The synthesis and fungicidal activity of 2-substituted 1-azol-1-ylmethyl-6-arylidenecyclohexanols

Article abstract of DOI:10.1002/(SICI)1096-9063(199702)49:2<125::AID-PS506>3.0.CO;2-0

A number of substituted 2,2-dimethyl-6-arylidene-1-triazol-lylmethylcyclohexanols and 2,2-dimethyl-6-arylidene-1-imidazol-1-ylmethylcyclohexanols were prepared from 2-methylcyclohexanone in four steps: Claisen-Schmidt condensation with substituted benzald

Full text of DOI:10.1002/(SICI)1096-9063(199702)49:2<125::AID-PS506>3.0.CO;2-0

Pestic. Sci. 1997, 49, 125È129
The Synthesis and Fungicidal Activity of
2-Substituted 1-Azol-1-ylmethyl-6-
arylidenecyclohexanols
Sergey V. Popkov,a* Leonid V. Kovalenko,a Mikhail M. Bobylev,b Oleg Yu.
Molchanov,b Miron Z. Krimer,c Valery P. Tashchib & Yury G. Putsykinb
a Department of Chemical Technology of Organic Synthesis, D. Mendeleyev University of Chemical
Technology of Russia, 9, Miusskaya pl., 125047, Moscow, Russia
b Research Institute of Plant Protecting Chemicals, 33, Ugreshskaya ul., 109088, Moscow, Russia
c Institute of Chemistry, Academy of Sciences of Moldova, 3, Academicheskaya ul., 277028 Kishinev,
Moldova
(Received 21 July 1995; revised version received 6 February 1996; accepted 17 September 1996)
Abstract:
A
number of substituted 2,2-dimethyl-6-arylidene-1-triazol-1-
ylmethylcyclohexanols and 2,2-dimethyl-6-arylidene-1-imidazol-1-ylmethylcyclo-
hexanols were prepared from 2-methylcyclohexanone in four steps: ClaisenÈ
Schmidt condensation with substituted benzaldehydes, methylation of the
resulting 2-methyl-6-benzylidenecyclohexanones, conversion to the oxiranes by
interaction with dimethylsulfonium methylide and reaction of the oxiranes with
triazole or imidazole. The compounds obtained were tested for antifungal activ-
ity against Ðve phytopathogenic fungi of di†erent taxonomic classes. EC values
50
were determined for all compounds. StructureÈactivity relationships are dis-
cussed in broad terms. Some of triazolymethyl-substituted cyclohexanols
obtained are more active than triadimenol.
Key words: 2,2-dimethyl-6-arylidenecyclohexanones, 8-arylidene-4,4-dimethyl-1-
oxaspiro[2.5]octane, 2-substituted 6-arylidene-1-azolylmethyl-cyclohexanols,
azole fungicides, lanosterol, structureÈactivity relationship.
1
INTRODUCTION
compounds to this important element of the lanosterol
structure.
The biochemical site of action of the fungicidal azoles is
the oxidative transformation of lanosterol by the P-450
mixed function oxidase in fungal cells. This haem
protein binds tetracyclic steroid molecules, inserting one
oxygen atom into a CH bond of the C-14 methyl
group.1,2 Inhibitors of lanosterol oxidation must Ðt into
the target site of the enzyme in a similar way to the
natural substrate, which contains a gem-dimethylated
cyclohexanol fragment, and it is likely that the high
antifungal activity of triadimenol or tebuconazole is
based on the similarity of tert-butyl groups in these
2
EXPERIMENTAL
2.1 Synthetic methods
The synthetic routes employed are outlined in Fig. 1
and a list of the compounds obtained appears in Table
1. The 2-substituted-6-arylidenecyclohexanones (2) were
prepared by condensation of substituted cyclohexanones
with di†erent aromatic aldehydes, according to the
* To whom correspondence should be addressed.
125
Pestic. Sci. 0031-613X/97/$09.00 ( 1997 SCI. Printed in Great Britain

126
Sergey V . Popkov et al.
Fig. 1. Synthetic routes to 2-substituted-1-azolylmethyl-6-arylidenecyclohexanol.
