Indium Tribromide-Catalysed Transfer-Hydrogenation: Expanding the Scope of the Hydrogenation and of the Regiodivergent DH or HD Addition to Alkenes

Article abstract of DOI:10.1002/chem.202101259

The transfer-hydrogenation as well as the regioselective and regiodivergent addition of H?D from regiospecific deuterated dihydroaromatic compounds to a variety of 1,1-di- and trisubstituted alkenes was realised with InBr₃ in dichloro(m)ethane. In comparison with the previously reported BF₃?Et₂O-catalysed process, electron-deficient aryl-substituents can be applied reliably and thereby several restrictions could be lifted, and new types of substrates could be transformed successfully in hydrodeuterogenation as well as deuterohydrogenation transfer-hydrogenation reactions.

Full text of DOI:10.1002/chem.202101259

Accepted Article
Accepted Article
Title: Indium Tribromide-catalysed Transfer-Hydrogenation –
Expanding the Scope of the Hydrogenation and of the
Regiodivergent DH or HD Addition to Alkenes
Authors: Gerhard Hilt and Luomo Li
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To be cited as: Chem. Eur. J. 10.1002/chem.202101259
Link to VoR: https://doi.org/10.1002/chem.202101259
01/2020

10.1002/chem.202101259
Chemistry - A European Journal
ARTICLE
Indium Tribromide-catalysed Transfer-Hydrogenation –
Expanding the Scope of the Hydrogenation and of the
Regiodivergent DH or HD Addition to Alkenes
Luomo Li and Gerhard Hilt*[a]
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The transfer-hydrogenation as well as the regioselective
and regiodivergent addition of H-D from regiospecific deuterated
dihydroaromatic compounds to a variety of 1,1-di- and trisubstituted
alkenes was realised with InBr3 in dichloro(m)ethane. In comparison
with the previously reported BF3·Et2O-catalysed process, electron-
deficient aryl-substituents can be applied reliably and thereby several
restrictions could be lifted, and new types of substrates could be
transformed successfully in hydrodeuterogenation as well as
deuterohydrogenation transfer-hydrogenation reactions.
loading of 30 mol%. Nevertheless, good yields and a high
incorporation of deuterium at the desired positions was observed.
However, some functional groups, such as 1,2-dimethoxyaryl or
electron-deficient aryl substituents, were not compatible with the
reaction conditions and prompted us to search for alternative
catalysts with a higher reactivity.
Introduction
Dihydroaromatic compounds are relatively sensitive towards air
and other mild oxidising agents and can be converted easily into
the corresponding arenes.[1-9] Based on these characteristics,
dihydroaromatic compounds have found various applications10-15
and the use as a surrogate for molecular hydrogen is one of the
most prominent examples.16-23 Other applications of substituted
1,4-cyclohexadienes are the transfer of HBr,24 HCN25-26 and many
other hydrofunctionalisation reactions to transfer various
groups27-35 to unsaturated starting materials, which have been
summarised recently.36-39
Scheme 1. Previous work concerning regioselective hydrodeutero-
genation/deuterohydrogenation reactions.
The Oestreich group pioneered in the regioselective
hydrodeuterogenation of 1,1-diarylalkenes in 2018 by using an
unsymmetrical surrogate where the hydrogen and the deuterium
atoms are bound differently, so that the hydrogen acts as a
hydride equivalent (H-) and the deuterium atom as a “heavy”
proton (D+).40 The reactions were catalysed by B(C6F5)3 and the
desired reduced products were obtained in good to excellent
yields and regioisomeric ratios (rr = >95:5) with the deuterium
attached to the higher substituted carbon atom (Scheme 1). In
2020 our group reported the regiodiverse hydrodeuterogenation
and the deuterohydrogenation utilising two regioselectively
substituted dihydroaromatic compounds 3 and 4 (Scheme 1)
which originated from the cobalt-catalysed Diels-Alder reaction of
selectively deuterated 1,3-dienes with trimethylsilyl acetylene.41
For the reduction of 1,1-disubstituted diaryl alkenes, the catalyst
was altered from B(C6F5)3 to the less air- and moisture sensitive
BF3∙OEt2 complex, which had to be applied in a higher catalyst
The regioselective labelling of organic molecules is useful in
organic, organometallic and biochemistry, because labelled
compounds can be used to elucidate reaction mechanisms
and biosynthetic pathways.42 Kinetic isotope effects can be
measured when a deuterium-carbon bond cleavage is
incorporated in the rate determining step of a reaction.43
Also, 2H NMR can be used as probe for the determination of
Lewis acidities.44
Results and Discussion
