Solid-liquid two-phase alkylation of tetraethyl methylenebisphosphonate under microwave irradiation

Article abstract of DOI:10.1002/hc.20648

Optimum conditions for the solid-liquid phase alkylation of tetraethyl methylenebisphosphonate are dependent on the nature of the alkyl halide. The benzylation with benzyl bromide takes place efficiently in boiling acetonitrile in the presence of potassiu

Full text of DOI:10.1002/hc.20648

Heteroatom Chemistry
Volume 22, Number 1, 2011
Solid–Liquid Two-Phase Alkylation of
Tetraethyl Methylenebisphosphonate
under Microwave Irradiation
Istva´n Greiner,1 Alajos Gru¨n,2,3 Krisztina Luda´nyi,4,5
and Gyo¨rgy Keglevich2
1Gedeon Richter Plc., 1475 Budapest 10, P.O. Box 27, Hungary
2Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics, 1521 Budapest, Hungary
3Research Group of the Hungarian Academy of Sciences, Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, Budapest, Hungary
4Department of Pharmaceutics, Faculty of Pharmacy, Semmelweis University, 1092 Budapest,
Hungary
5Chemical Research Center, Hungarian Academy of Sciences, 1525 Budapest, Hungary
Received 22 July 2010; revised 22 September 2010
INTRODUCTION
ABSTRACT: Optimum conditions for the solid–
liquid phase alkylation of tetraethyl methylenebisphos-
phonate are dependent on the nature of the alkyl halide.
The benzylation with benzyl bromide takes place effi-
ciently in boiling acetonitrile in the presence of potas-
sium carbonate and a phase transfer catalyst. The ethy-
lation with ethyl iodide was best accomplished under
solventless microwave conditions in the presence of
cesium carbonate and in the absence of an onium
salt. The analogous propylation and butylation were
gem-Bis(phosphonic acids) are important drugs used
in the treatment of osteoporosis as they inhibit bone
resorption [1]. The corresponding alkyl esters can
be hydrolyzed to the related acids [2]. A represen-
tative method for the preparation of C-substituted
methylene bisphosphonates involves the Michael ad-
dition of simple Grignard reagents to the corre-
sponding ethenylidenebisphosphonate [3]. Another
possibility for the synthesis of methylenebisphos-
phonates involves the reaction of alkylphosphonates
with chlorophosphates via the corresponding lithi-
ated intermediate [4].
Bisphosphonates form a special group of CH-
acidic compounds, for which the anions, generated
with suitable bases, may undergo alkylation. Sur-
prisingly, such alkylations of methylene bisphospho-
nates carried out under different conditions are not
obviously a method of choice. Forming the potas-
sium salt of the bisphosphonate by reacting it with
potassium in xylene followed by alkylation led to
“rather unsatisfactory yields” [5]. When sodium hy-
dride was used as the base, the alkylation was more
efficient as indicated by the yield of 58% [6].
ꢀ
C
complicated by the formation of mixed esters. 2010
Wiley Periodicals, Inc. Heteroatom Chem 22:11–14, 2011;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.20648
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@mail
.bme.hu.
Contract grant sponsor: Hungarian Scientific Research Fund.
Contract grant number: OTKA K067679 and K83118.
Contract grant sponsor: Richter Plc.
c
ꢀ
2010 Wiley Periodicals, Inc.
11

