Direct, oxidative halogenation of diaryl- or dialkylphosphine oxides with (dihaloiodo)arenes

Article abstract of DOI:10.1016/j.tetlet.2018.06.044

The oxidative halogenation of diaryl- or dialkylphosphine oxides with the hypervalent iodine reagents (difluoroiodo)toluene (p-TolIF₂, 1) and (dichloroiodo)benzene (PhICl₂, 2) is reported. Phosphoric fluorides could be recovered in 32–75% yield, or they could be trapped with EtOH to give the corresponding phosphinate in typically good yield. Phosphoric chlorides were not readily isolable, and were trapped with alcohol and amine nucleophiles, giving diaryl- or dialkylphos-phinates and phosphinamides in up to 90% yield.

Full text of DOI:10.1016/j.tetlet.2018.06.044

Accepted Manuscript
Direct, Oxidative Halogenation of Diaryl- or Dialkylphosphine oxides with
(Dihaloiodo)arenes
Jasmin Eljo, Graham K. Murphy
PII:
S0040-4039(18)30798-6
https://doi.org/10.1016/j.tetlet.2018.06.044
TETL 50082
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Tetrahedron Letters
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9 June 2018
16 June 2018
Please cite this article as: Eljo, J., Murphy, G.K., Direct, Oxidative Halogenation of Diaryl- or Dialkylphosphine
oxides with (Dihaloiodo)arenes, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.044
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Tetrahedron Letters
Direct, Oxidative Halogenation of Diaryl- or Dialkylphosphine oxides with
(Dihaloiodo)arenes
Jasmin Eljoa and Graham K. Murphya,
aDepartment of Chemistry, University of Waterloo, 200 University Ave. W., Waterloo, ON, Canada, N2L3G1
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The oxidative halogenation of diaryl- or dialkylphosphine oxides with the hypervalent iodine
reagents (difluoroiodo)toluene (TolIF2, 1) and (dichloroiodo)benzene (PhICl2, 2) is reported.
Phosphoric fluorides could be recovered in 32-75% yield, or they could be trapped with EtOH to
give the corresponding phosphinate in typically good yield. Phosphoric chlorides were not
readily isolable, and were trapped with alcohol and amine nucleophiles, giving diaryl- or
dialkylphos-phinates and phosphinamides in up to 90% yield.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Phosphoric chloride
Phosphoric fluoride
Hypervalent iodine
Phosphinate
Phosphinamide
———
 Corresponding author. Tel.: +1-519-888-4567; fax: +0-000-000-0000; e-mail: graham.murphy@uwaterloo.ca

