Gold-Catalyzed Access to Isophosphinoline 2-Oxides

Article abstract of DOI:10.1021/acs.joc.1c00648

Gold(I)-catalyzed reactions of electron-poor alkynes are still a challenging process. A straightforward synthesis of phosphorus-based heterocycles, namely, 2-phenyl 1H-isophosphinoline 2-oxides 1, is reported. The reaction used PPh3AuCl precatalyst in com

Full text of DOI:10.1021/acs.joc.1c00648

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Gold-Catalyzed Access to Isophosphinoline 2‑Oxides
Mina Hariri, Fatemeh Darvish, Karen-Pacelye Mengue Me Ndong, Nora Sechet, Geraud Chacktas,
Hooriye Boosaliki, Minh Loan Tran Do, Gabin Mwande-Maguene, Jacques Lebibi, Alexander R. Burilov,
Tahar Ayad, David Virieux,* and Jean-Luc Pirat*
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ABSTRACT: Gold(I)-catalyzed reactions of electron-poor alkynes are still a
challenging process. A straightforward synthesis of phosphorus-based hetero-
cycles, namely, 2-phenyl 1H-isophosphinoline 2-oxides 1, is reported. The
reaction used PPh3AuCl precatalyst in combination with triflic acid under
microwave activation and afforded isophosphinoline 2-oxides 1 in moderate to
quantitative yields through a fully regioselective 6-endo-dig hydroarylation
cyclization, paving the way toward an effective synthesis of phosphorus
heterocycles.
eterocyclic compounds play a determinant role in
Hpresent-day living organisms, and their broad occurrence
underlines this significance in several fundamental biological
pathways. When practicing medicinal chemistry, the bioisos-
teric concept proved to be a fruitful approach in the design of
new drugs with potent activity and reduced risks through
modulation of the metabolic and/or pharmacokinetic proper-
ties.1,2
Consequently, bioisosteric replacements have known
successful stories in drug discovery.3 Phosphorus is a key
ingredient of life as a vital nutrient, for instance, the transfer of
energy in any leaving cells by phosphate group which is
probably the most representative feature of its biological
importance. In spite of the considerable amount of knowledge
harvested over the last few decades, organophosphorus
heterocycles are still the poor sibling in the development of
new drugs.4 Our group contributed with numerous others to
the rebirth of phosphorus chemistry in life science through the
development of two series of bioactive six-membered hetero-
cycles.5 We already demonstrated that phosphinolactone could
potentially be an “ideal” bioisostere of the biologically and
configurationally unstable lactol functional group.6
In another way, targeted covalent inhibitors are a re-
emerging class of compounds in medicinal chemistry. The so-
called warheads received increased attention, and an increased
number of functional groups have now been exploited to target
specific amino acid residues.7 The balance between toxicity
versus efficacy is the main reason for drug attrition, and
covalent inhibitors benefited from several advantages, i.e.,
improved efficiency and lower dose response. To highlight the
recent successes of this approach, more than 50 approved
covalent inhibitors are on the market.7a
isophosphinoline 2-oxides 1 (Figure 1). Such compounds
can be seen as hydrolytically stable surrogates of combined
coumarins 2a and substituted flavonoids 2b, natural com-
pounds which express a wide range of potent activities.8 It is
also envisioned that the vinylphosphine oxide moiety may act
as a new covalent inhibitor scaffold. The electrophilic character
of such a functional group was thoroughly illustrated in the
literature, and it was proved to react with a broad range of
nucleophiles.9 The low conjugation of the alkene moiety with
the phosphoryl group makes them less electrophilic compared
to the parent carbonyl derivatives.10
However, the lack of published synthetic approaches
prompted us to develop an affordable access to variously
substituted 2-phenyl H-isophosphinoline 2-oxides 1. To the
best of our knowledge, only Lee and colleagues and Gao and
colleagues disclosed an efficient synthesis of phosphacoumarins
3 (phosphinate analogues) through catalytic approaches.11 Our
group also published a synthesis of bridgehead phosphorus
heterobicycles, methanophosphocines which are eight-mem-
bered heterocycles using a gold-catalyzed cyclization of
bis(arylmethyl) ethynylphosphine oxides.12 This cascade
reaction may have the potential to be extended to such target
derivatives 1, and gold-catalyzed reactions are the best effective
processes.13
Our synthetic pathway began by the preparation of diversely
substituted phenyl(arylmethyl)phosphinic acids 5. Synthetic
Received: March 18, 2021
Published: May 19, 2021
Therefore, the present paper is focused on the synthesis of
phosphorus-based heterocycles, namely, the 2-phenyl H-
https://doi.org/10.1021/acs.joc.1c00648
© 2021 American Chemical Society
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Figure 1. Isophosphinoline 2-oxide 1 as combined bioisosteres of coumarins 2a and flavonoids 2b, analogue of phosphacoumarins 3.
approaches to such precursors are poorly reported in the
literature. Nevertheless, Montchamp and colleagues developed
an efficient Pd/xantphos-catalyzed benzylation of phenyl-
phosphinic acid 4 using benzyl alcohol derivatives as
nucleophiles,14 and Boyd and colleagues reported a metal-
free synthesis of phenyl phosphinic acid derivatives through
the reaction of benzyl bromides with in situ formation of
bis(trimethylsilyl)phosphonites under mild conditions.15 Based
on these precedent studies, as well as our own experiences,12,16
we decided to use a slight modification of Boyd’s procedure
(instead of triethylamine or diisopropylethylamine and
trimethylsilyl chloride, we used directly hexamethyldisilazane
as a silylating agent (HMDS)) for the preparation of
phosphinic acids 5a−h. As highlighted in Table 1, compounds
With the desired phenyl(arylmethyl)phosphinic acids 5 in
hand, we turned our attention to the synthesis of phenyl-
(arylmethyl)(alkynyl)phosphine oxides 7 which are the key
intermediates for the intramolecular hydroarylation step.
Toward this end, phosphinic chlorides 6a−g were easily
obtained, generally in quantitative yields, by chlorination of the
corresponding acids 5a−g using an excess of thionyl
chloride.17 It can be noticed that phenyl(4-vinylbenzyl)-
phosphinic acid 5h failed to give the desired chloride derivative
6h under such conditions. A polymeric content was observed
in the reaction mixture. Under these conditions, phenyl-
(arylmethyl)phosphinic chlorides 6a−g were found to be
sufficiently pure to be directly engaged in the next step without
purification. Therefore, they were consecutively reacted with
various alkynylmagnesium bromides (R2 = H, Me, Ph), leading
to the nucleophilic substitutions without any problem, thus
affording a wide range of diverse phenyl(arylmethyl)(alkynyl)-
phosphine oxides 7a−u in good to excellent isolated yields
(Table 2).18 This straightforward method allowed variable aryl
groups as well as different substituents to be easily introduced
on the alkyne function.
Table 1. Synthesis of Phenyl (Arylmethyl) Phosphinic Acids
5a−h
The reaction conditions for the intramolecular gold-
catalyzed hydroarylation were then examined, and the results
are reported in Table 3. Initially, the conditions were then
examined for the formation of the isophosphinoline 2-oxide 1a
starting from phenylbenzyl(ethynyl)phosphine oxide 7a as a
model reagent. The reaction was first conducted under thermic
activation in 1,2-dichloroethane using Ph3PAuCl as catalyst
(2.5 mol %) in the presence of triflic acid as additive (3 equiv).
Under these conditions, the reaction required 4 days to reach
89% as the relative percentage of 1a in the crude mixture as
determined by 31P{1H} NMR (entry 1). More importantly, the
addition of the arene group to the alkyne appeared fully
regioselective, giving as expected exclusively the 6-endo-dig
cyclization product. The corresponding 5-exo-dig products
were not observed, while in some cases gold-catalyzed
reactions followed this mode of cyclization.19 Microwave-
assisted heating (MW) was attempted, since such technology
has been shown to dramatically reduce the reaction times for
processes that require prolonged heating. We were pleased to
observe the formation of phosphinoline 1a in 93% yield by
running the reaction under microwave activation at 140 °C for
1.5 h (entry 2). Increasing both the temperature and the
reaction time to 160 °C and 3 h, respectively, resulted in the
formation of 1a in excellent >99% yield (entry 3). By contrast,
6 h of heating at 180 °C had a detrimental effect, giving
compound 1a in lower yield 79% (entry 4). We suspected that
this result could be attributed to the thermal instability of
isophosphinoline 2-oxide 1a at this temperature. This
hypothesis was confirmed by a reaction time extended to 11
h, which resulted in significant yield reduction to 64% (entry
a
b
entry
Ar
5
yield (%)
1
2
3
4
5
6
7
8
Ph
5a
5b
5c
5d
5e
5f
76
49
95
26
73
61
88
>99
2-MeC6H4
4-MeC6H4
2-BrC6H4
4-ClC6H4
1-Napht
2-Napht
4-vinylC6H4
5g
5h
a
b
Reaction run >1 mmol. Isolated yields.
5 were straightforwardly obtained in moderate to quantitative
yields using a two-step/one-pot sequence. The reaction
involves in situ formation of bis(trimethylsilyl)-
phenylphosphonite from cheap and commercially available
phenylphosphinic acid 4 using hexamethyldisilazane followed
by reaction with various arylmethyl halides (Table 1). It turned
out that steric hindrance in the ortho position had deleterious
effects leading to phosphinic acids 5b and 5d in 49 and 26%
yields, respectively (entries 2 and 3). Similar trends were
observed when the reaction was performed with hindered
naphthyl derivatives. Indeed, 1-naphthylmethyl(phenyl)-
phosphinic acid 2f was obtained in 61% yield, while the less
hindered 2-naphthyl derivative 2g was isolated in 88% yield
(entry 6 vs entry 7). The best yields were observed when para-
substituted benzyl bromides were used whatever the nature of
the para-substituents (entries 4 and 5).
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7a−u were engaged in the cyclization to evaluate the scope of
the reaction (Table 4). Isophosphinoline 2-oxides 1a−n were
mostly formed in high to quantitative yields, irrespective of the
nature and position of the substituents attached to both the
aromatic and alkyne partners. For instance, reactions carried
out with substrates bearing electron-donating substituents on
the aryl group tend to give lower yields than those having
electron-withdrawing substituents (entries 2−9 vs 10−13).
The results depicted in Table 4 also showed that the
substitution pattern on the alkyne moiety has an impact on
the outcome of the reaction. Terminal alkynes tend to provide
higher catalytic activity than substituted ones with isolated
yields ranging from 85 to 100% (Table 4: compounds 1a, 1d,
1g, 1j, 1l, and 1n). It was noticed that the reaction of phenyl-
substituted alkynes 7f and 7i also afforded the ketone resulting
from the hydration of the alkyne substituent which is known to
be catalyzed by gold.21 Lee and colleagues also observed this
side reaction when gold catalyst was used with silver salts.
However, hydration of alkyne was drastically reduced in the
presence of strong Brønsted acids (TFA, TfOH) even in the
presence of silver triflate.
Table 2. Synthesis of
Phenyl(arylmethyl)(alkynyl)phosphine Oxides 7a−u
a
entry
Ar
R2
7
yield (%)
1
2
3
Ph
Ph
Ph
H
7a
7b
7c
7d
7e
7f
7g
7h
7i
91
72
70
53
>99
75
95
>99
91
60
80
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2-MeC6H4
2-MeC6H4
2-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
1-Napht
7j
7k
7l
93
7m
7n
7o
7p
7q
7r
7s
7t
>99
>99
97
30
65
77
58
56
41
In summary, gold complexes were acting as mild π-Lewis acids
in a facile 6-endo-dig arylation of electron-poor alkynes.
Isophosphinoline oxides 1 were generally obtained in high
yields using an unusual combination of gold(I) precatalyst with
triflic acid as the sole additive. Further studies of isophosphino-
line oxides 1 as the potential warhead on research applications
are currently underway in our laboratory.
1-Napht
1-Napht
2-Napht
2-Napht
Me
Ph
2-Napht
7u
EXPERIMENTAL SECTION
■
a
Isolated yields.
Measurement. All experiments were carried out under a nitrogen
atmosphere unless otherwise stated. Unless specified, all of the
commercially available reagents and starting materials purchased from
commercial sources were used as received without further purification.
Thin layer chromatography (TLC) was performed on precoated
plates of silica gel 60 F254 Merck. Visualization was performed with
UV light and sometimes with phosphomolybdic acid solution or
permanganate solution followed by heating. Flash chromatography
Table 3. Optimization of the Intramolecular Hydroarylation
Reaction
1
was performed manually with silica gel (60 Å, 35−70 μm SDS). H,
13C, and 31P{1H} NMR spectroscopic data were recorded at 400, 100,
a
and 162 MHz, respectively. The chemical shifts are reported in ppm,
and the coupling constants (J) are reported in Hz. The chemical shift
values are referenced against the residual proton in the deuterated
solvents. In the 13C{1H} NMR spectra, signals corresponding to C,
CH, CH2, or CH3 were assigned from the JMOD sequence. The
multiplicities are given as s (singlet), d (doublet), t (triplet), q
(quadruplet), and m (multiplet). Low and high resolution mass
spectra were recorded with a time-of-flight mass spectrometer using
electrospray ionization (ESI). Melting points were measured with an
automatic melting point apparatus SMP50 from Stuart. HRMS (Q-
TOF) were performed on a JEOL JMS-DX300 spectrometer (3 keV,
xenon) in a m-nitrobenzyl alcohol matrix. Gas chromatography−mass
spectra (GC-MS) were recorded on a Shimadzu QP2012-SE with a
Zebron ZB-5MS (20 m × 0.18 mm), capillary nonpolar column
(stationary phase: 0.18 μm film). GC-MS method: initial temperature,
50 °C; initial time, 2 min; ram, 22 °C/min; final temperature, 280 °C;
final time, 15 min. Microwave reactions (MW) were performed using
a CEM Discover apparatus in 10 and 35 mL sealed reactors for,
respectively, small- and large-scale synthesis. Reactions were
performed by maintaining the temperature to the set point. For
reactions that require heating, the heat source was “heat on” systems.
