Catalytic hydrophosphorylation of semicarbazones, thiosemicarbazones, carbonohydrazones, and oxalyldihydrazones

Article abstract of DOI:10.1007/s11172-012-0054-1

Reaction of diethyl phosphite with semicarbazones, thiosemicarbazones, carbonohydrazones, and oxalyldihydrazones of aliphatic and carbocyclic ketones catalyzed by [tetra(tert-butyl)phthalocyanine]aluminum chloride resulted in hydrophosphorylation of the C

Full text of DOI:10.1007/s11172-012-0054-1

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 386—391, February, 2012
386
Catalytic hydrophosphorylation of semicarbazones,
thiosemicarbazones, carbonohydrazones, and oxalyldihydrazones
E. D. Matveeva,a,b T. A. Podrugina,a I. V. Sharutin,b and N. S. Zefirova,b
aDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 0290. Eꢀmail: matveeva@org.chem.msu.ru
bInstitute of Physiologically Active Substances, Russian Academy of Sciences,
1 Severnyi proezd, Chernogolovka, 142432 Moscow Region, Russian Federation
Reaction of diethyl phosphite with semicarbazones, thiosemicarbazones, carbonohydrazones,
and oxalyldihydrazones of aliphatic and carbocyclic ketones catalyzed by [tetra(tertꢀbutyl)ꢀ
phthalocyanine]aluminum chloride resulted in hydrophosphorylation of the C=N bonds of
hydrazones under study.
Key words: ꢀhydrazino phosphonates, the Pudovik reaction, [tetra(tertꢀbutyl)phthaloꢀ
cyanine]aluminum chloride, semicarbazones, thiosemicarbazones, carbonohydrazones,
oxalyldihydrazones, hydrazones.
The design of hybrid molecules incorporating several
a series of semicarbazones, effective antibacterial,13 antiꢀ
tuberculosis,14 antiviral,15 and antitumor16 agents were
found. The aim of the present work is the incorporation of
the NHC(X)NHN moiety into the aminophosphonate
fragment.
pharmacophoric groups is one of the promising trends of
the modern organic synthesis. For compounds combining
both the phosphonate and hydrazide groups, the PASS
software and the molecular docking predict properties simꢀ
ilar to those of endogenous ligands of ꢀaminobutyric acid
and glutamic receptors, which are the targets in the treatꢀ
ment of neurodegenerative diseases.
A limited number of synthetic strategies toward hydrꢀ
azino phosphonate moiety are known. Among them it is
of note nucleophilic substitution of mesitylated hydroxy
groups of hydroxy phosphonates in the presence of hydrꢀ
azine,1 their reduction with NaBH3CN,2 the Lewis acidꢀ
mediated threeꢀcomponent Kabachnik—Fields reaction
involving hydrazines as amine component,3,4 hydrophosꢀ
phorylation of hydrazones under conditions of acid5,6 or
basic7 catalysis. The type of the carbonyl component sigꢀ
nificantly limits application of all these methods, thus,
target hydrazone phosphonates can be prepared mainly
from aldehydes.
Earlier, we developed synthetic approach toward amiꢀ
no phosphonates employing catalysis by tetra[tertꢀbutylꢀ
phthalocyanine]aluminum chloride (tPcAlCl). This method
allows synthesis of hitherto unknown phosphonates from
various ketones, thus extending the scope of the carbonyl
compounds used in the Kabachnik—Fields reaction.8 It
was also shown9—12 that this strategy could be applied for
the synthesis of hydrazino phosphonates.
The reaction cannot be carried out in a threeꢀcompoꢀ
nent system (carbonyl compound, amine, and phosphite).
On the example of the reaction of NꢀBocꢀpiperidone,
semicarbazide, and diethyl phosphite catalyzed by tPcAlCl
it was shown that no step of hydrophosphorylation virtuꢀ
ally occurred due to low solubility of in situ formed semiꢀ
carbazone precipitating from the reaction mixture. Solꢀ
ventꢀfree twoꢀcomponent procedure involving hydrophosꢀ
phorylation of preliminary synthesized semicarbazones
1—9 with excess diethyl phosphite was more promising.
Comparative analysis of the catalytic activity of
tertꢀbutylphthalocyanine (tPcH2), its complexes with metals
(Mg, Al, Cr), and other catalysts commonly used for
hydrophosphorylation, e.g., Lewis acids (manganese perꢀ
chlorate,17 aluminum and zinc chlorides18) were perꢀ
formed on an example of twoꢀcomponent hydrophosꢀ
phorylation of semicarbazone 1 (Scheme 1).
The obtained data revealed stronger catalytic effect of
complexes of tPcH2 with chromium and zinc; the highest
yields (70—80%) were achieved in the presence of tPcCrCl
and tPcAlCl.
