Synthesis of (aminomethylene)bisphosphonic acid derivatives

Article abstract of DOI:10.1007/s11172-016-1289-z

Amino derivatives of methylenebisphosphonic acids were synthesized by phosphorylation of formamide, nitriles or hydrochlorides of alkyl imidates with H₃PO₃—PCl₃—(Me₃Si)₂NH.

Full text of DOI:10.1007/s11172-016-1289-z

Russian Chemical Bulletin, International Edition, Vol. 65, No. 1, pp. 228—232, January, 2016
228
Synthesis of (aminomethylene)bisphosphonic acid derivatives*
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, and V. S. Petrosyan
Department of Chemistry, M. V. Lomonosov Moscow State University,
3 Build., 1 Leninskie Gory, 119991 Moscow, Russian Federation.
Eꢀmail: aprishchenko@yandex.ru
Amino derivatives of methylenebisphosphonic acids were synthesized by phosphorylation
of formamide, nitriles or hydrochlorides of alkyl imidates with H3PO3—PCl3—(Me3Si)2NH.
Key words: phosphorous acid, phosphorus(III) trichloride, formamide, nitriles, trimethylꢀ
silyl esters, methylenebisphosphonic acids, boron trifluoride diethyl etherate, organophosꢀ
phorus compounds.
Functionalized methylenebisphosphonic acids and
amide, phosphorous acid, and phosphorus trichloride with
water and hexamethyldisilazane (see Scheme 1).
A similar reaction involving carboxamides results in
bisphosphonates 2 bearing primary amino group (see
Scheme 2).
their derivatives are promising organophosphorus bioꢀ
mimetics of natural pyrophosphates, hydroxy and amino
acids, which have found wide applications as efficient polyꢀ
dentate ligands and biologically active substances demonꢀ
strating a multifactorial activity.1—5 They are known as
active complexones and extensively applied in medicinal
practice.6—8 Some of these compounds are antioxidants
and cytoproptectors possessing multitarget activity.9—14
Recently, we have synthesized (aminomethylene)ꢀ
bisphosphonic acids and their derivatives starting from
formamides and protected ethoxymethylene imines.15—17
A series of promising bidentate ligands, i.e., functionalꢀ
ized Nꢀformylaminomethylene phosphonates, has also
been synthesized.18
In the present work, with the aim to synthesize new
types of substituted (aminomethylene)bisphosphonates
and their derivatives we choose tetrakis(trimethylsilyl)
(aminomethylene)bisphosphonates 1 and 2 as the starting
materials (Schemes 1 and 2). Compounds 1 and 2 were
first obtained in high yields by treatment of formamide or
nitriles with phosphorous acid and phosphorus trichloride
(cf. Refs 19—21). Thus, bisphosphonate 1 was synthesized
by sequential treatment of a mixture containing formꢀ
Scheme 2
2: R = Me (a), Ph (b), 3ꢀpyridyl (с)
Reagents and conditions: 1) H3PO3, PCl3, 5—80 °C; 2) H2O,
80 °C; 3) (Me3Si)2NH, 120 °C.
Both reaction proceed smoothly since activation of the
starting formamide or nitrile with a H3PO3—PCl3 mixture
produces highly reactive imidoyl chlorides A, C (cf. Refs 17,
19—21; Scheme 3).
It is of note that the product 1 is a result of Nꢀformylaꢀ
tion of intermediate B with highly reactive salt A.
Trimethylsilylated biphosphonates 1 and 2 were sucꢀ
cessfully used as the building blocks in the synthesis of the
corresponding diphosphonic acids and their esters. Thus,
bisphosphonates 1 and 2 react with the methanol excess
under mild conditions to give diphosphonic acids 3 and 4
(Scheme 4). Compounds 3 and 4 are the hygroscopic white
crystalline substances. A series of similar (aminomethylꢀ
ene)bisphosphonic acids has been earlier synthesized in
low yields as hydrates.19,21
Scheme 1
Trimethylsilylated bisphosphonates 1 and 2 on treatꢀ
ment with excess of triethyl orthoformate and ethanol unꢀ
der mild conditions undergo replacement of the Me3SiO
group by the EtO group (Scheme 5). In the case of amino
derivatives 2, Nꢀformylation also takes place.
