Borane Catalyzed Redox Isomerization of 2-Amino Chalcones: Hydride Abstraction or Hydride Migration?

Article abstract of DOI:10.1002/ejoc.202100883

The borane catalyzed redox isomerization of 2-amino chalcones was developed. The tetrahydroquinolines are obtained in high yield as a mixture of cis/trans diastereomers in a ratio of 2 : 1 to >95 : 5. The reaction mechanism is investigated by mechanistic,

Full text of DOI:10.1002/ejoc.202100883

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Borane catalyzed redox isomerization of 2-amino chalcones:
hydride abstraction or hydride migration.
Authors: Rundong Zhou and Jan Paradies
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100883
Link to VoR: https://doi.org/10.1002/ejoc.202100883
01/2020

10.1002/ejoc.202100883
European Journal of Organic Chemistry
FULL PAPER
Borane catalyzed redox isomerization of 2-amino chalcones:
hydride abstraction or hydride migration.
Rundong Zhou, Jan Paradies*
In memory of Klaus Hafner
M.Sc. R. Zhou, Dr. J. Paradies
Chemistry Department
Paderborn University
Warburger Strasse 100, D-33098 Paderborn
E-mail: jan.paradies@uni-paderborn.de
URL: https://chemie.uni-paderborn.de/arbeitskreise/organische-chemie/paradies
Supporting information for this article is given via a link at the end of the document.
Abstract: The borane catalyzed redox isomerization of 2-amino
chalcones is developed. The tetrahydroquinolines are obtained in high
yield as a mixture of cis/trans diastereomers in a ratio of 2:1 to >95:5.
The reaction mechanism is investigated by mechanistic, kinetic and
computational methods, concluding that the reaction proceeds
through concerted [1,5] hydride shift in contrast to borane-mediated
C(sp3)–H hydride abstraction.
The [1,5] hydride migration reaction has been intensively
investigated[2] and challenged scientists to develop more
sophisticated annulation cascades through sequential [1,n]
hydride migration processes of up to n = 6 or even n = 7.[3] Such
redox isomerization can be efficiently catalyzed by magnesium,[4]
platinum,[5] rare earth element[6] complexes or by Brønsted acids
e.g. phosphoric acid[7] derivatives. Also boron derived Lewis acids
were employed in redox isomerizations although with limited
success.[3e,8]. The Wasa group demonstrated that the strong
Lewis acidic borane B(C6F5)3 [3e, 9] is capable to transfer a hydride
from an amine to a Michael-system by dual activation and can be
exploited for intermolecular C–C bond formation (Scheme 1 B).[10]
The mechanistic picture of the activation of both the carbonyl
group and the C(sp3)–H bond was supported by kinetic
experiments. The reaction order in borane was determined to
close to two, sustaining the role of the borane as Lewis acid and
as hydride shuttle reagent.[11] However, borohydride species were
not detected by NMR spectroscopy.[12] Recently we investigated
if such process can be utilized for an intramolecular reaction in
order to construct dihydro quinoline-4-one scaffolds (Scheme 1
C).[8b] We found that the hydride abstraction from the borane
coordinated substrate is 5-15 kcal/mol higher in energy that the
corresponding [1,7] endo hydride shift, which renders this reaction
pathway unfavorable. The reaction order in borane of close to one
corroborated the concerted hydride shift as operative mechanism.
The discrepancy in reaction mechanism of the inter- and the
intramolecular reaction was attributed to the reduced electron
density of the nitrogen atom affected by the electron-withdrawing
carbonyl group. Thus, positioning the carbonyl group in a remote
location, as in 1, may trigger a change in reaction mechanism in
favor to the two-step hydride abstraction/Michael-addition
sequence.
Introduction
The organocatalytic C(sp3)–H bond activation emerged as a
versatile tool for the construction of complex organic structures.[1]
Particularly, 2-substituted anilines with a strongly activated double
bond e.g. malonates, malonitriles, ketones, imines, undergo an
intramolecular hydride shift (Scheme 1 A). [1]
X
X
R1
X
A)
[1,5] hydride
transfer
H
R1
H
R1
H
N
R2
N
R2
R3
N
R2
R3
R3
X = O, NR, C(CN)2, C(CO2R)2
B)
R1 R2
R1 R2
N
ML*
cat. B(C6F5)3
cat. ML*
O
R1 R2
N
O
O
N
+
+
R3
X
X
X
R3
R3
H
C(sp3)–H
activation
H
Mannich
reaction
H
H–B(C6F5)3
C)
B(C6F5)3
B(C6F5)3
O
[1,7] hydride
transfer
O
H
O
H
R1
R1
R1
Mannich
reaction
R3
H
N
R2
N
R2
N
R2
R3
R3
O
D)
Results and Discussion
R1
C(sp3)–H
activation ?
