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The Reaction of Cyanoacetylhdrazine with Furan-2-Aldehyde: Novel Synthesis of Thiophene, Azole, Azine and Coumarin Derivatives and Their Antitumor Evaluation

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The Reaction of Cyanoacetylhdrazine with Furan-2-Aldehyde: Novel Synthesis of Thiophene, Azole, Azine and Coumarin Derivatives and Their Antitumor Evaluation International Journal of Organic Chemistry, 2012, 2, 321-331 http://dx.doi.org/10.4236/ijoc.2012.24044 Published Online December 2012 (http://www.SciRP.org/journal/ijoc) The Reaction of Cyanoacetylhdrazine with Furan-2-Aldehyde: Novel Synthesis of Thiophene, Azole, Azine and Coumarin Derivatives and Their Antitumor Evaluation Wagnat W. Wardakhan1, Sherif M. Sherif2, Rafat M. Mohareb2*, Amr S. Abouzied1 1National Organization for Drug Control & Research, Cairo, Egypt 2Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt Email: *[email protected] Received August 20, 2012; revised September 27, 2012; accepted October 16, 2012 ABSTRACT The reaction of cyanoacetylhydrazine 1 with furan-2-aldehyde 2 gives the hydrazide-hydrazone derivative 3. The latter compound undergoes a series of heterocyclization reactions to give new heterocyclic compounds. The antitumor evalua- tion of the newly synthesized products against three cancer cell lines, namely breast adenocarcinoma (MCF-7), non- small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were recorded. Some of the synthesized compounds show high inhibitory effects. Keywords: Acetylhydrazine; Hydrazide-Hydrazone; Thiophene; Thiazole; Pyridine; Coumarin; Antitumor 1. Introduction zine (1) with furan-2-aldehyde (2) to give the hydrazide- hydrazone derivative 3, the structure of which was con- Substituted aminothioxomethyl hydrazides are important firmed on the basis of analytical and spectral data. Thus, building blocks in synthetic heterocyclic chemistry. The the 1H NMR spectrum showed a singlet at δ 6.60 (2H) S/N regioselective nucleophilic competition in the syn- ppm corresponding to CH2 group, a multiplet at δ 6.52 - thesis of heterocyclic systems by intermolecular and in- 7.88 (3H) ppm corresponding to furan protons, a singlet tramolecular cyclization, as well as the change in reac- at δ 7.54 (1H) ppm corresponding to CH group, and a tion conditions which might favor N-attack or S-attack or singlet (D2O-exchangeable) at δ 11.62 (1H) ppm corre- even attack on the substituted terminals are important sponding to NH group. factors for the diversity of the produced heterocyclic The formed hydrazide-hydrazone derivative 3 was systems from the title reaction precursor. On the other subjected through a series of heterocyclization reactions hand, the synthetic potential and biological activity of to form products with expected pharmaceutical applica- several heterocyclic related to the named hydrazides have tions. Thus, condensation of 3 with benzaldehyde (4) in been explored to the maximum extent. Among the phar- ethanolic/piperidene solution gave the benzylidene de- macological profiles are their antimicrobial [1,2], antitu- rivative 5. The reaction of compound 5 with either hy- bercular [3,4], anticonvulsant [5,6] anti-inflammatory [7, drazine hydrate (6a) or phenylhydrazine (6b) gave the 8], antidepressant [9], antitumor [10], and analgesic ac- pyrazole derivatives 7a and 7b, respectively. tivities [11]. Continuing our interest in developing new On the other hand, the reaction of compound 5 with heterocyclic systems based on hydrazide-hydrazones [12, either malononitrile (8a) or ethyl cyanoacetate (8b) gave 13] as well as design and synthesis of heterocyclic with the pyridone derivatives 10a and 10b, respectively. The promising biological activities [14-17], we focused our reaction took place via 1,6-intramolecular dipolar cycli- work on developing novel polyfunctionalized heterocyc- zation of the intermediate 9a,b (cf. Scheme 1), analytic- lic compounds with potential bioactivity. cal and spectral data of the latter compounds were con- sistent with the assigned structures. Thus, the 1H NMR 2. Results and Discussion spectrum of 10b showed, a triplet at δ 1.29 (3H) ppm In this work we report the reaction of cyanoacetylhydra- indicating the presence of the CH3 group, a quartet at δ 4.24 (2H) ppm corresponding to CH2 group, a multiplet *Corresponding author. at δ 6.52 - 7.88 (3H) ppm for furan protons, a singlet Copyright © 2012 SciRes. IJOC 322 W. W. WARDAKHAN ET AL. 1,4-dioxane CH2 CONHNH2 CHO + CH2 CONH N CH O O CN CN 1 2 3 CHO 3 + EtOH/pip CH C CONHN CH O 4 CN 5 Ph CONHN CH RNHNH O 5 + 2 N R N NH2 7a, R = H 6a, R = H b, R = Ph b, R = Ph Ph CH X Et3N 5 2 CH C CONHN CH + H 1,4-dioxane O CN CN CH 8a, X = CN X 9a,b b, X = COOEt CN CN Ph O N N CH X O NH2 10a, X = CN b, X = COOEt Scheme 