Diastereoselective synthesis of dihydro-quinolin-4-ones by a borane-catalyzed redox-neutral endo-1,7-hydride shift

Article abstract of DOI:10.1021/acs.orglett.1c01018

The borane-catalyzed synthesis of dihydroquinoline-4-ones is developed. The amino-substituted chalcones undergo a 1,7-hydride shift upon Lewis acid activation to form a zwitterionic iminium enolate, which collapses to the dihydroquinoline-4-one scaffold.

Full text of DOI:10.1021/acs.orglett.1c01018

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Letter
Diastereoselective Synthesis of Dihydro-quinolin-4-ones by a
Borane-Catalyzed Redox-Neutral endo-1,7-Hydride Shift
Garrit Wicker, Roland Schoch, and Jan Paradies*
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ABSTRACT: The borane-catalyzed synthesis of dihydroquinoline-4-ones is
developed. The amino-substituted chalcones undergo a 1,7-hydride shift upon
Lewis acid activation to form a zwitterionic iminium enolate, which collapses to
the dihydroquinoline-4-one scaffold. The reaction proceeds in high yields (75−
99%) with an excellent diastereoselectivity of up to >99:1 (cis:trans). The reaction
mechanism is investigated by kinetic, isotope labeling, and computational
experiments.
rganocatalytic C(sp3)−H activations offer an exceptional
Otool for the construction of complex heterocyclic
molecules.1 In particular, ortho-substituted anilines featuring
polarized C(sp3)−H bonds undergo intramolecular redox
isomerization through migration of a hydride to a suitable
acceptor. This intramolecular hydride transfer can be induced
by the activation of a strongly electron deficient group,
commonly malonates, malonitriles, ketones, imines, or
iminium, by Lewis or Brønsted acids (Scheme 1, top).2
ketone4 with comparably low electron-withdrawing properties
is a challenging task (Scheme 1, bottom). Nonetheless, such a
process would allow the efficient synthesis of dihydroquino-
line-4-ones, which offer a variety of biological properties,
including strong antiparasitic and antibacterial activity as well
as cytotoxicity.10
Herein, we describe the diastereoselective construction of
dihydroquinoline-4-ones from so far unrecognized o-amino-
substituted α,β-unsaturated ketones through a rare [1,7]
hydride shift catalyzed by a borane-derived Lewis acid.
We initiated our investigation with the reaction of 2-amino-
substituted chalcone 1a with 10 mol % Yb(OTf)3. Even at an
increased temperature (60 °C), no reaction was observed
(Table 1, entry 1). Similarly, other strong Lewis acids or
Brønsted acids were ineffective for initiating the redox
isomerization (entries 2−7). Finally, borane-derived Lewis
acids were investigated. BF3·Et2O remained unreactive despite
reports that show the reactivity of this Lewis acid in redox
isomerizations.8d,11 Eventually, fluorinated boranes proved to
be active catalysts in the reaction (entries 10−14).
Surprisingly, the strongest borane-derived Lewis acid in this
study, tris(pentafluorophenyl)borane [2l, B(C5F5)3], provided
dihydroquinoline-4-one 3a in quantitative yield with a dr of
89:11 (cis:trans) within 18 h at room temperature (entry 12).12
Lower catalyst concentrations resulted in significantly
decreased yields, so that further experiments were conducted
with 10 mol % catalyst loading. Operando NMR studies show
the formation of Lewis adducts of 1a with B(C6F5)3 as
Scheme 1. Redox Isomerization through a Hydride Shift
Most effective Lewis acids are based on magnesium,3
platinum,4 and rare earth elements5 or on phosphoric acid6
derivatives. The [1,5] hydride migration has been extensively
investigated, sparking considerable interest in finding new
catalysts and reactive scaffolds.7 Only recently have Akiyama
and Mori reported annulation cascades through sequential
[1,n] hydride migration processes of up to n = 6 or even n = 7.8
Such homologous [1,n] hydride shifts with n > 5 have been
