Reactions of nitroxides with sulfur-containing compounds, part IV: Synthesis of novel nitroxide (thio)ureas

Article abstract of DOI:10.1002/hc.20228

The reactions of 4-isothiocyanato-2,2, 6,6-tetramethylpiperidine-1-oxyl 2 and 4-isocyanato-2,2,6,6-tetramethylpiperidine-1-oxyl 3 with selected amines and lower alcohols give the corresponding novel thioureas 4, ureas 5, thiocarbamates 6, and carbamates 7, all bearing the nitroxyl moiety. The characteristic features of EI mass spectra of (thio)ureas 4 and 5 are described. Some of the synthesized thioureas 4, ureas 5, thiocarbamates 6, and carbamates 7 are moderately or weakly active against pathogenic fungi.

Full text of DOI:10.1002/hc.20228

Heteroatom Chemistry
Volume 17, Number 5, 2006
Reactions of Nitroxides with Sulfur-Containing
Compounds, Part IV: Synthesis of Novel
Nitroxide (Thio)ureas
Jerzy Zakrzewski and Maria Krawczyk
Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland
Received 7 September 2005; revised 9 December 2005
[11–17]. Here, in relation to our previous studies on
ABSTRACT: The reactions of 4-isothiocyanato-2,2,
6,6-tetramethylpiperidine-1-oxyl 2 and 4-isocyanato-
2,2,6,6-tetramethylpiperidine-1-oxyl 3 with selected
amines and lower alcohols give the corresponding
novel thioureas 4, ureas 5, thiocarbamates 6, and car-
bamates 7, all bearing the nitroxyl moiety. The char-
acteristic features of EI mass spectra of (thio)ureas 4
and 5 are described. Some of the synthesized thioureas
4, ureas 5, thiocarbamates 6, and carbamates 7
are moderately or weakly active against pathogenic
the nitroxides containing sulfur functional groups
[1], we present the synthesis, mass spectral fea-
tures, and some pesticidal properties of the novel
(thio)ureas bearing the nitroxyl moiety [18].
RESULTS AND DISCUSSION
Thioureas (4a–h), ureas (5a–h), thiocarbamates (6a,
b), and carbamates (7a,b) bearing nitroxyl moiety
were synthesized according to Scheme 1.
ꢀ
C
fungi.
2006 Wiley Periodicals, Inc. Heteroatom Chem
The synthesis of 4-isothiocyanato-2,2,6,6-tetra-
methylpiperidine-1-oxyl 2 from 4-amino-2,2,6,6-
tetramethylpiperidine-1-oxyl 1 and thiophosgene
has been described earlier [19–21]. The reaction of
the isothiocyanate 2 with corresponding secondary
amines leads to the thioureas 4a–g (Table 1).
In order to obtain 4-isocyanato-2,2,6,6-tetra-
methylpiperidine-1-oxyl 3, the nitroxyl amine 1 was
phosgenated with phosgene dimer (trichloromethyl
chloroformate) [12,22,23]. The isolation and purifi-
cation of 3 by crystallization resulted in a low yield
of 3. Attempts to purify 3 by column chromatog-
raphy (silica gel) caused the decomposition of 3.
The crude nitroxyl isocyanate 3 was used without
further purification in the synthesis of the ureas 5.
The crude 3 was converted to the ureas 5a–g by the
reaction with the corresponding secondary amines
(Table 1).
17:393–401, 2006; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20228
INTRODUCTION
Due to the significant biological importance of (thio)-
urea derivatives, their synthesis is the subject of a
number of recently published papers [2–9]. Proeco-
logical synthesis of N,Nꢁ symmetric substituted ureas
has recently been described [10].
To the best of our knowledge, no thiourea deriva-
tives bearing nitroxyl groups are known. However,
some urea nitroxides have already been reported
Part III: [1].
Correspondence to: Jerzy Zakrzewski; e-mail: zakrzewski@ipo.
waw.pl.
When the starting amine radical 1 was applied as
an amine, the bi-radicals 4h and 5h were obtained
(Table 1). When 2,2,6,6-tetramethylpiperidine 8 was
used as an amine, none of the expected (thio)ureas
Contract grant sponsor: Polish State Committee for Scientific
Research.
