Novel Base-Free Catalytic Wittig Reaction for the Synthesis of Highly Functionalized Alkenes

Article abstract of DOI:10.1002/chem.201503744

A highly efficient catalyst system for base-free catalytic Wittig reactions has been developed and optimized. Initially, several potential (pre)catalysts as well as different silanes as reducing agents were screened. A system based on a readily available

Full text of DOI:10.1002/chem.201503744

DOI: 10.1002/chem.201503744
Full Paper
&
Wittig Reactions |Hot Paper|
Novel Base-Free Catalytic Wittig Reaction for the Synthesis of
Highly Functionalized Alkenes
Marie-Luis Schirmer, Sven Adomeit, Anke Spannenberg, and Thomas Werner*[a]
Abstract: A highly efficient catalyst system for base-free cat-
alytic Wittig reactions has been developed and optimized.
Initially, several potential (pre)catalysts as well as different si-
lanes as reducing agents were screened. A system based on
a readily available phosphine oxide as precatalyst and trime-
thoxy silane as reducing agent proved to be optimal. The
effect of various Brønsted acidic additives was studied. Sub-
sequently, the reaction conditions were optimized and stan-
dard reaction conditions were determined. Under these con-
ditions the scope of this new protocol was evaluated. Nine
activated olefins and 33 aldehydes were converted into 42
highly functionalized alkenes. Notably, aromatic, aliphatic as
well as heteroaromatic aldehydes could be converted, giving
the desired products in isolated yields up to 99% and with
good to excellent E/Z selectivities. These results underline
the remarkable efficiency of this protocol considering the
complexity of the reaction mixture and the four reaction
steps that proceed in parallel in one pot.
quently elaborated this methodology further.[10] Most recently,
Plietker et al. utilized a highly active iron catalyst for the reduc-
tion of phosphine oxides within the context of catalytic Wittig
reactions.[11] Our interest in the utilization of phosphorus-based
organocatalysts[12] has led to several contributions to this
field;[13] inter alia, we reported the first catalytic asymmetric
Wittig reaction.[14] An attractive route to highly functionalized
alkenes 3 is the base-free Wittig reaction, which is based on
the direct phosphine-mediated olefination of an aldehyde
1 with an electron-deficient alkene 2 through formation of
a phosphorus ylide in situ (Scheme 1).[15] This strategy has
Introduction
Alkenes are ubiquitous compounds in organic chemistry. They
serve as feedstock for further chemical transformations as well
as synthetic targets in their own right. In organic synthesis, car-
bonyl olefinations are fundamental and commonly employed
methods for the preparation of alkenes.[1] Since its discovery in
1953 by Wittig and Geissler, the Wittig reaction has become
the most recognized method for the chemo- and regioselec-
tive olefination of carbonyl groups.[2] This reaction has been in-
tensively studied and also employed on an industrial scale.[3]
Moreover, a variety of reagents and numerous modifications of
the Wittig reaction have emerged over the past six deca-
des.[1b,4] Nevertheless, the formation of phosphine oxides as by-
products in these reactions often hampers the purification of
the desired products and leads to an increase in the associated
costs because of low atom economy.[5] One option to over-
come this intrinsic inefficiency is the development of catalytic
Wittig reactions that exploit a redox-based strategy. The key
step in this reaction is the in situ reduction of the formed
phosphine oxide by a suitable silane reducing agent enabling
the employment of catalytic amounts of phosphine.[5a,6] This
strategy has also been applied to the Appel, aza-Wittig, and
Staudinger reaction.[6a,7] First examples in this respect on cata-
lytic Wittig-type reactions have been described based on tribu-
tylarsine and dibutyl telluride as viable catalysts.[8] Notably,
O’Brien et al. reported the first Wittig reaction that was catalyt-
ic in phosphine utilizing this concept.[9] The same group subse-
Scheme 1. Base-free Wittig reaction yielding highly functionalized alkenes.
been used for the synthesis of trisubstituted alkenes for exam-
ple, by the groups of McCombie,[15c] Jiang,[15f] and Argade.[15e]
Notably, neither a base nor a halogen substrate is necessary,
which leads to a remarkable increase in atom economy com-
pared with conventional ylide formation in the classic Wittig
reaction.
Recently, we reported the first catalytic version of this reac-
tion utilizing tri-n-butylphosphine as the catalyst.[13b] We envi-
sioned developing a novel base-free catalytic Wittig reaction
that operates under much milder conditions. Therefore, we in-
tended taking advantage of the fact that Brønsted acids facili-
tate the reduction of the thermodynamically highly stable
phosphine oxide under comparably mild conditions.[16] More-
[a] M.-L. Schirmer, S. Adomeit, A. Spannenberg, T. Werner
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
E-mail: thomas.werner@catalysis.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503744.
Chem. Eur. J. 2016, 22, 2458 – 2465
2458
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
over, the aim was to identify a suitable (pre)catalyst that is
readily available as well as stable under ambient conditions.
