Convenient synthesis of analogs of aminomethylene gem-diphosphonic acid from amines without catalyst

Article abstract of DOI:10.1081/SCC-120030688

A simple, novel, and convenient synthesis of analogs of aminomethylene gem-diphosphonic acids in one-pot from primary and secondary amines in moderate yields was reported without catalyst.

Full text of DOI:10.1081/SCC-120030688

This article was downloaded by: [University of Sydney]
On: 14 March 2013, At: 07:44
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Convenient Synthesis of Analogs of Aminomethylene
gem‐Diphosphonic Acid from Amines Without
Catalyst
Mingshu Wu a , Ruyu Chen a & You Huang a
a Institute and National Key Laboratory of Elemento‐Organic Chemistry, Nankai
University, Tianjin, 300071, China
Version of record first published: 21 Aug 2006.
To cite this article: Mingshu Wu , Ruyu Chen & You Huang (2004): Convenient Synthesis of Analogs of Aminomethylene
gem‐Diphosphonic Acid from Amines Without Catalyst, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:8, 1393-1398
To link to this article: http://dx.doi.org/10.1081/SCC-120030688
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 8, pp. 1393–1398, 2004
Convenient Synthesis of Analogs of
Aminomethylene gem-Diphosphonic
Acid from Amines Without Catalyst
*
Mingshu Wu, Ruyu Chen, and You Huang
Institute and National Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin, China
ABSTRACT
A simple, novel, and convenient synthesis of analogs of aminomethylene
gem-diphosphonic acids in one-pot from primary and secondary amines
in moderate yields was reported without catalyst.
Key Words: Aminomethylene gem-diphosphonic acid; bisphospho-
nates; Primary and secondary amines; Aromatic and aliphatic analogs.
INTRODUCTION
Geminal bisphosphonates and the corresponding acids which are
characterized by a P–C–P linkage are stable pyrophosphates analogs
*
Correspondence: Ruyu Chen, Institute and National Key Laboratory of Elemento-
Organic Chemistry, Nankai University, Tianjin 300071, China; E-mail: ruyuchen@
mail.zlnet.com.cn.
1393
DOI: 10.1081/SCC-120030688
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
1394
Wu, Chen, and Huang
which are completely resistant to enzymatic hydrolysis. They are widely
used in the treatment of a number of diseases characterized by an abnormal
calcium metabolism, such as Paget’s disease, osteoporosis.[1,2] Recently, a
lot of studies have shown that the use of bisphosphonates might be con-
sidered as an improvement in the management of cancer.[3] Owing to the
interest of this class of compounds, different synthetic routes have been
reported in literature. For the main methods there are two categories. The
first method involves the treatment of an amide with water and phosphorus
trichloride in the presence of an organic base.[4–7] The second involves the
bisphosphorylation of an amine with triethyl orthoformate and dialkyl phos-
phite. Subsequent hydrolysis of the aminomethylenebisphosphonate ester
under acidic conditions gave the desired product.[8,9] However, to the
best of our knowledge, simple and novel methods for the synthesis of
aromatic and aliphatic analogs of aminomethylene gem-diphosphonic
acids have rarely been reported.
In this paper, we wish to report a simple, novel, and convenient synthesis
of aminomethylene gem-diphosphonic acids in one-pot from primary and sec-
ondary amines in moderate yields (Sch. 1) (Table 1). Amines (3) are formy-
lated by formic acid to give the intermediate formamides (2) which are
isolated unnecessarily and directly react with water and phosphorus trichloride
without any catalysis to afford aminomethylene gem-diphosphonic acids (1).
In this method we examined primary and secondary amines using as the start-
ing materials, respectively, and found that the reaction of primary amines was
carried out more easily than that of secondary amines. When di-isopropyl-
amine is used as the starting material, no product was obtained due to a larger
steric hindrance.
In summary, a facile and novel synthesis of compounds (1a–1j) in one-
pot is described without any catalyst using amines as starting materials in
modest yields. The synthesis pathway appears to provide a simple, general
method for synthesis of aminomethylene gem-diphosphonic acids derivatives
and it is also be applicable to a large scale production.
Scheme 1.

