Br?nsted Acid Enabled Nickel-Catalyzed Hydroalkenylation of Aldehydes with Styrene and its Derivatives

Article abstract of DOI:10.1002/anie.201801817

A Br?nsted acid enabled nickel-catalyzed hydroalkenylation of aldehydes and styrene derivatives has been developed. The Br?nsted acid acts as a proton shuttle to transfer a proton from the alkene to the aldehyde, thereby leading to an economical and byproduct-free coupling. A series of synthetically useful allylic alcohols were obtained through one-step reactions from readily available styrene derivatives and aliphatic aldehydes in up to 88 % yield and with high linear selectivity.

Full text of DOI:10.1002/anie.201801817

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Accepted Article
Title: Brønsted Acid Enabled Nickel-Catalyzed Hydroalkenylation of
Aldehydes with Styrene and Derivatives
Authors: Mengchun Ye, Xing-Wang Han, Tao Zhang, Yan-Long Zheng,
Wei-Wei Yao, Jiang-Fei Li, You-Ge Pu, and Qi-Lin zhou
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801817
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10.1002/anie.201801817
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COMMUNICATION
Brønsted Acid Enabled Nickel-Catalyzed Hydroalkenylation of
Aldehydes with Styrene and Derivatives
Xing-Wang Han, Tao Zhang, Yan-Long Zheng, Wei-Wei Yao, Jiang-Fei Li, You-Ge Pu, Mengchun Ye*,
Qi-Lin Zhou
Abstract:
A
Brønsted
acid
enabled
nickel-catalyzed
regeneration of the activator became an elusive challenge in the
reaction. Herein, we report a discovery on using a catalytic or
substoichiometric amount of Brønsted acid, phenylboronic acid
(PhB(OH)2), as an efficient activator to facilitate a nickel-
catalyzed hydroalkenylation reaction of styrene and derivatives
with various aliphatic aldehydes in highly linear-selectivity
(Scheme 1d).
hydroalkenylation of aldehyde and styrene derivatives has been
developed. The Brønsted acid acted as a proton shuttle to transfer a
proton from the alkene to the aldehyde, leading to an economical
and byproduct-free coupling. A series of synthetically useful allylic
alcohols were obtained by one-step reaction from readily available
styrene and aliphatic aldehyde in up to 88% yield and high linear
selectivity.
Construction of allylic alcohol motifs received intensive
attentions from very early time owing to their being versatile
precursors of various functionalities and moieties in organic
synthesis.[1] Traditional method uses pre-formed alkenylmetal
reagents to couple with various carbonyl compounds (Scheme
1a). These alkenylmetal reagents are generally prepared in situ
by the reaction of alkenylhalides with stoichiometric amounts or
excesses of metallic reagents (Mg, Li and Zn),[2] or by the
reaction of alkenylhalides with a Cr catalyst and an excess of
reductants (Nozaki–Hiyama–Kishi reaction),[3] or by the
hydrometallation of alkyne with metallic hydride reagents.[4]
Another important alternative method employs transition metal-
catalyzed reductive coupling of alkynes with carbonyls in the
presence of metallic reductants,[5] hydrogen gas or hydrogen
donors,[6,7] avoiding the use of pre-formed alkenylmetal reagents
(Scheme 1b). Despite these advances, the direct coupling
reaction of abundantly available alkenes such as styrene and -
olefins with unactivated carbonyls to allylic alcohols is still highly
desirable because not only these alkenes are readily available
and inexpensive but also such coupling would eliminate the use
of external metallic reagents and reductants, leading to a more
atom-economical and more environmental-friendly reaction.[8–10]
In 2005, an important breakthrough was achieved in this regard
by Jamison and co-workers,[11] who used a Lewis acid activator,
triethylsilyl triflate (TESOTf), to facilitate a nickel-catalyzed direct
coupling of unactivated alkenes mainly with aromatic aldehydes,
affording a series of highly branched-selective allylic alcohol
derivatives (Scheme 1c). However, the use of TESOTf resulted
in its irreversible incorporation into the product, so that the
Scheme 1. Common strategies to allylic alcohols via C–C coupling reactions
of -compounds and carbonyls.
