Synthesis and antinematodal activity of 3-n-alkylphenols

Article abstract of DOI:10.1271/bbb.68.2398

Several 3-alkylphenols including 3-undecylphenol, which was isolated from a Sumatran rainforest plant, were synthesized to investigate their antinematodal activity against the phytopathogenic nematodes, Bursapherencus xylophilus. A three-step synthesis involving the treatment of 2-cyclohexen-1-one with the Grignard reagent, oxidation of the resulting 1-alkyl-2-cyclohexen-1-ol and subsequent aromatization of 3-alkyl-2-cyclohexen-1-one successfully afforded such phenols. Among the 3-alkylphenols, 3-nonylphenol showed the highest activity, while 3-decylphenol and 3-undecylphenol also showed high activity.

Full text of DOI:10.1271/bbb.68.2398

Bioscience, Biotechnology, and Biochemistry
ISSN: 0916-8451 (Print) 1347-6947 (Online) Journal homepage: http://www.tandfonline.com/loi/tbbb20
Synthesis and Antinematodal Activity of 3-n-
Alkylphenols
Kazuto TAKAISHI, Yohannes ALEN, Kazuyoshi KAWAZU, Naomichi BABA &
Shuhei NAKAJIMA
To cite this article: Kazuto TAKAISHI, Yohannes ALEN, Kazuyoshi KAWAZU, Naomichi BABA &
Shuhei NAKAJIMA (2004) Synthesis and Antinematodal Activity of 3-n-Alkylphenols, Bioscience,
Biotechnology, and Biochemistry, 68:11, 2398-2400, DOI: 10.1271/bbb.68.2398
To link to this article: http://dx.doi.org/10.1271/bbb.68.2398
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Date: 05 November 2015, At: 13:30

Biosci. Biotechnol. Biochem., 68 (11), 2398–2400, 2004
Note
Synthesis and Antinematodal Activity of 3-n-Alkylphenols
Kazuto TAKAISHI,1 Yohannes ALEN,2 Kazuyoshi KAWAZU,2
y
2;
Naomichi BABA,2 and Shuhei NAKAJIMA
1The Graduate School of Natural Science and Technology, Laboratory of Natural Product Chemistry,
Okayama University, Tsushimanaka 3-1-1, Okayama 700-8530, Japan
2Faculty of Agriculture, Okayama University, Tsushimanaka 1-1-1, Okayama 700-8530, Japan
Received May 21, 2004; Accepted July 20, 2004
Several 3-alkylphenols including 3-undecylphenol,
which was isolated from a Sumatran rainforest plant,
were synthesized to investigate their antinematodal
activity against the phytopathogenic nematodes, Bursa-
pherencus xylophilus. A three-step synthesis involving
the treatment of 2-cyclohexen-1-one with the Grignard
reagent, oxidation of the resulting 1-alkyl-2-cyclohexen-
1-ol and subsequent aromatization of 3-alkyl-2-cyclo-
hexen-1-one successfully afforded such phenols. Among
the 3-alkylphenols, 3-nonylphenol showed the highest
activity, while 3-decylphenol and 3-undecylphenol also
showed high activity.
the related 3-alkylphenols to investigate their activity.
We describe in this paper a synthesis of 3-alkylphenols
and their antinematodal activity.
The Scheme illustrates the synthesis of 3-alkylphenols
4a–4g. We used a series of three reactions, the Grignard
reaction,4) oxidation4) and aromatization,5) for the prep-
aration of the desired 3-alkylphenol. For example, 3-
heptylphenol (4a) was synthesized by coupling 2-cyclo-
hexen-1-one with the Grignard reagent, heptylmagnesi-
um bromide (1a), at ꢀ78 ꢁC in tetrahydrofuran (THF) to
give 1-heptyl-2-cyclohexen-1-ol (2a, 42%). The oxida-
tion reaction of 2a in dichloromethane at room temper-
ature was then carried out over the CrO3–pyridine
complex (Collins reagent) in order to prepare 3-heptyl-2-
cyclohexen-1-one (3a, 20%). Finally, aromatization of
3a in the presence of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) in toluene under reflux gave 4a
(19%). Aromatization of 3-alkyl-2-cyclohexen-1-one by
DDQ is a new approach for the synthesis of 3-alkyl-
phenol and resulted in a suitable yield of 3-alkylphenol,
although aromatization of 3a by palladium-activated
charcoal (10%) was not fruitful. The overall yield of 4a
was 1.6% from 2-cyclohexen-1-one. All reactions were
carried out in an atmosphere of nitrogen while contin-
uously stirring. The phenols, 4b–4g, were also synthe-
sized by the same procedure with the suitable Grignard
reagent, and there was no significant difference in the
yield of each reaction to 4a–4g.