ClaisenÈSchmidtreaction.32-Benzylidenecyclohexanones
were prepared in two steps: reaction of 1-trimethylsilyl-
oxycyclohexene with substituted benzaldehydes in the
presence of titanium tetrachloride followed by dehydra-
tion of the corresponding aldols with p-toluenesulfonic
acid in reÑuxing benzene.4 Spiro[4.5]decan-5-one was
prepared by rearrangement of the corresponding
pinacol. This was formed by reduction of cyclo-
pentanone with aluminium amalgam in benzene.5
The 2-methyl-6-arylidenecyclohexanones (2) were
methylated with methyl iodide in the presence of pot-
assium tert-butoxide in good yields. The cyclo-
hexanones (2 and 3) were transformed to oxiranes (4)
using the CoreyÈChaykovsky reaction.6,7 The substi-
tuted 1-azolylmethyl-6-arylidenecyclohexanols (5È32)
were produced by interaction between oxiranes (4) and
1,2,4-triazole or imidazole.8h10 Our research group per-
formed this investigation at the same time, but indepen-
dently from a French group.11
Representative syntheses are described below. Start-
ing materials were obtained from commercial suppliers
and were used without further puriÐcation. Organic sol-
vents were dried over 4 Ó molecular sieves prior to use.
Infrared spectra were recorded in liquid Ðlm or pot-
assium bromide discs in a Specord Model M-80 infra-
red spectrometer. NMR spectra were recorded in
hexadeuteroacetone or in deuterochloroform on a
Varian XL-400 spectrometer at 400 MHz. For all com-
pounds the infrared and NMR spectra were in agree-
ment with the expected structure.
The following sequential procedure for the prep-
aration of compound 18 is typical.
2.1.1 2-(4-Chlorobenzylidene)-6-methylcyclohexanone (2)
A mixture of 2-methylcyclohexanone (50 g, 0É45 mol), 4-
chlorobenzaldehyde (75É3 g, 0É53 mol) and methanol
(110 ml) was stirred for 15 min, after which time
aqueous potassium hydroxide (150 g litre~1, 75 ml) was
added dropwise. The mixture was reÑuxed for 2 h and,
after cooling, extracted with chloroform (2 ] 50 ml) and
washed three times with water (3 ] 40 ml). After drying
over magnesium sulfate and evaporation of the solvents
under vacuum, the liquid residues were distilled at
reduced pressure (144È150¡C/0É01 mm Hg) and rec-
rystallized from isopropanol to furnish 2-(4-chloro-
benzylidene)-6-methylcyclohexane as pale yellow
needles (67É3 g, 65%), m.p. 63È64¡C. d(deuteroacetone):
1É13 (3H, d, J \ 6É7 Hz, CH ), 1É87È3É04 (7H, series of
3
m, CH cyclohex.), 7É26 (1H, t, J \ 6É2 Hz, CH \ C),
7É48 (4H, s, ArH). IR (potassium bromide disc)
1670 cm~1 (C \ 0), 1580 cm~1 (CH \ C).