Contract grant numbers: 429/E-142/S/2004 and 429/E-142/S/
2005.
c
ꢀ
2006 Wiley Periodicals, Inc.
393

394 Zakrzewski and Krawczyk
SCHEME 1 (i) CSCl2[19]; (ii) ClCOOCCl3, Bz3N, benzene; (iii) (4a–h, 5a–h) HR, benzene; (iv) (6a,b, 7a,b) HR/NaR.
were obtained. This was probably due to the limited
access to the nitrogen atom in 8 caused by steric
hindrance.
The alternative preparation of 5g and 5h from
4-isocyano-2,2,6,6-tetramethylpiperidine-1-oxyl [24]
was recently reported [17].
The reactions of isothiocyanate 2 and isocyanate
3 with methanol or ethanol led to the corresponding
nitroxyl thiocarbamates 6a,b and carbamates 7a,b
(Table 1).
In order to synthesize 4, 6 by an alternative
route, we tried to use the Lawesson reagent (2,4-
bis(4-methoxyphenyl)-1,3-dithia-2,4-phosphetane-
2,4-disulphide) with the intention to convert the
carbonyl group in 5, 7 directly to the thiocarbonyl
group in 4, 6. 2,2,6,6-Tetramethylpiperidine-1-oxyl
(TEMPO, a test nitroxyl radical), 5e (as an example
of a nitroxide urea), TEMPO-4-ONE, TEMPO-4-OL
were heated in toluene with the Lawesson reagent.
No expected thiourea 4e was observed. A darkening
of the reaction mixture and decomposition of the
starting radicals was observed. Many unidentified,
strongly colored and polar products were detected
by means of TLC.
TABLE 1 Synthesized Thioureas (4a–h), Ureas (5a–h), Thiocarbamates (6a,b), and Carbamates (7a,b)
X = S, 4a–h, 6a–b
X = O, 5a–h, 7a–b
Puri cation Yield
mp
Rf
Puri cation
Method a
Yield
mp
Rf
(BM9)
R
Cmpd
Method a
(%)
( ◦C)
(BM9) Cmpd
(%) b
( ◦C)
N(CH3)2
4a
4b
4c
4d
4e
K (B)
K (B)
K (B)
K (B)
K (B)
66.1
157—159
0.15
5a
5b
5c
5d
5e
K (B), C (BM9)
K (B), C (BM9)
K (B), C (BM9)
K (B), C (BM9)
K (B), C (BM9)
35.2
49.5
73.9
74.5
89.7
165—169 0.08
145—148 0.10
148—152 0.17
182—186 0.19
162—166 0.23
N(C2H5)
76.7 166.5—167.5 0.21
N(n-C H27)
67.6
64.5
74.3
154—156
155—157
143—145
0.25
0.35
0.36
N(i-C 3H7) 2
3
2
N(n-C4H9)2
4f
4g
4h
K (B)
K (B)
82.4 172.5—173.5 0.20
5f
5g
5h
K (B), C (BM9)
83.5
glass
0.17
0.23
0.18
c
42.0
48.4
173—174
Glass
0.23
0.16
C (BM9), K (B),
C (BM9)
90.9 157—161
d
C (BM9)
(twice)
C (BM9)
88.7 118—120
OCH3
OC2H5
6a
6b
C (BM9)
C (BE9)
62.8
72.4
135—137.5 0.33
153—155
0.40f
7a
7b
C (BM9), K (CHx)
C (BE9), K (CHx) 63.8 118—120
75.7
123—126 0.29
e
0.32f
aK (B), K (CHx): crystallization from benzene and cyclohexane, respectively, C: Column chromatography.
bThe yields refer to the isolated ureas 5 and carbamate◦s 7 and are calculated on the starting nitroxyl amine 1 used in the preceding step.
cEarlier th◦is value was erroneously described as 85—87C [17].
◦
◦
d116—118C (EtOAc/pentane) [13], 145◦C (benzene) [14], 198—199C (hexane) [15], and 203—204C (ethyl acetate) [16].
◦
emp 121—122C [16].
fMobile phase: BE9.
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Reactions of Nitroxides with Sulfur-Containing Compounds, Part IV 395
The distinct molecular ions are observed in the
mass spectra of all described thiourea and urea
nitroxides. However, the molecular peaks in mass
spectra of thiourea nitroxides 4a–g are greater than
the molecular peaks of urea nitroxides 5a–g (int.