nificantly from 56 to 9%, which indicated the high impact of
the Brønsted acidic additive and the potential for further opti-
mization of this catalytic system. The hydrogenated derivative
previously reported for catalytic Wittig reactions by O’Brien
and co-workers only gave 4%.[9] The same group observed
a catalytic effect of Brønsted acids, for example benzoic acid,
in “classic” catalytic Wittig reactions (Table 1, entry 8).[10c] Subse-
quently, we evaluated other reducing agents in combination
with precatalyst 4. Polymethylhydrosiloxane (PMHS) showed
no significant conversion into the product whereas triethoxysi-
lane and dimethoxymethylsilane gave 3aa in 31 and 27%
yield, respectively (entries 9–11). Phenyl- and diphenylsilane
have previously been reported to be efficient reducing agents
in PIII/PV based catalytic processes. In the presence of those re-
ducing agents, product 3aa was obtained in 26 and 28%, re-
spectively, whereas Ph3SiH proved to be unsuitable (en-
Results and Discussion
We initially screened various phosphines and phosphine oxides
as potential (pre)catalysts (10 mol%) in the conversion of ben-
zaldehyde (1aa) with diethyl maleate (2a) as a benchmark re-
action (Table 1). Based on our previous work on catalytic Wittig
Table 1. Screening of phosphines and phosphine oxides as (pre)catalysts
for the base-free catalytic Wittig reaction.[a]
Entry
(Pre)catalyst
Silane
Yield [%][b]
E/Z[c]
1
2
3
4
5
–
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
0
13
32
0
–
Table 2. Screening of Brønsted acids as additives in the base-free catalyt-
ic Wittig reaction.[a]
Me3P
Bu3P
tBu3P
Ph3P
92:8
94:6
–
Entry
Additive
pKa in water
Yield [%][b]
E/Z[c]
0
–
1
2
3
4
5
6
7
8
–
--
9
59
44
52
62
62
55
6
>99:1
88:12
87:13
87:13
85:15
87:13
83:17
>99:1
–
6
(MeO)3SiH
(MeO)3SiH
(MeO)3SiH
14
56 (9)[d]
4
79:21
88:12
PhCO2H
4.20[17]
4.36[17]
4.48[18]
3.93[19]
4.16[20]
3.41[21]
1.62[22][e]
À12[23]
3.88[24],[e]
3.61[25][f]
3.40[26][f]
pMePhCO2H
pOMePhCO2H
pClPhCO2H
pFPhCO2H
pNO2PhCO2H
MeSO3H
7
4
8[e]
>99:1
9
4
4
4
4
4
4
(EtO)3SiH
(MeO)2MeSiH
PMHS[f]
PhSiH3
Ph2SiH2
31
27
6
25
28
0
87:13
85:15
100:0
84:16
85:15
–
10
11
12
13
14
9
CF3SO3H
0
10
11
12
(PhO)2PO2H
isophthalic acid[d]
terephthalic acid[d]
10
49
14
>99:1
80:20
>99:1
Ph3SiH
[a] Reaction conditions: 1aa (1.0 mmol, 1.0 equiv), 2a (1.1 equiv),
4
[a] Reaction conditions: 1aa (1.0 mmol, 1.0 equiv), 2a (1.2 equiv),
10 mol% (pre)catalyst, (MeO)3SiH (2.6 equiv), toluene (2.0 mL), 75–1008C,
3 h. Note: 1aacontained traces of PhCO2H (ꢀ1 mol%). [b] Yield was de-
termined by GC-FID with hexadecane as internal standard. [c] E/Z ratios
were determined by GC-FID analysis. [d] Yield when freshly distilled ben-
zaldehyde (1aa) was used. [e] Phosphine oxide was employed as a mixture
of diastereoisomers (d.r. 58:42). [f] Polymethylhydrosiloxane (PMHS).
(0.05 equiv), additive (0.05 equiv), (MeO)3SiH (4.0 equiv), toluene (2.0 mL),
1008C, 3 h. Note: Freshly distilled benzaldehyde (1aa) was employed.
[b] Yield was determined by GC-FID with hexadecane as internal stan-
dard. [c] E/Z ratios were determined by GC-FID analysis. [d] 2.5 mol%.
[e] DMSO. [f] pKa1.
Table 3. Optimization of the reaction conditions for the base-free catalyt-
ic Wittig reaction utilizing phospholene oxide 4 as precatalyst.[a]
reactions, (MeO)3SiH was utilized as reducing agent.[13a] Nota-
bly, no product formation was observed after 3 h at 1008C in
the absence of a (pre)catalyst (entry 1). Me3P gave the desired
product in 13% yield (entry 2). In the presence of Bu3P, which
has previously been reported as a stoichiometric reagent[15c,e]
and catalyst,[13b] this reaction gave 3aa in 32% yield. In con-
trast, tBu3P and air stable Ph3P showed no conversion into 3aa
(entries 4 and 5). In the presence of 2-phenylisophosphindoline
2-oxide, which has been reported to be an efficient (pre)cata-
lyst for catalytic Wittig reactions[13a] of aldehydes and methyl
bromo acetate, the product 3aa was obtained in a yield of
14% (entry 6). However, in the presence of readily available
phospholene 4, a satisfactory yield of 56% was achieved under
the screening conditions (entry 7).
Entry PhCO2H
[equiv][b]
(MeO)3SiH
[equiv]
T
t
Yield
E/Z[d]
[8C] [h] [%][c]
1
2
3
4
5
6
7
8
9
0.05
0.05
0.05
0.025
0.01
0.05
0.05
0.05
0.05
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3.0
2.0
100
100
3
7
59
92
88:12
87:13
88:12
89:11
89:11
88:12
>99:1
88:12
87:13
100 14 >99
100 14
100 14
75 14
50 14
100 14 >99[e]
100 14 88
97
81
70
17
[a] Reaction conditions: 1aa (1.0 mmol, 1.0 equiv), 2a (1.1 equiv), catalyst
4 (0.05 equiv), additive (0.01–0.05 equiv), (MeO)3SiH (2.0–4.0 equiv), tolu-
ene (2.0 mL), 75–1008C, 3–14 h. [b] If not otherwise stated 5 mol% of the
additive was employed. [c] Yield was determined by GC-FID with hexade-
cane as internal standard. [d] E/Z ratios were determined by GC-FID analy-
sis. [e] In the absence of catalyst 4 no product formation was observed.
Given that benzaldehyde (1aa) contained traces of benzoic
acid, we repeated the experiment with freshly distilled benzal-
dehyde (1aa) and 4 as the precatalyst. The yield dropped sig-
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2459
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tries 12–14). We then focused on the effects of different
Brønsted acidic additives to promote the in situ reduction of
the phosphine oxide to the phosphine (Table 2). Recently
Beller et al. reported that diaryl phosphate derivatives are suit-
able catalysts for this reaction.[16] We assumed that the pKa of
the acid might have a significant impact on the outcome of
the reaction. Notable, when freshly distilled 1aa was utilized in
the absence of an additive, 3aa was obtained in only 9% yield
(entry 1). However, when 5 mol% benzoic acid was employed
the yield increased to 59% (entry 2). We tested various benzoic
acid derivatives (5 mol%) with different pKa values as additives.
