Synthesis of pyridine-containing α-hydrazino phosphonates by two-component catalytic procedure

Article abstract of DOI:10.1007/s11172-011-0042-x

Pyridine-containing α-hydrazino phosphonates were synthesized in high yields by reaction of hydrazones of pyridine series with diethyl phosphite in the presence of [tetra(tert-butyl)-phthalocyanine]aluminum chloride as a catalyst.

Full text of DOI:10.1007/s11172-011-0042-x

Russian Chemical Bulletin, International Edition, Vol. 60, No. 2, pp. 254—257, February, 2011
254
Synthesis of pyridineꢀcontaining αꢀhydrazino phosphonates
by twoꢀcomponent catalytic procedure
E. D. Matveeva, T. A. Podrugina, I. N. Kolesnikova, and N. S. Zefirov
Department 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
Pyridineꢀcontaining αꢀhydrazino phosphonates were synthesized in high yields by reaction
of hydrazones of pyridine series with diethyl phosphite in the presence of [tetra(tertꢀbutyl)ꢀ
phthalocyanine]aluminum chloride as a catalyst.
Key words: hydrazones, phosphorylation, pyridine derivatives, the Pudovik reaction,
[tetra(tertꢀbutyl)phthalocyanine]aluminum chloride, diethyl phosphite.
Scheme 1
One of the approaches to the potent twinꢀdrugs is the
combination of two pharmacophores in one molecule. The
aim of the present work is the combination of such
pharmacophores as phosphonate group and the pyridine
ring, which is the principal fragment of a series of vitamins
and medications,1—3 in one molecule. Earlier, we develꢀ
oped procedure toward hybrid molecules of this type,
which involved catalytic preparation of αꢀamino phosꢀ
phonates in the presence of [tetra(tertꢀbutyl)phthaloꢀ
cyanine]aluminum chloride (tPcAlCl). This method was
applied for the synthesis of αꢀamino phosphonates on the
base of 2ꢀ, 3ꢀ, and 4ꢀaminopyridines.4 Catalysis with
tPcAlCl was also successfully used for hydrophosphorylaꢀ
tion of azines and hydrazones.5—7 Present work is devoted
to the extension of this catalytic procedure on the synꢀ
thesis of hydrazino phosphonates from pyridineꢀcontainꢀ
ing hydrazones.
i. tPcAlCl, argon, 80 °C.
R =
(1, 6),
(2, 7),
Hydrazones 1—5 bearing the pyridine ring were preꢀ
pared by the reaction of cyclohexanone with 2ꢀhydrazinoꢀ
pyridine, pyridinecarboxhydrazides, and 6ꢀhydrazinoꢀ
pyridineꢀ3ꢀcarboxhydrazide in 85—90% yield.
Hydrophosphorylation of pyridineꢀcontaining hydrꢀ
azones 1—4 in the presence of tPcAlCl resulted in hitherto
unknown αꢀhydrazino phosphonates 6—9 (Scheme 1,
Table 1).
As it can be seen from the data in Table 1, the reaction
of cyclohexanone pyridinꢀ2ꢀylhydrazone (1) with diethyl
phosphite proceeded with low rate even under catalytic
conditions and afforded αꢀhydrazino phosphonate 6
in 35% yield.
(3, 8),
(4, 9)
Table 1. Synthetic conditions and yields of
pyridineꢀcontaining αꢀhydrazinophosphoꢀ
nates 6—9
Starting
τ/h
Product
Yield
(%)
hydrazone
Due to electronꢀwithdrawing carbonyl group, which
increased the electrophilicity of the imine bond, hydroꢀ
phosphorylation of acylhydrazones derived from hydrꢀ
azides of picolinic (2), nicotinic (3), and isonicotinic
acids (4) proceeded noticeably faster and the correspondꢀ
1
2
3
4
50
2
8
6
7
8
9
35
85
80
75
8
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 249—251, February, 2011.
1066ꢀ5285/11/6002ꢀ254 © 2011 Springer Science+Business Media, Inc.

Pyridineꢀcontaining αꢀhydrazinophosphonates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
255
ing αꢀhydrazino phosphonates 7—9 were prepared in
75—85% yield within 2—8 h.
In summary, the developed catalytic procedure allows
the synthesis of hitherto unknown pyridineꢀcontaining
αꢀhydrazino phosphonates.
