Phosphetane oxides as redox cycling catalysts in the catalytic wittig reaction at room temperature

Article abstract of DOI:10.1021/acscatal.9b02456

Recently, phosphorus redox cycling has gained significant importance for a number of transformations originally requiring the use of stoichiometric amounts of phosphorus reagents. While these methodologies have several benefits, high catalyst loadings (≥10 mol percent) and harsh reaction conditions (T ≥ 100 °C) often limit their versatility and applicability. Herein, we report differently substituted phosphetane oxides as efficient catalysts for the catalytic Wittig reaction. The phosphetane scaffold is easy to modify, and a number of catalysts can be obtained in a simple two-step synthesis. The activity in the Wittig reaction significantly surpasses previously reported phospholane-based catalysts and the reaction can be conducted with catalyst loadings as low as 1.0 mol percent even at room temperature. Furthermore, a Br?nsted acid additive is no longer required to achieve high yields at these mild conditions. A methyl-substituted phosphetane oxide was employed to synthesize 25 different alkenes with yields of up to 97percent. The methodology has a good functional group tolerance and the reaction can be performed starting with alkyl chlorides, bromides, or iodides. Additionally, it was possible to use poly(methylhydrosiloxane) as the terminal reductant in the catalytic Wittig reaction employing 2-MeTHF as a renewable solvent. The intermediates of the Wittig reaction were analyzed by ³¹P NMR spectroscopy, and in situ NMR experiments confirmed phosphane oxide as the resting state of the catalyst. Further kinetic investigations revealed a striking influence of the base on the rate of phosphane oxide reduction.

Full text of DOI:10.1021/acscatal.9b02456

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Article
Phosphetane Oxides as Redox Cycling Catalysts in
the Catalytic Wittig Reaction at Room Temperature
Lars Longwitz, Anke Spannenberg, and Thomas Werner
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02456 • Publication Date (Web): 29 Aug 2019
Downloaded from pubs.acs.org on August 29, 2019
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Phosphetane Oxides as Redox Cycling Catalysts in
the Catalytic Wittig Reaction at Room Temperature
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Lars Longwitz,† Anke Spannenberg,† Thomas Werner†*
†Leibniz-Institute for Catalysis e.V. at the University of Rostock, Albert-Einstein-Straße 29a,
18059 Rostock, Germany.
Abstract: Recently, phosphorus redox cycling gained significant importance for a number of
transformations originally requiring the use of stoichiometric amounts of phosphorus reagents.
While these methodologies have several benefits, high catalyst loadings (≥10 mol%) and harsh
reaction conditions (T≥100 °C) often limit their versatility and applicability. Herein, we report
differently substituted phosphetane oxides as efficient catalysts for the catalytic Wittig reaction.
The phosphetane scaffold is easy to modify and a number of catalysts can be obtained in a simple
two step synthesis. The activity in the Wittig reaction significantly surpasses previously reported
phospholane-based catalysts and the reaction can be conducted with catalyst loadings as low as
1.0 mol% even at room temperature. Furthermore, a Brønsted acid additive is no longer required
to achieve high yields at these mild conditions. A methyl-substituted phosphetane oxide was
employed to synthesize 25 different alkenes with yields up to 97%. The methodology has a good
functional group tolerance and the reaction can be performed starting with alkyl chlorides,
bromides or iodides. Additionally, it was possible to use polymethylhydrosiloxane as the terminal
reductant in the catalytic Wittig reaction employing 2-MeTHF as a renewable solvent. The
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intermediates of the Wittig reaction were analyzed by P NMR spectroscopy and in situ NMR
experiments confirmed the phosphane oxide as the resting state of the catalyst. Further kinetic
investigations revealed a striking influence of the base on the rate of phosphane oxide reduction.
