A facile synthesis of aminomethylene bisphosphonates through rhodium carbenoid mediated N-H insertion reaction. Application to the preparation of powerful uranyl ligands

Article abstract of DOI:10.1016/j.tetlet.2008.01.127

A straightforward procedure ensuring the anchoring of bisphosphonate moiety onto aromatic amines is described. The procedure yields aminoaryl 1,1-bisphosphonates known to display multiple biological activities. The described methodology has also been applied to the synthesis of ligands whose uranyl-binding properties have been studied.

Full text of DOI:10.1016/j.tetlet.2008.01.127

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2083–2087
A facile synthesis of aminomethylene bisphosphonates through
rhodium carbenoid mediated N–H insertion reaction.
Application to the preparation of powerful uranyl ligands
*
´
´ ´
Delphine Lecercle, Sandra Gabillet, Jean-Marie Gomis, Frederic Taran
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette F-91191, France
Received 18 December 2007; revised 23 January 2008; accepted 30 January 2008
Available online 2 February 2008
Abstract
A straightforward procedure ensuring the anchoring of bisphosphonate moiety onto aromatic amines is described. The procedure
yields aminoaryl 1,1-bisphosphonates known to display multiple biological activities. The described methodology has also been applied
to the synthesis of ligands whose uranyl-binding properties have been studied.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Carbenoids; Insertions; Rhodium; Bisphosphonates; Uranyl
Aminomethylene 1,1-bisphosphonates are known to dis-
play important biological activities. They are powerful
inhibitors of the enzyme farnesyl pyrophosphate synthase
(FPPS), a key regulatory enzyme in the mevalonate path-
way. The blockade of this pathway is a concept that has
found widespread clinical use; bisphosphonate drugs thus
display therapeutic properties for several human patho-
logies such as osteoporosis,1 rheumatoid arthritis,2 and
cancer.3 In addition, aminomethylene bisphosphonates
have interesting activities against many parasites including
trypanosamid parasites.4
The structure of the side chain connected through the N-
atom to the geminal carbon has a huge influence on the
biological activities. Scheme 1 shows examples of impor-
tant aminomethylene bisphosphonate drugs with aromatic
(NE-97220) or aliphatic (incadronate, YM-175) side
chains.
O
P
O
P
H
H
OH
OH
OH
OH
N
N
N
OH
OH
OH
OH
P
P
O
O
NE-97220
YM-175
Scheme 1. Examples of aminomethylene bisphosphonates used clinically.
with ethylorthoformate and phosphites,6 bisphosphoryl-
ation of formamides,7 Beckman rearrangement of oximes
in the presence of phosphites,8 and reductive amination
of carbonyl derivatives with aminomethyldiphosphonate.9
In connection with our efforts to develop new synthetic
routes to bisphosphonates,10 we recently developed a
Cu-carbenoid O–H insertion reaction that allows an easy
anchoring of the bisphosphonate moiety into alcohols
and phenols.11 In the present Letter, we describe the corre-
sponding reaction with amine substrates as a new method
for aminomethylene bisphosphonate preparation.
Classical synthetic routes to aminomethylene bisphos-
phonates involve acid catalyzed reactions of nitriles with
phosphorous acid or phosphites,5 condensation of amines
The use of in situ generated metallacarbenoid species for
the transfer of a carbene moiety from a diazo source to
organic substrates has a long history of successful appli-
cations in organic synthesis.12 Although N–H insertion
*
Corresponding author. Tel.: +33 (1)69082685; fax: +33 (1)69087991.
E-mail address: frederic.taran@cea.fr (F. Taran).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.127

