Metal-Free, N-Iodosuccinimide-Induced Regioselective Iodophosphoryloxylation of Alkenes with P(O)?OH Bonds

Article abstract of DOI:10.1002/chem.202000575

A simple and efficient method for the regioselective iodophosphoryloxylation of alkenes with P(O)?OH bonds has been established by using NIS (N-iodosuccinimide) as the iodination reagent under transition-metal-free conditions. The present protocol is compatible with different functional groups, and suitable for various alkenes and P(O)?OH compounds. A variety of functionalized β-iodo-1-ethyl phosphinic/phosphoric acid esters are obtained in good to excellent yields, which could be further transformed to diversified building blocks for the synthesis of bioactive compounds, pharmaceuticals and functional materials.

Full text of DOI:10.1002/chem.202000575

A Journal of
Accepted Article
Title: Metal-Free, NIS-Induced Regioselective Iodophosphoryloxylation
of Alkenes with P(O)-OH bonds
Authors: Biquan Xiong, Shipan Xu, Yu Zhu, Lei Yao, Congshan Zhou,
Yu Liu, Kw-Wen Tang, and Wai-Yeung Wong
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To be cited as: Chem. Eur. J. 10.1002/chem.202000575
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Metal-Free, NIS-Induced Regioselective Iodophosphoryloxylation of Alkenes with
P(O)-OH bonds
Biquan Xiong,*, a,b Shipan Xu, a Yu Zhu,a Lei Yao,a Congshan Zhou,a Yu Liu,a Ke-Wen Tang,*, a Wai-Yeung Wong*, b
in the presence of a source of I+ for the enantioselective generation
Abstract: A simple and efficient method for the regioselective
iodophosphoryloxylation of alkenes with P(O)-OH bonds has been
of five- and six-membered lactones.4a Since then, Fujioka et al. and
Yeung et al. further demonstrated the enantioselective
established by using NIS (N-iodosuccinimide) as the iodination
bromolactonization of 5-substituted 5-hexenoic acids catalyzed by
reagent under transition-metal-free conditions. The present
the tris(imidazoline) and L-proline-derived S-alkyl thiocarbamate,
protocol is compatible with different functional groups, and
respectively.4b,4c Feng et al. found a highly efficient catalytic
suitable for various alkenes and P(O)-OH compounds. A variety of
functionalized β-iodo-1-ethyl phosphinic/phosphoric acid esters are
chloroamination reaction of α,β-unsaturated γ-keto esters and
chalcones via a chloronium-based mechanism to deliver anti-
obtained in good to excellent yields, which could be further
regioselective vicinal chloroamines instead of the aziridinium
intermediates delivered aminochlorides.4d In 2012, Toste et al.
transformed to diversified building blocks for the synthesis of
bioactive compounds, pharmaceuticals and functional materials.
invented a chiral anion phase-transfer system for enantioselective
6-exo-trig bromocyclization of styrenyl amides.4e Later, Mukherjee
et al. discovered the catalytic asymmetric iodoetherification of
oximes with the help of a bifunctional thiourea catalyst.4f In
addition, Denmark and Burk have systematically studied the Lewis
base catalyzed bromo- and iodolactonization reactions and also
explored the effects of catalyst structure on the rate and cyclization
selectivity.4g Although some elegant studies on the selective
difunctionalization of carbon-carbon double bonds were achieved
by these scientists,5 the use of P(O)-OH compounds as starting
materials has not been reported. Herein, we demonstrate an
efficient regioselective iodophosphoryloxylation of alkenes with
P(O)-OH bonds by using NIS (N-iodosuccinimide) as the
iodination reagent under transition-metal-free conditions (Scheme
1).6
Introduction
Organophosphorus compounds have been recognized as the
important intermediates in biological chemistry, asymmetric
catalysis, and preparation of functional materials for a half century,
due to their unique structural features and potential
pharmacological activities.1,2 In particular, some β-iodo-α-alkyl
phosphinic/phosphoric acid esters are significant building blocks
present in a variety of biologically interesting natural products,
pharmaceuticals, and synthetic intermediates of broad utility.
