Borane-Catalyzed Synthesis of Quinolines Bearing Tetrasubstituted Stereocenters by Hydride Abstraction-Induced Electrocyclization

Article abstract of DOI:10.1002/chem.201804777

The borane-catalyzed synthesis of quinoline derivatives bearing tetrasubstituted stereocenters from vinyl anilines has been developed. Mechanistic studies and quantum-mechanical investigations support the hydride abstraction/electrocyclization/hydride add

Full text of DOI:10.1002/chem.201804777

A Journal of
Accepted Article
Title: Borane-catalyzed synthesis of quinolines bearing tetrasubstituted
stereocenters by hydride abstraction-induced electrocyclization
Authors: Alexander F. G. Maier, Sebastian Tussing, Hui Zhu, Garrit
Wicker, Pavleta Tzvetkova, Ulrich Flörke, Constantin G.
Daniliuc, Stefan Grimme, and Jan Henry Hakan Paradies
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To be cited as: Chem. Eur. J. 10.1002/chem.201804777
Link to VoR: http://dx.doi.org/10.1002/chem.201804777
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10.1002/chem.201804777
Chemistry - A European Journal
COMMUNICATION
Borane-catalyzed synthesis of quinolines bearing tetrasub-
stituted stereocenters by hydride abstraction-induced
electrocyclization
Alexander F. G. Maier,[a] Sebastian Tussing,[a] Hui Zhu,[b] Garrit Wicker,[a] Pavleta Tzvetkova,[c] Ulrich
Flörke,[a] Constantin G. Daniliuc,[d] Stefan Grimme,[b]* Jan Paradies[a]*
Dedicated to Douglas W. Stephan on the occasion of his 65th birthday
B(C6F5)3
(1)
R1
R2
R1
R2
Abstract: The borane-catalyzed synthesis of quinoline derivatives
bearing tetrasubstituted stereocenters from vinyl anilines has been
developed. Mechanistic studies and quantum-mechanical investi-
gations support the hydride abstraction/electrocyclization/hydride
addition mechanism. The products were obtained in up to 99% yield
with a diastereoselectivity of >99% in favour for the 3a-5-cis isomer.
R3
R3
N
N
H
H–B(C6F5)3
– B(C6F5)3
R1
–
R1
+
R3
R3
(1)
N
N
H
iminium
(I)
borohydride
R2
R2
H
R1
H
R3
R1
R2
R3
R1
R1
R2
R3
B(C6F5)3
R3
N
N
N
N
+
+
R2
Iminium ions are versatile reactive species in biochemistry[1] and
organic synthesis.[2] These intermediates are commonly
accessed by condensation of ketones or aldehydes with amines,
quaternization of imines or by elimination of half aminals or
aminals.[2b, 2d, 2i, 3] Moreover, Nature uses the hydride abstraction
from activated C(sp3)–H positions of amines to access iminium
intermediates e.g. in transaminases[4] or in dehydrogenases.[5]
Apart from this biomimetic approach, this exceptional activation
method is rarely realized in synthetic organic chemistry since a
very specific structural setup is required. A strong electrophile in
5-position to the activated C(sp3)–H bond induces a 1,5-hydride
shift to generate a cyclic iminium ion, which finally gives rise to
complex molecular structures.[6]
In this light, new methods for the unconstrained access to cyclic
iminium ions are highly desired. Polycyclic tetrahydroquinoline
derivatives are pharmacologically active but very few examples
with tetrasubstituted stereocenters have been reported so far,
potentially due to the limited synthetic access.[7]
In the last decade, organoboranes attracted increased attention
due to their potential in hydrogen activation as Lewis acid in
frustrated Lewis pairs (FLP).[8] Not only metal-free FLP-catalyzed
hydrogenations were realized,[9] but also acceptorless dehydro-
genations,[10] transfer hydrogenations[11] and transfer hydro-
silylations.[12] These reactions are initiated by the hydride ab-
straction from activated C(sp3)–H positions of amines or 1,4-
R2
B(C6F5)3
H–B(C6F5)3
(II)
H–B(C6F5)3
(III)
zwitterionic
iminium borate (IV)borohydride (III)
ammonium
Scheme 1. Equilibrium of amine and organoborane with the zwitterionic iminium
borate IV and the ammonium borohydride III.[13]
hexadienes. The fundamental reaction of tertiary amines with
B(C6F5)3 (1) was investigated by Basset (Scheme 1).[13] In a
temperature and solvent polarity-controlled equilibrium, the amine,
borane 1, iminium borohydride I, enamine II, ammonium
borohydride salt III and the zwitterionic iminium borate IV coexist
in solution. This fragile equilibrium features several synthetically
exciting intermediates, yet, it is highly challenging to find suitable
downstream reactions of selected intermediates for catalytic
purposes.
