Reactions of nitroxides XIV. Analogs of phenoxy carboxylic herbicides based on the piperidine scaffold; Unexpected fungicidal activity of the 2-[(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy] butanoic acid

Article abstract of DOI:10.1515/hc-2013-0169

Alkanoic acid derivatives bearing a nitroxyl moiety 3a-e were synthesized from 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (1) and the corresponding 2-bromoalkane carboxylic acids 2a-e. The herbicidal and antifungal activity of 3a-e was tested. No herbicidal activity of the tested compounds was found. The 2-[(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy]butanoic acid 3c revealed a strong antifungal activity against the pathogenic fungus Phytophthora cactorum.

Full text of DOI:10.1515/hc-2013-0169

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2014; 20(2): 89–91
DOI 10.1515/hc-2013-0169ꢀ
JRerezyaZacktrzieowsnkis* aondfMnariiatrKorawxcizdykes XIV. Analogs of phenoxy
carboxylic herbicides based on the piperidine
scaffold; unexpected fungicidal activity of the
2-[(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy]
butanoic acid
Abstract: Alkanoic acid derivatives bearing a nitroxyl
To synthesize the compounds generally abbreviated
moiety 3a–e were synthesized from 4-hydroxy-2,2,6,6- above as N-O, alkylation of 4-hydroxy-2,2,6,6-tetrameth-
tetramethylpiperidine-1-oxyl (1) and the corresponding ylpiperidine-1-oxyl (1) with a bromoalkanoic acid in the
2-bromoalkane carboxylic acids 2a–e. The herbicidal presence of a base is required. Alkylation of the hydroxyl
and antifungal activity of 3a–e was tested. No herbicidal group in 1 is usually performed under basic conditions.
activity of the tested compounds was found. The 2-[(1-oxyl- Examples are phase transfer catalysis (PTC) method (50%
2,2,6,6-tetramethylpiperidin-4-yl)oxy]butanoic acid 3c aqueous sodium hydroxide as a base) with tetrabutylam-
revealed a strong antifungal activity against the patho- monium bromide [5, 6], hydrogen sulfate [7, 8] or trieth-
genic fungus Phytophthora cactorum.
ylbenzylammonium chloride [9] as PTC catalysts and the
reactions conducted in the presence of sodium hydride
Keywords: bromoalkanoic acids; fungicides; herbicides; [10–14], sodium amide, cesium fluoride or potassium car-
nitroxides; piperidine ring; sodium hydride.
bonate [15].
*Corresponding author: Jerzy Zakrzewski, Institute of Industrial
Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland,
e-mail: zakrzewski@ipo.waw.pl
Maria Krawczyk: Institute of Industrial Organic Chemistry,
Annopol 6, 03-236 Warsaw, Poland
Results and discussion
Alkanoic acid derivatives bearing the nitroxyl moiety 3a–e
were obtained by the alkoxylation of 2-bromoalkanecar-
boxylic acids 2a–e with an alkoxide anion of 4-hydroxy-
2,2,6,6-tetramethylpiperidine-1-oxyl 1 generated in the
presence of sodium hydride (Scheme 1). Briefly, 2-bro-
Introduction
Aryloxy herbicides such as 2,4-D, MCPA, MCPB are widely mocarboxylic acid 2 was added to the excess of sodium
known commercial products against many weeds [1–3]. hydride in THF, and then a nitroxyl alcohol 1 was added.
Herein (as a continuation of the investigations of the The mixture was heated under reflux for 24 h.
research concerning nitroxides [4]), we present the syn-
The nitroxyl radicals 3a–ewere identified using spectro-
thesis and both herbicidal and fungicidal screening of scopic methods (EI MS, ESI MS, HRMS and IR). The 1H NMR
the nitroxyl derivatives of alkanoic acids with the nitroxyl spectra are not informative in these cases because signals
moiety instead of the aryl group found in the typical of protons are paramagnetically broadened and unresolved
aryloxy herbicides. These compounds are schematically owing to the presence of nitroxide radicals [16–20].
presented below as structures Ar and N-O.
