New type of hypophosphites

Article abstract of DOI:10.1080/104265090508262

Optimal conditions were found for the synthesis of hypophosphoric acid esters with the cyclic systems of cyclohexanol and 1,2;5,6-O-diisopropylidene- α-D-glycofuranose as an example. It was shown that these hypophosphoric acid esters have high reactivity

Full text of DOI:10.1080/104265090508262

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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New Type of Hypophosphites
E. E. Nifantyev a , T. S. Kukhareva a , D. V. Khodarev
a , L. K. Vasyanina a & A. V. Vasil'ev a
a Moscow Pedagogical , State University , Moscow,
Russia
Published online: 21 Dec 2010.
To cite this article: E. E. Nifantyev , T. S. Kukhareva , D. V. Khodarev , L. K.
Vasyanina & A. V. Vasil'ev (2005) New Type of Hypophosphites, Phosphorus, Sulfur, and
Silicon and the Related Elements, 180:2, 331-338, DOI: 10.1080/104265090508262
To link to this article: http://dx.doi.org/10.1080/104265090508262
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Phosphorus, Sulfur, and Silicon, 180:331–338, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090508262
New Type of Hypophosphites
E. E. Nifantyev
T. S. Kukhareva
D. V. Khodarev
L. K. Vasyanina
A. V. Vasil’ev
Moscow Pedagogical State University, Moscow, Russia
Optimal conditions were found for the synthesis of hypophosphoric acid es-
ters with the cyclic systems of cyclohexanol and 1,2;5,6-O-diisopropylidene-α-D-
glycofuranose as an example. It was shown that these hypophosphoric acid esters
have high reactivity and are candidates for processes resulting in the formation
of P C bonds. The structure of the products was reliably supported by spectral
methods.
Keywords 1,2;5,6-O-Diisopropylidene-α-D-glycofuranose hypophosphite; cyclohexyl
hypophosphite; hydrophosphoryl compounds; hypophosphites; phosphorus–carbon bond;
phosphorylation
INTRODUCTION
Hypophosphoric acid esters (hypophosphites) are the least under-
stood hydrophosphoryl compounds. A few of the simplest alkyl
hypophosphites1 and a nucleoside hypophosphite2 have been obtained
to date. All these compounds are unstable; they decompose sponta-
neously under short storage. At the same time, some reactions of freshly
prepared hypophosphites produced difficultly available compounds.3−6
In this context, our object was to evaluate the possibility of expanding
the scope of work on compounds in whose molecules the hypophosphite
function is bound to the alicyclic framework. The main objects of study
were hypophosphites of cyclohexanol and 1,2;5,6-O-diisopropylidene-α-
D-glycofuranose.
The above esters were synthesized by the reaction of the correspond-
ing alcohols with triethylammonium salt of hypophosphoric acid 1 in the
Received June 3, 2004; in final form July 6, 2004.
Address correspondence to E. E. Nifantyev, Chemistry Department, Moscow State
Pedagogical University, Nesvizky per. 3, Moscow 119021, Russia. E-mail: chemdept@
mtu–net.ru
331

332
E. E. Nifantyev et al.
presence of pivaloyl chloride (2, 2-dimethylpropanoic acid chloride). The
reaction probably involves the transformation of hypophosphorous acid
into pivaloyl hypophosphite, which acts as a phosphorylating agent.
RESULTS AND DISCUSSION
Cyclohexyl hypophosphite (2) was synthesized according to Scheme 1:
SCHEME 1 Synthesis of Cyclohexyl Hypophosphite (2).
Reaction conditions were selected to obtain the target product 2 with
a good yield.
Compound 2 was isolated in the individual form by high-vacuum
sublimation. Its structure was supported by 1H, 13C, and 31P NMR spec-
troscopy (see Experiment). The obtained hypophosphite 2 is an unsta-
ble compound; it spontaneously disproportionates when stored under
an inert atmosphere but can exist in solution for a relatively long time.
The obtained cyclohexyl hypophosphite was introduced into the
Abramov reaction with chloral to give phosphonite (Scheme 2):
SCHEME 2 Abramov’s reaction with Cyclohexyl Hypophosphite (2).

