Direct Access to Allenylphosphine Oxides via a Metal Free Coupling of Propargylic Substrates with P(O)H Compounds

Article abstract of DOI:10.1021/acs.orglett.9b03645

A direct and convenient approach for the coupling of propargylic substrates with diphenylphosphine oxide in the presence of Tf₂O and 2,6-lutidine has been developed. The method provides a general approach for the construction of attractive allenylphosphoryl skeletons with high atom and step economy under metal free conditions.

Full text of DOI:10.1021/acs.orglett.9b03645

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Access to Allenylphosphine Oxides via a Metal Free Coupling
of Propargylic Substrates with P(O)H Compounds
Chun-Hua Yang,† Huihui Fan,†,§ Huimin Li,†,§ Shenyin Hou,† Xiangkun Sun,† Donghao Luo,†
Yinchao Zhang,† Zhantao Yang,*,†,‡ and Junbiao Chang*,‡
†Henan Key Laboratory of New Optoelectronic Functional Materials, College of Chemistry and Chemical Engineering, Anyang
Normal University, 436 Xian’ge Road, Anyang 455000, P. R. China
‡School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
S
* Supporting Information
ABSTRACT: A direct and convenient approach for the
coupling of propargylic substrates with diphenylphosphine
oxide in the presence of Tf2O and 2,6-lutidine has been
developed. The method provides a general approach for the
construction of attractive allenylphosphoryl skeletons with
high atom and step economy under metal free conditions.
Scheme 1. Synthetic Methods for Allenylphosphoryl
Compounds
rganophosphorus compounds have found widespread
1
Oapplication in organic synthesis and material chemistry,
and they are privileged frameworks in biological and medicinal
chemistry.2 Allene motifs, which have two π-orbitals
perpendicular to each other, have attracted a tremendous
amount of attention recently.3 Among them, phosphoryl
allenes are versatile reagents that are widely used in organic
synthesis.4 For example, phosphoryl allenes can be transformed
into functionalized olefins,4d,j,k,5 chiral organophosphorus
compounds,4b,c and phosphorus-containing heterocyclic
drugs.4f,g,6 In addition, some allenylphosphine oxides have
good bioactive ability.7
As such, this is significant for the construction of
phosphorylated allenes. Traditionally, these compounds were
prepared through the Horner−Mark [2,3] rearrangement
reaction discovered in 1962.8 It is a general approach for the
synthesis of phosphorylated allenes.9 However, this process
requires the previous preparation of a rearrangement precursor
and the use of phosphorus chlorides that are unstable and
hazardous. Recently, substitution reactions of propargylic
substrates with P(O)H compounds catalyzed by a transition
metal affording allenylphosphoryl moieties have been reported
(Scheme 1). Stawinski et al. developed a Pd(0)-catalyzed
substitution reaction of propargylic substrates with H-
phosphonate diesters for the preparation of allenylphospho-
nates.10 In 2016, Zhao et al. reported a method for the
synthesis of allenylphosphoryl compounds via a Cu-catalyzed
coupling of propargylic alcohols with diphenylphosphine
oxide.11 This provides a new method for the construction of
a C−P bond via an SN1-type reaction. Han et al. realized the
preparation of phosphoryl allenes directly using copper as the
catalyst12 and described a coupling reaction of propargyl
alcohols with diarylphosphine oxides catalyzed by CdCl2 in
2017.13 However, the use of precious metals is usually
necessary for efficient catalytic conversion, which limits the
substrate scope and the actual application of these methods.
Recently, Miura and Hirano reported a strategy for the
generation of phosphenium cations from secondary phosphine
oxides promoted by Tf2O. The phosphenium cations have high
electrophilicity and reactivity and could be used for
phosphinative cyclization,1j [3+2] cycloaddition14 with al-
kynes, and the preparation of dibenzophospholes.15 We are
interested in the reactivity of the phosphenium cations
generated in situ with propargylic substrates and report our
results on the coupling of propargylic substrates with
diphenylphosphine oxide to afford allenylphosphine oxides
(Scheme 1).
We initially studied the coupling reaction with 3-
(trimethylsilyl)prop-2-yn-1-ylmethanesulfonate (1a) and di-
phenylphosphine oxide (2a). Gratifyingly, with the treatment
of 2,6-lutidine and Tf2O under a N2 atmosphere, the desired
Received: October 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03645
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
product allenylphosphoryl compound 3a was obtained in 55%
yield (Scheme 2).