25–42% and 10–23%, respectively) except for that
of 4e.
As expected, the signal of a carbamoyl frag-
ment (R1)2N C O is abundant (except 5a). It is the
base peak in the mass spectra of the urea nitrox-
ides 5b,c,e,g. On the contrary, the thiocarbamoyl
fragments (R1)2N C S are observed, but (except
4a, int. 100%) their intensity (4b–g) is much less
abundant.
The most characteristic feature of the mass spec-
tra for both (thio)urea nitroxides 4a–g and 5a–g is
the presence of the signal M-73 (4a–g) and M-86
(5a–g). In the case 4b–g and 5a, they are the base
signals. The probable origin of the M-73 for 4a–g is
M − (CH3)2C N OH [30] and of the M-86 for 5a–g
is M − O N C(CH3)2 CH2.
SCHEME 2 (i) CHCl3, 50% NaOH, TEBACl; (ii) boiling
toluene, 3.5 h.
In order to confirm that the nitroxide group is
unstable in the reaction conditions, the test com-
pound 9, the simplest 2,2,6,6-tetramethylpiperidine
derivative bearing the formyl group instead the
nitroxyl one, was designed and synthesized [25,26].
9 was converted with a poor yield (probably due
to steric hindrance) to 10 by the thionation with
the Lawesson reagent (Scheme 2, Table 2). The
formation of the side-product 11 was observed.
The structure of 11 was attributed by means of
its spectral data, especially by the A2B nature of
1
its 31P{ H} NMR spectrum (Table 4, footnotes d–f).
Surprisingly, signal M-33 (M-SH), which is very
characteristic for thiourea derivatives [31] is not ob-
served in the spectra of thiourea nitroxides 4a–g.
Due to the similarity of the structures of the
synthesized (thio)ureas 4a–h, 5a–h, and (thio)carba-
mates 6a,b, 7a,b with the structure of the known pes-
ticide isoproturon [4-i-C3H7 C6H4 NHCON(CH3)2]
[32] and its thio analog [33], pesticidal activity of the
synthesized 4–7 was tested using preliminary screen-
ing tests.
Several fungicidally active compounds against
pathogenic fungi have been identified (Table 5).
In vitro test. A slight inhibition of the colony for-
mation of the following fungi at the concentration
200 mg L−1 was observed:
Recently, a trimer, analogous and similar to 11,
1
has been identified by 31P{ H} NMR analysis
[27,28].
The purities of all synthesized nitroxyl radicals
(1–7) were checked by means of the iodometric titra-
tion according to [29]. The structures of synthesized
compounds were confirmed by MS, IR and for 8–11
additionally by NMR (1H, 13C, 31P) spectra (Tables 3
and 4).
The EI mass spectra of synthesized thioureas
4a–g and ureas 5a–g were analyzed. Example graphs
for 4b and 5g are presented on Figs. 1 and 2,
respectively.
TABLE 2 Synthesized Derivatives of 2,2,6,6-Tetramethyl-
piperidine 8
•
Botrytis cinerea: 6a (weak activity), 4h and 6b
(moderate activity);
Yield
bp
•
Fusarium culmorum: 4c, 4d, 6a, and 6b (weak
activity);
Cmpd m (g) (%) ( ◦C/mmHg) mp ( ◦C)
Rf
•
Phytophthora cactorum: 4h, 5e, 6a, and 6b (weak
activity);
9
2.3
45.4 65/0.2
47.5–49a 0.20 (BA95)
0.60 (BM9)
•
Rhizoctonia solani: 4c, 4d, and 6b (weak activity).
10 0.0518 28.0
–
89–92
0.05 (HA9)
0.67 (BM9)
0.53 (BA9)
0.65 (CM9)
In vivo test. The infection of wheat leaves
induced by powdery mildew (Blumeria graminis)
was reduced by up to 50% and 90% after single
sprayings with 7b and 6a solution (1000 mg L−1),
respectively.
11 0.1692
–
–
155–163 0.23 (HA9)c
(benzene)b 0.83 (BM9)
0.66 (BA9)
The additional experiments were conducted with
several weed species to investigate herbicidal activity
of synthesized compounds at the dose 1 kg/ha. None
of the compounds showed significant activity against
weeds when applied via leaves or via soil.
