Synthesis of gem-bisphosphonates with (3-aryl-4,5-dihydroisoxazol-5-yl)methylamino moiety

Article abstract of DOI:10.1016/j.mencom.2015.05.027

Three-component reaction between N-allyl-N-methylamine, triethyl orthoformate and diethyl phosphite affords N-[bis(diethoxyphosphoryl)methyl]-N-methyl-3-arylprop-3-en-1-amine whose cycloaddition with nitrile N-oxides gives 5-{N-[bis(diethoxyphosphoryl)met

Full text of DOI:10.1016/j.mencom.2015.05.027

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 234–235
Synthesis of gem-bisphosphonates with
(3-aryl-4,5-dihydroisoxazol-5-yl)methylamino moiety
Valery K. Brel*a,b
a A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 6373; e-mail: v_brel@mail.ru
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation. Fax: +7 496 135 6373
DOI: 10.1016/j.mencom.2015.05.027
Three-component reaction between N-allyl-N-methylamine, triethyl orthoformate and diethyl phosphite affords N-[bis(diethoxyphos-
phoryl)methyl]-N-methyl-3-arylprop-3-en-1-aminewhosecycloadditionwithnitrileN-oxidesgives5-{N-[bis(diethoxyphosphoryl)-
methyl]-N-methylamino}methyl-4,5-dihydroisoxazoles.
Nitrogen-containing gem-bisphosphonates (N-BPs), stable to
hydrolysis analogues of pyrophosphates, represent an important
class of pharmacologically active compounds.1 Aminomethylene
1,1-bisphosphonates are powerful inhibitors of the enzyme
farnesyl pyrophosphate synthase, a key regulatory enzyme in
the mevalonate pathway,2 and are recognized as therapeutically
active molecules for treatment of several human pathologies, e.g.,
cancer.3 Due to their exceptional bone affinity, they can also be
used as drugs or prodrugs in the treatment of bone diseases, such as
osteoporosis, hypercalcaemia, and rheumatoid arthritis.4 Today
some synthetic routes to aminomethylene 1,1-bisphosphonates,
including reactions of nitriles with phosphorous acid or phos-
phites,5 synthesis from carboxylic acid amides,6 from imines and
related compounds,7 and three-component reaction involving an
amine, triethyl orthoformate and diethyl phosphite,8 are known.
In this work a strategy for the synthesis of compounds with
two pharmacophore sites: aminomethylene 1,1-bisphosphonate
fragment and 3-arylisoxazoline moiety is demonstrated. Disub-
stituted isoxazolines are frequently used in design of pharma-
ceutical agents and for syntheses of natural products.9 The use
of methodology of three-component reaction made it possible
to access aminomethylene 1,1-bisphosphonate with the allylic
group which on cycloaddition with nitrile N-oxides produced
dihydroisoxazole cycle (Scheme 1).
at 70°C under a nitrogen atmosphere in sealed glass ampoules
for 2 h. 31P NMR analysis of the reaction mixture revealed some
starting diethyl phosphite and product 1. Column chromato-
graphy afforded the desired compound 1 in 72% yield.†
To prepare nitrile N-oxides necessary for isoxazole con-
structing, a two-step procedure was used. At first an aldoxime was
chlorinated with N-chlorosuccinimide,10 and then the obtained
hydroximoyl chloride was dehydrochlorinated with triethyl-
amine11 (see Scheme 1). The [3+2] cycloaddition of the resultant
nitrile oxides to the double bond of 1 was performed in diethyl
ether at –40°C. In the optimized procedure, a solution of triethyl-
amine in diethyl ether was added dropwise for 2 h to the mixture
ofhydroximoylchlorideandolefin1giving4,5-dihydroisoxazoles
2a–d in yields of ca. 80%.‡ Diesters 2a–d can be easily trans-
formed into the corresponding acids by standard technique.12
In conclusion, complex polyfunctional compounds, gem-bis-
phosphonates with (3-aryl-4,5-dihydroisoxazol-5-yl)methylamino
†
N-[Bis(diethoxyphosphoryl)methyl]-N-methylprop-3-en-1-amine 1.
