Rhodium-Catalyzed Regioselective Hydroformylation of Alkynes to α,β-Unsaturated Aldehydes Using Formic Acid

Article abstract of DOI:10.1021/acs.orglett.1c00234

A rhodium-catalyzed hydroformylation of alkynes with formic acid was developed. The method provides α,β-unsaturated aldehydes in high yield and E-selectivity without the need to handle toxic CO gas.

Full text of DOI:10.1021/acs.orglett.1c00234

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Letter
Rhodium-Catalyzed Regioselective Hydroformylation of Alkynes to
α,β-Unsaturated Aldehydes Using Formic Acid
Chao Fan,§ Jing Hou,§ Yu-Jia Chen, Kui-Ling Ding,* and Qi-Lin Zhou*
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ABSTRACT: A rhodium-catalyzed hydroformylation of alkynes
with formic acid was developed. The method provides α,β-
unsaturated aldehydes in high yield and E-selectivity without the
need to handle toxic CO gas.
ydroformylation of olefins, discovered by Otto Roelen in
1938, has been extensively studied and has become one
In the initial investigation, we evaluated a series of
phosphine ligands in the rhodium-catalyzed hydroformylation
reaction of diphenylacetylene (1a) with formic acid. All the
tested phosphine ligands, which were commonly used in the
hydroformylation of alkenes,1c can push the substrate to full
conversion (Table 1, entries 1−6, see Supporting Information
for details). However, they mostly afforded the hydrogenation
product of alkyne. Only the ligands Xantphos (L5) and SKP
ligand (L6), which have a large bite angle when complexing
with rhodium,10 gave the desired α,β-unsaturated aldehydes 2a
in low yield. We then studied the reaction parameters using
ligand L5. Solvent evaluation showed that the reaction in
toluene has higher selectivity (entry 7, see Supporting
Information for details). Increasing the amount of HCO2H
and Ac2O simultaneously has no effect on the selectivity of the
reaction (entry 8), while increasing the L/Rh ratio from 1 to 2
improved the yield of 2a to 55% (entry 9). A careful
investigation on the amounts of HCO2H and Ac2O further
improved the yield of 2a to 73% (entry 10, see Supporting
Information for details). At last, the effects of reaction
temperature and the catalyst loading were studied. It was
found that an increase or decrease of temperature would lead
to the decrease of 2a yield, and the use of 2 mol % of catalyst
could increase the 2a yield to 85% (entry 11).11
H
of the most important industry processes catalyzed by
homogeneous catalysts.1 In contrast, the hydroformylation of
alkynes to give α,β-unsaturated aldehydes which are important
intermediates in organic synthesis has received less attention.2
In early studies, hydroformylation of alkynes usually suffered
from poor chemoselectivity and low yields due to the
formation of undesired alkenes and saturated aldehydes.3 In
the past two decades, more effective and selective palladium
catalysts4 and rhodium catalysts5 have been developed.
However, these catalytic systems have a major drawback, the
use of toxic CO gas.
Formic acid is a renewable, nontoxic liquid and can be
produced by catalytic hydrogenation of CO2 and oxidation of
biomass.6 It is an ideal substitute for CO gas and has been used
in organic synthesis.7 Recently, we developed a catalytic
hydrocarboxylation of alkynes with formic acid, producing α,β-
unsaturated acid in high yield (Scheme 1a).8 However, the
Scheme 1. Transition-Metal-Catalyzed Carbonylation Using
Formic Acid
Under the optimized reaction conditions, a variety of alkynes
were studied using L5 as the ligand (Scheme 2). The
symmetric diaryl acetylenes with electron-donating substitu-
ents afforded corresponding E-α,β-unsaturated aldehydes in
good yields. The exception is alkyne 1d with two o-
methylphenyl groups, which has a slightly lower yield (56%)
due to the steric effects. Diaryl acetylenes with halogen
substituents such as fluorine, chlorine, and bromine gave a low
catalytic hydroformylation of alkynes with formic acid to form
α,β-unsaturated aldehydes remains unexplored. In 1994, Alper
et al. performed a rhodium-catalyzed hydroformylation of
alkynes with formic acid under 8 atm of CO gas; however, they
only obtained saturated aldehydes.9 As a part of our continuing
efforts to develop synthetic methods using formic acid, we
herein report the rhodium-catalyzed hydroformylation of
alkynes with formic acid, producing α,β-unsaturated aldehydes
in high selectivity (Scheme 1b).
Received: January 21, 2021
Published: March 4, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00234
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2074−2077
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Table 1. Optimization of Reaction Conditions for
Hydroformylation of Diphenylacetylene (1a)
Scheme 2. Hydroformylation of Various Alkynes Using
Formic Acid
a
HCO2H
(equiv)
Ac2O
(equiv) solvent
yield 2a yield 3a/4a
entry ligand
(%)
(%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
6.0
6.0
9.0
9.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
4.5
4.5
THF
THF
THF
THF
THF
THF
tol
tol
tol
tol
tol
−
−
−
−
25
11
31
33
55
73
85
0/99
0/99
0/99
0/99
2/70
trace/85
0/65
0/60
2/40
0/25
2/8
b
b
10
11
b c
,
a
Reaction conditions: 1a (0.5 mmol), solvent (3 mL), HCO2H (1.5
mmol), Ac2O (0.75 mmol), Rh(acac)(CO)2 (0.005 mmol), ligand
(0.005 mmol), 100 °C, 12 h. Reaction was conducted in a 15 mL
1
