Reactions of nitroxides. Part VIII [1]: Nitroxides with a cyanato substituent

Article abstract of DOI:10.1007/s00706-010-0272-x

Nitroxides bearing a cyanato group were synthesized from nitroxides containing a phenolic hydroxyl group using both cyanogen chloride and bromide.

Full text of DOI:10.1007/s00706-010-0272-x

Monatsh Chem (2010) 141:445–449
DOI 10.1007/s00706-010-0272-x
ORIGINAL PAPER
Reactions of nitroxides. Part VIII [1]: nitroxides with a cyanato
substituent
Jerzy Zakrzewski
Received: 16 September 2009 / Accepted: 17 February 2010 / Published online: 27 March 2010
Ó Springer-Verlag 2010
Abstract Nitroxides bearing a cyanato group were syn-
thesized from nitroxides containing a phenolic hydroxyl
group using both cyanogen chloride and bromide.
To the best of our knowledge, nitroxyl radicals with a
cyanato function are unknown. Herein we report the
synthesis of nitroxides bearing the cyanato group
(Scheme 1).
Keywords Cyanate esters Á Nitroxyl radicals Á
Cyanogen chloride Á Cyanogen bromide
Results and discussion
Introduction
Triacetonamine (2a) and 2,2,6,6-tetramethyl-4-piperidinol
(2b) were chosen as precursors of the two structures con-
taining a nitroxyl fragment (2,2,6,6-tetramethylpiperidin-1-
oxyl) and a phenolic hydroxyl functional group, which in
turn were assumed to be starting materials to target com-
pounds bearing a cyanato group. The synthesized phenols
and cyanates containing the nitroxyl fragment are pre-
sented in Schemes 2 and 3.
Cyanate esters (R–O–C:N) may be regarded as organic
compounds with a reactive cyanato functional group
[2, 3]. Dicyanate esters (in general, commercially avai-
lable derivatives of bis(4-cyanatoaryl)methane) undergo
polycyclotrimerisation. The resulting cyanate resins have
excellent dielectric properties and good flammability char-
acteristics [4–8].
Condensation of phenol (1a) with triacetonamine (2a) in
the presence of hydrochloric acid leads to amine 3a. Oxi-
dation of 3a with hydrogen peroxide leads to the nitroxyl
radical 4a containing a phenolic hydroxyl group [14–16].
4a was converted into the corresponding cyanate 6a with
both cyanogen chloride (5a) and cyanogen bromide (5b).
There is no essential difference between the results
obtained with 5a and 5b. As expected, use of 5b is more
convenient because of easier manipulation of 5b which is
solid at rt. However, a cyanate obtained in this way may be
contaminated with the starting 5b, because of poor chro-
matographic separation.
Synthesis of the cyanate esters involves the reaction of
compounds bearing a phenolic hydroxyl group with cyan-
ogen halides in the presence of triethylamine [2, 3, 6, 7, 9,
10]. The reaction is realized at -10 to -15 °C in acetone
[11, 12] or DMF [13]. In some preparations preliminary
reaction of triethylamine with a phenol derivative is sug-
gested. The resulting salt is added dropwise to the solution
of cyanogen bromide in methyl isobutyl ketone at ?40 °C
[10].
Nitroxides with reactive functional groups can be used
for modification of biologically active synthetic or natural
molecules or macromolecules, and for investigation of their
properties with EPR spectroscopy (spin labelling).
Direct transesterification of methyl 4-hydroxybenzoate
(1b) with 2,2,6,6-tetramethyl-4-piperidin-1-oxyl using
either sodium methoxide or potassium hydroxide as cata-
lysts failed. This result is consistent with the literature
observation [17] that esterification of 2,2,6,6-tetramethyl-
4-piperidin-1-oxyl with 4-hydroxybenzoic acid using either
PCl3 or SOCl2 in the presence of NEt3 was unsuccessful.
J. Zakrzewski (&)
Institute of Industrial Organic Chemistry,
Annopol 6, 03-236 Warsaw, Poland
e-mail: zakrzewski@ipo.waw.pl
123

446
J. Zakrzewski
OCN
was converted with cyanogen bromide into the corre-
sponding cyanate 6b.
OH
The structures of synthesized nitroxyl radicals bearing a
cyanato functional group (6a, 6b) were characterized by
use of MS, HR MS, and IR spectroscopy.
