Golden Face of Phosphine: Cascade Reaction to Bridgehead Methanophosphocines by Intramolecular Double Hydroarylation

Article abstract of DOI:10.1021/acs.orglett.8b03474

Reported herein is the first example of a gold-catalyzed cyclization of bis(arylmethyl)ethynylphosphine oxides. This represents an original approach to bridgehead methanophosphocines 1, eight-membered heterocycles. Gold catalyst in combination with triflic acid activates alkyne and induces a double hydroarylation. Mechanistic studies suggest that the reaction proceeds stepwise, forming first the 1H-isophosphinoline 2-oxide 5. Reduction and protection of the corresponding phosphine oxides 1 described herein also highlight the effectiveness of our approach to this new class of electron-rich ligands.

Full text of DOI:10.1021/acs.orglett.8b03474

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Golden Face of Phosphine: Cascade Reaction to Bridgehead
Methanophosphocines by Intramolecular Double Hydroarylation
†,§
Rachida Babouri,†,‡ Lancine Traore, Yves-Alain Bekro,§ Victoria I. Matveeva,∥ Yulia M. Sadykova,∥
́
∥
∥
⊥
†
,†
̈
Julia K. Voronina, Alexander R. Burilov, Tahar Ayad, Jean-Noel Volle, David Virieux,*
and Jean-Luc Pirat*,†
†ICGM, ENSCM, CNRS, Univ Montpellier, Montpellier, France
‡
́
́
́
Laboratoire d’Obtention de Substances Therapeutiques (LOST), Universite Mentouri-Constantine, Departement de Chimie,
Campus Chaabet Ersas, 25000 Constantine, Algeria
§
́
Laboratoire de Chimie Bio Organique et de Substances Naturelles, UFR-SFA, Universite Nangui Abrogoua, 02 BP 801 Abidjan 02,
̂
Cote d’Ivoire
∥Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, Kazan 420088, Russian
Federation
⊥Institut de Recherche de Chimie Paris, PSL Research University, Chimie ParisTech − CNRS, 75005 Paris, France
S
* Supporting Information
ABSTRACT: Reported herein is the first example of a gold-catalyzed
cyclization of bis(arylmethyl)ethynylphosphine oxides. This represents
an original approach to bridgehead methanophosphocines 1, eight-
membered heterocycles. Gold catalyst in combination with triflic acid
activates alkyne and induces a double hydroarylation. Mechanistic
studies suggest that the reaction proceeds stepwise, forming first the
1H-isophosphinoline 2-oxide 5. Reduction and protection of the corresponding phosphine oxides 1 described herein also
highlight the effectiveness of our approach to this new class of electron-rich ligands.
mportant toolboxes of organic transformations rely on the
(Figure 1). When unsymmetrical alkynes were used, the
Iuse of transition-metal catalysts. Among them, gold catalysis regioselective formation of a specific adduct was clearly
has emerged in the past recent years as an expanding field of
research.1 Compared to other common Lewis acids or
transition metals, gold complexes show high preferences for
unsaturated C−C bonds (e.g., alkenes, alkynes) because they
are less oxophilic than other Lewis acids.2 Therefore, gold
predominantly activates C−C π-systems, making them prone
to be attacked by nucleophiles including the weakest ones.3
Established methodologies are using this unique catalytic
activity of gold complexes to increase molecular complexity in
mild reaction conditions. In this context, activation of alkynes
by gold catalysts has emerged as a powerful method for the
efficient synthesis of carbo- and heterocycles, including barely
accessible ring systems.4 As carbophilic Lewis acids, gold
Figure 1. Bridgehead phosphine synthesis.
complexes may even activate electron-poor C−C π-bonds.5 In
affected by the nature of the alkyne, and both isomers were
a similar fashion, gold can also promote Friedel−Crafts-type
generally obtained, making this method not completely
additions formerly resulting on C−H hydroarylation of the
alkynes.6
generalizable.