0.79 (CM9)
a47.5—48.5C [25].
◦
b160◦C [35], 158—159C [36], 155—156C (benzene) [37, 38].
◦
◦
c0.14 (HA6) [36].
Heteroatom Chemistry DOI 10.1002/hc

396 Zakrzewski and Krawczyk
TABLE 3 Spectral Data of (Thio)ureas 4, 5 and (Thio)carbamates 6, 7
MS, EI, 70 eV, m/e
Cmpd int (%)
IR, ν(cm−1), KBr
Cmpd MS, EI, 70 eV, m/e int (%)
IR, ν (cm−1), KBr
4a
4b
4c
259 (28), 258 (33,
M), 185 (74), 88
(100)
287 (19), 286 (42,
M), 213 (100)
3363, 2982, 2929, 5a
243 (8), 242 (23, M), 156 (100), 141 (49),
72 (39)
3391, 2988,
2972, 2940,
1641, 1529
3408, 2974, 2932,
1633, 1528
1542, 1344
3374, 2971, 2932, 5b
1534, 1358,
271 (7), 270 (10, M), 184 (52), 100 (100)
1331, 1261
3365, 2966,
1531, 1347
315 (20), 314 (25,
M), 241 (100)
5c
299 (7), 298 (13, M), 212 (70), 145 (53),
128 (100), 72 (89), 43 (67)
3324, 2968,
2934, 2873,
1617, 1538
4d
4e
4f
315 (18), 314 (34,
M), 241 (100)
343 (16.5), 342 (31, 3310, 2957,
M), 269 (100)
301 (21), 300 (36,
M), 227 (100),
147 (58), 130
3442, 2965,
1537, 1328
5d
5e
299 (4), 298 (12, M), 212 (34), 145 (34),
128 (85), 86 (100), 44 (42), 43 (43)
327 (9), 326 (16, M), 240 (80), 197 (34),
173 (59), 156 (100), 86 (99), 57 (89)
285 (8), 284 (15, M), 198 (100), 183 (39),
154 (43), 140 (43), 131 (60), 124 (62),
114 (91), 88 (70), 70 (53)
3418, 2969, 2930,
1635, 1529
3329, 2962, 2932,
1616, 1544
3429, 2973,
2931, 2856,
1627, 1536
1533, 1362
3347, 2970, 2955, 5f
2926, 2861,
1533, 1336
(50), 124 (34)
299 (17), 298 (35,
M), 225 (100),
169 (27), 145
(41), 128 (53)
385 (4), 384 (3, M), 3470, 3322, 2972, 5h
140 (38), 124
(100), 58 (70),
55 (45), 42 (32),
41 (50)
4g
4h
3304, 3000, 2977, 5g
2939, 2858,
1539, 1347
283 (9), 282 (10, M), 196 (74), 129 (54),
112 (100)
3424, 2975,
2934, 2851,
1617, 1537
369 (3), 368 (M, 5), 199 (23), 140 (32),
124 (100), 84 (56.5), 70 (40)
3380, 2976, 2938,
1645, 1580
2935, 1541
6a
6b
246 (17), 245 (12,
M), 172 (38), 154
(86), 140 (70.5),
124 (100), 109
(60), 41 (74)
3224, 3033,
2994, 2943,
1533, 1208
7a
229 (15, M), 154 (23), 143 (44), 128 (100), 3334, 2976,
124 (56), 109 (33)
2940, 1695,
1544, 1317,
1241, 1035
260 (15), 259 (10.5, 3223, 2977, 2937, 7b
243 (27, M), 157 (59), 142 (71), 128 (100), 3297, 2992, 2941,
M), 154 (82), 140
(67), 124 (100),
109 (53), 41 (66)
1536, 1206
124 (57)
1718, 1536,
1307, 1237,
1137, 1041
EXPERIMENTAL
General
5554 and Merck 1.09385.1000 (0.040–0.063 mm,
230–400 mesh), respectively.
The following abbreviations for mobile phases
were used throughout the text:
4-Isothiocyanate-2,2,6,6-tetramethylpiperidin-1-oxyl
2 and 2,2,6,6-tetramethylpiperidine 8 were synthe-
sized as described previously [19,34]. All reagents
were commercially available and used as received
without further purification.
