The preparation of N-substituted aminomethylidenebisphosphonates and their tetraalkyl esters via reaction of isonitriles with trialkyl phosphites and hydrogen chloride. Part 1

Article abstract of DOI:10.1016/j.tetlet.2012.07.085

The reaction of isonitriles with trialkyl phosphites in the presence of hydrogen chloride gives tetraalkyl N-substituted aminomethylidenebisphosphonates via N-methylideneaminium (isonitrilium) salts. Hydrolysis or dealkylation of these tetraalkyl esters gives N-substituted aminomethylidenebisphosphonic acids in high yields.

Full text of DOI:10.1016/j.tetlet.2012.07.085

Tetrahedron Letters 53 (2012) 5290–5292
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Tetrahedron Letters
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The preparation of N-substituted aminomethylidenebisphosphonates
and their tetraalkyl esters via reaction of isonitriles with trialkyl phosphites
and hydrogen chloride. Part 1
⇑
´
Waldemar Goldeman , Artur Kluczynski, Mirosław Soroka
_
´
Wrocław University of Technology, Department of Chemistry, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of isonitriles with trialkyl phosphites in the presence of hydrogen chloride gives tetraalkyl
N-substituted aminomethylidenebisphosphonates via N-methylideneaminium (isonitrilium) salts.
Hydrolysis or dealkylation of these tetraalkyl esters gives N-substituted aminomethylidenebisphosphonic
acids in high yields.
Received 9 May 2012
Revised 4 July 2012
Accepted 19 July 2012
Available online 27 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aminobisphosphonate
Bisphosphonate
Bisphosphonic acid
Aminomethylidenebisphosphonate
Aminomethylidenebisphosphonic acid
Isonitrile
Proton-assisted nucleophilic addition
Addition reactions
In 1974, Pudovik et al.1 described the preparation of tetraalkyl
phenylaminomethylidenebisphosphonates (PhNHCH[P(O)(OR)2]2)
by treating phenylisonitrile with dialkyl phosphonates in the pres-
ence of catalytic amounts of an alkali metal alkoxide. Later the
same authors published2 an extension of this reaction to substi-
tuted phenylisonitriles, and reported the preparation of tetraalkyl
arylaminomethylidenebisphosphonates in 58–75% yield. It is hard
to believe, but this potentially useful method for the preparation of
aminobisphosphonates was totally overlooked by the ‘bisphospho-
nate society’.3 Moreover, we found that this paper has only one
citation.4
Although on the list of so-called bisphosphonate drugs, there is
only one example of an aminobisphosphonate, which possesses an
N–C(PO3H2)2 moiety, namely cycloheptylaminomethylidenebis-
phosphonic acid (incadronic acid, Astellas Pharma, formerly Yama-
nouchi Pharma). Many groups have published papers concerning
the synthesis and biological activity of N-substituted amin-
omethylidenebisphosphonates.5 These compounds were prepared
by the reaction of amines with trialkyl orthoformates and dialkyl
phosphonates. It is interesting that this reaction was well known
to chemists long before Suzuki et al. claimed it in many patents is-
sued to Nissan Chemical Ind. (the first examples in 1978 and
1979),6 and then by Takeuchi and co-workers as claimed in many
patents issued to Yamanouchi Pharmaceutical (the first in 1988),7a
and finally published in 1993.7b We (M.S.) knew this procedure
from personal discussions with Hans Gross.
In continuation of our research on the reaction of trialkyl phos-
phites with onium salts,8 we turned our attention to isonitrilium
salts which could be generated from isonitriles. According to pub-
lished data,9 isonitriles are C-bases with high affinity for protons,
therefore they should be easily converted into the corresponding
N-methylideneaminium (isonitrilium) salts using hydrogen chlo-
ride, for example. Next, the isonitrilium salt should react with a
Cl
H-Cl
Cl
(AlkO)3P
O
R
N+
C
R
N+
H
OAlk
R
N
R
N
- Alk-Cl
P+ OAlk
OAlk
P
⇑
H
H
OAlk
Corresponding author. Tel.: +48 71 320 2422; fax: +48 71 320 2427.
E-mail addresses: waldemar.goldeman@pwr.wroc.pl (W. Goldeman), miroslaw.
OAlk
soroka@pwr.wroc.pl (M. Soroka).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.085

W. Goldeman et al. / Tetrahedron Letters 53 (2012) 5290–5292
5291
H
References and notes
R
N
R
N+
O
P
O
P
H-Cl
(AlkO)3P
1. Pudovik, A. N.; Nikitina, V. I.; Zimin, M. G.; Vostretsova, N. L. SU445675, 1974;
Chem. Abstr. 1975, 82, 73171.
