Rationally designed guanidine and amidine fungicides

Article abstract of DOI:10.1002/(SICI)1096-9063(199707)50:3<258::AID-PS587>3.0.CO;2-3

A previous investigation established that compounds containing a guanidinium or amidinium grouping are effective inhibitors of sterol Δ⁸-Δ⁷ isomerase and/or Δ¹⁴ reductase activity in plant pathogenic fungi. A binding model for known fungicidal inhibitors of this enzyme has now been used to rationally design further guanidinium or amidinium inhibitors. Three novel classes of chemistry were investigated. The results of biochemical testing against ergosterol biosynthesis in Ustilago maydis (DC) Corda and of in-vivo testing for fungicidal activity against Erysiphe graminis DC f. sp. hordei Marchal (powdery mildew of barley), do much to support the binding model, and compounds with significant fungicidal activity have been found.

Full text of DOI:10.1002/(SICI)1096-9063(199707)50:3<258::AID-PS587>3.0.CO;2-3

Pestic. Sci. 1997, 50, 258È274
Rationally Designed Guanidine and Amidine
Fungicides
John W. Liebeschuetz,* Ruth B. Katz,” Albert D. Duriatti° & Mary L. Arnold
DowElanco Europe Ltd, Letcombe Regis, Wantage, Oxon OX12 9JT, UK
(Received 21 February 1996; revised version received 21 November 1996; accepted 26 March 1997)
Abstract: A previous investigation established that compounds containing a gua-
nidinium or amidinium grouping are e†ective inhibitors of sterol *8È*7 isom-
erase and/or *14 reductase activity in plant pathogenic fungi. A binding model
for known fungicidal inhibitors of this enzyme has now been used to rationally
design further guanidinium or amidinium inhibitors. Three novel classes of
chemistry were investigated. The results of biochemical testing against ergosterol
biosynthesis in Ustilago maydis (DC) Corda and of in-vivo testing for fungicidal
activity against Erysiphe graminis DC f. sp. hordei Marchal (powdery mildew of
barley), do much to support the binding model, and compounds with signiÐcant
fungicidal activity have been found.
Pestic Sci., 50, 258È274, 1997
No. of Figures: 15; No. of Tables: 7; No. of Refs: 16
Key words: ergosterol biosynthesis, carbocation mimetic, fungicide, cereal patho-
gen
1
INTRODUCTION
ago maydis (DC) Corda, the *14 reductase and *8È*7
isomerase.1 The reaction mechanisms of both these
enzymes are thought to involve a carbocation as a high
energy intermediate or transition state. The
morpholine/piperidine fungicides are at least partially
protonated at physiological pH, and there is consider-
able evidence to support the hypothesis that they act by
mimicking the cationic transition state of the substrate
at the active site of the enzyme.1h6 A possible mode of
binding of fenpropimorph at the active site of the *8È*7
isomerase enzyme is shown schematically in Fig. 1.4,7h9
The protonated nitrogen atom has been positioned over
the positively charged centre of the sterol transition
state. The binding to the *14 reductase enzyme may be
similar, as the charge on the postulated cationic inter-
mediate occupies a similar region in space to that in the
*8È*7 isomerase reaction. Extensive studies aimed at
optimising the activity of the morpholine/piperidine
fungicides based on this model have been published.4
Although the level of activity at the enzyme level was
signiÐcantly increased, no compounds were shown to
have any advantage over fenpropimorph in the Ðeld.
The consideration that the steroid carbocation is
likely to be Ñat whereas that in fenpropimorph is prob-
ably pyramidal led us to investigate cyclic guanidines
Ergosterol is a component of cell membranes of certain
classes of fungi. It is well established that inhibition of
certain enzymatic steps in the production of ergosterol
from lanosterol can be associated with fungicidal or
fungistatic e†ects. For the control of diseases of tem-
perate cereals, the majority of fungicides used belong to
two major classes of sterol biosynthesis inhibitors (SBI).
Azole fungicides, such as propiconazole and prochloraz
inhibit the 14C demethylation step. These were not
included in this study.
The other important class of SBI fungicides is com-
posed of the morpholines and piperidines, principally
fenpropimorph and fenpropidin. They are highly active
in the control of powdery mildew (Erysiphe graminis
DC) and have been shown to inhibit two enzymes in the
sterol biosynthesis pathways of the model organisms
Saccharomyces cerevisiae Meyer ex Hanson and Ustil-
* To whom correspondence should be addressed at: Proteus
Molecular Design Ltd, Proteus House, Lyme Green Business
Park, MacclesÐeld, Cheshire SK11 0JL UK.
” Present address: Chiroscience Limited, Cambridge Science
Park, Milton Rd, Cambridge, CB4 4WE UK.
° Present address: 576 rue de Bernis, 30980 Langlade, France.
258
( 1997 SCI. Pestic. Sci. 0031-613X/97/$17.50. Printed in Great Britain

Rationally designed guanidine and amidine fungicides
259
sible interactions with the enzyme in the region
occupied by ring A of the sterol. Hydrophobic inter-
actions may exist in this region and the sterol hydroxyl
group may form a hydrogen bond with some elements
in the active site leading to a signiÐcant increase in the
binding energy. This could be exploited to give rise to
an increase in inhibitory activity at the enzyme level.
One way to investigate potential binding sites normally
occupied by ring A was to introduce a hydroxy propyl
chain onto the structures of 1 and 2, respectively, such
that the chain could sit in the area of the binding site
normally occupied by ring A of the sterol and its
hydroxyl group. This concept is illustrated in Fig. 3,
along with a schematic binding model. The compounds
synthesised are shown in Table 1.
Fig. 1. Superposition of fenpropimorph over the isomerase
carbocationic intermediate.
and amidines as inhibitors of the *8È*7 isomerase and
the *14 reductase enzymes (Fig. 2).9 Both the guanidine
and the amidine functional groups, when protonated,
give rise to a planar carbocation. It was hoped that this
feature would lead to enhanced binding to the enzyme
active site, compared with fenpropimorph. Our results
in this area have been reported previously.9 Molecules
with good in-vivo fungicidal activity, and corresponding
activity against ergosterol biosynthesis in vitro were
obtained. It was shown that the structureÈactivity
relationship (SAR) in this area closely followed that for
fenpropimorph. We have now extended our investiga-
tions to three novel series of compounds to explore
further the limitations of the enzyme binding models
already developed.
2.2 Cyclic “rigidÏ guanidines
It has been reported previously that the gas phase
“openÏ conformation of fenpropimorph consistent with
Ðtting the commonly recognised binding model in the
manner of Fig. 2 is several kcal mol~1 above that of the
lowest energy gas phase conformation.8 A similar
analysis carried out on 1 using the molecular mechanics
2
DESIGN OF NOVEL STEROL
BIOSYNTHESIS INHIBITORS
2.1 Hydroxypropyl guanidine and amidines
One of the most active compounds in our previously
reported SAR study of the guanidine and amidine series
is the amidine hydrochloride salt 2 (Fig. 2).9 Its activity
is closely matched by the corresponding guanidine salt
1. A schematic representation of its possible action as a
sterol carbocation mimic is shown in Fig. 2. This
diagram shows that no account has been taken of pos-
Fig. 3. Schematic representation of the binding model for
hydroxypropyl guanidine and amidines.
Fig. 2. Schematic representation of guanidine 1 and amidine 2 in relation to the sterol cationic intermediate.

260
John W . L iebeschuetz et al.
TABLE 1
Comparison of In-vivo and Biochemical Activity of Hydroxypropyl Compounds
Calculated L C (mg litre~1)a
90
E. graminis
f. sp. hordei
Prot.
E. graminis f. sp. tritici
IC (kM)b
50
Prot.
Erad
U. maydis
2
5
6
\1É56
\1É56
1
9
[100
8
6
27
È
8É6
76
3É5
a These compounds were compared in a 24-h test at 100, 25, 6É25 and 1É56 mg litre~1.
b Inhibition values from the whole cell assay.
programme MM2 found that the conformation that
superimposed best was 2É5 kcal mol~1 above the gas
phase global energy minimum. The ordering of the con-
formations in the gas phase does not necessarily reÑect
their ordering in aqueous solution. Nevertheless it sug-
gests that the free energy of binding of both fenpropi-
morph and 1 may be less than optimal due to the
existence of a signiÐcant population of conformations
which are unfavourable to binding. A common strategy
used when dealing with conformationally Ñexible
enzyme inhibitors is to construct rigid analogues that
present the proposed active conformation in “frozenÏ
form.10 Examination of Fig. 2 shows that the possibility
exists of exploiting the binding area of ring D in the
sterol for this purpose. Tying together N1 and C3 of the
chain of 1 in a Ðve-membered ring not only creates a
rigid analogue but could also exploit extra hydrophobic
binding in the area of the active site normally occupied
by ring D.
groups of fenpropimorph11 and 19 has a considerable
e†ect on the activity of the compound. It was therefore
decided to investigate the e†ect on the activity of these
compounds of introducing a “buttressingÏ methyl group
to mimic C-18 of the sterol. The superposition of a low-
energy conformation of a model pyrrolinyl tetra-
hydropyrimidine
over
the
postulated
*8È*7
carbocationic intermediate is illustrated in Fig. 5, which
shows two views perpendicular to each other. Both
model structures were energy minimised in vacuo using
the AM1 semi-empirical quantum chemical program.
It was also felt important to clarify the mode of
action of the compounds in this series, by a limited SAR
study analogous to the SAR established previously for 1
and 2. The compounds prepared in this series are shown
in Table 2.
In a related study, the e†ects of morpholines of type 3
and 4 (Fig. 6) were examined.12 All four diastereromers
were synthesised and tested separately. The 1R 3S
isomer 3a had in-vivo activity against E. graminis f. sp.
hordei up to 20 times that of fenpropimorph.
A schematic representation of the binding model for
these compounds is shown in Fig. 4. It has been shown
that the stereochemistry of the “buttressingÏ methyl
2.3 Open-chain phenyl amidines
The Ðnal class of compounds examined here have an
open-chain structure. It was envisaged that a phenyl
group would mimic ring A, whilst rings B, C and D
would be covered in outline. The tert-butylphenyl group
was retained to maintain the cover of the sterol side
chain. The use of a phenyl group to mimic ring A would
enable a wide range of functionality to be examined and
allow determination of the e†ects of changing the elec-
tronic nature of this part of the molecule. The binding
Fig. 4. Schematic representation of the binding model for the
pyrrolinyl tetrahydropyrimidines.