Typical Procedure for the Preparation of Aryl(phenyl)-
phosphinic Acids 5a−i.12 In a dried and N2 flushed 100 mL two-
necked flask equipped with a condenser, the mixture of phenyl-
phosphinic acid 4 (10 g, 70 mmol, 1 equiv), hexamethyldisilazane (15
mL, 70 mmol, 1 equiv), arylmethyl bromide, or arylmethyl chloride
entry
catalyst
additive
conditions
time
1a (%)
1
2
3
4
5
6
7
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
none
TfOH
TfOH
TfOH
TfOH
TfOH
none
80 °C
4 d
1.5 h
3 h
6 h
11 h
3 h
89
93
100
79
64
0
140 °C, MW
160 °C, MW
180 °C, MW
180 °C, MW
160 °C, MW
160 °C, MW
TfOH
3 h
39
a
Relative % of compound 1a determined by 31P{1H} NMR
5). It was already reported that alkenes can be effective
substrates in intermolecular arylations and high temperature
may induce over-reaction.20 As seen in Table 3, the reaction
carried out with gold catalyst alone failed to give compound 1a
(entries 6). The reaction performed with triflic acid led to the
expected product 1a in a low 38% yield. Under such
conditions, 39% of the starting material 7a remained along
with the formation of 23% of side-products (entry 7).
Consequently, combination of Ph3PAuCl and triflic acid
exhibited a positive synergistic enhancement of the catalytic
effect.
Using the optimized conditions (160 °C, MW, 3 h), a wide
range of substituted phenyl benzyl(ethynyl)phosphine oxides
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Table 4. Synthesis Isophosphinoline 2-Oxides 1a−q
a
b
Isolated yields. An inseparable mixture of isophosphinoline 2-oxide 1 and the ketone 8 resulting from the hydration of the alkyne function was
c
obtained. Relative % of compounds 1/8 determined by GC-MS analysis.
(1.5 equiv) was stirred at 105 °C for 4 h. After cooling to room
temperature, ethanol (400 mL) was added and the mixture was stirred
for 30 min and concentrated under a vacuum. Cyclohexane (2 × 250
mL) was added to the resulting crude, mixed, and filtered to remove
the remaining excess of arylmethyl bromide or chloride. The crude
was dissolved in 100 mL of 3 N HCl solution, and the solution was
stirred for 10 min, then extracted with dichloromethane, dried over
MgSO4, and filtrated. The pure resulting solid 5 was obtained after
evaporation of dichloromethane.
equiv), benzyl bromide (12.5 mL, 105 mmol, 1.5 equiv). The title
product 5a was obtained as a white solid (175.7−178.8 °C), 12.38 g
(76% yield).22
1H NMR (400 MHz, DMSO-d6) δ 7.66−7.56 (m, 2H), 7.55−7.48
(m, 1H), 7.43 (ddd, J = 8.6, 6.6, 3.3 Hz, 2H), 7.32 (s, 1H), 7.25−7.14
(m, 3H), 7.08 (d, J = 9.0 Hz, 2H), 3.23 (d, J = 17.6 Hz, 2H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 133.6 (d, J = 126.5 Hz),
133.0 (d, J = 7.7 Hz), 131.5 (d, J = 2.7 Hz), 131.1 (d, J = 9.8 Hz),
129.8 (d, J = 5.7 Hz), 128.1 (d, J = 12.3 Hz), 127.9 (d, J = 2.7 Hz),
126.0 (d, J = 3.2 Hz), 37.9 (d, J = 92.2 Hz). 31P{1H} NMRP{1H}
(Benzyl)(phenyl)phosphinic Acid (5a). Phenylphosphinic acid
4 (10 g, 70 mmol, 1 equiv), hexamethyldisilazane (15 mL, 70 mmol, 1
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NMR (162 MHz, DMSO-d6) δ 32.87. HRMS: m/z calcd for
C13H14O2P 233.0726 [M + H]+, found 233.0729.
HRMS: m/z calcd for C17H16O2P [M + H]+ 283.0882, found
283.0891.
(2-Methylbenzyl)(phenyl)phosphinic Acid (5b). Phenylphos-
phinic acid 4 (4.3 g, 30.28 mmol, 1 equiv), hexamethyldisilazane (6.0
mL, 28.15 mmol, 1 equiv), 2-methylbenzyl bromide (5.7 mL, 42.22
mmol, 1.5 equiv). The title product 5b was obtained as a white solid
(160.7−171.3 °C), 3.41 g (49% yield).
(Naphthalen-2-ylmethyl)(phenyl)phosphinic Acid (5g). Phe-
nylphosphinic acid 4 (0.58 g, 4.05 mmol, 1 equiv), hexamethyldisi-
lazane (0.8 mL, 3.98 mmol, 1 equiv), 2-bromomethyl-naphtalene
(1.34 g, 6.07 mmol, 1.5 equiv). The title product 5g was obtained as a
white solid (207.7−215.9 °C), 1.0 g (88% yield).
1H NMR (400 MHz, DMSO-d6) δ 7.79−7.29 (m, 5H), 7.17−6.85
(m, 4H), 3.21 (d, J = 17.5 Hz, 2H), 2.14 (d, J = 1.6 Hz, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 136.8 (d, J = 5.7 Hz),
134.0 (d, J = 125.8 Hz), 131.6 (d, J = 2.7 Hz), 131.5 (d, J = 8.2 Hz),
131.1 (d, J = 9.8 Hz), 130.6 (d, J = 4.8 Hz), 129.9 (d, J = 3.0 Hz),
128.1 (d, J = 12.3 Hz), 126.2 (d, J = 3.4 Hz), 125.3 (d, J = 3.2 Hz),
35.6 (d, J = 92.4 Hz), 19.6 (d, J = 1.6 Hz). 31P{1H} NMRP{1H}
NMR (162 MHz, DMSO-d6) δ 32.96. HRMS: m/z calcd for
C14H16O2P 247.0882 [M + H]+, found 247.0883.
1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 7.9 Hz, 1H), 7.90−
7.82 (m, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.70−7.58 (m, 2H), 7.55−
7.38 (m, 5H), 7.35 (t, J = 7.7 Hz, 1H), 7.24 (dd, J = 6.7, 2.9 Hz, 1H),
3.72 (d, J = 17.5 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
134.2 (d, J = 126.5 Hz), 133.3 (d, J = 2.7 Hz), 132.0, 131.99 (d, J =
3.0 Hz), 131.6 (d, J = 9.5 Hz), 131.3 (d, J = 8.2 Hz), 128.9 (d, J = 4.3
Hz), 128.7, 128.6, 128.6, 127.9 (d, J = 1.6 Hz), 127.7, 126.5, 125.9,
38.7 (d, J = 92.0 Hz). 31P{1H} NMR (162 MHz, DMSO-d6) δ 32.44.
HRMS: m/z calcd for C17H16O2P [M + H]+ 283.0882, found
283.0886.
(4-Methylbenzyl)(phenyl)phosphinic Acid (5c). Phenylphos-
phinic acid 4 (4.1 g, 28.85 mmol, 1 equiv), hexamethyldisilazane (6.1
mL, 28.85 mmol, 1 equiv), 4-methylbenzyl bromide (5.8 mL, 43.27
mmol, 1.5 equiv). The title product 5c was obtained as a white solid
(175.9−176.7 °C), 6.80 g (95% yield).
(4-Vinylbenzyl)(phenyl)phosphinic Acid (5h). Phenylphos-
phinic acid 4 (4.0 g, 28.15 mmol, 1 equiv), hexamethyldisilazane
(5.6 mL, 28.15 mmol, 1 equiv), 4-vinylbenzyl chloride (3.5 mL, 42.22
mmol, 1.5 equiv). The title product 5h was obtained as a white solid
(169.2−172.2 °C), 7.3 g (yield >99%).
1H NMR (400 MHz, DMSO-d6) δ 7.75−7.32 (m, 5H), 7.12−6.73
(m, 4H), 3.18 (d, J = 17.6 Hz, 2H), 2.22 (d, J = 2.2 Hz, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 135.0 (d, J = 3.4 Hz), 133.8
(d, J = 126.2 Hz), 131.5 (d, J = 2.7 Hz), 131.1 (d, J = 9.5 Hz), 129.8
(d, J = 7.7 Hz), 129.7 (d, J = 5.7 Hz), 128.5 (d, J = 3.0 Hz), 128.1 (d,
J = 12.0 Hz), 37.5 (d, J = 92.9 Hz), 20.6 (d, J = 1.1 Hz). 31P{1H}
NMR (162 MHz, DMSO-d6) δ 33.09. HRMS: m/z calcd for
C14H16O2P 247.0882 [M + H]+, found 247.0887.
1H NMR (400 MHz, DMSO-d6) δ 7.68−7.60 (m, 2H), 7.53 (td, J
= 7.5, 1.4 Hz, 1H), 7.48−7.40 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.06
(dd, J = 8.2, 2.2 Hz, 2H), 6.66 (dd, J = 17.7, 10.9 Hz, 1H), 5.76 (d, J
= 17.7 Hz, 1H), 5.19 (d, J = 10.9 Hz, 1H), 3.25 (d, J = 17.8 Hz, 2H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 136.9 (d, J = 2.0 Hz), 135.4
(d, J = 3.4 Hz), 134.2 (d, J = 126.5 Hz), 133.3 (d, J = 7.9 Hz), 132.0
(d, J = 2.7 Hz), 131.6 (d, J = 9.8 Hz), 130.5 (d, J = 5.9 Hz), 128.6 (d,
J = 12.3 Hz), 126.2 (d, J = 3.0 Hz), 114.1 (d, J = 1.8 Hz), 38.2 (d, J =
92.0 Hz). 31P{1H} NMR (162 MHz, DMSO-d6) δ 32.68. HRMS: m/
z calcd for C15H16O2P [M + H]+ 259.0882, found 259.0892.
Typical Procedure for the Preparation of (Arylmethyl)-
phenylphosphinic Chlorides 6a−g. In a 250 mL two-necked flask
equipped with a condenser under N2, the mixture of thionyl chloride
(20 equiv) and (arymethyl)phenylphosphinic acid 5 (1 equiv) was
refluxed at 76 °C for 30 min. The excess of thionyl chloride was
removed by distillation. The resulting phosphinic chlorides 6 were
consecutively engaged in the reaction with alkynylmagnesium
bromides without purification.
Benzyl(phenyl)phosphinic Chloride (6a). Benzyl phenylphos-
phinic acid 5a (0.8 g, 3.4 mmol, 1 equiv), thionyl chloride (5 mL, 68.9
mmol, 20 equiv). The title product 6a was obtained as a yellow solid.
1H NMR (400 MHz, chloroform-d) δ 7.80−7.67 (m, 2H), 7.59
(td, J = 7.3, 1.5 Hz, 1H), 7.47 (td, J = 7.6, 4.3 Hz, 2H), 7.25 (d, J =
6.5 Hz, 3H), 7.12 (dd, J = 4.6, 2.3 Hz, 2H), 3.89−3.58 (m, 2H).
31P{1H} NMR (162 MHz, DMSO-d6) δ 52.25 (s).
(2-Bromobenzyl)(phenyl)phosphinic Acid (5d).23 Phenyl-
phosphinic acid 4 (4.1 g, 28.85 mmol, 1 equiv), hexamethyldisilazane
(6.1 mL, 28.85 mmol, 1 equiv), 2-bromobenzyl bromide (5.7 mL,
43.27 mmol, 1.5 equiv). The title product 5d was obtained as a white
solid (149−150.4 °C), 2.33 g (26% yield).
1H NMR (400 MHz, DMSO-d6) δ 7.18−7.06 (m, 3H), 7.03 (dd, J
= 4.9, 4.0 Hz, 1H), 7.01−6.94 (m, 2H), 6.87 (dt, J = 7.7, 2.1 Hz, 1H),
6.81 (ddd, J = 7.8, 7.2, 0.7 Hz, 1H), 6.71−6.62 (m, 1H), 2.96 (d, J =
17.8 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 133.6 (d, J =
135.6 Hz), 133.0, 132.4 (d, J = 2.7 Hz), 131.8, 131.7−131.6 (m),
131.2 (d, J = 9.8 Hz), 129.0 (d, J = 3.2 Hz), 128.1 (d, J = 12.3 Hz),
127.3 (d, J = 3.2 Hz), 124.6 (d, J = 7.3 Hz), 37.9 (d, J = 91.7 Hz).
31P{1H} NMR (162 MHz, DMSO-d6) δ 31.21 (s). HRMS: m/z calcd
for C13H13BrO2P 310.9831 [M + H]+, found 310.9833.
(4-Chlorobenzyl)(phenyl)phosphinic Acid (5e).24 Phenyl-
phosphinic acid 4 (4.1 g, 28.85 mmol, 1 equiv), hexamethyldisilazane
(6.1 mL, 28.85 mmol, 1 equiv), 4-chloromethyl-benzyl bromide (5.6
mL, 43.27 mmol, 1.5 equiv). The title product 5e was obtained as a
white solid (201.9−207.8 °C), 5.6 g (73% yield).
(2-Methylbenzyl)(phenyl)phosphinic Chloride (6b). (2-
Methylbenzyl)(phenyl)phosphinic acid 5b (0.8 g, 3.25 mmol, 1
equiv), thionyl chloride (4.71 mL, 64.9 mmol, 20 equiv). The title
product 6b was obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.72−7.56 (m, 2H), 7.54−7.33
(m, 3H), 7.32−7.18 (m, 2H), 7.10 (dd, J = 8.6, 2.4 Hz, 2H), 3.25 (d,
J = 17.6 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 133.5 (d, J
= 126.9 Hz), 132.3 (d, J = 7.7 Hz), 131.6 (d, J = 5.5 Hz), 131.1 (d, J =
9.8 Hz), 130.9 (d, J = 3.9 Hz), 128.1 (d, J = 12.0 Hz), 127.9 (d, J =
2.7 Hz), 37.2 (d, J = 92.0 Hz). 31P{1H} NMR (162 MHz, DMSO-d6)
δ 32.54 (s). HRMS: m/z calcd for C13H13ClO2P 267.0336 [M + H]+,
found 267.0346.
31P{1H} NMR (162 MHz, chloroform-d) δ 51.74.
(4-Methylbenzyl)(phenyl)phosphinic Chloride (6c). (4-
Methylbenzyl)(phenyl)phosphinic acid 5c (0.8 g, 3.25 mmol, 1
equiv), thionyl chloride (4.71 mL, 64.9 mmol, 20 equiv). The title
product 6c was obtained as a yellow solid.
