Double Arbuzov Reaction. Synthesis of Bis(ω-cyanoalkyl)phosphinic Acids

Article abstract of DOI:10.1134/S1070363219080292

A general method for the synthesis of symmetric bis(ω-cyanoalkyl)phosphinic acids from ammonium hypophosphite was proposed. The reaction of bis(trimethylsilyl)hypophosphite generated in situ with the ω-bromoalkylnitrile molecule according to the Arbuzov r

Full text of DOI:10.1134/S1070363219080292

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 8, pp. 1728–1730. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 8, pp. 1305–1308.
LETTERS
TO THE EDITOR
Double Arbuzov Reaction. Synthesis
of Bis(ω-cyanoalkyl)phosphinic Acids
V. V. Ragulina*
a Institute of Physiologically Active Substances of the Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, 142432 Russia
*e-mail: rvalery@dio.ru
Received March 7, 2019; revised March 7, 2019; accepted March 21, 2019
Abstract―A general method for the synthesis of symmetric bis(ω-cyanoalkyl)phosphinic acids from ammo-
nium hypophosphite was proposed. The reaction of bis(trimethylsilyl)hypophosphite generated in situ with the
ω-bromoalkylnitrile molecule according to the Arbuzov reaction and the subsequent silylation of the hydrophos-
phoryl intermediate leads to the formation of bis(trimethylsilyl)phosphonite. The latter reacts with the second
ω-haloalkylnitrile molecule by the Arbuzov reaction with the formation of the second phosphorus-carbon bond.
Keywords: Double Arbuzov reaction, ammonium hypophosphite, bis(trimethylsilyl)hypophosphite,
ω-haloalkylnitriles, bis(ω-cyanoalkyl)phosphinic acids
DOI: 10.1134/S1070363219080292
Recently, we have described the double reaction of
trivalent phosphorus silyl esters generated in situ from
hypophosphites with two haloalkane molecules accord-
ing to the Arbuzov reaction scheme, which leads to the
sequential formation of two phosphorus-carbon bonds
and, as a result, symmetric dialkylphosphinic acids [1].
Introduction of α,ω-dielectrophiles into the reaction
made it possible to carry out one-pot synthesis of 5- and
6-membered cyclic phosphinic acids [2]. The use of
a wider range of dielectrophiles in boiling mesitylene
made it possible to obtain 4-, 7-, and 8-membered cyclic
phosphinic acids [3]; this reaction has been called the
Double Arbuzov reaction. The efficiency of the reaction
is due to the combination of the processes of formation
of two phosphorylating agents and two phosphoryla-
tion processes in one reaction vessel, which allowed the
synthesis of various symmetric dialkylphosphinic acids,
including functionally substituted phosphinic acids con-
taining various phosphoryl or aminocarboxylic functions
[1, 4–6 ]. The unknown symmetric phosphinic acids
bearing a nitrile function can be of interest for further
transformations with the construction of heterocyclic or
phosphoryl fragments.
phosphite 2 and the corresponding ω-haloalkyl nitriles
3 (Scheme 1).
As proposed earlier [1, 2], the double Arbuzov reac-
tion is a five-stage process, including in situ generation of
bis(trimethylsilyl)hypophosphite 4 (Scheme 1), the first
phosphorylating agent, as well as in situ generation of
bis(trimethylsilyl)phosphonite 5 as a second phosphory-
lating agent. The product of the first phosphorylation is
hydrophosphoryl intermediate 6, the silylation of which
under the reaction conditions leads to the formation of
phosphonite 5. The latter can interact with the second
molecule of electrophile 3 according to the Arbuzov re-
action [1, 2]. As a result of the second phosphorylation,
silylphosphinate 7 is formed, the alcoholysis of which
gives rise to symmetric phosphinic acid 1 (Scheme 1).
An advantage of the studied reaction is the absence of
the products of reaction between silyl esters of trivalent
phosphorus 4–6 generated in situ with the nitrile function
of ω-haloalkyl nitriles 3 and intermediates 5–7 under the
reaction conditions.
In summary, the introduction of ω-haloalkyl nitriles
as an electrophilic component into the double Arbuzov
reaction allows one to obtain new symmetric bis(ω-
cyanoalkyl)phosphinic acids.
The aim of this work was the synthesis of bis(ω-
cyanoalkyl)phosphinic acids 1 from ammonium hypo-
1728

DOUBLE ARBUZOV REACTION
1729
Scheme 1.
O
ꢀ
3
ꢀ
NC A X
NC
OSiMe3
OSiMe3
(Me3Si)2NH
 
