Design and Synthesis of Novel Hydrazides, Thiosemicarbazides

Ind. Eng. Chem. Res. 2004, 43, 4979-4999

4979

Design and Synthesis of Novel Hydrazides, Thiosemicarbazides, Oxadiazoles, and Triazoles of N,N′-Bis(1-carboxy-15-hydroxy-npentadec-8-yl)alkyl or -aryl Diamides: An Approach for Their Biological Evaluation and Possible Industrial Utilization Kallappa M. Hosamani* and Raviraj S. Pattanashettar P.G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad-580 003, India

Among the extensive applications of oleochemicals as industrial products, nitrogen derivatives of fatty acids such as amides have been extensively used as antislip and antiblock additives for polythene films in which they are incorporated. They are also used as wall repellents for textiles and as mold release agents, and they are employed in rubber goods and printing inks. Because of this interest in the biological and industrial potential of oleochemicals, a series of novel N,N′bis(1-carboxy-15-hydroxy-n-pentadec-8-yl)alkyl or -aryl amides derivatives such as hydrazides, thiosemicarbazides, oxadiazoles, and triazoles has been synthesized. These newly synthesized oleochemicals have been studied and characterized by FTIR, 1H NMR, and 13C NMR spectroscopies and elemental analyses. Introduction In continuation of our research work on synthetic potentially biologically active oleochemicals,1 a series of novel hydrazides, thiosemicarbazides, oxadiazoles, and triazoles derivatives of N,N′-bis(1-carboxy-15-hydroxy-n-pentadec-8-yl)alkyl or -aryl amides has been synthesized. Amides and hydrazides are known to be associated with antibacterial,2 antifungal,3 anthelmintic,4 and anticonvulsant5 activities. The various thiosemicarbazide derivatives are reported to exhibit interestingpharmacologicalpropertiessuchasantitubercular,6 antidepressant,7 antiinflammatory, and analgesic8 activities. Several triazole derivatives have also been examined for their antibacterial,9 fungicidal and herbicidal,10 and analgesic and antiinflammatory11 activities. The oxadiazoles and their derivatives are wellknown chemotherapeutic agents as muscle relaxants,12 hypoglycemic agents,13 and antibacteriostatic agents.14 Thus, interest in the biological and industrial potential of oleochemicals has resulted in the development of various synthetic procedures for the introduction of heterocyclic a moiety into the hydrocarbon chain. As far as the authors are aware, there are no reports in the literature on the oleochemicals comprising a series of N,N′-bis(1-carboxy-15-hydroxy-n-pentadec-8-yl)alkyl or -aryl amides derivatives such as hydrazides, thiosemicarbazides, oxadiazoles, and triazoles. Results and Discussion Spectral Studies: Diesters. The substituted dicarboxylic acids were converted into their corresponding methyl esters by the Fischer esterification method. The IR spectra of all the diester compounds (Ia-Ih) showed absorption bands at 3430-3320 cm-1 indicating the presence of -NH and at 1743-1752 cm-1 indicating the presence of ester carbonyl functional groups. The other usual absorption bands were also observed. * To whom correspondence should be addressed. Fax: 08362771275. E-mail: [email protected].

1H NMR spectra of all of the diester compounds (IaIh) showed sharp singlet signals at δ 3.5-3.8 for ester methyl protons. The other usual signals were also observed. The 13C NMR spectra of all of the diester compounds (Ia-Ih) showed sharp singlet signals at δ 61-72 for the ester carbonyl carbon. The other usual signals were also observed. Hydrazides. The substituted diesters were converted into their corresponding hydrazides by refluxing with 95% hydrazine hydrate. The IR spectra of all hydrazide derivatives (IIa-IIh) showed absorption bands at 34303422 cm-1 indicating the presence of -NH and -NH2 functions merged with -OH group. Strong bands were also present at 1654-1660 cm-1 that are attributed to the carbonyl group. The other usual absorption bands were also observed. The 1H NMR spectra of hydrazide derivatives (IIaIIh) showed sharp singlet signals at δ 8.6-8.9 for -CONH-NH2 protons, which disappeared upon D2O addition. The singlet signals at δ 7.2-7.9 are due to the protons of -CO-NH-NH2. The other usual signals were also observed. The 13C NMR spectra of compounds IIa-IIh all showed sharp singlet signals at δ 176-172 for the carbonyl carbon of -CO-NH-NH2. The other usual signals were also observed. 2-Substituted 5-Mercapto-1,3,4-oxadiazoles. 2-Substituted 5-mercapto-1,3,4-oxadiazoles were obtained by the cyclization of the substituted hydrazides with CS2 in KOH. The IR spectra of all 5-mercapto-oxadiazole derivatives (IIIa-IIIh) showed characteristic absorption bands at 3066-3073 and 1622-1628 cm-1 for -NH stretching and -CdN stretching, respectively. Bands at around 1263-1269 and 1124-1127 cm-1 were observed for the -CdS stretching and dC-O-C) functions, respectively. The other usual absorption bands were also observed. 1H NMR spectra of 5-mercapto-oxadiazole derivatives IIIa-IIIh showed sharp singlet signals at δ 10.5-10.8

