Cycloalkyl substituted N-nitrourea derivatives: A convenient synthesis and biological evaluation

Article abstract of DOI:10.1007/s11164-011-0293-z

A series of N-nitrourea derivatives bearing various cycloalkyl were conveniently obtained via three steps including nitration, carbamic chlorination, and aminolysis reactions. The structures of all newly synthesized compounds were elucidated and confirmed

Full text of DOI:10.1007/s11164-011-0293-z

Res Chem Intermed (2011) 37:859–868
DOI 10.1007/s11164-011-0293-z
Cycloalkyl substituted N-nitrourea derivatives:
a convenient synthesis and biological evaluation
•
Zhongyuan Bai Zengjun Wei Yunchun Wang
•
•
•
•
•
Shengzhen Xu Xuegang Li Changshui Chen
Xiufang Cao
Received: 28 December 2010 / Accepted: 20 January 2011 / Published online: 15 February 2011
Ó Springer Science+Business Media B.V. 2011
Abstract A series of N-nitrourea derivatives bearing various cycloalkyl were
conveniently obtained via three steps including nitration, carbamic chlorination, and
aminolysis reactions. The structures of all newly synthesized compounds were
1
elucidated and confirmed by IR, H NMR, 13C NMR, and elemental analysis. The
preliminary bioassay indicated that the target compounds exhibited moderate her-
bicidal activity against Amaranthus albus and Sorghum sudanense. However, some
of the title compounds presented high plant growth regulating activity against rice.
Keywords N-nitrourea ꢀ Synthesis ꢀ Herbicidal activity ꢀ
Plant growth regulating activity
Introduction
Urea derivatives are well-known scaffolds for a significantly broad range of
biological activities such as herbicidal activities [1, 2], antimicrobial, bactericidal,
anti-HIV [3–6], and so on, which have occupied a pivotal position in medicine and
pesticide chemistry due to their structural and bioactivity diversity. Up to now,
many structural optimization studies on both sides of carbamide bridge’s amines
have been investigated. On the other hand, N-nitro substituted anilines have also
been demonstrated to exhibit diversely biological activities, including herbicidal
properties [7], antifungal effects [8], and plant growth regulating activities [9].
Z. Bai ꢀ Z. Wei ꢀ Y. Wang ꢀ S. Xu ꢀ C. Chen (&)
College of Science, Huazhong Agricultural University, Wuhan 430070, People’s Republic of China
e-mail: chenchang@mail.hzau.edu.cn
X. Li ꢀ X. Cao (&)
Department of Applied Chemistry, Biochemical Institute, Huazhong Agricultural University,
Wuhan 430070, People’s Republic of China
e-mail: caoxiufang@mail.hzau.edu.cn
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In view of these observations, we attempt to synthesize N-nitro substituted anilines
incorporating NH–CO–NH bridge units and search novel potential agrochemical
agents with broad bioactivities.
Earlier work [10, 11] in our laboratory involved some aromatic ring and
heterocyclic derivatives with moderate herbicidal and plant growth regulating
activities. As a continuation of our ongoing project aim, we designed and
synthesized a series of new N-nitro urea derivatives with various cycloalkyl
substituents (Scheme 1). Preliminary bioassay showed that some of the target
compounds had good herbicidal and plant growth regulating activities.
Results and discussion
Synthesis for cycloalkyl substituted N-nitrourea derivatives 4a–t
The target compounds N-nitro-N-2,4,6-trisubstituted phenyl-N0-cycloalkyl urea
derivatives 4a–t were conveniently synthesized according to Scheme 1.
Traditionally, trisubstituted phenylnitramines are prepared by reaction with nitric
acid in the presence of acetic anhydride [9]. However, the aforementioned method
always involves a large amount of organic solvent as well as having low yields. In
order to overcome some of these problems, our team developed a convenient and
efficient method for preparation of N-nitro-2,4,6-trichloroaniline in 90% yield [12].
As a continuation of our studies and to extend the range of substrates, we
conveniently constructed a series of trisubstituted phenylnitramine 2 with 47–81%
yields (Table 1).