We were interested in an approach to conformationally
Inspired by the work of François Mathey et al. on
restrained bridgehead phosphine derivatives. The 1-
phosphabicyclo[3,3,1]-nonane core 1 (methanophosphocine
core) was originally described by Issleib in the late seventies
through the radical cyclization of unsaturated and pyrophoric
phosphanorbornadienes, we were interested in the formation
of bridgehead phosphorus derivatives through an amenable
approach. The synthesis of such phosphines is sparsely
described.7 Mathey et al. have probably developed to date
one of the most straightforward syntheses of monodentate 1-
phosphanorbornadienes from the formal [4 + 2]-cycloaddition
of 1-arylphospholes and disubstituted alkynes at 160 °C
Received: October 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
primary alkenylphosphine.8 Interestingly, he also studied metal
carbonyl complexes of such phosphines and concluded that
they have virtually no π-acceptor character for the metal,
making them a particularly attractive class of electron-rich
phosphines. Despite these intrinsic properties, the lack of
effective synthetic method impeded their development and
prompted us to develop a general route to this class of
compounds.
We envisioned that bis(arylmethyl)alkynylphosphine oxides
might be an affordable reagent to reach this objective. Reaction
with gold(I) catalysts potentially led to methanophosphocines
1 as the result of a double addition. Moreover, such
intramolecular dihydroarylation of alkynes is poorly reported
in the literature and is often limited to electron-rich alkynes.9
We began our studies by reacting ammonium hypophos-
phite with hexamethyldisilazane.10 The resulting bis-
(trimethylsilyl) phosphonite was subjected to react with
various arylmethyl halides followed by ethanolysis of the
resulting phosphinic silyl ester. The expected bis(arylmethyl)-
phosphinic acids 2 were isolated in yields comparable of those
from the literature and ranging from 34% to 58% (Table 1,
Table 2. Optimization of the Reaction Conditions
ratio
T (°C) 4/5/1a (%)
a
b
entry
catalyst [mol %]
Ph3PAuCl (2.5)
AgOTf (2.5)
none
additive
none
none
3 equiv
TfOH
1
2
3
80
80
80
100/0/0
100/0/0
100/0/0
4
5
6
7
Ph3PAuCl (2.5), AgOTf
(2.5)
Ph3PAuCl (2.5), AgOTf
(2.5)
Ph3PAuCl (2.5), AgOTf
(2.5)
Ph3PAuCl (2.5)
none
80
80
rt
100/0/0
73/22/5
100/0/0
12/1/87
3 equiv
TfOH
3 equiv
TfOH
3 equiv
TfOH
80
a
b
Equivalent of triflic acid compared to reagent 4a. Determined
directly by 31P NMR with 1H decoupling and with transfer of
polarization (NOE).
Table 1. Synthesis of Bis(arylmethyl)alkynylphosphine
Oxides 4a−h
anion exchange from the relatively inert gold chloride
complexe (LAuCl) through the reaction with silver triflate.13
When silver and gold salts were used alone (entry 4), the
reaction did not proceed at all. Triflic acid was next evaluated
́
as an additive. Grise et al. reported the benzannulation of 3-
hydroxy-1,5-enynes mediated by such combination.9b,14
Gratifyingly, methanophosphocine 1a was formed in 5%
yield within 2 h (entry 5) from the combination of gold,
silver salts, and triflic acid. This reaction was then continued,
and we were pleased to isolate the expected methanophos-
phocine oxide 1a.
yield
a
yield
b
yield
a
Ar
R1
2
(%)
3
(%)
4
(%)
Ph
H
H
H
H
H
H
Me
Ph
2a
2b
2c
2d
2e
2f
2a
2a
2a
53
58
41
42
34
42
-
3a
3b
3c
3d
3e
3f
3a
3a
3a
99
96
100
100
0
96
-
-
4a
4b
4c
4d
4e
4f
4g
4h
4i
52
52
75
84
-
81
58
59
50
In another set of experiments, the influence of triflic acid was
4-MeC6H4
4-BrC6H4
2-BrC6H4
4-NCC6H4
1-Naphth
Ph
́
evaluated. On the contrary to the results from Grise, triflic acid
alone was not able to catalyze the reaction (entry 3) even in
the presence of silver triflate, excluding its role as a simple
Brønsted acid catalyst.15 Surprisingly, gold chloride combined
with triflic acid afforded the desired methanophosphocine 1a
in better yield (87%, entry 7) after 2 h of reaction.
