Ionic-liquid-promoted Michaelis-Arbuzov rearrangement

Article abstract of DOI:10.1016/j.tetlet.2006.08.050

Room-temperature imidazolium ionic liquids, [Rmim][X], proved to be environmentally benign recyclable solvents promoting the Michaelis-Arbuzov rearrangement, which can be performed even at room temperature in a short period of time. The best ionic liquid of choice depended on the starting phosphorus(III) ester, namely, for triethyl phosphite [bmim][NTf₂] demonstrated better results while for ethyl diphenylphosphinite it was [hmim][Br].

Full text of DOI:10.1016/j.tetlet.2006.08.050

Tetrahedron Letters 47 (2006) 7645–7648
Ionic-liquid-promoted Michaelis–Arbuzov rearrangement
E. V. Matveeva, I. L. Odinets,* V. A. Kozlov, A. S. Shaplov and T. A. Mastryukova
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova Street, 28,
119991 Moscow GSP-1, Russian Federation
Received 24 May 2006; revised 8 August 2006; accepted 16 August 2006
Available online 7 September 2006
Abstract—Room-temperature imidazolium ionic liquids, [Rmim][X], proved to be environmentally benign recyclable solvents pro-
moting the Michaelis–Arbuzov rearrangement, which can be performed even at room temperature in a short period of time. The
best ionic liquid of choice depended on the starting phosphorus(III) ester, namely, for triethyl phosphite [bmim][NTf2] demonstrated
better results while for ethyl diphenylphosphinite it was [hmim][Br].
ꢀ 2006 Elsevier Ltd. All rights reserved.
Currently, ionic liquids due to their potential for recy-
clability, ability to dissolve a variety of organic, inor-
ganic and metal complex materials and non-volatile
nature, are of interest in chemistry in the search for
green alternatives of traditional organic solvents.1 De-
spite wide synthetic potential, only a few applications
of ionic liquids in organophosphorus chemistry can be
found in the literature. The Wittig–Horner reaction of
ethyl diethylphosphonoacetate and aldehydes affording
b-substituted acrylic esters was carried out in such media
in the presence of lithium hydroxide.2 a-Aminophosph-
onates were synthesized via Kabachnik–Fields reactions
in ionic liquids by the one-pot, three-component lantha-
nide triflates-catalyzed reaction of an aromatic
aldehyde, aniline and diethyl phosphite.3 Among the
catalysts, Sm(OTf)3 was superior and the reactions in
[bmim][PF6] were the most effective (20 ꢁC, 1 mol % of
the catalyst, 27 h, >99% yield). The same reaction can
be performed avoiding the use of heavy-metal Lewis
acids and in this version [bmim][BF4] showed better re-
sults in terms of reaction rate and yields in comparison
to the hydrophobic [bmim][PF6].4 Also, it was reported
that the esterification of phosphonic and phosphinic
acids occurred with triethyl(methyl) orthoacetate in
[bmim][PF6] in high yields under neutral conditions.5
The Michaelis–Arbuzov rearrangement is a highly
important reaction of general value in the conversion
of 3-coordinate phosphorus esters to 4-coordinate
species. In its most common form, the procedure often
requires prolonged heating at moderately high tempera-
tures. A variety of simple and complex alkyl groups
including functionalized examples have been substituted
on the phosphorus using this route.6
R2
P
R2
P
R1
R
R1R2P
OCH2R3
R1
R
+
RX
-XCH2R3
CH2-R3
O
O
X
The mechanism of the Michaelis–Arbuzov rearrange-
ment has been studied widely7 and involves the attack
of a phosphorus lone pair on the electrophilic carbon
atom of an alkyl halide to form an intermediate phos-
phonium salt followed by its rapid dealkylation via the
action of a halide anion. Phosphonium intermediates
were observed in the reaction of diethyl phosphinite with
an alkyl halide at low temperatures where the two alkyl
groups on the phosphorus atom decreased its reactivity8
and also in the case of sterically hindered phosphonites.9
Weak electrophiles such as vinyl and aryl halides were
introduced under the catalysis of various metals and
metal halides; nickel(II) halides (5–10 mol %, tempera-
ture around 150 ꢁC) appeared to be the most useful.10
Keywords: Ionic liquids; Michaelis–Arbuzov rearrangement; P–C bond
formation.
