Synthesis of the mixed alkyl esters of phenylphosphonic acid by two variations of the Atherton-Todd protocol

Article abstract of DOI:10.1002/hc.21204

Phenylphosphonates with mixed alkyl groups were synthesized from ethyl phenyl-H-phosphinate by twomodified Atherton-Todd methods. Using aqueous sodium hydroxide under phase transfer catalytic conditions, the alkyl ethyl phosphonates were obtained in onlym

Full text of DOI:10.1002/hc.21204

Heteroatom Chemistry
Volume 26, Number 1, 2015
Synthesis of the Mixed Alkyl Esters of
Phenylphosphonic Acid by Two Variations of
the Atherton–Todd Protocol
Gheorghe Ilia,1 Mihaela Petric,1 Erika Ba´lint,2
and Gyo¨rgy Keglevich3
1Institute of Chemistry Timisoara of Romanian Academy, R-300223 Timisoara, Romania
2MTA-BME Research Group for Organic Chemical Technology, 1521 Budapest, Hungary
3Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
Received 7 March 2014; revised 29 May 2014
sis [1]. Alkyl/aryl phosphonates are frequent inter-
ABSTRACT: Phenylphosphonates with mixed alkyl
mediates in the synthesis of various bioactive com-
groups were synthesized from ethyl phenyl-H-
pounds. The P C bond present in these compounds
phosphinate by two modified Atherton–Todd methods.
makes them resistant to enzymatic hydrolysis [2].
Using aqueous sodium hydroxide under phase transfer
Phosphonates are widely applied as synthetic in-
catalytic conditions, the alkyl ethyl phosphonates were
termediates [3–7]. Phosphonates were also recog-
obtained in only moderate yields. However, applying 1-
nized as “markers” of chemical warfare agents and
methylimidazole as the base, the diesters could be pre-
are indexed in the CWC text under 2 B4 category
pared in yields of 76–85%. The imidazole hydrochlo-
[8,9].
ride formed as a by-product acts as an ionic liquid
A number of different methods are available for
phase in the reaction, from which the base can be re-
the synthesis of alkyl/aryl phosphonates. A common
ꢀC
generated. 2014 Wiley Periodicals, Inc. Heteroatom
method for the synthesis of phosphonic acid di-
esters is the reaction of phosphonic dichlorides with
aliphatic alcohols or phenols [10].
Chem. 26:29–34, 2015; View this article online at wi-
leyonlinelibrary.com. DOI 10.1002/hc.21204
Esterification of alkyl/aryl phosphonic acids to
the corresponding alkyl/aryl phosphonates/phosph-
ates was performed under mild conditions with
quantitative yields using silica chloride as an effec-
tive heterogeneous catalyst [11].
Phenyl-H-phosphinic acid was converted to the
diesters by microwave (MW)-assisted esterification,
followed by oxidation and then by a second esterifi-
cation [12].
The Michaelis–Arbuzov reaction, or simply the
Arbuzov reaction, is one of the most versatile tech-
niques for the formation of carbon–phosphorus
bonds, which implies the reaction of a trialkyl phos-
phite with an alkyl halide, involving the change
of valency of phosphorus from the trivalent to
INTRODUCTION
Phosphonates have an ever-increasing importance
as reagents and intermediates in organic synthe-
Correspondence to: Gheorghe Ilia; e-mail: ilia@acad-icht.tm.
edu.ro.
Contract grant sponsor: Romanian National Authority for Sci-
entific Research, CNCS–UEFISCDI (project number PN-II-CT-
RO-H-2012-699).
Contract grant sponsor: Romanian–Hungarian Scientific Re-
search program (project numbers BI-HU/01-11-467 and 2013-
0002).
ꢀC
2014 Wiley Periodicals, Inc.
29

30 Ilia et al.
the pentavalent state. Using other P-reagents, the
method may also be employed for the synthesis of
phosphinates and phosphine oxides [13]. Since its
discovery a lot of phosphonate esters were prepared
including haloalkyl phosphonates and substituted
diethyl arylphosphonates. The Michaelis–Arbuzov
reaction shows remarkable rate acceleration under
MW irradiation [14–16]. The interaction of aryl-
methyl halides with triethyl phosphite in the pres-
ence of a Lewis acid at room temperature afforded
the corresponding phosphonate esters in good yields
[17].