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Keywords: Wittig reaction, olefination, organocatalysis, phosphorus, green chemistry,
phosphacycles
Introduction
One of the most prominent reactions in organic chemistry is the Wittig olefination.1 While it is
a common tool for the introduction of a carbon-carbon double bond even in complex
molecules,2, 3 the formation of stoichiometric amounts of phosphane oxide byproduct is a definite
disadvantage of this transformation. Generally, phosphane oxides, especially triphenyl phosphane
oxide, complicate the work up of the reaction and hamper the product purification.4 Furthermore,
to recycle the phosphane, which is required in larger scale applications, the phosphane oxide is
reduced back utilizing hazardous reagents like phosgene or oxalyl chloride. The stoichiometric
amounts of phosphorus reagent also limit the scope of suitable phosphanes, because phosphanes
that are specially designed for the desired substrates might be significantly more expensive than
the commonly employed triphenyl phosphane. A catalytic variant of the Wittig reaction, in which
the produced phosphane oxide is reduced back to the phosphane in situ, minimizes phosphane
oxide waste and allows for more efficient reactions. The first phosphorus based catalytic Wittig
reaction was reported by O’Brien in 2009 and since then, a variety of catalyst systems and
applications have been investigated for this transformation (Scheme 1).5-7 Based on these findings
the idea of phosphorus redox cycling has been applied to a number of classic organic
transformations, including the Mitsunobu8, 9, Staudinger10, 11, Cadogan12, Appel13 or base-free
Wittig14-16 reaction.17 The key step in these reactions is the chemoselective in situ reduction of the
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phosphane oxide in the reaction mixture. A recent life cycle assessment of the Wittig reaction
shows a significant environmental benefit of using a catalytic variant employing silanes as the
terminal reductant.18 Preferably the organosilanes employed should be cheap and readily
available e.g. polymethylhydrosiloxane (PMHS), which is a waste product from silicone
production.19-21 While PMHS has been used for a catalytic variant of the Staudinger reaction,11
application in other redox cycling reactions like the Wittig reaction has not been realized so far.
After their initial success, further advances in the catalytic Wittig reaction were made by O’Brien
et al. by optimizing the catalyst structure to allow for a reaction at room temperature and
broadening the substrate scope (Scheme 1).22, 23 Nonetheless, the efficiency of the reaction
especially at mild conditions is still low overall: high catalyst loadings up to 20 mol% and an
acidic additive is required at room temperature.22 Brønsted acids are known to facilitate the
reduction of phosphane oxides with silanes24-27 and even under basic conditions of the Wittig
reaction the acid can significantly improve the yield of olefination product. However, the
development of an additive-free protocol operating under mild conditions and low catalyst
loadings would be a significant advancement.
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Previous studies showed a critical role of the ring size on the catalyst activity and also of major
importance for a fast reduction of the phosphane oxide.27, 28 Van Delft et al. studied the reduction
of five, six and seven membered phosphane oxides. Notably, the reduction rate increases with
decreasing ring size and only the reduction of the five membered phospholane catalysts proceed
at a rate, which is suitable for redox cycling catalysis. Due to this correlation in ring size and rate
of reduction, we were interested in the effect of using 4-membered phosphetane oxides as
catalysts for the catalytic Wittig reaction. Following the trend of activity and ring size, we
envisioned an efficient reaction utilizing these catalysts under mild conditions. Phosphetane
oxides were first synthesized in 1962 by McBride et al.29, but were only recently established as
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organocatalysts in different transformations, including P(III)/P(V) redox cycling by the
Radosevich group.12, 30-34 Recently, we contributed to the field of redox cycling catalysis by the
development of a microwave-assisted Wittig reaction using tributylphosphane oxide as the
catalyst (Scheme 1).35 Herein, we present a phosphetane-based catalyst for the catalytic Wittig
reaction, which operates at low catalyst loadings at room temperature.
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O
P
Ar
O
Bu
R
+
Br
O
EWG
P
R3PIII
1
2
O'Brien 2013
O'Brien 2014
Wittig reaction
Redox catalysis
O
O
P
V=O
R3P
Bu P Bu
Bu
EWG
R
R
3
Our Group 2015
This work
Scheme 1. General concept of the catalytic Wittig reaction and catalysts investigated for the
reaction.