*
Corresponding author. Tel.: +7 495 135 9356; fax: +7 495 135 5085;
e-mail: odinets@ineos.ac.ru
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.050

7646
E. V. Matveeva et al. / Tetrahedron Letters 47 (2006) 7645–7648
The Michaelis–Arbuzov reaction is reported to be
effected under microwave irradiation where simple alkyl
halides reacted with trialkyl phosphites without solvent
in only 5 min.11 This method is suitable for the scale
up to 0.2 mol of the halide substrate.
dealkylated products were observed in the reaction
mixture [(EtO)2P(O)H and (EtO)(HO)P(O)H in a 1:1
ratio]. The same reaction in [(C14H29)(C6H13)3P]BF4
gave the desired product in 50% yield after heating for
1 h while the second product was (EtO)2P(O)H (yield
48%).
As amines are found to be more nucleophilic in ionic liq-
uids than in common organic solvents12 we considered
that ILs might be used as activating media for the above
reaction. In fact, the use of room-temperature imidazo-
lium ionic liquids [Rmim][X] [X = Br, BF4, PF6, NTf2;
Rmim = 1-butyl-3-methylimidazolium (bmim) or 1-hex-
yl-3-methylimidazolium (hmim)] significantly enhanced
the rate of the Michaelis–Arbuzov rearrangement. How-
ever, the counteranion of the ionic liquids affected their
catalytic activity considerably depending on the struc-
ture of the starting phosphorus ester and reaction condi-
tions. The results are summarized in Tables 1 and 2.13
If ethyl diphenylphosphinite was used instead of the
less reactive triethyl phosphite in the reaction with ethyl
bromoacetate under similar conditions (110 ꢁC), the
effect of ionic liquids on the reaction rate did not
change in the above series, that is, [bmim]Br 6
[bmim]PF6 < [bmim]BF4 < [bmim]NTf2 (Table 2, runs
1–4). However, this reaction was found to proceed
easily under ambient conditions in nearly the same
period of time giving the product in higher yields.
The most suitable ionic liquid in this case was
[hmim]Br which we had used instead of [bmim]Br, a solid
at room temperature. For ethyl diphenylphosphoryl-
acetate formation, all the ionic liquids were comparable
in terms of the final yields. In [bmim]Br and [bmim]-
NTf2, about 10% of the starting ester did not react over
20 min, but the reaction was completed within half an
hour (Table 2, runs 5 and 8). In [bmim]BF4, following
the reaction course by 31P NMR, we did not observe
the signals of the starting substrate after 20 min but a
signal at dP 65.3 ppm was assigned to the corresponding
intermediate phosphonium salt stabilized by the non-
nucleophilic tetrafluoroborate anion. Over time, the
phosphonium salt was transformed into the final prod-
uct (Table 2, run 7). The application of [bmim]PF6 as
the reaction media resulted in the formation of
Ph2P(O)H as a side product in 10% yield (dP 20.2
Thus, [bmim][NTf2] appeared to be the most suitable
ionic liquid to perform the rearrangement of triethyl
phosphite where the reaction proceeded in 5 min with
dropwise addition of ethyl bromoacetate and was com-
pleted in 20 min when using benzyl bromide (Table 1).
Good results were achieved using [bmim][BF4].
[Bmim][Br] accelerated the side dealkylation process
resulting in hydrophosphoryl compounds rather than
the Arbuzov rearrangement giving diethylphosphono-
acetate in 25% yield only (Table 1, run 3). It should be
noted that triethyl phosphite rapidly underwent dealkyl-
ation in [bmim][Br] in the absence of alkyl halide giving
ca. 60% (EtO)2P(O)H and ca. 40% (EtO)(HO)P(O)H in
1 h at 110 ꢁC while in [bmim][NTf2] under identical
conditions, only traces of dealkylated products were
registered by 31P NMR. [Bmim][PF6] accelerated
not only the Arbuzov rearrangement but also further
1
ppm, JPH 483 Hz).
