Synthesis of new aryl-substituted methylphosphonic and methylenediphosphonic acids and their derivatives

Article abstract of DOI:10.1007/s11172-017-1736-5

Simple and versatile synthetic procedures towards new aryl-substituted hydroxymethylphosphonic and methylenediphosphonic acids via reactions of either aromatic aldehydes or their derivatives with phosphites were elaborated.

Full text of DOI:10.1007/s11172-017-1736-5

Russian Chemical Bulletin, International Edition, Vol. 66, No. 2, pp. 336—341, February, 2017
336
Synthesis of new arylꢀsubstituted methylphosphonic and
methylenediphosphonic acids and their 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
Simple and versatile synthetic procedures towards new arylꢀsubstituted hydroxymethylphosꢀ
phonic and methylenediphosphonic acids via reactions of either aromatic aldehydes or their
derivatives with phosphites were elaborated.
Key words: arylꢀsubstituted hydroxymethyl phosphonates, methylene diphosphonates,
trimethylsilyl phosphites, trimethylsilyl trifluoromethanesulfonate.
Scheme 1
Functionalized (hydroxymethyl)phosphonates, (methꢀ
ylene)diphosphonates, and their derivatives are widely used
in organic synthesis. These compounds are of significant
interest as efficient ligands and promising biologically acꢀ
tive substances.1,2 Reactions of trimethylsilyl esters of
trivalent phosphorus acids with different carbonyl comꢀ
pounds constitute a convenient approach to a series of
functionalized hydroxymethyl organophosphorus comꢀ
pounds, for instance, structural biomimetics of αꢀhydroxyꢀ
alkyl carboxylic acids.3—7 In the present work, we perꢀ
formed a detail study of the reactions of diethyltrimethylꢀ
silyl and tris(trimethylsilyl) phosphites with different aroꢀ
matic aldehydes and their functional derivatives catalyzed
by trimethylsilyl triflate, zinc chloride, and cadmium
iodide. This approach is interesting as a plausible direct
pathway towards new arylꢀsubstituted (methylene)diꢀ
phosphonates, important structural analogs of natural
pyrophosphates. It was found that trimethylsilyl triflate
noticeably accelerates an exothermic addition of trisꢀ
(trimethylsilyl) phosphite to the carbonyl group of aroꢀ
matic aldehydes. The reactions produce phosphonates 1
in high yields (Scheme 1). Apparently, the reaction proꢀ
ceeds via intermediate adducts, i.e., electrophilic sulfonyl
acetals (cf. Ref. 8).
Ar = 4ꢀMeOC6H4 (a),
2,3ꢀ(MeO)2C6H3 (b),
(c),
(d)
Reagents and conditions: i. CF3SO3SiMe3, CH2Cl2, 40 °C;
ii. (Me3SiO)3P, —CF3SO3SiMe3.
Scheme 2
It is of note that high isolated yield of phosphonate 1e
can be achieved only under catalystꢀfree reaction condiꢀ
tions. Reaction carried out in the presence of trimethylsiꢀ
lyl triflate unexpectedly gives high yield of diphosphonate
2a instead of 1e (Scheme 2). Under these conditions, phosꢀ
phonate 1e was detected by NMR 1H, 13C, and 31P specꢀ
troscopy only in trace amounts (5%) and only before disꢀ
tillation of the reaction mixture.
Reagents and conditions: i. (Me3SiO)3P, CH2Cl2, 40 °C;
ii. (Me3SiO)3P, CF3SO3SiMe3, –(Me3Si)2O.
Indeed, the easy substitution of trimethylsilyloxy group
of phosphonate 1e is a result of the activating effect exertꢀ
ed by the dimethylamino group in paraꢀposition to the
trimethylsilyloxymethyl group, which facilitates formaꢀ
tion of highly reactive intermediate methylene quinone
(Scheme 3).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0336—0341, February, 2017.
1066ꢀ5285/17/6602ꢀ0336 © 2017 Springer Science+Business Media, Inc.

Methylphosphonic and methylenediphosphonic acid Russ.Chem.Bull., Int.Ed., Vol. 66, No. 2, February, 2017
337
Scheme 3
Reagents and conditions: i. CF3SO3SiMe3, —(Me3Si)2O; ii. (Me3SiO)3P, —CF3SO3SiMe3.
Scheme 4
Reagents and conditions: i. (Me3SiO)3P, CF3SO3SiMe3, 100 °C; ii. (EtO)2POSiMe3, CdI2, ZnCl2, 150 °C; iii. 2 CF3SO3SiMe3,
CH2Cl2, 40 °C; iv. (Me3SiO)3P.