A mixture of N-allyl-N-methylamine (0.71 g, 0.01 mol), triethyl ortho-
formate (1.48 g, 0.01 mol) and diethyl phosphite (2.76 g, 0.02 mol) was
heated in a sealed glass ampoule at 70°C for 3 h. The crude product was
purified by column chromatography (column: l = 30 cm, d = 2 cm)
using gradient 0®3% MeOH in CHCl3 as an eluent. Evaporation of the
appropriate fractions afforded product 1 as viscous liquid, yield 72%.
1H NMR (400 MHz, CDCl3) d: 1.22 (t, 12H, 4POCH2Me, JHH 7.1 Hz), 2.49
(s, 3H, NMe), 3.31 (d, 2H, NCH2, JHH 6.2 Hz), 3.42 (t, 1H, CH[P(O)OEt]2,
JHP 25.1 Hz), 4.02–4.06 (m, 8H, 4POCH2), 5.02 (d, 1H, =CHH, JHH 10.0 Hz),
5.11 (d, 1H, =CHH, JHH 17.2 Hz), 5.66 (ddt, 1H, =CHCH2, JHH 10.0 Hz,
JHH 17.2 Hz, JHH 6.2 Hz). 13C NMR (100 MHz, CDCl3) d: 16.28–16.40
(m, 4POCH2Me), 40.50 (t, NMe, JPC 3.5 Hz), 58.12 (t, NCH, JPC 141.1 Hz),
59.65 (t, NCH2, JPC 5.2 Hz), 62.25 (d, OCH2Me, JPC 3.5 Hz), 62.29
(d, OCH2Me, JPC 6.6 Hz), 62.65 (d, OCH2Me, JPC 3.5 Hz), 62.68 (d,
OCH2Me, JPC 3.5 Hz), 118.07 (s, =CH2), 135.97 (s, =CH). 31P NMR
(162 MHz, CDCl3) d: 19.15. Found (%): C, 43.84; H, 8.23; N, 3.84;
P, 7.23. Calc. for C13H29NO6P2 (%): C, 43.70; H, 8.18; N, 3.92; P, 7.33.
For the synthesis of intermediate 1, the modified multicom-
ponent reaction8 was used by mixing stoichiometric amounts
of N-allyl-N-methylamine, triethyl orthoformate, and diethyl
phosphite. Unlike described procedure,8 the reactants were heated
HC(OEt)3
Me
N
O
+
P(OEt)2
(EtO)2P(O)H
70 °C, 2 h
O
P(OEt)2
+
NHMe
1
‡
Compounds 2a–d (general procedure). Compound 1 (0.35 g, 1 mmol)
N
O
Me
O
Et3N
1
was dissolved in Et2O (10 ml). Arylhydroximoyl chloride (1.5 mmol) in
Et2O (5 ml) was added at –40°C. Triethylamine (0.303 g, 3 mmol) was
then added dropwise over 2 h. Stirring was continued at –40°C until the
reaction was complete (TLC control, 2–3 h) and at room temperature for
2 h. The mixture was then quenched with sat. NH4Cl (10 ml), extracted
with Et2O, dried (Na2SO4), and concentrated. The residue was purified by
column chromatography (column: l = 30 cm, d = 2 cm) using gradient
0®7% MeOH in CHCl3 as an eluent. Evaporation of appropriate fractions
afforded the desired compounds as viscous oils.
ArC(Cl)=NOH
N
P(OEt)2
ArC
N
O
Ar
O
P(OEt)2
2a Ar = Ph
2b Ar = 4-MeC6H4
2c Ar = 4-FC6H4
2d Ar = 4-BrC6H4
Scheme 1
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 234 –

Mendeleev Commun., 2015, 25, 234–235
moiety, have been prepared in good yields by simple methods,
References
which may be useful for drug design and fine organic synthesis.