Extension of these reaction conditions to the other types
of haloalkanes led to a decrease in the reaction rate to
some extent in the case of benzyl halides and a drastic
decline in product yields in the case of the weaker elec-
trophiles such as chloroacetonitrile or ethyl chloro-
acetate. For the latter, it was necessary to perform the
reaction at an elevated temperature.
dealkylation
of
the
final
product
resulting
mostly in C6H5CH2P(O)(OH)(OEt) (65% vs 25% of
C6H5CH2P(O)(OEt)2) (Table 1, run 4). Phosphonium
ionic liquids gave undesired results in this reaction.
Thus, when using [(C14H29)(C6H13)3P]Cl for the
reaction of (EtO)3P with benzyl bromide, only
Table 1. The Michaelis–Arbuzov rearrangement of triethyl phosphite in ionic liquids
ðEtOÞ P þ RX
ðEtOÞ PðOÞR
ƒƒƒ!
3
2
Run
RX
Temp (ꢁC)
Solvent or ionic liquid
Time
Yield (%)a
1b
2b
3
4
5
BrCH2Ph
BrCH2Ph
BrCH2Ph
BrCH2Ph
BrCH2Ph
BrCH2Ph
120–150
150
Xylene14a
(EtO)3P14b
[bmim]Br
[bmim]PF6
[bmim]BF4
[bmim]NTf2
3 h
4 h
92
87
25c
25d
78
110
110
110
110
20 min
20 min
20 min
5 min
20 min
6
80
94
7b
8b
9b
10
BrCH2COOEt
BrCH2COOEt
BrCH2COOEt
BrCH2COOEt
110
Toluene14c
Xylene14d
(EtO)3P14e
[bmim]NTf2
6 h
3 h
30 min
5 min
87
93
Quant
94
130–140
60–80
110
a Isolated yield.
b Literature data provided for comparison.
c 40% (EtO)2P(O)H, 25% (EtO)(HO)P(O)H, and 10% (EtO)3P were obtained.
d 10% (EtO)2P(O)H and 65% C6H5CH2P(O)(OH)(OEt) were obtained.

E. V. Matveeva et al. / Tetrahedron Letters 47 (2006) 7645–7648
7647
Table 2. The Michaelis–Arbuzov rearrangement of diphenylethylphosphinite in ionic liquids
Ph POEt þ RX
Ph PðOÞR
ƒƒƒ!
2
2
Run
1
RX
Temp (ꢁC)
Ionic liquid
Time
Yield (%)a
BrCH2COOEt
110
[bmim]Br
5 min
20 min
5 min
20 min
5 min
20 min
5 min
20 min
20 min
30 min
30 min
20 min
24 h
20 min
20 min
40 min
20 min
30 min
20 min
40 min
24 h
53
77
27
61
63
78
69
83
2
3
4
5
BrCH2COOEt
BrCH2COOEt
BrCH2COOEt
BrCH2COOEt
110
110
110
20
[bmim]PF6
[bmim]BF4
[bmim]NTf2
[hmim]Br
91
Quant (70)
98 (76)
85
Quant
90b
6
7
BrCH2COOEt
BrCH2COOEt
20
20
[hmim]Br/Et2O
[bmim]BF4
8
9
BrCH2COOEt
BrCH2COOEt
20
20
[bmim]PF6
[bmim]NTf2
90
Quant
77 (70)b
Quant (98)
54
10
11
12
BrCH2Ph
BrCH2Ph
BrCH2Ph
20
20
20
[hmim]Br
[hmim]Br/Et2O
[bmim]BF4
70
Quant (95)
58
13
14
1,3-(BrCH2)2C6H4
1,3-(BrCH2)2C6H4
140
20
Xylene15
[hmim]Br
3 h
20 min
24 h
20 min
20 min
24 h
25
81 (76)b
27
15
16
ClCH2COOEt
ClCH2CN
20
20
[hmim]Br
[hmim]Br
2.5
11
17
ClCH2CN
110
[hmim]Br
20 min
70 (64)
a Yield according to 31P NMR data, isolated yield are shown in brackets.
b Formation of Ph2P(O)H in 10%, 23% and 19% yields for runs 8, 10 and 14 was observed.