We commenced our studies by evaluating a wide range of
Brønsted acids in the reaction of styrene (1a) and 3-
phenylpropanal (2a) under the following conditions: 10 mol% of
Ni(cod)2 (cod
=
1,5-cyclooctadiene) and 20 mol% of
tricyclohexylphosphine (PCy3) in toluene at 75 °C (Scheme 2).[12]
In the absence of Brønsted acid, no direct addition reaction
occurred; instead a hydroacylation product was obtained in 24%
yield (entry 1). In the presence of Brønsted acid, such as TsOH,
PhCO2H, or AcOH (entries 2–4), desired allylic alcohol 3a was
indeed obtained with complete linear selectivity, albeit in very
low yield. The unique selectivity was presumably attributed to
the formation of a more stable benzylic nickel species during the
cyclometallation step. Encouraged by this result, we then tested
a broad range of Brønsted acids of various strengths (entries 5–
11) and found that phenol and phenylboronic acid showed
promise, affording 3a in 14% and 28% yields, respectively
(entries 6 and 9). Evaluation of electronic effect and loading
effect of them did not lead to significant improvements.
Surprisingly, subsequent experiments using PhB(OH)2 as the
activator revealed that various alcoholic solvents—including
primary, secondary, and tertiary alcohols—dramatically
promoted the reaction (entries 12–19). Ethanol was optimal,
[*]
Q.-S. Liu, Z.-J. Yang, D.-Y. Wang, Y.-L. Zheng, J.-F. Yang, Y.-G.
Pu, Prof. Dr. M. Ye
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071 (China)
E-mail: mcye@nankai.edu.cn
Prof. Dr. M. Ye
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300071 (China)
These authors contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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affording the desired product in 90% yield (entry 17). The
reaction was highly dependent on the nature of the phosphine
ligand (entries 20–22). Only certain phosphine ligands, including
PCy3, PCyp3, and PhPCy2, were effective; other commonly used
ligands,
such as trialkylphosphines,
triarylphosphines,
bisphosphines and carbenes, were unsuitable.
Scheme 2. Reaction optimization. 1a (0.625 mmol), aldehyde 2a (0.25 mmol),
solvent (2.0 mL) under N2 for 16 h. [a] Determined by 1H NMR using CH2Br2
as the internal standard. [b] PCyp3. [c] PhPCy2. [d] Ph2PCy. HFIP
hexafluoroisopropanol.
=
Scheme 3. Scope of aldehyde. 1a (1.25 mmol), 2 (0.5 mmol), EtOH (2.0 mL)
under N2 for 16 h. [a] Isolated yields and diastereoisomer ratios in parentheses
determined by 1H NMR of crude products. [b] 5 equivalents of styrene were
used.
With the optimized conditions in hand, we explored a series of
aliphatic aldehydes 2 to test the generality of the coupling
reaction with styrene (1a) (Scheme 3). The aldehydes without α-
substituents were well tolerated, affording corresponding
products 3a–3e in 46–82% yield with complete linear selectivity.
The presence of α-substituents did not retard the reaction and in
fact afforded better yields for those -substituents containing
heteroatoms (3i–3n). For example, aldehydes derived from
natural or unnatural amino acids reacted smoothly to produce
synthetically useful alkenylated amino alcohols 3i–3l in up to
88% yield. However, mixed diastereoisomers with ratios from
1.0:1 to 4.6:1 were obtained in these cases. Attempts to
enhance the diastereoselectivity by tuning ligands were not
successful owing to extremely limited scope of ligands.
Impressively, the most sterically demanding substrate,
pivaldehyde, underwent the hydroalkenylation to afford
corresponding alcohol 3o in 50% yield. In addition,
paraformaldehyde, an important C1 feedstock, was also
compatible with the reaction conditions, although at least 5
equivalents of styrene were required for a reasonable yield (45%,
3p). Notably, aromatic aldehydes such as benzaldehyde and 2-
furanaldehyde displayed low reactivity in this reaction, providing
the corresponding allylic alcohol in 34% yield (3q) and 24% yield
(3r), respectively.
Next, we examined the compatibility of various arylalkenes in
the hydroalkenylation reaction with 3-phenylpropanol (2a)
(Scheme 4).
Scheme 4. Scope of alkene. 1 (1.25 mmol), 2a (0.5 mmol), EtOH (2.0 mL)
under N2 for 16 h. [a] Isolated yields. [b] PhB(OH)2 (0.2 mmol, 40 mol%).