Hypophosphites
333
Compound 3 is obtained as two diastereomers, as is evidenced by the
31P NMR spectrum of the reaction mixture, which show two doublets
with chemical shifts of 26.3 and 20.7 ppm and coupling constants of
593.04 and 586.33 Hz, respectively.
We isolated one of the isomers in the pure form. Its 31P NMR spec-
trum showed a doublet with a chemical shift of 26.3 ppm and a coupling
constant of 593.04 Hz.
Next, we attempted to obtain a compound with two P–C bonds,
i.e., a phosphinic acid derivative from cyclohexyl hypophosphite. This
task was implemented by mixing cyclohexyl hypophosphite with
bis(diethylamino)methane. Note that the reaction of 1 equivalent of
compound 2 with 2.5 equivalents of bis(diethylamino)methane gives
two products with mono- and disubstituted phosphorus atoms in a pro-
portion of 1:5, as is evidenced by the 31P NMR spectrum which shows
a doublet with a chemical shift of 34.5 ppm and a coupling constant
of 550.25 Hz, as well as a singlet with a chemical shift of 51.1 ppm.
The reaction was shifted toward the formation of the phosphinic acid
derivative only under heating for several hours (Scheme 3).
SCHEME 3 Kabachnik-Fields’ reaction with Cyclohexyl Hypophosphite (2).
The structure of compound 4 was supported by 1H, 13C, and 31P NMR
spectroscopy and by elemental analysis.
Next, glucofuranose hypophosphite 5 was synthesized analogously
to product 2 (Scheme 4).
Hypophosphite 5 is a very labile compound, which decomposes by
77% in 30–40 min. Therefore, syntheses with hypophosphite 5 were
performed without isolating it from the reaction mixture.
To synthesize new phosphorus derivatives of glucose, hydrophos-
phoryl compound 5 was introduced into the Abramov and Kabachnik–
Fields reactions (Scheme 5).

334
E. E. Nifantyev et al.
SCHEME 4 Synthesis of 3-O-Hypophosphite-1,2;5,6-O-diisopropylidene-α-D-
glucofuranose (5).
SCHEME 5 Electrophil reactions with 3-O-Hypophosphite-1,2;5,6-O-diiso-
propylidene-α-D-glucofuranose (5).

Hypophosphites
335
It is interesting that phosphinate was not formed even when an ex-
cess of chloral was used; the single reaction product was always phos-
phonite 6, which was isolated as an individual compound and whose
structure was supported by spectral methods. Compound 6 is formed
as two stereoisomers, with one being predominant; therefore, it was
isolated in the pure form by column chromatography.
Hypophosphite 5 exhibits high reactivity in the reaction with benza-
laniline and forms phosphinate 7, in spite of spatial hindrance.
Compound 7 was isolated in the individual form and characterized
by spectral methods, as well as by elemental analysis (see Experiment).
The performed study of the synthesis and properties of cyclohex-
anol and 1,2;5,6-O-diisopropylidene-α-D-glycofuranose hypophosphites
showed that these compounds are candidates for processes resulting in
the formation of P C bonds.
EXPERIMENT
1H NMR spectra were recorded on a Bruker WM-250 spectrometer
(250 MHz). 13C NMR spectra were recorded on a Bruker AC-200 in-
strument (50.32 MHz). 31P NMR spectra were recorded on a Bruker
WP-80SY instrument (32.4 MHz) against 85% H3PO4. Adsorption col-
umn chromatography was performed on silica gel L 100/160 and neutral
alumina oxide (Brockman activity II). Thin layer chromatography was
carried out on Silufol UV-254 plates using benzene–dioxane, 3:1 (A) and
hexane-dioxane, 1:1 (B) systems as eluants; detection was achieved us-
ing iodine vapor or calcinations.
All syntheses were performed in dry chloroform under dry oxygen-
free argon. The target hypophosphorous acid derivatives were used
without isolation.
General Procedure for the Synthesis of 1–7
Triethylammonium Hypophosphite (1)
Hypophosphoric acid was synthesized according to the known
procedure7 from 10.00 g (0.0961 mol) of KPH2O2. Triethylamine (9.73 g,
0.0961 mol) was dropped to an aqueous solution of freshly prepared hy-
pophosphorous acid under stirring and cooling in an ice bath, and the
mixture was left for 12 h. Next, water was evaporated under vacuum
to a volume of about 5–7 ml. The resulting oily product was 4–5 times
evacuated with dry benzene (10 ml) to remove residual water. The col-
orless oil was filtered and dried over P2O5 under vacuum for 3 h. Yield,
9.00 g (56%); the compound is soluble in acetonitrile, acetone, dioxane,
1
benzene, and chloroform. H NMR (CDCl3): δ 1.03 (t 9H, CH3), 2.81

