Efficient synthesis of N-allylated 2-nitroiminoimidazolidine analogues from Baylis–Hillman bromides

Article abstract of DOI:10.1080/00397911.2016.1255333

Various Baylis–Hillman–derived new N-allylated 2-nitroiminoimidazolidine analogs were efficiently prepared using potassium carbonate as base. Simple workup procedure, excellent yields, and mild reaction conditions are the salient features of this method. All the synthesized compounds are screened for their larvicidal activity on fourth instar mosquito larvae, Culex quinquefasciatus.

Full text of DOI:10.1080/00397911.2016.1255333

Efficient Synthesis of N-Allylated 2- Nitroiminoimidazolidine Analogues from
Baylis-Hillman Bromides
Sriramoju Bharath Kumar1, Chebolu Naga Sesha Sai Pavan Kumar1,2,, Amlipur
Santhoshi1,3, Koochana Pranay Kumar4, U. S. N. Murthy4, Vaidya Jayathirtha Rao1
1Crop Protection Chemicals Division, Indian Institute of Chemical Technology,
Hyderabad, Telangana, India
2Division of Chemistry, Department of Sciences and Humanities, Vignan′s Foundation
for Science, Technology & Research, Vignan University, Vadlamudi, Andhra Pradesh,
India
3Department of Chemistry, Hussaini alam Degree College, Osmania University,
Hyderabad, Telangana, India
4Biology Division, Indian Institute of Chemical Technology, Hyderabad, Telangana,
India
Corresponding author Chebolu Naga Sesha Sai Pavan Kumar Division of Chemistry,
Department of Sciences and Humanities, Vignan’s Foundation for Science, Technology
& Research, Vignan University, Vadlamudi, Guntur 522 213, Andhra Pradesh, India. E-
mail: pavaniict@gmail.com
Abstract
Various Baylis-Hillman derived new N-allylated 2-nitroiminoimidazolidine analogues
were efficiently prepared using potassium carbonate as base. Simple workup procedure,
excellent yields and mild reaction conditions are the salient features of this method. All
the synthesized compounds are screened for their larvicidal activity on fourth instar
mosquito larvae, a culex quinquefasciatus.
1

KEYWORDS: Baylis-Hillman bromides, 2-nitroiminoimidazolidines, N-cinnamyl nitro
imino imidazole derivatives, Insecticidal activity
1. INTRODUCTION
Discovery of new insecticides is an ongoing process and challenging area for organic
chemists worldwide.[1] Earlier generation of insecticides include nicotine, a most well
known and widely used alkaloid containing pyridine as a basic moiety. Analogue
molecules were introduced into market as most potent insecticides include imidacloprid,
acetamprid, thiacloprid etc. When the structures of these compounds are compared with
nicotine, it appears that only minor changes were made on pyridine moiety of nicotine
and major changes incorporated in the side chain heterocyclic moiety (Fig 1).
Imidacloprid[2] is a relatively new insecticide, first registered for use as a pesticide in the
U. S. in 1994, and was the first insecticide in its chemical class to be developed for
commercial use. The neonicotinoid imidacloprid is currently one of the most widely used
insecticides in the world.[3] Imidacloprid, and other insecticides in the nicotionid
chemical family, are “similar to and modeled after the natural nicotine [a tobacco toxin].”
Because of their molecular shape, size, and charge, nicotine and nicotinoids fit into
receptor molecules in the nervous system that normally receive the molecule
acetylcholine. Acetylcholine carries nerve impulses from one nerve cell to the tissue that
a nerve controls. Imidacloprid and other nicotinoids irreversibly block acetylcholine
receptors.[4]
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The nicotinoids are a newer class of insecticides with a new mode of action. Imidacloprid
is a systemic insecticide, used as a soil, seed or foliar treatment in cotton, rice cereals,
peanuts, potatoes, vegetables, pome fruits, pecans and turf, for the control of sucking
insects, soil insects, whiteflies, termites, turf insects and the Colorado potato beetle, with
long residual control. Like nicotine, it acts on the nervous system. It has wide diversity of
applications in agriculture. The development of resistance to imidacloprid by pest insects
is a significant concern,[5] so there is a need to synthesize new insecticides, to show better
results than earlier reported. Motivated by these findings, and in continuation of our
ongoing efforts endowed with the discovery of nitrogenated heterocycles with potential
chemotherapeutic activities,[6] herein we report the facile synthesis and larvicidal activity
of various Baylis-Hillman derived N-cinnamyl substituted nitro imino imidazole
derivatives.
2. RESULTS AND DISCUSSION
Baylis–Hillman reaction[7] is a standard C–C bond formation reaction generally used
in synthetic organic chemistry. The reaction has been greatly studied and various
applications are reported in the literature.[8] Various Baylis-Hillman bromides were
prepared from respective Baylis-Hillman adducts by using the literature procedure.[9]
Present work deals with the synthesis of new N-allylated 2-nitroiminoimidazolidine
analogues derived from Baylis-Hillman bromides. The target compounds (4a-j) can be
obtained by the reaction between Baylis-Hillman bromides and 2-nitro imino imidazole
moiety in acetonitrile solvent using K2CO3 at room temperature. Variety of new N-
3