12 Greiner et al.
The use of phase transfer catalysis would be an
MW
120°C, 1.5 h
TEBAC
up-to-date method [7]. During the solid–liquid phase
alkylation of a variety of common CH acidic com-
pounds, it was found that the phase transfer catalyst
can be substituted by microwave (MW) irradiation;
moreover, there was no need to use any solvent [8,9].
It seemed to be interesting to see what the situation is
in this respect with bisphosphonates. For this pur-
pose, we wished to study the effect of MW on the
solid–liquid phase alkylation of bisphosphonates in
the presence and in the absence of a phase transfer
catalyst.
P(O)(OEt)(OBn)
M2CO3
1
+
BnBr
2 +
MeCN
P(O)(OEt)2
3
M
1
2
(%)
3
K
60
5
35
Cs
46 11 43
SCHEME 2
RESULTS AND DISCUSSION
ther the acid function may react with the alkyl halide
or the ester itself with the alcohol to furnish mixed
ester 3.
In the first experiment, tetraethyl methylenebispho-
sphonate 1 was alkylated with benzyl bromide in
the presence of potassium carbonate and triethyl-
benzylammonium chloride (TEBAC) in acetonitrile
at reflux. Completion of the benzylation to afford
benzyl-methylenebisphosphonate 2 required 40 h.
The isolated yield of compound 2 was 83% after col-
umn chromatography (Scheme 1). No bisbenzylated
product could be detected in the crude mixture.
Carrying out the reaction under similar con-
ditions but with MW irradiation and at 120◦C,
the conversion was 40% after 1.5 h and along
with the benzyl-methylenebisphosphonate 2 (5%), a
monobenzyl triethyl ester (3) (5%) was also present.
Replacing potassium carbonate by cesium carbon-
ate, the conversion was 54% and the reaction mix-
ture contained 11% of the C-benzylated product
(2) and 43% of the monobenzyl triethyl ester (3)
along with the unreacted starting material (46%)
(Scheme 2).
By-product 3 was isolated from the reaction mix-
ture by column chromatography. In respect of the
model reaction under discussion, the solventless ac-
complishment was not appropriate.
The formation of the by-product 3 can be ex-
plained by assuming that water is released in the
reaction of hydrogen halide (formed in the alkyla-
tion) with alkali carbonate under the circumstances
of the reaction that may lead to the partial hydrolysis
of the tetraethyl ester or the alkyl halide. Then, ei-
It can be seen that due to a side reaction, the
use of MW irradiation is not helpful in the solid–
liquid phase benzylation of tetraethyl methylenebis-
phosphonate (1). In this case, the phase transfer cat-
alyzed thermal accomplishment remains the method
of choice providing the expected product (2) in good
yield (∼90%), but in a rather slow reaction.
Then, the alkylation of methylenebisphospho-
nate 1 was investigated with ethyl iodide at 140◦C
under MW irradiation, in the presence of cesium
carbonate without the use of any solvent. After a re-
action time of 1.5 h, the conversion was complete
and the C-ethyl methylenebisphosphonate 4 was ob-
tained in 80% yield. In a small amount (∼3%), the
bisalkylated by-product (5) was also present in the
reaction mixture (Scheme 3).
At 120◦C, the conversion was not complete, but
reacting the crude mixture so obtained with a second
portion of ethyl iodide (as in the first “round”), the
ethylation became complete. It is important to note
that in the case of the MW-promoted reaction of
methylenebisphosphonate 1 with ethyl iodide, there
was no need to use phase transfer catalyst. This
means that the situation is similar to that experi-
enced in the case of classical CH acidic compounds
by us as mentioned above [8,9]. According to this,
the 1 → 4 conversion is another example, when MW
Δ, 40 h
MW
140°C, 1.5 h
Cs2CO3
TEBAC
P(O)(OEt)2
P(O)(OEt)2
Bn
K2CO3
P(O)(OEt)2
P(O)(OEt)2
Et
Et
Et
+
BnBr
1 + EtI
+
MeCN
no solvent
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
1
2
4 (97%)
5 (3%)
SCHEME 1
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