Reagents and conditions: 1) H3PO3, PCl3, 5—80 °C; 2) H2O,
80 °C; 3) (Me3Si)2NH, 120 °C.
* Dedicated to Academician of the Russian Academy of Sciences
N. S. Zefirov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0228—0232, January, 2016.
1066ꢀ5285/16/6501ꢀ0228 © 2016 Springer Science+Business Media, Inc.

(Aminomethylene)bisphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 1, January, 2016
229
Scheme 3
2: R = Me (a), Ph (b), 3ꢀpyridyl (c)
Scheme 4
Scheme 6
6: R = Me (a), Ph (b)
Reagents and conditions: 1) (EtO)2POSiMe3 (2 equiv.),
(EtO)2P(O)H, BF3•Et2O, CH2Cl2, 20 °C; 2) (Me3Si)2NH, 120 °C.
Catalytic activity of boron trifluoride etherate is due to
activation of the C=N groups to produce electrophilic
intermediates D17 (Scheme 7).
2, 4: R = Me (a), Ph (b), 3ꢀpyridyl (c)
Scheme 7
Scheme 5
The structures of the synthesized bisphosphonates and
their derivatives 1—6 were elucidated by 1H, 13C{1H}, and
31P{1H} NMR spectroscopy. Note that compounds 1, 3,
and 5 bearing the Nꢀmethylformamide moiety are the mixꢀ
tures of two diastereomers, the diastereomeric ratios were
determined from the 31P NMR spectral data.
In summary, we elaborated versatile synthetic proceꢀ
dures towards new Nꢀformylꢀsubstituted and Nꢀunsubstiꢀ
tuted (aminomethylene)bisphosphonates and their derivꢀ
atives from available staring materials. Compounds 1—6
can serve as the key building blocks in the synthesis of
a wide variety of functionalized organophosphorus comꢀ
R = Me (2a, 5b), Ph (2b, 5c)
Apparently, bisphosphonates 5 arise from two or three
simultaneous reactions: ethanolysis, esterification, and
formylation of diphosphonates 1 and 2 (cf. Refs 22—24).
Poorly available (aminomethylene)bisphosphonates 6
bearing unsubstituted amino group (cf. Refs 25, 26) were
synthesized by the reaction of ethyl imidate hydrochlorides
with diethyl trimethylsilyl phosphite in dichloromethane
catalyzed by boron trifluoride diethyl etherate (cf. Refs 17,
25, 26; Scheme 6).

230
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 1, January, 2016
Prishchenko et al.
(CDCl3), δ: –0.21 (d, 18 H, 2 Me3Si, 4JP,H = 2.8 Hz); –0.18 (d,
18 H, 2 Me3Si, 4JP,H = 2.8 Hz); 1.74 (t, 2 H, NH2, 3JP,H = 13.2 Hz);
6.80—7.60 (m, 5 H, C6H5). 13C{1H} NMR (CDCl3), δ: 59.74 (t,
C(1), 1JP,C = 147.9 Hz), 135.82 (br.s, C(2)); 127.21 and 127.29
(both s, C(3), C(4)); 126.85 (s, C(5)); 0.49 (s, 2 Me3Si); 0.58
(s, 2 Me3Si). 31P{1H} NMR (CDCl3), δ: 2.26 (s).
pounds, e.g., bisphosphorylated peptides, and are also
promising polydentate ligands and biologically active subꢀ
stances.