The difference in the reactivity of two imine bonds in
dihydrazone 5 makes it possible to develop conditions for
chemoselective monoꢀ (compound 10) and diphosphoryꢀ
lations (compound 11). Thus, when the reaction was carꢀ
ried out for 6 h, monophosphonate 10 was isolated in 75%
yield, while prolongation of the reaction time up to 40 h
gave diphosphonate 11 as the main product in 50% yield
(Scheme 2).
Experimental
NMR spectra were run on a Bruker Avance 400 instrument
(400.13 (1H), 100.61 (13C), and 161.98 MHz (31P)) in CDCl3
relative of Me4Si (1H, 13C, internal standard) and 85% aqueous
H3PO4 (
31P, external standard). IR spectra were recorded on
a URꢀ20 in CCl4. Elemental analysis was carried out on a VarioꢀII
CHNꢀanalyzer.
Scheme 2
Diethyl phosphite (Aldrich) was used as purchased. [Tetraꢀ
(tertꢀbutyl)phthalocyanine]aluminum chloride was synthesized
according to the known procedure.8 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 (MN Kieselgel 60, 0.04—0.063 mm).
Cyclohexanone pyridinꢀ2ꢀylhydrazone (1). A mixture of cycloꢀ
hexanone (150 mg, 1.5 mmol) and 2ꢀhydrazinopyridine (110 mg,
1 mmol) was stirred at ambient temperature for 0.5 h, the preꢀ
cipitate that formed was filtered off, washed with diethyl ether,
and dried in vacuo. Yield 160 mg (85%), m.p. 92—93 °C (cf. Ref. 9:
92—92.5 °C).
Synthesis of hydrazones 2—5 (general procedure). A mixture
of cyclohexanone (9 mmol) and the corresponding hydrazide
(3 mmol) was refluxed for 3 h, the reaction mixture was cooled
to ambient temperature, the precipitate that formed was filtered
off, washed with diethyl ether, and dried in vacuo.
N´ꢀCyclohexylidenepyridineꢀ2ꢀcarboxhydrazide (2). Yield
90%, m.p. 148—149 °C (cf. Ref. 10: 148—150 °C).
N´ꢀCyclohexylidenepyridineꢀ3ꢀcarboxhydrazide (3). Yield
92%, m.p. 115—116 °C (cf. Ref. 11: 116—118 °C).
N´ꢀCyclohexylidenepyridineꢀ4ꢀcarboxhydrazide (4). Yield
90%, m.p. 166—168 °C (cf. Ref. 12: 168—169.5 °C).
N´ꢀCyclohexylideneꢀ6ꢀ(2ꢀcyclohexylidenehydrazino)pyridineꢀ
3ꢀcarboxhydrazide (5). Yield 88%, m.p. 294—296 °C. 1H NMR,
δ: 1.53—1.61 (m, 12 H, cycl.); 2.19—2.28 (m, 8 H, CH2, cycl.);
4.18 (br.s, 2 H, NHPy, NHC(O)); 7.08 (d, 1 H, Py, 3JH,H = 8.9 Hz);
7.91 (d, 1 H, Py, 3JH,H = 5.8 Hz); 8.40 (s, 1 H, Py). 13C NMR, δ:
25.35, 25.49, 25.72, 25.92, 26.03, 26.89, 26.95, 27.77, 35.23
(CH2, cycl.); 106.49, 119.78, 137.64, 147.10, 155.56 (C, Py);
158.71, 163.46 (C=N); 166.46 (C=O). IR, ν/cm–1: 1600 (C=N),
1640 (C=O); 3240 (NH). Found (%): C, 66.34; H, 7.50; N, 21.30.
C18H25N5O. Calculated (%): C, 66.03; H, 7.70; N, 21.39.
Synthesis of αꢀhydrazinophosphonates 6—11 (general proceꢀ
dure). Diethyl phosphite (5—8 mmol) and tPcAlCl (0.05 mmol)
were added to the corresponding hydrazone (1 mmol). The reꢀ
action mixture was stirred under argon at 80 °C until complete
(TLC monitoring). The volatiles were removed in vacuo, the
residue was dissolved in CH2Cl2—MeOH (70 : 1) and the product
was isolated by column chromatography (silica gel, column
height 15 cm, diameter 1.5—2.0 cm).
i. (EtO)2P(O)H, tPcAlCl, 80 °C, 6 h;
ii. (EtO)2P(O)H, tPcAlCl, 80 °C, 40 h.