Generally, these β-iodofunctionalized phosphinic/phosphoric acid
esters are prepared either by the substitution of phosphoryl
chlorides with β-iodo-α-ethanol compounds/direct iodination for
the methyl group of 1-phenylethyl phosphinic or phosphoric acid
esters or the direct cross coupling of (1-halo-2-iodo-alkyl)
compounds with phosphinic/phosphoric acids and transition-metal-
catalyzed [e.g., Fe, Cu, Pd] dehydrogenative coupling of β-iodo-α-
ethanol derivatives with P(O)-H/P(O)-Cl bonds.3 However, these
protocols suffer from certain disadvantages such as the use of a
large excess of P(O)-H motifs and co-oxidants, poor
regioselectivity, and low yields.
The direct dehydrogenative coupling of P(O)-H or P(O)-OH
bonds with C(sp3)−H bonds of the methyl group in arenes has been
achieved by Zhao and Xiong.5a-b In 2015, Wei and Wang et al.
established
a novel and efficient procedure for the direct
difunctionalization of alkenes with I2O5 and P(O)–H compounds.5c
Recently, Ishihara discovered a metal-free transesterification of
phosphinates
with
alcohols
via
the
catalysis
of
tetramethylammonium methyl carbonate.5d Jacobsen et al. reported
the intramolecular reaction of carboxylic acids with pendant olefins
Scheme 1. Synthesis of phosphonate/phosphate esters or β-iodophosphate.
Results and Discussion
[a]
[b]
Department of Chemistry and Chemical Engineering, Hunan Institute
of Science and Technology, Yueyang, 414006, P.R.China.
xiongbiquan@126.com (Dr. B. Xiong)
At the first stage of our study, we attempted to use NIS as the
activation reagent for the carbon-carbon double bond for the
generation of 2-phenyliodiran-1-ium, and then introduced a P(O)-
OH bond to realize the regioselective iodophosphoryloxylation of
alkenes. To test our initial hypothesis, the reaction of styrene (1a)
and diphenylphosphinic acid (2a) was investigated to delineate the
reaction parameters.7 The reaction of 1a with 2a was carried out at
room temperature in toluene under a N2 atmosphere with the
addition of iodine reagent NIS, and the corresponding addition
tangkewen@sina.com (Prof. K. Tang)
Department of Applied Biology and Chemical Technology, The Hong
Kong Polytechnic University, Hung Hom, Hong Kong, P. R. China.
wai-yeung.wong@polyu.edu.hk (Prof. W.-Y. Wong)
Supporting information for this article is given via a link at the end of
the document
1
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10.1002/chem.202000575
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product of 2-iodo-1-phenylethyl diphenylphosphinate (3a) was
generated in 7% yield. Besides toluene, other solvents, such as
THF, DMF, CH3CN, 1,4-dioxane and CH2Cl2 were further tested
(Table 1, entries 2-6), and THF gave the product in a preferable
yield of 78%. We then chose THF as the solvent for further
optimization. When the reaction was operated under an air
atmosphere, the expected product could only be produced in 66%
yield (Table 1, entry 7). This phenomenon may be ascribed to the
influence of water in air, which interrupted the
phosphoryloxylation path of the reaction. Besides NIS, other iodine
sources such as I2, KI, NaI and tetrabutylammonium iodide (TBAI)
showed negative results toward the reaction (Table 1, entries 8-11).