Then, we screened the scope of alkynes (Scheme 3). For R1
= alkyl, the reactions proceeded smoothly to afford the
Scheme 3. Coupling of Propargylic Substrates with Ph2P(O)
H (2a)
Scheme 2. Direct Coupling of 3-(Trimethylsilyl)prop-2-yn-
1-yl Methanesulfonate (1a) with Ph2P(O)H (2a) in the
Presence of 2,6-Lutidine and Tf2O
a
Then, we screened the scope of 3-silylprop-2-yn-1-yl
methanesulfonate, and the representative results are summar-
ized in Table 1. Furthermore, the reactions proceeded readily,
producing the desired allenylphosphine oxides with TES, TBS,
TIPS, and SiMe2Ph silyl groups (Table 1, entries 2−5,
respectively).
Table 1. Direct Coupling of 3-Silylprop-2-yn-1-yl
Methanesulfonate (1) with Ph2P(O)H (2a) Using Various
a
Silyl Substituents
b
entry
[Si]
product
yield (%)
1
2
3
4
5
TMS (1a)
TES (1b)
TBS (1c)
TIPS (1d)
SiMe2Ph (1e)
3a
3b
3c
3d
3e
65
88
79
70
73
c
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Tf2O (0.3
mmol), 2,6-lutidine (0.3 mmol), CH2Cl2 (2 mL), at room
b
temperature for 2 h under a N2 atmosphere. Yield of the isolated
c
product. The leaving group of Br took the place of OMs.
We next evaluated the leaving groups (LG) of the alkynes
(Table 2). When the leaving group used OTs in place of OMs,
allenylphosphine oxide 3a was acquired in 70% yield. Other
leaving groups, such as OAc, OP(O)(OPh)2, and bromine,
were suitable, and diphenyl[1-(trimethylsilyl)propa-1,2-dien-1-
yl]phosphine oxide (3a) was obtained with substrates bearing
these leaving groups.
a
Table 2. Scope of the Leaving Groups of Alkynes
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Tf2O (0.3
mmol), 2,6-lutidine (0.3 mmol), CH2Cl2 (2 mL), at room
b
b
temperature for 2 h under a N2 atmosphere. On a 2 g scale.
entry
LG
OTs (1f)
OAc (1g)
OP(O)(OPh)2 (1h)
Br (1i)
product
yield (%)
c
d
Byproduct of phosphonyl 1,3-diene (5l1) obtained in 14% yield. nd,
1
2
3
4
3a
3a
3a
3a
70
68
65
72
not detected.
corresponding allenylphosphine oxides in decent yields (5a−
5l). The numbers of carbon atoms in the substituents have less
influence on the reaction (5a−5f). When LG = I, the reaction
proceeds readily, producing the allene product (5e) in 85%
yield.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Tf2O (0.3
mmol), 2,6-lutidine (0.3 mmol), CH2Cl2 (2 mL), at room
temperature for 2 h under a N2 atmosphere. Yield of the isolated
product.
b
B
DOI: 10.1021/acs.orglett.9b03645
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Organic Letters
Letter
Substrates with R2 or R3 ≠ H reacted to a diminished extent
in the coupling reaction (5h−5k), with the generation of a
phosphonyl 1,3-diene byproduct. While substrates with R2 and
R3 ≠ H also reacted, the phosphonyl 1,3-diene byproduct was
formed even more readily. For example, the reaction of 1-(oct-
1-yn-1-yl)cyclohexyl acetate (4l) resulted in both allenylphos-
phine oxide (5l) and phosphonyl 1,3-diene (5l1) (see the
Supporting Information for details).
Scheme 5. 31P NMR Experiments of Ph2P(O)H (2a) with 4e
When R = aryl, the desired allenylphosphonates 5m−5r
were isolated in 65−79% yields, and the electronic effect of the
substituents on the aryl ring has no effect on the coupling
reaction. The reactions with substrates with electron-donating
or electron-withdrawing groups on the benzene ring could
proceed in moderate yields. Moreover, the reaction was not
sensitive to the position of the substituents on the aryl rings
(5q and 5r). When the substrate with a fluoride leaving group
(4n1; LG = F) was subjected to the reaction, the desired
product (5n) was not detected. To test the scalability of the
protocol, scale-up synthesis of 5a on a gram scale was carried
out. The reaction of 3-bromopropyne on a 2 g scale afforded
5a in 87% yield.