Key words: 3-alkylphenols; Bursapherencus xylophilus;
antinematodal activity; 3-nonylphenol; 3-
undecylphenol
The previous paper proposed a convenient screening
method for antinematodal activity against the phytopa-
thogenic nematodes, Bursapherencus xylophilus.1) We
found by this method that 3-undecylphenol from Knema
hookeriana, a Sumatran rainforest plant, had pronounced
activity with a minimum effective dose (MED) of
4.5 ꢀg/cotton ball (ꢀg/bl.)2,3) and might be effective
for controlling this nematode. We were interested in
investigating the structure-activity relationship, and
especially whether the length of the alkyl side-chain
affected the activity or not. However, it was difficult to
obtain some 3-alkylphenols with different length of the
alkyl side-chain, including 3-undecylphenol, because
most of them are not commercially available. Conse-
quently, we planned to synthesize 3-undecylphenol and
The antinematodal bioassay previously reported1) was
used with some modifications. The effect was estimated
by observing whether the mycelia were consumed by the
nematode or not, and is respectively denoted by the sign
Scheme 1. Synthetic Route to 3-Alkylphenols.
y
To whom correspondence should be addressed. Tel/Fax: +81-86-251-8302; E-mail: snaka24@cc.okayama-u.ac.jp
Abbreviations: MED, minimum effective dose; g/bl., g/cotton ball; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

Antinematodal 3-Alkylphenols
Table 1. Antinematodal Activity of 3-Alkylphenols
2399
sulfuric acid spray reagent. 3-Methylphenol (m-cresol,
Nacalai Tesque), 3-ethylphenol (Tokyo Kasei Kogyo
Co., Ltd.) and 3-pentadecylphenol (Tokyo Kasei Kogyo
Co., Ltd.) were commercially available.
Antinematodal bioassay. The bioassay previously
reported by Kawazu et al.1) was used with some
modifications: the cultivation temperature of the mycelia
was 21 ꢁC and incubation period for the nematodes was
96 h.
Dose (ꢀg/bl.)
Minimum effective
dose (MED) ꢀg/bl.
2.5 1.25
Compound
R
20 10
5
1-Heptyl-2-cyclohexen-1-ol (2a). Heptylmagnesium
bromide (1a) was obtained by the reaction of heptyl
bromide (14.3 g) and magnesium (10.0 g), using the
usual method. To a stirred and dry ice-acetone-cooled
solution of 1a in THF (50 ml) was added cyclohexen-1-
one (3.0 g). The mixture was warmed and stirred for 12 h
at room temperature, before adding a 10% NH4Cl
aqueous solution (150 ml). The mixture was filtered, and
the resulting filtrate was extracted with n-hexane
(200 ml ꢃ 3), before the n-hexane extract was dried
with anhydrous magnesium sulfate and concentrated in
vacuo. The residue was chromatographed on silica gel
(eluting with n-hexane–EtOAc (19:1, v/v)) to give 2a
(2.15 g, 42%) as a colorless oil; EIMS m=z (rel. int. %):
196 (Mþ, 4), 179 (3), 153 (6), 111 (5), 98 (48), 97 (100),
methyl
ethyl
ꢀ
ꢀ
ꢂ
ꢂ
þ
þ
þ
þ
þ
ꢂ
ꢀ
ꢀ
ꢂ
ꢀ
þ
þ
þ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂ
ꢂ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
n.a.
n.a.
10
20
2.5
5
4a
4b
4c
4d
4e
4f
heptyl
octyl
nonyl
decyl
undecyl
dodecyl
tridecyl
pentadecyl
5
20
20
20
4g
n.a., no activity.
þ or ꢀ. When only part of the mycelia was consumed
because of the weak activity of a test material, this is
denoted by the sign ꢂ. Based on the authors’ experi-
ence, the highest dose of 3-alkylphenols was 20 ꢀg/bl.,
and assay was done to obtain MED values by the serial
dilution method. The values are each defined as the
lowest dose of the test compound to show activity.