X-CN
(X=Cl, Br)
To synthesize compounds bearing both a nitroxyl moiety
and a cyanato group, we also attempted to use 4-isocyanato
[19] and 4-isothiocyanato-2,2,6,6-tetramethylpiperidinyl-1-
oxyl [20]. The iso(thio)cyanates were converted into the
corresponding (thio)ureas with amines such as 4-aminophe-
nol, 4-amino-4-acetoxybenzene, and tyramine (4-(2-amino-
ethyl)phenol). The resulting ureas and thioureas bearing both
nitroxyl and phenolic fragments were subsequently treated
with cyanogen halides, but no expected cyanates were
obtained; this was likely to be because of the possible tau-
tomerism of ureas and thioureas and the creation of the second
N
O
N
O
Scheme 1
O
OH
OH
OCN
OH
NH
2a
HCl
Cl-C
Br-C
≡
≡
N 5a
N 5b
2
-
H2O2/WO4
63%
possible reaction centre [RÁ–NH–C(=X)–NH–Ar–OH ¢ R –
Á
52%
72%
52%
NH–C(–XH)=N–Ar–OH, RÁ = nitroxyl moiety, X = O, S].
1a
NH
3a
N
O
N
O
4a
6a
Conclusion
Scheme 2
The synthesized compounds 6a and 6b are the first nitroxyl
radicals bearing a cyanato functional group.
Transesterification with methyl 4-hydroxybenzoate (1b) in
the presence of magnesium methoxide also failed [17].
Because the synthesis of 4b by direct transesterification
of methyl 4-hydroxybenzoate (1b) with 2,2,6,6-tetra-
methyl-4-piperidin-1-oxyl was unsuccessful, a two-step
method was applied. In the first step, methyl 4-hydroxy-
benzoate (1b) was transesterified with 2,2,6,6-tetramethyl-
4-piperidinol (2b). Three transesterification catalysts were
tested: titanium butanoate [17], sodium methoxide [18],
and potassium hydroxide [18]. Transesterification in the
presence of titanium butanoate [17] and sodium methoxide
[18] failed. When potassium hydroxide was used in the
melt at about 200 °C, 3b was obtained [18]. In the second
step 3b was oxidized with hydrogen peroxide to the
expected corresponding nitroxyl radical 4b which, in turn,
Experimental
General
Both cyanogen chloride (5a) and cyanogen bromide (5b)
were manufactured at the Institute of Industrial Organic
Chemistry. Thin-layer and column chromatography were
done on silica gel—Merck Alurolle 5562, Alufolien 5554
and Merck 1.09385.1000 (0.040–0.063 mm, 230–400
mesh), respectively. Visualization: UV 254 nm and/or I2
vapour. The following abbreviations for mobile phases are
used throughout the text: BM3, BM9, BM95 = benzene–
Scheme 3
O
O
O
N
O
N
OH
4b
6b
5b
OH
OCN
BrCN
54%
N
•
•
•
COOCH3
COOH
O
O
O
2-
H2O2/WO4
53%
CH3OH
91%
O
KOH
20%
OH
2b
O
OH
1b
OH
3b
OH
NH
NH
123

Nitroxides with a cyanato substituent
447
(CH), 51.82 (C), 50.04 (C), 40.08 (CH2), 31.49 (2 9 CH3),
methanol 3:1, 9:1, 95:5, respectively; BA9, BA95 = ben-
zene–ethyl acetate 9:1, 95:5, respectively; ClM1 =
chloroform–methanol 1:1 (all v/v). MS (EI, 70 eV) data
were recorded using AMD 604 and Agilent 5975 B mass
spectrometers. HR-MS (EI, 70 eV) data were recorded using
ꢀ
30.09 (2 9 CH3) ppm; IR (KBr): m = 3,410 (OH), 1,270,
1,230 (C–O) cm-1; UV–Vis (MeOH): kmax (e) = 204
(20,970), 254 (17,250) nm (mol-1 dm3 cm-1); MS
(70 eV): m/z = 231 (M?, 2), 216 (M? - CH3, 100), 200
(6), 199 (5), 159 (15), 149 (5), 131 (4), 115 (4), 107 (5),
105 (3), 100 (6), 93 (5), 91 (5), 81 (5), 77 (4), 71 (3), 69 (3),
58 (7), 57 (6), 56 (4), 55 (6), 43 (8), 42 (16), 41 (8).
1
an AMD 604 mass spectrometer. H NMR and 13C NMR
spectra were determined on a Bruker WP 100 SY (100 and
25 MHz for proton and carbon, respectively) and a Varian
UNITYplus 200 spectrometer. IR data were recorded using
a Jasco 420 FTIR spectrophotometer. UV–Vis spectra
were recorded on a Pye–Unicam SP-8 100 spectrometer
in methanol as solvent. EPR measurements were recorded
on a Radiopan spectrometer (9.3 GHz––X band) in chloro-
form as solvent (3.7 9 10-4 mol/dm3) using diph-
enylpicrylhydrazyl as standard.