We anticipated to use this intriguing amine-activation to obtain
unconstrained access cyclic iminium ions as precursors for an
electrocyclization[2g] leading to tetrahydroquinoline scaffolds
bearing tetrasubstituted stereocenters. This reaction would not
only extend the field of so far underrepresented borane-catalyzed
C–C bond forming reactions,[14] but would also break new grounds
in the synthesis of unprecedented, pharmacologically important
polycyclic tetrahydroquinoline derivatives.
We initiated our investigation by the reaction of 2-(2-propenyl)-
2,5-dimethylpyrrolidinobenzene (2a) as cis/trans mixture (ratio
1:1) with one equivalent of B(C6F5)3 (1) at room temperature
(Scheme 2). The instantaneous reaction furnished the stable
iminium hydroborate salt [3]+[H–1]– as product of the hydride
abstraction from the activated C(sp3)–H position. This inter-
mediate was characterized by NMR spectroscopy and featured
the characteristic NMR chemical shifts of the iminium borohydride
fragment (d(11B) = –25.3 ppm (R3B–H); d(13C) = 194.2 ppm
(R2N=CR2) d(15N) = 229.5 ppm (R2N=CR2)). Furthermore, the
structure was unambiguously characterized by single crystal
structure determination. The molecular structure (see inset
Scheme 2) features the trigonal-planar iminium carbon atom C1
[a]
Dr. A. F. G. Maier, Dr. S. Tussing, Dr. U. Flörke, BSc. G. Wicker, Dr.
J. Paradies, Department of Chemistry, University of Paderborn,
Warburger Strasse 100, D-33098 Paderborn, Germany;
jan.paradies@uni-paderborn.de
Dr. H. Zhu, Dr. S. Grimme, Mulliken Center for Theoretical
Chemistry, University of Bonn, Beringstr. 4, D-53115 Bonn,
Germany; grimme@thch.uni-bonn.de
Dr. Pavleta Tzvetkova, Institute of Organic Chemistry and Institute
for Biological Interfaces-4, Karlsruhe Institute of Technology (KIT),
Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany.
Dr. Constantin G. Daniliuc, Institute of Organic Chemistry, University
of Münster, Corrensstrasse 40, D-48149 Münster, Germany
[b]
[c]
[d]
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/chem.201804777
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COMMUNICATION
1 equiv.
Table 1. Substrate scope of the catalytic hydride abstraction-initiated
Me
Me
N
Me
Me
N
B(C6F5)3
redoxneutral cycloisomerization of amino styrenes.[a]
(1)
Me
120 °C
Me
+
Me
Me
N
R1
N
R1
RT,
H
B(C5F5)3
(10 mol%)
2a
Me
C2D2Cl4
R2
R3
3
R2
R3
R4
Me
Me
[H–B(C6F5)3]
Me
B(C6F5)3
[H–B(C6F5)3]
[5a–H]+[H–1]–
120 °C
C2H2Cl4
R4
4
N
R5
N
R5
(50%)
C15
(50%)
molecular structure
2a-n
5a-n
of [3]+[H–1 ]–
1 equiv. NEt3,
120 °C, 20 min.
C14
C13
C8
products
Me
Ph
N
F
C4
Me
C7
B1
H1
Me
5
Me
Me
Me
N1
+ 1-NEt
adduc3ts
Me
N
N
C1
N
3a
N
Me
Me
Me
Me
5d, 40%,[c] d.r. 1.4:1
1
Me
5a, 98%, d.r. 1.1:1[b] 5b, 35%, d.r. 2.1:1 5c, 78%, d.r. 2.4:1
(38%, d.r. 2.1:1)
5a (98%)
all-cis / trans-(1-3a)-cis-(3a-5) 80:20
Me
Ph
Scheme 2. Hydride abstraction-initiated redoxneutral cycloisomerization.
