Borane-Catalyzed Chemoselective and Enantioselective Reduction of 2-Vinyl-Substituted Pyridines

Article abstract of DOI:10.1002/anie.202007352

Herein, we report that highly chemoselective and enantioselective reduction of 2-vinyl-substituted pyridines has been achieved for the first time. The reaction, which uses chiral spiro-bicyclic bisboranes as catalysts and HBpin and an acidic amide as reducing reagents, proceeds through a cascade process involving 1,4-hydroboration followed by transfer hydrogenation of a dihydropyridine intermediate. The retained double bond in the reduction products permits their conversion to natural products and other useful heterocyclic compounds by simple transformations.

Full text of DOI:10.1002/anie.202007352

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Borane-Catalyzed Chemoselective and Enantioselective
Reduction of 2-Vinyl-Substituted Pyridines
Authors: Jun-Jie Tian, Zhao-Ying Yang, Xin-Shen Liang, Ning Liu,
Chen-Yu Hu, Xian-Shuang Tu, Xiang Li, 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.202007352
Link to VoR: https://doi.org/10.1002/anie.202007352

10.1002/anie.202007352
Angewandte Chemie International Edition
COMMUNICATION
Borane-Catalyzed
Chemoselective
and
Enantioselective
Reduction of 2-Vinyl-Substituted Pyridines
Jun-Jie Tian,# Zhao-Ying Yang,# Xin-Shen Liang, Ning Liu, Chen-Yu Hu, Xian-Shuang Tu, Xiang Li,
and Xiao-Chen Wang*
Abstract: Herein, we report that highly chemoselective and
enantioselective reduction of 2-vinyl-substituted pyridines has been
achieved for the first time. The reaction, which uses chiral spiro-
bicyclic bisboranes as catalysts and HBpin and an acidic amide as
reducing reagents, proceeds via a cascade process involving 1,4-
hydroboration followed by transfer hydrogenation of a dihydropyridine
intermediate. The retained double bond in the reduction products
permits their conversion to natural products and other useful
heterocyclic compounds via simple transformations.
hydrogenations of imines and quinolines catalyzed by chiral
boranes.[9–12] The major advantage of these reactions over
conventional transition-metal-catalyzed hydrogenation is the
excellent chemoselectivity. In particular, the reactions have
been found to occur highly selectively at very polarized π
bonds (e.g., imines and enamines) while leaving many other
unsaturated functional groups (including olefins, alkynes, and
carbonyl groups) intact. Therefore, we speculated that a
method for borane-catalyzed enantioselective pyridine
reduction would not suffer from the limited functional group
tolerance exhibited by existing methods. However, there are
no literature precedents for such a method.
Nitrogen heterocycles are among the most common
structural motifs in drug molecules. According to a 2014
structural analysis, piperidine is the most common nitrogen
heterocycle in drugs approved by the US Food and Drug
Administration,[1] and many of these drugs contain chiral
piperidines. Therefore, the development of methods for
enantioselective synthesis of chiral piperidines would be
highly desirable. Reduction of pyridines is the most
straightforward way to prepare piperidines,[2] but two major
hurdles have hindered the development of catalytic reduction
methods: the resistance of the pyridine ring to dearomatization
and catalyst poisoning by coordination of the nitrogen atom.
To overcome these problems, chemists have generally used
N-protected pyridine derivatives for studies of transition-
metal-catalyzed enantioselective hydrogenations. Specifically,
N-iminopyridinium ylides[3] or pyridinium salts,[4,5] which have
lower energy barriers for dearomatization than unprotected
pyridines and are less prone to catalyst poisoning, have been
successfully hydrogenated using chiral Ir and Rh catalysts
(Scheme 1a). For the most part, however, these reductions
have been carried out on pyridines bearing inert phenyl and
alkyl substituents, and thus the products lack opportunities for
further transformations. Alternatively, hydrogenation of
unprotected pyridines by using I2 as an activating reagent is
feasible, but the scope of this method is narrow.[6] Another
method involves the use of chiral phosphoric acid catalysts for
partial reduction of 2,6-dialkylpyridines bearing electron-
withdrawing groups at the 3-position (Scheme 1b).[7] To date,
these are the only methods for catalytic highly
enantioselective reduction of pyridines.