Aliphatic semicarbazones 1—4 (Scheme 2, Table 1)
react with excess diethyl phosphite in the presence of
tetra[tertꢀbutylphthalocyanine]aluminum chloride. Note
that attempts to involve aromatic semicarbazones 5—9 in
the reaction failed (see Experimental).
The NHC(X)NHN (X = O, S) moiety is the universal
pharmacophoric group since the carbonic acid derivatives
exhibit wide spectrum of biological activity. Thus, in
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 384—389, February, 2012.
1066ꢀ5285/12/6102ꢀ386 © 2012 Springer Science+Business Media, Inc.

Phosphorylation of hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
387
Scheme 1
yields were achieved for phosphonates 10 and 11 startꢀ
ing from NꢀBocꢀpyperidone (1) and cyclohexanone (2)
semicarbazones, respectively, which is apparently can
be explained by conformational effect of the sixꢀmemꢀ
bered ring.
In the present work, carbonohydrazones 14, 15 and
oxalyldihydrazones 16, 17 were used for the first time.
Two identical imine bonds of compounds 14—17 make
hydrophosphorylation of both imine fragments possible;
the corresponding diphosphonates 18—21 were obtained
in high yields (Scheme 3). The use of tPcAlCl as the cataꢀ
lyst shortened the reaction time twoꢀfold (Table 2).
Reagent and conditions: (EtO)2P(O)H, 1 : (EtO)2P(O)H = 1 : 20,
catalyst (5 mol.%), 80 C, 8 h.
Scheme 3
Catalyst
Yield of 10
Catalyst
Yield of 10
(%)
30
0
20
30
(%)
30
60
70
80
Without catalyst
Mg(ClO4)2
tPcMg
AlCl3
tPcH2
tPcCrCl
tPcAlCl
ZnCl2
Scheme 2
Compound
1, 10
2, 11
R1
R2
CH2CH2N(Boc)CH2CH2
(CH2)5
3, 12
Me
Me
4, 13
(CH2)6
Reagent and conditions: (EtO)2P(O)H, tPcAlCl, 80 C.
It should be noted that prolongation of catalystꢀfree
reaction does not increased the yield of the product of
hydrophosphorylation 10—13. The reaction time given in
Table 1 is optimal. In the presence of catalyst, twoꢀfold
increase in the product yields was observed. The highest
14, 16, 18, 20: R1 = R2 = Me
15, 17, 19, 21: R1 + R2 = (CH2)5
Reagent and conditions: (EtO)2P(O)H, tPcAlCl, 80 C.
The possibility to synthesize the products of monoꢀ
phosphorylation was also explored, however, due to low
solubility of compounds 14—17 in diethyl phosphite, reꢀ
action cannot be carried out at equimolar reactant ratio,
therefore, no solvent can be used.
Table 1. Synthesis of ꢀcarbamoylhydrazino phosphonates 10—13
from semicarbazones 1—4 in the presence and in the absence of
t
catalyst PcAlCl
Hydrophosphorylation of thiosemicarbazones 22—24
resulted in target thiocarbamoylhydrazino phosphonates
25—27 in 25—30% yields (Scheme 4, Table 3).
Semicarbꢀ /h
azone
Product
Yield (%)
Without catalyst tPcAlCl
Moderate yields of compounds 25—27 are due to side
reactions leading to unstable products, which were identiꢀ
fied in the reaction mixtures by the signals in the range of
 30—32 in the 31P NMR spectra. Low stable product 28
was obtained by the sequence involved chromatographic
1
2
3
4
8
16
20
30
10
11
12
13
30
40
30
20
80
70
50
50

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Matveeva et al.
Table 2. Synthesis of ꢀhydrazinophosphonates 18—21 from
carbonohydrazones 14—17 in the presence and in the absence of
catalyst PcAlCl
Table 3. Hydrophosphorylation of thiosemicarbazones 22—24
in the presence and in the absence of catalyst tPcAlCl
t
Thiosemiꢀ
carbazone
/h
Phosphonate Yield
(%)
Hydrꢀ
azone
/h
Without catalyst
Diphosꢀ
phonate
Yield
(%)
Without catalyst tPcAlCl
tPcAlCl
22
23
24
20
20
20
12
10
12
25
26
27
30
30
25
14
15
16
17
30
30
10
10
15
15
6
18
19
20
21
60
80
90
90
5
Apparently, product 28 formed as a result of alkylation
of the sulfur atom with diethyl phosphite in the molecule
of the starting thiosemicarbazone 23 and further hydrolyꢀ
sis of the resulting salt 28´ (see Scheme 5).
Scheme 4
Structures of the obtained phosphonates 10—13,
18—21, and 25—27 were established by IR, 1H, 13C, and
31P spectroscopy and confirmed by elemental analysis.
