Synthesis and fungicidal activities of (Z/E)-3,7-dimethyl-2,6-octadienamide and its 6,7-epoxy analogues

Article abstract of DOI:10.3390/molecules201219743

In order to find new lead compounds with high fungicidal activity, (Z/E)-3,7-dimethyl- 2,6-octadienoic acids were synthesized via selective two-step oxidation using the commercially available geraniol/nerol as raw materials. Twenty-eight different (Z/E)-3,7-dimethyl-2,6-octadienamide derivatives were prepared by reactions of (Z/E)-carboxylic acid with various aromatic and aliphatic amines, followed by oxidation of peroxyacetic acid to afford their 6,7-epoxy analogues. All of the compounds were characterized by HR-ESI-MS and ¹H-NMR spectral data. The preliminary bioassays showed that some of these compounds exhibited good fungicidal activities against Rhizoctonia solani (R. solani) at a concentration of 50 μg/mL. For example, 5C, 5I and 6b had 94.0%, 93.4% and 91.5% inhibition rates against R. solani, respectively. Compound 5f displayed EC₅₀ values of 4.3 and 9.7 μM against Fusahum graminearum and R. Solani, respectively.

Full text of DOI:10.3390/molecules201219743

Article
Synthesis and Fungicidal Activities of
(Z/E)-3,7-Dimethyl-2,6-octadienamide and
Its 6,7-Epoxy Analogues
Mingyan Yang, Hongbo Dong, Jiazhen Jiang and Mingan Wang *
Received: 10 October 2015; Accepted: 17 November 2015; Published: 25 November 2015
Academic Editor: Jean Jacques Vanden Eynde
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China;
yangmy@cau.edu.cn (M.Y.); dhb1986115@cau.edu.cn (H.D.); jiangjiazhen@cau.edu.cn (J.J.)
*
Correspondence: wangma@cau.edu.cn; Tel.: +86-10-6273-4093
Abstract: In order to find new lead compounds with high fungicidal activity, (Z/E)-3,7-dimethyl-
2,6-octadienoic acids were synthesized via selective two-step oxidation using the commercially
available geraniol/nerol as raw materials. Twenty-eight different (Z/E)-3,7-dimethyl-2,6-octadienamide
derivatives were prepared by reactions of (Z/E)-carboxylic acid with various aromatic and aliphatic
amines, followed by oxidation of peroxyacetic acid to afford their 6,7-epoxy analogues. All of
1
the compounds were characterized by HR-ESI-MS and H-NMR spectral data. The preliminary
bioassays showed that some of these compounds exhibited good fungicidal activities against
Rhizoctonia solani (R. solani) at a concentration of 50 µg/mL. For example, 5C, 5I and 6b had 94.0%,
93.4% and 91.5% inhibition rates against R. solani, respectively. Compound 5f displayed EC50 values
of 4.3 and 9.7 µM against Fusahum graminearum and R. Solani, respectively.
Keywords: 3,7-dimethyl-2,6-octadienamide; 3,7-dmethyl-6,7-epoxy-2-octadienamide; synthesis;
fungicidal activity
1. Introduction
Amide compounds were widely used in pharmaceutical and agrochemical fields due to
their wide range of biological activity. In pharmaceutical chemistry, some amides showed
potent antibacterial activities and antiproliferative against human cancer cell lines including the
drug-resistant cancer cells [1–3]. The other amides not only induce a significant decrease of antibiotic
resistance in Gram-negative bacteria [4], but also exhibit antimicrobial activity against Staphylococcus
aureus and Bacillus subtilis [5–7]. In agricultural chemicals, a lot of novel amide derivatives have been
synthesized, some of them showed good fungicidal or insecticidal activities, and the mode of action
on amide fungicides has been reviewed recently [8–16]. 2,6-Dimethyl-6-hydroxy-2E,4E-hepta-2,
4-diene acid and (6R)-3,7-dimethyl-7-hydroxyl-2-octen-1,6-olide were isolated from the fruit of Litsea
cubeba in Tibet, and they were evaluated to have good fungicidal activities in our laboratory [17,18].
Based on these results, some of the seven-membered lactone derivatives were synthesized and
confirmed to exhibit moderate to excellent fungicidal activities [19–21]. To the best of our knowledge,
the biological activities of monoterpene acid amides were seldom paid attention. In order to find
some novel derivatives with excellent fungicidal activity and explore the differences between
3,7-dimethyl-2,6-octadienoic acid and 3,7-dimethyl-7-hydroxyl-2-octen-1,6-olide (Scheme 1) against
phytopathogens, (Z/E)-3,7-dimethyl-2,6-octadienoic acids were synthesized via two-step selective
oxidation with the commercial available nerol/geraniol as the starting material [19,22,23]. Then,
28 different (Z/E)-3,7-dimethyl-2,6-octadienamide derivatives were designed and synthesized by
reaction of the acid chloride and various aromatic and aliphatic amines [24], and their 6,7-epoxy
Molecules 2015, 20, 21023–21036; doi:10.3390/molecules201219743
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Molecules 2015, 20, 21023–21036
derivatives were further obtained by epoxidation of the double bond between C-6 and C-7 [25]. The
fungicidal activities of these amides and their 6,7-epoxy analogues against Fusahum graminearum,
Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, and Botrytis cinerea were evaluated. The
synthetic route is shown as below (Scheme 2).
Scheme 1. Structures of (Z/E)-3,7-dimethyl-2,6-octadienoic acid and its 1,6-olide.
Scheme 2. Synthetic route of (Z/E)-3,7-dimethyl-2,6-octadienamide and their 6,7-epoxy analogues.
2. Results and Discussion
As we know, (Z)-3,7-dimethyl-2,6-octadienoic acid and (6R)-3,7-dimethyl-7-hydroxyl-2-octen-1,6-olide
exhibited certain fungicidal activities [17,18]. The racemic 3,7-dimethyl-7-hydroxyl-2-octen-1,6-olide,
the other seven-membered lactone derivatives and (E)-3,7-dimethyl-2,6-octadienoic acid were
synthesized and some of them were found to exhibit better fungicidal activities in our laboratory [19–21].
In the total synthesis, we found that (E)-6,7-dihydroxy-3,7-dimethyl-2,6-octadienoic acid is an unstable
compound because it is easily dehydrated under acid condition that needs to be purified rapidly and
kept in low temperature. In this case, the 6,7-epoxy moiety was designed to replace the 6,7-dihydroxy
group and keep the stability of the compound. Then 3,7-dimethyl-6,7-epoxy-2-octadienamides
were designed and synthesized to observe the effect of epoxy moiety on the fungicidal
activities. In consideration of the instability of epoxy moiety in strong acid condition, the route
strategy of epoxidation-amidation was abandoned due to low product yields, the approach of
amidation-epoxidation was selected to avoid the side reaction after optimizing repeatedly the
reaction condition. The key intermediates (Z/E)-3,7-dimethyl-2,6-octadienoic acid were easily
prepared in 85% and 76% yields over two steps with the Dess-Martin oxidant and Pinnick oxidation
utilizing the commercially available nerol/geraniol as raw material [19]. Finally, the amides and the
6,7-epoxy amide derivatives were afforded in 15%–79% yields and 63%–96% yields under the mild
condition, respectively.
1
In the H-NMR of compounds 5a–5n, the olefin protons on C-2 exhibited a singlet with the
chemical shifts δ 5.47–5.77, the olefin protons on C-6 displayed a multiplet at δ 4.90–5.20 due to the
coupling with the adjacent methylene protons at C-5 and long range coupling with CH3 at C-7. The
methyls on C-3 had a doublet at δ 2.23–2.05 with the coupling constant 1.2 Hz due to the long range
coupling with the proton on C-2, and the amide protons had the broad singlet with the chemical shifts
δ 5.27–7.57. While for the cis isomers 5A–5N, the amide protons had the similar chemical shifts as the
trans isomers, but the chemical shift of the protons on C-2 and C-6 shifted to the downfield about δ
0.02–0.10, and the methyls on C-3 shifted to the upfield about δ 0.30–0.40.