Ph2POEt can be reacted with alkyl halides using either
the ionic liquid alone as the reaction media followed
by ether extraction or the aqueous work-up procedure
or in a biphasic system where diethyl ether plays
the role of the second immiscible phase. The latter
variant seems more advantageous because the amount
of ionic liquid can be decreased to 1 mol equiv and
the target products are easily separated along with the
ether layer (Table 2, runs 6 and 11). The recovered
ionic liquid may be recycled at least 5 times without
any decrease in activity as shown using the reaction
In principle, when using a biphasic system, a catalytic
amount of [hmim]Br ionic liquid (5–10 mol %) can be
used to obtain ethyl diphenylphosphorylacetate. The
use of 5 mol % of ionic liquid resulted in 85% of
the product in 20 min but its purity was only 77%
according to the 31P NMR data (11% of Ph2POEt, 8%
of Ph2P(O)Et and 4% Ph2P(O)H). If the amount of
[hmim]Br was increased up to 10 mol %, the yield of
the desired product in the 1st run was 96% (98% purity)
but in the second run the yield decreased to 78% (95%
purity). It is interesting to note that the biphasic
[hmim]Br/Et2O system did not work for the reaction
of bromoacetate with the less nucleophilic triethyl phos-
phite, which remained unreacted in the ether layer for at
least 3 days followed by a slow dealkylation after a
prolonged period of time.
with
ethyl
bromoacetate
as
an
example
(Table 3).
Table 3. Recyclability of [hmim]Br ionic liquid
Furthermore, for the synthesis of phosphoryl acetic acid
esters the method described can be successfully achieved
in a one-step procedure employing the BASILTM
method16 used for the synthesis of trivalent phosphorus
acid esters. In the BASILTM process, 1-methylimidazole
is used as an acid scavenger giving 1-methylimidazolium
chloride. This ionic liquid can also serve as an effective
media for the step of Arbuzov rearrangement similar
to the other above mentioned ILs. Thus, the crude reac-
tion mixture of phosphorus(III) ester and 1-methylimid-
azolium chloride obtained during the first step can be
heated above the melting point of the latter (ꢀ100 ꢁC)
½hmimꢁBr=Et2O
Ph POEt þ BrCH COOEt
Ph PðOÞCH COOEt
ƒƒƒƒƒƒƒ!
2
2
2
2
30 min; rt
Run
Yield (%)a
Purity (%)b
1
2
3
4
5
98
99
93
94
99
93
97
98
89
87
a Isolated yield.
b Estimated from 31P and 1H NMR spectra.

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E. V. Matveeva et al. / Tetrahedron Letters 47 (2006) 7645–7648
3. Lee, S.-gi.; Park, J. H.; Kang, J.; Lee, J. K. Chem.
Commun. 2001, 1698.
4. Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P. Green Chem.
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followed by the reaction with ethyl bromoacetate.
Starting from chlorodiphenylphosphine, Ph2P(O)CH2-
COOEt was obtained in ca. 93% yield (based on Ph2PCl)
with a purity above 85% after aqueous work-up (unop-
timized). It should be noted that our attempt to
carry out the reaction with BrCH2COOEt at room
temperature in a biphasic system with diethyl ether
failed. Under such conditions, the ionic liquid-promoted
oxidation of the phosphinite to the corresponding
phosphinate, Ph2P(O)OEt, which was isolated in
ca.75% yield.
The general influence of ionic liquids on the rate of the
Michaelis–Arbuzov rearrangement may be connected
either with the polarity of these solvents which is similar
for most RTILs17 or with solvent–solute interactions
increasing the nucleophilicity of the phosphorus lone
pair. The difference in the reactivity between triethyl
phosphite and the more nucleophilic diphenylethyl
phosphinite is still well pronounced in the ionic liquids
being similar to common organic solvents. Therefore,
it can be suggested that ILs accelerate the second
reaction step (formal nucleophilic substitution
process),18 to a greater extent than the first nucleophilic
attack of phosphite (phosphinite). In [bmim]Br the
anion of the ionic liquid may assist the dealkylation
due to the increase in its concentration. However, the
same factor assists the side dealkylation reaction of the
less reactive starting phosphorus substrate (EtO)3P. In
ionic liquids such as [bmim]BF4, [bmim]PF6 and
[bmim]NTf2, dealkylation should proceed with the
halide anion and reactions in these media proceed
slowly and even allow the possibility to observe the
unstable phosphonium species stabilized by non-nucleo-
philic anions.
´
12. Crowhurst, L.; Lancaster, N. L.; Perez Arlandis, J. M.;
Welton, T. J. Am. Chem. Soc. 2004, 126, 11549.