Method A
PTC
ROH
O
P
H
O
50% NaOH/H2O
+ CCl4
OEt
P
OEt
or
ROH
1-Me-imidazole
OR
2
1
Method B
R = Me (a), Et (b), nPr (c), nBu (d), nC5H11 (e),
nC6H13 (f), nC7H15 (g), nC8H17 (h)
SCHEME 1 Two approaches used for the synthesis of mixed
alkyl phosphonates.
Another widely used method for the syn-
thesis of phosphonates is the Michaelis–Becker
reaction, in which dialkylphosphites react, in the
presence of a base, with different halogeno com-
pounds [18]. Since than, a lot of examples have
been described, but one of the most convenient
methods involves the use of phase transfer catalysis
that can be carried out in different ways [19].
The MW-assisted Michaelis–Becker synthesis is
another approach to obtain dialkyl phosphonates
and tetraalkylbisphosphonates [20]. The next
method for the synthesis of aryl phosphonates is
the coupling of dialkyl phosphites and aryl halides
using tetrakis(triphenylphosphine)palladium as
the catalyst in the presence of triethylamine.
Polyethylene glycol 600 was applied as an effi-
cient additive [21]. These kind of transforma-
tions belong to the group of the Hirao reaction
[22,23].
Phosphonic diesters with two different sub-
stituents can be obtained by the reaction of phos-
phonic ester chlorides with alcohols or phenols. If
no base is used, the reaction should be carried out
at low temperature and the hydrogen halide is re-
moved by reduced pressure or by a stream of an in-
ert gas, but normally the preparation of these esters
requires an acid scavenger [10]. Mixed phosphonate
diesters could also be synthesized under mild con-
ditions and in high yields using 1H-tetrazole, which
catalyzes the selective monoesterification of phos-
phonic dichlorides. The subsequent reaction of this
phosphonic ester chloride with a different alcohol
led to mixed esters. Tetrazole enhances the selective
reactivity of the phosphonic dichloride, probably via
nucleophilic catalysis [24].
50% NaOH/H2O
or
O
ROH
1-Me-imidazole
2
+
CCl4
P
OEt
1
− CHCl3
Cl
3
R = as above
SCHEME 2 Mechanism for the phosphorylation of ethyl
phenyl-H-phosphinate.
preparation of alkyl aryl phosphonates was reported
[26–28].
RESULTS AND DISCUSSION
The phase transfer catalyzed version of the
Atherton–Todd reactions is a powerful method for
the synthesis of phosphorus derivatives (phospho-
nates, phosphates, and related phosphorus com-
pounds) [19, 29, 30]. Zwierzak [29] showed that
dialkyl phosphites can be applied for phospho-
rylation in a liquid–liquid system, using a phase
transfer catalyst. In this paper, this method was
applied for the synthesis of mixed alkyl phenylphos-
phonates 2 by reacting ethyl phenyl-H-phosphinate
(1) with different alcohols in the presence of tetra-
chloromethane, aqueous sodium hydroxide, and
tetrabutylammonium halide (TBAX) (Scheme 1,
Method A). The other method used involved the
use of 1-methylimidazole as the base (Scheme 1,
Method B).
Both methods involve the transformation of
ethyl phenyl-H-phosphinate (1) into the corre-
sponding ester-chloride 3 [31] in the presence of
tetrachloromethane and a base (aqueous sodium hy-
droxide or 1-methylimidazole). Then, intermediate
3 reacts further with the alcohol to give the mixed
phosphonate (2) (Scheme 2).
In this paper, we describe the synthesis of
mixed alkyl esters of phenylphosphonic acid from
ethyl phenyl-H-phosphinate using two versions of
the Atherton–Todd reaction [25]. A literature sur-
vey showed that the Atherton–Todd protocol has
never been applied to the synthesis of phospho-
nates with two different alkyl groups. Only the
We used the above-mentioned methods for the
synthesis of mixed alkyl esters of phenyl phosphonic
acid starting from ethyl phenyl-H-phosphinate (1).