3,6-Dihydro-4-(4-hydroxyphenyl)-2,2,6,6-tetramethylpyri-
din-1(2H)-oxyl (4a)
4-(1,2,3,6-Tetrahydro-2,2,6,6-tetramethyl-4-pyridinyl)phe-
nol (3a, 3 g, 0.013 mol), sodium tungstate (0.24 g), and
triethylbenzylammonium chloride (0.24 g) were placed in a
conical flask of 200 cm3 capacity equipped with a magnetic
stirring bar. Methanol (52 cm3) and water (4.8 cm3) were
added. A solution of 30% hydrogen peroxide (4.2 g) in
methanol (9.3 cm3) was added. The reaction mixture was
stirred for 6 days. Methanol was evaporated under reduced
pressure. Dichloromethane (30 cm3) and water (50 cm3)
were added. The aqueous layer was acidified with hydro-
chloric acid solution (1:1, v/v) to pH 2. The dichloromethane
layer was separated, washed with water, and dried with
anhydrous magnesium sulfate. After filtration to remove the
magnesium sulfate and evaporation of the dichloromethane,
brick precipitate (2.9 g) of crude 4a was obtained. The crude
4a was subjected to column chromatography (BA95) to
afford a yellow precipitate of 2.02 g (63%) purified 4a. M.p.:
138-140 °C (134–135 °C [16]); Rf = 0.15 (BA95), 0.47
4-(1,2,3,6-Tetrahydro-2,2,6,6-tetramethyl-4-pyridinyl)-
phenol (3a)
Concentrated hydrochloric acid (70 cm3) was placed in a
reactor of 1 dm3 capacity, equipped with a heating mantle,
a bottom valve, a mechanical stirrer, a reflux condenser,
and
a
thermometer. Triacetonamine (2a, 60.2 g,
0.387 mol), phenol (1a, 73 g, 0.777 mol), and additional
hydrochloric acid (30 cm3) were added with vigorous
stirring. Hot water (70 °C) was introduced into the heating
mantle. The reaction mixture was stirred and heated to
70 °C for 10 h, then cooled to rt. Benzene (100 cm3) was
added. An efficiently stirred precipitate was transferred
through a bottom valve into a funnel with a sintered glass
disk. The precipitate was isolated by filtration under
reduced pressure, pressed, copiously washed with benzene,
and finally pressed again. The precipitate was gradually
added into a 20% potassium carbonate solution (300 g) in a
beaker. After all the carbon dioxide had evolved, the
precipitate was isolated by filtration, pressed, washed with
cold water, pressed again, and air-dried. Crude 3a (62 g,
69%, m.p. [ 240 °C) was obtained. 3a (10 g) was dis-
solved in a dilute solution of sodium hydroxide (28 g in
350 cm3 water) then 10% hydrochloric acid solution was
added until a titration curve measured with a pH meter
showed an inflection point at pH 10. The precipitate
(13.7 g) was isolated by filtration. After drying, 7.5 g
purified 3a (52%, m.p. 190–192 °C) was obtained. A
sample of purified 3a (1 g) was crystallized from 6.5 cm3
methanol–benzene 5:1 (v/v) affording fine colourless
crystals of 3a. M.p.: 192–194 °C (196–197 °C [15], 193–
195 °C [16]); Rf = 0.06 (BM9), 0.20 (BM3), 0.20 (ClM1);
1H NMR (100 MHz, CDCl3): d = 1.24 (s, 6H, 2 9 CH3),
1.28 (s, 6H, 2 9 CH3), 2.23 (d, 2H, J = 1.57 Hz, CH2),
3.02 (s, 1H, OH), 5.88 (t, 1H, J = 1.57 Hz, (CH3)2C-
CH=), 6.76–6.85 and 7.23–7.32 (m, 4H, C6H4OH) ppm;
13C NMR (25 MHz, CDCl3): d = 155.37 (C), 134.28 (C),
131.62 (CH=C), 129.73 (CH=C), 126.42 (CH), 115.48
1
(BM9), 0.65 (BM3), 0.93 (ClM1); H NMR (200 MHz,
CDCl3, after reduction with phenylhydrazine in CDCl3,
aliphatic part of the spectrum, in fact the spectrum of the
corresponding hydroxylamine [21]): d = 1.37 (s, 6H,
2 9 CH3), 1.44 (s, 6H, 2 9 CH3), 2.58 (s, 2H, CH2), 5.20
(s, 2H, 2 9 OH), 5.72 (s, 1H, (CH3)2C–CH=) ppm; 13C
NMR (50 MHz, CDCl3, after reduction with phenylhydr-
azine in CDCl3, aliphatic part of the spectrum, in fact the
spectrum of the corresponding hydroxylamine [21]):
d = 59.22 (C), 58.11 (C), 42.50 (CH2), 26.21 (2 9 CH3),
ꢀ
25.31 (2 9 CH3) ppm; IR(KBr): m = 3,260 (OH), 1,290,
1,240, 1,210 (C–O) cm-1; UV–Vis (MeOH): kmax (e) = 204
(21,490), 254 (19,000) nm (mol-1 dm3 cm-1); EPR
(3.7 9 10-4 mol/dm3, CHCl3): g = 2.0060, a = 1.576
mT; MS (70 eV): m/z = 246 (M?, 17), 232 (6), 216 (20),
201 (100), 186 (5), 173 (26), 159 (90), 145 (25), 141 (11), 131
(18), 115 (20), 107 (25), 105 (9), 91 (20), 77 (23), 65 (13), 56
(26), 41 (39).