Solid–Liquid Two-Phase Alkylation of Tetraethyl Methylenebisphosphonate under Microwave Irradiation 13
MW
120°C, 4 h
Cs2CO3
P(O)(OEt)2
P(O)(OEt)(OPr)
P(O)(OEt)(OPr)
Pr
Pr
Pr
1
+
PrX
+
+
no solvent
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)(OPr)
X = I, Br
6 (57%)
7 (33%)
8 (10%)
SCHEME 4
irradiation may substitute a phase transfer catalyst
in a solid–liquid phase alkylation.
couplings are given in hertz. Mass spectrometry was
performed on a ZAB-2SEQ instrument.
Next, methylenebisphosphonate 1 was reacted
with propyl bromide at 120◦C in the presence of
cesium carbonate. After an irradiation of 4 h, a
mixture was formed consisting of C-propyl bispho-
The MW-assisted reactions were carried out in a
CEM Discover MW reactor equipped with a pressure
controller using ca. 30 W irradiation.
sphonate 6 (57% δP (CDCl3) 25.0, (M + H)+
=
found
Tetraethyl Phenylethylidenebisphosphonate 2
331.1429, C12H29O6P2 requires 331.1439), and by-
products deriving from transesterification, such as
triethyl propyl ester 7 (33%) and diethyl dipropyl es-
ter 8 (10%). The situation was quite similar when
propyl iodide was used instead of the bromide
(Scheme 4).
The mixture of 0.50 g (1.74 mmol) of bishosphonate
1, 0.74 g (1.74 mmol) of K2CO3, 0.10 g (0.44 mmol) of
TEBAC, and 0.25 mL (2.08 mmol) of benzyl bromide
in 7 mL of acetonitrile was stirred under reflux for
40 h. Then the solid phase was removed by filtration,
washed with 5 mL of acetonitrile, and the combined
organic phases concentrated on vacuum. The crude
product so obtained was purified by column chro-
matography (silica gel, 3% methanol in chloroform)
to give 0.54 g (83%) of product 2.
Mixed esters 7 and 8 may be formed similarly as
3 (see above).
Disregarding the details, the alkylation with
butyl bromide took place analogously.
The use of phase transfer catalyst in the alkyla-
tion with propyl halide led to complex mixtures. On
the one hand, the conversion was not complete; on
the other hand, extensive decomposition of the prod-
ucts (6–8) could be observed. It can be seen that the
use of a phase transfer catalyst in the propylation of
methylenebisphosphonate 1 is surely harmful.
Products 2–4 were obtained in pure form by
column chromatography and were characterized by
31P, 13C, and 1H NMR spectral data, as well as
MS. Methylenebisphosphonates 2 and 4 were de-
scribed earlier [3,4], but only 2 was characterized
adequately.
31P NMR (CDCl3) δ: 23.9; 13C NMR (CDCl3) δ:
16.2 (d, J = 6.7, CH3), 31.1 (t, J = 4.8, CH2Ph), 39.0
(t, J = 132.5, CH), 62.3 (d, J = 6.8, OCH2), 62.5 (d,
ꢁ
ꢁ
J = 6.8, OCH2), 126.4 (s, C4 ), 128.1, 128.8 (2s, C2 ,
1
ꢁ
ꢁ
C3 ), 139.4 (t, J = 7, C1 ); H NMR (CDCl3) δ: 1.26 (t,
J = 8.2, 6H, CH3), 1.28 (t, J = 7.2, 6H, CH3), 2.66 (tt,
1H, J1 = 24, J2 = 6, CH), 3.25 (dt, J1 = 16.5, J2 = 6, 2H,
CH2Ph), 4.04–4.18 (m, 8H, OCH2), 7.18–7.28 (m, 5H,
Ph); [M + H]+
= 379.1427, C16H29O6P2 requires
found
379.1439. The NMR spectral data are identical with
those reported earlier [3].
It can be concluded that the MW technique of-
fers advantage in the alkylation of methylenebispho-
sphonates only when the alkyl groups of the two re-
actants are identical. The advantage is that there is
no need for a phase transfer catalyst and the reaction
time becomes much shorter.
Triethyl, Benzyl Methylidenebisphosphonate 3
0.50 g (1.74 mmol) of bishosphonate 1, 0.57 g (1.74
mmol) of Cs2CO3, 0.10 g (0.44 mmol) of TEBAC,
0.25 mL (2.08 mmol) of benzyl bromide, and
5 mL of acetonitrile was measured in a tube that
was irradiated at 120◦C applying 10 W under pres-
sure control. After a reaction time of 1.5 h, the
mixture was filtrated and the organic phase evapo-
rated. The reaction was repeated two times, and the
combined crude mixtures were subjected to column
chromatography (as above) to furnish 0.21 g (34%)
of compound 3.
EXPERIMENTAL
General
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
31P NMR (CDCl3) δ: 20.1 (d, J = 6.9), 20.9 (d,
J = 6.9); 13C NMR (CDCl3) δ: 16.39 (t, J = 3.5, CH3),
16.44 (d, J = 3.2, CH3), 25.7 (t, J = 136, PCH2P), 62.7
Heteroatom Chemistry DOI 10.1002/hc

14 Greiner et al.
(d, J = 6.5, OCH2CH3), 68.1 (d, J = 6, OCH2Ph), 128.1,
ACKNOWLEDGMENTS
ꢁ
ꢁ
ꢁ
ꢁ
128.7 (2s, C2 , C3 ), 128.5 (s, C4 ), 128.6 (d, J = 51, C1 );
1H NMR (CDCl3) δ: 1.24–1.34 (m, 9H, CH3), 2.46 (t,
J = 21, 2H, PCH2P), 4.06–4.19 (m, 6H, OCH2CH3),
5.14 (d, J = 8.5, 2H, CH2Ph), 7.33–7.43 (m, 5H, Ph);
MS.
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 Hun-
´
gary Development Plan (Project ID: TAMOP-4.2.1/
B-09/1/KMR-2010–0002).
Tetraethyl Propylidenebisphosphonate 4
The mixture of 0.50 g (1.74 mmol) of bishospho-
nate 1, 0.57 g (1.74 mmol) of Cs2CO3, and 0.17 mL
(2.08 mmol) of ethyl iodide was irradiated in a tube
at 140◦C applying 10 W under pressure control. After
a 1.5 h reaction time, the resulting mass was taken
up in 25 mL of ethyl acetate and the solid phase
was removed by filtration. The filtrate was evapo-
rated, and the residue obtained purified by column
chromatography (as above) to afford 0.44 g (80%) of
product 4.
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Heteroatom Chemistry DOI 10.1002/hc