Breathing air as oxidant: Optimization of 2-chloro-2-oxo-1,3,2-dioxaphospholane synthesis as a precursor for phosphoryl choline derivatives and cyclic phosphate monomers

Article abstract of DOI:10.1016/j.tet.2017.05.037

Phosphoryl choline derivatives are important compounds for drug development. Also other phosphoesters have received increased demand in recent years. Many of such compounds rely 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) as an intermediate. COP is available in a two-step reaction from the cyclic adduct of phosphorus chloride and ethylene glycol after oxidation. Although commercially available, in-house synthesis of COP is often required due to pricing, purity, and delivery issues. Air is a convenient and economical oxidizing agent, yet not used for synthesis of COP. While slow consumption of the P(III)-precursor 2-chloro-1,3,2-dioxaphospholane with molecular oxygen from a gas bottle, high amounts of unreacted oxygen are lavished and even may cause an explosion. Oxygen from air is a reasonable and safer alternative. Additionally, catalytic amounts of cobalt(II)chloride increase the reaction kinetics remarkably. The results presented allow a controlled and fast access to a variety of phosphoesters by optimized reaction conditions of COP and its derivatives.

Full text of DOI:10.1016/j.tet.2017.05.037

Tetrahedron 73 (2017) 3536e3540
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Breathing air as oxidant: Optimization of 2-chloro-2-oxo-1,3,2-
dioxaphospholane synthesis as a precursor for phosphoryl choline
derivatives and cyclic phosphate monomers
Greta Becker b, Frederik R. Wurm a
a
,
, *
a
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
Graduate School Materials Science in Mainz, Staudinger Weg 9, 55128 Mainz, Germany
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2017
Received in revised form
Phosphoryl choline derivatives are important compounds for drug development. Also other phos-
phoesters have received increased demand in recent years. Many of such compounds rely 2-chloro-2-
oxo-1,3,2-dioxaphospholane (COP) as an intermediate. COP is available in a two-step reaction from the
cyclic adduct of phosphorus chloride and ethylene glycol after oxidation. Although commercially avail-
able, in-house synthesis of COP is often required due to pricing, purity, and delivery issues. Air is a
convenient and economical oxidizing agent, yet not used for synthesis of COP. While slow consumption
of the P(III)-precursor 2-chloro-1,3,2-dioxaphospholane with molecular oxygen from a gas bottle, high
amounts of unreacted oxygen are lavished and even may cause an explosion. Oxygen from air is a
reasonable and safer alternative. Additionally, catalytic amounts of cobalt(II)chloride increase the reac-
tion kinetics remarkably. The results presented allow a controlled and fast access to a variety of phos-
phoesters by optimized reaction conditions of COP and its derivatives.
8
May 2017
Accepted 9 May 2017
Available online 11 May 2017
Keywords:
2
2
-Chloro-1,3,2-dioxaphospholane
-Chloro-2-oxo-1,3,2-dioxaphospholane
COP
Poly(phosphoester)
Phosphorylcholine derivative
Oxidation with air
© 2017 Elsevier Ltd. All rights reserved.
1. Introduction
biomedical applications13,20,21 or as flame retardant additives.22
The most common route for the synthesis of COP refers to
2
3
24
2
-Chloro-2-oxo-1,3,2-dioxaphospholane (COP) (also known as
protocols from Scully et al. and Edmundson from the 1950's and
1960's. Nowadays, COP is still synthesized via this route in a two-
step reaction: (i) esterification of phosphorus trichloride with
ethylene glycol generates 2-chloro-1,3,2-dioxaphospholane (CP)
(1a), which is (ii) oxidized by molecular oxygen in refluxing organic
solvent to prepare 2-chloro-2-oxo-1,3,2-dioxaphospholane (1)
(Scheme 2). For the oxidation reaction slight modifications are re-
ethylene chlorophosphate or ethylene phosphochloridate) is an
essential precursor and a key building block for mainly two pur-
poses: the synthesis of (i) phosphorylcholine (PC) derivatives, a
polar zwitterion naturally present in phospholipids of cell mem-
branes, which are used in diverse drug delivery applications. A
popular synthetic representative is the monomer 2-
methacryloyloxyethyl phosphorylcholine (MPC), which produces
the water-soluble and biocompatible polymer PMPC, mimicking
the phospholipids.1 Also the synthesis of small molecule PC's for
5
,25
ported, substituting the reaction solvent benzene using toluene
or dichloromethane instead. Also the reaction times from 8 h to
and temperatures from room temperature
vary. However, moderate yields from 37 to 83%
2
6
e5
24, 27
5,26
24,27
4d
to reflux
are reported so
6
e9
5,27
different polymers has been reported.
