Synthesis of α-hydroxy-methylenebisphos-phonates by the microwave-assisted reaction of α-oxophosphonates and dialkyl phosphites under solvent ess conditions

Article abstract of DOI:10.1002/hc.20558

The synthesis of hydroxy-methyl-enebisphosphonates (2a-c) by the addition of dialkyl phosphite to the carbonyl group of the corresponding α-oxophosphonate (1a-c) was studied under microwave irradiation (MW) and solventless conditions in the presence of di

Full text of DOI:10.1002/hc.20558

Heteroatom Chemistry
Volume 20, Number 6, 2009
S
ynthesis of α-Hydroxy-methylenebisphos-
phonates by the Microwave-Assisted Reaction
of α-Oxophosphonates and Dialkyl Phosphites
under Solventless Conditions
1,2
1
3
3
Alajos Gr u¨ n, Istv a´ n G a´ bor Moln a´ r, B e´ la Bert o´ k, Istv a´ n Greiner,
1
and Gy o¨ rgy Keglevich
1
Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary
2
Research Group of the Hungarian Academy of Sciences at the Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
3
Gedeon Richter Plc., H-1475 Budapest 10, PO Box 27, Hungary
Received 26 May 2009; revised 24 July 2009
INTRODUCTION
ABSTRACT: The synthesis of hydroxy-methyl-
enebisphosphonates (2a–c) by the addition of dialkyl
phosphite to the carbonyl group of the correspond-
ing α-oxophosphonate (1a–c) was studied under mi-
crowave irradiation (MW) and solventless conditions
in the presence of dialkylamine as the catalyst. After
optimization, products 2a and 2b were obtained selec-
tively and in good yields avoiding the formation of the
phosphonate-phosphate by-product (3a and 3b) that
is the result of a rearrangement. The MW-assisted syn-
thesis of hydroxybisphosphonates (2a and 2b) offers
complete conversions and a chemoselectivity of 100%
as compared to the not so efficient thermal reaction.
At the same time, the phenyl-substituted methylenebis-
phosphonate 2c could be obtained in only 75% selec-
tivity. ꢀC 2009 Wiley Periodicals, Inc. Heteroatom Chem
More than 50 years ago, McConnel and Coover
claimed that the reaction of α-oxophosphonates
(1) with dialkyl phosphites carried out in
the presence of
a base gave 1-substituted-1-
hydroxybisphosphonates (2a) (Scheme 1) [1]. The α-
oxophosphonate (1a) was added dropwise to the sol-
ventless equimolar mixture of diethyl phosphite and
diethylamine with stirring whereupon the temper-
◦
ature rose to 70 C. The product (2a) was identified
by boiling point, refractive index, elemental analysis,
and IR spectral data. Several years later, Fitch and
Moedritzer confuted the above results, stating that
reproduction of the experiment provides the corre-
sponding phosphonate-phosphate (3a) formed by re-
arrangement (Scheme 1) [2]. There were two signals
3
1
2
0:350–354, 2009; Published online in Wiley InterScience
at δ −1.3 and 20.2 in the P NMR spectrum of the
P
(
www.interscience.wiley.com). DOI 10.1002/hc.20558
product isolated. The IR spectrum of the product de-
scribed in [1] is identical to that of the phosphonate-
phosphate (3a) described in [2]. It was also observed
that if the reaction mixture was not heated above
◦
Correspondence to: Gy o¨ rgy Keglevich; e-mail: keglevich@mail.
bme.hu.
Contract grant sponsor: Hungarian Scientific Research Fund.
Contract grant number: OTKA T067679.
c 2009 Wiley Periodicals, Inc.
80 C, the bisphosphonate (2a) characterized by a δ
P
shift of 20.8 could be prepared by crystallization at
C. No rearrangement was observed by heating 2a
at 124 C for 10 min. On an attempted distillation
◦
0
◦
ꢀ
350

Synthesis of α-Hydroxy-methylenebisphosphonates by the Microwave-Assisted Reaction 351
O
OH O
experiments is described. The optimum conditions
are also surveyed.
(
R′O
) P
C
R
2
P(OR′)2
2
O
O
(
R′O) P(O)H
2
RC P(OR′ 2
)
RESULTS AND DISCUSSION
O
O
1
(
R′O)2P CH
O
P(OR′)2
The reaction of diethyl acetylphosphonate (AP)
1a with diethyl phosphite (DEP) was chosen
as the model to be studied in detail. Forma-
tion of the two possible products, tetraethyl
R
R
R′
3
Me Et (a)
Me Me (b)
Ph Me (c)
1-hydroxy-ethylidenebisphosphonate (BP) 2a and
phosphonate-phosphate (PP) 3a, and the conversion
of the starting acetylphosphonate 1a were monitored
SCHEME 1
31
by P NMR spectroscopy and/or GC. Using a column
◦
of 100 C, no isomerization of compound 1 occurred.