2084
D. Lecercle´ et al. / Tetrahedron Letters 49 (2008) 2083–2087
Table 2
reactions of metal carbenoid intermediates have been
widely explored (especially the intramolecular version),13
no reaction was described with tetraethyl diphosphonodi-
azomethane 1 probably due to the very low reactivity of
this particular diazo compound.14
We first investigated the reaction of aniline, used as a
model substrate, with 1 in the presence of a series of puta-
tive catalysts. Reactions were conducted under refluxed
toluene (Table 1).
Contrary to our previous finding showing a superior
activity of copper over rhodium complexes for the O–H
insertion reaction involving 1,11 Rh2(NHCOCF3)4 was
found to be the best catalyst for the reaction of 1 with
aniline affording almost quantitative yield of the expected
aminomethylene bisphosphonate 2a with a loading of only
1% mol (Table 1, entry 2). This dirhodium complex was
first identified by Moody and co-workers as an interesting
catalyst for O–H insertion reactions involving a-diazo
phosphonate compounds.15
Scope of the N–H insertion reaction involving aromatic aminesa
Rh2(NHCOCF3)4 (1% mol)
O
EtO
EtO
O
P
O
P
P
O
OEt
OEt
toluene, Δ - 12 h
EtO
EtO
P OEt
OEt
Ar
N
R
Ar NH
R
(1.1 equiv)
N2
2a-e
1
Entry
1
Ar
R
H
Product
Isolated yield (%)
80
2a
2b
2
3
4
H
87
78
76
66
MeO
O2N
H
2c
2d
2e
H
We therefore looked at the scope of this reaction by
applying the procedure to a variety of aromatic amines
(Table 2).
5
Me
a
Reactions were conducted with 1.1 equiv of PhNH2 and 1 equiv of 1.
The reaction worked successfully on several aniline
derivatives bearing either electronwithdrawing or donating
groups (Table 2, entries 1–4) and was also efficient on sec-
ondary aromatic amine (Table 2, entry 5) affording the
desired aminobisphosphonates in good yields. However,
despite our efforts, all attempts trying to apply this method
on aliphatic amines were unsuccessful. These nucleophilic
amines are known to coordinate to the metal13g and to a
certain extent poison the catalyst.16
Besides their biological importance, bisphosphonates
are also known for their ability to strongly chelate metals.
Dipodal and tripodal ligands bearing bisphosphonates
moieties are particularly interesting for uranyl sequestra-
tion.17 Encouraged by the efficiency of the above-described
methodology, we investigated the use of this new insertion
reaction for the construction of dipodal bisphosphonate
ligands by using diamines as starting materials (Table 3).
Deprotection of the bisphosphonate moieties was easily
carried out by conventional treatment with TMSBr.18
Ligands 3a–d were obtained in moderate yields through
double N–H insertion of aromatic diamines. The deprotec-
tion step of the corresponding dipodal bisphosphonates
occurred quantitatively and the final products were recov-
ered by precipitation with Et2O.
We then investigated the uranyl-binding properties of
these ligands by employing a colorimetric method that we
previously described.17 This method is based on competi-
tive uranium binding using Sulfochlorophenol S (SCP) as
Table 1
Optimization of the insertion reaction involving diazo compound 1 and anilinea
O
EtO
EtO
P
O
P OEt
NH OEt
O
P
O
P
OEt
OEt
MnLm
EtO
EtO
NH2
+
toluene, Δ, 3 h.
N2
2a
1
Entry
MnLm (% mol)
Yield of 2ab (%)
1
2
3
4
5
6
7
8
a
Rh2(NHCOCF3)4 (3%)
Rh2(NHCOCF3)4 (1%)
Rh2(OCOCH3)4 (1%)
ScOTf (1%)
Yb(OTf)3 (1%)
AgOTf (1%)
99
97
2
1
n.d.
4
Cu(OTf)2 (1%)
[Ru(pcym)Cl2]2 (1%)
72
36
Reactions were conducted with 1.1 equiv of PhNH2 and 1 equiv of 1.
b
31P NMR yields.

D. Lecercle´ et al. / Tetrahedron Letters 49 (2008) 2083–2087
2085
Table 3
Preparation of bis-aminomethylene bisphosphonates through double insertion reaction of 1 on diamines
HO
O
OH
OH
O
HO
P
P
HO
HO
OH
OH
1) 1 (4 equiv)
Rh2(NHCOCF3)4 (2% mol)
P
O
NH2
NH2
P
O
NH
HN
toluene, Δ - 12 h
spacer
spacer
2) TMSBr, CH3CN
3
Entry
Spacer
(o) –O–
Product
Global isolated yield (%)
1
2
3a
3b
49
48
(o) –CH2–CH2–
O
O
3
4
3c
3d
50
47
(p)
(p)
chromophoric reference chelate. In aqueous solution, this
dye compound displays a violet color whereas the SCP/
UO2 complex is blue. The conditional association con-
stants (Kcond) of the bisphosphonate ligands 3a–d toward
UO2 were therefore easily determined by following the
disappearance of the preformed SCP/UO2 at biologically
relevant pH values (pH 5.5, 7.4, and 9). The results (Table
4) indicate the strong uranyl binding properties of these
ligands with Kcond up to ꢀ1017 at pH 7.4.
As expected, higher association constants were observed
with ligands constructed with a spacer of sufficient size
separating the bisphosphonate chelating functions (com-
pare entries 2–4 with entry 1, Table 4). A decrease of the
uranyl binding properties of ligands 3a–d was also
2þ
Table 4
UO22þ-binding properties of ligands 3
HO
HO
OH
OH
OH
OH
O
U
O
O
O
O
O
O
O
P
P
P
P
P
P
O
O
HO
HO
OH
OH
P
O
P
NH
HN
HN
NH
OH
HO
O
O
O
K
2+
+
UO2
spacer
spacer
3
Entry
3
Kcond
pH 5.5
1012.8
pH 7.4
pH 9
1017.6
HO
HO
OH
OH
O
O
P
P
1015.6
HO
HO
OH
OH
1
P
NH
HN
P
O
O
O
3a
HO
P
OH
OH
O
O
HO
HO
HO
P
OH
OH
2
1012.7
1016.8
1018.8
HN
P
P
NH
O
O
3b
(continued on next page)