In the IR spectra of all hydrazino phosphonates synꢀ
thesized, absorption bands in the range of 1230—1260 cm–1
is corresponded to the P=O group, in the range of
3230—3290 cm–1 is attributed to the N—H bond, and in
the range of 1700—1720 cm–1 is assigned to the C=O
group. In the IR spectra of compounds 10—13, the abꢀ
sorption bands at 1720—1740 cm–1 characteristic of the
amide NH2 group are also observed. The IR spectra of
compounds 25—27 contained the absorption bands of the
22, 25: R1 = R2 = Me
23, 26: R1 + R2 = (CH2)5
24, 27: R1 + R2 = CH2CH2N(Boc)CH2CH2
Reagent and conditions: (EtO)2P(O)H, tPcAlCl, 80 C.
separation of the reaction mixture of cyclohexanone 23
with diethyl phosphite and subsequent hydrolysis of the
isolated fraction. The 31P NMR spectrum of compound
28 exhibits only one signal at  31.38; the 1H NMR specꢀ
trum contains triplet at  1.24 and multiplet in the range of
 4.00—4.07 attributed to the phosphonate ethoxy group,
as well as quartet at  2.88 and triplet at  1.24 characterisꢀ
tic of sulfide ethyl group. In the 13C NMR spectrum,
signal at  161.2 is attributed to the C atom of the carbonꢀ
yl group and doublet at  57.88 (1JC,P = 143.2 Hz)
is associated with ꢀC atom. Taking into account the
NMR spectral data and the MS data (molecular ion m/z
338 [M]+), for compound 28, the structure of phosphoꢀ
nate with alkyl group at the sulfur atom was suggested
(Scheme 5).
C—S bond in the C=S group at 810—850 cm–1
.
In the 31P NMR spectra of all carbamoylhydrazino
phosphonates synthesized, the signals of the P atom are
1
found in the range of  26—31. In the H NMR spectra,
the protons of the ethoxy groups resonate as triplets at
 1.27—1.35 and as multiplets at  4.00—4.20.
The signals of the ꢀC atom in the 13C NMR spectra
of compounds 10—13, 18—21, and 25—27 are observed
in the range of  56.0—61.87 (1JC,P = 140.4—150.0 Hz),
the C atoms of the phosphonate ethoxy groups resoꢀ
nate at  16.54—16.67 (3JC,P = 4.0—5.5 Hz) and at
 62.42—63.09 (2JC,P = 6.6—8.1 Hz). Other signals in the
1H and 13C NMR spectra of compounds 10—13, 18—21,
and 25—27 are in agreement with frameworks of the startꢀ
ing compounds.
Scheme 5

Phosphorylation of hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
389
Acetone thiosemicarbazone (22). Yield 65%, m.p. 181 C
(cf. Ref. 27: 132—136 C).
Experimental
Diethyl phosphite (Aldrich) was used as purchased. Tetraꢀ
[tertꢀbutylphthalocyanine]aluminum chloride (tPcAlCl) was synꢀ
thesized by known procedure.19
Cyclohexanone thiosemicarbazone (23). Yield 70%, m.p.
169 C (cf. Ref. 27: 154—155 C).
tertꢀButyl 4ꢀ(carbamoylthiohydrazono)piperidineꢀ1ꢀcarbꢀ
oxylate (24) was synthesized according to the known procedure23
from NꢀBocꢀpiperidone. Yield 70%, m.p. 151 C. 1H NMR
(CDCl3), : 1.19 (s, 9 H, But); 2.17—2.25 (m, 4 H, CH2CH2N);
3.25—3.34 (m, 4 H CH2CH2N). 13C NMR (CDCl3), : 26.75
(CH2CH2N); 27.69 (Me, But); 33.10 (CH2CH2N); 40.79
(CH2CH2N); 43.30 (CH2CH2N.); 80.24 (CMe3); 152.48 (C=N);
154.57 (C(O)OBut); 178.27 (NHCSNH2). IR, /cm–1: 810
(C=S), 1670, 1685 (C=O); 3280 (N—H). Found (%): C, 48.81;
H, 7.51; N, 20.74. C11H20N4O2S. Calculated (%): C, 48.51;
H, 7.40; N, 20.57.
1H (400.13 MHz), 13C (100.61 MHz), and 31P (161.98 MHz)
spectra were run on a Bruker Avance 400 instrument in CDCl3
relative to Me4Si (1H, 13C, internal standard) and 85% aqueous
H3PO4 (31P, external standard). IR spectra were recorded on an
URꢀ20 instrument in CCl4. Mass spectra (EI, 70 eV, direct inlet)
were run on a Finnigan Mat Incos50 quadruple mass spectroꢀ
meter. Elemental analysis was carried out on a VarioꢀII
CHNꢀanalyzer and using the straight empty tube method of Korꢀ
shun and Klimova.
The course of the reactions and the purity of compounds
were monitored by TLC carried out on a ALUGRAM SIL
G/UV254 plates. Column chromatography was performed on
silica gel (Merck 60, 70—230 mesh ASTM).
