A microwave-assisted solvent- and catalyst-free synthesis of aminomethylene bisphosphonates

Article abstract of DOI:10.1016/j.tetlet.2009.05.016

A convenient preparative approach for the synthesis of aminomethylene bisphosphonates is developed which involves treatment of amines with triethyl orthoformate and diethyl phosphite under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2009.05.016

Tetrahedron Letters 50 (2009) 4243–4245
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A microwave-assisted solvent- and catalyst-free synthesis of
aminomethylene bisphosphonates
*
Babak Kaboudin , Soheil Alipour
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient preparative approach for the synthesis of aminomethylene bisphosphonates is developed
which involves treatment of amines with triethyl orthoformate and diethyl phosphite under microwave
irradiation.
Received 19 February 2009
Revised 26 April 2009
Accepted 8 May 2009
Available online 13 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Phosphonic acids are of growing importance in understanding
and modulating biological processes.1 The synthesis of
-substi-
H
a
N
CH[P(O)(OH)2]2
N CH[P(O)(OH)2]2
tuted phosphoryl derivatives (phosphonic and phosphinic acids)
has attracted significant attention due to their biological activities
with broad applications as enzyme inhibitors, antimetabolites, and
antibiotics.2 Among
a-functionalized phosphonic acids, a-amin-
bone resorption inhibitor
inhibitor of Trypanosoma brucei
H
oalkylphosphonic derivatives have biological activities such as
H
N
anti-bacterial,2 herbicidal,3 and fungicidal.4 Aminoalkylphosphonic
N
N
CH[P(O)(OH)2]2
CH[P(O)(OH)2]2
acids, the phosphonic acid analogues of 2- or
a-amino carboxylic
acids, are an important class of compounds that exhibit a variety
of interesting and useful properties.
Me
used clinically
In contrast to the widely studied aminophosphonic acid deriva-
tives,5–8 relatively few papers describe the chemistry of aminom-
ethylene bisphosphonates. Aminomethylene bisphosphonates
have been used as powerful inhibitors of the enzyme farnesyl pyro-
phosphate synthase (FPPS).9 They display therapeutic properties
for conditions such as osteoporosis, rheumatoid arthritis, and can-
cer (Scheme 1).10 In addition to these, these compounds possess
interesting activities against many parasites including trypano-
soma.11 Besides their biological importance, aminomethylene bis-
phosphonates are also known for their metal-chelating ability.
Recently, the uranyl (UO22þ)-binding properties of these com-
pounds, showing excellent association constants, were reported.12
Synthetic routes to aminomethylene bisphosphonates involve
prolonged heating in acid-catalyzed reactions of nitriles with phos-
phites,13 Mannich-type reaction of amines with triethyl orthofor-
mate and phosphites under nitrogen,14 phosphorylation of
formamides,15 and Beckmann rearrangement of oximes in the
presence of POCl3 followed by treatment with trialkyl phos-
phites.16 Recently, a new preparation of aminomethylene bisphos-
phonates was reported involving the N–H insertion reaction of
amines with diphosphonodiazomethane carbene in the presence
[(HO)2(O)P]2HC NH
HN CH[P(O)(OH)2]2
X=O, -CH2CH2-
X
uranyl-binding ligands
Scheme 1. Examples of aminomethylene bisphosphonates used in pharmacy and
metal separation.
O
O
H P(OEt)2 + HC(OEt)3
(EtO)2HC P(OEt)2
Scheme 2. Reaction of diethyl phosphite with triethyl orthoformate.
O
O
O
MW, 120 °C
30-80 min
+
(EtO)2P
P(OEt)2
R NH
2
H P(OEt)2
2 + HC(OEt)3
NH
R
2
1
* Corresponding author. Tel.: +98 241 4153220; fax: +98 241 4214949.
E-mail address: kaboudin@iasbs.ac.ir (B. Kaboudin).
