Selective palladium-catalyzed hydroformylation of alkynes to α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1002/anie.201300759

Atom-efficient: A selective palladium catalyst system is used for the hydroformylation of alkynes (see picture). In this syngas reaction, various alkynes were smoothly transformed to synthetically interesting α,β-unsaturated aldehydes in good yields with high regio- and stereoselectivity. Copyright

Full text of DOI:10.1002/anie.201300759

Angewandte
Chemie
DOI: 10.1002/anie.201300759
Hydroformylation
Selective Palladium-Catalyzed Hydroformylation of Alkynes to
a,b-Unsaturated Aldehydes**
Xianjie Fang, Min Zhang, Ralf Jackstell, and Matthias Beller*
The hydroformylation of olefins to give aldehydes as the
predominant products, discovered by Otto Roelen in 1938, is
an intriguing and extensively studied reaction.[1,2] Owing to its
industrial importance, the hydroformylation of aliphatic
olefins has been widely explored and these processes
represent major applications of homogeneous catalysis for
the production of bulk chemicals.[3] Most of the currently
employed hydroformylation processes rely on rhodium- and
cobalt-based catalysts.[4] Hence, still today the development of
novel benign catalysts[5] and the extension of the basic
methodology for new feedstocks are challenging and relevant
topics for academic and industrial chemists.
hydroformylation catalysts. We demonstrated that metals
besides rhodium and cobalt[12a,c] can be successfully applied in
the hydroformylation of olefins. More specifically, we showed
that palladium complexes with heterocyclic phosphine ligands
are efficient and selective catalysts for the low-pressure
hydroformylation of aromatic and aliphatic olefins.[12c] There-
fore, we presumed that these complexes might be also suitable
for the hydroformylation of alkynes to give selectively a,b-
unsaturated aldehydes (Scheme 1).
Compared to the well-studied hydroformylation of ole-
fins, the corresponding reaction of alkynes has received only
scarce attention. This is somewhat surprising as such trans-
formations provide in principle a 100% atom-efficient route
for producing a,b-unsaturated aldehydes, which are impor-
tant intermediates in organic synthesis,[6] particularly for the
preparation of bioactive compounds, flavors, and fragrances.[7]
In early studies, it was found that the hydroformylation of
alkynes usually suffers from low chemoselectivity and/or low
yield of the desired unsaturated aldehyde, primarily because
the formation of the corresponding saturated aldehydes and
alkenes is hardly suppressed.[8] However, during the past two
decades, more effective catalysts such as [Rh(CO)2(acac)]/
Biphephos (acac = acetylacetonate, Biphephos = 6,6’-[(3,3’-
di-tert-butyl-5,5’-dimethoxy-1,1’-biphenyl-2,2’-diyl)bis(oxy)]-
bis(dibenzo[d,f][1,3,2]dioxaphosphepin)]),[9] the heterobi-
metallic catalyst [PdCl2(PCy3)2]/[Co2(CO)8],[10] and a zwitter-
ionic rhodium complex with PPh3 as a ligand[11] were
developed. With these catalysts, the hydroformylation of
some acetylenic substrates to produce a,b-unsaturated alde-
hydes with good selectivity is possible. Nevertheless, the
efficient hydroformylation of easily accessible aryl alkynes
and unsymmetrical alkynes was not possible and represents
a challenging problem until today.
Scheme 1. Hydroformylation and the competing hydrogenation of
alkynes.
Herein, we present an efficient and selective palladium-
based catalyst system for the general hydroformylation of
alkynes under mild conditions. Notably, the enal products
were obtained in high yields even from demanding substrates
such as aryl alkynes since the unwanted hydrogenation side
reactions were effectively suppressed.
It is well known that the influence of ligands on hydro-
formylation reactions is crucial. Thus, in our initial inves-
tigations we examined the effect of a series of phosphine
ligands on the model reaction of diphenylacetylene (1a) with
synthesis gas (Table 1). When monodentate ligands were
used, no conversion was observed (Table 1, entries 1–4).
However, the application of several commercially available
bidentate ligands provided low to moderate yields of the
desired product (Table 1, entries 5–9). Further investigations
showed that bidentate ligands with larger bite angles (i.e.
DPEphos, Naphos, and Xantphos) exhibited no activity in the
formation of the desired product (Table 1, entries 10–12).
Next, some of our own developed N-phenylpyrrole-based
bisphosphine ligands[13] with different steric properties were
tested (Table 1, entries 13–15). L5 was identified as the most
promising ligand and the reaction afforded the desired
product 3a in good yield with high stereoselectivity. Notably,
the hydrogenated product 2a formed in only 7% yield in this
case (Table 1, entry 15). In order to improve the reaction
further, we evaluated the influence of critical reaction
parameters such as temperature, acid co-catalyst, and gas
pressure in the presence of L5 as the ligand. As shown in
Table 1, the reaction temperature and the acid co-catalyst
In the context of our ongoing research in the field of
hydroformylation,[12] we recently set out to study less common
[*] X. Fang, Dr. M. Zhang, Dr. R. Jackstell, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
[**] This research was funded by Evonik Industries, Advanced Inter-
mediates, Performance Intermediates, and the Deutsche For-
schungsgemeinschaft (Leibniz Prize to M.B.). We thank Dr. C.
