N-Allyl-substituted aminomethylene-1,1-bisphosphonates in 1,3-dipolar cycloaddition reaction with aromatic nitrile N-oxides

Article abstract of DOI:10.1007/s11172-017-1881-x

A reaction of N-allyl-substituted aminomethylene-1,1-bisphosphonates with aromatic nitrile N-oxides was used to obtain new aminomethylenebisphosphonates with one or two 3-arylisoxazoline rings at the nitrogen atom. NMR spectroscopy studies showed that the

Full text of DOI:10.1007/s11172-017-1881-x

1
256
Russian Chemical Bulletin, International Edition, Vol. 66, No. 7, pp. 1256—1260, July, 2017
NꢀAllylꢀsubstituted aminomethyleneꢀ1,1ꢀbisphosphonates
in 1,3ꢀdipolar cycloaddition reaction with aromatic nitrile Nꢀoxides
O. V. Bykhovskaya, I. M. Aladzheva, and V. K. Brel
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
2
8 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: shipov@ineos.ac.ru
A reaction of Nꢀallylꢀsubstituted aminomethyleneꢀ1,1ꢀbisphosphonates with aromatic
nitrile Nꢀoxides was used to obtain new aminomethylenebisphosphonates with one or two
3
ꢀarylisoxazoline rings at the nitrogen atom. NMR spectroscopy studies showed that the bisꢀ
phosphonates with two isoxazoline fragments in the molecule exist in solution as a mixture of
two diastereomers.
Key words: Nꢀallylꢀsubstituted aminomethyleneꢀ1,1ꢀbisphosphonates, 1,3ꢀdipolar cycloꢀ
addition, 3ꢀarylisoxazolines, diastereomers.
Bisphosphonates with a geminal arrangement of phosꢀ
aminomethylenebisphosphonates broadens their synthetic
scope and allows one to design, in particular, new heteroꢀ
cyclic systems, using bisphosphonates as dipolarophiles.
The present work is devoted to the synthesis of Nꢀallylꢀ
substituted aminomethyleneꢀ1,1ꢀbisphosphonates and
their application in the 1,3ꢀdipolar cycloaddition reacꢀ
tion with aromatic nitrile Nꢀoxides, which allows one to
phonate groups are a class of organophosphorus comꢀ
pounds, which has been lately actively investigated.1
Among the different types of bisphosphonates, the most
interesting are nitrogenꢀcontaining bisphosphonates,
compounds possessing a wide spectrum of pharmacologꢀ
ical activity.3 It is known that 1ꢀaminomethyleneꢀ1,1ꢀ
bisphosphonates are potent inhibitors of enzymatic sysꢀ
,2
,4
introduce an isoxazoline ring in the molecule of bisphosꢀ
5
—7
17—19
tems and are used as anticancer drugs.
Apart from
phonate. As it is known,
substituted isoxazolines
that, due to the high affinity for bone tissue, bisphosphoꢀ
nates are widely used for the prevention and treatment of
osteoporosis and arthritis.
possess biological activity. The modification of bisphosꢀ
phonates with such fragment will undoubtedly broaden
the range of their use.
8
,9
There are various synthetic approaches to the prepaꢀ
ration of nitrogenꢀcontaining 1,1ꢀbisphosphonates, in
particular, reactions of nitriles with phosphites or phosꢀ
phorus acids,10 synthesis from amides, imines, and reꢀ
lated compounds.12 There is a widely used method based
on a threeꢀcomponent reaction of secondary amines with
Results and Discussion
11
Earlier,20 we have shown that the use of Nꢀmethylꢀ
allylamine as an amine component in the threeꢀcompoꢀ
nent reaction leads to the obtaining of aminomethyleneꢀ
bisphosphonate 1 containing an allyl substituent at the
nitrogen atom (Scheme 1).
1
3,14
triethylorthoformate and diethyl phosphite.
This synꢀ
thetic process makes available aminomethylenebisphosꢀ
phonates with different substituents at the nitrogen atom.
Structural modification of compounds already having
a bisphosphonate fragment in the molecule is yet another
efficient approach to the synthesis of new aminomethylꢀ
enebisphosphonate derivatives. Such bisphosphonate
structures can be subsequently used for the development
of bisphosphonate conjugates through sequential chemiꢀ
Scheme 1
1
5,16
cal conversions (blockꢀbuilding syntheses).
In this connection, aminomethylenebisphosphonates
having at the nitrogen atom functional groups, which can
be used for further structural modification of the moleꢀ
cule, are of undoubted interest. Among such compounds
are allylꢀsubstituted aminomethylenebisphosphonates.
The presence of an allylic fragment in the molecule of
R = Me (1), —CH CH=CH2 (2)
2
Bisphosphonate 1 was synthesized according to a modꢀ
ified procedure,1
3,14
using a stoichiometric amounts of
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1256—1260, July, 2017.
