6-Chloronicotinic Acid Synthesis Essay

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  • During the past decade, inspired by the remarkable success of novel insecticides belonging to the group generally known as neonicotinoids (e.g. Imidacloprid1, Acetamiprid2, Nitenpyram3), a number of research groups focused their attention on the synthesis of 2,5-disubstituted pyridine derivatives. Among them 2-chloro-5-substituted methylpyridine derivatives exhibited profound insecticidal activities4. In recent past, derivatives of 1,3,4-oxadiazole suitably substituted at 2,5-positions5-8 exhibitedconsiderable antibacterial and antifungal activities.

    In continuation of our work on development of novel agrochemicals, we were interested to explore insecticidal activity by synthesizing molecules containing both 2-chloro-5-methyl pyridine and 1,3,4-oxadiazole moieties. The results of such studies are discussed in this paper along with the reaction sequence leading to the formation of such compounds (Scheme I).

    2-Chloro-5-chloromethylpyridine 1 was prepared from 6-chloronicotinic acid through 2-chloro-5-hydroxymethylpyridine, followed by chlorination9,10. This compound was also prepared from picoline-N-oxide through 2-chloro-5-methylpyridine followed by chlorination11,12. Reaction of 1 with sodium cyanide under reflux in aqueous methanol afforded 2-chloro-5-cyano methylpyridine2. This was further converted into 2-chloropyridine-5-acetic acid 3 by hydrolysis. The methyl ester 4 was prepared by refluxing 3 in methanol with catalytic amount of conc. sulphuric acid. This ester was then converted into the desired 2-chloropyridine-5-acetic acid hydrazide 5 by refluxing with excess hydrazine hydrate in methanol. Treatment of 5 with different acid chlorides in dry ethylene dichloride followed by refluxing with POCl3 resulted in the formation of 2-chloro-5-(5-aryl-1,3,4-oxadiazole-2-yl)methylpyridines 6a-e.

    The structures of compounds 2-5 and 6a-e have been established on the basis of spectral data. Formation and purity of all the compounds 2-5 and 6a-e were checked by TLC and HPLC respectively. Characterization data of compounds 2-5 and 6a-e are given in Tables I and II,respectively.

    R = -H, -Cl, -F, -CH3, -OCH3

    Scheme I

    Table I ¾Physical data of compounds 2-5

    Compd

    X

    m.p./ b.p.
    °C

    Yield
    (%)

    Mol. formula

    HPLC *
    (RT min/ % a/a purity)

    2

    CN

    182 / 1Hgmm

    84.4

    C7H5ClN2

    3.69/94.2

    3

    CO2H

    171-72

    75/88**

    C7H6ClNO2

    3.00/94.9

    4

    CO2Me

    133-35/ 3 Hgmm

    93

    C8H8ClNO2

    2.99/97.5

    5

    CONHNH2

    148-50

    94.4

    C7H8ClN3O

    2.60/92.7

    *HPLC: Shimadzu LC 10AVP; Column: Inertsil ODS: C18: 250 ´ 4.5mm; Detector: UV spectrometric;
    Solvent: CH3CN : H2O:: 70 : 30 v/v; l = 254; Solvent flow:1mL/min

    ** NaOH/ H2SO4 hydrolysis

    Note: RT of compound 1 under the above condition is 5.1min

    Table II ¾Physical data of 2-chloro-5-(5-aryl-1,3,4-oxadiazol-2-yl)methyl-pyridines 6a-e

    Compd

    R

    m.p.
    °C

    Yield
    (%)

    Mol. formula

    HPLC *(RT min/
    % a/a purity)

    Recrystallization
    solvent

    6a

    H

    194-96

    75.1

    C14H10ClN3O

    2.94/95.7

    Ethyl acetate

    6b

    Cl

    138-39

    77

    C14H9Cl2N3O

    6.17/97.3

    Methanol

    6c

    F

    126-27

    75.2

    C14H9ClFN3O

    4.88/99.0

    Methanol

    6d

    OCH3

    108-11

    62

    C15H12ClN3O2

    4.68/97.7

    CCl4

    6e

    CH3

    206-08

    63.5

    C15H12ClN3O

    3.09/93.5

    Acetonitrile

    *HPLC: Shimadzu LC 10AVP; Column: Inertsil ODS: C18: 250 ´ 4.5mm;
    Detector: UV spectrometric; Solvent: CH3CN : H2O :: 70 : 30 v/v; l = 254; Solvent flow: 1mL/min

    IR spectra of all the compounds 2-5 and 6a-e showed absorption bands in the region of 3100-3008 cm-1 (aromatic C-H stretching), 1591-1454 cm-1 (C=C, C=N ring stretching), 743-703 cm-1(C-H out of plane bending). They also showed absorption bands due to -CH2 group in the region of 1422-1409 cm-1. In the IR spectrum of compound 2, the absorption band due to cyano group was observed at 2258 cm-1. The absence of this absorption band and appearance of another absorption band at 1715 cm-1, characteristic of carboxylic acid, in the IR spectrum of compound 3 confirmed the formation of 2-chloropyridine-5-acetic acid. In the IR spectrum of compound 4 absorption band at 1717 cm-1 is attributed to carbonyl group of methyl ester. The formation of the corresponding acid hydrazide 5 is confirmed by its IR spectrum. It showed absorption bands at 1627and 3321-3290 cm-1 corresponding to hydrazide carbonyl and NHNH2 absorptions, respectively.

