Syngas-Free Highly Regioselective Rhodium-Catalyzed Transfer Hydroformylation of Alkynes to α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1002/anie.201902553

The hydroformylation of alkynes is a fundamental and important reaction in both academic research and industry. Conventional methods focus on the conversion of alkynes, CO, and H₂ into α,β-unsaturated aldehydes, but they often suffer from problems associated with operation, regioselectivity, and chemoselectivity. Herein, we disclose an operationally simple, mild, and syngas-free rhodium-catalyzed reaction for the hydroformylation of alkynes via formyl and hydride transfer from an alkyl aldehyde. This synthetic method uses inexpensive and easy-to-handle n-butyraldehyde to overcome the challenge posed by the use of syngas in traditional approaches and employs a commercially available catalyst and ligand to transform a broad range of internal alkynes, especially alkynyl-containing complex molecules, into versatile stereodefined α,β-unsaturated aldehydes with excellent chemo-, regio-, and stereoselectivity.

Full text of DOI:10.1002/anie.201902553

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Accepted Article
Title: Syngas-Free Rhodium-Catalyzed Highly Regioselective Transfer
Hydroformylation of Alkynes to α, β-Unsaturated Aldehydes
Authors: Jingsong You, Guangying Tan, Yimin Wu, and Yang Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902553
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10.1002/anie.201902553
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Syngas-Free Rhodium-Catalyzed Highly Regioselective Transfer
Hydroformylation of Alkynes to α,β-Unsaturated Aldehydes
Guangying Tan, Yimin Wu, Yang Shi and Jingsong You*
Abstract: The hydroformylation of alkynes is a fundamental and
important reaction in both laboratory and industry. Conventional
methods are concentrated on the conversion of alkynes, CO and H2
into α,β-unsaturated aldehydes but often suffer from problems
associated with operation, regioselectivity and chemoselectivity.
Herein, we disclose an operationally simple, mild and syngas-free
rhodium-catalytic method for the hydroformylation of alkynes via the
transfer of formyl and hydride from an alkyl aldehyde. The current
synthetic version uses inexpensive and easy-to-handle n-
butyraldehyde to overcome the challenge posed by the use of syngas
in traditional approaches and employs commercially available catalyst
and ligand to transform a broad range of internal alkynes, especially
for alkynyl-containing complex molecules, into versatile stereodefined
Scheme 1. Hydroformylation of alkynes to α,β-unsaturated aldehydes.
α,β-unsaturated aldehydes with excellent chemo-, regio- and
stereoselectivity.
In 2015, Dong and coworkers reported an elegant rhodium-
α,β-Unsaturated
aldehydes
are
fundamental
synthetic
catalyzed dehydroformylation of aliphatic aldehydes to generate
alkenes under mild conditions.[10] This dehydroformylation
protocol employed highly strained norbornadiene as a sacrificial
acceptor to drive the reaction running smoothly because of the
release of its ring strain. Inspired by this work, we envisaged that
a mechanistically relevant transfer of formyl and hydride between
simple alkyl aldehyde and alkyne would fulfill the hydroformylation
without relying upon syngas (Scheme 1b). We reasoned that the
transfer hydroformylation of alkyne with simple alkyl aldehyde
would be unlocked through an elaborate rhodium-catalytic
pathway illustrated in Scheme 2, involving a sequence of
reversible aldehyde C–H bond activation to form acyl-Rh(III)-
hydride, reductive elimination, de-insertion of CO, β-hydride
elimination to forge Rh–hydrido–carbonyl IM4, and ligand
exchange.[10-12] In this proposed mechanism, the olefin exchange
of IM4 with alkyne to generate IM5 is the key step to drive the
transfer hydroformylation through CO insertion, oxidative addition,
and reductive elimination in reverse order. Such a transformation
would be particularly powerful because 1) no toxic and highly
flammable syngas would be required; 2) no special equipment
would be needed to handle pressurized gas; 3) cis-insertion of
CO would lead to (E)-α,β-unsaturated aldehyde; and 4) the
unwanted saturated aldehydes and hydrogenated products would
be mechanistically suppressed (complete chemoselectivity).
