Ni-Catalyzed Asymmetric Hydrophosphination of Unactivated Alkynes

Article abstract of DOI:10.1021/jacs.1c05649

The practical synthesis of P-stereogenic tertiary phosphines, which have wide applications in asymmetric catalysis, materials, and pharmaceutical chemistry, represents a significant challenge. A regio- and enantioselective hydrophosphination using cheap a

Full text of DOI:10.1021/jacs.1c05649

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Ni-Catalyzed Asymmetric Hydrophosphination of Unactivated
Alkynes
Xu-Teng Liu, Xue-Yu Han, Yue Wu, Ying-Ying Sun, Li Gao, Zhuo Huang, and Qing-Wei Zhang*
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ABSTRACT: The practical synthesis of P-stereogenic tertiary phosphines, which have wide applications in asymmetric catalysis,
materials, and pharmaceutical chemistry, represents a significant challenge. A regio- and enantioselective hydrophosphination using
cheap and ubiquitous alkynes catalyzed by a nickel complex was designed, in which the toxic and air-sensitive secondary phosphines
were prepared in situ from bench-stable secondary phosphine oxides. This methodology has been demonstrated with unprecedented
substrate scope and functional group compatibility to afford electronically and structurally diversified P(III) compounds. The
products could be easily converted into various precursors of bidentate ligands and organocatalysts, as well as a variety of transition-
metal complexes containing both P- and metal-stereogenic centers.
P-Stereogenic phosphines played a key role in the early stages
of homogeneous asymmetric catalysis as chiral ligands of
transition metals.1 Further development in this area has
culminated in the discovery of the ligand DiPAMP, which led
to the industrial production of L-Dopa by an asymmetric
hydrogenation reaction.2 As a continuous effort, several new
types of P-stereogenic phosphines have been developed in the
past two decades with significant applications as both ligands
and organocatalysts (Figure 1a).3−5
However, the challenges in the asymmetric synthesis of P-
stereogenic phosphines have been a persistent barrier to their
further investigations and applications.6,7 Among the strategies
developed, the catalytic asymmetric synthesis of P-stereogenic
phosphines,8 especially with strategies that could directly
create the chiral center by carbon−phosphine bond formation,
has shown great potential in the past two decades.9 Significant
advances have been made, in which the dynamic kinetic
resolution (DKR) of secondary phosphines is regarded as the
most straightforward and promising strategy (Figure 1b).10
However, there are two formidable challenges: i.e., the
handling of highly sensitive, volatile, and toxic secondary
phosphines and the catalyst inhibition or poisoning caused by
competitive coordination of P(III) starting materials and
Figure 1. Construction of P-chiral phosphines: (a) application of P-
stereogenic phosphines; (b) DKR reactions of secondary phosphines;
(c) this work.
products to transition metals. As a result, these reactions have
been accomplished with limited substrate scope and restricted
catalytic systems.
The hydrophosphination reaction of unactivated alkenes and
alkynes represents an economical and straightforward method
to acquire valuable tertiary phosphines.11 However, the
reaction often suffers from harsh conditions and elusive
regioselectivities and the catalytic asymmetric syntheses of the
P-stereogenic center by hydrophosphination type reactions
have had limited success.12−14 In particular, the direct
synthesis of P(III) stereogenic phosphines by the asymmetric
hydrophosphination of alkynes with free secondary phosphines
is unprecedented, and a general method to structurally
diversify chiral phosphines with universal applications is highly
desirable.
Received: June 1, 2021
Published: July 20, 2021
https://doi.org/10.1021/jacs.1c05649
J. Am. Chem. Soc. 2021, 143, 11309−11316
© 2021 American Chemical Society
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Table 1. Substrate Scope of Secondary Phosphine Oxides
a
b
c
d
e
−20 °C. L14 (6 mol %) as a chiral ligand. 25 °C. 0 °C. All reactions were performed on a 0.1 mmol scale. Reduction yields are given in
parentheses on the basis of 31P NMR analyses with P(O)(OMe)3 as an internal standard. Isolated yields were the combined yields of two isomers
based on secondary phosphines. ee values of the major isomers are shown and were determined by chiral HPLC analyses. rr values (branched/
linear) were determined by H NMR analyses of the crude reaction mixtures.