The herbicidal and antifungal activity of 3a–c, 3e
was assayed. Compound 3d was not tested, due to its
negligible yield. The compounds 3a,b,e show medium
activity against four species of pathogenic fungi Botrytis
cinerea, Fusarium culmorum, Phytophthora cactorum and
Rhizoctonia solani. The butanoic acid derivative 3c shows
strong antifungal activity against pathogenic fungus
P. cactorum (Table 1).
Q
Q
O
COOH
Rm
O
COOH
Rn
N
O
Ar
N-O
Q = CH2 or substituted CH2; Rn, Rm = various substituents
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90ꢀ ꢀJ. Zakrzewski and M. Krawczyk: Alkanoic acid derivatives bearing a nitroxyl moiety
R
acidified with 1 N hydrochloric acid to pH 2. The acidified aqueous
layer was extracted with dichloromethane (3 ꢀ× ꢀ 20 mL). The extract
was dried with anhydrous magnesium sulfate, filtered and concen-
trated. The residue was subjected to silica gel chromatography eluting
with benzene/methanol (9:1) to give product 3a–e as red oils.
OH
O
COOH
R
2a-e
COOH
Br
N
O
N
O
NaH, THF
1
3a-e
[(1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy]acetic
acid
(3a)ꢀYield 51%; IR (ν, cm-1, film): 2977, 2938 (C-H, stretch), 1737 (Cꢀ= ꢀO,
stretch), 1177, 1123 (C-O, stretch); EI MS: m/z 277 (4), 231 (7), 230 (7,
M+), 216 (100), 200 (40), 160 (6), 143 (18), 140 (87), 129 (11), 124 (51),
109 (19), 108 (28), 107 (34), 102 (33), 98 (39), 85 (61), 84 (21), 83 (20),
82 (22), 81 (25), 74 (28), 71 (91), 69 (27), 67 (28), 58 (43), 57 (29), 56
(44), 55 (59), 45 (23), 43 (57), 42 (57), 41 (97); ESI MS: m/z 230 (15, M-·),
229 (100, [M-H]-), 171 (5); HR ESI MS. Calcd for C11H19NO4 ([M-H]-): m/z
229.1314, found: m/z 229.1325.
a: R = H
b: R = Me
c: R = Et
d: R = C14H29
e: R = Ph
Scheme 1ꢀSynthesis of alkanoic acid derivatives bearing a nitroxyl
moiety 3a–e.
Table 1ꢁAntifungal activity of 3a–e at a concentration of 200 ppm.
No.ꢂ
Botrytisꢂ
Fusariumꢂ
Phytophthoraꢂ
Rhizoctonia 2-[(1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy]propanoic acid
solani (3b)ꢀYield 46%; IR (ν, cm-1, film): 3395, 2976, 2950 (C-H, stretch), 1732
cinerea
culmorum
cactorum
(Cꢀ= ꢀO, stretch), 1460 (CH3, bend), 1365 (CH2, CH3, bend), 1178, 1120,
3a ꢃ
3b ꢃ
3c ꢃ
3e ꢃ
32ꢃ
32ꢃ
36ꢃ
24ꢃ
44ꢃ
46ꢃ
34ꢃ
40ꢃ
9ꢃ
16ꢃ
100ꢃ
29ꢃ
0
1065 (C-O, stretch); EI MS: m/z 244 (4, M+), 230 (2), 172 (2), 157 (4), 154
20
(4), 149 (7), 143 (6), 140 (6), 139 (6), 124 (13), 109 (16), 98 (11), 85 (37),
0
26
71 (100), 69 (18), 57 (27), 56 (20), 55 (29), 45 (29), 43 (68), 42 (41), 41
(93); ESI MS: m/z 311 (3), 244 (20, M-·), 243 (100, [M-H]-), 171 (3); HR
ESI MS. Calcd for C12H21NO4 [M-H]-: m/z 243.1471, found: m/z 243.1474.
2-[(1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy]butanoic acid
(3c)ꢀYield 42%; IR (ν, cm-1, KBr): 2974, 2930 (C-H, stretch), 1726
(Cꢀ= ꢀO, stretch), 1460 (CH3, bend), 1389 (CH2, CH3, bend), 1178, 1130,
1080 (C-O, stretch); EI MS: m/z 258 (30, M+), 244 (32), 228 (4), 213 (2),
202 (4), 171 (14), 157 (21), 155 (15), 154 (17), 140 (26), 139 (24), 124 (60),
Experimental
General
116 (7), 109 (48), 98 (24), 85 (100), 71 (26), 69 (34), 57 (13), 56 (19), 55
(27), 43 (15), 41 (43); ESI MS: 258 (5, M-·), 257 (100, [M-H]-); HR ESI MS.