Then the key intermediates 2a–h were treated with the BTC (triphosgene) in the
presence of toluene solution to obtain various N-nitro-2,4,6-trisubstituted phenyl
carbamic chloride 3. Further purification of intermediates 3 could not be achieved
because of their air and water sensitivity. Hence, they were directly reacted with
various cycloalkyl amines in toluene in the presence of DMAP to afford target
compounds in 50–86% yields.
Biological activity evaluation
The herbicidal activities of the title compound 4a–t against Amaranthus albus and
Sorghum sudanense have been investigated at the dosages of 50 mg/l compared to
R1
R1
R1 NO2
N
R1 NO2
N
H
N
H
N
NH2
R3
Cl
i
ii
iii
NO2
R4
O
O
R2
R2
R3
R2
R3
R2
R3
1
2
3
4
Scheme 1 General synthetic route for cycloalkyl substituted N-nitrourea derivatives 4. Reagents and
conditions: (i) CH3COONO2, CH3COOH, Ac2O, 16–20 °C, 1–1.5 h, (ii) BTC, triethylamine, toluene,
0–5 °C, 1 h; then 50 °C, 2–3 h. (iii) Cycloalkyl amines, DMAP, triethylamine, toluene, 0–5 °C; then
60 °C, 2–3 h
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Cycloalkyl substituted N-nitrourea derivatives
861
Table 1 Preparation of 2,4,6-trisubstituted phenylnitramine 2a–h
Compound R1,2,3
Yield Compound R1,2,3
(%)
Yield
(%)
2a
2b
2c
2d
2,4,6-tri-Cl
2,4,6-tri-Br
71
67
2e
2f
2,6-di-Br; 4-Cl
2,4-di-Br; 6-Cl
2,6-di-Br; 4-F
70
61
59
R1
H
N
NO2
2,6-di-Br; 4-CH3 81
2,4-di-Br; 6-CH3 77
2g
2h
2,4-di-Br; 6-CF3 47
R2
R3
2
distilled water and the commercially available herbicide Diuron according to the
method described in the experimental section. The preliminary results of bioassay
(Table 2) showed that the target compounds possessed higher herbicidal activity
against root than that of hypocotyl. Especially, compounds 4a and 4r exhibited
considerable herbicidal activity to Diuron. These data show that the presence of the
electron-withdrawing group at the phenyl ring, such as fluorine, trifluoromethyl may
decrease their herbicidal activity.
The plant growth regulatory activity of title compounds against rice was also
evaluated at the concentration of 10 mg/l, and the results are shown in Table 2.
From Table 2, we can find that the compounds 4d, 4e, 4f, 4i, 4n, 4r exhibited higher
plant growth regulating activity than the other. This suggests that cyclopropane may
cause an increase of their plant growth regulatory activity.
Conclusions
In summary, we have conveniently constructed a novel series of cycloalkyl
substituted N-nitrourea derivatives 4a–t. The results of the preliminary bioassay
indicated that some of the title compounds possessed moderate herbicidal and plant
growth regulatory activities. Especially, compound 4r displayed high herbicidal
activity and excellent plant growth regulating activity, which may be used as a
potential lead compound for further optimization.