1
In the H-NMR of 6,7-epoxy compounds 6a–6j, the protons on C-2, the amide protons and the
methyls on C-3 also showed the similar chemical shifts and coupling constants as that of compounds
5a–5n. However, the protons on C-6 had the chemical shifts δ 2.53–2.76 due to existence of 6,7-epoxy
group and the peaks split into the double of doublet due to the coupling with the two protons at
C-5 with the coupling constants 5.5 and 7.0 Hz, the chemical shifts of the two methyls at C-7 shifted
to upfield about δ 0.30–0.35. Similarly, for the cis isomers 6A–6J, the protons on C-2, the protons on
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Molecules 2015, 20, 21023–21036
C-6, the amide protons, the methyls on C-3, and the two methyls at C-7 had the similar chemical
shifts and coupling constants. All of the new compounds were also characterized by HR-ESI-MS,
and the [M + H]+ peaks were detected; their exact mass numbers matched well with the calculated
molecule weights.
Based on the data in Table 1, compounds 5 and 6 showed a broad-spectrum of fungicidal
activities against five tested agriculturally important phytopathgens; they were found to be
particularly active against Rhizoctonia solani and Alternaria solani, for example, 5C, 5I and 6b,
respectively, exhibited 94.0%, 93.4% and 91.5% inhibition rates against R. solani, while 5a, 5c, 5d, 5g, 5I
and 5M showed 86.4%, 86.0%, 88.9%, 88.7%, 89.5%, and 85.5% inhibition rates against A. solani at the
concentration of 50 µg/mL, respectively. Greater than 70% inhibition at 50 µg/mL was considered to
be good in terms of antifungal inhibition, greater than 90% excellent in this paper.
In the Z/E-amides, comparison of the inhibition rates of 5l, 5m, 5n, 5L, 5M and 5N with
5a–5k and 5A–5K, we found that the aromatic amides showed much better fungicidal activities than
the aliphatic amides against R. solani and A. solani. It seemed that the aromatic substituted group
contributed a lot to the fungicidal activities. Thus, the different aromatic groups such as phenyl,
substituted phenyl, benzyl and substituted benzyl groups were selected to optimize the structure.
By comparing the inhibition rates of compounds 5b–5g, 5B–5G with compound 5a and 5A, we found
that the ortho-substitution (Cl, F) was beneficial to improve the fungicidal activities such as 5c, 5d, 5C
and 5D, while the activities at the para-substitution were kept or reduced such as 5b, 5e, 5f, 5B, 5e
and 5F. However, one more N-methyl group did not significantly change the activity comparing 5a
and 5A with 5g and 5G. So we concluded that the para-substitution was not helpful to improve the
activity, especially the electron-withdraw substitution groups. Further, the amides with benzyl and
substituted benzyl groups (compounds 5h–5k and 5H–5K) were synthesized and assayed. The results
in Table 1 indicated that amides with (substituted) benzyl groups had similar or increased fungicidal
activities against R. solani and A. solani comparing with compound 5a and 5A. Thus, the (substituted)
benzyl groups have similar effects on the fungicidal activities as the (substituted) phenyl groups. The
effect of the double bond configuration at C2 and C3 on the inhibition rates did not indicate significant
differences by comparison the inhibition data of 5a–5n and 5A–5N.
From the data in Table 1, it was very clear that compounds 5 showed much better fungicidal
activities against all tested phytopathgens than compounds 6. While compounds 6b and 6B were two
exceptions, which showed the inhibition rates of 91.5% and 82.7% against R. solani, respectively, much
higher than the 59.5% and 55.4% inhibition rates of 5b and 5B. The similar effects were observed for
the aromatic and aliphatic amides, the substitution on the benzene ring of phenyl and benzyl groups,
and the configuration of the double bond at C2 and C3. The double bond at C6 and C7 or adjacent
6,7-dihydroxy played an essential role for a better fungicidal activity when comparison the inhibition
rate data of compounds 5 and 6.
Based on the above results, the EC50 values (EC50 is the concentration of inhibition 50% fungus
growth at tested condition.) were determined further for these compounds with more than 70%
inhibition rates. The typical inhibition rates changing with the concentration could be seen in Figure 1.
The data in Table 2 confirmed that most of compounds exhibited an inhibition against R. solani and
A. solani with EC50 values between 9.7 and 677.8 µM, and several compounds were active against
F. graminearum, S. sclerotiorum and B. cinerea with EC50 values between 4.3 and 92.9 µM. Among
them, compound 5f had the best fungicidal activities with EC50 values of 4.3 and 9.7 µM against
F. graminearum and R. solani, respectively, and compounds 5g and 5I had the broad-spectrum of
fungicidal activities against four phytopathgens with EC50 values between 17.1 and 61.2 µM, most
of the other compounds have EC50 values between 13.4 and 97.9 µM against R. solani and A. solani
except 6d, 6f, 5M and 6H. These results indicated that there would be the possible improvement of
fungicidal activities against R. solani and A. solani if the chemical structures were further modified,
especially on the structures of 5f, 5g and 5I. Optimizations on the aromatic amine moieties around
compound 5 are in progress.
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Molecules 2015, 20, 21023–21036
Table 1. The fungicidal activities (inhibition rate, %) of compounds 5 and 6 at 50 µg/mL a.
Compd.
R
F. G
R. S
A. S
S. S
B. C
Compd.
R
F. G
R. S
A. S
S. S
B. C
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
2,4-Cl2Ph
2-ClPh
68.1
17.7
51.9
74.3
73.4
77.0
50.6
55.5
30.7
88.9
59.5
85.3
84.3
65.6
86.0
86.7
86.7
54.4
83.0
79.9
44.8
60.0
48.7
23.2
91.5
35.6
79.2
59.1
57.7
68.4
52.5
37.8
18.0
100
86.4
77.6
86.0
88.9
63.9
77.1
88.7
72.4
82.0
78.9
81.1
50.9
79.8
58.2
38.0
73.6
59.1
58.4
66.5
71.3
29.1
43.3
66.3
65.4
100
62.9
36.2
57.4
47.9
23.4
53.6
77.1
34.6
24.7
46.6
69.5
40.7
28.1
12.8
19.2
72.7
33.3
18.4
46.2
0.0
60.2
22.9
44.4
48.0
26.8
26.5
83.2
51.0
31.6
64.0
64.6
17.8
29.2
14.3
16.9
30.4
13.5
32.9
10.7
9.7
5A
5B
5C
5D
5E
5F
5G
5H
5I
Ph
2,4-Cl2Ph
2-ClPh
63.7
47.2
52.2
55.2
55.0
46.7
71.3
53.6
75.2
79.9
55.4
94.0
82.3
83.8
71.4
86.4
80.7
93.4
77.6
89.3
44.9
78.8
50.3
30.3
82.6
30.4
43.9
62.6
76.8
38.9
73.3
48.1
53.0
99.9
85.0
51.3
81.3
82.4
70.5
74.4
85.1
80.2
89.5
81.6
83.3
62.2
85.5
43.2
69.3
81.1
15.4
73.4
54.2
57.8
55.7
52.9
76.3
36.8
100
72.3
56.5
63.4
45.3
52.5
70.4
69.2
57.0
76.9
46.9
69.7
14.2
43.1
43.1
36.4
43.7
33.9
3.72
0.0
66.7
4.6
44.5
43.5
31.2
42.7
65.4
34.6
47.4
19.1
51.0
7.3
35.6
26.0
22.8
39.1
31.6
2.50
1.6
2-FPh
2-FPh
4-CF3Ph
4-CH3Ph
Ph, CH3
PhCH2
4-FPhCH2
4-OCH3PhCH2 45.3
2-ClPhCH2
morpholino
pyrrolidin-1-yl 39.7
isopropyl
Ph
2,4-Cl2Ph
2-ClPh
4-CH3Ph
Ph, CH3
PhCH2
4-FPhCH2
morpholino
pyrrolidin-1-yl
isopropyl
4-CF3Ph
4-CH3Ph
Ph, CH3
PhCH2
4-FPhCH2
4-OCH3PhCH2 52.5
2-ClPhCH2
morpholino
pyrrolidin-1-yl 63.4
isopropyl
Ph
2,4-Cl2Ph
2-ClPh
5j
5k
5l
5J
44.5
16.4
5K
5L
5M
5N
6A
6B
6C
6D
6E
6F
56.6
30.1
5m
5n
6a
6b
6c
6d
6e
6f
15.6
39.1
63.0
39.8
74.0
68.5
65.0
17.7
68.6
9.2
46.2
32.8
46.9
33.2
46.7
36.2
54.3
40.4
33.8
4-CH3Ph
Ph, CH3
PhCH2
4-FPhCH2
morpholino
31.7
28.7
0.0
0.0
10.6
100
19.8
10.9
17.6
12.1
38.4
100
6g
6h
6i
0.0
15.1
33.2
0.0
15.2
4.2
6G
6H
6I
38.7
19.9
8.4
pyrrolidin-1-yl 59.3
isopropyl
6j
22.6
100
6J
36.3
95.8
Carbendazim
81.0
Chlorothalonil
a
F. G: Fusahum graminearum, R. S: Rhizoctonia solani, A. S: Alternaria solani, S. S: Sclerotinia sclerotiorum, B. C: Botrytis cinerea. The data are the mean measurements were calculated
from the three replicates with 0 ˘ 5% errors.