Selected bond lengths and angles for [3]+[H–1]–: C1–N1 1.294 Å; C1–N1–C4
113.9 °; C1–N1–C7 126.0 °; C7–N1–C4 120.2 °; C13–C14: 1.389 Å; C–14–
C13–C15 122.9 °; C14–C13–C8 119.2 °; C8–C13–C15 117.4 °.[15] [16]
Me
N
Me
Me
N
N
Me
Me
5f, 83%,[c] d.r. 4:1 5g, 14%,[c][d] d.r. 2.6:1
Me
5e, 29%,[c] d.r. 1.1:1
Me
Me
Me
Me
Me
(C1–N1: 1.294 Å, sum of angles: 359.9°) in boot-type confor-
mation to the propenyl-group (C13–C14: 1.389 Å, sum of angles:
359.9°) as perfect setup for the disrotatory 6p-electrocylization
(C1–C14: 3.47 Å). Heating of the reaction mixture to 120 °C
induced the anticipated electrocyclization, yielding the cis-(3a-5)-
hexahydropyrrolo[1,2-a]quinoline scaffold, which was trapped as
zwitterionic salt 4 and ammonium hydroborate [5a–H]+[H–1]–.
These two products most likely arise from the addition of 1 to the
transiently formed enamine, which is accessible from a second
hydride abstraction/deprotonation sequence (compare Scheme
1).[10a, 13] These reaction intermediates were cleanly converted to
5a in quantitative yield by the addition of 1 equiv. triethyl amine at
the end of the reaction. The addition of triethylamine is required
to liberate the product by trapping the borane. The overall reaction
proceeded with a diastereoselectivity of 80:20:0:0 in favor to the
all-cis diastereomer as determined by 1H NOE NMR experiments.
The second observed diastereomer corresponds to the trans-(1-
3a)-cis-(3a-5) diastereomer (see SI).[17]
The stoichiometric reaction was advanced to the catalytic
process and the scope of the reaction was investigated using the
2-amino styrene derivatives 2a-n in the presence of 10-20 mol%
B(C6F5)3 (Table 1). The four pyrrolidinyl-substituted derivatives
2a-d were converted to the quinoline scaffolds 5a-d in moderate
to high yields (35%-98%). The high cis-(3a-5)-selectivity in the
tetrahydroquinoline fragment was conserved in 5a and 5b but the
stereocenter at C1 was unstable (d.r. 1:1) as a result of reversible
hydride abstraction/addition from the corresponding products
(see quantum-mechanical details below).[18] The corresponding
phenyl, annulated cyclopentyl and cyclohexyl derivatives 5b, 5c,
5d, 5g and 5i were prone to autoxidation during the workup.
Nevertheless, these tetracyclic dihydroquinoline derivatives were
obtained in low to moderate yields (14%-78%). The related
piperidinyl derivatives 2e-g were less reactive compared to the
pyrrolidine derivatives, yet, the products 5e-g were obtained in
14%-83% yield. Also, acyclic amino-substituents were well
tolerated in the reaction giving rise to the geminal disubstituted
tetrahydroquinolines 5h-n in 61-99% yield. The stabilization of the
benzylic carbocation in the electrocyclization is crucial for the
reactivity. The stilbene derivative 2m was unreactive, most likely
due to of the weak stabilization of the benzylic carbo cation
Me
Me
Me
5h, 99%
Me
Me
N
N
N
N
Me
Me
5k, 61%,[c] d.r. 1.3:1
Me
5i, 61%
(29%)
Me
5j, 82%[c]
Me
Ph
Ph
Me
Ph
Me
Me
N
Me
N
N
Me
Me
Me
Me
5n, 93%
5m, 0%
5l, 73%,[c] d.r. 1.4:1
[a] The reactions were performed on 0.5 mmol scale, 10 mol% B(C6F5)3 for 24-
48 h. The reactions were ended by the addition of 1.5 equiv. NEt3 in respect to
B(C6F5)3. Yields are given after column chromatography; yields in parentheses
correspond to the autoxidation product; [b] d.r. corresponds to the relative
configuration at C1 and C3a; [c] reaction was performed with 20 mol% B(C6F5)3;
[d] yield determined by NMR spectroscopy.