Experimental
Instrumentation and chemicals
All reagents were commercially available and all solvents and liquid reagents were
dried by standard methods and distilled before use. Melting points were determined
with a digital melting point apparatus and are uncorrected. IR spectra were recorded
on a Thermo Nicolet FT-IR Avatar 330 instrument. 1H NMR and 13C NMR spectra
were measured on a Bruker AM spectrometer with tetramethylsilane (TMS) as
internal standard and CDCl3 or DMSO-d6 as solvent. Elemental analysis was
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Table 2 Herbicidal and plant growth regulating activities of targeted compounds 4a–t
Compound R1,2,3
R4
Relative inhibition at 50 mg/l Active gradea of
(root %/hypocotyl %)
formation-promoting
against rice hypocotyl
A. albus S. sudanense
4a
4b
4c
4d
4e
4f
2,4,6-tri-Cl
Cyclopropane 85.2/57.3
2,6-di-Br; 4-CH3 Cyclopropane 76.9/72.1
2,4-di-Br; 6-CH3 Cyclopropane 34.4/57.3
57.9/39.0
47.9/55.7
45.3/25.1
73.1/57.5
55.6/40.3
52.0/54.0
50.2/41.0
43.3/29.8
54.2/37.2
17.6.19.2
70.2/46.9
42.6/40.7
69.6/43.3
54.8/46.8
63.1/47.8
47.4/54.4
40.9/41.1
51.1/57.4
55.1/71.2
44.4/46.1
87.0/57.6
C
B
B
A
A
A
B
C
A
D
D
D
D
A
C
C
C
A
C
C
–
2,6-di-Br; 4-Cl
2,4-di-Br; 6-Cl
Cyclopropane 54.4/42.4
Cyclopropane 69.7/51.1
2,4-di-Br; 6-CF3 Cyclopropane 46.9/53.8
2,6-di-Br; 4-CH3 Cyclopentane 61.6/52.9
4g
4h
4i
2,6-di-Br; 4-Cl
2,6-di-Br; 4-F
2,4,6-tri-Cl
Cyclopentane 51.6/51.2
Cyclopentane 44.4/46.8
Cyclohexane 63.4/53.8
4j
4k
4l
2,4-di-Br; 6-CH3 Cyclohexane 59.4/64.0
2,4-di-Br; 6-Cl
2,6-di-Br; 4-F
Cyclohexane 59.4/48.5
Cyclohexane 13.4/24.0
4m
4n
4o
4p
4q
4r
4s
2,4-di-Br; 6-CF3 Cyclohexane 50.0/45.9
2,4,6-tri-Br Cycloheptane 61.6/57.2
2,4-di-Br; 6-CH3 Cycloheptane 58.8/56.4
2,6-di-Br; 4-Cl
2,4-di-Br; 6-Cl
2,6-di-Br; 4-F
Cycloheptane 50.0/50.2
Cycloheptane 79.7/74.1
Cycloheptane 49.1/52.9
4t
2,4-di-Br; 6-CF3 Cycloheptane 48.4/48.5
88.4/63.1
Diuron
–
–
a
Active grade: A [ 70%, B [ 50%, C [ 30%, D \ 30% at the concentration of 10 mg/l
performed on a Vario EL III Elemental analysis instrument. The progress of the
reactions was monitored by TLC on silica gel plates visualized with UV light.
General synthetic procedures for 2,4,6-trisubstituted phenylnitramine 2a–h
Fuming nitric acid (1.01 ml, 24 mmol) was slowly added dropwise to the stirred
acetic anhydride (2.27 ml, 24 mmol) at 10–12 °C. After the addition, the
temperature of the reaction mixture was maintained between 10 and 12 °C for
40 min. Then a crude product of acetyl nitrate was obtained and was used directly
for the next step. The obtained acetyl nitrate was added dropwise to a solution of
2,4,6-trisubstituted aniline 1 (20 mmol) in dry acetic acid (20 ml) and acetic
anhydride (2 ml) at 16–20 °C. The reaction mixture was stirred for a further
45–90 min. The resulting purple solution was then poured into 60 ml of ice water,
and the resulting precipitate was filtered, washed with water (1 l), and dissolved in
aqueous 10% sodium carbonate. The solution was heated to boil for 10 min with a
small amount of activated carbon so as to decolorize the products and was then
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863
filtered off immediately. Filtrate was cooled to room temperature and acidified with
ice-cold 2N hydrochloric acid to precipitate the phenylnitramine product 2. The
nitramine was filtered, washed with cold water, dried in vacuo, and recrystallized
from hexane or cyclohexane. The physico-chemical spectral data and melting
point of compounds 2a–h were in agreement with the data reported in the literature
[8, 9, 13, 14].
