First Base-Free Catalytic Wittig Reaction

Article abstract of DOI:10.1021/acs.orglett.5b01352

The first base-free catalytic Wittig reaction utilizing readily available Bu₃P (5 mol %) as an organocatalyst is reported. The initial Michael addition of the phosphine to a suitable acceptor substituted alkene ultimately results in the formation of an ylide which is subsequently converted with an aldehyde. The presented ¹H NMR studies actually reveal evidence for the Michael addition and proposed ylide formation. Under the optimized reaction conditions various maleates and fumarates were converted with aromatic, heteroaromatic, and aliphatic aldehydes to evaluate the scope and limitations of this unprecedented reaction. Notably, maleates and fumarates react in a stereoconvergent fashion. The corresponding products were obtained in up to 95% isolated yield and E/Z-selectivities up to 99:1.

Full text of DOI:10.1021/acs.orglett.5b01352

Letter
pubs.acs.org/OrgLett
First Base-Free Catalytic Wittig Reaction
Marie-Luis Schirmer, Sven Adomeit, and Thomas Werner*
̈
Leibniz-Institut fur Katalyse e.V., Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
*
S Supporting Information
ABSTRACT: The first base-free catalytic Wittig reaction utilizing readily
available Bu P (5 mol %) as an organocatalyst is reported. The initial
3
Michael addition of the phosphine to a suitable acceptor substituted alkene
ultimately results in the formation of an ylide which is subsequently
1
converted with an aldehyde. The presented H NMR studies actually reveal
evidence for the Michael addition and proposed ylide formation. Under the
optimized reaction conditions various maleates and fumarates were
converted with aromatic, heteroaromatic, and aliphatic aldehydes to
evaluate the scope and limitations of this unprecedented reaction. Notably,
maleates and fumarates react in a stereoconvergent fashion. The
corresponding products were obtained in up to 95% isolated yield and
E/Z-selectivities up to 99:1.
arbon−carbon double bonds are essential and ubiquitous
diethyl maleate (1a), followed by a [1,2]-H-shift should
C
functional groups in chemistry, both as feedstock and as
ultimately lead to the corresponding ylide from nonhalide
10
synthetic targets in their own right. One of the most
fundamental transformations for their construction is the
olefination of carbonyl groups. Since its discovery in 1953 by
Wittig and Geissler, the so-called Wittig reaction is probably the
most recognized method for the chemo- and regioselective
compounds under base-free conditions. Subsequent con-
version with an aldehyde 2 should afford succinates 3 and
Bu P=O as a byproduct. The in situ reduction of the phosphine
3
oxide regenerating the phosphine would then close the catalytic
cycle.
1
olefination of carbonyl groups. Over the ensuing years this
Herein, we prove the feasibility of our proposed reaction
sequence and report the first base-free catalytic Wittig reaction.
Since we intended to develop a generally easy to apply protocol
only commercially available phosphines and phosphine oxides
reaction has been extensively studied and employed in
2
3
synthesis even on an industrial scale. A variety of reagents
4
and modifications have emerged. The reaction occurs between
11
carbonyl compounds, usually an aldehyde or ketone, and a
phosphonium ylide to give the corresponding alkene and a
phosphine oxide as a byproduct (Scheme 1).
were selected as catalysts and precatalysts, respectively.
We began our studies with the synthesis of succinate 3a at
defined reaction parameters (Table 1). Most of the employed
The classical Wittig reaction suffers from several drawbacks.
The ylide is usually prepared prior to the olefination by
alkylation of a suitable phosphine and subsequent deprotona4-
tion which requires stoichiometric amounts of a base.
Moreover, the separation of the phosphine oxide waste can
be challenging and sometimes significantly hampers product
purification. This reduces the overall efficiency and atom
catalysts and precatalysts showed no conversion while PBu was
3
identified as the most promising candidate (entry 1, see
Supporting Information). We increased the reaction temper-
ature and screened various silane reducing agents thereby we
kept the hydride equivalents constant (entries 2−5). Phenyl-
silane proved to be the most efficient, and the desired product
3a was obtained in 59% yield (entry 5). Final adjustments of
5
the reaction parameters allowed reducing the catalyst amount
to 5 mol %, still providing the desired product 3a in excellent
economy of this reaction. The first catalytic Wittig-type
reactions have been reported based on tributylarsine and
6
8
4% isolated yield (entry 6). Importantly, control experiments
dibutyl telluride as viable catalysts. In 2009, O’Brien et al.
