Synthesis of 2-ethyl-2-methyl-2,3-dihydro-1H-indole, a new insecticide exhibiting juvenile hormone activity

Article abstract of DOI:10.1134/S107036320612022X

Catalytic hydroamination of isoprene gave N-(1,2-dimethylprop-2-en-1-yl) aniline in a preparative yield. By heating at 260°C the product was converted into 2-ethyl-2-methyl-2,3-dihydro-1H-indole, a new ecologically safe insecticide exhibiting a juvenile h

Full text of DOI:10.1134/S107036320612022X

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 12, pp. 1953 1957.
Pleiades Publishing, Inc., 2006.
Original Russian Text
E.A. Petrushkina, V.N. Kalinin, G.B. Ivanova, V.A. Kheinman, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76,
No. 12, pp. 2042 2046.
Synthesis of 2-Ethyl-2-methyl-2,3-dihydro-1H-indole,
a New Insecticide Exhibiting Juvenile Hormone Activity
E. A. Petrushkinaa, V. N. Kalinina, G. B. Ivanovab, and V. A. Kheinmanb
a Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
e-mail: petrushkina@rambler.ru
b All-Russia Research Institute of Chemical Means for Plant Protection, Moscow, Russia
Received June 2, 2006
Abstract Catalytic hydroamination of isoprene gave N-(1,2-dimethylprop-2-en-1-yl)aniline in a preparative
yield. By heating at 260 C the product was converted into 2-ethyl-2-methyl-2,3-dihydro-1H-indole, a new
ecologically safe insecticide exhibiting a juvenile hormone activity. Its insecticide properties against Tenebrio
Molitor L. chrysalises were estimated at 7.5 points according to the Schmialek 9-point scale.
DOI: 10.1134/S107036320612022X
In the recent time, chemists and biologists give
much attention to the preparation of up-to-date insec-
ticides which are characterized by high selectivity,
satisfactory resistance to natural factors, and the
lowest possible toxicity toward all participants of
biocenosis. Considerable attention is also given to
economic aspects, such as accessibility of starting
present work we made an attempt to prepare in several
steps dihydroindole derivatives and test them for
juvenile activity.
An effective method for building up dihydroindole
or indole ring is based on heterocyclization of 2-(alk-
2-en1-yl)anilines. The latter can be prepared in turn
from N-(alk-2-en-1-yl)anilines by the amino-Claisen
rearrangement. The goal of the present study was to
synthesize indole derivatives possessing a juvenile
hormone activity from N-(alk-2-en-1-yl)anilines. A
one-step catalytic procedure for the preparation of N-
(alk-2-en-1-yl)anilines from isoprene and aniline was
described in [6 9]. Thus the key sage of our study
was investigation of the amino-Claisen rearrangement
of N-(alk-2-en-1-yl)anilines that are available via
direct amination of isoprene with aniline. The main
advances in the field of studying the amino-Claisen
rearrangement were reviewed in [10] (see also refe-
rences therein). The direction of the rearrangement is
determined by the nature and position of substituents
in allyl fragment, and in some cases these factors
facilitate the subsequent heterocyclization of 2-(alk-
2-en-1-yl)anilines thus formed. For example, Bunina-
Krivorukova et al. [11] showed that the presence of a
methyl group in the - rather than -position of the
allyl substituent leads to anomalous product composi-
tions in both thermal and catalytic (ZnCl2) Claisen
rearrangements of -methyl-, , - and , -dimethyl-,
and , , -trimethylallyl p-methylphenyl ethers. When
two -methyl groups are present in the allyl fragment,
the Claisen rearrangement follows a path different
from the classical one. In this case, the rearrangement
materials and
green chemistry
requirements.
Moreover, the main goal of modern studies is to
control over the magnitude of populations of insect
pests rather than their complete elimination. Advances
in agrochemical science over the past decades have
led to the discovery of insect growth regulators, i.e.,
ecologically safe insecticides that simulate two kinds
of insect hormones, steroid 20-hydroxyecdysone
(20E) and sesquiterpenoid juvenile hormones. The
low persistence of juvenile hormones and their
analogs (juvenoids) to photochemical degradation and
oxidation, as well as very expensive manufacture of
sesquiterpenoids, imposes strong limitations on the
application of juvenoids in agricultural practice. An
efficient way of enhancing the stability of juvenoids is
to introduce a heterocyclic fragment into their mole-
cules. Active insect esterase inhibitors whose me-
chanism of action is similar to that of juvenile hor-
mones were found among N-terpenyl-substituted
benzimidazoles [1 3], while indole derivatives were
reported to effectively inhibit biosynthesis of chitin,
thus corrupting the investment of insects during molt
[4 5]. In continuation of our studies on the synthesis
of practically important biologically active com-
pounds on the basis of butadiene and isoprene (which
are large-scale products in oil processing), in the
1953