General procedure for the preparation of N-nitro-N-2,4,6-trisubstituted
phenyl-N0-cycloalkyl urea 4a–t
A solution of 2,4,6-trisubstituted phenylnitramine 2 (10 mmol) in 50 ml of
anhydrous toluene with 2 ml triethylamine was added dropwise to a cold solution
(0–5 °C) of BTC (3.6 mmol) in dry toluene (20 ml). After the addition, the
temperature of the reaction mixture was maintained between 0 and 5 °C for 1 h and
then heated to 50 °C for a further 2–3 h. The intermediate 3 was formed and used
without further isolation. After quenching the unreacted phosgene with dry nitrogen,
the mixture was cooled to 0–5 °C and treated dropwise with a solution of cycloalkyl
amines (10 mmol) in anhydrous toluene (10 ml) with 2 ml of triethylamine in the
presence of DMAP (0.5 mmol). The reaction was carried out at 60 °C for 2 h with
vigorous stirring and then the mixture was cooled to 0 °C for 2–3 h. The respective
urea 4a–t were precipitated, filtered, and washed with excess water and acetone.
Crude products were further purified by recrystallization (DMF/acetone).
N-Nitro-N-(2,4,6-trichlorophenyl)-N0-cyclopropane urea (4a)
White needle crystal, yield 66%, m.p. 245–246 °C. IR (KBr, cm-1): m 3320 (NH),
1
3083 (ArH), 1649 (CO); H NMR (600 MHz, DMSO-d6), dH 0.43 (s, 2H, CH2,
cyclopropane), 0.62 (d, 2H, J = 5.4 Hz, CH2, cyclopropane), 3.86 (m, 1H, CH,
cyclopropane), 6.67 (s, 1H, NH), 7.68 (s, 2H, ArH). 13C NMR (150 MHz, DMSO-
d6), dC 6.5, 22.6, 128.5, 131.1, 133.5, 134.8, 155.6. Anal. Calcd for C10H8Cl3N3O3:
C, 37.01; H, 2.48; N, 12.95. Found: C, 37.11; H, 2.53; N, 12.86.
N-Nitro-N-(2,6-dibromo-4-methylphenyl)-N0-cyclopropane urea (4b)
White needle crystal, yield 54%, m.p. 308–309 °C. IR (KBr, cm-1): m 3300 (NH),
1
1638 (CO); H NMR (600 MHz, DMSO-d6), dH 0.44 (s, 2H, CH2, cyclopropane),
0.62 (d, 2H, J = 5.4 Hz, CH2, cyclopropane), 2.28 (s, 3H, CH3), 3.88 (q, 1H,
J = 20.4 Hz, CH, cyclopropane), 6.51 (s, 1H, NH), 7.50 (s, 2H, ArH). Anal. Calcd
for C11H11Br2N3O3: C, 33.62; H, 2.82; N, 10.69. Found: C, 33.70; H, 2.91; N,
10.53.
N-Nitro-N-(2,4-dibromo-6-methylphenyl)-N0-cyclopropane urea (4c)
White needle crystal, yield 66%, m.p. 316–317 °C. IR (KBr, cm-1): m 3300 (NH),
1
1638 (CO); H NMR (600 MHz, DMSO-d6), dH 0.43 (s, 2H, CH2, cyclopropane),
0.63 (q, 2H, J = 18.0 Hz, CH2, cyclopropane), 2.20 (s, 3H, CH3), 3.88 (m, 1H, CH,
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cyclopropane), 6.58 (s, 1H, NH), 7.48 (d, 1H, J = 1.2 Hz, ArH), 7.69 (d, 1H,
J = 1.8 Hz, ArH). Anal. Calcd for C11H11Br2N3O3: C, 33.62; H, 2.82; N, 10.69.
Found: C, 33.68; H, 2.89; N, 10.57.