ORDER
REPRINTS
Synthesis of Analogs of Aminomethylene gem-Diphosphonic Acid
Table 1. Results of the reactions.
1395
Product
R1
R2
M.p. (8C) Yield (%)a
1a
1b
1c
1d
Phenyl
H
H
H
H
189–191c
182–184b
261–263c
247–249d
60
40
70
72
o-Methylphenyl
Cyclohexyl
3-(N,N-dimethylamino)-
propyl
1e
1f
1g
1h
1i
n-Octyl
Methyl
H
Methyl
272–274c
240–242b
.300e
200–202
196–198
221–223
75
60
45
51
60
46
Hydroxylethyl
Ethyl
n-Propyl
Hydroxylethyl
Ethyl
n-Propyl
n-Butyl
1j
n-Butyl
aIsolated yield.
bHydrochloride.
cMonohydrate.
dDihydrate.
eTetrasodium salt.
EXPERIMENTAL
All melting points were determined on a Yanaco apparatus and they are
uncorrected. NMR spectra were measured on a Brucker AC-P200 NMR
instrument in D2O or þK2CO3 and chemical shifts are expressed as d units,
1
TMS being used as an internal standard for H NMR and 85% H3PO4 as an
external standard for 31P NMR spectroscopy. Elemental analysis was carried
out with a Yanaco CHNCORDER MT-3 Analyzer. All the amines were redis-
tilled before being used, except compound 1f synthesized by directly using
DMF as the starting material.
General Procedure
A 100 mL flask fitted with a reflux condenser and a distillation apparatus
and charged with 15 mmol of amines (3) and 19.5 mmol of anhydrous formic
acid. The mixture was refluxed for 5 hr, water produced and excess formic acid
was removed continuously by the distillation during reaction to give the inter-
mediate (2), and the resultant mixture was cooled to room temperature and
34 mmol of water was added. The flask was fitted with a mechanical stirrer
instead of distillation apparatus, and 31 mmol of phosphorus trichloride was
slowly added dropwise at such a rate that the internal temperature did not