2.1.2 2,2-Dimethyl-6-(4-chlorobenzylidene)cyclo-
hexanone (3)
The
2-(4-chlorobenzylidene)-6-methylcyclohexanone
(17É5 g, 75 mmol) was added to the solution of pot-
assium tert-butoxide prepared from potassium (10 g,
0É23 mol) and tert-butyl alcohol (250 ml) in an argon
atmosphere. The mixture was stirred at room tem-

Fungicidal activity of substituted azolylmethylcyclohexanols
TABLE 1
127
Characteristics of 2-Substituted-6-arylidene-1-azolylmethylcyclohexa-
nols
Compound
R1 a
R2 a
CH
R3 a
Za
m.p., (¡C)
5
6
CH
3
C H
N
CH
N
CH
N
CH
N
N
CH
N
CH
N
N
N
CH
N
N
CH
N
N
N
CH
N
CH
N
144È5
161È2
134È5
162È4
164È5
145È7
157È9
162È3
158È9
162È3
139È40
Oil
128È30
183È4
142È3
214È6
206È7
164È5
Oil
3
3
3
3
3
3
3
3
3
3
3
6
C H
6
5
CH
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
H
5
7
CH
3
3-CH C H
3 6
4
4
8
CH
3
3-CH C H
3 6
9
CH
3
4-iPrC H
6
4-iPrC H
6
4
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
CH
3
CH
3
4-t-BuC H
6
4
CH
3
2-FC H
6
6
4
4
4
4
CH
3
2-FC H
CH
3
4-FC H
6
4-FC H
6
CH
3
H
4-ClC H
6
4
4
4
4
4
4
4
CH
H
4-ClC H
4-ClC H
4-ClC H
4-ClC H
3
6
CH
3
CH
CH
3
3
6
CH
3
6
w(CH ) w
2 4
6
CH
CH
H
CH O
4-ClC H
3
3
3
CH O
3
6
4-ClC H
6
H
2,4-Cl C H
2 6
3
3
3
3
3
3
CH
CH
CH
H
2,4-Cl C H
2 6
143È4
182È3
121È2
202È5
212È3
Oil
3
3
3
CH
2,4-Cl C H
2 6
3
CH
3
2,4-Cl C H
2 6
w(CH ) w
2,4-Cl C H
2 6
2 4
w(CH ) w
2,4-Cl C H
2 4
2 6
H
H
4-BrC H
6
4-BrC H
6
4
4
CH
CH
N
191È3
3
3
3
3
31
CH
CH
N
N
118È20
126È7
32
CH
CH
3
3
a See Fig. 1.
perature until solution of the ketone was complete
(about 15 min), cooled in an ice-salt bath and methyl
iodide (62 g, 0É42 mol) was added dropwise. The
mixture was stirred under reÑux for 1É5 h and the
solvent was removed under reduced pressure. Water
was added and the crystalline residue was Ðltered o†
and washed with water. The Ðne crystalline precipitate
was dried and puriÐed by recrystallization from isopro-
iodide (8É6 g, 43 mmol) and dimethylsulfoxide (19 ml)
was stirred under argon. After cooling, the solution of
potassium tert-butoxide (4É3 g, 38 mmol); (prepared
from 1É5 g, 38 mmol of potassium and 30 ml of tert-
butyl alcohol) in dimethylsulfoxide (19 ml) was added
and stirring was continued for 15 min. The mixture was
cooled in ice-salt bath and then water (90 ml) was
added over a period of about 15 min. The mixture was
stirred for several minutes and then the ice-salt bath
was removed and stirring went on for 30 min. The pro-
ducts were extracted with diethyl ether (2 ] 30 ml),
washed with water and dried over magnesium sulfate.
After evaporation of the solvent, the solid residue was
recrystallized from isooctane to give 8-(4-chlorobenzyli-
dene)-4,4-dimethyl-1-oxaspiro[2.5]octane as colourless
needles (6É42 g, 81%), m.p. 66È67¡C. d(deuteroacetone):
0É85 (3H, s, CH ), 0É95 (3H, s, CH ), 1É57È2É86 (6H,
panol.
2,2-Dimethyl-6-(4-chlorobenzylidene)cyclo-
hexanone was obtained as yellowish crystals (17É5 g,
95%), m.p. 95È96¡C. d(deuteroacetone): 1É11 (6H, s,
CH ) gem.), 1É72È2É85 (6H, series of m, (CH ) cyclo-
3 2
2 3
hex.), 7É19 (1H, t, J \ 2É3 Hz, CH \ C), 7É37 (4H, s,
ArH). IR (potassium bromide disc) 1685 cm~1 (C \ O),
1625 cm~1 (CH \ C).
2.1.3 8-(4-Chlorobenzylidene)-4,4-dimethyl-
1-oxaspiro[2.5]octane (4)
The mixture of 2,2-dimethyl-6-(4-chlorobenzylidene)
cyclohexanone (7É5 g, 30 mmol), trimethylsulfonium
3
3
series of m, (CH ) cyclohex.), 2É44È2É99 (2H, AB
2 3
system, J \ 5É4 Hz, CH O), 6É44 (1H, t, CH \ C), 7É21È
2

128
Sergey V . Popkov et al.