Structures of αꢀhydrazino phosphonates 6—11 were
1
established by IR spectroscopy, H, 13C, and 31P NMR
spectroscopy, and confirmed by elemental analysis. The
IR spectra of the compounds synthesized exhibited the
absorption bands at 1230—1260 and 3230—3290 cm–1 atꢀ
tributed to the P=O group and the NH group, respectiveꢀ
ly. In the 31P NMR spectra of αꢀhydrazino phosphonates
6—10, the signals for the phosphorus atoms were observed
at the range of δ 27.85—30.51. The 31P NMR spectra
of αꢀhydrazino phosphonate 11 contained two signals
for the phosphorus atoms at δ 28.27 and 29.93. In the
13C NMR spectra of compounds 6—11 the signals for the
C(α) atoms appeared at the range of δ 58.38—58.93.
(1JC,P = 142.0—162.5 Hz). Other signals in 13C and
31P NMR spectra confirm also the structures of the comꢀ
pounds synthesized.
Diethyl 1ꢀ[2ꢀ(pyridinꢀ2ꢀyl)hydrazino]cyclohexylphosphonate
(6) was synthesized from hydrazone 1 at reactant ratio of 1 : 5,
the reaction time was 50 h. Yield 35%. 1H NMR, δ: 1.34 (t, 6 H,
3
2 Me, JH,H = 7.0 Hz); 1.41—1.50 (m, 2 H, CH2, cycl.);
1.59—1.75 (m, 6 H, CH2, cycl.); 1.82—1.89 (m, 2 H, CH2,
cycl.); 3.89 (br.s, 1 H, NH); 4.12—4.20 (m, 4 H, 2 OCH2);
3
6.57—6.60 (m, 2 H, Py); 7.06 (d, 1 H, Py, JH,H = 8.6 Hz);

256
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Matveeva et al.
7.45—7.49 (m, 1 H, Py); 8.02 (br.m, 1 H, NH). 13C NMR, δ:
16.67 (d, Me, 3JC,P = 5.1 Hz); 20.31 (d, 3JH,P = 11.0 Hz); 25.35,
6 h. Yield 75%. 1H NMR, δ: 1.16—1.23 (m, 1 H, CH2, cycl.);
1.33 (t, 6 H, 2 Me, 3JH,H = 7.1 Hz); 1.47—1.75 (m, 13 H, CH2,
cycl.); 1.86—1.95 (m, 2 H, CH2, cycl.); 2.30—2.36 (m, 4 H,
CH2, cycl.); 4.12—4.21 (m, 4 H, 2 OCH2); 5.43 (dd, 1 H,
1
27.61 (CH2, cycl.); 58.38 (d, C(α), JC,P = 142.0 Hz); 62.36
(d, OCH2, 2JC,P = 8.0 Hz); 106.92, 113.99, 137.61, 147.61, 161.06
(C, Py). 31P NMR, δ: 30.51. IR, ν/cm–1: 1040, 1080 (P—O—C);
1230 (P=O); 3290, 3330 (NH). Found (%): C, 55.13; H, 8.15;
N, 12.64. C15H26N3O3P. Calculated (%): C, 55.03; H, 8.01;
N, 12.84.
