A convenient synthesis of 2-hydrazinoethylphosphonic acid and derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.05.041

2-Hydrazinoethylphosphonic acid was prepared using a simple procedure involving Michael addition of hydrazine hydrate to diethyl ethenylphosphonate, followed by hydrolysis with hydrochloric acid. The product was converted into five- and six-membered heter

Full text of DOI:10.1016/j.tetlet.2012.05.041

Tetrahedron Letters 53 (2012) 3774–3776
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A convenient synthesis of 2-hydrazinoethylphosphonic acid and derivatives
Dariusz Cal
´
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, PL 91-403 Łódz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Hydrazinoethylphosphonic acid was prepared using a simple procedure involving Michael addition of
hydrazine hydrate to diethyl ethenylphosphonate, followed by hydrolysis with hydrochloric acid. The
product was converted into five- and six-membered heterocycles.
Received 26 March 2012
Revised 30 April 2012
Accepted 10 May 2012
Available online 16 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydrazinoalkylphosphonic acids
Azaheterocyclic phosphonates
Michael addition
Cyclisation
Diethyl ethenylphosphonate
Hydrazinophosphonic acids, as analogues of aminophosphonic
acids,1 are of potential biological importance. For example, they
have been demonstrated to protect cultivated plants from the
phytotoxic action of herbicides.2 Some synthetic approaches to
hydrazinoalkylphosphonic acids have already been reported. Thus,
1-hydrazinoalkylphosphonic acids can be prepared by addition of
diethyl phosphite to aldazines followed by subsequent acid
hydrolysis.3 Another method is based on the reaction of 1-sul-
fonyloxyalkylphosphonates with hydrazine hydrate.4 1-Hydrazino
or 2-hydrazinoalkylphosphonic acids can also be prepared by selec-
tive reduction with sodium cyanoborohydride or with borane–
tetrahydrofuran complexes of hydrazone derivatives prepared from
1-oxo or 2-oxophosphonates and subsequent hydrolysis of the
resulting hydrazinoalkylphosphonates.5 One example was pre-
sented in which the unstable monoammonium salt of 2-hydrazino-
ethyl-1,1-diphosphonic acid was prepared by addition of hydrazine
hydrate to vinylidenediphosphonic acid. The method required heat-
ing in a sealed ampoule and the contaminated product was purified
by chromatography.6 Furthermore, Diels–Alder reaction of 1-dieth-
oxyphosphorylbuta-1,3-diene and di-tert-butyl azodicarboxylate,
followed by catalytic hydrogenation and hydrolysis steps, was
shown to lead to 3-diethoxyphosphorylhexahydro-1,2-pyridazine.7
It has been shown that hydrazinoalkylphosphonates are useful
building blocks for the synthesis of novel phosphonoalkyl hetero-
cycles.8 Considering the importance of azaheterocyclic phospho-
nates in medicinal9 and coordination chemistry,10 we recently
reported a new strategy for the preparation of pyrazole-, thiazolid-
inone- and pyrrole-phosphonic acids.11 Herein, we report a conve-
nient method for the synthesis of 2-hydrazinoethylphosphonic
acid; examples of its utilisation for the synthesis of phospho-
noalkyl heterocycles are also given.
The synthetic route towards 2-hydrazinoethylphosphonic acid
(1) is depicted in Scheme 1.
Commercial diethyl ethenylphosphonate (1 equiv) was added to
hydrazine hydrate (20 equiv) and a mild exotherm was apparent.
The mixture was stirred at room temperature for 24 h, then the
unreacted hydrazine hydrate was distilled under reduced pressure
(the recovered hydrazine hydrate can be reused). To remove any
remaining traces of hydrazine hydrate the residue was evaporated
with aqueous sodium hydroxide solution (2 equiv) and with water.
Hydrolysis with hydrochloric acid (reflux 12 h) followed by treat-
ment with propylene oxide provided the hydrazinophosphonic acid
1 in 69% yield.12
Condensation of compound 1 with various aromatic aldehydes
or ketones resulted in the formation of stable hydrazone deriva-
tives 2a–e in good yields (Table 1).13,14 However, attempts to pre-
pare hydrazone derivatives from 1 and aliphatic aldehydes or
ketones failed.
To the best of our knowledge, free hydrazinoalkylphosphonic
acids have not been used for the synthesis of heterocycles.