2. Pudovik, A. N.; Nikitina, V. I.; Zimin, M. G.; Vostretsova, N. L. Zh. Obshch. Khim.
1975, 45, 1450–1455; Chem. Abstr. 1975, 83, 179217.
OAlk
OAlk
OAlk
OAlk
Cl
3. Contrary to the very long history of hydroxyalkylidenebisphosphonates,13 that
of aminoalkylidenebisphosphonates is rather short. The first syntheses of N-
unsubstituted aminobisphosphonates via the reaction of nitriles with
phosphorus trihalides, were described by Lerch and Kottler14 in 1957. About
ten years later, the same chemistry was applied for the synthesis of
aminobisphosphonates as ‘complex formers’ by Blaser, Germscheid, and
Worms.15 In 1959, Kreutzkamp and Cordes16 described the first examples of
N-substituted aminobisphosphonates from the reaction of PhC(Cl) = NPh with
P(OEt)3, and then with HP(O)(OEt)2. Later, many preparations of
H
H
- Alk-Cl
N
P(O)(OAlk)2
N
P(O)(OAlk)2
OAlk
R
R
AlkO P+ OAlk
O
P
OAlk
Cl
OAlk
Scheme 2.
aminobisphosphonates were described by Gross and Costisella (first paper17
starting from dialkylformamide acetals and dialkyl phosphonates, or the so-
called ‘ -substituted phosphonates’, mainly formylphosphonate derivatives.
)
a
Searching Chemical Abstracts we found as many as 3439 structures and more
than 1600 references to them. Most of the early development in this area was
done by chemists from companies including: Dr. Karl Thomae, Therachemie,
Henkel, Albright & Wilson, Procter & Gamble, Joh A. Benckiser, Benckiser-
Knapsack, Nissan Chemical Ind., and Yamanouchi Pharmaceutical.
It is worth noting that many applications of aminobisphosphonates were
described even earlier than their syntheses. For example, in 1965 Berth and
Reese18 patented ‘derivatives for protecting of hair’, and Smith and Dixon19
patented ‘stabilization of phosphate salts’. The first pharmaceutical application
of aminobisphosphonate was reported in 1968 by Francis,20 who patented a
‘composition for inhibiting anomalous deposition and mobilization of calcium
phosphate in human tissue’.
nucleophilic trialkyl phosphite to give the intermediate phospho-
nium salt, which should spontaneously transform into the
corresponding dialkyl N-substituted iminomethylidenephospho-
nate (Scheme 1).
The dialkyl N-substituted iminoalkylidenephosphonate is obvi-
ously a stronger base than the starting isonitrile, therefore it
should react instantly with another molecule of hydrogen chloride
to give the corresponding iminium salt—a very strong electrophile.
This should react with a second molecule of the trialkyl phosphite
to give another intermediate phosphonium salt, which, as we de-
scribed earlier,8 should be spontaneously transformed, as in the
last step in the Arbuzov reaction, to give the final tetraalkyl
N-substituted aminomethylidenebisphosphonate (Scheme 2).
Indeed, when we examined the reaction of butylisonitrile with
triethyl phosphite in the presence of greater than stoichiometric
amounts of hydrogen chloride in an aprotic solvent (CH2Cl2, e.g.),
at a temperature below À10 °C (to prevent dealkylation of the
starting triethyl phosphite), we found, by means of 31P NMR spec-
troscopy, that the crude reaction mixture contained as much as
88% of tetraethyl butylaminomethylidenebisphosphonate, traces
of unreacted triethyl phosphite, and about 10% of diethyl phospho-
nate. The crude tetraethyl butylaminomethylidenebisphosphonate
was hydrolyzed by refluxing with 6 M HCl in water to give buty-
laminomethylidenebisphosphonic acid in 61% yield, based on the
starting isonitrile. Similar results were obtained when other isoni-
triles were employed, for example: 2-methylpropylisonitrile gave a
77% yield of the corresponding aminobisphosphonic acid, pentyl-
isonitrile—86%, 3-methylpentylisonitrile—98%, benzylisonitrile—
95%, and cyclohexylisonitrile—82%. The tetraethyl ester obtained
from t-butylisonitrile gave after hydrolysis, only aminomethylid-
enebisphosphonic acid in 91% yield. Thus it was dealkylated using
a known procedure10 with bromotrimethylsilane to give t-buty-
laminomethylidenebisphosphonic acid in 76% yield. Also tetraethyl
phenylaminomethylidenebisphosphonate (obtained from phenyl-
isonitrile) was dealkylated using the same procedure, and gave
phenylaminomethylidenebisphosphonic acid in 99% yield.11
In summary, the protocol described in this Letter represents a
very efficient method for the preparation12 of tetraalkyl esters of
N-substituted aminomethylidenebisphosphonic acids as well as
N-substituted aminomethylidenebisphosphonic acids. Moreover,
it offers enormous opportunity to link an aminomethylidene-
bisphosphonate moiety to a broad spectrum of other compounds.