considerably less elaborated and may be attributed to the
unfavorable seven- or eight-membered transition state.8d,9 In
this light, the [1,7] hydride migration to an α,β-unsaturated
Received: March 24, 2021
Published: April 12, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01018
Org. Lett. 2021, 23, 3626−3630
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Table 1. Catalyst Screening for the Redox-Neutral Synthesis
of Dihydroquinoline-4-one 3a
Scheme 2. Scope for the Lewis Acid-Catalyzed Redox-
a
Neutral Synthesis of Dihydroquinoline-4-one
a
Derivatives ,14
b
entry
catalyst
solvent
yield (%)
1
2
3
4
Yb(OTf)3 (2a)
TiCl4·2THF (2b)
ZnCl2 (2c)
CDCl3
CDCl3
CDCl3
d8-THF,
CDCl3
CDCl3
d8-toluene
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
28
MgI2 (2d)
5
6
7
8
AcOH (2e)
pTSA (2f)
L-proline (2g)
BF3·Et2O (2h)
B(2,4,6-F2-C6H3)3 (2i)
B(2,3,6-F3-C6H2)3 (2j)
B(2,3,5,6-F4-C6H)3 (2k)
B(C6F5)3 (2l)
B(C6F5)3 (2l)
B(C6F5)3 (2l)
9
10
11
12
13
14
94
>99
c
47
4
d
a
Reactions were performed with 50 μmol of 1a and 10 mol % catalyst,
b
with the respective solvent at 1 M. Determined by 1H NMR
spectroscopy. Values in parentheses reflect the yield at 60 °C. With 5
mol % catalyst. With 2 mol % catalyst.
c
d
evidenced by the 11B NMR resonances at 1.6 and −3.7 ppm
for the B−O and B−N adducts, respectively.
These resonances persisted throughout the reaction and
support the idea that the hydride shift is induced by the
activation of the carbonyl and not by the C(sp3)−H
abstraction by the borane.13 This mechanistic picture is
substantiated by the activity of the weaker Lewis acids 2i−k
(entries 9−11, respectively) to induce redox isomerization,
which proved so far to be inactive for the C(sp3)−H
abstraction.
Next, we investigated the scope of the reaction using 10 mol
% 2l as the catalyst (Scheme 2). The reaction proceeded in
high yields with high cis diastereoselectivity. Except for 3h and
3l, only the cis diastereomer was obtained after column
chromatography. The molecular structures of 3c and 3d (see
the inset of Scheme 2) unambiguously confirm the formation
of the tetrahydroquinoline-4-one scaffold together with the cis
orientation of the substituents. The presence of donor
functionalities or N-alkyl substituents required slightly
increased temperatures of 60 °C without depletion of the
diastereoselectivity or the yield. One exception is pyridine
derivative 1f that remained unreactive due to catalyst
inhibition. The two noncyclic N,N-dialkyl-substituted amino-
chalcones 1j and 1k reacted in high yield but 1j with a reduced
diastereoselectivity of 2.6:1. In contrast, cyclic N,N-dialkyl
derivatives 1l and 1m cyclized with excellent diastereoselec-
tivity of 99:1. Notably, reaction of dimethyl derivative 1l
provided access to tetrahydroquinoline-4-one derivative 3l
featuring a tetrasubstituted quaternary stereocenter with an
exclusive cis orientation in the six-membered heterocycle. The
reaction of 1o with a dr of 1.2:1 slightly favors all-cis product
3o (dr of 3.2:1).
a
Performed on a 0.25 mmol scale, yields and diastereomeric ratio
after column chromatography. Values in parentheses are dr values of
1
the crude reaction mixture determined by H NMR spectroscopy.
b
Reaction performed at 60 °C.
incorporation) underwent quantitative conversion to d4-3a in
the presence of 10 mol % 2l (Scheme 3a).
The relative initial reaction rates of 1a and d4-1a were
determined at 30 °C by NMR experiments. A significant
primary isotope effect (kH/kD) of 5.7
which strongly supports the [1,7]-hydride shift as the rate-
determining step. It must be noted that the isotope effect is a
combination of the primary and secondary isotope effects,
which may account for the comparably high value.8a−c This
finding is also consistent with the hydride shuttle mechanism
of B(C6F5)3 (2l) but was thought to be unlikely for the
following reasons (see the Supporting Information for details).