In light of these preliminary works, we decided to investigate the
transfer-hydrogenation from dihydroaromatic compounds to
alkenes, also with indium-based catalysts in order to identify
substrates which will be accepted by those catalysts to enlarge
the scope of the reaction. The optimization for an indium-salt
catalysed process started with the readily available 1,1-
[a]
M.Sc. L. Li, Prof. Dr. G.Hilt
Institut für Chemie
diphenylethene
5
and 1,4-cyclohexadiene (= CHD) as
Oldenburg University
commercially and readily available starting materials under
modified conditions (Scheme 2).
Carl-von-Ossietzky-Str. 9-11
26111 Oldenburg, Germany
E-mail: Gerhard.Hilt@uni-oldenburg.de
1
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As can be seen from Scheme 3, the first results of the InBr3-
catalysed process are as efficient as the BF3∙OEt2-catalysed
reaction for the electron-rich substrates (8a-8c). Therefore, we
continued to direct our attention towards those substrates which
proved to be unreactive under the BF3∙OEt2-catalysed conditions
and skipped most of the previously positive reported substrates.
Early on in this investigation, the previously unreactive substrate
8d led to a low yield of 15%, which could be attributed to the
stronger interaction of the 1,2-dimethoxy subunit with BF3
compared to the much more inert InBr3 for ligand exchange and
inactivation of the catalyst. On the other hand, a slightly lower
yield for 8e was obtained for the InBr3- compared to the BF3∙OEt2-
catalysed reaction. Even more interesting results were obtained,
when halide-substituted electron-deficient 1,1-diaryl-substituted
diaryl ethenes were tested. These types of substrates were very
unreactive in the BF3∙OEt2-catalysed reactions (yields < 1%) and
consequently not investigated in more detail in the previous
report.41
Scheme 2. Hydrogenation of alkene 5 utilising CHD as reducing agent and
indium-based catalysts.
First, we investigated the influence of different solvents in the
transfer-hydrogenation. Donor-based solvents, such as THF and
acetonitrile revealed to be less favourable (Table 1, entries 1/2),
while surprisingly the non-polar solvent n-heptane (entry 3) and
the weakly coordinating solvent 1,2-dichloroethane (DCE, entry
4) proved to be very suitable for the reaction and gave the desired
product 6 in excellent to quantitative yields. The catalyst loading
of 5 mol% seems to be efficient while lower as well as higher
catalyst loadings resulted in lower yields (entries 5/6) for no
obvious reason. As a commercially available alternative to InBr3,
also indium triflate was tested, which resulted a lower yield of 6
(75%).
Table 1. Results of the InBr3/In(OTf)3-catalysed hydrogenation of
5 with CHD.a
no.
1
catalysta
solvent
yield 6
trace
InBr3 (5 mol%)
InBr3 (5 mol%)
InBr3 (5 mol%)
InBr3 (5 mol%)
InBr3 (3 mol%)
InBr3 (10 mol%)
In(OTf)3 (5 mol%)
THF
2
acetonitrile
n-heptane
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
8%
3
92%
4
99% (97%)b
88%
5
6
84%
7
75%
a) The yields were determined by GC-FID analysis of the crude mixture with
mesitylene as internal standard, added after the reaction from a stock solution.
b) Isolated yield.
The hitherto best results were obtained, when 5 mol% InBr3 was
used as a Lewis acid catalyst in DCE as solvent at elevated
temperatures (80 °C) for 12 h reaction time, which resulted in an
almost quantitative yield of 6 (by GC analysis) and an isolated
yield of 97% yield. With these reaction conditions in hand, we
started the investigation of the InBr3-catalysed transfer-
hydrogenation reaction from CHD to suitable alkenes with a
strong focus upon the previously reported results of the
corresponding BF3∙OEt2-catalysed hydrogenation reaction to
identify similarities or improvements. In this respect, we first
applied well-accepted substrates in the BF3∙OEt2-catalysed
reaction, such as several methoxy-substituted 1,1-diarylethenes,
in the indium tribromide-catalysed reaction. Later, also substrates
with electron-deficient substituents and tri-substituted alkenes
were tested, which were not applied in the BF3∙OEt2-catalysed
transfer-hydrogenation reaction because of the lower reactivity of
the boron-based catalyst system. The results of these reactions
and of the ongoing substrate screening process are summarised
in Scheme 3. For direct comparison of the indium- and the boron-
catalysed reactions, the yields in brackets refer to the previously
reported yields when BF3∙OEt2 was applied.40,41
Scheme 3. InBr3-catalysed transfer-hydrogenation to alkenes.
2
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The 4,4´-difluoro-derivative 8f and the 4,4´-dichloro-derivative 8g