Experimental
Tetrakis(trimethylsilyl) [1ꢀaminoꢀ1ꢀ(3ꢀpyridyl)methylene]bisꢀ
phosphonate (2c). Yield 85%, b.p. 152 °C (0.5 Torr). Found (%):
C, 38.68; H, 7.52. C18H42N2O6P2Si4. Calculated (%): C, 38.83;
H, 7.60. 1H NMR (CDCl3), δ: –0.17 (s, 18 H, 2 Me3Si); –0.14
(s, 18 H, 2 Me3Si); 1.83 (t, 2 H, NH2, 3JP,H = 14.0 Hz); 6.94 (dd,
1
H, 13C{1H}, and 31P{1H} NMR spectra were run on a Brukꢀ
er Avanceꢀ400 instrument with working frequencies of 400, 100,
and 162 MHz, respectively, relative to Me4Si (1H, 13C{1H}) and
85% H3PO4 in D2O (31P{1H}). The starting trimethylsilyl esters
of phosphorus(III) acids27,28 and ethyl imidate hydrochlorides20
were synthesized by the known procedures.
3
3
1 H, C(4)H, JH,H = 4.8 Hz, JH,H = 8.0 Hz); 7.88 (d, 1 H,
C(3)H, 3JH,H = 8.0 Hz); 8.19 (d, 1 H, C(5)H, 3JH,H = 4.8 Hz);
8.71 (s, 1 H, C(6)H). 13C{1H} NMR (CDCl3), δ: 0.13 (s, 2 Me3Si);
0.17 (s, 2 Me3Si); 58.04 (t, C(1), 1JP,C = 147.3 Hz); 151.26 (s, C(2));
Tetrakis(trimethylsilyl) (Nꢀformylaminomethylene)bisphosꢀ
phonate (1). To a stirred mixture of formamide (27 g, 0.60 mol)
and phosphorous acid (50 g, 0.61 mol), phosphorus trichloride
(124 g, 0.90 mol) was added dropwise at 5 °C. The mixture was
stirred for 1 h, maintained at 20 °C for 24 h, and then heated at
80 °C for 1 h. The reaction mixture was treated with water (400 ml)
and heating at 80 °C was continued for 1 h. Water was removed
in vacuo (7 Torr, 80 °C), the residue was treated with hexamethylꢀ
disilazane (280 g) and the mixture was refluxed until complete
dissolution of the precipitate. The excess of (Me3Si)2NH was
removed in vacuo (7 Torr). Vacuum distillation of the residue
afforded diphosphonate 1 in the yield of 112.6 g (74%), b.p. 142 °C
(0.5 Torr). Found (%): C, 32.94; H, 7.68. C14H39NO7P2Si4.
Calculated (%): C, 33.12; H, 7.74.
The first isomer, content of 55%. 1H NMR (CDCl3,), δ:
–(0.09—0.07) (m, 36 H, 4 Me3Si); 2.71 (t, C(1)H, JP,H
= 22.8 Hz); 7.28 (br.s, 1 H, CHO). 13C{1H} NMR (CDCl3), δ:
50.61 (t, C(1), 1JP,C = 154.1 Hz); 156.08 (t, CHO, 3JP,C = 13.5 Hz);
0.78 (s, 2 Me3Si); 0.81 (s, 2 Me3Si). 31P{1H} NMR (CDCl3),
δ: 3.37 (s).
3
131.94 (t, C(3), JP,C = 4.4 Hz); 134.62 (s, C(4)); 147.52
(s, C(5)); 148.14 (t, C(6), 3JP,C = 4.8 Hz). 31P{1H} NMR (CDCl3),
δ: 1.62 (s).
(NꢀFormylaminomethylene)bisphosphonic acid (3). A solution
of bisphosphonate 1 (9.9 g, (0.02 mol) in diethyl ether (15 mL)
was added to methanol (40 mL) at 10 °C with stirring. The mixꢀ
ture was heated to reflux, the solvent was removed in vacuo, the
obtained white crystals were dried in vacuo (1 Torr) for 1 h to
give acid 3 in the yield of 4.3 g (97%), b.p. 159 °C (decomp.).