The reaction is first order in 2l, which disagrees with the
hydride abstraction from 1a·2l by a borane molecule.13a
0.3 was observed,
Finally, we investigated the reaction by kinetic and quantum
chemical experiments. Isotope-labeled d4-1a (>99% deuterium
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Scheme 3. (a) Isotope Labeling Experiment and Kinetic
Isotope Effect and (b) Cross Experiment
Furthermore, the product isomerization of cis-3a to trans-3a in
the presence of 50 mol % 2l or the dehydrogenation of 3j or 3k
(see Scheme 2) was not observed.13,19 We conceived a cross
experiment that gives unmistakable information for the
operative mechanism as strong support for the kinetic data
(Scheme 3b). If the C(sp3)−H abstraction occurred, an
intermolecular transfer of a hydride or deuteride would be
expected, leading to isotope scrambling. However, the cross
experiment displays the clean formation of products d4-3a and
3g without isotope redistribution even after letting the reaction
mixture rest for 4 days after completion.
Figure 1. Calculated free energies in kilocalories per mole at the
PWPB95/def2-QZVPP//PBEh-3c/def2-mSVP level ( 3 kcal/
mol).18 Selected hydrogen atoms and the B(C6F5)3 fragment have
been omitted for the sake of clarity.
Quantum chemical calculations using density functional
theory (DFT) as implemented in the ORCA program suite15
on the PWPB95/def2-QZVPP//PBEh-3c/def2-mSVP16 level
of theory and SMD17 solvent correction gave further insight
into the reaction mechanism and the observed diastereose-
lectivity (Figure 1). The formation of the 1a·2l adduct is
exergonic, furnishing a stable Lewis adduct that has also been
identified by NMR spectroscopy. The steric bulk of the O-
bound Lewis acid imposes the change on the s-trans conformer
as a favorable setup for the hydride migration to the Michael
position. The Lewis acid-induced [1,7] hydride shift is feasible
for both benzylic positions, which leads to iminium enolate
intermediates INT-A and INT-B. The formation of INT-A
with the iminium moiety on the same side as the enolate with
respect to the bridging benzene backbone (endo-boat-like
eight-membered TS1A) proceeds over a barrier of 23.3 kcal/
mol. The formation of INT-B with the iminium moiety
opposite to the enolate (chair-like eight-membered TS1B) is
kinetically disfavored by 3.1 kcal/mol [red reaction path (see
the Supporting Information for details)]. The barriers of
iminium hydroborate formation through hydride abstraction
from 1a·2l by 2l to yield the two corresponding iminium
intermediates [not shown (see the Supporting Information)]
were computed to be 27 and 38 kcal/mol, which renders this
reaction pathway unfavorable. This higher barrier may be
explained by the reduced electron density at the nitrogen atom
and concomitant reduced ability to stabilize the iminium. The
comparably low barriers of 7 and 17 kcal/mol for the
conversion of INT-B and INT-A to trans-3a and cis-2a,
respectively, are in accord with the fact that the zwitterionic
iminium enolate intermediates cannot be detected by NMR
spectroscopy. The overall reaction is exergonic by −18.7 and
−21.4 kcal/mol after Lewis adduct dissociation. The
uncatalyzed [1,7] hydride shift was calculated to have a barrier
of 52.2 kcal/mol, ruling out this process as an operative
mechanism.
In summary, we have developed the diastereoselective
synthesis of 2,3-disubstituted dihydroquinoline-4-ones by the
redox-neutral borane-catalyzed endo-[1,7] hydride shift. The
products were obtained in high yields with excellent
diastereoselectivity (>99:1, cis:trans). The reaction mechanism
was investigated by kinetic and quantum chemical experiments
that support the hydride shift as the rate-determining step.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01018.
Experimental details and spectra (PDF)
Accession Codes
CCDC 2057310−2057311 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
Jan Paradies − Paderborn University, Chemistry Department,
D-33098 Paderborn, Germany; orcid.org/0000-0002-
3698-668X; Email: jan.paradies@uni-paderborn.de
Authors
Garrit Wicker − Paderborn University, Chemistry
Department, D-33098 Paderborn, Germany
Roland Schoch − Paderborn University, Chemistry
Department, D-33098 Paderborn, Germany; orcid.org/
0000-0003-2061-7289
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01018
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The German Science Foundation (DFG) is gratefully
acknowledged for financial support (PA 1562/16-1).
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