Selective rhodium-catalyzed hydroformylation of alkynes to α,β-unsaturated aldehydes with a tetraphosphoramidite ligand

Article abstract of DOI:10.1021/acs.orglett.6b01605

A tetraphosphoramidite ligand was successfully applied to a Rh-catalyzed hydroformylation of various symmetrical and unsymmetrical alkynes to afford corresponding α,β-unsaturated aldehyde products in good to excellent yields (up to 97% yield). Excellent chemo- and regioselectivities and high activities (up to 20 000 TON) were achieved. The corresponding α,β-unsaturated aldehyde products can be transformed into many useful and important organic molecules, such as indenamine derivatives and lukianol pyrroles. This great performance makes the hydroformylation of alkynes highly practical with great potential.

Full text of DOI:10.1021/acs.orglett.6b01605

Letter
pubs.acs.org/OrgLett
Selective Rhodium-Catalyzed Hydroformylation of Alkynes to α,β-
Unsaturated Aldehydes with a Tetraphosphoramidite Ligand
Zongpeng Zhang,†,§ Qian Wang,†,§ Caiyou Chen,† Zhengyu Han,† Xiu-Qin Dong,*,†
and Xumu Zhang*,†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
‡Department of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, P. R. China
S
* Supporting Information
ABSTRACT: A tetraphosphoramidite ligand was successfully applied to a Rh-catalyzed hydroformylation of various symmetrical
and unsymmetrical alkynes to afford corresponding α,β-unsaturated aldehyde products in good to excellent yields (up to 97%
yield). Excellent chemo- and regioselectivities and high activities (up to 20 000 TON) were achieved. The corresponding α,β-
unsaturated aldehyde products can be transformed into many useful and important organic molecules, such as indenamine
derivatives and lukianol pyrroles. This great performance makes the hydroformylation of alkynes highly practical with great
potential.
developed a heterobimetallic [PdCl2(PCy3)2]/[Co2(CO)8]
he hydroformylation of alkenes is one of the most
1
Timportant and efficient methods to access aldehydes. catalytic system for this transformation under very harsh
Since it was first discovered by Otto Roelen in 1938,2 this
reaction conditions, yet chemoselectivity and E/Z-selectivity
problems remain unresolved.8 Alper and Van den Hoven
transformation has been widely explored and has made great
introduced a zwitterionic Rh-PPh3 complex to realize the
hydroformylation of thiophenyl substituted alkynes.9 In 2013,
Breit and Beller respectively developed a Rh/self-assembling
ligand system10 and Pd/N-phenylpyrrole-based bisphosphine
system11 for the hydroformylation of alkynes with excellent
chemo- and stereoselectivities. Despite the great progress that
has been made, these catalytic systems did not exhibit high
activity and showed a low turnover number (TON), which
limited their practical application. To date, there has been no
effective catalytic system for achieving excellent chemo- and
stereoselective hydroformylations of various alkynes with a high
TON. Herein, we present our electron-deficient tetraphosphor-
amidite ligand providing a highly active rhodium catalytic
system for excellent chemo- and regioselective hydroformyla-
tion of symmetrical and unsymmetrical alkynes to furnish
various α,β-unsaturated aldehydes with good to excellent yields
and up to a 20 000 TON under mild reaction conditions.
