Phenyl-, benzyl-, and unsymmetrical hydroxy-methylenebisphosphonates as dronic acid ester analogues from α-oxophosphonates by microwave-assisted syntheses

Article abstract of DOI:10.1002/hc.20727

The microwave (MW)-assisted addition of dialkyl phosphites to α-oxophosphonates was investigated and optimized under solventless conditions to provide the phenyl- and benzyl-hydroxy-methylenebisphosphonates efficiently by suppressing the rearrangement sid

Full text of DOI:10.1002/hc.20727

Heteroatom Chemistry
Volume 22, Number 5, 2011
Phenyl-, Benzyl-, and Unsymmetrical
Hydroxy-Methylenebisphosphonates as
Dronic Acid Ester Analogues from
α-Oxophosphonates by Microwave-Assisted
Syntheses
Gyo¨rgy Keglevich,1 Alajos Gru¨n,1,2 Istva´n Ga´bor Molna´r,1
and Istva´n Greiner3
1Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics, 1521 Budapest, Hungary
2Research Group of the Hungarian Academy of Sciences at the Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
3Gedeon Richter Plc., P.O. Box 27, H-1475 Budapest 10, Hungary
Received 24 January 2011; revised 10 March 2011
place via the controlled decomposition of the precur-
ABSTRACT: The microwave (MW)-assisted ad-
sor and resulting in the intermediate formation of
dition of dialkyl phosphites to α-oxophosphonates
ꢀ
C
dialkyl phosphite were also studied in detail.
2011
was investigated and optimized under solventless
conditions to provide the phenyl- and benzyl-
hydroxy-methylenebisphosphonates efficiently by
suppressing the rearrangement side reaction. Methyl-
Wiley Periodicals, Inc. Heteroatom Chem 22:640–648,
2011; View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.20727
hydroxy-methylenebisphosphonates
with
mixed
ester functionalities and an analogous diester-
diacid were also synthesized. It was found that the
α-oxophosphonates may also be converted to hydroxy-
methylenebisphosphonates and/or rearranged prod-
ucts without using dialkyl phosphite as the reagent
and with the careful exclusion of water, simply on
standing at room temperature, on thermal treatment,
or on MW irradiation. These novel reactions taking
INTRODUCTION
1-Substituted-methylenebisphosphonates are im-
portant drugs in the treatment of osteoporosis
[2–4]. 1-Substituted-1-hydroxy-methylenes (bispho-
sphonic derivatives) are called dronic acids and
dronates. Their industrial synthesis involves the
condensation reaction of the corresponding substi-
tuted acetic acid, phosphorous acid, and phosphorus
trichloride under harsh conditions using a variety of
inert solvents [5–9]. This field is also covered by the
patent literature [10–20], which is rather complex.
There are also other possibilities for the
preparation of 1-hydroxy-methylenebisphosphonic
derivatives. A significant method comprises the
Part I of this article was published in 2009 [1].
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant number: OTKA K067679 and K83118).
2011 Wiley Periodicals, Inc.
c
ꢀ
640

Phenyl-, Benzyl-, and Unsymmetrical Hydroxy-Methylenebisphosphonates as Dronic Acid Ester Analogues 641
TABLE 1 Reaction of Diethyl Benzoylphosphonate 1a with Diethyl Phosphite under MW Conditions
Productsa
Entry
T (◦C)
t (min)
DEA (%)
Conversion (%)
2a
3a
1
2
3
4
5
6
60
60
60
60
80
20
10
20
40
10
0
5
5
5
5
5
12
80
97
100
100
100
53
60
47
24
6
47
40
53
76
94
100
<10
0
100
aOn the basis of relative 31P NMR intensities.
addition of dialkyl phosphites to the carbonyl
group of α-oxophosphonates. However, this re-
action has long been the subject of contro-
versy, thus McConnel and Coover published
erroneously that they had prepared hydroxy-
methylenebisphosphonates, although the prod-
ucts they obtained were in fact the rearranged
phosphonate-phosphates [21]. The situation was
clarified by Fitch and Moedritzer, who showed that
the hydroxy-methylenebisphosphonates can only be
synthesized under 80◦C and by avoiding distilla-
tion of the products [22]. Subsequently, Nichol-
son and Vaughn elaborated an exact procedure, by
reacting the α-oxophosphonate and dialkyl phos-
phite in ethereal solution at 0◦C in the presence
of dibutylamine as a catalyst [23]. This procedure
was further extended to a variety of model com-
pounds by Turhanen et al., giving the hydroxy-
methylenebisphosphonates in variable yields. The
reaction times were in the range of 3–30 h [24].