Readily available diethyl acetals of aromatic aldehydes9
Scheme 5
react with trimethylsilyl phosphites similarly to aldehydes
only when heated at 100—150 °C. Under these condiꢀ
tions, the reaction gives ethoxymethyl phosphonates 3 in
high yields. For the synthesis of phosphonate 3b, it is
necessary to use cadmium iodide and zinc chloride as the
catalysts, since the use of trimethylsilyl triflate is accomꢀ
panied with replacement of the ethoxysilyl groups at the
2: Ar = 4ꢀMeOC6H4 (b), 2,5ꢀ(MeO)2C6H3 (c)
phosphorus atom by the trimethylsilyl groups leading to
4
a
b
c
X
Et
Et
Ar
4ꢀFC6H4
2,3ꢀ(MeO)2C6H4
4ꢀMeOC6H4
a complex product mixture. Note that 4ꢀdimethylaminoꢀ
benzaldehyde diethyl acetal reacts with tris(trimethylsilyl)
phosphite similarly to the corresponding aldehyde proꢀ
ducing high yield of diphosphonate 2a in an exothermic
reaction (Scheme 4). Enhanced reactivity of this acetal as
compared with the corresponding aldehyde apparently can
be explained by the formation of more electrophilic interꢀ
mediate disulfonyl acetal.
For the reaction of readily available benzal chlorides10
with triethyl phosphites and tris(trimethylsilyl) phosphites
to occur, harsh conditions are required, i.e., heating at
150—160 °C and zinc chloride as a catalyst. The reaction
follows the Arbuzov reaction mechanism and produces
either arylꢀsubstituted chloromethyl phosphonates 4 or
methylene diphosphonates 2b,c depending on the starting
phosphite structure (Scheme 5).
Thus, the direction of this reaction is determined by
both the electronic effects of the substituents at the benzꢀ
ene ring of the starting benzal chlorides and the size of
substituents in phosphites. Electronic effects of oꢀ and
pꢀsubstituents in the aromatic fragment also facilitate forꢀ
mation of highly reactive intermediates, oꢀ and pꢀmethylꢀ
ene quinones (Scheme 6).
Me3Si
Conditions: 150—160 °C, ZnCl2.
Diethyl trimethylsilyl phosphite nonꢀselectively reacts
with anisal chloride under similar conditions to give a
mixture of diphosphonates 2b,d in a 1 : 1 ratio. Subseꢀ
quent treatment of the mixture of diphosphonates 2b,d
with concentrated hydrochloric acid and bis(trimethylꢀ
silyl)amine produces diphosphonate 2e in high yield
(Scheme 7).
Reaction of unsubstituted benzal chloride with excess
triethylphosphite under severe conditions follows comꢀ
plex redox pattern to afford a mixture of benzyl phosphoꢀ
nate, pyrophosphate, and resinous products (Scheme 8).
Compounds 1—3 are efficient building blocks for the
synthesis of the corresponding arylꢀsubstituted methylꢀ
phosphonic acids. The latter compounds can serve as the
polydentane ligands and show a wide range of biological
activities. Thus, trimethylsilyl esters 1 and 2 smoothly
react with excess methanol under mild conditions giving

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Prishchenko et al.
Scheme 6
Y = F, MeO; X = Et, Me3Si
Scheme 7
Reagents and conditions: i. 2 ArCHCl2, –EtCl, –3 Me3SiCl, ZnCl2, 160 °C; ii. HCl, H2O, 100 °C; iii. (Me3Si)2NH, 120 °C.
Scheme 8
functionalized monoꢀ and diphosphonic acids 5 and 6,
respectively (Scheme 9).
acid. Note that these conditions also bring about the C—Cl
bond cleavage (Scheme 10).
Scheme 9
Scheme 10
Compound
5a
Ar
X
H
H
H
H
Compound
5e
5f
6a
6b
Ar
X
H
Et
—
—
4ꢀMeOC6H4
4ꢀMe2NC6H4
4ꢀBrC6H4
4ꢀMeOC6H4
4ꢀMe2NC6H4
Ar = 4ꢀMeOC6H4 (5a), 4ꢀFC6H4 (5g)
5b
5c
5d
2,3ꢀ(MeO)2C6H3
3ꢀPy
Reagents and conditions: i. H2O, HCl, 100 °C.
4ꢀPy
In summary, we elaborate simple and versatile synꢀ
thetic procedures to access new arylꢀsubstituted hydrꢀ
oxymethylphosphonic and methylenediphosphonic acids
and their derivatives. The synthesized compounds 1—6
Chloromethyl phosphonates 4a,c and diphosphonate
2b readily hydrolyze to hydroxymethylphosphonic (5a,g)
and diphosphonic (6a) acids by refluxing with hydrochloric

Methylphosphonic and methylenediphosphonic acid Russ.Chem.Bull., Int.Ed., Vol. 66, No. 2, February, 2017
339
(s, Me3Si); 70.59 (d, C(1), 1JP,C = 174.7 Hz); 121.45 (s, CPy), 147.21
are of interest as promising polydentate ligands and valuꢀ
able biologically active substances.
(br.s, CPy); 148.54 (d, CPy,
3JP,C = 2.0 Hz). 31P{1H} NMR
(CDCl3), δ: 1.85 (s).
