Functionalization of 2-Phosphoryl-Substituted Phenols

Article abstract of DOI:10.1134/S1070363219080097

The nitration, bromination, diazo coupling, sulfonation, and alkylation of the aromatic ring of a series of 2-phosphoryl-substituted phenols have been studied for the first time. 2,6-Diphosphorylphenols have been obtained for the first time via 1,3-phosphorotropic phosphate-phosphonate rearrangement. The alkylation of 2-(diphenylphosphoryl)phenol at the hydroxy group with 2-bromo- and 2-chloroethanols has been studied under conventional heating and microwave irradiation conditions.

Full text of DOI:10.1134/S1070363219080097

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 8, pp. 1595–1603. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 8, pp. 1206–1215.
Functionalization of 2-Phosphoryl-Substituted Phenols
Yu. I. Rogachevaa, D. V. Baulinb*, V. E. Baulina,b, and A. Yu. Tsivadzeb
a Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Chernogolovka, Moscow oblast, Russia
b Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, Russia
*e-mail: ximik1988200811@rambler.ru
Received March 12, 2019; revised March 12, 2019; accepted March 14, 2019
Abstract—The nitration, bromination, diazo coupling, sulfonation, and alkylation of the aromatic ring of a series
of 2-phosphoryl-substituted phenols have been studied for the first time. 2,6-Diphosphorylphenols have been
obtained for the first time via 1,3-phosphorotropic phosphate–phosphonate rearrangement. The alkylation of
2-(diphenylphosphoryl)phenol at the hydroxy group with 2-bromo- and 2-chloroethanols has been studied under
conventional heating and microwave irradiation conditions.
Keywords: 2-phosphorylphenols, electrophilic substitution, 1,3-phosphate–phosphonate rearrangement, 2,6-di-
phosphorylphenols
DOI: 10.1134/S1070363219080097
2-Phosphoryl-substituted phenols and their metal
complexes are interesting subjects of studies in the
fields of organic, coordination, physical, and medicinal
chemistry. In particular, lanthanide (Eu3+, Gd3+, Tb3+,
Lu3+) complexes with 2-phosphorylphenols are potential
components of luminescent materials [1, 2]. 2-Phosphor-
ylphenols are ionophores selective for cesium cation in
the presence of other alkali metals and alkaline earths [3];
they also exhibit fairly high analgesic and anti-inflamma-
tory activity [4]. 2-Phosphorylphenols are used to obtain
phosphorylated phthalocyanines that are promising for
the design of new functional materials and photodynamic
therapy of cancer [5]. 2-Phosphorylphenols are particu-
larly interesting as starting compounds for the preparation
of phosphoryl-containing podands that are promising
organic complexing agents [6]. Variation of substituents
in the phosphoryl group underlies a quite efficient ap-
proach to control complexing properties of 2-phosphor-
ylphenols; in combination with the introduction of alkyl
and chromophoric substituents into the phenol ring, this
opens wide possibilities of purposeful modification of
physicochemical properties and physiological activity.
Though methods of synthesis of 2-phosphorylphenols
with different substituents in the phosphoryl group have
been well documented [7–11], their functionalization via
introduction of substituents into the benzene ring remains
poorly studied.
In this work we were the first to study the nitration,
bromination, sulfonation, diazo coupling, and alkylation
of the aromatic ring of 2-phosphorylphenols 1–4 (Scheme
1). The reduction of the corresponding nitro and diazo de-
rivatives afforded previously unknown amino-substituted
2-phosphorylphenol 17. 2,6-Diphosphorylphenols 22
and 23 were synthesixed for the first time by 1,3-phos-
phate–phosphonate rearrangement. Peculiar features of
the reaction of phosphorylphenol 1 with 2-bromoethanol
were studied under conventional heating and micriwave
irradiation conditions.
The electron-withdrawing phosphoryl group in
2-phosphorylphenols 1, 2, and 4 significantly reduces
their reactivity toward electrophilic substitution in the aro-
matic ring. In particular, 2-diphenylphosphorylphenol 1
failed to react with dilute (30%) nitric acid in the tempera-
ture range from 20 to 60°C. The nitration of 3 under these
conditions gave 30% of nitro compound 7 (Scheme 1).
This suggests that separation of the phosphoryl group
from the benzene ring by a methylene unit partially neu-
tralizes the electron-withdrawing effect of the former.
When the nitration of 1 was carried out using a mixture
of 60% nitric acid and 98% sulfuric acid at room tempera-
ture, the major product was 2-(diphenylphosphoryl)-4,6-
dinitrophenol 6. The nitration of 1 and 3 with a solution
of nitric acid in acetonitrile at 60°C afforded mononitro
derivatives 5 and 7, respectively, as the major products
1595

1596
ROGACHEVA et al.
Scheme 1.