ORDER
REPRINTS
1396
Wu, Chen, and Huang
rise above 258C with vigorous stirring in ice-water bath. After the completion
of the addition, the reaction mixture was heated to 100–1208C and maintained
at this temperature over 0.5 hr until solidified. It was quenched with 30 mL of
water and hydrolyzed at reflux for 1 hr. The aminobisphosphonic acid crystal-
lizes directly from the aqueous reaction mixture after cooling to room tem-
perature. Appropriate ethanol was added and the pH was adjusted to 1–2,
while the sodium salt was obtained upon cooling and adjusting the pH to
7–8 with aq. 20% NaOH.
N-Phenyl-aminomethylene-1,1-bisphosphonic Acid (1a). Preparation
procedure was the same as above. The crystal was collected by filtration,
washed with cool water, recrystallized from water and dried in vacuo at
1
458C to give pale white crystals as a monohydrate. H NMR (D2O) d 6.89–
7.47 (m, 5H, aromatic), 3.94 (t, JH–P ¼ 19.87 Hz, 1H, CH–P); 31P NMR
(D2O) d 16.80; Anal. Calcd for C7H11NO6P2 þ H2O: C, 29.49; H, 4.60; N,
4.91. Found: C, 29.21; H, 4.33; N, 4.70.
N-o-Methylphenyl-aminomethylene-1,1-bisphosphonic Acid (1b). The
crystal was collected by filtration, washed with ethanol, recrystallized from
water/ethanol ¼ 4 : 6 (v/v) to give a pale white crystalline as hydrochlori-
de.1H NMR (D2O) d 6.76–7.47 (m, 4H, aromatic), 2.25 (s, 3H, CH3), 4.13
(t, JH–P ¼ 19.82, 1H, CH–P); 31P NMR (D2O) d 17.66; Anal. Calcd for
C8H13NO6P2 þ HCl: C, 30.25; H, 4.44; N, 4.41. Found: C, 30.18; H, 4.12;
N, 4.61.
N-Cyclohexyl-aminomethylene-1,1-bisphosphonic Acid (1c). The desired
product crystallized directly from the aqueous reaction mixture after cooling.
Crystals were filtrated, washed with cool water, recrystallized from water
and dried at 1008C to afford a white crystalline monohydrate 1H NMR
(D2O þ K2CO3) d 1.33–2.08 (m, 11H, cyclohexyl), 3.23 (t, JH–P ¼ 17.24,
1H, CH–P); 31P NMR (D2O þ K2CO3) d 11.79; Anal. Calcd for C7H17
NO6P2 þ H2O: C, 28.87; H, 6.58; N, 4.81. Found: C, 28.54; H, 6.55; N, 4.45.
N-3-(N,N-Dimethylamino)propyl-aminomethylene-1,1-bisphosphonic
Acid (1d). Preparation procedure was the same as above to obtain a white
1
crystalline as dihydrate. H NMR (D2O ¼ K2CO3) 2.91 (s, 6H, 2CH3), 2.22
(m, 2H, CH2), 3.45 (m, 4H, CH2–N), 3.25 (t, JH–P ¼ 17.65 Hz, 1H, CH–P);
31P NMR (D2O þ K2CO3) d 9.97; Anal. Calcd for C6H20NO6P2 þ 2H2O:
C, 23.08; H, 7.10; N, 8.97. Found: C, 23.01; H, 7.23; N, 8.85.
N-Octyl-aminomethylene-1,1-bisphosphonic Acid (1e). Preparation
procedure was the same as above to obtain a white slice crystalline as mono-
1
hydrate. H NMR (D2O þ K2CO3) 0.754 (t, J ¼ 6 Hz, 3H, CH3), 1.16–1.62
(m, 12H, CH2), 3.22 (t, J ¼ 7.39 Hz, 3H, CH2–N), 2.99 (t, JH–P
¼
16.45 Hz,1H, CH–P); 31P NMR (D2O þ K2CO3) d 11.49; Anal. Calcd for
C9H23NO6P2 þ 2H2O: C, 31.86; H, 8.02; N, 4.13. Found: C, 31.76; H, 8.22;
N, 3.82.