In a preliminary study, we tried to make use of
the microwave (MW) and solventless techniques
in the above synthesis [1]. In this paper, possi-
ble extensions of our green procedure are inves-
tigated including also the preparation of mixed
derivatives. In addition, the synthesis of hydroxy-
methylenebisphosphonates from α-oxophosphonate
precursors as the only reagents is explored.
RESULTS AND DISCUSSION
At first, the reaction of diethyl benzoylphospho-
nate 1a [25] with diethyl phosphite was stud-
ied under solventless MW conditions (Scheme 1,
Table 1). At 60◦C, without the catalyst, the re-
action was slow and the proportion of hydroxy-
methylenebisphosphonate 2a and rearranged prod-
uct 3a was 53:47 after 20 min (Table 1, entry 1).
Adding 5% diethylamine (DEA) as the catalyst, the
reaction was faster, but to ensure a maximum pro-
portion of 2a (60%), the irradiation was stopped af-
ter 10 min (Table 1, entries 2 and 3). Further irradi-
ation resulted in an increase in the relative quantity
of the by-product (3a) (Table 1, entries 3 and 4). This
means that 2a may be converted to 3a under MW ir-
radiation. Higher temperatures (80 and 100◦C) also
favored the formation of the rearranged product (3a)
(Table 1, entries 5 and 6).
The reaction of dimethyl benzoylphosphonate
1b [1] with dimethyl phosphite was more reluc-
tant as compared to the above transformation
(Scheme 1, Table 2). It can be seen that at 60◦C,
there was no reaction without catalyst (Table 2,
entry 1), and using 5% of DEA the conversion
stopped at 62%. The maximum proportion of the
hydroxy-methylenebisphosphonate (2b) was 72% af-
ter 30 min, and this decreased significantly on fur-
ther irradiation (Table 2, entries 2 and 3). At higher
O
OH O
(RO)2P
C
P(OR)2
MW
T, t
O O
Ph
2
+ (RO)2P(O)H
Ph C P(OR)2
NHEt2
no solvent
O
O
1
(RO)2P CH
Ph
O
P(OR)2
R = Et (a), Me (b)
3
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

642 Keglevich et al.
TABLE 2 Reaction of Dimethyl Benzoylphosphonate 1b with Dimethyl Phosphite under MW Conditions
Productsa
Entry
T (◦C)
t (min)
DEA (%)
Conversion (%)
2b
3b
1
2
3
4
5
60
60
60
100
120
60
30
60
30
20
0
5
5
5
5
0
60
0
72
60
24
2
0
28
40
76
98
62b
94
100
aOn the basis of relative 31P NMR intensities.
bNo further reaction.
temperatures, the rearrangement to result in 3b pre-
dominated (Table 2, entries 4 and 5).
the reaction became faster, but the rearranged prod-
uct (6) also appeared (Table 3, entries 3–6). With
an increase in the temperature (≥100◦C), the reac-
tion was accelerated, but the proportion of the rear-
ranged product (6) increased and became the only
product at 120◦C/10 min in the presence of 20% of
DEA (Table 3, entries 7–12).
From the point of view of preparation of
hydroxy-methylenebisphosphonate 5, the experi-
ments covered by entries 2 and 6 were the best; 5
was obtained in a yield of 47% and 52%, respec-
tively. By-product 6 was isolated from the experi-
ment covered by entry 12. Both compounds 5 and
6 were fully characterized by NMR and mass spec-
tral data. Hydroxy-methylenebisphosphonate 5 was
known from earlier work [31].