R2
OH
OH
O
O
Fe, ɇɋl
PPh2
(CH )
PPh2
(CH )
R1
H2N
2 n
2 n
17, 18
5–8
Fe, ɇɋl
HNO3
R2
R2
R2
OH
O
OH
OH
(1) NaH
O
Br2
O
P
R3
PPh2
2 n
(2) +N{NꢀAr
R1
PPh2
(CH )
(CH )
2 n R3
R1
R1
(CH )
2 n
13–16
1–4
9–11
H2SO4 (98%)
t
-BuOH, PPA
OH
OH
O
H3C
H3C
O
P
NaO3S
P
Ph
Ph
CH3 Ph
12
Ph
19
1, R1 = R2 = H, R3 = Ph, n = 0; 2, R1 = R2 = H, R3 = EtO, n = 0; 3, R1 = R2 = H, R3 = Ph, n = 1; 4, R1 = Et, R2 = H, R3 = Ph,
n = 0; 5, R1 = O2N, R2 = H, n = 0; 6, R1 = R2 = O2N, n = 0; 7, R1 = O2N, R2 = H, n = 1; 8, R1 = Et, R2 = O2N, n = 0; 9, R1 = Br,
R2 = H, n = 0; 10, R1 = R2 = Br, n = 1; 11, R1 = Br, R2 = H, n = 1; 13, R1 = PhN=N, R2 = H, n = 0; 14, R1 = 4-MeOC6H4N=N,
R2 = H, n = 0; 15, R1 = PhN=N, R2 = H, n = 1; 16, R1 = Et, R2 = PhN=N, n = 0; 17, n = 0; 18, n = 1.
which can be readily separated from impurities by column
chromatography. On the basis of the 31PNMR data it was
found that only a small amount of dinitro compound 6 is
formed in the presence of excess nitric acid. If the initial
2-phosphorylphenol has a substituent in the 4-position
(compound 4), the nitration with a solution of nitric acid
in acetonitrile gave 6-nitro derivative 8.
sion or solution with some arenediazonium led to the
formation of previously unknown azo compounds 13–16
containing a chromophoric diazophenyl fragment. Sulfo
derivative was synthesized by reaction of 1 with excess
sulfuric acid at 80°C and was isolated as sodium sulfonate
19 (Scheme 1).
Electrophilic 1,3-phosphate–phosphonate rearrange-
ment involving cleavage of O–P bond and formation of
new Carom–Pbond is widely used in the synthesis of 2-hy-
droxyphenylphosphonates and bis(2-hydroxyphenyl)-
phosphinates [12–19]. In this work, we obtained new
2,6-diphosphorylphenols 22 and 23 by phosphate–phos-
phonate rearrangement of 2-(diphenylphosphoryl)phenyl
diphenylphosphinate 20 and 2-(diethoxyphosphoryl)phe-
nyl diphenylphosphinate 21; compounds 20 and 21 were
prepared in turn by treatment of 1 and 2, respectively, with
diphenylphosphinyl chloride in the presence of pyridine
as a base (Scheme 2).
By reacting 2-phosphorylphenols 1 and 3 with a solu-
tion of bromine in carbon tetrachloride in the presence of
iron as catalyst we obtained 4-bromo derivatives 9 and
11, respectively (Scheme 1). Dibromo derivative 10 was
formed when excess bromine was used.
Phenol 1 reacted with excess tert-butyl alcohol in the
presence of polyphosphoric acid (PPA) to give 4-tert-
butyl derivative 12 as the major product together with
the ortho isomer and/or disubstitution product as minor
ones. The reactions of 1, 3, and 4 in an alkaline suspen-
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FUNCTIONALIZATION OF 2-PHOSPHORYL-SUBSTITUTED PHENOLS
1597
Scheme 2.
OH
OP(O)Ph2
R
Ph2P(O)Cl, Py
O
P
P
R
R
R
O
20, 21
1, 2
P(O)Ph2
OH
Li
OP(O)Ph2
LDA, THF, ꢀ78oC
H+, 20oC
O
R
P
P
R
R
R
O
20a, 21a
1, 20, 20a, 22, R = Ph; 2, 21, 21a, 23, R = EtO.
22, 23
Presumably, by analogy with phenyl diphenylphosphi-
nate [9], in the first stage ester 20 and 21 reacted with
lithium diisopropylamide in THF at –78°C to give or-
ganolithium derivatives 20a and 21a which rearranged to
the corresponding phenols 22 and 23 as the temperature
rose (Scheme 2). It should be noted that no expected
2,6-diphosphorylphenol was obtained from 2-diphenyl-
phosphorylmethyldiphenylphosphinate under analogous
conditions; from the reaction mixture we isolated and
identified only diphenylphosphinic acid.
to an appreciable extent. In order to improve the yield of
24, it was necessary to successively add several times ad-
ditional amounts of sodium hydroxide and 2-bromoetha-
nol, which considerably increased reagent consumption.
Presumably, under the given conditions 2-haloethanols
undergo intramolecular cyclization to low-boiling ethyl-
ene oxide which is removed from the reaction mixture. By
carrying out the reaction with equimolar amounts of the
reactants in a closed vessel (sealed ampule) at 100–120°C
for 12 h, we succeeded in raising the yield of 24 to 94%.