13. General procedure: The corresponding phosphorus(III)
ester (1 mmol) was added to a solution of alkyl halide
(1 mmol) in an ionic liquid (0.5 g) either at 110 ꢁC or at
room temperature as indicated. The mixture was stirred at
the same temperature over the time mentioned in Tables 1
or 2, respectively. If the reaction was performed at an
elevated temperature, the reaction mixture was cooled to
ambient conditions before the work-up procedure. The
products, excluding 1,3-bis(diphenylphosphorylmethyl)-
benzene, were extracted with diethyl ether (3 · 10 ml)
followed by solvent evaporation. 1,3-Bis(diphenylphos-
phorylmethyl)benzene, which is not soluble in ether, was
precipitated by the addition of water (5 ml) then collected
by filtration and dried under vacuum. In the recycling
experiments reactants were added to the ionic liquid
solution remaining in the reaction vessel to start the next
run. Similar results were obtained using 0.1 mol of
phosphorus(III) substrate indicating the possibility of
further scaling up if necessary.
All the compounds obtained are known and after isola-
tion, their physicochemical constants and spectral data
compared well with the literature data. The conversion
was determined by the integration of signals in the 31P
NMR spectra [85% H3PO4 (31P) as an external standard].
14. (a) Gronowitz, S.; Stenhammar, K.; Svensson, L. Hetero-
cycles 1981, 15, 947; (b) Egbe, D. A. M.; Cornelia, B.;
Nowothy, J.; Klemm, E. Macromolecules 2003, 36, 5459;
(c) Rodrigues, J. M.; DaCosta, J. B. N. Phosphorus, Sulfur
Silicon Relat. Elem. 2002, 177, 137; (d) Shrestha-Dawadi,
P. B.; Lugtenburg, J. Eur. J. Org. Chem. 2003, 23, 4654; (e)
van der Klei, A.; deJong, R. L. P.; Lugtenburg, J.;
Aloysius, A. G. M. Eur. J. Org. Chem. 2002, 17, 3015.
15. Bodrin, G. V.; Kabachnik, M. I.; Kochetkova, N. E.;
Medved’, T. Ya.; Myasoedov, B. F.; Polikarpov, Yu. M.;
Chmutova, M. K. Izv. Akad. Nauk SSSR, Ser. Khim
(Russ.) 1984, 1841, [Bull. Acad. Sci. USSR Div. Chem.
Sci. (Engl. Transl.), 1984, 33, 1682].
16. Volland, M.; Seitz, V.; Maase, M.; Flores, M.; Papp, R.;
Massonne, K.; Stegmann, V.; Halbritter, K.; Noe, R.;
Bartsch, M.; Siegel, W.; Becker, M.; Huttenloch, O. PCT
Int. Appl. 2003, WO 2003062251; Chem. Abstr. 2003, 139,
149757.
17. Anderson, J. L.; Ding, J.; Welton, T.; Armstrong, D. W. J.
Am. Chem. Soc. 2002, 124, 14247.
18. Regularities of nucleophilic substitution reactions in ionic
liquids were recently published: Jorapur, Y. R.; Chi, D. Y.
Bull. Korean Chem. Soc. 2006, 27, 345.
In conclusion, we have found that 1-methyl-3-alkyl-
imidazolium ionic liquids promote the Michaelis–Arbu-
zov rearrangement in high yields under mild conditions.
[Bmim]NTf2 is the ionic liquid of choice for triethyl
phosphite reactions while [hmim]Br is the best for the
rearrangement of diphenylethylphosphinite. Finally,
all these reactions were performed without any protec-
tive atmosphere of an inert gas.
Acknowledgements
This work was supported by the Russian Basic Research
Foundation (Grant No. 05-03-32692) and the German
Science Foundation (436 RUS 113/766/1-1). A.S.S.
thanks the Fund for Russian Science Assistance for
the financial support.
References and notes
1. Ionic Liquids as Green Solvents: Progress and Prospects;
Rogers, R. D., Seddon K. R., Eds.; ASC Symposium
Series; American Chemical Society: Washington, DC,
2003.
2. Kryshtal, G. V.; Zhdankina, G. M.; Zlotin, S. G.
Mendeleev Commun. 2002, 176.