It is well-known that a ligand is one of the most crucial
factors to achieve high activity and selectivity for hydro-
formylation. We have successfully developed a variety of
efficient and privileged ligands for Rh-catalyzed hydro-
formylation of alkenes with excellent selectivities in recent
progress in recent decades. Compared with the well-developed
hydroformylation of alkenes, the corresponding hydroformyla-
tion of alkynes to produce α,β-unsaturated aldehydes in a
perfect atom economic manner has received little attention.3
The generated α,β-unsaturated aldehyde products and their
derivatives are very valuable intermediates in organic synthesis
for the construction of building blocks for agrochemicals,
pharmaceuticals, and fine chemicals.4 The early research on the
hydroformylation of alkynes demonstrated that this trans-
formation was extremely challenging owing to the poor
reactivity and selectivity.5 The byproducts of hydrogenated
products and saturated aldehydes were difficult to suppress
(Scheme 1).6 After decades of strenuous effort, several
relatively efficient catalytic systems have been developed. In
1995, Buchwald and co-workers applied Rh-Biphephos into the
hydroformylation of some symmetric and unsymmetric alkynes
with moderate results.7 Subsequently, Hidai and co-workers
Scheme 1. Challenges for the Hydroformylation of Alkynes
Received: June 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01605
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
decades, such as phosphite ligands,12 phosphorus ligands,13 and
phosphoramidite ligands.14 Based on our ongoing research
interest in this field, we made efforts to improve the selectivity
and activity of hydroformylation of alkynes. Highly electron-
deficient phosphine ligands contribute to largely accelerating
the hydroformylation step by facile CO dissociation and
suppressing the hydrogenation step in the hydroformylation of
alkynes (Scheme 2).
Table 1. Screening Conditions for Hydroformylation of
Diphenylacetylene 1a
a
temp
(°C)
conv
b
2a yield
3a yield
b
c
entry
L
L/Rh
S/C
(%)
(%)
(%)
Scheme 2. Features of Tetraphosphoramidite Ligand and the
Application for the Hydroformylation of Alkenes and
Alkynes
1
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
1
1
1
1
1
1
1
1
2
3
4
8
2
2
2000
2000
2000
2000
2000
2000
2000
5000
5000
5000
5000
5000
5000
5000
80
80
80
80
80
80
80
80
80
80
80
80
60
80
23.8
30.7
32.7
57.1
87.4
93.8
98.2
98.4
98.8
99.1
99.0
98.3
37.5
99.4
11.7
20.9
22.0
23.4
55.8
66.7
85.6
86.2
91.2
90.8
90.9
88.3
36.0
93.3
1.4
1.8
1.6
14.2
10.2
9.7
7.5
8.9
6.1
6.4
7.1
8.3
0.7
5.9
2
3
4
5
6
7
8
9
10
11
12
13
d
We began our initial investigation by evaluating a series of
phosphine ligands in our laboratory (Figure 1) in the
14
a
[Rh(acac) (CO)2] = 0.1 μM, toluene as solvent, diphenylacetylene 1a
as the substrate, reaction time was 24 h, reaction temperature was 80
b
°C, decane as internal standard, L = ligand. Determined on the basis
c
d
of GC analysis. Yield was isolated yield. CO/H2 = 5/5.
result corresponded to the hypothesis we made that the highly
electron-deficient catalytic system can largely facilitate the
hydroformlation step by facile dissociation of CO via the trans
effect and at the meantime largely suppress the hydrogenation
step; as a result, excellent activity and selectivity were observed.
When the ratio of substrate and catalyst (S/C) was increased
from 2000 to 5000, a similar result was observed (Table 1,
entry 8). Then we investigated the effect of the ratio of ligand
L7/metal. Increasing the ratio from 1:1 to 2:1 led to an
excellent yield of 2a and trace hydrogenation product (Z)-3a
(Table 1, entry 9). The yield became lower when the ligand/
metal ratio was gradually increased to 8:1 resulting in no
improvement (Table 1, entries 10−12). In addition, decreasing
the reaction temperature from 80 to 60 °C provided extremely
low reactivity (Table 1, entry 9 vs 13). We further found that
syngas pressure played an important role in the result. When
the pressure of CO/H2 was decreased from 10:10 to 5:5,
excellent reactivity and yield were obtained (93.3% yield, Table
1, entry 14).