In this case, ethylene oxide remains in the reaction vessel
and reacts almost quantitatively with the initial phenol.
When the reaction was carried out in a hermetically closed
laboratory system under microwave irradiation, the reac-
tion time was shortened to 10 min; the yield of 24 was
91% at a power of 30 W and at a maximum temperature
We studied the reaction of phosphorylphenol 1 with
2-haloethanols (Scheme 3). In the reaction of sodium
phenoxide 1 with 2-bromoethanol in boiling dioxane at
100°C the reaction mixture rapidly became neutral, and
the yield of 24 was 20–25%. Replacement of 2-bromo-
ethanol by its chloro analog did not affect the yield of 24
Scheme 3.
O OH
O
20ꢀ25%
P
Ph
Ph
ONa
24
Hlg(CH2)2OH
O
100ꢀ120oC
94%
P
Ph
Ph
1
OH
O
MW
+
O
P
Ph
Ph
Hlg = Cl, Br.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1598
ROGACHEVA et al.
Elemental analyses of 2-phosphorylphenols 4–24
Found, %
Comp. no.
Calculated, %
Н
Formula
С
Н
Р
С
Р
4
74.32, 74.65
63.58, 63.94
56.17, 56.31
64.51, 65.62
65.27, 65.43
57.88, 57.94
48.86, 48.98
58.89, 58.95
75.37, 75.43
72.28, 71.41
70.06, 70.10
72.77, 72.84
73.19, 73.25
69.88, 69.93
70.53, 70.61
54.51, 54.57
72.86, 72.93
61.20, 61.70
72.86, 72.90
61.00, 60.90
70.07, 70.09
5.56, 6.03
4.10, 4.21
3.27, 3.45
4.52, 4.61
4.89, 4.97
3.74, 3.86
3.14, 3.33
4.13, 4.18
6.57, 6.63
4.79, 4.86
4.88, 4.96
5.10, 5.16
5.39, 5.46
9.43, 9.68
9.06, 9.14
8.01, 8.11
8.58, 8.82
8.39, 8.47
7.91, 8.31
6.63, 6.68
7.98, 8.02
8.78, 8.86
7.66, 7.89
7.21, 7.25
7.49, 7.53
7.23, 7.28
C20H19O2P
74.52
63.72
56.26
64.59
65.39
57.93
48.96
58.94
75.41
72.35
70.09
72.81
73.23
69.90
70.58
54.55
72.87
61.40
72.87
61.40
70.08
5.94
4.16
3.41
4.56
4.94
3.78
3.24
4.16
6.62
4.81
4.94
5.13
5.44
5.21
5.61
3.56
4.89
5.62
4.89
5.60
5.70
9.61
9.13
8.06
8.77
8.43
8.30
6.65
8.00
8.84
7.77
7.23
7.51
7.26
10.01
9.58
7.82
12.53
14.39
12.53
14.40
9.20
5
C18H14NO4P
C18H13N2O6P
C19H16NO4P
C20H18NO4P
C18H14BrO2P
C19H15Br2O2P
C19H16BrO2P
C22H23O2P
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
C24H19 N2O2P
C25H21N2O3P
C25H21N2O2P
C26H23N2O2P
C18H16NO2P
C19H18NO2P
C18H14NaO5PS
C30H24O3P2
C22H24O5P2
C30H24O3P2
C22H24O5P2
C20H19O3P
5.18, 5.23 9.99, 10.04
5.59, 5.63
3.53, 3.59
9.53, 9.59
7.79, 7.85
4.83, 4.90 12.50, 12.56
5.58, 5.66 14.37, 14.41
4.87, 4.93 12.49, 12.55
5.51, 5.67 14.00, 14.49
5.55, 5.78
8.92, 8.99
of 120°C. Excess 2-bromoethanol promoted formation
of unidentified tarry products.
position if the para position is occupied. The reactions
of 2-(diphenylphosphoryl)phenyl diphenylphosphinate
and 2-(diethoxyphosphoryl)phenyl diphenylphosphinate
with lithium diisopropylamide as a version of intramo-
lecular electrophilic substitution afforded new 2,6-di-
phosphorylphenols in preparative yields. O-Alkylation
of 2-phosphorylphenols with 2-haloethanols occurs both
as direct nucleophilic replacement of the halogen atom by
phenoxide ion and through ring opening of intermediate
ethylene oxide.
The structure of the isolated compounds was deter-
mined on the basis of their NMR spectra and elemental
analyses (see the table).
In summary, our study of electrophilic substitution
reactions of diphenylphosphoryl-, diphenylphosphor-
ylmethyl-, and diethoxyphosphorylphenols has shown
that electron-withdrawing phosphoryl group significantly
deactivates the aromatic ring therein. The presence of a
methylene unit between the phosphoryl group and the
benzene ring reduces deactivating effect of that group.