1
Herein, we conceived an enantioselective hydrophosphina-
tion reaction with inexpensive alkynes and free secondary
phosphines by solving the two challenges arising from both the
substrate and the catalyst. We acquired the labile secondary
phosphines by in situ reduction of bench-stable secondary
phosphine oxides, avoiding their isolation and purification
while maintaining their structural diversity. In addition, the
relatively “hard” Ni along with universal bidentate ligands was
introduced as the catalyst to minimize the competitive
coordination of relatively “soft” monodentate secondary
phosphines and the tertiary phosphine products, thus
eliminating the possible background reactions (Figure 1c).15
The hypothesis started from the reduction of secondary
phosphine oxides (SPOs), which could serve as bench-stable
precursors of secondary phosphines (SPs). PhSiH3 was found
to be an ideal reductant to realize the transformation under
mild conditions.16 After an extensive evaluation, we identified
the optimized reaction conditions with in situ generated
secondary phosphines. The reaction was accomplished with
the best results by introducing [Ni(COD)2] (5 mol %) as the
catalyst, (S,S)-BDPP (6 mol %) as the ligand, and
(PhO)2PO2H (5 mol %) as an additive in toluene (0.1 M)
at −30 °C. The Markovnikov product was obtained in
excellent regio- and enantioselectivity (see Tables S1−S4 for
details).17
We then evaluated the scope of secondary phosphines
(Table 1). A variety of secondary phosphines were synthesized
via in situ reduction of the corresponding SPO with PhSiH3 in
78% to quantitative NMR yield. The tertiary phosphine
products were protected as either phosphine boranes or
sulfides, which could be easily deprotected or derivatized.18
The Markovnikov addition products were generally obtained
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Table 2. Substrate Scope of Alkynes
a
b
c
d
e
0 °C. −10 °C. 0.2 mmol of SPO1 and 0.1 mmol of alkyne were employed. rt, w/o (PhO)2PO2H, 48 h. All reactions were performed on a 0.1
mmol scale. Isolated yields are the combined yields of two isomers based on SPO1. ee values were determined by chiral HPLC analyses. rr values
(branched/linear) were determined by H NMR analyses of crude reaction mixtures.
1
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Figure 2. Synthetic applications: (a) transformations of 1; (b) transformations of phosphine sulfide 1-S; (c) synthesis of chiral transition-metal
complexes; (d) proposed mechanism. See the Supporting Information for experimental details.
with moderate to excellent results (Table 1). The stereo-
hindrance of the alkyl group substituent of phosphines was
critical to the enantioselectivities of the reaction. Secondary
alkyl groups including isopropyl (1), cyclopentyl (2), and
cyclohexyl (3) could give excellent enantioselectivities (99 to
>99% ee) and high yields and regioselectivities (80−86% yield,
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4:1 to >20:1 rr), while primary alkyl groups could only give
moderate enantioselectivities. In these cases, L14 was used
instead as the chiral ligand and the reactions could give the
desired products in 74−96% yield, 61−82% ee, and 10:1 to
>20:1 rr (4−12). Substituents at the para and meta positions
of the phenyl group were all compatible to give excellent
enantioselectivities and regioselectivities along with moderate
to high yields (14−20). Unfortunately, the secondary
phosphine with an o-MeO-phenyl group was unreactive even
at rt, possibly because the substrate could serve as a bidentate
ligand to the nickel catalyst and deactivate the reaction. The
reactions of secondary phosphines with naphthyl, thiophenyl,
and furyl groups could also proceed facilely to afford the
corresponding products in high to excellent ee (97%, 92%, and
88% ee; 21−23, respectively).
The scope of alkynes was then evaluated (Table 2).