Fisher, S. Buchholz, and S. Schareina for their excellent technical
and analytical support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300759.
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Table 1: Hydroformylation of diphenylacetylene (1a): Evaluation of
only 3% yield when the pressure of syngas (Table 1,
entries 21–22) is increased to 50 bar. Among the different
metal catalysts tested, only [Rh(CO)2(acac)] gave the desired
product 3a in 41% yield (GC analysis) along with significant
amount of the byproducts 2a (yield: 24%), saturated
aldehyde 2a’, and lactone 2a’’ (Table 1, entry 23). In contrast,
other catalysts such as [Co2(CO)8] [Ir(cod)(acac)],
[Ru3(CO)12], [Fe3(CO)12], and [Ni(acac)2] led to the recovery
of the starting materials under the reaction conditions.
Applying these optimized reaction conditions (Table 1,
entry 21), we examined the general scope and the limitations
of our synthetic protocol. As shown in Scheme 2, a variety of
internal aryl alkynes underwent efficient hydroformylation to
afford the corresponding a,b-unsaturated aldehydes in good
to excellent yields. Various substrates with electron-neutral,
electron-deficient, and electron-rich substituents led to good
product yields and high E stereoselectivity (3a–3i). Sub-
strates having different functional groups (i.e. -Br, -COMe,
-NPhth, and -CO2Et) were well tolerated, too (3e–3g and 3o–
3q). However, the use of the more bulky substrate 1i gave
product 3i in moderate yield with decreased stereoselectivity,
presumably due to steric effects. Moreover, substrates with
heterocyclic substituents (such as pyridyl and thiophenenyl
groups) proved also to be efficient coupling partners to
generate the corresponding products in acceptable to good
yields (3j and 3k). From a synthetic point of view, it is
important that reactions using unsymmetrical aryl alkynes
(1l–1q) mainly occurred at the benzylic position. Thus, good
regioselectivity is observed, which is attributed to the
formation of the kinetically favored vinyl palladium species
stabilized by aryl groups.[15] The reaction employing phenyl-
acetylene 1r resulted only in a low product yield, which is
similar to reactions of the known rhodium-based catalysts.[16]
All the yields of hydrogenation byproducts (alkenes) are less
than 5% according to GC analysis.
Next, we turned our attention to the hydroformylation of
aliphatic alkynes, which is a class of less reactive substrates
than aryl alkynes. When the catalyst loading was increased to
1 mol% [Pd(acac)2] and the reaction temperature to 1008C,
all the reactions proceeded smoothly and afforded the desired
products in reasonable to excellent yields. As shown in
Scheme 3, all the symmetrical alkyl alkynes were smoothly
converted to the corresponding a,b-unsaturated aldehydes
with high stereoselectivity (5a–5d). The hydroformylation of
the unsymmetrical alkyl alkyne 4,4’-dimethylpent-2-yne (4e)
gave the product 5e exclusively in 65% yield. Here, the
specific regioselectivity is attributed again to the steric effect.
Alkynes 4 f and 4g bearing different alkyl substituents
resulted in mixed regioisomers in ratios of 1:1 and 1.4:1,
respectively (5 f and 5g). The latter results clearly indicate
that there is little differentiation between groups R1 and R2.
Similar to the hydroformylation of phenylacetylene 1r
(Scheme 2), the terminal alkyl alkyne 4h gave the desired
product (5h) in lower yield (17%). It is noteworthy that
alkene byproducts arising from hydrogenation of alkynes
were not observed.
reaction conditions.[a]
Entry Ligand
CO/H2 [bar] Conv.
2a Yield[b]
(E/Z)
3a Yield[b]
(E/Z)
1
2
3
4
PPh3
PCy3
nBuPAd2
L1
15:15
15:15
15:15
15:15
NR
NR
NR
NR
5
6
7
8
Dppp
Dppb
Dppf
BINAP
L2
DPEphos
Naphos
Xantphos
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
15:15
15:15
15:15
15:15
15:15
15:15
15:15
15:15
15:15
15:15
15:15
15:15
15:15
10:20
20:10
5:5
23%
37%
45%
45%
21%
9% (71:29)
7% (59:41)
4% (54:46)
5% (37:63)
10% (96:4)
24% (96:4)
35% (96:4)
34% (95:5)
9
9% (88:12) 9% (>99:1)
10
11
12
13
14
15
16[c]
17[d]
18
19
20
21
22
23[e]
NR
NR
NR
NR
NR
100% 7% (76:24)
37%
86% (96:4)
30% (96:4)
1% (79:21)
NR
13% (58:42) 59% (94:6)
77%
85%
7% (77:23)
73% (94:6)
84% (93:7)
92% (95:5)
92% (95:5)
100% 9% (80:20)
100% 3% (79:21)
100% 3% (79:21)
25:25
30:30
25:25
100% 24% (17:83) 41% (98:2)
[a] Reaction conditions: 1a (0.5 mmol), [Pd(acac)2] (0.5 mol%), mono-
dentate ligand (2 mol%) or bidentate ligand (1 mol%), p-TsOH
(2 mol%), THF (2 mL). [b] Yield determined by GC analysis using
isooctane as the internal standard; the ratios of E to Z isomers were
determined by GC–MS analysis; NR=no reaction. [c] Reaction temper-
ature: 508C. [d] Without p-TsOH. [e] Using [Rh(CO)2(acac)] as catalyst,
2a’=2,3-diphenylpropanal (GC yield: 14%), 2a’’=3,4-diphenylfuran-
2(5H)-one (GC yield: 17%). Ad=adamantyl, DPEphos=bis(diphenyl-
phosphinophenyl)ether; Naphos=2,2-bis[(diphenylphosphino)methyl]-
1,1-binaphthyl; Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene.
