Spiro-Bicyclic Bisborane Catalysts for Metal-Free Chemoselective and Enantioselective Hydrogenation of Quinolines

Article abstract of DOI:10.1002/anie.201900907

A new series of spiro-bicyclic bisborane catalysts has been prepared by means of hydroboration reactions of C₂-symmetric spiro-bicyclic dienes with HB(C₆F₅)₂ and HB(p-C₆F₄H)₂. When used for hydrogenation of quinolines, these catalysts give excellent yields and enantiomeric excesses, and show turnover numbers of up to 460. The most attractive feature of these metal-free hydrogenation reactions was the broad functional-group tolerance, making this method complementary to existing methods for quinoline hydrogenation.

Full text of DOI:10.1002/anie.201900907

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Accepted Article
Title: Spiro Bicyclic Bisborane Catalysts for Metal-Free Chemoselective
and Enantioselective Hydrogenation of Quinolines
Authors: Xiang Li, Jun-Jie Tian, Ning Liu, Xian-Shuang Tu, Ning-Ning
Zeng, and Xiao-Chen Wang
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10.1002/anie.201900907
Angewandte Chemie International Edition
COMMUNICATION
Spiro Bicyclic Bisborane Catalysts for Metal-Free Chemoselective
and Enantioselective Hydrogenation of Quinolines
Xiang Li,# Jun-Jie Tian,# Ning Liu, Xian-Shuang Tu, Ning-Ning Zeng, and Xiao-Chen Wang*
Dedicated to the 100th anniversary of Nankai University
Abstract: We have prepared a new series of spiro bicyclic bisborane
catalysts by means of hydroboration reactions of C2-symmetric spiro
bicyclic dienes with HB(C6F5)2 and HB(p-C6F4H)2. When used for
hydrogenation of quinolines, these catalysts gave excellent yields and
enantiomeric excesses and showed turnover numbers up to 460. The
most attractive feature of these metal-free hydrogenation reactions
was the broad functional group tolerance, making this method
complementary to existing methods for quinoline hydrogenation.
success with di- and trisubstituted quinolines using Du’s
catalysts[9a,b] implies that the steric influence from additional
substituents might be essential for enantiocontrol. Second,
the compatible di- and trisubstituted quinolines in Du’s studies
all have an aryl substituent at the 2-position; we suspect that
the 2-aryl substituent increases the steric bulk around the
nitrogen atom, thereby preventing undesired coordination of
the nitrogen to the Lewis acid catalyst. Third, the functional
group tolerance is limited. Therefore, the development of more
effective catalytic systems is highly desirable.
Because of the prevalence of chiral tetrahydroquinoline
scaffolds in natural products and drugs,[1] the development of
methods for enantioselective hydrogenation of quinolines is
an important area of research. Methods that use transition-
metal catalysts with chiral ligands have been extensively
investigated,[2] and the good performing catalysts are
generally iridium- and ruthenium-centered.[3–5] However, the
need to use precious metals, especially when the turnover
numbers are not high, limits the attractiveness of these
methods, for both economic and environmental reasons. More
important, because other unsaturated functional groups, such
as olefins, alkynes, and electron-rich heteroarenes, are
reactive under metal-catalyzed hydrogenation conditions, it is
very difficult to preserve these groups during hydrogenation of
the quinoline core. Indeed, most of the existing methods have
been used only on substrates that have relatively inert
substituents and thus lack handles for further elaboration.[2–5]
With the emergence of frustrated Lewis pair chemistry,[6]
studies on metal-free borane-catalyzed hydrogenations of N-
heteroarenes have grown rapidly.[7] Particularly, chiral borane
Lewis acids have been tested for enantioselective
hydrogenation of quinolines. The first report appeared in 2011:
the Repo group used a chiral ansa-ammonium borate as a
catalyst for hydrogenation of 2-phenylquinoline, and obtained
an ee value of 37%.[8] Subsequently, the Du group made a
breakthrough by using binaphthyl-diene-derived bisborane
catalysts; they reported excellent enantioselectivities in the
hydrogenations of 2,3- and 2,4-disubstituted quinolines, 2,3,4-
trisubstituted quinolines, and 2,3-disubstituted quinoxalines.[9]
However, the methods described in these pioneering studies
have limitations. First, monosubstituted quinolines remain
mostly unexplored. Besides the results for 2-phenylquinoline
reported by Repo (37% ee),[8] there is only one report of Du,
who tested their catalysts with methyl quinoline-2-carboxylate
but obtained an ee of merely 14%.[10] By comparison, the
Recently, we developed a series of chiral C2-symmetric
bisborane catalysts that are prepared by hydroboration
reactions of bicyclic [3.3.0] dienes with HB(C6F5)2 and HB(p-
C6F4H)2.[11] These catalysts are highly effective and selective
in asymmetric imine hydrogenations. We attempted to use
them for the hydrogenation of 2-methylquinoline, a less bulky
substrate that was not studied by Repo[8] or Du[9,10]
.
