Reduction of Activated Alkenes by PIII/PV Redox Cycling Catalysis

Article abstract of DOI:10.1002/anie.201912991

The carbon–carbon double bond of unsaturated carbonyl compounds was readily reduced by using a phosphetane oxide catalyst in the presence of a simple organosilane as the terminal reductant and water as the hydrogen source. Quantitative hydrogenation was observed when 1.0 mol % of a methyl-substituted phosphetane oxide was employed as the catalyst. The procedure is highly selective towards activated double bonds, tolerating a variety of functional groups that are usually prone to reduction. In total, 25 alkenes and two alkynes were hydrogenated to the corresponding alkanes in excellent yields of up to 99 %. Notably, less active poly(methylhydrosiloxane) could also be utilized as the terminal reductant. Mechanistic investigations revealed the phosphane as the catalyst resting state and a protonation/deprotonation sequence as the crucial step in the catalytic cycle.

Full text of DOI:10.1002/anie.201912991

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Accepted Article
Title: Reduction of activated alkenes by P(III)/P(V) redox cycling
catalysis
Authors: Lars Longwitz and Thomas Werner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912991
Angew. Chem. 10.1002/ange.201912991
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10.1002/anie.201912991
Angewandte Chemie International Edition
COMMUNICATION
Reduction of activated alkenes by P(III)/P(V) redox cycling
catalysis
Lars Longwitz[a] and Thomas Werner*[a]
Abstract: In this work, the carbon-carbon double bond of
unsaturated carbonyl compounds is readily reduced by
employed for the deoxygenation of -ketoesters, nitro aryls and
a
sulfonyl chlorides by the Radosevich group.[10] Another example
is the catalytic Staudinger reduction, where an azide is
converted into an amine (Scheme 1, A).[11] In this case, an aza
phosphetane oxide catalyst in the presence of a simple organosilane
as terminal reductant and water as the hydrogen source. A catalyst
screening was conducted and quantitative hydrogenation was
observed when 1.0 mol% of a methyl substituted phosphetane
oxides was employed as the catalyst. The procedure is highly
selective towards activated double bonds tolerating a variety of
functional groups which are usually prone to reduction. In total, 25
alkenes and two alkynes were hydrogenated to the corresponding
alkanes in excellent yields up to 99%. Notably, less active
poly(methylhydrosiloxane) could also be utilized as the terminal
reductant. Mechanistic investigation revealed the phosphane as the
catalyst resting state and a protonation/deprotonation sequence as
the crucial step in the catalytic cycle.
ylide is formed which is reduced to
a silylamine and
subsequently hydrolyzed liberating the amine. Based on our
investigations on the catalytic base-free Wittig reaction,[12] we
envisioned that a reduction of alkenes by the in situ formation of
an ylide and subsequent reaction with water could be achieved
under phosphorus redox cycling conditions (Scheme 1, B).
The selective hydrogenation of unsaturated carbonyl
compounds is a reaction of major importance. In nature, enoate
reductases are capable of selectively reducing the activated
carbon-carbon double bond of a -unsaturated substrate,
which plays a crucial role in multiple important processes like the
biosynthesis of fatty acids.[1] In organic synthesis, the reaction is
dominated by transition metal catalysis or the use of
stoichiometric amounts of metal hydride reagents.[2] A metal-free
organocatalytic approach can overcome some problems
regarding purification encountered by these systems and also
lead to new useful reaction pathways. In recent years multiple
organocatalytic systems were developed for the reduction with
hydrogen[3] or other reactive reducing agents such as the
Hanztsch ester[4] to achieve metal-free double bond
hydrogenation. An alternative strategy for the reduction of
unsaturated carbonyl compounds involves Lewis basic addition
to the double bond and subsequent hydrolysis.[5] In this respect,
alkyl phosphanes and N-heterocyclic carbenes show good
chemoselectivities and allow for efficient reduction at room
temperature. However, stoichiometric amounts of these
expensive and sensitive reagents are still required. We
envisioned phosphorus redox cycling as a solution to the
challenge of metal-free reduction. In phosphorus redox cycling
catalysis, the active phosphane reagent is regenerated in situ by
a terminal reducing agent, most commonly an organosilane.
This can avoid stoichiometric phosphane oxide waste in
reactions like the Wittig[6], Appel[7] or Mitsunobu[8] reaction.[9]
Recently, phosphorus redox cycling catalysis has also been
Scheme 1. Phosphorus redox cycling in the reduction of azides (catalytic
Staudinger reaction)[11] and the reduction of activated alkenes using water as
hydrogen source (this work).