(2-Bromobenzyl)(phenyl)phosphinic Chloride (6d). (2-
Bromobenzyl)(phenyl)phosphinic acid 5d (0.8 g, 2.57 mmol, 1
equiv), thionyl chloride (3.73 mL, 51.42 mmol, 20 equiv). The title
product 6d was obtained as a red solid.
(4-Chlorobenzyl)(phenyl)phosphinic Chloride (6e). (4-
Chlorobenzyl)(phenyl)phosphinic acid 5e (0.8 g, 3 mmol, 1 equiv),
thionyl chloride (4.35 mL, 60 mmol, 20 equiv). The title product 6e
was obtained as a yellow solid.
(Naphthalen-1-ylmethyl)(phenyl)phosphinic Chloride (6f).
(Naphthalene-1-ylmethyl)(phenyl)phosphinic acid 5f (0.7 g, 2.48
mmol, 1 equiv), thionyl chloride (3.6 mL, 49.60 mmol, 20 equiv).
The title product 6f was obtained as a yellow solid.
(Naphthalen-1-ylmethyl)(phenyl)phosphinic Acid (5f).24
Phenylphosphinic acid 4 (2.24 g, 15.8 mmol, 1 equiv), hexamethyldi-
silazane (3.5 mL, 15.8 mmol, 1 equiv), 1-chloromethyl-naphtalene
(3.5 mL, 23.70 mmol, 1.5 equiv). The title product 5f was obtained as
a white solid (162.7−163.9 °C), 2.71 g (61% yield).
1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.1 Hz, 1H), 7.86
(d, J = 9.2 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 11.7, 7.3
Hz, 2H), 7.57−7.38 (m, 5H), 7.34 (t, J = 7.6 Hz, 1H), 7.24 (dd, J =
7.2, 3.5 Hz, 1H), 3.72 (d, J = 17.5 Hz, 2H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 134.0 (d, J = 126.3 Hz), 133.3 (d, J = 2.4 Hz),
132.0 (d, J = 4.3 Hz), 131.5 (d, J = 2.7 Hz), 131.2 (d, J = 9.8 Hz),
129.7 (d, J = 8.7 Hz), 128.3 (d, J = 6.5 Hz), 128.1, 128.1 (d, J = 12.2
Hz), 126.7 (d, J = 3.7 Hz), 125.6−125.34 (m), 125.2 (d, J = 2.1 Hz),
35.1 (d, J = 92.2 Hz). 31P{1H} NMR (162 MHz, DMSO-d6) δ 32.46.
(Naphthalen-2-ylmethyl)(phenyl)phosphinic Chloride (6g).
(Naphthalene-2-ylmethyl)(phenyl)phosphinic acid 5g (0.59 g, 2.09
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Note
mmol, 1 equiv), thionyl chloride (3 mL, 41.80 mmol, 20 equiv). The
title product 6g was obtained as a yellow solid.
from 8:2 to 0:10.The title product 7d was obtained as a creamy solid,
0.26 g (53% yield).
1H NMR (400 MHz, chloroform-d) δ 7.68−7.53 (m, 2H), 7.45
(td, J = 7.3, 1.6 Hz, 1H), 7.34 (dt, J = 7.5, 3.7 Hz, 2H), 7.12−6.88 (m,
4H), 3.66−3.21 (m, 3H), 2.05 (s, 3H). 13C{1H} NMR (101 MHz,
chloroform-d) δ 137.3 (d, J = 5.9 Hz), 132.6 (d, J = 3.0 Hz), 130.9 (d,
J = 5.0 Hz), 130.7 (d, J = 10.4 Hz), 130.6 (d, J = 116.3 Hz), 130.5 (d,
J = 3.4 Hz), 128.8 (d, J = 8.6 Hz), 128.5 (d, J = 13.2 Hz), 127.4 (d, J
= 3.9 Hz), 125.9 (d, J = 3.6 Hz), 94.3 (d, J = 25.2 Hz), 78.1 (d, J =
199.6 Hz), 38.9 (d, J = 78.6 Hz), 19.9 (d, J = 1.8 Hz). 31P{1H} NMR
(162 MHz, chloroform-d) δ 13.84. HRMS: m/z calcd for C16H16OP
255.0939 [M + H]+, found 255.0947.
Typical Procedure for the Preparation of (Substituted-
benzyl)(phenyl)(R-yl)phosphine Oxide 7a−u. Under N2, alkyl-
magnesium bromide or chloride in solution (3.5 equiv) was added
dropwise to a solution of (phenyl)phosphinic chloride 6 (1 equiv) in
THF at 0 °C. The mixture was stirred for 1 h at room temperature
until 31P{1H} NMR indicated the disappearance of the benzyl-
(phenyl)phosphinic chloride. Saturated aqueous solution of NH4Cl
was added to the mixture. The aqueous layer had been separated and
extracted with 2 × 5 mL of DCM, dried with MgSO4, and
concentrated under a vacuum. The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10.
Benzyl(ethynyl)(phenyl)phosphine oxide (7a). Benzylphenyl-
phosphinic chloride 6a (0.5 g, 2 mmol, 1 equiv), 0.5 M
ethynylmagnesium bromide in THF (14 mL, 7 mmol, 3.5 equiv).
The crude mixture was purified by flash chromatography in the
respective proportions of n-hexane/DCM from 8:2 to 0:10. The title
product 7a was obtained as a brown solid (94.0−96.1 °C), 0.44 g
(91% yield).
(2-Methylbenzyl)(phenyl)(prop-1-yn)phosphine Oxide (7e).
(2-Methylbenzyl)(phenyl)phosphinic chloride 6b (0.5 g, 1.89 mmol,
1 equiv), prop-1-yn-1-ylmagnesium bromide 0.5 M in THF (13 mL,
6.61 mmol, 3.5 equiv). The crude mixture was purified by flash
chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7e was obtained as a red oil, 0.50 g
(yield >99%).
1H NMR (400 MHz, chloroform-d) δ 7.60−7.54 (m, 2H), 7.39 (d,
J = 1.5 Hz, 1H), 7.35−7.19 (m, 2H), 7.08−6.73 (m, 4H), 3.54−3.19
(m, 2H), 2.02 (d, J = 1.7 Hz, 3H), 1.92 (d, J = 3.8 Hz, 3H). 13C{1H}
NMR (101 MHz, chloroform-d) δ 137.0 (d, J = 5.9 Hz), 131.9 (d, J =
3.2 Hz), 130.8, 130.6 (d, J = 5.2 Hz), 130.4 (d, J = 10.4 Hz), 130.1 (d,
J = 3.2 Hz), 129.2 (d, J = 8.4 Hz), 128.1 (d, J = 12.9 Hz), 126.9 (d, J
= 3.9 Hz), 125.4 (d, J = 3.6 Hz), 104.6 (d, J = 28.8 Hz), 73.8 (d, J =
166.4 Hz), 38.9 (d, J = 78.8 Hz), 19.6 (d, J = 1.4 Hz), 4.5 (d, J = 3.4
Hz). 31P{1H} NMR (162 MHz) δ 12.86 (s). HRMS: m/z calcd for
C17H18OP 269.1095 [M + H]+, found 269.1103.
1H NMR (400 MHz, chloroform-d) δ 7.68 (ddd, J = 13.3, 8.3, 1.3
Hz, 2H), 7.53 (dd, J = 7.4, 1.8 Hz, 1H), 7.48−7.32 (m, 2H), 7.25−
7.09 (m, 3H), 7.14−6.96 (m, 2H), 3.45 (d, J = 16.5 Hz, 2H), 3.21 (d,
J = 9.5 Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 132.7
(d, J = 3.0 Hz), 130.8 (d, J = 10.6 Hz), 130.2 (d, J = 5.5 Hz), 130.0
(d, J = 117.6 Hz), 128.6, 128.5, 128.4, 127.3 (d, J = 3.8 Hz), 94.4 (d, J
= 25.4 Hz), 77.9 (d, J = 153.6 Hz), 41.7 (d, J = 78.4 Hz). 31P{1H}
NMR (162 MHz, chloroform-d) δ 14.40 (s). HRMS: m/z calcd for
C15H14OP 241.0782 [M + H]+, found 241.0781.
(2-Methylbenzyl)(phenyl)(phenylethynyl)phosphine Oxide
(7f). (2-Methylbenzyl)(phenyl)phosphinic chloride 6b (0.5 g, 1.89
mmol, 1 equiv), (phenylethynyl)magnesium bromide 1 M in THF
(6.5 mL, 6.61 mmol, 3.5 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7f was obtained as a creamy solid,
0.46 g (75% yield).
Benzyl(phenyl)(prop-1-yn-1-yl)phosphine Oxide (7b). Ben-
zylphenylphosphinic chloride 6a (0.5 g, 2 mmol, 1 equiv), 0.5 M
prop-1-yn-1-ylmagnesium bromide in THF (14 mL, 7 mmol, 3.5
equiv). The crude mixture was purified by flash chromatography in
the respective proportions of n-hexane/DCM from 8:2 to 0:10. The
title product 7b was obtained as a white solid, 0.36 g (72% yield).
1H NMR (400 MHz, chloroform-d) δ 7.76−7.56 (m, 2H), 7.49
(dd, J = 7.5, 1.7 Hz, 1H), 7.41 (dd, J = 7.8, 3.3 Hz, 2H), 7.20 (dd, J =
4.9, 1.8 Hz, 3H), 7.05 (dd, J = 4.5, 2.8 Hz, 2H), 3.39 (d, J = 16.6 Hz,
2H), 2.03 (d, J = 3.8 Hz, 3H).
1H NMR (400 MHz) δ 7.74−7.69 (m, 2H), 7.57−7.47 (m, 3H),
7.46−7.38 (m, 3H), 7.34 (dd, J = 8.0, 6.6 Hz, 2H), 7.19−7.02 (m,
4H), 3.56 (d, J = 16.9 Hz, 2H), 2.15 (s, 3H). 13C{1H} NMR (101
MHz, chloroform-d) δ 137.2 (d, J = 6.0 Hz), 132.2, 131.8, 130.8 (d, J
= 5.1 Hz), 130.7, 130.55 (d, J = 4.1 Hz), 130.3 (d, J = 3.4 Hz), 129.2
(d, J = 8.7 Hz), 128.4, 128.3 (d, J = 13.1 Hz), 127.2 (d, J = 3.9 Hz),
125.6 (d, J = 3.7 Hz), 119.6 (d, J = 3.9 Hz), 104.6 (d, J = 27.6 Hz),
82.4 (d, J = 161.1 Hz), 39.1 (d, J = 78.6 Hz), 19.8 (s). 31P{1H} NMR
(162 MHz) δ 14.53 (s). HRMS: m/z calcd for C22H20OP 331.1252
[M + H]+, found 331.1259.
13C{1H} NMR (101 MHz, chloroform-d) δ 132.2 (d, J = 3.0 Hz),
131.9, 131.1 (d, J = 8.1 Hz), 130.8 (d, J = 10.4 Hz), 130.2 (d, J = 5.7
Hz), 128.4, 128.3, 128.2, 127.03 (d, J = 3.6 Hz), 105.2 (d, J = 29.3
Hz), 73.9 (d, J = 167.8 Hz), 42.2 (d, J = 78.8 Hz), 4.9 (d, J = 3.4 Hz).
31P{1H} NMR (162 MHz, chloroform-d) δ 13.78 (s). HRMS: m/z
calcd for C16H16OP 255.0939 [M + H]+, found 255.0938.
Benzyl(phenyl)(phenylethynyl)phosphine Oxide (7c). Ben-
zylphenylphosphinic chloride 6a (0.5 g, 2 mmol, 1 equiv), 1 M
(phenylethynyl)magnesium bromide in THF (7 mL, 7 mmol, 3.5
equiv). The crude mixture was purified by flash chromatography in
the respective proportions of n-hexane/DCM from 8:2 to 0:10. The
title product 7c was obtained as a white solid (150.8−152.3 °C), 0.44
g (70% yield).
(Ethynyl)(4-methylbenzyl)(phenyl)phosphine Oxide (7g).
(4-Methylbenzyl)(phenyl)phosphinic chloride 6c (0.5 g, 1.89 mmol,
1 equiv), ethynylmagnesium bromide 0.5 M in THF (13 mL, 6.61
mmol, 3.5 equiv). The crude mixture was purified by flash
chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7g was obtained as a red oil, 0.47 g
(95% yield).
1H NMR (400 MHz, chloroform-d) δ 7.63−7.57 (m, 2H), 7.40−
7.39 (m, 1H), 7.33−7.30 (m, 2H), 6.93−6.86 (m, 4H), 3.34 (d, J =
9.5 Hz, 1H), 3.31 (d, J = 16.3 Hz, 2H), 2.16 (d, J = 2.6 Hz, 3H).
13C{1H} NMR (101 MHz, chloroform-d) δ 136.5 (d, J = 3.9 Hz),
1H NMR (400 MHz) δ 7.83−7.74 (m, 2H), 7.62−7.53 (m, 3H),
7.52−7.45 (m, 3H), 7.45−7.37 (m, 2H), 7.27 (dd, J = 4.9, 1.7 Hz,
3H), 7.23−7.10 (m, 2H), 3.53 (dq, J = 16.4, 14.4 Hz, 2H). 13C{1H}
NMR (101 MHz, chloroform-d) δ 132.39 (d, J = 1.9 Hz), 132.35 (d, J
= 3.0 Hz), 131.05 (d, J = 117.3 Hz), 130.82 (d, J = 10.5 Hz), 130.74
(d, J = 12.9 Hz), 130.21 (d, J = 5.7 Hz), 128.48 (d, J = 19.7 Hz),
128.43 (d, J = 16.1 Hz), 127.10 (d, J = 3.8 Hz), 119.83 (d, J = 4.0
Hz), 105.16 (d, J = 27.6 Hz), 82.15 (d, J = 162.2 Hz), 42.22 (d, J =
78.3 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 14.77 (s).
HRMS: m/z calcd for C21H18OP 317.1095 [M + H]+, found
317.1092.