Disappointingly, we observed no reaction (the upper equation
in Scheme 1). We hypothesized that our catalysts were not
sterically hindered enough to prevent the coordination of this
quinoline to the boron center. To increase the steric bulk, we
intended to change the fused bicyclic structure to a spiro
bicyclic structure because the latter consists of two
perpendicular rings, which produce a steric environment
similar to that in compounds with geminal dialkyl substituents.
Furthermore, the presence of Ar and BArF2 groups attached to
the rings would further increase the steric bulkiness. We
hoped that such catalysts would show better activities than the
existing borane catalysts. Herein, we report that these new
spiro bicyclic bisboranes have now been synthesized and that,
to our delight, they exhibit excellent catalytic activities and
selectivities for the hydrogenation reactions of quinolines (the
lower equation in Scheme 1).
R
H
R = 3,5-tBu2C6H3
ArF = C6F5 or p-C6F4H
ArF2B
BArF
2
(10 mol %)
H
R
no reaction
+
H2
N
Me
toluene, 25 °C, 24 h
50 bar
greater steric bulk
Ar
ArF2B
BArF
2 new catalysts
Ar
+
H2
N
R'
N
R'
H
alkyl, aryl, styryl, dienyl,
alkynyl, hetereoaryl etc.
TON up to 460
up to 99% ee
R' =
Scheme 1. Hydrogenation of quinolines with chiral bicyclic bisborane
X. Li,# J.-J. Tian,# N. Liu, X.-S. Tu, N.-N. Zeng, Prof. Dr. X.-C. Wang
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University
catalysts
[*]
We began our study by synthesizing the necessary spiro
[4.4] diene precursors (Scheme 2a) as follows. First, racemic
spiro [4.4]nonane-1,6-dione 2 was prepared from ethyl 2-
oxocyclopentanecarboxylate (1) via a previously reported
three-step synthesis.[12] Then 2 was resolved by condensation
with (R)-2-hydrazinyl-2-oxo-N-(1-phenylethyl)acetamide and
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.
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10.1002/anie.201900907
Angewandte Chemie International Edition
COMMUNICATION
multiple recrystallizations of the obtained diastereomeric
mixture.[13] After hydrolysis of the pure hydrazone
diastereomer, (R)-2 was obtained in enantiopure form. Dione
(R)-2 was then transformed into enol triflate 3 by reaction with
N-(2-pyridyl)triflimide in the presence of potassium
bis(trimethylsilyl)amide (KHMDS). It is worth mentioning that
for this step, we tested several triflyl sources under various
reaction conditions, and only N-(2-pyridyl)triflimide gave the
desired product in a high yield without the loss of enantiomeric
purity.[14] From common intermediate 3, we were able to
prepared four aryl-substituted spiro [4.4] dienes, 4a–4d, via
Suzuki coupling reactions. These dienes served as precursors
for the corresponding bisborane catalysts.