4-(4-Cyanatophenyl)-3,6-dihydro-2,2,6,6-tetramethylpyri-
din-1(2H)-oxyl (6a, C16H19N2O2)
From Br-CN: In a three necked flask of 5 cm3 capacity
equipped with a magnetic stirring bar 4a (0.246 g, 1 mmol)
was dissolved in 1 cm3 anhydrous acetone (dried over
magnesium sulfate). Cyanogen bromide (5b, 0.110 g,
123

448
J. Zakrzewski
1.04 mmol) was added at\0 °C. Anhydrous triethylamine
(150 mm3) was added dropwise with a syringe (ice–salt
bath). A copious precipitate of triethylamine hydrochloride
was formed. The reaction mixture was stirred at *0 °C for
2 h. The precipitate of triethylamine hydrochloride was
removed by filtration and washed with acetone. The filtrate
was evaporated. The residue (0.4388 g) was subjected to
column chromatography (BA95) to give 0.1958 g (72%)
6a as a red oil.
From Cl-CN: In a three necked flask of 5 cm3 capacity
equipped with a magnetic stirring bar 4a (0.246 g, 1 mmol)
was dissolved in anhydrous acetone (1 cm3, dried over
magnesium sulfate). Excess cyanogen chloride (5a, 1.2–
2.4 g, 1–2 cm3, 20–40 mmol) was added at \0 °C. Anhy-
drous triethylamine (140 mm3) was added with a syringe in
three portions at about -20 °C. A copious precipitate of
triethylamine hydrochloride was formed. The reaction
mixture was stirred at 0 °C for 0.5 h. The precipitate of
triethylamine hydrochloride was removed by filtration and
washed with acetone. The filtrate was evaporated. The dark
residue was subjected to column chromatography (BA95) to
give 0.14 g (52%) 6a as a red solid.
flask was dissolved in a small amount of methanol (about
2 cm3). The solution was subjected to chromatographic
filtration (mobile phase: methanol) to give a solid residue
(1.55 g). The residue was dissolved in methanol, silica gel
was added, and the suspension was evaporated to dryness.
The residual powder was placed on the top of the silica bed
of a chromatography column. Two column chromato-
graphic separations gave 0.22 g (20%) 3b. M.p.: 245–
248 °C (252 °C [17]); Rf = 0.37 (MeOH); IR (KBr):
ꢀ
m = 3,272, 1,694, 1,607, 1,279 cm-1
; MS (70 eV):
m/z = 277 (M?, 1), 262 (M?––15, 10), 140 (5), 124
(100), 121 (10), 107 (5), 93 (4), 65 (4), 58 (21).
4-(4-Hydroxybenzoyloxy)-2,2,6,6-tetramethylpiperidin-1-
oxyl (4b)
2,2,6,6-Tetramethylpiperidin-4-yl 4-hydroxybenzoate (3b,
0.1394 g, 0.5 mmol), sodium tungstate (0.07 g), triethyl-
benzylammonium chloride (0.01 g), and sodium versenate
(0.01 g) were suspended in a mixture of methanol (5–
6 cm3) and water (0.2 cm3) in a flask of 5 cm3 capacity.
Hydrogen peroxide (50%, 0.715 cm3) was added to the
reaction mixture. The suspension was magnetically stirred
for 27 h at rt. The oxidation was monitored by use of TLC
(BM9). The precipitate was isolated by filtration directly
into a separation funnel and washed with dichloromethane
(2 9 5 cm3) and 20 cm3 water. The organic layer was
separated and dried over anhydrous magnesium sulfate.