Herein we disclose a syngas-free rhodium-catalyzed transfer
hydroformylation of alkynes via shuttle catalysis (Scheme 1b).[13]
This protocol uses accessible and inexpensive n-butyraldehyde
as a donor of formyl and hydride to transform a broad range of
alkynes into α,β-unsaturated aldehydes with excellent chemo,
regio- and E/Z-selectivity.
intermediates
for
the
preparation
of
agrochemicals,
pharmaceuticals, biologically active molecules, and fine
chemicals.[1] Among various synthetic approaches to α,β-
unsaturated aldehydes, the hydroformylation of alkynes is
generally regarded as one of the most efficient and rapid methods
and has been of great interest to synthetic chemists.[2] Over the
past few decades, a lot of catalytic systems have been reported,
as exemplified by the pioneering works of Buchwald,[3] Hidai,[4]
Alper,[5] Beller,[6] Breit,[7] and Zhang,[8] all of which are
concentrated on the conversion of alkynes, CO, and H2 into
aldehydes (Scheme 1a). Despite strenuous effort, two
fundamental issues might plague the further application of the
hydroformylation reaction. First, although "syngas", a 1:1 mixture
of CO and H2, is inexpensive and abundant, it is very toxic,
volatile and highly flammable. Moreover, in most cases, to obtain
a satisfactory conversion ratio, a highly pressurized syngas is
generally required, thereby needing a special equipment to
handle pressurized gas. Second, compared with the
hydroformylation of alkenes, the hydroformylation of alkynes is
more challenging because the regioselectivity is difficult to be
controlled and the byproducts such as hydrogenated products of
alkynes and saturated aldehydes are hardly suppressed.[9] Thus,
considering the importance of hydroformylation of alkynes in both
laboratory and industry, it is highly desirable to develop a syngas-
free hydroformylation reaction, ideally with
selectivity, albeit it is thought as one of the most challenging tasks
in the synthetic chemistry.
a controllable
Our investigation commenced with the reaction between
hexadec-8-yne (1) and n-butyraldehyde (2a). After a systematic
evaluation of the reaction parameters, the best yield for (E)-2-
heptyldec-2-enal (A1) reached 86% under the catalytic system
composed of [Rh(cod)OMe]2 (2.0 mol %), Xantphos (4.0 mol %),
and 4-NO2PhCO2H (4.0 mol %) in tetrahydrofuran (THF) at 80 oC
for 24 h (Table 1) (For detailed optimization, see Table S1). The
[]
G. Tan, Y. Wu, Y. Shi, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry
Sichuan University
29 Wangjiang Road, Chengdu 610064, P. R. China
E-mail: jsyou@scu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201902553
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choice of the phosphine ligands is critical to this transfer
hydroformylation and only bidentate phosphine ligands were
proven to be effective. As shown in Table 1, Xantphos (L1) is
obviously superior to other bidentate ligands such as DPEphos
(L2), Dppf (L3), and Dppb (L4). The natural bite angles βn of
Xantphos, DPEphos, Dppf and Dppb are around 107o, 102o, 96o,
and 98o, respectively.[14] Thus, it seems that the reaction efficacy
is correlated to the bite-angle of the bidentate ligand and the
ligand with a larger natural bite-angle might be more efficient.
Next, a series of benzoic acids and alkyl carboxylic acids were
screened and 4-NO2PhCO2H proved to be superior to PhCO2H,
3-MeOPhCO2H, 4-tBuPhCO2H, 1-AdCO2H, and PivOH. From
Scheme 2, the acid additive could play the important role in three
steps of this catalytic cycle. At the beginning of the reaction, 4-
NO2PhCO2H could react with [Rh(cod)OMe]2 and Xantphos to
generate the catalytic active rhodium benzoate complex RhLnX (L
yields (A7-A8). A series of asymmetric aryl alkyl alkynes gave
remarkably high regioselectivity at the distal position relative to
the aryl group (A9-A13). To our delight, the free hydroxyl-
containing asymmetric dialkyl alkynes smoothly reacted with 2a,
delivering the corresponding unsaturated aldehydes in good
yields with a relatively high regioselectivity probably because of
the chelation of hydroxyl group (A14-A17). Similarly, the ester-
containing asymmetric dialkyl alkyne also gave the desired
product with almost complete regioselectivity (A18).
Table 1: Evaluation of the reaction parameters.[a,b]
–
= Xantphos; X = 4-NO2PhCO2 ). The benzoate counterion could
also participate in the deprotonation (reductive elimination
process between intermediates IM1 and IM2) and the protonation
(oxidative addition process between intermediates IM6 and IM7)
steps.[12] Moreover, aldehyde donors significantly influenced the
transfer hydroformylation. Replacing n-butyraldehyde with 2-
methylbutanal, 3-methylbutanal, or 3-phenylpropanal led to a
diminished yield of A1 and the reaction was shut down
completely when using cyclohexanecarbaldehyde as the donor.