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The presence of either electron-donating groups or electron-
withdrawing groups on the phenyl ring of styrene derivatives had
little influence on the yield or selectivity of the reaction; the
corresponding products (4a–4k) were obtained in moderate to
good yields. However, the substrate bearing a meta-methoxy
group was an exception, only providing the corresponding
product in 40% yield (4b). We reasoned that a steric repulsion of
the meta-substituted group with the cyclohexyl group of the
ligand could give rise to the low reactivity. The presence of a
tracing experiments suggested a possible coordination of EtOH
to PhB(OH)2 could be formed in the excess of EtOH, which
could play an in-situ Brønsted acid role. Considering that nickel
easily catalyze the direct couplings of alkenes and carbonyls to
form a rigid oxanickellacycle,[16] we proposed that herein either
PhB(OH)2 or the coordinated complex of PhB(OH)2 with EtOH
could facilitate the ring opening of the oxanickellacycle through
protonation,[17] leading to subsequent -hydride elimination and
reductive elimination to provide the desired product and
regenerate PhB(OH)2 and the nickel catalyst (Scheme 6).
strongly electron-withdrawing substituent, CF3, led to
a
significantly decreased yield (34%, 4l). Notably, aliphatic
alkenes were incompatible with the reaction conditions,
providing either no reaction or homoallylic alcohols with linear
selectivity (see the Supporting Information).
To demonstrate the applicability of the current method, some
bio-active molecules were synthesized (Scheme 5). First, the
hydroalkenylation protocol could easily be carried out on a gram
scale with excellent yields. For instance, the reaction of amino-
acid-derived aldehyde 2i with styrene afforded 1.59 g of allylic
alcohol 3i (90% yield), which could be further transformed into
various biologically active molecules.[13] Starting from styrene
and aliphatic aldehyde 5, the natural product, darlinine (6),[14]
was obtained in 30% overall yield of two steps. Likewise, direct
coupling between styrene and pivalaldehyde produced a 50%
yield of the drug molecule, stiripentol (7). Compared with
traditional routes, these synthetic procedures eliminated the use
of an alkenylmetal reagent and external reductants, providing a
greener and more economical route.
Scheme 6. Proposed catalytic cycle of Brønsted acid.
In summary, we have developed a one-step hydroalkenylation
of unactivated aldehydes with styrene and derivatives. This new
C–C bond forming method relies on the use of a nickel catalyst
and a Brønsted acid co-catalyst to achieve an efficient route to
synthetically useful allylic alcohols. This co-catalyst strategy may
provide useful insights into transformations of oxanickellacycle.
Additionally, our substrate scope and linear selectivity is
complementary with that of Jamison’s system, thus offering a
useful complement. Further investigations to find more
promising ligands and more powerful co-catalysts for wider
substrate scope and enantioselective control are underway in
our lab.
Acknowledgements
We thank the National Natural Science Foundation of China
(21672107) for financial support.
Scheme 5. Reaction utilization.
Keywords: nickel • hydroalkenylation • alkene • aldehyde •
Brønsted acid
To understand the mechanism of this reaction, we conducted
some experiments. The absence of either nickel or phsophine
would shut down this reaction (see Table S1), and electron-rich
olefins such as isobutylene and 2,3-dimethylbutadiene cannot
deliver any desired products. These result suggested this
reaction may not proceed through a typical Prins process.[15] To
clarify the role of phenylboronic acid and ethanol in the reaction,
some control experiments were performed. Results showed that
EtOH alone, in the absence of PhB(OH)2, also promoted the
reaction, but the EtOH loading was critical. At least 5 equivalents
were required for a detectable yield (see the Supporting
Information), and even with a large excess of EtOH, only 65%
yield was obtained. These results suggested that both PhB(OH)2
and EtOH were essential for good reactivity. Further 1H NMR
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Entry for the Table of Contents (Please choose one layout)
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Xing-Wang Han, Tao Zhang, Yan-Long
Zheng, Wei-Wei Yao, Jiang-Fei Li, You-
Ge Pu, Mengchun Ye*，Qi-Lin Zhou
Page No. – Page No.
Brønsted Acid Enabled Nickel-
Catalyzed Hydroalkenylation of
Aldehydes with Styrene and
Derivatives
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