Recently, we developed a protocol for pyridine reduction
by means of a B(C6F5)3-catalyzed cascade involving 1,4-
hydrosilylation (or hydroboration) and subsequent transfer
hydrogenation of the resulting dihydropyridine intermediate.[13]
We wondered whether this protocol could be accomplished
enantioselectively by using a chiral borane catalyst. This
potentially straightforward approach presents several
challenges, with the key one being achieving good
enantioselectivity while maintaining reactivity. Specifically, in
our B(C6F5)3-catalyzed cascade reactions, the resting state of
the catalyst is the B(C6F5)3–pyridine complex,[13,14] which must
undergo decomplexation so that B(C6F5)3 can activate the
hydrosilane.[15] However, decomplexation requires high
temperature (e.g., 110 °C; this phenomenon has been defined
as thermally induced frustration[16] by the frustrated Lewis pair
chemists), which is usually detrimental to enantiocontrol.
We reasoned that a catalyst with a sterically hindered
boron center might either prevent the complexation of a 2-
substituted pyridine with the catalyst or permit decomplexation
at ambient temperature. In particular, we speculated that our
previously reported spiro-bicyclic bisboranes,[12b] which
feature considerable steric bulk around the boron atoms owing
to the presence of perpendicular cyclopentane rings and the
adjacent aryl substituent, might be suitable. Indeed, we report
herein that these bisborane catalysts do in fact catalyze the
desired transformation at ambient temperature. Specifically,
2-vinyl-substituted pyridines could be efficiently reduced with
HBpin and an acidic amide as the reducing reagents in the
presence of as low as 0.5 mol % of the catalyst to afford chiral
2-vinylpiperidines with enantioselectivities up to 96% ee
(Scheme 1c).
The emergence of frustrated Lewis pair chemistry has led
to the development of protocols for hydrogenation reactions
promoted by unquenched Lewis acid/base pairs.[8] Research
in this area has resulted in breakthroughs in enantioselective
[*]
J.-J. Tian,# Z.-Y. Yang,# X.-S. Liang, N. Liu, C.-Y. Hu, X.-S. Tu, X.
Li, and Prof. Dr. X.-C. Wang
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University
94 Weijin Road, Tianjin 300071 (China)
E-mail: xcwang@nankai.edu.cn
Homepage: http://www.wangnankai.com/
These authors contributed equally to this work.
[#]
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.202007352
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of reaction conditions for reduction of (E)-2-
styrylpyridine[a]
entry catalyst
E-H
H+ donor yield
(%)[b]
ee
(%)[c]
1
1a
Ph2SiH2
Et2SiH2
PD1
PD1
8
n.d.
n.d.
n.d.
76
Scheme 1. Catalytic enantioselective reduction of pyridines.
2
1a
trace
trace
53
A
number of natural products—such as (+)-
3
1a
Ph2MeSiH PD1
caulophyllumine B,[17] (+)-dienomycin C,[18] and (+)-
inohanamine[19]—have 2-vinylpiperidine moieties. Previous
syntheses of enantioenriched 2-vinylpiperidines have relied
on asymmetric intramolecular amination/cyclization reactions
of allenes or olefins,[20] Wittig reactions of enantioenriched 2-
4
1a
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
HBpin
PD1
PD2
PD3
PD4
PD5
PD6
PD7
PD7
PD7
PD7
PD7
PD7
5
1a
trace
trace
64
n.d.
n.d.
80
6
1a
7
1a
piperidinecarboxaldehydes,[21]
lithiation/substitution reactions
or
of
asymmetric
N-Boc-protected
8
1a
49
82
9
1a
55
84
piperidines.[22] These routes either required lengthy syntheses
of the starting materials or used stoichiometric amounts of
organometallic reagents and chiral auxiliaries. Therefore, we
considered that the chemo- and enantioselective reduction of
2-vinylpyridines to generate 2-vinylpiperidines would be highly
useful.