Synthesis of hydrazino phosphonates (general procedure). To
a hydrazone (1 mmol), diethyl phosphite (10—20 mmol) and
tPcAlCl (0.05 mmol) were added. The stirred reaction mixture
was heated at 80 C under argon. The course of the reaction
was monitored by TLC. The excess diethyl phosphite was reꢀ
moved in vacuo, the residue was dissolved in a small amount of
CHCl3—MeOH and purified by column chromatography (silica
gel, column length 15 cm, column diameter 1.5—2.0 cm).
tertꢀButyl 4ꢀ(2ꢀcarbamoylhydrazino)ꢀ4ꢀ(diethyoxyphosphorꢀ
yl)piperidineꢀ1ꢀcarboxylate (10) was synthesized at the ratio
1 : (EtO)2P(O)H = 1 : 20. Reaction time was 8 h. Yield 80%.
1H NMR (CDCl3), : 1.29 (t, 6 H, POCH2CH3, 3JH,H = 7.1 Hz);
1.39 (s, 9 H, But); 1.65—1.74, 1.80—1.89 (both m, 4 H each,
CH2CH2N); 3.02—3.12, 3.76—3.87 (both m, 4 H each,
CH2CH2N); 4.07—4.15 (m, 4 H, POCH2CH3); 4.1 (br.s, 1 H,
NH); 5.3 (br.s, 2 H, NH2); 6.41 (s, 1 H, NH). 13C NMR
tertꢀButyl 4ꢀ(carbamoylhydrazono)piperidineꢀ1ꢀcarboxylate
(1). A mixture of NꢀBocꢀpiperidone (1 mmol), semicarbazide
hydrochloride (6 mmol), and NaOAc (6 mmol) was refluxed
for 1—3 h in ethanol—water, cooled to ambient temperaꢀ
ture, the precipitate formed was filtered, washed with waꢀ
ter, diethyl ether, and dried in a vacuum desiccator. Yield 90%,
m.p. 153 C. 1H NMR (CDCl3), : 1.47 (s, 9 H, But); 2.39—2.46
(m, 4 H, CH2CH2N); 3.50—3.63 (m, 4 H, CH2CH2N);
5.34 (br.s, NHCONH2); 6.06 (br.s, NHCONH2); 9.17 (br.s,
NHCONH2). 13C NMR (CDCl3), : 26.93 (CH2CH2N); 28.41
(Me, But); 33.69 (CH2CH2N); 41.91 (CH2CH2N); 43.81
(CH2CH2N); 80.03 (CMe3); 149.45 (C=N); 154.55 (C(O)OBut);
158.54 (NHCONH2). IR, /cm–1: 1670, 1685 (C=O);
1725 (NH2); 3280 (N—H). Found (%): C, 51.73; H, 7.88;
N, 21.76. C11H20N4O3. Calculated (%): C, 51.55; H, 7.87;
N, 21.86.
3
(CDCl3), : 16.67 (d, POCH2CH3, JC,P = 4.4 Hz); 27.26
(CH2CH2N); 28.48 (Me, But); 38.07 (CH2CH2N); 56.76
1
(d, C(1), cycl., JC,P = 147.8 Hz); 63.03 (d, POCH2CH3,
Cyclohexanone semicarbazone (2). Yield 85%, m.p. 165 C
(cf. Ref. 20: C).
Acetone semicarbazone (3). Yield 80%, m.p. 188 C (cf. Ref. 20:
190—191 C).
Cycloheptanone semicarbazone (4). Yield 80%, m.p. 173 C
(cf. Ref. 20: 173—174 C).
Benzaldehyde semicarbazone (5). Yield 95%, m.p. 212 C
(cf. Ref. 21: 214 C).
2JC,P = 7.6 Hz); 79.92 (CMe3); 154.70 (C(O)OBut); 159.76
(NHCONH2). 31P NMR (CDCl3), : 23.85. IR, /cm–1: 1040,
1060 (P—O—C); 1255 (P=O); 1670, 1685 (C=O); 1720 (NH2);
3280 (N—H). Found (%): C, 45.60; H, 7.93; N, 14.69.
C15H31N4O6P. Calculated (%): C, 45.7; H, 7.92; N, 14.21.
Diethyl [1ꢀ(2ꢀcarbamoylhydrazino)cyclohexyl]phosphonate
(11) was synthesized at the ratio 2 : (EtO)2P(O)H = 1 : 10. Reꢀ
action time was 16 h. Yield 70%, m.p. 58 C. 1H NMR (CDCl3),
4ꢀTrifluoromethylbenzaldehyde semicarbazone (6). Yield 95%,
: 1.24—1.30 (m, 1 H, cycl.); 1.35 (t, 6 H, POCH2CH3, 3JH,H
=
m.p. 199 C. 1H NMR (CDCl3), : 6.60 (br.s, 2 H); 7.70 (d, 2 H,
= 7.0 Hz); 1.55—1.60, 1.64—1.83 (both m, 9 H, cycl.); 3.98
(s, 1 H, NH); 4.12—4.19 (m, 4 H, POCH2CH3); 5.11 (br.s, 1 H,
NH); 5.85 (br.s, 1 H, NH); 6.38 (br.s, 1 H, NH). 13C NMR
3
3JH,H = 8.1 Hz); 7.87 (s, 1 H); 7.93 (d, 2 H, JH,H = 8.1 Hz);
1
10.05 (s, 1 H). H NMR spectrum is in agreement with that
3
published earlier.22
(CDCl3), : 16.64 (d, POCH2CH3, JC,P = 4.8 Hz); 20.39
3
4ꢀMethoxybenzaldehyde semicarbazone (7). Yield 95%, m.p.