All experiments were performed in a multi-
necked round-bottomed flask equipped with a mag-
netic stirrer, a thermometer, a dropping funnel, and
a reflux condenser protected against humidity. The
formation of products was monitored by means of
TLC. Molar ratios of reactants, parameters of the par-
ticular procedures, melting points, and chromato-
graphic data are shown in Tables 1 and 2. Spectral
data are shown in Tables 3 and 4.
•
•
•
BM9 = benzene : methanol 9 : 1;
BE9 = benzene : ethanol 9 : 1;
BA9, BA95 = benzene : ethyl acetate 9 : 1, 95 : 5,
respectively;
•
•
HA6, HA9 = hexane : ethyl acetate 6 : 1, 9 : 1,
respectively;
CM9 = carbon tetrachloride : methanol 9 : 1.
MS (EI, 70 eV, m/e, int. (%)) data were recorded
using AMD 604 apparatus, except 9: Finnigan MAT
8200 and 10: GC Varian 3300 with Finnigan MAT
ITD 800. IR (ꢀ/cm−1) data were recorded using
FT/IR Jasco 420 apparatus. 1H NMR (δ/ppm, J (Hz),
CDCl3, TMS),13C NMR (δ/ppm, CDCl3, TMS), and
TLC control and column chromatography were
done on silica gel Merck Alurolle 5562, Alufolien
Heteroatom Chemistry DOI 10.1002/hc

Reactions of Nitroxides with Sulfur-Containing Compounds, Part IV 397
Heteroatom Chemistry DOI 10.1002/hc

398 Zakrzewski and Krawczyk
FIGURE 1 The mass spectrum of the thiourea nitroxide 4b.
31P NMR (δ/ppm, J (Hz), CDCl3, H3PO4) (for non-
radical compounds 9–11) data were recorded using
Bruker WP 100 SY (100 MHz) (9), Varian UNITY-
plus 200 (200 MHz) (10), and Varian UNITYplus 500
(500 MHz) (11) apparatus.
Thioureas 4a–g: General Procedure
4-Isothiocyanate-2,2,6,6-tetramethylpiperidin-1-oxyl
2 (0.3195 g, 1.5 mmol) and anhydrous benzene
(8–10 mL) were placed in the reaction flask. The
appropriate amine (1.7 mmol) was added with
FIGURE 2 The mass spectrum of the urea nitroxide 5g.
Heteroatom Chemistry DOI 10.1002/hc

Reactions of Nitroxides with Sulfur-Containing Compounds, Part IV 399
TABLE 5 The Effect of Compounds on Mycelial Growth of Phytopathogenic Fungi
% Growth reductiona
Botrytis
Fusarium
Phytophthora
cactorumb
Rhizoctonia
solanib
Blumeria
graminisc
Compound No.
cinereab
culmorumb
4c
4d
4h
6a
6b
5e
7b
0
0
2
1
2
0
0
1
1
0
1
1
0
0
0
0
1
1
1
1
0
1
1
0
0
1
0
0
0
0
0
2
0
0
1
aScale:
0 = 0—20% growth reduction —no effect.
1 = 20.1—50% growth reduction —week activity.
2 = 50.1—90% growth reduction —moderate activity.
3 = 90.1—100% growth reduction —good activity.
bin vitro.
cin vivo.
a syringe at 15◦C. In the case of 4a, the gaseous
dimethylamine is introduced either through an
inlet tube, or as excess, chilled liquid directly into
the flask. The temperature of the suspension rises
up to about 20◦C, then lowered to about 18◦C.
Pink, crystalline precipitate is formed (4a–d, f ),
and the suspension is partially concentrated. If no
precipitate is observed (4e, g), the reaction mixture
is allowed to stand at about 0◦C (in a refrigerator)
overnight and/or partially concentrated. The pink,
fine, crystalline precipitate is collected, washed
with chilled benzene or hexane and repeatedly
crystallized from a small amount of benzene. The
crystals are air dried. The preparation details and
spectroscopic data of the synthesized nitroxide
thioureas 4a–g are presented in Tables 1 and 3,
respectively.