have a major influence on the product yields. For example, at
508C the conversion of 1a decreased dramatically (Table 1,
entry 16). No reaction occurred in the absence of p-toluene-
sulfonic acid monohydrate (p-TsOH), indicating the impor-
tance of the acid for the generation of the catalytically active
Pd hydride species (Table 1, entry 17).[14] Furthermore, chang-
ing the ratio of CO/H2 led to decreased conversion of 1a
(Table 1, entries 18 and 19). Lowering the syngas pressure
resulted in full conversion of 1a but increased the ratio of
byproduct 2a (Table 1, entry 20). In contrast, 2a is obtained in
Finally, we were interested in demonstrating the useful-
ness of our procedure for the synthesis of bioactive com-
pounds (Scheme 4). Hence, the synthesis of 3a was scaled up
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Scheme 3. Palladium-catalyzed hydroformylation of aliphatic alkynes.
[a] Reaction conditions: 4 (7.5 mmol), [Pd(acac)2] (1 mol%), L5
(4 mol%), p-TsOH (4 mol%), THF (30 mL); yield of isolated product
after column chromatography; the ratios of E to Z isomers and the
regioselectivity were determined by GC–MS analysis. [b] Yield deter-
mined by GC analysis using isooctane as the internal standard.
[c] Reaction temperature: 1308C.
Scheme 2. Palladium-catalyzed hydroformylation of aryl alkynes.
[a] Reaction conditions: 1 (0.5 mmol), [Pd(acac)2] (0.5 mol%), L5
(1 mol%), p-TsOH (2 mol%), THF (2 mL); yield of isolated product
after column chromatography; the ratios of E to Z isomers and the
regioselectivity were determined by GC–MS analysis. [b] Yield deter-
mined by GC analysis using isooctane as the internal standard.
[c] Reaction temperature: 1208C.
Scheme 4. Synthetic transformations of a,b-unsaturated aldehydes.
Moreover, a sequential one-pot methodology was applied
for the preparation of the tetrasubstitued 2H-pyran 7, which is
easily accessible from the simple alkyne 4a (yield: 68%) after
successive hydroformylation and electrocyclization with
methyl acetoacetate. Notably, product 7 proved to be a key
intermediate for the preparation of various functionalized
furans (Scheme 4b).[18]
by using 10 mmol of substrate 1a and gave 88% yield of the
a,b-unsaturated aldehyde. Subsequently, 3a was efficiently
transformed into the tetrasubstituted pyrrole 6 in 73% yield
by a multicomponent coupling reaction (Scheme 4a).[17]
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chromatography on silica gel (eluent: heptane/ethyl acetate = 20:1) to
give the desired product 3.
Although the detailed mechanism of the palladium-
catalyzed hydroformylation of alkynes is still under inves-
tigation, we suggest a simplified catalytic cycle based on the
known palladium-catalyzed carbonylation of olefins and
alkynes (Scheme 5).[5c,19] Initially, the active cationic palla-
Received: January 28, 2013
Published online: March 20, 2013
Keywords: alkynes · hydroformylation · hydrogenation ·
.
palladium · a,b-unsaturated aldehydes
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À
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Experimental Section
Typical procedure for the preparation of 3: A 20 mL Schlenk flask
was charged with [Pd(acac)2] (3.8 mg, 0.5 mol%), L5 (13.4 mg,
1 mol%), p-TsOH (9.5 mg, 2 mol%), and THF (10 mL). Then,
2 mL of this clear light yellow solution was transferred into four
vials (4 mL reaction volume) each equipped with a septum, a small
cannula, a stirring bar, and 0.5 mmol of the corresponding alkynes 1.
The vials were placed in an alloy plate, which was transferred into
a 600 mL autoclave under argon atmosphere. The autoclave was
flushed with nitrogen, pressurized with 50 bar synthesis gas, and
heated to 808C. The reaction was carried out for 20 h. Subsequently,
the autoclave was cooled down to room temperature, the pressure
was released, and isooctane (internal standard) was added to the
solution. The conversion and regio- and stereoselectivity were
measured by GC and GC–MS, respectively. After the solvent had
been removed by vacuum, the residue was directly purified by flash
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