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Molecules 2015, 20, 21023–21036
Table 2. The EC50 (µM) values with 95% confidential interval in parenthesis of compounds 5 and 6
against different phytopathgens for the compounds with more than 70% inhibition rates in Table 1.
Compd.
F. graminearum
R. solani
A. solani
S. sclerotiorum
B. cinerea
5a
5b
5c
5d
5e
-
-
-
-
26.1 (20.3–33.6)
-
33.9 (26.0–44.0)
19.2 (12.7–25.6)
-
19.8 (14.5–27.1)
51.0 (45.3–57.4)
28.6 (25.8–31.7)
39.8 (28.6–48.6)
-
-
-
-
-
-
-
-
202.7 (155.0–263.1)
11.9 (7.6–16.9)
-
-
5f
4.3 (3.2–5.8)
9.7 (25.1–56.2)
19.1 (13.9–26.1)
30.4 (24.5–37.6)
-
35.5 (25.2-44.4)
29.8 (24.1-32.9)
-
62.3 (44.9-86.6)
130.7 (92.1–185.1)
-
97.9 (88.3–108.4)
80.1 (56.4–113.4)
54.5 (35.6–73.5)
51.2 (42.5–55.5)
39.0 (29.5–51.4)
13.4 (11.6–15.5)
41.4 (26.8–63.6)
18.7 (12.6–27.6)
57.9 (38.9–76.7)
18.6 (14.9–20.8)
284.1(207.7–387.9)
31.6 (20.3–49.2)
-
37.6 (45.6–59.5)
27.2 (21.9–33.7)
27.6 (21.3-35.7)
32.8 (25.5–42.1)
27.8 (23.3–29.6)
41.3 (32.0–47.5)
50.3 (33.3–75.7)
43.4 (31.1–60.5)
-
189.4 (155.4–230.4)
14.0 (11.5–17.1)
62.6 (41.8–93.6)
26.0 (19.7–30.2)
22.9 (16.9–27.9)
42.6 (30.6–59.0)
35.9 (27.0–47.6)
21.2 (16.3–27.4)
17.1 (12.6–23.2)
31.1 (23.5–36.6)
32.0 (25.3–36.1)
63.8 (42.6–95.3)
43.4 (28.8–65.1)
667.3 (462.3–999.5)
-
-
-
5g
5h
5i
-
-
-
-
-
-
-
61.2 (44.5–101.2)
56.2 (38.2–82.6)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
5j
5k
5m
6b
6d
6f
5A
5C
5D
5E
5F
5G
5H
5I
-
21.6 (13.8–33.5)
57.4 (52.7–62.3)
-
-
-
-
-
-
-
-
-
-
92.9 (67.9–126.9)
-
-
-
23.2 (16.8–31.9)
125.2 (96.3–161.3)
-
38.8 (32.5–46.3)
40.7 (35.2–47.0)
5J
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
5K
5M
6B
6D
6F
6H
6I
>1000
677.8 (622.7–736.6)
-
-
83.8 (56.9–123.1)
Figure 1. Inhibition rates of 5a against A. solani at different concentrations.
3. Experimental Section
3.1. General Information
All reactions were performed with magnetic stirring. Unless otherwise stated, all reagents were
purchased from commercial suppliers and used without further purification. Organic solutions
were concentrated under reduced pressure using a rotary evaporator or oil pump. Melting points
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Molecules 2015, 20, 21023–21036
were measured on a Yanagimoto apparatus (Yanagimoto MFG Co., Kyoto, Japan) and uncorrected.
1H-NMR spectra were obtained on Bruker DPX 300 spectrometer (Bruker Biospin Co., Stuttgart,
Germany) with CDCl3 as a solvent and TMS as an internal standard. High-resolution mass spectral
analysis was performed on a LTQ Orbitrap instrument (ThermoFisher scientific Inc., Waltham,
MA, USA).
3.2. Synthesis
3.2.1. Synthesis of (Z/E)-3,7-Dimethyl-2,6-octadienal (2, Neral and Geranial)
According to the literature protocol [19,22], geraniol (8.0 g, 52 mmol), Dess-Martin Periodinane
(26.6 g, 63 mmol) and 320 mL DCM were added to a 500 mL three-necked flask at room temperature.
The mixture was stirred for 4 h at the room temperature. Then the mixture was filtered and the
filtrate was washed with saturated NaHCO3 solution, brine and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure. The residue was purified by column chromatography
using silica gel (petroleum ether/EtOAc 15:1) to give (E)-3,7-dimethyl-2,6-octadienal (7.9 g, 94%) as
a colorless oil; the (Z)-isomer (10.7 g, 88%) was also prepared as a colorless oil using nerol (12.3 g) as
starting material following the same procedure [26,27].
3.2.2. Synthesis of (Z/E)-3,7-Dimethyl-2,6-octadienoic Acid (3, Geranic Acid and Nerolic Acid)
According to the approaches in the literature [23], a solution of NaClO2 (22.0 g, 30 mmol)
and NaH2PO4¨ 2H2O (34.4 g, 22 mmol) in water was added dropwise to a solution of
(E)-3,7-dimethyl-2,6-octadienal (4.0 g, 22 mmol) and 2-methyl-2-butene in acetone (220 mL) at room
temperature and stirred for 4 h, the solution was extracted with ethyl acetate, and the organic
layer was washed with brine, dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by column chromatography using silica gel (petroleum
ether/EtOAc/CH3COOH 25:1:0.5) to afford (E)-3,7-dimethyl-2,6-octadienoic acid (4.0 g, 90%) as a
colorless oil; the (Z)-isomer (8.5 g, 86%) was also prepared as a colorless oil using (Z)-3,7-dimethyl-
2,6-octadienal (12.3 g) as the starting material following the same procedure [28].
3.2.3. General Procedure for the Synthesis of Compounds 5
Take compound 5a as an example: according to the procedure in the literature [22], SOCl2
(1.4 mL) was added to a solution of (E)-3,7-dimethyl-2,6-octadienoic acid (0.8 g, 5 mmol) in 40 mL
˝
DCM in a 100 mL flask at room temperature. The mixture was stirred and heated at 40 C for 4 h.
Then cool down to room temperature and remove the solvent under reduced pressure. The residue
was dissolved in 10 mL DCM, the 10 mL DCM solution of aniline (0.92 mL, 10 mmol) was added and
stirred for 10 h at room temperature. Quenched the reaction with water, extracted with DCM, and
the organic layer was washed with brine, dried over anhydrous Na2SO4. Removed the solvent under
reduced pressure and the residue was purified by column chromatography to afford compound 5a.
(E)-3,7-Dimethyl-N-phenyl-2,6-octadienamide (5a), grey oil, yield 79%. 1H-NMR (300 MHz, CDCl3) δ:
7.53 (d, J = 7.9 Hz, 2H, ArH), 7.34–7.29 (m, 2H, ArH), 7.11–7.06 (m, 2H, ArH + NH), 5.69 (s, 1H, =CH),
5.14–5.05 (m, 1H, =CH), 2.22 (d, J = 1.2 Hz, 3H, CH3), 2.17 (br.s, 4H, 2 ˆ CH2), 1.70 (s, 3H, CH3), 1.62
(s, 3H, CH3); HR-MS (ESI) m/z: C16H21NO [M + H]+, Calcd. 244.1696; Found 244.1693. The spectral
data were identical with those in the reference [29].