Thus, the desired product 3aa was obtained in yields between
44 and 62% (entries 3–7).
Table 4. Substrate scope for the conversion of aryl aldehydes 1aa and 1ab
with activated alkenes 2a–i.[a]
Entry
1
Product
Yield [%][b]
93
E/Z[c]
3aa
3ab
3ac
3ad
87:13
2
87
87
98
88:12
88:12
87:13
In contrast, strong acids such as methanesulfonic acid or tri-
fluoromethanesulfonic acid led to yields of less than 10%
(Table 2, entries 8 and 9). Diaryl phosphate, which showed
good catalytic activity in the reduction of phosphine oxides, in-
terestingly gave 3aa in only 10% yield (entry 10).[16] Isophthalic
and terephthalic acid gave the desired product in 49 and 14%,
respectively. Further optimizations were performed with readily
available and nonhazardous benzoic acid because the yields
were not significantly improved with other additives (Table 3).
The extension of the reaction time led selectively to complete
conversion into the desired product 3aa after 14 h (entries 1–
3). Reduction of the catalyst amount to 2.5 mol% still gave the
desired product in 97% (entry 4). Further reduction to 1 mol%
led to a significant drop in yield to 81% (entry 5). The reduc-
tion of the reaction temperature to 75 and 508C, respectively,
led to a decrease in yield to 17% (entries 6 and 7). Finally, we
varied the amount of silane and found that the amount could
be lowered to 3.0 equivalents without loss of efficiency (en-
tries 8 vs. 3); further reduction to 2.0 equivalents led to the for-
mation of 3aa in only 88% yield (entry 9).
3
4[d]
5
6
7
3ae
3af
3ag
91
95
99
99:1
99:1
96:4
8
9
3ah
3ai
51 (15)[e]
>99:1
>99:1
69
Based on the screening and optimization studies, we deter-
mined standard reaction conditions and subsequently evaluat-
ed the substrate scope for the conversion of various aromatic
aldehydes 1 with electron-deficient alkenes 2. Initially, we stud-
ied the conversion of benzaldehyde (1aa) with activated al-
kenes 2a–j (Table 4). Outstandingly, the desired highly func-
tionalized alkenes 3aa–aj were obtained in yields up to 99%
with very good E selectivity. Benzaldehyde 1aa could be con-
verted easily with maleates 2a–c and fumarate 2d (entries 1–
4). The products were obtained in similar E/Z selectivity, which
is associated with the stereoconvergent nature of the reac-
tion.[11] Even maleimides 2e–g could be converted and the cor-
responding products 3ae–ag were obtained in excellent yields
up to 99% and with E/Z selectivities up to 99:1 (entries 5–7).
Moreover, we converted unsymmetrically substituted activated
alkenes 2h and 2i and fumaric acid monomethyl ester (2j)
with 1aa. Whereas the latter gave no conversion, product 3ah
could be obtained in 51% yield and excellent E selectivity. The
respective regioisomer was observed in 15% yield (entry 8).
The conversion of 2h and 2i with benzaldehyde (1aa) and
1ab, respectively, gave the desired products 3ai–aj in good
yields and E/Z selectivities of >99:1 (entries 9 and 10).
10
3aj
67
>99:1
[a] Reaction conditions: 1aa or 1ab (1.0 equiv), 2a–i (1.1 equiv), catalyst 4
(0.05 equiv), (MeO)3SiH (3.0 equiv), toluene (2.0 mL), 1008C, 14 h. [b] Isolated
yield. [c] E/Z ratios were determined by GC-FID analysis. [d] Diisopropyl fu-
marate (2d; 1.1 equiv) was used. [e] The respective regioisomer.
ate (2b) under the standard reaction conditions (Table 5). Thus,
a broad range of substituted benzaldehydes as well as naph-
thaldehyde (1ar) were converted. The conversion of ortho-,
meta-, and para-methyl substituted benzaldehyde (1ac–ae)
showed no significant effect of the substitution pattern on the
E/Z selectivity. However, the yield of the para-substituted prod-
uct 3am was slightly higher than for the o-methyl derivative
3ak, which might be associated with steric interactions (en-
tries 1–3). The conversion of para-substituted aldehydes 1af–al
generally gave excellent yields of 75–97% and comparable E/Z
selectivities, irrespective of the nature of the substituent (en-
tries 4–10). Apparently the electronic properties of the sub-
stituents have no significant impact on either the yield or ste-
We turned our attention to the carbonyl substrate and con-
verted aryl substituted aldehydes 1ac–ar with dimethyl male-
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2460
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1bd–bf gave the olefination products in 80–93% yield. How-
ever, the conversion of acetal protected compound 1bg gave
trisubstituted alkene 3bg only in moderate yield of 65%,
whereas the conversion of cyclic substrates 1bh and 1bi led
to the desired products in 67 and 75% yield, respectively (en-
tries 7–9). Piperidine derivative 1bj could also be converted
into the corresponding alkene 3bj in a yield of 37% and with
moderate E/Z selectivity (entry 10). Notably, the stereoselectiv-
ity in the conversion of aliphatic substrates was, in general,
only moderate.
Table 5. Substrate scope for aromatic aldehydes under base-free catalytic
Wittig conditions.[a]
Entry
1
Product
Yield [%][b]
85
E/Z[c]
3ak, o-Me
91:9
Finally, we studied the substrate scope with respect to heter-
oaromatic aldehydes 1ca–cf (Table 7). Fortunately, furane 1ca
and benzofurane 1cb were readily converted with 2b under
our standard reaction conditions to yield 3ca and 3cb in 98
and 85% yield, respectively (entries 1 and 2). Sulfur analogues
3cc and 3 cd were obtained in comparable yields and selectivi-
ty. The desired heteroaryl functionalized alkenes 3ba–bd were
obtained in yields up to 98%. The conversion of substrates
containing nitrogen heterocycles proved to be difficult. Pyrrol
derivative 1ce and 2-quinolinecarboxaldehyde (1cf) could also
be converted, although the obtained yields of 51 and 24%, re-
spectively, were rather disappointing.