were obtained in good yields of >85%, however, elevated
temperatures had to be applied (120 °C in DCE). The mono-
bromide-substituted staring material 7h, which was unreactive
under the boron-catalysed conditions still shows a good reactivity
and resulted in the formation of the product 8h in 68% yield. Also,
the application of the 4-trifluoromethyl-substituted product 8i and
the 4-fluoro-substituted derivative 8j expanded the scope of the
reaction and led to the product in 67% yield.
In the BF3∙OEt2-catalysed transfer-hydrogenations, an aryl
substituent proved to be essential for the overall transfer-
hydrogenation process because an efficient mesomeric
carbenium ion stabilisation by the arene is needed and an
exocyclic carbon-carbon double bond was not applicable. When
InBr3∙was used as catalyst, the formation of 8o could be realised
with moderate success. Finally, we also tested a 1,1-dialky-
substituted alkene, namely 3-methylene-dodecane 7p in the
InBr3-catalysed process. While such substrates were completely
unreactive in the BF3∙OEt2-catalysed process, complete
conversion and an excellent yield of 8p was obtained when InBr3
was applied as catalyst.
For the functional group compatibility, we also applied an
aldehyde functionalised starting material 7k to determine the
compatibility of redox-active functional groups under the reaction
conditions. Although the desired aldehyde 8k was only isolated in
58% yield, the proof-of-principle was successful, in that respect
that the ionic mechanism outlined below is more receptible
towards the more stabilised cation intermediate formed upon
protonation of the diaryl-substituted double bound with respect to
the aldehyde functionality.
Then we turned our attention towards trisubstituted alkenes and
fortunately the indium-catalysed transfer-hydrogenation proved to
be superior to the boron-based transformation. Indeed, the
products 8l and 8m could be obtained in 90%, whereas product
8n was isolated in good 73% yield.
After these significant extensions of the scope of the transfer-
hydrogenation reaction from CHD to other alkenes via indium-
based catalysts, we turned our attention towards the selectivity of
a
regiodiverse hydrodeuterogenation / deuterohydrogenation
reaction when indium tribromide is applied as catalyst.
For this purpose, we used the deuterated dihydroaromatic
compounds 3 (99% D incorporation) and 4 (96% D incorporation,
see Scheme 1) to investigate the efficiency of regioselective
deuterium transfer to the substrates, outlined in Scheme 4. Similar
to the result presented in Scheme 3, the electron-rich substrate
7a showed a good reactivity in the hydrodeuterogenation as well
as the deuterohydrogenation with excellent yields and deuterium
incorporation at room temperature. The electron-deficient starting
material 7j gave product 9b with a similar yield compared to 8j
and an excellent deuterium incorporation, whereas product 10b
was formed in higher yield. On the other hand, products 9c and
10c were both formed in reduced yields but acceptable deuterium
incorporation. One should not forget that the reactivities of the
dihydroaromatic compounds CHD, 3 and 4 for the hydride transfer
to InBr3 or to intermediate A (see Scheme 5) are most likely
different, so that the yields may differ from substrate to substrate.
Scheme 5. Proposed mechanism of the deuterohydrogenation of alkenes of
type 7 utilising 4 as HD surrogate and InBr3 as catalyst.
Scheme 4. Investigation of the regiodiverse HD/DH addition to selected alkenes
utilising the HD surrogates 3 and 4.
3
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While the deuterium content of 9d was still high, only 54%
deuterium incorporation could be detected for 10d. Also, small
amounts of protodesilylated surrogate 4 (m/z = 158) as well as
biphenyl (m/z = 154) were detected by GCMS analysis of the
crude reaction mixture. In the latter case both deuterium atoms of
4 were removed and only in this reaction with this particular
substrate.
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Acknowledgement
The financial support by the German Science Foundation GRK 2226 is
gratefully acknowledged.
Keywords: alkenes • catalysis • indium tribromide • transfer-
hydrogenation • regioselectivity
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4
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Entry for the Table of Contents
The InBr3-catalysed transfer-hydrogenation from dihydroaromatic compounds to di- and trisubstituted alkenes was realised and the
scope of the reactions could be expanded towards electron-deficient alkenes.
5
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