Rationally designed guanidine and amidine fungicides
261
Fig. 5. Two perpendicular views of the superposition of a low-energy conformation of a model pyrrolinyl tetrahydropyrimidine
over the *8È*7 carbocationic intermediate.
model for these compounds is shown schematically in
Fig. 7. In Fig. 8 a low-energy structure for an N-phenyl-
N@-phenethyl acetamidine has been Ðtted on the
putative *8È*7 carbocationic sterol intermediate so that
the positive centres are superimposed. Two perpendicu-
lar views, 8(a) and 8(b) are shown. Both molecules were
minimised using the AM1 semi-empirical quantum
chemical program. The Ðt is reasonable and, although
the anilinyl group does not adopt the ideal conforma-
tion, it is worth observing that a polar substitution in
the 4-position of the phenyl ring (here represented by
Fig. 6. Morpholine compounds investigated by Huxley-
Tencer et al.12
Fig. 7. Schematic binding model for open-chain phenyl ami-
dines.
TABLE 2
Pyrrolidinyl Tetrahydropyrimidinium Compounds, “Rigid GuanidinesÏ

262
John W . L iebeschuetz et al.
Fig. 8. Two perpendicular views of a low-energy structure for an N-phenyl-N@-phenethyl acetamidine Ðtted on the *8È*7 carbo-
cationic intermediate.
OH) could make use of the putative polar binding site
for the OH of the sterol.
otherwise stated. Infra-red spectra were recorded on a
Perkin-Elmer 1420 Ratio Recording spectrophotometer
or on a Perkin Elmer 1760 FT spectrophotometer.
Mass spectra were recorded using a Finnegan-MAT
TSQ70 Triple Quadrupole mass spectrometer.
3
METHODS
In all cases, elemental analyses are in accord with
the proposed molecular formulae.
3.1 Synthesis of compounds
The general methods of synthesis are outlined below.
Details of syntheses of individual compounds and sup-
porting analytical data are given in the Appendix.
NMR spectra were run on a Bruker AC250 250 MHz
FT spectrometer, unless otherwise stated. A Varian EM
390 NMR spectrometer was used for 90 MHz spectra.
Deuterochloroform was the solvent of choice unless
3.1.1 Synthesis of hydroxypropyl guanidine and amidine
The synthesis of the guanidine 5 is shown in Fig. 9. The
b-diketone 30 was prepared by alkylation of the dianion
of acetylacetone with tert-butyldimethylsilyl iodoethane
at [20¡C.13
The guanidine 31 was prepared by heating the hydro-
chloride salt of amine 32 with cyanamide in the absence
Fig. 9. Synthesis of hydroxypropyl guanidine 5. (TBDMS \ tert-butyldimethylsilyl).

Rationally designed guanidine and amidine fungicides
263
Fig. 10. Synthesis of hydroxypropyl amidine 6. (Mes \ mesityl).
of solvent. Reaction of the guanidine 31 with diketone
30 in a bomb gave the pyrimidine 33. This was depro-
tected to give the hydroxypyrimidine 34 which was
reduced by treatment with sodium in ethanol at reÑux,
giving guanidine 5 after acidic work up.
(illustrated for 2-methyl-3-(4-tert-butylphenyl)pyrroli-
dine).
Wittig Horner condensation a†orded the cinnamate
41 from 4-tert-butylbenzaldehyde. Michael addition of
nitroethane to the cinnamate, followed by reduction,
gave 43. Dehydrative cyclisation under Mitsonobu con-
ditions then a†orded the desired pyrrolidine 44 as a 3 : 1
mixture of diastereomers which could not be separated.
The guanidines were prepared from the pyrrolidines
via a two-step route previously developed for the prep-
aration of acyclic guanidines.9 Thus, for example (Fig.
12), 44 was condensed with 2-chloropyrimidine and the
resulting aminopyrimidine was hydrogenated to a†ord
the target cyclic guanidine.
It was found possible to separate the cis and trans
diastereomeric aminopyrimidines 45 and 46 by careful
Ñash chromatography, prior to hydrogenation. Struc-
tural assignment of the isomers was based largely on
their [1H]NMR characteristics. The chemical shift of
the 2-methyl group di†ered between the isomers by
1 ppm. The most rational explanation of this is that the
shift is due to shielding/deshielding by the 3-phenyl
group. On this basis the isomer with the high Ðeld
The preparation of amidine 6 is shown in Fig. 10. The
anion of ethyl 2-oxocyclopentanecarboxylate was alkyl-
ated with 1-benzyloxy-3-bromopropane in the presence
of 15-crown-5. Demethoxycarbonylation using lithium
chloride in dimethylsulfoxide gave a cyclopentanone 36.
The oxime formation and Beckman rearrangement
using mesitylene sulfonyl chloride14 gave the lactam 38
which was obtained essentially as one isomer only.
The lactam 38 was used to prepare the amidine 40 by
previously developed procedures.9 Thus, imidate 39 was
prepared, and was condensed with amine 32. The benzyl
group was removed by hydrogenation, giving amidine
6.
3.1.2 Synthesis of rigid guanidines
Synthesis of the target guanidines required the prep-
aration of several key 2,3-disubstituted pyrrolidines.
These were prepared by the route shown in Fig. 11
Fig. 11. Synthesis of 2,3-disubstituted pyrrolidines, key intermediates in the synthesis of the pyrrolinyl tetrahydropyrimidines.
(DEAD \ diethyl azodicarboxylate).

264
John W . L iebeschuetz et al.
Fig. 12. Synthesis of pyrrolinyl tetrahydropyrimidines.
shifted methyl group (the major isomer) should be the
cis isomer, having the methyl group lying above the
plane of the phenyl ring and in its shielding cone; and
the isomer with the low Ðeld shifted methyl group
should be the minor, trans, isomer. Thus it was possible
to make assignments for all the aminopyrimidines syn-
thesised, including those in which the phenyl group was
absent, and therefore also to establish the stereoche-
mistry of the target guanidines.
prepared by demethylation of the methoxy amidine
salts using boron tribromide.
3.2 Biological screening methodology
3.2.1 In-vivo methods
Compounds were tested in vivo against E. graminis f. sp.
tritici, (wheat powdery mildew), E. graminis f. sp. hordei
(barley powdery mildew), and Puccinia recondita Rob.
ex Desm. (wheat leaf rust). In screens for protectant
activity, the plants were inoculated 24 h, or in some
cases 2 h, after being sprayed. In the curative screens
plants were inoculated 24 h before being sprayed. Com-
pounds were initially tested at 400 mg litre~1 and, if
active at this concentration, tested further at a range of
lower concentrations. All active compounds in a given
series were compared at a range of concentrations.
3.1.3 Synthesis of open-chain amidines
The open-chain amidines were prepared as shown in
Fig. 13. The methods used in the preparation of com-
pound 32 have been previously reported.9 The amine 32
was acetylated with acetyl chloride, and the resulting
amide was treated with phosphorus pentachloride, fol-
lowed by the appropriate aniline to give the Ðnal open-
chain amidine salts. The hydroxy compounds were
Fig. 13. Synthesis of open-chain amidines.

Rationally designed guanidine and amidine fungicides
265
LC values were estimated from a plot of concentra-
90
tions against bioactivity. In cases where the LC values
90
were outside the range of concentrations used, they
have been quoted as being either less or greater than the
minimum or maximum concentration screened. The full
experimental details have been described previously.9
3.2.2 In-vitro methods
Selected compounds were screened for activity against
ergosterol biosynthesis in vitro. An assay using HPLC
and radiolabel detection, designed to examine the con-
stitutive sterol proÐle in whole cells of the smut U.
maydis was used. Alternatively, a cell-free preparation
obtained from the same organism was used. Both assays
have been described previously.9,15 In both cell-free and
whole-cell assays, radiolabel incorporation into ergos-
terol as a proportion of incorporation into total cellular
sterols was determined over a range of inhibitor concen-
trations. A dose/response curve of decreasing ergosterol
content versus increasing concentration of inhibitor was
Fig. 14. E†ect of hydroxypropyl amidine 6 on ergosterol bio-
synthesis in whole cells of Ustilago maydis.
mode of action to fenpropimorph, albeit only inhibiting
one of the two enzymes *8È*7 isomerase enzyme and
*14-reductase.9
Despite equivalent or improved intrinsic efficacy, 6
had less in-vivo activity than 2 and this may be due to
the reduced lipophilicity of these compounds, associated
with the hydrophilic hydroxy group. This would
perhaps decrease the mobility of the compounds in and
around the plant and thus could have a negative e†ect
on activity. It should be noted that the compounds are
mixtures of diastereomers and, were these to be separat-
ed, considerable increases in activity might be observed
for the individual diastereomers.
plotted and used to determine IC values. In the main,
50
only a single e†ect was detected. In general, an increase
in the level of incorporation into abnormal sterol was
observed concomitantly with the reduction of incorpor-
ation into the ergosterol peak.
3.3 Molecular modelling
4.2 “RigidÏ guanidines
Molecular mechanics calculations and visualisations
were carried out either on a Microvax II workstation
using CHEM-X software (Chemical Design Ltd) or on
an Indigo Elan (Silicon Graphics Instruments) using
SYBYL (Tripos Inc.).
The compounds prepared in this series are shown in
Table 2. The majority of these compounds were
screened at 400 mg litre~1 only and the results obtained
at this rate versus E. graminis f. sp. hordei and P. recon-
dita are shown in Table 3. From the model discussed
earlier and from previous work in this area it could be
predicted the tert-butylphenyl group is necessary for
activity. This is conÐrmed by the results versus E. gra-
4
RESULTS AND DISCUSSION
4.1 Hydroxypropyl compounds
TABLE 3
In-vivo Activity of Pyrrolidinyl Tetrahydropyrimidinium
Compounds
Two compounds, 5 and 6, were prepared in this series
and the results of comparative testing alongside the
standard 2 are shown in Table 1. While the compounds
both showed good activity against E. graminis f. sp.
tritici (and E. graminis f. sp. hordei), their activity was no
better than that of the lead amidine 2.
Control at 400 mg litre~1 (%)a
E. graminis f. sp. hordei
P. recondita
The compounds were also tested for their activity
against ergosterol biosynthesis in the whole-cell assay
(Table 1). Their activity was compared to that of 2. The
hydroxy propylamidine 6 showed increased efficacy
over the parent amidine 2, indicating that the hydroxy
group may be favourably inÑuencing enzyme binding.
For both compounds the reduction of ergosterol levels
in treated cultures was concomittant with the pro-
duction of an abnormal sterol identical, in terms of
retention time, with that generated by compounds 1
and 2. This is illustrated for 6 (Fig. 14). It had pre-
viously been concluded that 1 and 2 have a similar
7
8
59
62
83
100
0
87
52
100
79
NT
NT
0
0
0
66
100
0
9
10
11
12
13
14
15
0
a These data were obtained from a 24-h protectant test at
400 mg litre~1 only.