Subsequently, a study of the reaction with S/C = 5000 in
various solvents was carried out. These results are summarized
in Table 2. Trace hydrogenation product (Z)-3a was observed
in these solvents. The reactions proceeded well in toluene and
CH2Cl2 with excellent results, but CH2Cl2 provided a slightly
lower yield of hydroformylation product 2a (Table 2, entries
1−2). The reactions displayed poor reactivities in polar
solvents, such as THF, i-PrOH, and CH3CN (Table 2, entries
3, 5, 7). In addition, ethyl acetate, n-hexane, and 1,4-dioxane
furnished moderate to good yields of hydroformylation product
2a (Table 2, entries 4, 6, 8). Therefore, solvents screening
showed that toluene was identified as the best choice.
Figure 1. A series of phosphine ligands in our laboratory.
hydroformylation of diphenylacetylene (1a)15 as the model
substrate with the catalyst generated in situ by mixing Rh(acac)
(CO)2 and ligands in toluene (S/C = 2000). As shown in Table
1, biphosphorus, triphosphorus, and tetraphosphorus ligands
(L1−L3) were applied, and low conversions and little
hydrogenation product (Z)-3a were observed (Table 1, entries
1−3). This is probably due to the electron-rich properties of
these ligands that tend to slow down the hydroformylation step.
The phosphite ligand L4 also obtained a similar result with
them (Table 1, entry 4 vs entries 1−3). However, the highly
electron-deficient biphosphoramidite, triphosphoramidite, and
tetraphosphoramidite ligands (L5−L7) worked well and
provided moderate to excellent yields of hydroformylation
product 2a and little hydrogenation product (Z)-3a (Table 1,
entries 5−7). To our delight, the tetraphosphoramidite ligand
L7 was revealed as the best ligand (Table 1, entry 7). This
Encouraged by these excellent results, we turned our
attention to the scope and generality of the hydromylation of
various alkynes under the optimized reaction conditions. As
shown in Scheme 3, a variety of diaryl alkynes proceeded
B
DOI: 10.1021/acs.orglett.6b01605
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Letter
unsaturated aldehyde products (2e−2g), we found a small
amount of hydrogenation products (3e−3g) in the reaction
systems. It was probably due to the electron-deficient
properties of these substrates that tend to slow down the
hydroformylation step. Remarkably, the heteroaromatic dithio-
phene alkyne (2h) also worked well in this catalytic system with
a good yield. When phenylacetylene was used as a substrate, the
reaction system did not produce good results. The terminal
alkyne was easily hydrogenated, and we only obtained a 10%
yield of the hydroformylation product (2i). It is noteworthy
that when we changed the alkyl group of the unsymmetric aryl-
alkyl alkynes from a methyl group (2j) to a bulky tert-butyl
group (2k), the regioselectivity was improved to 9.2:1. This is
mainly due to the steric effect, as it preferred to produce an
aldehyde group on the less steric side. In addition, dialkyl
alkynes (2l−2n) performed efficiently with excellent results
(93%−97% yields).
As we expected, the Rh−L7 complex was very stable and
highly active. When the catalyst loading was decreased to 0.01
mol % (S/C = 10 000), the hydroformylation product 2a was
obtained in 99% conversion and 90% yield within 24 h. When
the catalyst loading was further lowered to 0.005 mol % (S/C =
20 000), the reaction still proceeded well and provided 2a in
99% conversion and 85% yield within 24 h (Scheme 4). And
Table 2. Screening Solvents for Hydroformylation of
Diphenylacetylene 1a Catalyzed by Rh(acac)(CO)2/L7
a
b
c
b
entry
solvent
toluene
conv (%)
2a yield (%)
3a yield (%)
1
2
3
4
5
6
7
8
99.4
99.6
46.7
97.3
44.4
>99
7.9
93.3
90.3
36.7
81.8
35.4
84.3
6.3
5.9
7.8
CH2Cl2
THF
4.7
ethyl acetate
i-PrOH
8.1
4.7
n-hexane
CH3CN
1,4-dixoane
10.7
1.2
92.5
62.9
9.3
a
[Rh(acac) (CO)2] = 0.1 μM, diphenylacetylene 1a as the substrate,
L7 as the ligand, reaction temperature was 80 °C, reaction time was 24
b
h, decane as internal standard. Determined on the basis of GC
c
analysis. Yield was isolated yield.
