Catalytic synthesis of O-aryl methyl(phenyl)phosphonochloridates

Article abstract of DOI:10.1134/S001250081702001X

The reaction of methyl- and phenyldichlorophosphonates with phenols in the presence of anhydrous magnesium chloride (catalyst) or magnesium metal (procatalyst) has been used as a simple, efficient, and industrially feasible method for the synthesis of the

Full text of DOI:10.1134/S001250081702001X

ISSN 0012-5008, Doklady Chemistry, 2017, Vol. 472, Part 2, pp. 21–24. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © V.K. Brel, E.I. Goryunov, G.N. Molchanova, I.B. Goryunova, I.Yu. Kudryavtsev, T.V. Baulina, A.A. Khodak, T.V. Strelkova, E.E. Nifant’ev, 2017, published
in Doklady Akademii Nauk, 2017, Vol. 472, No. 5, pp. 534–537.
CHEMISTRY
Catalytic Synthesis
of O-Aryl Methyl(phenyl)phosphonochloridates
V. K. Brel, E. I. Goryunov*, G. N. Molchanova, I. B. Goryunova,
I. Yu. Kudryavtsev, T. V. Baulina, A. A. Khodak, T. V. Strelkova,
and Corresponding Member of the RAS E. E. Nifant’ev
Received September 19, 2016
Abstract—The reaction of methyl- and phenyldichlorophosphonates with phenols in the presence of anhy-
drous magnesium chloride (catalyst) or magnesium metal (procatalyst) has been used as a simple, efficient,
and industrially feasible method for the synthesis of the corresponding O-aryl alkyl(aryl)phosphonochlo-
ridates.
DOI: 10.1134/S001250081702001X
O-Aryl phenyl- and methylphosphonochloridates Sciences, to obtain O-polyfluoroalkyl phosphonochlori-
are widely used as precursors for the synthesis of vari- dates of different types [4].
ous types of organophosphorus compounds of practi-
Indeed, the phosphorylation of phenol with
cal interest, in particular, compounds showing biolog-
dichlorophosphonates Ia and Ib was found to be cata-
ical activity.
lyzed by a number of metal salts [4] showing Lewis
acid properties (for example, anhydrous lithium, mag-
However, until now, none of the realized methods
nesium, and calcium chlorides), MgCl being the
2
for the preparation of these compounds has been free
most efficient catalyst among them, as well as magne-
from drawbacks. In particular, the most common
1
method of their synthesis based on the reaction of the sium metal, which behaves as a procatalyst. Neither
corresponding organyldichlorophosphonates RP(O)Cl
hydrogen chloride scavenger nor organic solvent is
required in this case. The catalytic reactions proceed in
high rate even at moderate heating and with the use of
excess of the phosphorylating reagent, twofold is the best,
to give target phosphonochloridates RP(O)(Cl)OPh
IIa and IIb) of high purity in rather high yield (66–
1%) (see Scheme 1).
2
(
Ia, Ib; R = Ph (а), R = Me (b)) with phenols in the
presence of hydrogen chloride scavenger, tertiary
amine, requires the use of large amounts of organic
solvents and provides no compounds of required
purity [1, 2]. A variant of this reaction in the absence
of tertiary amine allows preparation of methylphos-
phonochloridates not contaminated with tertiary
amine hydrochlorides but requires long-term heating
at high temperature, which has a negative effect on the
yield of the final products [3].
(
7
120°C, [MgCl2/Mg]
PhOH + RP(O)Cl2
: 2
RP(O)(OPh)Cl
1
(
Ia, Ib)
(IIa, IIb)
One of the possible ways to enhance the efficiency of
this reaction can be the use of electrophilic catalysis,
which has been previously employed in the Laboratory of
Organophosphorus Compounds, Nesmeyanov Institute
of Organoelement Compounds, Russian Academy of
Yield 66−71%
(I), (II): R = Ph (a); R = Me (b)
Scheme 1.
These processes are readily scalable, while excess of
the phosphorylating reagent is recovered from the
reaction mixture in high yield and of purity that allows
its reuse in this reaction without additional purifica-
Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow, 119991 Russia
1
*
e-mail: gor.evg@rambler.ru
It dissolves during reaction to form magnesium chloride.
21