266
John W . L iebeschuetz et al.
TABLE 4
type fungicides exhibited in the two assays.9 This was
ascribed to poor cell penetration brought about by the
polar nature of the highly basic guanidine and amidine
moeities. Again, compound 10 is the most active in the
series. The sterol proÐles of cultures treated with these
compounds were similar to those obtained with 1 and 2,
indicating a common mode of action. Interestingly,
compound 15, not very active in vivo, gave rise to a dif-
ferent sterol proÐle. At concentrations of 10 kM or more
the appearance of a peak previously identiÐed as squa-
lene epoxide was observed, concomitant with reduction
in ergosterol.15 This suggests that this molecule may be
inhibiting epoxy squalene cyclase, another enzyme
thought act by a carbocationic mechanism.16
Activity of Most Active “Rigid GuanidinesÏ against Erisyphe
graminis f. sp. hordei
L C (mg litre~1)a
90
10
12
14
15
100
[400
200
[400
a These compounds were compared in a 24-h protectant test
at 400, 100, 50, 25 and 10 mg litre~1.
minis f. sp. hordei for compounds 7, 8, 11 and 15. Of the
remaining compounds, we had thought that the com-
pounds in which the methyl group and the phenyl
group were cis should have better activity than those
where the groups were trans, because, according to the
binding model, the groups in the natural carbocation
that these superimpose are themselves cis. (Fig. 5). This
is true in the case of 9 and 10, 10 being the most active
compound in the series (Table 3). However, it is not so
in the case of compounds 13 and 14. In the study on the
cyclopentyl compounds 3a and b and 4a and b related
to fenpropimorph and discussed earlier, this methyl
group is absent, but, nevertheless, compounds with very
high activities relative to fenpropimorph were
obtained.12 It is therefore possible that this methyl
group does not play a signiÐcant role in the rigid gua-
nidine series.
In conclusion it can be seen that the “rigidÏ guanidines
show some activity against the pathogens E. graminis f.
sp. hordei and P. recondita. The variations in the activ-
ity in this series are consistent with the binding model.
However it is clear that no compound in the series has
activity in any way comparable with the lead com-
pound in the guanidine series, compound 1, previously
shown to have an LD of the order of 10 mg litre~1
90
against these pathogens.9
4.3 Open-chain guanidines
The 14 compounds prepared in this series are shown in
Table 6. Also shown in this table are the LC values
90
for these compounds against E. graminis f. sp. tritici in
It is clear from Table 3 that the activities of these
compounds versus P. recondita are di†erent from those
versus E. graminis f. sp. hordei. In this case the most
active compound is 13. Four compounds in the series
were tested at lower concentrations. The activity for
these compounds versus E. graminis f. sp. hordei are rep-
TABLE 6
Activity of Open Chain Guanidines against Erisyphe graminis
f. sp. tritici
resented as LD values in Table 4. It can be seen that
90
compound 10 is the most active in the series. The activ-
ity of some of these compounds at the enzyme level
against ergosterol synthesis in the cell-free assay versus
U. maydis is shown in Table 5 relative to compound 2
R
R
L C (mg litre~1)a
1
2
90
and fenpropimorph. The IC values are lower than the
16
17
18
19
20
21
22
23
24
25
26
27
28
29
H
H
H
[400b
40
[400
[400
190
[400
300
150
[400
[400b
300
[400b
[400
[400
50
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
corresponding whole-cell assay results for compounds 5
2-OH
3-OH
4-OH
2-MeO
3-MeO
4-MeO
2-Me
3-Me
4-Me
3-Cl
and 6. It was established previously, however, that there
is generally a two orders of magnitude di†erence
between the activities of guanidinium and amidinium
TABLE 5
Activity of “Rigid GuanidinesÏ against Sterol Biosynthesis in
Ustilago maydis
IC (kM)a
50
7
8
2É8
1É3
0É95
0É61
4-Cl
3,4-diCl
9
a These compounds were compared in a 2-h protectant test at
400, 100, 25 and 6É25 mg litre~1.
b Compound was tested at 400 mg litre~1 only.
10
a These data were obtained from the cell-free assay.

Rationally designed guanidine and amidine fungicides
267
Fig. 15. The four possible geometrical isomers of the phenylacetamidines.
2-h protectant test. The model that we have proposed
for the mode of action for these compounds predicts
that the hydroxy compound, which can make use of the
OH binding pocket, and the unsubstituted compounds
are those likely to be the most active. The results shown
in Table 6 are in agreement with this expectation. It is
notable that the 4-OMe compound also exhibits good
activity. A possible explanation is that this molecule is
demethylated to the hydroxy compound in vivo.
Me the ZZ and EZ isomers were found to have similar,
low, energies. When R is H it was found that the ZE
isomer, the proposed active isomer, was 4É3 kcal mol~1
in energy above that of the ZZ isomer. This is a high
energy di†erence to be compensated for by extra
enzyme binding interactions and may explain why the
formamidines are only poorly active. In comparison,
when R is Me, the ZE isomer has a similar energy to
both the ZZ and EZ isomers. Another di†erence
between the two cases was that for R \ H, the phenyl
ring was found to be planar to the amidine system in
both isomers, whereas with R \ Me it was pushed out
of the plane. A planar phenyl group would provide a
better Ðt for the model. It would appear, therefore, that
the conformational energy argument could be the over-
riding e†ect.
Three compounds in this series were subject to
further comparative tests versus E. graminis f. sp. hordei
and E. graminis f. sp. tritici. The compounds were also
screened in the sterol biosynthesis whole-cell assay
(Table 7). The data show the hydroxy compound 20 to
be most active, followed by the unsubstituted com-
pound 17 and the methoxy compound 23, which is the
order of activity which might be expected from the
It is interesting to note that the formamidine 16,
which lacks the “buttressingÏ methyl group (R \ H) is
2
inactive. Four geometrical isomers of the phenyl aceta-
midines are possible (Fig. 15). Evidence from NMR
spectroscopy (Graupner, P, pers. comm.) suggests the
presence of an equilibrium mixture of more than one
isomer in solution. The isomer that best Ðts the binding
model is ZE. An analysis of the relative gas phase ener-
gies of these isomers was carried out in an attempt to
explain the di†erence in activities of the formamidine
and acetamidine analogues. The molecular mechanics
energy minimisation program Maximin 2, incorporating
the TRIPOS force Ðeld, was used for the modelling.
When R is H or Me, the EE isomer was found to be of
too high an energy to be of any account. For both H or
TABLE 7
In-vivo and In-vitro Activity of the Most Active Open-Chain Guanidines
L C (mg litre~1)
90
E. graminis
f. sp. tritici
E. graminis
f. sp. hordei
Prot.
IC (kM)a
50
R
R
U. maydis
Prot.
Erad.
1
2
17
20
23
H
4-OH
4-MeO
Me
Me
Me
19É6
4É91
43É2
50
5
[100
15
15
20
\1É56
50
[100
a These are data from the whole-cell assay.
b These compounds were compared in a 24-h protectant test and in an eradicant test at
100, 25, 6É25 and 1É56 mg litre~1.