Carrying out the reaction of 1a and DEP in di-
of 2a, however, quantitative isomerization of 2a to
phosphonate-phosphate 3a took place. Bisphospho-
nate 2a was prepared by adding a catalytic amount
of NaOEt (in ethanol) to the equimolar mixture of
oxophosphonate 1a and diethyl phosphite. The tem-
ethyl ether in the presence of 20% of diethylamine
at 0 C for 8 h, 95% of BP 2a and 5% of PP 3a
were formed (Table 1, entry 1). Hence, it is true that
the primary product of McConnel and Coover may
have been BP 2a.
◦
◦
◦
perature rose to 72 C. On cooling at 0 C, product
a crystallized from the mixture. In the light of the
We wished to study the effect of the presence
and quantity of the catalyst in solventless reactions.
To shorten the reaction times, a reaction tempera-
2
above observations, it is probable that McConnel and
Coover initially obtained the expected bisphospho-
nate (2a) that underwent isomerization on heating in
◦
ture of 120 C was chosen. Using 5%, 25%, and 50%
of diethylamine, the conversion was complete after
20 min and the ratio of the BP and the PP was 87:13,
20:80, and 0:100, respectively (Table 1, entries 2–4).
Performing the reaction in the absence of any
catalyst, the conversion was only 58% after 20 min
and the ratio of the BP (2a) and PP (3a) was 83:17
(Table 1, entry 5).
◦
an oil bath at 170 C. Finally, Nicholson and Vaughn
described an exact procedure for the preparation of
bisphosphonate 2c by adding dimethyl benzoylphos-
phonate dropwise to the stirred solution of dimethyl
phosphite and 0.05 equivalent of dibutylamine in
◦
diethyl ether at 0 C. The product (2c) precipitated
could be separated by filtration [3].
Using dibutylamine instead of diethylamine in
a quantity of 5%, 10%, 25%, and 50%, the relative
quantity of BP 2a and PP 3a was 94:6, 91:9, 36:64,
and 25:75, respectively, but in the first and second
case, the conversion was not complete (Table 1, en-
tries 6–9). The application of longer reaction times
in the presence of 5% of dibutylamine did not help
in attaining complete conversion (Table 1, entries 10
and 11). It can be seen that under thermal conditions
the use of dibutylamine is more advantageous than
that of diethylamine, as the proportion of BP 2a was,
in all cases, somewhat higher (Table 1, entries 2 vs.
6, 3 vs. 8, and 4 vs. 9). Applying the secondary amine
in 5%–10%, in all cases the BP 2a predominated
(Table 1, entries 2, 6, and 7).
It can be seen that the synthesis of hydroxy-
bisphosphonates 2 from α-oxophosphonate and di-
alkyl phosphite can be best accomplished in the pres-
ence of base as the catalyst, such as diethylamine,
dibutylamine, or NaOEt. The use of a solvent may
promote the selectivity, and the temperature should
◦
be kept below 100 C. Consequently, the bisphospho-
nates cannot be purified by distillation at reduced
pressure.
α-Oxophosphonates may be prepared by the
Arbuzov reaction of carboxylic acid chlorides and
trialkyl phosphites [3,4]. In most cases, the reaction
◦
takes place at as low as 0–35 C. The oxophosphonate
can be purified by distillation in vacuum.
The reaction of acid chlorides with 2 equivalents
of diethyl phosphite leads also to hydroxybisphos-
phonates [5]. In these cases, the formation of the
by-product by rearrangement is inevitable even in
the presence of a base.
In this paper, the microwave-assisted and sol-
ventless accomplishment of the addition reaction
under discussion together with some comparing
Just to try another simple accomplishment, the
reaction was carried out under solid–liquid phase
transfer catalytic conditions using K
2
CO as the
3
base, acetonitrile as the solvent, and triethylbenzy-
lammonium chloride (TEBAC) as the catalyst. In
boiling acetonitrile, the reaction time was 8 h and
only the rearranged product (3a) was found to have
been formed (Table 1, entry 12).