10
11[d]
12
13
14
15
16
1a
80
89
1a
88
91
1b
1c
62
67
52
81
1d
B(C6F5)3
1a
71
82
trace
trace
n.d.
n.d.
We began by evaluating reactions of (E)-2-styrylpyridine
(S1) as the model substrate (Table 1). Spiro-bicylic bisborane
catalysts 1a–1d were prepared in situ by the hydroboration
reactions of the bicyclic dienes with HB(C6F5)2.[12b] Our work
on B(C6F5)3-catalyzed cascade reduction of pyridines
revealed that Ph2SiH2 and Ph2NH (PD1) are the optimal
hydride and proton donors, respectively.[13] However, when
we tested these reductants with catalyst 1a at 25 °C, the
reduction product was obtained in only 8% yield, and the
majority of pyridine S1 was recovered (entry 1). Additional
tests with Et2SiH2 and Ph2MeSiH, both of which have been
found to be suitable for B(C6F5)3-catalyzed reductions, were
also unsuccessful (entries 2 and 3). Encouragingly, when
HBpin was used[23] instead of a hydrosilane, a significant
amount of S1 was reduced. GC-MS analysis of the reaction
mixture suggested the formation of Bpin-protected piperidine.
Exposure to moisture during workup easily hydrolyzed the N-
Bpin moiety, and 2-vinylpiperidine P1 was isolated in 53%
yield with 76% ee (entry 4).
H2
[a] Unless otherwise specified, all reactions were performed with 0.2
mmol of S1, 5 equiv. of E-H, and 2.5 equiv. of H+ donor in 4 mL of PhCF3
under N2. [b] Isolated yield. [c] Determined by HPLC with a Chiralcel OJ-H
column after protection of the N atom of P1 with benzyl chloroformate; n.d.
= not determined. [d] The reaction was carried out with 1 mol % of 1a, 5
mol % of nBu3BnNCl, 3 equiv. of PD7, 5 equiv. of HBpin, and 3 mL of
PhCF3.
fore, we subsequently tested various substituted N-
acetylanilines, and the results of three representative
examples are shown in entries 8–10. With p-methoxyaniline
(PD5), the yield dropped, but the enantioselectivity remained
essentially the same. The enantioselectivity was slightly
improved with anilines bearing electron-withdrawing groups
(PD6 and PD7), and the use of N-acetyl-3,5-di-
trifluoromethylaniline (PD7) resulted in an 89% ee and an
isolated yield of 80%. Because PD7 is a solid that does not
dissolve completely in PhCF3, we also carried out a reaction
in the presence of a phase-transfer catalyst (nBu3BnNCl, 5
mol %). Gratifyingly, under these conditions, the loading of 1a
could be decreased to 1 mol %, the yield of P1 improved to
88%, and the enantioselectivity improved to 91% ee (entry 11).
Three bisborane catalysts with other substituted aryl rings
(1b–1d) failed to give better results than 1a (entries 12–14),
Screening of alternative proton donors with HBpin
revealed that N-alkyl-substituted secondary amines (PD2 and
PD3) were not reactive (entries 5 and 6), but N-acetylaniline
(PD4) gave a 64% yield of P1 with 80% ee (entry 7). There-
This article is protected by copyright. All rights reserved.

10.1002/anie.202007352
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Substrate scope[a]
and B(C6F5)3 (10 mol %) was completely inactive under these
conditions (entry 15). The high activity and high turnover
numbers obtained with the spiro-bicyclic bisborane catalysts
may be attributable to the steric bulk around the boron atom,
which not only permits Lewis acid activation of HBpin at
ambient temperature by destabilizing the complex between
the pyridine substrate and the catalyst (for the overall reaction
mechanism, see Figure S1 in the supporting information) but
also enhances the chemostability of the catalyst by preventing
the attack of other nucleophiles (that is, other than hydride) at
the Lewis acidic boron. When H2 gas was used instead of the
pair of reducing reagents, the substrate did not undergo
reduction (entry 16). In addition, we subjected S1 to the
conditions used for several reported metal-catalyzed
hydrogenation methods, but the olefin underwent
hydrogenation (see the supporting information).