Results and discussion
Evaluation of different functionalized phosphetane oxide catalysts. We first started out by
evaluating differently substituted phophetane oxides as catalyst for the catalytic Wittig reaction
using benzaldehyde (1a) and bromo methyl acetate (2a) as the model substrates. It is known from
previous reports that iPr2NEt is an excellent base for the selective deprotonation of the in situ
formed phosphonium salts.22 We synthesized several differently substituted phosphetane oxides 4
and employed them with a catalyst loading of 1.0 mol% in the model reaction. The penta-methyl
substituted ring structure was chosen due to synthetic availability and due to the lability of
unprotected phosphetane derivates under basic conditions.36 When the methyl substituted catalyst
4a was employed, a yield of 46% of the desired product 3a with a good E/Z selectivity of 91:9
was achieved (Table 1, entry 1). It is noteworthy that the chemoselectivities of the reaction with
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all catalyst at room temperature were very high (>95%) and lower yields were only achieved due
to poor conversion. Introducing a more bulky iso propyl substituent on the phosphorus in catalyst
4b, only 5% of the product was formed (entry 2). This demonstrates the importance of the steric
environment at the phosphorus atom, which is relevant in multiple steps of the reaction,
especially in the reduction of the oxide by the silane. We then turned our attention to aryl
substituted phosphetane oxides (entries 3–5). The use of phenyl substituted phosphetane oxide 4c
lead only to a poor yield of 8%, although with an excellent E/Z selectivity of 97:3 (entry 3). We
envisioned to increase the conversion of the reaction by introducing electron donating groups on
the aryl substituent in order to enhance the nucleophilicity of the corresponding phosphane.
When catalyst 4d, bearing a dimethyl amino group in para position on the aryl substituent, was
employed, a higher yield of 17% was achieved (entry 4). It should be noted that the E/Z
selectivity remained excellent. Interestingly, when substituents like methoxy groups in ortho
position were introduced, the catalyst was completely deactivated, likely due to steric demand
(entry 5). A previously used catalyst in the catalytic Wittig reaction is the 5-membered phosphane
oxide 5, which showed a low conversion and poor stereoselectivity at room temperature (entry 6).
These results lead us to continue our investigations with the methyl substituted catalyst 4a, which
showed the highest yield with good E/Z selectivity.
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Table 1. Screening of different organocatalysts 4a–4e and 5 for the catalytic Wittig reaction at
room temperature.a
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or (1.0 mol%)
iPr2NEt (1.0 equiv)
PhSiH3 (1.0 equiv)
O
O
OMe
Br
+
OMe
O
O
toluene, 25 °C, 24 h
7
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9
1a
2a
3a
(1.0 equiv)
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Me
4c
4d
4e
, Ar= Ph
, Ar= 4-(NMe2)-Ph
, Ar= 2,4,6-(OMe)-Ph
O
O
4a
4b
, R= Me
, R= iPr
P
P
P
R
Ar
Ph
5
Entry
Catalyst
Yield 3a/ %b
E:Zb
1
2
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4
5
6
4a
4b
4c
4d
4e
5
46
5
91:9
99:1
97:3
98:2
-
8
17
0
10
72:28
a Reaction conditions: 1a (0.50 mmol, 1.0 equiv), 2a (1.0 equiv), iPr2NEt (1.0 equiv), PhSiH3
b
(1.0 equiv), phosphane oxide 4 or 5 (1.0 mol%), solvent (0.33 M), 25 °C, 24 h. Yields and
selectivities of 3a determined with GC-FID using hexadecane as internal standard.