2
2
BREL et al.
31
1
19
1
Constants, elemental analysis data, and Р{ H} and F{ H} spectral data of O-aryl methylphosphonochloridates
МеP(O)(Cl)OAr IVa–IVh
Found, %
calculated, %
31
1
Compo-
und
Bp, °C/mmHg
(mp, °C)
Molecular
formula
Р{ H}NMR
6
Ar
(C D , δ, ppm)
6
C
H
Cl
P
IVa
IVb
p-EtC H4
99–101/1
С H ClO P
35.39 s
35.30 s
6
9
12
2
5
1.68
6.16
6.06
15.22
15.24
13.32
13.31
p-iso-PrC H4
101–102/0.5
С H ClO P
10 14 2
6
51.63
5
5
3.62
3.56
6.50
6.54
14.24
14.37
12.57
12.56
IVc
IVd
p-tert-BuC H4
130–131/1
С H ClO P
35.04 s
35.52 s
6
11 16
2
1
29–130/1*
p-ClC H4
–
–
–
–
–
–
–
–
–
6
(36–38)
35.48 (d, 6JP,F
9
1–92/1**
IVe
p-FC H
–
6
4
(35–37)
=
2.5 Hz)***
4
4
3.59
3.56
4.70
4.57
16.23
16.07
14.04
14.04
IVf
IVg
IVh
p-MeOC H4
131–132/1
126–127/1
115–116/0.1
С H ClO P
8 10 3
33.84 s
6
4
4
9.48
9.45
5.57
5.53
15.98
16.22
14.19
14.17
2,6-Me C H
С H ClO P
34.35 s
2
6
3
9
12
2
4
0.61
3.98
3.80
29.95
29.66
13.53
12.96
2-Cl-5-MeC H3
С H Cl O P
35.76 s
6
8
9
2
2
40.20
Lit.: bp 119–121°C/0.14 mmHg [10]. ** Lit.: bp 89–91°C/1 mmHg [11]. *** 19F{ H} NMR (C D , δ, ppm): –116.42 (d, J
1
6
=
F,P
*
2
6
6
.5 Hz).
tion, which as a whole makes these catalytic processes phosphoryl chlorides by the example of the corre-
attractive from industrial point of view.
sponding P-methyl derivatives. For this purpose, we
The next stage of our work was to determine the studied the phosphorylation of a number of com-
scope of use of catalytic phosphorylation methodol-
mercially available mono- and disubstituted phe-
ogy for the synthesis of the corresponding
nols (IIIa–IIIh, where a Ar = p-EtC H , b Ar = p-
6
4
aroxy(organyl)phosphoryl chlorides.
iso-PrC H , c Ar = p-tert-BuC H , d Ar = p-
6
4
6
4
It should be noted that O-phenyl phenylphospho-
ClC H , e Ar = p-FC H , f Ar = p-MeOC H ,
nochloridate IIa is used for preparing physiologically
6
4
6
4
6
4
active organophosphorus compounds [5] (the main g Ar = 2,6-Me C H , h Ar = 2-Cl-5-MeC H ) with
2
6
3
6
3
field of preparative application for these unsymmetri-
cal monochlorophosphonates), but O-phenyl methyl-
phosphonochloridate IIb proved to be the most neces-
twofold excess of methyldichlorophosphonate Ib on
heating in the presence of magnesium metal as a
2
sary for this purpose (see [1, 6, 7] and references procatalyst (see Scheme 2).
therein).
2
It should be emphasized that this technique provides the best
Taking into account this fact, we determined the
scope of applicability for the method of catalytic
phosphorylation to prepare unsymmetrical aroxy-
combination of a high performance catalyst and handling con-
venience; therefore, this variant of catalytic synthesis of O-aryl
phosphonomonochloridates seems to be preferable.
DOKLADY CHEMISTRY
Vol. 472
Part 2
2017

