Synthesis and in vitro antifungal activity of 1-amino-3,4-dialkylnaphthalene-2-carbonitriles and their analogues

Article abstract of DOI:10.1002/ps.338

Twenty-four 3- and/or 4-alkyl-substituted 1-aminonaphthalene-2-carbonitriles and their analogues were prepared and evaluated for growth-inhibiting activity against four phytopathogenic fungi: Fusarium culmorum, Alternaria brassicicola, Botrytis cinerea an

Full text of DOI:10.1002/ps.338

Pest Management Science
Pest Manag Sci 57:625±632 ꢀ2001)
DOI: 10.1002/ps.338
Synthesis and in vitro antifungal activity of
1-amino-3,4-dialkylnaphthalene-2-carbonitriles
and their analogues
Jarosław Wilamowski,1 Ewa Kulig,1 Janusz J Sepioł1* and Zbigniew J Burgieł2
1
´
Department of Organic Chemistry, Jagiellonian University, Ingardena 3, PL-30-060 Krakow, Poland
2
´
Department of Plant Protection, University of Agriculture, 29 Listopada 54, PL-31-425 Krakow, Poland
Abstract: Twenty-four 3- and/or 4-alkyl-substituted 1-aminonaphthalene-2-carbonitriles and their
analogues were prepared and evaluated for growth-inhibiting activity against four phytopathogenic
fungi: Fusarium culmorum, Alternaria brassicicola, Botrytis cinerea and Penicillium expansum. The
results obtained were compared with the activity of a commercial fungicide. The highest fungistatic
activity was revealed by amino nitriles having hydrogen atoms or only one short alkyl group "CH3,
C2H5) at the 3- or 4-position of the naphthalene system. The minimum values of calculated EC50 and
EC95 indexes were 1.1 and 5.1mg litreÀ1,respectively. These values were considerably lower than those
for the reference fungicide.
# 2001 Society of Chemical Industry
Keywords: alkylidenemalonodinitriles; amino nitriles; fungistatic activity; phytopathogenic fungi; structure-
activity relationships
1
INTRODUCTION
cyano groups are stepwise introduced onto an aro-
matic system. However, a synthetic method has been
found that allows the preparation of a variety of
carbocyclic, aromatic amino nitriles from acyclic
precursors in a single and simple synthetic step.4±6
This approach involves the cyclization of alkylidene-
malonodinitriles which have aromatic, alkenyl or
cycloalkenyl groups as substituents on an alkyl chain
at an appropriate distance from the cyano function.
On cyclization of alkylidenemalonodinitriles in con-
centrated sulfuric acid, the cyano group is protonated
and acts as an electrophile. Electrophilic substitution
of an aromatic ring is followed by the aromatization of
a six-membered, newly formed, carbocyclic ring,
usually to afford a benzene ring bearing the amino
and the cyano groups annulated to the benzene or
cycloalkenyl rings. In this manner we have synthesized
a variety of alkyl-substituted 1-aminonaphthalene-2-
carbonitriles from derivatives of a-phenylalkanones
and from 2-phenylalkanals.
The search for non-halogenated, easily biodegradable
fungicides is of continued interest and a challenge for
organic chemists and plant-protection specialists. In
preliminary tests we found that some carbocyclic
amino nitriles ꢀsuch as compound 1, Fig 1), which
have the amino and the cyano functions in neighbour-
ing positions on the aromatic systems, are active
against Fusarium species. In the next stage of the
investigations, the tests have been extended to include
Fusarium culmorum ꢀWG Smith)Sacc, Alternaria
brassicicola ꢀSchw)Wilts, Botrytis cinerea Pers, and
Penicillium expansum link fungi species. These tests
have shown moderate to high activity of the amino
nitriles 1 and 4 against the fungi investigated. The
results obtained encouraged us to extend the investi-
gations to compounds 5±10 which have a similar
structure.
To the best of our knowledge, no reports on the
fungitoxicity of carbocyclic, aromatic and vicinal
amino nitriles have been published in the chemical
literature. The closest investigations involved a study
of fungicidal activity of N-benzoyl- and N-dithiazoli-
dene-substituted anthranilic acid derivatives1,2 and 4-
amino-3-cinnolinecarboxylic acid derivatives.3
2
EXPERIMENTAL METHODS
2.1 Chemical synthesis
1-Aminonaphthalene-2-carbonitriles 1±5 bearing alkyl
groups at the 3- and 4-positions on the naphthalene
system were synthesized from aldehydes or ketones 11
in a two-step sequence. Carbonyl compounds 11 were
condensed with malonodinitrile under Knoevenagel's
The limited interest in research into the biological
activity of the amino nitriles to date appears to be
caused by the tedious synthetic routes to these com-
pounds. In the classical approach, the amino and the
´
* Correspondence to: Janusz J Sepioł, Department of Organic Chemistry, Jagiellonian University, Ingardena 3, PL-30-060, Krakow, Poland
E-mail: sepiol@chemia.uj.edu.pl
Contract/grant sponsor: State Committee for Scientific Research (KBN, Poland); contract/grant number: 3 T09B 030 14
(Received 17 November 2000; revised version received 9 February 2001; accepted 13 March 2001)
# 2001 Society of Chemical Industry. Pest Manag Sci 1526±498X/2001/$30.00
625

J Wilamowski et al
Figure 1. Chemical structures of tested compounds.
conditions5,6 and the resulting ꢀa-phenylalkylidene)-
malonodinitriles 12 were then cyclized in cold sulfuric
acid to give the amino nitriles 1±5 ꢀFig 2).