Optimization of the reaction parameters. Subsequently, we set out to optimize the reaction
conditions.37 As mentioned above Brønsted acids are known to be effective co-catalysts in the
catalytic Wittig reaction due to their ability to facilitate the reduction of phosphane oxides. Even
though a base is present in the reaction mixture, O’Brien et al. reported the use of benzoic acid
derivates as additives enabling to perform this reaction at room temperature.22 However, in our
case the addition of 5.0 mol% of benzoic acid only lead to a small increase in yield compared to
the standard reaction conditions without additive (Table 2, entry 1 vs. 2). This led us to the
conclusion that an acid is not required to efficiently reduce phosphetane oxide 4a even at room
temperature. Subsequently, we evaluated the effect of different solvents on the reaction (entries
3–7). Under solvent-free conditions, a yield of 20% was obtained. When acetonitrile was used as
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a solvent, a low yield of only 18% could be observed. Otherwise, polar aprotic solvents like
EtOAc, acetone or THF lead to good yields up to 68% for THF. Further optimization experiments
were conducted using THF as the solvent (entries 8–11). Recently, diphenyl disiloxane (DPDS)
was utilized as a superior reductant compared to traditional organosilanes by Aldrich et al. for the
reduction of tertiary phosphane oxides.38-40 In the presence of DPDS as a reducing agent the yield
increased to 74% (entry 8). However, DPDS is not commercially available and this rather minor
increase did not justify the relatively inefficient synthesis. PMHS is a waste product generated by
the silicon industry and thus it would be an optimal candidate for a cheap and green terminal
reductant.19, 20 Unfortunately, no reaction utilizing PMHS at room temperature was observed
(entry 9). Furthermore, substitution of the base by Na2CO3 did also not lead to notable product
formation, likely due to the low solubility at room temperature (entry 10). Finally, we increased
the catalyst loading to 2 mol% and were able to isolate the product in 90% yield with a E/Z
selectivity of 92:8 (entry 11).
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Table 2. Optimization of reaction parameters employing 4a as the catalyst in the model reaction
to form methyl cinnamate (3a).a
4a
(1.0 mol%)
iPr2NEt (1.0 equiv)
PhSiH3 (1.0 equiv)
O
O
O
O
P
+
OMe
H
Br
Me
OMe
(1.0 equiv)
toluene, 25 °C, 24 h
4a
1a
2a
3a
Entry
Deviation from standard conditions
Yield 3a/ %b
E/Zb
1
2
3
4
-
46
53
20
18
91:9
91:9
91:9
89:11
5.0 mol% PhCOOH
neat
MeCN
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EtOAc
52
61
68
74
0
92:8
91:9
92:8
92:8
-
6
Acetone
7
THF
8
THF, DPDS (1.0 equiv)
THF, PMHS (5.0 equiv)
THF, Na2CO3 (1.0 equiv)
THF, 2.0 mol% 4a
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2
-
90c
92:8
a Reaction conditions: 1a (0.50 mmol), 2a (1.0 equiv), iPr2NEt (1.0 equiv), PhSiH3 (1.0 equiv),
b
phosphane oxide 4a (1.0 mol%), solvent (0.33 M), 25 °C, 24 h. Yields and selectivities of 3a
determined with GC-FID using hexadecane as internal standard. c Isolated yield is given.
Evaluation of the substrate scope. We then set out to investigate the scope of the reaction at
room temperature (Scheme 2). Due to the good stability of the catalyst and high chemoselectivity
of the reaction it was possible to prolong the reaction time up to 48 h to generally increase the
conversion and yield.37 The model substrate methyl cinnamate (3a) was obtained in an excellent
isolated yield of 97% under the standard reaction conditions, revealing the strength of the mild
conditions of this method. When scaling up the reaction, we were able to isolate the product in a
good yield of 78% as a single stereoisomer after aqueous work up and recrystallization without
the need of column chromatography. We further investigated the effect of different substituents
on the aldehyde. Conversion of a biphenylic aldehyde 1b or napthaldehyde 1c proceeded
smoothly with excellent isolated yields of the desired products 3b and 3c. The introduction of an
electron withdrawing ester group led to an excellent yield of 97%, while the methoxy substituted
aldehyde 1e was only isolated in a moderate yield of 65%. In this case the conversion of the
aldehyde 1e was incomplete even after 48 h, likely due to a slower reaction of the in situ
generated ylid with the electron rich aldehyde 1e. The chloro-substituted olefins 3f–3h were
obtained in good to excellent yields, although lower yields were obtained for the olefin
substituted in ortho position. Additionally, isophthalaldehyde 1i was converted by doubling the
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amount of alkyl bromide, base, reducing agent and catalyst and the respective bisolefine 3i was
isolated in a yield of 85%. Strong electron withdrawing groups like a nitro group lead to
significant aldehyde reduction to the respective alcohol under catalytic Wittig reaction
conditions. Thus, the temperature and catalyst loading was slightly increased and 3j was isolated
in a high yield of 90%. Furan and thiophene-based aldehydes 1k and 1l were converted under
standard conditions to afford the olefins 3k and 3l in yields of 93% and 78%, respectively.