Next we investigated the scope of this catalytic
enantioselective cascade reduction by carrying out reactions
of various 2-vinyl-substituted pyridines (Table 2). Note that the
isolated piperidines were protected with a carboxybenzyl
group or a p-nitrobenzenesulfonyl group for ee determination
by HPLC because the unprotected piperidines were too polar
for separation on normal-phase chiral columns. And, the
overall yield of the reduction reaction and subsequent
protection reaction is given for each substrate in Table 2. 2-
Styryl-substituted pyridines with an electron-donating or
t
electron-withdrawing substituent—methoxy (P2), butyl (P3),
phenyl (P4), fluoro (P5), or bromo (P6)—at the para position
of the phenyl ring of the styrene moiety were tolerated,
affording the desired products in good yields with high
enantioselectivities (91–92% ee). To demonstrate the
excellent functional group tolerance of our method, we also
tested substrates bearing methylthio (P7), trifluoromethoxy
(P8), ester (P9 and P10), ketone (P11), and nitro (P12)
substituents. Remarkably, the coordinative methylthio and
nitro groups did not quench the catalyst; all the functional
groups, including the ketone and the ester, were preserved
during the reduction; and the enantioselectivities exceeded 90%
ee in all cases. Substrates with meta-substituted (P13 and
P14), ortho-substituted (P15), and disubstituted (P16) phenyl
rings were also suitable, giving the desired reduction products
with 90–93% ee. The phenyl ring could be replaced by other
aromatic rings, including 2-naphthyl (P17), 2-furyl (P18), and
2-thienyl (P19). The reaction was also feasible with a 2-dienyl-
substituted pyridine (P20), with pyridines bearing conjugated
(P21) or unconjugated double and triple bonds (P22), and with
(E)-ethyl 3-(pyridin-2-yl)acrylate (P23). The double and triple
bonds were retained in all of these reactions. Furthermore,
substrates with methyl (P24), n-propyl (P25), benzyl (P26), n-
nonyl (P27), and cyclohexyl (P28) substituents also
underwent the reaction, as did a substrate with an n-pentyl
chain bearing a terminal benzyloxy group (P29), although the
yields for these alkyl-substituted compounds were relatively
low. Substrates with trisubstituted olefins (P30–P33) were
also reactive, giving the corresponding products with ee
values of 73–89%.
[a]Unless otherwise specified, all reactions were performed with 0.2 mmol of
substrate, 1 mol % of 1a, 5 mol % of nBu3BnNCl, 5 equiv. of HBpin, and 3 equiv.
of PD7 in 3 mL of PhCF3 under N2; the percentages shown are isolated yields
and enantiomeric excesses, respectively. PG, protecting group. [b] Used 2.0
mol % of 1a, 2.5 equiv. of PD7, and 4 mL of PhCF3. [c] Used 2.0 mol % of 1a
and 5 mL of PhCF3; reaction temperature, 30 °C. [d] Used 5.0 mol % of 1a and
5 mL of PhCF3; reaction temperature, 30 °C. [e] Used 2.0 mol % of 1a and 6 mL
of PhCF3; reaction temperature, 30 °C.
This article is protected by copyright. All rights reserved.

10.1002/anie.202007352
Angewandte Chemie International Edition
COMMUNICATION
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21871147, 91956106, and
21602114) and the Fundamental Research Funds for Central
Universities (2122018165). X.-C.W. thanks the Tencent
Foundation for support via the Xplorer Prize.
Keywords: boron • asymmetric catalysis • pyridine • reduction •
heterocycles
[1] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257–10274.
[2] For selected reviews, see: a) D.-S. Wang, Q.-A. Chen, S.-M. Lu,
Y.-G. Zhou, Chem. Rev. 2012, 112, 2557–2590; b) Y.-M. He, F.-T.