enantiopure diene and HB(C6F5)2 were first allowed to react in
toluene at 25 °C for 15 min to generate the active catalyst, and
then 2-methylquinoline was added. The resulting mixture was
hydrogenated in an autoclave. We were pleased to find that
these spiro bicyclic bisborane catalysts were active and
selective: the use of 5 mol % of catalyst 5a resulted in
complete conversion to the corresponding tetrahydroquinoline
product (P1) with 63% ee (entry 1). Although 5b exhibited
markedly diminished activity (30% conversion, entry 2), both
5c and 5d were very active, providing P1 in complete
conversion (entries 3 and 4). However, the enantioselectivities
of these catalysts were no better than that of 5a. Gratifyingly,
after an extensive optimization study, we discovered that
changing the B(C6F5)2 group in 5a to B(p-C6F4H)2 to afford
5a4F improved the enantioselectivity to 78% ee (entry 5).[17]
With this catalyst, the ee gradually increased with decreasing
reaction temperature (entries 6 and 7); at −20 °C, the
substrate was completely consumed, and P1 was obtained
with 84% ee. Moreover, switching the solvent to PhCF3
markedly improved the enantioselectivity (to 92% ee, entry 9).
Under these conditions, the same result was obtained even
when the hydrogen pressure was decreased from 50 to 20 bar
(entry 10).
To study the process for catalyst formation, we subjected
dienes 4a–4d in their racemic form to hydroboration with Piers
borane, HB(C6F5)2 (Scheme 2b).[15] In toluene at 25 °C, the
dienes were completely consumed within 15 min, at which
point a strongly coordinative base (isoquinoline or pyridine)
was added to the reaction mixture to capture the resulting
bisborane species as stable Lewis acid/base adducts 5a·2L–
5d·2L. Remarkably, despite the possibility for formation of
multiple regioisomers and diastereomers, single isomers of
the bisborane adducts were obtained in high yields as
determined by NMR analyses using CH2Br2 as an internal
standard. Single crystals of 5a·2L and 5d·2L were obtained
via recrystallization from 20:1 (v/v) hexane/dichloromethane
at room temperature. X-ray crystallographic analyses
revealed that the aryl groups were trans to the B(C6F5)2
groups in both cyclopentane rings and that the overall
Table 1. Study of Reaction Conditions for Hydrogenation of 2-
Methylquinoline[a]
Ph
catalyst
(p-C6F4H)2B
B(p-C6F4H)2
(5 mol %)
H2
+
N
Me
solvent, T, 24 h
N
Me
Ph
H
50 bar
5a4F
S1
P1
structures
were
C2-symmetric.[16]
Notably,
unlike
entry
catalyst
5a
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
n-hexane
PhCF3
T (°C)
25
conv. (%)[b] ee (%)[c]
hydroboration reactions of bicyclic [3.3.0] dienes,[11] these
hydroborations gave the same isomers when they were
performed at higher temperatures (e.g., 80 °C).
1
100
30
63
45
62
53
78
81
84
79
92
92
2
5b
25
(a) Syntheses of the spiro [4.4] dienes:
3
5c
25
100
100
100
100
100
95
1) condensation with
Me
O
O
O
H
4
5d
25
N
O
Ph
N
NH2
3 steps
O
H
5a4F
5a4F
5a4F
5a4F
5a4F
5a4F
25
O
(Ref. 12 and 13)
5
and recrystallizations
2) hydrolysis
OEt
O
O
6
0
1
rac-2
(R)-2
7
−20
−20
−20
−20
Tf
N
N
(3 equiv)
OTf
Ar
8
ArB(OH)2 (4 equiv)
Tf
4a
: Ar = Ph, 55% yield
4b: Ar = 4-FC6H4, 59% yield
4c: Ar = 4-PhC6H4, 51% yield
KHMDS (3 equiv)
Pd(PPh3)4 (10 mol%)
9
10[d]
100
100
THF, -78 °C
Na2CO3 (2 M)
PhMe:EtOH (3:1)
80 °C
4d
: Ar = 3-PhC6H4, 56% yield
TfO
Ar
PhCF3
3, 88% yield
[a] Unless otherwise specified, all hydrogenations were performed with
0.1 mmol of S1 in 2 mL of solvent in a 30 mL autoclave. [b] Determined by
NMR. [c] Determined by HPLC with a Chiralcel OD-H column. [d] H2
pressure, 20 bar.