Found (%): C, 10.85; H, 3.26. C2H7NO7P2. Calculated (%):
C, 10.97; H, 3.22.
The first isomer, content of 85%. 1H NMR (CDCl3), δ: 2.83
2
(t, 1 H, C(1)H, JP,H = 17.4 Hz); 7.14 (s, 1 H, CHO). 13C{1H}
1
2
NMR (CDCl3), δ: 47.40 (t, C(1), JP,C = 123.7 Hz); 153.45
=
(s, CHO). 31P{1H} NMR (CDCl3), δ: 8.58 (s).
1
The second isomer, content of 15%. H NMR (CDCl3), δ:
2
3.56 (t, 1 H, C(1)H, JP,H = 18.8 Hz); 7.17 (s, 1 H, CHO).
1
13C{1H} NMR (CDCl3), δ: 51.04 (t, C(1), JP,C = 125.3 Hz);
157.19 (s, CHO). 31P{1H} NMR (CDCl3), δ: 9.50 (s).
1
The second isomer, content of 45%. H NMR (CDCl3), δ:
–(0.09—0.07) (m, 36 H, 4 Me3Si); 2.74 (t, 1 H, C(1)H, 2JP,H
=
Acids 4a—c were synthesized similarly; their physicochemiꢀ
cal properties are in agreement with the earlier published data17
.
= 22.4 Hz); 7.28 (br.s, 1 H, CHO). 13C{1H} NMR (CDCl3),
1
(1ꢀAminoethaneꢀ1,1ꢀdiyl)bisphosphonic acid (4a). Yield 98%,
δ: 49.64 (t, C(1), JP,C = 150.1 Hz); 155.94 (br.s, CHO); 0.65
1
(s, 2 Me3Si); 0.67 (s, 2 Me3Si). 31P{1H} NMR (CDCl3), δ: 2.60 (s).
Tetrakis(trimethylsilyl) (1ꢀaminoethaneꢀ1,1ꢀdiyl) bisphosphoꢀ
nate (2a). To a stirred mixture of acetonitrile (6.2 g, 0.15 mol),
phosphorous acid (39 g, 0.48 mol), and dichloromethane (5 mL),
phosphorus trichloride (42 g, 0.31 mol) was added dropwise at
5 °C. The mixture was stirred for 3 h, maintained at 20 °C for 24 h,
and heated at 80 °C for 2 h. Then the reaction mixture was
treated with water (300 mL), and heating at 80 °C was continued
for 1 h. Water was removed in vacuo (7 Torr, 80 °C), the residue
was treated with (Me3Si)2NH (250 g), and the mixture was reꢀ
fluxed until complete dissolution of the residue. The excess of
(Me3Si)2NH was removed in vacuo (7 Torr). Vacuum distillaꢀ
tion of the residue afforded bisphosphonate 2a in the yield of
59.7 g (80%), b.p. 144 °C (2 Torr). 1H NMR (CDCl3), δ: –0.03
m.p. 250 °C. H NMR (D2O—C5D5N), δ: 1.15 (t, 3 H C(2)H3,
3JP,H = 13.3 Hz). 13C{1H} NMR (D2O—C5D5N), δ: 51.74
1
(t, C(1), JP,C = 122.7 Hz); 15.69 (c, C(2)). 31P{1H} NMR
(D2O—C5D5N), δ: 10.95 (s).
(1ꢀAminoꢀ1ꢀphenylmethylene)bisphosphonic acid (4b). Yield
96%, m.p. 225 °C. 1H NMR (D2O—C5D5N), δ: 6.80—7.60 (m,
5 H, C6H5). 13C{1H} NMR (D2O—C5D5N), δ: 60.48 (t, C(1),
1JP,C = 121.2 Hz); 131.26, 125.58, 126.23, 124.30 (all s, C(2),
C(3), C(4), C(5)). 31P{1H} NMR (D2O—C5D5N), δ: 8.59 (s).