Song, Q.-H. Fan, Top. Curr. Chem. 2013, 343, 145–190; c) M. P.
Wiesenfeldt, Z. Nairoukh, T. Dalton, F. Glorius, Angew. Chem. Int.
Ed. 2019, 58, 10460–10476; Angew. Chem. 2019, 131, 10570–
10586.
[3] C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005, 127, 8966–
8967.
[4] For selected reports on hydrogenations of N-alkyl pyridinium salts,
see: a) Z.-S. Ye, M.-W. Chen, Q.-A. Chen, L. Shi, Y. Duan, Y.-G.
Zhou, Angew. Chem. Int. Ed. 2012, 51, 10181–10184; Angew.
Chem. 2012, 124, 10328–10331; b) M. Chang, Y. Huang, S. Liu,
Y. Chen, S. W. Krska, I. W. Davies, X. Zhang, Angew. Chem. Int.
Ed. 2014, 53, 12761–12764; Angew. Chem. 2014, 126, 12975–
12978; c) W.-X. Huang, C.-B. Yu, Y. Ji, L.-J. Liu, Y.-G. Zhou, ACS
Catal. 2016, 6, 2368−2371.
Scheme 2. Gram-scale reactions and transformations of products.
To demonstrate the strength of our method, we performed
a gram-scale reaction of S1 in the presence of only 0.5 mol %
of 1a. The reaction afforded piperidine P1 in 89% yield with
90% ee (Scheme 2a), and almost all of the proton donor could
be recovered after hydrolysis of the 3,5-(CF3)2C6H3NAc(Bpin)
generated as
a
byproduct. We then carried out
[5] For selected reports on hydrogenations of pyridinium hydrogen
halide salts, see: a) Y. Kita, A. Iimuro, S. Hida, K. Mashima, Chem.
Lett. 2014, 43, 284–286; b) M.-W. Chen, Z.-S. Ye, Z.-P. Chen, B.
Wu, Y.-G. Zhou, Org. Chem. Front. 2015, 2, 586–589; c) M.-W.
Chen, Y. Ji, J. Wang, Q.-A. Chen, L. Shi, Y.-G Zhou, Org. Lett.
2017, 19, 4988−4991.
transformations of P1 involving the retained olefin unit. First,
we protected the nitrogen with a vinylacetyl group (by reaction
with vinylacetic acid), and then the protected compound was
converted to the corresponding bicyclic quinolizidine (2) in 83%
yield with no loss of ee by means of a ring-closing metathesis
reaction catalyzed by the Grubbs II catalyst. In addition, we
prepared an N-propionyl-protected piperidine by reaction of
P1 with propionyl chloride. Subsequent aza-Claisen
[6] a) X.-B. Wang, W. Zeng, Y.-G. Zhou, Tetrahedron Lett. 2008, 49,
4922–4924; b) W. Tang, Y. Sun, L. Xu, T. Wang, Q. Fan, K.-H.
Lam, A. S. C. Chan, Org. Biomol. Chem. 2010, 8, 3464–3471.
[7] M. Rueping, A. P. Antonchick, Angew. Chem. Int. Ed. 2007, 46,
4562–4565; Angew. Chem. 2007, 119, 4646–4649.
rearrangement
in
the
presence
of
lithium
bis(trimethylsilyl)amide gave ring-expansion product 3[24] in
good yield and good diastereoselectivity with 89% ee. These
results demonstrate that our reduction method can provide
rapid access to enantioenriched olefin-containing bicyclic
quinolizidines and 10-membered lactams. We also used our
method for natural product synthesis. Gram-scale
enantioselective reduction of S9 under the optimal reaction
conditions generated piperidine P9, and protection of the
nitrogen of P9 with a Boc group gave compound 4, which is
[8] For selected reviews, see: a) D. W. Stephan, G. Erker, Angew.
Chem. Int. Ed. 2015, 54, 6400–6441; Angew. Chem. 2015, 127,
6498–6541; b) M. Oestreich, J. Hermeke, J. Mohr, Chem. Soc.