Heteroatom Chemistry DOI 10.1002/hc

352 Gr u¨ n et al.
TABLE 1 Results of the Reaction of 1a with 1 Equivalent of (EtO) P(O)H under Different Conditions
2
Conditions
Result
3a (%)
◦
Catalyst
Temperature ( C)
Time
Solvent
Conversion (%)
2a (%)
Yield (%)
71
Entry
DEA (20%)
DEA (5%)
DEA (25%)
DEA (50%)
–
DBA (5%)
DBA (10%)
DBA (25%)
DBA (50%)
DBA (5%)
DBA (5%)
TEBAC (10%)
0
8 h
Ether
100
100
100
100
58
92
95
100
100
94
94
100
95
87
20
0
83
94
91
36
25
91
83
0
5
13
80
100
17
6
a
a
a
b
b
b
b
a
b
b
b
a
1
2
3
4
5
6
7
8
9
120
120
120
120
120
120
120
120
120
120
20 min
20 min
20 min
20 min
20 min
20 min
20 min
20 min
40 min
90 min
–
–
–
–
–
–
–
–
–
–
83
9
64
75
9
17
100
10
11
12
K CO /MeCN/ꢀ/8 h
2
3
Abbreviations: DEA: Diethylamine; DBA: dibuthylamine.
a
b
31
Determined on the basis of relative P NMR intensities.
Determined by GC.
From among the solventless reactions men-
tioned above, the ones giving the best results
Table 1, entries 2 and 6) were repeated and the
expected product, BP 2a, was separated by col-
umn chromatography (in 71% and 83% yield,
respectively).
only 45%, but extending the reaction time to 1 h,
the conversion still remained incomplete (69%)
(Table 2, entries 1 and 2). After an irradiation of 1.5
h, the conversion was almost quantitative (98%), but
in this case, the proportion of 2a over 3a changed
to 65:35 (3:1, Table 2, entry 3).
(
It seemed to be interesting to study the reac-
tion of AP 1a with DEP under microwave (MW)
The use of diethylamine as the catalyst led to a
dramatic change. Adding diethylamine in a quantity
of 5%, 10%, 25%, and 50% to the reaction mixtures,
product compositions (BP (2a)/PP (3a)) of 100:0,
90:10, 53:47, and 7:93 could be observed, in all cases
conditions. In the first experiments carried out at
◦
1
20 C, the ratio of BP 2a and PP 3a was ca. 4:1.
After an irradiation of 20 min, the conversion was
TABLE 2 Result of the Reaction of 1a with 1 Equivalent of (EtO) P(O)H under MW and Solventless Conditions
2
Conditions
Result
3a (%)
◦
Catalyst
Temperature ( C)
Time (min)
Conversion (%)
2a (%)
Yield (%)
Entry
–
–
–
120
120
120
120
120
120
120
120
120
120
120
60
80
100
60
80
100
20
60
90
20
20
20
20
20
20
20
20
30
30
20
30
30
20
45
69
98
79
81
65
100
90
53
7
100
82
27
0
100
100
100
69
51
35
21
19
35
0
10
47
93
0
18
72
100
0
0
0
31
49
65
b
b
a
a
a
a
a
a
b
a
a
a
a
a
a
b
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
DEA (5%)
DEA (10%)
DEA (25%)
DEA (50%)
DBA (5%)
DBA (10%)
DBA (25%)
DBA (50%)
DEA (5%)
DEA (5%)
DEA (5%)
DBA (25%)
DBA (25%)
DBA (25%)
100
100
100
100
100
100
98
100
100
100
100
100
100
100
81
76
Abbreviations: DEA: Diethylamine; DBA: dibuthylamine.
a
b
31
Determined on the basis of relative P NMR intensities.
Determined by GC.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of α-Hydroxy-methylenebisphosphonates by the Microwave-Assisted Reaction 353
with complete conversion of the AP (1a) (Table 2,
entries 4–7).
Replacing diethylamine by dibutylamine, the
tendency regarding the ratio of products remained
the same, but from the point of view of the desired
product (2a), the relative proportions were some-
what unfavorable. Using 5%, 10%, 25%, and 50%
of dibutylamine, the BP (2a) to PP (3a) ratios were
ethyl phosphite. This interesting reaction is to be
studied further.
It can be concluded that after optimiza-
tion, the MW-assisted solventless reaction of α-
oxophosphonates (1a–c) with dialkyl phosphates
gives the corresponding 1-hydroxy-methylenebis-
phosphonates (2a–c) in a higher (in most cases quan-
titative) selectivities and in complete conversions, as
compared to the thermal variations.