Scheme 3. Study Scope for Hydroformylation of Various
a
Alkynes 1 Catalyzed by Rh(acac)(CO)2/L7
Scheme 4. Hydroformylation of Diphenylacetylene 1a with
High S/C
traces of the hydrogenation product (Z)-3a were found in these
reaction systems. This efficient performance contributes toward
this transformation being used in industrial application with
great potential.
To our delight, indenamine derivative 3a can be obtained
through condensation of the readily accessible cinnamylalde-
hyde 1a via our excellent catalytic system and sulfonylamine
under mild conditions (Scheme 5).16 In addition, the
Scheme 5. Synthetic Transformation
a
[Rh(acac) (CO)2] = 0.1 μM, toluene as solvent, reaction temperature
was 80 °C, reaction time was 24 h, S/C = 5 000. Yield of 2 was
corresponding products can be applied to synthesize lukianol
pyrroles, such as lukianol A, which have been found to have
activity against human epidermatoid carcinoma.17
isolated yield. The yields of 3 are in parentheses, and E/Z selectivities
b
were determined by 1H NMR. S/C = 1000, reaction temperature was
c
100 °C. S/C = 100.
In summary, we successfully developed the Rh-catalyzed
hydroformylation of various symmetrical and unsymmetrical
alkynes to afford corresponding α,β-unsaturated aldehyde
products in good to excellent yields utilizing our previously
developed highly electron-deficient tetraphosphoramidite li-
gand L7. It was possible that the highly electron-deficient
feature of L7 can largely accelerate the hydroformylation step
and suppress the hydrogenation step. As a result, excellent
chemo- and regioselectivities and high activities (up to 20 000
smoothly and formed the desired corresponding diaryl-
substituted α,β-unsaturated aldehyde products (2a−2g) in
good to excellent yields (60%−93% yields) with high E
stereoselectivity (E/Z > 20:1) with S/C = 5000. In addition,
although electron-deficient diaryl alkynes with different
substitution patterns on the aromatic ring were tolerated in
these reactions with 60%−82% yields of the corresponding α,β-
C
DOI: 10.1021/acs.orglett.6b01605
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Wang, Y.; Lv, H.; Zhang, X. Org. Chem. Front. 2014, 1, 947−951.
(c) Yu, S.; Zhang, X.; Yan, Y.; Cai, C.; Dai, L.; Zhang, X. Chem. - Eur. J.
2010, 16, 4938−4943.
(13) (a) Yu, S.; Chie, Y.; Zhang, X. Adv. Synth. Catal. 2009, 351, 537.
(b) Zhang, Z.; Chen, C.; Wang, Q.; Han, Z.; Dong, X.-Q.; Zhang, X.
RSC Adv. 2016, 6, 14559−14562.
TON) were achieved by our catalytic system. The great
performance of this hydroformylation makes the preparation
for α,β-unsaturated aldehydes practical and should broaden its
utility in organic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
(14) (a) Yan, Y.; Zhang, X.; Zhang, X. J. Am. Chem. Soc. 2006, 128,
16058−16061. (b) Chen, C.; Qiao, Y.; Geng, H.; Zhang, X. Org. Lett.
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01605.
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Chem. Commun. 2014, 50, 4119−4122.
Experimental details and NMR data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xumu@whu.edu.cn.
*E-mail: xiuqindong@whu.edu.cn.
Author Contributions
§Z.Z. and Q.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the grant from Wuhan University
(203273463, 203410100064) and thank “111” Project of the
Ministry of Education of China for financial support and the
National Natural Science Foundation of China (Grant Nos.
21372179, 21432007, and 21502145).
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DOI: 10.1021/acs.orglett.6b01605
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