066ꢀ5285/17/6607ꢀ1256 © 2017 Springer Science+Business Media, Inc.
1

Nꢀsubstituted aminomethyleneꢀ1,1ꢀbisphosphonates Russ. Chem. Bull., Int. Ed., Vol. 66, No. 7, July, 2017
1257
diethyl phosphite, triethylorthoformate, and Nꢀmethylꢀ
allylamine. The reaction was carried out in a sealed glass
tube during 3 h at 70 °C. The yield of compound 1 after
column chromatography was 72%. Aminomethylenebisꢀ
phosphonate 2 with two allyl substituents at the nitrogen
atom (see Scheme 1) was synthesized according to the
known procedure by reflux of a mixture containing stoiꢀ
chiometric amounts of diallylamine, triethylorthoforꢀ
mate, and diethyl phosphite in the presence of boron triꢀ
fluoride diethyl etherate as a catalyst and distilling off the
formed ethyl alcohol. The yield of compound 2 after puꢀ
rification by column chromatography was 71% (data in
Ref. 21: 42% after distillation). It should be noted that
carrying out the reaction under conditions described above
for bisphosphonate 1 gave diallyl derivative 2 in the yield
no more than 40%.
allylꢀsubstituted bisphosphonates 1 and 2 (Scheme 2).
The Nꢀoxides were generated in situ by treatment
of the corresponding hydroxyimidoyl chlorides
2
2
RC H CCl=N—OH with Et N, which were in turn
6
4
3
obtained by the reaction of aldoximes ArCH=N—OH
with NCS.23 In the case of bisphosphonate 1, the cycloꢀ
addition was carried out based on the published proceꢀ
2
1
dure,22 according to which Et N was added slowly to
3
a solution of a dipolarophile and a corresponding hydrꢀ
oxyimidoyl chloride in diethyl ether at low temperaꢀ
ture. Thus, the reaction of bisphosphonate 1 with
RC H CCl=N—OH (R = H, F, Cl, Me) under condiꢀ
6
4
tions given above (at –40 °C) was used to obtain adducts
3—6, containing in the molecule 3ꢀarylisoxazoline ring
with different substituents in the phenyl ring. Reaction
progress was monitored by thinꢀlayer chromatography.
The yields of isoxazolines 3—6 after purification by
column chromatography were within 80—82%.2 The reꢀ
The structures of aminomethylenebisphosphonates 1
and 2 were inferred from the NMR spectroscopy data
0
(
bisphosphonate 2 has been characterized only by the
action of nitrile oxides RC H CNO (R = H, F) with
6 4
2
1
1
value δP = 19.8 ). For the H NMR spectra of these
compounds, the most characteristic and informative is
the presence of the triplets for the methane protons
P—CH—P in the region of δ 3.42 and 3.81 with JP,H
=
bisphosphonate 2 bearing two allyl groups in the moleꢀ
cule leads to the formation of two types of compounds:
bisphosphonates 7 and 8 with one isoxazoline ring and
bisphosphonates 9 and 10 with two isoxazoline rings at
the nitrogen atom (see Scheme 2).
=
25.0 Hz. The 13C NMR spectra exhibit the triplets with
δC 58.0 and 55.00 and JP,C = 141.0 Hz, which indicate the
presence of the fragment P—C—P in compounds 1 and 2.
In this work, we also studied 1,3ꢀdipolar cycloaddiꢀ
tion of aromatic nitrile Nꢀoxides at the double bonds of
The yields of the target products 7—10 depended on
the ratio of starting reagents, the order of their addition,
reaction temperature and time. Thus, when a twoꢀfold
excess of the starting bisphosphonate 2 was used monoꢀ
Scheme 2
R = H (3, 7, 9); F (4, 8, 10); Cl (5), Me (6)

1
258
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 7, July, 2017
Bykhovskaya et al.
cyclic bisphosphonates 7 and 8 were the main cycloaddiꢀ
tion products (a decrease in the excess of bisphosphonate 2
led to the increase in the content of bicyclic derivatives 9
and 10 in the reaction mixture). At the same time, when
the corresponding nitrile oxides were in a twoꢀfold excess
the reaction predominantly gave bisphosphonates 9 and
CH proton of the double bond in the allyl group. In the
C NMR spectra of bisphosphonates 3—10, the isoxꢀ
1
3
azoline ring is represented by three singlets with δ in the
C
regions of 37.0—39.0 (CH2 cycl), 80.0—84.0 (CHcycl), and
155—157 ppm (C=N). The signals for the carbon atom of
the methine group (CHcycl) are shifted downfield as comꢀ
pared to the signals for the carbon atom of the methylene
group (CH2 cycl), that also confirmed the structure of the
regioisomer. In the case of bisphosphonates 7 and 8, the
1
0 with two isoxazoline fragments in the molecule. The
temperature in the range from –3 to +3 °C is the optimal
for this reaction. No cycloaddition takes place at –40 °C,
the temperature used in the synthesis of compounds 3—6.