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of the Mixed Alkyl Esters of Phenylphosphonic Acid by Two Variations of the Atherton–Todd Protocol 31
TABLE 1 Synthesis of the Mixed Esters of Phenylphospho-
nic Acid (2a–h)
All reactions were performed with a 25% excess
of phenyl-H-phosphinate (1) to compensate the in-
evitable hydrolysis of starting material 1. The reac-
tion is exothermic and, in most of the cases, needs
external cooling. When methanol was phosphory-
lated by the tetrachloromethane and 50% aqueous
sodium hydroxide system using a catalytic amount
(5 mol%) of TBAX (where X = Cl or Br), mixed
ethyl methyl ester 2a was obtained in a low (20%)
yield. The crude mixture was complex and the pu-
rification process was difficult. The predominant by-
product was phenylphosphonic acid formed by hy-
drolysis. When ethanol was used, the yield of the
corresponding ester 2b was increased to 35%. Fur-
ther increasing the length of the alkyl chain, the
yield amounted to 46–50%. At the end of the re-
action, the mixtures were filtered or diluted with
water or dichloromethane in order to be able to
work up the reaction. When secondary or even ter-
tiary alcohols were used, only traces of the phos-
phonates (2) were obtained that is probably the
consequence of steric hindrance. The nature of the
anion (chloride or bromide) of the catalysts had not
much impact. The process was not fully optimized;
however, certain changes such as the use of lower
concentration of sodium hydroxide, the order of the
addition of reagents, and change in the reaction time
led to side reactions and the formation of undesir-
able compounds. It can be concluded that the yields
of mixed diesters 2a–h synthesized by this method
were low (20–50%). Hence, the above process has a
limited usefulness, especially, when secondary and
tertiary alcohols were employed.
Yield Using
Method A (%)
Yield Using
Method B (%)
Entry
Compound
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
20
35
46
49
47
50
49
48
85
83
85
82
80
79
78
76
2g
2h
nate 1 could be eliminated. All compounds (2a–-h)
1
synthesized were characterized by 31P, 13C, and H
NMR, as well as HR-MS spectral data. Only phos-
phonic ester 2b was known from the literature.
Experimental data are listed in Table 1.
Analyzing the experimental data, it is obvious
that in respect of the synthesis of dialkyl phenylphos-
phonates with mixed alkyl groups, the Atherton–
Todd method applying 1-methylimidazole gives bet-
ter results than the phase transfer catalyzed version.
It can also be seen that the Atherton–Todd
synthesis is suitable for the preparation of alkyl
alkyl’ (mixed) phosphonates. Moreover, the use of 1-
methylimidazole as the base is a novelty, as it means
an advantage during the work-up procedure and the
regeneration of the amine, decreasing the costs, and
making possible a greener synthesis.
CONCLUSIONS
The Atherton–Todd synthesis was applied to the
preparation of dialkyl phosphonates with two dif-
ferent alkyl groups. Alkyl ethyl phenylphosphonates
were synthesized from ethyl phenyl-H-phosphinate
by two modified versions of the original protocol.
The liquid–liquid phase transfer catalytic accom-
plishment using aqueous sodium hydroxide as the
base led to more modest results than the novel vari-
ation applying 1-methylimidazole as the base. In the
latter case, the (with one exception) new products
were obtained in yields of 76–85%. The novelty of
our results, on the one hand, is that the Atherton–
Todd protocol was extended to the synthesis of di-
alkyl phosphonates with mixed alkyl groups. On the
other hand, it is a noteworthy invention that, if 1-
methylimidazole is used as the base, the hydrochlo-
ride salt formed (as an ionic liquid) can be easily
separated and the N-heterocycle can be regenerated.