10.1021/ie030257g CCC: $27.50 © 2004 American Chemical Society Published on Web 07/21/2004

Table 1. Spectral Analysis

4980 Ind. Eng. Chem. Res., Vol. 43, No. 17, 2004

Table 1. Continued

Ind. Eng. Chem. Res., Vol. 43, No. 17, 2004 4981

Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


Table 1. Continued


4996 Ind. Eng. Chem. Res., Vol. 43, No. 17, 2004 Scheme 1a

a

Where R ) (a) -CH2-, (b) -(CH2)2-, (c) -(CH2)3-, (d) -(CH2)4-, (e) -(CH2)5-, (f) -(CH2)6-, (6) -(CH2)7-, (h) -C6H4- (1, 2).

for the -NH-CdS protons. The other usual signals were also observed. The 13C NMR spectra of all the compounds (IIIaIIIh) showed sharp singlet signals at δ 155-152 and 150-146 for carbon atoms of the oxadiazole ring. The other usual signals were also observed. Thiosemicarbazides. The corresponding substituted hydrazides were further converted into the substituted thiosemicarbazides by treating with KCNS in HCl. In the IR spectra of all of the thiosemicarbazide derivatives (IVa-IVh) were observed the characteristic absorption bands at 3291-3296, 1630-1634, and 1160-1171 cm-1 for -NH stretching, the carbonyl function, and -CdS, respectively. The other usual absorption bands were also observed. 1H NMR spectra of all the thiosemicarbazide derivatives (IVa-IVh) showed singlet signals at δ 7.6-7.8 for the protons of -CS-NH2, which disappeared upon D2O addition. The doublet signals are due to -CO-NH-NH protons that also disappeared upon D2O addition. The other usual signals were also observed. The 13C NMR spectra of compounds IVa-IVh all showed sharp singlet signals at δ 180-178 for -CS-

and at δ 176-172 for carbonyl carbon. The other usual signals were also observed. 3-Substituted 5-Mercapto-4H-1,2,4-triazoles. The most interesting 3-substituted 5-mercapto-4H-1,2,4triazoles were obtained by refluxing of an appropriate thiosemicarbazide in ethanolic KOH solution followed by acidification. The IR spectra of all 5-mercaptotriazole derivatives (Va-Vh) showed the characteristic absorption bands at 3200-3203, 1581-1585, and 1259-1263 cm-1 for -NH stretching merged with the -OH group, -CdN stretching, and the thione function, respectively. The other usual absorption bands were also observed. The 1H NMR spectra of all of the 5-mercapto-triazole derivatives (Va-Vh) showed singlet signals at δ 9.710.1 for the protons of the -NH-CdS- function. Other singlet signals were also observed at δ 5.4-5.6 for d C-NH-C), which disappeared upon D2O addition. The other usual signals were also observed. The 13C NMR spectra of compounds Va-Vh all showed sharp singlet signals at δ 142-138 and 138136 forthe carbon atoms of the triazole ring. The other usual signals were also observed.

Ind. Eng. Chem. Res., Vol. 43, No. 17, 2004 4997 Table 2. Elemental Analyses, Yields, and Melting Points of All Compounds composition (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

carbon found

compd

molecular formula

yield (%)

mp (°C)

calc

Ia Ib Ic Id Ie If Ig Ih IIa IIb IIc IId IIe IIf IIg IIh IIIa IIIb IIIc IIId IIIe IIIf IIIg IIIh IVa IVb IVc IVd IVe IVf IVg IVh Va Vb Vc Vd Ve Vf Vg Vh VIa VIb VIc VId VIe VIf VIg VIh