Rev. 2015, 44, 2202–2220; c) D. W. Stephan, Science 2016, 354,
aaf7229.
[9] a) D. Chen, J. Klankermayer, Chem. Commun. 2008, 2130–2131;
b) D. Chen, Y. Wang, J. Klankermayer, Angew. Chem. Int. Ed.
2010, 49, 9475–9478; Angew. Chem. 2010, 122, 9665–9668.
[10] a) V. Sumerin, K. Chernichenko, M. Nieger, M. Leskelä, B. Rieger,
T. Repo, Adv. Synth. Catal. 2011, 353, 2093–2110; b) M. Lindqvist,
K. Borre, K. Axenov, B. Kótai, M. Nieger, M. Leskelä, I. Pápai, T.
Repo, J. Am. Chem. Soc. 2015, 137, 4038–4041.
an intermediate in
a previously reported synthesis of
caulophyllumine B[17] (Scheme 2b).
In conclusion, we have developed a method for metal-free
enantioselective reduction of 2-vinylpyridines with catalysis by
chiral spiro-bicyclic bisboranes. The reaction is the first
example of a metal-free borane-catalyzed enantioselective
pyridine reduction and a rare example of an enantioselective
reduction of unprotected pyridines. The excellent functional
group tolerance of this method is its major advantage relative
to all the other existing methods. In addition, the low catalyst
loading and the mild reaction conditions (ambient temperature
and no use of compressed hydrogen gas) make it attractive
for industrial applications. Currently, work on using this
method for the reduction of other pyridine substrates and
heteroaromatics is underway in our laboratory.
[11] a) Y. Liu, H. Du, J. Am. Chem. Soc. 2013, 135, 6810–6813; b) Z.
Zhang, H. Du, Org. Lett. 2015, 17, 2816–2819; c) Z. Zhang, H. Du,
Org. Lett. 2015, 17, 6266–6269; d) S. Li, G. Li, W. Meng, H. Du, J.
Am. Chem. Soc. 2016, 138, 12956–12962; e) Q. Zhou, W. Meng,
J. Yang, H. Du, Angew. Chem. Int. Ed. 2018, 57, 12111–12115;
Angew. Chem. 2018, 130, 12287–12291; f) W. Meng, X. Feng, H.
Du, Acc. Chem. Res. 2018, 51, 191–201.
[12] a) X.-S. Tu, N.-N. Zeng, R.-Y. Li, Y.-Q. Zhao, D.-Z. Xie, Q. Peng,
X.-C. Wang, Angew. Chem. Int. Ed. 2018, 57, 15096–15100;
Angew. Chem. 2018, 130, 15316–15320; b) X. Li, J.-J. Tian, N. Liu,
This article is protected by copyright. All rights reserved.

10.1002/anie.202007352
Angewandte Chemie International Edition
COMMUNICATION
X.-S. Tu, N.-N. Zeng, X.-C. Wang, Angew. Chem. Int. Ed. 2019,
58, 4664–4668; Angew. Chem. 2019, 131, 4712–4716.
[13] Z.-Y. Liu, Z.-H. Wen, X.-C. Wang, Angew. Chem. Int. Ed. 2017,
56, 5817–5820; Angew. Chem. 2017, 129, 5911–5914.
[14] For a comprehensive study of the interactions of pyridines and
B(C6F5)3, see: S. J. Geier, A. L. Gille, T. M. Gilbert, D. W. Stephan,
Inorg. Chem. 2009, 48, 10466–10474.
[15] For selected reports on hydrosilane activation by boranes, see: a)
D. J. Parks, W. E. Piers, J. Am. Chem. Soc. 1996, 118, 9440–9441;
b) D. J. Parks, J. M. Blackwell, W. E. Piers, J. Org. Chem. 2000,
65, 3090–3098; c) A. Y. Houghton, J. Hurmalainen, A.
Mansikkamäki, W. E. Piers, H. M. Tuononen, Nat. Chem. 2014, 6,
983–988; d) S. Rendler, M. Oestreich, Angew. Chem. Int. Ed. 2008,
47, 5997–6000; Angew. Chem. 2008, 120, 6086–6089; e) J.