N-Nitro-N-(2,6-dibromo-4-chlorophenyl)-N0-cyclopropane urea (4d)
White needle crystal, yield 80%, m.p.[330 °C. IR (KBr, cm-1): m 3307 (NH), 1644
(CO); 1H NMR (600 MHz, DMSO-d6), dH 0.44 (s, 2H, CH2, cyclopropane), 0.63 (d,
2H, J = 4.8 Hz, CH2, cyclopropane), 3.88 (q, 1H, J = 20.4 Hz, CH, cyclopropane),
6.63 (s, 1H, NH), 7.84 (s, 2H, ArH). Anal. Calcd for C10H8Br2ClN3O3: C, 29.05; H,
1.95; N, 10.16. Found: C, 29.13; H, 2.01; N, 10.01.
N-Nitro-N-(2,4-dibromo-6-chlorophenyl)-N0-cyclopropane urea (4e)
White needle crystal, yield 78%, m.p. 313–314 °C. IR (KBr, cm-1): m 3307 (NH),
1
1646 (CO); H NMR (600 MHz, DMSO-d6), dH 0.43 (s, 2H, CH2, cyclopropane),
0.62 (d, 2H, J = 5.4 Hz, CH2, cyclopropane), 3.88 (m, 1H, CH, cyclopropane), 6.68
(s, 1H, NH), 7.78 (s, 1H, ArH), 7.90 (s, 1H, ArH). Anal. Calcd for
C10H8Br2ClN3O3: C, 29.05; H, 1.95; N, 10.16. Found: C, 29.17; H, 2.06; N, 10.02.
N-Nitro-N-[2,4-dibromo-6-(trifluoromethyl)phenyl]-N0-cyclopropane urea (4f)
White needle crystal, yield 52%, m.p. 296–297 °C. IR (KBr, cm-1): m 3317 (NH),
1
1637 (CO); H NMR (600 MHz, DMSO-d6), dH 0.46 (q, 2H, CH2, J = 20.8 Hz,
cyclopropane), 0.62 (q, 2H, J = 22.6 Hz, CH2, cyclopropane), 3.88 (q, 1H,
J = 14.4 Hz, CH, cyclopropane), 6.36 (s, 1H, NH), 7.91 (d, 1H, J = 1.8 Hz, ArH),
8.27 (d, 1H, J = 2.4 Hz, ArH). Anal. Calcd for C11H8Br2F3N3O3: C, 29.56; H, 1.80;
N, 9.40. Found: C, 29.65; H, 1.87; N, 9.31.
N-Nitro-N-(2,6-dibromo-4-methylphenyl)-N0-cyclopentane urea (4g)
White needle crystal, yield 70%, m.p. 298–299 °C. IR (KBr, cm-1): m 3301 (NH),
1
2922, 2851 (CH), 1637 (CO); H NMR (600 MHz, DMSO-d6), dH 1.36 (m, 2H,
CH2, cyclopentane), 1.47 (m, 2H, CH2, cyclopentane), 1.59 (m, 2H, CH2,
cyclopentane), 1.79 (m, 2H, CH2, cyclopentane), 2.28 (s, 3H, CH3), 3.87 (q, 1H,
J = 20.4 Hz, CH, cyclopropane), 6.23 (d, 1H, J = 7.2 Hz, NH), 7.45 (s, 2H, ArH).
Anal. Calcd for C13H15Br2N3O3: C, 37.08; H, 3.59; N, 9.98. Found: C, 37.12; H,
3.66; N, 9.90.
N-Nitro-N-(2,6-dibromo-4-chlorophenyl)-N0-cyclopentane urea (4h)
White needle crystal, yield 86%, m.p. 297–298 °C. IR (KBr, cm-1): m 3301 (NH),
1
2922, 2850 (CH), 1637 (CO); H NMR (600 MHz, DMSO-d6), dH 1.37 (m, 2H,
CH2, cyclopentane), 1.50 (m, 2H, CH2, cyclopentane), 1.62(m, 2H, CH2,
cyclopentane), 1.79 (m, 2H, CH2, cyclopentane), 3.87 (q, 1H, J = 20.4 Hz, CH,
cyclopropane), 6.35 (d, 1H, J = 7.2 Hz, NH), 7.79 (s, 2H, ArH). 13C NMR
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Cycloalkyl substituted N-nitrourea derivatives
865
(150 MHz, DMSO-d6), dC 23.2, 32.7, 51.2, 128.0, 130.7, 133.6, 134.4, 154.2. Anal.