C37H70N2O8 C38H72N2O8 C39H74N2O8 C40H76N2O8 C41H78N2O8 C42H80N2O8 C43H82N2O8 C42H72N2O8 C35H70N6O6 C36H72N6O6 C37H74N6O6 C38H76N6O6 C39H78N6O6 C40H80N6O6 C41H82N6O6 C40H72N6O6 C37H66N6O6S2 C38H68N6O6S2 C39H70N6O6S2 C40H72N6O6S2 C41H74N6O6S2 C42H76N6O6S2 C43H78N6O6S2 C42H68N6O6S2 C37H72N8O6S2 C38H74N8O6S2 C39H76N8O6S2 C40H78N8O6S2 C41H80N8O6S2 C42H82N8O6S2 C43H84N8O6S2 C42H74N8O6S2 C37H68N8O4S2 C38H70N8O4S2 C39H72N8O4S2 C40H74N8O4S2 C41H76N8O4S2 C42H78N8O4S2 C43H80N8O4S2 C42H70N8O4S2 C37H68N8O6 C38H70N8O6 C39H72N8O6 C40H74N8O6 C41H76N8O6 C42H78N8O6 C43H80N8O6 C42H70N8O6

71.0 68.0 68.5 70.0 67.5 68.5 71.5 72.5 66.0 64.0 70.5 64.5 69.0 61.0 60.5 64.5 62.0 60.5 58.5 61.3 70.0 71.0 73.0 78.0 53.0 50.5 49.5 51.5 73.0 69.2 72.0 78.5 60.0 64.5 60.5 63.5 68.3 58.0 62.1 71.0 63.0 68.0 65.5 66.0 66.5 59.5 61.5 76.0

semisolid semisolid semisolid semisolid semisolid semisolid semisolid semisolid 72-74 130-132 semisolid semisolid semisolid semisolid 170-172 123-125. 110-112 78-80 136-138. 162-164 142-144 104-106 88-90 90-94 154-156 110-112 115-117 86-88 74-77 82-84 103-104 155-156 72-74 142-144 90-93 132-134 162-164 124-126 106-108 130-132 195-196 223-225 198-200 210-212 186-188 165-166 172-174 183-185

66.26 66.66 67.04 67.41 67.76 68.10 68.43 68.85 66.68 63.07 63.61 63.84 64.46 64.86 65.25 65.57 58.88 59.37 56.16 59.25 59.71 60.14 60.56 61.76 55.94 56.85 57.35 57.83 58.29 58.74 59.17 59.15 58.88 59.53 60.00 60.45 60.89 61.31 61.72 61.92 61.27 62.12 62.24 62.99 62.97 63.79 64.17 64.00

2-Substituted 5-Amino-1,3,4-oxadiazoles. The most potent 2-substituted 5-amino-1,3,4-oxadiazoles were obtained by cyclization of an appropriate thiosemicarbazide in ethanolic solution of NaOH along with a solution of KI in I2. The IR spectra of all of the 5-aminooxadiazole derivatives (VIa-VIh) showed the characteristic absorption bands at 3471-3475, 3057-3061, 1630-1634, and 1112-1116 cm-1 for the -NH2 group merged with the -OH function, the -NH function, the -CdN function, and the dC-O-C) function, respectively. The other usual absorption bands were also observed. 1H NMR spectra of all of the 5-amino-oxadiazole derivatives (VIa-VIh) showed sharp singlet signals at δ 6.6-7.0 for dC-NH2 protons, which disappeared upon D2O addition. The other usual signals were also observed. All the 13C NMR spectra of compounds VIa-VIh showed sharp singlet signals at δ 172-168 and 162158 for the carbon atoms of the oxadiazole ring. The other usual signals were also observed.

66.15 66.58 66.91 67.22 67.63 67.91 68.24 68.68 66.56 62.96 63.50 63.72 64.33 64.75 65.14 65.45 58.79 59.26 56.08 59.14 59.59 60.01 60.43 61.64 55.82 56.73 57.23 57.72 58.17 58.62 59.06 59.03 58.72 59.42 59.89 60.33 60.77 61.29 61.60 61.80 61.18 62.01 62.12 62.87 62.87 63.66 64.04 63.89

hydrogen calc found 10.44 10.52 10.60 10.67 10.74 10.81 10.87 09.83 10.44 10.52 10.36 10.67 10.74 10.81 10.88 09.84 08.75 09.92 08.40 08.85 08.98 09.07 09.15 08.33 09.07 09.17 09.12 09.36 09.48 09.56 09.63 08.69 08.97 09.10 08.64 09.25 09.38 09.36 09.52 08.59 09.38 09.52 09.57 09.71 09.28 09.82 09.92 08.89