Ethynyl(2-methylbenzyl)(phenyl)phosphine Oxide (7d). (2-
Methylbenzyl)(phenyl)phosphinic chloride 6b (0.5 g, 1.89 mmol, 1
equiv), ethynylmagnesium bromide 0.5 M in THF (13 mL, 6.61
mmol, 3.5 equiv). The crude mixture was purified by flash
chromatography in the respective proportions of n-hexane/DCM
132.2 (d, J = 3.0 Hz), 130.4 (d, J = 10.6 Hz), 130.1 (d, J = 116.7 Hz),
129.7 (d, J = 5.7 Hz), 128.9 (d, J = 3.4 Hz), 128.2 (d, J = 13.3 Hz),
126.7 (d, J = 8.5 Hz), 94.2 (d, J = 25.3 Hz), 77.8 (d, J = 152.4 Hz),
41.0 (d, J = 78.8 Hz), 20.8 (d, J = 1.4 Hz). 31P{1H} NMR (162
MHz) δ 14.49 (s). HRMS: m/z calcd for C16H16OP 255.0939 [M +
H]+, found 255.0947.
(4-Methylbenzyl)(phenyl)(prop-1-yn-1-yl)phosphine Oxide
(7h). (4-Methylbenzyl)(phenyl)phosphinic chloride 6c (0.5 g, 1.89
mmol, 1 equiv), prop-1-yn-1-ylmagnesium bromide 0.5 M in THF
(13 mL, 6.61 mmol, 3.5 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7h was obtained as a brown oil,
0.50 g (yield >99%).
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Note
1H NMR (400 MHz, chloroform-d) δ 7.61−7.56 (m, 2H), 7.37
(dd, J = 7.5, 1.7 Hz, 1H), 7.29−7.26 (m, 2H), 6.91−6.83 (m, 4H),
3.26 (d, J = 16.5 Hz, 2H), 2.16 (d, J = 2.4 Hz, 3H), 1.88 (d, J = 3.8
Hz, 3H). 13C{1H} NMR (101 MHz) δ 136.4 (d, J = 3.9 Hz), 132.1
(d, J = 2.9 Hz), 130.7 (d, J = 10.4 Hz), 130.7 (d, J = 10.4 Hz), 129.9
(d, J = 5.7 Hz), 128.9 (d, J = 3.3 Hz), 128.3 (d, J = 13.0 Hz), 127.6
(d, J = 8.4 Hz), 105.0 (d, J = 29.0 Hz), 73.7 (d, J = 167.4 Hz), 41.5
(d, J = 79.0 Hz), 21.0 (d, J = 1.1 Hz), 4.7 (d, J = 3.3 Hz). 31P{1H}
NMR (162 MHz) δ 12.61 (s). HRMS: m/z calcd for C17H18OP
269.1095 [M + H]+, found 269.1104.
8.4 Hz), 131.2 (dd, J = 63.2, 54.9 Hz), 131.1−130.8 (m, J = 10.7 Hz),
130.8−130.66 (m), 128.9 (d, J = 3.5 Hz), 128.7 (s), 128.6 (s), 128.5
(s), 127.5 (d, J = 3.3 Hz), 125.5 (d, J = 7.5 Hz), 119.9 (d, J = 3.9 Hz),
105.1 (d, J = 28.5 Hz), 82.2 (d, J = 164.6 Hz), 41.5 (d, J = 78.6 Hz).
31P{1H} NMR (162 MHz) δ 12.75 (s). HRMS: m/z calcd for
C21H17BrOP 395.0200 [M + H]+, found 395.0204.
(4-Chlorobenzyl)(ethynyl)(phenyl)phosphine Oxide (7m).
(4-Chlorobenzyl)(phenyl)phosphinic chloride 6e (0.5 g, 1.75 mmol,
1 equiv), 0.5 M ethynylmagnesium bromide in THF (13 mL, 6.14
mmol, 3.5 equiv). The crude mixture was purified by flash
chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7m was obtained as a red solid
(102.3−105.1 °C), 0.48 g (yield >99%).
(4-Methylbenzyl)(phenyl)(phenylethynyl)phosphine Oxide
(7i). (4-Methylbenzyl)(phenyl)phosphinic chloride 6c (0.5 g, 1.89
mmol, 1 equiv), 1 M (phenylethynyl)magnesium bromide (6.5 mL,
6.61 mmol, 3.5 equiv) in THF. The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7i was obtained as a yellow solid
(129.6−132.1 °C), 0.56 g (91% yield).
1H NMR (400 MHz) δ 7.66−7.61 (m, 2H), 7.51 (dt, J = 7.3, 3.7
Hz, 1H), 7.42 (td, J = 7.5, 3.4 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.97
(dd, J = 8.5, 2.5 Hz, 2H), 3.35 (d, J = 16.3 Hz, 2H), 3.31 (d, J = 9.6
Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 133.3 (d, J =
4.6 Hz), 132.8 (d, J = 3.0 Hz), 131.4 (d, J = 5.7 Hz), 130.7 (d, J =
10.6 Hz), 129.9 (d, J = 117.7 Hz), 128.8 (d, J = 8.4 Hz), 128.7 (d, J =
9.2 Hz), 128.6, 94.4 (d, J = 25.5 Hz), 77.8 (d, J = 153.3 Hz), 41.2 (d, J
= 78.1 Hz). 31P{1H} NMR (162 MHz) δ 13.38 (s). HRMS: m/z
calcd for C15H13ClOP 275.0393 [M + H]+, found 275.0403.
(4-Chlorobenzyl)(phenyl)(prop-1-yn-1-yl)phosphine Oxide
(7n). (4-Chlorobenzyl)(phenyl)phosphinic chloride 6e (0.5 g, 1.75
mmol, 1 equiv), 0.5 M prop-1-yn-1-ylmagnesium bromide in THF
(13 mL, 6.14 mmol, 3.5 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7n was obtained as a yellow solid
(93.7 °C), 0.50 g (yield >99%).
1H NMR (400 MHz) δ 7.74 (dd, J = 12.6, 7.6 Hz, 2H), 7.46−7.26
(m, 8H), 7.00 (s, 4H), 3.47−3.41 (m, 2H), 2.24 (s, 3H). 13C{1H}
NMR (101 MHz) δ 136.4 (d, J = 3.5 Hz), 132.0 (s, J = 1.6 Hz), 131.5
(s), 130.5 (d, J = 10.3 Hz), 130.3 (d, J = 4.3 Hz), 129.8 (d, J = 5.6
Hz), 128.8 (d, J = 3.2 Hz), 128.3 (s), 128.2 (d, J = 13.0 Hz), 127.3 (d,
J = 8.3 Hz), 119.5 (d, J = 3.4 Hz), 104.7 (d, J = 27.3 Hz), 82.1 (d, J =
161.1 Hz), 41.4 (d, J = 78.7 Hz), 20.8 (s). 31P{1H} NMR (162 MHz)
δ 14.35 (s). HRMS: m/z calcd for C22H20OP 331.1252 [M + H]+,
found 331.1259.
(2-Bromobenzyl)(ethynyl)(phenyl)phosphine Oxide (7j). (2-
Bromobenzyl)(phenyl)phosphinic chloride 6d (0.5 g, 1.51 mmol, 1
equiv), 0.5 M ethynylmagnesium bromide in THF (11 mL, 5.31
mmol, 3.5 equiv). The crude mixture was purified by flash
chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7j was obtained as a red creamy
solid, 0.29 g (60% yield).
1H NMR (400 MHz) δ 7.69−7.64 (m, 2H), 7.54−7.50 (m, 1H),
7.45−7.40 (m, 2H), 7.19−7.17 (m, 2H), 7.02−6.97 (m, 2H), 3.35 (d,
J = 16.4 Hz, 2H), 2.03 (d, J = 3.7 Hz, 3H). 13C{1H} NMR (101
MHz) δ 133.0 (d, J = 4.2 Hz), 132.3 (s), 131.6 (s), 131.4 (d, J = 5.4
Hz), 130.7 (d, J = 10.5 Hz), 130.0 (d, J = 92.2 Hz), 129.6 (s), 128.4
(d, J = 12.8 Hz), 128.4 (d, J = 2.7 Hz), 105.4 (d, J = 29.4 Hz), 73.5
(d, J = 168.6 Hz), 41.5 (d, J = 78.5 Hz), 4.9 (s). 31P{1H} NMR (162
MHz) δ 13.81 (s). HRMS: m/z calcd for C16H15ClOP 289.0549 [M +
H]+, found 289.0557.
1H NMR (400 MHz) δ 7.72−7.66 (m, 2H), 7.53−7.51 (m, 1H),
7.45−7.37 (m, 4H), 7.25 (t, J = 7.5 Hz, 1H), 7.9−7.05 (m, 1H),
3.79−3.62 (m, 2H), 3.27 (d, J = 9.6 Hz, 1H). 13C{1H} NMR (101
MHz) δ 133.0 (d, J = 2.8 Hz), 132.8 (d, J = 2.9 Hz), 132.0 (d, J = 5.0
Hz), 130.8 (d, J = 10.8 Hz), 130.6 (s), 130.2 (d, J = 100.2 Hz), 128.9
(d, J = 3.5 Hz), 128.6 (d, J = 13.3 Hz), 127.5 (d, J = 3.3 Hz), 125.5
(d, J = 7.7 Hz), 93.9 (d, J = 26.0 Hz), 41.1 (d, J = 78.7 Hz). 31P{1H}
NMR (162 MHz) δ 12.71 (s). HRMS: m/z calcd for C15H13BrOP
318.9887 [M + H]+, found 318.9896.
(4-Chlorobenzyl)(phenyl)(phenylethynyl)phosphine Oxide
(7o). (4-Chlorobenzyl)(phenyl)phosphinic chloride 6e (0.5 g, 1.75
mmol, 1 equiv), 1 M (phenylethynyl)magnesium bromide in THF
(6.5 mL, 6.14 mmol, 3.5 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7o was obtained as a yellow solid
(113.2−122.8 °C), 0.59 g (97% yield).
(2-Bromobenzyl)(phenyl)(prop-1-yn-1-yl)phosphine Oxide
(7k). (2-Bromobenzyl)(phenyl)phosphinic chloride 6d (0.5 g, 1.51
mmol, 1 equiv), 0.5 M prop-1-yn-1-ylmagnesium bromide in THF
(11 mL, 5.31 mmol, 3.5 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7k was obtained as a yellow
creamy solid, 0.4 g (80% yield).
1H NMR (400 MHz, chloroform-d) δ 7.77−7.72 (m, 2H), 7.57−
7.42 (m, 6H), 7.38−7.34 (m, 2H), 7.21−7.19 (m, 2H), 7.05 (dd, J =
8.5, 2.8 Hz, 2H), 3.47 (dd, J = 16.5, 3.1 Hz, 2H). 13C{1H} NMR (101
MHz, chloroform-d) δ 133.1 (d, J = 4.3 Hz), 132.5, 132.3, 131.4 (d, J
= 5.2 Hz), 130.7, 130.6, 129.4 (d, J = 8.4 Hz), 128.6, 128.5, 119.5 (d,
J = 3.4 Hz), 105.4 (d, J = 27.7 Hz), 81.9 (d, J = 164.2 Hz), 41.5 (d, J
= 78.1 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 14.08.
HRMS: m/z calcd for C21H17ClOP 351.0706 [M + H]+, found
351.0712.
1H NMR (400 MHz) δ 7.69−7.64 (m, 2H), 7.48−7.29 (m, 5H),
7.19−7.15 (m, 1H), 7.05−7.00 (m, 1H), 3.63 (dd, J = 14.9, 13.1 Hz,
1H), 3.55 (dd, J = 15.6, 13.1 Hz, 1H), 1.95 (d, J = 3.8 Hz, 3H).
13C{1H} NMR (101 MHz) δ 132.8 (d, J = 3.0 Hz), 132.3 (d, J = 3.0
Hz), 132.0 (d, J = 4.9 Hz), 131.3 (d, J = 117.9 Hz), 131.3 (d, J = 8.3
Hz), 130.8 (d, J = 10.7 Hz), 128.7 (d, J = 3.6 Hz), 128.4 (d, J = 13.2
Hz), 125.3 (d, J = 7.5 Hz), 105.3 (d, J = 30.0 Hz), 73.7 (d, J = 169.7
Hz), 41.3 (d, J = 78.7 Hz), 5.0 (d, J = 3.3 Hz). 31P{1H} NMR (162
MHz) δ 11.97 (s). HRMS: m/z calcd for C16H15BrOP 333.0044 [M +
H]+, found 333.0053.
(Naphthalen-1-ylmethyl)(ethynyl)(phenyl)phosphine Oxide
(7p). (Naphthalene-1-ylmethyl)(phenyl)phosphinic chloride (0.75 g,
2.49 mmol, 1 equiv) 6f, 0.5 M ethynylmagnesium bromide in THF
(15 mL, 7.5 mmol, 3 equiv). The crude mixture was purified by flash
chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7p was obtained as an orange solid
(126.4−137.9 °C), 0.22 g (30% yield).
(2-Bromobenzyl)(phenyl)(phenylethynyl)phosphine Oxide
(7l). (2-Bromobenzyl)(phenyl)phosphinic chloride 6d (0.5 g, 1.51
mmol, 1 equiv), 1 M (phenylethynyl)magnesium bromide in THF
(5.5 mL, 5.31 mmol, 3.5 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7l was obtained as a red oil, 0.55 g
(93% yield).
1H NMR (400 MHz, chloroform-d) δ 7.86−7.83 (m, 1H), 7.76−
7.61 (m, 4H), 7.42−7.26 (m, 7H), 3.93 (dd, J = 16.9, 2.0 Hz, 2H),
3.16 (d, J = 9.5 Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ
133.8 (d, J = 2.7 Hz), 132.5 (d, J = 3.0 Hz), 132.2 (d, J = 4.5 Hz),
130.7 (d, J = 10.4 Hz), 130.4 (d, J = 116.9 Hz), 130.0 (d, J = 7.0 Hz),
128.6, 128.5, 128.4, 128.1 (d, J = 4.1 Hz), 126.9 (d, J = 9.1 Hz), 125.9
(dd, J = 25.9, 1.1 Hz), 125.2 (d, J = 4.3 Hz), 124.2 (d, J = 2.0 Hz),
94.4 (d, J = 25.4 Hz), 78.1 (d, J = 203.7 Hz), 38.7 (d, J = 78.8 Hz).