268
John W . L iebeschuetz et al.
fungicide fenpropimorph by molecular mechanics calcu-
lations and NMR spectroscopy. Pestic. Sci., 36 (1992)
309È18.
model. The whole-plant data in the three screens shown
are a little more complex, which one might expect given
the added complexity in in-vivo systems. The lower lipo-
philicity of 20 compared to 17 may account for its
decreased activity in the E. graminis f. sp. tritici curative
screen, where penetration into the plant is likely to be
particularly important. In each case the 4-OMe com-
pound 23 is the least active.
In conclusion, it can be seen that some members of
this series exhibit moderate activity versus E. graminis f.
sp. hordei, and E. graminis f. sp. tritici, although none is
more active than the amidine 2. The strong activity
exhibited by the 4-OH compound is good supporting
evidence for the type of binding model we propose for
this class of chemistry.
9. Arnold, M., Duriatti, A., Katz, R. B., Liebeschuetz, J. W.
& Jung, M., Guanidinium and amidinium fungicides: A
new class of carbocation mimetic ergosterol biosynthesis
inhibitors. Pestic. Sci., 44 (1995) 341È55.
10. Silverman, R. T he Organic Chemistry of Drug Design and
Drug Action. Academic Press, San Diego, 1991, pp. 83È6.
11. Pommer, E-H., Chemical structureÈfungicidal activity
relationships in substituted morpholines. Pestic. Sci., 15
(1984) 285È95.
12. Huxley-Tencer, A., Francotte, E. & Bladocha-Moreau,
M., 1(R)-(2,6-cis-dimethylmorpholino)-3(S)-(p-tert-butyl-
phenyl)cyclopentane: A representative of a novel, potent
class of bio-rationally designed fungicides. Pestic Sci., 34
(1992) 65È74.
13. Buynak, J. D. & Rao, M. N., a-Alkylidene b-lactams. 2. A
formal stereocontrolled total synthesis of ^ carpetimycin
A. J. Org. Chem., 51 (1986) 1571È4.
14. Grieco, P. A., Flynn, D. L. & Zelle, R. E., b-Lactam
antibiotics: A formal stereocontrolled total synthesis of
^thienamycin. J. Am. Chem. Soc., 106 (1984) 6414È17.
15. Peacock, G. A. & Goosey, M. W., Separation of fungal
sterols by normal phase high performance liquid chroma-
tography. Application to the evaluation of ergosterol bio-
synthesis inhibitors. J. Chromatogr., 293 (1989) 293È304.
16. Duriatti, A., Bouvier-Nave, P., Benveniste, P., Schuber, F.,
Delprino, L., Ballliano, G. & Cattel. L., In-vitro inhibition
of animal and higher plant 2,3-oxidosqualene-sterol
cyclases by 2-aza-2,3-dihydrosqualene and derivatives,
and by other ammonium-containing molecules. Biochem.
Pharm., 34 (1985) 2765È77.
ACKNOWLEDGEMENTS
The authors would like to thank Sarah Perman, Pat
Lush, Andrea Hiltensperger, Helen Stewart, Sharon
Noble, Tony Sturz and Mary Barkham for carrying out
the in-vivo biological evaluations, Michael Goosey for
cell-free assay data, Paul Graupner for invaluable NMR
analysis and Jill Bennett for analytical assistance.
Thanks are also due to Roobina Baloch, Neil Kirby,
Michel Jung and Hak-Fun Chow for helpful dis-
cussions.
APPENDIX
REFERENCES
SpeciÐc compounds tested were synthesised as follows:
1. Baloch, R. & Mercer, E. I., Inhibition of sterol *8È*7
isomerase and *14-reductase by fenpropimorph, tri-
demorph and fenpropidin in cell-free enzyme systems from
Saccharomyces cerevisiae. Phytochemistry, 26 (1987) 663È8.
2. Steel, C. C., Baloch, R., Mercer, E. I. & Baldwin, B. C.,
The intracellular location and physiological e†ects of
abnormal sterols in fungi grown in the presence of morp-
holine and functionally related fungicides. Pestic. Biochem.
Physiol., 33 (1989) 101È11.
3. Rahier, A., Schmitt, P., Huss, B., Benveniste, P. &
Pommer, E. H., Chemical structureÈactivity relationships
of the inhibition of sterol biosynthesis by N-substituted
morpholines in higher plants. Pestic. Biochem. Physiol., 25
(1986) 112È24.
4. Akers, A., Ammermann, E., Buschmann, E., Gotz, N.,
Himmele, W., Lorenz, G., Pommer, E. H., Rentzea, C.,
Rohl, F., Siegel, J., Zipperer, B., Sauter, H. & Zipplies, M.,
Chemistry and biology of novel amine fungicides:
Attempts to improve the antifungal activity of fenpropi-
morph. Pestic. Sci., 31 (1991) 521È38.
5. Taton, M., Benveniste, P. & Rahier, A., Mechanism of
inhibition of sterol biosynthesis enzymes by N-substituted
morpholines. Pestic. Sci., 21 (1987) 269È80.
1-tert-Butyldimethylsilyloxyhexane-4,6-dione, 30
Sodium hydride (11 mmol) was washed with dime-
thoxyethane (DME), then suspended in 20 ml DME.
Acetylacetone (1 ml, 10 mmol) was added dropwise at
0¡C. After 30 min, the mixture was cooled to [ 20¡C
then treated dropwise with butyl lithium (4É4 ml,
11 mmol, 2É5 M in hexane). After a further 30 min, tert-
butyl-dimethylsilyliodoethane (3É4 g, 12 mmol) was
added dropwise as a solution in 5 ml of DME. The
reaction was allowed to warm to room temperature and
stirred for 16 h then heated at reÑux for 8 h. After
cooling to room temperature, the reaction was
quenched with ammonium chloride solution. The
aqueous phase was extracted with ether, and the com-
bined ethereal phases dried, and concentrated. The
crude product was distilled at 2 mm Hg, 150¡C, giving
30 in 35% yield. d 5É52 (s, 1H), 3É60 (s, 1H); 3É64 (2H, t,
H
J \ 7 Hz), 2É34 (2H, t, J \ 7 Hz), 2É05 (3H, s), 1É79È1É82
6. Taton, M., Benveniste, P. & Rahier, A., Biorganic Chem-
istry in Healthcare and T echnology, ed. U. K. Pandit &
F. C. Alderweireldt. Plenum Press, New York, 1991, pp.
265È8.
(2H, m), 0É9 (9H, s), 0É0 (6H, s), MS 258 (1%, M`) 201É1
(100), V
(Ðlm) 2960, 2940, 1610, 1100 cm~1.
max
1-[(4-tert-Butylphenyl)-2-propyl]guanidine
hydrochloride, 31
7. Baloch, R., PhD T hesis, University College of Wales,
Aberystwyth.
A
mixture of 1-(4-tert-butylphenyl)-2-propylamine
8. Jensen, J. S., Jorgensen, F. S., Klemmensen, P. D., Hack-
sell, U. & Petterson, I., Conformational analysis of the
hydrochloride, 32 (4É55 g, 20 mmol) and cyanamide

Rationally designed guanidine and amidine fungicides
269
(1É68 g, 40 mmol) was heated to 150¡C for 10 h. The
mixture was cooled to room temperature, treated with
hydrochloric acid (4 M) and left to dissolve over several
days. The aqueous phase was extracted into chloroform.
The combined organic phase was dried and concen-
trated, giving 5É25 g of 31 (98%). d (CDCl ] NaOD)
TLC showed the reaction to be complete. The reaction
was cautiously acidiÐed with 2 M hydrochloric acid. The
solvents were evaporated, the solid residue was
extracted with chloroform and the organic phase con-
centrated. The crude product was columned on silica
gel, eluting with ethanol ] chloroform (5 ] 95 to
15 ] 85 by volume), with a trace of acetic acid. Com-
pound 5 (990 mg) was obtained in 86% yield as a
H
3
7É70 (H, brd, J \ 7 Hz), 7É20 (2H, d, J \ 7 Hz), 7É10
(2H, d, J \ 7 Hz), 3É70È3É80 (1H, m), 3É1 (3H, brs), 2É87
(1H, dd, J \ 12, 5 Hz), 2É60 (1H, dd, J \ 12, 7 Hz), 1É25
mixture of diastereomers. d (MeOD ] NaOD) 7É15È
H
(9H, s), 1É10 (3H, d, J \ 7 Hz). d 20É3, 31É3, 34É3, 42É3,
7É50 (6H, m, incl 7É12 (d, J \ 7 Hz) and 7É42 (d,
C
50É0, 125É5, 129É0, 134É2, 149É6, 156É5. MS 234 (100%,
J \ 7 Hz), 4É40È4É50 (1H, m), 3É85È4É00 (1H, m), 3É50È
3É70 (2H, m), 3É00 (dd, J \ 12, 5 Hz), 2É50È3É10 (3H, m,
incl 2É80) (dd, J \ 12, 7 Hz)), 1É70È2É10 (2H, m), 1É40È
1É65 (2H, m), 1É05È1É40 (17H, m, incl 1É30 (d,J \ 7 Hz
M` [ HCl), 147 (30). V
1656 cm~1.
(KBr) 3300, 3517, 2967,
max
N-(1-(4-tert-Butylphenyl)-2-propyl)-2-amino-4-
(3-tert-butyldimethylsilyloxypropyl)-6-methylpyrimidine,
33
and 1É35 (s)), MS 346 (100%, M` [ HCl), 328 (18). V
3400È2500. (br), 1650, 1620, 1520, 800, 750 cm~1.
max
A mixture of 31 (700 mg, 2É6 mmol) and 30 was heated
in a bomb at 180¡C for 12 h. The mixture was cooled,
dissolved in water and extracted into dichloromethane.
The organic phase was dried and concentrated. The
crude product was columned on silica gel eluting with
ethyl acetate ] hexane (10 ] 90 by volume). Compound
33 (220 mg) was obtained in 40% yield. d (CDCl ) 7É30
(2H, d, J \ 7 Hz), 7É15 (2H, d, J \ 7 Hz), 6É30 (1H, s),
4É90 (1H, d, J \ 7 Hz), 4É25È4É42 (1H, m), 3É65 (2H, t,
J \ 7 Hz), 2É87 (1H, dd, J \ 12, 5 Hz), 2É62 (1H, dd,
J \ 12, 7 Hz), 2É58 (2H, t, J \ 7 Hz), 2É25 (3H, s), 1É82È
2É00 (2H, m), 1É20 (9H, s), 1É15 (3H, d, J \ 7 Hz), 0É90
(9H, s), 0É01 (6H, s). MS 455 (5%, M`), 308 (100).
Methyl 1-(3-benzyloxypropyl)-2-
oxocyclopentanecarboxylate, 35
Sodium hydride (7É9 g, 0É2 mol) was washed with THF
and suspended in 200 ml THF at 0¡C. Methyl 2-
oxocyclopentanecarboxylate (22É3 ml, 0É18 mol) was
added dropwise as a solution in 30 ml THF. The reac-
tion was stirred for 15 min, then treated with 15-crown-
5 (1É79 ml, 0É9 mol), followed by 1-benzyloxy-3-bromo-
propane (42É3 g, 0É18 mol), added dropwise as a solu-
tion in 30 ml THF. The reaction was heated under
reÑux for 10 h, after which GC analysis showed essen-
tially complete disappearance of the starting material.
The reaction was quenched with ammonium chloride
solution and the aqueous phase was extracted with
ether. The combined ethereal phase was dried and con-
centrated. The crude product was distilled at 1 mm Hg,
and the fraction boiling from 100 to 140¡C was col-
lected, and chromatographed on silica gel, eluting with
ethyl acetate ] hexane (20 ] 80 by volume). Methyl
1-(3-benzyloxypropyl)-2-oxocyclopentanecarboxylate 35
was obtained (20É2 g) in 39% yield. d (CDCl ,
H
3
N-(1-(4-tert-Butylphenyl)-2-propyl)-2-amino-4-
(3-hydroxypropyl)-6-methylpyrimidine 34
A solution of 33 (8É3 g, 18 mmol) and hydrochloric acid
(2 M, 18 ml, 36 mmol) in water (50 ml) and dioxane
(100 ml) was stirred at room temperature for three days.
The mixture was then basiÐed with sodium hydroxide
solution and the dioxane was evaporated. The residue
was extracted into dichloromethane. The organic phase
was dried and concentrated. This was columned on
silica gel, eluting with ethyl acetate ] hexane (20 ] 80
by volume). Compound 34 (4 g) was obtained as a crys-
talline solid in 65% yield. d (CDCl ) 7É32 (2H, d,
H
3
90 MHz) 7É25È7É45 (5H, m), 4É50 (2H, s), 3É70 (3H, m),
3É50 (2H, t, J \ 6 Hz), 1É50È2É60 (10H, m). V
2960, 2860, 1755, 1730, 1100 cm~1.
(Ðlm)
max
H
3
2-(3-Benzyloxypropyl)cyclopentan-1-one, 36
J \ 7 Hz), 7É16 (2H, d, J \ 7 Hz), 6É29 (1H, s), 5É27 (1H,
d, J \ 7 Hz), 4É60 (1H, br), 4É20È4É40 (1H, m), 3É70 (2H,
t, J \ 7 Hz), 2É95 (1H, dd, J \ 12, 5 Hz), 2É70 (2H, t,
J \ 7 Hz), 2É65 (1H, dd, J \ 12, 7 Hz), 2É30 (3H, s),
1É90È2É00 (2H, m), 1É30 (9H, s), 1É15 (3H, d, J \ 7 Hz),
A solution of 35 (20 g, 0É07 mol) and LiCl (9É3 g,
0É22 mol) in DMSO (250 ml) was heated under reÑux
for 3É5 h. GC analysis showed the reaction to be com-
plete. The reaction was cooled, poured into water and
extracted with ether ] hexane (25 ] 75 by volume). The
combined organic phase was washed with water, dried
d . 19É9, 21É6, 30É4, 31É3, 34É3, 34É4, 42É2, 47É7, 62É0,
C
108É9, 125É0, 129É1, 148É8, 161É2, 167É9, 170É1. MS 342
and concentrated, giving 36 (12É95 g) in 81% yield. d
(15%, M` ] H`), 314 (35). V
1104 cm~1.
3250, 2956, 1582,
H
max
(CDCl , 90 MHz) 7É20È7É50 (5H, m), 4É50 (2H, s), 3É50
3
(2H, t, J \ 6 Hz), 1É00È2É40 (11H, m). V
(Ðlm) 2950,
max
N-(1-(4-tert-Butylphenyl)-2-propyl)-2-amino-4-
(3-hydroxypropyl)-6-methyl-3,4,5,6-tetrahydropyrimidine
hydrochloride, 5
A solution of 34 (1É02 g, 3 mmol) in methanol under
reÑux was treated with sodium pellets (90 mmol) until
2880, 1740, 1100 cm~1.
2-(3-Benzyloxypropyl)cyclopentan-1-one oxime, 37
A solution of sodium carbonate in 20 ml water was
added slowly to a solution of 36, (1É4 g, 6 mmol), and