allylated 2-nitroiminoimidazolidines are synthesized and analyzed for their insecticidal
activity.
This invention relates in essence to cinnamyl substituted-nitro imino imidazoline
derivatives. Baylis-Hillman derived N-cinnamyl substituted nitro imino imidazole
derivatives were effectively prepared by the reaction between Baylis-Hillman bromides
2a-j and 2-nitro imino imidazole 3, the starting materials Baylis-Hillman bromides 2a-j
were synthesized according to the literature procedure.[9] 2-nitro imino imidazole was
treated with Baylis-Hillman bromide, 2a in acetonitrile solvent in the presence of K2CO3
at room temperature for 5 h, the desired product was obtained in very good yield. The
sequence of synthetic methodology is depicted in Scheme 1.
During the optimization studies, the reaction was carried out in different bases such as
NaH, K2CO3, NaOMe in MeOH, NEt3, and also with hindered amine DABCO.
Compared with other bases, it was observed that with K2CO3, the imino derivative was
obtained at ambient temperature in excellent yield. To demonstrate the general utility of
the method, we applied these conditions to a variety of Baylis-Hillman bromides having
ester and nitrile functionality (2a-j). In all the cases, the reactions occurred smoothly,
affording products in very good yields (Table 1). All the synthesized products were
characterized well by spectroscopic data.
The preparation of another half of heterocyclic moiety of the target molecule (nitro imino
imidazole) can be synthesized under different experimental conditions.[10, 11] The nitro
4

imino imidazole 3 is conveniently and efficiently prepared from ethylenediamine and
nitroguanidine in presence of hydrochloric acid (Scheme 2).[12]
The present study was carried out to determine the insecticidal (larvicidal) activity of
compounds 4(a-j). Larvae mortality was recorded after 24 hours. Toxicity or activity was
reported as LC50 and LC90 that is ppm of compound 4(a-j) that killed 50% and 90%
larvae respectively in 24 hours. This calculation was carried out using probit analysis
software. The detail results are presented in Table 2. Mosquito larvicidal test was
performed according to the standard methodology (WHO, 1978). Fourth instar mosquito
larvae, a Culex quinquefasciatus were reared under laboratory conditions (temperature 25
3 and relative humidity 75 5 ). The insecticidal (larvicidal) activity was compared
with a standard insecticide imidacloprid whose LC50 is 0.1 ppm against fourth instar
larvae of Culex quinquefasciatus.
3. CONCLUSION
In conclusion, Baylis-Hillman derived N-cinnamyl substituted nitro imino imidazole
derivatives were prepared in an efficient manner. The prepared compounds were tested
for their larvicidal activity on fourth instar mosquito larvae, a culex quinquefasciatus and
compared with a standard insecticide imidacloprid.
4. EXPERIMENTAL SECTION
4.1 General Methods
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All the chemicals used were of reagent grade obtained from local suppliers, Aldrich and
Fluka. All reactions were performed in oven-dried glassware under nitrogen atmosphere.
Analytical thin layer chromatography (TLC) was performed on silica gel plates and TLC
visualization was carried out with UV, using TLC aluminium sheets precoated with silica
gel 60 F254 to a thickness of 0.25 mm (Merck). Flash column chromatography was done
using silica gel (Merck, 60-120 mesh). Melting points were determined on a Mettlers-
Temp apparatus and are uncorrected. IR Spectra were recorded using a Perkin-Elmer FT-
IR spectrometer; ν in cm-1. 1H and 13C-NMR spectrum (CDCl3/DMSO-d6) was recorded
with Gemini-200 and Bruker-Avance-300 instruments; chemical shifts δ in ppm relative
to SiMe4 as an internal standard, couplings in Hz. Mass spectra were recorded on VG
Micromass 7070 H (EI), Thermofinnigan ESI ion trap mass spectrometer. HRMS (ESI)
data were recorded on a QSTAR XL High resolution mass spectrometer; in m/z (rel. %).
4.2 General Procedure For The Synthesis Of {(Substituted Cinnamyl)-] Tetrahydro-
1H-2-Imidazolyliden}-1-Hydraziniumolate (4a-J): 2-{1-[(E)-2-(Methoxycarbonyl)-
3-Phenyl-2-Propenyl] Tetrahydro-1H-2-Imidazolyliden}-1-Oxo-1-Hydraziniumolate
(4a):
To a solution of 2-nitro imino imidazole (3) (156 mg, 1.2 mmol) in acetonitrile (3 mL)
was added K2CO3 (165 mg, 1.2 mmol), Baylis-Hillman bromide (2a) (254 mg, 1 mmol)
sequentially at room temperature and the reaction mixture was stirred for 5 h at room
temperature. After complete consumption of starting material as monitored by TLC, the
reaction mixture was filtered and the filtrate was washed with water and extracted with
ethyl acetate (2 x 15 mL), dried (Na2SO4), concentrated under reduced pressure and the
6