It can be seen that, in contrast to the re-
action of dialkyl oxoethylphosphonates with di-
alkyl phosphite [1], the benzoylphosphonates (1a,b)
cannot be transformed selectively to the hydroxy-
methylenebisphosphonates (2a,b) as, due to the
presence of the phenyl-substituent, the 2 → 3 re-
arrangement takes place more easily.
Products 2a and 2b were isolated from the best
experiments (entry 2 of Table 1 and entry 2 of
Table 2) in yields of 40% and 34%, respectively. Com-
pounds 2a and 2b were described earlier [23,26],
but 2a was not characterized. The phosphonate-
phosphates (3a and 3b) were identified on the basis
of their 31P NMR spectra described in the literature
[27–29].
The reaction of dimethyl phenylacetylphospho-
nate 4A with dimethyl phosphite served as the next
model to be studied. It is noteworthy that the ke-
tophosphonate 4A exists in equilibrium with the cor-
responding enolphosphonate form (4B) (Scheme 2)
[30]. The reactivity of phenylacetylphosphonate
4A/4B toward dimethyl phosphite was somewhat
lower than that of benzoylphosphonate 1b. In the
absence of catalyst, the reaction was slow (Table 3,
entries 1 and 2). Using 5%, 10%, or even 20% of DEA,
The yields of 34–52% obtained for products 2a,
2b, and 5 after optimization are comparable with
those described in the literature [23,26,31].
Then, we wished to synthesize mixed ester
derivatives of hydroxy-methylenebisphosphonates.
A few examples were described [32]. Either diethyl
oxoethylphosphonate 7a was reacted with dimethyl
phosphite (Scheme 3, route A) or the dimethyl ana-
logue 7b with diethyl phosphite (Scheme 3, route B).
As can be seen from entries 1 and 3 of Table 4, after a
reaction at 120◦C for 20 min in the presence of 5% of
O
O
OH O
P(OMe)2
P(OMe)2
(MeO)2P
O
4A
MW
T, t
5
+
(MeO)2P(O)H
+
NHEt2
O
O
no solvent
O
(MeO)2P
O
P(OMe)2
P(OMe)2
OH
4B
6
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Phenyl-, Benzyl-, and Unsymmetrical Hydroxy-Methylenebisphosphonates as Dronic Acid Ester Analogues 643
TABLE 3 Reaction of Dimethyl Phenylacetylphosphonate 4A/4B with Dimethyl Phosphite under MW Conditions
Productsa
Entry
T ( ◦C)
t (min)
DEA (%)
Conversion (%)
5
6
1
2
3
4
5
6
7
8
80
80
80
80
80
90
180
20
180
20
20
90
20
10
40
20
0
0
5
35
56
47
77
84
100
70
59
92
61
100
100
84
77
84
59
65
74
23
47
38
0
0
0
16
23
16
41
35
26
77
53
62
5
10
20
0
5
20
0
80
100
100
100
120
120
120
9
10
11
12
5
20
75
100
10
100
aOn the basis of relative 31P NMR intensities.
TABLE 4 Reaction of Dialkyl Acetylphosphonate 7 with Dialkyl Phosphite Possessing Different Alkyl Groups under MW
Conditions at 120◦C/20 min
Product Compositiona
Entry
Route
DEA (%)
Conversion (%)
8c
8a
8b
9c/1
9c/2
1
2
3
4
A
B
5
25
5
95
100
94
81
48
79
59
7
6
0
0
0
0
10
11
4
15
7
8
31
4
25
100
9
22
aOn the basis of relative 31P NMR intensities.