autoclave. Yields were determined by H NMR analysis using 1,3,5-
b
c
trimethoxybenzene as internal standard. L/Rh = 2:1. Catalyst
loading was 2 mol %.
yield (1h−1j, 41−54%), and dehalogenated cis-stilbenes are
observed in the reaction;12 however, the substrate 1k
containing two p-CF3 groups gave only a hydrogenation
product. Dipiperonylacetylene (1n) and di(3-furyl)acetylene
(1o) can also undergo the hydroformylation reaction to
produce α,β-unsaturated aldehydes with high yields. Terminal
alkynes, as exemplified by phenylacetylene (1p), are very low
yielding (9%) because they are easily hydrogenated under the
reaction conditions.5e
a
Standard conditions: 1 (0.5 mmol), HCO2H (4.5 mmol), Ac2O (3.0
mmol), Rh(acac)(CO)2 (0.01 mmol), Xantphos (0.02 mmol),
toluene (3 mL), 100 °C, 12 h. Isolated yield GC yield using
tridecane as the internal standard. The aldehyde product is not stable
b
c
and is converted to alcohol for analysis.
Scheme 3. Gram-Scale Experiment
Next, we studied dialkyl acetylenes and found that they also
undergo hydroformylation under the same reaction conditions.
For symmetrical alkynes, the reaction yielded E-α,β-unsatu-
rated aldehydes in good yields (2q−2s, 61−86%), while for the
cyclic alkyne substrate 1t the reaction formed E-product 2t in
78% yield. When unsymmetrical alkynes such as 1u and 1v
were used, hydroformylation products can be obtained, but
with low regioselectivity. It is noteworthy that in the reaction
of arylalkyl acetylenes (1w−1y) the CHO group tends to be
installed at the β-position, with a regioselectivity (β/α) of 4:1
to 10:1. Similar to the terminal aromatic alkyne, the 1-heptyne
(1z) has a very low yield in the hydroformylation reaction.4b
To test the application potential of this protocol in mass
production, a gram-scale reaction of 1a was conducted. The E-
α,β-unsaturated aldehyde 2a was obtained in 87% yield
(Scheme 3).
Scheme 4. Proposed Mechanism
In Alper’s work, formic acid only serves as a hydrogen
donor, and CO was used to achieve hydroformylation.9 In this
study, CO was formed by the decomposition of the acetic
formic anhydride generated in situ from HCO2H and Ac2O.7a
Recently, Liu et al. have extensively studied the interactions
between rhodium, Ac2O, and HCO2H.7h On the basis of those
mechanistic studies in the literature, we proposed a plausible
mechanism in Scheme 4. The ligand exchange of a rhodium
precursor with formic acid forms rhodium formate I. The
coordination of I with another HCO2H gives intermediate II.
The decarboxylation of II yields rhodium hydride III. The
hydride III can either be quenched with formic acid to
generate hydrogen gas or coordinate with CO to initiate the
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Table 2. Control Experiments
entry
VII (equiv)
HCO2H (equiv)
additive
yield 2a (%)
yield 3a (%)
yield 4a (%)
1
2
3
4
5
6.0
0
6.0
0
0
0
3.0
9.0
0
0
30
2
49 (Z isomer)
Ac2O (6.0)
0
0
no conversion
62
−
6
−
28 (Z isomer)
>99 (E isomer)
0
HOAc (9.0)
no conversion
hydroformylation. The hydrorhodation of alkyne by IV
generates alkenylrhodium complex V, which would undergo
migratory insertion to form acylrhodium complex VI in a CO
atmosphere. The hydrogenolysis of VI with hydrogen gas leads
to product 2 and regenerates the rhodium hydride III.
To investigate whether the mixed anhydride VII is involved
in the reaction, we performed the reaction using prepared
mixed anhydride VII. As shown in Table 2, anhydride VII is
necessary for the hydroformylation reaction, and the addition
of formic acid increases the selectivity of hydroformylation
product (entry 3). Using formic acid alone can easily generate
H2, which hydrogenates alkynes to thermodynamically stable
E-alkenes (entry 4). Employing only acetic anhydride or acetic
acid showed no reaction (entries 2 and 5). These results
indicated that the mixed anhydride VII is involved in the
reaction.
In summary, we have developed a Rh-catalyzed regiose-
lective hydroformylation of alkynes using HCO2H/Ac2O
under mild reaction conditions. By using this protocol, a
variety of alkyl and aryl alkynes were converted to E-α,β-
unsaturated aldehydes with high yields. This hydroformylation
reaction uses HCO2H as the CO surrogate, is easy to operate,
and can be scalable, thus having high potential for application
in the synthesis of α,β-unsaturated aldehydes.
Jing Hou − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, P.R. China; orcid.org/0000-0002-1892-
2025
Yu-Jia Chen − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00234
Author Contributions
§Chao Fan and Jing Hou contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Liang-Nian He for providing advice and
instruments for GC analysis. We thank the National Natural
Science Foundation of China (No. 21790330, 21532003,
91956000) and the “111” project (B06005) of the Ministry of
Education of China for financial support.
DEDICATION
■
Dedicated to the 100th Anniversary of Chemistry at Nankai
University.
ASSOCIATED CONTENT
* Supporting Information
■
sı
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AUTHOR INFORMATION
Corresponding Authors
■
Qi-Lin Zhou − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P.R. China; orcid.org/0000-
0002-4700-3765; Email: qlzhou@nankai.edu.cn
Kui-Ling Ding − State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, P.R. China;
orcid.org/0000-0003-4074-1981; Email: kding@
mail.sioc.ac.cn
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