C2-Symmetric Bicyclic Bisborane Catalysts: Kinetic or Thermodynamic Products of a Reversible Hydroboration of Dienes

Article abstract of DOI:10.1002/anie.201808289

We prepared a new class of chiral C₂-symmetric bicyclic bisborane catalysts by addition reactions of internal dienes with the Piers borane, HB(C₆F₅)₂, and an analogue, HB(p-C₆F₄H)₂. The dependence of the addition pattern on the reaction temperature allowed us to selectively prepare two diastereomeric catalysts from a single diene precursor. The bisboranes prepared in situ exhibited excellent activity (turnover numbers up to 200 at ?40 °C) and enantioselectivity (up to 95 % ee) in imine hydrogenation reactions.

Full text of DOI:10.1002/anie.201808289

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: C2-Symmetric Bicyclic Bis-Borane Catalysts: Kinetic or
Thermodynamic Products from a Reversible Hydroboration of
Dienes
Authors: Xian-Shuang Tu, Ning-Ning Zeng, Ru-Ye Li, Yu-Quan Zhao,
De-Zhen Xie, Qian Peng, and Xiao-Chen Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808289
Angew. Chem. 10.1002/ange.201808289
Link to VoR: http://dx.doi.org/10.1002/anie.201808289
http://dx.doi.org/10.1002/ange.201808289

10.1002/anie.201808289
Angewandte Chemie International Edition
COMMUNICATION
C2-Symmetric Bicyclic Bis-Borane Catalysts: Kinetic or
Thermodynamic Products from a Reversible Hydroboration of
Dienes
Xian-Shuang Tu, Ning-Ning Zeng, Ru-Ye Li, Yu-Quan Zhao, De-Zhen Xie, Qian Peng* and Xiao-Chen
Wang*
Abstract: We prepared a new class of chiral C2-symmetric bicyclic
bis-borane catalysts by addition reactions of internal dienes with Piers’
borane, HB(C6F5)2, and an analogue, HB(p-C6F4H)2. The dependence
of the addition pattern on the reaction temperature allowed us to
selectively prepare two diastereomeric catalysts from a single diene
precursor. The in situ–prepared bis-boranes exhibited excellent
activity (turnover numbers up to 200 at -40 °C) and enantioselectivity
(up to 95% ee) in imine hydrogenation reactions.
upon hydroboration of internal olefins can actually be utilized.
Specifically, we found that hydroboration of C2-symmetric
bicyclic [3.3.0] dienes L[10] gave one bis-borane at 25 °C via a
kinetically controlled process or its diastereomer at 80 °C via
a thermodynamically controlled process (Scheme 1c). The
excellent specificity allowed us to prepare the catalysts in situ,
thereby obviating problems associated with catalyst
purification. These bis-borane compounds are powerful
catalysts for enantioselective hydrogenation of imines.
The ground-breaking discovery that the boron-containing
frustrated Lewis pairs (FLPs) were capable of mimicking the
activity of transition metals in dihydrogen activation[1] has
invoked extensive research efforts towards the development
of new catalytic processes promoted by a borane catalyst.[2]
With asymmetric catalysis in particular, the research groups
of Klankermayer,[3] Oestreich,[4] Repo,[5] Du,[6] Erker,[7] and
Stephan[8] have synthesized various chiral boranes and have
applied them in asymmetric hydrogenations and
hydrosilylations. Despite these advances, the catalytic activity
and selectivity of chiral boranes have not been extensively
explored owing to the limited number of such catalysts. For
instance,
with
imine
hydrogenation,
the
highest
enantioselectivity reported to date is around 80s% ee by using
Du’s catalyst.[6a] And, the good performing catalysts are
mainly binaphthyl-derived. Therefore, the development of new
catalysts is highly desirable.