1. Synthesis of compounds 3, 5, 7a,b and 10a,b. (D2O-exchangeable) at δ 7.05 (2H) ppm equivalent to the the reaction of compound 3 with the cinnamonitrile re- NH2 group, a multiplet at δ 7.17 - 7.40 (5H) ppm indi- agents 11a,b to afford the same pyridone derivatives 10a, cating the phenyl protons and a singlet at δ 7.56 (1H) b (finger print IR, mp. and mixed mp.) with better yields ppm corresponding to the CH group. (95%, 98%) than in their formation by the reaction of Further confirmation of the structures of 10a,b was compound 5 and either malononitrile (75% yield) or achieved through an alternative synthetic route involving ethyl cyanoacetate (74% yield) (cf. Scheme 2). On the Copyright © 2012 SciRes. IJOC W. W. WARDAKHAN ET AL. 323 CN PhHC X CN 11a, X= CN b, X= COOEt CH CONH N CH CH3 CONH N CH O O CN Ph CH X 12a,b 3 CH NC Ph X CN H2N N O N CH O 10a, X= CN b, X= COOEt CHO CONHN CH 1,4-dioxane O 3 + pip. O O OH 13 14 O OO NC N N CH O 3 + CH3 R CH3 R 15a, R = CH3 16a, R = CH3 b, R = OEt b, R = OEt Scheme 2. Synthesis of compounds 10a,b, 14 and 16a,b. other hand, compound 3 condensed with salicylaldehyde derivatives with wide range of biological activities thus, (13) to give the coumarin derivative 14. The analytical the reaction of 3 with either acetylacetone (15a) or ethyl and spectral data of compound 14 are in agreement with acetoacetate (15b) gave the pyridine derivatives 16a and the proposed structure. Thus, the 1H NMR spectrum show- 16b, respectively (cf. Scheme 2). The structures of the ed, a singlet at δ 6.95 (1H) ppm corresponding to cou- latter products were established on the basis of analytical marin H-4, a singlet at δ 7.52 (1H) ppm corresponding to and spectral data. Thus, 1H NMR spectrum of 16b CH group, a multiplet at δ 6.52 - 7.88 (3H) ppm corre- showed a triplet at δ 1.35 (3H) ppm corresponding to sponding to furan protons, a multiplet at δ 7.33 - 7.55 CH3 group, a singlet at δ 2.34 (3H) ppm corresponding to (4H) ppm corresponding to aromatic protons and a sing- CH3 group, a quartet at δ 4.22 (2H) ppm corresponding let (D2O-exchangeable) at δ 11.61 (1H) ppm correspond- to CH2 group, a singlet at δ 5.79 (1H) ppm corresponding ing to NH group. The reactivity of compound 3 towards to pyridine proton, a singlet at δ 7.51 (1H) ppm corre- 1,3-dicarbonyl compounds was studied to afford pyridine sponding to CH group and a multiplet at δ 6.52 - 7.88 Copyright © 2012 SciRes. IJOC 324 W. W. WARDAKHAN ET AL. (3H) ppm corresponding to furan protons. On the other corresponding to aromatic protons, a multiplet at δ 6.52 - hand, we studied the reactivity of compound 3 with 7.88 (3H) ppm corresponding to furan protons, a singlet cyanomethylene reagents thus, the reaction of 3 with at δ 7.52 (1H) ppm corresponding to CH group and a either malononitrile (8a) or ethyl cyanoacetate (8b) gave singlet (D2O-exchangeable) at δ 11.62 (1H) ppm corre- the 2-pyridone derivatives 19a,b. The formation of the sponding to NH group. latter products took place via the intermediate formation of 17a,b (cf. Scheme 3). The 1H NMR spectrum of 18b 2.1. Antitumor Activity as an example showed a singlet at δ 5.80 (1H) ppm cor- responding to the pyridine proton, a multiplet at δ 6.52 - 2.1.1. Material, Methods and Reagents 7.88 (3H) ppm corresponding to furan protons, a singlet Fetal bovine serum (FBS) and L-glutamine, were from Gibco Invitrogen Co. (Scotland, UK). RPMI-1640 me- (D2O-exchangeable) at δ 7.00 (2H) ppm corresponding to dium was from Cambrex (New Jersey, USA). Dimethyl NH2 group, a singlet at δ 7.52 (1H) ppm corresponding to sulfoxide (DMSO), doxorubicin, penicillin, streptomycin CH group, and a singlet (D2O-exchangeable) at δ 12.56 (1H) ppm corresponding to OH group. and sulforhodamine B (SRB) were from Sigma Chemical The reaction of 3 with either acetophenone (19) or 4- Co. (Saint Louis, USA). Samples Stock solutions of se- methoxy acetophenone (20) in ammonium acetate gave lected compounds from 3-34a,b were prepared in DMSO the Knoevenagel condensated products 21 and 22 respec- and kept at −20˚C. Appropriate dilutions of the com- tively. pounds were freshly prepared just prior the assays. Final Next, we studied the reactivity of the active methylene concentrations of DMSO did not interfere with the cell group present in compound 3 towards diazonium salts. growth. Thus, the reaction of compound 3 with aryldiazonium chlorides 23a-23d gave the phenylhydrazone derivatives 2.1.2. Cell Cultures 24a-24d. Analytical and spectral data of the latter prod- Three human tumor cell lines, MCF-7 (breast adenocar- ucts are all consistent with the proposed structures (see cinoma), NCI-H460 (non-small cell lung cancer), and experimental section). Compound 24a reacted with ethyl SF-268 (CNS cancer) were used.
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