ꢀ
H P
A
P
OSiMe3
H2POONH4
ꢀ
Me
3SiX
H
2
4
6
(Me3Si)2NH
O
OSiMe3
O
ꢀ ꢀ
3
NC A X
NC
CN
NC
NC
H
2O/EtOH

A
P
 
A
A
P
 
A
P
A
ꢀ
Me
3SiX
OSiMe3
CN
OSiMe3
OH
1
7
5
A = (CH2)n, n = 2–4; o-CH2C6H4; X = Br, Cl.
3
General procedure for the synthesis of symmet-
ric bis(ω-cyanoalkyl)phosphinic acids. A mixture of
0.02 mol of ammonium hypophosphite, 0.04 mol of hexa-
methyldisilazane and 0.04–0.45 mol of the corresponding
ω-haloalkylnitrile was boiled with stirring for ~ 7–8 h.
After cooling in an argon stream to room temperature,
12 mL of aqueous alcohol (5:1)was slowly added drop-
wise to the reaction mixture with cooling. The resulting
crystalline product was isolated and recrystallized from
a concentrated aqueous solution. Thus, phosphinic acids
1c and 1d were isolated. If the crystalline product does
not form after alcoholysis, the reaction mixture was
evaporated in vacuum, the residue was twice evaporated
with water, and acids 1a and 1b were isolated from con-
centrated aqueous solution. The resulting compounds
were white crystalline substances in the form of hydrates
melting with decomposition.
1.80–2.20 m (8Н, СН2), 2.61 t (4H, СН2, JHH = 6.4
Hz). 13С NMR spectrum (D2О), δС, ppm: 17.58 d (3JРС
=
19.9 Hz), 17.73, 27.10 d (1JРС = 91.4 Hz), 120.99 (СN).
31Р NMR spectrum (D2О): δР 53.15 ppm. Mass spec-
trum, m/z: 201.2 [M + H+] (calcd. C8H13N2O2P: 200.2).
Found, %: С 43.87, 44.10; Н 7.05, 7.11; N 14.07, 13.98.
C8H13N2O2P·H2O. Calculated, %: C 44.04; H 6.93; N
14.04.
Bis(4-cyanobutyl)phosphinic acid (1c). Yield 64%,
mp 103–109°С (foaming with subsequent hardening),
1
263–269°С (dec.). H NMR spectrum (D2О), δ, ppm:
3
1.47–1.88 m (12Н, СН2), 2.46 t (4H, СН2, JHH = 6.4
Hz). 13С NMR spectrum (D2О), δС, ppm: 16.43, 20.84 d
(2JРС = 3.9 Hz), 25.92 d (3JРС = 16.4 Hz), 27.36 d (1JРС
90.08 Hz), 122.06 (СN). 31Р NMR spectrum (D2О): δР
58.62 ppm. Mass spectrum, m/z: 229.2 [M + H+] (calcd.
C10H17N2O2P: 228.2). Found, %: С 48.60, 48.52; Н 8.02,
7.86; N 11.23, 11.10. C10H17N2O2P·H2O. Calculated, %:
C 48.78; H 7.78; N 11.38.
Bis(2-cyanoethyl)phosphinic acid (1a). Yield 67%,
mp 102–107°С (foaming with subsequent hardening),
244–249°С (dec.). 1H NMR spectrum (D2О), δ, ppm: 2.02
d. t(4Н, СН2, 3JHH =7.3, 2JРH =12.8Hz), 2.66d. t(4Н, СН2,
3JHH = 7.3, 3JРH = 13.4 Hz). 13С NMR spectrum (D2О), δС,
ppm: 10.76 d (2JРС = 2.9 Hz), 24.74 d (1JРС = 92.1 Hz),
121.04 d (3JРС = 13.6 Hz). 31Р NMR spectrum (D2О): δР
43.82 ppm. Mass spectrum, m/z: 173.1 [M + H+] (calcd.
C6H9N2O2P: 172.1). Found, %: С 37.68, 37.54; Н 6.08,
6.14; N 15.03, 14.90. C6H9N2O2P·H2O. Calculated,%: C
37.90; H 5.83; N 14.73.
Bis(o-cyanobenzyl)phosphinic acid (1d). Yield 92%,
mp 188–193°С (foaming with subsequent hardening),
267–274°С (dec.). H NMR spectrum (D2О), δ, ppm:
1
3.01 d (4Н, СН2, 2JРH = 16.1 Hz), 7.18–7.38 m (4Н, СН),
7.43–7.65 m (4Н, СН). 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.94 d (4Н, СН2, 2JРH = 16.1 Hz), 7.23–7.75 m
(8Н, СН). 13С NMR spectrum (DMSO-d6), δС, ppm:
38.08 d (1JРС = 81.5 Hz), 111.93 d (4JРС = 5.9 Hz), 118.40
d (4JРС = 1.5 Hz), 125.94 d (4JРС = 2.2 Hz), 130.56 d
(3JРС = 4.1 Hz), 132.33 (2С), 140.72 d (3JРС = 7.4 Hz). 31Р
NMR spectrum (D2О): δР 33.14 ppm. 31Р NMR spectrum
(DMSO-d6): δР 22.61 ppm. Found, %: С 60.86, 61.01; Н
Bis(3-cyanopropyl)phosphinic acid (1b). Yield 53%,
mp 98–105°С (foaming with subsequent hardening),
1
254–261°С (dec.). H NMR spectrum (D2О), δ, ppm:
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1730
RAGULIN
5.12, 5.16; N 9.03, 9.08; P 10.03, 10.11. C16H13N2O2P.
Calculated, %: C 61.15; H 4.81; N 8.91; P 9.86.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
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Bruker DPX-200 Fourier spectrometer. Melting points
were determined in a block in an open capillary. Chro-
matographic analysis was performed on an Agilent 1100
series LC/MSD system with DAD, ELSD and a single
quadrupole mass-selective detector using electrospray
ionization mode.
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FUNDING
This work was financially supported by the Presidium
of the RussianAcademy of Sciences (Program no. 14), the
Russian Foundation for Basic Research (grants no. 18-03-
00959, 18-03-01123) and the Russian Science Foundation
(grant no. 19-13-00294, chromatographic, spectral and
elemental analysis) within the frame of governmental task
for the Institute of Physiologically Active Substances of
the Russian Academy of Sciences for 2019.
4. Kurdyumova, N.R., Ragulin, V.V., and Tsvetkov, E.N.,
Zh. Obshch. Khim., 1996, vol. 66, no. 8, p. 1402.
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