By applying this sequence of reactions, we have prepared a very
large collection—hundreds of N-substituted derivatives of amin-
omethylidenebisphosphonates—starting from easily available
isonitriles. We will publish these results soon.
4. Hirai, T.; Han, L.-B. J. Am. Chem. Soc. 2006, 128, 7422–7423.
5. For recent examples see: (a) Hudock, M. P.; Sanz-Rodrıguez, C. E.; Song, Y.;
Chan, J. M. W.; Zhang, Y.; Odeh, S.; Kosztowski, T.; Leon-Rossell, A.; Concepción,
J. L.; Yardley, V.; Croft, S. L.; Urbina, J. A.; Oldfield, E. J. Med. Chem. 2006, 49,
215–223; (b) Ghosh, S.; Chan, J. M. W.; Lea, C. R.; Meints, G. A.; Lewis, J. C.;
Tovian, Z. S.; Flessner, R. M.; Loftus, T. C.; Bruchhaus, I.; Kendrick, H.; Croft, S. L.;
Kemp, R. G.; Kobayashi, S.; Nozaki, T.; Oldfield, E. J. Med. Chem. 2004, 47, 175–
187; (c) Widler, L.; Jaeggi, K. A.; Glatt, M.; Müller, K.; Bachmann, R.; Bisping, M.;
Born, A.-R.; Cortesi, R.; Guiglia, G.; Jeker, H.; Klein, R.; Ramseier, U.; Schmid, J.;
Schreiber, G.; Seltenmeyer, Y.; Green, J. R. J. Med. Chem. 2002, 45, 3721–3738;
(d) Roth, A. G.; Drescher, D.; Yang, Y.; Redmer, S.; Uhlig, S.; Arenz, C. Angew.
Chem., Int. Ed. 2009, 48, 7560–7563; (e) Occhipinti, A.; Berlicki, Ł.; Giberti, S.;
Dziedzioła, G.; Kafarski, P.; Forlani, G. Pest Manag. Sci. 2010, 66, 51–58; (f)
Forlani, G.; Occhipinti, A.; Berlicki, Ł.; Dziedzioła, G.; Wieczorek, A.; Kafarski, P.
J. Agric. Food Chem. 2008, 56, 3193–3199; (g) Lin, Y.-S.; Park, J.; De Schutter, J.
W.; Huang, X. F.; Berghuis, A. M.; Sebag, M.; Tsantrizos, Y. S. J. Med. Chem. 2012,
55, 3201–3215.
6. (a) Suzuki, F.; Yamamoto, S.; Kasai, Y.; Oya, T.; Ikai, T. JP 53066431, 1978; Chem.
Abstr. 1978, 89, 158771; (b) Suzuki, F.; Fujikawa, Y.; Yamamoto, S.; Mizutani,
H.; Funabashi, C. Ohya, T.; Ikai, T.; Oguchi T. DE 2831578, 1979; Chem. Abstr.
1979, 90, 187124; (c) Suzuki, F.; Fujikawa, Y.; Yamamoto, S.; Mizutani, H.;
Iwasawa, Y. JP 54135724, 1979; Chem. Abstr. 1980, 92, 146905.
7. (a) Sakamoto, S.; Takeuchi, M.; Isomura, Y.; Niigata, K.; Abe, T.; Kawamuki, K.;
Kudo, M. EP 282320, 1988; Chem. Abstr. 1989, 110, 128650; (b) Takeuchi, M.;
Sakamoto, S.; Yoshida, M.; Abe, T.; Isomura, Y. Chem. Pharm. Bull. 1993, 41, 688–
693.
8. (a) Goldeman, W.; Soroka, M. Synthesis 2010, 2437–2445; (b) Goldeman, W.;
Soroka, M. Synthesis 2006, 3019–3024.
9. (a) Meot-Ner (Mautner), M.; Karpas, Z.; Deakyne, C. A. J. Am. Chem. Soc. 1986,
108, 3913–3919; (b) Meot-Ner (Mautner), M.; Sieck, L. W.; Koretke, K. K.;
Deakyne, C. A. J. Am. Chem. Soc. 1997, 119, 10430–10438; (c) Meot-Ner
(Mautner), M.; Karpas, Z. J. Phys. Chem. 1986, 90, 2206–2210; (d) Legon, A. C.;
Lister, D. G.; Warner, H. E. J. Am. Chem. Soc. 1992, 114, 8177–8180.