1H NMR (400 MHz) δ 7.71−7.65 (m, 2H), 7.41−7.17 (m, 10H),
7.11−7.07 (m, 1H), 6.96−6.93 (m, 1H), 3.84 (dd, J = 15.9, 14.6 Hz,
1H), 3.76 (dd, J = 18.0, 14.7 Hz, 1H). 13C{1H} NMR (101 MHz) δ
133.0 (d, J = 2.8 Hz), 132.6 (s), 132.2 (d, J = 4.9 Hz), 131.3 (d, J =
7819
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Note
31P{1H} NMR (162 MHz, chloroform-d) δ 13.85. HRMS: m/z calcd
105.33 (d, J = 29.1 Hz), 73.81 (d, J = 167.6 Hz), 42.3 (d, J = 78.3
Hz), 4.8 (d, J = 3.2 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ
13.95. HRMS: m/z calcd for C20H18OP 305.1095 [M + H]+, found
305.1106.
(Naphthalen-2-ylmethyl)(phenyl)(phenylethynyl)-
phosphine Oxide (7u). (Naphthalene-2-ylmethyl)(phenyl)-
phosphinic chloride 6g (0.61 g, 2.02 mmol, 1 equiv), 1 M
(phenylethynyl)magnesium bromide in THF (6 mL, 6.08 mmol, 3
equiv). The crude mixture was purified by flash chromatography in
the respective proportions of n-hexane/DCM from 8:2 to 0:10. The
title product 7u was obtained as a yellow solid (170.1−173.3 °C),
0.31 g (41% yield).
for C19H16OP 291.0939 [M + H]+, found 291.0944.
(Naphthalen-1-ylmethyl)(phenyl)(prop-1-yn-1-yl)-
phosphine Oxide (7q). (Naphthalene-1-ylmethyl)(phenyl)-
phosphinic chloride 6f (0.75 g, 2.49 mmol, 1 equiv), 0.5 M prop-1-
yn-1-ylmagnesium bromide in THF (15 mL, 7.5 mmol, 3 equiv). The
crude mixture was purified by flash chromatography in the respective
proportions of n-hexane/DCM from 8:2 to 0:10. The title product 7q
was obtained as an orange liquid, 0.49 g (65% yield).
1H NMR (400 MHz, chloroform-d) δ 8.05−8.04 (m, 1H), 7.89−
7.75 (m, 4H), 7.56−7.40 (m, 6H), 7.31 (dd, J = 7.2, 3.7 Hz, 1H),
4.06−3.94 (m, 2H), 1.91 (d, J = 3.8 Hz, 3H). 13C{1H} NMR (101
MHz, chloroform-d) δ 133.8 (d, J = 2.7 Hz), 132.2, 132.2 (d, J = 3.0
Hz), 131.5 (d, J = 116.9 Hz), 130.7 (d, J = 10.4 Hz), 128.8 (d, J = 6.8
Hz), 128.5, 128.4, 128.2, 127.8 (d, J = 4.1 Hz), 127.6 (d, J = 8.9 Hz),
125.8−125.5 (m), 125.1 (d, J = 4.1 Hz), 124.4 (d, J = 2.0 Hz), 105.5
(d, J = 29.3 Hz), 74.0 (d, J = 167.8 Hz), 38.9 (d, J = 78.8 Hz).
31P{1H} NMR (162 MHz, chloroform-d) δ 13.36. HRMS: m/z calcd
1H NMR (400 MHz, chloroform-d) δ 7.82−7.67 (m, 5H), 7.60−
7.53 (m, 2H), 7.49−7.42 (m, 7H), 7.37−7.33 (m, 2H), 7.26−7.24
(m, 1H), 3.76−3.62 (m, 2H). 13C{1H} NMR (101 MHz, chloroform-
d) δ 133.4 (d, J = 3.4 Hz), 132.5, 132.5, 132.4, 131.1 (d, J = 117.4
Hz), 130.9 (d, J = 10.4 Hz), 130.7, 129.2 (d, J = 7.5 Hz), 128.6, 128.5,
128.5, 128.4, 128.3 (d, J = 4.3 Hz), 128.0 (d, J = 2.7 Hz), 127.7 (d, J =
1.8 Hz), 127.6 (d, J = 1.6 Hz), 126.2 (d, J = 1.6 Hz), 125.9 (d, J = 1.8
Hz), 119.8 (d, J = 3.9 Hz), 105.4 (d, J = 27.7 Hz), 82.2 (d, J = 162.6
Hz), 42.5 (d, J = 78.1 Hz). 31P{1H} NMR (162 MHz, chloroform-d)
δ 14.83. HRMS: m/z calcd for C25H20OP 367.1252 [M + H]+, found
367.1261.
for C20H18OP 305.1095 [M + H]+, found 305.1102.
(Naphthalen-1-ylmethyl)(phenyl)(phenylethynyl)-
phosphine Oxide (7r). (Naphthalene-1-ylmethyl)(phenyl)-
phosphinic chloride 6f (0.66 g, 2.20 mmol, 1 equiv), 1 M
(phenylethynyl)magnesium bromide in THF (6.6 mL, 6.59 mmol, 3
equiv). The crude mixture was purified by flash chromatography in
the respective proportions of n-hexane/DCM from 8:2 to 0:10. The
title product 7r was obtained as a yellow solid (99.9−106.6 °C), 0.62
g (77% yield).
Optimization of the Cyclization Conditions to Prepare 2-
Phenyl-1H-isophosphinoline 2-oxide (1a−r). A solution of
benzyl(ethynyl)(phenyl)phosphine oxide 7a (0.2 g, 0.83 mmol, 1
equiv), Ph3PAuCl (10 mg, 0.02 mmol, 0.025 equiv), and TfOH (0.2
a
1H NMR (400 MHz, chloroform-d) δ 7.98 (d, J = 8.4 Hz, 1H),
7.82−7.80 (m, 1H), 7.76−7.70 (m, 3H), 7.51−7.47 (m, 1H), 7.43−
7.23 (m, 11H), 4.09−3.92 (m, 2H). 13C{1H} NMR (101 MHz,
chloroform-d) δ 133.9 (d, J = 3.0 Hz), 132.4 (d, J = 3.0 Hz), 132.3 (d,
J = 2.0 Hz), 132.1 (d, J = 31.3 Hz), 130.8 (d, J = 10.4 Hz), 130.8,
130.6, 129.0 (d, J = 7.0 Hz), 128.6, 128.6, 128.5, 128.4, 128.0 (d, J =
4.1 Hz), 127.5 (d, J = 9.1 Hz), 125.8 (d, J = 31.6 Hz), 125.2 (d, J =
4.3 Hz), 124.4 (d, J = 2.0 Hz), 119.7 (d, J = 4.1 Hz), 105.3 (d, J =
27.5 Hz), 82.5 (d, J = 162.4 Hz), 39.0 (d, J = 78.6 Hz). 31P{1H}
NMR (162 MHz, chloroform-d) δ 14.45. HRMS: m/z calcd for
C25H20OP 367.1252 [M + H]+, found 367.1261.
(Naphthalen-2-ylmethyl)(ethynyl)(phenyl)phosphine Oxide
(7s). (Naphthalene-2-ylmethyl)(phenyl)phosphinic chloride 6g (0.63
g, 2.09 mmol, 1 equiv), 0.5 M ethynylmagnesium bromide in THF
(12,5 mL, 6.29 mmol, 3 equiv). The crude mixture was purified by
flash chromatography in the respective proportions of n-hexane/DCM
from 8:2 to 0:10. The title product 7s was obtained as a brown
creamy solid, 0.35 g (58% yield).
mL, 2.5 mmol, 3 equiv) (see footnote
in Table 5) in 1,2-
dichloroethane (2 mL) was stirred at room temperature, under
N2 atmosphere, before setting up the reaction conditions.
Table 5
b
entry
catalyst
acid
activation
time
T (°C) 1a (%)
1
2
3
4
5
6
7
(Ph)3PAuCl
(Ph)3PAuCl
(Ph)3PAuCl
(Ph)3PAuCl
(Ph)3PAuCl
(Ph)3PAuCl
TfOH
TfOH
TfOH
TfOH
TfOH
thermic
MW
MW
MW
MW
MW
MW
4 days
1.5 h
3 h
6 h
11 h
3 h
80
140
160
180
180
160
89
93
100
79
64
0
TfOH
3 h
160
39
a
b
3 equiv of TfOH was optimized in a recent paper.12 Relative % of
compound 1a determined by 31P{1H} NMR.
1H NMR (400 MHz, chloroform-d) δ 7.78−7.68 (m, 5H), 7.55−
7.49 (m, 2H), 7.44−7.37 (m, 4H), 7.22−7.19 (m, 1H), 3.60 (d, J =
16.5 Hz, 2H), 3.29 (d, J = 9.5 Hz, 1H). 13C{1H} NMR (101 MHz,
chloroform-d) δ 133.3 (d, J = 3.4 Hz), 132.7 (d, J = 3.0 Hz), 132.5 (d,
J = 2.5 Hz), 130.8 (d, J = 10.4 Hz), 130.3 (d, J = 117.6 Hz), 129.2 (d,
J = 7.5 Hz), 128.1, 128.1, 128.1, 127.8 (d, J = 8.6 Hz), 127.7, 126.2
(d, J = 1.1 Hz), 125.9 (d, J = 1.6 Hz), 94.3 (d, J = 25.2 Hz), 42.0 (d, J
= 78.1 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 14.39.
HRMS: m/z calcd for C19H16OP 291.0939 [M + H]+, found
291.0948.
(Naphthalen-2-ylmethyl)(phenyl)(prop-1-yn-1-yl)-
phosphine Oxide (7t). (Naphthalene-2-ylmethyl)(phenyl)-
phosphinic chloride 6g (0.46 g, 1.52 mmol, 1 equiv), 0.5 M prop-1-
yn-1-ylmagnesium bromide in THF (7 mL, 3.5 mmol, 2.3 equiv). The
crude mixture was purified by flash chromatography in the respective
proportions of n-hexane/DCM from 8:2 to 0:10. The title product 7t
was obtained as a brown solid (88.0−89.7 °C), 0.26 g (56% yield).
1H NMR (400 MHz, chloroform-d) δ 7.77−7.73 (m, 1H), 7.70−
7.65 (m, 4H), 7.51−7.45 (m, 2H), 7.42−7.35 (m, 4H), 7.17 (dt, J =
8.4, 1.9 Hz, 1H), 3.54 (d, J = 16.6 Hz, 2H), 1.97 (d, J = 3.7 Hz, 3H).
13C{1H} NMR (101 MHz, chloroform-d) δ 133.3 (d, J = 3.4 Hz),
The reaction was first conducted under thermic activation in 1,2-
dichloroethane using Ph3PAuCl as catalyst in the presence of triflic
acid as additive. Under these conditions, the reaction required 4 days
to reach 89% as the relative percentage of 1a in the crude mixture as
determined by 31P{1H} NMR (entry 1). More importantly, it turned
out that the addition of the arene group to the alkyne is fully
regioselective, giving as expected exclusively the 6-endo-dig cyclization
product. The corresponding 5-exo-dig products were not observed,
while in some cases gold-catalyzed reactions followed this mode of
cyclization. With the aim to shorten the reaction time, microwave-
assisted heating was attempted, since such technology has been shown
to dramatically reduce the reaction times for processes that require
prolonged heating. We were pleased to observe the formation of 1a in
93% yield by running the reaction under microwave activation at 140
°C for 1.5 h (entry 2). Increasing both the temperature and the
reaction time to 160 °C and 3 h, respectively, resulted in the
formation of 1a in excellent >99% yield (entry 3). By contrast, heating
the reaction mixture at 180 °C for 6 h had a detrimental effect and
gave compound 1a in lower yield, 79% (entry 4). We suspected that
this result could be attributed to the thermal instability of
isophosphinoline 2-oxide 1a at this temperature. Indeed, our
hypothesis was confirmed by entry 5 when the extended reaction
time of 11 h resulted in significant yield reduction, 64% (entry 5).
Alkenes were already shown to be effective substrates in
132.3 (d, J = 2.5 Hz), 132.2 (d, J = 3.0 Hz), 131.4 (d, J = 116.9 Hz),
130.7 (d, J = 10.4 Hz), 129.0 (d, J = 7.3 Hz), 128.6 (d, J = 8.9 Hz),
128.4 (d, J = 13.2 Hz), 128.2 (d, J = 4.3 Hz), 127.8 (d, J = 2.5 Hz),
127.60, 127.57, 127.55, 126.07 (d, J = 1.4 Hz), 125.76 (d, J = 1.8 Hz),
7820
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Note
intermolecular arylations, and high temperature may induce over-
reaction.25 As can be seen in Table 3, the reaction carried out without
triflic acid failed to give compound 1a, whereas the reaction
performed without gold catalyst provides the expected product 1a
in 78% yield (entries 6 and 7). It seems that Ph3PAuCl and triflic acid
have a synergistic catalytic effect.
Typical Procedure for the Preparation of Substituted 2-
Phenyl-1H-isophosphinoline 2-Oxide 1a−q. Under N2, to a
stirred solution of Ph3PAuCl (0.02 mmol, 2.5 mol %) in 1,2-
dichloroethane (2 mL), were added TfOH (2.5 mmol, 3 equiv) and 7
(0.83 mmol, 1 equiv). The reaction mixture was heated under
microwave irradiation at 160 °C for 3 h and then quenched with
saturated aqueous solution of Na2CO3. The aqueous layer was
separated and extracted with DCM. The combined organic layers
were washed with water, dried over MgSO4, filtered, and concentrated
under a vacuum. The obtained oil was purified by flash column
chromatography eluting with DCM/EtOAC (1/1 to 0/1).
2-Phenyl-1H-isophosphinoline 2-Oxide (1a). Benzyl(ethynyl)-
(phenyl)phosphine oxide 7a (0.2 g, 0.83 mmol, 1 equiv), Ph3PAuCl
(10 mg, 0.02 mmol, 2.5 mol %), TfOH (0.2 mL, 2.5 mmol, 3 equiv).