Cyclization of dinitriles 12a±k and 12m±o in
sulfuric acid gave the expected amino nitriles 1±4 in
satisfactory to good yield ꢀ74±95%). In the case of 12e
ꢀR1=i-C3H7, R2=CH3, Table 1, entry 5)the amino
nitrile 1e was obtained only in 21% yield. In this
reaction the amino nitrile 1a ꢀR1=H, R2 =CH3)was
the main product ꢀ44% yield), presumably resulting
from the dealkylation of the starting dinitrile 12e in the
ring-closure step. Loss of the relatively stable isopropyl
cation by 1e in a transitory step might relieve steric
congestion of alkyl groups in the 3- and 4- positions of
the ®nal, aromatic product. Similar cyclizations are
usually accompanied by the loss of a proton from the
same position of the intermediate product.4
Commercially available ketones 11 ꢀR1=H,
R2=CH3, C2H5, n-C3H7)were alkylated with a variety
of alkyl halides R1ÐX ꢀX=Br, I)under the PTC
conditions6,7 to afford ketones 11 ꢀR1, R2=alkyl)
which were then used in the condensation step. 2-
Phenylalkanals 11 ꢀR1=C2H5 or n-C3H7, R2 =H)
were obtained through Darzen condensation of
propiophenone or butyrophenone with ethyl chloroa-
cetate, followed by hydrolysis and decarboxylation of
the resulting 3-alkyl-3-phenyloxirane-2-carboxylic
acid.8
In the case of ketones 11 having long alkyl chains or
branched alkyl groups in the a-position with respect to
the carbonyl group, the conditions of condensation
with malonodinitrile had to be substantially modi®ed.
Due to steric hindrance of the carbonyl function, the
condensation time was extended from 4 to 16h. A
two- to four-fold excess of malonodinitrile, ammo-
nium acetate and acetic acid was used and the reagents
were stepwise introduced into the reaction solution
ꢀTable 1).
Phenylacetaldehyde 11 ꢀR1 =R2=H)cannot be
directly condensed with malonodinitrile due to its
predominant and competing self-condensation reac-
tion. The dinitrile 12l ꢀR1=R2=H)needed for the
preparation of 4a ꢀTable 1, entry 12)was therefore not
available by the route described here. This amino
nitrile was successfully obtained from 1-nitronaphtha-
lene, ethyl cyanoacetate, potassium cyanide and
sodium hydroxide in dry dimethylformamide accord-
ing to the reported method.9
Figure 2. Synthesis of alkyl substituted 1-aminonaphthalene-2-carbonitriles 1–5.
626
Pest Manag Sci 57:625±632 ꢀ2001)

1-Amino-3,4-dialkylnaphthalene-2-carbonitriles as fungicides
Amino nitrile 1±5
Dinitrile 12
Entry R1
R2
Yield ꢀ%) Mp ꢀ°C) Ref
Yield ꢀ%) Ref
1
2
H
CH3
CH3
CH3
1a
1b
1c
1d
1e
1f
1g
2a
2b
84
97
89
85
21a
79
93
91
90
83
87
48b
89
83
94
71
82
95
145±146
188±189
113±114
109±110
87±87.5
132±133
100±101
148±149
121±122
132±133
104±105
107±108
120±121
75±77
4
5
6
6
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
74
4
5
6
6
CH3
C2H5
77
3
79
4
n-C3H7 CH3
i-C3H7 CH3
76
c
c
5
75d
69e
72e
80e
74e
76d
76f
Ð
c
c
c
c
c
c
c
c
c
c
c
c
6
n-C4H9 CH3
n-C8H17 CH3
7
8
CH3
C2H5
C2H5
9
C2H5
C2H5
10
11
12
13
14
15
16
17
18
n-C3H7 3a
n-C3H7 n-C3H7 3b
H
H
H
H
H
4a
4b
4c
4d
5a
5b
5c
9
Ð
CH3
C2H5
n-C3H7
4
c
85
4
c
78
c
c
90±91
63
-ꢀCH2)3-
-ꢀCH2)4-
-ꢀCH2)5-
136±138
165±166
150±151
10 12p
12q
10 12r
60
10
4
4
72e
67e
10
a
Dealkylation product 1a in 44% yield.
b 4a was prepared from 1-nitronaphthalene according to Tomioka9 procedure.
c
All new compounds gave satisfactory analytical data:% CÆ0.3, HÆ0.2, NÆ0.2.
d Reaction time: 12h, malonodinitrile:ketone ratio=3:1.
Table 1. Synthesis and physical data of alkyl
substituted 1-aminonaphthalene-2-carbonitriles
1–5
e
Reaction time: 8h, malonodinitrile:ketone ratio=2:1.
f
Reaction time: 16h, malonodinitrile:ketone ratio=4:1.
Amino nitriles 5,106,11 and 712 were synthesized
from 2-phenylcycloalkanones, R-ꢀ‡)-pulegone and 2-
ꢀ1-cyclohexen-1-yl)cyclohexanone, respectively, using
essentially the same method as for preparation of
compounds 1±4. Amino amide 10a was prepared from
2-phenylpropanal according to the reported method.4
10-Aminophenanthrene-9-carbonitrile13 ꢀ8)was ob-
tained through aromatization of 7. Hydrolysis of amide
10a afforded amino acid 10b. Anthranilonitrile 9 was
commercially available ꢀAldrich).
washed successively with water, saturated aqueous
sodium hydrogen carbonate, and with water. The
product was crystalized from an appropriate solvent or
chromatographed on silica gel ꢀeluent: toluene).
Analytical samples were sublimed under reduced
pressure ꢀ1hPa).
2.1.2 Synthesis of 10-aminophenanthrene-9-carbonitrile
(8)
Amino nitrile 7 ꢀ510mg, 2.3mmol)and sulfur powder
ꢀ300mg, 9.4mmol)were heated to 200 °C for 5h and
then to 240°C for 15min. After cooling, the mixture
was extracted with boiling chloroform ꢀ3Â20ml). The
collected extracts were concentrated and chromato-
graphed ꢀsilica gel/chloroform). The obtained product
was sublimed under reduced pressure to give 380mg
ꢀ77%)of amino nitrile 8; colourless crystals, m p 176±
177°C ꢀlit13 174±178°C).