1 (a) V. D. Romanenko and V. P. Kukhar, Arkivoc, 2012, v, 127; (b) S. Zhang,
G. Gangal and H. Uludag˘, Chem. Soc. Rev., 2007, 36, 507.
2 (a) R. G. Russell, Ann. N. Y. Acad. Sci., 2006, 1068, 367; (b) F. H. M.
Ebetino, D. Francis, M. J. Rogers and R. G. G. Russell, Rev. Contemp.
Pharm., 1998, 9, 233; (c) S. H. Szajnman, G. E. G. Linares, Z.-H. Li,
C. Jiang, M. Galizzi, E. J. Bontempi, M. Ferella, S. N. J. Moreno,
R. Docampo and J. B. Rodriguez, Bioorg. Med. Chem., 2008, 16, 3283;
(d) V. Kunzmann, E. Bauer and M. N. Wilhelm, Engl. J. Med., 1999,
340, 737.
This work was supported by the Russian Foundation for Basic
Research (project no. 15-03-00663).
5-{N-[Bis(diethoxyphosphoryl)methyl]-N-methylamino}methyl-3-phenyl-
4,5-dihydroisoxazole 2a: viscous liquid, yield 80%. 1H NMR (400 MHz,
CDCl3) d: 1.31 (t, 6H, 2POCH2Me, JHH 7.2 Hz), 1.32 (t, 6H, 2POCH2Me,
JHH 7.2 Hz), 2.75 (s, 3H, NMe), 3.07–3.16 (m, 2H, CH2 cycle), 3.32 (d, 2H,
CH2N, JHH 9.2 Hz), 3.55 (t, 1H, CH[P(O)OEt]2, JHP 25.0 Hz), 4.13–4.25
(m, 8H, 4POCH2), 4.87 (ddt, 1H, CH=NO, JHH 3.9 Hz, JHH 5.3 Hz,
JHH 9.2 Hz), 7.37–7.39 (m, 3H, HAr), 7.64–7.65 (m, 2H, HAr). 13C NMR
(100 MHz, CDCl3) d: 16.39–16.51 (m, 4POCH2Me), 38.03 (s, CH2 cycle),
42.55 (br.s, NMe), 61.15 (br.s, NCH2), 61.18 (dd, NCH, JPC 143.6 Hz,
JPC 145.1 Hz), 62.53 (d, 2OCH2Me, JPC 6.6 Hz), 62.57 (d, OCH2Me,
JPC 6.6 Hz), 63.02 (d, OCH2Me, JPC 6.5 Hz), 81.03 (s, CH), 126.63 (s,
HCAr), 128.63 (s, HCAr), 129.70 (s, CAr), 129.95 (s, CAr), 156.80 (s, N=C).
31P NMR (162 MHz, CDCl3) d: 18.75 [d, 1P, P(O)OEt, JPP 58.5 Hz],
19.46 [d, 1P, P(O)OEt, JPP 58.5 Hz]. Found (%): C, 50.30; H, 7.07; N, 5.79;
P, 13.12. Calc. for C20H34N2O7P2 (%): C, 50.42; H, 7.19; N, 5.88; P, 13.00.
5-{N-[Bis(diethoxyphosphoryl)methyl]-N-methylamino}methyl-
3-(4-methylphenyl)-4,5-dihydroisoxazole 2b: viscous liquid, yield 82%.
