol %) was subjected to the reaction of imine 1a with
sulfinamide 3 (10 mol %) and ammonia borane (1.0 equiv). As shown in Scheme 6,
amine 4a was obtained in a quantitative conversion with 72% ee agreeing with the
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previous result (69% ee, Table 1, entry 7), which demonstrates that complex 7 can be
regenerated from compound 8 and serve as an active species. Compound 9, a dimer of
compound 8, can be observed in the catalytic reaction despite of its very limited amount.
The Xꢀray structure of compound 9 (Figure 7) provides an additional clue for the
determination of the structure of compound 8. When compound 9 was subjected to this
reaction, no desired product was observed, which indicates that compound 9 cannot react
with ammonia borane due to its stability (Scheme 6).
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Scheme 6. Control experiments on reduction of imine 1a
Figure 7. Xꢀray structure of 9
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The possibility that compound 8 plays a role as a chiral Brønsted acid catalyst is also
investigated by the DFT computation. As shown in Figure 8, treating complex 10 with
ammonia borane, a concerted and asynchronous hydrogen transfer occurs via a
6ꢀmembered ring transition state TS2 with an activating Gibbs free energy of 29.0
kcal/mol. The 0.48 kcal/mol energy difference between TS2ꢀ(R) and TS2ꢀ(S) predicts
40% ee in favor of (S)ꢀisomer, which is much lower than the experimental result. Notably,
compound 8 can react with ammonia borane to generate complex 7, which will further
diminish the possibility of compound 8 as a Brønsted acid catalyst. Moreover, as a Lewis
base, the pyridine additive might also partially inhibit this low enantioselective pathway
by a competitive interaction with compound 8. Overall, although this Brønsted acid
catalysis pathway cannot be completely precluded at the current stage, it is not likely to
be a major pathway for the catalytic reaction.
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Figure 8. DFT computation on the acidꢀcatalyzed reduction. Free energies and enthalpies
are calculated at 298.15 K and 1.0 atm in toluene.
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An NMR study indicates a complex of pyridine with Piers’ borane 2 can be formed
rapidly. Control experiments were next conducted to explore the possible role of pyridine
additive. As shown in Scheme 7, without pyridine additive, 67% conversion was obtained
in 2 h. In a sharp contrast, in the presence of pyridine (10 mol %), only 18% conversion
was obtained. One possible role of pyridine is to trap the free Piers’ borane and inhibit
the racemic reaction.
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Scheme 7. Control experiments on the role of pyridine additive
Figure 9. A plausible catalytic pathway.
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Based on the experiment results and the fact that complex 7 can be generated when
compound 8 and ammonia borane are coexisted, the mechanism with complexes 7 as
reactive species is preferred. A probable catalytic pathway is outlined as shown in Figure
9. Piers’ borane 2 and sulfinamide 3 forms a complex 7 (our proposed FLP), which binds
with imines followed by the hydrogen transfer via a 8ꢀmembered ring transition state TS
to generate amine product and compound 8. The complex 7 is regenerated by the reaction
of compound 8 with ammonia borane to complete a catalytic cycle.
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CONCLUSION
In summary, a metalꢀfree asymmetric transfer hydrogenation of imines using a
combination of Piers’ borane and chiral tertꢀbutylsulfinamide as a novel frustrated Lewis
pair has been realized to furnish the desired products in high yields with up to 95% ee.
Significantly, a further step on the catalytic transformation has been successfully
achieved using Piers’ borane (10 mol %), chiral tertꢀbutylsulfinamide (10 mol %), and
pyridine additive (10 mol %), with ammonia borane as hydrogen source. A variety of
optically active amines were obtained in 78ꢀ99% yields with 84ꢀ95% ees. Notably, this
work represents the first highly enantioselective reaction using ammonia borane as
hydrogen source. Mechanistic studies by experiments and theoretical calculations
indicate that Piers’ borane can complex with chiral tertꢀbutylsulfinamide to form a
reactive FLP, which binds with imine substrates to lead hydrogen transfer via a
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8ꢀmembered ring transition state to produce amines. Furthermore, the resulting
dehydrogenation product of Piers’ borane and chiral tertꢀbutylsulfinamide reacts with
ammonia borane to regenerate the reactive FLP. We believe that the current work will be
of broad synthetic and mechanistic interest for chemists. Further efforts on the
application of this novel frustrate Lewis pair for other asymmetric transfer
hydrogenations are underway in our laboratory.
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ASSOCIATED CONTENT
Supporting Information. Procedure for transfer hydrogenation of imines and
experimental mechanistic study, computational details and data for DFT calculations, the
determination of enantiomeric excesses, and characterization of products along with
NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mengwei@iccas.ac.cn, haifengdu@iccas.ac.cn
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
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We are grateful for the financial support from the National Natural Science Foundation of
China (21222207, 21572231, and 21521002).
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