194 C (cf. Ref. 21: 203—204 C).
Furanꢀ2ꢀcarboxaldehyde semicarbazone (8). Yield 90%,
m.p.197 C (cf. Ref. 21: 213—214 C).
(d, C(3), cycl., JC,P = 10.5 Hz); 25.14 (s, C(4), cycl.); 27.44
1
(s, C(2), cycl.); 58.2 (d, C(1), cycl., JC,P = 143.8 Hz), 62.62
(d, POCH2CH3, 2JC,P = 8.0 Hz); 160.20 (NHCONH2). 31P NMR
(CDCl3), : 29.54. IR, /cm–1: 1040, 1070 (P—O—C); 1230
(P=O); 1665 (C=O); 1735 (NH2); 3280 (N—H). Found (%):
C, 45.46; H, 7.94; N, 15.18. C11H24N3O4P. Calculated (%):
C, 45.05; H, 8.25; N, 14.33.
Pyridinꢀ3ꢀcarboxaldehyde semicarbazone (9). Yield 85%, m.p.
186 C.21
N,N´ꢀBis(1ꢀmethylethylidene)carbonohydrazide (14). Yield
95%, m.p. 166 C (cf. Ref. 23: 164—165 C).
Dicyclohexylidenecarbonohydrazide (15). Yield 90%, m.p.
144 C (cf. Ref. 24: 143—145 C).
N,N´ꢀBis(1ꢀmethylethylidene)ethanedihydrazide (16). Yield
95%, m.p. 208 C (cf. Ref. 25: 224—225 C).
N,N´ꢀDicyclohexylideneethanedihydrazide (17). Yield 90%,
m.p. 215 C (cf. Ref. 26: 224—225 C).
Diethyl [1ꢀ(2ꢀcarbamoylhydrazino)ꢀ1ꢀmethylethyl]phosphꢀ
onate (12) was synthesized at the ratio 3 : (EtO)2P(O)H = 1 : 10.
Reaction time was 20 h. Yield 50%, white crystals, m.p. 63 C.
1H NMR (CDCl3), : 1.27, 1.31 (both s, 6 H each, 2 Me); 1.33
3
(t, 6 H, POCH2CH3, JH,H = 7.1 Hz); 4.11—4.19 (m, 4 H,
POCH2CH3); 5.5 (br.s, 2 H, NHC(O)NH2); 6.51 (br.s, 1 H,
NHC(O)NH2). 13C NMR (CDCl3), : 16.56 (d, POCH2CH3,

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Matveeva et al.
3JC,P = 5.1 Hz); 20.96 (Me); 56.02 (d, C(1), 1JC,P = 145.5 Hz);
62.58, (d, POCH2CH3, 2JC,P = 8.1 Hz); 160.92 (NHC(O)NH2).
31P NMR (CDCl3), : 29.74. IR, /cm–1: 1030, 1070 (P—O—C);
1250 (P=O); 1660 (C=O); 1730 (NH2); 3230 (N—H). Found (%):
C, 38.02; H, 7.81; N, 16.78. C8H20N3O4P. Calculated (%):
C, 37.94; H, 7.96; N, 16.59.
ratio 17 : (EtO)2P(O)H = 1 : 10. Reaction time was 5 h. Yield
90%, m.p. 76 C. 1H NMR (CDCl3), : 1.16—1.26 (m, 2 H,
cycl.); 1.34 (t, 12 H, POCH2CH3, 3JH,H = 7.0 Hz); 1.49—1.56,
1.57—1.67, 1.68—1.83 (all m, 18 H each, cycl.); 4.14—4.21
(m, 8 H, POCH2CH3); 4.50 (br.s, 2 H, NH); 9.29 (br.s, 2 H, NH).
