Simple, efficient and one-pot method for synthesis of aminomethylene gem-diphosphonic acid derivatives from ketones via Beckmann rearrangement

Article abstract of DOI:10.1055/s-2004-831233

A simple, expeditious and convenient synthesis of aminomethylene gem-diphosphonic acid derivatives in one-pot reaction using ketones, hydroxylamine hydrochloride, phosphorus trichloride and water as starting materials in the presence of pyridine via Beckmann rearrangement is described in the modest yields.

Full text of DOI:10.1055/s-2004-831233

PAPER
2441
Simple, Efficient and One-Pot Method for Synthesis of Aminomethylene gem-
Diphosphonic Acid Derivatives from Ketones via Beckmann Rearrangement
S
M
ynthesis of
A
minome
i
thylene
n
gem-Dipho
g
s
D
erivative
h
s
F
romKeto
u
ne
s
Wu, Ruyu Chen,* You Huang*
Institute and National Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
Fax +86(22)23503438; E-mail: wums@eyou.com
Received 1 March 2004; revised 6 April 2004
advanced medicinal applications in recent years. Their
main therapeutic application is in diseases with high bone
turnover such as Paget’s diseases, tumoral bone diseases
Abstract: A simple, expeditious and convenient synthesis of ami-
nomethylene gem-diphosphonic acid derivatives in one-pot reaction
using ketones, hydroxylamine hydrochloride, phosphorus trichlo-
ride and water as starting materials in the presence of pyridine via and osteoporosis.5
Beckmann rearrangement is described in the modest yields.
O
Key words: aminomethylene gem-diphosphonic acid derivatives,
ketones, Beckmann rearrangement, hydroxylamine hydrochloride,
phosphorus trichloride
R1
P(OH)2
R2
P(OH)2
O
Figure 1
The methylene diphosphonic acids (Figure 1), carbon an-
alogues of inorganic pyrophosphate, exhibit unique phys-
ical and chemical properties in interaction with the
Owing to the interest in this class of compounds, several
methods have been reported in literature. For the main
methods there are three categories. The first method in-
volves the treatment of an amide with water and phospho-
1
alkaline earth cations or heavy metal cations. The central
core of geminal bisphosphonic acids (P–C–P) is charac-
terized by two carbon–phosphorus bonds. They are there-
fore metabolically more stable than pyrophosphates (P–
6
rus trichloride in the presence of an organic base. The
2
O–P) which are easily hydrolyzed by phosphatases, and
second involves the bisphosphorylation of an amine with
triethyl orthoformate and dialkyl phosphate. Subsequent
hydrolysis of the aminomethylenebisphosphonate ester
possess a number of useful biological properties including
antiviral, antiamoebic, herbicidal and ‘bone-seeking’ ac-
tivities which appear to be related to their ability to chelate
7
under acidic conditions gave the desired product. Third,
3
metal ions. Aminomethylene gem-diphosphonates were
comparatively few reports deal with the preparation of
aminomethylene gem-diphosphonic acids via Beckmann
rearrangement reaction (Scheme 1). Yokomatsu and co-
workers first described the synthesis of alicyclic ami-
nomethylene gem-diphosphonates by the bisphosphoryl-
found to possess inhibitory activity on squalene syn-
thetase, which plays an important role in the pathway of
4
8
cholesterol biosynthesis. Thus, research work on these
compounds has received considerable impulse from some
2
3
4
Cl
P
Cl
OH
O
N
N
PCl3
Rearrangement
R1
N
R2
C
R1
R2
R1
R2
HPO(OH)2
Py
NH2OH⋅HCl
O
O
O
P(OH)2
HPO(OH)2
N
P(OH)2
NH
R2
R1
P(OH)2
O
R1
R1
R2
R2
1
6
5
Scheme 1
SYNTHESIS 2004, No. 15, pp 2441–2444
x
x.
x
x
.
2
0
0
4
Advanced online publication: 22.09.2004
DOI: 10.1055/s-2004-831233; Art ID: F03204SS
Georg Thieme Verlag Stuttgart · New York
©