The hydroboration of olefins with Piers’ borane, HB(C6F5)2,
is an efficient method for assembling chiral borane catalysts.[9]
In most of the reported examples, monosubstituted terminal
olefins were used so that the bulky B(C6F5)2 group would add
selectively to the terminal carbon during the hydroboration
reaction, enabling the direct use of catalysts generated in situ
(Scheme 1a).[6,7] With internal olefins, however, their
hydroboration usually delivered multiple regioisomers and
diastereomers (Scheme 1b), whose separation was feasible
only after their hydrogen splitting reaction with a base.[3,7]
Despite this potential problem, we wanted to explore reactions
of internal olefins because an active boron center connected
to a chiral carbon instead of to a flexible nonchiral methylene
unit could be expected to facilitate chiral induction. Recently,
we discovered that the “problem” of varied addition patterns
Scheme 1. Chiral boranes prepared by hydroboration with HB(C6F5)2
We chose bicyclic dienes
L as candidate catalyst
precursors for the following reasons. First, previous studies[9]
have demonstrated that syn addition of HB(C6F5)2 to an α-aryl-
substituted cyclic olefin selectively delivers the B(C6F5)2 group
to the less substituted, β carbon atom, and trans to the aryl
group, thus eliminating the possibility of the formation of
multiple regioisomers. Second, in the cis configuration of the
bicyclic scaffold, the two carbocycles bend toward each other,
and we reasoned that the resulting steric hindrance might
favor addition of HB(C6F5)2 to the less hindered face via a
kinetically controlled process. Third, we expected that the
rigidity of the fused bicyclic structure and its C2-symmetry
would be beneficial for enantiocontrol.
We commenced our study with reactions of racemic dienes
L1–L4 with 2.0 equiv of HB(C6F5)2 in toluene at 25 °C
(Scheme 2). After complete consumption of the dienes (within
5 min, as indicated by 1H NMR), 2.1 equiv of isoquinoline was
added to react with the produced bis-borane compounds,
thereby generating stable Lewis acid/base adducts. 1H NMR
analysis of the reaction mixture using CH2Br2 as the internal
standard indicated clean formation of Lewis adducts
CAT1•2(C9H7N)–CAT4•2(C9H7N) as single isomers in high
yields. Subsequent washes with n-hexane afforded white
[*]
X.-S. Tu, N.-N. Zeng, R.-Y. Li, Y.-Q. Zhao, D.-Z. Xie, Prof. Dr. Q.
Peng, Prof. Dr. X.-C. Wang
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, and Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), Nankai University
94 Weijin Road, Tianjin 300071 (China)
E-mail: xcwang@nankai.edu.cn, qpeng@nankai.edu.cn
Homepage: http://www.wangnankai.com/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201808289
Angewandte Chemie International Edition
COMMUNICATION
crystalline powders. 2D–NMR analyses (see the supporting
information) suggested that these adducts adopted the
geometry that we proposed; that is, both of the B(C6F5)2
groups were attached to the less hindered face of the bicyclic
structure and were trans to the aryl groups. X-ray
crystallographic analyses of single crystals of CAT1•2(C9H7N)
and CAT4•2(C9H7N) confirmed their stereochemistries and
that the overall structure remained C2-symmetric.[11]
Scheme 3. Reactions of Dienes L3 and L4 with HB(C6F5)2 at 80 °C
We next investigated the hydroboration of L4 with HB(p-
C6F4H)2,[12] an analogue with weaker Lewis acidity (Scheme
4). The reaction at 25 °C was relatively slow; after 30 min,
followed by the isoquinoline coordination, the adduct of the
kinetically favored bis-borane (CAT7) was obtained in 30%
yield, with unreacted L4 and a mono-hydroboration product
accounting for the rest of materials. We attributed the poor
reactivity to the slow release of HB(p-C6F4H)2 from its stable
dimer [HB(p-C6F4H)2]2 at 25 °C.[12] In contrast, the
hydroboration at 80 °C reached completion within 5 min,
giving the thermodynamically controlled bis-borane adduct
CAT8•2(C9H7N)[11] in 90% yield.
Scheme 2. Reactions of Dienes L1–L4 with HB(C6F5)2 at 25 °C
Interestingly, when L3 and L4 were allowed to react with
HB(C6F5)2 at 80 °C, followed by addition of isoquinoline, a
different pair of bis-borane adducts was predominantly
produced (CAT5•2(C9H7N) and CAT6•2(C9H7N) in Scheme 3).