An increase in the temperature to 20 °C led to the deꢀ
crease in the yield of the target products 7—10, that is
apparently explained by dimerization of nitrile oxides.
From the monitoring of the reaction by 31P NMR spectroꢀ
scopy, it follows that in 4 h after the beginning of the
process the reaction mixture had the composition, which
did not change with time. The order of the addition of
reagents was an important factor affecting the yields of
the target bisphosphonates 7—10. As it follows from the
experiments, the highest yield of monocyclic derivatives
singlets at δC 118 (CH =) and 136 (=CH) indicate the
2
3
1
presence of a double bond in the molecule. The P NMR
spectra of bisphosphonates 3—8 are an AВꢀsystem cenꢀ
tered in the region of 18.5—20 ppm with a spinꢀspin couꢀ
pling constant JP,P = 57.5—58.5 Hz, that indicates the
nonequivalence of the P=O groups. The spectral data
showed that the bicyclic bisphosphonates 9 and 10 havꢀ
ing two asymmetric centers CHcycl in the molecule exist
in the solution as a mixture of two diastereomers in the
3
1
ratio of 1 : 1. Thus, the P NMR spectra of these
compounds exhibit a broadened singlet in the region of
δ 19—20 corresponding to one of the diastereomers; the
second diastereomer gives an ABꢀquartet with the center
in the same region and the spinꢀspin coupling constant
7
and 8 (after purification by column chromatography
4
6 and 30%, respectively) was obtained if Et N was addꢀ
3
ed to the solution of the starting bisphosphonate 2
and the corresponding Nꢀhydroxyimidoyl chloride
1
13
JP,P = 55.0 Hz. The H and C NMR spectra of bicyclic
bisphosphonates 9 and 10 do not exhibit signal characꢀ
teristic of the allyl group; in this case a double set of
signals attributed to the isoxazoline ring was observed.
Allylꢀsubstituted bisphosphonates 7 and 8, the moleꢀ
cule of which has both an isoxazoline ring and a double
bond, can be involved in the cycloaddition reaction with
the formation of the corresponding bicyclic aminomethꢀ
ylenebisphosphonates with the same or different aryl subꢀ
stituents in the isoxazoline ring. Thus, the reaction of
monocyclic bisphosphonate 8 with a 1.5ꢀfold excess of
pꢀfluorobenzonitrile Nꢀoxide in diethyl ether at 0 °C gave
66% yield of bicyclic bisphosphonate 10 described above.
Bisphosphonate 11 with two different aryl substituents in
the isoxazoline rings was obtained in 65% yield by the
reaction of bisphosphonate 8 with benzonitrile Nꢀoxide
under the same conditions (see Scheme 2). In the
RC H CCl=N—OH (R = H, F) in CH Cl at 0 °C over
6
4
2
2
1
h. Bicyclic bisphosphonates 9 and 10 were obtained in
the highest yields of 61 and 40%, respectively (after colꢀ
umn chromatography) by the addition of a solution of the
starting bisphosphonate 2 in CH Cl to the excess of
2
2
the corresponding nitrile oxide obtained in situ from
RC H CCl=N—OH (R = H, F) and Et N at 0 °C (this
6
4
3
2
4
order of addition was suggested in the work for the prepꢀ
aration of imidazolidine diisoxazoline derivatives). When
the order of addition used in the synthesis of monocyclic
bisphosphonates 7 and 8 was applied for obtaining biꢀ
cycles 9 and 10, the yield was no higher than 20%.
The structure of cycloaddition products 3—10 was
3
1
1
13
1
confirmed by NMR spectroscopy ( P, H, C). The H
and C NMR spectra of bisphosphonates 3—10 exhibit
1
3
signals characteristic of the isoxazoline ring. Thus, in the
1
31
H NMR spectra of these compounds two multiplets with
P NMR spectrum of bisphosphonate 11, a broad sinꢀ
δH in the region of 3.0—3.6 and 4.9 ppm belong to the
glet with δ 19.68 and an ABꢀquartet centered at δ 19.75
P
P
protons of the CH and CH groups of the isoxazoline
with the spinꢀspin coupling constant JP,P = 55.0 Hz indiꢀ
2
ring, respectively. A downfield shift of the signals for the
protons of the cyclic CH groups as compared to the sigꢀ
cate the presence of two diastereomers in the solution.
1
3
The C NMR spectrum of this compound exhibits four
singlets with δC in the range 82.3—82.9 ppm (CHcycl
nals for the protons of the CH groups in all the obtained
)
2
systems indicates the formation of the regioisomer with
the structure shown in Scheme 2. No formation of the
second regioisomer was observed. The presence of the
allylic fragment in the molecule of monocyclic bisphosꢀ
phonates 7 and 8 was confirmed by the presence in the
corresponding to four isoxazoline rings, that also conꢀ
firms the presence of two diastereomers in the solution.