Benzofurane and benzothiophene substituted olefins were obtained in isolated yields of 88% and
66%, indicating the same tendency of reactivity and a slightly lower yield was obtained for the
sulfur containing heterocycle. The methodology was also transferred to aliphatic aldehydes and
olefins 3o and 3p were isolated in moderate and good yield, respectively. Citronellal (1q) was
converted into the respective olefin 3q and isolated in a yield of 69%. The methodology tolerates
α-disubstituted aldehydes like 1r and the corresponding olefination product 3r was isolated in a
yield of 83%. Subsequently, synthetically relevant amino acid derived aldehydes 1s and 1t were
converted to alkenes 3s and 3t in good yields under standard reaction conditions. Notably, when
employing enantiopure aldehydes (S)-1s and (S)-1t, full retention of the configuration in the
products was observed, proving the benefit of the mild reaction conditions of the catalytic Wittig
reaction.
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4a
(2.0 mol%)
iPr2NEt (1.1 equiv)
O
5
6
7
8
PhSiH3 (1.0 equiv)
O
X
EWG
EWG
P
R
+
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R1
H
R2
(1.1 equiv)
THF, 25 °C, 48 h
R2
4a
1
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3
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CO2Me
CO2Me
CO2Me
O
R
Br
OMe
R
3a
3a
, 97% (93:7)
2a
3b
3f
3g
3h
, R= Ph, 97% (99:1)
, R= o-Cl, 75%, (89:11)
, R= m-Cl, 80%, (92:8)
, R= p-Cl, 96%, (92:8)
b
, 78%, (>99:1)
3c
3d
3e
, R= 1-Naph, 92%, (97:3)
, R= CO2Me, 97%, (93:7)
, R= OMe, 65%, (99:1)
MeO2C
CO2Me
3i
, 85%
O
CO2Me
CO2Me
CO2Me
O
S
CO2Me
CO2Me
S
NO2
c
3k
3l
3m
3n
, 93% (99:1)
, 78% (89:11)
Me
, 88% (99:1)
, 66% (98:2)
3j
, 90% (83:17)
Me
Me
CO2Me
OMe
CO2Me
CO2Me
Hex
Me
O
3o
3p
3q
3r
, 66% (96:4)
, 90% (98:2)
Boc
HN
, 69% (99:1)
, 83% (>99:1)
O
Boc
HN
O
Boc
HN
O
Boc
O
HN
OMe
OMe
OMe
OMe
Ph
Ph
3s
3t
(S)-3s
(S)-3t
, 61% (96:4), ee= 99%
, 69% (96:4)
, 67% (96:4)
, 64% (95:5), ee= 95%
O
O
CN
O
H
OMe
OMe
O
O
Me
c
c
c
3u
, 60% (94:6)
3a
3a
3r
3w
, 85% (99:1)
, X= Cl, 90% (94:6)
, X= I, 63% (91:9)
, 54% (97:3)
1a
CF3
O
O
Me
O
CO2Me
Me
O
P(III)
P(V)
Br
c
c
3y
, 68%
O
3x
, 66% (71:29)
Scheme 2. Evaluation of the substrate scope of the catalytic Wittig reaction using different
aldehydes 1 and alkyl halides 2. Reaction conditions: 1 (2.00 mmol), 2 (1.1 equiv), iPr2NEt
(1.1 equiv), PhSiH3 (1.0 equiv), phosphane oxide 4a (2.0 mol%), THF (0.66 M), 25 °C, 48 h.
a
Isolated yield are given. The E/Z selectivity is given in parenthesis. Isophthalaldehyde 1i was
converted in the presence of 2a (2.2 equiv), iPr2NEt (2.2 equiv), PhSiH3 (2.0 equiv) and 4a
(2 mol%). Reaction scaled up to 20 mmol and purified without column chromatography.c
b
Reaction carried out at 45 °C with 5 mol% 4a.