Then, another variation of the Atherton–Todd
reaction was tried out for the synthesis of our
target compounds 2. The classical Atherton–Todd
method [25] uses triethylamine as the base, which
has some of the following drawbacks: the product is
difficult to separate from the mixture and is con-
taminated with the ammonium salt, a higher re-
action temperature (reflux) is necessary, and the
yields are moderate. This method was modified by
us by using 1-methylimidazole as the acid scav-
enger. When triethylamine was replaced by 1-
methylimidazole, the 1-methylimidazolium chloride
resulted formed an ionic liquid that separated as a
distinct phase. In a few cases, the mixture has to
be heated, as 1-methylimidazolium chloride is vis-
cous at room temperature. After the reaction, the 1-
methylimidazolium chloride separated was treated
with a base and 1–methylimidazole was regenerated.
This is the advantage of this method. To increase the
yields (76–85%), the molar ratio of phosphinate (1)
alcohol was decreased from 1.25 to 1, taking into
account that the hydrolysis of the starting phosphi-
EXPERIMENTAL
31P, 13C, and 1H NMR spectra were obtained in
CDCl3 solution on a Bruker AV-300 spectrometer
Heteroatom Chemistry DOI 10.1002/hc

32 Ilia et al.
operating at 121.5, 75.5, and 300 MHz, respectively.
Chemical shifts are downfield relative to 85% H3PO4
and tetramethylsilane (TMS). Mass spectra were ob-
tained using a Shimadzu LCMS-ITTOF mass spec-
trometer.
Ethyl phenyl-H-phosphinate was synthesized
under MW conditions as described earlier [32],
or supplied by Sigma-Aldrich (St Louis, MO,
USA). Normal C1–C8 alcohols were purchased
from Aldrich and distilled prior to use. Tetra-
chloromethane, dichloromethane, sodium hydrox-
ide, hydrochloric acid, sodium sulfate, tetrabuthy-
lammonium chloride, and 1-methylimidazole were
also supplied by Aldrich and used without purifica-
tion.
added dropwise under stirring and external cool-
ing (if necessary) to a mixture of a 0.013 mol alco-
n
hol (MeOH: 0.50 mL, EtOH: 0.73 mL, PrOH: 0.93
n
n
n
mL, BuOH: 1.15 mL, PentOH: 1.35 mL, HexOH:
1.60 mL, nHeptOH: 1.75 mL, nOctOH: 1.95 mL) and
1.7 g (0.010 mol) of ethyl phenyl-H-phosphinate in
5 mL of tetrachloromethane. After the addition, the
mixture was stirred for another 3–4 h at 26°C, and
then kept overnight without stirring and the layers
were separated. The organic phase was washed with
2.5 mL of hydrochloric acid (2%), and then with
2.5 mL of distilled water, dried (Na2SO4), and sol-
vent was evaporated under reduced pressure. The
products (2) were purified by column chromatog-
raphy using ethylacetate/chloroform = 5/3 as the
eluent.
General Procedure for the Synthesis of Ethyl
Phenyl-H-Phosphinate (1) under MW
Conditions [32]
Ethyl Methyl Phenylphosphonate (2a)
Yield: 20% (Method A) and 85% (Method B); 31P
NMR (CDCl3) δ: 20.21; 13C NMR (CDCl3) δ: 16.2 (J =
6.3, CH3CH2O), 52.4 (J = 5.5, CH3O), 62.2 (J = 5.5,
(CH3CH2O), 127.5 (J = 188.4, C1), 128.4 (J = 15.0,
C2)*, 131.7 (J = 9.9, C3)*, 132.5 (J = 3.0, C4), *may
be reversed; 1H NMR (CDCl3) δ: 1.30 (t, J = 7.0, 3H,
CH3CH2O), 3.71 (d, J = 11.1, 2H, CH3O), 3.99–4.21
(m, 4H, CH2O), 7.39–7.58 (m, 3H, ArH), 7.72–7.84
A mixture of 0.10 g (0.70 mmol) of phenyl-H-
phosphinic acid and 1 mL (17.4 mmol) of ethanol
was irradiated in a closed vial in a CEM MW reac-
tor equipped with a pressure controller at 160°C for
1 h. Then, the alcohol was removed under reduced
pressure, and the residue obtained was purified by
flash column chromatography using silica gel and
3% methanol in dichloromethane as the eluant. The
ester (1) was obtained as colorless oil.