In conclusion, the 1,3ꢀcycloaddition reaction of allylꢀ
substituted aminomethyleneꢀ1,1ꢀbisphosphonates with
aromatic nitrile oxides leads to the compounds containꢀ
ing two pharmacophore groups in the molecule, namely,
a bisphosphonate fragment and a 3ꢀarylisoxazoline ring,
that can be used in the design of new pharmaceutiꢀ
cal agents.
1
H NMR spectra of two doublets with δH in the region of
5
ppm and JH,H = 10 and 17 Hz attributed to the cisꢀ and
transꢀprotons of the CH group of the double bond and
2
a multiplet in the region of δ 5.8 corresponding to the

Nꢀsubstituted aminomethyleneꢀ1,1ꢀbisphosphonates Russ. Chem. Bull., Int. Ed., Vol. 66, No. 7, July, 2017
1259
Experimental
(s, Cm, C6H5); 128.32 (s, Co, C6H5); 129.32 (s, Cipso, C6H5 ); 129.92
3
1
(
(
s, C , C H ); 136.47 (s, CH=); 157.00 (s, C=N). P NMR
p 6 5
2
CDCl ), δ: 19.75, 20.41 (ABꢀq., J
= 57.6 Hz).
3
P,P
Reactions were carried out in anhydrous solvents under dry
{Nꢀ[Bis(diethoxyphosphoryl)methyl]ꢀNꢀ[3ꢀ(4ꢀfluorophenꢀ
yl)isoxazolinꢀ5ꢀylmethyl]ꢀNꢀ(propenꢀ2ꢀyl)}amine (8) was obꢀ
tained and isolated similarly to compound 7: from bisphosphoꢀ
1
13
1
31
1
argon. H, C{ H}, and P{ H} NMR spectra were recorded
on a Bruker AMXꢀ400 spectrometer (400, 100, and 162 MHz,
respectively), using residual signals of the deuterated solvent
nate 2 (1.30 g, 3.40 mmol) in CH Cl (15 mL), pꢀfluorophenylꢀ
2
2
1
13
(
CDCl ) as references ( H and C) and 85% H PO as an
Nꢀhydroxyimidoyl chloride (0.30 g, 1.70 mmol) in CH Cl2
2
3
3
4
3
1
external standard ( P). Products were purified by column
(5 mL) and Et N (0.26 g, 2.55 mmol) in CH Cl (20 mL).
3
2
2
chromatography on SiO (Aldrich, 130—270 mesh, 60 Е), eluꢀ
ent hexane—acetone in gradient concentrations. The synthesis
The yield of monocyclic bisphosphonate 8 was 0.27 g (30%).
Found (%): C, 51.01; H, 6.87; N, 5.50; P, 11.54. C H FN O P .
2
22
35
2 7 2
1
and the structure of compounds 1 and 3—6 were described
Calculated (%): C, 50.77; H, 6.73; N, 5.38; P, 11.92. H NMR
(CDCl ), δ: 1.26—1.35 (m, 12 H, 4 Me); 3.14—3.38 (m, 4 H,
2
0
earlier.
Nꢀ[Bis(diethoxyphosphoryl)methyl]ꢀN,Nꢀbis(propenꢀ2ꢀ
3
{
2 NCH ); 3.61—3.65 (m, 2 H, CH2 cycl); 3.76 (t, 1 H, PCHP,
2
2
1
2
yl)}amine (2) was obtained according to the procedure from
JP,H = 25.3 Hz); 3.82—4.24 (m, 8 H, 4 OCH ); 4.88—4.90
(m, 1 H, CHcycl); 5.11 (d, 1 H, CH H, J
(d, 1 H, =CHHtrans
CH=); 7.05—7.28, 7.63—7.77 (both m, 4 H, FC H ). C NMR
2
3
diallylamine (1.46 g, 0.015 mol), triethyl orthoformate (2.66 g,
= 10.0 Hz); 5.19
H,H
JH,H = 17.2 Hz); 5.73—5.80 (m, 1 H,
cis
3
0
.018 mol), diethyl phosphite (4.14 g, 0.030 mol), and boron
,
1
3
trifluoride diethyl etherate (0.1 mL). The crude product was
6
4
purified by column chromatography on SiO , eluent hexane—
acetone in gradient of concentrations from 9 : 1 to 3 : 2. Bisphosꢀ
phonate 2 is a light yellow dense liquid. The yield was 71%.
(CDCl ), δ: 16.14—16.26 (m, Me); 37.67 (s, CH2 cycl); 55.26
2
3
1
(br.s, NCH ); 56.50 (t, PCP, J = 142.4 Hz); 57.48 (s, NCH );
2
P,C
2
2
2
62.15 (d, OCH , J = 5.8 Hz); 62.20 (d, OCH , J = 5.4 Hz);
2 P,C 2 P,C
62.26 (d, OCH , J = 6.0 Hz); 62.77 (d, OCH , J = 6.4 Hz);
2 P,C 2 P,C
81.79 (s, CHcycl); 115.50 (d, C , FC H , JC,F = 21.8 Hz);
m 6 4
2
2
Found (%): C, 47.11; H, 8.10; N, 3.59; P, 16.20. C15H NO P .