.
1. N2H4 H2O
2. HCl (aq), reflux 12 h
3.
O
H
P(OEt)2
O
N
H2N
PO3H2
1
(69%)
E-mail address: darekcal@uni.lodz.pl
Scheme 1. Synthesis of 2-hydrazinoethylphosphonic acid (1).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.041

D. Cal / Tetrahedron Letters 53 (2012) 3774–3776
3775
Table 1
Hydrazinohosphonic acid 1 and its heterocyclic derivatives 3a–
d and 4a,b are crystalline stable compounds and can be stored at
room temperature without decomposition. Their structures were
confirmed by NMR, IR and elemental analyses.
In conclusion, we have developed a simple and convenient one-
pot strategy for the preparation of a new hydrazinoethylphosphonic
acid. The product 1 was shown be a useful synthon for the synthesis
of five- and six-membered azaheterocyclic ethylphosphonic acids.
Condensation of 1 with aromatic aldehydes and ketones
R
H
N
O
H
N
a or b
+
H2N
PO3H2
Ar
N
PO3H2
Ar
R
1
2a-e
Entry
1a
Ar
R
Product
Yieldc (%)
79
H
H
2a
N
Acknowledgement
O
O
2a
2b
92
The author thanks R. Bartnik, Emeritus Professor for his keen
interest and encouragement.
3a
4b
H
2c
88
83
H3CS
Ph
Me
2d
References and notes
5b
Me
2e
67
S
1. Lejczak, B.; Kafarski, P. Top. Heterocycl. Chem. 2009, 20, 31.
2. Diel, P. J.; Maier, L. Eur. Pat. Appl. EP 143078 1985; Chem. Abstr. 1985, 103,
215544m.
3. (a) Wasilewski, C.; Rachon´ , J. Rocz. Chem. 1976, 50, 477; (b) Topolski, M.;
Rachon´ , J. Phosphorus Sulfur Silicon Relat. Elem. 1991, 55, 97; (c) Diel, P. J.; Maier,
L. Phosphorus Sulfur Silicon Relat. Elem. 1988, 36, 85.
a
b
c
Reaction conditions: MeOH–H2O, reflux 12 h.
Reaction conditions: (i) NaHCO3, MeOH–H2O, reflux 12 h; (ii) HCl (aq).
Isolated pure product.
4. Yuan, C.; Li, C. Synthesis 1996, 507.
5. Yuan, C.; Chen, S.; Xie, R.; Feng, H.; Maier, L. Phosphorus Sulfur Silicon Relat.
Elem. 1995, 106, 115.
Table 2
Synthesis of N-phosphonoethylheterocycles from 1
6. Alfer’ev, I. S.; Mikhalin, N. V.; Kotlyarevskii, I. L. Bull. Acad. Sci. USSR, Div. Chem.
Sci. 1984, 33, 1031.
O
R2
N
X
R1
7. Monbaliu, J.-C.; Marchand-Brynaert, J. Synthesis 2009, 1876.
8. (a) Xiao, L. X.; Li, K.; Meng, L.; Shi, D. Q. Heteroatom Chem. 2008, 19, 634; (b)
Xiao, L. X.; Shi, D. Q. J. Heterocycl. Chem. 2009, 46, 555; (c) Li, Z. G.; Sun, H. K.;
Wang, Q. M.; Huang, R. Q. Heteroatom Chem. 2003, 14, 384; (d) Hu, L.; Lu, S.;
Yang, F.; Feng, J.; Liu, Z.; Xu, H.; He, H. Phosphorus Sulfur Silicon Relat. Elem.
2002, 177, 2785.
9. (a) Moonen, K.; Laureyn, I.; Stevens, Ch. Chem. Rev. 2004, 104, 6177; (b) Elayadi,
H.; Smietana, M.; Pannecouque, C.; Leyssen, P.; Neyts, J.; Vasseur, J. J.; Lazrek, H.
B. Bioorg. Med. Chem. Lett. 2010, 20, 7365.
R1
PO3H2
PO3H2
a, b or c
N
H
3a-d
O
NH
N
H2N
PO3H2
Y
O
1
O
N
N
OH
Y
d
10. (a) Brunet, E.; Juanes, O.; Jiménez, L.; Rodríguez-Ubis, J. C. Tetrahedron Lett.