The result of the antinematodal bioassay for the
activity of the synthesized alkylphenols and commer-
cially available 3-methyl, 3-ethyl and 3-pentadecylphe-
nol is shown in Table 1. Among them, 3-nonylphenol
showed the highest activity (MED ¼ 2:5 ꢀg/bl.). Both
methyl and ethyl analogues were not active, even at the
highest dose of 20 ꢀg/bl. In addition, 3-decylphenol and
3-undecylphenol also showed considerably high activity
(MED ¼ 5 ꢀg/bl.). While the phenols bearing a longer
alkyl side-chain than the undecyl group exhibited only
weak activity. These results indicate that suitable length
of the alkyl group may be necessary for antinematodal
activity against B. xylophilus, and a further study on
other biological activities of these compounds is under-
way.
1
79 (25), 67 (12), 55 (26), 41 (72); H-NMR ꢁ (CDCl3):
0.86 (3H, t, J ¼ 7:0 Hz), 1.20–1.35 (8H, m), 1.52 (4H,
m), 1.63 (4H, m), 1.97 (2H, m), 5.58 (1H, br d, J ¼
10:0 Hz), 5.75 (1H, ddd, J ¼ 3:0, 3.0, 10.5 Hz); 13C-
NMR ꢁ (CDCl3): 14.5 (–CH3), 19.4 (–CH2–), 23.0
(–CH2–), 23.9 (–CH2–), 25.6 (–CH2–), 26.7 (–CH2–),
30.5 (–CH2–), 32.2 (–CH2–), 35.7 (–CH2–), 42.7
(–CH2–), 129.7 (–CH=), 133.1 (–C=).
3-Heptyl-2-cyclohexen-1-one (3a). 2a (1.0 g) was
added to the CrO3–pyridine complex (Collins reagent,
9.1 g) in dichloromethane (100 ml) and stirred for 12 h at
room temperature. To the mixture was added dry ether
(50 ml), and the solution filtered through Celite. The
filtrate was concentrated in vacuo, and the residue was
chromatographed on silica gel (eluting with n-hexane–
EtOAc (10:1, v/v)) to give 3a (197 mg, 20%) as a
colorless oil; EIMS m=z (rel. int. %): 194 (Mþ, 10), 151
(4), 137 (4), 124 (22), 123 (53), 110 (78), 95 (67), 82
1
(100), 67 (31), 55 (32), 41 (48); H-NMR ꢁ (CDCl3):
0.84 (3H, t, J ¼ 7:0), 1.23–1.27 (8H, m), 1.46 (2H, m),
1.95 (2H, m), 2.17 (2H, t, J ¼ 5:0), 2.25 (2H, t,
J ¼ 3:5), 2.32 (2H, t, J ¼ 3:5), 5.83 (1H, s); 13C-NMR ꢁ
(CDCl3): 14.3 (–CH3), 22.8 (–CH2–), 22.9 (–CH2–),
27.1 (–CH2–), 29.3 (–CH2–), 29.4 (–CH2–), 29.9
(–CH2–), 31.9 (–CH2–), 37.6 (–CH2–), 38.2 (–CH2–),
125.8 (–C=), 167.0 (–CH=), 200.2 (–C=O).
3-Heptylphenol (4a). 3a (150 mg) in toluene (10 ml)
was added to 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ, 180 mg), and the mixture refluxed for 2
days while continuously stirring. The mixture was
filtered through Celite and then concentrated in vacuo.
The residue was purified by preparative thin-layer
chromatography (developed by n-hexane–EtOAc (8:2,
v/v)) to give 4a (22.8 mg, 19%) as a colorless oil; EIMS
Experimental
1
General. H- and 13C-NMR spectra were recorded by
a Varian VXR-500 instrument at 500 MHz and 125 MHz,
respectively. EIMS data were measured by a Jeol HX-
110 instrument, and GC-MS data by an Automass 20
coupled with an HP 5980 instrument, using a DB-1
capillary column (0:32 mm ꢃ 30 m). Column chroma-
tography (CC) was carried out on silica gel 60 (Nacalai
Tesque, 230–400 mesh), thin-layer chromatography
(TLC) was on silica gel 60 F254 plates (Merck Art.
1.05554., 0.25 mm), and preparative thin-layer chroma-
tography (PTLC) was on silica gel 60 F254 plates (Merck
Art. 1.13895, 1 mm). Spots and bands were detected by
UV irradiation (254 nm) or by a sulfuric acid or vanillin

2400
K. TAKAISHI et al.
m=z (rel. int. %): 192 (Mþ, 51), 149 (8), 121 (23), 108
(100), 107 (97), 91 (12), 77 (31), 55 (10), 43 (18),
29.5 (–CH2–), 29.6 (–CH2–), 29.6 (–CH2–), 29.7
(–CH2–), 29.7 (–CH2–), 31.3 (–CH2–), 31.9 (–CH2–),
35.8 (–CH2–), 112.4 (–CH=), 115.3 (–CH=), 120.9
(–CH=), 129.3 (–CH=), 145.0 (–C=), 155.4 (–C=).