100:0, 82:18, 27:72, and 0:100, respectively (Table 2,
entries 8–11). It is interesting that while under ther-
mal conditions the use of dibutylamine seemed to
be advantageous, under MW irradiation the use of
diethylamine is more efficient from the point of view
of selectivity.
EXPERIMENTAL
31
13
1
The P, C, and H NMR spectra were obtained on
a Bruker DRX-500 spectrometer operating at 202.4,
125.7, and 500 MHz, respectively. Chemical shifts
are downfield relative to 85% H PO or TMS. The
Then, the effect of temperature was inves-
tigated in MW-assisted reactions. Using 5% of
3
4
◦
diethylamine and applying conditions of 60 C/
couplings are given in hertz. Mass spectrometry was
performed on a ZAB-2SEQ instrument.
◦
◦
3
0 min, 80 C/30 min, and 100 C/20 min, the conver-
sion was in all cases quantitative and BP 2a was the
only product (Table 2, entries 12–14). Applying 25%
of dibutylamine as the catalyst, the proportion of BP
The MW-assisted reactions were carried out in
a CEM Discover microwave reactor equipped with a
pressure controller using ca. 30 W irradiation.
All products were liquids.
2a decreased with the increase of the temperature
(Table 2, entries 15–17, 10).
Finally, we wished to see whether the optimized
Diethyl Acetylphosphonate (1a)
MW conditions can be used in the synthesis of other
related compounds (2b and 2c) as well. It was found
that dimethyl acetylphosphonate (1b) reacts with
Triethyl phosphite (0.05 mol, 8.3 g) was added drop-
wise to acetyl chloride (0.05 mol, 3.9 g) at 0 C on in-
tensive stirring. After all of the triethyl phosphite had
been introduced, the reaction mixture was allowed
to warm up to room temperature. Vacuum distilla-
tion of the crude product afforded 5.5 g (61%) of
◦
◦
◦
dimethyl phosphite at 120 C/20 min, 100 C/30 min,
◦
and 60 C/45 min in the presence of 5% of diethy-
lamine to afford the expected tetramethyl 1-hydroxy-
ethylidenebisphosphonate 2b in complete conver-
sions and in ca. 85% isolated yields.
◦
the acetylphosphonate (1a) [1]; bp: 86–88 C/6 Torr
◦
31
As regard the MW-assisted reaction of dimethyl
benzoylphosphonate (1c) and dimethyl phosphite,
the maximum selectivity for the formation of tetram-
ethyl 1-hydroxy-benzylidenebisphosphonate 2c was
(bp [1]: 62–65 C/1.5 Torr); P NMR (CDCl ) δ 2.9.
3
Dimethyl acetylphosphonate (1b) was prepared
similarly using trimethyl phosphite. Yield: 40%; bp:
◦
◦
31
82 C/6 Torr (bp [6]: 90–91 C/10 Torr); P NMR
◦
achieved at 60 C/1.5 h in the presence of 5% of di-
(CDCl ) δ −0.95.
3
ethylamine. In this case, the ratio of bisphosphonate
Dimethyl benzoylphosphonate (1c) was prepared
2
c and rearranged product 3c was 7:3. Moreover,
similarly using trimethyl phosphite and benzoyl
◦
this reaction was found to be quite sensitive to the
parameters applied. At 100 C, in the presence of 5%
of diethylamine, the ratio of 2c to 3c was 1:3. Car-
rying out the reaction at 60 C, but using 10% of di-
chloride. Yield: 80%; bp: 154–156 C/8 Torr (bp [3]:
◦
◦
31
130–134 C/3 Torr); P NMR (CDCl ) δ −0.85 (δ [3]
3
P
−1.0).
◦
ethylamine, only the rearranged compound (3c) was
formed.
Tetraethyl(1-hydroxyethylidene)-bisphosphonate
2a) [3]
(
It was interesting to find that heating
◦
α-oxophosphonate 1a at 160 C for 3 h in the ab-
A solution of diethyl phosphite (5.5 mmol, 0.76 g)
and diethylamine (1 mmol, 0.074 g) in diethyl ether
sence of diethyl phosphite, rearranged product 3a
◦
was formed in a 43% conversion. At the same time,
(15 mL) was cooled to 0 C, and diethyl acetylphos-
◦
MW irradiation of 1a at 120 C/20 min gave only bis-
phonate 1a (5.5 mmol, 1.0 g) in diethyl ether (5 mL)
phosphonate 2a in a conversion of 15%. The use
of 5% diethylamine as the catalyst was helpful, as
in this case the conversion to 2a was 58% under
similar conditions. It is obvious that some of the
oxophosphonate (1a) serves as the precursor for di-
was added dropwise with intensive stirring. The re-
action mixture was stirred further for 8 h at 0 C, then
it was allowed to warm up to room temperature. The
solvent was evaporated to afford 1.7 g (91%) of bis-
phosphonate 2a [3] in a purity of 95%.