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We then turned our attention to different alkyl halides and were able to synthesize 3a starting
from the respective chloride or iodide, but alkyl bromides seem to be the most suitable starting
materials for this reaction. The low yield obtained when the respective iodide 2c was used can be
explained by the formation of different side products originating from dehalogenation or reaction
with the ylid.37 Cinnamyl nitrile (3u) was isolated in a moderate yield of 60% from bromo
acetonitrile (2d). Secondary alkyl bromides were converted at 45 °C with a catalyst loading of
5 mol% and the respective trisubstituted alkenes 3v and 3w were isolated in yields of 54% and
85%, respectively. Some additional substrates were converted, which did not yield the desired
product under the standard reaction conditions.37 Aldehydes bearing strong electron donating
groups like trimethoxy benzaldehyde were not converted to the respective alkene. Ketones like
acetophenone were unsuitable substrates, even at harsh conditions (>100 °C). Although, at
slightly elevated temperature (45 °C) and catalyst loading (5 mol%) it was possible to convert the
activated ketone 1x and the respective olefination product 3x was isolated in a yield of 66%.
Notably, the E/Z ratio obtained for this product was 71:29, instead of a general selectivity to the E
isomer in the Wittig reaction with stabilized ylids, which mirrors the observations made in the
stoichiometric Wittig reaction of fluorinated ketones.41 Intramolecular Wittig reaction was also
achieved using the ketone 1y as the substrate without the addition of alkyl halide 2a. It is worth
mentioning that the stereoselectivity of this protocol for the catalytic Wittig reaction at room
temperature is excellent and in many cases, only the E isomer was isolated.
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Investigation of the reaction mechanism. Due to the high activity of the phosphetane oxide
catalysts, we were interested in the reaction mechanism and investigated the resting state of the
catalyst. Generally, the catalytic Wittig reaction proceeds in four steps: reduction of the
phosphane oxide 4a-A, nucleophilic attack of the phosphane 4a-B to form a phosphonium salt
4a-C, generation of ylid 4a-D by deprotonation of the phosphonium salt and subsequent reaction
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with the present electrophile to obtain the olefination product and regenerate the phosphane oxide
(Scheme 3). We prepared the intermediates of the reaction cycle separately and measured the
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corresponding P NMR spectra. After synthesizing the phosphetanium salt 4a-C, single crystals
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suitable for X-ray crystallography were obtained (Figure 1).