3
13C NMR (CDCl3), : 16.53 (d, POCH2CH3, JC,P = 5.1 Hz);
Diethyl [1ꢀ(2ꢀcarbamoylhydrazino)cycloheptyl]phosphonate
(13) was synthesized at the ratio 4 : (EtO)2P(O)H = 1 : 10. Reacꢀ
tion time was 30 h. Yield 50%, m.p. 65 C. 1H NMR (CDCl3), :
1.29 (t, 6 H, POCH2CH3, 3JH,H = 7.2 Hz); 1.46—1.51, 1.51—1.59,
1.85—1.96 (both m, 12 H each, cycl.); 4.06—4.14 (m, 4 H,
POCH2CH3); 6.32 (br.s, 2 H, NHCONH2); 6.61 (br.s, 1 H,
NHCONH2). 13C NMR (CDCl3), : 16.55 (d, POCH2CH3,
19.76 (d, C(3), cycl., 3JC,P = 11.0 Hz); 25.04 (C(4), cycl.); 27.54
1
(C(2), cycl.); 58.46 (d, C(1), cycl., JC,P = 156.7 Hz); 62.88
(d, POCH2CH3, 2JC,P = 8.0 Hz); 156.07 (NHCOCONH). 31P NMR
(CDCl3), : 28.17. IR, /cm–1: 1040, 1070 (P—O—C); 1230
(P=O); 1670 (C=O); 3280 (N—H). Found (%): C, 47.53;
H, 7.97; N, 9.97. C22H44N4O8P2. Calculated (%): C, 47.65;
H, 8.00; N, 10.10.
3
3JC,P = 5.0 Hz); 22.54 (d, C(3), cycl., JC,P = 8.0 Hz); 30.93
Diethyl [1ꢀ(2ꢀcarbamothioylhydrazino)ꢀ1ꢀmethylethyl]phosꢀ
phonate (25) was synthesized at the ratio 22 : (EtO)2P(O)H =
= 1 : 10. Reaction time was 20 h, elution with chloroform—methꢀ
anol, 40 : 1. Yield 30%. 1H NMR (CDCl3), : 1.23, 1.27 (both s,
2
(s, C(4), cycl.), 31.66 (d, C(2), cycl., JC,P = 3.1 Hz); 61.87 (d,
1
2
C(1), cycl., JC,P = 139.9 Hz); 62.73 (d, POCH2CH3, JC,P
=
= 8.1 Hz); 161.71 (NHCONH2). 31P NMR (CDCl3), : 30.53.
IR, /cm–1: 1030, 1060 (P—O—C); 1260 (P=O); 1710, 1740
(C=O); 1730 (NH2); 3300, 3390 (N—H). Found (%): C, 46.87;
H, 8.65; N, 13.46. C12H26N3O4P. Calculated (%): C, 46.73;
H, 8.53; N, 13.7.
3
6 H each, 2 Me); 1.31 (t, 6 H, POCH2CH3, JH,H = 7.0 Hz);
4.11—4.17 (m, 4 H, POCH2CH3); 6.75, 7.04 (both br.s, 2 H each,
NHCSNH2); 7.74 (br.s, 1 H, NHCSNH2). 13C NMR (CDCl3),
1
: 16.55 (s, POCH2CH3); 20.89 (Me); 56.23 (d, C(1), JC,P
=
2
2,8ꢀDimethylꢀ2,8ꢀbis(diethoxyphosphoryl)ꢀ3,4,6,7ꢀtetraazaꢀ
nonanꢀ5ꢀone (18) was synthesized at the ratio 14 : (EtO)2P(O)H =
= 1 : 10. Reaction time was 15 h. Yield 60%. 1H NMR (CDCl3),
: 1.23, 1.27 (both s, 12 H, 4 Me); 1.28 (t, 12 H, POCH2CH3,
= 146.7 Hz); 63.09, (d, POCH2CH3, JC,P = 6.8 Hz); 183.35
(NHCSNH2). 31P NMR (CDCl3), : 29.00. IR, /cm–1: 810
(C=S); 1030, 1070 (P—O—C); 1250 (P=O); 3230 (N—H).
Found (%): C, 35.46; H, 7.20; N, 15.81. C8H20N3O3PS. Calcuꢀ
lated (%): C, 35.68; H, 7.49; N, 15.6.
3JH,H = 7.0 Hz); 4.07—4.14 (m, 8 H, POCH2CH3); 4.08 (br.s, 2 H,
3
NH). 13C NMR (CDCl3), : 16.51 (d, POCH2CH3, JC,P
=
Diethyl [1ꢀ(2ꢀcarbamothioylhydrazino)cyclohexyl]phosꢀ
phonate (26) was synthesized at the ratio 23 : (EtO)2P(O)H =
= 1 : 10. Reaction time was 20 h, elution with chloroform—methꢀ
anol, 40 : 1. Yield 30%, m.p. 60 C. 1H NMR (CDCl3), : 1.14—1.29
= 4.8 Hz); 20.91 (Me); 56.23 (d, C(1), 1JC,P = 150.1 Hz); 62.46
(d, POCH2CH3, 2JC,P = 7.7 Hz); 159.48 (NHCONH). 31P NMR
(CDCl3), : 29.66. IR, /cm–1: 1030, 1070 (P—O—C); 1250
(P=O); 1680 (C=O); 3230 (N—H). Found (%): C, 40.22;
H, 8.08; N, 12.61. C15H36N4O7P2. Calculated (%): C, 40.36;
H, 8.13; N, 12.55.