Substituents with various electronic properties and at different
positions were considered. Trifluoromethyl groups at the ortho,
meta, and para positions could all give the chiral phosphine
products in 86%, 91%, and >99% ee with 65−99% yields (24−
26, respectively). Terminal alkynes with a variety of functional
groups, including electron-withdrawing groups (27−34) and
electron-donating groups (35−41) were all amenable to the
reaction, affording the corresponding phosphine boranes and/
or phosphine sulfides in 56−99% yield and 83−>99% ee. It is
worth mentioning that the labile aldehyde and bromide groups
were both compatible with the nickel catalysis system and
afforded the desired products in moderate to high yields (56%
and 80/96%). Functional groups with an acidic proton
including phenol, acetamido, and alcohol were tolerated in
the reaction, affording the major Markovnikov products with
91% (42), 87% (43), and 96% ee (44) albeit in modest
regioselectivity (1:1 to 3:1). Alkynes with naphthyl, thienyl,
and ferrocenyl groupd could generate the corresponding
phosphine adducts with excellent yields and enantio- and
regioselectivities (45−47) as well. Cyclopropylacetylene with
an alkyl substituent exhibited a moderate yield and stereo-
control (48) without the ring-opening product (67% yield,
51% ee). 1,4-Diethynylbenzene with two ethynyl groups could
also participate in the reaction, affording the double-hydro-
phosphination product 49-BH3 in 56% yield with 95% ee and
>20:1 rr and excellent dr (>20:1).
Internal alkynes were also examined. Symmetrical diaryl
alkynes could give exclusively the cis-hydrophosphination
products (50−53) in 76−94% ee and 65−82% yields. The
absolute configuration (SP) was also confirmed by an X-ray
single-crystal diffraction analysis of the compound 50-BH3.
Among them, the tertiary P-stereogenic phosphine 52 was
stable to oxygen and was isolated in 82% yield and 94% ee
directly without a protecting group. Unsymmetrical alkyne
with varied electronic properties could afford the desired
product 54-S in 84% ee, 67% yield, and 7:1 rr, in which the
electron-poor site of the alkyne was prone to P−C bond
formation. Internal alkynes with one aryl group and one alkyl
group could afford the desired products (55-BH3 and 56-BH3)
in excellent regioselectivities (>20:1), as well as high
enanantioselectivities (87%, 83% ee) and high yields (85%,
78%). Interestingly, the reaction of a diacetylene substrate
proceeded through monohydrophosphination, selectively
providing the desired product 57-S in 88% yield, 48% ee,
and >20:1 rr.
Initially, the reaction was scaled up to 1 mmol with comparable
results (98% ee, 95% yield, >20:1 rr) and further to a 5 mmol
scale, accomplishing the synthesis of 1-BH3 in 72% isolated
yield with 95% ee and >20:1 rr under the standard conditions.
Derivatives of phosphine, including phosphine oxides, sulfide,
and selenides, had been shown to exhibit diverse catalytic
activities in a series of reactions.19−21 Those compounds were
synthesized efficiently by adding respectively H2O2, S8 (also
see Table 1), and Se to the reaction mixture to afford the
corresponding products in high yields while maintaining the ee
values. A Staudinger reaction occurred smoothly when the
reaction mixture was treated with tosyl azide to afford the P-
stereogenic iminophosphorane product 58 in 82% overall yield
and 97% ee. The quaternary phosphonium salt 61 (85% yield,
95% ee) that could serve as a potential phase transfer catalyst22
was obtained when the reaction system was treated with
methyl iodide (Figure 2a).
The phosphine sulfide product 1-S (from 1 mmol scale)
could undergo 1,4-addition reactions with a variety of
nucleophiles to synthesize the potential chiral bidentate ligands
(Figure 2b). For example, diphenylphosphine can react with 1-
S under basic conditions to generate diphosphine sulfide 62 in
84% yield with 5:1 dr upon quenching with S8. The absolute
and relative configurations of 62 were determined by a X-ray
single-crystal diffraction analysis. Similarly, a triazole derivative
(63) and thioethers (64 and 65) were also accessible through
the 1,4-addition in good to excellent yields. These compounds
might serve as precursors of P−P, P−N, and P−S chiral
bidentate ligands to transition metals.