Figure 1. Molecular structure of 4a-C in the crystal. Displacement ellipsoids correspond to
30% probability. Only one molecule of the asymmetric unit is depicted for clarity. CCDC
1906079 contains the supplementary crystallographic data.37
The molecular structure of the phosphonium salt confirms the anti-orientation of the methyl
groups in the major isomer.31 The successful deprotonation of 4a-C and the formation of the
1
1
phosphonium ylid 4a-D was confirmed by H and H{31P} NMR.37 Notably, the phosphonium
salt showed poor solubility in THF at room temperature, but the results of the solvent screening
suggest that this is not an issue under the reaction conditions. We then performed the model
reaction with higher catalyst loading of 10 mol% in a Young NMR tube and measured a NMR
spectrum after 1 h. While product formation was observed and the conversion was not complete,
1
the only catalyst species observed was the phosphetane oxide. After 24 h, H NMR showed
complete conversion of the aldehyde and the 31P NMR showed several unknown phosphorus
species. The reduction of the phosphane oxide is reported as the rate determining step in the
catalytic Wittig reaction in a number of publications and the in situ NMR experiment indicates
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that this is also the case for the phosphetane oxide catalyst.37 This was initially a surprise due to
the fact that only a slightly improved result was achieved using DPDS instead of phenyl silane as
the much more active reductant (see Table 2, entries 7 and 8). Therefore, the reduction of
phosphane oxide 4a with different reduction systems was monitored by 31P NMR over 12 h
(Figure 2). Interestingly, even in large excess (50 equivalents) phenyl silane did not fully reduce
4a-A in this time frame. In contrast, reduction was complete using DPDS as the reductant at the
time of the NMR measurement. Subsequently, the influence of base on the reduction rate was
investigated and a tremendous rate increase was observed, achieving full conversion to the
phosphane 4a-B after 4 h. We suspected the in situ formation of siloxanes from phenyl silanes
with residue water to play a key role in accelerating the reaction, but the addition of water had no
major effect. A potential induction phase of the catalytic Wittig reaction due to initially slow
reduction of the phosphane oxide was not observed.37 While other possible methods of activation,
e. g. Lewis basic activation of the silane or Brønsted acid activation of the phosphane oxide with
an ammonium salt cannot be ruled out at this point, we believe that the in situ formation of
siloxanes is the main reason for an efficient reaction with phenyl silane. This an important insight
into the possible influence of reagents and traces of water on the P(III)/P(V) redox cycling
mechanism in general.
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Figure 2. Investigation into the reduction of phosphetane oxide 4a-A to phosphetane 4a-B by
31P NMR.
Due to lower yields obtained when converting secondary alkyl halides or electron rich
aldehydes, we investigated the resting state of the catalyst when converting methyl 2-
bromopropanoate (2e) as the substrate. Interestingly, the main phosphorus species detected under
reaction conditions was the free phosphane (4a-B), indicating a change of the rate determining
step. Trimethoxy benzaldehyde was not a suitable substrate for the reaction at room temperature
31
and the in situ P NMR spectroscopy showed multiple species, indicating side reaction of the
ylid when no suitable electrophile is present. Furthermore, the insignificant effect of Brønsted
acid addition suggests an increasing role of the other reaction steps in the overall reaction kinetics
for all substrates.37 As the last step of the reaction, the high stereoselectivity of the olefination
was investigated. O’Brien originally proposed a post-olefination isomerization to be the reason
for high E/Z selectivities observed during the catalytic Wittig reaction.5 To investigate this, Z-3a
1
was reacted with the phosphane 4a-B, and the isomerization was monitored by H NMR. Only
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very slow isomerization occurred at room temperature, which indicates that the post-Wittig
reaction isomerization only plays a minor role in the high selectivity.37
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O
Reduction
P Me
P
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O
Me
OMe
Br
Ph
OMe
O
4a-B
31P  29.0
4a-A
31P  53.7
O
2a
3a
Ph
O
Br
Me
O
Me
P
1a
P
OMe
OMe
Deprotonation
4a-D
31P  42.7
4a-C
31P  63.3
Scheme 3. General mechanism of the catalytic Wittig reaction and 31P shifts (in ppm) of the
intermediates.37
Catalytic Wittig Reaction with PMHS. As previously discussed, the use of PMHS as a
terminal reductant is very attractive not only due to the low price of this terminal reductant, but
also in regards to green chemistry.19, 20 It is absolutely essential to develop catalysts that are
working efficiently with PMHS to make the catalytic variant of the Wittig reaction competitive to
the classic Wittig reaction using stoichiometric amount of phosphane.18
Table 3. Optimization of the reaction conditions using PMHS as the terminal reductant for the
synthesis of methyl cinnamate (3a).a
4a
(x mol%)
iPr2NEt (1.5 equiv)
PMHS (5.0 equiv)
O
O
O
OMe
Br
P
+
OMe
Me
O
solvent, T, 24 h
4a
1a
2a
3a
(1.5 equiv)
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Entry
Solvent
T/ °C
x/ mol%
Yield 3a/ %b
E/Zb
6
7
8
9
1
2
3
4
5
6
7
9
THF
25
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5
5
0
-
Toluene
Dioxane
BuOAc
2-MeTHF
BuOAc
Toluene
2-MeTHF
80
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31
58
36
92c
91c
87:13
89:11
88:12
86:14
84:16
87:13
87:13
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a
Reaction conditions: 1a (0.50 mmol, 1.0 equiv), 2a (1.5 equiv), iPr2NEt (1.5 equiv), PMHS
b
(5.0 equiv), phosphane oxide 4a (1–5 mol%), solvent (0.33 M), 25 °C, 24 h. Yields and
selectivities of 3a determined with GC-FID using hexadecane as internal standard. Scale
increased to 2 mmol. Isolated yield is given.