(b) Preparation of the bisborane Lewis adducts:
Ar
1) HB(C6F5)2 (2 equiv)
Ar
5a•2L
5b•2L: 92% yield
5c•2L: 87% yield
5d•2L
: 95% yield
toluene, 25 °C, 15 min
(C6F5)2B
B(C6F5)2
L
2) (4 equiv)
•2L
25 °C, 30 min
: 90% yield
Ar
Ar
4a 4d
L
(
= pyridine or isoquinoline)
With the optimal conditions in hand, we investigated the
generality of this borane-catalyzed enantioselective
hydrogenation reaction by testing various quinoline substrates
(Table 2). A number of 2-alkyl substituents, including n-butyl,
n-pentyl, n-octyl, benzyl, and cyclohexyl, were compatible with
the reaction conditions; the corresponding products (P2–P6,
respectively) were obtained in 90–98% yields with 90–95% ee
values. Substrates with various co-existing substituents at the
6-position of the 2-methylquinolines were then studied (S7–
S10). Gratifyingly, bromo, Bpin, and terminal alkyne and
alkene substituents were preserved, giving the desired
products (P7–P10, respectively) with high ee values. Similarly,
when a substrate possessing an unconjugated internal olefin
at the 2-position was used, the double bond remained
untouched when the heterocycle was hydrogenated (P11).
-
5a•2L
5d•2L
Scheme 2. Preparation and characterization of bisborane catalysts
Knowing that hydroboration reactions of the spiro [4.4]
dienes could efficiently generate single bisborane isomers, we
investigated the use of in situ generated bisborane
compounds for enantioselective hydrogenation with 2-
methylquinoline (S1) (Table 1). For each reaction, an
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Table 2. Investigation of Quinolines with Various Substituents[a]
and styryl-substituted tetrahydroquinolines (P12–P16) were
obtained in high yields with excellent ee values. Furthermore,
the presence of a furyl (P17) or thiophenyl (P18) moiety did
not inhibit the reaction. Although the hydrogenation reaction
of a pyridyl-substituted substrate reduced the conjugated
olefin to afford P19, the reaction of a substrate with a terminal
alkyl substituent left the olefin unit untouched (P20). Moreover,
the reaction was feasible with 2-dienyl- (P21) and alkynyl-
substituted (P22–P25) quinolines, and even with a quinoline
bearing consecutive double and triple bonds (P26). Note that,
the asymmetric hydrogenation reactions of S12–S26 with
retention of the unsaturated functional groups are
unprecedented with any kind of catalysis.
5a4F
(2 or 5 mol %)
R2
R2
+
H2
R1
N
H
R1
N
PhCF3, -20 °C, 24 h
20 or 50 bar
S1-S26
P1-P26
nBu
(CH2)7CH3
N
H
N
H
N
H
N
Me
(CH2)4CH3
H
P1[b]
97%, 91% ee
P2[c]
98%, 92% ee
P3[d]
P4[e]
98%, 90% ee
93%, 90% ee
PinB
Br
N
H
N
H
Bn
N
H
Me
N
H
Me
P5[b]
P6[b]
P7[e]
P8[c]
95%, 91% ee
90%, 95% ee
91%, 90% ee
90%, 90% ee
2-Aryl-substituted quinolines were next studied (Table 3).
We discovered that catalyst 5d provided the highest
O
O
N
H
N
Me
N
Me
enantioselectivities,
and
addition
of
tris[3,5-
H
H
P9[b]
P10[d]
P11[b]
bis(trifluoromethyl)phenyl]phosphine improved the yields.