Electrophilic group enters preferentially the para posi-
tion with respect to the hydroxy group or second ortho
EXPERIMENTAL
1
The H and 31P NMR spectra were recorded on a
Bruker CXP-200 spectrometer. The melting points were
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FUNCTIONALIZATION OF 2-PHOSPHORYL-SUBSTITUTED PHENOLS
1599
2-(Diphenylphosphoryl)-4,6-dinitrophenol (6). A
mixture of 1.00 g (3.40 mmol) of compound 1, 0.35 g
(3.4 mmol) of 60% HNO3 (d = 1.37 g/mL), and 10 mL
of 98% H2SO4 was stirred for 4 h at 25°C. The mixture
was then poured into 100 mL of cold water, and the pre-
cipitate was filtered off, washed with water on a filter,
and dried in a vacuum desiccator over P2O5. Yield 0.90 g
(69%), mp 158–160°C (from DMF). 1H NMR spectrum
measured on a Boetius PHMK 05 melting point apparatus.
Microwave-assisted syntheses were carried out using a
Discover Focused MicrowaveTM Synthesis setup (CEM,
USA; maximum power 300 W, frequency 2450 MHz)
equipped with pressure and temperature sensors. The
progress of the reactions was monitored, and the purity
of the isolated compounds was checked, by thin-layer
chromatography on Silufol plates; spots were visualized
by treatment with iodine vapor. Silica gel L(100–160 μm)
was used for column chromatography.
(CDCl3), δ, ppm: 7.74 m (10H, Ph), 8.70 d (1H, Harom
,
3JHP = 9.3 Hz), 9.10 s (1H, Harom), 12.60 s (1H, OH). 13C
NMR spectrum (CDCl3), δC, ppm: 125.92 (Carom), 127.55
d (Carom, JCP = 109.5 Hz), 129.52 d (CPh, JCP = 12.1 Hz),
132.40 d (CPh, JCP = 11.2 Hz), 133.90 d (CPh, JCP = 2.6),
134.60 d (Carom, JCP = 10.77), 161.30 (Carom). 31P NMR
spectrum (CDCl3): δP 33.45 ppm.
All operations with organolithium compounds were
performed under dry argon atmosphere. Compounds 1
[4], 2 [7], and 3 [20] were synthesized by us previously.
2-(Diphenylphosphoryl)-4-ethylphenol (4) was syn-
thesized as described in [4] for compound 1 using 28.0 mL
of a 1.96 N solution of butyllithium in hexane, 9.3 g
(56.0 mmol) of 1-ethyl-4-methoxymethoxybenzene in
90 mL of THF, and 11.8 g (50.0 mmol) of diphenylphos-
phinic chloride. Yield 12.60 g (78%), mp 198–200°C
(from EtOH). 1H NMR spectrum (CDCl3), δ, ppm: 1.15
2-[(Diphenylphosphoryl)methyl]-4-nitrophenol (7)
was synthesized as described above for compound 5 from
1.05 g (3.40 mmol) of 2-[(diphenylphosphoryl)methyl]-
phenol (3) and 0.23 mL HNO3 (d = 1.5 g/mL) in 10 mL
of acetonitrile. Yield 0.67 g (58%), mp 179–181°C (from
EtOH). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.87 d
3
t (3H, CH2CH3, JHH = 7.3 Hz), 2.45 q (2H, CH2CH3,
2
3
(2H, Harom, JHH = 13.8 Hz), 6.80 d (1H, Harom, JHH
=
3JHH = 7.3 Hz), 6.77 d (1H, Harom, 3JHP = 8.3 Hz), 6.95
7.5 Hz), 7.50 m (6H, Ph), 7.80 m (5H, Ph, Harom), 8.10
m (1H, Harom), 10.94 s (1H, OH). 31P NMR spectrum
(DMSO-d6): δP 33.24 ppm.
d.d (1H, Harom, 4JHH = 8.3 Hz), 7.30 d (1H, Harom, 3JHH
=
10.0 Hz), 7.60 m (6H, Ph), 7.75 m (4H, Ph), 11.00 s
(1H, OH). 13C NMR spectrum (CDCl3), δC, ppm: 16.40
4-Ethyl-2-(diphenylphosphoryl)-6-nitrophenol
(8) was synthesized as described above for compound
5 from 1.10 g (3.40 mmol) of 2-(diphenylphosphoryl)-
4-ethylphenol (4) and 0.23 mLof HNO3 (d = 1.5 g/mL) in
10 mLof acetonitrile. Yield 0.76 g (64%), mp 229–231°C
(from EtOH). 1H NMR spectrum (CDCl3), δ, ppm: 1.24
(CH3CH2), 28.28 (CH3CH2), 118.90 d (Carom, JCP
8.2 Hz), 129.00 d (CPh, JCP = 12.5 Hz), 130.80 d (Carom
CP = 10.0 Hz), 132.35 d.d (Carom, JCP = 52.8 Hz), 132.50 d
=
,
J
(CPh, JCP = 10.8 Hz), 132.80 d (CPh, JCP = 2.5 Hz), 136.00
(Carom), 164.00 (Carom). 31P NMR spectrum (CDCl3): δP
40.7 ppm.