c
While the use of the waste product PMHS is generally preferably to other organosilanes, the
activity is severely decreased and under previously described conditions, no product formation
was observed (Table 3, entry 1). The temperature was increase to 80 °C and the solvent was
switched to the commonly used toluene and dioxane as well as the preferably used renewable
solvents 2-MeTHF and BuOAc (entries 2–5).42, 43 Even at these elevated temperatures reduction
using PMHS was too slow to achieve full conversion and thus we increased the temperature to
100 °C. While the yield obtained using BuOAc was rather low (entry 6), both toluene and 2-
MeTHF performed well and the product was isolated in an excellent yield of over 90% in both
cases (entries 7 and 8). To the best of our knowledge, this is the first time PMHS was
successfully employed in the catalytic Wittig reaction as the terminal reductant.
Conclusion
In conclusion, we present a series of phosphetane oxides as organocatalysts in the catalytic
Wittig reaction of stabilized ylids. This transformation allows for the synthesis of alkenes directly
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from the aldehyde and alkyl halide without preparation of the respective phosphonium salts or
ylids. The reaction is catalytic in phosphorus reagent and avoids large amounts of phosphane
oxide byproduct, which simplifies purification. Differently substituted phosphetane oxides were
synthesized and evaluated in the model reaction of benzaldehyde with methyl bromoacetate at
room temperature using iPr2NEt as the base and phenylsilane as the terminal reductant.
Compared to previous state of the art catalysts for the catalytic Wittig reaction, phosphetane
oxides are more active even at room temperature, which allows for the additive-free conversion
of aldehydes at room temperature using a catalyst loading of 1.0 mol% of a methyl substituted
phosphetane oxide. The reaction conditions were optimized and the Wittig olefination product
was isolated in a yield of 97% with excellent E/Z selectivity. The high isolated yield can be
attributed to the mild reaction conditions under which the catalyst is able to operate, which limits
side reactions. The substrate scope of the methodology was evaluated and in total, 25 olefins
were isolated in yields up to 97%. The scope showed a good compatibility with different
functional groups, but electron rich aldehydes showed lower activity and were isolated in only
moderate yields. The reaction mechanism was investigated and the reaction intermediates were
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characterized by P NMR spectroscopy. In situ NMR studies showed that the reduction of the
phosphane oxide is the rate determining step of the reaction for most substrates. Notably, the
strength of the phosphetane oxide catalyst could be shown by using polymethylhydrosiloxane,
which is a waste product from industry, as the terminal reductant to perform the reaction at
elevated temperatures.
Associated Content
Supporting Information. The following files are available free of charge.
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Additional information on the optimization experiments and extended substrate scope,
mechanistic studies, information on the synthesis of the catalysts and intermediates, NMR spectra
of the synthesized catalysts and substrates, and crystallographic data.
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Author Information
Corresponding Author
*E-Mail for T.W.: thomas.werner@catalysis.de.
ORCID
Thomas Werner: 0000-0001-9025-3244
Lars Longwitz: 0000-0002-2525-4678
Acknowledgements
This research was conducted in the scope of the Leibniz ScienceCampus Phosphorus Research
Rostock.
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Highly active C3PO catalyst: A phosphetane oxide catalyst was employed to efficiently
catalyze the Wittig reaction under mild conditions.
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