Ph
Ph
-
-
To decipher the respective roles of triflic acid and the silver
salt, a kinetic monitoring of the reaction in the presence or
absence of silver triflate was realized (see Supporting
Information §V pages 10−15). Both reagents exhibited a
determinant role in this process, and the rate of the reaction
was considerably enhanced without silver salts. Moreover, such
transformation was only possible in the presence of triflic acid.
If precipitation of silver chloride concomitantly with the
formation of the more reactive gold(I) triflate complex was
generally admitted when the gold chloride complex was used,
there are few but relevant examples where addition of silver
may have no positive or even detrimental effects.16 The
combination of silver salts and additives was not so innocent
with regard to the mechanism of the catalytic process itself. In
our reactions, no precipitation of silver chloride was observed
when silver triflate was used in combination with triflic acid
(Table 2, entries 5 and 6). Release of hydrogen chloride
mediated by the combination of the sole triflic acid as additive,
gold(I) chloride complex, and temperature directly afforded
the gold triflate catalyst. In parallel, a plausible explanation for
reaction rate enhancement might be a double activation of
alkynyl reagent 4. The phosphoryl group was basic enough to
cyclohexyl
-
a
b
Isolated yields. Yields without purification.
products 2a−f).11 In a second reaction, the phosphinic
chlorides 3a−f were obtained by chlorination of phosphinic
acids in almost quantitative yields. It can be noticed that 4-
cyano derivative 3e failed to be obtained in such conditions.
The phosphinic chlorides 3a−d and 3f were consecutively
engaged in the reaction with various alkynylmagnesium
bromides, thus affording the bis(arylmethyl)alkynylphosphine
oxides 4a−d and 4f−i in 50%−83% yields.12 This straightfor-
ward method allowed us to introduce variable aryl groups and
different substituents on the alkyne function (R = H, Me, Ph)
in multigram scales.
Readily available bis(benzyl)ethynylphosphine oxide 4a was
selected as the model substrate to explore the reaction
conditions for the double hydroarylation (Table 2). As
expected, gold(I) catalyst (entry 1) and silver(I) triflate
(entry 2) alone did not catalyze the transformation even in
refluxing dichloroethane. Generally, in gold-catalyzed trans-
formations, active gold catalysts have been prepared in situ by
B
DOI: 10.1021/acs.orglett.8b03474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
be protonated by triflic acid, making the alkyne reagent 4 and
the reactive intermediate 5 even more electrophilic. Con-
sequently, the double cyclization process was faster. To the
best of our knowledge, this unusual combination of synergetic
effects was still not described in gold-catalyzed reactions.
Using the optimized conditions (Table 2, entry 7), the
substrate scope of this new intramolecular double hydro-
arylation was then examined (Table 3). Regardless of the steric
intermediate species 5. Basically, conjugated alkynes afforded
selectively isophosphinoline 2-oxides 5. The addition of the
arene group to the alkyne was fully regioselective, giving
exclusively a 6-endo-dig cyclization by double activation of the
alkyne by the soft gold catalyst and the hard phosphoryl group
by triflic acid (Table 3). Consecutively, a methanophosphocine
eight-membered ring was also formed through a favorable 6-
endo-trig cyclization. For a structural confirmation of the
methanophosphocine framework, a single-crystal X-ray struc-
ture analysis of 1a was conducted (Figure 2).