3-Dodecylphenol (4f). Colorless oil (7.7% overall
yield); EIMS m=z (rel. int. %): 262 (Mþ, 71), 149 (15),
121 (33), 109 (38), 108 (100), 107 (100), 91 (11), 77
(31), 55 (18), 43 (33), 41 (37); 1H-NMR ꢁ (CDCl3): 0.88
(3H, t, J ¼ 7:0 Hz), 1.26–1.30 (18H, m), 1.59 (2H, m),
2.55 (2H, t, J ¼ 8 Hz), 4.67 (1H, br s), 6.64 (1H, br dd,
J ¼ 8, 2.5 Hz), 6.66 (1H, br m), 6.75 (1H, br d,
J ¼ 8 Hz), 7.13 (1H, t, J ¼ 8 Hz); 13C-NMR ꢁ (CDCl3):
14.4 (–CH3), 22.9 (–CH2–), 29.6 (–CH2–), 29.6
(–CH2–), 29.8 (–CH2–), 29.9 (–CH2–), 29.9 (–CH2–),
29.9 (–CH2–), 29.9 (–CH2–), 31.2 (–CH2–), 32.2
(–CH2–), 36.1 (–CH2–) 112.7 (–CH=), 115.5 (–CH=),
121.2 (–CH=), 129.6 (–CH=), 145.2 (–C=), 155.6
(–C=).
3-Tridecylphenol (4g). Colorless oil (5.7% overall
yield); EIMS m=z (rel. int. %): 276 (Mþ, 51), 149 (14),
121 (37), 109 (48), 108 (82), 107 (100), 77 (21), 55 (18),
43 (38), 41(37); 1H-NMR ꢁ (CDCl3): 0.88 (3H, t,
J ¼ 7:0 Hz), 1.25–1.36 (18H, m), 1.60 (2H, m), 2.56
(2H, t, J ¼ 8 Hz), 4.67 (1H, br s), 6.64 (1H, br dd, J ¼ 8,
2.5 Hz), 6.67 (1H, br m), 6.76 (1H, br d, J ¼ 8 Hz),
7.14 (1H, t, J ¼ 8 Hz); 13C-NMR ꢁ (CDCl3): 14.7
(–CH3), 23.2 (–CH2–), 29.9 (–CH2–), 29.9 (–CH2–),
29.9 (–CH2–), 30.0 (–CH2–), 30.0 (–CH2–), 30.0
(–CH2–), 30.0 (–CH2–), 30.0 (–CH2–), 31.9 (–CH2–),
32.5 (–CH2–), 36.4 (–CH2–), 112.9 (–CH=), 115.7
(–CH=), 121.3 (–CH=), 129.8 (–CH=), 145.3 (–C=),
155.7 (–C=).
1
41(18); H-NMR ꢁ (CDCl3): 0.88 (3H, t, J ¼ 7:0 Hz),
1.25–1.33 (8H, m), 1.59 (2H, m), 2.55 (2H, t), 4.63 (1H,
br s), 6.64 (1H, br dd, J ¼ 8, 2.5 Hz), 6.66 (1H, br m),
6.76 (1H, br d, J ¼ 8 Hz), 7.14 (1H, t, J ¼ 8 Hz);
13C-NMR ꢁ (CDCl3): 14.3 (–CH3), 22.9 (–CH2–), 29.4
(–CH2–), 29.5 (–CH2–), 31.5 (–CH2–), 32.0 (–CH2–),
36.1 (–CH2–), 112.7 (–CH=), 115.5 (–CH=), 121.2
(–CH=), 129.6 (–CH=), 145.2 (–C=), 155.6 (–C=).
4b–4g were each synthesized in a similar manner to
that for 4a, using the appropriate Grignard reagent.