Calcd for C12H12Cl3N3O3: C, 40.88; H, 3.43; N, 11.92. Found: C, 40.93; H, 3.47; N,
11.84.
N-Nitro-N-(2,6-dibromo-4-fluorophenyl)-N0-cyclopentane urea (4i)
White needle crystal, yield 56%, m.p. 300–301 °C. IR (KBr, cm-1): m 3305 (NH),
2929, 2853 (CH), 1635 (CO); 1H NMR (600 MHz, DMSO-d6), dH 1.37 (m, 2H, CH2,
cyclopentane), 1.50 (m, 2H, CH2, cyclopentane), 1.60(m, 2H, CH2, cyclopentane),
1.79 (m, 2H, CH2, cyclopentane), 3.87 (q, 1H, J = 20.4 Hz, CH, cyclopropane), 6.30
(d, 1H, J = 6.0 Hz, NH), 7.68 (d, 2H, J = 7.8 Hz, ArH). Anal. Calcd for
C12H12Br2FN3O3: C, 33.91; H, 2.85; N, 9.89; Found: C, 33.95; H, 2.89; N, 9.80.
N-Nitro-N-(2,4,6-trichlorophenyl)-N0-cyclohexane urea (4j)
White needle crystal, yield 62%, m.p. 268–269 °C. IR (KBr, cm-1): m 3304 (NH),
1
2920, 2850 (CH), 1638 (CO); H NMR (600 MHz, DMSO-d6), dH 1.15–1.78 (m,
10H, C5H10, cyclohexane), 3.38 (s, 1H, CH, cyclohexane), 6.30 (d, 1H, J = 6.6 Hz,
NH), 7.66 (s, 2H, ArH). Anal. Calcd for C13H14Cl3N3O3: C, 42.59; H, 3.85; N,
11.46. Found: C, 42.51; H, 3.89; N, 11.49.
N-Nitro-N-(2,4-dibromo-6-methylphenyl)-N0-cyclohexane urea (4k)
White needle crystal, yield 50%, m.p. 310–311 °C. IR (KBr, cm-1): m 3300 (NH),
1
2922, 2852 (CH), 1635 (CO); H NMR (600 MHz, DMSO-d6), dH 1.14–1.80 (m,
10H, C5H10, cyclohexane), 2.19 (s, 3H, CH3), 3.39 (t, 1H, J = 7.8 Hz, CH,
cyclohexane), 6.23 (d, 1H, J = 7.8 Hz, NH), 7.47 (s, 1H, ArH), 7.57 (s, 1H, ArH).
Anal. Calcd for C14H17Br2N3O3: C, 38.65; H, 3.94; N, 9.66. Found: C, 38.67; H,
3.96; N, 9.62.
N-Nitro-N-(2,6-dibromo-4-chlorophenyl)-N0-cyclohexane urea (4l)
White needle crystal, yield 76%, m.p. 311–312 °C,. IR (KBr, cm-1): m 3301 (NH),
1
2922, 2850 (CH), 1637 (CO); H NMR (600 MHz, DMSO-d6), dH 1.16–1.81 (m,
10H, C5H10, cyclohexane), 3.40 (d, 1H, J = 5.4 Hz, CH, cyclohexane), 6.25 (d, 1H,
J = 6.2 Hz, NH), 7.83 (s, 2H, ArH). 13C NMR (150 MHz, DMSO-d6), dC 24.4,
25.2, 33.0, 48.1, 125.1, 131.4, 131.5, 136.1, 153.9. Anal. Calcd for
C13H14Br2ClN3O3: C, 34.28; H, 3.10; N, 9.22. Found: C, 34.27; H, 3.16; N, 9.20.