336
E. E. Nifantyev et al.
(q, 6H, CH2, 3JHH = 7.7 Hz), 6.82 (d, 2H, PH2, 1JPH = 504.28 Hz), 11.01
(sb, 1H, NH), 14.75 (1H, OH in exchange with N). 31P NMR (without
solvent): δ 0.12 (t, 1JPH = 504.28 Hz).
Cyclohexyl Hypophosphite (2)
A solution of 0.87 g (0.0087 mol, 1.5 equiv.) of cyclohexanole in 3 ml
of chloroform and 0.92 g (0.0116 mol, 2 equiv.) of pyridine were added
to 0.98 g (0.0058 mol, 1 equiv.) of triethylammonium hypophosphite.
2,2-Dimethylpropanoic acid chloride (1.05 g, 0.0087 mol, 1.5 equiv.) in
3 ml of chloroform were slowly dropped to the obtained mixture under
stirring and cooling. The mixture was stirred for 7–10 min and used
for syntheses without further purification. To purify the product, the
solvent was removed under vacuum without heating; an inert gas was
bubbled through a capillary. Next, the mixture was treated with hexane
and filtered. The solvent was removed from the filtrate under vacuum
without heating. The resulting colorless oil was sublimated under high
vacuum (10−4 mm Hg) at a glycerol bath temperature of 80–90◦C. Col-
orless amorphous substance was obtained with a yield of 0.44 g (34%);
1
4
d.p. 95–100◦C; Rf 0.3 (B). NMR (CDCl3): δ 1.20 (m, 2H, CH2), 1.50
3
2
(m, 2H, CH2), 1.62 (m, 2H, CH2), 1.82 (m, 1H, CHOP), 7.08 (d, 2H,
PH2, 1JPH = 563.52 Hz). 31P NMR (CHCl3): δ 11.99 (t, 1JPH = 563.52 Hz,
3JPH = 9.85 Hz).
Cyclohexyl Ester of 1-Hydroxy-2,2,2-trichloroethyl-
phosphonous Acid (3)
Freshly distilled chloral (1.28 g, 0.0087 mol) in 3 ml of chloroform
was slowly dropped to a solution of 1.29 g (0.0087 mol) of cyclohexyl
hypophosphite in chloroform. The mixture was stirred for 1 h, and the
solvent was removed in vacuum. By-products were removed by precipi-
tation with hexane. The filtrate was purified by column chromatography
with system B as eluent. The isolated diastereomers were separated by
fractional crystallization from hexane. Yield, 1.03 g (40%); m.p. 148–
152◦C; Rf 0.56 (B). 1NMR (DMSO-d6): δ 1.28 (m, 2H, 4CH2), 1.49 (m, 2H,
2
3CH2), 1.68 (m, 2H, CH2), 1.88 (m, 1H, CHOP), 4.43 (dd, 1H, CHOH,
2
1
3JHH = 2.92 Hz, JPH = 8.77 Hz), 7.05 (dd, 1H, PH, JPH = 593.04
Hz, JHH = 2.92 Hz), 8.09 (sb, 1H, OH). 31P NMR (CHCl3): δ 25.19
3
(d, 1JPH = 593.04 Hz). Anal. calcd. for C8H14Cl3O3P: C, 32.51; H, 4.77;
P, 10.48. Found: C, 32.99; H, 4.81; P, 10.67.
Cyclohexyl Ester of Bis(diethylaminomethylene)phosphinic
Acid (4)
A solution of 2.04 g (0.0138 mol) bis(diethylamino)methane in 3 ml of
chloroform was dropped to a solution of 0.81 g (0.0055 mol) cyclohexyl

