First Microwave-Assisted Catalytic Wittig Reaction

Article abstract of DOI:10.1002/ejoc.201403113

We introduce a novel catalytic Wittig reaction based on an inexpensive and readily available phosphane oxide as a precatalyst. The performance of the reaction under microwave irradiation led to significantly improved yields and reaction rates relative to those obtained under conventional heating. Moreover, herein we enclose the first example of the asymmetric catalytic Wittig reaction based on a chiral phosphane as the catalyst.

Full text of DOI:10.1002/ejoc.201403113

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403113
First Microwave-Assisted Catalytic Wittig Reaction
Thomas Werner,*[a] Marcel Hoffmann,[a] and Sunetra Deshmukh[a]
Keywords: Organocatalysis / Homogeneous catalysis / Olefination / Wittig reactions / Alkenes / Microwave chemistry
We introduce a novel catalytic Wittig reaction based on an
rates relative to those obtained under conventional heating.
inexpensive and readily available phosphane oxide as a pre- Moreover, herein we enclose the first example of the asym-
catalyst. The performance of the reaction under microwave
irradiation led to significantly improved yields and reaction
metric catalytic Wittig reaction based on a chiral phosphane
as the catalyst.
duction of phosphane oxides to the corresponding phos-
phanes under various conditions.[13] Nevertheless, catalytic
Wittig reactions might be economically and ecologically
beneficial, as presented by Huijbregts et al. in a recently
published life-cycle assessment (LCA).[5a]
Introduction
Alkenes represent an essential class of key intermediates
as well as industrial feedstock and synthetic target in or-
ganic chemistry.[1] Since its discovery, the Wittig reaction[2]
and related transformations[3] have become the most fre-
quently employed and general methods for the chemo- and
regioselective preparation of alkenes and have even been
performed on industrial scale.[4] The major economic and
environmental drawback in classic Wittig reactions is the
formation of a phosphane oxide that hampers purification
of the product and lowers the atom economy of the reac-
tions dramatically.[5] In this context, many ingenious solu-
tions to the separation problem and recycling of the phos-
phane oxide have been developed on both the laboratory
and industrial scales.[6] However, the inert phosphane ox-
ides are often discarded as waste products, as their re-
duction requires harsh reaction conditions or the employ-
ment of highly toxic phosgene.[7] Hence, the intrinsic inef-
ficiency remains, which makes the Wittig reaction economi-
cally and practically disfavored on a large scale or if chiral
phosphanes[8] would be employed. Promising alternatives
are processes involving the in situ reduction of the phos-
phane oxide and, hence, the utilization of catalytic amounts
of the corresponding phosphane (Scheme 1).[9] The first
reported catalytic Wittig-type reactions relied on organo-
arsenic[10] and organotellurium compounds[11] as viable cat-
alysts. Even though O’Brien et al. recently reported the first
Wittig reaction that is catalytic with respect to the phos-
phane, examples remain rare considering the immense im-
portance of this reaction.[12] It should be emphasized that
the use of catalytic amounts of a phosphane still requires a
stoichiometric reductant. Silanes are one class of reducing
agents that are frequently employed for the efficient re-
Scheme 1. Catalytic Wittig reaction (CWR) based on the in situ
reduction of a phosphane oxide.
The objective of this work was to develop a fast and ef-
ficient catalytic Wittig reaction (CWR) based on commer-
cially available and easy-to-handle phosphane oxides. This
task is challenging, as a process catalytic with respect to the
phosphane relies on the completion of four consecutive
steps proceeding simultaneously and chemoselectively in
[a] Leibniz-Institut für Katalyse e.V., Universität Rostock,
Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
E-mail: Thomas.Werner@catalysis.de
http://www.catalysis.de/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403113.
Scheme 2. The four reaction steps in the catalytic Wittig reaction.
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Eur. J. Org. Chem. 2014, 6873–6876