However also the prep-
aration of (ii) cyclic phosphate monomers for the ring-opening
far, often lacking high purity of the product. Additionally, molecular
oxygen from a gas bottle in large excess is used in all cases as re-
agent and bubbled through the reaction, showing only poor and
slow consumption with unreacted oxygen being released in large
amounts (note: in a well-ventilated fume hood this should be un-
problematic, however flying sparks need to be prevented). Several
attempts in our group conducting the oxidation in a closed system
were sparsely satisfying and can cause unwelcome overpressure in
10e19
polymerization to produce poly(phosphoester)s (PPEs)
is a
valuable reaction pathway of COP (Scheme 1). Synthetic PPEs are
inspired by desoxyribose nucleic acid (DNA) and a versatile class of
polymers ranging from hydrophobic to water-soluble materials.
They find currently an increased attention as potential materials for
10
*
Corresponding author.
the system due to reflux conditions. In our search for alternative
E-mail address: wurm@mpip-mainz.mpg.de (F.R. Wurm).
http://dx.doi.org/10.1016/j.tet.2017.05.037
040-4020/© 2017 Elsevier Ltd. All rights reserved.
0

G. Becker, F.R. Wurm / Tetrahedron 73 (2017) 3536e3540
3537
spectrometer operating with 300 MHz, 75 MHz and 121 MHz or a
Bruker AVANCE III 700 spectrometer operating with 700 MHz,
1
76 MHz and 283 MHz. All spectra were measured either in DMSO-
1
13
d
6
or CDCl
3
. H and C spectra were calibrated against the solvent
3
1
signal, P spectra used as conducted. Spectra were analyzed using
MestReNova 8 from Mestrelab Research S.L. for 1D spectra All
and P NMR spectra are H-decoupled.
13
C
31
1
2
2
.3. Synthesis
.3.1. 2-Chloro-1,3,2-dioxaphospholane (CP, 1a)
A flame-dried 500 mL three-neck flask, equipped with a drop-
ping funnel and a reflux condenser, was charged with phosphorus
trichloride (137.3 g, 1.000 mol) in dry dichloromethane (150.0 mL).
Ethylene glycol (62.07 g, 1.000 mol) was added drop-wise to the
stirred solution, while argon was bubbled through the solution to
remove the released hydrogen chloride. The Ar-stream with
released hydrogen chloride was passed through a NaOH-solution
for neutralization. The reaction was continued for additional 2 h.
Scheme 1. Application examples for 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) as
precursor.
Then, the solvent was removed and the residue purified by distil-
ꢀ
lation at reduced pressure to give
a
fraction at 72e78 C/
6
0
5e67 mbar, obtaining the clear, colorless, liquid product (84.15 g,
31
.670 mol, yield: 67%). NMR data matches literature values.
1
H NMR (700 MHz, CDCl
3
):
d
4.35e4.13 (m, 4H, O-CH
2
-CH
2
-O).
):
13
31
C NMR (176 MHz, CDCl
167.80.
3
):
d
65.29. P{H}-NMR (283 MHz, CDCl
3
d
Scheme 2. Typical reaction protocol for the preparation of COP.