2
442
M. Wu et al.
PAPER
ation of oximes with dialkyl phosphite via Beckmann nucleophiles. Rearrangement reaction takes place in the
rearrangement to give the alicyclic aminomethylene gem- presence of phosphorus trichloride, which acts as not only
diphosphonates. Then the reaction of aminomethylene promoter but also reactant. The reaction of various ke-
gem-diphosphonates with trimethylsilyl bromide (TMS- tones including aliphatic and aromatic ketones is exam-
Br), followed by methanolysis gave the corresponding ined. The results are summarized in Table 1. All reactions
aminomethylene gem-diphosphonic acids. This method, gave the expected diphosphonic acid derivatives 1a–i in
however, is a multi-step reaction, needs harsh reaction modest yields. In the case of diphosphonylation reactions,
conditions and expensive reagents and gives lower yields we found that the reaction of aromatic ketones was carried
(
overall 30%). The development of a facile and efficient out more easily than that of aliphatic ketones. Diphospho-
method for synthesis of aminomethylene gem-diphospho- nylation reactions of oximes formed by unsymmetrical ar-
nic acid derivatives is still required. In this paper we wish omatic ketones gave the expected diphosphonic acids
to report a simple and convenient one-pot synthesis of regioselectively with migration of the aromatic groups. As
aminomethylene gem-diphosphonic acids using ketone, for oximes produced by aliphatic ketones, the reaction of
hydroxylamine hydrochloride, phosphorus trichloride and diphosphonylation also agrees with the regular features of
water as starting materials in the presence of pyridine via Beckmann rearrangement. The corresponding regioiso-
Beckmann rearrangement (Scheme 2).
Based on Beckmann rearrangement reaction mechanism All aminomethylene gem-diphosphonic acids derivatives
Scheme 1), the iminocarbocations 4 produced by Beck- thus obtained show diagnostic triplets due to carbons
mers were not formed in these reactions.
(
mann rearrangement of an oxime 2 formed by the reaction
of ketones with hydroxylamine hydrochloride with the
pyridine as a catalyst in one pot have been shown to be
useful reactive intermediates which react with a variety of
C-nucleophiles under the appropriate conditions to give
important nitrogen heterocycles after reductive or alkyla-
Table 1 Synthesis of Compounds 6a–i
Entry Product R1
R2
MP
°C)
Yield
(%)
h
(
9
tive work-up. Beckmann rearrangement of an oxime in
> 300a
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
C H
Me
61
51
59
60
56
50
53
40
59
6
5
the presence of suitable phosphorus nucleophiles would
constitute a facile formation of aminomethylene gem-
diphosphonic acids 6, if the phosphorus nucleophiles cap-
ture both the intermediate iminocarbocation 4 and the re-
sulting imino phosphonic acids 5, effectively under the
conditions. Yokomatsu and co-workers have successfully
adopted the diethyl phosphite as phosphorus nucleophile
to produce the aminomethylene gem-bisphosphonates and
subsequently obtained the aminomethylene gem-bisphos-
phonic acids under the action of trimethylsilyl bromide
1
2
-(CH ) -
R = R
251–253
2 5
> 300b
n-Pr
Me
Me
4-ClC H
> 300c
5
4
> 300d
4-CH OC H Me
3
5
4
i-Bu
Et
Me
Me
209–211
> 300e
> 300f
6g
6h
6i
1
2
(
TMSBr), followed by methanolysis. Then we directly
-(CH
2
)
6
-
R = R
use the phosphorous acid as phosphorus nucleophile to
give aminomethylene gem-bisphosphonic acids in one
pot, avoid dealkylation of esters, cut down the reaction
steps, effectively increase the product yields.
4-CH C H
4
Me
> 300g
3
5
a
b
c
d
e
f
Disodium salt with trihydrate.
Tetrasodium salt with 2.5 hydrate.
Disodium salt with monohydrate.
Tetrasodium salt with 3.5 hydrate.
Trisodium salt with monohydrate.
Disodium salt with monohydrate.
Monosodium salt.
Therefore, the ketones first react with the hydroxylamine
hydrochloride in the presence of pyridine to give oximes
using stoichiometric water as the solvent. Subsequent wa-
ter is exhausted by an excess amount of phosphorus
trichloride to afford phosphorous acid used as phosphorus
g
h
Isolated yield.
O
O
OH
O
N
(HO)2P
P(OH)2
Py
3 2
PCl + H O
+
NH2OH⋅HCl
r.t.