[1ꢀAminoꢀ1ꢀ(3ꢀpyridyl)methylene]bisphosphonic acid (4c).
Yield 95%, m.p. 191 °C (decomp.). Found (%): C, 26.74; H, 3.80.
C6H10N2O6P2. Calculated (%): C, 26.88; H, 3.76. 1H NMR
(D2O—C5D5N), δ: 7.00—8.10 (m, 4 H, C6H4N). 13C{1H} NMR
1
(D2O—C5D5N), δ: 60.83 (t, C(1), JP,C = 114.2 Hz); 151.31,
4
(d, 18 H, 2 Me3Si, JP,H = 2.0 Hz); –0.04 (d, 18 H, 2 Me3Si,
133.89, 137.96, 145.19, 147.21 (all s, C(2), C(3), C(4), C(5),
C(6)). 31P{1H} NMR (D2O—C5D5N), δ: 10.94 (s).
4JP,H = 1.6 Hz); 1.04 (t, 3 H, C(2)H3, 3JP,H = 16.4 Hz); 1.20 (t, 2 H,
NH2, 3JP,H = 12.6 Hz). 13C{1H} NMR (CDCl3), δ: 51.64 (t, C(1),
1JP,C = 152.4 Hz); 20.10 (s, C(2)); 0.79 (s, 2 Me3Si); 0.84
(s, 2 Me3Si). 31P{1H} NMR (CDCl3), δ: 6.68 (s).
Tetraethyl (Nꢀformylaminomethylene)bisphosphonate (5a). To
a stirred solution of bisphosphonate 1 (14 g, 0.03 mol) in dichloroꢀ
methane (20 mL), triethyl orthoformate (60 g, 0.41 mol) was
added at 10 °C followed by dropwise addition of ethanol (20 g).
The reaction mixture was slowly heated until boiling point of
triethyl orthoformate was reached simultaneously removing low
boiling volatiles, then the triethyl orthoformate excess was reꢀ
moved in vacuo (7 Torr). Vacuum distillation of the residue
Bisphosphonates 2b,c were synthesized similarly, their physꢀ
icochemical properties are in agreement with the earlier pubꢀ
lished data.17
Tetrakis(trimethylsilyl) (1ꢀaminoꢀ1ꢀphenylmethylene)bisꢀ
phosphonate (2b), yield 82%, b.p. 149 °C (1 Torr). 1H NMR

(Aminomethylene)bisphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 1, January, 2016
231
afforded bisphosphonate 5a in the yield of 7.6 g (83%), b.p. 182 °C
(1 Torr). Found (%): C, 36.03; H, 6.94. C10H23NO7P2. Calcuꢀ
lated (%): C, 36.26; H, 7.00.
in vacuo. Vacuum distillation (7 Torr) of the residue afforded
diphosphonate 6a in the yield of 12.7 g (42%), b.p. 128 °C
(1 Torr). Found (%): C, 37.55; H, 7.87. C10H25NO6P2. Calcuꢀ
lated (%): C, 37.86; H, 7.94. 1H NMR (CDCl3), δ: 0.75 (t, 12 H,
4 CH3, 3JH,H = 7.6 Hz); 0.92 (t, 3 H, C(2)H3, 3JP,H = 16.4 Hz);
1.13 (t, 2 H, NH2, 3JP,H = 12.4 Hz); 3.50—3.60 (m, 8 H, 4 CH2).
13C{1H} NMR (CDCl3), δ: 15.87 (s, CH3); 19.30 (br.s, C(2));
52.31 (t, C(1), 1JP,C = 144.5 Hz); 62.38 and 62.59 (both s, 2 CH2).
31P{1H} NMR (CDCl3), δ: 22.96 (s).