270
John W . L iebeschuetz et al.
hydroxylamine hydrochloride (4É2 g, 60 mmol) in
ethanol (15 ml) and water (40 ml). The reaction was
heated under reÑux for 7 h, then cooled to room tem-
perature. The aqueous phase was extracted with ether.
The combined organic phase was washed with water
and brine, dried and concentrated, giving 37 (1É23 g) in
83% yield. The material was used in the following reac-
tion without further puriÐcation. d (CDCl , 90 MHz)
extracted into chloroform. The combined chloroform
phase was washed with brine, dried and concentrated.
This material was distilled at 190¡C, 2 mm Hg. The
residue was chromatographed on silica, eluting with
ethanol in chloroform. Compound 40 (220 mg) was
obtained in 8% yield. d (CDCl ] NaOD) 7É20È7É40
H
3
(9H, m), 4É50 (2H, s), 4É10È4É20 (1H, m), 3É40È3É60 (2H,
m), 3É20È3É35 (1H, m), 2É63 (1H, dd, J \ 13, 7 Hz),
1É40È2É00 10H, m), 1É29 (9H, s), 1É05 (3H, d, J \ 7 Hz).
H
3
7É90 (1H, brs), 7É20È7É40 (5H, m), 4É50 (2H, s), 3É45 (2H,
t, J \ 6 Hz), 2É25È2É75 (3H, m), 1É10È2É10 (8H, m). V
(Ðlm) 3300 (br), 2930, 2850, 1730, 1690 cm~1.
d 19É7, 20É2, 26É4, 26É6, 28É7, 31É4. 34É0, 35É4, 41É6, 46É6,
max
C
55É1, 71É0, 72É7, 124É9, 125É0, 127É3, 127É6, 128É2, 129É0,
129É3, 136É1, 138É1, 155É5. MS 420 (20% M` [ HCl)
329(50), 273(75), 159(82).
760 cm~1.
V
3200, 2950, 1630,
6-(3-Benzyloxypropyl)-2-piperidinone, 38
max
A mixture of 37 (506 mg, 2 mmol), mesitylene sulfonyl
chloride (875 mg, 4 mmol), N,N-dimethylaminopyridine
(trace), pyridine (0É5 ml, 6 mmol), and carbon tetra-
chloride (15 ml) was heated at 60¡C for 5 h. Thin-layer
chromatography showed complete disappearance of the
oxime. The reaction was treated with water, and heating
was continued for a further 5 h. The carbon tetra-
chloride was removed by evaporation. The solution was
basiÐed with sodium hydrogen carbonate solution, then
extracted with dichloromethane. The combined organic
phase was dried and concentrated. The crude material
was chromatographed on silica gel, eluting with
methanolÈchloroform mixtures. Compound 38 (198 mg)
was obtained in 36% yield, essentially as one isomer
only. d (CDCl , 500 MHz), 7É35È7É45 (5H, m), 5É87
N-(1-(4-tert-Butylphenyl)-2-propyl)-2-amino-6-
(3-hydroxypropyl-3,4,5,6-tetrahydropyridine
hydrochloride, 6
A solution of 40 (220 mg, 0É5 mmol) in ethanol (20 ml)
and hydrochloric acid (2 M, 1É5 ml) with 10% Pd/C
(20 mg) was hydrogenated at 50 psi for 4 h. The
mixture was Ðltered through celite and concentrated,
giving 6 (180 mg) in 94% yield. d (CDCl ] NaOD),
H
3
7É30 (2H, d, J \ 8 Hz), 7É05 (2H, d, J \ 8 Hz), 4É05È
4É10 (1H, m), 3É50È3É80 (2H, m), 3É05È3É12 (1H, m), 2É82
(1H, dd, J \ 13, 5 Hz), 2É73 (1H, dd, J \ 13, 5 Hz),
1É60È2É05 (10H, m) 1É31 (9H, s), 1É04 (3H, d, J \ 7 Hz).
H
3
d 19É9, 20É4, 26É8, 30É4, 31É4, 32É6, 34É3, 39É0, 41É1, 45É9,
(14, brs), 4É51 (2H, s), 3É48 (2H, t, J \ 6 Hz), 3É35È3É45
C
56É1, 62É8, 125É0, 129É4, 135É3, 149É0, 156É0. MS 330
(1H, m), 2É20È2É45 (2H, m), 1É85È2É00 (2H, m), 1É55È
(100% M` [ HCl) 285(42), 271(70). V
1656, 1456 cm~1.
3392, 2961,
1É80 (5H, m), 1É30È1É45 (1H, m). V
1657, 1108 cm~1.
(KBr) 3200, 2940,
max
max
6-(3-Benzyloxypropyl)-2-ethoxy-3,4,5,6-
tetrahydropyridine, 39
Ethyl 3-(4-tert-butylphenyl)propenoate, 41
Sodium hydride (60% in mineral oil; 2É42 g) was
washed with hexane under nitrogen. Tetrahydrofuran
(30 ml) was added and the mixture cooled to 0¡C. Tri-
ethylphosphonoacetate (13É8 g) in THF (50 ml) was
added dropwise with stirring. Half an hour after com-
pletion of the addition 4-tert-butylbenzaldehyde (10 g)
in THF (40 ml) was added dropwise. The mixture was
allowed to warm to room temperature, the solvent
evaporated and the residue taken up in ethyl acetate.
The solution was washed with water, dried, Ðltered and
A solution of 38 (3É7 g, 15 mmol) and ethyl chlorofor-
mate (1É4 ml, 15 mmol) in dichloromethane (50 ml) was
heated under reÑux for 20 h. The reaction was cooled to
room temperature, and washed with a solution of
sodium carbonate. The aqueous phase was extracted
with dichloromethane. The combined organic phase
was washed with brine, dried and concentrated. The
crude material was distilled at 1 mm Hg, 180¡C, giving
39 (1É73 g) in 42% yield. d (CDCl ) 7É20È7É40 (5H, m),
H
3
4É52 (2H, s), 3É90È4É20 (2H, m), 3É40È3É60 (2H, m), 3É22È
3É40 (1H, m), 1É45È2É20 (10H, m), 1É25 (3H, t, J \ 7 Hz).
the solvent removed to a†ord 41 as an oil (12 g). d
H
(90 MHz) (CDCl ) 7É64 (1H, d, J \ 16 Hz), 7É50 (4H, s),
3
V
(Ðlm) 2950, 2870, 1670, 1100 cm~1.
6É47 (1H, d, J \ 16 Hz), 1É35 (9H, s). V , 2960, 1705,
max
max
1628, 1604, 1170 cm.
N-(1-(4-tert-Butylphenyl)-2-propyl)-2-amino-6-
(3-benzyloxypropyl-3,4,5,6-tetrahydropyridine
hydrochloride, 40
A mixture of 39 (1É73 g, 6 mmol) and 32 (1É14 g,
6 mmol) was heated in a bomb at 180¡C for 16 h. The
reaction was cooled and the mixture was dissolved in
3 M hydrochloric acid and washed with ether. The
ethereal phase was separated and the remainder was
Also in this manner:
Ethyl trans-undec-2-enoate, 47 was prepared from
nonanal. B.p. 105¡C (1É5 mm Hg). d (90 MHz) (CDCl )
H
3
6É98 (1H, dt, J \ 15, 7 Hz), 6É82 (1H, dt, J \ 15,
1É5 Hz), 4É22 (2H, q, J \ 7 Hz), 2É2 (2H, m), 1É25 (15H,
m), 0É88 (3H, m). V
1467 cm~1.
2929 (s), 1726 (s), 1657 (s),
max