Scheme 3. Reaction of amines with triethyl orthoformate and diethyl phosphite.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.016

4244
B. Kaboudin, S. Alipour / Tetrahedron Letters 50 (2009) 4243–4245
Table 1
One-pot reaction of aniline with triethyl orthoformate and diethyl phosphite under various reaction conditions
O
O
O
+
(EtO)2P
P(OEt)2
Ph NH
2
2 + HC(OEt)3
H P(OEt)2
NH
Ph
2a
1a
Entry
Reaction conditionsa
Reaction temperature (°C)
Reaction time (min)
Yieldb (%) 2a
1
2
3
4
5
6
7
A
A
B
B
B
B
B
70
120
80
100
120
140
120
48 (h)
48 (h)
30
30
30
11
15
25
45
75
75
75
30
40
a
A = thermal heating, B = microwave assisted.
Isolated yield.
b
of rhodium complexes.12 However, these methods have associated
problems, including harsh reaction conditions, long-reaction times
and side reactions. On the other hand, the key step in the one-pot
synthesis of aminomethylene bisphosphonates is nucleophilic
addition of an amine to triethyl orthoformate followed by addition
of a phosphite to the resulting imine. Therefore, the formation of
diethoxymethyl phosphonates frequently accompanies the forma-
tion of aminomethylene bisphosphonates (Scheme 2).17
The application of microwave energy to accelerate organic reac-
tions is of increasing interest and offers several advantages over
conventional techniques.18 Syntheses which normally require long
periods can be achieved conveniently and very rapidly in a micro-
wave reactor. As part of our efforts to introduce novel methods for
the synthesis of organophosphorus compounds,19 herein we report
a new method for the synthesis of aminomethylene bisphospho-
nates. We have found that microwave-assisted one-pot reactions
of amines with triethyl orthoformate and diethyl phosphite give
aminomethylene bisphosphonates in good yields (Scheme 3).
Thus, the one-pot reaction of aniline, chosen as a model amine,
with triethyl orthoformate and diethyl phosphite was studied un-
der various reaction conditions and the progress of the reaction
was monitored by TLC (Table 1). Treatment of 1a with a mixture
of triethyl orthoformate and diethyl phosphite gave the corre-
sponding aminomethylene bisphosphonate 2a in 11% yield after
48 h at 70 °C (entry 1). When the reaction temperature was raised
from 70 °C to 120 °C, the yield of 2a increased to 15% (entry 2). We
found that using a microwave reactor led to acceleration of the
reaction rate and an increase in the yield of 2a (entries 3–7). We
obtained the best results on heating at 120 °C for 30 min (entry
5). The yield of the reaction did not change on further increasing
the microwave reactor temperature and reaction time (entries 6
and 7).
This process was applied successfully to other amines as sum-
marized in Table 2. Substituted anilines reacted with triethyl
orthoformate and diethyl phosphite under microwave irradiation
to afford the desired products 2b–i in moderate to good yields.
1-Naphthylamine also reacted with triethyl orthoformate and
diethyl phosphite to give compound 2j in 55% yield. Reaction of
aliphatic amine 1k and 3-aminopyridine 1l with triethyl orthofor-
mate and diethyl phosphite gave unidentified mixed products.
Reaction of 4-aminodiphenylamine 1m (with two different amine
groups) gave compound 2m in 85% yield as the only product.
In summary, a series of aminomethylene bisphosphonates have
been synthesized via reactions of amines with diethyl phosphite
and triethyl orthoformate. The simple work-up, mild reaction con-
ditions, good yields, and clean reactions with no tar formation
make this method an attractive and novel contribution to present
methodologies.20
Acknowledgment
The Institute for Advanced Studies in Basic Sciences (IASBS) is
thanked for supporting this work.
References and notes
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Table 2
Synthesis of various aminomethylene bisphosphonates under microwave irradiation
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Amine 1 R
Product
Reaction time (min)
Yielda (%) 2
C6H5–
2a
2b
2c
2d
2e
2f
2g
2h
2i
30
30
30
30
30
50
30
30
80
60
60
60
60
75
70
80
70
82
56
81
76
75
55
p-ClC6H4–
p-MeC6H4–
p-BrC6H4–
p-MeOC6H4–
m-O2NC6H4–
m-EtC6H4–
o-EtC6H4–
4-Cl,2-O2NC6H3–
1-Naphthyl
PhCH2–
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2j
2k
2l
b
—
—
b
3-Pyridyl
4-PhNHC6H4–
2m
85
a
Isolated yield.