3
t (3H, CH3CH2, JHH = 7.8 Hz), 2.67 q (2H, CH3CH2,
2JHH = 7.4 Hz), 7.50 m (6H, Ph), 7.77 m (4H, Ph), 8.11
s (1H, Harom), 8.17 d (1H, Harom, 3JHP = 13.1 Hz), 11.20
s (1H, OH). 31P NMR spectrum (CDCl3): δP 28.36 ppm.
2-(Diphenylphosphoryl)-4-nitrophenol (5). Phe-
nol 1, 1.00 g (3.40 mmol), was dissolved in 10 mL of
acetonitrile, 0.23 mL of nitric acid (d = 1.5 g/mL) was
added, and the mixture was stirred for 30 min at 60°C
and poured onto ice. The precipitate was filtered off and
purified by column chromatography using chloroform as
eluent. Yield 0.58 g (50%), mp 243–245°C (from EtOH).
1H NMR spectrum (DMSO-d6–CCl4), δ, ppm: 7.05 m
(1H, Harom), 7.56 m (4H, Ph), 7.67 m (6H, Ph), 8.30 d
4-Bromo-2-(diphenylphosphoryl)phenol (9). Bro-
mine, 1.20 g (6.80 mmol), was added to a suspension
of 2.00 g (6.80 mmol) of 2-(diphenylphosphoryl)phenol
(1) and 0.10 g (0.18 mmol) of iron powder in 15 mL of
anhydrous carbon tetrachloride. The mixture was stirred
for 3 h at 50°C and for 2 h at 25°C, poured into 100 mL
of water, and extracted with chloroform (3 × 30 mL).
The extract was dried over Na2SO4, and the solvent was
removed under reduced pressure. The residue was treated
with 25 mL of diethyl ether, and the precipitate was fil-
tered off and dried. Yield 1.06 g (42%), mp 218–220°C
2
3
(1H, Harom, JHH = 4.0 Hz), 8.70 d (1H, Harom, JHP
6.0 Hz), 11.80 s (1H, OH). 13C NMR spectrum (CDCl3),
δC, ppm: 119.90 d (Carom, JCP = 7.2 Hz), 128.80 d (Carom
=
,
JCP = 11.6 Hz), 129.60 d (CPh, JCP = 13.8 Hz), 130.16
(Carom), 132.40 d (CPh, JCP = 11.6 Hz), 133.80 d (CPh,
JCP = 2.2 Hz), 164.00 (Carom). 31P NMR spectrum
(CDCl3): δP 40.96 ppm.
1
(from benzene). H NMR spectrum (CDCl3), δ, ppm:
3
7.08 d (1H, Harom, JHP = 8.4 Hz), 7.56 m (12H, Harom
,
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ROGACHEVA et al.
Ph), 10.40 s (1H, OH). 31P NMR spectrum (CDCl3):
δP 38.85 ppm.
ppm: 7.08 m (1H, Harom), 7.55 m (7H, Ph), 7.76 m (6H,
Ph), 7.82 m (2H, Ph), 8.05 d (1H, Harom, 3JHH = 7.1 Hz),
3
8.25 m (1H, Harom, JHP = 11.0 Hz), 11.25 s (1H, OH).
2,4-Dibromo-6-[(diphenylphosphoryl)methyl]phe-
nol (10) was synthesized in a similar way from 2.00 g
(6.80 mmol) of 1 and 2.40 g (13.60 mmol) of bromine
using 0.02 g (0.36 mmol) of iron powder and 25 mL of
carbon tetrachloride. Yield 3.13 g (51%), mp 178–180°C
(from EtOH). 1H NMR spectrum (CDCl3), δ, ppm: 3.74 d
[2H, CH2P(O), 2JHH = 13.1 Hz], 6.90 s (1H, Harom), 7.60
m (11H, Harom, Ph), 9.00 s (1H, OH). 31P NMR spectrum
(CDCl3): δP 39.92 ppm.
31P NMR spectrum (CDCl3): δP 41.10 ppm.
2-(Diphenylphosphoryl)-4-(4-methoxyphenyldia-
zenyl)phenol (14) was synthesized in a similar way from
3.60 g (12.40 mmol) of 3 and 6.75 g (50.00 mmol) of 4-
methoxybenzenediazonium salt using 0.54 g (12.40 mmol)
of a 55% suspension of sodium hydride in mineral oil.
1
Yield 2.39 g (45%), mp 259–260°C (from EtOH). H
NMR spectrum (DMSO-d6–CCl4), δ, ppm: 2.40 s (3H,
CH3O), 7.00 m (1H, Harom), 7.10 d (2H, 4-MeOC6H4,
2JHH = 6.9 Hz), 7.55 m (6H, Ph), 7.73 m (4H, Ph), 7.81
4-Bromo-2-[(diphenylphosphoryl)methyl]phe-
nol (11) was synthesized in a similar way from 2.10 g
(6.80 mmol) of 3 and 1.20 g (6.80 mmol) of bromine using
0.02 g (0.36 mmol) of iron powder and 15 mL of carbon
tetrachloride. Yield 1.16 g (44%), mp 194–195°C (from
d (2H, 4-MeOC6H4, 3JHH = 7.1 Hz), 7.95 d (1H, Harom
,
3JHH = 5.8 Hz), 8.20 d (1H, Harom, 3JHH = 5.8 Hz), 12.50
s (1H, OH). 31P NMR spectrum (DMSO-d6–CCl4): δP
40.87 ppm.