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D. Lecercle´ et al. / Tetrahedron Letters 49 (2008) 2083–2087
Table 4 (continued)
Entry
3
Kcond
pH 5.5
pH 7.4
pH 9
HO
HO
OH
O
O
P
P
OH
OH
OH
HO
HO
P
NH
HN
P
3
1015
1016.7
1017.6
O
O
O
O
3c
HO
OH
OH
O
O
HO
HO
HO
P
P
OH
OH
P
NH
HN
P
O
O
4
1015
1016.7
1017.8
3d
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explained by the protonation of the amine function result-
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In conclusion, we have developed a simple and practical
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phosphonate moiety onto aromatic amine starting materi-
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procedure is complementary to known protocols and, in
regard to its simplicity and efficiency, is of particular inter-
est for the straightforward synthesis of aromatic amin-
obisphosphonate products.
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Acknowledgments
This work was supported by a program of interdisciplin-
ary research called ‘Nuclear and Environmental Toxi-
cology, Tox-Nuc-E’ initiated by the CEA. We also thank
E. Zekri and D. Buisson for experimental assistance with
MS and LC/MS measurements.
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1
Selected data: Compound 2b: H NMR (400 MHz, DMSO) (d ppm):
1.11 (t, J = 7.2 Hz, 6H); 1.17 (t, J = 7.2 Hz, 6H); 3.62 (s, 3H); 3.94–
2
3
4.09 (m, 8H); 4.39 (dt, JH–P = 22.8 Hz; JNH–H = 10.8 Hz, 1H); 5.24
(dt, 3JNH–P = 3 Hz; 3JNH–H = 10.8 Hz, NH); 6.68 (d, J = 8.8 Hz, 2H);
6.81 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) (d ppm):
16.24–16.38 (m); 51.72 (t, J = 147 Hz); 55.59 (OMe); 63.15 (d,
J = 3.5 Hz); 63.18 (d, J = 3.5 Hz); 63.62 (d, J = 3.5 Hz); 63.65 (d,
J = 3.5 Hz); 114.64; 115.28; 140.37; 153.06. 31P NMR (160 MHz,
CDCl3) (d ppm): 17.99 (s, 2P). IR (NaCl): m 3491; 2984; 1514; 1243;
1026; 974 cmꢁ1. MS (ESI/TOF) m/z: 432 (100%, [M+23]+). HRMS:
Calcd for C16H29NO7NaP2: 432.1317 m/z. Found: 432.1331 m/z.
Compound 3a: This ligand was prepared according to the above-
described procedure using 4 equiv of 1. After purification by flash
chromatography, the tetraethyl esters were deprotected by treatment
with TMSBr (12 equiv) in 10 mL CH3CN. The mixture was heated
under reflux for 3 h, then quenched with 1 mL of water. After
refluxing for additional 15 min, the solvents were evaporated and co-
evaporated with MeOH. Resulting residues were dissolved in a
minimum of MeOH and precipitated with ether. The resulting slurry
was decanted, washed with ether and dried under high vacuum in the
presence of P2O5. 1H NMR (400 MHz, MeOD) (d ppm): 4.31 (t,
JH–P = 21.6 Hz, 2H); 6.74 (t, J = 7.2 Hz, 2H); 6.86 (d, J = 7.2 Hz,
2H); 6.99–7.08 (m, 4H). 13C NMR (100 MHz, MeOD) (d ppm): 50.68
(t,J = 144 Hz); 112.86; 116.99; 117.99; 126.09; 137.83; 143.85. 31P
NMR (160 MHz, MeOD) (d ppm): 16.20 (s, 4P). MS (ESI/TOF) m/z:
549 (100%, [M+1]+).
18. McConnell, R. L.; Coover, H. W. J. Am. Chem. Soc. 1956, 78, 4450–
4452.
19. Typical procedure for aminoaryl 1,1-bisphosphonates preparation: To a
solution of aromatic amine (0.35 mmol, 1.1 equiv) and
Rh2(NHCOCF3)4 (2 mg, 3.18 lmols) in 3 mL of dry toluene was