On the basis of the 31P NMR studies and previously
reported results, we propose a possible mechanism for the
coupling reaction of propargylic substrates with Ph2P(O)H
(Scheme 6). When diphenylphosphine oxide (2a) was mixed
Scheme 6. Proposed Reaction Mechanism
To examine the stereochemistry of this reaction, an
enantioenriched propargylic substrate (S)-4g (90% ee) was
subjected to the coupling reaction under the developed
conditions, and allenylphosphine oxide [(R)-5g] was acquired
in 90% ee (Scheme 4). The ee was not decreased compared
Scheme 4. Stereochemical Synthesis of Allenylphosphoryl
Product 5g
with trifluoromethanesulfonic anhydride (Tf2O), a phosphe-
nium species A was generated. The phosphenium species A
could couple with propargylic substrates 4 to form the
phosphirenium cation B. When the reaction was quenched
with a saturated aqueous NaHCO3 solution, a hydroxyl anion
would attack the phosphirenium cation B and form the
intermediate C. Then intermediate C removed a hydrogen ion,
producing allene product 5.
In summary, a general method for the synthesis of
allenylphosphine oxides with propargylic substrates is reported.
The phosphirenium species (Ph2POTf) produced in situ from
diphenylphosphine oxide promoted by Tf2O and 2,6-lutidine
reacts with propargylic substrates, yielding the allenylphosph-
onate products. 31P NMR studies suggest that the reaction
proceeds via an intermediate of phosphirenium species. The
mild reaction conditions, simple operation, good yields, and
high step and atom economy make this protocol a valuable
method for the preparation of various allenylphosphine oxides.
This method could be applied to the construction of (1-
silylpropa-1,2-dien-1-yl)phosphine oxides, and their further
applications are being investigated by our group.
with that of (S)-4g, but the allenylphosphoryl product 5g
prepared from (S)-oct-1-yn-3-ol by Horner−Mark [2,3]
rearrangement had the opposite configuration, (S)-5g (Scheme
4).
As reported by Miura and Hirano,1j,14,15 a phosphenium
species (Ph2POTf) would be generated from diphenylphos-
phine oxide promoted by Tf2O. The phosphenium species
(Ph2POTf) reacts with the propargylic substrates, yielding
allenylphosphonate products. To gain insights into the
pathway of the reaction, NMR experiments were carried out
using 4e as the substrate (see the Supporting Information for
details). The 31P NMR spectra showed that the signal of
phosphine oxide (2a) at δ 21.4 disappeared after the treatment
with 4e in CDCl3 under the standard conditions, and a signal
at δ −95.7 appeared. The signal at δ −95.7 corresponds to
phosphirenium species 6 (Scheme 5). When the reaction was
quenched with H2O, the signal at δ −95.7 disappeared and a
new signal at δ 29.5 was observed. The signal at δ 29.5 is
assigned to the allenylphosphonate (5e).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03645.
C
DOI: 10.1021/acs.orglett.9b03645
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Representative experimental procedures, characteriza-
Letter
Lian, X.; Zhao, J.; Yu, Y.; Ma, S. J. Org. Chem. 2009, 74 (3), 1130−
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Zhang, L.; Lu, A.-M.; Yang, F.; Wu, L. J. Org. Chem. 2015, 80 (1),
673−680.
tion data of substrates and products, and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(5) (a) Kumara Swamy, K. C.; Balaraman, E.; Satish Kumar, N.
Tetrahedron 2006, 62 (43), 10152−10161. (b) Chakravarty, M.;
Kumara Swamy, K. C. Synthesis 2007, 2007 (20), 3171−3178.
(c) Guo, H.; Qian, R.; Guo, Y.; Ma, S. J. Org. Chem. 2008, 73 (20),
7934−7938. (d) He, G.; Fu, C.; Ma, S. Tetrahedron 2009, 65 (38),
8035−8042. (e) He, G.; Guo, H.; Qian, R.; Guo, Y.; Fu, C.; Ma, S.
Tetrahedron 2009, 65 (25), 4877−4889. (f) Pavan, M. P.; Reddy, M.
N.; Kumar, N. N. B.; Swamy, K. C. K. Org. Biomol. Chem. 2012, 10
(40), 8113−8118.
*E-mail: changjunbiao@zzu.edu.cn.
*E-mail: zhantaoyang@163.com.
ORCID
Chun-Hua Yang: 0000-0002-3770-9887
Zhantao Yang: 0000-0003-1575-3665
Junbiao Chang: 0000-0001-6236-1256
Author Contributions
§H.F. and H.L. contributed equally to this work.
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the National
Natural Science Foundation of China (21801006 and
81703353), the China Postdoctoral Science Foundation
(2018T110744), the Natural Science Foundation of Henan
Province (182300410295), the project of Science and
Technology of the Department of Henan Province
(182102210202), and the Industrial Research Project of
Technology Bureau of Anyang.
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