(m, 2H, ArH); [M + H]+
= 201.0683, C9H14O3P
found
requires 201.0680.
General Procedure for the Preparation of Dialkyl
Phenyl Phosphonates
Diethyl Phenylphosphonate (2b)
Yield: 35% (Method A) and 83% (Method B); 31P
Method A. A solution of 2.1 g (0.0125 mol)
of ethyl phenyl-H-phosphinate in 5 mL of tetra-
chloromethane was added dropwise under stir-
ring and external cooling (5–10°C) to a mixture
of a 0.01 mol alcohol (MeOH: 0.40 mL, EtOH:
0.59 mL, nPrOH: 0.75 mL, nBuOH: 0.91 mL,
nPentOH: 1.10 mL, nHexOH: 1.25 mL, nHeptOH:
1.42 mL, nOctOH: 1. mL), 10 mL of tetra-
chloromethane, 3.8 g (0.090 mol) of NaOH in 5 mL
of water, and 0.14 g (0.5 mmol) of tetrabuthylam-
monium chloride, keeping the temperature below
15°C. After the addition, the mixture was stirred for
another 3–4 h at 26°C, and then the mixture was
diluted with 5 mL dichloromethane and the layers
were separated. The organic phase was washed with
2.5 × 2 mL of 2% hydrochloric acid, dried (Na2SO4),
and the solvent was evaporated under reduced pres-
sure. The products (2) were purified by column chro-
matography using ethylacetate/chloroform = 5/3 as
the eluent.
NMR (CDCl3) δ: 18.9; δ [33]: (CDCl3) 19.7; [M +
H]+
= 215.0839, C10H16O3P requires 215.0837.
found
Ethyl Propyl Phenylphosphonate (2c)
Yield: 46% (Method A) and 85% (Method B); 31P
NMR (CDCl3) δ: 19.76; 13C NMR (CDCl3) δ: 10.0
(CH3(CH2)2), 16.3 (J = 6.4, CH3CH2O), 23.7 (J = 6.6,
CH3CH2CH2), 62.0 (J = 5.4, (CH3CH2CH2O) 67.5
(J = 5.7, CH3CH2O), 128.2 (J = 188.1, C1), 128.4
(J = 15.0, C2)*, 131.7 (J = 9.8, C3)*, 132.3 (J = 3.0,
C4), *may be reversed; 1H NMR (CDCl3) δ: 0.91 (t, J =
7.4, 3H, CH3(CH2)2), 1.29 (t, J = 7.0, 3H, CH3CH2O),
1.59–1.74 (m, 2H, CH3CH2CH2), 3.87–4.20 (m, 4H,
CH2O), 7.39–7.57 (m, 3H, ArH), 7.73–7.84 (m, 2H,
ArH); [M + H]+found = 229.0995, C11H18O3P requires
229.0988.
Ethyl Butyl Phenylphosphonate (2d)
Yield: 49% (Method A) and 82% (Method B);
31P NMR (CDCl3) δ: 18.90; 13C NMR (CDCl3) δ:
13.5 (CH3(CH2)3), 16.2 (J = 6.4, CH3CH2O), 18.6
Method B. A solution of 0.80 g (0.010 mol) of 1-
methyl imidazole in 5 mL of tetrachloromethane was
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of the Mixed Alkyl Esters of Phenylphosphonic Acid by Two Variations of the Atherton–Todd Protocol 33
(CH3CH2CH2), 32.3 (J = 6.6, CH3CH2CH2), 62.1
(J 5.4, (CH3(CH2)2CH2O), 65.7 (J 5.7,
1.30 (t, J = 7.0, 3H, CH3CH2O), 1.58–1.70 (m, 2H,
CH2CH2O), 3.91–4.19 (m, 4H, CH2O), 7.40–7.57 (m,
=
=
CH3CH2O), 128.2 (J = 188.1, C1), 128.4 (J = 15.0,
C2)*, 131.7 (J = 9.8, C3)*, 132.3 (J = 3.0, C4), *may
be reversed; 1H NMR (CDCl3) δ: 0.87 (t, J = 7.3,
3H, CH3(CH2)3), 1.29 (t, J = 7.2, 3H, CH3CH2O),
1.31–1.43 (m, 2H, CH3CH2(CH2)2), 1.56–1.68 (m,
2H, CH3CH2CH2), 3.91–4.18 (m, 4H, CH2O), 7.38–
7.57 (m, 3H, ArH), 7.72–7.84 (m, 2H, ArH); [M +
3H, ArH), 7.74–7.84 (m, 2H, ArH); [M + H]+
=
found
285.1617, C15H26O3P requires 285.1614.