2.1.1 General procedure for the synthesis of amino nitriles
1±3, 4b±d and 5
In a 50-ml ¯ask equipped with a Dean±Stark water
trap and a re¯ux condenser were placed acetic acid
ꢀ1.20g, 20mmol), ammonium acetate ꢀ0.62g,
8mmol), malonodinitrile ꢀ1.78g, 27mmol), benzene
ꢀ20ml)and the appropriate phenylalkanone or 2-
phenylalkanal 11 ꢀ25mmol). After heating at re¯ux for
4h the reaction progress was monitored by GC and
additional portions of malonodinitrile, ammonium
acetate and acetic acid were added, if necessary ꢀTable
1). After cooling to room temperature the solution was
washed with water, saturated aqueous sodium hydro-
gen carbonate, and again with water, and dried over
anhydrous magnesium sulfate. Benzene was evapo-
rated and the remaining liquid was distilled under
reduced pressure to give dinitrile 12.
2.1.3 Synthesis of 1-amino-4-methylnaphthalene-2-
carboxylic acid( 10b)
Amino amide 10a4 ꢀ400mg, 2.0mmol), potassium
hydroxide ꢀ1.4g, 25mmol), ethanol ꢀ10ml) and water
ꢀ3ml)were heated under re¯ux for 24h. The solution
was diluted with water ꢀ100ml), ®ltered, and the
®ltrate was acidi®ed to pH 5.6 by addition of acetic
acid. The precipitate formed was ®ltered off, washed
with water and crystallized from methanol to give
352mg ꢀ88%)of amino acid 10b as pale yellow
needles;m p 195±197°C. IR ꢀKBr) n ꢀcmÀ1): 3500,
3369, 3280±2520, 1671, 1620, 1594, 1506, 1425,
1301, 1230, 747. 1H NMR ꢀDMSO-d6) d ꢀppm): 2.55
ꢀs, 3H), 7.45±7.62 ꢀm, 4H), 7.98 ꢀdd, 1H, J=8.5,
The dinitrile 12 ꢀ10mmol)was dropped slowly,
while stirring, into ice-cold concentrated sulfuric acid
ꢀ20ml). The ¯ask was kept in an ice-bath for 12h and
then the solution was poured onto 300g of crushed ice.
The resulting pale yellow precipitate was ®ltered off,
Pest Manag Sci 57:625±632 ꢀ2001)
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J Wilamowski et al
6.8Hz), 8.20 ꢀd, 1H, J=8.4Hz), 8.21 ꢀd, 1H,
J=8.5Hz). 13C NMR ꢀDMSO-d6) d ꢀppm): 20.2,
101.3, 120.2, 121.7, 124.1, 129.9, 124.9, 132.3,
135.8, 136.4, 148.7, 170.6. Anal calcd for
C12H11NO2 ꢀM=201.22):% C 71.27, H 5.98, N
6.93; found:% C 71.03, H 6.02, N 6.99.
2.2.4 1-Amino-4-butyl-3-methylnaphthalene-2-
carbonitrile (1f)
Pale yellow needles ꢀfrom ethanol). IR ꢀKBr) n
ꢀcmÀ1): 3471, 3372, 3263, 2955, 2927, 2873, 2858,
2203, 1640, 1616, 1569, 1440, 1367, 1248, 1170,
762, 682, 660, 1H NMR d ꢀppm): 0.98 ꢀt, 3H,
J=6.9Hz), 1.43±1.55 ꢀm, 4H), 2.54 ꢀs, 3H), 2.91 ꢀt,
2H, J=7.7Hz), 4.96 ꢀs, 2H, NH2), 7.45 ꢀdd, 1H,
J=8.3, 6.7Hz), 7.59 ꢀdd, 1H, J=8.6, 6.7Hz), 7.77 ꢀd,
1H, J=8.6Hz), 7.95 ꢀd, 1H, J=8.6Hz); 13C NMR d
ꢀppm): 14.0, 18.3, 23.0, 28.0, 32.3, 92.7, 118.5,
120.9, 121.6, 124.7, 124.8 126.7, 128.8, 131.4,
134.4, 146.9.
2.2 Physical and spectral data for new dinitriles
12e–k, 12n, 12o and amino nitriles 1e–g, 2, 3, 4c, 4d
Infra-red spectra were recorded on a Bruker IFS 48
spectrometer. 1H and 13C NMR spectra were taken at
500MHz and 125MHz, respectively, with a Bruker
AMX 500 spectrometer using deuterochloroform as
solvent and tetramethylsilane ꢀd=0ppm)as an inter-
nal standard. Elemental analyses were performed by
Regional Laboratory of Physical and Chemical Ana-
2.2.5 2-Methyl-3-phenylundec-1-en-1, 1-dicarbonitrile
(12g: R1=n-C8H17, R2 =CH3)
lyses ꢀKrakow)using a Perkin Elmer Analyzer Type
ꢀnine compounds)
ꢀnine com-
From 3-phenylundecan-2-one;7 b p 162±166°C at
Â
240. Dinitriles 12e±k,12n,12o
3hPa. IR ꢀKBr) n ꢀcmÀ1): 3086, 3062, 3028, 2952,
2926, 2854, 2229, 1588, 1494, 1454, 760, 700. H
1
and amino nitriles 1e±g,2,3,4c,4d
pounds)are all new and gave satisfactory elemental
analysis ꢀTable 1). Melting points were determined on
a Boetius hot-stage microscope and are uncorrected.
