P-arylation: Arynes to aryl-phosphonates, -phosphinates, and -phosphine oxides

Article abstract of DOI:10.1021/ol400780f

Synthesis of organo-phosphorus compounds and their application in organic synthesis and life sciences has been a topic of contemporary interest. Michaelis-Arbuzov reaction is the most extensively utilized method for their preparation, which works well only with aliphatic halides. Hence, relatively harsh reaction conditions using transition-metal-catalyzed P-arylation (Arbuzov/Hirao reaction) are used for the preparation of aryl-phosphorus compounds. Presented herein is a competent process for the synthesis of aryl-phosphonates, -phosphinates, and -phosphine oxides by making an efficient use of arynes for C-P bond construction.

Full text of DOI:10.1021/ol400780f

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
P‑Arylation: Arynes to
Aryl-Phosphonates, -Phosphinates,
and -Phosphine Oxides
Ranjeet A. Dhokale and Santosh B. Mhaske*
Division of Organic Chemistry, National Chemical Laboratory (CSIR-NCL),
Pune 411008, India
sb.mhaske@ncl.res.in
Received March 22, 2013
ABSTRACT
Synthesis of organo-phosphorus compounds and their application in organic synthesis and life sciences has been a topic of contemporary
interest. MichaelisÀArbuzov reaction is the most extensively utilized method for their preparation, which works well only with aliphatic halides.
Hence, relatively harsh reaction conditions using transition-metal-catalyzed P-arylation (Arbuzov/Hirao reaction) are used for the preparation of
aryl-phosphorus compounds. Presented herein is a competent process for the synthesis of aryl-phosphonates, -phosphinates, and -phosphine
oxides by making an efficient use of arynes for CÀP bond construction.
Organo-phosphorus compounds represent an impor-
tant class of chemicals, which are most extensively
used1 in organic synthesis as well as pharmaceuticals,
agrochemicals, and poultry chemicals and in the prepara-
tion of materials with desired properties. Particularly
aryl-phosphorus compounds find prime application as
ligands2 in metal-catalyzed reactions in addition to
other well-known organic transformations.3 The classical
MichaelisÀArbuzov reaction provides an easy access to
alkyl-phosphorus compounds;4 however, the synthesis of
aryl-phosphorus compounds posed a major challenge.5
They are usually prepared by a transition-metal-catalyzed
Arbuzov or Hirao CÀP bond construction reaction, which
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r
10.1021/ol400780f
XXXX American Chemical Society

Table 1. Synthesis of Various Phosphonates
Scheme 1. Previous Methods of P-Arylation and This Work
requires a high temperature, high pressure, and longer
reaction times (Scheme 1).6 With the broad application
of aryl-phosphorus compounds considered, the develop-
ment of novel and more efficient synthetic methods for
P-arylation has been a topic of extensive research interest.7
Recently, we8 and others9 have demonstrated a transition-
metal-free C-arylation at room temperature using arynes.
In continuation of our research interest in the develop-
ment and application of aryne chemistry, we envisioned
an efficient CÀP bond forming reaction to access various
aryl-phosphorus compounds utilizing the very high reac-
tivity of arynes toward nucleophiles (Scheme 1, this work).
We envisaged that the treatment of alkyl-phosphites
with arynes might furnish corresponding P-arylated pro-
ducts at much milder reaction conditions. It is important
ꢀ
10
to note that in the meantime Juge et al. reported the
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5032. (d) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.;Eur. J.
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Song, J. J.; Wang, G.; Senanayake, C. H. J. Am. Chem. Soc. 2013, 135,
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(e) Zhuang, R.; Xu, J.; Cai, Z.; Tang, G.; Fang, M.; Zhao, Y. Org. Lett.
formation of phosphonium salts on treatment of arynes
with several other phosphorus compounds. Our first at-
tempt was a reaction of silyl triflate 1 (1 equiv) with triethyl
phosphite (1 equiv) and cesium fluoride (1.2 equiv) in
acetonitrile at room temperature for 24 h. To our delight
we obtained the expected product ‘diethyl phenylphos-
phonate (2)’ in 47% yield. We report here the optimization
and application of the P-arylation protocol for an effi-
cient synthesis of aryl-phosphonates, -phosphinates, and
-phosphine oxides.
The protocol was first optimized on simple silyl triflate 1
using several permutations and combinations of triethyl
phosphite, fluoride-ion sources, and solvents. Phospho-
nate 2 was obtained in a maximum 92% yield when silyl
triflate 1 (1 equiv, 0.084 mmol) and triethyl phosphite
(4 equiv) were treated with cesium fluoride (5.5 equiv) in
acetonitrile at room temperature for 20 h. The same
€
€
2011, 13, 2110. (f) Andaloussi, M.; Lindh, J.; Savmarker, J.; Sjoberg,
P. J. R.; Larhed, M. Chem.;Eur. J. 2009, 15, 13069. (g) Kalek, M.;
Ziadi, A.; Stawinski, J. Org. Lett. 2008, 10, 4637. (h) Stadler, A.; Kappe,
C. O. Org. Lett. 2002, 4, 3541. (i) Griffin, C.; Castellucci, N. J. Org.
Chem. 1961, 26, 629.
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3994.
(9) Mohanan, K.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2012, 14,
4686.
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Org. Lett. 2010, 12, 1568. (b) Bayardon, J.; Laureano, H.; Diemer, V.;
Dutartre, M.; Das, U.; Rousselin, Y.; Henry, J.-C.; Colobert, F.;
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Leroux, F. R.; Juge, S. J. Org. Chem. 2012, 77, 5759. (c) Diemer, V.;
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Berthelot, A.; Bayardon, J.; Juge, S.; Leroux, F. R.; Colobert, F. J. Org.
Chem. 2012, 77, 6117.
B
Org. Lett., Vol. XX, No. XX, XXXX