1954
PETRUSHKINA et al.
was accompanied by heterocyclization only in the
presence of an acid catalyst. According to [12, 13],
acid-catalyzed (concentrated hydrochloric acid or
polyphosphoric acid) amino-Claisen rearrangement of
N-allylaniline, as well as of N-(but-2-en-1-yl)aniline
( -methyl-substituted allyl fragment) gives only
substituted dihydroindoles as products of heterocycli-
zation involving the most substituted carbon atom at
the double bond in the corresponding intermediate of
the classical amino-Claisen rearrangement. Jolidon
and Hansen [14] believe that - and -substituents in
the allyl fragment of N-allylanilines play the key role
in the thermal and catalytic amino-Claisen rearrange-
ment. Thus almost no amino-Claisen rearrangement
products are formed from N-( -methylallyl) and N-
( , -dimethylallyl)anilines at 260 335 C, but elimina-
tion of aniline occurs mainly. However, the thermal
rearrangement of N-( , -dimethylallyl)aniline at
200 260 C smoothly affords the classical Claisen
rearrangement product, while N-( -methylallyl)aniline
requires more severe conditions (290 C). The Claisen
rearrangement of N-( , -dimethylallyl)aniline in the
presence of organic acids in a 10:1 acetonitrile water
mixture gives up to 70% of the normal rearrangement
product [15] and no hydration products which are
sometimes formed in the presence of aqueous mineral
acids. Katayama et al. [16, 17] studied the effect of
alkyl substituents in the N-allyl fragment of 1-allyl-
1,2,3,4-tetrahydroquinoline and 1-allyl-6-methoxy-
1,2,3,4-tetrahydroquinoline in the reaction performed
in anhydrous boron trifluoride ether complex. Intro-
duction of one or two -methyl groups into the allyl
fragment increased the yield of nonclassical Claisen
rearrangement products (para-substituted) and pro-
ducts resulting from elimination of the substituted
allyl fragment. Here, the Claisen rearrangement was
not accompanied by heterocyclization. As shown in
[18, 19], the rearrangement of N-( , -dimethylallyl)-
anilines in the presence of HCl does not involve
inversion of the allyl fragment with formation, and
both ortho- and para-substituted anilines are formed.
N-(Cyclopent-2-en-1-yl)aniline hydrochloride having
an , -dimethylallyl fragment at 200 220 C gives rise
to dihydroindole derivative, and the reaction mixture
contained o-cyclopentenylaniline which gradually
disappeared, being converted into the corresponding
dihydroindole [20]. Thus the available published data
indicate that the presence of an -substituent in the
allyl fragment facilitates the amino-Claisen rearrange-
ment, -substituents hamper the process, while
-substituents exert almost no effect on the course of
the rearrangement.
No effective and convenient method for the syn-
thesis of all possible N-(mono-, di-, and trimethylal-
lyl)anilines has been proposed so far. The conventi-
onal procedure for the preparation of N-(methyl- or
dimethylalk-2-en-1-yl)anilines by reaction of aniline
with the corresponding substituted allyl chlorides does
not always lead to the desired products (see, e.g.,
[18]). Probably, this is the reason for the lack of data
for amino-Claisen rearrangement of N-( , -dimethyl-
allyl)aniline. An alternative synthetic route to such
compounds may be direct amination of isoprene with
aniline, catalyzed by palladium complexes (Scheme 1).
In the presence of PdX2 R3P HX (HX is an acid) as
catalytic system, the main products are adducts I IV:
N-(1,2-dimethylprop-2-en-1-yl)aniline
(I),
N-(3-
methylbut-2-en-1-yl)aniline (II), N-(2-methylbut-2-en-
1-yl)aniline (III), and N-(1,1-dimethylprop-2-en-1-
yl)aniline (IV). The selectivity of the process toward
formation of amines I IV can be changed by varying
the nature and ratio of the components of the catalytic
system and solvent nature. In such a way, we recently
obtained aniline I in acetonitrile with a selectivity of
31% [7, 8]. In the present article we describe the
synthesis of compound I in methanol with a slightly
lower selectivity (27%). As follows from the pub-
lished data considered above, the amino-Claisen rear-
rangement of adducts II and IV is well studied;
adduct III might be expected to give rise to a complex
mixture of products due to the presence of a -sub-
stituent in the allyl fragment. We presumed that
previously unknown rearrangement of compound I
should follow the classical scheme (see above), taking
into account that -substituents facilitate the process
and that -substituent should exert no appreciable
effect.
In most experiments, by heating amine I in a
sealed ampule at 220 350 C we obtained dihydroin-
Scheme 1.
NH
NH
NH
NH
[Pd]
+
+
+ PhNH2
+
I
II
III
IV
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 12 2006