NMR d ꢀppm): 0.88 ꢀt, 3H, J=6.7Hz), 1.21±1.42 ꢀm,
12H), 1.83±1.91 ꢀm, 1H), 1.97±2.05 ꢀm, 1H), 2.07 ꢀs,
3H), 4.30 ꢀt, 1H, J=7.7Hz), 7.24±7.39 ꢀm, 5H). 13
C
NMR d ꢀppm): 14.0, 18.2, 22.6, 27.3, 29.1, 29.3,
29.4, 31.7, 31.8, 51.6, 85.7, 111.9, 112.1, 127.7 ꢀ2C),
128.1, 129.1 ꢀ2C), 138.0, 183.3.
2.2.1 2,4-Dimethyl-3-phenylpent-1-en-1, 1-
dicarbonitrile (12e: R1=i-C3H7, R2=CH3)
The dinitrile was obtained from 4-methyl-3-phenyl-
pentan-2-one;7 b p 134±137°C at 3hPa. IR ꢀKBr) n
ꢀcmÀ1): 3086, 3067, 3029, 2967, 2938, 2872, 2232,
1586, 1492, 1469, 1452, 1398, 1379, 1071, 777, 710,
538. 1H NMR d ꢀppm): 0.92 ꢀd, 3H, J=6.4Hz), 0.99
ꢀd, 3H, J=6.5Hz), 2.15 ꢀs, 3H), 2.38±2.46 ꢀm, 1H),
3.86 ꢀd, 1H, J=11.3Hz), 7.25±7.40 ꢀm, 5H). 13C
NMR d ꢀppm): 18.2, 20.7, 20.8, 29.2, 60.5, 85.7,
111.9, 112.2, 128.2, ꢀ2C), 128.3, 129.2 ꢀ2C), 137.6,
183.0.
2.2.6 1-Amino-3-methyl-4-octylnaphthalene-2-
carbonitrile (1g)
Pale yellow crystals ꢀfrom ethanol). IR ꢀKBr) n ꢀcmÀ1):
3475, 3375, 3249, 2955, 2923, 2873, 2848, 2205,
1643, 1568, 1504, 1442, 1373, 1248, 1166, 756, 688,
664. 1H NMR d ꢀppm): 0.89 ꢀt, 3H, J=6.9Hz), 1.24±
1.39 ꢀm, 8H), 1.45 ꢀquint., 2H, J=7.7Hz), 1.50±1.56
ꢀm, 2H), 2.55 ꢀs, 3H), 2.91 ꢀt, 2H, J=8.1Hz), 4.95 ꢀs,
2H, NH2), 7.46 ꢀdd, 1H, J=8.3, 6.8Hz), 7.60 ꢀdd,
1H, J=8.6, 6.8Hz), 7.78 ꢀd, 1H, J=8.3Hz). 7.95 ꢀd,
1H, J=8.6Hz). 13C NMR d ꢀppm): 14.1, 18.4, 22.6,
28.3, 29.3, 29.5, 30.0, 30.2, 31.9, 92.8, 118.5, 121.0,
121.6, 124.7, 124.8, 126.9, 128.8, 131.4, 134.4,
146.9.
2.2.2 1-Amino-3-methyl-4-(1-
methylethyl)naphthalene-2-carbonitrile (1e)
Colourless cubic crystals ꢀn-hexane). IR ꢀKBr) n
ꢀcmÀ1): 3450, 3369, 3243, 3055, 2967, 2862, 2201,
1636, 1574, 1505, 1433, 765, 747. 1H NMR d ꢀppm):
1.49 ꢀd, 6H, J=7.3Hz), 2.62 ꢀs, 3H), 3.68±3.84 ꢀm,
1H), 4.97 ꢀs, 2H, NH2), 7.46 ꢀdd, 1H, J=8.4, 6.7Hz),
7.56 ꢀdd, 1H, J=8.5, 6.8Hz), 7.80 ꢀd, 1H, J=8.4Hz),
8.21 ꢀd, 1H, J=8.5Hz). 13C NMR d ꢀppm): 19.5,
21.9, 28.6, 93.4, 118.6, 121.6, 121.8, 124.6, 128.0,
131.2, 131.8, 134.2, 147.0.
2.2.7 2-Ethyl-3-phenylbut-1-en-1, 1-dicarbonitrile
(12h: R1=CH3, R2=C2H5)
From 2-phenylpentan-3-one;14 bp 138±142°C at 3
hPa. IR ꢀKBr) n ꢀcmÀ1): 3090, 3067, 3030, 2979,
2942, 2884, 2228, 1580, 1496, 1466, 1450, 1379,
1
1028, 756, 716, 697. H NMR d ꢀppm): 0.92 ꢀt, 3H,
J=7.6Hz), 1.58 ꢀd, 3H, J=7.1Hz), 2.34±2.43 ꢀm,
2.2.3 2-Methyl-3-phenylhept-1-en-1, 1-dicarbonitrile
(12f: R1=n-C4H9, R2=CH3)
2H), 4.51 ꢀq, 1H, J=7.1Hz), 7.24±7.40 ꢀm, 5H). 13
C
NMR d ꢀppm): 14.0, 16.7, 25.8, 45.5, 85.3, 111.8,
112.1, 127.5 ꢀ2C), 128.1, 129.0 ꢀ2C), 138.2, 189.9.