Route
MW
120°C/20 min
A
Route
MW
120°C/20 min
B
O
O
O
OH O
P(OMe)2
O
O
O
H
O
H
P(OEt)2
7a
(MeO)2P
(EtO)2P
(EtO)2P
+
+
P(OMe)2
7b
NHEt2 (5%)
no solvent
NHEt2 (5%)
no solvent
8c
OH O
P(OEt)2
O
(EtO)2P
8a
O
OH O
(MeO)2P
P(OMe)2
8b
O
O
(MeO)2P
O P(OEt)2
9c/1
O
O
(EtO)2P
O
P(OMe)2
9c/2
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

644 Keglevich et al.
MW
120°C, t
O
O
O
OH O
P(OR)2
O
O
P(OR)2
7a,b
(RO)2P
(RO)2P
O
P(OR)2
+
NHEt2
no solvent
8a,b
9a,b
O
O
P(OR)2
7a,b
R = Et (a)
Me (b)
O
(RO)2P
H
SCHEME 4
DEA, both variations provided the expected diethyl-
dimethyl bisphosphonate 8c in ca. 80% proportion
and in 70% yield, which is much better than the ear-
lier described yield of 38% [24]. Rearranged prod-
ucts 9c/1 and 9c/2 were also present in the mixture.
It is noteworthy that following route A or route B,
the tetraethyl ester (8a) or the tetramethyl ester (8b)
was also formed in 7% and 10%, respectively. Us-
ing more (25%) of the catalyst, the proportion of the
rearranged products (9c/1 + 9c/2) increased more
than 30% (Table 4, entries 2 and 4).
Formation of the tetraethyl or tetramethyl es-
ters (8a and 8b) may be explained by assuming
that, under the conditions of the reaction, a part
of the oxoethylphosphonate 7 undergoes decompo-
sition to result in the corresponding dialkyl phos-
phite, which gives the tetraalkyl ester 8 on reaction
with the oxophosphonate that remains in the mix-
ture (Scheme 4).
To prepare another mixed ester of hydroxy-
methylenebisphosphonate, diethyl oxoethylphos-
phonate 7a was reacted with dibenzyl phosphite.
Under MW conditions at 120◦C for 20 min, in the
presence of 5% of DEA, the expected dibenzyl-
diethyl ester 10 was formed in 86% proportion,
together with 14% of the tetraethyl ester (8a)
(Scheme 5). Product 10 was isolated in 55% yield
and was characterized by NMR and mass spectral
data. Catalytic hydrogenation of the dibenzyl-diethyl
ester (10) afforded the diacid-diester derivative (11)
as a result of double debenzylation (Scheme 6). The
diacid-diester (11) [33] was also characterized by
spectral data.
It is known that α-oxophosphonates may un-
dergo the rupture of the P–C bond [34]. Such
a reaction is, for example, the hydrolysis of
PhC(O)P(O)(OMe)2 resulting in benzoic acid, phos-
phorous acid, and methanol [35]. It was found that
the α-oxophosphonates are hygroscopic and they get
decomposed on exposure to wet air [36,37].
In our pre-experiments, we observed that on
thermal treatment or on MW irradiation, depending
on the conditions, diethyl oxoethylphosphonate 7a
was transformed to bisphosphonate 8a and/or to re-
arranged product 9a [1]. It is important to note that
this was experienced with the exclusion of water in
sealed vessels.
We wished to study the conversion
of
oxoethylphosphonates
(7)
to
hydroxy-
methylenebisphosphonates (8) and rearranged
products (9) in detail. It is noteworthy that
diethyl oxoethylphosphonate 7a afforded hydroxy-
methylenebisphosphonate 8a in an entirely clear-cut
reaction on standing at 26◦C in a closed flask for
2 months. Product 8a was isolated in 95% yield
(Table 5, entry 1). The thermal transformations
were not so efficient; at 120◦C/4 h and 160◦C/3 h,
conversions of 29% and 43%, respectively, were
achieved. In the second case, only rearranged
product 9a was formed (Table 5, entries 2 and 3).