2
3
3al, m-Me
3am, p-Me
89
96
90:10
90:10
4
3an
97
94
87
93
93
75
92
86
89:11
87:13
93:7
5
3ao
6
3ap
7
3aq
89:11
91:9
Notably, the previously unknown compound (E)-3cd could
be obtained as colorless crystals that were suitable for X-ray
crystallographic analysis (Figure 1).
8
3ar
9
3as
93:7
10
11
3at
89:11
88:12
3au, X=F
12
13
14
3av, X=Cl
3aw, X=Br
3ax, X=I
93
91
93
89:11
89:11
87:13
15
16
3ay
3az
87
94
94:6
Figure 1. ORTEP representation of the molecular structure of (E)-3cd in the
crystal. Only one of the two molecules of the asymmetric unit is depicted.
Displacement ellipsoids correspond to 30% probability (see the Supporting
Information for crystallographic data).
87:13
[a] Reaction conditions: 1ac–ar (1.0 equiv), 2b (1.1 equiv), catalyst
4
(0.05 equiv), (MeO)3SiH (3.0 equiv), toluene (2.0 mL), 1008C, 14 h. [b] Isolated
yield. [c] E/Z ratios were determined by GC-FID analysis.
The putative catalytic cycle for the base-free catalytic Wittig
reaction is based on four consecutive reaction steps
(Scheme 2, I–IV). The key step is the reduction of precatalyst 4
to the corresponding phosphine 5 (I). This is probably facilitat-
ed by the Brønsted acidic additive.[10c,13b,16] In some cases we
observed the formation of hexamethoxydisiloxane as a byprod-
uct of the reduction process, which was detected by GC-MS
analysis.[27] This has been previously reported when (MeO)3SiH
was utilized as a reducing agent.[13a] The second step, the Mi-
chael addition of the phosphine to the activated alkene for ex-
ample, 2b, leads to an ester enolate (II). This is supported by
1H NMR experiments which show rapid phosphine-mediated
isomerization of maleate 2b to the respective fumarate at
1008C and even at 238C (see below). Subsequently the ylide is
formed by a proton shift, which might also be catalyzed by
reoselectivity of the reaction under standard conditions. A sim-
ilar result was obtained for halogen products 3au–ax, which
were obtained in excellent yields of 86–93% and with high E
selectivities (entries 11–14). Moreover, the reaction of 3-formyl-
benzonitrile (1aq) or 2-naphthaldehyde (1ar) with maleate 2b
gave the desired products 3ay and 3az in very good E selec-
tivity and yields of 87 and 94%, respectively (entries 15 and
16).
We then focused on the conversion of aliphatic aldehydes
1ba–bj with 2b (Table 6). Different saturated alkyl substituted
substrates 1ba–bc gave the desired products in good to excel-
lent isolated yields (entries 1–3). Even functionalized substrates
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2461
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 6. Substrate scope for aliphatic aldehydes under base-free catalytic
Wittig conditions.[a]
Table 7. Substrate scope for heteroaromatic aldehydes under base-free cat-
alytic Wittig conditions.[a]
Entry
1
Product
Yield [%][b]
98
E/Z[c]
Entry
1
Product
Yield [%][b]
81
E/Z[c]
3ca
3cb
3cc
3cd
84:16
3ba
3bb
76:24
2
3
4
85
95
88
98:2
85:15
87:13
2
3
4
88
93
92
76:24
76:24
76:24
3bc
3bd
5
6
3ce
3cf
51
24
88:12
5
6
3be
3bf
80
86
80:20
77:23
>99:1
[a] Reaction conditions: 1ca–cf (1.0 equiv), 2b (1.1 equiv), catalyst
4
(0.05 equiv), (MeO)3SiH (3.0 equiv), toluene (2.0 mL), 1008C, 14 h. [b] Isolated
yield. [c] E/Z ratios were determined by GC/FID analysis.
7
3bg
65
79:21
8
9
3bh
3bi
67
75
70:30
70:30
10
3bj
37
80:20
[a] Reaction conditions: 1ba–bj (1.0 equiv), 2b (1.1 equiv), catalyst
4
(0.05 equiv), (MeO)3SiH (3.0 equiv), toluene (2.0 mL), 1008C, 14 h. [b] Isolated
yield. [c] E/Z ratios were determined by GC/FID analysis.
the proton source in the reaction system (III).[28] This ultimately
leads to the in situ formation of the ylide, as previously report-
ed for the stoichiometric and catalytic reaction.[13b,15a–f] Notably,
this allows the generation of the usual waste products to be
bypassed and also avoids the commonly required preparation
of a phosphonium salt intermediate as a precursor for ylide
formation. Finally, the Wittig reaction between aldehyde 1aa
and the phosphorous ylide yields the desired highly functional-
ized alkene 3ab, with formation of precatalyst 4 closing the
catalytic cycle (IV).
Scheme 2. Putative mechanism for the base-free catalytic Wittig reaction.
I) Phosphine oxide reduction. II) Michael addition. III) Ylide formation. IV) Ca-
talytic Wittig reaction.
reduction of 4. Notably, at 1008C and even at 238C, almost in-
stant isomerization of 2b into dimethyl fumerate (2k) was ob-
served (Figure 2c and 1d). This might be explained by the pro-
posed Michael addition and subsequent elimination to the
thermodynamically more stable trans alkene 2k. Interestingly,
formation of the ylide could not be observed even after pro-
longed reaction times of 24 h.
We wondered whether ylide formation might be observed
by 1H NMR spectroscopic analysis as previously reported for
the conversion of Bu3P with 2b. Figure 2 shows segments of
1
the H NMR spectra of 2b and catalyst 4 (Figure 2a and 1b).