reaction at a higher scale (1, 1.68 mmol) furnished phos-
phonate 2 with a 96% yield (Table 1, entry 1).
inseparable mixture of regioisomers (R:β = 1:40) as re-
vealed from the 1H NMR spectra.
During optimization studies we also tried the reaction
using diethyl phosphite H(O)P(OEt)2; however a complex
TLC pattern was observed, and the expected product was
obtained only in trace amounts. Use of other trialkyl
phosphites provided the expected phosphonates in good
to excellent yields.
The generalization studies (Table 1, entries 1À9)
on various aryl triflates to obtain corresponding aryl-
phosphonates worked very well, which prompted us to
study further application of the protocol to obtain aryl-
phosphinates. The aryne precursor 1 was treated with
diethyl phenylphosphonite (16) under the standardized
protocol to obtain the expected product ethyl diphenyl-
phosphinate (17) in 76% yield (Table 2, entry 1). Similarly,
treatment with silyl triflate 5 smoothly furnished phosphi-
nate 18 in 62% yield (Table 2, entry 2).
Thus, treatment of trimethyl phosphite and tributyl
phosphite (Table 1, entries 2 and 3) with silyl triflate 1
using the optimized protocol furnished the corresponding
phosphonates 3 and 4 in 90% and 72% yields respectively.
The scope of the protocol for the synthesis of aryl-phos-
phonates was validated on various 2-(trimethylsilyl)aryl
triflates (Table 1, entries 4À9). Treatment of the symme-
trically substituted aryne precursor 5 with triethyl phos-
phite provided phosphonate 6 (Table 1, entry 4) in
87% yield, but the reaction required more time (35 h)
for completion as compared to other silyl triflates, most
probably due to steric reasons. The strong electronic and
steric effects were observed in the unsymmetrically sub-
stituted electron-rich aryne precursor 7, which showed
excellent regioselectivity and furnished phosphonate 8 as
the only regioisomer in 74% yield (Table 1, entry 5). The
highly electron-rich substrate 9 also gave the correspond-
ing phosphonate 10 (Table 1, entry 6) in good yields (85%)
in 16 h. This result confirms that the presence of electron-
donating groups on the aromatic ring does not affect
the yield of such reactions or the time required for their
completion. The aryne precursor 11 smoothly reacts with
triethyl phosphite and trimethyl phosphite to obtain phos-
phonates 12and 13in 78% and 71% yields respectively in a
short time (4 h), as expected (Table 1, entries 7 and 8). The
presence of fluorines on the aromatic ring further enhances
the overall electrophilicity of the aryne thus making itmore
reactive, which results in a shorter reaction time. The steric
and electronic factors also predominate in the case of
silyl triflate 14, which provides regioisomer 15 as the major
product (Table 1, entry 9). The obtained product was an
Table 3. Synthesis of Various Phosphine Oxides
These intriguing results (Tables 1 and 2) impelled us to
explore the applicability of the methodology for the pre-
paration of veryinteresting and important compounds, the
‘phosphine oxides’. They are considered as vital precursors
in the preparation of various aryl-phosphine ligands,
which are highly useful in organic synthesis. Toward this
direction, we first treated the simplest aryne precursor 1
with ethyl diphenylphosphinite (19) using the standardized
protocol, and to our immense interest the predicted pro-
duct triphenyl phosphine oxide (20) was obtained in 75%
yield (Table 3, entry 1). The substrate scope was studied by
treating various silyl triflates with ethyl diphenyl phosphi-
nite (19) to satisfyingly obtain corresponding phosphine
oxides in good yields (Table 3, entries 2À4). The steric
effect on the reaction time as observed in the case of entry 4
(Table 1) was also observed here (Table 3, entry 2) to
obtain phosphine oxide 21with81% yield in 30h. The high
regioselectivity observed on substrate 7 (Table 1, entry 5)
was retained during the formation of corresponding phos-
phine oxide 22 as well (Table 3, entry 3). Interestingly the
Table 2. Synthesis of Phosphinates
Org. Lett., Vol. XX, No. XX, XXXX
C