intermediate. In contrast, the corresponding isomer 2n was highly
reactive and furnished 5n in almost quantitative yield.[19] The
reaction mechanism was further investigated by kinetic
experiments and quantum-mechanical calculations. The free
energy of activation for the catalytic conversion of 2a to the
corresponding tetrahydroquinoline 5a was experimentally found
to be 37.3 ± 3.5 kcal/mol. The detailed quantum-chemical analysis
using density functional theory calculations was conducted on the
PW6B95-D3//TPSS-D3 + COSMO-RS level including conforma-
tional and reaction paths screening with the GFN-xTB method.[20]
It revealed that the hydride abstraction proceeds over a barrier of
25.7 kcal/mol to generate the separated ion pair 3+ and [H–1]–,
(Figure 1). The subsequent 6p-electrocyclization of the cation 3+
to form the benzylic tetrahydoquinolinium cation 6+ is prevented
by a slightly higher barrier (28.0 kcal/mol) than the initial hydride
abstraction. The subsequent hydride transfer from [H–1]- to the
concave side of the cation 6+ to form neutral all-cis-5a is kinetically
favored by 4.5 kcal/mol over the corresponding transfer to the
convex side (marked in red) to form cis-(1-3a)- trans-(3a-5)-5a,
leading to the observed high diastereoselectivity for the cis-(3a-5)
arrangement. The C1 stereocenter of all-cis-5a is also an
activated position resulting in a further hydride abstraction by
B(C6F5)3 over a barrier of 28.4 kcal/mol (all-cis-5a ® cis-7+) and
hydride re-addition from the convex side over a barrier of 27.6
kcal/mol (cis-7+®trans-(1-3a)-cis-(3a-5)-5a) giving rise to the
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hydride
Me
hydride
electro-
epimerization at C1
abstraction cyclization addition
Me
N
TS 2a-3+
25.7
3030
2020
1010
Me
TS 3+-6+
23.5
TS 6+-cis-(1-3a)-trans-(3a-5)-5a
17.1
TS 6+-all-cis-5a
TS 2a-3+
N
H
Me
[3]+ [H–1]–
2a
12.6
TS all-cis-5a-cis-7+
Me
TS cis-7+-trans-(1-3a)-cis-(3a-5)-5a
12.4
Me
H–B(C6F5)3
9.9
B(C6F5)3
1
Me
TS 3+-6+
0
0
5
2a + 1
0.0
Me
N
Me
3a
3+ + [H–1]–
–4.5
TS 6+-cis-(1-3a)-
trans-(3a-5)-5a
6+ + [H–1]–
–5.7
N
-10-10
-20-20
Me
1
Me
Me
H
all-cis-5a
–16.0
H
trans-(1-3a)-cis-(3a-5)-5a
Me
cis-7+ + [H–1]–
–17.7
–16.7
TS
6+-all-cis-5a
5
Me
Me
Me
Me
5
Me
5
H–B(C6F5)3
[6]+[H–1]–
N
N
1
3a
4 + [5a–H]+[H–1]–
borane trap
via enamine pathway
all-cis-5a
Me
3a
Me
Me
3a
not
observed
N
1
Me
cis-(1-3a)-trans-(3a-5)-5a
(not observed)
N
1
(compare Scheme 1)
B(C6F5)3
Me
Me
cis-(1-3a)-trans-(3a-5)-5a
all-cis-5a
+ 5a
[5a–H]+
[H–1]–
Me
–18.7
Me
Me
–
B(C6F5)3
Me
Me
Figure 1. Quantum-mechanical analysis of the hydride abstraction-initiated
cycloisomerization of 2a.
Me
N
N
N
H–B(C6F5)3
Me
Me
Me
[7]+[H–1]–
B(C6F5)3
8
4
marginally more stable trans-(1-3a)-cis-(3a-5) isomer of product
5a. Indeed, catalytic reactions with each of the two individual
diastereomers all-cis-5a and trans-(1-3a)-cis-(3a-5)-5a with 10
mol% B(C6F5)3 resulted in equilibration of the system restoring the
1:1 diastereomeric ratio, consistent with their rather similar
thermodynamic stability (see SI for experimental details).
