Addition of phthalimide and acetone to phosphorylated methylene quinones

Article abstract of DOI:10.1134/S1070363216020213

New method for synthesis of phosphorylated methylene quinones via bromination of the sterically hindered phenol [prepared via benzylation of secondary chlorophosphines with 4-(methoxymethyl)-2,6-di-tert-butylphenol] with N-bromosuccinimide followed by dehydrobromination with trimethyl orthoformate has been developed. Tertiary phosphine oxides containing the fragment of sterically hindered phenol and amine or acetonyl group have been synthesized for the first time in the reaction of phosphorylated methylene quinones with N- and C-nucleophiles.

Full text of DOI:10.1134/S1070363216020213

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 2, pp. 326–330. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © M.B. Gazizov, A.L. Tarakanova, R.K. Ismagilov, L.P. Shamsutdinova, R.F. Karimova, R.N. Burangulova, 2016, published in
Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 2, pp. 298–302.
Addition of Phthalimide and Acetone
to Phosphorylated Methylene Quinones
M. B. Gazizov, A. L. Tarakanova, R. K. Ismagilov,
L. P. Shamsutdinova, R. F. Karimova, and R. N. Burangulova
Kazan National Research Technological University, ul. K. Marksa 68, Kazan, Tatarstan, 420015 Russia
e-mail: mukattisg@mail.ru
Received July 9, 2015
Abstract—New method for synthesis of phosphorylated methylene quinones via bromination of the sterically
hindered phenol [prepared via benzylation of secondary chlorophosphines with 4-(methoxymethyl)-2,6-di-tert-
butylphenol] with N-bromosuccinimide followed by dehydrobromination with trimethyl orthoformate has been
developed. Tertiary phosphine oxides containing the fragment of sterically hindered phenol and amine or
acetonyl group have been synthesized for the first time in the reaction of phosphorylated methylene quinones
with N- and C-nucleophiles.
Keywords: phosphorylated methylene quinone, secondary chlorophosphine, trialkyl orthoformate, benzylation,
phthalimide, bromination
DOI: 10.1134/S1070363216020213
Phosphorylated sterically hindered phenols and
methylene quinones are of increased interest in view of
their application in the synthesis of polyfunctional
organic compounds, potential biological activity, and
complex formation properties [1–6]. Development of
novel methods for preparation of highly reactive
phosphorylated methylene quinones is a topical issue.
We have recently described a new method for syn-
thesis of such compounds, based on the successive
reactions of secondary chlorophosphines with 4-hyd-
roxy-3,5-di-tret-butylbenzylidenchloride and trimethyl
orthoformate [1]. In this work we reported on another
approach towards synthesis of phosphorylated me-
thylene quinones and their reactions with N- and C-
nucleophiles.
led to the formation of diphenyl(diethyl)-4-hydroxy-
3,5-di-tert-butylbenzylphosphine oxides 4a and 4b in
high yield. The reaction proceeded at heating of
equimolar amounts of the reagents (Scheme 1).
We suggested that chlorophosphines 1a and 1b
exhibited nucleophilic properties; they reacted with
phenol 2 to form quasi-phosphonium salts 3 further
stabilized according to the second stage of the Arbuzov–
Michaelis reaction to form phosphine oxides 4a and 4b.
Subsequent bromination of compounds 4 with N-
bromosuccinimide (NBS) and dehydrobromination of
the so formed bromo(4-hydroxy-3,5-di-tert-butyl-
phenyl)methanediphenyl(diethyl)phosphine oxides 5
aided by trimethyl orthoformate provided the target
phosphorylated methylene quinones 6 with yield of
65–70% (Scheme 2).
4-Methyl-2,6-di-tert-butylphenol derivatives con-
taining an easily leaving group (Hlg, NMe2, Ac, or
OMe) in α-position have been recognized for promo-
tion of benzylation of certain P(III) acids derivatives
such as dialkyl and trialkyl phosphites and secondary
chlorophosphines [7–11]. The reaction of secondary
chlorophosphines with 4-methoxymethyl-2,6-di-tert-
butylphenol has not been studied earlier.
Aiming to obtain new polyfunctional organic com-
pounds, we performed addition of N- and C-nucleo-
philes such as phthalimide and acetone to methylene
quinones 6.