Bis(trimethylsilyl) 4ꢀdimethylaminophenyl(trimethylsilyloxy)ꢀ
methylphosphonate (1e). Yield 89%, b.p. 164 °C (1 Torr.), m.p.
55 °C. Found (%): C, 48.03; H, 8.49. C18H38NO4PSi3. Calculatꢀ
ed (%): C, 48.29; H, 8.55. 1H NMR (CDCl3), δ: –0.29 (s, Me3Si);
–0.19 (s, Me3Si); –0.16 (s, Me3Si); 2.59 (s, Me2N); 4.64
(d, C(1)H, 2JP,H = 16.0 Hz); 6.43 (d 2 CHPh, 3JH,H = 7.2 Hz); 6.93
Experimental
1
H, 13C{1H}, and 31P{1H} NMR spectra were recorded with
a Bruker Avance 400 instrument at working frequencies of 400,
100, and 162 MHz, respectively. The chemical shifts are given
in the δ scale relative to Me4Si (1H, 13C{1H}) and a 85% solution
of H3PO4 in D2O (31P{1H}). All reactions were carried out under
dry argon in anhydrous solvents. The starting acetals of aromatic
aldehydes,9 substituted benzal chlorides,10 and trimethylsilyl
esters of trivalent phosphorus acids3,4 were synthesized by the
known procedures.
3
(d, 2 CHPh, JH,H = 7.2 Hz). 13C{1H} NMR (CDCl3), δ: –0.68
(s, Me3Si); 0.12 (s, Me3Si); 40.47 (s, Me2N); 71.40 (d, C(1),
1JP,C = 181.4 Hz); 112.22 (s), 127.79 (d, 3JP,C = 6.0 Hz); 130.52
(s), 148.76 (s, CPh). 31P{1H} NMR (CDCl3), δ: 4.44 (s) (cf. Ref. 5).
Tetrakis(trimethylsilyl) (4ꢀdimethylaminophenyl)methyleneꢀ
diphosphonate (2a). To a solution of 4ꢀdimethylaminobenzaldeꢀ
hyde diacetal (3.4 g, 0.015 mol) and tris(trimethylsilyl) phosꢀ
phite (18.0 g, 0.060 mol) in dichloromethane (15 mL), a solution
of trimethylsilyl trifluoromethanesulfonate (0.9 g, 0.004 mol) in
dichloromethane (5 mL) was added. After an exothermic reacꢀ
tion ceased, the reaction mixture was kept at 20 °C for 24 h and
concentrated in vacuo. The precipitate formed was collected and
washed with chilled hexane to afford 8.6 g (96%) of diphosphoꢀ
Bis(trimethylsilyl) 4ꢀmethoxyphenyl(trimethylsilyloxy)methylꢀ
phosphonate (1a). To a stirred solution of tris(trimethylsilyl) phosꢀ
phite (30 g, 0.10 mol) and pꢀanisaldehyde (5.5 g, 0.04 mol) in
dichloromethane (40 mL), trimethylsilyl trifluoromethaneꢀ
sulfonate (0.6 g, 003 mol) was added. After an exothermic reacꢀ
tion ceased, the mixture was refluxed for 1 h and concentrated
in vacuo. Vacuum distillation of the residue afforded 15.1 g (86%)
of phosphonate 1a, b.p. 144 °C (2 Torr). Found (%): C, 46.72;
H, 8.02. C17H35O5PSi3. Calculated (%): C, 46.97; H, 8.12.
nate 2a, m.p. 144 °C. Found (%): C, 43.06; H, 8.06.
1
C
21H47NO6P2Si4. Calculated (%): C, 43.20; H, 8.11. H NMR
(CDCl3), δ: 0.07 (s, 4 Me3Si); 3.22 (s, Me2N); 3.48 (t, C(1)H,
2JP,H = 25.2 Hz); 7.53 (d, 2 CPhH, 3JH,H = 8.4 Hz); 7.65 (d, 2 CPhH,
3JH,H = 8.4 Hz). 13C{1H} NMR (CDCl3), δ: 0.32 (s, 2 Me3Si);
1H NMR (CDCl3), δ: –0.17 (s, Me3Si); –0.06 (s, 2 Me3Si); 3.56
2
(s, MeO); 4.62 (d, C(1)H, JP,H = 12.0 Hz); 6.62 (d, 2 CHPh
,
3JP,H = 8.0 Hz); 7.08 (d, 2 CHPh
,
3JP,H = 8.0 Hz). 13C{1H}
46.82 (s, Me2N); 48.33 (t, C(1), JP,C = 135.9 Hz); 120.28 (s),
1
3
3
NMR (CDCl3), δ: –0.26 (s, Me3Si); 0.49 (s, 2 Me3Si); 54.89
(s, MeO); 71.76 (d, JP,C = 180.0 Hz); 113.14 (s), 128.32
(d, JP,C = 7.0 Hz); 129.92 (s), 159.20 (s, CPh). 31P{1H} NMR
(CDCl3), δ: –3.96 (s) (cf. Ref. 5).