Phosphine 5 can be easily obtained by Brønsted acid catalyzed
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2462
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
1
Figure 2. a) Segment of the H NMR spectra of 2b. b) Segment of the 1H NMR spectra of 4. Segment of the H NMR spectra of a 1:1 mixture of 4 (3.0 mmol)
and 2b (3.0 mmol) in [D8]toluene: c) at 1008C, ꢀ15 min and d) at 238C, ꢀ15 min.
argon and the reaction mixture was stirred for 14 h at 1008C. The
mixture was then cooled to ambient temperature and all volatiles
Conclusions
were removed in vacuum. The crude product was purified by
We developed a novel, highly efficient protocol for base-free
column chromatography (SiO2; cyclohexene/EtOAc). All volatiles
catalytic Wittig reactions. The commercially available phos-
were removed in vacuum to yield 3.
phine oxide 4 (5 mol%) was identified as an easy to handle
Diethyl 2-benzylidenesuccinate (3aa):[13b] According to the GP, 4
precatalyst. In combination with benzoic acid as additive
(9.9 mg, 0.052 mmol), benzaldehyde (1aa; 106 mg, 1.00 mmol), di-
(5 mol%) and (MeO)3SiH as reducing agent, yields of more
ethyl maleate (2a; 195 mg, 1.13 mmol), PhCO2H (6.1 mg,
0.050 mmol), and (MeO)3SiH (386 mg, 3.16 mmol) were converted
than 99% were achieved in the benchmark reaction under the
optimized conditions (1008C, 14 h). We evaluated the scope of
the reaction by converting nine activated alkenes and 33 alde-
hydes. The remarkable efficiency of this method is underlined
by the excellent yields that were obtained in spite of the com-
plex reaction mixture and the four reaction steps that proceed
in parallel in one pot. In the conversion of aromatic aldehydes
with symmetric and asymmetric maleates and maleimides into
the corresponding highly functionalized alkenes, excellent
yields of up to 99% were obtained. Moreover, the method
proved to be generally applicable to the conversion of various
other aromatic aldehydes giving the desired products in 75–
97% yield and with very high E-selectivities. Aliphatic alde-
hydes also proved to be suitable substrates, giving the respec-
tive products in yields up to 93% albeit with lower stereoselec-
tivity. The conversion of heteroaromatic aldehydes with di-
methyl maleate was also possible, giving the heteroaryl substi-
tuted alkenes in moderate to excellent yields and with high E-
selectivity. The proposed reaction mechanism is supported in
part by experimental evidence.
in toluene (2 mL). After chromatography (SiO2; CH/EtOAc, 20:1)
and removal of all volatiles in vacuum (ꢀ1 mbar, 608C), 3aa
(245 mg, 0.934 mmol, 93%, E/Z=87:13) was obtained as a colorless
1
oil. Rf 0.53 (SiO2; cyclohexane (CH)/EtOAc, 2:1); H NMR (300 MHz,
CDCl3, 278C): d (E isomer)=1.27 (t, J=7.1 Hz, 3H), 1.34 (t, J=
7.1 Hz, 3H), 3.53 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 4.29 (q, J=7.1 Hz,
2H), 7.28–7.44 (m, 5H), 7.90 ppm (s, 1H); 13C{1H} NMR (75 MHz,
CDCl3, 278C): d (E isomer)=14.3 (CH3), 14.3 (CH3), 33.8 (CH2), 61.0
(CH2), 61.2 (CH2), 126.5 (C), 128.7 (2”CH), 128.9 (CH), 129.1 (2”CH),
135.2 (C), 141.8 (CH), 167.5 (C=O), 171.3 ppm (C=O); IR (ATR): n˜ =
2981 (w), 2937 (vw), 2906 (vw), 1733 (m), 1706 (s), 1640 (w), 1576
(vw), 1494 (vw), 1477 (vw), 1465 (vw), 1447 (w), 1412 (vw), 1391
(vw), 1368 (w), 1323 (w), 1265 (m), 1221 (m), 1200 (m), 1176 (s),
1094 (s), 1028 (m), 956 (w), 932 (w), 899 (vw), 860 (w), 834 (w), 810
(vw), 767 (m), 695 cmÀ1 (m); MS (EI, 70 eV): E isomer: m/z (%)=262
(16) [M+], 217 (21) [M+ÀOEt], 216 (13), 189 (11) [M+ÀCO2Et], 188
(19), 133 (11), 117 (69), 116 (52) [M+À2”CO2Et], 115 (100), 91 (10);
HRMS (ESI): m/z calcd for C15H18O4: 262.1200; found: 262.1196 [M+
]; elemental analysis calcd (%) for C15H18O4: C, 68.68, H, 6.92;
found: C, 68.48, H, 6.96.
Dimethyl 2-(3,5,5-trimethylhexylidene)succinate (3bc): According
to the GP, 4 (10 mg, 0.052 mmol), 3,5,5-trimethylhexanal (1bc;
156 mg, 1.10 mmol), dimethyl maleate (2b; 174 mg, 1.21 mmol),
PhCO2H (6.4 mg, 0.052 mmol), and (MeO)3SiH (407 mg, 3.33 mmol)
were converted in toluene (2 mL). After chromatography (SiO2; CH/
EtOAc, 20:1) and removal of all volatiles in vacuum, 3bc (275 mg,
1.02 mmol, 93%, E/Z=76:24) was obtained as a yellow solid. Rf
0.53 (SiO2; CH/EtOAc, 2:1); 1H NMR (300 MHz, CDCl3, 228C): d (E
isomer)=0.89 (s, 9H), 0.94 (d, J=6.7 Hz, 3H), 1.05–1.14 (m, 1H),
1.20–1.29 (m, 1H), 1.57–1.79 (m, 1H), 1.97–2.23 (m, 2H), 3.35 (s,
2H), 3.67 (s, 3H), 3.75 (s, 3H), 6.98 ppm (t, J=7.5 Hz, 1H); 13C{1H}
NMR (75 MHz, CDCl3, 228C): d (E isomer)=22.7 (CH3), 29.5 (CH3),
Experimental Section
For detailed experimental procedures and characterization of all
compounds, see the Supporting Information.