Unidentified mixture of products.
b

B. Kaboudin, S. Alipour / Tetrahedron Letters 50 (2009) 4243–4245
4245
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120 °C at ambient pressure in a microwave reactor (a Milestone, Micro SYNTH
Microwave Labstation for Synthesis, microwave reactor was used for all
experiments). The resulting mixture was subjected to column chromatography
on silica gel with EtOAc/n-hexane (9:1) and evaporation of the solvent under
reduced pressure gave pure products in 55–85% yields. All products gave
satisfactory spectral data in accord with the assigned structures and literature
reports (compounds 2a, 2e, 2f, and 2g).11,12 Analytical and spectral data for
compounds 2: Compound 2b: white solid, mp: 137–138 °C; 1H NMR
(CD3SOCD3—250 MHz), d: 1.05–1.23 (m, 12H), 3.91–4.18 (m, 8H), 4.53 (dt,
1H, JHP = 22.8 Hz, J = 10.5 Hz), 5.97 (d, 1H, NH, J = 10.5 Hz), 6.90 (d, 2H,
J = 8.8 Hz), 7.06 (2H, J = 8.8 Hz). 31P NMR (CD3SOCD3—101.25 MHz), d: 18.36.
13C NMR (CD3SOCD3—62.9 MHz), d: 16.6 (d, JPC = 2.5 Hz), 48.8 (t,
JPC = 145.2 Hz), 62.7–63.2 (m), 114.9, 120.6, 128.6, 146.5 (t, JPC = 3.7 Hz). Anal.
Calcd for C15H26NO6P2Cl: C, 43.57; H, 6.29; N, 3.39. Found: C, 43.63; H, 6.20; N,
3.45. Compound 2c: white solid, mp: 70–71 °C; 1H NMR (CD3SOCD3—250 MHz),
d: 1.05–1.25 (m, 12H), 2.13 (s, 3H), 3.90–4.13 (m, 8H), 4.42 (dt, 1H,
JHP = 22.8 Hz, J = 10.5 Hz), 5.42 (d, 1H, NH, J = 10.5 Hz), 6.76 (d, 2H, J = 8.2 Hz),
6.87 (2H, J = 8 Hz). 31P NMR (CD3SOCD3—101.25 MHz), d: 18.69. 13C NMR
(CD3SOCD3—62.9 MHz), d: 16.5 (d, JPC = 2.5 Hz), 20.4, 49.1 (t, JPC = 145.9 Hz),
62.8–63.4 (m), 113.6, 126.1, 129.5, 144.9 (t, JPC = 4.4 Hz). Anal. Calcd for
C16H29NO6P2: C, 48.84; H, 7.43; N, 3.56. Found: C, 48.61; H, 7.55; N, 3.50.
Compound 2d: white solid, mp: 139–140 °C; 1H NMR (CD3SOCD3—250 MHz), d:
1.03–1.30 (m, 12H), 3.89–4.18 (m, 8H), 4.53 (dt, 1H, JHP = 22.8 Hz, J = 10.5 Hz),
6.00 (d, 1H, NH, J = 10.5 Hz), 6.86 (d, 2H, J = 8.5 Hz), 7.17 (2H, J = 8.5 Hz). 31P
NMR (CD3SOCD3—101.25 MHz), d: 18.31. 13C NMR (CD3SOCD3—62.9 MHz), d:
16.1 (d, JPC = 1.8 Hz), 48.7 (t, JPC = 145.2 Hz), 62.7–63.2 (m), 108.0, 115.5, 131.4,
146.9 (t, JPC = 3.7 Hz). Anal. Calcd for C15H26NO6P2Br: C, 39.38; H, 5.73; N, 3.06.