Phosphonates 1b—e were synthesized similarly; the only exꢀ
ception was a catalystꢀfree reaction in the case of 1e.
Bis(trimethylsilyl) 2,3ꢀdimethoxyphenyl(trimethylsilyloxy)ꢀ
methylphosphonate (1b). Yield 84%, b.p. 143 °C (0.5 Torr), m.p.
29 °C. Found (%): C, 46.26; H, 7.94. C18H37O6PSi3. Calculatꢀ
ed (%): C, 46.52; H, 8.02. 1H NMR (CDCl3), δ: –0.21 (s,
Me3SiOC); –0.02 (s, 2 Me3Si); 3.56 (s, MeO); 3.63 (s, MeO);
5.17 (d, C(1)H, 2JP,H = 14.4 Hz); 6.55—6.90 (m, C6H3). 13C{1H}
NMR (CDCl3), δ: –0.31 (s, Me3Si); 0.52 (s, 2 Me3Si); 55.44
(s, MeO); 60.25 (s, MeO); 65.16 (d, 1JP,C = 182.8 Hz); 111.93 (s),
132.12 (t, JP,C = 5.9 Hz); 135.42 (t, JP,C = 8.5 Hz); 141.60
1
(s, CPh). 31P{1H} NMR (CDCl3), δ: –1.47 (s).
3
Bis(trimethylsilyl) 4ꢀbromophenyl(ethoxy)methylphosphonate
(3a). To a solution of 4ꢀbromobenzaldehyde diethylacetal (3.9 g,
0.015 mol) and tris(trimethylsilyl) phosphite (19.0 g, 0.08 mol)
in dichloromethane (15 mL), a solution of trimethylsilyl trifluoꢀ
romethanesulfonate (1.0 g, 0.0045 mol) in dichloromethane
(5 mL) was added. The reaction mixture was heated (a boiling
water bath) for 2 h with simultaneous distillation off of dichloroꢀ
methane. Vacuum distillation of the residue afforded 5.0 g (74%)
of phosphonate 3a, b.p. 104 °C (2 Torr). Found (%): C, 40.86;
H, 6.33. C15H28BrO4PSi2. Calculated (%): C, 41.00; H, 6.42.
3
1H NMR (CDCl3), δ: 0.07 (s, 2 Me3Si); 1.05 (t, CH3, JH,H
=
= 7.2 Hz); 3.30—3.40 (m, CH2O); 4.43 (d, C(1)H, 2JP,H = 7.2 Hz);
7.15 (d, 2 CHPh, 2JH,H = 8.0 Hz); 7.30 (d, 2 CHPh, 2JH,H = 8.0 Hz).
13C{1H} NMR (CDCl3), δ: 0.67 (s, 2 Me3Si); 15.03 (s, Me);
66.38 (d, CH2O, 3JP,C = 13.8 Hz); 78.11 (d, C(1), 1JP,C = 175.6 Hz);
121.89 (d, 2JP,C = 4.6 Hz); 129.49 (d, 2JP,C = 5.6 Hz); 131.16 (s),
134.70 (s, CPh). 31P{1H} NMR (CDCl3), δ: 0.65 (s).
3
120.41 (d, JP,C = 3.2 Hz); 123.34 (s), 130.96 (s), 145.94 (d,
3JP,C = 8.0 Hz); 151.89 (s, CPh). 31P{1H} NMR (CDCl3), δ: 3.71 (s).
O,OꢀBis(trimethylsilyl) pyridineꢀ3ꢀyl(trimethylsilyloxy)methꢀ
ylphosphonate (1c). Yield 89%, b.p. 152 °C (1 Torr). Found (%):
C, 44.26; H, 7.89. C15H32NO4PSi3. Calculated (%): C, 44.41;
H, 7.95. 1H NMR (CDCl3), δ: –0.11 (s, Me3Si); –0.10
Diethyl 4ꢀdimethylaminophenyl(ethoxy)methylphosphonate
(3b). A mixture of 4ꢀdimethylaminobenzaldehyde diethylacetal
(3.4 g, 0.015 mol), diethyl trimethylsilyl phosphite (12.6 g,
0.060 mol), cadmium iodide (0.1 g, 0.0003 mol), and zinc chlorꢀ
ide (0.1 g, 0.0004 mol) was heated at 140 °C until complete
distillation off of ethoxytrimethylsilane (b.p. 74 °C). Vacuum
distillation of the residue afforded 4.2 g (86%) of phosphonate 3b,
b.p. 195 °C (2 Torr). Found (%): C, 56.94; H, 8.26. C15H26NO4P.