It was shown that compounds 6a and 6b reacted
with phthalimide in the presence of triethylamine in
DMF solution to give diphenyl(diethyl)(1,5-dihydro-
2,7-dioxo-7H-benz[c]azol-1-yl)(4-hydroxy-3,5-di-tert-
It was found that the reaction of compounds 1a and
1b with 4-methoxymethyl-2,6-di-tert-butylphenol 2
326

ADDITION OF PHTHALIMIDE AND ACETONE
327
Scheme 1.
+
CH3
Bu-t
OH
Bu-t
Bu-t
O
_
Cl
R2PCl
O
CH2
R
P CH2
R
+
CH3
OH
Bu-t
1a, 1b
3
2
Bu-t
O
+
CH3Cl
R
P
CH2
OH
Bu-t
R
4a, 4b
R = Ph (a), Et (b).
Scheme 2.
Bu-t
OH
Bu-t
OH
Bu-t
O
P
O
P
NBS, hν
_C4H4O2NH
R
CH2
R
CH
Br
R
R
Bu-t
5a, 5b
4a, 4b
Bu-t
O
CH(OMe)3
MeOH
+
MeCl
R
P
CH
+ HC(O)OMe
+
O
R
Bu-t
R = Ph (a), Et (b).
6a, 6b
butylphenyl)methanephosphine oxides 7a and 7b.
Those compounds were converted into diphenyl(di-
ethyl)amino(4-hydroxy-3,5-di-tert-butylphenyl)methane-
phosphine oxides 8a and 8b via the modified Gabriel
reaction [12] (Scheme 3).
EXPERIMENTAL
1H NMR spectra were recorded using Tesla BS-
567A (100 MHz), Bruker WP-250 (250 MHz), or
Bruker MSL-400 (400 MHz) spectrometers with the
signals of residual protons of the deuterated solvent
(CDCl3) as reference. 31P NMR spectra were registered
using Bruker MSL-400 (162 MHz) and Bruker WP-
250 (101 MHz) instruments with external 85% H3PO4
reference.
In addition, acetonylation of phosphorylated
methylene quinone 6a in the presence of dimethyl-
amine as a base was performed for the first time.
Refluxing of compound 6a in a mixture of acetone and
33% aqueous solution of dimethylamine led to the
formation of diphenyl(4-hydroxy-3,5-di-tert-butylphenyl)-
(2-oxopropyl)methanephosphine oxide 9 in 98% yield.
The suggested mechanism of the basic catalysis of the
performed reaction is shown in Scheme 4.
4-Methoxymethyl-2,6-di-tert-butylphenol 2 was pre-
pared via reaction of 4-hydroxy-3,5-di-tert-butylbenzyl-
bromide with excess of methanol.
4-(Hydroxy-3,5-di-tert-butylbenzyl)diphenylphos-
phine oxide (4a). A mixture of 4-methoxymethyl-2,6-
di-tert-butylphenol (2.50 g, 0.01 mol), diphenyl-
chlorophosphine (2.20 g, 0.01 mol), and 2 mL of
The structure and composition of the prepared
compounds were confirmed by elemental analysis as
well as NMR and IR spectroscopy data.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

328
GAZIZOV et al.
Scheme 3.
Bu-t
Bu-t
R P(O)
O
HC
N
OH
2
Bu-t
C
O
O
C
R P(O)
NH
C
HC
+
O
C
2
Bu-t
O
7a, 7b
6a, 6b
O
Bu-t
OH
Bu-t
O
NH
NH
5a, 5b + NH2NH2
R2
P
CH
+
NH2
O
8a, 8b
R = Ph (a), Et (b).
Scheme 4.
_
+
Me2NH + HOH
Me2NH2 + OH
O
O
_
_
C
CH3
C
CH3
CH2 + HOH
+ OH
CH3
t-Bu
t-Bu
O
C
_
_O
CH3
O
+ CH2
CHP(O)R2
CHP(O)R2
_CH2
t-Bu
t-Bu
C
O
6a
CH3
t-Bu
HO
t-Bu
+
Me2NH2
CHP(O)R2 + Me2NH
CH2
C
O
CH3
9
2
benzene was heated at 150–160°C for 2 h. The reac-
tion was accompanied by vinous coloration of the
reaction mixture and gas evolution. After the reaction
was complete, the mixture was treated with hexane.