1
i-PrOH). H NMR spectrum (SDCl3), δ, ppm: 3.64 d
[2H, CH2P(O), 2JHP = 12.2 Hz], 6.65 d (1H, Harom, 3JHH
=
2-[(Diphenylphosphoryl)methyl]-4-(phenyldi-
azenyl)phenol (15) was synthesized in a similar way
from 3.82 g (12.40 mmol) of 3, and 5.30 g (50.00 mmol)
of benzenediazonium salt using 0.54 g (12.40 mmol)
of a 55% suspension of sodium hydride in mineral oil.
5.6 Hz), 7.02 d (1H, Harom, 3JHH = 7.4 Hz), 7.27 s (1H,
H
arom), 7.47 m (6H, Ph), 7.75 m (4H, Ph), 9.74 s (1H,
OH). 31P NMR spectrum (CDCl3): δP 33.64 ppm.
4-(tert-Butyl)-2-(diphenylphosphoryl)phenol (12).
A mixture of 5.00 g (17.00 mmol) of 1, 6.00 g of poly-
phosphoric acid, and 10 mL of tert-butyl alcohol was
stirred for 8 h at 80°C. The mixture was diluted with
100 mL of cold water and extracted with chloroform
(3 × 30 mL), the combined extracts were washed with wa-
ter (3 × 30 mL), a 10% solution of NaHCO3 (5 × 30 mL),
and water again (3 × 30 mL), the solvent was removed,
and the residue was purified by chromatography using
chloroform as eluent. Yield 4.40 g (70%), mp 213–215°C
1
Yield 2.49 g (48%), mp 213–215°C (from EtOH). H
NMR spectrum (CDCl3), δ, ppm: 3.85 d [2H, CH2P(O),
3
2JHH = 11.8 Hz], 7.09 d (1H, Harom, JHH = 8.6 Hz),
7.40–7.65 m (10H, Ph), 7.73–7.84 m (7H, Harom), 11.70
s (1H, OH). 31P NMR spectrum (CDCl3): δP 39.70 ppm.
2-(Diphenylphosphoryl)-4-ethyl-6-(phenyldi-
azenyl)phenol (16) was synthesized in a similar way
from 4.00 g (12.40 mmol) of 4 and 5.30 g (50.00 mmol)
of benzenediazonium salt using 0.54 g (12.40 mmol) of
a 55% suspension of sodium hydride in mineral oil. Yield
1
(from EtOH); published data [19]: mp 213–215°C. H
1
NMR spectrum (CDCl3), δ, ppm: 1.15 s (9H, t-Bu),
6.85–7.80 m (13H, Harom, Ph), 10.50 s (1H, OH). 31P
NMR spectrum (CDCl3): δP 40.10 ppm.
1.19 g (48%), mp 141–143°C (from EtOH). H NMR
spectrum (CDCl3), δ, ppm: 1.30 t (3H, CH3CH2, 3JHH
=
7.6 Hz), 2.76 m (2H, CH3CH2), 7.42–7.98 m (17H, Ph,
arom), 13.53 s (1H, OH). 31P NMR spectrum (CDCl3):
H
2-(Diphenylphosphoryl)-4-(phenyldiazenyl)phenol
(13). Phenol 1, 3.60 g (12.4 mmol), was dispersed in
30 mL of anhydrous dioxane, 0.54 g (12.40 mmol) of a
55% suspension of sodium hydride in mineral oil was
added, and the mixture was refluxed for 0.5 h. The mixture
was cooled to 0°C and added to a solution of benzenedia-
zonium salt prepared from 4.70 g (50.00 mmol) of aniline,
3.50 g (50.00 mmol) of sodium nitrite, and 20 mLof 35%
aqueous HCl, maintaining the temperature at 2–5°C. The
mixture was stirred for 2 h at room temperature, and the
precipitate was filtered off, washed with dilute aqueous
HCl (1 : 3, 3 × 30 mL), and dried. Yield 2.27 g (46%), mp
193–195°C (from EtOH). 1H NMR spectrum (CDCl3), δ,
δP 28.34 ppm.
4-Amino-2-(diphenylphosphoryl)phenol (17). a. A
mixture of 1.00 g (2.94 mmol) of 2-(diphenylphosphoryl)-
4-nitrophenol (5) and 0.50 g (8.92 mmol) of iron chips
in 10 mL of aqueous HCl was refluxed for 2 h. The
mixture was cooled, the precipitate was filtered off and
washed with cold water, and the residue was dissolved in
20 mL of chloroform. The solution was washed with di-
lute aqueous HCl (1 : 1, 2 × 15 mL) and water (2 × 15 mL)
and evaporated under reduced pressure, and the residue
was purified by silica gel column chromatography using
chloroform as eluent. Yield 0.64 g (64%), mp 196–197°C
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FUNCTIONALIZATION OF 2-PHOSPHORYL-SUBSTITUTED PHENOLS
1601
(from i-PrOH). 1H NMR spectrum (DMSO-d6), δ, ppm:
4.76 s (2H, NH2), 6.70 m (3H, Harom), 7.58 m (10H,
Ph), 9.59 s (1H, OH). 31P NMR spectrum (DMSO-d6):
δP 30.41 ppm.