Notably, A1 could also be obtained in 75% yield by using
paraformaldehyde as aldehyde donor (Table S1, entry 23).
[a] Standard conditions: alkyne (0.4 mmol), aldehyde (0.2 mmol),
[Rh(cod)OMe]2 (2.0 mol %), phosphine ligand (4.0 mol %), and carboxylic acid
(4.0 mol %) in THF (100 μL) at 80 oC under N2 for 24 h. [b] Isolated yields.
To further test the compatibility of the protocol in more
structurally intricate contexts, a variety of asymmetric internal
alkynes embedded in pharmaceutical agents and biologically
relevant molecules were tested (A19-A37), including those
derived from tyrosine (A21), vanillin (A22), pterostilbene (A23), δ-
tocopherol (A24), estrone (A25-A27), mestranol (A28),
ethisterone (A29-A30), probenecid (A31), ferrocenecarboxylic
acid (A32), dehydrocholic acid (A33), (S)-(+)ketopinic acid (A35),
D-methionine (A36), and epristeride (A37). Satisfactorily, the
above alkynyl-containing complex molecules were compatible
well with this protocol to provide α,β-unsaturated aldehydes in
mediate to good yields and with almost complete
regioselectivities because of steric encumbrance and/or chelation.
The structure of A30 was confirmed by X-ray crystallography.[15]
These examples highlight the synthetic utility of this transfer
hydroformylation and its compatibility with complex molecules.
Finally, we tried to couple butyraldehyde with internal alkyne
bearing the more sterically hindered group at both sides, such as
Scheme 2. Proposed mechanism involved in the transfer hydroformylation
reaction of alkynes.
With the optimized conditions in hand, we investigated the
scope of this transfer hydroformylation using internal alkynes with
n-butyraldehyde (2a) (Table 2). First, various symmetric alkyl
alkynes smoothly underwent the transfer hydroformylation
reaction, producing the desired α,β-unsaturated aldehydes with
almost complete E-selectivity in good to excellent yields (A1-A6).
Satisfactorily, when the amount of [Rh(cod)OMe]2 was reduced to
0.5 mol %, A1 could still be obtained in 72% yield (Table 2; Table
S1, entry 22). The transfer hydroformylation can be extended to
cyclic alkynes, giving the corresponding products in excellent
2,5-dimethylhex-3-yne-2,5-diol
and
2,5-dimethoxy-2,5-
dimethylhex-3-yne, but none of these could work.
To obtain a clearer perception of the reaction, a set of control
experiments were performed. First, the transfer hydroformylation
of terminal alkyne (38) with 2a did not afford any hydroformylated
product A38 (Scheme 3a, (i)). In order to address this limitation,
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Table 2: Scope of rhodium-catalyzed transfer hydroformylation of internal alkynes with n-butyraldehyde to α,β-unsaturated aldehydes.[a,b]
[a] Reaction conditions: 1-37 (0.4 mmol), 2a (0.2 mmol), [Rh(cod)OMe]2 (2.0 mol %), Xantphos (4.0 mol %), and 4-NO2PhCO2H (4.0 mol %) in THF (100 μL) at 80 oC
under N2 for 24 h. [b] Isolated yields. [c] The reaction was performed with [Rh(cod)OMe]2 (0.5 mol %), Xantphos (1.0 mol %), and 4-NO2PhCO2H (1.0 mol %) in
THF (100 μL) at 80 oC under N2 for 24 h.
employing TMS-protected dodec-1-yne (39) as a reactant, the
desired hydroformylated product A39 was obtained in 47% yield
(Scheme 3a, (ii)). Treatment of A1 with 5 under the standard
reaction conditions for 24 h did not lead to any transfer
hydroformylated product A5 except for the recovery of A1 in 82%
yield (Scheme 3a, (iii)). This is likely due to the poor reactivity of
A1, because after CO de-insertion the beta-H elimination of the
alkenyl group to give an alkyne is generally thermodynamically
uphill.
Next, two deuteration experiments were conducted to study the
transfer process (Scheme 3b). Under the standard conditions, the
reaction of 1 with 2a in the presence of 1 equiv of CD3OD led to 7%
and 24% deuterations of alkenyl hydrogen and aldehyde
hydrogen of [D]-A1, respectively, suggesting that the aldehyde
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proton of 2a could be transferred to the product through the
benzoate counterion as a proton shuttle, in which 4-NO2PhCO2H
could undergo proton exchange with CD3OD (Scheme 3b, (i)).