N-Nitro-N-(2,6-dibromo-4-fluorophenyl)-N0-cyclohexane urea (4m)
White needle crystal, yield 54%, m.p. 298–299 °C. IR (KBr, cm-1): m 3305 (NH),
1
2929, 2853 (CH), 1635 (CO); H NMR (600 MHz, DMSO-d6), dH 1.16–1.81 (m,
10H, C5H10, cyclohexane), 3.39 (d, 1H, CH, J = 7.8 Hz, cyclohexane), 6.21 (d, 1H,
J = 3.6 Hz, NH), 7.69 (s, 2H, ArH). Anal. Calcd for C13H14Br2FN3O3: C, 35.56; H,
3.21; N, 9.57. Found: C, 35.54; H, 3.33; N, 9.60.
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N-Nitro-N-[2,4-dibromo-6-(trifluoromethyl)phenyl]-N0-cyclohexane urea (4n)
White needle crystal, yield 51%, m.p. 289–290 °C. IR (KBr, cm-1): m 3315 (NH),
1
2928, 2853 (CH), 1637 (CO); H NMR (600 MHz, DMSO-d6), dH 1.15–1.78 (m,
10H, C5H10, cyclohexane), 3.39 (t, 1H, J = 7.8 Hz, CH, cyclohexane), 6.27 (d, 1H,
J = 27 Hz, NH), 7.92 (s, 1H, ArH), 8.27 (s, 1H, ArH). Anal. Calcd for
C14H15Br2F3N3O3: C, 33.03; H, 2.97; N, 8.43. Found: C, 33.08; H, 2.39; N, 8.38.
N-Nitro-N-(2,4,6-tribromophenyl)-N0-cycloheptane urea (4o)
White needle crystal, yield 78%, m.p. 298–299 °C. IR (KBr, cm-1): m 3322 (NH),
1
2931, 2855 (CH), 1645 (CO); H NMR (600 MHz, DMSO-d6), dH 1.39–1.83 (m,
12H, C6H12, Cycloheptane), 3.58 (m, 1H, CH, Cycloheptane), 6.30 (d, 1H,
J = 8.4 Hz, NH), 7.93 (s, 2H, ArH). 13C NMR (150 MHz, DMSO-d6), dC 23.5,
27.6, 34.9, 50.3, 119.4, 125.5, 134.0, 136.5, 153.7. Anal. Calcd for C14H16Br3N3O3:
C, 32.71; H, 3.14; N, 8.18. Found: C, 32.66; H, 3.17; N, 8.12.
N-Nitro-N-(2,4-dibromo-6-methylphenyl)-N0-cycloheptane urea (4p)
White needle crystal, yield 53%, m.p. 292–293 °C. IR (KBr, cm-1): m 3318 (NH),
1
2928, 2856 (CH), 1638 (CO). H NMR (600 MHz, DMSO-d6), dH 1.40–1.83 (m,
12H, C6H12, Cycloheptane), 2.19 (s, 3H, CH3), 3.60 (m, 1H, CH, Cycloheptane),
6.27 (d, 1H, J = 7.8 Hz, NH), 7.47 (s, 1H, ArH), 7.55 (s, 1H, ArH). Anal. Calcd for
C15H19Br2N3O3: C, 40.11; H, 4.26; N, 9.36. Found: C, 40.20; H, 4.18; N, 9.33.
N-Nitro-N-(2,6-dibromo-4-chlorophenyl)-N0-cycloheptane urea (4q)
White needle crystal, yield 69%, m.p. 296–297 °C. IR (KBr, cm-1): m 3330 (NH),
1
2927, 2853 (CH), 1638 (CO). H NMR (600 MHz, DMSO-d6), dH 1.40–1.83 (m,
12H, C6H12, Cycloheptane), 3.58 (m, 1H, CH, Cycloheptane), 6.29 (d, 1H,
J = 7.8 Hz, NH), 7.83 (s, 1H, ArH). Anal. Calcd for C14H16Br2ClN3O3: C, 35.81;
H, 3.43; N, 8.95. Found: C, 35.87; H, 3.46; N, 8.95.