The increase of reaction temperature within the 25-40 °C range is
beneficial, but a further increase from 40 to 80 °C results in a little
decrease of the product yield (Table 1, entries 12-14). Additionally,
it is worth noting that the reaction would not produce any products
in the absence of NIS (Table 1, entry 15). We further optimized the
amount of NIS used, and the optimal condition was obtained at a
“diphenyl phosphinic acid/styrene/NIS molar ratio” of 1:1:1.2
(Table 1, entries 16-18). Some other iodination systems were
further screened for the reaction, and I2 still showed negative
results for the reaction even with the addition of an oxidant (H2O2,
TBHP, DTBP, K2S2O8). According to M. C. Mattos’s method,
bromo-2-vinylbenzene (1e) and 1-fluoro-4-vinylbenzene (1f) can
react efficiently with diphenylphosphinic acid (2a) under the
optimized reaction conditions, affording the corresponding
iodophosphoryloxylation products of 3a-3f in 85-95% isolated
yields. For most cases, electron-donating or electron-withdrawing
groups which are located on the aryl ring of styrenes do not change
the yields of the products significantly. In addition, special alkenes
such as allylbenzene (2g) and 1-allylnaphthalene (2h) could also
afford the desired products of 3g and 3h in 58% and 45% yields,
respectively.8 To our delight, when cyclic alkenes (2i-2k) were
employed as the starting materials, 3i-3k were synthesized in 75-
82% yield. In addition, straight-chain alkenes such as cinnamyl
alcohol (1l), and methyl cinnamate (1m) also showed positive
results toward the reaction, and the expected products of 3l and 3m
were generated in 86% and 90% yields, respectively. Furthermore,
various kinds of alkenes containing ester group (1o-1t) also
exhibited high reactivities for the present reaction, affording the
corresponding addition products in 63-94% yields. While 1-
methoxy-4-vinylbenzene (1u) and (E)-1-methoxy-4-(prop-1-en-1-
yl)benzene (1v) were used for the reaction, the desired
iodophosphoryloxylation products can be synthesized in 91% and
80% 31P NMR yields, but unfortunately, these compounds could
not be isolated from the reaction mixture via the short silica-
column. It is deduced that these compounds might decompose
during the purification process.
7e
TICA (triiodoisocyanuric acid) was synthesized in 86% yield,
which could promote the reaction with the generation of the
desired product in 82% yield.
Table 2. Scope of alkenes. a
Table 1. Optimization of the reaction conditions.a
Entry
1
2
Solvent
toluene
THF
Iodine reagent
NIS
Temp.
r.t.
r.t.
Yield of 3a b
7%
NIS
78%
3
4
5
6
7
8
DMF
CH3CN
1,4-dioxane
CH2Cl2
THF
NIS
NIS
NIS
NIS
NIS
I2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
49%
58%
23%
65%
66% c
N.D.
THF
9
THF
KI
r.t.
N.D.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NaI
TBAI
NIS
NIS
NIS
r.t.
r.t.
N.D.
N.D.
95%
93%
92%
N.D.
40 oC
60 oC
80 oC
40 oC
40 oC
40 oC
40 oC
40 oC
40 oC
40 oC
40 oC
40 oC
-
NIS
NIS
NIS
I2/H2O2
I2/TBHP
I2/DTBP
I2/K2S2O8
TICA
22% d
46% e
96% f
N.D. g
N.D. h
N.D. i
N.D. j
82% k
THF
a
Reagents and conditions: styrene (1a, 0.5 mmol), diphenylphosphinic acid (2a, 0.5
mmol) and iodine reagent (1.0 eq) in solvent (1.0 mL), N2 atmosphere, temp., 6 h. b 31
P
c
d
e
NMR yields. Air conditions. NIS (0.125 mmol, 25 mol%). NIS (0.25 mmol, 50
f
g
h
mol%). NIS (0.6 mmol, 120 mol%). H2O2 (0.6 mmol, 25% solution in water).
a
Reagents and conditions: alkene (1a, 0.5 mmol), diphenylphosphinic acid (2a, 0.5
mmol) and NIS (0.6 mmol) in THF (1.0 mL), at 40 oC under a N2 atmosphere stirred
i
j
TBHP (0.6 mmol, 70% solution in water). DTBP (di-t-butyl peroxide, 0.6 mmol).
K2S2O8 (0.6 mmol). k TICA (triiodoisocyanuric acid, 0.6 mmol).
b
c
for 6 h. Isolated yields. 31P NMR yield, light sensitive, cannot be separated and
decomposed during passing through the silica gel column.