They had different proton correlations in their 2D-NOESY
spectra: the most notable change was the substantially
weakened NOE signal between the proton geminal to the aryl
substituent and the proton on the adjacent fused carbon. X-
ray crystallographic analysis of
a
single crystal of
CAT6•2(C9H7N) revealed that at 80 °C, HB(C6F5)2 had instead
added to the more hindered face of the bicyclic structure.[11]
We reasoned that the increased steric bulk of the aryl
substituents in L3 and L4 decreased the stability of their
kinetic products (CAT3 and CAT4 in Scheme 2), and a
thermodynamically controlled equilibration process occurred
via repeated retrohydroboration/rehydroboration[9] at 80 °C to
deliver the inverted products with both aryl substituents on the
less hindered face. This hypothesis was supported by the
observation that CAT3 and CAT4, without the isoquinoline
coordination, could be converted to these inverted bis-boranes
when they were further reacted in toluene at 80 °C. However,
when the isoquinoline adducts of CAT3 and CAT4 were reacted
at 80 °C, they remained unchanged. Therefore, the base
coordination had shut down the retrohydroboration, thereby
locking the configuration of these bis-borane species. Notably,
the reaction of L3 also produced a small amount (~15% yield)
of another bis-borane isomer. We suspect that this minor
isomer might be the partially inverted bis-borane with only one
set of aryl and B(C6F5)2 groups inverted. In contrast, the
reaction of L4 afforded CAT6•2(C9H7N) in 91% yield with only
a trace of other isomers. We have also tested the reactions of
L1 and L2 at 80 °C, but both reactions gave a mixture of
multiple borane isomers.
Scheme 4. Reactions of L4 with HB(p-C6F4H)2
After demonstrating that we could generate bis-borane
compounds in a highly-selective manner by means of the
hydroboration reaction of L (L1–L4 at 25 °C and L4 at 80 °C),
we investigated in situ formation of bis-borane catalysts from
enantiopure dienes for imine hydrogenation (Table 1). In a
typical run, L and HB(C6F5)2 were first reacted in toluene at
25 °C or at 80 °C for 5 min, followed by the addition of an imine,
and then the resulting mixture was transfered to an autoclave
for hydrogenation. Knowing that imine substrates can function
as Lewis bases to form FLPs with borane catalysts for
dihydrogen activation,[13] we did not add an external base. The
bis-boranes generated from hydroboration at 25 °C were
studied first. Hydrogenation of imine 1a in the presence of 2
mol% of CAT1 resulted in complete conversion to amine 2a
within 2 h with 62% ee (entry 1). Although CAT2 and CAT3
failed to improve the enantioselectivity (entries 2 and 3), CAT4
significantly enhanced the enantioselectivity to 81% ee (entry
4). When we tested the catalysts from hydroboration of L4 at
80 °C, CAT8 prepared from HB(p-C6F4H)2 provided 2a with 84%
This article is protected by copyright. All rights reserved.

10.1002/anie.201808289
Angewandte Chemie International Edition
COMMUNICATION
ee (entry 6).[14] We then optimized the reaction conditions with
CAT8. We were glad to discover that the enantioselectivity
gradually increased as the reaction temperature was
decreased (entries 6–9). Lowering the reaction temperature to
-40 °C increased the enantioselectivity to 94% ee (entry 9).
Remarkably, when the reaction time at -40 °C was extended,
complete conversion and 94% ee were maintained even when
the catalyst loading was reduced to 0.5 mol% (entry 10).
These are the highest activity and selectivity achieved to date
for imine hydrogenation promoted by a chiral borane catalyst.
catalyst by the coordination of heteroatoms, thiophene- and
pyridine-containing imines underwent hydrogenation to give
the desired products in excellent yields with moderate ee
values (2cc and 2dd). Changing the N protecting group from
Ph to p-MeOC6H4 (2ee) or p-CF3C6H4 (2ff) slightly decreased
the enantioselectivity. So far, we have been unsuccessful with
hydrogenation of diaryl- and dialkyl-substituted imines (2gg–
2jj).