We started our investigations using diethyl fumerate (1a) as the
model substrate and phosphetane oxide 3a as the oxidized form
of the catalyst. Using a slight excess of silane (1.5 equiv) and an
excess of water (3.0 equiv) in BuOAc an excellent yield of 95%
of the alkane was observed (Table 1, entry 1).[13] Under reaction
conditions at 80 °C silane hydrolysis was very slow and the
reduction of the phosphane oxide 3a proceeded smoothly. We
lowered the catalyst loading to 0.5 mol% and observed a
significant decrease in yield (entry 2). Commonly used solvents
in phosphorus redox cycling catalysis like dioxane or toluene
increased the yield to 35 and 38%, respectively (entries 3 and 4).
A catalyst screening was carried out using toluene as the
solvent. The introduction of a sterically more demanding group
or an aryl substituent on the phosphetane scaffold led to lower
yields (entries 5 and 6). Furthermore, other catalysts based on
phosphorus heterocycles 3d and 3e performed poorly as well
(entries 7 and 8). A common strategy in phosphorus redox
cycling is the addition of a Brønsted acid to facilitate the
phosphane oxide reduction. However, with 5 mol% of benzoic
acid as an additive a lower yield of only 16% was observed
(entry 9). We increased the catalyst loading to 1.0 mol% and
formation of alkane 2a was observed with a yield of ≥99% (entry
10). With these optimized conditions in hand, the substrate
scope of the reaction was evaluated, although in some cases
the catalyst loading was adjusted to 5.0 mol% or 20 mol% for
more challenging substrates.
[a]
L. Longwitz, PD Dr. T. Werner
Organocatalysis
Leibniz-Institute for Catalysis
Albert-Einstein-Straße 29a, Rostock, Germany
E-mail: thomas.werner@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201912991
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unsaturated esters bearing a-alkyl chain were unsuitable
substrates and only poor conversion was observed even at
elevated temperatures.[13] Interestingly, also acrylates proved to
be compatible substrates and moderate to good yields were
observed for substrates 2t–v. The glycerol derived acrylate 1w
was readily reduced and the product 2w was obtained in an
excellent yield of 93%. Furthermore, -nitro styrene (1x) was
converted, but only an unsatisfying yield of 2x was obtained.
The scope was extended to other unsaturated substrates, like
the acceptor substituted allene 1y, which resulted in the
formation of the partially hydrogenated product 2y in a yield of
33%. It was also possible to reduce alkyne 4a to the
corresponding alkane 5a in a yield of 89%. The monosubstituted
substrate 5b was obtained in yield of ≥99% after reduction of
alkyne 4b.
Table 1. Optimization of the reaction conditions and catalyst screening for the
organocatalytic reduction of activated alkenes.
Entry
1
Catalyst (x mol%)
3a (1.0)
Solvent
BuOAc
Yield 2a / %[a]
95
18
35
38
4
2
3a (0.5)
BuOAc
3
3a (0.5)
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
4
3a (0.5)
5
3b (0.5)
6
3c (0.5)
8
7
3d (0.5)
11
4
8
3e (0.5)
9[b]
10
3a (0.5)
16
>99
3a (1.0)
Reaction conditions: 1a (0.50 mmol, 1.0 equiv), PhSiH3 (1.5 equiv), H2O
(3.0 equiv), phosphane oxide (3, 0.5 or 1.0 mol%), solvent (0.33 M), 80 °C,
24 h. [a]Yields determined by 1H NMR spectroscopy using mesitylene as
internal standard. [b] PhCO2H (5.0 mol%) was used as an additive.
Other fumaric or maleic acid diesters 1b–d were reduced to the
respective succinic acid derivates in yields of ≥99%. Notably, the
terminal unsubstituted double bonds in substrate 1d stayed
untouched during the reaction, demonstrating the selectivity of
the procedure towards electron deficient alkenes. The
trisubstituted alkene 1e was also a suitable substrate, although
harsher reaction conditions were required to obtain a very good
yield of 87%. The malonic acid derived substrate 2f was isolated
in a yield of only 39% likely due to partial hydration of the double
bond as described by Toste and co-workers.[14] Other
disubstituted alkanes 2g–i bearing different electron withdrawing
groups were obtained in moderate to excellent yields. When 2,5-
dimethyl-1,4-benzoquinone (1j) was employed as the substrate
aromatization occurred after the reduction of one double bond
and dihydroquinone 2j was isolated in a good yield of 83%. Next,
several differently functionalized aryl substituted maleimides
were employed as the substrates to evaluate the functional
group tolerance of the methodology. In total, seven succinimides
2k–q were obtained in yields greater than 90%. Functional
groups that might be problematic when using traditional
reduction methods like an aryl chloride (2l), aryl iodide (2m),
benzo nitrile (2n) or nitro aryl (2o) were well tolerated. Methyl
and tert-butyl substituted succinimides 2r and 2s were isolated
from the corresponding maleimides in 76 and 98%, respectively.