◦
Heteroatom Chemistry DOI 10.1002/hc

354 Gr u¨ n et al.
3
1
13
◦
P NMR (CDCl
3
) δ 20.3; δ
CH
), 20.1 (t, J = 1.1 Hz,
CH
), 71.4 (t, J = 156.1 Hz,
P
[2] 20.8. C NMR
1b and dimethyl phosphite at 120 C/20 min in the
31
1
6.4 (t, J = 2.7 Hz, CH
2
3
presence of 5% of diethylamine. Yield: 85%.
NMR (CDCl ) δ 22.3, δ [3] 22.0.
Tetramethyl hydroxybenzylylidenebisphosphonate
(2c) was prepared according to the general proce-
dure reacting dimethyl benzoylphosphonate 1c and
P
CCH
CCH
3
), 63.6 (m, CH
2
3
3
P
1
3
). H NMR 1.31 (12H, t, J = 6.9 Hz), 1.62 (3H,
t, J = 16.2 Hz), 4.20 (9H, bs).
◦
dimethyl phosphite at 60 C/1.5 h in the presence of
Reaction of diethyl acetylphosphonate and
diethyl phosphite (2a) under heating
General Procedure)
31
5
% of diethylamine. Yield: 55%. P NMR (CDCl
8.4, δ [3] 18.0.
Diethyl 1-(diethylphosphono)ethyl phosphate (3a)
3
) δ
1
P
(
Diethyl acetylphosphonate (0.55 mmol, 0.099 g), di-
ethyl phosphite (0.55 mmol, 0.076 g), and diethy-
lamine or dibuthylamine (catalyst) were measured
in a small flask that was placed in a preheated bath
of 120 C. The mixture, after complete reaction, was
purified by flash column chromatography (silica gel,
was obtained from experiment 4 of Table 1 in 85%
yield after column chromatography (silica gel, 3%
methanol in chloroform).
31
P NMR (CDCl
(d, J = 32.4 Hz); δ [2] −1.9 and 19.9.
The other phosphonate-phosphates (3b and 3c)
3
) δ −1.2 (d, J = 32.4 Hz), 20.3
◦
P
31
3% methanol in chloroform) to give a mixture of the
were identified from unoptimized reactions (3b:
NMR (CDCl
) δ 1.0 (d, J = 27.6), 22.4 (d, J = 27.6)
and 3c: P NMR (CDCl
) δ 1.4 (d, J = 32.6), 18.9
P
two isomers (2a and 3a). The details are listed in
Table 1.
3
31
3
(
d, J = 32.8)). The NMR data are in accord with
those described in the literature [7].
Reaction of diethyl acetylphosphonate and
diethyl phosphite (2a) under microwave
conditions (General Procedure)
REFERENCES
Diethyl acetylphosphonate (0.55 mmol, 0.099 g), di-
ethyl phosphite (0.55 mmol, 0.076 g), and diethy-
lamine or dibuthylamine (catalyst) were measured in
a microwave tube that was placed in a microwave re-
actor equipped with a pressure controller. The mix-
ture, after complete reaction, was purified by flash
column chromatography (silica gel, 3% methanol in
chloroform) to provide a mixture of two possible
products (2a and 3a). Experimental details are given
in Table 2.
[
[
[
[
[
[
[
1] McConnel, R. L.; Coover, H. W. J Am Chem Soc 1956,
78, 4450.
2] Fitch, S. J.; Moedritzer, K. J Am Chem Soc 1962, 84,
1
876.
3] Nicholson, D. A.; Vaughn, H. J Org Chem 1971, 36,
843.
3
4] Berlin, K. D.; Taylor, H. A. J Am Chem Soc 1964, 86,
3862.
5] Ruel, R.; Bouvier, J.-P.; Young, R. N. J Org Chem
1
995, 60, 5209.
6] Al’fonsov, V. A. Izv Akad Nauk SSSR, Ser Khim 1985,
619.
Tetramethyl(1-hydroxyethylidene)-bisphosphona-
te 2b was prepared according to the general pro-
cedure reacting dimethyl 1-oxoethylphosphonate
2
7] Tromelin, A.; Elmanouni, D.; Burgada, R.
Phosphorus Sulfur Silicon 1986, 27, 301.
Heteroatom Chemistry DOI 10.1002/hc