More importantly, P-stereogenic phosphines play a signifi-
cant role in transition-metal catalysis. Herein we investigated
the coordination of the chiral phosphine products to transition
metals. The tertiary phosphine 1 with 98% ee was used in the
following reactions. When the reaction mixture containing 1
was treated with late transition metals, including [Ru(p-
cymene)Cl2]2, [Cp*RhCl2]2, and [Cp*IrCl2]2, coordination
followed by C−H bond metalation reaction occurred23 to
afford complexes 66−68 with both phosphorus and metal
stereogenic centers24 in 50−58% overall yields, 96−97% ee,
and (5−15):1 dr (Figure 2c). Palladium dichloride also
underwent C−H activation with the chiral phosphine product
under mild conditions to afford 69 in 56% yield with a slightly
decreased 90% ee, when it was treated further with sodium
acetylacetonate. In addition, the trans product 70 with two
chiral phosphine ligands was obtained without C−H bond
activation in 91% yield, >99% ee, and 20:1 dr when platinum
dichloride was introduced. The absolute configuration of 70
was also determined by an X-ray single-crystal analysis. It is
worth mentioning that all of the transition-metal complexes
could be easily isolated and purified by flash column
chromatography or by precipitation from the reaction mixture.
To further understand the mechanism of this reaction,
several experiments were carried out and analyzed by 31P NMR
(see the Supporting Information for details). The resting state
of the catalyst was different with or without the additive
(PhO)2PO2H in our reaction according to an NMR analysis.
As predicted, although the secondary phosphines (SP1) could
coordinate to the nickel complex to some extent, the
coordination is much weaker in comparison with alkynes
(A52) and (S,S)-BDPP. The binding between P(III)
compounds with Ni was reversible and could transform back
to the resting state when an alkyne was added. We also
monitored the ee of the product intermittently, and it did not
To demonstrate the synthetic utility of our protocols, further
transformations of P-stereogenic phosphines were investigated.
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change throughout the reaction period. Thus, we can conclude
as predicted that both the secondary phosphine starting
material and the tertiary phosphine product to a large extent
would not interfere with the enantioselectivity of the reaction.
On the basis of our observation and previous results, the
mechanism is proposed in Figure 2d.12,25 When the additive is
absent, the catalyst resting state II was generated from Ni-
BDPP-COD and alkyne via ligand exchange, which could
undergo hydronickelation with a secondary phosphine to
afford the intermediate II. Then the vinyl nickel intermediate
III could undergo reductive elimination to produce the chiral
phosphine product. On the other hand, the Ni(0) complex I
was first converted into Ni(II) intermediate IV via oxidative
addition in the presence of (PhO)2PO2H (please see the
Supporting Information). Ligand exchange by the secondary
phosphine and subsequent hydronickelation with alkyne could
produce intermediate V, which could then undergo reductive
elimination to afford the final product (Figure 2d).
In summary, an efficient and straightforward access to P-
stereogenic phosphines with excellent enantioselectivity was
developed. The products could be easily transformed directly
to a plethora of potential organocatalysts, chiral ligands, or
their precursors, as well as transition-metal complexes.
Notably, this method avoids the direct handling of toxic, air-
sensitive secondary phosphines, enables the synthesis of P-
stereogenic phosphines with a broad substrate scope and better
practicality, and offers new exciting opportunities in related
areas.
Ying-Ying Sun − Department of Chemistry, University of
Science and Technology of China, Hefei 230026, People’s
Republic of China
Li Gao − Department of Chemistry, University of Science and
Technology of China, Hefei 230026, People’s Republic of
China
Zhuo Huang − Department of Chemistry, University of Science
and Technology of China, Hefei 230026, People’s Republic of
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05649
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the
National Key R&D Program of China (2018YFA0702001),
the NSFC (21901235, 22071224), the USTC
(KY2060000121, WK2060190095, and KY2060000143), the
USTC Research Funds of the Double First-Class Initiative
(YD2060002010), the Anhui Provincial Natural Science
Foundation (BJ2060190092), and the key laboratory of drug
targeting and drug delivery system, ministry of education
(Sichuan University).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05649.
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(PDF)
Accession Codes
CCDC 2048638−2048642 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Qing-Wei Zhang − Department of Chemistry, University of
Science and Technology of China, Hefei 230026, People’s
Republic of China; orcid.org/0000-0002-8577-6304;
Email: qingweiz@ustc.edu.cn
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Xu-Teng Liu − Department of Chemistry, University of Science
and Technology of China, Hefei 230026, People’s Republic of
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Xue-Yu Han − Department of Chemistry, University of Science
and Technology of China, Hefei 230026, People’s Republic of
China
Yue Wu − Department of Chemistry, University of Science and
Technology of China, Hefei 230026, People’s Republic of
China
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