3
3
NHNHC(O), JH,P = 29.1 Hz, JH,H = 6.8 Hz); 7.17 (d, 1 H,
Py, 3JH,H = 9.3 Hz); 7.88 (d, 1 H, Py, 3JH,H = 8.8 Hz); 8.27 (br.s,
1 H, NHPy); 8.54 (s, 1 H, Py); 8.73 (d, 1 H, NHNHC(O),
3
3JH,H = 6.3 Hz). 13C NMR, δ: 16.55 (d, Me, JC,P = 5.1 Hz);
Diethyl 1ꢀ[2ꢀ(pyridinꢀ2ꢀylcarbonyl)hydrazino]cyclohexylꢀ
phosphonate (7) was synthesized from hydrazone 2 at reactant
ratio of 1 : 5, the reaction time was 2 h. Yield 85%. 1H NMR, δ:
1.15—1.27 (m, 1 H, CH2, cycl.); 1.35 (t, 6 H, 2 Me, 3JH,H = 7.1 Hz);
1.49—1.57 (m, 2 H, CH2, cycl.); 1.61—1.76 (m, 5 H, CH2,
cycl.); 1.86—1.97 (m, 2 H, CH2, cycl.); 4.17—4.25 (m, 4 H,
2 OCH2); 4.83 (br.s, 1 H, NHNHC(O)); 7.37 (ddd, 1 H, Py,
3JH,H = 4.8 Hz, 3JH,H = 4.6 Hz, 3JH,H = 1.2 Hz); 7.79 (ddd, 1 H,
Py, 3JH,H = 7.5 Hz, 3JH,H = 7.6 Hz, 3JH,H = 1.7 Hz); 8.09 (d, 1 H,
19.86, 19.97, 25.13, 25.66, 25.73, 25.86, 27.01, 27.52, 35.41
(CH2, cycl.); 58.91 (d, C(α), JC,P = 162.5); 62.90 (d, OCH2,
1
2JC,P = 7.4 Hz); 106.09, 119.38, 136.24, 147.57, 153.70 (C, Py);
159.14 (s, C=N); 163.01 (s, C=O). 31P NMR, δ: 28.33. IR,
ν/cm–1: 1025, 1060 (P—O—C); 1225 (P=O); 1650 (C=O); 3260
(NH). Found (%): C, 56.84; H, 7.89; N, 14.98. C22H36N5O4P.
Calculated (%): C, 56.76; H, 7.79; N, 15.04.
Diethyl 1ꢀ{2ꢀ[5ꢀ({2ꢀ[1ꢀ(diethyloxyphosphoryl)cyclohexyl]ꢀ
hydrazino}carbonyl)pyridinꢀ2ꢀyl]hydrazino}cyclohexylphosphonꢀ
ate (11) was synthesized from hydrazone 5 at reactant ratio of
1 : 8, the reaction time was 40 h. Yield 50%. 1H NMR, δ:
1.17—1.25 (m, 1 H, CH2, cycl.); 1.33, 1.36 (both t, 12 H, 2 Me,
3JH,H = 7.1 Hz); 1.45—1.58 (m, 4 H, CH2, cycl.); 1.60—1.72
(m, 13 H, CH2, cycl.); 1.73—1.93 (m, 2 H, CH2, cycl.); 3.98
(br.s, 1 H, NHNHPy); 4.13—4.22 (m, 8 H, 4 OCH2); 5.34
3
3
Py, JH,H = 7.9 Hz); 8.54 (d, 1 H, Py, JH,H = 6.4 Hz); 10.01
3
(br.s, 1 H, NHNHC(O)). 13C NMR, δ: 16.51 (d, Me, JC,P
=
= 5.1 Hz); 19.89 (d, 3JH,P = 10.9 Hz); 25.11, 27.48 (CH2, cycl.);
1
2
58.72 (d, C(α), JC,P = 162.5 Hz); 62.80 (d, OCH2, JC,P
=
= 7.3 Hz); 121.95, 125.98, 137.14, 148.41, 149.20 (C, Py); 161.06
(s, C=O). 31P NMR, δ: 28.16. IR, ν/cm–1: 1040, 1080 (P—O—C);
1230 (P=O); 1690 (C=O); 3260 (NH). Found (%): C, 54.15;
H, 7.25; N, 11.71. C16H26N3O4P. Calculated (%): C, 54.08;
H, 7.37; N, 11.82.