10.25 10.41 10.49 10.57 10.60 10.66 10.68 09.75 10.32 10.41 10.23 10.53 10.61 10.69 10.76 09.72 08.63 09.81 08.28 08.71 08.87 08.96 09.02 08.21 08.98 09.06 09.01 09.23 09.35 09.43 09.51 08.56 08.85 09.00 08.52 09.13 09.26 09.23 09.40 08.46 09.16 09.40 09.45 09.60 09.17 09.71 09.80 08.77

nitrogen calc found 04.17 04.09 04.01 03.93 03.85 03.78 03.71 03.82 12.53 12.26 11.76 11.76 11.57 11.35 11.14 11.48 11.08 12.26 10.08 10.33 10.19 10.02 09.86 10.29 14.11 10.41 10.08 10.08 13.27 13.05 12.84 13.15 14.78 14.56 13.44 14.00 13.77 13.44 13.32 13.76 15.45 15.23 14.89 14.67 14.33 14.11 13.88 14.22

04.08 04.01 03.90 03.81 03.72 03.61 03.62 03.74 12.41 12.13 11.65 11.64 11.45 11.23 11.02 11.34 10.97 12.13 09.97 10.22 10.07 09.90 09.74 10.17 14.00 10.29 09.95 09.97 13.15 12.93 12.72 13.02 14.65 14.44 13.32 13.89 13.65 13.31 13.20 13.64 15.32 15.12 14.78 14.53 14.10 13.99 13.76 14.12

The details regarding all spectra of the compounds are summarized in the Table 1. Experimental Section Aleuritic acid (95%, lot no. A013141301, Acros Organics), nitriles (Aldrich, Acros Organics, Fluka AG), and sulfuric acid AR (98%, Glaxo Laboratories India Ltd.) were used. Instrumentation. IR spectra were recorded on an Impact 410 model instrument, using KBr pellets. 1H NMR spectra were recorded on a Bruker (300 and 400 MHz) spectrometer using CDCl3 and D6 DMSO as solvents. The chemical shifts were measured in parts per million (ppm) downfield from internal TMSi at δ ) 0. The mass spectra were recorded on a Finnigan Mat instrument with PDP Micro Computer 810, at 70 eV with a source temperature of 250 °C. Preparation of Diesters (Fischer Esterfication). Dicarboxylic acid was refluxed in excess absolute methanol containing 1% sulfuric acid (v/v). The resulting


mixture was diluted with water and then extracted with diethyl ether. The combined ether extracts were dried over anhydrous sodium sulfate, and the solvent was removed in a stream of nitrogen. Preparation of Hydrazides.15 To a solution of an appropriate acid ester (0.1 mol) in 150 mL of ethanol was added 95% hydrazine hydrate (0.2 mol), and the mixture was refluxed for 4-5 h. It was allowed to cool, and the obtained solid was washed with ethanol and dried. The crude compounds were recrystalized from ethanol. Preparation of 2-Substituted 5-Mercapto-1,3,4oxadiazoles.16 To a solution of an appropriate hydrazide (0.01 mol) in 10 mL of ethanol was added a solution of CS2 (2 mL) in 3 mL of water and 1 g of KOH, and the mixture was refluxed for 8-10 h until the release of H2S had ceased. The mixture was was then cooled and acidified with dilute HCl. The solid mass that separated was collected and was filtered, washed with distilled water, and dried. The crude compounds were recrystalized from ethanol. Preparation of Thiosemicarbazides.17 To a solution of an appropriate acid hydrazide (0.02 mol) in 50 mL of methanol was added a solution of KCNS (0.03 mol) and 3 mL of HCl with constant stirring. The mixture was immediately evaporated to dryness on a steam bath and heated for an additional 1 h with another 50 mL of methanol. The resulting solid was treated with distilled water and with a small amount of ethanol. The crude compounds were recrystalized from ethanol. Preparation of 3-Substituted 5-Mercapto-4H1,2,4-triazoles.18 To a solution of an appropriate thiosemicarbazide (0.01 mol) in 15 mL of ethanol was added a solution of 10.0% KOH (20 mL), and the reaction mixture was refluxed immediately for 8-10 h on a boiling water bath. The mixture was cooled and acidified with dilute HCl at pH 5-6. The resulting solid was filtered, washed with distilled water, and dried. The crude compounds were recrystalized from ethanol. Preparation of 2-Substituted 5-Amino-1,3,4-oxadiazoles.19 To a solution of an appropriate thiosemicarbazide (0.01mol) in 15 mL of ethanol was added a solution of 5 N NaOH (5 mL) with cooling and stirring. To this clear solution was added a solution of KI/I2 until a permanent tinge color of iodine persisted at room temperature. The mixture was immediately refluxed, and more KI/I2 solution was added until the permanent tinge color of iodine remained at the higher temperature. The solution was then cooled and poured into icecold water. The solid that separated was collected by filtration and was then washed with distilled water, with dilute thiosulfate solution, and again with distilled water before being dried. The crude compounds were recrystalized from ethanol. A summary of the overall synthetic process is presented in Scheme 1. Elemental analyses, yields, and melting points of all compounds are reported in Table 2. Melting points were determined by the open capillary method and are uncorrected. Biological Evaluation. The newly synthesized N,N′bis(1-carboxy-15-hydroxy-n-pentadec-8-yl)alkyl or -aryl amide derivatives such as hydrazides, thiosemicarbazides, oxadiazoles, and triazoles were screened for their antibacterial and antifungal activities at concentrations

