S YNTHESIS OF HETEROCYCLIC CARBAMATES WITH POTENTIAL ACTIVITY IN PLANT PROTECTION

Aryland heteroaryl carbamates are known as plant protection agents. Because many pests develop resistances, new carbamate structures are of interest in plant protection research. Our synthetic approach started with the preparation of heterocyclic enoles such as hydroxypyrones B and H, hydroxyquinolones C, hydroxytetrahydroquinolines E, hydroxy-cycloheptapyridones F and hydroxypyridones G. They were obtained from 1,3-dinucleophiles such as anilines or azomethines A by cyclocondensation with malonates. Monocyclic hydroxypyridones were also accessible from dehydracetic acid, followed by oxygen exchange with amines. These heterocyclic enols B H react with dialkylcarbamoylchlorides in the presence of a base to carbamates B1 H1. With alkylor arylisocyanates carbamates C2 are formed. The evaluation of the biological activity shows, that representatives from structures C1 and G1 exhibit strong plant protection properties. NH R 1 R 1 N O O

Our synthetic approach started with the preparation of heterocyclic enoles such as hydroxypyrones B and H, hydroxyquinolones C, hydroxytetrahydroquinolines E, hydroxy-cycloheptapyridones F and hydroxypyridones G.They were obtained from 1,3-dinucleophiles such as anilines or azomethines A by cyclocondensation with malonates.Monocyclic hydroxypyridones were also accessible from dehydracetic acid, followed by oxygen exchange with amines.
These heterocyclic enols B -H react with dialkylcarbamoylchlorides in the presence of a base to carbamates B1 -H1.With alkyl-or arylisocyanates carbamates C2 are formed.
The evaluation of the biological activity shows, that representatives from structures C1 and G1 exhibit strong plant protection properties.

Introduction
Aryl-and heteroaryl carbamates such as Carbaryl or Pirimicarb are well known since several decades as plant protection agents [1,2].Both carbamates are insecticides and act as inhibitors of the enzyme acetylcholinesterase.

Carbaryl Pirimicarb
The latter one is registered in the European Union since 2006 as a selective carbamate insecticide used to control aphids on vegetable, cereal and orchard crops by inhibiting acetylcholinesterase activity, but does not affect useful predators [3,4].Because many pests are known to develop resistances against carbamates, new types of carbamate structures are of interest in plant protection research [5].
The aim of our work was to synthesize heterocyclic carbamates starting from N,N-dialkylcarbamoylchlorides or alkylisocyanates and heterocyclic enols in order to search for new and active derivatives in plant protection.The synthesis of reactive enols started from 1,3-dinucleophiles such as anilines, azomethines or phenols, which were cyclized with malonates to pyridone or pyrone derivatives.
The 4-hydroxy group of quinolones 5 possesses phenolic properties and is easily esterificated either by addition reaction with isocyanates or by attack with acyl chlorides.Alkyl-or arylisocyanates 6 give with 5 N-monosubstituted carbamates 8a-d using a basic catalyst.Best results were obtained with tri-ethylamine as the base and p-dimethylaminopyridine (p-DMAP) as acylating agent.The reaction of hydroxyquinolones 5 with N,N-dialkylcarbamoyl chlorides 7 leads to N,N-dialkylcarbamoyloxyquinolones 9a-r.In this reaction, best results were obtained with a mixture of pyridine and p-DMAP acting as solvent, basic catalyst and acid trapping agent (Scheme 1).Spectral data confirm the structures of carbamates 8 and 9. Infrared spectra of 8 and 9 show ester carbonyl signals between 1725 -1740 cm -1 , and amide carbonyl signals between 1630 -1650 cm -1 . 1 H-NMR spectral data of the methylamino groups in 8 show one dublet between 2.7 -2.9 ppm.The diethylamino groups are visible as triplets between 1.0 -1.3 ppm (methyl group), and one multiplet between 2.9 -3.3 ppm (methylene group).The dimethylamino groups in 9 show two singlets between 2.75 -2.85 ppm.The diethylamino groups show one multiplet between 0.9 -1.4 ppm (2 methyl signals), and a further multiplet between 3.0 -3.5 ppm (2 methylene groups).