N-Nitro-N-(2,4-dibromo-6-chlorophenyl)-N0-cycloheptane urea (4r)
White needle crystal, yield 69%, m.p. 294–295 °C. IR (KBr, cm-1): m 3322 (NH),
1
2922, 2850 (CH), 1638 (CO). H NMR (600 MHz, DMSO-d6), dH 1.41–1.88 (m,
12H, C6H12, Cycloheptane), 3.60 (m, 1H, Hz, CH, Cycloheptane), 6.27 (d, 1H,
J = 7.8 Hz, NH), 7.49 (s, 1H, ArH), 7.65 (s, 1H, ArH). Anal. Calcd for
C14H16Br2ClN3O3: C, 35.81; H, 3.43; N, 8.95. Found: C, 35.78; H, 3.47; N, 8.90.
N-Nitro-N-(2,6-dibromo-4-fluorophenyl)-N0-cycloheptane urea (4s)
White needle crystal, yield 53%, m.p. 289–290 °C. IR (KBr, cm-1): m 3317 (NH),
1
2929, 2853 (CH), 1635 (CO); H NMR (600 MHz, DMSO-d6), dH 1.40–1.83 (m,
12H, C6H12, Cycloheptane), 3.58 (m, 1H, CH, Cycloheptane), 6.27 (d, 1H,
123

Cycloalkyl substituted N-nitrourea derivatives
867
J = 7.8 Hz, NH), 7.88 (s, 1H, ArH). Anal. Calcd for C14H16Br2FN3O3: C, 37.11; H,
3.56; N, 9.27. Found: C, 37.14; H, 3.53; N, 9.20.
N-Nitro-N-[2,4-dibromo-6-(trifluoromethyl)phenyl]-N0-cycloheptane urea (4t)
White needle crystal, yield 55%, m.p. 285–286 °C. IR (KBr, cm-1): m 3322 (NH),
1
2928, 2858 (CH), 1637 (CO). H NMR (600 MHz, DMSO-d6), dH 1.42–1.89 (m,
12H, C6H12, Cycloheptane), 3.60 (m, 1H, CH, Cycloheptane), 6.28 (d, 1H,
J = 7.8 Hz, NH), 7.47 (s, 1H, ArH), 7.57 (s, 1H, ArH). Anal. Calcd for
C15H16Br2F3N3O3: C, 35.81; H, 3.21; N, 8.35. Found: C, 35.88; H, 2.27; N, 8.38.
Herbicidal activity testing
Herbicidal testing of the title compound was carried out in a greenhouse, with
temperature 25 1 °C, relative humidity (RH) 60 5%, light intensity 10 Klux,
photoperiod 8 h/day. Twenty seeds of each weed species including Amaranthus
albus and Sorghum sudanense were chosen for testing. Seedlings were grown in a
test plate of 9-cm diameter containing two pieces of filter paper and 9 ml of solution
of tested compound (50 mg/l). Distilled water and Diuron were used as the
comparison compounds. The herbicidal activity was assessed as the inhibitory rate
in comparison to the distilled water. The lengths of roots and hypocotyl are
measured and the means were calculated. The percentage inhibition was used to
describe the control efficiency of the compounds. For the entire bioassay test, each
treatment was repeated twice. The herbicidal activity is summarized in Table 2.
Plant growth regulating activity testing
A solution of title compounds in a small amount of dimethyl sulfoxide (DMSO) was
diluted with distilled water that contained 0.1% Tween 80 to the concentration of
10 mg/l. Twenty seeds of rice were placed into a 9-cm-diameter plate containing
two pieces of filter paper and a 9-ml solution of tested compound. The plate was
placed in a greenhouse and allowed to germinate for 96 h at a temperature of
25 1 °C. The mixture of the same amount of water, DMSO, and Tween 80 was
used as the control. Weeds treated with water were the blank test. Each treatment
was repeated twice and the lengths of hypocotyl of seedlings in each plate were
measured. The hypocotyl formation-promoting activity was calculated by the
method of (test-control)/blank (Table 2).
Acknowledgments The author gratefully acknowledge the financial support from the Academic
Discipline-Crossed Project (2010JC001) and the Research Initiation Funds (2009BQ027) of the
Huazhong Agricultural University.
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