Table 2. Investigation of imine substrate scope.[a]
Table 1. Investigation of Chiral Bis-Borane Catalysts for Imine
Hydrogenation.[a]
[a] Unless otherwise specified, all hydrogenations were performed
with 0.25 mmol of 1a in 2 mL of toluene in a 30 mL autoclave. [b]
Determined by NMR analysis. [c] Determined by HPLC with a
Chiralcel OD-H column; the absolute configuration was assigned by
comparison with the literature optical rotation. [d] Isolated yield. [e]
Reaction with 1.0 mmol of 1a.
Using the optimal conditions, we surveyed the generality of
this enantioselective hydrogenation reaction by evaluating
various imine substrates (Table 2). Electron-donating and
electron-withdrawing substituents at the para position of the
aryl ring of imines 1a–1f were well tolerated; amines 2a–2f
were generated in excellent yields with 89–94% ee. F- and Cl-
Substituted imines reacted readily under the standard
conditions (2g and 2h), but Br- and I-substituted imines
required an elevated reaction temperature (0 °C), owing to
their poor solubilities in toluene at lower temperatures; the
enantioselectivities under these conditions decreased to 85%
ee (2i and 2j). The presence of meta (2k–2o) and ortho
substituents (2p) on the aryl ring did not influence the
reactivity or selectivity. Hydrogenation of a benzodioxole-
substituted imine and a 2-naphthyl-substituted imine also
efficiently generated the desired amine products (2q and 2r)
in excellent yields with high ee values. Changing the alkyl
substituent from methyl to ethyl (2s–2u), n-propyl (2v) or
benzyl (2w) was also feasible. Remarkably, coexisting alkene
and alkyne functional groups, whether they were terminal or
internal, were untouched during the reduction of imines 1x–
1bb. Moreover, despite the potential for inhibition of the
[a] Unless otherwise specified, all hydrogenations were performed with
0.25 mmol of 1 in 2 mL of toluene. Isolated yields are reported. The
directions of optical rotations or the absolute configurations are given in
parenthesis. [b] Used 4 mol% catalyst. [c] Reaction temperature, -20 °C.
[d] Reaction temperature, 0 °C. [e] Reaction temperature, -30 °C. [f] Used
10 mol% catalyst. [g] Used mesitylene as solvent.
The unique temperature-dependent selectivity of the
hydroboration reaction prompted us to study the process by
means of density functional theory (DFT) calculations. The
hydroboration of L4 with HB(p-C6F4H)2 was chosen for
computational studies because it produced the optimum
catalyst. This reaction occurs via four-membered-ring
transition states, and two consecutive additions from either the
bottom face (cis to the hydrogens on the fused carbons) or the
top face (trans to the hydrogens on the fused carbons) give
CAT7 and CAT8, respectively (Figure 1). DFT calculations at
the ω-B97XD/6-31G(d)/def2-tzvpp level of theory[15] indicated
that the consecutive additions from the bottom face have a
lower activation barrier (21.1 kcal/mol), whereas the additions
from the top face are more exothermic (-14.4 kcal/mol).[16]
This article is protected by copyright. All rights reserved.

10.1002/anie.201808289
Angewandte Chemie International Edition
COMMUNICATION
Figure 1. Energy profile of hydroboration of L4 with HB(p-C6F4H)2 at 298 K.
Close examination of the transition states in Figure 1 suggests
that the steric repulsion between the rigid bicyclic structure
and HB(p-C6F4H)2 is quite strong in TS1a and TS2a. To
overcome this repulsion, the angle of the bicyclic structure
(~117°–119°) and the ArF–B–ArF angle (~114°–117°) are
distorted relative to the same angles in the free diene (114°)
and HB(p-C6F4H)2 (125°). Moreover, the overall barrier to
conversion from the kinetic product to the thermodynamic
product via retrohydroboration/rehydroboration is 31.1
kcal/mol,[17] which is difficult to overcome at 25 °C . In
comparison, the barrier for the same process decreases to
26.4 kcal/mol at 80 °C (see Figure S1 in the SI), which is
relatively easy to overcome at this elevated temperature. This
energy diagram also showed that the release of HB(p-C6F4H)2
from its dimeric form was rather endothermic (14.8 kcal/mol),
which explained its slow hydroboration at 25 °C . We have also
studied the enantioselective imine hydrogenation by DFT
calculations (see Figure S3 and S4 in the SI), and our
calculations indicate that the hydrogen activation step is rate-
limiting and the interactions between two B(p-C6F4H)2 groups
in CAT8 are contributing to the enantiocontrol.