Phenyl rings bearing various electron-donating and electron-
withdrawing groups were tolerated, giving products P27–P35
in high yields and ee values. The presence of a Bpin moiety
(P36) or internal and terminal double and triple bonds (P37–
P40) did not influence the reactivity or selectivity. Furthermore,
coordinative MeS (P41) and heterocyclic substituents (P42–
P45) were compatible.
98%, 91% ee
63%, 91% ee
93%, 87% ee
N
N
H
N
H
Ph
H
Me
OMe
P12[e]
P13[e]
87%, 98% ee
P14[b]
94%, 98% ee
95%, 97% ee
O
N
H
N
H
N
H
Table 3. Investigation of 2-Aryl-Substituted Quinolines [a]
Br
CF3
P15[b]
89%, 98% ee
P16[c]
90%, 97% ee
P17[b]
95%, 98% ee
5d
(2 or 4 mol %)
[3,5-(CF3)2C6H3]3P (5 or 10 mol %)
H2
+
PhCF3, -20 °C, 24 h
N
H
Ar
N
Ar
50 bar
N
N
H
S27-S45
P27-P45
S
N
H
N
H
P27 [b]
,
R = H, 99%, 91% ee
P18[e]
80%, 99% ee
P19[d]
94%, 96% ee
P20[f,g]
93%, 95% ee
P28,[b] R = tBu, 97%, 93% ee
P29,[b] R = NMe2, 94%, 86% ee
P30 [c]
OMe
N
N
H
H
,
R = Br, 93%, 92% ee
R
P31 [c]
P33[b]
99%, 91% ee
,
R = CO2Me, 90%, 91% ee
P32,[c] R = TMS, 93%, 93% ee
N
N
H
N
H
Ph
H
2-naphthyl
Ph
F
P21[b]
86%, 96% ee
P22[e]
98%, 96% ee
P23[b]
99%, 95% ee
N
O
O
N
H
H
N
H
BPin
P34[c]
P35[c]
P36[c]
Ph
N
H
N
H
98%, 92% ee
99%, 88% ee
N
H
97%, 88% ee
TMS
P24[c]
P25[b]
P26[f]
93%, 91% ee
94%, 97% ee
91%, 98% ee
N
H
N
H
N
H
[a] Unless otherwise specified, hydrogenations were performed
with 0.25 mmol of the quinoline substrate in 5 mL of PhCF3 in a 30 mL
autoclave; the percentages shown are isolated yields and
enantiomeric excesses, in that order. [b] Used 5 mol % of 5a4F and 20
bar of H2. [c] Used 2 mol % of 5a4F, 50 bar of H2, and 2 mL of PhCF3.
[d] Used 5 mol % of 5a4F and 50 bar of H2. [e] Used 2 mol % of 5a4F,
20 bar of H2, and 2 mL of PhCF3. [f] Used 5 mol % of 5a and 50 bar
of H2. [g] Reaction temperature, 25 °C.
Ph
P37[c]
96%, 92% ee
P38[c]
95%, 90% ee
P39[c]
96%, 92% ee
O
N
H
N
H
N
H
O
S
P40[c]
91%, 90% ee
P41[d]
95%, 88% ee
P42[e]
88%, 90% ee
Various quinolines with conjugated olefins at the 2-position
(S12–S20) were subsequently tested. These olefin units are
highly susceptible to hydride reduction due to the activation by
the adjacent heteroarene.[3e,4b,7b] In fact, only a transfer
hydrogenation protocol that uses chiral phosphoric acids and
Hantzsch ester can enantioselectively reduce 3-nitro-2-
styrylquinolines while preserving the olefin group.[18] However,
we were gratified to find that when 2-styrylquinolines were
tested with our bisborane catalyst, hydrogenation
preferentially occurred at the heteroaromatic ring regardless
of the electronic nature of the substituents on the phenyl ring,
S
N
H
N
H
N
H
O
N
piv
P43[b]
P44[b]
92%, 90% ee
P45[c,f]
95%, 88% ee
97%, 87% ee
[a] Unless otherwise specified, hydrogenations were performed with 0.25
mmol of substrate in 2 mL of PhCF3 in a 30 mL autoclave; the percentages
shown are isolated yields and enantiomeric excesses, in that order. [b]
Used 2 mol % of 5d and 5 mol % of the phosphine. [c] Used 4 mol % of 5d
and 10 mol % of the phosphine. [d] Used 6 mol % of 5d, 12 mol % of the
phosphine, 60 bar of H2, and 4 mL of PhCF3. [e] Used 4 mol % of 5d4F and
10 mol % of the phosphine. [f] Used 60 bar of H2 and 4 mL of PhCF3.
