Novel 4-Methylumbelliferone Amide Derivatives: Synthesis, Characterization and Pesticidal Activities

A series of novel 4-methylumbelliferone amide derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HR-ESI-MS. The structures of compounds 4bd and 4be (compounds named by authors) were further confirmed by X-ray single crystal diffraction. The acaricidal, herbicidal and antifungal activities of the synthesized compounds were assayed for their potential use as pesticide. The results indicated that compounds 4bi, 4ac and 4bd were strong acaricidals against Tetranychus cinnabarinus, with 72h corrected mortalities of greater than 80% at 1000 mg/L. Meanwhile, compounds 4bh and 4bf exhibit the strongest inhibition against the taproot development of Digitaria sanguinalis and Chenopodium glaucum, and were even more potent than the commercial herbicide Acetochlor against D. sanguinalis. In addition, compounds 4bk, 4bh and 4bp showed the highest antifungal activity against the mycelium growth of Valsa mali, which makes them more effective than commercial fungicide Carbendazim.

4-Methylumbelliferone and its derivatives exhibited interesting pesticidal activities as well. These compounds displayed strong inhibition to weeds Setaria viridis and Amaranthus retroflexus. The C7 hydroxyl group was considered as a potentially active site and a methyl substitution at the C4 position contributed significantly to the activity [29]. 4-Methylumbelliferone derivatives also showed strong growth inhibition against phytopathogenic fungi Alternaria alternata, Alternaria solani, Botrytis cinerea and Fusarium oxysporum, and a C4 methyl in the compounds contributed to the fungicidal activity [30]. Moreover, brominated 4-methylumbelliferone showed remarkable larvicidal and ovicidal activities against vectors Aedes aegypti and Culex quinquefasciatus [31]. 4-Methylumbelliferone esters of the chrysanthemic acid type could be metabolized by glutathione S-transferase from the mosquito Culex pipiens pipiens [32]. The Schiff base and its metal complexes of 4-methylumbelliferone derivatives showed anthelmintic to Pheretima posthuma [33].
The amide group is a common functional group in natural compounds. Many commercial pesticidal compounds have acylamino group in the molecule, for example carbamates and benzoylphenyl urea insecticides, anilide fungicides, ureas, amides and carbamates herbicides [34]. As a continuous study on the development of novel pesticides based on the coumarin scaffold [35,36], by introducing amides to 4-methylumbelliferone, a series of novel 4-methylumbelliferone amide derivatives were designed and synthesized through the principle of bioactive substructure combination. The acaricidal, herbicidal and antifungal activities of these new compounds were tested.

Chemistry
The synthetic route of the target compounds is illustrated in Scheme 1. Resorcinol and ethylacetoacetate occurred following a Pechmann reaction with catalyst of Con. H 2 SO 4 to produce compound 1 [22]. Nitration of 4-methylumbelliferone can be achieved with HNO 3 /H 2 SO 4 [37], HNO 3 /HOAc [37], Cr(NO 3 ) 3 /Ac 2 O [38], (NH 2 ) 2 CNH·HNO 3 /H 2 SO 4 [39], Ce(NH 4 ) 2 (NO 3 ) 6 / H 2 O 2 [40] and NO 2 BF 4 [41]. Each method was reported to have some regioselectivity, but it is obvious that HNO 3 /HOAc was more safe and accessible. Thus, in the present study, compound 1 was nitrated by Conc. HNO 3 in acetic acid to give the mixture of compounds 2a and 2b [37]. Nitro 4-methylumbelliferone can be reduced by SnCl 2 /HCl [22], Na 2 S 2 O 4 /NH 3 ·H 2 O [42] and D-glucose/KOH [43] to give an amino product. Considering the temperature requirement, time requirements and ease of the operation, Na 2 S 2 O 4 /NH 3 ·H 2 O was used as reductant. Thus the mixtures 2a and 2b were reduced in whole with Na 2 S 2 O 4 in aqueous NH 3 to obtain the mixture of compounds 3a and 3b [41]. The target compounds 4aa-4ah and 4ba-4bq were furnished by the acylazation of compounds 3a and 3b, respectively, with a series of acyl chlorides catalyzed by triethylamine [44]. The structures of all target compounds were well characterized by 1 H NMR, 13 C NMR and HR-ESI-MS. Additionally, to confirm the three-dimensional structural information of the target compounds, the single-crystal structures of 4bd and 4be were determined by X-ray crystallography as illustrated in Figure 1. Crystallographic data (excluding structure factors) for the structures of 4bd and 4be have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 1584028 and 1584029 (12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk). The C6 substituted target compounds were more polar than the C8 substituted compounds with the same group. Many fewer pure C6 substituted target compounds were created by column chromatography (CC). Moreover the C6 substituted target compounds 4aa-4ah were dissolved by DMSO-d 6 to determine the NMR, while the C8 substituted compounds 4ba-4bq were dissolved by CDCl 3

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl S 4bq Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl S 4bq Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl S 4bq Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl S 4bq Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl S 4bq Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl S 4bq Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl Scheme 1. Synthetic route of target compounds.