18JCYBJC21400), the 1000-Talent Youth Program, and the
Fundamental Research Funds for Central Universities. We
thank Prof. Guo-Qiang Lin’s group at SIOC, Prof. Qi-Lin Zhou
at Nankai University and Prof. Michael P. Doyle at UTSA for
helpful discussions.
Keywords: boron • asymmetric catalysis • hydrogenation •
homogeneous catalysis • frustrated Lewis pair
[1] G. C. Welch, R. R. S. Juan, J. D. Masuda, D. W. Stephan, Science 2006,
314, 1124.
[2] For reviews, see: a) D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2015,
54, 6400; Angew. Chem. 2015, 127, 6498; b) M. Oestreich, J. Hermeke, J.
Mohr, Chem. Soc. Rev. 2015, 44, 2202; c) D. W. Stephan, Science 2016,
354, aaf7229.
[3] a) D. Chen, J. Klankermayer, Chem. Commun. 2008, 2130; b) D. Chen, Y.
Wang, J. Klankermayer, Angew. Chem. Int. Ed. 2010, 49, 9475; Angew.
Chem. 2010, 122, 9665; c) D. Chen, V. Leich, F. Pan, J. Klankermayer,
Chem. Eur. J. 2012, 18, 5184; d) G. Ghattas, D. Chen, F. Pan, J.
Klankermayer, Dalton Trans. 2012, 41, 9026.
[4] a) M. Mewald, R. Fröhlich, M. Oestreich, Chem. Eur. J. 2011, 17, 9406; b)
M. Mewald, M. Oestreich, Chem. Eur. J. 2012, 18, 14079; c) J. Hermeke, M.
Mewald, M. Oestreich, J. Am. Chem. Soc. 2013, 135, 17537; d) L. Süsse, J.
Hermeke, M. Oestreich, J. Am. Chem. Soc. 2016, 138, 6940.
[5] a) V. Sumerin, K. Chernichenko, M. Nieger, M. Leskelä, B. Rieger, T. Repo,
Adv. Synth. Catal. 2011, 353, 2093; b) M. Lindqvist, K. Borre, K. Axenov, B.
Kótai, M. Nieger, M. Leskelä, I. Pápai, T. Repo, J. Am. Chem. Soc. 2015,
137, 4038.
In conclusion, we have developed a new protocol for the
preparation of C2-symmetric bis-borane catalysts by means of
hydroboration reactions of chiral internal dienes with
HB(C6F5)2 or HB(p-C6F4H)2. Remarkably, either a kinetic or a
thermodynamic product could be selectively produced from
one diene precursor depending on the reaction temperature.
The outstanding activity and selectivity of the catalysts, as
demonstrated by their use in imine hydrogenation reactions,
together with other attractive characteristics, including ease of
preparation, low cost, and lack of transition metals, attest to
their great potential utility. Moreover, this study reveals
several criteria for choosing an internal diene for highly
selective hydroboration. Further studies aimed at investigating
other chiral internal dienes for new catalysts and at extending
the use of these bis-borane catalysts to other transformations
are underway in our laboratory.
[6] a) Y. Liu, H. Du, J. Am. Chem. Soc. 2013, 135, 6810; b) S. Wei, H. Du, J.
Am. Chem. Soc. 2014, 136, 12261; c) Z. Zhang, H. Du, Angew. Chem. Int.
Ed. 2015, 54, 623; Angew. Chem. 2015, 127, 633; d) X. Ren, H. Du, J. Am.