The first isomer, content of 60%. 1H NMR (CDCl3), δ:
0.75—0.86 (m, 12 H, 4 CH3); 3.60—3.70 (m, 8 H, 4 CH2); 4.53
2
(t, 1 H, C(1)H, JP,H = 22.0 Hz); 7.79 (s, 1 H, CHO). 13C{1H}
1
NMR (CDCl3), δ: 15.77 (s, 3 H, CH3); 57.88 (t, C(1), JP,C
=
= 150.9 Hz); 62.54 and 62.84 (both s, 2 CH2); 160.31 (t, CHO,
3JP,C = 14.4 Hz). 31P{1H} NMR (CDCl3), δ: 16.32 (s).
1
The second isomer, content of 40%. H NMR (CDCl3), δ:
Bisphosphonate 6b was synthesized similarly.
0.75—0.86 (m, 12 H, 4 CH3); 3.60—3.70 (m, 8 H, 4 CH2); 4.51
Tetraethyl (1ꢀaminoꢀ1ꢀphenylmethylene)bisphosphonate (6b),
yield 34%, b.p. 165 °C (1 Torr). Found (%): C, 47.26; H, 7.02.
C15H27NO6P2. Calculated (%): C, 47.50; H, 7.17. 1H NMR
(t, 1 H, C(1)H, 2JP,H = 22.0 Hz); 7.26 (s, CHO). 13C{1H} NMR
1
(CDCl3), δ: 15.68 (s, CH3); 41.43 (t, C(1), JP,C = 146.1 Hz);
62.45 and 62.71 (both s, 2 CH2); 160.79 (br.s, CHO). 31P{1H}
NMR (CDCl3), δ: 15.57 (s).
(CDCl3), δ: 0.77 (t, 6 H, 2 CH3, JH,H = 7.2 Hz); 0.92 (t, 6 H,
3
3
3
2 CH3, JH,H = 7.2 Hz); 1.99 (t, 2 H, NH2, JP,H = 12.8 Hz);
3.50—3.70 (m, 8 H, 4 CH2); 6.90—7.60 (m, 5 H, C6H5). 13C{1H}
NMR (CDCl3), δ: 15.85 and 15.99 (both s, 4 CH3); 60.05
(t, C(1), 1JP,C = 139.7 Hz); 63.19 and 63.49 (both s, 4 CH2); 133.80
(br.s, C(2)); 127.18 (t, C(3), 3JP,C = 4.8 Hz), 127.35 and 128.15
(both s, C(4), C(5)). 31P{1H} NMR (CDCl3), δ: 18.97 (s).
Bisphosphonates 5b,c were synthesized similarly.
Tetraethyl (1ꢀformylaminoethaneꢀ1,1ꢀdiyl)bisphosphonate
(5b). Yield 80%, b.p. 139 °C (0.3 Torr). Found (%): C, 38.12;
H, 7.23. C11H25NO7P2. Calculated (%): C, 38.26; H, 7.30.
The first isomer, content of 85%. 1H NMR (CDCl3), δ:
0.67—0.72 (m, 12 H, 4 CH3); 3.50—3.60 (m, 8 H, 4 CH2); 1.04
3
4
This work was financially supported by the Russian
Science Foundation (Project Nos 14ꢀ03ꢀ00001 and 15ꢀ
03ꢀ00002).
(t, 3 H, C(2)H3, JP,H = 15.6 Hz); 7.18 (t, 1 H, CHO, JP,H
=
= 2.8 Hz). 13C{1H} NMR (CDCl3), δ: 15.75 (s, CH3); 17.76 (s,
C(2)); 59.90 (t, C(1), 1JP,C = 149.3 Hz); 62.43 and 62.63 (both s,
2 CH2); 157.31 (t, CHO, JP,C = 12.0 Hz). 31P{1H} NMR
3
(CDCl3), δ: 19.74 (s).