Treatment of 1 with deuterated [D]-2d, the deuterated ratios of
the corresponding alkenyl hydrogen and aldehyde hydrogen of
[D]-A1 were approximately 14% and 81%, respectively, implying
that the aldehyde proton of A1 mainly came from the aldehyde of
2d rather than the β-hydrogen (Scheme 3b, (ii)). These results
provided a powerful support for the proposed mechanism
illustrated in Scheme 2. In addition, two parallel competition
reactions between 1 with 2d or [D]-2d gave a kinetic isotope
effect (KIE) value of 1.08 (Scheme 3c), suggesting that the C−H
bond cleavage of alkyl aldehyde might not be related with the
rate-determining step. In 2016, Lan and coworkers demonstrated
protocol uses inexpensive and easy-to-handle n-butyraldehyde as
a donor of formyl and hydride to overcome the challenge posed
by the use of syngas in traditional approaches. We believe that
this method would offer an operationally simple, effective and
practical route to α,β-unsaturated aldehydes in both laboratory
and industry.
Acknowledgements
This work was supported by grants from the National NSF of
China (No 21432005) and Graduate Student’s Research and
Innovation Fund of Sichuan University (Grant No. 2018YJSY006).
a
computational
study
of
the
rhodium-catalyzed
Keywords: transfer hydroformylation • rhodium catalysis • C–C
bond cleavage • α,β-unsaturated aldehyde • syngas free
dehydroformylation of aliphatic aldehydes and indicated that the
β-hydride elimination might be the rate-determining step of the
catalytic cycle.[12] As
a
mechanistically relevant transfer
[1]
[2]
a) E. F. Glorius in Science of Synthesis, Vol. 25 (Ed.: R. Bruckner),
Georg Thieme, Stuttgart, 2007, p. 733; b) D. J. Rowe, Perfum. Flavor.
2000, 25, 1.
hydroformylation, we reasoned that the β-hydride elimination
might also be the rate-determining step of this reaction.
To further highlight the synthetic utility of our strategy, a one-
pot reaction was performed to produce (E)-5-(cyclopentadec-1-
en-1-yl)oxazole (A40, 72% yield) (Scheme 3d).[16]
For selected reviews on carbonylation, see: a) Q. Liu, H. Zhang, A. Lei,
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[3]
[4]
[5]
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4743; Angew. Chem. Int. Ed. 2013, 52, 4645.
[7]
[8]
V. Agabekov, W. Seiche, B. Breit, Chem. Sci. 2013, 4, 2418.
Z. Zhang, Q. Wang, C. Chen, Z. Han, X.-Q. Dong, X. Zhang, Org. Lett.
2016, 18, 3290.
[9]
a) G. Natta, P. Pino, The 12th International Congress of Pure and
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Wotiz, I. Wender, J. Org. Chem. 1957, 22, 542; c) B. Fell, M. Beutler,
Tetrahedron Lett. 1972, 13, 3455; d) C. Botteghi, C. Salomon,
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[12] X. Luo, R. Bai, S. Liu, C. Shan, C. Chen, Y. Lan, J. Org. Chem. 2016, 81,
2320.
[13] For selected reviews on shuttle catalysis, see: a) B. N. Bhawal, B.
Morandi, ACS Catal. 2016, 6, 7528; b) B. N. Bhawal, B. Morandi, Chem.
Eur. J. 2017, 23, 12004. For selected examples, see: c) C.-H. Jun, H.
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Masui, M. Yoshida, T. Hayashi, J. Am. Chem. Soc. 2012, 134, 272; e) X.
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[15] CCDC 1885349 (A30) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data
request/cif.
Scheme 3. Control experiments and one-pot reactions. TOSMIC = tosylmethyl
isocyanide.
[16] A. M. van Leusen, B. E. Hoogenboom, H. Siderius, Tetrahedron Lett.
1972, 13, 2369.
In summary, we have demonstrated a syngas-free rhodium-
catalyzed highly chemo-, regio- and E/Z-selective transfer
hydroformylation of alkynes under safe and mild conditions. This
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10.1002/anie.201902553
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COMMUNICATION
Guangying Tan, Yimin Wu, Yang Shi,
and Jingsong You*
Page No. – Page No.
Syngas-Free Rhodium-Catalyzed
Highly Regioselective Transfer
Hydroformylation of Alkynes to α,β-
Unsaturated Aldehydes
Overcoming the challenge posed by the use of syngas: A syngas-free highly
chemo-, regio- and E/Z-selective transfer hydroformylation of internal alkynes with
simple alkyl aldehydes under safe and mild conditions has been developed to
provide a broad range of stereodefined α,β-unsaturated aldehydes.
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