Under MW conditions at 120◦C, the transformation
of precursor 7a was faster, but the conversions were
far from complete, and with increasing reaction
times, the proportion of the rearranged product 9a
increased (Table 5, entries 4–6). After irradiation
for 1 h at 140◦C, the conversion was 33% and
MW
120°C/20 min
O
OH O
P(OH)2
O
OH O
P(OBn)2
H2 /Pd(C)
O
H
10
(EtO)2P
7a
+
+
8a
(14%)
(BnO)2P
(EtO)2P
NHEt2 (5%)
11
10 (86%)
SCHEME 5
SCHEME 6
Heteroatom Chemistry DOI 10.1002/hc

Phenyl-, Benzyl-, and Unsymmetrical Hydroxy-Methylenebisphosphonates as Dronic Acid Ester Analogues 645
TABLE 5 Conversion of α-Oxoethylphosphonates 7a,b to Hydroxy-Methylenebisphosphonates 8a,b and Rearranged Products
9a,b in the Absence of Dialkyl Phosphite under Different Conditions
Conditions
t
Product Ratioa (%)
Starting
Material
Mode of
Heating
Entry
T (◦C)
Catalyst
Conversiona (%)
8
9
Yield (%)
95c
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
–
ꢀ
ꢀ
26
120
160
120
120
120
140
120
120
120
120
120
2 monthsb
4 h
–
–
–
–
–
–
–
100
29
43
29
34
40
33
65
86
10
15
59
100
72
0
0
28
100
10
20
32
50
9
16
0
10
10
3 h
MW
MW
MW
MW
MW
MW
MW
MW
MW
20 min
1.5 h
3 h
1 h
20 min
1 h
20 min
1.5 h
1 h
90
80
68
50
91
84
100
90
90
5% DEA
5% DEA
–
9
10
11
12
–
5% DEA
aOn the basis of relative 31P NMR intensities.
bSimply by standing at 26◦C.
cBased on the 2 → 1 stoichiometry.
compounds 8a and 9a were formed in equal
proportions (Table 5, entry 7). Using 5% DEA as
the catalyst, the transformation became faster,
the conversion better and the desired product 8a
predominated in the mixture (Table 5, entries 8
and 9). Hence, this is the choice for the preparation
of product 8a if simple standing of 7a at room
temperature for 2 months cannot be realized.
The similar transformation of dimethyl ox-
oethylphosphonate 7b was slower. At 120◦C in the
absence of catalyst, the conversions remained be-
low 15% (Table 5, entries 10 and 11). In the pres-
ence of 5% of DEA, a conversion of 59% could
be achieved after 1 h, giving rise to hydroxy-
methylenebisphosphonate 8b in 90% yield (Table 5,
entry 12).
In summary, the MW-assisted and solvent-
less reaction of α-oxophosphonates with dialkyl
phosphites was studied and optimized to min-
imize the quantity of the rearranged products
whose formation is inevitable. Mixed esters of
hydroxy-methylenebisphosphonates and a diester-
diacid were also synthesized. A novel observation
is that the α-oxophosphonates themselves may also
be converted to hydroxy-methylenebisphosphonates
via a controlled decomposition resulting in the in-
termediate formation of dialkyl phosphite.
EXPERIMENTAL
The 31P, 13C, and, 1H 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% H3PO4 or TMS. The
couplings are given in hertz. Mass spectrometry was
performed on a ZAB-2SEQ instrument.
It is noted that the corresponding dialkyl phos-
phite formed from precursors 7a/7b on MW irradia-
tion could be well detected by 31P NMR in the crude
reaction mixtures.
The analogous transformation of benzoylphos-
phonates 1 was reluctant even under MW con-
ditions at 120◦C. The corresponding hydroxy-
methylenebisphosphonates (2) were formed in
low conversions (<19%) after a reaction time of
20 min.
To the best of our knowledge, the α-
oxophosphonate → hydroxy-methylenebisphospho-
nate transformation has not been described in the
literature and has not been utilized. However, the
hydrolytic decomposition of α-oxophosphonates to
degradated product is well known [35–37]. The novel
decomposition and, especially, the possible role of
traces of water are to be studied further.
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.
Synthesis of the Starting α-Oxophosphonates
Dimethyl benzoylphosphonate 1b was prepared as
described earlier [1], whereas diethyl benzoylphos-
phonate 1a analogously by the reaction of ben-
zoyl chloride and triethyl phosphite. (Yield: 72%,
δP (CDCl3) −1.2; δP [25] −1.1) Dimethyl and diethyl
acetylphosphonates 7b and 7a were also synthesized
as described earlier [1].