31
6
2
1
2
Calculated (%): C, 47.00; H, 8.09; N, 3.69; P, 16.19. H NMR
3
(
4
(
5
CDCl ), δ: 1.35 (t, 12 H, 4 Me, J
= 7.0 Hz); 3.52 (br.s,
118.00 (s, =CH ); 125.81 (s, C
, FC H ); 128.30 (d, C ,
3
H,H
2
ipso 6 4 o
H, 2 NCH ); 3.70 (t, 1 H, PCHP, 2JP,H = 25.0 Hz); 4.19
FC H , J
163.39 (d, C , FC H , J
F 6 4
3
= 8.3 Hz); 136.18 (s, CH=); 155.80 (s, C=N);
2
6
4
C,F
br.s, 8 H, 4 OCH ); 5.14 (d, 1 H, =CHcisH, 3JH,H = 10.0 Hz);
1
= 248.9 Hz). P NMR (CDCl ),
31
2
C,F
3
3
2
.23 (d, 1 H, =CHH
, J
= 17.4 Hz); 5.76—5.81 (m, 1 H,
д: 19.38, 20.06 (ABꢀq., J
= 57.5 Hz).
trans
H,H
P,P
1
3
CH=). C NMR (CDCl ), δ: 16.35—16.49 (m, CH ); 55.00
{Nꢀ[Bis(diethoxyphosphoryl)methyl]ꢀN,Nꢀbis[3ꢀphenylꢀ
3
3
3
(
6
1
t, PCP, 1JP,C = 141.0 Hz); 55.34 (t, NCH , J
= 4.4 Hz);
isoxazolinꢀ5ꢀylmethyl]}amine (9). A solution of Et N (0.26 g,
2
P,C
3
2
2
2.34 (d, OCH , J = 6.0 Hz); 62.79 (d, OCH , J = 6.0 Hz);
17.83 (s, =CH ); 136.44 (s, CH=). P NMR (CDCl ),
2.64 mmol) in CH Cl (5 mL) was added to a solution of phenꢀ
2
P,C
2
P,C
2 2
3
1
ylꢀNꢀhydroxyimidoyl chloride (0.41 g, 2.64 mmol) in CH Cl2
2
3
2
δ: 19.74.
(5 mL) at 0 °C with vigorous stirring. The resulting mixture was
{
Nꢀ[Bis(diethoxyphosphoryl)methyl]ꢀNꢀ(3ꢀphenylisoxazolꢀ
inꢀ5ꢀylmethyl)ꢀNꢀ(propenꢀ2ꢀyl)}amine (7). A solution of phenꢀ
ylꢀNꢀhydroxyimidoyl chloride (0.12 g, 0.70 mmol) in CH Cl
allowed to stand at this temperature for 10 min and then
a solution of bisphosphonate 2 (0.25 g, 0.66 mmol) in CH Cl2
2
(10 mL) was added. The temperature of the reaction mixture
was raised to 20 °C and the solution was allowed to stand at this
temperature for 4 h. The workꢀup of the reaction mixture and
the isolation of product 9 were carried out similarly to the proꢀ
cedure for compound 7. Compound 9 (0.25 g, 61%) was obꢀ
tained as a light yellow dense oil. Found (%): C, 55.97; H,6.81;
2
2
(
3 mL) was added to a solution of bisphosphonate 2 (0.54 g,
.41 mmol) in CH Cl (7 mL) at 0 °C. Then, a solution of Et N
0.11 g, 1.10 mmol) in CH Cl (10 mL) was added to the resultꢀ
ing solution with vigorous stirring over 1 h at 0—3 °C. The
temperature of the reaction mixture was increased to 20 °C.
The solution was allowed to stand at this temperature for 4 h.
After the reaction reached completion, the reaction mixture
was workedꢀup with saturated aqueous solution of NaCl (20 mL),
the aqueous layer was extracted with CH Cl (2×10 mL), the
1
2
2
3
(
2 2
N, 6.74; P, 9.77. C29H41N O P . Calculated (%): C, 56.04;
3
1
8 2
H, 6.60; N, 6.76; P, 10.00. H NMR (CDCl ), δ: 1.15—1.46
3
(m, 12 H, 4 Me); 3.32—3.52 (m, 4 H, 2 NCH , 4 H, 2 CH2 cycl);