References
1
The second isomer, content of 15%. H NMR (CDCl3), δ:
0.67—0.72 (m, 12 H, 4 CH3); 3.5—3.6 (m, 8 H, 4 CH2); 1.10
(t, 3 H, C(2)H3, 3JP,H = 15.6 Hz); 7.03 (s, 1 H, CHO). 13C{1H}
NMR (CDCl3), δ: 15.56 (s, CH3); 17.20 (s, C(2)), 53.46 (t, C(1),
1JP,C = 147.6 Hz); 62.95 and 63.19 (both s, 2 CH2); 163.98 (br.s,
CHO). 31P{1H} NMR (CDCl3), δ: 18.86 (s).
1. V. P. Kukhar, H. R. Hudson, Aminophosphonic and Aminoꢀ
phosphinic Acids. Chemistry and Biological Activity, Wiley,
New York, 2000, 634 pp.
2. F. H. Ebetino, Phosphorus, Sulfur Silicon Relat. Elem., 1999,
144—146, 9.
Tetraethyl (1ꢀformylaminomethyleneꢀ1ꢀphenyl)bisphosphonꢀ
ate (5c). Yield 84%, b.p. 198 °C (2 Torr). Found (%): C, 47.03;
H, 6.59. C16H27NO7P2. Calculated (%): C, 47.18; H, 6.68.
The first isomer, content of 80%. 1H NMR (CDCl3), δ:
0.50—0.60 (m, 12 H, 4 CH3); 3.30—3.60 (m, 8 H, 4 CH2);
6.60—7.50 (m, 5 H, C6H5); 7.86 (s, 1 H, CHO). 13C{1H} NMR
3. S. C. Fields, Tetrahedron, 1999, 55, 12237.
4. E. V. Grigoriev, N. S. Yashina, A. A. Prishchenko, M. V.
Livantsov, V. S. Petrosyan, L. Pellerito, M. J. Schafer, Appl.
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Livantsov, V. S. Petrosyan, W. Massa, K. Harms, S. Wocadlo,
L. Pellerito, Appl. Organomet. Chem., 1995, 9, 11.
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Chem. Pharm. Bull., 1993, 41, 688.
3
(CDCl3), δ: 15.16 (d, CH3, JP,C = 3.0 Hz); 15.14 (d, CH3,
3JP,C = 2.5 Hz); 62.48 and 62.68 (both s, 2 CH2); 65.45 (t, C(1),
2
1JP,C = 132.2 Hz); 135.00 (t, C(2), JP,C = 4.7 Hz); 127.95
(t, C(3), 3JP,C = 4.0 Hz); 126.31 (s, C(4)), 127.29 (s, C(5)); 158.80
(t, CHO, 3JP,C = 7.7 Hz). 31P{1H} NMR (CDCl3), δ: 15.83 (s).
1
The second isomer, content of 20%. H NMR (CDCl3), δ:
0.50—0.60 (m, 12 H, 4 CH3); 3.30—3.60 (m, 8 H, 4 CH2);
6.60—7.50 (m, 5 H, C6H5); 7.76 (s, 1 H, CHO). 13C{1H} NMR
(CDCl3), δ: 14.95 and 14.99 (both s, 2 CH3); 62.40 and 62.75
(both s, 2 CH2); 62.33 (t, C(1), 1JP,C = 131.8 Hz); 135.00 (t, C(2),
2JP,C = 4.7 Hz); 127.95 (t, C(3), 3JP,C = 4.0 Hz); 126.31 (s, C(4)),
127.29 (s, C(5)); 164.69 (br.s, CHO). 31P{1H} NMR (CDCl3), δ:
15.23 (s).
Tetraethyl (1ꢀaminoethaneꢀ1,1ꢀdiyl)bisphosphonate (6a). To
a stirred mixture of 1ꢀiminoꢀ1ꢀethoxyethane hydrochloride (11.7 g,
0.09 mol) and dichloromethane (35 mL), diethyl phosphite (15 g,
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trifluoride diethyl etherate (1.2 g, 0.08 mol). The reaction mixꢀ
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removed in vacuo, the reaction mixture was refluxed until comꢀ
plete dissolution of the residue, and the volatiles were removed
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Received October 15, 2015;
in revised form November 3, 2015