Heteroatom Chemistry DOI 10.1002/hc

646 Keglevich et al.
Dimethyl phenylacetylphosphonate 4A/4B was
prepared by the controlled reaction of 4.3 mL
(32.3 mmol) of phenylacetyl chloride with 3.8 mL
(32.3 mmol) of trimethyl phosphite in 13 mL of di-
ethyl ether at 0◦C. The precipitated product was fil-
trated and washed to afford 5.4 g (74%) of 4 as a
2:98 mixture of the keto (4A) and the enol (4B) form.
(4A: δP (CDCl3) −0.70 (δP [30] −1.1), 4B: δP (CDCl3)
15.7 (δP [30] 15.4).
2b. Products 5 and 6 were isolated from the exper-
iments presented in Table 3, entry 2 and Table 3,
entry 12, respectively.
Tetramethyl 1-Hydroxy-phenylethylidenebispho-
sphonate (5) [31]
Yield: 52%. 31P NMR (CDCl3) δ: 21.0; δ 13C
NMR (CDCl3) δ: 39.2 (CCH2), 54.2 (dt, J = 8.0,
J = 3.5, OCH3), 75.8 (t, J = 151.9, CPC), 127.2
(Ar), 128.0 (Ar), 131.4 (Ar), 134.5 (t, J = 8.6, Ar);
1H NMR (CDCl3) δ: 3.38 (t, J = 13.8, 2H, CH2), 3.76
(m, 12H, CH3), 7.41–7.24 (m, 5H, ArH); [M +
H]+found = 339.0761, C12H21O7P2 requires 339.0763.
Reaction of Diethyl Benzoylphosphonate (1a)
and Diethyl Phosphite under MW Conditions
(General Procedure): Tetraethyl 1-Hydroxy-
benzylidenebisphosphonate 2a
0.10 g (0.55 mmol) of diethyl benzoylphosphonate
1a, 71 μL (0.55 mmol) of diethyl phosphite, and, oc-
casionally, 3.1 μL (0.03 mmol) of diethylamine (cata-
lyst) were measured in a tube that was placed in a mi-
crowave reactor equipped with a pressure controller.
After an irradiation at 60–120◦C for 10–60 min, the
residue passed through a column (adsorbent: silica
gel, eluent: 3% methanol in chloroform) to provide
a mixture of two possible products (2a and 3a). Ex-
perimental details are given in Table 1. The experi-
ment covered by entry 2 was utilized in the prepara-
tive experiment. Yield of 2a: 40%. δP (CDCl3) 17.3;
(M + H)+found = 381.1225 C15H27O7P2 requires
381.1232. Compound 2a was described, but no spec-
tral data were provided [26].
Dimethyl 1-(Dimethylphosphoryloxy)-1-benzyl-
methylphosphonate (6)
Yield: 61%. 31P NMR (CDCl3) δ: 0.9 (d, J = 14.7),
22.0 (d, J = 14.7); 13C NMR (CDCl3) δ: 37.0 (dd, J =
3.8, J = 1.6, CH2), 53.5 (J = 2.8, CH3), 53.6 (J = 1.8,
CH3), 54.0 (J = 6.0, CH3), 54.5 (J = 6.1, CH3), 73.4
(dd, J = 167.7, J = 7.2, CH), 127.1 (Ar), 128.6 (Ar),
1
129.7 (Ar), 135.9 (J = 13.3, Ar); H NMR (CDCl3)
δ: 3.09 (dt, J = 14.5, J = 10.8, 1H, CH), 3.23
(d, J = 11.4, 3H, CH3), 3.36–3.27 and 5.03–4.92
(m, 2H, CH2), 3.70 (d, J = 11.4, 3H, CH3), 3.82
(d, J = 10.6, 6H, CH3), 7.35–7.21 (m, 5H, ArH); [M
+ H]+found = 339.0763, C12H21O7P2 requires 339.0763.