2
4.14—4.30 (m, 1 H, PCHP, 8 H, 4 OCH ); 4.90, 4.98 (both br.s,
2
2
2
organic fractions were combined and dried with Na SO . After
2 H, 2 CH ); 7.32—7.46, 7.70—7.74 (both m, 10 H, 2 C H ).
cycl 6 5
C NMR (CDCl ), δ: 15.90 (d, CH , JP,C = 5.4 Hz);
3 3
2
4
1
3
3
removal of CH Cl in vacuo, the residue was purified by colꢀ
2
2
3
umn chromatography on SiO , eluent hexane—acetone in the
15.95—16.12 (m, CH ); 16.18 (d, Me, J
= 5.7 Hz); 37.08,
P,C
2
3
1
gradient of concentrations from 4 : 1 to 1 : 1. Amine 7 (0.16 g,
37.14 (both s, CH
); 58.47 (t, PCP, J
= 140.0 Hz); 58.50
P,C
2
cycl
1
2
4
6%) was obtained as a dense oil. Found (%): C, 52.71; H, 7.21;
(t, PCP, J
= 140.0 Hz); 61.70 (d, OCH , J
62.09 (d, OCH , J = 6.9 Hz); 62.13 (t, NCH , J = 2.9 Hz);
62.27 (t, NCH , J = 3.1 Hz); 62.43 (d, OCH , J = 6.9 Hz);
2 P,C 2 P,C
= 6.4 Hz);
P,C
P,C
2
2
3
N, 5.51; P, 12.30. C22H36N O P . Calculated (%): C, 52.59;
2
1
7
2
2
P,C
2
P,C
3
2
H, 7.17; N, 5.58; P, 12.35. H NMR (CDCl ), δ: 1.27—1.38
3
2
(
2
m, 12 H, 4 Me); 3.17—3.41 (m, 4 H, 2 NCH ); 3.62—3.72 (m,
62.60 (d, OCH , J
= 6.0 Hz); 82.38, 82.73 (both s, CHcycl);
P,C
2
2
2
H, CH2 cycl); 3.81 (t, 1 H, PCHP, J
= 25.0 Hz); 4.13—4.28
126.21, 126.25 (both s, C , C H ); 128.32 (s, C , C H ); 129.32,
m 6 5 o 6 5
P,H
(
=
=
m, 8 H, 4 OCH ); 4.92—4.94 (m, 1 H, CH ); 5.14 (d, 1 H,
129.34 (both s, Cipso, C H ); 129.58, 129.65 (both s, C , C H );
6 5 p 6 5
2
cycl
3
3
31
CHcis H, J
= 10.1 Hz); 5.22 (d, 1 H, =CHHtrans, J
=
157.24 (s, C=N). P NMR (CDCl ), δ: 19.28, 20.26 (ABꢀq,
H,H
H,H
3
2
17.3 Hz); 5.76—5.85 (m, 1 H, CH=); 7.28—7.43, 7.67—7.70
JP,P = 55.5 Hz); 19.72 (br.s).
1
3
(
both m, 5 H, C H ). C NMR (CDCl ), δ: 16.39—16.51 (m,
{Nꢀ[Bis(diethoxyphosphoryl)methyl]ꢀN,Nꢀbis[3ꢀ(4ꢀfluoroꢀ
phenyl)isoxazolinꢀ5ꢀylmethyl]}amine (10) was obtained and isoꢀ
lated similarly to the procedure for compound 9 from bisphosꢀ
6
5
3
CH ); 37.87 (s, CH
1
); 55.55 (s, NCH ); 56.80 (t, PCP,
3
2 cycl
2
2
JP,C = 141.0 Hz); 57.70 (s, NCH ); 62.45 (d, OCH , J
=
2
2
P,C
2
=
2
6.6 Hz); 62.51 (d, OCH , J
= 6.6 Hz); 63.05 (d, OCH2,
phonate 2 (0.27 g, 0.72 mmol) in CH Cl (15 mL), pꢀfluoroꢀ
2
P,C
2 2
JP,C = 6.3 Hz); 81.90 (s, CHcycl); 118.22 (s, =CH ); 126.62
phenylꢀNꢀhydroxyimidoyl chloride (0.50 g, 2.88 mmol) in
2

1
260
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 7, July, 2017
Bykhovskaya et al.
CH Cl (10 mL), and Et N (0.29 g, 2.88 mmol) in CH Cl
2
Bicyclic bisphosphonate 10 was obtained and isolated simiꢀ
larly to the procedure for compound 11 from monocyclic bisꢀ
phosphonate 8 (0.30 g, 0.60 mmol) in diethyl ether (10 mL),
pꢀfluorophenylꢀNꢀhydroxyimidoyl chloride (0.21 g, 1.20 mmol)
2
2
3
2
(
5 mL). The yield of bisphosphonate 10 was 0.27 g (40%).
Found (%): C, 52.87; H,5.94; N, 6.36; P, 9.54. C H F N O P .