From 3-phenylheptan-2-one;7 b p 144±146°C at
3hPa. IR ꢀKBr) n ꢀcmÀ1): 3095, 3067, 3029, 2958,
2933, 2866, 2230, 1586, 1497, 1454, 1379, 1109,
764, 702, 557. 1H NMR d ꢀppm): 0.93 ꢀt, 3H,
J=7.2Hz), 1.18±1.28 ꢀm, 1H), 1.30±1.40 ꢀm, 1H),
1.39±1.48 ꢀm, 2H), 1.85±1.94 ꢀm, 1H), 1.98±2.07
ꢀm, 1H), 2.07 ꢀs, 3H), 4.30 ꢀdd, 1H, J=8.4, 6.9Hz),
7.24±7.39 ꢀm, 5H). 13C NMR d ꢀppm): 14.0, 18.2,
22.5, 29.4, 30.8, 51.6, 85.6, 111.9, 112.0, 127.7 ꢀ2C),
128.1, 129.1 ꢀ2C), 137.9, 183.3.
2.2.8 1-Amino-3-ethyl-4-methylnaphthalene-2-
carbonitrile (2a)
Pale yellow crystals ꢀfrom ethanol). IR ꢀKBr) n ꢀcmÀ1):
3475, 3375, 3243, 3080, 2967, 2937, 2882, 2867,
2198, 1630, 1570, 1504, 1450, 1433, 1390, 1228,
1
758. H NMR d ꢀppm): 1.25 ꢀt, 3H, J=7.6Hz), 2.49
ꢀs, 3H), 2.96 ꢀq, 2H, J=7.6Hz), 4.54 ꢀbrs, 2H, NH2),
7.47 ꢀdd, 1H, J=8.4, 6.8Hz), 7.60 ꢀdd, 1H, J=8.5,
628
Pest Manag Sci 57:625±632 ꢀ2001)

1-Amino-3,4-dialkylnaphthalene-2-carbonitriles as fungicides
6.8Hz), 7.78 ꢀd, 1H, J=8.5Hz), 7.97 ꢀd, 1H,
J=8.5Hz); 13C NMR d ꢀppm): 13.7, 14.7, 26.1,
91.9, 118.4, 120.9 ꢀ2C), 121.5, 124.9, 125.0, 128.8,
135.3, 138.0, 147.3.
2.2.13 3-Phenyl-2-propylhex-1-en-1, 1-dicarbonitrile
(12k: R1=R2=n-C3H7)
From 5-phenyloctan-4-one;16 bp 144±149°C at 2
hPa. IR ꢀKBr) n ꢀcmÀ1): 3092, 3066, 3029, 2961,
2937, 2872, 2228, 1580, 1492, 1464, 1454, 1084,
752, 701. 1H NMR d ꢀppm): 0.85 ꢀt, 3H, J=7.1),
0.86±0.97 ꢀm, 1H), 1.00 ꢀt, 3H, J=7.3Hz), 1.27±1.40
ꢀm, 2H), 1.37±1.47 ꢀm, 1H), 1.84±1.92 ꢀm, 1H),
2.00±2.08 ꢀm, 1H), 2.24±2.30 ꢀm, 1H), 2.33±2.39
ꢀm, 1H), 4.33 ꢀt, 1H, J=7.6Hz), 7.24±7.39 ꢀm, 5H).
13C NMR d ꢀppm): 13.9, 14.6, 20.7, 23.5, 33.2, 34.7,
51.7, 85.8, 112.0, 112.3, 127.9 ꢀ2C), 128.2, 129.1
ꢀ2C), 137.5, 187.7.
2.2.9 2-Ethyl-3-phenylpent-1-en-1, 1-dicarbonitrile
(12i: R1=R2=C2H5)
From 4-phenylhexan-3-one;15 bp 134±138°C at 3.5
hPa. IR ꢀKBr) n ꢀcmÀ1): 3092, 3067, 3029, 2973,
2940, 2879, 2232, 1580, 1492, 1464, 1448, 1379,
1090, 764, 707. 1H NMR d ꢀppm): 0.86 ꢀt, 3H,
J=7.6Hz), 1.02 ꢀt, 3H, J=7.6Hz), 1.90±2.01 ꢀm,
1H), 2.06±2.17 ꢀm, 1H), 2.29±2.38 ꢀm, 1H), 2.38±
2.47 ꢀm, 1H), 4.24 ꢀt, 1H, J=7.6Hz), 7.24±7.40 ꢀm,
5H). 13C NMR d ꢀppm): 12.0, 13.9, 24.2, 25.6, 53.6,
85.9, 111.8, 112.3, 127.9 ꢀ2C), 128.1, 129.1 ꢀ2C),
137.3, 189.0.
2.2.14 1-Amino-3,4-dipropylnaphthalene-2-
carbonitrile (3b)
Colourless crystals ꢀfrom ethanol). IR ꢀKBr) n ꢀcmÀ1):
3481, 3356, 3237, 3084, 2961, 2925, 2872, 2217,
1630, 1574, 1504, 1485, 1450, 1435, 1391, 1166,
1084, 758, 670. 1H NMR d ꢀppm): 1.08 ꢀt, 3H,
J=7.3Hz), 1.24 ꢀt, 3H, J=7.3Hz), 1.57±1.66 ꢀm,
2H), 1.65±1.74 ꢀm, 2H), 2.84±2.93 ꢀm, 4H), 4.97
ꢀbrs, 2H, NH2), 7.47 ꢀdd, 1H, J=8.4, 6.8Hz), 7.56
ꢀdd, 1H, J=8.6, 6.8Hz), 7.79 ꢀd, 1H, J=8.4Hz), 7.96
ꢀd, 1H, J=8.6Hz); 13C NMR d ꢀppm): 14.4, 14.5,
24.3, 24.4, 30.1, 36.9, 92.3, 118.5, 121.1, 121.6,
124.9, 125.1, 127.6, 128.8, 134.6, 136.6, 147.2.
2.2.10 1-Amino-3,4-diethylnaphthalene-2-carbonitrile
(2b)
Colourless crystals ꢀfrom ethanol). IR ꢀKBr) n ꢀcmÀ1):
3475, 3381, 3249, 3080, 2967, 2925, 2867, 2198,
1636, 1611, 1567, 1508, 1436, 1228, 1170, 758, 670.
