Stereo- And Regioselective cis-Hydrophosphorylation of 1,3-Enynes Enabled by the Visible-Light Irradiation of NiCl2(PPh3)2

Article abstract of DOI:10.1021/acs.orglett.1c00626

Described herein is a stereo- and regioselective cis-hydrophosphorylation reaction of the internal alkyne of 1,3-enynes that accesses various 1,3-dienes in good isolated yields. The visible-light irradiation of NiCl2(PPh3)2 allows the generation of highly reactive nickel(II)-phosphorus species that subsequently migrate into the internal alkyne of the 1,3-enynes and protonate the resulting vinyl nickel species, leading to various phosphinoyl 1,3-butadienes under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.1c00626

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Letter
Stereo- and Regioselective cis-Hydrophosphorylation of 1,3-Enynes
Enabled by the Visible-Light Irradiation of NiCl2(PPh3)2
Hong Hou,* Bing Zhou, Jiawei Wang, Dengyang Zhao, Duhao Sun, Xiaoyun Chen, Ying Han,
Chaoguo Yan, Yaocheng Shi, and Shaoqun Zhu*
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ABSTRACT: Described herein is a stereo- and regioselective cis-hydrophosphorylation reaction of the internal alkyne of 1,3-enynes
that accesses various 1,3-dienes in good isolated yields. The visible-light irradiation of NiCl2(PPh3)2 allows the generation of highly
reactive nickel(II)-phosphorus species that subsequently migrate into the internal alkyne of the 1,3-enynes and protonate the
resulting vinyl nickel species, leading to various phosphinoyl 1,3-butadienes under mild reaction conditions.
Scheme 1. Different Activation Strategies for the
Hydrophosphorylation and Visible-Light-Driven In Situ
Generation of Active NiII Species
lkenyl phosphine oxide is of great importance in
medicinal, agricultural, and material chemistry,1,2 as well
A
as in organic synthesis, and can not only be used as a synthetic
intermediate but also widely act as a versatile ligand precursor
in transition-metal catalysis.3,4 As such, it is not surprising that
the development and simplification of synthetic catalytic
methodologies to access alkenyl phosphine oxide have received
great attention, and great improvements have been achieved.5
The direct activation of (O)P−H bonds and their addition
to unsaturated bonds is one of the most straightforward
methods, and different activation strategies have been reported
for the addition of phosphine oxide to CC and CC
bonds.6 The treatment of diaryl phosphine oxide by transition
metals and stoichiometric oxidants or the presence of radical
initiators was demonstrated to generate phosphorus radicals
that reacted with various alkynes. The reaction outcomes were
dependent on the alkyne substrate, and a Z/E mixture of anti-
Markovnikov hydrophosphorylation products from the termi-
nal alkyne and benzophosphole oxide products was obtained
from the internal alkynes (Scheme 1a).7−9 The Wu, Lei, and
Han groups reported the generation of phosphine radicals and
their addition to terminal alkynes, affording (Z)-alkenylphos-
phine oxides via visible-light photochemical conditions.10−12
Alternatively, active metal hydride species generated by the
oxidative addition of (O)P−H bonds to a zero-valent
transition metal were well-developed for the phosphorylation
reactions, as Ni0 and Pd0 were reported to effectively catalyze
the syn-addition of P(O)−H bonds to alkynes. Han and co-
workers demonstrated various additions of P(O)−H bonds to
terminal alkynes, but a mixture of regioisomers was obtained
(Scheme 1b).13
Received: February 24, 2021
Published: March 30, 2021
https://doi.org/10.1021/acs.orglett.1c00626
© 2021 American Chemical Society
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a
Table 1. Reaction Development and Optimization
Table 2. Scope of 1,3-Enynes for Stereo- And Regioselective
cis-Hydrophosphorylation
a
b
entry
deviation from the standard conditions
yield (%)
c
1
2
3
4
5
6
7
L-1
L-2
82 (75)
36
<5
40
18
L-3, L-4, or without a ligand
THF instead of MeOH
MeCN instead of MeOH
toluene instead of MeOH
NiBr2(PPh3)2, NiCl2DME, NiCl2(PMe3)2, or NiCl2 as
the catalyst
27
n.r.