2
9
39
2
3 8 2
1
Calculated (%): C, 52.96; H, 5.94; N, 6.39; P, 9.43. H NMR
CDCl ), δ: 1.09—1.37 (m, 12 H, 4 Me); 3.24—3.52 (m, 4 H,
(
in diethyl ether (5 mL), and Et N (0.18 g, 1.80 mmol) in diꢀ
3
3
2
4
7
1
3
NCH , 4 H, 2 CH2 cycl); 3.99—4.28 (m, 1 H, PCHP, 8 H,
OCH ); 4.81, 4.89 (both br.s, 2 H, 2 CHcycl); 7.00—7.08,
ethyl ether (10 mL). The yield of bisphosphonate 10 was
0.26 g (67%).
2
2
1
3
.51—7.65 (both m, 8 H, 2 FC H ). C NMR (CDCl ), δ:
6.06—16.20 (m, Me); 16.33 (d, Me, J
7.47 (both s, CH
6
4
3
3
= 6.0 Hz); 37.28,
= 140.5 Hz); 58.64
P,C
References
1
); 58.59 (t, PCP, J
2
cycl
P,C
1
2
(
t, PCP, J
= 140.5 Hz); 61.86 (d, OCH , J
= 6.7 Hz);
P,C
P,C
2
3
2
1. V. D. Romanenko, V. P. Kukhar, Arkivoc, 2012, 4, 127.
2. S. Zhang, G. Gangal, H. Uludaр, Chem. Soc. Rev., 2007,
36, 507.
3. R. G. Russell, Ann. N. Y. Acad. Sci., 2006, 1068, 367.
4. A. G. Roth, D. Drescher, Y. Yang, S. Redmer, S. Uhlig,
C. Arenz, Angew. Chem., Int. Ed. Engl., 2009, 48, 7560.
5. H. Fleisch, Breast Cancer Res., 2002, 4, 30.
6. A. A. Reszka, G. A. Rodan, Mini Rev. Med. Chem., 2004,
4, 711.
6
6
6
1
2.29 (t, NCH , J = 3.2 Hz); 62.29 (d, OCH , J = 6.6 Hz);
2 P,C 2 P,C
2.44 (t, NCH , J = 3.2 Hz); 62.56 (d, OCH , J = 7.1 Hz);
2.85 (d, OCH , J
15.50 (d, C , FC H , J = 21.8 Hz); 125.71, 125.74, 125.77
C,F
3
2
2
P,C
2
2
P,C
= 6.6 Hz); 82.59, 82.94 (both s, CHcycl);
P,C
2
2
m
6
4
3
(
all s, Cipso , FC H ); 128.29 (d, C , FC H , J
= 8.3 Hz);
C,F
6
4
o
6
4
3
1
28.32 (d, C , FC H , J
= 8.3 Hz); 156.21 (s, C=N); 156.33
C,F
= 249.0 Hz); 163.46
C,F
= 249.0 Hz). P NMR (CDCl ), δ: 19.36,
C,F 3
o
6
4
1
(
s, C=N); 163.45 (d, C , FC H , J
F
6
4
1
31
(
d, C , FC H , J
F
6
4
2
2
0.20 (ABꢀq., J
= 55.2 Hz); 19.67 (br.s).
P,P
7
. X. Chen, X. Li, J. Yuan, L. Qu, H. Wang, H Shi, Y. Tang,
L. Duan, Bioorg. Med. Chem., 2011, 21, 6456.
. H. Fleisch, Endocrine Rev., 1998, 19, 80.
. R. G. G. Russell, P. I. Croucher, M. J. Rogers, Osteoporos
Int., 1999, 2, 66.
{
Nꢀ[Bis(diethoxyphosphoryl)methyl]ꢀNꢀ(3ꢀphenylisoxazoꢀ
linꢀ5ꢀylmethyl)ꢀNꢀ[3ꢀ(4ꢀfluorophenyl)isoxazolinꢀ5ꢀylmethyl]}ꢀ
amine (11). A solution of phenylꢀNꢀhydroxyimidoyl chloride
8
9
(
0.18 g, 1.15 mmol) in diethyl ether (5 mL) was added to
a solution of amine 8 (0.40 g, 0.77 mmol) in diethyl ether
1
0. T. M. Balashova, I. D. Kolpakova, Metody polucheniya
khimicheskikh reaktivov i preparatov [Methods for Preparaꢀ
tion of Chemical Reactants], 1973, 25, 11 (in Russian).
1. W. Plцger, N. Schindler, K. Wollmann, K. H. Worms,
Z. Anorg. Allg. Chem., 1972, 389, 119.
2. A. A. Prischenko, M. V. Livantsov, O. P. Novikova, L. I.
Livantsova, Russ. J. Gen. Chem., 2009, 79, 1936.
3. L. Maier, Phosphorus Sulfur Relat. Elem., 1981, 11, 311.
4. F. H. Ebetino, L. A. Jamieson, Phosphorus Sulfur Silicon
Relat. Elem., 1990, 51, 23.