After extraction, the combined organic layers were washed with water,
dried over MgSO4, filtered, and concentrated under a vacuum. The
crude obtained was purified by flash column chromatography eluting
with DCM/EtOAC (1/1 to 0/1). 1a was obtained as a yellow solid
(79.9 °C), 0.19 g (96% yield).
128.6, 128.5, 127.5 (d, J = 1.8 Hz), 118.8 (d, J = 96.0 Hz), 34.8 (d, J =
71.1 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 17.06. HRMS:
m/z calcd for C21H18OP 317.1095 [M + H]+, found 317.1107.
8-Methyl-2-phenyl-1H-isophosphinoline 2-Oxide (1d).
Ethynyl(2-methylbenzyl)(phenyl)phosphine oxide 7d (0.1 g, 0.39
mmol, 1 equiv), Ph3PAuCl (0.005 g, 0.0098 mmol, 2.5 mol %), TfOH
(0.1 mL, 1.17 mmol, 3 equiv). After extraction, the combined organic
layers were washed with water, dried over MgSO4, filtered, and
concentrated under a vacuum. The crude obtained was purified by
flash column chromatography eluting with DCM/EtOAC (1/1 to 0/
1). The title product 1d was obtained as a brown solid (155.4 °C), 0.1
g (yield >99%).
1H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz,
chloroform-d) δ 7.77−7.71 (m, 2H), 7.51−7.15 (m, 7H), 6.28 (td, J =
12.7, 0.8 Hz, 1H), 3.56−3.47 (m, 1H), 3.22−3.15 (m, 1H), 2.26 (s,
3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 146.6, 137.7 (d, J =
9.4 Hz), 133.3 (d, J = 105.6 Hz), 132.0 (d, J = 2.8 Hz), 131.9, 131.1
(d, J = 17.1 Hz), 130.5 (d, J = 10.0 Hz), 129.1 (d, J = 2.1 Hz), 128.8,
128.7 (d, J = 12.1 Hz), 127.2, 118.8 (d, J = 93.8 Hz), 30.5 (d, J = 71.6
Hz), 19.8. 31P{1H} NMR (162 MHz, chloroform-d) δ 18.67. HRMS:
m/z calcd for C16H16OP 255.0939 [M + H]+, found 255.0952.
4,8-Dimethyl-2-phenyl-1H-isophosphinoline 2-Oxide (1e).
(2-Methylbenzyl)(phenyl)(prop-1-yn-1-yl)phosphine oxide 7e (0.1 g,
0.37 mmol, 1 equiv), Ph3PAuCl (0.005 g, 0.009 mmol, 2.5 mol %),
TfOH (0.1 mL, 1.11 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1e was obtained as a brown creamy solid, 0.09
g (90% yield).
1H NMR (400 MHz, chloroform-d) δ 7.75−7.70 (m, 2H), 7.51−
7.32 (m, 4H), 7.28−7.22 (m, 3H), 7.15−7.14 (m, 1H), 6.27 (t, J =
12.6 Hz, 1H), 3.59 (dd, J = 20.3, 17.3 Hz, 1H), 3.29 (dd, J = 17.3,
11.4 Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 146.0 (s),
132.1 (d, J = 2.8 Hz), 131.4 (d, J = 16.4 Hz), 131.0 (d, J = 10.5 Hz),
130.5 (s), 130.5 (s), 130.4 (s), 130.2 (d, J = 7.5 Hz), 129.7 (s), 128.6
(d, J = 12.1 Hz), 127.7 (d, J = 1.0 Hz), 119.7 (d, J = 93.8 Hz), 33.9
(d, J = 71.0 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 18.16
(s). HRMS: m/z calcd for C15H14OP 241.0782 [M + H]+, found
241.0793.
4-Methyl-2-phenyl-1H-isophosphinoline 2-Oxide (1b).
Benzyl(phenyl)(prop-1-yn-1-yl)phosphine oxide 7b (0.2 g, 0.78
mmol, 1 equiv), Ph3PAuCl (0.01 g, 0.02 mmol, 2.5 mol %), TfOH
(0.2 mL, 2.34 mmol, 3 equiv). After extraction, the combined organic
layers were washed with water, dried over MgSO4, filtered, and
concentrated under a vacuum. The crude obtained was purified by
flash column chromatography eluting with DCM/EtOAC (1/1 to 0/
1). The title product 1b was obtained as a brown solid (184.3 °C),
0.15 g (75% yield).
1H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz,
chloroform-d) δ 7.74−7.69 (m, 2H), 7.50−7.34 (m, 4H), 7.06 (s,
2H), 6.15 (dd, J = 12.0 Hz, 1H), 3.52 (dd, J = 20.2, 16.7 Hz, 1H),
3.23 (dd, J = 16.7, 11.4 Hz, 1H), 2.39 (d, J = 1.3 Hz, 3H), 2.36 (s,
3H). 13C{1H} NMR (101 MHz, chloroform-d) 153.6, 137.7 (d, J =
8.9 Hz), 133.2 (d, J = 14.6 Hz), 132.4, 132.1, 131.9, 130.8 (d, J = 8.9
Hz), 129.1 (d, J = 5.0 Hz), 128.7 (d, J = 11.4 Hz), 127.0, 124.8, 117.3
(d, J = 104.2 Hz), 30.6 (d, J = 72.0 Hz), 25.1 (d, J = 15.4 Hz), 20.7.
31P{1H} NMR (162 MHz, chloroform-d) δ 17.66. HRMS: m/z calcd
for C17H18OP 269.1095 [M + H]+, found 269.1107.
6-methyl-2-phenyl-1H-isophosphinoline 2-Oxide (1g).
Ethynyl(4-methylbenzyl)(phenyl)phosphine oxide 7g (0.1 g, 0.4
mmol, 1 equiv), Ph3PAuCl (0.005 g, 0.01 mmol, 2.5 mol %),
TfOH (0.1 mL, 1.18 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1g was obtained as a brown creamy solid,
0.085 g (85% yield).
1H NMR (400 MHz, chloroform-d) δ 7.76−7.71 (m, 2H), 7.55−
7.39 (m, 4H), 7.29 (dt, J = 23.9, 7.5 Hz, 2H), 7.21−7.14 (m, 1H),
6.18 (d, J = 12.5 Hz, 1H), 3.60−3.51 (m, 1H), 3.32−3.25 (m, 1H),
2.40 (s, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 152.5,
133.3 (d, J = 13.9 Hz), 132.5 (d, J = 104.9 Hz), 131.9 (d, J = 2.7 Hz),
131.2 (d, J = 10.7 Hz), 130.6 (d, J = 9.8 Hz), 130.4 (d, J = 7.3 Hz),
129.4, 128.5 (d, J = 12.0 Hz), 127.7, 126.4 (d, J = 2.0 Hz), 117.9 (d, J
= 97.4 Hz), 34.7 (d, J = 70.8 Hz), 24.1 (d, J = 15.2 Hz). 31P{1H}
NMR (162 MHz, chloroform-d) δ 17.18. HRMS: m/z calcd for
C16H16OP 255.0939 [M + H]+, found 255.0951.
2,4-Diphenyl-1H-isophosphinoline 2-Oxide (1c). Benzyl-
(phenyl)(phenylethynyl)phosphine oxide 7c (0.2 g, 0.63 mmol, 1
equiv), Ph3PAuCl (0.008 g, 0.016 mmol, 2.5 mol %), TfOH (0.17
mL, 1.9 mmol, 3 equiv). After extraction, the combined organic layers
were washed with water, dried over MgSO4, filtered, and concentrated
under a vacuum. The crude obtained was purified by flash column
chromatography eluting with DCM/EtOAC (1/1 to 0/1). The title
product 1c was obtained as a brown solid (187.3−193.1 °C), 0.2 g
(yield >99%).
1H NMR (400 MHz, chloroform-d) 7.75−7.70 (m, 2H), 7.51−
7.29 (m, 4H), 7.09−7.04 (m, 3H), 6.25 (t, J = 12.5 Hz, 1H), 3.58
(dd, J = 20.7, 17.2 Hz, 1H), 3.27 (dd, J = 17.3, 11.5 Hz, 1H), 2.34 (s,
3H).
13C{1H} NMR (101 MHz, chloroform-d) δ 146.4, 137.6, 132.7 (d,
J = 104.0 Hz), 132.1 (d, J = 2.7 Hz), 131.3 (d, J = 2.3 Hz), 131.2,
131.0 (d, J = 10.6 Hz), 130.6, 130.5, 128.6 (d, J = 12.2 Hz), 127.2 (d,
J = 7.5 Hz), 119.6 (d, J = 93.9 Hz), 33.5 (d, J = 71.2 Hz), 29.8, 21.0.
31P{1H} NMR (162 MHz, chloroform-d) δ 19.11. HRMS: m/z calcd
for C16H16OP 255.0939 [M + H]+, found 255.0948.
4,6-Dimethyl-2-phenyl-1H-isophosphinoline 2-Oxide (1h).
(4-Methylbenzyl)(phenyl)(prop-1-yn-1-yl)phosphine oxide 7h (0.1 g,
0.37 mmol, 1 equiv), Ph3PAuCl (0.005 g, 0.009 mmol, 2.5 mol %),
TfOH (0.1 mL, 1.11 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1h was obtained as a brown solid (124.3 °C),
0.097 g (97% yield).
1H NMR (400 MHz, chloroform-d) δ 7.84−7.78 (m, 2H), 7.44−
7.14 (m, 12H), 6.35 (dd, J = 13.4, 1.0 Hz, 1H), 3.70−3.61 (m, 1H),
3.41 (dd, J = 16.4, 10.9 Hz, 1H). 13C{1H} NMR (101 MHz,
chloroform-d) δ 157.2 (d, J = 2.0 Hz), 140.7 (d, J = 14.5 Hz), 133.7
(d, J = 19.1 Hz), 133.2 (d, J = 13.4 Hz), 132.1 (d, J = 105.1 Hz),
132.1 (d, J = 3.0 Hz), 131.4 (d, J = 10.0 Hz), 131.0 (d, J = 7.9 Hz),
130.9 (d, J = 9.8 Hz), 130.1 (d, J = 2.3 Hz), 129.7, 128.9, 128.7,
1H NMR (400 MHz, chloroform-d) δ 7.74−7.69 (m, 2H), 7.48−
7.46 (m, 1H), 7.43−7.38 (m, 2H), 7.34 (s, 1H), 7.06 (s, 2H), 6.15
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Note
(dd, J = 12.3, 1.5 Hz, 1H), 3.52 (dd, J = 20.2, 16.7 Hz, 1H), 3.23 (dd,
J = 16.7, 11.4 Hz, 1H), 2.39 (d, J = 1.4 Hz, 3H), 2.36 (s, 3H).
13C{1H} NMR (101 MHz, chloroform-d) δ 152. 7, 137.4, 133.3 (d, J
= 13.0 Hz), 132.3, 131.9 (d, J = 2.8 Hz), 131.2 (d, J = 10.7 Hz), 130.7
(d, J = 9.7 Hz), 130.2, 128.6 (d, J = 12.0 Hz), 127.4 (d, J = 7.0 Hz),
127.3 (d, J = 2.1 Hz), 118.0 (d, J = 97.6 Hz), 34.3 (d, J = 70.9 Hz),
29.8, 24.3 (d, J = 15.2 Hz), 21.4. 31P{1H} NMR (162 MHz,
chloroform-d) δ 17.80. HRMS: m/z calcd for C17H18OP 269.1095 [M
+ H]+, found 269.1106.
8-Bromo-2-phenyl-1H-isophosphinoline 2-Oxide (1j). (2-
Bromobenzyl)(ethynyl)(phenyl)phosphine oxide 7j (0.1 g, 0.31
mmol, 1 equiv), Ph3PAuCl (0.004 g, 0.008 mmol, 2.5 mol %),
TfOH (0.08 mL, 0.94 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1j was obtained as a brown creamy solid,
0.096 g (97% yield).
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1m was obtained as a brown solid (174.4−
178.6 °C), 0.097 g (quantitative yield)
1H NMR (400 MHz, chloroform-d) δ 7.72−7.67 (m, 2H), 7.44−
7.06 (m, 11H), 6.30 (d, J = 13.2 Hz, 1H), 3.58−3.49 (m, 1H), 3.32−
3.25 (m, 1H).13C{1H} NMR (101 MHz, chloroform-d) δ 156.4,
140.0 (d, J = 13.6 Hz), 134.9 (d, J = 12.9 Hz), 133.5, 132.7 (d, J = 9.8
Hz), 132.4, 131.0 (d, J = 9.3 Hz), 129.9, 129.6, 129.5 (d, J = 6.8 Hz),
129.4, 128.9, 128.8, 128.5, 120.2 (d, J = 96.0 Hz), 34.3 (d, J = 71.8
Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 16.89 (s). HRMS:
m/z calcd for C21H17ClOP 351.0706 [M + H]+, found 351.0711.
2-Phenyl-1H-benzo[h]isophosphinoline 2-Oxide (1n).
(Naphthalen-1-ylmethyl)(ethynyl)(phenyl)phosphine oxide 7p (0.2
g, 0.68 mmol, 1 equiv), Ph3PAuCl (0.008 g, 0.017 mmol, 2.5 mol %),
TfOH (0.2 mL, 2.06 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1n was obtained as a brown solid (160.9 °C),
0.18 g (91% yield).
1H NMR (400 MHz, chloroform-d) δ 7.75−7.19 (m, 9H), 6.37 (t,
J = 12.5 Hz, 1H), 3.79 (dd, J = 20.6, 18.0 Hz, 1H), 3.39 (dd, J = 18.1,
10.9 Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 145.3,
134.2, 133.3 (d, J = 17.3 Hz), 132.5 (d, J = 107.2 Hz), 132.4 (d, J =
3.0 Hz), 130.7 (d, J = 10.2 Hz), 130.3, 130.2, 128.9, 128.8 (d, J = 3.9
Hz), 127.2 (d, J = 10.4 Hz), 120.5 (d, J = 92.9 Hz), 33.8 (d, J = 71.5
Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 18.60. HRMS: m/z
calcd for C15H13BrOP 318.9887 [M + H]+, found 318.9898.
8-Bromo-2,4-diphenyl-1H-isophosphinoline 2-Oxide (1k).