3-Octylphenol (4b). Colorless oil (2.7% overall yield);
EIMS m=z (rel. int. %): 206 (Mþ, 70), 149 (10), 121
(51), 108 (100), 107 (97), 91 (17), 77 (48), 55 (19), 43
(33), 41(52); 1H-NMR ꢁ (CDCl3): 0.90 (3H, t, J ¼
7:0 Hz), 1.28–1.33 (8H, m), 1.60 (2H, m), 2.56 (2H, t),
5.31 (1H, br s), 6.67 (1H, br dd, J ¼ 8, 2.5 Hz), 6.69
(1H, br m), 6.78 (1H, br d, J ¼ 8 Hz), 7.16 (1H, t,
J ¼ 8 Hz); 13C-NMR ꢁ (CDCl3): 14.4 (–CH3), 23.0
(–CH2–), 29.5 (–CH2–), 29.6 (–CH2–), 29.7 (–CH2–),
31.6 (–CH2–), 32.2 (–CH2–), 36.1 (–CH2–), 112.8
(–CH=), 115.6 (–CH=), 121.3 (–CH=), 129.6
(–CH=), 145.3 (–C=), 155.6 (–C=).
3-Nonylphenol (4c). Colorless oil (4.1% overall
yield); EIMS m=z (rel. int. %): 220 (Mþ, 100), 149
(19), 121 (71), 108 (82), 107 (83), 91 (45), 77 (98), 55
1
(35), 43 (71), 41(96); H-NMR ꢁ (CDCl3): 0.88 (3H, t,
J ¼ 7:0 Hz), 1.25–1.31 (12H, m), 1.59 (2H, m), 2.55
(2H, t, J ¼ 8), 4.66 (1H, br s), 6.64 (1H, br dd, J ¼ 8,
2.5 Hz), 6.66 (1H, br m), 6.75 (1H, br d, J ¼ 8 Hz), 7.14
(1H, t, J ¼ 8 Hz); 13C-NMR ꢁ (CDCl3): 14.4 (–CH3),
22.9 (–CH2–), 29.6 (–CH2–), 29.6 (–CH2–), 29.8
(–CH2–), 29.8 (–CH2–), 31.2 (–CH2–), 32.1 (–CH2–),
36.1 (–CH2–), 112.7 (–CH=), 115.5 (–CH=), 121.2
(–CH=), 129.6 (–CH=), 145.2 (–C=), 155.6 (–C=).
3-Decylphenol (4d). Colorless oil (5.7% overall
yield); EIMS m=z (rel. int. %): 234 (Mþ, 29), 149 (5),
121 (15), 108 (100), 107 (71), 91 (7), 77 (21), 43 (16),
Acknowledgments
We thank to The SC-NMR Laboratory of Okayama
University for 500 MHz NMR experiments and The MS
Laboratory of Faculty of Agriculture at Okayama
University for the GCEIMS measurements.
1
41 (20); H-NMR ꢁ (CDCl3): 0.88 (3H, t, J ¼ 7:0 Hz),
References
1.22–1.35 (14H, m), 1.61 (2H, m), 2.55 (2H, t, J ¼
8 Hz), 4.72 (1H, br s), 6.64 (1H, br dd, J ¼ 8, 2.5 Hz),
6.66 (1H, br m), 6.75 (1H, br d, J ¼ 8 Hz), 7.13 (1H,
t, J ¼ 8 Hz); 13C-NMR ꢁ (CDCl3): 14.4 (–CH3), 22.9
(–CH2–), 29.6 (–CH2–), 29.6 (–CH2–), 29.8 (–CH2–),
29.9 (–CH2–), 29.9 (–CH2–), 31.2 (–CH2–), 32.2
(–CH2–), 36.1 (–CH2–), 112.7 (–CH=), 115.6
(–CH=), 121.2 (–CH=), 129.6 (–CH=), 145.2 (–C=),
155.6 (–C=).
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convenient screening method for nematicidal activity.
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55c, 300–303 (2000).
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Kawazu, K., Antinematodal activity of some tropical
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Bursaphelenchus xylophilus. Z. Naturforsch., 55c, 295–
299 (2000).
4) Shoji, H., Sonoda, S., and Takehara, H., Japan Kokai
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3-Undecylphenol (4e). Colorless oil (2.3% overall
yield); EIMS m=z (rel. int. %): 248 (Mþ, 11), 121 (8),
108 (100), 107 (30), 77 (12), 43 (25); 1H-NMR ꢁ
(CDCl3): 0.88 (3H, t, J ¼ 7:0 Hz), 1.20–1.35 (16H, m),
1.60 (2H, m), 2.55 (2H, t, J ¼ 8 Hz), 4.63 (1H, br s),
6.64 (1H, br dd, J ¼ 8, 2.5 Hz), 6.66 (1H, br m), 6.75
(1H, br d, J ¼ 8 Hz), 7.13 (1H, t, J ¼ 8 Hz); 13C-NMR ꢁ
(CDCl3): 14.1 (–CH3), 22.7 (–CH2–), 29.3 (–CH2–),