2
Tetrahedron
Organophosphorus compounds that possess P(O)-F bonding
yield of 4a (entry 10), whereas lowering it to nearly equimolar
caused a significant decrease in yield (entry 11). The addition of
Lewis acidic activating agents23b, 27 failed to improve the reaction
(entries 12-15), presumably because the phosphine oxides are
sufficiently nucleophilic to engage the iodane without prior
activation. Throughout these trials, we consistently observed
diaryl phosphinic acid 5a, and 31P NMR analysis of the reaction
mixture showed this to be present prior to reaction workup.
Using recrystallized reagents and conducting the reaction in a
glovebox or with activated molecular sieves failed to prevent its
formation. Nonetheless, the desired oxidative fluorination proved
to be a viable strategy for phosphoric fluoride synthesis from
secondary phosphine oxide precursors.
are a class of biologically-active compound that has received
considerable attention over the last century. The biological
activity displayed by these synthetic fluorine-containing
organophosphorus compounds is highly structure dependent:1
whereas sarin and soman are highly toxic nerve agents,
diisopropyl fluorophosphate (DPF)2 is a therapeutic agent used in
the treatment of chronic glaucoma (Figure 1). Phosphoric
fluorides are selective mechanistic probes, as well as potent
cholinesterase enzyme inhibitors, and both the fluorides and
chlorides are powerful phosphorylating reagents, serving as
precursors to other organophosphorus compounds. 3,4
Table 1. Optimization of the phosphoric fluoride
synthesis.a
Figure 1. Examples of biologically active phosphoric fluorides.
Oxidative halogenation of P(O)-H compounds is a well-
established approach to phosphoric halides. For example, their
chlorination has been prepared with chlorine gas,5 with sulfuryl
chloride6 or CuCl2,7 or with chloramines,8 TCICA9 or NCS.10
These chlorination reactions can also be employed in strategies
for the synthesis of phosphoric fluorides by simply adding a
fluoride source. For example, in reactions with TCICA–KF,11
trichloroacetonitrile–KF12 or CuCl2–CsF,13 the initially-formed
chlorides are intercepted by the fluoride. Electrophilic
fluorination of a phosphine oxide is achieved with reagents such
as XeF2,14 Selectfluor®15 or DDQ/CuBr2/NaF.16 Drawbacks of
these methods include harsh reaction conditions, the need for
excess reagent, or use of reagents that are corrosive, toxic, costly
or moisture sensitive, therefore the continued development of
synthetic strategies remains important.
entry solvent temp TolIF2
(°C) (equiv)
additive
(mol%)
time
4a
%yield
50
46
53
58
51
38
64
69
60
67
55
1
2
CH2Cl2
CHCl3
DCE
rt
rt
rt
rt
rt
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.4
1.02
1.1
-
-
-
-
-
-
-
-
-
-
-
1 h
1 h
1 h
1 h
1 h
3
4
PhCl
5
THF
6
CH3CN rt
1 h
7
8
9
10
11
12
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
40
60
110
60
60
60
10 min
10 min
10 min
10 min
10 min
BF3•OEt2 10 min
(10)
67
13
14
15
PhCl
PhCl
PhCl
60
60
60
1.1
1.1
1.1
TiF3 (10) 10 min
TiF4 (10) 10 min
FeF3 (10) 10 min
57
52
57
Phosphines and phosphine oxides react with hypervalent
iodine reagents to undergo oxidative arylation,17 alkynylation,18
vinylation19 and trifluoromethylation20 of P-H bonds.21
Hypervalent iodine reagents commonly effect oxidative
halogenation reactions,22 and so they are an attractive strategy for
the synthesis of phosphoric halides from secondary phosphine
oxides. As part of our ongoing interest in oxidative halogenation
reactions of phosphines,23 we were intrigued by the potential for
generating phosphoric fluorides and chlorides from secondary
phosphine oxides and TolIF2 (1)24 and PhICl2 (2),25 respectively.
As oxidants and sources of halide nucleophiles, these reagents
offer a facile and eco-friendly approach to the derivatization of
organophosphorus compounds.26 We report here that phosphoric
fluorides and chlorides could be rapidly prepared by reacting
secondary phosphine oxides with either 1 or 2, and furthermore
that the intermediates could be trapped in situ with nucleophiles
to give phosphinate and phosphinamide products.
a
Reaction conditions: To 1 in solvent (0.25 mL) at temp (°C)
was added 3a and stirred. Isolated yields.
With the optimized conditions in hand, we tested a variety of
substituted diarylphosphine oxides (3b-i) in the fluorination
reaction (Scheme 1). Substrates possessing strongly (3a, p-OMe)
or moderately electron-donating (3b, p-Me and 3c, o-Me)
substituents were all viable, and gave the corresponding
phosphoric fluorides 4a-c in higher yield than did
diphenylphosphine oxide 3d, which gave 4d in 46% yield. The
moderately electron-poor para-chloro substrate 3e gave 4e in a
similarly low yield of 47%, whereas the di(naphthalen-1-
yl)phosphine oxide (3f) gave 4f in 75% yield. We also employed
dialkylphosphine oxides in this process, and while the dibenzyl
derivative 3g only gave 4g in 32% yield, the di-n-hexyl- and
dicyclohexyl- derivatives (3h and 3i) were converted to the
corresponding phosphoric fluorides 4h and 4i in 60% and 54%
yield, respectively.
Our investigation into the synthesis of phosphoric fluorides
began by reacting bis(4-methoxyphenyl)phosphine oxide (3a),
prepared via double Grignard addition into diethyl phosphite, and
TolIF2 (1) in CH2Cl2 at room temperature. After 1 h, 31P NMR
indicated the consumption of 3a, and phosphoric fluoride 4a was
recovered in 50% yield (Table 1, entry 1). Various other solvents
were screened, and while the reaction proceeded in chlorinated,
ethereal and even highly polar solvents, we found chlorobenzene
to give 4a in 58% yield (entries 2-6; see Supporting information
for complete optimization table). The reaction temperature was
then gradually increased from room temperature to 110 °C, and
we found 60 °C to be optimal, giving 4a in 69% yield (entries 7-
9). Increasing the loading of TolIF2 (1) failed to increase the
We attempted to fluorinate diethylphosphite under these
reaction conditions, and though consumption of the phosphite
was rapid, diethyl phosphorofluoridate (6) was only recovered in
34% yield (eq 1). Throughout these