(2-Bromobenzyl)(phenyl)(phenylethynyl)phosphine oxide 7l (0.1 g,
0.25 mmol, 1 equiv), Ph3PAuCl (0.003 g, 0.006 mmol, 2.5 mol %),
TfOH (0.07 mL, 0.76 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
by flash column chromatography eluting with DCM/EtOAC (1/1 to
0/1). The title product 1k was obtained as a brown solid (224.0−
226.0 °C), 0.098 g (98% yield).
1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J = 8.2 Hz, 1H),
7.82−7.76 (m, 4H), 7.59−7.36 (m, 7H), 6.41 (t, J = 12.7 Hz, 1H),
4.04 (dd, J = 21.8, 18.0 Hz, 1H), 3.64 (dd, J = 18.2, 12.0 Hz, 1H).
13C{1H} NMR (101 MHz, chloroform-d) δ 147.0, 134.0, 133.8,
132.8, 132.2 (d, J = 2.8 Hz), 130.5 (d, J = 10.1 Hz), 128.8, 128.7 (d, J
= 12.2 Hz), 128.3 (d, J = 18.2 Hz), 128.0, 120.0 (d, J = 2.1 Hz), 127.1
(d, J = 27.3 Hz), 126.8 (d, J = 7.1 Hz), 123.6, 119.4 (d, J = 94.0 Hz),
29.7, 29.7 (d, J = 72.2 Hz). 31P{1H} NMR (162 MHz, chloroform-d)
δ 18.60. HRMS: m/z calcd for C19H16OP 291.0939 [M + H]+, found
291.0948.
4-Methyl-2-phenyl-1H-benzo[h]isophosphinoline 2-Oxide
(1o). (Naphthalen-1-ylmethyl)(phenyl)(prop-1-yn-1-yl)phosphine
oxide 7r (0.15 g, 0.49 mmol, 1 equiv), Ph3PAuCl (0.006 g, 0.012
mmol, 2.5 mol %), TfOH (0.12 mL, 1.37 mmol, 3 equiv). After
extraction, the combined organic layers were washed with water, dried
over MgSO4, filtered, and concentrated under a vacuum. The crude
was purified by flash column chromatography eluting with DCM/
EtOAC (1/1 to 0/1). The title product 1o was obtained as a brown
solid (201.9−203.1 °C), 0.12 g (80% yield).
1H NMR (400 MHz, chloroform-d) δ 7.89−7.75 (m, 2H), 7.66−
7.33 (m, 9H), 7.21−7.04 (m, 2H), 6.41 (dd, J = 13.5, 1.2 Hz, 1H),
3.99 (ddd, J = 19.0, 17.2, 1.2 Hz, 1H), 3.46 (dd, J = 17.2, 10.5 Hz,
1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 157.1 (d, J = 2.2
Hz), 140.7 (d, J = 14.6 Hz), 135.4 (d, J = 14.2 Hz), 134.2, 132.5,
132.4 (d, J = 2.8 Hz), 131.3 (d, J = 27.8 Hz), 129.6 (d, J = 1.7 Hz),
129.0 (d, J = 23.1 Hz), 128.7, 128.6 (d, J = 12.3 Hz), 128.3 (d, J = 1.7
Hz), 127.2 (d, J = 10.2 Hz), 119.9 (d, J = 95.1 Hz), 34.2 (d, J = 71.6
Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 15.96. HRMS: m/z
calcd for C21H17BrOP 395.0200 [M + H]+, found 395.0205.
(4-Chlorobenzyl)(ethynyl)(phenyl)phosphine Oxide (1l). (4-
Chlorobenzyl)(ethynyl)(phenyl)phosphine oxide 7m (0.1 g, 0.36
mmol, 1 equiv), Ph3PAuCl (0.005 g, 0.009 mmol, 2.5 mol %), TfOH
(0.1 mL, 1.1 mmol, 3 equiv). After extraction, the combined organic
layers were washed with water, dried over MgSO4, filtered, and
concentrated under a vacuum. The crude obtained was purified by
flash column chromatography eluting with DCM/EtOAC (1/1 to 0/
1). The title product 1l was obtained as a liquid, 0.098 g (yield
>99%).
1H NMR (400 MHz, chloroform-d) δ 8.06−8.04 (m, 1H), 7.85−
7.70 (m, 5H), 7.54−7.42 (m, 5H), 6.34 (d, J = 12.6 Hz, 1H), 4.08
(dd, J = 21.4, 17.6 Hz, 1H), 3.64 (dd, J = 17.5, 12.0 Hz, 1H), 2.53 (d,
J = 1.3 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d) δ 153.6,
133.9, 132.1, 131.5, 131.4, 130.9 (d, J = 9.9 Hz), 128.8, 128.7 (d, J =
7.8 Hz), 127.9, 127.3, 127.1 (d, J = 33.8 Hz), 124.2, 123.7, 117.8 (d, J
= 97.9 Hz), 29.8 (d, J = 71.9 Hz), 25.7 (d, J = 15.6 Hz). 31P{1H}
NMR (162 MHz, chloroform-d) δ 17.47. HRMS: m/z calcd for
C20H18OP 305.1095 [M + H]+, found 305.1104.
2,4-Diphenyl-1H-benzo[h]isophosphinoline 2-Oxide (1p).
(Naphthalen-1-ylmethyl)(phenyl)(phenylethynyl)phosphine oxide
7s (0.2 g, 0.54 mmol, 1 equiv), Ph3PAuCl (0.007 g, 0.014 mmol,
2.5 mol %), TfOH (0.14 mL, 1.64 mmol, 3 equiv). After extraction,
the combined organic layers were washed with water, dried over
MgSO4, filtered, and concentrated under a vacuum. The crude
obtained was purified by flash column chromatography eluting with
DCM/EtOAC (1/1 to 0/1). The title product 1p was obtained as a
brown solid (155.1−160.2 °C), 0.175 g (88% yield).
1H NMR (400 MHz, chloroform-d) δ 7.75−7.69 (m, 2H), 7.53−
7.44 (m, 4H), 7.29−7.24 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 6.38 (t, J
= 12.5 Hz, 1H), 3.59 (dd, J = 20.5, 17.2 Hz, 1H), 3.27 (dd, J = 17.4,
11.4 Hz, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ 144.9,
133.6, 132.9 (d, J = 16.5 Hz), 132.5, 132.4, 132.3, 130.6 (d, J = 9.9
Hz), 130.3 (d, J = 2.5 Hz), 129.6, 128.9 (d, J = 12.2 Hz), 128.7 (d, J =
7.6 Hz), 128.6 (d, J = 12.4 Hz), 121.4 (d, J = 93.1 Hz), 33.4 (d, J =
71.0 Hz). 31P{1H} NMR (162 MHz, chloroform-d) δ 17.62 (s).
HRMS: m/z calcd for C15H13ClOP 275.0393 [M + H]+, found
275.0403.
6-Chloro-2,4-diphenyl-1H-isophosphinoline 2-Oxide (1m).
(4-Chlorobenzyl)(phenyl)(phenylethynyl)phosphine oxide 7o (0.1 g,
0.28 mmol, 1 equiv), Ph3PAuCl (0.004 g, 0.007 mmol, 2.5 mol %),
TfOH (0.08 mL, 0.85 mmol, 3 equiv). After extraction, the combined
organic layers were washed with water, dried over MgSO4, filtered,
and concentrated under a vacuum. The crude obtained was purified
1H NMR (400 MHz, chloroform-d) δ 8.2 (d, J = 7.5 Hz, 1H),
7.79−7.71 (m, 3H), 7.57 (d, J = 8.6 Hz, 1H), 7.44−7.34 (m, 10H),
7.18 (d, J = 8.8 Hz, 1H), 6.43−6.40 (m, 1H), 4.16−4.07 (m, 1H),
3.65−3.58 (m, 1H). 13C{1H} NMR (101 MHz, chloroform-d) δ
158.5 (d, J = 2.3 Hz), 141.5 (d, J = 14.5 Hz), 134.1, 133.1, 132.4 (d, J
= 8.2 Hz), 132.2 (d, J = 2.7 Hz), 132.0, 131.0 (d, J = 9.8 Hz), 130.5
(d, J = 15.4 Hz), 128.9, 128.8, 128.7, 128.7, 128.6, 128.0 (d, J = 7.5
Hz), 127.3, 127.1 (d, J = 15.0 Hz), 127.0 (d, J = 2.0 Hz), 124.2, 119.0
(d, J = 97.0 Hz), 29.8 (d, J = 72.7 Hz). 31P{1H} NMR (162 MHz,
chloroform-d) δ 16.90. HRMS: m/z calcd for C25H20OP 367.1252 [M
+ H]+, found 367.1259.
7822
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J. Org. Chem. 2021, 86, 7813−7824

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Covid-19 context, and Timethe Dumas for his help on the
bibliography.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00648.
REFERENCES
■
(1) (a) Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M.
Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64,
150−183. (b) Jampilek, J. Heterocycles in Medicinal Chemistry.
Molecules 2019, 24, 3839.
HR-ESI-MS, 1H, 13C, and 31P{1H} spectra for the
described compounds (PDF)
(2) Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. Spirocyclic
Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64, 150−183.
(3) (a) Cerulli, R. A.; Kritzer, J. A. Phosphotyrosine isosteres: past,
present and future. Org. Biomol. Chem. 2020, 18, 583−605. (b) Patani,
G. A.; LaVoie, E. J. Bioisosterism: A Rational Approach in Drug
Design. Chem. Rev. 1996, 96, 3147−3176. (c) Wermuth, C. G.;
Ciapetti, P.; Giethlen, B.; Bazzini, P. Comprehensive Medicinal
Chemistry II; Elsevier: 2007; Vol. 2, pp 649−711.
AUTHOR INFORMATION
■
Corresponding Authors
David Virieux − ICGM, Univ. Montpellier, ENSCM, CNRS,
Montpellier, France; orcid.org/0000-0002-6495-9478;
Email: david.virieux@enscm.fr
Jean-Luc Pirat − ICGM, Univ. Montpellier, ENSCM, CNRS,
Montpellier, France; orcid.org/0000-0002-3688-2047;
Email: jean-luc.pirat@enscm.fr
(4) (a) Finkbeiner, P.; Hehn, J. P.; Gnamm, C. Phosphine Oxides
from a Medicinal Chemist’s Perspective: Physicochemical and in
Vitro Parameters Relevant for Drug Discovery. J. Med. Chem. 2020,
63, 7081−7107. (b) Volle, J.-N.; Guillon, R.; Bancel, F.; Bekro, Y.-A.;
Pirat, J.-L.; Virieux, D. Phosphono- and Phosphinolactones in the Life
Sciences. Adv. Heterocycl. Chem. 2016, 118, 129−193. (c) Brewster,
R.; Vandergeten, M. C.; Montel, F. Syntheses of Heteraphosphacy-
clanes: Follow the Guide! Eur. J. Org. Chem. 2014, 2014, 905−917.
(d) Mucha, A.; Kafarski, P.; Berlicki, L. Remarkable Potential of the
α-Aminophosphonate/Phosphinate Structural Motif in Medicinal
Chemistr. J. Med. Chem. 2011, 54, 5955−5980. (e) Moonen, K.;
Laureyn, I.; Stevens, C. V. Synthetic Methods for Azaheterocyclic
Phosphonates and Their Biological Activity. Chem. Rev. 2004, 104,
6177−6215.
Authors
Mina Hariri − ICGM, Univ. Montpellier, ENSCM, CNRS,
Montpellier, France; Department of Chemistry, K. N. Toosi
University of Technology, Tehran, Iran
Fatemeh Darvish − Department of Chemistry, K. N. Toosi
University of Technology, Tehran, Iran
Karen-Pacelye Mengue Me Ndong − ICGM, Univ.
Montpellier, ENSCM, CNRS, Montpellier, France; Université
des Sciences et Techniques de Masuku, Franceville, Gabon
Nora Sechet − ICGM, Univ. Montpellier, ENSCM, CNRS,
Montpellier, France
Geraud Chacktas − ICGM, Univ. Montpellier, ENSCM,
CNRS, Montpellier, France
(5) Virieux, D.; Volle, J.-N.; Bakalara, N.; Pirat, J.-L. In Phosphorus
Chemistry I. Topics in Current Chemistry, Vol. 360; Montchamp, J. L.,
Ed.; Springer: 2014; pp 39−114.
(6) Volle, J.-N.; Filippini, D.; Krawczyk, B.; Kaloyanov, N.; Van der
Lee, A.; Maurice, T.; Pirat, J.-L.; Virieux, D. Drug discovery:
phosphinolactone, in vivo bioisostere of the lactolgroup. Org. Biomol.
Chem. 2010, 8, 1438−1444.
(7) (a) Sutanto, F.; Konstantinidou, M.; Dömling, A. Covalent
inhibitors: a rational approach to drug discovery. RSC Med. Chem.
2020, 11, 876−884. (b) Gehringer, M.; Laufer, S. A. Emerging and
Re-Emerging Warheads for Targeted Covalent Inhibitors: Applica-
tions in Medicinal Chemistry and Chemical Biology. J. Med. Chem.
2019, 62, 5673−5724. (c) De Cesco, S.; Kurian, J.; Dufresne, C.;
Mittermaier, A. K.; Moitessier, N. Covalent inhibitors design and
discovery. Eur. J. Med. Chem. 2017, 138, 96−114.
(8) (a) Patil, V. M.; Masand, N. Anticancer Potential of Flavonoids:
Chemistry, Biological Activities, and Future Perspectives. Studies in
Natural Products Chemistry; Elsevier B.V.: 2018; Vol. 59, pp 401−430.
(b) Ullah, A.; Munir, S.; Badshah, S. L.; Khan, N.; Ghani, L.; Poulson,
B. G.; Emwas, A.; Jaremko, M. Important Flavonoids and Their Role
as a Therapeutic Agent. Molecules 2020, 25, 5243. (c) Wang, J.; Liu,
S.-S.; Song, Z.; Xu, T.; Liu, C.; Hou, Y.-G.; Huang, R.; Wu, S.-H.
Naturally Occurring Flavonoids and Isoflavonoids and Their Micro-
bial Transformation: A Review. Molecules 2020, 25, 5112. (d) Jucá, M.