CATALYTIC SYNTHESIS
23
120°C, [Mg]
ArOH + MeP(O)Cl2
: 2
MeP(O)(OAr)Cl
1
(
IIIa−IIIh)
(Ib)
(
IVa−IVh)
Yield 70−75%
III, IV: Ar = p-EtC H (a), p-iso-PrC H (b), p-tert-BuC H (c),
6
4
6
4
6
4
p-ClC H (d), p-FC H (e), p-MeOC H (f), 2,6-Me C H (g),
6
4
6
4
6
4
2
6
3
2
-Cl-5-MeC H (h)
6 3
Scheme 2.
Analytically pure O-aryl methylphosphonochlori- lution ceased, the mixture was kept for 0.5 h in vacuum
3
(∼15 mmHg) at ambient temperature and fractionally
distilled in vacuum to give 17.2 g of O-phenyl phenyl-
phosphonochloridate IIa. Yield 66%. Bp 154–
dates (IVa–IVh) of spectral grade were isolated from
reaction mixture by fractional vacuum distillation in
rather high yields (70–75%) (table). Like in the cata-
lytic synthesis of methylphosphonochloridate IIb,
excess phosphorylating agent is recovered in rather
pure state for its reuse.
1
55°C/0.5 mmHg. Lit.: bp 152–155°C/0.3 mmHg [8].
31
1
Р{ H} NMR (neat, δ, ppm): 24.13 s.
Synthesis of O-phenyl methylphosphonochloridate
Thus, these data indicate that the method of cata- IIb. Molten methyldichlorophosphonate Ib (133 g,
lytic phosphorylation is a general simple, efficient, 1 mol) and next 300 mg (0.0125 mol) of magnesium
and industrially feasible approach to the synthesis of metal was added to 47 g (0.5 mol) of phenol under an
various O-aryl methylphosphonochloridates, which argon atmosphere, the mixture was heated for 2.5 h at
makes these organophosphorus reagents of practical 120°C until hydrogen chloride evolution ceased, the
interest readily available.
mixture was kept for 0.5 h in vacuum (∼15 mmHg) at
Moreover, other compounds of this series and akin ambient temperature and fractionally distilled in vac-
molecules of O-aryl alkyl(aryl)phosphonochloridate uum to give 68 g of O-phenyl methylphosphonochlor-
series can be undoubtedly prepared by this procedure idate IIa. Yield 71%. Bp 107°C/1 mmHg. Lit data:
by the analogy with O-aryl phenylphosphonochlori- bp 80°С/0.5 mmHg [9].
3
1
1
date IIa.
Р{ H} NMR (neat, δ, ppm): 36.31 s.
Synthesis of O-aryl methylphosphonochloridates
IVa–IVh (general procedure). Molten methyldichloro-
phosphonate Ib (67 g, 0.5 mol) and next 150 mg
EXPERIMENTAL
31
1
P{ H} NMR spectra of the obtained phospho-
(6.25 mmol) of magnesium metal was added to 0.25 mol)
19
1
nochloridates and F{ H} NMR spectra of phospho-
of mono- or disubstituted phenol IIIa–IIIh under an
nochloridate IVe were recorded on a Bruker AV-400
argon atmosphere, the mixture was heated for several
3
1
spectrometer operating at 161.98 MHz ( P) and hours at 120°C until hydrogen chloride evolution
19
31
3
76.49 MHz ( F). External reference for P NMR ceased, the mixture was kept for 0.5 h in vacuum
19
spectra was 85% H PO , External reference for
F
(∼15 mmHg) at ambient temperature and fractionally
3
4
distilled in vacuum. The constants, elemental analysis
NMR spectra was CFCl .
3
31
1
data, and Р{ H} spectral data of the prepared O-aryl
methylphosphonochloridates are presented in the
table.
Phenyldichlorophosphonate Ia (Acros, 97%) and
methyldichlorophosphonate Ib (Aldrich, 98%) were
distilled in vacuum prior to use. Phenol and its mono-
and disubstituted derivatives IIIa–IIIh (Acros, 97–
9
9%), as well as anhydrous magnesium chloride
ACKNOWLEDGMENTS
This work was supported by the Russian Founda-
tion for Basic Research, project no. 14–03–00525-a.
(
Acros, 99.9%) and magnesium metal (granules, 20–
2
30 mesh, Aldrich, 98%) were used as received.
Synthesis of O-phenyl phenylphosphonochloridate IIa.
Phenyldichlorophosphonate Ia (40 g, 0.205 mol) and
next 0.243 g (0.00256 mol) of finely divided anhydrous
magnesium chloride was added to 9.7 g (0.102 mol) of
phenol under an argon atmosphere, the mixture was
heated for 1.5 h at 120°C until hydrogen chloride evo-
REFERENCES
. Reddy, P.M., Viragh, C., and Kovach, I.M., Phospho-
rus, Sulfur Silicon, 2002, vol. 177, nos. 6/7, pp. 1597–
1
1600.
2
. Kluger, R., Thatcher, G.R.J., and Stallings, W.C., Can.
3
It should be noted that phosphoryl chlorides IVd and IVe previ-
J. Chem., 1987, vol. 65, no. 8, pp. 1838–1844.
ously obtained by classical methods were high-boiling liquids,
whereas both these compounds prepared by catalytic phosphor-
ylation are crystalline solids.
3. Gefter, E.L., Zh. Obshch. Khim., 1961. vol. 31, no. 10,
pp. 3316–3319.
DOKLADY CHEMISTRY Vol. 472 Part 2 2017

2
4
BREL et al.
4
. Kabachnik, M.I., Zakharov, L.S., Goryunov, E.I.,
8. Marsi, K.L., VanderWerf, C.A., and McEwen, W.E.,
J. Am. Chem. Soc., 1956, vol. 78, no. 13, pp. 3063–
3066.
et al., Zh. Obshch. Khim., 1994, vol. 64, no. 6, pp. 902–
12.
9
9
. Hudson, R.F. and Keay, L., J. Chem. Soc., 1960, no. 4,
5
. El Mastri, M. and Berlin, K.D., Org. Prep. Proc. Int.,
995, vol. 27, no. 2, pp. 161–169.
pp. 1859–1864.
1
10. Mel'nikov, N.N., Grapov, A.F., and Lebedeva, N.V.,
6. Makarov, M.V., Leonova, E.S., Rybalkina, E.Yu.,
Zh. Obshch. Khim., 1966, vol. 36, no. 3, pp. 457–461.
et al., Eur. J. Med. Chem., 2010, vol. 45, no. 3, pp. 992–
11. Sharova, E.V., Genkina, G.K., Matveeva, E.V., et al.,
1000.
Izv. Akad. Nauk, Ser. Khim., 2014, no. 11, pp. 2546–
2550.
7
. Leonova, E.S., Makarov, M.V., Rybalkina, E.Yu.,
et al., Eur. J. Med. Chem., 2010, vol. 45, no. 12,
pp. 5926–5934.
Translated by I. Kudryavtsev
DOKLADY CHEMISTRY
Vol. 472
Part 2
2017