Calculated (%): C, 57.13; H, 8.31. 1H NMR (CDCl3), δ: 0.97
2
(s, Me3Si); 0.02 (s, Me3Si); 4.72 (d, C(1)H, JP,H = 15.2 Hz);
7.09—7.13 (m, CHPy); 7.65 (d, CHPy, 3JH,H = 8.0 Hz); 8.32—8.34
(m, CHPy); 8.43 (s, CHPy). 13C{1H} NMR (CDCl3), δ: –0.26
(s, Me3Si); 0.62 (s, Me3Si); 0.74 (s, Me3Si); 69.90 (d, C(1),
1JP,C = 179.3 Hz); 123.05 (s), 134.32 (s), 135.37 (d, 3JP,C = 4.6 Hz);
147.85 (d, JP,C = 6.5 Hz); 148.39 (s, CPy). 31P{1H} NMR
3
(CDCl3), δ: 2.43 (s).
O,OꢀBis(trimethylsilyl) pyridinꢀ4ꢀyl(trimethylsilyloxy)methylꢀ
phosphonate (1d). Yield 86%, b.p. 149 °C (1 Torr). Found (%):
C, 44.28; H, 7.86. C15H32NO4PSi3. Calculated (%): C, 44.41;
H, 7.95. 1H NMR (CDCl3), δ: –0.09 (s, Me3Si); –0.07 (s, Me3Si);
3
3
(t, CH3, JH,H = 7.2 Hz); 0.98 (t, CH3, JH,H = 7.2 Hz); 1.05
(t, CH3, 3JH,H = 6.8 Hz); 2.72 (s, Me2N); 3.20—3.35 (m, CH2O);
3.60—3.90 (m, 2 CH2O); 4.29 (d, C(1)H, 2JP,H = 15.2 Hz); 6.47
(d, 2 CHPh, 3JH,H = 8.8 Hz); 7.08 (d, 2 CHPh, 2JH,H = 8.8 Hz).
0.06 (s, Me3Si); 4.68 (d, C(1)H, 2JP,H = 17.2 Hz); 7.18 (d, 2 CHPy
,
3JH,H = 5.6 Hz); 8.35 (d, 2 CHPy
,
3JH,H = 5.6 Hz). 13C{1H}
13C{1H} NMR (CDCl3), δ: 14.93 (s, Me); 16.17 (d, Me, 3JP,C
= 5.5 Hz); 40.15 (s, Me2N); 62.37 (d, CH2O, JP,C = 6.5 Hz);
=
3
NMR (CDCl3), δ: –0.70 (s, Me3Si); 0.15 (s, Me3Si); 0.38

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Prishchenko et al.
62.58 (d, CH2O, 2JP,C = 6.4 Hz); 65.39 (d, CH2O, 3JP,C = 14.7 Hz);
77.99 (t, C(1), 1JP,C = 171.0 Hz); 111.84 (s), 121.87 (s), 128.86
H, 5.01. C8H11O5P. Calculated (%): C, 44.05; H, 5.08. 1H NMR
(D2O), δ: 3.44 (s, MeO); 4.71 (d, C(1)H, 2JP,H = 12.0 Hz); 6.67
(d, 1 H, CHPh, 3JH,H = 8.0 Hz); 7.12 (d, CHPh, 3JH,H = 8.0 Hz).
3
(d, JP,C = 5.5 Hz); 150.33 (s, CPh). 31P{1H} NMR (CDCl3),
δ: 19.97 (s).
13C{1H} NMR (D2O), δ: 55.16 (s, MeO); 69.77 (d, C(1), 1JP,C
=
3
Diethyl (4ꢀfluorophenyl)chloromethylphosphonate (4a).
A mixture of 4ꢀfluorobenzaldehyde (3.0 g, 0.017 mol), triethyl
phosphite (7.0 g, 0.042 mol), and zinc chloride (0.1 g, 0.0007 mol)
was heated at 150—160 °C for 2 h. Vacuum distillation of the
reaction mixture afforded 3 g (64%) of phosphonate 4a, b.p.
152 °C (2 Torr). Found (%): C, 46.89; H, 5.26. C11H15ClFO3P.
Calculated (%): C, 47.07; H, 5.39. 1H NMR (CDCl3), δ: 4.75
(d, 1 H, C(1)H, 2JP,H = 12.0 Hz); 6.82 (d, CHPh, 3JH,H = 8.0 Hz);
= 160.0 Hz); 113.87 (s), 128.52 (d, JP,C = 6.0 Hz); 129.02 (s),
158.29 (s, CPh). 31P{1H} NMR (D2O), δ: 20.76 (s) (cf. Ref. 5).
Acids 5b—f and 6a,b were synthesized similarly.
2,3ꢀDimethoxyphenyl(hydroxymethyl)phosphonic acid (5b).
Yield 95%, heavy oil. Found (%): C, 43.46; H, 5.30. C9H13O6P.