[1,5] hydride
transfer ?
H
In order to explore this reaction, we first investigated the reactivity
of 1a in the presence of 10 mol% of different Lewis acids,
including the triaryl boranes 3a-e,[13] featuring graduated Lewis
acidity and Yb(OTf)3 as common hydride shift catalyst (Table 1).
R3
N
1
R2
Scheme 1. A) Redox isomerization; B) borane catalyzed Mannich reaction by
C(sp3)–H activation; C) [1,7] endo hydride shift; D) hydride shift or C(sp3)–H
activation.
1
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10.1002/ejoc.202100883
European Journal of Organic Chemistry
FULL PAPER
O
H
O
Table 1. Redoxneutral isomerization of 1a to tetrahydroquinoline 2a.
B(C6F5)3 (10 mol%)
R1
R1
H
CHCl3, 60 °C
18h
R2
R2
O
H
O
N
R3
N
cat. (10 mol%)
R3
1a-h
2a-h
Ph
Ph
H
Products
CDCl3, temp.
18h
N
Ph
N
Ph
O
Ph
O
O
H
Bn
1a
Bn
2a
Ph
Ph
triaryl boranes:
N
N
Bn
Ph
N
F
F
F
F
F
F
H
F5
)
2a, 85%
d.r. 2.1:1 (cis/trans)
2b, 66%
d.r. 1.2:1 (cis/trans)
2c, 71%
d.r. > 95:5 (cis/trans)
(
(
)
(
3 B
)
)
3
B
B
)
3
(
B
(
3
3
B
F
F
F
O
O
H
F
F
O
F
3d
3a
3b
3c
3e
Ph
Me
Me
Ph
entry
cat.
temp. [°C]
yield [%][a]
d.r.[b]
N
N
H
N
Bn
(cis/trans)
n.d.
2d, 77%
2f, 80%
d.r. > 95:5 (cis/trans)
2e, 84%
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
24
60
60
60
60
60
60
90
<1
>95
33
7
d.r. 2.0:1 (cis/trans)
d.r. 3.1:1 (cis/trans)
O
O
2.2:1
1:1.5
n.d.
Me
OtBu
N
N
Ph
Bn
2g, 85%
d.r. 5.1:1 (cis/trans)
2h, 0%
8
n.d.
6
n.d.
Scheme 2. Examples for the redox-neutral borane-catalyzed isomerization of
chalcone derivatives.
Yb(OTf)3
Yb(OTf)3
17
91
>95:1
>95:1
[a] yields were determined by 1H NMR spectroscopy using hexamethylbenzene
as internal standard. [b] determined from crude reaction mixture; [b] determined
by 1H NMR of the crude reaction mixture.
We found that reaction required slight heating to 60 °C in the
presence of the strong Lewis acid B(C6F5)3 (3a) for completion
within 18h (Table 1, entries 1 and 2). The reaction became
significantly less efficient with triaryl borane catalysts having
reduced Lewis acidity as a result of their reduced fluorine content
(entries 3-6). This finding already indicates that the formation of
2a is most likely the result of Lewis acid activation of the Michael-
system. Boranes with less Lewis acidity than 3a have so far not
been reported to initiate the C(sp3)–H bond activation.
Furthermore, this is supported by the observation that Yb(OTf)3 is
able to trigger the redox neutral isomerization of 1a to 2a in
quantitative yield, though elevated temperatures of 90 °C were
required.
Next, we investigated the impact of the substituents at the amine
and ketone on the diastereoselectivity (Scheme 2). Generally, the
tetrahydroquinolines were obtained in 66% to 85% yield. The
diastereoselectivity was less affected by the carbonyl substituent,
e. g. when 1a and 1e is compared, but rather dominated by the
amine substituents. The hexahydro-1H-pyrido[1,2-a]quinoline
derivatives 2d and 2g were obtained with slightly enhanced d.r. of
2:1 to 5:1. However, the corresponding hexahydropyrrolo[1,2-
a]quinoline derivatives 2c and 2f were obtained an excellent d.r.
of > 95:5. The tertbutyl ester underwent cleavage of the ester
group, which inhibited the redox isomerization.