M.; Cysne Filho, F. M. S.; de Almeida, J. C.; Mesquita, D. da S.;
Barriga, J. R. de M.; Dias, K. C. F.; Barbosa, T. M.; Vasconcelos, L. C.;
Leal, L. K. A. M.; Ribeiro, J. E.; Vasconcelos, S. M. M. Flavonoids:
biological activities and therapeutic potential. Nat. Prod. Res. 2020, 34,
692−705.
Hooriye Boosaliki − ICGM, Univ. Montpellier, ENSCM,
CNRS, Montpellier, France; Department of Chemistry, K. N.
Toosi University of Technology, Tehran, Iran
Minh Loan Tran Do − ICGM, Univ. Montpellier, ENSCM,
CNRS, Montpellier, France
Gabin Mwande-Maguene − Université des Sciences et
Techniques de Masuku, Franceville, Gabon
Jacques Lebibi − Université des Sciences et Techniques de
Masuku, Franceville, Gabon
Alexander R. Burilov − Arbuzov Institute of Organic and
Physical Chemistry, FRC Kazan Scientific Center of RAS,
Kazan 420088, Russian Federation
Tahar Ayad − ICGM, Univ. Montpellier, ENSCM, CNRS,
Montpellier, France; orcid.org/0000-0003-4210-5997
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00648
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated to Dr. Liliya Vagapova (Arbuzov
Institute of Organic and Physical Chemistry of FRC Kazan
Scientific Center of RAS, Kazan, Russia). The research leading
to these results received funding from the French Embassies in
Iran, Gabon, and Russia. The Ministry of Science, Research
and Technology of the Islamic Republic of Iran is gratefully
acknowledged for the financial support provided to M.H. and
H.B. (Ph.D. student at the K. N. Toosi University of
Technology of Tehran, Iran). We are grateful to the National
Graduate School of Chemistry of Montpellier that offered to
N.S. and G.C. the possibility to participate in this project in the
(9) (a) Wallis, C. J.; Virieux, D.; Cristau, H.-J. Diphenyl(vinyl)-
phosphine Oxide. Encyclopedia of Reagents for Organic Synthesis; John
Wiley & Sons, Ltd: Chichester, U.K., 2005; Vol. 1, pp 1−9.
(b) Rahman, M. S.; Steed, J. W.; Hii, K. K. Scope and Limitations of
the Preparation of Aminophosphines R-NH(CH2CH2PPh2) and
Aminodiphosphines R-N(CH2CH2PPh2)2 via Michael Addition of
Amines to Vinylphosphines (Mimi). Synthesis 2000, 2000, 1320−
̈
1326. (c) Scherner, C.; Erguden, J.-K.; Adiwidjaja, G.; Schaumann, E.
A Novel Route to 6-Substituted Piperidin-3-ols via Domino
Cyclization of 2-Hydroxy-6-phosphinyl-5-hexenyl Tosylates with
7823
https://doi.org/10.1021/acs.joc.1c00648
J. Org. Chem. 2021, 86, 7813−7824

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Primary Amines: Synthesis of ( )-Pseudoconhydrine and ( )-epi-
Pseudoconhydrine. Synthesis 2014, 46, 2506−2514. (d) Gonzalez-
Nogal, A. M.; Cuadrado, P.; Sarmentero, M. A. Some synthetic
applications of vinylphosphane oxides. Tetrahedron 2010, 66, 9610−
9619.
(17) Iorga, B.; Carmichael, D.; Savignac, P. Phosphonate−
phosphonochloridate conversion. C. R. Acad. Sci., Ser. IIc: Chim.
2000, 3, 821−829.
(18) (a) Eymery, F.; Iorga, B.; Savignac, P. Synthesis of
phosphonates by nucleophilic substitution at phosphorus: The
SNP(V) reaction. Tetrahedron 1999, 55, 13109−13150. (b) Lecerclé,
D.; Sawicki, M.; Taran, F. Phosphine-Catalyzed α-P-Addition on
Activated Alkynes: A New Route to P−C−P Backbones. Org. Lett.
2006, 8, 4283−4285. (c) Ashburn, B. O.; Carter, R. G. Diels−Alder
Approach to Polysubstituted Biaryls: Rapid Entry to Tri- and Tetra-
ortho-substituted Phosphorus-Containing Biaryls. Angew. Chem., Int.
Ed. 2006, 45, 6737−6741. (d) Lin, Y.; Bernardi, D.; Doris, E.; Taran,
F. Phosphine-Catalyzed Synthesis of Unsymmetrical 1,3-Bis- and
Trisphosphorus Ligands. Synlett 2009, 2009, 1466−1470. (e) Okuda,
Y.; Seo, T.; Shigezane, Y.; Watanabe, H.; Akashi, H.; Iwanaga, T.;
Orita, A. Synthesis of Ph2P(O)-stabilized Ynamines via C(sp)−N
Bond Formation and Their Dephosphorylative Copper-catalyzed
Click Reaction. Chem. Lett. 2019, 48, 1484−1487.
(10) (a) Katsyuba, S. A.; Burganov, T. I. A fresh look at participation
of phosphorus atom in conjugation. Phosphorus, Sulfur Silicon Relat.
̋
Elem. 2016, 191, 417−422. (b) Nyulászi, L.; Benko, Z. Aromatic
Phosphorus Heterocycles. Aromaticity in Heterocyclic Compounds;
Springer: Berlin, Heidelberg, 2016; Vol. 3, pp 27−81.
(11) (a) Kim, C.-E.; Ryu, T.; Kim, S.; Lee, K.; Lee, C.-H.; Lee, P. H.
Gold-Catalyzed Hydroarylation of Aryl Alkynylphosphonates for the
Synthesis of Phosphacoumarins. Adv. Synth. Catal. 2013, 355, 2873−
2883. (b) Ma, D.; Hu, S.; Chen, S.; Pan, J.; T, S.; Gao, Y.; Zhao, Y.
Palladium-Catalyzed Addition/Cyclization of (2-Hydroxyaryl)boronic
Acids with Alkynylphosphonates: Access to Phosphacoumarins. Org.
Lett. 2020, 22, 8156−8160.
(12) Babouri, R.; Traore, L.; Bekro, Y.-A.; Matveeva, V. I.; Sadykova,
Y. M.; Voronina, J. K.; Burilov, R.; Ayad, T.; Volle, J.-N.; Virieux, D.;
Pirat, J.-L. Golden Face of Phosphine: Cascade Reaction to
Bridgehead Methanophosphocines by Intramolecular Double Hydro-
arylation. Org. Lett. 2019, 21 (1), 45−49.
(13) (a) Modern Gold Catalyzed Synthesis; Hashmi, A. S. K., Toste,
F. D., Eds.; Wiley-VCH: Weinheim, Germany, 2012. (b) Furstner, A.;
̈
Davies, P. W. Catalytic Carbophilic Activation: Catalysis by Platinum
(19) (a) Ito, H.; Makida, Y.; Ochida, A.; Ohmiya, H.; Sawamura, M.
Cyclization of Nonterminal Alkynic β-Keto Esters Catalyzed by
Gold(I) Complex with a Semihollow, End-Capped Triethynylphos-
phine Ligand. Org. Lett. 2008, 10, 5051−5054. (b) Barabé, F.;
Levesque, P.; Korobkov, I.; Barriault, L. Synthesis of Fused
Carbocycles via a Selective 6-Endo Dig Gold(I)-Catalyzed Carbocyc-
lization. Org. Lett. 2011, 13, 5580−5583. (c) Mallampudi, N. A.;
Choudhury, U. M.; Mohapatra, D. K. Total Synthesis of
(−)-Citreoisocoumarin, (−)-Citreoisocoumarinol, (−)-12-epi-Cit-
reoisocoumarinol, and (−)-Mucorisocoumarins A and B Using a
Gold(I)-Catalyzed Cyclization Strategy. J. Org. Chem. 2020, 85,
4122−4129.
(20) (a) Wang, M.-Z.; Wong, M.-K.; Che, C.-M. Gold(I)-Catalyzed
Intermolecular Hydroarylation of Alkenes with Indoles under
Thermal and Microwave-Assisted Conditions. Chem. - Eur. J. 2008,
14, 8353−8364. (b) Hu, X.; Martin, D.; Melaimi, M.; Bertrand, G.
Gold-Catalyzed Hydroarylation of Alkenes with Dialkylanilines. J. Am.
Chem. Soc. 2014, 136, 13594−13597. (c) Campeau, D.; León Rayo,
D. F.; Mansour, A.; Muratov, K.; Gagosz, F. Gold-Catalyzed
Reactions of Specially Activated Alkynes, Allenes, and Alkenes.
Chem. Rev. 2020, DOI: 10.1021/acs.chemrev.0c00788.
(21) For reviews dealing with oxidative reaction of alkynes with gold,
see: Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of
Alkynes for the Construction of Molecular Complexity. Chem. Rev.
2015, 115, 9028−9072.
(22) (a) Trost, B. M.; Spohr, S. M.; Rolka, A. B.; Kalnmals, C. A.
Desymmetrization of Phosphinic Acids via Pd-Catalyzed Asymmetric
Allylic Alkylation: Rapid Access to P-Chiral Phosphinates. J. Am.
Chem. Soc. 2019, 141, 14098−14103. (b) Pirat, J.-L.; Monbrun, J.;
Virieux, D.; Cristau, H.-J. Pallado-catalysed P-arylations and P-
vinylation of 2-hydrogeno-2-oxo-1,4,2-oxazaphosphinanes. Tetrahe-
dron 2005, 61, 7029−7036.
(23) Montgomery, R. E.; Incho, H. H. US Patent 3557259 A
19710119, 1971.
(24) Berger, O.; Petit, C.; Deal, E. L.; Montchamp, J.-L. Phosphorus-
Carbon Bond Formation: Palladium-Catalyzed Cross-Coupling of H-
Phosphinates and Other P(O)H-Containing Compounds. Adv. Synth.
Catal. 2013, 355, 1361−1373.
(25) (a) Wang, M.-Z.; Wong, M.-K.; Che, C.-M. Gold(I)-Catalyzed
Intermolecular Hydroarylation of Alkenes with Indoles under
Thermal and Microwave-Assisted Conditions. Chem. - Eur. J. 2008,
14, 8353−8364. (b) Hu, X.; Martin, D.; Melaimi, M.; Bertrand, G.
Gold-Catalyzed Hydroarylation of Alkenes with Dialkylanilines. J. Am.
Chem. Soc. 2014, 136, 13594−13597. (c) Campeau, D.; León Rayo,
D. F.; Mansour, A.; Muratov, K.; Gagosz, F. Gold-Catalyzed
Reactions of Specially Activated Alkynes, Allenes, and Alkenes.
Chem. Rev. 2020, DOI: 10.1021/acs.chemrev.0c00788.
and Gold π Acids. Angew. Chem., Int. Ed. 2007, 46, 3410−3449.
(c) Fu
̈
rstner, A. Gold and platinum catalysisa convenient tool for
generating molecular complexity. Chem. Soc. Rev. 2009, 38, 3208−
3221. (d) Hashmi, A. S. K. Gold-Catalyzed Organic Reactions. Chem.
Rev. 2007, 107, 3180−3211. (e) Jiménez-Nunez, E.; Echavarren, A.
M. Gold-Catalyzed Cycloisomerizations of Enynes: A Mechanistic
Perspective. Chem. Rev. 2008, 108, 3326−3350. (f) Li, Z.; Brouwer,
C.; He, C. Gold-Catalyzed Organic Transformations. Chem. Rev.
2008, 108, 3239−3265. (g) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Ligand Effects in Homogeneous Au Catalysis. Chem. Rev. 2008, 108,
3351−3378. (h) Lee, S. I.; Chatani, N. Catalytic skeletal
reorganization of enynes through electrophilicactivation of alkynes:
double cleavage of C−C double and triple bonds. Chem. Commun.
2009, 371−384. (i) Abu Sohel, S. M.; Liu, R.-S. Carbocyclisation of
alkynes with external nucleophiles catalysed by gold, platinum and
other electrophilic metals. Chem. Soc. Rev. 2009, 38, 2269−2281.
(j) Leyva-Perez, A.; Corma, A. Similarities and Differences between
the “Relativistic” Triad Gold, Platinum, and Mercury in Catalysis.
Angew. Chem., Int. Ed. 2012, 51, 614−635. (k) Bandini, M. Gold-
catalyzed decorations of arenes and heteroarenes with C−C multiple
bonds. Chem. Soc. Rev. 2011, 40, 1358−1367. (l) Boorman, T. C.;
Larrosa, I. Gold-mediated C−H bond functionalization. Chem. Soc.
Rev. 2011, 40, 1910−1925. (m) Merino, E.; Nevado, C. On Gold
Catalysis and Beyond. Chimia 2013, 67, 663−668. (n) Qian, D.;
Zhang. Gold-catalyzed cyclopropanation reactions using a carbenoid
precursor toolbox. Chem. Soc. Rev. 2015, 44, 677−698. (o) Goodwin,
J. A.; Aponick, A. Regioselectivity in the Au-catalyzed hydration and
hydroalkoxylation of alkynes. Chem. Commun. 2015, 51, 8730−8741.
(p) Fructos, M. R.; Diaz-Requejo, M. M.; Pérez, P. J. Gold and diazo
reagents: a fruitful tool for developing molecular complexity. Chem.
Commun. 2016, 52, 7326−7335.
(14) Coudray, L.; Montchamp, J.-L. Green, Palladium-Catalyzed
Synthesis of Benzylic H-Phosphinates from Hypophosphorous Acid
and Benzylic Alcohols. Eur. J. Org. Chem. 2008, 2008, 4101−4103.
(15) (a) Jiajun, M.; Junxiao, Y.; Yawen, H.; Ke, C. Aluminum−
organophosphorus hybrid nanorods for simultaneously enhancing the
flame retardancy and mechanical properties of epoxy resin. J. Mater.
Chem. 2012, 22, 2007−2017. (b) Boyd, E. A.; Boyd, M. E. K.; Loh, V.
M., Jr Facile synthesis of functionalised phenylphosphinic acid
derivatives. Tetrahedron Lett. 1996, 37, 1651−1654.
(16) Cristau, H.-J.; Hervé, A.; Loiseau, F.; Virieux, D. Synthesis of
New Arylhydroxymethylphosphinic Acids and Derivatives. Synthesis
2003, 2216−2220.
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J. Org. Chem. 2021, 86, 7813−7824