Chem. Soc. 2016, 138, 810.
[7] a) X. Wang, G. Kehr, C. G. Daniliuc, G. Erker, J. Am. Chem. Soc. 2014, 136,
3293; b) K.-Y. Ye, X. Wang, C. G. Daniliuc, G. Kehr, G. Erker, Eur. J. Inorg.
Chem. 2017, 368.
[8] J. Lam, B. A. R. Günther, J. M. Farrell, P. Eisenberger, B. P. Bestvater, P. D.
Newman, R. L. Melen, C. M. Crudden, D. W. Stephan, Dalton Trans. 2016,
45, 15303.
[9] a) D. J. Parks, W. E. Piers, G. P. A. Yap, Organometallics 1998, 17, 5492; b)
D. J. Parks, R. E. von H. Spence, W. E. Piers, Angew. Chem. Int. Ed. Engl.
1995, 34, 809; Angew. Chem. 1995, 107, 895.
[10] For preparation of the enantiopure dienes, see: a) Z.-Q. Wang, C.-G. Feng,
M.-H. Xu, G.-Q. Lin, J. Am. Chem. Soc. 2007, 129, 5336; b) S. Helbig, S.
Sauer, N. Cramer, S. Laschat, A. Baro, W. Frey, Adv. Synth. Catal. 2007,
349, 2331; c) C.-G. Feng, Z.-Q. Wang, P. Tian, M.-H. Xu, G.-Q. Lin, Chem.
Asian J. 2008, 3, 1511.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21602114, 21702109), the
Natural Science Foundation of Tianjin (16JCYBJC42500,
[11] CCDC 1575679, 1584683, 1817472 and 1829595 contain the
This article is protected by copyright. All rights reserved.

10.1002/anie.201808289
Angewandte Chemie International Edition
COMMUNICATION
supplementary crystallographic data for this paper. These data are provided
free of charge by The Cambridge Crystallographic Data Centre.
[12] D. Winkelhaus, B. Neumann, H.-G. Stammler, N. W. Mitzel, Dalton Trans.
2012, 41, 8609.
[13] a) P. A. Chase, T. Jurca, D. W. Stephan, Chem. Commun. 2008, 1701; b)
T. A. Rokob, A. Hamza, A. Stirling, I. Pápai, J. Am. Chem. Soc. 2009, 131,
2029; c) T. A. Rokob, A. Hamza, I. Pápai, J. Am. Chem. Soc. 2009, 131,
10701.
[14] Since the hydroboration reactions that gave CAT5 and CAT7 also
generated considerable amounts of other borane species (another bis-
borane isomer and a mono-hydroboration product, respectively), we were
unable to test these two catalysts in their relatively pure forms.
[15] DFT calculations were performed using Gaussian 09, Revision D.01, M. J.
Frisch, et al. Gaussian, Inc., Wallingford CT, 2009. For details, see the SI.
[16] The Markovnikov hydroborations and the pathways giving the partially
inverted product were found unfavorable energetically. See the SI for details.
[17] This barrier was also evaluated with another two functionals (M06-2X and
B3LYP-D3), and the values were 32.2 and 28.2 kcal/mol, respectively.
This article is protected by copyright. All rights reserved.

10.1002/anie.201808289
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Xian-Shuang Tu, Ning-Ning Zeng, Ru-
Ye Li, Yu-Quan Zhao, De-Zhen Xie,
Qian Peng,* Xiao-Chen Wang*
Page No. – Page No.
C2-Symmetric Bicyclic Bis-Borane
Catalysts: Kinetic or Thermodynamic
Products from a Reversible
C2-symmetric Bicyclic Bis-Boranes: we have developed a new class of C2-
symmetric bicyclic bis-borane catalysts by reacting bicyclic dienes with HB(C6F5)2
and HB(p-C6F4H)2. Remarkably, two diastereomeric catalysts could be selectively
accessed by simply varying the reaction temperature. These catalysts exhibited
excellent activity and selectivity in imine hydrogenation reactions.
Hydroboration of Dienes
This article is protected by copyright. All rights reserved.