regioselectivity noticed during the reaction of silyl triflate
14 with triethyl phosphite (Table 1, entry 9) was found to
be enhanced with ethyl diphenylphosphinite (19), as ex-
pected, due to the bulkier nucleophile (Table 3, entry 4).
Only one regioisomer, naphthalen-2-yldiphenylphosphine
oxide (23), was observed in this case. Several other phos-
phine oxides can be easily prepared following this process.
Use of varyingly substituted aromatic/heteroaromatic, or
aryl-alkyl ethylphosphinate, should provide an easy access
to interesting phosphine oxides with three different sub-
stituents attached to phosphorus. This process will be
also useful to generate chiral phosphine oxides under very
mild conditions. These products will serve as precursors
to obtain novel phosphine ligands. The conversion of
phosphine oxides to phosphines is considered as the best
method for their preparation among the others,11 and
recently Beller et al. reported an efficient method for this
useful transformation.11
The methodology developed herein works well to fur-
nish several aryl-phosphorus compounds as demonstrated
in Table 1À3. A plausible mechanism for the observed
transformation has been depicted in Scheme 2. ‘Path A’
which follows a concerted type of mechanism and ‘Path B’
which follows a MichaelisÀArbuzov type of mechanism
are two probable ways. ‘Path B’ involving fluoride ion
participation appears more appropriate (Scheme 2); how-
ever, a detailed study on the mechanism is warranted.
In conclusion a mild and convenient aryl-CÀP bond
forming reaction protocol has been demonstrated
using facile aryne reactivity. The scope of the reaction
has been extended to the synthesis of aryl-phosphonates,
- phosphinates, and -phosphine oxides. Notable features of
the process developed herein are as follows: a metal-free
straightforward approach to a variety of aryl-phosphorus
Scheme 2. Proposed Mechanism
compounds, efficiency, regioselectivity, convenient reac-
tion conditions, and generality. This finding opens whole
new possibilities, and the utility of the process developed
herein for the synthesis of various aryl-phosphorus com-
pounds is vast. We believe that this might become one of
the leading methods for their preparation in the near
future. Further investigations are focused on the applica-
tion of the process to synthesize complex bioactive mole-
cules as well as chiral aryl-phosphorus compounds.
Acknowledgment. R.A.D. thanks UGC, New Delhi for
the Research fellowship. S.B.M. thanks DST, New Delhi
for the Ramanujan Fellowship and FAST-Track research
grant. S.B.M. also thanks CSIR, New Delhi and Dr.
Sourav Pal, Director NCL for support and encouragement.
Supporting Information Available. Experimental de-
tails, characterization data, and copies of spectra of all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(11) Li, Y.; Das, S.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc.
2012, 134, 9727.
The authors declare no competing financial interest.
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