Calculated (%): C, 43.56; H, 5.18. 1H NMR (CD3OD), δ: 3.84
(s, 3 H, MeO); 3.88 (s, MeO); 5.47 (d, C(1)H, 2JP,H = 12.8 Hz);
6.98 (d, CHPh, 3JH,H = 8.0 Hz); 7.12 (t, CHPh, 3JH,H = 8.0 Hz);
7.32 (d, CHPh
,
3JH,H = 8.0 Hz). 13C{1H} NMR (CDCl3), δ:
7.28 (d, CHPh,
3JH,H = 8.0 Hz). 13C{1H} NMR (CD3OD), δ:
52.52 (d, C(1), 1JP,C = 160.0 Hz); 115.26 (d, CPh, 2JF,C = 22.0 Hz);
55.14 (s, MeO); 60.15 (s, MeO); 63.89 (d, C(1), 1JP,C = 164.5 Hz);
130.16 (t, CPh, 2JP,C = 3.5 Hz, 4JF,C = 3.5 Hz); 130.69 (dd, CPh
3JP,C = 6.0 Hz, 3JF,C = 8.0 Hz); 162.68 (d, CPh, 1JF,C = 248.0 Hz).
31P{1H} NMR (CDCl3), δ: 16.89 (s).
,
112.13 (s), 120.37 (d, JP,C = 2.7 Hz); 123.83 (s, 131.57 (s),
3
3
146.52 (d, JP,C = 7.4 Hz); 152.29 (s, CPh). 31P{1H} NMR
(CD3OD), δ: 21.26 (s).
Compounds 4b,c and 2b,c were synthesized similarly.
Diethyl (2,3ꢀdimethoxyphenyl)chloromethylphosphonate (4b).
Yield 68%, b.p. 184 °C (2 Torr). Found (%): C, 48.23; H, 6.16.
3ꢀPyridyl(hydroxy)methylphosphonic acid (5c). Yield 94%,
m.p. 219 °C (decomp.). Found (%): C, 37.89; H, 4.15. C6H8NO4P.
Calculated (%): C, 38.11; H, 4.26. 1H NMR (D2O—C5D5N), δ:
2
C
13H20ClO5P. Calculated (%): C, 48.38; H, 6.25. 1H NMR
4.40 (d, C(1)H, JP,H = 13.6 Hz); 6.53 (br.s, CHPy); 7.38 (br.s,
(CDCl3), δ: 5.35 (d, 1 H, C(1)H, 2JP,H = 16.0 Hz); 3.60 and 3.65
CHPy); 7.42 (br.s, CHPy); 7.96 (br.s, CHPy). 13C{1H} NMR
(both s, 6 H, 2 MeO); 6.64—7.17 (m, 3 CHPh). 13C{1H} NMR
(D2O—C5D5N), δ: 69.12 (d, C(1), 1JP,C = 148.3 Hz); 122.91 (s),
1
3
(CDCl3), δ: 45.63 (d, C(1), JP,C = 163.0 Hz); 55.52 and 55.73
136.54 (s), 136.07 (s), 144.17 (s), 144.46 (d, JP,C = 3.0 Hz);
3
(both s, 2 MeO); 112.81 (d, JP,C, = 3.0 Hz); 117.97 (s), 121.56
all CPy.
31P{1H} NMR (D2O—C5D5N), δ: 14.72 (s).
(d, 2JP,C = 4.0 Hz); 124.04 (s), 146.59 (d, 3JP,C = 9.0 Hz); 152.04
4ꢀPyridyl(hydroxy)methylphosphonic acid (5d). Yield 96%,
m.p. 239 °C (decomp.). Found (%): C, 37.99; H, 4.12. C6H8NO4P.
Calculated (%): C, 38.11; H, 4.26. 1H NMR (D2O—C5D5N),
(s, CPh). 31P{1H} NMR (CDCl3), δ: 17.96 (s).
Bis(trimethylsilyl) (4ꢀmethoxyphenyl)chloromethylphosphonꢀ
ate (4c). Yield 81%, b.p. 166 °C (1 Torr), m.p. 65 °C. Found (%):
C, 43.98; H, 6.81. C14H26ClO4PSi2. Calculated (%): C, 44.14;
H, 6.88. 1H NMR (CDCl3), δ: 0.09 and 0.19 (both s, Me3Si);
δ: 6.69 (br.s, C(1)H); 7.20 (d, CHPy
,
3JH,H = 5.2 Hz); 7.87
(d, CHPy, 3JH,H = 5.2 Hz). 13C{1H} NMR (D2O—C5D5N), δ: 71.26
2
3
(d, C(1), JP,C = 141.4 Hz); 122.03 (d, JP,C = 3.5 Hz); 145.50
(s), 152.96 (s, CPy). 31P{1H} NMR (D2O—C5D5N), δ: 13.77 (s).
4ꢀDimethylaminophenyl(hydroxy)methylphosphonic acid (5e).
Yield 96%, m.p. 152 °C. Found (%): C, 46.64; H, 6.16.