TABLE 2
(3H, s, CH ), 1É15 (3H, s, CH ), 1É43È2É64 (6H, series of
3
3
Fungicidal Activity of 6-Substituted-2-arylidene-1-azolyl-
methylcyclohexanols
m, (CH ) cyclohex.), 4É19 (1H, s, OH), 4É28È4É97 (2H,
2 3
AB system, J \ 14É3 Hz, CH N), 6É19 (1H, s, CH \ C),
2
6É83È7É81 (4H, AB system, J \ 8É3 Hz, ArH), 7É70 (1H,
s, \ CH-N), 8É21 (1H, s, \ CH-N). IR (potassium
bromide disc) 3200 cm~1 (OH), 1650 cm~1 (CH \ C).
Compound
EC (mg litre~1)
50
Sc. sc.a
F. ga
Rh. s.a
H. s.a
V. i.a
5
2É5
12É7
1É6
10É7
9É0
36É6
16É0
4É6
16É7
1É5
0É40
14É7
0É39
11É0
15É3
33É4
32É7
3É1
2É4
4É6
2É4
3É9
25É5
3É2
20É3
20É8
23É5
50É0
1É7
3É1
1É2
3É2
1É5
0É15
0É64
2É4
2É4
34É9
16É6
22É7
2É3
1É8
2É9
2É7
21É2
0É62
11É7
17É6
15É1
18É6
1É9
10É0
0É94
5É9
3É9
4É4
0É90
2É0
4É9
14É3
13É1
40É3
1É6
3É7
5É0
12É5
5É0
1É1
6
2.3 Biological assays
7
8
3É9
The compounds were tested for fungicidal activity on
Sclerotinia sclerotiorum (Lib.) deBary, Fusarium gramin-
earum Schwabe, Rhizoctonia solani Kuhn. Helmintho-
sporium sativum Pammel, King & Bakke and V enturia
inaequalis Wint. The e†ect of the chemicals on mycelial
radial growth was determined by dissolving them at
various concentrations in acetone, and suspending ali-
quots in potato-glucose agar (PGA) at 50¡C to give the
required series of concentrations (0É1È150 mg ml~1).
The Ðnal acetone concentration of both fungicide-
containing and control samples was 10 ml litre~1. Petri
dishes containing 10 ml of the agar medium were inocu-
lated by placing 6-mm fungus-coated discs upside down
on the agar surface. Plates were incubated at 25¡C and
9
10É6
11É5
9É5
3É3
2É9
2É3
3É8
3É5
3É8
1É0
4É6
46É3
5É7
11É5
7É1
5É2
5É0
19É2
11É7
19É2
4É0
10
11
12
13
5É4
0É95
14
15
8É9
3É6
1É3
0É47
2É4
3É9
5É3
3É2
9É2
9É5
16
\1É0
0É46
0É79
14É9
9É7
5É2
38É2
4É6
17
18
19
20
21
22
23
radial growth was measured after three days. The EC
was calculated for each fungicide.
24
3É8
5É7
10É0
50
25
5É3
21É6
16É1
21É6
0É09
0É25
18É3
0É15
77É6
26
15É7
19É4
13É5
0É68
3É9
9É9
0É82
21É9
27
6É4
2É9
28
29
0É30
0É61
23É2
0É16
59É0
3
RESULTS
30
1É9
8É5
2É3
104É5
0É55
22É4
0É40
31É5
31
32
The results of the tests are given in Table 2. Most
compounds showed good activity. Triazolylmethyl-
cyclohexanols appear to be more potent than imidazole
analogues.
Triadimenol
a Sc. sc.ÈSc. sclerotiorum; F. g.ÈF. graminearum; Rh. s.ÈR.
solani; H. s.ÈH. sativum; V. i.ÈV . inaequalis.
7É33 (4H, AB system, J \ 8É4 Hz, ArH). IR (potassium
bromide disc) 1590 cm~1 (CH \ C), 850 cm~1
(oxirane).