R1
R2
H
N
R2
R1
R2
R1
1
2
6
1
2
1
2
1
2
a: R = C6H5, R = Me; b: R = R = -(CH2)5-; c: R = n-Pr, R = Me
1
2
1
2
1
2
d: R = 4-ClC6H4, R = Me; e: R = 4-CH3OC5H4, R = Me; f: R = i-Bu, R = Me
1
2
1
2
1
2
g: R = Et, R = Me; h: R = R = -(CH2)6- ; i: R = 4-CH3C5H4, R = Me
Scheme 2
Synthesis 2004, No. 15, 2441–2444 © Thieme Stuttgart · New York

PAPER
Synthesis of Aminomethylene gem-Diphosphonic Acid Derivatives from Ketones
2443
1
3
bearing gem-diphosphonic acid groups in their C NMR 1-Methyl-1-(n-propyl)aminomethylenediphosphonic Acid (6c)
1
1
H NMR (D O): d = 3.23 (t, J = 8.24 Hz, 2 H, CH NH), 1.47–1.65
2 2
or H NMR spectra. Structures of 6a, 6d, 6e, 6i were de-
(
1
m, 5 H, CH , CH ), 0.865 (t, J = 7.12 Hz, 3 H, CH ).
3 2 3
duced by diagnosis of triplets [d = 1.41–1.51 (J = 15 Hz)]
attributed to the methyl protons coupled to two phospho-
rus atoms in their H NMR spectra.
3
1
C NMR (D O): d = 57.6, 59.7, 61.5 (t, J = 156.8 Hz), 47.2, 20.2,
2
PC
1
16.7, 10.2.
3
1
P NMR (D O): d = 14.7.
2
In summary, a facile and novel synthesis of compounds
a–i in a one-pot reaction is described in the presence of
pyridine using ketones, hydroxylamine hydrochloride,
phosphorus trichloride and water as starting materials in
modest yields. Some advantageous features are: (a) the
starting materials are cheap; (b) the experimental proce-
Anal. Calcd for C H O NP Na ·2.5H O: C, 15.78; H, 4.21; N,
3
6
5
11
6
2
4
2
.68. Found: C, 15.57; H, 3.98; N, 3.81.
1
-Methyl-1-(4-chlorophenyl)aminomethylenediphosphonic
Acid (6d)
1
3
H NMR (D O): d = 7.19–7.34 (m, 4 H, C H ), 1.48 (t, J = 14.5
2
6
4
PH
dure is simple; and (c) the products can be obtained by Hz, 3 H, CH3).
simple precipitation and crystallization workup without
chromatographic separation.
31
P NMR (D O): d = 17.45.
2
Anal. Calcd for C H O NP Na ·H O: C, 25.43; H, 3.17; N, 3.71.
8
10
6
2
2
2
Found: C, 25.34; H, 2.88; N, 3.81.
All melting points were determined on a Yanaco apparatus and are
uncorrected. NMR spectra were measured on a Brucker AC-P200
or 300 NMR instrument in D O or D O–K CO and chemical shifts
1
-Methyl-1-(4-methoxyphenyl)aminomethylenediphosphonic
Acid (6e)
2
2
2
3
1
H NMR (D O): d = 6.97–7.45 (m, 4 H, C H ), 3.78 (s, 3 H, CH O),
are expressed as d. Tetramethyl silane was used as an internal stan-
2
6
4
3
3
1
13
dard for H and C NMR, and 85% H PO as an external standard
1.51 (t, JPH = 13.1 Hz, 3 H, CH ).
3
3
4
3
1
for P NMR spectroscopy. Elemental analysis was carried out on a
Yanaco CHNCORDER MT-3 Analyzer. All the ketones were redis-
tilled before use.
31
P NMR (D O): d = 14.52.
2
Anal. Calcd for C H O NP Na ·3.5H O: C, 23.37; H, 3.89; N,
3
9
11
7
2
4
2
.03. Found: C, 23.24; H, 3.81; N, 3.12.
Synthesis of Aminomethylene gem-Diphosphonic Acids Deriva-
tives 1; General Procedure
1
-Methyl-1-(i-butyl)aminomethylenediphosphonic Acid (6f)
1
3
H NMR (D O): d = 3.03 (d, J = 6.9 Hz, 2 H, CH NH), 1.74 (m, 1
H, CH), 1.45 (t, J = 14.1 Hz, 3 H, CH ), 0.776 (d, J = 6.3 Hz, 6
2
2
To the aq solution (0.06 mol) of hydroxylamine hydrochloride (1.4
g, 0.02 mol) were added ketones (0.02 mol) in the presence of pyri-
dine (2.4 g, 0.03 mol). The mixture was stirred at r.t. for 30 min to
give the oximes 2. Then the solution of phosphorus trichloride (6.9
g, 0.05 mol) in toluene (5 mL) was slowly added dropwise under
ice-cooling with vigorous stirring at a rate such that the internal
temperature did not rise above 25 °C. After the completion of the
addition, the ice-bath was removed and the temperature of the reac-
tion mixture was allowed to rise spontaneously (due to the exother-
mic reaction) until reflux at 110 °C for over 0.5 h. Upon cooling to
r.t., the resulting mixture partitioned into two layers. The lower lay-
er solidified and the upper layer was decanted. The lower layer was
3
PH
3
H, 2 × CH ).