Table 3. Gold-Catalyzed Cascade Cyclization to
Methanophosphocines 1a−g
Figure 2. Ortep plot (50% thermal ellipsoids) of the solid-state
structure of methanophosphocine 1a. Phosphorus atom is shown in
orange and oxygen in red.
a
entry
Ar
R1
1
yield 5 (%) yield 1 (%)
a
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
Me
Ph
1a
1b
1c
1d
1f
1g
1h
1i
-
-
-
-
-
-
98
96
88
74
86
48
a
b
b
a
b
4-MeC6H4
4-BrC6H4
2-BrC6H4
1-Naphth
Ph
Reduction of phosphine chalcogenides provides a general
access to phosphines and still undergoes extensive develop-
ments.17 Silane reagents are commonly used for such
transformation with various modifiers, more specifically tertiary
amines.18 Reduction of methanophosphocines 1 was accom-
plished by direct reaction of trichlorosilane in the presence of
pyridine. The heterocyclic ring proved to be tolerant to
nucleophilic reductive agent, giving phenyl and naphthyl
bridgehead phosphines 6a,b in high yields (Scheme 1). As
expected, these trialkylphosphines were highly sensitive to
oxidation, and the prominent unshared pair of electrons on the
phosphorus center readily reacted with oxygen.
b
b
Ph
Ph
85
-
0
cyclohexyl
-
a
b
Isolated yields. Required μ-wave activation.
hindrance and the electronic properties of the substituents on
the aromatic ring, the expected methanophosphocines 1a−d
and 1f−g were formed. To our delight, reaction of the phenyl
derivative (entry 1) and the 4-tolyl derivative (entry 2) was
almost quantitative, and the desired products were isolated in
98% and 96% yield, respectively. Similarly, even hindered
bis(1-naphthyl)ethynylphosphine oxide 4f (entry 5) was
obtained in 86% yield. On the contrary, the double cyclization
proved to be more difficult from 4- and 2-bromobenzyl
phosphine oxides 1c and 1d (entries 3 and 4). Using the
previous conditions, the second cyclization step appeared
sluggish, affording a mixture of 1c and 5c in a ratio of 5/95
after 4 h of heat. The latter isophosphinoline 2-oxide 5c was
isolated and characterized confirming the sequential cycliza-
tions to form methanophosphocines 1. Consequently, the
double cyclization was attempted under microwave irradiation,
keeping the temperature at 140 °C. The expected meth-
anophosphocines 1c−d were isolated in 88% and 74% yield,
respectively.
Scheme 1. Reduction of Methanophosphocine Oxides 1 into
Phosphines 6a,b and Phosphine-boranes 7a,b
When 2-substitued alkynes were used, the reactions
considerably slowed down, and methyl derivative 1g (entry
6) was isolated in medium yield (48%). However, phenyl-
substituted phosphine oxide 4h (entry 7) only afforded
isophosphinoline 2-oxide 5h. We were not able to isolate
any product from the reaction with 3-cyclohexylethynylphos-
phine oxide 4h. A multitude of peaks in 31P NMR highlighted
the potential formation of rearranged products.
To circumvent the oxidation reaction, synthesis of the
protected phosphine-boranes 7a,b was engaged (Scheme 1).19
Reduction by sodium borohydride in the presence of acetic
acid in THF afforded the desired products 7a,b, albeit isolated
in moderate yields after purification by chromatography on
silica gel.
Combination of steric hindrance and conjugation on the
alkyne moiety appeared to have a deep influence not only on
the rate of the reaction but also on the reactivity of
In summary, gold complexes proved again their unique
ability to act as mild π-Lewis acids. We have found a facile
C
DOI: 10.1021/acs.orglett.8b03474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03474.
Synthesis, characterizations, and spectra of the com-
pounds 1−7 (PDF)
Accession Codes
́
M.; Huck, J.; Frey, W.; Bats, J. W.; Hamzic, M. Angew. Chem., Int. Ed.
CCDC 1855934 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,
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AUTHOR INFORMATION
Corresponding Authors
■
̀
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*E-mail: david.virieux@enscm.fr.
*E-mail: jean-luc.pirat@enscm.fr.
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ORCID
David Virieux: 0000-0002-6495-9478
Author Contributions
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The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
The research leading to these results has received funding from
the French Ambassy in Ivory Coast (Dr. Lancine Traore) and
from the French Ambassy in Russia (Dr. Victoria Matveeva).
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DOI: 10.1021/acs.orglett.8b03474
Org. Lett. XXXX, XXX, XXX−XXX