Carbamates from 3-alkyl-and 3-arylsubstituted 4-hydroxyquinolones 10:
2-Alkyl-or 2-arylmalonates 2i-m react with anilines 1 in a thermal induced cyclization reaction without catalyst to 3-alkyl-and 3-aryl-4-hydroxyquinolones 10 [9].The reaction proceeds as a one-pot reaction via 2 steps, in the first step forming at about 200 °C a malonoesteranilide, which is then cleaved in a second step at temperatures above 250 °C to give a ketene-anilide intermediate ketene attacks easily the ortho-position of the aniline part to cyclize to the desired quinolone 10 (Scheme 2).
The reaction of 4-hydroxyquinolones 10 with N,N-dialkylcarbamoyl chlorides 7 leads to N,Ndialkylcarbamoyloxy-quinolones 11a-p.Best results were obtained with a mixture of pyridine and p-DMAP as solvent and basic catalyst.Alkyl-or arylisocyanates 6 react with the reactive enol group at position 4 of quinolones 10 to give N-monosubstituted carbamates 12 using again triethylamine and pdimethylaminopyridine (p-DMAP) as basic catalysts (Scheme 2).
Infrared spectral data of 11 and 12 show ester carbonyl signals between 1725 -1735 cm -1 , and amide carbonyl signals between 1630 -1670 cm -1 . 1 H-NMR spectral data of the dimethylamino groups in 11 show one dublet at 2.7 -2.85 ppm.The phenyl group in 12 is confirmed by the ratio of aromatic protons (14 H) compared with the benzylic CH 2 group (2 H).The NH group of the carbamate is visible at 10.0 ppm, while the ring-NH appears at 11.6 ppm.
Another approach to 4-hydroxypyridones allows a versatile substitution pattern in position 1, 3, 5 and 6.The starting 1,3-dinucleophiles are azomethines 22, which are best obtained from the appropriate ketones 20 in a mild two step reaction via aminonitriles 21 followed by subsequent elimination of hydrogen cyanide [12b, 13].The direct formation of the Schiff bases 22 by reaction with anilines or aliphatic amines gives lower yields and large amounts of impurities caused by the high temperatures and the necessary acidic catalysts [7b].Aniles 22 react in good yields with bis- (2,4,6-trichlorophenyl)malonates 2n,o to 4-hydroxypyridones 23 [7b, 14] (Scheme 5).

Conclusion
It could be shown, that heterocyclic enols could be easily esterificated with either dialkylcarbamoylchloride or alkyl-and arylisocyanates in a smooth reaction and good yields to give carbamates.As catalyst and solvent pyridine or triethylamine werde used, in combination with p-dimethylaminopyridine to accelerate the acylation reaction.The biological properties -especially for plant protection purposes -were investigated by academic and industrial cooperation.It could be detected that 2 representatives (9a and 16b) possess insecticidal properties to control aphids comparable with Pirimicarb.

General
IR spectra were taken either on a Bruker Alpha-P with Attenuated Total Reflectance (ATR) measurement, using a reflexion method, or with a Mattson Galaxy Series FTIR 7020 instrument in KBr discs.NMR spectra were measured on a Bruker AMX 360 instrument (360 MHz 1 H) or a Bruker Avance III instrument (300 MHz 1 H).Chemical shifts are given in ppm (d) from the internal TMS standard.Elemental analyses were performed at the Microanalytical Laboratory of the University of Vienna, Austria.
Melting points were determined with a Stuart SMP3 melting point apparatus.Thin layer chromatography was carried out on 0.2 mm silica gel F 254 plates (Merck, Darmstadt, Germany) using UV light (254 and 366 nm) for detection.

General method for the synthesis of hetaryl alkyl-and arylcarbamates (8, 12) from isocyanates:
To a solution of 4-hydroxyquinolone 5 or 10 (10 mmol) and isocyanate 6 (25 mmol) in dry acetonitrile (20 mL), p-N,N-dimethylaminopyridine (0.1 g) and triethylamine (1 mL) were added and the mixture stirred at 50 °C for 12 h.Then the reaction mixture was poured onto ice/water (50 mL), and after 30 min filtered by suction.The remaining solid was extracted in portions with hot petroleum benzin (ligroin, bp 120-140 °C) and the residue recrystallized from the solvent given below.
Step 2: N-Cycloheptylidenphenyl-amin (29b): 1-Phenylamino-cycloheptancarbonitril (28b) (55.0 g, 0.26 mol) in methanol (300 mL) was heated to reflux and then potassium hydroxide (58 g, 1.0 mol) added slowly through the condenser and heated then 1 h under reflux.The mixture was cooled to room temperature, then water (800 mL) was added and the formed oily product extracted in several portions with hexane.The combined hexane-extracts were dried with sodium sulphate, the solvent removed i.vac.and the residue crystallized in a crystallization dish.The yield was 14.56 g (48%) yellow crystals.IR (KBr): 3350 s, 2840 -3100 m, 1630 m, 1590 cm -1 .