residue was purified by silica gel column chromatography using EtOAc:hexane (1:1) as
eluent to afford pure product (280 mg, 92%) as white solid. 1H NMR (CDCl3, 300 MHz):
δ 3.41-3.47 (t, J = 9.1 Hz, 2H), 3.58-3.64 (t, J = 9.1 Hz, 2H), 3.83 (s, 3H), 4.44 (s, 2H),
7.34-7.43 (m, 5H), 7.92 (s, 1H), 8.05 (s, NH). 13C NMR (DMSO-d6, 50 MHz): δ 41.2,
41.4, 45.2, 52.5, 127.3, 129.1, 129.3, 129.8, 135.4, 142.9, 160.9, 167.1. IR (KBr): 3411,
2923, 1711,1561, 1434, 1285, 1251. Mass (ESI): m/z 305 [M+H] + HRMS (ESI) m/z
calcd for C14H17N4O4: [M+H]+ 305.1249; found: 305.1263.
ACKNOWLEDGMENT
The authors thank the Director, IICT for support. 12th 5 Yr Plan Project ORIGIN-CSC-
0108 is acknowledged for financial assistance. SBK, CHNSSPK, AS thanks CSIR-New
Delhi, for the fellowship.
SUPPLEMENTARY INFORMATION
The supplementary information includes all experimental procedures, characteristic data
and spectra of new compounds (4a-j). This material can be found via the “Supplementary
Content” section of this article’s webpage.’
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10

Table 1: /V-Cinnamyl nitro imino imidazole derivatives from Baylis-Hillman bromides
S.No.
1
Product
Time (h) Yield (%)a Mp (°C)
4a; R = H; EWG = COOMe
5
92
146-148
2
3
4
5
4b; R = p-Br; EWG =
4c; R = p-CI; EWG =
4d; R = p-CH3; EWG =
4e; R = m-CI; EWG =
5.5
6
91
90
92
91
98-100
Viscous
106-108
118-120
5
5.5
6
7
4f; R = p-CF3; EWG =
4g; R = H; EWG = COOEt
6
5.5
94
90
182-184
126-128
8
4h; R = H; EWG = CN
4i; R = p-CH3; EWG = CN
4j; R = p-CI; EWG = CN
5.5
6
87
88
87
116-118
110-112
122-124
g
10
6.5
aisolated yield
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Table 2:Larvicidal activity of compounds 4a-j on mosquito larvae
S. No
1
Compound
4a
LC50 Values
41.22
LC90 Values
118.48
2
3
4
5
4b
4c
4d
4e
92.37
38.56
95.45
12.49
287.24
119.38
412.58
108.21
6
7
8
4f
72.16
> 100
> 100
252.04
> 100
> 100
4g
4h
9
4i
4j
> 100
> 100
> 100
> 100
10
12

Figure 1: Potent insecticides available in the market
13

Scheme 1: Synthesis of N-allylated 2-Nitroiminoimidazolidines analogues from Baylis-
Hillman bromides
14

Scheme 2: Synthesis of Nitro imino imidazole
15