3
1
3
1
C NMR (D O): d = 56.5, 58.7, 60.3 (t, J = 120.8 Hz), 48.2, 22.2,
2
PC
16.8, 9.2.
31
P NMR (D O): d = 12.2.
2
Anal. Calcd for C H O NP : C, 27.58; H, 6.51; N, 5.36. Found: C,
2
6
17
6
2
7.46; H, 6.61; N, 5.52.
1
-Methyl-1-ethyl-aminomethylenediphosphonic Acid (6g)
1
3
H NMR (D O): d = 3.48 (q, 2 H, CH NH), 1.58 (t, J = 15.4 Hz,
2
2
PH
3
3
H, CH ), 1.19 (t, J = 6.8 Hz, 3 H, CH ).
3 3
then quenched with H O (50 mL) and hydrolyzed at reflux for 0.5
2
h. After the solution was cooled to r.t. the pH was adjusted to 7–8
with aq 20% NaOH, and then an appropriate amount of EtOH was
added. The product was precipitated from the resulting solution, and
the solid was collected by filtration, washed with cold water and fur-
13
1
C NMR (D O): d = 57.3, 59.8, 61.9 (t, J = 161.9 Hz), 40.8, 16.6,
2
PC
1
1.7.
3
1
P NMR (D O): d = 14.7.
2
ther purified by crystallization from H O–EtOH to yield 6 as white
Anal. Calcd for C H O NP Na ·H O: C, 15.14; H, 3.78; N, 4.42.
4 10 6 2 3 2
2
crystals.
Found: C, 14.80; H, 3.49; N, 4.60.
1
-Methyl-1-anilinomethylenediphosphonic Acid (6a)
Azacyclooctane-2,2-diphosphonic Acid (6h)
1
3
1
H NMR (D O): d = 6.87–7.15 (m, 5 H, C H ), 1.51 (t, J = 15.47
Hz, 3 H, CH ).
H NMR (D O): d = 2.88 (t, 2 H, CH NH), 2.27 (m, 2 H, CH ),
2
6
5
PH
2
2
2
1.27–1.72 [m, 8 H, (CH ) ].
3
2 4
3
1
13
1
P NMR (D O): d = 15.1.
C NMR (D O): d = 65.0, 63.4, 61.9 (t, J = 112.9 Hz), 44.2, 26.9,
2
2
PC
2
5.9, 25.1, 24.2, 23.3.
Anal. Calcd for C H NO P Na ·3H O: C, 25.32; H, 4.48; N, 3.69.
Found: C, 25.37; H, 4.61; N, 3.82.
8
11
6
2
2
2
3
1
P NMR (D O): d = 13.1.
2
Anal. Calcd for C H O NP Na ·H O: C, 25.07; H, 5.07; N, 4.17.
Found: C, 25.23; H, 5.39; N, 4.30.
7
15
6
2
2
2
Azacycloheptane-2,2-diphosphonic Acid (6b)
1
H NMR (D O + K CO ): d = 3.29 (t, J = 4.9 Hz, 2 H, CH NH),
2
2
3
2
2
.08–2.19 (m, 2 H, CH CP ), 1.47–1.69 (m, 6 H, CH CH CH ).
2 2 2 2 2
1
-Methyl-1-(4-methylphenyl)aminomethylenediphosphonic
1
3
1
C NMR (D O + K CO ): d = 64.3, 62.7, 61.2 (t, J = 119.7 Hz),
Acid (6i)
2
2
3
PC
1
4
5.6, 29.5, 28.5, 27.7, 23.4.
H NMR (D O): d = 6.97–7.45 (m, 4 H, C H ), 2.08 (s, 3 H, CH ),
2
6
4
3
3
3
1
1.43 (t, JPH = 14.7 Hz, 3 H, CH ).
3
P (D O + K CO ): d = 16.1.
2
2
3
3
1
P NMR (D O): d = 20.28.
2
Anal. Calcd for C H O NP : C, 27.74; H, 5.83; N, 5.41. Found: C,
6
15
6
2
2
7.74; H, 5.61; N, 5.22.
Anal. Calcd for C H O NP Na: C, 31.92; H, 4.56; N, 4.56. Found:
9 14 6 2
C, 32.01; H, 4.29; N, 4.59.
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M. Wu et al.
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Synthesis 2004, No. 15, 2441–2444 © Thieme Stuttgart · New York