The obtained precipitate was filtered off and recrys-
tallized from heptane. Yield 2.89 g (72.2%), mp 175–
179°С (heptane) (mp 174–176°С [8]). IR spectrum, ν,
δ, ppm: 1.42 s (18H, CМе3), 3.64 d (2Н, СН2P, JPH =
14 Hz), 5.73 s (1H, OH), 6.83 d (2H, C6Н2, 4JНH 2 Hz),
7.58–7.80 m (10Н, Ph).
4-(Hydroxy-3,5-di-tert-butylbenzyl)diethylphos-
phine oxide (4b) was prepared similarly from 4-meth-
oxymethyl-2,6-di-tert-butylphenol (5.90 g, 0.024 mol)
and diethylchlorophosphine (2.95 g, 0.024 mol). Yield
1
cm–1: 3420 br (ОН), 1240 (Р=О). Н NMR spectrum,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

ADDITION OF PHTHALIMIDE AND ACETONE
329
4.30 g (56.0%), mp 134–135°С (heptane) (mp 136–
138°С [8]). IR spectrum, ν, cm–1: 3200 br, 1200
(Р=О). Н NMR spectrum, δ, ppm: 1.10–1.32 m (6H,
2.0 Hz), 7.40–7.80 m (14Н, Ph, С6Н4). Found, %: N
2.60, 2.70; Р 5.29, 5.38. С35Н36О4NР. Calculated, %:
N 2.47; Р 5.49.
1
MeCH2P), 1.45 s (18H, CMe3), 1.71–1.93 m (4Н, Me
СН2P), 3.02 d (2H, CН2Р, JРH = 15 Hz), 5.83 s (1Н,
ОН), 6.98 s (2Н, С6Н2).
(1,5-Dihydro-2,7-dioxo-7Н-benz[c]azol-1-yl)(4-hyd-
roxy-3,5-di-tert-butylphenyl)methanediethylphos-
phine oxide (7b) was prepared similarly from phthal-
imide (0.59 g, 0.004 mol), phosphinylmethylene
quinone 6b, and 1 mL of triethylamine. Yield 1.41 g
(75.2%), mp 205–207°С (heptane). 1Н NMR spectrum,
δ, ppm: 1.14–1.34 m (6Н, Ме), 1.55 s (18H, CМе3),
1.6–2.4 m (4H, CH2Me), 5.42 s (1Н, ОН), 5.82 d (1Н,
СНР, 2JPH = 17.0 Hz), 7.31 s (С6Н2), 7.97–8.01 m (4Н,
С6Н4). Found, %: N 3.20, 3.30; Р 6.50, 6.30.
С27Н36О4NР. Calculated, %: N 2.98; P 6.61.
2
4-(Diphenylphosphinylmethylene)-2,6-di-tert-butyl-
cyclohexadiene-2,5-one (6a). A suspension of phos-
phine oxide 4a (2.94 g, 0.007 mol) and N-bromo-
succinimide (1.25 g, 0.007 mol) in 100 mL of carbon
tetrachloride was microwave-irradiated (300 W)
during 5 h. The formed succinimide was filtered off;
the filtrate was evaporated in vacuum. The residue was
refluxed with trimethyl orthoformate (7.42 g, 0.07 mol)
in 10 mL of toluene during 3 h; methyl bromide was
liberated. The crystalline product precipitated after the
reaction mixture cooling was filtered off, and volatile
compounds were distilled off from the mother liquid;
the residue was compound 6a (2.05 g, 69.9%). Mp
218–220°С (isooctane–toluene) (mp 219–221°С [8]).