Acaricidal Activities
The acaricidal activities of the 25 synthesized target compounds against the phytophagous mite T. cinnabarinus were evaluated. The 72 h corrected mortalities of the mitetreated bythe compounds are listed in Table 1. The results indicate that most of the title compounds exhibited moderate to high acaricidal potency. Among them, the most attractive compounds were 4bi, 4ac and 4bd with 72 h corrected mortalities of greater than 80% at 1000 mg/L. Especially 4bi showed equal toxicity with the commercial acaricide Bifenazate. In the 6-substituted derivatives, the methacryloyl substituted compound 4ac was the most active, followed by the aroyl substituted compounds 4ae-4ah. The alkanoyl substituted compounds 4aa, 4ab and 4ad were inferior. Meanwhile, in the 8-substituted derivatives, the most active was the hydrocinnamoyl substituted compound 4bi, though its 6-position isomer 4ad and cinnyl substituted compound 4bj were much less potent. In the chain alkanoyl substituted compounds 4ba-4bc, long chains seem favorable for the activity, however the 4-chloro-butanoyl substituted compound 4bd was an exception. The smaller cyclopropyl formyl substituted compound was more active than the larger cyclohexyl formyl substituted one. The electron withdrawing groups on the aromatic ring of the amide group were favorable for the activity, but the 4-methyl benzoyl substituted compound 4bk was more active.
Molecules 2018, 23, 122 4 of 12 substituted compound was more active than the larger cyclohexyl formyl substituted one. The electron withdrawing groups on the aromatic ring of the amide group were favorable for the activity, but the 4-methyl benzoyl substituted compound 4bk was more active.

Herbicidal Activities
The herbicidal activities of the target compounds against the taproot and caulis development of dicotyledonous weed C. glaucum and monocotyledonous weed D. sanguinalis were screened. The inhibitory rates of the compounds an effectiveness greater than 30% at 100 mg/L to at least one organ of the weeds are displayed in Table 2. The data indicate that more compounds show stronger inhibition against D. sanguinalis than against C. glaucum. More specifically, compounds 4bh and 4bf exhibit the strongest inhibition against the taproot development of D. sanguinalis, which makes them even more potent than the commercial herbicide Acetochlor. In fact 4bh and 4bf were the most potent against the taproot development of C. glaucum. Regarding effectiveness against D. sanguinalis, the chain alkanoylsubstituted compounds 4ba-4bd (long chain compounds) seem unfavorable for the activity. Meanwhile the larger cyclohexyl formyl substituted compound was more active than the smaller cyclopropyl formyl substituted one.

Herbicidal Activities
The herbicidal activities of the target compounds against the taproot and caulis development of dicotyledonous weed C. glaucum and monocotyledonous weed D. sanguinalis were screened. The inhibitory rates of the compounds an effectiveness greater than 30% at 100 mg/L to at least one organ of the weeds are displayed in Table 2. The data indicate that more compounds show stronger inhibition against D. sanguinalis than against C. glaucum. More specifically, compounds 4bh and 4bf exhibit the strongest inhibition against the taproot development of D. sanguinalis, which makes them even more potent than the commercial herbicide Acetochlor. In fact 4bh and 4bf were the most potent against the taproot development of C. glaucum. Regarding effectiveness against D. sanguinalis, the chain alkanoylsubstituted compounds 4ba-4bd (long chain compounds) seem unfavorable for the activity. Meanwhile the larger cyclohexyl formyl substituted compound was more active than the smaller cyclopropyl formyl substituted one.

Antifungal Activities
The in vitro antifungal activities of the target compounds against the mycelium growth of the phytopathogens Colletotrichum glecosporioides, B. cinerea, F. oxysporum and V. mali were assayed. The inhibitory rates of the compounds with effectiveness greater than 30% at 100 mg/L are listed in Table 3. The data indicate that more compounds showed stronger inhibition against V. mali than against the other 3 plant disease fungi. More specifically, compounds 4bk, 4bh and 4bp exhibited the strongest inhibition against the mycelium growth of V. mali, which makes them even more potent than the commercial fungicide Carbendazim. Furthermore, the effectiveness of compounds 4be, 4bi and 4bd against B. cinerea were superior than or comparable with that of the fungicide Carbendazim, though they are all only moderately active against the fungi. The inhibition of compound 4bq against F. oxysporium was comparable with that of fungicide Carbendazim.

Chemistry
All chemicals were obtained from commercial sources and used without further purification. Analytical thin-layer chromatography (TLC) was performed with silica gel plates using silica gel 60 GF 254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China). Melting points were determined on a WRS-1B digital melting-point apparatus (Shanghai Precision Optical Instrument Co., Ltd., Shanghai, China) without further calibration. Nuclear magnetic resonance spectra (NMR) were recorded on a Bruker Avance III HD 500 MHz instrument (Bruker, Faellanden, Switzerland) in CDCl 3 or DMSO-d 6 ( 1 H at 500 MHz and 13 C at 126 MHz) using tetramethylsilane (TMS) as the internal standard. High-resolution mass spectra (HRMS) were carried out with an IonSpec 4.7 T FTMS instrument. Single-crystal structure was determined by a Bruker AXS D8 QUEST X-ray single crystal diffractometer.