Dimethyl-, Diethyl(1-hydroxy-ethylidene)
bisphosphonate (8c)
Tetramethyl 1-hydroxy-benzylidenebisphosphonate 2b
was prepared according to the General Proce-
dure, reacting dimethyl benzoylphosphonate 1b and
dimethyl phosphite at 60◦C/30 min in the presence
of 5% of diethylamine (see Table 2, entry 2). Yield of
2b: 34%. δP (CDCl3) 18.4, δP [23] 18.0
The phosphonate-phosphates 3a and 3b were
identified from unoptimized reactions (3a: δP
(CDCl3) −0.14 (d, J = 34.5), 17.7 (d, J = 34.5), δP
[27] −0.76 (d, J = 34.5), 17.2 (d, J = 34.5) and 3b: δP
(CDCl3) 1.4 (d, J = 32.6), 18.9 (d, J = 32.8), δP [29]
6.2 (d, J = 28.3), 24.2 (d, J = 28.3).
0.10 g (0.55 mmol) of diethyl 1-oxoethylphosphonate
(7a), 50 μL (0.55 mmol) of dimethyl phos-
phite [or 0.10 g (0.66 mmol) of dimethyl 1-
oxoethylphosphonate (7b), 90 μL (0.66 mmol) of
diethyl phosphite] and 3.0 μL (0.03 mmol) of di-
ethylamine were irradiated in a tube at 120◦C for
20 min. The mixture was purified roughly by column
chromatography (silica gel, 3% methanol in chloro-
form) to provide a mixture of the products shown in
Scheme 3/route A and route B, as well as in Table 4.
The main component 8c was separated by repeated
column chromatography (as above).
8c: Yield: 70% (Table 4, entry 1). 31P NMR
(CDCl3) δ: 19.9, (d, J = 40.1), 22.7 (d, J = 40.1),
δP [24] 20.6 (d, J = 39.3), 23.4 (d, J = 39.3).
Reaction of Dimethyl Phenylacetylphosphonate
(4A/4B) with Dimethyl Phosphite under MW
Conditions (General Procedure)
0.15 g (0.66 mmol) of dimethyl phenylacetylphos-
phonate (4A/4B), 60 μL (0.66 mmol) of dimethyl
phosphite and 3.3 μL (0.03 mmol) of diethylamine
in a tube was heated in the MW reactor at the given
temperature for the given time (see Table 3). The
work-up was similar as described above for 2a and
Dibenzyl, Diethyl(1-hydroxy-ethylidene)
bisphosphopnate (10)
0.10 g (0.56 mmol) of diethyl 1-oxoethylphosphonate
(7a), 0.12 mL (0.56 mmol) of dibenzyl phosphite,
and 5.5 μL (0.06 mmol) of diethylamine in a tube
Heteroatom Chemistry DOI 10.1002/hc

Phenyl-, Benzyl-, and Unsymmetrical Hydroxy-Methylenebisphosphonates as Dronic Acid Ester Analogues 647
were irradiated in the MW reactor at 120◦C for
ACKNOWLEDGMENTS
20 min. The work-up was similar as described above
for 8c. Yield: 0.14 g (55%) as an oil. 31P NMR (CDCl3)
δ: 20.3 (d, J = 40.7), 21.4 (d, J = 40.7); 13C NMR
(CDCl3) δ: 16.3 (J = 5.5, CH2CH3), 16.4 (J = 5.5,
CH2CH3), 20.2 (bs, CCH3), 63.9 (J = 7.0, OCH2CH3),
64.0 (J = 7.2, OCH2CH3), 69.0 (J = 7.6, OCH2Ph),
69.1 (J = 7.4, OCH2Ph), 71.6 (t, J = 156.8, PCP),
127.8 (J = 1.3, Ar), 128.1 (J = 1.4, Ar), 128.3 (Ar),
136.2 (J = 6.0, Ar); 1H NMR (CDCl3) δ: 1.25 (t,
J = 7.0, 3H, CH2CH ), 1.26 (t, J = 7.0, 3H, CH2CH ),
This work is connected to the scientific program of
the “Development of quality-oriented and harmo-
nized R + D + I strategy and functional model at
BME” project. This project is supported by the New
Hungary Development Plan (project ID: TAMOP-
4.2.1/B-09/1/KMR-2010-0002).
´
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3
3
1.75 (t, J = 16.4, 3H, CCH3), 4.20 (m, 4H, OCH CH3),
2
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