As
shown
in
Table
2,
the
regioselective
iodophosphoryloxylation of alkenes with NIS and P(O)-OH bonds
leading to β-iodophosphates can be applied to different kinds of
alkenes. It is clear that styrene (1a), 1-methyl-4-vinylbenzene (1b),
1-bromo-4-vinylbenzene (1c), 1-bromo-3-vinylbenzene (1d), 1-
As depicted in Table 3, a range of substituted P(O)-OH
compounds (2b-2o) were screened under the optimized reaction
conditions with styrene. It is clear that symmetrically substituted
2
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sodium azide to afford 2-azido-1-phenylethyl diphenylphosphinate
(5a) in 96% yield.9 This compound provides great synthetic
versatility to the phosphorus derivatives, allowing a variety of
subsequent structural modification such as radical reaction for the
synthesis of triazolyl-functionalized phosphinates with distinct
biological activity. In addition, we further conducted the reaction
of 3a with water in the presence of silver nitrate (2.0 equiv.), and
the corresponding hydroxylation product of 2-hydroxy-1-
phenylethyl diphenylphosphinate (5b) was obtained in 99% yield.9
diarylphosphinic acid with electron-donating groups such as di-p-
tolylphosphinic acid (2b), di-m-tolylphosphinic acid (2c), bis(3,5-
dimethylphenyl)phosphinic
acid
(2d)
and
bis(4-
methoxyphenyl)phosphinic acid (2e), exhibit high reactivity toward
styrene, giving the corresponding products of 4a-4d in 83-92%
yields. For large functional groups in substituted diarylphosphinic
acids, such as di(naphthalen-1-yl)phosphinic acid (2f) and
di(naphthalen-2-yl)phosphinic acid (2g), they also showed positive
results, affording the corresponding products in 80% and 78%
yields.
When bis(3-fluorophenyl)phosphinic acid (2h) was used, the
corresponding iodophosphoryloxylation product of 2-iodo-1-
phenylethyl bis(3-fluorophenyl)phosphinate (4g) could be
produced in 68% yield. Moreover, asymmetric phosphonic acid,
such as methyl(phenyl)phosphinic acid (2i), is also suitable for the
reaction and yielded the product of 4h in 85% yield. Notably,
different kinds of hydrogen phosphates such as diethyl hydrogen
phosphate (2j), dibutyl hydrogen phosphate (2k), 2-ethylhexyl (2-
ethylpentyl) hydrogen phosphate (2l), dibenzyl hydrogen
phosphate (2m) and diphenyl hydrogen phosphate (2n) were also
appropriate for this protocol to generate the corresponding products
(4i–4m) in moderate to good yields. When (S)-(+)-1,1'-binaphthyl-
2,2'-diyl hydrogenphosphate (2o) was used for the reaction, despite
its low solubility and reactivity as a nucleophile, in this case it was
quite effective with 53% yield for the synthesis of (11bS)-4-(2-
Scheme 2. Large-scale production and selective functionalization of 3a.
iodo-1-phenylethoxy)dinaphtho[2,1-d:1',2'-f][1,3,2]
dioxaphos-
phepine 4-oxide (4n) as the desired product. The fact of substituent
insensibility in alkenes to the reaction yields shows that
substituents probably do not influence the rate determining step of
the reaction. Furthermore, the difference in the yields of
phosphates and phosphonates indicates that the phosphonates are
more reactive than phosphates due to the pKa differences.
Table 3. Scope of the P(O)-OH compounds.a
Scheme 3. Control experiments.