8
9
10
no light
no Cs2CO3
in air
<5
0
0
a
1a (0.3 mmol), 2a (0.2 mmol), catalyst (0.02 mmol), ligand (0.024
mmol), Cs2CO3 (0.4 mmol), and MeOH (2.0 mL); for details, see
b
the Supporting Information. NMR yield using 1,3,5-trimethoxyben-
c
zene as the internal standard. Yield of isolated 3aa.
The photoredox and nickel dual-catalyzed cross-coupling
reaction and C−H functionalization have drawn great
attention, and most of the reported examples underwent either
a single-electron transfer or energy-transfer process.14,15 More
recently, Miyake and co-workers demonstrated a C−N cross-
coupling reaction via the photoexcitation of nickel(II)−amine
complexes.16 Doyle, Xue, and their co-workers individually
reported the photoinduced nickel-catalyzed C−O bond
formation via homolysis of NiII−aryl bonds for aryl radicals,
and NiI generation was the key step.17,18
We envisaged that visible-light irradiation of an electron-
deficient ligand derived NiII complexes, such as NiX2(PPh3)2,
could result in a NiI species and halogen atom radical
generation via a ligand-to-metal charge-transfer process
(LMCT).19 Hydrogen atom transfer (HAT) between R−H
and a halogen atom radical species would give radical R·, and
rebonding with the NiI species would give the active X−NiII−R
species in a redox-neutral manner, which could enable the
stereo- and regioselective cis-hydrofunctionalization of alkynes
(vide infra) (Scheme 1d).
In continuing our research program on visible-light photo-
chemistry, as well as alkenyl phosphine oxide synthesis,20 we
describe the visible-light-driven nickel-catalyzed stereo- and
regioselective cis-hydrophosphorylation of 1,3-enynes that
accesses various (E)-1,3-dienes without using an added
photocatalyst (Scheme 1c).
a
1 (0.3 mmol), 2a (0.2 mmol), NiCl2(PPh3)2 (0.02 mmol), L-1
(0.024 mmol), Cs2CO3 (0.4 mmol), and MeOH (2.0 mL); for details,
b
see the Supporting Information. Yield of isolated 3aa−3va;
c
PheOMe, methyl L-phenylalaninate. The reaction was run on a 6.0
mmol scale; see the Supporting Information for details.
Initially, the reaction of 1,3-enyne (1a, 0.3 mmol) with
diphenylphosphine oxide (2a, 0.2 mmol) was carried out using
NiCl2(PPh3)2 (10.0 mol %) as the catalyst, 1,10-phenanthro-
line (L-1, 12.0 mol %) as the ligand, 2.0 equiv of Cs2CO3 as
the base, and 2.0 mL of MeOH as the solvent. After the
reaction mixture was stirred at room temperature and
irradiated by a blue LED strip for 12 h, the (E)-1,3-diene
3aa was generated, detected in an 82% NMR yield, and
isolated in a 75% yield (entry 1, Table 1). The (E)-
configuration of the internal CC bond and the (S)-trans-
configuration of the 1,3-diene were determined by a single-
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Table 2). The ferrocene group was tested and proved to be
compatible, and the desired product 3ra was obtained in a 41%
yield (entry 18, Table 2).
Table 3. Phosphine Oxide Scope for Stereo- And
Regioselective cis-Hydrophosphorylation
a
In view of the vinyl group of the 1,3-enynes, different alkyl
groups on the α- or β-position were tested, and all were
compatible under the current reaction conditions. 3sa and 3ta,
with cyclopropyl groups or hydrogen atoms at the α-position,
respectively, were obtained in 65% and 58% yields (entries 19
and 20, Table 2). The gem-dimethyl groups at the terminal
position also successfully gave the desired product 3ua,
although the yield was low (34% yield, entry 21, Table 2).