(CDCl3), δ, ppm: 7.01 m (1H, Harom), 7.23–7.56 m (13H,
Harom), 7.63–7.90 m (10H, Harom). 31P NMR spectrum
(CDCl3), δP, ppm: 28.72, 32.25.
Diethyl 2-(diphenylphosphoryloxy)phenylphos-
phonate (21) was synthesized in a similar way from 5.00 g
(21.74 mmol) of phenol 4 and 5.12 g (21.73 mmol) of
diphenylphosphinic chloride using 1.71 g (21.73 mmol)
of anhydrous pyridine and 50 mL of anhydrous ben-
zene. Yield 5.70 g (63%), mp 65–67°C (from hexane).
1H NMR spectrum (CDCl3), δ, ppm: 1.26 t (6H, CH3CH2,
3JHH = 7.5 Hz), 4.16 m (4H, OCH2), 7.20 m (1H, Harom),
7.10–8.32 m (13H, Harom). 31P NMR spectrum (CDCl3),
δP, ppm: 20.33, 33.03.
b.Asuspension of 1.00 g (2.51 mmol) of 2-(diphenyl-
phosphoryl)-4-(phenyldiazenyl)phenol (13) and 0.50 g
(8.92 mmol) of iron chips in 10 mL of aqueous HCl was
refluxed for 2 h. The mixture was poured into 50 mL of
cold water and extracted with chloroform (3 ×25 mL), the
combined extracts were washed with a saturated solution
of NaHCO3 (3 × 25 mL) and with water (2 × 25 mL) and
evaporated under reduced pressure, and the residue was
dried in a vacuum desiccator over P2O5. Yield 0.73 g
(73%), mp 196–198°C (from i-PrOH). The NMR spectra
of the product were identical to those of a sample prepared
as described above in a.
2,6-Bis(diphenylphosphoryl)phenol (22).Asolution
of 1.02 g (10.00 mmol) of diisopropylamine in 35 mL
of anhydrous THF was cooled to –75 ± 5°C, 10.00 mL
of a 1.0 N solution of butyllithium in hexane was added
dropwise with stirring, and the mixture was stirred for
0.5 h. A solution of 4.94 g (10.00 mmol) of compound
20 in 35 mL of anhydrous THF was added dropwise with
stirring at –75 ± 5°C to the resulting solution of lithium
diisopropylamide, and the mixture was stirred for 45 min
at –75 ± 5°C, allowed to warm up to room temperature,
and stirred for 2 h more. The solvent was removed, 15 mL
of dilute aqueous HCl (1 : 3) was added to the residue,
and the mixture was extracted with chloroform (3 ×
15 mL). The combined extracts were washed with water,
dried over Na2SO4, and evaporated under reduced pres-
sure. The residue was purified by chromatography using
chloroform–ethanol (1 : 0.35) as eluent. Yield 3.29 g
(66%), mp 202–205°C (from hexane). 1H NMR spectrum
(CDCl3), δ, ppm: 7.24 m (3H, Harom), 7.38–7.50 m (20H,
Ph), 7.76–7.80 m (8H, Ph), 12.20 s (1H, OH). 31P NMR
spectrum (CDCl3), δP, ppm: 32.11, 34.37.
4-Amino-2-[(diphenylphosphoryl)methyl]phe-
nol (18) was synthesized in a similar way from 1.00 g
(3.53 mmol) from 2-[(diphenylphosphoryl)methyl]-
4-nitrophenol (7) using 0.50 g (8.92 mmol) of iron chips
and 10 mL of aqueous HCl. Yield 0.71 g (70%), mp
170–172°C (from i-PrOH). 1H NMR spectrum (CDCl3),
4
δ, ppm: 3.80 d [2H, CH2P(O), JHP = 12.4 Hz], 6.11 d
2
(1H, Harom, JHH = 18.0 Hz), 6.46 m (1H, Harom), 6.86
m (1H, Harom), 7.72 m (10H, Ph), 10.70 s (1H, OH). 31P
NMR spectrum (CDCl3): δP 38.96 ppm.
Sodium 2-(diphenylphosphoryl)-4-hydroxyben-
zenesulfonate (19). A mixture of 1.00 g (3.40 mmol) of
2-(diphenylphosphoryl)phenol (1) and 15 mL of 98%
H2SO4 was stirred for 4 h at 80°C and poured into 300 mL
of brine. After 24 h, the precipitate was filtered off and
recrystallized from brine. Yield 0.85 g (63%,), decom-
poses above 230°C. 1H NMR spectrum (D2O), δ, ppm:
6.84–7.44 m (11H), 7.76 m (2H), 11.20 s (1H, OH). 31P
NMR spectrum (D2O): δP 35.08 ppm.