Diethyl 1ꢀ[2ꢀ(pyridinꢀ3ꢀylcarbonyl)hydrazino]cyclohexylꢀ
phosphonate (8) was synthesized from hydrazone 3 at reactant
ratio of 1 : 5, the reaction time was 8 h. Yield 80%. 1H NMR, δ:
1.17—1.25 (m, 1 H, CH2, cycl.); 1.35 (t, 6 H, 2 Me, 3JH,H = 7.1 Hz);
1.50—1.73 (m, 7 H, CH2, cycl.); 1.90—1.95 (m, 2 H, CH2,
cycl.); 4.16—4.23 (m, 4 H, 2 OCH2); 5.41 (br.d, 1 H, NHNHC(O),
3
(d, 1 H, NHNHC(O), JH,P = 27.1 Hz); 7.04 (d, 1 H, Py,
3JH,H = 8.8 Hz); 7.07 (br.s, 1 H, NHNHPy); 7.85 (dd, 1 H, Py,
4
3JH,H = 8.9 Hz, JH,H = 2.0 Hz); 8.51 (s, 1 H, Py); 8.71 (br.s,
1 H, NHNHC(O)). 13C NMR, δ: 16.55 (d, Me, 3JC,P = 5.8 Hz);
16.63 (d, Me, 3JC,P = 5.1 Hz); 19.89 (d, 3JC,P = 10.9 Hz); 20.29
3
3
(d, JC,P = 11.0 Hz); 25.18 (d, JC,P = 11.0 Hz); 27.49 (CH2,
cycl.); 58.38 (d, C(α), 1JC,P = 142.7 Hz); 58.91 (d, C(α), 1JC,P
=
2
= 161.7 Hz); 62.54, 62.94 (both d, OCH2, JC,P = 7.3 Hz);
105.74, 118.37, 136.03, 147.66, 162.23 (C, Py); 163.22 (s, C=O).
31P NMR, δ: 28.27, 29.93. IR, ν/cm–1: 1040, 1060 (P—O—C);
1225 (P=O); 1645 (C=O); 3280 (NH). Found (%): C, 51.43;
H, 7.72; N, 11.39. C26H47N5O7P2. Calculated (%): C, 51.73;
H, 7.85; N, 11.60.
3
3
3JH,P = 28.8 Hz); 7.35 (dd, 1 H, Py, JH,H = 7.8 Hz, JH,H
=
3
= 4.8 Hz); 8.06 (d, 1 H, Py, JH,H = 7.9 Hz); 8.70 (d, 1 H, Py,
3JH,H = 4.8 Hz); 9.03 (s, 1 H, Py); 9.13 (br.s, 1 H, NHNHC(O)).
13C NMR, δ: 16.53 (d, Me, JC,P = 4.8 Hz); 19.89 (d, JH,P
3
3
=
= 10.5 Hz); 25.12, 27.62 (CH2, cycl.); 58.93 (d, C(α),
2
1JC,P = 162.2 Hz); 63.05 (d, OCH2, JC,P = 7.2 Hz); 123.37,
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 08ꢀ03ꢀ00611),
the Council on Grants at the President of the Russian
Federation (the Program for the State Support of Leading
Scientific Schools of the Russian Federation, Grant
NShꢀ65546.2010.3), the Russian Academy of Sciences
(the Division of Chemistry and Materials Sciences, Proꢀ
grams Nos 1 and 9), and the Presidium of the Russian
Academy of Sciences (Program 9P).
128.49, 134.38, 148.21, 152.25 (C, Py); 162.30 (s, C=O).
31P NMR, δ: 28.13. IR, ν/cm–1: 1040, 1080 (P—O—C); 1230
(P=O); 1660 (C=O); 3290 (NH). Found (%): C, 54.27; H, 7.39;
N, 11.75. C16H26N3O4P. Calculated (%): C, 54.08; H, 7.37;
N, 11.82.
Diethyl 1ꢀ[2ꢀ(pyridinꢀ4ꢀylcarbonyl)hydrazino]cyclohexylꢀ
phosphonate (9) was synthesized from hydrazone 4 at reactant
ratio of 1 : 5, the reaction time was 8 h. Yield 75%. 1H NMR, δ:
1.12—1.20 (m, 1 H, CH2, cycl.); 1.30 (t, 6 H, 2 Me, 3JH,H = 7.1 Hz);
1.45—1.65 (m, 7 H, CH2, cycl.); 1.82—1.90 (m, 2 H, CH2,
cycl.); 4.11—4.18 (m, 4 H, 2 OCH2); 5.39 (br.s, 1 H, NHNHC(O));
7.60 (d, 2 H, Py, 3JH,H = 4.3 Hz); 8.65 (d, 2 H, Py, 3JH,H = 4.3 Hz);
9.33 (br.s, 1 H, NHNHC(O)). 13C NMR, δ: 16.48 (d, Me,
3JC,P = 5.1 Hz); 19.76 (d, 3JH,P = 11.0 Hz); 25.01, 27.49 (CH2,
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Pyridineꢀcontaining αꢀhydrazinophosphonates
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Received July 8, 2010;
in revised form December 13, 2010