in the absence of Bu P yielded no product and resulted in the
described the first catalytic Wittig reaction (CWR, in
3
recovery of the starting material.
phosphine) and subsequently further elaborated this method-
7
The above-mentioned results represent to the best of our
knowledge the first base-free catalytic Wittig reaction. More-
over it is an easy access to alkylidene and arylidene succinates
which are commonly prepared via Heck- or Stobbe-type
ology. The catalytic cycle is based on the in situ reduction of
the formed phosphine oxide. This reduction strategy has also8
been applied to the Appel, aza-Wittig, and Staudinger reaction.
Recently, we reported the first asymmetric catalytic Wittig
12
9
reactions. Following the protocol optimizations the substrate
reaction as well as a microwave assisted version. We
envisioned a base-free catalytic Wittig reaction based on a
three-step process depicted in Scheme 2. The Michael addition
Received: May 8, 2015
of a phosphine, e.g. Bu P, to an acceptor substituted alkene, e.g.
3
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01352
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Wittig Reaction
Scheme 3. Conversion of Aromatic Aldehydes 2a−2m with
a
Diethyl Maleate (1a) under Base-Free Wittig Conditions
Scheme 2. Proposed Reaction Sequence for the Base-Free
Catalytic Wittig Reaction
a
Reaction conditions: 1a (1.1 mmol), 2a−2m (1.0 mmol), Bu P
3
(5 mol %), PhSiH (1.0 mmol), toluene (2.0 mL), 125 °C, 24 h.
3
b
Isolated yields are given. E/Z ratios were determined by GC/FID. 5
mol % benzoic acid was added as cocatalyst.
Scheme 4. Conversion of Various Aldehydes 2 with Acceptor
Substituted Alkenes 1 under Base-Free Catalytic Wittig
Conditions
Table 1. Optimization of the Catalytic Base-Free Wittig
Reaction
a
a
temp
(°C)
yield
b
c
entry
Bu3P
silane
equiv
(%)
E/Z
1
2
3
4
5
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
5 mol %
HSi(OMe)3
HSi(OMe)3
HSi(OEt)3
Ph SiH
2.0
2.0
2.0
1.0
0.7
1.0
100
125
125
125
125
125
22
35
17
20
59
95/5
94/6
94/6
95/5
93/7
96/4
2
2
PhSiH3
d
e
6
PhSiH3
84
a
b
1
a (1.2 mmol), 2a (1.0 mmol), toluene (2.0 mL), 16 h. Yield
determined by GC methods using n-hexadecane as an internal
c
d
standard. E/Z ratios were determined by GC/FID. 1a (1.1 mmol),
2
e
4 h. Isolated yield.
scope and limitation had been evaluated. Initially we converted
a
aromatic aldehydes 2a−2m with diethyl maleate (1a) in the
Reaction conditions: 1 (1.1 mmol), 2 (1.0 mmol), Bu P (5 mol %),
3
PhSiH (1.0 mmol), toluene (2.0 mL), 125 °C, 24 h. Isolated yields
are given. E/Z ratios were determined by GC/FID. Dimethyl
fumarate (1c). Diisopropyl fumarate (1d). Bu P (10 mol %), 48 h.
presence of 5 mol % Bu P as the catalyst and 1 equiv of
3
3
b
phenylsilane as the reducing agent at 125 °C for 24 h (Scheme
c
d
3
3
). Under these conditions various donor and acceptor
substituted aldehydes 2a−2m with different substitution
patterns could be converted into the corresponding succinates
substrates 2n−2q were reacted with dimethyl maleate 1b giving
the desired products 3n−3q in good to excellent yields up to
91%. These products were obtained in comparable E/Z-
selectivities which were slightly lower than those observed for
aromatic products 3a−3m.
Moreover furane 3r and thiophene 3s derivatives could be
obtained in 70% and 88% yield, respectively. For both products
the E/Z-selectivities were similar to those obtained for the aryl
compounds 3a−3m. Besides, we tested various acceptor
substituted alkenes 1b−1e in the conversion with 2a to yield
3
a−3m. The products were obtained in good to excellent yields
and very high E-selectivities. Interestingly, p-iodide derivative 3j
was obtained in only 42% yield. However, upon addition of
5
mol % benzoic acid as a cocatalyst the yield could be
improved to 86%. We assume that the addition of the Brønsted
acid on the one hand activates the aldehyde 2 and on the other
13
hand facilitates the in situ reduction of the phosphine oxide.
Subsequently, we studied the conversion of aliphatic 2n−2q
and heteroaromatic aldehydes 2r and 2s (Scheme 4). Aliphatic
B
DOI: 10.1021/acs.orglett.5b01352
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The support of C. Grimmer and M. Hoffmann as well as the
advice from Prof. M. Beller, all from the Leibniz Institute for
Catalysis, is gratefully acknowledged. Dedicated to Prof. Dr.
Uwe Rosenthal on the occasion of his 65th birthday.
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AUTHOR INFORMATION
Corresponding Author
■
11) See Supporting Information for screening results of other tested
*E-mail: thomas.werner@catalysis.de.
commercially available phosphines and phosphine oxides.
C
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Organic Letters
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DOI: 10.1021/acs.orglett.5b01352
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