(E)-N-(2,4-Dichlorophenyl)-3,7-dimethyl-2,6-octadienamide (5b), pale yellow oil, yield 78%. 1H-NMR
(300 MHz, CDCl3) δ: 8.44 (d, J = 8.9 Hz, 1H, ArH), 7.50 (s, 1H, NH), 7.37 (d, J = 2.4 Hz, 1H, ArH), 7.24
(dd, J = 8.9, 2.4 Hz, 1H, ArH), 5.73 (s, 1H, =CH), 5.13–5.04 (m, 1H, =CH), 2.23 (d, J = 1.2 Hz, 3H, CH3),
2.20–2.18 (m, 4H, 2 ˆ CH2), 1.70 (s, 3H, CH3), 1.63 (s, 3H, CH3); HR-MS (ESI) m/z: C16H19Cl2NO
[M + H]+, Calcd. 312.0916; Found 312.0917.
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Molecules 2015, 20, 21023–21036
(E)-N-(2-Chlorophenyl)-3,7-dimethyl-2,6-octadienamide (5c), yellow oil, yield 69%. 1H-NMR (300 MHz,
CDCl3) δ: 8.45 (d, J = 8.1 Hz, 1H, ArH), 7.57 (s, 1H, NH), 7.35 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 7.30–7.23
(m, 1H, ArH), 7.04–6.98 (m, 1H, ArH), 5.75 (s, 1H, =CH), 5.14–5.04 (m, 1H, =CH), 2.23 (d, J = 1.2 Hz,
3H, CH3), 2.20 (br.s, 4H, 2 ˆ CH2), 1.71 (s, 3H, CH3), 1.64 (s, 3H, CH3); HR-MS (ESI) m/z: C16H20ClNO
[M + H]+, Calcd. 278.1306; Found 278.1303.
(E)-N-(2-Fluorophenyl)-3,7-dimethyl-2,6-octadienamide (5d), brown oil, yield 35%. 1H-NMR (300 MHz,
CDCl3) δ: 8.42–8.36 (m, 1H, ArH), 7.29 (s, 1H, NH), 7.15–6.99 (m, 3H, ArH), 5.73 (s, 1H, =CH),
5.16–5.09 (m, 1H, =CH), 2.23 (d, J = 1.2 Hz, 3H, CH3), 2.19 (br.s, 4H, 2 ˆ CH2),1.70 (s, 3H, CH3),
1.63 (s, 3H, CH3); HR-MS (ESI) m/z: C16H20FNO [M + H]+, Calcd. 262.1601; Found 262.1600.
(E)-N-(4-Trifluoromethylphenyl)-3,7-dimethyl-2,6-octadienamide (5e), yellow oil, yield 16%. 1H-NMR
(300 MHz, CDCl3) δ: 7.66 (d, J = 8.7 Hz, 2H, ArH), 7.55 (d, J = 8.7 Hz, 2H, ArH), 7.26 (s, 1H, NH), 5.70
(s, 1H, =CH), 5.15–5.08 (m, 1H, =CH), 2.23 (d, J = 1.2 Hz, 3H, CH3), 2.19 (br.s, 4H, 2 ˆ CH2), 1.70 (s, 3H,
CH3), 1.62 (s, 3H, CH3); HR-MS (ESI) m/z: C17H20F3NO [M + H]+, Calcd. 312.1569; Found 312.1568.
(E)-N-(4-Methylphenyl)-3,7-dimethyl-2,6-octadienamide (5f), brown oil, yield 74%. 1H-NMR (300 MHz,
CDCl3) δ: 7.42 (d, J = 7.5 Hz, 2H, ArH), 7.11 (d, J = 7.5 Hz, 3H, ArH + NH), 5.68 (s, 1H, =CH), 5.14–5.07
(m, 1H, =CH), 2.31 (s, 3H, ArCH3), 2.21 (d, J = 1.2 Hz, 3H, CH3), 2.18–2.15 (m, 4H, 2 ˆ CH2), 1.70 (s,
3H, CH3), 1.62 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO [M + H]+, Calcd. 258.1852; Found 258.1852.
1
(E)-N-Phenyl-N,3,7-trimethyl-2,6-octadienamide (5g), brown oil, yield 76%. H-NMR (300 MHz, CDCl3)
δ: 7.40–7.34 (m, 2H, ArH), 7.30–7.24 (m, 1H, ArH), 7.18–7.14 (m, 2H, ArH), 5.47 (br.s, 1H, =CH),
4.96–4.91 (m, 1H, =CH), 3.32 (s, 3H, NCH3), 2.10 (d, J = 1.2 Hz, 3H, CH3), 1.95 (br.s, 4H, 2 ˆ CH2),
1.63 (s, 3H, CH3), 1.51 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO [M + H]+, Calcd. 258.1852; Found
258.1850. The spectral data were identical with those in the reference [30].
(E)-N-Benzyl-3,7-dimethyl-2,6-octadienamide (5h), yellow oil, yield 71%. 1H-NMR (300 MHz, CDCl3)
δ: 7.36–7.25 (m, 5H, ArH), 5.66 (br.s, 1H, NH), 5.56 (s, 1H, =CH), 5.10–5.05 (m, 1H, =CH), 4.47 (d,
J = 6.0 Hz, 2H, ArCH2), 2.18 (d, J = 1.2 Hz, 3H, CH3), 2.14–2.08 (m, 4H, 2 ˆ CH2), 1.68 (s, 3H, CH3),
1.60 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO [M + H]+, Calcd. 258.1852; Found 258.1850. The
spectral data were identical with those in the reference [31].
(E)-N-(4-Fluorobenzyl)-3,7-dimethyl-2,6-octadienamide (5i), yellow oil, yield 73%. 1H-NMR (300 MHz,
CDCl3) δ: 7.30–7.23 (m, 2H, ArH), 7.05–6.98 (m, 2H, ArH), 5.64 (br.s, 1H, NH), 5.55 (s, 1H, =CH),
5.09–5.04 (m, 1H, =CH), 4.44 (d, J = 5.8 Hz, 2H, ArCH2), 2.18 (d, J = 1.2 Hz, 3H, CH3), 2.14–2.08 (m,
4H, 2 ˆ CH2), 1.68 (s, 3H, CH3), 1.60 (s, 3H, CH3); HR-MS (ESI) m/z: C17H22FNO [M + H]+: Calcd.
276.1758; Found 276.1754.
1
(E)-N-(4-Methoxybenzyl)-3,7-dimethyl-2,6-octadienamide (5j), yellow oil, yield 53%. H-NMR (300 MHz,
CDCl3) δ: 7.23 (d, J = 8.7 Hz, 2H, ArH), 6.86 (d, J = 8.7 Hz, 2H, ArH), 5.57 (s, 1H, NH), 5.53 (s, 1H, =CH),
5.08–5.05 (m, 1H, =CH), 4.41 (d, J = 6.0 Hz, 2H, ArCH2), 3.80 (s, 3H, OCH3), 2.17 (d, J = 1.2 Hz, 3H,
CH3), 2.13–2.08 (m, 4H, 2 ˆ CH2), 1.68 (s, 3H, CH3), 1.60 (s, 3H, CH3); HR-MS (ESI) m/z: C18H25NO2
[M + H]+: Calcd. 288.1958; Found 288.1954.
(E)-N-(2-Chlorobenzyl)-3,7-dimethyl-2,6-octadienamide (5k), yellow oil, 45%. 1H-NMR (300 MHz,
CDCl3) δ: 7.43–7.32 (m, 2H, ArH), 7.24–7.18 (m, 2H, ArH), 5.83 (s, 1H, NH), 5.57 (s, 1H, =CH),
5.08–5.04 (m, 1H, =CH), 4.55 (d, J = 6.0 Hz, 2H, CH2), 2.15 (d, J = 1.2 Hz, 3H, CH3), 2.11 (br.s, 4H,
2 ˆ CH2), 1.67 (s, 3H, CH3), 1.59 (s, 3H, CH3); HR-MS (ESI) m/z: C17H22ClNO [M + H]+: Calcd.
292.1462; Found 292.1460.
(E)-3,7-Dimethyl-1-morpholino-2,6-octadien-1-one (5l), yellow oil, yield 70%. 1H-NMR (300 MHz,
CDCl3) δ: 5.72 (s, 1H, =CH), 5.09–5.05 (m, 1H, =CH), 3.67 (br, 6H, 3 ˆ CH2), 3.50 (br, 2H, CH2),
21029

Molecules 2015, 20, 21023–21036
2.17–2.13 (m, 4H, 2 ˆ CH2), 1.88 (d, J = 1.2 Hz, 3H, CH3), 1.67 (s, 3H, CH3), 1.61 (s, 3H, CH3); HR-MS
(ESI) m/z: C14H23NO2 [M + H]+, Calcd. 238.1800; Found 238.1801.