Control experiments were conducted for the reaction in order to
gain the insight of the reaction mechanism. As depicted in Scheme
3, while the reactions were only performed with diphenyl
phosphinic acid (2a) and NIS under the optimized reaction
conditions, the desired coupling product was not detected after the
reaction. Meanwhile, while we employed H2O instead of diphenyl
phosphinic acid in the reaction, the corresponding product of 2-
iodo-1-phenylethanol (6b) could be obtained in 76% yield.10
Besides diphenyl phosphinic acid, diphenyl phosphine chloride and
diphenylphosphinic iodide were also tested for the reaction, but
unfortunately, the desired adducts were not formed during the
reaction. A competitive reaction between diphenyl phosphinic acid
(2a) and water was operated under the optimized reaction
conditions, and 2-iodo-1-phenylethyl diphenylphosphinate (3a) and
2-iodo-1-phenylethanol (6b) were generated in 72% and 21%
yields, respectively. It is deduced that diphenyl phosphinic acid (2a)
has a higher reactivity than water as a nucleophile.
a
Reagents and conditions: styrene (1, 0.5 mmol), P(O)-OH compounds (0.5 mmol),
NIS (0.6 mmol), THF (1.0 mL), under N2 atmosphere, 40 oC , 6 h. b Isolated yields.
In order to demonstrate the practical application of this method,
we further performed a large-scale reaction of styrene (1a, 20
mmol) with diphenyl phosphinic acid (2a, 20 mmol) in the
presence of NIS which afforded 3a in 81% yield (7.257 g)
(Scheme 2). In the solvent of DMF, 3a could react efficiently with
3
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Scheme 4. Plausible mechanism.
A
plausible mechanism for the present regioselective
iodophosphoryloxylation reaction is proposed as illustrated in
Scheme 4.11 The N-iodosuccinimide (B) first undergoes the attack
of styrene (A) leading to the formation of iodonium intermediate D
with the release of pyrrolidine-2,5-dione anion (C). In the presence
of P(O)-OH compound (E), which could easily operate the ring-
opening reaction with D to form the unstable corresponding
oxonium intermediate (F). In the presence of pyrrolidine-2,5-dione
anion (C), F could undergo the deprotonation process to give the
iodophosphoryloxylation product H with the release of one
molecule of pyrrolidine-2,5-dione (G).
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Conclusion
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[8] Due to the special intrinsic property of this type of compounds, a cyclization
reaction would occur during the reaction with the generation of a cyclic
phosphorus compounds, leading to the low yields of 3g and 3h. The study for the
cyclization reaction is under way.
In summary, we have developed an efficient NIS-induced
regioselective iodophosphoryloxylation of unactivated alkenes with
P(O)-OH bonds under transition metal-free conditions. A wide
range of P(O)-OH compounds and alkenes bearing diverse
functional groups were applicable for this protocol, providing the
related β-iodo-1-ethyl phosphinic/phosphoric acid esters with good
to excellent yields. To the best of our knowledge, it appears that
the regioselective iodophosphoryloxylation of alkenes with P(O)-
OH bonds has not been exploited previously, and the salient
features of the reaction include its broad substrate scope, high step
economy, and good chemoselectivity. The synthetic method also
exhibits high potential for the construction of biologically active
molecules, and organophosphorus compounds
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Acknowledgement
This work was supported by National Natural Science Foundation of
China (21606080), Natural Science Foundation of Hunan Province
(2019JJ50203), Scientific Research Fund of Hunan Provincial
Education Department (19A197) and Hunan Provincial Innovation
Foundation for Postgraduate (CX2018B774). W.-Y.W. thanks the
Hong Kong Polytechnic University (1-ZE1C) and the Endowed
Professorship in Energy from Ms Clarea Au (847S) for the financial
support.
Conflicts of interest
There are no conflicts to declare
Keywords: P(O)-OH bonds • Iodophosphoryloxylation • alkenes •
transition metal-free
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Soc. 2005, 127, 2960-2965; b) J. Yang, T. Q. Chen, L. B. Han, J. Am. Chem. Soc.
4
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Entry for the Table of Contents
A simple and efficient method for the regioselective iodophosphoryloxylation of alkenes with P(O)-OH bonds has been established by using NIS
(N-iodosuccinimide) as the iodination reagent under transition-metal-free and mild conditions. A wide range of P(O)-OH compounds and alkenes
bearing diverse functional groups were applicable for this protocol. The synthetic method also exhibits high potential for the construction of
biologically active molecules, and organophosphorus compounds.
5
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