Table 3. Antibacterial Activity zone of inhibition (activity)a Escherichia Bacillus Pseudomonas Staphlococcus compd coli cirroflagellosus putida aureus 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


+ ++ ++ + + ++ + ++ + + + + + + ++ + + + + + + + ++ + + ++ + + + ++ + + ++ ++ + + ++ + ++ + ++ ++ + + ++ ++ + +

+ + + + ++ + + + ++ + + + + + ++ ++ ++ ++ + ++ + ++ ++ + + ++ ++ + + + + + + ++ + + + + ++ ++ ++ + + + + + + ++

++ + + ++ + + + + + + ++ + + + + + ++ + + + + ++ ++ ++ + + + + ++ + + ++ ++ + + ++ + + + + ++ + + ++ ++ + + ++

+ ++ + + ++ + ++ ++ + + + + + + + + ++ + + + + + + ++ + + + + + + + + ++ ++ ++ ++ ++ + + + + + ++ + + + + +

a Zones of inhibition activity are as follows (mm, symbol, activity, percent transmission): 0, -, no activity, 0%; 11-15, +, positive activity, 25%; 16-20, ++, positive activity, 50%; 21-25, +++, positive activity, 75%; 26-30, ++++, positive activity, 100%.

of 1000 µg/mL, according to the cup-and-plate method.20 The compounds were tested against Escherichia coli, Bacillus cirroflagellosus, Pseudomonas putida, and Staphylococcus aureus for antibacterial activity. Antifungal activity was tested against Candida albicans, Aspergillus niger, Penicillium notatum, and Sclerotium rolfsii. The antimicrobial activities of the compounds were compared with that of tetracycline at the same concentration. To summarize, the conditions of the biological evaluation experiments were as follows: concentration of the test compound in dimethyl formamide (DMF), 1000 µg/ mL (i.e., 1 mg/mL); test solution, 0.1 mL of the above solution (i.e., 100 µg of the test compound); diameter of the cup, 10 mm; control, tetracycline. The results and observations of the cup-and-plate method are summarized in the Tables 3 and 4.

Ind. Eng. Chem. Res., Vol. 43, No. 17, 2004 4999 Table 4. Antifungal Activity zone of inhibition (activity)a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

compd

Candida albicans

Aspergillus niger

Penicillium notatum

Sclerotium rolfsil


++ + ++ ++ ++ + + + + + ++ + + + + ++ ++ ++ ++ ++ ++ + + + ++ ++ ++ + ++ ++ + + + ++ ++ + + + + ++ + ++ + + + + + +

+ + + + ++ + ++ + + + + + + + + + ++ ++ + + ++ + ++ +

++ + + ++ + ++ + ++ + + + + + + + + ++ + ++ ++ ++ ++ + ++ ++ ++ + + + + + + + ++ + + + + + ++ + + + + + + + ++

+ ++ + + + + ++ + ++ + ++ + + + + + + + + + ++ ++ + + + ++ + ++ + + ++ + ++ + ++ + + + + ++ + + + + ++ ++ ++ +

++ + + + + ++ + + + + ++ + + + ++ + ++ + + ++ + ++ +

a Zones of inhibition activity are as follows (mm, symbol, activity, percent transmission): 0, -, no activity, 0%; 11-15, +, positive activity, 25%; 16-20, ++, positive activity, 50%; 21-25, +++, positive activity, 75%; 26-30, ++++, positive activity, 100%.