T. Werner, M. Hoffmann, S. Deshmukh
SHORT COMMUNICATION
one reaction vessel (Scheme 2). We chose the conversion of Table 1. Effect of selected reaction parameters on the catalytic Wit-
tig reaction.[a]
benzaldehyde (1a) with methyl bromoacetate (2a) to form
methyl phenylpropenoate (3a) as a model reaction to estab-
lish a new CWR process. The first step is the in situ forma-
tion of a phosphonium salt from alkyl halide 2a and a
phosphane as a precursor for the generation of a phos-
phorus ylide by deprotonation with a suitable base in the
second step. Subsequently, the formed ylide reacts with 1a
in the Wittig reaction to generate desired product 3a and
the phosphane oxide as a byproduct. The last step requires
the chemoselective reduction of the phosphane oxide in the
presence of 1a and 3a to regenerate the phosphane and to
close the catalytic cycle.
[a] Screening reactions were performed on a 1.5 mmol scale.
R3P=O (10 mol-%), benzaldehyde (1a, 1.0 equiv.), methyl bromo-
acetate (2a, 1.2 equiv.), silane (2.0 equiv.), butylene oxide, toluene
Results and Discussion
(0.75 mL), 150 °C. [b] Yields and E/Z ratios were determined by
GC with hexadecane as an internal standard and were performed
Given that the performance of chemical reactions under
microwave conditions is often beneficial, we envisioned that
dielectric heating might be of considerable advantage in
CWRs.[14] A series of phosphanes and phosphane oxides
were tested in combination with various silanes, bases, and
in duplicate. [c] Na2CO3 was used as a base instead of butylene
oxide. [d] Conventional heating. [e] Dioxane (0.75 mL).
Subsequent to the optimization of the protocol, we
solvents to identify an efficient catalyst and reaction condi- evaluated the scope and limitations of the microwave-as-
tions. Because alkylphosphanes in particular are often air sisted catalytic Wittig reaction (Table 2). Initially, we
sensitive, we generally employed phosphane oxides as pre- studied the conversion of various aromatic aldehydes with
catalysts. The reaction was performed under conventional methyl bromoacetate (2a) to corresponding alkenes 3a–j,
heating as well as under microwave dielectric heating which were obtained with excellent stereoselectivity in
(MWI) in the temperature range from 100 to 150 °C. From yields up to 76%. Notably, the yields of 3i for the conver-
our initial screening, tributylphosphane oxide was identified sion of aldehyde 1i with methyl acetate derivatives 2 (X =
as a promising precatalyst in combination with 1,2-butylene Cl, Br, I) decreased in the order BrϾClϾI. Similar results
oxide as a capped base and phenylsilane as a reducing agent were obtained for the conversion of aliphatic and heteroaro-
(Table 1, entry 1). The base is actually generated by ring matic aldehydes. Aliphatic products 3k–n were obtained in
opening of the oxirane by the bromide anion of the in situ up to 83% yield. Remarkably, partial double-bond isomer-
formed phosphonium salt. Under the same reaction condi- ization of 3l was observed. Most probably this is caused by
tions, Na2CO3 proved to be unsuitable as a base (Table 1, addition of the nucleophilic phosphane to the α,β-unsatu-
entry 2). The main advantage of the epoxide application is rated ester and subsequent elimination.[16] Furan derivative
the inhibition of possible side reactions induced by the base. 3n, which was originally produced from a renewable feed-
Moreover, the corresponding halohydrine might be easily stock, was obtained in 73% yield, whereas the conversion
removed owing to its low volatility, and it may possibly be of thiophenecarbaldehyde and benzofuranyl carbaldehyde
recycled with inorganic bases.[15] Conventional heating led with 2a led to alkenes 3o and 3p in 58% yield. Utilization
to a yield that was significantly lower than that obtained of alternative halogen substrates 2 was accomplished, for
with dielectric heating (Table 1, entry 3). Utilization of the example, to afford benzyl derivative 3q (EWG = m-
phospholane oxide derivative, previously reported by F3CC4H4) and acetonitrile derivative 3r (EWG = CN) in
O’Brien et al. to be an efficient catalyst, did not yield de- moderate to good yields.