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10.1002/anie.201900907
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COMMUNICATION
2009, 74, 2780.
To further demonstrate the power of our catalytic system,
we performed gram-scale reactions with styryl- (S12) and
alkynyl-substituted (S22) quinolines (Scheme 3). We
discovered that running these hydrogenations at 25 °C did not
compromise the enantioselectivities substantially. In addition,
by using only 0.2 mol % of catalyst 5a[19] and extending the
reaction time to 48 h, we obtained P12 and P22 in high yields
with excellent ee values. Notably, the turnover number of 460,
obtained in the hydrogenation reaction of S12, represents the
highest turnover number so far for asymmetric hydrogenation
reactions promoted by a chiral borane catalyst. We reason
that the rigidity of the bicyclic scaffold and the steric bulk that
shields boron centers from attack or coordination by
nucleophiles (e.g., tetrahydroquinolines) might have
contributed to the enhanced stability and activity of these
catalysts.
[4] For selected studies using ruthenium catalysts, see: a) H.-F. Zhou, Z.-W. Li,
Z.-J. Wang, T.-L. Wang, L.-J. Xu, Y.-M. He, Q.-H. Fan, J. Pan, L.-Q. Gu, A.
S. C. Chan, Angew. Chem. Int. Ed. 2008, 47, 8464; Angew. Chem. 2008,
120, 8592; b) T.-L. Wang, L. G. Zhuo, Z.-W. Li, F. Chen, Z.-Y. Ding, Y.-M.
He, Q.-H. Fan, J.-F. Xiang, Z.-X. Yu, A. S. C. Chan, J. Am. Chem. Soc. 2011,
133, 9878; c) Q.-A. Chen, K. Gao, Y. Duan, Z.-S. Ye, L. Shi, Y. Yang, Y.-G.
Zhou, J. Am. Chem. Soc. 2012, 134, 2442; d) W. Ma, J. Zhang, C. Xu, F.
Chen, Y.-M. He, Q.-H. Fan, Angew. Chem. Int. Ed. 2016, 55, 12891; Angew.
Chem. 2016, 128, 13083.
[5] For selected reports using other metals as well as enantioselective transfer
hydrogenations, see: a) M. Rueping, A. P. Antonchick, T. Theissmann,
Angew. Chem. Int. Ed. 2006, 45, 3683; Angew. Chem. 2006, 118, 3765; b)
C. Wang, C. Li, X. Wu, A. Pettman, J. Xiao, Angew. Chem. Int. Ed. 2009, 48,
6524; Angew. Chem. 2009, 121, 6646; c) X.-F. Tu, L.-Z. Gong, Angew. Chem.
Int. Ed. 2012, 51, 11346; Angew. Chem. 2012, 124, 11508; d) X.-F. Cai, W.-
X. Huang, Z.-P. Chen, Y.-G. Zhou, Chem. Commun. 2014, 50, 9588; e) J.
Wen, R. Tan, S. Liu, Q. Zhao, X. Zhang, Chem. Sci. 2016, 7, 3047.
[6] For recent reviews, see: a) D. W. Stephan, G. Erker, Angew. Chem. Int. Ed.
2015, 54, 6400; Angew. Chem. 2015, 127, 6498; b) D. W. Stephan, Science
2016, 354, aaf7229; c) J. Lam, K. M. Szkop, E. Mosaferi, D. W. Stephan,
Chem. Soc. Rev. 2019, DOI:10.1039/C8CS00277K; d) M. Oestreich, J.