IR spectrum, ν, cm–1: 1650, 1630 (С=О), 1590 (С=СН),
Amino(4-hydroxy-3,5-di-tert-butylphenyl)methane-
diphenylphosphine oxide (8a). A solution of com-
pound 7a (0.90 g, 0.0016 mol) and hydrazine hydrate
(0.8 g, 0.016 mol) in 20 mL of methanol was refluxed
during 2 h. The cyclic hydrazide of phthalic acid
precipitated at cooling was filtered off. The residue
after evaporation of the filtrate was treated with 100 mL
of 10% solution of sodium chloride. Yield 0.50 g
1
1250 (Р=О). Н NMR spectrum, δ, ppm: 1.36 s and
1.40 s (18H, CMe3), 6.62 d (1Н, СНР, 2JPH = 21.0 Hz),
6.91 s and 8.34 s (2Н, С=СН), 7.40–7.99 m (10Н, Ph).
1
(72.5%), mp 160–161°С (heptane–toluene). Н NMR
spectrum, δ, ppm: 1.42 s (18H, CМе3), 2.05 br.s (2Н,
3
4-(Diethylphosphinylmethylene)-2,6-di-tert-butyl-
cyclohexadiene-2,5-one (6b) was prepared similarly
from phosphine oxide 4b (2.45 g, 0.0075 mol), N-bromo-
succinimide (1.35 g, 0.0075 mol), and trimethyl ortho-
formate (7.95 g, 0.075 mol). Yield 1.57 g (65.0%), mp
174–175°С (heptane) (mp 173–175°С [8]). IR spec-
trum, ν, cm–1: 1647, 1624 (С=О), 1581 (С=СН), 1252
NH2), 4.77 d (1Н, СНР, JPH = 12.0 Hz), 5.25 s (1Н,
4
ОН), 6.92 d (2Н, С6Н2, JPH = 1.0 Hz). Found, %: N
3.05, 3.10; Р 7.10, 7.15. С27Н34О2NР. Calculated, %:
N 3.22; P 7.12.
Amino(4-hydroxy-3,5-di-tert-butylphenyl)methane-
diethylphosphine oxide (8b) was prepared similarly
from compound 7b (0.94 g, 0.002 mol) and hydrazine
hydrate (1 g, 0.02 mol). Yield 0.39 g (57.4%), mp
1
(Р=О). Н NMR spectrum, δ, ppm: 1.21–2.42 m (6Н,
Ме), 1.43 s (18H, CМе3), 1.63–2.13 m (4H, СН2Р),
1
2
159–162°С. Н NMR spectrum, δ, ppm: 1.05–1.21 m
6.03 d (1Н, СНР, JPH = 22.0 Hz), 6.83 s and 8.47 s
(6H, Ме), 1.55 s (18Н, CМе3), 1.60–1.90 m (4Н,
(2Н, С=СН), 8.47 s (1Н, С=СН).
2
РСН2Me), 1.99 s (2Н, NH2), 4.20 d (1Н, CHP, JРH
=
(1,5-Dihydro-2,7-dioxo-7Н-benz[c]azol-1-yl)(4-hyd-
roxy-3,5-di-tert-butylphenyl)methanediphenylphos-
phine oxide (7a). A solution of phthalimide (0.30 g,
0.002 mol), phosphinylmethylene quinone 6a (0.84 g,
0.002 mol), and triethylamine (1 mL) in 10 mL of
dimethylformamide was stirred at 60°C during 60 min.
The reaction mixture was then poured into 100 mL of
10% aqueous solution of sodium chloride. The formed
precipitate was filtered off, washed with water, and
dried in vacuum desiccator over P2O5 till constant mass.
Yield 0.93 g (82.30%), mp 209–212°С (heptane–
toluene). IR spectrum, ν, cm–1: 3416 br (ОН), 1720
9.0 Hz), 5.40 s (1Н, ОН), 7.26 d (2Н, С6Н2, 4JPH = 2.0 Hz).
(4-Hydroxy-3,5-di-tert-butylphenyl)(2-oxopropyl)-
methanediphenylphosphine oxide (9). A mixture of
solution of phosphinylmethylene quinone 6a (0.63 g,
0.0015 mol) and 33% aqueous solution of dimethyl-
amine (1.05 g) in 10 mL of acetone was incubated
during 24 h at room temperature. The residue after
distilling the volatile components off in vacuum was
treated with hexane. Yield 0.70 g (98.0%), mp 204–
205°С (heptane–toluene). IR spectrum, ν, cm–1: 3353
br (ОН), 1724 (С=О), 1117 (Р=О). 1Н NMR spectrum,
δ, ppm: 1.43 s (18Н, CМе3), 2.11 s (3Н, МеСО), 2.90–
3.40 m [2Н, СН2С(О)], 4.10–4.40 m (1Н, СНР), 5.15
1
(С=О, amide I), 1160 (Р=О). Н NMR spectrum, δ,
ppm: 1.46 s (18H, СMe3), 5.23 br.s (1Н, ОН), 6.19 d
4
2
4
br.s (1Н, ОН), 7.05 d (2Н, С6Н2, JРH = 2.0 Hz), 7.20–
(1Н, СНР, JPH = 14.0 Hz), 7.27 d (2Н, С6Н2, JРH
=
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

330
GAZIZOV et al.