General procedure for the synthesis of succinates 3 (GP): Alde-
hyde 1 (1.0 equiv), substrate 2 (1.1 equiv), PhCO2H (0.05 equiv),
and (MeO)3SiH (3.0 equiv) were added successively to a solution of
3-methyl-1-phenyl-2-phospholen-1-oxide (4; 0.05 equiv) in toluene
(c=0.025 mmolmLÀ1) in a reaction vial. The vial was flushed with
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2463
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
30.0 (2”CH3), 30.1 (CH), 31.2 (C), 32.4 (CH2), 38.6 (CH2), 50.8 (CH2),
52.1 (2”CH3), 126.0 (C), 145.3 (CH), 167.5 (C=O), 171.4 ppm (C=O);
IR (ATR): n˜ =2953 (m), 2903 (w), 2869 (w), 1742 (s), 1714 (s), 1651
(w), 1477 (w), 1460 (w), 1435 (m), 1394 (w), 1377 (w), 1365 (m),
1329 (m), 1282 (m), 1255 (m), 1194 (s), 1168 (s) 1114 (m), 1072 (m),
1011 (m), 935 (w), 895 (w), 822 (w), 769 (m), 685 cmÀ (w); MS (EI,
70 eV): E isomer: m/z (%)=239 (19) [M+ÀOMe], 238 (30), 172 (12),
167 (19), 154 (16), 140 (100), 139 (12), 127 (10), 112 (31), 109 (10),
83 (17), 79 (12), 59 (11), 57 (63), 43 (10), 41 (17); HRMS (ESI): m/z
calcd for C15H26O4: 293.1723; found: 293.1726 [M+ <M+ >Na]; el-
emental analysis calcd (%) for C15H26O4: C, 67.57, H, 9.92; found: C,
67.57, H, 9.86.
plementary crystallographic data for this paper. These data are pro-
vided free of charge by The Cambridge Crystallographic Data
Centre.
Acknowledgements
We gratefully acknowledged the support of Jana Modenbach
as well as the advice and support from Professor M. Beller.
Keywords: homogeneous
catalysis
·
olefination
·
Dimethyl 2-(furan-2-ylmethylene)succinate (3ca):[29] According to
the GP, 4 (9.9 mg, 0.052 mmol), furan-2-carbaldehyde (1ca; 98 mg,
1.02 mmol), dimethyl maleate (2b; 165 mg, 1.14 mmol), PhCO2H
(6.1 mg, 0.050 mmol), and (MeO)3SiH (386 mg, 3.16 mmol) were
converted in toluene (2 mL). After chromatography (SiO2; CH/
EtOAc, 20:1) and removal of all volatiles in vacuum, 3ca (223 mg,
0.995 mmol, 98%, E/Z=84:16) was obtained as a colorless oil. Rf
0.43 (SiO2, CH/EtOAc, 2:1); 1H NMR (300 MHz, CDCl3, 278C): d (E
isomer)=3.67 (s, 3H), 3.77 (s, 3H), 3.84 (s, 2H), 6.42–6.48 (m, 1H),
6.60–6.65 (m, 1H), 7.48–7.51 (m, 1H), 7.52 ppm (s, 1H); 13C{1H}
NMR (75 MHz, CDCl3, 278C): d (E isomer)=33.4 (CH2), 52.1 (CH3),
52.3 (CH3), 112.2 (CH), 116.8 (CH), 121.1 (C), 127.8 (CH), 145.1 (C),
150.9 (CH), 168.0 (C=O), 171.5 ppm (C=O); IR (ATR): n˜ =3128 (vw),
2997 (vw), 2952 (w), 2846 (vw), 1736 (m), 1703 (s), 1638 (m), 1553
(vw), 1477 (w), 1459 (vw), 1435 (m), 1414 (w), 1390 (vw), 1367 (w),
1327 (w), 1281 (m), 1266 (m), 1210 (vs), 1194 (vs), 1168 (vs), 1114
(w), 1092 (m), 1018 (m), 949 (w), 920 (m), 885 (m), 861 (w), 842 (w),
785 (w), 749 (s), 686 (w), 660 cmÀ (vw); MS (EI, 70 eV): E isomer: m/
z (%)=224 (71), 193 (19) [M+ÀOMe], 192 (52), 166 (10), 165 (100)
[M+ÀCO2Me], 164 (20), 137 (21), 133 (11), 111 (27), 106 (16), 105
(42), 91 (13), 78 (22), 77 (29), 59 (17), 51 (12); Z isomer: m/z (%)=
224 (58), 193 (14) [M+ÀOMe], 192 (42), 166 (10), 165 (100) [M+
ÀCO2Me], 164 (19), 137 (22), 133 (12), 121 (10), 111 (32), 106 (19),
105 (49), 91 (17), 78 (28), 77 (37), 59 (25), 51 (16); HRMS (ESI): m/z
calcd for C11H12O5: 247.0577; found: 247.0576 [M++Na]; elemental
analysis calcd (%) for C11H12O5: C, 58.93, H, 5.39; found: C, 58.89; H,
5.48.
organocatalysis · Wittig reactions · ylides
[1] a) R. C. Larock, Comprehensive Organic Transformations, 2 ed., Wiley-
VCH, Weinheim, 2010; b) T. Takeda, Modern Carbonyl Olefination, Wiley-
VCH, Weinheim, 2004.
[2] a) G. Wittig, G. Geissler, Liebigs Ann. Chem. 1953, 580, 44–57; b) G.
Wittig, U. Schçllkopf, Chem. Ber. 1954, 87, 1318–1330.
[3] a) H. Ernst, Pure Appl. Chem. 2002, 74, 2213–2226; b) C. Mercier, P. Cha-
bardes, Pure Appl. Chem. 1994, 66, 1509–1518; c) H. Pommer, Angew.