To evaluate the synthetic utility of the stereo- and
regioselective cis-hydrophosphorylation protocol, the reaction
was scaled up to 6.0 mmol 1a and 2a under the standard
reaction conditions, affording 1.67 g of 3aa in a 74% isolated
yield (entry 1, Table 2).
The phosphine oxide scope for the present stereo- and
regioselective cis-hydrophosphorylation reaction was tested
next, and various phosphine oxides (2b−2p) were subjected to
the reaction conditions. Both the same and different aryl
group-derived phosphine oxides were tested, and all could be
used. Different aryl group-derived phosphine oxides were
tested next. All the reactions were successful, and the
corresponding products 3ab−3af and 3kg−3kn were obtained
in moderate to good yields (40−80%, entries 1−13, Table 3).
Different alkyl groups such as n-butyl- and benzyl-derived
phenyl phosphine oxides were successfully subjected to the
reaction conditions, and 3ko and 3kp were obtained in 45%
and 40% yields, respectively (entries 14 and 15, Table 3).
To identify the role of the alkene in cis-hydrophosphor-
ylation, the reaction of prop-1-yn-1-ylbenzene 4 with 2a under
standard reaction conditions was carried out, and the reaction
gave an inseparable mixture of products 5 and 6 in a 53%
combined yield. The 31P NMR analysis indicated that 5 and 6
were in a 2:1 ratio (Scheme 2). The above results
demonstrated that the alkene motif of the 1,3-enynes was
crucial for excellent stereo- and regioselectivities (see the
Supporting Information for details).
a
1a or 1j (0.3 mmol), 2 (0.2 mmol), NiCl2(PPh3)2 (0.02 mmol), L-1
(0.024 mmol), Cs2CO3 (0.4 mmol), and MeOH (2.0 mL); for details,
see the Supporting Information. Yield of isolated 3ab−3jp.
b
crystal diffraction analysis.21 Different ligands were tested next,
and a more sterically hindered ligand gave the product in a
lower yield; when 2,9-dimethyl-1,10-phenanthroline L-2 was
used, 3a was detected in a 36% NMR yield (entry 2, Table 1).
When L-3 or L-4 was used, no reaction was observed (entry 3,
Table 1). Different solvents, such as THF, MeCN, and toluene,
were tested next, and no better results were obtained (entries
4−6, respectively, Table 1). Various NiII complexes, such as
NiBr2(PPh3)2, NiCl2DME, NiCl2(PMe3)2, and NiCl2, were
tested and failed to furnish 3aa (entry 7, Table 1). The
background reactions were carried out carefully, and 3aa was
not observed when the reactions were performed in the
absence of visible light, without the base or ligand, or under air
conditions (entries 8−10, respectively, Table 1).
Under the above standard reaction conditions, different 1,3-
enynes were tested. Terminal phenyl groups with different
substituents at the o-, p-, and m-positions were tested and
shown to be compatible, yielding the corresponding products
3aa−3oa in moderate to good yields (48−95%, entries 1−15,
Table 2). The complex substrate was tested next, and the
natural amino acid-derived product 3ja was obtained in a 58%
yield (entry 10, Table 2). Heteroaromatic groups such as 3-
thienyl and 3-pyridyl gave the corresponding products 3pa and
3qa in 35% and 48% yields, respectively (entries 16 and 17,
Scheme 2. Hydrophosphorylation of the Internal Alkyne
Preliminary mechanistic studies were carried out next, and
the results are listed in Scheme 3. The deuteration experiment
of 1k and d-2a (80% percent deuteration ratio) in d4-MeOH
successfully gave d-3ka in a 51% yield at a 70% deuteration
ratio (Scheme 3a). Switching the solvent from d4-MeOH to
MeOH led to the formation of 3ka without deuteration (see
the Supporting Information for details).