1H NMR (400 MHz, CDCl3) d: 1.33 (t, 6H, 2POCH2Me, JHH 7.2 Hz),
1.34 (t, 6H, 2POCH2Me, JHH 7.0 Hz), 2.38 (s, 3H, Ar–Me), 2.77 (s, 3H,
NMe), 3.08–3.17 (m, 2H, CH2 cycle), 3.31 (dd, 2H, CH2N, JHH 10 Hz,
JHH 5.2 Hz), 3.58 (t, 1H, CH[P(O)OEt]2, JHP 25.2 Hz), 4.16–4.25 (m, 8H,
4POCH2), 4.83–4.91 (m, 1H, CH=NO), 7.20 (d, 2H, HAr, JHH 8.0 Hz),
7.56 (d, 2H, HAr, JHH 8.0 Hz). 13C NMR (100 MHz, CDCl3) d: 16.42–16.54
(m, 4POCH2Me), 21.44 (s, C6H4Me), 38.22 (s, CH2 cycle), 42.54 (br.s,
NMe), 59.71 (br.s, NCH2), 61.10 (dd, NCH, JPC 143.6 Hz, JPC 145.0 Hz),
62.56 (d, 2OCH2Me, JPC 6.6 Hz), 62.60 (d, OCH2Me, JPC 6.6 Hz), 63.07
(d, OCH2Me, JPC 6.5 Hz), 80.85 (s, CH), 126.59 (s, HCAr), 126.86
(s, CAr), 129.35 (s, HCAr), 140.19 (s, CAr), 156.77 (s, N=C). 31P NMR
(162 MHz, CDCl3) d: 18.75 [d, 1P, P(O)OEt, JPP 58.5 Hz], 19.46 [d, 1P,
P(O)OEt, JPP 58.5 Hz]. Found (%): C, 51.32; H, 7.51; N, 5.84; P, 12.50.
Calc. for C21H36N2O7P2 (%): C, 51.43; H, 7.40; N, 5.71; P, 12.63.
5-{N-[Bis(diethoxyphosphoryl)methyl]-N-methylamino}methyl-
3-(4-fluorophenyl)-4,5-dihydroisoxazole 2c: viscous liquid, yield 81%.
1H NMR (400 MHz, CDCl3) d: 1.30 (t, 6H, 2POCH2Me, JHH 7.0 Hz),
1.31 (t, 6H, 2POCH2Me, JHH 7.0 Hz), 2.70 (s, 3H, NMe), 3.08–3.16 (m,
2H, CH2 cycle), 3.30 (d, 2H, CH2N, JHH 9.2 Hz), 3.52 (t, 1H, CH[P(O)OEt]2,
JHP 25.0 Hz), 4.10–4.22 (m, 8H, 4POCH2), 4.82–4.90 (m, 1H, CH=NO),
7.04–7.08 (m, 2H, HAr), 7.62–7.65 (m, 2H, HAr). 13C NMR (100 MHz,
CDCl3) d: 16.38–16.49 (m, 4POCH2Me), 38.05 (s, CH2 cycle), 42.62 (br.s,
NMe), 59.42 (br.s, NCH2), 61.20 (dd, NCH, JPC 143.2 Hz, JPC 145.0 Hz),
62.53 (d, 2OCH2Me, JPC 6.4 Hz), 62.54 (d, OCH2Me, JPC 6.4 Hz), 62.98
(d, OCH2Me, JPC 6.5 Hz), 81.16 (s, CH), 115.74 (d, HCAr, JCF 21.9 Hz),
126.01 (d, CAr, JCF 3.0 Hz), 128.54 (d, HCAr, JCF 8.0 Hz), 155.85 (s,
C=N), 163.63 (d, CAr, JCF 248.6 Hz). 31P NMR (162 MHz, CDCl3) d:
18.74 [d, 1P, P(O)OEt, JPP 58.5 Hz], 19.46 [d, 1P, P(O)OEt, JPP 58.5 Hz].
Found (%): C, 48.65; H, 6.77; N, 5.84; P, 12.40. Calc. for C20H33FN2O7P2
(%): C, 48.58; H, 6.73; N, 5.67; P, 12.53.
3 (a) H. Fleisch, Breast Cancer Res., 2002, 4, 30; (b) X. Chen, X. Li,
J. Yuan, L. Qu, S. Wang, H. Shi, Y. Tang and L. Duan, Bioorg. Med.
Chem., 2011, 21, 6456.