sired product 3a (Table 1, entry 4). It should be emphasized
We also explored the possibility of employing this
that in the absence of a catalyst no product formation was method in catalytic asymmetric Wittig reactions.[17] There
observed (Table 1, entry 5). Utilization of triphenylphos- are only a few stoichiometric variants of this reaction.[18]
phine oxide gave 3a in 10% yield (Table 1, entry 6). The However, a catalytic asymmetric version has not been re-
advantage of Bu3P=O as the precatalyst in our case might ported so far, to the best of our knowledge. Hence, we pre-
be explained by steric effects. Further optimization with re- pared prochiral carbonyl compound 4 (Scheme 3).[19] We
spect to the solvent led to dioxane as the solvent of choice envisioned that selective olefination should lead to enantio-
(Table 1, entry 7). An increase in the E selectivity with a merically enriched 5. Initial experiments revealed that the
longer reaction time suggests isomerization subsequent to intramolecular stereoselective olefination of 4 in the pres-
olefination (Table 1, entries 1, 3, and 7). A feasible explana- ence of catalytic amounts of phosphanes is feasible, in gene-
tion is a reaction sequence involving the Michael addition ral. In the presence of various chiral monophosphanes, the
of the in situ formed phosphane, isomerization, followed by enantiomeric excess was Յ30%. Nevertheless, the applica-
elimination, as suggested by O’Brien and co-workers.[12a]
tion of the diphosphane (+)-1,2-bis[(2S,5S)-2,5-dimethyl-
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First Microwave-Assisted Catalytic Wittig Reaction
Table 2. Scope and limitations of the MW-assisted catalytic Wittig enantiomeric ratio of 81:19. Moreover, this is remarkable
reaction.[a]
as conversion of ketones in CWRs has not been reported
before.
Conclusions
In summary, a microwave-assisted catalytic Wittig reac-
tion based on commercially available tributylphosphane
oxide as a precatalyst was established. Under the optimized
reaction conditions, good yields and excellent E/Z selectivi-
ties for aromatic, heteroaromatic, and aliphatic olefins were
in general achieved. Furthermore, we reported a stereo-
selective catalytic Wittig reaction by utilizing a chiral phos-
phane, which resulted in an enantiomerically enriched alk-
ene in a good yield of 39% with a good enantiomeric ratio
of 81:19. This represents the first microwave-assisted cata-
lytic Wittig reaction as well as asymmetric catalytic Wittig
Reaction.
Experimental Section
Microwave-Assisted Catalytic Wittig Reaction (3a as an Example):
A 10 mL microwave vial equipped with a stirring bar was charged
with Bu3P=O (31 mg, 0.14 mmol, 10 mol-%), benzaldehyde
(151 mg, 1.42 mmol), methyl bromoacetate (261 mg, 1.70 mmol),
PhSiH3 (230 mg, 2.13 mmol), 1,2-epoxybutane (205 mg,
2.84 mmol), and dioxane (0.7 mL). The vial was then purged with
argon and sealed with a septum, and the mixture was heated by
microwave irradiation at 150 °C for 3 h (150 W). After cooling to
23 °C, dioxane (10 mL) and satd. aq. NH4F solution (3 mL) were
added to the mixture, which was stirred at 23 °C for another 16 h.
The mixture was diluted with H2O (25 mL), and the aqueous layer
was extracted with Et2O (3ϫ 10 mL). The combined organic layer
was dried with MgSO4 and all volatiles were removed in vacuo.
Purification was performed by flash chromatography (SiO2, hex-
ane/EtOAc, 20:1), which afforded 3a (152 mg, 66%, E/Z = 96:4) as
a colorless oil.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H NMR and
13C NMR spectra.
Acknowledgments
[a] Reactions were conducted on
a 1–2 mmol scale. R3P=O
(10 mol-%), aldehyde 1 (2.0 m in dioxane, 1.0 equiv.), 2 (1.2 equiv.),
PhSiH3 (1.5 equiv.), butylene oxide (2.0 equiv.), 3 h, yields of iso-
lated products are given. E/Z ratio was determined by 1H NMR
spectroscopy. [b] 2 h. [c] Bu3PO (15 mol-%). [d] 1 h.
Financial support from the Deutsche Forschungsgemeinschaft
(DFG) (WE 3605/3-1) is gratefully acknowledged.
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Received: August 19, 2014
Published Online: September 24, 2014
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