Diethyl 3-(diphenylphosphoryl)-2-hydroxyphenyl-
phosphonate (23) was synthesized in a similar way
from 5.30 g (10.00 mmol) of compound 21 using 1.09 g
(10.00 mmol) of diisopropylamine and 11.67 mL of a
1.0 N solution of butyllithium in hexane. Yield 4.35 g
(88%), mp 80–82°C (from heptane). 1H NMR spectrum
(CDCl3), δ, ppm: 1.37 t (6H, CH3CH2O, 3JHH = 7.5 Hz),
3.95 m (4H, CH2O), 7.25 m (1H, Harom), 7.00–7.95 m
(13H, Ph, Harom), 10.00 s (1H, OH). 31P NMR spectrum
(CDCl3), δP, ppm: 19.56, 32.55.
2-(Diphenylphosphoryl)phenyl diphenylphosph-
inate (20). Diphenylphosphinic chloride, 5.12 g
(21.74 mmol), was added with stirring at room tem-
perature to a solution of 6.40 g (21.74 mmol) of 2-(di-
phenylphosphoryl)phenol (1) and 1.69 g (21.74 mmol)
of anhydrous pyridine in 50 mL of anhydrous benzene.
The mixture was refluxed for 2 h, poured into 100 mL
of water, and extracted with benzene (3 × 30 mL). The
combined extracts were washed with dilute aqueous HCl
(1 : 3) and with water (3 × 30 mL), dried over Na2SO4,
and evaporated under reduced pressure. The residue was
recrystallized from benzene–hexane. Yield 7.23 g (69%),
2-[2-(Diphenylphosphoryl)phenoxy]ethanol (24).
a. Phenol 1, 8.40 g (30.00 mmol), was dissolved in
50 mLof anhydrous ethanol, 1.30 g (30.00 mmol) of sodi-
um hydride (a 55% suspension in mineral oil) was added,
1
mp 175–177°C (from benzene). H NMR spectrum
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1602
ROGACHEVA et al.
and the mixture was refluxed for 20 min and evaporated
under reduced pressure. The residue was treated with
50 mLof anhydrous diethyl ether, and the precipitate was
filtered off and dried under reduced pressure (1 mmHg,
80°C, 6 h). A solution of 4.30 g (35.00 mmol) of freshly
distilled 2-bromoethanol in 50 mL of anhydrous diox-
ane was added to the sodium phenoxide thus obtained,
and the mixture was refluxed for 1 h (the mixture was
neutral, pH 7). According to the 31P NMR and TLC data,
the conversion of the initial phenol did not exceed 20%.
The mixture was cooled to 25°C, 1.30 g (15.00 mmol)
of a 55% suspension of sodium hydride was added, the
mixture was heated to the boiling point and refluxed for
20 min, 4.30 g (35.00 mmol) of 2-bromoethanol was
added, and the mixture was refluxed for 1 h. The pH value
of the reaction mixture was equal to 7, and the conver-
sion of the initial phenol was no higher than 40%. The
addition of NaH and 2-bromoethanol was repeated two
more times, and the solvent was removed under reduced
pressure. The residue was treated with 15 mL of acetone,
the mixture was refluxed for 15 min, and the precipitate
of unreacted phenol 1 was filtered off, washed with hot
acetone (2 × 15 mL), and dried for 5 h at 100°C (2.01 g,
mp 232–233°C). The filtrate was evaporated to a vol-
ume of 10 mL and cooled to 0°C, and the precipitate of
24 was filtered off. Yield 7.71 g (76%), mp 154–155°C
(from acetone). 1H NMR spectrum (SDCl3), δ, ppm: 3.56
t (2H, CH2OH, 3JHH = 7.4 Hz), 4.02 t (2H, CH2OC6H4,
3JHH = 7.4 Hz), 6.92 m (2H, Harom), 7.40–7.61m (6H, Ph),
7.68–7.80 m (6H, Harom, Ph), 5.04 s (1H, OH). 31P NMR
spectrum (CDCl3): δP 26.43 ppm.
irradiation in a laboratory system for 0.6 h at a power of
30 W. The maximum temperature was 120°C.After cool-
ing, the mixture was dissolved in 25 mL of chloroform,
50 mL of water was added, and the mixture was was
acidified with concentrated aqueous HCl to pH 1. The
organic phase was separated, washed with water (2 ×
25 mL), dried over Na2SO4, and evaporated under reduced
pressure. The residue was dissolved in 7 mL of acetone,
the solution was cooled to 0°C, and the precipitate was
filtered off. Yield 2.95 g (91%).
FUNDING
This study was performed under partial financial
support by the Russian Foundation for Basic Research
(project no. 19-03-00262) in the framework of state
assignment for the Institute of Physiologically Active
Compounds of the Russian Academy of Sciences.
CONFLICT OF INTERESTS
No conflict of interest was declared by the authors.
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