Hermeke, M. Mewald, M. Oestreich, J. Am. Chem. Soc. 2013, 135,
17537−17546.
[16] For selected examples, see: a) T. A. Rokob, A. Hamza, A. Stirling,
I. Pápai, J. Am. Chem. Soc. 2009, 131, 2029–2036; b) V. Sumerin,
F. Schulz, M. Nieger, M. Leskelä, T. Repo, B. Rieger, Angew.
Chem. Int. Ed. 2008, 47, 6001–6003; Angew. Chem. 2008, 120,
6090–6092; c) Y. Hoshimoto, T. Kinoshita, M. Ohashi, S. Ogoshi,
Angew. Chem. Int. Ed. 2015, 54, 11666−11671; Angew. Chem.
2015, 127, 11832–11837; d) L. Fan, A. R. Jupp, D. W. Stephan, J.
Am. Chem. Soc. 2018, 140, 8119−8123.
[17] P. R. Krishna, B. K. Reddy, Tetrahedron Lett. 2010, 51, 6262–
6264.
[18] D. L. Comins, G. M. Green, Tetrahedron Lett. 1999, 40, 217–218.
[19] M. A. Arai, N. Ishikawa, M. Tanaka, K. Uemura, N. Sugimitsu, A.
Suganami, Y. Tamura, T. Koyano, T. Kowithayakorn, M. Ishibashi,
Chem. Sci. 2016, 7, 1514–1520.
[20] a) S. Hong, A. M. Kawaoka, T. J. Marks, J. Am. Chem. Soc. 2003,
125, 15878–15892; b) C. Welter, A. Dahnz, B. Brunner, S. Streiff,
P. Dübon, G. Helmchen, Org. Lett. 2005, 7, 1239–1242; c) D.
Berthold, A. G. A. Geissler, S. Giofré, B. Breit, Angew. Chem. Int.
Ed. 2019, 58, 9994–9997; Angew. Chem. 2019, 131, 10099–
10102; d) X. Ma, I. R. Hazelden, T. Langer, R. H. Munday, J. F.
Bower, J. Am. Chem. Soc. 2019, 141, 3356−3360.
[21] S. H. Lim, S. Ma, P. Beak, J. Org. Chem. 2001, 66, 9056–9062.
[22] T. K. Beng, R. E. Gawley, J. Am. Chem. Soc. 2010, 132, 12216–
12217.
[23] For studies of pyridine hydroborations catalyzed by sterically
hindered Lewis acids, see: a) X. Fan, J. Zheng, Z. H. Li, H. Wang,
J. Am. Chem. Soc. 2015, 137, 4916−4919; b) C. C. Chong, R.
Kinjo, ACS Catal. 2015, 5, 3238−3259; c) B. Rao, C. C. Chong, R.
Kinjo, J. Am. Chem. Soc. 2018, 140, 652−656; d) T. Hynes, E. N.
Welsh, R. McDonald, M. J. Ferguson, A. W. H. Speed,
Organometallics 2018, 37, 841−844.
[24] CCDC 2003665 contain the supplementary crystallographic data
for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
This article is protected by copyright. All rights reserved.

10.1002/anie.202007352
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Jun-Jie Tian,# Zhao-Ying Yang,# Xin-
Shen Liang, Ning Liu, Chen-Yu Hu,
Xian-Shuang Tu, Xiang Li, Xiao-Chen
Wang*
Page No. – Page No.
Borane-Catalyzed Chemoselective
and Enantioselective Reduction of 2-
Vinyl-Substituted Pyridines
Enantioselective pyridine reduction: A protocol for Lewis acid-catalyzed highly
chemoselective and enantioselective reduction of 2-vinyl-substituted pyridines has
been developed. The reactions were catalyzed by chiral spiro-bicyclic bisboranes,
and occurred under mild reaction conditions with high turnover numbers.
This article is protected by copyright. All rights reserved.