2.3.2. 2-Chloro-2-oxo-1,3,2-dioxaphospholane (COP, 1)
routes, reported literature protocols include the use of dinitrogen
A flame-dried 500 mL three-neck flask, equipped with a reflux
28
29
tetroxide (N
2
O
4
)
or ozone (O
3
)
as oxidants, also resulting in
condenser, was charged with 2-chloro-1,3,2-dioxaphospholane
(20.00 g, 0.160 mol) dissolved in benzene (250.0 mL) and dry
poor yields in the case of N
2 4
O and challenging handling of reac-
ꢁ
4
tant. Also phosphorus oxychloride, ethylene glycol and catalytic
amounts of copper(I)chloride (CuCl) were reported to produce COP
in a one-step reaction, but several attempts of this protocol in our
CoCl (20.50 mg, 1.590*10 mol) was added. A stream of dried air
2
(passed through conc. H SO ) was passed through the solution for
2
4
ꢀ
3 h at 80 C and for 12h at room temperature (overnight). Subse-
quently, the solvent was removed in vacuo and the residue purified
by fractionated distillation at reduced pressure to give a fraction at
3
0
group did not produce COP in reasonable yields or purity.
There is a high demand in COP. Although commercially avail-
able, price, delivery time and purity of the commercial product are
often unsatisfactory. Therefore an efficient, inexpensive and safer
in-house preparation is indispensable. Herein, we present a facili-
tated synthesis protocol using the oxygen from air as oxidant,
instead of molecular oxygen from a gas bottle. Still used in excess,
large amounts of wasted unreacted molecular oxygen can be
avoided. Additionally, cobalt(II)chloride has been found to be an
efficient catalyst that accelerates the reaction from days to several
hours, resulting in COP with a very high purity and overall
acceptable yields of 70%.
ꢀ
66e74 C/0.13e0.15 mbar, obtaining the clear, colorless, liquid
product COP in high purity (15.82 g, 0.110 mol, yield: 70%, 99%
2
6 1
purity). NMR data matches literature values.
H NMR (300 MHz,
1
3
CDCl ):
3
d
d
4.61e4.44 (m, 4H, O-CH -CH -O), C{H}-NMR (176 MHz,
2
2
31
CDCl ):
3
3
66.54, P{H}-NMR (121 MHz, CDCl ): d 22.74.
2.3.3. Isolation of byproduct in entry 3
After fractionated distillation, 1.500 g of product with non-
phosphorus containing byproduct was stirred in 10 mL DCM with
5.000 g silica gel for 10 min. The silica gel was removed by filtration
and the solvent removed, obtaining the byproducts 1-(benzyl)-4-
methylbenzene and 1-(benzyl)-2-methylbenzene (180.0 mg,
2
. Experimental section
ꢁ
4
6
.420*10 mol, yield: 12%).
2
.1. Materials
Ratio 1-(benzyl)-4-methylbenzene: 1-(benzyl)-2-methylbenzene
1
from H NMR is 0.42: 0.57.
NMR data matches literature values32,33
methylbenzene: H NMR: d 7.29e7.09, 3.93, 2.30. C NMR: d
:
1-(benzyl)-4-
141.5,
138.2, 135.6, 130.4, 129.3, 129.0, 128.6, 126.0, 41.7, 21.1. 1-(benzyl)-2-
All reagents were used without further purification, unless
1
13
otherwise stated. Solvents, dry solvents (over molecular sieves) and
deuterated solvents were purchased from Acros Organics, Sigma-
Aldrich, Deutero GmbH (Germany) or Fluka. Ethylene glycol was
purchased from Sigma-Aldrich, dried prior to use with NaH,
1
13
methylbenzene: H NMR:
d 7.35e7.11, 4.03, 2.23. C NMR: d 140.8,
139.4, 137.1, 130.7, 130.4, 129.2, 128.8, 126.9, 126.4, 126.3, 39.9, 20.1.
3
distilled and stored over molecular sieves. PCl was purchased from
Acros Organics. Cobalt(II)chloride hexahydrate was purchased from
Sigma Aldrich, and dried at reduced pressure at ~500 C directly
prior to use.
2.3.4. 1-(benzyl)-2-methylbenzene
ꢀ
1
2 2
H NMR (300 MHz, CD Cl ): d 7.32e7.11 (m, 8H, aromatic pro-
13
tons), 3.94 (s, 2H, Ar-CH -Ar-CH ), 2.32 (s, 3H, Ar-CH -Ar-CH ).