(E)-3,7-Dimethyl-1-(pyrrolidin-1-yl)-2,6-octadien-1-one (5m), colorless oil, yield 61%. 1H-NMR (300 MHz,
CDCl3) δ: 5.77 (s, 1H, =CH), 5.10–5.07 (m, 1H, =CH), 3.50 (t, J = 6.6 Hz, 2H, NCH2), 3.42 (t, J = 6.6 Hz,
2H, NCH2), 2.18–2.12 (m, 4H, 2 ˆ CH2), 2.05 (d, J = 1.2 Hz, 3H, CH3), 1.95–1.83 (m, 4H, 2 ˆ CH2),
1.69 (s, 3H, CH3), 1.61 (s, 3H, CH3); HR-MS (ESI) m/z: C14H23NO [M + H]+, Calcd. 222.1852; Found
222.1849. The spectral data were identical with those in the reference [28].
1
(E)-N-Isopropyl-3,7-dimethyl-2,6-octadienamide (5n), yellow oil, yield 70%. H-NMR (300 MHz, CDCl3)
δ: 5.51 (s, 1H, =CH), 5.27 (br.s, 1H, NH), 5.11–5.05 (m, 1H, =CH), 4.15–4.08 (m, 1H, NCH), 2.14 (d,
J = 1.2 Hz, 3H, CH3), 2.12–2.06 (m, 4H, 2 ˆ CH2), 1.68 (s, 3H, CH3), 1.61 (s, 3H, CH3), 1.16 (d, J = 6.6 Hz,
6H, 2 ˆ CH3); HR-MS (ESI) m/z: C12H21NO [M + H]+, Calcd. 196.1696; Found 196.1694. The spectral
data were identical with those in the reference [29].
1
(Z)-N-Phenyl-3,7-dimethyl-2,6-octadienamide (5A), brown oil, yield 70%. H-NMR (300 MHz, CDCl3) δ:
7.52 (d, J = 7.8 Hz, 2H, ArH), 7.33–7.28 (m, 2H, ArH), 7.16 (s, 1H, NH), 7.11–7.06 (m, 1H, ArH), 5.70
(s, 1H, =CH), 5.22–5.16 (m, 1H, =CH), 2.70 (t, J = 7.8 Hz, 2H, CH2), 2.26–2.18 (m, 2H, CH2), 1.89 (d,
J = 1.2 Hz, 3H, CH3), 1.68 (s, 3H, CH3), 1.63 (s, 3H, CH3); HR-MS (ESI) m/z: C16H21NO [M + H]+,
Calcd. 244.1696; Found 244.1691. The spectral data were identical with those in the reference [29].
1
(Z)-N-(2,4-Dichlorophenyl)-3,7-dimethyl-2,6-octadienamide (5B), yellow oil, yield 65%. H-NMR (300 MHz,
CDCl3) δ: 8.43 (d, J = 8.7 Hz, 1H, ArH), 7.47 (s, 1H, NH), 7.37 (d, J = 2.4 Hz, 1H, ArH), 7.22 (dd, J = 8.7,
2.4 Hz, 1H, ArH), 5.73 (s, 1H, =CH), 5.18–5.14 (m, 1H, =CH), 2.71 (t, J = 7.5 Hz, 2H, CH2), 2.26–2.17
(m, 2H, CH2), 1.93 (d, J = 1.2 Hz, 3H, CH3), 1.67 (s, 3H, CH3), 1.63 (s, 3H, CH3); HR-MS (ESI) m/z:
C16H19Cl2NO [M + H]+, Calcd. 312.0916; Found 312.0915.
1
(Z)-N-(2-Chlorophenyl)-3,7-dimethyl-2,6-octadienamide (5C), brown oil, yield 67%. H-NMR (300 MHz,
CDCl3) δ: 8.44 (d, J = 8.0 Hz, 1H, ArH), 7.54 (s, 1H, NH), 7.34 (dd, J = 8.0, 1.5 Hz, 1H, ArH), 7.28–7.23
(m, 1H, ArH), 7.04–6.98 (m, 1H, ArH), 5.75 (s, 1H, =CH), 5.19–5.14 (m, 1H, CH), 2.72 (t, J = 7.5 Hz,
2H, CH2), 2.24–2.18 (m, 2H, CH2), 1.93 (d, J = 1.2 Hz, 3H, CH3), 1.68 (s, 3H, CH3), 1.63 (s, 3H, CH3);
HR-MS (ESI) m/z: C16H20ClNO [M + H]+, Calcd. 278.1306; Found 278.1304.
(Z)-N-(2-Fluorophenyl)-3,7-dimethyl-2,6-octadienamide (5D), brown oil, 15%. 1H-NMR (300 MHz,
CDCl3) δ: 8.43–8.36 (m, 1H, ArH), 7.26 (s, 1H, NH), 7.15–6.99 (m, 3H, ArH), 5.73 (s, 1H, =CH),
5.19–5.10 (m, 1H, =CH), 2.72 (t, J = 7.5 Hz, 2H, CH2), 2.24–2.17 (m, 2H, CH2), 1.92 (d, J = 1.2 Hz,
3H, CH3), 1.70 (s, 3H, CH3), 1.63 (s, 3H, CH3); HR-MS (ESI) m/z: C16H20FNO [M + H]+, Calcd.
262.1601; Found 262.1597.
(Z)-3,7-Dimethyl-N-(4-(trifluoromethyl)phenyl)octa-2,6-dienamide (5E), brown oil, yield 16%. 1H-NMR
(300 MHz, CDCl3) δ: 7.66 (d, J = 8.7 Hz, 2H, ArH), 7.55 (d, J = 8.7 Hz, 2H, ArH), 7.29 (s, 1H, NH), 5.71
(s, 1H, =CH), 5.19–5.11 (m, 1H, =CH), 2.71 (t, J = 7.5 Hz, 2H, CH2), 2.26–2.21 (m, 2H, CH2), 1.92 (d,
J = 1.2 Hz, 3H, CH3), 1.69 (s, 3H, CH3), 1.63 (s, 3H, CH3); HR-MS (ESI) m/z: C17H20F3NO [M + H]+,
Calcd. 312.1569; Found 312.1565.
1
(Z)-N-(4-Methylphenyl)-3,7-dimethyl-2,6-octadienamide (5F), brown oil, yield 60%. H-NMR (300 MHz,
CDCl3) δ: 7.40 (d, J = 7.8 Hz, 2H, ArH), 7.11 (d, J = 7.8 Hz, 2H, ArH), 7.07 (s, 1H, NH), 5.68 (s, 1H,
=CH), 5.20–5.16 (m, 1H, =CH), 2.69 (t, J = 7.5 Hz, 2H, CH2), 2.31 (s, 3H, CH3), 2.25–2.16 (m, 2H, CH2),
1.89 (d, J = 1.2 Hz, 3H, CH3), 1.68 (s, 3H, CH3), 1.62 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO
[M + H]+, Calcd. 258.1852; Found 258.1850.
(Z)-N-Phenyl-N,3,7-trimethyl-2,6-octadienamide (5G), brown oil, yield 67%. 1H-NMR (300 MHz, CDCl3)
δ: 7.40–7.34 (m, 2H, ArH), 7.30–7.24 (m, 1H, ArH), 7.18–7.14 (m, 2H, ArH), 5.46 (br.s, 1H, =CH),
5.22–5.16 (m, 1H, =CH), 3.31 (s, 3H, NCH3), 2.61 (t, J = 7.5 Hz, 2H, CH2), 2.22–2.14 (m, 2H, CH2), 1.70
21030

Molecules 2015, 20, 21023–21036
(d, J = 1.2 Hz, 3H, CH3), 1.67 (s, 3H, CH3), 1.64 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO [M + H]+,
Calcd. 258.1852; Found 258.1849. The spectral data were identical with those in the reference [31].