observed a slight decrease in product yield when conducting the
reaction in DMF (68% yield, entry 6); however, conducting the
reaction in EtOH as solvent have 7e in 83% yield (entry 7), even
though alcohol oxidation by 2 is a possible competing process.28
Decreasing the loading of EtOH threefold had a slight effect on
the yield (entry 9), and further decreasing the loading 2 from 1.1
to 1.02 equivalents had no adverse effect on the reaction
outcome. The high chemoselectivity observed in this reaction,
even when run in ethanol, comes from the increased
nucleophilicity of the phosphine oxide starting material over
ethanol, leading to the diarylphosphinate in high yield.29
Table 2. Optimization of the phosphoric chloride
synthesis and trapping with EtOH.a
Scheme 1. Oxidative fluorination of diaryl- and
dialkylphosphine oxides.
entry solvent PhICl2 (2) EtOH yield
(equiv)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
(equiv)
30
30
30
30
30
30
-
%
92
85
85
81
83
68
83
83
85
85
1
2
CH2Cl2
DCE
studies, the missing mass balance consisted predominantly of
phosphinic acids 5a-i, where its recovery increased with
substrates where the phosphoric fluoride was poorly stabilized by
the arene’s substituents (eg. 4e/4g). This undesired reactivity
indicated that these phosphoric fluorides might be easily trapped
by an alcoholic nucleophile like ethanol, resulting in a one-pot
synthesis of ethyl diarylphosphinates. To test this hypothesis, we
repeated the reaction with substrates 3a, 3d and 3e in the
presence of excess ethanol (eq 2-4). The yield of phosphinate 7a
was only moderately higher than the isolated yield of phosphoric
fluoride 4a (76%), but the esterification required 25 h to consume
the fluoride. The yield of phosphinates 7d and 7e (65% and 79%,
respectively) was significantly higher than those observed for 4d
and 4e, requiring significantly less time to consume the
phosphoric fluoride. This demonstrated that in cases where lower
yields were observed for phosphoric fluorides, efficient trapping
the fluoride with an alcoholic nucleophile was viable.
3
4
toluene
THF
5
6
CH3CN
DMF
7
8
EtOH
PhCl
1.1
1.1
1.02
30
10
10
9
10
CH2Cl2
CH2Cl2
a
Reaction conditions: To 2 in solvent was added EtOH then 3b,
and the reaction stirred for 30 minutes. Isolated yields.
We then subjected the diaryl- and dialkylphosphine oxides to
the optimized reaction conditions and found the process to be
generally high yielding for all diaryl substrates, regardless of
their substituents. Electron-rich, -neutral or -poor substrates all
resulted in the corresponding diarylphosphinates in 68-90% yield
(Scheme 2). The yield was significantly lower for the dibenzyl
(3g) and di-n-hexyl (3h) derivatives, which gave 7g and 7h in
59% and 48% yield.
The oxidative chlorination of secondary phosphine oxides
with PhICl2 (2) was next investigated, using para-chloro
derivative 3e as the model substrate. And as the high reactivity of
phosphoric chlorides was anticipated to preclude their isolation,
we attempted to trap the initially-formed product in situ with
ethanol. We discovered that the oxidative chlorination/trapping
reaction proceeded in over 80% yield in nearly all chlorinated,
ethereal, polar and non-polar solvents (Table 2, entries 1-5). We
Scheme 2. Oxidative chlorination of diaryl- and
dialkylphosphine oxides, followed by EtOH trap.
Given the ease with which the diarylphosphinates could be
prepared by this tandem process, we investigated various other
nucleophiles as trapping agents (eq 5). Employing the primary

4
Tetrahedron
alcohol 3-phenylpropanol gave 8a 69% yield, but the reaction
Supplementary Material
failed with the very hindered alcohol t-amyl alcohol (8b), and
gave 41% yield of phosphinamide 8c when trapping with
diethylamine.
Supplementary data associated with this article can be found,
in the online version, at
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analogous fluorides suggested that were hydrolysis due to
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the electrophilic iodanes 1 or 2, giving phosphonium adduct A
(Scheme 3). Subsequent attack by the expelled halide on the
phosphonium gives B, whose deprotonation results in the
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fluorides (C, X = F), or intercepted with external nucleophiles
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7 or 8.
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Scheme 3. Proposed mechanism of the oxidative
halogenation reaction.
In conclusion, we have developed a mild and efficient
synthesis of diaryl- and dialkylphosphoric fluorides and chlorides
from secondary phosphine oxides. The hypervalent iodine
reagents TolIF2 (1) and PhICl2 (2) served as both oxidants and
sources of chloride and fluoride ions, which resulted in a
chemoselective and operationally-simple process. Yields of the
phosphoric fluorides were variable due to the formation of
phosphinic acid byproducts; however, this could be overcome by
trapping the intermediates with external nucleophiles.
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Acknowledgments
This work was supported by the Natural Sciences and
Engineering Research Council (NSERC) of Canada, the
University of Waterloo and the Early Researcher Award from the
Province of Ontario.
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4106. Also see Ref 23.
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K., Eur. J. Org. Chem. 2016, 2016, 4603.
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Tetrahedron 1983, 39, 1187.
(29) We did not observe significant quantities of the phosphinic acids in these
reactions, even though the phosphoryl chlorides are more susceptible to
hydrolysis by residual water than the phosphoryl fluorides. The increased
occurrence of the phosphinic acid byproducts in the fluorination reactions
might result from attack by oxygen nucleophiles that are generated in situ via
glass
etching
by
fluoride.

3
Highlights of this manuscript:




New oxidative halogenation of secondary diaryl- or dialkyl phosphine oxides
Phosphoric chlorides and fluorides are made with hypervalent iodine reagents
One-pot esterification and amidation reactions of secondary phosphine oxides
Typically mild, rapid and chemoselective reactions with yields up to 90%

Tetrahedron
4
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Direct, Oxidative Halogenation of Diaryl-
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Jasmin Eljo and Graham K. Murphy*