Hypophosphites
337
hypophosphite in chloroform. The mixture was stirred for 1 h and next
heated at a glycerol bath temperature of 40◦C for 3 h. The solvent was
distilled off. By-products were removed by precipitation with hexane.
The resulting mixture was purified by column chromatography using
system B as eluent and alumina oxide as stationary phase. Yellow oily
substance was obtained with a yield of 1.40 g (80%); Rf 0.4 (B). 13C NMR
(CDCl3): δ 9.45–10.96 (s, 4C, CH3), 23.33 (s, C(5)), 24.88 (s, C(3)), 27.20
(s, C(4)), 33.85 (s, 2C, C(2), C(6)), 47.77 (d, 4C, N-CH2, 3JPC = 8.02 Hz),
50.12 (d, 2C, P(CH2)2, 1JPC = 109.60 Hz), 73.63 (d, C(1), 2JPC = 7.60 Hz).
31P NMR (without solvent): δ 51.49 (s). Anal. calcd. For C16H35N2O2P:
C, 60.35; H, 11.08; N, 8.80; P, 9.73. Found: C, 59.95; H, 11.01; N, 8.62;
P, 9.63.
3-O-Hypophosphite-1,2;5,6-O-diisopropylidene-α-D-
glucofuranose (5)
A solution of 1.25 g (0.0048 mol, 1.5 equiv.) of 1,2;5,6-O-
diisopropylidene-α-D-glucofuranose in 3 ml of chloroform and 0.51 g
(0.0064 mol, 2 equiv.) of pyridine were added to 0.54 g (0.0032 mol,
1 equiv.) of triethylammonium hypophosphite. 2,2-Dimethylpropanoic
acid chloride (0.58 g, 0.0048 mol, 1.5 equiv.) in 3 ml of chloroform was
slowly dropped to the obtained mixture under stirring and cooling.
The mixture was stirred for 7–10 min and used for the next synthe-
ses without further purification. Rf 0.62 (A). 31P NMR (CHCl3): δ 17.64
(t, 1JPH = 575.17 Hz).
3-O-(1ꢀ-hydroxy-2ꢀ,2ꢀ,2ꢀ-trichloroethylphosphinite)-1,2;
5,6-diisopropylidene-α-D-glucofuranose (6)
Freshly distilled chloral (1.17 g, 0.0080 mol) in 3 ml of chloroform was
added to a solution of 0.99 g (0.0379 mol) of 3-O-hypophosphinite-
1,2;5,6-diisopropylidene-α-D-glucofuranose. The reaction mixture was
stirred for 10 h. The solvent was removed under vacuum, and the mix-
ture was chromatographed on a column using system A as eluent. Col-
orless oily liquid crystallized when stored. Yield of 0.55 g (40%), m.p.
90–92◦C. Rf 0.62 (A). 13C NMR (CDCl3) δ 26.03–26.95 (s, 4C, CH3),
1
67.64 (s, C(6)), 72.85 (s, C(5)), 74.67 (d, CHOH, JCP = 12.2 Hz), 81.02
(s, C(4)), 83.65 (d, C(3), 2JPC = 2.52 Hz), 84.96 (s, C(2)), 106.24 (s, C(1)),
2
109.30 and 111.58 (s, C(CH3)2), 112.54 (d, CCl3, JPC = 6.00 Hz). 31P
1
NMR (CHCl3): δ 30.1 (d, JPH = 608.45 Hz). Analuse calculated for
C14H22Cl3O8P: C, 36.90; H, 4.87; P, 6.80. Found: C, 35.44; H, 4.67;
P, 6.69.

338
E. E. Nifantyev et al.
3-O-[bis-α-(N-phenylaminobenzyl)-phosphinate]-1,2:5,6-
diisopropylidene-α-D-glucofuranose (7)
Benzalaniline (0.54 g, 0.0032 mol) in 3 ml of chloroform was added
to a solution of 0.99 (0.0032 mol) g of 3-O-hypophosphinite-1,2;5,6-
diisopropylidene-α-D-glucofuranose. The reaction mixture was stirred
for 30 min. The solvent was next removed under vacuum, and the mix-
ture was chromatographed on a column using benzene as eluent. Yel-
lowish scummy substance was obtained with a yield of 0.26 g (12%), m.p.
98–100◦C. Rf 0.68 (benzene-dioxane, 5:1) 13C NMR (CDCl3): δ 25.34–
27.24 (4C, CH3), 52.61–57.14 (CH-Ph), 67.30–67.68 (C(6), 72.29–72.53
(C(5)), 73.12 (C(3)), 79.26–80.08 (C(4)), 83.50–83.83 (C(2)), 104.59–
104.87 (C(1)), 109.36–112.03 (C(CH3)2), 113.84–114.45 (C(2ꢀꢀ)), 118.83–
119.34 (C(4ꢀꢀ)), 127.48–129.37 (C(2ꢀ), C(3ꢀ), C(3ꢀꢀ)), 133.80–136.08 (C(1ꢀ)),
145.31–146.67 (C(1ꢀꢀ)). 31P NMR (CHCl3): δ 45.33 and 45.80 (s). Anal.
calcd for: C38H43N2O7P C, 68.05; H, 6.46; N, 4.18; P, 4.62. Found: C,
68.11; H, 6.54; N, 4.03; P, 4.39.
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