4-Isocyanate-2,2,6,6-tetramethylpiperidine-1-
oxyl 3
Tribenzylamine (1.745 g, 6.1 mmol), benzene (28 ml)
were placed in the reaction flask. Stirred solution
was cooled to 5◦C with ice-water bath. The solution
of trichloromethyl chloroformate (“diphosgene”)
(0.415 g, 253 ꢁL, 2.1 mmol) in benzene (3.5 mL) was
added dropwise. The solution of 4-amino-2,2,6,6-
tetramethylpiperidine-1-oxyl 1 (0.513 g, 3 mmol)
in benzene (7 mL) was added in the same way at
5–7◦C. The dropping funnel was washed with ad-
ditional amount of benzene (2 mL). The reaction
mixture becomes cloudy, brown and the precipitate
is formed. Ice-water bath was removed and reac-
tants were stirred at ambient temperature for ad-
ditional 2 h. Tribenzylamine hydrochloride was fil-
tered off. Benzene was evaporated under reduced
pressure to give the crude, red 4-isocyanate-2,2,6,6-
tetramethylpiperidine-1-oxyl 3. It is acceptable as a
starting material for the next step (the reaction with
either amines or alkoxylates). The crude 3 may be pu-
rified by means of crystallization from hexane (10–
15 mL of hexane /0.1–0.15 g of crude 3) (18–34%),
mp 100–102◦C (102◦C [23]), MS (70 eV, m/e, int /%):
197 (39, M), 140 (43), 124 (66), 110 (100), 96 (78),
68 (66), 56 (25), 55 (23), 41 (47), IR (ꢀ, cm−1, KBr):
2981, 2942, 2260.
N,Nꢁ-Bis(2,2,6,6-tetramethyl-1-oxyl-4-piperidyl)
thiourea 4h
4-Isothiocyanate-2,2,6,6-tetramethylpiperidin-1-oxyl
2 (0.1385 g, 0.65 mmol) and anhydrous benzene
(3 mL) were placed in the reaction flask. The solu-
tion of 4-amine-2,2,6,6-tetramethylpiperidin-1-oxyl
1 (0.1167 g, 0.68 mmol) in anhydrous benzene
(0.5 mL) was added with a syringe at 22◦C. The
stirring was continued at ambient temperature
for 24 h. The formation of the product was mon-
itored by means of TLC (BM9). Benzene was
evaporated under reduced pressure. The residue
(0.3146 g) was subjected to column chromatography
(mobile phase: BM9). to give the red, glassy N,Nꢁ-
bis(2,2,6,6-tetramethyl-1-oxyl-4-piperidyl) thiourea
4h (0.1216 g, 48.4%); Rf 0.16 (BM9).
Ureas 5a–h: General Procedure
Crude 4-isocyanate-2,2,6,6-tetramethylpiperidin-1-
oxyl 3 (obtained from 3 mmol of 4-amine-2,2,6,6-
tetramethylpiperidin-1-oxyl 1) and anhydrous ben-
zene (16 mL) were placed in the reaction flask. The
appropriate amine was added dropwise at 15–20◦C.
The solution was stirred at ambient temperature for
Heteroatom Chemistry DOI 10.1002/hc

400 Zakrzewski and Krawczyk
1 h (control with TLC, BM9) and evaporated under
reduced pressure. The residue was carefully crystal-
lized (chilling and concentration) from benzene (2–
3 mL) and then purified by means of column chro-
matography (BM9) to give pink crystals of ureas 5.
The preparation details and spectroscopic data of the
synthesized nitroxide ureas 5a–h are presented in
Tables 1 and 3, respectively.
cold water bath was applied if needed. The reac-
tion mixture was vigorously stirred at 50◦C for 5.5 h,
then allowed to cool to ambient temperature, di-
luted with water and methylene chloride. Organic
layer was separated, washed with water and dried
over magnesium sulfate. Drying agent was filtered
off, and solvent was evaporated under reduced pres-
sure. The residue (5.4 g) was subjected to distillation
under reduced pressure to give 9 (2.3 g, 45.4%); bp
65◦C/0.2 mmHg, mp 47.5–49◦C (47.5–48.5◦C [25]); R
f
Thiocarbamates 6 and carbamates 7:
General Procedure
0.2 (BA95); 0.6 (BM9).