4 DISCUSSION
The substituted azolylmethylcyclohexanols prepared
showed strong activity on Ðve fungi. Examination of
Table 2 shows that fungicidal activity depends strongly
on both the arylidene fragment in the 6-position and the
groups in the 2-position of the cyclohexanol. Products
7, 14, 16–19, 29, 30 and 32 showed very good activity
against all the tested fungi. 12 and 25 were active on H.
sativum, and 12 and 24 inhibited mycelial growth of V .
inaequalis signiÐcantly. From this classiÐcation, certain
structureÈactivity relationships can be deduced.
Comparison of the structures of lanosterol and 2-
substituted 6-arylidene-1-azolylmethylcyclohexanols by
computer modelling12 in Fig. 2 suggests that the benzyl-
idene fragment of our compounds models the A-ring of
lanosterol. On the other hand, the gem-dimethyl group
in the 2-position of cyclohexanol is similar to the fork of
the C-13 atom of the sterol, so that the cyclohexanol
2.1.4 T ypical procedure for synthesis of compounds
5È32
The mixture of 8-(4-chlorobenzylidene)-4,4-dimethyl-1-
oxaspiro[2.5]octane (6É2 g, 24 mmol), 1,2,4-triazole
(1É63 g, 24 mmol) and N-methylpyrrolidone (10 ml) was
stirred, heated to about 80¡C and sodium hydroxide
(0É32 g, 8 mmol) and water (0É08 ml, 4É4 mmol) was
added. The reaction mixture was heated at about 120¡C
in an oil bath, and stirring continued for 4 h. After
cooling, the mixture was poured into water (50 ml).
The precipitate was Ðltered o†, washed with water,
dried and puriÐed by crystallization from ethanol.
6-(4-Chlorobenzylidene)-1-(1,2,4-triazol-1-ylmethyl)-2,2-
dimethylcyclohexanol was obtained as colourless prisms
(4É9 g, 62%), m.p. 183È184¡C. d(deuteroacetone): 0É99

Fungicidal activity of substituted azolylmethylcyclohexanols
129
Fig. 2. Comparison of the structures of Compound 18 and lanosterol.
ring can perhaps occupy a similar position as the
D-ring of lanosterol. This suggested arrangement of the
2-substituted-6-arylidene-1-azolylmethylcyclohexanol in
the active site of P-450 oxidase supports the explana-
tion of the inhibition of sterol biosynthesis by inter-
action of triazole ring with the active centre of the
enzyme. Inspection of the overlay suggests that at least
one methyl in the 2-position of the cyclohexanol is
required for good overlap with the methyl on the 13-
carbon (and therefore for good activity), but that a
second methyl may not be necessary. This is supported
by comparison of the activities of 16, 17 and 18. The
activity of the monomethyl compound 17 is approx-
imately the same as that of the gem-dimethyl compound
16. However, the picture is confused by 19, which lacks
any methyls, but which is at least as active as its gem-
dimethyl analogue 30. Clearly more work will be
needed to understand these structureÈactivity relation-
ships fully. When the gem-dimethyl group was replaced
with a tetramethylene chain, as in 20, the activity was
greatly reduced, probably because of the steric hin-
drance of this structural unit. Replacement of the
methyl group in 18 by a methoxy group (21) caused a
great reduction of fungicidal activity.
The inÑuence of the benzylidene group on C6 of the
azolylmethylcyclohexanol is not so obvious. In general,
compounds with a single halogen substituent in the 4-
position are very active, e.g. 14, 18 and 30, while addi-
tion of a second halogen in the 2-position reduces
activity. A bulky alkyl group in the 4-position also
reduces activity. This trend can be explained in a
number of ways. For example, the spatial disposition of
the halogen atom in the 4-position of the azolyl-
methylcyclohexanols coincides with the electronegative
hydroxyl group of C-3 of lanosterol. The 3-methyl com-
pound is surprisingly active. This anomalously high
activity can be rationalized by the similarity of the 3-
methylbenzylidene fragment to the C-4 methyl group in
lanosterol. The corresponding 4-methyl compound was
not available for comparison.
ity of our compounds on the fungi tested can be
explained by the similarity between lanosterol and the
substituted azolylcyclohexanols. These compounds will
be further studied as potential fungicides.
ACKNOWLEDGEMENT
The authors thank L. Ya. Bogelfer for carrying out
NMR spectra measurements.
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