4.71 (d, C(1)H, 2JP,H = 12.0 Hz); 3.72 (s, MeO); 6.80 (d, CHPh
,
3JH,H = 8.0 Hz); 7.36 (d, CHPh, 3JH,H = 8.0 Hz). 13C{1H} NMR
(CDCl3), δ: 0.63 and 0.79 (both s, Me3Si); 54.63 (d, C(1),
1JP,C = 168.2 Hz); 55.21 (s, MeO); 113.75 (s), 126.90 (t, 2JP,C
=
C9H14NO4P. Calculated (%): C, 46.46; H, 6.10. 1H NMR
3
2
= 3.0 Hz); 130.21 (d, JP,C = 6.0 Hz); 159.94 (s, CPh). 31P{1H}
(D2O—C5D5N), δ: 1.85 (s, 2 CH3); 4.30 (d, C(1)H, JP,H
=
NMR (CDCl3), δ: –0.79 (s).
Tetraethyl (4ꢀmethoxyphenyl)methylenediphosphonate (2b).
Yield 78%, b.p. 202 °C (2 Torr). Found (%): C, 48.59; H, 7.05.
= 11.6 Hz); 5.85 (d, CHPh
, ,
3JH,H = 8.0 Hz); 6.73 (d, CHPh
3JH,H = 8.0 Hz). 13C{1H} NMR (D2O—C5D5N), δ: 40.07 (s, 2 Me);
71.08 (d, C(1); 1JP,C = 152.4 Hz); 113.06 (s), 127.36 (d, 3JP,C
= 4.9 Hz); 129.67 (s), 147.82 (s, C(Ph)). 31P{1H} NMR
(D2O—C5D5N), δ: 17.22 (s).
=
C
16H28O7P2. Calculated (%): C, 48.73; H, 7.16. 1H NMR
2
(CDCl3), δ: 3.47 (t, C(1)H, JP,H = 24.0 Hz); 3.54 (s, MeO);
6.63 (d, CHPh, 3JH,H = 8.0 Hz); 7.17 (d, CHPh, 3JH,H = 8.0 Hz).
4ꢀBromophenyl(ethoxy)methylphosphonic acid (5f). Yield
96%, heavy oil. Found (%): C, 36.52; H, 4.03. C9H12BrO4P.
Calculated (%): C, 36.64; H, 4.10. 1H NMR (CD3OD), δ: 1.21
13C{1H} NMR (CDCl3), δ: 44.37 (t, C(1), JP,C = 132.5 Hz);
1
2
54.89 (s, MeO); 113.69 (s); 121.66 (t, JP,C = 8.0 Hz); 131.29
(t, JP,C = 6.5 Hz); 158.90 (s, CPh). 31P{1H} NMR (CDCl3),
3
3
3
(t, Me, JH,H = 7.2 Hz); 3.53 (q, CH2O, JH,H = 7.2 Hz); 4.62
2
δ: 18.74 (s).
(d, C(1)H, JP,H = 16.4 Hz); 7.40 (d, CHPh
7.50 (d, CHPh
,
3JH,H = 7.2 Hz);
,
3JH,H = 7.2 Hz). 13C{1H} NMR (CD3OD), δ:
Tetraethyl (2,5ꢀdimethoxyphenyl)methylenediphosphonate
(2c). Yield 76%, b.p. 212 °C (2 Torr). Found (%): C, 48.02;
H, 7.06. C17H30O8P2. Calculated (%): C, 48.11; H, 7.131H NMR
14.56 (s, Me); 66.50 (d, CH2O, 2JP,C = 12.8 Hz); 78.01 (d, C(1),
1JP,C = 164.5 Hz). 31P{1H} NMR (CD3OD), δ: 17.82 (s).
4ꢀMethoxyphenylmethylenediphosphonic acid (6a). Yield
96%, b.p. 92 °C. Found (%): C, 33.94; H, 4.38. C8H12O7P2.
(CDCl3), δ: 3.52 and 3.55 (both s, MeO); 4.35 (t, C(1)H, 2JP,H
=
= 26.0 Hz); 6.45—6.60 (m), 7.18 (s, 4 CHPh). 13C{1H} NMR
1
(CDCl3), δ: 35.48 (t, C(1), JP,C = 133.0 Hz); 55.29 and 56.30
Calculated (%): C, 34.06; H, 4.29. 1H NMR (D2O), δ: 3.59
(both s, OMe); 111.78 (s), 113.94 (s), 116.21 (t, 3JP,C = 4.5 Hz);
(t, C(1)H, JP,H = 26.2 Hz); 3.57 (s, MeO); 6.65 (d, CHPh
3JP,H = 8.0 Hz); 7.20 (d, CHPh, 3JP,H = 8.0 Hz). 13C{1H} NMR
,
2
2
3
119.28 (t, JP,C = 8.0 Hz); 150.78 (t, JP,C = 7.0 Hz); 153.08
(s, CPh). 31P{1H} NMR (CDCl3), δ: 19.05 (s).