Rationally designed guanidine and amidine fungicides
271
Ethyl 4-nitro-3-(4-tert-butylphenyl)pentanoate, 42
3-(4-tert-Butylphenyl)-2-methylpyrrolidine, 44
Compound 41 (6 g), nitroethane (35 ml) and 40% tetra-
butylammonium hydroxide solution in methanol (6 ml)
were mixed and heated at reÑux under nitrogen for 3 h.
The resulting mixture was poured into 10% aqueous
ammonium chloride (85 ml) and this was extracted
several times with ethyl acetate. The organic solution
was washed three times with 10% ammonium chloride,
dried, Ðltered and concentrated to a†ord 42 (4É2 g) as
Aminoalcohol 43 (4É2 g), triphenylphosphine (4É69 g)
and diethyl azodicarboxylate (3É1 g) were dissolved in
THF (100 ml). Two drops of glacial acetic acid were
added and the solution was heated under reÑux for 2 h.
During this time the initially red solution became
yellow. On cooling, hexane was added until precipi-
tation started. The mixture was then cooled in the
freezer and the crystalline precipitate Ðltered o†. The
solvent was removed under reduced pressure and the
residue taken up in chloroform and washed with water.
The organic layer was dried and concentrated and the
residue vacuum distilled (130¡C, 2 mm Hg) to a†ord a
mobile oil (3 g). NMR and IR spectra of the product
indicated a mixture of the two possible diastereoisomers
an oil consisting of a mixture of diastereoisomers. d
H
(90 MHz) (CDCl ) 7É33 (2H, dd), 7É1 (2H, d,
3
J \ 7É5 Hz), 4É83 (1H, m), 4É00 (q, J \ 6 Hz). 3É68 (2H
quin., J \ 7 Hz), 2É71 (2H, dd), 1É61 (d, J \ 6 Hz) 1É38
(d, J \ 6 Hz) 1É3 (9H, s,), 1É13 (t, J \ 6 Hz) 1É06 (t,
J \ 6 Hz). V 2970, 1740, 1555, 1366 cm~1.
max
in a ratio of 2 : 1. d (250 MHz) 7É35 (2H, m), 7É14 (2H,
Also in this manner:
H
m), 4É2 (1H, brs),3É63 (m), 3É3 (m), 1É9È2É9 (m@s), 1É3 (brs,
Ethyl 4-nitro-3-phenylpentanoate, 48 was prepared
from ethyl 3-phenyl pentenoate. d (90 MHz) (CDCl )
CH s), 0É88 (d, J \ 6 Hz, CH ). V
3280, 2970, 1617,
3
3
max
1515, 1463 cm~1.
H
3
7É3 (5H, m) 4É88 (1H, m), 4É00 (2H, m), 3É70 (1H, m),
2É78 (2H, m), 1É55 (1H, d, J \ 6É5 Hz) 1É30 (1H, d,
J \ 6É5 Hz) 1É07 (3H, m)
In a similar manner:
3-Phenyl-2-methyl pyrrolidine, 52 was prepared from
50. d (250 MHz) 7É2 (5H, m), 3É35 (m), 3É27 (m), 3É16
Ethyl 3-(1-nitroethyl)undecanoate, 49 was prepared
from 47. B.p. 150¡C (0É2 mm Hg). d (90 MHz) (CDCl )
H
(m), 3É04 (m), 2É73 (1H, brs), 2É24 (1H, m), 1É97 (1H, m),
H
3
1É13 (d, J \ 6 Hz), 0É72, (d, J \ 6 Hz). V
2968, 2878, 1728, 1605, 1498, 1454 cm~1.
3238, 3035,
4É75 (1H, m), 4É20 (2H, q, J \ 7 Hz), 2É45 (2H, m), 1É43
max
(3H, d, J \ 6 Hz), 1É3 (17H, m), 0É9 (3H, m). V
2859, 1741, 1557, 1466 cm~1.
2931,
max
3-Octyl-2-methyl pyrrolidine, 53 was prepared from
51. B.p. 100¡C (0É4 mm Hg), d (90 MHz) (CDCl ) 3É85
3-(4-tert-Butylphenyl)-4-aminopentan-1-ol, 43
H
3
(1H, brs), 2É7È3É4 (3H, m), 1É9 (2H, m), 1É3 (m), 0É9 (d,
J \ 6 Hz), 0É85 (m).
Nitroester 42 (6É5 g) was added dropwise to lithium alu-
minium hydride (5 g) suspended in anhydrous diethyl
ether (200 ml) under nitrogen with stirring. The mixture
was heated under reÑux for ten h. Water ] THF
(50 ] 50 by volume) was added slowly dropwise with
vigorous stirring until e†ervescence ceased. Sodium
hydroxide solution (1 M) was then added dropwise until
the slurry coagulated to a course sandy consistency.
The mixture was Ðltered and the solid washed with
diethyl ether. The organic fractions were combined,
washed with water, dried, Ðltered and the solvent
evaporated o† at reduced pressure to a†ord a gum (4 g).
NMR and IR spectra of the product indicated a
mixture of the two possible diastereoisomers in a ratio
Cis- and trans 1-(pyrimidine-2-yl)-2-methyl-3-(4-tert-
butylphenyl)pyrrolidine, 45 and 46
Substituted pyrrolidine 44 (1É4 g), 2-chloropyrimidine
(0É74 g) and diisopropylethyamine (0É83 g) were mixed
together in pentanol (40 ml) and heated under reÑux for
6 h. The pentanol was distilled o† under reduced pres-
sure. The residue was taken up in dichloromethane,
washed with water and concentrated. Column chroma-
tography of the residue (toluene ] ethyl acetate) a†ord-
ed both cis and trans isomers, stereochemically pure in
a 2 : 1 ratio, yield 70%.
of 2 : 1. d (90 MHz) 7É25 (4H, m), 3É55 (2H, m) 3É15
H
(1H, m), 2É57 (1H, m), 2É05 (2H, m) 1É33 (9H, s), 1É10 (d,
Cis-isomer: 45. d (90 MHz) 8É46 (2H, d, J \ 5 Hz),
H
J \ 5 Hz), 0É93 (d, J \ 6 Hz). V
2876, 1603 cm~1.
3349, 3280, 2932,
7É4 (4H, ABq, J \ 8 Hz), 6É52 (1H, t, J \ 5 Hz), 4É70
max
(1H, quin, J \ 7 Hz), 3É70 (3H, m), 2É35 (3H, m), 1É35
(9H, s), 0É90 (3H, d, J \ 7 Hz). V
1544, 1513, 1477 cm~1.
3420, 2970, 1584,
In a similar manner:
max
3-Phenyl-4-aminopentanol, 50 was prepared from 48.
d (90 MHz), (CDCl /D O shake) 7É3 (5H, m), 3É45 (2H,
Trans-isomer: 46.
d
(90 MHz) 8É38 (2H, d,
H
H
3
2
J \ 4É5 Hz), 7É26 (4H, ABq, J \ 8 Hz), 6É50 (1H, t,
J \ 4É5 Hz), 4É33 (1H, quin, J \ 6 Hz), 3É75 (2H, m),
3É13 (1H, q, J \ 6 Hz), 2É2 (2H, brm), 1É41 (3H, d,
m) 3É06 (1H, m) 2É53 (1H, m) 1É95 (2H, m) 1É07 (d,
J \ 6 Hz) 0É88 (d, J \ 6 Hz). V
2876, 1602, 1496, 1453 cm~1.
3350, 3279, 2932,
max
J \ 6 Hz).
1465 cm~1.
V
3420, 2970, 1580, 1549, 1499,
3-(1-Aminoethyl)dodecanol, 51 was prepared from 49.
(90 MHz) 3É7 (2H, m) 3É35 (3H, brs) 3É1 (1H, m)
1É1È1É8 (19H, m), 1É05, (d, J \ 6 Hz), 0É88 (3H, m).
max
d
H
In a similar manner:

272
Cis-and trans-1-pyrimidin-2-yl-2-methyl-3-phenylpyr-
rolidine 54 and 55 were prepared from 50 and 2-
chloropyrimidine.
John W . L iebeschuetz et al.
1É25 (9H, s), 0É80 (3H, d). V
1450, 1400 cm~1.
3180, 2980, 1640, 1583,
max
In a similar manner:
Cis-isomer: 54, d (CDCl 500 MHz) 8É32 (2H, d,
Trans-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-(4-tert-
butylphenyl)pyrrolidinium acetate, 9, was prepared from
H
3
J \ 4É5 Hz), 7É34 (3H, m), 7É25 (2H, m), 6É45 (1H, d,
J \ 4É5 Hz), 4É60 (1H, quin. J \ 7 Hz), 3É84 (1H, m),
3É63 (2H, m) 2É50 (1H, m), 2É27 (1H, m), 0É88 (3H, d,
46. d (90 MHz) 9É35 (2H, m), 7É21 (4H, ABq, J \ 8 Hz),
H
4É26 (1H, m) 3É63 (2H, m) 3É32 (4H, m), 2É96 (1H, m),
J \ 6 Hz). V
1340 cm~1.
3100, 2970, 2400, 1580, 1550, 1500,
2É16 (2H, m), 1É82 (3H, s), 1É80 (2H, m), 1É30 (9H, s), 1É25
max
(3H, d). V 3180, 2980, 1640, 1583, 1450, 1400 cm~1.
max
Trans-isomer: 55, d (CDCl ) 500 MHz), 8É33 (2H, d,
Cis-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-(4-tert-
butylphenyl)pyrrolidinium chloride 61 was prepared from
H
3
J \ 4É5 Hz), 7É3 (3H, m), 7É23 (2H, m), 6É48 (1H, t,
J \ 4É5 Hz), 4É32 (1H, m), 3É92 (1H, m), 3É67 (1H, m),
3É16 (1H, m), 2É44 (1H, m), 2É05 (1H, m), 1É42 (3H, d,
45. d (250 MHz) 8É1 (2H, brs), 7É29 (2H, d, J \ 8 Hz)
H
7É12 (2H, d, J \ 8 Hz), 4É73 (1H, m), 3É95 (1H, m), 3É5È
J \ 6 Hz).
1335 cm~1.
V
3100, 2770, 2400, 1580, 1550,
3É7 (2H, m), 3É4 (4H, m), 2É2È2É4 (2H, m), 1É83 (1H, m)
1É275 (9H, s), 0É835 (3H, d, J \ 6 Hz). MS (FAB
Ionisation) 300(M`), 112.
max
Cis-and trans-1-(4,6-dimethyl pyrimidin-2-yl)-2-methyl-
3-(4-tert-butylphenyl)pyrrolidine 56 and 57 were pre-
pared from 45 and 2-chloro-3,5-dimethylpyrimidine.
Trans-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-(4-tert-
butylphenyl)pyrrolidinium chloride, 12 was prepared
from 46. d (90 MHz) 7É35 (2H, m), 7É3 (4H, m), 4É2 (1H,
Cis-isomer: 56, d (90 MHz) 7É30 (4H, m), 6É28 (1H,
H
H
m), 3É5 (4H, m), 3É05 (2H, m), 2É15 (1H, m), 1É8 (4H, m),
s), 4É70 (1H, m), 3É5È4É0 (3H, m), 2É2È2É5 (2H, m), 2É3
1É3 (12H, m).
(6H, s), 1É3 (9H, s), 0É90 (3H, D, J \ 6 Hz).
Cis-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-phenyl
Trans-isomer: 57, d (90 MHz) 7É30 (4H, m), 6É28
H
pyrrolidinium acetate, 8 was prepared from 54. d
(1H, s), 4É27 (1H, m), 3É5È4É1 (2H, m), 3É15 (1H, m), 2É3
H
(90 MHz) (CDCl /D O), 7É22 (5H, m), 4É58 (1H, m),
(6H, s), 1É85È2É5 (2H, m), 1É35 (12H, m). V
2933, 2861, 1646, 1490 cm~1.
3270, 3035,
3
2
max
3É5È4É0 (3H, m), 3É37 (4H, m), 2É0È2É6 (2H, m), 1É98 (3H,
s), 1É85 (2H, m), 0É75 (3H, d,J \ 6 Hz). V
2970, 2900, 1640, 1575, 1320 cm~1.
3300, 3200,
max
Cis and trans 1-(pyrimidin-2-yl)-2-methyl-3-octylpyr-
rolidine 58 and 59 were prepared from 53 and 2-
chloropyrimidine.
Trans-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-phenyl-
pyrrolidinium acetate 7 was prepared from 55. d
H
(90 MHz) (CDCl ) 9É2 (2H, m), 7É2 (5H, m), 4É27 (1H,
3
Cis-isomer: 58, d (90 MHz) (CDCl ) 8É40 (2H, d,
H
3
J \ 4É5 Hz), 6É47 (1H, t, J \ 4É5 Hz), 4É35 (1H, m), 3É60
(2H, m), 2É05 (3H, m), 1É35 (14H, m), 1É1 (3H, d,
J \ 7 Hz), 0É9 (3H, m).
m), 3É60 (2H, m), 2É95 (1H, m), 2É0È2É4 (2H, m), 1É84
(3H, s), 1É75 (2H, m), 1É25 (3H, d, J \ 6 Hz). V
3400,
max
3300, 3200, 2970, 2900, 1640, 1575, 1430, 1320 cm~1.
Trans-isomer: 59,
d
(90 MHz) 8É28 (2H, d,
J \ 5 Hz), 6É42 (1H, t, J \ 5 Hz), 3É4È4É3 (3H, m), 1É9
Cis - N - (4,6 - dimethyltetrahydropyrimidin - 2 - yl) - 2 -
methyl-3-(4-tert-butylphenyl)pyrrolidinium chloride, 13
H
(2H, m), 1É3 (17H, m), 0É9 (1H, m).
was prepared from 56. d (250 MHz) 7É66 (1H, brs),
H
7É315 (2H, d, J \ 8 Hz), 7É16 (2H, d, J \ 8 Hz), 7É07
1-pyrimidin-2-yl-pyrrolidine, 60 was prepared from
(1H, brs), 5É00 (1H, m), 4É06 (1H, m), 3É5È3É8 (4H, m),
2É2È2É5 (2H, m), 2É00 (1H, m), 1É9 (1H, brm), 1É45 (3H, d,
J \ 6 Hz), 1É43 (3H, d, J \ 6 Hz), 1É28 (9H, s), 0É82 (3H,
pyrrolidine and 2-chlorpyrimidine. d (90 MHz) 8É37
H
(2H, d, J \ 4É5 Hz), 6É50 (1H, t, J \ 4É5 Hz), 3É60 (4H,
m) 2É0 (4H, m). V
1340 cm~1.
2950, 2870, 1590, 1560, 1520, 1390,
max
d, J \ 6 Hz). V
3420, 3230, 2980, 1640, 1580,
1470 cm~1. MS (FAB) 328 (M`).
max
Cis-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-
(4-tert-butylphenyl)pyrrolidinium acetate, 10
Trans - N - (4,6 - dimethyltetrahydropyrimidin - 2 - yl) - 2 -
methyl-3-(4-tert-butylphenyl)pyrrolidinium chloride, 14
Cis-pyrimidinylamine 45 (540 mg) was dissolved in
ethanol (20 ml) containing 10% Pd/C (100 mg) and
acetic acid (0É5 ml) added. The mixture was hydro-
genated at room temperature and pressure with shaking
for 8 h until the theoretical quantity of hydrogen had
been absorbed. The mixture was passed through celite
and the Ðltrate evaporated under reduced pressure. A
was prepared from 57. V
1576 cm~1.
3180, 3060, 2980, 1630,
max
Cis-N-tetrahydropyrimidin-2-yl)-2-methyl-3-octylpyr-
rolidinium chloride, 62 was prepared from 58. d
H
(250 MHz) 8É02 (2H, brs), 4É38 (1H, m), 3É76 (1H, m)
3É58 (1H, m), 3É42 (4H, m), 2É05 (2H, m), 1É87 (2H, m),
1É63 (1H, m), 1É25 (15H, m), 1É03 (3H, d, J \ 6 Hz), 0É88
gum 10 (0É5 g) was collected. d (90 MHz) 9É1 (2H,
H
NHs), 7É22 (4H, ABq, J \ 8 Hz), 4É6 (1H, m), 3É84 (2H,
(3H, t). V
max
MS (FAB) 280 (M`).
3400, 3180, 3070, 2935, 1660, 1600 cm~1.
m), 3É34 (4H, m), 2É26 (2H, m), 1É93 (3H, s), 1É90 (2H, m),

Rationally designed guanidine and amidine fungicides
273
Trans-N-(tetrahydropyrimidin-2-yl)-2-methyl-3-octyl-
129É7, 129É8, 133É6, 150É4, 152. V
1603, 1501, 1353 cm~1.
3177, 2968, 1695,
max
pyrrolidinium chloride, 15 was prepared from 59. d
H
(250 MHz), 7É89 (2H, brs), 3É95 (1H, m), 3É5È3É8 (2H, m),
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-phenylforma-
1É89 (2H, m), 1É63 (1H, m), 1É25 (18H, m), 0É88 (3H, t).
MS (FAB) 280 (M`).
midine, 64 was prepared from 16. d 7É3 (8H, m), 7É0
H
(1H, m), 6É85 (1H, brs), 2É8 (3H, m), 1É3 (9H, s), 1É26 (3H,
1-(Hexahydropyrimidin-2-yl)pyrrolidinium acetate, 11
d, J \ 7 Hz). V
3213, 2968, 1667, 1641, 1593, 1490,
max
was prepared from 60. d (90 MHz) 8É8 (2H, brs), 3É45
1192 cm~1.
H
(8H, m) 1É9 (3H, s), 1É85 (6H, m).
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(4-methyl-
phenyl)acetamidine hydrochloride 26 was prepared from
47 R = Me and 4-methylaniline. Yield 40% as a colour-
less solid recrystallised from ethyl methyl ketone, m.p.
(corrected) 167É4¡C. d (CDCl ) 11É46 (1H, brs), 10É74
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-phenylacetamidine
hydrochloride, 17.
N-(1-(4-tert-Butylphenyl prop-2-yl) acetamide 47
R = Me, (2É1 g, 8É5 mmol) and aniline (2É44 g,
26É2 mmol) were dissolved in dry chloroform (50 ml)
and the mixture cooled to 0¡C and stirred under nitro-
gen. Phosphorus pentachloride (2É48 g, 11É80 mmol)
was added and the mixture allowed to warm to room
temperature. An exotherm was noticed. The mixture
was then heated under reÑux for 1 h. Water (30 ml) was
added to the cooled mixture and the whole stirred
vigorously for 30 min. The aqueous layer was separated
and the organic layer washed with water until the
washings had a pH of greater than 4. The organic layer
was dried and concentrated. The residue was triturated
with ethyl methyl ketone and the resulting colourless
solid collected. This was recrystallised from ethyl methyl
H
3
(1H, brd, J \ 9 Hz), 7É38 (2H, d, J \ 10 Hz), 7É25 (2H,
d, J \ 10 Hz), 7É12 (2H, d, J \ 8 Hz), 6É84 (2H, d,
J \ 8 Hz), 3É73 (1H, m), 2É91 (2H, m), 2É33 (3H, s), 1É48
(3H, d, J \ 6É5 Hz), 1É32 (9H, s), 1É28 (3H, s); d 13É5,
C
21É1, 31É4, 34É5, 43É6, 53É9, 125É7, 126É1, 129É7, 130É1,
132É2, 134É6, 138É6, 150É3, 165É7. V
1650, 1614, 1582, 1519, 1434 cm~1.
3427, 3196, 2967,
max
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(3-methyl-
phenyl)acetamidine hydrochloride 25 was prepared from
47 R = Me and 3-methylaniline. Yield 16% as a colour-
less solid recrystallised from ethyl methyl ketone, m.p.
(corrected) 192É9¡C. d 11É62 (1H, brs), 10É76 (1H, brd,
H
J \ 9É6 Hz), 7É37 (2H, d, J \ 8 Hz), 7É2 (4H, m), 6É83
(1H, brs), 6É74 (1H, d, J \ 8 Hz), 3É73 (1H, m), 2É92 (2H,
ketone. Yield 1É4 g (45%), m.p. 212É9¡C (corrected); d
H
(CDCl ) 11É62 (1H, brs), 10É76 (1H, brd, J \ 9É6 Hz),
3
m), 2É31 (3H, s), 1É51 (3H, d, J \ 6É5 Hz); d 13É3, 21,
C
31É3, 34É4, 43É5, 53É8, 123É1, 125É6, 126É6, 129É0, 129É2,
7É37 (2H, d, J \ 8 Hz), 7É2 (4H, m), 6É83 (1H, brs), 6É74
129É6, 134É5, 134É7, 139É8, 150É2, 165É4. V
2966, 1647, 1609, 1591, 1515, 1491, 1431 cm~1.
3429, 3188,
(1H, d, J \ 8 Hz), 3É73 (1H, m), 2É92 (2H, m), 2É31 (3H,
max
s), 1É5 (3H, d, J \ 6É5 Hz), 1É34 (3H, s), 1É32 (9H, s) d
C
13É3, 21É1, 31É3, 34É4, 43É5, 53É8, 123É1, 125É6, 126É6,
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(2-methyl-
phenyl)acetamidine hydrochloride 24 was prepared from
47 R = Me and 2-methylaniline. Yield 32% as a colour-
less solid recrystallised from ethyl methyl ketone, m.p.
129É0, 129É2, 129É6, 134É5, 134É7, 139É8, 150É2, 165É4.
V
3429, 2971, 2881, 1653, 1595, 1497 cm~1.
max
N-(1-(4-tert-Butyl phenyl)prop-2-yl)-N@-
(corrected) 191É8¡C. d 11É46 (1H, brs), 10É74 (1H, d,
H
phenylacetamidine 63.
J \ 9É6 Hz), 7É39 (2H, m), 7É25 (2H, m), 7É1 (2H, d,
A sample of 17 was dissolved in water and basiÐed with
2 M sodium hydroxide. The mixture was extracted with
ether, the organic layer washed once with water, dried
and concentrated to a†ord a gummy residue in quanti-
tative yield. d (CDCl ) 7É25 (5H, m), 6É97 (1H, m), 6É73
J \ 8 Hz), 6É84 (2H, d, J \ 8 Hz), 3É73 (1H, m), 2É95
(2H, m), 2É33 (3H, s), 1É45 (3H, d, J \ 6 Hz), 1É32 (9H, s),
1É28 (3H, s). V
1519, 1434, 1383 cm~1.
3428, 3191, 2968, 1651, 1614, 1582,
max
H
3
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(4-chlorophenyl)-
acetamidine hydrochloride 28 was prepared from 47
R = Me and 4-chloroaniline. Yield 90% as colourless
needles from ethanol/ethyl methyl ketone, m.p.
(2H, d, J \ 8 Hz), 4É35 (1H, m), 2É85 (2H, m), 1É7 (3H, s),
1É33 (9H, s), 1É2 (3H, d, J \ 7 Hz); d 7É6, 20É0, 31É4,
34É4, 41É5, 46É6, 121É6, 122É2, 125É1, 128É6, 129É3, 135É4,
C
148É9, 151É9, 154É2. V
1231 cm~1.
3275, 2967, 1634, 1595, 1490,
max
(corrected) 234É8¡C. d 11É65 (1H, s), 10É70 (1H, d,
H
J \ 10 Hz), 7É3 (6H, m), 7É93 (2H, d, J \ 8 Hz), 3É75
In a similar manner:
(1H, m), 2É9 (2H, m), 1É5 (3H, d, J \ 6 Hz), 1É35 (3H, s),
1É32 (9H, s); d 12É6, 21É1, 31É5, 34É4, 43É5, 54É1, 125É8,
N-(1-(4-tert-butylphenyl)-prop-2-yl)-N@-phenylforma-
midine hydrochloride 16 was prepared from 47 R = H
and aniline. Yield 75% (as a gum). d (CDCl ) 12É1 (1H,
C
128É9, 129É7, 133É3È134É9, 149É3, 161É9. V
3426, 3190,
max
2967, 1647, 1593, 1515, 1496, 1459, 1432 cm~1.
H
3
d, J \ 12 Hz), 10É65 (1H, dd, J \ 12É9 Hz), 7É25 (8H, m),
6É8 (2H, d, J \ 8 Hz), 2É95 (1H, dd, J \ 5 Hz), 2É84 (1H,
N-1-(4-tert-Butylphenyl)prop-2-yl)-N@-(3-chlorophenyl)-
acetamidine hydrochloride 27 was prepared from 47
R = Me and 3-chloroaniline. Yield 50% as a colourless
solid from methanol/ethyl methyl ketone, m.p.
dd, J \ 8 Hz), 1É5 (3H, d, J \ 7 Hz), 1É25 (9H, s), d
C
20É4, 13É3, 34É5, 43É4, 57É6, 118É7, 126É0, 126É8, 129É2,