3
(m, 1 H, cycl.); 1.31 (t, 6 H, POCH2CH3, JH,H = 7.0 Hz);
1.45—1.66, 1.67—1.74 (both m, 9 H each, cycl.); 4.09—4.16
(m, 4 H, POCH2CH3); 6.54 (br.s, 1 H, NH); 6.99 (br.s, 1 H, NH);
7.74 (br.s, 1 H, NH). 13C NMR (CDCl3), : 16.61 (d, POCH2CH3,
Tetraethyl [carbonylbis(hydrazineꢀ2,1ꢀdiylcyclohexaneꢀ1,1ꢀ
diyl)]bisphosphonate (19) was synthesized at the ratio
15 : (EtO)2P(O)H = 1 : 10. Reaction time was 15 h. Yield 80%.
1H NMR (CDCl3), : 1.13—1.19 (m, 2 H, cycl.); 1.27 (t, 12 H,
POCH2CH3, 3JH,H = 7.0 Hz); 1.42—1.48, 1.53—1.71, 1.72—1.80
(all m, 18 H each, cycl.); 4.05—4.13 (m, 8 H, POCH2CH3);
3.98 (br.s, 2 H, NH); 7.0 (br.s, 2 H, NH). 13C NMR (CDCl3), :
3
3JC,P = 5.5 Hz); 20.44 (d, C(3), cycl., JC,P = 10.6 Hz); 25.01
1
(C(4), cycl.); 27.49 (C(2), cycl.); 58.38 (d, C(1), cycl., JC,P
=
2
= 144.6); 62.86 (d, POCH2CH3, JC,P = 8.0 Hz); 182.86
(NHCSNH2). 31P NMR (CDCl3), : 28.75. IR, /cm–1: 810
(C=S), 1040, 1070 (P—O—C); 1230 (P=O); 3280 (N—H).
Found (%): C, 42.97; H, 7.65; N, 13.78. C11H24N3O3PS. Calcuꢀ
lated (%): C, 42.7; H, 7.82; N, 13.6.
3
16.57 (d, POCH2CH3, JC,P = 4.0 Hz); 20.00 (d, C(3), cycl.,
3JC,P = 10.8 Hz); 25.34 (C(4), cycl.); 27.53 (C(2), cycl.); 58.36
tertꢀButyl 4ꢀ(2ꢀcarbamothioylhydrazino)ꢀ4ꢀ(diethoxyphosꢀ
phoryl)piperidineꢀ1ꢀcaroxylate (27) was synthesized at the ratio
24 : (EtO)2P(O)H = 1 : 10. Reaction time was 20 h. Yield 25%.
1H NMR (CDCl3), : 1.36 (t, 6 H, POCH2CH3, 3JH,H = 7.1 Hz);
1.45 (s, 9 H, But); 1.74—1.81, 1.86—1.96 (both m, 4 H,
CH2CH2N); 3.08—3.18, 3.81—3.97 (both m, 4 H each,
CH2CH2N); 4.12—4.20 (m, 4 H, POCH2CH3); 5.50 (br.s, 2 H,
NH); 6.52 (br.s, 1 H, NH). 13C NMR (CDCl3), : 16.64
1
(d, C(1), cycl., JC,P = 148.6 Hz); 62.42 (d, POCH2CH3,
2JC,P = 7.7 Hz); 158.2 (NHCONH). 31P NMR (CDCl3), :
29.17. IR, /cm–1: 1040, 1070 (P—O—C); 1230 (P=O); 1665
(C=O); 3280 (N—H). Found (%): C, 47.85; H, 8.41; N, 10.51.
C21H44N4O7P2. Calculated (%): C, 47.9; H, 8.42; N, 10.64.
2,9ꢀDimethylꢀ2,9ꢀbis(diethoxyphosphoryl)ꢀ3,4,7,8ꢀtetraazaꢀ
decaneꢀ5,6ꢀdione (20) was synthesized at the ratio
16 : (EtO)2P(O)H = 1 : 10. Reaction time was 6 h. Yield 90%,
m.p. 85 C. 1H NMR (CDCl3), : 1.25, 1.29 (both s, 12 H,
3
(d, POCH2CH3, JC,P = 5.1 Hz); 27.30 (CH2CH2N); 28.46
1
(Me, But); 38.34 (CH2CH2N); 56.99 (d, C(1), cycl., JC,P
=
3
2
4 Me); 1.30 (t, 12 H, POCH2CH3, JH,H = 7.0 Hz); 4.10—4.17
= 148.2 Hz); 63.41 (d, POCH2CH3, JC,P = 6.6 Hz); 80.10
(CMe3); 154.65 (C(O)OBut); 183.02 (NHCSNH2). 31P NMR
(CDCl3), : 27.33. IR, /cm–1: 1040, 1060 (P—O—C); 805
(C=S); 1255 (P=O); 1685 (C=O); 3280 (N—H). Found (%):
C, 43.66; H, 7.65; N, 13.61. C15H31N4O5PS. Calculated (%):
C, 43.9; H, 7.61; N, 13.65.