1H NMR d ꢀppm): 1.24 ꢀt, 3H, J=7.5Hz), 1.31 ꢀt,
3H, J=7.6Hz), 2.94 ꢀq, 2H, J=7.6Hz), 2.99 ꢀq, 2H,
J=7.5Hz), 4.95 ꢀbrs, 2H, NH2), 7.49 ꢀdd, 1H, J=8.4,
6.8Hz), 7.61 ꢀdd, 1H, J=8.6, 6.8Hz), 7.80 ꢀd, 1H,
J=8.4Hz), 8.00 ꢀd, 1H, J=8.5Hz); 13C NMR d
ꢀppm): 15.3, 15.4, 20.9, 25.6, 91.8, 118.4, 121.1,
121.6, 124.9 ꢀ2C), 127.3, 128.9, 134.4, 137.7, 147.3.
2.2.15 3-Phenylpent-1-en-1, 1-dicarbonitrile (12n:
R1=C2H5, R2=H)
From 2-phenylbutanal;17 bp 110±112°C/2 hPa. IR
ꢀKBr) n ꢀcmÀ1): 3042, 2968, 2935, 2884, 2236, 1598,
1493, 1454, 1080, 742, 700. 1H NMR d ꢀppm): 0.97
ꢀt, 3H, J=7.4Hz), 1.84±1.99 ꢀm, 2H), 3.84 ꢀdt, 1H,
J=11.0, 7.5Hz), 7.33 ꢀd, 1H, J=11.0Hz), 7.22±7.48
ꢀm, 5H). 13C NMR d ꢀppm): 11.7, 27.9, 50.9, 88.6,
110.7, 111.9, 127.5 ꢀ2C), 128.2, 129.5 ꢀ2C), 138.2,
170.8.
2.2.11 3-Phenyl-2-propylpent-1-en-1, 1-dicarbonitrile
(12j: R1 =C2H5, R2=n-C3H7)
From 3-phenylheptan-4-one;14 bp 128±134°C at 1.5
hPa. IR ꢀKBr) n ꢀcmÀ1): 3090, 3067, 3029, 2961,
2937, 2872, 2228, 1580, 1492, 1468, 1454, 1084,
764, 743, 700. 1H NMR d ꢀppm): 0.84 ꢀt, 3H,
J=7.2Hz), 0.87±0.98 ꢀm, 1H), 1.01 ꢀt, 3H,
J=7.4Hz), 1.31±1.42 ꢀm, 1H), 1.90±2.00 ꢀm, 1H),
2.06±2.16 ꢀm, 1H), 2.22±2.28 ꢀm, 1H), 2.32±2.38
ꢀm, 1H), 4.21 ꢀt, 1H, J=7.6Hz), 7.24±7.39 ꢀm, 5H).
13C NMR d ꢀppm): 12.0, 14.5, 23.4, 24.3, 34.6, 53.6,
86.0, 112.0, 112.4, 127.9 ꢀ2C), 128.2, 129.1 ꢀ2C),
137.4, 187.5.
2.2.16 1-Amino-4-ethylnaphthalene-2-carbonitrile (4c)
Colourless crystals ꢀfrom ethanol). IR ꢀKBr) n ꢀcmÀ1):
3488, 3431, 3387, 3243, 3061, 2961, 2925, 2866,
2195, 1636, 1608, 1495, 1436, 1150, 758. 1H NMR d
ꢀppm): 1.31 ꢀt, 3H, J=7.5Hz), 2.94 ꢀq, 2H,
J=7.5Hz), 4.96 ꢀbrs, 2H, NH2), 7.15 ꢀs, 1H), 7.53
ꢀdd, 1H, J=8.3, 6.8Hz), 7.63 ꢀdd, 1H, J=8.6,
6.8Hz), 7.83 ꢀd, 1H, J=8.3Hz), 7.98 ꢀd, 1H,
J=8.6Hz); 13C NMR d ꢀppm): 14.5, 25.0, 89.4,
118.9, 121.8, 122.4, 124.1, 124.7, 125.8, 128.7,
130.5, 134.3, 146.8.
2.2.12 1-Amino-4-ethyl-3-propylnaphthalene-2-
carbonitrile (3a)
Colourless crystals ꢀfrom ethanol). IR ꢀKBr) n ꢀcmÀ1):
3481, 3356, 3237, 3080, 2961, 2925, 2867, 2217,
1
1630, 1574, 1508, 1483, 1435, 1391, 763, 680. H
NMR d ꢀppm): 1.09 ꢀt, 3H, J=7.3Hz), 1.24 ꢀt, 3H,
J=7.5Hz), 1.65±1.74 ꢀm, 2H), 2.85±2.90 ꢀm, 2H),
2.98 ꢀq, 2H, J=7.5Hz), 4.45 ꢀbrs, 2H, NH2), 7.47
ꢀdd, 1H, J=8.6, 6.8Hz), 7.61 ꢀdd, 1H, J=8.6,
6.8Hz), 7.80 ꢀd, 1H, J=8.4Hz), 7.99 ꢀd, 1H,
J=8.6Hz); 13C NMR d ꢀppm): 14.4, 15.4, 21.0,
24.4, 34.4, 92.3, 118.5, 121.2, 121.6, 124.9 ꢀ2C),
127.3, 128.9, 134.3, 136.2, 147.2.