10. (a) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M. C. Tetrahedron Lett.
1977, 155–158; (b) Boduszek, B. Tetrahedron 1996, 52, 12483–12494.
11. This chemistry was previously described in part in two Polish patents: (a)
´
Soroka, M.; Goldeman, W.; Kluczynski, A. Polish Patent PL208806, 2011; Chem.
Abstr. 2011, 155, 241101; (b) Soroka, M.; Goldeman, W.; Kluczyn´ ski, A. Polish
Patent PL208807, 2011; Chem. Abstr. 2011, 155, 271405. However, both patents
are printed in Polish, and therefore without the literature background, we
would like to publish this excellent method for the synthesis of
aminomethylidenebisphosphonic acids, especially the tetraalkyl esters.
12. General procedure: To a cold (ca. À10 °C, ice/NaCl stirred bath) solution of
isonitrile (0.050 mol) and trialkyl phosphite (0.10 mol) in CH2Cl2 (100 mL) was
added dropwise a cold (ca. À10 °C) solution of ꢀ4 M HCl (0.15 mol in 1,4-
dioxane, 38 ml). The mixture was stirred for about 1 h at the same temperature
(the ice-NaCl bath must also be stirred). Further CH2Cl2 (100 mL) was added,
and the reaction washed with cold (ꢀ0 °C) saturated NaHCO3 solution
(5 Â 100 mL), dried (anhydrous Na2SO4), and evaporated under vacuum to
give the dialkyl N-substituted aminomethylidenebisphosphonate, which was
practically pure for most applications.
Acknowledgement
For the preparation of N-substituted aminomethylidenebisphosphonic acids,
the mixture from the above reaction was evaporated under vacuum, and the
residue was refluxed with HCl in H2O (6 M, 300 mL) for about 8 h. The
Financial support of our research by the National Science Centre
is appreciated (grant N204 122240).
hydrolysate was evaporated under vacuum using
a water bath (final

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W. Goldeman et al. / Tetrahedron Letters 53 (2012) 5290–5292
temperature ꢀ100 °C), the residue dissolved in H2O (100 mL), and the solution
1388, 1352, 1216, 1196 (P = O), 1132, 1049 (P-O), 1030 (P-O), 965, 929, 913,
810, 780, 738, 704, 575, 524, 512, 463, 430 cmÀ1
13. Menschutkin, N. Liebigs Ann. Chem. 1865, 133, 317–320.
evaporated again. This procedure (dissolution/evaporation) was repeated
3–5 times to give the final crystalline N-substituted aminomethyliden-
ebisphosphonic acid, which could be recrystallized from boiling H2O, if
.
14. Lerch, I.; Kottler, A. DE 1002355, 1957; Chem. Abstr. 1959, 53, 121856.
15. Blaser, B.; Germscheid, H. G.; Worms, K. H. NL 3303139, 1967; Chem. Abstr.
1967, 66, 96503.
16. Kreutzkamp, N.; Cordes, G. Justus Liebigs Ann. Chem. 1959, 623, 103–108.
17. Gross, H.; Costisella, B. Angew. Chem., Int. Ed. Engl. 1968, 7, 391–392.
18. Berth, P.; Reese, G. US 3202579, 1965; Chem. Abstr. 1965, 63, 23382.
19. Smith, R. A.; Dixon, J. T. GB 1143123, 1969; Chem. Abstr. 1969, 70, 90779.
20. Francis M.D. DE 1813659, 1969; Chem. Abstr. 1969, 71, 89977.
necessary.
Spectroscopic
data
for
representative
example:
n-
butylaminomethylidenebisphosphonic acid: white solid; 31P NMR {1H}
(D2O + NaOD, 121 MHz): d 16.48 (s), 1H NMR (D2O + NaOD, 300 MHz): d 0.70
(t, J = 7.3 Hz, 3H, CH3), 1.14 (sextet, J = 7.3 Hz, 2H, CH2CH3), 1.31 (quin,
J = 7.3 Hz, 2H, CH2CH2CH3), 2.50 (t, J = 17.3 Hz, 1H, CHP), 2.75 (t, J = 7.3 Hz,
2H, NCH2); 13C NMR (D2O + NaOD, 75 MHz): d 13.49 (s, CH3), 19.86 (s, CH2CH3),
31.61 (s, NCH2CH2), 50.82 (t, J = 5.6 Hz, NCH2), 59.52 (t, J = 129.5 Hz, CH); IR
(KBr): 3207, 3070, 2963, 2934, 2876, 2791, 2257, 1652, 1589, 1566, 1467, 1428,