(m, 8 H, POCH2CH3); 4.25 (br.s, 2 H, NH). 13C NMR (CDCl3),
3
: 16.53 (d, POCH2CH3, JC,P = 4.8 Hz); 21.26 (Me); 56.66
1
2
(d, C(1), JC,P = 156.6 Hz); 62.98 (d, POCH2CH3, JC,P
=
= 7.23 Hz); 157.12 (NHCOCONH). 31P NMR (CDCl3), :
28.42. IR, /cm–1: 1030, 1070 (P—O—C); 1250 (P=O); 1675
(C=O); 3230 (N—H). Found (%): C, 40.36; H, 7.80; N, 11.61.
C16H36N4O8P2. Calculated (%): C, 40.5; H, 7.65; N, 11.8.
Tetraethyl [(1,2ꢀdioxoethaneꢀ1,2ꢀdiyl)bis(hydrazineꢀ2,1ꢀdiylꢀ
cyclohexaneꢀ1,1ꢀdiyl)]bisphosphonate (21) was synthesized at the
SꢀEthyl 2ꢀ[1ꢀ(diethoxyphosphoryl)cyclohexyl]hydrazinecarboꢀ
thioate (28) was synthesized at the ratio 23 : (EtO)2P(O)H =
= 1 : 10. Reaction time was 20 h, elution with chloroform—methꢀ
anol, 3 : 1. Further hydrolysis of the eluate separated was perꢀ

Phosphorylation of hydrazones
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
391
formed with 5% aqueous Na2CO3, yield 50%. 1H NMR (CDCl3),
11. E. D. Matveeva, T. A. Podrugina, I. N. Kolesnikova, N. S.
Zefirov, Izv. Akad. Nauk, Ser. Khim., 2010, 403 [Russ. Chem.
Bull., Int. Ed., 2010, 59, 411].
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Kolesnikova, G. G. Karateev, N. S. Zefirov, Izv. Akad. Nauk,
Ser. Khim., 2010, 409 [Russ. Chem. Bull., Int. Ed., 2010,
59, 418].
: 1.17—1.20 (m, 1 H, cycl.); 1.24 (t, 6 H, POCH2CH3, 3JH,H
=
= 7.0 Hz); 1.24 (t, 3 H, SCH2CH3,) 1.40—1.48, 1.50—1.59,
1.60—1.70 (all m, 7 H, cycl.); 1.90—2.88 (q, 2 H, SCH2CH3);
4.00—4.10 (m, 4 H, POCH2CH3); 4.05 (br.s, 1 H, NH); 4.66
(br.s, 1 H, NH). 13C NMR (CDCl3), : 14.01 (SCH2CH3); 15.56
3
3
(d, POCH2CH3, JC,P = 6.0 Hz); 19.42 (d, C(3), cycl., JC,P
=
= 10.1 Hz); 24.05 (SCH2CH3); 24.50 (C(4), cycl.); 28.00 (C(2),
cycl.); 57.88 (d, C(1), cycl., JC,P = 143.7 Hz); 60.77
(d, POCH2CH3, 2JC,P = 7.2 Hz); 161.20 (NHCOSEt). 31P NMR
(CDCl3), : 31.47. IR, /cm–1: 1040, 1070 (P—O—C); 1230
(P=O); 1670 (C=O); 3280 (N—H). MS, m/z: 338 [M]+, 278
[M + H – SEt]+, 221 [M – P(O)(OEt)2]+.
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hury, Bioorg. Med. Chem. Lett., 2010, 20, 1040.
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1
15. D. C. Quenelle, K. A. Keith, E. R. Kern, Antiviral Res.,
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
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 11ꢀ03ꢀ00641),
the Council for Grants at the President of the Russian
Federation (the Program for the State Support of Leading
Scientific Schools of the Russian Federation, Grant NShꢀ
65546.2010.3), the Department of Chemistry and Material
Sciences of the Russian Academy of Sciences (Programs
for Basic Research 1ꢀOKhNM RAS and 9ꢀOKhNM
RAS), and the Presidium of the RAS (Program P).
–
16. I. Dilovic´, M. Rubcic´, V. Vrdoljak, S. Kraljevic´ Pavelic´,
M. Kralj, I. Piantanida, M. Cindric´, Bioorg. Med. Chem.,
2008, 16, 5189.
17. J. Wu, W. Sun, H.ꢀG. Xia, X. Sun, Org. Biomol. Chem., 2006,
4, 1663.
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[Russ. Chem. Rev. (Engl. Transl.), 1998, 67, 857].
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21. A. R. Hajipour, I. MohammadpoorꢀBaltork, M. Bigdeli,
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Received June 30, 2011;
in revised form September 29, 2011