Found: C, 39.15; H, 5.70; N, 2.93. Compound 2h: colorless oil; 1H NMR
(CD3SOCD3–TMS, 250 MHz), d: 1.02–1.25 (m, 15H), 2.40 (q, 2H, J = 7.5 Hz),
3.90–4.18 (m, 8H), 4.71 (dt, 1H, JHP = 22 Hz, J = 10.25 Hz), 6.64 (t, 1H, J = 7.5 Hz),
7.85–7.08 (m, 3H). 31P NMR (CD3SOCD3–TMS, 101.25 MHz), d: 18.70. 13C NMR
(CD3SOCD3–TMS, 62.9 MHz), d: 13.5, 16.4–16.6 (m), 23.8, 49.1 (t,
JPC = 144.6 Hz), 62.6–63.2 (m), 112.0, 118.3, 127.1, 128.0, 128.5, 143.8 (t,
JPC = 4.4 Hz). Anal. Calcd for C17H31NO6P2: C, 50.10; H, 7.67; N, 3.44. Found: C,
49.95; H, 7.55; N, 3.52. Compound 2i: colorless oil; 1H NMR (CD3SOCD3—
250 MHz), d: 1.03–1.24 (m, 12H), 3.98–4.17 (m, 8H), 5.36 (dt, 1H,
JHP = 21.75 Hz, J = 10.5 Hz), 7.53 (d, 1H, J = 9.25 Hz), 7.56 (dd, 1H, J = 9.25 Hz,
J = 2.5 Hz), 8.08 (d, 1H, J = 2.5 Hz), 8.27 (d, 1H, NH, J = 7.5 Hz). 31P NMR
(CD3SOCD3—101.25 MHz), d: 16.75. 13C NMR (CD3SOCD3—62.9 MHz), d: 16.3–
16.7 (m), 48.1 (t, JPC = 143.4 Hz), 62.5, 118.5, 120.8, 125.3, 132.6, 136.6, 143.0 (t,
J = 5.03 Hz). Anal. Calcd for C15H25N2O8P2Cl: C, 39.29; H, 5.50; N, 6.11. Found:
C, 39.11; H, 5.67; N, 6.05. Compound 2j: white solid, mp: 63–64 °C; 1H NMR
(CD3SOCD3–TMS, 250 MHz), d: 1.01–1.28 (m, 12H), 3.90–4.21 (m, 8H), 4.83 (dt,
1H, JHP = 22.5 Hz, J = 10 Hz), 5.34 (d, 1H, NH, J = 9.5 Hz), 6.98 (d, 1H, J = 7 Hz),
7.17–7.60 (m, 4H), 7.72–7.85 (m, 1H), 7.95–8.09 (m, 1H). 31P NMR (CD3SOCD3–
TMS, 101.25 MHz), d: 18.55. 13C NMR (CD3SOCD3–TMS, 62.9 MHz), d: 16.3, 49.1
(t, JPC = 146.5 Hz), 63.5–64.0 (m), 106.3, 118.5, 120.6, 123.4, 125.5, 126.3, 126.7,
128.7, 134.2, 141.5. Anal. Calcd for C19H29NO6P2: C, 53.13; H, 6.81; N, 3.26.
Found: C, 52.95; H, 6.63; N, 3.10. Compound 2m: white solid, mp: 81–82 °C; 1H
NMR (CD3SOCD3—250 MHz), d: 1.03–1.25 (m, 12H), 3.92–4.24 (m, 8H), 4.44
(dt, 1H, JHP = 22.5 Hz, J = 10.5 Hz), 5.37 (d, 1H, NH, J = 10.5 Hz), 6.62 (t, 1H,
J = 7.5 Hz), 6.77–6.95 (m, 6H,), 7.09 (t, 2H, J = 8.25 Hz), 7.57 (s, NH, 1H). 31P
NMR (CD3SOCD3—101.25 MHz), d: 18.77. 13C NMR (CD3SOCD3—62.9 MHz), d:
16.4, 49.6 (t, JPC = 145.9 Hz), 63.3–63.7 (m), 114.5, 114.6, 118.2, 121.5, 129.4,
133.9, 141.9 (t, JPC = 4.3 Hz), 146.0. Anal. Calcd for C21H32N2O6P2: C, 53.60; H,
6.86; N, 5.96. Found: C, 53.51; H, 6.74; N, 5.86.
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20. Diethyl phosphite (15 mmol) was added to a mixture of amine (5 mmol) and
triethyl orthoformate (5 mmol) and the solution was stirred for 30–80 min at