Monosubstituted alkenes, like the cinnamate methyl ester or -
Scheme 2. Substrate scope of activated alkenes and alkynes. Reaction
conditions: 1 or 4 (1.0 mmol, 1.0 equiv), PhSiH3 (1.5 equiv), H2O (3.0 equiv),
a
b
3a (1.0 mol%), toluene (0.33 M), 80 °C, 24 h. 5.0 mol% 3a. 20 mol% 3a,
T= 100 °C, PhSiH3 (3.0 equiv), H2O (6.0 equiv). c Yield was determined by
1H NMR spectroscopy using mesitylene as internal standard.
An essential idea of phosphorus redox cycling catalysis is the
shift from stoichiometric phosphorus reagent to organosilane,
which is beneficial in terms of reaction efficiency and product
purification. A further improvement is the use of siloxanes
originating as waste from the silicone industry, e.g.
poly(methylhydrosiloxane) (PMHS).[15] Even though PMHS is
preferred over the other common organosilanes, the low activity
of the polymer limits its application.[16] To showcase compatibility
of catalyst 3a with low activity siloxanes as terminal reductants
the reaction conditions were optimized utilizing five equivalents
of PMHS.[13] The product 2a was isolated in a yield of ≥99%
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employing 10 mol% of catalyst using BuOAc as a renewable
solvent (Scheme 3).[17]
Scheme 3. Reduction of diethyl fumerate 1a using PMHS as the terminal
reductant and water as the hydrogen source.
We set out to investigate the mechanism of the reaction, which
can be divided into four steps: phosphane oxide reduction,
Michael addition, ylide formation and hydrolysis. First, in situ 31
P
NMR spectroscopy was used to investigate the resting state of
the catalyst, which was found to be the phosphane as the
reduced form of the catalyst.[13] No other species like the ylide
were observed even in control experiments using stoichiometric
amounts of phosphane and alkene in the absence of water.[13]
Even though the product of the Michael addition cannot be
observed via NMR spectroscopy, a quick isomerization of diethyl
maleate (Z-1a) to diethyl fumerate (E-1a) in the presence of the
phosphetane indicates a reversible addition to the alkene. In our
previous report on the base-free intramolecular Wittig reaction,
deuterium labeling experiments lead to the assumption that the
ylide is formed by a intermolecular protonation/deprotonation
sequence and not by an intramolecular 1,2-hydrogen shift.[12b, 18]
We investigated the reactivity of the deuterated fumerate D2-1a
and a mixture of deuterated products was obtained with an
overall H:D ratio of 71:29. The loss of one deuterium from the
substrate supports the protonation/deprotonation as the ylide
forming mechanism. Furthermore, when deuterated water (D2O)
was used incorporation of deuterium in the alkane was observed
(H:D= 55:45). When PhSiD3 was employed as the deuterium
source instead, only traces of deuterium could be found in the
product (H:D= 97:3), likely due to H/D exchange with the water.
This confirms that all additional hydrogens in the alkane
originate from the water. Furthermore, no major difference was
observed in the reaction rate when using either H2O or D2O in
the reaction.[13] On the basis of the results of our investigations
and recent literature reports we propose the following
mechanism (Scheme 4).[5a, 5c, 12b, 19] At first the oxidized form of
the catalyst is reduced by the silane forming the corresponding
phosphane. The phosphane reacts with the alkene in a
reversible Michael addition. Subsequently, the ylide intermediate
is formed by a protonation/deprotonation sequence. Hydrolysis
of the ylide occurs,liberates the product and the phosphane
oxide is regenerated.[20]
Scheme 4. Proposed mechanism for the organocatalytic reduction of activated
alkenes by phosphorus redox cycling.
In conclusion, a protocol for the organocatalytic reduction of
alkenes was developed using water as the hydrogen source. A
phosphetane oxide catalyst enables phosphorus redox cycling in
the presence of water and allows for the selective reduction of
activated alkenes to alkanes. The substrate scope was
evaluated and several disubstituted and monosubstituted
alkenes were converted to the corresponding alkanes in yields
up to ≥99% with high functional group tolerance. It was possible
to use inexpensive and less active poly(methylhydrosiloxane) as
the terminal reductant and a yield of ≥99% was obtained
employing the renewable solvent BuOAc. The mechanism of the
reaction was investigated and it was revealed that the
phosphane oxide is firstly reduced to the respective phosphane,
which subsequently reacts with the substrate in a Michael
reaction. A protonation/deprotonation sequence finally leads to
the formation of an ylide, which is then hydrolyzed under
reaction conditions.
Acknowledgements
This work was conducted in the scope of the Leibniz
ScienceCampus Phosphorus Research. L.L. would like to thank
Richy Hauptmann, Alexander Linke and Christoph Kubis for their
advice and support.
Keywords: organocatalysis • reduction • phosphorus • redox
catalysis • water
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Lars Longwitz, Thomas Werner*
Page No. – Page No.
Reduction of activated alkenes by
P(III)/P(V) redox cycling catalysis
The organocatalytic reduction of activated alkenes to the corresponding alkanes
has been realized using phosphorus redox cycling and water as the hydrogen
source.
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