1
(Z)-N-Benzyl-3,7-dimethyl-2,6-octadienamide (5H), yellow oil, yield 57%. H-NMR (300 MHz, CDCl3) δ:
7.31–7.26 (m, 5H, ArH), 5.66 (br.s, 1H, NH), 5.58 (s, 1H, =CH), 5.18–5.12 (m, 1H, =CH), 4.47 (d, J = 6.0 Hz,
2H, ArCH2), 2.64 (t, J = 7.8 Hz, 2H, CH2), 2.22–2.18 (m, 2H, CH2), 1.84 (d, J = 1.2 Hz, 3H, CH3), 1.64 (s,
3H, CH3), 1.60 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO [M + H]+, Calcd. 258.1852; Found 258.1848.
The spectral data were identical with those in the reference [30].
(Z)-N-(4-Fluorobenzyl)-3,7-dimethyl-2,6-octadienamide (5I), brown oil, yield 72%. 1H-NMR (300 MHz,
CDCl3) δ: 7.29–7.23 (m, 2H, ArH), 7.03–6.97 (m, 2H, ArH), 5.71 (br.s, 1H, NH), 5.58 (s, 1H, =CH),
5.17–5.11 (m, 1H, =CH), 4.43 (d, J = 5.8 Hz, 2H, ArCH2), 2.64 (t, J = 7.2 Hz, 2H, CH2), 2.21–2.16 (m, 2H,
CH2), 1.84 (d, J = 1.2 Hz, 3H, CH3), 1.65 (s, 3H, CH3), 1.60 (s, 3H, CH3); HR-MS (ESI) m/z: C17H22FNO
[M + H]+: Calcd. 276.1758; Found 276.1754.
(Z)-N-(4-Methoxybenzyl)-3,7-dimethyl-2,6-octadienamide (5J), yellow oil, 27%. 1H-NMR (300 MHz,
CDCl3) δ: 7.20 (d, J = 8.4 Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz, 2H, ArH), 5.71 (s, 1H, NH), 5.56 (s, 1H,
=CH), 5.17–5.11 (m, 1H, =CH), 4.38 (d, J = 6.0 Hz, 2H, ArCH2), 3.79 (s, 3H, OCH3), 2.64 (t, J = 7.5 Hz,
2H, CH2), 2.21–2.13 (m, 2H, CH2), 1.83 (d, J = 1.2 Hz, 3H, CH3), 1.64 (s, 3H, CH3), 1.60 (s, 3H, CH3);
HR-MS (ESI) m/z: C18H25FNO2 [M + H]+: Calcd. 288.1958; Found 288.1955.
(Z)-N-(2-Chlorobenzyl)-3,7-dimethyl-2,6-octadienamide (5K), yellow oil, 40%. 1H-NMR (300 MHz,
CDCl3) δ: 7.40–7.33 (m, 2H, ArH), 7.24–7.19 (m, 2H, ArH), 5.90 (s, 1H, NH), 5.59 (s, 1H, =CH),
5.15–5.10 (m, 1H, =CH), 4.54 (d, J = 6.0 Hz, 2H, CH2), 2.63 (t, J = 7.5 Hz, 2H, CH2), 2.20–2.11 (m,
2H, CH2), 1.83 (d, J = 1.2 Hz, 3H, CH3), 1.64 (s, 3H, CH3), 1.59 (s, 3H, CH3); HR-MS (ESI) m/z:
C17H22ClNO [M + H]+: Calcd. 292.1462; Found 292.1461.
(Z)-3,7-Dimethyl-1-morpholino-2,6-octadien-1-one (5L), yellow oil, yield 60%. 1H-NMR (300 MHz,
CDCl3) δ: 5.74 (s, 1H, =CH), 5.13–5.07 (m, 1H, =CH), 3.66 (br, 6H, 3 ˆ CH2), 3.50 (br, 2H, CH2),
2.33 (t, J = 7.5 Hz, 2H, CH2), 2.18–2.10 (m, 2H, CH2), 1.83 (d, J = 1.2 Hz, 3H, CH3), 1.68 (s, 3H, CH3),
1.61 (s, 3H, CH3); HR-MS (ESI) m/z: C14H23NO2 [M + H]+, Calcd. 238.1802; Found 238.1800.
(Z)-3,7-Dimethyl-1-(pyrrolidin-1-yl)-2,6-octadien-1-one (5M), pale yellow oil, yield 65%. 1H-NMR
(300 MHz, CDCl3) δ: 5.77 (s, 1H, =CH), 5.18–5.11 (m, 1H, =CH), 3.49 (t, J = 6.9 Hz, 2H, NCH2),
3.42 (t, J = 6.9 Hz, 2H, NCH2), 2.53 (t, J = 7.5 Hz, 2H, CH2), 2.20–2.15 (m, 2H, CH2), 1.95–1.82 (m, 7H,
2 ˆ CH2 + CH3), 1.67 (s, 3H, CH3), 1.61 (s, 3H, CH3); HR-MS (ESI) m/z: C14H23NO [M + H]+, Calcd.
222.1852; Found 222.1850. The spectral data were identical with those in the reference [28].
1
(Z)-N-Isopropyl-3,7-dimethyl-2,6-octadienamide (5N), yellow oil, yield 62%. H-NMR (300 MHz, CDCl3)
δ: 5.51 (s, 1H, =CH), 5.27 (br.s, 1H, NH), 5.19–5.14 (m, 1H, =CH), 4.15–4.08 (m, 1H, NCH), 2.59 (t,
J = 7.2 Hz, 2H, CH2), 2.21–2.14 (m, 2H, CH2), 1.86 (d, J = 1.2 Hz, 3H, CH3), 1.69 (s, 3H, CH3), 1.62 (s,
3H, CH3), 1.16 (d, J = 6.6 Hz, 6H, 2 ˆ CH3); HR-MS (ESI) m/z: C12H21NO [M + H]+, Calcd. 196.1696;
Found 196.1694. The spectral data were identical with those in the reference [28].
3.2.4. General Procedure for the Synthesis of Compounds 6
Take compound 6a as an example: according to the approach in the literature [25,32], compound
5a 0.24 g (1 mmol), CH3COOOH (2 mL), Na2CO3 (0.7 g) and DCM (10 mL) were added to a 50 mL
flask and stirred at room temperature for 2–4 h, quenched the reaction with water, and extracted with
DCM. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was
removed under reduce pressure, and the residue was purified by column chromatography to give the
compounds 6a.
(E)-N-Phenyl-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6a), yellow solid, yield 80%. m.p.
˝
82–84 C, 1H-NMR (300 MHz, CDCl3) δ: 7.54 (d, J = 7.8 Hz, 2H, ArH), 7.29 (t, J = 7.8 Hz, 2H, ArH),
7.21 (s, 1H, NH), 7.09 (t, J = 7.8 Hz, 1H, ArH), 5.76 (s, 1H, =CH), 2.74 (dd, J = 5.1, 7.2Hz, 1H, OCH),
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Molecules 2015, 20, 21023–21036
2.36–2.25 (m, 2H, CH2), 2.24 (d, J = 1.2 Hz, 3H, CH3), 1.78–1.66 (m, 2H, CH2), 1.33 (s, 3H, CH3), 1.29
(s, 3H, CH3); HR-MS (ESI) m/z: C16H21NO2 [M + H]+, Calcd. 260.1645; Found 260.1643.
(E)-N-(2,4-Dichlorophenyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6b), yellow oil, yield
1
63%. H-NMR (300 MHz, CDCl3) δ: 8.42 (d, J = 8.7 Hz, 1H, ArH), 7.53 (s, 1H, NH), 7.26 (d, J = 2.4 Hz,
1H, ArH), 7.24 (dd, J = 8.7, 2.4 Hz, 1H, ArH), 5.80 (s, 1H, =CH), 2.74 (dd, J = 7.2, 5.1 Hz, 1H, OCH),
2.40–2.30 (m, 2H, CH2), 2.25 (d, J = 1.2 Hz, 3H, CH3), 1.82–1.66 (m, 2H, CH2), 1.33 (s, 3H, CH3), 1.30
(s, 3H, CH3); HR-MS (ESI) m/z: C16H19Cl2NO2 [M + H]+, Calcd. 328.0866; Found 328.0864.
(E)-N-(2-Chlorophenyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6c), yellow oil, yield 80%.