2.2.17 3-Phenylhex-1-en-1, 1-dicarbonitrile (12o:
R1=n-C3H7, R2=H)
From 2-phenylpentanal;18 bp 126±132°C/3 hPa. IR
ꢀKBr) n ꢀcmÀ1): 3029, 2967, 2935, 2872, 2239, 1598,
1496, 1454, 756, 700. 1H NMR d ꢀppm): 0.95 ꢀt, 3H,
J=7.4Hz), 1.26±1.37 ꢀm, 2H), 1.80±1.93 ꢀm, 2H),
3.95 ꢀdt, 1H, J=11.0, 7.5Hz), 7.33 ꢀd, 1H,
J=11.0Hz), 7.21±7.42 ꢀm, 5H). 13C NMR d ꢀppm):
Pest Manag Sci 57:625±632 ꢀ2001)
629

J Wilamowski et al
13.7, 28.8, 36.7, 50.0, 84.8, 110.6, 111.9, 127.4 ꢀ2C),
128.2, 129.2 ꢀ2C), 138.3, 171.1.
at 45°C. In primary screenings compounds were used
in a concentration of 20mg litreÀ1. The control sample
contained only one equivalent of acetone. The media
were poured onto 8-cm Petri dishes ꢀ10ml for each
dish)and after 2 days were inoculated with 5-mm
PDA discs of overgrown mycelium. In the case of
P expansum the medium was inoculated by a prick of
laboratory needle containing fungus spores. The Petri
dishes were incubated at room temperature in the
dark. Four days after inoculation the diameters of the
cultures were measured. The percentage inhibition of
fungal growth was determined by comparison between
the development of fungi colonies on media containing
compounds and on the control. Six replicates of each
test were carried out. Results were examined statisti-
cally using analysis of variance. The signi®cance of the
differences between combinations was estimated using
Duncan's test ꢀa=0.05).
In the secondary screening, only compounds which
showed more than 50% fungal growth inhibition were
used. In these experiments the media contained 0.2, 2,
20, 50 or 100mg litreÀ1 of the compounds. Concen-
trations that would give 50% and 95% growth
inhibition ꢀEC50 and EC95)were calculated by the
statistical method of linear regression between the
activity and the logarithm of the concentration.19
Comparative studies involving captan were carried out
under the same conditions using solutions in acetone,
and the concentrations of the fungicide were related to
its active component.
2.2.18 1-Amino-4-propylnaphthalene-2-carbonitrile
(4d)
Colourless needles ꢀfrom cyclohexane). IR ꢀKBr) n
ꢀcmÀ1): 3444, 3325, 3237, 3080, 2954, 2930, 2866,
2195, 1645, 1513, 1454, 1247, 871, 759. 1H NMR d
ꢀppm): 1.01 ꢀt, 3H, J=7.3Hz), 1.68±1.75 ꢀm, 2H),
2.89 ꢀt, 2H, J=7.6Hz), 4.96 ꢀbrs, 2H, NH2), 7.16 ꢀs,
1H), 7.54 ꢀdd, 1H, J=8.4, 6.9Hz), 7.63 ꢀdd, 1H,
J=8.4, 6.9Hz), 7.83 ꢀd, 1H, J=8.4Hz), 8.00 ꢀd, 1H,
J=8.4Hz); 13C NMR d ꢀppm): 14.0, 23.4, 34.3, 89.3,
118.9, 121.8, 122.5, 124.9, 125.2, 125.8, 128.6,
129.1, 134.5, 146.8.
2.3 Biological assays
The fungistatic activity of compounds 1±10 against
fungi F culmorum, B cinerea, A brassicicola and P
expansum was investigated. The results were compared
with the activity of a commercial fungicide, captan,
from a 500g kgÀ1 WP, `Kaptan 50 WP'. This was
checked for the content of the active component, and
the fungicide dissolved in acetone and the solution was
®ltered to remove insoluble mineral support. The
fungi were obtained from the Department of Plant
Protection, University of Agriculture Cracow,
Poland.
The tested compounds were dissolved in acetone
and added to a sterile agarized Czapek±Dox medium
Table 2. Fungistatic activitya of compounds 1–10: primary screening results at concentrations of 20mg litreÀ1
Compound 1±10
Inhibition of growth a
Fusarium culmorum Alternaria brassicicola Botrytis cinerea Penicillium expansum
Entry
R1
R2
1
2
1a
1b
1c
1d
1e
1f
H
CH3
CH3
CH3
CH3
CH3
CH3
‡‡
0
‡
0
‡‡
‡
‡‡
‡
CH3
3
C2H5
n-C3H7
i-C3H7
n-C4H9
‡
‡‡
‡
‡
0
‡‡
0
‡‡
0
4
‡
5
‡‡
0
0
0
6
0
0
7
1g
2a
2b
3a
3b
4a
4b
4c
4d
5a
5b
5c
6
n-C8H17 CH3
0
0
0
0
8
CH3
C2H5
C2H5
n-C3H7
n-C3H7
H
‡
0
0
0
9
C2H5
C2H5
n-C3H7
H
0
0
0
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
0
0
0
0
‡
‡
‡
‡‡
‡
‡
‡
0
‡
0
‡‡
‡‡
‡‡
‡
‡‡‡
‡‡‡
‡‡‡
‡‡
‡
‡‡
‡‡
‡‡‡
‡‡
‡
CH3
C2H5
n-C3H7
H
H
H
-ꢀCH2)3-
0
-ꢀCH2)4-
-ꢀCH2)5-
Ð
0
0
0
0
0
0
0
Ð
Ð
Ð
Ð
‡‡
0
‡
0
‡
‡
7
8
9
Ð
0
0
Ð
0
0
‡
0
Ð
‡
0
0
0
10a
10b
Captan
Y=NH2
Y=OH
‡
‡
0
‡
0
‡
‡
‡
0
‡‡
‡
‡
a Activity is expressed in four categories: ꢀ0)<20%, ꢀ‡) 21±50%, ꢀ‡‡) 51±80% and ꢀ‡‡‡) 81±100%.