Hermeke, J. Mohr, Chem. Soc. Rev. 2015, 44, 2202; e) W. Meng, X. Feng,
H. Du, Acc. Chem. Res. 2018, 51, 191; f) J. Paradies, Coord. Chem. Rev.
2019, 380, 170; g) J. R. Lawson, R. L. Melen, Inorg. Chem. 2017, 56, 8627.
[7] For selected reports, see: a) S. J. Geier, P. A. Chase, D. W. Stephan, Chem.
Commun. 2010, 46, 4884; b) G. Erős, K. Nagy, H. Mehdi, I. Pápai, P. Nagy,
P. Király, G. Tárkányi, T. Soós, Chem. Eur. J. 2012, 18, 574; c) T. Mahdi, J.
N. del Castillo, D. W. Stephan, Organometallics 2013, 32, 1971; d) Y. Liu, H.
Du, J. Am. Chem. Soc. 2013, 135, 12968; e) P. Eisenberger, B. P. Bestvater,
E. C. Keske, C. M. Crudden, Angew. Chem. Int. Ed. 2015, 54, 2467; Angew.
Chem. 2015, 127, 2497; f) W. Wang, X. Feng, H. Du, Org. Biomol. Chem.
2016, 14, 6683; g) W. Wang, W. Meng, H. Du, Dalton Trans. 2016, 45, 5945;
h) X. Liu, T. Liu, W. Meng, H. Du, Org. Lett. 2018, 20, 5653.
N
Ph
N
Ph
H
5a (0.2 mol %)
S12
P12
, 92% yield, 97% ee (TON = 460)
(5 mmol, 1.16 g)
H2
+
PhCF3, 25 °C, 48 h
50 bar
N
N
H
Ph
S22 (5 mmol, 1.15 g)
Ph
P22, 69% yield, 90% ee (TON = 345)
Scheme 3. Gram-scale reactions with 0.2 mol % catalyst
In conclusion, we have synthesized a new class of spiro
bicyclic bisborane catalysts that exhibit excellent activities and
selectivities in asymmetric hydrogenation reactions of 2-
substituted quinolines. The unprecedented broad functional
group tolerance observed in these hydrogenation reactions
demonstrates the unique advantages of these catalysts over
transition metals and other borane catalysts. Our group is
currently investigating the origin of this excellent
chemoselectivity, as well as the potential applications of these
catalysts in other enantioselective transformations.
[8] V. Sumerin, K. Chernichenko, M. Nieger, M. Leskelä, B. Rieger, T. Repo,
Adv. Synth. Catal. 2011, 353, 2093.
[9] a) Z. Zhang, H. Du, Org. Lett. 2015, 17, 2816; b) Z. Zhang, H. Du, Org. Lett.
2015, 17, 6266; c) Z. Zhang, H. Du, Angew. Chem. Int. Ed. 2015, 54, 623;
Angew. Chem. 2015, 127, 633.
[10] C. Han, E. Zhang, X. Feng, S. Wang, H. Du, Tetrahedron Lett. 2018, 59,
1400.
Acknowledgements
[11] 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; Angew. Chem. 2018, 130, 15316.
[12] J. A. Nieman, B. A. Keay, Synth. Commun. 1999, 29, 3829.
[13] N. Harada, N. Ochiai, K. Takada, H. Uda, J. Chem. Soc., Chem. Commun.
1977, 495.
We thank financial support from the National Natural Science
Foundation of China (21602114 and 21871147), the Natural
Science Foundation of Tianjin (16JCYBJC42500), the 1000-
Talent Youth Program, and the Fundamental Research Funds
for Central Universities. We thank Professor Qi-Lin Zhou and
Fang Lan at Nankai University for helpful discussions.
[14] Because the spiro bicyclic structure forms via a reversible ring-closure
reaction, the erosion of enantiomeric excesses may have occurred via a
sequential ring-opening and reclosing process.