    The retention of 2-chloropyridin-5-yl-methyl group in all the compounds 2 to 6a-e was supported by their 1H NMR spectra. All of them showed a sharp singlet at d 3.6 to 4.26, corresponding to the protons of the -CH2- group (H4 & H5). The three hydrogens of 2,5-disubstituted pyridine ring resonated as a quartet and two doublets in the region d, 8.27 to 8.44, 7.67 to 7.69 and 7.31 to 7.35 for H1, H2, H3, respectively. This pattern was also seen in the spectrum of compound 113. The formation of carboxylic acid, ester and hydrazide was also confirmed from 1H NMR spectra. In the 1H NMR spectrum of compound 4, the signal due to the methyl group of the carboxylic acid estermerged with that of methylene protons at d 3.6, integrating for five protons. In the case of compound 5, protons of hydrazide group resonated at d 4.3 and 9.3, integrating for two and one hydrogen atoms, respectively.

    The mass spectra of the compounds 2-5 showed peaks at 152, 171, 185 and 185 corresponding to their molecular formula C7H5ClN2, C7H6ClNO2, C8H8ClNO2
    and C7H8ClN3O respectively. All the spectra showed a common peak at m/z 126 corresponding to the 2-chloropyridin-5-yl-methyl cation.

    The typical absorption bands due to carbonyl and hydrazide moieties in the IR spectrum of hydrazide 5 were absent in the IR spectra of compounds 6a-e. This confirmed the formation of the oxadiazoles. It is further supported by recording 1H NMR and mass spectra of these compounds. In 1H NMR spectrum of compound 6b, in addition to the peaks corresponding to the hydrogens of 2-chloropyridine-5-yl-methyl group, the hydrogens of 4-chloro substituted aromatic ring resonated as two doublets at d 7.94 and 7.48, integrating for four protons.

    Scheme II

    The mass spectral fragmentation pattern of compound 6b is shown in Scheme II. It showed a molecular ion peak at m/z 306 corresponding to the molecular formula C14H9Cl2N3O along with M+2 peak indicating the presence of one chlorine atom in the molecule. The peaks at m/z 126 and 112 may be attributed to the 2-chloropyridin-5-yl-methyl and chlorophenyl residues, respectively. Base peak at m/z 140 corresponds to Cl-C6H4-CºO+ and peak at m/z 168 is due to Cl-C5H3N.CH2-CNO+. The peak at m/z 152 corresponds to the formation of 2-chloropyridin-5-yl-acetonitrile during the fragmentation.

    Bio-assay

    Laboratory reared insects namely, the Cotton bollworm, Helicoverpa armigera; tobacco leaf eating caterpillar, Spodoptera litura; Cotton aphid, Aphis gossypi; Cabbage diamondback moth, Plutella xylostella; and rice brown plathopper, Nilapavata lugens; were used for the experiments. Leaf dipping technique and spraying with spray turntable method14 were followed for assessing the efficacy of new molecules. The new molecules were evaluated at 2500 and 5000 ppm a.i. against the above said insects in comparison with standard checks, Imidacloprid 200SL and Cypermethrin 25%EC. Observations were recorded for mortality and behavioral changes of the pests.

    The results of screening studies are given in
    Table III.The results revealed that new molecules tested against various insect pests are found ineffective in checking the populations as compared to standard checks.

    Table III¾ Effect of certain new molecules against crop pests

    Compd

    Conc.
    (ppm a.i.)

    % mortality after 48 hr

    Helicoverpa
    armigera

    Spodoptera
    litura

    Aphis
    gossiypi*

    Plutella
    xylostella

    Nilapavata
    lugens*

    6a

    2500

    0

    1.8

    4.1

    0

    3.8

    5000

    0

    3.0

    6.6

    0

    6.5

    6b

    2500

    3.1

    0

    4.5

    3.5

    4.0

    5000

    5.3

    0

    6.9

    5.4

    6.4

    6c

    2500

    0

    0

    4.5

    0

    4.2

    5000

    0

    0

    7.2

    0

    7.0

    6d

    2500

    0

    1.9

    3.8

    0

    3.5

    5000

    0

    2.8

    5.4

    0

    6.1

    6e

    2500

    2.1

    0

    3.2

    0

    3.8

    5000

    3.5

    0

    6.9

    0

    6.3

    Imidacloprid 200SL

    10

    0

    0

    100

    0

    100

    Cypermethrin 25%EC

    250

    98.5

    89.6

    25.7

    92.3

    38.4

    Experimental Section

    2-Chloro-5-chloromethyl pyrdine was prepared according to methods reported earlier 9,10.