Synthesis of 1
A solution of resorcinol (5.5 g, 50 mmol) and ethyl acetoacetate (6.5 g, 50 mmol) in ethanol (10 mL) was added dropwise to H 2 SO 4 (5 mL) with stirring at 0-5 • C. After the complete addition, the reaction mixture was stirred for 4 h at room temperature. Then the reaction mixture was poured onto ice-water (100 mL) with vigorous stirring for 1h. The white precipitate which formed was collected, and washed with cold water to neutral. The product was dried and crystallized, and separated from ethanol. Yield 88%, m.p. 185-186 • C (as reported) [22].

Synthesis of 2a and 2b
To a solution of 1 (8.8 g, 50 mmol) in acetic acid (20 mL) kept at a temperature below 10 • C, a mixture of 65% nitric acid (5.8 g, 60 mmol) and acetic acid (20 mL) was added dropwise with stirring. After the complete addition, the reaction mixture was stirred for another 6 h at room temperature and then poured onto ice-water. The orange precipitate obtained was filtered off, washed with water to neutral, and air-dried. The solid product was washed with hot acetonitrile to give the yellow mixtures 2a and 2b (3:1) with a yield of 70% [37].

Synthesis of 3a and 3b
To a suspension of 2a and 2b mixtures (11.1 g, 50 mmol) in 60 mL of concentrated aqueous ammonia, 70 mL of 15% sodium hydrosulfite was added slowly with stirring at room temperature. After the complete addition, the reaction mixture was stirred for 6 h until the color changed from bright orange to light green. The mixture was then boiled for 15 min, cooled to 5 • C, and the solid was filtered off to give the mixtures 3a and 3b (3:1) with a yield of 93% [41]. To a suspension of 1.91 g of 6-amino-7-hydroxyl-4-methylcourmin (10 mmol) and 100 uL of triethylamine in 30 mL of dichloromethane (DCM), a solution of acyl chloride (10 mmol) in 20 mL DCM was added with stirring at 0-5 • C. The mixture was allowed to restore to room temperature and was stirred until the end of the reaction. The resulting organic mixture was washed with 30 mL of water (producing Na 2 SO 4 ), then dried, filtered and concentrated in vacuo sequentially. The obtained residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate = 1:1 for 4aa-4ah, petroleum ether-ethyl acetate = 4:1 for 4ba-4bq) to give the target compounds [44]. The yield, appearance, m.p., the 1 H-NMR and 13     (3:7) was used as a blank control, and Bifenazate was used as a positive control. Each treatment was conducted in four replicates. The dead mites were recorded every 24 h under a stereoscope and the corrected mortalities of T. cinnabarinus treated by the compounds were calculated.

Herbicidal Activity
The herbicidal activities of the synthesized compounds against the taproot and caulis development of the dicotyledonous weed C. album and the monocotyledonous weed D. sanguinalis were determined in vitro [38]. A suspension of 5 g agar powder in 1 L distilled water was heated to melt, and then cooled to 40-50 • C. Each title compound was dissolved by acetone to give a stock solution of 10 g/L, and 0.1 or 0.5 mL of the stock solution was added to 50 mL of the melting agar at 45 • C to achieve the required concentrations. Then, 5 mL of the agar-containing compound was added to a beaker (10 mL) and cooled, and uniform germinating seeds were placed on the surface of the agar mass. The beaker was sealed by a piece of plastic wrap with several small holes on it, and then the cultivations were carried out in an illumination incubator set at 28 ± 1 • C and 50-55% relative humidity in alternating 12 h of light and 12 h of dark for 3 days. Acetone was used as a blank control, and Acetochlor was used as a positive control. Each treatment was conducted in three replicates. After 3 days of cultivation, the taproot and caulis lengths were measured, and the growth inhibitory rate related to the untreated control was determined.

Antifungal Activity
The antifungal activities of the title compounds against B. cinerea, C. gloeosporioides, A. brassicae and G. gramini were tested in vitro using the mycelium growth rate test [46]. The test compound was dissolved in acetone to form a series of proper concentration solutions. Then 1 mL of the solution was added to 100 mL melting potato dextrose agar (PDA) at 45 • C, and the mixture was shaken up to obtain the required concentration of the poisoned medium. 5 mL of the poisoned medium was poured into a 6 cm petri dish and cooled to room temperature to get a solid plate. After that, a 4 mm activated mycelium disk was inoculated on the PDA plate and incubated in the dark at 28 • C for 48 h. The mycelium elongation radius (mm) of the fungus settlements was measured and the growth inhibition rate related to the untreated control was calculated. Acetone was used as a blank control, and Carbendazim was used as a positive control. Each treatment was repeated for 3 times.

Conflicts of Interest:
The authors declare no conflict of interest.