2
3
2
3
C
{
H}-NMR (75 MHz, CD
2
2
Cl ): d 141.19, 138.86, 136.18, 130.79, 130.41,
2.2. Methods
129.33, 128.96, 126.95, 126.50, 126.44, 39.89, 19.98.
For nuclear magnetic resonance (NMR) analysis H, 13C and 31
1
P
2.3.5. 1-(benzyl)-4-methylbenzene
1
NMR spectra were recorded either on a Bruker AVANCE III 300
2 2
H NMR (300 MHz, CD Cl ): d 7.32e7.11 (m, 8H, aromatic

3538
G. Becker, F.R. Wurm / Tetrahedron 73 (2017) 3536e3540
Table 1
Overview on the reaction conditions for the oxidation of 2-chloro-1,3,2-dioxaphospholane (CP) to 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP).
ꢀ
a
b
Entry
Reactant
Catalyst
Solvent
T/ C
t/h
Conversion /%
Yield COP/%
Purity /%
1
2
3
4
5
6
7
8
O
2
e
e
e
benzene
benzene
toluene
benzene
80
80/rt
111
80/rt
80/120/rt
80
96
96/72
23
3/12
3/10/14
13
>90
98
98
97
100
10
83
86
e
98
97
93
99
e
air
air
air
air
air
air
air
CoCl
CoCl
CoCl
CoCl
CoCl
2
2
2
2
2
70
c
d
PC
8
5
e
d
EA
e
ACNf
80
80
25
16
17
69
15
10
d
e
d
chlorobenzene
e
a
Conversion of reagent 2-chloro-1,3,2-dioxaphospholane.
Determined by P NMR.
PC: propylene carbonate.
Not distilled.
EA: ethyl acetate.
ACN: acetonitrile.
b
c
d
e
f
31
protons), 4.01 (s, 2H, Ar-CH
2
-Ar-CH
3
), 2.26 (s, 2H, Ar-CH
2
-Ar-CH
3
).
After fractionated distillation, an overall yield of 86% can be reached
with typically ca. 97% purity of the product.
13
C{H}-NMR (75 MHz, CD
2
Cl ):
2
d 142.27, 139.72, 137.20, 129.65,
1
29.27, 129.25, 128.90, 126.50, 42.04, 21.28. FD-MS: 182.35 (calcu-
Instead, the reaction is much faster in refluxing toluene (<1d)
reaching a conversion of starting material of >98% (entry 3, Fig. 2).
lated for C14H14: 182.11).
31
After fractionated distillation, P{H}-NMR spectroscopy shows
purity of 93% of product and 7% opened ring as byproduct. How-
ever, a second, non-phosphorus-containing byproduct can be
3
. Results and discussion
Following the protocol of Edmundson,24 the oxidation of 2-
1
observed in H NMR spectroscopy (Fig. S7). The second byproduct
was isolated by filtration over silica gel and identified as 1-(benzyl)-
chloro-1,3,2-dioxaphospholane (CP) with molecular oxygen from
a gas bottle bubbled through the reaction in benzene under reflux
shows slow consumption and requires several days (4d) for the
reaction to reach full conversion to 2-chloro-2-oxo-1,3,2-
dioxaphospholane (COP) (yields up to 83%, 98% purity, Table 1,
entry 1). The major disadvantage of the set-up is the waste of
unreacted molecular oxygen and the potential risk with high
amounts of oxygen in the atmosphere. Previously, we reported on
the conduction of the reaction in a closed system using a peristaltic
4-methylbenzene and 1-(benzyl)-2-methylbenzene (Figs. S8e11),
resulting from coupling of the solvent during reaction. The product
COP cannot be purified from the byproduct by distillation due to
very similar boiling points. However, for the purpose of COP as
precursor for cyclic phosphate monomers, the byproduct disturbs
neither the synthesis of the monomers nor their ring-opening
polymerization.