Chem. 1960, 72, 811 –819; d) H. Pommer, Angew. Chem. 1960, 72, 911 –
915; e) H. Pommer, A. Nürrenbach, Pure Appl. Chem. 1975, 43, 527–551;
f) H. Pommer, Angew. Chem. Int. Ed. 1977, 16, 423–429; Angew. Chem.
1977, 89, 437–443;; g) K. C. Nicolaou, M. W. Härter, J. L. Gunzner, A.
Nadin, Liebigs Ann./Recl. 1997, 1997, 1283–1301.
[4] a) C. Müller, M. Cokoja, F. E. Kühn in C-1 Building Blocks in Organic Syn-
thesis 2: Alkenations, Cross Couplings, Insertions, Substitutions, and Halo-
methylations, Thieme, Stuttgart, 2014, pp. 1–29; b) Organophosphorus
Reagents (Ed.: P. J. Murphy), Oxford University Press, Oxford, 2004;
c) O. I. Kolodiazhnyi in Phosphorus Ylides, Wiley-VCH, Weinheim, 2007,
pp. 359–538; d) P. A. Byrne, D. G. Gilheany, Chem. Soc. Rev. 2013, 42,
6670–6696; e) B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863–
927; f) P. J. Murphy, J. Brennan, Chem. Soc. Rev. 1988, 17, 1–30.
[5] a) H. A. van Kalkeren, F. L. van Delft, F. P. J. T. Rutjes, ChemSusChem 2013,
6, 1615–1624; b) H. A. van Kalkeren, A. L. Blom, F. P. J. T. Rutjes, M. A. J.
Huijbregts, Green Chem. 2013, 15, 1255–1263.
[6] a) S. P. Marsden, Nat. Chem. 2009, 1, 685–687; b) I. J. Fairlamb, Chem-
SusChem 2009, 2, 1021–1024; c) D. HØrault, D. H. Nguyen, D. Nuel, G.
Buono, Chem. Soc. Rev. 2015, 44, 2508–2528.
[7] a) J. An, R. M. Denton, T. H. Lambert, E. D. Nacsa, Org. Biomol. Chem.
2014, 12, 2993–3003; b) H. A. van Kalkeren, J. J. Bruins, F. P. J. T. Rutjes,
F. L. van Delft, Adv. Synth. Catal. 2012, 354, 1417–1421; c) H. A. van Kal-
keren, C. te Grotenhuis, F. S. Haasjes, C. A. Hommersom, F. P. J. T. Rutjes,
F. L. van Delft, Eur. J. Org. Chem. 2013, 7059–7066; d) H. A. van Kalkeren,
S. H. A. M. Leenders, C. R. A. Hommersom, F. P. J. T. Rutjes, F. L. van Delft,
Chem. Eur. J. 2011, 17, 11290–11295; e) A. D. Kosal, E. E. Wilson, B. L.
Ashfeld, Angew. Chem. Int. Ed. 2012, 51, 12036–12040; Angew. Chem.
2012, 124, 12202–12206; f) A. D. Kosal, E. E. Wilson, B. L. Ashfeld,
Angew. Chem. Int. Ed. 2012, 51, 12036–12040; Angew. Chem. 2012, 124,
12202–12206.
[8] a) Y.-Z. Huang, L.-L. Shi, S.-W. Li, X.-Q. Wen, J. Chem. Soc. Perkin Trans.
1 1989, 2397–2399; b) L. Shi, W. Wang, Y. Wang, Y. Huang, J. Org. Chem.
1989, 54, 2027–2028.
[9] C. J. O’Brien, J. L. Tellez, Z. S. Nixon, L. J. Kang, A. L. Carter, S. R. Kunkel,
K. C. Przeworski, G. A. Chass, Angew. Chem. Int. Ed. 2009, 48, 6836–
6839; Angew. Chem. 2009, 121, 6968–6971.
[10] a) E. E. Coyle, B. J. Doonan, A. J. Holohan, K. A. Walsh, F. Lavigne, E. H.
Krenske, C. J. O’Brien, Angew. Chem. Int. Ed. 2014, 53, 12907–12911;
Angew. Chem. 2014, 126, 13121–13125; b) C. J. O’Brien, Z. S. Nixon, A. J.
Holohan, S. R. Kunkel, J. L. Tellez, B. J. Doonan, E. E. Coyle, F. Lavigne,
L. J. Kang, K. C. Przeworski, Chem. Eur. J. 2013, 19, 15281–15289; c) C. J.
O’Brien, F. Lavigne, E. E. Coyle, A. J. Holohan, B. J. Doonan, Chem. Eur. J.
2013, 19, 5854–5858.
[11] S. Rommel, C. Belger, J.-M. Begouin, B. Plietker, ChemCatChem 2015, 7,
1292–1301.
[12] a) H. Büttner, J. Steinbauer, T. Werner, ChemSusChem 2015, 8, 2655-
2669; b) T. Werner, H. Büttner, ChemSusChem 2014, 7, 3268–3271; c) T.