In order to shed light into the reaction mechanism, we conducted
mechanistic and kinetic experiments. The primary kinetic isotope
effect was determined to 4.7 which is in good agreement with the
C–H bond breaking being the rate determining step (Scheme 3a).
Scheme 3. a) Kinetic isotope effect data in the borane-catalyzed redox-
isomerization of 1a and d4-1a (both reactions run at 0.1 M).
data for 1a;
£ ¯
data for d4-1a; each data point reflects the average of three individual
experiments; error bars correspond to standard deviation; b) cross isotope
experiment.
2
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10.1002/ejoc.202100883
European Journal of Organic Chemistry
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The incorporation of deuterium in 3-position was not observed,
which suggest that the observed diastereoselectivity results from
the differences in transition state energies and not from prototopic
reactions. This was further confirmed by control experiments in
which nor isomerizations were induced by extended heating in the
presence of 3a or base (see Supporting Information) neither cross
isotope exchange using the labelled d4-1a and 1e (Scheme 3b).
However, the primary KIE does not exclude the hydride
abstraction mechanism from the list of potential hydride transfer
mechanisms. According to Wasa’s mechanism for the
intermolecular hydride transfer two borane molecules are
involved in the rate determining step. In order to examine this, we
determined the reaction rates with catalyst loadings of 10 mol%,
20 mol% and 30 mol% (see Figure 1).
from the free 2-amino chalcone by 3a in order to generate an
iminium borohydride salt, which would be in agreement with our
kinetic data. All four benzylic hydrogen atoms of the dibenzyl
amino moiety were considered to participate in this process (see
Supporting Information for details). The barriers for the
intermolecular hydride abstraction by B(C6F5)3 were calculated to
27.8 kcal•mol–1 to 37.9 kcal•mol–1. A most unlikely mechanism
and not supported by our kinetic data is the Lewis acid activation
of the Michael-system in combination with borane-induced
hydride abstraction (a reaction second order in borane) in analogy
to Wasa’s mechanism.[10] The activation barrier is by 15-22
kcal•mol–1 higher in energy compared to the Lewis acid induced
hydride migration (13.9 kcal•mol–1) and renders this mechanism
as kinetically highly unfavorable (see Supporting Information).
The energies for the hydride abstraction by B(C6F5)3 are
significantly higher than the computed energies of 13.9 to 21.1
kcal•mol–1 for the concerted hydride shift mechanism (compare
Figure 2). Furthermore, this mechanism is supported by the
detection of oxygen-coordinated tetragonal boron species by 11
B
NMR (d = 0.7 ppm) and the absence of any resonance accounting
for a borohydride species. Having established that the reaction
proceeds most likely through Lewis acid induced [1,5] hydride
migration, we investigated the stereochemical features in more
detail. The diastereselectivity in the product is established by
double stereodifferentiation of the two double bonds (iminium and
enolate) and their relative orientation (Scheme 4).
Figure 1. Determination of reaction rates at different catalyst loadings (¢ 10
mol%, p 20 mol%,
¯
30 mol%) and determination of reaction order in borane
(inset); each data point reflects the average of three independent experiments;
error bars correspond to standard deviation of the three individual experiments.
The reaction order in borane was determined to 0.98 which
indicates that one borane molecule is incorporated in the rate
determining step. This kinetic picture clearly rules out that the
reaction proceeds through hydride abstraction and transfer to a
borane-activated Michael-system. This is also in agreement with
our computational studies using density functional theory (DFT)
on
the
dispersion
corrected
(D3BJ)
PW6B95/def2-
QZVPP//PBEh-3c/def2-mSVP[14] level of theory with CPCM
solvent correction[15] for dichloromethane as implemented in the
ORCA software package.[16] All molecules were preoptimized with
the tight-binding method xTB-GFN2.[17] Transition states were
either found by potential energy scans on the tight-binding level
along the reaction coordinate or by the growing string method[18]
prior to final geometry optimization on DFT level. The connectivity
of transition states to minimum energy structures were verified by
the intrinsic reaction coordinate (IRC) method. The kinetic
experiments revealed a reaction order of one in catalyst.