(
(
10 mL) at 0 °C with vigorous stirring. Then, a solution of Et N
0.17 g, 1.72 mmol) in diethyl ether (10 mL) was added to the
3
resulting solution with vigorous stirring in the temperature range
from 0 to 5 °C over 1 h. Then, the temperature of the reaction
mixture was raised to 20 °C and the solution was allowed to
stand at this temperature for 4 h. The workꢀup of the reaction
mixture and the isolation of product 11 were carried out simiꢀ
larly to the procedure for compound 7, using diethyl ether
for extraction. The yield of compound 11 was 0.32 g (65%).
1
1
1
1
Found (%): C, 54.50; H,6.39; N, 6.44; P, 9.51. C H FN O P .
29
40
3
8 2
1
15. A. A. ElꢀMabhouh, C.A. Angelov, R. Cavell, J. R. Mercer,
Calculated (%): C, 54.46; H, 6.26; N, 6.57; P, 9.70. H NMR
CDCl ), δ: 1.13—1.42 (m, 12 H, 4 Me); 3.31—3.59 (m, 4 H,
Nucl. Med. Biol., 2006, 33, 715.
(
3
1
6. M. V. Schevchuk, A. E. Sorochinsky, V. P. Khilya, V. D.
2
4
7
NCH , 4 H, 2 CH2 cycl); 3.99—4.28 (m, 1 H, PCHP, 8 H,
2
Romanenko, V. P. Kukhar, Synlett, 2010, 73.
OCH ); 4.85, 4.94 (both br.s, 2 H, 2 CH ); 7.05—7.12,
2
cycl
1
3
17. S. K. Prajapti, S. Shrivastava, U. Bihade, A. K. Gupta,
V. G. M. Naidi, U. C. Banerjee, B. N. Babu, Med. Chem.
Commun., 2015, 6, 839.
18. L. Kiss, M. Nonn, F. Fьlцp, Synthesis, 2012, 44, 13, 1951.
19. Y. Koyama, SꢀP. Huang, D. Ikeda, S. Kondo, T. Takeuchi,
J. Antibiot., 1992, 45, 1930.
20. V. K. Brel, Mendeleev Commun., 2015, 25, 234.
21. EP Pat. 0563730 A2, 1993; CAN 120:167314, 1994.
22. T. Olsson, K. Stern, S. Sundell, J. Org. Chem., 1988,
53, 2468.
.41—7.69 (both m, 4 H, 1 FC H , 5 H, 1 C H ). C NMR
6
4
6
5
3
(
CDCl ), δ: 15.97 (d, Me, J
= 5.4 Hz); 16.09 (br.s, Me),
P,C
3
3
1
5
6
6
6.22 (d, Me, J = 5.8 Hz); 37.14, 37.24, 37.33 (all s, CH2 cycl);
P,C
1
1
8.57 (t, PCP, J = 140.2 Hz); 58.60 (t, PCP, J = 139.9 Hz);
1.77 (d, OCH , J = 6.6 Hz); 62.17 (d, OCH , J = 6.2 Hz);
2.21 (br.s, NCH ); 62.34 (t, NCH , J = 3.2 Hz); 62.34
P,C
P,C
P,C
2
2
2
P,C
2
P,C
3
2
2
2
2
(
d, OCH , J
= 6.4 Hz); 62.48 (d, OCH , J
= 6.9 Hz);
P,C
2
P,C
2
2
6
2.69 (d, OCH , J
= 6.4 Hz); 82.38, 82.52, 83.73, 82.91
P,C
2
2
(
(
all s, CHcycl); 115.46 (d, C , FC H , J
d, C , FC H , JC,F = 21.8 Hz); 125.73 (s, Cipso, FC H );
= 21.9 Hz); 115.48
m
6
4
C,F
2
m
6
4
6
4
2
3. K.ꢀCh. Liu, B. R. Shelton, R.K. Howe, J. Org. Chem., 1980,
45, 3916.
1
26.28, 126.30 (both s, C , C H ); 128.21 (d, C , FC H ,
m 6 5 o 6 4
3
3
JC,F = 8.2 Hz); 128.26 (d, C , FC H , J = 8.3 Hz); 128.38
C,F
o
6
4
2
4. S. Kanemasa, K. Onimura, Tetrahedron, 1992, 48, 8645.
(
s, C , C H ); 129.37, 129.41 (both s, C , C H ); 129.69,
o 6 5 ipso 6 5
1
1
29.72 (both s, C , C H ); 156.23, 157.07, 157.18 (all s, C=N);
p 6 5
1
63.43 (d, C , FC H , J
= 249.0 Hz); 163.45 (d, C , FC H ,
F
6
4
C,F F 6 4
1
31
JC,F = 249.0 Hz). P NMR (CDCl ), δ: 19.25, 20.25 (ABꢀq.,
3
2J = 55.0 Hz); 19.68 (br.s).
Received March 16, 2017
P,P