A modified reaction in benzene with air and 0.1 mol% of anhy-
drous CoCl as catalyst shows high conversions (>98%) within 15 h
2
pump to reuse the unreacted oxygen and to avoid wasting high
amounts of oxygen.10 However, care has to be taken that no over- or
(3 h under reflux and 12 h at room temperature (entry 4)). After
fractionated distillation, purity of 99% of the desired product and 1%
opened ring as a byproduct (yields: 70e75%, Figs. S4e6).
Several other solvents were screened for the reaction to sub-
stitute benzene. While the reaction in the “green” solvent propyl-
under pressure is produced in the set-up; also the organic solvent
vapors are problematic for tubing and they have to be replaced
regularly.
The use of oxygen from air would be a cheap, easy, and safer
alternative, however has not been reported in literature before and
also previous attempts in our laboratory remained unsatisfactory in
terms of reaction time and product purity. Detailed optimization of
this oxidation step allowed us to prepare COP by a set-up with dried
air bubbled through the reaction (entry 2), but turned out to be
very slow (similar to the one with pure oxygen): in benzene 4d at
reflux temperatures and 3d at room temperature were necessary to
reach almost full conversion (98%) (Fig. 1). Small amounts of ring-
opened side-product were also found in the reaction mixture.
ene carbonate (PC) with air and 0.1 mol% of dry CoCl
2
(entry 5)
ꢀ
shows 21% product after 13 h at high temperature (3 h at 80 C and
ꢀ
1
0 h at 120 C), further 14 h at room temperature does not lead to
an increase in the COP amount, but instead opening of the ring was
31
detected in NMR kinetics (Fig. S12). Since P{H}-NMR shows 92%
byproduct and only 8% COP product at that point, purification was
not attempted. The reaction in ethyl acetate (entry 6) after 13 h at
ꢀ
8
0 C also shows low conversion of CP, only 5% formed product COP
and 5% byproduct. Two solvents suitable for radical reactions were
Fig. 1. a) 31P NMR spectra (121 MHz, CDCl
, 298 K) of the oxidation reaction of CP to COP in benzene (Table 1, entry 2), b) plotted conversion of reagent and formation of COP in
entry 2, measured by P NMR spectroscopy.
3
31

G. Becker, F.R. Wurm / Tetrahedron 73 (2017) 3536e3540
3539
Fig. 2. a) 31P NMR spectra (121 MHz, CDCl
3
, 298 K) of the oxidation reaction of CP to COP in toluene (Table 1, entry 3), b) plotted conversion of reagent and formation of COP in entry
, measured by P NMR spectroscopy. Note: only phosphorus-containing byproducts are considered.
3
31
further investigated: acetonitrile and chlorobenzene. The reaction
in acetonitrile (entry 7) after 25 h at 80 C shows only 15% for-
Conflict of interest
ꢀ
mation of COP. Although the solvent is generally suitable for the
reaction and only 2% byproduct is formed, conversion is very slow
The authors declare no competing financial interest.
Acknowledgments
and time consuming. Finally, the reaction in chlorobenzene (entry
ꢀ
8
, Fig. S13) at 80 C shows after 7 h 49% product, but also 10%
opened ring byproduct. Longer reaction times do not show any
increase in the yields, but instead degradation of COP was detected
G.B. is recipient of a fellowship through funding of the Excel-
lence Initiative (DFG/GSC 266) in the context of the graduate school
of excellence “MAINZ” (Material Sciences in Mainz). F.R.W. is
grateful to the Max Planck Graduate School (MPGC) for support.
(
51%).
In summary, from the solvent studied, benzene and toluene
remain the most suitable reaction media. However, as toluene is not
inert in radical reactions, the coupling products might be contam-
inants of the product. Greener solvents, such as ethyl acetate and
propylene carbonate34 were suitable for the oxidation of CP, but
lower yields are accessible. For radical reactions generally only few
inert solvents are convenient, e.g. benzene, chlorobenzene, aceto-
nitrile, carbon tetrachloride or tetrachloroethane. The less
hazardous-ranked solvents chlorobenzene and acetonitrile might
be used, but both did not show satisfying results in our studies.
Therefore, we consider benzene still to be the most eligible solvent
for this reaction.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.05.037.
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