1H-NMR (300 MHz, CDCl3) δ: 8.44 (d, J = 7.8 Hz, 1H, ArH), 7.59 (s, 1H, NH), 7.36 (dd, J = 7.8,
1.8 Hz, 1H, ArH), 7.30–7.23 (m, 1H, ArH), 7.05–6.99 (m, 1H, ArH), 5.81 (s, 1H, =CH), 2.74 (dd, J = 7.2,
5.4 Hz, 1H, OCH), 2.40–2.29 (m, 2H, CH2), 2.25 (d, J = 1.2 Hz, 3H, CH3), 1.82–1.67 (m, 2H, CH2), 1.33
(s, 3H, CH3), 1.30 (s, 3H, CH3); HR-MS (ESI) m/z: C16H20ClNO2 [M + H]+, Calcd. 294.1255; Found
294.1257.
(E)-N-(4-Methylphenyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6d), colorless oil, yield 75%.
1H-NMR (300 MHz, CDCl3) δ: 7.42 (d, J = 7.8 Hz, 2H, ArH), 7.11 (d, J = 7.8 Hz„ 3H, ArH + NH), 5.74
(s, 1H, =CH), 2.74 (dd, J = 7.2, 5.1 Hz, 1H, OCH), 2.35–2.25 (m, 5H, CH2 + CH3), 2.23 (d, J = 1.2 Hz,
3H, CH3), 1.80–1.64 (m, 2H, CH2), 1.32 (s, 3H, CH3), 1.29 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO2
[M + H]+, Calcd. 274.1802; Found 274.1798.
(E)-N-Phenyl-5-(3,3-dimethyloxiran-2-yl)-N,3-dimethylpent-2-enamide (6e), yellow oil, yield 96%.
1H-NMR (300 MHz, CDCl3) δ: 7.40–7.33 (m, 2H, ArH), 7.31–7.25 (m, 1H, ArH), 7.17–7.13 (m, 2H,
ArH), 5.51 (br.s, 1H, =CH), 3.32 (s, 3H, CH3), 2.55 (t, J = 6.3 Hz, 1H, OCH), 2.11 (d, J = 1.2 Hz, 3H,
CH3), 2.08–2.03 (m, 2H, CH2),1.53–1.45 (m, 2H, CH2), 1.25 (s, 3H, CH3), 1.18 (s, 3H, CH3); HR-MS
(ESI) m/z: C17H23NO2 [M + H]+, Calcd. 274.1802; Found 274.1792.
(E)-N-Benzyl-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6f), yellow oil, yield 80%. 1H-NMR
(300 MHz, CDCl3) δ: 7.36–7.25 (m, 5H, ArH), 5.68 (br.s, 1H, NH), 5.62 (s, 1H, =CH), 4.47 (d, J = 6.0 Hz,
2H, ArCH2), 2.71 (dd, J = 7.2, 5.4 Hz, 1H, OCH), 2.30–2.22 (m, 2H, CH2), 2.20 (d, J = 1.2 Hz, 3H, CH3),
1.75–1.62 (m, 2H, CH2), 1.32 (s, 3H, CH3), 1.26 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO2 [M + H]+,
Calcd. 274.1802; Found 274.1799.
(E)-N-(4-Fluorobenzyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6g), white solid, yield 84%.
˝
m.p. 50–52 C, 1H-NMR (300 MHz, CDCl3) δ: 7.29–7.23 (m, 2H, ArH), 7.04–6.97 (m, 2H, ArH), 5.76
(br.s, 1H, NH), 5.62 (s, 1H, =CH), 4.43 (d, J = 5.8 Hz, 2H, ArCH2), 2.71 (dd, J = 7.2, 5.1 Hz, 1H, OCH),
2.30–2.19 (m, 5H, CH2 + CH3), 1.76–1.62 (m, 2H, CH2), 1.30 (s, 3H, CH3), 1.26 (s, 3H, CH3); HR-MS
(ESI) m/z: C17H22FNO2 [M + H]+, Calcd. 292.1707; Found 292.1706.
(E)-5-(3,3-Dimethyloxiran-2-yl)-3-methyl-1-morpholinopent-2-en-1-one (6h), pale yellow oil, yield 71%.
1H-NMR (300 MHz, CDCl3) δ: 5.81 (s, 1H, =CH), 3.67 (br, 6H, 3 ˆ CH2), 3.51 (br, 2H, CH2), 2.71
(dd, J = 7.2, 5.1 Hz, 1H, OCH), 2.32–2.23 (m, 2H, CH2), 1.92 (d, J = 1.2 Hz, 3H, CH3), 1.81–1.63 (m, 2H,
CH2), 1.31 (s, 3H, CH3), 1.25 (s, 3H, CH3); HR-MS (ESI) m/z: C14H23NO3 [M + H]+, Calcd. 254.1751;
Found 254.1747.
(E)-5-(3,3-Dimethyloxiran-2-yl)-3-methyl-1-(pyrrolidin-1-yl)pent-2-en-1-one (6i), yellow oil, yield 70%.
1H-NMR (300 MHz, CDCl3) δ: 5.84 (s, 1H, =CH), 3.50 (t, J = 6.6 Hz, 2H, NCH2), 3.43 (t, J = 6.6 Hz,
2H, NCH2), 2.72 (dd, J = 6.9, 5.7 Hz, 1H, OCH), 2.32–2.22 (m, 2H, CH2), 2.09 (d, J = 1.2 Hz,
3H, CH3), 1.96–1.65 (m, 6H, 3 ˆ CH2), 1.31 (s, 3H, CH3), 1.28 (s, 3H, CH3); HR-MS (ESI) m/z:
C14H23NO2 [M + H]+, Calcd. 238.1802; Found 238.1799.
1
(E)-N-Isopropyl-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6j), yellow oil, yield 79%. H-NMR
(300 MHz, CDCl3) δ: 5.55 (s, 1H, =CH), 5.24 (br.s, 1H, NH), 4.16–4.08 (m, 1H, NCH), 2.72 (dd, J = 7.0,
5.4 Hz, 1H, OCH), 2.29–2.14 (m, 5H, CH2 + CH3), 1.76–1.62 (m, 2H, CH2), 1.31 (s, 3H, CH3), 1.27 (s,
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Molecules 2015, 20, 21023–21036
3H, CH3), 1.16 (d, J = 6.5 Hz, 6H, 2 ˆ CH3); HR-MS (ESI) m/z: C13H24NO2 [M + H]+, Calcd. 226.1807;
Found 226.1799.
(Z)-N-Phenyl-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6A), brown oil, yield 80%. 1H-NMR
(300 MHz, CDCl3) δ: 7.62 (s, 1H, NH), 7.54 (d, J = 7.5 Hz, 2H, ArH), 7.33–7.26 (m, 2H, ArH), 7.10–7.04
(m, 1H, ArH), 5.76 (s, 1H, =CH), 2.95–2.60 (m, 3H, OCH + CH2), 1.89 (d, J = 1.2 Hz, 3H, CH3), 1.82–1.72
(m, 2H, CH2), 1.30 (s, 3H, CH3), 1.29 (s, 3H, CH3); HR-MS (ESI) m/z: C16H21NO2 [M + H]+, Calcd.
260.1645; Found 260.1641.
(Z)-N-(2,4-Dichlorophenyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6B), pale yellow oil,
yield 68%. 1H-NMR (300 MHz, CDCl3) δ: 8.37 (d, J = 8.7 Hz, 1H, ArH), 7.57 (s, 1H, NH), 7.35 (d,
J = 2.1 Hz, 1H, ArH), 7.21 (dd, J = 8.7, 2.1 Hz, 1H, ArH), 5.79 (s, 1H, =CH), 2.98–2.73 (m, 3H,
OCH + CH2), 1.93 (d, J = 1.2 Hz, 3H, CH3), 1.82–1.74 (m, 2H, CH2), 1.30 (s, 3H, CH3), 1.29 (s, 3H,
CH3); HR-MS (ESI) m/z: C16H19Cl2NO2 [M + H]+, Calcd. 328.0866; Found 328.0865.
(Z)-N-(2-Chlorophenyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6C), yellow oil, yield 76%.