ORDER
REPRINTS
Synthesis of Analogs of Aminomethylene gem-Diphosphonic Acid
1397
N,N-Dimethyl-aminomethylene-1,1-bisphosphonic Acid (1f). Crys-
tals were filtrated, washed with ethanol, recrystallized from water/ethanol
1
and dried at 1008C to afford a white crystalline as hydrochloride. H NMR
(D2O) d 2.97 (s, 6H, CH3), 3.53 (t, JH–P ¼ 19.49 Hz, 1H, CH–P); 31P NMR
(D2O) d 9.52; Anal. Calcd for C3H11NO6P2 þ HCl: C, 14.10; H, 4.70;
N, 5.48. Found: C, 13.83; H, 4.50; N, 5.48.
N,N-Dihydroxylethyl-aminomethylene-1,1-bisphosphonic Acid (1g). The
resulting reaction mixture was cooled to room temperature, and pH was adjusted
to 7–8 with aq. 20% NaOH. Appropriate ethanol was added to give a white crystal
which was purified by recrystallizing from ethanol/water to furnish 1g as
1
tetrasodium salt. H NMR (D2O) d 2.50–2.92 (m, 4H, CH2–N), 3.88–4.35
(m, 4H, HO–CH2), 3.56 (t, JH–P ¼ 19.45 Hz, 1H, CH–P); 31P NMR (D2O)
d 9.94; Anal. Calcd for C5H11NNa4O6P2: C, 17.92; H, 3.31; N, 4.18. Found:
C, 17.71; H, 3.40; N, 4.25.
N,N-Diethyl-aminomethylene-1,1-bisphosphonic Acid (1h). Crystals
were filtrated, washed with ethanol, recrystallized from water/ethanol and
dried at 1008C to afford a white crystalline. 1H NMR (D2O) d 1.17
(t, J ¼ 7.22 Hz, 6H, CH3), 3.45 (q, J ¼ 6.5 Hz, 4H, CH2), 3.63 (t, JH–P
¼
20.16 Hz, 1H, CH–P); 31P NMR (D2O) d 9.93; Anal. Calcd for
C5H15NO6P2: C, 24.30; H, 6.12; N, 5.67. Found: C, 24.62; H, 6.10; N, 6.00.
N,N-Dipropyl-aminomethylene-1,1-bisphosphonic Acid (1i). Prep-
aration procedure was the same as above to obtain a white crystalline.
1H NMR (D2O) d 0.688 (t, J ¼ 7.29 Hz, 6H, CH3), 1.50 (q, J ¼ 7.55 Hz,
4H, CH2), 3.36 (q, J ¼ 6.65 Hz, 4H, CH2–N), 3.53 (t, JH–P ¼ 20.44 Hz,
1H, CH–P); 31P NMR (D2O) d 9.69; Anal. Calcd for C7H19NO6P2:
C, 30.55; H, 6.96; N, 5.09. Found: C, 30.71; H, 6.94; N,5.24.
N,N-Dibutyl-aminomethylene-1,1-bisphosphonic Acid (1j). Prepara-
tion procedure was the same as above to obtain a white crystalline. 1H NMR
(D2O) d 0.835 (t, J ¼ 7.29 Hz, 6H, CH3), 1.25 (q, J ¼ 7.25 Hz, 4H, CH2), 1.59
(q, J ¼ 6.35 Hz, 4H, CH), 3.42 (br, 4H, CH2–N), 3.54 (t, JH–P ¼ 15.2 Hz, 1H,
CH–P); 31P NMR (D2O) d 9.37; Anal. Calcd for C9H23NO6P2: C, 35.65;
H, 7.65; N, 4.62. Found: C, 35.59; H, 7.55; N, 4.43.
REFERENCES
1. Rodan, G.A.; Martin, T.J. Therapeutic approaches to bone diseases.
Science 2000, 289, 1508–1514.
2. Szabo, C.M.; Martin, M.B.; Oldfield, E. An investigation of bone resorp-
tion and dictyostelium discoideum growth inhibition by bisphosphonate
drugs. J. Med. Chem. 2002, 45, 2894–2903.

ORDER
REPRINTS
1398
Wu, Chen, and Huang
3. Mundy, G.R. Bisphosphonates as anticancer drugs. Expert Opin. Invest.
Drugs 1999, 8 (12), 2009–2015.
4. Bamber, M.; Woodcoard, C. Preparation of Substituted Cycloalkylbisphos-
phonic Acids. EP 657462, Jun 14, 1995.
5. Gaffar, A.; Affihtlo, J.J.; Polefka, T.G.; Nabi, N.; Joziak, M.T. Oral
Compositions Containing Anticalculus and Antiplaque Agents. US
6214320, 2001.
6. Alferev, I.S.; Alferleva, L.P.; Glyadinskaya, S.A.; Kotlyarevskii, I.L.;
Krasnvkhina, A.V.; Mikhalin, N.V. Preparation of aminomethylenebis-
phosphonic acids and its N-substituted homologs. Izobreteniya. 1998, 5,
510.
7. Duesseldorf, H.B.; Meerbusch, S.H. Process for Synthesis of Azacyclo-
alkane-2,2-diphosphonic Acids. US 4876339, Oct 24, 1989.
8. Takeuchi, M.; Sakamoto, S.; Yoshida, M.; Abe, T.; Isomura, Y. Studies on
novel bone resorption inhibitors. Chem. Pharm. Bull. 1993, 41, 688–693.
9. Soloducho, J.; Gancar, R.; Wieczorek, P.; Korf, I.; Hafner, J.; Lefczak, B.;
Kafarshi, P. Preparation of Novel Derivatives of Aminomethylenebis-
phosphonic Acids as Herbicides. PL 172268, Aug 29, 1997; (Chem.
Abstr. 1998, 128, 61631).
Received in Japan October 20, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120030688