    2-Chloro-5-cyanomethylpyridine 2. To a mixture of 2-chloro-5-chloromethyl pyridine 1 (16.2g, 0.1 mole) and ethanol (25 mL), sodium cyanide (5.88g, 0.12 mole) in water (9 mL) was added at 0-5°C with stirring during 15 min. It was refluxed for about 10 hr on a water-bath. Excess ethanol was distilled off. The reaction mixture was cooled and poured into water (100 mL). The product was extracted with dichloro­methane (250 mL). On removal of dichloromethane, the crude product was obtained, which was purified by high vacuum distillation. Yield 12.9 g (cf. Table I); IR: 2258 cm-1 (CºN); 1H NMR: d, 4.2 (s, 2H, -CH2-), 7.6 (d, 1H, pyridyl H3), 8.0 (q, 1H, pyridyl H2), 8.6 (d, 1H, pyridyl H1); Mass: m/z, 152 (M+), 126 (M-ClC5H3NCH2+ ).

    2-Chloropyridine-5-acetic acid 3.Method 1.Compound 2 (15.6 g, 0.1 mole) was refluxed with mixture of 50 mL conc. H2SO4 and 50 mL water for 3 hr, cooled to 20°C, neutralized with dilute NaOH till basic and then acidified with dilute HCl. It was filtered and dried to get 3 (cf. Table I), yield 15.2 g.

    Method 2. Compound 2 (15.6 g, 0.1 mole) was refluxed with a mixture of NaOH (9 g ) in 25mL of water for 8 hr, cooled to 20°C, acidified with dilute HCl. It was filtered and dried (cf. Table I), yield 13.4 g; IR: 1715 cm-1 (C=O); 1H NMR: d, 3.6 (s, 2H, -CH2-), 7.31 (d, 1H, pyridyl H3), 7.67 (q, 1H, pyridyl H2), 8.27 (d, 1H, pyridyl H1); Mass: m/z, 171 (M+), 172 (M++1), 173 (M++2), 126 (M-ClC5H3NCH2+ ), 127 (126 +1), 128 (126+2).

    Methyl 2-chloropyridine-5-acetate 4.A mixture of 3 (17.15 g, 0.1mole), methanol (7.4 g, 0.2 mole) dichloroethane (100 mL) and conc. H2SO4 (5 drops) was refluxed for 5 hr and cooled to 5°C. The contents were poured into ice water (100 mL). The organic layer was separated and dichloroethane was distilled off to get the crude product. The high vacuum distillation of this crude product afforded the pure compound 4 (cf. Table I), Yield 17.2 g; IR: 1717 cm-1 (C=O); 1H NMR: d, 3.6 (s, 5H, -CH2- & OCH3), 7.3 (d, 1H, pyridyl H3), 7.9 (q, 1H, pyridyl H2), 8.3
    (d, 1H, pyridyl H1); Mass: m/z, 185 (M+), 126
    (M-ClC5H3NCH2+).

    2-Chloropyridine-5-acetic acid hydrazide 5.To a boiling solution of 4 (18.55 g, 0.1mole) in methanol (30 mL), hydrazine hydrate (99%, 7.5 g, 0.15 mole) was added and refluxed for 1 hr and cooled to 0°C. The precipitated product 5 was filtered and dried (cf. Table I), yield 17.5 g; IR: 1627 cm-1 (C=O amide), 3321 cm-1 (NH-NH2); 1H NMR: d, 3.4 (s, 2H, -CH2-), 4.3 (s, 2H, NH2), 7.5 (d, 1H, pyridyl H3), 7.8 (q, 1H, pyridyl H2), 8.3 (d, 1H, pyridyl H1), 9.3 (s, 1H, NH); Mass: m/z, 185 (M+), 126 (M-ClC5H3NCH2+), 154 (M-ClC5H3NCH2CºO+).

    2-Chloro-5-(5-aryl-1,3,4-oxadiazol-2-yl-methyl)-pyridine 6a-e.To a solution of 4-substituted benzoyl chloride (0.01mole) in dichloroethane (10 mL) and compound 5 (0.01 mole), phosphorous oxychloride (5mL) was added and contents were refluxed for 8 hr on an oil-bath. After the reaction, excess of solvent and POCl3 were distilled at reduced pressure. Reaction mass was cooled and poured into ice, left overnight. The product was obtained by filtration. The characterization data of 6a-e prepared according to this method are given in Table II. 6b:1H NMR: d, 4.26 (s, 2H, -CH2), 7.35 (d, 1H, pyridyl H3), 7.48 (d, 2H, phenyl H), 7.69 (q, 1H, pyridyl H2), 7.94 (d, 2H phenyl H), 8.44 (d, 1H pyridyl H1); Mass: m/z, 306 (M+), 140 (M-ClC6H4CO +), 126 (m-ClC5H3NCH2+ ), 112 (M-ClC6H4+).

    Acknowledgement

    Authors are grateful to Dr M S Mithyantha, Vice President (R&D) and the Management of Rallis India Limited, , for extending the laboratory facilities and constant encouragement.

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