274
John W . L iebeschuetz et al.
chromatography (silica, chloroform
(corrected) 217É8¡C. d 11É95 (1H, brs), 10É89 (1H, brd,
column
H
J \ 9É9 Hz), 7É39 (2H, d, J \ 8 Hz), 7É27 (4H, m), 7É0
] methanol), m.p. (corrected) 164É5¡C. d (CDCl )
H
3
(1H, brs), 6É9 (1H, m), 3É72 (1H, m), 2É92 (2H, m), 1É53
11É08 (1H, brs), 10É97 (1H, d), 7É3 (5H, m), 6É93 (3H, m),
3É80 (3H, s), 3É73 (1H, m), 2É93 (2H, d, J \ 7 Hz), 1É39
(3H, d, J \ 6É5 Hz), 1É32 (9H, s); d 13É4, 21É0, 31É3,
43É5, 54É1, 124É3, 125É7, 126É3, 128É5, 128É5, 129É6, 130É5,
134É3, 135É1, 151, 165É4. V
max
1594, 1513, 1479, 1434 cm~1.
C
(3H, s), 1É30 (9H, s); d 13É1, 21É0, 31É3, 34É4, 43É3, 53É8,
55É8, 111É9, 120É7, 123É6, 125É5, 127É9, 129É4, 129É8,
C
3426, 3194, 2969, 1647,
134É5, 150, 154, 166.
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(3,4-dichloro-
phenyl)acetamidine hydrochloride 29 was prepared from
47 R = Me and 3,4-dichloroaniline. Yield 38% as a
colourless solid from methanol/ethyl methyl ketone,
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(4-hydroxyphenyl)-
acetamidine hydrochloride 20.
Compound 23 (2É5 g, 6É67 mmol) in dry dichloro-
methane (40 ml) was cooled to [ 78¡C. A solution of
boron tribromide in dichloromethane (1 M; 13 ml,
13É3 mmol) was added dropwise to the stirred solution.
The mixture was allowed to warm to room temperature
and was left for 48 h. The mixture was diluted with
dichloromethane and poured into saturated sodium
hydrogen carbonate solution. The organic layer was
separated and the precipitaginous aqueous layer
extracted twice with dichloromethane. The organic
extracts were combined and washed twice with water.
They were then dried over sodium sulfate, Ðltered and
the solvent removed under vacuum to a†ord a gum.
This was triturated with ethyl methyl ketone ] hexane
to a†ord a colourless crystalline solid which was col-
lected and recrystallised from ethyl methyl ketone. Yield
40%, m.p. (corrected) 235É2¡C. d (CDCl , NaOD),
m.p. (corrected) 214É8¡C. d 10É9 (1H, brd, J \ 9É6 Hz),
H
7É4 (3H, m), 7É25 (2H, d, J \ 8 Hz), 7É11 (1H, d,
J \ 2É4 Hz), 6É86 (1H, dd, J \ 8É5, 2É4 Hz), 3É75 (1H, m),
2É93 (2H, m), 1É54 (3H, d, J \ 6É4 Hz), 1É33 (12H, s).
V
3428, 2968, 1650, 1591, 1568, 1517, 1475,
max
1430 cm~1.
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(4-methoxy-
phenyl)acetamidine hydrochloride 23 was prepared from
47 R = Me and 4-methoxyaniline. Yield 93% as a
colourless powder from ethyl methyl ketone, m.p.
(corrected) 188É6¡C. d 11É4 (1H, s), 10É78 (1H, d,
H
J \ 9É6 Hz), 7É37 (2H, d, J \ 8 Hz), 7É25 (2H, d,
J \ 8 Hz), 6É9 (2H, d, J \ 8 Hz), 6É81 (2H, d, J \ 8 Hz),
3É79 (3H, s), 3É72 (1H, m), 2É92 (2H, m), 1É5 (3H, d,
J \ 6É5 Hz), 1É3 (9H, s), 1É29 (3H, s); d 13É3, 21É0, 31É3,
C
34É4, 43É5, 53É8, 55É4, 114É6, 125É6, 127É7, 129É6, 134É5,
H
3
7É295 (2H, d, J \ 8 Hz), 7É09 (2H, brd, J \ 8 Hz), 6É67
(2H, d, J \ 8 Hz), 6É55 (2H, d, J \ 8 Hz), 4É55 (1H, m),
2É75 (2H, m), 1É75 (3H, brs), 1É31 (9H, s), 1É15 (3H, d,
150É2, 159É3, 165É8. V
1518, 1433 cm~1.
3428, 2968, 1649, 1613, 1581,
max
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(3-methoxy-
phenyl)acetamidine hydrochloride 22 was prepared from
47 R = Me and 3-methoxyaniline. Yield 43% as a
colourless powder after column chromatography (silica
gel, chloroform ] methanol) and recrystallisation from
ethyl methyl ketone, m.p. 188É5¡C. d (CDCl ) 10É81
(1H, d, J \ 9É5 Hz), 7É38 (2H, d, J \ 8 Hz), 7É32 (1H,
6É5), 7É25 (3H, m), 6É83 (4H, dd, J \ 2É8 Hz), 6É54 (2H,
m), 3É77 (3H, s), 3É75 (1H, m), 2É9 (2H, m), 1É52 (3H, d,
J \ 6 Hz), 1É37 (3H, s), 1É31 (9H, s).
J \ 6 Hz); d 17, 20É9, 31É4, 34É4, 42É6, 49, 116É4, 124É2,
C
125É3, 129É2, 134É8, 149É4, 153, 158, 163.
In a similar manner:
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(3-hydroxy-
phenyl)acetamidine hydrochloride 19 was prepared from
H
3
22. Yield 73% as
a
colourless powder from
methanol ] ethyl methyl ketone, m.p. (corrected)
253É4¡C.
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(2-hydroxy-
phenyl)acetamidine hydrochloride 18 was prepared from
N-(1-(4-tert-Butylphenyl)prop-2-yl)-N@-(2-methoxy-
phenyl)acetamidine hydrochloride 21 was prepared from
47 R = Me and 2-methoxyaniline. Yield 52% as a
colourless powder from ethyl methyl ketone after
21. Yield 63% as
a
colourless powder from
methanol ] ethyl methyl ketone, m.p. (corrected)
213É0¡C.