2009, 50, 5361; (b) Villemin, E.; Elias, B.; Robiette, R.; Robeyns, K.; Hernet, M.-
F.; Habib-Jiwan, J.-L.; Marchand-Brynaert, J. Tetrahedron Lett. 2011, 52, 5140.
11. (a) Bartnik, R.; Cal, D. Phosphorus Sulfur Silicon Relat. Elem. 1858, 2010, 185; (b)
Cal, D. Phosphorus Sulfur Silicon Relat. Elem. 2010, 185, 2233; (c) Cal, D.;
Zagórski, P. Phosphorus Sulfur Silicon Relat. Elem. 2011, 186, 2295.
12. 2-Hydrazinoethylphosphonic acid (1): Diethyl ethenylphosphonate (21.53 g,
0.131 mol) was added to N2H4ÁH2O (131.3 g 2.623 mol) during which time a
mild exotherm occurred. The mixture was stirred at rt for 24 h, then the
unreacted hydrazine hydrate was distilled under reduced pressure. The residue
was evaporated with NaOH/H2O soln (2.0 mol/L, 131.0 mL) and with H2O
(3 Â 330 mL), to remove any remaining traces of hydrazine hydrate. Then
concd HCl (aq) solution (330 mL) was added and the mixture refluxed for 12 h.
After evaporation of HCl, the residue was dissolved in MeOH (164 mL), filtered,
and the filtrate treated with propylene oxide (20 mL) and left in a refrigerator
for 24 h. The crude product (15.90 g, mp 186–196 °C) was dissolved in boiling
H2O (131 mL) and boiling MeOH/H2O (4/1, 328 mL) was added. The pure
product precipitated as colourless crystals (12.60 g, 69%, mp 204–206 °C): IR
(KBr): 3309–2507 (NH, OH), 1630 (NH), 1516 (NH), 1142 (P@O), 924 (P–O)
4a-b
Entry
X
Y
R1
R2
Product
Yielde (%)
1a
2a
3b
4c
Ac
—
—
—
—
Me
Me
CF3
Ph
Me
OH
OH
3a
3b
3c
3d
56
87
32
67
CO2Et
CO2Et
CN
NH2
5d
6d
—
—
—
—
—
4a
4b
56
90
—
a
Reaction conditions: (i) NaHCO3, H2O–MeOH, reflux 15 min; (ii) concd HCl (aq);
(iii) propylene oxide, MeOH.
cmÀ1
;
1H NMR (600 MHz, D2O): d = 1.91–1.99 (m, 2H, CH2P), 3.27–3.34 (m, 2H,
b
Reaction conditions: (i) NaHCO3, H2O, reflux 3 h; (ii) HCl (aq).
Reaction conditions: (i) MeOH–H2O, reflux 18 h.
Reaction conditions: (i) Na2CO3, H2O, reflux 15 min; (ii) HCl (aq).
1
CH2N); 13C NMR (151 MHz, D2O): d = 24.1 (d, JPC = 131.9 Hz, CH2P), 46.9
(CH2N); 31P NMR (243 MHz, D2O): d = 18.67; Anal. Calcd for C2H9N2O3P: C,
17.15; H, 6.48. Found: C, 17.21; H, 6.37.
c
d
e
Isolated pure product.
13. Synthesis of hydrazones 2a–c; general procedure:
A mixture of 1 (0.70 g,
5.0 mmol) and aromatic aldehyde (5.0 mmol) in MeOH/H2O (6/1, 35 mL) was
refluxed and stirred for 12 h. The resulting precipitate was filtered and washed
with H2O (2 Â 5 mL), MeOH (2 Â 5 mL) and Et2O (5 mL) and dried (90 °C, 2 h).
2-[(2-(2-Quinolylmethylene)hydrazino]ethylphosphonic acid (2a): Yield: 1.10 g
(79%); colorless crystals: mp 211–214 °C. IR (KBr): 3424–2316 (OH, NH), 1657
Examples of the synthetic application of hydrazinophosphonic acid
1 for the preparation of azaheterocycles bearing a phosphonoalkyl
moiety are shown in Table 2.15–18
(C@N), 1571, 1501, 1455, 1223 (P@O), 1122, 1027, 933 (P–OH) cmÀ1 1H NMR
;
(600 MHz, D2O/NaOD): d = 1.76–1.81 (m, 2H, CH2P), 3.44–3.48 (m, 2H,CH2N),
7.44–7.97 (m, 7H, CHarom, CHN); 13C NMR (151 MHz, D2O/NaOD): d = 28.1 (d,
1JPC = 126.8 Hz, CH2P), 44.6 (CH2N), 117.5 (CH), 126.7 (CH), 126.9 (CH), 127.4
(Carom), 128.0 (CH), 130.3 (CH), 137.3 (CH), 137.4 (CH), 146.3 (Carom),
154.1 (Carom); 31P NMR (243 MHz, D2O/NaOD): d = 18.59; Anal. Calcd
for C12H14N3O3P: C, 51.62; H, 5.05. Found: C, 51.57; H, 4.98.
Thus, hydrazinophosphonic acid 1 (entry 4) or its disodium salt
(entries 1–3, 5 and 6) and cyanocarbonyl (entry 4) or dicarbonyl
compounds (entries 1–3, 5 and 6) were refluxed in methanol–
water or in water. After acidification, the products 3c and 4a,b
were obtained (entries 3, 5 and 6). In the case of pyrazoles 3a,b
additional treatment with propylene oxide was required (entries
1 and 2). The aminopyrazole 3d crystallised after concentration
of the reaction mixture (entry 4). The structures of 3b–d were con-
firmed by heteronuclear multiple bond correlation (HMBC) exper-
iments in which the signal of the pyrazole carbon atom C-5
correlates with the signal of the methylene protons CH2N.
2-[(2-(1,3-Benzodioxol-5-ylmethylene)hydrazino]ethylphosphonic
acid
(2b):
Yield: 1.25 g (92%); colorless crystals: mp 196–198 °C; IR (KBr): 3447–2341
(OH, NH), 1629 (C@N), 1600, 1503, 1463, 1258 (P@O), 1145, 1021, 917 (P–OH)
cmÀ1 1H NMR (600 MHz, D2O/NaOD): d = 1.64–1.70 (m, 2H, CH2P), 3.29–3.33
;
(m, 2H,CH2N), 5.99 (s, 2H, CH2O), 6.90–7.16 (m, 3H, CHarom), 7.86 (s, 1H, CHN);
13C NMR (151 MHz, D2O/NaOD): d = 28.3 (d, 1JPC = 127.0 Hz, CH2P), 45.4 (CH2N),
101.5 (CH2O), 105.5 (CHarom), 108.7 (CHarom), 122.5 (CHarom), 129.1 (Carom), 145.0
(CHN), 147.8 (Carom), 148.3 (Carom); 31P NMR (243 MHz, D2O/NaOD): d = 18.81;
Anal. Calcd for C10H13N2O5P: C, 44.13; H, 4.81. Found: C, 44.02; H, 4.84.

3776
D. Cal / Tetrahedron Letters 53 (2012) 3774–3776
1545, 1119 (P@O), 1050 (P–OH), 965 cmÀ1
2-[2-[(4-Methylsulfanylphenyl)methylene]hydrazino]ethylphosphonic acid (2c):
;
1H NMR (600 MHz, H2O/D2O, 9/1,
Yield: 1.20 g (88%); colorless crystals: mp 175–177 °C; IR (KBr): 3432–2333
NaOH): d = 1.75–1.80 (m, 2H, CH2P), 2.01 (s, 3H, CH3), 3.83–3.87 (m, 2H, CH2N),
(OH, NH), 1623 (C@N), 1595, 1227 (P@O), 1129, 1112, 1092, 1012, 940 (P–OH)
4.92 (s, 1H, CH); 13C NMR (151 MHz, H2O/D2O, 9/1, NaOH): d = 13.3 (CH3), 36.6
cmÀ1
;
1H NMR (600 MHz, D2O/NaOD): d = 1.65–1.71 (m, 2H, CH2P), 2.49 (s, 3H,
(d, JPC = 124.4 Hz, CH2P), 41.2 (CH2N), 86.0 (CHarom), 149.2 (C-3), 162.1 (C-5);
1
CH3) 3.31–3.35 (m, 2H,CH2N), 7.31–7.52 (m, 4H, CHarom), 7.89 (s, 1H, CHN); 13
C
31P NMR (243 MHz, H2O/D2O, 9/1, NaOH): d = 18.01; Anal. Calcd for
C6H11N2O4PÁH2O: C, 32.15; H, 5.85. Found: C, 32.15; H, 5.81.
NMR (151 MHz, D2O/NaOD): d = 14.4 (CH3), 28.3 (d, 1JPC = 127.0 Hz, CH2P), 45.3
(CH2N), 126.3 (CHarom), 127.1 (CHarom), 131.6 (Carom), 139.4 (Carom), 144.3 (CHN);
31P NMR (243 MHz, D2O/NaOD): d = 18.79; Anal. Calcd for C10H15N2O3PS: C,
43.79; H, 5.51. Found: C, 43.60; H, 5.42.
16. 2-[5-Hydroxy-3-(trifluoromethyl)pyrazol-1-yl]ethylphosphonic acid (3c):
A
solution of 1 (1.40 g, 10.0 mmol) and NaHCO3 (1.68 g, 20.0 mmol) in H2O
(8 mL) was refluxed for 1 min. Next, ethyl 3-oxo-4,4,4-trifluorobutyrate (1.84 g
10.0 mmol) was added and the mixture refluxed for 3 h. The mixture was
concentrated to ꢀ4 mL and extracted with Et2O (3 Â 5 mL). The aqueous phase
was acidified with HCl (aq) solution (4 mol/L, 5 mL) and evaporated. The
residue was crystallised from H2O to give the product as colourless crystals
(0.82 g, 32%); mp 192–196 °C; IR (KBr): 3420–2340 (OH), 1571, 1505, 1418,
14. Synthesis of hydrazones 2d,e; general procedure:
A solution of 1 (1.40 g,
10.0 mmol) and NaHCO3 (1.68 g, 20.0 mmol) in H2O (10 mL) was refluxed for
1 min. Next, the dicarbonyl compound (13.0 mmol) and MeOH (30 mL) were
added. The mixture was heated to 60 °C, and H2O was added dropwise (to
obtain a homogenous solution) which was refluxed for 12 h. The mixture was
cooled and the solvent evaporated. The residue was dissolved in H2O (10 mL)
and extracted with Et2O (3 Â 50 mL). The aqueous phase was acidified with
HCl (aq) solution (4 mol/L, 5 mL). The resulting precipitate was filtered and
washed with H2O (2 Â 5 mL), cold MeOH (2 Â 5 mL) and Et2O (5 mL) and dried
(90 °C, 2 h).
1180, 1127 (P@O), 1022 (P–OH), 992 cmÀ1 1H NMR (600 MHz, H2O/D2O, 9/1,
;
NaOH): d = 2.17–2.23 (m, 2H, CH2P), 4.19–4.24 (m, 2H,CH2N), 5.88 (s, 1H, CH);
1
13C NMR (151 MHz, H2O/D2O, 9/1, NaOH): d = 27.3 (d, JPC = 133.4 Hz, CH2P),
41.6 (CH2N), 86.2 (CH), 120.9 (q, 1JFC = 268.1 Hz, CF3), 140.6 (q, 2JFC = 37.9, C-3),
153.0 (C-5); 31P NMR (243 MHz, H2O/D2O, 9/1, NaOH): d = 23.33; Anal. Calcd
for C6H8N2O4P.0.27 H2O: C, 27.20; H, 3.25. Found: C, 27.20; H, 3.29.
2-[(2-(1-Phenylethylidene)hydrazino]ethylphosphonic acid (2d): Yield: 2.00 g
(83%); colorless crystals: mp 208–209 °C; IR (KBr): 3432–2337 (OH, NH),
17. 2-(5-Amino-3-phenylpyrazol-1-yl)ethylphosphonic acid (3d):
A mixture of 1
1622 (C@N), 1447, 1245 (P@O), 1222, 1134, 1078, 918 (P–OH) cmÀ1
;
1H NMR
(0.70 g, 5.0 mmol) and benzoylacetonitrile (0.73 g, 5.0 mmol) in MeOH/H2O (3/
1, 40 mL) was refluxed and stirred for 18 h. The clear solution thus obtained
was concentrated to 10 mL. The crude product was separated by filtration,
washed with H2O (2 Â 5 mL), acetone (2 Â 5 mL) and Et2O (5 mL) and
crystallised from H2O to give the pure product as colourless crystals (0.90 g,
67%); mp 116–118 °C; IR (KBr): 3335–2362 (OH, NH), 1648, 1598, 1561, 1508,
(600 MHz, D2O/NaOD): d = 1.69–1.74 (m, 2H, CH2P), 2.18 (s, 3H, CH3) 3.35–3.40
(m, 2H, CH2N), 7.41–7.60 (m, 5H, CHarom); 13C NMR (151 MHz, D2O/NaOD):
1
d = 14.2 (CH3), 29.1 (d, JPC = 126.5 Hz, CH2P), 46.7 (CH2N), 126.4 (CHarom),
128.7 (CHarom), 129.0 (CHarom), 139.2 (Carom), 152.8 (C@N); 31P NMR (243 MHz,
D2O/NaOD): d = 19.13; Anal. Calcd for C10H15N2O3P: C, 49.59; H, 6.24. Found: C,
49.32; H, 6.14.
1473, 1238 (P@O), 1135, 1050, 1028, 923 (P–OH) cmÀ1 1H NMR (600 MHz,
;
2-[2-[1-(2-Thienyl)ethylidene]hydrazino]ethylphosphonic acid (2e): Yield: 1.66 g
(67%); colorless crystals: mp 216–218 °C; IR (KBr): 3439–2047 (OH, NH), 1605
H2O/D2O, 9/1, NaOH): d = 1.87–1.93 (m, 2H, CH2P), 4.12–4.16 (m, 2H, CH2N),
5.97 (s, 1H, CH), 7.35–7.68 (m, 5H, CHarom); 13C NMR (151 MHz, H2O/D2O, 9/1,
1
(C@N), 1420, 1242 (P@O), 1220, 1131, 920 (P–OH) cmÀ1
;
1H NMR (600 MHz,
NaOH): d = 30.1 (d, JPC = 123.6 Hz, CH2P), 44.1 (CH2N), 88.5 (C-4), 125.4
D2O/NaOD): d = 1.67–1.73 (m, 2H, CH2P), 2.20 (s, 3H, CH3) 3.33–3.37 (m,
(CHarom), 128.4 (CHarom), 129.1 (CHarom), 132.6 (Carom), 147.3 (C-5), 150.8 (C-3);
2H,CH2N), 7.08–7.40 (m, 3H, CHarom); 13C NMR (151 MHz, D2O/NaOD): d = 13.8
31P NMR (243 MHz, H2O/D2O, 9/1, NaOH): d = 16.66; Anal. Calcd for
1
(CH3), 29.0 (d, JPC = 127.1 Hz, CH2P), 46.7 (CH2N), 126.9 (CHarom), 127.9
C
11H14NO3P: C, 49.44; H, 5.28; N, 15.72. Found: C, 49.12; H, 5.24; N, 15.45.
(CHarom), 143.0 (Carom), 147.6 (C@N); 31P NMR (243 MHz, D2O/NaOD):
d = 19.13; Anal. Calcd for C8H13N2O3PS: C, 38.71; H, 5.28. Found: C, 38.33; H,
5.29.
18. Phthalazine derivatives 4a,b; general procedure: To soln of (1.40 g,
a
1
10.0 mmol) and Na2CO3 (1.06 g, 10.0 mmol) in H2O (10 mL), was added the
dicarbonyl compound (10.0 mmol) and the mixture was refluxed for 15 min.
The resulting clear solution was cooled and acidified with concd HCl (aq) soln
(3 mL). The precipitate was filtered, washed with H2O (2 Â 5 mL) and acetone
(5 mL) and dried (100 °C, 6 h).
15. Pyrazole derivatives 3a,b: general procedure: A soln of 1 (1.40 g, 10.0 mmol) and
NaHCO3 (1.68 g, 20.0 mmol) in H2O (8 mL) was refluxed for 1 min. Next, the
dicarbonyl compound (10.0 mmol) and MeOH (15 mL) were added and the
mixture refluxed for 15 min. The mixture was cooled and the solvent was
evaporated. The residue was dissolved in cold (À20 °C) concd HCl (aq) soln
(30 mL) and left at this temperature for 1 h. The resulting precipitate of NaCl
was removed by filtration, and HCl was evaporated under reduced pressure
(0.5 mm Hg). The residue was dissolved in MeOH (30 mL), then filtered, and
the filtrate treated with propylene oxide (3 mL). The mixture was left for 12 h.
After evaporation of the solvent, the residue was stirred with MeOH/Et2O (4/1,
20 mL) for 12 h. The resulting precipitate was filtered, washed with MeOH/
Et2O (4/1, 5 mL) and dried (90 °C, 2 h).
2-(4-Hydroxy-1-oxophthalazin-2-yl)ethylphosphonic acid (4a): Yield: 1.95 g
(56%); colorless crystals: mp 249–253 °C; IR (KBr): 3423–2275 (OH), 1618,
1568, 1548, 1497, 1452, 1254 (P@O), 1074, 1021 (P–OH), 980 cmÀ1 1H NMR
;
(600 MHz, D2O/NaOD): d = 1.91–1.96 (m, 2H, CH2P), 4.13–4.17 (m, 2H, CH2N),
7.76–7.84 (m, 2H, H-6, H-7), 8.01–8.13 (m, 2H, H-5, H-8); 13C NMR (151 MHz,
1
D2O/NaOD): d = 28.9 (d, JPC = 124.4 Hz, CH2P), 48.2 (CH2N), 125.5 (C-5), 125.7
(C-8), 128.4 (C-4a), 129.4 (C-8a), 131.6 (C-6), 132.9 (C-7), 161.5 (C-4); 31P NMR
(243 MHz, D2O/NaOD): d = 17.65; Anal. Calcd for C10H11N2O5P: C, 44.46; H,
4.10. Found: C, 44.35; H, 4.25.
2-(3,5-Dimethylpyrazol-3-yl)ethylphosphonic acid (3a): Yield: 1.15 g (56%);
white solid: mp 169–172 °C; IR (KBr): 3140–2346 (OH), 1265 (P@O), 1556,
2-(4-Hydroxy-1-oxo-5,6,7,8-tetrahydrophthalazin-2-yl)ethylphosphonic
(4b): Yield: 2.47 g (90%); colorless crystals: mp 255–258 °C; IR (KBr): 3440–
2259 (OH), 1551, 1485, 1452, 1311, 1274, 1140 (P@O), 993 (P–OH) cmÀ1 1H
acid
1470, 1425, 1053, 969 (P–OH) cmÀ1
;
1H NMR (600 MHz, H2O/D2O, 9/1):
;
d = 2.10–2.15 (m, 2H, CH2P), 2.31 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.36–4.41 (m,
NMR (600 MHz, H2O/D2O, 9/1, NaOH): d = 1.61–1.66 (m, 4H, 2CH2), 1.97–2.02
(m, 2H, CH2P), 2.35–2.38 (m, 4H, 2CH2), 4.08–4.12 (m, 2H, CH2N); 13C NMR
(151 MHz, H2O/D2O, 9/1, NaOH): d = 20.4 (C-6 or C-7), 20.6 (C-7 or C-6), 23.5
2H,CH2N), 6.24 (s, 1H, CH); 13C NMR (151 MHz, H2O/D2O, 9/1): d = 10.2 (CH3),
1
10.4 (CH3), 28.0 (d, JPC = 131.1 Hz, CH2P), 43.7 (CH2N), 107.4 (CHarom),
145.9 (Carom), 146.0 (Carom); 31P NMR (243 MHz, D2O): d = 18.37; Anal.
Calcd for C7H13N2O3P: C, 41.18; H, 6.42. Found: C, 40.97; H, 6.47.
2-(5-Hydroxy-3-methylpyrazol-1-yl)ethylphosphonic acid (3b): Yield: 1.95 g
(87%); white solid: mp 204–207 °C; IR (KBr): 3297–2302 (OH), 1801, 1603,
(C-5 or C-8), 23.6 (C-8 or C-5), 27.6 (d, JPC = 128.7 Hz, CH2P), 46.9 (CH2N),
1
138.0 (C-4a or C-8a), 138.7 (C-8a or C-4a), 157.9 (C-4), 159.3 (C-3); 31P NMR
(243 MHz, H2O/D2O, 9/1, NaOH): d = 20.13; Anal. Calcd for C10H15N2O5P: C,
43.80; H, 5.51. Found: C, 43.79; H, 5.42.