Conclusion The newly synthesized N,N′-bis(1-carboxy-15-hydroxyn-pentadec-8-yl)alkyl or -aryl amides derivatives such as hydrazides, thiosemicarbazides, oxadiazoles, and triazoles were tested for antibacterial and antifungal

activities by the cup-and-plate method. In an initial screening, all these compounds were found to inhibit microorganisms. Thus, it was observed that most of the compounds showed a moderate activity against different strains of bacteria and fungii. Acknowledgment This research work is financially supported by the Department of Science & Technology (DST), New Delhi, India (Ref. No. SP/S1/G-15/99 dated 14-03-2000). Literature Cited (1) Hosamani, K. M.; Pattanshettar, R. S. Ind. Eng. Chem. Res., manuscript accepted. (2) Lieberman, D.; Rist, N.; Grumbach, F.; Moyewx, M.; Gauthier, B.; Rouaix, A.; Millard, J.; Himbert, J. G.; Cals, S. Bull. Soc. Chim. Fr. 1954, 1440; Chem. Abstr. 1956, 50, 351. (3) Degener, E.; Scheinpflug, H.; Schemelzer, H. G. British Patent 1,085,474, 1967; Chem. Abstr. 1968, 68, 95567. (4) Cavier, R.; Rips, R. J. Med. Chem. 1965, 8, 706. (5) Renz, J.; Bourquin, J. P.; Winkler, H.; Bruiesh Weiler, C.; Reush, L.; Schwarb, G. Swiss Patent 419,136, 1967; Chem. Abstr. 1968, 68, 29709. (6) (a) Brown, R. K.; Snider, R. F.; Stevenson, M. D. J. Org. Chem. 1956, 21, 261. (b) Yale, H. L.; Loose, K.; Martins, J.; Holsings, M.; Perry, F. M.; Bernstein, J. J. Chem. Soc. 1953, 75, 1933. (c) Doyle, P. B.; Ferrier, W.; Holland, D. O.; Mehta, M. D.; Nayler, J. H. C. J. Chem. Soc. 1956, 2853. (7) Allais, A.; Meier, J. French Patent 1,363,855; Chem. Abstr. 61, 14641. (8) Alvarex, E. F.; Pajares, M. B.; Lopez, O. N. Spanish Patent; Chem. Abstr. 1967, 67, 32590. Alvarex, E. F.; Pajares, M. B.; Lopez, O. N. Spanish Patent 324,608; Chem. Abstr. 1967, 67, 82098. (9) Mir, I.; Siddiqui, M. T.; Comrie, A. Tetrahedron 1970, 26, 5235. (10) Greenfield, S. A.; Seidel, M. C.; VonMeyer, W. C. German Patent 1,966,806, 1974; Chem. Abstr. 1975, 82, 150485. (11) George, T.; Mehta, D. V.; Tahiramani, R.; David, J.; Talwalker, P. K. J. Med. Chem. 1971, 14, 335. (12) Piala, J. J.; Yale, H. L. U.S. Patent 3,166,566, 1965; Chem. Abstr. 1965, 62, 10444. (13) O’Neal, J. B.; Rosen, H.; Russel, P. B.; Adams, Ac.; Blumenthal, A. J. Med. Pharm. Chem. 1962, 5, 617; Chem. Abstr. 1962, 57, 9168. (14) Sherman, W. R. J. Org. Chem. 1961, 26, 88. (15) Kyame, L.; Fisher, G. S.; Beckford, W. G. J. Am. Chem. Soc. 1947, 24, 332. (16) Hoggarth, E. J. Chem. Soc. 1952, 4811. (17) Boots, S. G.; Cheng, C. C. J. Heterocylclic Chem. 1967, 4, 272. (18) Hoggarth, E. J. Chem. Soc. 1949, 1163. (19) Silberg, Al.; Cosma, N. Acad. Ref. Pop. Romine, Filiala Cluj, Stud. Cercetari Chim. 1959, 10, 151. (20) Seely, H. W.; VanDemane, P. J. Microbes in Action: A Laboratory Manual of Microbiology, 2nd ed.; D. M. Taraporevala Sons Co., Pvt. Ltd.: Bombay, India, 1975; p 55.

Received for review March 21, 2003 Revised manuscript received April 5, 2004 Accepted May 1, 2004 IE030257G

Design and Synthesis of Novel Hydrazides, Thiosemicarbazides

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