SYNTHESIS OF 2-ETHYL-2-METHYL-2,3-DIHYDRO-1H-INDOLE
1955
dole V as the major product (Scheme 2). The data in
table show that the reaction performed in the tempera-
ture range from 300 to 350 C is accompanied by
considerable elimination of aniline (33 41%) and that
dihydroindole V is formed with a selectivity of 50
52%. Heating of aniline I for 30 min at 260 C gave a
complex mixture containing initial amine I, product
V, and unknown compound A. Presumably, the latter
is the normal Claisen rearrangement product. Upon
subsequent heating at 260 C (6 h), compound A
disappeared from the reaction mixture together with
initial aniline I, being converted into product V. When
aniline I was heated at 250 254 C, dihydroindole V
was formed with a selectivity of 47 57%. The con-
tribution of the aniline elimination process did not
exceed 5% at 200 220 C; however, the conversion of
aniline I reached 97% only after prolonged heating
(19 h), and the products were compound A and di-
hydroindole V.
Amino-Claisen rearrangement of N-(1,2-dimethylprop-2-
en-1-yl)aniline
Product composition,a %
Tempera- Time,
Unreacted
ture, C
min
aniline I, %
PhNH2
V
A
350
302
300
260
10
40
20
30
7
6
9
38
41
33
13
12
11
8
5
5
3
50
52
50
15
56
47
60
2
5
1
8
65
11
13
22
51
58
39
7
254/250 60/300
21
25
10
42
31
4
250
250
220
360
540
80
220/200 60/180
220/200 60/1080
6
54
a
According to the GLC data.
Scheme 2.
instance, the presence of two methyl groups in the -
and -positions of the allyl fragment, as well as of
two methyl groups at the -carbon atom [14], facili-
tates the process, so that it can be performed at a
lower temperature (200 260 C), as compared to com-
pounds having only one -substituent in the allyl
fragment. The thermal rearrangement of N-( , -di-
methylallyl)aniline is accompanied by heterocycliza-
tion to dihydroindole derivative.
2a
2c
2
2b
1NH
NH2
3
7a
I
4a
6
4
5
A
V
Two protons on C3 in molecule V are diastereo-
Compound V was tested for juvenile hormone ac-
tivity in Tenebrio molitor L. chrysalises (laboratory
strain, AllRussian Research Institute of Chemical
Means for Plant protection). The insecticide activity
was estimated by applying 4.4 g of an acetone solu-
topic due to the presence of the neighboring chiral C2
1
atom. Their signals appear in the H NMR spectrum
as an AB quartet with a coupling constant J of 15.5 Hz;
this value is typical of a CH2 group linked to aromatic
ring in 2,2-disubstituted dihydroindoles (see, e.g.,
[21]). In keeping with the above discussed published
data, heterocyclization products are formed (with a
few exceptions) with participation of the most sub-
stituted carbon atom at the double bond. Therefore,
we can assure with a high degree of certainty that
compound V is formed from the classical amino-
Claisen rearrangement product (A). Abdrakhmanov et
al. [22] previously reported that compound V was
formed as anomalous product of the reaction of
2-( , -dimethylallyl)aniline with polyphosphoric acid;
this was rationalized [22] in terms of 1,2-methyl
group shift in allyl fragment, followed by heterocyc-
lization at the most substituted carbon atom. However,
1
tion containing 10 g l of compound V to the ter-
minal abdomen segment of a chrysalis in 0 to 6 h after
its delivery. Compound V was tested on two series
each containing 15 species. The effect was determined
according to the Schmialek 9-point scale [23] by the
imago delivery. Point 0 was assigned to a chrysalis
delivering a normal imago, and point 9 was given to
a chrysalis producing no imago and not differing from
the intact chrysalis. Intermediates points corresponded
to different degrees of morphogenetic disorders in the
transformation of chrysalises into imago. After
examination of morphological variations of each
species, an average estimate (N) was calculated by the
formula
1
the H NMR spectrum of V given in [22] contained a
x1 1 + x2 2 + x3 3 + ... + xn n
singlet from the C3H2 protons, which contradicts their
diastereotopic character. Presumably, the product
isolated [22] is not dihydroindole V. Comparison of
our results with published data revealed some specific
features of the amino-Claisen rearrangement. For
N =
.
A
The absolute error ( N) was calculated by the
formula
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 12 2006