Calcd for C13H23NO4 [M-H]-: 257.1627, found: m/z 257.1622.
4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (1) was synthesized
by oxidation of 2,2,6,6-tetramethyl-4-piperidinol with 30% hydro-
gen peroxide (76% yield, mp 71–73°C), as previously described [21–
23]. THF was distilled over sodium under argon in the presence of
benzophenone. The experiments were performed in a two-necked
round-bottom flask of 25 mL capacity, equipped with a magnetic stir
bar, reflux condenser protected against humidity, under an argon
atmosphere. TLC was carried out on silica gel Merck Alurolle 5562 or
Alufolien 5554. Column chromatography was performed using Merck
silica gel, 230–400 mesh. TLC visualization was performed using
UV 254 nm light and/or iodine vapor. EI MS data were recorded on
an AMD 604 and Agilent Technologies 5975 B mass spectrometers.
EI mass spectra were obtained at 70 eV. ESI mass spectra (negative
ionisation, CH3OH as solvent) were recorded on a Micromass LCT
apparatus. IR spectra were recorded on an FT/IR Jasco 420 spectro-
photometer. Conditions of the fungicidal bioassay in vitro are identi-
cal to those described previously [24].
2-[(1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy]hexadecanoic
acid (3d)ꢀYield 3%; IR (ν, cm-1, KBr): 2925, 2854 (C-H, stretch), 1717
(Cꢀ= ꢀO, stretch), 1462 (CH3, bend), 1378 (CH2, CH3, bend), 1109 (C-O,
stretch); EI MS: m/z 426 (7, M+), 412 (100), 396 (57), 156 (16), 155 (11),
154 (9), 140 (43), 124 (43), 109 (11), 100 (14), 98 (17), 87 (10), 85 (21), 83
(19), 74 (20), 71 (22), 69 (21), 67 (9), 58 (19), 57 (20), 56 (16), 55 (30), 43
(43), 41 (25); ESI MS: 426 (100, M-·), 313 (5), 221 (10); HR ESI MS. Calcd
for C25H48NO4 (M-·): 426.3583, found: m/z 426.3569.
[(1-Oxyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy](phenyl)acetic
acid (3e)ꢀYield 53%; IR (ν, cm-1, KBr): 3430, 2976, 2960 (C-H, stretch),
1736 (Cꢀ= ꢀO, stretch), 1460 (CH3, bend), 1389 (CH2, CH3, bend), 1177, 1099
(C-O, stretch); EI MS: m/z 306 (33, M+), 292 (55), 276 (10), 261 (10), 155
(23), 154 (24), 140 (28), 139 (18), 136 (80), 135 (100), 124 (52), 118 (18), 109
(31), 107 (42), 105 (10), 100 (13), 98 (16), 85 (17), 83 (12), 82 (13), 81 (14),
79 (44), 77 (27), 74 (11), 69 (23), 67 (12), 57 (17), 56 (19), 55 (25), 41 (34);
ESI MS: 306 (30, M-·), 305 (100, [M-H]-), 261 (10), 239 (8), 171 (35); HR
ESI MS. Calcd for C17H23NO4 [M-H]-: m/z 305.1627, found: m/z 305.1640.
General procedure for 3a–e
Anhydrous THF (5 mL) and 2-bromoalkanecarboxylic acid 2a–e
(1 mmol) were placed in a flask and the resultant solution was treated
with a 60% slurry of sodium hydride in mineral oil (0.9 g). Afer the
evolution of hydrogen ceased, compound 1 (0.17 g, 1 mmol) was
added. The mixture was stirred while it foamed again, then heated
under gentle reflux under argon for 24 h. Afer cooling, water (20 mL)
was carefully added and the resultant dark orange solution was trans-
ferred to a separation funnel. The aqueous mixture was washed with
Acknowledgment: This work was supported by the
Polish Ministry of Science and Higher Education,
4180/E-142/S/2013.
diethyl ether (2 ꢀ× ꢀ 25 mL), with dichloromethane (2 ꢀ× ꢀ 20 mL) and then Received November 4, 2013; accepted February 6, 2014
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