[15] For Piers borane, see: a) D. J. Parks, R. E. von H. Spence, W. E. Piers,
Angew. Chem. Int. Ed. Engl. 1995, 34, 809; Angew. Chem. 1995, 107, 895;
b) D. J. Parks, W. E. Piers, G. P. A. Yap, Organometallics 1998, 17, 5492;
For pioneering studies of using this hydroboration for preparation of chiral
catalysts, see: c) D. Chen, J. Klankermayer, Chem. Commun. 2008, 2130; d)
D. Chen, Y. Wang, J. Klankermayer, Angew. Chem. Int. Ed. 2010, 49, 9475;
Angew. Chem. 2010, 122, 9665.
Keywords: boron • asymmetric catalysis • hydrogenation •
heterocycles • homogeneous catalysis
[1] a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257;
b) V. Sridharan, P. A. Suryavanshi, J. C. Menéndez, Chem. Rev. 2011, 111,
7157.
[16] CCDC 1872176 and 1872179 contain the supplementary crystallographic
data for this paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
[17] For in situ generation of catalyst 5a4F, diene 4a was allowed to react with
H(p-C6F4H)2 in toluene at 80 °C for 10 min. The structure of 5a4F was
confirmed by a crystal structure of its adduct with isoquinoline (CCDC
1872178). For preparation of H(p-C6F4H)2, see: D. Winkelhaus, B. Neumann,
H.-G. Stammler, N. W. Mitzel, Dalton Trans. 2012, 41, 8609.
[2] For selected reviews, see: a) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G. Zhou,
Chem. Rev. 2012, 112, 2557; b) Y.-M. He, F.-T. Song, Q.-H. Fan, Top. Curr.
Chem. 2013, 343, 145.
[3] For selected studies using iridium catalysts, see: a) W.-B. Wang, S.-M. Lu,
P.-Y. Yang, X.-W. Han, Y.-G. Zhou, J. Am. Chem. Soc. 2003, 125, 10536; b)
S.-M. Lu, Y.-Q. Wang, X.-W. Han, Y.-G. Zhou, Angew. Chem. Int. Ed. 2006,
45, 2260; Angew. Chem. 2006, 118, 2318; c) L.-J. Xu, K. H. Lam, J. X. Ji, J.
Wu, Q.-H. Fan, W.-H. Lo, A. S. C. Chan, Chem. Commun. 2005, 1390; d) L.
Q. Qiu, F. Y. Kwong, J. Wu, W. H. Lam, S. Chan, W.-Y. Yu, Y.-M. Li, R. W.
Guo, Z. Zhou, A. S. C. Chan, J. Am. Chem. Soc. 2006, 128, 5955; e) D.-W.
Wang, X.-B. Wang, D.-S. Wang, S.-M. Lu, Y.-G. Zhou, Y.-X. Li, J. Org. Chem.
[18] X.-F. Cai, M.-W. Chen, Z.-S. Ye, R.-N. Guo, L. Shi, Y.-Q. Li, Y.-G. Zhou,
Chem. Asian J. 2013, 8, 1381.
[19] For these reactions, catalysts 5a and 5a4F gave similar enantioselectivities,
but 5a gave higher turnover numbers than 5a4F
.
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10.1002/anie.201900907
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Xiang Li,# Jun-Jie Tian,# Ning Liu, Xian-
Shuang Tu, Ning-Ning Zeng, Xiao-Chen
Wang*
Page No. – Page No.
Spiro Bicyclic Bisborane Catalysts
for Metal-Free Chemoselective and
Enantioselective Hydrogenation of
Quinolines
Spiro B,B bicycles: we have prepared a new series of C2-symmetric spiro bicyclic
bisboranes. These bisboranes have been demonstrated highly effective and
selective in promoting asymmetric hydrogenation of quinolines. The exceedingly
broad functional group tolerance allows the access to various enantioenriched and
functionalized tetrahydroquinilines that were inaccessable with previous methods
using borane or transition metal catalysts.
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