The thus far computed overall barrier of 28.0 kcal/mol for the
direct formation of product 5a is somewhat lower than the experi-
mentally determined apparent value one of 37.3 kcal/mol, which
is due to the formation of thermodynamically more stable
zwitterion 4 accompanied by the ammonium borohydride [5a–H]+
and [H-1]- as both, energetic sink and catalyst-trap. In the 1:1
stoichiometric reaction of 2a and 1, only 4 + [5a–H]+ + [H–1]- were
found as products, clearly confirming their increased thermo-
dynamic stability compared to 5a + 1. Our DFT calculations show
that the proton transfer from cis-7+ to 5a may lead to the enamine
intermediate cis-8 together with the release of the ammonium
cation [5a–H]+ over a barrier of 31.4 kcal/mol, followed by the fast
addition of 1 to the enamine 8 to form the zwitterion 4, which is
thus accessible under moderate heating at 120 °C. In slow (long-
time ~2 days) catalytic reactions with low catalyst ratio of 1, almost
all of the borane catalyst is trapped in the form of 4 + [5a–H]+ +
[H–1]- (but in low concentration); the experimentally observed
catalytic barrier of 36.7 kcal/mol must also account for the off-
cycle release of the borane from 4/[5a–H]+[H–1]- to form product
5a rather than from the actual borane-catalyzed cycloisomeri-
zation of 2a over a lower barrier of 28.0 kcal/mol.
Scheme 3. Proposed mechanism cycle for the borane-catalyzed redoxneutral
cycloisomerization.
The reaction is initiated by the hydride abstraction form the
activated position of the pyrrolidine ring to yield the iminium
hydroborate salt [3]+[H–1]– which undergoes a 6p-electrocycli-
zation to yield the cyclic carbocation [6+]. The hydride transfer by
[H–1]– from the same side of the 3a-Me-group in the
tetrahydroquinolinium ring is less favored by 4.5 kcal mol–1 than
the transfer from the opposite side, resulting in the exclusive cis-
(3a-5) arrangement in the tetrahydroquinoline unit. The product
all-cis-5a and the borane-catalyst are intertwined in an off-cycle
equilibrium which accounts for the high apparent experimentally
observed barrier.
In summary, we have developed the first borane-catalyzed
synthesis of quinolines derivatives by hydride abstraction-induced
electrocyclization. The reaction proceeds via the hydride
abstraction from the activated C(sp3)–H position, generating the
2-aza-hexatriene unit as prelude to the 6p-electrocyclization.
Using this novel approach to cyclic iminium intermediates, a
series of so far unprecedented quinolines bearing tetrasubstituted
stereocenters were synthesized in high yield and high diastereo-
selectivity. The mechanism is supported by kinetic and quantum-
mechanical experiments, which now opens up for novel hydride
abstraction initiated reactions.
The individual steps are summarized in a proposed catalytic cycle
for the borane-catalyzed redoxneutral cycloisomerization
(Scheme 3).
Acknowledgements
The German science foundation (DFG) is gratefully
acknowledged for financial support (PA 1562/6-1, PA 1562/16-1
and Gottfried Wilhelm Leibnitz prize to SG)
Keywords: tetrahydroquinoline • electrocyclization • hydride
abstraction • borane catalysis • amines
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10.1002/chem.201804777
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This article is protected by copyright. All rights reserved.

10.1002/chem.201804777
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
The borane-catalyzed synthesis of
quinoline derivatives bearing tetrasub-
stituted stereocenters from vinyl
Alexander F. G. Maier, Sebastian
Tussing, Hui Zhu, Pavleta Tzvetkova,
Ulrich Flörke, Constantin G. Daniliuc,
Stefan Grimme,* Jan Paradies*
cat.
B(C5F5)3
R1
anilines
has
been
developed.
R1
H
R2
R3
R4
R2
R3
R4
Mechanistic and quantum-mechanical
investigations support the hydride
abstraction/electrocyclization/ hydride
addition mechanism. The products
were obtained in up to 97% yield with a
diastereoselectivity of >99% for the 3a-
5-cis isomer.
H–
Page No. – Page No.
shuttle
N
R5
N
R5
Borane-catalyzed synthesis of
quinolines bearing tetrasubstituted
stereocenters by hydride abstraction-
induced electrocyclization
H
13 examples
up to 99 % yield
This article is protected by copyright. All rights reserved.