Dimethyl 2-(benzo[b]thiophen-2-ylmethylene)succinate (3cd):
According to the GP, 4 (9.9 mg, 0.052 mmol), benzo[b]thiophene-2-
carbaldehyde (1 cd; 167 mg, 1.03 mmol), dimethyl maleate (2b;
165 mg, 1.14 mmol), PhCO2H (6.1 mg, 0.050 mmol), and (MeO)3SiH
(386 mg, 3.16 mmol) were converted in toluene (2 mL). After chro-
matography (SiO2; CH/EtOAc, 20:1) and removal of all volatiles in
vacuum, 3 cd (264 mg, 0.909 mmol, 88%, E/Z=87:13) was ob-
tained as colorless crystals. Rf 0.29 (SiO2; CH/EtOAc, 5:1); 1H NMR
(300 MHz, CDCl3, 228C): d (E isomer)=3.76 (s, 3H), 3.86 (s, 3H),
3.87 (s, 2H), 7.35–7.43 (m, 2H), 7.53 (s, 1H), 7.78–7.88 (m, 2H),
8.06–8.07 ppm (m, 1H); 13C{1H} NMR (75 MHz, CDCl3, 248C): d (E
isomer)=33.8 (CH2), 52.4 (CH3), 52.6 (CH3), 122.4 (CH), 124.2 (C),
125.5 (CH), 125.1 (CH), 126.1 (CH), 129.9 (CH), 135.0 (CH), 137.5 (C),
138.8 (C), 141.3 (C), 167.8 (C=O), 170.9 ppm (C=O); IR (ATR): n˜ =
2957 (m), 2850 (w), 1739 (s), 1701 (vs), 1625 (m), 1591 (m), 1502
(m), 1437 (s), 1399 (m), 1379 (m), 1328 (vs), 1315 (s), 1273 (s), 1237
(m), 1211 (vs), 1192 (s), 1158 (vs), 1131 (s), 1089 (s), 1010 (s), 980
(m), 968 (m), 948 (m), 931 (m), 915 (m), 898 (m), 868 (m), 839 (s),
770 (m), 754 (vs), 727 (s), 707 (m), 678 (m), 655 cmÀ (m); MS (EI,
70 eV): E isomer: m/z (%)=290 (68) [M+], 258 (9), 231 (41) [M+
ÀCO2Me], 230 (20), 177 (19) 172 (46), 171 (100); HRMS (ESI): m/z
calcd for C15H14O4S: 290.0607; found: 290.0609 [M+]; elemental
analysis calcd (%) for C15H14O4S: C, 62.05, H, 4.86, S, 11.04; found:
C, 62.13, H, 4.91, S, 10.94. CCDC 1411832 [(E)-3cd] contains the sup-
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2464
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ˇ ˇ
Werner, A. M. Riahi, H. Schramm, Synthesis 2011, 3482–3490; d) T.
Werner, Adv. Synth. Catal. 2009, 351, 1469–1481.
[20] V. B. M. Ludwig, K. Kalfus, O. Pytela, M. Vecera, Collect. Czech. Chem.
Commun. 1986, 51, 2135–2142.
[13] a) T. Werner, M. Hoffmann, S. Deshmukh, Eur. J. Org. Chem. 2015, 3286–
3295; b) M.-L. Schirmer, S. Adomeit, T. Werner, Org. Lett. 2015, 17,
3078–3081; c) M. Hoffmann, S. Deshmukh, T. Werner, Eur. J. Org. Chem.
2015, 4532–4543; d) T. Werner, M. Hoffmann, S. Deshmukh, Eur. J. Org.
Chem. 2014, 6873–6876.
[21] A. d. Bettencourt-Dias, S. Viswanathan, Dalton Trans. 2006, 4093–4103.
[22] F. G. Bordwell, D. Algrim, J. Org. Chem. 1976, 41, 2507–2508.
[23] E. Raamat, K. Kaupmees, G. Ovsjannikov, A. Trummal, A. Kütt, J. Saame,
I. Koppel, I. Kaljurand, L. Lipping, T. Rodima, V. Pihl, I. A. Koppel, I. Leito,
J. Phys. Org. Chem. 2013, 26, 162–170.
[14] T. Werner, M. Hoffmann, S. Deshmukh, Eur. J. Org. Chem. 2014, 6630–
6633.
[24] P. Christ, A. G. Lindsay, S. S. Vormittag, J.-M. Neudçrfl, A. Berkessel, A. C.
O’Donoghue, Chem. Eur. J. 2011, 17, 8524–8528.
[15] a) K.-i. Morita, T. Kobayashi, Bull. Chem. Soc. Jpn. 1969, 42, 2732–2732;
b) S. Xu, Z. He, RSC Adv. 2013, 3, 16885–16904; c) S. W. McCombie, C. A.
Luchaco, Tetrahedron Lett. 1997, 38, 5775–5776; d) R. Oda, T. Kawabata,
S. Tanimoto, Tetrahedron Lett. 1964, 5, 1653–1657; e) U. A. Kshirsagar,
N. P. Argade, Synthesis 2011, 1804–1808; f) L. Yan, W. Yang, L. Li, Y.
Shen, Z. Jiang, Chin. J. Chem. 2011, 29, 1906–1910; g) Y.-L. Tsai, S.-e.
Syu, S.-M. Yang, U. Das, Y.-S. Fan, C.-J. Lee, W. Lin, Tetrahedron 2014, 70,
5038–5045.
[25] S. Venimadhavan, K. P. Shelly, R. Stewart, J. Org. Chem. 1989, 54, 2483–
2485.
´
[26] T. J. Janjic, L. B. Pfendt, M. B. Pasulj, Monatsh. Chem. 1984, 115, 125–
133.
[27] See the Supporting Information for details.
[28] a) Y. Liang, S. Liu, Y. Xia, Y. Li, Z.-X. Yu, Chem. Eur. J. 2008, 14, 4361–
4373; b) Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu, Y. Li,
Z.-X. Yu, J. Am. Chem. Soc. 2007, 129, 3470–3471.
[16] Y. Li, L.-Q. Lu, S. Das, S. Pisiewicz, K. Junge, M. Beller, J. Am. Chem. Soc.
2012, 134, 18325–18329.
[29] J. M. M. del Corral, M. Gordaliza, M. A. Castro, M. A. Salinero, J. M.
Dorado, A. S. Feliciano, Synthesis 2000, 154–164.
[17] T.-X. Xlang, B. D. Anderson, J. Pharm. Sci. 1994, 83, 1511–1518.
ˇ
ˇ
ˇ
[18] J. K. K. Waisser, J. Klimes, M. Polµsekc, Z. Odlerovµd, Collect. Czech.
Chem. Commun. 1993, 58, 191–196.
Received: September 17, 2015
[19] G. Bouchard, P.-A. Carrupt, B. Testa, V. Gobry, H. H. Girault, Chem. Eur. J.
2002, 8, 3478–3484.
Published online on January 13, 2016
Chem. Eur. J. 2016, 22, 2458 – 2465
www.chemeurj.org
2465
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim