Synthesis of new heterocyclic mono- and bisorganophosphorus acids and their derivatives with 1,2-phenylene fragments

Article abstract of DOI:10.1002/hc.21098

The interaction of esters of phosphorous acid containing POSiMe₃ and PH fragments with anhydrides of phthalic and 2-sulfobenzoic acids is proposed as convenient methods for the synthesis of new heterocyclic mono- and bisorganophosphorus acids a

Full text of DOI:10.1002/hc.21098

Heteroatom Chemistry
Volume 00, Number 0, 2013
Synthesis of New Heterocyclic Mono- and
Bisorganophosphorus Acids and Their
Derivatives with 1,2-Phenylene Fragments
Andrey A. Prishchenko, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, and Valery S. Petrosyan
Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
Received 14 February 2013; revised 7 May 2013
rus acids, which were interesting as effective antioxi-
ABSTRACT: The interaction of esters of phospho-
dants with the multifunctional mode of action [4–8].
rous acid containing POSiMe3 and PH fragments with
In the present work, we report the results of the in-
anhydrides of phthalic and 2-sulfobenzoic acids is pro-
teraction of the esters of phosphorous acid contain-
posed as convenient methods for the synthesis of new
ing POSiMe3 and PH fragments with anhydrides of
heterocyclic mono- and bisorganophosphorus acids
phthalic and 2-sulfobenzoic acids. This interaction
and their derivatives with 1,2-phenylene fragments,
results in the formation of new heterocyclic mono-
carboxyl and sulfonyl groups. Also some properties of
and bisorganophosphorus acids and their deriva-
ꢀC
the obtained compounds are presented.
2013 Wi-
tives with 1,2-phenylene fragments and carboxyl and
sulfonyl groups.
ley Periodicals, Inc. Heteroatom Chem 00:1–4, 2013;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21098
RESULTS AND DISCUSSION
Anhydrides of phthalic and 2-sulfobenzoic acids
readily react with various nucleophiles and are
widely used in the organic and organometallic syn-
thesis [9–11]. Previously, we had developed the
convenient methods for the synthesis of the func-
tionalized organophosphorus amides of iso- and
terephthalic acids [12]. In this work, we studied
the reactions of trimethylsilyl phosphites with ph-
thalic and 2-sulfobenzoic anhydrides and showed
that different results of these reactions were deter-
mined by different reactive precursors. Thus, an ex-
cess of tris(trimethylsilyl) phosphite reacts slowly
with phthalic anhydride in methylene chloride in
the presence of bis(trimethylsilyl) phosphite and
trimethylchlorosilane already at 20◦C. The reaction
proceeds via an intermediate formation of cyclic
phosphonate 1 detected by the NMR and results
in cyclic diphosphonate 2, which was isolated af-
ter distillation in 87% yield (cf. [13,14]) (Scheme 1).
Perhaps this interaction easily proceeds due to the
INTRODUCTION
The functionalized derivatives of mono- and
bisorganophosphorus acids containing aromatic
and heterocyclic fragments with various hydroxyl
groups present great interest as promising poly-
dentate ligands and organophosphorus biomimetics
of hydroxylcarboxylic acids and natural pyrophos-
phates. Various derivatives of substituted hydrox-
ymethylenebisphosphonic acids are good complex-
ones and widely used in medicine [1–3]. Recently,
we have proposed the convenient methods of syn-
thesis of a series of mono- and bisorganophospho-
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic Research.
Contract grants numbers: 11–03–00402 and 12–03–00003.
ꢀC
2013 Wiley Periodicals, Inc.
1

2
Prishchenko et al.
O
O
(Me3SiO)2P(O)H, Me3SiCl
Me3SiCl
O
O
+ (Me3SiO)3P
- (Me3Si)2O
Me Si
P(OSiMe3)2
O
3
O
O
1
O
O
O
(Me3SiO)3P
- Me3SiCl
O
(Me3SiO)
2 P
P(OSiMe3)2
P(OSiMe3)2
Cl
O
O
O
2
A
SCHEME 1 Synthesis of diphosphonate 2.
O
O
O
SO3SiMe3
COOSiMe3
S
(XO)2P(O)H
(EtO)2POSiMe3
O
(EtO)2P(O)H
O
+ (XO)2POSiMe3
CHP(OX)2
O
C-P(OEt)2
(XO)2PO
O
O
O
O O
5,7
COOSiMe3
COOSiMe3
O
O
S
CHP(OEt)2
O
C
O
P(OEt)2
O
+
(XO)2POSiMe3
O
O
(EtO)2PO
O
H
2
P(OX)2
O
3
O
6,8
X= Me3Si (5,6), Et (7,8)
+
(EtO)2POSiMe3
O
O
P(OEt)2
SCHEME 3 Synthesis of phosphonates 6,8.
4
O
SCHEME 2 Synthesis of phosphonate 4.
The reaction of diphosphonate 2 and phospho-
nate 6 with an excess of methanol results in cyclic
mono- and diphosphonic acids 9, 10, which are
white hygroscopic crystals (Scheme 4).
The resulting compounds, 2, 3, 6, and 8–10,
containing phosphonate, and carboxyl and sulfonyl
groups along with the heterocyclic moieties are of
interest as potential ligands and biologically active
substances. The NMR spectra of compounds 1–10
contain the characteristic signals of the B–D frag-
ments (Fig. 1) whose parameters are listed in the
Experimental.
possible formation of the highly reactive chloroester
A as an intermediate in the reaction mixture.
Under the same conditions, the similar reac-
tion of more nucleophilic diethyl trimethylsilyl phos-
phite and diethyl phosphite with phthalic anhydride
proceeds exothermally and results in the product
of a phosphonate–phosphate rearrangement 3 in
89% yield. On distilling compound 3, the formation
of cyclic phosphonate 4 and diethyl trimethylsilyl
phosphate was registered by the NMR (cf. [15, 16])
(Scheme 2).
Under similar conditions, more electrophilic 2-
sulfobenzoic anhydride reacts with both trimethylsi-
lylphosphites to give only the phosphonate–
phosphates 5 and 7, which are transformed into
cyclic phosphonates 6, 8, and the corresponding
trimethylsilyl phosphates at distillation (Scheme 3).
EXPERIMENTAL
The 1H, 13C, and 31P NMR spectra were registered on
the Bruker Avance-400 spectrometer (400, 100, and
162 MHz, respectively) in CDCl3 (1–8) or CD3OD
(9,10) against TMS (1H and 13C) and 85% H3PO4 in
D2O (31P). All reactions were carried out under dry
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New Heterocyclic Mono- and Bisorganophosphorus Acids and Their Derivatives with 1,2-Phenylene Fragments
3
3
125.3 (m, С2, С5, С6), 145.20 (t, С3, JPС = 5.6 Hz),
133.63 (s, С4), 129.40 (s, С7), 169.04 (s, С8), –0.23 (s,
2 Ме3Si), and –0.09 (s, 2 Ме3Si). 31Р NMR, δ, ppm:
–8.91 (s). Found: С 41.03; Н 6.84. С20Н40О8P2Si4.
Calcd.: С 41.22; Н 6.92.
O
4 MeOH
2
O
- 4 Me3SiOMe
(HO)
2P
P(OH)2
Trimethylsilyl 2-{(diethoxyphosphoryl)[(diethoxy-
phosphoryl)oxy]methyl}benzoate (3). A solution of
12 g of diethyl trimethylsilyl phosphite and 3.8 g
of diethyl phosphite in 20 mL of methylene chloride
was added to a mixture of 3.7 g of phthalic anhy-
dride and 15 mL of methylene chloride. After the
completion of the exothermic reaction, the solvent
was distilled off and the residue was distilled. Yield
O
O
9
O
O
S
2 MeOH
6
O
- 2 Me3SiOMe
1
11 g (89%), bp 187◦C (1 mm Hg). Н NMR, δ, ppm:
P(OH)2
6.79 (dd, С1Н, 2JPH = 14.8 Hz, 3JРH = 10.8 Hz), 6.9–
7.6 (m, С6Н4), 3.4–3.7 (m, 4 СН2ОР), 0.7–0.9 (m, 4
СН3), –0.04 (s, Ме3Si). 13С NMR, δ, ppm: 69.70 (dd,
O
10
1
2
С1, JРС = 166.9 Hz, JРС = 5.6 Hz), 129.41 (d, С2,
2JPС = 5.6 Hz), 135.61(s, С3), 131.72 (s, С4), 127.81 (s,
С5, С6), and 127.97 (s, С5, С6), 130.80 (s, С7), 166.11
(s, С8), 62.5–63.7 (m, 4 СН2ОР), 15.5–16.1 (m, 4 Ме),
–0.74 (s, Ме3Si). 31Р NMR, δ, ppm: 16.45 (d. Р1, 3JРР
SCHEME 4 Synthesis of acids 9 and 10.
4
7
4
C8(O)
3
SO3
3
5
5
P2(O)OC1HP1(O)
2
2
3
= 33.4 Hz), –1.49 (d, Р2, JРР = 33.4 Hz). Found: С
C1P(O)
6
C1P(O)
6
7
45.82; Н 6.78. С19Н34О9P2Si. Calcd.: С 45.96; Н 6.90.
The fraction boiling at 110–130◦C (1 mm Hg) con-
tains phosphonate 4, 1Н NMR, δ, ppm: 5.44 (d, С1Н,
D
C
B
1
2JPH = 8.3 Гц), 13С NMR, δ, ppm: 75.10 (d, С1, JРС
FIGURE 1 Fragments B–D.
= 163.4 Гц), 31Р NMR, δ, ppm: 13.48 (s), and diethyl
trimethylsilyl phosphate (δР –9.32 ppm, (s)).
The phosphonates 6 and 8 were obtained simi-
larly.
argon in anhydrous solvents. Starting trimethylsilyl
esters of phosphorous acid were prepared according
to the procedures described in [17].
Bis(trimethylsilyl) (1,1-dioxido-3Н-2,1-benzoxa-
thiol-3-yl)phosphonate (6). Yield 52%, bp 142◦C
Tetra(trimethylsilyl) (3-oxo-1,3-dihydro-2-benzo-
furan-1,1-diyl)bisphosphonate (2). A mixture of
16.4 g of tris(trimethylsilyl) phosphite, 5.7 g of
bis(trimethylsilyl) phosphite, 3.7 g of phthalic anhy-
dride, and 2 mL of trimethylchlorosilane in 15 mL
of methylene chloride was stirred for 1 h. Then the
solvent was distilled off. In the NMR spectrum of
the mixture, the signals of the phosphonate 1 were
observed. 1Н NMR, δ, ppm: 7.25–7.50 (m, С6Н4),
–0.05 (s, Ме3SiОС), –0.31 (s, Ме3SiОР), and –0.38
2
(1 mm Hg). 1Н NMR, δ, ppm: 5.53 (d, С1Н, JPH
= 8.2 Hz), 7.3–7.5 (m, С6Н4), –0.01 (m, Ме3Si). 13С
NMR, δ, ppm: 77.85 (d, С1, 1JРС = 171.2 Hz), 130.91
2
3
(d, С2, JPС = 5.3 Hz), 135.61 (d, С3, JPС = 4 Hz),
133.56 (s, С4), 127.30 (s, С5, С6), and 125.04 (s, С5,
С6), 130.34 (s, С7), 0.23 (s, Ме3Si). 31Р NMR, δ, ppm:
–6.80 (s). Found: С 39.43; Н 5.72. С13Н23О6PSSi2.
Calcd.: С 39.58; 5.88. The fraction boiling at 90–
110◦C (1 mm Hg) contains tris(trimethylsilyl) phos-
phate (δР –26.01 ppm). Before the distillation, the
(s, Ме3SiОР). 13С NMR, δ, ppm: 101.86 (d, С1, JPС
1
= 227.5 Hz), 126.32 (s, С2), 145.98 (d, С3, JPС
=
3
1
reaction mixture contained compound 5, Н NMR,
9.5 Hz), 133.66 (s, С4), 124.26 (s, С5, С6), and 124.29
(s, С5, С6), 130.35 (s, С7), 166.60 (s, С8), 0.85 (s,
Ме3SiОС), 0.54 (s, Ме3SiОР), and 0.14 (s, Ме3SiОР).
31Р NMR, δ, ppm: –6.45 (s). Then trimethylchlorosi-
lane (2 mL) was added to the reaction mixture. The
mixture was kept at 20◦C for 2 weeks and then dis-
tilled to obtain 12.7 g of bisphosphonate 2. Yield
87%, boiling point (bp) 172◦C (1 mm Hg), melting
point (mp) 52◦C. 1Н NMR, δ, ppm: 7.25–7.55 (m,
δ, ppm: 6.15 (dd, С1Н, 2JPH = 14.8 Гц, 3JРH = 10 Hz),
13С NMR, δ, ppm: 69.90 (dd, С1, JРС = 179.5 Гц,
1
3JРС = 6.6 Гц). 31Р NMR, δ, ppm: –1.76 (d, Р1, 3JРР
=
41.6 Hz), –19.66 (d, Р2, 3JРР = 41.6 Hz).
Diethyl
(1,1-dioxido-3H-2,1-benzoxathiol-3-yl)
phosphonate (8). Yield 47%, bp 133◦C (1 mm Hg). 1Н
NMR, δ, ppm: 5.79 (d, С1Н, JPH = 8.1 Hz), 7.4–7.9
2
(m, С6Н4), 3.7–3.9 (m, 2 СН2О), 1.1–1.3 (m, 2 СН3).
13С NMR, δ, ppm: 77.15 (d, С1, JPС = 165.3 Hz),
1
С6Н4), –0.23 (s, 2 Ме3Si), and –0.09 (s, 2 Ме3Si). 13
С
130.78 (d, С2, JPС = 5.2 Hz), 132.30 (d, С3, JPС
=
2
3
NMR, δ, ppm: 83.14 (t, С1, JPС = 162.5 Hz), 124.8–
1
4.3 Hz), 133.95 (s, С4), 121.63 (s, С5, С6), and 124.79
Heteroatom Chemistry DOI 10.1002/hc

4
Prishchenko et al.
2
(s, С5, С6), 130.57 (s, С7), 64.61 (d, 2 СН2ОР, JPС
[2] Ebetino, F. H. Phosphorus Sulfur Silicon Relat Elem
1999, 144–146, 9–12.
[3] Widler, L.; Jaeggi, K. A.; Glatt, M.; Muller, K.;
Bachmann, R.; Bisping, M.; Born, A. R.; Cortesi,
R.; Guiglia, G.; Jeker, H.; Klein, R.; Ramseier, U.;
Schmid, J.; Schreiber, G.; Seltenmeyer, Y.; Green, J.
R. J Med Chem 2002, 45, 3721.
[4] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.;
Livantsova, L. I.; Milaeva, E. R. Heteroat Chem 2008,
19, 490–494.
[5] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.;
Livantsova, L. I.; Milaeva, E. R. Heteroat Chem 2008,
19, 562–568.
[6] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O.
P.; Livantsova, L. I.; Petrosyan, V. S. Heteroat Chem
2012, 23, 32–40.
[7] Berberova, N. T.; Osipova, V. P.; Koljada, M. N.;
Antonova, N. A.; Zefirov, N. S.; Milaeva, E. R.; Fil-
imonova, S. I.; Gracheva, Yu. A.; Prishchenko, A. A.;
Livantsov, M. V.; Livantsova, L. I.; Novikova, O. P.
Patent RU 2405032 C 1, Int. Cl. C11B 5/00. Russian
Patent Bull 2010, 33 (in Russian).
[8] Berberova, N. T.; Chernushkina, I. M.; Osipova,
V. P.; Kolyada, M. N.; Pimenov, Yu. I.; Gracheva,
Yu. A.; Prishchenko, A. A.; Livantsov, M. V.;
Livantsova, L. I.; Novikova, O. P.; Milaeva, E. R.;
Zefirov, N. S. Patent RU 2457240 C 2, Int. Cl. C11B
5/00, A23K 1/10. Russian Patent Bull 2012, 21 (in
Russian).
2
= 7Hz), and 64.30 (d, 2 СН2ОР, JPС = 7 Hz), 15.92
(d, СН3, JPС = 5.9 Hz). 31Р NMR, δ, ppm: 11.11
3
(s). Found: С 42.94; Н 4.87. С11Н15О6PS. Calcd.: С
43.14; 4.94.The fraction boiling at 80–100◦C (1 mm
Hg) contains diethyl trimethylsilyl phosphate (δР
–9.46 ppm (s)). Before the distillation, the reaction
1
mixture contained compound 7, Н NMR, δ, ppm:
6.41 (dd, С1Н, JPH = 12 Hz, JРH = 11.2 Hz), С
2
3
3
NMR 1, δ, ppm: 69.20 (dd, С1, 1JРС = 167.9 Hz, 3JРС
= 5.4 Hz). 31Р NMR, δ, ppm: 15.73 (d, Р1, JРР
=
3
29.8 Hz), –2.42 (d, Р2, 3JРР = 29.8 Hz).
(3-Oxo-1,3-dihydro-2-benzofuran-1,1-diyl)di-
phosphonic acid (9). A mixture of 12.7 g of diphos-
phonate 2 and 50 mL of methanol was heated to
boiling. The solvent was distilled off and the residue
was kept in a vacuum at 1 mm Hg for 1 h. Yield 6.2 g
(97%), mp >250◦C. 1Н NMR, δ, ppm: 7.60–8.05
(m, С6Н4). 13С NMR, δ, ppm: 84.25 (t, С1, JРС
=
1
149.3 Hz), 125.15 (t, С2, JPС = 3.9 Hz), 145.71 (s,
С3), 134.07 (s, С4), 124.78 (s, С5, С6), and 125.03 (s,
С5, С6), 129.41 (s, С7), 170.83 (s, С8). 31Р NMR, δ,
ppm: 9.17 (s). Found: С 32.42; Н 2.92. С8Н8О8P2.
Calcd.: С 32.67; Н 2.74.
2
The acid 10 was obtained similarly.
[9] Kehler, J.; Breuer, E. Synthesis 1998, 10, 1419–
1420.
[10] Love, B.; Kormendy, M. J Org Chem 1962, 27, 1703.
[11] Trinkhaus, S.; Holz, J.; Selke, R.; Boerner, A. Tetra-
hedron Lett 1997, 38, 807–808.
[12] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O.
P.; Livantsova, L. I.; Petrosyan, V. S. Heteroat Chem
2012, 23, 27–31.
[13] Griffiths, D. V.; Duncanson, P. Phosphorus Sulfur Sil-
icon Relat Elem 2002, 177, 2213.
(1,1-Dioxido-3H-2,1-benzoxathiol-3-yl)phos-
phonic acid (10). Yield 96%, mp 70◦C. Н NMR, δ,
1
ppm: 6.07 (d, С1Н, 2JPH = 8 Hz), 7.6–7.9 (m, С6Н4).
13С NMR, δ, ppm: 78.90 (d, С1, JPС = 162 Hz),
1
130.73 (d, С2, JPС = 4.2 Hz), 133.69 (d, С3, JPС
=
2
3
4 Hz), 134.06 (s, С4), 121.44 (s, С5, С6), and 124.71
(s, С5, С6), 130.47 (s, С7). 31Р NMR, δ, ppm: 9.81 (s).
Found: С 33.37; Н 2.74. С7Н7О6PS. Calcd.: С 33.61;
Н 2.82.
[14] Guenin, E.; Dedache, E.; Liquier, J.; Lecouvey, M.
Eur J Org Chem 2004, 14, 2983–2987.
[15] Lecouvey, M.; Mallard, I.; Bailly, T.; Burgada, R.; Ler-
oux, Y. Tetrahedron Lett 2001, 42, 8475–8478.
[16] Zemlyanoi, V. N.; Kukhar, V. P.; Kolodyazhnyi, O. I.
Zh Obshch Khim 2010, 80, 1399–1400.
[17] Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45,
2465–2524.
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Heteroatom Chemistry DOI 10.1002/hc