Ethyl Octyl Phenylphosphonate (2h)
Yield: 48% (Method A) and 76% (Method B);
31P NMR (CDCl3) δ: 18.66; 13C NMR (CDCl3)
δ: 14.0 (CH3(CH2)7), 16.3 (J = 6.5, CH3CH2O),
22.6 (CH3CH2CH2), 25.5 (CH3CH2CH2), 29.0
(CH3CH2CH2CH2), 29.1 (CH3CH2CH2CH2CH2),
30.4 (J = 6.6, CH2CH2O), 31.7 (CH2CH2CH2O),
62.1 (J = 5.5, (CH3(CH2)6CH2O), 66.1 (J = 5.6,
CH3CH2O), 128.3 (J = 188.2, C1), 128.4 (J = 15.0,
C2)*, 131.7 (J = 9.8, C3)*, 132.3 (J = 2.7, C4), *may
be reversed; 1H NMR (CDCl3) δ: 1H NMR (CDCl3) δ:
0.85 (t, J = 7.0, 3H, CH3(CH2)7), 1.16–1.28 (m, 10H,
CH2), 1.30 (t, J = 7.0, 3H, CH3CH2O), 1.61–1.68 (m,
2H, CH2CH2O), 3.94–4.17 (m, 4H, CH2O), 7.41–7.55
H]+
= 243.1139, C12H20O3P requires 243.1145.
found
Ethyl Pentyl Phenylphosphonate (2e)
Yield: 27% (Method A) and 80% (Method B);
31P NMR (CDCl3) δ: 18.89; 13C NMR (CDCl3) δ:
13.8 (CH3(CH2)4), 16.2 (J = 6.4, CH3CH2O), 22.1
(CH3CH2CH2), 30.0 (J = 6.5, CH3CH2CH2), 62.0
(J
=
5.5, (CH3(CH2)3CH2O), 66.0 (J
=
5.7,
CH3CH2O), 128.2 (J = 188.0, C1), 128.3 (J = 15.0,
C2)*, 131.7 (J = 9.8, C3)*, 132.3 (J = 3.0, C4), *may
be reversed; 1H NMR (CDCl3) δ: 0.84 (t, J = 6.4,
3H, CH3(CH2)4), 1.29 (t, J = 6.2, 7H, CH3CH2O and
CH2), 1.58–1.70 (m, 2H, CH2), 3.90–4.17 (m, 4H,
CH2O), 7.38–7.56 (m, 3H, ArH), 7.72–7.84 (m, 2H,
ArH); [M + H]+found = 257.1303, C13H22O3P requires
257.1301.
(m, 3H, ArH), 7.76–7.82 (m, 2H, ArH); [M + H]+
found
= 299.1782, C16H28O3P requires 299.1771.
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Ethyl Heptyl Phenylphosphonate (2g)
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δ: 13.8 (CH3(CH2)6), 16.1 (J = 6.4, CH3CH2O),
22.3 (CH3CH2CH2), 25.2 (CH3CH2CH2), 28.5
(CH3CH2CH2CH2), 30.2 (J = 6.5, CH2CH2O), 31.5
(CH2CH2CH2O), 61.9 (J = 5.4, (CH3(CH2)5CH2O),
65.9 (J = 5.7, CH3CH2O), 128.0 (J = 188.2, C1), 128.2
(J = 15.0, C2)*, 131.5 (J = 9.8, C3)*, 132.1 (J = 2.7,
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