The solution of sodium alkoxide (1 mmol/1 mL)
was prepared by dissolving of elemental natrium
(0.23 g, 0.01 g atom) in the appropriate anhydrous
alcohol and diluting the resulting solution with the
same alcohol up to the 10 mL volume. The start-
ing 4-isothiocyanate-2,2,6,6-tetramethylpiperidin-1-
oxyl 2 (0.3195 g, 1.5 mmol), or crude 4-isocyanate-
2,2,6,6-tetramethylpiperidin-1-oxyl 3 (obtained from
3 mmol of 4-amine-2,2,6,6-tetramethylpiperidin-1-
oxyl) is placed in the reaction flask and dissolved in
the anhydrous alcohol (methanol, ethanol, 4–8 mL).
The mixture is slightly warmed if necessary to dis-
solve the starting 2 or 3. The alcohol solution of the
appropriate sodium alkoxide (1.2 mmol/1 mmol of
the starting 2 or 3) was added with a pipette at 20◦C.
The temperature of the solution raised up to 24◦C.
The solution was stirred for 10 min at ambient tem-
perature. The solvent was evaporated under reduced
pressure. Diethyl ether (20–30 mL) was added to the
residue. The mixture was stirred for about 30 min,
and additional amount of diethyl ether (15 mL)
was added. White precipitate was thoroughly tritu-
rated with diethyl ether, filtered off, and washed with
the same solvent (5–10 mL). The filtrate was dried
over anhydrous magnesium sulfate overnight. Dry-
ing agent was filtered off, ether was evaporated un-
der reduced pressure. The crude thiocarbamates 6 or
carbamates 7 were subjected to column chromatog-
raphy (mobile phase benzene: appropriate alcohol
9:1, i.e. BM9 or BE9, respectively). The preparation
details and spectroscopic data of the synthesized ni-
troxide thiocarbamates 6a–b and carbamates 7a–b
are presented in Tables 1 and 3, respectively.
1-Thioformyl-2,2,6,6-tetramethylpiperidine 10
1-Formyl-2,2,6,6-tetramethylpiperidine
9
(0.169,
1 mmmol), Lawesson’s reagent (0.55 g, 1.36 mol),
and toluene (about 3–4 mL) were placed in the
reaction flask. The reaction mixture was stirred
at reflux for 3.5 h, then at ambient temperature
overnight. The progress of the reaction was moni-
tored by means of TLC (silica gel, BM9). Reaction
mixture was filtered through Cellite and washed
with benzene. Benzene was evaporated and the
residue (0.5021 g) was subjected to twice repeated
column chromatography (mobile phase BA95) to
give
•
11-colorless side-product of the Lawesson’s
reagent transformation as the first fraction:
0.1692 g, 155–163◦C.
•
the yellow zone of the expected product 10 as the
second fraction: 0.0518 g, 28.0%, 89–92◦C.
In vitro Fungicidal Bioassay
Fungitoxicity of compounds against phytopath-
ogenic fungi: Botrytis cinerea, Rhizoctonia solani,
Fusarium culmorum, Phytophthora cactorum was as-
sessed in vitro using agar growth medium poison
technique.
PDA media in 100 mm Petri plates containing
synthesized compounds (at concentration 200 g L−1)
were infected with agar disks with thin mycelium
of fungi cultures. Linear growth of each colony was
determined after 3–5 days. The effect of each com-
pound on mycelial growth was assessed by calculat-
ing the percentage of growth reduction.
1-Formyl-2,2,6,6-tetramethylpiperidine 9
Triethylbenzylammonium chloride (0.5 g, 2.2mmol),
chloroform (about 25 mL), and 2,2,6,6-tetra-
methylpiperidine 8 (4.23 g, 0.03 mol) were placed in
the reaction flask. Into the vigorously stirred reaction
mixture, 50% aqueous sodium hydroxide solution
(16 mL) was added dropwise. The temperature of
the reaction mixture raised up to 60◦C. Cooling with
In vivo Fungicidal Bioassay
Wheat plants (Triticum aestivum, L.) were grown
to growth stage 11 (Zadoks scale) under normal
glasshouse propagation conditions (temperature,
20–25◦C; lighting, 14 h photoperiod of daylight sup-
plemented by lamps 400 W). They were inoculated
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