1H-NMR (300 MHz, CDCl3) δ: 8.42 (d, J = 8.4 Hz, 1H, ArH), 7.57 (s, 1H, NH), 7.36 (dd, J = 7.8,
1.5 Hz, 1H, ArH), 7.30–7.24 (m, 1H, ArH), 7.06–6.99 (m, 1H, ArH), 5.80 (s, 1H, =CH), 2.98–2.74 (m,
3H, OCH + CH2), 1.96 (d, J = 1.2 Hz, 3H, CH3), 1.83–1.75 (m, 2H, CH2), 1.30 (s, 6H, 2 ˆ CH3); HR-MS
(ESI) m/z: C16H20ClNO2 [M + H]+, Calcd. 294.1255; Found 294.1255.
(Z)-N-(4-Methylphenyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6D), brown oil, yield 69%.
1H-NMR (300 MHz, CDCl3) δ: 7.92 (s, 1H, NH), 7.43 (d, J = 8.1 Hz, 2H, ArH), 7.07 (d, J = 8.1 Hz, 2H,
ArH), 5.75 (s, 1H, =CH), 2.94–2.70 (m, 3H, OCH + CH2), 2.28 (s, 3H, CH3), 1.86 (d, J = 1.2 Hz, 3H,
CH3), 1.83–1.71 (m, 2H, CH2), 1.28 (s, 3H, CH3), 1.27 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO2
[M + H]+, Calcd. 274.1802; Found 274.1798.
(Z)-N-Phenyl-5-(3,3-dimethyloxiran-2-yl)-N,3-dimethylpent-2-enamide (6E), brown oil, yield 65%.
1H-NMR (300 MHz, CDCl3) δ: 7.41–7.35 (m, 2H, ArH), 7.31–7.28 (m, 1H, ArH), 7.18–7.14 (m, 2H,
ArH), 5.51 (s, 1H, =CH), 3.31 (s, 3H, NCH3), 2.87–2.65 (m, 3H, OCH + CH2), 1.77–1.70 (m, 5H,
CH2 + CH3), 1.32 (s, 3H, CH3), 1.30 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO2 [M + H]+, Calcd.
274.1801; Found 274.1794.
(Z)-N-Benzyl-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6F), yellow oil, yield 71%. 1H-NMR
(300 MHz, CDCl3) δ: 7.35–7.26 (m, 5H, ArH), 5.78 (br.s, 1H, NH), 5.61 (s, 1H, =CH), 4.46 (d, J = 6.0 Hz,
2H, ArCH2), 2.92–2.70 (m, 3H, OCH + CH2), 1.86 (d, J = 1.2 Hz, 3H, CH3), 1.78–1.69 (m, 2H, CH2),
1.28 (s, 3H, CH3), 1.27 (s, 3H, CH3); HR-MS (ESI) m/z: C17H23NO2 [M + H]+, Calcd. 274.1802; Found
274.1800.
(Z)-N-(4-Fluorobenzyl)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6G), yellow oil, yield 72%.
1H-NMR (300 MHz, CDCl3) δ: 7.29–7.21 (m, 2H, ArH), 7.02–6.96 (m, 2H, ArH), 6.09 (br.s, 1H, NH),
5.62 (s, 1H, =CH), 4.40 (d, J = 5.8 Hz, 2H, ArCH2), 2.93–2.66 (m, 3H, OCH + CH2), 1.85 (d, J = 1.2 Hz,
3H, CH3), 1.77–1.68 (m, 2H, CH2), 1.27 (s, 3H, CH3), 1.26 (s, 3H, CH3); HR-MS (ESI) m/z: C17H22FNO2
[M + H]+, Calcd. 292.1707; Found 292.1707.
(Z)-5-(3,3-Dimethyloxiran-2-yl)-3-methyl-1-morpholinopent-2-en-1-one (6H), yellow oil, yield 64%.
1H-NMR (300 MHz, CDCl3) δ: 5.82 (s, 1H, =CH), 3.66 (br, 6H, 3 ˆ CH2), 3.51 (br, 2H, CH2), 2.76
(t, J = 6.3 Hz, 1H, OCH), 2.49 (t, J = 7.8 Hz, 2H, CH2), 1.87 (d, J = 1.2 Hz, 3H, CH3), 1.75–1.68 (m, 2H,
CH2), 1.30 (s, 3H, CH3), 1.28 (s, 3H, CH3); HR-MS (ESI) m/z: C14H23NO3 [M + H]+, Calcd. 254.1751;
Found 254.1747.
(Z)-5-(3,3-Dimethyloxiran-2-yl)-3-methyl-1-(pyrrolidin-1-yl)pent-2-en-1-one (6I), yellow oil, yield 65%.
1H-NMR (300 MHz, CDCl3) δ: 5.84 (s, 1H, =CH), 3.51 (t, J = 6.6 Hz, 2H, NCH2), 3.44 (t, J = 6.6 Hz,
2H, NCH2), 2.72 (t, J = 6.3 Hz, 1H, OCH), 2.27–2.21 (m, 2H, CH2), 1.86 (d, J = 1.2 Hz, 3H, CH3),
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Molecules 2015, 20, 21023–21036
1.71–1.65 (m, 6H, 3 ˆ CH2), 1.31 (s, 3H, CH3), 1.28 (s, 3H, CH3); HR-MS (ESI) m/z: C14H23NO2
[M + H]+, Calcd. 238.1802; Found 238.1801.
1
(Z)-N-Isopropyl-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enamide (6J), yellow oil, yield 79%. H-NMR
(300 MHz, CDCl3) δ: 5.55 (s, 1H, =CH), 5.35 (br.s, 1H, NH), 4.14–4.06 (m, 1H, NCH), 2.90–2.63 (m,
3H, OCH + CH2), 1.84 (d, J = 1.2 Hz, 3H, CH3), 1.82–1.70 (m, 2H, CH2), 1.38 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 1.15 (d, J = 6.5 Hz, 6H, 2 ˆ CH3); HR-MS (ESI) m/z: C13H24NO2 [M + H]+, Calcd. 226.1807;
Found 226.1797.
3.3. Bioassay of Fungicidal Activity
The preliminary fungicidal activities of compounds 5–6 against F. graminearum, R. solani,
A. solani, S. sclerotiorum, and B. cinerea were evaluated using methods in the references [33–37] by
˝
the mycelium growth rate [38]. The culture was incubated at 25 ˘ 0.5 C. Procedure for inhibition
rate: The stock 2000 mg/L DMSO solution of tested compounds were prepared in advance. Then hot
PDA culture medium was added into a plate, added sample solution or blank DMSO to the plate and
mix with PDA culture medium, made the final concentration as desired. When plate was made, put a
˝
5 mm diameter fungus cake into the center of plate, incubated them at 25 ˘ 0.5 C for 24–48 h, checked
the growth status and calculated the inhibition rate according to the reference. Three replicates were
performed and the mean measurements were calculated from the three replicates for each compound.
The EC50 values were determined from the inhibition rates of five different concentrations
based on the statistics method of [39] for the compounds that had more than 70% inhibition rates.
Procedure for EC50 determination: the inhibition rates of compounds against different fungus at five
concentrations were evaluated as before. Toxicity regression equations were obtained by statistics
analysis and the EC50 values (µM) were calculated from the regression equations with excel program.
Carbendazim and Chlorothalonil were used as positive control in the mycelium growth rate test.
4. Conclusions
(Z/E)-3,7-dimethyl-2,6-octadienamide derivatives and their 6,7-epoxy analogues were
synthesized in moderate to excellent yields in four steps with the commercially available
nerol/geraniol as raw materials. All the compounds were characterized by HR-ESI-MS and
1H-NMR spectral data. The preliminary bioassays showed that some of these compounds, such as
5C, 5I and 6b exhibit 94.0%, 93.4% and 91.5% inhibition rates against R. solani at the concentration
of 50 µg/mL, respectively. The EC50 values of compounds 5f and 5G were 9.7 and 13.4 µM against
R. solani, respectively, while compound 5f had EC50 value of 4.3 µM against F. graminearum. Further
syntheses and structure optimization studies on the replacement of aromatic and aliphatic amines
with nitrogen-containing heterocyclic amines are in progress in our laboratory.
Acknowledgments: This project was co-founded by the National Natural Science Foundation of China
(No. 21172254) and the 12th Five-year National Key Technologies R & D Program of China (No. 2011BAE06B04).
Author Contributions: M. Yang and H. Dong synthesized all of new compounds; J. Jiang ran the bioassay
evaluation and statistics analysis; M. Yang drafted the paper; and M. Wang started the project, designed the
molecules and revised the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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