4 H. Fleisch, Endocrine Rev., 1998, 19, 80.
5 T. M. Balashova and I. D. Kolpakova, in Metody polucheniya khimi-
cheskikh reaktivov i preparatov (Methods of Obtaining of Chemical
Reagents and Preparations), 1973, vol. 25, p. 11 (in Russian).
6 W. Plöger, N. Schindler, K. Wollmann and K. H. Worms, Z. Anorg. Allg.
Chem., 1972, 389, 119.
7 A. A. Prishchenko, M.V. Livantsov, O. P. Novikova and L. I. Livantsova,
Russ. J. Gen. Chem., 2009, 79, 1936 (Zh. Obshch. Khim., 2009, 79, 1580).
8 (a) L. Maier, Phosphorus Sulfur Silicon Relat. Elem., 1981, 11, 311;
(b) M. Mimura, M. Hayashida, K. Nomiyama, S. Ikegami, Y. Iida,
M. Tamura,Y. Hiyama andY. Ohishi, Chem. Pharm. Bull., 1993, 41, 1971.
9 V. Jager and P. A. Colinas, in The Chemistry of Heterocyclic Com-
pounds, eds. A. Padwa and W. H. Pearson, Wiley, New York, 2002,
vol. 59, pp. 361–472.
10 K.-Ch. Liu, B. R. Shelton and R. K. Howe, J. Org. Chem., 1980, 45, 3916.
11 T. Olsson, K. Stern and S. Sundell, J. Org. Chem., 1988, 53, 2468.
12 H. B. Lazrek, A. Rochdi, H. Khaider, J.-L. Barascut, J.-L. Imbach,
J. Balzarini, M. Witvrouw, C. Pannecouque and E. De Clercq, Tetrahedron,
1998, 54, 3807.
Received: 17th November 2014; Com. 14/4504
5-{N-[Bis(diethoxyphosphoryl)methyl]-N-methylamino}methyl-
3-(4-bromophenyl)-4,5-dihydroisoxazole 2d: viscous liquid, yield 80%.
1H NMR (400 MHz, CDCl3) d: 1.32 (t, 6H, 2POCH2Me, JHH 7.1 Hz),
1.34 (t, 6H, 2POCH2Me, JHH 7.0 Hz), 2.80 (s, 3H, NMe), 3.07–3.18 (m,
2H, CH2 cycle), 3.31 (dd, 2H, CH2N, JHH 10.2 Hz, JHH 5.2 Hz), 3.56 (t,
1H, CH[P(O)OEt]2, JHP 25.0 Hz), 4.16–4.25 (m, 8H, 4POCH2), 4.82–4.90
(m, 1H, CH=NO), 7.15 (d, 2H, HAr, JHH 8.0 Hz), 7.36 (d, 2H, HAr
,
JHH 8.0 Hz). 13C NMR (100 MHz, CDCl3) d: 16.35–16.43 (m, 4POCH2Me),
38.72 (s, CH2 cycle), 42.56 (br.s, NMe), 59.41 (br.s, NCH2), 61.16 (dd,
NCH, JPC 143.0 Hz, JPC 145.0 Hz), 62.56 (d, 2OCH2Me, JPC 6.6 Hz),
62.60 (d, OCH2Me, JPC 6.6 Hz), 63.07 (d, OCH2Me, JPC 6.5 Hz), 80.85
(s, CH), 125.69 (s, HCAr), 126.86 (s, CAr), 128.35 (s, HCAr), 147.4 (s, CAr),
156.73 (s, N=C). 31P NMR (162 MHz, CDCl3) d: 18.77 [d, 1P, P(O)OEt,
JPP 58.8 Hz], 19.43 [d, 1P, P(O)OEt, JPP 58.5 Hz]. Found (%): C, 52.85;
H, 7.25; N, 6.04; P, 13.52. Calc. for C20H33BrN2O7P2 (%): C, 52.76;
H, 7.30; N, 6.15; P, 13.60.
– 235 –