Shamsutdinova, L.P., Tarakanova, A.L., and Karimo-
va, A.A., Vestn. Kazan. Tekhnol. Univ., 2014, no. 5, p. 29.
8.20 m (10Н, Ph). Found Р, %: 6.25, 6.30. С30Н37О3Р.
Calculated Р, %: 6.51.
5. Gibadullina, E.M., Shaekhov, T.R., Badrtdinov, A.K.,
Voronina, Yu.K., and Burilov, A.R., Russ. Chem. Bull.,
2013, vol. 62, no. 7, p. 1609. DOI: 10.1007/s11172-013-
0233-8.
6. Oludina, Yu.N., Bukharov, S.V., Burilov, A.R.,
Tagasheva, R.G., Syakaev, V.V., Musin, R.Z., Akhme-
tova, E.F., and Nugumanova, G.N., Russ. Chem. Bull.,
2014, vol. 63, no. 1, p. 115. DOI: 10.1007/s11172-014-
0403-3.
ACKNOWLEDGMENTS
This work was financially supported by the
Ministry of Education and Science of Russian
Federation in the frame of the basic part of
governmental task (contract no. 2014/56).
REFERENCES
7. Gross, H., Seibt, H., and Keitel, I., J. Prakt. Chem.,
1975, vol. 317, no. 6, p. 890.
1. Gazizov, M.B., Ismagilov, R.K., Shamsutdinova, L.P.,
Tarakanova, A.L., Khayarov, Kh.R., and Karimova, R.F.,
Russ. J. Gen. Chem., 2014, vol. 84, no. 11, p. 2275.
DOI: 10.1134/S1070363214110413.
2. Gazizov, M.B., Ismagilov, R.K., Karimova, R.F.,
Shamsutdinova, L.P., Burangulova, R.N., and Ivano-
va, S.Yu. , Russ. J. Gen. Chem., 2014, vol. 84, no. 4,
p. 654. DOI: 10.1134/S1070363214040094.
8. Ismagilov, R.K., Moskva, V.V., Arkhipov, V.P.,
Ivantsev, A.E., and Kopylova, L.Yu., Zh. Obshch.
Khim., 1991, vol. 61, no. 2, p. 387.
9. Mukmenova, N.A., Cherezova, E.N., and Zhukova, R.S.,
Zh. Obshch. Khim., 1994, vol. 64, no. 6, p. 1049.
10. Mukmenova, N.A., Cherkasova, O.A., and Kadyrova, V.Kh.,
Zh. Obshch. Khim., 1992, vol. 62, no. 2, p. 468.
11. Gazizov, M.B., Ismagilov, R.K., Shamsutdinova, L.P.,
Musin, R.Z., Karimova, R.F., Bashkirtsev, A.A., and
Sinyashin, O.G., Russ. J. Gen. Chem., 2010, vol. 80,
no. 3, p. 533. DOI: 10.1134/S1070363210030278.
12. Gibson, M.S., and Bradshawi, R.W., Angew. Chem. Int.
Ed., 1968, vol. 7, no. 12, p. 919.
3. Gazizov, M.B., Ismagilov, R.K., Shamsutdinova, L.P.,
Karimova, R.F., Musin, R.Z., Nikitina, K.A., Bashkir-
tsev, A.A., and Sinyashin, O.G., Russ. J. Gen. Chem.,
2012, vol. 82, no. 9, p. 1587. DOI: 10.1134/
S1070363212090241.
4. Gazizov, M.B., Ismagilov, R.K., Karimova, R.F.,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016