Therefore, we investigated scenarios in which only one 3a
molecule interacts with 1a as model substrate in its lowest energy
conformation as identified by Grimme’s CREST method.[19] One
reasonable reaction is the abstraction of one of the hydride atoms
Scheme 4. Conceptional origin of diastereoselectivity in the redox isomerization
of 1a ([B] = B(C6F5)3).
The complexation and activation of the chalcone 1a occurs from
its s-cis conformation as most stable conformer. Subsequent
3
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10.1002/ejoc.202100883
European Journal of Organic Chemistry
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Figure 2. Details of the computational studies for the conversion of 1a to cis/trans-2a via the Z-enolate intermediate (top); transition state structures and energies
for the E-iminium enolates C’ and D’ (bottom). Values in parentheses correspond to free energies of ground state and transition states in kcal•mol–1 (± 3 kcal•mol–
1). Selected hydrogen atoms and C6F3 fragments were omitted for clarity. Representations generated by ChemCraft.[20]
intramolecular hydride shift generates the corresponding transient
favorable by a barrier of 21.5 kcal•mol–1 and 25.0 kcal•mol–1. The
iminium enolate with exclusive cis enolate configuration. However, exergonically formed Z-iminium enolates C and D (–1.9 kcal•mol–
1
the hydride shift may generate both E- and Z-iminium moieties,
leading to the cis- and trans-isomers of 2a.
and –2.6 kcal•mol–1) are converted into the cis- and trans-
products as B(C6F5)3 adducts over small barriers of 2.9 kcal•mol–
1 and 3.9 kcal•mol–1 respectively. Although the rotation around a
C–C bond in order to interconvert C into D through the TSrot
Detailed computational studies support the exergonic formation of
two 1a•B(C6F5)3 adducts (–3.1 kcal•mol–1 and –1.9 kcal•mol–1),
one conformer with the O–[B] group pointing away from the NBn2
group and one pointing towards the NBn2 group, the latter being
1.2 kcal•mol–1 less stable compared to the first conformer (Figure
2). Nonetheless, the small energy difference and the comparable
low exergonicity of the complexation suggests that the two
adducts are in equilibrium (Figure 2). The intramolecular hydride
shift proceeds through transfer of one of the inner-lying hydrogen
atoms to the activated Michael-position leading to the two Z-
à
C D
has a very low barrier of 2.8 kcal•mol–1 and 2.1 kcal•mol–1, such
movement requires extensive atomic redistribution so that the
direct conversion of C
E and D F over comparable energy
à à
barriers is most likely to occur. This picture is corroborated by the
transient nature of the iminium enolates C and D, which were not
1
detected by H NMR spectroscopy. The small difference in free
energies of the hydride migration barrier in TSA and TSB is
à
C
à
D
reflected by the slight preference for cis-2a in the catalytic
iminium enolate intermediates
C
and
D
(Figure 2) with
experiments.
comparable reaction barriers of 17.0 kcal•mol–1 and 18.1
kcal•mol–1. In contrast, the formation of the corresponding E-
iminium enolates C’ and D’ Figure 2 bottom) is kinetically less
4
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10.1002/ejoc.202100883
European Journal of Organic Chemistry
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Conclusion
In summary, we have shown that B(C6F5)3 is a viable catalyst for
the redox isomerization of 2-amino chalcones. The
tetrahydroquinoline derivatives are formed in high yield. In
particular, the pyrrolo derivative cis-2f was obtained as single
diastereomer.
Mechanistic,
kinetic
and
computational
experiments support that the redox isomerization proceeds
through Lewis acid induced hydride shift in contrast to hydride
abstraction by the borane.
[2]
[3]
[4]
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Exemplary procedure for the redox isomerization of 1a.
In a glovebox, a vial was charged with the α,β-unsaturated ketone 1a (0.25
mmol, 1.00 equiv.) and B(C6F5)3 (3a) (10 mol%, 0.025 mmol, 12.8 mg,
0.010 equiv.). The mixture was dissolved in abs. CHCl3 (2.50 mL). The vial
was heated to 60 °C for 18 h. The reaction mixture was cooled to room
temperature, diluted with CH2Cl2 (10 ml) and poured into water (10 mL).