(D2O), δ: 45.06 (t, C(1), JP,C = 126.5 Hz); 54.74 (s, MeO);
1
4ꢀMethoxyphenyl(hydroxymethyl)phosphonic acid (5a). A soluꢀ
tion of phosphonate 1a (10.6 g, 0.025 mol) in diethyl ether
(15 mL) was added to methanol (40 mL) with stirring under
cooling to 10 °C. The mixture was heated to reflux and concenꢀ
trated. The obtained white crystals were dried in vacuo (1 Torr)
to give 4.7 g (96%) of acid 5a, m.p. 78 °C. Found (%): C, 43.96;
114.72 (s); 124.96 (t, 2JP,C = 7.5 Hz); 131.08 (t, 3JP,C = 6.0 Hz);
157.76 (s, CPh). 31P{1H} NMR (D2O), δ: 17.92 (s).
4ꢀDimethylaminophenylmethylenediphosphonic acid (6b).
Yield 98%, m.p. 147 °C. Found (%): C, 36.52; H, 5.06.
C9H15NO6P2. Calculated (%): C, 36.62; H, 5.12. 1H NMR
(D2O), δ: 2.45 (s, Me2N); 3.75 (t, C(1)H, 2JP,H = 23.2 Hz); 6.26

Methylphosphonic and methylenediphosphonic acid Russ.Chem.Bull., Int.Ed., Vol. 66, No. 2, February, 2017
341
(d, CHPh
,
2JP,H = 6.8 Hz); 7.40 (d, CHPh
,
3JH,H = 6.8 Hz).
2. O. I. Kolodiazhnyi, Russ. Chem. Rev., 2006, 75, 227.
1
13C{1H} NMR (D2O), δ: 40.76 (s, Me2N); 48.21 (t, JP,C
=
3. L. Wozniak, J. Chojnowski, Tetrahedron, 1989, 45, 2465.
4. V. D. Romanenko, M. V. Shevchuk, V. P. Kukhar, Current.
Org. Chem., 2011, 15, 2774.
2
= 117.2 Hz); 113.14 (s), 125.62 (t, JP,C = 6.5 Hz); 131.33 (s),
147.55 (s, CPh). 31P{1H} NMR (D2O), δ: 16.96 (s).
4ꢀFluorophenyl(hydroxymethyl)phosphonic acid (5g). A mixꢀ
ture of phosphonate 4a (3 g, 0.011 mol) and concentrated hydroꢀ
chloric acid (20 mL) was heated at 100 °C (a boiling water bath)
for 4 h and then concentrated to dryness under vacuum (7 Torr).
The residue was coꢀevaporated with water (30 mL) to give 2 g
(92%) of acid 5g, m.p. 69 °C. Found (%): C, 49.52; H, 3.94.
C7H8FO4P. Calculated (%): C, 40.79; H, 3.91. 1H NMR (D2O),
5. A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I.
Livantsova, V. S. Petrosyan, Heteroat. Chem., 2008, 19, 352.
6. A. A. Prishchenko, Z. S. Novikova, I. F. Lutsenko, Russ. J.
Gen. Chem. (Engl. Transl.), 1977, 47, 2689 [Zh. Obshch.
Khim., 1977, 47, 2689].
7. M.ꢀP. Teulade, P. Savignac, E. E. Aboujaoude, S. Lietge,
N. Collignon, J. Organom. Chem., 1986, 304, 283.
8. A. D. Dilman, S. L. Ioffe, Chem. Rev., 2003, 103, 733.
9. J. Klein, E. Bergmann, J. Am. Chem. Soc., 1957, 79, 3452.
10. WeygandꢀHilgetag, Organischꢀchemische Experimentierkunst,
3. neubearb. Aufl., Johann Ambrosius Barth Verlag, Leipzig,
1964, 1142 S.
2
δ: 4.72 (q, C(1)H, JP,H = 12.0 Hz); 7.10—7.15 and 7.41—7.44
(both m, CHPh). 13C{1H} NMR (D2O), δ: 70.10 (d, C(1),
1JP,C = 160.0 Hz); 114.69 (d, 2JF,C = 21.0 Hz), 129.66 (s), 136.71 (s),
1
161.76 (d, JF,C = 244.0 Hz); all CPh
.
31P{1H} NMR (D2O),
δ: 18.52 (s), (cf. Ref. 11).
Acids 5a and 6a were synthesized similarly.
11. A. A. Prishchenko, M. V. Livantsov, O. P. Novikova,
L. I. Livantsova, A. V. Maryashkin Russ. J. Gen. Chem.
(Engl. Transl.), 2005, 75, 1965 [Zh. Obshch. Khim., 2005,
75, 2055].
This work was financially supported by the Russian
Foundation for Basic Research (Projects Nos. 14ꢀ03ꢀ
00001, 15ꢀ03ꢀ00002, and 17ꢀ03ꢀ00169).
References
1. V. P. Kukhar, H. R. Hudson, Aminophosphonic and Aminoꢀ
phosphinic Acids. Chemistry and Biological Activity, Wiley,
New York, USA, 2000, 634 p.
Received June 21, 2016;
in revised form October 12, 2016