1956
PETRUSHKINA et al.
37% of II, 25% of III, and 11% of IV. Their retention
x1|N 1| + x2|N 2| + ... + xn|N n|
times (GLC) were consistent with those reported in
[6]. Aniline I was isolated by fractional distillation
through a laboratory rectification column; a fraction
N =
.
A
1
Here, 1, 2, 3, ..., n are estimates in points from 0 to 9;
x1, x2, x3, ..., xn are the numbers of chrysalises
assigned the corresponding point; and A is the overall
number of chrysalises. As a result of biological tests
for juvenile hormone activity, compound V in solu-
tion with a concentration of 10 g l was assigned
N = 7.5 (from 9 possible), N = 0.38, relative error
N/N = 5.1%.
boiling at 104 C (15 mm) was collected; its H NMR
spectrum was identical to that given in [6]; IR spec-
1
trum, , cm : 1660 (C=C); 1520, 1615 (C=Carom);
2960, 2990, 3070 br (C Harom); 3440 (NH); 700
[ (=CH2)].
1
2-Ethyl-2-methyl-2,3-dihydro-1H-indole (V).
Aniline I, 1.98 g, was heated in a sealed ampule for
9 h at 250 C. According to the GLC data, the result-
ing mixture contained 60% of compound V. Distilla-
tion gave 1.19 g (60%) of dihydroindole V with bp
144 146 C (15 mm). Electronic absorption spectrum,
EXPERIMENTAL
The reagents used in this work had a purity of 99%;
the solvent and liquid reagents were distilled just
before use and were stored under argon; Pd(acac)2
was prepared as described in [24]. All reactons were
carried out under argon. GLC analysis was performed
on an LKhM-8MD (5) chromatograph equipped with
a 2000 3-mm steel column; stationary phase 15% of
SKTFT-50 on Chromaton N-AW; carrier gas helium.
The NMR spectra were recorded from solutions in
CDCl3 on Bruker WR-200SY and Varian VXR-400
spectrometers using TMS as internal reference. The
IR spectra were measured from thin films on a UR-20
instrument. The electronic absorption spectrum of
compound V was recorded on a Specord M-40 spec-
trophotometer from a solution in ethanol (c = 10 3 M).
3
max, nm ( 10 ): 233 (7.4), 244 (7.4), 294 (2.7). IR
1
spectrum, , cm : 1490, 1618 (C=Carom), 2990 br
1
(C Harom), 3400 (N H), 765 [ (C=Carom)]. H NMR
spectrum, , ppm (J, Hz): 1.10 t (3H, 2-CH2CH3, J =
7.4), 1.39 s (3H, 2-CH3), 1.76 q (2H, 2-CH2CH3, J =
7.4); 2.89 and 3.08 (1H each, 3-H, AB system, JAB
=
15.5), 3.68 s (1H, NH), 6.70 d (1H, 4-H, J = 7.7),
6.84 d.d (1H, 5-H, J = 7.4), 7.17 d.d (1H, 6-H, J =
7.4), 7.21 d (1H, 7-H, J = 7.7). 13C NMR spectrum,
C, ppm: 8.82 (2-CH2CH3), 26.23 (2-CH3), 34.41
(2-CH2CH3), 41.67 (C3), 63.67 (C2), 108.83 (C4),
117.81 (C5), 124.65 (C6), 127.17 (C7), 127.96 (C4a),
150.11 (C7a); the signals were assigned using APT
pulse sequence. Found, %: C 81.74; H 9.25; N 8.67.
C11H15N. Calculated, %: C 81.94; H 9.38; N 8.67.
Reaction of isoprene with aniline in methanol in
the presence of the catalytic system Pd(acac)2
P(OEt)3 CF3CO2H. A mixture of 0.92 g Pd(acac)2,
2.0 g P(OEt)3, 120 ml of isoprene, 55.8 g aniline,
3.4 g CF3COOH, and 150 ml of methanol was stirred
at 20 C under argon until it became homogeneous.
The resulting solution was transferred under argon
into a 250-ml steel high-pressure reactor, and the re-
actor was heated for 34 h at 100 C. The low-boiling
fraction was distilled off under atmospheric pressure,
and the residue was distilled under reduced pressure
(water-jet pump) to obtain 70 g of a mixture of pro-
ducts with bp 91 108 C (8 mm). Amines I IV were
isolated through transformation into the corresponding
hydrochlorides. For this purpose, the product mixture
was dissolved in hexane, the solution was treated with
cold dilute hydrochloric acid, the aqueous phase was
separated and treated with a cold solution of potas-
sium hydroxide, an oily material separated and was
extracted into benzene, the extract was dried over
Na2SO4 and evaporated, and the residue was distilled
under reduced pressure. We thus isolated 48.8 g
(60%) of a mixture of compounds I IV with bp 104
118 C (15 mm), which contained 27% of aniline I,
ACKNOWLEDGMENTS
This study was performed under financial support
by the Presidium of the Russian Academy of Sciences
(program no. P-9).
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