The aqueous phase was extracted twice with CH2Cl2 and the combined
organic phase was dried over Na2SO4. The solvent was removed under
reduced pressure. After purification by column chromatography (silica,
mixtures of cyclohexane and ethyl acetate (50:1) the product was obtained
as yellow solid in 85% yield as diastereomeric mixture with a ratio of
cis/trans 2.1:1.
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1H-NMR (700 MHz, 298 K, CDCl3) cis diastereomer δ = 7.80-7.76 (m, 2H,
HAr), 7.49 (m, 1H, HAr), 7.41-7.36 (m, 3H, HAr), 7.34-7.31 (m, 1H, HAr), 7.27-
7.14 (m, 8H, HAr), 7.07 (m, 1H, HAr), 7.01 (m, 1H, HAr), 6.68-6.65 (m, 2H,
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3
2
HAr), 4.98 (d, JHH = 5.9 Hz, 1H, NCHPh), 4.63 (d, JHH = 16.8 Hz, 1H,
NCH2), 4.14 (d, 2JHH = 16.8 Hz, 1H, NCH2), 3.98-3.94 (m, 1H, C(=O)CH),
2
3
3.06 (dd, JHH = 15.5 Hz, JHH = 7.2 Hz, 1H, C(=O)CHCH2), 2.97 (dd,
2JHH = 15.5 Hz, JHH = 4.8 Hz, 1H, C(=O)CHCH2); trans diastereomer
3
[8]
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δ = 7.88-7.84 (m, 2H, HAr), 7.58 (m, 1H, HAr), 7.47-7.43 (m, 2H, HAr), 7.34-
7.31 (m, 1H, HAr), 7.27-7.14 (m, 8H, HAr), 7.12 (m, 1H, HAr), 6.77-6.74 (m,
2H, HAr), 6.72 (m, 1H, HAr), 6.70-6.68 (m, 1H, HAr), 5.04 (d, 3JHH = 4.3 Hz,
1H, NCHPh), 4.75 (d, 2JHH = 17.2 Hz, 1H, NCH2), 4.22 (dt, 3JHH = 13.1 Hz,
4.0 Hz, 1H, C(=O)CH), 4.16 (d, 2JHH = 17.2 Hz, 1H, NCH2), 3.25-3.18 (m,
1H, C(=O)CHCH2), 2.80-2.74 (m, 1H, C(=O)CHCH2).
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13C-NMR (176 MHz, 298 K, CDCl3) cis diastereomer δ = 200.5 (Cq), 145.4
(Cq), 142.9 (Cq), 138.5 (Cq), 136.5 (Cq), 133.4 (CH), 128.9 (CH), 128.8
(CH), 128.6 (CH), 128.5(CH), 128.4 (CH), 127.8(CH), 127.4 (CH), 127.1
(CH), 126.9 (CH), 122.1 (Cq), 117.0 (CH), 112.2 (CH), 63.5 (CH), 53.1
(NCH2), 49.0 (CH), 29.4 (C(=O)CHCH2); trans diastereomer δ = 199.1 (Cq),
144.9 (Cq), 139.1 (Cq), 138.7 (Cq), 136.9 (Cq), 133.1 (CH), 129.9 (CH),
129.2 (CH), 129.1 (CH), 128.3(CH), 128.1 (CH), 127.9(CH), 127.7 (CH),
127.4 (CH), 126.7 (CH), 120.7 (Cq), 116.6 (CH), 112.5 (CH), 63.3 (CH),
53.1 (NCH2), 45.8 (CH), 25.2 (C(=O)CHCH2).
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Acknowledgements
The German Science Foundation (DFG) and the Paderborn
University is acknowledged for financial support to J.P. (PA
1562/16-1) and for a PhD scholarship to R. Z.
Keywords: Redox isomerization • Tert-amino effect • Nitrogen
heterocycle • Boranes • Hydride shift
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Entry for the Table of Contents
The borane catalyzed redox isomerization of 2-amino chalocones is developed. Mechanistic investigations by kinetic, isotopic
labelling and competition experiments as well as computational studies corroborate the concerted [1,5] hydride shift as operative
mechanism. The redox isomerization products are obtained in high yield and with up to > 95:5 diastereoselectivity.
7
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