Radical survey and radical initiation experiments were next
performed. When 1.0 equiv of TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) was used as the additive, 3aa was not observed,
and diphenylphosphinic chloride 7 and its ester-derived 8 were
detected by high-resolution mass spectrometry (HRMS)
analysis (Scheme 3b). When BHT (2,6-di-tert-butyl-4-methyl-
phenol) 4 was used as the additive, 3aa was isolated in a 24%
yield; products 7, 8, and 9, the cross-coupling products of BTH
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Scheme 3. Preliminary Mechanistic Studies
Scheme 4. Proposed Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00626.
with a chlorine atom, were detected; and possible product 10
of the cross-coupling reaction of 2a with BTH was not
detected. The above results indicated that the present
transformation underwent a radical reaction pathway, and
the chlorine atom radical was generated under the present
reaction conditions (Scheme 3c).22
The possible radical addition mechanism for CC bond
hydrophosphorylation was ruled out by radical initiation
experiments. When tBuOOtBu was used as the radical initiator,
the hydroxyl phosphorylation product 11, which was generated
by the regioselective addition of the phosphorus atom radical
to the terminal CC bond of the 1,3-enyne, was observed and
isolated in a 78% yield. The possible products generated by the
addition of phosphorus atom radicals to the CC bond of the
1,3-enyne were not detected (Scheme 3d).
From the above reaction development, as well as previous
reports,23 the generation of nickel phosphine species induced
by visible light via a NiII/NiI/NiII cycle and their cis-addition to
the CC bond, followed by electrophilic protonation by
MeOH, is proposed in Scheme 4. The NiII intermediate A was
generated by the coordination of the Ni(PPh3)2Cl2 1,3-enyne
1a in the presence of the L-1, and visible-light irradiation of
complexes A generated the NiI species B and the chlorine atom
radical Cl· via the LMCT process.24 The hydrogen atom
abstraction of 2a by Cl· would generate the phosphorus atom
radical C, and rebonding with the NiI species would result in
the formation of the Cl−NiII−P(O)Ph2 species D. D would
then be inserted into the CC bond of 1,3-enyne 1a,
affording intermediate E, and rapid protonation by MeOH
would give the desired cis-hydrophosphorylation product
3aa.26
NMR spectra and X-ray data (PDF)
Accession Codes
CCDC 2020827 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Hong Hou − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China;
orcid.org/0000-0002-9103-9888; Email: hhou@
yzu.edu.cn
Shaoqun Zhu − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China;
orcid.org/0000-0003-2639-4098; Email: shaoqun.zhu@
yzu.edu.cn
Authors
Bing Zhou − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China
Jiawei Wang − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China
Dengyang Zhao − School of Chemistry & Chemical
Engineering, Yangzhou University, Yangzhou 225009, China
Duhao Sun − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China
Xiaoyun Chen − School of Environmental and Chemical
Engineering, Jiangsu University of Science and Technology,
Zhenjiang 212005, China
In conclusion, we have developed a visible-light-induced
nickel-catalyzed stereo- and regioselective cis-hydrophosphor-
ylation reaction of 1,3-enynes, which gives various phosphinoyl
1,3-butadienes in good yields.
Ying Han − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China
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Methods for the Introduction of a Phosphonic Acid Group. Chem.
Rev. 2011, 111, 7981−8006.
Chaoguo Yan − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China;
orcid.org/0000-0002-2777-9582
Yaocheng Shi − School of Chemistry & Chemical Engineering,
Yangzhou University, Yangzhou 225009, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00626
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (21602085 and 21702179), the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, the Natural Science Foundation of the Jiangsu
Higher Education Institutions of China (17KJB150042), and
the Lvyangjinfeng Talent Program of Yangzhou. We also thank
the Testing Centre of Yangzhou University for sample analysis.
We thank Prof. Dr. Hon Wai Lam and Prof. Dr. Zhixiang Yu
for fruitful discussions.
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