630
Pest Manag Sci 57:625±632 ꢀ2001)

1-Amino-3,4-dialkylnaphthalene-2-carbonitriles as fungicides
Table 3. EC50 and EC95 values (mg litreÀ1) of selected amino nitriles 1a,c,e and 4a–d
Amino nitrile
R1
Fusarium culmorum
Alternaria brassicicola
Botrytis cinerea
Penicillium expansum
Entry
R2
EC50
EC95
EC50
EC95
EC50
EC95
EC50
EC95
1
2
3
4
5
6
7
8
1a
1c
1e
4a
4b
4c
4d
H
CH3
CH3
CH3
H
18.5
92.7
20.0
2.8
806
Ða
168
Ða
Ða
31.9
10.8
87.3
5.4
363
Ða
27.9
20.4
38.3
5.4
240
Ða
C2H5
i-C3H7
H
30.5
52.6
12.4
24.6
18.5
154
298
5.1
Ða
500
21.6
10.2
8.6
133
22.0
594
22.0
Ða
54.3
Ða
Ða
Ða
CH3
C2H5
n-C3H7
H
3.4
44.4
488
Ða
1.6
8.6
H
15.6
38.0
743
1.1
2.6
H
18.2
18.2
256
61.8
28.1
45.4
Captan
Ða
10.8
77.2
70.0
a EC95 >1000mg litreÀ1
.
3
RESULTS AND DISCUSSION
investigated amino nitriles, especially to 4a±c. The
EC50 index of this fungus was <2mg litreÀ1. In
contrast, A brassicicola showed, in the second stage of
screening, the highest tolerance to the tested amino
nitriles, with EC95 >1000mg litreÀ1. The exception
was 4a with EC95 =54.3mg litreÀ1. None of the com-
pounds investigated altered the morphology of the
fungi even when they stopped the growth of fungal
colonies. An exception among the amino nitriles
studied was 4c. This compound in concentrations
higher than 2.0mg litreÀ1 retarded the growth of aerial
mycelium. However, a loose submerged mycelium
could develop under these concentrations of 4c. The
preliminary investigation revealed only very weak
activity in the tested compounds against the germina-
tion of the fungi spores. All amino nitriles at the
concentrations of 100mg litreÀ1 caused less than 20%
inhibition of germination. Complete inhibition of the
germination of F culmorum, B cinerea and P expansum
spores was observed at the concentrations of
1000mg litreÀ1 only for amino nitriles 2a and 2b.
Other compounds investigated were much less active.
The fungistatic activity of the compounds investigated
was related both to the structure of the amino nitriles
and to the fungi tested ꢀTable 2). The highest activity
was shown by amino nitriles 1 and 4 which have only
hydrogen atoms or short alkyl groups at the 3- or 4-
position of the naphthalene amino nitriles. In contrast
to these compounds, amino nitrile 1b with methyl
groups at both 3- and 4-positions showed only very
weak fungistatic properties. The presence of ethyl or n-
propyl group at the 3-position ꢀcompounds 2 and 3)
resulted in a complete loss of fungistatic activity.
Amino nitriles 5 with a cycloalkene ring fused to a
naphthalene system in positions 3 and 4 showed lower
activity than their analogues having alkyl groups in
these positions. It appears that the presence of the
naphthalene system along with the amino and nitrile
function in vicinal positions on that system is essential
for the activity of the compounds tested. Moderate
activity was also shown by a derivative of 2-amino-
naphthalene-1-carbonitrile 6. A comparison of com-
pounds 4b and 10 revealed that replacement of the
nitrile function by the carboxylic or carbamoyl func-
tion leads to a considerable lowering of their fungicidal
properties. Derivatives of sym-octahydro-phenan-
threne 7, phenanthrene 8 or benzene 9 appeared to
be only weak fungicides.
4
CONCLUSIONS
The highest fungistatic activity among the investigated
compounds 1±10 was revealed by amino nitriles 1 and
4 having hydrogen atoms or only one short alkyl group
ꢀCH3, C2H5)at the 3- or 4-position of the naphthalene
system. These compounds exhibited stronger fungi-
static activity than the commercial fungicide, captan.
The results obtained justify further investigation of the
most active amino nitriles and their analogues against a
greater variety of fungi. The amino nitriles under
consideration are relatively easy to synthesize from
inexpensive, commercially available starting com-
pounds.
1-Aminonaphthalene-2-carbonitriles 1 and 4 having
a hydrogen atom or methyl group at the 3-position and
hydrogen, methyl, ethyl, n-propyl or isopropyl groups
at the 4-position were selected for the second stage of
screening ꢀTable 3). The highest activity of all the
amino nitriles investigated was exhibited by 4a
ꢀR1=H). Its EC50 index for all tested fungi was in
the range 2.8±12.4mg litreÀ1 and the EC95 index was
in the range 5.1±54mg litreÀ1. Amino nitriles 4b
ꢀR1=CH3)and 4c ꢀR1 =C2H5)showed similar, high
fungistatic activity for all tested fungi.
Compounds 1a, 1c and 4 have considerably higher
fungicidal activity at lower concentrations ꢀ<20mg
litreÀ1)than the reference fungicide, captan. Amino
nitriles 4a±c have higher activity than captan at all
concentrations and their activity against F culmorum
and B cinerea is especially notable.
ACKNOWLEDGEMENTS
The support of these investigations by the State
Committee for Scienti®c Research ꢀKBN, Poland)
within grant No 3 T09B 030 14 is gratefully acknowl-
edged.
B cinerea was the fungus most sensitive to the
Pest Manag Sci 57:625±632 ꢀ2001)
631

J Wilamowski et al
nitro compounds. V. A simple one-pot preparation of o-
aminoaroylnitriles from some aromatic nitro compounds.
Chem Pharm Bull 33:1360±1366 ꢀ1985).
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