After filtration and evaporation crude 4b was obtained
(0.1012 g, 69%). The crude product 4b was subjected to
column chromatography (BM95) to give 0.0778 g (53%)
4b as a red solid. M.p.: 179–180 °C (175 °C [17]),
ꢀ
M.p.: 75–78 °C; Rf = 0.36 (BA9); IR (KBr): m = 2,983,
2,265, 2,231, 1,504, 1,356, 1,190, 1,168 cm-1; MS
(70 eV): m/z = 271 (M?, 53), 257 (13), 241 (15), 226
(100), 184 (43), 156 (13), 142 (20); HR-MS: calc. for
C16H19N2O2: 271.14465, found: 271.14378.
Methyl 4-hydroxybenzoate (1b)
4-Hydroxybenzoic acid (13.8 g, 0.1 mol) and methanol
(100 cm3) were placed in a round-bottomed flask of 0.5 dm3
capacity. Concentrated sulfuric acid (2 g, 1.08 cm3) was
added dropwise. The solution was heated under reflux for
6.5 h and allowed to cool to rt. The excess methanol was
removed by evaporation under reduced pressure and the
residue was transferred to a separation funnel filled with a
saturated sodium bicarbonate solution (50 cm3) and diethyl
ether (50 cm3). The organic layer was washed with water
and dried with anhydrous magnesium sulfate. Removal of
the drying agent by filtration and evaporation of diethyl
ether afforded 13.8 g (91%) colourless, crystalline 1b. M.p.:
121–124 °C (127.7–128.3 °C [22]).
ꢀ
Rf = 0.44 (BM9); IR (KBr): m = 3,296, 1,699, 1,609,
1,280 cm-1; MS (70 eV): m/z = 292 (M?, 9), 278 (1), 262
(7), 206 (3), 155 (5), 154 (18), 140 (11), 139 (13), 124 (71),
121 (100), 109 (57), 93 (10), 82 (8), 81 (6), 69 (6), 68 (5),
67 (7), 65 (7), 56 (3), 55 (4), 41 (8), 39 (5).
4-(4-Cyanatobenzoyloxy)-2,2,6,6-tetramethylpiperidin-1-
oxyl (6b, C17H21N2O4)
In a flask of 5 cm3 capacity, 4b (0.0778 g, 0.266 mmol)
was dissolved in anhydrous acetone (0.5 cm3, dried over
magnesium sulfate). The reaction mixture was cooled to
0 °C. A cooled solution of 5b (0.055 g, 0.52 mmol) in
acetone (0.5 cm3) was added with a syringe. Then,
triethylamine (40 mm3) was added dropwise using a
syringe. A precipitate was formed. The reaction mixture
was magnetically stirred at 0 °C for 30 min. The progress
of the reaction was monitored by TLC (BM9, BA9). The
reagents were warmed to rt. A precipitate (0.0327 g) was
isolated by filtration. The filtrate was evaporated, and the
residue (0.0790 g) was subjected to column chromatogra-
phy (BA95) to give 0.046 g (54%) 6b as a red solid. M.p.:
115–118 °C, Rf = 0.38 (BA9), 0.76 (BM9); IR (KBr):
2,2,6,6-Tetramethylpiperidin-4-yl 4-hydroxybenzoate (3b)
Methyl 4-hydroxybenzoate (1b, 0.608 g, 4 mmol), 1.57 g
2,2,6,6-tetramethyl-4-piperidinol (2b, 10 mmol), and
potassium hydroxide (0.056 g, 1 mmol) were triturated in
a mortar and placed in a two-necked flask equipped with a
distillation condenser. The mixture was magnetically
stirred and heated to about 200 °C for 35 min. The
condenser was occasionally connected to a vacuum line
to remove, by distillation, the methanol formed. The
reaction mixture was cooled to 70 °C. The content of the
ꢀ
m = 2,285, 2,258, 2,239, 1,717 (C=O), 1,600, 1,498,
123

Nitroxides with a cyanato substituent
449
1,280 cm-1; MS (70 eV): m/z = 317 (M?, 12), 154 (24),
146 (100), 140 (7), 139 (11), 124 (90), 109 (77), 82 (15), 81
(12), 76 (5), 69 (11), 68 (12), 56 (6), 55 (10), 41 (19); HR-
MS: calc. for C17H21N2O4: 317.15013, found: 317.14892.
7. Hamerton I, Hay JN (1998) Polym Int 47:465
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Acknowledgments The work was supported by the Polish Ministry
of Science and Higher Education, 429/E-142/S/2008.
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